Total Synthesis of Salvinorin a Via an IMDA-Tsuji Allylation Strategy

Total Synthesis of Salvinorin A via an IMDA-Tsuji Allylation Strategy

DISSERTATION

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University

Nathan Jeffrey Line

Graduate Program in Chemistry

The Ohio State University

2016

Dissertation Committee:

Professor Craig J. Forsyth, Advisor

Professor Anita Mattson

Professor David Nagib

Nathan Jeffrey Line

2016

ABSTRACT

Salvia divinorum, a Mexican sage, was used for hundreds of years by the Mazatec

Indians for both medicinal and religious purposes. These hallucinogenic properties have caused a recent interest in the recreational drug world and therefore, resulted in a multitude of laws/restrictions banning Salvia from the United States as well as many other countries around the world. In 1982, Ortega reported the first isolation of the neoclerodane diterpenoid, salvinorin A, from Salvia divinorum. Valdes later confirmed this finding independently two years later. It was determined that salvinorin A was the compound responsible for the hallucinogenic effects experienced through ingestion or inhalation of Salvia. Interestingly, salvinorin A was and has remained the only non- alkaloid hallucinogen as well as the first highly potent and selective κ-opioid receptor agonist. These properties have not only piqued the interest of synthetic chemists but also medicinal chemists towards its potential role as a therapeutic agent.

Herein is a summary of my total synthesis of salvinorin A with the goals to innovate a flexible and reliable total synthesis of salvinorin A and analogs to pursue SAR studies. I have developed an efficient synthesis of the decalin core that overcame obstacles and scale-up issues in the routes established by previous members. Utilizing the linear dithiane Diels-Alder precursor, I was able to implement an intramolecular

Diels-Alders (IMDA)/Tsuji allylation combination to stereoselectively install the decalin core with both quaternary centers. Bistriflate formation followed by a palladium- ii mediated methoxy carbonylation provided the functional group handles needed to construct the skeletal framework. The furan moiety was installed selectively using a

BINOL-titanium catalyst with a furyltitanim nucleophile. Conjugate reduction of both the methyl ester and furyl-lactone functional groups using SmI2 followed by diol manipulation provided targeted natural product salvinorin A.

iii

This work is dedicated to my family for their everlasting

support and love through all my endeavors.

ACKNOWLEDGEMENTS

First and foremost, I have to thank God for bestowing upon me the intellectual capabilities and determination necessary to pursue a career as challenging and rewarding as that of organic synthesis. It is only through Him that I am able to do anything and am unspeakable grateful for the opportunities of my past and of those yet to come.

Secondly, I would like to thank my advisor, Professor Craig J. Forsyth, for the opportunity to work in this group. The knowledge that I have acquired during by time in this lab has provided me with the tools and techniques necessary in order to succeed in both chemistry and life. I will always be grateful for your advice, support, and confidence throughout my graduate career.

My greatest experience and memories would be incomplete without the countless individuals that I have had the pleasure to meet. There is obviously not enough space to thank all of you for what you have done for me.

I would like to start by thanking Dr. Matt Jackel for providing me with not only the first but also the most impactful graduate experiences I could have asked for. Your teachings of laboratory techniques along with your chemical wisdom have shaped me into the chemist that I am today. Not only that, you were and continue to be one of my greatest friends and I will always remember our times spent both inside and outside lab.

My time spent in 4028 Evans Lab/190 CBEC has provided me many fond memories and relationships. To Mr. Kedwin Rosa, words cannot express the value in our friendship. You have not only been a great source of intellectual discussion but our times together outside lab have been some of the best of my life. To Daniel Adu-Ampratwum,

I thank you for all your chemical and technical advice. Your dedication and work ethic was impressive and impactful. To the rest of the Forsyth group members, Antony

Okumu, Daniel Akwaboak, Nate Kenton, Li Xiao, and Charles Clay, you have all provided me with a great work environment and lasting friendships.

I would not be were I am today without the love and support of my parents, Jeff and Mardee, and my brother, Ian. Growing up, you taught me a vast array of important life values including hard work, determination, sacrifice, and love, which have molded me into the man I am. I love you very much and hope I have made you proud.

I would also like to thank Dick and Cyndy Fields for their continual support and encouragement. From the beginning, you cared for me like one of your own and for that

I am ever grateful. I appreciate all you have done for Bethany and I and look forward to the future.

Finally and most importantly, to my wife and the love of my life, Bethany, words cannot describe my gratitude. You sacrificed everything to be here with me. You have stood be my side this entire journey, through my highest high and lowest low. You are my biggest supporter, my best friend, and the rock with which I stand on. I hope that you are proud to call me your husband and I look forward to the rest of our lives together. I love you: FOREVER AND FOR ALWAYS!

VITA

August 1988 ...... Born, Crawfordsville, Indiana

May 2007 ...... Southmont High School

May 2011 ...... B.A. Chemistry, Wabash College

June 2011-present ...... Graduate Teaching and Research Associate

Department of Chemistry and Biochemistry

The Ohio State University

PUBLICATIONS

Line, N. J.; Burns, A. C.; Butler, S.; Casbohm, J.; Forsyth, C. J. Total Synthesis of Salvinorin A. J. Am. Chem. Soc. 2016, Submitted.

FIELDS OF STUDY

Major Field: Chemistry

vii

TABLE OF CONTENTS

Page

Abstract ...... ii

Dedication ...... iv

Acknowledgments ...... v

Vita ...... vii

List of Figures ...... xiii

List of Schemes ...... xiv

List of Tables ...... xvii

List of Abbreviations ...... xviii

Chapters:

1. Isolation and Biological Significance of Salvinorin A ...... 1

1.1 Historical Background of Salvia divinorum ...... 1

1.2 Isolation and Structure Elucidation of Salvinorin A ...... 2

1.3 Salvinorin Family...... 7

1.4 A Potent κ-Opioid Receptor Agonist ...... 8

1.4.1 Opioid Receptors ...... 8

1.4.2 κ-Opioid Receptor Binding ...... 8

viii

1.5 Biological Activity ...... 13

1.5.1 Potential Medicinal and Therapeutic Role ...... 13

1.5.2 Structure-Activity Relationship Studies ...... 13

2. Previously Completed Total Synthesis/Additional Efforts Towards Salvinorin A ...... 15

2.1 Introduction to Prior Synthetic Efforts ...... 15

2.2 Evans’ Total Synthesis ...... 16

2.2.1 Retrosynthetic Analysis ...... 16

2.2.2 Preparation of the Aldehyde Fragment 2.3 ...... 17

2.2.3 Synthesis of Vinyl Iodide 2.4...... 19

2.2.4 Fragment Coupling and Transformation ...... 19

2.2.5 TBAF-Mediated Transannular Cyclization ...... 21

2.2.6 Completion of the Total Synthesis ...... 22

2.3 Hagiwara 1st-Generation Total Synthesis ...... 23

2.3.1 Retrosynthetic Analysis from (−)-Methyl Barbascoate ...... 23

2.3.2 Synthesis of Diene 2.27 ...... 25

2.3.3 Elaboration of Diene to Furylalcohol 2.26 ...... 25

2.3.4 Conclusion of the Total Synthesis ...... 27

2.4 Hagiwara 2nd-Generation Total Synthesis ...... 28

2.4.1 Purpose and Goals ...... 28

2.4.2 Furylketone 2.44 Formation ...... 29

2.4.3 Construction of the Carbon Skeleton 2.48 ...... 30

2.4.4 2nd-Generation Total Synthesis Endgame ...... 31

2.5 Rook’s Synthetic Approach ...... 32

2.5.1 Retrosynthetic Analysis ...... 32

2.5.2 Preparation of Aminofurans 2.56a/2.56b ...... 33

2.5.3 Diels-Alder Studies and THF Ring Opening ...... 34

2.5.4 Furan Fragment 2.52 Synthesis ...... 35

2.6 Burns Synthetic Approach ...... 36

2.6.1 Retrosynthesis ...... 36

2.6.2 Preparation of Diels-Alder Precursor 2.66 ...... 36

2.6.3 IMDA/Tsuji Allylation Sequence ...... 38

2.7 Butler Synthetic Approach ...... 40

2.7.1 Goals and Modifications ...... 40

2.7.2 Retrosynthetic Analysis ...... 41

2.7.3 Construction of Aldehyde 2.76 ...... 41

2.7.4 Synthesis of Enol Carbonate 2.75 ...... 43

2.7.5 IMDA Improvement ...... 43

2.7.6 Post-IMDA and Carboskeleton Framework ...... 46

3. Early Route Improvements and Diels-Alder Optimization Towards Common Dione Intermediate ...... 49

3.1 Synthetic Issues ...... 49

3.2 Synthetic Revision of Aldehyde 2.76 ...... 49

3.2.1 Cyanide Substitution ...... 49

3.2.2 α-Bromination/Reduction Sequence ...... 51

3.2.3 Cuprate Substitution...... 52 x

3.3 Scale-Up Towards Enol Carbonate 2.75 ...... 53

3.4 Inverse-Demand IMDA Studies/Optimization ...... 54

3.5 Formation of Dione 2.65 Through Tsuji Allylation ...... 56

4. Construction of Full Carboskeleton Through Asymmetric 3-FurylTitanium Addition ...... 59

4.1 Late-Stage Retrosynthetic Analysis ...... 59

4.2 Oxidative Cleavage of Terminal Alkene 2.65 ...... 60

4.3 End Game Furan Installation ...... 62

4.4 Unexpected Furan Selectivity ...... 67

4.5 Attempted Stereochemical Inversion of C12-Furylalcohol 4.19 ...... 70

4.5.1 Intermolecular/Intramolecular Mitsunobu Reactions ...... 70

4.5.2 Oxidation/Reduction Sequence ...... 73

4.5.3 Asymmetric 3-Furanyl Titanium Addition ...... 74

4.6 Unexpected Asymmetric 3-Furyltitanium Success ...... 76

5. Need for a More Efficient, Higher Throughput Route: The Dithiane Solution ...... 79

5.1 Need for Higher Throughput Route ...... 79

5.2 Exploiting Current Knowledge of Inverse-Demand IMDA ...... 79

5.3 Efficient Scale-up of Dione 2.65 via New Dithiane Route ...... 81

6. Total Synthesis of Salvinorin A: Reduction and End Game ...... 83

6.1 Reduction of α, β-Unsaturated Lactone 4.39 ...... 83

6.2 Derivation of Vicinal Diol 6.2 ...... 85

7. Salvinorin Analogues and Future Work ...... 87

7.1 Future Work ...... 87 xi

7.2 Summary ...... 88

List of References ...... 90

Appendix A: Experimental Detail ...... 97

Appendix B: 1H/13C NMR Spectra ...... 123

xii

LIST OF FIGURES

Figure Page

1.1 Structure of salvinorin A 1.1 ...... 2

1.2 Salvinorin Family...... 5

1.3 Divinatorin, salvinicin, and salvidivin families ...... 6

1.4 Additional compounds isolated from S. divinorum ...... 7

1.5 Originally proposed binding mode of 1.1 to the KOR ...... 10

1.6 Revised binding mode of 1.1 to the KOR ...... 11

1.7 Binding mode of 1.1 following KOR crystal structure ...... 12

1.8 Summary of SAR studies of various analogues of 1.1 ...... 14

xiii

LIST OF SCHEMES

Scheme Page

1.1 Biosynthesis of 1.1 ...... 4

2.1 Evans’ retrosynthesis of 1.1 ...... 16

2.2 Synthesis of aldehyde 2.3 ...... 18

2.3 Synthesis of vinyl iodide fragment 2.4 ...... 19

2.4 Fragment coupling and transformation ...... 20

2.5 TBAF-mediated transannular cyclization ...... 21

2.6 Evans’ completion of salvinorin A ...... 22

2.7 Hagiwara 1st-generation retrosynthesis of 1.1 ...... 23

2.8 Preparation of diene 2.27 ...... 24

2.9 Installation of furylalcohol moiety ...... 26

2.10 Hagiwara 1st-generation completion of salvinorin A ...... 28

2.11 Preparation of furylketone 2.44 ...... 29

2.12 Construction of carbon skeleton framework ...... 30

2.13 2nd-generation completion of 1.1 ...... 32

2.14 Rook’s retrosynthetic analysis ...... 33

2.15 Preparation of furans 2.56a and 2.56b ...... 33

xiv

2.16 Diels-Alder reactions with methyl acrylate ...... 34

2.17 Preparation of ketone 2.51 ...... 35

2.18 Racemic synthesis of furyllactone 2.52 ...... 36

2.19 Burns retrosynthetic analysis ...... 37

2.20 Synthesis of Diels-Alder precursor 2.66 ...... 38

2.21 Diels-Alder/Tsuji allylation sequence ...... 39

2.22 Proposed transition states of endo/exo Diels-Alder reaction ...... 40

2.23 Butler retrosynthetic analysis ...... 41

2.24 Construction of aldehyde 2.76 ...... 42

2.25 Synthesis of enol carbonate 2.75 ...... 44

2.26 Inverse-demand IMDA ...... 44

2.27 Proposed transition states of inverse-demand IMDA ...... 45

2.28 Proposed transition states of Tsuji allylation reaction ...... 47

2.29 Post-IMDA and carboskeleton framework ...... 48

3.1 Cyanide substitution of alkyl iodide ...... 50

3.2 α-Bromination/reduction sequences ...... 51

3.3 Cuprate substitution of alkyl iodide 3.2 ...... 53

3.4 Scale-up of enol carbonate 2.75 ...... 54

3.5 C4 alcohol deprotection prior to Tsuji allylation ...... 57

3.6 Formation of dione 2.65 via Tsuji allylation ...... 58

4.1 Late-state retrosynthetic analysis ...... 60

4.2 Stable ozonide of terminal alkene ...... 61

4.3 Lemieux-Johnson oxidation of dione 2.65 ...... 61

4.4 Preparation of dimethyl ester 2.88 ...... 62

4.5 Mechanism of magnesium in methanol reduction ...... 64

4.6 Route A/Route B towards synthesis of 1.1 ...... 65

4.7 Route A towards salvinorin A ...... 66

4.8 Formation of aldehyde 4.18 ...... 67

4.9 Tetrahydropyran formation during ketal-hydrolysis ...... 69

4.10 Mechanism of Mitsunobu reaction ...... 71

4.11 Intramolecular/Intermolecular Mitsunobu reactions ...... 72

4.12 Explaination of selectivity/yield for Mitsunobu reactions ...... 72

4.13 K-Selectride®-chelated reduction as proposed by Hagiwara ...... 73

4.14 Oxidation/reduction sequence of furylalcohol 4.22 ...... 74

4.15 Asymmetric titanium additions by Gau and coworkers ...... 75

4.16 Failed asymmetric (3-furyl)Ti(Oi-Pr)3 addition ...... 75

4.17 Unexpected 3-furyltitanium addition to aldehyde 4.37 ...... 77

4.18 Mechanism for 3-furyltitanium addition ...... 78

5.1 Dithiane IMDA reaction ...... 80

5.2 Efficient dithiane route to dione 2.65 ...... 82

6.1 Reduction of lactone 4.39 with SmI2 ...... 85

6.2 Line total synthesis of salvinorin A 1.1 ...... 86

7.1 Future analogues for SAR/KOR binding studies ...... 88

xvi

LIST OF TABLES

Table Page

1.1 Metabolites of pro-dynorphin ...... 9

2.1 Rook’s Diels-Alder results ...... 34

3.1 Summary of aldehyde routes ...... 53

3.2 Inverse-demand IMDA optimization ...... 55

4.1 Conditions for conjugate reduction ...... 63

4.2 3-Metallofuran addition to aldehyde 4.18 ...... 69

5.1 Overall route comparisons to dione 2.65 ...... 82

6.1 Reduction conditions for lactone 4.39 ...... 83

xvii

LIST OF ABBREVIATIONS

1D one-dimensional

2D two-dimensional

α alpha

[α] specific rotation

Å angstrom(s)

Ac acetyl app apparent atm atmosphere(s)

β beta

BAIB bis(acetoxy)iodobenzene

BHB butylated hydroxy benzene (2,6-di-t-butylphenol)

BHT butylated hydroxyl toluene (2,6-di-t-butyl-4-methylphenol)

BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl

BINOL 1,1’-bi-2-naphthol

Bn benzyl

BOM benzyloxymethyl br broad (NMR)

xviii n-Bu normal-butyl t-Bu tert-butyl

Bz benzoyl

°C degrees Celsius

13C carbon-13 calcd calculated

CAN ceric ammonium nitrate

CBS Corey-Bakshi-Shibata cm-1 wavenumbers (IR)

Comins’ reagent N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonamide)

COSY correlation spectroscopy (NMR)

Cp cyclopentadienyl

δ delta; chemical shift in ppm downfield from tetramethylsilane d day(s); doublet (NMR)

DA Diels-Alder

Davis oxaziridine 2-(phenylsulfonyl)-3-phenyloxaziridine dba dibenzylideneacetone

DCC N,N’-dicyclohexylcarbodiimide

DCE dichloroethane

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DEAD diethyl azodicarboxylate

DIBAL-H diisobutylaluminum hydride

xix

DMAP 4-(N,N-dimethylamino)pyridine

DMAPP dimethylallyl pyrophosphate

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMP Dess-Martin periodinane

DMSO dimethylsulfoxide

DOR δ-opioid receptor

DOX 1-deoxy-D-xylulose

DOXP 1-deoxy-D-xylulose 5-phosphate dppf 1,1’-bis(diphenylphosphino)ferrocene dr diastereomeric ratio ee enantiomeric excess

Et ethyl

ESI electrospray ionization

γ gamma g gram(s)

GABA γ-aminobutyric acid

GPCR G-protein coupled receptor

GC gas chromatography h hour(s)

1H proton

HMBC heteronuclear multiple-bond correlation (NMR)

HMPA hexamethylphosphoramide

HMQC heteronuclear multiple-quantum coherence (NMR)

HRMS high-resolution mass spectrometry

HSQC heteronuclear single-quantum coherence (NMR)

Hünig’s base diisopropylethylamine

Hz hertz

IPP isopentenyl pyrophosphate

IMDA intramolecular Diels-Alder imid imidazole

IR infrared

J coupling constant in hertz (NMR)

κ kappa

K-Selectride® potassium tri-sec-butylborohydride

KHMDS potassium hexamethyldisilazide

KOR κ-opioid receptor

L liter(s)

L-Selectride® lithium tri-sec-butylborohydride

LDA lithium diisopropylamide

LiHMDS lithium hexamethyldisilazide

2,6-lutidine 2,6-dimethylpyridine

µ mu; micro m meter(s); milli; multiplet (NMR)

xxi

M mega; moles per liter; molecular ion (MS) mCPBA meta-chloroperoxybenzoic acid

Me methyl

MEP 2-C-methyl-D-erythritol 4-phosphate min minute(s)

MNBA 2-methyl-6-nitrobenzoic anhydride mol mole(s)

MOR µ-opioid receptor

MTPA α-methoxy-α-trifluoromethylphenylacetate

MVA mevalonic acid m/z mass to charge ratio (MS) n nano n.d. not determined

NaHMDS sodium hexmethyldisilazide

NBS N-bromosuccinamide

NHK Nozaki-Hiyama-Kishi reaction

NMO N-methylmorpholine-N-oxide

NMR nuclear magnetic resonance

NOE nuclear Overhauser effect (NMR)

NOESY nuclear Overhauser effect spectroscopy (NMR)

NOR nociception/orphanin FQ receptor o ortho

xxii o-dichlorobenzene o-DCB obsd observed

π pi p para p-TsOH p-toluene sulfonic acid

PDC pyridinium dichromate

Ph phenyl

PhMe toluene pKa -log[Ka]

PMB p-methoxybenzyl ppm parts per million

PPTS pyridinium p-toluenesulfonate i-Pr isopropyl psi pounds per square inch pyr pyridine q quartet (NMR)

Red-Al® sodium bis(2-methoxyethoxy)aluminum hydride

Rf retention factor rt room temperature (ca. 23 °C) s second(s); singlet (NMR)

SAR structure-activity relationship

Stryker’s reagent (triphenylphosphine)copper hydride hexamer

xxiii t tertiary (tert) t triplet (NMR)

TBAF tetrabutylammonium fluoride

TBAI tetrabutylammonium iodide

TBDPS tert-butyldiphenylsilyl

TBS tert-butyldimethylsilyl

TES triethylsilyl

Tf trifluoromethanesulfonyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl

Ts tosyl, p-toluenesulfonyl

TS transition state

xxiv

CHAPTER 1

ISOLATION AND BIOLIGICAL SIGNIFICANCE OF SALVINORIN A

1.1 Historical Background of Salvia divinorum

Salvia divinorum is an indigenous herb found in the region of Oaxaca, Mexico and was first seen used by the Mazatec Indians for both religious and medical purposes.

Upon his arrival in the 1980s, Valdés first witnessed its use during his encounter with a

Mazatec shaman while attempting to heal several different types of illness.1,2 In addition to its medical properties, Valdés also describes the Mazatec culture ingesting large doses of the plant in order to induce religious “visions”.1

Due to these hallucinogenic properties, Salvia divinorum, became a target of high interest within the recreational drug world. In the early 2000s, Giroud and coworkers reported observing a large population, mainly younger people, smoking the dried leaves as a marijuana substitute.3 This report quickly sparked the U.S., as well as many other countries, to ban the use and selling of what had become know as Salvia.

1.2 Isolation of Structure Elucidation of Salvinorin A

Salvinorin A (1.1, Figure 1) is a potent non-alkaloid hallucinogen natural product isolated from the perennial herb Salvia divinorum. This natural product is a neoclerodane diterpenoid biosynthesized by the monophosphate of the 1-deoxy-D-xylulose (DOX) pathway rather than the traditional mevalonic acid (MVA) pathway.4-11 Zjawiony and coworkers studied this biosynthetic route by using a combination of NMR and high- resolution mass spectrometry (HRMS). This was accomplished by growing microshoots of S. divinorum in the presence of [1-13C]-glucose and then analyzing the resulting 13C- radiolabeled salvinorin A. This result was further confirmed by examining plants grown

13 2 12-13 in the presence of [1- C; 3,4- H2]-1-deoxy-D-xylulose (Scheme 1.1).

O O AcO H H O

CO2Me

Figure 1.1. Structure of salvinorin A 1.1

Salvinorin A contains several interesting and challenging structural functional groups. Structurally, 1.1 features a tricyclic core containing a trans-decalin system along with a 6-membered lactone. In addition, the core includes two quaternary centers as well as a 3-substituted furan in the δ-position of the lactone. Although, the number of

2 substituents in this natural product seem small and straight-forward in comparison to many others, their reactivity and thermodynamic stability make 1.1 an extremely challenging target for organic chemists.

Two separate groups, Ortega and Valdés, accomplished the structure elucidation of 1.1 independently. The Ortega group published the first isolation of 1.1, in 1982 from chloroform extracts from the dried leaves of S. divinorum.14 In 1984, Valdés and coworkers published a separate isolation of 1.1 from a common sage plant.15 However,

Valdés refers to 1.1 as divinorum A. Structure elucidation by both groups using 1H and

13C NMR techniques coupled with independent single-crystal X-ray analysis confirmed that both salvinorin A and divinorum A were identical in structure.

Although both groups agreed upon the structure of 1.1, there were discrepancies between their NMR data. It wasn’t until more recently, in 2007, the Giner group determined the complete assignments of the 1H and 13C NMR spectra utilizing 2D NMR techniques including HSQC, HMBC, and COSY along with a variety of solvents. These experiments resulted in the resolution of all 1H signals and allowed the group to unambiguously spectral assignments of 1.1.16 It was realized that their data coincided closer to the data interpretation by Valdés rather than Ortega.

[1-13C]-D-Glucose

• • • • OPP • OPP isopentenyl pyrophosphate O experimental • isotopic pattern •

O O OPP H • H cyclization O •• • • O O • + • H • • • O O • = 13C geranylgeranyl pyrophosphate

OPP

O predicted pattern methyl shift (MVA pathway) • • O • O H H H O H • • • O methyl shift H O • • • • labdanyl cation O • O

OPP oxidation/furan • O formation oxidation predicted pattern • (DOXP pattern) oxidation/ O O oxidation H • H acetylation O • • O O • oxidation/ oxidation/ • methylation • lactonization O O clerodane pyrophosphate

Scheme 1.1. Biosynthesis of 1.1 4

OH ) O O H 1.10 ( J Me 3 2 H OH OAc H R O CO O HO 2 O OAc OH OH R H Salvinorin ) ) ) AcO Me 1.4 1.5 1.6 2 ( ( ( H 2 D E F CO R 3 R Salvinorin Salvinorin Salvinorin OH O ) O H 1.9 ( I Me 2 H

CO HO O Salvinorin ) O HO O H 1.3 ( C Me 2 H . Salvinorin Family . Salvinorin CO O AcO ) O Salvinorin O H 1.8 ( AcO Figure 1.2 Figure H Me 2 H CO HO Salvinorin HO O 1 OAc OH R O ) ) O H 1.2 1.1 ( ( O A B Me ) 2 O H O 1.7 H CO O ( G Me 1 2 H R Salvinorin Salvinorin CO AcO Salvinorin O

OMe O ) O O H 1.18 ( H B 2 Me O HO 2 H ) MeO CO HO O CO O H 1.22 ( D Salvinicin Me 2 HO H AcO CO O Salvidivin AcO OMe O ) O O H 1.17 ( H 2 A OH Me HO 2 ) H CO MeO HO O

CO O

H 1.21 ( C O Salvinicin Me 2 H AcO CO O Salvidivin AcO natorin, salvinicin, natorin, OH ) O and salvidivin families salvidivin and 1.16 H ( . Divi O O F ) Me O 2 O H H 1.20 ( CO B HO Me 2 HO H Figure 1.3 Figure Divinatorin CO O HO Salvidivin AcO 3 Me Me Me H H R OH OAc OAc 2 2 2 OH O 2 ) O CH CH CH CHO Me R O H 1.19 2 1 ( OH OH OH OH H R R A O O Me ) ) ) ) ) 2 H H 3 CO O 1.14 1.13 1.12 1.15 1.11 ( R ( ( ( ( 2 H A D C B E 1 Salvidivin CO R AcO Divinatorin Divinatorin Divinatorin Dininatorin Divinatorin

1.3 Salvinorin Family

Currently, several classes of compounds have been isolated from the leaves of S. divinorum. The first set of members of the salvinorin family (1.1-1.10)15,17-21 differ primarily in the oxidation/aceylation patterns and stereochemistry of the western ring

(Figure 1.2). The divinatorins (1.11-1.16)19,,20,22 all contain an α,β-unsaturated methyl ester in the western ring. In addition, this subset is also missing the lactone moiety

(Figure 1.3). Exhaustive oxidation of the furan ring of 1.1 gives rise to the salvinicins

(1.17 and 1.18).23 The class of salvidivins comprises of a hydroxyl-furanone functionality

(1.19-1.22);20 however, salvidivins A and B have an intact lactone whereas C and D do not. In addition to these compounds, several other known terpenes were isolated from samples of S. divinorum including (−)-hardwickiic acid (1.23), oleanic acid (1.24), presqualene alcohol (1.25), peplusol (1.26), and (E)-phytol (1.27) (Figure 1.4).22 Several products derived from thermal degradation studies have also been reported.24

O H

CO2H H H H HO Oleanic acid (1.24) H

CO2H (−)-Hardwickiic acid (1.23) OH Peplusol (1.26) H

Presqualene alcohol (1.25) OH OH

(E)-Phytol (1.27)

Figure 1.4. Additional compounds isolated from S. divinorum

1.4 A Potent κ-Opioid Receptor Agonist

1.4.1 Opioid Receptors

Opioid receptors belong within a class of seven transmembrane-spanning (7TM)

G-protein coupled receptors (GPCRs).25-27 These receptors are essential in monitoring and controlling the actions of most physiologically relevant neurotransmitters and hormones. They are stimulated by both endogenous opioid peptides and by administered opioid drugs.

At this time, four opioid receptors have been cloned and studied: µ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and nociception/orphanin FQ receptor (NOR).25 The KOR will be discussed in further detail due to its highly selective and potent affinity for 1.1.28

1.4.2 κ-Opioid Receptor Binding

KORs have an extremely high binding affinity for the endogenous peptide dynorphin A, which was discovered by Goldstein and coworkers in 1979.29 Although dynorphin and related peptides (Table 1.1) expressed potent and fairly selective substrates for the KOR, other types of naturally occurring non-alkaloidal agonists had yet to be identified prior to the discovery of 1.1.28

In order to understand the binding pocket of the KOR, the structure of the KOR- ligand complex needed to be solved. Without any concrete structural information, Roth and coworkers proposed a binding mode of 1.1 to the KOR by performing a variety of experiments including radioligand-binding assays, functional assays, as well as KOR

8 molecular modeling and ligand docking studies.28,30 This initial model was based on the structural similarities between 1.1 and another known KOR ligand U69,593 (1.28)

(Figure 1.5).28 However, Roth and coworkers pointed out these two compounds share very few functional similarities.

Metabolite Amino acid sequence

α-Neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys

β-Neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro

Dynorphin (1-32)a Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn- Gln-Lys-Arg-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr

Dynorphin A (1-17) Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn- Gln

Dynorphin A (1-13) Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys

Dynorphin A (1-8) Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile

Dynorphin B (1-29) Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr-Arg-Ser-Gln- Glu-Asp-Pro-Asn-Ala-Tyr-Ser-Gly-Glu-Leu-Phe-Asp-Ala

Dynorphin B (1-13) Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr

Leu-Enkephalinb Tyr-Gly-Gly-Phe-Leu aDynorphin (1-32) is a product of pro-dynorphin, which can be cleaved into dynorphins A and B. bThe amino acid sequence of Leu-enkephalin is found in all cleaved products of pro-dynorphin.

Table 1.1. Metabolites of pro-dynorphin

N N O O H H AcO O O O

U69,593 (1.28) CO2Me 1.1 O

H2N Gln115

O O HO−Tyr139 O H H O O Tyr313−OH

O O HO−Tyr312

Figure 1.5. Originally proposed binding mode of 1.1 to the KOR

In a second study, it was observed that 1.1 was stabilized in the binding pocket of the KOR by tyrosine residues in helix 7 (Tyr313 and Tyr320) and helix 2 (Tyr119)

(Figure 1.6).30 Activation of the KOR not only required these same three tyrosine amino acids necessary for stabilization but also Tyr139 in helix 3. This evidence demonstrated the uniqueness of 1.1 within the KOR compared to other known ligands U69,593 and dynorphin A that exhibited different requirements for the binding and activation.

HO−Tyr119

Tyr313 O HO−Tyr320

HO O O H C 3 O H H O O

O O Glu297

Ile294

Figure 1.6. Revised binding mode of 1.1 to the KOR

In a large collaborative study published in Nature (2012), the KOR ligand-binding pocket was studied in extensive detail.31 This publication reports the first crystal structure of the KOR in complex with the selective antagonist JDTic (1.29) (Figure 1.7). The information obtained from the newly found crystal structure was then used to model a more finely detailed binding model of other KOR selective ligands including morphinan- 11 derived antagonists norbinaltorphimine and 5’-guanidinonaltrindole, and the diterpene salvinorin A. However, instead of modeling 1.1 directly, they decided to investigate the binding of analogue 22-thiocyanatosalvinorin A (1.30). Modeling showed that exposure of the KOR to the thiocyanato-analogue produced two irreversible covalent bound adducts with Cys315. From this model, the groups were able to obtain a list of amino acid residues within the binding pocket that were deemed important to the ligand-complex including Tyr313, Tyr312, Val118, Thr111, and Asp138. However, due to the covalent bond formation of the thiocyanato-analogue with Cys315 that cannot exist with 1.1, there is still much debate within the scientific community as to the overall accuracy of this model.

O OH

O O N H H O O S O N N O H HN OH CO2Me (1.29) (1.30)

(a) Putative binding mode of the RB-64 +463 AMU (b) Putative binding mode of the RB-64 +431 AMU

Figure 1.7. Binding mode of 1.30 following KOR crystal structure 12

1.5 Biological Activity

1.5.1 Potential Medicinal and Therapeutic Role

The discovery of KOR as a highly potent and selective target of 1.1 has created many opportunities for the drug discovery and development realm of both psychiatric and non-psychiatric disorders.32 KOR agonists, in addition to treating pain, have also been shown to treat depression,33,34 obesity,35 alcoholism,36 and gambling addiction.37

Several studies involving 1.1 and the KOR have already been conducted using animal models including mice, zebrafish, and non-humanoid primates. Results of these studies revealed the rewarding effects,37,38 discriminative stimulus effects,39,40 in addition to antinociceptive41,42 and hypothermic effects41 of 1.1.

1.5.2 Structure-Activity Relationship Studies

A plethora of structure-activity relationship (SAR) studies using semi-synthetic analogues of 1.1 have been conducted in order to explore and understand the binding affinities to the KOR. At this time, these studies have focused on the following main functionalities: (1) the C2 acetoxy/ester group,43-47 (2) the C4 methyl ester,48-50 (3) the

C17 carbonyl,51 and (4) the furan moiety.51-54 Overall, the binding affinities were determined by competitive inhibition of these semi-synthetic analogues and a variety of other known KOR ligands. In 2008, Rothman and Prisinzano published an in-depth review that highlighted a large library of compounds in SAR studies and tabulated their binding affinities for the KOR.55 However, many of their listed compounds were not tested against the same cloned KOR or compared to the same KOR ligand. A general

13 summary of SARs dealing with the four above mentions categories as well as a 5th categories (C1 carbonyl) is shown below (Figure 1.8).

• Reduction is tolerated • Removal or replacement decreases affinity

• Reduction or removal is tolerated O • 1,10-olefin likely to be antagonist • Reduction or removal is tolerated 12 • 8,17-olefin is tolerated O O O H H 17 2 10 8 O

O 4

• Small alkyl groups favor KORs CO2Me • Aromatic groups favor MORs • Small alkyl esters preferred • Bioisosteric replacements tolerated • Hydrolysis or reduction reduces affinity

Figure 1.8. Summary of SAR studies of various analogues of 1.155

CHAPTER 2

PREVIOUSLY COMPLETED TOTAL SYNTHESIS/ADDITIONAL EFFORTS

TOWARDS SALVINORIN A

2.1 Introduction to Prior Synthetic Efforts

The molecular complexity and density, interesting synthetic challenges, and highly remarkable biological activity of 1.1 have drawn significant interest from the synthetic community over the past decade. One potential problem that all groups had to overcome was the known epimerization equilibration issue of the C8 α-lactone stereocenter. In addition, the two quaternary centers at C5 and C9 as well as the C12 3- furanyl stereocenter have also proved to be difficult synthetic hurdles. Prior to the

Forsyth group, there have been three completed total syntheses of 1.1. In 2007, the Evans research group reported the first total synthesis.56 Over the next two years in 2008 and

2009, the Hagiwara team published a series of first- and second-generation syntheses, respectively.57,58 In regards to other efforts towards the synthesis of 1.1, the Rook group has been the only other to publish their synthetic efforts.59 The Forsyth group has most recently also published a completed total synthesis, which will be discussed in full detail as the main topic of this written work.60,61 15

2.2 Evans’ Total Synthesis

2.2.1 Retrosynthetic Analysis

In their synthetic design, Evans and coworkers utilized a transannular Michael reaction cascade of bisenone (2.2) to install both C5 and C9 quaternary centers at the key transformation. Retrosynthetically, they disconnected 1.1 into the trans, trans-fused decalin acetal (2.1), which was generated from macrolactone 2.2 by the key bis-Michael reaction. Lactone 2.2 was then broken into two fragments: vinyl iodide (2.4) and aldehyde (2.3) (Scheme 2.1).

O O

O O O O H H H BOMO AcO O O OH

(MeO)2HC CO2Me 2.1 1.1

BOMO CHO OTBS O CO2Me

CH(OMe)2 O BOMO 2.3 O O + O O

CH(OMe)2 I OTES 2.2 2.4

Scheme 2.1. Evans’ retrosynthesis of 1.1

2.2.2 Preparation of the Aldehyde Fragment 2.3

In the forward direction, the synthesis of aldehyde 2.3 began with a Ni(II)-

BINAP-catalyzed orthoester alkylation of thiazolidinethione (2.5). A subsequent Claisen condensation with mono-ethyl malonate gave β-keto ester (2.6). Formation of the (Z)- enol phosphate was accomplished selectively using LiHMDS and diethyl chlorophosphate. This set-up an iron-catalyzed cross-coupling with methylmagnesium chloride to yield trisubstituted alkene (2.7). Reduction of the ester with diisobutylaluminum hydride (DIBAL-H) followed by reoxidation with manganese dioxide (MnO2) gave α,β-unsaturated aldehyde. This aldehyde was then used in a selective aldol addition with N-acetyl-4-(S)-isopropyl-thiazolidinethione (Nagao’s chiral auxiliary (Xc-2.8)) with the resulting allylic alcohol being protected as the tert- butyldimethylsilyl (TBS) ether (2.10).

The chiral auxiliary was removed via methanolysis using potassium carbonate

(K2CO3) in methanol. Johnson-Lemieux oxidation of the terminal olefin revealed aldehyde (2.11). An (−)-N-methyl-ephedrine-mediated zinc acetylide addition gave propargylic alcohol (2.12) in fair diastereoselectivity (dr = 6:1). This secondary alcohol was then protected as the benzyloxymethyl ether (BOM) (2.13) with Barbier conditions using NaHMDS and BOMCl. Partial reduction of the alkyne allowed selective dihydroxylation of newly formed alkene with catalytic potassium osmate and N-methylmorpholine-N-oxide (NMO) as the reoxident. Oxidative cleavage of the diol with

Pb(OAc)4 afforded aldehyde 2.3.

1. Ni-(R)-BINAP(OTf)2 O S 2,6-lutidine, BF3•OEt2 O HC(OMe)3 N S 2. HO CCH CO Et 2 2 2 (MeO) HC i-PrMgCl, 65 °C 2 O OEt 2.5 (78%, 94% ee, 2 steps) 2.6

1. LiHMDS; ClPO(OEt)2 2. Fe(acac)2, MeMgCl, -20 °C (65%, 2 steps)

OR O S 1. DIBAL-H CO2Et N S 2. MnO2 CH(OMe)2 CH(OMe)2 3. Sn(OTf)2, Xc-2.8 i-Pr N-ethylpiperidine 2.7 TBSOTf 2.9 (R = H) 2,6-lutidine O S (56%, 4 steps 2.10 (R = TBS) N S

1. K2CO3, MeOH i-Pr 2. OsO4, NMO; NaIO4 Xc-2.8

Ph CHO OTBS RO Zn(OTf)2 OTBS CO2Me (−)-N-Me-ephedrine CO2Me Et N, 4-phenyl-1-butyne CH(OMe)2 3 (90%, dr = 6:1, 3 steps) CH(OMe)2 2.11 2.12 (R = H) BOMCl 2.13 (R = BOM) NaHMDS

BOMO CHO OTBS 1. H2, Lindlar's cat. CO2Me 2. K2OsO4, NMO citric acid, 50 °C CH(OMe)2 Pb(OAc)4, K2CO3 2.3 (70%, 3 steps)

Scheme 2.2. Synthesis of aldehyde 2.3

2.2.3 Synthesis of Vinyl Iodide 2.4

The synthesis of vinyl iodide 2.4 began with an Itsuno-Corey (CBS) reduction of the known ynone (2.14) using (R)-B-Me-oxazaborolidine as the catalyst to yield alcohol

(2.15). Following isomerization to the terminal alkyne via an alkyne-zipper reaction, this intermediate underwent a carboalumination providing the (E)-trisubstituted vinyl iodide.

Protection of the secondary alcohol as the triethylsilyl (TES) ether completed the synthesis of vinyl iodide fragment 2.4.

O OH (R)-B-Me-CBS

BH3•Me2S O (85%) O 2.14 2.15

KH H2N(CH2)3NH2 (77%)

O 1. Me3Al, Cp2ZrCl2 OH I2, -45 °C I 2. TESCl, imid OTES O (68%, 2 steps) 2.16 2.4

Scheme 2.3. Synthesis of vinyl iodide fragment 2.4

2.2.4 Fragment Coupling and Transformation

The authors attained the coupling of aldehyde 2.3 and vinyl iodide 2.4 fragments using a chelation-controlled lithio-grignard addition resulting in allylic alcohol (2.17) in

19 modest diastereoselectivity (dr = 7:1). A series of silyl manipulations as well as a saponification of the methyl ester gave seco-acid (2.18). Macrolactonization was accomplished through the Shiina conditions, using 2-methyl-6-nitrobenzoic anhydride

(MNBA) and N,N-dimethylaminopyridine (DMAP), to produce macrocycle (2.19).

Cleavage of the bis-TBS ethers followed by a double oxidation of the corresponding diol with Dess-Martin periodinane (DMP) provided their key bisenone precursor 2.2.

BOMO CHO OTBS O CO2Me OH CH(OMe)2 BOMO 2.3 n-BuLi, MgBr2•OEt2; OTES OTBS + then 2.3, MgBr2•OEt2 CO2Me -78 °C to rt O (86%) CH(OMe)2 dr = 7:1 2.17 I OTES 1. TBSOTf 2,6-lutidine 2.4 2. PPTS, MeOH 3. LiOH, i-PrOH/H2O (75%, 3 steps)

O O R R BOMO BOMO OH O MNBA, DMAP R R CO H [0.0015 M] 2 O CH(OMe)2 CH(OMe) 2 2.18 (R = OTBS) 2.19 (R = OTBS) TBAF 2.20 (R = OH) DMP (85%, 2.2 (R = (=O)) 3 steps)

Scheme 2.4. Fragment coupling and transformation 20

2.2.5 TBAF-Mediated Transannular Cyclization

Construction of the trans,trans-decalin fused skeletal framework of 1.1 was completed by subjecting bisenone 2.2 to TBAF at low temperature (-78 °C) and slowly warming the mixture to 5 °C giving tricycle 2.1. Through conformation analysis, the researchers were able to explain the extremely high diastereoselectivity (dr > 95:5) of this reaction. They propose this transformation occurs via a bis-Michael reaction because the three stereocenters, all in pseudo-equatorial positions, allow the reaction to proceed through a more favorable chair-like transition state, reinforcing the observed diastereoselective outcome. However, the authors do mention that they could not eliminate the possibility of an exo-Diels-Alder reaction.

H H H Ar H O BOMO O (MeO)2HC O - O O

O bis-Michael (stepwise) O O O TBAF H BOMO -78 to 5 °C BOMO O O O dr > 95:5 OH O (MeO)2HC (MeO)2HC 2.2 2.1

H H H Ar O BOMO O- (MeO)2HC O O

exo-Diels-Alder (concerted)

Scheme 2.5. TBAF-mediated transannular cyclization 21

2.2.6 Completion of the Total Synthesis

Treatment of the enol tautomer 2.1 with sodium hydride (NaH) and Comins’ reagent (2.21) afforded an enol triflate, which was reductively removed with Pd(OAc)2 and triethylsilane as the reducing agent. Conjugated reduction of the α,β-unsaturated lactone using L-Selectride® yielded (2.22) as the C8-epimer of the natural product.

Deprotection of both and BOM and dimethoxyacetals with lithium tetrafluoroborate followed by Pinnick oxidation and esterification of the resulting aldehyde and carboxylic acid sequentially provided 8-epi-salvinorin B (2.23). Epimerization of the C8-epimer lactone with K2CO3/methanol gave the undesired yet expected ratio of (2.23) to known salvinorin B (2.24) (dr = 2.5:1). Acylation of 2.24 concluded the total synthesis of 1.1.

O O Cl

N NTf2 O O O O 1. NaH, 2.21 H H H BOMO BOMO O O 2. Pd(OAc)2 dppf, Et3SiH OH 3. L-Selectride® (MeO)2HC 2.22 (MeO) HC (64%, 3 steps) 2 2.1 (dr > 20:1)

1. LiBF4, MeCN/H2O 2. NaClO2; TMSCHN2 (83%, 2 steps)

O O

O O H H O O Ac2O HO H H AcO 8 O O pyr, DMAP (78%)

CO2Me CO2Me 2.23 (C8-H = α) 1.1 K2CO3, MeOH 2.24 (C8-H = β)

Scheme 2.6. Evans’ completion of salvinorin A 22

2.3 Hagiwars 1st-Generation Total Synthesis

2.3.1 Retrosynthetic Analysis from (−)-Methyl Barbascoate

In 2005, Hagiwara and coworkers published their total synthesis of (−)-methyl barbascoate (2.25) and due to its structural similarities, led them to pursue a total synthesis of 1.1 via a similar route.62 Therefore, much of their original synthesis of 1.1 streamlines the successes and challenges seen in the preparation of 2.25. Starting from

1.1, the authors disconnected the natural product to the (S)-C12 furylalcohol (2.26), which was envisioned to come from exo-cyclic diene (2.27). Diene 2.27 could be traced back to known allylic alcohol (2.28) originating from the enantiomerically pure (R)-(−)-

Wieland Miescher ketone (2.29) (Scheme 2.7).

O O O

12 OH PMBO O O H H O O H AcO H H O O O

CO2Me CO Me 2 O O 2.26 (12S) (−)-Methyl Barbascoate 1.1 2.25

OH PMBO OTBS H O O

O O O O 2.29 2.28 2.27

Scheme 2.7. Hagiwara 1st-generation retrosynthesis of 1.1 23

OH O O O2, KOH O MeOH O O 2.29 O 2.28

Li / NH3, THF

EtO2C I

CO Et CO2Et HO 2 H O O + O O 3M HCl O O aq EtOH 2.31 (51%) 2.30 (21%) (quant)

O CO Et HO 2 O H H O NaHMDS

Ph3PCH3Br

O 2.32 2.33

1. LiAlH4, Et2O (57%, 2 steps) 2. TBSCl, DMAP PMBO OTBS Et N (99%) H 3 3. NaH, PMBCl DMF (94%)

2.27

Scheme 2.8. Preparation of diene 2.27

2.3.2 Synthesis of Diene 2.27

The synthesis of 1.1 began in the same manner as that of 2.25, from known

Wieland-Miescher ketone analogue 2.29 (Scheme 2.8).57 The C1-hydroxyl group was installed through an allylic oxidation with potassium hydroxide in methanol in the presence of molecular oxygen to give alcohol 2.28. After failed attempts of installing the furan moiety by reductive alkynlation with 2-alkoxy-2-(3-furyl)ethyliodide derivatives using lithium in ammonium, the researchers invoked the less sterically hindered ethyl iodoacetate. This strategy, however, afforded a mixture of des-hydroxy (2.30) and desired ethyl ester (2.31). Ethanolysis of ketal 2.31 with aqueous acid in ethanol gave dione

(2.32), which was converted into bis-exo-cyclic diene (2.33). Reduction of the lactone with lithium aluminum hydride (LAH) provided the expected diol. Selective protection of as a TBS-ether (primary) and a p-methoxybenzyl (PMB) ether (secondary) gave desired diene 2.27.

2.3.3 Elaboration of Diene to Furylalcohol 2.26

Derivatization of diene 2.27 began with hydroboration of the alkenes using borane-THF complex followed by oxidation of the resulting diol with PDC and subsequent treatment with base to provide thermodynamically more stable bis-α-aldehdye

(2.34) preferentially (Scheme 2.9). Prior to arranging the oxidation state of the C1, C4, and C8 functional groups (ketone, ester, ester respectively), the furyl unit needed to be installed. This was due to the anticipated, and undesired, lactonization between C12 and

C17 during the deprotection of the TBS-ether. Therefore, the C4/C8 moieties were left as

25 aldehydes and protected of the corresponding acetals to give (2.35). TBAF deprotection of the TBS-ether followed by oxidation with PDC provided aldehyde (2.36), which was reacted with 3-lithiofuran to give a mixture of desired 12S-furylalcohol 2.26 and its 12R- epimer (2.37) in an unfavorable diastereomeric mixture (dr = 3:2 12R:12S).

PMBO OTBS 1. BH •THF; PMBO OTBS H 3 H H2O2, NaOH CHO 2. PDC, NaOAc 3. NaOMe, MeOH (85%, 3 steps) OHC 2.27 2.34

ethylene glycol p-TsOH, 40 °C O O (99%)

O OTBS PMBO O H PMBO O H O 1. TBAF (quant) O 2. PDC, NaOAc (78%) O O 2.36 O O 2.35

3-bromofuran, t-BuLi THF, -78 °C (66%, 12R:12S = 3:2)

O O

12 12 OH OH PMBO PMBO H O H O + O O

O O 2.37 (12R) O O 2.26 (12S)

Scheme 2.9. Installation of furylalcohol moiety 26

2.3.4 Conclusion of the Total Synthesis

The synthesis of 1.1 was completed using various oxidation state manipulations to four carbon centers. Starting with furylalcohol 2.26, a one-pot sequential acetal deprotection followed by hemiketalization of the furylalcohol with the C8 aldehyde gave the stable hemiketal (2.38) (Scheme 2.10). PMB-ether deprotection with 2,3-dichloro-

5,6-dicyanobenzoquinone (DDQ) reveled the C1 alcohol, which was oxidized to the corresponding ketone using chromium-mediated PDC conditions. The C4 aldehyde and

C12 hemiacetal were also oxidized under these conditions to the carboxylic acid and lactone respectively. Steglich esterification of the acid with dicyclohexylcarbodiimide

(DCC) and methanol provided methyl ester (2.39).

The task of installing the acetoxy moiety was met with difficulty regarding C8 epimerization, which always resulted in the same unfavorable ratio as seen in the Evans synthesis and semi-synthetic analogue synthesis. The authors used a variety of unsuccessful conditions including bis(acetoxy)iodobenzene (BAIB), acetoxymethylamine, and both acidic and basic Davis oxaziridine conditions. In the end, the epimerization problem was solved via the Rubottom oxidation. Brief exposure of ketone 2.39 to NaHMDS at -78 °C followed by addition of TESCl gave silyl enol ether

(2.40) without epimerization of the C12 stereocenter. Epoxidation of the electron-rich olefin with mCPBA, then acetic acid quench provided 2-epi-salvinorin B. Inversion of C2 alcohol with Mitsunobu conditions and acetic acid gave 1.1.

O O O

12 OH 1. DDQ, CH Cl /H O O O PMBO PMBO O 2 2 2 H H H O p-TsOH H H 2. PDC, DMF O OH Acetone/H O 2-methylbutene O 2 (40%, 3 steps) 3. DCC, DMAP, MeOH CHO (90%) CO2Me O O 2.39 2.26 (12S) 2.38

NaHMDS; TESCl THF, -78 °C (quant)

O O

1. mCPBA, NaHCO3, toluene, H O, 0 C; O O 2 ° TESO O then AcOH (70%) H H AcO H H O O 2. PPh3, DIAD, AcOH (86%)

CO2Me CO2Me 1.1 2.40

Scheme 2.10. Hagiwara 1st-generation completion of salvinorin A

2.4 Hagiwars’s 2nd-Generation Total Synthesis

2.4.1 Purpose and Goals

In 2009, the Hagiwara group released their 2nd-generation total synthesis of 1.1.

The purpose behind this revamped synthesis was to create a route to 1.1 that solved the unfavorable selectivity of the 3-lithiofuran addition as well as establish a shorter more efficient route to the natural product. These goals were accomplished by generating furylketone rather than a furyalcohol via a Weinreb amide. In addition, the researchers were able to simultaneously convert the C4/C12 ketones to the desired methyl ester and lactone respectively to create a much shorter, higher yielding route to 1.1.

2.4.2 Furylketone 2.44 Formation

This new 2nd-generation synthesis again began with the same conversion of known Wieland-Miescher ketone 2.29 into alcohol 2.32 (Scheme 2.11).57 Triethylsilyl trifluoromethanesulfonante (TESOTf) at unusually high temperature was used in order to protect the hydroxyl group as the TES-ether (2.41) while suppressing the formation of the

TES enol ethers. Comins’ reagent with NaHMDS was invoked to form the bis-triflate

(2.42). Conversion of the ethyl ester into the Weinreb amide opened the door for a 3- lithiofuran addition without obtaining a mixture of diastereomers. The efficient establishment of the furylketone (2.44) accomplished their first goal in this revised synthesis.

CO2Et CO Et HO TESO 2 O First generation H H O TESOTf, pyr O O DMAP, DMF O 100 °C, (93%) 2.29 O O 2.32 2.41

Comins' reagent NaHMDS O (66%) OMe N CO Et TESO 2 TESO O TESO O H H H OTf OTf OTf i-PrMgBr, THF 3-bromofuran

t-BuLi MeN(OMe)H2Cl (70%) (quant) OTf OTf OTf 2.42 2.44 2.43

Scheme 2.11. Preparation of furylketone 2.44

O O O

TESO O TESO O Pd(PPh3)4, dppf TESO O H H H OTf CO, Et3N, 60 °C OTf CO Me + 2 MeOH/DMF (3:1)

OTf CO2Me CO2Me 2.44 2.45 (7%) 2.46 (69%)

same conditions (84%) K-Seletride® t-BuOH, THF (95%)

O O

TESO O TESO O H H H SmI2, Et3N, AcOH O O toluene O2 quench (64%) 2.47 2.48 CO2Me CO2Me

Scheme 2.12. Construction of carbon skeleton framework

2.4.3 Construction of the Carbon Skeleton 2.48

The construction of the decalin core of 1.1 was undertaken using a proficient bis- palladium catalyzed methoxycarbonylation of bis-vinyl triflate 2.44 (Scheme 2.12).

However, the authors obtained a mixture of mono (2.45) and bis-carbonylation (2.46) products. The mono-product could be resubjected under the same original conditions to afford the desired bis-α,β-unsaturated methyl esters 2.46 in good yield. At this point in time, the researchers attempted a triple reduction with L-Selectride® in hopes to complete a double 1,4-conjugate reduction of the methyl esters as well as reduction of the

30 furylketone. The triple reduction was successful; however, it gave a complex mixture of diastereomers with no selectivity. Therefore, a two-step reduction protocol was used in order to gain more control over the products obtained. The use of K-Selectride® facilitated solely a 1,2-reduction of the ketone with the resulting alkoxide spontaneously lactonizing with the C12 methyl ester to form lactone (2.47) as a single diastereomer.

After a variety of attempts at the 1,4-conjugate reduction of the unsaturated esters (e.g. magnesium in methanol, lithium naphthalenide, and catalytic hydrogenation using various metals), they finally found that single-electron reduction with samarium iodide in the presence of triethylamine as an activator ligand, acetic acid as the proton source, and an oxygen quench gave lactone (2.48) as the sole yet undesired diastereomer. The oxygen quench was used in order to prevent any side reactions from excess samarium iodide during an aqueous workup.

2.4.4 2nd-Generation Total Synthesis Endgame

As with the Evans total synthesis and others, the Hagiwara 2nd-generation total synthesis was afflicted by the epimerization of the C8 carbon. While removing the TES- ether with TBAF, the authors saw epimerization of the C8 center to the expected diastereomeric mixture of (2.49):(2.50) (dr = 7:3) and again, just like the Evans group, they were able to funnel material through the pipeline by using K2CO3 in methanol

(Scheme 2.13). Oxidation of alcohol 2.50 gave the same ketone 2.39 as in the 1st- generation synthesis. Completion of 1.1 was accomplished in the same manner as before through a Rubottom oxidation/Mitsunobu sequence.

O O O

HO O HO O TESO O TBAF, THF H H H H H H + O O O

2.48 CO Me 2.49 (64%) CO2Me 2.50 (26%) CO2Me 2

K2CO3, MeOH

(94%; 2.49:2.50 = 7:3) DMP, CH2Cl2 (98%)

O O

O O O O H H H H AcO 3 steps O O First Generation

CO2Me CO2Me 2.39 1.1

Scheme 2.13. 2nd-generation completion of 1.1

2.5 Rook’s Synthetic Approach

2.5.1 Retrosynthetic Analysis

In 2006, Rook and coworkers published their synthetic efforts towards the total synthesis of 1.1.59 Retrosynthetically, they envisioned breaking 1.1 down into two main fragments ketone (2.51) and diene (2.52) that would be coupled via a late-stage Michael addition. This would then be followed by an olefin metathesis and reduction of the newly formed double bond (Scheme 2.14).

O O O AcO O O H H + AcO O O

CO2Me O 2.51 CO2Me 2.52 1.1

Scheme 2.14. Rook’s retrosynthetic analysis

2.5.2 Preparation of Aminofurans 2.56a/2.56b

Construction of ketone 2.51 began with a Michael addition of ynone (2.53) with either amino alcohols (+)-pseudoephedrine or (−)-ephedrine, individually, to give enamines (2.54a) or (2.54b) respectively (Scheme 2.15). Treatment of the corresponding enamine with trifluoroacetic acid (TFA) followed by aqueous sodium hydroxide (NaOH) yielded furans (2.55a) or (2.55b). Deprotection of the THP group with p-TsOH in ethanol revealed alcohol (2.56a) or (2.56b), which were then used in their Diels-Alder studies.

Ph OH Ph ∗ ∗ 1. TFA, DCE OR O a:(+)-pseudoephedrine 2. NaOH, H2O N O N -or- OTHP b: (−)-ephedrine O 2.54a (S)-carbinol 2.53 2.54b (R)-carbinol 2.55a (R = THP) p-TsOH 2.55b (R = THP) EtOH, 60 °C 2.56a (R = H) 2.56b (R = H)

Scheme 2.15. Preparation of furans 2.56a and 2.56b

2.5.3 Diels-Alder Studies and THF Ring Opening

Both of the aminofurans were used in a series of Diels-Alders (DA) reactions with methyl acrylate in either dichloromethane or water (Scheme 2.16, Table 2.1). In the case of 2.56a, the endo/exo selectivity was extremely high (99:1); however, the desired product was that derived from the exo-transition state. Unfortunately, the best results obtained were using 2.56b in water to give a 1:1 endo/exo mixture of DA products and

60% ee of the desired methyl ester (2.57b). The enantioenriched mixture was recrystallized to provide a single enantiomer 2.57b containing the correct stereochemistry at C2 and C4 of the natural product.

O O 1. methyl acrylate CH2Cl2 or H2O + 2.56a or 2.56b O O 2. AcOH, NaOAc H2O CO2Me CO2Me 2.57a 2.57b endo exo

Scheme 2.16. Diels-Alder reactions with methyl acrylate

%ee %ee yield entry solvent endo/exo (2.57a) (2.57b) (%)

1 2.56a CH2Cl2 99:1 85 n.d. 90

2 2.56a H2O 9:1 75 75 83

3 2.56b CH2Cl2 3:1 56 46 87

4 2.56b H2O 1:1 16 60 81

Table 2.1. Rook’s Diels-Alder results 34

Boron tribromide-mediated tetrahydrofuan (THF) ring opening followed by quenching with collidine formed alcohol (2.58), which was then acetylated with acetyl chloride (Scheme 2.17). At this point in the synthesis, the authors state that though the

1,4-addition of the vinyl Gilman reagent is expected to produce the desired product, it is still the subject of future work.

O O O HO AcO (i) BBr3 AcCl 2.51 O (ii) collidine (61%) CO Me CO2Me CO2Me 2 2.58 2.59 2.57b

Scheme 2.17. Preparation of ketone 2.51

2.5.4 Furan Fragment 2.52 Synthesis

The authors began the furan fragment synthesis with an aldol reaction between acetone and 3-furaldehyde to give β-hydroxy ketone (2.61) (Scheme 2.18). This intermediate is coupled with an in situ generated ketene, which is formed from the acyl chloride (2.63) and triethylamine, to yield α-bromo ester (2.64). The Reformatsky reaction using Rieke zince provided furan 2.52 as a racemic mixture.

To our knowledge at this time, Rook and coworkers have not published any further results regarding their progress towards the total synthesis of salvinorin A.

CHO OH O NaOH acetone O O O 2.60 2.61 O Br Et3N O O Rieke zinc Et O THF 2 Ar O O 2.64 O (±)-2.52 1. Br2, pyr Cl HO 2. SOCl2 Br 2.62 2.63

Scheme 2.18. Racemic synthesis of furyllactone 2.52

2.6 Burns Synthetic Approach

2.6.1 Retrosynthesis

Burns envisioned that 1.1 could be traced back to the dione decalin core (2.65)

(Scheme 2.19). Dione 2.65 was thought to come from the key intramolecular Diels-Alder

(IMDA)/Tsuji allylation sequence from triene (2.66). This IMDA precursor would then originate from known alkyl iodide (2.67).60

2.6.2 Preparation of Diels-Alder Precursor 2.66

In the forward direction, known dithiane (2.68) was deprotonated with tert- butyllithium (t-BuLi) followed by the addition of alkyl iodide 2.67 to provide allylic ditihiane (Scheme 2.20). The TBS-ether was removed with TBAF in THF to give primary alcohol (2.69). Due to the presence of the dithiane moiety, a Parikh-Doering oxidation was used rather than Swern conditions to oxidize alcohol 2.69 to the aldehyde, which was subjected to olefination under Horner-Wadsworth-Emmons conditions with 2- oxo-3-(diethylphosphono)butane to furnish enone (2.70). Kinetic deprotonation with 36

KHMDS formed the corresponding potassium enolate, which was quenched with allyl chloroformate to afford the O-acylation product (2.71) in modest selectivity over the C- acylation alternative. The use of hexamethylphosphoramide (HMPA) was necessary to minimize the amount of C-acylation obtained in the reaction.

O H O O O O AcO H H O

O CO Me 2 2.65 1.1

O O O OCO2Allyl O OTBS

O 2.66 I 2.67

Scheme 2.19. Burns retrosynthetic analysis

At this stage in the synthesis, detrimental problems arose when attempting to deprotect the allylic dithiane to the desired enone. Allyic dithianes are known to be difficult to remove;63,64 yet, the researchers went ahead to screen a vast array of conditions such as: MeI/CaCO3, Dess-Martin periodinane, IBX, PIFA, AgNO3, Tl(NO3)3,

AgClO4/NBS, mCPBA/Ac2O/Et3N, and HgCl2/CaCO3. However, the highest yield,

37 though still low, was witnessed using Hg(ClO4)2/CaCO3 to give enol carbonate IMDA precursor 2.66.

O O 1. SO •pyr 3 O 1. t-BuLi, THF/HMPA O OH Et N, CH Cl O S -78 °C to rt, then 2.67 3 2 2 2. TBAF, THF S 2. O O (84%, 2 steps) 2.69 S P(OEt) S S 2.68 S 2 2.70

NaH, THF (55%, 2 steps) KHMDS THF/HMPA, -78 °C; then allyl chloroformate (62%; 15% C-acylation

O O O O OCO2Allyl OCO2Allyl Hg(ClO4)2 CaCO3

THF/H2O S S O 2.66 (33%) 2.71

Scheme 2.20. Synthesis of Diels-Alder precursor 2.66

2.6.3 IMDA/Tsuji Allylation Sequence

The IMDA reaction of triene precursor 2.66 proceeded in good yield but gave an endo/exo mixture of 1:1 corresponding to the cis-decalin (2.73) and trans-decalin (2.72)

(Scheme 2.21). Cis-decalin was separated from non-crystalline product 2.72 and the stereochemistry confirmed by single-crystal X-ray analysis. Analysis of the transition states for both products can be seen in Scheme 2.22. As shown in the first transition state model, (TS-2.73) was formed through a proposed boat-like, endo transition state. It was believed that the secondary orbital interactions predominated over the ring strain from the boat comformation, which led to the cis-decalin core. Inversely, intermediate 2.72 was 38 likely formed through a more favorable chair-like transition state (TS-2.72), placing the ketone and α-vinyl methyl substituent in an anti relationship with each other, therefore alleviating 1,2-allylic strain and producing the exo-product. Each of the IMDA adducts were subjected to in situ generated Pd(PPh3)4 for the stereospecific Tsuji allylation reaction affording diones 2.65 and (2.74). It was interesting to note that the stereospecificity of the reaction was directly dependent on the stereochemistry of the corresponding decalin core. This work will be discussed in a later section.

O O OCO2Allyl

O 2.66

toluene, BHB 110 °C, 36 h (77%, 2.72:2.73 = 1:1)

O O O H H OCO2Allyl O O Pd2(dba)3, PPh3 toluene, rt, 1 h (86%) O O 2.72 2.65 +

O O H H O OCO Allyl O O 2 Pd2(dba)3, PPh3 toluene, rt, 1 h (61%) O O 2.73 2.74

Scheme 2.21. Diels-Alder/Tsuji allylation sequence 39

O O OCO2Allyl

O 2.66

toluene, BHB (2.72:2.73 = 1:1) 110 °C, 36 h (77%)

H O H O O O O OCO2Allyl O OCO2Allyl

endo-TS (TS-2.73) exo-TS (TS-2.72)

O H O O O H OCO2Allyl OCO2Allyl

O O 2.73 2.72

Scheme 2.22. Proposed transition states of endo/exo Diels-Alder reaction

2.7 Butler Synthetic Approach

2.7.1 Goals and Modifications

In the Butler approach to 1.1, Dr. Butler set goals to modify the IMDA precursor route to avoid the low yielding allylic dithiane deprotection. In addition, the IMDA reaction itself needed to be investigated in order to hopefully improve the selectivity.

2.7.2 Retrosynthetic Analysis

Because most of the post-IMDA/Tsuji allylation had not yet been explored, 1.1 was still viewed to come from dione 2.65, which was constructed through the

IMDA/Tsuji allylation process as before (Scheme 2.23). However, the IMDA precursor was modified to a more general protected allylic alcohol (2.75). This alcohol derivative was envisioned to come from a Grignard addition between isopropenylmagnesium bromide Grignard reagent and the corresponding aldehyde (2.76), which, like for Burns, would originate from tartaric acid (2.77).61

O H O O O O AcO H H O

O CO Me 2 2.65 1.1

O O O OCO Allyl L-(+)-tartaric acid O OTBDPS 2

2.77 H 2.76 OTBS 2.75 O

Scheme 2.23. Butler retrosynthetic analysis

2.7.3 Construction of Aldehyde 2.76

The new route for the IMDA precursor would begin from naturally abundant L-

(+)-tartaric acid 2.77 (Scheme 2.24). Ketalization and Fischer esterification of 2.77 led to 41 dimethyl ester (2.78), which was subjected to reduction with LAH to yield the C2- symmetric diol (2.79). Monoprotection with NaH followed by tert-butyldiphenylsilyl chloride (TBDPSCl) formed the TBDPS-ether (2.80) thus desymmeterizing the compound. Oxidation of the unprotected alcohol via Swern conditions yielded the expected aldehyde, which was subjected to a Wittig olefination with methoxymethyltriphenylphosphonium chloride to provide methyl enol ether (2.81).

Though the standard protocol for converting the enol ether to the corresponding aldehyde

2.76 is aqueous acidic conditions, the acid-sensitivity of the acetonide limited the researchers to only using Hg(OAc)2 and tetrabutylammonium iodide (TBAI).

Nevertheless, the modified route was able to produce the desired aldehyde in decent overall yield.

OH O O LiAlH4 O HO (MeO)2CMe2 O OH CO2H CO2Me Et2O CO H p-TsOH, MeOH 2 cyclohexane CO Me (81%) 2 HO 2.79 L-(+)-tartaric acid (64%) 2.77 2.78 NaH, TBDPSCl (81%)

1. (COCl) , DMSO O O O 2 Et N, CH Cl O O OTBDPS O 3 2 2 OTBDPS Hg(OAc)2, TBAI OTBDPS -78 °C to rt H THF/H O 2 2. MeOCH2PPh3Cl HO (76%) 2.80 2.76 KHMDS, THF O OMe 2.81 (1:1 E/Z) -78 °C to rt (62%, 2 steps)

Scheme 2.24. Construction of aldehyde 2.76

2.7.4 Synthesis of Enol Carbonate 2.75

Now that aldehyde 2.76 was readily available, Butler focused on improving the synthesis of the IMDA enol carbonate. Isopropenylmagnesium bromide addition into the aldehyde at low temperature with a very slow addition of the Grignard reagent gave a mixture of allylic alcohols (2.82) (Scheme 2.25). This diastereometic mixture was insignificant due to oxidation of the stereocenter later in the synthesis. Protection of the secondary alcohol with TBSCl followed by a selective deprotection of the TBDPS-ether under basic conditions with NaOH (10%) in methanol provided primary alcohol (2.84).

Swern oxidation followed by a Horner-Wadsworth-Emmons olefination with the same 2- oxo-3-(diethylphosphono)butane reagent gave enone (2.85). Construction of the enol carbonate was vastly improved from Burns original work. Rather than using a

THF/HMPA solvent mixture, Butler was able to obtain selective O-acylation using the chelating solvent dimethoxyethane (DME) to help release the naked enolate for acylation.

The new conditions provided enol carbonate 2.75 in 88% yield compared to the 62%.

2.7.5 IMDA Improvement

Due to the poor selective of the IMDA with the enone dieneophile (viewed as a normal-demand DA), the researchers attempted the IMDA on the allylic silyl ether in hopes that the change in electronics (now viewed as inverse-demand) as well as the removal of the secondary orbital overlap stabilization would help to enhance the amount of exo-product (Scheme 2.26). Indeed, this modification worked out greater than expected providing only the trans-decalin core (2.86) in o-dichlorobenzene (225-250 °C)

43 in a sealed tube. However, these conditions were never fully optimized and improvements in regards to consistency and isolation still needed to be undertaken. The allylic diastereomers each contribute differently towards the observed selectivity of the

IMDA reaction. As seen in Scheme 2.27, the (R)-configuration ((R)-2.75) provides a transition state that contains all pseudoequatorial substituents (TS-(R)-2.75) while the

(S)-configuration ((S)-2.75) minimizes the 1,2-allylic strain though the allylic TBS-ether is in the axial position (TS-(S)-2.75). In either case, the IMDA reaction proceeds in approximately equal efficiency. It is to be noted that these IMDA results were obtained towards the very end of Dr. Butler’s graduate career.

O O O O OTBDPS O O OTBDPS Br, Mg 10% NaOH, MeOH OH

H THF, -78 °C 65 °C, 2.5 h (87%) (92%) OR O 2.76 OTBS TBSCl, imid 2.82 (R = H) 2.84 DMAP, DMF (99%) 2.83 (R = TBS)

O O 1. (COCl)2, DMSO O OCO2Allyl KHMDS (solid) O O Et3N, CH2Cl2 DME, -78 °C; 0 °C to rt

allyl chloroformate 2. O O (88%) OTBS 2.75 OTBS 2.85 P(OEt)2

NaH, THF (72%, 2 steps) Scheme 2.25. Synthesis of enol carbonate 2.75

O O O O H OCO2Allyl o-dichlorobenzene, BHT OCO2Allyl

225-250 °C, 3 d (63%) OTBS 2.75 OTBS 2.86 Scheme 2.26. Inverse-demand IMDA 44

Allyl 2 OCO )-2.75 TBS R = O H R H Substituents TS-( Allyl Pseudoequitorial R 2 O All OCO Allyl

O 2 )-2.75 OCO R ( O H )-2.86 demand IMDA demand - O R OTBS ( OTBS O O (63%) Allyl 2 Allyl 2 OCO OCO . Proposed transition states of states inverse . Proposed transition H )-2.86 )-2.75 S ( OTBS S O ( O O Scheme 2.27 Scheme O OTBS Allyl 2 Strain OCO )-2.75 TBS 1,2-Allylic S = of H H R O TS-( R O O Reduction

2.7.6 Post-IMDA and Carboskeleton Framework

Even though the above-mentioned IMDA results were incomplete, a sufficient amount of enol carbonate 2.72 had been made via the IMDA route using enone 2.66.

With that material in hand, the researchers were able to make a small amount of progress towards the entire skeletal framework of 1.1. First, enol carbonate 2.72 was subject again to Pd(0) and underwent a stereoselective Tsuji allylation. The stereoselectivity can be explained in Scheme 2.28. Following palladium coordination to the olefin, a π-allyl complex is generated and a decarboxylation takes place freeing a corresponding enolate.

The resultant π-allyl complex can then only approach the face opposite the C5 quaternary methyl group providing diones 2.65 and 2.74 for the trans-decalin and cis-decalins respectively. It is again worth noting the efficiency of the IMDA/Tsuji allylation combination, as it not only provides an extremely substituent-dense decalin core but also introduces two quaternary center both in very high stereoselectivity.

n face

se Pd-L TS O O n -fused TS-2.73 cis Pd-L O O

Allyl 2 OCO O 2.74 2.73 H H O O O O (64%) O O 3 h 1 PPh , rt, rt, 3 (dba) 2 Allyl 2 toluene, Pd O OCO 2.65 (94%) H 2.72 H O O . Proposed transition states of Tsuji allylation reactions reactions of states Tsuji allylation . Proposed transition O O O O n Scheme 2.28 Scheme face

re Pd-L n O TS Pd-L -fused O H TS-2.72 trans O O

After many different routes and ideas, Butler settled on a path inspired by the

Hagiwara 2nd-generation synthesis.58 Treatment of dione 2.65 with KHMDS and Comins reagent yielded bisvinyl triflate (2.87). Exposure of 2.87 to palladium-mediated methoxy carbonylation conditions led to α,β-unsaturated diester (2.88). This was the final intermediate synthesized by Dr. Butler before his graduation from The Ohio State

University.

O O O O H O H OCO2Allyl OCO2Allyl O OCO Allyl toluene, BHT 2 + 110 °C, 6 d (96%, 2.72:2.73 = 1:1.3) O O O 2.66 2.72 2.73

Pd2(dba)3, PPh3 toluene, rt, 1 h

O O O H O H H O O O O OTf KHMDS, THF Comins' Reagent -78 °C O 2.74 (72%) O 2.65 OTf 2.87 (94%) (64%)

Pd(PPh3)4, dppf Et3N, MeOH/DMF CO, 60 °C (73%)

O O H CO2Me

CO2Me 2.88

Scheme 2.29. Post-IMDA and carboskeleton framework

CHAPTER 3

EARLY ROUTE IMPROVEMENTS AND DIELS-ALDER OPTIMIZATION

TOWARDS COMMON DIONE INTERMEDIATE

3.1 Synthetic Issues

Though the original Burns route was innovative and unique and the Butler modified route solved some of the issues and founded the selective inverse-demand

IMDA, there was still much work that needed to be completed. Unfortunately, there had been no progress in addressing two of the most difficult issues with salvinorin A syntheses: stereoselective installation of the furylalcohol and avoidance of the unfavorable C8 lactone epimerization. In addition, portions of the Butler route required revisions (formation of aldehyde 2.76) and optimization (IMDA) in order to create a safer and more scalable path towards dione 2.65. The conceptual innovations and experimental work described henceforth are those of the author.

3.2 Synthetic Revision of Aldehyde

3.2.1 Cyanide Substitution

Due to the linearity of the overall synthetic route, early-stage chemistry needed to be performed on fairly large scale to produce enough material for exploration of late-state transformations. Therefore, the first issue that needed to be addressed in the synthesis was the preparation of aldehyde 2.76 from tartaric acid. The use of Hg(OAc)2 was an unacceptable reagent and without the ability to invoke acidic conditions an alternative method of one carbon homologation was necessary. The first method attempted was direct cyanide SN2 displacement of primary iodide (3.2) to give nitrile (3.4) (Scheme 3.1).

Unfortunately, due to the base sensitivity of the TBDPS-ether and the slight basicity of the cyanide anion, alkyl iodide 3.2 proved to be a poor substrate. However, this issue was quickly fixed by exchanging the TBDPS-ether for a PMB-ether, which is stable under basic conditions. Alkyl iodide (3.3) was then reacted with sodium cyanide to provide nitrile (3.5) in 82% yield.

O O O OR PPh3, imid., I2 O OR PhMe, 110 °C HO (95% 3.2) I (88% 3.3) 2.80 (R = TBDPS) 3.2 (R = TBDPS) 3.1 (R = PMB) 3.3 (R = PMB)

NaCN DMSO (56% 3.4) (82% 3.5)

O O O OPMB DIBAL-H O OR toluene, -78 °C H Citric acid (1M) quench NC 3.6 (56%) O 3.4 (R = TBDPS) 3.5 (R = PMB)

Scheme 3.1. Cyanide substitution of alkyl iodide

Reduction of the corresponding nitrile proved to be more of a challenge.

Subjecting nitrile 3.5 to DIBAL-H at low temperature in either toluene or diethyl ether afforded the corresponding stable imine. Hydrolysis was attempted using several different conditions including sodium/potassium tartrate (Rochelle’s Salt), dilute acetic acid, or citric acid (1 M); all resulted in either poor yield or competitive hydrolysis of the acetonide protecting group and was deemed an unacceptable route towards aldehyde

(3.6).

1. (COCl) , DMSO 2 O Et N, CH Cl O 3 2 2 O -78 °C to rt OTBDPS O OTBDPS 2. MeOCH2PPh3Cl KHMDS, THF HO 2.80 -78 °C to rt OMe 2.81 (1:1 E/Z) (62%, 2 steps) NBS THF/H2O

O O O OTBDPS O OTBDPS Zn, AcOH H 30%-60% H 2.76 Br O O 3.7

Scheme 3.2. α-Brominiation/reduction sequence

3.2.2 α-Bromination/Reduction Sequence65

Knowing there was good access to methyl enol ether 2.81, we turned our attention towards finding an alternative transformation of this intermediate. It was envisioned that reacting enol ether 2.81 with N-bromosuccinamide would provide α-bromoaldehyde (3.7)

(Scheme 3.2). The bromide would then be reductively removed using zinc in acetic acid conditions. Unfortuately, numerous attempts with various conditions resulted in extremely variable yields (30-60%) for reasons that are still unknown. Therefore, this idea was also abandoned.

3.2.3 Cuprate Substitution66

It was realized that though a one carbon homologation provided the desired aldehyde 2.76, a multiple carbon extension could be used so long as it could be cleaved 52 down to the correct number of carbons. We accomplished this idea by first performing a curpate substitution using an in situ generated vinyl cuprate reagent with alkyl iodide 3.2 to give alkene (3.8) in good yield (Scheme 3.3). It is worth pointing out, though this route uses HMPA, it is only a cosolvent and used in minimal amounts. Ozonolysis of alkene

3.8 followed by the addition triphenylphosphine provided desired aldehyde 2.76 in very good yield (94%). In summary, the overall preparation of 2.76 was drastically improved from 41% to 63% over four steps while completely eliminating the use of toxic mercury

(Table 3.1).

O O O OTBDPS PPh3, imid., I2 O OTBDPS PhMe, 110 °C (95%) HO 2.80 I 3.2

MgBr CuI, THF/HMPA -40 °C to 0 °C (80%)

O O O OTBDPS O OTBDPS O3, then PPh3

H CH2Cl2/MeOH -78 C to rt 2.76 ° 3.8 O (94%)

Scheme 3.3. Cuprate substitution of alkyl iodide 3.2

Route # of Steps Yield Issues Mercury 4 41% Very Toxic Cyanide 4 35% Toxic/Low Yield Bromination 5 "30%" Decomposition Cuprate 4 63% HMPA/Lg. Grignard Addition

Table 3.1. Summary of aldehyde routes 53

3.3 Scale-up Towards Enol Carbonate 2.75

With a new efficient alternative towards aldehyde 2.76, we were able to make a huge push of material towards enol carbonate 2.75 in preparation of optimization of the

IMDA/Tsuji sequence. Isopropenylmagnesium bromide addition into aldehyde 2.76 gave an irrelevant diastereomeric mixture of alcohols, which were protected as the corresponding TBS-ether 2.83 with TBSCl in dimethylformamide (DMF) (Scheme 3.4).

Selective deprotection of the primary TBDPS-ether in the presence of the secondary

TBS-ether was accomplished under basic conditions with sodium hydroxide in methanol to expose alcohol 2.84. Oxidation with Swern conditions followed by Horner-

Wadsworth-Emmons olefination with 2-oxo-3-(diethylphosphono)butane yielded enone

2.85. Kinetic deprotonation of 2.85 with KHMDS in the highly chelating solvent DME exposed a naked enolate that underwent selective O-acylation upon being quenched with allyl chloroformate providing enol carbonate 2.75 ready for IMDA studies.

O O O O OTBDPS O O OTBDPS Br, Mg 10% NaOH, MeOH OH

H THF, -78 °C 65 °C, 2.5 h (87%) (92%) OR O 2.76 OTBS 2.82 (R = H) TBSCl, imid 2.84 DMAP, DMF (99%) 2.83 (R = TBS)

O O 1. (COCl)2, DMSO O OCO2Allyl KHMDS (solid) O O Et3N, CH2Cl2 DME, -78 °C; 0 °C to rt

allyl chloroformate 2. O O (88%) OTBS 2.75 OTBS 2.85 P(OEt)2

NaH, THF (82%, 2 steps)

Scheme 3.4. Scale-up of enol carbonate 2.75 54

3.4 Inverse-demand IMDA Studies/Optimization

With enol carbonate 2.75 in hand, optimization of the inverse-demand IMDA reaction was completed. Utilizing the microwave reactor, a variety of conditions were screened (Table 3.2) on small scale. Starting with the polar solvent, acetonitrile, the

IMDA reaction was first attempted at 80 °C for up to 2 hours (entry 2) and then at extended temperature (150 °C) for 9 hours (entry 3). However, neither of these resulted in any conversion of starting material. Therefore, the solvent was changed to the higher boiling, nonpolar toluene. Excessive temperature (185 °C) in a sealed tube resulted in slight conversion to the product; however, prolonged heating did not produce full conversion. Addition of a Lewis acid (ZnCl2) starting at 22 °C to 185 °C only gave decomposition of the enol carbonate functionality. Knowing that a nonpolar solvent was required and more energy was needed, o-dichlorobenzene (o-DCB) was used. Full conversion of starting material to expected trans-decalin 2.86 was observed at 260 °C for two hours in 73% yield. It is again worth noting that the allylic silyl ether dienophile selectively produced only the desired exo-IMDA product.

O O O O H OCO2Allyl Microwave Conditions OCO2Allyl Table 3.2

OTBS 2.75 OTBS 2.86 Solvent μW Temp. (°C) Time Result MeCN 80 30 min No Rxn MeCN 80 2 h No Rxn MeCN 150 9 h No Rxn Toluene 185 30 min Small Conversion Toluene 185 4 h More Conversion

Toluene (ZnCl2) 22 to 185 12 h Decomposition o-DCB 225 30 min Most Conversion o-DCB 260 2 h Full Conversion (73%)

Table 3.2. Inverse-demand IMDA optimization

Upon scaling up, the conditions needed to be adjusted slightly though they were still very effective and consistent. Scaling up to the largest microwave vial (50 mL) required an increase in overall time from two hours to 8.5 hours. This was due to the extra time needed to heat the larger vial and solvent volume to the desired temperature.

Unfortunately, even the largest microwave vial did not allow a very high throughput of material at this stage. Due to the high dilution (0.02 M), a 50 mL vial containing the appropriate 30 mL of solvent would only allow for approximately 250 mg of material to be converted per vial. Thus, thermal conditions needed to be optimized with 500 mL sealed flasks in order to alleviate this problem. Indeed, heating the sealed tube in a sand bath at 260 °C for 24 hours gave decalin 2.86 in comparable yields (70%) to the

56 microwave. At this point, the IMDA reaction had been optimized via both microwave- assisted and thermally for scale-up.

3.5 Formation of Dione 2.65 Through Tsuji Allylation

Due to the steric bulk of the TBS-ether, especially the 5S-isomer, there was concern for the efficiency of the Tsuji allylation. It was believed that the C4 alcohol needed to be functionalized to the ketone before allylation. Deprotection of the C4 alcohol using TBAF afforded what was believed to be a mixture of secondary hydroxyl groups (3.9) (Scheme 3.5). Oxidation with Dess-Martin periodinane, however, revealed a mixture of diastereomers. Mass spectrometry and 1H NMR spectroscopy indicated a mixture of C9 methyl diastereomers (3.10) signifying the cleavage of the enol carbonate in one of the previous steps; most likely due to the slight basicity/nucleophilicity of the

TBAF.

O O O H H H O OCO2Allyl O OCO2Allyl O O TBAF DMP

THF, 8 h. CH2Cl2 OTBS 2.86 OH O 3.9 3.10

Scheme 3.5. C4 alcohol deprotection prior to Tsuji allylation

Before spending resources optimizing the deprotection/oxidation of the C4 alcohol, the Tsuji allylation reaction was attempted on enol carbonate 2.86 in order to verify if the sterics of the TBS-ether would really be a problem. To our surprise, allyl 57 transfer with Pd2(dba)3 and PPh3 produced expected ketone (3.11). Further optimization unveiled the best conditions to be direct use of Pd(PPh3)4 in anhydrous toluene to afford ketone 3.11 in 93% yield. This result was competitive with the Tsuji allylation of ketone

3.11 used by Burns/Butler (94%) though longer reaction time was needed (5 hours).

With the enol carbonate functionality removed, the use of TBAF for deprotection was no longer a concern. Cleavage of the TBS-ether using multiple equivanlents of

TBAF exposed secondary alcohol (3.12). Oxidation with Dess-Martin periodinane, however, still gave low conversion to dione 2.65. Instead, Ley-Griffith oxidation67 with catalytic tetrapropylammonium perruthenate and stoichiometric N-methylmorpholine N- oxide as the oxidant proved very effective and yielded dione 2.65, which spectroscopically matched with previous data obtained by both Burns and Butler.

O O H H O OCO2Allyl O O Pd(PPh3)4 PhMe, rt, 5 h (93%) OTBS 2.86 OTBS 3.11

TBAF THF, 8 h (87%)

O O H H O O O O TPAP, NMO DCM (91%) O OH 3.12 2.65

Scheme 3.6. Formation of dione 2.65 via Tsuji allylation 58

CHAPTER 4

CONSTRUCTION OF FULL CARBOSKELETON THROUGH ASYMMETRIC 3-

FURYLTITANIUM ADDITION

4.1 Late-Stage Retrosynthetic Analysis

With an efficient and scalable synthesis of dione 2.65 in hand, attention was turned to the late-stage chemistry, which included installation of the 3-furyl functionality, lactonization of the furylalcohol, addressing the epimerizable C8 stereocenter, and derivitization of the acetonide protected diol. Retrosynthetically, 1.1 was broken down to saturated lactone (4.1) (Scheme 4.1). Disconnection of the lactone revealed furylalcohol

(4.2) constructed from a selective Nozaki-Hiyama-Kishi (NHK)68,69 reaction of 3- bromofuran and aldehyde (4.3), which was generated from oxidative cleavage of the terminal alkene of dione 2.65. This order of functional group installation would, hopefully, address all the above issues and allow for versatility within the synthesis.

O O O

O O O O O OH H H H H H AcO O O O O O

1.1 CO2Me CO2Me 4.1 O 4.2

O O H H H O O O O

O O 2.65 4.3

Scheme 4.1. Late-stage retrosynthetic analysis

4.2 Oxidative Cleavage of Terminal Alkene 2.65

The first step in the synthetic plan was to install the 3-furyl moiety. This design allowed for a selective installation of the furan ring without risk of spontaneous lactonization that would occur following the C8 methoxy carbonylation, thereby, opening an opportunity to selectively install the C8 stereocenter. However, oxidative cleavage of the terminal alkene of dione 2.65 proved to be much more difficult than expected.

Ozonolysis of the olefin followed by either triphenphosphine or dimethyl sulfide workup yielded no aldehyde 4.3 by crude 1H NMR spectroscopy. An extensive literature search produced a previous total synthesis of an antibacterial clerodane, by Hagiwara and coworkers, in which they observed that ozonolysis of alkene (4.4) gave them a stable

60 ozonide capable of only being reduction with LAH (Scheme 4.2).70 Unfortunately, LAH was not a viable option for our synthesis.

O O OH O H H H O O OH O3 LiAlH4

CH Cl , -78 °C Et2O, -78 °C O 2 2 O O O O O 4.4 4.5 4.6

Scheme 4.2. Stable ozonide of terminal alkene

With ozonolysis no longer compatible, attention was turned to performing a

71 Lemieux-Johnson oxidation with osmium tetroxide and sodium periodate (NaIO4).

Nevertheless, subjecting dione 2.65 to these conditions did not result in formation of aldehyde 4.3 either. Instead, mass spectrometry and 1H NMR spectroscopy revealed the formation of hemiacteal (4.7) or (4.8) (Scheme 4.3), which was stable to a variety of acidic and basic conditions and, therefore, this method had to be discarded as well.

OH OH O O O H H H OsO4, NaIO4 O O O O O O 2,6-lutidine OH -OR- OH Dioxane/H2O O O O 4.7 4.8 2.65

Scheme 4.3. Lemieux-Johnson oxidation of dione 2.65

4.3 End Game Furan Installation

Since the desired aldehyde needed for the furan installation could not be formed in the presence of the C8 ketone, we decided to proceed with the bis-one carbon homologation before revisiting the incorporation of the furan moiety. Dione 2.65 was subjected to KHMDS and Comins’ reagent to yield bis-vinyl triflate 2.87 (Scheme 4.4).

Palladium-mediated methoxycarbonylation of triflate 2.87 with methanol provided bis-α,

β-unsaturated methyl ester 2.88. This intermediate became the new foundation for further routes and derivations.

O O O H H H O OTf O CO Me O O KHMDS, THF Pd(PP3)4, dppf 2

Comins' Reagent Et3N, MeOH/DMF -78 °C CO, 60 °C (73%) CO Me O 2.65 (72%) OTf 2.87 2 2.88

Scheme 4.4. Preparation of dimethyl ester 2.88

Before installation of the furan, we envisioned introducing the desired C8 stereocenter. We believed the epimerization issues observed in salvinorin chemistry only occurred in the presence of the lactone moiety. Therefore, saturation of the methyl ester could be completely thermodynamically controlled and provide solely the desired 8R- methyl ester. Numerous attempts at reduction of the bis-unsaturated ester were conducted

(Table 4.1). Interestingly, a simple, yet effective method was found in the magnesium in methanol reduction.72 This reaction is a very mild equivalent to the more well known lithium in ammonium reduction. The reaction proceeds through single electron transfer 62 from the magnesium metal to the substrate and protonation with methanol to generate magnesium methoxide. As seen in Scheme 4.5, a single electron transfer to the β-position forms enolate (4.12), which is protonated with methanol to generate β-radical (4.13). A second single electron transfer to the radical carbon gives β-anion (4.14) that is again protonated with methanol to provide fully saturated ester (4.15).74

O O O H O H O H O CO Me CO2Me CO2Me Table 4.1 2 +

CO Me CO2Me CO2Me 2 4.10 2.88 4.9

Conditions Results Pd/C, Hydrogen No Rxn Wilkinson cat., Hydrogen No Rxn Stryker's reagent No Rxn L-Selectride® Over-reduction

NaBH4 Over-reduction Mg, methanol 73% (10:1 4.9:4.10)

Table 4.1. Conditions for conjugate reduction

O O O H H O H O O

e e O OMe O OMe O OMe 4.13 4.11 MeO H 4.12

O O H O H O

O OMe O OMe MeO H 4.14 4.15

Scheme 4.5. Mechanism of magnesium in methanol reduction

Subjecting diester 2.88 under Mg/MeOH reduction conditions gave an inseparable mixture of bis (4.9):mono (4.10) reduced product (10:1) with complete equilibration of the methyl esters to their thermodynamically stable configurations. At this stage, a decision had to made on what order to proceed. Route A was to completely functionalize the diol to the C2-actoxy ketone and then install the furan last (Scheme 4.6). Route B was to incorporate the furan first followed by diol functionalization. At the time, we selected

Route A knowing that if there were issues with generating the desired furylalcohol stereochemistry or epimerization issues at C8, they would be at the end of the synthesis and could hopefully be dealt with appropriately.

O O O AcO H CO2Me AcO H H O

CO2Me CO2Me 1.1

Route A

O O H O OH Route B CO2Me O H CO2Me

CO2Me CO2Me 4.9

Scheme 4.6. Route A/Route B towards synthesis of 1.1

Acid hydrolysis with trifluroracetic acid (TFA) of the acetonide of diester 4.9, exposed diol (4.16) and allowed removal of the leftover mono-unsaturated ester 4.10

(Scheme 4.7). Selective acylation with acetic anhydride and triethylamine of the least hindered alcohol without competition of C1-acylation or bis-acylation followed by Ley-

Griffith oxidation provided ketone (4.17). It is worth noting that once again oxidation with Dess-Marin periodinane was unsuccessful.

O HO H HO H O CO Me CO2Me 2 TFA

CH2Cl2/H2O CO Me CO2Me 2 4.9 4.16

1. Ac2O, Et3N, DMAP CH2Cl2, 0 °C 2. TPAP, NMO CH2Cl2, rt (74%, 2 steps)

O H AcO CO Me Same Results Ozonolysis 2 as with 2.65 -OR- Lemieux-Johnson oxidation CO2Me 4.17

Scheme 4.7. Route A towards salvinorin A

With the ketone 4.17 in hand, installation of the furan moiety could once again be investigated. First though, oxidative cleavage of the terminal alkene needed to be accomplished via either ozonolysis or Lemieux-Johnson conditions. Unfortunately, both of these methods gave the same results as with dione 2.65, a stable ozonide and hemiacetal respectively. Though this was disappointing, a close comparison of the dione

2.65 and ketone 4.17 revealed structural similarities that explain these experimental results.

4.4 Unexpected Furan Selectivity

With the options in Route A exhausted, efforts on Route B were undertaken.

Again starting from diester 4.9, oxidative cleavage of the terminal alkene was attempted for the third time in this project. Ozonolysis with triphenylphosphine cleavage, for the first time, gave aldehyde (4.18) (Scheme 4.8). In addition, this conversion was accomplished via conditions generated by K. C. Nicolaou using osmium tetroxide/NMO mediated vicinal dihydroxylation followed by bis(acetoxy)iodobenzene (BAIB) cleavage.74 Unfortunately, the 10:1 mixture of esters derived from 4.9 and 4.10, respectively was still inseparable at this stage. With aldehyde 4.18 finally in hand, we began studies to install the 3-furyl functionality. Our original idea was to use the NHK reaction not only for its high functional group tolerability but also due to the high potential to induce stereoselective additions through chiral ligands.

O3, then PPh3 O H H O CH2Cl2/MeOH O CO Me O H -78 °C to rt 2 CO2Me -OR- OsO4, NMO 2,6-lutidine CO2Me CO2Me Acetone/H O (10:1) 2 4.18 then BAIB 4.9

Scheme 4.8. Formation of aldehyde 4.18

Exposing aldehyde 4.18 and 3-bromofuran to chromium(II) chloride and nickel(II) chloride resulting in no conversion of starting material (Table 4.2, entry 1).

After several attempts, a literature search over 3-metallofuran species showed that most

3-metallofurans are unstable above -40 °C.75 This led us to conclude that the 3- chromofuran complex was simply decomposing before addition into the aldehyde could take place. Unfortunately, the NHK reaction does not proceed at these low temperatures and so therefore had to be discarded. Other metals including lithium, magnesium, and zinc were also studied but all resulted in low selectivity, decomposition, and poor yields

(entries 2-4). A paper by Sibi and coworkers on their total synthesis of (+)-Ricciocarpin

A provided a potential solution to this problem.76 Not only were they able to selectively add a 3-furyltitanium nucleophile into an aldehyde but the resulting alkoxide was capable of in situ lactonization with the nearby methyl ester. Mimicking their procedure of lithium-halogen exchange with 3-bromofuran followed by transmetallation with chlorotitaniumtriisopropoxide gave the 3-furyltitanium nucleophile. Addition of aldehyde

4.18 to the reaction mixture provided furylalcohol (4.19) as a single diastereomer in an extremely high 81% yield over five steps. Initial attempts at simultaneous lactonization and acetonide hydrolysis gave only tetrahydropyran (4.20). Believing the free rotation of the furylalcohol was the source of this result, lactonization was first induced using

NaHMDS at low temperature to provide lactone (4.21). However, methanolysis of the acetonide moiety under aqueous acid or Lewis acidic conditions resulted in the formation of the same tetrahydropyran 4.20 as before. A closer inspection of the 1H NMR spectrum of lactone 4.21 and comparison with similar structures in the literature revealed a misassignment of the C12 stereochemistry of the furylalcohol. Therefore, the high yield and selectivity of the sequence generated the C12 epimer (4.22) of 4.21.

O H O OH O H O H CO2Me 3-bromofuran, "Metal" CO2Me Table 4.2

CO2Me CO2Me 4.18 4.19

Nucleophile Reagent Temp. (0 °C) Result Yield

Chromium CrCl2/NiCl2 0 to 22 No Conversion 0% Lithium t-BuLi -78 Mutiple Prod. N/A Lithium n-BuLi -78 Mutiple Prod. N/A Magnesium Mg -78 Mutiple Prod. N/A

Zinc ZnBr2 -78 Mutiple Prod. N/A

Titanium ClTi(Oi-Pr)3 -78 Single Isomer 81%, 5 steps

Table 4.2. 3-Metallofuran addition to aldehyde 4.18

O O

O O OH H HO CO Me O H 2 CO2Me p-TsOH, MeOH

CO2Me CO2Me 4.20 4.19 O O O

O O H O OH O HO H H CO2Me O H O Lewis acid CO2Me NaHMDS (1M) O -OR- THF, -78 °C Bronsted acid CO2Me CO Me CO2Me 2 4.20 4.21 4.19

Scheme 4.9. Tetrahydropyran formation during ketal-hydrolysis

4.5 Attempted Stereochemical Inversion of C12-Furylalcohol 4.19

4.5.1 Intermolecular/Intramolecular Mitsunobu Reactions

With our ability to generate furylalcohol 4.19 in high selectivity and yield, as well as establishing the correct C8 stereocenter, pushed us to find a solution for the dilemma.

A very common method for inversion of alcohols is the Mitsunobu reaction.77 This reaction utilizes diethyl azodicarboxylate (DEAD) and triphenylphosphine to generate a good leaving group from the alcohol, which is then attacked by various nucleophiles resulting in an overall inversion of stereochemistry. The following Scheme 4.10 breaks down a stepwise mechanism of the reaction. In the first step, triphenylphosphine attacks a nitrogen atom of DEAD creating a basic nitrogen (4.24), which is then protonated by the carboxylic acid in the solution. The alcohol of interest then attacks the electron deficient phosphorus atom of PPh3 (4.25), releasing the DEAD byproduct and generating a triphenylphosphine oxide leaving group (4.26). The in situ generated carboxylate attacks the stereocenter forcing out the leaving group in an SN2-like process (4.27). The final product contains an inverted stereocenter protected as an acylated alcohol (4.28).

Ph3P Ph P CO Et CO Et 3 2 2 N N N N O EtO2C OH Ph P CO Et EtO2C H 3 2 O R N NH 4.23 4.25 4.24 EtO2C

O B O O O O H R O O Ph P CO Et O R PPh3 3 2 O N NH EtO2C 4.28 4.27 4.26

Scheme 4.10. Mechanism of Mitsunobu reaction

Ideally, an intramolecular Mitsunobu reaction would not only invert the C12 stereocenter but also generate the desired lactone in the same process. However in order for this to be accomplished, the C8 carboxylic acid needed to be created. Unfortunately, a variety of saponification conditions including LiOH, refluxing KOH, and Me3SnOH all resulted in either decomposition or very low yield of the expected bis-acid (4.29)

(Scheme 4.11). Therefore, an intermolecular Mitsunobu reaction was attempting using the very common and easily removable acid, 4-nitrobenzoic acid. Nevertheless, the intermolecular version only produced low yield and poor selectivity. This result can be explained by analyzing the known mechanism. Observing the Scheme 4.12 intermediate

4.27, a benzylic leaving group is formed. With the electron-rich furan ring and through resonance, the leaving group can be forced away to generate a semi-stable benzylic cation

(4.31) before the addition of the nucleophile. At this point, not only is all stereochemistry lost resulting in no selectivity but also the very reactive ionic intermediate can be quenched by almost any species.

O O

O OH O OH H O O H CO2Me Saponification CO2H Intramolecular Mitsunobu (LiOH/KOH/Me3SnOH)

CO Me CO H 2 2 4.29 4.22 O

p-nitrobenzoic acid O O H NO2 DEAD, PPh3, THF O Intermolecular CO2Me Mitsunobu

4.30 CO2Me

Scheme 4.11. Intramolecular/Intermolecular Mitsunobu reactions

O O O

PPh3 O O=PPh3 4.31 4.27

Scheme 4.12. Explaination of selectivity/yield for Mitsunobu reactions

4.5.2 Oxidation/Reduction Sequence

After full exploration of the Mitsunobu options, an oxidation/reduction sequence became the next idea. We were inspired by the accomplishments of the Hagiwara group in their 2nd-generation total synthesis. As discussed in Chapter 2.4.3, the authors were able to generate the desired 12S-stereocenter through a chelated reduction with K-

Selectride®(Scheme 4.13). Hoping to apply this same idea, oxidation of furylalcohol 4.22 under Ley-Griffith conditions provided furylketone (4.32) still as the inseparable 10:1 mixture (Scheme 4.14). Exposure of the ketone to the same K-Selectride® protocol as

Hagiwara, resulted in only decomposition of starting material. However, the only identifiable compound from the reaction was actually the reduced and lactonization product (4.35) from the 9% mono-unsaturated starting material. This result let us know that in the very least, we could perform a similar selective reduction of the furylketone using bis-unsaturated methyl ester 2.88. However, this method was not preferred due to the formation of the unsaturated lactone, which would result in battling the unfavorable

C8 epimerization equilibrium.

H- MeO2C MeO2C O O + OMe O K O MeO O + K O

Scheme 4.13. K-Selectride®-chelated reduction as proposed by Hagiwara

O O O

O O O OH O O O H H H ® O H TPAP, NMO O K-Selectride O CO2Me CO2Me DCM THF, -78 °C

CO2Me CO2Me CO2Me 4.1 4.22 4.32

O O O

O OH O O H H O O O CO Me O H 2 CO2Me O TPAP, NMO K-Selectride® O DCM THF, -78 °C

CO2Me CO2Me CO2Me 4.33 4.34 4.35

Scheme 4.14. Oxidation/reduction sequence of furylalcohol 4.22

4.5.3 Asymmetric 3-Furanyl Titanium Addition

Before settling for the oxidation/reduction of the unsaturated diester, one last strategy needed to be examined: an asymmetric titanium addition. With the substrate controlled 3-furyltitanium addition providing only 12R-furylalcohol, the effect of a chiral ligand addition needed to be investigated. Work by Gau and coworkers provided much insight into this idea. In 2010, the authors published a paper focusing on not only performing an asymmetric Lewis acid catalyzed 3-furyltitanium addition into ketones but also revealed detailed experimentals on the synthesis of a stable (3-furyl)Ti(Oi-Pr)3 reagent, one of few stable above -78 °C (Scheme 4.15).78 In this work, the researchers used an in situ generated BINOL-titanium catalyst to induce the asymmetric process.

Soon after, the Gau group published a second paper utilizing a pre-synthesized H8-

BINOL-titanium catalyst in order accomplish asymmetric additions into aldehydes.79 In addition to their work in 2010, the authors explored in great detail the variety of aryltitanium nucleophiles and aldehydes compatible under these conditions (Scheme

4.15). After fully synthesizing both the known (3-furyl)Ti(Oi-Pr)3 and BINOL-titanium catalyst, aldehyde 4.18 was subjected to the conditions established by Gau (Scheme

4.16). Surprisingly, the catalyst was unable to induce a chiral bias and the sole product formed was still 12R-furylalcohol 4.22 and this strategy, like the others, had to be discarded.

O 10 mol% (S)-BINOL HO R' + (3-furyl)Ti(Oi-Pr)3 R R' toluene, 0 °C, 12 h R 80-96% 83-97% ee O

O ((R)-H8-BINOL)Ti(Oi-Pr)2 OH + ArTi(Oi-Pr)3 R H THF, rt, 1 min R Ar 88-96% 90-99% ee

Scheme 4.15. Asymmetric titanium additions by Gau and coworkers

O O

O H H O O O CO Me (3-furyl)Ti(Oi-Pr)3 2 O H H O ((R)-BINOL)Ti(Oi-Pr)2 THF, 0 °C CO2Me CO2Me 4.18 4.36

Scheme 4.16. Failed asymmetric (3-furyl)Ti(Oi-Pr)3 addition 75

4.6 Unexpected Asymmetric 3-Furyltitanium Success

With all the saturated ester options exhausted, we had no choice but to revert to the unsaturated diester for the 3-furyl addition. Due to observations seen in the oxidation/reduction experiments, there was a high chance for success. Selective oxidative cleavage of the terminal alkene of diester 2.88 provided aldehyde (4.37). This was accomplished via osmium tetroxide/NMO mediated dihydroxylation of the most electron- rich alkene followed by cleavage of the diol with BAIB. Aldehyde 4.37 was then intended to undergo the same substrate controlled 3-furyltitanium addition to yield furylalcohol 4.19, which would be subjected to the oxidation/reduction sequence used before. As stated previously, odds of success were high due to observed stereoselective reduction of the 10% mono-unsaturated ester 4.10 and substrate similarity to Hagiwara’s

2.46.

However, since effort had already been taken to synthesize both BINOL-titanium catalyst and the (3-furyl)Ti(Oi-Pr)3, it was decided to make another attempt at a Lewis acid-mediated asymmetric addition. To our surprise, these conditions exhibited desired selectivity for the formation of the 12S-furyllactone (4.39). Optimization led to an asymmetric 3-furyltitanium addition that gave unsaturated ester, which underwent spontaneously lactonization to provide unsaturated lactone 4.39 in 74% yield with a diastereomeric ratio of 8:1 (12S:12R). These studies provided the singularly effective method to installing the desired furan moiety chemo- and stereoselectively.

O O

O H 1. 3-bromofuran O H O O H OsO4, NMO O n-BuLi, ClTi(Oi-Pr)3 H O CO2Me O CO2Me 2,6-lutidine THF, -78 °C CO2Me

Acetone/H2O (10:1) 2. TPAP, NMO, DCM then BAIB (75%) CO2Me CO2Me CO2Me 2.88 4.37 4.38

K-Selectride® THF, -78 °C O

(3-furyl)Ti(Oi-Pr) O O 3 H ((R)-BINOL)Ti(Oi-Pr)2 O O THF, 0 °C (74%, dr = 8:1) CO2Me 4.39

Scheme 4.17. Unexpected 3-furyltitanium addition to aldehyde 4.37

When comparing the selectively of our reaction to the results published by Gau, we expected a slightly better ratio. However, analysis of the mechanism revealed the reason behind the lower than expected result (Scheme 4.18). Beginning with aldehyde

4.37, the chiral catalyst and (3-furyl)Ti(Oi-Pr)3 are added and a chiral bimetallic species is formed (4.40). This chiral transition state enforces a selective addition creating a titanium alkoxide. Coordination of the titanium center with a neighboring carbonyl of the methyl ester generated titanate species (4.41), which spontaneously lactonizes with the ester providing lactone 4.39 and also achiral catalyst (4.42). This achiral catalyst can then be reinserted in the cycle resulting in indiscriminate addition and thereby reducing observed overall selectivity. Experiments using higher catalyst loading unfortunately only slightly increased the selectivity (10:1) but drastically lowered the yield (30%). These results were unacceptable and the original 10 mol% loading was deemed optimal.

O O O H O H CO2Me Ti (i-OPr)3 R H (R-BINOL)Ti(Oi-Pr)2 O Re O O CO2Me Oi-Pr 4.37 i-PrO Ti Ti O Oi-Pr i-PrO i-Pr 4.40 O

(R-BINOL)Ti(Oi-Pr)2

O O

Ti(Oi-Pr)3 O O O H O O O O H O OMe

MeOTi(Oi-Pr)3 CO2Me 4.42 CO2Me 4.41

Scheme 4.18. Mechanism for 3-furyltitanium addition

CHAPTER 5

NEED FOR A MORE EFFICIENT, HIGHER THROUGHPUT ROUTE: THE

DITHIANE SOLUTION

5.1 Need For Higher Throughput Route

Even though the route to lactone 4.39 was fully optimized, the long linear synthesis (16 steps) from tartaric acid to dione 2.65 was time consuming and contained several bottlenecks. In addition, we knew the reduction of lactone 4.39 would result in an uphill battle with the unfavorable equilibration of the C8 stereocenter. Therefore a more efficient, higher throughput route was necessary in order to provided enough material for end-game chemistry to be thoroughly investigated.

5.2 Exploiting Current Knowledge of Inverse-Demand IMDA

After analyzing a vast amount of potential routes, it was realized that the most efficient route was that developed by Burns using the allylic dithiane. As discussed earlier, this route was abandoned due to the issues of removing the dithiane moiety to generate the enone dienophile. However, at the time of Burns’ research, the ability to change the IMDA from normal-demand to inverse-demand was unknown. It was hypothesized that the electron-rich TBS-ether, in addition to the electron-withdrawing

79 nature of the allyl carbonate, helped to facilitate the IMDA. We theorized that the replacement of the TBS-ether with the still electron-rich dithiane under the same conditions would also induce the desired IMDA; in fact, it was believed the dithiane would be an even better donator. Replicating the IMDA conditions of the TBS-ether

(DCB, 260 °C, 8.5 hours, sealed tube) with dithiane 2.71 provided a low yield of enol carbonate (5.1) and a large portion of decomposition (Scheme 5.1). Though this result initially seemed disheartening, it was envisioned the decomposition was a product of excessive heating rather than poor reactivity or conversion. The reaction conditions were modified to a standard reflux (185 °C) in a round-bottom flask. Remarkably, these conditions exhibited a high exo-selective IMDA giving trans-decalin 5.1 in 90% yield.

o-dichlorobenzene, BHT µW 260 °C, 8.5 h

O O O H O O O OCO2Allyl O S S S S 2.71 5.1

o-dichlorobenzene reflux, 16 h (90%)

Scheme 5.1. Dithiane IMDA reaction

5.3 Efficient Scale-up of Dione (2.65) via New Dithiane Route

The development of the dithiane IMDA bridged a major gap towards a more efficient, higher throughput route in the overall synthesis. Effort was then spent optimizing the new route to the common intermediate dione 2.65. Starting from known dithiane 2.68, deprotonation with n-butyllithium (n-BuLi), rather than the highly pyrophoric t-BuLi as with Burns, followed by addition of known alkyl iodide 2.67 provided allylic dithiane. Deprotection of the primary TBS-ether was accomplished using the much cheaper ammonium fluoride (NH4F), instead of TBAF, in refluxing methanol gave alcohol 2.69 in 81% yield over two steps. Sequential Parikh-Doering oxidation and

Horner-Wadsworth-Emmons olefination with 2-oxo-3-(diethylphosphono)butane generated enone 2.70. Kinetic deprotonation with KHMDS in DME followed by allyl chloroformate quench yielded known enol carbonate 2.71. Heating a solution of triene

2.71 in DCB at 185 °C provided trans-decalin 5.1 in high yield.

At this point, the dithiane moiety was not longer allylic and could therefore be more easily removed without fear of unwanted side reactions. A variety of conditions were screened including MeI/CaCO3, Dess-Martin periodinane, BAIB, PIFA, Tl(NO3)3,

80 AgClO4/NBS, and mCPBA/Ac2O/Et3N with PIFA providing the best result (67% yield).

Tsuji allylation of ketone 2.72 provided desired dione 2.65 as previously reported. This new route drastically improved the route towards the synthesis of dione 2.65. Table 5.1 compares the three routes to dione 2.65: 1) Butler’s original route 2) Improved TBS-ether route 3) New dithiane route. Not only was it fewer steps, higher yielding, and quicker to process, it removed problematic bottlenecks in the previous route such large vinyl-

Grignard addition and an IMDA that was restricted to the size of the sealed tube. This route is now the most current in our work with salvinorin A and analogues.

O O 1. SO •pyr 3 O 1. n-BuLi, THF/HMPA O OH Et N, CH Cl O S -78 °C to rt, then 2.67 3 2 2 2. NH F, MeOH, reflux S 4 2. O O (81%, 2 steps) 2.69 S P(OEt) S S 2.68 S 2 2.70 KHMDS (solid) NaH, THF (85%, 2 steps) DME, -78 °C; then allyl chloroformate (80%)

O O O O OCO Allyl H O H 2 O OCO Allyl OCO2Allyl 2 PIFA o-DCB MeCN: sat. aq NaHCO S 3 reflux, 16 h S (4:1), 10 min S S 2.71 O 5.1 (90%) 2.72 (67%)

O O H Pd(PPh3)4 O toluene, rt, 30 min (94%) O 2.65

Scheme 5.2. Efficient dithiane route to dione 2.65

Butler Route TBS-ether Route Dithiane Route 16 steps 16 steps 12 steps 2.8% yield 8.6% yield 16.2% yield 4.5 weeks 3.5 weeks 8 days

Table 5.1. Overall route comparisons to dione 2.65

CHAPTER 6

TOTAL SYNTHESIS OF SALVINORIN A: REDUCTION AND END GAME

6.1 Reduction of α, β-Unsaturated Lactone 4.39

With unsaturated lactone 4.39 in hand through the chiral Lewis acid-mediated addition as well as a new efficient route to dione 2.65, experimental screening for reduction conditions could be undertaken. Previous success using magnesium in methanol with substrate 2.88 led it to be the potential candidate for this reaction.

However, exposure of lactone 4.39 to these conditions provided a mixture of lactone diastereomers (6.1) in low yield with an unidentified side product as the major result. A variety of other conditions were then investigated in order to find a viable method for this conversion (Table 6.1).

Conditions Results Pd/C, Hydrogen No Rxn Wilkinson cat., Hydrogen No Rxn Stryker's reagent No Rxn L-Selectride® Over-reduction

NaBH4 Over-reduction Mg, methanol Major side product

SmI2, AcOH, Et3N, PhMe Good conversion Inseparable impurity SmI2, MeOH/THF 51% following next step

Table 6.1. Reduction conditions for lactone 4.39

Heterogeneous catalysis failed most likely due to the steric bulk of the quaternary centers and from the furan group’s tendency to be reduced under these conditions (entry

1). Homogeneous hydrogenation via Wilkinson’s catalyst also provided no conversion even under high pressure (entry 2). Various borohydride reagents were screened

® including NaBH4 and L-Selectride , all yielding mixtures of over-reduction or decomposistion products (entry 4,5). Several attempts at utilizing copper(I) hydride, including commonly used Stryker’s reagent, also lacked any conversion (entry 3).

Throughout these experiments, a trend had developed indicating larger reducing agents were not capable of interfacing with the substrate in order to react. The magnesium in methanol protocol, though it provided a major side product, induced the most conversion.

Therefore, attention was turned to another single-electron transfer agent, samarium diiodide (SmI2). Samarium diiodide is a well-known single-electron reagent also utilized in 1,4-conjugate reductions.81 However, its extreme sensitivity to oxygen causes it to be a difficult reagent to handle and especially to store at times. Luckily, methods of preparing this reagent easily in the lab have been published. Using samarium powder and iodoform

82 in THF with sonication generates SmI2, which is used immediately and then discarded.

Bis-conjugate reduction of both the unsaturated lactone and methyl ester with SmI2 in methanol/THF resulted in the anticipated 2.5:1 (8S:8R) mixture of inseparable C8 lactone epimers 6.1 (Scheme 6.1).

O O

O SmI , Et N O O O 2 3 H H O H O O MeOH/THF O -78 °C

CO Me CO2Me 2 4.39 6.1

Scheme 6.1. Reduction of lactone 4.39 with SmI2

6.2 Derivation of the Vicinal Diol (6.2)

Methanolysis of the acetonide moiety revealed the chromatographically separable diols 6.2 and (6.3) in 51% yield over two steps. Separation of these epimeric diols proved to be extremely difficult with standard (40-63 µm particle size) silica gel. Due to the absence of normal-phase preparative HPLC, these diols were separated using HPLC grade (5-20 µm particle size) silica gel at high pressure (12 psi). Epimerization of the C8 stereocenter could be accomplished using K2CO3 in methanol as demonstrated by the

Evans’ group synthesis. Completion of 1.1 from diol 6.2 was achieved by a two-step acylation/oxidation sequence. Exposing 6.2 to acetic anhydride and 2,6-lutidine in dichloromethane for 1.5 days gave selective C2 acylation of the least hindered alcohol.

Minimal competition between C1 acylation or bis-acylation was observed during this process. Oxidation of the C1 alcohol was attempted with Dess-Martin periodinane and once again it failed to facilitate conversion. Reverting to the consistently successful Ley-

Griffith oxidation provided 1.1 in good yield (72% over two steps). Our synthesis

85 provided salvinorin A in an overall yield of 7.1% over 16 steps from known starting material 2.67.

O O O

1. SmI2, Et3N MeOH/THF O O -78 °C HO O HO O H H H H O H HO HO O 2. p-TsOH, MeOH O + O (51%, 2 steps, dr = 2.5:1 8S:8R) 6.2 6.3 CO Me CO2Me CO2Me 4.39 2 (8R) (8S)

K2CO3, MeOH 1. Ac2O, 2,6-lutidine (99%, dr = 2.5:1 8S:8R) DCM, 36 h 2. TPAP, NMO, CH2Cl2 (72%, 2 steps) O

O O AcO H H O

1.1 CO2Me

Scheme 6.2. Line total synthesis of salvinorin A (1.1)

CHAPTER 7

SALVINORIN ANALOGUES AND FUTURE WORK

7.1 Future Work

Now that we have developed a flexible and concise total synthesis of 1.1, we intend to prepare a number of analogues that are not easily constructed via semi- synthesis. To the best of our knowledge, there are no reports indicating completion or efforts towards non semi-synthetic analogues.

There are two main objectives behind the synthesis of salvinorin analogues. The first, and more obvious, is the use of these analogues to further probe the structure activity relationship between salvinorin and the KOR. Currently, the role of the C5 and C9 methyl groups has yet to be investigated; therefore, compounds (7.1) and (7.2) are of interest. In addition, a bis-unsaturated derivative has yet to be studied though similar compounds in the salvinorin family (7.3) have been isolated.

The second main objective is related to the binding studies that have been conducted and modeled for salvinorin A. As discussed in Section 1.4.2, the currently accepted binding model for salvinorin is based on computational analysis of the KOR with the thioacetate 1.30. However, there is still some debate within the scientific community as to whether or not this model is completely accurate due to the covalent

87 disulfide bond that is formed in the model, which cannot exist with 1.1. Efforts to address this issue will be attempted using several analogues in hopes that a crystal structure of the analogues and KOR can be obtained. We envision one of the following derivatives, especially pyridine derivative (7.5), to possess a binding strong enough to generate this crystal structure without creating an arguably different binding within the pocket.

O O O

O O O O O O AcO H H AcO H H AcO H O O O H

7.1 H 7.2 CO2Me MeO2C CO2Me 7.3

N N HN

O O O O O O H H AcO H H AcO H H AcO O O O

7.4 7.5 CO Me 7.6 CO2Me CO2Me 2

Scheme 7.1. Future analogues for SAR/KOR binding studies

7.2 Summary

Up to this point, we have developed a highly versatile, efficient route to salvinorin

A (1.1) and several potential analogues of interest. During the synthesis of 1.1, we were able to, first, modify the original Butler route to aldehyde 2.76. This modification

88 allowed for better access to IMDA precursor 2.75. Extensive optimization of the inverse- demand IMDA, both under thermal and microwave conditions, generated easy access to dione 2.65. Exhaustion of material due to transformations of late-stage chemistry, revealed a need for a better route to dione 2.65. Combining the advantages of the Burns dithiane route with the knowledge of the current IMDA, we were able to fashion the current high throughput route leading to the same dione intermediate. With large quantities of dione 2.65 available, exploration on the construction of the carboskeleton framework was undertaken. After examining several routes to the installation of the 3- furan moiety, the use of unsaturated diester aldehyde 4.37 was deemed the best path. A surprising BINOL-Lewis acid-mediated titanium addition provided 3-furyllactone 4.39 in good yield with decent selectivity. A single-electron bis-reduction of the unsaturated lactone and methyl ester with SmI2 in methanol/THF afforded the anticipated 2.5:1

(8S:8R) C8 α-lactone epimers, which were separated as the diols 6.2 and 6.3, respectively using HPLC-grade silica gel. Selective acylation followed by oxidation provided the natural product 1.1 in 7.1% yield (16 steps) from know starting material.

LIST OF REFERENCES

(1) Valdés, L. J. I.; Hatfield, G. M.; Koreeda, M.; Paul, A. G. Econ. Bot. 1987, 41, 283.

(2) Valdés, L. J. I.; Díaz, J. L.; Paul, A. G. J. Ethnopharmacol. 1983, 7, 287.

(3) Giroud, C.; Felber, F.; Augsburger, M.; Horisberger, B.; Rivier, L.; Mangin, P. Forensic Sci. Int. 2000, 112, 143.

(4) Eisenreich, W.; Bacher, A.; Arigoni, D.; Rohdich, F. Cell. Mol. Life Sci. 2004, 61, 1401.

(5) Porter, J. W.; Spurgeon, S. L. Biosynthesis of Isoprenoid Compounds; Wiley: New York, 1981.

(6) Rohmer, M.; Knami, M.; Simonin, P.; Sutter, B.; Sahm, H. Biochem. J. 1993, 295, 517

(7) Broers, S. T. J. Ph.D. Dissertation, ETH-Zurich, 1994.

(8) Schwarz, M. K. Ph.D. Dissertation, ETH-Zurich, 1994.

(9) Eisenreich, W.; Rohdich, F.; Bacher, A. Trends Plant Sci. 2001, 6, 78.

(10) Eisenreich, W.; Schwarz, M.; Cartayrade, A.; Arigoni, D.; Zenk, M. H.; Bacher, A. Chem. Biol. 1998, 5, R221.

(11) Rohmer, M. Nat. Prod. Rep. 1999, 16, 565.

(12) Samanani, N.; Facchini, P. J.; In Recent Advances in Phytochemistry; Romeo, J. T., Ed.; Elsevier: New York, 2006; Vol. 40, p 55. 90

(13) Kutrzeba, L.; Dayan, F. E.; Howell, J.; Feng, J.; Giner, J.-L.; Zjawiony, J. K. Phytochem. 2007, 68, 1872.

(14) Ortega, A.; Blount, J. F.; Manchand, P. S. J. Chem. Soc. Perkin Trans I 1982, 2505.

(15) Valdés, L. J. I.; Butler, W. M.; Hatfield, G. M.; Paul, A. G.; Koreeda, M. J. Org. Chem. 1984, 49, 4716.

(16) Giner, J.-L.; Kiemle, D. J.; Kutrzeba, L.; Zjawiony, J. Magn. Reson. Chem. 2007, 45, 351.

(17) Valdés, L. J. I.; Chang, H.-M.; Visger, D. C.; Koreeda, M. Org. Lett. 2001, 3, 3935.

(18) Munro, T. A.; Rizzacasa, M. A. J. Nat. Prod. 2003, 66, 703.

(19) Lee, D. Y. W.; Ma, Z.; Liu-Chen, L.-Y.; Wang, Y.; Chen, Y.; Carlezon, W. A. J.; Cohen, B. Bioorg. Med. Chem. 2005, 13, 5635.

(20) Shirota, O.; Nagamatsu, K.; Sekita, S. J. Nat. Prod. 2006, 69, 1782.

(21) Kutrzeba, L.; Ferreira, D.; Zjawiony, J. J. Nat. Prod. 2009, 72, 1361.

(22) Bingham, A. K.; Munro, T. A.; Rizzacasa, M. A.; Robins-Browne, R. M. J. Nat. Prod. 2003, 66, 1242.

(23) Harding, W. W.; Tidgewell, K.; Schmidt, M.; Shah, K.; Dersch, C. M.; Snyder, J.; Parrish, D.; Deschamps, J. R.; Rothman, R. B.; Prisinzano, T. E. Org. Lett. 2005, 7, 3017.

(24) Ma, Z.; Deng, G.; Dai, R.; Xu, W.; Liu-Chen, L.-Y.; Lee, D. Y. W. Tetrahedron Lett. 2010, 51, 5480.

(25) Waldhoer, M.; Barlett, S. E.; Whistler, J. L. Annu. Rev. Biochem. 2004, 73, 953.

(26) Janecka, A.; Fichna, J.; Janecki, T. Curr. Top. Med. Chem. 2004, 4, 1.

(27) Dhawan, B. N.; Cesselin, F.; Raghubir, R.; Reisine, T.; Bradley, P. B.; Portoghese, P. S.; Hamon, M. Pharmacol. Rev. 1996, 48, 567.

(28) Roth, B. L.; Baner, K.; Westkaemper, R.; Siebert, D.; Rice, K. C.; Steinberg, S.; Ernsberger, P.; Rothman, R. B. Proc. Nat. Acad. Sci. USA 2002, 99, 11934.

(29) Goldstein, A.; Tachibana, S.; Lowney, L. I.; Hunkapiller, M.; Hood, L. Proc. Nat. Acad. Sci. USA 1979, 76, 6666.

(30) Yan, F.; Mosier, P. D.; Westkaemper, R. B.; Stewart, J.; Zjawiony, J. K.; Vortherms, T. A.; Sheffler, D. J.; Roth, B. L. Biochemistry 2005, 44, 8643.

(31) Wu, H.; Wacker, D.; Mileni, M.; Katritch, V.; Han, G. W.; Vardy, E.; Liu, W.; Thompson, A. A.; Huang, X.-P.; Carroll, F. I.; Mascarella, S. W.; Westkaemper, R. B.; Mosier, P. D.; Roth, B. L.; Cherezov, V.; Stevens, R. C. Nature 2012, 485, 327.

(32) Vortherms, T. A.; Roth B. L. Mol. Interventions 2006, 6, 257.

(33) Zhang, H.; Shi, Y. G.; Woods, J. H.; Watson, S. J.; Ko, M. C. Eur. J. Pharmacol. 2007, 570, 89.

(34) Jutkiewicz, E. M. Mol. Interventions 2006, 6, 162.

(35) Cota, D.; Tschop, M. H.; Horvath, T. L.; Levine, A. S. Brain Res. Rev. 2006, 51, 85.

(36) Koob, G. F.; Roberts, A. J.; Kieffer, B. L.; Heyser, C. J.; Katner, S. N.; Ciccocioppo, R.; Weiss, F. Res. Dev. Alcohol 2003, 16, 263.

(37) Braida, D.; Limonta, V.; Pegorini, S.; Zani, A.; Guerini-Rocco, C.; Gori, E.; Sala, M. Psychopharmacol. 2007, 190, 441.

(38) Braida, D.; Limonta, V.; Capurro, V.; Fadda, P.; Rubino, T.; Mascia, P.; Zani, A.; Gori, E.; Fratta, W.; Parolaro, D.; Sala, M. Biol. Psychiatry 2008, 63, 286.

(39) Willmore-Fordham, C. B.; Krall, D. M.; McCurdy, C. R.; Kinder, D. H. Neuropharmacol. 2007, 53, 481.

(40) Butelman, E. R.; Harris, T. J.; Kreek, M. J. Psychopharmacol. 2004, 172, 220.

(41) Ansonoff, M. A.; Zhang, J.; Czyzyk, T.; Rothman, R. B.; Stewart, J.; Xu, H.; Zjawiony, J.; Siebert, D.; Yang, F.; Roth, B. L.; Pintar, J. E. J. Pharmacol. Exp. Ther. 2006, 318, 641.

(42) John, T. F.; French, L. G.; Erlichman, J. S. Eur. J. Pharmacol. 2006, 545, 129.

(43) Béguin, C.; Richards, M. R.; Wang, Y.; Chen, Y.; Liu-Chen, L.-Y.; Ma, Z.; Lee, D. Y. W.; Carlezon, W. A. J.; Cohen, B. M. Bioorg. Med. Chem. Lett. 2005, 15, 2761.

(44) Tidgewell, K.; Harding, W. W.; Lozama, A.; Cobb, H.; Shah, K.; Kannan, P.; Dersch, C. M.; Parrish, D.; Deschamps, J. R.; Rothman, R. B.; Prisinzano, T. E. J. Nat. Prod. 2006, 69, 914.

(45) Bikbulatov, R. V.; Yan, F.; Roth, B. L.; Zjawiony, J. Bioorg. Med. Chem. Lett. 2007, 17, 2229.

(46) Béguin, C.; Potter, D. N.; DiNieri, J. A.; Munro, T. A.; Richards, M. R.; Paine, T. A.; Berry, L.; Zhao, Z.; Roth, B. L.; Xu, W.; Liu-Chen, L.-Y.; Charlezon, W. A. J.; Cohen, B. M.; J. Pharmacol Exp. Ther. 2008, 324, 188.

(47) Harding, W. W.; Schmidt, M.; Tidgewell, K.; Kannan, P.; Holden, K. G.; Gilmour, B.; Navarro, H.; Rothman, R. B.; Prisinzano, T. E. J. Nat. Prod. 2006, 69, 107.

(48) Béguin, C.; Richards, M. R.; Li, J.-G.; Wang, Y.; Xu, W.; Liu-Chen, L.-Y.; Carlezon, W. A. J.; Cohen, B. M. Bioorg. Med. Chem. Lett. 2006, 16, 4679.

(49) Lee. D. Y. W.; He, M.; Liu-Chen, L.-Y.; Wang, Y.; Li, J.-G.; Xu, W.; Ma, Z.; Carlezon, W. A. J.; Cohen, B. M. Bioorg. Med. Chem. Lett. 2006, 16, 5498.

(50) Lee, D. Y. W.; He, M.; Kondaveti, L.; Liu-Chen, L.-Y.; Ma, Z.; Wang. Y.; Chen, Y.; Li, J.-G.; Béguin, C.; Carlezon, W. A. J.; Cohen, B. M. Bioorg. Med. Chem. Lett. 2005, 15, 4169.

(51) Munro, T. A.; Rizzacasa, M. A.; Roth, B. L.; Toth, B. A.; Yan, F. J. Med. Chem. 2005, 48, 345.

(52) Simpson, D. S.; Katavic, P. L.; Lozama, A.; Harding, W. W.; Parrish, D.; Deschamps, J. R.; Dersch, C. M.; Partilla, J. S.; Rothman, R. B.; Navarro, H.; Prisinzano, T. E. J. Med. Chem. 2007, 50, 3596.

(53) Béguin, C.; Duncan, K. K.; Munro, T. A.; Ho, D. M.; Xu, W.; Liu-Chen, L.- Y.; Carlezon, W. A. J.; Cohen, B. M. Bioorg. Med. Chem. 2009, 17, 1370.

(54) Harding, W. W.; Schmidt, M.; Tidgewell, K.; Kannan, P.; Holden, K. G.; Dersch, C. M.; Rothman, R. B.; Prisinzano, T. E. Bioorg. Med. Chem. Lett. 2006, 16, 3170.

(55) Prisinzano, T. E.; Rothman, R. B. Chem. Rev. 2008, 108, 1732.

(56) Scheerer, J. R.; Lawrence, J. F.; Wang, G. C.; Evans, D. A. J. Am. Chem. Soc. 2007, 129, 8968.

(57) Nozawa, M.; Suka, T.; Hoshi, T.; Suzuki, T.; Hagiwara, H. Org. Lett. 2008, 10, 1365.

(58) Hagiwara, H.; Suka, Y.; Nojima, T.; Hoshi, T.; Suzuki, T. Tetrahedron 2009, 65, 4820.

(59) Lingham, A. R.; Hügel, H. M.; Rook, T. J. Aust. J. Chem. 2006, 59, 340.

(60) Burns, A. C.; Forsyth, C. J. Org. Lett. 2008, 10, 97.

(61) Butler, S. C.; Forsyth, C. J. J. Org. Chem. 2013, 78, 3895.

(62) Hagiwara, H.; Hamano, K.; Nozawa, M.; Hoshi, T.; Suzuki, T.; Kido, F. J. Org. Chem. 2005, 70, 2250.

(63) Vedejs, E.; Fuchs, P. L. J. Org. Chem. 1971, 36, 366.

(64) Nickon, A.; Rodriguez, A. D.; Ganguly, R.; Shirhatti, V. J. Org. Chem. 1985, 50, 2767.

(65) Kim, Y. J.; Lee, D. Org. Lett. 2006, 8, 5219.

(66) Liu, J.-H.; Long, Y.-Q. Tetrahedron 2009, 50, 4592.

(67) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, 1625.

(68) Okude, Y.; Hirano, S.; Hiyama, T.; Nozkai, H. J. Am. Chem. Soc. 1977, 99, 3179.

(69) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644.

(70) Hagiwara, H.; Inome, K.; Uda, H. J. Chem. Soc. Perkin Tran. I 1995, 757.

(71) Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem. 1956, 21, 478.

(72) Lee, G. H.; Youn, I. K.; Choi, E. B.; Lee, H. K.; Yon, G. H.; Yang, H. C.; Pak, C. S. Curr. Org. Chem. 2004, 8, 1263.

(73) Bidar, M.; Tokmajyan, G.; Nasiri, F. Chem. Nat. Compd. 2013, 48, 942.

(74) Nicolaou, K. C.; Adsool, V. A.; Hale, C. R. H. Org. Lett. 2010, 12, 1552.

(75) Bock, I.; Bornowski, H.; Ranft, A.; Theis, H. Tetrahedron 1990, 46, 1199.

(76) Sibi, M. P.; He, L. Org. Lett. 2004, 6, 1749.

(77) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1967, 40, 935.

(78) Zhou, S.; Chen, C.-R.; Gau, H.-M. Org. Lett. 2010, 12, 48.

(79) Wu, K.-H.; Zhou, S.; Chen, C.-A.; Yang, M.-C.; Chiang, R.-T.; Chen, C.-R.; Gau, H.-M. Chem. Commun. 2011, 47, 11668.

(80) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.

(81) Dahlén, A.; Hilmersson, G. Chem. Eur. J. 2003, 9, 1123.

(82) Concellón, J. M.; Rodríguez-Solla, H.; Bardales, E.; Huerta, M. Eur. J. Org. Chem. 2003, 1775.

APPENDIX A:

EXPERIMENTAL DETAILS

General Methods: Unless otherwise stated, all oxygen and moisture-sensitive reactions were performed under anhydrous conditions (oven-dried glassware sealed under a dry argon atmosphere). Solutions and solvents sensitive to moisture were transferred using standard syringe and cannula techniques. All commercial reagents were purchased as reagent grade and, unless otherwise noted, used without further purification. All organic solvents were used dry: tetrahydrofuran (THF), diethyl ether (Et2O), dichloromethane (CH2Cl2), and toluene were purified via a Pure Solv MD-6 Solvent

Purification System; triethylamine (Et3N), diisopropylamine, and diisopropylethylamine

(DIPEA) were distilled from CaH2; dimethyl sulfoxide (DMSO) was stored over freshly activated 4Å molecular sieves; 1,2-dimethoxyethane (DME) was distilled from

Na/benzophenone ketyl. Thin-layer chromatography was performed on using Silicycle

Glass Backed TLC Extra Hard Layer 60Å, 250 µm, F-254 TLC plates that were visualized via UV light (254 nm) or by p-anisaldehyde (PAA), phosphomolybdic acid

(PMA), or ceric ammonium molybdate (CAM) stains and the column chromatographic

97 separations were performed using Silicycle SiliaFlash® P60 silica gel (40–63 µm) unless otherwise noted. Melting points were measured on a Thomas Hoover (Uni-melt) capillary melting point apparatus. Optical rotations were measured by a Perkin-Elmer

Model 241 Polarimeter at 589 nm with a sodium lamp and concentrations are reported in g/100 mL. Nuclear Magnetic Resonance (NMR) spectra were obtained for proton (1H) and carbon (13C) nuclei using Bruker DPX-400, Bruker DRX-500, and Bruker Avance III

HD 600 NMR spectrometers; residual solvent peak signals for CDCl3 were set at 7.26 and 77.16 ppm in the 1H and 13C spectra, respectively. A Perkin-Elmer 1600 Series FT-

IR spectrometer was used to record infrared spectra and absorptions are reported in reciprocal centimeters. High-resolution mass spectrometric data were obtained using a

Bruker MicroTOF (ESI) Mass Spectrometer.

Iodide (3.2)

O O O OTBDPS PPh3, imid., I2 O OTBDPS PhMe, 110 °C HO (95%) I 2.80 3.2

To a refluxing solution of known alcohol 2.80 (1.00 g, 2.50 mmol) in PhMe (18 mL), were added PPh3 (0.786 g, 3.00 mmol), imidazole (511 mg, 7.50 mmol), and iodine

(825 mg, 3.25 mmol) sequentially. This solution was refluxed for 30 minutes before being cooled to rt. The reaction was washed with sat. aq. Na2S2O3 (3 x 30 mL) upon which the brown color disappeared. The layers were separated and the aq. layer was extracted with Et2O (4 x 30 mL) and the combined organic phases were dried and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 10:1, v/v) of the residue gave 3.2 (1.20 g, 95%) as a colorless oil: Rf 0.45 (hexanes-ethyl acetate, 12:1,

23 v/v); [α]D -5.31 (c 1.01, CHCl3); IR (neat) 2985, 2932, 2858, 1427, 1379, 1369, 1112,

-1 1 823 cm ; H NMR (CDCl3, 500 MHz) δ 7.71-7.68 (m, 4H), 7.47-7.39 (m, 6H), 3.98

(ddd, J = 5, 5, 7 Hz, 1H), 3.91-3.84 (m, 2H), 3.80 (dd, J = 5.5, 10.5 Hz, 1H), 3.40 (dd, J =

4.5, 10.5 Hz, 1H), 3.31 (dd, J = 5, 10.5 Hz, 1H), 1.48 (s, 3H), 1.41 (s, 3H), 1.09 (s, 9H);

13 C NMR (CDCl3, 125 MHz) δ 135.7, 135.6, 133.0, 133.0, 129.9, 129.9, 127.8, 109.6,

+ 81.2, 77.7, 64.2, 27.5, 27.4, 26.9, 19.3, 6.9; HRMS calcd for C23H31IO3Si [M+Na]

533.0979, found 533.0979.

Alkene (3.8)

O O MgBr, CuI O OTBDPS O OTBDPS THF/HMPA -40 °C to 0 °C I 3.2 (80%) 3.8

To a flame-dried flask was added CuI (3.08 g, 16.2 mmol) from a glovebox.

Iodide 3.2 (41.2 g, 80.8 mmol) in THF (93 mL) was added followed by HMPA (58 mL).

The suspension was cooled to -30 °C and a solution of vinyl magnesium bromide (1.0 M in THF, 162 mL, 162 mmol) was added dropwise. The reaction was stirred at -30 °C for

1 hour, then was warmed to 0 °C and quenched with sat. aq. NH4Cl (50 mL). The aq. layer was extracted with Et2O (3 x 100 mL) and the organic layers were dried and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 25:1, v/v) of the crude product gave 3.8 (26.5 g, 80%) as a colorless oil: Rf 0.45 (hexanes-ethyl acetate,

23 12:1, v/v); [α]D -10.2 (c 1.06, CHCl3); IR (neat) 3071, 2984, 2858, 1959, 1890, 1825,

-1 1 1774, 1642, 1428, 1369 cm ; H NMR (CDCl3, 400 MHz) δ 7.74-7.70 (m, 4H), 7.46-

7.39 (m, 6H), 5.88 (dddd, J = 6.8, 6.8, 10.0, 13.6 Hz, 1H), 5.17-5.09 (m, 2H), 4.13-4.08

(m, 1H), 3.84-3.80 (m, 3H), 2.51-2.35 (m, 2H), 1.45 (s, 3H), 1.43 (s, 3H), 1.11 (s, 9H);

13 C NMR (CDCl3, 100 MHz) δ 135.9 (4C), 134.3, 133.5, 133.4, 130.01, 129.98, 128.0

(4C), 117.6, 108.9, 80.8, 77.8, 64.4, 37.8, 27.6, 27.3, 27.1 (3C), 19.5; HRMS calcd for

+ C25H34O3Si [M+Na] 433.2169, found 433.2180.

100

Aldehyde (2.76)

O O O OTBDPS O3, then PPh3 O OTBDPS CH2Cl2/MeOH -78 °C to rt H 3.8 (94%) 2.76 O

A solution of alkene 3.8 (10.71 g, 26.08 mmol) in DCM/MeOH (263 mL/50 mL) was cooled to -78 °C. Ozone was bubbled through until the solution turned a bright blue color. Excess ozone was removed by purging with oxygen until colorless. PPh3 (17.24 g, 65.75 mmol) was added and stirred at -78 °C for 30 minutes, rt for 30 minutes, and was then concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 12:1 then 6:1, v/v) of the residue gave 2.76 (10.12 g, 94%) as a colorless oil: Rf 0.31 (hexanes-

23 ethyl acetate, 6:1, v/v); [α]D -13.1 (c 1.00, CHCl3); IR (neat) 2986, 2932, 2858, 1727,

-1 1 1474, 1428, 1379, 1218, 1112, 1084 cm ; H NMR (CDCl3, 400 MHz) δ 9.79 (t, J = 2

Hz, 1H), 7.70-7.64 (m, 4H), 7.47-7.36 (m, 6H), 4.42 (ddd, J = 4.4, 7.2, 7.2 Hz, 1H), 3.88-

3.75 (m, 3H), 2.70-2.65 (m, 2H), 1.41 (s, 3H), 1.39 (s, 3H), 1.07 (s, 9H); 13C NMR

(CDCl3, 100 MHz) δ 200.1, 135.7 (4C), 133.1, 133.1, 130.1, 130.0, 127.9 (4C), 109.6,

80.5, 73.8, 64.0, 47.0, 27.3, 27.0, 27.0 (3C), 19.4; HRMS calcd for C24H32O4Si

[M+MeOH+Na]+ 467.2224, found 467.2244.

101

Silyl Ethers (2.83)

1. O Br, Mg O O OTBDPS THF, -78 °C O OTBDPS

H 2. TBSCl, imid DMAP, DMF 2.76 2.83 O (87%, 2 steps) OTBS

To a solution of aldehyde 2.76 (10.11 g, 24.50 mmol) in THF (17 mL) at -78 °C was added dropwise a freshly prepared solution of isopropenylmagnesium bromide (0.49

M in THF, 110 mL, 53.9 mmol). The dark solution was stirred at -78 °C for 1 hour and then at rt for 30 minutes. The reaction was quenched slowly with sat. aq. NH4Cl (50 mL) and water (10 mL) was added. The aq. layer was extracted with EtOAc (3 x 50 mL) and the organic phases were dried and concentrated to afford a crude mixture of alcohols

2.82.

The crude mixture was dissolved in DMF (49 mL) and imidazole (5.00 g, 73.4 mmol), DMAP (200 mg, 2.45 mmol), and TBSCl (5.54 g, 36.8 mmol) were added sequentially. The solution was allowed to stir at rt overnight before being quenched with sat. aq. NH4Cl (25 mL). The aq layer was extracted with EtOAc (3 x 20 mL) and the combined organic layers were dried and concentrated. Silica gel column chromatography

(hexanes-ethyl acetate, 35:1, v/v) afforded 2.83 (12.0 g, 87%) as a colorless oil: Rf 0.61

(hexanes-ethyl acetate, 7:1, v/v); IR (neat) 2957, 2929, 2893, 2857, 1473, 1428, 1378,

-1 1 1251, 1113 cm ; H NMR (CDCl3, 400 MHz) δ 7.75-7.66 (m, 8H), 7.47-7.35 (m, 12H),

4.97-4.94 (m, 1H), 4.93-4.90 (m, 1H), 4.86-4.82 (m, 1H), 4.78-4.75 (m, 1H), 4.38-4.31

102

(m, 2H), 4.26-4.19 (m, 1H), 3.95-3.88 (m, 1H), 3.83-3.62 (m, 6H), 1.94 (ddd, J = 2, 10.8,

13.6 Hz, 1H), 1.85-1.75 (m, 3H), 1.71 (s, 3H), 1.68 (s, 3H), 1.42 (s, 6H), 1.37 (s, 3H),

1.35 (s, 3H), 1.07 (s, 9H), 1.06 (s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s,

13 3H), 0.04 (s, 6H); C NMR (CDCl3, 100 MHz) δ 148.6, 146.7, 135.82 (2C), 135.79 (2C),

135.77 (4C), 133.5, 133.4 (2C), 133.3, 129.9, 129.81 (2C), 129.79, 127.83 (6C), 127.80

(2C), 112.2, 110.6, 108.7, 108.6, 81.5, 81.1, 75.6, 75.5, 74.7, 73.5, 64.4, 64.0, 41.0, 39.9,

27.71, 27.66, 27.0 (2C), 26.95 (3C), 26.93 (3C), 26.03 (3C), 25.97 (3C), 19.4, 19.3, 18.4,

+ 18.3, 17.2, 16.7, -4.57, -4.64, -4.9, -5.0; HRMS calcd for C33H52O4Si2 [M+Na] 591.3296 found 591.3282.

Alcohols (2.84)

O O O OTBDPS O OH 10% NaOH, MeOH 65 °C, 2.5 h OTBS 2.83 (92%) OTBS 2.84

Silyl ethers 2.83 (421.6 mg, 741 µmol) were dissolved in 10% NaOH in MeOH

(7.5 mL) and heated to 65 °C for 2.5 hours. The reaction was cooled to rt and quenched with sat. aq. NH4Cl (10 mL). The aq. layer was extracted with EtOAc (3 x 15 mL) and the combined organic phases were dried and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 8:1, v/v) of the residue gave 2.84 (224.9 mg,

92%) as a colorless oil: Rf 0.34 (hexanes-ethyl acetate, 4:1, v/v); IR (neat) 3469, 2954,

-1 1 2929, 2889, 2857, 1472, 1463, 1380, 1251, 1165 cm ; H NMR (CDCl3, 400 MHz) δ

103

4.94-4.92 (m, 1H), 4.92-4.90 (m, 1H), 4.84-4.81 (m, 1H), 4.77-4.74 (m, 1H), 4.30-4.24

(m, 2H), 4.06-3.98 (m, 1H), 3.82-3.71 (m, 5H), 3.70-3.64 (m, 1H), 3.63-3.54 (m, 2H),

2.19 (brs, 2H), 1.92-1.81 (m, 1H), 1.77-1.69 (m, 1H), 1.68 (s, 3H), 1.66 (s, 3H), 1.61-1.52

(m, 1H), 1.40 (s, 3H), 1.39 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H), 0.88 (s, 9H), 0.87 (s, 9H),

13 0.053 (s, 3H), 0.050 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); C NMR (CDCl3, 100 MHz) δ

148.2, 146.3, 112.2, 110.8, 108.8, 108.7, 81.8, 81.7, 74.4, 74.2, 73.6, 73.4, 62.1, 62.0,

40.4, 39.5, 27.6, 27.5, 27.11, 27.07, 25.9 (6C), 18.3 (2C), 17.3, 17.0, -4.6, -4.7, -5.0, -5.1;

+ HRMS calcd for C17H34O4Si [M+Na] 353.2119, found 353.2128.

Enones (2.85)

O 1. (COCl)2, DMSO O O OH Et3N, CH2Cl2 0 °C to rt O O O O 2.84 2. OTBS P(OEt)2 OTBS 2.85 NaH, THF (82%, 2 steps)

To a solution of DMSO (6.70 mL, 94.0 mmol) in DCM (75 mL) at -78 °C was added (COCl)2 (4.03 mL, 47.0 mmol) slowly and stirred for 15 minutes. A solution of alcohols (7.77 g, 23.5 mmol) in DCM (19 mL) was added dropwise and stirred for 1 hour. Et3N (26.0 mL, 188 mmol) was added and the solution was allowed to warm to rt.

Sat. aq. NH4Cl (50 mL) was added and the two layers were separated. The aq. layer was extracted with EtOAc (3 x 50 mL) and the organic layers were dried and concentrated to give crude aldehydes. 104

To a suspension of NaH (60%, 1.13g, 28.2 mmol) in THF (15 mL) at 0 °C was added dropwise a solution of diethyl (3-oxobutan-2-yl)phosphonate (6.12 g, 29.4 mmol) in THF (27 mL). The reaction stirred at 0 °C for 1 hour at which time a solution of crude aldehyde in THF (27 mL) was added and stirred overnight. The reaction was quenched with sat. aq. NH4Cl (40 mL) and the aq. layer was extracted with EtOAc (3 x 30 mL).

The resulting organic phases were dried and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 20:1, v/v) afforded enones 2.85 (7.30 g, 82%) as a pale yellow oil: Rf 0.39 (hexanes-ethyl acetate, 7:1, v/v); IR (neat) 2955, 2928, 2897,

-1 1 2858, 1680, 1473, 1379, 1252, 1076 cm ; H NMR (CDCl3, 400 MHz) δ 6.44-6.41 (m,

1H), 6.41-6.39 (m, 1H), 4.94-4.91 (m, 1H), 4.89-4.86 (m, 1H), 4.83-4.79 (m, 1H), 4.78-

4.75 (m, 1H), 4.47 (t, J = 8.4 Hz, 1H), 4.41 (t, J = 8.4 Hz, 1H), 4.29-4.20 (m, 2H), 3.98-

3.91 (m, 1H), 3.70 (ddd, J = 3.6, 8.4, 8.4 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H), 1.86 (d, J =

1.6 Hz, 3H), 1.45 (s, 3H), 1.44 (s, 6H), 1.40 (s, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.07 (s,

13 3H), 0.03 (s, 3H), 0.00 (s, 6H); C NMR (CDCl3, 100 MHz) δ 199.6, 199.5, 148.0,

146.5, 141.0, 140.9, 138.1, 137.1, 112.3, 111.0, 109.6, 109.5, 78.0, 77.92, 77.87, 77.4,

74.4, 73.3, 39.3, 38.5, 27.6, 27.5, 27.1, 27.0, 25.9 (6C), 25.79, 25.76, 18.34, 18.31, 17.3,

+ 16.5, 12.3, 12.2, -4.5, -4.6, -5.0, -5.1; HRMS calcd for C21H38O4Si [M+Na] 405.2432, found 405.2433.

105

Enol Carbonates (2.75)

O O O O KHMDS (solid) O OCO2Allyl DME, -78 °C; allyl chloroformate (88%) OTBS 2.85 OTBS 2.75

To a solution of KHMDS (71.0 mg, 365 µmol) in DME (7 mL) at -78 °C was added dropwise a solution of enones 2.85 (68.1 mg, 178 µmol) in DME (2 mL). The reaction was warmed to -50 °C for 1 hour during which time the solution turned a deep- orange color. The mixture was again cooled to -78 °C and neat allyl chloroformate (37.8

µL, 356 µmol) was added. The reaction was warmed to rt and stirred for 1 hour before being quenched with sat. aq. NH4Cl (6 mL). The aq. phase was extracted with EtOAc (3 x 15 mL) and the combined organic layers dried and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 15:1, v/v) yielded 2.75 (73.5 mg, 88%) as a colorless oil: Rf 0.57 (hexanes-ethyl acetate, 4:1, v/v); IR (neat) 2955, 2930, 2889, 2857,

-1 1 1764, 1458, 1370, 1224 cm ; H NMR (CDCl3, 400 MHz) δ 6.01-5.87 (m, 2H), 5.75-

5.66 (m, 2H), 5.41-5.38 (m, 1H), 5.37-5.34 (m, 1H), 5.31-5.28 (m, 1H), 5.28-5.25 (m,

1H), 5.14-5.10 (m, 2H), 5.04-4.99 (m, 2H), 4.93-4.89 (m, 1H), 4.87-4.84 (m, 1H), 4.80-

4.77 (m, 1H), 4.76-4.73 (m, 1H), 4.69-4.62 (m, 4H), 4.37 (t, J = 8.4 Hz, 1H), 4.32 (t, J =

8.4 Hz, 1H), 4.27-4.20 (m, 2H), 3.84 (ddd, J = 2.4, 8.8, 8.8 Hz, 1H), 3.55 (ddd, J = 3.2,

8.8, 8.8 Hz, 1H), 1.90 (d, J = 1.2 Hz, 3H), 1.88 (d, J = 1.2 Hz, 3H), 1.79-1.71 (m, 1H),

1.67 (s, 3H), 1.65-1.58 (m, 5H), 1.58-1.53 (m, 1H), 1.41 (s, 3H), 1.40 (s, 3H), 1.38 (s,

106

3H), 1.34 (s, 3H), 0.87 (s, 9H), 0.86 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H), 0.00 (s, 3H), -0.01

13 (s, 3H); C NMR (CDCl3, 100 MHz) δ 154.0 (2C), 152.97, 152.96, 148.2, 146.5, 133.3,

133.1, 131.4 (2C), 125.0, 124.8, 119.29, 119.26, 112.3, 110.8, 108.9, 108.8, 103.4 (4C),

78.1, 77.8, 77.7, 77.4, 74.7, 73.3, 68.98, 68.97, 39.2, 38.2, 27.6, 27.4, 27.1, 27.0, 25.92

(3C), 25.90 (3C), 18.29, 18.26, 17.3, 16.2, 14.1, 14.0, -4.6, -4.7, -5.0, -5.1; HRMS calcd

+ for C25H42O6Si [M+Na] 489.2643, found 489.2569.

Decalins (2.86)

O O O H OCO2Allyl O OCO Allyl o-dichlorobenzene, BHT 2 µW 260 °C, 8.5 h (73%) OTBS 2.75 OTBS 2.86

Triene 2.75 (54.2 mg, 116 µmol) in 1,2-dichlorobenzene (11.6 mL) was inserted into a microwave pressure flask. Additive BHT (5.1 mg, 23 µmol) was added and the flask sealed. The reaction was performed in a microwave reactor (222 °C, 300 Watts) for

8.5 hours. The solution was cooled and concentrated. Silica gel column chromatography

(hexanes-ethyl acetate, 20:1, v/v) afforded 2.86 (39.1 mg, 73%) as a colorless oil:

23 Less Polar Isomer: Rf 0.83 (hexanes-ethyl acetate, 15:1 (eluted 5x), v/v); [α]D -39.5 (c

-1 1 1.04, CHCl3); IR (neat) 2953, 2929, 2858, 1752, 1239, 1151, 1104, 1074 cm ; H NMR

(CDCl3, 400 MHz) δ 5.96 (dddd, J = 5.6, 5.6, 10.8, 16.4 Hz, 1H), 5.42-5.35 (m, 1H),

5.31-5.26 (m, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.50 (dd, J = 8.4, 11.2 Hz, 1H), 3.44 (dd, J =

4.4, 10.8 Hz, 1H), 3.32 (ddd, J = 4.0, 8.8, 12.8 Hz, 1H), 2.37-2.25 (m, 1H), 2.25-2.12 (m, 107

3H), 1.95 (dd, J = 6.8, 12.8 Hz, 1H), 1.87 (q, J = 12.0 Hz, 1H), 1.70 (s, 3H), 1.40 (s, 3H),

1.39 (s, 3H), 1.37-1.31 (m, 1H), 0.97 (s, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C

NMR (CDCl3, 100 MHz) δ 153.3, 142.4, 131.6, 121.6, 119.1, 109.7, 79.0, 78.0, 76.5,

68.8, 45.6, 41.1, 34.0, 33.8, 27.2, 27.1, 25.9 (3C), 24.3, 18.2, 14.1, 12.3, -3.9, -4.8;

+ HRMS calcd for C25H42O6Si [M+Na] 489.2643, found 489.2644.

23 More Polar Isomer: Rf 0.70 (hexanes-ethyl acetate, 15:1 (eluted 5x), v/v); [α]D -9.90 (c

-1 1 0.53, CHCl3); IR (neat) 2953, 2929, 2858, 1751, 1239, 1067, 833 cm ; H NMR (CDCl3,

400 MHz) δ 5.96 (dddd, J = 6.0, 6.0, 10.8, 16.4 Hz, 1H), 5.42-5.35 (m, 1H), 5.31-5.27

(m, 1H), 4.68-4.64 (m, 2H), 3.83 (ddd, J = 5.6, 8.8, 11.6 Hz, 1H), 3.63 (dd, J = 2.4, 2.4

Hz, 1H), 3.50 (dd, J = 8.8, 11.6 Hz, 1H), 2.70-2.64 (m, 1H), 2.36-2.26 (m, 1H), 2.21-2.12

(m, 1H), 2.09-2.02 (m, 2H), 2.01-1.95 (m, 1H), 1.72 (d, J = 1.2 Hz, 3H), 1.41 (s, 3H),

1.40 (s, 3H), 1.28-1.18 (m, 1H), 0.98 (s, 3H), 0.90 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H); 13C

NMR (CDCl3, 100 MHz) δ 153.4, 141.7, 131.7, 122.7, 119.1, 108.9, 78.5, 77.6, 75.9,

68.8, 42.7, 40.9, 32.7, 32.6, 27.2 (2C), 26.0 (3C), 24.6, 18.2, 17.8, 14.4, -4.4, -4.7; HRMS

+ calcd for C25H42O6Si [M+Na] 489.2643, found 489.2650.

108

Alkenes (3.11)

O O H H O OCO2Allyl O O Pd(PPh3)4 PhMe, r.t., 5 h (93%) 2.86 OTBS OTBS 3.11

To a flame-dried flask under inert atmosphere was added Pd(PPh3)4 (37.0 mg,

31.6 µmol) in a nitrogen glovebox. Enol carbonates 2.86 (294.8 mg, 632 µmol) in toluene (31.6 mL) were added to the flask and the reaction was stirred at rt for 5 hours before being concentrated. Silica gel column chromatography (hexanes-ethyl acetate,

15:1, v/v) of the residue gave 3.11 (247.7 mg, 93%) as a colorless oil:

23 Less Polar Isomer: Rf 0.74 (hexanes-ethyl acetate, 15:1 (eluted 3x), v/v); [α]D -40.6 (c

-1 1 1.00, CHCl3); IR (neat) 3076, 2982, 2955, 2930, 1703, 1460, 1381, 1078, 837 cm ; H

NMR (CDCl3, 500 MHz) δ 5.60 (dddd, J = 6.0, 9.0, 10.0, 15.0 Hz, 1H), 5.09-5.00 (m,

2H), 3.55 (dd, J = 9, 11.5 Hz, 1H), 3.42-3.37 (m, 2H), 2.53-2.35 (m, 4H), 2.17 (dt, J =

4.5, 4.5, 12.0 Hz, 1H), 2.00-1.94 (m, 2H), 1.76 (q, J = 11.5 Hz, 1H), 1.42 (s, 3H), 1.41 (s,

3H), 1.26 (s, 3H), 1.01 (s, 3H), 0.89-0.88 (m, 1H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H);

13 C NMR (CDCl3, 125 MHz) δ 216.1, 134.9, 119.0, 109.8, 78.0, 77.9, 77.8, 49.9, 45.6,

45.5, 40.8, 35.4, 35.1, 34.0, 27.0, 26.9, 25.8 (3C), 22.1, 18.0, 13.2, -4.0, -4.9; HRMS

+ calcd for C24H42O4Si [M+Na] 445.2745, found 445.2745.

23 More Polar Isomer: Rf 0.45 (hexanes-ethyl acetate, 15:1 (eluted 3x), v/v); [α]D +2.65 (c

-1 1 0.99, CHCl3); IR (neat) 3074, 2955, 2930, 2858, 1701, 1460, 1258, 1101, 831 cm ; H

109

NMR (CDCl3, 500 MHz) δ 5.57 (dddd, J = 5.5, 9.0, 10.0, 15.0 Hz, 1H), 5.05-5.00 (m,

2H), 3.87 (ddd, J = 4.5, 9.0, 13.0 Hz, 1H), 3.56 (dd, J = 9.0, 11.5 Hz, 1H), 3.49 (dd, J =

2.5, 2.5 Hz, 1H), 2.58 (d, J = 11.5 Hz, 1H), 2.53-2.43 (m, 3H), 2.35 (ddd, J = 3.0, 7.0,

18.0 Hz, 1H), 2.14 (ddd, J = 7.0, 13.0, 13.0, 1H), 2.07 (ddd, J = 3.5, 4.5, 12.5 Hz, 1H),

1.90 (ddd, J = 2.5, 12.5, 12.5 Hz, 1H), 1.42 (s, 3H), 1.41 (s, 3H), 1.30-1.27 (m, 1H), 1.24

13 (s, 3H), 1.06 (s, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.02 (s, 3H); C NMR (CDCl3, 125

MHz) δ 216.2, 135.1, 119.0, 108.9, 78.1, 77.1, 76.7, 49.9, 45.1, 41.6, 41.0, 35.7, 32.6,

32.4, 27.0, 26.9, 25.8 (3C), 22.6, 19.3, 18.0, -4.4, -5.0; HRMS calcd for C24H42O4Si

[M+Na]+ 445.2745, found 445.2747.

Alcohols (3.12)

O O H H O O O O TBAF THF, 8 h (87%) OTBS 3.11 OH 3.12

To a solution of silyl ethers 3.11 (424.9 mg, 1.01 mmol) in THF (3.4 mL) at 0 °C was added TBAF (1.0M in THF, 4.0 mL, 4.0 mmol) dropwise. The reaction was allowed to warm to rt and stir for 8 hours before being quenched with sat. aq. NH4Cl (5 mL). The aq. layer was extracted with EtOAc (3 x 5 mL) and the combined organic layers was dried and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 2:1, v/v) gave 3.12 (269.0 mg, 87%) as a colorless oil: Rf 0.26 (hexanes-ethyl acetate, 3:2, v/v); IR (neat) 3447, 3074, 2981, 2924, 1695, 1458, 1371, 1232, 1068, 1007 cm-1; 1H 110

NMR (CDCl3, 500 MHz) δ 5.68-5.56 (m, 2H), 5.09-5.01 (m, 4H), 3.89 (ddd, J = 4.0, 8.5,

12.5 Hz, 1H), 3.62 (brs, 1H), 3.60-3.56 (m, 1H), 3.55-3.52 (m, 1H), 3.47 (brs, 1H), 3.46-

3.39 (m, 2H), 2.58-2.39 (m, 10H), 2.30-2.18 (m, 3H), 2.08-1.95 (m, 3H), 1.79 (q, J =

11.5 Hz, 1H), 1.56 (ddd, J = 8.5, 10.0, 13.0 Hz, 1H), 1.47-1.44 (m, 1H), 1.43 (s, 9H),

13 1.42 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H), 1.06 (s, 3H), 1.04 (s, 3H); C NMR (CDCl3, 125

MHz) δ 216.1, 216.0, 134.8, 134.7, 119.1, 118.9, 109.9, 109.2, 78.2, 77.9, 77.8, 77.3,

76.5, 76.4, 50.0, 49.9, 45.7, 45.6, 45.5, 42.6, 40.4, 40.1, 35.5, 35.2, 34.6, 33.7, 32.7, 31.8,

+ 27.0, 26.9, 26.8, 22.3, 22.1, 19.7, 12.9; HRMS calcd for C18H28O4 [M+Na] 331.1880, found 331.1884.

Dione (2.65)

O O H H O O O O TPAP, NMO DCM (91%) OH O 3.12 2.65

To a solution of NMOH2O (241 mg, 1.78 mmol) in DCM (3 mL) was added anhydrous MgSO4 (143 mg, 1.19 mmol) and stirred for 20 minutes. This solution was then filtered into a flask containing alcohols 3.12 (91.5 mg, 297 µmol), 4 Å MS, and flushed with argon. Following stirring for 10 minutes, TPAP (5.0 mg, 15 µmol) was added which turned the solution black and was stirred for 30 minutes. The mixture was filtered through a silica plug, flushed with EtOAc, and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 6:1, v/v), afforded 2.65 (82.7 mg, 91%) as a 111

23 white solid: Rf 0.33 (hexanes-ethyl acetate, 4:1, v/v); mp 69-70 °C; [α]D -25.6 (c 0.52,

-1 1 CHCl3); IR (neat) 2985, 2935, 1708, 1702, 1382, 1234, 1114 cm ; H NMR (CDCl3, 400

MHz) δ 5.55 (dddd, J = 6.4, 8.4, 9.6, 14.8 Hz, 1H), 5.12-4.96 (m, 2H), 3.95 (dd, J = 8.8,

11.2 Hz, 1H), 3.60-3.50 (m, 1H), 2.92-2.82 (m, 2H), 2.54-2.40 (m, 4H), 2.28 (d, J = 11.6

Hz, 1H), 2.00-1.85 (m, 2H), 1.49 (s, 3H), 1.44 (s, 3H), 1.32 (s, 3H), 1.18 (s, 3H); 13C

NMR (CDCl3, 100 MHz) δ 215.0, 209.1, 134.1, 119.6, 111.2, 77.8, 77.5, 50.3, 47.7, 45.9,

+ 44.7, 42.5, 35.1, 30.6, 27.1, 27.0, 21.7, 19.7; HRMS calcd for C18H26O4 [M+Na]

329.1723, found 329.1732.

Decalin (5.1)

O O O H OCO2Allyl O OCO2Allyl o-dichlorobenzene S reflux, 16 h S 2.71 (90%) S S 5.1

A solution of enol carbonate 2.71 (393 mg, 892 µmol) in dichlorobenzene (89 mL) was heated to reflux for 16 hours. The reaction was cooled to room temperature and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 10:1, v/v) gave

5.1 (350 mg, 90%) as a white solid: Rf 0.41 (hexanes-ethyl acetate, 4:1, v/v); mp 152-153

23 -1 °C; [α]D 46.9 (c 1.00, CHCl3); IR (neat) 3055, 2986, 1751, 1423, 1369, 1241, 738 cm ;

1 H NMR (CDCl3, 400 MHz) δ 5.96 (dddd, J = 5.7, 5.7, 11.4, 16.2 Hz, 1H), 5.41 (dd, J =

1.4, 17.2 Hz, 1H), 5.29 (dd, J = 1.2, 10.4 Hz, 1H), 4.66 (dd, J = 1.1, 5.7 Hz, 2H), 3.91

112

(ddd, J = 4.2, 8.8, 12.6 Hz, 1H), 3.55 (dd, J = 8.8, 11.6 Hz, 1H), 3.11-2.96 (m, 3H), 2.89

(d, J = 11.5 Hz, 1H), 2.72 (dd, J = 3.8, 14.6 Hz, 2H), 2.35-2.15 (m, 5H), 2.06 (ddd, J =

4.0, 4.0, 8.4 Hz, 1H), 1.87-1.76 (m, 1H), 1.70 (s, 3H), 1.43 (s, 3H), 1.39 (s, 3H), 1.23 (s,

13 3H); C NMR (100 MHz, CDCl3) δ 153.3, 142.4, 131.6, 122.3, 119.1, 109.4, 78.5, 77.8,

68.8, 60.1, 45.3, 44.2, 35.0, 31.0, 27.3, 27.1, 26.6, 26.3, 25.3, 24.7, 16.3, 14.5; HRMS

+ calcd for C22H32O5S2 [M+Na] 463.1583, found 463.1579.

Ketone (2.72)

O O O H H OCO2Allyl O OCO Allyl PIFA 2

MeCN: sat. aq NaHCO3 S (4:1), 10 min S O 5.1 (67%) 2.72

To a solution of decalin 5.1 (105.9 mg, 240 µmol) in MeCN:sat. aq. NaHCO3

(9:1, 2.4 mL) was added PIFA (155 mg, 361 µmol) in one portion. The mixture was stirred for 30 minutes and then quenched with sat. aq. Na2S2O3:sat. aq. NaHCO3 (1:1, 5 mL). The aq. layer was extracted with EtOAc (3 x 10 mL) and the combined organic layers were dried and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 7:1, v/v), afforded 2.72 (53.0 mg, 63%) as a colorless oil: Rf 0.41 (hexanes-ethyl

23 acetate, 4:1, v/v); [α]D 49.4 (c 1.00, CHCl3); IR (neat) 2987, 2936, 1751, 1718, 1376,

-1 1 1239 cm ; H NMR (CDCl3, 400 MHz) δ 5.95 (dddd, J = 6.0, 6.0, 10.4, 17.2 Hz, 1H),

5.38 (dddd, J = 1.6, 1.6, 1.6, 17.2 Hz, 1H), 5.29 (dddd, J = 0.8, 0.8, 0.8, 10.4 Hz, 1H),

4.66 (d, J = 5.6 Hz, 2H), 3.92 (dd, J = 8.4, 11.2 Hz, 1H), 3.50 (ddd, J = 5.2, 8.4, 13.4 Hz, 113

1H), 3.02 (t, J = 13.6 Hz, 1H), 2.81 (dd, J = 4.8, 13.2 Hz, 1H), 2.57-2.50 (m, 1H), 2.33-

2.24 (m, 2H), 2.00 (ddd, J = 2.8, 6.4, 14.0 Hz, 1H), 1.79-1.73 (m, 3H), 1.69-1.59 (m, 1H),

13 1.47 (s, 3H), 1.43 (s, 3H) 1.24 (s, 3H); C NMR (100 MHz, CDCl3) δ 209.3, 153.2,

142.3, 131.5, 120.7, 119.2, 111.0, 79.1, 77.4, 68.9, 47.8, 44.3, 41.6, 29.6, 27.12, 27.10,

+ 24.0, 17.7, 14.0; HRMS calcd for C19H26O6 [M+Na] 373.1622, found 372.1627.

Dione (2.65)

O O O H OCO2Allyl O H Pd(PPh3)4 O toluene, rt, 30 min (94%) O 2.72 O 2.65

To a solution of enol carbonate 2.72 (2.69 g, 7.68 mmol) in toluene (384 mL) was added Pd(PPh3)4 (444 mg, 384 µmol). The reaction was stirred for 1 hour and then concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 6:1,v/v) afforded 2.65 (2.21 g, 94%) as a white solid: Rf 0.33 (hexanes-ethyl acetate, 4:1, v/v); mp

23 69-70 °C; [α]D -25.6 (c 0.52, CHCl3); IR (neat) 2985, 2935, 1708, 1702, 1382, 1234,

-1 1 1114 cm ; H NMR (CDCl3, 400 MHz) δ 5.55 (dddd, J = 6.4, 8.4, 9.6, 14.8 Hz, 1H),

5.12-4.96 (m, 2H), 3.95 (dd, J = 8.8, 11.2 Hz, 1H), 3.60-3.50 (m, 1H), 2.92-2.82 (m, 2H),

2.54-2.40 (m, 4H), 2.28 (d, J = 11.6 Hz, 1H), 2.00-1.85 (m, 2H), 1.49 (s, 3H), 1.44 (s,

13 3H), 1.32 (s, 3H), 1.18 (s, 3H); C NMR (CDCl3, 100 MHz) δ 215.0, 209.1, 134.1,

114

119.6, 111.2, 77.8, 77.5, 50.3, 47.7, 45.9, 44.7, 42.5, 35.1, 30.6, 27.1, 27.0, 21.7, 19.7;

+ HRMS calcd for C18H26O4 [M+Na] 329.1723, found 329.1732.

Bis-enol Triflate (2.87)

O O O H H O KHMDS, THF O OTf Comins' Reagent -78 °C O (72%) OTf 2.87 2.65

A solution of dione 2.65 (76.0 mg, 248 µmol) and Comins’ Reagent (486.9 mg,

1.24 mmol) in THF (2.5 mL) was cooled to -78 °C. A solution of KHMDS (247.4 mg,

1.24 mmol) in THF (12.4 mL) was added dropwise (during which time the reaction turned a dark orange color) and stirred for 1 hour. The reaction was quenched with sat. aq. NH4Cl (10 mL) and the aq. layer was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried and concentrated. The residue was passed through a small silica plug in order to remove the solids. Silica gel column chromatography

(hexanes-dichloromethane, 9:1, v/v, then hexanes-ethyl acetate 50:1, v/v) gave bis-enol triflate 2.87 (102.4 mg, 72%) as a cloudy, colorless oil: Rf 0.69 (hexanes-ethyl acetate,

23 4:1, v/v); [α]D -42.8 (c 0.58, CHCl3); IR (neat) 2987, 2926, 2860, 1416, 1385, 1248,

-1 1 1213, 1141, 1006, 991, 866 cm ; H NMR (CDCl3, 400 MHz) δ 6.03 (d, J = 1.2 Hz, 1H),

5.79 (dd, J = 2.0, 6.4 Hz, 1H), 5.62 (dddd, J = 4.8, 10.0, 10.0, 16.8 Hz, 1H), 5.20-5.15

(m, 1H), 5.11-5.04 (m, 1H), 4.20 (dd, J = 1.6, 8.0 Hz, 1H), 3.76 (dd, J = 8.0, 12.0 Hz,

115

1H), 2.68 (dd, J = 10.4, 14.0 Hz, 1H), 2.45 (d, J = 11.6 Hz, 1H), 2.34-2.27 (m, 2H), 2.22

(dd, J = 6.4, 16.8 Hz, 1H), 1.50 (s, 3H), 1.48 (s, 3H), 1.37 (s, 3H), 1.33 (s, 3H); 13C NMR

(CDCl3, 100 MHz) δ 153.7, 152.1, 133.6, 120.4, 118.5 (q, J = 317 Hz), 118.4 (q, J = 317

Hz), 115.4, 113.8, 112.9, 77.4, 75.7, 44.5, 42.9, 42.3, 41.5, 34.9, 26.74, 26.70, 20.3, 19.3;

+ HMRS calcd for C20H24F6O8S2 [M+Na] 593.0709, found 593.0695.

Diester (2.88)

O O H O H O CO2Me OTf Pd(PPh3)4, dppf Et3N, MeOH/DMF CO, 60 °C (73%) OTf CO2Me 2.87 2.88

To a flame-dried flask was added Pd(PPh3)4 (49 mg, 42 µmol) and dppf (70 mg,

126 µmol) from a glovebox. The flask was evacuated and refilled with carbon monoxide

(3x). Bistriflate 2.87 (119.7 mg, 210 µmol) in MeOH (3 mL) was added followed by

DMF (1 mL) and Et3N (88.0 µL, 630 µmol). Carbon monoxide was bubbled through the solution for 5 minutes before being heated to 60 °C for 20 hours under CO atmosphere

(1atm). The reaction was diluted with EtOAc and filtered through Celite. Silica gel column chromatography (hexanes-ethyl acetate, 20:1, v/v) of the residue gave diester

23 2.88 (59.3 mg, 73%) as a colorless oil: Rf 0.53 (hexanes-ethyl acetate, 4:1, v/v); [α]D -

-1 103.4 (c 0.56, CHCl3); IR (neat) 2986, 2951, 1718, 1437, 1380, 1232, 1174, 1035 cm ;

1 H NMR (CDCl3, 400 MHz) δ 7.05 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 2.0, 6.8 Hz, 1H),

116

5.52 (dddd, J = 5.6, 9.6, 9.6, 15.6 Hz, 1H), 5.02-4.92 (m, 2H), 4.19 (dd, J = 1.6, 8.4 Hz,

1H), 3.84 (dd, J = 8.4, 11.6 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.00 (dd, J = 6.8, 18.8 Hz,

1H), 2.78 (dd, J = 9.6, 14.0 Hz, 1H), 2.75-2.68 (m, 1H), 2.31 (d, J = 11.6 Hz, 1H), 2.07

13 (d, J = 18.0 Hz, 1H), 1.49 (s, 3H), 1.48 (s, 6H), 1.33 (s, 3H); C NMR (CDCl3, 100

MHz) δ 167.1, 166.2, 139.1, 139.0, 136.1, 135.1, 134.8, 118.1, 111.7, 79.5, 76.2, 51.9,

51.5, 47.1, 44.2, 41.9, 40.0, 37.8, 27.0, 26.8, 21.6, 21.4; HRMS calcd for C22H30O6

[M+Na]+ 413.1935, found 413.1931.

Aldehyde (4.37)

O O H OsO4, NMO H O H O CO2Me 2,6-lutidine CO2Me

Acetone/H2O (10:1) then BAIB (75%) CO Me CO2Me 2.88 2 4.37

Diester 2.88 (100.0 mg, 256 µmol) was dissolved in acetone:water (10:1, 2.6 mL) and NMOH2O (52 mg, 384 µmol), 2,6-lutidine (60 µL, 512 µmol), and OsO4 (0.164 M in H2O, 160 µL, 25.6 µmol) were added sequentially. The reaction was stirred until starting material was fully consumed (by TLC analysis). BAIB (124 mg, 384 µmol) was added and stirred for 1 hour. Sat. aq. Na2S2O8 (2 mL) was added and stirred for 10 minutes. The aq. layer was extracted with EtOAc (4 x 10 mL) and the combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography (hexanes-ethyl acetate, 5:1, v/v) to give aldehyde 4.37 (75.2 mg, 75%)

117

23 as a white foam: Rf 0.72 (hexanes-ethyl acetate, 1:1, v/v); [α]D -137.0 (c 0.73, CHCl3);

IR (neat) 2988, 2950, 2932, 2849, 1710, 1708, 1702, 1376, 1229, 1034 cm-1; 1H NMR

(CDCl3 400 MHz) δ 9.62 (dd, J = 1.6, 3.2 Hz, 1H), 7.08 (dd, J = 2.0, 7.2 Hz, 1H), 7.06

(d, J = 1.6 Hz, 1H), 4.19 (dd, J = 2.0, 8.8, Hz, 1H), 3.85 (dd, J = 8.8, 11.6 Hz, 1H), 3.73

(s, 3H), 3.72 (s, 3H), 3.27 (dd, J = 1.2, 16.4 Hz, 1H), 3.17 (dd, J = 3.2, 16.4 Hz, 1H), 3.11

(dd, J = 6.8, 18.8 Hz, 1H), 2.37 (d, J = 11.6 Hz, 1H), 2.21 (dd, J = 0.8, 18.4 Hz, 1H), 1.49

13 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H), 1.34 (s, 3H); C NMR (CDCl3, 100 MHz) δ 203.5,

166.6, 166.0, 140.4, 138.5, 134.8, 133.8, 112.1, 79.9, 75.7, 53.4, 52.0, 51.7, 49.3, 42.2,

+ 38.7, 37.7, 27.0, 26.8, 21.8, 21.0; HRMS calcd for C21H28O7 [M+Na] 415.1727, found

415.1734.

Lactone (4.39)

O O

O H O H (3-furyl)Ti(Oi-Pr)3 O O CO2Me H ((R)-BINOL)Ti(Oi-Pr)2 O O THF, 0 °C (74%, dr = 8:1) CO2Me 4.37 CO Me 2 4.39

To a flame-dried flask was added (3-furyl)Ti(Oi-Pr)3 (30.0 mg, 103 µmol) and (R-

BINOL)Ti(Oi-Pr)2 (3.7 mg, 8.2 µmol) from the glovebox and dissolved in THF (1.0 mL).

The solution was cooled to 0 °C followed by the dropwise addition of aldehyde 4.37

(32.3 mg, 82.3 µmol) in THF (0.82 mL). The reaction was stirred for 15 minutes before being quenched with 1M NaOH (1 mL). The aq. layer was separated and extracted with 118

EtOAc (3 x 10 mL). The org. layers were combined, dried, and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 3:1, v/v) provided lactone 4.39 (25.8 mg,

23 74%) as a white solid: Rf 0.26 (hexanes-ethyl acetate, 3:1, v/v); [α]D -11.8 (c 1.00,

-1 1 CHCl3); IR (neat) 2953, 2924, 2852, 1715, 1643, 1456, 1377, 1224, 1208 cm ; H NMR

(CDCl3 500 MHz) δ 7.47-7.46 (m, 1H), 7.41 (t, J = 1.7 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H),

6.89 (dd, J = 2.3, 5.8 Hz, 1H), 6.43-6.42 (m, 1H), 5.62 (dd, J = 4.1, 12.3 Hz, 1H), 4.18

(dd, J = 1.8, 8.5 Hz, 1H), 3.90 (dd, J = 8.5, 11.7 Hz, 1H), 3.74 (s, 3H), 3.17 (dd, J = 5.9,

19.4 Hz, 1H), 2.81 (dd, J = 4.2, 13.8 Hz, 1H), 1.91 (d, J = 11.7 Hz, 1H), 1.69-1.61 (m,

13 2H), 1.50 (s, 3H), 1.49 (s, 3H), 1.45 (s, 3H), 1.43 (s, 3H); C NMR (CDCl3, 125 MHz) δ

165.84, 165.81, 143.6, 139.7, 138.4, 137.7, 134.6, 133.0, 125.4, 112.0, 108.6, 79.7, 75.5,

71.2, 51.9, 51.3, 45.5, 41.7, 38.1, 35.4, 26.9, 26.7, 22.7, 17.5; HRMS calcd for C24H28O7

[M+Na]+ 451.1727, found 451.1713.

Diols (6.2 & 6.3)

O O O

1. SmI2, Et3N MeOH/THF O O -78 °C HO O HO O H H H H O H HO HO O 2. p-TsOH, MeOH O + O (51%, 2 steps, dr = 2.5:1 8S:8R) 6.2 6.3 CO Me CO Me (8R) CO2Me (8S) 2 4.39 2

To a solution of lactone 4.39 (61.9 mg, 145 µmol) in degassed THF:MeOH (9:1,

2.4 mL) at -78 °C was added a freshly prepared solution of SmI2 (0.1 M in THF, 11.6 mL, 1.16 mmol) with Et3N additive (0.32 mL, 2.3 mmol). The reaction was stirred for 30

119 min before being quenched with O2 (exposure to air). The mixture was diluted with

EtOAc (50 mL), filtered through a silica gel plug, and concentrated. This crude mixture was dissolved in MeOH (14.5 mL) followed by the addition of p-TsOH (2.8 mg, 14

µmol). The reaction stirred for 2 hours and was then quenched with sat. aq. NaHCO3 (2 mL). The aq. layer was extracted with EtOAc (4 x 5 mL) and the combined organic layers were dried and concentrated. Silica gel column chromatography (5-20 µm particle size) (hexanes-ethyl acetate, 1:1, v/v) gave (8S)-diol 6.3 (20.0 mg, 36%) and (8R)-diol

6.2 (8.0 mg, 15%) both as white amorphous solids:

23 Less polar isomer (6.3): Rf 0.45 (hexanes-ethyl acetate, 1:1 (eluted 4x), v/v); [α]D -29.1

-1 1 (c 1.00, CHCl3); IR (neat) 3430, 2927, 2857, 1728, 1455, 1370, 1201, 1075, 757 cm ; H

NMR (CDCl3, 600 MHz) δ 7.46 (s, 1H), 7.39 (t, J = 1.5 Hz, 1H), 6.42 (d, J = 1.0 Hz,

1H), 5.22 (d, J = 12.0 Hz, 1H), 3.73 (dd, J = 8.7, 11.0 Hz, 1H), 3.64 (s, 3H), 3.44 (dddd, J

= 6.4, 8.7, 10.7, 15.1 Hz, 1H), 2.49-2.42 (m, 3H), 2.21 (dd, J = 4.3, 12.3 Hz, 1H), 2.17-

2.13 (m, 1H), 2.02 (dd, J = 12.3, 15.3 Hz, 2H), 1.98-1.90 (m, 3H), 1.79 (dddd, J = 3.3,

4.6, 8.2, 13.9 Hz, 1H), 1.72 (ddd, J = 2.1, 13.1, 13.1 Hz, 1H), 1.41 (s, 3H), 1.16 (d, J =

13 11.0 Hz, 1H), 1.14 (s, 3H); C NMR (150 MHz, CDCl3) δ 174.9, 173.3, 143.6, 139.8,

124.4, 108.8, 75.9, 73.8, 70.0, 55.9, 53.5, 51.5, 51.3, 45.5, 38.4, 36.4, 34.9, 32.2, 24.5,

+ 18.1, 15.7; HRMS calcd for C21H28O7 [M+Na] 415.1727, found 415.1712.

23 More polar isomer (6.2): Rf 0.34 (hexanes-ethyl acetate, 1:1 (eluted 4x), v/v); [α]D -

-1 1 22.0 (c 0.31, CHCl3); IR (neat) 3401, 3143, 2924, 2854, 1727, 1435, 1373, 1160 cm ; H

NMR (CDCl3, 600 MHz) δ 7.43 (s, 1H), 7.40 (t, J = 1.3 Hz, 1H), 6.41 (s, 1H), 5.47 (dd, J

120

= 6.0, 11.3 Hz, 1H), 3.84 (dd, J = 8.8, 10.8 Hz, 1H), 3.67 (s, 3H), 3.48 (ddd, J = 6.4, 8.8,

10.6 Hz, 1H), 3.41 (dd, J = 5.7, 14.1 Hz, 1H), 2.24 (dd, J = 4.2, 12.4 Hz, 1H), 2.19 (dd, J

= 3.3, 12.6 Hz, 1H), 2.06 (dddd, J = 3.1, 3.1, 3.1, 14.3 Hz, 1H), 2.01-1.93 (m, 3H), 1.74

(dd, J = 11.3, 14.0 Hz, 2H), 1.67-1.58 (m, 2H), 1.26 (s, 3H), 1.17 (s, 3H), 1.14 (d, J =

13 10.9 Hz, 1H); C NMR (150 MHz, CDCl3) δ 173.0, 172.6, 143.7, 139.4, 126.4, 108.8,

76.1, 74.3, 71.9, 56.1, 54.0, 52.1, 51.7, 46.3, 38.9, 38.5, 37.6, 32.2, 18.5, 16.4, 15.0;

+ HRMS calcd for C21H28O7 [M+Na] 415.1727, found 415.1715.

Salvinorin A (1.1)

O O

1. Ac O, 2,6-lutidine HO O 2 O O H H DCM, 36 h HO AcO H H O 2. TPAP, NMO, CH2Cl2 O (72%, 2 steps)

CO Me 6.2 1.1 2 CO2Me

To a solution of diol 2 (3.9 mg, 9.9 µmol) in DCM (0.5 mL) was added 2,6- lutidine (2.3 µL, 20 µmol) followed by Ac2O (1.9 µL, 20 µmol). The reaction was stirred at room temperature for 24 hours before being quenched with 1 M HCl (1 mL). The aq. layer was extracted with EtOAc (4 x 5 mL) and the combined organic layers were dried and concentrated. A separate solution containing NMOH2O (8.1 mg, 60 µmol) and

MgSO4 (4.8 mg, 40 µmol) in DCM (0.6 mL) was stirred for 30 minutes before being filtered into a flask containing 4Å MS and the crude mixture above. Following stirring for 10 minutes, TPAP (1 crystal) was added and the black mixture was stirred for 30

121 minutes. The reaction was filtered through a silica gel plug, flushed with EtOAc, and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 2:1, v/v) afforded 1.1 (3.1 mg, 72%) as a white solid: Rf 0.40 (hexanes-ethyl acetate, 1:1, v/v);

23 [α]D -40.8 (c 0.15, CHCl3); IR (neat) 3131, 2924, 2853, 1731, 1454, 1378, 1235, 1052,

-1 1 875 cm ; H NMR (CDCl3, 600 MHz) δ 7.41 (s, 1H), 7.39 (s, 1H), 6.37 (s, 1H), 5.53 (dd,

J = 5.1, 11.7 Hz, 1H), 5.14 (m, 1H), 3.73 (s, 3H), 2.75 (dd, J = 6.0, 10.8 Hz, 1H), 2.51

(dd, J = 5.2, 13.6 Hz, 1H), 2.33-2.26 (m, 2H), 2.18-2.15 (m, 5H), 2.07 (dd, J = 2.8, 11.7

Hz, 1H), 1.80 (ddd, J = 2.3, 2.3, 12.8 Hz, 1H), 1.68-1.57 (m, 3H), 1.45 (s, 3H), 1.12 (s,

13 3H); C NMR (150 MHz, CDCl3) δ 202.1, 171.7, 171.2, 170.1, 143.9, 139.6, 125.4,

108.5, 75.2, 72.2, 64.3, 53.8, 52.1, 51.6, 43.6, 42.3, 38.3, 35.6, 30.9, 20.7, 18.3, 16.6,

+ 15.4; HRMS calcd for C23H28O8 [M+Na] 455.1676, found 455.1678.

122

APPENDIX B:

1H/13C NMR SPECTRA

123

124

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1 H NMR Spectrum of 3.2 (500 MHz, CDCl3) 125

130 120 110 100 90 80 70 60 50 40 30 20 10 ppm 13 C NMR Spectrum of 3.2 (125 MHz, CDCl3) 126

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1 H NMR Spectrum of 3.8 (400 MHz, CDCl3) 127

130 120 110 100 90 80 70 60 50 40 30 ppm 13 C NMR Spectrum of 3.8 (100 MHz, CDCl3) 128

10 9 8 7 6 5 4 3 2 ppm 1 H NMR Spectrum of 2.76 (400 MHz, CDCl3) 129

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm

13 C NMR Spectrum of 2.76 (100 MHz, CDCl3) 130

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1 H NMR Spectrum of 2.83 (400 MHz, CDCl3) 131

140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

13 C NMR Spectrum of 2.83 (100 MHz, CDCl3) 132

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1 H NMR Spectrum of 2.84 (400 MHz, CDCl3) 133

140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 13 C NMR Spectrum of 2.84 (100 MHz, CDCl3) 134

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1 H NMR Spectrum of 2.85 (400 MHz, CDCl3) 135

180 160 140 120 100 80 60 40 20 ppm

13 C NMR Spectrum of 2.85 (100 MHz, CDCl3) 136

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1 H NMR Sprectrum of 2.75 (400 MHz, CDCl3) 137

150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

13 C NMR Spectrum of 2.75 (100 MHz, CDCl3) 138

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 1 H NMR Spectrum of 2.86 Less Polar (400 MHz, CDCl3) 139

150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

13 C NMR Spectrum of 2.86 Less Polar (100 MHz, CDCl3) 140

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 1 H NMR Spectrum of 2.86 More Polar (400 MHz, CDCl3) 141

150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 13 C NMR Spectrum of 2.86 More Polar (100 MHz, CDCl3) 142

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 1 H NMR Spectrum of 3.11 Less Polar (500 MHz, CDCl3) 143

200 180 160 140 120 100 80 60 40 20 0 ppm

13 C NMR Spectrum of 3.11 Less Polar (125 MHz, CDCl3) 144

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 1 H NMR Spectrum of 3.11 More Polar (500 MHz, CDCl3) 145

200 180 160 140 120 100 80 60 40 20 ppm

13 C NMR Spectrum of 3.11 More Polar (125 MHz, CDCl3) 146

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1 H NMR Spectrum of 3.12 (500 MHz, CDCl3) 147

200 180 160 140 120 100 80 60 40 20 0 ppm

13 C NMR Spectrum of 3.12 (125 MHz, CDCl3) 148

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1 H NMR Spectrum of 2.65 (400 MHz, CDCl3) 149

200 180 160 140 120 100 80 60 40 20 0 ppm 13 C NMR Spectrum of 2.65 (100 MHz, CDCl3) 150

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1 H NMR Spectrum of 5.1 (400 MHz, CDCl3) 151

150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 13 C NMR Spectrum of 5.1 (100 MHz, CDCl3) 152

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1 H NMR Spectrum of 2.72 (400 MHz, CDCl3) 153

200 180 160 140 120 100 80 60 40 ppm 13 C NMR Spectrum 2.72 (100 MHz, CDCl3) 154

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1 H NMR Spectrum of 2.87 (400 MHz, CDCl3) 155

150 140 130 120 110 100 90 80 70 60 50 40 30 ppm 13 C NMR Spectrum of 2.87 (100 MHz, CDCl3) 156

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 ppm 1 H NMR Spectrum of 2.88 (400 MHz, CDCl3) 157

160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm 13 C NMR Spectrum of 2.88 (100 MHz, CDCl3) 158

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 ppm 1 H NMR Spectrum of 4.37 (400 MHz, CDCl3) 159

200 180 160 140 120 100 80 60 40 ppm 13 C NMR Spectrum of 4.37 (100 MHz, CDCl3) 160

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 ppm 1 H NMR Spectrum of 4.39 (500 MHz, CDCl3) 161

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 13 C NMR Spectrum of 4.39 (125 MHz, CDCl3) 162

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1 H NMR Spectrum of 6.3 (600 MHz, CDCl3) 163

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm 13 C NMR Spectrum of 6.3 (150 MHz, CDCl3) 164

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1 H NMR Spectrum of 6.2 (600 MHz, CDCl3) 165

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm 13 C NMR Spectrum of 6.2 (125 MHz, CDCl3) 166

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1 H NMR Spectrum of 1.1 (600 MHz, CDCl3) 167

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm 13 C NMR Spectrum of 1.1 (150 MHz, CDCl3)