NORTHWESTERN UNIVERSITY

A Multi-Component Catalytic Assembly Reaction for the Synthesis of Nitrogen- Containing Heterocycles and Umpolung Transformations of Aldehydes and Acylsilanes.

A DISSERTATION

SUBMITTED TO THE GRADUATE SCHOOL IN PARTIAL FULFILLMENT OF

THE REQUIREMENTS

For the degree

DOCTOR OF PHILOSOPHY

Field of Chemistry

By

Chris Galliford

EVANSTON ILLINOIS

June 2007

2

© Copyright by Chris Galliford 2007

All rights reserved

3 ABSTRACT

A Multi-Component Catalytic Assembly Reaction for the Synthesis of Nitrogen- Containing Heterocycles and Umpolung Transformations of Aldehydes and Acylsilanes.

Chris Galliford

A catalytic, multi-component coupling reaction for the synthesis of nitrogen- containing heterocycles has been developed. The reaction of an imine, α-diazoester and unsaturated coupling partner in the presence of a copper(I) or rhodium(II) transition metal catalyst with excellent diastereoselectivities and high yields. The transition metal- catalyzed decomposition of a diazo compound in the presence of an imine generates a transient azomethine ylide that undergoes addition with various dipolarophiles in a convergent manner to substituted pyrrolidine and 3-pyrroline heterocycles.

In addition to examining the general scope of the multi-component reaction, modification of the dipolarophile allowed access to more structurally complex 3,3’- pyrroldinyl spirooxindoles. Substitution of the α-diazoester with diazoacetonitrile allowed access to 1,2-diarylpyrroles.

Umpolung reactions involving acylsilanes and aldehydes have also been developed.

Acylsilanes treated sequentially with α-lithio diazoacetates followed by alkyl halides lead 4 to substituted β-ketoesters in a single-flask, multi-component operation. The treatment of aryl acylsilanes with tosylmethyl isocyanide (TosMIC) leads to the formation of 5- aryl-substituted oxazoles in excellent yield.

Two catalytic Umpolung reactions of aldehydes were also developed. Using an azolium salt as a precursor to a N-heterocylic carbene (NHC) catalyst, a mechanistic investigation into the nucleophilic acylation of 2-chlorooxazoles was conducted. Finally, investigations into a reaction using a 2,3-epoxyalcohol as a starting material, a tandem oxidation mediated bis-acetoxyiodosobenzene (BAIB) with catalytic TEMPO followed by NHC-catalyzed esterification leading to acetate aldol-products is reported.

______

Thesis Advisor: Professor Karl A. Scheidt

5 ACKNOWLEDGEMENTS

I’d like to thank my advisor Professor Karl A. Scheidt for the opportunity to study towards a Ph.D. in his research group. In addition to helpful discussions, advice and project guidance, he has played an important role in allowing me to develop scientific ideas and concepts into concrete experiments and results, and to mature as a scientist. In this regard I would also like to acknowledge my committee members Professors T. J.

Marks and J. B. Lambert for illuminating conversations and feedback during my studies here at Northwestern.

I would also like to thank my co-workers, who have provided me with a stimulating and entertaining environment, especially those who I have worked most closely alongside in the lab, including Bill Morris, Dan Custar, Brooks Maki and Anita Mattson and

Audrey Chan. I am also grateful to Dr. Ashwin Bharadwaj, Dr. Margaret Biddle, Bob

Lettan II, Dr. Alex Mathies, Dr. Juli Gibbs-Davis, Troy Reynolds, Eric Philips, Dr.

Manabu Wadamoto for incisive and friendly advice. I’d also like to give a special mention to James Martenson, a talented undergraduate student who I had the opportunity to work closely with during my Ph.D. I have learned much from interacting with all of these people and I am grateful for their time and support. Recently joined Scheidt group members Dr. Tom Zabawa, Dustin Raup and Antoinette Nibbs have also been most personable, and I have enjoyed interacting with them. I would like to acknowledge

Melissa Beenen for the synthesis of imines (Chapter 2) David Ballweg for solving crystal structure II-18, and Ms. Alisha Taylor for recording mass spectrometry samples. 6 I also benefited significantly from discussions with other group members, particularly Dr. Sven Schneider, (Marks laboratory) Dr. So-hye Cho (Nguyen group).

Huihe Zhu (Lewis), Brooks Jones and Mike Salata (Marks).

In addition to my colleagues friends and co-workers here at Northwestern, there are several other people I’d like to thank for helping me make the decision to pursue a Ph.D. in a foreign country. These are Professor Jonathan Clayden and Dr. Ian Watt, who were extremely supportive and kind in lending their time and advice. I also wish to thank

Grace Yang, Dr. Suzy Kim, Dr. Ijen Chen, Dr. Claire Nunns, Geraint Jones, Dr. Justin

Bower, Dr. Andy Potter, Dr. Andrew McRiner, and Alex Wormall for their roles in influencing my decision to come here.

I would like to thank Dan Custar for proofreading this document, and lastly, I would like to thank my family and friends for their support and understanding during this period of my life.

7 LIST OF ABBREVIATIONS

Ac acetyl

AcOH acetic acid

AcOEt ethyl acetate

AS azolium salt

BAIB bis-acetoxyiodosobenzene

Bn benzyl

Bz benzoyl

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DIPEA diisopropylethylamine

DMF dimethylformamide dr diasteroisomeric ratio

EDA ethyl diazoacetate ee enantiomeric excess equiv equivalents

GC gas chromatography

HMPA hexamethyl phosphoramide

HPLC high performance liquid chromatography

IPA isopropanol

IR infrared spectroscopy

LDA lithium diisoproylamide

LRMS low resolution mass spectormetry

MALDI-TOF matrix-assisted laser desorption ionization time-of-flight 8 MCAR multi-component assembly reaction

MOF metal-organic framework mp melting point

NHC N-heterocyclic carbene

NMR nuclear magnetic resonance

SAR structure-activity relationship

TEA triethylamine

TEMPO 2,2,6,6-Tetramethylpiperidine-1-oxyl radical

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl

9 Dedication

For Dad, who will be remembered long after the content of this thesis is forgotten

10 TABLE OF CONTENTS

Chapter 1. Pyrrolidinyl Spirooxindole Natural Products as Inspirations for 18 the Development of Potential Therapeutic Agents

1.1 The 3,3’-pyrrolidnyl Spiorooxindole Heterocycle in Natural Products 19

1.2 Danishefsky’s Synthetic Approach 22

1.3 MgI2-Promoted Ring Opening of Cyclopropyloxindoles 23

1.4 Asymmetric 1,3-Dipolar Cycloaddition Strategy 25

1.5 Schreiber’s Diversity-Oriented Synthesis Approach 27

1.6 Structure-Based Design of Potent MDM2 Inhibitors 34

1.7 Conclusion 41

Chapter 2. A Catalytic Multi-Component Assembly Reaction (MCAR) for 44 the Synthesis of Nitrogen-Containing Heterocycles

2.1 Introduction: Significance of the Pyrrolidine Heterocycle 45

2.1.1 Synthetic Approaches to the Heterocyclic Pyrrolidine Core 45

2.1.2 Synthesis of Pyrrolidines by 1,3-Dipolar Cycloaddition 46

2.2.1 Multi-Component React ions 46

2.2.2 MCAR for the Synthesis of 3-Pyrrolines and Pyrrolidines 47

2.3 3,3-[Pyrrolidinyl]spirooxindoles 47

2.3.1 Significance and occurrence of bioactive spirooxindoles 55

2.3.2 MCAR for the Synthesis of 3,3-[Pyrrolidinyl]spirooxindoles 55 11 2.3.3 Synergistic Activation of Forskolin in the Gene Transcription pathways 57

2.4 Pyrroles 61

2.4.1 Introduction: Significance of the Pyrrole Heterocycle 62

2.4.2 MCAR for the Synthesis of 3-Pyrroles 62

2.5 Experimental Section 63

2.5.1 General Information 68

2.6 MCAR for the Synthesis of Nitrogen-Containing Heterocycles 68

2.6.1 General Experimental Procedure A: MCAR for the Synthesis of 3- 69

Pyrrolines and Pyrrolidines

2.6.2 Characterization Data for 3-Pyrrolines and Pyrrolidines (II-12 to II-31) 69

2.7 MCAR for the Synthesis of 3,3-[Pyrrolidinyl]spirooxindoles 70

2.7.1 General Experimental Procedure A: MCAR for the Synthesis of 3,3- 78

[Pyrrolidinyl]spirooxindoles

2.7.2 Characterization Data for 3,3-Pyrrolinyl-spirooxindoles (II-33 to II-44) 78

2.8 MCAR for the Synthesis of Pyrroles 85

2.8.1 General Experimental Procedure A: MCAR for the Synthesis of 3- 85

Pyrrolines and Pyrrolidines

2.8.2 Characterization Data for Pyrroles (II-47 to II-54) 86

Chapter 3. Polarity-Reversal or Umpolung Chemistry of Acylsilanes 90

3.1 Introduction 91

3.2 Reaction of α-Lithio-Diazoacetates 94 12 3.3 Reaction of TosMIC with Acylsilanes Leading to 5-Aryl Oxazoles 98

3.4 Experimental Section 102

3.4.1 General Information 102

3.5 Synthesis of β-Ketoesters from Acylsilanes and Lithio-Diazoacetates 103

3.5.1 General Experimental Procedure A: Synthesis of β-Ketoesters 103

3.5.2 Characterization Data for β-Ketoesters 104

3.6 Synthesis of 5-Aryl Oxazoles from Acylsilanes and TosMIC 105

3.6.1 General Experimental Procedure A: Synthesis 5-Aryl Oxazoles 105

3.6.2 Characterization Data for 5-Aryl Oxazoles 105

Chapter 4. Polarity-Reversal or Umpolung Chemistry of Acylsilanes 107

4.1 Introduction to Umpolung or Polarity-Reversal 108

4.1.1 Catlaytic Umpolung Strategies 109

4.1.2 NHC-Catalyzed Nucleophilic Acylations of Aromatic Systems 110

4.2 NHC-Catalyzed Nucleophilic Acylations of 2-Chlorooxazoles 111

4.2.1 Mechanistic Investigation 112

4.2.2 Nucleophilic Acylation with Benzoyltrimethylsilane 115

4.2.3 2-Keotooxazoles as Bidentate Dyads for Metal-Organic Frameworks 116

4.4 Experimental Section 122

4.5 General Information 122

4.5.1 General Experimental Procedure A: Preparation of 2-Ketooxazoles 123

from Aldehydes and 2-Chloroxazoles 13 4.5.2 Characterization Data for 2-Ketooxazoles IV-10, IV-15, IV-18 and IV- 124

19

4.5.3 Characterization Data for Side Products IV-11 and IV-13 125

4.5.4 General Experimental Procedure B: Preparation of 2-Ketooxazoles 125

from Benzoyltrimethylsilane III-26 and 2-Chloroxazole IV-9

4.5.5 General Experimental Procedure C: Preparation of Deuterio-IV-11 126

4.5.6 General Experimental Procedure D: Sonogashira Coupling for MOF- 126

dyad Synthesis

4.5.7 Characterization Data for MOF-Dyad Synthesis 127

4.6 General Experimental Procedure E: BAIB-TEMPO, NHC-catalyzed 127

Oxidation-Esterification Reaction

LIST OF FIGURES

1-1. Representative Pyrrolidinyl-spirooxindole natural products 19

1-2. Improved performance of synthetic analogs 22

1-3. Diversity elements used in the elaboration of the 3-CR template 32

1-4. Scheiber’s lead compound 33

1-5. Rational structure-based approach by Wang and co-workers 35

1-6. Development of a potent MDM2-binding compound 36

1-7. Lead compound I-43 and Optimized inhibitor I-44 38

1-8. Non-peptide based p53-MDM2 inhibitors 41

2-1. Illustrative examples of the pervasive pyrrolidine heterocycle 45 14 2-2. General methods for the generation of azomethine ylides 47

2-3. ORTEP representation of the crystal structure of II-18. 53

2.4. Proposed model for the three-component assembly of 2,5-trans 55

pyrrolidines

2-5. ORTEP representation of the crystal structure of II-38. 58

2-6. Synergistic activation of forskolin in the CREB gene transcription 62

pathway

3-1. Representative acylsilanes 91

4-1. Proposed mechanistic cycle for nucleophilic acylation of 2- 112

chlorooxazoles 112

4-2. Isolated side products from the reaction 113

4-3. Proposed mechanistic rationale for side product formation 114

4-4. Comparison of reactive species in aldehyde and acylsilane 116

4-5. MOF-dyad building blocks 116

LIST OF SCHEMES

1-1. Danishefsky’s synthetic approach to the core (I-5) 22

1-2. Danishefsky’s synthetic approach to spirotryprostatin B (I-6) 22

1-3. Carreira’s proposed pathway for the MgI2-catalyzed ring-expansion 24

reaction

1-4. Synthetic utility of the ring-expansion reaction 25

1-5. Williams’s asymmetric 3-CR for the synthesis of spirotryprostatin B 26 15 1-6. Schreiber’s preliminary rendering of the macrobead 3-CR 29

1-7. Schreiber’s library scaffold-diversification strategy 31

1-8. Modified Williams 3-CR for the synthesis of p53-MDM2 inhibitors 37

2-1. Examples of multi-component assembly reactions 48

2-2. MCAR for the synthesis of 3-pyrrolines 49

2-3. MCAR for the synthesis of pyrrolidinyl-spirooxindoles 57

2-4. Mechanistic and stereochemical considerations of the MCAR 59

2-5. MCAR for the synthesis of pyrroles 63

2-6. Proposed reaction mechanism 65

3-1. First observation of 1,2-silyl shift with silyllithium nucleophiles 92

3-2. Illustrative examples of acylsilane chemistry in synthesis 93

3-3. Johnson’s metallophosphite-catalyzed crossed-benzoin reaction 94

3-4. Reaction of lithio-diazoester with benzoyltrimethylsilane 95

3-5. Alternative routes to β-ketoesters using diazo compounds 96

3-6. Proposed mechanism 97

3-7. van Leusen oxazole synthesis from the reaction of TosMIC with 98

aldehydes

3-8. Mechanism of van Leusen 5-substituted oxazole synthesis 99

3-9. Reaction of TosMIC 100

4-1. Dithiane Umpolung reactivity of carbonyl compounds 109

4-2. The cyanide-catalyzed benzoin reaction 109

4-3. Miyashita’s catalytic nucleophilic acylation reaction 111 16 4-4. Nucleophilic acylation of 2-chlorooxazoles 112

4-5. Use of acylsilane as an “aldehyde equivalent” 116

4-6. Synthesis of MOF-dyads 117

LIST OF TABLES

2-1. Optimization of the MCAR conditions 50

2-2. Effect of catalyst loading on product yield 50

2-3. Effect of N-substitution of imine on catalytic 3-pyrrolidine synthesis 51

2-4. Catalytic MCAR of EDA, DMAD and various electrophiles 52

2-5. Scope of the spirooxindole reaction 54

2-6. Scope of the MCAR for the synthesis of pyrroles 68

3-1. Multicomponent synthesis of β-ketoesters 97

3-2. 5-Aryl oxazoles prepared form corresponding acylsilanes 100

17

Chapter 1

A Review: Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents

A mini-review accepted for publication in Angewandte Chemie,

International Edition, 2007.

18 1.1 The 3,3’-Pyrrolidinyl−Spirooxindole Heterocycle in Natural Products

Based on a structural core derived from tryptamine, the spirooxindole alkaloids belong to a family of natural products that were first isolated from fauna of the

Apocynaceae and Rubiacae families.1 The key structural characteristic of these compounds is the spiro ring fusion at the 3-position of the oxindole core, with varying degrees of substitution around the pyrrolidine and oxindole rings. In addition to the interesting molecular architecture and dense functional core, several natural products possessing this heterocyclic motif exhibit significant bioactivity (Figure 1-1). Alstonisine

(I-1) was first isolated from Alstonia muelleriana,2-4 and its biomimetic transformations have been studied by LeQuesne.5 Isolated in 1991,6 the relatively unsubstituted spirooxindole core of (–)-horsfiline (I-2a) has proven to be a popular target among chemists, with numerous syntheses reported.

OMe H Me O OMe H N OH OH Me R MeO O N NH O N H N O N O H Me Me R = MeO, horsfiline (I-2a) alstonisine (I-1) chitosenine (I-3) R = H, coerulescine (I-2b)

H N N H N O O O Me O Me H N N HO H H O Me Me N NH H MeN O O N N H H MeO strychnofoline (I-4) spirotryprostatin A (I-5) spirotryprostatin B (I-6)

Figure 1-1. Representative pyrrolidinyl-spirooxindole natural products 19 The related compound coerulescine (I-2b) possesses an even simpler structure, and was isolated in 1998, and its synthesis is often reported together with horsfiline.7

Chitosenine is another structurally interesting natural product, which exhibits short-lived inhibitory activity of ganglionic transmission in vivo in rats and rabbits.8-10

Strychnofoline (I-4), inhibits mitosis in a number of cell lines including mouse melanoma

B16, Ehrlich and Hepatom HW165.11 The spirotryprostatins A and B12-16 (I-5) and (I-6), were isolated from the fermentation broth of Aspergillus fumigatus and have been shown to completely inhibit the G2/M progression of mammalian tsFT210 cells at concentrations in excess of 12.5 mg/mL.17,18

In 2003, Carreira and Marti published a review on the synthesis of natural products containing this fused heterocyclic system.19 The authors discussed approaches based on intramolecular Mannich reactions,20-37, 38 various methods involving the classical oxidative rearrangement of tetrahydro-β-carbolines,39-44,45-57 radical cyclizations,58-62 intramolecular Heck reactions,63-72 a nitroolefination strategy,73-77 a novel rearrangement of 3-[(aziridinyl)(methylthio)methylene]-2-oxindoles,78 dipolar cycloadditions,79-94 as

95-99 well as their own MgI2-catalyzed ring expansion methodology. Since this review, several alternative methods have been reported.100-102

These synthetic advances have been fuelled by the continued isolation of attractive bioactive molecules possessing this core structure. In particular, the efforts of Carreira,

Danishefsky and Williams towards the synthesis of pyrrolidinyl-spirooxindole natural products such as the spirotryprostatins have generated new strategies to construct these compact alkaloids. In turn, the resulting synthetic methodologies employed and 20 developed by these laboratories have facilitated the synthesis of sufficient quantities of material for biological evaluation, as well as the preparation of analogs for SAR studies.

These synthetic studies represent the first significant efforts to carry out natural product analog synthesis and testing for this attractive heterocyclic system. The promising biological data from these analogs prompts the question: “Can a therapeutic agent or important biological tool be derived from spirooxindole natural products?”

1.2 Danishefsky’s Synthetic Approach

In 1998, Danishefsky and Edmonton reported the first total synthesis of spirotryprostatin A using a NBS-promoted oxidative rearrangement of the corresponding

β-carboline (Scheme 1-1).57 In 1999, an improved synthesis was reported, utilizing the same NBS-promoted oxidative rearrangement chemistry in the key step. With the synthesis completed, the natural product and several analogs were evaluated using MCF-

7 and MB-468 human breast cancer cells. Compounds I-12, I-13 and I-14 were clearly superior to the natural product spirotryprostatin A against both cell lines (Figure 1-2).56

Notably, the highly active spirooxindole I-14 is prepared in only three steps from commercially available starting materials.

21 Scheme 1-1. Danishefsky’s synthetic approach to the core of (I-5)

1. TFA, CO2Me CO2Me 4Å MS, CH2Cl2, NBoc 88% MeO NH2 N Me MeO H N 2. (Boc)2O, SPh H I-10 I-7 CH3CN, Et3N, Me !, 84% Me 1. NBS, THF/H2O, PhS AcOH, 46% CHO Me 2. TFA, CH2Cl2, I-8 93% H N Me O H Me O Me MeO C N 2 N H Me O O NH N H MeO MeO I-11 spirotryprostatin A (I-5)

Interestingly, the configuration of the spirooxindole’s stereogenic center (C3) appears unimportant, given the high activities of epimers I-10 and I-11. Compound I-12, missing both the prenyl group and diketopiperazine portions of the natural product also retains a high level of activity.

H H N O N O H OBn OBn OBn MeO C O N O N 2 N H H C3 O C3 O O

NH NH NH I-12 I-13 I-14

Anchorage dependent human breast cancer cell line* I-12 I-13 I-14

IC50 MDA MB-468 25 nM 20 nM 20 nM IC50 MCF7 10 µM 80 µM 40 µM

*Spirotryprostatin A (I-5) returned results of 110 µM and >>300 µM for the MDA MB-468 and MCF7 assays respectively.

Figure 1-2. Improved performance of synthetic analogs 22 The total synthesis of the more active spirotryprostatin B from the Danishefsky group followed in 2000 (Scheme 1-2).38 In this approach, the synthesis featured an intramolecular Mannich reaction between L−tryptophan-derived methyl ester and aldehyde I-15, rather than the oxidative rearrangement strategy they had previously published. This reaction generated a mixture of diastereoisomers, which were separated later in the synthesis. Using this route, spirotryprostatin B could be accessed in batch quantities of 500 mg via a five-step sequence. Although these approaches were not enantioselective, each route allowed for sufficient quantities to be prepared to allow for both analogue synthesis and biological studies.

Scheme 1-2. Danishefsky’s synthetic approach to spirotryprostatin B (I-6)

Me Me CO Me 2 Me H Me CHO MeO2C N NH2•HCl

O NEt3, 3Å MS O N H pyr, 0 to 23 °C NH indolone I-15 I-16 73% yield of a diastereomeric mixture of products

1.3 MgI2-Promoted Ring Expansion of Cyclopropyloxindolones

Carreira and coworkers have developed a reliable methodology to access the pyrrolidinyl-spirooxindole structure starting from imines and spirocyclopropyl oxindoles.

The dual role of the MgI2 is proposed to provide Lewis acid activation as well as a nucleophilic counter ion to promote the ring expansion. The authors suggested mechanistic pathway is shown in Scheme 1-3. They propose that intermediate I-19 is the 23 initial product of ring opening, followed by either: (a) enolate attack of the oxindole to the imine and subsequent nucleophilic displacement of the iodide to form the pyrrolidine ring (I-20 then I-21), or (b) these last two steps occur in the reverse order. There is some likelihood that the electronic nature of the starting imine may be responsible for the precise order of these last two steps of the mechanism. The alternative possibility, involving the direct ring opening of the cyclopropane by the imine leading directly to I-

22, was judged less plausible by the authors.

Scheme 1-3. Carreira’s proposed pathway for the MgI2-catalyzed ring-expansion

I R1 N MgI2 O H R2 N N OMgI R I-17 I-18 R I-19 Imine Imine displacement addition

1 R I N R1 R2 N H R2

N OMgI R1 N O R N R I-22 I-20 2 R SN2 N O R I-21

The reaction can accommodate several imine precursors that can be employed to produce the pyrrolidinyl-oxindole structure in good to excellent yield with useful levels of diastereoselectivity (Scheme 1-4, eq 1 & 2). A range of alkyl and aryl imines, N-tosyl imines I-26, and even N-tosylisocyanate are compatible substrates,95 The cyclopropyl unit can also be mono-substituted allowing for significant elaboration in the resulting products. 24 Scheme 1-4. Synthetic utility of the catalytic ring expansion reaction

1 R R1 N 10 mol % I-23 N MgI 2 2 H R 2 O R (1) N THF, 80 °C N O Bn I-24 sealed tube Bn I-25 55-98% R1 and R2 = alkyl, aryl dr = 80:20-91:9

Ts Ts N 10 mol % N 26 MgI2 2 H R 2 O R (2) N THF, 60 °C N O Bn I-24 Bn I-27 55-97% dr = 52:48-98:2 R2 = aryl, alkyl Me N MeO MeO 6 mol % MgI O 2 (3) N N O Bn I-28 THF, 125 °C Bn sealed tube Me Me N N 83% N-benzylhorsfiline

N I-29 Me

In addition, the reaction has been used to synthesize a range of natural products by employing modified imine equivalents or more complex imines and appropriately substituted spiro-cyclopropylindolones in the reaction. The first and simplest of these total syntheses is illustrated in Scheme 1-4, (eq 3). The synthesis of racemic horsfiline was executed using trimethyltriazinane (I-29) in just 5 steps and 41% overall yield using commercially available reagents.99 Other targets completed using this methodology include spirotryprostatins B,96 and strychnofoline,97,98

25 1.4 Asymmetric 1,3-Dipolar Cycloaddition Strategy

In their synthesis of spirotryprostatin B, Williams and Sebehar accessed both antipodes of the target molecule and prepared analogs of the natural products.103-105 In their elegant approach, a three-component reaction (3-CR) of morpholinone I-31, aldehyde I-32, and oxindolylideneacetate I-33, is used to construct the spirooxindole core

(Scheme 1-5). The combination of I-31 and I-32 generates a chiral azomethine ylide, with an E-geometry which efficiently undergoes a [3+2] cycloaddition with dipolarophile

I-33 affording cycloadduct I-34.106 The product is formed as a single diastereoisomer in

82% yield with the desired stereochemistry of the natural product.

Scheme 1-5. Williams’s asymmetric 3-CR for the synthesis of spirotryprostatin B

MeO Ph CHO Ph Ph I-32 Me Me Me O Ph O 3Å MS, toluene MeO N O HN Me O O EtO2C CO2Et I-31 HN O I-34 N H I-33

82% H2 PdCl2, THF, EtOH, 60 psi, 36 h, 99%

Me H H H MeO N Ph CO2H O Ph Me O H N O CO2Et Me O CO2Et HN MeO Me N I-35 H

7 steps

E-beta-exo transition state spirotryprostatin B 26 The stereochemical outcome of this reaction was confirmed by single crystal X-ray analysis, with the authors describing the required geometry of cycloaddition as “E-beta- exo” (E referring to the ylide geometry, beta to the top face of the approach of the dipolarophile, exo to the transition state). The removal of the dibenzyl portion of the oxazinone occurred readily to yield amino acid I-35.

The synthesis was completed in a further seven steps: the diketopiperazine unit installed by a coupling reaction with D−proline benzyl ester, the isoprenyl olefin was installed by treatment with TsOH in refluxing toluene (without the formation of other olefin isomers). Finally, the ester group was removed using a three-step sequence involving hydrolysis, followed by a modified Hunsdieker reaction to afford (–)- spirotryprostatin B (I-6). In 2003 Williams reported the synthesis of spirotryprostatin A

(I-5) by a similar route.107,108

1.5 Schreiber’s Diversity-Oriented Synthesis Approach

Schreiber has pioneered “diversity-oriented synthesis“ (DOS) as a method of generating small molecules with useful biological properties.109-113 The rigid three- dimensional structure of the pyrrolidinyl-spirooxindole core allows for the exploration of neighbouring space along a variety of trajectories. Additionally, this architecture is featured in numerous bioactive alkaloids and patented medicinal compounds making it an ideal scaffold for DOS. Schreiber has reported a combinatorial-based approach to the development of active natural product-like compounds for biological evaluation.114 The stereoselective three-component reaction of Williams and coworkers was utilized as the 27 key synthetic operation for generating the pyrrolidinyl-spirooxindole core (Schemes 1-

5 and 1-6). The Williams 3-CR was particularly attractive for library synthesis, providing a highly convergent approach, allowing for simple diversification of stereochemistry and structure.

The spirooxindole skeleton was assembled in the first step, through a highly diastereoselective cycloaddition using macrobead-supported aldehydes, with either enantiomer of the Williams’s chiral auxiliary I-31, and an isatin-derived dipolarophiles bearing the allyl ester I-37. The spirooxindoles were then elaborated using building blocks, which possess diverse structural features and compatible functionalities. Initially,

Schreiber and coworkers were unable to effect the 3-CR on solid support using the original solution phase conditions (3 Å sieves, toluene). However after investigating a range of Lewis acids to promote the reaction, Mg(ClO4)2 was successful in furnishing the

3-CR products in high purity and excellent diastereoselectivity. The reaction medium was buffered using pyridine to minimize acidic cleavage of the loaded aldehyde from the silicon linker, and molecular sieves were replaced with methyl orthoformate as the dehydrating agent.

28 Scheme 1-6. Schreiber’s preliminary rendering of the macrobead 3-CR

Ph * i-Pr i-Pr Ph Si O O CHO HN Mg(ClO4)2 I-36 O pyridine I-31 HC(OMe)3 PhMe CO2allyl Ph X i-Pr i-Pr Ph O * Si O N O H N I-37a (X= H) O O I-37b (X= I) CO allyl HN 2 I-38 X

entry aldehyde dipolarophile conv. (%) d.r.

O 1 O I-37a 89 88:12 2 I-36a I-37b 89 >95:5 CHO

O CHO 3 O I-37a >95 >95:5 4 I-36b I-37b >95 >95:5

5 I-36c I-37a >95 >95:5 6 CHO I-37b >95 >95:5 O O

O 7 I-37a >95 91:9 8 I-37b 94 92:8 I-36d CHO O I-36e 9 I-37a >95 77:23 10 MeO CHO I-37b >95 72:28

O CHO 11 O I-37a >95 82:18 12 I-36f I-37b >95 85:15

With the new reaction conditions established, the authors chose aromatic aldehydes of various substitution patterns, which afforded good yields and high levels of diastereoselectivity in the range of 72:28 to >95:5 depending on the starting aldehyde structure. The desired library was generated by a split-pool synthesis involving solid- phase synthesis.115-118 The elaboration reactions were carefully chosen according to their 29 solid-phase efficiency and ability to modify the initial chemical properties of the starting material, such as the number of rotatable bonds or cLogP value. To elaborate the macrobead–supported heterocyclic core, the feasibility of the following three synthetic operations was evaluated:

a) palladium-catalyzed carbon-carbon bond formation with concomitant allyl ester

cleavage;

b) amide formation between the resultant carboxylic acid with amines; and

c) N-acylation of δ-lactams with electrophiles.

The authors found Sonogashira coupling with aryl iodospirooxindoles to be the most reliable, and the alkynes shown in Figure 1-3 were found to be proficient coupling partners and were employed in the elaboration studies. High catalyst loadings of palladium and copper were used to ensure reliable coupling on the solid support. The authors took great care to remove excess metal reagents by using glyoxal bis(thiosemicarbazone) as a metal scavenger.

On solid support, the amide coupling conditions using PyBOP/(i-Pr)2NEt were consistently effective (Scheme 1-7). Finally, three electrophiles from a panel of isocyanates and chloroformates were identified for the N-acylation, with optimal conditions showing a strong dependency on the electrophile used.

With the three candidate diversification reactions chosen and validated, the library synthesis was executed. Starting from solid-supported aldehydes, a Lewis acid-mediated

3-CR was performed with four aldehydes, two morpholinones, and two dipolarophiles to 30 yield 16 spirooxindole cores. Each diversification operation was accompanied by a tagging step for later decoding of the beads.119 The sequence of reaction for the eight cores containing the aryl iodide was as follows (Scheme 1-7, Figure 1-3):

Scheme 1-7. Schreiber’s library scaffold-diversification strategy

tag-1 1. morpholine, 1. alkyne dipolarophile Pd(II) * i-Pr i-Pr Si Mg(ClO4)2 Cu(II) O CHO I-38 I-39 HC(OMe) , py 2. tag-3 I-36 3 2. tag-2 1. amine PyBOP tag-1 Ph i-Pr NEt tag-2 2 Ph * i-Pr i-Pr 2. tag-4 Si O tag-3 O N N-acylating tag-4 O O H agent O CONR2R3 I-40 I-41 N R4 R1

Over 3000 compounds were generated from the above sequence of reactions. The sequence of reaction for the eight cores lacking the aryl iodide were as follows: (a) ester cleavage (omit + deprotection); (b) amidation (omit + 11 amines); and (c) N-acylation

(omit + 3 N-acylating reagents). An additional 416 members were generated using this sequence, leading to a total of 3520 theoretical compounds. The selection of different building blocks was based on factors aimed at maximizing diversity (e.g. functional groups, heterocycles, degree of substitution) and on calculations to diversify the cLogP values of the library members. To verify the success of the approach, thirteen library compounds-with each building block represented at least once- were randomly selected for synthesis on the macrobead support and full characterization data was obtained. With robust and proven conditions in hand, split-pool synthesis was used to construct the 31 library. The four aromatic aldehydes I-36a-d, (Figure 1-3), were loaded onto the solid support.120

aldehyde morpholine Ph Ph OH OH Ph Ph O O HN HN I-36b O O O O CHO I-31a I-31b I-36a CHO dipolarophile O O CHO O O CHO I HO O O O I-36d I-36c N N H H OH I-37a I-37b

alkyne O OMe HO MeO2C

H2N N "omit" H CO2Me

HO Bn N N Me N N amine H N O N "omit" NH NH N NH2 2 O

Ph O HO N NH2 NH NH 3

H2N

MeO S N N NH2 N NH NH N N NH2 MeO

N-acylating agent

"omit" O MeO2C NCO Ph NCO MeO O Cl Me Me Me

Figure 1-3. Diversity elements used in the elaboration of the 3-CR template

Encoding difficulties associated with two of the building blocks were encountered during the library’s development. The beads from these two reactions were separated and the remaining synthetic operations performed in parallel. As a result of this change, the number of library members was reduced to 3232. 32 The authors then employed a chemical genetic modifier screen to search for bioactive compounds. An assay was developed to identify enhancers of the growth arrest induced by latrunculin B, a natural product that sequesters monomeric actin and prevents the formation of actin microfilaments.121,122 The initial screen was performed in 384-well plates using wild-type yeast growing in a nutrient-rich medium. Latrunculin B was added to a final concentration of 7 µM, followed by pin transfer of library stock solutions to a final concentration of approximately 33 µM. 36 compounds were then scored as enhancers, based on a comparison of the observed growth in the assay wells compared to control wells lacking library members. Two building blocks, aldehyde I-36d, and the

(5R, 6S)-morpholinone I-31, were strongly represented among the 33 positive results.

Compound I-42 was chosen for resynthesis and tested further (Figure 1-4). For these assays, the amount of latrunculin B was reduced to 1.0 µM, which is 12.5% of the experimentally determined EC50 value.

Ph O Ph HO O N O H O O N HN O I-42

Figure 1-4. Schreiber’s lead compound

At this concentration, latrunculin B has no observable effect on yeast growth. When

I-42 was added to this same medium, the inhibitory effect of latrunculin B was enhanced.

The EC50 value for I-42 was determined to be 550 nM. As a control experiment, yeast 33 cells were treated with I-42 alone, up to the solubility limit of 30 µM, and yeast growth was unaffected. This experiment shows that I-42 does not show the same phenotype as latrunculin B and that it is only lethal in tandem with latrunculin B.

From the biological screening, spirooxindole I-42 is interesting in terms of its synergistic activation of latrunculin B’s actin polymerase inhibition. However, Schreiber notes that the future for this compound as a potential molecular therapeutic is not promising. The four-step library synthesis is significant since the exercise clearly established that natural product-inspired compounds made in parallel could drive a medicinal or chemical biology program when efficient synthetic methods are in place.

1.6 Structure-Based Design of Potent MDM2 Inhibitors

Wang and coworkers have employed a structure-based design approach toward the development of a non-peptide based small molecule inhibitor of the p53-MDM2 interaction.123,124 As a starting point, the authors used the known structural basis of the p53-MDM2 interaction, which has been established by X-ray crystallographic studies.

Furthermore, the crystal structure reveals that the interaction between p53 and MDM2 is primarily mediated by three hydrophobic residues (Phe19, Trp23, and Leu26) of p53 and a small and deep hydrophobic cleft in MDM2.125-127 The authors envisaged this hydrophobic cleft is an ideal site for designing small-molecule MDM2 inhibitors that can block the p53-MDM2 interaction. In p53, the indole ring of the Trp23 residue of p53 is buried deeply inside a hydrophobic cavity in MDM2 with a hydrogen bond formed between the amino group and a backbone carbonyl in MDM2, thus Trp23 appears to be 34 the most critical residue for binding of p53 to MDM2. The authors targeted this key interaction for their structure-based design of a small molecule that can mimic the interaction of Trp23 with MDM2.

Initially, a substructure search led to the key observation that the oxindole core structure is a potential replacement for the tryptophan residue. The authors then went on to identify the bioactive natural products spirotryprostatin A (I-5) and alstonisine (I-1), which both contain a spirooxindole core structure (Figure 1-5). With these structures as a starting point, the authors undertook computational modelling studies and determined that these compounds fit poorly into the MDM2 pocket due to steric hindrance. Despite this initial setback, the heterocyclic core structure was used as the scaffold from which to develop other potential MDM2 binders.

H O N Substructure search HN

HN R O Oxindole core Trp in p53 structure

O H O H O HN H N N Me O MeO H NH O Me N O Me Me spirotryprostatin A (I-5) alstonisine (I-1)

Figure 1-5. Rational structure-based approach by Wang and co-workers 35 The next key insight was that the oxindole can closely mimic the Trp23 side chain in p53 in both hydrogen-bonding formation and hydrophobic interactions with MDM2.

Additionally, the spiropyrrolidine ring could provide a rigid scaffold from which two hydrophobic groups can be projected to mimic the side chain of Phe19 and Leu26.

Candidate compounds using different substituents with different structural configurations were computationally docked into the MDM2 binding cleft. The oxindole ring of I-43 bears a chloro substituent designed to occupy a second, smaller hydrophobic cavity in

MDM2. The docking studies clearly showed that spirooxindole I-44 could closely mimic p53 in its interaction with MDM2 (Figure 1-6).

R2

alstonisine (I-1) R3 NH Structure-based or R1 design O of initial lead spirotryprostatin A (I-5) N H

Me Me Cl N N Me O Me Structure-based O optimization NH NH Me Me Me O Me O Me N Cl N Cl H H I-44 I-43

Figure 1-6. Development and optimization of a potent MDM2-binding compound

An enantioselective approach based on the methodology of Sebehar and Williams afforded optically active compound I-43 for biological studies. Using a fluorescence polarization-based binding assay, the in vitro efficacy of I-43 as an MDM2-p53 inhibitor was established using a fluorescence polarization-based (FP) binding assay. The assay 36 uses a p53-based peptide labeled with a fluorescent tag and a recombinant human

MDM2 protein. The peptide has a high-affinity for MDM2, (Kd value of 1 nM).

Compound I-43 has a Ki value of 8.46 µM in the (FP)-based assay, comparing well to a natural p53 peptide (16-27 residues), which was determined to have a Ki value of 1.52

µM in the binding assay. Thus spirooxindole I-43 showed considerable promise as a lead compound.

Additional detailed analysis of the predicted binding model of I-43 to MDM2 suggested the possibility of further refinement of the lead structure. Specifically, the authors observed that the phenyl ring occupies a hydrophobic binding pocket normally for the side chain of Phe19 and the isobutyl group almost fills the hydrophobic binding pocket for Leu26. However, for both of these hydrophobic interactions, additional space was available in the respective cavities. Thus, more analogs of lead compound I-43 were specifically designed to further delineate the interactions at these two hydrophobic binding sites (Scheme 1-8).

37 Scheme 1-8. Modified Williams 3-CR for synthesis of p53-MDM2 inhibitors

R O O Ph R NMe OH O 2 N Ph Ph H N Ph I-31 a,b R1 OH O Cl N O H N H R1 Cl H I-45 I-46 I-47 c I-43 R = H, R1 = i-Pr 1 R NMe I-48 R = m-Cl, R = i-Pr O 2 I-49 R = p-Cl, R1 = i-Pr 1 I-44 R = m-Cl, R = t-Bu I-43, I-44 & NH I-50 R = m-Cl, R1 = Et I-48 to I-51 R1 R = m-Cl, R1 = i-Bu I-51 O N Cl H

Reagents and conditions: (a) 4 Å sieves, toluene 70 °C; ° (b) dimethylamine; (c) Pd(OAc)2 CH2Cl2-MeOH (1:1), 0 C.

Guiding the synthesis were the results of the modeling studies that predicted two minor modifications of the core structure I-43 would lead to occupation of the additional space in the binding site. A chlorine atom at the meta-position of the phenyl ring of I-43 was introduced to improve the established hydrophobic interaction. Additionally, compound I-47 (with a m-Cl substituent) was synthesized and found to have a Ki value of

300 nM- 28 times more potent than the previous lead compound I-43. To further confirm the modeling study’s predictions, I-49 with a p-Cl substituent was synthesized and found to be 26 times less potent than I-48 with a Ki value of 7.68 µM. 38 Me Me H Cl N N O Me enhance O Me H hydrophobic H NH interactions Me NH Me Me Me O O Me N Cl N H Cl H lead compound I-43 optimized inhibitor I-44

Figure 1-7. Lead compound I-43 and optimized MDM2 inhibitor I-44

Addressing the isobutyl group in I-43 next, further optimization of the hydrophobic interaction at this site using I-48 as the template was undertaken. Again using modeling studies as the basis for predictions, the isobutyl group was replaced with a tert-butyl group in an effort to enhance the hydrophobic interaction. The resulting compound I-44 had a Ki value of 86 nM in the FP-based assay, 98 times more potent than the initial lead compound I-43. The relevance of the hydrophobic interaction at this site was further affirmed when the authors synthesized I-50 and I-51 with, respectively, a hydrophobic group smaller or larger than that in I-44. The prediction that both I-50 and I-51 should be less potent than I-44, was proven to be correct by FP-based binding experiments, which showed that I-50 and I-51 with Ki values of 0.65 and 0.39 µM, respectively, were significantly less potent than I-44.

A disadvantage of peptide-based MDM2 inhibitors over non-peptide inhibitors is their inferior cell permeability, thus non-peptide-based alternatives are popular and attractive targets.128,129 Wang’s MDM2 inhibitors were evaluated in p53-wildtype LNCaP human prostate cancer cells for their ability to inhibit cell growth.127 Spirooxindole I-44 is a highly effective inhibitor of cell growth in this tumor cell line with an IC50 value of 39 830 nM. In contrast, structurally related compounds I-43, I-48, I-49, I-50 and I-51 inhibit cell growth of LNCaP cells with IC50 values of 9.7, 2.1, 6.7, 2.7, and 1.9 µM, respectively.

In a second series of experiments, the selectivity of these compounds was then evaluated in human prostate cancer cells lacking p53 (PC-3). In these cells, spirooxindole I-44 is less potent with an IC50 value of 22.5 µM. This observed selectivity is consistent with the inhibitor design targeting p53 since the PC-3 inhibition for heterocycle I-44 is 27 times less than against LNCaP cells which express wild-type p53.

Another key result is the relative toxicity of these MDM2 inhibitors towards normal cells with wild-type p53. The authors evaluated compound I-44 in normal human prostate epithelial cells with wild-type-p53 and determined that it has an IC50 value of 10.5 µM for inhibition of cell growth, 13 times less toxic than to LNCaP cancer cells.

In a subsequent publication, the authors further optimized the binding affinity of spirooxindole I-44 to MDM2 from Ki = 86 nM to 3 nM by further investigation of the binding mode of their compounds when “docked” to MDM2 using computational methods (Figure 1-8).130 The authors also conducted a head-to-head comparison of the binding efficacy of the most potent non-peptide based inhibitor of the p53-MDM2 interaction, (termed nutlin-3) with their own first and second-generation compounds

(Figure 1-8).128,131 From this analysis, it is clear that the second-generation optimized structure (I-52) is significantly more potent than nutlin-3. Spirooxindole I-52 was found to have a Ki for binding to MDM2 of 3 nM (compared to 36 nM for that of nutlin-3). 40 The two optimized compounds were also evaluated for their potency of cell growth inhibition. Prostate cancer LNCaP cells with wild type-p53 were again used for comparison, and spirooxindole I-52 once again outperformed nutlin-3 with IC50 values of

280 nM and 1500 nM respectively. Significantly, compound I-52 retains selectivity in terms of cellular specificity; with an IC50 value of 18 µM in human prostate cancer PC-3 cells with deleted p53. This result also suggests that spirooxindoles I-44 and I-52 have the same mode of action.

Wang and coworkers Me N Cl N NH O O Me Cl FO H H NH NH Me Me Me Me O Me O Me N Cl N Cl H H

first-generation second generation optimized inhibitor I-44 optimized inhibitor I-52

MDM2 binding: Ki = 86 nM MDM2 binding: Ki = 3 nM

Hoffman-La Roche group

Me Cl Me O N Me O nutlin-3 N MDM2 binding: Ki = 86 nM N O NH Cl O

Figure 1-8. Non-peptide based p53-MDM2 inhibitors

1.7 Conclusion

Bioactive pyrrolidinyl-spirooxindole natural products such as spirotryprostatin B (I-6) and strychnofoline (I-4) have provided the impetus for significant progress toward the 41 synthesis of this class of heterocycle. These new methods have led to the development of analogs that are often more efficacious and selective than the natural products themselves. In two distinct approaches the research groups of Schreiber and Wang have attempted to capitalize on the fusion of facile and expedient analog synthesis with the promising biological potential of this privileged heterocyclic structure. Schreiber’s collection of over 3000 natural product-inspired compounds represents a significant synthetic achievement leading to the identification of a compound that enhances the inhibitory efficacy of latrunculin B towards actin polymerase.132-135 Additionally, this work resulted in several significant synthetic advances, namely the development of a sufficiently robust synthesis of a large family of analogs using a solid-phase variant of the

Williams 3-CR. Attaining sufficiently high levels of diastereoselectivity to retain the structural integrity of the library members is particularly noteworthy, although the potential of I-42 as a therapeutic agent is somewhat limited. An analogous library of related bioactive compounds; furanyl spirooxindoles featuring silyl group substituents has recently been reported by Schreiber and coworkers.136

Wang’s rational design paid high dividends due to the insightful computational studies combined with the authors’ intuition for analog synthesis and testing. They have successfully completed the first and second generation of a structure-based design of a novel class of potent, non-peptide small-molecule MDM2 inhibitors to target the p53-

MDM2 interaction. Although this pathway has proven to be a popular research area with several classes of compounds reported, the spirooxindole-derived compounds are as promising as any of the other non-peptide derived compounds.131,137-142 Additionally, the 42 known mode of action and selectivity profile alludes to significant potential for further development as an anti-cancer agent.

Both Schreiber’s and Wang’s synthetic programs relied on a modified, stereoselective

Williams 3−CR as the key synthetic tool for the production of candidate lead compounds.

The many noteworthy advances in synthetic methods for the construction of the privileged pyrrolidinyl-spirooxindole core have driven the rapid access to highly promising lead compounds worthy of further study and development. Continued research towards the synthesis of additional privileged natural products will undoubtedly make these approaches more common. By drawing inspiration from bioactive natural products in the manner summarized herein, it may indeed be possible to obviate the traditional hit- to-lead stage of medicinal and chemical biology programs.143

43

Chapter 2

Catalytic, Multi-Component Assembly Reactions for the Synthesis of Nitrogen-Containing Heterocycles

Portions of this chapter feature in the following publications:

Galliford, C. V.; Scheidt, K. A. “A Catalytic, Multi-Component Assembly Reaction for the Synthesis of Pyrroles” J. Org. Chem. 2007, 72, 1811-1813.

Galliford, C. V.; Martenson J. A.; Stern, C.; Scheidt, K. A. “A Highly Diastereoselective, Catalytic, Multi-Component Assembly Reaction for the Synthesis of Spiro-[pyrrolidinyl]oxindoles” Chem. Commun. 2007, 631-633.

Galliford, C. V.; Beenen, M. A.; Nguyen, S. T.; Scheidt, K. A. “Catalytic, Three-Component Assembly Reaction for the Synthesis of Pyrrolidines” Org. Lett. 2003, 5, 19, 3487-3490.

44 Chapter 2. A Catalytic Multi-Component Reaction for the Synthesis of

Nitrogen-Containing Heterocycles

2.1 Introduction: Significance of the Pyrrolidine Heterocycle

Pyrrolidines are found in numerous natural products and medicinal structures (Figure

2-1).144-148 From simple, well known and neuroactive compounds such as cocaine (II-2) and kainic acid (II-3),149,150 to the more structurally complex natural products such the coccinine (II-4),151 lepadiformine (II-5),152 cyllindricine C (II-6)153 and the family of martinelline-natural products derived from martinellic acid (II-7), the pyrrolidine heterocycle (II-1) is a recurring motif that features in numerous naturally occurring bioactive structures (Figure 2-1).154 The FDA-approved compound Xinlay (atrasentan)

(II-8) is a selective endothelin A receptor agonist and is currently under development for a variety of advanced prostrate cancer treatments.155

O CO2CH3 HO2C CH3 HO CO2H H C N O 3 OBz N HO2C N OCH O H 3 n-C6H13 N kainic acid cyllindricine C cocaine (II-3) (II-2) O (II-6) N(n-Bu)2

TM Xinlay (atrasentan) (II-8) N H CH3 pyrrolidine H3C NH (II-1) N N O H N HO O HO2C n-C5H11 H H H3CO N N CH3 lepadiformine (II-5) N H NH CH HO N 3 H martinellic acid (II-7) coccinine (II-4)

Figure 2-1 Illustrative examples of bioactive pyrrolidines 45 2.1.1. Synthetic Approaches to the Heterocyclic Core of Pyrrolidines

The efficient construction of this class of heterocycle has received significant attention in the chemical literature.156-161 Numerous synthetic methods exist for the synthesis of pyrrolidines and their derivatives. Full or partial reduction of the parent pyrrole heterocycle was first achieved by Wibaut and de Jong in 1930 using platinum oxide as a hydrogenation catalyst.162 Since this discovery, reductive strategies have been used to good effect by several researchers.163,164 Notably, Schafer and Donohoe have utilized Birch-type conditions to access 3-pyrroline structures in a diastereoselective manner.165,166 In this attractive approach, substitution around the pyrrole ring can direct/control the stereochemical outcome and subsequent reactions. In addition to modifications of an existing pyrrole skeleton, cyclizations of appropriately functionalized precursors remain a common method for pyrrolidine synthesis. These methods can be ionic, radical, stoichiometric, catalytic and/or asymmetric in nature, and provide access to a large variety of different substitution patterns around the heterocyclic core.167-177

2.1.2. Synthesis of Pyrrolidines via Azomethine Ylide Cycloadditions

Dipolar cycloadditions utilizing azomethine ylides and related species are convergent methods for the stereoselective synthesis of nitrogen-containing five-membered rings.178,179 Past approaches to generate 1,3-dipolar species have focused predominantly on thermal ring opening of aziridines,180-184 deprotonation of α-imino esters,84,86 and exposure of α-silyl ammonium salts to fluoride (Figure 2-2).185 Azomethine ylides have also been generated and/or utilized via decarboxylative processes from either iminium species derived from α-amino acids,83,85,186-191 or mesoionic 1,3-oxazolium intermediates 46 (munchnones).192-195

Ph Ph N CO Me Heine, Padwa, Grigg, Zhang 2 [M] ! N Huisgen & & Schreiber MeO C H Et3N 2 De Shong

" " N azomethine ylide

—CO n-Bu NF Me R O 2 4 SiMe N OMe Grigg & R1 N ! 3 West & Mortier O Vedejs Ph R2 X Figure 2-2. General methods for the generation of azomethine ylides

2.2. A Catalytic, Multi-Component Assembly Reaction for the Synthesis of 3-

Pyrrolines and Pyrrolidines

2.2.1. Multi-Component Assembly Reactions (MCARs)

Inspired by processes in nature, researchers are increasing their focus on multi-step, single operations towards the synthesis of complex molecules in which multiple bonds are formed in one sequence without isolating intermediates (Scheme 2-1).196-198 These tandem or cascade reactions are highly efficient strategies for the synthesis of a wide range of organic molecules.199 Multi-component assembly reactions (MCARs) are powerful variants of tandem reactions and typically involve a one-pot process that combines at least three easily accessible reactants. MCAR strategies usually incorporate a majority of the starting material atoms into the product molecule and are ideally suited for combinatorial platforms. Well known examples of these processes are the Strecker synthesis of amino nitriles200,201 and the Ugi four-component condensation of an 47 isocyanide, primary amine, aldehyde and carboxylic acid (Scheme 2-1).202,203 Both of these reactions rapidly generate molecular complexity and provide access to important compounds. The atom economy of MCARs,204 combined with the minimized environmental burden make these reactions extremely attractive.

Scheme 2-1. Examples of multi-component assembly reactions

catalyst O CN A B C A B C + HCN + NH3 Strecker Reaction R H R NH2 general multicomponent A B C reaction

O R2 O O H Ugi Four-Component Condensation + R1 NH + + 3 N 2 R N C R N R3 R OH R2 H R1 O

2.2.2. A Catalytic Multi-Component Method for the Generation of Azomethine

Ylides

An attractive and mild method to access azomethine ylides is the combination of a metallocarbenoid species (generated from diazoester II-10) with an imine (II-9, Scheme

2-2). The 1,3-dipole intermediate A generated in situ can then be employed in a multi- component cycloaddition process when an appropriate dipolarophile (II-11) is present.205,206 A related strategy has been very successful involving rhodium(II)-catalyzed intramolecular cycloadditions of imino-substituted α-diazo carbonyl compounds.207,208

However, the intermolecular, multi-component strategy has not received the same attention. Our current investigations of new catalytic reactions led us to explore this 48 process, with the intention of differentiating all positions of the pyrrolidine ring in a convergent, one-pot reaction.

Scheme 2-2. MCAR for the synthesis of 3-pyrrolines

II-11 CO2Et CO R X Y Ar Cu(I) 2 H CO R Ar 2 Y N 2 catalyst Ar N + N H 5 N H R 2 CH2Cl2 [2+3] R X H R

II-9 II-10 A II-12 2,5-trans azomethine ylide

We began the exploration of this cycloaddition process by surveying different potential catalysts and solvents in the presence of N-benzylidene imine (II-9a), dimethyl acetylenedicarboxylate (DMAD, II-11a), and ethyl diazoacetate (EDA, II-10a) (Table 2-

1). Gratifyingly, both copper(I) trifluoromethanesulfonate, (C6H6)•[Cu(OTf)]2, and rhodium(II) acetate dimer are catalysts for the reaction, with copper(I) being superior in terms of yield and reliability. The cycloaddition is highest yielding in chlorinated solvents such as dichoromethane (entry 2, 91%), dichloroethane (entry 4, 71%) and chloroform (entry 3, 40%). The reaction performed in diethyl ether proceeds in 75% yield (entry 5), but does not afford desired product in more coordinating ethereal solvents such as THF and DME (entries 6-7), possibly due to interactions with the copper(I) catalyst. When hydrocarbon solvents such as hexanes (entry 8) or toluene (entry 9) are employed, the yield of II-12a is moderate (58% and 54% respectively). In all solvents we examined, the diastereoselectivity of the reaction was determined to be exclusively the 2,5-trans pyrrolidine stereoisomer by 1H NMR spectroscopy (500 MHz, >20:1) analysis of the unpurified reaction mixtures. 49 Table 2-1. Optimization of the MCAR conditions

CO2Et O Ph CO2Me catalyst Ph CO Me N H N 2 + OEt + solvent Ph H N2 Ph CO2Me CO2Me d.r. > 20:1 II-9 II-10 II-11 II-12a

entry catalyst solvent time, (T) yield (%)

1 Rh2OAc4 CH2Cl2 13.5 h, (40 °C) 62 2 [Cu(SO3CF3)] CH2Cl2 4 h, (40 °C) 91 3 [Cu(SO3CF3)] CHCl3 4 h, (60 °C) 40 4 [Cu(SO3CF3)] ClCH2CH2Cl 4 h, (60 °C) 71 5 [Cu(SO3CF3)] Et2O 6 h, (38 °C) 75 6 [Cu(SO3CF3)] THF 14 h, (60 °C) N.R. 7 [Cu(SO3CF3)] DME 13.5 h, (60 °C) N.R. 8 [Cu(SO3CF3)] hexanes 6 h, (65 °C) 58 9 [Cu(SO CF )] toluene 6 h, (65 °C) 54 3 3

The effect of catalyst loading was then determined using the same reaction conditions

(Table 2-2). Although copper(I) triflate is commercially available as the dimer•benzene complex, we observe higher yields with catalyst prepared in our laboratory.209 The reaction proceeds well with 10 mol% (entry 1, 91% yield) and 5 mol % (entry 2, 60% yield) of [Cu(OTf)]. However, the yield decreases to less than 20% after the catalyst loading is reduced to 2.5 mol % and 1 mol % (entries 3 and 4).

Table 2-2. Effect of catalyst loading on product yield

O CO R Ph CO2Me x mol % 2 N H [CuOTf] Ph CO Me + OR + N 2 Ph H solvent N2 CO Me 2 Ph CO2Me

II-9 II-10a R = Et II-11 II-12a, b II-10b R = t-Bu entry mol% [CuOTf] diazo ester yield (%) d.r. compound 1 10 II-10a 91 20:1 II-12a 2 5 II-10a 60 20:1 II-12a 3 2.5 II-10a 18 20:1 II-12a 4 1 II-10a 12 20:1 II-12a 5 10 II-10b 83 20:1 II-12b 50 In order to differentiate the resulting esters from the reaction for future synthetic endeavors, various α-diazo esters were utilized in the reaction (Table 2.2). As indicated earlier, commercial ethyl diazoacetate affords high yields of the desired pyrrolidine II-

12a (Table 1). Additionally, use of t-butyl diazoacetate (entry 5) produces the substituted pyrrolidine II-12b in 83% yield.

Encouraged by the results from optimizing this initial reaction, we examined the scope of this process regarding substitution on the nitrogen atom (Table 2-3). As with our earlier optimization studies, dimethyl acetylene-dicarboxylate (DMAD, II-11) was employed as the dipolarophile, ethyl diazoacetate (EDA, II-10a) as the carbenoid source and 10 mol% [CuOTf] as the catalyst. As the data from Table 3 indicates, the reaction proceeds with halogen or alkoxy substitution on the N-phenyl ring (entries 2 and 3), but not an electron-withdrawing nitro group (entry 4). Surprisingly, the reaction with the more basic N-benzyl imine of benzaldehyde (II-9e, entry 5) generated the N-benzyl pyrrolidine (II-15), although only in 43% yield.

Table 2-3. Effect of N-substitution of imine on catalytic 3-pyrrolidine synthesis

O CO Et R CO2Me 10 mol% 2 N H [CuOTf] R CO Me + OEt + N 2 Ph H CH Cl N2 2 2 CO Me 2 Ph CO2Me II-9a-e II-10a II-11a

entry R yield (%) d.r. compound 1 Ph (II-9a) 91 >20:1 II-12a 2 4-ClPh (II-9b) 75 >20:1 II-13 3 4-OMePh (II-9c) 43 >20:1 II-14 4 4-NO2Ph (II-9d) no reaction – – 5 PhCH (II-9e) 43 10:1 II-15 2

The impact of substitution on the benzylidene portion of N-phenyl imines on the 51 cycloaddition process was also explored. We again employed dimethyl acetylene- dicarboxylate (DMAD, II-11) as the dipolarophile and ethyl diazoacetate (EDA, II-10a) as the carbenoid source with 10 mol% [CuOTf] as the catalyst. As Table 2-4 indicates, the reaction tolerates electron-withdrawing substituents (entries 4-6). Interestingly, inclusion of a nitro group in the substrate produces no reaction (entry 3). This deleterious effect of a nitro group on pyrrolidine formation was previously observed (Table 2-3, entry 4) and we postulate that the nitro group is binding to the copper catalyst in both cases. Electron-donating groups decrease the yield of the reaction (entries 8-9) but substantial quantities of product are still isolated. Cyclohexyl-N-phenyl imine was also utilized in the reaction (entry 10, 35% yield). Presumably the low yield is due to the instability of the starting material imine under the reaction conditions.

Table 2-4. Catalytic, MCAR of EDA, DMAD, and various imines

O 10 mol% CO Et Ph CO2Me 2 N H [CuOTf] Ph CO Me + OEt + N 2 R H CH Cl N2 2 2 CO Me 2 R CO2Me II-9a, f-n II-10a II-11

entry R yield (%) d.r. compound 1 Ph 91 20:1 II-12a 2 4-CH3Ph 86 20:1 II-16 3 4-NO2Ph no reaction – II-17 4 4-BrPh 79 20:1 II-18 5 4-ClPh 77 20:1 II-19 6 2-ClPh 74 20:1 II-20 7 2-Furyl 94 20:1 II-21 8 4-OMePh 54 20:1 II-22 9 3-OMePh 51 20:1 II-23 10 Cyclohexyl 35 20:1 II-24

Crystallization of II-18 (Table 2-4, entry 4) from ether yielded single crystals that were analyzed by X-ray crystallography (Figure 2-3). The relative stereochemistry of II-18 52 was determined to be trans with respect to the 2 and 5 positions of the pyrrolidine ring.

We have also examined the scope of our three-component coupling with regard to dipolarophile structure (Table 2-5). Electron-deficient alkenes undergo cycloaddition readily to afford the desired substituted pyrrolidines (entries 1-7).

Figure 2-3. ORTEP representation of crystal structure of substituted pyrrolidine II-18.

Thermal ellipsoids are drawn at 50% probability

53 Table 2-5. MCAR of N-benzylidene aniline (II-9a), EDA (II-10a), and Various dipolarophiles

entry dipolarophile major product yield (%) d.r.

CO2Et

Ph CO2Et CO2Et N 1 EtO2C II-25 77 2:1 II-11b Ph CO2Et

CO2Et

Ph CO Me N 2 2 MeO2C CO2Me II-26 51 3:1 II-11c

Ph CO2Me

CO2Et N Ph CN C N C 3 N II-27 83 3:2 II-11d Ph CN CO Et CH 2 3 O Ph N N 4 O O II-28 70 2:1 N CH3 Ph II-11e O

CO2Et O Ph Ph N 5 Ph Ph II-29 43 5:1 II-11f Ph COPh

CO2Et O O O O Ph N 6 II-30 55 O 5:1 II-11g Ph O

CO2Et

CO Et Ph 2 N II-31 47 7 II-11h 2:1 Ph CO Et 2

Our current working model of this reaction is shown in Figure 2-4. The combination of copper(I) and diazo compounds produces the corresponding metallocarbenoid. The presence of an imine during this process generates an azomethine ylide intermediate with the carbenoid carbon cis to the benzylidene substituent. The rate of E-Z isomerization of the azomethine ylide is apparently slower than the rate of the cycloaddition since only

2,5-trans stereochemistry of the resulting substituted pyrrolidine is observed.210,211 54 O Cu(I) Ar RO2C RO2C N H catalyst H H + OR Ar N X Ar N R H R H N2 H R

X Y CO2Et

Ar Y 2,5-cis N 2,5-trans not observed endo and exo R X Figure 2-4. Proposed model for the three-component assembly of 2,5-trans-pyrrolidines

In addition, the dipolarophile alkene geometry is directly translated to the cycloaddition products: trans alkenes (Table 2-5, entries 1, 3, and 5) give 3,4-trans products and cis alkenes (entries 2) afford 3,4 cis products. In summary, the combination of an α-diazo ester and an imine in the presence of a copper(I) catalyst generates a transient azomethine ylide. This 1,3-dipole undergoes diastereoselective cycloadditions with activated dipolarophiles to afford a highly-substituted pyrrolidine in a convergent, three-component assembly reaction. This process is a general method for pyrrolidine synthesis, capable of generating four contiguous stereogenic centers in one operation by employing a commercially available catalysts. In particular,

the high diastereoselectivity and convergent nature of this reaction suggests good potential as a method for the target synthesis of pyrrolidine alkaloid natural products.

55 2.2. 3,3’-[Pyrrolidinyl]spirooxindoles

2.3.1 Significance and Occurrence of Bioactive Spirooxindoles

With a general method for for heterocycle synthesis in place, we were interested to see if we could apply this method to the synthesis of more structurally challenging pyrrolidine- containing structures. In particular, the multi-component nature of the reaction lends itself to the rapid generation of complex molecular frameworks, and our interest was drawn to the pyrrolidinyl-spirooxindole family of natural products (Chapter 1). The spirooxindole core features in a number of natural products such as (–)-horsfiline,6 elacomine,212 alstonisine,2 strychnofoline11,213 and spirotryprostatins A and B,17 as well as medicinally relevant compounds (Figure 1-1).30,214-218

Recently, the spiropyrrolidinyl-oxindole core of these molecules has been the subject of significant synthetic interest.93,219-227 In addition to the classical oxidative rearrangement of

β-carbolines,35,123,228,229 and the intramolecular Mannich reaction between an oxindole and an imine derivative of L-tryptophan,38 there have been several approaches to this alkaloid

60,61,230,231 core using radical cyclizations. Carreira and co-workers have developed a MgI2- catalyzed ring expansion of a spirocyclopropane-1,3’-oxindole and an aldimine for the synthesis of several related natural products.97,99,232 In 2000, Overman demonstrated the total synthesis of spirotryprostatin B via the intramolecular trapping of a π-allyl complex by a oxindole enolate, and more recently a synthesis of (–)-horsfiline was disclosed involving a related palladium-catalyzed asymmetric allylic alkylation.102 Williams reported an elegant asymmetric synthesis of the spirotryprostatins using a chiral azomethine ylide generated from chiral 5,6-diphenylmorpholin-2-one and a substituted aldehyde in four 56 steps,104 which has provided the synthetic platform for library-based medicinal evaluation of these spiroxindoles and their analogues.114,233 Consequently, an efficient non- linear synthetic strategy to access spiropyrrolidinyloxindoles efficiently could advance the understanding of how these compounds interact with biological systems.

2.3.2. MCAR for the synthesis of 3,3’-pyrrolidinylspirooxindoles

We were able to effect a catalytic, multi-component approach employing dipolarophile

II-32 derived from isatin,19 using our multi-component reaction manifold.

Scheme 2-3. MCAR for the synthesis of spirooxindoles

2 MeO2C CO2R R1 [Cu(I)] R1 H CO R2 3 N CO Me N 2 R catalyst 2 O O R H N2 R N CH2Cl2 3 N R4 R 4 single R II-10 II-32 diastereoisomer II-33 II-9

The diastereoselectivity of the cycloaddition was determined by single crystal X-ray diffraction (Figure 2-5). As in the case for the 3-pyrroline and pyrrolidines described earier our understanding of this process relies on the rate of E-Z isomerization of the azomethine ylide being slower than the rate of the cycloaddition since only 2,5-trans stereochemistry of the resulting cycloadduct is observed (Scheme 2-3). 210,234 In addition, the dipolarophile alkene geometry is directly translated to the cycloaddition products. Our model involves an Ε-exo transition state (E referring to the imine geometry and exo to the relative 57 orientation of the two ester groups – as described by Williams and Sebehar)104 leading to the observed regio- and diasteroselectivity.

Figure 2-5. ORTEP representation of crystal structure of substituted spiro- pyrrolidinyloxindole II-38. Thermal ellipsoids are drawn at 50% probability. Hydrogen atoms other than those in the pyrrolidine ring have been omitted for clarity.

Gratifyingly, each component of the reaction manifold allows for facile diversification.

Thus a collection of spiro-pyrrolidinyloxindoles can be readily prepared (Table 2-5).

Substitution on the starting imine is tolerated, especially on the benzylidene aryl ring 58 (compounds II-34 to II-39, entries 2-4), although a para-methoxy group leads to a lower yield (compound II-37, entry 5) and the formation of side products.

Even a 2-chlorophenyl (compound II-38, entry 6), and a heterocyclic imine (compound II-

39, entry 7), could be employed in the reaction. Substituted aniline imines lead to a decrease in yield of product (compounds II-40 and II-41 entries 8 and 9), most likely due to a destabilising effect on the putative azomethine ylide.

Scheme 2-4. Mechanistic and stereochemical considerations of the MCAR

Ar Ar Ar Cu(I) N H CO2Et H N CO Et Ar N CO Et catalyst 2 2 Ar H N2 Ar H

MeO2C Ar N E-exo Ar CO2Et transition state O N CO2Me Bn O Ar N N CO Et Bn H 2 Ar O Ph no 2,5-cis N OMe observed O

To further differentiate the esters for future synthetic endeavors, t-Butyl diazoacetate could be readily substituted in place of EDA, (II-33b, 74% yield). Alternative N- substituents (methyl and acetate) were introduced at the dipolarophile nitrogen atom

(entries 10 and 11). Finally, a substituted dipolarophile undergoes cycloaddition smoothly (20 mol % of catalyst used, 84% yield, entry 12). Of particular note, no carbon-hydrogen insertion is observed at the N-benzylic position, although in the event this amide nitrogen is left unprotected, significant nitrogen-hydrogen insertion of the carbenoid occurs (ca. 30%). Commercial copper(I) trifluoromethane sulfonate dimer- 59 benzene complex, copper(I) hexafluorophosphate tetrakisacetonitrile and dirhodium tetraacetate all yield significantly less product.

Table 2-5. Scope of the spirooxindole reaction

2 CO2R MeO2C 1 1 R R 2 3 N CO2Me N H CO2R R [CuOTf] O O R R H N CH Cl 2 N 2 2 3 R N 4 R4 reflux R II-9 II-10 II-32 entry substituents product yield (%) d.r. entry substituents product yield (%) d.r.

2 CO R2 CO2R 2 1 Ph Ph 1 R=R =Ph, N CO2Me (a) 79 20:1 7 R=2-thiophenyl, N CO2Me 43 20:1 2 (b) 74 1 2 R =(a)Et, (b)t-Bu Ph O R =Ph, R =Et, O 3 4 3 4 R =H, R =Bn NBn R =H, R =Bn S NBn II-33a & b II-39 Cl CO2Et CO2Et Ph 1 2 R=4-CH3C6H4, N CO2Me 72 20:1 8 R=Ph, R =4- N CO2Me 50 20:1 R1=Ph, R2=Et, 2 O ClC6H4, R =Et, Ph O R3=H, R4=Bn 3 4 NBn R =H, R =Bn Me NBn II-34 II-40

CO2Et CO2Et Ph N CO Me 1 F N CO Me 3 R=4-ClC6H4, 2 60 20:1 9 R=Ph, R =3- 2 41 20:1 2 R1=Ph, R2=Et, O FC6H4, R =Et, Ph O R =H, R =Bn 3 4 3 4 NBn R =H, R =Bn NBn Cl II-35 II-41

CO2Et CO2Et Ph Ph 1 4 R=4-BrC6H4, N CO2Me 55 20:1 10 R=R =Ph, N CO2Me 69 20:1 R =Ph, R =Et, 2 1 2 O R =Et, Ph O R =H, R =Bn 3 4 3 4 NBn R =H, R =Me Br NMe II-36 II-42

CO Et CO Et 2 Ph 2 Ph 1 2 5 R=4-CH3OC6H4, N CO2Me 46 20:1 11 R=R =Ph, R =Et, N CO2Me 56 20:1 1 2 3 4 R =Ph, R =Et, O R =5'Cl, R =Ac Ph O 3 4 R =H, R =Bn NBn NAc H3CO II-37 Cl II-43 CO Et CO Et Ph 2 Ph 2 Cl N CO Me 1 2 N CO Me 6 R=2-ClC6H4, 2 53 20:1 12 R=R =Ph, R =Et, 2 84 20:1 1 2 R =Ph, R =Et, O R3=5'Cl, R4=Bn Ph O R3=H, R4=Bn NBn NBn II-38 Cl II-44

Typically 10 mol % of copper complex is sufficient to produce good yields of product, although in some cases 15-20 mol % of the dimer complex is required to produce 60 synthetically useful yields (entries 5 & 7-9). Despite the lower chemical yields of these entries, this privileged alkaloid structure is accessed from readily available starting materials in a rapid and efficient manner.

In summary, the combination of an α-diazoester and an imine in the presence of a copper(I) catalyst generates a reactive, transient azomethine ylide. This 1,3-dipole undergoes a highly diastereoselective cycloaddition with a dipolarophile to afford a highly- substituted spiropyrrolidinyloxindole heterocycle in a convergent, three-component assembly reaction.

2.3.3. Synergistic Activation of Gene Transcription Pathways by Forskolin and II-

32

The collection of spirooxindole compounds were evaluated for bioactivity against in collaboration with the MIT/Harvard Broad institute for Chemical Biology.235 At the time of writing, none of the the pyrrolidinyl-spirooxindole natural products have demonstrated any promising bioactivity. However, one of the cycloaddition precursors II-32a demonstrated an interesting result in the CREB gene transcription pathway. CREB is a transcription factor which is activated by the cAMP pathway. cAMP activates protein kinase A, which in turn phosphorylates CREB. Phosphorylated-CREB then binds to the transcription cofactor CBP, and these events lead to gene transcription.236-238 The natural product forskolin is able to produce a 5-fold activation of the reporter gene by increasing concentrations of intracellular cAMP.239 When tested in conjunction with II-32a, a 40- fold increase in the activation of the reporter gene was observed.

This result was confirmed by retesting II-32a and evaluating three further analogs 61

Me O MeO2C MeO2C OH MeO2C MeO2C Me Me O Cl Cl HO O O O O OAc N N N N Me Me Ac OH Ph Me Ph

forskolin II-32a II-32b II-32c II-32d II-32b-d, each of which produced a 30 to 40-fold increase in the efficacy of forskolin to increase intracellular cAMP (Figure 2-6). When tested alone II-32a-d produced no measurable elevation in the levels of intracellular cAMP. The mode of this activation is unknown and is currently under investigation.

Figure 2-6. Synergistic Activation of forskolin in the CREB gene transcription pathway

2.4. MCAR for the Synthesis of Pyrroles

Our multi-component reaction manifold had allowed us to synthesize a variety of pyrrolidine and pyrroline-based structures. In addition to these saturated or partially unsaturated heterocycles, we were interested in applying our methodology to the synthesis of aromatic pyrroles. We envisaged diazoacetonitrile as having similar electronic properties to diazoesters, and so should be compatible with our optimized reaction conditions. Additionally, the cyano group might serve as a leaving group to generate an aromatic pyrrole.

62 2.4.1. Background

Pyrroles are ubiquitous motifs in natural products, medicinal agents and in materials chemistry. 156,158-160,240,241 While there are many efficient methods for the synthesis of this important class of heterocycle, all of the various approaches have certain restrictions regarding the scope and placement of the substitution pattern around the heterocyclic core. In many instances, specific pyrrole substitution patterns are more important than others for reactivity or biological activity, thus underpinning the need to access a wide variety of pyrrole scaffolds efficiently from straightforward starting materials. In addition to restrictions based on the substitution pattern of the target compound, various methods to synthesize differentially substituted pyrroles can require expensive reagents, prolonged reaction times or numerous synthetic steps.

2.4.2. Catalytic MCAR for the synthesis of pyrroles

We were able to prepare aromatic pyrroles instead of the pyrrolidine and 3-pyrroline heterocycles described previously by employing diazoacetonitrile, II-46, as the carbene source. The multi-component reaction using rhodium(II) acetate as catalyst led to the formation of II-47 in 71% yield (Scheme 2-5).

Scheme 2-5. MCAR for the synthesis of pyrroles

CO R2 R1 2 1 mol% H CN R1 CO R2 N + + Rh2(OAc)4 N 2 N R H 2 CH2Cl2 2 2 R CO2R CO2R reflux

II-9 II-46 II-11 II-47

Surprisingly, relatively few methods for the synthesis of these 3,4-substituted pyrroles 63 exist in the literature. For example, II-47 has been reported on four previous occasions, but none of the synthetic routes were amenable to accommodate various substitution efficiently in a single flask operation. Boyd and Wright have described the preparation and chemistry of range of unstable mesoionic oxazolium-5-oxide perchlorates, including the dipolar cycloaddition of these compounds with dimethyl acetylene dicarboxylate (DMAD) to yield compound II-47.242-245 Yamanaka has reported the synthesis of the related 4-polyfluoroalkylated pyrrole-3-carboxylates through the 1,3- dipolar cycloaddition of a fluoroalkylated acetylenecarboxylate ester with the munchnones described by Boyd.246 Additionally, phenylsydnonyl-substituted pyrroles have been reported via a related cycloaddition.247 In this approach, the pyrroles are prepared in five linear steps starting from an N-aryl glycine derivative.

In 1984, Reutrakul reported the preparation of phenylsulfinyl aziridines in modest to good yields from benzylideine anilines and α-chloro α−lithio sulfoxides.248,249 Pyrolysis of these compounds in the presence of DMAD promoted the thermal ring opening of the aziridine at 90 °C to the corresponding azomethine ylide. Cycloaddition followed by elimination of sulfinic acid afforded the pyrroles in good yield. Similarly, Katritzky has reported the synthesis of the compound II-53 from the analogous thermal reaction of 2- benzotriazolylaziridines in the presence of diethyl acetylenedicarboxylate.250 Although the aziridine precursors are readily accessed in this case, the cycloaddition step requires a prolonged reaction time (48 h at 100 °C) to access the target pyrroles. Here we report a concise approach to 1,2-diarylpyrroles using a multi-component assembly reaction of an imine, diazoacetonitrile and an activated alkyne dipolarophile (Scheme 2-6).

As in the previous sections combination of transition metal salt [in this case 64 rhodium(II)] with a diazoacetonitrile produces the corresponding metallocarbenoid.

The presence of an imine during this process generates an azomethine ylide intermediate, which is trapped via a Huisgen [3+2] cycloaddition onto an alkynyl dipolarophile.180 The resultant adduct then undergoes elimination in situ to form the aromatic pyrrole (Scheme

2-6).251,252

Scheme 2-6. Proposed reaction mechanism

CN Ph Rh(II) [3+2] H CN N catalyst Ph cycloaddition + N H H Ph N2 CH2Cl2 H Ph CO2Me II-9a II-46 A azomethine ylide II-11a

CO2Me

H CN

Ph CO Me Ph CO Me N 2 elimination N 2

Ph CO2Me Ph CO2Me II-47 B not isolated After examining a number of possible transition metal salts for this reaction, we determined that rhodium acetate is the catalyst of choice for this transformation, proving superior to 10 mol% copper triflate (as in our previous work), which surprisingly yielded no product in this case. Other rhodium salts also promoted the transformation,

(dirhodium tetraoctanoate, and dirhodium tetrahexaflurobutyrate) albeit in lower yields

(27% and 12% respectively). We were pleased to discover that as little as 1 mol% catalyst smoothly effected the transformation.

Gratifyingly, several imines and can be employed in this reaction manifold (Table 2-

7). Substitution on the starting imine is tolerated, especially on the benzylidene aryl ring

(compounds II-50 to II-54, entries 4-8). Compound II-54 requires a longer reaction time after the syringe pump addition was complete (12 h). 65 Table 2-6. Scope of the MCAR for the synthesis of pyrroles

2 H 1 CO2R R H CN 1 mol% N [Rh (OAc) ] R1 CO R2 + + 2 4 N 2 N2 R H CH2Cl2 2 2 CO2R R CO2R II-9a-h II-46 II-3a-b

entry pyrrole yield entry pyrrole yield

Ph CO CH Ph CO CH N 2 3 N 2 3 1 II-47 71% II-51 53% 5 CO2CH3 Ph CO2CH3

Br

Ph CO2CH3 I N 2 CO CH N 2 3 61% 6 II-52 59% CO2CH3

Ph CO CH II-48 2 3 Cl

Ph CO C H N 2 2 5 3 CO CH 63% 7 II-53 55% N 2 3 H3C CO2C2H5

Ph CO2CH3 II-49 Cl

Ph CO CH Ph CO2CH3 N 2 3 N 4 66% 8 II-54 47%

CO CH CO2CH3 2 3 Cl

H C II-50 Cl 3

Most likely this is due to a destabilizing effect on the putative azomethine ylide.

Diethyl acetylenedicarboxylate II-11b, is readily used in place of DMAD to yield the

3,4-diethyl ester in good yield (compound II-53, entry 7). In addition to our proposed mechanism, we could not discount the possibility of a pathway involving initial formation of an aziridine that undergoes ring opening (similar to that of Katritzky and

Reutrokul), in particular compound II-51 required prolonged reaction times (after the syringe pump addition of the diazo compound was complete). Doyle has shown that the 66 analogous Rh(II)-catalyzed aziridination of imines by carbene transfer of ethyl diazoacetate shows a strong structure dependency on the imine substituents, with respect to the reaction’s product distribution, (the azomethine ylide can undergo ring closure to yield aziridines, or cycloaddition to afford alternative products).253 In our case, this may suggest competing pathways leading to the same product, with a strong dependency on the imine structure a prerequisite for this second pathway to be substantial.

Under our optimized reaction conditions, we did not isolate any aziridine products.

However, other side products are known to form diazoacetonitrile.254 Additionally the pyrrole-3,4-diester products are known to undergo other side reactions with acetylene dicarboxylates,255 our optimization efforts were therefore primarily directed at the minimization of these side products. Diazoacetonitrile was conveniently prepared by the diazotization of the commercially available aminoacetonitrile bisulfate according to the procedure of Witiak and Lu and handled only as a solution in methylene chloride.256

Several explosions caused by concentrating diazoacetonitrile solutions have been

257,258 reported, but solutions (approximately 0.4-0.5 M in CH2Cl2) could be safely prepared in our laboratory and handled without incident.

In summary, this last application of our MCAR demonstrates that the reaction has significant synthetic utility and generality, with a wide substrate scope leading to a range of different pyrrolidine-derived heterocycles formed in a catalytic, single-flask operation.

67 2.5. Experimental Section

2.5.1. General Information.

All reactions were carried out under an atmosphere of argon or nitrogen in flame- dried glassware with magnetic stirring. THF, Et2O, CH2Cl2 and toluene were purified by passage through a bed of activated alumina.259 DME was distilled from sodium.

Reagents were purified prior to use unless otherwise stated following the guidelines of

Perrin and Armarego.260 Purification of reaction products was carried out by flash chromatography using EM Reagent silica gel 60 (230-400 mesh). Analytical thin layer chromatography was performed on EM Reagent 0.25 mm silica gel 60-F plates.

Visualization was accomplished with UV light and anisaldehyde, ceric ammonium nitrate stain, or phosphomolybic acid followed by heating. Melting points were obtained on a

Melt-temp 3 instrument and are uncorrected. Infrared spectra were recorded on a Perkin

Elmer 1600 series FT-IR spectrometer. 1H-NMR spectra were recorded on a Varian

Inova 500 (500 MHz) or Mercury 400 (400 MHz) spectrometer and are reported in ppm using solvent as an internal standard (CDCl3 at 7.26 ppm). Data are reported as (ap = apparent, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad; coupling constant(s) in Hz; integration. Proton-decoupled 13C-NMR spectra were recorded on a Varian Inova 500 (125 MHz) or Mercury 400 (100 MHz) spectrometer and are reported in ppm using solvent as an internal standard (CDCl3 at 77.0 ppm). Mass spectra data were obtained on either a Thermo-Finnigan MAT900 high resolution mass spectrometer, a VG 70-250SE HRMS or Thermo-Finnigan LCQ Advantage HPLC-MS in the Northwestern University Analytical Services Laboratory. Single crystal X-ray data 68 were collected using a Bruker SMART-1000 diffractometer equipped with a CCD detector and processed using SAINT-NT from Bruker.

Ethyl diazoacetate (EDA, II-10a), t-butyl diazoacetate (II-10b), dimethyl acetylene dicarboxylate (DMAD, 3a) and diethyl acetylene dicarboxylate (DEAD, II-10b) were purchased from Aldrich Chemical Company and used without purification. Copper(I) trifluoromethanesulfonate was prepared by a modified method of Kochi and Salomon.261-

263 Imines were prepared by combining the corresponding aldehyde (freshly distilled), appropriately substituted aniline, and either activated 4Å molecular sieves or anhydrous magnesium sulfate in dichloromethane.264-266 The reactions were stirred for 16 h, then filtered and concentrated in vacuo. If necessary, the resulting imines were re-crystallized from a suitable organic solvent mixture to afford imines that were >95% pure by 1H

NMR spectrometry analysis. Diazoacetonitrile solutions were prepared according to the procedure of Witiak and Lu.256 Due to the known explosion hazards associated with this compound, these solutions were never concentrated to dryness. Isatin-derived dipolarophiles II-32a-d were prepared as a single olefin isomer in each case according the procedure of Zhen, Fan and Kende.267

2.6. Multi-Component Assembly Reaction (MCAR) for the Synthesis of Nitrogen-

Containing Heterocycles

2.6.1. General Experimental Procedure A: MCAR for 3-Pyrrolines and

Pyrrolidines: 69 To a solution of imine (1.5 mmol) and dipolarophile (0.5 mmol) in CH2Cl2 (5.0 mL) heated at reflux was added a solution of a diazo ester (1.5 mmol) in CH2Cl2 via syringe pump over 3 h. After complete addition, the reaction was heated for an additional hour, cooled to 23 ºC and then filtered through silica gel using CH2Cl2 (50 mL). The solvent was removed and diastereoselectivities were assigned by analysis of 1H

NMR (500 MHz) spectra and correlated with GC-MS integrations. The reaction mixture was purified by flash column chromatograph (ether/hexanes mixtures as eluent), usually by dry loading the sample, to afford the desired cycloaddition product.

2.6.2. Characterization Data for 3-Pyrroline and Pyrrolidine Compounds II-12

to II-31

Analytical data for II-12a: Rf = 0.3 (50% Et2O/hexanes); IR

CO2Et (film) 3054, 2987, 1740, 1422, 1265, 896, 740, 705 cm-1; 1H CO Me N 2

NMR (400 MHz, CDCl3) δ 7.41-7.14 (m, 7H), 7.10-6.95 (m, CO2Me 3H), 6.71 (m, 1H), 6.55 (m, 2H), 6.03 (d, J = 7.6 Hz, 1H), 5.77

(d, J = 7.6 Hz, 1H), 4.14 (m, 3H), 3.80 (m, 3H), 3.65 (m, 3H), 1.09 (m, 3H); 13C NMR

(100 MHz, CDCl3) d 169.8, 164.1, 150.9, 144.1, 143.6, 138.1, 130.1, 129.2, 129.1, 128.6,

127.5, 118.5, 114.1, 72.1, 69.8, 61.8, 53.5, 53.3, 14.4. LRMS (electrospray): 432, 410,

+ 232, 213, 149, 130; Mass calcd for C23H23NO6 [M] , 409.43. Found 410.

Analytical data for II-13: Rf = 0.3 (50% Et2O/hexanes); mp = CO2Et Cl CO Me N 2 158-159 °C; IR (film) 2985, 2954, 2848, 1738, 1599, 1497,

-1 1 CO2Me 1437, 1348, 1275, 1242, 1193, 1096, 1028, 817 cm ; H 70

NMR (500 MHz, CDCl3) δ 7.35-7.22 (m, 5H), 7.05 (m, 1H), 6.50 (m, 2H), 6.01 (d, J =

6.2 Hz, 1H), 5.25 (d, J = 6.2 Hz, 1H), 4.24-4.16 (2H, m), 3.84 (s, 3H), 3.64 (s, 3H), 1.16

13 (m, 3H); C NMR (125 MHz, CDCl3) δ 169.9, 162.2, 162.4, 143.8, 142.9, 137.6, 129.7,

129.5, 128.0, 115.3, 71.3, 69.9, 62.2, 52.8, 52.6, 14.3; LRMS (electrospray): 466, 444,

+ 365, 357, 337, 232, 149; Mass calcd for C23H22NO6Cl [M] , 443.88. Found 444.

Analytical data for II-14: Rf = 0.3 (50% Et2O/hexanes); mp CO2Et MeO CO Me N 2 = 138-141 °C; IR (film) 3054, 2987, 1738, 1513, 1421,

-1 1 CO Me 2 1266, 896, 738, 705 cm ; H NMR (500 MHz, CDCl3) δ

7.41-7.25 (m, 5H), 6.80 (d, J = 9.0 Hz, 1H), 6.72 (m, 3H),

6.57 (d, J = 9.1 Hz, 2H), 6.03 (d, J = 7.0 Hz, 1H), 5.77 (d, J = 7.3 Hz, 1H), 4.24-4.16 (m,

2H), 3.89 (s, 3H), 3.78 (m, 2H), 3.68 (s, 3H), 3.62 (s, 3H), 1.17 (t, J = 6.9 Hz, 3H); 13C

NMR (125 MHz, CDCl3) δ 170.1, 164.0, 152.8, 138.1, 137.8, 130.8, 129.0, 128.3, 127.5,

116.5, 115.3, 115.3, 114.9, 71.5, 70.3, 61.9, 55.8, 53.0, 52.9, 14.3; LRMS (electrospray):

+ 462, 440, 124; Mass calcd for C24H25NO7 [M+H] , 439.36. Found 440.

O Ot-Bu Analytical data for II-12b: Rf = 0.38 (50% Et2O/hexanes); mp =

CO Me 131-133 °C; IR (film) 2978, 2931, 1732, 1664, 1602, 1503, 1454, N 2 1436, 1348, 1260, 1152, 1104, 1030 cm-1; 1H NMR (500 MHz, CO2Me

CDCl3) δ 7.40-7.21 (m, 5H), 7.10 (m, 2H), 6.75 (m, 1H), 6.55

(m, 2H), 5.99 (d, J = 5.4 Hz, 1H), 5.73 (d, J = 5.4 Hz, 1H), 3.88 (s, 3H), 3.65 (s, 3H),

13 1.29 (s, 9H); C NMR (100 MHz, CDCl3) δ 178.0, 169.0, 144.0, 144.0, 138.5, 129.1, 71 128.9, 127.1, 127.1, 118.6, 114.1, 71.5, 53.0, 52.6, 28.0. LRMS (electrospray): 460,

+ 438, 382, 360, 279, 149; Mass calcd for C25H28NO6 [M+H] , 437.48. Found 438.

Analytical data for II-16: Rf = 0.42 (50% Et2O/hexanes); IR CO2Et

CO Me N 2 (film) 3054, 2987, 1739, 1601, 1504, 1438, 1422, 1349, 11265,

-1 1 CO2Me 1197, 1105, 1025, 896, 737, 705 cm ; H NMR (500 MHz,

CDCl ) δ 7.28-7.09 (m, 5H), 6.78 (m, 1H), 6.61 (m, 2H), 6.02 (d, H3C 3

J = 6.5 Hz, 1H), 5.79 (d, J = 6.5 Hz, 1H), 4.29-4.12 (m, 2H), 3.86 (s, 3H), 3.67 (s, 3H),

13 2.31 (s, 3H), 1.12 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.0, 163.5, 162.7, 144.2,

143.7, 138.3, 1135.1, 130.9, 129.8, 129.2, 127.4, 118.4, 114.1, 71.0, 69.9, 62.0, 52.8,

52.6, 21.5, 14.3. LRMS (electrospray): 446, 424, 387, 213, 149; Mass calcd for

+ C24H25NO6 [M] , 423.46. Found 424.

CO2Et Analytical data for II-18: Rf = 0.4 (50% Et2O/hexanes); mp =

CO Me N 2 117-119 °C; IR (film) 3050, 3000, 1736, 1664, 1601, 1503, 1436,

CO2Me 1348, 1271, 1245, 1191, 1104, 1010 cm-1; 1H NMR (500 MHz,

Br CDCl3) δ 7.42 (m, 2H), 7.21 (m, 2H), 7.11 (m, 2H), 6.23 (m,

1H), 6.52 (m, 2H), 6.00 (d, J = 6.8 Hz, 1H), 5.75 (d, J = 6.8 Hz, 1H), 4.19-4.04 (m, 2H),

13 3.83 (m, 3H), 3.64 (m, 3H), 1.09 (m, 3H); C NMR (125 MHz, CDCl3) δ 170.0, 163.0,

162.3, 142.8, 142.6, 137.2, 132.0, 131.9, 129.1, 129.0, 122.3, 118.6, 113.9, 70.2, 69.7,

61.8, 52.7, 52.4, 14.0. LRMS (electrospray): 510, 489, 488, 413, 374, 365, 337, 292, 251,

+ 213, 199, 171, 149, 141; Mass calcd for C23H23NO6Br [M] , 488.33. Found 489.

72

CO2Et Analytical data for II-19: Rf = 0.45 (50% Et2O/hexanes); mp =

CO Me N 2 112-115 °C; IR (film) 2985, 2954, 1738, 1664, 1601, 1503, 1437,

CO2Me 1349, 1273, 1245, 1193, 1104, 1014, 751, 692 cm-1; 1H NMR

Cl (500 MHz, CDCl3) δ 7.28-7.20 (m, 3H), 7.05 (m 2H), 6.75 (m,

1H), 6.50 (m, 2H), 5.95 (d, J = 6.7 Hz, 1H), 5.75 (d, J = 6.7 Hz, 1H), 4.20-4.03 (m, 2H),

13 3.82 (s, 3H), 3.61 (s, 3H), 1.08 (m, 3H); C NMR (125 MHz, CDCl3) δ 169.8, 163.0,

162.7, 143.7, 143.5, 137.0, 134.2, 132.1, 129.1, 129.3, 118.8, 114.2, 70.4, 70.0, 62.1,

53.0, 52.7, 14.3. LRMS (electrospray): 466, 444, 391, 232, 213, 149; Mass calcd for

+ C23H22NO6Cl [M] , 443.88. Found 444.

CO2Et Analytical data for II-20: Rf = 0.31 (50% Et2Ohexanes); mp =

CO2Me N 112-113 °C; IR (film) 2954, 1741, 1664, 1601, 1503, 1437, 1349,

CO Me 2 1274, 1249, 1192, 1104, 1026,751, 691 cm-1; 1H NMR (500 MHz, Cl

CDCl3) δ 7.40 (m, 1H), 7.30-7.09 (m, 5H), 6.75 (t, J = 5.8 Hz, 1H), 6.59 (m, 3H), 5.78

(d, J = 5.8 Hz, 1H), 4.25-4.11 (m, 2H), 3.91 (m, 3H), 3.68 (m, 3H), 1.13 (m, 3H); 13C

NMR (125 MHz, CDCl3) δ 170.1, 163.5, 162.9, 143.9, 143.2, 135.8, 133.8, 131.7, 129.8,

129.4, 128.9, 128.0, 118.8, 113.9, 69.6, 66.8, 62.1, 52.9, 52.7, 14.3. LRMS

+ (electrospray): 466, 444, 232, 149; Mass calcd for C23H22NO6Cl [M] , 443.88. Found

444.

CO2Et Analytical data for II-21: Rf = 0.23 (50% Et2O/hexanes); mp =

CO Me N 2 136-138 °C; IR (film) 2954, 2850, 1738, 1668, 1601, 1504, 1437,

CO2Me O 73 -1 1 1348, 1271, 1245, 1191, 1105, 1013, 750 cm ; H NMR (500 MHz, CDCl3) δ 7.16 (m,

3H), 6.77 (m, 1H), 6.69 (m, 3H), 6.67 (s, 1H), 6.16 (m, 1H), 5.69 (d, J = 7.5 Hz, 1H),

13 4.19-4.05 (m, 2H), 3.90 (s, 3H), 3.75 (s, 3H), 1.15 (m, 3H); C NMR (125 MHz, CDCl3)

δ 169.5, 150.1, 144.1, 143.0, 142.1, 139.5, 132.6, 119.5, 114.7, 111.0, 110.2, 79.0, 64.1,

62.0, 53.9, 53.1, 14.5; LRMS (electrospray): 422, 400, 354, 232, 228, 149, 123; Mass

+ calcd for C21H21NO7 [M] , 399.39. Found 400.

CO2Et Analytical data for II-22: Rf = 0.25 (50% Et2O/hexanes); mp =

CO Me N 2 138-140 °C; IR (film) 3055, 2987, 1740, 1437, 1438, 1422, 1265,

CO2Me -1 1 896, 740, 705 cm ; H NMR (500 MHz, CDCl3) δ 7.38-7.25 (m,

MeO 5H), 7.11 (m, 1H), 7.06 (m, 2H), 5.99 (d, J = 6.8 Hz, 1H), 5.74

(d, J = 6.8 Hz, 1H), 4.22-4.11 (m, 2H), 3.82 (s, 3H), 3.62 (s, 3H), 1.15 (s, 3H); 13C NMR

(100 MHz, CDCl3) δ 169.8, 163.0, 162.4, 143.9, 142.2, 137.7, 131.1, 129.4, 129.2, 128.9,

127.5, 123.6, 116.5, 115.2, 71.3, 69.9, 62.2, 52.9, 52.7, 14.4 LRMS (electrospray): 462,

+ 440, 213, 182, 130, 128; Mass calcd for C24H25NO7 [M] , 439.46. Found 440.

Analytical data for II-23: Rf = 0.26 (50% Et2O/hexanes); IR CO2Et

CO Me N 2 (film) 3054, 2988, 1740, 1497, 1437, 1421, 1265, 908, 735, 650

-1 1 CO2Me cm ; H NMR (500 MHz, CDCl3) δ 7.25-718 (m, 3H), 7.15 (m,

1H), 6.90 (m, 2H), 6.80 (m, 1H), 6.75 (m, 1H), 6.58 (m, 2H), OMe 6.00 (d, J = 5.8 Hz, 1H), 5.81 (d, J = 5.8 Hz, 1H), 4.26-4.09 (m, 2H), 3.85 (s, 3H), 3.77

13 (s, 3H), 3.68 (s, 3H), 1.10 (m, 3H); C NMR (125 MHz, CDCl3) δ 169.9, 163.2, 162.4,

144.5, 144.3, 140.8, 130.9, 129.8, 129.2, 119.9, 118.5, 14.2, 114.1, 113.8, 71.2, 69.9, 74 61.9, 55.4, 52.8, 52.6, 14.3. LRMS (electrospray): 462, 440. 316, 212, 149, 135, 123,

+ 121, 119; Mass calcd for C24H25NO7 [M] , 439.46. Found 440.

CO2Et Analytical data for II-24: Rf = 0.30 (50% Et2O/hexanes); mp =

CO2Me N 107-108°C; IR (film) 2933, 2856, 1736, 1601, 1501, 909 cm-1; 1H

CO2Me NMR (500 MHz, CDCl3) δ 7.25 (m, 2H), 6.79 (m, 1H), 6.68 (m,

2H), 5.50 (d, J = 7.4 Hz, 1H), 5.33 (d, J = 7.4 Hz, 1H), 4.10-3.95 (m, 2H), 3.90 (s, 3H),

3.81 (s, 3H), 2.00 (m, 1H), 1.80-1.45 (m, 6H), 1.25 (m, 7H); 13C NMR (125 MHz,

CDCl3) δ 169.1, 165.5, 162.1, 144.6, 131.5, 131.4, 71.8, 70.3, 61.7, 52.7, 52.6, 39.8, 29.4,

27.1, 26.6, 26.4, 14.2. LRMS (electrospray): 438, 417, 416, 260, 228, 186; Mass calcd for

+ C23H29NO6 [M] , 415.48. Found 416.

CO Et 2 Analytical data for II-25: Rf = 0.27 (40% Et2O/hexanes); IR (film) Ph CO Et N 2 2984, 2918, 2850, 1727, 1629, 1602, 1503, 1300, 1266, 1030 cm-1; 1H

Ph CO2Et NMR (500 MHz, CDCl3) δ 7.27−7.04 (m, 14H), 6.69-6.60 (m, 4H),

6.46 (m, 2H), 5.38 (d, J = 4.0 Hz, 1H), 5.30 (m, 2H), 5.25, (d, J = 9.1 Hz, 1H), 4.28-3.96

(m, 12H), 3.82 (m, 2H), 3.73 (m, 1H), 3.52 (m, 1H), 1.40-0.96 (b, m, 18H); 13C NMR

(125 MHz, CDCl3) δ 172.3, 170.6, 164.1, 161.8, 152.0, 148.7, 145.4, 142.9, 142.3, 129.5,

129.5, 129.3, 129.0 128.9, 128.2, 127.5, 127.3, 126.2, 125.5, 121.3, 118.4, 118.1, 115.2,

113.5, 112.7, 69.0, 67.0, 64.4, 64.0, 62.8, 61.8, 61.5, 61.2, 55.8, 48.8, 46.6, 16.3, 14.4,

14.4, 14.2, 14.2, 14.1; LRMS (electrospray): 440, 290, 288, 182, 104 Mass calcd for

+ C25H29NO6 [M] , 439.50. Found 440.

75 CO2Et Analytical data for II-26: Rf = 0.37 (40% Et2O/hexanes); IR (film)

Ph CO2Me N 2984, 2919, 2850, 1727, 1629, 1601, 1503 cm-1; 1H NMR (500 MHz,

Ph CO2Me CDCl3) δ 7.45−7.25 (b, m 8H), 7.22-7.14 (m, 6H), 6.85-6.71 (m, 4H),

6.61-6.49 (m, 2H), 5.39 (d, J = 2.5 Hz, 1H), 5.32 (d, J = 2.5 Hz, 1H), 5.28 (m, 1H), 5.05

(m, 1H), 4.35-4.28 (m, 3H), 4.26-4.17 (m, 5H), 4.11- 4.04 (m, 3H), 3.85-3.72 (m, 6H),

13 3.66 (m, 2H), 3.40 (m, 1H), 1.36-1.05 (m, 6H); C NMR (125 MHz, CDCl3)

δ 178.4, 178.2, 172.0, 171.5, 162.1, 162.1, 159.1, 151.3, 130.0, 129.8, 129.6, 129.4, 129.1

, 129.0127.6, 127.4, 126.4, 126.2, 124.2, 123.4, 121.2, 118.6, 115.3, 112.8, 65.7, 64.4, 61.

6, 61.3, 58.8, 55.6, 53.8, 53.1, 48.6, 29.9, 14.4, 14.3; LRMS (electrospray): 434, 412,

+ 391, 359, 306, 286, 260, 232, 199, 164; Mass calcd for C23H25NO6 [M] , 411.45. Found

412.

CO2Et Analytical data for II-27: Rf = 0.25 (33% Et2O/hexanes); IR (film)

Ph CN N 3100, 2950, 2254, 1741, 1601, 1503, 1203, 908, 734 cm-1; 1H NMR

Ph CN (500 MHz, CDCl3) δ

7.45−7.27 (m, 6Η), 7.26−7.18 (m, 4Η), 7.15−7.04 (m, 4Η), 6.82 (m, 4H), 6.68 (m, 2H),

5.35 (d, J = 8.6 Hz, 1H), 5.18 (d, J = 6.4 Hz, 1H), 5.12 (d, J = 4.1 Hz, 1H), 4.96 (d, J =

8.4 Hz, 1H), 4.36 (m, 3H), 4.13 (m, 2H), 3.87 (m, 1H), 3.73 (m, 1H), 3.41 (m, 1H), 1.38-

13 1.35 (m, 3H), 1.09-1.05 (m, 3H); C NMR (125 MHz, CDCl3)

δ 169.1, 169.0, 138.0, 136.5, 129.8, 129.7, 129.6, 129.2, 129.2, 126.8, 126.4, 121.4, 119.6

, 117.9, 117.3, 117.0, 116.9, 116.1, 114.8, 113.6, 94.4, 94.4, 67.1, 67.0, 63.2, 63.2, 62.7,

62.1, 42.4, 38.6, 35.0, 33.8, 14.5, 14.1; LRMS (electrospray): 346, 272, 196; Mass calcd

+ for C21H19N3O2 [M] , 345.39. Found 346. 76

CO2Et Analytical data for II-28: Rf = 0.15 (50% Et2O/hexanes); IR (film) O Ph N -1 1 cm ; H NMR (500 MHz, CDCl3) δ 7.28−7.24 (m, 4H), 7.11 (m, N CH3 Ph O 2H), 6.77 (m, 2H), 6.65 (m, 2H), 5.41, (d, J = 4.5 Hz, 1H), 5.20 (d,

J = 10.3 Hz, 1H), 4.07 (m, 2H), 3.98 (dd, J = 10.3, 4.5 Hz, 1H), 3.42 (dd, = 4.1, 9.3

13 Hz1H), 3.05-3.00 (s, 3H), 1.12 (m, 3H); C NMR (125 MHz, CDCl3)

δ 177.2, 175.2, 171.0, 144.9, 141.8, 129.4, 129.2, 127.9, 126.3, 120.1, 11

CO Et 2 7.1, 65.3, 65.0, 61.9, 54.6, 46.6, 25.5, 14.2; LRMS (electrospray): 401, Ph Ph N + 379, 305, 182, 149; Mass calcd for C22H22N2O4 [M] , 378.42, Found Ph COPh 379.

Analytical data for II-29: Rf = 0.61 (40% Et2O/hexanes); IR (film) 2984, 2919, 2850,

-1 1 1726, 1695, 1627, 1602 cm ; H NMR (500 MHz, CDCl3) δ 7.41−6.95 (m, 16H), 6.72

(m, 2H), 6.44 (m, 2H), 4.74 (d, J = 1H), 4.30-4.05 (m, 3H), 3.52-3.47 (dd, J = 13.1 Hz, J

= 9.0 Hz, 1H), 3.24-3.21 (dd, J = 13.1 Hz, J = 9.0 Hz, 1H), 1.12 (m, 3H); 13C NMR (125

MHz, CDCl3)

δ 207.1, 171.2, 146.2, 144.7, 140.8, 140.5, 131.5, 131.4, 129.1, 128.9, 128.7, 128.6, 128.5

, 127.1, 126.7, 126.2, 119.5, 115.1, 86.5, 82.3, 62.6, 6.4, 54.2, 14.4; Mass calcd for

+ C32H29NO3 [M] , 475.58. Found 476

CO2Et Analytical data for II-30: Rf = 0.35 (45% Et2O/hexanes); IR (film) O Ph N 2921, 2850, 1718, 1687, 1639, 1278, 1179, 1030 cm-1; 1H NMR (400 O Ph O 77

MHz, CDCl3) δ 7.41−7.22 (µ, 5Η), 7.15−7.08. m, 2H), 6.81-6.74 (m, 2H), 6.65 (m,

1H), 5.52 (dd, J1 = 6.5 Hz, 6.8 Hz, 1H), 5.45 (d, J = 6.1 Hz, 1H), 4.21-3.98 (m, 3H), 3.60,

13 (m, 1H), 1.12 (s, 3H); C NMR (100 MHz, CDCl3)

δ 175.2, 173.8, 137.6, 131.5, 129.2, 129.2, 128.8, 128.6, 126.0, 92.7, 74.4, 65.7, 64.5, 61.

8, 49.9, 49.6, 14.4; LRMS (electrospray): 388, 366, 288, 182, 104 Mass calcd for

+ C21H19NO5 [M] , 365.38. Found 366.

CO Et 2 Analytical data for II-31: Rf = 0.31 (45% Et2O/hexanes); IR (film) Ph N 2989, 2919, 2850, 1726, 1630, 1602, 1504 cm-1; 1H NMR (400 MHz,

Ph CO2Et CDCl3) δ 7.29−7.21 (m, 4H), 7.17-7.07 (m, 4H), 6.64-6.54 (m, 2H), 5.27

(d, J = 9.1 Hz, 1H), 4.73 (d, J = 8.6 Hz, 1 H), 3.85 (m, 1H), 3.81-3.65 (m, 4H), 2.96-2.84

(ddd, J = 13.4 Hz, 13.4 Hz, 9.2 Hz, 1H), 2.21-2.18 (dd, J1 = 12.8 Hz, 6.1 Hz, 1H), 1.22-

13 1.10 (m, 6H); C NMR (100 MHz CDCl3),

δ 139.3, 138.3, 129.1, 128.6, 128.0, 127.3, 117.4, 114.1, 113.6, 113.1, 61.5, 56.9, 39.6, 30

+ .4, 30.1, 14.5, 14.2; LRMS (electrospray): Mass calcd for C22H25NO4 [M] , 367.44.

Found 368.

2.7. Multi-Component Assembly Reaction for the Synthesis of Spiro- pyrrolidinyloxindoles

2.7.1. General Experimental Procedure B: MCAR for the Synthesis of Spiro- pyrrolidinyloxindoles: 78 To a solution of imine (1.3 mmol) dipolarophile (0.41 mmol) and catalyst (0.04-

0.08 mmol) in CH2Cl2 (3.0 mL) heated at reflux was added a solution of a diazo ester (1.3 mmol) in CH2Cl2 (4.5 mL) via syringe pump over 3 h. After complete addition, the reaction was heated for an additional 1-2 hours, cooled to 23 ºC and then filtered through a pad of silica gel using CH2Cl2 (50 mL). The solvent was removed and diastereoselectivities were assigned by analysis of 1H NMR spectra (500 MHz) and correlated with GC integrations. The reaction mixture was purified by flash column chromatography (mixtures of ether/hexanes or EtOAc/hexanes as eluent), usually by dry loading the sample, to afford the desired cycloaddition product.

2.7.2. Characterization Data for Spirooxindoles II-33 to II-44

Analytical data for II-33a: Purified with 40% ether/hexanes, yielding

N 181 mg (79%) of II-33a as a light brown oil. Rf = 0.26 (40:60 CO2Et -1 1 N CO2Me ether/hexanes); IR (film) 2980, 1742, 1716, 1606 cm ; H NMR (500 O Ph MHz, CDCl3) δ 7.37-6.34 (m, 19H); 5.62-5.60 (m, 2H); 4.98-4.76 (m,

2H); 4.23-4.21 (d, J = 7.9, 1H); 4.21-4.02 (m, 2H); 3.18 (s, 3H); 0.99-0.95 (m, 3H); 13C

NMR (125 MHz, CDCl3) δ 172.5, 169.9, 169.0, 163.2, 162.5, 145.5, 144.2, 143.8, 142.7,

138.1, 135.7, 134.6, 129.3, 129.1, 128.8, 128.6, 127.8, 127.6, 127.5, 122.4, 120.4, 119.2,

118.6, 114.0, 71.3, 70.0, 62.1, 52.8, 52.6, 44.5, 14.7; Mass calculated for C35H36N2O5,

560.6. Found: 561.7 [M+H]+, 583.8 [M+Na]+, 1144.2 [(2M)+Na]+.

79 Analytical data for II-33b: Purified with 40% ether/hexanes, yielding

N 178 mg (74%) of II-33b as a white solid (m. p. 100-102 C). R = CO2t-Bu ° f

N CO2Me O 0.32 (40/60 ether/hexanes); IR (film) 2977, 2947, 2906, 1739, 1719, Ph -1 1 1605 cm ; H NMR (500 MHz, CDCl3) δ 7.39-6.38 (m, 19H); 5.47-5.41 (b, m, 2H);

4.98-4.72 (m, 2H); 4.19-4.17 (d, J = 7.9, 1H); 3.18 (s, 3H); 1.19 (s, 9H); 13C NMR (125

MHz, CDCl3) δ 175.4, 171.5, 169.1, 142.7, 135.7, 134.8, 128.8, 128.6, 127.8, 127.7,

127.6, 126.5, 126.0, 122.3, 120.3, 119.4, 108.8, 82.3, 71.7, 66.7, 61.6, 53.9, 52.2, 44.2,

27.8; LRMS (electrospray): Mass calculated for C37H36N2O5, 588.7. Found: 589.6

[M+H]+, 611.6 [M+Na]+, 1200.2 [(2M)+Na]+.

H3C Analytical data for II-34: Purified with 40% ether/hexanes, yielding

N 169 mg (72%) of II-34 as a waxy solid. R = 0.27 (40/60 CO2Et f

N CO2Me O ether/hexanes); IR (film) 2953, 2950, 2946, 1742, 1716, 1606 cm-1; Ph 1 H NMR (500 MHz, CDCl3) δ 7.43-6.39 (m, 18H); 5.61-5.59 (d, J = 7.9 Hz, 1H); 5.54 (s,

1H); 4.91-4.81 (m, 2H); 4.23-4.21 (d, J = 7.9, 1H); 4.13-3.97 (m, 2H); 3.18 (s, 3H); 0.95-

13 0.91 (m, 3H); C NMR (125 MHz, CDCl3) δ 175.3, 172.4, 169.0, 145.6, 142.8, 137.2,

135.7, 131.6, 128.8, 128.7, 128.6, 128.5, 127.7, 127.6, 127.5, 126.5, 125.9, 122.3, 120.3,

119.3, 108.9, 71.6, 65.6, 61.6, 61.5, 53.9, 52.2, 44.1, 21.3, 14.1; LRMS (electrospray):

+ + Mass calculated for C36H34N2O5, 575.7. Found 575.7 [M] , 576.7 [M+H] .

Cl Analytical data for II-35: Purified with 40% ether/hexanes, yielding

N 157 mg (60%) of II-35 as a waxy white solid. R = 0.26 (40/60 CO2Et f

N CO2Me O Ph 80 ether/hexanes); IR (film) 2950, 2942, 2936, 2910, 1742, 1716, 1609 cm-1; 1H NMR

(500 MHz, CDCl3) δ 7.39-6.40 (m, 18H); 5.61-5.59 (d, J = 7.9 Hz, 1H); 5.50 (s, 1H);

4.93-4.76 (m, 2H); 4.22-4.20 (d, J = 7.9, 1H); 4.10-3.95 (m, 2H); 3.18 (s, 3H); 0.94-0.92

13 (m, 3H); C NMR (125 MHz, CDCl3) δ 174.9, 172.3, 168.8, 145.2, 142.8, 135.6, 133.4,

133.4, 129.2, 129.0, 128.9, 128.7, 128.0, 127.9, 127.6, 126.0, 125.8, 122.5, 120.8, 119.3,

109.2, 71.1, 65.6, 61.6, 61.4, 53.8, 52.3, 44.2, 14.1; LRMS (electrospray): Mass

+ + calculated for C35H31ClN2O5, 595.1. Found: 596.7 [M+H] , 618.9 [M+Na] , 1213.3

[(2M)+Na]+.

Br Analytical data for II-36: Purified with 40% ether/hexanes, yielding

N 144 mg (55%) of II-36 as an off-white solid (m.p. 95-96 C). R = CO2Et ° f

N CO2Me O 0.20 (33/67 ether/hexanes); IR (film) 2953, 2950, 2946, 2933, 2890, Ph -1 1 1742, 1716, 1609, 1590 cm ; H NMR (500 MHz, CDCl3) δ 7.41-6.46 (m, 18H); 5.61-

5.59 (d, J = 7.9 Hz, 1H); 5.51 (s, 1H); 4.94-4.80 (m, 2H); 4.25-4.22 (d, J = 7.9, 1H);

13 4.09-3.97 (m, 2H); 3.18 (s, 3H); 0.98-0.94 (m, 3H); C NMR (125 MHz, CDCl3) δ

175.0, 172.2, 168.8, 145.1, 142.8, 135.5, 133.9, 131.0, 129.3, 129.2, 127.9, 128.7, 127.9,

127.6, 125.9, 125.8, 122.5, 121.7, 120.8, 119.3, 109.2, 71.1, 65.6, 61.6, 61.3, 53.8, 52.3,

44.2, 14.1; LRMS (electrospray): Mass calculated for C35H31BrN2O5, 639.6. Found:

640.8 [M+H]+, 662.8 [M+Na]+, 1301.5 [(2M)+Na]+.

H3CO Analytical data for II-37: Purified with 40% ether/hexanes, yielding

N 111 mg (46%) of II-37 as a colorless oil. R = 0.27 (50/50 CO2Et f

N CO2Me O Ph 81 ether/hexanes); IR (film) 2953, 2950, 2933, 1741, 1716, 1605 cm-1; 1H NMR (500

MHz, CDCl3) δ 7.40-6.38 (m, 18H); 6.13 (s, 1H); 5.62-5.59 (d, J = 7.9 Hz 1H); 5.00-4.81

(m, 2H); 4.37-4.33 (d, J = 7.9, 1H); 4.22-3.99 (m, 2H); 3.82 (s, 3H); 3.20 (s, 3H); 1.01-

13 0.98 (s, 3H); C NMR (125 MHz, CDCl3) δ 175.1, 172.8, 159.0, 145.9, 142.2, 135.7,

129.1, 129.0, 128.9, 128.7, 128.0, 127.9, 127.8, 127.6, 126.4, 126.0, 122.1, 120.6, 119.1,

113.3, 109.2, 71.1, 65.6, 61.6, 61.5, 55.4, 52.1, 44.3, 14.0; LRMS (electrospray): Mass

+ calculated for C36H33N2O6 590.7. Found: 591.6 [M+H] .

Cl Analytical data for II-38: Purified with 35% ether/hexanes, yielding

N 130 mg (53%) of II-38 as an off-white solid (m.p. 151-153 C). Rf = CO2Et °

N CO2Me O 0.15 (30/70 ether/hexanes); IR (film) 2970, 2940, 2921, 2901, 1739, Ph -1 1 1710, 1605 cm ; H NMR (500 MHz, CDCl3) δ 7.40-6.39 (m, 18H); 6.13 (s, 1H); 5.62-

5.59 (d, J = 7.9 Hz 1H); 5.00-4.81 (m, 2H); 4.37-4.33 (d, J = 7.9, 1H); 4.22-3.99 (m,

13 2H); 3.16 (s, 3H); 1.01-0.98 (s, 3H); C NMR (125 MHz, CDCl3) δ 175.0, 172.3, 169.1,

145.1, 143.1, 135.8, 133.3, 129.5, 129.3, 128.8, 127.7, 127.5, 126.4, 125.7, 121.8, 120.6,

119.0, 109.0, 67.0, 65.6, 62.1, 62.0, 61.6, 54.2, 53.0, 52.2, 52.3, 44.4, 14.3; LRMS

+ (electrospray): Mass calculated for C35H31ClN2O5, 595.1. Found: 595.8 [M] , 618.8

[M+Na]+, 1213.2 [(2M)+Na]+.

Analytical data for II-39: Purified with 40% ether/hexanes, yielding

S N 100 mg (43%) of II-39 as a powdery off-white solid (m.p. 195-198 °C). CO2Et

N CO2Me Rf = 0.22 (40/60 ether/hexanes); IR (film) 2954, 2923, 1741, 1717, O

Ph -1 1 1601 cm ; H NMR (500 MHz, CDCl3) δ 7.40-6.38 (m, 18H); 5.60-

5.58 (d, J = 7.9 Hz, 1H); 5.52 (s, 1H); 4.94-4.76 (m, 2H); 4.23-4.22 (d, J = 7.9, 1H); 82 13 4.14-4.02 (m, 2H); 3.18 (s, 3H); 1.04-1.01 (m, 3H); C NMR (125 MHz, CDCl3) δ

174.8, 172.1, 168.9, 145.4, 143.1, 138.2, 135.6, 129.2, 128.9, 128.6, 127.8, 127.4, 126.7,

126.4, 126.1, 125.9, 125.6, 122.6, 121.1, 119.6, 109.1, 68.2, 65.6, 61.6, 61.4, 53.6, 52.3,

44.2, 14.1; LRMS (electrospray): Mass calculated for C35H31ClN2O5, 566.7. Found:

568.6 [M+H]+.

Cl Analytical data for II-40: Purified with 40% ether/hexanes, yielding

122 mg (50%) of II-40 as a powdery off-white solid (m.p. 189-193 °C). N CO2Et Rf = 0.24 (40/60 ether/hexanes); IR (film) 2955, 2931, 2926, 2890, N CO2Me O -1 1 Ph 1742, 1716, 1608 cm ; H NMR (500 MHz, CDCl3) δ 7.40-6.38 (m,

18H); 5.60-5.58 (d, J = 7.9 Hz, 1H); 5.52 (s, 1H); 4.94-4.76 (m, 2H); 4.23-4.22 (d, J =

7.9, 1H); 4.14-4.02 (m, 2H); 3.18 (s, 3H); 1.04-1.01 (m, 3H); 13C NMR (125 MHz,

CDCl3) δ 175.0, 172.1, 168.8, 144.2, 142.8, 135.6, 134.2, 129.0, 128.8, 128.6, 127.9,

127.8, 127.6, 127.5, 126.1, 125.8, 125.5, 122.4, 120.3, 109.0, 71.8, 65.6, 61.7, 61.5, 53.9,

52.3, 44.2, 14.3; LRMS (electrospray): Mass calculated for C35H31ClN2O5, 595.1. Found:

595.8 [M]+, 618.8 [M+Na]+, 1213.2 [(2M)+Na]+.

F Analytical data for II-41: Purified with 40% ether/hexanes, yielding

N 97 mg (41%) of II-41 as a colourless oil. Rf = 0.26 (40/60 CO2Et

N CO2Me -1 1 O ether/hexanes); IR (film) 2946, 2921, 1743, 1717, 1606, 1603 cm ; H Ph

NMR (500 MHz, CDCl3) δ 7.36-6.38 (m, 18H); 5.59-5.57 (d, J = 7.9 Hz, 1H); 5.50 (s,

1H); 4.94-4.75 (m, 2H); 4.23-4.22 (d, J = 7.9, 1H); 4.17-4.06 (m, 2H); 3.17 (s, 3H); 1.02-

13 1.01 (m, 3H); C NMR (125 MHz, CDCl3) δ 175.0, 172.1, 168.7, 135.6, 134.2, 129.8, 83 129.7, 129.0, 128.8, 128.0, 127.8, 127.6, 126.1, 125.8, 122.4, 114.6, 109.2, 109.0,

107.2, 107.0, 106.3, 106.1, 71.8, 65.6, 61.7, 53.9, 52.3, 44.2, 14.3; LRMS (electrospray):

+ + Mass calculated for C35H31FN2O5, 578.6. Found: 601.3 [M+Na] , 1180.2 [(2M)+Na] .

Analytical data for II-42: Purified with 40% ether/hexanes, yielding

N 137 mg (69%) of II-42 as a light yellow oil. Rf = 0.11 (40/60 CO2Et -1 1 CO2Me N O ether/hexanes); IR (film) 2930, 2923, 1741, 1719, 1606 cm ; H NMR H3C

(500 MHz, CDCl3) δ 7.40-7.41 (m, 14H); 5.61-5.60 (d, J = 7.9 Hz,

1H); 5.49 (s, 1H); 4.19-4.17 (d, J = 7.9 Hz, 1H); 4.13-3.99 (m, 2H); Cl N CO2Et 3.28 (s, 3H); 3.12 (s, 3H); 0.93-0.96 (m, 3H); 13C NMR (125 MHz, N CO2Me O Ph CDCl3) δ 175.0, 172.5, 169.0, 145.5, 143.5, 134.7, 128.9, 128.6,

127.6, 127.5, 127.3, 126.3, 125.7, 122.3, 120.3, 119.1, 151.2, 71.5, 65.7, 61.7, 61.5, 53.6,

52.4, 26.7, 13.9; LRMS (electrospray): Mass calculated for C29H28N2O5 484.5. Found

485.6 [M+H]+.

Analytical data for II-43: Purified with 40% ether/hexanes, yielding 136 mg (56%) of

II-43 as a viscous yellow oil. Rf = 0.45 (40:60 ether/hexanes); IR (film) 2921, 1747,

-1 1 1726, 1725, 1588 cm ; H NMR (500 MHz, CDCl3) δ 7.89-6.68 (m, 14H); 5.58-5.57 (d,

J = 7.9 Hz 1H); 5.53 (s, 1H); 4.22-4.20 (d, J = 7.9 Hz, 1H); 4.13-4.02 (m, 2H); 3.30 (s,

13 3H); 2.74 (s, 3H); 0.99-0.96 (m, 3H); C NMR (125 MHz, CDCl3) δ 176.7, 172.3, 170.5,

168.6, 145.1, 139.0, 134.2, 129.3, 128.7, 128.2, 128.0, 127.7, 127.1, 126.7, 125.4, 125.2,

124.9, 120.9, 120.0, 119.4, 119.2, 116.1, 72.5, 65.4, 62.2, 62.0, 61.7, 62.7, 52.7, 27.0, 84 14.1; LRMS (electrospray): Mass calculated for C30H27ClN2O6 546.9. Found: 547.8

[M+H]+, 1116.9 [(2M)+Na]+

Analytical data for II-44: Purified with 25% EtOAc/hexanes,

Cl yielding 207 mg (84%) of II-44 as a white solid. Rf = 0.24 (25:75 N CO2Et EtOAc/hexanes); IR (film) 3054, 2985, 1742, 1710, 1598 cm-1; 1H CO2Me N O O CH 3 NMR (500 MHz, CDCl3) δ 7.40-6.34 (m, 18H); 5.59-5.58 (d, J = 7.9

Hz, 1H); 5.56 (s, 1H); 4.94-4.75 (m, 2H); 4.24-4.25 (d, J = 7.9, 1H); 4.14-3.98 (m, 2H);

13 3.28 (s, 3H); 1.01-0.97 (m, 3H); C NMR (125 MHz, CDCl3) δ 174.8, 172.3, 168.7,

145.2, 141.4, 135.2, 134.3, 129.5, 129.0, 128.9, 128.8, 128.7, 128.2, 128.0, 127.9, 127.7,

127.5, 126.0, 120.8, 119.4, 118.8, 115.3, 109.8, 71.6, 65.5, 61.6, 53.8, 52.5, 44.3, 14.1;

+ LRMS (electrospray): Mass calculated for C35H31ClN2O5, 595.1. Found: 595.8 [M] ,

618.8 [M+Na]+, 1213.2 [(2M)+Na]+.

2.8. Multi-Component Assembly Reaction for the Synthesis of Pyrroles

2.8.1. General Experimental Procedure C: MCAR for the Synthesis of Pyrroles:

To a flame-dried two-necked round bottom flask fitted with a reflux condenser containing a magnetic stirring bar was added catalyst, imine and acetylene diester in

CH2Cl2 (3 mL). The mixture was heated to a gentle reflux and the diazoacetonitrile solution was added via syringe pump (1.5 mL per hour). After complete addition, the mixture was heated for a further 1-12 hours and then allowed to cool to 23 ºC. The crude 85 reaction mixture was filtered through a silica plug with CH2Cl2 (50 mL). The solvent was evaporated, and purification by flash chromatography on silica gel provided the title compounds as described below.

2.8.2. Characterization Data for Pyrroles II-47 to II-54

Ph CO Me N 2 Analytical data for dimethyl 1,2-diphenyl-1H-pyrrole-3,4-

Ph CO2Me dicarboxylate II-47: Purified by flash column chromatography using gradient elution mixtures of EtOAc/toluene (6-12%) afforded 94 mg (71%) of II-47 as a

-1 viscous white foam. Rf 0.24 (3:1 EtOAc/hexanes); IR (film) cm 2947.9, 2860.2, 1722.7,

1 1560.1; H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.36-7.08 (m, 10H), 3.84 (s, 3H),

13 3.77 (s, 3H); C NMR (125 MHz, CDCl3) δ 165.5, 163.6, 138.7, 135.1, 130.4, 129.9,

129.0, 128.1, 127.9, 127.7, 125.9, 117.0, 115.7; LRMS (electrospray): Exact mass calcd

+ for C20H17NO4 [M] , 335.12. Found [M+H], 336.5. See: Katritzky, A. R.; Yao, J.; Bao,

W.; Qi, M.; Steel, P. J. J. Org. Chem. 1999, 64, 346-350.

Analytical data for dimethyl 1-(4-iodophenyl)-2-phenyl-1H- I CO Me N 2 pyrrole-3,4-dicarboxylate II-48: Purified by medium pressure

Ph CO2Me liquid chromatography EtOAc/toluene (1:9) afforded 111 mg

-1 (61%) of II-48 as a waxy solid. Rf 0.27 (3:1 EtOAc/hexanes); IR (film) cm 3130.7,

3001.3, 2947.5, 1722.8; 1H NMR (400 MHz, acetone-d6) δ 7.62-7.60 (d, 2H), 7.44 (s,

1H), 7.28-7.07 (m, 5H), 6.79-6.81 (m, 2H) 3.85 (s, 3H), 3.75 (s, 3H); 13C NMR, (125

MHz CDCl3)

165.1, 163.0, 138.8, 135.1, 130.0, 129.9, 129.1, 128.1, 127.9, 127.7, 126.0, 117.1, 115.7, 86 + 51.4, 51.3; LRMS (electrospray): Exact mass calcd for C20H16NIO4 [M] , 461.01.

Found [M+H], 462.3.

H3C Analytical data for dimethyl 1-(3-methylphenyl)-2-phenyl-1H-

CO Me pyrrole-3,4-dicarboxylate II-49: Purified by medium pressure N 2 liquid chromatography using gradient elution mixtures of Ph CO2Me

EtOAc/toluene (4-8%) afforded 88 mg (63%) of II-49 as a viscous white foam. Rf 0.25

(3:1 EtOAc/hexanes); IR (film) cm-1 2935.4, 2858.9, 1721.3; 1H NMR (500 MHz,

CDCl3) δ 7.47 (s, 1H), 7.26-7.08 (m, 7H), 6.92 (s, 1H), 6.79-6.81 (m, 1H), 3.85 (s, 3H),

3.75 (s, 3H), 2.78, (s, 3H); 13C NMR (100 MHz, acetone-d6)

δ 166.3, 164.3, 139.6, 138.7, 135.6, 130.6, 130.2, 129.9, 129.1, 128.9, 128.4, 128.2, 126.6

, 123.2, 115.5, 52.3, 51.8, 21.5; LRMS (electrospray): Exact mass calcd for C21H18NO4

[M]+, 349.13. Found [M+H], 350.5.

Ph CO Me Analytical data for dimethyl 1-phenyl-2-p-tolyl-1H-pyrrole-3,4- N 2 dicarboxylate II-50: Purified by flash column chromatography CO2Me using gradient elution mixtures of EtOAc/toluene (5-15%) H3C -1 afforded 92 mg (66%) of II-50 as an oil. Rf 0.25 (3:1 EtOAc/hexanes); IR (film) cm

1 2935.4, 2858.9, 1721.3; H NMR (500 MHz, CDCl3) δ 7.48 (s, 1H), 7.32-7.04 (m, 9H),

13 3.86 (s, 3H), 3.78 (s, 3H), 2.31 (s, 3H); C NMR (125 MHz, CDCl3)

δ 166.4, 164.3, 138.9, 138.4, 135.9, 130.4, 129.8, 129.4, 128.9, 128.1, 127.0, 126.1, 115.5

+ , 52.4, 51.8, 21.6; LRMS (electrospray): Exact mass calcd for C21H18NO4 [M] , 349.13.

Found [M+H], 350.4. 87

Ph CO Me N 2 Analytical data for dimethyl 2-(4-bromophenyl)-1-phenyl-1H-

CO2Me pyrrole-3,4-dicarboxylate II-51: Purified by flash column

chromatography using gradient elution mixtures of EtOAc/toluene Br

(5-15%) afforded 98 mg (59%) of II-51 as a viscous white foam. Rf 0.27 (3:1

EtOAc/hexanes); IR (film) cm-1 2922.6, 2852.9, 1722.5, 1597.0, 1499.5; 1H NMR (500

13 MHz, CDCl3) δ 7.43 (s, 1H), 7.30-7.04 (m, 9H), 3.82 (s, 3H), 3.76 (s, 3H); C NMR

(100 MHz, acetone-d6) δ 166.2, 164.1, 138.5, 135.1, 132.2, 131.9, 129.7, 128.7, 128.1,

127.9, 127.7, 122.9, 117.1, 115.7, 52.4, 51.9; LRMS (electrospray): Exact mass calcd for

+ C18H26O2 [M] , 413.29. Found [M+H], 414.5.

Analytical data for dimethyl 2-(4-chlorophenyl)-1-phenyl-1H- Ph CO Me N 2 pyrrole-3,4-dicarboxylate II-52: Purified by flash column CO2Me chromatography using EtOAc/pentanes (10%) afforded 78 mg Cl (53%) of II-52 as a viscous white viscous foam. Rf 0.27 (3:1

EtOAc/hexanes); IR (film) cm-1 3004.1, 2955.0, 1722.0, 1507.8; 1H NMR (500 MHz,

13 CDCl3) δ 7.47 (s, 1H), 7.30-7.04 (m, 9H), 3.82 (s, 3H), 3.75 (s, 3H); C NMR (125

MHz, CDCl3)

δ 165.4, 163.4, 138.0, 134.2, 133.9, 131.5, 131.4, 129.2, 128.1, 128.0, 127.9, 125.7, 116.8

+ , 115.4 51.4, 51.3; LRMS (electrospray): Exact mass calcd for C20H16NClO4 [M] ,

369.08. Found [M+H], 370.5. See: Katritzky, A. R.; Yao, J.; Bao, W.; Qi, M.; Steel, P. J.

J. Org. Chem. 1999, 64, 346-350.

88 Ph CO Et N 2 Analytical data for diethyl 2-(4-chlorophenyl)-1-phenyl-1H-

CO2Et pyrrole-3,4-dicarboxylate II-53: Purified by flash column

chromatography using gradient elution mixtures of EtOAc/toluene Cl

(4-12%) afforded 87 mg (55%) of II-53 as a white foam. Rf 0.30 (3:1 EtOAc/hexanes);

-1 1 IR (film) cm 3056.7, 2946.0, 1720.9, 1480.2; H NMR (400 MHz, CDCl3) δ 7.51 (s,

1H), 7.32-7.05 (m, 9H), 4.36-4.33 (t, J = 6.9 Hz, 2H), 4.26-4.22 (t, J = 6.9 Hz, 2H), 1.38-

13 1.35 (t, J = 7.2 Hz, 3H), 1.22-1.19 (q, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3)

δ 165.8, 163.0, 138.0, 134.2, 133.9, 131.5, 131.4, 129.2, 128.1, 128.0, 127.9, 125.7,

116.8, 115.4, 60.3, 60.0, 14.3, 13.9; LRMS (electrospray): Exact mass calcd for

+ C20H16NIO4 [M] , 397.11. Found [M+H], 398.4. See: Katritzky, A. R.; Yao, J.; Bao, W.;

Qi, M.; Steel, P. J. J. Org. Chem. 1999, 64, 346-350.

Ph CO Me N 2 Analytical data for dimethyl 2-(3,4-idichlorophenyl)-1-phenyl-

CO2Me 1H-pyrrole-3,4-dicarboxylate II-54: Purified by flash column Cl chromatography using gradient elution mixtures of Cl

EtOAc/toluene (4-12%) afforded 87 mg (55%) of II-54 as a white foam. Rf 0.32 (3:1

EtOAc/hexanes); IR (film) cm-1 3010.2, 2954.0, 1720.9, 1480.2; 1H NMR (400 MHz,

13 CDCl3) δ 7.50 (s, 1H), 7.38-6.99 (m, 9H), 3.87 (s, 3H), 3.81 (s, 3H); C NMR (125

MHz, CDCl3) δ 165.8, 163.0, 138.0, 134.2, 133.9, 131.5, 131.4, 129.2, 128.1, 128.0,

127.9, 125.7, 116.8, 115.4, 60.3, 60.0, 14.3, 13.9; LRMS (electrospray): Exact mass calcd

+ for C20H14NCl2O4 [M] , 403.04. Found [M+H], 404.4.

89

Chapter 3

Umpolung Transformations of Acylsilanes

90 3. Polarity-Reversal or Umpolung Chemistry of Acylsilanes

3.1. Introduction to Acylsilane Chemistry

Acylsilanes are a class of carbonyl compounds characterized by a silyl substituent directly bound to a carbonyl group (Figure 3-1). Structural variation of the acylsilane is possible based on alkyl or aryl substitution on the other side of the carbonyl or different substituents at the silicon atom. First isolated by Brook and coworkers in 1957,268 acylsilanes were initially studied mainly due to their unusual spectral properties.

However, it was only later that acylsilanes were demonstrated to possess their own distinct mode of reactivity.269-271

O O O O

H3C Me Si(SiMe)3 SiMe2Ph SiEt3 Me3Si SiMe3 III-1 III-2 III-3 III-4

O O O O O R

SiMe3 SiMe2Ph Ph Si Ph Si R O R R Br Br

III-5 III-6 III-7 III-8

Figure 3-1. Representative acylsilanes

Over the past 50 years, acylsilanes have been used as aldehyde equivalents,272 since the silyl group can readily undergo protodesilylation after a nucleophilic addition to yield the corresponding product of aldehyde addition. Although the synthesis and chemistry acylsilanes is precedented in a number of synthetic applications,272-293 the chemistry of acylsilanes is dominated by nucleophilic additions that provoke a 1,2-silyl shift from 91 carbon to oxygen, known as the 1,2-Brook rearrangement.270,282,294-307 This rearrangement was first demonstrated by A. G. Brook in 1958 by the addition of various silyllithium species to benzophenone III-9, (Scheme 3-1). Instead of the expected silylcarbinol III-12 derived from the tetrahedral intermediate III-10, the silylated alcohol

III-13 was isolated, presumably formed from protonation of the lithium anion III-11.

The 1,2-Brook rearrangement is the enabling factor allowing acylsilanes to be utilized in

Umpolung or polarity-reversal reactions (Section 4.1), since the formerly electrophilic carbonyl carbon bears a nucleophilic lithium anion.

Scheme 3-1. First observation of 1,2-silyl shift with silyllithium nucleophiles

O O Li OH R3SiLi protonation NOT OBSERVED Ph Ph THF Ph Ph III-10 Ph Ph R3Si R3Si

III-9 1,2-shift III-12

OSiR OSiR 3 Li protonation 3 ISOLATED PRODUCT Ph Ph III-11 Ph Ph H III-13

An alternative strategy for accessing intermediates such as III-11 involves treatment of the acylsilanes with an organolithium reagent, which also furnishes a carbon-based anion. Takeda and co-workers have utilized this to develop an interesting application of substituted acylsilanes such as III-14 with lithium enolates derived from methyl vinylketone III-15 toward the synthesis of 7-membered carbocycles III-16. (Scheme 3-2, eq 1).308 Fleming has used acylsilanes III-18 treated with silyllithium reagents to form

1,1-disilyl carbinol anions, which rearrange to the carbanion III-19 in synthesis after 1,2- 92 Brook rearrangement (Scheme 3-2, eq 2).309 Acylsilane intermediate III-18 can be generated in situ by treating acid chlorides III-17 with two equivalents of the silyllithium reagent. III-19 can then be trapped with electrophiles, and the disilylated products can then undergo further synthetic operations.

Scheme 3-2. Illustrative examples of acylsilane chemistry in synthesis

Takeda O R= alkyl, aryl O O Li formal [4+3] O (1) Me3SiO R Me3Si SiMe3 R

III-14 III-15 III-16 OSiMe3

Fleming

SiMe2Ph SiMe2Ph O O O O Me2PhSiLi Me2PhSiLi E-X (2) R SiMe2Ph R SiMe2Ph R Cl R SiMe2Ph E Li E= alkyl, silyl, stannyl

III-17 III-18 III-19 III-20

In such reactions the nature of the nucleophile (especially the counter cation), reaction temperature and substitution on the silicon atom are all relevant factors that determine the extent to which Brook rearrangement occurs. In the majority of cases though, aryl acylsilanes, reacted with lithium anions predominate as the conditions that favor Brook rearrangement, as the carbanion formed is stabilized by the adjacent aryl rings or an alternative stabilizing group.

Lewis bases are also capable of promoting the 1,2-Brook rearrangement in catalytic fashion (see also Section 4.1). Most notably Mattson, Bharadwaj and Scheidt have reported a nucleophilic acylation reaction,310-313 which utilizes catalytic quantities of N- 93 heterocyclic carbenes (NHCs) to effect the key Brook rearrangement step that forms the acyl anion. Additionally, Johnson and coworkers have employed a metallophosphite catalyst to the asymmetric synthesis of crossed-benzoin products such as III-21 (Scheme

3-3).314,315 In this case, the Lewis base (LB) is first generated by deprotonation and the resulting lithiated metallophosphite undergoes nucleophilic addition to the acyl triethylsilane III-20, forming tetrahedral intermediate III-22. A Brook rearrangement then accounts for the carbanion III-23, which then adds to an aldehyde forming intermediate III-24. Intermediate III-24 undergoes silyl transfer followed by expulsion of the Li-LB to complete the catalytic cycle and furnish silylated benzoin product III-21.

Scheme 3-3. Johnson’s Metallophosphite-catalyzed crossed-benzoin reaction

1.Lewis base (LB), Optimal LB: O 5 mol % & n-BuLi O 5-20 mol % up to 100% 3 Ar3 Ar2 Ar Ar1 SiEt Ar1 conversion, 3 2 O O 2. Ar CHO 90% ee Me O OSiEt3 P H Me O O 3 III-20 III-21 Ar Ar3

LB 5 mol % n-BuLi (2- Et3Si O O O 20 mol %) Li 1,2-Brook Li 1 1 1 Ar SiEt3 Ar SiEt3 Ar LB LB III-23 III-20 III-22 O

Ar2 H

O Et SiO LB 2 Li O LB 3 Ar 2 Ar1 Ar2 Ar Ar1 Ar1 OSiEt 3 OSiEt O 3 Li III-21 III-25 III-24

94 3.2. Reaction of α-Lithio-Diazoacetates with Acylsilanes

Our interest in acylsilane chemistry arose from utilizing unusual nucleophiles with acylsilanes. Lithiated diazoesters were identified as potential nucleophiles that might also lead to aldol-like products. In particular, we were interested in exploiting the diazo group as a handle for further stereoselective elaboration leading to structurally more complex molecules which retained the aldol motif. α-lithio diazo compounds generated by deprotonation with n-butyllithium are known to react readily with aldehydes and ketones.316,317 In the case of diazoacetates, deprotonation is facile and several bases have been used for the deprotonation of diazoacetates including LDA,318,319 sodium hydride,320 potassium hydroxide321 and catalytic DBU.322 Nucleophilic addition of the corresponding organozinc complex to carbonyl compounds has also been reported.323,324 Lewis acid activation of the electrophile has also been used to promote additions of diazo compounds.325,326

We were surprised to discover however, that treatment of a mixture of benzoyl trimethylsilane III-26, (1 equiv) and EDA II-10a (1 equiv) in THF at –78 ºC with a solution of LDA (1.05 equiv) led exclusively to the formation of ethyl benzoylacetate III-

27 after addition of MeOH and work up with saturated ammonium chloride (Scheme 3-

4). The reaction is rapid (complete in ca. 20 minutes at –78 ºC) and no other products are observed.

95 Scheme 3-4. Reaction of lithio-diazoester with benzoyltrimethylsilane

O O 1. LDA, THF, O O H 78 ºC Ph SiMe OEt Ph OEt 3 2. MeOH, then N 2 sat. NH4Cl(aq) III-26 II-10a 99% III-27

Alternative routes to these β-ketoesters involving diazoesters include Roskamp’s tin(II) chloride-catalyzed homologation reaction with aldehydes.327-330 These compounds can also be prepared by a related tin-mediated process, or accessed via a two-step protocol, both of which were reported by Padwa and coworkers in 1990.331,332 In the latter case, the carbinol product derived from addition of the α-lithio diazoester to an aldehyde or ketone undergoes a subsequent rhodium-catalyzed diazodecomposition yields β-ketoesters as products (Scheme 3-5).

Scheme 3-5. Alternative routes to β-ketoesters using diazo compounds

Roskamp:

O O O H CO Et 2 10 mol % SnCl2 R H R OEt N2

Padwa:

O O O H CO2Et 1. LDA R H R OEt N2 2. Rh2(OAc)4

While both of these processes allow efficient access to unsubstituted β-ketoesters, it is not possible to introduce substitution between the carbonyl groups by this method.

Other limitations include the use of toxic stannous chloride and low yields for aryl aldehydes (Roskamp), or require two separate synthetic operations (Padwa). Our 96 working model of the acylsilane-lithiated diazoester reaction involves the following proposed mechanistic pathway (Scheme 3-6). Nucleophilic addition of the α-lithio diazoester to the acylsilane leading to tetrahedral intermediate III-28, at this point a rapid

Brook rearrangement, stabilized by the adjacent diazo group occurs. The loss of nitrogen then generates III-30, an unusual β-silyloxyallenoate intermediate, which is protonated by MeOH (Scheme 3-4). The putative silylenol ether is most likely hydrolyzed to the β- ketoester upon workup.

Scheme 3-6. Proposed mechanism for the β-ketoester formation

O III-26 OLi H CO Et Li CO Et Ph CO R1 2 LDA 2 Ph SiMe3 2 Me3Si N2 N2 N2 II-10a III-28

1,2-Brook

Me Me Me Li Si OSiMe3 OSiMe3 O O O O –N 1 1 H3O 2 CO2R CO2R Ph Ph Ph OEt Ph OEt N N N N III-27 III-30 III-29

Me3SiO OLi OSiMe3 1 C CO2R Ph Ph OR1

!-silyloxy allenolates

Based on this hypothesis, we envisaged the possibility of another multi-component reaction, with the β-silyloxyallenoate intermediate III-30 being utilized to trap other electrophiles in a convergent multi-component approach (Table 3-1).

97 Table 3-1. Multi-component synthesis of β-ketoesters

O O O 1 H CO2R 1. i-Pr2NLi + 1 R SiX R OR 3 2 N2 2. R –X R2

entry R R1 R2–X yield (%) compound 1 Ph Et MeOH 99 III-27 2 CH3 Et BnBr 79 III-31 3 Ph Et MeI 98 III-32 4 Ph Et BnBr 88 III-33

Initial experiments employing simple electrophiles were successful. Quenching with a proton source (entries 1-5) allowed access to both alkyl and aryl β-ketoesters in excellent yields. Monoalkylated β-ketoesters were also readily accessed by employing alkyl halides as electrophiles. In this case the reaction mixture was usually allowed to warm to

23 °C and was stirred for 16 h.

3.3. Reaction of TosMIC with Acylsilanes leading to 5-substituted Oxazoles

In 1972, van Leusen and coworkers reported that 5-substituted oxazoles could be readily prepared by treatment of aromatic aldehydes with p-toluenesulfonyl methylisocyanide (TosMIC) and potassium carbonate in refluxing methanol (Scheme 3-

7).333,334 This versatile reagent has found utility in the synthesis of numerous heterocycles,333-355 and in particular the van Leusen oxazole synthesis has become one of the more important methods for the preparation of oxazoles, finding a wide variety of applications in the scientific literature.356-363

Scheme 3-7. van Leusen oxazole synthesis from the reaction of TosMIC with aldehydes 98 O O K CO S N 2 3 N PhCHO C O MeOH Me ! Ph 91% TosMIC III-34

The accepted mechanism of this reaction is depicted in Scheme 3-8. The pKa of TosMIC is estimated to be 14, and so initial deprotonation by potassium carbonate is invoked as the first step. Nucleophilic addition of the anion III-35 to aldehyde forms a tetrahedral intermediate III-36, the carbinol anion of which is trapped by the nearby isocyanide, forming the heterocyclic intermediate III-37. An internal proton transfer then occurs rapidly to furnish the aromatic oxazole product III-34.333

Scheme 3-8. Mechanism of van Leusen 5-substituted oxazole synthesis

O O S N O O C S N K2CO3 C Me Me O K H Ar TosMIC III-35

K

C C N N N O O O TsOH O O K O S O S Ar Ar Ar

Me Me III-34 III-37 III-36

The corresponding reaction of TosMIC anion with ketones and certain aldehydes does not yield aromatic oxazoles. Instead, after nucleophilic addition, the tetrahedral 99 intermediate undergoes a reorganization, and in the case of reaction of the potassium salt of TosMIC with ketones, (Scheme 3-9) the products are α-cyano ketones, with optimal conditions for this process requiring stronger base (potassium tert-butoxide).364

Scheme 3-9. Reaction of TosMIC anion with ketones – reductive cyanation

O O K O CN S N C

Me III-35 III-38

We were interested in seeing the result of a TosMIC anion reaction employing acylsilanes in place of aldehydes or ketones. In particular, we wanted to determine which of these two carbonyl compounds that acylsilanes would more closely mimic in terms of reactivity. When acylsilane III-26 was subjected to the original van Leusen conditions for oxazole formation, 5-substituted aryl oxazoles were isolated in excellent yields as the only product of the reaction (Table 3-2). Just as with alkyl aldehydes in van Leusen’s original chemistry, attempts to employ alkyl acylsilanes such as III-2, were unsuccessful under these conditions, with significant decomposition of the acylsilane. No α-silyl alkyl nitrile compounds were observed in this reaction.

Table 3-2. 5-aryl oxazoles prepared form the corresponding acylsilanes 100 O 1 K CO N H CO2R 2 3 + Ar Ar SiX3 O N2 MeOH, !

entry acylsilane Product Yield (%) Compound

O N 1 SiMe3 96 III-35 Ph O

O N

SiMe 2 3 O 98 III-39 Me Me

O N H3C 3 H3C no reaction III-40 SiMe2Ph O

In order to furnish aromatic oxazoles as products, the silyl group must be lost at some point in the reaction pathway. Under the reaction conditions (refluxing MeOH, K2CO3) it is possible that the acylsilane undergoes protodesilylation to the aldehyde faster than the nucleophilic addition by TosMIC anion. To test this possibility we subjected acylsilane

III-26 to the reaction conditions and found that in the absence of TosMIC, complete conversion to p-tolualdehyde took place in less than 15 min under the reaction conditions

(reaction progress was monitored by thin layer chromatographic analysis). When

TosMIC is present in the reaction mixture it appears that aldehyde formation occurs prior to the TosMIC anion addition. The reaction therefore most likely involves protodesilylation of the acylsilane to the aldehyde followed by subsequent nucleophilic addition by TosMIC anion and oxazole formation. Tosyl-substituted oxazolines can be formed from TosMIC and aldehydes under the reaction conditions when refluxing temperatures are not used.333 however, when we attempted this using benzaldehyde, only the protio-oxazoline was observed. 101 This result appears to preclude the possibility of preparing non-aromatic, silylated oxazoline heterocycles utilizing these reaction conditions. The lability of the silyl group in the presence of a protic solvent, along with the nucleofugality of the tosyl group, driven as it is by the formation of an aromatic heterocycle is an incompatible factor for the synthesis of silylated oxazolines under the conditions attempted here. Potentially however, an isocyanide bearing an electron-withdrawing group at the α−postion such as an isocyanoacetate might be a viable precursor. These isocyanacetates are known to form oxazolines efficiently under non-protic solvent conditions,365 and might allow access to a limited set of silylated oxazolines.

3.4. Experimental Section

3.4.1. General Information

General experimental information can be found in Chapter 2, section 2.6. Acylsilanes were prepared according to the methods of Yamamoto and coworkers,366 or Clark,

Milgram and Scheidt.367 Allyl palladium chloride dimer complex was purchased from

Strem Chemicals, Inc. and used without further purification. Ethyl diazoacetate (EDA, 102 II-10a), t-butyl diazoacetate (II-10b), Tosylmethyl isocyanide (TosMIC) were purchased from Aldrich Chemical Company and used without purification.

3.5. Synthesis of β-ketoesters from Lithio-Diazoacetates and Acylsilanes

3.5.1. General Experimental Procedure A: Multi-Component Preparation of

Unsubstituted β-ketoesters

To a solution of acylsilane (0.4 mmol) and diazoester (0.4 mmol) in THF (2.0 mL) at –78

°C was added a solution of a LDA (0.405 mmol) in THF. After complete addition, the reaction allowed to stir at –78 °C for 30 minutes and then either MeOH (1 mL), or an alkyl halide was added. After consumption of the electrophile (monitored by TLC), the reaction was diluted with EtOAc (10 mL) and brine (10 mL). The layers were separated, and the aqueous layer extracted twice more with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent was removed in vacuo. The reaction mixture was purified by flash column chromatograph (ether/hexanes mixtures as eluent), usually by dry loading the sample, to afford the desired product.

3.5.2. Characterization Data for β-ketoesters III-27 and III-31 to III-33

1 O O Analytical data for III-27: Rf = 0.6 (10% EtOAc/hexanes); H NMR (500

Ph OEt MHz, CDCl3) δ 7.93-7.91 (d, J = 7.6 Hz, 2H), 7.76-7.74 (d, J = 7.0), 7.59-

7.55 (m, 1H), 7.47-7.37 (m, 2H), 5.64 (s, 1H), 4.25-4.16 (m, 2H), 1.24-1.21 (m, 3H); 13C

NMR (100 MHz, CDCl3) δ 192.7, 167.6, 136.2, 134.0, 133.0, 131.4, 130.6, 129.0, 128.7, 103 126.2, 87.6, 61.7, 60.5, 46.2, 14.5, 14.3. LRMS (electrospray): 432, 410, 232, 213,

+ 149, 130; Mass calcd for C11H12NaO3 [M] , 215.07. Found 215.

O O 1 Analytical data for III-31: Rf = 0.72 (10% EtOAc/hexanes); H NMR (400 Me OEt

Ph MHz, CDCl3) δ 7.25-7.14 (m, 5H), 4.20-4.11 (m, 2H), 3.79-3.75 (m, 1H),

13 3.16-3.11 (m, 2H), 2.09 (s, 3H); C NMR (100 MHz, CDCl3) δ 202.7, 169.3, 138.3,

129.0, 128.8, 126.9, 61.7, 61.5, 34.2, 29.9, 14.2. LRMS (electrospray): Mass calcd for

+ C13H16NaO3 [M] , 243.25. Found 243.

O O 1 Analytical data for III-32: Rf = 0.9 (50% Et2O/hexanes); H NMR (500 Ph OEt Me MHz, CDCl3) δ 8.0-7.98 (d, J = 7.3 Hz, 2H), 7.62-6.55 (m, 1H), 7.52-7.48

(m, 2H), 4.41-4.38 (m, 1H), 4.18-4.14 (m, 2H), 1.52-1.51 (m, 3H), 1.20-1.17 (m, 3H),;

+ LRMS (electrospray): Mass calcd for C12H15O3 [M] , 206.9. Found 207.

1 O O Analytical data for III-33: Rf = 0.85 (30% Et2O/hexanes); H NMR (500

Ph OEt

Ph MHz, CDCl3) δ 7.97-7.95 (d, J = 7.3 Hz, 2H), 7.58-7.55 (m, 1H), 7.49-7.41

(m, 4H), 7.24-7.17 (m, 3H), 4.63-4.60 (m, 1H), 4.13-4.07 (m, 2H), 3.34-3.32 (m, 2H),

+ 1.13-1.07 (m, 3H); LRMS (electrospray); Mass calcd for C18H18NaO3 [M] , 305.12.

Found 305.

104 3.6. Synthesis of 5-aryl Oxazoles from Acylsilanes and TosMIC

3.6.1. General Experimental Procedure B: 5-aryl Oxazoles

A solution of acylsilane (0.4 mmol) and TosMIC (0.4 mmol) in MeOH (3.0 mL) was heated at 60 °C for 2 h. The reaction mixture was evaporated and the residue partitioned between CH2Cl2 and saturated aqueous sodium chloride solution. After the layer were separated, the aqueous layer was extracted twice more with CH2Cl2 (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and solvent was removed to yield virtually pure product. The reaction mixture was purified by flash column chromatograph (ether/hexanes mixtures as eluent), usually by dry loading the sample, to afford the desired product.

3.5.2. Characterization Data for 5-aryl Oxazoles

1 N Analytical data for III-34: Rf = 0.15 (50% EtOAc/hexanes); H NMR (500

O MHz, CDCl3) δ 7.93 (s, 1H), 7.57-7.56 (m, 2H), 7.25 (s, 1H), 7.31-7.24 (m,

3H). See: Monahan, S.; Vedejs, E. J. Org. Chem. 1996, 61, 16, 5192.

N 1 Analytical data for III-39: Rf = 0.15 (50% EtOAc/hexanes); H NMR O

(500 MHz, CDCl3) δ 7.91 (s, 1H), 7.56-7.54 (d, J = 7.94, 2H), 7.26 (s, Me 1H), 7.25-7.23 (d, J = 7.94, 2H), 2.39 (s, 3H). See: Monahan, S.; Vedejs, E. J. Org.

Chem. 1996, 61, 16, 5192.

105

Chapter 4

N-Heterocyclic Carbene-Catalyzed Transformations of Aldehydes and Acylsilanes

106 Chapter 4. N-Heterocyclic Carbene-Catalyzed Transformations of Aldehydes and Acylsilanes

4.1. Introduction to Umpolung or Polarity-Reversal Chemistry

The term Umpolung is defined by the International Union of Pure and Applied chemists as: “Any process by which the normal alternating donor and acceptor reactivity pattern of a chain, which is due to the presence of O or N heteroatoms, is interchanged.”

The original meaning of the term has since been extended to the reversal of any commonly accepted reactivity pattern.368 Seebach and Corey were the first to develop this concept into a synthetic strategy, with reference to reactions of carbonyl compounds that proceed with inversion of the established mode of reactivity.369-375 In particular, Seebach has exploited lithiated dithianes as masked aldehyde (or acyl anion) nucleophiles. In this procedure, the aldehyde is first converted to a dithiane, and subsequently deprotonated adjacent to the two sulfur groups, which serve to stabilize the newly formed carbanion.

Although such reactivity was previously known, the replacement of sodium amide with n-butyllithium rendered the process consistently high yielding as an acyl anion equivalent or d1 synthon. The dithiane heterocycle could subsequently be hydrolyzed to regenerate the carbonyl group of the starting aldehyde (Scheme 4-1). In addition to dithiane chemistry, Stork and Maldonado reported the use of trimethylsilyl cyanohydrin anions as acyl anion equivalents,376 and this chemistry has been further developed as a reliable synthetic method by Hünig and coworkers.377-400 Other carbonyl derivatives such as hydrazones,401,402 oximes403 and α-lithiated vinyl ethers404,405 have also been demonstrated to act as acyl anion equivalents. 107 Scheme 4-1. Dithiane Umpolung reactivity of carbonyl compounds

carbonyl lithiated dithiane compound 1. O O SH SH H3O 1. E S S Li R H 2. n-BuLi 2. Hg(II) R E R Umpolung ELECTROPHILE NUCLEOPHILE Umpolung Product

4.1.2. Catalytic Umpolung Strategies

Acyl anion equivalents are one of the oldest and most common areas for Umpolung operations. In addition to these stoichiometric procedures, catalytic methods are well precedented. In 1832, Wöhler and Liebig reported the benzoin reaction of two aldehydes promoted by cyanide anion.406 In 1903 Lapworth proposed a mechanism to account for the formation of the acyloin product in the presence of catalytic amounts of sodium cyanide.407 In 1943, Ukai and coworkers reported that cyanide could be replaced as catalyst by a thiazolium salt to yield the same benzoin products (Scheme IV-2).408 In

1958, partially based on the mechanistic investigation of Lapworth, Breslow advanced a mechanistic rationale for the thiazolium salt-catalyzed process.409

Scheme 4-2. The cyanide-catalyzed benzoin reaction

O via: O NaCN OH R R R H R CN OH

The Ukai and Breslow work seems to have been inspired to a large extent by a related process in nature. The vitamin B12 cofactor thiamine pyrophosphate (TPP), generates an 108 acyl anion equivalent which is part of the biosynthesis of acetyl coenzyme A. In this case the acyl anion is generated from an α-ketoacid, which serves as an aldehyde surrogate. The acyl anion equivalent is formed after decarboxylation.

In addition to benzoin and crossed benzoin reactions, other electrophiles have been successfully added to acyl anions. In 1973, Stetter reported the addition of acyl anion equivalents generated by the action of thiazolium salts with aldehydes to a range of α,β- unsaturated systems.409 Since the work by Stetter, the scope of the electrophilic component has been expanded.310-313,410 including aromatic systems (discussed in Section

4.1.2), which have been utilized as electrophiles in conjunction with acyl anion equivalents.

4.1.2. Azolium-Catalyzed Nucleophilic Acylations of Aromatic Systems

In 1984, Miyashita and coworkers began a study of the nucleophilic acylation of aldehydes to halogenated heterocyclic systems and chloroimidates using 1,3-dimethyl azolium salts as precursors to N-heterocyclic carbenes catalysts.411-442 More recently, they have reported the traditional nucleophilic aromatic substitution of p-fluoro-nitrobenzene using aldehyde-derived acyl anion equivalents as the nucleophilic components of the reaction.443 A selection of compatible electrophiles with this catalytic acyl anion equivalent appears in Scheme 4-3.

109 Scheme 4-3. Miyashita’s catalytic nucleophilic acylation reaction

O Ar Azolium salts: Cl Azolium salt CH3 N AS-I or AS-II N N ArCHO I NaH, DMF, ! N

IV-1 IV-2 AS-I CH3

CH3 Compatible electrophiles: N I Cl Cl Cl NO2 N Ar N N N N N AS-II CH3 N N N N N N Cl Ar R R R F IV-3 IV-4 IV-5 IV-6 IV-7

4.2. Azolium-Catalyzed Nucleophilic Acylations of 2-Chlorooxazoles

Prompted by an interest in bioactive 2-ketooxazoles,444 and inspired by Miyashita’s reaction manifold (Section 4.1.2), previous work in our group by Michael C. Myers led to the discovery that the 2-chlorooxazole IV-9 is a competent electrophile for this nucleophilic acylation, providing access to ketooxazole IV-10 in 44% yield (Scheme 4-

4).445 Treatment of p-tolualdehyde IV-8 with 30 mol% of imidazolium salt AS-II in the presence of 2.0 equivalents of sodium hydride and 1.0 equivalent of chlorooxazole IV-9 at room temperature yielded 44% yield of the ketooxazole product IV-10. Additionally, a side product in the reaction was identified, the des-chloro IV-11 (Scheme 4-4).

110 Scheme 4-4. Nucleophilic acylation of 2-chlorooxazoles

O O N Ph H Ph 30 mol % Ph N AS-II O Ph N Cl H NaH, DMF, ! O Ph O Ph H3C H C 3 44% by-product IV-8 IV-9 IV-10 IV-11

4.2.1. Mechanistic Investigation

We set about conducting a more thorough investigation of this process in the hope of optimizing the reaction in terms of scope and yield. A catalytic cycle for Miyashita’s chemistry appears in Figure 4-1. The initial deprotonation of the azolium salt AS-I or

AS-II generates a NHC, which adds to the aldehyde forming tetrahedral intermediate I.

A second deprotonation then ensues, leading to intermediate II, which is the reactive nucleophilic acylating species. The addition of intermediate II to IV-9 forms a second tetrahedral intermediate, which collapses to form the product ketooxazole IV-10 with 111 H I Me Me N N AS-II O base O N Ph Ar Me Me Ar H O N N

Ph + base NHC IV-10

Ar O Me Ar O N N Ph H intermediate I Me Me O N N N Me Ph

Ar O N Cl Ph + base Me Me O N N

Ph intermediate II IV-9 acyl anion equivalent

Figure 4-1. Proposed mechanistic cycle for nucleophilic acylation of 2-chlorooxazoles regeneration of the NHC catalyst.

The other side products of the reaction were identified as benzoin-type products IV-

12 (derived from the addition of intermediate II to the starting aldehyde) and the acylated benzoin adduct IV-13. An inspection of IV-11 and IV-13 suggested that they were derived from chlorooxazole IV-9 and three equivalents of the aldehyde component IV-8

(two to produce benzoin, and a third to acylate the secondary hydroxyl group).

Ph O N Ar Ph N OH O O O Ph H Ar Ar = p-tolyl Ar O Ar Ph Ar O O H3C IV-10 IV-11 IV-12 IV-13

Figure 4-2. Isolated side products from the reaction 112 The appearance of these undesired products under the reaction conditions appears to suggest that an internal redox process had occurred. A close inspection of the proposed mechanistic cycle led us to examine the tetrahedral intermediate I, formed after initial addition of the NHC to the aldehyde as a potential hydride transfer candidate. We were able to support this hypothesis using a deuterium labeling experiment (employing

C1-deuterated benzaldehyde) to determine that the formation of IV-11 and IV-13 was the result of an interesting redox process.

Ar

O O Ar O Ar Me Me N N O Ar D IV-13 NHC

Cl N Ar O Me O Ar Ph Ar N O O D IV-9 O N Me Me Ph Me N N Ar intermediate I

Ar O OH D N Ar Me Me Ar N N Ph O O deuterio-IV-11 acyl azolium Ph IV-12 intermediate III

Figure 4-3. Proposed mechanistic rationale for side product formation

The deuterium atom of PhCDO was quantitatively transferred to the des-chlorooxazole deuterio-IV-11, supporting a mechanism involving a hydride transfer from intermediate

I (Figure 4-3), formed from addition of NHC to the aldehyde (instead of the formal 1,2- 113 hydrogen shift), to the chlorooxazole, followed by elimination of chloride ion. A similar reductive process involving hydride transfer has been observed in a related NHC- catalyzed process.446

The ratio of IV-10 to IV-11 is strongly dependent on the structure of the aldehyde starting material. Our optimized reaction conditions employ 20-25 mol% of the imidazolium salt AS-II with 2.0 equivalents of NaH at room temperature for 5 h, with

DMF as the solvent (0.16 M). For benzaldehyde, this reaction affords IV-10 and IV-11 in a ratio of 4.2:1, with an isolated yield of 65% of IV-15. Our extensive attempts to increase the yield of IV-10 by heating the reaction mixture, increasing the catalyst loading or increasing the amount of aldehyde starting material all drastically increased the relative amount of IV-11 formed.

4.3.2. Catalytic Nucleophilic Acylation with Acylsilanes

In an attempt to circumvent the reduction pathway, benzoyltrimethylsilane was employed as the nucleophilic component (Scheme 4-5). The presence of IV-11 was not detected during the course of this reaction. However 4 equiv of the acylsilane and 1 equiv of AS-II were required to afford acceptable yields of product (IV-15 in 64%). 0.5 equivalents of AS-II, in conjunction with only two equivalents of the acylsilane afforded only 24% of the product.

114 Scheme 4-5. Use of acylsilane as an “aldehyde equivalent”

Ph O 100 mol % O N SiMe3 N Ph AS-II O Cl Ph NaH, DMF, ! O Ph 64% 4 equiv 1 equiv

IV-14 IV-9 IV-15

In order to rationalize this result, it appears that acylsilane–NHC intermediate IV is substantially less nucleophilic than the corresponding IV-II acyl anion equivalent in the aldehyde pathway. Intermediate IV is presumably silylated in the acylsilane pathway

(Figure 4-4), which may account for this difference in reactivity.

Ar O Ar OSiMe3 acyl anion Me Me equivalents Me Me N N N N

intermediate II intermediate IV

Figure 4-4. Comparison of reactive species in aldehyde and acylsilane pathway

4.3.3. 2-Ketooxazoles as Bidentate Dyads for Metal-Organic Frameworks (MOFs)

In addition to these mechanistic studies, we were intrigued by the potential of these ketooxazole products as bidentate ligands for metal organic frameworks. Our investigation began with a simple feasibility study to establish whether simple dyads, bearing the acyl heterocycle functionality at either end could be prepared using the nucleophilic acylation chemistry. By employing p-bromobenzaldehyde IV-16 and p- trimethylsilylethynyl benzaldehyde IV-17, we were able to prepare simple precursors for

MOF-dyad synthesis in a single step (Figure 4-5). Gratifyingly, the trimethylsilyl group 115 attached to the alkyne is lost under the work up conditions, leading directly to the

Sonogashira coupling precursor IV-18.

H O H O O O N N Ph O O Br Ph Ph Br IV-18 O IV-19 39% yield N 44% yield Ph IV-16 SiMe3 O Br Ph IV-17 IV-20 32% yield

Figure 4-5. MOF-dyad building blocks

Although the yields are modest (32-44%), two bis-ketooxazole dyads, IV-23 and IV-

24 featuring an internal spacer unit were then synthesized using facile Sonogashira coupling conditions (Scheme 4-6).

Scheme 4-6. Synthesis of MOF-dyads

Ph Ph O O O [PdCl2(PPh3)2], N N O N CuI, NEt3, THF Ph Ph O O 16 h, 95% Br N O Ph Ph O Ph IV-18 IV-20 Ph IV-23

Ph

O O [PdCl2(PPh3)2], O N N CuI, NEt3, THF O 26 h, 98% Br N O Ph O

Ph IV-19 IV-22 IV-24

116 In each dyad, the ketooxazole units are separated by a different spacer unit

(Scheme IV-6). The potential scope for this facile and modular methodology for ligand synthesis is potentially unlimited, and using this NHC-catalyzed acylation reaction followed by a homo or heterocoupling reaction to another ketooxazole monomer, it will be possible to demonstrate high levels of control over the rigidity, length and spacing of the organic framework.

4.3. Tandem Catalytic Oxidation-Esterification of 2,3-Epoxy Alcohols

4.3.1. Introduction

Synthetic methods involving acyl anions generated by the interaction of NHCs with carbonyl compounds ca promote the Umpolung operation of generating an acyl anion equivalent. It is then possible to access other types of reactivity from the acyl anion by starting with a substituted aldehyde bearing a nucleofugal group or degree of unsaturation located α to the aldehyde. In these cases, an elimination by the acyl anion can occur, allowing access to an acyl-azolium species (Scheme 4-7).449-456

117 Scheme 4-7. Examples of modified reactivity of aldehydes with α−nucleofugal groups

O OH Me proton- H O AS-I source N (1) Ph H Ph Ph OR base N ROH Me IV-25 71-90% IV-26 yield

Cl N N N Ph OH Ph O H O AS-III N eliminate Br Ph (2) Ph H N Ph OR Br N Br base ROH 60-99% IV-27 yield IV-28

Alternatively, the normal course of events of events leading to acyl anion formation may be interrupted by the presence of an exogenous reagent, for example Maki, Phillips, Chan and Scheidt have developed an NHC-catalyzed oxidation system for allylic alcohols mediated by manganese dioxide (Scheme 4-8).457

Scheme 4-8. NHC-catalyzed, MnO2-mediated tandem oxidation sequence

Me N N I N Me OH Me O Me O AS-IV MnO ROH N 2 N Ph OH Ph Ph Ph OR N N base, MnO2 [O] N N 65-93% IV-27 Me Me yield IV-28 acyl triazolium

In this process, the cinammyl alcohol IV-27 undergoes MnO2-mediated oxidation to the

α,β-unsaturated aldehyde, which is then intercepted by the NHC forming a carbinol 118 intermediate. This carbinol undergoes a second MnO2-mediated oxidation, generating an acyl-triazolium species capable of acylating alcohols, leading to the product, α,β-unsaturated ester IV-28.

We were interested to see whether we could utilize an oxidation process similar to that of Maki, Phillips, Chan and Scheidt in tandem with an α-nucleofugal group to generate new patterns of reactivity. We selected 2,3-epoxy alcohols such as IV-29 as our reaction substrate, with the idea that after oxidation to the aldehyde IV-30, the epoxide would undergo ring-opening, leading eventually to the acetate aldol products IV-31 shown in Scheme 4-9.

Scheme 4-9. Planned tandem oxidation-esterification sequence

O OH 1. proton source O [O] O NHC O OH O Ph OH Ph H Ph NHC 2. acylation Ph OR 2,3-epoxy alcohol 2,3-epoxy aldehyde acetate aldol product IV-29 IV-30 IV-31

Although a related strategy has been utilized starting from trisubstituted 2,3- epoxyaldehydes in an effort to exert impoved stereocontrol in the anti-selectivity of propionate aldol products.458 This strategy has not yet been exploited for the corresponding acetate aldol framework. Additionally, a single-flask, tandem synthetic operation would increase the operational simplicity of the procedure, and would represent an attractive strategy for the synthesis of acetate aldol products.

An alternative oxidant was necessary to obviate the requirement of benzylic or allylic alcohols for efficient oxidation by manganese dioxide. The NHC might be incompatible 119 with strong oxidizing reagents, so the mild oxidation system bisacetoxy- iodosobenzene (BAIB) in the presence of catalytic TEMPO was chosen due to its selectivity and broad compatibility with other functional groups.459,460

IV-29 was treated sequentially with the BAIB-TEMPO oxidant, and then three equivalents of ethanol, as well as 10 mol % of the thiazolium catalyst AS-IV. We were delighted to discover that the desired product IV-31, was formed in 42% yield. The oxidation step appears to be the yield-limiting step, as isolated yields of the epoxyaldehyde were low, in the range of 26-51% for the oxidation step alone.

Our working model of the dual catalytic reaction is outlined in Figure 4-6. 2,3-epoxy alcohol IV-29 is selectively oxidized to IV-30 by intermediate V, according to the established mechanism for BAIB-TEMPO oxidation reported by Piancatelli and coworkers.461 Intermediate is formed in situ by the acid-promoted disproportionation of two equivalents of TEMPO. The acidic species is acetic acid, which is formed by a ligand-exchange process around the hypervalent iodine center (equation 1).

Epoxy aldehyde, IV-30 then reacts with the NHC derived from AS-IV, leading to formation of the acyl anion precursor intermediate VI, with undergoes rapid ring opening of the epoxide to yield intermediate VII. This acyl imidazolium species formed is then acylated by exogenous alcohol, (added in a second step in the case of ethanol), affording an acetate aldol product IV-31.

120 H

Cl Bn N S AS-IV

H O OH i-PrNEt2 O O Ph RO Ph Bn N S IV-30 PhI(OAc)2 IV-31 N NHC OH

H Bn O OH OH N N Bn Ph O N O OR Ph S 2 equiv intermediate VIII S intermediate VI TEMPO

O Bn O O N H HO Ph N Ph O ROH IV-29 S intermediate VII intermediate V

PhI(OAc)2 + n ROH PhI(OAc)2-n(OR)n + n ROH PhI(OR)2n + 2 AcOH (1)

Figure 4-6. Dual catalytic cycles for the oxidation-esterification reaction

Given the efficiency of the Sharpless asymmetric epoxidation reaction to form 2,3- epoxy alcohols in enantiopure form,462-467 this process may provide an attractive, catalytic method for the synthesis of asymmetric acetate aldol products in both inter and intramolecular platforms. Oxidation-Esterification or Oxidation-Lactonization could allow access to the skeleton of numerous natural products that possess an acetate aldol functionality motif.

121 4.4. Experimental Section

4.4.1. General Information

General experimental information can be found in Chapter 2, section 2.6. 2- chlorooxazoles were prepared according the procedure of Vedejs or Momose.360,362,468

Benzoyltrimethylsilane III-26 was prepared according to the method of Yamamoto and coworkers.366 Allyl palladium chloride dimmer complex was purchased from Strem

Chemicals, Inc. and used without further purification. 2,3-epoxy alcohol IV-29 was prepared according to the protocol of Wroblewski,469 an authentic sample of the 2,3- epoxy aldehyde IV-30, was prepared by the method of Righi and coworkers.459

4.5.1. General Experimental Procedure A: Preparation of 2-ketooxaxoles from aldehydes and 2-chlorooxazoles

To a solution of aldehyde (0.4 mmol), azolium salt AS-II (0.08 mmol) and 2- chlorooxazole (0.4 mmol) in DMF (2.25 mL) at 23 °C was added dried NaH (0.8 mmol).

The reaction mixture was allowed to stir at 23 °C for 5-8 hours. The reaction was immediately diluted with EtOAc (10 mL) and brine (20 mL), and extracted with EtOAc

(6 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and solvent was removed. The reaction mixture was purified by flash column chromatograph (ethyl acetate/hexanes mixtures as eluent), to afford the pure 2-ketooxazole product.

122 4.5.2. Characterization Data for ketooxazoles IV-10, IV-15, IV-18 and IV-19

O Analytical data for IV-10: Rf = 0.3 (50% Et2O/hexanes); IR (film) N Ph O -1 1 H3C 3054, 2987, 1740, 1422, 1265, 896, 740, 705 cm ; H NMR (500 Ph

MHz, DMSO-d6) δ 8.50 (d, J = 8.5 Hz, 2H), 7.75 (m, 4H), 7.44-7.42 (m, 6H), 7.34 (d, J

13 = 8.0 Hz, 1H), 2.46 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 178.3, 156.1, 148.4,

144.9, 137.2, 132.8, 131.6, 131.1, 129.8, 129.2. 128.8, 128.7, 128.7, 128.2, 127.7, 127.3,

+ 21.8. LRMS (electrospray): Mass calcd for C23H17NNaO2 [M] , 362.38. Found 362.

1 O Analytical data for IV-15: Rf = 0.3 (15% EtOAc/hexanes); H NMR N Ph O (500 MHz, CDCl3) δ 8.60 (d, J = 7.33 Hz, 1H), 8.01-7.99 (m, 4H), Ph 7.78-7.66 (m, 3H), 7.58-7.50 (m, 3H), 7.49-7.44 (m, 4H); LRMS (electrospray): Mass

+ calcd for C22H15NNaO2 [M] , 348.38. Found 348.

O 1 Analytical data for IV-18: Rf = 0.5 (75% Et2O/hexanes); H NMR N Ph O (500 MHz, CDCl3) δ 8.57 (d, J = 8.5 Hz, 1H), 7.99-7.96 (m, 4H), Ph

13 7.78-7.62 (m, 6H), 7.38-7.45 (, 3.38 (s, 1H); C NMR (100 MHz, CDCl3) δ 178.3, 156.1,

148.4, 144.9, 137.2, 132.8, 131.6, 131.1, 129.8, 129.2. 128.8, 128.7, 128.7, 128.2, 127.7,

+ 127.3, 21.8. LRMS (electrospray): Mass calcd for C24H15NO2 [M] , 349.11 Found 349.

O 1 Analytical data for IV-19: Rf = 0.32 (50% Et2O/hexanes); H NMR N Ph O Br (500 MHz, CDCl3) δ 8.41 (d, J = 8.6 Hz, 2H), 7.84-7.83 (d, 7.0 Hz, Ph 2H), 7.69-7.53 (m, 4H), 7.50-7.43 (m, 6H); LRMS (electrospray): Mass calcd for

+ C23H16NBrNaO2 [M] , 426.54. Found 426. 123 4.5.3. Characterization Data for Side Products IV-11 and IV-13

1 H N Analytical data for IV-11: Rf = 0.25 (25% EtOAc/hexanes); H NMR (500 Ph O 13 Ph MHz, CDCl3) δ 7.97 (s, 1H), 7.68-7.62 (m, 4H), 7.41-7.36 (m, 6H); C NMR

(100 MHz, CDCl3) δ 178.3, 156.1, 148.4, 144.9, 137.2, 132.8, 131.6, 131.1, 129.8, 129.2.

128.8, 128.7, 128.7, 128.2, 127.7, 127.3, 21.8. LRMS (electrospray): Mass calcd for

+ C51H12NO [M] , 222.08. Found 222.

1 CH3 Analytical data for IV-13: Rf = 0.8 (5% Et2O/hexanes); H NMR (500

MHz, CDCl3) δ 8.02-8.07 (d, J = 8.3 Hz, 2H), 7.92-7.91 (d, J = 7.8 Hz,

O O O 2H), 7.47-7.45 (d, J = 7.8, 2H), 7.25-7.19 (m, 6H), 7.05 (s, 1H), 2.42 (s,

H3C 3H), 2.38 (s, 3H), 2.35 (s, 3H).

CH3

4.5.4. General Experimental Procedure B: Preparation 2-ketooxaxoles from benzoyltrimethylsilane III-26 and 2-chlorooxazole IV-9.

O To a solution of benzoyltrimethylsilane (1.6 mmol), azolium salt AS-II N Ph O (0.4 mmol) and 2-chlorooxazole (0.4 mmol) in DMF (2.25 mL) at 23 °C Ph was added dried NaH (0.8 mmol)., the reaction mixture was heated at 70 °C (oil bath temperature) for 16 hours. The reaction was allowed to cool to room temperature, diluted with EtOAc (10 mL) and brine (20 mL), and extracted with EtOAc (6 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and solvent was removed. The reaction mixture was purified by flash column chromatograph (ethyl acetate/hexanes 124 mixtures as eluent), to afford the pure 2-ketooxazole product. Characterization data was identical to that of compound Analytical data for IV-15.

4.5.5. Experimental Procedure C: Preparation of Deuterio-II-11

To a solution of C1-deuterated benzaldehyde (0.4 mmol), azolium salt AS-II (0.4 mmol) and 2-chlorooxazole (0.4 mmol) in DMF (4.0 mL) at 23 °C was added dried NaH

(0.8 mmol)., the reaction mixture was heated at 70 °C (oil bath temperature) for 16 hours.

The reaction was allowed to cool to room temperature, diluted with EtOAc (10 mL) and brine (20 mL), and extracted with EtOAc (6 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and solvent was removed. The crude reaction mixture was then analyzed by 1H NMR spectroscopy. On comparison with a 1H NMR spectrum of pure

IV- 11, all signals are present in the crude reaction spectrum, with the exception of the signal for the C2-hydrogen (δ 7.97 ppm, s, 1H), which was absent.

4.5.6. Experimental Procedure D: Sonogashira Coupling for MOF-dyad synthesis

To a mixture of IV-18 (1.0 mmol) and IV-20 (1.0 mmol), or IV-19 (1.0 mmol) and

1,4-diethynyl benzene IV-22 (0.4 mmol) was added distilled triethylamine (1 mmol),

PdCl2(PPh3)2 (0.05 mmol), triphenylphosphine (0.035 mmol), and CuI (0.015 mmol) in dry THF (2 mL) was stirred at 23 °C for 16-26 h. The reaction mixture was diluted with

CH2Cl2 (30 mL), washed with an aqueous solution of EDTA (0.01 M), (20 mL) and brine

(2 x 20 mL), and then filtered and dried over Na2SO4 and the solvent removed. The resulting solid was purified by flash column chromatography.

125 4.5.7. Characterization Data for MOF-dyad IV-23

Ph Analytical data for IV-23: Rf = 0.4 (75%

O 1 N O Et2O/hexanes); H NMR (500 MHz, CDCl3) δ

O N O 8.43 (d, J = 8.8 Hz, 4H), 7.86 (m, 4H), 7.72-

Ph 7.67 (m, 6H), 7.64 (s, 2H), 7.44-7.42 (m,

13 12H), 7.56-7.46 (m, 8H); C NMR (100 MHz, CDCl3) δ 177.6, 156.9, 134.2, 133.7,

132.5, 132.4, 132.3, 132.0, 130.4, 129.0, 128.8, 126.8, 128.7, 125.6, 128.2, 124.2. LRMS

+ (electrospray): Mass calcd for C42H22N2O4 [M] , 620.65. Found 620.

4.6. Experimental Procedure E: BAIB-TEMPO/NHC Oxidation/Esterification

OH O TEMPO (0.058 mmol) was added to a solution of epoxy alcohol IV-29

Ph OEt (0.56 mmol) and BAIB (0.59 mmol) in CH2Cl2 (1.0 mL) at 23 °C. After 4 h, DIPEA (1.2 mmol) was added and the reaction allowed to stir for 5 minutes. Thiazolium salt AS-V

(0.11 mmol) and EtOH (1.7 mmol) were next added and the reaction mixture warmed to

30 °C for 14 h. After this time, the mixture was treated with aqueous saturated ammonium chloride solution and the mixture extracted with EtOAc (3 x 20 mL). The combined organic layers were then washed with brine, dried and concentrated.

Purification was carried out by Flash column chromatography. Rf = 0.2 (25%

1 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.41-7.29 (m, 5H), 5.17-5.14 (m, 1H),

13 4.23-4.18 (m, 2H), 2.77-2.74 (m, 2H), 1.29-1.24 (m, 3H); C NMR (125 MHz, CDCl3) δ

172.7, 142.7, 128.9, 128.8, 128.1, 125.9, 125.9, 70.6, 61.1, 43.6, 14.4. See: Wessjohann,

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157

APPENDIX A

Crystallographic data for compound II-18

Data Collection

A colorless columnar crystal of C23H22BrNO6 having approximate dimensions of 0.240 x 0.104 x 0.090 mm was mounted using oil (Infineum V8512) on a glass fiber. All measurements were made on a CCD area detector with graphite monochromated MoK\α radiation.

158 Cell constants and an orientation matrix for data collection corresponded to a Monoclinic cell with dimensions:

a = 10.1952(17) Å b = 12.015(2) Å β = 95.28(2)º c = 17.932(4) Å V = 2187.2(8) Å3

For Z = 4 and F.W. = 488.33, the calculated density is 1.483 g/cm3. Based on systematic absences, and the successful solution and refinement of the structure, the space group was unambiguously determined to be:

P2(1)/c The data were collected at a temperature of 153(2)K with a theta range for data collection of 2.01 to 28.85º. Data were collected in 0.3º oscillations with 20 second exposures. The crystal-to-detector distance was 50.00 mm with the detector at the 28º swing position.

Data Reduction

Of the 19796 reflections which were collected, 5306 were unique (Rint = 0.0600). Data were collected using Bruker SMART detector and processed using SAINT-NT from Bruker.

The linear absorption coefficient, mu, for MoK\a radiation is 1.919 mm-1. An integration absorption correction was applied. Minimum and maximum transmission factors were: 0.7049 and 0.8521, respectively. The data were corrected for Lorentz and polarization effects.

Structure Solution and Refinement

The structure was solved by direct methods1 and expanded using Fourier techniques.2 The non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included but not refined. The final cycle of full-matrix least-squares refinement3 on F2 was based on 5306 reflections and 283 variable parameters and converged (largest parameter shift was 0.003 times its esd) with unweighted and weighted agreement factors of:

R1 = Σ| |Fo|-|Fc| |/Σ|Fo| = 0.0358

2 2 2 2 2 2 1/2 wR = (Σ[w(Fo -Fc ) ]/Σ[w(Fo ) ]) = 0.0785

The weighting scheme was calc. 2 2 2 2 2 calc w=1/[σ (Fo )+(0.0441P) + 0.0000P] where P=(Fo +2Fc )/3

159

The standard deviation of an observation of unit weight4 was 0.993. The weighting scheme was based on counting statistics and included a factor to downweight the intense 2 reflections. Plots of Σ w (|Fo| - |Fc|) versus |Fo|, reflection order in data collection, sin θ/λ and various classes of indices showed no unusual trends. The maximum and minimum peaks on the final difference Fourier map corresponded to 0.520 and -0.474 e- /Å3, respectively.

Neutral atom scattering factors were taken from Cromer and Waber5. Anomalous dispersion effects were included in Fcalc6; the values for Df' and Df" were those of Creagh and McAuley7. The values for the mass attenuation coefficients are those of Creagh and Hubbell8. All calculations were performed using the Bruker SHELXTL9 crystallographic software package.

References

(1) SHELXS-97 (Sheldrick, 1990)

(2) SHELXL-97 (Sheldrick, 1997)

(3) Full-Matrix Least-Squares refinement on F2:

2 2 2 2 2 2 1/2 wR = (Σ[w(Fo -Fc ) ]/Σ[w(Fo ) ])

2 2 2 1/2 (4) GooF = S = (S[w(Fo -Fc ) ]/(n-p)) n = number of reflections; p = total number of reflections refined

(5) Cromer, D. T. & Waber, J. T.; "International Tables for X-ray Crystallography Vol. IV, The Kynoch Press, Birmingham, England, Table 2.2 A (1974).

(6) Ibers, J. A. & Hamilton, W. C.; Acta Crystallogr., 17, 781 (1964).

(7) Creagh, D. C. & McAuley, W.J .; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992).

(8) Creagh, D. C. & Hubbell, J.H..; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.4.3, pages 200-206 (1992).

(9) Shelxtl for WindowsNT: Crystal Structure Analysis Package, Bruker (1997). 160

Table 1. Crystal data and structure refinement for II-18.

Identification code II-18

Empirical formula C23 H22 Br N O6

Formula weight 488.33

Temperature 153(2) K

Wavelength 0.71073 Å

Crystal system, space group Monoclinic, P2(1)/c

Unit cell dimensions a = 10.1952(17) Å b = 12.015(2) Å β = 95.28(2) º c = 17.932(4) Å

Volume 2187.2(8) Å3

Z, Calculated density 4, 1.483 Mg/m3

Absorption coefficient 1.919 mm-1

F(000) 1000

Crystal size 0.240 x 0.104 x 0.090 mm

Theta range for data collection 2.01 to 28.85 º

Limiting indices -13<=h<=13, -15<=k<=15, -23<=l<=23

Reflections collected / unique 19796 / 5306 [R(int) = 0.0600]

Completeness to theta = 28.85 92.5 %

Absorption correction Integration

Max. and min. transmission 0.8521 and 0.7049

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 5306 / 0 / 283 161

Goodness-of-fit on F^2 0.993

Final R indices [I>2sigma(I)] R1 = 0.0358, wR2 = 0.0785

R indices (all data) R1 = 0.0770, wR2 = 0.0925

Largest diff. peak and hole 0.520 and -0.474 e-/Å-3

Table 2. Atomic coordinates and equivalent isotropic displacement parameters (A^2 x 10^3) for II-18. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______

x y z U(eq) ______

Br(1) 0.65539(3) 1.03663(2) 1.151831(16) 49(1) O(1) 0.66429(15) 0.35665(13) 0.88697(9) 37(1) O(2) 0.86117(14) 0.27323(11) 0.91350(8) 29(1) O(3) 0.92955(15) 0.62024(12) 0.76520(8) 29(1) O(4) 0.96641(15) 0.44350(12) 0.80431(9) 31(1) O(5) 0.76236(17) 0.82423(12) 0.85729(9) 38(1) O(6) 0.63890(14) 0.70728(12) 0.78170(8) 29(1) N(1) 0.78066(17) 0.52306(13) 0.99431(9) 21(1) C(1) 0.6954(2) 0.61169(16) 0.96109(11) 21(1) C(2) 0.7550(2) 0.63223(16) 0.88855(11) 21(1) C(3) 0.8410(2) 0.55321(16) 0.87513(12) 22(1) C(4) 0.8497(2) 0.46714(16) 0.93645(11) 22(1) C(5) 0.7457(2) 0.46219(16) 1.05640(11) 22(1) C(6) 0.8216(2) 0.37050(17) 1.08226(12) 28(1) C(7) 0.7899(2) 0.31197(18) 1.14460(13) 33(1) C(8) 0.6834(2) 0.34226(19) 1.18240(13) 34(1) C(9) 0.6086(2) 0.43306(18) 1.15730(12) 30(1) C(10) 0.6384(2) 0.49271(17) 1.09499(12) 25(1) C(11) 0.6883(2) 0.71518(16) 1.00939(11) 21(1) C(12) 0.5711(2) 0.77462(17) 1.00541(12) 28(1) C(13) 0.5614(2) 0.87145(17) 1.04757(13) 31(1) C(14) 0.6690(2) 0.90539(17) 1.09369(13) 29(1) C(15) 0.7865(2) 0.84773(18) 1.09839(12) 30(1) C(16) 0.7954(2) 0.75196(17) 1.05548(12) 26(1) C(17) 0.7787(2) 0.35945(17) 0.90870(11) 23(1) C(18) 0.8100(3) 0.16400(17) 0.88985(14) 37(1) 162 C(19) 0.8402(3) 0.0838(2) 0.95265(16) 53(1) C(20) 0.9159(2) 0.54553(17) 0.80870(12) 24(1) C(21) 1.0472(2) 0.4234(2) 0.74318(14) 37(1) C(22) 0.7210(2) 0.73289(17) 0.84101(12) 25(1) C(23) 0.6012(2) 0.79958(19) 0.73200(13) 37(1) ______

Table 3. Bond lengths [A] and angles [deg] for II-18.

Br(1)-C(14) 1.902(2) O(1)-C(17) 1.196(2) O(2)-C(17) 1.332(2) O(2)-C(18) 1.461(2) O(3)-C(20) 1.206(2) O(4)-C(20) 1.335(2) O(4)-C(21) 1.451(3) O(5)-C(22) 1.202(2) O(6)-C(22) 1.327(3) O(6)-C(23) 1.452(2) N(1)-C(5) 1.405(3) N(1)-C(1) 1.466(2) N(1)-C(4) 1.469(3) C(1)-C(2) 1.506(3) C(1)-C(11) 1.521(3) C(1)-H(1) 1.0000 C(2)-C(3) 1.330(3) C(2)-C(22) 1.502(3) C(3)-C(20) 1.476(3) C(3)-C(4) 1.506(3) C(4)-C(17) 1.543(3) C(4)-H(4) 1.0000 C(5)-C(10) 1.397(3) C(5)-C(6) 1.401(3) C(6)-C(7) 1.384(3) C(6)-H(6) 0.9500 C(7)-C(8) 1.381(3) C(7)-H(7) 0.9500 C(8)-C(9) 1.382(3) C(8)-H(8) 0.9500 C(9)-C(10) 1.384(3) C(9)-H(9) 0.9500 C(10)-H(10) 0.9500 C(11)-C(16) 1.380(3) C(11)-C(12) 1.388(3) 163 C(12)-C(13) 1.396(3) C(12)-H(12) 0.9500 C(13)-C(14) 1.374(3) C(13)-H(13) 0.9500 C(14)-C(15) 1.380(3) C(15)-C(16) 1.392(3) C(15)-H(15) 0.9500 C(16)-H(16) 0.9500 C(18)-C(19) 1.492(3) C(18)-H(18A) 0.9900 C(18)-H(18B) 0.9900 C(19)-H(19A) 0.9800 C(19)-H(19B) 0.9800 C(19)-H(19C) 0.9800 C(21)-H(21A) 0.9800 C(21)-H(21B) 0.9800 C(21)-H(21C) 0.9800 C(23)-H(23A) 0.9800 C(23)-H(23B) 0.9800 C(23)-H(23C) 0.9800 C(17)-O(2)-C(18) 118.24(16) C(20)-O(4)-C(21) 116.51(17) C(22)-O(6)-C(23) 115.24(17) C(5)-N(1)-C(1) 121.06(16) C(5)-N(1)-C(4) 119.64(16) C(1)-N(1)-C(4) 110.49(15) N(1)-C(1)-C(2) 101.47(16) N(1)-C(1)-C(11) 114.84(16) C(2)-C(1)-C(11) 113.71(16) N(1)-C(1)-H(1) 108.8 C(2)-C(1)-H(1) 108.8 C(11)-C(1)-H(1) 108.8 C(3)-C(2)-C(22) 126.43(19) C(3)-C(2)-C(1) 111.39(18) C(22)-C(2)-C(1) 122.14(17) C(2)-C(3)-C(20) 126.15(19) C(2)-C(3)-C(4) 110.70(19) C(20)-C(3)-C(4) 123.12(18) N(1)-C(4)-C(3) 101.65(15) N(1)-C(4)-C(17) 111.74(16) C(3)-C(4)-C(17) 110.24(17) N(1)-C(4)-H(4) 111.0 C(3)-C(4)-H(4) 111.0 C(17)-C(4)-H(4) 111.0 C(10)-C(5)-C(6) 118.47(19) 164 C(10)-C(5)-N(1) 121.56(18) C(6)-C(5)-N(1) 119.94(19) C(7)-C(6)-C(5) 120.3(2) C(7)-C(6)-H(6) 119.9 C(5)-C(6)-H(6) 119.9 C(8)-C(7)-C(6) 121.0(2) C(8)-C(7)-H(7) 119.5 C(6)-C(7)-H(7) 119.5 C(7)-C(8)-C(9) 118.9(2) C(7)-C(8)-H(8) 120.5 C(9)-C(8)-H(8) 120.5 C(8)-C(9)-C(10) 121.1(2) C(8)-C(9)-H(9) 119.5 C(10)-C(9)-H(9) 119.5 C(9)-C(10)-C(5) 120.3(2) C(9)-C(10)-H(10) 119.9 C(5)-C(10)-H(10) 119.9 C(16)-C(11)-C(12) 119.74(19) C(16)-C(11)-C(1) 121.74(18) C(12)-C(11)-C(1) 118.52(18) C(11)-C(12)-C(13) 120.3(2) C(11)-C(12)-H(12) 119.9 C(13)-C(12)-H(12) 119.9 C(14)-C(13)-C(12) 118.7(2) C(14)-C(13)-H(13) 120.6 C(12)-C(13)-H(13) 120.6 C(13)-C(14)-C(15) 121.9(2) C(13)-C(14)-Br(1) 118.76(17) C(15)-C(14)-Br(1) 119.31(17) C(14)-C(15)-C(16) 118.8(2) C(14)-C(15)-H(15) 120.6 C(16)-C(15)-H(15) 120.6 C(11)-C(16)-C(15) 120.5(2) C(11)-C(16)-H(16) 119.7 C(15)-C(16)-H(16) 119.7 O(1)-C(17)-O(2) 126.2(2) O(1)-C(17)-C(4) 122.93(19) O(2)-C(17)-C(4) 110.88(17) O(2)-C(18)-C(19) 108.50(19) O(2)-C(18)-H(18A) 110.0 C(19)-C(18)-H(18A) 110.0 O(2)-C(18)-H(18B) 110.0 C(19)-C(18)-H(18B) 110.0 H(18A)-C(18)-H(18B) 108.4 C(18)-C(19)-H(19A) 109.5 165 C(18)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 C(18)-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)-O(4) 125.3(2) O(3)-C(20)-C(3) 125.08(19) O(4)-C(20)-C(3) 109.63(18) O(4)-C(21)-H(21A) 109.5 O(4)-C(21)-H(21B) 109.5 H(21A)-C(21)-H(21B) 109.5 O(4)-C(21)-H(21C) 109.5 H(21A)-C(21)-H(21C) 109.5 H(21B)-C(21)-H(21C) 109.5 O(5)-C(22)-O(6) 126.0(2) O(5)-C(22)-C(2) 122.7(2) O(6)-C(22)-C(2) 111.32(18) O(6)-C(23)-H(23A) 109.5 O(6)-C(23)-H(23B) 109.5 H(23A)-C(23)-H(23B) 109.5 O(6)-C(23)-H(23C) 109.5 H(23A)-C(23)-H(23C) 109.5 H(23B)-C(23)-H(23C) 109.5 ______

166 Table 4. Anisotropic displacement parameters (A^2 x 10^3) for II-18.

The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]

______

U11 U22 U33 U23 U13 U12

______

Br(1) 61(1) 30(1) 57(1) -18(1) 9(1) 6(1) O(1) 26(1) 31(1) 53(1) -9(1) -8(1) 0(1) O(2) 32(1) 19(1) 34(1) -3(1) -3(1) 2(1) O(3) 35(1) 27(1) 26(1) 4(1) 5(1) 0(1) O(4) 36(1) 25(1) 33(1) -1(1) 13(1) 3(1) O(5) 61(1) 24(1) 29(1) 2(1) 6(1) -8(1) O(6) 31(1) 29(1) 27(1) 9(1) -3(1) 3(1) N(1) 28(1) 17(1) 18(1) 0(1) 2(1) 3(1) C(1) 23(1) 21(1) 18(1) 1(1) 0(1) 1(1) C(2) 23(1) 21(1) 19(1) 0(1) 0(1) -4(1) C(3) 25(1) 20(1) 20(1) 0(1) 1(1) -1(1) C(4) 23(1) 20(1) 23(1) -2(1) 1(1) 1(1) C(5) 28(1) 19(1) 19(1) -1(1) -3(1) -4(1) C(6) 31(1) 23(1) 28(1) 1(1) -5(1) -1(1) C(7) 39(1) 26(1) 32(1) 7(1) -11(1) -4(1) C(8) 45(2) 33(1) 22(1) 6(1) -4(1) -14(1) C(9) 38(1) 28(1) 23(1) -3(1) 1(1) -10(1) C(10) 30(1) 21(1) 23(1) -2(1) -2(1) -3(1) C(11) 26(1) 20(1) 17(1) 2(1) 3(1) 0(1) C(12) 27(1) 26(1) 31(1) 1(1) -1(1) -1(1) C(13) 32(1) 23(1) 40(1) 3(1) 8(1) 5(1) C(14) 39(1) 20(1) 29(1) -3(1) 9(1) -1(1) C(15) 34(1) 28(1) 27(1) -5(1) 1(1) -3(1) C(16) 25(1) 24(1) 27(1) -2(1) 2(1) 2(1) C(17) 29(1) 22(1) 19(1) 0(1) 2(1) 1(1) C(18) 46(2) 19(1) 44(2) -7(1) -1(1) -2(1) C(19) 72(2) 27(1) 57(2) 10(1) -5(2) -8(1) C(20) 23(1) 25(1) 25(1) -3(1) -2(1) -1(1) C(21) 41(1) 33(1) 41(2) -6(1) 18(1) 4(1) C(22) 29(1) 23(1) 25(1) 3(1) 9(1) 2(1) C(23) 41(1) 38(1) 34(1) 15(1) 3(1) 11(1) ______

167 Table 5. Hydrogen coordinates ( x 10^4) and isotropic displacement parameters (A^2 x 10^3) for s33n1m.

______

x y z U(eq) ______

H(1) 6044 5814 9496 25 H(4) 9435 4518 9548 26 H(6) 8952 3484 10569 33 H(7) 8422 2500 11616 39 H(8) 6619 3014 12250 40 H(9) 5356 4549 11832 36 H(10) 5855 5547 10784 30 H(12) 4971 7493 9739 34 H(13) 4818 9131 10444 37 H(15) 8601 8729 11303 35 H(16) 8758 7116 10579 31 H(18A) 8515 1389 8450 44 H(18B) 7136 1683 8769 44 H(19A) 9353 836 9672 79 H(19B) 8119 90 9364 79 H(19C) 7933 1062 9956 79 H(21A) 9974 4428 6956 56 H(21B) 10718 3446 7426 56 H(21C) 11269 4692 7501 56 H(23A) 5663 8603 7608 56 H(23B) 5334 7749 6933 56 H(23C) 6784 8258 7084 56

168 APPENDIX B

Crystallographic Data for compound II-38

Data Collection

A colorless plate crystal of C35H31ClN2O5 having approximate dimensions of 0.348 x 0.220 x 0.010 mm was mounted using oil (Infineum V8512) on a glass fiber. All measurements were made on a CCD area detector with graphite monochromated MoK\α radiation.

Cell constants and an orientation matrix for data collection corresponded to a Monoclinic cell with dimensions:

a = 13.1699(14) Å b = 16.1972(17) Å β = 103.160(2)º c = 14.1817(14) Å V = 2945.7(5) Å3

169 For Z = 4 and F.W. = 595.07, the calculated density is 1.342 g/cm3. Based on Systematic absences, and the successful solution and refinement of the structure, the space group was determined to be:

P2(1)/c

The data were collected at a temperature of 153(2)K with a theta range for data collection of 1.59 to 28.90º. Data were collected in 0.3º oscillations with 25 second exposures. The crystal-to-detector distance was 50.00 mm with the detector at the 28º swing position.

Data Reduction

Of the 26840 reflections which were collected, 7120 were unique (Rint = 0.1034). Data were collected using Bruker SMART detector and processed using SAINT from Bruker.

The linear absorption coefficient, mu, for MoK\a radiation is 0.177 mm-1. An analytical absorption correction was applied. Minimum and maximum transmission factors were: 0.9560 and 0.9982, respectively. The data were corrected for Lorentz and polarization effects.

Structure Solution and Refinement

The structure was solved by direct methods1 and expanded using Fourier techniques.2 The non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included in idealized positions, but not refined. The final cycle of full-matrix least-squares refinement3 on F2 was based on 7120 reflections and 390 variable parameters and converged (largest parameter shift was 0.001 times its esd) with unweighted and weighted agreement factors of:

R1 = Σ| |Fo|-|Fc| |/Σ|Fo| = 0.0524

2 2 2 2 2 2 1/2 wR = (Σ[w(Fo -Fc ) ]/Σ[w(Fo ) ]) = 0.1000

The weighting scheme was calc. 2 2 2 2 2 calc w=1/[σ (Fo )+(0.0513P) + 0.0000P] where P=(Fo +2Fc )/3

The standard deviation of an observation of unit weight4 was 0.929. The weighting scheme was based on counting statistics and included a factor to downweight the intense 2 reflections. Plots of Σ w (|Fo| - |Fc|) versus |Fo|, reflection order in data collection, sin θ/λ and various classes of indices showed no unusual trends. The maximum and minimum 170 peaks on the final difference Fourier map corresponded to 0.321 and -0.256 e-/Å3, respectively.

Neutral atom scattering factors were taken from Cromer and Waber.5 Anomalous dispersion effects were included in Fcalc6; the values for Df' and Df" were those of Creagh and McAuley.7 The values for the mass attenuation coefficients are those of Creagh and Hubbell.8 All calculations were performed using the Bruker SHELXTL9 crystallographic software package.

References

(1) Bruker SMART, Version 5.054 Bruker Analytical X-ray Instruments, Inc.: Madison, WI, 2000

(2) Saint-Plus, version 6.02A; Bruker Analytical X-ray Instruments, Inc.: Madison, WI, 2000.

(3) Sheldrick, G.M. SHELXTL Version 6.14; Bruker Analytical X-ray Instruments, Inc.: Madison, WI, 2003

(4) Full-Matrix Least-Squares refinement on F2:

2 2 2 2 2 2 1/2 wR = (Σ[w(Fo -Fc ) ]/Σ[w(Fo ) ])

2 2 2 1/2 (5) GooF = S = (S[w(Fo -Fc ) ]/(n-p)) n = number of reflections; p = total number of reflections refined

(6) Cromer, D. T. & Waber, J. T.; "International Tables for X-ray Crystallograph Vol. IV, The Kynoch Press, Birmingham, England, Table 2.2 A (1974).

(7) Ibers, J. A. & Hamilton, W. C.; Acta Crystallogr., 17, 781 (1964).

(8) Creagh, D. C. & McAuley, W.J .; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992).

(9) Creagh, D. C. & Hubbell, J.H..; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.4.3, pages 200-206 (1992).

Table 1. Crystal data and structure refinement for II-38.

171

Identification code II-38

Empirical formula C35 H31 Cl N2 O5

Formula weight 595.07

Temperature 153(2) K

Wavelength 0.71073 Å

Crystal system, space group Monoclinic, P2(1)/c

Unit cell dimensions a = 13.1699(14) Å b = 16.1972(17) Å β = 103.160(2) º c = 14.1817(14) Å

Volume 2945.7(5) Å3

Z, Calculated density 4, 1.342 Mg/m3

Absorption coefficient 0.177 mm-1

F(000) 1248

Crystal size 0.348 x 0.220 x 0.010 mm

Theta range for data collection 1.59 to 28.90 º

Limiting indices -16<=h<=17, -21<=k<=21, -18<=l<=18

Reflections collected / unique 26840 / 7120 [R(int) = 0.1034]

Completeness to theta = 28.90 91.8 %

Absorption correction Integration

Max. and min. transmission 0.9982 and 0.9560

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 7120 / 0 / 390

Goodness-of-fit on F^2 0.929

172 Final R indices [I>2sigma(I)] R1 = 0.0524, wR2 = 0.1000

R indices (all data) R1 = 0.1613, wR2 = 0.1330

Largest diff. peak and hole 0.321 and -0.256 e-/Å-3

Table 2. Atomic coordinates and equivalent isotropic displacement parameters (A^2 x 10^3) for II-38.

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

______

x y z U(eq) ______

Cl(1) 0.13166(7) 0.93986(5) 0.04255(6) 43(1) O(1) 0.16776(16) 0.56960(12) 0.31596(15) 37(1) O(2) 0.10761(15) 0.65250(11) 0.18773(14) 28(1) O(3) 0.43235(15) 0.61854(12) 0.35038(14) 32(1) O(4) 0.49485(15) 0.69664(12) 0.24625(15) 33(1) O(5) 0.32057(14) 0.79617(11) 0.05909(13) 25(1) N(1) 0.18802(17) 0.78738(13) 0.30711(16) 20(1) N(2) 0.43492(17) 0.88570(13) 0.15592(15) 20(1) C(1) 0.2398(2) 0.70632(16) 0.3142(2) 21(1) C(2) 0.3196(2) 0.71554(16) 0.2502(2) 21(1) C(3) 0.3265(2) 0.80897(16) 0.23306(19) 20(1) C(4) 0.2121(2) 0.83585(16) 0.22782(19) 19(1) C(5) 0.0913(2) 0.79211(16) 0.33376(19) 21(1) C(6) 0.0061(2) 0.83618(17) 0.2804(2) 26(1) C(7) -0.0852(2) 0.84021(19) 0.3121(2) 31(1) C(8) -0.0956(2) 0.80023(18) 0.3951(2) 31(1) C(9) -0.0120(2) 0.75562(19) 0.4468(2) 33(1) C(10) 0.0803(2) 0.75201(17) 0.4175(2) 27(1) C(11) 0.1677(2) 0.63476(17) 0.2753(2) 24(1) C(12) 0.0572(2) 0.58246(19) 0.1319(2) 36(1) C(13) 0.1328(3) 0.5436(2) 0.0791(3) 52(1) C(14) 0.4211(2) 0.67134(17) 0.2902(2) 22(1) C(15) 0.5968(2) 0.6594(2) 0.2804(2) 42(1) C(16) 0.3579(2) 0.82762(17) 0.1373(2) 20(1) C(17) 0.4697(2) 0.89925(16) 0.25605(19) 21(1) C(18) 0.5523(2) 0.94707(17) -0.3031(2) 26(1) C(19) 0.5735(2) 0.94784(18) 0.4044(2) 30(1) C(20) 0.5140(2) 0.90298(17) 0.4544(2) 27(1) 173 C(21) 0.4310(2) 0.85527(16) 0.40577(19) 24(1) C(22) 0.4084(2) 0.85444(16) 0.30581(19) 20(1) C(23) 0.4828(2) 0.92081(16) 0.08143(19) 22(1) C(24) 0.5853(2) 0.88058(17) 0.07791(18) 21(1) C(25) 0.5902(2) 0.79610(17) 0.0648(2) 30(1) C(26) 0.6832(2) 0.75845(19) 0.0594(2) 36(1) C(27) 0.7722(2) 0.8052(2) 0.0678(2) 33(1) C(28) 0.7680(2) 0.88936(19) 0.0802(2) 32(1) C(29) 0.6750(2) 0.92747(18) 0.08525(19) 26(1) C(30) 0.1963(2) 0.92755(16) 0.2392(2) 22(1) C(31) 0.1605(2) 0.97924(17) 0.1599(2) 27(1) C(32) 0.1449(2) 1.06356(18) 0.1708(2) 32(1) C(33) 0.1648(2) 1.09701(18) 0.2619(2) 32(1) C(34) 0.2006(2) 1.04799(18) 0.3423(2) 31(1) C(35) 0.2157(2) 0.96472(17) 0.3304(2) 24(1)

Table 3. Bond lengths [A] and angles [deg] for II-38 ______

Cl(1)-C(31) 1.741(3) O(1)-C(11) 1.202(3) O(2)-C(11) 1.343(3) O(2)-C(12) 1.454(3) O(3)-C(14) 1.193(3) O(4)-C(14) 1.333(3) O(4)-C(15) 1.451(3) O(5)-C(16) 1.218(3) N(1)-C(5) 1.410(3) N(1)-C(4) 1.464(3) N(1)-C(1) 1.472(3) N(2)-C(16) 1.364(3) N(2)-C(17) 1.407(3) N(2)-C(23) 1.463(3) C(1)-C(11) 1.520(4) C(1)-C(2) 1.544(4) C(1)-H(1) 1.0000 C(2)-C(14) 1.509(4) C(2)-C(3) 1.539(4) C(2)-H(2) 1.0000 C(3)-C(22) 1.504(4) C(3)-C(16) 1.537(4) C(3)-C(4) 1.554(3) C(4)-C(30) 1.513(4) C(4)-H(4) 1.0000 174 C(5)-C(10) 1.390(4) C(5)-C(6) 1.398(4) C(6)-C(7) 1.378(4) C(6)-H(6) 0.9500 C(7)-C(8) 1.376(4) C(7)-H(7) 0.9500 C(8)-C(9) 1.380(4) C(8)-H(8) 0.9500 C(9)-C(10) 1.372(4) C(9)-H(9) 0.9500 C(10)-H(10) 0.9500 C(12)-C(13) 1.513(4) C(12)-H(12A) 0.9900 C(12)-H(12B) 0.9900 C(13)-H(13A) 0.9800 C(13)-H(13B) 0.9800 C(13)-H(13C) 0.9800 C(15)-H(15A) 0.9800 C(15)-H(15B) 0.9800 C(15)-H(15C) 0.9800 C(17)-C(18) 1.378(4) C(17)-C(22) 1.392(3) C(18)-C(19) 1.400(4) C(18)-H(18) 0.9500 C(19)-C(20) 1.377(4) C(19)-H(19) 0.9500 C(20)-C(21) 1.387(4) C(20)-H(20) 0.9500 C(21)-C(22) 1.381(4) C(21)-H(21) 0.9500 C(23)-C(24) 1.511(4) C(23)-H(23A) 0.9900 C(23)-H(23B) 0.9900 C(24)-C(25) 1.384(4) C(24)-C(29) 1.388(4) C(25)-C(26) 1.386(4) C(25)-H(25) 0.9500 C(26)-C(27) 1.378(4) C(26)-H(26) 0.9500 C(27)-C(28) 1.377(4) C(27)-H(27) 0.9500 C(28)-C(29) 1.387(4) C(28)-H(28) 0.9500 C(29)-H(29) 0.9500 C(30)-C(31) 1.395(4) 175 C(30)-C(35) 1.397(4) C(31)-C(32) 1.395(4) C(32)-C(33) 1.369(4) C(32)-H(32) 0.9500 C(33)-C(34) 1.382(4) C(33)-H(33) 0.9500 C(34)-C(35) 1.379(4) C(34)-H(34) 0.9500 C(35)-H(35) 0.9500 C(11)-O(2)-C(12) 115.9(2) C(14)-O(4)-C(15) 115.7(2) C(5)-N(1)-C(4) 122.9(2) C(5)-N(1)-C(1) 117.6(2) C(4)-N(1)-C(1) 110.6(2) C(16)-N(2)-C(17) 111.1(2) C(16)-N(2)-C(23) 123.5(2) C(17)-N(2)-C(23) 125.0(2) N(1)-C(1)-C(11) 114.4(2) N(1)-C(1)-C(2) 103.9(2) C(11)-C(1)-C(2) 108.3(2) N(1)-C(1)-H(1) 110.0 C(11)-C(1)-H(1) 110.0 C(2)-C(1)-H(1) 110.0 C(14)-C(2)-C(3) 116.5(2) C(14)-C(2)-C(1) 113.4(2) C(3)-C(2)-C(1) 105.1(2) C(14)-C(2)-H(2) 107.1 C(3)-C(2)-H(2) 107.1 C(1)-C(2)-H(2) 107.1 C(22)-C(3)-C(16) 102.4(2) C(22)-C(3)-C(2) 115.6(2) C(16)-C(3)-C(2) 111.8(2) C(22)-C(3)-C(4) 115.6(2) C(16)-C(3)-C(4) 110.8(2) C(2)-C(3)-C(4) 101.0(2) N(1)-C(4)-C(30) 112.7(2) N(1)-C(4)-C(3) 101.0(2) C(30)-C(4)-C(3) 115.2(2) N(1)-C(4)-H(4) 109.2 C(30)-C(4)-H(4) 109.2 C(3)-C(4)-H(4) 109.2 C(10)-C(5)-C(6) 118.3(3) C(10)-C(5)-N(1) 118.7(2) C(6)-C(5)-N(1) 123.0(2) C(7)-C(6)-C(5) 120.0(3) 176 C(7)-C(6)-H(6) 120.0 C(5)-C(6)-H(6) 120.0 C(8)-C(7)-C(6) 121.4(3) C(8)-C(7)-H(7) 119.3 C(6)-C(7)-H(7) 119.3 C(7)-C(8)-C(9) 118.5(3) C(7)-C(8)-H(8) 120.7 C(9)-C(8)-H(8) 120.7 C(10)-C(9)-C(8) 121.1(3) C(10)-C(9)-H(9) 119.5 C(8)-C(9)-H(9) 119.5 C(9)-C(10)-C(5) 120.7(3) C(9)-C(10)-H(10) 119.7 C(5)-C(10)-H(10) 119.7 O(1)-C(11)-O(2) 124.5(3) O(1)-C(11)-C(1) 124.3(3) O(2)-C(11)-C(1) 111.1(2) O(2)-C(12)-C(13) 108.9(2) O(2)-C(12)-H(12A) 109.9 C(13)-C(12)-H(12A) 109.9 O(2)-C(12)-H(12B) 109.9 C(13)-C(12)-H(12B) 109.9 H(12A)-C(12)-H(12B) 108.3 C(12)-C(13)-H(13A) 109.5 C(12)-C(13)-H(13B) 109.5 H(13A)-C(13)-H(13B) 109.5 C(12)-C(13)-H(13C) 109.5 H(13A)-C(13)-H(13C) 109.5 H(13B)-C(13)-H(13C) 109.5 O(3)-C(14)-O(4) 124.7(3) O(3)-C(14)-C(2) 124.3(3) O(4)-C(14)-C(2) 110.9(2) O(4)-C(15)-H(15A) 109.5 O(4)-C(15)-H(15B) 109.5 H(15A)-C(15)-H(15B) 109.5 O(4)-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)-N(2) 126.4(2) O(5)-C(16)-C(3) 126.0(2) N(2)-C(16)-C(3) 107.6(2) C(18)-C(17)-C(22) 122.2(3) C(18)-C(17)-N(2) 128.1(3) C(22)-C(17)-N(2) 109.7(2) C(17)-C(18)-C(19) 116.9(3) 177 C(17)-C(18)-H(18) 121.5 C(19)-C(18)-H(18) 121.5 C(20)-C(19)-C(18) 121.3(3) C(20)-C(19)-H(19) 119.3 C(18)-C(19)-H(19) 119.3 C(19)-C(20)-C(21) 120.9(3) C(19)-C(20)-H(20) 119.5 C(21)-C(20)-H(20) 119.5 C(22)-C(21)-C(20) 118.5(3) C(22)-C(21)-H(21) 120.7 C(20)-C(21)-H(21) 120.7 C(21)-C(22)-C(17) 120.1(3) C(21)-C(22)-C(3) 131.5(2) C(17)-C(22)-C(3) 108.4(2) N(2)-C(23)-C(24) 113.1(2) N(2)-C(23)-H(23A) 109.0 C(24)-C(23)-H(23A) 109.0 N(2)-C(23)-H(23B) 109.0 C(24)-C(23)-H(23B) 109.0 H(23A)-C(23)-H(23B) 107.8 C(25)-C(24)-C(29) 119.1(3) C(25)-C(24)-C(23) 120.0(2) C(29)-C(24)-C(23) 120.9(2) C(24)-C(25)-C(26) 120.7(3) C(24)-C(25)-H(25) 119.7 C(26)-C(25)-H(25) 119.7 C(27)-C(26)-C(25) 119.9(3) C(27)-C(26)-H(26) 120.0 C(25)-C(26)-H(26) 120.0 C(28)-C(27)-C(26) 119.8(3) C(28)-C(27)-H(27) 120.1 C(26)-C(27)-H(27) 120.1 C(27)-C(28)-C(29) 120.6(3) C(27)-C(28)-H(28) 119.7 C(29)-C(28)-H(28) 119.7 C(28)-C(29)-C(24) 119.9(3) C(28)-C(29)-H(29) 120.0 C(24)-C(29)-H(29) 120.0 C(31)-C(30)-C(35) 116.4(2) C(31)-C(30)-C(4) 122.2(2) C(35)-C(30)-C(4) 121.4(2) C(32)-C(31)-C(30) 121.9(3) C(32)-C(31)-Cl(1) 117.4(2) C(30)-C(31)-Cl(1) 120.7(2) C(33)-C(32)-C(31) 119.4(3) 178 C(33)-C(32)-H(32) 120.3 C(31)-C(32)-H(32) 120.3 C(32)-C(33)-C(34) 120.5(3) C(32)-C(33)-H(33) 119.8 C(34)-C(33)-H(33) 119.8 C(35)-C(34)-C(33) 119.5(3) C(35)-C(34)-H(34) 120.3 C(33)-C(34)-H(34) 120.3 C(34)-C(35)-C(30) 122.2(3) C(34)-C(35)-H(35) 118.9 C(30)-C(35)-H(35) 118.9

Symmetry transformations used to generate equivalent atoms: Table 4. Anisotropic displacement parameters (A^2 x 10^3) for II-38

The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]

______

U11 U22 U33 U23 U13 U12 ______

Cl(1) 70(1) 29(1) 26(1) 4(1) 5(1) 11(1) O(1) 43(1) 23(1) 44(1) 11(1) 6(1) -5(1) O(2) 32(1) 23(1) 27(1) -1(1) 1(1) -6(1) O(3) 37(1) 28(1) 34(1) 10(1) 13(1) 10(1) O(4) 25(1) 36(1) 44(1) 13(1) 17(1) 7(1) O(5) 29(1) 29(1) 18(1) -3(1) 5(1) -4(1) N(1) 21(1) 17(1) 25(1) 4(1) 11(1) 4(1) N(2) 23(1) 21(1) 17(1) 0(1) 7(1) -1(1) C(1) 26(2) 16(2) 23(2) 4(1) 9(1) 3(1) C(2) 21(2) 23(2) 21(2) 2(1) 6(1) 1(1) C(3) 20(2) 20(2) 21(2) 0(1) 9(1) -1(1) C(4) 20(2) 18(2) 21(2) 0(1) 8(1) -1(1) C(5) 22(2) 17(2) 25(2) -2(1) 8(1) -2(1) C(6) 29(2) 27(2) 23(2) 4(1) 9(1) 0(1) C(7) 27(2) 35(2) 32(2) 1(1) 7(1) 5(1) C(8) 24(2) 37(2) 36(2) 3(2) 16(2) 3(2) C(9) 36(2) 36(2) 33(2) 7(2) 18(2) 2(2) C(10) 27(2) 28(2) 29(2) 5(1) 12(1) 6(1) C(11) 24(2) 23(2) 27(2) 2(1) 10(1) 5(1) C(12) 35(2) 31(2) 39(2) -9(2) 5(2) -11(2) 179 C(13) 55(3) 49(2) 55(2) -25(2) 20(2) -9(2) C(14) 29(2) 17(2) 22(2) -4(1) 9(1) -1(1) C(15) 23(2) 47(2) 60(2) 7(2) 17(2) 10(2) C(16) 18(2) 21(2) 23(2) 1(1) 7(1) 3(1) C(17) 21(2) 18(2) 23(2) 0(1) 4(1) 1(1) C(18) 26(2) 20(2) 32(2) -3(1) 6(1) -5(1) C(19) 27(2) 29(2) 32(2) -6(1) 3(1) -6(1) C(20) 32(2) 29(2) 19(2) -4(1) 2(1) 3(1) C(21) 30(2) 21(2) 21(2) 1(1) 8(1) 4(1) C(22) 20(2) 18(2) 25(2) -1(1) 8(1) 1(1) C(23) 27(2) 21(2) 22(2) 1(1) 10(1) -3(1) C(24) 23(2) 23(2) 17(2) 1(1) 7(1) -1(1) C(25) 29(2) 24(2) 38(2) -3(1) 11(2) -1(1) C(26) 36(2) 29(2) 45(2) -5(2) 15(2) 6(2) C(27) 25(2) 43(2) 33(2) -7(2) 13(1) 3(2) C(28) 28(2) 35(2) 33(2) 1(2) 9(1) -5(2) C(29) 30(2) 23(2) 26(2) 2(1) 9(1) 0(1) C(30) 21(2) 21(2) 25(2) 0(1) 8(1) 2(1) C(31) 35(2) 22(2) 25(2) -1(1) 11(1) 1(1) C(32) 39(2) 21(2) 37(2) 6(1) 12(2) 5(1) C(33) 34(2) 18(2) 48(2) -4(2) 15(2) 2(1) C(34) 33(2) 27(2) 35(2) -4(1) 13(2) -2(1) C(35) 23(2) 24(2) 27(2) -1(1) 8(1) 2(1)

Table 5. Hydrogen coordinates ( x 10^4) and isotropic displacement parameters (A^2 x 10^3) for II-38

______

x y z U(eq) ______

H(1) 2769 6953 3828 25 H(2) 2879 6898 1862 26 H(4) 1670 8168 1650 23 H(6) 112 8633 2223 31 H(7) -1421 8712 2760 37 H(8) -1589 8033 4162 37 H(9) -184 269 5035 40 H(10) 1373 7218 4550 32 H(12A) -61 6011 847 43 H(12B) 362 5415 1756 43 H(13A) 1545 5848 371 78 H(13B) 988 4974 397 78 180 H(13C) 1941 5234 1263 78 H(15A) 6174 6635 3512 63 H(15B) 6479 6883 2519 63 H(15C) 5939 6011 2613 63 H(18) 5931 9781 2684 31 H(19) 6300 9800 4394 36 H(20) 5300 9047 5232 32 H(21) 3906 8239 4405 28 H(23A) 4944 9806 940 27 H(23B) 4340 9146 175 27 H(25) 5291 7636 594 36 H(26) 6855 7005 499 43 H(27) 8363 7795 651 39 H(28) 8293 9216 854 38 H(29) 6728 9856 937 32 H(32) 1208 10975 1156 38 H(33) 1538 11543 2698 38 H(34) 2147 10715 4054 37 H(35) 2402 9315 3862 29

Table 6. Torsion angles [deg] for II-38. ______

C(5)-N(1)-C(1)-C(11) 44.0(3) C(4)-N(1)-C(1)-C(11) -104.4(3) C(5)-N(1)-C(1)-C(2) 161.9(2) C(4)-N(1)-C(1)-C(2) 13.5(3) N(1)-C(1)-C(2)-C(14) 142.9(2) C(11)-C(1)-C(2)-C(14) -95.1(3) N(1)-C(1)-C(2)-C(3) 14.5(3) C(11)-C(1)-C(2)-C(3) 136.5(2) C(14)-C(2)-C(3)-C(22) -35.9(3) C(1)-C(2)-C(3)-C(22) 90.6(3) C(14)-C(2)-C(3)-C(16) 80.7(3) C(1)-C(2)-C(3)-C(16) -152.8(2) C(14)-C(2)-C(3)-C(4) -161.4(2) C(1)-C(2)-C(3)-C(4) -34.9(3) C(5)-N(1)-C(4)-C(30) 54.9(3) C(1)-N(1)-C(4)-C(30) -158.8(2) C(5)-N(1)-C(4)-C(3) 178.3(2) C(1)-N(1)-C(4)-C(3) -35.4(3) C(22)-C(3)-C(4)-N(1) -83.6(3) C(16)-C(3)-C(4)-N(1) 160.6(2) C(2)-C(3)-C(4)-N(1) 42.0(2) 181 C(22)-C(3)-C(4)-C(30) 38.1(3) C(16)-C(3)-C(4)-C(30) -77.8(3) C(2)-C(3)-C(4)-C(30) 163.6(2) C(4)-N(1)-C(5)-C(10) -171.8(2) C(1)-N(1)-C(5)-C(10) 44.0(3) C(4)-N(1)-C(5)-C(6) 7.4(4) C(1)-N(1)-C(5)-C(6) -136.8(3) C(10)-C(5)-C(6)-C(7) 1.1(4) N(1)-C(5)-C(6)-C(7) -178.1(3) C(5)-C(6)-C(7)-C(8) -1.3(4) C(6)-C(7)-C(8)-C(9) 0.2(5) C(7)-C(8)-C(9)-C(10) 1.1(5) C(8)-C(9)-C(10)-C(5) -1.2(5) C(6)-C(5)-C(10)-C(9) 0.1(4) N(1)-C(5)-C(10)-C(9) 179.4(3) C(12)-O(2)-C(11)-O(1) -13.5(4) C(12)-O(2)-C(11)-C(1) 163.5(2) N(1)-C(1)-C(11)-O(1) -135.0(3) C(2)-C(1)-C(11)-O(1) 109.6(3) N(1)-C(1)-C(11)-O(2) 48.0(3) C(2)-C(1)-C(11)-O(2) -67.4(3) C(11)-O(2)-C(12)-C(13) -84.1(3) C(15)-O(4)-C(14)-O(3) -4.0(4) C(15)-O(4)-C(14)-C(2) 178.8(2) C(3)-C(2)-C(14)-O(3) 139.7(3) C(1)-C(2)-C(14)-O(3) 17.5(4) C(3)-C(2)-C(14)-O(4) -43.0(3) C(1)-C(2)-C(14)-O(4) -165.2(2) C(17)-N(2)-C(16)-O(5) -171.2(3) C(23)-N(2)-C(16)-O(5) 1.7(4) C(17)-N(2)-C(16)-C(3) 8.8(3) C(23)-N(2)-C(16)-C(3) -178.2(2) C(22)-C(3)-C(16)-O(5) 171.4(3) C(2)-C(3)-C(16)-O(5) 47.1(4) C(4)-C(3)-C(16)-O(5) -64.8(3) C(22)-C(3)-C(16)-N(2) -8.7(3) C(2)-C(3)-C(16)-N(2) -133.0(2) C(4)-C(3)-C(16)-N(2) 115.1(2) C(16)-N(2)-C(17)-C(18) 173.4(3) C(23)-N(2)-C(17)-C(18) 0.6(4) C(16)-N(2)-C(17)-C(22) -5.3(3) C(23)-N(2)-C(17)-C(22) -178.1(2) C(22)-C(17)-C(18)-C(19) 1.0(4) N(2)-C(17)-C(18)-C(19) -177.6(3) C(17)-C(18)-C(19)-C(20) -0.2(4) 182 C(18)-C(19)-C(20)-C(21) 0.1(4) C(19)-C(20)-C(21)-C(22) -0.7(4) C(20)-C(21)-C(22)-C(17) 1.5(4) C(20)-C(21)-C(22)-C(3) 178.8(3) C(18)-C(17)-C(22)-C(21) -1.6(4) N(2)-C(17)-C(22)-C(21) 177.2(2) C(18)-C(17)-C(22)-C(3) -179.5(2) N(2)-C(17)-C(22)-C(3) -0.7(3) C(16)-C(3)-C(22)-C(21) -172.0(3) C(2)-C(3)-C(22)-C(21) -50.2(4) C(4)-C(3)-C(22)-C(21) 67.4(4) C(16)-C(3)-C(22)-C(17) 5.6(3) C(2)-C(3)-C(22)-C(17) 127.3(2) C(4)-C(3)-C(22)-C(17) -115.0(2) C(16)-N(2)-C(23)-C(24) -98.3(3) C(17)-N(2)-C(23)-C(24) 73.6(3) N(2)-C(23)-C(24)-C(25) 56.3(3) N(2)-C(23)-C(24)-C(29) -125.3(3) C(29)-C(24)-C(25)-C(26) 0.3(4) C(23)-C(24)-C(25)-C(26) 178.7(3) C(24)-C(25)-C(26)-C(27) 0.5(5) C(25)-C(26)-C(27)-C(28) -0.9(5) C(26)-C(27)-C(28)-C(29) 0.6(5) C(27)-C(28)-C(29)-C(24) 0.1(4) C(25)-C(24)-C(29)-C(28) -0.6(4) C(23)-C(24)-C(29)-C(28) -179.0(2) N(1)-C(4)-C(30)-C(31) -145.4(3) C(3)-C(4)-C(30)-C(31) 99.5(3) N(1)-C(4)-C(30)-C(35) 33.7(4) C(3)-C(4)-C(30)-C(35) -81.4(3) C(35)-C(30)-C(31)-C(32) 0.1(4) C(4)-C(30)-C(31)-C(32) 179.3(3) C(35)-C(30)-C(31)-Cl(1) -179.0(2) C(4)-C(30)-C(31)-Cl(1) 0.1(4) C(30)-C(31)-C(32)-C(33) -0.3(5) Cl(1)-C(31)-C(32)-C(33) 178.8(2) C(31)-C(32)-C(33)-C(34) 0.5(5) C(32)-C(33)-C(34)-C(35) -0.4(4) C(33)-C(34)-C(35)-C(30) 0.2(4) C(31)-C(30)-C(35)-C(34) 0.0(4) C(4)-C(30)-C(35)-C(34) -179.2(3) ______