MULTICOMPONENT CYCLIZATION REACTIONS: A GENERAL APPROACH TO DIBENZOCYCLOOCTADIENE LIGNAN NATURAL PRODUCTS

DISSERTATION

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy

in the Graduate School of The Ohio State University

By

Wei Gong

Graduate Program in Chemistry

The Ohio State University

2012

Dissertation Committee:

Professor T. V. RajanBabu

Professor Jovica Badjic

Professor Anita Mattson

Copyright by

Wei Gong

2012

Abstract

Aiming at finding a general and broadly applicable route to dibenzocyclooctadiene

(DBCOD) lignans, an important class of natural products with wide-ranging biological activities, we applied Pd-catalyzed bis-metallative cyclizations mediated by a [B-Sn] reagent,

1-trimethylstannyl-2,5-dimethyl-2,5-diazaborolidine, to access the core DBCOD systems.

2,2’-Dipropargyl biphenyls are suitable precursors of [B-Sn] reagent mediated cyclizations and their acetylene moieties can be installed by addition of lithium acetylides to

2’-substituted biphenyl aldehydes. Most of these acetylide additions are highly stereoselective and chelating models have been proposed to rationalize their stereochemical results. The viability of the [B-Sn]-mediated cyclizations of these dipropargyl biphenyls depends on the chirality of the biphenyl scaffolding and the configuration of the propargylic center. Models based on steric arguments can be used to rationalize the stereochemical outcomes in successful cyclizations, and the reluctance in others to undergo the cyclization.

A racemic synthesis of steganone was achieved from a 1,2-bisalkylidenecyclooctadiene prepared via the [B-Sn]-mediated cyclization. A novel AD-mix mediated tandem process quickly led to the formation of the key lactone, which was converted to steganone after three steps.

ii

Eight fully substituted DBCOD lignans, including compounds such as kadsuralignan B,

tiegusanin D, and schizanrin F, with a tertiary center at C7, were first synthesized using an

intermediate prepared by the [B-Sn]-mediated cyclization. The unique conformations of

DBCOD intermediates are crucial for different reactivities of certain functional groups (e.g.,

C-C double bonds, hydroxyl and carbonyl groups), which can explain the stereochemical

outcome of related transformations, for example, the hydrogenation reactions, Mitsunobu

reactions, electrophilic additions to C-C double bonds and nucleophilic additions to carbonyl

groups. The conformations of DBCODs containing C6 and/or C9 carbonyl groups are also discussed based on experimental data. We provide a general approach to the syntheses of highly functionalized DBCOD lignan natural products (>100) and unnatural analogs with different configurations and/or oxidation states at C6, C7, C8 and C9.

iii

Dedication

This document is dedicated to my family.

iv

Acknowledgments

First and foremost, I would like to thank Professor T.V. RajanBabu for allowing me to join his group in early 2008 and therefore get the chance to spend the following five years doing research under his guidance. It has been such an incredible experience that I believe I will benefit from it for the rest of my life. Babu is a real mentor to me, because I have learned a lot from him, not only about chemistry, but also the attitude towards many aspects of the life as a person. Before joining the graduate program at the Ohio State

University, I knew that I would learn much about chemistry here, however, it turned out that chemistry is only a part of it. I have been so fortunate to stay in Babu group and thus could have intensive discussion with him about our research as well as my personal career plan. The latter could be equally as important as the former, because the time I leave this group could just be when my real career starts. Another important thing I feel lucky about is that I chose the research projects that I like and during the whole four years in Babu group, I have worked on projects that are directly related. Everyday is a joyful experience working in Babu’s lab, as in every morning I would expect something new or exciting in our research and I would never be hesitate to tell Babu in the first instance. One important philosophy of life I have learned from Babu is that although life is tough at most occasions,

I have to get used to it and persist on my goal. If I am lucky, I will get the rewards I

v deserve, and if not, the lessons you have learned are equally important, as they could direct you towards the correct road leading to success.

I would also like to thank all other current and former group members. Dr. Singidi made significant contributions to the [B-Sn] chemistry, which laid the basis of all my work.

Dr. Sharma has been one of my best friends in this lab, with whom I had thorough discussion about chemistry and personal life as well.

Dr. Galucci in this department is acknowledged for assistance for X-ray crystallographic analysis of more than ten compounds.

I would like to acknowledge my father Jingfu and my mother Yuyi. They provide me whatever they have and never ask for anything. They are great parents and always support my decisions.

I would like to acknowledge my wife Yongxue and two boys Chuxuan (Eric) and

Hanyuan (Samuel). All of the nice memories of this time in my life will be cherished because they were shared with them. You are always accompanying me and supportive during the years. I can never thank Yongxue enough for taking care of the boys and doing an excellent work for educating them. Without your support, this work could not have been possible.

vi

Vita

Oct 13, 1979…………………………………Born - Jianli, China June 2002……………………………………B. S. Chemistry Wuhan University, China June 2005……………………………………M. S. Organic Chemistry Wuhan University, China 2005-2006………………………………… Research Scientist Shenzhen Taitai Pharmaceutical Co., China 2006-2007………………………………… Research Scientist Shanghai Chempartner Co., China 2007-2008………………………………… Mathematical and Physical Sciences Fellow The Ohio State University 2008-2010………………………………….Teaching Assistance The Ohio State University 20010-2012………………………………...Research Assistance The Ohio State University

Publications

1. Wei Gong, T. V. RajanBabu. “A General Approach to Dibenzocyclooctadiene (DBCOD)

Natural Products via Borostannylative Cyclization of 2,2’-Dipropargyl biaryls. Syntheses

vii

of Prototypical Lignans including Steganone, Ananolignans, Tiegusanin D and

Schizanrin F”, Manuscript in preparation.

2. Wei Gong, T. V. RajanBabu. “Multi-component Cyclization Reactions Mediated by [X-Y]

Reagents [X-Y= R3Si-SnR’3 or (R2N)2B-SnR’3]”, Manuscript in preparation.

3. Wei Gong, T. V. RajanBabu. “Borostannylative Cyclization of 2,2’-Dipropargylbiaryls

and New Chemistry of the Resulting bis-Alkylidenes. Total Synthesis of Steganone”,

Manuscript in preparation.

4. Wei Gong, T. V. RajanBabu. “Conformation and Reactivity in Dibenzocyclooctadiene

Derivatives. A General Approach to Fully Substituted Dibenzocyclooctadiene Lignans”,

Submitted.

5. Wei Gong, Ramakrishna Reddy Singidi, Judith C. Gallucci, T. V. RajanBabu. “On the

Stereochemistry of Acetylide additions to Highly Functionalized Biphenylcarboxaldehyde

and Multi-component Cyclization of 1, n- Diynes. Syntheses of Dibenzocyclooctadiene

Lignans”, Chemical Science, 2012, 3, 1221-1230.

6. Wei Gong, Qianqian Li, Suyue Li, Changgui Lu, Zhen Li, Jing Zhu, Zhichao Zhu,

Zhong'an Li, Qingrong Wang, Yiping Cui, Jingui Qin. “New Y type nonlinear optical

chromophores with good transparency and enhanced nonlinear optical effects”, Materials

Letters, 2007, 61, 1151-1153.

7. Qianqian Li, Zhen Li, Fanxin Zeng, Wei Gong, Zhong'an Li, Zhichao Zhu, Qi Zeng,

Shanshan Yu, Cheng Ye, and, and Jingui Qin, “From Controllable Attached Isolation

Moieties to Possibly Highly Efficient Nonlinear Optical Main-Chain Polyurethanes

Containing Indole-Based Chromophores”, Journal of Physical Chemistry B, 2007, 111,

508-514.

viii

8. Wei Gong, Qianqian Li, Zhen Li, Changgui Lu, Jing Zhu, Sueyue Li, Junwei Yang,

Yiping Cui, Jingui Qin, “Synthesis and Characterization of Indole-Containing

Chromophores for Second-Order Nonlinear Optic”, Journal of Physical Chemistry B,

2006, 110, 10241-10247.

9. Zhen Li, Wei Gong, Jingui Qin, Zhou Yang, Cheng Ye, “Second-Order Nonlinear Optical

Property of Polyphosphazenes Containing Charge-transporting Agents and Indole-Based

Chromophore”, Polymer, 2005, 46, 4971–4978.

Fields of Study

Major Field: Chemistry

ix

TABLE OF CONTENTS

Abstract…………………………………………………………..……….……………… ii

Dedication……………………………………………………………………...………....iv

Acknowledgements…………………………………………………………………..…....v

Vita……..……………………………………………………………………..………....vii

List of Schemes …………………………...…………………………………...………...xx

List of Tables ……………………………………………………………...…….…....xxvii

List of Figures ………………………………………………………………...…….....xxxi

List of Abbreviations………………………………………………………...……...... xxxv

Chapter 1. Multi-component Cyclization Reactions and Dibenzocyclooctadiene

Lignans………………………….……………………………………………...1

1.1 Multi-component Cyclization Reactions………………………………………...…....1

1.1.1 R3Si-BR2 Mediated Cyclization of 1, n-Diynes…………………………………1

1.1.2 R3Si-SnR’3 Mediated Cyclization of 1, n-Diynes……………………………….2

1.1.3 R3Si-SnR’3 Mediated Cyclization of 1, n-Allenynes and Allene-aldehyde……..4

x

1.1.4 R3Si-SnR’3 Mediated Cyclization of Enynes……………..……………..………7

1.1.5 (R2N)2B-SnR’3 Mediated Cyclization of 1, n-Diynes and Enynes…………...…8

1.2 Dibenzocyclooctadiene Lignans…………………………………………………..…14

1.2.1 Biological Activities of Dibenzocyclooctadiene Lignans…...... 14

1.2.2 Previous Synthetic Studies of DBCOD Lignans……...…………………….…16

1.2.3 Pd-catalyzed Bismetallative Cyclization of 1,n-Diynes (2, 2’-Dipropargyl

Biphenyls): General Solutions to Access a Broad Range of DBCOD

Lignans…………………………...... 22

1.2.4 Syntheses of Prototypical DBCOD Lignans Including Gomisin E and

Interiotherin A via Pd-catalyzed Bismetallative Cyclization of 1,6

Diynes…………………………………………………………..…………..….23

1.3 The Overall Goals of this Research……………………..……………………….…..26

Chapter 2. Synthesis and Cyclization of 2,2’-Dipropargylbiphenyls………….….….…27

2.1 A General Synthetic Strategy Towards Dibenzocyclootadiene Lignans…………….27

2.2 Synthesis of 2,2’-Dipropargyl Biphenyls……………...………………………...…..29

2.2.1 Synthesis of Enantiomerically Pure Biaryl Oxazolines………..….……...……29

xi

2.2.2 Magnesium-mediated Biaryl Coupling Reactions between the Tetramethoxy

Oxazoline 2.18 and Aryl Bromides………………….…..…………….………31

2.2.3 Synthesis of Biphenyl Aldehydes and Subsequent Acetylide Addition

Reactions…………………………………………………………………..…...32

2.2.3.1 Hydrolysis of Acetals 2.20a and 2.20b and Subsequent Acetylide

Additions to Biphenyl Aldehydes………...... 32

2.2.3.2 Diastereoselective Acetylide Addition to Biphenyl Aldehyde 2.24…...34

2.2.3.3 Synthesis of the Biphenyl Aldehyde 2.26 and the Following

Acetylide Addition…………………………………………………..….35

2.2.3.4 Synthesis of the Biphenyl Aldehyde 2.28 and the Subsequent

Acetylide Addition……………………………...…………………...…37

2.2.4 Synthesis of Diynes with C7-OBn Protection Group…………………..………37

2.2.5 Synthesis of Diynes with C7-OTIPS Protection Group …………………....….39

2.2.6 Proposed Chelation Models for Acetylide Additions to Biphenyl

Aldehydes……………………………………………………….….………….41

2.2.6.1 Chelation Model for Acetylide Addition to the Biphenyl Aldehyde

xii

2.24 with a 6’-Propargyl Substituent……………………..………… 42

2.2.6.2 Chelation Model for Acetylide Addition to the Biphenyl Aldehyde

2.22a with a 6’-Oxazoline Ring …………………………..…...... …..43

2.2.6.3 Chelation Models for Acetylide Addition to the Biphenyl Aldehyde

2.26 with a 6’-Oxazoline Ring and a 6-Methoxy Group………...... 44

2.2.6.4 Intramolecular Hydrogen Bonding as Supporting Evidence for the

Models………………………………………………………..…….....45

2.2.6.5 Chelation Models for the Acetylide Addition to the Biphenyl

Aldehyde 2.28 with a 6’-Silyloxymethyl Group and a 6-Methoxy

Group …………………………………………………….….……..…46

2.3 Preparation of the Substrates for [B-Sn] Reagent Mediated Cyclizations ……….....47

2.4 Results of [B-Sn] Reagent Mediated Cyclizations and Proposed Models…….....….50

2.4.1 Results of [B-Sn] Reagent Mediated Cyclization 2,2’-Dipropargyl

biphenyls ……..………………………………………………………....…….50

2.4.2 Different Results of Cyclization of the Diyne 2.54 with (Sa, S) Configuraton

and the Diyne 2.55 with (Sa, R) Configuration………………………..…...….55

xiii

2.4.3 Formation of Two Atropisomeric Cyclization Products from the Diyne

2.37………………………………………………………………………..…....59

2.4.4 Formation of Fully Substituted DBCODs from Diynes 2.39b and 2.39c...... 61

2.4.5 Proposed Mechanism for the Cyclization of the Diyne 2.39c…….…….……..63

2.5 Conclusions……………………………………………………………………..……64

2.6 Experimental Section…………………………………………………….……..……65

2.6.1 General Methods……………………………………………………..………...65

2.10.2 Synthetic Procedures and Spectral Data.……………………………...... …..66

Chapter 3. Total Synthesis of Steganone via Multi-component Cyclization...…….….105

3.1 Synthetic Approach to Steganone via a Multi-component Cyclization Strategy…..105

3.2 Attempted Enantiomeric Synthesis of Steganone……………………...……….…..105

3.2.1 Magnesium-Mediated Biphenyl Coupling Reactions between the Oxazoline

2.18 and Aryl bromides…………………………...……………...……….…..105

3.2.2 Hydrolysis of Biphenyl Acetals and Subsequent Nucleophilic Addition….....106

3.2.2.1 Meyers’ Optimization of Hydrolysis Condition for Acetal 3.5a…….107

3.2.2.2 Hydrolysis of Biphenyl Acetals 2.20a and 2.20b and Subsequent

xiv

Acetylide Additions…………………………………...……….……..108

3.2.2.3 Mechanistic Consideration on the Atropisomerization between Biaryl

Aldehydes 2.22a and 2.22b……………….…………..……….……..111

3.2.3 Preparation of the Benzyl Bromide 3.10……………………………….…….113

3.2.4 Attempted Coupling Reactions between the Benzyl Bromide 3.10 and

Various Metallated Acetylides……………………………………...…….….116

3.2.5 Preparation of the Benzyl Bromide 3.17 and Attempted Coupling Reactions

with Various Metallated Acetylides…………………………...……….…….118

3.3 Racemic Synthesis of Steganone…………………..………………...………….….120

3.3.1 Synthetic Plan for the Racemic Synthesis of Steganone…………….……….120

3.3.2 Synthesis of the Alcohol 3.3 from Biaryl Oxazolines 2.20a and 2.20b……...121

3.3.3 The Stille Coupling Reaction between the Benzyl Bromide 3.19 and

Trimethylstannyl Trimethylsilylacetylene…………………………...…….…123

3.3.4 Synthesis of the Bistrimethylsilyl Alcohol 2.25…………………………...…125

3.3.5 Benzylation of the Bistrimethylsilyl Alcohol 2.25 and Synthesis of the

Diyne 2.37…………………………………………………...………….....….125

xv

3.3.6 [B-Sn] Reagent Mediated Cyclization Reaction of the Diyne 2.37 and

Subsequent Conversion to the Diene 2.46………………………...…….....….127

3.3.7 Attempted Hydroboration/Oxidation on the Boronate Ester 2.46………..…..127

3.3.8 A Novel Tandem Process Mediated by AD-mix to Form the α, β-

Unsaturated Lactone 3.24……………………………………………..…...….128

3.3.9 Proposed Mechanism of this Novel Tandem Process Mediated by AD-

Mix...…………………………………………………………………..……...131

3.3.10 Hydrogenation of the Unsaturated Lactone 3.24………………………...….133

3.3.11 Completion of the Synthesis of Steganone………………………….....……133

3.4 Conclusions……………………………...………………………………..………...134

3.5 Experimental Section………………...……….…………………………..………...135

3.5.1 General Methods……………...……..….……………………………..……...135

3.5.2 Synthetic Procedures and Spectral Data………..……………………..……...135

Chapter 4. Conformation and Reactivity in Dibenzocyclooctadiene Derivatives.

Total Syntheses of Fully Substituted Dibenzocyclooctadiene Lignans…...155

4.1Synthetic Plan towards Fully Substituted DBCOD Lignans from Bisalkylidene

xvi

dibenzocyclootadiene 2.47c…………………………………………………..…….155

4.2 Derivatization of Bisalkylidene 2.47c…………………………………….…….…..157

4.3 Inversion of C6 and C9 Chirality via Mitsunobu Reactions……………….….…….160

4.3.1 Unsuccessful Mitsunobu Reactions…………………..…………….….…..…161

4.3.2 Successful Mitsunobu Reactions…………..…..………………………..……161

4.4 Alternative Routes Involving Oxidation-Reduction Sequences to Invert C6 and C9

Configurations……………………………………………..……………...………165

4.5 Syntheses of Ananolignans and Interiotherin C………………………….……...….166

4.6 Syntheses of DBCOD Lignans with C7-α-Hydroxyl Group Including Kadsuralignan

B, Tiegusanin D and Schizanrin F………………………………………………….169

4.6.1 Attempted Electrophilic Reactions at C7 as an Approach to Introduction of

the C7-α-Hydroxyl group……………………………………..…………..…..169

4.6.1.1 Reactions of Dibenzocyclooctadienes with C6-Carbonyl: α-

Hydroxylation or Silyl Enol Ether Formation………………………..170

4.6.1.2 Electrophilic Functionalization of Substrates with the C6-C7 Double

Bonds.……………………………………………………………..…174

xvii

4.6.1.3 Synthesis and Osmylation of the Alkene 4.32 that Contains a C6-C7

Double Bond……………………………….…………….…….…….177

4.6.1.4 Epoxidation and Woodward/Prévost Dihydroxylation on Alkenes

4.31 and 4.32………………………………………………..………...179

4.6.2 Introduction of the C7-α-Hydroxyl Group via a Nucleophilic Addition to a

C7-Carbonyl Substrate 4.41 (Figure 4.7)…………………………………..…181

4.6.2.1 Preparation of Ketone Substrate 4.41 for Nucleophilic Addition…....182

4.6.2.2 Successful Introduction of C7-α-Hydroxyl Group via Nucleophilic

Addition to the Ketone 4.41……………………………………..……184

4.6.3 Synthesis of Kadsuralignan B and Tiegusanin D……………………….……185

4.6.4 Synthesis of Schizanrin F………………………………………….…….……187

4.7 Conformations of DBCODs with C6 and (or) C9 Carbonyl Groups.…...…….…….190

4.7.1 1H NMR Spectra……………………………………….……………….…….190

4.7.2 13C NMR spectra…………………………………….…………….….………192

4.7.3 IR spectra…………………………………………………………….……….192

4.7.4 X-ray Crystallography…………………………………………….…….……194

xviii

4.7.5 Conformations of DBCODs with the C6/C9-Carbonyl group…….…….….…194

4.8 Conclusions and outlook………………………………….……….……….……….199

4.9 Experimental Section……………………………………………….…….………...201

4.9.1 General Methods…………………………………………..….….…………...201

4.9.2 Synthetic Procedures and Spectral Data………………………….…………..201

4.9.3 Comparison of Spectroscopic and Chiroptical Data of Synthetic and Natural

1 13 Compounds ( H NMR, C NMR and [α]D)………….………………………237

Bibliography…………………………………………….……………………….……..249

Appendices………..…...…..…..…..…..…..…..…..…..…..…..…..…..…..………..…..256

Appendix A: 1H, 13C and 2D NOESY NMR Spectra of Important Compounds…....…256

Appendix B: X-ray Crystallographic Data of Compounds 2.47c, 3.24, 4.46 and

Kadsuralignan B……………………………………………………….....449

xix

LIST OF SCHEMES

1.1 R3Si-BR2 Mediated Cyclization of 1, n-Diynes……………………………………….2

1.2 R3Si-SnR’3 Reagent Mediated Cyclization of 1, 6-Diynes……………………………3

1.3 Proposed Mechanism for the [X-Y] Mediated Cyclization of 1,6-Diynes.…………...3

1.4 R3Si-SnR’3 Mediated Cyclization of 1, 6-Diyne 1.16 without Regioselectivity…...…5

1.5 R3Si-SnR’3 Mediated Cyclization of Allenynes 1.18……………………………...….5

1.6 Proposed Mechanism for Silylstannylation-Cyclization of Allenynes………………..6

1.7 Synthesis of Indolizidines via R3Si-SnR’3 Mediated Cyclization of Allenyne

1.27…………………………….…………………………………………………...….8

1.8 Synthesis of Indolizidines via R3Si-SnR’3 Mediated Cyclization of Allene-aldehyde

1.29………………………………………………….……………………...………….8

1.9 R3Si-SnR’3 Mediated Cyclization of Enynes…………………………………...……. 8

1.10 Unsuccessful Attempt to Cyclize Diynes 1.33 and 1.34 Using R3Si-SnR’3

Reagent…………………………….………………………………………….……. 9

xx

1.11 [B-Sn]-Mediated Cyclization of Diynes to Form Compounds of Different Ring

Sizes…………………………….…………………………………………….…….10

1.12 [B-Sn]-Mediated Cyclization of Diynes followed by Pinacol Exchange to Form Air-

stable 1,2-Bisalkylidenes with two Useful Metallic Functionalities.…….……..….11

1.13 Derivatization of 1,3-Diazaborolidines……………………………………………..11

1.14 [B-Sn] Reagent 1.37 Mediated Cyclizations of the Enyne and Allenyne…………..12

1.15 [B-Sn] Reagent Mediated Cyclization of the 2, 2’-Dipropargyl Biphenyls 1.67a and

1.67b and Related Syntheses of Gomisin E and other DBCOD Lignans from the

[B-Sn]-Adducts………………………………...……………………………….…..13

1.16 Meyers’ Syntheses of Steganone and Isochizandrin Using the Chiral Oxazoline

Strategy…………………………….……………………………………………….18

1.17 Uemura’s Formal Synthesis of Steganone………………………………………….19

1.18 Molander’s Synthesis of (-)-Steganone and (+)-Isoschizandrin……………………20

1.19 Koga’s Synthesis of Steganacin Utilizing Oxidative Phenolic Coupling of a Chiral

1,4-Diarylbutane 1.113…………………………….……………………………….21

1.20 Coleman’s Synthesis of Gomisin O and Interiotherin A…………………………...21

xxi

1.21 Silyl-Stannylation Cyclization of a 2,2′-Dipropargylbiphenyl Derivative 1.117…24

1.22 [B-Sn]-Mediated Regio- and Stereoselective Cyclization of an Axially Chiral Diyne

1.117…………………………………………………………….……………….….25

1.23 The General Approach to DBCOD Lignans Utilizing [B-Sn]-Mediated Cyclization

of 1, 6-Diynes…………………………….…………………………..………….….25

2.1 A Five-step Synthesis of the Aryl Bromide 2.14…………………………………….30

2.2 A Seven-step Synthesis of the Phenyl Bromide 2.14………………………………..31

2.3 Synthesis of Enantiopure Biaryl Oxazolines………………………………………...32

2.4 Hydrolysis of Acetals 2.20a and 2.20b and Subsequent Acetylide Additions to

Biphenyl Aldehydes 2.22a and 2.22b………………………………………………..33

2.5 The Diastereoselective Acetylide Addition to the Biphenyl Aldehyde 2.24………...34

2.6 Synthesis of the Biphenyl Aldehyde 2.26 and the Following Acetylide Addition…..36

2.7 Synthesis of the Biphenyl Aldehyde 2.28 and the Subsequent Acetylide Addition…37

2.8 Synthesis of the Biaryl Aldehyde 2.31 from the Propargyl Alcohol 2.29a………….38

2.9 Synthesis of the Biphenyl Aldehyde 2.34 and Subsequent Acetylide addition……...40

2.10 Proposed Chelation Model for Acetylide Addition to Biphenyl Aldehyde 2.24…...43

xxii

2.11 Proposed Chelation Model for Acetylide Addition to Biphenyl Aldehyde 2.22a….44

2.12 Proposed Chelation Models for Acetylide Addition to Biphenyl Aldehyde 2.26….45

2.13 Supporting Evidence for the Models Based on X-ray Structures of Proparylic

Alcohols…………….………………………………………………………………46

2.14 Proposed Chelation Models for Acetylide Addition to Biphenyl Aldehyde 2.28….47

2.15 Synthesis of the Dipropargyl Biphenyl 2.37 from the Alcohol 2.25……………….48

2.16 Preparation of Precursor Diynes for Cyclization…………………………………...48

2.17 Preparation of Cyclization Precursor Diynes (2.41 and 2.42) and Allene (2.43)….49

2.18 [B-Sn]-Mediated Cyclization of the Diyne 2.37 with C7’-OBn Substituent 50

2.19 Cyclization of 2,2’-Dipropargyl Biphenyls………………………...... …………….52

2.20 Cyclization of the 2,2’-Dipropargyl Biphenyl 2.39c…………………………….…54

2.21 [B-Sn]-Mediated Cyclization of Substrates with a C7-OTIPS Substituent .....……..55

2.22 [B-Sn]-Mediated Cyclization of the 2,2'-Dipropargyl Biphenyl 2.54……………...56

2.23 Effect of C6-Configuration on Borostannylation/cyclization……………………....58

2.24 [B-Sn]-Mediated Cyclization of 2, 2'-Dipropargyl Biphenyls………………...……59

2.25 [B-Sn]-Mediated Cyclization of Dipropargyl Biphenyls with both C7- and C7’-

xxiii

oxygenated Substituents…………………………….………………………………62

2.26 Proposed Catalytic Cycle of the [B-Sn] Mediated Cyclization of the Dipropargyl

Biphenyl 2.39c (R=TBS)…………………..……….………………………………64

3.1 Magnesium Mediated Biaryl Coupling Reactions………………………………….106

3.2 Hydrolysis of the Biaryl Oxazoline 2.20a………………………………………….110

3.3 Hydrolysis of the Biaryl Acetals 2.20a and 2.20b and Subsequent Acetylide

Additions ……………………………………………………………………...……111

3.4 Possible Rationale for the Atropisomerization of 2.22b to 2.22a………………...... 113

3.5 Synthesis of the Biaryl Aldehyde 3.8 from the Acetylide Addition Product 2.23a...114

3.6 Preparation of the Alcohol 3.9…………………………….………………………..115

3.7 Proposed Mechanism for the Formation of the Ether 3.11…………………………116

3.8 Synthesis of the Biaryl Bromide 3.17 from Biaryl Oxazolines 2.20a and 2.20b…..119

3.9 Synthesis of the Alcohol 3.3 from Biaryl Oxazolines.………………..……………122

3.10 Synthesis of the Biaryl Aldehyde 3.19 from the Alcohol 3.3…………………..…122

3.11 Synthesis of the Biphenyl Aldehyde 2.24 via a Stille Coupling Reaction………...125

3.12 Synthesis of the Diyne 2.37 from the Alcohol 2.25……………………...…..……127

xxiv

3.13 Proposed Mechanism of this Novel Tandem Process Mediated by AD-Mix……..132

3.14 Completion of the Synthesis of Steganone…………………………...…………...134

4.1 Synthesis of α, β-Unsaturated Aldehyde 4.5……………………………………….157

4.2 Synthesis of the Alcohol 4.9 from the Cyclization Products 2.47c……………...…158

4.3 Synthesis of Substrates 4.12 for Mitsunobu Reaction from The Alcohol 4.9……...161

4.4 Unsuccessful Mitsunobu Reactions…………………………….…..………………162

4.5 Inversion of the C6 Configuration Using p-Nitrobenzoic Acid as the Nucleophile..163

4.6 Attempted Double-Mitsunobu Reactions on the Diol 4.12………………………...164

4.7 Synthesis of Ananolignan C from the Alcohol 4.12 via a Known Diketone

Intermediate……………………...…………………………………………………166

4.8 Syntheses of Ananolignan B, D, F and Interiotherin C………………………….....168

4.9 Preparation of the C6-Carbonyl Precursor for Potential α-Hydroxylation at C7……170

4.10 Attempted α-Hydroxylation or Silyl Enol Ether Formation in DBCODs.…….….171

4.11 α-Hydroxylation of the Ketone 4.20…………………………………………...….173

4.12 Synthesis of the Diene 4.31 with a C6-C7 Double Bond………………..…………176

4.13 Osmylation of the Diene 4.31………………………...…………………..……….177

xxv

4.14 Synthesis and Osmylation of the Alkene 4.32………………………...…………. 179

4.15 Other Attempts to Introduce C7-Hydroxyl Group…………………………...……180

4.16 β-Face of some of the DBCODs Favoring Electrophilic Oxygenation and Catalyzed

Hydrogenation……………………………………………………………………...181

4.17 Synthesis of the Ketone 4.41 from the Diene 4.6………………...……………….183

4.18 Nucleophilic Addition to the Ketone 4.41…………………………………..…….184

4.19 Synthesis of Kadsuralignan B and Tiegusanin D…………………………………186

4.20 Oxidation of the Diol 4.42 with PCC………………………………………….….188

4.21 Synthesis of the Alcohol 4.52…………………………….…………………….…188

4.22 Synthesis of Schizanrin F…………………………………………………………189

xxvi

LIST OF TABLES

2.1 Acetylide Addition to 2.31. Effect of Reagents and Reaction Conditions on

Diastereoselectivity…………………………….…………………………………….39

2.2 Cyclization of 2,2’-Dipropargyl Biphenyls with 2.5 eq. of [B-Sn] 1.37………..…...53

1 2.3 Reaction Progress by HNMR in C6D6………………………………………………60

3.1 Meyers’ Optimization of Hydrolysis Conditions for the Acetal 3.5a……………....107

3.2 Optimization of Hydrolysis Conditions for the Acetal 2.20b…………………..…..109

3.3 Optimization of Bromination of the Alcohol 3.9…………………………………...115

3.4 Coupling Conditions between Benzyl Bromide 3.10 and Metallated Acetylides….117

3.5 Coupling Conditions between Benzyl Bromide 3.17 and Metallated Acetylides….120

3.6 Hydroboration/Oxidation Conditions on the Dienyl Boronate Ester 2.46………….128

3.7 Optimization of the Dihydroxylation Condition………………………...………….129

3.8 Optimization of Hydrogenation Conditions for the Substrate 3.24…………….…..134

xxvii

4.1 α-Hydroxylation or Silyl Enol Ether formation of DBCODs with C6 Carbonyls.....172

4.2 Dehydration conditions for the alcohol 4.9………………………………………....178

4.3 Epoxidation and Woodward/Prévost Dihydroxylation on Alkenes 4.31 and 4.32…180

1 13 4.4 Comparison of the H absorption of H4 and the C Absorption of the Conjugated C6-

Carbonyl in Compounds 4.26, 4.25, 4.20, 4.27, 4.19 and Ananolignan B…………193

4.5 Data Comparison of Synthetic and Natural Ananolignan B……………………..…238

4.6 Data Comparison of Synthetic and Natural Ananolignan C……………………..…240

4.7 Data Comparison of Synthetic and Natural Ananolignan D……………………..…241

4.8 Data Comparison of Synthetic and Natural Ananolignan F………………………..242

4.9 Data Comparison of Synthetic and Natural Interiotherin C……………………...…244

4.10 Data Comparison of Synthetic and Natural Kadsuralignan B…………………….245

4.11 Data Comparison of Synthetic and Natural Tiegusanin D……………………...…246

4.12 Data Comparison of Synthetic and Natural Schizanrin F…………………..……..248

B.1 Crystallographic details for RajanBabu 1872……………………………………...450

4 2 B.2 Atomic coordinates (x 10 ) and equivalent isotropic displacement parameters (Å x

3 10 ) for RajanBabu 1872. ………………………………………………………….451

B.3 Bond lengths [Å] and angles [°] for RajanBabu 1872. ……………………………453

2 3 B.4 Anisotropic displacement parameters (Å x 10 ) for RajanBabu 1872. ……………456

4 B.5 Calculated hydrogen coordinates (x 10 ) and isotropic displacement parameters

2 3 (Å x 10 ) for RajanBabu 1872. …………………………………...………………467 xxviii

B.6 Torsion angles [°] for RajanBabu 1872. ………………………………..…………470

B.7 Crystallographic details for RajanBabu 1787…………………………...…………475

4 2 B.8 Atomic coordinates (x 10 ) and equivalent isotropic displacement parameters (Å x

3 10 ) for RajanBabu 1787…………….………………………………………..……476

B.9 Bond lengths [Å] and angles [°] for RajanBabu 1787…………………………..…478

2 3 B.10 Anisotropic displacement parameters (Å x 10 ) for RajanBabu 1787………..… 484

4 B.11 Calculated hydrogen coordinates (x 10 ) and isotropic displacement parameters

2 3 (Å x 10 ) for RajanBabu 1787…………..……………………………………..…486

B.12 Torsion angles [°] for RajanBabu 1787………………………………………..…487

B.13 Crystallographic details for RajanBabu 1913………………………………….…490

4 2 B.14 Atomic coordinates (x 10 ) and equivalent isotropic displacement parameters (Å x

3 10 ) for RajanBabu 1913……………………………..………………………...…491

B.15 Bond lengths [Å] and angles [°] for RajanBabu 1913……………………………493

2 3 B.16 Anisotropic displacement parameters (Å x 10 ) for RajanBabu 1913………...…501

4 2 3 B.17 Hydrogen coordinates (x 10 ) and isotropic displacement parameters (Å x 10 )

for RajanBabu 1913…………………………………………………………..… 503

B.18 Torsion angles [°] for RajanBabu 1913…………………………………….……505

B.19 Crystallographic details for RajanBabu 1916……………………………………508

4 2 B.20 Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters (Å x

3 10 ) for RajanBabu 1916…………………………………………………………509

B.21 Bond lengths [Å] and angles [°] for RajanBabu 1916……………………………512 xxix

2 3 B.22 Anisotropic displacement parameters (Å x 10 ) for RajanBabu 1916……...……525

4 B.23 Hydrogen coordinates (x 10 ) and isotropic displacement parameters (Å2x 103)

for RajanBabu 1916…………………………………………………………...…528

B.24 Hydrogen bonds for RajanBabu 1916 [Å and °]…………………………………531

xxx

LIST OF FIGURES

1.1 Atropisomerization of (Z, Z)-1,3-Dienes 1.9a and 1.9b………………………………4

1.2 Derivatives of the Diazaborolidine Products from the [B-Sn] Mediated

Cyclizations. …………………………………………………………………………13

1.3 Prototypical Biologically Active Dibenzocyclooctadiene Lignans…………………..15

1.4 Approaches to Dibenzocyclooctadiene Lignans…………………………….……….22

2.1 General Strategy toward the Syntheses of DBCOD Lignans………………………..28

2.2 The ORTEP Drawings of the Alcohols 2.23a and 2.23b……………………………34

2.3 The ORTEP Drawings of the Alcohol 2.25………………………………………….35

2.4 The ORTEP Drawings of the Alcohol 2.27a………………………………..……….36

2.5 The ORTEP Drawing of the Alcohol 2.35a………………………………………….41

2.6 Common Structural Features of the Biphenyl Aldehydes.……………………..……42

2.7 The ORTEP Representations of 2.45a and 2.46……………………………………..51

2.8 The ORTEP Drawing of the Cyclized Product 2.47c……………………………..…53 xxxi

2.9 Mechanism and Possible Origin of Stereoselectivity in the Cyclization of the Diyne

2.54. Interactions of the Axial-X (= OBn) Group Prevents the Cyclization of 2.58 to

Form 6-epi-2.55…………………………………….…………..……………………57

2.10 Atropisomerization between 2.44a and 2.44b…………………………………..….61

3.1 Synthetic Plan for Steganone.…………………………….…………………..…….105

3.2 Synthetic Plan for the Dipropargyl Biphenyl 2.37 from the Oxazolines 2.20a and

2.20b…………………………….………………………………………………….121

3.3 Complication in the Stille Reaction and the Quality of the Reagents………………124

3.4 Benzylation condition for the Alcohol 2.25……………………………..………….126

3.5 The ORTEP Drawing of the Lactone 3.24 ……………………………...………….130

4.1 Comparison of the Structures of Fully Substituted DBCOD Lignans with that of 2.47c

…………………………….…………………………………………………………156

4.2 Synthetic Plans to Convert 2.47c to Fully Substituted DBCOD Lignans…………..156

4.3 Proposed Inversion of Configuration at C6 and C9 in the Alcohol 4.9 via Mitsunobu

Reactions……………………………………………………………………………160

4.4 Inversion of C6 and C9 Configurations via Oxidation-Reduction Sequences.…...…165

xxxii

4.5 Introduction of the C7-α-Hydroxyl Group via α-Hydroxylation of C6-Ketones…....170

4.6 Synthetic Plan Involving Oxygenation of Substrates with C6-C7 Double bond……175

4.7 Synthetic Strategy Involving a Nucleophilic Addition to the C7-Carbonyl Substrate

4.41…………………………………………………………………………………182

4.8 The ORTEP Drawing of Kadsuralignan B…………………………………………187

1 13 4.9 The Chemical Shifts of H11 and H4 in H NMR and those of C6 and C9 in C NMR in

DBCODs with C6 and (or) C9 Carbonyl Groups and the Carbonyl Stretching

Frequencies in their IR Spectra…………………………………………………….191

4.10 Solid-state Structure (X-ray) of the Ketone 4.46………………………………….194

4.11 The TB Conformation of the Ketone 4.26……………………………………..….195

4.12 The TBC Conformation of the Ketone 4.13…………………………………...….195

4.13 The TBC Conformation of the Diketone 4.19…………………………………….196

4.14 The Conformations of Diketones 4.28, 4.47 and 4.47a……………….………..…197

4.15 The TBC Conformations of Diketones 4.40 and 4.46……………………….……199

4.16 A General Approach to the Syntheses of Fully or Tri-substituted DBCOD Lignan

Natural Products (>50) and Unnatural Analogs with Different Configurations and/or

xxxiii

Oxidation States at C6, C7, C8 and C9……………………………………………..200

4.16 CD Spectrum of Synthetic Ananolignan B…………………………..……………239

xxxiv

LIST OF ABBREVIATIONS

T [α]D specific rotation at temperature T at the sodium D line

Ac acetyl aq. Aqueous atm atmosphere

9-BBN 9-borabicyclo [3.3.1] nonane

Bn benzyl br broad

Bu butyl

Bz benzoyl

°C degrees Celsius calcd calculated cat. catalytic cm–1 reciprocal centimeters

xxxv

CSA 10-camphorsulfonic acid

CSO camphorylsulfonyl oxaziridine

Cy cyclohexyl

δ NMR chemical shift in ppm downfield from a standard d day, doublet dba dibenzylideneacetone

DBCOD dibenzocyclooctadiene

DBDMH 1,3-dibromo-5,5-dimethylhydantoin

DCC N, N’-dicyclohexylcarbodiimide

DEAD diethyl azodicarboxylate

DIBAL-H diisobutylaluminum hydride

DMAP 4-N, N’-dimethylamino pyridine

DME dimethoxyethane

DMF N, N-dimethyl formamide

DMP Dess-Martin periodinane

DMSO dimethylsulfoxide

xxxvi

DPEphos bis[(2-diphenylphosphino)phenyl]methane dppf 1,1’-bis(diphenylphosphino)ferrocene d.r. diastereomeric ratio

EDTA ethylenediaminetetraacetic acid

EI electron impact ionization ent enantiomer epi epimeric epto 4-ethyl-2,6,7-trioxa-1-phosphabicyclo [2.2.2]octane equiv. equivalent

ESI electron spray ionization

Et ethyl

EtOAc ethyl acetate et al. and others g gram h hour

HMPA hexamethylphosphictriamide

xxxvii

HR high resolution

Hz Hertz i iso

IBX 2-iodoxybenzoic acid

IR infrared

J coupling constant (expressed in Hertz)

KHMDS potassium 1,1,1,3,3,3-hexamethyldisilazide

LDA lithium diisopropyl amide

L-selectride lithium tri-sec-butylborohydride m multiplet m meta

M molecule ion, molar mCPBA 3-chloroperoxybenzoic acid

Me methyl

MeOTf methyl trifluoromethanesulfonate mg milligram

xxxviii

MHz megahertz

min minute

mL milliliter

mp melting point

mmol millimole

mol% mole per cent

MOM methoxymethyl

MoOPH oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide)

MoO5•pyr•HMPA

Ms methylsulfonyl

MS mass spectrometry

NBS N-bromosuccinimide

NMO N-methyl morpholine N-oxide

NMR nuclear magnetic resonance

NOE nuclear Overhauser enhancement

ν vibration frequency in cm–1

xxxix o ortho

Oxone potassium peroxymonosulfate p para

PCC pyridinium chlorochromate pH negative logarithm of hydrogen ion concentration

Ph phenyl ppm parts per million

PPTS pyridinium 4-toluenesulfonate

Pr propyl

PSPO 2-phenylsulfonyl-3-phenyloxaziridine p-TLC preparative thin layer chromatography p-TsOH p-toluenesulfonic acid pyr pyridine q quartet quant. quantitative

Rf retention factor

xl rt room temperature s singlet sat. saturated

Super-hydride lithium triethylborohydrate t triplet t tert

T temperature

TB twist-boat

TBAF tetra-n-butylammonium fluoride

TBAI tetra-n-butylammonium iodide

TBC twist-boat-chair

TBS tert-butyldimethylsilyl

THF tetrahydrofuran

TIPS triispropylsilyl

TLC thin layer chromatography

TMEDA N, N, N’, N’-tetramethylethylenediamine

xli

TMS trimethylsilyl

TS transition state

xlii

CHAPTER 1

MULTI-COMPONENT CYCLIZATION REACTIONS AND

DIBENZOCYCLOOCTADIENE LIGNANS

1.1 Multi-component Cyclization Reactions

Transition-metal catalyzed cyclizations are very important and useful reactions for synthesis of a variety of carbocyclic and heterocyclic compounds.1,2 Well-known

examples include Pauson–Khand reaction,3 intramolecular Heck reaction,2,4

intramolecular Tsuji-Trost allylation5 and ring-closing metathesis reaction.6 These

catalyzed annulation processes involve carbon-carbon bond formation via

carbametallation, which distinguishes them from radical cyclization as well as thermal

and photochemical cyclizations. Our group has been particularly interested in developing

transition-metal catalyzed cyclization reactions mediated by main-group bismetallic [X-

7-14 Y]-type reagents (X, Y = R3Si, R3Sn or BR2). Starting from relatively simple substrates containing (1,n)-π-systems such as diynes,8,9,13,14 alleneynes.10,11 and allene- aldehydes,12 These reactions give highly functionalized cyclic products with versatile

latent functionalities such as vinyl or alkyl stannane, silane and boronate ester, which

could serve as useful handles for further manipulations.

1.1.1 R3Si-BR2 Mediated Cyclization of 1, n-Diynes

1

One of the earliest studies in this area by Tanaka involved the [B-Si] reagent (1.1)-

mediated cyclization catalyzed by Pd (0) and epto-(4-ethyl-2,6,7-trioxa-1-phosphabi cyclo[2.2.2]octane) as the ligand (Scheme 1.1).15 This method gave 1,2-bisalkylidine

cyclopentanes 1.5 and 1.6 in good yield from 1,6-diynes 1.2 and 1.3, respectively.

However, the formation of a six-membered ring is not satisfactory as only 17% yield of

the cyclized product 1.7 was isolated from diyne 1.4 under the cyclization condition.

N B SiMe2Ph N N (1.1) B N

Pd2(dba)3/etpo(cat.) SiMe2Ph o C6D6, 110 C, 18h 1.2 (86%) 1.5

N B SiMe2Ph N N (1.1) B N EtO2C EtO2C EtO2C EtO2C Pd2(dba)3/etpo(cat.) SiMe2Ph o C6D6, 110 C, 18h 1.3 (84%) 1.6

N B SiMe2Ph N N (1.1) B N

Pd2(dba)3/etpo(cat.) SiMe2Ph o C6D6, 110 C, 18h 1.4 (17%) 1.7

Scheme 1.1 R3Si-BR2 Mediated Cyclization of 1,n-Diynes

1.1.2 R3Si-SnR’3 Mediated Cyclization of 1, n-Diynes

Our early studies8,9 described the synthesis of helically chiral 1,4-disubstituted (Z,

Z)-1,3-dienes (1.9) via Pd(0)-catalyzed silylstannylation/cyclization of 1,6-diynes (1.8)

16 mediated by R3Si-SnR’3 reagents (Scheme 1.2). In these reactions, only (Z, Z)-dienes

2

are formed, and common functional groups such as silyl and alkyl ethers, esters, amides,

nitriles, chlorides, and even free amines in the starting diynes are tolerated.

Z Z R3SiSnR'3(1 eq.), r.t.

Pd2(dba)3/(C6F5)3P (cat.) 66-79% SiR SnR' 1.8 3 3 1.9

Z=C(CO2R)2; N-Ts; 1,4-disubstituted (Z,Z)-1,3-dienes C(H)CO2Me; N-C(H)(Me)Ph(R)

t R3SiSnR'3 = Me3SiSnBu3, BuMe2SiSnPh3 or Et3SiSnBu3

Scheme 1.2 R3Si-SnR’3 Reagent Mediated Cyclization of 1, 6-Diynes

To explain the exceptional control of regio- and stereoselectivity of this cyclization event, a mechanism was proposed (Scheme 1.3). After oxidative addition of Pd(0) into the [X-Y]-type reagent 1.10 (X, Y = R3Si, R3Sn or BR2), the resulting species adds to one of the triple bond in the substrate 1.8 via a cis-addition to form the σ-Pd(Sn)-intermediate

1.12. The adduct 1.12 immediately undergoes a cis-carbametallation to provide the cyclized species 1.13 followed by reductive elimination to form the (Z, Z)-1,3-diene 1.14.

Z (1.8) Y

X PdII Y Z PdII cis-addition X (1.11) (1.12)

X Y X cis-carbametallation (1.10) Z (1.14) Y X

PdII Pd(0) Z reductive elimination Y with retention (1.13)

Scheme 1.3 Proposed Mechanism for the [X-Y] Mediated Cyclization of 1,6-Diynes 3

The configurational stability (towards helical isomerization) of these chiral 1,3-

dienes 1.15 depends on the size of the groups on Si and Sn and the substitution pattern

around the ring (Figure 1.1).7 In monocyclic systems, this atropisomerization is facile in solution and the two isomers are in rapid equilibrium at room temperature. Variable- temperature (VT) NMR spectroscopy was employed to monitor this atropisomerization process and we observed that these 1,3-dienes undergo rapid isomerization when the

temperature is higher than -20 oC. For example, the diastereotopic methylene protons

o (HA and HB) in 1.15 appear as a broad singlet above 25 C, however, when the temperature is lowered to -20 oC, they show up as two AB quartets. These results were

used to accurately measure the kinetic parameters for the enantiomerization by line-shape

analysis.9

Z Z MeO2C CO2Me HA 0 > -20 C HB

SnR'3 SiR3 SnR'3 SiR3 SiMe3 SnBu3

1.9a 1.9b 1.15

helical isomerization 'enantiotopic' at r.t. H H (atropisomerization) A B 'diastereotopic' at -40 0C

Figure 1.1 Atropisomerization of (Z, Z)-1,3-Dienes 1.9a and 1.9b

1.1.3 R3Si-SnR’3 Mediated Cyclization of 1, n-Allenynes and Allene-aldehydes

One major limitation of R3Si-SnR’3 and all other related [X-Y] reagents mediated cyclization of 1, n-diynes is lack of regioselectivity in unsymmetrically substituted diynes

(one example is shown in Scheme 1.4).

4

Me SiSnBu /C D /60 0C N 3 3 6 6 N N Pd2(dba)3/(C6F5)3P (cat.) + H H H (1.17a:1.17b=1:1) SnBu3 SiMe3 SiMe3 SnBu3 1.16 1.17a 1.17b

Scheme 1.4 R3Si-SnR’3 Mediated Cyclization of 1, 6-Diyne 1.16 without

Regioselectivity

In order to circumvent this regioselectivity problem, we explored the cyclization of

1,n-allenynes which bear two distinct π-systems (allene and acetylene) with different reactivity.10,11 Under optimized conditions at room temperature, the cyclization of 1, n-

t allenynes 1.18 mediated by BuMe2SiSnPh3 proceeds with high chemo-, regio- and stereoselectivity to afford 2-vinylalkylidenecyclopentanes with silicon and tin substituents on the double bonds (Scheme 1.5). When the less reactive Me3SiSnBu3 was

used, uncyclized products 1.19 were isolated in high yields, or, alternatively, simply

raising the reaction temperature to 45 oC or 80 oC, the intermediates 1.19 could be quantitatively converted to the cyclic products 1.20.

SnR' R • R 3

R3SiSnR'3(1 eq.), SiR3 Z Z Pd2(dba)3/(C6F5)3P (cat.)

1.18 1.19 R SiSnR' = Z=C(CO Et) ; 3 3 2 2 (41-95%) N-Ts; O; Me3SiSnBu3 t R=H; Ph or BuMe2SiSnPh3 R SiR3

Z SnR'3 1.20

Scheme 1.5 R3Si-SnR’3 Mediated Cyclization of Allenynes 1.18 5

A possible mechanism that accounts for the observed results is shown in Scheme

1.6.11 The adduct [Si]-PdII-[Sn] from oxidative addition adds to the terminal π-bond of

the more reactive allene moiety, resulting in the formation of an anti π-allyl Pd-complex

1.23, which upon reductive elimination provides the simple addition product 1.24. At

higher temperature, the carbametallation step is feasible. This crucial step involves a more energetically demanding insertion of the acetylene into 1.23 leading to the cyclic product 1.26 via 1.25. Extra support for such a mechanism comes from the observation that isolated 1.24 can be converted into 1.26 using Pd(0) and (C6F5)3P at elevated temperatures. The cis-addition in the carbametallation step and retention of configuration in the following reductive elimination step ensure the exquisite stereoselectivity observed

in these reactions.

Si E • E Pd(0) 1.21 E Sn E 1.26 + Si-Sn

Si Si H E • E H Pd H Pd E E Sn Sn 1.25 1.22

E

E H 1.23 (anti-) Pd Si Sn ? Sn E Sn E Si E Si E + Pd 1.24 (E-) Pd(0)

Scheme 1.6 Proposed Mechanism for Silylstannylation-Cyclization of Allenynes

6

Indolizidines, which are the core skeletons for a class of alkaloids found in various

terrestrial and marine sources, could be accessed via R3Si-SnR’3 mediated cyclization of

allenynes.12 Under the standard cyclization condition, we were able to prepare alkylated

indolzines 1.28 and its C5-epimer from the alleneyne 1.27 (Scheme 1.7).

H 8 H 8 H Pd (dba) /(C F ) P (cat.) 7 7 2 3 6 5 3 Ph Sn 3 + Ph3Sn N tBiMe SiSnPh , tBuMe Si 6 N t 6 • 2 3 2 BuMe2Si N 5 C H , 45 oC, 24h 5 5 O 6 6 O O (78%) 1.28:5-epi-1.28=1.5:1 1.27 1.28 5-epi-1.28 (2 diastereomers epimeric at C5)

Scheme 1.7 Synthesis of Indolizidines via R3Si-SnR’3 Mediated Cyclization of Allenyne

1.27

Indolizidines could also be prepared via R3Si-SnR’3 mediated cyclization of the

allene-aldehyde 1.29 under milder reaction condition (Scheme 1.8).12 After simple

functional group manipulations, these indolizidines were converted to epimers of the

naturally occurring indolizidine 223A.

1.1.4 R3Si-SnR’3 Mediated Cyclization of Enynes

After Lautens17 reported a Pd-catalyzed stannylative cyclization of enynes with

Bu3SnH to form homoally stannanes, Mori investigated the R3Si-SnR’3 mediated cyclization of enynes, adopting ligand-free catalystic systems [Pd2(dba)3 or Pd(OH)2 on

charcoal] (Scheme 1.9).18 Generally the latter heterogenous catalyst gave better yields,

albeit requiring longer reaction time.

7

O H 8 H H Pd2(dba)3/(C6F5)3P (cat.) HO HO 7 + N Me SiSnBu , C H , Me Si N Me Si N • 3 3 6 6 3 3 5 r.t., 10 min 6 5 O O O

1.29 1.30a (32%) 1.30b (24%) (4 diastereomers)

8 H H HO HO 7 + Me3Si N Me3Si N 6 5 O O

1.30c (12%) 1.30d (14%)

H H H steps steps steps 1.30a N 1.30b N 1.30c N O O O

5,8-epi-indolizidine 223A 6,8-epi-indolizidine 223A 8-epi-indolizidine 223A

Scheme 1.8 Syntheses of Indolizidines via R3Si-SnR’3 Mediated Cyclization of Allene-

aldehyde 1.29

SnBu3

Me3SiSnBu3 Z Z Pd2(dba)3 or Pd(OH)2/C (cat.), SiMe3 THF, r.t. 1.31 (22-82%) 1.32 Z=C(CH2OBz)2; C(CH2OBz)2; N-Ts; etc.

Scheme 1.9 R3Si-SnR’3 Mediated Cyclization of Enynes

1.1.5 (R2N)2B-SnR’3 Mediated Cyclization of 1, n-Diynes and Enynes

One serious limitation of the Pd-catalyzed silylstannylation-cyclization is that it is not effective for the formation of carbocyclic and heterocyclic compounds of ring sizes

8

other than cyclopentane system. For example, under the standard condition for R3Si-

SnR’3 mediated cyclization, only very small amount of the cyclized product 1.35 (<5%)

were observed from the 1,9-diyne 1.33, while the 1,7-diyne 1.34 underwent dimerization

to give the compound 1.36 (Scheme 1.10).

R3SiSnR'3, Pd2(dba)3/(C6F5)3P (cat.), o SiR3 C6D6, 25-80 C.

(<5%) SnR'3

1.33 1.35

Me3SiSnBu3,

Pd2(dba)3/(C6F5)3P (cat.), SiMe3 C D , r.t. O O 6 6 O (60%) O O O Bu3Sn

1.34 1.36

Scheme 1.10 Unsuccessful Attempt to Cyclize Diynes 1.33 and 1.34 Using R3Si-SnR’3

Reagent

When we were screening various main group bis-metallic [X-Y]-type reagents (X, Y

19 = R3Si, R3Sn, BR2) known to effect such cyclizations, a report by Tanaka attracted our

attention, which described the facile cyclization of 1, n-diynes 1.38-1.41 using a [B-Sn] reagent 1.3720 to construct various carbocyclic and heterocyclic systems (e.g., four-, five-

or six-membered rings such as 1.42, 1.43 and 1.44, respectively, Scheme 1.11).

However, the highly moisture-sensitive nature of these diazaborolidines renders this

protocol not practical, as significant loss of the product was observed during separation.

9

N N B SnMe3 N B SnMe3 N N N (1.37) B (1.37) N B N SnMe PdCl2(PPh3)2(cat.) 3 PdCl2(PPh3)2(cat.) SnMe3 C6D6, r.t., 18h C6D6, r.t., 18h 1.38 (64%) 1.42 1.39 (79%) 1.43 N N B SnMe B SnMe3 N 3 N N N (1.37) (1.37) B B N N O O SnMe SnMe PdCl2(PPh3)2(cat.) 3 PdCl2(PPh3)2(cat.) 3 C6D6, r.t., 18h C6D6, r.t., 18h 1.40 (74%) 1.44 1.41 (83%) 1.45

Scheme 1.11 [B-Sn]-Mediated Cyclization of Diynes to Form Compounds of Different

Ring Sizes

We found that the diazaborolidine products from the [B-Sn]-reagent mediated cyclization could be easily converted in situ into corresponding vinyl boronate esters by

treatment with pinacol.14,21 There boronates are air-stable and could be separated by

column chromatography and stored at 0 oC without decomposition after months. For

example, after pinacol exchange the hydrolytically unstable primary products 1.46, 1.48

and 1.51 were converted to boronate esters 1.47, 1.49 and 1.52, respectively. These

bismetallated cyclization products contains boron and stannyl groups and thus are

valuable intermediates. Obviously, from these cyclized products, the cross-coupling

protocols such as Stille and Miyaura-Suzuki reactions could provide rapid access to

stereodefined alkenes and polyalkenes.

We also discovered that the direct cyclization products, the diazaborolidines, could

either be converted to alkenes after protio-destannylation, or to the air-stable halo-

dioxaborolidines using a two-step derivatization protocol (halodestannylation and

10 subsequent pinacol exchange, Scheme 1.13).14 The halo-dioxaborolidines 1.53, 1.55 and

1.57 could serve as electrophilic partners in other cross-coupling reactions.

N B SnMe3 N O N B (1.37) B N Pinacol O

SnMe 78% SnMe PdCl2(PPh3)2(cat.) 3 3 over two steps C6D6, r.t., 18h 1.33 1.46 1.47 racemates racemates N B SnMe3 N O N B O (1.37) O N Pinacol O B O 83% O O SnMe3 O SnMe3 PdCl2(PPh3)2(cat.) over two steps C6D6, r.t., 18h 1.34 1.48 1.49 N B SnMe3 N O N (1.37) B N Pinacol B O Ts N Ts N Ts N SnMe3 73% SnMe3 PdCl2(PPh3)2(cat.) over two steps C6D6, r.t., 18h 1.50 1.51 1.52

Scheme 1.12 [B-Sn]-Mediated Cyclization of Diynes followed by Pinacol Exchange to Form Air-stable 1,2-Bisalkylidenes with two Useful Metallic Functionalities

N 1. NBS O B O B N 2. Pinacol O O

O SnMe3 O Br 1.48 1.53 N 1. NBS O B B N 2. Pinacol O Ts N Ts N SnMe3 Br 1.54 1.55 MeO MeO 1. NBS SnMe3 Br MeO 2. Pinacol MeO MeO B N MeO B O N O MeO OBn MeO OBn 1.56 1.57

Scheme 1.13 Derivatization of 1,3-Diazaborolidines

11

We found that this general cyclization protocol using [B-Sn]-reagent 1.37 could

also effect the cyclization of enynes and allenynes (e.g., 1.58 and 1.60 in Scheme 1.14)

and obtain the air-stable pinacolboronates 1.59 and 1.61 from the corresponding

diazaborolidines.14

N 1. B SnMe3 SnMe3 N (1.37) O MeO2C MeO2C O MeO2C MeO C 2 O B O PdCl2(PPh3)2(cat.) C6D6, r.t., 18h 1.58 1.59 2. Pinacol (88%)

N 1. B SnMe3 SnMe3 • N (1.37 MeO C O MeO2C 2 O MeO C MeO2C 2 O B PdCl2(PPh3)2(cat.) O C D , r.t., 18h 1.60 6 6 1.61 2. Pinacol (85%)

Scheme 1.14 [B-Sn] Reagent 1.37 Mediated Cyclizations of the Enyne and Allenyne

We also studied the atropisomerization of the derivatives of the diazaborolidine

products (Figure 1.2), including the monocyclic vinyl halides (1.62, 1.63 and 1.55) and

bicyclic vinyl boronate esters (1.64, 1.65 and 1.66).14 Variable-temperature NMR analysis showed that monocyclic systems undergo rapid isomerization at or near room temperature. On the other hand, bicyclic systems such as 1.64, 1.65 and 1.66, could be configurationally stable at 75 oC. The significant higher activation barrier for helical

isomerization, compared with that in the monocyclic system, could be attributed to the

additional conformational restraints imposed by their backbones.

12

O O O B B B O O O Ts N Br Br Br

1.62 1.63 1.55

O O O B B B O O O Br I SnMe3 1.64 1.65 1.66

Figure 1.2 Derivatives of the Diazaborolidine Products from [B-Sn] Mediated

Cyclizations

O O O N O 1. B SnMe3 N SnMe MeO (1.37) MeO 3 2. H2O2, NaOH MeO MeO PdCl2(PPh3)2(cat.) B N (76%, 2 steps) C6D6, r.t N R1O OBn R1O OBn R O OR2 2

1.67a R1~R2=CH2 1.68a R1~R2=CH2

1.67b R1=R2=CH3 1.68b R1=R2=CH3

O O O O O O steps CHO MeO MeO MeO or MeO MeO MeO CH3 OH R1O OBn MeO O OBz

R2O MeO O

1.69a R1~R2=CH2 gomisin E interiotherin A 1.69b R1=R2=CH3

Scheme 1.15 [B-Sn]-Reagent Mediated Cyclization of the 2, 2’-Dipropargyl Diphenyls

1.67a and 1.67b and Subsequent Syntheses of Gomisin E and other DBCOD Lignans

from the [B-Sn]-Adducts

13

In order to provide rapid access to some dibenzocyclootadiene lignans (an important

class of natural products, see details in Section 1.2 of Chapter 1), we envisioned the bismetallic [X-Y] reagent could be utilized to form the crucial eight-membered ring from corresponding diynes. After less successful attempts with [Si-Sn] reagents, we switched to the borostannylation/cyclization protocol and were pleased to find out that diynes

1.67a and 1.67b could undergo smooth cyclization to provide the diazaborolidines 1.68a and 1.68b, respectively (Scheme 1.15).13 A few more steps could subsequently transform

these diazaborolidines to DBCOD lignans including gomisin E23j and interiotherin A.23m

1.2 Dibenzocyclooctadiene Lignans

1.2.1 Biological Activities of Dibenzocyclooctadiene Lignans

Dibenzocyclooctadiene (DBCOD) lignans,22 an important class of natural products

that include several biologically active compounds such as gomisins, schisandrins,

interiotherins and kadsura lignans, have been isolated from a variety of plant sources

including the genus Kadsura (Schizadraceae).22,23 These lignans have the basic dibenzocyclooctadiene skeleton 1.70, which is believed to form biosynthetically from an acyclic lignan precursor through an enzyme-catalyzed oxidative coupling of the aryl groups via a radical cation mechanism (disconnection A in structure 1.70, Figure 1.3).24

Because of the possible variations in the substitution patterns both on the 8-membered

ring and the biaryl unit, and the differing configurations of the stereogenic centers and the

atropisomeric biaryl unit, a variety of dibenzocyclooctadienes such as (−)-wuweizisu C

14

12 O O 11 12 11 O O 13 10 9 13 10 8 9 14 15 MeO 15 MeO A B 14 8 16 1 16 7 5 6 MeO MeO 1 7 5 6 * 2 2 4 MeO O 4 R OH 3 3 O MeO

1.70 Dibenzocyclo- 1.71 (–)-Wuweizisu C R = H 1.74 Gomisin O * = (R) octadiene skeleton 1.72 Interiotherin A R = O-benzoyl 1.75 epi-Gomisin O * = (S) 1.73 Gomisin R R = OH

MeO O O MeO O OAc O OAc R MeO 1 MeO MeO R MeO 2 MeO MeO

MeO MeO OH MeO O MeO MeO MeO

1.76 (+)-Schizandrin R = Me R = OH 1 2 1.78 Ananolignan C 1.79 Ananolignan B 1.77 (+)-Isoschizandrin R1 = OH; R2 = Me

O O O O OAc O OR O OAc

MeO MeO MeO MeO MeO MeO OH OH MeO MeO OR OR' MeO O MeO MeO MeO O 1.80 Ananolignan D R'= H 1.83 Kadsuralignan B R=R'=Ac 1.81 Ananolignan F R'= Ac 1.84 Tiegusanin D R=R'=Bz 1.86 (–)-Kadsurarin 1.82 Interiotherin C R'= Ang 1.85 Schizanrin F R=Ac R'=Bz

O O MeO O OBz O R MeO OCOPh Me O O MeO O MeO O Me OH O OAc MeO MeO O MeO O O

1.87 Kadsulignan E 1.88 (–)-Schiarisanrin C 1.89 Steganone R=O 1.90 Steganacin R=α-OAc

Figure 1.3 Prototypical Biologically Active Dibenzocyclooctadiene Lignan

15

(1.71) with no oxygen on the aliphatic bridge,23n mono-oxygenated compounds such as

interiotherin A (1.72),23m gomisin R (1.73),23n gomisin O (1.74),23p and a 7-epimer epi- gomisin O (1.75),23p (+)-schizandrin (1.76),23r (+)-isoschizandrin (1.77),23u and even more oxidized congeners such as ananolignan C (1.78),23y ananolignan B (1.79),23y ananolignan

D (1.80),23y ananolignan F (1.81),23y (+)-interiotherin C (1.82),23j kadsuralignan B

(1.83),23ab tiegusanin D (1.84),23y schizanrin F (1.85),23aa (−)-kadsurarin (1.86),23s

kadsulignan E (1.87),23d (–)-schiarisanrin C (1.88),23k steganone (1.89)23t and (−)- steganacin (1.90),23t have been identified (Figure 1.3). Extracts from DBCOD lignan-rich

plant families such as Kadsura and Schisandra have been used as traditional Chinese

medicines as anti-tussives and as tonics with anti-viral activity.23b Interiotherin A, schisandrin D, kadsuranin, gomisin G tiegusanin D and their derivatives are known to have wide ranging biological activities including inhibition of HIV replication at µg/mL levels.22b,23l,23m,23y Kadsurarin derivatives have pronounced inhibitory activity against human type –B hepatitis.23h Schiarisanrin C (1.88)23k has cytotoxic activity with ED50 values in the sub-µg/mL range against several human cancer cell lines. In addition to insecticidal and antifeedant activities, DBCOD lignans have been reported to inhibit cyclic-AMP phosphodiesterases, enzymes which are integral to the regulation of many cellular processes.23u Ananolignans show significant anti-neurodegenerative properties.23z Biological studies with several of these natural lignans reveal that the

position and substitution of the hydroxyl groups in the cyclooctane ring are important for

enhanced anti-HIV activity.23l More recently DBCOD lignans have been identified as novel inhibitors of multidrug resistance-associated protein 1.23d Synthetic analogs of

16

schisantherins have been shown to be comparable to the clinical sensitizer verapamil.23w

Nitric oxide production inhibitory23x,23ab and antioxidant activity23g have also been

associated with products from Schisandraceae family of plants.

1.2.2 Previous Synthetic Studies of DBCOD Lignans

These impressive biological properties and structural similarities of the various

lignans made them synthetic targets since 1970, and eventually several racemic25 and

enantioselective approaches26 for the syntheses of the simplest members of this family of natural products have been reported. Typical among the syntheses in the racemic series are those of (±)-wuweizisu,25a (±)-schizandrin,25b,25c (±)-deoxyschizandrin,25h,25j (±)- isoschizandrin,25c and (±)-gomisin A,25c (±)steganone,25e (±)-steganacin,25i (±)-

kadsurin,25f and deoxyschizandrin.25h,25j Notable enantiopure syntheses of the natural

products are represented by those of steganone,26a,26c,26i stegane,26b isostegane,26b

picrostegane,26b schizandrin,26d,26e,26g isoschizandrin,26d,26g,26j,26m gomisin A,26e,26g

wuweizisu C,26f,26h,26n gomisin J,26h gomisin N,26h gomisin R26k,26l and interiotherin

A.25k,25l Previous synthetic strategies relied on two major disconnections of dibenzocyclooctadiene skeleton 1.70, which differ in the order of the biaryl coupling

(disconnection A, in structure 1.70, Figure 1.3) and closure of the eight membered ring

(disconnection B, in structure 1.70, Figure 1.3).

Meyers et al used the chiral oxazoline strategy26c,26d,27a to prepare the optically pure biaryl derivatives 1.93 and 1.96 from the oxazoline 1.91 and the aryl bromides 1.92a and

1.92b, respectively (Scheme 1.16). They closed the cyclooctadiene ring either employing

17

26c intramolecular alkylation of the bromide 1.94 to synthesize (-)-steganone or SmI2- mediated reductive cyclization of the bromoaldehyde 1.97 to synthesize the (-)-

schizandrin and (-)- isoschizandrin.26d

O O O Ph O OMe O O O steps MeO Br O O N OMe (1.92a) Ph MeO O MeO Mg N OMe MeO MeO OMe 1.91 1.93

O O O O O O O O O Br steps KOtBu MeO O MeO CO2Me MeO CO2Me CO2Me MeO O CO2Me MeO MeO OMe MeO MeO 1.94 1.95 1.89 (-)-steganone OMe MeO OMe Ph MeO OTBS OMe O MeO OTBS steps MeO Br MeO N OMe (1.92b) Ph MeO O MeO Mg N OMe MeO MeO OMe 1.91 1.96

OMe MeO MeO MeO MeO MeO

Br 1. SmI O MeLi MeO 2 MeO MeO OH MeO 2. PCC MeO MeO

CHO MeO MeO MeO OMe MeO MeO 1.97 1.98 (-)-1.77 (-)-isoschizandrin

Scheme 1.16 Meyers’ Syntheses of Steganone and Isochizandrin Using the Chiral

Oxazoline Strategy 18

Uemura utilized the planar chiral (arene)Cr(CO)3 complex 1.101 in a Suzuki

coupling to construct the axial chirality in the biaryl 1.103.26n The optically pure biaryl

1.103 was subsequently transformed to the known ether 1.104, which had been converted to (-)-steganone by Meyers (Scheme 1.17).

O O Br MeO MeO steps MeO Pd(PPh3)4 O Cr(CO)6 O OH OMe OMe MeO MeO MeO O OMe OMe OMe O (OC) Cr 3 (OC)3Cr 1.99 1.100 1.101 CHO B(OH) (1.102) O O O 2 O O O O O steps steps CHO MeO O MeO MeO CO Me OH 2 CO Me MeO O MeO MeO 2 OMe OMe MeO (OC)3Cr 1.103 1.104 1.89 (-)-steganone

Scheme 1.17 Uemura’s Formal Synthesis of Steganone

In their synthesis of (−)-steganone26i, Molander et al prepared the formyl lactone

1.105 from the Uemura’s intermediate 1.103 (Scheme 1.18). A SmI2-promoted ketyl-

olefin cyclization of 1.105 provided the alcohol 1.106, which was easily converted to (−)-

steganone after a few steps. In order to construct the correct axial configuration as that in

(+)-isoschizandrin, another DBCOD lignan, they synthesized the racemic biaryl 1.109

using a Ullman coupling and employed Bringman’s27c method (kinetic resolution of

1.109 with oxazaborolidine 1.110) to obtain enantiomerically pure biaryl 1.111. A

26j similar SmI2-promoted cyclization of 1.112 provided (+)-isoschizandrin.

19

O O O O O O O OH O O steps steps CHO CHO O SmI 2 MeO O MeO O MeO MeO OH O MeO O MeO O MeO MeO OMe OMe MeO MeO (OC)3Cr (OC)3Cr 1.103 1.105 1.106 1.89 (-)-steganone

OMe OMe MeO MeO OMe Bringman's method MeO Ullman coupling MeO CHO KOH MeO O MeO CHO MeO Ph MeO CHO Cu, DMF H O Ph Br MeO MeO O N OMe OMe B (1.110) 1.107 1.108 1.109

OMe OMe MeO MeO MeO MeO O steps OH SmI MeO MeO MeO 2 O MeO MeO MeO O MeO MeO MeO MeO OMe OMe 1.111 1.112 1.77 (+)-isoschizandrin

Scheme 1.18 Molander’s Synthesis of (−)-Steganone and (+)-Isoschizandrin

Both Meyers and Molander used the absolute configuration of the biaryl axis to

introduce the remaining stereogenic centers on the cyclooctane ring. Alternatively,

following a biomimetic strategy, Koga utilized oxidative phenolic coupling of a chiral

1,4-diarylbutane 1.113 for the synthesis of (+)-steganacin analogues.27d,27e This approach was later utilized by a number of workers including Lipshutz et al to synthesize

schizandrin analogues.27e-h

Coleman et al26k,26l used the intramolecular Ullmann coupling strategy27g,27h to form the carbon-carbon biaryl bond from the 1,4-diarylbutane 1.115 to synthesize the

20 interiotherin A and gomisin O and E. The most recent entry in this area utilizes an asymmetric Ni-catalyzed biaryl coupling to form the Molander intermediates useful in the Sm(II)-mediated DBCOD formation.26m The oxidative phenolic coupling of 1,4- diarylbutanes in general gives low yield and/or diastereoselectivity and is somewhat limiting in terms of manipulations of the intermediates for further functionalization of the

8-membered ring, once the biaryl unit is formed.

O O H O O O O Ac O steps VOF3 O H O MeO MeO O

O MeO MeO O MeO OMe OMe MeO MeO 1.113 (-)-isostegane (+)-steganacin

Scheme 1.19 Koga’s Synthesis of Steganacin Utilizing Oxidative Phenolic Coupling of a

Chiral 1,4-Diarylbutane 1.113

O O oxidative O O cuprate steps coupling OTBS OTBS MeO MeO t Br Br 1. BuLi 2. CuCN O O 3.1,3-dinitrobenzene

BnO O Br O 1.114 1.115 OMe OMe O O O OTBS O OR steps MeO MeO MeO MeO

O O gomisin O R=H O 1.116 O interiotherin A R=Bz

Scheme 1.20 Coleman’s Synthesis of Gomisin O and Interiotherin A 21

1.2.3 Pd-catalyzed Bismetallative Cyclization of 1, 6-Diynes (2, 2’-Dipropargyl

Biphenyls): General Solutions to Access a Broad Range of DBCOD Lignans

A critical examination of the two principal strategies outlined here, viz., construction of the requisite tether with the right configurations of the carbons involved, followed by biaryl formation (path A in Figure 1.4) versus the stereoselective formation of the biaryl unit first, cyclization to form the 8-membered ring, followed by installation of the stereocenters of the aliphatic bridge (path B in Figure 1.4), might lead one to conclude that the former approach has serious limitations because of the number and efficiency of the steps involved in setting up the acyclic unit. In addition, several instances of failure of heavily substituted 1,4-diarylbutanes to undergo the oxidative dimerization have been documented. The predictability of the stereochemical outcome of the biaryl formation is also somewhat tenuous. Only the simplest members of the DBCOD family of compounds have been prepared by this route.

Z Z 8 * C Y * [X-Y] = R3Si-SnR’3 or (R N) B-SnR’ * 7 X 2 2 3 [X-Y]/Pd(0) * Z atrop-selective multicomponent Z cyclization

Z Z

A B FG * * * ring biaryl * * closure formation * * * * * FG

Z Z

Figure 1.4 Approaches to Dibenzocyclooctadiene Lignans

22

Thus we believe that for a general synthesis of highly functionalized DBCODs, including the compounds with full substitution around the cyclooctadiene moiety (e.g., interiotherin C, 1.82), or compounds with further annulations on the cyclooctadiene moiety (e.g., steganacin, 1.90), an approach that involves the initial formation of the biaryl unit, followed by subsequent manipulations is potentially more versatile.

However, current methodologies for the construction of the 8-membered ring are severely limiting. For example, it is not clear how the Meyers intramolecular alkylation approach26c,26d,27a or the highly reducing conditions of the Molander’s approach26i,26j would work for the fully functionalized derivatives such as (–)-kadsurarin or spirocyclic compounds kadsulignan E (1.87) or schiarisanrin C (1.88). In an attempt to find general solutions for the construction of advanced DBCOD derivatives, we sought to develop new methods that would place useful latent functionalities that can be converted into the requisite substituents on the cyclooctadiene ring. We envisioned that the bismetallated cyclization of 1,6-diynes (2, 2’-dipropargyl biphenyls)8,14 in which highly functionalized

1,2-bis-alkylidenes are created may serve this purpose. The functionalized alkylidene moieties on C7 and C8 and the resident helical chirality of the non-planar diene should provide unprecedented opportunities for either installation of new chiral centers at these carbons, and/or, for subsequent oxidative transformations.

1.2.4 Syntheses of Prototypical DBCOD Lignans including Gomisin E and

Interiotherin A via Pd-catalyzed Bismetallative Cyclization of 1, 6-Diynes

23

Exploratory studies on model substrate 1.117 employing silyl-stannylation

cyclization protocol gave only low to moderate yields of the expected product 1.118,

together with significant amount of acyclic adducts 1.119 and 1.120 (Scheme 1.21).13

MeO MeO t BuMe2SiSnPh3 TBS MeO MeO . MeO Pd2(dba)3 CHCl3 MeO SnPh3 (C6F5)P3(cat.) MeO OBn MeO OBn C6H6, r.t. 1.117 1.118 (43%)

MeO MeO TBS

MeO TBS MeO SnPh + + 3 MeO MeO SnPh3 MeO OBn MeO OBn 1.119 (46%) 1.120 (10%)

Scheme 1.21 Silyl-Stannylation Cyclization of the Diyne 1.117

Further screening of other types of [X-Y] reagent revealed that [B-Sn]-reagent 1.37 could effect the cyclization of the diyne 1.117 with high yield as well as excellent region-

and stereoselectivity (atropselectivity), to provide the diazaborolidine 1.56 (Scheme

1.22). Pinacol exchange could in situ convert the moisture-sensitive diazaborolidine 1.56

to air-stable boronate ester 1.21.

With the goal of finding a broadly applicable approach to various DBCOD lignans,

the enantiopure diynes 1.67a and 1.67b which carry the most common aryl substitution

patterns as the cyclization precursors were prepared (Scheme 1.23).13 When diynes 1.67a and 1.67b were subjected to the cyclization reactions, they reacted with the [B-Sn] reagent 1.37 smoothly to form the (Z,Z)-1,2-bisalkylidenes 1.68a and 1.68b, respectively. 24

Further manipulations of these diazaborolidines eventually provided a few prototypical

DBCOD lignans including gomisin E23p and interiotherin A.23m

N MeO B SnMe3 MeO N (1.37) SnMe MeO 3 (S *) MeO (Ra*) a (Sa*) (S*) MeO (S*) MeO B N PdCl (PPh ) (cat.) 2 3 2 N C6D6, r.t MeO OBn MeO OBn a rare example of 1.56 1.117 axial-axial chirality tranfer Pinacol 72% over two steps MeO

SnMe3 MeO (Sa*) (Ra) MeO (S*) B O O MeO OBn 1.121

Scheme 1.22 [B-Sn]-Mediated Regio- and Stereoselective Cyclization of an Axially

Chiral Diyne1.117

O O

MeO O O O N MeO O 1. B SnMe3 OH N SnMe steps MeO MeO (1.37) MeO 3 MeO gomisin E MeO MeO PdCl (PPh ) (cat.) B N 2 3 2 O or C6D6, r.t N R1O OBn R1O OBn O R O OR2 2 MeO 1.67a R ~R =CH 1.68a R ~R =CH 1 2 2 1 2 2 MeO 1.68b R1=R2=CH3 1.68b R1=R2=CH3 O OBz O interiotherin A

Scheme 1.23 The General Approach to DBCOD Lignans Utilizing [B-Sn]-Mediated

Cyclization of 1, 6-Diynes

25

1.3 The Overall Goals of this Research

The primary goal of this research is to explore a general synthesis of highly functionalized DBCODs, including the compounds with full substitution around the cyclooctadiene moiety based on a Pd-catalyzed bismetallic cyclization of 2,2’-

dipropargyl biphenyls. No such DBCODs [e.g., ananolignan B (1.79), interiotherin C

(1.82), and kadsuralignan B (1.83)] have been synthesized before. Stereoselective

synthesis of viable propargylic substrates for this key cyclization will form a major part

of this effort. We will also attempt to use the primary product of the multi-component

cyclization for the synthesis of more oxidized DBCOD derivatives such as steganone.

26

CHAPTER 2

SYNTHESIS AND CYCLIZATION OF 2,2’-DIPROPARGYL BIPHENYLS

Portions of this chapter have been previously published in the following publication:

Gong, W.; Singidi, R. R.; Gallucci, J. C.; RajanBabu, T. V. “On the stereochemistry of acetylide additions to highly functionalized biphenylcarbaldehydes and multi-component cyclization of 1,n-diynes. Syntheses of dibenzocyclooctadiene lignans”, Chem. Sci. 2012,

3, 1221-1230.

2.1 A General Synthetic Strategy Towards Dibenzocyclootadiene Lignans

We envisioned that the key eight-membered-ring systems (2.1 and 2.2) of these dibenzocyclooctadiene (DBCOD) lignans could be assembled via [B-Sn] reagent mediated cyclization reactions of 2,2’-dipropargyl biphenyls (2.3 and 2.4), which in turn, may be derived from acetylide additions to corresponding biphenyl aldehydes (2.5 and

2.6). In the course of this study we found that the viability of the crucial cyclization reactions relies on the chirality of propargylic centers in the substrates. We also discovered that most acetylide additions leading to the forging of these chiral centers are highly stereoselective. The biphenyl aldehydes could originate from related biphenyl oxazolines (2.7 and 2.8), in which the axial chirality could be introduced by Meyers nucleophilic aromatic substitution strategy.28,29 27

O O O O O O OR O OR

MeO MeO MeO O OH MeO MeO

O MeO MeO MeO R' OR' MeO MeO MeO Ananolignan B R=Ac Ananolignan C R=Ac R'= α-OH Kadsuralignan B R=R'=Ac Steganone Ananolignan D R=Ac R'= β-OH Tiegusanin D R=R'=Bz Ananolignan F R=Ac R'= β-OAc Schizanrin F R=Ac R'=Bz Interiotherin C R=Ac R'= β-OAng

O O

O OPG N O OPG1 N B B * N * N MeO MeO SnMe3 * SnMe3 MeO MeO OPG2 2.1 2.2 MeO MeO [B-Sn] reagent mediated cyclization O O O O OPG OPG1 * * OPG2 MeO MeO *

MeO MeO OMe OMe 2.3 2.4 Acetylide addition O O O O

OPG CHO MeO 3 MeO MeO CHO TMS MeO MeO OMe OMe 2.5 2.6

O O O O O OTBS O Biphenyl MeO O MeO O coupling MeO N N MeO MeO OMe OMe 2.7 2.8

Figure 2.1 General Strategy toward the Syntheses of DBCOD Lignans 28

2.2 Synthesis of 2,2’-Dipropargyl Biphenyls

2.2.1 Synthesis of Enantiomerically Pure Biaryl Oxazolines

Aiming to prepare multi-gram quantities of the bromide 2.14, which is a coupling partner for Meyers nucleophilic aromatic substitution, two synthetic routes were explored. The first one involves only five steps (Scheme 2.1).30 Commercially available methyl 3,4,5-trihydroxyl benzoate (2.9) was chosen as the starting material.

Methylenedioxy protection of the triol turned out to be the most problematic step among

this short synthesis. First, the reaction is conducted in DMF, a high boiling solvent, and the concentration of the substrate (0.1 M) is low due to the poor solubility of the triol in

DMF, which means an experiment using 20 g triol (about 200 mmol) needs 2 L of DMF and thus the workup process would be quite troublesome. Second, under the reaction

condition (1 eq. K2CO3 and 1.5 eq. CH2I2, or 5 eq. KF and 1.5 eq. CH2I2 at 40 ºC for 18

hours) only about 60% conversion was achieved and extending reaction time was not

effective. Column purification of the desired product (2.10) on large scale was also

plagued by the poor solubility of the product in the eluent system (ethyl acetate/ hexanes

= 1:3) and the existence of another by-product with a similar polarity. Bromination of the

phenol with one equivalent of DBDMH (1,3-dibromo-5,5-dimethylhydantoin) gave a

mixture of monobromide 2.11 (major) and dibromide (minor). Recrystallization of the crude products from ethyl acetate and hexanes cleanly afforded the desired monobromide

2.11 with 75% yield. The remaining three steps leading to the TBS ether 2.14 went

smoothly without complication. Methylation of the phenol 2.11 was effected with MeI

29

and K2CO3 in acetone. Subsequent reduction of the resulting ester 2.12 with DIBAL-H in

CH2Cl2 at –78 ºC to furnish the primary alcohol 2.13, which was then protected as TBS

ether 2.14 using TBSCl and imidazole in DMF. It should be noted that the overall yield of this sequence is 97% and only a final column was used for separation of the TBS ether, while only simple workup of the first and second steps were required, and the crude product of each step was used directly for the following reaction.

O OH O K CO ,CH I , DMF, O HO 2 3 2 2 O MeI, K CO 40 0C, 18h DBDMH 2 3 (75%) (40%) HO CO2Me HO CO2Me HO CO Me 2 Br 2.9 2.10 2.11

O O O O O O DIBAL-H TBSCl, imidazole OH (97% from 2.11) OTBS MeO CO2Me MeO MeO Br Br Br 2.12 2.13 2.14

Scheme 2.1 A Five-step Synthesis of the Aryl Bromide 2.14

Due to the difficulties encountered in the above synthetic route, especially the practical synthesis of the phenol 2.10, another reaction sequence (Scheme 2.2) was

explored.31 The synthesis commenced with the same starting material, methyl 3,4,5-

trihydroxyl benzoate (2.9), and dioxydiphenylmethyl group was chosen as the protecting

32 group of the vicinal diol. In the presence of Ph2CCl2 and K2CO3, the triol was converted to a phenol 2.15 in 62% yield on a 30 g scale. Bromination of the phenol involving bromine (1 eq.) and t-BuNH2 (2 eq.) at low temperature was adopted, which furnished a

30

clean reaction with 88% monobromide 2.16 and 12% starting material (based on crude 1H

NMR). Methylation of the crude monobromide with MeI and K2CO3 afforded

bromoester 2.17 in 85% yield over two steps. A two-step sequence involved removal of

the diphenylmethyl protection group in 2.17 with Amberlyst 15, followed by the 1,3-

dioxolane formation using CH2Br2 and KF to provide the ester 2.12. DIBAL-H reduction and silyl ether formation protocols converted 2.12 to TBS ether 2.14 in 98% yield.

Ph Ph OH Ph O Ph O HO O O Ph2CCl2, K2CO3, Br2, t-BuNH2 MeI, K2CO3 (62%) (85% for 2 steps) HO CO2Me HO CO2Me HO CO2Me Br 2.9 2.15 2.16

Ph Ph O O O 1. Amberlyst 15, O O 1. DIBAL-H O 2. CH Br , KF, 2 2 2. TBSCl, (75%) OTBS MeO CO2Me MeO CO2Me imidazole, MeO Br Br (98%) Br 2.17 2.12 2.14

Scheme 2.2 A Seven-step Synthesis of the Phenyl Bromide 2.14

2.2.2 Magnesium-mediated Biaryl Coupling Reactions between Tetramethoxy

Oxazoline 2.18 and Aryl Bromides

The magnesium-mediated biaryl coupling reaction between the known tetramethoxy oxazoline 2.1827a and the aryl bromide 2.1926c proceeded in high yield (85% based on oxazoline 2.18), albeit with poor diastereoselectivity (2.20a: 2.20b = 1 : 1.1). The assignment of absolute configurations of the diastereomers was deduced from the X-ray crystal structures of alcohols 2.23a and 2.23b derived from 2.20a and 2.20b (see Scheme 31

2.4). Although the diastereoselecivity of this coupling reaction was rather unsatisfactory,

we decided to carry both diastereomers to the following transformations. The magnesium-mediated biaryl coupling between tetramethoxy-oxazoline (2.18) and aryl bromide (2.14) proceeded in high yield (82% based on the oxazoline) and high diastereoselectivity (d.r. = 94:6) to give 2.21 (Scheme 2.3). The assignment of absolute configurations of the diastereomers was deduced from the X-ray crystal structure of alcohol 2.27a derived from the TBS ether 2.21 (see Scheme 2.6 and Figure 2.4).

O O O O OMe O O Mg, BrCH CH Br, O O MeO O 2 2 O N THF, 80 0C, 18h O + O + MeO O MeO MeO O (85%) N N Br O 2.20a:2.20b=1:1.1 OMe MeO MeO OMe OMe 2.18 2.19 2.20a 2.20b O O OMe O O Mg, BrCH CH Br, OTBS MeO O 2 2 MeO N THF, 80 0C, 18h MeO O + OTBS MeO MeO (82%) d.r. 15:1 N OMe Br MeO OMe 2.21 2.18 2.14

Scheme 2.3. Synthesis of Enantiopure Biaryl Oxazolines

2.2.3 Synthesis of Biphenyl Aldehydes and Subsequent Acetylide Addition Reactions

2.2.3.1 Hydrolysis of Acetals 2.20a and 2.20b and Subsequent Acetylide Additions to

Biphenyl Aldehydes

After optimization of the hydrolysis condition for acetals 2.20a and 2.20b, we found that the hydrolysis of 2.20a proceeded to full conversion in one hour and subsequent 32 acetylide addition to the crude biphenyl aldehyde gave a single propargylic alcohol 2.23a in 83% yield. To our surprise, when the diastereomeric acetal 2.20b was subjected to this hydrolysis-addition sequence under identical condition, we obtained two diastereomeric alcohols 2.23a and 2.23b. The structures and stereochemistry of both alcohols were established by X-ray crystallographic analysis. See Section 3.2.2 of Chapter 3 for details of the optimization of hydrolysis condition and subsequent acetylide addition reactions.

O O O O O O OH THF/CH2Cl2 (1:1), O HCl (3M), -10 0C,1h, O 0 LiC CTMS (S) then workup at 0 C (Ra) 6 2 CHO (Ra) O O (Ra) O TMS MeO MeO 2' 0 MeO 100% conversion 6' THF,-78 C N N 83% N MeO (S) MeO over two steps MeO (S) OMe OMe OMe 2.20a 2.22a 2.23a

O O O O O O THF/CH2Cl2 (1:1), O 0 HCl (3M), -10 C,1h, (S ) 0 a O then workup at 0 C 6 2 CHO (Ra) 6 2 CHO (Sa) O MeO MeO O O 70% conversion 2' 6' MeO 2' 6' N N N MeO (S) MeO MeO OMe OMe OMe 2.20b 2.22b 2.22a

LiC CTMS 51% over two steps LiC CTMS THF,-78 0C variable ratios of 2.23b to 2.23a THF,-78 0C

O O O OH O OH

(R) (S) (Sa) O TMS (Ra) O TMS MeO + MeO N N MeO (S) MeO (S) OMe OMe 2.23b 2.23a

Scheme 2.4 Hydrolysis of Acetals 2.20a and 2.20b and Subsequent Acetylide Additions

to Biphenyl Aldehydes 2.22a and 2.22b 33

2.23a 2.23b

Figure 2.2 The ORTEP Drawings of the Alcohols 2.23a and 2.23b

2.2.3.2 Diastereoselective Acetylide Addition to Biphenyl Aldehyde 2.24

Starting with a mixture of biphenyl oxazolines 2.20a and 2.20b, we obtained a

racemic biphenyl aldehyde 2.24 after a few steps (details are described in Section 3.3.2

and 3.3.3 of Chapter 3). At this stage, an acetylide addition was necessary to install the

propargylic portion in the upper phenyl ring. When 2.24 was treated with lithium

trimethylsilylacetylide, the alcohol 2.25 formed (d.r. = 20:1) as the major product and its

structure was established by the X-ray crystallographic analysis of a crystal grown with

the vapor diffusion method.

O O O O O O OH (S*) O LiC CTMS (3 eq.), THF, O steps 7' CHO -78 0C, 30 min (R *) O a TMS MeO MeO (80%) MeO N TMS d.r. 20:1 TMS MeO MeO MeO OMe OMe OMe 2.20a & 2.20b 2.24 2.25 (racemates)

Scheme 2.5 The Diastereoselective Acetylide Addition to the Biphenyl Aldehyde 2.24 34

Figure 2.3 The ORTEP Drawings of the Alcohol 2.25

2.2.3.3 Synthesis of Biphenyl Aldehyde 2.26 and the Following Acetylide Addition

The structure of the aldehyde substrate 2.26 is very similar to that of 2.22a (Scheme

2.4), and the only difference is that the substituent of the C6 position of the top aryl ring is a hydrogen instead of a methoxy group here). Lithium trimethylsilylacetylide addition to the aldehyde 2.22a (Scheme 2.4) gave exclusively one diastereomer (2.23a) in high yield.

With the expectation that a highly diastereoselective addition could be achieved in the

present case, the reaction sequence leading to the aldehyde substrate (2.26) was probed.

A two-step sequence involving desilylation of 2.21 followed by oxidation of the resulting

alcohol with pyridium chlorochromate (PCC) afforded the aldehyde 2.26 in 85% yield

(Scheme 2.6).

With the aldehyde in hand, we immediately tested the trimethylsilylacetylide addition

reaction. To our surprise, the reaction could only reach about 83% conversion with a

good diastereoselectivity [major (2.27a): minor (2.27b) = 5:1] (Scheme 2.6). We

suspected that the chelation between the metal (lithium cation) and the electron-rich

heteroatoms (oxygen and nitrogen) in these substituents may contribute to the observed

35 result. Thus TMEDA, a well-known solvating reagent for lithium cation, was examined as an additive and the result was encouraging: not only the reaction proceeded to about

98% conversion, but also with a slightly better diastereoselectivity (major : minor =

6.6:1.0). We were able to get crystals suitable for X-ray structure determination by recrystallizing the major product from ethyl acetate and hexane. The chirality of the newly generated stereogenic center matches that of the alcohol 2.23a (Figure 2.2).

O O O O 1) TBAF, THF, r.t., 2h OTBS 2) PCC, p-TsOH, Celite, LiC CTMS (3 eq.), TMEDA, MeO 6 2 CH2Cl2, r..t.,18h MeO CHO THF, -78 0C, 30 min O MeO 2' 6' MeO O (85%) d.r. 6.8:1 N N MeO MeO OMe OMe 2.21 2.26

O O O OH O OH (R) (S) MeO MeO TMS TMS MeO O + MeO O N N MeO MeO OMe OMe 2.27a (75%) 2.27b (11%)

Scheme 2.6 Synthesis of Biphenyl Aldehyde 2.26 and the Following Acetylide Addition

Figure 2.4 The ORTEP Drawings of the Alcohol 2.27a 36

2.2.3.4 Synthesis of Biphenyl Aldehyde 2.28 and the Subsequent Acetylide Addition

Through sequential treatment with MeOTf, L-selectride and aqueous silica gel,

reductive cleavage of the oxazoline ring in 2.21 provided the benzaldehyde 2.28 with

90% overall yield, which was subjected to the acetylide addition to give a mixture of two

propargylic alcohols (2.29a : 2.29b = 15 : 1). The configuration of the newly generated

chiral center in the major product 2.29a was established after it was transformed

eventually to the corresponding cyclized product 2.47c (Scheme 2.19 and Figure 2.8).

O O O O

OTBS OTBS MeO 1. MeOTf MeO O MeO 2. L-selectride; MeO CHO then SiO N 2 MeO (90%) MeO OMe OMe 2.21 2.28

O O O O (3 eq.), THF, LiC CTMS OTBS OTBS -78 0C, 30 min MeO MeO TMS + TMS MeO MeO 7 7 (S) (R) MeO OH MeO OH OMe OMe 2.29a (90%) 2.29b (6%)

Scheme 2.7 Synthesis of Biphenyl Aldehyde 2.28 and the Subsequent Acetylide Addition

2.2.4 Synthesis of Diynes with C7-OBn Protection Group

Treatment of 2.29a with excess NaH and BnBr in DME, for protection of the free hydroxyl group as a benzyl ether followed by the removal of the TMS group were achieved in 90% yield (Scheme 2.8). Now with the propargylic motif in the lower aryl

37

ring installed, we turned our attention to the elaboration of the substituent of the 2’

position in the upper aryl ring. The TBS group was smoothly removed with TBAF in

THF, affording the primary alcohol, 2.30, which was subsequently oxidized to the

aldehyde (2.31) with PCC in 90% yield.

O O O O O O 1. NaH, BnBr OTBS 2. TBAF OH MeO MeO PCC MeO CHO TMS (90%) MeO (90%) MeO 7 MeO

MeO OH MeO OBn MeO OBn OMe OMe OMe 2.29a 2.30 2.31

Scheme 2.8. Synthesis of the Biaryl Aldehyde 2.31 from the Propargyl Alcohol 2.29a

Next the aldehyde (2.31) was subjected to acetylide addition, which would install a

new stereogenic center in the upper aryl ring. However, this time a disappointing

diastereoselectivity [1.5:1.0, in favor of the (S, S) isomer 2.32a] was obtained when

alkynyl magnesium bromide was used in THF (Table 4.1, entry 1). Switching to the

lithium trimethylsilylacetylide (0.5 M THF solution) slightly improved the selectivity to

2:1 (90% overall isolated yield after desilylation with K2CO3 in MeOH). Literature precedents38 on nucleophilic carbonyl addition reactions show that incorporation of

additives and/or solvent exchange may have significant influence on stereoselectivity.

Thus we first tried to replace THF with diethyl ether as the solvent, while still using 0.5

M THF solution of lithium trimethylsilylacetylide. This produced a mixture of two

diastereomers (3:1 in favor of 2.32a). However, with TMEDA as the additive a lower

diastereoselectivity (2.7:1) was observed. Switching to 0.5 M ether solution of lithium 38 trimethylsilylacetylide gave the best selectivity (3.5:1, 73% isolated yield of 2.32a after desilylation). Switching the solvent to completely nonpolar hexane was also attempted, but the result was not satisfactory due to the poor solubility of substrate in the solvent system and a few unidentified byproducts further eroded the yield.

O O O O O O

7' 7' MeO CHO conditions MeO MeO (S) + (R) MeO OH MeO OH MeO 7 (S) 7 (S) 7 (S) MeO OBn MeO OBn MeO OBn OMe OMe OMe

2.31 2.32a 2.32b

Entry Reaction condition Resulta,b

1 TMSC CMgBr, THF, 0 0C, 30 min 90% (1.5 : 1)

2 LiC CTMS (3 eq.), THF, -78 0C, 30 min; 90% (2 : 1)

then K2CO3, MeOH, r.t., 12 h 3 LiC CTMS (THF solution, 3 eq.), ether, 91% (3 : 1)

0 -78 C, 30 min; then K2CO3, MeOH, r.t., 12 h

4 LiC CTMS (THF solution,3 eq.), TMEDA, ether, 90% (2.7 : 1)

0 –78 C, 30 min; then K2CO3, MeOH, r.t., 12 h

5 LiC CTMS (ether solution, 3 eq.), ether, 94% (3.5 : 1)

0 -78 C, 30 min; then K2CO3, MeOH, r.t., 12 h aYield; bRatio of 2.32a to 2.32b

Table 2.1 Acetylide Addition to 2.31. Effect of Reagents and Reaction Conditions on

Diastereoselectivity

39

2.2.5 Synthesis of Diynes with C7-OTIPS Protection Group

In order to prepare substrates with different oxygenated substituents at the propargylic center in the lower phenyl ring, we protected the free hydroxyl group in the alcohol 2.29a with TIPS group (Scheme 2.9). After removal of the TBS group in 2.33 and oxidization of the corresponding alcohol, the biphenyl aldehyde 2.34 was obtained, which was subjected to the acetylide addition reaction to install the propargyl substituent in the upper phenyl ring. This time the acetylide addition gave a mixture of two diastereomeric alcohols (2.35a and 2.35b, 75% and 11% isolated yield, respectively) with a better diastereoselectivity (6.8:1.0, Scheme 2.9), and the stereochemistry in the major product (2.35a) was confirmed as C7’ (R) by X-ray crystallographic analysis.

O O O O 1. K2CO3 2. TIPSOTf, 1. PPTS (1 eq.) OTBS OTBS 2. PCC, NaOAc MeO 2,6-lutidine MeO TMS MeO MeO 7 (90%) 7 (88%) (S) (S) MeO OH MeO OTIPS OMe OMe 2.29a 2.33

O O O O O O TMS TMS LiCCTMS, THF, 7' -78 0C, 30 min 7' MeO CHO MeO MeO (R) + (S) MeO 7 d.r. 6.8:1.0 MeO OH MeO OH (S) 7 (S) 7 (S) MeO OTIPS MeO OTIPS MeO OTIPS OMe OMe OMe 2.34 2.35a (75%) 2.35b (11%)

Scheme 2.9 Synthesis of Biphenyl Aldehyde 2.34 and Subsequent Acetylide addition

40

Figure 2.5 The ORTEP Drawing of the Alcohol 2.35a

2.2.6 Proposed Chelation Models for Acetylide Additions to Biphenyl Aldehydes33

As many of the acetylide addition reactions to the biphenyl aldehydes proceed with good to excellent diastereoselectivity, we attempted to rationalize these results. First we noticed the common structural features of these biphenyl aldehydes: they all possess a formyl group as the C2-substituent and a methoxy group as the C2’-substituent. The C6

and C6’ substituents (R1 and R2, respectively) may be different: R1 could be a hydrogen

atom or a methoxy group, while R2 could be a propargylic substituent, or an oxazoline, or a silyloxylmethyl group. It is well known that an important factor that affects stereoselectivity of carbonyl addition reactions is chelation.34 We envisioned that

appropriate chelation models may serve to explain the high stereoselectivity observed in

these acetylide addition reactions, and the difference in the chelating ability of these

ortho-substituents could lead to different products that correspond to different model

transition states. 41

R1 R2 O O H H2C TMS or or O R1 6 2 CHO MeO 2' 6' R 2 OMe N or MeO t OMe CH2OSi BuMe2

Figure 2.6 Common Structural Features of the Biphenyl Aldehydes

We employed Dreiding stereomodels to construct the chelation transition states with the hope that some generalizations would emerge from the examination of such a diverse group of compounds. Dreiding models, made of slim stainless steel tubes and rods, allow the rapid assembly of closely related structures with high geometric precision. Due to their precision in representing the molecular geometry, Dreiding stereomodels could even be used to determine inter-atomic distances and angles by rulers and protractors. In the event, the models constructed for analysis of the DBCOD conformations coincided with solid-state structures obtained by X-ray crystallography in almost all case where they were compared, thereby validating some of the underlying assumptions involved.

2.2.6.1 Chelation Model for Acetylide Addition to the Biphenyl Aldehyde 2.24 with a

6’-Propargyl Substituent

The first example involves the acetylide addition to the biphenyl aldehyde 2.24

(Scheme 2.10). As the 6’-propargyl substituent is weakly or non-coordinating to the metal cation, only ‘O’ of the 2’-methoxy group could form a strong chelate with the carbonyl ‘O’ and lithium cation. This eight-membered transition state (conformation A) consists of two C-C bonds from the aryl rings, one C=O bond from the carbonyl group, 42

therefore it could be very rigid. The Re and Si faces of the carbonyl are clearly different

according to the model: the Si face (bottom face) is blocked either by the lower aryl ring

or its C6’-substituent while the Re face (top face) is more exposed. Therefore the nucleophile would preferably approach the carbonyl group from its Re face via a Burgi-

Dunitz trajectory.

O O O O O Nu 8-membered O OH cyclic TS CHO LiC CTMS Li Re face addition 6 2 TMS 6' H MeO 2' O O MeO Me TMS TMS X TMS MeO MeO MeO OMe OMe OMe 2.24 2.25 (80%) conformation A d.r. 20:1

Scheme 2.10 Proposed Chelation Model for Acetylide Addition to the Biphenyl

Aldehyde 2.24

2.2.6.2 Chelation Model for Acetylide Addition to the Biphenyl Aldehyde 2.22a with

a 6’-Oxazoline Ring

The second substrate 2.22a contains a 6’-oxazoline ring (Scheme 2.11). Two

competing chelates (conformation B and C) would result in the formation of 2.23a and 7- epi-2.23a, respectively. ‘N’ of the 6’-oxazoline is known to be a better electron donor than ‘O’ of the 2’-methoxy group. Thus we considered conformation B should be favored, which now is a rigid nine-membered ring system with two C-C bonds from the phenyl rings, one C=O bond and another C=N bond from the oxazoline ring. The

43

nucleophile chooses to approach the more exposed Re face (top face) to give the alcohol

2.23a as the exclusive product.

O Nu O O 9-membered O OH cyclic TS Re face addition 7 O H O TMS N OMe MeO O Li X N O MeO O OMe OMe OMe conformation B 2.23a 6 2 CHO LiC CTMS favored single diastereomer O MeO 2' 6' N O + MeO O O O OH OMe Nu 8-membered cyclic TS 2.22a Si face addition 7 Li MeO N O TMS H MeO

O O Me O X N MeO OMe OMe OMe conformation C 7-epi-2.23a disfavored not observed

Scheme 2.11. Proposed Chelation Model for Acetylide Addition to the Biphenyl

Aldehyde 2.22a

2.2.6.3 Chelation Models for Acetylide Addition to the Biphenyl Aldehyde 2.26 with

a 6’-Oxazoline Ring and a 6-Methoxy Group

The third biphenyl aldehyde 2.26 is very similar to 2.22a, except that it contains a

6-methoxy group (Scheme 2.12). The mode of addition here is different from the

acetylide addition to 2.22a, which gives the alcohol 2.23a exclusively; the addition to

2.26 gave 2.27a (75%) and its C7-epimer 2.27b (12%). The major product 2.27a could

derive from the chelate D, which resembles the conformation B in Scheme 2.11. We did obtain 2.27b as the minor product, which may originate from the less favored 44

conformation E. The coordination between excess lithium cation, ‘N’ of the 6’-oxazoline

and ‘O’ of the 2-methoxy group might help to stabilize this conformation via double-

chelation.

‡ O O Nu O 9-membered O OH cyclic TS 7 Re face addition MeO O H OMe O TMS N OMe MeO

O Li O X O N OMe MeO LiC CTMS OMe OMe MeO 6 2 CHO TMEDA conformation D O 2.27a (75%) MeO 2' 6' favored major diastereomer N MeO + O ‡ OMe O O 2.26 O OH Nu 8-membered cyclic TS Me Li 7 Li Si face addition MeO N O TMS H MeO O

O O Me O X N MeO OMe OMe OMe conformation E 2.27b (12%) disfavored minor diastereomer

Scheme 2.12 Proposed Chelation Models for Acetylide Addition to the Biphenyl

Aldehyde 2.26

2.2.6.4 Intramolecular Hydrogen Bonding as Supporting Evidence for the Models

Careful examination of the solid-state structures of 2.23a, 2.23b (Figure 2.2) and

2.27a (Figure 2.4) reveal a strong H-bonding between the O–H group and the nitrogen of the oxazoline, indicating the close proximity of the oxygen to this nitrogen in a favorable conformation of the biaryl backbone (Scheme 2.13). Replacement of the H with a Li would correspond to the primary product (2.36) of organometallic addition to the

45

aldehyde from which these species arise. While it is generally accepted that a ground-

state structure need not resemble a possible transition state, such a structure can lend

some support to its overall conformational features. To that extent these structures

support the models we have proposed for the acetylide addition.

O O O O Nu O O

LiC CTMS 6 2 CHO O Nu O O H MeO 2' 6' N OMe N OMe Li O Li O H N X MeO OMe OMe OMe OMe OMe 2.22a conformation B 2.36

O O OH

TMS MeO O N MeO OMe 2.23a X-ray structure of 2.23a

Scheme 2.13 Supporting Evidence for the Models Based on X-ray Structures of

Proparylic Alcohols

2.2.6.5 Chelation Models for the Acetylide addition to the Biphenyl Aldehyde 2.28 with a 6’-Silyloxymethyl Group and a 6-Methoxy Group

In the fourth acetylide addition reaction, the substrate 2.28 possesses a 6’- silyloxymethyl group and a 2’-methoxy group (Scheme 2.14). It is known that ‘O’ of the

TBSO- group forms a much weaker bond to Li compared to ‘O’ in a methoxy group,

46

probably due to both steric (the bulkiness of the silyl group) and electronic (the lone pair

electron partially delocalizes into the empty 3d orbital of the silicon atom) reasons, as

proposed initially by Keck35 and recently supported by computational studies.36

Therefore the favored conformation F involves the coordination between lithium cation,

‘O’ of the 2’-methoxy group and ‘O’ of the 2-formyl group, which leads to the major product 2.29a via a Si face nucleophilic addition.

O ‡ O O

O Me X OTBS 8-membered O H cyclic TS OTBS O MeO Li OMe Si face addition TMS MeO

O OMe Nu MeO OH O OMe OMe OTBS conformation F 2.29a (90%) MeO 2' 6' LiC CTMS favored major diastereomer MeO 6 2 CHO + O ‡ MeO O 9-membered O OMe X TBS O cyclic TS O Li 2.28 MeO Re face addition H O OTBS MeO MeO TMS MeO

MeO Nu MeO OH OMe OMe conformation G 2.29b (6%) disfavored minor diastereomer

Scheme 2.14. Proposed Chelation Models for Acetylide Addition to the Biphenyl

Aldehyde 2.28

2.3 Preparation of the Substrates for [B-Sn] Reagent-Mediated Cyclizations

With propargylic alcohols 2.25, 2.32a, 2.32b and 2.35a in hand, we were at a stage to convert them to the substrates suitable for the crucial [B-Sn] reagent mediated cyclization. First, the dipropargyl biphenyl 2.37 was prepared from the propargylic 47

alcohol 2.25 by protection of the C7’-hydroxyl group as a benzyl ether and subsequent desilylation (Scheme 2.15) (see section 3.3.5 of chapter 3 for details).

O O O O OH O OBn O OBn (S*) (S*)

7' 0 7' (Ra*) 1) NaH, BnBr, DME, 0 C (R *) TMS a H + H MeO MeO MeO • 2) K2CO3, MeOH,r.t. TMS H H MeO MeO MeO H OMe OMe OMe 2.25 2.37 (72%) 2.38 (8%)

Scheme 2.15. Synthesis of the Dipropargyl Biphenyl 2.37 from the Alcohol 2.25

With both the C7’ (S) alcohol 2.32a and C7’ (R) alcohol 2.32b in hand, we synthesized

methyl ethers (2.39a and 7’-epi-2.39a), MOM ethers (2.39b and 7’-epi-2.39b), TBS

ether (2.39c) and TIPS ether (2.39d) as substrates for the key [B-Sn] reagent mediated

cyclizations following general protocols (Schemes 2.16).

O O O O NaH, MeI (90%) 7' or 7' MeO NaH, MOMCl (90%) MeO MeO OH MeO OR or 7 TBSCl, Imidazole (95%) 7 OBn or OBn MeO TIPSOTf, 2,6-lutidine (90%) MeO OMe OMe 2.32a 2.39a R= Me 2.39b R=MOM 2.39c R=TBS 2.39d R=TIPS O O O O NaH, MeI (90%) 7' or 7' MeO NaH, MOMCl (90%) MeO MeO OH MeO OR 7 7 MeO OBn MeO OBn OMe OMe 2.32b 7'-epi-2.39a R= Me 7'-epi-2.39b R=MOM

Scheme 2.16 Preparation of Precursor Diynes for Cyclization 48

Another set of substrates for cyclization containing the TIPS protection group is

shown in Scheme 2.17. Removal of the trimethylsilyl group from 2.35a with K2CO3 in

MeOH smoothly provided the alcohol 2.40, which was acetylated with Ac2O to give acetate 2.41. When 2.35a was treated with BnBr and NaH in DME, to our surprise, we obtained a mixture of benzyl ether 2.42 (20%) and allene 2.43 (60%). Treatment of the alcohol 2.40 with NaH and BnBr in DMF for 10 min afforded a mixture of two similar products (4:1 ratio), major one being the benzyl ether 2.42 (72%).

O O O O O O TMS 7' K2CO3, MeOH MeO MeO Ac2O, Et3N MeO MeO OH (95%) MeO OH (80%) MeO OAc 7 MeO OTIPS MeO OTIPS MeO OTIPS OMe OMe OMe 2.35a 2.40 2.41

O O O O O O H TMS BnBr, NaH, DME, H 7' r.t., 18h • MeO MeO A:B=1:3 MeO MeO OH MeO OBn + MeO OBn 7 MeO OTIPS MeO OTIPS MeO OTIPS OMe OMe OMe 2.35a 2.42 (20%) 2.43 (60%) O O O O O O H BnBr, NaH, DMF, H 7' r.t., 10 min • MeO A:B=4:1 MeO MeO MeO OH MeO OBn + MeO OBn 7 MeO OTIPS MeO OTIPS MeO OTIPS OMe OMe OMe 2.40 2.42 (72%) 2.43 (18%)

Scheme 2.17 Preparation of Cyclization Precursor Diynes (2.41 and 2.42) and Allene

(2.43)

2.4 Results of [B-Sn] Reagent Mediated Cyclization Reactions and Proposed Models 49

2.4.1 Results of [B-Sn] Reagent Mediated Cyclization of 2.2’-Dipropargyl Biphenyls

When the diyne 2.37 was subjected to the [B-Sn] reagent (1.37) mediated cyclization

reaction condition,14 we observed two major products 2.44a and 2.44b after 18 h by

1HNMR spectroscopy in a ratio of 2.5:1.0 (2.44a: 2.44b). Compounds 2.44a and 2.44b are moisture-sensitive and could not be isolated by column. It is known from other research done in our group that similar cyclized products could be converted in situ to corresponding vinyl boronates by treatment with pinacol, and the boronates are air-stable and could be isolated and stored for months. Thus 2.44a and 2.44b were converted to

2.45a and 2.45b in situ smoothly, which could be easily separated by column. The ratio of 2.45a to 2.45b remained the same as that of 2.44a to 2.44b (2.5:1.0).

OMe MeO MeO MeO SnMe MeO 3 H MeO B N SnMe3 MeO MeO (S*) N MeO (R *) a (Ra*) (S*) O 7' (Ra*) 6 OBn B (S*) N O O OBn O OBn B SnMe3 O 2.44a N O O (1.37) Pinacol O 2.45a (55%) MeO + 2.44a:2.44b = + PdCl2(PPh3)2(cat.) Me Sn MeO 3 2.5:1.0 O C6D6, r.t. MeO H O MeO OBn (2.44a:2.44b = 2.5:1.0) H (S*) OBn SnMe3 MeO H MeO 7' (S*) (Ra*) (S*) O (Ra*) (Ra*) B MeO B O N O O OBn O N MeO O 2.45b (23%) OMe 2.44b MeO 2.37 MeO MeO p-TsOH 2.45a + 2.45b B O (81%) O O OBn O 2.46

Scheme 2.18 [B-Sn]-Mediated Cyclization of the Diyne 2.37 with a C7’-OBn Substituent 50

The structure of the major atropisomer 2.45a was deduced from its 1H NMR and 2D

NOESY spectra, and eventually confirmed by X-ray crystallography (Figure 2.7).

Although the structure of 2.45b has not been established conclusively, from NMR studies it appears to be the atropisomer of 2.45a. The results of the following protodestannylation of vinyl stanne 2.45a and 2.45b, both of which gave the same product, confirmed the structure of 2.45a. Thus when 2.45a and 2.45b were treated with

p-TsOH in CH2Cl2 separately, the same boronate ester 2.46 was obtained, whose structure was established by X-ray crystallographic analysis (Figure 2.7).

2.45a 2.46

Figure 2.7 ORTEP Representations of 2.45a and 2.46

Cyclization of biphenyl-2,2’-dipropargyl ethers (Scheme 2.19 and 2.21, 2.39a-2.39d) would provide the fastest entry into fully substituted DBCODs. When the diyne 2.39a with (Sa, S, S) configuration (entry 1 in Table 4.2) was subjected to the [B-Sn] reagent

(1.37) mediated cyclization protocol, very small amount (<10%) of the cyclized product

2.47a was formed together with the compound 2.48a derived from simple addition of the 51

[B-Sn] reagent to both triple bonds in 2.39a. When MOM ether 2.39b was tested for the

cyclization reaction (entry 2), a 1:1 mixture of cyclized product 2.47b and di-addition

product 2.48b was isolated (70% yield in total). Switching to the TBS ether further increased the yield of the cyclized product 2.47c to 60%, together with 25% di-addition product 2.48c (entry 3). The cyclization reaction of another silyl ether 2.39d (entry 4)

with a bulkier TIPS group could not reach 50% conversion even after treatment with 4

eq. [B-Sn] reagent 1.37 for a prolonged period (48 h). However, under the standard cyclization condition, the diynes 7’-epi-2.39a with (Sa, R, S) configuration (entry 5) only gave trace amount of the cyclized product 7’-epi-2.47a, together with 70% di-addition product 7’-epi-2.48a. At the same time, MOM ether 7’-epi-2.39b completely failed to give any cyclized product and only di-addition product 7’-epi-2.48b was isolated (85%).

O O O O O N O B O OR O O 1. B SnMe3 7' N B O MeO (1.37) MeO SnMe (S ) (S) MeO 3 a + SnMe MeO OR MeO SnMe MeO OR 3 PdCl2(PPh3)2(cat.) 3 O 7 C6D6, r.t. B (S) MeO OBn OBn MeO OBn 2. Pinacol MeO O OMe MeO OMe

2.39a R= Me 2.39b R=MOM 2.47a R= Me 2.47b R=MOM 2.48a R= Me 2.48b R=MOM 2.39c R=TBS 2.39d R=TIPS 2.47c R=TBS 2.48c R=TBS

O O O O O B O N O O OR O 1. B SnMe3 7' N (1.37) B O MeO (R) MeO MeO SnMe3 (Sa) + MeO SnMe3 MeO OR MeO SnMe OR PdCl2(PPh3)2(cat.) 3 O 7 C6D6, r.t. B (S) MeO OBn OBn MeO OBn 2. Pinacol MeO O OMe MeO OMe 7'-epi-2.39a R= Me 7'-epi-2.47a R= Me 7'-epi-2.48a R= Me 7'-epi-2.39b R=MOM 7'-epi-2.47b R=MOM 7'-epi-2.48b R=MOM

Scheme 2.19 Cyclization of 2,2’-Dipropargyl Biphenyls

52

No Substrate Result of the cyclization reaction 1 2.39a <10% 2.47a (2.47a : 2.48a =1 : 9) 2 2.39b 35% 2.47b (2.47b : 2.48b =1 : 1) 3 2.39c 60% 2.47c (2.47c : 2.48c =2.4 : 1) 4 2.39d About 50% conversion of 2.39a with 4eq. of the [B-Sn] reagent 5 C7’-epi- 70% 7’-epi-2.48a and trace amount of 7’-epi-2.47a 2.39a 6 C7’-epi- 85% 7’-epi-2.48b 2.39b

Table 2.2 Cyclization of 2,2’-Dipropargyl Biphenyls with 2.5 eq. of [B-Sn] 1.37

Figure 2.8 The ORTEP Drawing of the Cyclized Product 2.47c

We were able to isolate small amount of mono-addition product (10%) from the dipropargyl biphenyl 2.49 in one experiment when 2.39c was treated with 1.5 equivalent

of [B-Sn] reagent 1.37, together with 70% cyclized product 2.47c and 10% di-addition

product 2.48c (Scheme 2.20). These boronate esters should derive from corresponding

diazaborolidines 2.51, 2.50 and 2.52, respectively.

53

O O O OTBS N O OTBS O B N B O MeO MeO

MeO SnMe3 MeO SnMe3 MeO OBn MeO OBn

MeO 2.50 MeO 2.47c (70%)

+ + N O B SnMe3 O O O N O O (1.37, 1.5 eq) MeO MeO PdCl2(PPh3)2 Pinacol MeO OTBS MeO C6D6, r.t. SnMe MeO OTBS 3 SnMe3 MeO OTBS O N MeO OBn B B MeO OBn O MeO OBn OMe N OMe OMe 2.51 2.49 (10%) 2.39c

+ +

O O O O SnMe SnMe 3 N 3 O B B MeO N MeO O MeO OTBS MeO OTBS SnMe3 SnMe3 N O MeO OBn B MeO OBn B OMe N OMe O 2.52 2.48c (10%)

Scheme 2.20 Cyclization of 2,2’-Dipropargyl Biphenyl 2.39c

Another series of dipropargyl biphenyls with the C7-OTIPS substituent, including

alcohol 2.40, acetate 2.41 and benzyl ether 2.42, were also tested under the standard

cyclization condition. However, these reactions provided complex mixtures and no

cyclized products were isolated in all cases. To our surprise, a cyclized product 2.53 was isolated from the cyclization reaction of the allenyne 2.43, although its structure has not yet been rigorously established.

54

O N O O 1. B SnMe3 O OR O N 7' (1.37) B O MeO (R) MeO (Sa) X MeO OR MeO SnMe3 PdCl2(PPh3)2(cat.) C D , r.t. 7 6 6 MeO OTIPS MeO (S) OTIPS OMe 2. Pinacol MeO 2.40 R= H 2.41 R=Ac O O 2.42 R=Bn O O B HH

SnMe3 MeO RO MeO OTIPS

MeO (not formed) OMe O O O N 1. B SnMe3 O OBn SnMe3 • N (1.37) MeO MeO (Sa) O MeO OBn MeO B PdCl (PPh ) (cat.) O 7 2 3 2 C6D6, r.t. MeO MeO (S) OTIPS OTIPS OMe 2. Pinacol MeO 2.43 2.53

Scheme 2.21 [B-Sn]-Mediated Cyclization Reactions of Substrates with a C7-OTIPS

Substituent

2.4.2 Different Results of Cyclization of Diyne 2.54 with (Sa, S) Configuration and

Diyne 2.55 with (Sa, R) Configuration

Previous study13,14 from our group showed that under standard cyclization conditions, the diyne 2.54 underwent a clean reaction to give the cyclized product 2.55.

After pinacol exchange, 2.55 was converted to the boronate ester 2.56, and the structure

of 2.56 was confirmed by X-ray crystallography of destannylated derivative 2.57

(Scheme 2.22).

55

SnMe3 MeO H MeO B N SnMe3 MeO N MeO 6 MeO 6 B O MeO OBn O twist-boat-chair MeO OBn MeO favored N MeO 2.55 2.56 (72%) B SnMe3 N MeO Pinacol (Sa*) MeO 7 (S*) PdCl2(PPh3)2(cat.) C6H6, r.t. MeO OBn Me3Sn MeO MeO H SnMe 2.54 3 H MeO OBn [note the differering carbon MeO H MeO 6 B O numbering in the DBCOD MeO twist-boat O OBn compared to the precursor] B disfavored MeO MeO N N 2.55-conf C not formed

MeO O p-TsOH MeO B 2.56 MeO O (86%) 6 MeO OBn

2.57 X-ray structure of 2.57

Scheme 2.22 [B-Sn]-Mediated Cyclization of 2,2'-Dipropargyl Biphenyl 2.54

The regio- and stereochemical outcomes of the cyclization can be understood if one were to assume that the addition of the [B-Sn]-reagent is initiated at the less substituted, electron-rich alkyne (Figure 2.9) with initial formation of the [C–B] bond (see structure A in Figure 2.9). The σ-Pd(Sn)-intermediate A formed after the initial addition undergoes cyclization via carbametallation followed by reductive elimination with the formation of the C–Sn bond in the final product and regeneration of the Pd(0)-species. It is during the formation of the 7,8-bisalkylidenecyclooctadiene moiety via the carbametallation process the configuration of the newly created axial chirality is set. Apparently, the (Sa, Ra)

56

configuration of the product, and by extension the TS leading to this product, have

relatively strain-free twist-boat-chair conformation (B, Figure 2.9), as compared to the

corresponding twist-boat conformation (C) for the atropisomeric (Sa, Sa)-1,3-diene,

resulting in the exclusive formation of the former (see the box for the assignment of

stereochemical designations of the helically chiral 1,2-bis-alkylidenes). Such a conformation for the initially formed [B-Sn] adduct is also consistent with the solid-state structure of the destannylated derivative 2.57 (Scheme 2.22) derived from 2.55 and related cyclic adducts 2.45a and 2.46 derived from 2.37 (Figure 2.7).

4 H 3 (B) Me SnMe3 [Ln]Pd(B)(Sn) O N Pd(Sn) B N 1 B N 2 Me N H OBn [BSn] O Pd Me [Sn] B

Pd(Sn) O 6 3 [Ln]Pd(0) (Ra) OBn (B) O 2 1 (Sn) Me (Ra OR Sa) A B 4 (B)

twist-boat-chair twist-boat conformation Me conformation Me Me Me Sn O 3 O N O Me3Sn H B X 8 N X N Me B Me N Me O Y O OBn Me O Me Pd [Sn] 7 (S ) Me H (S ) 6 (Ra) a O a O Y (Sa) O 6 B H O N N O O B C Me Me Me 2.55-conf B X = H; Y = OBn 2.55-conf C X = H; Y = OBn 6-epi-A 6-epi-2.55-conf B X = OBn; Y = H 6-epi-2.55-conf C X = OBn; Y = H

Figure 2.9 Mechanism and Possible Origin of Stereoselectivity in the Cyclization of

Diyne 2.54. Interactions of the Axial-X (= OBn) Group Prevents the Cyclization of 2.58

to Form 6-epi-2.55

57

Support for such a model comes from the reluctance of the diyne 2.58, which is

epimeric at C6, to undergo cyclization (Scheme 2.23). Borostannylative cyclization of the diyne 2.58 only produced a mixture of adducts that included the mono- and di-

addition products (2.59 and 2.60, respectively) with no trace of the expected cyclic product (6-epi-2.55) or any of its isomers. This can be understood based on the proposed model, since in the resulting cyclic product (6-epi-2.55, formed via intermediate 6-epi-A, see Figure 2.9), the C6-OBn substituent would have to be axial even in the most favorable conformation (B), and this group encounters serious 1,3-diaxial interactions with either one of the aromatic rings or the diazaborolidene ring. Significant quantities of the

product in which the oxygen-bearing alkyne remains unreacted (2.59) also supports the

previous contention that the cyclization of 2.54 is initiated at the less substituted (more

electron-rich) alkyne.

N O 1. B SnMe3 O N MeO B MeO MeO B O O PdCl2(PPh3)2, C6H6 MeO Me Sn SnMe3 MeO MeO SnMe3 3 (S *) + O a 2. pinacol, H+ MeO MeO 6 MeO 7 6 B O (R*) OBn MeO MeO OBn MeO OBn 2.58 2.59 (30%) 2.60 (10%)

Me3Sn [note the differering carbon MeO H numbering in the DBCOD SnMe BnO compared to the precursor] MeO OBn 3 H MeO H B N MeO MeO N B MeO 6 H MeO N N MeO 6-epi-2.55 (not formed) 6-epi-2.55-conf C (not formed)

Scheme 2.23 Effect of C6-configuration on Borostannylation/cyclization 58

2.4.3 Formation of Two Atropisomeric Cyclization Product from the Diyne 2.37

The structure of the major product 2.44a from the substrate 2.37 can also be rationalized using similar models (Figure 2.9) as shown in Scheme 2.24.. The twist-boat- chair conformation seen in the product (Scheme 2.24) is reminiscent of 2.57 derived from

2.54 (Scheme 2.22). While the regioselectivity in the addition of the [B-Sn] reagent is the same for substrates 2.54 and 2.37, there is erosion in the atropselectivity in the

formation of the axially chiral diene, resulting the formation of up to 29% of an isomer,

2.44b. It is conceivable that a more flexible biphenyl backbone, due to the absence of a

2’-OMe substituent, might reduce the internal strain of the twist-boat transition state and

permit higher proportion of conformations similar to 2.55-conf-C (Fig 2.9) leading to

2.44b. Thus the high selectivity in the axial-to-axial chirality transfer appears to be facilitated by the biphenyl system with a higher barrier for helical isomerization.

MeO MeO SnMe3 MeO MeO H SnMe3 B N MeO MeO N 6 B O 6 OBn O O OBn OMe twist-boat-chair MeO O conformation O 2.45a (55%) O [B-Sn] 2.44a Pinacol X-ray structure of 2.45a MeO + (Ra*) 7' MeO MeO (S*) Me3Sn OBn O MeO H MeO O H 2.37 OBn SnMe3 MeO H MeO 6 B O B O twist-boat N O OBn conformation O O N O 2.45b (23%) 2.44b

Scheme 2.24 [B-Sn]-Mediated Cyclization of 2, 2'-Dipropargyl Biphenyls

59

When the diyne 2.37 was subjected to the [B-Sn] reagent mediated cyclization

reaction condition, the progress was monitored by 1H NMR. As shown in Table 4.3, it

took 2 h for full conversion of the diyne 2.37. After 15 min, we observed the formation

of two new species 2.44a (23%) and 2.44b (3%), indicating a ratio of about 7:1. After 1

hour, the ratio of 2.44a (64%) to 2.44b (15%) became about 4:1. Eventually the ratio became about 2.5:1 which did not change for the following 18 h before the addition of pinacol.

MeO MeO OMe Me3Sn MeO N SnMe3 MeO H MeO H B SnMe3 H N OBn B N + MeO MeO MeO N H (Ra*) 6 OBn 7' PdCl2(PPh3)2(cat.) B (S*) C6D6, r.t. N O O OBn O O N O O 2.37 2.44a 2.44b

Entry Reaction time Ratio of 2.37 to 2.44a to 2.44b

1 15 min 74:23:3

2 1 h 21:64:15

3 1.5 h 4:72:24

4 2 h 0:71:29

1 Table 4.3 Reaction Progress by H NMR in C6D6

The above result may illustrate a possible mechanistic scenario in this Pd-catalyzed

reaction: the atropisomer 2.44a derived from a stable transition state (I) adopting a twist-

boat-chair conformation, forms first after reductive elimination (RE) step. As the RE

60

step is reversible, 2.44a could undergo oxidative insertion to form TS I, which isomerizes to another TS II adopting a twist-boat conformation with comparable stability.

Reductive elimination of TS II gave 2.44b.

MeO SnMe3 MeO Pd SnMe MeO 3 MeO H H B N B N (S*) MeO (S*) N MeO N (R *) 6 (Ra*) 6 OBn a OBn

O O O O TS I 2.44a

Me Sn MeO 3 MeO Pd Me3Sn MeO H MeO H H H OBn OBn MeO H MeO H

B B N N O O O N O N TS II 2.44b

Figure 2.10 Atropisomerization between 2.44a and 2.44b

2.4.4 Formation of Fully Substituted DBCODs from Diynes 2.39b and 2.39c

The successful cyclizations of the diynes with (Sa, S, S) configuration including

2.39b and 2.39c, again, suggest the relatively stable transition states leading to the

cyclized products adopt twist-boat-chair conformations where both C6-O and C9-O substituents occupy the pseudo-equatorial positions (Scheme 2.25). The various ratios of the cyclized products to the corresponding 1, 2-addition products could be attributed to different steric and/or electronic effects of the C7’-oxgenated substituents (for example, t-

61

butyldimethylsilyl group in 2.39c versus methoxymethyl group in 2.39b). The

diastereomer 7’-epi-2.39b with C7-(S), C7’-(R) configuration failed to cyclize and gave

exclusively a di-addition product 7’-epi-2.48b in excellent yield (85%). The reluctance

of a propargyl ether with a (Sa, S)-configuration to cyclize is consistent with results obtained in simpler systems (for example, see diyne 2.58 in Scheme 2.23). In the

expected cyclization product from 7’-epi-2.39b, one of the benzylic alkoxy group must

occupy a sterically encumbered axial position, which results in a truncated reaction

leading to simple 1, 2-addition of the [B-Sn] reagent.

[note the differering carbon numbering in the DBCOD compared to the precursor]

O N O O O 1. B SnMe O 3 O B N ROH 7' MeO 9 SnMe3 (S ) (S) MeO H MeO a OR PdCl2(PPh3)2(cat.) MeO 6 C D , r.t. OBn 7 6 6 MeO OBn (S) 2. Pinacol MeO OMe OMe

2.39b R=MOM 2.47b R=MOM 35% X-ray structure of 2.47c 2.39c R=TBS 2.47c R=TBS 60%

N O O O O B N O N O O B HH 1. B SnMe3 O 7' N 9 SnMe MeO (R) SnMe 3 (S ) MeO 3 MeO RO MeO a OMOM SnMe3 O 6 MeO OR MeO OBn PdCl2(PPh3)2(cat.) B 7 (S) O MeO OBn C6D6, r.t. MeO OBn MeO OMe OMe 2. Pinacol OMe 7'-epi-2.39b 7'-epi-2.48b R=MOM 85% Not formed (R=MOM)

Scheme 2.25 [B-Sn] Mediated Cyclization of Dipropargyl Biphenyls with both C7- and

C7’-oxygenated Substituents

62

2.4.5 Proposed Mechanism for the Cyclization of the Diyne 2.39c

We proposed a possible mechanistic pathway for the cyclization of diyne 2.39c with both C7- and C7’-oxygenated substituents (Scheme 2.26). Oxidative addition of Pd(0)

into the [B-Sn] reagent 1.37 gave B-Pd(II)-Sn 2.61, which adds regioselectively to the

C8-C9 triple bond to form σ-Pd(Sn)-intermediate 2.62. The explanation for the selective addition of 2.61 to the C8-C9 triple bond adjacent to the OBn group, instead of the C8’-C9’

triple bond adjacent to the OTBS group remains unclear, however, it is likely that the C8-

C9 triple bond could be more sterically accessible and more electron-rich than the C8’-C9’

triple bond, due to the steric and electronic differences of Bn and TBS groups. The

following carbametallation step is crucial as it leads to the formation of

dibenzocyclooctadiene ring. Compared with similar diynes without C7’-oxygenated substituents (2.54 in Scheme 2.22 and 2. 37 in Scheme 2.24), 2.39c bears a C7-OTBS group which causes the carbametallation step more difficult. Fortunately, we eventually were able to isolate up to 70% boronate ester 2.47c (Scheme 2.20 and 2.25), and this indicates the carbametallation followed by reductive elimination of the σ -Pd(Sn)- intermediate 2.64 to give the final product 2.47c is indeed the major reaction pathway.

On the other hand, direct reductive elimination of intermediate 2.62 provides the mono- addition product 2.51 (10% yield, deduced from the amount of corresponding boronate ester 2.49 in Scheme 2.20). In the presence of extra [B-Sn] reagent 1.37, the di-addition product 2.52 also forms after the reductive elimination step from 2.63.

63

MeO RO MeO H 9' 8' MeO 7' 8 9 7 N N OBn B SnMe B PdII SnMe 3 3 (2.39c) N N O O (2.61) (1.37) oxidative addition

MeO

MeO MeO RO 9' RO SnMe3 8' MeO SnMe3 H MeO PdII Pd0 B N MeO N OBn B N OBn N O (2.62) (2.50) O O twist-boat-chair O carbametallation conformation reductive elimination N MeO N B N RO MeO H N reductive MeO B PdII elimination MeO MeO RO SnMe3 OBn SnMe3 MeO SnMe3 (2.64) O Pd0 O MeO OBn B N O N MeO RO O (2.52) N 9' 8' N reductive MeO B MeO SnMe3 elimination MeO RO OBn B N PdII N Pd0 SnMe3 O MeO SnMe3 O (2.51) OBn B N N N II O B Pd SnMe3 O N (2.63) (2.61)

Scheme 2.26 Proposed Catalytic Cycle of the [B-Sn] Mediated Cyclization of

Dipropargyl Biphenyl 2.39c (R=TBS)

2.5 Conclusions

Dipropargyl-2,2’-biphenyls are suitable precursors for the synthesis of highly functionalized dibenzocyclooctadienes. The acetylene moieties can be installed by 64 addition of lithium acetylides to 2’-substituted biphenyl aldehydes. We observed high stereoselectivity of these acetylide additions and proposed chelating models to rationalize their stereochemical results. We also discovered that the exceptionally high stereoselectivity in the formation of the axially chiral diene (axial-to-axial chirality transfer) via the [B-Sn] reagent mediated cyclization depends on the chirality of the biphenyl scaffolding and the configuration of the propargylic center. Based on the solid- state structures of several isolated intermediates, a twist-boat-chair conformation for the

7,8-bis-alkylidenedibenzocycloocta diene can be predicted. Simple models based on steric arguments can be used to rationalize the stereochemical outcomes in successful cyclizations, and, the reluctance in others to undergo the cyclization. The diynes that fail to cyclize yield simple, 1,2-addtions of the [B-Sn] reagent.

2.6 Experimental Section

2.6.1 General Methods

Unless otherwise mentioned, all chemicals were purchased from commercial sources and were used as received. Reactions requiring air–sensitive manipulations were conducted under an inert atmosphere of nitrogen using Schlenk techniques or in a glovebox. Dichloromethane was distilled from calcium hydride under a dry atmosphere and stored over molecular sieves. Tetrahydrofuran (THF) was distilled under nitrogen from sodium/benzophenone ketyl. Solvents were degassed by sonication under vacuum for 10 minutes. Analytical thin layer chromatography (TLC) was performed using Merck

60 F254 precoated silica gel plate (0.2 mm thickness). Column chromatography was

65

performed using Merck silica gel 60-120 using analytical grade solvents. Flash columns

were typically packed as slurry and equilibrated with the appropriate solvent system prior

to use. Optical rotations were recorded at the sodium D line in solvents indicated using

filtered (45 µ nylon filter). 1H NMR and 13C NMR spectra were recorded on Bruker

AMX 500 spectrometer operating at 500 MHz for 1H and 125 MHz for 13C at 298 K, or

Bruker AMX 400 spectrometer operating at 400 MHz for 1H and 100 MHz for 13C at 298

K. Proton chemical shifts were internally referenced to the residual solvent proton

resonance (CDCl3, δ 7.26 or C6D6, δ 7.16).

2.6.2 Synthetic Procedures and Spectral Data

O O

HO CO2Me

Phenol 2.10: 30 Diiodomethane (7.5 mL, 0.09 mol) was added dropwise to a solution of

methyl gallate 2.9 (17.2 g, 0.09 mol) and potassium carbonate (12.9 g, 0.09 mol) in dry

DMF (200 mL) at 40 oC. The resulting mixture was stirred for 20 h at 40 oC before being

poured into water (600 mL), and extracted with ethyl acetate. The combined organic

extracts were washed with brine (100 mL), then dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography (EtOAc :

hexanes = 1: 2) to give the phenol 2.10 (7.06 g, 49%) as a white solid.

O O

HO CO2Me Br

66

30 Bromophenol 2.11: A solution of DBDMH (1.79 g, 6.24 mmol) in CH2Cl2 (80 mL)

was added in a few portions to a solution of the phenol 2.10 (2.4 g, 12.24 mol) in CH2Cl2

(40 mL) at room temperature. The resulting mixture was stirred for 1 h, then evaporated

under reduced pressure. The residue was directly purified by flash chromatography

(EtOAc : hexanes = 1: 5) to give the bromide 2.11 (2.52 g, 75%) as a white solid. 1H

+ NMR (acetone-d6) δ 6.90 (1H, s), 6.11 (2H, s), 3.84 (3H, s). HRMS (ESI) [M+Na] calcd for C9H7BrO5Na 296.9375, found 296.9380.

O O

OTBS MeO Br

TBS ether 2.14: To a mixture of the phenol 2.11 (500 mg, 1.82 mmol), potassium carbonate (500 mg, 3.64 mmol) and acetone (15 mL), was added MeI (775 mg, 0.34 mmol). The resulting mixture was heated to reflux for 4 h. The solid was filtered off. The filtrate was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 and

to the resulting solution at –78 °C was added DIBAL-H (1.5 M in toluene, 3 mL, 4.5

mmol) dropwise. After stirring at the same temperature for 30 min, the reaction was

quenched by the addition of methanol (0.05 mL) followed by 1 N HCl solution (0.5 mL).

The aqueous layer was extracted with Et2O and the organic layer washed with water, brine and dried over Na2SO4. The solvent was evaporated under reduced pressure to

afford the crude alcohol, which was dissolved in DMF (5 mL) at 0 oC was added imidazole (186 mg, 2.73 mmol) followed by TBSCl (412 mg, 2.73 mmol) and the reaction mixture was gradually brought to room temperature over 2 h. To this solution

67

was added saturated aq. NaHCO3 solution. Extraction with CH2Cl2, washing with brine,

drying over anhydrous Na2SO4 and removal of the solvent under reduced pressure

afforded the crude product, which was purified by silica gel column chromatography

(EtOAc : hexanes = 1: 30) provided the TBS ether 2.14 (664 mg, 97% yield from phenol

1 2.11) as a light yellow viscous oil. H NMR (400 MHz, CDCl3): δ 6.84 (s, 1H), 5.96 (s,

13 2H), 4.64 (s, 2H), 4.02 (s, 3H), 0.96 (s, 9H), 0.13 (s, 6H). C NMR (100 MHz, CDCl3) δ

148.71, 140.02, 135.99, 134.98, 105.05, 102.19, 101.45, 64.74, 60.09, 25.95, 18.39, -

5.34. IR (neat, cm–1): 2953, 2884, 2856, 1603, 1480, 1412, 1258, 1128, 838, 766, 750.

+ HRMS (ESI) [M+Na] calcd for C15H23BrO4SiNa 399.0422, found 399.0424.

Ph Ph O O

HO CO2Me

32 Phenol 2.15: To a solution of the triol 2.9 (30 g, 0.163 mol) and K2CO3 (67.5 g, 0.489 mol) in acetonitrile (300 mL) was added Ph2CCl2 (50 g, 0.212 mol) and the mixture was

stirred for 18 h. The reaction was quenched with saturated aq. NH4Cl solution. After

extraction with ethyl acetate (3 X 200 mL), drying with anhydrous MgSO4, filtration and

removal of the solvent under vacuum, the crude product was obtained as a yellow oil.

Column chromatography (EtOAc : hexanes = 1: 4) afforded the phenol 2.15 as a white

1 solid (35.16 g, 62% yield). H NMR (400 MHz, CDCl3) δ 7.57-7.54 (m, 4 H), 7.52-7.48

(m, 1 H), 7.39-7.35 (m, 5 H), 7.31-7.22 (m, 2 H), 5.44 (br, 1 H), 3.86 (s, 3 H). 13C NMR

(100 MHz, CDCl3) δ 166.64, 148.32, 142.42, 139.41, 138.86, 129.44, 128.35, 127.98,

68

127.43, 126.90, 126.32, 124.36, 118.82, 114.01, 103.41, 52.23, 49.31. HRMS (ESI)

+ [M+Na] calcd for C21H16O5Na 371.0896, found 371.0891.

Ph Ph O O

MeO CO2Me Br

Bromide 2.17: 32 To a solution of t-butylamine (12.6 g, 173 mmol) in anhydrous toluene

(250 mL) was added bromine (13.8 g, 86.2 mmol) in 10 min at -78 oC under an argon

atmosphere. After the mixture was stirred for 1h, a solution of the phenol 2.15 (30 g, 86.2

o mmol) in CHCl3 (400 mL) was added at -78 C in 1h. The reaction mixture was stirred at room temperature for 4 h and then concentrated under vacuum. The residue was purified by chromatography on silica gel (CHCl3:EtOAc = 9:1) to give 2.17 (547.7 mg, 80%) as a

1 colorless plate crystal. H NMR (400 MHz, CDCl3) δ 7.55-7.53 (m, 4 H), 7.41-7.37 (m,

6 H), 7.09 (s, 1 H), 4.10 (s, 3 H), 3.88 (s, 3 H). HRMS (ESI) [M+Na]+ calcd for

C22H17BrO5Na 463.2488, found 463.2480.

O O

OTBS MeO MeO O N MeO OMe

Biphenyl oxazoline 2.21: To a solution of the phenyl bromide 2.14 (5.75 g, 15.33 mmol)

in THF (40 mL) was added Mg turnings (736 mg, 30.66 mmol), and then the reaction

was bought to reflux under N2. A solution of 1,2-dibromoethane (2.88 g, 15.33 mmol) in

69

THF (10 mL) was added in portions over 1 h and refluxing was maintained for another 3

hours. To this refluxing solution, a solution of the oxazoline 2.18 (3.16 g, 10.22 mmol)

in THF (10 mL) was added, and the mixture was stirred for 18 h. The reaction mixture

was cooled to room temperature and quenched by the addition of a saturated aqueous

NH4Cl solution. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the organic layer washed with water, brine and dried over Na2SO4. The solvent was

evaporated under reduced pressure to afford the crude product which was purified by

silica gel chromatography (EtOAc : hexanes = 1: 10) to yield the major compound 2.21

1 (Sa, S) (4.58 g, 82 % yield) as a yellow viscous oil. [α]D -48.5 (c 0.935, CHCl3). H

NMR (400 MHz, CDCl3) δ 7.18 (s, 1 H), 6.81 (s, 1 H), 5.93-5.92 (m, 2 H), 4.28 (d, J =

13.6 Hz, 1 H), 4.21 (d, J = 13.6 Hz, 1 H), 4.11-4.07 (m, 1 H), 3.93 (s, 3 H), 3.91 (s, 3 H),

3.78 (s, 3 H), 3.69 (t, J = 7.6 Hz, 1 H), 3.62 (s, 3 H), 1.62-1.55 (m, 1 H), 0.85 (s, 9 H),

0.83 (d, J = 6.8 Hz, 1 H), 0.77(d, J = 6.8 Hz, 1 H), -0.05 (s, 3 H), -0.06 (s, 3 H). 13C

NMR (100 MHz, CDCl3) δ 163.59, 152.47, 151.63, 148.52, 144.21, 140.86, 134.92,

134.72, 124.46, 123.36, 119.68,108.72, 100.66, 100.60, 72.52, 70.23, 62.63, 60.85, 60.68,

59.45, 56.01, 32.74, 25.94, 18.74, 18.31, 18.21, -5.42, -5.45. IR (neat, cm–1): 2952, 2856,

1651, 1622, 1454, 1368, 1278, 1079, 980, 775, 749. HRMS (ESI) [M+H]+ calcd for

C30H44NO8Si 574.2831, found 574.2830.

O O O O O O O O O MeO O MeO N N MeO MeO OMe OMe 2.20a 2.20b 70

Biphenyl oxazolines 2.20a and 2.20b. To a solution of the phenyl bromide 2.19 (4.4 g,

15.3 mmol) in anhydrous THF (40 mL) was added Mg turnings (0.76 g, 31.6 mmol), and

then the reaction was brought to reflux under N2. A solution of 1, 2-dibromoethane (3.04

g, 16.2 mmol) in THF (5 mL) was added in portions over 1 h. Refluxing was continued

until there was complete disappearance of bromide as monitored by TLC (ca. 2 h). To

this refluxing solution, a solution of the oxazoline 2.18 (2.50 g, 8.1 mmol) in THF (20

mL) was added, and after refluxing for 18 h the oxazoline was completely consumed.

The reaction was cooled to room temperature, quenched with 30 mL of sat. NH4Cl. After

separation, the organic portion was washed with brine (2 X 30 mL), dried over MgSO4,

and concentrated to obtain a crude brown oil. The crude oil was purified by flash

chromatography (EtOAc: hexanes = 1:10 to 2:1) to afford 2.20a as a yellow oil (1.57 g,

40%) and 2.20b as a yellow oil (1.77 g, 45%). Compound 2.20a: [α]D -33.6 (c 0.5,

1 CHCl3). H NMR (400 MHz, CDCl3) δ 7.18 (s, 1 H), 7.17 (s, 1 H), 6.62 (s, 1 H), 5.98 (d,

J = 1.2 Hz, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 5.05 (s, 1 H), 4.11-4.05 (m, 1 H), 3.99-3.96

(m, 1 H), 3.95 (s, 3 H), 3.78-3.64 (m, 3 H), 3.60 (s, 3 H), 3.56-3.50 (m, 1 H), 2.11-2.04

(m, 1 H), 1.66-1.63 (m, 1 H), 1.27-1.22 (m, 1 H), 0.94 (d, 6.4 Hz, 3 H), 0.79 (d, 6.4 Hz, 3

13 H). C NMR (100 MHz, CDCl3) δ 164.14, 152.55, 146.98, 146.94, 144.20, 131.19,

129.02, 127.06, 124, 24, 110.15, 108.32, 106.01, 101.02, 99.87, 72.63, 70.89, 67.21,

67.15, 60.89, 60.79, 60.38, 56.12, 32.78, 25.63, 21.03, 19.32, 18.40. IR (neat, cm–1):

2960, 1649, 1484, 1415, 1369, 1274, 1259, 1108, 750. HRMS (ESI) [M+H]+ m/z calcd

for C26H32NO8 486.2122, found 486.2110. Compound 2.20b: [α]D –6.5 (c 0.675, CHCl3).

1 H NMR (400 MHz, CDCl3) δ 7.16 (s, 1 H), 7.15 (s, 1 H), 6.66 (s, 1 H), 5.96 (d, J = 2

71

Hz, 2 H), 5.02 (s, 1 H), 4.081-4.00 (m, 4 H), 3.95 (s, 3 H), 3.93 (s, 3 H), 3.85-3.72 (m, 3

H), 3.71-3.65 (dt, J = 12 Hz, 2.4 Hz, 1 H), 3.59-3.52 (m, 1 H), 3.56 (s, 3 H), 2.12-2.04

(m, 1 H), 1.65-1.62 (m, 1 H), 1.26-1.23 (m, 1 H), 0.83 (d, 6.8 Hz, 3 H), 0.81 (d, 6.8 Hz, 3

13 H). C NMR (100 MHz, CDCl3) δ 164.07, 152.53, 151.96, 147.05, 144.28, 131.02,

128.82, 126.93, 124.52, 110.32, 108.14, 106.07, 101.03, 99.91, 72.27, 70.59, 67.25,

67.10, 60.95, 60.77, 56.04, 32.66, 25.59, 18.69, 18.25. IR (neat, cm–1): 2959, 1484, 1467,

1415, 1369, 1274, 1259, 1108, 1038, 764, 750. HRMS (ESI) [M+H]+ calcd for

C26H32NO8 486.2122, found 486.2113.

O O OH

(S) (Ra) TMS MeO O N MeO (S) OMe

Biphenyl alcohol 2.23a: To a solution of the biaryl oxazoline 2.20a (1.33 g, 2.74 mmol)

in THF/CH2Cl2 (v : v = 1 : 1, 30 mL) at -10 ºC was added 3M HCl solution (9.1 mL, 27.4 mmol) dropwise. After stirring at this temperature for 1 h, TLC showed full conversion of the oxazoline 2.20a. The temperature was allowed to warm to 0 ºC and solid K2CO3

(3.79 g, 27.4 mmol) was added by portion to quench the reaction. Cold ether (0 ºC) was

used for extraction and the combined organic phase was dried over anhydrous MgSO4 at

0 ºC. After filtration and removal of the solvent under vacuum at 0 ºC, the crude

aldehyde 2.22a as a yellow oil was used directly for the next step without further

purification. The crude aldehyde was redissolved in THF (50 mL) at -78 ºC. To this

solution was added a solution of LiC≡CTMS in THF (0.5 M solution, 27.4 mL, 13.7 72

mmol) dropwise at -78 ºC. After stirring for 30 min at this temperature, the solution was

allowed to warm to room temperature before it was quenched with saturated aq. NH4Cl

solution. After ether extraction, drying with anhydrous MgSO4, filtration and removal of the solvent under vacuum, the crude product was obtained as a yellow oil. Flash column

(CH2Cl2) gave 2.23a as a light yellow foam (1.20 g, 83% yield). [α]D 80 (c 0.25, CHCl3).

1 H NMR (400 MHz, CDCl3) δ 7.41 (s, 1 H), 6.98 (s, 1 H), 6.41 (s, 1 H), 5.98 (d, J = 1.2

Hz, 1 H), 5.93 (d, J = 1.2 Hz, 1 H), 5.22 (s, 1 H), 4.27 (dd, J = 8.4 Hz, 10Hz, 1 H), 3.97

(m, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H), 3.67 (3 H), 1.37-1.34 (m, 1 H), 0.62 (d, J = 6.8 Hz,

13 3 H), 0.51 (d, J = 6.8 Hz, 3 H), 0.17 (s, 9 H). C NMR (100 MHz, CDCl3) δ 163.37,

152.98, 151.97, 147,57,147.06, 144.58, 134.90, 128.79, 127.83, 123.21, 108.82, 108.23,

107.96, 105.67, 101.12, 89.62, 72.14, 70.31, 62.89, 61.01, 60.95, 56.18, 32.63, 18.31,

17.41, -0.07. IR (neat, cm–1): 3193, 2959, 2176, 1650, 1590, 1501, 1481, 1366, 1250,

+ 1233, 1131, 1104, 1053, 1038, 844. HRMS (ESI) [M+H] calcd for C28H36NO7Si

526.2256, found 526.2257.

O O O OH O OH

TMS TMS MeO O MeO O N N MeO MeO OMe OMe 2.23b 2.23a

Biphenyl alcohols 2.23b and 2.23a: To a solution of the biphenyl oxazoline 2.20b (200 mg, 0.41 mmol) in THF/CH2Cl2 (v : v = 1 : 1, 10 mL) at -10 ºC was added 3M HCl

solution (1.4 mL, 4.1 mmol) dropwise. After stirring at this temperature for 1 h, TLC

showed about 70% conversion of the oxazoline. The temperature was allowed to warm 73

to 0 ºC and solid K2CO3 (560 mg, 4.1 mmol) was added by portion to quench the

reaction. Cold ether (0 ºC) was used for extraction and the combined organic phase was

dried over anhydrous MgSO4 at 0 ºC. After filtration and removal of the solvent under vacuum at 0 ºC, the crude aldehydes 2.22a and 2.22b as a yellow oil was used directly for

the next step without further purification. The crude aldehydes was redissolved in 10 mL

THF at -78 ºC. To this solution was added a solution of LiC≡CTMS in THF (0.5 M, 4.1

mL, 2.05 mmol) dropwise at -78 ºC. After stirring for 30 min at this temperature, the

solution was allowed to warm to room temperature before it was quenched with saturated

aq. NH4Cl solution. After ether extraction, drying with anhydrous MgSO4, filtration and

removal of the solvent under vacuum, the crude product was obtained as a yellow oil.

Flash column (CH2Cl2) gave a mixture of two diastereomers 2.23b and 2.23a (molar ratio

3:1 by HNMR) as a white foam (110 mg, 51% yield). Compound 2.23b : 1H NMR (400

MHz, CDCl3) δ 7.36 (s, 1 H), 6.92 (s, 1 H), 6.40 (s, 1 H), 6.01 (d, J = 1.2 Hz, 1 H), 5.98

(d, J = 1.2 Hz, 1 H), 5.22 (s, 1 H), 4.23 (dd, J =8.4 Hz, 10 Hz, 1 H), 3.94 (s, 3 H), 3.91 (s,

3 H), 3.73 (m, 1 H), 3.67 (3 H), 1.73-1.69 (m, 1 H), 0.85 (d, J = 6.8 Hz, 3 H), 0.80 (d, J =

13 6.8 Hz, 3 H), 0.18 (s, 9 H). C NMR (100 MHz, CDCl3) 163.58, 153.07, 152.01, 147.56,

146.98, 144.40, 134.88, 128.31, 127.59, 123.67, 108.73, 108.25, 107.80, 105.56, 101.21,

89.63, 72.36, 70.13, 62.91, 62.75, 61.04, 56.20, 32.07, 18.72, 17.96, -0.07.

74

Biphenyl alcohol 2.25: To a solution of the aldehyde 2.24 (1.0 g, 2.35 mmol, see

Experimental section in Chapter 3) in THF (50 mL) at -78 ºC was added a solution of

LiC≡CTMS in THF (0.5 M, 27.4 mL, 13.7 mmol) dropwise. After stirring for 30 min at

this temperature, the solution was allowed to warm to room temperature before it was

quenched with saturated aq. NH4Cl solution. After ether extraction, drying with

anhydrous MgSO4, filtration and removal of the solvent under vacuum, the crude product was obtained as a yellow oil. Flash column (EtOAc : Hexanes = 1: 4) gave the alcohol

1 2.25 a yellow solid (987 mg, 80% yield). H NMR (400 MHz, CDCl3) δ 7.40 (s, 1 H),

7.10 (s, 1 H), 6.58 (s, 1 H), 6.03(s, 2 H), 4.97 (s, 1 H), 3.93 (s, 3 H), 3.87 (s, 3 H), 3.58 (s,

3 H), 3.39 (s, 1 H), 3.33(d, J = 15.6 Hz, 1 H), 3.18 (d, J = 15.6 Hz, 1 H). 13C NMR (100

MHz, CDCl3) δ 153.15, 150.51, 147.81, 147.66, 140.89, 133.93, 130.92, 127.65, 125.27,

109.88, 108.44, 108.13, 104.69, 104.69, 104. 11, 101.44, 90.75, 87.97, 62.75, 61.47,

61.17, 55.91, 24.60, 0.06, -0.14. IR (neat, cm–1): 3442, 2958, 2898, 2175, 1599, 1480,

1462, 1402, 1250, 1232, 1140, 1104, 1042, 843, 761. HRMS (ESI) [M+Na]+ calcd for

C28H36O6NaSi2 547.1943, found 547.1940.

Diyne 2.37: To a solution of the alcohol 2.25 (903 mg, 1.72 mmol) and BnBr (1.08 g,

6.88 mmol) in DME (10 mL) was added NaH (275 mg, 6.88 mmol, 60% w/w in paraffin

oil) at 0 ºC. One drop of water was added to the above mixture. The mixture was stirred 75

at 0 ºC for 3.5 h, and then quenched with sat. aq. NH4Cl solution. Ether extraction, drying with anhydrous MgSO4 and removal of the solvent under vacuum gave an oil, which was directly used without further purification. The crude oil was dissolved in

MeOH (100 mL) followed by the addition of solid K2CO3 (950 mg, 6.88 mmol) at 0 ºC

while stirring. Then the mixture was allowed to warm to room temperature and further

stirring for 6h. The reaction was quenched with sat. aq. NH4Cl solution. Ether

extraction, drying with anhydrous MgSO4 and removal of the solvent under vacuum gave an oil. Purification by flash column (EtOAc: hexanes = 1: 15) gave the diyne 2.37 as a yellow solid (584 mg, 72% yield over two steps) and allene 2.38 as yellow solid. 2.37:

1 H NMR (400 MHz, CDCl3) δ 7.32 (s, 1 H), 7.29-7.20 (m, 5 H), 6.99 (s, 1 H), 6.58 (s, 1

H), 6.02 (s, 2 H), 4.76 (d, J = 2 Hz, 1 H), 4.58 (d, J = 11.6 Hz, 1 H), 4.20 (d, J = 11.6 Hz,

1 H), 3.93 (s, 3 H), 3.80 (s, 3 H), 3.59 (s, 3 H), 3.22 (dd, J = 4 Hz, 2.8 Hz, 2 H), 2.54 (d, J

13 = 2 Hz, 1 H), 2.14 (t, J = 2.8 Hz, 1 H). C NMR (100 MHz, CDCl3) δ 153.27, 150.93,

147.77, 147.55, 140.84, 137.62, 131.72, 130.86, 128.47, 128.23, 128.16, 128.05, 127.94,

127.55, 125.09, 109.92, 107.52, 107.35, 101.38, 82.30, 82.12, 75.04, 70.70, 70.57, 67.56,

60.86, 60.82, 55.97, 22.95. IR (neat, cm–1): 3435, 3287, 2955, 1597, 1480, 1462, 1402,

+ 1234, 1040, 749, 700. HRMS (ESI) [M+Na] calcd for C29H26O6Na 493.1622, found

1 493.1589. 2.38: H NMR (400 MHz, CDCl3) δ 7.34 (s, 1 H), 7.27-7.20 (m, 5 H), 6.79 (s,

1 H), 6.59 (s, 1 H), 6.01 (s, 2 H), 5.76 (t, J = 6.8 Hz, 1 H), 5.03 (d, J = 6.8 Hz, 2 H), 4.85

(d, J = 2 Hz, 1 H), 4.57 (d, J = 11.6 Hz, 1 H), 4.38 (d, J = 11.6 Hz, 1 H), 3.90 (s, 3 H),

3.81 (s, 3 H), 3.57 (s, 3 H), 2.53 (d, J = 2 Hz, 1 H). HRMS (ESI) [M+Na]+ calcd for

C29H26O6Na 493.1622, found 493.1629.

76

MeO MeO

MeO MeO SnMe3 SnMe3 MeO MeO B O B O O O O OBn O OBn O O 2.45a 2.45b

Boronate esters 2.45a and 2.45b: To a solution of the diyne 2.25 (40 mg, 0.084 mmol)

and PdCl2(PPh3)2 (3 mg, 0.002 mmol) in benzene (0.6 mL) was added 1,3-dimethyl-2-

(trimethylstannyl)-2-bora-1,3-diazocyclopentane 1.37 (26 mg, 0.1 mmol) in benzene (0.6

mL) and the mixture was stirred at room temperature for 18 hours. Then pinacol (15 mg,

0.126 mmol) was added and the mixture was stirred after for 6 h. The solvent was

evaporated under reduced pressure to afford the crude product, which was purified by

flash column (EtOAc: hexanes = 1: 5) to yield compound 2.45a (14 mg, 23% yield) as a

light yellow waxy solid and compound 2.45b (34 mg, 55% yield) as a light yellow waxy

1 solid. Compound 2.45a: H NMR (400 MHz, C6D6) δ 7.52 (s, 1 H), 7.37 (d, J = 7.2 Hz,

2 H), 7.12-7.10 (d, J = 7.2 Hz, 2 H), 7.05 (t, J = 7.2 Hz, 1 H), 6.97 (s, 1 H), 6.51 (s, 1 H),

6.47 (s, 1 H), 6.15 (d, J = 0.8 Hz, 1 H), 5.40 (d, J = 1.2 Hz, 1 H), 5.36 (d, J = 1.2 Hz, 1

H), 5.31 (s, 1 H), 4.73 (d, J = 12 Hz, 1 H), 4.62 (d, J = 12 Hz, 1 H), 3.86 (s, 3 H), 3.63 (d,

J = 13.2 Hz, 1 H), 3.51 (s, 3 H), 3.49 (d, J = 13.2 Hz, 1 H), 3.41 (s, 3 H), 1.04 (s, 6 H),

13 1.03 (s, 6 H), 0.35 (s, 9 H). C NMR (100 MHz, C6D6) δ 176.34, 174.86, 153.32, 151.38,

147.58, 146.51, 141.45, 139.46, 134.87, 133.79, 130.67, 128.18, 127.92, 127.68, 127.65,

127.09, 126.75, 110.56, 109.98, 107.93, 100.77, 85.89, 83.07, 82.97, 71.19, 60.65, 60.55,

55.34, 47.90, 29.96, 24.80, 24.68, -5.74. IR (neat, cm–1): 2976, 2924, 2853, 1593, 1477,

1351, 1274, 1260, 1143, 1040, 764, 750. HRMS (ESI) [M+Na]+ calcd for

77

1 C38H47BSnO8Na 785.2292, found 785.2309. Compound 2.45b: H NMR (400 MHz,

C6D6) δ 7.70 (s, 1 H), 7.43 (d, J = 7.2 Hz, 2 H), 7.12 (d, J = 7.2 Hz, 2 H), 7.05 (t, J = 7.2

Hz, 1 H), 6.84 (s, 1 H), 6.83 (s, 1 H), 6.51 (S, 1 H), 5.70 (s, 1 H), 5.29 (d, J = 1.6 Hz,

1H), 5.22 (d, J = 1.6 Hz, 1 H), 5.01 (d, J = 12 Hz, 1 H), 4.99 (s, 1 H), 4.53 (d, J = 12 Hz,

1 H), 3.75 (s, 3 H), 3.42 (s, 3 H), 3.34 (s, 3 H), 3.24 (d, J = 11.6 Hz, 1 H), 3.16 (d, J =

13 11.6 Hz, 1 H), 1.04 (s, 6 H), 1.01 (s, 6 H), 0.24 (s, 9 H). C NMR (100 MHz, C6D6) δ

164.62, 160.87, 153.96, 151.60, 148.23, 146.39, 141.96, 139.50, 137.35, 135.73, 128.28,

127.80, 127.68, 127.25, 125.90,123.94, 110.32, 107.90, 104.97, 100.79, 82.84, 79.76,

70.79, 60.47, 60.32, 55.26, 53.09, 45.99, 29.96, 24.92, 24.86, -7.70. IR (neat, cm–1):

2925, 1595, 1480, 1379, 1329, 1271, 1260, 1142, 764, 750. HRMS (ESI) [M+Na]+ calcd for C38H47BSnO8Na 785.2292, found 785.2291.

MeO

MeO MeO B O O O OBn O 2.46

Compound 2.46: To a mixture of cyclized boronesters 2.45a and 2.45b (50 mg, 0.068

mmol) in CH2Cl2 was added p-TsOH (26 mg, 0.137 mmol) and the mixture was stirred

for 2 h. The reaction was quenched with Et3N (14 mg, 0.137 mmol). Ether extraction,

drying with anhydrous MgSO4 and removal of the solvent under vacuum gave an oil.

Purification by flash column (EtOAc: hexanes = 1: 5) gave the diene 2.46 as a yellow

1 solid (33 mg, 81% yield). H NMR (400 MHz, C6D6): δ 7.62 (s, 1 H), 7.13-7.09 (m, 3

H), 7.05 (t, J = 7.2 Hz, 1 H), 6.90 (s, 1 H), 6.50 (s, 1 H), 5.78 (s, 1 H), 5.66 (s, 1 H), 5.39 78

(d, J = 2 Hz, 1 H), 5.33 (d, J = 1.2 Hz, 2 H), 4.89 (s, 1 H), 4.65(d, J = 12 Hz, 1 H), 4.44

(d, J = 12 Hz, 1 H), 4.31 (s, 1 H), 3.81 (s, 3 H), 3.42 (s, 3 H), 3.27 (s, 3 H), 3.16 (s, 2 H),

13 1.06 (s, 12 H). C NMR (100 MHz, CDCl3): δ 159.32, 153.15, 150.69, 150.60, 147.64,

146.05, 140.99, 138.80, 135.59, 135.01, 128.57, 128.12, 127.34, 127.26, 127.18, 125.48,

111.58, 109.46, 108.03, 105.12, 101.02, 83.08, 70.04, 61.09, 60.67, 56.05, 44.55, 29.70,

24.92, 24.54. IR (neat, cm–1): 2922, 1612, 1478, 1406, 1328, 1260, 1235, 1195, 1039,

+ 750. HRMS (ESI) [M+Na] calcd for C35H39BO8Na 621.2636, found 621.2634.

O O

MeO CHO MeO O N MeO OMe

Biphenyl aldehyde 2.26: To a solution of biaryl oxazoline 2.21 (250 mg, 0.436 mmol) in

THF (10 mL) at room temperature was added 1 M TBAF solution (0.52 mL, 0.52 mmol)

dropwise. After stirring for 2 h the reaction was quenched by the addition of saturated

aq. NH4Cl solution. The reaction mixture was diluted with CH2Cl2 and washed with

water, brine and dried over anhydrous MgSO4. The solvent was evaporated under

reduced pressure to afford a yellow oil which was then dissolved in CH2Cl2 (10 mL). To

this solution was added pyridinium chlorochromate (187 mg, 0.87 mmol), p-TsOH·H2O

® (165 mg, 0.87 mmol) and Celite (210 mg). After stirring for 18 h, Et3N (1 mL) was

added. The resulting brown suspension was directly loaded into column (EtOAc :

hexanes = 1: 2), which afforded the aldehyde 2.26 as a light yellow oil (169 mg, 85%

1 from 2.21). [α]D -50.4 (c 0.635, CHCl3). H NMR (400 MHz, CDCl3) δ 9.45 (s, 1 H), 79

7.24 (s, 1 H), 7.17 (s, 1 H), 6.05 (d, J = 1.6 Hz, 1 H), 6.04 (d, J = 1.6 Hz, 1 H), 6.12-6.08

(m, 1 H), 3.93 (s, 3 H), 3.90 (s, 3 H), 3.84-3.77 (m, 4 H), 3.71 (t, J = 8 Hz, 1 H), 3.62 (s,

3 H), 1.57-1.52 (m, 1 H), 0.77 (d, J = 6.8 Hz, 1 H), 0.73 (d, J = 6.8 Hz, 1 H). 13C NMR

(100 MHz, CDCl3) δ 190.30, 162.69, 153.19, 152.11, 149.11, 144.11, 141.66, 141.03,

130.60, 129.99, 124.66, 120.56, 108.56, 101.87, 100.37, 72.74, 70.26, 60.93, 60.69,

59.70, 56.10, 32.78, 18.57, 18.28. IR (neat, cm–1): 2956, 1682, 1607, 1470, 1392, 1285,

+ 1106. HRMS (ESI) [M+H] calcd for C24H28NO8 458.1809, found 458.1805.

O O O OH O OH

MeO MeO TMS TMS MeO O MeO O N N MeO MeO OMe OMe 2.27a 2.27b

Synthesis of compounds 2.27a and 2.27b. To a solution of the arylaldehyde 2.26 (200 mg, 0.438 mmol) and TMEDA (203 mg, 1.75 mmol) in THF (10 ml) at -78 ºC was added a solution of LiC≡CTMS in THF (0.5 M, 2.6 mL, 1.3 mmol) dropwise. After stirring for

30 min at this temperature, the solution was allowed to warm to room temperature before

it was quenched with saturated aq. NH4Cl solution. After ether extraction, drying with

anhydrous MgSO4, filtration and removal of the solvent under vacuum, the crude product was obtained as a yellow oil. Flash column (EtOAc : hexanes = 1: 2) gave the alcohol

2.27a as a white foam (183 mg, 75% yield) and the alcohol 2.27b as a colorless oil (27

1 mg, 11%). Compound 2.27a: [α]D 72.5 (c 1.03, CHCl3). H NMR (400 MHz, CDCl3) δ

7.16 (s, 1 H), 6.99 (s, 1 H), 6.74 (s, 1 H), 5.96 (d, J = 1.2 Hz, 1 H), 5.90 (d, J = 1.2 Hz, 1

80

H), 5.13 (s, 1 H), 4.27 (t, J = 8.8 Hz, 1 H), 3.99-3.95 (m, 1 H), 3.93 (s, 3 H), 3.89 (s, 3H),

3.70 (s, 3H), 3.66 (s, 3H), 1.38-1.35 (m, 1H), 0.64 (d, J = 6.8 Hz, 3H), 0.53 (d, J = 6.8

13 Hz, 3 H). 0.14 (s, 9 H). C NMR (100 MHz, CDCl3) δ 163.73, 152.91, 152.20, 149.08,

144.61, 139.99, 136.59, 135.53, 123.66, 123.53, 121.61, 108.23, 105.68, 102.55, 101.09,

89.45, 72.04, 70.32, 62.89, 60.90, 60.78, 59.59, 56.06, 32.75, 18.38, 17.30, -0.10. IR

(neat, cm–1): 3186, 2959, 2899, 1651, 1590, 1470, 1366, 1274, 1109, 1058, 981, 846.

+ HRMS (ESI) [M+H] calcd for C29H38NO8Si 556.2361, found 556.2363. Compound

1 2.27b: [α]D -33.2 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) 7.19 (s, 1 H), 7.04 (s, 1

H), 5.96 (d, J = 1.2 Hz, 1 H), 5.95 (d, J = 1.2 Hz, 1 H), 5.08 (s, 1 H), 4.14 (t, J = 8 Hz, 1

H), 3.94-3.89 (m, 4 H), 3.88 (s, 3 H), 3.78 (s, 3 H), 3.63 (s, 3 H), 1.56-1.50 (m, 1 H), 0.76

(d, J = 0.8 Hz, 3 H), 0.74 (d, J = 0.8 Hz, 3 H), 0.12 (s, 9 H). 13C NMR (100 MHz,

CDCl3) δ 163.39, 153.83, 151.55,148.79, 144.29, 140.93, 136.24, 134.09, 124.42, 123.30,

121.77, 108.97, 104.97, 102.61, 101.08, 90.39, 72.34, 70.33, 63.83, 61.05, 60.98, 59.48,

56.02,32.77, 18.37, 18.34, -0.14. IR (neat, cm–1): 2958, 1475, 1402, 1366, 1108, 845,

+ 756. HRMS (ESI) [M+H] calcd for C29H38NO8Si 556.2361, found 556.2365.

O O

OTBS MeO MeO CHO

MeO OMe

Biphenyl aldehyde 2.28: To a solution of the oxazoline 2.21 (8.35 g, 14.55 mmol) and

2,6-di-tertbutylpyridine (3.61 g, 18.92 mmol) in CH2Cl2 (30 mL) was added MeOTf

(2.86 g, 17.46 mmol) at room temperature. The mixture was stirred for 2h before L- 81

Selectride (1 M in THF, 12.3 mL, 12.3 mmol) was added dropwise at 0°C. The mixture

was stirred at 0 °C for 30 min, and then quenched with saturated aq. NH4Cl solution.

Ether extraction, drying with anhydrous MgSO4 and removal of the solvent under

vacuum gave an oil. To this oil was added CH2Cl2 (50 mL) and silica gel (10 g) were

added. The reaction mixture was vigorously stirred for 18 h at room temperature. After

removing the solvent under vacuum, the silica gel was loaded onto a column and column

chromatography (EtOAc : hexanes = 1: 5) afforded the aldehyde 2.28 (6.41 g, 90% yield)

1 as a yellow oil. [α]D -13.3 (c 0.87, CHCl3). H NMR (400 MHz, CDCl3) δ 9.54 (s, 1 H),

7.35 (s, 1 H), 6.83 (s, 1 H), 6.00 (d, J = 1.2 Hz, 1 H), 5.99 (d, J = 1.2 Hz, 1 H), 4.29 (d, J

= 12.8 Hz, 1 H), 4.13 (d, J = 12.8 Hz, 1 H), 3.97 (s, 3 H), 3.96 (s, 3 H), 3.84 (s, 3 H), 3.63

13 (s, 3 H), 0.83 (s, 9 H), -0.07 (s, 3 H), -0.08 (s, 3 H). C NMR (100 MHz, CDCl3) δ

191.20, 153.23, 151.38, 149.56, 147.17, 135.29, 134.92, 130.09, 128.07, 115.93, 104.99,

101.88, 101.09, 67.96, 62.97, 61.00, 60.83, 59.42, 56.05, 25.88, 25.61, 18.32, -5.52, -

5.54. IR (neat, cm–1): 2956, 2866, 1645, 1260, 1152, 765, 750. HRMS (ESI) [M+Na]+

calcd for C25H34O8SiNa 513.1915, found 513.1917.

O O O O

OTBS OTBS MeO MeO TMS + TMS MeO MeO

MeO OH MeO OH OMe OMe 2.29a 2.29b

Biphenyl alcohols 2.29a and 2.29b: To a stirred solution of the aldehyde 2.28 (236 mg,

0.48 mmol) in dry THF (5 mL) at –78 °C was added lithium trimethylsilylacetylide (0.5

82

M THF solution, 2.88 mL, 1.44 mmol). After stirring at –78 °C for 30 min, the reaction

was quenched by the addition of aq. sat. NH4Cl solution. The reaction mixture was diluted with CH2Cl2 and washed with water, brine and dried over Na2SO4. The solvent

was evaporated under reduced pressure to afford the crude product, which was purified

by silica gel column chromatography. Elution with 25 % EtOAc/pentane provided the

major product 2.29a (254 mg, 90% yield) as a light yellow solid and the minor product

2.29b (17 mg, 6% yield) as a light yellow solid. The major product 2.29a: [α]D -23.4 (c

1 1.07, CHCl3). H NMR (400 MHz, CDCl3) δ 7.28 (s, 1 H), 6.88 (s, 1 H), 5.99 (d, J = 1.2

Hz, 1 H), 5.97 (d, J = 1.2 Hz, 1 H), 5.03 (d, J = 1.6 Hz, 1 H), 4.29 (d, J = 14 Hz, 1 H),

4.09 (d, J = 14 Hz, 1 H), 3.95 (s, 3 H), 3.89 (s, 3 H), 3.84 (s, 3 H), 3.63 (s, 3 H), 2.87 (d, J

= 1.6 Hz, 1 H), 0.87 (s, 9 H), 0.16 (s, 9 H), -0.03 (s, 3 H), -0.04 (s, 3 H). 13C NMR (100

MHz, CDCl3) δ 153.37, 151.10, 149.25, 142.25, 140.25, 135.66, 135.49, 135.14, 120.79,

117.82, 106.61, 104.84, 101.97, 90.84, 62.87, 62.66, 60.84, 60.73, 59.77, 55.79, 53.41,

25.98, 18.35, -0.16, -5.37, -5.41. IR (neat, cm–1): 3428, 2929, 2884, 1638, 1320, 1146,

+ 1076. HRMS (ESI) [M+Na] calcd for C30H44O8Si2Na 611.2467, found 611.2463. The

1 minor product 2.29b: [α]D -5.6 (c 0.9, CHCl3). H NMR (400 MHz, CDCl3) δ 7.26 (s, 1

H), 6.66 (s, 1 H), 6.00 (d, J = 1.2 Hz, 1 H), 5.98 (d, J = 1.2 Hz, 1 H), 5.08 (d, J = 1.6 Hz,

1 H), 4.25 (d, J = 11.6 Hz, 1 H), 4.15 (d, J = 11.6 Hz, 1 H), 3.95 (s, 3 H), 3.87 (s, 3 H),

3.82 (s, 3 H), 3.65 (d, J = 1.6 Hz, 1 H), 3.62 (s, 3 H), 2.87 (d, J = 1.6 Hz, 1 H), 0.80 (s, 9

13 H), 0.15 (s, 9 H), 0.02 (s, 3 H), -0.01 (s, 3 H). C NMR (100 MHz, CDCl3) δ 153.26,

150.76, 149.08, 142.11, 141.07, 136.49, 136.08, 133.67, 121.32, 120.78, 107.01, 105.45,

103.89, 101.17, 90.21, 63.90, 62.08, 60.88, 60.69, 59.57, 55.84, 29.70,26.04, 18.57, -

83

0.09, -5.17, -5.43. IR (neat, cm–1): 3388, 2940, 2876, 1148, 776. HRMS (ESI) [M+Na]+

calcd for C30H44O8Si2Na 611.2467, found 611.2462.

O O

OH MeO MeO

MeO OBn OMe

Biphenyl alcohol 2.30:33 To a stirred solution of TBS ether 2.29a (648 mg, 1.0 mmol) in

THF (4 mL) was added TBAF (1 M in THF, 1.5 mL, 1.5 mmol) at 0 oC and stirring was

continued at the same temperature for 2h. The solvent was evaporated under reduced

pressure to afford the crude product, which was purified by silica gel chromatography

using 30 % EtOAc/hexane as the eluent to yield the alcohol 2.30 (457 mg, 93% yield) as

1 a viscous oil. [α]D – 33.5 (c 1, CHCl3). H NMR (500 MHz, CDCl3): δ 7.29-7.23 (m, 5

H), 7.15 (s, 1 H), 6.71 (s, 1 H), 5.95 (s, 2 H), 4.73 (d, J = 2.0 Hz, 1 H), 4.63 (d, J = 11.6

Hz, 1 H), 4.45 (d, J = 11.6 Hz, 1 H), 4.10-4.08 (bs, 2 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.75

13 (s, 3 H), 3.61 (s, 3 H), 2.47 (d, J = 2.5 Hz, 1 H). C NMR (125 MHz, CDCl3) δ 153.48,

150.92, 149.26, 142.13, 140.54, 137.40, 135.26, 135.06, 133.57, 128.20, 128.05, 127.61,

121.61, 119.04, 106.05, 103.26, 100.93, 81.96, 74.94, 70.63, 67.32, 63.61, 60.92, 60.89,

59.10, 55.90. MS (ESI): m/z: 551.1663 [M+Na]+.

O O

MeO CHO MeO

MeO OBn OMe 84

Biphenyl aldehyde 2.31: 33 To a solution of the substrate 2.30 (240 mg, 0.5 mmol) in

CH2Cl2 (4 mL) at 0 °C was added PCC (215 mg, 1 mmol) and NaOAc (123 mg, 1.5 mmol). After stirring at rt for 4 h, the reaction mixture was quenched with aq. sat.

NaHCO3 solution. The reaction mixture was diluted with CH2Cl2 and washed

successively with water, brine and dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure to afford the crude product which was purified by column chromatography on silica gel using 15 % EtOAc/hexane as the eluent to get the

1 aldehyde 2.31 (214 mg, 90% yield) as a viscous oil. [α]D – 11.0 (c 1, CHCl3). H NMR

(500 MHz, CDCl3): δ 9.39 (s, 1 H), 7.28-7.22 (m, 6 H), 7.15 (s, 1 H), 6.05 (s, 2 H), 4.70

(d, J = 1.6 Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 3.92 (s, 3 H),

3.87 (s, 3 H), 3.73 (s, 3 H), 3.63 (s, 3 H), 2.49 (d, J = 1.6 Hz, 1 H). 13C NMR (100 MHz,

CDCl3) δ 190.49, 154.32, 151.84, 149.81, 142.15, 141.73, 140.90, 137.37, 133.81,

130.35, 128,43, 128.38, 127.89, 118.84, 105.93, 102.16, 100.77, 81.31, 76.19, 70.81,

67.57, 61.04, 60.87, 59.70, 56.19. MS (ESI): m/z: 513.1468 [M+Na]+.

O O O O

MeO MeO + MeO OH MeO OH

MeO OBn MeO OBn OMe OMe 2.32a 2.32b

Biphenyl alcohols 2.32a and 2.32b: To a solution of the aldehyde 2.31 (900 mg, 1.83 mmol) in ether (100 mL) at -78 ºC was added a solution of LiC≡CTMS in ether (0.5 M,

18.3 mL, 9.15 mmol) dropwise. After stirring for 30 min at this temperature, the solution

85

was allowed to warm to room temperature before it was quenched with saturated aq.

NH4Cl solution. After ether extraction, drying with anhydrous MgSO4, filtration and

removal of the solvent under vacuum, the crude product was obtained as a yellow oil,

which was then dissolved in MeOH (10 mL). To this solution was added K2CO3 (252

mg, 1.83 mmol) and after stirring for 18 hours at room temperature, the solution was

quenched with saturated aq. NH4Cl solution. After removal of the solvent under vacuum, ether was used for extraction. The combined organic phase was dried over anhydrous

Na2SO4, The solvent was evaporated under reduced pressure to afford the crude product,

which was purified by silica gel column chromatography. Elution with 15%

EtOAc/hexane provided the major product 2.32a (690 mg, 73%) as a yellow solid and the

minor product 2.32b (198 mg, 21%) as a yellow solid. Compound 2.32a: [α]D –28.6 (c 1,

1 CHCl3).; H NMR (400 MHz, CDCl3): δ 7.30-7.23 (m, 5 H), 7.17 (s, 1 H), 6.13 (s, 1 H),

5.97 (s, 2 H), 4.92-4.86 (m, 1 H), 4.77 (d, J = 2.0 Hz, 1 H), 4.67 (d, J = 12.0 Hz, 1 H),

4.49 (d, J = 12.0 Hz, 1 H), 3.91 (s, 3 H), 3.86 (s, 3 H), 3.72 (s, 3 H), 3.60 (s, 3 H), 326-

3.18 (bs, 1 H), 2.47 (d, J = 2.0 Hz, 1 H), 2.46 (d, J = 2.4 Hz, 1 H). 13C NMR (100 MHz,

CDCl3) δ 153.97, 150.93, 149.90, 142.28, 140.29, 137.69, 136.10, 135.27, 134.55,

128.52, 128.44, 128.26, 127.93, 120.74, 119.15, 106.06, 102.50, 101.44, 83.53, 81.51,

77.43, 75.60, 73.87, 70.95, 67.59, 63.12, 61.51, 61.31, 59.39, 56.23, 53.62. MS (ESI):

+ 1 m/z: 539.1608 [M+Na] . Compound 2.32b: [α]D +14.8 (c 0.5, CHCl3). H NMR (400

MHz, CDCl3): δ 7.27-7.21 (m, 5 H), 7.11 (s, 1 H), 6.98 (s, 1 H), 5.97 (d, J = 1.2 Hz, 1 H),

5.96 (d, J = 1.2 Hz, 1 H), 5.0-4.92 (m, 1 H), 4.79 (d, J = 2.4 Hz, 1 H), 4.56 (d, J = 11.6

Hz, 1 H), 4.38 (d, J = 11.6 Hz, 1 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.74 (s, 3 H), 3.65 (s, 3

86

H), 2.59 (d, J = 2.4 Hz, 1 H), 2.45 (d, J = 2.4 Hz, 1 H), 2.42-2.33 (bs, 1 H). 13C NMR

(100 MHz, CDCl3): δ 153.97, 151.89, 149.78, 142.56, 140.90, 137.46, 136.58, 134.55,

133.34, 128.48, 128.44, 127.90, 121.50, 120.09, 106.79, 102.02, 101.45, 83.75, 82.99,

77.43, 75.87, 74.11, 70.93, 67.82, 61.90, 61.10, 60.99, 59.56, 56.18. MS (ESI): m/z:

539.1608 [M+Na]+.

O O

OTBS MeO MeO

MeO OTIPS OMe

TBS ether 2.33: To a solution of the alcohol 2.29a (711 mg, 1.21 mmol) was added

K2CO3 (167 mg, 1.21 mmol) and after stirring for 18 hours at room temperature, the solution was quenched with saturated aq. NH4Cl solution. After removal of the solvent

under vacuum, ether was used for extraction. The combined organic phase was dried

over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to afford the

o crude product, which was dissolved in CH2Cl2 (10 mL) at 0 C. To the resulting solution was added 2, 6-lutidine (518 mg, 4.84 mmol) followed by TIPSOTf (1.12 g, 3.64 mmol) and the reaction mixture was gradually brought to room temperature over 3 h.

Afterwards, the reaction was quenched with saturated aq. NaHCO3 solution, diluted with

CH2Cl2 and washed subsequently with water, brine and dried over Na2SO4. The solvent was evaporated under reduced pressure to afford the crude product which was purified by silica gel column chromatography. Elution with 5 % EtOAc/hexane provided the TBS

1 ether product 2.33 (732 mg, 90% yield) as a viscous oil. H NMR (400 MHz, CDCl3) δ 87

7.21 (s, 1 H), 6.88 (s, 1 H), 5.94 (s, 2 H), 5.22 (d, J = 2.4 Hz, 1 H), 4.33 (d, J = 14 Hz, 1

H), 4.26 (d, J = 14 Hz, 1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.82 (s, 3 H), 3.61 (s, 3 H), 2.24

(d, J = 2.4 Hz, 1 H), 1.19-1.02 (m, 21H), 0.88 (s, 9H), 0.00 (s, 3H), -0.02 (s, 3H). 13C

NMR (100 MHz, CDCl3) δ 152.93, 150.90, 149.01, 141.20, 139.77, 136.73, 134.04,

128.79, 119.47, 116.73, 104.53, 100.65, 84.72, 72.20, 62.60, 61.63, 60.86, 60.68, 58.95,

55.71, 25.97, 18.33, 17.99, 17.97, 17.70, 12.29, -5.33, -5.40. HRMS (ESI) [M+Na]+ m/z

calcd for C36H56O8Si2Na 695.3412, found 695.3406.

O O

MeO CHO MeO

MeO OTIPS OMe

TIPS ether 2.34: To a solution of the TBS ether 2.33 (804 mg, 1.19 mmol) was added

PPTS (300 mg, 1.19 mmol) and after stirring for 18 hours at room temperature, the

solution was quenched with saturated aq. NaHCO3 solution. After removal of the solvent under vacuum, ether was used for extraction. The combined organic phase was dried over anhydrous Na2SO4, The solvent was evaporated under reduced pressure to afford the

o crude product, which was dissolved in CH2Cl2 (10 mL) at 0 C. To this solution was

added pyridinium chlorochromate (512 mg, 2.38 mmol), NaOAc (195 mg, 2.38 mmol)

and Celite® (500 mg). After stirring for 18 h, the resulting brown suspension was directly

loaded into column (EtOAc : hexanes = 1: 4), which afforded the aldehyde 2.34 as a light

1 yellow oil (582 mg, 88%). H NMR (400 MHz, CDCl3) δ 9.38 (s, 1 H), 7.24 (s, 1 H),

7.22 (s, 1 H), 6.08 (s, 1 H), 6.07 (s, 1 H), 5.17 (d, J = 2 Hz, 1 H), 3.92 (s, 3 H), 3.88 (s, 3 88

H), 3.83 (s, 3 H), 3.63 (s, 3 H), 2.24 (d, J = 2 Hz, 1 H), 1.07-1.02 (m, 21H). 13C NMR

(100 MHz, CDCl3) δ 191.01, 153.86, 151.45, 149.58, 141.18, 140.97, 140.09, 136.86,

130.79, 127.58, 116.59, 104.08, 101.92, 100.67, 83.82, 73.57, 61.92, 60.88, 60.58, 59.37,

+ 55.80, 17.94, 12.17. HRMS (ESI) [M+Na] m/z calcd for C30H40O8SiNa 579.2390, found 579.2396.

O O O O TMS TMS

MeO MeO + MeO OH MeO OH 7 MeO OTIPS MeO OTIPS OMe OMe 2.35a 2.35b

Biphenyl alcohols 2.35a and 2.35b: To a solution of the aryl aldehyde 2.34 (467 mg,

0.838 mmol) in THF (10 ml) at -78 ºC was added a solution of LiC≡CTMS in THF (0.5

M, 6.7 mL, 3.35 mmol) dropwise. After stirring for 30 min at this temperature, the

solution was allowed to warm to room temperature before it was quenched with saturated

aq. NH4Cl solution. After ether extraction, drying with anhydrous MgSO4, filtration and

removal of the solvent under vacuum, the crude product was obtained as a yellow oil.

Flash column (EtOAc : hexanes = 1: 5) gave the alcohol 2.35a as a white solid (411 mg,

75% yield) and the alcohol 2.35b as a white solid (60 mg, 11%). Compound 2.35a: 1H

NMR (400 MHz, CDCl3) δ 7.18 (s, 1 H), 7.07 (s, 1 H), 5.99 (d, J = 1. 2 Hz, 1 H), 5.97 (d,

J = 1. 2 Hz, 1 H), 5.17 (d, J = 2 Hz, 1 H), 5.06 (d, J = 2.8 Hz, 1 H), 3.92 (s, 3 H), 3.90 (s,

3 H), 3.77 (s, 3 H), 3.70 (s, 3 H), 2.62 (d, J = 2.8 Hz, 1 H), 2.44 (d, J = 2 Hz, 1 H), 2.44

13 (d, J = 2 Hz, 1 H), 1.10-0.99 (m, 21H), 0.10 (s, 9 H). C NMR (100 MHz, CDCl3) δ 89

153.52, 151.38, 149.48, 141.36, 139.81, 136.47, 136.25, 135.92, 119.31, 118.91, 105.20,

104.82, 102.36, 101.18, 89.92, 86.60, 73.26, 62.28, 61.68, 60.87, 60.83, 59.15, 55.80,

+ 53.41, 29.69, 17.94, 12.23, -0.19. HRMS (ESI) [M+Na] m/z calcd for C35H50O8Si2Na

1 677.2942, found 677.2948. Compound 2.35b: H NMR (500 MHz, CDCl3) δ 7.32-7.26

(m, 5 H), 7.21 (s, 1 H), 7.14 (s, 1 H), 5.99 (s, 2 H), 4.92 (s, 1 H), 4.83 (d, J = 1.5 Hz, 1

H), 4.69 (d, J = 12 Hz, 1 H), 4.50 (d, J = 12 Hz, 1 H), 3.93 (s, 3 H), 3.87 (s, 3 H), 3.73 (s,

13 3 H), 3.61 (s, 3 H), 2.44 (d, J = 2 Hz, 1 H), 0.16 (s, 9H). C NMR (125 MHz, CDCl3) δ

153.69, 150.79, 149.65, 142.08, 140.04, 137.52, 135.86, 135.42, 134.29, 128.32, 128.01,

127.71, 120.72, 118.93, 105.85, 105.02, 102.36, 101.20, 90.12, 81.37, 75.36, 70.75,

67.48, 63.43, 61.29, 61.08, 59.18, 56.03, -0.13. HRMS (ESI) [M+Na]+ m/z calcd for

C35H50O8Si2Na 677.2942, found 677.2937.

O O

MeO MeO OMe

MeO OBn OMe

Methyl ether 2.39a:33 To a solution of the alcohol 2.32a (117 mg, 0.2 mmol) in DME

(2mL) at 0 °C was added methyl iodide (0.5 mL). After stirring at 0 °C for 20 min, to the above solution was added NaH (50% in paraffin oil, 37 mg, 0.5 mmol). The reaction mixture was stirred at 0 °C for 1 h and quenched with aq. sat. NH4Cl solution. The reaction mixture was diluted with diethyl ether and washed successively with water, brine and dried over Na2SO4. The organic layer was evaporated under reduced pressure to afford the crude product which was purified by column chromatography on silica gel 90

using 10 % EtOAc/hexane as the eluent to get the methyl ether 2.39a (95 mg, 90% yield).

1 [α]D –39.2 (c 0.7, CHCl3). H NMR (400 MHz, CDCl3) δ 7.23-7.17 (m, 6 H), 6.93 (s, 1

H), 5.97 (d, J = 1.5 Hz, 1 H), 5.94 (d, J = 1.5 Hz, 1 H), 4.80 (d, J = 2.0 Hz, 1 H), 4.54 (d,

J = 11.5 Hz, 1 H), 4.46 (d, J = 2.0 Hz, 1 H), 4.31 (d, J = 11.5 Hz, 1 H), 3.92 (s, 3 H), 3.86

(s, 3 H), 3.72 (s, 3 H), 3.67 (s, 3 H), 3.12 (s, 3 H), 2.60 (d, J = 2.0 Hz, 1 H), 2.50 (d, J =

13 2.0 Hz, 1 H). C NMR (100 MHz, CDCl3) δ 153.67, 152.07, 149.47, 142.44, 141.28,

137.56, 136.52, 133.01, 131.98, 128.58, 128.36, 127.79, 122.12, 121.19, 106.87, 102.17,

101.34, 82.18, 82.10, 77.43, 76.10, 75.48, 70.92, 70.31, 68.09, 60.86, 60.76, 59.47, 56.54,

56.14, 53.63. MS (ESI): m/z: 553.1749 [M+Na]+.

O O

MeO MeO OMOM

MeO OBn OMe

MOM ether 2.39b:33 To a solution of the compound 2.32a (117 mg, 0.2 mmol) in DME

(2 mL) at 0 °C was added methoxymethylchloride (0.2 mL). After stirring at 0 °C for 20

min, to the above solution was added NaH (50% in paraffin oil, 37 mg, 0.5 mmol). The

reaction mixture was stirred at 0 °C for 1 h and quenched with aq. sat. NH4Cl solution.

The reaction mixture was diluted with diethyl ether and washed successively with water,

brine and dried over Na2SO4. The organic layer was evaporated under reduced pressure to afford the crude product which was purified by column chromatography on silica gel using 10 % EtOAc/hexane as the eluent to get the compound 2.39b (100 mg, 90% yield)

91

1 as a viscous oil. [α]D – 26.2 (c 1, CHCl3). H NMR (500 MHz, CDCl3) δ 7.22-7.16 (m, 6

H), 6.92 (s, 1 H), 5.97 (d, J = 1.6 Hz, 1 H), 5.94 (d, J = 1.6 Hz, 1 H), 4.85 (d, J = 2.0 Hz,

1 H), 4.83 (d, J = 2.0 Hz, 1 H), 4.71 (d, J = 6.8 Hz, 1 H), 4.55 (d, J = 11.2 Hz, 1 H), 4.39

(d, J = 6.8 Hz, 1 H), 4.27 (d, J = 11.2 Hz, 1 H), 3.92 (s, 3 H), 3.83 (s, 3 H), 3.72 (s, 3 H),

3.69 (s, 3 H), 3.16 (s, 3 H), 2.60 (d, J = 2.0 Hz, 1 H), 2.50 (d, J = 2.0 Hz, 1 H). 13C

NMR (100 MHz, CDCl3) δ 153.66, 151.86, 149.56, 142.44, 141.22, 137.55, 136.34,

133.03, 131.95, 128.63, 128.33, 127.76, 122.03, 120.95, 107.33, 102.17, 101.32, 94.27,

82.11, 82.07, 77.43, 76.26, 75.57, 70.92, 68.31, 64.82, 60.79, 60.77, 59.38, 56.13, 55.91.

MS (ESI): m/z: 583.1866 [M+Na]+.

O O

MeO MeO OTBS

MeO OBn OMe

TBS ether 2.39c: To a stirred solution of the alcohol 2.32a (900 mg, 1.74 mmol) in DMF

(10 mL) at room temperature was added imidazole (473 mg, 6.96 mmol) followed by

TBSCl (1.05 g, 6.96 mmol). The reaction mixture was stirred for 18 h at room

temperature. After ether extraction, the organic phase was washed with water three times

before it was dried with anhydrous MgSO4. After filtration and removal of the solvent under vacuum, the crude oil was subjected to flash column (EtOAc : hexanes = 1: 6) gave

1 TBS ether 2.39c (1.06 g, 97%) as a white waxy solid. [α]D -29.0 (c 0.145, CHCl3). H

NMR (500 MHz, C6D6) δ 7.48 (s, 1 H), 7.41 (d, J = 2.5 Hz, 1 H), 7.28 (d, J = 7 Hz, 2 H),

7.13 (t, J = 7.5 Hz, 2 H), 7.06 (t, J = 7.5 Hz, 1 H), 5.38 (s, 1 H), 5.34 (s, 1 H), 5.30 (d, J = 92

1.5 Hz, 1 H), 5.21 (d, J = 1.5 Hz, 1 H), 4.73 (d, J = 11.5 Hz, 1 H), 4.36 (d, J = 11.5 Hz, 1

H), 3.85 (s, 3 H), 3.77 (s, 3 H), 3.64 (s, 3 H), 3.40 (s, 3 H), 2.30 (d, J = 2 Hz, 1 H), 2.27

(d, J = 2 Hz, 1 H), 0.96 (s, 9 H), 0.15 (s, 3 H), 0.05 (s, 3 H). 13C NMR (125 MHz,

CDCl3) δ 153.85, 151.62, 149.78, 143.14, 141.42, 138.37, 136.01, 135.66, 133.72,

128.12, 127.37, 122.72, 119.43, 108.76, 101.14, 100.68, 85.28, 82.94, 75.65, 74.04,

70.52, 69.47, 62.32, 60.44, 60.29, 58.77, 55.23, 25.79, 18.14, -4.60, -4.88. IR (neat, cm–

1): 2953, 2929, 2856, 1622, 1454, 910. HRMS (ESI) [M+Na]+ m/z calcd for

C36H42O8SiNa 653.2547, found 653.2555.

O O

MeO MeO OTIPS

MeO OBn OMe

TIPS ether 2.39d: To a stirred solution of the alcohol 2.32a (90 mg, 0.174 mmol) in

DMF (10 mL) at room temperature was added imidazole (59 mg, 0.87 mmol) followed by TIPSCl (0.167 g, 0.87 mmol). The reaction mixture was stirred for 18 h at room

temperature. After ether extraction, the organic phase was washed with water three times

before it was dried with anhydrous MgSO4. After filtration and removal of the solvent under vacuum, the crude oil was subjected to flash column (EtOAc : hexanes = 1: 6) gave

1 the TIPS ether 2.39d (108 mg, 92%) as a white waxy solid. H NMR (500 MHz, C6D6) δ

7.49 (s, 1 H), 7.48 (s, 1 H), 7.30 (d, J = 7.5 Hz, 2 H), 7.13 (t, J = 7.5 Hz, 2 H), 7.07 (t, J =

7.5 Hz, 1 H), 5.48 (d, J = 2 Hz, 1 H), 5.34 (d, J = 2 Hz, 1 H), 5.28 (d, J = 1.5 Hz, 1 H),

5.19 (d, J = 1.5 Hz, 1 H), 4.75 (d, J = 11 Hz, 1 H), 4.36 (d, J = 11 Hz, 1 H), 3.87 (s, 3 H), 93

3.78 (s, 3 H), 3.64 (s, 3 H), 3.39 (s, 3 H), 2.32 (d, J = 1.5 Hz, 1 H), 2.21 (d, J = 1.5 Hz, 1

H), 1.15-1.11 (m, 21 H).

O O

MeO MeO OH

MeO OTIPS OMe

Biphenyl alcohol 2.40: To a solution of the alcohol 2.35a (50 mg, 0.076 mmol) was added K2CO3 (11 mg, 0.076 mmol) and after stirring for 18 hours at room temperature,

the solution was quenched with saturated aq. NH4Cl solution. After removal of the

solvent under vacuum, ether was used for extraction. The combined organic phase was

dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to

afford the crude product. Flash column (EtOAc : hexanes = 1: 3) gave the alcohol 2.40

1 as a white solid (42 mg, 95% yield). H NMR (400 MHz, CDCl3) δ 7.19 (s, 1 H), 7.08 (s,

1 H), 5.98 (s, 2 H), 5.18 (d, J = 2 Hz, 1 H), 5.06 (t, J = 2 Hz, 1 H), 3.92 (s, 3 H), 3.89 (s, 3

H), 3.79 (s, 3 H), 3.69 (s, 3 H), 2.59 (d, J = 2.8 Hz, 1 H), 2.47 (d, J = 2.4 Hz, 1 H), 2.44

13 (d, J = 2 Hz, 1 H), 1.07-0.96 (m, 21 H). C NMR (100 MHz, CDCl3) δ 153.57, 151.40,

149.59, 141.33, 139.83, 136.42, 136.18, 135.57, 119.17, 118.75, 104.77, 102.11, 101.21,

86.58, 83.67, 73.43, 73.21, 61.70, 60.83, 59.12, 55.81, 17.95, 17.92, 12.23. HRMS (ESI)

+ [M+Na] m/z calcd for C32H42O8SiNa 605.2547, found 605.2550.

94

O O

MeO MeO OAc

MeO OTIPS OMe

Biphenyl acetate 2.41: To a stirred solution of the alcohol 2.40 (10 mg, 0.017 mmol) in

CH2Cl2 (3 mL) was added Ac2O (9 mg, 0.085 mmol), Et3N (8 mg, 0.085 mmol) and

DMAP (one crystal) at 0 oC and stirring was continued at the same temperature for 2h.

The solution was quenched with saturated aq. NaHCO3 solution. After ether extraction,

drying with anhydrous MgSO4, filtration and removal of the solvent under vacuum, the crude product was obtained as a yellow oil. Flash column (EtOAc : hexanes = 1: 3) gave

1 the acetate 2.41 (8.5 mg, 80% yield) as a white solid. H NMR (500 MHz, C6D6) δ 7.42

(s, 1 H), 7.41 (s, 1 H), 6.42 (d, J = 2.5 Hz, 1 H), 5.61 (d, J = 2 Hz, 1 H), 5.26 (d, J = 1 Hz,

1 H), 5.18 (s, 1 H), 3.81 (s, 3 H), 3.74 (s, 6 H), 3.47 (s, 3 H), 2.10 (t, J = 1 Hz, 1 H), 2.06

(d, J = 1 Hz, 1 H), 1.66 (s, 3 H), 1.20-1.15 (m, 21 H). HRMS (ESI) [M+Na]+ m/z calcd

for C34H44O9SiNa 647.2653, found 647.2455

O O O O H H • MeO MeO MeO OBn MeO OBn

MeO OTIPS MeO OTIPS OMe OMe 2.42 2.43

Benzyl ether 2.42 and benzyl allene 2.43: To a stirred solution of the alcohol 2.40 (10

mg, 0.017 mmol) and BnBr (13 mg, 0.085 mmol) in DMF (1 mL) at room temperature 95

was added NaH (3.4 mg, 0.085 mmol). The reaction mixture was stirred for 10 min

before quenching with aq. sat. NH4Cl solution. After ether extraction, the organic phase

was washed with water three times before it was dried with anhydrous MgSO4. After filtration and removal of the solvent under vacuum, the crude oil was subjected to p-TLC

(MeOH : CH2Cl2 = 1: 50) gave benzyl ether 2.42 (2.0 g, 18%) as an oil and benzyl allene

1 2.43 (8.0 mg, 72%) also as an oil. [α]D -29.0 (c 0.145, CHCl3). H NMR (400 MHz,

C6D6) δ 7.49 (s, 1 H), 7.46 (s, 1 H), 7.31 (d, J = 7.2 Hz, 2 H), 7.16-6.95 (m, 3 H), 5.67 (d,

J = 2.5 Hz, 1 H), 5.26 (d, J = 1.5 Hz, 1 H), 5.17 (s, 1 H), 5.12 (d, J = 2.5 Hz, 1 H), 4.90

(d, J = 11.6 Hz, 1 H), 4.32 (d, J = 11.6 Hz, 1 H), 3.81 (s, 3 H), 3.80 (s, 3 H), 3.79 (s, 3 H),

3.54 (s, 3 H), 2.11 (d, J = 2.5 Hz, 1 H), 2.00 (d, J = 2.5 Hz, 1 H), 1.21-1.12 (m, 21 H).

+ HRMS (ESI) [M+Na] m/z calcd for C39H48O8SiNa 695.3016, found 695.3010. Benzyl

1 allene 2.43: H NMR (400 MHz, C6D6) δ 7.47 (s, 1 H), 7.43 (s, 1 H), 7.28 (d, J = 8.8 Hz,

1 H), 7.16-7.07 (m, 3 H), 5.33 (d, J = 1.5 Hz, 1 H), 5.21 (d, J = 1 Hz, 1 H), 5.08 (d, J = 1

Hz, 1 H), 4.88 (d, J = 10 Hz, 1 H), 4.78 (d, J = 10 Hz, 1 H), 4.73 (d, J = 11.5 Hz, 1 H),

4.73 (d, J = 11.5 Hz, 1 H), 4.36 (d, J = 9.2 Hz, 1 H), 3.80 (s, 6 H), 3.78 (s, 3 H), 3.61 (s, 3

H), 3.57 (s, 3 H), 2.11 (d, J = 1.6 Hz, 1 H), 1.14-1.12 (m, 21 H). HRMS (ESI) [M+Na]+

m/z calcd for C39H48O8SiNa 695.3016, found 695.3022.

O O O SnMe3 O OMe O O B B O MeO O MeO MeO OMe SnMe MeO SnMe3 3 O MeO OBn MeO OBn B O MeO OMe 2.47a 2.48a

96

Synthesis of compound 19a:33 To a solution of 1,3-dimethyl-2-(trimethylstannyl)-2-

bora-1,3-diazocyclopentane (29 mg, 0.11mmol) in benzene (0.8 mL) added

PdCl2.(PPh3)2 (1 mg) and the mixture was stirred at room temperature for 10 min and

was followed by addition of a solution of diynes 18a (26 mg, 0.05 mmol) in benzene (0.3

mL). After stirring the reaction mixture at rt for 6 h., a solution of pinacol (13 mg, 0.11

mmol) in benzene (0.2 mL). After 2 h, the reaction was quenched by the addition of Et3N

(0.02 mL) and the solvent was evaporated under reduced pressure to afford the crude

product, which was purified by silica gel chromatography using 10 % EtOAc/hexane as

the eluent to yield the compound 2.47a (3.8 mg, 0.004 mmol). Compound 2.47a: 1H

NMR (400 MHz, CDCl3) δ 7.29-7.21 (m, 5 H), 6.99 (s, 1 H), 6.79 (s, 1 H), 6.48 (t, J = 35

Hz, 1H), 5.97 (ABq, 2 H), 5.81 (s, 1 H), 4.79 4.33 (ABq, 2 H), 3.95 (s, 1 H), 3.89 (s, 3H),

3.85 (s, 3 H), 3.70 (s, 3 H), 3.55 (s, 3 H), 3.10 (s, 3 H), 1.18-1.13 (m, 12 H), 0.04-0.09

(m, SnCH3’s H).

1 Compound 2.48a: H NMR (500 MHz, CDCl3) δ 7.22-7.11 (m, 5 H), 6.54 (s, 1 H), 6.46

(s, 1 H), 6.17 (dd, J = 80.0, 1.0 Hz, 1 H), 6.11 (dd, J = 80.0, 1.0 Hz, 1 H), 5.86 (d, J = 1.5

Hz, 1 H), 5.71 (d, J = 1.5 Hz, 1 H), 4.70 (dd, J = 20.0, 1.0 Hz, 1 H), 4.35 (dd, J = 20.0,

1.0 Hz, 1 H), 4.10 (d, J = 10.5 Hz, 1 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 3.72 (s, 3 H), 3.70 (d,

97

J = 10.5 Hz, 1 H), 3.57 (s, 3 H), 2.82 (s, 3 H), 1.24-1.17 (m, 24 H), 0.14- −0.01 (m, 18

H). MS (ESI): m/z: 1134.3350 [M+Na]+.

O O O SnMe3 O OMOM O O B B O MeO O MeO MeO OMOM SnMe MeO SnMe3 3 O MeO OBn MeO OBn B O MeO OMe 2.47b 2.48b

Cyclized product 2.47b and di-addition product 2.48b:33 To a solution of 1,3- dimethyl-2-(trimethylstannyl)-2-bora-1,3-diazocyclopentane 1.37 (32 mg, 0.12 mmol) in

benzene (0.8 mL) added PdCl2(PPh3)2 (1 mg) and the mixture was stirred at room

temperature for 10 min and was followed by addition of a solution of the diyne 2.39b (26

mg, 0.05 mmol) in benzene (0.3 mL). After stirring the reaction mixture at room

temperature for 12 h, a solution of pinacol (16 mg, 0.12 mmol) in benzene (0.2 mL)

followed by p-TsOH (24 mg, 0.12 mmol) were added. After 2 h, the reaction was

quenched by the addition of Et3N (0.02 mL) and the solvent was evaporated under reduced pressure to afford the crude product, which was purified by silica gel chromatography using 10 % EtOAc/hexane as the eluent to yield compound 2.47b (14 mg, 35% yield) and compound 2.48b (20 mg, 35% yield). Compound 2.47b: [α]D – 62.5

1 (c 0.8, CHCl3). H NMR (500 MHz, CDCl3) δ 7.26-7.22 (m, 5 H), 6.95 (s, 1 H), 6.88 (s,

1 H), 6.37 (t, J = 35 Hz, 1 H), 5.98 (d, J = 1.0 H, 1 H), 5.97 (d, J = 1.0 Hz, 1 H), 5.91 (s,

1 H), 4.97 (d, J = 6.5 Hz, 1 H), 4.60 (s, 1 H), 4.61 (d, J = 6.5 Hz, 1 H), 4.32 (d, J = 11.0

Hz, 1 H), 4.24 (s, 1 H), 4.2 (d, J = 11.0 Hz, 1 H), 3.93 (s, 3 H), 3.83 (s, 3 H), 3.82 (s, 3

98

H), 3.51 (s, 3 H), 3.15 (s, 3 H), 1.16 (s, 6 H), 1.16 (s, 6 H), 0.05 (t, J = 22 Hz, 9 H). 13C

NMR (125 MHz, CDCl3) δ 164.63, 158.45, 154.32, 151.28, 149.89, 141.33, 140.31,

138.43, 137.84, 137.09, 135.83, 128.33, 128.03, 127.85, 127.53, 127.17, 120.93, 118.87,

103.18, 101.26, 99.27, 94.01, 83.17, 80.00, 74.98, 70.58, 61.27, 60.69, 59.92, 56.17,

55.43, 53.62, 31.13, 29.22, 29.58, 25.36, 24.99, 22.91, 14.32, 1.23. MS (ESI): m/z:

+ 1 875.2716 [M+Na] . Compound 2.48b: H NMR (500 MHz, C6D6) δ 7.27 (d, J = 7.5 Hz,

2 H), 7.16-7.04 (m, 4 H), 6.87 (s, 1 H), 6.67 (d, J = 8.5 Hz, 1 H), 6.63 (d, J = 8.5 Hz, 1

H), 5.25-5.18 (m, 4 H), 4.60 (d, J = 6.0 Hz, 1 H), 4.50 (d, J = 6.0 Hz, 1 H), 4.44 (d, J =

11.0 Hz, 1 H), 4.07 (d, J = 11.0 Hz, 1 H), 3.89 (s, 6 H), 3.70 (s, 3 H), 3.48 (s, 3 H), 3.16

(s, 3 H),1.13-1.06 (m, 24 H), 0.53-0.39 (m, 18 H). MS (ESI): m/z: 1163.3460 [M+Na]+.

O O O O O O O H SnMe3 O OTBS O O 0.82(s) CH3 B B MeO O MeO O MeO Si CH3 -0.17(s) MeO 4.85(d) O MeO OTBS MeO OTBS MeO H SnMe SnMe SnMe3 0.11(s) MeO SnMe3 3 3 4.92(s) O O O H MeO OBn MeO OBn B MeO OBn B MeO O B H O O Ph H H O OMe OMe OMe MeO 4.20(d) 6.09(s) 2.48c 2.49 2.47c 2.49

Cyclized product 2.47c, di-addition product 2.48c and mono-addition product 2.49:

To a solution of diyne 2.39c (100 mg, 0.159 mmol) and PdCl2(PPh3)2 (6 mg, 0.008 mmol) in benzene (4 mL) was added 1,3-dimethyl-2-(trimethylstannyl)-2-bora-1,3- diazocyclopentane 1.37 (62 mg, 0.239 mmol) and the mixture was stirred at room temperature for 18 hours. Then pinacol (47 mg, 0.4 mmol) was added and the mixture was diluted with CH2Cl2 (10 mL). The resulting mixture was stirred for 18 h. The solvent was evaporated under reduced pressure to afford the crude product, which was purified by flash column (EtOAc: hexanes = 1: 10) to yield the compound 2.47c (102 mg, 99

70% yield) as a white foam, compound 2.48c (15 mg, 10% yield) and compound 2.49 (19

1 mg, 10% yield). Compound 2.47c: [α]D -111.6 (c 0.095, CHCl3). H NMR (500 MHz,

C6D6) δ 7.38 (s, 1 H), 7.28 (d, J = 7 Hz, 2 H), 7.14-7.10 (m, 2 H), 7.04 (t, J = 7.5 Hz, 1

H), 6.91 (s, 1 H), 6.50 (s, 1 H), 5.23 (s, 1 H), 5.04 (s, 1 H), 5.21 (d, J = 1.5 Hz, 1 H), 4.73

(s, 1 H), 4.46 (d, J = 11.5 Hz, 1 H), 4.32 (d, J = 11.5 Hz, 1 H), 3.92 (s, 3 H), 3.85 (s, 3 H),

3.79 (s, 3 H), 3.25 (s, 3 H), 1.10 (s, 6 H), 1.07 (s, 6 H), 1.02 (s, 9 H), 0.30 (s, 9 H), 0.16

13 (s, 3 H), 0.04 (s, 3 H). C NMR (125 MHz, C6D6) δ163.66, 160.54, 155.05, 151.45,

150.03, 141.37, 140.93, 140.10, 138.50, 137.34, 135.25, 128.25, 127.41, 126.03, 120.51,

118.73, 102.66, 100.64, 99.35, 82.78, 79.71, 73.09, 70.59, 60.73, 60.21, 59.02, 54.95,

25.98, 25.91, 25.05, 24.60, 18.26, -4.52, -4.92, -7.10. IR (neat, cm–1): 2954, 2927, 2854,

1614, 1593, 1454, 1267, 1143, 1105, 1049, 920. HRMS (ESI) [M+Na]+ m/z calcd for

C45H63BO10SiSnNa 945.3204, found 945.3211. A sample was recrystallized from

CH2Cl2 and EtOH by slow diffusion of hexane to a concentrated solution at room

1 temperature. Compound 2.48c: H NMR (500 MHz, CDCl3) δ 7.25-7.16 (m, 3 H), 7.05

(d, J = 7.5 Hz, 2 H), 6.85 (s, 1 H), 6.43 (s, 1 H), 5.70 (d, J = 1.5 Hz, 1 H), 5.30 (d, J = 5.5

Hz, 1 H), 4.81 (s, 1 H), 4.42 (s, 1 H), 4.14 (d, J = 11.5 Hz, 1 H), 3.89 (s, 3 H), 3.84 (s, 3

H), 3.63 (s, 3 H), 3.49 (s, 3 H), 3.20 (d, J = 11.5 Hz, 1 H), 1.27 (s, 6 H), 1.24 (s, 6 H),

1.23 (s, 6 H), 1.22 (s, 6 H), 0.85 (s, 9 H), 0.23 (s, 9 H), 0.13 (s, 9 H), -0.09 (s, 3 H), -0.14

(s, 3 H). IR (neat, cm–1):2978, 2958, 2929, 2856, 1593, 1462, 1350, 1143, 1031. HRMS

+ (ESI) [M+Na] m/z calcd for C54H84B2O12SiSn2Na 1189.4102, found 1189.4110.

1 Compound 2.49: H NMR (500 MHz, CDCl3) δ 7.26-7.16 (m, 5 H), 6.98 (s, 1 H), 6.68 (s,

1 H), 6.09 (s, 1 H), 5.92 (d, J = 1 Hz, 1 H), 5.84 (d, J = 1 Hz, 1 H), 4.92 (s, 1 H), 4.85 (d,

100

J = 2 Hz, 1 H), 4.20 (d, J = 11.5 Hz, 1 H), 4.01 (d, J = 11.5 Hz, 1 H), 3.88 (s, 3 H), 3.84

(s, 3 H), 3.71 (s, 3 H), 3.65 (s, 3 H), 2.42 (d, J = 1.5 Hz, 1 H), 1.24 (s, 6 H), 1.21 (s, 6 H),

1 0.82 (s, 9 H), 0.10 (s, 9 H), -0.17 (s, 3 H), -0.23 (s, 3 H). H NMR (500 MHz, C6D6) δ

7.26 (s, 1H), 7.21-7.03 (m, 6 H), 5.79 (s, 1 H), 5.72 (s, 1 H), 5.39 (d, J = 2.5 Hz, 1 H),

5.35 (d, J = 2.5 Hz, 1 H), 5.32 (d, J = 1 Hz, 1 H), 5.25 (d, J = 1 Hz, 1 H), 5.12 (m, 3 H),

4.99 (s, 1 H), 4.75 (s, 1 H), 4.32 (d, J = 11.5 Hz, 1 H), 4.17 (d, J = 11.5 Hz, 1 H), 3.97 (s,

3 H), 3.87 (s, 3 H), 3.80 (s, 3 H), 3.36 (s, 3 H), 0.89 (s, 9 H), -0.09 (s, 3 H), -0.10 (s, 3 H).

IR (neat, cm–1):2954, 2927, 2855, 1643, 1634, 1076. HRMS (ESI) [M+Na]+ m/z calcd

for C45H63BO10SiSnNa 945.3204, found 945.3200.

O O

MeO MeO OMe

MeO OBn OMe

Compound 7’-epi-2.39a:33 Compound 7’-epi-2.39a was prepared from the compound

2.32a in 90 % yield following the procedure described for the synthesis of 2.39a: [α]D

1 +6.2 (c 0.8, CHCl3). H NMR (500 MHz, CDCl3) δ 7.25-7.18 (m, 6 H), 6.94 (s, 1 H),

5.97 (d, J = 1.5 Hz, 1 H), 5.96 (d, J = 1.5 Hz, 1 H), 4.90 (d, J = 2.0 Hz, 1 H), 4.56 (d, J =

11.5 Hz, 1 H), 4.43 (d, J = 2.0 Hz, 1 H), 4.28 (d, J = 11.5 Hz, 1 H), 3.93 (s, 3 H), 3.87 (s,

3 H), 3.72 (s, 3 H), 3.65 (s, 3 H), 3.20 (s, 3 H), 2.57 (d, J = 2.0 Hz, 1 H), 2.47 (d, J = 2.0

13 Hz, 1 H). C NMR (125 MHz, CDCl3) δ 153.57, 151.75, 149.39, 142.49, 141.55,

137.72, 136.61, 133.36, 131.74, 128.62, 128.31, 127.70, 122.29, 121.11, 107.51, 102.18,

101

101.36, 82.60, 81.74, 75.41, 75.34, 71.00, 70.39, 68.22, 60.98, 60.93, 59.52, 56.56, 56.16,

29.92. MS (ESI): m/z: 553.1749 [M+Na]+.

O O SnMe 3 O B MeO O MeO OMe SnMe3 O MeO OBn B O OMe

Compound 7’-epi-2.48a:33 Borostannylation of 7’-epi-2.39a using the procedure described for the borostannylation of 2.39a yielded the compound 7’-epi-2.48a as a major

1 product in 70% yield. H NMR (500 MHz, CDCl3) δ 7.25-7.16 (m, 5 H), 6.65 (s, 1 H),

6.64 (s, 1 H), 6.05 (dd, J = 80.0, 1.0 Hz, 1 H), 5.92 (d, J = 1.5 Hz, 1 H), 5,88 (d, J = 1.5

Hz, 1 H), 5.67 (dd, J = 80.0, 1.0 Hz, 1 H), 4.90 (dd, J = 20.0, 1.5 Hz, 1 H), 4.40 (dd, J =

20.0, 1.5 Hz, 1 H), 3.78 (dd, J = 19., 4.5 Hz, 2 H), 3.80 (s, 3 H), 3.76 (s, 3 H), 3.75 (s, 3

H), 3.58 (s, 3 H), 2.30 (s, 3 H), 1.22 (s, 6 H), 1.21 (s, 6 H), 1.18 (s, 6 H), 1.17 (s, 6 H),

0.1- −0.11 (m, 18 H). MS (ESI): m/z: 1134.3350 [M+Na]+.

O O

MeO MeO OMOM

MeO OBn OMe

Synthesis of compound 7’-epi-2.39b:33 Compound 7’-epi-2.39b was prepared from the

compound 7’-epi-2.32b in 90 % yield following the procedure described for the synthesis

1 of 2.32b: [α]D +11.6 (c 0.6, CHCl3). H NMR (500 MHz, CDCl3) δ 7.25-7.18 (m, 6 H), 102

6.98 (s, 1 H), 5.95 (s, 2 H), 4.91 (d, J = 2.0 Hz, 1 H), 4.81 (d, J = 6.5 Hz, 1 H), 4.79 (d, J

= 2.5 Hz, 1 H), 4.58 (d, J = 11.5 Hz, 1 H), 4.42 (d, J = 6.5 Hz, 1 H), 4.20 (d, J = 11.5 Hz,

1 H), 3.91 (s, 3 H), 3.85 (s, 3 H), 3.68 (s, 3 H), 3.21 (s, 3 H), 2.59 (d, J = 2.0 Hz, 1 H),

13 2.49 (d, J = 2.5 Hz, 1 H). C NMR (125 MHz, CDCl3) δ 153.51, 152.05, 149.45, 142.6,

141.65, 137.70, 136.42, 132.65, 131.57, 128.64, 128.32, 127.73, 122.32, 12.84, 107.75,

102.14, 101.34, 95.28, 82.28, 81.83, 76.07, 75.53, 71.20, 68.59, 66.0, 61.03, 60.87, 59.43,

56.36, 56.20, 53.64, 29.92, 14.34. MS (ESI): m/z: 583.1866 [M+Na]+.

O O SnMe 3 O B MeO O MeO OMOM SnMe3 O MeO OBn B O OMe

Synthesis of the compound 7’-epi-2.48b:33 Compound 7’-epi-2.48b was prepared from

the compound 7’-epi-2.39b in 85 % yield following the procedure described for the

1 synthesis of 2.48b: H NMR (500 MHz, C6D6) δ 7.33 (d, J = 7.5 Hz, 2 H), 7.28 (s, 1 H),

7.16-7.05 (m, 3 H), 6.93 (s, 1 H), 6.71 (d, J = 85 Hz, 1 H), 6.10 (d, J = 85 Hz, 1 H), 5.31

(s, 1 H), 5.26 (s, 1 H), 5.22 (s, 2 H), 4.71 (d, J = 6.0 Hz, 1 H), 4.66 (d, J = 6.0 Hz, 1 H),

4.49 (d, J = 11.0 Hz, 1 H), 4.32 (d, J = 11.0 Hz, 1 H), 3.91 (s, 3 H), 3.84 (s, 3 H), 3.74 (s,

3 H), 3.34 (s, 3 H), 3.25 (s, 3 H), 1.08 (s, 6 H), 1.07 (s, 6 H), 0.98 (s, 12 H), 0.49-0.29 (m,

18 H). MS (ESI): m/z: 1165.2950 [M+Na]+.

103

O

O OBn SnMe3

MeO O MeO B O MeO OTIPS MeO

Compound 2.53: Compound 2.53 was prepared from the allene 2.43 in 70 % yield

1 following the procedure described for the synthesis of 2.47c: H NMR (400 MHz, C6D6)

δ 7.44 (d, J = 7.6 Hz, 2 H), 7.41 (s, 1H), 7.25 (s, 1H), 7.20 (d, J = 7.6 Hz, 2 H), 7.07 (m,

1 H), 6.25 (s, 1 H), 5.39 (d, J = 1.2 Hz, 1 H), 5.25 (d, J = 1.2 Hz, 1 H), 5.24 (s, 1 H), 4.89

(d, J = 10 Hz, 1 H), 4.82 (d, J = 10 Hz, 1 H), 4.63 (s, 1 H), 3.90 (s, 1 H), 3.87 (s, 3 H),

3.83 (s, 1 H), 3.81 (s, 3 H), 3.62 (s, 3 H), 1.16-1.13 (m, 21 H), 0.98 (s, 6 H), 0.97 (s, 6 H),

1.02 (s, 9 H), 0.30 (s, 9 H), 0.16 (s, 3 H), 0.04 (s, 3 H). HRMS (ESI) [M+Na]+ m/z calcd

for C48H69BO10SiSnNa 987.3673, found 987.3670.

104

CHAPTER 3

Total Synthesis of Steganone via Multi-component Cyclization

3.1.0 Synthetic Approach to Steganone via a Multi-component Cyclization Strategy

Our synthetic strategy involves the preparation of the dipropargyl biphenyl 2.37,

which may undergo [B-Sn] reagent mediated cyclization to give the 1,2-bis-alkylidene

3.1. As the compound 3.1 already contains the correct number of carbon atoms in

steganone, proper oxidative protocols would be implemented to convert 3.1 to steganone.

The dipropargyl biphenyl 2.37 could be derived from the biphenyl oxazoline 2.20, the

axial chirality of which may be set via Meyers nucleophilic biaryl coupling strategy.37,38

O O O O O O N OBn O OBn [B-Sn] Reagent B N Mediated Cyclization O MeO MeO MeO O SnMe3 N MeO MeO B SnMe3 MeO OMe OMe N OMe (1.37) Steganone 3.1 2.37

O O O O O O Mg-mediated OBn OMe O O biaryl coupling O MeO O N O CHO O O or + MeO MeO MeO MeO O OH Br O N N OMe MeO MeO MeO 2.18 2.19 OMe OMe OMe 2.20 3.2 3.3

Figure 3.1 Synthetic Plan for Steganone 105

3.2 Attempted Enantioselective Synthesis of Steganone

3.2.1 Magnesium-Mediated Biphenyl Coupling Reactions between the Oxazoline

2.18 and Arylbromides

As described in section 2.3.0, of chapter 2, the magnesium mediated biaryl coupling between tetramethoxyl oxazoline 2.18 and phenyl bromide 2.19 proceeded with a high yield (85% based on oxazoline), albeit with poor diastereoselectivity (2.20a: 2.20b = 1 :

1.1). Based on a different oxazoline 3.4, Meyers reported a biphenyl coupling with good overall yield (74%) and high diastereoselectivity (7.2:1 in favor of the desired diastereomer 3.5a).3 Although the diastereoselectivity of this coupling reaction was

unsatisfactory, we decided to carry both diastereomers to the following transformations.

O O O O OMe O O Mg, BrCH CH Br, O O MeO O 2 2 O N THF, 80 0C, 18h O + O + MeO O MeO MeO O (85%) N O 2.20a:2.20b=1:1.1 N OMe Br MeO MeO OMe OMe 2.18 2.19 2.20a 2.20b

O O Ph O O O OMe O O O O Mg, BrCH2CH2Br, MeO THF, 80 0C, 18h O O N OMe Ph Ph O MeO O + MeO + MeO O (74% 3.5a) N N Br O 3.5a:3.5b=7.2:1 OMe MeO MeO MeO MeO OMe OMe 3.4 2.19 3.5a 3.5b

Scheme 3.1 Magnesium Mediated Biaryl Coupling Reactions

3.2.2 Hydrolysis of Biphenyl Acetals and Subsequent Nucleophilic Addition 106

3.2.2.1 Meyers’ Optimization of Hydrolysis Condition for the Acetal 3.5a

According to Meyers’ report,26c the biphenyl aldehyde 3.6a remained

atropisomerically stable at -5 ºC. It is known that an sp2 substituent (formyl group) ortho to the biphenyl linkage could result in the phenyl-phenyl bond free rotation at room or even lower temperature.39 The biphenyl acetal 3.5a was smoothly cleaved with 3 M HCl

in THF at room temperature to give two aldehydes (3.6a and 3.6b) in the ratio 7:1,

indicating that under this hydrolytic condition, atropisomerization (aryl-aryl bond

rotation) occurred. Repeating the hydrolysis (3 M HCl in THF) at 0 ºC gave these

aldehydes in a 15:l ratio. Finally, the cleavage of 3.5a to was performed at -5 ºC workup

carried out at 0 ºC, including solvent evaporation to afford exclusively 3.6a, whose 1H

NMR spectrum was taken immediately after isolation.

O O O O O O O atropisomerization 6 2 O hydrolysis condition 6 2 CHO 6 2 CHO Ph O Ph Ph MeO 2' 6' O MeO 2' 6' MeO 2' 6' O N N N MeO MeO MeO MeO MeO MeO OMe OMe OMe 3.5a 3.6a 3.6b

Entry Solvent Acid Temperature Conversion Ratioa

1 THF HCl (3 M) 23 ºC 100% 7:1

2 THF HCl (3 M) 0 ºC 100% 15:1

3 THF HCl (3 M) -5 ºC 100% 1:0b

a3.6a to 3.5a. bexclusive formation of 3.6a

Table 3.1 Meyers’ Optimization of Hydrolysis Conditions for the Acetal 3.5a

107

3.2.2.2 Hydrolysis of Biphenyl Acetals 2.20a and 2.20b and Subsequent Acetylide

Additions

We need to determine the appropriate temperature for the hydrolysis reaction,

which turned out to be nontrivial. Due to the structural difference between our substrates

and Meyers’, specifically, the absence of a phenyl group in the 6’-oxazoline ring of 2.22a

and 2.22b compared with 3.6a and 3.6b, it was anticipated the rotational barriers of 2.22a

and 2.22b would be somewhat lower than those of 3.6a and 3.6b. Biphenyl acetal 2.20b was tested first and at 0 ºC, it took 5 hours in THF for full conversion of the substrate, however, the 1H NMR spectrum of the crude product immediately taken after simple

workup showed the existence of two formyl hydrogen peaks, indicating that the

atropisomerization occurred (entry 1). At -10 ºC, even after a reaction time of 16 hours,

the reaction could only reach 80% conversion and again two aldehydes were detected

based on HNMR (entry 3). At -5 ºC, the reaction still could not proceed to completion

(entry 4). Thus it seemed that the reaction was too slow under low temperature and it

was reasoned that the effective [H+] was low due to the coordination of proton with the

solvent, THF. Then a 1:1 mixture (v/v) of THF and CH2Cl2 (a non-coordinating solvent), was tested for the acetal hydrolysis, and it proved to be rather effective. In fact, after one hour, about 70% conversion of the substrate was achieved (entry 5) and when 6 M HCl

solution was used, the reaction after 3 h reached 86% conversion.

108

O O O O O O O hydrolysis condition atropisomerization 6 2 O 6 2 CHO 6 2 CHO O O MeO 2' 6' MeO 2' 6' O MeO 2' 6' N N N MeO MeO MeO OMe OMe OMe 2.20b 2.22b 2.22a

Entry Solvent Acid Temperature Time Conversion 1 THF HCl (3 M) 0 ºC 5h 100% 2 THF HCl (3 M) -10 ºC 3.5h 50% 3 THF HCl (3 M) -10 ºC 16h 80% 4 THF HCl (3 M) -5 ºC 5h 75%

5 THF/CH2Cl2(1:1) HCl (3 M) -10 ºC 1h 70%

6 THF/CH2Cl2(1:1) HCl (6 M) -10 ºC 3h 86%

Table 3.2 Optimization of Hydrolysis Conditions on the Acetal 2.20b

Since the next step in the synthesis involved addition of lithium

trimethylsilylacetylide to the aldehyde(s) and the resulting secondary alcohol(s) should,

with its sp3 nature, be stable to bond rotation, a protocol was invoked which required that the immediately isolated aldehyde be rapidly treated with the nucleophile. However, after workup at 0 ºC when the crude product was subjected to lithium trimethylacetylide at -78 ºC, two diastereomeric alcohols (2.23a and 2.23b) were obtained and the diastereomeric ratios varied from batch to batch (i.e., d.r. = 1:3, 1:1, or 2:1). In one batch

(1.55 mmol substrate scale) 70% overall yield of 2.23a and 2.23b was obtained over two steps, and 14% biaryl acetal 2.20b was recovered. The diastereomeric ratio of the crude aldehydes determined by crude 1H NMR at room temperature may not accurately reflect

the real situation. The axial rotation barrier for 2.22b is lower than that of 2.22a and it 109

could atropisomerize to 2.22a at room temperature quickly. To our surprise, the

hydrolysis of 2.20a, the atropisomer of 2.20b, proved to be much faster under the same

reaction condition [THF/CH2Cl2 (1:1), HCl (3 M), -10 ºC]: just within one hour, the

reaction reached full conversion (Scheme 3.2).

O O O O O O O THF/CH Cl (1:1), atropisomerization 2 2 (very slow) 6 2 O HCl(3M), -10 0C,1h 6 2 CHO 6 2 CHO O MeO 2' 6' MeO 2' 6' O MeO 2' 6' O N N N MeO MeO MeO OMe OMe OMe 2.20a 2.22a 2.22b

Scheme 3.2 Hydrolysis of the Biaryl Oxazoline 2.20a

Even more surprisingly, after workup at 0 ºC the crude aldehyde 2.22a was treated

with lithium TMS acetylide at -78 ºC to give an alcohol 2.23a as a single diastereomer

with 83% overall yield over two steps. When we went back to examine the 1HNMR spectrums of the alcohols obtained from the hydrolysis of 2.20b and subsequent nucleophilic addition to the aldehyde, we found that 2.23a was one of these two diastereomers. We were fortunate to grow a crystal out of a mixture of two diastereomeric alcohols (2.23a and 2.23b) and its structure, as determined by X-ray crystallography, turned out to be 2.23b. According to all these information, the hydrolysis of 2.20a under this reaction condition gives the aldehyde 2.22a, which is configurationally stable at -10 ºC within one hour and the subsequent nucleophilic addition of the trimethylsilylacetylide to the formyl group is highly stereoselective to give the alcohol 2.23a as a single diastereomer (Scheme 3.3). 110

O O O O O O OH THF/CH2Cl2 (1:1), O HCl (3M), -10 0C,1h, O 0 LiC CTMS (S) then workup at 0 C (Ra) 6 2 CHO (Ra) O O (Ra) O TMS MeO MeO 2' 0 MeO 100% conversion 6' THF,-78 C N N 83% N MeO (S) MeO over two steps MeO (S) OMe OMe OMe 2.20a 2.22a 2.23a

O O O O O O THF/CH2Cl2 (1:1), O 0 HCl (3M), -10 C,1h, (S ) 0 a atropisomerization O then workup at 0 C 6 2 CHO (Ra) 6 2 CHO (Sa) O MeO MeO O O 70% conversion 2' 6' MeO 2' 6' N N N MeO (S) MeO MeO OMe OMe OMe 2.20b 2.22b 2.22a

LiC CTMS 51% over two steps LiC CTMS variable ratios of 16 to 15 THF,-78 0C THF,-78 0C

O O O OH O OH

(R) (S) (Sa) O TMS (Ra) O TMS MeO + MeO N N MeO (S) MeO (S) OMe OMe 2.23b 2.23a

Scheme 3.3 Hydrolysis of Biaryl Acetals 2.20a and 2.20b and Subsequent Acetylide

Additions

3.2.2.3 Mechanistic Consideration on the Atropisomerization between Biaryl

Aldehydes 2.22a and 2.22b

While the hydrolysis of 2.20b affords the aldehyde 2.22b first, which partially undergoes atropisomerization to 2.22a, and the additions of the trimethylsilylacetylide to the formyl group of 2.22a and 2.22b are highly stereoselective to give 2.23a and 2.23b, respectively. However, in this particular experiment, the hydrolysis last three hours. It is 111

not clear why there is such a difference. Two explanations may be provided for the

observation that under the same condition 2.20a only gives one aldehyde, while 2.20b

gives two products. The first explanation is that these two diastereomeric aldehydes, or

more precisely, the protonated forms of 2.22a and 2.22b have different aryl-aryl rotational barriers. Specifically, the rotational barrier of 2.22a is higher than that of

2.22b. Alternatively, atropisomerization could occur between 2.22a and 2.22b, not only

the 2-CHO substituent and 2’-OMe substituent should pass each other, but also the 6’-

oxazoline ring should pass 6-H (it can also be 6’-oxazoline passing over –CHO, even

though this is less likely on steric grounds). The latter could be energetically more

demanding for 2.22a than for 2.22b, stemming from the different orientation of the

isopropyl groups in the 6’-oxazoline and subsequently their different interactions with 6-

H. One possible scenario deals with intramolecular hydrogen bonding between the ‘O’ of

the carbonyl group, and the ‘H’ of the protonated oxazoline, resulting in the restricted

oxazoline rotation (Scheme 3.4) and therefore formation of a thermodynamically more

stable product. Therefore at -10 ºC 2.22b can atropisomerize to 2.22a immediately after

its formation while the reversal cannot occur or the process is very slow.

If the rotational barriers are the same or very close for 2.22a and 2.22b, a second

reason may explain: since 2.20b is more difficult to hydrolyze than 2.20a, after 1 h while

the hydrolysis of 2.20b is still proceeding, the hydrolyzed product 2.22b begins to

atropisomerize to 2.22a slowly. For 2.20a the hydrolysis is complete after one hour, so

little atropisomerization occurs. So we carried out a few experiments with 2.20b under

the same reaction condition with the hydrolysis step lasting only one hour. Eventually a 112

mixture of 2.23b and 2.23a (the ratio of 2.23b to 2.23a varied for different batches) was obtained. A typical experiment gave 2.23b and 2.23a in a 51% combined yield and 30%

2.20b was recovered. This could be well explained by the first rationale.

O O O O

6 2 CHO 6 2 CHO MeO 2' 6' O MeO 2' 6' O N N MeO H MeO H OMe OMe 2.22a 2.22b

O O O O

6 6 H H O + + O H N HN OMe H O MeO O H H OMe MeO OMe OMe

Scheme 3.4 Possible Rationale for the Atropisomerization of 2.22b to 2.22a

In other words, the Curtin-Hammett principle40 applies to this situation. The barrier

for hydrolysis of 2.20a is lower than that for atropisomerization and also lower than that

for hydrolysis of 2.20b.

3.2.3 Preparation of the Benzyl Bromide 3.10

The subsequent transformations would be protection of the hydroxyl group and

removal of the trimethylsilyl groups in 2.23a. At first, direct benzylation of alcohol

2.23a was attempted with BnBr and NaH in DME (dimethoxyethane) and some desilylated alcohol formed, so we decided to remove the TMS group before the 113

protection of the hydroxyl group. So the alcohol 2.23a was treated with TBAF in THF at room temperature to give the intermediate alkyne cleanly, which was used without further purification for the next step. Direct benzylation with BnBr and NaH in DMF afforded the biphenyl oxazoline 3.7 with 91% overall yield over two steps.

O O O 1. MeI, acetone, O OH O OBn 70 0C,18 h O OBn 1. TBAF, THF, r.t.,1 h 2. L-selectride, CH Cl ,0 0C, 2 h TMS H 2 2 H MeO O 2. BnBr, NaH, MeO O MeO CHO DMF, r.t., 2 h 3. SiO2, DCM, N N r.t. 18 h MeO (91%) MeO (90%) MeO OMe OMe OMe 2.23a 3.7 3.8

Scheme 3.5 Synthesis of Biaryl Aldehyde 3.8 from the Acetylide Addition Product 2.23a

The oxazoline ring opening of 3.7 began with the N-methylation of the oxazoline

ring using MeI in acetone. When the mixture was stirred at room temperature for 18

hours, very little conversion was achieved as monitored by TLC. Increasing the

temperature to 60 ºC and adding excess MeI did not significantly improve the conversion.

Considering the volatile nature of MeI (b.p. 40 ºC), we chose the sealed tube as the

reaction vessel and after 18 hours at 70 ºC the reaction reached full conversion. The resulting oxazolinium salt was reduced to the oxazolidine smoothly with L-selectride.

Original acidic ring opening of the oxazolidine with citric acid led to partial decomposition of the product, presumably because of the liability of the benzylic propargylic ether in the presence of acid. It was found that the slightly acidic silica gel could well serve to cleave the oxazolidine ring without detectable decomposition of the aldehyde product. The overall yield of this three-step sequence was 90%.

114

O O O O OBn O OBn O OBn

NaBH4, MeOH, r.t., 2 h Conditions H H H MeO CHO MeO MeO (88%) OH Br

MeO MeO MeO OMe OMe OMe 3.8 3.9 3.10

Scheme 3.6 Preparation of the Alcohol 3.9

Entry Reagents Result

1 CBr4, PPh3 Cyclized product 3.11, 60%

2 PBr3, Pyridine 20% bromide (significant amount of substrate decomposition)

3 MsCl, Et3N; then LiBr, DMF Mixture of bromide and chloride

4 Ms2O, Et3N; then LiBr, DMF 80% bromide 3.10

Table 3.3 Optimization of Bromination of the Alcohol 3.9

The aldehyde 3.8 was reduced to the corresponding alcohol 3.9 smoothly in 88%

yield. The bromination of the alcohol 3.9 turned out to be nontrivial. The common

protocol involving CBr4 and PPh3 was attempted first (entry 1) and a major product 3.11

was isolated (60%). To our surprise, there were no corresponding proton signals

belonging to the benzyl protection group in the 1HNMR spectrum of 3.11. It was reasoned that after the formation of triphenylphosphonium bromide, it could add either to the propargylic oxygen or the benzylic oxygen. In the former situation, due to the presence of a good leaving group at C7 and an adjacent nucleophile (the C7’-OH group), a

fast intramolecular SN2 reaction could occur to provide the ether 3.11. 115

Br O O Bn O H O OBn O O PPh3 O Br PPh 7 3 H H O MeO MeO MeO 7' OH OH MeO MeO MeO OMe OMe OMe 3.9 3.11 possible structure for major product from entry 1

Scheme 3.7 Proposed Mechanism for the Formation of the Ether 3.11

When the condition was switched to PBr3 and pyridine, we were able to isolate

desired bromide in 20% (entry 2). The majority of the mass balance was some

unidentified polar products, probably arising from decomposition of the acid-labile

starting material. Then a two-step sequence involving the sulfonation with MsCl

followed by displacement with LiBr was tested (entry 3), however, we obtained a mixture

of the bromide and related chloride, which could be formed during the first step as a

common side reaction for sulfonation when MsCl was used. Finally, by switching the

sulfonating reagent to Ms2O we were able to isolate the desired bromide 3.10 in 80% yield after two steps (entry 4).

3.2.4 Attempted Coupling Reactions between the Benzyl Bromide 3.10 and Various

Metallated Acetylides

The installation of the 6’-propargyl substituent turned out to be problematic (Table

3.4). Direct replacement of the bromide with nucleophilic lithium trimethylsilylacetylide in the presence of HMPA gave no conversion (entry 1). Stille coupling conditions were tested using tributyltin trimethylsilylacetylide, Pd2(dba)3 and various ligands such as 116

O O O OBn O OBn

2 coupling conditions 2 H H MeO 6' MeO 6' Br TMS MeO MeO OMe OMe 3.10 3.12

Entry Reaction condition Result 1 LiC≡CTMS, HMPA, DME, -78 ºC to r.t., 18 h No conversion

2 Bu3SnC≡CTMS, As3P (8 mol%), Pd2(dba)3 Partial conversion, (2 mol%), DME, 80 ºC, 15 h no desired product

3 Bu3SnC≡CTMS, trifuryl phosphine (8 mol%), Pd2(dba)3 Partial conversion, (2 mol%), DME, 80 ºC, 15 h no desired product

4 BrZnC≡CTMS, Pd(DPEphos)Cl2 40% conversion, (5 mol%), THF, r.t., 4 h 10% product 3.12

5 BrZnC≡CTMS, Pd(DPEphos)Cl2 80% conversion, (10 mol%), THF, 70 ºC, 18 h 15% product 3.12

6 (TMSC≡C)3In, Pd(DPEphos)Cl2 65% conversion, (5 mol%) THF, 70 ºC, 18 h no desired product

Table 3.4 Coupling Conditions between the Benzyl Bromide 3.10 and Metallated

Acetylides triphenylarsine or trifuryl phosphine, however, no desired coupling product was detected

(entry 2 and 3). Recently Negishi reported successful coupling between benzyl bromide and indium acetylide or in situ generated zinc acetylides using 1 mol% of

41 Pd(DPEphos)Cl2 as the catalyst. When zinc trimethylsilylacetylide and 5 mol% of

Pd(DPEphos)Cl2 were used at room temperature after 4 hours, small amount of desired

product 3.12 (10%) was obtained together with 60% bromide recovered (entry 4). With a 117

higher loading of the catalyst (10 mol%), higher temperature (70 ºC) and longer reaction

time (18 hours), only slightly improved yield (15%) of the coupling product 3.12 was obtained together with 20% recovered bromide and other unidentified byproducts (entry

5). Sarandeses described the reactions of (PhC≡C)3In and (TMSC≡C)3In with benzyl

bromide produce the corresponding benzylated alkynes in excellent yields in the presence

42 of 1 mol% of Pd(dppf)Cl2. The coupling of the bromide 3.10 and (TMSC≡C)3In, which is prepared in situ from LiC≡CTMS and InCl3, turned out to be unsuccessful with 65% conversion of the bromide to unidentified product (entry 6).

Based on the above experimental results, we reasoned that the terminal alkynyl group in the upper portion of the molecule may, to some extent, coordinate with the catalyst at certain stages of the coupling process and thus lead to the observed low yield even with a high catalyst loading (10 mol%). Or, the terminal triple bond itself may even be unstable under coupling conditions. We thus considered that the protection of the terminal triple bond with a bulky silyl group might effectively shield the triple bond from coordination with the catalyst and increase its stability.

3.2.5 Preparation of the Benzyl Bromide 3.17 and Attempted Coupling Reactions with Various Metallated Acetylides

We synthesized the TIPS bromide 3.17 from the oxazoline 2.20a following the same

sequence leading to the bromide 3.10 with similar overall yield (Scheme 3.8). Although

various metal acetylides (zinc, magnesium, tin and indium) were screened to react with

benzyl bromide 3.17, under certain coupling conditions either little or no conversion was

118

observed (Table 3.5, entry 1, 2 and 4). We believed that this indicates the expected

stability of the protected triple bond in the 2-propargyl substituent under these coupling

conditions. On the other hand, the increased steric hindrance due to the incorporation of

the bulky TIPS group may cause the coupling very difficult to occur. Surprisingly, Stille

coupling condition with a high catalyst loading (10 mol% of Pd(0) and 40 mol% ligand)

gave full conversion of the bromide 3.17, but none of desired product 3.18 was detected

(entry 3).

O O O O OH O 1. HCl(3M), THF/DCM(1:1), BnBr, NaH, DMF, O -10 0C,1h, then workup at 0 0C 0 0C to r.t., 2 h TIPS MeO O MeO O 2. LiC CTIPS (90%) N THF, -78 0C to r.t.,2 h N MeO MeO OMe (71% over two steps) OMe 2.20a 3.13

O O O OBn O OBn 1. MeI, acetone, 68 0C, 20 h NaBH4, MeOH, 2. L-selectride, DCM, 0 0 0C to r.t., 2 h 0 C to r.t., 2 h O TIPS TIPS MeO MeO CHO 3. SiO2, DCM, 18 h (90%) N (86%) MeO MeO OMe OMe 3.14 3.15

O O O OBn O OBn 0 1. Ms2O, Pyr, DCM, 0 C, 1 h 2 TIPS 2. LiBr, DMF, 18 h TIPS MeO MeO 6' OH Br (79%) MeO MeO OMe OMe 3.16 3.17

Scheme 3.8 Synthesis of the Biaryl Bromide 3.17 from the Biaryl Oxazoline 2.20a

119

O O O OBn O OBn coupling conditions 2 2 TIPS X TIPS MeO 6' MeO 6' Br TMS MeO MeO OMe OMe 3.17 3.18

Entry Reagents Result

1 BrZnC≡CTMS, Pd(DPEphos)Cl2 (10 mol%), Little conversion, THF, 70 ºC, 18 h no desired product 2 BrMgC≡CTMS, CuI (cat.), THF, 70 ºC, 6 h Little conversion, no desired product 3 Me3SnC≡CTMS, Ph3As (40 mol%), Full conversion, Pd2(dba)3 (10 mol%), DME, 80 ºC, 15 h no desired product 4 (TMSC≡C)3In, Pd(DPEphos)Cl2 (10 mol%), No conversion THF, 70 ºC, 20 h

Table 3.5 Coupling Conditions between Benzyl Bromide 3.17 and Metallated Acetylides

3.3 Racemic Synthesis of Steganone

3.3.1 Synthetic Plan for the Racemic Synthesis of Steganone

Due to the difficulty encountered installing the 6’-propargylic substituent from benzyl bromides 3.10 and 3.18, we decided to adopt a different route, in which the order of installing the 2- and 6’-propargyl substituents in the biphenyl system is reversed

(Figure 3.2). We planned to introduce the 2-propargyl substituent by an acetylide addition to the biphenyl aldehyde 2.24, which already bears a 6’-propargyl substituent.

The 6’-propargyl group in 2.24 could be accessed via a Stille coupling reaction of tin acetylide and the benzyl bromide 3.19, based on a recent successful example reported by our group involves a substrate very similar to 3.19. The related formyl alcohol 3.3 120 contains three ortho substituents and the 6’-hydoxylmethylene group is significantly less bulkier than an oxazoline, therefore 3.3 is unlikely to be configurationally stable at room temperature and should exist as racemates. The alcohol 3.3 could be easily prepared from the two diastereomeric biphenyl oxazolines 2.20a and 2.20b.

O O O O O OBn O O O O 6 2 2 CHO 2 CHO O MeO 2' 6' MeO 6' MeO 6' MeO O R TMS N MeO MeO MeO MeO OMe OMe OMe OMe 2.37 2.24 3.19 R=Br 2.20a & 2.20b 3.3 R=OH

Figure 3.2 Synthetic Plan for the diyne 2.37 from Oxazolines 2.20a and 2.20b

3.3.2 Synthesis of the Alcohol 3.3 from Biaryl Oxazolines 2.20a and 2.20b

The racemic synthesis of (±)-steganone then began with the oxazoline ring opening.

Using the same protocol used for the oxazoline ring opening of the substrate 3.7 (MeI as the methylating reagent in the first step), the sequence was suitable for small scale reactions (85% overall yield with 200 mg substrate). However, when scaled up using 1 g of the substrate, the first step (methylation) did not go to completion after 20 hours

(conversion was less than 50%) and significant amount of by-products were formed.

Then the more powerful methylation reagent methyl triflate (MeOTf) was tried and at room temperature full conversion was obtained within 2 to 3 hours together with the formation of small amount of by-products. In a 10 g scale (the substrate) experiment, the overall yield of the aldehyde was 80% from biaryl oxazolines 2.20a and 2.20b.

121

O O O O O 1)MeOTf, DCM, r.t , 2h O O 2)L-selectride, DCM, O 0 0C to r.t., 2h O O 1. NaBH4, MeOH, r.t., 2h CHO O MeO 3)SiO2, DCM, 18h MeO CHO MeO 2. HCl (3M), OH N (80%) THF/CH2Cl2(1:1), r.t., 1h MeO MeO (82%) MeO OMe OMe OMe 2.20a & 2.20b 3.20 3.3

Scheme 3.9 Synthesis of the Alcohol 3.3 from Biaryl Oxazolines 2.20a and 2.20b

A conventional method for the conversion of an alcohol to the corresponding

43 bromide uses PPh3 and CBr4. Another well-known protocol, the Corey-Fuchs reaction,

converts an aldehyde to a homologated terminal alkyne via a two-step sequence, the first

step of which involves the formation of vinyl dibromide from the aldehyde with PPh3 and

CBr4. As both hydroxyl and formyl groups are present in the substrate, some

complication may occur. When the alcohol 3.3 (1 eq.) and CBr4 (2 eq.) were mixed in

CH2Cl2 at 0 ºC, PPh3 (2 eq.) in CH2Cl2 solution was added dropwise. After 5 hours, TLC

showed full conversion of the starting material and significant amount of by-product

formation.

O O O O O O Br PPh3, CBr4, CHO CH2Cl2, r.t. CHO Br MeO MeO MeO OH (90%) Br Br

MeO MeO MeO OMe OMe OMe 3.3 3.19 3.21

Scheme 3.10 Synthesis of the Biaryl Aldehyde 3.19 from the Alcohol 3.3

122

The optimization of this reaction began with mixing CBr4 and PPh3 (both are 1.2 eq.) in CH2Cl2 for 30 min, followed by the dropwise addition of the alcohol 3.3 in a CH2Cl2

solution. After 10 h, although no dibromoolefin 3.21 was detected, the reaction did not

reach full conversion. Eventually, when 2 eq. CBr4 and PPh3 were tried, after stirring

overnight, full conversion of the substrate was achieved and the isolated yield of the

desired bromide was 90%. Flash column provided the bromide as a brown oil, which

became a solid upon storage. Due to the importance of the quality of the bromide 3.19

for the following coupling reaction with metallated trimethylsilylacetylide, a trituration

operation with diethyl ether was necessary to provide the pure bromide as a white

powder.

3.3.3 The Stille Coupling Reaction between the Benzyl Bromide 3.19 and

Trimethylstannyl trimethylsilylacetylene

We planned to install the requisite 6’-propargyl substituent via the Stille cross-

coupling reaction. With tributylstannyl trimethylsilylacetylene, Pd2(dba)3 and trifuryl phosphine as the reagents, it was observed that if this reaction proceeded smoothly, before the temperature reaches 70 ºC, the color should be light orange. As the temperature increased and refluxing was maintained, the mixture gradually became dark, which was a sign for the formation of palladium black and completion of the reaction.

But if some reagents or the solvent were not dry, the color became dark immediately once heating began. When some aged DME was used in one experiment, the solution became dark quickly upon heating. After 1 h at 80 ºC, TLC showed partial conversion of the

123

starting material together with the small amount of the product 2.24 and considerable

amount of the dialdehyde 3.22. Upon longer heating no further conversion was observed, and this clearly indicated complete decomposition of the Pd catalyst.

Subsequently we found that the aged DME contained considerable amount of water.

The color change implied that the water in the system participates in the formation of

dialdehyde (besides the influence of water, the quality of the bromide was also very

important, as the reaction did not reach full conversion (<50%) when the impure bromide

(isolated prior to trituration, a brown oil) was used. Utilizing completely dried bromide

and DME, this Stille coupling reaction gave a satisfactory 90% yield.

O O O O O O

CHO CHO CHO MeO MeO MeO CHO Br TMS MeO MeO MeO OMe OMe OMe 2.24 3.3 3.22

2.24 2.24 3.3 3.3 3.22 3.22

S.M. bromide is oil. The color S.M. bromide is dried (powder) Both S.M and DME are fully of solutionbecame dark upon but DME contains some water. dried. Color changedat 72 0C. heating. No conversion after 0 extended time. Color changed at 50 C.. TLC TLC showed full conversion showed the same result after after 1h at 80 0C. 1h and 3hrs.

Figure 3.3 Complication in the Stille Reaction and the Quality of the Reagents

124

O O O O Me3SnC CSiMe3 Pd2dba3, trifuryl phosphine 2 CHO DME, 80 0C 2 CHO MeO 6' MeO 6' Br (90%) TMS MeO MeO OMe OMe 3.3 2.24

Scheme 3.11 Synthesis of the Biphenyl Aldehyde 2.24 via a Stille Coupling Reaction

3.3.4 Synthesis of the Bistrimethylsilyl Alcohol 2.25

See Section 2.2.3.2 of Chapter 2 for details.

3.3.5 Benzylation of the Bistrimethylsilyl Alcohol 2.25 and Synthesis of Diyne 2.37

When completely dried starting material and DME were used, at the beginning of the reaction, and when the temperature was strictly maintained at 0 ºC, the reaction proceeded very slowly: after 4 hours only very small amount of product 3.23a was formed. The color of the solution was white. Then at elevated temperature (5 ºC for 1 h,

10 ºC for 1 h, 15 ºC for 1 h) TLC showed no further conversion. When aged DME was used for this reaction, once NaH was added, vigorous gas evolution was observed. This indicates that NaH reacts with water in the solvent, and at 0 ºC the color of the solution became yellow gradually. TLC showed that significant amount of allene formed. It was reasoned that it was NaOH, formed by NaH and water, instead of NaH (barely soluble in

DME at 0 ºC), that acts as the base in this reaction. Based on this rationale, optimization of the reaction condition was attempted by adding just one equivalent of water. The

125

O O O O OH O OBn O OBn

Benzylation conditions TMS TMS H MeO MeO MeO

TMS TMS TMS MeO MeO MeO OMe OMe OMe 2.25 3.23a 3.23b

O O O O OBn O OH O OH

H MeO TMS H • MeO MeO H TMS TMS MeO H MeO MeO OMe OMe OMe 2.38 2.25 (S.M.) 3.23c

Reaction condition: r.t, 3 eq. NaH, DME

1 h 1.5 h 2.5 h 3 h 3.5 h 5 h 8 h Overnight 3.23a 3.23b 2.38

2.25 3.23c

0 Reaction condition: 0 C, 5 eq. NaH, DME( one drop of H2O was added)

0.5 h 1 h 1.5 h 2 h 2.5 h 2.75 h 3 h 3.25 h 3.23a 3.23b 2.38

2.25 3.23c

Figure 3.4 Benzylation Condition for the Alcohol 2.25

NaOH generated in an appropriate concentration ensured the reaction to proceed in a reasonable rate that could be well monitored by TLC. 126

Under the optimized condition, the substrate 2.25 and benzyl bromide were dissolved

in DME at 0 ºC, to which NaH in paraffin oil was added. To this mixture was added one

equivalent of water and the color of the solution gradually became yellow. As monitored

by TLC, after 1 h the bistrimethylsilyl benzyl ether 3.23a and mono-trimethylsilyl

alcohol 3.23b formed. The color became yellow and the temperature need to be maintained at 0 ºC, as higher temperature led to the formation of significant amount of the allene 2.38. When no intermediate 3.23c existed, the reaction was quenched with sat. aq. NH4Cl solution. The crude mixture of 3.23a and 3.23b was treated with K2CO3 in

MeOH to give the desired diyne 2.37 (72%) and minor amount of allene 2.38 (8%)

(Scheme 3.12).

O O O O OH O OBn O OBn

1) NaH, BnBr, DME, 0 0C TMS H + H MeO MeO MeO • 2) K2CO3, MeOH,r.t. TMS H H MeO MeO MeO H OMe OMe OMe 2.25 2.37 (72%) 2.38 (8%)

Scheme 3.12 Synthesis of the Diyne 2.37 from the Alcohol 2.25

3.3.6 [B-Sn] Reagent Mediated Cyclization Reaction of the Diyne 2.37 and

Subsequent Conversion to the Diene 2.46

See Section 2.4.1 of Chapter 2 for details.

3.3.7 Attempted Hydroboration/Oxidation on the Boronate Ester 2.46

127

Until this stage the synthesis of steganone went well according to the original plans.

However, unexpected difficulties were encountered in the hydroboration of the dienyl

boronate ester 2.46. The original retrosynthetic strategy involved the hydroboration of

the diene followed by oxidation of the resulting borane under basic condition to give the

hydroxyl aldehyde or hemiacetal. When 3 equivalents of borane·THF complex was used,

all alkene was consumed after 4 hours, but after treated with H2O2/ aq. NaOH a mixture

of unidentified products were obtained with no desired alcohol or lactol was detected

(entry 1, Table 3.6). Then other hydroboration reagents such as 9-BBN and

catecholborane were tested, and, little or no conversion of the alkene was observed (entry

2 and 3), presumably due to steric reason.

O O O O O O OBn hydroboration OBn OBn conditions H2O2 BR2 NaOH O O OH MeO B MeO B MeO CHO O O MeO MeO MeO OMe OMe OMe 2.46

Entry Hydroboration Condition Result

1 BH3·THF (3 eq.), THF, r.t., 4 h Full conversion, then H2O2/NaOH, a mixture of unidentified products. 2 9-BBN (6 eq.), THF, 50 ºC, 24 h Little conversion of alkene (<10%) 3 Catecholborane (3 eq.) No conversion of alkene [cat. Rh(PPh3)3Cl], r.t., 24 h

Table 3.6 Hydroboration/Oxidation Conditions on the Dienyl Boronate Ester 2.46

3.3.8 A Novel Tandem Process Mediated by AD-mix to Form the α, β-Unsaturated

Lactone 3.24 128

An alternative oxidizing approach would be dihydroxylation. We envisioned that

Sharpless dihydroxylation protocol44 could be tested as AD-mix could not only serve to dihydroxylate the C8-exocyclic double bond, but also oxidize the C7 vinyl boronate ester

portion.

O O O O OBn OBn AD-mix-α O B O MeO t-BuOH/H O/THF( 1:1:1), MeO O 2 10 h O MeO MeO OMe OMe

2.46 (diene) 3.24 (lactone)

O O O O O O OBn OBnOH OBn CH3 + + O + OH MeO MeO MeO CHO COO K O MeO MeO MeO OMe OMe OMe 3.25 (enal) 3.26 (keto-lacto)l 3.27 [acid salt (proposed)]

Entry Dihydroxylation condition Result

a 1 Standard , t-BuOH/H2O (1:1), 36 h Lactone (20%), enal (13%)

2 Double, t-BuOH/H2O (1:1), 24 h lactone (33%)

3 Double, t-BuOH/H2O/THF( 1:1:1), 10 h lactone (50%), enal (12%), keto-lactol (14%)

4 Triple, t-BuOH/H2O/THF( 1:1:1), 7 h lactone (42%), enal (12%), keto-lactol (16%) aSee text for standard recipe. Table 3.7 Optimization of the Dihydroxylation Condition

129

Figure 3.5 The ORTEP Drawing of the Lactone 3.24

In our first attempt, the diene 2.46 was treated with AD-mix-α using the standard

Sharpless asymmetric dihydroxylation (SAD) recipe [0.4 mol% K2OsO2(OH)2, 1 mol%

PHAL ligand, 3 eq. K3Fe(CN)6, 3 eq. K2CO3 in a mixture of t-BuOH and H2O (v/v=1:1)].

It took about 36 h for the full conversion of the diene and two products were isolated.

One of them was identified as the α, β-unsaturated aldehyde 3.25 (13%), which was not

surprising as it is formed via a direct oxidization of the vinyl boronate ester. What indeed

is surprising is the structure of the second product (20%), which was confirmed as the α,

β-unsaturated lactone 3.24 by X-ray structure analysis of a crystal grown via the vapor diffusion method. We also observed some very polar byproduct (the bottom spot on the

TLC plate), which may derive from the decomposition of the lactone. In order to speed up the reaction, we decided to double the amount of the AD-mix-α. After full

consumption of the starting material for 24 h, a better yield (33%) of the desired lactone

3.24 was obtained along with lesser amount of the polar byproduct. It was observed that

the dienyl boronate ester is poorly soluble in the SAD solvent system [t-BuOH and H2O

(v/v = 1:1)], and it could well dissolve in THF. We envisioned that adding THF as a cosolvent may increase the reaction rate and result in less decomposed byproduct. To our 130

delight, changing the solvent system to a mixture of t-BuOH, H2O and THF (v/v/v =

1:1:1) led to a faster reaction (full conversion was achieved in 10 h) with 50% isolated yield of the lactone 3.24. We also separated a keto-lactol 3.26 as another byproduct.

Further increasing the amount of AD-mix-α to triple of the SAD recipe did shorten the reaction time to 7 h, however, only 42% yield of the lactone 3.24 was obtained.

Eventually under the optimized condition for this novel tandem process (doubled standard SAD recipe [0.8 mol% K2OsO2(OH)2, 2 mol% PHAL ligand, 6 eq. K3Fe(CN)6,

6 eq. K2CO3 in a mixture of t-BuOH/H2O/THF (1:1:1) for 10 hours at room temperature) the following ratio of products was obtained: lactone 3.24 (50%), enal 3.25 (12%) and keto-lactol 3.26 (14%).

3.3.9 Proposed Mechanism of this Novel Tandem Process Mediated by AD-Mix

Under basic condition the vinyl boronate ester was first oxidized to an enolate, which has two resonance forms: the anionic α, β-unsaturated aldehyde 3.29 and the terminal

alkene 3.28 (Scheme 3.13). The anion 3.29 would be protonated to afford the unsaturated

aldehyde 3.25. In the latter case, the terminal alkene could be protonated at the α-position

followed by dihydroxylation. The resulting dihydroxy-aldehyde cyclizes immediately to

form a five-membered lactol. In the presence of the oxidant [Fe (III) salt], the hydroxyl

lactol would be oxidized to a lactone 3.30, which then eliminates one molecule of water

in this basic medium to give the α, β-unsaturated lactone 3.24. This base-labile lactone

would partially hydrolyze to give the hydroxy-carboxylic acid 3.27, which is

subsequently oxidized to the aldehyde and then cyclizes under basic condition to furnish

131

the keto-lactol 3.26. It could be reasoned that with the original SAD recipe in t-BuOH and H2O, the rate of dihydroxylation of the intermediate alkene 3.28 is too slow, and the

long reaction time results in the decomposition of the base-labile lactone. Adding THF

as a cosolvent and doubling the amount of AD-mix significantly speed up the

dihydroxylaiton step and thus full conversion is achieved in a much shorter time, leading

to good isolated yield (50%) of the desired lactone 3.24.

O O O O O O OBn OBn OBn

O [O], HO- B MeO MeO MeO O O O MeO MeO MeO OMe OMe OMe 2.46 3.28 3.29 (diene) protonation

O O O O O O OBn OBn OBn OH OH CH3 OH O MeO MeO MeO CHO cyclization O followed by O MeO oxidation MeO MeO OMe OMe OMe 3.25 dehydration (enal, 12%) under basic condition

O O O O oxidation O partial lactone hydrolysis O OBn followed by OBn OBn under basic condition cyclization OH OH O MeO O MeO COOH MeO O O MeO MeO MeO OMe OMe OMe 3.27 3.26 3.24 [acid salt (proposed)] (lactone,50%) (keto-lactol, 14%, d.r.=2:1)

Scheme 3.13 Proposed Mechanism of this Novel Tandem Process Mediated by AD-Mix

132

3.3.10 Hydrogenation of the Unsaturated Lactone 3.24

The hydrogenation of the unsaturated lactone 3.24 was first tested with Pd/C. The

substrate is poorly soluble in EtOAc, MeOH or EtOH, and is soluble in THF and CH2Cl2.

Therefore we first chose a mixture of EtOAc and CH2Cl2, however, no reaction occurred

at room temperature under atmospheric hydrogen (Table 3.8, entry 1). Then when pure

THF was used as the solvent and the pressure of the hydrogen increased to 300 psi, 10%

conversion was observed (entry 2). Switching the solvent system to a mixture of THF

and EtOH proved to be ineffective (entry 3). Finally at elevated temperature (50 ºC) in

MeOH/ CH2Cl2 under hydrogen (500 psi) after 24 hours a major product was obtained with 95% yield (entry 4). Gratifyingly, we found that the 1H NMR and C13 NMR spectra

of the product matched those of isopicrosteganol, which is an intermediate synthesized by

Molander et al. in their synthesis of steganone.26i Both debenzylation and stereoselective reduction of the C-C double bond were achieved in this one-pot process. The stereoselectivity could arise from a directing effect of the free hydroxyl group after removal of the benzyl protection group in 3.24.

3.3.11 Completion of the Synthesis of Steganone

Following Molander’s procedure,26i we obtained steganone via an oxidation- epimerization sequence (PCC oxidation of isopicrosteganol to the corresponding ketone followed by NaOAc-induced epimerization of C8 chirality, 80% yield over two steps).

133

O O O O OBn OH hydrogenation conditions O O MeO MeO O O MeO MeO OMe OMe 3.24 isopicrosteganol

Entry Solvent Pressure (H2) Catalyst Temperature Result and time 1 EtOAc/ 1 atm 5% Pd/C r.t., 18 h No reaction CH2Cl2(5:1) 2 THF 300 psi 5% Pd/C r.t., 18 h 10% conversion 3 THF/EtOH (1:2) 300 psi 5% Pd/C r.t., 18 h No reaction

4 MeOH/CH2Cl2(2:1) 500 psi 5% Pd/C 50 ºC, 18 h 95%

Table 3.8 Optimization of Hydrogenation Conditions for the Substrate 3.24

O O O O OH O 1. Dess-Martin periodinane O O MeO 2. NaOAc, EtOH, 800C MeO O (80%) O MeO MeO OMe OMe Isopicrosteganol Steganone

Scheme 3.14 Completion of the Synthesis of Steganone

3.4 Conclusions

Our initial attempts to achieve an enantioselective synthesis of steganone were unsuccessful, as we were not able to synthesize the dipropargyl biphenyl by introducing the 6’-propargyl substituent to a substrate already bearing the 2-propargyl substituent.

134

The racemic synthesis of steganone was achieved via an alternative route, in which the crucial dipropargyl biphenyl was prepared in a reversed order for installing the 6’- propargyl substituent (introduced first) and the 2-propargyl substituent. The DBCOD skeleton of steganone was assembled by the [B-Sn] reagent mediated cyclization. A novel AD-mix mediated tandem process quickly led to the formation of the key lactone, which was converted to steganone after three steps. Thus isopicrosteganol and steganone was synthesized in nine steps and eleven steps respectively from a readily available biphenylaldehyde 3.3.

3.5 Experimental Section

3.5.1 General Methods

See Section 2.6.1 of chapter 2 for details.

3.5.2 Synthetic Procedures and Spectral Data

O O OBn

H MeO O N MeO OMe

Biphenyl oxazoline 3.7: To a stirred solution of the alcohol 2.23a (1.18 g, 2.25 mmol) in

THF (10 mL) was added TBAF (1 M in THF, 3.4 mL, 3.4 mmol) at 0 oC and stirring was continued at the same temperature for 2 h. The mixture was quenched with saturated aq.

NH4Cl solution. Ether extraction, drying with anhydrous MgSO4 and removal of the

135

solvent under vacuum gave an oil. To this oil was added BnBr (1.41 g, 9 mmol) and

DMF (10 mL) before the mixture was cooled to 0 oC. NaH (60%w/w, 360 mg, 9 mmol)

was added to the solution in one portion. Then the mixture was allowed to warm to room

temperature. After stirring for 18 h, the reaction was quenched with saturated aq. NH4Cl

solution. Ether extraction, washing with brine for three times, drying with anhydrous

MgSO4 and removal of the solvent under vacuum gave an oil, which was purified by silica gel chromatography using 30 % EtOAc/hexane as the eluent to yield the benzyl

1 ether 3.7 (1.11 g, 91% yield). H NMR (400 MHz, CDCl3) δ 7.33 (s, 1 H), 7.19-7.16 (m,

6 H), 6.58 (s, 1 H), 5.98 (s, 2 H), 4.87 (d, J = 2 Hz, 1 H), 4.41 (d, J = 16.8 Hz, 1 H), 4.38

(d, J = 16.8 Hz, 1 H), 3.99-3.98 (m, 1 H), 3.95 (s, 3 H), 3.84 (s, 3 H), 3.79-3.77 (m, 2 H),

1.37-1.34 (m, 1 H), 0.62 (d, J = 6.8 Hz, 3 H), 0.51 (d, J = 6.8 Hz, 3 H). 13C NMR (100

MHz, CDCl3) δ 163.29, 152.66, 151.54, 147.20, 146.97, 143.96, 138.08, 131.39, 129.63,

127.99, 127.76, 127.18, 126.88, 124.00, 110.04, 108.95, 107.75, 101.14, 82.88, 74.15,

72.54, 70.42, 69.87, 67.76, 60.89, 60.82, 56.12, 32.89, 18.82, 18.36. IR (neat, cm–1):

2987, 1480, 1359, 1275, 1260, 1105, 1038, 764, 750. HRMS (ESI) [M+H]+ calcd for

C28H36NO7Si 544.2330, found 544.2328.

136

Biphenyl aldehyde 3.8: A mixture of the oxazoline 3.7 (820 mg g, 1.51 mmol) and MeI

(2.14 g, 15.1 mmol) in acetone (5 mL) was stirred at 70 °C for 3 h in a sealed tube. After

removing the solvent, the resulting grey solid was dissolved in CH2Cl2 (20 mL). To this solution was added at 0°C L-Selectride (1 M in THF, 4.5 mL, 4.5 mmol). The mixture was stirred at 0 °C for 30 min, and then quenched with saturated aq. NH4Cl solution.

Ether extraction, drying with anhydrous MgSO4 and removal of the solvent under

vacuum gave an oil. To this oil was added CH2Cl2 (20 mL) and silica gel (10 g) were

added. The reaction mixture was vigorously stirred for 18 h at room temperature. After

removing the solvent under vacuum, the silica gel was loaded onto a column and column

chromatography (EtOAc : hexanes = 1: 5) affored the aldehyde 3.8 (625 mg, 90% yield)

1 as a yellow solid. H NMR (400 MHz, CDCl3) δ 9.49 (s, 1 H), 7.41 (s, 1 H), 7.24 (s, 1

H), 7.20-7.18 (m, 3 H), 7.07-7.05(m, 2 H), 6.61 (s, 1 H), 6.04 (d, J = 1.2 Hz, 1 H), 6.02

(d, J = 1.2 Hz, 1 H), 4.71 (d, J = 2 Hz, 1 H), 4.52 (d, J = 11.6 Hz, 1 H), 4.27 (d, J = 11.6

Hz, 1 H), 3.96 (s, 3 H), 3.91 (s, 3 H), 3.59 (3 H), 2.65 (d, J = 2 Hz, 1 H). 13C NMR (100

MHz, CDCl3) δ 190.79, 153.31, 150.77, 148.02, 147.65, 147.07, 136.57, 131.53, 131.16,

130.30, 128.63, 128.17, 127.72, 126.98, 126.25, 110.83, 108.83, 105.08, 101.64, 81.38,

76.09, 70.47, 67.31, 61.05, 61.00, 56.08. IR (neat, cm–1): 2922, 1682, 1586, 1479, 1388,

137

+ 1329, 1237, 1142, 1106, 1037. HRMS (ESI) [M+Na] calcd for C27H24O7Na 483.1414, found 483.1411.

Biphenyl alcohol 3.9: To a solution of the aldehyde 3.8 (540 mg, 1.17 mmol) in MeOH

(10 mL) at 0 °C was added NaBH4 (89 mg, 2.34 mmol) in one portion. After stirring at

the same temperature for 1 h, the reaction was quenched by the addition of aq. NH4Cl

(5.0 mL). The organic solvent was evaporated under reduced pressure to afford the crude

product, which was diluted with ethyl acetate and washed successively with water, brine

and dried over Na2SO4. The organic layer was evaporated under reduced pressure to afford the crude product which was purified by column chromatography on silica gel

(EtOAc : hexanes = 1: 3) to yield the benzyl alcohol 3.9 (475 mg, 88% yield) as a viscous

1 oil. H NMR (400 MHz, CDCl3) δ 7.42 (s, 1 H), 7.24-7.20 (m, 3 H), 7.14-7.12 (m, 2 H),

6.80 (s, 1 H), 6.56 (s, 1 H), 6.02 (s, 2 H), 4.80 (d, J = 2 Hz, 1 H), 4.64 (d, J = 11.2 Hz, 1

H), 4.33 (d, J = 11.2 Hz, 1 H), 4.25 (d, J = 11.6 Hz, 1 H), 4.13-4.08 (m, 1 H), 3.95 (s, 3

H), 3.81 (s, 3 H), 3.57 (s, 3 H), 2.69 (d, J = 2 Hz, 1 H), 2.48 (d, J = 6.8 Hz, 1 H). 13C

NMR (100 MHz, CDCl3) δ 153.23, 150.72, 147.88, 147.39, 141.19, 136.20, 135.86,

130.47, 129.50, 128.85, 128.22, 127.96, 124.98, 110.23, 109.04, 108.12, 101.48, 80.88,

76.89, 70.47, 67.47, 62.96, 60.92, 60.85, 55.97, 29.70. IR (neat, cm–1): 3283, 2933, 1597,

138

1480, 1462, 1403, 1331, 1235, 1142, 1106, 1038. HRMS (ESI) [M+Na]+ calcd for

C27H26O7Na 485.1571, found 485.1580.

Biphenyl bromide 3.10: To a solution of the alcohol 3.9 (165 mg, 0.36 mmol) and

pyridine (57 mg, 0.72 mmol) in CH2Cl2 (3 mL) was added Ms2O (93 mg, 0.54 mmol) at 0

°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. A solution of LiBr (310 mg, 3.6 mmol) in DMF (3 mL) was added to the mixture. After stirring for 18 h, the reaction was quenched with saturated aq. NaHCO3 solution. Ether extraction, washing with brine for three times, drying with anhydrous MgSO4 and

removal of the solvent under vacuum gave an oil, which was purified by silica gel

chromatography (EtOAc : hexanes = 1: 5) to afford the bromide 3.10 (151 mg, 80%

1 yield) as a yellow oil. H NMR (400 MHz, CDCl3) δ 7.39 (s, 1 H), 7.25-7.23 (m, 3 H),

7.13-7.11 (m, 2 H), 6.72 (s, 1 H), 6.67 (s, 1 H), 6.04-6.02 (m, 2 H), 4.70 (d, J = 2 Hz, 1

H), 4.61 (d, J = 11.2 Hz, 1 H), 4.21 (d, J = 11.2 Hz, 1 H), 3.95 (q, 2 H), 3.92 (s, 3 H),

13 3.86 (s, 3 H), 3.60 (s, 3 H), 2.62 (d, J = 2.4 Hz, 1 H). C NMR (100 MHz, CDCl3) δ

153.19, 151.01, 147.63, 147.55, 142.05, 137.16, 132.31, 130.79, 128.50, 128.39, 128.21,

127.73, 126.24, 110.36, 109.02, 108.54, 101.46, 81.57, 75.83, 70.60, 67.77, 60.96, 60.90,

56.00, 32.58. IR (neat, cm–1): 3282, 2932, 1400, 1335, 1237, 1038. HRMS (ESI)

+ [M+Na] calcd for C27H25BrNaO6 547.0727, found 547.0678. 139

O O OBn

H MeO

TMS MeO OMe

Benzyl ether 3.12: To a solution of lithium trimethylsilylacetylide (0.16 mL, 0.08 mmol,

0.5 M solution in THF, prepared from n-BuLi and trimethylsilylacetylene) was added

ZnBr2 (10 mg, 0.04 mmol) at 0 °C. The mixture was gradually warmed to room temperature and stirred for 30 min before the benzyl bromide 3.10 (20 mg, 0.038 mmol) and Pd(DPEphos)Cl2 (2.7 mg, 0.004 mmol) were added. The resulting mixture was

heated to reflux for 18 h, before the reaction was quenched with saturated aq. NH4Cl

solution. Ether extraction, washing with brine for three times, drying with anhydrous

MgSO4 and removal of the solvent under vacuum gave an oil, which was purified by silica gel chromatography (EtOAc : hexanes = 1: 5) to afford the benzyl ether 3.12 (3 mg,

1 15% yield) as a yellow solid. 3.12: H NMR (400 MHz, CDCl3) δ 7.37 (s, 1 H), 7.25-

7.22 (m, 3 H), 7.16-7.13 (m, 2 H), 6.99 (s, 1 H), 6.54 (s, 1 H), 6.00 (s, 1 H), 5.99 (s, 1 H),

4.67 (d, J = 2 Hz, 1 H), 4.59 (d, J = 11.2 Hz, 1 H), 4.28 (d, J = 11.2 Hz, 1 H), 3.94 (s, 3

H), 3.81 (s, 3 H), 3.59 (s, 3 H), 3.21 (s, 2 H), 2.61 (d, J = 2 Hz, 1 H), 0.19 (s, 9 H).

+ HRMS (ESI) [M+Na] calcd for C32H34O6SiNa 565.2023, found 565.2013.

140

O H O

O MeO

MeO OMe

Ether 3.11: To a mixture of CBr4 (43 mg, 0.13 mmol) and PPh3 (34 mg, 0.13 mmol) in a round-bottle flask was added CH2Cl2 (5 mL). After the solution was stirred for 30 min, a

solution of the alcohol 3.9 (50 mg, 0.108 mmol) in CH2Cl2 (2 mL) was added dropwise at

room temperature. The mixture was stirred for 2 hours and the reaction was quenched

with saturated aq. NaHCO3 solution. Ether extraction, washing with brine for three times, drying with anhydrous MgSO4 and removal of the solvent under vacuum gave an

oil, which was purified by silica gel chromatography (EtOAc : hexanes = 1: 5) to afford

1 the ether 3.11 (40 mg, 59% yield) as a yellow oil. H NMR (500 MHz, CDCl3) δ 7.47 (s,

1 H), 7.14 (s, 1 H), 6.74 (s, 1 H), 6.06 (s, 1 H), 6.04 (s, 1 H), 4.88 (d, J = 2.5 Hz, 1 H),

4.42 (d, J = 11.5 Hz, 1 H), 4.21 (d, J = 11.2 Hz, 1 H), 3.97 (d, J = 11 Hz, 1 H), 3.94 (s, 3

H), 3.91 (s, 3 H), 3.71 (s, 3 H), 2.71 (d, J = 2.5 Hz, 1 H). HRMS (ESI) [M+Na]+ calcd for C20H18O6Na 377.3431, found 377.3423.

Biphenyl alcohol 3.13: To a solution of the biaryl oxazoline 2.20a (400 mg, 0.82 mmol)

in 10 ml of THF/CH2Cl2 (v : v=1 : 1) at -10 ºC was added 3 M HCl solution (2.8 mL,8.2 141

mmol) dropwise. After stirring at this temperature for 1h, the temperature was allowed to

warm to 0 ºC and 1.12 mg (8.2 mmol) of solid K2CO3 was added by portion to quench

the reaction. Cold ether (0 ºC) was used for extraction and the combined organic phase

was dried over anhydrous MgSO4 at 0 ºC. After filtration and removal of the solvent

under vacuum at 0 ºC, the crude aldehyde as a yellow oil was used directly for the next

step without further purification. The crude aldehyde was redissolved in 10 mL THF at -

78 ºC. To this solution was added a solution of 8.2 mL (0.5 M, 4.1 mmol) of LiC≡CTIPS

in THF dropwise at -78 ºC. After stirring for 30 min at this temperature, the solution was

allowed to warm to room temperature before it was quenched with saturated aq. NH4Cl

solution. After ether extraction, drying with anhydrous MgSO4, filtration and removal of the solvent under vacuum, the crude product was obtained as a yellow oil. Flash column

(CH2Cl2) gave the alcohol 3.13 as a white foam (355 mg, 71% yield). [α]D 70.8 (c 0.6,

1 CHCl3). H NMR (400 MHz, CDCl3) δ 7.42 (s, 1 H), 7.03 (s, 1 H), 6.41 (s, 1 H), 5.98 (d,

J = 1.2 Hz, 1 H), 5.93 (d, J = 1.2 Hz, 1 H), 5.26 (s, 1 H), 4.27 (t, J = 9.2 Hz, 1 H), 4.00 (t,

J = 7.6 Hz, 1 H), 3.94 (s, 3 H), 3.93 (s, 3 H), 3.66 (3 H), 1.37-1.34 (m, 1 H), 1.05 (s, 21

13 H), 0.62 (d, J = 6.8 Hz, 3 H), 0.55 (d, J = 6.8 Hz, 3 H). C NMR (100 MHz, CDCl3) δ

152.97, 152.06, 147.65, 147.03, 135.40, 128.49, 127.98, 108.69, 108.28, 107.93, 107.76,

101.10, 85.52, 72.05, 70.20, 63.00, 60.97, 60.91, 56.19, 32.57, 18.60, 18.14, 17.70, 17.43,

12.29, 11.20. IR (neat, cm–1): 3432, 1650, 1480, 1366, 1275, 1150. HRMS (ESI)

+ [M+H] calcd for C34H48O7Si 610.3195, found 610.3192.

142

Biphenyl oxazoline 3.14: To a solution of the alcohol 3.13 (100 mg, 0.164 mmol) was added BnBr (103 mg, 0.66 mmol) and DMF (5 mL) before the mixture was cooled to 0

oC. NaH (60%w/w, 26 mg, 0.66 mmol) was added to the solution in one portion. Then

the mixture was allowed to warm to room temperature. After stirring for 18 h, the

reaction was quenched with saturated aq. NH4Cl solution. Ether extraction, washing with brine for three times, drying with anhydrous MgSO4 and removal of the solvent under vacuum gave an oil, which was purified by silica gel chromatography (EtOAc : hexanes

1 = 1: 5) to yield the benzyl ether 3.14 (103 mg, 90% yield). H NMR (400 MHz, CDCl3)

δ 7.35 (s, 1 H), 7.22 (s, 1 H), 7.17-7.12 (m, 1 H), 6.56 (s, 1 H), 5.99 (d, J = 1.2 Hz, 1 H),

5.98 (d, J = 1.2 Hz, 1 H), 4.83 (s, 1H), 4.57(d, J = 11.6 Hz, 1 H), 4.43(d, J = 11.6 Hz, 1

H), 3.95 (s, 3 H), 3.93-3.91 (m, 1 H), 3.84 (s, 3 H), 3.80-3.75 (m, 2 H), 3.50 (s, 3 H),

1.62-1.57 (m, 1 H), 1.07 (s, 21 H), 0.88 (d, J = 6.8 Hz, 3 H), 0.77 (d, J = 6.8 Hz, 3 H).

13 C NMR (100 MHz, CDCl3) δ 152.47, 151.32, 147.00, 146.86, 138.16, 131.56, 129.77,

127.90, 127.88, 127.21, 127.06, 109.97, 109.03, 108.35, 106.27, 101.06, 87.59, 72.34,

70.54, 69.59, 68.27, 60.88, 60.70, 56.12, 53.43, 32.87, 18.94, 18.63, 18.31, 11.25.

+ HRMS (ESI) [M+H] calcd for C41H54NO7Si 701.3742, found 701.3742.

143

Biphenyl aldehyde 3.15: The same procedure as the synthesis of 3.8 to give the aldehyde

1 3.15 (86% yield) as a yellow oil. H NMR (400 MHz, CDCl3) δ 9.49 (s, 1 H), 7.44 (s, 1

H), 7.24 (s, 1 H), 7.19-7.17 (m, 3 H), 7.07-7.04 (m, 2 H), 6.61 (s, 1 H), 6.05 (d, J = 1.2

Hz, 1 H), 6.01 (d, J = 1.2 Hz, 1 H), 4.71 (s, 1 H), 4.55 (d, J = 11.2 Hz, 1 H), 4.30 (d, J =

11.2 Hz, 1 H), 3.96 (s, 3 H), 3.91 (s, 3 H), 3.56 (s, 3 H), 1.10 (s, 21 H). 13C NMR (100

MHz, CDCl3) δ 190.90, 153.23, 150.78, 147.94, 147.55, 147.05, 136.72, 132.06, 131.40,

130.37, 128.81, 127.67, 126.23, 110.71, 108.97, 105.02, 104.77, 101.56, 89.64, 70.37,

+ 67.96, 60.98,60.93, 56.08, 18.64, 11.22. HRMS (ESI) [M+Na] calcd for C36H44O7NaSi

637.2749, found 639.2751.

Biphenyl alcohol 3.16: The same procedure as the synthesis of 3.9 to give the alcohol

1 3.16 (90% yield) as a light yellow solid. H NMR (400 MHz, CDCl3) δ 7.44 (s, 1 H),

7.23-7.18 (m, 3 H), 7.14-7.12 (m, 2 H), 6.81 (s, 1 H), 6.54 (s, 1 H), 6.02 (d, J = 1.2 Hz, 1

H), 6.00 (d, J = 1.2 Hz, 1 H), 4.83 (d, J = 2 Hz, 1 H), 4.67 (d, J = 11.2 Hz, 1 H), 4.38 (d,

J = 11.2 Hz, 1 H), 4.26 (d, J = 12 Hz, 1 H), 4.13-4.09 (m, 1 H), 3.95 (s, 3 H), 3.82 (s, 3 144

13 H), 3.57 (s, 3 H), 2.70 (d, J = 2 Hz, 1 H), 1.11 (s, 21 H). C NMR (100 MHz, CDCl3) δ

153.19, 150.77, 147.80, 147.34, 141.15, 136.33, 135.98, 130.96, 129.48, 128.97, 128.19,

127.94, 125.20, 110.17, 109.16, 108.23, 104.23, 101.42, 90.53, 70.30, 68.18, 62.97,

+ 60.85, 60.81, 55.96, 18.65, 11.23. HRMS (ESI) [M+Na] calcd for C36H46O7NaSi

641.2905, found 641.2903.

Biphenyl bromide 3.17: The same procedure as the synthesis of 3.10 to give the bromide

1 3.17 (79% yield) as a light yellow oil. H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.24-

7.23 (m, 3 H), 7.12-7.09 (m, 2 H), 6.72 (s, 1 H), 6.67 (s, 1 H), 6.03 (d, J = 1.2 Hz, 1 H),

6.02 (d, J = 1.2 Hz, 1 H), 4.72 (s, 1 H), 4.63 (d, J = 11.2 Hz, 1 H), 4.23 (d, J = 11.2 Hz, 1

H), 4.04 (d, J = 10 Hz, 1 H), 3.99 (d, J = 10 Hz, 1 H), 3.92 (s, 3 H), 3.86 (s, 3 H), 3.58 (s,

13 3 H), 1.10 (s, 21 H). C NMR (100 MHz, CDCl3) δ 153.09, 151.06, 147.540, 147.46,

142.02, 137.32, 132.47, 131.24, 128.57, 128.52, 128.19, 127.70, 126.49, 110.32, 109.00,

108.73, 105.01, 101.39, 89.35, 70.49, 68.49, 60.88, 60.85, 55.99, 32.77, 18.64, 18.63,

+ 11.23. HRMS (ESI) [M+Na] calcd for C36H45BrO6NaSi 705.2048, found 705.2043.

145

Biphenyl aldehyde 3.20: A mixture of oxazolines 2.20a and 2.20b (2.0 g, 4.1 mmol) and

MeOTf (1.36 g, 8.2 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 3 h.

To this solution was added at 0°C L-Selectride (1 M in THF, 12.3 mL, 12.3 mmol). The mixture was stirred at 0 °C for 30 min, and then quenched with saturated aq. NH4Cl

solution. Ether extraction, drying with anhydrous MgSO4 and removal of the solvent under vacuum gave an oil. To this oil was added CH2Cl2 (50 mL) and silica gel (10 g) were added. The reaction mixture was vigorously stirred for 18 h at room temperature.

After removing the solvent under vacuum, the silica gel was loaded onto a column and column chromatography (EtOAc : hexanes = 1: 5) affored the aldehyde 3.20 (1.32 g, 80% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.45 (s, 1 H), 7.33 (s, 1 H), 7.23

(s, 1 H), 6.66 (s, 1 H), 6.01 (d, J = 1.2 Hz, 1 H), 5.99 (d, J = 1.2 Hz, 1 H), 4.91 (s, 1 H),

4.10 (dd, J = 5.2 Hz, 7.2Hz, 1 H), 3.99 (s, 3 H), 3.96-3.91 (m, 1 H), 3.65-3.58 (m, 4 H),

3.42 (dt, J = 12Hz, 2.4 Hz, 1 H), 2.09-1.99 (m, 1 H), 1.25-1.18 (m, 1 H). 13C NMR (100

MHz, CDCl3) δ 190.93, 153.30, 151.19, 147.91, 147.54, 147.27, 132.28, 131.46, 130.33,

125.16, 110.44, 106.54, 104.53, 101.47, 99.69, 67.28, 66.97, 61.03, 60.95, 56.10, 29.68,

25.40. IR (neat, cm–1): 2938, 2855, 1686, 1587, 1481, 1414, 1323, 1258, 1243, 1142,

+ 1110, 1039, 764, 750. HRMS (ESI) [M+Na] calcd for C21H22O8Na 425.1207, found

425.1201.

146

Biphenyl aldehyde 3.3: To a solution of aldehyde 3.20 (450 mg, 1.12 mmol) in MeOH

(10 mL) was added NaBH4 (85 mg, 2.24 mmol) at 0 ºC. After removing the ice bath, the mixture was allowed to warm to room temperature and stirred for 1h. The reaction was quenched with sat. aq. NH4Cl solution. Ether extraction, drying with anhydrous MgSO4

and removal of the solvent under vacuum gave a crude oil. This oil was redissolved in

THF/CH2Cl2 (20 mL, v : v=1 : 1) at 0 ºC. To this solution was added 3 M HCl solution

(3.7 mL, 11.2 mmol) dropwise. After stirring at 0 ºC for 1 h, solid K2CO3 (1.55 g, 11.2

mmol) was added by portion to quench the reaction. Ether extraction, drying with

anhydrous MgSO4 and removal of the solvent under vacuum gave an oil. Purification by

flash column (EtOAc : Hexanes = 1: 2) gave the aldehyde 3.3 as a light yellow glassy

1 solid (317 mg, 82 % yield). H NMR (400 MHz, CDCl3) δ 9.49 (s, 1 H), 7.43 (s, 1 H),

6.92 (s, 1 H), 6.69 (s, 1 H), 6.09 (s, 2 H), 4.31 (dd, J = 12.8 Hz, 2 H), 3.92 (s, 3 H), 3.87

13 (s, 3 H), 3.615 (s, 3 H), 1.89 (br, 1 H). C NMR (100 MHz, CDCl3) δ 190.38, 153.81,

152.30, 151.39, 148.01, 141.29, 136.92, 135.05, 129.63, 122.60, 110.92, 106.94, 106.11,

102.15, 62.79, 60.95, 60.85, 56.07. IR (neat, cm–1): 3429, 2937, 1677, 1611, 1478, 1262,

+ 1139, 1104, 1036, 764, 750. HRMS (ESI) [M+Na] calcd for C18H18O7Na 369.0945,

found 369.0931.

147

Biphenyl bromide 3.19: To a solution of PPh3 (377 mg, 1.44 mmol) in CH2Cl2 (10 mL)

was added CBr4 (478 mg, 1.44 mmol) in one portion at room temperature. The mixture was stirred for 30 min and the color became yellow. To the resulting mixture was added a solution of the alcohol 3.3 (250 mg, 0.72 mmol) dropwise. The mixture was stirred for

12h. Purification by direct flash column (EtOAc : hexanes = 1: 3) gave a light yellow oil, which was further purified by trituration with Et2O to afford a white solid (276 mg, 94 %

1 yield). H NMR (400 MHz, CDCl3) δ 9.50 (s, 1 H), 7.49 (s, 1 H), 6.82 (s, 1 H), 6.77 (s, 1

H), 6.13(d, J = 1.2 Hz, 1 H), 6.11(d, J = 1.2 Hz, 1 H), 4.25 (d, J = 10.4 Hz, 1 H), 4.15 (d,

13 J = 10.4 Hz, 1 H), 3.93 (s, 3 H), 3.89 (s, 3 H), 3.62 (s, 3 H). C NMR(100 MHz, CDCl3)

δ 189.98, 153.88, 152.29, 151.66, 148.25, 142.34, 136.09, 131.69, 129.78, 124.47,

110.73, 109.21, 106.25, 102.22, 60.99, 60.85, 56.13, 31.74. IR (neat, cm–1): 3430, 3003,

2935, 2840, 1681, 1612, 1478, 1403, 1333, 1266, 764, 750. HRMS (ESI) [M+Na]+ calcd for C18H17BrO6Na 431.0101, found 431.0104.

148

Biphenyl aldehyde 2.24: To a stirred solution of the bromide 3.19 (860 mg, 2.11 mmol)

in DME (25 mL) at room temperature was added Pd2(dba)3·CHCl3 (39 mg, 0.04 mmol)

followed by tris-2-furylphosphine (39 mg, 0.02 mmol) and the reaction mixture was

stirred for 10 min until it became a clear yellow solution. Then

tributyltintrimethylsilylacetylene (845 mg, 2.18 mmol) in DME (3 mL) was added to the

reaction mixture and stirring was continued at 80 ºC for 1 h. Afterwards, the reaction

mixture was diluted with CH2Cl2 and washed with water, brine and dried over anhydrous

Na2SO4. The solvent was evaporated under reduced pressure to afford the crude product,

which was purified by silica gel column chromatography. Purification by flash column

(EtOAc : hexanes = 1: 5) gave the aldehyde 2.24 as a white solid (980 mg, 90 % yield).

1 H NMR (400 MHz, CDCl3) δ 9.49(s, 1 H), 7.46 (s, 1 H), 6.97 (s, 1 H), 6.67 (s, 1

H), 6.09 (t, J = 1.2 Hz, 1 H), 4.15 (d, J = 10.4 Hz, 1 H), 3.93 (s, 3 H), 3.88 (s, 3 H), 3.62

(s, 3 H), 3.28 (d, J = 19.2 Hz, 1 H), 3.13 (d, J = 19.2 Hz, 1 H), 0.14 (s, 9 H). 13C NMR

(100 MHz, CDCl3) δ 190.20, 153.60, 152.40, 151.53, 148.02 140. 74, 137.27, 130.63,

129.63, 123.14, 110.82, 107.85, 106.09, 103.55, 102.12, 87.67, 60.96, 60.48, 55.94,

24.85, -0.08. IR (neat, cm–1): 2958, 2850, 1682, 1613, 1478, 1403, 1242, 845. HRMS

+ (ESI) [M+Na] calcd for C23H26O6NaSi 449.1391, found 449.1380.

149

O O O O OBn O OBn O OH

TMS H H MeO MeO MeO

TMS TMS TMS MeO MeO MeO OMe OMe OMe 3.23a 3.23b 3.23c

Compounds 3.23a, 3.23b and 3.23c: these compounds were isolated during the two-step

sequences transforming alcohol 2.25 to diyne 2.37 (see Page 75). 2.23a: 1H NMR (400

MHz, CDCl3) δ 7.29 (s, 1 H), 7.27-7.23 (m, 5 H), 7.08 (s, 1 H), 6.54 (s, 1 H), 6.02 (d, J =

1.2 Hz, 1 H), 6.00 (d, J = 1.2 Hz, 1 H), 4.76 (s, 1 H), 4.54 (d, J = 11.2 Hz, 1 H), 4.38 (d, J

= 11.2 Hz, 1 H), 3.93 (s, 3 H), 3.79 (s, 3 H), 3.58 (s, 3 H), 3.34 (d, J = 20 Hz, 1 H), 3.23

(d, J = 20 Hz, 1 H), 0.18 (s, 9 H), 0.15 (s, 9 H). HRMS (ESI) [M+Na]+ calcd for

1 C35H42O6SiNa 637.2418, found 637.2426. 2.23b: H NMR (400 MHz, CDCl3) δ 7.31 (s,

1 H), 7.27-7.22 (m, 5 H), 7.03 (s, 1 H), 6.56 (s, 1 H), 6.01 (s, 2 H), 4.75 (d, J = 2 Hz, 1

H), 4.57 (d, J = 11.6 Hz, 1 H), 4.40 (d, J = 11.6 Hz, 1 H), 3.93 (s, 3 H), 3.80 (s, 3 H), 3.59

(s, 3 H), 3.25 (d, J = 1.6 Hz, 1 H), 2.53 (d, J = 2.4 Hz, 1 H), 0.17 (s, 9 H). HRMS (ESI)

+ 1 [M+Na] calcd for C32H34O6SiNa 565.2023, found 565.2029. 2.23c: H NMR (400 MHz,

CDCl3) δ 7.42 (s, 1 H), 7.09 (s, 1 H), 6.59 (s, 1 H), 6.03 (s, 2 H), 4.98 (d, J = 2.4 Hz, 1

H), 3.94 (s, 3 H), 3.88 (s, 3 H), 3.58 (s, 3 H), 3.43 (s, 1 H), 3.34 (d, J = 19.6 Hz, 1 H),

3.16 (d, J = 19.6 Hz, 1 H), 2.53 (d, J = 2.4 Hz, 1 H), 0.17 (s, 9 H). HRMS (ESI)

+ [M+Na] calcd for C25H28O6SiNa 475.1553, found 475.1548.

150

O O O O O O OBn OBn OBnOH CH3 O + + O MeO MeO CHO MeO O O MeO MeO MeO OMe OMe OMe 3.24 3.25 3.26

Lactone 3.24, aldehyde 3.25 and lactol 3.26: To a solution of the boronate ester 2.46

(50 mg, 0.0836 mmol) in t-BuOH/H2O/THF( 1mL:1mL:1mL) was added AD-mix- α

(230 mg). The mixture was stirred at room temperature of 10 h. Ether extraction, drying

with anhydrous MgSO4 and removal of the solvent under vacuum gave a crude oil.

Purification by flash column (EtOAc : Hexanes = 1: 3) gave the lactone 3.24 as a white

solid (21 mg, 50 % yield), the aldehyde 3.25 as a light yellow solid (5 mg, 12% yield)

and the lactol 3.26 as a white solid ( 6 mg, d.r. =2:1, 14% yield). Lactone 3.24: 1H NMR

(400 MHz, CDCl3) δ 7.22-7.12 (m, 5 H), 6.92 (s, 1 H), 6.67 (s, 1 H), 6.42 (s, 1 H), 5.98

(s, 1 H), 5.92 (s, 1 H), 5.00 (s, 1 H), 4.89 (s, 1 H), 4.78 (dd, J = 9.2 Hz, 18 Hz, 2 H), 4.49

(d, J = 11.6 Hz, 1 H), 4.10 (d, J = 11.6 Hz, 1 H), 3.83 (s, 3 H), 3.79 (s, 3 H), 3.63 (s, 3 H),

13 3.39 (s, 1 H), 2.75 (dd, J = 2.8 Hz, 15.2 Hz, 1 H). C NMR (100 MHz, CDCl3) δ 173.99,

162.16, 153.90, 150.30, 148.46, 146.88, 141.04, 136.93, 131.23, 129.26, 128.53, 128.31,

128.07, 127.76, 125.78, 125.26, 109.91, 108.11, 104.13, 101.47, 75.03, 70.90, 69.89,

61.00, 60.79, 56.02, 29.71,28.95. IR (neat, cm–1): 2922, 1752, 1274, 764. HRMS (ESI)

+ 1 [M+Na] calcd for C29H26O8Na 525.1525, found 525.1519. Aldehyde 3.25: H NMR

(500 MHz, CDCl3) δ 10.18 (s, 1 H), 7.30-7.20 (m, 5 H), 7.00 (s, 1 H), 6.90 (s, 1 H), 6.51

(s, 1 H), 6.06 (s, 1 H), 5.99 (s, 1 H), 4.89 (s, 1 H), 4.33 (d, J = 11 Hz, 1 H), 4.07 (d, J =

151

16 Hz, 1 H), 3.98 (d, J = 11 Hz, 1 H), 3.92 (s, 3 H), 3.85 (s, 3 H), 3.77 (s, 3H), 2.46 (s, 3

13 H), 2.42 (d, J = 16 Hz, 1 H). C NMR (125 MHz, CDCl3) δ 190.38, 160.76, 153.71,

149.73, 148.20, 146.52, 140.82, 137.85, 134.58, 132.30, 130.82, 129.61, 128.30, 127.59,

127.49, 126.50, 108.48, 105.02, 77.14, 70.30, 61.03, 60.80, 56.02, 29.81, 29.71, 13.16.

+ 1 HRMS (ESI) [M+Na] calcd for C29H28O7Na 511.1733, found 511.1725. Lactol 3.26: H

NMR (400 MHz, CDCl3) major isomer δ 7.32-7.26 (m, 5H), 7.06 (s, 1 H), 6.74 (s, 1 H),

6.51 (s, 1 H), 6.29 (s, 1 H), 6.08 (s, 1 H), 6.02 (s, 1 H), 5.12 (d, J = 3.6 Hz, 1 H), 4.89 (s,

1 H), 4.61 (d, J = 11.6 Hz, 1 H), 4.29 (d, J = 11.6 Hz, 1 H), 3.89 (s, 3 H), 3.86 (s, 3 H),

3.74 (s, 3H), 2.85 (m, 1 H), 2.42 (d, J = 16 Hz, 1 H). Minor isomer δ 7.32-7.26 (m, 5 H),

7.06 (s, 1 H), 6.77 (s, 1 H), 6.51 (s, 1 H), 6.16 (s, 1 H), 6.08 (s, 1 H), 6.02 (s, 1 H), 5.14

(d, J = 3.6 Hz, 1 H), 4.64 (d, J = 11.6 Hz, 1 H), 4.22 (d, J = 11.6 Hz, 1 H), 3.89 (s, 3 H),

+ 3.85 (s, 3 H), 3.69 (s, 3H), 2.82 (m, 1 H). HRMS (ESI) [M+Na] calcd for C29H26O9Na

514.1475, found 514.1484.

O O OH

O MeO O MeO OMe

Isopicrosteganol: To a solution of the lactone 3.24 (30 mg, 0.06 mmol) in

MeOH/CH2Cl2 (v:v = 2:1, 3 mL) was added 5% Pd/C (30 mg). The mixture was stirred

at 50 ºC under hydrogen (500 psi) for 18 h. A quick filtration of the mixture with Celite®

followed by removal of the solvent under vacuum provided the crude product, which

upon column chromatography separation afforded isopicrosteganol as a white solid (24 152

1 mg, 95% yield). H NMR (400 MHz, CDCl3) δ7.13 (s, 1 H), 7.00 (s, 1 H), 6.70 (s, 1 H),

6.03 (s, 1 H), 6.00 (s, 1 H), 4.75 (d, J = 9.6 Hz, 1 H), 4.36 (d, J = 11.2 Hz, 1 H), 4.26 (dd,

J = 6.8 Hz, 20 Hz, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.74 (s, 3 H), 3.11-3.03 (m, 2 H),

13 2.70 (dd, J = 9.6 Hz, 19.2 Hz, 1 H), 2.34 (m, 1 H). C NMR (100 MHz, CDCl3) δ

177.56, 149.98, 147.86, 146.54, 141.03, 136.14, 133.19, 128.20, 125.40, 111.47, 109.22,

105.05, 101.26, 68.61, 67.84, 61.15, 60.85, 55.98, 45.60, 42.69, 29.70, 29.29. IR (neat, cm–1): 3426, 1765, 1641, 1481, 1275, 764, 750. HRMS (ESI) [M+Na]+ calcd for

C22H22O8Na 437.1207, found 437.1208.

O O O

O MeO O MeO OMe

Steganone:26i To a mixture of the alcohol isopicrosteganol (24 mg, 0.058 mmol) and pyridine (46 mg, 0.58 mmol) in CH2Cl2 was added Dess-Martin periodinane (DMP, 49 mg, 0.116 mmol). The mixture was stirred for 18 h at room temperature and then diluted with CH2Cl2. The organic phase was washed with water, brine and dried over anhydrous

Na2SO4. After removal of the solvent, the crude ketone was dissolved in EtOH (3 mL).

To this solution was added NaOAc (14 mg, 0.174 mmol) and the resulting mixture was

heated to reflux. After 3 h, saturated aq. NH4Cl was added to quench the reaction. After

extracting with CH2Cl2, the organic phase was washed with water, brine and dried over anhydrous Na2SO4. The residue was subjected to purification by flash column (EtOAc :

1 hexanes = 1: 3) to give a white solid (19 mg, 80 % yield). H NMR (400 MHz, CDCl3) δ 153

7.53 (s, 1 H), 6.63 (s, 1 H), 6.53 (s, 1 H), 6.10 (d, J = 1.2 Hz, 1 H), 6.09 (d, J = 1.2 Hz, 1

H), 4.48 (t, J = 9.6 Hz, 1 H), 4.36 (m, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.60 (s, 3 H),

13 3.24-3.22 (m, 1 H), 3.14-3.07 (m, 1 H), 2.82-2.75 (m, 2 H). C NMR (100 MHz, CDCl3)

δ 195.16, 175.91, 154.01, 151.82, 151.41, 147.86, 133.45, 132.07, 131.49, 126.70,

112.57, 108.58, 107.43, 102.23, 66.93, 61.09, 61.04, 56.10, 49.82, 44.66, 30.20. IR (neat,

–1 + cm ): 3431, 1644, 1275, 1260, 764, 750. HRMS (ESI) [M+Na] calcd for C22H20O8Na

435.1056, found 435.1060.

154

CHAPTER 4

Conformation and Reactivity in Dibenzocyclooctadiene Derivatives. Total

Syntheses of Fully Substituted Dibenzocyclooctadiene Lignans

4.1 Synthetic Plan towards Fully Substituted DBCOD Lignans from Bisalkylidene cyclooctadiene 2.47c

An examination of the structures of fully substituted dibenzocyclootadiene lignans and that of the cyclization product 2.47c (Section 2.7.0 of Chapter 2) reveals that 2.47c

bears the required C-C bonds at C7 and C8 and the C-O bonds at C6 and C9 (Figure 4.1).

The challenge in front of us became how to establish the relative configurations at C6~C9

through proper functional group transformations.

We envisioned that the establishment of C7 and C8 configuration could be achieved

stereoselectively employing appropriate reducing condition (Figure 4.2). Based on the

X-ray structure of the bisalkylidene 2.47c, its twist-boat-chair conformation and the

orientation of protection groups (t-butyldimethylsilyl and benzyl groups) may render

certain transformations to proceed with desired stereochemical outcome. Following the

correct installation of C7 and C8 configurations, the introduction of C7-hydroxyl at the appropriate time would be necessary for the syntheses of this type of DBCOD lignans.

In order to access DBCOD lignans 4.1 and 4.2 with correct C9 and C6 configurations,

155 either Mitsunobu reactions45 (with inversion of configuration) or oxidation-reduction sequences could be utilized.

O O O O

O OAc O OR1 O OAc O OR1 9 9 9 9 MeO 8 MeO 8 MeO 8 MeO 8 MeO 7 MeO 7 MeO 7 MeO 7 6 6 6 6 OH MeO MeO MeO MeO O OH OR OR2 MeO MeO MeO MeO

Kadsuralignan B R1=R2=Ac Ananolignan C R1=H Interiotherin C R=Ang Ananolignan B Tiegusanin D R1=R2=Bz Ananolignan D R1=Ac Ananolignan F R=Ac Schizanrin F R1=Ac R2=Bz how to establish the relative configurations at C6~C9

O O OTBS O 2.47c bears the required 9 B O MeO 8 C-C bonds at C7 and C8 7 MeO SnMe and C-O bonds at C6 and C9 6 3 MeO OBn MeO 2.47c

Figure 4.1 Comparison of the Structures of Fully Substituted DBCODs with that of 2.47c

O O

O OAc O OR1 9 9 MeO 8 MeO 8 7 7 MeO 6 MeO 6 MeO MeO OR OR2 MeO MeO O inversion of C6 and 4.1 C9 configurations reduction of C=C bonds O OTBS O via Mitsunobu reactions at C and C 7 8 9 B O MeO 8 MeO 7 or via introduction of 6 SnMe3 oxidation-reduction the C7-OH group MeO OBn O sequences O at proper timing MeO O OR1 O OR1 2.47c 9 9 MeO 8 MeO 8 MeO 7 MeO 7 6 OH 6 OH MeO MeO OR2 OR2 MeO MeO 4.2

Figure 4.2 Synthetic Plans to Convert 2.47c to Fully Substituted DBCOD Lignans 156

4.2 Derivatization of Bisalkylidene cyclooctadiene 2.47c

We have reported a myriad of ways of functionalizing the bisalkylidene derivatives

such as 2.47c, including protio- and bromodestannylation, directed hydrogenation, and

direct oxidation with basic hydrogen peroxide (to give an α, β-unsaturated aldehyde).13,14

Most disappointingly, none of these procedures allowed facile conversion of these

adducts into useful precursors for the projected synthesis.

O O O OTBS O O OTBS B O NaOH, H O MeO 2 2 MeO MeO SnMe or MeO 3 CHO Me3N=O MeO OBn reflux MeO MeO 2.47c MeO 4.5 destannylation base induced and C-B oxidation debenzyloxygenation (slow) (fast) O O O H O H SiR3 SiR3 H O base-induced O MeO Base H isomerization MeO H H H MeO (fast) MeO OBnCHO OBnCHO

MeO H MeO H OMe OMe 4.3 4.4

Scheme 4.1 Synthesis of α, β-Unsaturated Aldehyde 4.5

When the 7,8-bis-alkylidenedibenzocyclooctadiene 2.47c was subjected to basic

hydrogen peroxide solution, a major product 4.5 was formed (Scheme 4.1). Originally

based on the previous result13 of this reaction with a similar substrate, the expected

product from this transformation should be α, β-unsaturated aldehyde 4.4. However, to

our surprise, in the 1H NMR spectrum of the major product the peaks of the benzyl protection group were missing. Based on the two diagnostic terminal vinyl hydrogen peaks of this product, among other peaks, its structure was confirmed as a 1,3-diene 4.5. 157

The possible mechanistic pathway (Scheme 4.1) involves initial formation of unconjugated aldehyde 4.3 via destannylation and C-B oxidation, and subsequent isomerization to the α, β -unsaturated aldehyde 4.4. Due to the twist-boat-chair conformation of this compound, a base-induced elimination of BnOH proceeds from a

W-shaped conformation leading to the observed 1, 3-diene 4.5. Switching to another oxydeborylation condition (Me3N=O, which is less basic, in refluxing THF) also provided the diene 4.5 as the exclusive product, indicating the ease of debenzyloxylation on the intermediate 4.4.

We also screened methods for removing the dioxaborolane ring. Both destannylation and deborylation could be achieved simultaneously by simply mixing the substrate with acetic acid at reflux for 18 h (Scheme 4.2). This one-pot process gave a diene 4.6 with an impressive 92% yield. It is worth mentioning that, although decorated with two highly sensitive functionalities such as the benzylic-allylic silyl and benzylic-allylic benzyl

O O O O O OTBS O O OTBS O HOAc, reflux, 6h Si B O MeO Bn H MeO 9 8 MeO O (92%) MeO H MeO 7 MeO 6 SnMe3 MeO OBn MeO OBn MeO MeO MeO 2.47c 4.6 OMe steric directed reduction Pd/C, H2 (230 psi), of C=C bond THF, 50 0C, 6h O O O O O O OTBS hydroxyl group directed O O reduction of C=C bond Si debenzylation Si H MeO 9 8 MeO H H MeO Bn O O MeO 6 7 (88% MeO H MeO H +11% C epimer) MeO OH 7 MeO MeO MeO OMe OMe 4.9 4.8 4.7

Scheme 4.2 Synthesis of the Alcohol 4.9 from the Cyclization Products 2.47c 158

ethers, the product could survive in acetic acid at 120 ºC after 10 h. We reason that the

special architecture of the twist-boat-chair conformation of the diene should be

responsible for its uncommon stability under this harsh condition. That is, the C6-OBn bond has a small dihedral angle both with the lower phenyl ring and C7-exocyclic double bond, and similarly C9-OTBS bond has a small dihedral angle both with the upper phenyl

ring and C8-exocyclic double bond. In other words, the C6-O and C9-O bonds are not in

alignment with the p-orbitals of the phenyl rings or the C-C double bonds for facile

ionization. Despite the structural difference between 2.47c and the diene 4.6, the X-ray

structure of 2.47c may still provide some useful information as supporting evidence, as

the dihedral angle between the C6-OBn bond and its adjacent phenyl ring is 33º, while that between C9-OTBS bond and related phenyl ring is 36º. At the same time, the dihedral angle between the C6-OBn bond and C7-exocyclic double bond is 15º, and that

between the C9-OTBS bond and C8-exocyclic double bond is 29º.

Hydrogenation of diene 4.6 with Pd/C in THF gave two saturated diastereomeric alcohols (d.r. =8:1, 99%) in favor of 4.9, in which the configurations of C7 (S) and C8 (S) match those in ananolignans and intertherin C (Figure 1). This particular hydrogenation reaction deserves further discussion, as it achieved reduction of two C=C bond and debenzylation in one pot with high stereoselectivity. With the help of Dreiding models and X-ray structures of related molecules, we proposed one possible pathway for this reaction. First, hydrogenation of the more exposed C8-exocyclic double-bond occurs from the β-face (top) as the bulky t-butyldimethylsilyl group completely blocked the α- face (bottom). The pseudo-equatorial C8-methyl group could partially block the α-face of 159

C7-exocyclic double bond, and this bond is also reduced from the β-face. The removal of

the protecting C6-benzyl group occurs sometime during these events, and, if it happens before the second hydrogenation, the resulting allylic alcohol could benefit from the –OH group directing the hydrogenation from the β-face (see structure 4.8 in Scheme 4.2).

4.3 Inversion of C6 and C9 Chirality via Mitsunobu Reactions

Upon inspection of the structures of ananolignan F,23z interiotherin C,23j

kadsuralignan B,23e tiegusanin D,23y schizanrin F23aa and the potential precursor, the dibenzocyclooctadiene 4.9, it is obvious that the configuration of C6 and C9 need to be

inverted in order to transform 4.9 to these natural products (Figure 4.3). At the first

glance, this issue could be resolved directly via Mitsunobu reactions45 from corresponding alcohols (installation of the C7-tertiary-OH for kadsuralignan B at a proper

stage would be necessary).

O O O OR O OTBS

MeO 9 MeO 9 MeO 6 MeO 6 first O MeO OR' second MeO OR' Mitsunobu Mitsunobu O OTBS MeO Ananolignan F R=R'=Ac MeO reaction 4.10 reaction MeO 9 interiotherin C R=Ac, R'=Ang MeO O O 6 O OR O OTBS MeO OH 9 9 MeO MeO MeO 4.9 MeO 6 6 OH MeO OH MeO OR' MeO OR' MeO kadsuralignan B R=R'=Ac MeO Tiegusanin D R=R'=Bz 4.11 Schizanrin F R=Ac, R'=Bz

Figure 4.3 Proposed Inversion of Configuration at C6 and C9 in the Alcohol 4.9 via

Mitsunobu Reactions 160

4.3.1 Unsuccessful Mitsunobu Reactions

Fluoride-induced desilylation of 4.9 turned out to be extremely slow as upon

treatment with TBAF, even after refluxing in THF for two days, the full conversion of 4.9

could not be achieved. Fortunately, acid-induced removal of TBS group with 3M HCl in

MeOH cleanly gave diol 4.12 after 18 h at room temperature (Scheme 4.3). Again, the stability of this double-benzylic alcohol under strong acidic condition is quite impressive.

The synthesis of another substrate 4.13 for the Mitsunobu reaction is described in Section

4.5.0 of Chapter 4.

O O O OTBS O OH

MeO HCl, MeOH MeO MeO (98%) MeO MeO OH MeO OH MeO MeO 4.9 4.12

Scheme 4.3 Synthesis of Substrates 4.12 for Mitsunobu Reaction from Alcohol 4.9

When these alcohols (4.9, 4.12 and 4.13, see Scheme 4.4) were subjected to common

Mitsunobu reaction conditions (acetic acid or angelic acid as the nucleophile, PPh3,

DEAD and THF as the solvent for 24 h or 48 h), to our disappointment, very little to no

conversions of the starting materials were observed (Scheme 4.4).

4.3.2 Successful Mitsunobu Reactions

161

O O O O O O OH O OTBS Angelic acid, OTBS AcOH, O OAc PPh , DEAD MeO 3 MeO MeO PPh3, DEAD MeO X X MeO MeO MeO MeO

MeO OH MeO OR MeO OH MeO OAc MeO MeO MeO MeO 4.9 4.12

O O O O O O AcOH, PPh , DEAD MeO 3 MeO MeO X MeO or MeO OH angelic acid, MeO OR PPh , DEAD MeO 3 MeO 4.13

Scheme 4.4 Unsuccessful Mitsunobu Reactions

It is known that the acidity of the nucleophiles could be crucial for successful

Mitsunobu reactions and in many occasions, p-nitrobenzoic acid serves as a good nucleophile.46 Thus we tried the particular nucleophile for this substrate and it gave a very clean reaction with full conversion. After separation of the product (4.15) by chromatography, we identified its structure first by 1H NMR and mass spectra as a p- nitrobenzoate. After DIBAL-H reduction of this compound to the corresponding alcohol

4.16, mass spectrum showed it has the same molecular weight as that of 4.9, but its 1H

NMR spectrum was different from that of 4.9, therefore the structure of 4.16 was confirmed as arising from inversion of configuration at C6. Models support the

contention that the formation of oxophosphonium as a good leaving group at C6, and the

nucleophilic attack on the back side (β) of C6-O bond, are not hampered by steric constraints (Scheme 4.5).

162

O O O O TBS OTBS DEAD, PPh , 3 O p-NO -BzOH MeO CH MeO 2 Nu: 3 MeO MeO 95% O CH3 MeO OH +PPh3 MeO MeO OMe

4.9 4.14

O O O OTBS O OTBS

MeO DIBAL-H MeO MeO MeO

MeO OH MeO O MeO MeO O

NO2 4.16 4.15

Scheme 4.5 Inversion of the C6 Configuration Using p-Nitrobenzoic Acid as the

Nucleophile in a Mitsunobu Reaction

Encouraged by this result, we considered a double Mitsunobu reaction of the diol

4.12 (Scheme 4.6). In order to synthesize ananolignan F, we need to invert the C6 and C9

chirality in the alcohol 4.12. A one-pot double Mitsunobu reaction seemed to be the

optimal strategy. However, when the diol 4.12 was subject to the same reaction condition used to convert alcohol 4.9 to p-nitro-benzoate 4.15, we were only able to

isolate the desired di-p-nitrobenzoate 4.18 in a disappointing 10% yield even after

extended time. The major product from this reaction was mono-p-nitrobenzoate 4.17, in which the configuration of C6 alone was inverted. The facile inversion of C6 chirality is easily explained as discussed earlier (Scheme 4.5). Model of 4.12, shows that the

163

difficulty of inverting the C9 chirality could be due to the existence of C7-methyl group

(α), which partially blocks the back side of the C9-O leaving group (Scheme 4.6).

O O O O OH H OH MeO MeO H CH3 H MeO MeO H OH CH3 MeO OH MeO MeO 4.12 OMe

DEAD, PPh , NO2 3 O p-NO2-BzOH MeO O O OH O MeO O O H 9 H 6 MeO 8 Nu: O MeO 7 MeO 7 MeO H CH 8 6 3 MeO 9 MeO MeO O O CH O OH 3 MeO O +PPh3 O MeO

4.17 (60%) NO2 OMe

DEAD, PPh3,

p-NO2-BzOH NO2 NO2

MeO O O O OMe MeO O O O MeO H3C Nu: 7 MeO 6 MeO 9 MeO H H MeO 9 MeO 6 CH3 MeO MeO OR O O O O +PPh 3 O O MeO O O NO NO O 4.18 (10%) 2 2

Scheme 4.6 Attempted Double-Mitsunobu Reactions on the Diol 4.12

So it seems that only p-nitrobenzoic acid could be the proper nucleophile in

Mitsunobu reactions under the conditions screened, which means two more steps

(hydrolysis followed by esterification) are required to install the desired ester groups as

those in the natural products. At the same time, the steric constraints imposed by C7- 164

methyl group make the inversion of the configuration at C9 very difficult. Due to both of these factors, we believe that the Mitsunobu reaction is unlikely to be an efficient way of introducing the appropriate alkoxy sidechain at C6 and C9.

4.4 Alternative Routes Involving Oxidation-Reduction Sequences to Invert C6 and

C9 Configurations

Alternative routes involving oxidation-reduction sequences can be envisioned for inversion of the configurations of C6 ad C9 in a conventional manner (Figure 4.4).

However, challenges still exist as chemoselectivity between the carbonyls and the stereoselectivity of the reduction of either one (C6 and C9) could raise difficulties. It is

conceivable that the unique conformational features of the DBCODs could lend a hand in

solving these stereochemical issues as previously seen in some of transformations (e.g.,

C=C reductions and Mitsunobu reactions).

O O O O OTBS O OR O OTBS

9 second 9 first MeO 9 MeO MeO oxidation-reduction oxidation-reduction MeO 6 MeO 6 MeO 6 OH OH sequence OH sequence MeO OH MeO OR' MeO OR' MeO MeO MeO kadsuralignan B R=R'=Ac Tiegusanin D R=R'=Bz Schizanrin F R=Ac, R'=Bz O O O O O OTBS conformation-controlled 9 9 MeO stereoselective MeO 6 MeO MeO OH reduction 6 OH MeO OR' ? MeO O MeO MeO

Figure 4.4 Inversion of C6 and C9 Configurations via Oxidation-Reduction Sequences

165

4.5 Syntheses of Ananolignans and Interiotherin C

With the advanced intermediate 4.12 in hand, we turned our attention to the relatively

simple fully substituted DBCOD lignans including ananolignans and interiotherin C. As

the stereochemistry at C7 and C8 of these natural products have been secured in the alcohol 4.12 (Scheme 4.2) what needs to be accomplished would be to invert the chirality of C6 and/or C9.

O O non-conjugated O O with aromatic O O OH O O O OH O CH3 t 9 LiAl(O Bu)3H MeO 9 PCC MeO MeO MeO MeO MeO MeO 6 (90%) 6 MeO CH3 (80%, d.r.=6:1) O MeO MeO OH MeO O O MeO coplanar MeO MeO with aromatic MeO OMe 4.12 4.19 4.20 Pd/C, H2 (95%) O O O O OH O O O OAc NaBH MeO 4 MeO MeO MeO (90%) MeO MeO

MeO OH MeO OH MeO MeO MeO MeO (-)-ananolignan C kadsurin 4.13

Scheme 4.7 Synthesis of Ananolignan C from the Alcohol 4.12 via a Known Diketone

Intermediate

The diol 4.12 was smoothly oxidized to the diketone 4.19 upon treatment with PCC.

This diketone is a known intermediate used by Ghera group in their synthesis of racemic

kadsurin.25f The reactivities of these two carbonyl groups are significantly different, as this molecule adopts a twist-boat (TB) conformation in which the C6-carbonyl is coplanar 166

with the adjacent phenyl ring, while the C9-carbonyl is not conjugated at all with the

upper phenyl ring. This reactivity difference was utilized by Ghera for selective

reduction of these two carbonyl groups.25f According to their report, treatment of 4.19

t with a bulky hydride source [LiAl(O Bu)3H] gave C9-reduction product 4.20 in 80% yield, together with the C6-α-OH/C9-ketone 4.13 (13%). On the other hand,

hydrogenation of the diketone 4.19 in acetic acid with Pd/C provided the ketone 4.13 as

the exclusive product. Ghera prepared kadsurin (Scheme 4.7) from 4.13 in a few steps. 25f

In our hands, when the ketone 4.13 was directly reduced by NaBH4, ananolignan C was formed as the exclusive product (Scheme 4.7). The spectroscopic data (1H and 13C

NMR) and optical rotation of the synthetic sample match those reported in the

literature.23z When the ketone 4.20 was treated with AcCl, ananolignan B (Scheme 4.8)

was obtained in 95% yield. A natural product with all spectroscopic [1H and 13C NMR

and circular dichroism (CD)] and chiroptical properties matching with our synthetic

compound has been described in the literature,23z but with a different structure. We believe that the originally assigned structure of ananolignan B is thus incorrect. Side-by- side comparisons of the data for both synthetic and natural ananolignan B and C could be

found in the experimental section.

Similar to the conversion of the diketone 4.19 to the alcohol 4.13, hydrogenation with

Pd/C in acetic acid of ananolignan B gave ananolignan D as the exclusive product. A

quick comparison of the structure of ananolignan D with those of interiotherin C and

ananolignan F indicated that inversion of C6 chirality is necessary. Attempts to directly

167

O O O O OH O OAc O OAc AcCl MeO MeO MeO MeO (95%) MeO MeO

MeO O MeO O MeO O MeO MeO MeO 4.20 (-)-ananolignan B originally assigned revised structure structure

Pd/C, H2 (96%)

O O O O OAc Nu: H Ms2O, MeO then H2O H CH3 MeO CH3 MeO OR MeO 6 OMs MeO OH MeO MeO OMe (-)-ananolignan D 4.21 (97%)

O O O O OAc O OAc O OAc Angeloyl chloride MeO (85%) MeO MeO or MeO 6 or MeO MeO Ac2O, p-TsOH MeO OH (96%) MeO O MeO OAc MeO MeO O MeO 4.22 interiotherin C ananolignan F

Scheme 4.8 Syntheses of Ananolignan B, D, F and Interiotherin C convert ananolignan D to ananolignan F via the Mitsunobu transformation using acetic acid as the nucleophile, PPh3 and DEAD in THF were not successful. In order to convert the C6-OH to a good leaving group, sulfonation with Ms2O in the presence of Et3N was attempted. After workup the only product isolated had a similar Rf value on the TLC plate, but different 1H NMR spectrum. Its structure was confirmed as the alcohol 4.22

with inversion of chirality at C6. The rationale is very similar to that was provided for the 168

previous successful Mitsunobu reaction: after the formation of the methylsulfonate at C6,

H2O now acts as a good nucleophile to attack from the back side of the leaving group.

Esterification of 4.22 with angeloyl chloride or acidic anhydride smoothly provided

interiotherin C or ananolignan F, respectively. The structures of ananolignan D, F and

interiotherin C was confirmed by comparisons of 1H and 13C NMR spectra with those

reported for the natural products.23aa These data can be found in side-by-side

comparisons in the experimental section.

4.6 Syntheses of DBCOD Lignans with C7-α-Hydroxyl Group Including

Kadsuralignan B, Tiegusanin D and Schizanrin F

4.6.1 Attempted Electrophilic Reactions at C7 as an Approach to Introduction of the

C7-α-Hydroxyl group

Upon inspection of the structures of kadsuralignan B23e (Figure 4.5) and dibenzocyclooctadiene intermediate 4.9, the most obvious differences are the configurations of C6 and C9 and the presence of a tertiary hydroxyl group at C7, which has to be introduced stereoselectively. Since an ethereal substituent is already built in the ketone 4.23 at the C6-position, it would appear that the crucial tert-OH could arise from

α-hydroxylation of ketone or silyl enol ether, that can be accessed from this O-containing intermediate. In order to access the key C7 tertiary hydroxyl group with the correct stereochemistry [(S)-configuration at C7], our first-generation strategy involved α - hydroxylation of the ketone 4.23, which could be derived from alcohol 4.9.

169

O O O OAc O OR

MeO MeO 7 6 MeO OH MeO OH MeO OAc MeO O

MeO kadsuralignan B MeO 4.24 α-hydroxylation of C6 carbonyl group O O O OTBS O OR

MeO MeO 7 7 MeO 6 MeO 6

MeO OH MeO O MeO MeO 4.9 4.23

Figure 4.5 Introduction of the C7-α-Hydroxyl Group via α-Hydroxylation of C6- Ketones

With the C6-hydroxyl alcohol in hand (e. g., 4.9), we could access various C6-ketones via common oxidation/deprotection manipulations. Direct oxidation of the alcohol 4.9 with PCC provided the ketone 4.25 (Scheme 4.9). Acid-mediated deprotection (3M HCl) went smoothly to provide the keto-alcohol 4.26 after 18 h at room temperature.

O O O O OTBS O OTBS O OH PCC HCl MeO MeO MeO 7 7 MeO (90%) MeO 6 (98%) MeO 6

MeO OH MeO O MeO O MeO MeO MeO 4.9 4.25 4.26

Scheme 4.9 Preparation of C6-Carbonyl Precursor for Potential α-Hydroxylation at C7

4.6.1.1 Reactions of Dibenzocyclooctadienes with C6-Carbonyl: α-Hydroxylation or

Silyl Enol Ether Formation

170

With these C6-carbonyl compounds in hand, we are now at a stage to introduce the

key C7-hydroxyl group. Molecular models of related enolates are not particularly revealing but suggestive of the Si face (top face) of the enolate being more sterically congested. Initially we focused on α-hydroxylation of the ketones (Scheme 4.10). There are plenty of precedents of hydroxylation reagents in the literature47 including both non- asymmetric and asymmetric versions. This transformation requires (1) a strong base to generate an enolate, and (2) a good oxygenated electrophile to trap the enolate. The bases we screened included NaOH, KOH, LDA and KHMDS. The tested electrophiles

48 49 were (TMSO)2, MoOPH(MoO5·Py·HMPA), PSPO (2-phenylsulfonyl-3- phenyloxaziridine),50 and (-)-CSO (Camphorylsulfonyl oxaziridine).51

O O O O OTBS O OH O OR

MeO MeO MeO or MeO 7 MeO 7 MeO 7 OH MeO O MeO O MeO O MeO MeO MeO 4.25 4.26 reaction condition or O O O O OH O OTMS O OR

MeO MeO MeO or or MeO 7 MeO 7 MeO MeO MeO O MeO O OSiR3 MeO MeO MeO 4.20 4.27

Scheme 4.10 Attempted α-Hydroxylation or Silyl Enol Ether Formation in DBCODs

171

Entry Substrate Reaction condition Result 1 4.25 LDA, THF, -78 oC to r.t., 30 min; No reaction MoOPH, -22 oC to r.t., 18 h 2 4.25 LDA, THF, -78 oC to r.t., 30 min; No reaction TMSCl or TBSCl, r.t., 18 h 3 4.25 LDA, THF, -78 oC to r.t., 30 min; Partial conversion TMSOTf, r.t., 18 h no silyl enol ether formed 4 4.25 KH, THF, r.t., 30 min; desilylated alcohol 30 TBSCl, r.t., 18 h 5 4.26 KHMDS, THF, -78 oC to r.t., 30 min; Full conversion, PSPO, -78 oC to r.t., 18 h no desired product 6 4.20 KHMDS, THF, -78 oC to r.t., 30 min; No reaction PSPO, -78 oC to r.t., 18 h 7 4.20 KHMDS, THF, -78 oC to r.t., 30 min; No reaction o (TMSO)2, -78 C to r.t., 18 h 8 4.20 LDA, THF, -78 oC to r.t., 30 min; 75% Conversion MoOPH, -22 oC to r.t., 18 h 50% hydroxylated product 4.28, 25% diketone 4.19 9 4.20 LDA, THF, -78 oC to r.t., 30 min; No reaction (-)-CSO, -22 oC to r.t., 18 h, 10 4.20 TMSOTf, Et3N, CH2Cl2, r.t., 18 h Full conversion TMS ether 4.27 11 4.27 LDA, THF, -78 oC to r.t., 30 min; No reaction MoOPH, -22 oC to r.t., 18 h 12 4.27 TMSOTf, Et3N, CH2Cl2, r.t., 18 h No reaction

Table 4.1 α-Hydroxylation or Silyl Enol Ether Formation of DBCODs with C6 Carbonyls

Among all the conditions attempted only one experiment with the combination of

LDA and MoOPH provided a hydroxylated product (4.28) starting with the ketone 4.20.

As mentioned earlier, these C6-ketones adopt twist-boat (TB) conformations in which the carbonyl group is coplanar with the lower phenyl ring to gain extra stability through resonance. The molecular models clearly indicated that the C7-H bond could have a very small dihedral angle with the carbonyl C–O bond, resulting in diminished acidity of α-

172 hydrogen (C7-H). We employed large excess of LDA and warmed the solution to room temperature for facilitating the enolate formation (Scheme 4.11).

O O O LDA, -78 0C to r.t. O O O O OH then MoOPH, O -23 0C to r.t MeO MeO MeO 7 + OH MeO 6 75% conversion MeO MeO 6 7 MeO O MeO O MeO O MeO MeO MeO 4.20 4.19 (25%) 4.28 (50%) Undesired [O] stereochemistry [O] at C7 O O O O O O H H E+ CH3 H H H MeO H MeO H H CH LDA +M-O MoOPH MeO CH3 OH 3 - + O MeO O M CH3 OH CH MeO X O 3 MeO OH CH3 E+ MeO MeO MeO H OMe OMe OMe 4.29 MoOPH= MoO5.pyr.HMPA 4.30 O O H H O MeO O CH3 OH 4.28 MeO CH3 nOe MeO H OMe

Scheme 4.11 α-Hydroxylation of the Ketone 4.20

Large excess of MoOPH was then added. To our surprise, we did observe the hydroxylated product 4.28 in a 50% yield, although in a diketone form, together with

25% non-hydroxylated diketone and equal amount of starting material recovered.

1 However, 2D HNMR (NOSEY) spectrum revealed that C7-β–hydroxyl group (top-face addition) was present in the product 4.28. In other words, the introduction of the tertiary hydroxyl group proceeded in an undesired fashion. 173

Mechanistically, after the formation of the enolate 4.29, the electrophile approaches

the Si face of 4.29 to give the diol 4.30. We speculate that there may be two reasons for this selectivity: (1) the upper phenyl ring is likely to direct the electrophilic attack of

MoOPH); (2) the trend to achieve the maximum resonance between the lower phenyl ring and enolate π -system, which opens up the original pocket, resulting in the Si face becoming more accessible. The oxidation of a secondary hydroxyl group to the carbonyl group in the presence of excess MoOPH is also known,52 which explains the formation of the diketone 4.19.

α-Hydroxylation of silyl enol ethers is another conventional method to introduce α- hydroxyl groups.47 We also attempted to synthesize silyl enol ethers from corresponding

C6-carbonyl compounds. Unfortunately, we were not able to obtain the desired products

after screening different combinations for this transformation including TBSCl/KH,

TMSCl/LDA, TBSCl/LDA, TMSOTf/LDA and TMSOTf/Et3N (entry 2, 3, 4, 10 and 12

in Table 4.1). Thus this route was eventually abandoned.

4.6.1.2 Electrophilic Functionalization of Substrates with the C6-C7 Double Bonds

Our revised synthetic strategy now called for the functionalization of alkenes 4.31 or

4.32 with C6-C7 double bonds via dihydroxylation or epoxidation to introduce the C7- hydroxyl group (Figure 4.6). Dihydroxylation could be performed under different protocols such as the Sharpless asymmetric dihydroxylation,44 the Woodward hydroxylation53 or the Prevost procedure.54

174

O O O OAc O OR

MeO MeO 7 6 MeO OH MeO OH MeO OAc MeO OH

MeO kadsuralignan B MeO 4.24 or dihydroxylation of epoxidation then C6-C7 double bond expoxide-opening O O O O O OTBS O OTBS O OTBS O OTBS

MeO MeO MeO MeO or 7 MeO MeO MeO MeO 6 7 CHO 7 7 6 6 6 MeO MeO MeO MeO OH MeO MeO MeO MeO 4.5 4.31 4.32 4.9

Figure 4.6 Synthetic Plan Involving Oxygenation of Substrates with C6-C7 Double bond

Among these protocols, Sharpless and Woodward dihydroxylations give cis-diol while Prevost procedure affords trans-diol. Alternatively, epoxidation followed by epoxide-opening may form a trans-diol. Alkenes 4.31 and 4.32 could be derived from

DBCOD intermediates 4.5 and 4.9, respectively.

Although the aldehyde 4.5 formed by peroxide oxidation of 2.47c (Scheme 4.1) lost

C6-O substituent, it contains the C6-C7 double bond and could be converted to

corresponding diene 4.31 (Scheme 4.12), which could serve as the dihydroxylation

substrate. To set up the substrate, the aldehyde 4.5 was selectively reduced to an allylic

alcohol 4.33 with DIBAL-H (Scheme 4.12). We envisioned a two-step sequence involving converting the alcohol to an allyl halide followed by hydride reduction, which should furnish a diene. However, when the alcohol was subjected to TsCl and Et3N, we

obtained a mixture of two compounds, which upon super hydride reduction provided two

175

isomeric dienes (4.31 and 4.34). We reasoned that during the tosylation with TsCl, some

allylic tosylate was converted to chloride via SN2’ mechanism. When the sulfonation reagent was switched to methanesulfonic anhydride, the two-step sequence (sulfonation followed by in-situ reduction with Super-hydride) cleanly gave the diene 4.31 as the

exclusive product. While we attempted to isolate the mesylate after aqueous workup,

only 50% yield of mesylate 4.35 was obtained together with alcohols 4.33 and 4.36, which most possibly formed via SN2 and SN2’ substitution reactions.

O O O O OTBS O OTBS O OTBS DIBAL-H TsCl, Et N MeO MeO 3 MeO MeO (95%) MeO OH MeO OTs CHO MeO MeO MeO Cl- MeO MeO MeO 4.33 4.5 Ms2O, Et3N

O O O O O O OTBS OTBS O OTBS O OTBS MeO Super-H MeO CH MeO MeO MeO 3 MeO + (90% OMs MeO MeO H over two steps) H MeO MeO Cl MeO MeO Cl MeO OMe OMe MeO 4.31 4.35

sat. aq. NaHCO3 Super-H

O O O O O O OTBS OTBS O OTBS O OTBS MeO MeO MeO + MeO MeO MeO MeO MeO

MeO MeO OH MeO MeO

MeO MeO MeO MeO 4.31 4.36 (10%) 4.34 (45%) 4.31 (45%) + 4.33 (40%) + 4.35 (50%)

Scheme 4.12 Synthesis of the Diene 4.31 with a C6-C7 Double Bond

176

O O O OTBS O AD-mix-β,OsO4 , OTBS t-BuOH/H2O, r.t., 8h, MeO MeO MeO 75% MeO OH 7 6 MeO MeO OH MeO MeO 4.31 4.37

OsO4 O O H O H SiR O 3 O H OTBS MeO HO H MeO O OsO MeO H 4 CH3 H MeO CH3 X H H H MeO nOe observed MeO OMe OMe

Scheme 4.13 Osmylation of the Diene 4.31

With the alkene 4.31 in hand, we were ready for the osmylation. When AD-mix-β and OsO4 were employed (Scheme 4.13), a diol 4.37 formed after 8 h (75% yield) and its

1 structure, as confirmed by 2D HNMR (NOESY) spectrum, contains an undesired C7-β-

hydroxyl group. This result indicated that the electrophile attacks from the β-face of the

C6-C7 double bond of 4.31.

4.6.1.3 Synthesis and Osmylation of Alkene 4.32 that Contains C6-C7 Double Bond

Another dihydroxylation substrate 4.32 that contains the C6-C7 double bond could be envisioned to derive from dehydration of alcohol 4.9. This substrate contains a C8-α-

methyl group, which we expected could increase the steric congestion in the α-face of the

C6-C7 double bond as seen in the corresponding Dreiding model. Hopefully this modification of the substrate structure could partially change the bias for hydroxylation.

177

O O O O OTBS O OTBS O OTBS dehydration condition MeO MeO MeO MeO MeO MeO

MeO OH MeO MeO O F3C MeO MeO MeO F3C Ph 4.9 4.32 4.38

Entry Deydration condition Result o 1 Burgess’ reagent, CHCl3, 70 C, 3 h Complex mixtures (no alkene 4.32) 2 Martin's sulfurane, CHCl3, r.t., 18 h Ether 4.38 (80%) o 3 (S)-camphorsulfonic acid, CHCl3, 70 C, 10 h Alkene 4.32 (90%)

Table 4.2 Dehydration Conditions for the Alcohol 4.9

The transformation of the alcohol 4.9 to the alkene 4.32 required a proper

dehydrating reagent. To our surprise, Burgess’ reagent55 and Martin’s sulfurane,56 which are commonly employed for such a transformation, did not deliver the desired alkene

4.32. Burguess’ reagent affords complex mixtures without detection of 4.32, while

Martin’s sulfurane reacted with the alcohol 4.9 to give a product in high yield, which was

identified as the ether 4.38. We were not able to convert 4.38 to the alkene 4.32 under

basic condition (DBU, 130 oC in toluene for 24 h). Eventually, when stoichiometric

amount of (S)-camphorsulfonic acid was used, a clean conversion of the alcohol 4.9 to

the alkene 4.32 was achieved in 90% yield.

When the alkene 4.32 was subjected to the osmylation conditions (Scheme 4.14), it took 3 days to reach 80% conversion leading to a hydroxyl ketone 4.40 as the exclusive product (80%). The oxidation of the C6-hydroxyl group in the intermediate diol 4.39

178

could be effected by Fe (III) salts in AD-mix-β. Its structure, as confirmed by 2D

1 HNMR (NOESY) spectrum, contains an undesired C7-β-hydroxyl group. This

unfavorable result, again, indicated the strong preference of the electrophile to attack the

C6-C7 double bond from the β-face.

O O O O TBS O OTBS O OTBS (S)-camphorsulfonic OH AD-mix-β, OsO4, acid MeO 3 days MeO CH MeO OsO4 3 MeO (90%) MeO (80%) MeO CH3 7 6 H MeO OH MeO H MeO MeO MeO 4.9 4.32 OMe

O O O O H SiR3 H O OTBS O O OTBS CH MeO O 3 [O] OH MeO MeO MeO H MeO OH MeO OH CH3 H MeO O MeO OH MeO nOe OMe observed MeO MeO 4.40 4.39

Scheme 4.14 Synthesis and Osmylation of the Alkene 4.32

4.6.1.4 Epoxidation and Woodward/Prévost Dihydroxylation on the Alkenes 4.31 and 4.32

Other approaches to convert alkenes 4.31 and 4.32 to diols were also attempted, including epoxidation-epoxide-opening sequence, Woodward hydroxylation or Prévost protocol. The results are summarized in Table 4.3. The epoxidation of 4.31 and 4.32 did occur in the presence of different epoxidation reagents, including acidic H2O2 solution

(entry 1 for 4.31), m-CPBA (entry 2 for 4.31) and Oxone® (entry 3 for 4.32). However,

179

O O O OTBS O OTBS

MeO MeO MeO MeO OH MeO MeO OH 4.31 epoxidation followed by expoxide opening MeO (entry 1,2 and 3) MeO O or or OR O O OTBS Woodward /Prevost dihydroxylation O OTBS (entry 4, 5, 6 and 7) MeO MeO MeO MeO OH

MeO MeO OH 4.32 MeO MeO

Scheme 4.15 Other Attempts to Introduce the C7-Hydroxyl Group

Entry Substrate Reaction condition Result

1 4.31 HCOOH, H2O2, then KOH full conversion Polar product

2 4.31 m-CPBA, NaHCO3, CH2Cl2, multiple products 00C to r.t., 3 h, decomposition upon separation

3 4.32 Oxone, NaHCO3, Na2(EDTA), Full conversion acetone, 00C, 3 h polar product

4 4.31 AgOAc, I2, Benzene, reflux, 3 h, complex mixtures

5 4.32 AgOAc, I2, Benzene, reflux, 3 h complex mixtures 0 6 4.32 AgOAc, I2, AcOH, H2O, 95 C, 18 h iodoacetate isolated as the major product

Table 4.3. Epoxidation and Woodward/Prévost Dihydroxylation on Alkenes 4.31 and

4.32 it seemed the resulting epoxides were unstable under reaction conditions, as when the reaction reached full conversion, only unidentified polar products were observed and we 180

O O O O O O-M+ O OTBS O OTBS O OTBS

MeO MeO MeO MeO 7 7 MeO 6 MeO MeO MeO 7 7 MeO O-M+ MeO 6 MeO 6 MeO OR

MeO 4.29 MeO 4.31 MeO 4.32 MeO 4.8 R=H or 4.7 r=Bn

electrophile (MoOPH or OsO4) H2 attack from the β-face

attacks from the β-face of of C7 exocyclic double bond

C6-C7 double bond O O O O OTBS

MeO MeO MeO 7 OH MeO 6 MeO OR MeO OH MeO MeO 4.9

Scheme 4.16 β-Face of Some of the DBCODs Favoring Electrophilic Oxygenation and

Catalyzed Hydrogenation

were not able to isolate any desired epoxide (entry 2 and 3) or diol (entry 1). Direct

dihydroxylation procedures [Woodward and Prévost protocols (entry 4 and 5 for the

former and entry 6 for the latter)] were also investigated. These conditions led to the

formation of complex mixtures, among which only an iodoacetate was identified by mass

spectroscopy (entry 6).

4.6.2 Introduction of the C7-α-Hydroxyl Group via a Nucleophilic Addition to a C7-

Carbonyl Substrate 4.41 (Figure 4.7)

Based on the previous results in effecting the C7 α-hydroxylation, the electrophiles

(MoOPH or OsO4) approach the C6-C7 double bonds of these DBCOD intermediates

(4.29, 4.31 or 4.32) from the β -face (Scheme 4.16). Another result obtained from the

181

transformation from the benzyl ether 4.7 to the alcohol 4.8 indicates that H2 also attacks from the β-face of the C7-exocyclic double bond. One useful piece of information that

could be extracted from these results is that reagents generally prefer the β-face attack on

the C6 or C7 double bond, presumably for steric reasons. Thus, a new strategy to exploit these results could involve a nucleophilic attack at a C7-carbonyl, which may also occur

at the β-face (of ketone 4.41, for example, Figure 4.7).

O O O OAc O OTBS

MeO MeO 7 6 MeO OH MeO OH MeO OAc MeO OH MeO MeO kadsuralignan B 4.24

nucleophilic addition

O O O OTBS O OTBS

MeO MeO MeO MeO O MeO OBn MeO OH MeO MeO 4.6 4.41

Figure 4.7 Synthetic Strategy Involving a Nucleophilic Addition to the C7-Carbonyl

Substrate (4.41)

4.6.2.1 Preparation of Ketone Substrate 4.41 for Nucleophilic Addition

In order to prepare the C7-carbonyl ketone 4.41, we adopted a commonly employed two-step sequence involving dihydroxylation of the C7-exocyclic double bond in 4.6,

followed by oxidative cleavage of the resulting diol (Scheme 4.17). The dihydroxylation

182

protocol using the combination of OsO4 and NMO cleanly provided two diastereomeric diols (4.43:4.44 = 3:1 ratio). Gratifyingly, the osmylation occurred preferentially at the

C7-exocyclic double bond to give the major product 4.43. 2D NOSEY spectrum clearly indicated that the diol 4.43 bears a C7-β-OH group, providing a further evidence to support our previous argument that electrophilic reagents prefer the β-face attack on this type of DBCOD substrate. The minor product 4.44 from osmylation contains a C8-β-OH group, and this could be partially attributed to the fact that the bulky TBS group blocks the α-face of the C8-exocyclic double bond.

O O O O OTBS O OTBS O OTBS

OsO4, NMO OH MeO 8 MeO 8 + MeO 8 7 7 OH 7 OH MeO (A : B = 69%:23%) MeO MeO OH MeO OBn MeO OBn MeO OBn MeO MeO MeO 4.6 4.43 4.44

NaIO4 O (80%) O H H O O TBS O H O OTBS O OTBS MeO H H O Pd/C, H , 50 0C MeO MeO 8 2 MeO 8 H OBn C OH 7 (99%, dr=10:1) 7 MeO O MeO O H H MeO H MeO OH MeO OBn nOe OMe MeO MeO observed 4.41 4.45 4.43

O O O O H H H SiR3 TBS H O O H MeO MeO H CH3 H H H MeO MeO OH O OBnO nOe MeO H MeO H nOe observed observed OMe OMe

Scheme 4.17 Synthesis of the Ketone 4.41 from the Diene 4.6 183

The subsequent oxidative cleavage of the diol 4.43 with NaIO4 went smoothly to give the C7-carbonyl ketone 4.45. Reduction of the C8-exocyclic double bond and removal of the benzyl protection group of 4.45 were achieved in one pot under hydrogenation condition with Pd/C. This one-pot process gave a mixture of two diastereomeric alcohols (d.r.=10:1) and the major one, 4.41, possesses the desired C8-α-

methyl group. The same rationale for the formation of the diol 4.44 could be used here:

H2 instead of OsO4, preferably adds to the β-face of the C7-exocyclic double bond.

4.6.2.2 Successful Introduction of C7-α-Hydroxyl Group via Nucleophilic Addition to the Ketone 4.41

With this crucial ketone 4.41 in hand, we are ready for the nucleophilic addition.

When 4.41 was treated with excess MeLi at –78 ºC, two products were isolated. We

were pleased to find that the major product (82%) contains the desired C7-α-hydroxyl

group, based on its 2D 1HNMR (NOESY) spectrum. Its structure was later confirmed

after obtaining solid-state-structure (X-ray) of a ketone 4.46 derived form this molecule.

O O tBu O O H Si O OTBS H O OTBS O MeLi MeO CH3 MeO Li Nu MeO 7 MeO 7 MeO (82%, d.r.=10:1) O O O MeO OH Li MeO OH MeO OH MeO H desired MeO IBX MeO stereochemistry OMe 4.41 (95%) 4.42 at C7

O O tBu O H Si O OTBS H O MeO CH MeO H 3 H CH3 MeO MeO OH OHOH MeO O MeO H MeO nOe X-ray structure of 4.46 4.46 OMe observed

Scheme 4.18 Nucleophilic Addition to the Ketone 4.41 184

4.6.3 Synthesis of Kadsuralignan B and Tiegusanin D

Syntheses of Kadsuralignan B and Tiegusanin D starting from 4.42 are shown in

Scheme 4.19. Removal of the silyl protection group in 4.42 with HCl (3 M) in methanol

cleanly afforded the triol, which upon treatment with excess IBX (o-iodoxybenzoic acid)

in DMSO, was oxidized to the diketone 4.47 at 40 ºC after18 h with an excellent yield

(90% over two steps from TBS ether 4.42). The 1H NMR and 13C NMR of this diketone

indicated that it adopts the twist-boat-chair conformation (see details in Section 4.7 of

Chapter 4), matching our initial projection. We found that the non-basic workup

condition after IBX oxidation was critical, since in one experiment when aq. NaHCO3

was used for workup, another diketone 4.47a was isolated instead of 4.47. The results of

1 13 NMR analysis ( H NMR, 2D NOESY and C NMR) confirmed it is the C8-epimer of diketone 4.47, indicating the facile epimerization at C8 of 4.47 under weakly basic condition. This should be attributed to the good alignment of C8-H with adjacent C9

carbonyl group, a result of the twist-boat-chair conformation of the diketone 4.47.

Now we are at a crucial stage as the reduction of this diketone, reduction of which

would install two new stereogenic centers (C6 and C9). Careful examination of the

Dreiding model of this diketone revealed that the top face of C6-carbonyl group and bottom face of C9-carbonyl are relatively open for hydride attack. In addition, a neighboring C7-hydroxyl group could also direct the hydride addition and thus improve the stereoselectivity. If these were to happen, the configuration of these two new chiral centers would match those in the natural products. After the diketone 4.47 was treated

185

non-conjugated O O O H– with aromatic O O OTBS O O H 1. HCl 2. IBX 9 NaBH4 MeO MeO MeO O CH3 7 O CH (93%, 2 steps) 6 MeO 3 MeO OH MeO OH O MeO OH MeO O H non-conjugated MeO – MeO MeO B with aromatic OMe 4.42 4.47 (82%, d.r.=10:1) O O O O H O OBz H O OH H MeO HO CH3 MeO MeO BzCl O CH3 MeO H MeO OH H MeO (90%) OH OH MeO OBz MeO OH MeO H nOe MeO observed MeO OMe tiegusanin D 4.48 Ac2O, p-TsOH (98%)

O O O O O OAc 9 MeO 8 MeO 7 MeO MeO 6 OH OH MeO O MeO OAc MeO MeO kadsuralignan B X-ray structure 4.47a

Scheme 4.19 Synthesis of Kadsuralignan B and Tiegusanin D

with NaBH4 in MeOH at room temperature, to our great satisfaction, we observed a highly diastereoselective reduction reaction (d.r.=10:1) to get a triol (4.48) with all stereochemical elements matching those in Tiegusanin D and Kadsuralignan B. At this stage only one esterification step is required to obtain these two natural products.

Acetylation of triol went smoothly with Ac2O in the present of p-TsOH to provide

kadsuralignan B23e, whose structure was confirmed by 1H and 13C NMR and X-ray crystallography. While no conversion was observed with the routine benzoylation protocol (BzCl, DMAP and Et3N in CHCl3) at room temperature, simply raising the 186

temperature to 70 ºC resulted in full conversion of triol 4.48 to tiegusanin D in high yield

(90%). The structures were confirmed by comparison of 1H and 13C NMR spectra the

synthetic materials with those of the natural products.23e,23y

Figure 4.8 The ORTEP Drawing of Kadsuralignan B

4.6.4 Synthesis of Schizanrin F

Different from tiegusanin D and kadsuralignan B which have the same ester groups,

schizanrin F possesses different ester groups at C6 and C9 (C6-OBz and C9-OAc). We planned to prepare the C6-benzoate 4.53 by inversion of C6 chirality in alcohol 4.42 via an oxidation-reduction sequence followed by esterification (Scheme 4.22). A second oxidization-reduction sequence would ensue to invert the C9 chirality.

When diol 4.42 was treated with PCC, a single product formed and it was directly subjected to NaBH4 reduction to afford one compound (Scheme 4.20). However, mass

spectrum indicated its molecular weight to be 564 instead of 562 (MW of desired diol).

After careful examination of the 1H NMR spectrum, we believe that this compound 4.50

is derived from a keto-aldehyde (4.49) via reduction, whose structure was later confirmed

by 1HNMR. The formation of dicarbonyl compounds via vicinal-diol cleavage with PCC

have already been described in the literature.57 187

O O O O OTBS O OTBS O OTBS

PCC, NaOAc NaBH , MeOH MeO MeO 4 MeO (95%) (96%) MeO OH MeO O MeO OH CHO Single diastereomer MeO OH MeO MeO OH MeO MeO MeO 4.42 4.49 4.50

Scheme 4.20 Oxidation of the Diol 4.42 with PCC

A quick literature survey revealed that IBX would oxidize secondary OH group in

vicinal diols without bond cleavage. When the diol 4.42 was reacted with excess IBX,

ketone 4.46 was formed cleanly in a 95% yield (Scheme 4.21). As revealed by the

Dreiding model of this ketone, and its X-ray structure, 4.46 has a twist-boat-chair (TBC)

conformation, and a nucleophile such as a hydride reducing agent would attack from the

bottom face. Such reduction may further be assisted by the neighboring C7-α-OH group.

To our delight, NaBH4 reduction of ketone 4.46 did provide alcohol 4.52 as the exclusive product, with the correct stereochemistry at C6 as that in several natural products.

O O O OTBS O OTBS

MeO 8 IBX MeO 7 6 MeO 6 OH (95%) MeO OH MeO OH MeO O non- MeO MeO conjugated 4.42 4.46

NaBH4 O X-ray structure of 4.46 O O O OTBS OTBS MeO O CH3 CH MeO MeO 3 O MeO OH (95%) -H B MeO OH MeO MeO OMe 4.52 4.51

Scheme 4.21 Synthesis of the Alcohol 4.52 188

Completion of the synthesis of schizanrin F is shown in Schemes 4.22. Benzoylation

of the alcohol 4.52 was very slow, as it took 4 days to achieve full conversion, which

could be attributed to the presence of the C7-β-CH3 group and the attendant steric congestion. After desilylation of the benzoate 4.53 under the acid condition (HCl,

MeOH), the resulting alcohol was oxidized to corresponding ketone 4.54, which adopts a

twist-boat-chair conformation. As we were already aware, the C9-carbonyl reduction with the TBC conformation would proceed with high diastereoselectivity. Not surprisingly, reduction of the ketone 4.54 using NaBH4 afforded the alcohol 4.55 with a

C9-α-OH group as the exclusive product (85% yield over three steps from the TBS ether

4.53). Acetylation of 4.55 gave schizanrin F, the structure of which was confirmed by

comparison of 1H and 13C NMR spectra with those reported for the natural products.23aa

This data can be found in a side-by-side comparison in the experimental section.

O O O non-conjugated O OTBS O OTBS 1. HCl O O with aromatic BzCl 9 2. IBX 9 MeO MeO MeO 7 6 6 MeO OH (88%) MeO OH MeO OH MeO OH MeO OBz MeO OBz

MeO 4.52 MeO 4.53 MeO 4.54

3. NaBH4 O O O H– O O O OAc OH H Bz 9 MeO AcCl MeO MeO O CH3 O CH MeO MeO 3 MeO OH (92%) OH H (85%, 3 steps) OH MeO OBz MeO OBz MeO MeO MeO Schizanrin F 4.55 OMe

Scheme 4.22 Synthesis of Schizanrin F

189

4.7 Conformations of DBCODs with C6 and (or) C9 Carbonyl Groups

2 Dibenzocyclooctadiene lignans with sp -C at C6 or C9 have two types of conformations: twist-boat-chair (TBC) and twist-boat (TB).58 Conformations of

DBCODs with one carbonyl group at either the C6 or C9 position, or two at both positions, however, are controlled by both steric and electronic factors. Information based on spectroscopic methods could reveal the conformation of a particular DBCOD

1 (Figure 4.9). The chemical shifts of H4 and H11 in H NMR, as well as those of C6 and C9

(carbonyl carbons) in 13C NMR are diagnostic.

4.7.1 1H NMR Spectra

The chemical shifts of aromatic hydrogens are of diagnostic value. Among the

compounds we prepared are C6-carbonyl mono-ketones without C7-hydroxyl group which include compounds 4.26, 4.25, 4.20, 4.27 and ananolignan B. The chemical shifts

of H4 in these compounds (see Figure 4.9) are quite downfield ranging from 7.46-7.70 ppm, due to the large deshielding effect of the neighboring conjugated C6-carbonyl

group. The orientation of C9-oxygenated substituent also influences the chemical shift of

H11 on the aromatic ring: C9-β-oxygenated groups have larger deshielding effect (6.85

ppm in 4.26 and 6.81 in 4.25) than C9-α-oxygenated groups (6.33-6.51 ppm in 4.20, 4.27 and ananolignan B). Mono-ketone 4.13 contains a C9-carbonyl group adjacent to the upper phenyl ring, however, the chemical shift of H11 is quite upfield (6.34 ppm),

indicating no conjugation between the C9-carbonyl group and the phenyl ring. The

190

chemical shifts of H11 in diketones 4.19 and 4.28 (6. 41 ppm in 4.19 and 6. 56 ppm in

4.28) are similar to that of ketone 4.13 (6.34 ppm), indicating the non-

O O O O 11 6.85 6.81 6.37 O O OH O OTBS O OH 9 MeO 8 MeO MeO MeO MeO 6 7 MeO MeO MeO 1668 201.0 201.1 200.9 MeO MeO O MeO O MeO O 4 7.46 7.49 7.60 MeO MeO MeO MeO 4.26 4.25 4.20

O O O O 6.51 6.33 6.34 6.41 O OAc O OTMS O O O O 209.3 209.2 MeO MeO MeO 1699 MeO 1710 MeO 1664 MeO MeO MeO 1668 200.4 200.9 201.9 MeO O MeO O MeO OH MeO O 7.70 7.62 6.93 7.18 MeO MeO MeO MeO ananolignan B 4.27 4.13 4.19

O O O O O 6.56 6.37 7.12 6.74 6.34 O O O O O O O OTBS O OTBS

MeO 1714 MeO 1697 MeO MeO MeO OH OH MeO 1666 1714 MeO 1689 1699 MeO OH MeO OH MeO OH 208.5 MeO O MeO O MeO O MeO O MeO O 7.10 6.58 C C 6.64 C C 6.47 6.93 MeO MeO 6 9 MeO 6 9 MeO MeO 210.1 209.9 205.5 202.8 4.28 4.47 4.47a 4.40 4.46

1 13 Figure 4.9 The Chemical Shifts of H11 and H4 in H NMR and those of C6 and C9 in C

NMR in DBCODs with C6 and (or) C9 Carbonyl Groups and the Carbonyl Stretching

Frequencies in their IR Spectra

conjugation nature of C9 carbonyl group. Although the chemical shifts of H4 in 4.19 and

4.28 (7.18 ppm in 4.19 and 7.10 ppm in 4.28) are smaller than those in 4.26, 4.25, 4.20,

4.27 and ananolignan B (7.46-7.70 ppm), they are larger than those in ketones 4.40 and

4.46 with C6 carbonyl groups and C7-hydoxyl groups (6.47 ppm in 4.40 and 6.93 ppm in

191

4.46). The chemical shift of H11 in 4.47a (7.12 ppm) indicates that the C9-carbonyl is

partially conjugated to its adjacent phenyl ring. The X-ray crystallographic analysis

clearly shows ketone 4.46 adopts a twist-boat-chair conformation, in which the C6

carbonyl group is not in conjugation with the adjacent aromatic ring. Taken this

information into consideration, the C6 carbonyl in 4.19, 4.28 and the C9 carbonyl in 4.47a could be in an intermediate state (partially in conjugation with its adjacent aromatic ring) compared to those in 4.26, 4.25, 4.20 and 4.27 (almost fully conjugated with the aromatic ring) and those in 4.40 and 4.46 (nearly perpendicular to the aromatic ring and thus non- conjugated).

4.7.2 13C NMR spectra

Only the chemical shifts of the carbonyl groups are discussed here, as they are significantly influenced by the extent of their conjugation with adjacent phenyl rings and therefore most diagnostic. The 13C absorptions of the carbonyls in these DBCODs are

clearly divided into two ranges, 200.4-202.8 ppm and 208.5-210.1 ppm, with one

exception (205.5 ppm in 4.47a). A quick comparison of these data with the absorption of

the carbonyl group in acetophenone (195.6 ppm, fully conjugated) and that in cyclohexyl

methyl ketone (210.2 ppm, non-conjugated), indicates the carbonyl groups in these

DBCODs with smaller chemical shifts (around 201 ppm) are in good conjugation, while

those with larger chemical shifts (around 209 ppm) are non-conjugated. The only

exception, the chemical shift of C6-carbonyl group in 4.47a (205.5 ppm), could be a

result of its partial conjugation with the adjacent phenyl ring.

192

1 13 The comparison of the H absorption of H4 and the C absorption of the conjugated

C6 carbonyl in structurally similar ketones 4.26, 4.25, 4.20, 4.27, 4.19 and ananolignan B shows a clear trend: as the chemical shift of H4 decreases from 7.70 ppm (ananolignan B)

to 7.18 ppm (4.19), that of C6 increases from 200.4 ppm (ananolignan B) to 201.9 ppm

(4.19). In fact, this trend may reveal that minor changes in the structure of these

DBCODs, for example, orientation of the C9-hydroxyl group (α or β) and

substitution/hybridization pattern on C9-oxygen atom (hydrogen atom in 4.26 and 4.20,

trimethylsilyl group in 4, acetate in ananolignan B or carbonyl in 4.19, etc.), could alter

the extent of the conjugation between C6-carbonyls with the phenyl rings. Interestingly,

1 13 the H absorption of H11 and the C absorption of the conjugated C9 carbonyl in diketone

4.47a also followed this trend.

Compound Ananolignan B 4.27 4.20 4.25 4.26 4.19 4.47a a H4 (ppm) 7.70 7.62 7.60 7.49 7.46 7.18 7.12 b C6 (ppm) 200.4 200.9 200.9 201.1 201.0 201.9 202.8 a b H11. C9

1 13 Table 4.4 Comparison of the H Absorption of H4 and the C Absorption of the

Conjugated C6-Carbonyl in 4.26, 4.25, 4.20, 4.27, 4.19, 4.47a and Ananolignan B

13 The C absorptions of the C9 carbonyls in ketones 4.13, 4.19 and 4.47, and C6- carbonyls in 4.47 and 4.46 as well are between 208.5-210.1 ppm, indicating these

carbonyls are non-conjugated with the adjacent phenyl rings.

4.7.3 IR spectra

193

Examination of the carbonyl stretching frequency in the IR spectra further supports

the previous conclusion based on 1H and 13C NMR spectra. The absorptions of the carbonyls in these DBCODs fall into two ranges, 1664-1668 cm-1 and 1689-1714 cm-1,

which could relate to conjugated and non-conjugated carbonyl groups, respectively.

4.7.4 X-ray Crystallography

The non-conjugated nature between the C6-carbonyl group and its adjacent phenyl

ring in ketone 4.46 was established unambiguously by the x-ray crystallographic analysis.

Of course this assumes that the conformation of these molecules remain the same in solid

phase and in solution.

O O OTBS

MeO MeO OH MeO O 6.93 MeO

4.46 X-ray

Figure 4.10 Solid-state Structure (X-ray) of the Ketone 4.46

4.7.5 Conformations of DBCODs with the C6/C9-carbonyl group

DBCODs with C6 or C9 carbonyl group(s) could exist as either of two types of

conformations: twist-boat-chair (TBC) or twist-boat (TB). The specific conformation of

a particular DBCOD is controlled by steric effect (the orientation and size of the

substituents on C7 and C8, e.g., C8-α or C8-β-CH3, C7-α-OH or C7-α-CH3) and electronic

effect (C6 or C9 carbonyl group conjugated or non-conjugated with the aromatic ring).

194

O O O O O O OH OH OH CH3 MeO MeO MeO O CH3 H MeO MeO 6 MeO CH3 O CH3 MeO O MeO MeO MeO OMe OMe 4.26

TB favored TBC no conjugation conjugation at C6

Figure 4.11 The TB Conformation of the Ketone 4.26

As revealed by Ghera, the mono-ketone 4.26 with a C6-carbonyl group conjugated to

the aromatic ring adopts TB conformation instead of TBC conformation, mainly because

the extra energy gained from the conjugation could be more than enough to compensate

for the inherent advantages of TBC conformation (Figure 4.11). Other mono-ketones

with conjugated C6-carbonyls including 4.25, 4.20, 4.27 and ananolignan B also exist as

TB conformations.

O O O O O H O O O MeO H MeO HO CH3 HO H 9 O H MeO MeO MeO H H C CH3 MeO CH3 3

MeO OH MeO MeO OMe MeO OMe 4.13 TBC favored TB no conjugation conjugation at C9

Figure 4.12 The TBC Conformation of the Ketone 4.13

The ketone 4.13 possesses a non-conjugated C9-carbonyl group and adopts a TBC

conformation (Figure 4.12). In the possible TB conformation, the C8-α-methyl group

195

could cause strong steric repulsion with the lower phenyl ring, which may not

compensate for the stabilizing energy achieved by conjugation at the C9 carbonyl. By

avoiding steric hindrance with the C8-α-methyl group, the TBC conformation

predominates at the cost of giving up conjugation at the C9 carbonyl.

Diketone 4.19 could exist as either one of three possible conformations: TBC, TB with conjugation at C6 or another TB with conjugation at C9. Based on previous spectroscopic data, its C6 carbonyl is conjugated and C9-carbonyl is not, therefore diketone 4.19 should adopt the TB conformation with conjugation at C6 (Figure 4.13).

As pointed out by Ghera, the carbonyl group could not conjugate with the aromatic ring

in the TBC conformation. The TB conformation with conjugation at C9 suffers from

severe steric repulsion from the C8-α-methyl group, thus even the conjugation at the C9

carbonyl could not provide sufficient stability. On the other hand, conjugation at the C6

carbonyl alone is enough to stabilize the TB conformation.

O O O O O O O H O O O OCH 3 MeO H H MeO MeO CH3 O 9 O O MeO H MeO MeO CH MeO MeO 3 CH3 CH3 6 O CH3 MeO O MeO MeO MeO MeO OMe OMe OMe 4.19 TB favored TBC TB

conjugation at C6 no conjugation conjugation at C9 sterics between CH3(C8-) and phenyl ring

Figure 4.13 The TBC Conformation of the Diketone 4.19

Diketones 4.28, 4.47 and 4.47a are diastereomers, differing in the C7 and/or C8

chirality. Although 4.28 and 4.47 are structurally very similar, the spectrum data 196

O O O O O O O O O H O OCH OH 9 3 MeO MeO MeO MeO O CH3 O H OH HO O OH MeO 6 MeO MeO MeO CH CH3 3 CH H3C O 3 MeO O MeO MeO MeO MeO 4.28 OMe OMe OMe TB favored TBC TB

conjugation at C6 no conjugation conjugation at C9

sterics between OH(C7-) and phenyl ring sterics between CH3(C8-) and phenyl ring

O O O O O O O O O H O O 9 OH MeO CH3 MeO MeO O CH3 MeO O CH H3C O H MeO 6 MeO 3 MeO MeO OH CH3 OH OH H3C MeO O O MeO MeO MeO MeO 4.47 OMe OMe OMe

TBC favored TB TB

no conjugation conjugation at C6 conjugation at C9

sterics between CH3(C7-) sterics between CH3(C8-) and phenyl ring and phenyl ring

O O O O O O O CH O 3 O O O CH OH CH3 MeO 3 MeO MeO H O CH H3C O 9 3 O CH3 MeO MeO MeO H MeO H OH OH MeO 6 OH O MeO MeO O MeO MeO OMe MeO OMe OMe

4.47a TB favored TB TBC favored

conjugation at C9 conjugation at C6 no conjugation

sterics between CH3(C7-) and phenyl ring

Figure 4.14 The Conformations of Diketones 4.28, 4.47 and 4.47a

indicates they should adopt different conformations as both C9-carbonyl groups in 4.28 and 4.47, and the C6-carbonyl in 4.47 are non-conjugated, while the C9-carbonyl in 7 is coplanar with the aromatic ring. In fact, 4.28 exists as a TB conformation and 4.47 197

adopts a TBC conformation (Figure 4.14). For the diketone 4.28 with a C7-β-OH group,

as discussed previously, the TB with the conjugation at C9 and TBC conformations are not favored due to either the presence of the C8-α-CH3 (the former) or no conjugation (the latter). Although the existence of a C7-β-OH group may cause some steric repulsion with the upper phenyl ring, the conjugation could still ensure the TB conformation most energetically favorable. On the other hand, the diketone 4.47 adopts the TBC conformation, suggesting that the interaction between the C7-β-CH3 group and the upper

phenyl ring is energetically so unfavorable that the conjugation at C6 carbonyl could not compensate at all. Diketone 4.47a possesses two carbonyl groups, C9-carbonyl in good

conjugation with the upper phenyl ring and C6-carbonyl only in partial conjugation with

the lower phenyl ring, according to its spectra data. Based on the above information,

4.47a should adopt a TB conformation with conjugation at C9. Different from 4.28 and

4.47 with C8-α-CH3 groups, the C8-β-CH3 group in 4.47a in this TB conformation does not have steric repulsion with the lower phenyl ring. Diketone 4.47a prefers the TB conformation due to the good conjugation at C9 and partial conjugation at C6 with related phenyl rings, which do not exist in its TBC conformation.

Compounds 4.40 and 4.46 are also diastereomers with different chirality at C7 and

both adopt the TBC formation according to the non-conjugated nature of the C6- carbonyls (Figure 4.15). For the ketone 4.40, the severe crowding caused by the C7-β-

CH3 group and the upper phenyl ring makes its TB conformation highly unfavorable, even with the energy compensation gained from conjugation. The fact that the ketone

198

O O O O O O OTBS OTBS OTBS OH CH MeO MeO MeO O 3 H3C CH 6 MeO 3 MeO MeO OH CH3 OH O MeO O MeO MeO MeO 4.40 OMe OMe

TBC favored TB

no conjugation conjugation at C6

sterics between CH3(C7-) and phenyl ring

O O O O O O OTBS OTBS O Si CH3 CH3 CH MeO 9 MeO MeO O 3 HO 8 CH3 OH OH )( MeO 6 MeO MeO CH3 CH O MeO O 3 MeO MeO MeO 4.46 OMe OMe

TBC favored TB

no conjugation conjugation at C6 sterics between CH3(C7-) and phenyl ring

Figure 4.15 The TBC Conformations of Diketones 4.40 and 4.46

4.46 exists as a TBC conformation was confusing at the first glace, as the structurally similar diketone 4.47 adopts the TB conformation. The only difference of these two compounds is that 4.46 possesses a C9-α-OTBS group while 4.47 contains a C9-carbonyl

group. We do not have a definite explanation for this difference, however, a possible

rationale could involve the unfavorable interaction between one of the methyl groups in

the C9-OTBS substituent and the C8-α-methyl group, which cancels the energy benefit achieved through conjugation at the C6 carbonyl group and eventually makes this TB

conformation unfavorable.

4.8 Conclusions and Outlook 199

O O O O O OR O OR O OR O OH 9 MeO 9 MeO MeO 9 MeO O MeO MeO 6 MeO MeO 6 6 O OAc OH MeO MeO O MeO MeO OR' OR' 9 OR MeO MeO MeO MeO MeO MeO 6 unnatural analogs C9-β-oxygenated natural product analogs with different configurations and oxidation states at C MeO R with C8-β-CH3 6 MeO ananolignan C R=α-OH ananolignan B R=O ananolignan D R'= β-OH O O O O ananolignan F R'= β-OAc O O O OTBS O OTBS O OTBS interiotherin C R'= β-OAng 9 9 9 9 MeO MeO 8 MeO 8 MeO 8 C9-α-oxygenated natural products MeO 7 MeO 7 MeO 7 MeO 7 with different configurations 6 OH 6 6 6 and oxidation states at C6 MeO MeO MeO O MeO OH O OH MeO MeO MeO MeO

O O O O N 1. B SnMe3 O OR O O R1 N * B O steps MeO 9 9 R2 C9 R1=α or β-OR or O or H MeO 8 MeO 8 * C8 R2=α or β-Me MeO OR MeO 7 MeO 7 R3 Pd(0) (cat.) 6 SnMe3 6 C R = Me R = -OH * R4 7 3 β− 4 α 2. pinacol * or R3=β−OH R4=α-Me MeO OR' MeO R MeO OR' 5 C6 R1=α or β-OR' or O or H OMe MeO MeO

O O O O O O OTBS O OTBS O OR O OTBS O OTBS 9 9 MeO 8 MeO 8 9 9 9 MeO MeO MeO 7 OH 7 OH MeO 6 MeO 6 MeO 7 MeO 7 MeO 7 6 OH 6 OH 6 OH MeO O MeO OH MeO MeO OBz MeO OH OH MeO MeO MeO MeO MeO tiegusanin D R=Bz schizanrin F R=Ac

C6-β-oxygenated and O O O O C9-α-oxygenated O OR O OR O OR O natural product with C7-α-OH 9 9 MeO MeO 9 MeO 9 MeO 7 OH 7 OH MeO MeO 7 MeO 7 MeO 6 6 OH 6 OH 6 MeO MeO MeO OR' OR' MeO OR' OBz MeO MeO MeO MeO arisanschinin K unnatural analogs with C7-α-OH natural product and analogs with C7-β-OH

Figure 4.16 A General Approach to the Syntheses of Highly Functionalized DBCOD

Lignan Natural Products (>100) and Unnatural Analogs with Different Configurations

and/or Oxidation States at C6, C7, C8 and C9

200

Eight fully substituted DBCOD lignans, including compounds such as kadsuralignan

B, tiegusanin D, and schizanrin F, with a tertiary center at C7, were synthesized for the first time. The unique conformations of DBCOD intermediates are crucial for different reactivities of certain functional groups (e.g., C-C double bonds, hydroxyl and carbonyl groups), which can explain the stereochemical outcome of related transformations, for example, the hydrogenation reactions, Mitsunobu reactions, electrophilic additions to C-

C double bonds and nucleophilic additions to carbonyl groups. The conformations of

DBCODs containing C6 and/or C9 carbonyl groups are also discussed based on experimental data.

We provide a general approach to the syntheses of highly functionalized DBCOD lignan natural products (>100) and unnatural analogs with different configurations and/or oxidation states at C6, C7, C8 and C9 (Figure 4.16). Due to the generality of this method, we are able to, in principle, rapidly access a large number of unnatural analogs of the

DBCOD lignans to test their biological activities.

4.9 Experimental Section

4.9.1 General Methods

See Section 2.6.1 of chapter 2 for details.

4.9.2 Synthetic Procedures and Spectral Data

201

O O OTBS

MeO MeO CHO MeO MeO

Compound 4.5: Procedure A (H2O2, NaOH): To a stirred solution of cyclized product

2.47c (50 mg, 0.0543 mmol) in THF (3 mL) at 0 °C was added 1N NaOH solution (0.4 mL) and 30% H2O2 (0.6 mL). The reaction mixture was stirred for 18 h at room temperature. Saturated aq. NaHCO3 solution was added to the mixture. After extraction with CH2Cl2, drying with anhydrous MgSO4, filtration, and removal of the solvent under

vacuum, the crude oil was subjected to flash column (EtOAc : hexanes = 1: 4) to give 4.5

(25 mg, 84%) as a light yellow solid. Procedure B (Me3N=O, THF): cyclized product

2.47c (40 mg, 0.0434 mmol) and Me3N=O (65 mg, 0.868 mmol) in THF (3 mL) was

heated to reflux for 2 days. The mixture was filtered over celite®. After removing the solvent of the filtrate under vacuum, the crude oil was subjected to flash column (EtOAc : hexanes = 1: 4) to give 4.5 (21 mg, 90%) as a light yellow solid. [α]D: +114.4 (c 0.675,

1 CHCl3). H NMR (500 MHz, CDCl3) δ 9.52 (s, 1 H), 7.06 (s, 1 H), 6.60 (s, 1 H), 6.58 (s,

1 H), 5.95 (s, 1 H), 5.89 (s, 2 H), 5.80 (s, 3 H), 5.23 (s, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H),

13 3.86 (s, 6 H), 0.85 (s, 9 H), -0.14 (s, 3 H), -0.18 (s, 3 H). C NMR (125 MHz, CDCl3) δ

194.04, 153.22, 151.76, 149.26, 145.99, 143.54, 141.90, 139.86, 138.63, 136.71, 134.84,

132.63, 128.57, 127.65, 126.98, 121.01, 118.87, 114.67, 105.81, 11.85, 99.27, 71.35,

60.92, 60.62, 59.43, 55.97, 28.82, -4.84, -5.44. IR (neat, cm–1):2951, 2929, 2854, 1697,

202

+ 1620, 1469, 1107, 837. HRMS (ESI) [M+Na] m/z calcd for C29H36O8SiNa 563.2077, found 563.2085.

O O OTBS

MeO MeO

MeO OBn MeO

Synthesis of compound 4.6: A solution of 2.47c (300 mg, 0.336 mmol) in AcOH (10 mL) was stirred at 120 °C for 12h under nitrogen. After removing the solvent under vacuum, the red crude oil was directly subjected to flash chromatography (EtOAc: hexanes = 1: 6) to give diene 4.6 as a white solid (195 mg, 92%). [α]D -125.8 (c 0.12,

1 CHCl3). H NMR (400 MHz, CDCl3) δ 7.28-7.22 (m, 5 H), 6.93 (s, 1 H), 6.84 (s, 1 H),

5.99 (d, J = 1.2 Hz, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 5.44 (m, 1 H), 5.12 (m, 3 H), 4.51 (s,

1 H), 4.38 (s, 1 H), 4.33 (d, J = 12 Hz, 1 H), 4.28 (d, J = 12 Hz, 1 H), 3.89 (s, 3 H), 3.87

(s, 3 H), 3.83 (s, 3 H), 3.80 (s, 3 H), 0.82 (s, 9 H), -0.17 (s, 3 H), -0.23 (s, 3 H). 1H NMR

(500 MHz, C6D6) δ 7.26 (s, 1H), 7.21-7.03 (m, 6 H), 5.79 (s, 1 H), 5.72 (s, 1 H), 5.39 (d,

J = 2.5 Hz, 1 H), 5.35 (d, J = 2.5 Hz, 1 H), 5.32 (d, J = 1 Hz, 1 H), 5.25 (d, J = 1 Hz, 1

H), 5.12 (m, 3 H), 4.99 (s, 1 H), 4.75 (s, 1 H), 4.32 (d, J = 11.5 Hz, 1 H), 4.17 (d, J =

11.5 Hz, 1 H), 3.97 (s, 3 H), 3.87 (s, 3 H), 3.80 (s, 3 H), 3.36 (s, 3 H), 0.89 (s, 9 H), -0.09

13 (s, 3 H), -0.10 (s, 3 H). C NMR (125 MHz, C6D6) δ 154.95, 153.23, 151.21, 150.67,

149.98, 141.52, 140.20, 139.03, 138.69, 137.24, 135.50, 128.36, 127.80, 127.70, 127.61,

127.34, 120.86, 119.22, 110.34, 109.99, 103.36, 100.70, 100.22, 77.59, 71.19, 70.45,

60.68, 60.19, 59.05, 55.17, 25.80, 18.15, -5.12, -5.29. IR (neat, cm–1): 3442, 2954, 2927, 203

+ 2855, 1643, 1634, 1076. HRMS (ESI) [M+Na] m/z calcd for C36H44O8SiNa 655.2703, found 655.2710.

O O O O 6.96(s) 6.75(s) O O H H 2.07(m) H O OTBS O OTBS TBS H TBS 3.94(d) 3.62(d) O O MeO MeO H CH3 H CH3 0.98(d) 1.02(d) MeO MeO 4.45(s) H H H 2.01(m) CH3 MeO MeO MeO 1.10(d) MeO OH OH H CH3 0.76(d) 1.45(m) MeO MeO OH OH H H MeO nOe observed MeO nOe observed 6.81(s) 6.91(s) MeO MeO OMe 4.9 4.10 OMe 4.9 4.10

Synthesis of compound 4.9 and its C7 epimer 4.10: To a solution of diene 4.6 (200 mg,

0.317 mmol) in THF was added Pd/C (5%w/w) (150 mg). The mixture was stirred at 50

°C under H2 (230 psi) for 24h before it was filtered through celite. After removing the

solvent under vacuum, the crude white solid was subjected to flash chromatography

(EtOAc: hexanes = 1: 8) to give 4.9 (152 mg, 88%) as a white solid and its C7 epimer

1 4.10 (19 mg, 11%) as a light yellow solid. Alcohol 4.9: [α]D -74.8 (c 0.115, CHCl3). H

NMR (500 MHz, CDCl3) δ 6.96 (s, 1 H), 6.81 (s, 1 H), 5.97 (d, J = 1.5 Hz, 1 H), 5.94 (d,

J = 1.5 Hz, 1 H), 4.45 (s, 1 H), 3.94 (s, 1 H), 3.84 (s, 6 H), 3.81 (s, 3 H), 3.84 (s, 3 H),

2.07 (m, 1 H), 2.01 (m, 1 H), 0.98 (d, J = 7.5 Hz, 3 H), 0.82 (s, 9H), 0.76 (d, J = 7.5 Hz, 3

H), -0.22 (s, 3H), -0.31 (s, 3H). (500 MHz, C6D6) δ 7.14 (s, 1 H), 7.00 (s, 1 H), 5.38 (d, J

= 1 Hz, 1 H), 5.27 (d, J = 1 Hz, 1 H), 4.45 (d, J = 1 Hz, 1 H), 4.22 (d, J = 8.5 Hz, 1 H),

3.95 (s, 3 H), 3.83 (s, 3 H), 3.82 (s, 3 H), 3.48 (s, 3 H), 2.12 (m, 1 H), 1.98 (m, 1 H), 1.08

(d, J = 7 Hz, 3 H), 0.92 (s, 9H), 0.91 (d, J = 7 Hz, 3 H), -0.6 (s, 3H), -0.08 (s, 3H). 13C

NMR (125 MHz, CDCl3) δ 152.55, 151.00, 149.34, 142.89, 140.19, 139.67, 136.88,

134.34, 119.47, 117.27, 105.31, 100.75, 99.52, 73.50, 68.11, 60.80, 60.52, 59.48, 55.89,

204

45.09, 42.92, 30.33, 25.85, 18.14, 16.13, 8.31, -4.63, -5.35. IR (neat, cm–1):3466, 1622,

+ 1595, 1454, 1271, 1103, 1078, 875. HRMS (ESI) [M+Na] m/z calcd for C29H42O8SiNa

1 569.2547, found 569.2540. Alcohol 4.10: [α]D -78.1 (c 0.16, CHCl3). H NMR (500

MHz, CDCl3) δ 6.91 (s, 1 H), 6.75 (s, 1 H), 5.96 (s, 1 H), 5.95 (s, 1 H), 3.94 (s, 3 H), 3.92

(s, 3 H), 3.91 (s, 3 H), 3.84 (s, 3 H), 3.63 (d, J = 9.5 Hz, 1 H), 1.45 (m, 1 H), 1.10 (d, J =

6 Hz, 3 H), 1.02 (d, J = 6 Hz, 3 H), 0.79 (s, 9H), -0.29 (s, 3H), -0.40 (s, 3H). (500 MHz,

C6D6) δ 7.08 (s, 1 H), 6.98 (s, 1 H), 5.37 (d, J = 1 Hz, 1 H), 5.32 (d, J = 1 Hz, 1 H), 4.05

(s, 3 H), 4.00 (d, J = 9.5 Hz, 1 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 3.41 (s, 3 H), 1.65 (m, 1

H), 1.23 (d, J = 6 Hz, 3 H), 1.19 (d, J = 6 Hz, 3 H), 0.91 (s, 9H), -0.14 (s, 3H), -0.15 (s,

13 3H). C NMR (100 MHz, CDCl3) δ 153.83, 150.18, 149.01, 141.83, 140.33, 139.27,

134.33, 119.66, 118.56, 102.98, 100.72, 100.63, 72.95, 72.75, 60.72, 60.42, 59.36, 55.96,

48.67, 47.40, 25.87, 19.89, 19.22, 18.06, -4.67, -5.51. IR (neat, cm–1): 3468, 2956, 2924,

+ 2852, 1595, 1452, 1107, 1082, 837. HRMS (ESI) [M+Na] m/z calcd for C29H42O8SiNa

569.2547, found 569.2550.

O O OH

MeO MeO

MeO OH MeO

Diol 4.12: To a solution of alcohol 4.9 (60 mg, 0.11 mmol) in MeOH (3 mL) was added 3

M HCl solution (0.5 mL). The mixture was stirred at room temperature for 18 h. K2CO3

and water were added to quench the reaction. After extraction with CH2Cl2, drying with

anhydrous MgSO4, filtration and removal of the solvent under vacuum, the crude diol 205

was subjected to flash chromatography (EtOAc: hexanes = 1: 2) to give 4.12 (46 mg,

1 96%) as a white solid. H NMR (500 MHz, CDCl3) δ 6.95 (s, 1 H), 6.85 (s, 1 H), 5.94 (s,

2 H), 4.39 (s, 1 H), 4.01 (d, J = 8.5 Hz, 1 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.82 (s, 3 H),

3.61 (s, 3 H), 2.10 (m, 1 H), 1.99 (m, 1 H), 1.03 (d, J = 7 Hz, 3 H), 0.75 (d, J = 7 Hz, 3

13 H); C NMR (125 MHz, CDCl3) δ 152.54, 150.81, 149.73, 141.84, 140.53, 139.78,

136.88, 134.92, 123.47, 119.60, 117.86, 106.04, 100.96, 98.73, 73.04, 67.88, 60.90,

60.79, 59.54, 55.93, 43.72, 42.91, 30.33, 29.69, 14.95, 8.34. IR (neat, cm–1): 3479, 2966,

+ 2929, 2854, 1597, 1398, 1103. HRMS (ESI) [M+Na] m/z calcd for C23H28O8Na

455.1784, found 455.1775.

O O OTBS

MeO MeO

MeO O

MeO O

NO2

Ester 4.15: To a mixture of the alcohol 4.9 (20 mg, 0.037 mmol), PPh3 (97 mg, 0.37

mmol) and p-nitro-benzoic acid (62 mg, 0.37 mmol) in THF (2 mL) was added DEAD

[40% toluene solution (w/w), 161 mg, 0.37 mmol] dropwise. The mixture was stirred at

room temperature for 18 h. After removal of the solvent under vacuum, the crude oil was

subjected to flash chromatography (EtOAc: hexanes = 1: 10) to give the ester 4.15 (24

1 mg, 96%) as a yellow oil. H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.5 Hz, 1 H), 8.05

(d, J = 8.5 Hz, 1 H), 6.84 (s, 1 H), 6.73 (s, 2 H), 6.06 (s, 1 H), 6.04 (s, 1 H), 5.76 (d, J =

10 Hz, 1 H), 3.93 (d, J = 8 Hz, 1 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.85 (s, 3 H), 3.72 (s, 3 206

H), 1.76 (m, 1 H), 1.57 (m, 1 H), 0.97 (d, J = 7 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 0.87

13 (s, 9 H), -0.17 (s, 3 H), -0.21 (s, 3 H). C NMR (125 MHz, CDCl3) δ 164.00, 152.50,

151.57, 150.36, 149.44, 142.45, 140.93, 138.17, 136.17, 134.39, 133.41, 130.88, 125.52,

123.23, 122.77, 118.36, 111.09, 100.87, 98.35, 83.40, 76.56, 60.61, 60.56, 60.38, 59.13,

56.07, 47.88, 38.95, 34.23, 30.33, 25.84, 18.07, 12.29, -4.35, -5.12. HRMS (ESI)

+ [M+Na] m/z calcd for C36H45NO11Na 718.2660, found 718.2654.

O O OTBS

MeO MeO

MeO OH MeO

Alcohol 4.16: To a solution of the benzoate 4.15 (20 mg, 0.029 mmol) in CH2Cl2 (3 mL)

at 0 °C was added DIBAL-H (0.1 mL, 1.2 M solution in toluene, 0.12 mmol). The

mixture was stirred for 30 min at 0 °C, to which a saturated aq. NaHCO3 solution was added. After extraction with CH2Cl2, drying with anhydrous MgSO4, filtration, and

removal of the solvent under vacuum, the crude oil was subjected to flash column

(EtOAc: hexanes =1:4) to give the alcohol 4.16 as a light yellow oil (14 mg, 90%). 1H

NMR (500 MHz, CDCl3) δ 6.69 (s, 1 H), 6.60 (s, 1 H), 6.02 (d, J = 1 Hz, 1 H), 5.96 (d, J

= 1 Hz, 1 H), 4.08 (m, 1 H), 3.95 (s, 3 H), 3.91 (s, 3 H), 3.89 (d, J = 8 Hz, 1 H), 3.86 (s, 3

H), 3.72 (s, 3 H), 1.77 (m, 1 H), 1.03 (d, J = 7 Hz, 3 H), 0.87 (d, J = 7 Hz, 3 H), 0.85 (s, 9

+ H), -0.18 (s, 3 H), -0.23 (s, 3 H). HRMS (ESI) [M+Na] m/z calcd for C29H42O8SiNa

569.2547, found 569.2550.

207

NO2

O O O O O O OH

MeO MeO MeO MeO

MeO O MeO O MeO MeO O O NO 4.17 NO2 4.18 2

Alcohol 4.17 and diester 4.18: To a mixture of alcohol 4.12 (16 mg, 0.037 mmol), PPh3

(97 mg, 0.37 mmol) and p-nitro-benzoic acid (62 mg, 0.37 mmol) in THF (2 mL) was

added DEAD [40% toluene solution (w/w), 161 mg, 0.37 mmol] dropwise. The mixture

was stirred at room temperature for 2 days. After removal of the solvent under vacuum,

the crude oil was subjected to flash chromatography (EtOAc: hexanes = 1: 10) to give the

alcohol 4.17 (13 mg, 60%) as a yellow oil and the diester 4.18 (2.7 mg, 10%). Alcohol

1 4.17: H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 7.5 Hz, 1 H), 8.05 (d, J = 7.5 Hz, 1 H),

6.86 (s, 1 H), 6.81 (s, 1 H), 6.46 (s, 1 H), 6.08 (d, J = 1.5 Hz, 1 H), 6.03 (d, J = 1.5 Hz, 1

H), 5.79 (d, J = 9.5 Hz, 1 H), 4.45 (s, 1 H), 3.90 (s, 6 H), 3.88 (s, 3 H), 3.62 (s, 3 H), 1.81

(m, 1 H), 1.57 (m, 1 H), 1.07 (d, J = 7 Hz, 3 H), 0.95 (d, J = 7.5 Hz, 3 H). HRMS (ESI)

+ 1 [M+Na] m/z calcd for C30H31NO11Na 604.1795, found 604.1802. Diester 4.18: H

NMR (500 MHz, CDCl3) δ 8.30 (m, 1 H), 8.23 (d, J = 7.5 Hz, 1 H), 8.18 (d, J = 7.5 Hz, 1

H), 8.13 (d, J = 7.5 Hz, 1 H), 6.84 (s, 1 H), 6.64 (s, 1 H), 6.14 (d, J = 1.5 Hz, 1 H), 6.95

(s, 1 H), 5.89 (s, 1 H), 4.02 (s, 1 H), 3.62 (s, 6 H), 3.35 (s, 3 H), 3.17 (s, 3 H), 2.40 (m, 1

+ H), 2.02 (m, 1 H). HRMS (ESI) [M+Na] m/z calcd for C37H34N2O14Na 753.1908, found

753.1916.

208

O O O

MeO MeO

MeO O MeO

Diketone 4.19: To a solution of alcohol 4.12 (65 mg, 0.119 mmol) in CH2Cl2 (5 mL) was added PCC (102 mg, 0.476 mmol), NaOAc (39 mg, 0.476 mmol) and celite (50 mg). The mixture was stirred for 18 h at room temperature before it was directly subjected to flash chromatography (EtOAc: hexanes = 1: 4) to give 4.19 (45 mg, 90%) as a light yellow

1 solid. [α]D +47.0 (c 0.725, CHCl3). H NMR (500 MHz, CDCl3) δ 7.16 (s, 1 H), 6.40 (s,

1 H), 6.04 (s, 2 H), 4.75(s, 1 H), 3.93 (s, 3 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.47 (s, 3 H),

3.33 (m, 1 H), 2.50 (m, 1 H), 1.18 (d, J = 6.5 Hz, 3 H), 0.90 (d, J = 6.5 Hz, 3 H). 13C

NMR (125 MHz, CDCl3) δ 209.10, 201.78, 153.31, 151.66, 150.06, 146.19, 142.04,

136.94, 135.59, 131.77, 122.03, 117.80, 108.36, 101.64, 97.12, 60.98, 60.46, 59.77,

55.92, 52.46, 47.18, 30.32, 15.28, 8.42. IR (neat, cm–1): 2926, 2852, 1710, 1668, 1606,

+ 1101. HRMS (ESI) [M+Na] m/z calcd for C23H24O8Na 451.1369, found 451.1360.

O O O

MeO MeO

MeO OH MeO

Ketone 4.13: To a solution of diketone 4.19 (16.0 mg, 0.037 mmol) in AcOH (3 mL) was

added Pd/C (5% w/w) (20 mg). The mixture was stirred at 50°C under H2 (230 psi) for

18 h before it was filtered through celite. After removing the solvent under vacuum, the 209

crude white solid was subjected to flash chromatography (EtOAc: hexanes = 1: 3) to give

1 4.13 (15.1 mg, 95%) as a white solid. [α]D -105.9 (c 0.375, CHCl3). H NMR (500 MHz,

CDCl3) δ 6.92 (s, 1 H), 6.34 (s, 1 H), 6.02 (d, J = 1.5 Hz, 1 H), 6.01 (d, J = 1.5 Hz, 1 H),

4.87(d, J = 1 Hz, 1 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 3.86 (s, 3 H), 3.58 (s, 3 H), 3.34 (m, 1

H), 2.28 (m, 1 H), 1.12 (d, J = 7 Hz, 3 H), 0.68 (d, J = 7 Hz, 3 H). 13C NMR (125 MHz,

CDCl3) δ 209.33, 152.63, 151.63, 149.54, 141.28, 141.19, 140.76, 136.60, 134.19,

120.40, 115.70, 106.83, 101.44, 97.19, 73.11, 61.08, 60.73, 59.82, 55.92, 48.76, 43.23,

14.10, 7.93. IR (neat, cm–1): 2924, 2853, 1699, 1456, 1404, 1394, 1107. HRMS (ESI)

+ [M+Na] m/z calcd for C23H26O8Na 453.1526, found 453.1535.

O O OH

MeO MeO

MeO O MeO

Ketone 4.20: To a solution of ketone 4.19 (45 mg, 0.105 mmol) in THF (5 mL) at 0 °C

t was added LiAl(O Bu)3H (267 mg, 1.05 mmol). The mixture was stirred for 4h at 0 °C,

t to which a saturated solution of Na2SO4 was added to quench excess LiAl(O Bu)3H.

Then dry Na2SO4 was added and the mixture was filtered over celite. Removal of solvent and flash chromatography (EtOAc: hexanes = 1: 3) gave the alcohol 4.20 as a white solid

(36 mg, 80%) and the alcohol 4.13 as a white solid (6 mg, 13%). [α]D +21.5 (c 0.545,

1 CH2Cl2). H NMR (500 MHz, CDCl3) δ 7.60 (s, 1 H), 6.37 (s, 1 H), 6.03 (s, 1 H), 6.02

(s, 1 H), 4.75 (s, 1 H), 3.95 (s, 3 H), 3.93 (s, 3 H), 3.87 (s, 3 H), 3.51 (s, 3 H), 2.95 (m, 1

H), 1.96 (m, 1 H), 1.01 (d, J = 7 Hz, 3 H), 0.92 (d, J = 7 Hz, 3 H). 13C NMR (125 MHz, 210

CDCl3) δ 200.93, 152.74, 151.66, 149.44, 146.36, 142.14, 136.07, 135.67, 130.81,

125.07, 119.42, 108.09, 101.43, 101.38, 79.40, 60.98, 60.42, 59.79, 55.82, 48.01, 43.94,

15.75, 10.28. IR (neat, cm–1): 3502, 2964, 2935, 2852, 1685, 1456, 1107. HRMS (ESI)

+ [M+Na] m/z calcd for C23H26O8Na 453.1526, found 453.1530.

O O OH

MeO MeO

MeO OH MeO (-)-ananonlignan C

Ananolignan C: To a stirred solution of ketone 4.13 (12.0 mg, 0.0279 mmol) in MeOH

(3 mL) at room temperature was added NaBH4 (10 mg, 0.28 mmol). The reaction

mixture was stirred for 18 h at room temperature. The reaction was quenched with water

(2 mL). After extraction with CH2Cl2, drying with anhydrous MgSO4, filtration, and

removal of the solvent under vacuum, the crude solid was subjected to flash column

(EtOAc : hexanes = 1: 2) to give ananolignan C (10.8 mg, 90%) as a white solid. [α]D -

1 42.1(c 0.380, CHCl3). H NMR (400 MHz, CDCl3) δ 7.04 (s, 1 H), 6.33 (s, 1 H), 5.98 (d,

J = 1.2 Hz, 1 H), 5.96 (d, J = 1.2 Hz, 1 H), 4.74 (d, J = 1.6 Hz, 1 H), 4.59 (s, 1 H), 3.92

(s, 3 H), 3.91(s, 3 H), 3.86 (s, 3 H), 3.67 (s, 3 H), 2.18 (m, 1 H), 2.06 (m, 1 H), 1.20 (d, J

13 = 7.2 Hz, 3 H), 0.92 (d, J = 7.2 Hz, 3 H). C NMR (125 MHz, CDCl3) δ 153.04, 151.19,

149.06, 141.06, 140.92, 138.62, 135.48, 135.35, 119.81, 117.59, 106.47, 102.20, 101.19,

83.87, 72.62, 61.00, 60.63, 59.71, 55.96, 43.67, 41.70, 20.29, 9.85. IR (neat, cm–1): 3441,

211

+ 2924, 2852, 1599, 1454, 1105. HRMS (ESI) [M+Na] m/z calcd for C23H28O8Na

455.1682, found 455.1690.

O O OAc

MeO MeO

MeO O MeO (-)-ananonlignan B revised structure

Ananolignan B (structure revised): To a solution of the alcohol 4.20 (10.0 mg, 0.023 mmol) in CH2Cl2 (2 mL) at room temperature was added AcCl (0.2 mL). After stirring

for 18 h the solvent and excess AcCl were removed under vacuum to give a crude oil,

which was subjected to flash chromatography (EtOAc: hexanes = 1: 4) to give

1 ananolignan B (10.4 mg, 95%) as a light yellow solid. [α]D: +46.4 (c 0.455, CHCl3). H

NMR (500 MHz, CDCl3) δ 7.70 (s, 1 H), 6.50 (s, 1 H), 6.04 (s, 1 H), 6.03 (s, 1 H), 5.67

(d, J = 5.5 Hz, 1 H), 3.95 (s, 6 H), 3.89(s, 3 H), 3.37 (s, 3 H), 3.10 (m, 1 H), 2.02 (m, 1

H), 1.43 (s, 3 H), 1.04 (d, J = 6.5 Hz, 3 H), 0.87 (d, J = 7 Hz, 3 H). 13C NMR (125 MHz,

CDCl3) δ 200.42, 169.84, 152.20, 151.42, 149.47, 145.93, 142.24, 136.48, 132.19,

131.93, 125.66, 120.01, 107.81, 101.60, 101.46, 79.31, 60.88, 60.18, 59.87, 55.93, 46.28,

42.71, 20.10, 15.51, 10.43. IR (neat, cm–1):2929, 2852, 1734, 1585, 1456, 1234, 1109,

+ 975. HRMS (ESI) [M+Na] m/z calcd for C25H28O9Na 495.1631, found 495.1620.

212

O O OAc

MeO MeO

MeO OH MeO (-)-ananonlignan D

Ananolignan D: To a solution of ananolignan B (18.0 mg, 0.038 mmol) in AcOH (3

mL) was added Pd/C (5%w/w) (20 mg). The mixture was stirred at 50 °C under H2 (230

psi) for 18 h before it was filtered through celite. After removing the solvent under

vacuum, the crude white solid was subjected to flash chromatography (EtOAc: hexanes =

1: 3) to give ananolignan D (16.7 mg, 94%) as a white solid. [α]D -16.7 (c 0.245,

1 CHCl3). H NMR (400 MHz, CDCl3) δ 7.01 (s, 1 H), 6.44 (s, 1 H), 5.97 (d, J = 1.2 Hz, 1

H), 5.96 (d, J = 1.2 Hz, 1 H), 5.60 (s, 1 H), 4.75 (s, 1 H), 3.93 (s, 3 H), 3.88(s, 3 H), 3.85

(s, 3 H), 3.64 (s, 3 H), 2.15 (m, 2 H), 1.58 (s, 3 H), 1.10 (d, J = 7.2 Hz, 3 H), 0.90 (d, J =

13 7.2 Hz, 3 H). C NMR (125 MHz, CDCl3) δ 169.90, 152.11, 150.35, 148.99, 141.03,

140.13, 135.85, 135.56, 135.26, 121.13, 118.67, 105.95, 102.27, 101.21, 82.15, 72.78,

60.65, 60.31, 59.63, 55.98, 43.45, 40.64, 20.67, 19.99, 9.48. IR (neat, cm-1): 3444, 2926,

2854, 1732, 1453, 1371, 1234,1107, 1068. HRMS (ESI) [M+Na]+ m/z calcd for

C25H30O9Na 497.1788, found 497.1781.

O O OAc

MeO MeO

MeO OH MeO

213

Alcohol 4.22: To a solution of ananolignan D (20.0 mg, 0.042 mmol) in CH2Cl2 (3 mL) was added Ms2O (36 mg, 0.21 mmol), Et3N (21 mg, 0.21 mmol), and one crystal of

DMAP. The mixture was stirred at room temperature for 18 h and quenched with H2O

(0.5 mL) before it was directly subjected to flash chromatography (EtOAc: hexanes = 1:

1 3) to give 4.22 (19.4 mg, 97%) as a white solid. [α]D +4.9 (c 0.285, CHCl3). H NMR

(400 MHz, CDCl3) δ 6.55 (s, 1 H), 6.45 (s, 1 H), 5.99 (s, 2 H), 5.73 (d, J = 4.4 Hz, 1 H),

3.90 (s, 3 H), 3.89(s, 3 H), 3.88 (s, 3 H), 3.58 (s, 3 H), 2.00 (m, 2H), 1.57 (s, 3 H), 0.99

13 (d, J = 7.2 Hz, 3 H), 0.84 (d, J = 7.2 Hz, 3 H). C NMR (125 MHz, CDCl3) δ 170.07,

152.14, 151.70, 149.18, 141.81, 141.11, 136.16, 133.30, 132.21, 109.90, 102.51, 101.30,

81.31, 60.64, 60.13, 59.63, 56.07, 41.00, 31.42, 22.70, 20.62, 14.10. IR (neat, cm–1):

3444, 2956, 2924, 2852, 1732, 1454, 1259, 1238; HRMS (ESI) [M+Na]+ m/z calcd for

C25H30O9Na 497.1788, found 497.1779.

O O OAc

MeO MeO

MeO O

MeO O interiotherin C

Interiotherin C: To a solution of alcohol 4.22 (5.0 mg, 0.0105 mmol) in CH2Cl2 (2 mL)

was added angeloyl chloride (37 mg, 0.315 mmol). The mixture was stirred at room

temperature for 18 h and directly subjected to flash chromatography (EtOAc: hexanes =

1: 3) to give interiotherin C (5.0 mg, 85%) as a white solid. [α]D +38.6 (c 0.295,

1 CHCl3). H NMR (400 MHz, CDCl3) δ 6.71 (s, 1 H), 6.44 (s, 1 H), 5.95 (m, 1 H), 5.94

214

(s, 2 H), 5.83 (d, J = 7.6 Hz, 1 H), 5.73 (d, J = 3.6 Hz, 1 H), 3.90 (s, 3 H), 3.88(s, 3 H),

3.78 (s, 3 H), 3.57 (s, 3 H), 2.22 (m, 1 H), 2.13 (m, 1 H), 1.85 (dd, J = 7.2 Hz, 1.6 Hz,

2H), 1.58 (s, 3 H), 1.51 (s, 3 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H). 13C

NMR (125 MHz, CDCl3) δ 170.06, 166.70, 151.78, 151.58, 148.60, 141.78, 141.29,

138.60, 135.96, 133.09, 131.32, 127.80, 121.15, 102.27, 110.55, 110.47, 101.02, 80.71,

60.59, 60.17, 59.29, 56.01, 38.74, 38.03, 37.63, 20.68, 19.88, 15.59. IR (neat, cm–1):

2956, 2924, 2852, 1741, 1714, 1506, 1456, 1361, 1105. HRMS (ESI) [M+Na]+ m/z

calcd for C30H36O10Na 579.2206, found 579.2214.

O O OAc

MeO MeO

MeO OAc MeO ananonlignan F

Ananolignan F: To a solution of alcohol 4.22 (6.0 mg, 0.0127 mmol) in CH2Cl2 (2 mL) was added Ac2O (13 mg, 0.127 mmol) and one crystal of p-TsOH. The mixture was

stirred at room temperature for 18 h and directly subjected to flash chromatography

(EtOAc: hexanes = 1: 3) to give Ananolignan F (6.3 mg, 96%) as a white solid. [α]D

1 +34.5 (c 0.235, CHCl3). H NMR (400 MHz, CDCl3) δ 6.69 (s, 1 H), 6.44 (s, 1 H), 5.99

(d, J = 1.2 Hz, 1 H), 5.97 (d, J = 1.2 Hz, 1 H), 5.75 (d, J = 4.8 Hz, 1 H), 5.71 (d, J = 8.4

Hz, 1 H), 3.88 (s, 6 H), 3.85(s, 3 H), 3.58 (s, 3 H), 2.14 (m, 1 H), 2.01 (m, 1H), 1.79 (s, 3

H), 1.57 (s, 3 H), 0.96 (d, J = 7.2 Hz, 3 H), 0.91 (d, J = 7.2 Hz, 3 H). 13C NMR (125

MHz, CDCl3) δ 170.11, 170.06, 151.91, 151.53, 148.61, 141.77, 141.44, 141.14, 136.22,

215

135.68, 131.24, 128.13, 127.97, 121.45, 110.63, 102.33, 101.19, 100.58, 81.02, 60.60,

60.12, 59.53, 56.04, 38.03, 37.63, 20.96, 20.63. IR (neat, cm–1):2956, 2852, 1737, 1732,

+ 1454, 1105. HRMS (ESI) [M+Na] m/z calcd for C27H32O10Na 539.1893, found

539.1885.

O O OTBS

MeO MeO

MeO O MeO

Ketone 4.25: To a solution of alcohol 4.9 (12 mg, 0.022 mmol) in CH2Cl2 (5 mL) was

added PCC (24 mg, 0.11 mmol), NaOAc (9 mg, 0.11 mmol) and celite (10 mg). The

mixture was stirred for 18 h before it was directly subjected to flash chromatography

(EtOAc: hexanes = 1: 4) to give 4.25 (10.8 mg, 90%) as a light yellow solid. 1H NMR

(500 MHz, CDCl3) δ 7.49 (s, 1 H), 6.81 (s, 1 H), 6.03 (d, J = 1.5 Hz, 1 H), 6.00 (s, J = 1.5

Hz, 1 H), 4.17(d, J = 9 Hz, 1 H), 3.95 (s, 3 H), 3.93 (s, 3 H), 3.86 (s, 3 H), 3.63 (s, 3 H),

2.49 (m, 1 H), 1.56 (m, 1 H), 0.99 (d, J = 7 Hz, 3 H), 0.87 (s, 9 H), 0.84 (d, J = 7 Hz, 3

13 H), -0.15 (s, 3H), -0.21 (s, 3H). C NMR (125 MHz, CDCl3) δ 201.12, 152.68, 151.42,

149.71, 145.79, 140.88, 137.57, 135.11, 134.59, 123.32, 118.69, 107.47, 101.04, 98.39,

76.27, 60.81, 60.72, 59.61, 55.87, 49.21, 46.24, 25.84, 18.10, 15.25, 12.37, -4.33, -5.12.

+ HRMS (ESI) [M+Na] m/z calcd for C29H40O8SiNa 567.2390, found 567.2386.

216

O O OH

MeO MeO

MeO O MeO

Ketone 4.26: To a solution of the TBS ether 4.25 (20 mg, 0.037 mmol) in MeOH (3 mL) was added 3 M HCl solution (0.5 mL). The mixture was stirred at room temperature for

18 h. K2CO3 and water were added to quench the reaction. After extraction with

CH2Cl2, drying with anhydrous MgSO4, filtration and removal of the solvent under

vacuum, the crude diol was subjected to flash chromatography (EtOAc: hexanes = 1: 3)

1 to give the ketone 4.26 (15.5 mg, 98%) as a white solid. H NMR (400 MHz, CDCl3) δ

7.46 (s, 1 H), 6.85 (s, 1 H), 6.00 (s, 1 H), 5.99 (s, 1 H), 4.28(d, J = 9.6 Hz, 1 H), 3.93 (s, 3

H), 3.91(s, 3 H), 3.84 (s, 3 H), 3.52 (s, 3 H), 2.50 (m, 1 H), 1.56 (m, 1 H), 0.99 (d, J = 6.4

13 Hz, 3 H), 0.90 (d, J = 6.4 Hz, 3 H). C NMR (125 MHz, CDCl3) δ 201.00, 152.71,

151.20, 149.99, 145.95, 141.07, 137.12, 135.29, 134.45, 123.47, 118.76, 107.79, 101.14,

97.59, 75.47, 67.93, 60.87, 60.71, 59.62, 55.86, 48.17, 46.62, 25.58, 15.22, 12.37.

+ HRMS (ESI) [M+Na] m/z calcd for C23H26O8Na 453.1526, found 453.1520.

O O OTMS

MeO MeO

MeO O MeO

Ketone 4.27: To a mixture of the alcohol 4.20 (10 mg, 0.023 mmol) and Et3N (7 mg,

0.07 mmol) in CH2Cl2 (2 mL) was added TMSOTf (15 mg, 0.07 mmol). The mixture 217

was stirred at room temperature for 18 h, to which a saturated aq. NaHCO3 solution was added. After extraction with CH2Cl2, drying with anhydrous MgSO4, filtration, and

removal of the solvent under vacuum, the crude oil was subjected to flash column

(EtOAc : hexanes = 1:6) to give 4.27 (10.4 mg, 90%) as a colorless oil. 1H NMR (500

MHz, CDCl3) δ 7.62 (s, 1 H), 6.33 (s, 1 H), 6.02 (s, 2 H), 4.63(d, J = 4.5 Hz, 1 H), 3.93

(s, 3 H), 3.91 (s, 3 H), 3.86 (s, 3 H), 3.63 (s, 3 H), 3.06 (m, 1 H), 1.80 (m, 1 H), 0.98 (d, J

= 6.5 Hz, 3 H), 0.86 (d, J = 6.5 Hz, 3 H), -0.25 (s, 9 H). HRMS (ESI) [M+Na]+ m/z calcd

for C26H34O8SiNa 525.1921, found 525.1928.

O 6.56(s) O H O H 3.18(m) O O MeO CH O 3 0.98(d) O OH MeO MeO OH CH3 MeO 1.14(s)

H MeO nOe observed MeO O 7.10(s)

OMe MeO 4.28

Diketone 4.28: To a solution of ketone 4.20 (4.0 mg, 0.009 mmol) in THF (2 mL) at -23

°C was added LDA (2 M solution in THF, 0.05 mL, 0.1 mmol). The mixture was

warmed to 0 °C for 30 min and then cooled down to -23 °C again. To the mixture was

. . added MoOPH (MoO5 Pyridine HMPA, 86 mg, 0.2 mmol). The resulting mixture was

gradually warmed to room temperature and stirred for 18 h. After extraction with

CH2Cl2, drying with anhydrous MgSO4, filtration, and removal of the solvent under

vacuum, the crude oil was subjected to flash column (MeOH : CH2Cl2 = 1:20) to give

1 diketone 4.28 as a light yellow solid (2.0 mg, 50%). [α]D +40.0 (c 0.035, CHCl3). H

NMR (500 MHz, CDCl3) δ 7.10 (s, 1 H), 6.56 (s, 1 H), 6.07 (s, 1 H), 6.06 (s, 1 H), 3.95

218

(s, 3 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.50 (s, 3 H), 3.18 (m, 1 H), 1.22 (d, J = 6.5 Hz, 1

H), 1.14 (s, 3 H). IR (neat, cm–1): 2953, 2924, 2854, 1714, 1666, 1469, 1454, 1099.

+ HRMS (ESI) [M+Na] m/z calcd for C23H24O9Na 467.1318, found 467.1325.

O O OTBS

MeO MeO OH

MeO MeO

Alcohol 4.33: To a solution of aldehyde 4.5 (20 mg, 0.037 mmol) in CH2Cl2 (3 mL) at 0

°C was added DIBAL-H (0.31 mL, 1.2 M solution in toluene, 0.37 mmol). The mixture

was stirred for 30 min at 0 °C, to which a aq. NaHCO3 solution was added. After

extraction with CH2Cl2, drying with anhydrous MgSO4, filtration, and removal of the solvent under vacuum, the crude oil was subjected to flash column (EtOAc : hexanes =

1 1:4) to give the alcohol 4.33 as a white solid (19 mg, 95%). H NMR (500 MHz, CDCl3)

δ 6.57 (s, 1 H), 6.54 (s, 1 H), 6.52 (s, 1 H), 5.94 (d, J = 1.5 Hz, 1 H), 5.90 (d, J = 1.5 Hz,

1 H), 5.70 (s, 1 H), 5.28 (s, 1 H), 5.25 (s, 1 H), 5.20 (s, 1 H), 4.28 (d, J = 3 Hz, 1 H), 3.87

(s, 6 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 1.92 (s, 3 H), 0.84 (s, 9 H), -0.18 (s, 3 H), -0.22 (s, 3

+ H). HRMS (ESI) [M+Na] m/z calcd for C29H38O8SiNa 565.2234, found 565.2226.

O O OTBS

MeO MeO

MeO MeO

219

Diene 4.31: To a solution of the alcohol 4.33 (20 mg, 0.037 mmol) in CH2Cl2 (3 mL) at 0

°C was treated with Ms2O (34 mg, 0.19 mmol) and Et3N (20 mg, 0.19 mmol). The

reaction mixture was stirred for 18 h at room temperature. To this mixture was added

Super-hydride (0.37 mmol, 1 M solution in THF, mmol) at 0 °C. After 30 min, to this

solution was added aq. NH4Cl solution. After extraction with CH2Cl2, drying with

anhydrous MgSO4, filtration, and removal of the solvent under vacuum, the crude solid was subjected to flash column (EtOAc: hexanes =1:6) to give diene 4.31 as a yellow

1 syrup (18.5 mg, 90%). [α]D -27.5 (c 0.04, CHCl3). H NMR (500 MHz, CDCl3) δ 6.58

(s, 1 H), 6.49 (s, 1 H), 6.30 (s, 1 H), 5.94 (d, J = 1 Hz, 1 H), 5.91 (d, J = 1 Hz, 1 H), 5.65

(d, J = 1 Hz, 1 H), 5.28 (s, 1 H), 5.14 (s, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.84 (s, 3 H),

3.81 (s, 3 H), 1.92 (s, 3 H), 0.83 (s, 9 H), -0.19 (s, 3 H), -0.23 (s, 3 H). 13C NMR (125

MHz, CDCl3) δ152.55, 151.26, 150.94, 148.80, 140.42, 139.80, 138.63, 134.14, 134.61,

134.54, 126.55, 120.90, 119.31, 109.65, 106.67, 100.68, 99.09, 70.98, 60.78, 60.58,

59.47, 55.82, 25.83, 25.10, 18.17, -4.87, -5.01. IR (neat, cm–1): 2956, 2854, 1681, 1107,

+ 837. HRMS (ESI) [M+Na] m/z calcd for C29H38O7SiNa 549.2285, found 549.2280.

O O O OTBS O OTBS

MeO + MeO MeO MeO

MeO MeO

MeO MeO 4.34 4.31

Diene 4.34: To a solution of the alcohol 4.33 (20 mg, 0.037 mmol) in CH2Cl2 (3 mL) at 0

°C was treated with p-TsCl (15 mg, 0.21 mmol), Et3N (21 mg, 0.21 mmol) and one

220

crystal of DMAP. The reaction mixture was stirred for 18 h at room temperature. To this

mixture was added Super-hydride (0.37 mmol, 1 M solution in THF, mmol) at 0 °C.

After 30 min, to this solution was added saturated aq. NH4Cl solution. After extraction

with CH2Cl2, drying with anhydrous MgSO4, filtration, and removal of the solvent under

vacuum, the crude solid was subjected to flash column (EtOAc: hexanes =1:6) to give a

mixture of 4.31 and 4.34 as a syrup (18.5 mg, 90% over two steps, 4.31 : 4.33 =1:1).

1 Diene 4.34: H NMR (500 MHz, CDCl3) δ 6.61 (s, 1 H), 6.49 (s, 1 H), 6.30 (s, 1 H), 5.98

(s, 1 H), 5.94 (s, 1 H), 5.43 (d, J = 1 Hz, 1 H), 5.09 (s, 1 H), 5.01 (d, J = 1.6 Hz, 1 H),

4.89 (s, 1 H), 4.62 (s, 1 H), 3.91 (s, 3 H), 3.86 (s, 3 H), 3.85 (s, 6 H), 3.79 (s, 3 H), 3.15

(d, J = 10 Hz, 1 H), 2.87 (d, J = 10 Hz, 1 H), 0.82 (s, 9 H), -0.18 (s, 3 H), -0.23 (s, 3 H).

O 6.77(s) 4.22(d) O H H O TBS 5.04(d) H O O OTBS MeO HO H OH MeO MeO 6.40(s)H OH CH3 MeO 1.81(s)

H nOe observed MeO OH MeO 6.57(s)

OMe MeO 4.37

Diol 4.37: To a solution of diene 4.31 (5 mg, 0.01 mmol) in t-BuOH/H2O (v/v=1/1, 2 mL)

was added AD-mix-α (50 mg) and OsO4 (0.02 M solution in t-BuOH, 0.5 mL, 0.01

mmol). The mixture was stirred for 8 h at room temperature. After extraction with

CH2Cl2, drying with anhydrous MgSO4, filtration, and removal of the solvent under

vacuum, the crude oil was subjected to flash column (EtOAc : hexanes = 1: 3) to give

1 4.37 (4.2 mg, 75%) as a light yellow solid. [α]D +18.3 (c 0.175, CHCl3). H NMR (500

MHz, CDCl3) δ 6.77 (s, 1 H), 6.57 (s, 1 H), 6.40 (s, 1 H), 6.01 (d, J = 1.5 Hz, 1 H), 5.98

221

(d, J = 1.5 Hz, 1 H), 5.04 (d, J = 1 Hz, 1 H), 4.21(d, J = 12 Hz, 1 H), 3.89 (s, 3 H), 3.88

(s, 3 H), 3.85 (s, 3 H), 3.81 (s, 3 H), 1.81 (s, 3 H), 0.83 (s, 9H), -0.17 (s, 3H), -0.25 (s,

3H). IR (neat, cm–1): 3439, 2956, 2924, 2854, 1728, 1454, 1259, 1105, 798. HRMS

+ (ESI) [M+Na] m/z calcd for C29H40O9SiNa 583.3232, found 583.3225.

O O OTBS

MeO MeO

MeO MeO

Alkene 4.32: To a solution of alcohol 4.9 (32 mg, 0.059 mmol) in CHCl3 (3 mL) was added (S)-camphorsulfonic acid (41 mg, 1.77 mmol). The mixture was stirred at 70 °C for 10 h and then cooled to room temperature. After removal of the solvent under vacuum, the crude oil was subjected to flash column (EtOAc : hexanes = 1:6) to give 4.32

1 (28 mg, 90%) as a light yellow solid. [α]D +51.1 (c 0.135, CHCl3). H NMR (400 MHz,

CDCl3) δ 6.68 (s, 1 H), 6.44 (s, 1 H), 5.96 (d, J = 1.6 Hz, 1 H), 5.94 (d, J = 1.6 Hz, 1 H),

5.93 (s, 1 H), 4.28 (d, J = 9.2 Hz, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.81 (s,

3 H), 2.04 (m, 1H), 1.65 (s, 3 H), 1.08 (d, J = 6.8 Hz, 1 H), 0.84 (s, 9 H), -0.19 (s, 3 H), -

13 0.27 (s, 3 H). C NMR (125 MHz, CDCl3) δ152.63, 151.21, 148.35, 143.47, 140.18,

139.75, 138.86, 135.58, 134.62, 122.04, 121.09, 120.45, 106.14, 100.64, 98.78, 75.16,

60.70, 60.62, 59.42, 55.82, 51.24, 26.56, 25.87, 18.41, 18.08, -4.39, -5.05; IR (neat, cm–

1):2954, 2927, 2854, 1463, 1400, 1107, 1074, 1047. HRMS (ESI) [M+Na]+ m/z calcd for

C29H40O7SiNa 551.2441, found 551.2435.

222

O O OTBS

MeO MeO

MeO O F C MeO 3 F3C Ph

Ether 4.38: To a solution of alcohol 4.9 (5 mg, 0.01 mmol) in CHCl3 (3 mL) was added

Martin’s sulfurane (12 mg, 0.02 mmol). The mixture was stirred at room temperature for

10 h. After removal of the solvent under vacuum, the crude oil was subjected to flash column (EtOAc : hexanes = 1:10) to give 4.38 (6.2 mg, 80%) as a solid. 1H NMR (500

MHz, CDCl3) δ 7.43 (d, J = 7.5 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 7.07 (t, J = 7.5 Hz, 1

H), 6.68 (s, 1 H), 6.04 (s, 1 H), 6.02 (s, 1 H), 4.47 (d, J = 10 Hz, 1 H), 4.10 (s, 1 H), 3.78

(s, 3 H), 3.75 (d, J = 10 Hz, 1 H), 3.68 (s, 3 H), 3.40 (s, 3 H), 1.83 (m, 1 H), 1.56 (m, 1

H), 1.05 (d, J = 6 Hz, 1 H), 0.85 (d, J = 7.5 Hz, 1 H), 0.83 (s, 9 H), -0.26 (s, 3 H), -0.29

+ (s, 3 H). HRMS (ESI) [M+Na] m/z calcd for C38H46F6O8SiNa 795.2764, found

795.2755.

O 6.74(s) O H 1.85(m) O TBS H 4.29(d) O O OTBS MeO O CH3 1.16(d) H OH MeO MeO OH CH3 MeO 1.37(s)

H MeO nOe observed MeO O 6.47(s) MeO OMe 4.40

Ketone 4.40: To a solution of alkene 4.32 (10 mg, 0.019 mmol) in t-BuOH/H2O

(v/v=1/1, 2 mL) was added AD-mix-α (50 mg) and OsO4 (0.02 M solution in t-BuOH, 0.8

mL, 0.016 mmol). The mixture was stirred for 72 h at room temperature. After

223

extraction with CH2Cl2, drying with anhydrous MgSO4, filtration, and removal of the solvent under vacuum, the crude oil was subjected to flash column (EtOAc : hexanes

=1:3) to give 4.40 ( 8.5 mg, 80%) as a light yellow solid. [α]D -39.6 (c 0.470, CHCl3).

1 H NMR (500 MHz, CDCl3) δ 6.74 (s, 1 H), 6.47 (s, 1 H), 5.96 (d, J = 1 Hz, 1 H), 5.93

(d, J = 1 Hz, 1 H), 4.29 (d, J = 9 Hz, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.79

(s, 3 H), 1.85 (m, 1 H), 1.37(s, 3 H), 1.16 (d, J = 7 Hz, 3 H), 0.85 (s, 9 H), -0.18 (s, 3 H),

-0.29 (s, 3 H). IR (neat, cm–1): 3485, 2956, 2924, 2852, 1689, 1464, 1398, 1259, 1103,

+ 1047, 800. HRMS (ESI) [M+Na] m/z calcd for C29H40O9SiNa 583.2340, found

583.2336.

O 7.30(s) 6.01(s) O O O H H TBS 5.97 (d) O 4.97(s) H OTBS O OTBS O MeO H OH 4.39(s) H OH 3.91(s) MeO + MeO MeO OH O Ph OH 4.24(d) OH H C MeO MeO H H 3.53(d) 3.77(d) H OH 3.96(d) H MeO OBn MeO OBn MeO 7.11(s) nOe observed

MeO MeO OMe 4.43 4.44 4.43

Diol 4.43 and 4.44: To a solution of diene 4.6 (80 mg, 0.127 mmol) in t-BuOH/H2O

(v/v=1/1, 20 mL) was added NMO (74 mg, 0.635 mmol) and OsO4 (0.02 M solution in t-

BuOH, 4 mL, 0.08 mmol). The mixture was stirred for 18 h at room temperature. After extraction with CH2Cl2, drying with anhydrous MgSO4, filtration, and removal of the solvent under vacuum, the crude oil was subjected to flash column (MeOH : CH2Cl2 =

1:100 ) to give 4.43 (58 mg, 69%) as a light yellow oil and 4.44 (19 mg, 23%). [α]D -61.6

1 (c 0.750, CHCl3). Compound 4.43: H NMR (400 MHz, CDCl3) δ 7.33-7.28 (m, 3 H),

7.24-7.21 (m, 2 H), 6.89 (s, 1 H), 6.86 (s, 1 H), 5.99 (d, J = 1.2 Hz, 1 H), 5.93 (d, J = 1.2

224

Hz, 1 H), 5.78 (s, 1 H), 5.52 (d, J = 2 Hz, 1 H), 4.58 (s, 1 H), 4.41 (d, J = 11.2 Hz, 1 H),

4.16 (s, 1 H), 4.12 (d, J = 11.2 Hz, 1 H), 3.91 (s, 3 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.78 (s,

3 H), 3.85-3.80 (m, 2 H), 3.25 (d, J = 10.8 Hz, 1 H), 0.81 (s, 9 H), -0.16 (s, 3 H), -0.24 (s,

1 3 H). H NMR (500 MHz, C6D6) δ 7.30 (s, 1 H), 7.11 (s, 1 H), 7.08-6.99 (m, 5 H), 6.01

(s, 1 H), 5.97 (d, J = 2 Hz, 1 H), 5.33 (s, 1 H), 5.23 (s, 1 H), 4.97 (s, 1 H), 4.39 (s, 1 H),

4.24 (d, J = 11 Hz, 1 H), 3.96 (d, J = 11 Hz, 1 H), 3.91 (s, 1 H), 3.86 (s, 3 H), 3.85 (s, 3

H), 3.84 (s, 3 H), 3.77 (d, J = 11 Hz, 1 H), 3.53 (d, J = 11 Hz, 1 H), 3.42 (s, 3 H), 0.90 (s,

13 9 H), 0.02 (s, 3 H), -0.09 (s, 3 H). C NMR (125 MHz, CDCl3) δ 153.51, 151.34,

150.43, 149.75, 141.54, 139.49, 139.29, 136.94, 135.11, 131.80, 128.53, 128.18, 122.47,

117.20, 111.30, 104.37, 100.96, 99.92, 81.14, 76.25, 71.70, 68.36, 64.53, 60.75, 60.74,

59.50, 55.97, 25.71, 17.98, -5.11, -5.33. HRMS (ESI) [M+Na]+ m/z calcd for

1 C36H46O10SiNa 689.2758, found 689.2755. Compound 4.44: H NMR (500 MHz,

CDCl3) δ 7.30-7.20 (m, 5 H), 6.94 (s, 1 H), 6.71 (s, 1 H), 6.01 (d, J = 1 Hz, 1 H), 5.96 (d,

J = 1 Hz, 1 H), 5.78 (s, 1 H), 5.59 (d, J = 1.5 Hz, 1 H), 4.35-4.30 (m, 2 H), 4.22 (s, 1 H),

3.90 (s, 3 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 3.71-3.66 (m, 2 H), 3.16 (d, J = 8

Hz, 1 H), 0.87 (s, 9 H), -0.16 (s, 3 H), -0.24 (s, 3 H). HRMS (ESI) [M+Na]+ m/z calcd

for C36H46O10SiNa 689.2758, found 689.2749.

O 7.08(s) 6.01(t) O H H O TBS 5.14(s) H O 6.22(t) O OTBS MeO H 4.99(s) H MeO MeO OBn O MeO O H MeO nOe observed MeO OBn 7.18(s) OMe MeO 4.45

225

Ketone 4.45: To a solution of diol 4.43 (70 mg, 0.105 mmol) in t-BuOH/H2O (v/v=1/1,

15 mL) was added NaIO4 (70mg, 0.327 mmol). The mixture was stirred for 18 h at room

temperature. After extraction with CH2Cl2, drying with anhydrous MgSO4, filtration, and removal of the solvent under vacuum, the crude oil was subjected to flash column

(EtOAc : hexanes =1:6) to give 4.45 (53 mg, 80%) as a light yellow oil. [α]D -220 (c

1 0.195, CHCl3). H NMR (400 MHz, CDCl3) δ 7.23-7.17 (m, 5 H), 6.91 (s, 1 H), 6.69 (s,

1 H), 6.00 (s, 1 H), 5.93-5.89 (m, 3 H), 4.67 (s, 1 H), 4.62 (s, 1 H), 4.41 (d, J = 12 Hz, 1

H), 4.29 (d, J = 12 Hz, 1 H), 3.92 (s, 6 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 3.25 (d, J = 10.8

1 Hz, 1 H), 0.80 (s, 9 H), -0.21 (s, 3 H), -0.25 (s, 3 H). H NMR (500 MHz, C6D6) δ 7.24

(d, J = 7 Hz, 2 H), 7.20 (s, 1 H), 7.10-7.07 (m, 4 H), 7.04-7.02 (m, 1 H), 6.22 (t, J = 2 Hz,

1 H), 6.01 (t, J = 2 Hz, 1 H), 5.32 (d, J = 1.5 Hz, 1 H), 5.25 (d, J = 1.5 Hz, 1 H), 5.14 (s, 1

H), 4.99 (s, 1 H), 4.45 (d, J = 12 Hz, 1 H), 4.26 (d, J = 12 Hz, 1 H), 4.00 (s, 3 H), 3.81 (s,

3 H), 3.75 (s, 3 H), 3.17 (s, 3 H), 0.83 (s, 9 H), -0.13 (s, 3 H), -0.17 (s, 3 H). 13C NMR

(125 MHz, C6D6) δ194.65, 155.08, 151.89, 150.00, 142.33, 140.16, 138.61, 138.12,

135.74, 131.10, 128.18, 121.54, 120.73, 119.90, 105.03, 100.80, 100.31, 82.10, 70.91,

70.17, 60.77, 60.12, 59.01, 55.08, 29.96, 25.70, 18.10, 1.16, -5.12, -5.63. IR (neat, cm–

1):2953, 2928, 2854, 1699, 1614, 1599, 1454, 1105, 867. HRMS (ESI) [M+Na]+ m/z

calcd for C35H42O9SiNa 657.2496, found 657.2490.

O 6.84(s) O H 2.70(m) O TBS H 4.01(s) O O OTBS 1.22(d) MeO 4.80(d) CH H 3 H MeO MeO OH O 4.47(d) MeO O nOe observed H MeO MeO OH 6.67(s) OMe MeO 4.41 226

Ketone 4.41: To a solution of ketone 4.45 (40 mg, 0.063 mmol) in THF (3 mL) was

added Pd/C (5%w/w) (40 mg). The mixture was stirred at 50 °C under H2 (230 psi) for

18 h before it was filtered through Celite®. After removing the solvent under vacuum,

the crude white solid was subjected to flash chromatography (EtOAc: hexanes = 1: 3) to

give 4.41 and one diastereomer (34 mg, 99%, d.r.=10:1) as a white solid. [α]D -131.1 (c

1 0.19, CHCl3). H NMR (500 MHz, CDCl3) δ 6.84 (s, 1 H), 6.67 (s, 1 H), 6.02 (d, J = 1

Hz, 1 H), 5.97 (d, J = 1 Hz, 1 H), 4.80 (d, J = 5 Hz, 1 H), 4.47 (d, J = 5 Hz, 1 H), 4.01 (d,

J = 10 Hz, 1 H), 3.94 (s, 6 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 2.70 (m, 1 H),

1.21 (d, J = 7 Hz, 3 H),0.83 (s, 9 H), -0.21 (s, 3 H), -0.28 (s, 3 H). 13C NMR (125 MHz,

CDCl3) δ 208.76, 154.05, 150.92, 149.58, 141.33, 140.05, 139.65, 135.53, 131.61,

120.72, 119.16, 103.17, 101.07, 100.35, 75.46, 70.77, 60.79, 60.50, 59.44, 55.92, 54.99,

25.79, 18.04, 13.80, -4.71, -5.30. IR (neat, cm–1): 3479, 2954, 2854, 1699, 1444, 1259,

+ 873. HRMS (ESI) [M+Na] m/z calcd for C28H38O9SiNa 569.2183, found 569.2193.

O 7.06(s) O H 1.98(m) O TBS H 4.21(d) O 1.31(d) O OTBS MeO 4.27(s) CH3 H H CH3 MeO 1.36(s) OH MeO 1.45(s) OH 0.50 (s) MeO OH H nOe observed MeO MeO OH 6.95(s) OMe MeO 4.42

Diol 4.42: To a solution of ketone 4.41 (65mg, 0.119 mmol) in diethyl ether (10 mL) at -

78 °C was added MeLi (0.4 mL, 1.6 M solution in ether, 0.64 mmol). The mixture was

warmed to 0 °C within 30 min. Water was added to quench excess MeLi. After

extraction with CH2Cl2, drying with anhydrous MgSO4, filtration, and removal of the

227

solvent under vacuum, the crude oil was subjected to flash column (EtOAc : hexanes =

1 1:3) to give diol 4.42 as a white solid (55 mg, 82%). [α]D -93.5 (c 0.155, CHCl3). H

NMR (500 MHz, C6D6) δ 7.06 (s, 1 H), 6.95 (s, 1 H), 5.35 (d, J = 1 Hz, 1 H), 5.27 (d, J =

1 Hz, 1 H), 4.27 (s, 1 H), 4.21 (d, J = 10 Hz, 1 H), 4.04 (s, 3 H), 3.85 (s, 3 H), 3.84 (s, 1

H), 3.40 (s, 1 H), 1.98 (m, 1 H), 1.36 (s, 3 H), 1.31 (d, J = 7 Hz, 1 H), 0.91 (s, 9 H), -0.14

13 (s, 3 H), -0.15 (s, 3 H). C NMR (125 MHz, CDCl3) δ153.21, 150.64, 149.26, 142.20,

140.70, 139.20, 136.77, 134.31, 120.50, 118.09, 105.58, 100.77, 100.22, 75.47, 75.00,

69.53, 60.80, 60.39, 59.35, 56.00, 52.16, 26.18, 25.58, 18.08, 12.68, -4.69, -5.20. IR

(neat, cm–1): 3442, 2954, 2856, 1643, 1469, 1271, 1043. HRMS (ESI) [M+Na]+ m/z

calcd for C29H42O9SiNa 585.2496, found 585.2490.

O O OTBS

MeO MeO OH MeO O MeO

Ketone 4.46: The diol 4.42 (16 mg, 0.0285 mmol) was dissolved in DMSO (3 mL). To

the resulting solution was added IBX (40 mg, 0.143 mmol). The mixture was stirred at

room temperature for 18 h and then cooled to room temperature. Ethyl acetate was used

for extraction (three times). The combined organic phase was washed with water three

times. After removal of the solvent under vacuum, the crude oil was subjected to

preparative TLC separation (MeOH : CH2Cl2 = 1:40 ) to give 4.46 (15.2 mg, 95%) as a

1 white solid. [α]D -40.0 (c 0.045, CHCl3). H NMR (500 MHz, CDCl3) δ 6.90 (s, 1 H),

6.79 (s, 1 H), 5.99 (d, J = 1.5 Hz, 1 H), 5.95 (d, J = 1.5 Hz, 1 H), 4.28 (d, J = 9 Hz, 1 H), 228

3.93 (s, 3 H), 3.90 (s, 3 H), 3.81 (s, 3 H), 3.79 (s, 3 H), 1.95 (m, 1 H), 1.05 (d, J = 6.5 Hz,

1 H), 0.93 (s, 3H), 0.85 (s, 9 H), -0.16 (s, 3 H), -0.26 (s, 3 H). 13C NMR (125 MHz,

CDCl3) δ 208.52, 152.89, 151.65, 149.71, 143.95, 140.67, 138.23, 136.24, 135.68,

120.11, 119.59, 106.44, 101.09, 100.75, 80.51, 72.26, 60.97, 60.65, 59.58, 56.07, 53.14,

26.31, 25.82, -4.37, -5.33. IR (neat, cm–1):3480, 2927, 2854, 1699, 1614, 1591, 1454,

+ 1045. HRMS (ESI) [M+Na] m/z calcd for C29H40O9SiNa 583.2340, found 583.2331.

O O O

MeO MeO OH MeO O MeO

Diketone 4.47: To a solution of alcohol 4.42 (18.0 mg, 0.032 mmol) in MeOH (3 mL)

was added 3 M HCl solution (0.5 mL). The mixture was stirred at room temperature for

18 h. K2CO3 and water were added to quench the reaction. After extraction with

CH2Cl2, drying with anhydrous MgSO4, filtration and removal of the solvent under

vacuum, the crude diol was dissolved in DMSO (3 mL) and IBX (36 mg, 0.128 mmol)

was added. The mixture was stirred at 40 °C for 18 h and then cooled to room

temperature. Ethyl acetate was used for extraction (three times). The combined organic

phase was washed with water three times. After removal of the solvent under vacuum,

the crude oil was subjected to preparative TLC separation (MeOH : CH2Cl2 = 1:40 ) to

1 give 4.47 (12.8 mg, 90%) as a white solid. [α]D -101.3 (c 0.08, CHCl3). H NMR (500

MHz, CDCl3) δ 6.58 (s, 1 H), 6.37 (s, 1 H), 6.03 (d, J = 1.2 Hz, 1 H), 6.02 (d, J = 1.2 Hz,

1 H), 3.93 (s, 3 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.69 (s, 3 H), 3.20 (m, 1 H), 1.46 (s, 3 H), 229

13 1.23 (d, J = 6.8 Hz, 1 H). C NMR (125 MHz, CDCl3) δ 210.06, 209.87, 152.64,

149.64, 143.24, 141.82, 138.14, 137.75, 134.03, 119.67, 118.68, 106.04, 101.81, 98.67,

81.37, 61.09, 61.04, 56.20, 56.00, 53.42, 42.68, 21.93, 9.73. IR (neat, cm–1): 3444, 2956,

+ 2852, 1714, 1697, 1105, 952. HRMS (ESI) [M+Na] m/z calcd for C23H24O9Na

467.1318, found 467.1310.

O 7.12(s) O H O O CH O O MeO 1.94(s) 3 O CH3 MeO 1.02(d)

MeO H OH MeO H OH MeO MeO O 6.64(s) OMe MeO 4.47a

Diketone 4.47a: The same procedure as the synthesis of diketone 4.47 from the alcohol

4.42 except for a basic workup with aq. NaHCO3 gave 4.47a a light yellow solid (92%).

1 H NMR (500 MHz, CDCl3) δ 7.12 (s, 1 H), 6.64 (s, 1 H), 6.03 (d, J = 1 Hz, 1 H), 6.01

(d, J = 1 Hz, 1 H), 4.40 (d, J = 11.6 Hz, 1 H), 3.99 (s, 3 H), 3.96 (s, 3 H), 3.93 (s, 3 H),

3.54 (m, 1 H), 3.49 (s, 3 H), 1.94 (s, 3 H), 1.02 (d, J = 7 Hz, 3 H). 13C NMR (125 MHz,

CDCl3) δ 205.51, 202.79, 153.05, 152.77, 149.92, 141.84, 140.82, 139.06, 136.34,

132.69, 18.95, 117.18, 104.45, 101.80, 101.70, 79.79, 61.12, 61.06, 59.59, 56.37, 56.09,

+ 24.98, 10.29. HRMS (ESI) [M+Na ] calcd for C23H24O9Na 467.1318, found 467.1326.

230

O 6.34(s) O H 1.93(m) O H 4.82(d) H 1.36(d) O OH MeO CH3 HO OH CH3 MeO 1.41(s) MeO H 4.67(d) OH MeO OH nOe observed H MeO MeO OH 6.63(s) OMe MeO 4.48

Triol 4.48: To a stirred solution of ketone 4.47 (10.0 mg, 0.0225 mmol) in MeOH (3 mL) at room temperature was added NaBH4 (15 mg, 0.40 mmol). The mixture was stirred for

18 h at room temperature. The reaction was quenched with water (2 mL). After extraction with CH2Cl2, drying with anhydrous MgSO4, filtration, and removal of the solvent under vacuum, the crude solid was subjected to flash column (EtOAc : hexanes =

1 1: 1) to give 4.48 (8.3 mg, 82%) as a white solid. [α]D -26.3 (c 0.19, CHCl3). H NMR

(500 MHz, CDCl3) δ 6.63 (s, 1 H), 6.34 (s, 1 H), 6.00 (d, J = 1.5 Hz, 1 H), 5.98 (d, J =

1.5 Hz, 1 H), 4.82 (d, J = 4 Hz, 1 H), 4.67 (d, J = 7.6 Hz, 1 H), 3.89 (s, 9 H), 3.74 (s, 3

13 H), 2.00 (m, 1 H), 1.41 (s, 3 H), 1.36 (d, J = 7 Hz, 3 H). C NMR (125 MHz, CDCl3) δ

151.92, 151.12, 149.58, 141.05, 136.40, 135.98, 133.81, 119.88, 118.70, 111.15, 102.23,

101.39, 86.50, 83.56, 75.84, 60.81, 60.76, 59.69, 55.97, 53.41, 42.40, 29.49, 17.65.

+ HRMS (ESI) [M+Na] m/z calcd for C23H28O9Na 471.1631, found 471.1640.

O O OBz

MeO MeO OH MeO OBz MeO tiegusanin D

231

Tiegusanin D: To a solution of alcohol 4.48 (6.0 mg, 0.0134 mmol) in CHCl3 (2 mL)

was added BzCl (0.1 mL). The mixture was stirred at 80 °C for 2 days and directly

subjected to flash chromatography (EtOAc: hexanes = 1: 2) to give tiegusanin D (7.9

1 mg, 90%) as a light yellow solid. [α]D -86.7 (c 0.390, CHCl3). H NMR (400 MHz,

CDCl3) δ 7.53-7.43 (m, 5H), 7.35-7.27 (m, 5 H), 6.97 (s, 1 H), 6.64 (s, 1 H), 6.13 (s, 1

H), 5.99 (s, 1 H), 5.79 (d, J = 1.6 Hz, 1 H), 5.67 (d, J = 1.6 Hz, 1 H), 4.02 (s, 3 H), 3.42

(s, 3 H), 3.31 (s, 3 H), 3.17 (s, 3 H), 2.45 (m, 1 H), 1.45 (s, 3 H), 1.37 (d, J = 7.2 Hz, 3

13 H). C NMR (125 MHz, CDCl3) δ 164.90, 164.72, 152.25, 151.69, 148.85, 141.74,

140.79, 135.85, 133.46, 132.95, 132.55, 129.49, 129.38, 129.14, 128.81, 128.64, 128.47,

127.90, 127.35, 122.33, 120.64, 110.67, 102.03, 100.91, 85.26, 83.87, 74.22, 60.03,

59.99, 58.79, 56.17, 43.58, 28.94, 17.10. IR (neat, cm–1): 3580, 2924, 2852, 1714, 1454,

+ 1107. HRMS (ESI) [M+Na] m/z calcd for C37H36O11Na 679.2156, found 679.2162.

O O OAc

MeO MeO OH MeO OAc MeO kadsuralignan B

Kadsuralignan B: To a solution of alcohol 4.48 (6.0 mg, 0.0134 mmol) in CH2Cl2 (2

mL) was added Ac2O (13 mg, 0.134 mmol) and one crystal of p-TsOH. The mixture was stirred at room temperature for 18 h and directly subjected to flash chromatography

(EtOAc: hexanes = 1: 3) to give kadsuralignan B (7.0 mg, 98%) as a light yellow solid.

1 [α]D -10.5 (c 0.37, CHCl3). H NMR (500 MHz, CDCl3) δ 6.75 (s, 1 H), 6.45 (s, 1 H),

232

5.95 (d, J = 1 Hz, 1 H), 5.94 (d, J = 1 Hz, 1 H), 5.66 (s, 1 H), 5.65 (s, 1 H), 4.67 (d, J =

7.6 Hz, 1 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 3.63 (s, 3 H), 2.08 (m, 1 H), 1.63

(s, 3 H), 1.58 (s, 3 H), 1.30 (s, 3 H), 1.23 (d, J = 7 Hz, 3 H). 13C NMR (125 MHz,

CDCl3) δ 169.31, 168.87, 151.88, 151.15, 148.60, 141.15, 140.62, 135.50, 132.92,

130.01, 121.86, 120.47, 110.34, 102.09, 101.06, 84.47, 83.42, 73.78, 60.58, 60.36, 59.29,

56.03, 42.70, 28.58, 20.49, 20.19, 16.88. IR (neat, cm–1): 3566, 2924, 2853, 1747, 1732,

+ 1622, 1597, 1456, 1226. HRMS (ESI) [M+Na] m/z calcd for C27H32O11Na 555.1843, found 555.1846. A sample was recrystallized from C6H6 and EtOH by slow diffusion of hexane to a concentrated solution at room temperature.

O O OTBS

MeO MeO OH

MeO OH MeO

Diol 4.50: To a solution of diol 4.42 (2 mg, 0.0035 mmol) in CH2Cl2 (5 mL) was added

PCC (4 mg, 0.018 mmol), NaOAc (1.5 mg, 0.018 mmol) and celite (10 mg). The mixture

was stirred for 18 h at room temperature before it was directly subjected to flash

chromatography (EtOAc: hexanes = 1: 4) to give the aldehyde 4.49 as a light yellow

solid. The aldehyde was dissolved in MeOH (1 mL) and then treated with NaBH4 (10 mg,

0.25 mmol) at 0 °C. The mixture was stirred at room temperature for 18 h. Water was

added to quench the reaction. After extraction with CH2Cl2, drying with anhydrous

MgSO4, filtration and removal of the solvent under vacuum, the crude alcohol was subjected to preparative-TLC (EtOAc: hexanes = 1: 1) to give 4.50 (1.8 mg, 90% from 233

1 4.42) as a white solid. H NMR (500 MHz, CDCl3) δ 6.90 (s, 1 H), 6.85 (s, 1 H), 6.02 (d,

J = 1 Hz, 1 H), 5.98 (d, J = 1 Hz, 1 H), 4.95 (s, 1 H), 4.13 (s, 1 H), 3.92 (s, 3 H), 3.89 (s,

3 H), 3.86 (s, 3 H), 3.62 (s, 3 H), 3.35 (s, 2 H), 2.01 (m, 1 H), 1.55 (s, 3 H), 0.94 (s, 9 H),

0.80 (d, J = 6.5 Hz, 3 H), 0.07 (s, 3 H), -0.12 (s, 3 H). HRMS (ESI) [M+Na]+ m/z calcd for C29H44O9SiNa 587.2653, found 587.2650.

O O OTBS

MeO MeO OH MeO OH MeO

Diol 4.52: To a solution of the ketone 4.46 (10 mg, 0.0178 mmol) in CH2Cl2 (2 mL) was

added NaBH4 (10 mg, 0.25 mmol) at 0 °C. The mixture was stirred at room temperature

for 18 h. Water was added to quench the reaction. After extraction with CH2Cl2, drying with anhydrous MgSO4, filtration and removal of the solvent under vacuum, the crude alcohol was subjected to preparative-TLC (EtOAc: hexanes = 1: 1) to give the diol 4.52

1 (9.5 mg, 95%) as a white solid. [α]D -56.8 (c 0.220, CHCl3). H NMR (400 MHz,

CDCl3) δ 6.80 (s, 1 H), 6.56 (s, 1 H), 6.00 (d, J = 1.2 Hz, 1 H), 5.96 (d, J = 1.2 Hz, 1 H),

4.53 (d, J = 10.8 Hz, 1 H), 4.08 (d, J = 8.8 Hz, 1 H), 3.91 (s, 3 H), 3.89 (s, 3 H), 3.88 (s, 1

H), 3.83 (s, 1 H), 2.01 (m, 1 H), 1.41 (s, 1 H), 1.10 (d, J = 7.2 Hz, 1 H), 0.81 (s, 9 H), -

13 0.24 (s, 3 H), -0.34 (s, 3 H). C NMR (125 MHz, CDCl3) δ152.24, 151.96, 150.02,

140.97, 140.76, 139.50, 134.79, 134.42, 119.13, 117.69, 109.33, 101.03, 100.38, 85.83,

74.37, 68.25, 60.92, 59.47, 56.02, 48.03, 29.51, 25.83, 18.11, 11.41, -4.74, -5.20. HRMS

+] (ESI) [M+Na ) m/z calcd for C29H42O9SiNa 585.2496, found 585.2502. 234

O O OTBS

MeO MeO OH MeO OBz MeO

TBS ether 4.53: To a stirred solution of ketone 4.46 (10.0 mg, 0.0225 mmol) in MeOH

(3 mL) at room temperature was added NaBH4 (15 mg, 0.40 mmol). The reaction

mixture was stirred for 18 h at room temperature. The reaction was quenched with water

(2 mL). After extraction with CH2Cl2, drying with anhydrous MgSO4, filtration, and

removal of the solvent under vacuum, the crude solid was dissolved in CHCl3. To the solution was added BzCl (0.1 mL), DMAP (one piece of crystal) and Et3N (0.1 mL). The mixture was stirred at 80 °C for 3 days and directly subjected to flash chromatography

(EtOAc: hexanes = 1: 2) to give 4.53 (12.6 mg, 84%) as a light yellow solid. [α]D -87.2

1 (c 0.195, CHCl3). H NMR (400 MHz, CDCl3) δ 7.52-7.48 (m, 3 H), 7.34-7.30 (m, 2 H),

6.83 (s, 1 H), 6.75 (s, 1 H), 5.80 (d, J = 1.6 Hz, 1 H), 5.75 (s, 1 H), 5.65 (d, J = 1.6 Hz, 1

H), 4.16 (d, J = 8.8 Hz, 1 H), 3.95 (s, 3 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 3.28 (s, 3 H), 2.30

(m, 1 H), 1.37 (s, 3 H), 1.16 (d, J = 7.2 Hz, 3 H), 0.83 (s, 9 H), -0.22 (s, 3 H), -0.33 (s, 3

13 H). C NMR (125 MHz, CDCl3) δ 164.69, 152.24, 152.08, 149.01, 140.56, 139.00,

133.66, 132.89, 131.12, 130.70, 130.17, 129.56, 127.87, 120.42, 119.04, 117.15, 109.12,

100.31, 99.30, 84.76, 73.04, 68.35, 60.81, 60.29, 58.31, 55.97, 49.13, 29.22, 25.88, 18.16,

11.39, -4.68, -5.25. IR (neat, cm–1): 3460, 3365, 2954, 2926, 2853, 1735, 1716, 1470,

+ 1108. HRMS (ESI) [M+Na] m/z calcd for C36H46O10SiNa 689.2758, found 689.2750.

235

O O OH

MeO MeO OH MeO OBz MeO

Alcohol 4.55: To a solution of TBS ether 4.53 (11.0 mg, 0.0165 mmol) in MeOH (5 mL)

was added 3 M HCl solution (0.5 mL). The mixture was stirred at room temperature for

18 h. K2CO3 and water were added to quench the reaction. After extraction with

CH2Cl2, drying with anhydrous MgSO4, filtration and removal of the solvent under

vacuum, the crude diol was dissolved in DMSO (3 mL). To this solution was added IBX

(14 mg, 0.05 mmol). The mixture was stirred for 18 h at room temperature. Ethyl acetate was used for extraction (three times). The combined organic phase was washed with water three times. After removal of the solvent under vacuum, the crude oil was treated with NaBH4 (15 mg, 0.40 mmol) at 0 °C. The mixture was stirred at room temperature for 18 h. Water was added to quench the reaction. After extraction with

CH2Cl2, drying with anhydrous MgSO4, filtration and removal of the solvent under

vacuum, the crude alcohol was subjected to preparative-TLC (EtOAc: hexanes = 1: 1) to

give 4.55 (7.7 mg, 85% from TBS ether 36) as a white solid. [α]D -111.0 (c 0.10,

1 CHCl3). H NMR (400 MHz, CDCl3) δ 7.53-7.46 (m, 3 H), 7.34-7.30 (m, 2 H), 6.83 (s, 1

H), 6.38 (s, 1 H), 5.87 (m, 1 H), 5.80 (d, J = 1.6 Hz, 1 H), 5.62 (d, J = 1.6 Hz, 1 H), 4.93

(s, 1 H), 3.93 (s, 3 H), 3.86 (s, 3 H), 3.72 (s, 3 H), 3.31 (s, 3 H), 2.16 (m, 1 H), 1.42 (d, J

13 = 7.2 Hz, 3 H), 1.37 (s, 3 H). C NMR (125 MHz, CDCl3) δ 164.81, 152.03, 151.16,

148.72, 141.32, 140.60, 135.91, 135.21, 132.87, 130.77, 129.53, 129.49, 127.86, 120.53,

236

120.02, 110.94, 101.40, 100.78, 85.66, 84.03, 74.36, 60.79, 60.70, 58.71, 55.92, 43.59,

29.13, 17.74. IR (neat, cm–1): 3445, 2960, 2924, 2852, 1722, 1665, 1455, 1414, 1260,

+ 1104. HRMS (ESI) [M+Na] m/z calcd for C30H32O10Na 575.1893, found 575.1888.

O O OAc

MeO MeO OH MeO OBz MeO Schizanrin F

Schizanrin F: To a solution of alcohol 4.55 (6.0 mg, 0.0109 mmol) in CH2Cl2 (2 mL) was added AcCl (0.1 mL). The mixture was stirred at room temperature for 18 h. After removal of the solvent and extra AcCl, the resulting crude oil was directly subjected to preparative-TLC (EtOAc: hexanes = 1: 2) to give schizanrin F (5.9 mg, 92%) as a white

1 solid. [α]D -101.9 (c 0.215, CHCl3). H NMR (400 MHz, CDCl3) δ 7.53-7.45 (m, 3 H),

7.34-7.30 (m, 2 H), 6.84 (s, 1 H), 6.52 (s, 1 H), 5.88 (m, 1 H), 5.78 (d, J = 1.6 Hz, 1 H),

5.76 (s, 1H), 5.63 (d, J = 1.6 Hz, 1 H), 3.95 (s, 3 H), 3.87 (s, 3 H), 3.62 (s, 3 H), 3.32 (s, 3

H), 2.31 (m, 1 H), 1.60 (s, 3 H), 1.39 (s, 3 H), 1.31 (d, J = 6.8 Hz, 3 H). 13C NMR (125

MHz, CDCl3) δ 168.85, 164.71, 151.95, 151.39, 148.79, 141.19, 140.56, 135.53, 132.93,

132.66, 129.71, 129.46, 129.37, 127.89, 121.91, 120.24, 110.28, 101.70, 100.84, 85.21,

83.43, 74.03, 60.48, 58.70, 56.04, 43.26, 28.82, 20.49, 17.07. IR (neat, cm–1): 3566,

3059, 2924, 2852, 1747, 1717, 1504, 1373, 1107. HRMS (ESI) [M+Na]+ m/z calcd for

C32H34O11Na 617.1999, found 617.1992.

237

4.9.3 Comparison of Spectroscopic and Chiroptical Data of Synthetic and Natural

1 13 Compounds ( H NMR, C NMR and [α]D)

Ananolignan B [Corrected Structure]

1HNMR 13CNMR Optical rotation CDCl3, δ in ppm, J in Hz CDCl3, δ in ppm CHCl3 Reported2 Synthesized Reported2 Synthesized Reported2 Synthesized 500MHz 500MHz 125 MHz 125MHz [α]D [α]D (27 oC) (23 oC) c 0.19 c 0.455 7.70(s) 7.70(s) 200.4 200.42 +47.8 +46.4 6.51 (s) 6.50 (s) 169.8 169.84 6.05 (s) 6.04 (s) 152.2 152.20 6.04 (s) 6.03 (s) -- 151.42 5.66(d, 5.0) 5.67(d, 5.5) 149.5 149.47 3.96 (s) 3.95 (s) 145.7 145.93 3.90 (s) 3.89 (s) 142.2 142.24 3.37(s) 3.37(s) 136.5 136.48 3.10(s) 3.10(s) 132.2 132.19 2.02 (s) 2.02 (s) 131.9 131.93 1.40 (s) 1.43 (s) 125.7 125.66 1.04 (d, 6.7) 1.04 (d, 6.5) 120.0 120.01 0.87 (d, 7.2) 0.87 (d, 7) 107.8 107.81 101.6 101.60 101.4 101.46 79.3 79.31 60.9 60.88 60.2 60.18 59.9 59.87 55.9 55.93 46.3 46.28 42.7 42.71 20.1 20.10 15.5 15.51 10.4 10.43

Table 4.5 Data Comparison of Synthetic and Natural Ananolignan B

238

60

40

20

0 190 240 290 340 390 Series1 -20

-40

-60

-80

Figure 4.16 CD Spectrum of Synthetic Ananolignan B

CD spectrum of synthetic ananolignan B: (MeOH) λmax 213 (-59), 232 (+46)

23y Reported : (MeOH) λmax 210 (-7), 240 (+7)

239

Ananolignan C

1HNMR 13CNMR Optical rotation CDCl3, δ in ppm, J in Hz CDCl3, δ in ppm CHCl3 Reported Synthesized Reported Synthesized Reported Synthesized o o 400MHz 400MHz 100 MHz 125MHz [α]D (27 C) [α]D (23 C) c 0.17 c 0.380 7.06 (s) 7.04 (s) 153.0 153.04 -35.5 -42.1 6.33 (s) 6.33 (s) 151.1 151.19 6.00 (s) 5.98 (d, 1.2) 149.0 149.06 5.99 (s) 5.96 (d, 1.2) 141.0 141.06 4.76 (d, 1.7) 4.74 (d, 1.6) 140.8 140.92 4.61 (s) 4.59 (s) 138.6 138.62 3.94 (s) 3.92 (s) 135.4 135.48 3.94(s) 3.91(s) 135.3 135.35 3.89(s) 3.86(s) 119.7 119.81 3.69 (s) 3.67 (s) 117.5 117.59 2.19 (m) 2.18 (m) 106.4 106.47 2.08 (m) 2.06 (m) 102.2 102.20 1.22 (d, 7,2) 1.20 (d, 7.2) 101.2 101.19 0.94 (d, 7.4) 0.92 (d, 7.2) 83.3 83.87 72.6 72.62 61.0 61.00 60.6 60.63 59.7 59.71 55.9 55.96 43.6 43.67 41.6 41.70 20.3 20.29 9.8 9.85

Table 4.6 Data Comparison of Synthetic and Natural Ananolignan C

240

Ananolignan D

1HNMR 13CNMR Optical rotation CDCl3, δ in ppm, J in Hz CDCl3, δ in ppm CHCl3 Reported Synthesized Reported Synthesized Reported Synthesized 500MHz 400MHz 100 MHz 125MHz [α]D [α]D (27 oC) (23 oC) c 0.20 c 0.245 7.01 (s) 7.01 (s) 169.9 169.90 -26.6 -16.7 6.44 (s) 6.44 (s) 152.1 152.11 5.97 (d, 1.2) 5.97 (d, 1.2) 150.3 150.35 5.96 (d, 1.2) 5.96 (d, 1.2) 149.0 148.99 5.59 (s) 5.60 (s) 141.0 141.3 4.75 (s) 4.75 (s) 140.1 140.13 3.93 (s) 3.93 (s) 135.8 135.85 3.88(s) 3.88(s) 135.5 135.56 3.84(s) 3.85(s) 135.2 135.26 3.64 (s) 3.64 (s) 121.1 121.13 2.15 (m) 2.15 (m) 118.6 118.67 2.14 (m) 2.15 (m) 105.8 105.95 1.57 (s) 1.58 (s) 102.2 102.27 0.98 (d, 6.6) 1.10 (d, 7.2) 101.2 101.21 0.89 (d, 6.7) 0.90 (d, 7.2) 82.1 82.15 72.8 72.78 60.6 60.65 60.3 60.31 59.5 59.63 55.9 55.98 43.4 43.45 40.6 40.64 20.6 20.67 20.0 19.99 9.4 9.48

Table 4.7 Data Comparison of Synthetic and Natural Ananolignan D

241

Ananolignan F

1HNMR 13CNMR Optical rotation CDCl3, δ in ppm, J in Hz CDCl3, δ in ppm CHCl3 Reported Synthesized Reported Synthesized Reported Synthesized 500MHz 400MHz 125 125MHz [α]D [α]D MHz (27 oC) (23 oC) c 0.21 c 0.235 6.68 (s) 6.69 (s) 170.1 170.11 +74.3 +34.5 6.44 (s) 6.44 (s) 170.0 170.06 5.99 (d, 1.2) 5.99 (d, 1.2) 151.9 151.91 5.97 (d, 1.2) 5.97 (d, 1.2) 151.5 151.53 5.75 (d, 4.8) 5.75 (d, 4.8) 148.6 148.61 5.70 (d, 8.5) 5.71 (d, 8.4) 141.8 141.77 3.88 (s) 3.88 (s) 141.4 141.44 3.85 (s) 3.85 (s) 141.14 3.58 (s) 3.58 (s) 136.2 136.22 2.12 (m) 2.14 (m) 135.68 2.01 (m) 2.01 (m) 132.9 - 1.78 (s) 1.79 (s) 131.2 131.24 1.57 (s) 1.57 (s) - 128.13 0.96 (d, 6.8) 0.96 (d, 7.2) - 127.97 0.90 (d, 7.0) 0.91 (d, 7.2) 123.3 - 121.4 121.45 110.63 102.3 102.33 101.2 101.19 100.6 100.58 80.9 81.02 79.6 60.6 60.60 60.1 60.12 59.5 59.53 56.0 56.04 39.8 - 38.0 38.03 - 37.63 20.9 20.96

Table 4.8 Data Comparison of Synthetic and Natural Ananolignan F 242

Table 4.8 Continued

13CNMR CDCl3, δ in ppm Reported Synthesized 125 125MHz MHz 20.6 20.63 16.7 - 16.8 -

243

Interiotherin C

1HNMR 13CNMR Optical rotation CDCl3, δ in ppm, J in Hz CDCl3, δ in ppm CHCl3 Reported Synthesized Reported Synthesized Reported Synthesized 300MHz 400MHz 75 MHz 125MHz [α]D [α]D c 1.175 (23 oC) c 0.295 6.71 (s) 6.71 (s) 170.0 170.06 +127.66 +38.6 6.44 (s) 6.44 (s) 166.7 166.70 5.98 (q) 5.95 (m) 151.8 151.78 5.95 (s) 5.94 (s) 151.5 151.58 5.84 (d, 7.5) 5.83 (d, 7.6) 148.6 148.60 5.73 (d, 3.5) 5.73 (d, 3.6) 141.7 141.78 3.90 (s) 3.90 (s) 141.2 141.29 3.88 (s) 3.88 (s) 138.6 138.60 3.78 (s) 3.78 (s) 135.9 135.96 3.58 (s) 3.57 (s) 133.1 133.09 2.22 (m) 2.22 (m) 131.3 131.32 2.12 (m) 2.13 (m) 127.8 127.80 1.86 (dq) 1.85 (dd) 121.1 121.15 1.59 (s) 1.58 (s) 110.4 110.55 1.50 (s) 1.51 (s) 110.4 110.47 1.03 (d, 7.0) 1.02 (d, 6.8) 102.2 102.27 0.94 (d, 7.0) 0.94 (d, 6.8) 101.0 101.02 80.7 80.71 60.6 60.59 60.2 60.17 59.3 59.29 56.0 56.01 38.7 38.74 20.7 20.68 19.9 19.88 15.6 15.59

Table 4.9 Data Comparison of Synthetic and Natural Interiotherin C

244

Kadsuralignan B

1HNMR 13CNMR Optical rotation CDCl3, δ in ppm, J in Hz CDCl3, δ in ppm CHCl3 Reported Synthesized Reported Synthesized Reported Synthesi 600MHz 500MHz 150 MHz 125MHz [α]D zed [α]D (23 oC) c 0.37 6.74 (s) 6.75 (s) 169.3 169.31 N/A -10.5 6.45 (s) 6.45 (s) 168.8 168.87 5.96 (d, 1.4) 5.95 (d, 1.0) 151.8 151.88 5.94 (d, 1.4) 5.94 (d, 1.0) 151.1 151.15 5.66 (s) 5.66 (s) 148.6 148.60 5.65 (s) 5.65 (s) 141.1 141.15 4.67 (d, 7.6) 4.67 (d, 7.6) 140.6 140.62 3.91 (s) 3.91 (s) 135.4 135.50 3.88 (s) 3.88 (s) 132.9 132.92 3.85 (s) 3.86 (s) 130.0 130.01 3.62 (s) 3.63 (s) 121.8 121.86 2.08 (m) 2.08 (m) 120.4 120.47 1.62 (dd) 1.63 (dd) 110.3 110.34 1.58 (s) 1.58 (s) 102.0 102.09 1.30 (s) 1.30 (s) 101.0 101.06 1.23 (d, 9) 1.23 (d, 7.0) 84.4 84.47 83.4 83.42 73.7 73.78 60.5 60.58 60.3 60.36 59.3 59.29 56.0 56.03 42.6 42.70 28.5 28.58 20.5 20.49 20.1 20.19 16.8 16.88

Table 4.10 Data Comparison of Synthetic and Natural Kadsuralignan B

245

Tiegusanin D

1HNMR 13CNMR Optical rotation CDCl3, δ in ppm, J in Hz CDCl3, δ in ppm CHCl3 Reported Synthesized Reported Synthesized Reported Synthesize 500MHz 400MHz 125 MHz 125MHz [α]D d o (20.9 C) [α]D c 0.22 (23 oC) c 0.37 7.53-7.43(m) 7.53-7.43(m) 164.9 164.90 -200.0 -86.7 7.35-7.27(m) 7.35-7.27(m) 164.7 164.72 6.97 (s) 6.97 (s) 152.2 152.25 6.64 (s) 6.64 (s) 151.6 151.69 6.13 (s) 6.13 (s) 148.8 148.85 5.99 (s) 5.99 (s) 141.6 141.74 5.79 (s) 5.79 (d, 1.6) 140.7 140.79 5.67 (s) 5.67 (d, 1.6) 135.8 135.85 4.02 (s) 4.02 (s) 133.5 133.46 3.41 (s) 3.42 (s) 133.0 132.95 3.30 (s) 3.31 (s) 132.5 132.55 3.16 (s) 3.17 (s) 129.4 129.49 2.45 (m) 2.45 (m) 129.0 129.38 1.44 (s) 1.45 (s) 129.1 129.14 1.36 (d, 7.2) 1.37 (d, 7.2) 128.7 128.81 128.7 128.64 128.4 128.47 127.9 127.90 127.9 127.35 122.2 122.33 120.5 120.64 110.5 110.67 102.0 102.03 100.9 100.91 85.2 85.26 83.8 83.87 74.2 74.22 60.0 60.03 59.9 59.99 58.8 58.79

Table 4.11 Data Comparison of Synthetic and Natural Tiegusanin D 246

Table 4.11 Continued

13CNMR CDCl3, δ in ppm Reported Synthesized 125 MHz 125MHz 56.1 56.17 43.5 43.58 28.9 28.94 17.1 17.10

247

Schizanrin F

1HNMR 13CNMR Optical rotation CDCl3, δ in ppm, J in Hz CDCl3, δ in ppm CHCl3 Reported Synthesized Reported Synthesized Reporte Synthesized 300MHz 400MHz 75 MHz 125MHz d [α]D o [α]D (23 C) c 0.215 7.53-7.43(m) 7.53-7.43(m) 168.8 168.85 N/A -101.9 7.34-7.30(m) 7.34-7.30(m) 164.6 164.71 6.82 (s) 6.84 (s) 151.9 151.95 6.49 (s) 6.52 (s) 151.3 151.39 5.86 (s) 5.88 (s) 148.7 148.79 5.76 (d, 2.0) 5.78 (d, 1.6) 141.1 141.19 5.75 (s) 5.76 (s) 140.5 140.56 5.61 (d, 2.0) 5.63 (d, 1.6) 135.4 135.53 3.93 (s) 3.95 (s) 132.9 132.93 3.85 (s) 3.87 (s) 132.6 132.66 3.60 (s) 3.62 (s) 129.6 129.71 3.30 (s) 3.32 (s) 129.4 129.46 2.29 (m) 2.31 (m) 129.3 129.37 1.58 (s) 1.60 (s) 127.8 127.89 1.37 (s) 1.39 (s) 121.8 121.91 1.29 (d, 7.0) 1.31 (d, 6.8) 120.1 120.24 110.2 110.28 101.6 101.70 100.8 100.84 85.1 85.21 83.3 83.43 73.9 74.03 60.4 60.48 58.6 58.70 55.9 56.04 43.1 43.26 28.7 28.82 20.4 20.49 17.0 17.07

Table 4.12 Data Comparison of Synthetic and Natural Schizanrin F

248

Bibliography

(1) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. Rev. 1996, 96, 635.

(2) Negishi, E.-i.; Copéret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996, 96, 365.

(3) (a) Pauson, P. L.; Khand, I. U. Ann. N.Y. Acad. Sci. 1977, 295, 2. (b) Schore, N. E. Org. React. 1991, 40, 1.

(4) Heck, R. F. Org. React. 1982, 27, 345.

(5) (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.

(6) (a) Grubbs, R. H. (Ed.). Handbook of Metathesis, Vols. 1–3, Wiley-VCH, New York (2003). (b) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2000, 34, 18.

(7) (a) Itoh, K.; Matsuda, I.; Yamamoto, K. J. Synth. Org. Chem., Jpn. 1999, 57, 912. (b) Suginome, M.; Ito, Y. Chem. Rev. 2000, 100, 3221.

(8) Gréau, S.; Radetich, B.; RajanBabu, T. V. J. Am. Chem. Soc. 2000, 122, 8579.

(9) Warren, S.; Chow, A.; Fraenkel, G.; RajanBabu, T. V. J. Am. Chem. Soc. 2003, 125, 15402.

249

(10) Shin, S.; RajanBabu, T. V. J. Am. Chem. Soc. 2001, 123, 8416.

(11) Kumareswaran, R.; Shin, S.; Gallou, I.; RajanBabu, T. V. J. Org. Chem. 2004, 69, 7157.

(12) Kumareswaran, R.; Gallucci, J.; RajanBabu, T. V. J. Org. Chem. 2004, 69, 9151.

(13) Singidi, R. R.; RajanBabu, T. V. Org. Lett. 2008, 10, 3351.

(14) Singidi, R. R.; Kutney, A. M.; Gallucci, J. C.; RajanBabu, T. V. J. Am. Chem. Soc. 2010, 132, 13078.

(15) Onozawa, S.-y.; Hatanaka, Y.; Tanaka, M. Chem. Commun. 1997, 1229.

(16) Chenard, B. L.; Laganis, E. D.; Davidson, F.; RajanBabu, T. V. J. Org. Chem. 1985, 50, 3666.

(17) Lautens, M.; Mancuso, J. Org. Lett. 2000, 2, 671.

(18) Mori, M.; Hirose, T.; Wakamatsu, H.; Imakuni, N.; Sato, Y. Organometallics 2001, 20, 1907.

(19) Onozawa, S.-y.; Hatanaka, Y.; Choi, N.; Tanaka, M. Organometallics 1997, 16, 5389.

(20) Preparation of the [B-Sn]-reagent: (a) Niedenzu, K.; Rothgery, E. F. Synth. Inorg. Met. Org. Chem. 1972, 2, 1. (b) For a review of 1,3-dimethyl-2-trimethylstannyl-2-bora- 1,3- diazacyclopentane: Tanaka, M. In Encyclopedia of Reagents for Organic Synthesis;

250

Paquette, L. A., Ed.; Wiley: New York, 2004. (c) For details of a modified procedure, see reference 14.

(21) Suginome, M.; Yamamoto, A.; Murakami, M. Angew. Chem. Int. Ed. 2005, 44, 2380.

(22) For monographs and reviews, see: (a) Ayers, D. D.; Loike, J. D. Lignans: Chemical, Biological and Clinical Properties; Cambridge University Press: Cambridge, U. K., 1990. (b) Charlton, J. L. J. Nat. Prod. 1998, 61, 1447. (c) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75, and previous biannual reports in this series. (d) Apers, S.; Vlietinck, A.; Pieters, L. Phytochem. Rev. 2003, 2, 201. (e) Chang, J.; Reiner, J.; Xie, J. Chem. Rev. 2005, 105, 4581. Reviews of recent synthetic efforts: (f) Sefkow, M. Top. Curr. Chem. 2005, 243, 185. (g) Pan, J.-Y.; Chen, S.-L.; Yang, M.-H.; Wu, J.; Sinkkonen, J.; Zou, K. Nat. Prod. Rep. 2009, 26, 1251.

(23) For representative references to the isolation and biological activities of these classes of compounds, see: (a) Li, Y.; Wang, Q.; Dong, L.; Guo, X.; Wang, W.; Xie, J.; Chang, J. Synthesis 2009, 3383. (b) Chang, J. B.; Wang, Q.; Li, Y. F. Curr. Top. Med. Chem. 2009, 9, 1660. (c) Li, H.; Wang, L.; Yang, Z.; Kitanaka, S. J. Nat. Prod. 2007, 70, 1999. (d) Li, L.; Pan, Q.; Sun, M.; Lu, Q.; Hu, X. Life Sciences 2007, 80, 741. (e) Li, H.-R.; Feng, Y.-L.; Yang, Z.-G.; Wang, J.; Daikonya, A.; Kitanaka, S.; Xu, L.-Z.; Yang, S.-L. Chem. Pharm. Bull. 2006, 57, 1022. (f) Shen, Y.-C.; Liaw, C.-C.; Cheng, Y.-B.; Ahmed, A. F.; Lai, M.-C.; Liou, S.-S.; Wu, T.-S.; Kuo, Y.-H.; Lin, Y.-C. Phytochemistry 2006, 69, 963. (g) Choi, Y.-W.; Takamatsu, S.; Khan, S. I.; Srinivas, P. V.; Ferreira, D.; Zhao, J.; Khan, I. A. J. Nat. Prod. 2006, 69, 356. (h) Kuo, Y.-H.; Wu, M.-D.; Hung, C.-C.; Huang, R.-L.; Kuo, Y. L.-M.; Shen, Y.-C.; Ong, C.-W. Bioorg. Med. Chem. Let. 2005, 13, 1555. (i) Chen, M.; Liao, Z.; Chen, D. Helv. Chim. Acta 2004, 87, 1368. (j) Chen, D.-F.; Zhang, S.-X.; Kozuka, M.; Sun, Q.-Z.; Feng, J.; Wang, Q.; Mukainaka, T.; Nobukuni, Y.; Tokuda, H.; Nishino, H.; Wang, H.-K.; Morris-Natschke, S. L.; Lee, K.-H. J. Nat. Prod. 2002, 65, 1242. (k) Kuo, Y.-H.; Kuo, L.-M. Y.; Chen, C.-F. J. Org. Chem. 1997, 62, 3242. (l) Chen, D.-F.; Zhang, S.-X.; Xie, L.; Xie, J.-X.; Chen, K.; Kashiwada, Y.; Zhou, B.-N.; Wang, P.; Cosentino, L. M.; Lee, K.-H. Bioorg. Med. Chem. 1997, 5, 1715. (m) Chen, D.-F.; Zhang, S.-X.; Chen, K.; Zhou, B.-N.; Wang, P.; Cosentino, L. M.; Lee, K.-H. J. Nat. Prod. 1996, 59, 1066. (n) Ikeya, Y.; Taguchi, H.; Yosioka, I. Chem. Pharm. Bull. 1982, 30, 3207. (o) Liu, J.-S.; Huang, M. F. Phytochemistry 1992, 31, 957. (p) Ikeya, Y.; Taguchi, H.; Yosioka, I.; Kobayashi, H. Chem. Pharm. Bull. 1979, 27, 2695. (q) Ikeya, Y.; Taguchi, H.; Yosioka, I.; Kobayashi, H. Chem. Pharm. Bull. 1979, 27, 1583. (r) Ikeya, Y.; Taguchi, H.; Yosioka, I.; Kobayashi, H. Chem. Pharm. Bull. 1979, 27, 1383. (s) Chen, Y.-P.; Liu, R.; Hsu, H.-Y.; Yamamura, S.; Shizuri, Y.; Hirata, Y. Bull. Chem. Soc. Jpn 1977, 50, 1824. (t) Kupchan, S. M.; Britton, 251

R. W.; Ziegler, M. F.; Gilrnore, C. J.; Restivo, R. J.; Bryan, R. F . J. Am. Chem. Soc.1973, 95, 1335. (u) Ikeya, Y.; Taguchi, H.; Mitsuhashi, H.; Takeda, S.; Kase, Y.; Aburada, M. Phytochemistry 1988, 27, 569. (v) Liu, J.-S.; Huang, M. F. Phytochemistry 1992, 31, 957. (w) Schobert, R.; Kern, W.; Milius, W.; Ackermann, T.; Zoldakova, M. Tetrahedron Lett. 2008, 49, 3359. (x) Li, H.; Wang, L.; Yang, Z.; Kitanaka, S. J. Nat. Prod. 2007, 70, 1999. (y) Li, X.-N.; Pu, J.-X.; Du, X.; Yang, L.-M.; An, H.-M.; Lei, C.; He, F.; Luo, X.; Zheng, Y.-T.; Lu, Y.; Xiao, W.-L.; Sun, H.-D. J. Nat. Prod. 2009, 72, 1133-1141. (z) Yang, J.-H.; Zhang, H.-Y.; Wen, J.; Du, X.; Chen, J.-H.; Zhang, H.-B.; Xiao, W.-L.; Pu, J.-X.; Tang, X.-C.; Sun, H.-D. J. Nat. Prod. 2011, 74, 1028-1035. (aa) Wu, M. D.; Huang, R. L.; Kuo, L. M. Y.; Hung, C. C.; Ong, C. W.; Kuo, Y. H. Chem. Pharm. Bull. 2003, 51, 1233-1236. (ab) Li, H.-R.; Feng, Y.-L.; Yang, Z.-G.; Wang, J.; Daikonya, A.; Kitanaka, S.; Xu, L.-Z.; Yang, S.-L. Chem. Pharm. Bull. 2006, 57, 1022.

(24) (a) Erdtmann, H. Leibigs. Ann. Chem. 1933, 503, 283. (b) Robin, J. P.; Landais, Y. J. Org. Chem. 1988, 53, 224. (c) Cambie, R. C.; Clark, G. R.; Craw, P. A.; Rutledge, P. S.; Woodgate, P. D. Aust. J. Chem. 1984, 37, 1775. (d) Burden, J. K.; Cambie, R. C.; Craw, P. A.; Rutledge, P. S.; Woodgate, P. D. Aust. J. Chem. 1988, 41, 919. (e) Pelter, A.; Ward, R. S.; Venkateswarlu, R.; Kamakshi, C. Tetrahedron 1991, 47, 1275. (f) Pelter, A.; Ward, R. S.; Abd-El-Ghani, A. J. Chem. Soc., Perkin Trans. I 1992, 2249.

(25) (a) Schneiders, G. E.; Stevenson, R. J. Org. Chem. 1981, 46, 2969. (b) Takeya, T.; Ohguchi, A.; Ara, Y.; Tobinaga, S. Chem. Pharm. Bull. 1994, 42, 430. (c) Takeya, T.; Yamaki, S.; Itoh, T.; Hosogai, H.; Tobinaga, S. Chem. Pharm. Bull. 1996, 44, 909. (d) Magnus, P.; Schultz, J.; Gallagher, T. J. Chem. Soc., Chem. Commun. 1984, 1179. (e) Magnus, P.; Schultz, J.; Gallagher, T. J. Am. Chem. Soc. 1985, 107, 4984. (f) Mervic, M.; Ghera, E. J. Am. Chem. Soc. 1977, 99, 7673. (g) Ghera, E.; Bendavid, Y. J. Chem. Soc., Chem. Commun. 1978, 480. (h) Biftu, T.; Hazra, B. G.; Stevenson, R. J. Chem. Soc., Perkin Trans. 1 1979, 2276. (i) Ziegler, F. E.; Fowler, K. W.; Sinha, N. D. Tetrahedron Lett. 1978, 2767. (j) Carroll, A. R.; Read, R. W.; Taylor, W. C. Aust. J. Chem. 1994, 47, 1579.

(26) (a) Robin, J. P.; Gringore, O.; Brown, E. Tetrahedron Lett. 1980, 21, 2709. (b)Tomioka, K.; Mizuguchi, H.; Ishiguro, T.; Koga, K. Chem. Pharm. Bull. 1985, 33, 121. (c) Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc. 1987, 109, 5446. (d) Warshawsky, A. M.; Meyers, A. I. J. Am. Chem. Soc. 1990, 112, 8090. (e) Tanaka, M.; Mukaiyama, C.; Mitsuhashi, H.; Wakamatsu, T. Tetrahedron Lett. 1992, 33, 4165. (f) Tanaka, M.; Mitsuhashi, H.; Maruno, M.; Wakamatsu, T. Tetrahedron Lett. 1994, 35, 3733. (g) Tanaka, M.; Mukaiyama, C.; Mitsuhashi, H.; Maruno, M.; Wakamatsu, T. J. Org. Chem. 1995, 60, 4339. (h) Tanaka, M.; Ohshima, T.; Mitsuhashi, H.; Maruno, M.; Wakamatsu, T. Tetrahedron 1995, 51, 11693. (i) Monovich, L. G.; Huérou, Y. L.; Röon, 252

M.; Molander, G. A. J. Am. Chem. Soc. 2000, 122, 52. (j) Molander, G. A.; George, K. M.; Monovich, L. G. J. Org. Chem. 2003, 68, 9533. (k) Coleman, R. S.; Gurrala, S. R. Org. Lett. 2005, 7, 1849. (l) Coleman, R. S.; Gurrala, S. R.; Mitra, S.; Raao, A. J. Org. Chem. 2005, 70, 8932. (m) Chen, W.-W.; Zhao, Q.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2010, 12, 1072. (n) Kamikawa, K.; Watanabe, T.; Daimon, A.; Uemura, M. Tetrahedron 2000, 56, 2325.

(27) (a) Meyers, A. I.; Nelson, T. D.; Moorlag, H.; Rawsond, D. J.; Meiere, A. Tetrahedron 2004, 60, 4459. (b) Uemura, M.; Daimon, A.; Hayashi, Y. J. Chem. Soc., Chem. Commun. 1995, 1943. (c) Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34, 615. (d) Tomioka, K.; Ishiguro, T.; Iitaka, Y.; Koga, K. Tetrahedron 1984, 40, 1303. (e) Tomioka, K.; Ishiguro, T.; Mizuguchi, H.; Komeshima, N.; Koga, K.; Tsukagoshi, S.; Tsuruo, T.; Tashiro, T.; Tanida, S.; Kishi, T. J. Med. Chem. 1991, 34, 54. (f) Takeya, T.; Yamaki, S.; Itoh, T.; Hosogai, H.; Tobinaga, S. Chem. Pharm. Bull. 1996, 44, 909. (g) Lipshutz, B. H.; Kayser, F.; Liu, Z.-P. Angew. Chem., Int. Ed. Engl. 1994, 33, 1842. (h) Li, Y.; Wang, Q.; Dong, L.; Guo, X.; Wang, W.; Xie, J.; Chang, J. Synthesis 2009, 3383.

(28) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.

(29) Mortier, J. Curr. Org. Chem. 2011, 15, 2413.

(30) Song, C.; Zhao, P.; Hu, Z.; Shi, S.; Cui, Y.; Chang, J. Bioorg. Med. Chem. Lett. 2010, 20, 2297.

(31) Alam, A.; Takaguchi, Y.; Ito, H.; Yoshida, T.; Tsuboi, S. Tetrahedron 2005, 61, 1909.

(32) Takaoka, S.; Takaoka, N.; Minoshima, Y.; Huang, J.-M.; Kubo, M.; Harada, K.; Hioki, H.; Fukuyama, Y. Tetrahedron 2009, 65, 8354.

(33) Gong, W.; Singidi, R. R.; Gallucci, J. C.; RajanBabu, T. V. Chem. Sci. 2012, 3, 1221.

(34) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191.

253

(35) Kahn, S. D.; Keck, G. E.; Hehre, W. J. Tetrahedron Lett. 1987, 28, 279.

(36) Ye, J.-L.; Huang, P.-Q.; Lu, X. J. Org. Chem. 2006, 72, 35.

(37) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.

(38) Mortier, J. Curr. Org. Chem. 2011, 15, 2413.

(39) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.;

Breuning, M. Angew. Chem. Int. Ed. 2005, 44, 5384.

(40) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry Part A Structure and

Mechanisms, 5th ed.; Springer: New York N.Y, 2007.

(41) Qian, M.; Negishi, E.-i. Tetrahedron Lett. 2005, 46, 2927.

(42) Pérez, I.; Sestelo, J. P. r.; Sarandeses, L. A. J. Am. Chem. Soc. 2001, 123, 4155.

(43) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.

(44) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.

(45) Hughes, D. L. Org. React. 1992, 42, 335.

(46) Swamy, K. C.; Kumar, N. N.; Balaraman, E.; Kumar, K. V. Chem. Rev. 2009, 109, 2551.

(47) Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. In Organic Reactions; Wiley: 2004.

254

(48) Taddei, M.; Ricci, A. Synthesis 1986, 1986, 633.

(49) Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43, 188.

(50) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. G.; Finn, J. J. Org. Chem. 1984, 49, 3241.

(51) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919.

(52) Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43, 188.

(53) Woodward, R. B.; Brutcher, F. V. J. Am. Chem. Soc. 1958, 80, 209.

(54) Prévost, C. Compt. Rend. 1933, 196, 1129.

(55) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744.

(56) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327.

(57) Cisneros, A.; Fernández, S.; Hernández, J. E. synth. Commun. 1982, 12, 833.

(58) Gottlieb, H. E.; Mervic, M.; Ghera, E.; Frolow, F. J. Chem. Soc. Perkin Trans. 1 1982, 2353.

255

Appendix A: 1H, 13C and 2D NOESY NMR Spectra of Important Compounds

256

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.14

257

) Spectrum of Compound 253 3 C NMR (125 MHz, CDCl 13

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.14

258

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.15

259

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.15 260

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.17

261

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.20a

262

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.20a

263

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.20b

264

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.20b

265

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.21

266

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.21

267

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.23a

268

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.23a

269

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.23a and 2.23b 270

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.23a and 2.23b

271

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.24

272

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.24

273

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.25

274

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.25

275

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.26

276

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.26

277

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.27a

278

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.27a

279

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.27b

280

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.27b

281

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.28

282

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.28

283

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.29a

284

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.29a

285

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.29b

286

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.29b

287

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.33

288

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.33

289

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.34

290

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.34

291

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.35a

292

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.35a

293

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.37

294

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.37

295

1 H NMR (500 MHz, CDCl6) Spectra of Compound 2.38

296

1 H NMR (500 MHz, C6D6) Spectra of Compound 2.39b

297

1 H NMR (500 MHz, C6D6) Spectra of Compound 2.39c

298

13 C NMR (125 MHz, C6D6) Spectra of Compound 2.39c

299

1 H NMR (500 MHz, C6D6) Spectra of Compound 2.39d

300

1 H NMR (400 MHz, CDCl3) Spectra of Compound 2.40

301

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.40

302

1 H NMR (500 MHz, C6D6) Spectra of Compound 2.41

303

1 H NMR (400 MHz, C6D6) Spectra of Compound 2.42

304

1 H NMR (400 MHz, C6D6) Spectra of Compound 2.43

305

1 H NMR (400 MHz, C6D6) Spectra of Compound 2.45a

306

13 C NMR (100 MHz, C6D6) Spectra of Compound 2.45a

307

1 H NMR (400 MHz, C6D6) Spectra of Compound 2.45b

308

13 C NMR (100 MHz, C6D6) Spectra of Compound 2.45b

309

1 H NMR (400 MHz, C6D6) Spectra of Compound 2.46c

310

13 C NMR (100 MHz, CDCl3) Spectra of Compound 2.46c

311

1 H NMR (500 MHz, C6D6) Spectra of Compound 2.47c

312

13 C NMR (125 MHz, C6D6) Spectra of Compound 2.47c

313

1 H NMR (500 MHz, CDCl3) Spectra of Compound 2.48c

314

1 H NMR (500 MHz, CDCl3) Spectra of Compound 2.49

315

2D NOESY NMR (500 MHz, CDCl3) Spectra of Compound 2.49

316

1 H NMR (400 MHz, C6D6) Spectra of Compound 2.53

317

2D NOESY NMR (400 MHz, C6D6) Spectra of Compound 2.53

318

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.3

319

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.3

320

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.7

321

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.7

322

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.8

323

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.8

324

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.9

325

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.9

326

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.10

327

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.10

328

1 H NMR (500 MHz, CDCl3) Spectra of Compound 3.11

329

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.13

330

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.13

331

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.14

332

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.14

333

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.15

334

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.15

335

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.17

336

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.17

337

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.18

338

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.19

339

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.19

340

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.20

341

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.20

342

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.24

343

13 C NMR (100 MHz, CDCl3) Spectra of Compound 3.24

344

1 H NMR (500 MHz, CDCl3) Spectra of Compound 3.25

345

13 C NMR (125 MHz, CDCl3)Spectra of Compound 3.25

346

1 H NMR (400 MHz, CDCl3) Spectra of Compound 3.26

347

1 H NMR (400 MHz, CDCl3) Spectra of isopicrosteganol

348

13 C NMR (100 MHz, CDCl3) Spectra of isopicrosteganol

349

1 H NMR (400 MHz, CDCl3) Spectra of steganone

350

13 C NMR (100 MHz, CDCl3) Spectra of steganone

351

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.5

352

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.5

353

1 H NMR (400 MHz, CDCl3) Spectra of Compound 4.6 354

1 H NMR (500 MHz, C6D6) Spectra of Compound 4.6

355

13 C NMR (125 MHz, C6D6) Spectra of Compound 4.6

356

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.9

357

1 H NMR (500 MHz, C6D6) Spectra of Compound 4.9

358

2D NOESY NMR (500 MHz, CDCl3) Spectra of Compound 4.9

359

2D NOESY NMR (500 MHz, C6D6) Spectra of Compound 4.9

360

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.9

361

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.10

362

1 H NMR (500 MHz, C6D6) Spectra of Compound 4.10

363

2D NOESY NMR (500 MHz, CDCl3) Spectra of Compound 4.10

364

2D NOESY NMR (500 MHz, C6D6) Spectra of Compound 4.10

365

13 C NMR (100 MHz, CDCl3) Spectra of Compound 4.10

366

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.12

367

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.12

368

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.13

369

13 C NMR (500 MHz, CDCl3) Spectra of Compound 4.13

370

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.15

371

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.15

372

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.16

373

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.17

374

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.18

375

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.19

376

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.19

377

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.20

378

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.20

379

1 H NMR (400 MHz, CDCl3) Spectra of Compound 4.22

380

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.22

381

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.25

382

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.25

383

1 H NMR (400 MHz, CDCl3) Spectra of Compound 4.26

384

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.26

385

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.27

386

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.28

387

2D NOESY NMR (500 MHz, CDCl3) Spectra of Compound 4.28

388

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.31

389

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.31

390

1 H NMR (400 MHz, CDCl3) Spectra of Compound 4.32

391

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.32

392

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.33

393

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.34 and 4.31

394

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.37

395

2D NOESY NMR (500 MHz, CDCl3) Spectra of Compound 4.37

396

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.38

397

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.40

398

2D NOESY NMR (500 MHz, CDCl3) Spectra of Compound 4.40

399

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.41

400

2D NOESY (500 MHz, CDCl3) NMR Spectra of Compound 4.41

401

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.41

402

1 H NMR (500 MHz, C6D6) Spectra of Compound 4.42

403

2D NOESY NMR (500 MHz, C6D6) Spectra of Compound 4.42

404

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.42

405

1 H NMR (400 MHz, CDCl3) Spectra of Compound 4.43

406

1 H NMR (500 MHz, C6D6) Spectra of Compound 4.43

407

2D NOESY NMR (500 MHz, C6D6) Spectra of Compound 4.43

408

13 C NMR (500 MHz, CDCl3) Spectra of Compound 4.43

409

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.44

410

1 H NMR (400 MHz, CDCl3) Spectra of Compound 4.45

411

1 H NMR (500 MHz, C6D6) Spectra of Compound 4.45

412

2D NOESY NMR (500 MHz, C6D6) Spectra of Compound 4.45

413

13 C NMR (125 MHz, C6D6) Spectra of Compound 4.45

414

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.46

415

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.46

416

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.47

417

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.47

418

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.47a

419

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.47a

420

2D NOESY NMR (500 MHz, CDCl3) Spectra of Compound 4.47a

421

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.48

422

2D NOESY NMR (500 MHz, CDCl3) Spectra of Compound 4.48

423

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.48

424

1 H NMR (500 MHz, CDCl3) Spectra of Compound 4.50

425

2D NOESY NMR (500 MHz, CDCl3) Spectra of Compound 4.50

426

1 H NMR (400 MHz, CDCl3) Spectra of Compound 4.52 in CDCl3

427

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.52 in CDCl3

428

1 H NMR (400 MHz, CDCl3) Spectra of Compound 4.53 in CDCl3

429

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.53 in CDCl3

430

1 H NMR (400 MHz, CDCl3) Spectra of Compound 4.55 in CDCl3

431

13 C NMR (125 MHz, CDCl3) Spectra of Compound 4.55 in CDCl3

432

1 H NMR (500 MHz, CDCl3) Spectra of Synthetic Ananolignan B

433

13 C NMR (125 MHz, CDCl3) Spectra of Synthetic Ananolignan B

434

1 H NMR (400 MHz, CDCl3) Spectra of Synthetic Ananolignan C

435

13 C NMR (125 MHz, CDCl3) Spectra of Synthetic Ananolignan C

436

1 H NMR (400 MHz, CDCl3) Spectra of Synthetic Ananolignan D

437

13 C NMR (125 MHz, CDCl3) Spectra of Synthetic Ananolignan D

438

1 H NMR (400 MHz, CDCl3) Spectra of Synthetic Ananolignan F

439

13 C NMR (125 MHz, CDCl3) Spectra of Synthetic Ananolignan F

440

1 H NMR (400 MHz, CDCl3) Spectra of Synthetic Interiotherin C

441

13 C NMR (125 MHz, CDCl3) Spectra of Synthetic Interiotherin C

442

1 H NMR (500 MHz, CDCl3) Spectra of Synthetic Kadsuralignan B

443

13 C NMR (125 MHz, CDCl3) Spectra of Synthetic Kadsuralignan B

444

1 H NMR (400 MHz, CDCl3) Spectra of Synthetic Tiegusanin D

445

13 C NMR (125 MHz, CDCl3) Spectra of Synthetic Tiegusanin D

446

1 H NMR (400 MHz, CDCl3) Spectra of Synthetic Schizanrin F

447

13 C NMR (125 MHz, CDCl3) Spectra of Synthetic Schizanrin F

448

Appendix B: X-ray Crystallographic Data of Compounds 2.47c, 3.24, 4.46 and

Kadsuralignan B

449

X-ray Crystallographic Data of Compounds 2.47c

Table B.1 Crystallographic details for RajanBabu 1872

Formula C45 H63 B O10 Si Sn Formula weight 921.54 Temperature 150(2) K Wavelength 0.71073 Å Crystal system triclinic Space group P1 Unit cell dimensions a = 11.9576(1) Å 〈= 96.233(1)° b = 12.6539(1) Å = 98.572(1)° c = 16.2477(1) Å  = 100.371(1)° Volume 2367.98(3) Å3 Z 2 Density (calculated) 1.292 Mg/m3 Absorption coefficient 0.617 mm-1 F(000) 964 Crystal size 0.12 x 0.31 x 0.31 mm3 Theta range for data collection 1.76 to 27.48° Index ranges -15<=h<=15, -16<=k<=16, -21<=l<=20 Reflections collected 71828 Independent reflections 10850 [R(int) = 0.040] Completeness to theta = 27.48° 99.9 % Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 10850 / 0 / 523 Goodness-of-fit on F2 1.034 Final R indices [I>2sigma(I)] R1 = 0.0397, wR2 = 0.1017 R indices (all data) R1 = 0.0553, wR2 = 0.1099 Largest diff. peak and hole 1.246 and -0.899 e/Å3

450

Table B.2 Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for RajanBabu 1872. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______C(1) 5029(2) 8532(2) 2972(1) 23(1) C(2) 6209(2) 8667(2) 3258(1) 23(1) C(3) 6652(2) 8748(2) 4119(2) 27(1) C(4) 5871(2) 8688(2) 4653(2) 30(1) C(5) 5008(2) 8585(3) 5777(2) 40(1) C(6) 4693(2) 8560(2) 4386(2) 30(1) C(7) 4239(2) 8482(2) 3545(2) 27(1) C(8) 4558(2) 8387(2) 2052(1) 24(1) C(9) 4037(2) 9184(2) 1699(1) 24(1) C(10) 3590(2) 9053(2) 843(2) 27(1) C(11) 3684(2) 8121(2) 327(1) 29(1) C(12) 4217(2) 7346(2) 664(2) 28(1) C(13) 4642(2) 7463(2) 1522(1) 24(1) C(14) 5210(2) 6570(2) 1860(2) 25(1) C(15) 6479(2) 6789(2) 1761(1) 23(1) C(16) 7304(2) 7545(2) 2450(1) 23(1) C(17) 7069(2) 8692(2) 2648(1) 22(1) C(18) 2287(2) 8401(3) 3759(2) 41(1) C(19) 2987(2) 10467(2) 2263(2) 38(1) C(20) 3727(3) 10617(3) 157(2) 46(1) C(21) 3335(3) 7137(3) -1047(2) 54(1) C(22) 3495(2) 5160(2) 1489(2) 43(1) C(23) 3375(2) 4884(2) 2358(2) 42(1) C(24) 3106(3) 5620(3) 2950(3) 65(1) C(25) 3023(5) 5394(4) 3757(3) 93(2) C(26) 3207(4) 4397(4) 3970(3) 85(1) C(27) 3422(4) 3636(4) 3372(3) 75(1) C(28) 3519(3) 3892(3) 2573(2) 56(1) C(29) 6842(2) 6360(2) 1088(2) 26(1) 451

Table B.2 Continued

C(30) 9725(2) 7889(2) 794(2) 40(1) C(31) 9639(3) 6832(2) 225(2) 44(1) C(32) 10124(3) 8917(3) 463(3) 60(1) C(33) 10466(3) 7919(3) 1661(2) 60(1) C(34) 9248(4) 6905(4) -704(2) 75(1) C(35) 10702(3) 6355(3) 309(3) 74(1) C(36) 8168(2) 7221(2) 2910(2) 27(1) C(37) 6652(3) 4624(3) 2955(3) 63(1) C(38) 9289(5) 5689(4) 4247(2) 102(2) C(39) 9297(3) 4846(3) 2190(2) 53(1) C(40) 7194(2) 11371(2) 3093(2) 40(1) C(41) 8643(3) 10792(3) 1776(2) 43(1) C(42) 9756(2) 11321(2) 3657(2) 31(1) C(43) 9516(3) 11306(3) 4556(2) 49(1) C(44) 10182(3) 12497(3) 3521(2) 55(1) C(45) 10687(3) 10656(3) 3537(2) 57(1) O(1) 6106(2) 8762(2) 5516(1) 45(1) O(2) 4138(2) 8543(2) 5075(1) 52(1) O(3) 3097(1) 8337(2) 3203(1) 34(1) O(4) 4063(1) 10124(1) 2223(1) 30(1) O(5) 3024(2) 9813(2) 512(1) 34(1) O(6) 3228(2) 8064(2) -503(1) 40(1) O(7) 4678(2) 5528(1) 1393(1) 32(1) O(8) 8537(2) 7836(1) 950(1) 35(1) O(9) 8683(2) 6112(2) 482(1) 37(1) O(10) 8122(1) 9415(1) 3026(1) 24(1) B 8046(2) 6763(2) 849(2) 25(1) Si 8407(1) 10702(1) 2875(1) 23(1) Sn 8339(1) 5589(1) 3015(1) 37(1) ______

452

Table B.3 Bond lengths [Å] and angles [°] for RajanBabu 1872. ______C(1)-C(2) 1.391(3) C(1)-C(7) 1.419(3) C(1)-C(8) 1.496(3) C(2)-C(3) 1.405(3) C(2)-C(17) 1.531(3) C(3)-C(4) 1.364(3) C(3)-H(3) 0.9500 C(4)-O(1) 1.378(3) C(4)-C(6) 1.385(4) C(5)-O(2) 1.414(3) C(5)-O(1) 1.426(3) C(5)-H(5A) 0.9900 C(5)-H(5B) 0.9900 C(6)-C(7) 1.380(3) C(6)-O(2) 1.385(3) C(7)-O(3) 1.368(3) C(8)-C(13) 1.403(3) C(8)-C(9) 1.407(3) C(9)-O(4) 1.377(3) C(9)-C(10) 1.394(3) C(10)-O(5) 1.381(3) C(10)-C(11) 1.403(4) C(11)-O(6) 1.366(3) C(11)-C(12) 1.381(4) C(12)-C(13) 1.392(3) C(12)-H(12) 0.9500 C(13)-C(14) 1.530(3) C(14)-O(7) 1.433(3) C(14)-C(15) 1.528(3) C(14)-H(14) 1.0000 C(15)-C(29) 1.334(3) C(15)-C(16) 1.497(3) 453

Table B.3 Continued

C(16)-C(36) 1.336(3) C(16)-C(17) 1.536(3) C(17)-O(10) 1.425(3) C(17)-H(17) 1.0000 C(18)-O(3) 1.426(3) C(18)-H(18A) 0.9800 C(18)-H(18B) 0.9800 C(18)-H(18C) 0.9800 C(19)-O(4) 1.438(3) C(19)-H(19A) 0.9800 C(19)-H(19B) 0.9800 C(19)-H(19C) 0.9800 C(20)-O(5) 1.427(3) C(20)-H(20A) 0.9800 C(20)-H(20B) 0.9800 C(20)-H(20C) 0.9800 C(21)-O(6) 1.427(4) C(21)-H(21A) 0.9800 C(21)-H(21B) 0.9800 C(21)-H(21C) 0.9800 C(22)-O(7) 1.444(3) C(22)-C(23) 1.511(4) C(22)-H(22A) 0.9900 C(22)-H(22B) 0.9900 C(23)-C(28) 1.373(4) C(23)-C(24) 1.378(5) C(24)-C(25) 1.387(6) C(24)-H(24) 0.9500 C(25)-C(26) 1.390(7) C(25)-H(25) 0.9500

454

Table B.3 Continued

C(26)-C(27) 1.377(7) C(26)-H(26) 0.9500 C(27)-C(28) 1.388(6) C(27)-H(27) 0.9500 C(28)-H(28) 0.9500 C(29)-B 1.558(4) C(29)-H(29) 0.9500 C(30)-O(8) 1.471(3) C(30)-C(32) 1.487(4) C(30)-C(31) 1.520(4) C(30)-C(33) 1.541(5) C(31)-O(9) 1.470(3) C(31)-C(35) 1.496(5) C(31)-C(34) 1.531(5) C(32)-H(32A) 0.9800 C(32)-H(32B) 0.9800 C(32)-H(32C) 0.9800 C(33)-H(33A) 0.9800 C(33)-H(33B) 0.9800 C(33)-H(33C) 0.9800 C(34)-H(34A) 0.9800 C(34)-H(34B) 0.9800 C(34)-H(34C) 0.9800 C(35)-H(35A) 0.9800 C(35)-H(35B) 0.9800 C(35)-H(35C) 0.9800 C(36)-Sn 2.134(2) C(36)-H(36) 0.9500 C(37)-Sn 2.144(4)

455

Table B.3 Continued

C(37)-H(37A) 0.9800 C(37)-H(37B) 0.9800 C(37)-H(37C) 0.9800 C(38)-Sn 2.129(4) C(38)-H(38A) 0.9800 C(38)-H(38B) 0.9800 C(38)-H(38C) 0.9800 C(39)-Sn 2.136(3) C(39)-H(39A) 0.9800 C(39)-H(39B) 0.9800 C(39)-H(39C) 0.9800 C(40)-Si 1.864(3) C(40)-H(40A) 0.9800 C(40)-H(40B) 0.9800 C(40)-H(40C) 0.9800 C(41)-Si 1.860(3) C(41)-H(41A) 0.9800 C(41)-H(41B) 0.9800 C(41)-H(41C) 0.9800 C(42)-C(43) 1.532(4) C(42)-C(45) 1.533(4) C(42)-C(44) 1.534(4) C(42)-Si 1.883(3) C(43)-H(43A) 0.9800 C(43)-H(43B) 0.9800 C(43)-H(43C) 0.9800 C(44)-H(44A) 0.9800 C(44)-H(44B) 0.9800 C(44)-H(44C) 0.9800

456

Table B.3 Continued

C(45)-H(45A) 0.9800 C(45)-H(45B) 0.9800 C(45)-H(45C) 0.9800 O(8)-B 1.360(3) O(9)-B 1.368(3) O(10)-Si 1.6564(17)

C(2)-C(1)-C(7) 120.8(2) C(2)-C(1)-C(8) 120.8(2) C(7)-C(1)-C(8) 118.4(2) C(1)-C(2)-C(3) 121.2(2) C(1)-C(2)-C(17) 121.4(2) C(3)-C(2)-C(17) 117.4(2) C(4)-C(3)-C(2) 116.7(2) C(4)-C(3)-H(3) 121.6 C(2)-C(3)-H(3) 121.6 C(3)-C(4)-O(1) 126.9(2) C(3)-C(4)-C(6) 123.3(2) O(1)-C(4)-C(6) 109.7(2) O(2)-C(5)-O(1) 109.0(2) O(2)-C(5)-H(5A) 109.9 O(1)-C(5)-H(5A) 109.9 O(2)-C(5)-H(5B) 109.9 O(1)-C(5)-H(5B) 109.9 H(5A)-C(5)-H(5B) 108.3 C(7)-C(6)-O(2) 129.6(2) C(7)-C(6)-C(4) 120.9(2) O(2)-C(6)-C(4) 109.5(2) O(3)-C(7)-C(6) 126.4(2)

457

Table B.3 Continued

O(3)-C(7)-C(1) 116.5(2) C(6)-C(7)-C(1) 117.1(2) C(13)-C(8)-C(9) 118.7(2) C(13)-C(8)-C(1) 120.8(2) C(9)-C(8)-C(1) 120.5(2) O(4)-C(9)-C(10) 121.8(2) O(4)-C(9)-C(8) 117.1(2) C(10)-C(9)-C(8) 120.9(2) O(5)-C(10)-C(9) 120.4(2) O(5)-C(10)-C(11) 120.3(2) C(9)-C(10)-C(11) 119.2(2) O(6)-C(11)-C(12) 124.5(2) O(6)-C(11)-C(10) 115.2(2) C(12)-C(11)-C(10) 120.3(2) C(11)-C(12)-C(13) 120.6(2) C(11)-C(12)-H(12) 119.7 C(13)-C(12)-H(12) 119.7 C(12)-C(13)-C(8) 120.2(2) C(12)-C(13)-C(14) 118.2(2) C(8)-C(13)-C(14) 121.5(2) O(7)-C(14)-C(15) 107.61(18) O(7)-C(14)-C(13) 111.04(19) C(15)-C(14)-C(13) 108.99(19) O(7)-C(14)-H(14) 109.7 C(15)-C(14)-H(14) 109.7 C(13)-C(14)-H(14) 109.7 C(29)-C(15)-C(16) 120.9(2) C(29)-C(15)-C(14) 122.4(2) C(16)-C(15)-C(14) 116.70(19) C(36)-C(16)-C(15) 121.6(2)

458

Table B.3 Continued

C(36)-C(16)-C(17) 121.0(2) C(15)-C(16)-C(17) 117.19(19) O(10)-C(17)-C(2) 109.47(18) O(10)-C(17)-C(16) 109.33(18) C(2)-C(17)-C(16) 108.96(18) O(10)-C(17)-H(17) 109.7 C(2)-C(17)-H(17) 109.7 C(16)-C(17)-H(17) 109.7 O(3)-C(18)-H(18A) 109.5 O(3)-C(18)-H(18B) 109.5 H(18A)-C(18)-H(18B) 109.5 O(3)-C(18)-H(18C) 109.5 H(18A)-C(18)-H(18C) 109.5 H(18B)-C(18)-H(18C) 109.5 O(4)-C(19)-H(19A) 109.5 O(4)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 O(4)-C(19)-H(19C) 109.5 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 O(5)-C(20)-H(20A) 109.5 O(5)-C(20)-H(20B) 109.5 H(20A)-C(20)-H(20B) 109.5 O(5)-C(20)-H(20C) 109.5 H(20A)-C(20)-H(20C) 109.5 H(20B)-C(20)-H(20C) 109.5 O(6)-C(21)-H(21A) 109.5 O(6)-C(21)-H(21B) 109.5 H(21A)-C(21)-H(21B) 109.5 O(6)-C(21)-H(21C) 109.5

459

Table B.3 Continued

H(21A)-C(21)-H(21C) 109.5 H(21B)-C(21)-H(21C) 109.5 O(7)-C(22)-C(23) 113.3(2) O(7)-C(22)-H(22A) 108.9 C(23)-C(22)-H(22A) 108.9 O(7)-C(22)-H(22B) 108.9 C(23)-C(22)-H(22B) 108.9 H(22A)-C(22)-H(22B) 107.7 C(28)-C(23)-C(24) 118.5(3) C(28)-C(23)-C(22) 120.8(3) C(24)-C(23)-C(22) 120.7(3) C(23)-C(24)-C(25) 121.6(4) C(23)-C(24)-H(24) 119.2 C(25)-C(24)-H(24) 119.2 C(24)-C(25)-C(26) 119.0(4) C(24)-C(25)-H(25) 120.5 C(26)-C(25)-H(25) 120.5 C(27)-C(26)-C(25) 119.8(4) C(27)-C(26)-H(26) 120.1 C(25)-C(26)-H(26) 120.1 C(26)-C(27)-C(28) 119.8(4) C(26)-C(27)-H(27) 120.1 C(28)-C(27)-H(27) 120.1 C(23)-C(28)-C(27) 121.1(4) C(23)-C(28)-H(28) 119.4 C(27)-C(28)-H(28) 119.4 C(15)-C(29)-B 124.3(2) C(15)-C(29)-H(29) 117.8 B-C(29)-H(29) 117.8 O(8)-C(30)-C(32) 109.6(2)

460

Table B.3 Continued

O(8)-C(30)-C(31) 103.0(2) C(32)-C(30)-C(31) 117.5(3) O(8)-C(30)-C(33) 105.6(2) C(32)-C(30)-C(33) 108.4(3) C(31)-C(30)-C(33) 112.0(3) O(9)-C(31)-C(35) 110.7(3) O(9)-C(31)-C(30) 102.3(2) C(35)-C(31)-C(30) 115.6(3) O(9)-C(31)-C(34) 106.0(2) C(35)-C(31)-C(34) 108.7(3) C(30)-C(31)-C(34) 113.0(3) C(30)-C(32)-H(32A) 109.5 C(30)-C(32)-H(32B) 109.5 H(32A)-C(32)-H(32B) 109.5 C(30)-C(32)-H(32C) 109.5 H(32A)-C(32)-H(32C) 109.5 H(32B)-C(32)-H(32C) 109.5 C(30)-C(33)-H(33A) 109.5 C(30)-C(33)-H(33B) 109.5 H(33A)-C(33)-H(33B) 109.5 C(30)-C(33)-H(33C) 109.5 H(33A)-C(33)-H(33C) 109.5 H(33B)-C(33)-H(33C) 109.5 C(31)-C(34)-H(34A) 109.5 C(31)-C(34)-H(34B) 109.5 H(34A)-C(34)-H(34B) 109.5 C(31)-C(34)-H(34C) 109.5 H(34A)-C(34)-H(34C) 109.5 H(34B)-C(34)-H(34C) 109.5 C(31)-C(35)-H(35A) 109.5 C(31)-C(35)-H(35B) 109.5 H(35A)-C(35)-H(35B) 109.5 461

Table B.3 Continued

C(31)-C(35)-H(35C) 109.5 H(35A)-C(35)-H(35C) 109.5 H(35B)-C(35)-H(35C) 109.5 C(16)-C(36)-Sn 126.88(19) C(16)-C(36)-H(36) 116.6 Sn-C(36)-H(36) 116.6 Sn-C(37)-H(37A) 109.5 Sn-C(37)-H(37B) 109.5 H(37A)-C(37)-H(37B) 109.5 Sn-C(37)-H(37C) 109.5 H(37A)-C(37)-H(37C) 109.5 H(37B)-C(37)-H(37C) 109.5 Sn-C(38)-H(38A) 109.5 Sn-C(38)-H(38B) 109.5 H(38A)-C(38)-H(38B) 109.5 Sn-C(38)-H(38C) 109.5 H(38A)-C(38)-H(38C) 109.5 H(38B)-C(38)-H(38C) 109.5 Sn-C(39)-H(39A) 109.5 Sn-C(39)-H(39B) 109.5 H(39A)-C(39)-H(39B) 109.5 Sn-C(39)-H(39C) 109.5 H(39A)-C(39)-H(39C) 109.5 H(39B)-C(39)-H(39C) 109.5 Si-C(40)-H(40A) 109.5 Si-C(40)-H(40B) 109.5 H(40A)-C(40)-H(40B) 109.5 Si-C(40)-H(40C) 109.5 H(40A)-C(40)-H(40C) 109.5 H(40B)-C(40)-H(40C) 109.5 Si-C(41)-H(41A) 109.5 Si-C(41)-H(41B) 109.5 462

Table B.3 Continued

H(41A)-C(41)-H(41B) 109.5 Si-C(41)-H(41C) 109.5 H(41A)-C(41)-H(41C) 109.5 H(41B)-C(41)-H(41C) 109.5 C(43)-C(42)-C(45) 108.5(3) C(43)-C(42)-C(44) 109.2(2) C(45)-C(42)-C(44) 109.9(3) C(43)-C(42)-Si 110.42(19) C(45)-C(42)-Si 109.15(18) C(44)-C(42)-Si 109.7(2) C(42)-C(43)-H(43A) 109.5 C(42)-C(43)-H(43B) 109.5 H(43A)-C(43)-H(43B) 109.5 C(42)-C(43)-H(43C) 109.5 H(43A)-C(43)-H(43C) 109.5 H(43B)-C(43)-H(43C) 109.5 C(42)-C(44)-H(44A) 109.5 C(42)-C(44)-H(44B) 109.5 H(44A)-C(44)-H(44B) 109.5 C(42)-C(44)-H(44C) 109.5 H(44A)-C(44)-H(44C) 109.5 H(44B)-C(44)-H(44C) 109.5 C(42)-C(45)-H(45A) 109.5 C(42)-C(45)-H(45B) 109.5 H(45A)-C(45)-H(45B) 109.5 C(42)-C(45)-H(45C) 109.5 H(45A)-C(45)-H(45C) 109.5 H(45B)-C(45)-H(45C) 109.5 C(4)-O(1)-C(5) 105.54(19) C(6)-O(2)-C(5) 105.7(2) C(7)-O(3)-C(18) 118.16(19) C(9)-O(4)-C(19) 117.67(19) 463

Table B.3 Continued

C(10)-O(5)-C(20) 114.8(2) C(11)-O(6)-C(21) 116.5(2) C(14)-O(7)-C(22) 114.1(2) B-O(8)-C(30) 106.1(2) B-O(9)-C(31) 106.9(2) C(17)-O(10)-Si 122.66(14) O(8)-B-O(9) 113.2(2) O(8)-B-C(29) 121.8(2) O(9)-B-C(29) 124.9(2) O(10)-Si-C(41) 109.90(12) O(10)-Si-C(40) 110.09(11) C(41)-Si-C(40) 110.23(14) O(10)-Si-C(42) 104.54(10) C(41)-Si-C(42) 111.52(13) C(40)-Si-C(42) 110.42(13) C(38)-Sn-C(36) 103.80(13) C(38)-Sn-C(39) 105.68(18) C(36)-Sn-C(39) 117.98(11) C(38)-Sn-C(37) 108.7(2) C(36)-Sn-C(37) 108.35(12) C(39)-Sn-C(37) 111.71(14) ______

464

Table B.4 Anisotropic displacement parameters (Å2x 103) for RajanBabu 1872. The anisotropic displacement factor exponent takes the form: -2π2[ h2a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______C(1) 21(1) 27(1) 21(1) 0(1) 2(1) 7(1) C(2) 24(1) 24(1) 21(1) 0(1) 3(1) 6(1) C(3) 23(1) 33(1) 24(1) -1(1) 0(1) 9(1) C(4) 30(1) 41(1) 19(1) 1(1) 0(1) 11(1) C(5) 34(2) 64(2) 21(1) 7(1) 4(1) 11(1) C(6) 28(1) 44(2) 20(1) 0(1) 8(1) 11(1) C(7) 22(1) 36(1) 24(1) 0(1) 3(1) 9(1) C(8) 16(1) 33(1) 22(1) 0(1) 3(1) 2(1) C(9) 17(1) 30(1) 25(1) 1(1) 3(1) 3(1) C(10) 17(1) 38(1) 27(1) 8(1) 2(1) 5(1) C(11) 23(1) 41(1) 19(1) 3(1) -1(1) 0(1) C(12) 24(1) 34(1) 23(1) -3(1) 3(1) 3(1) C(13) 18(1) 30(1) 22(1) 2(1) 5(1) 2(1) C(14) 23(1) 24(1) 24(1) -2(1) 4(1) 0(1) C(15) 22(1) 22(1) 24(1) 2(1) 2(1) 4(1) C(16) 23(1) 26(1) 20(1) 2(1) 6(1) 5(1) C(17) 21(1) 26(1) 20(1) 2(1) 1(1) 5(1) C(18) 23(1) 71(2) 33(1) 4(1) 9(1) 15(1) C(19) 31(1) 46(2) 39(2) -3(1) 3(1) 18(1) C(20) 42(2) 46(2) 53(2) 21(1) 7(1) 8(1) C(21) 74(2) 61(2) 21(1) -6(1) -7(1) 15(2) C(22) 28(1) 40(2) 54(2) 4(1) 2(1) -8(1) C(23) 32(2) 36(2) 57(2) 9(1) 13(1) -3(1) C(24) 73(3) 47(2) 85(3) 13(2) 46(2) 6(2) C(25) 121(4) 74(3) 91(3) 4(3) 71(3) 0(3) C(26) 88(3) 97(4) 70(3) 28(3) 37(2) -7(3) C(27) 65(3) 74(3) 98(3) 48(3) 28(2) 16(2) C(28) 54(2) 48(2) 74(2) 17(2) 24(2) 13(2) C(29) 27(1) 26(1) 24(1) -1(1) 3(1) 4(1) 465

Table B.4 Continued

C(30) 32(2) 37(2) 50(2) -2(1) 16(1) 1(1) C(31) 34(2) 41(2) 54(2) -6(1) 19(1) 0(1) C(32) 46(2) 41(2) 100(3) 18(2) 35(2) 7(2) C(33) 46(2) 73(2) 50(2) -2(2) -1(2) -3(2) C(34) 70(3) 98(3) 44(2) -4(2) 22(2) -18(2) C(35) 46(2) 49(2) 130(4) -11(2) 42(2) 5(2) C(36) 29(1) 25(1) 27(1) 0(1) 2(1) 7(1) C(37) 70(2) 39(2) 89(3) 17(2) 29(2) 13(2) C(38) 189(6) 66(3) 44(2) -1(2) -36(3) 59(3) C(39) 63(2) 50(2) 52(2) 6(2) 15(2) 28(2) C(40) 32(2) 40(2) 56(2) 12(1) 13(1) 17(1) C(41) 51(2) 49(2) 29(1) 8(1) 7(1) 10(1) C(42) 27(1) 30(1) 31(1) -2(1) 0(1) 1(1) C(43) 58(2) 50(2) 30(1) -1(1) -1(1) 1(2) C(44) 63(2) 38(2) 51(2) 1(1) 4(2) -14(2) C(45) 25(2) 69(2) 69(2) -12(2) -7(1) 13(2) O(1) 32(1) 86(2) 18(1) 5(1) 4(1) 18(1) O(2) 30(1) 110(2) 19(1) 5(1) 7(1) 20(1) O(3) 20(1) 59(1) 23(1) 0(1) 4(1) 10(1) O(4) 25(1) 35(1) 30(1) -3(1) -1(1) 10(1) O(5) 27(1) 43(1) 33(1) 12(1) 1(1) 11(1) O(6) 44(1) 50(1) 20(1) 1(1) -6(1) 8(1) O(7) 28(1) 28(1) 35(1) -3(1) 5(1) -3(1) O(8) 35(1) 30(1) 45(1) 3(1) 20(1) 6(1) O(9) 32(1) 33(1) 46(1) -6(1) 18(1) 1(1) O(10) 20(1) 23(1) 27(1) 2(1) 0(1) 2(1) B 24(1) 31(1) 20(1) 1(1) 3(1) 7(1) Si 23(1) 24(1) 24(1) 2(1) 4(1) 7(1) Sn 53(1) 31(1) 28(1) 2(1) 1(1) 18(1) ______

466

Table B.5 Calculated hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for RajanBabu 1872. ______x y z U(eq) ______H(3) 7457 8841 4319 32 H(5A) 4882 7895 6016 47 H(5B) 4980 9181 6217 47 H(12) 4294 6726 307 34 H(14) 5151 6563 2467 30 H(17) 6741 8941 2117 27 H(18A) 1507 8280 3432 62 H(18B) 2470 9121 4095 62 H(18C) 2329 7846 4133 62 H(19A) 3124 11141 2654 57 H(19B) 2456 9903 2459 57 H(19C) 2647 10590 1703 57 H(20A) 3260 11119 -62 69 H(20B) 4037 10264 -301 69 H(20C) 4365 11019 591 69 H(21A) 2977 7178 -1622 81 H(21B) 2949 6477 -860 81 H(21C) 4154 7119 -1031 81 H(22A) 3150 4510 1072 51 H(22B) 3055 5733 1367 51 H(24) 2975 6298 2801 78 H(25) 2842 5912 4158 111 H(26) 3186 4241 4527 102 H(27) 3503 2938 3506 89 H(28) 3689 3371 2168 68 H(29) 6333 5770 729 31 H(32A) 10148 9535 889 89 H(32B) 9590 8961 -46 89 H(32C) 10898 8930 328 89 467

Table B.5 Continued

H(33A) 10214 7247 1889 90 H(33B) 10376 8540 2044 90 H(33C) 11279 7989 1602 90 H(34A) 8551 7215 -768 112 H(34B) 9080 6178 -1027 112 H(34C) 9862 7370 -912 112 H(35A) 10957 6298 902 111 H(35B) 11314 6823 102 111 H(35C) 10530 5632 -21 111 H(36) 8771 7776 3225 33 H(37A) 6206 4571 2389 95 H(37B) 6258 4965 3367 95 H(37C) 6722 3896 3080 95 H(38A) 9406 4966 4353 153 H(38B) 8859 5973 4660 153 H(38C) 10040 6176 4296 153 H(39A) 8900 4779 1608 79 H(39B) 9358 4123 2333 79 H(39C) 10071 5293 2250 79 H(40A) 7079 11319 3673 61 H(40B) 6487 11010 2705 61 H(40C) 7379 12137 3015 61 H(41A) 9285 10442 1671 64 H(41B) 8826 11556 1695 64 H(41C) 7941 10425 1385 64 H(43A) 9247 10556 4646 73 H(43B) 8922 11728 4642 73 H(43C) 10226 11625 4955 73 H(44A) 10330 12510 2944 82 H(44B) 10897 12809 3918 82 H(44C) 9593 12922 3614 82 H(45A) 10847 10654 2963 86 468

H(45B) 10416 9910 3635 86 H(45C) 11395 10981 3938 86

469

Table B.6 Torsion angles [°] for RajanBabu 1872. ______C(7)-C(1)-C(2)-C(3) 0.6(4) C(8)-C(1)-C(2)-C(3) -176.7(2) C(7)-C(1)-C(2)-C(17) 178.4(2) C(8)-C(1)-C(2)-C(17) 1.1(3) C(1)-C(2)-C(3)-C(4) 0.0(4) C(17)-C(2)-C(3)-C(4) -177.9(2) C(2)-C(3)-C(4)-O(1) -179.1(2) C(2)-C(3)-C(4)-C(6) -0.4(4) C(3)-C(4)-C(6)-C(7) 0.2(4) O(1)-C(4)-C(6)-C(7) 179.0(2) C(3)-C(4)-C(6)-O(2) -179.2(3) O(1)-C(4)-C(6)-O(2) -0.3(3) O(2)-C(6)-C(7)-O(3) -2.0(5) C(4)-C(6)-C(7)-O(3) 178.8(3) O(2)-C(6)-C(7)-C(1) 179.6(3) C(4)-C(6)-C(7)-C(1) 0.5(4) C(2)-C(1)-C(7)-O(3) -179.3(2) C(8)-C(1)-C(7)-O(3) -2.0(3) C(2)-C(1)-C(7)-C(6) -0.8(4) C(8)-C(1)-C(7)-C(6) 176.6(2) C(2)-C(1)-C(8)-C(13) 65.5(3) C(7)-C(1)-C(8)-C(13) -111.8(3) C(2)-C(1)-C(8)-C(9) -113.5(3) C(7)-C(1)-C(8)-C(9) 69.2(3) C(13)-C(8)-C(9)-O(4) -174.3(2) C(1)-C(8)-C(9)-O(4) 4.8(3) C(13)-C(8)-C(9)-C(10) 1.3(3) C(1)-C(8)-C(9)-C(10) -179.7(2) O(4)-C(9)-C(10)-O(5) -8.2(3) C(8)-C(9)-C(10)-O(5) 176.4(2) O(4)-C(9)-C(10)-C(11) 174.1(2) C(8)-C(9)-C(10)-C(11) -1.3(3) 470

Table B.6 Continued

O(5)-C(10)-C(11)-O(6) 2.6(3) C(9)-C(10)-C(11)-O(6) -179.7(2) O(5)-C(10)-C(11)-C(12) -177.9(2) C(9)-C(10)-C(11)-C(12) -0.2(4) O(6)-C(11)-C(12)-C(13) -178.9(2) C(10)-C(11)-C(12)-C(13) 1.6(4) C(11)-C(12)-C(13)-C(8) -1.5(4) C(11)-C(12)-C(13)-C(14) 179.3(2) C(9)-C(8)-C(13)-C(12) 0.1(3) C(1)-C(8)-C(13)-C(12) -178.9(2) C(9)-C(8)-C(13)-C(14) 179.3(2) C(1)-C(8)-C(13)-C(14) 0.2(3) C(12)-C(13)-C(14)-O(7) -33.1(3) C(8)-C(13)-C(14)-O(7) 147.7(2) C(12)-C(13)-C(14)-C(15) 85.3(2) C(8)-C(13)-C(14)-C(15) -93.9(2) O(7)-C(14)-C(15)-C(29) 27.7(3) C(13)-C(14)-C(15)-C(29) -92.8(3) O(7)-C(14)-C(15)-C(16) -154.28(19) C(13)-C(14)-C(15)-C(16) 85.2(2) C(29)-C(15)-C(16)-C(36) -63.5(3) C(14)-C(15)-C(16)-C(36) 118.5(2) C(29)-C(15)-C(16)-C(17) 120.6(2) C(14)-C(15)-C(16)-C(17) -57.5(3) C(1)-C(2)-C(17)-O(10) 146.3(2) C(3)-C(2)-C(17)-O(10) -35.8(3) C(1)-C(2)-C(17)-C(16) -94.1(2) C(3)-C(2)-C(17)-C(16) 83.7(2) C(36)-C(16)-C(17)-O(10) 28.6(3) C(15)-C(16)-C(17)-O(10) -155.38(18) C(36)-C(16)-C(17)-C(2) -91.0(3) C(15)-C(16)-C(17)-C(2) 85.0(2) 471

Table B.6 Continued

O(7)-C(22)-C(23)-C(28) -82.5(4) O(7)-C(22)-C(23)-C(24) 98.1(4) C(28)-C(23)-C(24)-C(25) 2.4(6) C(22)-C(23)-C(24)-C(25) -178.2(4) C(23)-C(24)-C(25)-C(26) -0.5(7) C(24)-C(25)-C(26)-C(27) -2.6(8) C(25)-C(26)-C(27)-C(28) 3.8(7) C(24)-C(23)-C(28)-C(27) -1.3(5) C(22)-C(23)-C(28)-C(27) 179.3(3) C(26)-C(27)-C(28)-C(23) -1.8(6) C(16)-C(15)-C(29)-B -13.5(4) C(14)-C(15)-C(29)-B 164.5(2) O(8)-C(30)-C(31)-O(9) -28.5(3) C(32)-C(30)-C(31)-O(9) -149.1(3) C(33)-C(30)-C(31)-O(9) 84.5(3) O(8)-C(30)-C(31)-C(35) -148.9(3) C(32)-C(30)-C(31)-C(35) 90.5(4) C(33)-C(30)-C(31)-C(35) -35.9(4) O(8)-C(30)-C(31)-C(34) 85.0(3) C(32)-C(30)-C(31)-C(34) -35.6(4) C(33)-C(30)-C(31)-C(34) -162.0(3) C(15)-C(16)-C(36)-Sn -16.6(3) C(17)-C(16)-C(36)-Sn 159.25(17) C(3)-C(4)-O(1)-C(5) -176.6(3) C(6)-C(4)-O(1)-C(5) 4.6(3) O(2)-C(5)-O(1)-C(4) -7.3(3) C(7)-C(6)-O(2)-C(5) 176.6(3) C(4)-C(6)-O(2)-C(5) -4.2(3) O(1)-C(5)-O(2)-C(6) 7.1(3) C(6)-C(7)-O(3)-C(18) 8.3(4) C(1)-C(7)-O(3)-C(18) -173.3(2) C(10)-C(9)-O(4)-C(19) 56.9(3) 472

Table B.6 Continued

C(8)-C(9)-O(4)-C(19) -127.6(2) C(9)-C(10)-O(5)-C(20) 95.8(3) C(11)-C(10)-O(5)-C(20) -86.5(3) C(12)-C(11)-O(6)-C(21) -0.9(4) C(10)-C(11)-O(6)-C(21) 178.6(3) C(15)-C(14)-O(7)-C(22) 174.5(2) C(13)-C(14)-O(7)-C(22) -66.3(3) C(23)-C(22)-O(7)-C(14) -69.0(3) C(32)-C(30)-O(8)-B 151.3(3) C(31)-C(30)-O(8)-B 25.5(3) C(33)-C(30)-O(8)-B -92.1(3) C(35)-C(31)-O(9)-B 145.8(3) C(30)-C(31)-O(9)-B 22.1(3) C(34)-C(31)-O(9)-B -96.5(3) C(2)-C(17)-O(10)-Si -94.27(19) C(16)-C(17)-O(10)-Si 146.44(15) C(30)-O(8)-B-O(9) -12.6(3) C(30)-O(8)-B-C(29) 171.0(2) C(31)-O(9)-B-O(8) -6.7(3) C(31)-O(9)-B-C(29) 169.7(2) C(15)-C(29)-B-O(8) -39.0(4) C(15)-C(29)-B-O(9) 145.0(3) C(17)-O(10)-Si-C(41) -70.0(2) C(17)-O(10)-Si-C(40) 51.6(2) C(17)-O(10)-Si-C(42) 170.21(17) C(43)-C(42)-Si-O(10) -65.2(2) C(45)-C(42)-Si-O(10) 54.0(2) C(44)-C(42)-Si-O(10) 174.4(2) C(43)-C(42)-Si-C(41) 176.1(2) C(45)-C(42)-Si-C(41) -64.7(2) C(44)-C(42)-Si-C(41) 55.7(2) C(43)-C(42)-Si-C(40) 53.2(2) 473

Table B.6 Continued

C(45)-C(42)-Si-C(40) 172.4(2) C(44)-C(42)-Si-C(40) -67.2(2) C(16)-C(36)-Sn-C(38) -150.2(3) C(16)-C(36)-Sn-C(39) 93.4(2) C(16)-C(36)-Sn-C(37) -34.8(3)

474

X-ray Crystallographic Data of Compounds 3.24

Table B.7 Crystallographic details for RajanBabu 1787

Formula C29 H26 O8 Formula weight 502.50 Temperature 150(2) K Wavelength 0.71073 Å Crystal system triclinic Space group P1 Unit cell dimensions a = 9.7843(1) Å 〈= 97.125(1)° b = 10.8634(1) Å = 105.104(1)° c = 12.3994(1) Å  = 109.463(1)° Volume 1167.073(19) Å3 Z 2 Density (calculated) 1.430 Mg/m3 Absorption coefficient 0.104 mm-1 F(000) 528 Crystal size 0.08 x 0.27 x 0.35 mm3 Theta range for data collection 2.04 to 27.47° Index ranges -12<=h<=12, -14<=k<=14, -16<=l<=16 Reflections collected 34124 Independent reflections 5339 [R(int) = 0.034] Completeness to theta = 27.47° 99.9 % Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5339 / 0 / 337 Goodness-of-fit on F2 1.031 Final R indices [I>2sigma(I)] R1 = 0.0379, wR2 = 0.0936 R indices (all data) R1 = 0.0536, wR2 = 0.1012 Largest diff. peak and hole 0.286 and -0.223 e/Å3

475

Table B.8 Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for RajanBabu 1787. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______C(1) 169(1) 8540(1) 1210(1) 19(1) C(2) -1105(1) 7316(1) 841(1) 19(1) C(3) -1517(1) 6485(1) -235(1) 20(1) C(4) -642(1) 6873(1) -959(1) 21(1) C(5) 601(1) 8087(1) -609(1) 21(1) C(6) 1009(1) 8927(1) 466(1) 19(1) C(7) 687(1) 9357(1) 2408(1) 19(1) C(8) -192(1) 10026(1) 2759(1) 21(1) C(9) 393(1) 10799(1) 3860(1) 21(1) C(10) 1780(1) 10922(1) 4603(1) 21(1) C(11) 2655(1) 10278(1) 4295(1) 21(1) C(12) 2078(1) 9472(1) 3178(1) 19(1) C(13) -3445(2) 6690(2) 1279(1) 39(1) C(14) -2368(2) 4196(2) -263(2) 38(1) C(15) -133(2) 6295(2) -2684(1) 35(1) C(16) 929(2) 12299(2) 5478(1) 29(1) C(17) 3029(1) 8739(1) 2818(1) 19(1) C(18) 4163(1) 9597(1) 2334(1) 19(1) C(19) 3855(1) 10204(1) 1483(1) 20(1) C(20) 2368(1) 10256(1) 802(1) 22(1) C(21) 2813(2) 7160(1) 3969(1) 30(1) C(22) 3590(2) 6829(1) 5040(1) 25(1) C(23) 2918(2) 6620(2) 5893(1) 33(1) C(24) 3618(2) 6268(2) 6870(1) 41(1) C(25) 5013(2) 6160(2) 7012(1) 40(1) C(26) 5694(2) 6376(2) 6175(2) 39(1) C(27) 4978(2) 6685(1) 5184(1) 31(1) C(28) 5842(1) 9874(2) 2738(1) 26(1) C(29) 5298(1) 10897(1) 1265(1) 23(1) 476

Table B.8 Continued

O(1) -1846(1) 6917(1) 1616(1) 25(1) O(2) -2761(1) 5280(1) -592(1) 25(1) O(3) -1086(1) 5967(1) -1980(1) 27(1) O(4) -246(1) 11538(1) 4405(1) 26(1) O(5) 2089(1) 11745(1) 5651(1) 27(1) O(6) 3832(1) 8336(1) 3758(1) 21(1) O(7) 5538(1) 11569(1) 580(1) 30(1) O(8) 6455(1) 10675(1) 2005(1) 29(1) ______

477

Table B.9 Bond lengths [Å] and angles [°] for RajanBabu 1787. ______C(1)-C(6) 1.4017(17) C(1)-C(2) 1.4062(17) C(1)-C(7) 1.4937(17) C(2)-O(1) 1.3761(14) C(2)-C(3) 1.3914(18) C(3)-O(2) 1.3800(14) C(3)-C(4) 1.4036(17) C(4)-O(3) 1.3706(15) C(4)-C(5) 1.3859(17) C(5)-C(6) 1.3947(18) C(5)-H(5) 0.9500 C(6)-C(20) 1.5199(17) C(7)-C(12) 1.3998(17) C(7)-C(8) 1.4115(17) C(8)-C(9) 1.3721(18) C(8)-H(8) 0.9500 C(9)-C(10) 1.3798(18) C(9)-O(4) 1.3836(15) C(10)-C(11) 1.3676(18) C(10)-O(5) 1.3814(15) C(11)-C(12) 1.4021(17) C(11)-H(11) 0.9500 C(12)-C(17) 1.5245(17) C(13)-O(1) 1.4352(16) C(13)-H(13A) 0.9800 C(13)-H(13B) 0.9800 C(13)-H(13C) 0.9800 C(14)-O(2) 1.4294(17) C(14)-H(14A) 0.9800 C(14)-H(14B) 0.9800 C(14)-H(14C) 0.9800 C(15)-O(3) 1.4279(16) 478

Table B.9 Continued

C(15)-H(15A) 0.9800 C(15)-H(15B) 0.9800 C(15)-H(15C) 0.9800 C(16)-O(5) 1.4333(16) C(16)-O(4) 1.4396(16) C(16)-H(16A) 0.9900 C(16)-H(16B) 0.9900 C(17)-O(6) 1.4301(14) C(17)-C(18) 1.5024(17) C(17)-H(17) 1.0000 C(18)-C(19) 1.3335(18) C(18)-C(28) 1.4980(17) C(19)-C(29) 1.4747(17) C(19)-C(20) 1.5025(17) C(20)-H(20A) 0.9900 C(20)-H(20B) 0.9900 C(21)-O(6) 1.4366(15) C(21)-C(22) 1.4978(19) C(21)-H(21A) 0.9900 C(21)-H(21B) 0.9900 C(22)-C(27) 1.387(2) C(22)-C(23) 1.388(2) C(23)-C(24) 1.393(2) C(23)-H(23) 0.9500 C(24)-C(25) 1.376(2) C(24)-H(24) 0.9500 C(25)-C(26) 1.376(2) C(25)-H(25) 0.9500 C(26)-C(27) 1.388(2) C(26)-H(26) 0.9500 C(27)-H(27) 0.9500 C(28)-O(8) 1.4408(16) 479

Table B.9 Continued

C(28)-H(28A) 0.9900 C(28)-H(28B) 0.9900 C(29)-O(7) 1.2048(16) C(29)-O(8) 1.3701(16)

C(6)-C(1)-C(2) 118.90(11) C(6)-C(1)-C(7) 120.64(11) C(2)-C(1)-C(7) 120.28(11) O(1)-C(2)-C(3) 121.10(11) O(1)-C(2)-C(1) 117.70(11) C(3)-C(2)-C(1) 120.97(11) O(2)-C(3)-C(2) 120.91(11) O(2)-C(3)-C(4) 119.70(11) C(2)-C(3)-C(4) 119.39(11) O(3)-C(4)-C(5) 124.48(11) O(3)-C(4)-C(3) 115.53(11) C(5)-C(4)-C(3) 119.97(11) C(4)-C(5)-C(6) 120.74(11) C(4)-C(5)-H(5) 119.6 C(6)-C(5)-H(5) 119.6 C(5)-C(6)-C(1) 119.99(11) C(5)-C(6)-C(20) 118.68(11) C(1)-C(6)-C(20) 121.32(11) C(12)-C(7)-C(8) 120.07(11) C(12)-C(7)-C(1) 119.04(11) C(8)-C(7)-C(1) 120.88(11) C(9)-C(8)-C(7) 117.24(11) C(9)-C(8)-H(8) 121.4 C(7)-C(8)-H(8) 121.4 C(8)-C(9)-C(10) 121.99(12) C(8)-C(9)-O(4) 128.24(11) C(10)-C(9)-O(4) 109.77(11) 480

Table B.9 Continued

C(11)-C(10)-C(9) 122.37(12) C(11)-C(10)-O(5) 127.57(11) C(9)-C(10)-O(5) 110.05(11) C(10)-C(11)-C(12) 116.85(11) C(10)-C(11)-H(11) 121.6 C(12)-C(11)-H(11) 121.6 C(7)-C(12)-C(11) 121.45(11) C(7)-C(12)-C(17) 120.73(11) C(11)-C(12)-C(17) 117.81(11) O(1)-C(13)-H(13A) 109.5 O(1)-C(13)-H(13B) 109.5 H(13A)-C(13)-H(13B) 109.5 O(1)-C(13)-H(13C) 109.5 H(13A)-C(13)-H(13C) 109.5 H(13B)-C(13)-H(13C) 109.5 O(2)-C(14)-H(14A) 109.5 O(2)-C(14)-H(14B) 109.5 H(14A)-C(14)-H(14B) 109.5 O(2)-C(14)-H(14C) 109.5 H(14A)-C(14)-H(14C) 109.5 H(14B)-C(14)-H(14C) 109.5 O(3)-C(15)-H(15A) 109.5 O(3)-C(15)-H(15B) 109.5 H(15A)-C(15)-H(15B) 109.5 O(3)-C(15)-H(15C) 109.5 H(15A)-C(15)-H(15C) 109.5 H(15B)-C(15)-H(15C) 109.5 O(5)-C(16)-O(4) 107.82(10) O(5)-C(16)-H(16A) 110.1 O(4)-C(16)-H(16A) 110.1 O(5)-C(16)-H(16B) 110.1 O(4)-C(16)-H(16B) 110.1 481

Table B.9 Continued

H(16A)-C(16)-H(16B) 108.5 O(6)-C(17)-C(18) 109.02(9) O(6)-C(17)-C(12) 111.60(10) C(18)-C(17)-C(12) 111.25(10) O(6)-C(17)-H(17) 108.3 C(18)-C(17)-H(17) 108.3 C(12)-C(17)-H(17) 108.3 C(19)-C(18)-C(28) 109.52(11) C(19)-C(18)-C(17) 126.51(11) C(28)-C(18)-C(17) 123.96(11) C(18)-C(19)-C(29) 108.02(11) C(18)-C(19)-C(20) 130.54(11) C(29)-C(19)-C(20) 121.44(11) C(19)-C(20)-C(6) 114.08(10) C(19)-C(20)-H(20A) 108.7 C(6)-C(20)-H(20A) 108.7 C(19)-C(20)-H(20B) 108.7 C(6)-C(20)-H(20B) 108.7 H(20A)-C(20)-H(20B) 107.6 O(6)-C(21)-C(22) 110.92(10) O(6)-C(21)-H(21A) 109.5 C(22)-C(21)-H(21A) 109.5 O(6)-C(21)-H(21B) 109.5 C(22)-C(21)-H(21B) 109.5 H(21A)-C(21)-H(21B) 108.0 C(27)-C(22)-C(23) 118.50(13) C(27)-C(22)-C(21) 120.56(13) C(23)-C(22)-C(21) 120.91(12) C(22)-C(23)-C(24) 120.75(14) C(22)-C(23)-H(23) 119.6 C(24)-C(23)-H(23) 119.6 C(25)-C(24)-C(23) 120.02(15) 482

Table B.9 Continued

C(25)-C(24)-H(24) 120.0 C(23)-C(24)-H(24) 120.0 C(24)-C(25)-C(26) 119.67(14) C(24)-C(25)-H(25) 120.2 C(26)-C(25)-H(25) 120.2 C(25)-C(26)-C(27) 120.54(14) C(25)-C(26)-H(26) 119.7 C(27)-C(26)-H(26) 119.7 C(22)-C(27)-C(26) 120.48(14) C(22)-C(27)-H(27) 119.8 C(26)-C(27)-H(27) 119.8 O(8)-C(28)-C(18) 104.64(10) O(8)-C(28)-H(28A) 110.8 C(18)-C(28)-H(28A) 110.8 O(8)-C(28)-H(28B) 110.8 C(18)-C(28)-H(28B) 110.8 H(28A)-C(28)-H(28B) 108.9 O(7)-C(29)-O(8) 121.36(12) O(7)-C(29)-C(19) 129.96(12) O(8)-C(29)-C(19) 108.68(11) C(2)-O(1)-C(13) 116.27(10) C(3)-O(2)-C(14) 112.61(10) C(4)-O(3)-C(15) 116.24(10) C(9)-O(4)-C(16) 105.14(10) C(10)-O(5)-C(16) 105.26(10) C(17)-O(6)-C(21) 110.48(9) C(29)-O(8)-C(28) 109.11(9) ______

483

Table B.10 Anisotropic displacement parameters (Å2x 103) for RajanBabu 1787. The anisotropic displacement factor exponent takes the form: -2π2[ h2a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______C(1) 16(1) 23(1) 18(1) 7(1) 3(1) 8(1) C(2) 16(1) 25(1) 19(1) 10(1) 6(1) 9(1) C(3) 15(1) 21(1) 22(1) 7(1) 3(1) 6(1) C(4) 21(1) 23(1) 17(1) 5(1) 4(1) 9(1) C(5) 19(1) 25(1) 19(1) 9(1) 7(1) 9(1) C(6) 16(1) 22(1) 20(1) 7(1) 3(1) 8(1) C(7) 18(1) 21(1) 18(1) 7(1) 7(1) 5(1) C(8) 18(1) 25(1) 22(1) 9(1) 6(1) 8(1) C(9) 21(1) 23(1) 24(1) 9(1) 13(1) 10(1) C(10) 22(1) 23(1) 16(1) 5(1) 7(1) 5(1) C(11) 16(1) 25(1) 19(1) 7(1) 5(1) 6(1) C(12) 17(1) 20(1) 19(1) 7(1) 7(1) 5(1) C(13) 19(1) 55(1) 38(1) 4(1) 12(1) 8(1) C(14) 37(1) 24(1) 50(1) 13(1) 13(1) 9(1) C(15) 46(1) 32(1) 25(1) 5(1) 19(1) 7(1) C(16) 34(1) 31(1) 25(1) 5(1) 10(1) 16(1) C(17) 17(1) 22(1) 16(1) 6(1) 3(1) 7(1) C(18) 18(1) 21(1) 18(1) 2(1) 6(1) 7(1) C(19) 19(1) 20(1) 18(1) 3(1) 6(1) 5(1) C(20) 19(1) 23(1) 20(1) 8(1) 5(1) 6(1) C(21) 23(1) 29(1) 33(1) 15(1) 5(1) 3(1) C(22) 25(1) 20(1) 26(1) 7(1) 6(1) 6(1) C(23) 36(1) 38(1) 35(1) 14(1) 16(1) 19(1) C(24) 52(1) 47(1) 30(1) 15(1) 17(1) 22(1) C(25) 45(1) 33(1) 32(1) 13(1) -1(1) 11(1) C(26) 28(1) 40(1) 50(1) 19(1) 5(1) 14(1) C(27) 28(1) 31(1) 36(1) 12(1) 12(1) 11(1) C(28) 19(1) 35(1) 25(1) 12(1) 9(1) 11(1) C(29) 22(1) 24(1) 22(1) 3(1) 8(1) 5(1) 484

Table B.10 Continued

O(1) 19(1) 33(1) 22(1) 9(1) 9(1) 5(1) O(2) 19(1) 21(1) 28(1) 5(1) 4(1) 3(1) O(3) 30(1) 26(1) 21(1) 2(1) 11(1) 5(1) O(4) 28(1) 32(1) 25(1) 6(1) 12(1) 15(1) O(5) 27(1) 34(1) 20(1) 1(1) 8(1) 13(1) O(6) 18(1) 23(1) 22(1) 9(1) 5(1) 7(1) O(7) 28(1) 32(1) 29(1) 12(1) 14(1) 6(1) O(8) 20(1) 40(1) 31(1) 14(1) 11(1) 10(1) ______

485

Table B.11 Calculated hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for RajanBabu 1787. ______x y z U(eq) ______

H(5) 1181 8349 -1106 25 H(8) -1150 9944 2255 25 H(11) 3609 10373 4814 25 H(13A) -3615 7394 905 59 H(13B) -3776 6710 1960 59 H(13C) -4036 5813 743 59 H(14A) -1587 4102 -589 56 H(14B) -3281 3362 -550 56 H(14C) -1965 4379 576 56 H(15A) -112 7140 -2895 53 H(15B) -542 5577 -3381 53 H(15C) 908 6394 -2259 53 H(16A) 1373 13254 5455 34 H(16B) 493 12242 6115 34 H(17) 2321 7915 2207 22 H(20A) 2485 10551 96 26 H(20B) 2150 10938 1260 26 H(21A) 2469 6392 3308 36 H(21B) 1899 7315 4048 36 H(23) 1969 6719 5811 40 H(24) 3133 6101 7437 49 H(25) 5503 5939 7685 48 H(26) 6663 6312 6277 47 H(27) 5442 6799 4599 38 H(28A) 6318 10372 3552 31 H(28B) 6021 9028 2658 31 ______

486

Table B.12 Torsion angles [°] for RajanBabu 1787. ______C(6)-C(1)-C(2)-O(1) 175.69(10) C(7)-C(1)-C(2)-O(1) 0.44(17) C(6)-C(1)-C(2)-C(3) 1.16(18) C(7)-C(1)-C(2)-C(3) -174.09(11) O(1)-C(2)-C(3)-O(2) 5.19(18) C(1)-C(2)-C(3)-O(2) 179.52(11) O(1)-C(2)-C(3)-C(4) -173.99(11) C(1)-C(2)-C(3)-C(4) 0.35(18) O(2)-C(3)-C(4)-O(3) -2.12(17) C(2)-C(3)-C(4)-O(3) 177.07(11) O(2)-C(3)-C(4)-C(5) 179.47(11) C(2)-C(3)-C(4)-C(5) -1.34(18) O(3)-C(4)-C(5)-C(6) -177.44(11) C(3)-C(4)-C(5)-C(6) 0.81(19) C(4)-C(5)-C(6)-C(1) 0.72(18) C(4)-C(5)-C(6)-C(20) -179.18(11) C(2)-C(1)-C(6)-C(5) -1.69(18) C(7)-C(1)-C(6)-C(5) 173.54(11) C(2)-C(1)-C(6)-C(20) 178.21(11) C(7)-C(1)-C(6)-C(20) -6.56(17) C(6)-C(1)-C(7)-C(12) -64.41(16) C(2)-C(1)-C(7)-C(12) 110.75(13) C(6)-C(1)-C(7)-C(8) 114.43(13) C(2)-C(1)-C(7)-C(8) -70.41(16) C(12)-C(7)-C(8)-C(9) 1.39(17) C(1)-C(7)-C(8)-C(9) -177.44(11) C(7)-C(8)-C(9)-C(10) -0.22(18) C(7)-C(8)-C(9)-O(4) -179.52(11) C(8)-C(9)-C(10)-C(11) -0.4(2) O(4)-C(9)-C(10)-C(11) 179.00(11) C(8)-C(9)-C(10)-O(5) -179.49(11) O(4)-C(9)-C(10)-O(5) -0.08(14) 487

Table B.12 Continued

C(9)-C(10)-C(11)-C(12) -0.13(18) O(5)-C(10)-C(11)-C(12) 178.77(11) C(8)-C(7)-C(12)-C(11) -1.99(18) C(1)-C(7)-C(12)-C(11) 176.86(11) C(8)-C(7)-C(12)-C(17) 179.04(11) C(1)-C(7)-C(12)-C(17) -2.10(17) C(10)-C(11)-C(12)-C(7) 1.32(18) C(10)-C(11)-C(12)-C(17) -179.68(11) C(7)-C(12)-C(17)-O(6) -146.94(11) C(11)-C(12)-C(17)-O(6) 34.06(15) C(7)-C(12)-C(17)-C(18) 91.05(13) C(11)-C(12)-C(17)-C(18) -87.95(13) O(6)-C(17)-C(18)-C(19) -177.00(12) C(12)-C(17)-C(18)-C(19) -53.50(16) O(6)-C(17)-C(18)-C(28) 4.27(16) C(12)-C(17)-C(18)-C(28) 127.77(12) C(28)-C(18)-C(19)-C(29) 0.85(14) C(17)-C(18)-C(19)-C(29) -178.04(11) C(28)-C(18)-C(19)-C(20) -179.05(13) C(17)-C(18)-C(19)-C(20) 2.1(2) C(18)-C(19)-C(20)-C(6) -41.42(19) C(29)-C(19)-C(20)-C(6) 138.70(12) C(5)-C(6)-C(20)-C(19) -94.45(14) C(1)-C(6)-C(20)-C(19) 85.66(14) O(6)-C(21)-C(22)-C(27) -53.41(18) O(6)-C(21)-C(22)-C(23) 128.57(14) C(27)-C(22)-C(23)-C(24) -0.3(2) C(21)-C(22)-C(23)-C(24) 177.77(14) C(22)-C(23)-C(24)-C(25) 1.9(2) C(23)-C(24)-C(25)-C(26) -1.3(2) C(24)-C(25)-C(26)-C(27) -0.7(2) C(23)-C(22)-C(27)-C(26) -1.8(2) 488

Table B.12 Continued

C(21)-C(22)-C(27)-C(26) -179.84(14) C(25)-C(26)-C(27)-C(22) 2.3(2) C(19)-C(18)-C(28)-O(8) -1.58(14) C(17)-C(18)-C(28)-O(8) 177.34(11) C(18)-C(19)-C(29)-O(7) -179.48(14) C(20)-C(19)-C(29)-O(7) 0.4(2) C(18)-C(19)-C(29)-O(8) 0.25(14) C(20)-C(19)-C(29)-O(8) -179.85(11) C(3)-C(2)-O(1)-C(13) -63.33(16) C(1)-C(2)-O(1)-C(13) 122.16(13) C(2)-C(3)-O(2)-C(14) -88.38(15) C(4)-C(3)-O(2)-C(14) 90.79(14) C(5)-C(4)-O(3)-C(15) 3.32(18) C(3)-C(4)-O(3)-C(15) -175.01(12) C(8)-C(9)-O(4)-C(16) -172.11(13) C(10)-C(9)-O(4)-C(16) 8.52(13) O(5)-C(16)-O(4)-C(9) -13.64(13) C(11)-C(10)-O(5)-C(16) 172.54(13) C(9)-C(10)-O(5)-C(16) -8.45(14) O(4)-C(16)-O(5)-C(10) 13.60(13) C(18)-C(17)-O(6)-C(21) -158.86(10) C(12)-C(17)-O(6)-C(21) 77.85(13) C(22)-C(21)-O(6)-C(17) -172.92(11) O(7)-C(29)-O(8)-C(28) 178.48(12) C(19)-C(29)-O(8)-C(28) -1.28(14) C(18)-C(28)-O(8)-C(29) 1.72(14) ______

489

X-ray Crystallographic Data of Compounds 4.46

Table B.13 Crystallographic details for RajanBabu 1913

Formula C29 H40 O9 Si Formula weight 560.70 Temperature 150(2) K Wavelength 0.71073 Å Crystal system orthorhombic

Space group P212121 Unit cell dimensions a = 10.7843(1) Å b = 14.0454(2) Å c = 19.3783(2) Å Volume 2935.23(6) Å3 Z 4 Density (calculated) 1.269 Mg/m3 Absorption coefficient 0.131 mm-1 F(000) 1200 Crystal size 0.15 x 0.19 x 0.35 mm3 Theta range for data collection 2.10 to 27.50° Index ranges -13<=h<=13, -18<=k<=18, -25<=l<=25 Reflections collected 50819 Independent reflections 6718 [R(int) = 0.039] Completeness to theta = 27.50° 99.9 % Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 6718 / 0 / 367 Goodness-of-fit on F2 1.032 Final R indices [I>2sigma(I)] R1 = 0.0345, wR2 = 0.0751 R indices (all data) R1 = 0.0457, wR2 = 0.0801 Flack parameter -0.08(10) Largest diff. peak and hole 0.203 and -0.190 e/Å3

490

Table B.14 Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for RajanBabu 1913. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______C(1) 3736(1) 3059(1) 1703(1) 23(1) C(2) 3208(2) 2175(1) 1854(1) 23(1) C(3) 2479(2) 1708(1) 1361(1) 24(1) C(4) 2245(2) 2123(1) 727(1) 23(1) C(5) 2764(1) 3009(1) 583(1) 21(1) C(6) 2492(2) 3483(1) -96(1) 22(1) C(7) 1215(1) 3974(1) -182(1) 24(1) C(8) 1355(1) 5049(1) 3(1) 23(1) C(9) 1906(1) 5172(1) 746(1) 22(1) C(10) 3315(1) 5217(1) 730(1) 22(1) C(11) 3846(2) 6098(1) 553(1) 26(1) C(12) 5107(2) 6142(1) 517(1) 26(1) C(13) 5864(2) 5359(1) 631(1) 23(1) C(14) 5367(1) 4489(1) 796(1) 21(1) C(15) 4057(2) 4425(1) 866(1) 20(1) C(16) 3517(1) 3482(1) 1054(1) 21(1) C(17) 7069(2) 6604(2) 410(2) 57(1) C(18) 4263(2) 3548(2) 2865(1) 42(1) C(19) 4255(2) 1032(2) 2527(1) 53(1) C(20) 1216(2) 374(2) 1079(1) 47(1) C(21) 770(2) 3832(1) -918(1) 32(1) C(22) 113(2) 5571(1) -78(1) 33(1) C(23) 2004(2) 5446(2) 2439(1) 40(1) C(24) -603(2) 5418(1) 1868(1) 31(1) C(25) 739(2) 7357(1) 2056(1) 30(1) C(26) 1990(2) 7868(2) 1972(1) 41(1) C(27) 297(2) 7455(2) 2809(1) 43(1) C(28) -220(2) 7823(1) 1577(1) 44(1) C(29) 7220(2) 3728(1) 1192(1) 34(1) 491

Table B.14 Continued

O(1) 4505(1) 3542(1) 2139(1) 32(1) O(2) 3359(1) 1773(1) 2502(1) 28(1) O(3) 2025(1) 840(1) 1558(1) 31(1) O(4) 3250(1) 3497(1) -558(1) 30(1) O(5) 342(1) 3597(1) 303(1) 31(1) O(6) 1463(1) 6036(1) 1049(1) 25(1) O(7) 5834(1) 6919(1) 352(1) 39(1) O(8) 7093(1) 5608(1) 523(1) 32(1) O(9) 6030(1) 3661(1) 856(1) 25(1) Si 904(1) 6059(1) 1845(1) 24(1) ______

492

Table B.15 Bond lengths [Å] and angles [°] for RajanBabu 1913. ______C(1)-O(1) 1.3644(19) C(1)-C(2) 1.397(2) C(1)-C(16) 1.412(2) C(2)-O(2) 1.3872(19) C(2)-C(3) 1.401(2) C(3)-O(3) 1.3675(19) C(3)-C(4) 1.384(2) C(4)-C(5) 1.393(2) C(4)-H(4) 0.9500 C(5)-C(16) 1.391(2) C(5)-C(6) 1.504(2) C(6)-O(4) 1.2128(19) C(6)-C(7) 1.549(2) C(7)-O(5) 1.432(2) C(7)-C(21) 1.517(2) C(7)-C(8) 1.559(2) C(8)-C(22) 1.535(2) C(8)-C(9) 1.567(2) C(8)-H(8) 1.0000 C(9)-O(6) 1.4296(19) C(9)-C(10) 1.522(2) C(9)-H(9) 1.0000 C(10)-C(15) 1.394(2) C(10)-C(11) 1.406(2) C(11)-C(12) 1.363(2) C(11)-H(11) 0.9500 C(12)-O(7) 1.381(2) C(12)-C(13) 1.387(2) C(13)-C(14) 1.372(2) C(13)-O(8) 1.387(2) C(14)-O(9) 1.3708(19) C(14)-C(15) 1.422(2) 493

Table B.15 Continued

C(15)-C(16) 1.491(2) C(17)-O(7) 1.408(2) C(17)-O(8) 1.416(2) C(17)-H(17A) 0.9900 C(17)-H(17B) 0.9900 C(18)-O(1) 1.431(2) C(18)-H(18A) 0.9800 C(18)-H(18B) 0.9800 C(18)-H(18C) 0.9800 C(19)-O(2) 1.420(2) C(19)-H(19A) 0.9800 C(19)-H(19B) 0.9800 C(19)-H(19C) 0.9800 C(20)-O(3) 1.433(2) C(20)-H(20A) 0.9800 C(20)-H(20B) 0.9800 C(20)-H(20C) 0.9800 C(21)-H(21A) 0.9800 C(21)-H(21B) 0.9800 C(21)-H(21C) 0.9800 C(22)-H(22A) 0.9800 C(22)-H(22B) 0.9800 C(22)-H(22C) 0.9800 C(23)-Si 1.8639(19) C(23)-H(23A) 0.9800 C(23)-H(23B) 0.9800 C(23)-H(23C) 0.9800 C(24)-Si 1.8578(18) C(24)-H(24A) 0.9800 C(24)-H(24B) 0.9800 C(24)-H(24C) 0.9800 C(25)-C(28) 1.537(3) 494

Table B.15 Continued

C(25)-C(26) 1.537(3) C(25)-C(27) 1.541(3) C(25)-Si 1.8773(18) C(26)-H(26A) 0.9800 C(26)-H(26B) 0.9800 C(26)-H(26C) 0.9800 C(27)-H(27A) 0.9800 C(27)-H(27B) 0.9800 C(27)-H(27C) 0.9800 C(28)-H(28A) 0.9800 C(28)-H(28B) 0.9800 C(28)-H(28C) 0.9800 C(29)-O(9) 1.4409(19) C(29)-H(29A) 0.9800 C(29)-H(29B) 0.9800 C(29)-H(29C) 0.9800 O(5)-H(1O5) 0.84(3) O(6)-Si 1.6580(12)

O(1)-C(1)-C(2) 124.03(15) O(1)-C(1)-C(16) 116.43(14) C(2)-C(1)-C(16) 119.50(15) O(2)-C(2)-C(1) 120.28(15) O(2)-C(2)-C(3) 119.50(14) C(1)-C(2)-C(3) 120.18(15) O(3)-C(3)-C(4) 123.91(15) O(3)-C(3)-C(2) 115.35(14) C(4)-C(3)-C(2) 120.74(15) C(3)-C(4)-C(5) 118.72(15) C(3)-C(4)-H(4) 120.6 C(5)-C(4)-H(4) 120.6 C(16)-C(5)-C(4) 122.06(15) 495

Table B.15 Continued

C(16)-C(5)-C(6) 118.47(14) C(4)-C(5)-C(6) 119.46(14) O(4)-C(6)-C(5) 121.43(14) O(4)-C(6)-C(7) 120.86(14) C(5)-C(6)-C(7) 117.69(13) O(5)-C(7)-C(21) 111.14(14) O(5)-C(7)-C(6) 110.41(13) C(21)-C(7)-C(6) 108.89(14) O(5)-C(7)-C(8) 105.72(13) C(21)-C(7)-C(8) 111.95(14) C(6)-C(7)-C(8) 108.67(12) C(22)-C(8)-C(7) 110.79(13) C(22)-C(8)-C(9) 111.84(13) C(7)-C(8)-C(9) 110.81(13) C(22)-C(8)-H(8) 107.7 C(7)-C(8)-H(8) 107.7 C(9)-C(8)-H(8) 107.7 O(6)-C(9)-C(10) 107.87(13) O(6)-C(9)-C(8) 110.15(13) C(10)-C(9)-C(8) 111.43(13) O(6)-C(9)-H(9) 109.1 C(10)-C(9)-H(9) 109.1 C(8)-C(9)-H(9) 109.1 C(15)-C(10)-C(11) 120.94(14) C(15)-C(10)-C(9) 122.44(15) C(11)-C(10)-C(9) 116.60(14) C(12)-C(11)-C(10) 117.30(16) C(12)-C(11)-H(11) 121.3 C(10)-C(11)-H(11) 121.3 C(11)-C(12)-O(7) 127.84(16) C(11)-C(12)-C(13) 122.87(16) O(7)-C(12)-C(13) 109.26(14) 496

Table B.15 Continued

C(14)-C(13)-C(12) 120.91(15) C(14)-C(13)-O(8) 129.27(15) C(12)-C(13)-O(8) 109.77(14) O(9)-C(14)-C(13) 124.89(14) O(9)-C(14)-C(15) 117.19(14) C(13)-C(14)-C(15) 117.79(15) C(10)-C(15)-C(14) 120.10(14) C(10)-C(15)-C(16) 122.01(14) C(14)-C(15)-C(16) 117.82(14) C(5)-C(16)-C(1) 118.79(15) C(5)-C(16)-C(15) 119.51(14) C(1)-C(16)-C(15) 121.70(14) O(7)-C(17)-O(8) 109.90(16) O(7)-C(17)-H(17A) 109.7 O(8)-C(17)-H(17A) 109.7 O(7)-C(17)-H(17B) 109.7 O(8)-C(17)-H(17B) 109.7 H(17A)-C(17)-H(17B) 108.2 O(1)-C(18)-H(18A) 109.5 O(1)-C(18)-H(18B) 109.5 H(18A)-C(18)-H(18B) 109.5 O(1)-C(18)-H(18C) 109.5 H(18A)-C(18)-H(18C) 109.5 H(18B)-C(18)-H(18C) 109.5 O(2)-C(19)-H(19A) 109.5 O(2)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 O(2)-C(19)-H(19C) 109.5 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 O(3)-C(20)-H(20A) 109.5 O(3)-C(20)-H(20B) 109.5 497

Table B.15 Continued

H(20A)-C(20)-H(20B) 109.5 O(3)-C(20)-H(20C) 109.5 H(20A)-C(20)-H(20C) 109.5 H(20B)-C(20)-H(20C) 109.5 C(7)-C(21)-H(21A) 109.5 C(7)-C(21)-H(21B) 109.5 H(21A)-C(21)-H(21B) 109.5 C(7)-C(21)-H(21C) 109.5 H(21A)-C(21)-H(21C) 109.5 H(21B)-C(21)-H(21C) 109.5 C(8)-C(22)-H(22A) 109.5 C(8)-C(22)-H(22B) 109.5 H(22A)-C(22)-H(22B) 109.5 C(8)-C(22)-H(22C) 109.5 H(22A)-C(22)-H(22C) 109.5 H(22B)-C(22)-H(22C) 109.5 Si-C(23)-H(23A) 109.5 Si-C(23)-H(23B) 109.5 H(23A)-C(23)-H(23B) 109.5 Si-C(23)-H(23C) 109.5 H(23A)-C(23)-H(23C) 109.5 H(23B)-C(23)-H(23C) 109.5 Si-C(24)-H(24A) 109.5 Si-C(24)-H(24B) 109.5 H(24A)-C(24)-H(24B) 109.5 Si-C(24)-H(24C) 109.5 H(24A)-C(24)-H(24C) 109.5 H(24B)-C(24)-H(24C) 109.5 C(28)-C(25)-C(26) 109.17(17) C(28)-C(25)-C(27) 109.01(17) C(26)-C(25)-C(27) 109.31(15) C(28)-C(25)-Si 110.21(13) 498

Table B.15 Continued

C(26)-C(25)-Si 110.31(13) C(27)-C(25)-Si 108.81(13) C(25)-C(26)-H(26A) 109.5 C(25)-C(26)-H(26B) 109.5 H(26A)-C(26)-H(26B) 109.5 C(25)-C(26)-H(26C) 109.5 H(26A)-C(26)-H(26C) 109.5 H(26B)-C(26)-H(26C) 109.5 C(25)-C(27)-H(27A) 109.5 C(25)-C(27)-H(27B) 109.5 H(27A)-C(27)-H(27B) 109.5 C(25)-C(27)-H(27C) 109.5 H(27A)-C(27)-H(27C) 109.5 H(27B)-C(27)-H(27C) 109.5 C(25)-C(28)-H(28A) 109.5 C(25)-C(28)-H(28B) 109.5 H(28A)-C(28)-H(28B) 109.5 C(25)-C(28)-H(28C) 109.5 H(28A)-C(28)-H(28C) 109.5 H(28B)-C(28)-H(28C) 109.5 O(9)-C(29)-H(29A) 109.5 O(9)-C(29)-H(29B) 109.5 H(29A)-C(29)-H(29B) 109.5 O(9)-C(29)-H(29C) 109.5 H(29A)-C(29)-H(29C) 109.5 H(29B)-C(29)-H(29C) 109.5 C(1)-O(1)-C(18) 120.04(14) C(2)-O(2)-C(19) 114.18(13) C(3)-O(3)-C(20) 116.37(14) C(7)-O(5)-H(1O5) 105.0(19) C(9)-O(6)-Si 121.35(10) C(12)-O(7)-C(17) 105.65(14) 499

Table B.15 Continued

C(13)-O(8)-C(17) 104.76(14) C(14)-O(9)-C(29) 116.58(13) O(6)-Si-C(24) 109.34(7) O(6)-Si-C(23) 109.53(8) C(24)-Si-C(23) 108.55(9) O(6)-Si-C(25) 104.83(7) C(24)-Si-C(25) 112.52(8) C(23)-Si-C(25) 111.98(9) ______

500

Table B.16 Anisotropic displacement parameters (Å2x 103) for RajanBabu 1913. The anisotropic displacement factor exponent takes the form: -2π2[ h2a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______C(1) 21(1) 24(1) 23(1) -3(1) 0(1) 2(1) C(2) 23(1) 24(1) 21(1) 3(1) 4(1) 2(1) C(3) 24(1) 20(1) 27(1) 1(1) 5(1) 0(1) C(4) 23(1) 21(1) 25(1) -2(1) -1(1) -1(1) C(5) 19(1) 23(1) 21(1) -1(1) 2(1) 2(1) C(6) 25(1) 18(1) 22(1) -3(1) -1(1) -3(1) C(7) 23(1) 26(1) 24(1) 2(1) -2(1) -2(1) C(8) 21(1) 24(1) 24(1) 3(1) -1(1) 1(1) C(9) 21(1) 22(1) 23(1) -1(1) 2(1) 2(1) C(10) 20(1) 25(1) 21(1) -1(1) 1(1) -1(1) C(11) 25(1) 23(1) 31(1) 3(1) -1(1) 2(1) C(12) 29(1) 22(1) 27(1) 5(1) -1(1) -4(1) C(13) 19(1) 29(1) 22(1) 1(1) -1(1) -3(1) C(14) 21(1) 22(1) 20(1) -2(1) -1(1) 1(1) C(15) 22(1) 22(1) 16(1) -1(1) -2(1) -2(1) C(16) 18(1) 21(1) 23(1) 0(1) 2(1) 1(1) C(17) 28(1) 34(1) 109(2) 16(1) -4(1) -8(1) C(18) 61(1) 39(1) 25(1) -1(1) -7(1) -10(1) C(19) 73(2) 58(1) 30(1) 13(1) -1(1) 33(1) C(20) 65(2) 32(1) 43(1) 4(1) -8(1) -23(1) C(21) 36(1) 31(1) 30(1) -1(1) -11(1) 1(1) C(22) 30(1) 33(1) 36(1) 0(1) -7(1) 5(1) C(23) 38(1) 48(1) 34(1) 2(1) -7(1) 6(1) C(24) 31(1) 29(1) 32(1) -3(1) 3(1) -4(1) C(25) 29(1) 27(1) 34(1) -7(1) 5(1) -3(1) C(26) 38(1) 37(1) 49(1) -10(1) 9(1) -13(1) C(27) 44(1) 39(1) 46(1) -17(1) 13(1) -12(1) C(28) 47(1) 27(1) 58(1) -2(1) -2(1) 5(1) C(29) 24(1) 34(1) 44(1) -2(1) -12(1) 4(1) 501

Table B.16 Continued

O(1) 35(1) 37(1) 23(1) 2(1) -6(1) -10(1) O(2) 35(1) 27(1) 21(1) 5(1) 3(1) 2(1) O(3) 40(1) 24(1) 30(1) 4(1) 1(1) -8(1) O(4) 29(1) 36(1) 25(1) -1(1) 4(1) -2(1) O(5) 24(1) 31(1) 38(1) 6(1) 3(1) -5(1) O(6) 25(1) 22(1) 28(1) -2(1) 2(1) 4(1) O(7) 28(1) 28(1) 60(1) 13(1) -3(1) -8(1) O(8) 22(1) 30(1) 43(1) 7(1) 0(1) -5(1) O(9) 19(1) 24(1) 33(1) -2(1) -4(1) 2(1) Si 22(1) 24(1) 25(1) -3(1) -1(1) 0(1) ______

502

Table B.17 Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for RajanBabu 1913. ______x y z U(eq) ______

H(4) 1739 1809 396 27 H(8) 1954 5336 -331 28 H(9) 1642 4622 1038 27 H(11) 3346 6641 463 31 H(17A) 7480 6934 798 69 H(17B) 7527 6758 -19 69 H(18A) 3366 3508 2944 63 H(18B) 4583 4138 3067 63 H(18C) 4672 3001 3081 63 H(19A) 4000 514 2220 80 H(19B) 4320 791 3001 80 H(19C) 5061 1280 2379 80 H(20A) 492 778 991 70 H(20B) 944 -236 1273 70 H(20C) 1660 261 645 70 H(21A) 725 3149 -1020 48 H(21B) 1351 4138 -1237 48 H(21C) -54 4117 -972 48 H(22A) -166 5525 -559 49 H(22B) 218 6243 46 49 H(22C) -507 5280 225 49 H(23A) 2030 4765 2329 60 H(23B) 1727 5530 2917 60 H(23C) 2834 5720 2384 60 H(24A) -1194 5735 1561 46 H(24B) -928 5420 2341 46 H(24C) -481 4759 1716 46 H(26A) 2252 7836 1488 62 503

Table B.17 Continued

H(26B) 2614 7557 2263 62 H(26C) 1904 8535 2111 62 H(27A) 919 7181 3119 65 H(27B) -492 7118 2867 65 H(27C) 181 8130 2920 65 H(28A) -311 8497 1698 66 H(28B) -1021 7501 1629 66 H(28C) 59 7768 1097 66 H(29A) 7815 4033 879 51 H(29B) 7514 3089 1310 51 H(29C) 7140 4109 1613 51 H(1O5) 110(30) 3077(19) 133(13) 67(9)* ______*Refined isotropically

504

Table B.18 Torsion angles [°] for RajanBabu 1913. ______O(1)-C(1)-C(2)-O(2) 5.9(2) C(16)-C(1)-C(2)-O(2) -176.59(14) O(1)-C(1)-C(2)-C(3) -176.73(15) C(16)-C(1)-C(2)-C(3) 0.8(2) O(2)-C(2)-C(3)-O(3) -3.7(2) C(1)-C(2)-C(3)-O(3) 178.92(14) O(2)-C(2)-C(3)-C(4) 175.69(14) C(1)-C(2)-C(3)-C(4) -1.7(2) O(3)-C(3)-C(4)-C(5) -179.69(15) C(2)-C(3)-C(4)-C(5) 1.0(2) C(3)-C(4)-C(5)-C(16) 0.6(2) C(3)-C(4)-C(5)-C(6) -178.37(14) C(16)-C(5)-C(6)-O(4) 77.2(2) C(4)-C(5)-C(6)-O(4) -103.74(19) C(16)-C(5)-C(6)-C(7) -101.53(17) C(4)-C(5)-C(6)-C(7) 77.51(18) O(4)-C(6)-C(7)-O(5) 159.78(15) C(5)-C(6)-C(7)-O(5) -21.47(19) O(4)-C(6)-C(7)-C(21) 37.5(2) C(5)-C(6)-C(7)-C(21) -143.75(14) O(4)-C(6)-C(7)-C(8) -84.69(18) C(5)-C(6)-C(7)-C(8) 94.06(16) O(5)-C(7)-C(8)-C(22) -61.81(16) C(21)-C(7)-C(8)-C(22) 59.35(18) C(6)-C(7)-C(8)-C(22) 179.66(13) O(5)-C(7)-C(8)-C(9) 62.94(15) C(21)-C(7)-C(8)-C(9) -175.90(13) C(6)-C(7)-C(8)-C(9) -55.59(16) C(22)-C(8)-C(9)-O(6) -26.02(18) C(7)-C(8)-C(9)-O(6) -150.17(13) C(22)-C(8)-C(9)-C(10) -145.70(14) C(7)-C(8)-C(9)-C(10) 90.15(16) 505

Table B.18 Continued

O(6)-C(9)-C(10)-C(15) 141.19(15) C(8)-C(9)-C(10)-C(15) -97.79(18) O(6)-C(9)-C(10)-C(11) -40.40(19) C(8)-C(9)-C(10)-C(11) 80.62(18) C(15)-C(10)-C(11)-C(12) 0.4(2) C(9)-C(10)-C(11)-C(12) -178.05(15) C(10)-C(11)-C(12)-O(7) 179.70(16) C(10)-C(11)-C(12)-C(13) 1.4(3) C(11)-C(12)-C(13)-C(14) -0.7(3) O(7)-C(12)-C(13)-C(14) -179.25(15) C(11)-C(12)-C(13)-O(8) 176.90(16) O(7)-C(12)-C(13)-O(8) -1.65(19) C(12)-C(13)-C(14)-O(9) 173.85(15) O(8)-C(13)-C(14)-O(9) -3.2(3) C(12)-C(13)-C(14)-C(15) -1.8(2) O(8)-C(13)-C(14)-C(15) -178.89(15) C(11)-C(10)-C(15)-C(14) -2.9(2) C(9)-C(10)-C(15)-C(14) 175.46(14) C(11)-C(10)-C(15)-C(16) -179.89(14) C(9)-C(10)-C(15)-C(16) -1.5(2) O(9)-C(14)-C(15)-C(10) -172.45(14) C(13)-C(14)-C(15)-C(10) 3.5(2) O(9)-C(14)-C(15)-C(16) 4.7(2) C(13)-C(14)-C(15)-C(16) -179.32(14) C(4)-C(5)-C(16)-C(1) -1.5(2) C(6)-C(5)-C(16)-C(1) 177.49(14) C(4)-C(5)-C(16)-C(15) 179.34(14) C(6)-C(5)-C(16)-C(15) -1.6(2) O(1)-C(1)-C(16)-C(5) 178.50(14) C(2)-C(1)-C(16)-C(5) 0.8(2) O(1)-C(1)-C(16)-C(15) -2.4(2) C(2)-C(1)-C(16)-C(15) 179.90(14) 506

Table B.18 Continued

C(10)-C(15)-C(16)-C(5) 62.7(2) C(14)-C(15)-C(16)-C(5) -114.40(17) C(10)-C(15)-C(16)-C(1) -116.43(18) C(14)-C(15)-C(16)-C(1) 66.5(2) C(2)-C(1)-O(1)-C(18) -39.2(2) C(16)-C(1)-O(1)-C(18) 143.21(16) C(1)-C(2)-O(2)-C(19) -102.78(19) C(3)-C(2)-O(2)-C(19) 79.8(2) C(4)-C(3)-O(3)-C(20) -3.0(2) C(2)-C(3)-O(3)-C(20) 176.39(16) C(10)-C(9)-O(6)-Si -105.80(13) C(8)-C(9)-O(6)-Si 132.38(11) C(11)-C(12)-O(7)-C(17) 178.0(2) C(13)-C(12)-O(7)-C(17) -3.5(2) O(8)-C(17)-O(7)-C(12) 7.4(3) C(14)-C(13)-O(8)-C(17) -176.6(2) C(12)-C(13)-O(8)-C(17) 6.0(2) O(7)-C(17)-O(8)-C(13) -8.3(3) C(13)-C(14)-O(9)-C(29) 40.6(2) C(15)-C(14)-O(9)-C(29) -143.70(15) C(9)-O(6)-Si-C(24) -69.54(13) C(9)-O(6)-Si-C(23) 49.29(14) C(9)-O(6)-Si-C(25) 169.61(12) C(28)-C(25)-Si-O(6) 63.95(14) C(26)-C(25)-Si-O(6) -56.67(14) C(27)-C(25)-Si-O(6) -176.57(13) C(28)-C(25)-Si-C(24) -54.77(15) C(26)-C(25)-Si-C(24) -175.39(13) C(27)-C(25)-Si-C(24) 64.71(16) C(28)-C(25)-Si-C(23) -177.37(14) C(26)-C(25)-Si-C(23) 62.01(16) C(27)-C(25)-Si-C(23) -57.89(16) 507

X-ray Crystallographic Data of Kadsuralignan B

Table B.19 Crystallographic details for RajanBabu 1916

Formula C27 H32 O11 Formula weight 532.53 Temperature 150(2) K Wavelength 0.71073 Å Crystal system triclinic Space group P1 Unit cell dimensions a = 9.4188(2) Å α= 96.812(1)° b = 9.7589(1) Å β= 97.849(1)° c = 15.1515(3) Å γ = 109.187(1)° Volume 1282.95(4) Å3 Z 2 Density (calculated) 1.379 Mg/m3 Absorption coefficient 0.107 mm-1 F(000) 564 Crystal size 0.15 x 0.35 x 0.38 mm3 Theta range for data collection 2.48 to 27.44° Index ranges -12<=h<=12, -12<=k<=12, -19<=l<=19 Reflections collected 41126 Independent reflections 11557 [R(int) = 0.027] Completeness to theta = 27.44° 99.8 % Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 11557 / 3 / 709 Goodness-of-fit on F2 1.032 Final R indices [I>2sigma(I)] R1 = 0.0353, wR2 = 0.0800 R indices (all data) R1 = 0.0443, wR2 = 0.0849 Absolute structure parameter 0.2(4) Largest diff. peak and hole 0.308 and -0.347 e/Å3

508

Table B.20 Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for RajanBabu 1916. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______O(1A) 7946(1) 3561(1) 988(1) 29(1) O(2A) 10879(1) 4973(1) 688(1) 31(1) O(3A) 13194(1) 3962(1) 1275(1) 32(1) O(4A) 8414(1) -763(1) 2651(1) 26(1) O(5A) 8854(2) -1730(2) 1339(1) 41(1) O(6A) 11573(2) 2416(2) 3961(1) 38(1) O(7A) 9221(1) 3641(1) 3476(1) 30(1) O(8A) 7455(2) 4733(2) 3316(1) 46(1) O(9A) 2829(2) -968(2) 2271(1) 45(1) O(10A) 3313(2) -1281(2) 822(1) 46(1) O(11A) 6482(1) 261(2) 402(1) 39(1) C(1A) 9118(2) 3071(2) 1259(1) 23(1) C(2A) 10591(2) 3747(2) 1103(1) 24(1) C(3A) 11768(2) 3262(2) 1449(1) 25(1) C(4A) 11447(2) 2144(2) 1953(1) 26(1) C(5A) 9985(2) 1507(2) 2140(1) 23(1) C(6A) 9866(2) 429(2) 2792(1) 26(1) C(7A) 10227(2) 1134(2) 3814(1) 31(1) C(8A) 8900(2) 1476(2) 4189(1) 34(1) C(9A) 8070(2) 2348(2) 3663(1) 31(1) C(10A) 6891(2) 1455(2) 2830(1) 27(1) C(11A) 5422(2) 736(2) 2994(1) 32(1) C(12A) 4337(2) -130(2) 2274(1) 32(1) C(13A) 4624(2) -301(2) 1403(1) 29(1) C(14A) 6058(2) 406(2) 1223(1) 27(1) C(15A) 7217(2) 1293(2) 1962(1) 24(1) C(16A) 8799(2) 1950(2) 1785(1) 23(1) C(17A) 10696(3) 54(2) 4337(1) 41(1) C(18A) 9436(3) 2270(3) 5181(1) 53(1) 509

Table B.20 Continued

C(19A) 2151(3) -1518(3) 1331(2) 63(1) C(20A) 5354(3) -276(3) -396(2) 58(1) C(21A) 7622(2) 3652(3) 53(1) 44(1) C(22A) 11526(2) 4920(2) -110(1) 38(1) C(23A) 14320(2) 3295(2) 1476(2) 36(1) C(24A) 8040(2) -1773(2) 1889(1) 29(1) C(25A) 6520(2) -2933(2) 1848(1) 39(1) C(26A) 8730(2) 4748(2) 3273(1) 34(1) C(27A) 9923(2) 5928(2) 2965(1) 39(1) O(1B) 8842(1) 7041(1) 8057(1) 28(1) O(2B) 10333(1) 10078(1) 8568(1) 30(1) O(3B) 8910(1) 11945(1) 8019(1) 31(1) O(4B) 3330(1) 6528(1) 6398(1) 24(1) O(5B) 3116(2) 7696(2) 7719(1) 37(1) O(6B) 5837(2) 8933(1) 5144(1) 33(1) O(7B) 7358(1) 6945(1) 5545(1) 28(1) O(8B) 8675(2) 5410(2) 5623(1) 55(1) O(9B) 3498(2) 1273(1) 6611(1) 41(1) O(10B) 4237(2) 2487(1) 8097(1) 37(1) O(11B) 6059(1) 5699(1) 8616(1) 33(1) C(1B) 8125(2) 8001(2) 7833(1) 23(1) C(2B) 8850(2) 9523(2) 8082(1) 24(1) C(3B) 8125(2) 10456(2) 7764(1) 24(1) C(4B) 6703(2) 9854(2) 7203(1) 25(1) C(5B) 5988(2) 8332(2) 6942(1) 22(1) C(6B) 4478(2) 7867(2) 6277(1) 23(1) C(7B) 4581(2) 7697(2) 5257(1) 26(1) C(8B) 4687(2) 6213(2) 4830(1) 29(1) C(9B) 5921(2) 5700(2) 5321(1) 27(1) C(10B) 5530(2) 4984(2) 6134(1) 24(1) C(11B) 4677(2) 3467(2) 5929(1) 30(1) C(12B) 4264(2) 2764(2) 6634(1) 30(1) 510

Table B.20 Continued

C(13B) 4689(2) 3481(2) 7519(1) 28(1) C(14B) 5545(2) 4965(2) 7738(1) 25(1) C(15B) 5935(2) 5743(2) 7024(1) 23(1) C(16B) 6683(2) 7379(2) 7259(1) 21(1) C(17B) 3167(2) 7904(2) 4759(1) 35(1) C(18B) 4885(3) 6218(3) 3838(1) 45(1) C(19B) 3140(3) 1206(2) 7501(2) 45(1) C(20B) 4902(3) 5579(3) 9154(1) 47(1) C(21B) 9547(2) 7223(2) 8985(1) 38(1) C(22B) 10521(3) 10852(2) 9470(1) 44(1) C(23B) 8115(2) 12883(2) 7724(1) 32(1) C(24B) 2740(2) 6599(2) 7159(1) 26(1) C(25B) 1566(2) 5144(2) 7193(1) 37(1) C(26B) 8652(2) 6634(2) 5737(1) 34(1) C(27B) 10007(2) 7994(2) 6122(1) 38(1) ______

511

Table B.21 Bond lengths [Å] and angles [°] for RajanBabu 1916. ______O(1A)-C(1A) 1.3733(19) O(1A)-C(21A) 1.428(2) O(2A)-C(2A) 1.3824(19) O(2A)-C(22A) 1.429(2) O(3A)-C(3A) 1.370(2) O(3A)-C(23A) 1.432(2) O(4A)-C(24A) 1.349(2) O(4A)-C(6A) 1.444(2) O(5A)-C(24A) 1.203(2) O(6A)-C(7A) 1.427(2) O(6A)-H(06A) 0.87(3) O(7A)-C(26A) 1.358(2) O(7A)-C(9A) 1.456(2) O(8A)-C(26A) 1.206(2) O(9A)-C(12A) 1.385(2) O(9A)-C(19A) 1.438(3) O(10A)-C(13A) 1.393(2) O(10A)-C(19A) 1.398(3) O(11A)-C(14A) 1.363(2) O(11A)-C(20A) 1.414(2) C(1A)-C(2A) 1.393(2) C(1A)-C(16A) 1.406(2) C(2A)-C(3A) 1.405(2) C(3A)-C(4A) 1.381(2) C(4A)-C(5A) 1.396(2) C(4A)-H(4A) 0.9500 C(5A)-C(16A) 1.390(2) C(5A)-C(6A) 1.515(2) C(6A)-C(7A) 1.560(2) C(6A)-H(6A) 1.0000 C(7A)-C(17A) 1.531(2) C(7A)-C(8A) 1.556(3) 512

Table B.21 Continued

C(8A)-C(18A) 1.541(3) C(8A)-C(9A) 1.548(2) C(8A)-H(8A) 1.0000 C(9A)-C(10A) 1.518(3) C(9A)-H(9A) 1.0000 C(10A)-C(15A) 1.394(2) C(10A)-C(11A) 1.402(3) C(11A)-C(12A) 1.363(3) C(11A)-H(11A) 0.9500 C(12A)-C(13A) 1.385(3) C(13A)-C(14A) 1.381(2) C(14A)-C(15A) 1.418(2) C(15A)-C(16A) 1.492(2) C(17A)-H(17A) 0.9800 C(17A)-H(17B) 0.9800 C(17A)-H(17C) 0.9800 C(18A)-H(18A) 0.9800 C(18A)-H(18B) 0.9800 C(18A)-H(18C) 0.9800 C(19A)-H(19A) 0.9900 C(19A)-H(19B) 0.9900 C(20A)-H(20A) 0.9800 C(20A)-H(20B) 0.9800 C(20A)-H(20C) 0.9800 C(21A)-H(21A) 0.9800 C(21A)-H(21B) 0.9800 C(21A)-H(21C) 0.9800 C(22A)-H(22A) 0.9800 C(22A)-H(22B) 0.9800 C(22A)-H(22C) 0.9800 C(23A)-H(23A) 0.9800 C(23A)-H(23B) 0.9800 513

Table B.21 Continued

C(23A)-H(23C) 0.9800 C(24A)-C(25A) 1.493(3) C(25A)-H(25A) 0.9800 C(25A)-H(25B) 0.9800 C(25A)-H(25C) 0.9800 C(26A)-C(27A) 1.492(3) C(27A)-H(27A) 0.9800 C(27A)-H(27B) 0.9800 C(27A)-H(27C) 0.9800 O(1B)-C(1B) 1.3695(19) O(1B)-C(21B) 1.435(2) O(2B)-C(2B) 1.3827(19) O(2B)-C(22B) 1.440(2) O(3B)-C(3B) 1.375(2) O(3B)-C(23B) 1.433(2) O(4B)-C(24B) 1.3498(19) O(4B)-C(6B) 1.4464(19) O(5B)-C(24B) 1.202(2) O(6B)-C(7B) 1.432(2) O(6B)-HO6B 0.87(3) O(7B)-C(26B) 1.352(2) O(7B)-C(9B) 1.456(2) O(8B)-C(26B) 1.195(2) O(9B)-C(12B) 1.389(2) O(9B)-C(19B) 1.437(3) O(10B)-C(13B) 1.386(2) O(10B)-C(19B) 1.440(2) O(11B)-C(14B) 1.373(2) O(11B)-C(20B) 1.432(2) C(1B)-C(2B) 1.395(2) C(1B)-C(16B) 1.407(2) C(2B)-C(3B) 1.397(2) 514

Table B.21 Continued

C(3B)-C(4B) 1.384(2) C(4B)-C(5B) 1.395(2) C(4B)-H(4B) 0.9500 C(5B)-C(16B) 1.394(2) C(5B)-C(6B) 1.523(2) C(6B)-C(7B) 1.555(2) C(6B)-H(6B) 1.0000 C(7B)-C(17B) 1.524(2) C(7B)-C(8B) 1.554(2) C(8B)-C(18B) 1.540(2) C(8B)-C(9B) 1.546(2) C(8B)-H(8B) 1.0000 C(9B)-C(10B) 1.517(2) C(9B)-H(9B) 1.0000 C(10B)-C(15B) 1.397(2) C(10B)-C(11B) 1.406(2) C(11B)-C(12B) 1.369(3) C(11B)-H(11B) 0.9500 C(12B)-C(13B) 1.376(3) C(13B)-C(14B) 1.379(2) C(14B)-C(15B) 1.415(2) C(15B)-C(16B) 1.493(2) C(17B)-H(17D) 0.9800 C(17B)-H(17E) 0.9800 C(17B)-H(17F) 0.9800 C(18B)-H(18D) 0.9800 C(18B)-H(18E) 0.9800 C(18B)-H(18F) 0.9800 C(19B)-H(19C) 0.9900 C(19B)-H(19D) 0.9900 C(20B)-H(20D) 0.9800 C(20B)-H(20E) 0.9800 515

Table B.21 Continued

C(20B)-H(20F) 0.9800 C(21B)-H(21D) 0.9800 C(21B)-H(21E) 0.9800 C(21B)-H(21F) 0.9800 C(22B)-H(22D) 0.9800 C(22B)-H(22E) 0.9800 C(22B)-H(22F) 0.9800 C(23B)-H(23D) 0.9800 C(23B)-H(23E) 0.9800 C(23B)-H(23F) 0.9800 C(24B)-C(25B) 1.497(3) C(25B)-H(25D) 0.9800 C(25B)-H(25E) 0.9800 C(25B)-H(25F) 0.9800 C(26B)-C(27B) 1.493(3) C(27B)-H(27D) 0.9800 C(27B)-H(27E) 0.9800 C(27B)-H(27F) 0.9800

C(1A)-O(1A)-C(21A) 117.19(13) C(2A)-O(2A)-C(22A) 116.90(13) C(3A)-O(3A)-C(23A) 116.82(13) C(24A)-O(4A)-C(6A) 117.11(13) C(7A)-O(6A)-H(06A) 108.3(19) C(26A)-O(7A)-C(9A) 115.99(14) C(12A)-O(9A)-C(19A) 105.03(15) C(13A)-O(10A)-C(19A) 105.43(16) C(14A)-O(11A)-C(20A) 119.91(16) O(1A)-C(1A)-C(2A) 121.83(14) O(1A)-C(1A)-C(16A) 116.55(14) C(2A)-C(1A)-C(16A) 121.30(14) O(2A)-C(2A)-C(1A) 118.59(14) 516

Table B.21 Continued

O(2A)-C(2A)-C(3A) 121.74(14) C(1A)-C(2A)-C(3A) 119.35(14) O(3A)-C(3A)-C(4A) 123.70(14) O(3A)-C(3A)-C(2A) 117.03(14) C(4A)-C(3A)-C(2A) 119.26(15) C(3A)-C(4A)-C(5A) 121.35(15) C(3A)-C(4A)-H(4A) 119.3 C(5A)-C(4A)-H(4A) 119.3 C(16A)-C(5A)-C(4A) 120.08(14) C(16A)-C(5A)-C(6A) 124.96(15) C(4A)-C(5A)-C(6A) 114.81(14) O(4A)-C(6A)-C(5A) 115.46(13) O(4A)-C(6A)-C(7A) 106.15(13) C(5A)-C(6A)-C(7A) 115.07(13) O(4A)-C(6A)-H(6A) 106.5 C(5A)-C(6A)-H(6A) 106.5 C(7A)-C(6A)-H(6A) 106.5 O(6A)-C(7A)-C(17A) 104.98(15) O(6A)-C(7A)-C(8A) 111.64(14) C(17A)-C(7A)-C(8A) 109.50(16) O(6A)-C(7A)-C(6A) 107.89(14) C(17A)-C(7A)-C(6A) 106.26(14) C(8A)-C(7A)-C(6A) 115.89(14) C(18A)-C(8A)-C(9A) 108.03(15) C(18A)-C(8A)-C(7A) 110.77(17) C(9A)-C(8A)-C(7A) 118.34(15) C(18A)-C(8A)-H(8A) 106.3 C(9A)-C(8A)-H(8A) 106.3 C(7A)-C(8A)-H(8A) 106.3 O(7A)-C(9A)-C(10A) 113.21(14) O(7A)-C(9A)-C(8A) 108.33(15) C(10A)-C(9A)-C(8A) 115.41(15) 517

Table B.21 Continued

O(7A)-C(9A)-H(9A) 106.4 C(10A)-C(9A)-H(9A) 106.4 C(8A)-C(9A)-H(9A) 106.4 C(15A)-C(10A)-C(11A) 120.96(16) C(15A)-C(10A)-C(9A) 123.90(16) C(11A)-C(10A)-C(9A) 115.09(15) C(12A)-C(11A)-C(10A) 117.42(16) C(12A)-C(11A)-H(11A) 121.3 C(10A)-C(11A)-H(11A) 121.3 C(11A)-C(12A)-C(13A) 122.88(16) C(11A)-C(12A)-O(9A) 127.95(17) C(13A)-C(12A)-O(9A) 109.17(16) C(14A)-C(13A)-C(12A) 120.83(16) C(14A)-C(13A)-O(10A) 129.52(16) C(12A)-C(13A)-O(10A) 109.61(15) O(11A)-C(14A)-C(13A) 125.61(16) O(11A)-C(14A)-C(15A) 116.80(14) C(13A)-C(14A)-C(15A) 117.49(15) C(10A)-C(15A)-C(14A) 120.40(15) C(10A)-C(15A)-C(16A) 121.82(14) C(14A)-C(15A)-C(16A) 117.65(14) C(5A)-C(16A)-C(1A) 118.59(14) C(5A)-C(16A)-C(15A) 121.91(14) C(1A)-C(16A)-C(15A) 119.49(13) C(7A)-C(17A)-H(17A) 109.5 C(7A)-C(17A)-H(17B) 109.5 H(17A)-C(17A)-H(17B) 109.5 C(7A)-C(17A)-H(17C) 109.5 H(17A)-C(17A)-H(17C) 109.5 H(17B)-C(17A)-H(17C) 109.5 C(8A)-C(18A)-H(18A) 109.5 C(8A)-C(18A)-H(18B) 109.5 518

Table B.21 Continued

H(18A)-C(18A)-H(18B) 109.5 C(8A)-C(18A)-H(18C) 109.5 H(18A)-C(18A)-H(18C) 109.5 H(18B)-C(18A)-H(18C) 109.5 O(10A)-C(19A)-O(9A) 108.90(18) O(10A)-C(19A)-H(19A) 109.9 O(9A)-C(19A)-H(19A) 109.9 O(10A)-C(19A)-H(19B) 109.9 O(9A)-C(19A)-H(19B) 109.9 H(19A)-C(19A)-H(19B) 108.3 O(11A)-C(20A)-H(20A) 109.5 O(11A)-C(20A)-H(20B) 109.5 H(20A)-C(20A)-H(20B) 109.5 O(11A)-C(20A)-H(20C) 109.5 H(20A)-C(20A)-H(20C) 109.5 H(20B)-C(20A)-H(20C) 109.5 O(1A)-C(21A)-H(21A) 109.5 O(1A)-C(21A)-H(21B) 109.5 H(21A)-C(21A)-H(21B) 109.5 O(1A)-C(21A)-H(21C) 109.5 H(21A)-C(21A)-H(21C) 109.5 H(21B)-C(21A)-H(21C) 109.5 O(2A)-C(22A)-H(22A) 109.5 O(2A)-C(22A)-H(22B) 109.5 H(22A)-C(22A)-H(22B) 109.5 O(2A)-C(22A)-H(22C) 109.5 H(22A)-C(22A)-H(22C) 109.5 H(22B)-C(22A)-H(22C) 109.5 O(3A)-C(23A)-H(23A) 109.5 O(3A)-C(23A)-H(23B) 109.5 H(23A)-C(23A)-H(23B) 109.5 O(3A)-C(23A)-H(23C) 109.5 519

Table B.21 Continued

H(23A)-C(23A)-H(23C) 109.5 H(23B)-C(23A)-H(23C) 109.5 O(5A)-C(24A)-O(4A) 123.39(16) O(5A)-C(24A)-C(25A) 126.04(17) O(4A)-C(24A)-C(25A) 110.56(15) C(24A)-C(25A)-H(25A) 109.5 C(24A)-C(25A)-H(25B) 109.5 H(25A)-C(25A)-H(25B) 109.5 C(24A)-C(25A)-H(25C) 109.5 H(25A)-C(25A)-H(25C) 109.5 H(25B)-C(25A)-H(25C) 109.5 O(8A)-C(26A)-O(7A) 122.82(18) O(8A)-C(26A)-C(27A) 125.03(17) O(7A)-C(26A)-C(27A) 112.11(16) C(26A)-C(27A)-H(27A) 109.5 C(26A)-C(27A)-H(27B) 109.5 H(27A)-C(27A)-H(27B) 109.5 C(26A)-C(27A)-H(27C) 109.5 H(27A)-C(27A)-H(27C) 109.5 H(27B)-C(27A)-H(27C) 109.5 C(1B)-O(1B)-C(21B) 117.70(13) C(2B)-O(2B)-C(22B) 115.32(14) C(3B)-O(3B)-C(23B) 115.84(13) C(24B)-O(4B)-C(6B) 116.41(12) C(7B)-O(6B)-HO6B 105.4(17) C(26B)-O(7B)-C(9B) 116.80(13) C(12B)-O(9B)-C(19B) 103.88(14) C(13B)-O(10B)-C(19B) 103.15(14) C(14B)-O(11B)-C(20B) 115.32(15) O(1B)-C(1B)-C(2B) 121.77(14) O(1B)-C(1B)-C(16B) 116.39(14) C(2B)-C(1B)-C(16B) 121.51(14) 520

Table B.21 Continued

O(2B)-C(2B)-C(1B) 119.08(14) O(2B)-C(2B)-C(3B) 121.18(14) C(1B)-C(2B)-C(3B) 119.45(14) O(3B)-C(3B)-C(4B) 123.86(14) O(3B)-C(3B)-C(2B) 116.71(14) C(4B)-C(3B)-C(2B) 119.41(14) C(3B)-C(4B)-C(5B) 121.14(15) C(3B)-C(4B)-H(4B) 119.4 C(5B)-C(4B)-H(4B) 119.4 C(16B)-C(5B)-C(4B) 120.43(14) C(16B)-C(5B)-C(6B) 125.49(14) C(4B)-C(5B)-C(6B) 114.04(13) O(4B)-C(6B)-C(5B) 114.54(12) O(4B)-C(6B)-C(7B) 106.94(12) C(5B)-C(6B)-C(7B) 116.06(13) O(4B)-C(6B)-H(6B) 106.2 C(5B)-C(6B)-H(6B) 106.2 C(7B)-C(6B)-H(6B) 106.2 O(6B)-C(7B)-C(17B) 104.59(14) O(6B)-C(7B)-C(8B) 111.78(14) C(17B)-C(7B)-C(8B) 109.74(14) O(6B)-C(7B)-C(6B) 107.67(13) C(17B)-C(7B)-C(6B) 106.56(13) C(8B)-C(7B)-C(6B) 115.79(13) C(18B)-C(8B)-C(9B) 108.19(14) C(18B)-C(8B)-C(7B) 110.80(15) C(9B)-C(8B)-C(7B) 117.59(14) C(18B)-C(8B)-H(8B) 106.5 C(9B)-C(8B)-H(8B) 106.5 C(7B)-C(8B)-H(8B) 106.5 O(7B)-C(9B)-C(10B) 112.12(13) O(7B)-C(9B)-C(8B) 108.06(13) 521

Table B.21 Continued

C(10B)-C(9B)-C(8B) 115.76(14) O(7B)-C(9B)-H(9B) 106.8 C(10B)-C(9B)-H(9B) 106.8 C(8B)-C(9B)-H(9B) 106.8 C(15B)-C(10B)-C(11B) 121.01(15) C(15B)-C(10B)-C(9B) 124.13(15) C(11B)-C(10B)-C(9B) 114.85(14) C(12B)-C(11B)-C(10B) 117.57(16) C(12B)-C(11B)-H(11B) 121.2 C(10B)-C(11B)-H(11B) 121.2 C(11B)-C(12B)-C(13B) 122.37(16) C(11B)-C(12B)-O(9B) 128.26(16) C(13B)-C(12B)-O(9B) 109.18(15) C(12B)-C(13B)-C(14B) 121.14(15) C(12B)-C(13B)-O(10B) 110.31(15) C(14B)-C(13B)-O(10B) 128.37(16) O(11B)-C(14B)-C(13B) 122.72(15) O(11B)-C(14B)-C(15B) 119.16(15) C(13B)-C(14B)-C(15B) 118.10(15) C(10B)-C(15B)-C(14B) 119.70(15) C(10B)-C(15B)-C(16B) 122.64(14) C(14B)-C(15B)-C(16B) 117.53(14) C(5B)-C(16B)-C(1B) 118.05(14) C(5B)-C(16B)-C(15B) 122.24(14) C(1B)-C(16B)-C(15B) 119.70(13) C(7B)-C(17B)-H(17D) 109.5 C(7B)-C(17B)-H(17E) 109.5 H(17D)-C(17B)-H(17E) 109.5 C(7B)-C(17B)-H(17F) 109.5 H(17D)-C(17B)-H(17F) 109.5 H(17E)-C(17B)-H(17F) 109.5 C(8B)-C(18B)-H(18D) 109.5 522

Table B.21 Continued

C(8B)-C(18B)-H(18E) 109.5 H(18D)-C(18B)-H(18E) 109.5 C(8B)-C(18B)-H(18F) 109.5 H(18D)-C(18B)-H(18F) 109.5 H(18E)-C(18B)-H(18F) 109.5 O(9B)-C(19B)-O(10B) 107.01(15) O(9B)-C(19B)-H(19C) 110.3 O(10B)-C(19B)-H(19C) 110.3 O(9B)-C(19B)-H(19D) 110.3 O(10B)-C(19B)-H(19D) 110.3 H(19C)-C(19B)-H(19D) 108.6 O(11B)-C(20B)-H(20D) 109.5 O(11B)-C(20B)-H(20E) 109.5 H(20D)-C(20B)-H(20E) 109.5 O(11B)-C(20B)-H(20F) 109.5 H(20D)-C(20B)-H(20F) 109.5 H(20E)-C(20B)-H(20F) 109.5 O(1B)-C(21B)-H(21D) 109.5 O(1B)-C(21B)-H(21E) 109.5 H(21D)-C(21B)-H(21E) 109.5 O(1B)-C(21B)-H(21F) 109.5 H(21D)-C(21B)-H(21F) 109.5 H(21E)-C(21B)-H(21F) 109.5 O(2B)-C(22B)-H(22D) 109.5 O(2B)-C(22B)-H(22E) 109.5 H(22D)-C(22B)-H(22E) 109.5 O(2B)-C(22B)-H(22F) 109.5 H(22D)-C(22B)-H(22F) 109.5 H(22E)-C(22B)-H(22F) 109.5 O(3B)-C(23B)-H(23D) 109.5 O(3B)-C(23B)-H(23E) 109.5 H(23D)-C(23B)-H(23E) 109.5 523

Table B.21 Continued

O(3B)-C(23B)-H(23F) 109.5 H(23D)-C(23B)-H(23F) 109.5 H(23E)-C(23B)-H(23F) 109.5 O(5B)-C(24B)-O(4B) 123.61(16) O(5B)-C(24B)-C(25B) 125.73(16) O(4B)-C(24B)-C(25B) 110.65(14) C(24B)-C(25B)-H(25D) 109.5 C(24B)-C(25B)-H(25E) 109.5 H(25D)-C(25B)-H(25E) 109.5 C(24B)-C(25B)-H(25F) 109.5 H(25D)-C(25B)-H(25F) 109.5 H(25E)-C(25B)-H(25F) 109.5 O(8B)-C(26B)-O(7B) 123.12(18) O(8B)-C(26B)-C(27B) 125.16(17) O(7B)-C(26B)-C(27B) 111.71(16) C(26B)-C(27B)-H(27D) 109.5 C(26B)-C(27B)-H(27E) 109.5 H(27D)-C(27B)-H(27E) 109.5 C(26B)-C(27B)-H(27F) 109.5 H(27D)-C(27B)-H(27F) 109.5 H(27E)-C(27B)-H(27F) 109.5 ______

524

Table B.22 Anisotropic displacement parameters (Å2x 103) for RajanBabu 1916. The anisotropic displacement factor exponent takes the form: -2π2[ h2a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______O(1A) 31(1) 38(1) 29(1) 15(1) 9(1) 21(1) O(2A) 36(1) 26(1) 38(1) 14(1) 14(1) 14(1) O(3A) 23(1) 28(1) 47(1) 12(1) 7(1) 9(1) O(4A) 33(1) 24(1) 24(1) 6(1) 7(1) 10(1) O(5A) 46(1) 40(1) 33(1) -3(1) 13(1) 11(1) O(6A) 43(1) 33(1) 33(1) 2(1) -9(1) 14(1) O(7A) 38(1) 28(1) 28(1) 4(1) 2(1) 19(1) O(8A) 54(1) 52(1) 52(1) 17(1) 17(1) 37(1) O(9A) 29(1) 52(1) 59(1) 21(1) 21(1) 12(1) O(10A) 25(1) 55(1) 49(1) 10(1) 6(1) 4(1) O(11A) 32(1) 58(1) 22(1) 3(1) 3(1) 9(1) C(1A) 25(1) 27(1) 22(1) 5(1) 4(1) 14(1) C(2A) 29(1) 20(1) 26(1) 5(1) 5(1) 10(1) C(3A) 23(1) 22(1) 28(1) 1(1) 3(1) 7(1) C(4A) 27(1) 24(1) 29(1) 4(1) 1(1) 12(1) C(5A) 28(1) 21(1) 20(1) 2(1) 1(1) 10(1) C(6A) 29(1) 24(1) 25(1) 6(1) 2(1) 13(1) C(7A) 41(1) 29(1) 25(1) 5(1) -2(1) 17(1) C(8A) 52(1) 36(1) 21(1) 7(1) 6(1) 26(1) C(9A) 43(1) 33(1) 23(1) 7(1) 9(1) 20(1) C(10A) 35(1) 28(1) 25(1) 10(1) 9(1) 18(1) C(11A) 41(1) 36(1) 32(1) 13(1) 18(1) 22(1) C(12A) 29(1) 33(1) 44(1) 16(1) 17(1) 16(1) C(13A) 25(1) 28(1) 35(1) 8(1) 4(1) 11(1) C(14A) 29(1) 31(1) 26(1) 10(1) 7(1) 15(1) C(15A) 27(1) 26(1) 24(1) 10(1) 7(1) 14(1) C(16A) 26(1) 24(1) 21(1) 3(1) 4(1) 10(1) C(17A) 62(1) 40(1) 28(1) 9(1) -1(1) 31(1) C(18A) 89(2) 61(1) 22(1) 4(1) 3(1) 49(1) 525

Table B.22 Continued

C(19A) 42(1) 53(1) 75(2) -22(1) 28(1) -4(1) C(20A) 51(1) 77(2) 30(1) -2(1) 1(1) 6(1) C(21A) 39(1) 70(1) 37(1) 31(1) 9(1) 28(1) C(22A) 42(1) 43(1) 39(1) 19(1) 17(1) 23(1) C(23A) 26(1) 33(1) 54(1) 10(1) 7(1) 13(1) C(24A) 39(1) 26(1) 24(1) 7(1) 2(1) 13(1) C(25A) 44(1) 31(1) 35(1) 11(1) 2(1) 6(1) C(26A) 47(1) 33(1) 25(1) 0(1) -1(1) 24(1) C(27A) 44(1) 28(1) 42(1) 1(1) -4(1) 14(1) O(1B) 29(1) 29(1) 28(1) 5(1) -1(1) 15(1) O(2B) 22(1) 31(1) 33(1) 2(1) -3(1) 7(1) O(3B) 26(1) 22(1) 40(1) 5(1) 0(1) 7(1) O(4B) 22(1) 27(1) 22(1) 3(1) 5(1) 7(1) O(5B) 36(1) 42(1) 28(1) -1(1) 10(1) 11(1) O(6B) 31(1) 42(1) 33(1) 18(1) 10(1) 16(1) O(7B) 25(1) 36(1) 28(1) 11(1) 8(1) 16(1) O(8B) 47(1) 54(1) 67(1) -9(1) -6(1) 35(1) O(9B) 45(1) 23(1) 47(1) 4(1) 7(1) 4(1) O(10B) 42(1) 29(1) 39(1) 14(1) 8(1) 7(1) O(11B) 39(1) 36(1) 20(1) 6(1) 5(1) 8(1) C(1B) 25(1) 27(1) 20(1) 5(1) 5(1) 12(1) C(2B) 20(1) 28(1) 22(1) 4(1) 3(1) 8(1) C(3B) 24(1) 23(1) 26(1) 5(1) 6(1) 7(1) C(4B) 26(1) 26(1) 26(1) 8(1) 6(1) 12(1) C(5B) 23(1) 27(1) 20(1) 5(1) 5(1) 11(1) C(6B) 20(1) 27(1) 22(1) 6(1) 4(1) 9(1) C(7B) 25(1) 37(1) 22(1) 10(1) 4(1) 15(1) C(8B) 31(1) 44(1) 18(1) 4(1) 4(1) 20(1) C(9B) 28(1) 33(1) 21(1) 3(1) 4(1) 14(1) C(10B) 24(1) 28(1) 23(1) 4(1) 3(1) 13(1) C(11B) 32(1) 30(1) 26(1) -1(1) 0(1) 13(1) C(12B) 28(1) 22(1) 39(1) 4(1) 2(1) 10(1) 526

Table B.22 Continued

C(13B) 26(1) 27(1) 31(1) 12(1) 4(1) 9(1) C(14B) 26(1) 27(1) 22(1) 5(1) 1(1) 11(1) C(15B) 20(1) 24(1) 24(1) 5(1) 2(1) 9(1) C(16B) 25(1) 24(1) 17(1) 5(1) 6(1) 10(1) C(17B) 35(1) 51(1) 26(1) 10(1) 2(1) 25(1) C(18B) 55(1) 78(2) 20(1) 10(1) 8(1) 45(1) C(19B) 46(1) 29(1) 54(1) 10(1) 13(1) 2(1) C(20B) 57(1) 64(1) 32(1) 9(1) 14(1) 32(1) C(21B) 41(1) 34(1) 35(1) 9(1) -11(1) 14(1) C(22B) 50(1) 37(1) 37(1) -6(1) -13(1) 16(1) C(23B) 34(1) 24(1) 40(1) 8(1) 6(1) 11(1) C(24B) 22(1) 36(1) 21(1) 6(1) 2(1) 10(1) C(25B) 29(1) 44(1) 33(1) 12(1) 6(1) 6(1) C(26B) 35(1) 51(1) 26(1) 8(1) 9(1) 26(1) C(27B) 27(1) 52(1) 39(1) 14(1) 11(1) 17(1) ______

527

Table B.23 Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for RajanBabu 1916. ______x y z U(eq) ______

H(06A) 11340(30) 3090(30) 3709(19) 68(8)* H(4A) 12238 1802 2177 31 H(6A) 10650 -34 2702 31 H(8A) 8105 502 4194 40 H(9A) 7502 2720 4088 37 H(11A) 5192 848 3583 39 H(17A) 11513 -182 4090 61 H(17B) 9810 -851 4279 61 H(17C) 11063 503 4977 61 H(18A) 9851 1673 5543 79 H(18B) 8567 2412 5417 79 H(18C) 10232 3231 5213 79 H(19A) 1551 -2584 1244 76 H(19B) 1451 -1002 1130 76 H(20A) 4728 -1302 -398 88 H(20B) 5851 -225 -925 88 H(20C) 4701 325 -419 88 H(21A) 8086 4675 -29 66 H(21B) 6511 3319 -155 66 H(21C) 8045 3025 -301 66 H(22A) 12391 4576 0 56 H(22B) 11881 5907 -267 56 H(22C) 10748 4240 -610 56 H(23A) 14578 3363 2133 55 H(23B) 15241 3810 1249 55 H(23C) 13910 2257 1185 55 H(25A) 6114 -3462 1225 58 H(25B) 5811 -2472 2047 58 528

Table B.23 Continued

H(25C) 6637 -3627 2245 58 H(27A) 9591 5935 2324 59 H(27B) 10887 5738 3045 59 H(27C) 10074 6886 3323 59 HO6B 6660(30) 8750(30) 5346(17) 55(7)* H(4B) 6204 10488 6991 30 H(6B) 4052 8670 6396 27 H(8B) 3676 5435 4820 35 H(9B) 6068 4944 4871 32 H(11B) 4397 2948 5324 36 H(17D) 3096 8833 5036 52 H(17E) 2251 7083 4798 52 H(17F) 3246 7930 4122 52 H(18D) 5875 6953 3816 68 H(18E) 4061 6462 3503 68 H(18F) 4845 5241 3565 68 H(19C) 3208 296 7701 54 H(19D) 2088 1205 7501 54 H(20D) 4112 5908 8855 71 H(20E) 5362 6196 9751 71 H(20F) 4439 4550 9225 71 H(21D) 10619 7874 9079 57 H(21E) 9501 6261 9134 57 H(21F) 9005 7659 9377 57 H(22D) 10057 11614 9449 67 H(22E) 11614 11313 9730 67 H(22F) 10021 10156 9845 67 H(23D) 7909 12732 7061 48 H(23E) 8747 13915 7965 48 H(23F) 7146 12645 7944 48 H(25D) 1432 5091 7819 55 H(25E) 1907 4347 6962 55 529

Table B.23 Continued

H(25F) 590 5043 6818 55 H(27D) 10392 7961 6750 57 H(27E) 9708 8863 6102 57 H(27F) 10812 8050 5766 57 *Refined isotropically

530

Table B.24 Hydrogen bonds for RajanBabu 1916 [Å and °].

______D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ______O(6B)-HO6B...O(7B) 0.87(3) 2.11(3) 2.8377(17) 140(2) O(6A)-H(06A)...O(7A) 0.87(3) 2.23(3) 2.8957(18) 133(2) ______

531