Modifications to the Synthesis of the Salvinorin a Carbon Skeleton

Modifications to the Synthesis of the Salvinorin A Carbon Skeleton

THESIS

Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University

Jerry Casbohm

Graduate Program in Chemistry.

The Ohio State University

2016

Thesis Committee:

Professor Craig J. Forsyth, Advisor

Professor Jon Parquette

Jerry Casbohm

2016

Abstract

The mint, Salvia divinorum, has been used many years by the Mazatec Indians of

Oaxaca, Mexico, for religious and medical purposes. Its hallucinogenic properties have captivated the interest of recreational drug users inspiring significant discussion of how to the control it and other drugs. In 1982, Ortega reported the first isolation of salvinorin A from S. divinorum with a subsequent report from another independent isolation by the

Valdés group in 1984. Following its discovery, salvinorin A was found to be responsible for the hallucinogenic effects attributed to S. divinorum. This has characterized salvinorin A as the only non-nitrogenous hallucinogen and a selective κ-opioid agonist.

Its potent agonist properties have instilled significant interest from both biochemists and chemists.

Herein are reported our efforts towards synthesizing salvinorin A. Difficulties in developing a scalable synthesis of the Diels-Alder precursor have been circumvented with a copper mediated coupling. We have developed an intramolecular Diels-

Alder/Tsuji allylation that diastereoselectively produces the salvinorin A trans-decalin core. Optimization of the post Tsuji allylation has been accomplished by changing various methods of deprotection and oxidations.

This work is dedicated to my wife and daughters for their continual support throughout all of my endeavors

iii

Acknowledgments

First and foremost, I thank my advisor, Professor Craig Forsyth, for giving me the opportunity to work in his group. He has directed me throughout my graduate experience and helped give me the expertise needed to succeed. I will always be grateful for his advice and understanding to make it though my graduate school.

Additionally, I would like to thank the members of the Forsyth group. They have provided me the insight and humor to make the graduate experience something I will never forget. To Nathan Line, thank you for all the technical advice and our many discussions about the greatest of entertainment. I want to thank Kedwin Rosa for providing the constant motivation and excellent conversation. I would also like to thank

Daniel Adu-Ampratwum, Antony Okumu, Daniel Akwaboah, Li Xiao and Nate Kenton for providing me a great work environment.

Vita

April 1984 ...... Born – Meadville, Pennsylvania

May 2002 ...... Conneaut Valley High School

May 2012 ...... B.S. Chemistry

Penn State Erie, The Behrend College

2012 to present ...... Graduate Teaching and Research Associate

The Ohio State University

Publications

1. Kociolek, M. G.; Casbohm, J. S. “Benzisoxazole 2-oxides as novel UV

absorbers and photooxidation inhibitors.” J. Phys. Org. Chem. 2013,

26, 863-867.

2. Kociolek, M.; Bennett, J.; Casbohm, J. “Electrochemical reduction of

3-phenyl-1,2-benzisoxazole 2-oxide on boron-doped diamond.” J. Phys.

Org. Chem. 2014, 27, 540-544.

3. 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 v

Table of Contents

Abstract ...... ii

Acknowledgments ...... iv

Vita ...... v

Publications ...... v

Fields of Study ...... v

Table of Contents ...... vi

List of Schemes ...... ix

List of Figures ...... xi

List of Abbreviations ...... xii

Chapter 1 ...... 1

1.1 Biological Significance of Salvinorin A ...... 1

1.1.1 Salvia Divinorum ...... 1

1.1.2 Salvinorin A ...... 1

1.1.3 Structure-activity relationship and molecular studies of salvinorin A...... 3

Chapter 2 ...... 8 vi

2.1 Introduction to Prior Total Synthesis Efforts ...... 8

2.2 Evans’ Total Synthesis ...... 8

2.2.1 Retrosynthetic Analysis ...... 8

2.2.2 Preparation of Aldehyde 2.4 ...... 9

2.2.3 Preparation of Iodide 2.3 ...... 10

2.2.4 Synthesis of Macrocycle 2.2 ...... 11

2.2.5 Transannular Michael Reaction Cascade ...... 11

2.2.6 Completion of the Total Synthesis ...... 12

2.3 Hagiwara’s First-Generation Total Synthesis ...... 13

2.3.1 Functionalization of Wieland-Miesher Ketone Derivative 2.22 ...... 14

2.3.2 Introduction of the Furolactone Moiety ...... 15

2.3.3 Completion of Hagiwara’s First-Generation Total Synthesis ...... 16

2.4 Hagiwara’s Second-Generation Total Synthesis ...... 17

2.4.1 Synthetic Plan ...... 17

2.4.2 Synthesis of bis-Triflate 2.42 ...... 18

2.4.3 Synthesis of Ketone 2.32 ...... 18

2.5 Burns and Forsyth’s Progress Towards Salvinorin A ...... 20

2.5.1 Retrosynthetic Analysis ...... 20

2.5.2 Synthesis of Triene 2.50 ...... 20

vii

2.5.3 IMDA and Tsuji Allylation ...... 21

2.6 Butler and Forsyth’s Progress Towards Salvinorin A ...... 22

2.6.1 Modified Retrosynthesis ...... 22

2.6.2 Synthesis of Enone 2.50 ...... 23

2.6.3 Diels-Alder Reaction and Tsuji Allylation ...... 24

Chapter 3 ...... 27

3.1 Modifications of the Synthesis of Salvinorin A Carbon Skeleton ...... 27

3.1.1 Improved One-Carbon Homologation ...... 27

3.1.2 Modifications of the Diels-Alder Reaction ...... 29

3.1.3 Elaboration of the Decalin Core ...... 30

3.1.4 Summary ...... 32

Chapter 4 ...... 34

Experimental Details ...... 34

List of References ...... 50

Appendix A: ...... 54

1H / 13C NMR Spectra ...... 54

viii

List of Schemes

Scheme 2.1. Evans’ retrosynthesis...... 9

Scheme 2.3. Evans’ vinyliodide 2.3 fragment synthesis...... 10

Scheme 2.4. Evans’ synthesis of macrocycle 2.2...... 11

Scheme 2.5. Evans’ transannular Michael reaction...... 12

Scheme 2.6. Evans’ completion of the synthesis of salvinorin A ...... 13

Scheme 2.7. Hagawara’s synthesis of diene 2.26...... 15

Scheme 2.8. Introduction of furanolactone moiety...... 16

Scheme 2.9. Hagiwara’s completion of salvinorin A...... 17

Scheme 2.10. Hagiwara’s second-generation synthetic plan...... 17

Scheme 2.11. Hagiwara’s synthesis of bis-triflate 2.42...... 18

Scheme 2.12. Hagiwara’s second-generation completion of salvinorin A...... 19

Scheme 2.13. Forsyth and Burns’ retrosynthesis of salvinorin A...... 20

Scheme 2.14. Synthesis of fragment 2.50...... 21

Scheme 2.15. Burns’ synthesis of dione 2.48...... 22

Scheme 2.16. Butler’s modified retrosynthesis...... 23

Scheme 2.17. Synthesis of enone 2.50...... 24

Scheme 2.18. Diels-Alder/Tsuji allylation sequence...... 25

Scheme 2.19. Elaboration of the decalin core...... 26

Scheme 3.1. Olefin addition...... 28

Scheme 3.2. Application of olefin addition...... 28

Scheme 3.3. Unmasking of aldehyde 2.64...... 29

Scheme 3.4. Synthesis of carbonate 2.69...... 29

Scheme 3.5. Microwave assisted Diels-Alder reaction ...... 30

Scheme 3.6. Modified Tsuji-allylation...... 31

Scheme 3.7. Convergence to dione 2.48...... 31

Scheme 3.8. Attempts to improve the synthesis of bis-enol triflate...... 32

List of Figures

Figure 1.1. Salvinorin A...... 2

Figure 1.2. Summary of SAR studies of various analogues of 1.1.24 ...... 3

Figure 1.3. Binding model of RB-64 1.2 in the KOR binding pocket.25 ...... 5

Figure 1.4. Structure of JDTic...... 5

Figure 1.5. Binding of JDTic with the KOR.26 ...... 6

Figure 1.6. Model of covalently bound RB-64 1.2 in the KOR binding pocket...... 6

Figure 2.1. Comparision of methyl barbascoate and salvinorin A...... 14

List of Abbreviations

1D one-dimensional

2D two-dimensional

7TM seven transmembrane

α alpha

[α] specific rotation

Å angstrom(s)

Ac acetyl aq. aqueous atm atmosphere(s)

β beta

BAIB bis(acetoxy)iodobenzene

9-BBN 9-borabicyclo[3.3.1]nonane

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

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

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

Bn benzyl

BOM benzyloxymethyl

xii br broad (NMR) 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

Crabtree’s catalyst (1,5-Cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I)

hexafluorophosphate

CSA (1S)-(+)-10-camphorsulfonic acid

Cys cysteine

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

xiii

DCC N,N’-dicyclohexylcarbodiimide

DCE 1,2-dichloroethane

DCM dichloromethane

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

DIBAL-H diisobutylaluminum hydride

DMAP 4-(N,N-dimethylamino)pyridine

DMAPP dimethylallyl pyrophosphate

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMP Dess–Martin periodinane

(1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one)

DMPU N,N’-dimethyl-N,N’-propylene urea

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

EtOAc ethyl acetate

xiv

ESI electrospray ionization

γ gamma g gram(s)

GABA γ-aminobutyric acid

GPCR G-protein coupled receptor

GC gas chromatography h hour(s)

1H hydrogen atom

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)

JDTic (3R)-1,2,3,4-tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-

(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-

methylpropyl]-3-isoquinolinecarboxamide),

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

LSD lysergic acid diethylamide lut 2,6-lutidine; 2,6-dimethylpyridine

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

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

Me methyl

5-MeO-DMT 5-methoxy-dimethyltryptamine

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

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

xvi

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 hexamethyldisilazide

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 obsd observed

ORTEP Oak Ridge thermal ellipsoid plot program

π pi p para

PCP phencyclidine (1-(1-phenylcyclohexyl)piperidine)

PDC pyridinium dichromate

Ph phenyl pKa –log[Ka]

PMB p-methoxybenzyl

xvii 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 t tertiary (tert) t triplet (NMR)

TBAF tetra-n-butylammonium fluoride

TBAI tetra-n-butylammonium iodide

TBDPS tert-butyldiphenylsilyl

TBS tert-butyldimethylsilyl

TES triethylsilyl

Tf trifluoromethanesulfonyl

TFA trifluoroacetic acid

THF tetrahydrofuran

xviii

TLC thin layer chromatography

TMS trimethylsilyl

TPAP tetra-n-propylammonium perruthenate

Ts tosyl, p-toluenesulfonyl

TS transition state

xix

Chapter 1

ISOLATION AND BIOLOGICAL SIGNIFICANCE OF SALVINORIN A

1.1 Biological Significance of Salvinorin A

1.1.1 Salvia Divinorum

Salvia divinorum is a sage of the mint family (Labiatae) native to the humid moist areas of the Sierra Mazateca region of Oaxaca, Mexico. The herb is one of several vision inducing plants used in healing and spiritual rituals of the Mazatec Indians.1 While S. divinorum originates from Mexico, it has been cultivated in Switzerland2 and other regions.3 Its hallucinogenic properties and its ease of cultivation have made it popular internationally as a recreational drug.

1.1.2 Salvinorin A

The interesting properties of S. divinorum had sparked significant interest in its agent of action. In 1982 the Ortega group isolated and identified salvinorin A 1.1 through single crystal X-ray studies.4 Shortly after the publication of the Ortega’s group’s results, the Valdes group independently provided similar results on the identification of salvinorin A.5 1

O O H H AcO O

CO2Me 1.1

Figure 1.1. Salvinorin A.

Salvinorin A is a neoclerodane diterpene that sparks an intense hallucinogenic high.6 It was found through the National Institute of Mental Health Psychoactive Drug

Screening Program to be a selective κ-opioid agonist with a negligible activity towards µ- opioid or δ-opioid receptors. Additionally, it was found to have no affinity towards the 5-

HT2A serotonin receptors, which are targeted by the major hallucinogens such as LSD,

N,N’-dimethyltryptamine, mescaline, and psilocybin.7

The κ-opioid receptor (KOR) is a G-protein coupled receptor (GPCR), a superfamily of proteins characterized by a series of seven transmembrane hydrophobic domains.8-9 GPCRs are one of the largest families of human proteins, with nearly half of all drugs on the market targeting them. Another factor of its large drug research presence is due to the many roles GPCRs play in physiological processes, including cell proliferation, cognition, metabolism, inflammation and immunity.10 KORs are a member of the Gi/Go subfamily of G-proteins and are predicted to be involved in inhibition of adenyl cyclases, the activation of inward rectifying K+ channels, and the inhibition of N-,

P-, Q- and R-type voltage-activated Ca2+ channels.11 Activation of these receptors is linked with analgesia, sedation, depression, dysphoria and euphoria.9

1.1.3 Structure-activity relationship and molecular studies of salvinorin A.

The interactions of the 1.1 synthetic analogues with KORs have been extensively explored through structure-activity relationship (SAR) studies. These studies have elucidated a significant amount of information about the interactions of 1.1 with the receptor. The studies focus primarily on the following areas: (1) the C2 acetoxy group,12-

16 (2) the C4 methyl ester,17-19 (3) the C17 carbonyl,20 and (4) the furan moiety.20-23 In

2008, Prisinzano and Rothman published a review24 on the SARs of 1.1 and KORs including a general summary of the interactions of each functional group, as shown below (Figure 1.2).

Reduction or removal is tolerarted Reduction is tolerated 1,10-Alkene likely to be antagonist Removal or replacemnt decreases affinity O

12 O O Reduction or removal is tolerated H H 17 8,17-Alkene is tolerated Small alkyl groups favor KORs O Aromatic groups favor MORs 2 10 8 O α>β substituents O 4 Bioisosteric replacements tolerated CO2Me

Small alkyl esters preferred Hydrolysis or reduction reduces affinity

Figure 1.2. Summary of SAR studies of various analogues of 1.1.24

With a wide library of SAR studies available, further information on the specific interactions of the KOR residues and 1.1 and its various analogues is highly desired. One

3 method of accomplishing this is through covalent binding studies. As the association between receptor and ligand is believed to be highly specific, the covalent binding is expected to also be highly selective. It was found that the RB-64 salvinorin analogue 1.2 was able to covalently bind to Cys-315,25 allowing the binding pocket to be modeled

(Figure 1.3). As 1.2 has two electrophilic sites, it formed two adducts with the KOR binding site; RB-64 + 431 1.3 and RB-64 + 463 1.4. Following this covalent binding study, a large collaborative study was able to crystallize the KOR with the selective agonist JDTic 1.5 in its binding pocket (Figure 1.4).26 Using these data and the previous models of RB-64 1.2 with KOR25 provided significant progress towards elucidating the exact mechanism of salvinorin A’s 1.1 interaction within the KOR binding site.

O O O

Cys315 SH

O O O O O O H H Cys O H H + H H NC O 315 S S O S O O Cys315 S O O O O

CO2Me CO2Me CO2Me RB-64 RB-64 + 431 RB-64 + 463 1.2 1.3 1.4

Scheme 1.1. Formation of RB-64 + 431 and RB-64 +463 adducts.

Figure 1.3. Binding model of RB-64 1.2 in the KOR binding pocket.25

HO NH H N N O

OH JDTic

1.5

Figure 1.4. Structure of JDTic.

Figure 1.5. Binding of JDTic with the KOR.26

Figure 1.6. Model of covalently bound RB-64 1.2 in the KOR binding pocket.

(a) Putative binding model of RB-64 + 463 (b) Putative binding model of RB-64 + 431.26

As the SAR studies have shown, 1.1 and analogues provide significant interest towards probing the activities of KORs. With just a modification to the C2 acetoxy group to benzoate, the selectivity shifts from κ to µ-opioid agonist.27 The recent SAR and modeling studies have provided promising potential of improved KOR probes for advanced analogues. To date, there has only been the synthesis of semi-synthetic analogues. Total synthesis will provide access to analogues that semi-synthesis are unable to obtain, including substitution of the furan and various degrees of unsaturation in the decalin core.

Chapter 2

PREVIOUSLY COMPLETED SYNTHESES OF SALVINORIN A

2.1 Introduction to Prior Total Synthesis Efforts

The unique biological activity of salvinorin A provides significant interest in it and its analogues. Salvinorin A has been synthesized three times: first by the Evans’ group in 2007,28 second by Hagiwara’s group in 2008,29 and finally a second-generation synthesis by Hagiwara’s group in 2009.30

2.2 Evans’ Total Synthesis

2.2.1 Retrosynthetic Analysis

The Evans’ synthesis relies on decalin 2.1, which would be obtained from a transannular Michael reaction cascade of macrocycle 2.2. The macrocycle 2.2 would be able to be prepared from the iodide 2.3 and aldehyde 2.4.

O O O

O I OTES O O O O O H H H 2.3 AcO BOMO BOMO O O O Me Me O + OH O Me MeO C (MeO) HC BOMO CHO 2 2 (MeO)2HC OTBS

1.1 2.1 2.2 CO2Me

(MeO)2HC 2.4

Scheme 2.1. Evans’ retrosynthesis.

2.2.2 Preparation of Aldehyde 2.4

The synthesis of aldehyde 2.4 began with a Ni(II)-(R)-BINAP-catalyzed orthoester alkylation of thiazolidinethione 2.5, followed by a Claisen condensation with ethyl hydrogen malonate to give β-ketoester 2.6 (Scheme 2.2). The conversion of the β- ketoester 2.6 into the (Z)-enol phosphate was followed by a Fe-catalyzed cross-coupling with methylmagnesium chloride giving the olefin 2.7. The ester 2.7 was reduced and then oxidized to an unsaturated aldehyde and chiral auxiliary 2.8 was added into the unsaturated aldehyde by an aldol addition. The resulting alcohol was protected as the

TBS-silyl ether 2.9. The chiral auxiliary was removed through alcoholysis and was followed by an (−)-N-methyl-ephedrine-mediated zinc acetylide addition to provide propargylic alcohol 2.10. Then alcohol 2.10 was protected as the BOM acetal followed by a partial hydrogenation, dihydroxylation, and oxidative cleavage to give aldehyde 2.4.

O O S a,b c,d e-h O O OTBS EtO2C N N S CH(OMe) S 2 65% CH(OMe)2 56% 78% EtO O CH(OMe) i-Pr 2 2.5 2.6 2.7 2.9

O O i-k O OTBS Ph O OTBS O l-n S N 2.9 MeO MeO H 90% 70% i-Pr (MeO)2HC OH (MeO)2HC OBOM 2.10 2.4 2.8

Conditions: (a) Ni-(R)-BINAP(OTf)2, 2,6-lutidine, BF3OEt2, HC(OMe)3; (b) HO2CCH2CO2Et, i-PrMgCl, 65 °C; (c) LiHMDS; ClPO(OEt)2; (d) Fe(acac)3, MeMgCl, −20 °C; (e) DIBAL-H, −78 °C; (f)

MnO2; (g) Sn(OTf)2, N-ethylpiperdine, 2.8, −78 °C; (h) TBSOTf, 2,6-lutidine; (i)K2CO3, MeOH; (j) OsO4,

NMO; NaIO4; (k) Zn(OTf)2, (−)-N-Me-ephedrine, Et3N, 4-phenyl-1-butyne; (l) BOMCl, NaHMDS,

−78 °C; (m) Lindlar catalyst, H2; (n) K2OsO4, NMO, citric acid, 50 °C; Pb(OAc)4, K2CO3.

Scheme 2.2. Evans’ aldehyde fragment synthesis.

2.2.3 Preparation of Iodide 2.3

The vinyl iodide fragment 2.3 began with the asymmetric reduction of ketone

2.11 through the employment of (R)-B-Me-oxazaborolidene as catalyst, giving alcohol

2.12. The alkyne was isomerized to the terminal alkyne 2.13, which was followed by a carboalumination and TES-silyl ether protection producing iodide fragment 2.3.

O OH OH a b c,d 2.3 85% 77% 68% Me O Me O O 2.11 2.12 2.13

Conditions: (a) (R)-B-Me-CBS catalyst, BH3Me2S, −30 °C; (b) KH, H2N(CH2)3NH2, 0 °C; (c)

Me3Al, Cp-2ZrCl2; I2, −45 °C; (d) TESCl, imidazole.

Scheme 2.3. Evans’ vinyliodide 2.3 fragment synthesis. 10

2.2.4 Synthesis of Macrocycle 2.2

The synthesis of bisenone macrocycle 2.2 employed a chelation controlled

Grignard addition of iodide 2.3 into aldehyde 2.4 to give allylic alcohol 2.14. Allylic alcohol 2.14 was put through a series of protecting group manipulations to give the seco- acid 2.15. Then, the seco-acid 2.15 was lactonized through the Shiina procedure and then was desilylated and oxidized to afford macrocycle 2.2.

O O

OH OTBS a BOMO b-d BOMO e-g 2.3 OH OH Me OTBS Me OTBS 2.2 86% 75% 85% CO2Me CO2H

(MeO)2HC (MeO)2HC 2.14 2.15

Conditions: (a) n-BuLi, MgBr2(OEt)2; −78 °C, then 2.4, MgBr2OEt2, CH2Cl2; −78 °C to 0 °C; (b)

TBSOTf, 2,6-lutidine; (c) PPTS, MeOH; (d) LiOH, i-PrOH, H2O; (e) MNBA, DMAP, [0.0015 M]; (f)

TBAF; (g) Dess−Martin periodinane.

Scheme 2.4. Evans’ synthesis of macrocycle 2.2.

2.2.5 Transannular Michael Reaction Cascade

The macrocycle 2.2 was treated with TBAF at −78 °C and then warmed to 5 °C to produce the transannular reaction cascade giving tricycle 2.1. The authors give a conformational analysis to support the idea of a Michael reaction cascade through

11 intermediate 2.16, but cannot rule out a concerted mechanism involving intermediate 2.17 through an exo-selective Diels-Alder cycloaddition.

Ar H H H O BOMO

O Me O (MeO)2HC Me O O 2.16 O

O O O BOMO H O TBAF BOMO Me O O -78 °C to 5 °C O OH

(MeO)2HC (MeO)2HC 2.2 2.1 H H Ar BOMO O O O Me (MeO)2HC Me O 2.17

Scheme 2.5. Evans’ transannular Michael reaction.

2.2.6 Completion of the Total Synthesis

The completion of the total synthesis was initiated through an enol triflation, followed by a palladium-catalyzed triflate reduction and a reduction of the resulting enolate giving 2.18. The tricycle 2.18 was subjected to a Lewis acid deprotection of the dimethyl and BOM acetals followed by an oxidation under Pinnick conditions and subsequent esterification with TMS-diazomethane to give a mixture of diastereomers

2.19 and 2.20. The lactone 2.19 was epimerized to 2.20 via potassium carbonate in methanol. The enriched 2.20 was finally acetylated to give salvinorin A 1.1.

O O O

d,e a-c O O O O O O g 2.1 H H H H H H 1.1 BOMO HO HO 64% O 83% O O 78% +

(MeO)2HC MeO2C MeO2C 2.18 2.19 f 2.20

2.19:2.20 2.5:1

Conditions: (a) NaH, Comins reagent: (b) Pd(OAc)2, dppf, Et3SiH; (c) L-selectride, t-BuOH, −78 °C to −55 °C; (d) LiBF4, MeCN/H2O; (e) NaClO2; TMSCHN2; (f) K2CO3, MeOH, quant. mass recovery; (g)

Ac2O, py., DMAP.

Scheme 2.6. Evans’ completion of the synthesis of salvinorin A

2.3 Hagiwara’s First-Generation Total Synthesis

Prior to their work on salvinorin A, the Hagiwara group worked on (−)-methyl barbascoate 2.21 (Figure 2.1).31 The similarities between salvinorin A and 2.21 and the difficulties incurred during the synthesis of 2.21 inspired much of the Hagiwara group’s first-generation synthesis of salvinorin A.29

O O

O O O H H H H AcO O O

MeO2C MeO2C 1.1 2.21

Figure 2.1. Comparision of methyl barbascoate and salvinorin A.

2.3.1 Functionalization of Wieland-Miesher Ketone Derivative 2.22

The Hagiwara group began their synthesis of salvinorin A with the Wieland-

Miescher ketone derivative 2.22 (Scheme 2.7). A dissolving metal reduction in ammonia with lithium followed by an in situ alkylation with ethyl iodoacetate gave ester 2.23.

The diketone 2.24 was revealed after a deprotection of the acetal 2.23 with HCl. The diketone was further functionalized by a double Wittig methylenation to give bis-exo- methylene δ-lactone 2.25. The lactone was reduced with LiAlH4 followed by a protection of the primary alcohol with TBSCl and the secondary alcohol was protected as a PMB-ether to give diene 2.26.

O O OH Li/NH , THF HO OEt 3 H OH OEt O -78°C 3M HCl H O O O OEt quant O O O I O O 2.22 51% 2.23 2.24

O OTBS

NaHMDS O 1. LAH, Et2O, 0 °C PMBO H Ph3PCH3Br H 57% (2 steps from 2.24) 2.24 2. TBSCl, DMAP, Et3N 99% 3. NaH, MPMCl, DMF 94% 2.25 2.26

Scheme 2.7. Hagawara’s synthesis of diene 2.26.

2.3.2 Introduction of the Furolactone Moiety

Diene 2.26 was subjected to hydroboration, followed by oxidation and treatment of base to give bis-α-aldehyde 2.27 (Scheme 2.8). The bis-α-aldehyde 2.27 was then protected as a bis-acetal 2.28 to prevent epimerization of the formyl groups. The resulting TBS-silyl ether 2.28 was cleaved and the alcohol was oxidized with PDC to give aldehyde 2.29, which was reacted with 3-furyllithium to give alcohols 2.30 and 2.31 with a diasteromeric ratio of 2:3. Acid deprotection of the diacetal 2.31 gave hemiacetal

2.32. Subsequently, the hemiacetal 2.32 was globally oxidized with PDC and the resulting acid was subjected to a DCC and methanol esterification to give lactone 2.33.

OTBS O OTBS 1. BH3•THF; O H O , NaOH PMBO PMBO O 2 2 H H 2. PDC, NaOAc CHO ethyleneglycol 2.26 O 3. NaOMe, MeOH PTSA, 40 °C 65% (3 steps from 2.26) 99% OHC O O 2.27 2.28 O O O

PMBO O OH OH H PMBO PMBO 1. TBAF (quant) 3-bromofuran, t-BuLi H O H O 2.28 O + 2. PDC, AcONa -78° C O O 78% 66% O O O O O O 2.29 2.30 2.31

O O 1. DDQ, H2O 2. PDC, 2-methyl-2- butene MPMO O PTSA H H 40% (3 steps from 2.30) O O 2.30 H H acetone, H2O OH 3. DCC, DMAP, MeOH O reflux 90%

OHC MeO2C 2.31 2.32

Scheme 2.8. Introduction of furanolactone moiety.

2.3.3 Completion of Hagiwara’s First-Generation Total Synthesis

The Hagiwara group’s synthesis avoided the C8 epimerization issues experienced by the Evans’ group by employing the Rubottom oxidation. This was facilitated by first forming the TES-silylenol ether 2.33 (Scheme 2.9). The silylenol ether 2.33 was then oxidized with m-CPBA to give 2-epi-salvinorin A 2.34. Finally, 2.34 was epimerized with a Mitsunobu reaction to give salvinorin A 1.1.

O O

TESO O O O H H H H NaHMDS, TESCl m-CPBA, NaHCO3, HO PPh3, DIAD, AcOH 2.32 O O 1.1 -78 °C toluene, H2O, 0 °C; 86% (quant) then AcOH MeO2C 70% MeO2C 2.33 2.34

Scheme 2.9. Hagiwara’s completion of salvinorin A.

2.4 Hagiwara’s Second-Generation Total Synthesis

2.4.1 Synthetic Plan

The Hagiwara group envisioned shortening their first-generation synthesis by instating a more direct method of instituting the one carbon homologation initiated in the transformation of 2.24 to 2.25 (Scheme 2.10).30 Introducing the esters 2.36 in a palladium-catalyzed carbonylation from bis-enoltriflates 2.37 would facilitate the desired subsequent introduction of the esters.

O O O CO Et RO 2 H RO O RO O RO O O H H H H OTf O O O

CO2Me CO2Me OTf 2.35 2.36 2.37 2.38

Scheme 2.10. Hagiwara’s second-generation synthetic plan.

2.4.2 Synthesis of bis-Triflate 2.42

The Hagiwara group’s synthesis of bis-triflate 2.37 began with the alcohol 2.24 from their first-generation synthesis (Scheme 2.11). First, the alcohol 2.24 was protected as the TES-silyl ether 2.39. Then the silyl ether 2.39 was converted to the bis-enol triflate 2.40 via Comin’s reagent. The bis-enol triflate 2.40 was converted to the Weinreb amide 2.41 in order to facilitate the addition of the furan moiety. Subsequently, the furan was introduced with 3-furyllithium to give ketone 2.42.

CO Et CO Et CO Et OH 2 TESO 2 TESO 2 H H H O O OTf TESOTf, pyridine Comins' reagent DMAP, 100 °C NaHMDS 93% 66% O O OTf 2.24 2.39 2.40 O OMe N

i-PrMgBr TESO O 3-bromofuran H TESO O 2.40 MeNH(OMe)•HCl OTf t-BuLi H quant. 70% OTf

OTf OTf 2.41 2.42

Scheme 2.11. Hagiwara’s synthesis of bis-triflate 2.42.

2.4.3 Synthesis of Ketone 2.32

Introduction of the esters were produced from a palladium-catalyzed carbonylation of bis-enol triflate 2.42 to give bis-ester 2.43 (Scheme 2.12). Next, a diastereoselective K-Selectride reduction of ketone 2.43 resulted in a lactonization of the

18 resulting alcohol and gave lactone 2.44 as the sole diastereomer. The resulting bis- enooate 2.45 was then subjected to a samarium diiodide 1,4-conjugate reduction to produce the decalin 2.45. Subsequent cleavage of the silyl ether 2.45 resulted in alcohol

2.46 and its diastereomer 2.47. The diastereomeric mixture resulted from the instability of the C8 center to basic conditions, as has been expounded upon in the Evans’ synthesis.

As in the Evans’ synthesis, the undesired alcohol 2.46 was able to be epimerized in a 7:3 ratio disfavoring the desired alcohol 2.47. Finally, the enriched alcohol 2.47 was oxidized by Dess-Martin periodane to the ketone 2.32 of the Hagiwara group’s first- generation synthesis.

O O O

TESO O Pd(PPh3)4, CO TESO O K-Selectride TESO O SmI2, Et3N H H H dppf, Et3N t-BuOH H AcOH 2.42 CO2Me O 95% O 60 °C 64% 69%

CO2Me CO2Me CO2Me 2.45 2.43 2.44

O O O

TBAF HO O HO O Dess-Martin O O 2.45 H H + H H H H 98% O O O

CO2Me CO2Me CO2Me 64% 26% 2.32 2.46 2.47

K2CO3, MeOH 2.46 : 2.47 = 7 : 3 94%

Scheme 2.12. Hagiwara’s second-generation completion of salvinorin A.

2.5 Burns and Forsyth’s Progress Towards Salvinorin A

2.5.1 Retrosynthetic Analysis

Burns and Forsyth envisioned the key disconnect in their synthesis to be from the decalin core 2.48 which could come from an IMDA/Tsuji allylation of triene 2.50. The stereochemistry of triene 2.50 could easily be accessed from tartaric acid derivative 2.51.

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

O O O CO2Me 1.1 2.48 2.49 2.50

O HO OTBS OH O HO O I HO O 2.51 2.52 L-(+)-tartaric acid

Scheme 2.13. Forsyth and Burns’ retrosynthesis of salvinorin A.

2.5.2 Synthesis of Triene 2.50

Known iodide 2.51 was added to deprotonated dithiane 2.53 to give dithiane 2.54.

The dithaine was subsequently treated with TBAF to give alcohol 2.55. The alcohol 2.55 was then oxidized under Parikh-Doering conditions giving aldehyde 2.56. The resulting aldehyde 2.56 was reacted with the β-ketophosphonate 2.57 to give enone 2.58. The enone 2.58 was then reacted with allyl chloroformate to give enol carbonate 2.59.

Finally, the enone 2.50 was revealed by removal of the dithiane. This reaction was problematic and after attempting various conditions the best reproducible removal of the dithiane was with mercuric perchlorate at a 33% yield.

t-BuLi; 2.51 O O O OTBS TBAF OH SO3•Py; DMSO O O O O S S HMPA 97% i-Pr2NEt S S S H -78 °C to 0 °C S S 0 °C S 87% 90%

2.53 2.54 2.55 2.56 O O

(EtO)2P O O O O KHMDS; O O O 2.57 allyl chloroformate 2.56 S NaH S HMPA O -78 °C to rt -78 °C to rt 62% S S 73% 2.58 2.59

O O O O Hg(ClO4)2, CaCO3 2.59 O 0 °C 33% O 2.50

Scheme 2.14. Synthesis of fragment 2.50.

2.5.3 IMDA and Tsuji Allylation

The enone 2.50 was heated in toluene at reflux to produce the decalins 2.49 and

2.60 in a 1:1 ratio. The decalins were separated by fractional crystallization, where decalin 2.49 was identified by single-crystal X-ray diffraction. The resulting purified decalin 2.49 underwent the Tsuji allylation to give a single diastereomer of the ketone

2.48.

O O O H O O O O H Pd (dba) O O BHB OCO2Allyl 2 3 O toluene reflux PPh3 toluene 77% O O O 93% 2.49 2.48 2.50 + (1:1)

O O H OCO2Allyl

O 2.60

Scheme 2.15. Burns’ synthesis of dione 2.48.

2.6 Butler and Forsyth’s Progress Towards Salvinorin A

2.6.1 Modified Retrosynthesis

A significant disadvantage in the Burns synthesis was the deprotection of the dithiane to reveal enone 2.50. Butler sought to alleviate this issue by forgoing the dithiane completely. In lieu of a masked acyl anion, it was imagined to disconnect in the typical 1,2 fashion from the bis-enone 2.61, which the imagined handle would be aldehyde 2.61. This would require a one-carbon homologation of iodide 2.51 in order to facilitate the transformation from a tartaric acid derivative.

O O O O O O OTBS O I O

2.50 2.51

O O O O O OTBS

O O

2.61 2.62

Scheme 2.16. Butler’s modified retrosynthesis.

2.6.2 Synthesis of Enone 2.50

Various methods of performing the one-carbon homologations from various tartaric acid derivatives were explored. The most successful method involved an oxidation of alcohol 2.62 followed by a Wittig reaction to give the methyl enol ether

2.63. Aldehyde 2.64 was then revealed through treatment of the methyl enol ether 2.63 with mercuric acetate and TBAI. The resulting aldehyde was then treated with the

Grignard reagent isopropenylmagnesium bromide to give secondary alcohol 2.65.

Subsequently, the secondary alcohol was protected as the TBS-silyl ether 2.66. Next, the

TBDPS-silyl ether 2.66 was selectively deprotected under basic conditions to give alcohol 2.67. The primary alcohol was then oxidized under Swern conditions and then

23 treated with diethyl (3-oxobutan-2-yl)phosphonate 2.57 anion to give enone 2.68. The enone was then treated with KHMDS and allyl chloroformate to give the enol carbonate

2.69. Converging with the Burns’ synthetic plan, secondary alcohol 2.70 was revealed from the TBS-silyl ether 2.69 with TBAF and acetic acid. Finally, the secondary alcohol was oxidized to the previously synthesized enone 2.50.

O O 1) (COCl) , DMSO O 2 O OTBDPS O OTBDPS Et3N O OTBDPS Hg(OAc)2, TBAI

2) MeOCH2PPh3Cl THF/H2O H HO KHMDS 76% -78 °C to rt MeO O 62% 2.62 2.63 2.64

O O Br , Mg O O OTBDPS TBSCl, imid. O OTBDPS NaOH 2.64 O OH -78 °C DMAP MeOH 87% 99% 65 °C 92% OH OTBS OTBS 2.65 2.66 2.67

1) (COCl)2, DMSO O KHDMS O Et N O allyl chloroformate OCO Allyl 2.67 3 O O 2 2) 2.57, NaH -78 °C 0 °C to rt 88% 72% OTBS OTBS

2.68 2.69

O O O OCO2Allyl OCO Allyl TBAF, AcOH DMP, NaHCO3 O 2 2.69 63% 96% OH O 2.70 2.50

Scheme 2.17. Synthesis of enone 2.50.

2.6.3 Diels-Alder Reaction and Tsuji Allylation

Butler revisited performing the Diels-Alder reaction on enone 2.50, similar to the

Burns’ synthetic approach. Covering various manipulations of the enone 2.50, along 24 with Lewis acid additives resulted in small variations of selectivity of the endo/exo adducts. The typical result was similar selectivity of endo:exo adducts. After further probing the reaction, only the exo product 2.71 was received when the allylic silyl ether

2.69 was used in the Diels-Alder reaction in a sealed tube at 280 °C. With the trans- decalin core in hand, the enol carbonate 2.71 was subjected to Pd(dba)2, treated with

TBAF and then oxidized with Dess-Martin periodinane to give a single diastereomer of ketone 2.48.

O O 1) Pd(PPh3)4, dba O o-dichlorobenzene O O OCO2Allyl OCO2Allyl 2) TBAF O O BHT, 280 °C sealed tube, 3 days 3) Dess-Martin Periodinane 63% unoptimized OTBS TBSO O 2.69 2.71 2.48

Scheme 2.18. Diels-Alder/Tsuji allylation sequence.

Finally, Butler explored various methods of installing the bis-ester moiety. The best results were found to be the ones used in the Hagiwara second-generations synthesis.

This involved treatment of the bis-ketone 2.48 with Comins’ reagent producing bis-enol triflate 2.72 followed by a palladium-catalyzed carbonylation to give bis-unsaturated ester 2.73. Finally, the decalin core was manipulated further by attempting the cleavage of terminal alkene 2.73. It was found that a one-pot treatment of the terminal alkene with osmium tetraoxide and bis-acetoxy iodobenzene was able to successfully facilitate the cleavage to give aldehyde 2.74.

O O O O H O KHMDS O H O O OTf Pd(PPh ) , CO CO2Me O Comins' Reagent 3 4 OsO4, NMO•H2O CO2Me -78 °C dppf, Et3N 2,6-lutidine, BAIB MeOH/DMF 60 °C 72% Acetone/H2O O OTf 73% CO2Me 53% CO2Me 2.48 2.72 2.73 2.74

Scheme 2.19. Elaboration of the decalin core.

Chapter 3

REVISION OF THE DECALIN CORE SYNTHESIS OF SALVINORIN A

3.1 Modifications of the Synthesis of Salvinorin A Carbon Skeleton

3.1.1 Improved One-Carbon Homologation

As previously discussed in the Burns and Butler synthesis, there have been significant difficulties in the synthesis of enol carbonate 2.50 and its analogs. Burns dealt with poor yields while revealing the enone from dithiane 2.49. Despite this issue, he was able to move forward and explore much of the initially outlined chemistry.

Butler improved upon this by forgoing the acyl anion addition and adapting a one- carbon homologation to get aldehyde 2.64. It was found that a Wittig reaction giving methyl enol ether 2.63 was successful without issues of β-elimination. Unfortunately, the best yielding cleavage of the methyl enol ether involved stoichiometric quantities of mercuric acetate.

The nature of the synthesis of salvinorin A requires a linear approach. This involves large reactions in the initial synthesis to acquire small quantities of advanced intermediates. While Butler’s synthesis of aldehyde 2.64 had an attractive yield,

27 stoichiometric quantities of mercuric acetate in an early stage intermediate would not be desirable for the work required to finish the synthesis of salvinorin A.

O CuI, MgBr O I O O THF, HMPA -30 °C OPMB OPMB 3.1 3.2

Scheme 3.1. Olefin addition.

It has been shown by other groups that vinylmagnesium bromide could be added into another tartaric acid derivative, iodide 3.1, in the presence of a catalytic amount of

CuI to give olefin 3.2.32 Treatment of iodide 3.3 with a catalytic amount of copper (I) iodide in THF and HMPA at -30 °C gave alkene 3.4 in moderate yield.

O O MgBr, CuI O OTBDPS O OTBDPS HMPA, THF -40 °C-0 °C I 80% 3.3 3.4

Scheme 3.2. Application of olefin addition.

The addition of vinylmagnesium bromide into iodide 3.3 allowed the expansion of the starting tartaric acid derivative with only a minimal amount of β-elimination. Finally, alkene 3.4 was exploited as a functional handle to unmask it as an aldehyde. This was accomplished via ozonolysis of alkene 3.4 to give aldehyde 2.64 in good yield.

O O O O , PPh OTBDPS 3 3 O OTBDPS DCM:MeOH -78 °C - rt 94 % O 3.4 2.64

Scheme 3.3. Unmasking of aldehyde 2.64.

Aldehyde 2.64 was treated with isopropenylmagnesium bromide and then immediately protected as TBS-silyl ether 2.66. The TBDPS-silyl ether was then selectively removed under basic conditions to give alcohol 2.67. The resulting alcohol

2.67 was subjected to an oxidation/HWE olefination to give enone 2.68. Finally enone

2.68, was treated with allyl chloroformate to give carbonate 2.69.

O O Br , Mg O O OTBDPS TBSCl, imid. O OTBDPS NaOH 2.64 O OH -78 °C DMAP MeOH 87% 99% 65 °C 92% OH OTBS OTBS 2.65 2.66 2.67

1) (COCl)2, DMSO O KHDMS O Et N O allyl chloroformate OCO Allyl 2.67 3 O O 2 2) 2.57, NaH -78 °C 0 °C to rt 88% 72% OTBS OTBS 2.68 2.69

Scheme 3.4. Synthesis of carbonate 2.69.

3.1.2 Modifications of the Diels-Alder Reaction

The Diels-Alder reaction has previously been explored extensively, with Butler showing that it could be done stereoselectively in moderate yield. It was found that heating enol carbonate 2.69 in a sealed tube would only provide the exo product. This 29 highly selective Diels-Alder reaction provided the highest yield of the desired exo product, but required a lengthy reaction time of 3 days. This was further explored by employing a microwave reactor to accelerate the reaction and provide a better yield.

The improvement of the Diels-Alder reaction began by working with the previously optimized conditions of dichlorobenzene as a solvent and with a temperature of 220 °C. With these conditions applied in a microwave reactor, it was found that the reaction time was reduced to 8.5 hours and the yield of decalin 2.71 was improved by a moderate amount to 73%.

O O H O OCO2Allyl O OCO2Allyl BHT 1,2-dichlorobenzene µW 260 °C, 8.5 h 73 % OTBS OTBS

2.69 2.71

Scheme 3.5. Microwave assisted Diels-Alder reaction

3.1.3 Elaboration of the Decalin Core

Butler had previously performed the next sequence of Tsuji-allylation, TBAF deprotection and DMP oxidation on 2.71, but had not determined a yield. Butler had previously found that the Tsuji-allylation could also proceed from carbonate 2.71, but had not optimized the route. The possible degradation of the allyl carbonate during functional group interconversion from the silyl ether 2.71 to ketone 2.49 led to the optimization of

Butler’s route. Previously, the allylation had been performed with Pd2(dba3) and PPh3 in

30 toluene and was found to proceed cleanly from carbonate 2.49. When the allylation was performed on 2.71 a degradation product was formed that ran in silica chromatography with the terminal alkene 3.5. The reaction was attempted without the dba ligand and was found to run cleanly without any degradation product.

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

2.71 3.5

Scheme 3.6. Modified Tsuji-allylation.

Further exploration of the revised synthesis required optimization of the synthesis of bis-enone 2.48. Butler’s previous cleavage of TBS-silyl ether 3.5 worked adequeately at an 87% yield. Attempts to oxidize the resulting alcohols 3.6 with Dess-Martin periodane failed with no dione formed. Exploration of mild oxidation conditions found

TPAP ideal with a yield of 91%.

O H O O O O H TPAP, NMO H TBAF O O O O THF, 8 h. DCM 87 % 91 % OTBS OH O 3.5 3.6 2.48

Scheme 3.7. Convergence to dione 2.48.

The formation of bis-enol trilfate 2.72 was examined in hopes to optimize its synthesis. The use of Comins’ reagent provided a moderate yield, but produced a UV- active side product that co-eluted with 2.72. Various conditions with triflic anhydride 31 were attempted to clean up the reaction. Trifilic anhydride and 2,6-lutidine was found to be completely ineffective with no consumption of 2.48 after 24 hours. Changing the base to triethylamine led to immediate decomposition of the dione to multiple products with none corresponding to 2.72.

Tf2O, 2,6-lutidine CH Cl O 2 2 O H 0 °C to rt H O O O OTf -or- Tf2O, Et3N CH2Cl2 O 0 °C to rt OTf 2.48 2.72

Comins' Reagent THF KHMDS -78 °C 72%

O H O OTf

OTf 2.72

Scheme 3.8. Attempts to improve the synthesis of bis-enol triflate.

3.1.4 Summary

Up to this point, we have developed improved access to the Diels-Alder core that avoids stoichiometric amounts of mercury. Additionally, we have optimized the Diels-

Alder/Tsuji allylation sequence to produce terminal alkene 3.5 cleanly. Further work on

32 the elaboration of the decalin core has produced an efficient synthesis of 2.73, providing an excellent scaffold for the completion of 1.1. Dr. Nathan Line of our research group recently completed the synthesis of 1.1

Chapter 4

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 4 Å molecular sieves; 1,2-dimethoxyethane (DME) was distilled from Na with benzophenone ketyl as oxygen scavenger / indicator. Thin-layer chromatography was performed 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 separations were performed using Silicycle SiliaFlash® P60 silica gel (40-63 µm). Melting points were measured on a Thomas Hoover (Uni-melt) 34 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 and DRX-500 NMR spectrometers;

1 residual solvent peak signals for CDCl3 were set at 7.261 ppm for H and 77.16 ppm for

13C. A Perkin-Elmer 1600 Series FT-IR spectrometer was used to record infrared spectra absorptions are reported in reciprocal centimeters. High-resolution mass spectrometric data were obtained using a Bruker MicroTOF (ESI) Mass Spectrometer.

O I , PPh , imid O 2 3 O HO O I toluene OTBDPS reflux OTBDPS 95% E.1 3.1

Iodide (3.1)

To a solution of known alcohol33 E.1 (1.00 g, 2.50 mmol) in PhMe (18 mL) heated at reflux, 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 (3x30 mL) upon which the brown color disappeared. The layers were separated and the aq. layer was extracted with Et2O (4x30 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 3.1 (1.20 g, 95%) as a colorless oil: Rf 0.45 (hexanes-ethyl acetate, 12:1,

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

-1 1 1112, 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

13 (s, 9H); 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.

O CuI, MgBr O I O O THF, HMPA -30 °C OTBDPS OTBDPS 3.1 3.4

Alkene (3.2)

To a flame-dried flask was added CuI (15 mg, 78 µmol) from a glovebox. Iodide 3.1

(200 mg, 392 µmol) in THF (0.45 mL) was added followed by HMPA (0.28 mL). The suspension was cooled to -30 °C and a solution of vinyl magnesium bromide (1.0 M in

THF, 784 µL, 784 µmol) was added dropwise. The reaction was stirred at -30 °C for 1 h, then warmed to 0 °C and quenched with sat. aq. NH4Cl (2 mL). The aq. layer was extracted with Et2O (3x10 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 3.1 (124.5 mg, 80%) as a colorless oil: Rf 0.45 (hexanes-ethyl acetate, 12:1, v/v);

23 23 [α]D [α]D (c 1.06, CHCl3); IR (neat) 3071, 2984, 2858, 1959, 1890, 1825, 1774, 1642,

-1 1 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); 13C NMR 36

(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.

O O O O , PPh OTBDPS 3 3 O OTBDPS DCM:MeOH -78 °C - rt 94 % O 3.4 2.64

Aldehyde (2.64)

A solution of alkene 3.1 (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.

Excess ozone was removed by purging the oxygen until colorless. PPh3 (17.24 g, 65.75 mmol) was added and the mixture was stirred at -78 °C for 30 min, at rt for 30 min, and was then concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 12:1 then 6:1, v/v) of the residue gave 2.64 (10.12 g, 94%) as a colorless oil: Rf 0.31 (hexanes-

23 23 ethyl acetate, 12:1, v/v); [α]D [α]D -13.1 (c 1.00, CHCl3); IR (neat) 2986, 2932, 2858,

-1 1 1727, 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.

O O O O OTBDPS Br , Mg O OTBDPS TBSCl, imid. O OTBDPS

H THF DMAP -78 °C DMF 99% O 87% OH OTBS 2.64 2.65 2.66

Silyl Ethers (2.66)

To a solution of aldehyde 2.64 (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 h and then at rt for 30 min. The reaction was quenched slowly with sat. aq. NH4Cl (50 mL) and water

(10 mL) was added. The aq. layer was extracted with EtOAc (3x50 mL) and the organic phases were dried and concentrated to afford a crude mixture of alcohols 2.65.

The crude mixture was dissolved in DMF (49 mL) and imidazole (5.00 g, 73.4 mmol),

DMAP (0.2 g, 2 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 ethyl acetate (3x20 mL) and the combined organic layers were dried and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 35:1, v/v) afforded 2.66 (12.03 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, 1251, 1113 cm-1;

1 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 (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, 3H), 0.04 (s, 6H); 38

13 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.

O O O OTBDPS 10 % NaOH O OH in MeOH 65 °C 92% OTBS OTBS 2.66 2.67

Alcohols (2.67)

Silyl ethers 2.66 (421.6 mg, 741 µmol) were dissolved in 10% NaOH in MeOH (7.5 mL) and heated at 65 °C for 2.5 h. The reaction was cooled to rt and quenched with sat. aq.

NH4Cl (10 mL). The aq. layer was extracted with ethyl acetate (3x15 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 2.67 (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

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.

O O O EtO P NaH O (COCl)2, DMSO O Et N, DCM O O EtO O OH 3 O -78 °C to rt H THF 0 °C to rt O OTBS OTBS OTBS 2.67 E.2 2.68

Enones (2.68)

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, 47.02 mmol) slowly and stirred for 15 min. A solution of alcohols

2.67 (7.77 g, 23.51 mmol) in DCM (19 mL) was added dropwise and stirred for 1 h.

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 (3x50 mL) and the organic layers were dried and concentrated to give crude aldehydes E.2.

To a suspension of NaH (60%, 1.13 g, 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 was stirred at 0 °C for 1 h at which time a solution of crude aldehyde E.1 in THF (27 mL) was added and stirred 12 hrs. The reaction was quenched with sat. aq. NH4Cl (40 mL) and the aq. layer was extracted with EtOAc (3x30 mL). The resulting organic phases were dried and concentrated. Silica gel column chromatography

(hexanes-ethyl acetate, 20:1, v/v) afforded enones 2.68 (7.30 g, 82%) as a pale yellow oil:

Rf 0.39 (hexanes-ethyl acetate, 7:1, v/v); IR (neat) 2955, 2928, 2897, 2858, 1680, 1473,

-1 1 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, 3H), 0.03 (s, 3H),

13 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.

O O O O KHMDS, DME O OCO2Allyl Allyl Chloroformate -78 °C OTBS 88 % OTBS 2.68 2.69

Enol Carbonates (2.69)

To a solution of KHMDS (71.0 mg, 365 µmol) in DME (7 mL) at -78 °C was added dropwise a solution of enones 2.68 (68.1 mg, 178 µmol) in DME (2 mL). The reaction was warmed to -50 °C 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 h before being quenched with sat. aq. NH4Cl (6 mL). The aq. phase was extracted with EtOAc (3x15 mL) and the 41 combined organic layers dried and concentrated. Silica gel column chromatography

(hexanes-ethyl acetate, 15:1, v/v) yielded 2.69 (73.5 mg, 88%) as a colorless oil: Rf 0.57

(hexanes-ethyl acetate, 4:1, v/v); IR (neat) 2955, 2930, 2889, 2857, 1764, 1458, 1370,

-1 1 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, 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 (s, 3H); 13C 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.

O O H O OCO2Allyl O OCO2Allyl BHT 1,2-dichlorobenzene µW 260 °C, 8.5 h 73 % OTBS OTBS

2.69 2.71

Decalins (2.71)

Triene 2.69 (54.2 mg, 116 µmol) in 1,2-dichlorobenzene (11.6 mL) was inserted into a microwave pressure flask. 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 h. The solution was cooled and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 20:1, v/v) afforded 2.71 (39.1 mg, 73%) as a colorless oil:

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

-1 1 39.5 (c 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, 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

13 (s, 3H); C 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 23 More Polar Isomer: Rf 0.70 (hexanes-ethyl acetate, 15:1 (eluted 5x), v/v); [α]D [α]D -

-1 1 9.9 (c 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,

13 3H); C 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.

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

2.71 3.5

Alkenes (3.5)

To a flame-dried flask under nitrogen was added Pd(PPh3)4 (37 mg, 32 µmol) in a nitrogen glovebox. Enol carbonates 2.71 (294.8 mg, 632 µmol) in toluene (7 mL) were added to the flask and the reaction was stirred at rt for 30 min before being concentrated.

Silica gel column chromatography (hexanes-ethyl acetate, 15:1, v/v) of the residue gave

3.5 (247.7 mg, 93%) as a colorless oil:

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

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

1 1 ; 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,

13 3H); 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. 44

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

- +2.7 (c 0.99, CHCl3); IR (neat) 3074, 2955, 2930, 2858, 1701, 1460, 1258, 1101, 831 cm

1 1 ; H 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.

O H O O O H TBAF O O THF, 8 h. 87 % OTBS OH 3.5 3.6

Alcohols (3.6)

To a solution of silyl ethers 3.5 (424.9 mg, 1.01 mmol) in THF (3.4 mL) at 0 °C was added TBAF (1M in THF, 4 mL, 4 mmol) dropwise. The reaction was allowed to warm to rt and stir for 8 h before being quenched with sat. aq. NH4Cl (5 mL). The aq. layer was extracted with EtOAc (3x5 mL) and the combined organic layers was dried and concentrated. Silica gel column chromatography (hexanes-ethyl acetate, 2:1, v/v) gave 45

3.6 (269.0 mg, 87%) as a colorless oil: Rf 0.26 (hexanes-ethyl acetate, 3:2, v/v); IR (neat)

-1 1 3447, 3074, 2981, 2924, 1695, 1458, 1371, 1232, 1068, 1007 cm ; H 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), 1.42 (s, 3H), 1.27 (s,

13 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.

O O H TPAP, NMO H O O O O DCM 91 %

OH O 3.6 2.48

Dione (2.48)

To a solution of NMOH2O (241 mg, 1.782 mmol) in DCM (3 mL) was added anhydrous

MgSO4 (143 mg, 1.19 mmol) and the mixture was stirred for 20 min. It was then filtered into a flask containing alcohols 3.6 (91.5 mg, 297 µmol), 4 Å MS (150 mg), and flushed with argon. Following stirring for 10 min, TPAP (5 mg, 0.01 mmol) was added which turned the mixture black, and it was stirred for 30 min. The mixture was filtered through a silica gel plug, which was flushed with EtOAc, and the filtrate was concentrated. Silica 46 gel column chromatography (hexanes-ethyl acetate, 6:1, v/v), afforded 2.48 (82.7 mg,

23 23 91%) as a white solid: Rf 0.33 (hexanes-ethyl acetate, 4:1, v/v); mp 69-70 °C; [α]D [α]D

-1 1 -26 (c 0.52, 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,

13 3H); C 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.

O Comins' Reagent O H KHMDS H O O O OTf THF -78 °C 72% O OTf 2.48 2.72

Bis-enol Triflate (2.72)

A solution of dione 2.48 (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 solution turned dark orange) and the solution was stirred for 1 h. The reaction was quenched with sat. aq.

NH4Cl (10 mL) and the organic layer was extracted with EtOAc (3x15 mL). The combined organic layers were dried and concentrated. The residue was passed through a small silica plug to remove the solids. Silica gel column chromatography (hexanes-

47 dichloromethane, 9:1, v/v, then hexanes-ethyl acetate 50:1, v/v) gave bis-enol triflate 2.72

(102.4 mg, 72%) as a cloudy, colorless oil: Rf 0.69 (hexanes-ethyl acetate, 4:1, v/v);

23 23 [α]D [α]D -43 (c 0.58, CHCl3); IR (neat) 2987, 2926, 2860, 1416, 1385, 1248, 1213,

-1 1 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, 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.

O O O O CO Me OTf Pd(PPh3)4, CO 2

dppf, Et3N MeOH/DMF 60 °C OTf 73% CO2Me

2.72 2.73

Diester(2.73)

To a flame-dried flask was added Pd(PPh3)4 (49 mg, 42 µmol) and dppf (70 mg, 0.13 mmol) in a nitrogen atmosphere glovebox. The flask was evacuated and refilled with carbon monoxide (3 times). Bistriflate 2.72 (119.7 mg, 210 µmol) in methanol (3 mL) was added followed by DMF (1 mL) and Et3N (88 µL, 63 µmol). Carbon monoxide was bubbled through the solution for 5 min before it was heated to 60 °C for 20 h under a CO

48 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 reside gave diester 2.73 (59.3 mg, 73%) as a colorless oil: Rf 0.53 (hexanes-ethyl acetate, 4:1, v/v);

23 23 [α]D [α]D -103 (c 0.56, CHCl3); IR (neat) 2986, 2951, 1718, 1437, 1380, 1232, 1174,

-1 1 1035 cm ; H NMR (CDCl3, 400 MHz) δ 7.05 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 2.0, 6.8

Hz, 1H), 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,

13 1H), 2.07 (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.

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Appendix A:

1H / 13C NMR Spectra

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 3.1 (500 MHz, CDCl3)

130 120 110 100 90 80 70 60 50 40 30 20 10 ppm 13 C NMR Spectrum of 3.1 (125 MHz, CDCl3)

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 3.4 (400 MHz, CDCl3)

130 120 110 100 90 80 70 60 50 40 30 ppm 13 C NMR Spectrum of 3.4 (100 MHz, CDCl3)

10 9 8 7 6 5 4 3 2 ppm 1 H NMR Spectrum of 2.64 (400 MHz, CDCl3)

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm 13 C NMR Spectrum of 2.64 (100 MHz, CDCl3)

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 2.66 (400 MHz, CDCl3)

140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm 13 C NMR Spectrum of 2.66 (100 MHz, CDCl3)

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 2.67 (400 MHz, CDCl3)

140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 13 C NMR Spectrum of 2.67 (100 MHz, CDCl3)

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 2.68 (400 MHz, CDCl3)

180 160 140 120 100 80 60 40 20 ppm 13 C NMR Spectrum of 2.68 (100 MHz, CDCl3)

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 2.69 (400 MHz, CDCl3)

150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 13 C NMR Spectrum of 2.69 (100 MHz, CDCl3)

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 2.71 Less Polar (400 MHz, CDCl3)

150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm 13 C NMR Spectrum of 2.71 Less Polar (100 MHz, CDCl3)

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 2.71 More Polar (400 MHz, CDCl3)

150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 13 C NMR Spectrum of 2.71 More Polar (100 MHz, CDCl3)

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 3.5 Less Polar (500 MHz, CDCl3)

200 180 160 140 120 100 80 60 40 20 0 ppm 13 C NMR Spectrum of 3.5 Less Polar (125 MHz, CDCl3)

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 3.5 More Polar (500 MHz, CDCl3)

200 180 160 140 120 100 80 60 40 20 ppm 13 C NMR Spectrum of 3.5 More Polar (125 MHz, CDCl3)

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 3.6 (500 MHz, CDCl3)

200 180 160 140 120 100 80 60 40 20 0 ppm 13 C NMR Spectrum of 3.6 (125 MHz, CDCl3)

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 2.48 (400 MHz, CDCl3)

200 180 160 140 120 100 80 60 40 20 0 ppm 13 C NMR Spectrum of 2.48 (100 MHz, CDCl3)

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)

150 140 130 120 110 100 90 80 70 60 50 40 30 ppm 13 C NMR Spectrum of 2.72 (100 MHz, CDCl3)

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 2.73 (400 MHz, CDCl3)

160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm 13 C NMR Spectrum of 2.73 (100 MHz, CDCl3)