Approaches to Marine-Derived Polycyclic Ether Natural Products: First Total Syntheses of the Asbestinins and a Convergent Strategy for Brevetoxin A

APPROACHES TO MARINE-DERIVED POLYCYCLIC ETHER NATURAL PRODUCTS: FIRST TOTAL SYNTHESES OF THE ASBESTININS AND A CONVERGENT STRATEGY FOR BREVETOXIN A

J. Michael Ellis

A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry

Chapel Hill 2007

Approved by:

Advisor: Professor Michael T. Crimmins

Reader: Professor Michel R. Gagné

Reader: Professor Jeffrey S. Johnson

J. Michael Ellis

ABSTRACT

J. Michael Ellis

Approaches to the Marine-derived Polycyclic Ether Natural Products: First Total Syntheses of the Asbestinins and a Convergent Strategy for Brevetoxin A (Under the direction of Professor Michael T. Crimmins)

Glycolate aldol reactions and glycolate alkylations, followed by ring-closing metatheses, are used to prepare medium ring ethers used as building blocks for polycyclic ether containing natural products. Using the glycolate aldol/ring-closing metathesis strategy, an approach to a previously unprepared subclass of the C2–

C11 cyclized cembranoids known as the asbestinins is described. An oxonene is efficiently synthesized and utilized as a manifold for an intramolecular Diels–Alder cycloaddition to form a hydroisobenzofuran moiety characteristic of the asbestinins.

This tricyclic adduct represents the bulk of the framework of the asbestinins.

Ultimately, the tricycle was progressed to two different natural products, 11-acetoxy-

4-deoxyasbestinin D and asbestinin-12, via a late-stage divergent route. The completion of these natural products represented the first instance of preparing an asbestinin using chemical synthesis, and served to confirm the absolute configuration of the subclass.

Additionally, a glycolate alkylation/ring-closing metathesis strategy was used to prepare the B ring of brevetoxin A on multigram scale. Novel reactivity was discovered and exploited along this route. Namely, it was found that glycolate alkylation adducts can undergo direct Claisen condensation or reduction to the

iii aldehyde to provide useful synthons. The B ring has been progressed to the BCDE tetracycle in a convergent fashion, and portions of this supply have been carried forward to provide possible coupling partners for the GHIJ fragment in hopes of completing brevetoxin A in a convergent manner.

ACKNOWLEDGEMENTS

First, I would like to acknowledge Professor Michael T. Crimmins for being an advisor and a friend to me during the past five years. Graduate school can be quite a test of perseverance, and his leadership style made my time here not only tolerable, but enjoyable. I have become an independent thinker and a scientist under his direction, and I owe my professional future to the time and energy he poured into my development.

Nearly every member I have overlapped with in the Crimmins laboratory contributed to me reaching this point, but several deserve special thanks. Dr.

Brandon Brown and Dr. Jon Parrish were my mentors from day one, and I appreciate all they did to get me off on the right foot and show me how to still enjoy life while in graduate school. The third year is a crucial time for a Ph.D. candidate, and I was fortunate to be surrounded by a number of inspiring postdocs during this portion of my studies. Specifically, Dr. Franck Caussanel and Dr. Hilary Plake motivated me with their strong work ethic and were always there to lend advice. Dr.

Hamish Christie brought the entire lab to a new level during his time here, and I was one of the many positively impacted by his contagious passion for science. I would also like to thank Dr. Aaron Smith and Matt Haley for their friendships and for making lab a fun place to be every single day. Special thanks are also extended to

Danielle Jacobs for providing this dissertation, and many other things I have written during my time here, with her proofreading prowess.

v During the latter half of my time here, I have had the privilege of being part of

“Team Brevetoxin”. Many have contributed to this project, but I would like to specifically acknowledge Dr. Patrick McDougall and Luke Zuccarello for allowing me to join them on this task they have poured so much into and take part in the effort toward this natural product. It has been a privilege to be on the same team with such intelligent and talented chemists.

Finally, a number of family members have been vital to getting me to this point. My mom and dad have sacrificed countless times to provide me with every opportunity they could. The years put in before getting here equipped me with the abilities to get through this experience. And most importantly, I want to thank my wife Erin. She has been my source of inspiration and energy for the past five years.

I could not have done this without all of her love, support, and understanding, which allowed me to focus on the task at hand while she gave our life balance.

TABLE OF CONTENTS

Page

List of Tables………………………………………………………..……………………….x

List of Figures………………………….……………………………………………………xi

List of Abbreviations………………………………….………………...………………….xii

Chapter I: An Aldol/Ring-Closing Metatheis/Intramolecular Diels–Alder Approach to the Asbestinins: Total Syntheses of 11-Acetoxy-4-deoxyasbestinin D and Asbestinin-12 ...... 1

A. Background...... 1

B. Previous Total Syntheses of C2–C11 Cyclized Cembranoids...... 3

1. Prins–pinacol Condensation–rearrangement...... 3

2. Claisen Rearrangement Strategy ...... 8

3. A Return to the Prins–pinacol Condensation–rearrangement...... 12

4. [4+3] Annulation Strategy ...... 17

5. Intramolecular Amide Enolate Alkylation ...... 19

6. Wittig Rearrangement/Intermolecular Diels–Alder Strategy...... 23

7. Miscellaneous Strategies...... 25

C. Medium Ring Ether Synthesis via Ring-closing Metathesis...... 35

1. Catalyst Development...... 35

vii 2. Aldol/Ring-closing Metathesis in the Crimmins Laboratory...... 38

3. Alkylation/Ring-closing Metathesis in the Crimmins Laboratory...... 42

4. Total Syntheses of the Eunicellin Diterpenes via Alkylation/...... 44

D. Total Syntheses of 11-Acetoxy-4-deoxyasbestinin D and...... 51

1. Background...... 51

2. Retrosynthetic Analysis...... 52

3. Oxonene Formation ...... 54

4. Synthesis of the Diels–Alder Candidate...... 61

5. Revised Retrosynthesis ...... 76

6. Synthesis of the Revised Diels–Alder Substrate...... 77

7. Refunctionalization of the Six- and Nine-membered Rings...... 79

8. Oxepane Formation to Complete 11-Acetoxy-4-deoxyasbestinin D ...... 82

9. Total Synthesis of Asbestinin-12...... 90

E. Summary...... 93

Chapter II: A Convergent Strategy for the Total Synthesis of Brevetoxin A ...... 97

A. Background...... 97

B. Approaches to Polycyclic Ether Synthesis ...... 99

1. Iterative Ring Formation...... 99

2. Biomimetic Epoxide Opening...... 100

3. [X + 1 + X] Approach ...... 101

4. [X + 2 +X] Strategy ...... 104

C. Brevetoxin A ...... 105

1. Characterization and Biological Activity ...... 105

viii 2. Nicolaou’s Total Synthesis of Brevetoxin A...... 108

D. Previous Efforts in the Crimmins Laboratory Toward Brevetoxin A ...... 119

1. Seminal Efforts Toward the BCDE Fragment ...... 119

E. Preparation of the BCDE and GHIJ Fragments ...... 124

1. A Revised Route to a Homologated B Ring...... 125

2. Formation of the BCDE Fragment ...... Error! Bookmark not defined.

3. Formation of the GHIJ Fragment ...... 131

F. Model Studies of F Ring Formation...... 132

G. Progressing the BCDE Fragment ...... 137

1. Preparation of the BCDE Coupling Partner...... 137

2. Analog Syntheses...... 139

H. Union of the BCDE and GHIJ Fragments and Proposed Completion of Brevetoxin A...... 140

I. Summary...... 143

Chapter III: Experimental ...... 145

A. Materials and Methods...... 145

B. Procedures...... 146

References ...... 210

ix LIST OF TABLES

Table 1. Cyclic Constraints for Ring-closing Metathesis ...... 37

Table 2. Small and Medium Ring Ether Formation ...... 40

Table 3. Base Screening for Glycolate Aldol Reaction...... 56

Table 4. Selective Deprotection Attempts...... 65

x LIST OF FIGURES

Figure 1. Proposed Biosynthesis ...... 1

Figure 2. Transition States for Prins–pinacol Condensation–rearrangement...... 4

Figure 3. Claisen Rearrangement Transition States ...... 10

Figure 4. Olefin Metathesis Catalysts ...... 36

Figure 5. Acyclic Conformational Constraint via Gauche Effect...... 39

Figure 6. Aldol/Ring-Closing Metathesis Strategy...... 39

Figure 7. Diels–Alder Transition States...... 47

Figure 8. Targeted Asbestinins ...... 51

Figure 9. Conformational Analysis of Oxonene Formation...... 61

Figure 10. Asbestinin Cycloaddition Transition States...... 76

Figure 11. C3 Protecting Group Effects in the Ophirin B Synthesis ...... 76

Figure 12. Two-dimensional NMR Data ...... 80

Figure 13. X-ray Crystallographic Data of Ketone...... 81

Figure 14. Hydrogenation Strategy ...... 87

Figure 15. trans -Fused Polycyclic Ethers...... 98

Figure 16. GHIJ Fragments ...... 132

xi LIST OF ABBREVIATIONS

Ac Acetyl

Acac Acetylacetonate

AIBN Asobis(isobutyronitrile)

9-BBN 9-Borabicyclo[3.3.1]nonane

BHT Butylated hydroxytoluene

Bn Benzyl

Boc t-Butyloxycarbonyl

Bu Butyl

Bz Benzoyl

COD Cyclooctadiene

Cp Cyclopentadienyl

CSA Camphorsulfonic acid

Cy Cyclohexyl

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

DCC Dicyclohexyl carbodiimide

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

DHP Dihydropyran

DIAD Diisobutyl azodicarboxylate

DMAP 4-Dimethylaminopyridine

DMDO Dimethyldioxirane

DMF Dimethylformamide

DMS Dimethyl sulfide

xii DMSO Dimethyl sulfoxide

Et Ethyl

Hfacac Hexafluoroacetylacetonate

HMDS Hexamethyldisilazide

HMPA Hexamethylphosphoramide

IBX 2-Iodoxybenzoic acid

Imid. Imidazole

Ipc Isopinocampheol

LDA Lithium diisopropylamide

LiDBB Lithium di-tert -butylbiphenylide

Lut. Lutidine m-CPBA meta -Chloroperoxybenzoic acid

Me Methyl

MEM Methoxyethoxymethyl

Men Menthyl

MOM Methoxymethyl

MOP Methoxypropyl

MS Molecular Sieves

Ms Methanesulfonyl

NBS N-Bromo succinimide

NIS N-Iodo succinimide

NMO N-Methylmorpholine-N-oxide

NMP N-Methylpyrrolidinone

xiii PCC Pyridinium chlorochromate

Ph Phenyl

Piv Pivaolyl

PMB p-Methoxybenzyl

PPTS Pyridinium p-toluenesulfonate

Pr Propyl

Pyr. Pyridine

Red-Al Sodium bis(2-methoxyethoxy)aluminumhydride

TBDPS t-Butyldiphenylsilyl

TBS t-Butyldimethylsilyl

TES Triethylsilyl

Tf Trifluoromethanesulfonyl

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TIPS Triisopropylsilyl

TMEDA N,N,N’ ,N’ -Tetramethylethylenediamine

TMS Trimethylsilyl

TPAP Tetrapropylammonium perruthenate

Tr Triphenylmethyl

Ts p-Toluenesulfonyl

xiv

Chapter I

An Aldol/Ring-Closing Metatheis/Intramolecular Diels–Alder Approach to the Asbestinins: Total Syntheses of 11-Acetoxy-4-deoxyasbestinin D and Asbestinin-12

A. Background

A wide array of C2–C11 cyclized cembranoid natural products have been

isolated from marine sources.1 These diterpenes are grouped into four categories:

the cladiellins (eunicellins), the briarellins, the asbestinins, and the sarcodictyins. A

biosynthetic pathway has been proposed by Faulkner relating each of these

subclasses (Figure 1).2 Beginning with the cembrane skeleton, C2–C11 cyclization provides the cladiellin framework. An intramolecular etherification of the cladiellin tricycle affords the tetracyclic framework of the briarellin subclass, and a 1,2-

19 19 17 20

7 7 12 11 11 9 9 C2-C11 10 11 1 12 10 1 O 1 O 2 14 2 14 2 3 3

18 15 16 O 18 19 20 15 17

cembranes cladiellins briarellins (eunicellins)

C2-C11 1,2-Me shift

19 17 16

20 7 11 7 9 10 11 O 5 12 10 14 1 4 1 O 14 2 3 18 15 15 16 O 18 19 20 17 sarcodyctins asbestinins

Figure 1. Proposed Biosynthesis suprafacial methyl shift on the briarellin structure is further predicted to deliver the asbestinins. These speculations are corroborated by the isolation of a cembrane metabolite with cladiellin metabolites in Alcyonium molle and with asbestinin metabolites in Briareum steckii .3 The sarcodictyins are also proposed to arise from a

C2–C11 cyclization of the cembrane skeleton; however, in these systems, the

cyclization results in a fused cyclohexyl and oxonane in place of the

hydroisobenzofuran of the cladiellins, briarellins, and asbestinins. As a result of this

significant structural variation of the sarcodyctins, the synthetic approaches to these

molecules are quite different than those for the other three related subclasses. 4,5

Eunicellin was the first reported member of the C2–C11 cyclized cembranoid

natural products, isolated in 1968 by Djerassi and co-workers from the soft coral

Eunicella stricta found off the coast of Banyuls-sur-Mer in France. 6 Since this

discovery, over one hundred unique secondary metabolites of gorgonian octocorals

have been characterized, including the first asbestinin in 1980 2 and the first briarellin

in 1995. 7 The sum of these marine natural products provides a range of structural

diversity. The natural role of these cembranoids is proposed, based upon mollusk

and fish lethality assays, to involve predation deterrence. 7 Upon further

investigation, several of the members of these subclasses have demonstrated

remarkable pharmacological potential. 7-13 Particularly, these diterpenes have been shown to possess in vitro cytotoxicity against various cancer cell lines, anti- inflammatory properties, antimicrobial activities, and histamine and acetylcholine antagonism. The fascinating molecular architecture of these cembranoids, as well as their potential as therapeutic agents, has sparked much interest in the synthetic

2 community over the past decade, resulting in a variety of approaches toward these challenging structural motifs and several total syntheses.

B. Previous Total Syntheses of C2–C11 Cyclized Cembranoids

1. Prins–pinacol Condensation–rearrangement

The first total synthesis of a cembranoid natural product was completed by

Overman and co-workers, who reported the total synthesis of (-)-7- deacetoxyalcyonin acetate ( 1), 14 a cladiellin, in 1995.15 The strategy relies upon the formation of the hydroisobenzofuran functionality via a Prins–pinacol condensation– rearrangement approach, which had been previously employed in the Overman laboratory to stereoselectively form tetahydrofurans.16 ( S)-Dihydrocarvone ( 2)17 was

utilized as the starting material to prepare dienyl diol 3 suitable for the proposed transformation (Scheme 1). Formation of the kinetic enol triflate,18 followed by

iodination 19 provided the dienyl iodide 4.20 Subsequent transmetalation and

exposure to alkynyl aldehyde 5 (prepared in four steps from ( S)-glycidyl pivalate) 21

provided diol 3 upon deprotection. 22 With the stage set for the key Prins–pinacol condensation–rearrangement, diol 3 was combined with enal 6 in the presence of

BF 3·OEt 2 to provide the hydroisobenzofuran 7 as a single diastereomer in 79%

yield. The stereochemical outcome of this transformation is predicted to arise from

transition state 8 (Figure 2). Following formation of the more stable ( E)-

oxocarbenium ion, 23 the molecule adopts the chair conformation necessary for the 6- endo cyclization process. Transition state 8 orients all substituents pseudoequatorially while also allowing the oxocarbenium ion to approach the diene

3 from the opposite face of the bulky isopropyl substituent. 16 The observed stereochemistry supports this model.

H O Me TMS OMe Me Me Me Me OH 5 O 1. LDA; PhN(Tf)2 I 1. t-BuLi

2. Me6Sn2, 2. PPTS, MeOH OH TMS H Pd(PPh3)4; NIS H H Me Me (64%) (78%) Me Me Me Me 2 4 3

Me Me O H TMS OTIPS R 6 O . OTIPS BF3 OEt2 H H H Me (79%) Me Me R = CHO 7

Scheme 1. Prins–pinacol Condensation–rearrangement

- Me - Me OBF OBF R' 3 R' 3 favored + + O O R R Me Me Me Me 8 R' R' Me - Me- F3BO F BO disfavored 3 + O + O R R Me Me Me Me 9

Figure 2. Transition States for Prins–pinacol Condensation–rearrangement With the cyclohexene and tetrahydrofuran in place, attention was turned toward formation of the oxonane (Scheme 2). Removal of the primary silyl ether and

4 photochemical decarbonylation of the formyl group gave bicycle 10 .24 The allylic alcohol was next exploited to achieve a Sharpless asymmetric epoxidation of the trisubstituted alkene, 25,26 and the epoxide was regioselectively reduced using bis(2-

methoxy)aluminum hydride (Red-Al). 27-29 Addition of water produced NaOH, which also effected desilylation in one-pot delivering diol 11 . A series of protections

Me H Me R TMS H H TMS 1. AcOH, H O 1. Ti(O-i-Pr)4, t-BuOOH O 2 O OTIPS υ OH 2. Red-Al; H2O H H 2. h H H H H Me Me (79%) Me Me (72%) Me Me R = CHO 10 7 Me Me H H H H 1. B-I-9-BBN, AcOH 1. PivCl, pyr. 2. i-Bu2AlH O OH O OPiv 2. TBSOTf, 2,6-lut. 3. (n-Pr4)NRuO4, NMO H H H H Me H (84%) H Me Me Me OH Me Me OR (77%) 11 R = TBS 12 Me Me Me H H H H H H O I I OH 1. Ph3P=CHOMe NiCl2-CrCl2 O O O O 2. TfOH (65%) H H H H H Me H H Me H H Me Me Me OR (77%) Me Me OR Me Me OR R = TBS R = TBS R = TBS 13 14 15 Me H H 1. Ac O, pyr. OAc 2 O 2. n-Bu4NF H H H Me (88%) Me Me OH (-)-7-deacetoxyalcyonin acetate (1)

Scheme 2. Completion of (-)-7-Deacetoxyalcyonin Acetate followed by iodoboration of the alkyne provided the vinyl iodide, 30 Reduction and oxidation revealed the aldehyde 13 ,31 which, following a one-carbon homologation, was utilized in an intramolecular Nozaki–Hiyama–Kishi coupling using NiCl 2–

5 32,33 CrCl 2. Markedly, the resultant tricycle 15 was formed in 65% yield with high

diastereoselection (>20:1 dr). Selective acetylation of diol 15 , with subsequent

removal of the silyl ether, provided (-)-7-deacetoxyalcyonin acetate ( 1), marking the

first successful total synthesis of a member of the C2–C11 cyclized cembranoid

family.

The Overman laboratory next extended the Prins–pinacol condensation– rearrangement approach to a cladiellin of potential pharmacological utility.

Sclerophytin A ( 16 ) was characterized as a tetracyclic diether and showed promising in vitro cytotoxicity against the L1210 leukemia cell line (1 ng/mL). 9,34,35 The strategy

envisioned for sclerophytin A involved a Prins–pinacol approach, this time using a

(Z)-α,β-unsaturated aldehyde as the nucleophile. The synthesis would provide the opportunity to assess the viability of using an aldehyde of this sort without observing isomerization of the alkene configuration, while accomplishing the first total synthesis of this therapeutically intriguing natural product. Utilizing diol 3 from the (-

)-7-deacetoxyalcyonin acetate synthesis 15 and aldehyde 17 (prepared in four steps

from 3-buten-1-ol), 36 a two step condensation and rearrangement procedure was employed (Scheme 3).37,38 Condensation of the two components using acidic

conditions provided an acetal that efficiently delivered bicycle 18 upon treatment with

tin tetrachloride. The (Z)-olefin remained in tact throughout the cyclization with no

stereomutation observed. Deformylation 24 and deprotection of the silyl protecting

groups gave the allylic alcohol 19 , suitably poised for a substrate-controlled

epoxidation. Treatment with ( t-BuO) 3Al/ t-BuO 2H provided a separable 7:1 mixture of epoxides, favoring the desired diastereomer 20 .39 Opening of the epoxide and

6 sequential protection provided alkyne 21 . Refunctionalization to the Nozaki–

Hiyama–Kishi candidate as before completed a more efficient synthesis of vinyl

15,30 iodide 14 . Upon treatment with NiCl 2–CrCl 2, the oxonane was formed, delivering the desired isomer of allylic alcohol 15 in good yield. 32,33 Deprotection of the tertiary silyl group and treatment with Hg(OAc) 2 followed by NaBH 4 provided diether 22 in

moderate yield. 40 Photoisomerization to the exocyclic olefin gave the reported

1. Me Me OH O Me R H TMS OTIPS 17 O OTIPS 1. hυ OH TMS H H H 2. n-Bu4NF p-TsOH, MgSO4 H o Me Me Me Me Me 2. SnCl4, -50 C (63%) 3 (67%) R = CHO 18

Me H H Me H H 1. LiAlH4 (t-BuO)3Al, 2. PivCl O OH O OH o 3. TBSOTf H H t-BuO2H, -20 C H H H Me Me Me H O (76%, 7:1 dr) Me Me Me (90%) 19 20 Me H H 1. B-I-9-BBN, AcOH Me H H O O 2. i-Bu2AlH I NiCl2-CrCl2 OPiv O H H 3. Dess-Martin (61%) H Me H H Me Me OR periodinane H Me Me Me OR R = TBS (67%) 21 R = TBS 14

Me Me H H H H H Me H Me OH OH OH 1. n-Bu4NF hυ O O O O O 6 2. Hg(OAc) ; H H 2 H (80%) H H Me NaBH , NaOH H H H OR 4 H Me Me Me Me Me Me Me Me (41%) R = TBS 22 16 15

Scheme 3. Overman's Completion of Sclerophytin A

7 structure of sclerophytin A ( 16 ). 41,42 However, the data for the synthetic and natural

material differed greatly. 13 The C6 epimer of tetracycle 16 was also prepared via oxidation 43 and reduction, but also failed to correlate with the natural product.

2. Claisen Rearrangement Strategy

Simultaneously, the Paquette group had made efforts to synthesize sclerophytin A ( 16 ) via a unique route. 13,34,35,44 Their strategy relied upon a Claisen

rearrangement as the key step to provide the functionalized oxonane core of the

natural product. 45 The synthesis commenced with a Diels–Alder cycloaddition

involving the Danishefsky diene (23 ) and chiral dienophile 24 (Scheme 4).46,47 The

labile enolsilane was hydrolyzed 48 and the resultant enone was reduced under

Luche conditions 49 to provide allylic alcohol 25 in good yield. Ensuing silylation of the allylic alcohol and hydrolysis of the menthyl ether delivered lactone 26 . Allylation

of lactone 26 afforded a 13:1 ratio of adducts, favoring the desired diastereomer. 50

Reduction, acetylation, and treatment of the derived oxocarbenium ion with

trimethylsilyl cyanide gave a 1:1 mixture of nitriles 27 and 28 .51,52 Efficient conversion of nitrile 27 to nitrile 28 was achieved under alkaline conditions. Wacker oxidation 53 and vinylation provided tertiary alcohol 29 in 75% yield for two steps.

Mild hydrolysis of the nitrile provided an acid, 54-56 which was used in a Yamaguchi

lactonization to give the lactone. 57,58 A Tebbe methylenation provided the target

diene 30 for the key Claisen rearrangement. 59 Gratifyingly, treatment of the mixture of dienes with sodium tetrafluoroborate in refluxing toluene provided the desired oxonene 31 , but at two distinctly different rates.45 The noted variation in reaction

8 rate can be explained by examining the transition states for each rearrangement

(Figure 3). The requisite chair conformations to access the desired rearranged product should both be accessible, however, transition state 30a suffers from

OMen 1. O

OMen H OH TMSO O 24 H 1. TBDPSCl, imid. HO TBDPSO O 2. TMSOTf, O 2. pyr. CSA,H2O, pyr. OMe H 3. NaBH4, CeCl3, H O (81%) O MeOH 26 23 25 (71%)

1. AllylBr, In, Bu4NBr 1. O , PdCl , 2. i-Bu AlH H H 2 2 2 TBDPSO TBDPSO CuCl, H2O O + O 3. Ac2O, Et3N 2. CeCl , 4. TMSCN, 3 BF OEt H H 3 2 CN CN MgBr 27 28 (79%) KO-t-Bu, t-BuOH (75%) (83%)

Me 1. NaOMe, MeOH; H HO + TBDPSO NaBF H3O ; LiOH, H2O Me 4 H O TBDPSO O 2. Cl C H COCl, (75%) O 3 6 2 H Et3N,DMAP H CN 3. Cl 30 Cp2Ti AlMe2 29 -50 oC (52%) Me H H TBDPSO O

H H O 31

Scheme 4. Claisen Rearrangement

9 Me HH Me HH TBDPSO TBDPSO O O O O HH HH 30a 30b

H H H H O TBDPSO Me TBDPSO Me O H O H O

p-cymene, p-cymene, o 140 oC, 3 h 130 C, 1.5 h Me H H TBDPSO O

H H O 31

Figure 3. Claisen Rearrangement Transition States

enhanced steric interactions over its corresponding epimer 30b , resulting in kinetically slower Claisen rearrangement.

With the formation of the oxonene completed, attention was turned toward properly functionalizing the six- and nine-membered rings. Diastereoselective alkylation of the ketone, protection of the resultant tertiary alcohol as a benzoate ester, removal of the silyl protecting group, and oxidation provided enone 32

(Scheme 5). Hydroxymethylation of the enone utilizing ytterbium triflate,60 followed

by silyl protection of the resultant alcohol delivered the silyl ether.

Diastereoselective conjugate addition of isopropyl Grignard reagent completed the

diterpene skeleton of sclerophytin A ( 16 ). A Luche reduction, 49 formation of the

thiocarbonyl imidazole, and reduction under radical conditions served to

deoxygenate the cyclohexyl unit giving ester 34 . Reduction of the benzoate ester,

10 followed by oxymercuration and oxidative demercuration gave a 3:7 mixture of epimeric alcohols 35 in 54% yield, forming the final ring of the natural product. 61

Transient protection of the secondary alcohol as an acetate ester was followed by

deprotection of the silyl ether and Grieco elimination. 62 Reduction of the acetate ester provided the purported structure of sclerophytin A ( 16 ). However, as expected based upon the Overman result, the spectroscopic data for this material differed significantly from that reported for the natural product. 9 Oxidation 31 and reduction of the secondary alcohol provided the C6 epimer 36 , which still did not match the data

1. LiHMDS, TMSCl; Me Me 37% HCHO, Yb(OTf) H 1. MeLi, NaBF4 H 3 H H 2. TBDPSCl, imid. TBDPSO 2. KH, BzCl O O 3. n-Bu NF O 4 3. i -PrMgCl, CuBr SMe2, 4. (n-Pr)4NRuO4, NMO H H Me TMSCl, Et3N, HMPA, H H + O (76%) OBz H3O 31 32 (25%)

TBDPSO Me TBDPSO Me 1. NaBH , CeCl , MeOH 1. i-Bu AlH H 4 3 H H 2 H 2. Im C=S 2. Hg(OCOCF ) , O 2 3 2 O O 3. Bu3SnH, AIBN O2, NaBH4, H Me (68%) H H Me (54%, 3:7 dr) H OBz Me Me OBz Me Me 33 34 TBDPSO H H 1. Ac O, pyr. H Me H Me 2 1. (n-Pr)4NRuO4, OH 2. n-Bu4NF OH NMO O O 6 O O 3. o-NO2C6H4SeCN, 2. i-Bu AlH H H 2 H H PBu3, pyr.; H H H O Me (90%) Me Me Me 2 2 Me Me 4. i-Bu AlH 35 2 16 (73%) H H Me OH O O H H H Me Me Me 36

Scheme 5. Paquette's Sclerophytin A Endgame

11 for the naturally isolated material. Additionally, tetracyle 16 was much less polar than an authentic sample of the natural compound.

Armed with the knowledge that the true structure of the natural product was not merely an epimer, the Paquette group performed extensive NMR and literature investigation and proposed a new structure for sclerophytin A (37 ).63 To access this material, in all of its C6 and C7 epimeric forms, alkene 34 was dihydroxylated using osmium tetraoxide to provide a nearly equal mixture of diastereomers (1.5:1 dr,

Scheme 6). 64,65 Oxidation 66 and cleavage of the silyl ether with fluoride gave ketone

39 . Greico elimination was next executed.62 Using one of three different reductive

conditions, each of the four possible C6, C7 diastereomers of sclerophytin A ( 37 ) were accessed. Gratifyingly, triol 37 matched the data for the natural product, serving to establish the true structure of sclerophytin A.

TBDPSO Me TBDPSO Me H OH H H H OsO 1. IBX, DMSO 4 OH O O (80%, 1:1.5 dr) 2. n-Bu4NF H H Me H Me (70%) OBz H Me Me Me Me OBz 34 38 HO Me Me OH OH H H 1. o-NO2C6H4SeCN, H PBu , pyr.; H O 3 7 6 OH H2O2 O O 2. Na, EtOH H H Me H Me OBz (49%) H Me Me Me Me OH 39 sclerophytin A (37)

Scheme 6. Paquette's Synthesis of Authentic Sclerophytin A

3. A Return to the Prins–pinacol Condensation–rearrangement

12 With knowledge of the reassignment of the structure by the Paquette group, the Overman laboratory had concurrently targeted authentic sclerophytin A ( 37 ) using an intermediate from their previous synthesis of the purported structure. 37,38,64

Hydroxyl-directed epoxidation of tricycle 15 gave 95% of the desired epoxide

(Scheme 7).67 Reductive opening of the epoxide 50 preceded cleavage of the silyl ether to give triol 40 . Finally, photochemical isomerization provided sclerophytin A

(37 ), albeit in lower yield than the previous photoisomerization (vide supra, Scheme

3). 30

Me Me Me H Me OH H H OH H H 1. VO(acac) , H OH 2 OH OH t-BuO H,C H 1. n-Bu NF, O 2 6 6 O 4 O ν H H 2. i-Bu2AlH, C6H6 H 2. h H Me H H H Me OR H Me (28%) Me Me (74%) Me Me OR Me Me OH R = TBS R = TBS sclerophytin A (37) 15 40

Scheme 7. Overman's Synthesis of Authentic Sclerophytin A

In 2003, Overman applied the Prins–pinacol condensation–rearrangement approach to the synthesis of another cladiellin, alcyonin ( 41 ).68 Protection of epoxide 20 (previously prepared in the synthesis of sclerophytin A, Scheme 2) 15,37,38

as its acetate ester and treatment with aqueous trifluoroacetic acid prompted a 6-exo

opening of the epoxide to provide diol 42 (Scheme 8). 69-71 Reduction of the ester, selective protection of the primary alcohol as a pivalate ester, and protection of the resultant diol as silyl ethers provided alkyne 43 . Following iodoboration, 30,72,73

reduction of the ester, and oxidation 31 to provide the alkenyl iodide 44 , the Nozaki–

Hiyama–Kishi protocol was used to form the oxonane 45 , again in excellent diastereoselectivity. 32,33 Fluoride-promoted cleavage of the silyl ethers and careful

13 acetylation of the C4 hydroxyl provided the proposed structure of alcyonin ( 41).

However, reminiscent of the sclerophytin A saga, the spectral data for the synthetic and natural material did not match. A C6 peroxide analog 46 was proposed by the

Overman group based upon the observed spectral data and reactivity of the synthetic and natural molecules, 74-77 but no total synthesis of this reassigned compound has been achieved to date.

Me H Me H H H 1. LiAlH4, O OH 1. Ac2O, DMAP, pyr. O OH 2. PivCl, pyr. OAc H H 2. TFA, H2O H 3. TBSOTf, 2,6-lut. H O H H OH Me Me Me (95%) Me Me Me (83%) 20 42

Me H Me H 1. B-I-9-BBN; H H NiCl2-CrCl2 AcOH; NaBO3 I OPiv O O O 2. i-Bu AlH DMSO-SMe2 OTBS 2 H 3. Dess-Martin H OTBS H H OTBS H (55%) Me periodinane H OTBS Me Me Me Me Me 43 (72%) 44

Me H Me Me H H H H H OH 1. n-Bu4NF OH 6 OOH O O O 2. Ac2O, DMAP, 4 H H OR H H OAc H Me pyr. H OAc H H Me OR H Me OH Me Me (60%) Me Me OH Me Me R = TBS 41 alcyonin (46) 45

Scheme 8. Attempted Synthesis of Alcyonin

The Overman laboratory next turned its attention to the briarellin subclass of the C2–C11 cyclized cembrane natural products. 7,78,79 Again envisioning a Prins– pinacol reaction as the key step in forming the characteristic hydroisobenzofuran portion of the molecule (Scheme 9),16 the synthesis commenced via protonolysis of

the silyl ketene acetal of lactone 47 (prepared in two steps from ( S)-(+)-carvone).80,81

Reduction of the lactone gave diol 48 , which was selectively protected as a silyl

14 ether and oxidized to the corresponding enone 49 .82 Synthesis of the enol triflate 18,83 preceded coupling with a tin reagent 19 followed by iodination to give dienyl iodide 50 .20 The lithiated diene was then treated with chiral aldehyde 51 and gave the diol 52 in 62% yield (3:1 dr) following methanolysis of the acetal. The stage was set for the key Prins–pinacol condensation–rearrangement. Treatment of diol 52

Me Me 1. LDA; TMSCl; Me AcOH OH 1. TIPSCl, imid. O Me 2. PCC, NaOAc O 2. LiAlH4 O H H (78%) (87%) 47 Me Me OH OTIPS 48 49

O MeO O Me Me Me TMS Me OH I 1. LDA; 1. t-BuLi, 51 2-(NTf2)-5-Cl-C5H3N H 2. PPTS, MeOH OH TMS 2. Pd(PPh3)4, LiCl, H (62%, 3:1 dr) (Me3Sn)2; NIS Me Me (65%) OTIPS OTIPS 50 52

1. Me Me O R H TMS Me H H 53 OTBDPS O OTBDPS 1. hυ O OH p-TsOH, MgSO4 H H 2. KOH H 2. SnCl4 H H H Me Me (55%) Me Me OTIPS (84%) OTIPS R = CHO 55 54 Me Me H H H H 1. (t-BuO)3Al, t-BuO H OAc 2 O OAc 1. TFA; H2O O OAc 2. Ac2O, DMAP, pyr. H 2. Ac O, DMAP, pyr. H H H H O 2 H OH Me (86%) Me Me (79%) Me OTIPS OTIPS 56 57

Scheme 9. Forming the Hydroisobenzofuran of the Briarellins

15 with acid in the presence of aldehyde 53 , followed by subjection of the condensed product to tin-catalyzed rearrangement conditions, provided the hydroisobenzofuran

54 in 82% yield as a single detectable diastereomer. Photolytic deformylation 24 and selective basic hydrolysis of the t-butyldiphenylsilyl and trimethylsilyl protecting

groups gave alcohol 55 . Stereoselective epoxidation 84 and protection of the primary alcohol then allowed for acetate-assisted opening of the epoxide. 69 In the event,

treatment with aqueous acid, followed by acetylation of the resultant alcohol

efficiently provided alkyne 57 .

With two of the rings of the tetracyle formed, epoxidation of the trisubstituted olefin proceeded with good stereoselectivity, and attention was turned to the formation of the oxepane of the briarellin core (Scheme 10). Cleavage of the silyl ether and formation of the primary triflate under basic conditions triggered an intramolecular etherification, forming the third ring of the tetracyclic natural product.

Next, to install the C12 carbinol, acid-catalyzed opening, followed by removal of the resultant C12 hydroxyl provided tricycle 59 . A two step procedure was next used to

install the octanoyl side chain and provide ester 60 .85 Stannylalumination–

protonolysis and a subsequent iododestannylation incorporated the vinyl iodide for

the Nozaki–Hiyama–Kishi reaction. 86 The acetate group was selectively removed using a tin reagent 87 and oxidation provided the aldehyde. 43 The cyclization again

proceeded with complete stereoselection in 79% yield to provide briarellin E ( 62 ). 32,33

Oxidation of the allylic alcohol provided the enone, briarellin F ( 63 ). 43

16 Me H H Me H 1. m-CPBA, KHCO O H 3 1. H SO ,H O OAc 2. n-Bu4NF 2 4 2 O O OAc OAc 2. MsCl, Et3N; LiAlH4 H 3. Tf2O, 2,6-lut. OAc H H OH H H Me (45%) H Me (72%) Me Me O OTIPS 58 57

Me Me H HO H H HO H 1. Bu8Sn4Cl4O2, 12 O OAc isoprenyl acetate O OAc 1. Bu3SnAlEt2, CuCN OAc H O2CC7H15 H H 2. C7H15COCl, pyr. H 2. I2 H Me H Me Me O (76%) Me O (66%) 59 60

Me Me H HO H H HO H I 1. (t-Bu)2(OH)ClSn, MeOH OH 2. Dess-Martin periodinane Dess-Martin O OAc O O CC H 3. CrCl -NiCl , DMSO-SMe H periodinane H H 2 7 15 2 2 2 H H O2CC7H15 H Me Me (79%) Me O (59%) Me O 61 briarellin E (62)

Me HO H H O O

H H O CC H H Me 2 7 15 Me O briarellin F (63)

Scheme 10. Total Syntheses of Briarellins E and F

4. [4+3] Annulation Strategy

The Molander laboratory has developed a [4+3] annulation strategy amenable to the construction of the hydroisobenzofuran of the cembranoids. 88-90 (-)-7-

Deacetoxyalcyonin acetate ( 1), previously synthesized by the Overman group, was

chosen as the initial target for their investigations. 14,15 To prepare a dialdehyde

surrogate, bis-acetal 64 was synthesized via a [2+2] cycloaddition of methoxy ketene

and α-phellandrene ( 65 ), 91,92 followed by photochemical rearrangement (Scheme

11).93,94 Treatment of this bis-acetal 64 with a bis-nucleophile 66 in the presence of

17 titanium tetrachloride effected the formal [4+3] addition in a single step, establishing five of the seven stereocenters of their target molecule. A diastereoselective methyl alkylation was followed by a Krapcho decarboxylation of the methyl ester, which also epimerized the newly-formed methyl stereocenter. 95 Since the stereochemistry of the methyl substituent was crucial for the subsequent silyl enol ether formation, the stereocenter of the minor diastereomer was epimerized to the necessary configuration under basic conditions. Formation of the silyl enol ether, 96 selenation, and selenoxide elimination delivered enone 69 .97 Conjugate addition 98,99 and in situ formation of the vinyl triflate provided aldehyde 70 following hydrolysis. 83 A Nozaki–

Hiyama–Kishi cyclization gave the cyclopentane in good yield as a mixture of

diastereomers. 32,33 After a Mitsunobu reaction that served to transform the

undesired cyclopentanol into the desired, 100 the merged material was progressed to the acetate ester 71 . The trisubstituted olefin was selectively protected as an epoxide, and the tetrasubstituted olefin cleaved under ozonolysis conditions, forming the nine-membered diketone 72 . The Sharpless tungsten reagent was used to reduce the epoxide and restore the trisubstituted olefin. 101 Finally, selective protection of the C3 ketone as the enol silane, methylenation of the C7 ketone, and subsequent hydrolysis of the silyl enol ether provided the ketone. Methylation provided (-)-7-deacetoxyalcyonin acetate ( 1)14 as a single detectable

diastereomer.102

18 TESO OMe Me Me Me OMe H H CO2Me H OTES 1. MeOC(O)Cl, Et N 3 66 OH O O 2. AcOH, hν o TiCl4, -80 C H (22%) H OAc H Me Me Me Me (43-80%) Me Me 67 65 64

1. n-BuLi, LiCl; MeI Me H Me H 2. LiCl, H2O, DMSO H H 130 oC O 1. KH, TBSCl O O O 3. NaOMe, MeOH 2. PhSeCl; m-CPBA H H Me H (72%) H (50%) Me Me Me Me 68 69

Br OEt Me Me H H H H 1. t-BuLi; CuBr-SMe2; Comins reagent 1. CrCl2, NiCl2 O OTf O OAc 2. HCl, THF 2. Ac2O, DMAP, pyr. H H H (63%) H (71%) Me Me O Me Me 70 71 O Me H Me H O H 1. WCl6, n-BuLi H 1. m-CPBA 7 OAc 2. KHMDS, TBSOTf OAc O O 2. O3; SMe2 3. Ph3PCH3Br, t-BuOK; 3 H H HCl H (43%) H H O 4. MeLi, Yb(OTf) H Me Me Me 3 Me Me OH 72 (38%) (-)-7-deacetoxyalcyonin acetate (1)

Scheme 11. Molander's Approach to the Cladiellins

5. Intramolecular Amide Enolate Alkylation

Each of the previous syntheses have targeted cembranoids containing a (Z)- olefin or lacking an endocyclic olefin within the nine-membered ring of the natural products. In 2006, the Kim laboratory reported a route to the more sensitive (E)- olefin containing cladiellins that are also ubiquitous in the isolation literature. 103 The

proposed approach would involve an intramolecular amide enolate alkylation, which

has been well-documented within their group for the efficient formation of medium

19 ring ethers. 104-106 Upon forming the oxonene via this process, an intramolecular

Diels–Alder cycloaddition analogous to that reported in a previous synthesis by the

Crimmins laboratory 107-110 would be used to form the remaining two rings of several cladiellin natural products. Their synthesis commenced with an asymmetric glycolate aldol reaction under Evans’s dibutylboron triflate conditions (Scheme

12).111-113 Reduction of the chiral auxiliary and sequential protection of the diol

provided alkene 75 . Oxidative removal of the p-methoxybenzyl ether 114 and

alkylation with an amide proceeded efficiently. Selective allylic oxidation 115 and

chlorination of the resultant alcohol 116 afforded amide 76 prepared for the key

intramolecular alkylation. In the event, treatment with lithium hexamethyldisilazide

led to formation of the desired (E)-oxonene 77 in 92% yield as a single detectable

diastereomer. 104-106

O Me

74 Me Me Me 1. DDQ O O 1. n-Bu2BOTf, Et3N 2. ClCH2CONMe2, NaH OPMB PMBO O N 2. NaBH4, THF, H2O 3. SeO2, pyr.; NaBH4, EtOH 3. TBDPSCl, imid. TBDPSO H 4. PPh3, CCl4, pyr. Bn 4. trityl bromide, H OTr (55%) 73 DMAP, pyr. 75 (58%)

Me Cl Me Me N Me Me N H Me LiHMDS O O O O (92%) TBDPSO H TBDPSO H H H OTr OTr 77 76

Scheme 12. Formation of ( E)-Oxonene

Following formation of the medium ring ether 77 , the functionalization to an appropriate Diels–Alder candidate commenced (Scheme 13). Reduction of the

20 amide to the aldehyde 117 and olefination by the Corey protocol gave an enal. 118

Methylenation and fluoride-promoted removal of the silyl ether gave alcohol 78 .

Oxidation 43 and a stabilized Wittig reaction gave the intramolecular Diels–Alder

substrate, which was treated with BHT in refluxing xylene to afford the desired

tricycle 79 as a single detectable diastereomer via an exo-cycloaddition. Alkylation of the ester and protection of the tertiary alcohol as an acetate ester set the stage for a dissolving metal reduction to deoxygenate the ester and remove the trityl protecting group. 119 Oxidation 43 and methylation provided a single diastereomer of

the tertiary alcohol in 82% yield over two steps, completing the total synthesis of (-)-

cladiella-6,11-dien-3-ol ( 81 ),35,120 which represents the first total synthesis of an (E)-

olefin containing C2–C11 cyclized cembrane natural product.

Me Me 1. i-Bu AlH/n-BuLi Me N H Me 2 Me 2. CH3CH(TMS)C=N-t-Bu, n-BuLi 1. Dess-Martin periodinane O O O 3. Ph3PCH3Br, n-BuLi 2. Ph3P=CHCO2Me H TBDPSO H 4. n-Bu4NF HO 3. BHT H H OTr OTr (62%) (67%) 77 78

Me H 1. MeLi, CeCl Me H Me 3 H H Me 2. Ac2O, DMAP, 1. Dess-Martin periodinane O Et3N O 2. MeLi, NaBF H H 3. K, 18-crown-6, H 4 H H H H t-BuNH2 H MeO O OTr Me Me OH (82%) (56%) 79 80 Me H H Me

O H H H Me Me Me OH (-)-cladiella-6,11-dien-3-ol (81)

Scheme 13. Completion of First ( E)-Olefin Containing Cladiellin

21 Seeking to further illustrate the versatility of their synthetic material, three other cembranoid natural products were targeted. Stereoselective dihydroxylation of tricycle 81 allowed access to (-)-cladiell-11-ene-3,6,7-triol (82 ) in 94% yield (Scheme

14).121 A one-pot procedure was also developed involving oxymercuration of both

olefins of (-)-cladiella-6,11-dien-3-ol (81 ) and demercuration to provide the tetracycle in 69% yield. 122 Acetylation of the resultant tertiary alcohol provided (+)-polyanthellin

A ( 83 ),78,123 marking the first total synthesis of this natural product. Finally, following protection of the tertiary alcohol of (-)-cladiella-6,11-dien-3-ol ( 81 ), stereoselective

Me Me H Me Me OH H H H OH OsO4, NMO O O H (94%) H H H H Me H Me Me Me OH Me Me OH 81 (-)-cladiell-11-ene-3,6,7-triol (82)

Me H Me Me H AcO H H Me 1. Hg(OAc)2; Et3B, NaBH4 O O O 2. Ac O, DMAP, Et N H 2 3 H H H H Me (54%) H Me Me OH Me Me Me 81 (+)-polyanthellin A (83)

Me Me H H Me Me H OH Me H 1. TESOTf, 2,6-lut H H 2. OsO , NMO OAc OAc O 4 1. Burgess salt O O H 3. Ac2O, DMAP, 2. n-Bu4NF H H H H H Me Et3N H Me (92%) H H Me Me Me OP OH OH (94%) Me Me Me Me 81 P = TES (-)-7-deacetoxyalcyonin acetate (1) 84

Scheme 14. Versatile Syntheses of Several Natural Cladiellins dihydroxylation and acetylation of the secondary alcohol gave tertiary alcohol 84 .

Dehydration using Burgess salt provided the exocyclic olefin, 124 and removal of the

22 silyl protecting group afforded (-)-7-deacetoxyalcyonin acetate ( 1), 14,15,88

representing the third total synthesis of this natural product.

6. Wittig Rearrangement/Intermolecular Diels–Alder Strategy

In 2007, the Clark laboratory reported another unique approach to cladiellin diterpenes, hinging upon a [2,3]-sigmatropic rearrangement that would be used to form the five- and nine-membered rings of the tricycle. Following bicycle formation, an intermolecular Diels–Alder was envisioned to install the cyclohexyl moiety.125

Vigulariol ( 85 ) was chosen as the initial target, a molecule possessing in vitro

126 cytotoxicity against human-lung adenocarcinoma (IC 50 = 18 nM). To begin, a

Grignard reagent 86 was added to methacrolein ( 87 ) to give a secondary alcohol

(Scheme 15). The reported synthesis of vigulariol ( 85 ) is racemic due to the use of a racemic preparation of the secondary alcohol, but could be rendered enantioselective if a stereoselective method of preparing this alcohol was employed.127 O-alkylation with ethyl propiolate gave enoate 88 .128,129 Deprotection and Swern oxidation130 gave the aldehyde. A samarium-mediated reductive cyclization delivered the tetrahydropyran 89 diastereoselectively,131 and protection of the alcohol, followed by hydrolysis of the ester provided the acid. The acid was converted to the corresponding anhydride and treated with diazomethane to give diazo ketone 90 . At this point, the copper carbenoid of diazo ketone 90 was formed and an ensuing oxonium formation and [2,3]-Wittig rearrangement occurred to deliver the oxonene 91 of the cladiellins.132,133 A 5:1 Z:E mixture of alkenes was

obtained, but the material possessing the ( E)-oxonene could be converted to the

desired material using AIBN and ethanethiol.134,135 The ketone appended to the

23 tetrahydrofuran was converted to a vinyl triflate and a Stille coupling was used to form the diene 92 .136 Intermolecular Diels–Alder cycloaddition with methyl vinyl

ketone ( 93 ) gave a 2:1 exo:endo mixture of isomers, which were equilibrated to the desired exo-adduct 94 under basic conditions.

1. BrMg OTBS 1. n-Bu4NF O O 2. (COCl) , DMSO, 86 O 2 Me Et3N Me O OEt 2. HCCO2Et, N-methylmorpholine 3. SmI2, MeOH 87 (82%) 88 (58%)

OH 1. TBSCl, imid. OTBS O O 2. LiOH, H2O Cu(CF3COCHCOCF3)2 Me Me O OEt O H H 3. i-BuO2CCl, Et3N; H H CH N (96%, 5:1 Z:E) 89 2 2 N2 (61%) 90

Me Me OTBS H OEt H O 1. PhN(OTF)2, NaHMDS Me + O O O H H 2. CH2C(OEt)SnBu3, - H H LiCl, Pd(PPh3)4 H H O OTBS (67%) OTBS 91 92

Me EtO H 1. CH2=CHC(O)Me O 2. K2CO3, MeOH H (87%) H H H Me O OTBS 94

Scheme 15. Intermolecular Diels–Alder

With the tricycle elaborated, the ketone 94 was methylenated, and the enol ether was hydrolyzed under acidic conditions (Scheme 16). Selective hydrogenation of the 1,1-disubstituted olefin was followed by methylenation of the ketone to give diene 95 . Deprotection of the silyl ether, oxidation to the ketone, 43 and addition of

24 methyl Grignard reagent efficiently provided alcohol 96 . Finally, an epoxidation with

m-CPBA delivered the epoxide, which was opened intramolecularly by the tertiary

alcohol to afford (±)-vigulariol ( 85 ). 126

Me Me EtO H H H 1. n-Bu4NF 1. Ph3PCH3Br, KO-t-Bu 2. HCl 2. Dess-Martin periodinane O O 3. MeMgCl 3. H2, PtO2 H H H H H H H 4. Ph3PCH3Br, KO-t-Bu H (75%) Me O OTBS Me Me OTBS (59%) 94 95 Me OH H H Me H H O O m-CPBA O H H H H Me (69%) H H Me Me Me Me Me OH vigulariol (85) 96

Scheme 16. Completion of (±)-Vigulariol

7. Miscellaneous Strategies

A variety of approaches leading to partial syntheses of cladiellins have been reported. Among these, some unique strategies have been elucidated adding to the methods for the synthesis of C2–C11 cyclized cembranoid natural products. Though none of the following attempts have resulted in a total synthesis, they provide valuable insight into several approaches that have shown promise in the setting of cladiellin, briarellin, and asbestinin syntheses, as well as some routes that have proven to be less amenable to these natural products.

Some of the earliest reported work involving cladiellins employed an annulation–fragmentation strategy for the formation of the five- and nine-membered rings of these cembranoids. The Hoffmann laboratory began with symmetrical ketone 97 137 and performed a diastereoselective allylation in high yield (Scheme

25 17).138 Hydrobromination provided the alkyl bromide, which was uneventfully

converted to the alkyl iodide 98 under Finkelstein conditions. A samarium-mediated

Barbier-like cyclization provided the cyclopentanol, 139 which was fragmented using cerium(IV) ammonium nitrate to provide bicycles 99 and 100 in 27% yield and 7% yield, respectively. 140 No further efforts have been reported within the past decade utilizing this strategy.

Me O Me O Me 1. LDA, allyl bromide, Me 2. HBr, hν 1. SmI2 O O O O O O 3. NaI, (CH3)2CO 2. Ce(NH4)2(NO3)6, CH CN/H O Me Me 3 2 ONO (37%) Me 2 97 I (30%) 98 99 100

Scheme 17. Annulation-Fragmentation Strategy

The Clark group reported an approach to a similar oxabicycloundecane core of the cladiellins in 2000. Their strategy featured a novel rearrangement to form the five- and nine-membered rings of these natural products. Beginning with ( R)-γ-

butyrolactone-γ-carboxylic acid ( 101 ), 141 acid-catalyzed ring opening of the lactone 142 was followed by allylation of the resultant secondary alcohol (Scheme

18).143 Hydrolysis and acetylation afforded anhydride 102 . Treatment with

diazomethane regioselectively opened the ring and formation of the rhodium

carbenoid provided furanone 103 in 50% yield. 134,135,144 A diastereoselective methylation 145 preceded acetylation and hydrolysis to give acid 104 . Again,

treatment with diazomethane followed by formation of the copper carbenoid set the

stage for a spontaneous [2,3]-Wittig rearrangement to give bicycle 105 .132,133 As the key step of the synthesis, bicycle 105 was treated with phenylselenyl chloride, which

26 triggered a rearrangement to yield oxabicycloundecane 106 in 78% yield.

Additionally, treatment of ketone 105 with phenylselenyl trifluoroacetate gave tricycle

107 , albeit in lower yield. Recently, in a separate publication, the Clark group reported that reduction of tricycle 107 , protection of the resultant secondary alcohol, and oxidative elimination o the selenide gave bicycle 108 , which represents a framework that could be used to complete a cladiellin natural product.

O O 1. n-BuOH, CSA 2. allyl bromide, Ag O O 1. CH2N2 O 2 O 3. LiOH 2. Rh2(O2CCPh3)4 OMe HO O O O 4. Ac2O O (30%) O (58%) 102 101 103 OAc Me 1. AlMe3; Et3N, MeOH AcO PhSeCl 2. Ac2O, DMAP 1. (COCl)2;CH2N2 O Me O H H 3. K2CO3, MeOH, H2O OH 2. Cu(hfacac)2 (78%) O (34%) (63%) O 104 105 SePh H Cl O Me O AcO H 106 OH H OTBS 1. NaBH , MeOH H AcO 4 PhSeO2CCF3 2. TBSOTf, 2,6-lut. O O O Me O H H OAc 3. m-CPBA (53%) PhSe 4. Ph-Me OAc O H Me H Me 105 OH 107 (29%) 108

Scheme 18. Clark's Rearrangement Approach

The McIntosh laboratory has developed two strategies for the synthesis of the hydroisobenzofuran of the C2–C11 cyclized cembranoids. The first report relied upon a cycloaldol approach to form the furan portion of these molecules. 146

27 Beginning with ( S)-carvone ( 109 ), an aldol reaction 147 with methacrolein and

Williamson etherification of the resultant alcohol provided ester 110 (Scheme

19). 82,148 An intramolecular aldol reaction delivered bicycle 111 in 87% yield.

Oxidation gave the enone, 149 which was converted to the tosylhydrazone 112 .

Reduction with catecholborane and heating the reaction gave the cis -fused isobenzofuran 113 .150-152 A similar route was also developed to access natural

products containing oxygenation at C13.107,108,120,153 To this end, ester 111 was

reduced to the primary alcohol, protected as a silyl ether, and allylic oxidization

afforded the enone 114 (Scheme 20). Rubottom oxidation 154 gave predominantly

the undesired configuration of the C13 alcohol 115 (7:1 dr), and formation of the tosylhydrazone proceeded smoothly. Reduction with catecholborane again and in situ allylic diazene rearrangement gave the trisubstituted olefin 116 ,150-152 and a

Mitsunobu reaction gave the correct C13 configuration for bicycle 117 .100 No further

efforts utilizing this route have been reported since 2003.

O EtO C O O CO2Et 2 Me 1. LDA, CH2CH(CH3)CHO, H O AcOH Me KHMDS H Me Me Me (87%) OH 2. Ag2O, BrCH2CO2Et, Me 2,6-lut. Me 109 (68%) Me 110 111 TsHN Me Me CO2Et H CO2Et N 1. PCC, silica gel catecholborane, O O 2. TsNHNH NaOAc 2 H H Me (81%) Me (75%) Me Me 112 113

Scheme 19. Cycloaldol Route to the Isobenzofuran

28 EtO2C Me O OTIPS H O Me 1. LiAlH4 1. KHMDS, TMSCl O OH Me 2. TIPSOTf, 2,6-lut. 2. m-CPBA, NaHCO3 H 3. PCC, celite Me (75%) Me (70%) Me 111 114

Me OTIPS Me OTIPS H 1. DIAD, PPh , O 3 1. TsNHNH2, AcOH p-NO2C6H4CO2H O O 2. catecholborane, HO HO 2. LiAlH4 H NaOAc H Me Me (75%) Me (70%) Me 115 116

Me OTIPS H

O HO H Me Me 117

Scheme 20. C13 Oxidized Isobenzofuran

The second route recently reported by the McIntosh group involves an

Ireland–Claisen rearrangement (Scheme 21). The approach commenced with ester

118 (available in three steps from ( S)-carvone). 155,156 Treatment with base in the presence of triisopropylsilyl triflate triggered the rearrangement to give acid 119 following deprotection. 157 Lactonization 158 set the stage for installation of an additional oxygen substituent via S N2’ addition of an alkoxy methyl copper nucleophile 159 and formation of the methyl ester 120 . Selective hydrogenation and cleavage of the methoxymethyl ether gave alcohol 121 . A Swern oxidation 130 and a

Horner–Wadsworth–Emmons reaction provided sulfone 122 . Dihydroxylation 160 and oxidation 130 gave ketone 123 . Allylic alcohol transposition 161,162 preceded formation of the tetrahydrofuran 124 via subjection to alkaline conditions. Formation of the

29 tosylhydrazone and reduction triggered an allylic diazene rearrangement once again to give bicycle 125 ,150-152 characteristic of the cladiellin subclass.

O OBn Me Me O HO OBn 1. Ag2O 1. KHMDS, TIPSOTf 2. Bu3SnCH2OMOM, O Me Cl n-BuLi, CuCn, ZnBr , 2. HF, CH3CN Me Cl 2 LiCl Me (83%) Me 3. CH2N2 (80%, 8:1 dr) 118 119

O O Me Me MeO OBn MeO OBn 1. Rh(PPh ) Cl, 1. (COCl) , DMSO, OMOM 3 3 2 H2 OH Et3N Me Me 2. i-PrOH, HCl 2. (EtO)2P(O)CH(SO2Ph)CH3, Me (89%) Me KHMDS, 18-crown-6 (65%) Me 120 121

O O Me Me MeO OBn MeO OBn 1. OsO4, (DHQ)2pyr, SO Ph K3Fe(CN)6,K2CO3, SO Ph 2 CH SO NH Me 2 1. MeReO3 Me 3 2 2 HO Me 2. (COCl) , DMSO, Et N Me 2. K2CO3, MeOH Me 2 3 Me (55%) O (90%) Me Me 122 123

Me H Me Me H Me O OBn OBn 1. NH2NHTs O CO2Me O CO2Me SO2Ph 2. catecholborane, SO2Ph H NaOAc H Me Me Me Me Me Me (77%) 124 125

Scheme 21. Rearrangement Approach to the Cladiellins

In 2003, the Jung group reported efforts toward the initially reported structure of sclerophytin A ( 16 ). 9,34,35,163 Formation of the silyl enol ether of ketone 126 using a chiral base 164 and subsequent alkylation gave bicycle 127 (Scheme 22). 165 A

30 second alkylation using a palladium mediated coupling gave alkene 128 in 83% yield. 166,167 Hydroboration and oxidation of the terminal olefin 168 preceded protection

of the resultant alcohol as an ester functionality. A Baeyer–Villiger oxidation

provided the lactone, 169 from which the ester was removed 170 and the alcohol was

protected as a silyl ether to give bicycle 130 . A Tebbe olefination proceeded in good

yield, 59 however, the trisbustituted olefin 131 was isolated rather than the desired

exocyclic olefin. The original synthetic plan involved a [3+2] cycloaddition reaction,

but the inability to access the exocyclic olefin in good yield precluded this prospect,

so the group redirected their strategy taking advantage of the alkene 131 .

Hydrolysis of the enol ether provided the ketone, and the diol was bis-protected as

silyl ethers. Selective removal of the primary silyl ether gave ketone 132 . Oxidation

of the primary alcohol to the aldehyde 31 provided a substrate that was proposed to be suitable for a pinacol coupling. 171 However, no productive reaction could be

achieved with the dicarbonyl. In an attempt to overcome this inactivity and form the

nine-membered ring, methylenation of both carbonyls gave a diene 133 that was

treated to the Grubbs second generation catalyst to attempt a ring-closing

metathesis, 172 but again this was met with no success. Frustrated by the numerous

roadblocks, this program was abandoned.

31 Ph Ph

Me N Me 1. Li 1. KH; BEt 1. Cy2BH; NaBO3 O TMSCl 3 O O O O O 2. (ClCH CO) O, 2. MeLi; MeI 2. Pd(PPh3)4, 2 2 DMAP, Et N 126 Me allyl chloride Me 3 (72%) 127 (86%) (83%) 128

O O O 1. m-CPBA, NaHCO3 Cp2TiCH2ClAlMe2 O O O Cl 2. N H -CS OTBS (97%) Me 2 4 2 O 2. TBSCl, DMAP, Et3N Me 129 (62%) 130

Me Me O 1. PPTS, H2O O 1. n-Pr4NRuO4, NMO O O OTBS 2. TMSCl, DMAP, TMSO 2. Ph3PCH3Br, n-BuLi Me Et3N Me 3. PPTS, MeOH OH (74%) 131 (72%) 132

Me O

TMSO Me 133

Scheme 22. Fragmentation Approach to the Furan

As alluded to earlier, the Holmes laboratory reported a route to cladiellin natural products that employed an intramolecular Diels–Alder cycloaddition (Scheme

23).110 Their efforts were published shortly after the Crimmins laboratory divulged

their synthesis of ophirin B. 107 The Holmes group has developed a Claisen rearrangement for accessing medium ring lactones. 173,174 Their synthesis commenced with the acid-catalyzed glycosidation of 2-deoxy-D-ribose ( 134 ), 175

followed by protection of the diol as silyl ethers. The acetal was demethylated 176,177

and treatment with a Grignard reagent gave diol 135 . Formation of the dioxepane 178

preceded oxidation of the selenide, which triggered a Claisen rearrangement to give

32 lactone 136 .179 With an efficient route to lactone 136 , attention was turned toward

preparing an appropriate Diels–Alder candidate. Methylenation 180 and selenation

gave selenide 137 . Oxidation of selenide 137 , Pummerer rearrangement, and loss

of methoxide gave aldehyde 138 as a single diastereomer.181 A stabilized Wittig reaction gave the enal, and methylenation delivered triene 139 . Selective removal of the primary protecting group and oxidation gave the aldehyde, 31 which upon treatment with a stabilized Wittig reagent 182 formed the enone and spontaneously

cyclized. Upon deprotection, tricycles 140 and 141 were isolated. However, the

endo-adduct 140 was the major product of this cyclization (3:1 dr). This reversal of

OTBDPS O OH 1. HCl, MeOH 1. PhSeCH2CH(OEt)2, PPTS 2. TBDPSCl, pyr. 2. NaIO4, NaHCO3

HO OTBDPS 3. DBU 3. BCl3 DMS OH HO OH 4. CH =CHMgBr 2 135 (84%) 134 (70%)

1. Cp TiMe 2 1. m-CPBA, NaOAc, Ac2O OTBDPS OTBDPS 2. PhSeCl; 2. MeOH, K CO O PhSe O OTBDPS 2 3 O OTBDPS LiAlH4 (88%) 136 (44%) 137

O OMe H 1. HF-pyr 1. Ph3P=CH(Me)CHO H O 2. n-Pr4NRuO4,NMO TBDPSO O 2. Ph PCH Br, n-BuLi 3 3 TBDPSO 3. Ph P=CHC(O)Me H 3 (62%) 4. HF, CH3CN H OTBDPS H H OTBDPS 138 (53%, 3:1 dr) 139 Me H Me H H H

O O

3 H H H H H OH H OH Me O H Me O H 140 141

Scheme 23. Cycloaddition Approach of Holmes

33 selectivity from the cladiellin and asbestinin syntheses from the Crimmins laboratory demonstrates the crucial nature of the C3 configuration and protecting group. 107-109

When the opposite configuration at C3 is employed, the endo-adduct is the dominant

product, whereas the exo-adduct is favored when using the C3 epimer. The

undesired result of the Diels–Alder cycloaddition brought an untimely end to this

project.

Me Me H H CO2Me 1. n-BuLi, LiCl, H H CH2=CHCH2I O OH 2. LiCl, DMSO O O 1. Cy2BH; NaBO3

H 3. NaOMe, MeOH H 2. Cl3CCOCCl3, H H PPh Me Me (70%, 1:3 dr) Me Me 3 (75%) 67 142 Me H Me H AcO H H 1. NBS, H2O O 2. Bu3SnH, AIBN SmI2, HMPA O O O 3. Ac2O, DMAP, (88%) H H H Et3N H Me Me 4. NaI, Acetone Me Me (40%) 143 144 Cl I Me H O AcO H 1. Ph3PCH3Br, t-BuOK OH Me H 1. Burgess reagent AcO H 2. MeLi, Yb(OTf)3 O 3. Hg(OCOCF3)2; NaBH4 2. O3; SMe2 O H H H (37%) (74%) H Me Me H H O 145 Me Me 146 Me H AcO H Me

O 7 O H 3 H H Me Me Me 147

Scheme 24. Samarium-mediated Cyclization to Polyanthellin A Diastereomer

Finally, the Molander group has reported a second route to the cladiellins that extends the [4+3] annulation strategy discussed earlier (Scheme 11). 88-90 Using tricycle 67 from their earlier synthesis (vide supra), an alkylation and Krapcho

34 decarboxylation gave the ketone 142 as a mixture of epimers (3:1 dr), 95 which could

be epimerized to the desired configuration under basic conditions (Scheme 24).

Selective hydroboration and oxidation of the terminal olefin 168 was followed by

chorination to give alkyl chloride 143 .183 A three step sequence installed the tertiary

acetate, 184-187 and the alkyl chloride was transformed into alkyl iodide 144 .188 At this point, a key samarium iodide-mediated cyclization provided tetracycle 145 .189

Dehydration 124 and ozonolysis gave the cladiellin skeleton 146 . Chemoselective methylenation was followed by alkylation. 102 At this point, oxymercuration and reduction 190 gave the 3,7-epimer of polyanthellin A 147 .78

C. Medium Ring Ether Synthesis via Ring-closing Metathesis

1. Catalyst Development

The olefin metathesis reaction is recognized as an efficient method for the

construction of carbon–carbon bonds. Early efforts in this field utilized poorly

defined catalyst systems that were difficult to employ and featured a narrow

substrate scope due to functional group compatibility issues. 191 However, in 1990,

the Schrock laboratory divulged a highly efficient catalyst system using molybdenum

alkylidene complex 148 , which showed broader functional group than its predecessors (Figure 4). 192,193 As a result, this catalyst became widely-used among

synthetic chemists for the formation of olefins, including medium ring ethers.

However, the catalyst is not ideal due to its oxophilicity, rendering it highly air and

moisture sensitive, as well as the difficulty in synthesizing the active catalyst.

35 Despite these drawbacks, the efforts of Schrock represent a major step forward in the history of olefin metathesis.

i-Pr i-Pr PCy3 F C N Me Cl PCy 3 O Me Ru Ph Cl 3 Mes N N Mes F3C Mo Cl Ru Ph PCy Cl Me O 3 Cl Ph Ru Ph PCy3 F C Cl Ph 3 PCy3 F3C Me

148 149 150 151

Figure 4. Olefin Metathesis Catalysts

Concurrently, the Grubbs laboratory focused efforts toward ruthenium-based alkylidene complexes they hoped to apply to olefin metathesis reactions. 194,195

Notably, catalysts 149 and 150 showed similarly high reactivity when compared to

the Schrock system (Figure 4). Additionally, these catalysts demonstrated high

thermal stability and broad functional group tolerance. Further, the ruthenium-based

catalysts 149 and 150 showed lower air and moisture sensitivity than the Schrock

systems. With the advent of a new catalyst species, featuring a 4,5-dihydroimidazol-

2-ylidene ligand and coined the Grubbs second generation catalyst (151 ), the scope of potential products grew dramatically as the reactivity of the catalyst increased. 172

Di-, tri-, and tetrasubstituted olefins could efficiently be formed using catalyst 151 .

Within the past decade, other novel ruthenium-based catalysts have been developed that have found great success in the ring-closing, ring-opening, and cross metathesis reactions. 196,197

Early reports documented efficient formation of five-, six-, and seven-

membered rings using the ruthenium-based catalyst systems, while the formation of

36 eight- and nine-membered rings remained more elusive due to unfavorable transannular interactions and entropic difficulties. To combat these challenges encountered in medium ring synthesis, extra rigidifying elements, such as cyclic constraints, have been employed successfully. 198-200 Grubbs demonstrated that

such cyclic constraints greatly improve the efficiency of the formation of medium

rings, due to the decreased rotational freedom of these dienes (Table 1). 201

However, the employment of these synthetic tactics greatly minimizes the utility of

this reaction since the cyclic constraints are often not desired in the target molecule.

In 1995, Grubbs reported the successful ring-closing metathesis of an eight-

membered dipeptide lacking a cyclic constraint (Scheme 25). 201 The following year, the Hoveyda laboratory divulged the ring-closing metathesis of an even more simplified medium ring. 202 The success of these reactions is credited to the steric

TESO TESO PCy 33% Cl 3 Ru Ph Cl H H PCy3 Ph TESO TESO 149 75%

H H

H H O O 60%

O H O H

H O H O 20% O H H O

Table 1. Cyclic Constraints for Ring-closing Metathesis

37 and electronic requirements of the substituents on the respective dienes producing a rotamer that places the dienes in close proximity, favoring ring-closing metathesis.

At the time, these served as very rare, but promising, examples of eight-membered ring formation via these processes.

O 10 mol % 149, O NN NN MeO Boc MeO Boc o C6H6, 60 C O Me O Me 51%

2 mol % 149,

o CH2Cl2, 45 C N N 68% Ts Ts

Scheme 25. Early Ring-closing Metathesis Lacking Cyclic Constraint

2. Aldol/Ring-closing Metathesis in the Crimmins Laboratory

Around the same time that olefin metathesis was becoming more practical for target-directed synthesis, the Crimmins laboratory was developing auxiliary-based methodology for the synthesis of subunits of polyketide-containing natural products.

Seeking to apply these reactions to the synthesis of medium ring ethers, efforts focused on the development of two distinct approaches to these cyclic units, namely a glycolate aldol or glycolate alkylation reaction, followed by ring-closing metathesis using the Grubbs catalysts. This approach was predicated on the expected gauche effect present in dienes derived from aldol adducts (Figure 5). 203 As demonstrated,

the stabilizing interaction involving donation of the C-H σ orbital into the C-O

σ* ο rbital places the two olefins in a favorable conformation for ring-closing

metathesis to occur. Alternatively, the dipole minimized conformation also leads to a

38 more favorable orientation for ring-closing metathesis. These acyclic conformational constraints were proposed to deliver medium ring ethers efficiently.

OR OR

O O OR OR

OR H O O O OR OR OR HOR H RO H H H

Olefin chains gauche Olefin chains gauche Olefin chains anti

Figure 5. Acyclic Conformational Constraint via Gauche Effect

To synthesize the desired dienes, glycolate aldol reactions were utilized, allowing access to a variety of ring sizes by varying the chain length of the respective glycolate or aldehyde (Figure 6). Initially, the conditions developed by

Evans using dibutylborontriflate for enolization were exploited in the asymmetric aldol additions. 111 Eventually, the Crimmins laboratory developed more cost efficient

conditions using titanium tetrachloride, diisopropylethylamine, and later N-methyl pyrrolidinone for these additions, which proved to be applicable to a plethora of simple and complex oxazolidinone and oxazolidinethione glycolates to deliver the corresponding Evans-syn adducts in good yield and excellent diastereoselectivity. 204

X O O OR OR O y x OR O N z OR y O O Bn z y

X = S, O y = 0, 1, 2 z = 0, 1, 2

Figure 6. Aldol/Ring-Closing Metathesis Strategy

39 A systematic study examining the formation of six-, seven-, eight-, and nine- membered rings via ring-closing metathesis reactions of various aldol adducts was undertaken. 205 A variety of dienes accessible via Evans-syn glycolate aldol reactions were prepared and treated to Grubbs catalyst 150 in refluxing methylene chloride (Table 2). The results confirmed the hypothesis that the gauche effect present within these 1,2-dioxygenated compounds was sufficient to orient the olefins proximally and allow for small and medium ring ether formation. The desired unsaturated products were formed in less than two hours and were isolated in 73-

95% yields.

Table 2. Small and Medium Ring Ether Formation

OBz OBz OAc OAc

OBz OBz OAc OAc O O O O 90%, 1 h 94%, 30 min OAc OAc OAc OAc

OAc OAc O O O OAc O OAc 95%, 2 h 89%, 1 h

OAc OAc

OAc OAc O O

73%, 2 h

These findings concerning the glycolate aldol addition and the ring-closing metathesis reaction have been applied repeatedly in the setting of natural product synthesis in the Crimmins laboratory. The improved syn glycolate aldol conditions were applied to form two small rings in the total synthesis of gigantecin ( 152 ,

Scheme 26). 206 The chlorotitanium enolate of complex glycolate 153 reacted with

40 ynal 154 to provide the desired Evans-syn adduct 155 in 93% yield (>19:1 dr).

Standard transformations prepared a diene 156 that served as a ring-closing metathesis candidate. Upon subjecting the diene 156 to the Grubbs second

generation catalyst 151 in refluxing methylene chloride, the furan 157 was formed in

nearly quantitative yield. Further manipulations afforded gigantecin ( 152 ).

O O TiCl4, i-Pr2NEt, O O OH O NMP, CH2Cl2, O N OBn O N H -78 oC to -40 oC O H TIPS Bn Bn TIPS OBn 153 O 154 155 93%, >19:1 dr

Mes N N Mes Cl Ru Cl Ph PCy3 MOMO MOMO H H H H O 151 O OBn OBn o TIPS CH2Cl2, 40 C TIPS 99% 157 156

OH O O n-C12H25 O O OH OH OH Me gigantecin (152)

Scheme 26. Total Synthesis of Gigantecin

In 2000, the Crimmins laboratory applied this aldol/metathesis approach to the synthesis of a medium ring ether natural product, prelaureatin ( 158 , Scheme

27). 207 The use of titanium tetrachloride and diisopropylethylamine to form the

corresponding enolate of glycolate 159 , followed by addition of 3-butenal ( 160 ), led

to the desired aldol adduct 161 in good yield and good diastereoselectivity.

41 Protection of the secondary alcohol and treatment with catalyst 151 provided the

oxocene 162 in 95% yield, which was carried on to prelaureatin ( 158 ). The

aforementioned total syntheses represent a fraction of the natural products prepared

in the Crimmins laboratory via the aldol/ring-closing metathesis strategy.

O O O O OH TiCl4, i-Pr2NEt, O NMP, CH Cl , OTBS O N OBn 2 2 O N H O o o O H -78 C to -40 C O H O Bn Bn H N 3-butenal (160) OBn BnO 159 65%, 8:1 dr Bn O

162 161

OTBS OH

151 O O O H O H o H N H CH2Cl2, 40 C BnO Br 95% Bn O Me 163 prelaureatin (158)

Scheme 27. Prelaureatin Total Synthesis

3. Alkylation/Ring-closing Metathesis in the Crimmins Laboratory

The Crimmins laboratory has also developed a useful extension to the Evans asymmetric alkylation which involves the formation of the sodium enolate of oxazolidinone glycolates and addition to a variety of electrophiles. 208 Most often,

allylic iodides serve as electrophiles in the reaction, but other halides, such as

propargylic bromides and benzyl iodomethyl ether have also been shown to deliver

useful handles for natural product total synthesis. Silyl, benzyl, allyl, and alkyl

protected glycolates perform well under these conditions providing the desired

alkylation adducts in good yield and high diastereoselection. This alkylation strategy

42 has also been utilized to arrive at dienes useful for ring-closing metathesis to give small and medium ring ethers.

In 2003, the Crimmins laboratory divulged the total synthesis of rogioloxepane

A ( 164 ) using the glycolate alkylation and ring-closing metathesis reactions as key steps (Scheme 28). 209 Alkylation of glycolate 165 with allyl iodide provided diene

166 in 86% yield as a single detectable diastereomer. Using Grubbs catalyst 150 ,

diene 166 underwent facile ring-closing metathesis to give the corresponding oxepene 167 in high yield. A series of manipulations provided rogioloxepane A

(164 ).

PCy Cl 3 Ru Cl Ph Na(SiMe3)2, PCy3 O O OBn O O OBn H CH2=CHCH2I, H H O Me O Me 150 O N O N o o o THF, -78 C to -40 C CH2Cl2, 40 C i-Pr 86% i-Pr 95%

165 166

O O OBn H H Cl Br O Me H H O N O Me

i-Pr

167 rogioloxepane A (164)

Scheme 28. Total Synthesis of Rogioloxepane A

Crimmins and co-workers have also employed the alkylation/ring-closing metathesis strategy in the total synthesis of a medium ring ether-containing natural product, isolaurallene ( 168 , Scheme 29).210 The sodium enolate of complex

oxazolidinone glycolate 169 was alkylated with allylic iodide 170 to give diene 171 .

Several steps gave ring-closing metathesis candidate 172 , which was treated with

43 Grubbs catalyst 150 to efficiently deliver oxonene 173 . Medium ring ether 173 was carried on to isolaurallene ( 168 ).

Na(SiMe3)2, I BnO O O O BnO O BnO H H O 170 O O N O N H Me THF, -78 oC to -40 oC H H Me Bn 75% Bn

169 OBn 171

HO O HO O H H H H O Me 150 O Me

AcO OTES o AcO OTES CH2Cl2, 40 C 94%

173 172 Br H C H H O Me H O Br

isolaurallene (168)

Scheme 29. Isolaurallene Total Synthesis

4. Total Syntheses of Eunicellin Diterpenes via Alkylation/Ring-closing

Metathesis in the Crimmins Laboratory

As detailed, the Crimmins laboratory has extensively demonstrated the ability to form medium ring ethers 209,211-214 via the ring-closing metathesis reaction 172,195 of

dienes generated by glycolate alkylation 208 and glycolate aldol reactions. 204,213,215,216

As an extension of these methods, a novel strategy was envisioned for the

cembranoid natural products involving initial formation of the oxonene ring prior to

the hydroisobenzofuran moiety. This would represent the first total synthesis at the

44 time to form the nine-membered ring prior to formation of either of the other two rings. The synthesis of these final two rings hinged upon an intramolecular Diels–

Alder approach that would form the tricycle while concomitantly establishing the C1,

C10, C13, and C14 stereocenters. Ophirin B ( 174 )120 was first targeted, representing the first C13, C18 oxygenated cladiellin to be prepared via total synthesis. 107,108 The synthesis commenced with the methylenation of ( S)-

benzylglycidyl ether ( 175 )217 followed by proection as a p-methoxybenzyl ether

(Scheme 30). Wacker oxidation provided ketone 176 in 80% yield over three steps. 218,219 Chelation-controlled stereoselective alkylation and protection of the

1. CH =CHCH MgBr 1. Me3SI, n-BuLi 2 2 H 2. NaH, PMBCl 2. NaH, BnBr O H OPMB OBn BnO Me 3. HCl, MeOH 3. Hg(OAc)2,H2O; PdCl , LiCl, CuCl , 175 2 2 O (75%) H O, O 2 2 176 (80%)

H OH O O Me 1. NaH, BrCH2CO2H OBn BnO O O N 2. Me3COCl, Et3N; H OBn (S)-lithio-4-isopropyl- H 177 oxazolidinin-2-one i-Pr OBn (88%) 178

OH 1. NaHMDS, CH =C(CH )CH I 2 3 2 Me 2. LiBH , MeOH 4 H O 3. Cl2(Cy3P)2Ru=CHPh BnO (74%) H BnO Me 179

Scheme 30. Ophirin B Oxonene Formation resultant alcohol as a benzyl ether preceded deprotection of the secondary alcohol under acidic conditions. Standard formation of the corresponding glycolic acid and glycolate provided imide 178 , prepared for a glylcolate alkylation. The sodium

45 enolate of imide 178 was alkylated with methyallyl iodide in 93% yield to provide a single detectable diastereomer of the diene. 208 Reduction of the chiral auxiliary and

ring-closing metathesis efficiently provided the oxonene 179 .172

With the nine-membered ring 179 in hand, careful ordering was necessary for

the installation of the diene and dienophile for the key Diels–Alder cycloaddition. To

this end, an oxidation 43 and stabilized Wittig reaction provided the enoate, which was reduced to the allylic alcohol and protected as a tetrahydropyranyl ether to provide oxonene 180 (Scheme 31). Dissolving metal reduction of the benzyl ethers provided the diol, and the primary alcohol was oxidized 43 and treated with a stabilized Wittig reagent to give the enoate, which would be employed as the dienophile in the pending Diels–Alder reaction. The tertiary alcohol was protected as a triethylsilyl ether. The pyran was then removed under acidic conditions and the resultant alcohol was oxidized to the aldehyde. 31 Treatment with benzyloxymethyl- enetriphenylphosphorane gave tetraene 181 as a 3:1 mixture of E:Z isomers. Under ambient conditions, tetraene 182 underwent a spontaneous, highly exo-selective

Diels–Alder cycloaddition. The minor isomer from the Wittig reaction could be

photochemically recycled to the reactive tetraene 182 , providing an overall 78% yield

of tricycle 183 .220 The observed stereochemistry from the cycloaddition can be rationalized using transition states 182a and 182b, which demonstrate the

importance of the C3 protecting group (Figure 7). Namely, the bulk at C3 has a

significant steric interaction with the C14 proton and carbon in the endo case which

is mitigated for the exo transition state. This hypothesis has been corroborated by

varying the size of the C3 protecting group and observing the diastereoselectivity of

46 OH THPO Me Me 1. Dess-Martin periodinane H Me 2. Ph3P=C(Me)CO2Et O H BnO 3. i-Bu AlH O 2 BnO H 4. DHP, PPTS Me BnO (91%) H 179 BnO Me 180

THPO Me 1. Na, NH3 1. TESOTf, 2,6-lut. 2. Dess-Martin periodinane Me 2. PPTS, MeOH H 3. Ph3P=CHCO2Me O O 3. Dess-Martin periodinane 4. Ph3PCH2OBnCl, t-BuOK (83%) MeO H HO Me (75%) 181 BnO Me Me Me H H Me H O O 14 O BnO H H H Me 3 OTES MeO H O OMe TESO Me 183 182

Scheme 31. Intramolecular Diels–Alder Cycloaddition

OBn OBn

MeO O O OMe H H 14 Me H Me H H H H OR H OR O O 3 H Me H Me Me Me 182a 182b

exo endo

Me Me Me Me H H H H

O O BnO H BnO H H H Me H H Me O OMe OR O OMe OR

Figure 7. Diels–Alder Transition States

47 the cycloaddition. Additionally, the work of Holmes using C3 epimers (vide supra,

Scheme 23) supports these selectivity models. 110

With the tricyclic core formed, alkylation of ester 183 delivered the tertiary alcohol (Scheme 32). A careful acetylation sequence was required to preclude formation of tetracycle 184 . Removal of the silyl ether provided the diol, and the C18 hydroxyl was selectively acetylated under basic conditions. 44 The C3 hydroxyl was

then converted to its acetate ester 185 in the presence of a Lewis acid. 87,221 Finally,

cleavage of the benzyl ether, and acetylation under basic conditions provided ophirin

B ( 174 ), which possessed identical spectroscopic properties in all respects to the

natural material.

Me Me Me Me H H H H 1. MeMgCl 2. KHMDS, Ac O O 2 O BnO 3. Bi(OTf) , Ac O BnO H 3 2 H H Me H H Me H O OMe OTES (58%) Me Me OAc OAc 183 185

Me Me H Me H Me H O H 1. H2, Pd/C 10 13 1 O 14 Me O 2. Ac2O, DMAP, pyr. AcO 18 H H Me Me H H Me (69%) Me Me OAc H H OAc OH 184 ophirin B (174)

Scheme 32. Completion of Ophirin B

During the course of the synthesis of ophirin B ( 174 ), 107,108 the Crimmins group pursued the synthesis of a biologically active cadiellin, astrogorgin ( 186 ). 120,153

Identical to ophirin B ( 174 ), except for an additional oxygenated stereocenter at C6,

it was believed that astrogorgin ( 186 ) could be constructed utilizing a different

48 electrophile for the glyclolate alkylation reaction. 208 This electrophile would possess a latent synthetic handle that could be used to install the C6 stereocenter following construction of the tetracyle (Scheme 33). Alkylation, reduction and ring-closing metathesis each proceeded in greater than 90% yield to provided oxonene 188

(Scheme 33).172 An identical sequence was utilized to install the diene and

dienophile as was applied in the ophirin B ( 174 ) synthesis, 107,108 and the key

TIPSO OH I OTIPS O O Me 1. NaHMDS, H OBn 2. LiBH , MeOH O 4 187 O O N BnO H 3. Cl2(Cy3P)2Ru=CHPh H i-Pr OBn (78%) BnO Me 178 188 TESO Me 1. Na, NH 1. Dess-Martin periodinane OTIPS 3 2. Ph3P=C(Me)CO2Et H 2. TPAP, NMO O 3. i-Bu2AlH BnO 3. Ph3P=CHCO2Me 4. TESOTf, 2,6-lut. H (60%) (84%) BnO Me 189 BnO TESO Me Me 1. TESOTf, 2,6-lut. OTIPS 2. PPTS, MeOH OTIPS H H O O 3. Dess-Martin periodinane O O 4. Ph P+CH OBnCl, t-BuOK i-Pr-O 3 2 H i-Pr-O H HO Me (67%) TESO Me 190 191

OTIPS Me H H

O BnO H H H Me i-Pr-O O OTES 192

Scheme 33. Synthetic Approach to Astrogorgin

49 intramolecular Diels–Alder cycloaddition again proceeded under ambient conditions to provide tricycle 192 as a single diastereomer.

Upon completion of the tricycle 192 , methylation and acetylation of the C18 tertiary alcohol proceeded uneventfully, followed by careful hydrogenation of the benzyl ether (Scheme 34). Acetylation and deprotection of the allylic triisopropylsilyl protecting group provided an alcohol that was utilized in an allylic transposition to provide the epimeric C6 hydroxyl for astrogorgin ( 186 ). 222,223 An oxidation 23 and

Luche reduction 49 delivered the desired C6 alcohol stereoselectively. Esterification,

deprotection, and installation of the fourth and final acetate group was accomplished

to provide astrogorgin ( 186 ), which was identical in all regards to the naturally isolated material.120,153

OTIPS OTIPS Me Me H H 1 . MeMgCl H H 2. NaHMDS, Ac2O O O BnO 3. H2, Pd/C HO H H Me H H Me H (89%) H i-Pr-O O OTES Me Me OTES OAc 192 193

Me H 1. Ac2O, DMAP, Et3N H 1. TPAP, NMO 2. n-Bu4NF OH 2. NaBH4, CeCl3, MeOH O 3. o-NO2C6H4SeCN, n-Bu3P AcO 3. Ac2O, DMAP, pyr. 4. H2O2,C5H5N H H Me H (82%) (86%) Me Me OTES OAc 194

Me Me H H H H OAc 6 OAc 1. n-Bu4NF 10 O 13 1 O 14 2. Bi(OTf) , Ac O 3 AcO 3 2 AcO H H H Me H Me H (21%) H Me Me OTES Me Me OAc OAc OAc 195 astrogorgin (186)

Scheme 34. Total Synthesis of Astrogorgin

50 D. Total Syntheses of 11-Acetoxy-4-deoxyasbestinin D and Asbestinin-12

1. Background

The asbestinins represent the farthest evolved subclass from the original cembrane skeleton of the C2–C11 cyclized cembranoids (Figure 1). The first asbestinin was discovered and its structure elucidated in 1980. 2 For 25 years, no total synthesis of any member of this subclass had been reported. A diverse array of structures have been found within the asbestinins, which differ from the cladiellins and briarellins in that C12, C13, and C15 are never oxygenated and there is never a lactone moiety at C16. 1 This subclass features a range of biological activity, including antimicrobial, acetylcholine antagonism, and antitumor properties. Though an X-ray diffraction study of asbestinin-1 confirmed the relative stereochemistry of this subclass, some discrepancy exists in the literature regarding the absolute configuration of this family of natural products. 1,2 The biosynthetic hypothesis would suggest that the stereochemistry would correlate to that of the cladiellins and briarellins, but the isolation literature consistently portrays the enantiomer as the natural configuration.

Me Me AcO AcO H H H H Me 9 Me 9 11 11 12 10 12 10 1 O 1 O 14 2 14 2 3 3 H H H H OAc 15 H Me 15 H Me Me O Me O H H 11-acetoxy-4-deoxyasbestinin D (196) asbestinin-12 (197)

Figure 8. Targeted Asbestinins

51 11-Acetoxy-4-deoxyasbestinin D ( 196 ) was isolated in 1990 by Rodríguez and co-workers from Briareum asbestinum off the coast of Puerto Rico (Figure 8). 11

The title compound represented 0.072% of the dry weight of the isolated sponge.

The natural product features a fascinating molecular structure, with nine contiguous

stereocenters and a fully-substituted tetrahydrofuran. Further, 11-Acetoxy-4-

deoxyasbestinin D ( 196 ) demonstrates strong antimicrobial activity against Klebsiella

pneumoniae and cytotoxicity against CHO–K1 cells (ED 50 = 4.82 µg/mL). A related

member of this subclass, asbestinin-12 ( 197 ), features a similar structure with an

additional stereocenter at C4,224 which is more ubiquitious within the asbestinins.

The sum of the biological benefits and structural intrigue, as well as the lack of a

total synthesis of any member of this subclass piqued our interest in these two

natural products. We set out to apply a strategy similar to that employed in the

cladiellin syntheses in our laboratory, 107,108 this time targeting members of the

asbestinin subclass, in hopes of verifying the viability of our plan and confirming the

absolute configuration of the asbestinins.

2. Retrosynthetic Analysis

Strategically, ketone 198 was targeted as a point of divergence for the

syntheses of 11-acetoxy-4-deoxyasbestinin D ( 196 ) and asbestinin-12 ( 197 )

(Scheme 35). The desire to apply the previously developed Diels–Alder strategy

used for the cladiellins to complete the first total synthesis of a member of the

asbestinin subclass of natural products resulted in selection of tetraene 199 as the

Diels–Alder substrate. Tetraene 199 was an attractive Diels–Alder substrate in that it

would incorporate the required stereochemistry of the C15 methyl group prior to the

52 Diels–Alder reaction. While the 2,3-substitution on the diene was viewed as a potential liability with regard to the possibility of the diene to adopt the required s-cis conformation, and the electronic character of the dienophile was less than optimal, the facility of the Diels–Alder reaction in the ophirin B ( 174 ) synthesis 107 provided

optimism for the success of the Diels–Alder reaction of tetraene 199 . Thus, we set

out to prepare tetraene 199 and investigate its performance in the designed

cycloaddition. Tetraene 199 would be prepared from diene 200 by ring-closing

metathesis followed by further functionalization. While construction of the diene

metathesis substrate for the ophirin B and astrogorgin syntheses was accomplished

Me Me Me AcO AcO H MeO H H H H H Me Me 9 Me 11 9 11 10 12 10 O 12 O O 1 14 1 14 2 2 3 3 H H H H 15 H OAc H 15 H Me H Me H Me O Me O Me O H H H OMOM 11-acetoxy-4-deoxyasbestinin D (196) asbestinin-12 (197) 198

OMe OBn Me Me H H O O MOMO TBSO H H Me H TBSO H TBSO H 200 199

Me BnO H O BnO Bn H O N O 202 O S 201

Scheme 35. Retrosynthetic Analysis

53 through the use of an asymmetric glycolate alkylation as the key step, 107,108,208 the strategy for the synthesis of diene 200 hinged upon the development and application of an asymmetric glycolate aldol reaction to establish the ether linkage stereochemistry of the oxonene precursor. 204,205 The required thioimide 201 for the aldol reaction would be prepared from ( R)-benzyl glycidyl ether ( 202 ).

3. Oxonene Formation

An initial goal of this project was to probe the effectiveness of oxazolidinethione glycolate 201 and oxazolidinone glycolate 203 in the glycolate

aldol reaction to determine which substrate was more useful for this transformation.

The preparation of each of these glycolates commenced with a copper iodide-

mediated propenyl Grignard addition to commercially available ( R)-benzyl glycidyl

ether ( 202). 225,226 A quantitative yield of the desired secondary alcohol 204 was

routinely obtained, and alcohol 204 was transformed into the corresponding glycolic

acid (Scheme 36). For this alkylation, three solvent systems were examined,

tetrahhydrofun, N,N-dimethylformamide, and an equal mixture of the two

aforementioned solvents. As has been previously observed, a 1:1 ratio of

tetrahydrofuran and N,N-dimethylformamide provided the highest yields of acid

205 .107,108 Attention was next turned to formation of the targeted glycolates 201 and

203 to probe the glycolate aldol reaction. The oxazolidinethione 201 was formed by either in situ acylation of the intermediate acid chloride with auxiliary 206 or standard

peptide DCC coupling conditions. The latter method provided a higher yield of the

glycolate 201 and also allowed for recovery of unreacted acid 205 , which was not

54 possible using the acid chloride route. Alternatively, for the oxazolidinone glycolate

203 , the mixed anhydride of acid 205 was formed and treated in situ with lithiated oxazolidinone 207 , providing glycolate 203 in high yield. It was also discovered that the oxazolidinethione glycolate 201 could be hydrolyzed to again provide glycolic acid 205 under basic conditions if a change of chiral auxiliary was desired following glycolate formation.

BrMg Me Me Me BnO BrCH2CO2H, BnO BnO H H O CuI, THF, H NaH, THF, DMF O o 95% 202 -40 C HO (Quant.) 204 HO O 205 Me (COCl)2, DMF, Me CH Cl ; Et N, BnO 2 2 3 S BnO CH2Cl2, 206 H H 60% O O NH Bn O or DCC, DMAP, N O Bn HO O CH2Cl2, 206 206 86% O S 205 201

LiOH, THF, H2O 89%

Me Me BnO PivCl, Et N,THF, O BnO 3 H -78 oC to 0 oC; Li-207, H O O NH O Bn THF, -78 oC Bn 95% N O HO O 207 O 205 O 203

Scheme 36. Formation of the Glycolates

For the preparation of 4-pentenal ( 208 ), the aldehyde necessary for the

proposed glycolate aldol reaction, we chose to utilize an oxidative cleavage of 5-

55 hexene-1,2-diol ( 209 ). To that end, racemic glycidol ( 210 ) was treated with

allylmagnesium chloride to provide diol 209 (Scheme 37). Diol 209 was then

subjected to sodium periodate to provide 4-pentenal ( 208 ) in good yield following

purification via distillation. It was discovered that using unpurified aldehyde 208 led

to poor results in the glycolate aldol reaction.

CH2=CHCH2MgCl, OH NaIO4,CH2Cl2, O O OH o OH THF, -20 C H2O 210 (Quant.) 209 60% 208

Scheme 37. 4-Pentenal Synthesis

The glycolate aldol reactions of thiomide 201 and imide 203 with 4-pentenal

(208 ) were probed using three different enolization conditions (Table 3). Initially, the

conditions that had previously been optimized for glycolate aldol reactions within the

Crimmins laboratory were used; 207 namely, 1.0 equivalents of titanium tetrachloride

were added to the cooled glycolates 201 and 203 , followed by 2.5 equivalents of

N,N -diisopropylethylamine to form the chlorotitanium enolate. Also, the use of 1.0

equivalent of (-)-sparteine for enolization followed by the addition of 1.0 equivalent of

N-methyl pyrrolidinone ten minutes prior to aldehyde addition were tested, but with

limited success. Both methods exhibited higher reactivity and selectivity for the

oxazolidinethione glycolate 201 when compared to the oxazolidinone glycolate 203.

Still, the results left room for improvement. Concurrently, more general conditions

were being developed within our laboratory for use in the aldol addition of complex

glycolates. 204 As part of this program, these modified conditions, involving initial

enolization with N,N-diisopropylethylamine followed by the addition of 1.0 equivalent

of N-methyl pyrrolidinone ten minutes prior to addition of the aldehyde, were tested

56 with glycolates 201 and 203 . The results obtained were very encouraging, providing a higher yield and selectivity for the desired adducts 211 and 212 . These conditions have proven general for a range of glycolates to give reproducibly higher yields and selectivities compared with previous methods. Though the oxazolidinone adduct

212 was obtained in higher yield than the corresponding thioimide 211 , for our purposes, we chose to proceed with the oxazolidinethione variant due to the higher diastereoselectivity obtained and resultant ease of purification of alcohol 211 .

Table 3. Base Screening for Glycolate Aldol Reaction

Me Me O BnO BnO H H O 208 O H Bn Bn H OH TiCl , N O 4 N O base, CH2Cl2, o o O X -78 C to -40 C O X

201: X = S 211: X = S 203: X = O 212: X = O Base 211 Yield 211 dr 212 Yield 212 dr i-Pr 2NEt 59% 90:10 18% not measured i-Pr 2NEt, NMP 70% >95:5 78% 90:10 (-)-sparteine, NMP 18% 85:15 16% not measured

With the α,ω-diene 211 in hand, the key ring-closing metathesis to complete the oxonene was probed. Treatment of aldol adduct 211 with the Grubbs second generation catalyst (151 )172 led mostly to recovered starting material and unidentified

side products (Scheme 39). Protection of the secondary alcohol as the t- butyldimethylsilyl ether gave diene 213 , which did undergo ring-closing metathesis

using the Grubbs second generation catalyst 151 in refluxing dichloromethane to

form oxonene 214 (Scheme 38, 39). However, conversion was low, and loss of the

protecting group was observed during the course of the reaction and purification.

Other ring-closing metathesis candidates were also tested, including the reduced

57 product of silyl ether 213 , as we hoped to investigate whether the sulfur atom in the chiral auxiliary was poisoning the catalyst, as has been previously observed.

Treatment of alcohol 215 with ring-closing metathesis conditions led to a 98% yield of oxonene 216 . With this result in hand, we prepared diol 217 by reduction of aldol adduct 211 . However, under identical conditions, this substrate gave only dimer

218 . Finally, diol 217 was bis-protected as t-butyldimethylsilyl ethers and treated with the Grubbs second generation catalyst 151 . Excellent conversion to oxonene

219 was observed. Additionally, it was found that the concentration of the ring- closing metathesis of diene 200 could be increased from the traditionally-used 2 mM up to 10 mM. Though a seemingly small improvement, this finding paid dividends as throughput was greatly improved when processing material on larger scale as the

Me OBn OBn BnO Me Me H H H LiBH4, MeOH, TBSCl, imid., O H O O Bn H OH o o Et2O, 0 C HO DMF, 50 C TBSO N O H 87% H 211: 95% HO H TBSO H O X 212: 73% 217 200 211, X = S 212, X = O

Me Me BnO BnO OBn H H Me O H O H TBSOTf, 2,6-lut. H LiBH4, MeOH, Bn Bn H OH H OTBS O o o N O CH2Cl2, 0 C N O Et2O, 0 C HO H O 213: 75% H O X 211: 96% X TBSO 212: 87% 220: 77% 215 211, X = S 213, X = S 212, X = O 220, X = O

Scheme 38. Ring-closing Metathesis Candidates

58 project progressed. Following this modification, oxonene 219 could be isolated in

99% yield when 5 mol% of the catalyst 151 was used in refluxing dichloromethane.

Two-dimensional 1H NMR analysis (COSY, nOeSY) were performed on the bis-

acetate version 219b of oxonene 219. This data corroborated that the desired

configuration for the three stereocenters installed to this point was present, as strong

nOe interactions were observed between the hydrogens on C2 and C9, and C2 and

C3. The completion of oxonene 219 represents the first successful formation of a

nine-membered ring in the Crimmins laboratory via the glycolate aldol/ring-closing

metathesis strategy that resulted in a natural product total synthesis.

The sum of the results from the ring-closing metathesis studies can be

rationalized via a conformational analysis of some of the possible rotamers of the

diene (Figure 9). It is apparent from the data that the substituent at C3 is of utmost

importance for the ring closure to proceed successfully. As previously described,

gauche conformations place the olefins proximally allowing ring-closing metathesis

to occur. In the case where C3 is a hydroxyl substituent (R = H, 217 ), it is possible

that the anti conformation is the least sterically encumbered, placing the two olefins

distally. However, when C3 is a silyl ether (R = TBS, 200 , 215 ), the steric interaction

between the silyl ether and the ether linkage of the diene becomes more

pronounced in the anti conformation, and the gauche conformations, particularly the

dipole minimized conformation, become more readily accessible, leading to

productive oxonene formation.

59 Me BnO Mes N N Mes H Cl O H 5 mol % 151 Ru Bn Recovered Cl Ph H OH starting material PCy3 N O CH Cl , 40 oC 2 2 151 O S 211

Me BnO OBn H Bn Me 5 mol % 151 O H H O Bn O H OTBS o N CH2Cl2, 40 C N O 69% S H O H O S TBSO 214 213

OBn OBn Me Me H 5 mol % 151 H O O o HO CH2Cl2, 40 C HO H 76% H HO H HO H 2

217 218

OBn OBn Me Me 151 H 5 mol % H O O o RO CH2Cl2, 40 C RO H H 215: 98% H TBSO 200: 99% TBSO H 215: R = H 216: R = H 200: R = TBS 219: R = TBS

OBn Me

H 9 nOe O AcO 2 3 H AcO H

nOe 219b

Scheme 39. Ring-closing Metatheses

OBn OBn Me Me H H O O R'O R'O 3 3 H H H RO RO H

OR H Me O Me O Me O OR' OR' OR' HOR H RO H H H BnO BnO OBn

Olefinchainsgauche Olefinchainsgauche Olefinchainsanti

R = H or TBS R' = H or TBS

Figure 9. Conformational Analysis of Oxonene Formation

4. Synthesis of the Diels–Alder Candidate

Attention was next turned to installing the diene and dienophile necessary for the key intramolecular Diels–Alder cycloaddition. We chose to install the diene first.

To that end, the cleavage of the benzyl ether was examined. Dissolving metal reductions of oxonene 200 using sodium naphthalene or sodium and liquid ammonia proved successful in accessing alcohol 221 in good yield (Scheme 40). Care had to be taken to ensure that the primary silyl group was not cleaved due to prolonged reaction times with these reductions producing diol 222 . A six step method for recycling diol 222 to the desired alcohol 221 was devised involving formation of the triol and protection of the 1,3-diol as an acetonide to give alcohol 223 . Protection of the primary alcohol 223 as a pivalate ester and deprotection of the acetonide afforded diol 224 . Bis-protection as t-butyldimethylsilyl ethers and reduction of the ester functionality intercepted alcohol 221 . Oxidative cleavage of the benzyl ether

61 was also attemped using DDQ, but it was difficult to maintain the primary silyl ether within the slightly acidic reaction media. When using a basic buffer, such as sodium bicarbonate, the oxidation ceased to occur, and only starting material 200 was recovered. In the end, a sodium ammonia reduction became the most reproducible and scaleable method for transforming oxonene 200 into alcohol 221 .

Na, NH3, o OBn THF, -78 C OH OH Me 86% Me Me H or H H O O O TBSO TBSO HO Na, naphthalene, H THF, -78 oC H H TBSO H TBSO H 71% TBSO H 219 221 222

OH OH OPiv Me Me 1. PivCl, pyr. Me H H 1. n-Bu4NF, THF CH2Cl2 H O O O HO H HO 2. MeC(OMe)2Me 2. PPTS, MeOH p-TSA H (89%) H O H TBSO H (57%) O HO H Me 222 Me 224 223

OH 1. TBSCl, imid., Me DMF, 50 oC H O TBSO 2. i-Bu2AlH, CH2Cl2, -78 oC H (86%) TBSO H

221

Scheme 40. Benzyl Ether Cleavage

Oxidation of alcohol 221 was accomplished using Swern conditions 130 or n-

31 Pr 4NRuO 4/NMO (Scheme 41). The Swern oxidation was the most reproducible, regardless of scale. Dess-Martin periodinane was not useful in forming aldehyde

225 .43 With aldehyde 225 in hand, a one-step procedure for installing the diene 226

62 was attempted. 1-Alkyoxyallylphosphonium salts have been reported in the literature as useful substrates to effect a Wittig transformation, however, care must be exercised to maintain low temperatures to preclude allylic 1,3-rearrangement to afford 3-alkoxyphosphonium salts. However, if the salt is prepared from the corresponding acetal using a Lewis acid and triphenylphosphine at low temperature, it can be deprotonated in situ to form the ylide, and the aldehyde can be added to this solution to afford the Wittig adduct. This approach was reported by Kim and co- workers using similar acetals to the one we desired to employ, and the enol ether products were hydrolyzed to the corresponding enones. 227 The E:Z selectivity for

the Wittig reactions were not reported due to the immediate hydrolysis of these

adducts. With knowledge of this precedent, we prepared the dimethyl acetal 227 of methacrolein ( 228), and used the reported conditions in hopes of generating our desired diene 226. However, all attempts to isolate the desired Wittig adducts using simple aliphatic or aromatic aldehydes, as well as complex aldehyde 225 proved fruitless. Though other methods exist in the literature for generating α- alkoxyallylphosphonates and phosphine oxides, 228 our concern with E:Z selectivity of

these processes led us to try a two step method for installing the diene. The use of

1-methoxy-1-(triphenylphosphoranylidene)acetone ( 229 ) as a stabilized Wittig

reagent had been reported to give excellent yield and complete E selectivity with

aromatic aldehydes. 229 We prepared this reagent in three steps from pyruvic

aldehyde dimethyl acetal ( 230 ). Formation of the α-chloro ketone was followed by

displacement of the chloride with triphenylphosphine. Deprotonation of the resultant

salt provided stabilized ylide 229 . Productive Wittig reaction was observed with a

63 (COCl)2, DMSO, OH Et3N, CH2Cl2 -78 oC to 0 oC O Me Me H 94% H O O TBSO or TBSO H n-Pr4NRuO4, H TBSO H NMO, 4 A MS, TBSO H CH2Cl2 221 92% 225

1. PPh3, TMSOTf, OMe THF, -78 oC Me O OMe 2. n-BuLi, -78 oC HC(OMe)3,NH4NO3, H Me Me O MeOH OMe 3. Aldehyde 225, TBSO 62% -78 oC to 0 oC H 228 227 TBSO H 226

O 1. CH3C(O)Cl, O Cu bronze, reflux OMe OMe Me Me 2. PPh3, 1,2-dimethoxyethane OMe PPh 3. NaOH, H2O 3 230 229 (63%)

O O O OMe Me Me Me OMe H Ph PCH Br, KOtBu O PPh3 Me 3 3 TBSO 229 H O THF, 0 oC H Ph-Me, 110 oC TBSO 87% TBSO H 84% H H 225 TBSO 231 Me

OMe Me H O TBSO H TBSO H 226

Scheme 41. Diene Installation

64 simple aliphatic aldehyde using ylide 229 . Gratifyingly, treatment of aldehyde 225 with ylide 229 in refluxing toluene led to an 84% yield of the desired enone 231 with complete E selectivity observed. Methylenation of enone 231 gave desired diene

226 in good yield.

Installation of the dienophile required selective deprotection of the primary silyl ether, oxidation of the resultant alcohol, and another olefination reaction to join the two pieces. Selective deprotection of diene 226 proved quite difficult. 230 A number of buffered hydrogen fluoride conditions were employed, but all attempts that led to selective deprotection also resulted in hydrolysis of the enol ether to yield enone 232 (Scheme 42). PPTS in protic solvent gave identical results. Tetrabutyl-

Table 4. Selective Deprotection Attempts

Me Me Me Me

OMe O OMe OMe Me Me Me Me H H H H O O O O TBSO TBSO HO HO

H H H H TBSO H TBSO H HO H TBSO H 226 232 233 234

Conditions 226 232 233 234

PPTS, MeOH, CH(OMe) 3, CH 2Cl 2 ▲ o HF:CH 3CN, CH 3CN, -20 C ▲ HF:pyr., pyr., THF ▲ o Et 3N(HF) 3, CH 3CN, 0 C ▲ o n-Bu 4NF, THF, 0 C ▲ NaOH, EtOH, 78 oC ▲ o K2CO 3, MeOH, 65 C ▲

65 ammonium fluoride at low temperature resulted in unselective deprotection to provide diol 233. Sodium hydroxide in refluxing ethanol also gave diol 233 . Milder alkaline conditions, potassium carbonate in refluxing methanol, gave only recovered starting material 226 . The inability to access alcohol 234 led us to pursue initial installation of the dienophile prior to diene formation using alcohol 216 .

It was most expedient to use alcohol 216 (accessed in six steps from ( R)- benzyl glycidyl ether ( 202 )) to probe dienophile installation. Oxidation of alcohol 216 was accomplished using Swern conditions 130 to provide aldheyde 235 in high yield

(Scheme 42). A Wittig reaction was targeted for dienophile formation. To that end,

phosphonium salt 236 was prepared from Roche ester 237 in six steps. Protection and reduction of ester 237 gave alcohol 238.231 The alcohol 238 was then transformed into bromide 239 through the intermediate mesylate. 232 Finally, deprotection of the silyl ether gave the commercially available bromohydrin, which was converted to phosphonium salt 236 prepared for Wittig reaction. Kozikowski

and co-workers have reported the use of phosphonium salt 236 to provide a

Schlosser modified-type Wittig adduct favoring the E olefin due to the intramolecular

alkoxide present during the reaction. 233 Since we desired the E olefin geometry as

well, we attempted using this phosphonium salt with aldehyde 235. Although the salt was effective in providing the E isomer when reacted with simple aldehydes, no olefination product 240 was observed using aldehyde 235. Though we predicted a

salt lacking the free hydroxyl would favor Z alkene formation, we still attempted

using other protected Wittig substrates to investigate whether the free hydroxyl was

leading to unproductive side reactions (Scheme 43). Transient in situ protection as

66 a silyl ether was attempted, 234 as well as use of the methoxymethyl ether variant 241

of phosphonium salt 236 , but none of the desired product 240 or 243 was obtained

in any attempt.

OBn OBn Me (COCl) , DMSO, Me H 2 H Et N, CH Cl O 3 2 2 O HO O -78 oC to 0 oC H H 93% TBSO H TBSO H 216 235

1. TBDPSCl, imid., H Me DMAP, DMF 1. MsCl, Et N, H Me 3 HO OMe CH2Cl2 TBDPSO OH 2. i-Bu AlH, THF, O 2 2. LiBr, THF 0 oC to rt 238 237 (81%) (81%)

Br- H Me 1. n-Bu NF, THF 4 H Me + TBDPSO Br HO PPh3 o 2. PPh3,C6H6, 80 C 239 236 (Quant.)

OBn - Br OBn Me H Me + Me H HO PPh3 H O 236 O O HO H o H n-BuLi, THF, -78 C to rt Me H TBSO H TBSO H 235 240

Scheme 42. Wittig Olefination Attempts A modified Julia olefination was next investigated for installation of the dienophile, due to the efficiency and high E selectivity these reactions have displayed in the literature. 235 To that end, sulfone 244 was prepared in two steps from previously synthesized bromide 245 (Scheme 44). However, treatment of aldehyde 235 with the potassium anion of benzothiazole 244 did not provide any of the desired diene

67 243 . Though discouraged by these results, we chose to attempt a cross-metathesis reaction, since this has found prior success in the Crimmins laboratory for joining two olefinic fragments. 236

n-BuLi, THF, -78 oC to rt; OBn TMSCl, 0 oC to rt; Me Br - H Me + H HO PPh3 OBn HO O Me H 236 H Me H O TBSO H O 240 H TBSO H 235 THF, -78 oC to rt; NH4F, THF:H2O

1. MOMCl, i-Pr NEt, 2 Br- H Me CH Cl 2 2 H Me + HO Br MOMO PHPh3 2. PPh3,K2CO3, 242 o 241 CH3CN, 90 C (85%)

OBn Br - OBn Me H Me + MOMO PPh Me H 3 H O 241 O O MOMO o H H n-BuLi, THF, -78 C to rt Me H TBSO H TBSO H 235 243

Scheme 43. Protected Wittig Attempts

68 1. NaH, THF N SH S H Me H Me O N MOMO Br MOMO S 2. (NH ) Mo O 4H O, 4 6 7 24 2 O S 245 H2O2, EtOH (82%) 244

H Me O N OBn MOMO S OBn Me O S Me H 244 H O O O MOMO KHMDS, THF, -78 oC to rt H H Me H TBSO H TBSO H 235 243

Scheme 44. Modified Julia Attempt

The two desired cross-metathesis coupling partners were prepared in a straightforward manner. Methylenation of aldehyde 235 gave diene 246 in 81% yield (Scheme 45). Alcohol 238 was oxidized 130 and methylenated to give alkene

247. Homodimerization of alkene 247 with the Grubbs second generation catalyst

151 provided dimer 248 in good yield. 172 Unfortunately, combining alkene 248 and diene 246 in refluxing dichloromethane in the presence of catalyst 151 was not efficient in providing dienophile 249.237 At this point, we speculated that the steric

bulk of the t-butyldimethylsilyl ether protecting group at C3 was impeding addition of the olefination reagents, precluding dienophile formation. We chose to install a less sterically encumbering protecting group at C3 to reattempt dienophile installation.

69 OBn OBn Me Ph3PCH3Br, Me H KO-t-Bu, THF, H O O O 0 oC, 81% H H H TBSO TBSO H 235 246

1. (COCl)2, DMSO, Et3N, CH2Cl2, -78 oC to rt Me 5 mol % 151,CH2Cl2, H Me H TBDPSO OH TBDPSO 40 oC, 75% 2. Ph3PCH3Br, 238 KO-t-Bu, THF 247 0 oC to rt (75%) H Me TBDPSO OTBDPS H Me 248

OBn OBn o Me Me 10 mol % catalyst 151,CD2Cl2, 40 C H H O TBDPSO O Me H 3 TBDPSO H Me H OTBDPS H H TBSO H TBSO H Me 249 246 248

Scheme 45. Cross-Metathesis Attempt

A p-methoxybenzyl ether was installed at C3 in place of the t- butyldimethylsilyl ether present in aldehyde 235 (Scheme 46). Our synthesis of aldehyde 250 began with deprotection of the silyl ether of alcohol 216 (accessed in six steps from ( R)-benzyl glycidyl ether ( 202 )). The p-methoxyphenyl acetal 251 was formed under acidic conditions in 84% yield, and the acetal was reduced with complete regioselectivity to form the secondary p-methoxybenzyl ether. Oxidation under Swern conditions 130 delivered desired aldehyde 250 . Following preparation of the tetrazole 252 from bromide 235 in two steps, a Julia–Kocienski olefination was

70 attempted with aldehyde 250 , as was a modified Julia reaction using benzothiazole

244. Each of these reactions led to productive olefination to give diene 253, with the

OBn Me OBn H Me O H 1. i-Bu2AlH, CH2Cl2, H o 1. n-Bu4NF, THF 0 C O HO 2. p-MeOC H CH(OMe) , O H 3 6 4 2 O 2. (COCl) , DMSO, H PPTS, DMF 2 H Et N, CH Cl , -78 oC TBSO (72%) 3 2 2 to 0 oC 216 251 (81%) MeO OBn Me H O O 3 H PMBO H 250

1. NaH, DMF N N SH N H Me N H Me O N N MOMO Br MOMO S N 2. (NH4)6Mo7O24 4H2O, O N 235 H2O2, EtOH (76%) 252

Me O N OBn H MOMO S OBn Me O S Me H H O 244 O O MOMO 3 H o H H KHMDS, DMF, -78 C to rt, Me H PMBO H 69%, 5:1 E:Z PMBO 250 253 OBn Me O N OBn Me H N MOMO S H N Me N H O O 252 O MOMO O 3 H H PMBO H KHMDS, THF, -78 oC to rt, Me H PMBO H 53%, 2:1 E:Z 250 253

Scheme 46. Successful Julia Olefination

71 modified Julia substrate 244 performing better than the tetrazole 252 . These results support our hypothesis that it was indeed the bulk of the C3 protecting group preventing effective dienophile installation. With the dienophile installed, we targeted an installation of the diene that would allow us to test the viability of our intramolecular Diels–Alder strategy for the asbestinins.

Lithium di-t-butylbiphenylide was employed to selectively deprotect the benzyl

ether of diene 253 in the presence of the p-methoxybenzyl ether (Scheme 47).

Swern oxidation 130 of the resultant alcohol provided aldehyde 254. The previously

investigated two step procedure for diene installation was next utilized. First, a

stabilized Wittig reaction using ylide 229 gave enone 255,229 which was

methylenated to provide tetraene 256, prepared for intramolecular Diels–Alder reaction. Unfortunately, subjection of oxonene 256 to conventional thermal as well

as microwave conditions in an attempt to effect cycloaddition were unsuccessful

(Scheme 48). At least two possible sources were postulated for the observed low

reactivity. First, the 2,3-disubstituted diene hinders the rotation of the C11–C12

carbon–carbon bond due to the eclipsing interaction present in the necessary s-cis

conformation of the diene. Second, the dienophile is significantly reduced in

reactivity (compared to the dienophiles in the cladiellin series Diels–Alder reactions)

because of the absence of an electron withdrawing group. 107,108 Since changes to the C11–C12 substitution seemed less straightforward to implement into our synthetic plan, we set out to revise our strategy utilizing a more activated dienophile still possessing the C11–C12 substituted diene. We postulated that this change in

72 electronics should allow for more facile cycloaddition, providing a substrate that could be converted into an asbestinin.

OBn O Me 1. LiDBB, THF, Me H -78 oC H O MOMO MOMO O 2. (COCl)2, DMSO, H Me H Et N,CH Cl , H Me H H 3 2 2 PMBO -78 oC to 0 oC PMBO H 253 (71%) 254

O O Me OMe Me OMe Me OMe Me PPh3 Me Ph PCH Br, 3 3 H 229 H O O MOMO KO-t-Bu, THF, MOMO o PhMe, 110 C 0 oC H Me H Me H 78% H 86% PMBO H PMBO H 256 255

Scheme 47. Synthesis of the Diels–Alder Candidate

Me 12 Me 11 MeO OMe H H Me Me microwave 11 H and thermal 12 O O MOMO conditions H H H H H Me OPMB Me H H PMBO H OMOM 256 257

Scheme 48. Attempted Cycloaddition

Rather than spend time optimizing our route to an activated Diels–Alder candidate, we chose to proceed in the most expedient fashion possible toward a proof of concept. So, previously prepared alcohol 258 was protected as a silyl ether, and the benzyl ether was reductively removed in the presence of the p- methoxybenzyl ether to give alcohol 259 in only 40% yield due to loss of some of the

73 primary silyl ether during the course of the reaction and workup (Scheme 49).

Oxidation 130 and a Wittig reaction with ylide 229 provided enone 260 .229 Diene

formation and deprotection proceeded uneventfully to provide alcohol 261 , which upon oxidation gave aldehyde 262 .130 With the stage set to attempt the Wittig

reaction to prepare a more activated Diels–Alder candidate, two ylides were utilized

for the olefination reaction. When ylide 263 was employed, 238 enoate 264 was isolated after refluxing in benzene for one hour. However, using

(acetylmethylene)triphenylphosphorane ( 265), 182 intramolecular Diels–Alder

cycloaddition ensued under the conditions of the Wittig reaction, presumably via

intermediate enone to provide the desired tricycle 266 (76%, 4:1 dr) favoring the

exo-diastereomer. This successful cycloaddition result served to confirm our

hypothesis regarding the unfavorable electronics precluding reaction of the

unactivated Diels–Alder candidate (Scheme 48). We rationalize the stereochemistry

observed in this cycloaddition in an analogous manner to the cladiellin transition

states (Figure 7, Figure 10). 108 Again, the exo-adduct is the favored product, but we

hoped to improve the selectivity of this process by increasing the steric bulk at C3.

This had been shown to be effective in the cladiellin case where the

diastereoselection increased as the steric demand of the C3 substituent increased

(Figure 11). Particularly, the selectivity obtained when C3 was a p-methoxybenzyl

ether in the asbestinin case (4:1 dr) closely mirrored that obtained when C3 was a

benzyl ether in the ophirin B synthesis (4.5:1 dr). Therefore, we chose to revise our

approach to the asbestinins, ensuring a silyl ether was present at C3 in our modified

74 plan, since a silyl ether had demonstrated complete exo diastereoselection in the ophirin B case.

OBn OH 1. (COCl)2, DMSO, Me 1. TBSCl, imid., Me Et3N,CH2Cl2, H o o DMAP,CH2Cl2 H -78 C to 0 C O O HO TBSO 2. LiDBB, THF, 2. Ph-Me, 110 oC, H -78 oC H O PMBO H H (39%) PMBO OMe Me 258 259 PPh3 229

O Me (78%) Me 1. Ph PCH Br, OMe 3 3 OMe KO-t-Bu, THF, (COCl)2, DMSO, Me 0 oC Me Et3N,CH2Cl2 H H O O -78 oC to 0 oC TBSO 2. n-Bu4NF, THF HO 86% H (57%) H PMBO H PMBO H 260 261 Me

OMe Me H O O

H PMBO H 262

Scheme 49. Revised Synthesis of Cycloaddition Candidate

O Me Me O Me MeO Me EtO OMe H H OMe Me PPh PPh Me 3 Me 3 265 263 H O H O O H O H H C D CD , 100 oC, O o H 6 5 3 C6D6, 80 C, O Me OPMB 76%, 4:1 dr EtO H H 90% PMBO H PMBO H 266 264 262

Scheme 50. Successful Intramolecular Diels–Alder Reaction

75 Me Me Me O O Me H H MeO H MeO H H H OP H H OP O O H H H H Me Me

exo endo

Me Me MeO H MeO H H H Me Me O O H H H H H H H H O Me OP O Me OP

Figure 10. Asbestinin Cycloaddition Transition States

BnO Me Me Me H H Me H O O 14 O BnO H H Me 3 H MeO H O OMe OR RO Me 183 182 R=H,72h,3:1dr R =Bn,12 h,4.5:1 dr R =TES, 2 h,>19:1 dr

Figure 11. C3 Protecting Group Effects in the Ophirin B Synthesis

5. Revised Retrosynthesis

Armed with the knowledge gained from our investigations to this point, we set out to apply the activated Diels–Alder strategy to complete the synthesis of the asbestinins. Ketone 267 was targeted as a useful substrate for accessing the functionality of the five-, six-, and nine-membered rings of 11-acetoxy-4- deoxyasbestinin D ( 196 ) and asbestinin-12 ( 197 ). Triene 267 also features a handle that we envisioned to be useful for establishing the C15 stereochemistry of the

76 oxepane. An intramolecular Diels–Alder cycloaddition of tetraene 268, with a silyl ether in place at C3 would be exploited to prepare the tricyclic framework. And, oxonene 268 would be constructed via a ring-closing metathesis of previously synthesized diene 200 , which was accessed via our glycolate aldol addition of thioimide 201 , derived from ( R)-benzyl glycidyl ether ( 202 ).

Me Me Me AcO AcO H MeO H H H H H Me Me 9 Me 11 9 11 10 12 10 O 12 O O 1 14 1 14 2 2 3 3 H H H H 15 H OAc H 15 H Me H Me H Me O Me O Me O H H 267 11-acetoxy-4-deoxyasbestinin D (196) asbestinin-12 (197)

OMe OBn Me Me H H O O O TBSO H Me H TBSO H TBSO H 200 268 Me BnO H O BnO Bn H O N O 202 O S 201

Scheme 51. Revised Retrosynthesis

6. Synthesis of the Revised Diels–Alder Substrate

Utilizing previously prepared triene 226 , accessible in 11 steps from commercially available material, the issue of selectively deprotecting the primary silyl ether was revisited (Table 4, Scheme 52). After attempting several of the previously

77 examined conditions once again, it was finally found that ammonium fluoride in methanol promoted highly efficient selective deprotection, providing alcohol 234 in

79% yield, with the remainder of the material representing recovered starting material 226 and diol 233 (which was able to be reprotected and recycled). 239

Following this important result, oxidation gave aldehyde 269 in high yield. 130

Me OBn BnO Me H H BnO Three steps O Three steps O H O Bn TBSO 202 N O H TBSO H O S 200 201

Me Me

OMe OMe Me Me Five steps H NH4F, MeOH H O O TBSO 79% HO

H H TBSO H TBSO H 226 234

Me O Me (COCl) , DMSO, OMe 2 Me MeO H Et N,CH Cl H 3 2 2 Me PPh3 Me 265 H O -78 oC to 0 oC O O Ph-Me, 110 oC, 3 93% H H H 80% H H Me O OTBS TBSO H 270 269 Single Isomer

Scheme 52. Selective Deprotection and Improved Cycloaddition

Utilizing ylide 265 , the aldehyde 269 underwent a Wittig reaction and again cyclized to the desired tricycle 270 , this time with a single isomer observable by NMR

spectroscopy. This result is in agreement with our previous observations involving

78 the importance of the C3 protecting group, further supporting our transition state models (Figure 10).

7. Refunctionalization of the Six- and Nine-membered Rings

With an efficient, fourteen step route to tricycle 270 , attention was turned to refunctionalizing the six- and nine-membered rings with the substitution present within the asbestinin subclass. First, the ketone of cycloadduct 270 was

methylenated to provide a handle for a hydroboration/oxidation protocol that would

be used to provide the proper configuration at C15 at a later point (Scheme 53).

Triene 271 was then deprotected and oxidized to give ketone 264 , the targeted point

of divergence for the syntheses of 11-acetoxy-4-deoxyasbestinin D ( 196 ) and

asbestinin-12 ( 197 ).43 Two-dimensional 1H NMR analysis (COSY, nOeSY) was

performed at this point, since none of the previous substrates were amenable to

confirming the stereochemistry obtained in the cycloaddition (Figure 12). Strong

support was gleaned from this data that the desired configuration was the product of

the Diels–Alder reaction. Namely, a nOe was observed between the hydrogens of

C1 and C10 and C2 and C9. Further, the hydrogen of C2 was a singlet in the 1H

NMR, indicating that it does not couple with any other hydrogens. Via the Karplus equation, it can be deduced that it has a 90 o relationship with the C1 hydrogen,

indicating a trans relationship between those two protons. The C14 configuration

could not be definitively established from these data. However, ketone 264 was a

solid, white compound following purification, and some time later, a suitable crystal

was obtained for X-ray crystallographic analysis (Figure 13). The data obtained

79 confirmed that the desired configurations for the C1, C2, C9, C10, and C14 stereocenters were each as expected, definitively proving that the Diels–Alder cycloaddition proceeded to give the desired exo-adduct. Each of the five stereocenters matched the desired configuration for the asbestinin subclass.

Additionally, this data corroborated speculation gained from previous two- dimensional analysis of asbestinin and cladiellin intermediates that the oxonene was oriented in a bowl shape with the top face (as drawn) representing the concave face.

This conformational feature was present in the solid state, and we hoped to exploit this to execute a substrate-controlled diastereoselective reaction with the convex face of the oxonene.

Me Me Me MeO H MeO H MeO H H H H Me Ph3PCH3Br, Me 1. n-Bu4NF, THF Me O O O KO-t-Bu, THF 2. Dess-Martin H H 85% H periodinane, H H H H H H H OTBS pyr., CH Cl H Me 15 O Me OTBS 2 2 Me O (94%) 270 271 264

Scheme 53. Synthesis of the Ketone

Me MeO H H Me 9 10 nOe 1 O 2 H 14 H H Me O 264

Figure 12. Two-dimensional NMR Data

Figure 13. X-ray Crystallographic Data of the Ketone A substrate-controlled diastereoselective methylation served to complete the functionalization of the oxonene (Scheme 54). As hoped, a single isomer of tertiary alcohol 272 was obtained, presumably via attack on the convex face of the oxonene.

This stereochemical outcome was supported by two-dimensional 1H NMR analysis

(COSY, nOeSY), which showed a nOe between the newly installed methyl protons

at C3 and the proton at C2 of the ring juncture, suggested a cis relationship between

these two substituents.

Attention was then turned to functionalization of the cyclohexene (Scheme

54). Hydrolysis of the enol ether provided a 96% yield of a 10:1 mixture of α-methyl

ketone diastereomers 273 and 274 , favoring the undesired configuration. Again, nOeSY spectroscopy was used to reveal a nOe interaction between the C12 methyl protons and the C10 proton in ketone 273 , while ketone 274 showed a similar nOe between the C12 proton and the C10 proton. Facile epimerization was achieved

81 under alkaline conditions to provide a 1:1.2 mixture of diastereomers at equilibrium, favoring the undesired configuration. Two recycles allowed isolation of 83% of ketone 274 from enol ether 272 , along with 13% of ketone 273 remaining. Ensuing reduction of the ketone using sodium borohydride provided alcohol 275 in good yield with good diastereoselectivity (>4:1 dr) for the desired C11 stereocenter.

However, using a bulkier hydride source, L-selectride, provided a single isomer of diol 275 in 94% yield. Selective acetylation of the secondary alcohol was trivial and proceeded in nearly quantitative yield to deliver alcohol 276 .

Me Me MeO H MeO H H H Me MeMgCl, THF Me HCl, CHCl3, O O o 2 96%, 10:1 dr 0 C, 98% 3 nOe H H H H H H Me Me O Me OH 264 272

nOe nOe Me Me O O Me H H H H H L-selectride, THF, NaH, MeOH H 12 10 Me 12 10 O O 99%, 1:1.2 dr -78 oC H H H H Me H Me 94% OH H Me Me OH 273 274

Me HO Me H H AcO H Ac2O, Et3N, H Me Me O DMAP,CH2Cl2 O 99% H H H Me H H Me OH H Me Me OH 275 276

Scheme 54. Refunctionalization of the Six-membered Ring

8. Oxepane Formation to Complete 11-Acetoxy-4-deoxyasbestinin D

82 As previously mentioned, we had envisioned using a hydroboration/oxidation protocol to install the C15 stereocenter, hoping for a substrate-controlled diastereoselective reaction. The X-ray of ketone 264 revealed that, in the solid state, the 1,1-disubstituted olefin is oriented such that the face upon which we hoped to selectively operate appears unencumbered, while the undesired face of reactivity is shielded by the oxonene portion of the tricycle (Figure 13). We were hopeful that a similar low energy conformation would be operational in solution for diene 276 .

Numerous substrate-controlled highly diastereoselective hydroborations exist in the literature involving the reaction of a variety of 1,1-disubstituted olefins with 9-

BBN. 240-242 When diene 276 was treated with 9-BBN under ultrasonic conditions in

THF, the starting material was consumed, and upon oxidation, alcohol 277 was isolated (Scheme 55). To our delight, chemoselective and regioselective hydroboration had been achieved, however, an equal amount of each C15 epimer was obtained. After attempting similar hydroborations on ketone 264 , alcohol 272 , and ketone 274 with no success, we turned our attention toward improving the reaction with diene 276 . Namely, we hoped to install a protecting group on the C3 alcohol that would impede addition for one face of the alkene by altering the energies of each transition state for the hydroboration step. A trimethylsilyl group was installed uneventfully. Hydroboration and oxidation of this substrate 278 did demonstrate modest diastereoselection (1.7:1 dr), but certainly left room for improvement. A triethylsilyl variant 280 was prepared, and provided a 2.2:1 dr under the hydroboration/oxidation conditions. A t-butyldimethylsilyl ether 282 was also formed, but exhibited identical diastereoselection to the triethylsilyl substrate 280

83 Me Me AcO AcO H H H H Me 9-BBN, THF; Me O O H O , NaOH 2 2 3 H H H H H Me 71%, 1:1 dr 15 H Me Me OH Me OH H 276 OH 277 Me Me Me AcO H AcO AcO H H H H H Me TMSCl, DMAP, Me 9-BBN, THF; Me O O O CH2Cl2 H2O2, NaOH 3 H H Me 89% H H H Me H H H Me 70%, 1.7:1 dr 15 H Me OH OTMS Me OTMS Me H 276 278 OH 279

Me Me Me AcO H AcO AcO H H H H H Me TESOTf, 2,6-lut., Me 9-BBN, THF; Me O O O o H2O2, NaOH CH2Cl2, 0 C 3 H H Me H H H Me H 80% H H Me 80%, 2.2:1 dr 15 H Me OH OTMS Me OTES Me H 276 280 OH 281

Me Me Me AcO H AcO AcO H H H H H Me TBSOTf, 2,6-lut., Me 9-BBN, THF; Me O O O CH2Cl2 H2O2, NaOH 3 H H Me (Quant.) H H H Me H H H Me 74%, 2.2:1 dr 15 H Me OH OTMS Me OTBS Me H 276 282 OH 283 Me Me Me MeO H MeO O H H H H H Me Me Me O O O

H H H H H H H Me H H Me Me O Me OH Me OH 264 272 274

Unproductive hydroboration substrates

Scheme 55. Hydroboration Studies

84 (2.2:1 dr) under the reaction conditions. Formation of t-butyldimethylsilyl ether 282 proceeded slowly due to the orientation of the C3 alcohol within the concave face of the oxonene. Predictably, a triisopropylsilyl ether could not be formed at a useful rate. Since this strategy seemed to have a modest ceiling of diastereoselectivity, we hoped to improve the ratio via epimerization of the corresponding aldehyde.

Diastereoenriched alcohol 277, prepared via deprotection of alcohol 281 , was

oxidized to the aldehyde 284 under Swern conditions (Scheme 56). 130

Me Me AcO H AcO H H H (COCl)2, DMSO, Me Me n-Bu4NF, THF Et3N,CH2Cl2, O O 3 91% o o H H -78 C to 0 C 15 H Me H Me H H 71% Me OTES Me OH H H OH OH 281 2.2:1 dr 277 Me Me AcO AcO H H H 1. PPTS, MeOH, H Me Me BF OEt , Et SiH, CH(OMe)3 3 2 3 O O CH Cl , 0 oC 2. PPTS, C6H6, H 2 2 H H Me H H 45 oC H Me Me OH Me O H H O (42%, 71% brsm) OMe 1:1 dr 285 284 Me Me AcO AcO H H H H Me 9 Me 11 12 10 O 1 O 14 2 3 H H H H H Me 15 H Me Me OH Me O H H O 11-acetoxy-4-deoxyasbestinin D (196) 284

Scheme 56. Reductive Etherification Strategy

Unfortunately, during the course of the reaction, the material epimerized to an equal ratio of C15 epimers. Despite this undesired result, we attempted to proceed via

85 aldehyde 284 to form the oxepane using a ketal cyclization/reductive etherification strategy that had found use in our approach to brevetoxin A. 214,243,244 To that end,

the dimethyl ketal was formed. A solvent switch and heating of the dimethyl ketal

gave mixed methyl ketal 285 . Unfortunately, reductive etherification of mixed ketal

285 resulted in isolation of aldehyde 284 , rather than natural product 196 , most likely

due to adventitious water intercepting the oxocarbenium ion faster than hydride.

Use of i-Bu 2AlH led only to reduction of the acetate ester.

A revised route to install the C15 methyl stereocenter diastereoselectively was devised envisioning hydrogenation of an exocyclic C15 1,1-disubstituted olefin following oxepane formation (Figure 14). It was proposed that the concave nature of the tetracycle would allow selective reaction from the convex face, providing the desired C15 configuration. To install the olefin and form the oxepane, we hoped to open the epoxide 286 of tricycle 276 with lithium diethylamide (Scheme 57). 245 The diol would then undergo an intramolecular etherification, and hydrogenation would provide 11-acetoxy-4-deoxyasbestinin D ( 196 ). Unfortunately, attempts to

chemoselectively epoxidize the disubstituted olefin of diene 276 were unsuccessful, as the trisubstituted olefin reacted faster with m-CPBA to give epoxide 287 . Another method for installing the disubstituted epoxide was devised utilizing the Johnson–

Corey–Chaykovsky reaction. 246,247 However, none of the desired epoxide 288 was

isolated under these conditions. Finally, we envisioned using a modified dienophile

for the intramolecular Diels–Alder reaction that would allow exocyclic olefin

formation, while also providing a handle for oxepane cyclization. Again, our efforts

86 were thwarted as Wittig reaction with ylide 289 led to none of the desired tricycle 290 under the same conditions that were successful using ylide 265 .248

Me Me AcO H AcO H H H Me Me 11 9 O 12 10 1 O 14 2 3 H H H H H Me 15 H Me O Me O H H2 11-acetoxy-4-deoxyasbestinin D (196)

Figure 14. Hydrogenation Strategy

Me Me Me AcO AcO AcO H H H H H H O Me m-CPBA, Me Me O O O CH Cl 2 2 3 H H H H H H Me H Me 15 H Me H OH Me OH OH Me O Me 276 286 287

Me Me MeO H H MeO H Me H Me3SI, n-BuLi, Me O O THF, 0 oC to rt H H H H H H OTBS H H Me O Me OTBS O 269 288

Me O Cl Me OMe MeO H H Me PPh3 Me 289 H O O o 3 O Ph-Me, 110 C H H H H H O OTBS TBSO H Cl 269 290

Scheme 57. Hydrogenation Strategy

With the previous routes for diastereoselectively installing the C15

stereocenter proving fruitless, we returned to the hydroboration/oxidation strategy.

87 Although chiral hydroborating agents generally give poor results for diastereoselectively hydroborating 1,1-disubstituted olefins, our lack of success with achiral variants led us to attempt using diisopinocampheylborane. 249 Much to our delight, treatment of diene 280 with (+)-diisopinocampheylborane, followed by alkaline oxidation gave diol 281 as a single detectable diastereomer (Scheme 58).

This represents only the second example of the successful application of diisopinocampheylborane for the diastereoselective hydroboration of a 1,1- disubstituted alkene (Scheme 59).250 Formation of the corresponding mesylate 291

was followed by deprotection of the silyl ether with fluoride, which we hoped would

result in etherification via the intermediate alkoxide following deprotection. However,

fluoride 292 was instead isolated from the reaction mixture. Alternatively, mesylate

291 could be deprotected at lower temperature, to provide alcohol 293 . But, upon

treatment with a variety of bases (sodium hydride, 2,6-lutidine, 4-

dimethylaminopyridine, collidine), only elimination product 276 was isolated.

Overman has previously reported the formation of an oxepane in an analogous system for the total syntheses of briarellin E and F using an etherification that proceeds through the intermediate primary triflate (Scheme 10). 80 Application of the same conditions to diol 277 delivered 11-acetoxy-4-deoxyasbestinin D ( 196 ) in 66%

yield, with the remainder of the material representing elimination product 276 .

Whereas the Overman example required four days for complete reaction, the

primary triflate of diol 277 took only four hours to cyclize, likely due to the extra

rigidifying element present in our system of the closed oxonene. The synthetic

material corresponded to the natural material in all regards. 11 Additionally, though

88 26 the optical rotation of the synthetic material ([ α] D; CHCl 3 = -15) differed from the

29 reported literature value ([ α] D; CHCl 3 = -2.29), we were able to obtain a sample of

the natural product from the Rodríguez laboratory at the University of Puerto Rico,

Me Me Me AcO AcO H AcO H H H H H MsCl, Et3N, Me (+)-Ipc2BH, THF; Me Me O O CH Cl O NaOH, H2O2 2 2 3 75% 3 H H H Me H H Me 71%, >19:1 dr 15 H 15 H Me H Me OTES H Me OTES Me OTES H H 280 OH OMs 281 291

Me AcO H H Me n-Bu4NF, THF O 85% 3 H H 15 H Me Me OH H F 292

Me Me NaH, THF Me AcO H AcO H or AcO H H H H Me Me 2,6-lut., THF Me n-Bu4NF,THF, O O or O o 3 3 0 C H DMAP,THF H H H Me H 15 H Me 15 H or H Me 87% Me OH H Me OTES collidine, THF Me OH H H OMs OMs 276 291 293

Me Me Tf O, 2,6-lut., AcO H 2 AcO H H o H Me CHCl3, 0 C Me 11 9 O 12 10 1 O 14 2 3 to rt 3 H H Me 66% H H 15 H 15 H Me Me OH Me O H H OH 277 11-acetoxy-4-deoxyasbestinin D (196)

Scheme 58. Completion of 11-Acetoxy-4-deoxyasbestinin D

Río Piedras. Submission of the natural material to polarimetry under the same

26 conditions used for the synthetic material provided a matching optical rotation ([ α] D;

89 CHCl 3 = -15) to our synthetically prepared compound, further confirming the

synthetic material was indeed 11-acetoxy-4-deoxyasbestinin D ( 196 ). This 26 step

sequence from ( R)-benzyl glycidyl ether ( 202 ) represents the first total synthesis of a

member of the asbestinin subclass. Further, the optical rotations obtained for the

synthetic and natural materials serve to confirm the absolute configuration of the

asbestinin subclass, verifying that the biosynthetic proposal gives the proper

configuration, rather than the enantiomer featured in the isolation literature. 1,2,11

(-)-Ipc2BH, THF; O OTES OH tylonolide m-CPBA, 0 oC O OTES 90%, >50:1 dr TBSO Me Me OBn TBSO Me Me

OBn (+)-Ipc2BH, THF; O OTES OH

m-CPBA, 0 oC 90%, >50:1 dr TBSO Me Me OBn

Scheme 59. Masamune's Chiral Hydroboration

9. Total Synthesis of Asbestinin-12

For the synthesis of asbestinin-12 ( 197 ), 224 we again hoped to exploit the inherent concavity of ketone 264 to perform a diastereoselective transformation.

This time, an α-hydroxylation of the potassium enolate of ketone 264 using Davis

oxaziridine provided the alcohol 294 as a single diastereomer (Scheme 60). 251-253

When a greater number of equivalents of the Davis reagent were employed,

overoxidation was observed via epoxidation of the C11–C12 tetrasubstituted enol

ether to provide a mixture of hydroxy epoxides 295 (1.3:1 dr). However, use of just more than stoichiometric oxaziridine and careful monitoring of the reaction could

90 preclude formation of this undesired byproduct 295 . There was some concern that the presence of the C4 alcohol would adversely impact the diastereoselectivity of the subsequent alkylation via chelation of the carbonyl and hydroxyl to provide the epimeric C3 diol. Fortunately, this phenomenon was never observed. However, the conversion for this methylation was poor, perhaps due to competitive enolization of the C3 ketone, and prolonged reaction led to an unidentified byproduct. Attempted use of methyllithium (with or without sodium tetrafluoroborate) did not improve the yield of this reaction. 44,88,103 However, using a large excess of the Grignard reagent

(20.0 eq), provided diol 296 as a single diastereomer in 84% yield.

O H SO2Ph Me N Me MeO Ph MeO H H H H Me KHMDS, THF, Me MeMgCl, THF 11 12 O O o o 4 0 C, 84% 3 4 -78 C H H H OH H 84% H H O Me O Me 264 294

Me Me MeO H MeO H O H H Me Me 11 12 O O 4 4 3 H H H H OH H OH H Me O Me OH Me 295 296

Scheme 60. Hydroxylation and Grignard Reactions

Hydrolysis of enol ether 296 again provided the undesired C12 configuration of ketone 297 as the major product, in a similar ratio to that previously observed

(Scheme 61). Epimerization was again facile under alkaline conditions and gave some of the desired C12 methyl configuration 298 . A single diastereomeric triol was

obtained upon reduction of ketone 298 with L-Selectride, whereupon selective

91 protection of the secondary alcohols was accomplished in the presence of the tertiary alcohol providing diacetate 300 .

Me Me MeO H O H HCl, CHCl , H H Me 3 Me NaH, MeOH O 12 99%, 11:1 dr O 99%, 1:1.4 dr H H OH H H Me H OH OH H Me Me Me OH 296 297

Me Me O HO H H H H Me L-Selectride, THF, Me 11 Ac2O, Et3N, 12 O 12 O -78 oC DMAP, CH2Cl2 H H OH 94% H H OH 85% H Me H Me Me OH Me OH 298 299

Me AcO H H Me 11 O 3 4 H H OAc H Me Me OH 300

Scheme 61. Formation of the Hydroboration Candidate

At this point, we hoped to examine the role of the C3 protecting group in the diastereoselectivity of the hydroboration. Earlier, the triethylsilyl ether 280 was ultimately employed as the hydroboration substrate for monitoring purposes

(Scheme 58), but this was not necessary for diacetate 300 . Treatment of diene 300

with (+)-diisopinocampheylborane and oxidation provided the desired diol 301 as a single diastereomer in good yield, 249 confirming that the reagent controls the selectivity (Scheme 62). Oxidation with the milder sodium perborate conditions proved useful in this case to prevent hydrolysis of the labile C4 acetate. 73 Using

92 triflic anhydride and 2,6-lutidine, 80 asbestinin-12 ( 197 ) was obtained in good yield,

with the remainder of the material representing elimination product 300 . All data

reported for the natural material again corresponded well with the data for the

synthetic material. 224

Me Me AcO AcO H Tf O, 2,6-lut., H H H 2 Me (+)-Ipc BH, THF; Me CHCl , 0 oC 11 2 3 O O NaBO 4 3 4 3 3 to rt H H H OAc 15 H OAc H Me 74%, >19:1 dr H Me 69% OH Me OH Me H OH 300 301 Me AcO H H Me 11 9 12 10 1 O 14 2 3 4 H H OAc 15 H Me Me O H asbestinin-12 (197)

Scheme 62. Completion of Asbestinin-12

E. Summary

In summation, highly stereoselective syntheses of 11-acetoxy-4- deoxyasbestinin D ( 196 ) and asbestinin-12 ( 197 ) have been completed in 26 and 25 steps respectively. The strategy for completing these two molecules hinged upon the formation of an oxonene ring using an asymmetric gylcolate aldol reaction and subsequent ring-closing metathesis. This oxonene was used as a manifold for an intramolecular Diels–Alder cycloaddition to form the hydroisobenzofuran moiety. An

α-hydroxylation was utilized to diverge the two routes. A chiral hydroborating reagent proved crucial in establishing the stereocenter at C15. These syntheses

93 stand as the first molecules of the asbestinin subclass to be prepared by chemical methods and serve to confirm the absolute configuration of the asbestinins.

94 Me O Me BnO BnO H H 3 steps BnO O 208 H O O H Bn Bn TiCl4, i-Pr2NEt, H OH 202 N O NMP, CH2Cl2, N O -78 oC to -40 oC O S O 70%, >19:1 dr S 201 Glycolate Aldol Reaction 211

OBn 5 mol % Grubbs OBn Me 2nd Generation Me H H 2 steps Catalyst (151) 6 steps O O TBSO o TBSO CH2Cl2, 40 C H 99% H TBSO H TBSO H Ring-closing Metathesis 200 219 Me Me O Me OMe MeO OMe H H Me Me Me H PPh Me 3 H O O 265 O O O H H H Ph-Me, 110 oC, H H Me O OTBS TBSO H 80%, >19:1 dr Me H TBSO H 270 269

Intramolecular Diels-Alder Reaction

Me Me MeO H AcO H H H Me (+)-Ipc BH,THF; 3 steps 6 steps Me 2 O O NaOH, H2O2 H H H H H Me 71%, >19:1 dr O H Me Me OTES 264 280 Chiral Hydroboration

Me Me AcO H AcO H H H Me Me 11 9 2 steps 12 10 O 1 O 14 2 3 3 H H Me H H 15 H 15 H Me Me OTES Me O H H OH 281 11-acetoxy-4-deoxyasbestinin D (196)

Scheme 63. Summary for 11-Acetoxy-4-deoxyasbestinin D

95 O H SO2Ph Me N Me MeO Ph MeO H H H H Me KHMDS, THF, Me 11 5 steps 12 O O o 4 3 4 -78 C H H H H 84%, >19:1 dr H OH H O Me O Me ααα-Hydroxylation 264 294

Me Me AcO AcO H H H H Me (+)-Ipc BH, THF; Me 11 2 1 step O O NaBO 3 4 3 4 3 H H H OAc 15 H OAc H Me 74%, >19:1 dr H Me OH Me OH Me H Chiral Hydroboration OH 300 301 Me AcO H H Me 9 11 12 10 1 O 14 2 3 4 H H OAc 15 H Me Me O H asbestinin-12 (197)

Scheme 64. Summary for Asbestinin-12

Chapter II

A Convergent Strategy for the Total Synthesis of Brevetoxin A

A. Background

In addition to the previously described C2–C11 cyclized cembranoids, marine sources also provide an assortment of trans -fused polycylic ethers (Figure 15). 254

These molecules, generally produced by algae called dinoflagellates, make up a

class known as the ladder toxins, due to their ladder like structure and often toxic

biological effects. In 1981, brevetoxin B became the first member of this class to be

characterized. 255 Since this time, a number of other ladder toxins have been isolated and their structures elucidated. Each of the identified ladder toxins feature cylic ethers composed of five- to nine-membered rings, joined in a repeating trans /syn /trans pattern. The total number of rings within each molecule varies greatly, from hemibrevetoxin B ( 302 )256 possessing only four cyclic ethers and ten stereocenters, to maitotoxin, which features an impressive 32 ether rings and 98 stereocenters. 257

Beyond the fascinating complexity and uniformity of the structures of this class, the ladder toxins also display a range of biological properties. Many of the observed effects are harmful to humans, including strong ichthyotoxicity 255,258,259 and ciguatera poisoning. 260,261 These properties have been implicated as the potent

component of the red tides, resulting in massive fish kills and human sickness upon consumption of infected sea life. 262 Additionally, cases have been reported of some ladder toxins becoming aerosolized during red tides, resulting in respiratory irritation for those in the area. Despite these often harmful effects, some of the polycyclic ethers also feature beneficial biological effects, including antifungal properties 263 and

264,265 tumor cytotoxicity, with IC 50 values as low as 0.5 nM.

Due to the molecular intrigue, as well as the biological and ecological effects of trans -fused polycyclic ethers, a number of research groups have devoted effort toward the preparation of members of this class. Several total syntheses of these daunting natural products have resulted from these endeavors. 254,266 As part of this work, new synthetic strategies have been developed. The large number of steps

Me HO H Me H Me O H O J H B C H H H Me O D O O I O O A F H H O H H H O E G O O H H O H H H H

brevetoxin A (303)

OH Me H OH H O Me Me H H O BC D O H H H O O BC D A O O E H H A HO H H O O Me Me HO H H H H H Me Me O Me hemibrevetoxin B (302) brevenal (304) O

HO HO Me Me H H O O H ABDCE O H H H O O O F O H H H H H Me G Me O H H OH Me gambierol (305)

Figure 15. trans -Fused Polycyclic Ethers

generally required to prepare these molecules demand high throughput, and strategies for decreasing the total, and longest linear, number of steps have been described.

B. Approaches to Polycyclic Ether Synthesis

1. Iterative Ring Formation

The most straightforward method for forming polycyclic ethers involves applying approaches to medium ring ether formation in an iterative fashion to construct each ring of the ladder toxins sequentially. Clearly, this strategy requires highly efficient formation of each ring, since there is no convergency to reduce the longest linear sequence. One of the most effective methods of forming polycyclic ethers in a linear fashion was developed by the Rainier laboratory, centered upon C- glycoside synthesis. 267 The strategy has been applied to the preparation of the

ABCD 306 268 and FGH 269 subunits of gambierol, a natural product that causes ciguatera ( 305 ). 270 Namely, an enol ether–olefin ring-closing metathesis route was exploited to build each of these subunits. Beginning with pyran 307 , an epoxidation

and subsequent Grignard addition delivered the tertiary alcohol, which was acylated

to provide alkene 308 in 51% yield over two steps (Scheme 65). The theme of opening enol ether epoxides with nucleophiles was repeatedly utilized to build handles for establishing the subsequent rings. Methylenation 271 and treatment with the Grubbs second generation catalyst ( 151 )172 gave the AB ring unit 309 , again

possessing an enol ether ready for oxidation. Nine steps delivered ester 310 , which

was again methylenated 271 and subjected to a ring-closing metathesis 172 to provide

99 the ABC ring system 311 . Epoxidation, in situ reduction, and cyclodehydration gave the ABCD fragment 306 268 . Similar methods were employed to complete the FGH unit of gambierol ( 305 ). 269

1. DMDO, CH2Cl2, - 60 oC to rt; 1. TiCl , Zn, PbCl , PMBO CH2=CHCH2MgCl, PMBO 4 2 Me TMEDA, CH Br , Me THF 2 2 OAc THF A A 2. Ac O, i-Pr NEt, 2. 151,CH Cl BnO(H2C)3 O 2 2 BnO(H2C)3 O 2 2 H DMAP, CH Cl H H 2 2 (65%) 307 (51%) 308

PMBO TMSO 1. TiCl , Zn, PbCl Me Me Me 4 2 O Me O TMEDA, CH2Br2, 9 steps O THF A B AB OMe BnO(H2C)3 O BnO(H C) O O 2. 151,C H H H 2 3 H H H 6 6 OMe (77%) 309 310

TMSO HO Me Me 1. DMDO, i-Bu2AlH, Me Me H O o CH2Cl2, -60 C O O A B C AB C D OMe BnO(H2C)3 O O 2. PPTS, PhCl; pyr., BnO(H2C)3 O O H H H o H H H H OMe 135 C 311 (66%) 306

Scheme 65. Iterative Ladder Toxin Synthesis

2. Biomimetic Epoxide Opening

Nakanishi has proposed a biosynthetic pathway for the formation of polycyclic ethers involving a cascade of epoxide openings, with each epoxide opening simultaneously forming a new ring of the ladder toxins. 258 This sequential approach to the construction of marine ladder toxins has been examined by several research groups to test the probability of this hypothesis of origins. 272,273 One of the more

refined approaches has been reported by the Jamison group. They have used a

cascade opening of polyepoxides to form a tetrad of tetrahydropyrans, a unit which

100 is present in several of the ladder toxins. 274 Their strategy relies upon the use of trimethysilyl substituents on the epoxide, which serve to direct the cyclizations to favor the generation of tetrahydropyrans (6-endo) over the general bias for tetrahydrofuran formation (5-exo). Exemplary of their strategy is the formation of tetracycle 312 in one step from pyran 313 (Scheme 66). Pyran 313 was constructed using several iterations of the Shi epoxidation protocol to give the desired stereochemistry of each epoxide. 275 In the event, treatment with cesium carbonate and cesium fluoride in methanol at 65 oC provided the tetracycle, which was

acylated to provide ester 312 . During the course of the reaction, the trimethylsilyl groups served to direct the epoxidation to form the desired ring size; these directing groups are also cleaved following cyclization, a feature absent in other biomimetic routes. Although the yield for this transformation is low (20% overall), three new C–

O bonds and three new C–H bonds are formed in this example, translating to an average of 80% yield per bond formation.

1. Cs CO , CsF, H 2 3 H H H H HO MeOH, 65 oC O O TMS Me O O Me O 2. Ac2O, DMAP, AcO O O O H H H H H TMS TMS pyr., CH2Cl2 312 313 (20%)

Scheme 66. Biomimetic Approach

3. [X + 1 + X] Approach

As previously mentioned, convergent strategies have gained popularity within the synthetic community for the construction of polycyclic ethers to shorten the longest linear sequence and thereby increase throughput. An example of this strategy was described by Sasaki in his synthesis of brevenal ( 304 ). 266,276,277

101 Interestingly, brevenal ( 304 ) acts to competitively displace brevetoxin A ( 303 ) in rat brain synapses and antagonizes the toxic effects of its ten-ring counterpart. Due to this intriguing activity, as well as its potential utility for the treatment of cystic fibrosis, brevenal ( 303 ) has quickly garnered interest as a synthetic target. The Sasaki laboratory has applied their B-alkyl Suzuki strategy to couple two fragments and

form the central ring of the natural product. 278 To that end, phosphate 314 and the

hydroborated variant of alkene 315 were coupled under palladium-catalyzed

conditions to afford tetracycle 316 (Scheme 67). A second hydroboration and

oxidation of the B ring enol ether, followed by further oxidation of the resultant

secondary alcohol, gave ketone 317 in good yield.

OPh Me H O P OPh Me O H 9-BBN, THF; aq. Cs2CO3, O OTBS O E A B OBn o TBDPSO D O Pd(PPh3)4, DMF, 50 C O H H Me PMBO H 90% 314 315

TBDPSO Me Me H H 1. BH3-SMe2, THF; H OTBS OBn A O O E aq. NaHCO3,H2O2 H O B D O Me H H 2. n-Pr4NRuO4, NMO, o PMBO 4 A MS, CH2Cl2, 0 C 316 (92%)

TBDPSO Me Me H H H H OTBS OBn A O O E H O B D O Me O H H OPMB 317

Scheme 67. [X + 1 + X] Strategy

102 Installation of a secondary alcohol was next achieved in two steps (Scheme

68). 279 Protecting group manipulations and adjustment of the oxidation states of the

TBDPSO Me Me 1. LiHMDS, TMSCl, H H o H H OTBS OBn Et3N, THF, -78 C A O O E H O B D O 2. OsO4, NMO, THF, Me O H H OPMB H2O (87%) 317

TBDPSO Me Me o H H 1. i-Bu2AlH, THF, -78 C H H OTBS OBn o A O O E 2. TESOTf, Et3N,CH2Cl2, 0 C H O B D O H Me O H 3. DDQ, CH2Cl2/pH 7 buffer OPMB 4. n-Pr NRuO , NMO, 4 A MS, HO 4 4 CH2Cl2 318 (67%)

TBDPSO Me Me H H H H OTBS OBn 1. EtSH, Zn(OTf) , THF A O O E 2 H O B D O 2. TBSOTf, Et N,CH Cl , Me O H H 3 2 2 OTES 0 oC TESO (77%) 319

TBDPSO Me Me m-CPBA, CH Cl , H H H 2 2 O H OTBS OBn o o A O E -78 C; AlMe3, -78 C H O B C D O H o Me O H to 0 C H SEt 92% TBSO 320

TBDPSO Me Me H H H H OTBS OBn A O O E H O B C D O H Me O H H Me TBSO 321

103 Scheme 68. Completion of the ABCDE Rings alcohols on the B and D rings proceeded uneventfully. The triethylsilyl ethers were concomitantly cleaved under conditions used to form the dithioketal, and the alcohol spontaneously cyclized to form the mixed thioacetal. 280 Protection of the remaining

secondary alcohol gave pentacycle 320 . Oxidation of sulfur and in situ alkylation of

the resultant oxocarbenium ion provided polycycle 321 in 92% yield. All that

remained was installation of the A and E ring sidechains, which was completed to

achieve the first total synthesis of brevenal ( 304 ). 266,281

4. [X + 2 + X] Strategy

The final convergent approach developed to date involves the coupling of two fragments and subsequent formation of two rings between the previously independent moieties. An example of this can also be found in the synthesis of gambierol ( 305 ) by Rainier. 282 After iterative formation of the ABC 322 and FGH 323 fragments, 268,269 the group sought to join the two fragments and complete the E ring, followed by formation of the D ring to complete the octacycle. To that end, acid 322 was esterified with alcohol 323 under Yamaguchi conditions (Scheme 69). Takai–

Utimoto conditions were modified for direct formation of enol ether 324 from the

ester in 60% yield. 283 With the E ring formed, attention was turned to installing the D ring to complete the octacyclic core. Epoxidation and in situ reduction of ketone 324 gave the alcohol, which was oxidized to provide ketone 325 . Deprotection, formation of the thioacetal, 280 and radical reduction completed the D ring, to give the

framework 326 for gambierol ( 305 ). Eight more steps installed the side chains to complete the total synthesis of gambierol ( 305 ).

104

TIPSO Me Me H H H H H TBDPSO O OTES O OTBS O Me O AB C FG H OTBS O O OH HO O Me H H H H Me Me H 322 323

1. 2,4,6-Cl3C6H2C(O)Cl, o Et3N, THF, 40 C; DMAP, C H , 40 oC TIPSO 7 8 TBDPSO Me Me H OTES O H 2. CH CHBr , Zn, CH Cl , 3 2 2 2 ABC E O H PbCl2, TMEDA, THF, H O O O F H TiCl H H H H O 4 Me G OTBS (54%) Me O H H OTBS 324 Me

TIPSO TBDPSO 1. DMDO, CH Cl , -78 oC to Me Me HOTES 2 2 O O H 0 oC; i-Bu AlH, CH Cl 2 2 2 ABC E O H H O O O F H 2. n-Pr NRuO , NMO, 4 A MS, H H H H H O 4 4 Me G OTBS CH2Cl2 Me O H (88%) H OTBS 325 Me

TIPSO TBDPSO Me Me H H 1. CSA, MeOH, 0 oC O O H D O H 2. Zn(OTf)2, EtSH, CH2Cl2 ABC E H H O O O F O o H H H H H G 3. Ph3SnH, AIBN, C7H8, 110 C Me OH Me O H (78%) H OTBS 326 Me

Scheme 69. Formation of the D and E Rings

C. Brevetoxin A

1. Characterization and Biological Activity

Brevetoxin A ( 303 ) was isolated in 1975 by Alam and co-workers from the dinoflagellate Gymnodinium breve .284 This algal bloom has been implicated as the toxic component of the red tides in the Gulf of Mexico, causing massive fish kills.

105 The structure of brevetoxin A ( 303 ) was determined in 1986 via X-ray crystallographic analysis of its dimethyl ketal derivative. 285 The following year,

extensive NMR and MS analyses were reported which corroborated the previous

structural assignment. 286 Brevetoxin A ( 303 ) features a decacyclic structure with 22

stereocenters and four methyl substituents, two of which are angular. As with all

ladder toxins, each ring is trans -fused. Interestingly, brevetoxin A ( 303 ) is the only

Me HO Me H H Me O H O H B H H H Me J C O O I O O D O H A O F H H O H H E G O H O H H O H H H

brevetoxin A (303)

H+ Me HO Me Me Me O O O O -O O O O O O O O

Me HO Me Me O Me O

Scheme 70. Biosynthetic Hypothesis for Brevetoxin A

polycyclic ether that possesses five-, six-, seven-, eight-, as well as nine- membered rings within the same molecule. The Nakanishi proposal for the biosynthesis of the ladder toxins is demonstrated below for the natural formation of brevetoxin A ( 303 ). 258 The decacycle is derived from a polyolefin via stereoselective

106 epoxidation of the nine E-olefins in the chain (Scheme 70). The polyepoxide is then opened in cascade fashion, initiated by cyclization of the five-membered lactone and concluding with protonation of the J ring.

In depth studies have been undertaken to elucidate the mode of action for brevetoxin A ( 303 ) within humans. The brevetoxins bind strongly with neurological sodium ion channels. 287 This binding causes the sodium channels to remain open, allowing a harmful influx of sodium ions. As a result, the parent organism is eventually asphyxiated, causing death. Based upon extensive calculations and binding studies with brevetoxin derivatives, the Baden laboratory has gained much insight into the binding of brevetoxin A ( 303 ) within the cell. Calculations have

determined that two B ring conformers, five D ring conformers, three E ring

conformers, and five G ring conformers are possible, giving a total of 48 possible

conformations of the natural product within 6 kcal/mol of the global minimum. 288

Additionally, the F ring serves as a hinge point for the entire molecule, allowing the

decacycle to fold nearly in half on itself. These calculations, as well as a number of

synthetic manipulations on the natural material have elucidated which portions of

brevetoxin A ( 303 ) are most crucial for binding. The sum of these results suggest

that brevetoxin A ( 303 ) is a cigar-shaped molecule, about 30 Å in length, which binds primarily via hydrophobic and nonpolar solvation forces, potentially facilitated by hydrogen bond donors near the A ring lactone. 289 This greater understanding of

the mode of action of the brevetoxins should prove useful in attempting to deal with

this serious ecological concern.

107 2. Nicolaou’s Total Synthesis of Brevetoxin A

Naturally, the intriguing structure and biological properties of brevetoxin A

(303 ) have sparked interest within the synthetic community. This molecule is clearly quite daunting, and some inherent question as to whether or not a molecule of this size and complexity could even be prepared via purely synthetic means existed from the outset. Undeterred, or possibly inspired by these challenges, the Nicolaou laboratory initiated a program targeting the brevetoxins in the 1980’s. The group hoped to apply methods that they had developed specifically for the construction of oxygen-containing heterocycles to the total syntheses of the ladder toxins.

The Nicolaou group reported the total synthesis of the related undecacycle brevetoxin B in 1995, 145,290-295 and utilized a similar strategy for the preparation of brevetoxin A ( 303 ). 296-300 Strategically, the polycycle was envisioned to arise in a convergent [X + 1 + X] sense from the union of two fragments of similar complexity, the ABCD portion 327 and the FGHIJK fragment 328 (Scheme 71). The E ring was proposed to be formed via the coupling of these two fragments using a Wittig reaction and subsequent dithioketal cyclyization. For the ABCD fragment 327 , the B and D rings would be formed via a bis-lactonization of the C ring, derived from D- glucose ( 329 ). A late-stage lactonization would provide the A ring. The FGHIJ portion 328 would arise from a series of epoxide openings beginning with the J ring, derived from D-mannose ( 330 ), building the I and H rings in an iterative fashion.

Wittig coupling and dithioketal cyclization would be exploited to establish the G and

F rings.

108 Me HO H Me H Me O H O J H B C H H H Me O D O O I O O A F H H O H H H O E G O O H H O H H H H

brevetoxin A (303)

Me BnO H OTBDPS Me H O Me H O H B H EtS H Me J C OTBS EtS O I O D F H O H A O H H H O G O H MeO H H I- O H H H + PPh3 327 O 328

O OH OH HO C HO OH HO OH J OH OH HO O 329 330

Scheme 71. Nicolaou's Retrosynthetic Analysis To begin, tetrahydrofuran 331 was accessed in seven steps from D-glucose

(329 ) via protection, oxygenations, deoxygenation, and alkylations (Scheme 72).

Three steps delivered lactol 332 , which was converted in three steps to the C ring

333 . Fourteen steps were performed to prepare CD phosphonium salt 334 , to be used as a probe for the E ring formation. Similarly, F ring aldehyde 335 was synthesized in 24 steps from known diol 336 .301 Union of fragments 334 and 335

was accomplished using a Wittig coupling to provide the diene in 82% yield.

Deprotection provided the D ring alcohol 337 . However, upon subjecting the dithioketal 337 to the cyclization conditions developed in their laboratory, no E ring

109 Me HO Me O O OH OH O 3 steps HO 7 steps O C H Me HO OH BnO OBn O H H OH Me 331 332 329

Me H Me Me O OTBS Me H 3 steps 14 steps Me O H C CD BnO OBn CO2Me OTBS H H MEMO O H H H I- 333 + 334 PPh3

H O O EtS HO 24 steps F EtS O OPiv HO H H

336 O 335

335 Me H Me Me Me O H 1. n-BuLi, THF, Me H H o Me O H EtS O CD HMPA, -78 C EtS F OTBS CD MEMO O OH H H H I- MEMO O O 2. n-Bu4NF, THF H H H H OPiv PPh + H 334 3 (73%) 337

Me Me H H AgClO , NaHCO , Me O H H O 4 3 O CD F SiO , 4 A MS, MeNO 2 2 MEMO E O O H H H H H OPiv

338 0% Me Me Me H H Me H H Me O H O Me O H O EtS F CD CD O F OH OH MEMO O MEMO O O H O H H H H OPiv H H H H OPiv

339 340 56% 31% Scheme 72. Attempted E Ring Formation Model

110 Me HO Me H H Me O H O B Me J H C H H H O D O O I O O A F H H O H H H O E G O O H H O H H H H

brevetoxin A (303)

Me I- BnO H OTBDPS PPh + Me H Me 3 H O O O H Me J H B H H O I O C O H H TBDPSO D H O G O H H O E EtS H TrO H H OPiv EtS H H 341 342

O OH OH HO C HO OH HO OH J OH OH HO O 329 330

Scheme 73. Nicolaou’s Revised Retrosynthesis

was formed.280 Instead, elimination 339 and hydrolysis 340 products were isolated

in 87% combined yield. Due to this setback, a new approach to brevetoxin A was

envisioned that would involve formation of the F ring as the point of convergence

(Scheme 73). It was thought that the smaller size of the F ring, an oxocene

compared to the E ring oxonene, would facilitate the dithioketal cyclization. To that

end, BCDE phosphonium salt 341 was targeted along with GHIJ aldehyde 342 .

To model the revised coupling strategy, E ring 343 was prepared in 20 steps from 2-deoxy-D-ribose ( 344 , Scheme 74). Analogously, 16 steps delivered GH

111 aldehyde 345 from 2-deoxy-D-ribose ( 344 ). Again, Wittig coupling was effective in joining the two fragments and gave the diene in 77% yield. Deprotection provided a candidate for cyclization 346 , and this time, the conditions developed within the

Nicolaou laboratory were effective for giving pentacycle 347 .280 Radical reduction of

I- + O OH PPh3 20 steps O H H HO Ph O OH O E H OPiv 344 H

343 O OH 16 steps O H H O HO H OH EtS G O 344 EtS H

345

I- + 345 PPh3 1. n-BuLi, THF, O H H H H O H H HMPA, -78 oC O O O Ph EtS H Ph EtS O E G O O E 2. i-Bu AlH, CH Cl , H OH H OPiv 2 2 2 H H H -78 oC

343 (64%) 346

O H H H H Ph SnH, AIBN, AgClO4, NaHCO3, O O 3 Ph F H O o SiO2, 4 A MS, MeNO2 E G O Ph-Me, 111 C H O 81% H EtS H 80% 347

O H H H H O O Ph F H O E G O H O H H H

348

Scheme 74. Model of F Ring Formation

112 the mixed thioacetal delivered the EFGH fragment 348 in 80% yield as a single diastereomer.

With confidence in the main disconnection point chosen for brevetoxin A

(303 ), the group set out to prepare BCDE fragment 341 and GHIJ aldehyde 342 to complete their total synthesis. Previously described C ring 333 was converted in five steps to diacid 349 (Scheme 75). A bis-lactonization closed the B and D rings and four more steps gave dilactone 350 . Six further steps were exploited to vary the oxidation states of the B and D rings and deliver triol 351 . Protecting group manipulations proceeded for the subsequent six steps to give alcohol 352 , and the lactone was formed to close the E ring and give access in four steps to lactone 353 .

Four steps were utilized to prepared diene 354 , and alcohol 355 was accessed in six additional steps. Finally, the targeted phosphonium salt 341 was realized in four steps from alcohol 355 .

For the GHIJ aldehyde 342 , seven previously elucidated steps gave access to alkene 356 from D-mannose ( 330 , Scheme 76). 293 Six further transformations delivered epoxide 357 , which was altered in four additional steps to give alkene 358 .

Epoxide 359 was arrived upon in five steps from alkene 358 , and four more steps gave alkene 360 with the H ring in tact. Five manipulations gave acetonide 361 , and eight further steps provided the aldehyde 362 . The G ring was formed via a dithioketal cyclization and four additional steps to provide pentacycle 363 . Five steps delivered alcohol 364 , and four more transformations delivered targeted aldehyde 342 .

113 O OH Me H Me HO 13 steps O OTBS 5 steps C HO OH BnO OBn CO2Me OH H H 329 333

Me Me H Me Me H Me O OTBS O 5 steps 6 steps C CD HO2C B HO OH CO2H O O H H H H O O 349 350

Me Me Me Me H Me H Me O H 6 steps O H H OH H B C D B C D OAc TBDPSO O O TBDPSO O H H OH O H H OH H H H H BnO PivO 351 352

Me Me H Me O H O 4 steps 4 steps H O B C D TBDPSO O E O H H H H PivO 353

Me Me H Me OH Me Me H Me OTBS O H O H H O H C D OH 6 steps H O B B C D OH TBDPSO O E O H H H TBDPSO O E H H O H H H PivO H H TrO 354 355

Me I- Me PPh + H Me 3 4 steps O H B H H TBDPSO C D O O H H O E TrO H H OPiv H 341

Scheme 75. BCDE Phosphonium Salt Synthesis

114 OH OH 6 steps HO OH 7 steps HO J OH OTBDPS HO O O H 330 356

OBn OBn H H H TESO O 4 steps O J I J OTBDPS OTBDPS HO O TBSO O H H H 357 358

OBn H H 5 steps HO O 4 steps O J I OTBDPS TBSO O H H 359

OBn OBn H H H Me H H H HO O 5 steps O O Me H I J H I J OTBDPS O O O O O CO Me H H H H H H 2 360 361

OBn BnO SEt H H EtS O H 8 steps 5 steps H O H J H Me J R O I O O I O O R H O H H H H Ph H O G O H 362 H H 363

HO H H 5 steps TBSO O 4 steps H Me J R O I H O H H AcO G O H H H 364

TBSO H OTBDPS H O O H Me J R = (CH2)3OTBDPS O I H O H H EtS G O H EtS H 342

Scheme 76. GHIJ Aldehyde Synthesis

115

With each of the desired coupling partners in hand, attention was turned to the union of these units and formation of the F ring. Unfortunately, unlike in the model system (Scheme 74), the Wittig reaction was unsuccessful in delivering the desired olefinic product 365 (Scheme 77). The methyl substituent of the GH ring juncture was implicated as the culprit, as it had been omitted in the successful model system (Scheme 74). The steric interactions of the ylide of phosphonium salt 341 and the aldehyde 342 precluded productive olefination. As a result, a less bulky ylide was targeted, and alcohol 355 was transformed into phosphine oxide 366 in four steps (Scheme 78). It was predicted via extensive modeling that a small, chelating protecing group, in this case methoxypropyl, would be necessary to obtain good Z selectivity for the olefination.

I- TBSO Me H OTBDPS PPh + Me H Me 3 H O O O H Me J H H H O I O B C H H TBDPSO D O H O EtS G O H H H O E TrO H H OPiv EtS H H 342 341 n-BuLi, THF, HMPA or KHMDS, THF

Me TBSO Me H H Me O H O H B H H H Me J C O O I OTBDPS TBDPSO D EtS O H O EtS H H O H H E G O H TrO H H OPiv H H

365

Scheme 77. Attempted Wittig Coupling

116 Me Me Me H Me OTBS O Ph O H H Me H P Ph O O Me H OH 4 steps B CD H B H H TBDPSO C O O O E H TBDPSO D H H H O H H H O E TrO TrO H H OMOP 355 H 366

Scheme 78. Phosphine Oxide Formation

A Horner–Wittig coupling was employed to join the BCDE phosphine oxide

366 and GHIJ aldehyde 342 (Scheme 79). Base-induced elimination of the resultant adduct provided diene 367 in 56% yield over the two steps. Mild acidic conditions were useful in cleaving the ketal protecting group, and subjection to Nicolaou’s hydroxyl dithioketal cyclization conditions resulted in formation of mixed thioacetal

368 .280 Earlier investigations had revealed that radical reduction was not useful in

removing the thioether, so a two-step oxidation and reduction protocol was exploited

to deliver the fully functionalized F ring 369 . With the BCDEFGHIJ portion of

brevetoxin A ( 303 ) constructed, formation of the A ring and the J ring sidechain were next targeted. The trityl protecting group had been cleaved during the reduction of the mixed thioacetal, so the primary alcohol was oxidized to the aldehyde 43 and then the acid, followed by formation of the methyl ester 370 (Scheme 80). Acidic removal of the silyl protecting groups also resulted in lactonization of the A ring. Careful oxidation of the primary alcohol on the J ring was carried out in the presence of the secondary alcohol, 43 and the resultant aldehyde was treated with Eschenmoser’s

salt to provide brevetoxin A ( 303 ), 302 which was identical in all regards to the natural material. 284

117 Me TBSO O Ph H OTBDPS P Me H Me Ph H O O O H Me J H B H H O I O TBDPSO C O H H D H O G O H H O E EtS H TrO H H OMOP EtS H H 366 342

1. n-BuLi, THF, -78 oC 2. KH, DMF (56%) Me TBSO H Me H Me O H O J H B C H H H Me D O O I OTBDPS TBDPSO EtS H O H O EtS H H H O E G O TrO H H OR H H H

367 R = MOP 1. AcOH, THF 2. AgClO4, NaHCO3, SiO2, 4 A MS, MeNO2 Me (59%) TBSO Me H H Me O H O H B H H H Me J C O O I OTBDPS TBDPSO D O H O F H H O H H E G O H TrO H H O H EtS H

368

o 1. m-CPBA, CH2Cl2, 0 C o 2. BF3-OEt2, Et3SiH, CH2Cl2, -78 C (68%)

Me TBSO Me H H O Me H O J H B C H H H Me D O O I OTBDPS TBDPSO F H O H O H H H O E G O HO H H O H H H H

369

Scheme 79. Formation of the BCDEFGHIJ Portion

118 Me TBSO H Me H Me O H O J H B C H H H Me D O O I OTBDPS TBDPSO F H O H O H H H O E G O HO H H O H H H H

369

1. Dess-Martin periodinane, CH2Cl2 2. NaClO2, NaH2PO4, THF, t-BuOH, H2O o 3. CH2N2, Et2O, 0 C (71%)

Me TBSO H Me H Me O H O Me J H B C H H H TBDPSO D O O I O OTBDPS F H H O H MeO2C H H O E G O H H O H H H H

370

o 1. HF-pyr, CH2Cl2, 0 C o 2. Dess-Martin periodinane, CH2Cl2, 0 C + - 3. CH2=N (Me)2I , Et3N,CH2Cl2 (53%)

Me HO H Me H Me O H O J H B C H H H Me O D O O I O O A F H H O H H H O E G O O H H O H H H H

brevetoxin A (303)

Scheme 80. Completion of Brevetoxin A

D. Previous Work in the Crimmins Laboratory Toward Brevetoxin A

1. Seminal Efforts Toward the BCDE Fragment

In 2000, the Crimmins laboratory began investigating the syntheses of the B and E rings of brevetoxin A ( 303 ). The original intent was to probe the efficiency

with which the glycolate alkylation/ring-closing metathesis strategy would allow

119 access to subunits of the ladder toxins. In time, it was decided to pursue a total synthesis of this complex natural product. An [X + 1 + X] strategy highly analogous to the Nicolaou laboratory’s endgame would be exploited to form the F ring (Scheme

81). This completion strategy was selected for at least two reasons; first, it divides the molecule into two fragments of very similar complexity, and second, the final steps worked out by the Nicolaou group have been demonstrated to be highly

Me HO H Me H Me O H O J H B C H H H Me O D O O I O O A F H H O H H H O E G O O H H O H H H H

brevetoxin A (303)

Me O PO Ph H OP Me Ph P H Me H O O O J H B H H H Me C O I O PO D O H O EtS H H H O G O H PO H H E OP EtS H H 371 372

Me X OP Me Me PO H PO OH H H Me X H OP H O O B PO PO PO J O E PO G OP H H OP O PO H Y H H H H H 375 376 373 374

Scheme 81. Retrosynthetic Analysis of Brevetoxin A efficient. 300 The required BCDE 371 and GHIJ 372 fragments would arise from a

novel, convergent [X + 2 + X] strategy to form the CD and HI rings from their

120 respective peripheral rings. The overall strategy hinged upon initial formation of the

B 373 , E 374 , G 375 , and J 376 rings via methods developed in our laboratory.

Dr. Kyle A. Emmitte initiated these efforts, developing a 20 step approach to oxonene 377 , as well as providing seminal results for the B ring synthesis.

Following these findings, Dr. Patrick J. McDougall took on the task of improving routes to modified B and E rings, and developing a convergent [X + 2 + X] coupling strategy for the synthesis of the BCDE portion. 244 For the E ring, Dr. Emmitte utilized a glycolate alkylation to initiate the synthesis (Scheme 82). 208 Two steps

transformed alkylation adduct 379 into aldehyde 380 , which was used in a

thiazolidinethione propionate aldol reaction to give alcohol 382 .215 Four further transformations provided glycolate 383 , which was alkylated with prenyl iodide to yield alkene 384 . Five further steps, including an asymmetric Brown allylation to set the C21 stereocenter, 303 delivered diene 385 , which was efficiently closed using the

Grubbs catalyst 150 to provide oxonene 386 .195,201 Five steps gave E ring 377 , which could be utilized in a coupling reaction with the B ring.

Dr. McDougall next developed two possible pathways to form the E ring of brevetoxin A ( 303 ). The second route to the E ring was predicated upon the anti - glycolate aldol methodology that Dr. McDougall had previously developed in the

Crimmins laboratory (Scheme 83). 304 Using glycolic acid 387 from the previous E ring route, oxazolidinethione glycolate 388 was prepared and subjected to the optimized conditions for anti -aldol reaction with 3-butenal. This approach led to an E ring β-keto phosphonate 390 , which proved useful in a Horner–Wadsworth–Emmons reaction to couple to the B ring. 305,306 However, diene 390 was a truncated version

121 of the E ring, missing C24. It was determined that a homologated version of the E ring would be more amenable to the desired [X + 1 + X] convergent coupling strategy for the F ring formation. To that end, glycolate 391 , differing from previously

O O O O O NaHMDS, CH2=CHCH2I OBn OBn 2 steps OBn O N O N THF, -78 oC to -45 oC H H i-Pr 82% i-Pr 378 379 380

S O Me TIPSO S N Me S O OH H O 381 O O Bn OBn 4 steps S N BnO N H O TiCl4, (-)-sparteine, Me H o NMP,CH2Cl2, -78 C Bn i-Pr to 0 oC 382 383 92%

TIPSO Me NaHMDS, Me Me Me (CH ) C=CHCH I H TIPSO 3 2 2 O H Me Me O 5 steps i-Pr H H THF, -78 oC to -45 oC BnO O H 83% O N BnO E 21 H OAc O O H 384 385 Me Me TIPSO Me O HO OBn 5 mol% 150 Me H H 5 steps O H H o O CH2Cl2, 40 C BnO E OAc BnO 99% H E H H OBn H 386 377

Scheme 82. Dr. Emmitte's E Ring Synthesis prepared glycolate 383 only in the protecting group for the C16 hydroxyl moiety, was alkylated with bromoacetonitrile to afford nitrile 384 (Scheme 84). Thirteen steps provided diene 393 , prepared for ring-closing metathesis. 195,201 In the event, the

122 oxonene was formed, delivering phosphonate 394 . Both diene 389 and oxonene

394 were utilized for a convergent coupling with the B ring to form variants of the

BCDE portion of brevetoxin A ( 303 , vide infra).

TIPSO Me TIPSO Me TiCl , 3-butenal, H O 4 H O (-)-sparteine, O 1 step O S BnO OH BnO N CH Cl , -78 oC H H O 2 2 50%, 5:1 dr (80% brsm) Bn

387 388

MeO O TIPSO P MeBn O MeO O H H N O S Me 9 steps OPMB BnO O H H O 23 H OH H PMBO E H OPMB H 389 390

Scheme 83. Dr. McDougall's First Generation E Ring Synthesis

TIPSO Me TIPSO H O NaHMDS, Me N O O BrCH2CCN H H PMBO N O 13 steps H O THF, -78 oC to -45 oC BnO i-Pr i-Pr 75% H O N 391 O O 384

MeO O P MeO O O MeO P OBn MeO O Me OBn 24 5 mol% 150 H H Me 24 O H H CH Cl , 40 oC O TBSO 2 2 E (quant.) H OBn TBSO H E OBn H H

393 394

Scheme 84. Dr. McDougall's Second Generation E Ring Synthesis

123

For the B ring, Dr. McDougall built upon initial results obtained by Dr. Emmitte to develop an efficient strategy for oxocane 395 (Scheme 85). The approach commenced with an anti -glycolate aldol reaction of thioimide 396 with 3-methyl-3- butenal. Six steps provided glycolate 398 , a candidate for an asymmetric alkylation.

Treatment of the sodium enolate of glycolate 398 with benzyl iodomethyl ether prepared in situ gave adduct 399 . Three steps delivered diene 400 , which upon treatment with the Grubbs second generation catalyst 151 yielded oxocene 401 .172

Five further transformations led to B ring oxocane 395 , prepared for Horner–

Wadsworth–Emmons coupling.

PMBO Me S O TiCl4, (-)-sparteine, S O OH Me TIPSO 3-methyl-3-butenal, 6 steps O N O N O O o i-Pr CH2Cl2, -78 C O Bn 64%, 7:1 dr Bn O N 396 397 O O 398

PMBO Me H NaHMDS, TIPSO Me OH 5 mol% 151 (BnO)2CH2, TMSI 3 steps O OBn PMBO H i-Pr O H o THF, -78 oC to -45 oC OH CH2Cl2, 40 C TIPSO H 75% O N (75%) 400 O O 399

Me Me H Me OH OH 5 steps B PMBO O PMBO H O H O 2 O TIPSO H TIPSO H 401 395

Scheme 85. Dr. McDougall's B Ring Synthesis

E. Prepartion of the BCDE and GHIJ Fragments

124 1. A Revised Route to a Homologated B Ring

The aforementioned B ring 395 was also truncated by one carbon (analogous to E ring 390 ). Upon joining the effort toward brevetoxin A ( 303 ), my initial task was to develop an efficient, revised route to a homologated B ring, including C1, based upon Dr. McDougall’s efforts. It was chosen to incorporate C1 at an early stage, essentially intercepting the previous route for the majority of the synthesis. To that end, a one-carbon homologated variant of glycolate 398 was targeted. A glycolate alkylation strategy was selected to replace the anti -glycolate aldol reaction used to initiate the previous route (Scheme 85). Alkylation of glycolate 402 with methallyl iodide provided the desired adduct in 78% yield (Scheme 86). 208 Reduction and oxidation 130 delivered aldehyde 404 , which was utilized in an aldol reaction with t- butyl acetate to give alcohol 405 as a mixture of C3 epimers. Reduction was accomplished using lithium aluminum hydride to provide diol 406 . In an effort to shorten the synthesis of diol 406 , and further examine the versatility of glycolate alkylation adducts, we investigated other useful transformations using imide 403 .

After some optimization, it was found that very efficient Claisen condensation was possible using the lithium enolate of t-butyl acetate or ethyl acetate and imide 403 to yield β-keto ester 408 or 411 (Scheme 87). Additionally, it was discovered that i-

Bu 2AlH reduction of alkylation adduct 403 allowed for direct access to aldehyde 404 .

We propose that these manipulations are facilitated by the inductive effect of the ether oxygen, which increases the electrophilicity of the adjacent carbonyl. Since this discovery, these reactions have found use in other settings within our laboratory.

The most direct route to the B ring involved use of β-keto ester 407 . Reduction

125 provided diol 406 , this time in three steps from glycolate 402 as opposed to the previous five step route (Scheme 88).

Me O O NaHMDS, CH =C(CH )CH I 1. NaBH4, THF, H2O OPMB 2 3 2 H O N o o PMBO O THF, -78 C to -45 C 2. (COCl)2, DMSO, Et3N, 78% i-Pr N CH Cl , -78 oC to rt i-Pr O 2 2 402 O (96%) 403

Me Me Me

t-BuOAc, LDA, LiAlH4, Et2O H H H PMBO o o O THF, -78 C PMBO 3 0 C PMBO OH OH 92% t-Bu-O C 89% 404 2 H HO H 405 406

Scheme 86. Homologated Diol Synthesis

Me t-BuOAc, LDA, Me THF, -78 oC H 79% PMBO O H PMBO i-Pr N or O O RO C EtOAc, LDA, 2 o O THF, -78 C 407, R = Et 403 84% 408, R = t-Bu

Me Me H i-Bu AlH, CH Cl , PMBO 2 2 2 O H i-Pr N -78 oC PMBO O O 86% O 404 403

Scheme 87. Novel Glycolate Transformations

Selective protection of the primary alcohol of diol 406 was followed by oxidation to give ketone 409 (Scheme 88). 130 Chelation-controlled reduction

126 provided alcohol 410 in 79% yield (>15:1 dr). 307 It was not possible to effect direct diastereoselective reduction on β-keto ester 407 , likely due to favored formation of the zinc enolate. Alcohol 410 represents a one-carbon homologated variant of an intermediate from the previous B ring route. Formation of the glycolic acid and corresponding acylation to realize glycolate 411 proceeded uneventfully. Alkylation with benzyl iodomethyl ether afforded alkene 412 .208 Reduction and oxidation served to deliver aldehyde 413 .130 Direct reduction to the aldehyde was not possible

in this case, presumably due to either the increased steric demand of the alkylation

adduct or counterproductive participation of the benzyl ether oxygen. Vinyl Grignard

addition gave a 3:1 inseparable mixture of diastereomers, favoring the desired C8

configuration. Although this center would later be oxidized, the configuration of the

C8 alcohol had previously been demonstrated to be crucial for the impending

hydrogenation to establish the C6 stereocenter. Ring-closing metathesis delivered

oxocenes 414 and 415 . At this point, the C8 epimers were separable, and the minor diastereomer 415 could be recycled via a Swern oxidation 130 and Luche reduction

(Scheme 89). 49

With the oxocene in hand, the merged material was subjected to hydrogenation with Crabtree’s catalyst at low temperature (Scheme 90). 308 Since

hydrogenations of allylic alcohols with Crabtree’s catalyst often proceed via direction

from the hydroxyl group, it may appear counterintuitive that the C6 methyl and the

C8 hydroxyl are cis to one another. However, there are examples of

cyclopropanations and epoxidations of cyclooctenes proceeding to provide the

127 Me Me Me

LiAlH4, Et2O, 1. TIPSCl, imid., CH Cl H H 2 2 H PMBO PMBO 0 oC PMBO 3 O O OH 2. (COCl)2, DMSO, Et3N, EtO2C 80% o HO H CH2Cl2, -78 C to rt TIPSO 407 406 (quant.) 409

Me Me 1. NaH, BrCH CO H, H Zn(BH4)2, Et2O, 2 2 H THF, DMF PMBO O o PMBO 3 O -25 C H OH 2. PivCl, Et3N;(R)-lithio- TIPSO 79% (>15:1 dr) 1 4-isopropyloxazolidinin- O TIPSO H N 2-one 410 i-Pr O (81%) 411 Me Me NaHMDS, H 1. LiBH4, MeOH, (BnO) CH ,TMSI Et O, 0 oC O 2 2 PMBO 2 H O O PMBO THF, -78 oC to -45 oC TIPSO H 2. (COCl) , DMSO, O BnO 2 H O H 83% H N Et3N,CH2Cl2, TIPSO BnO -78 oC to rt i-Pr O 413 (86%) 412

Me 1. CH2=CHMgBr, THF, o H 0 C OH H 8 o PMBO 2. 151, CH2Cl2, 40 C O H (62%, 3:1 dr) TIPSO H BnO 414

Scheme 88. Oxocene Synthesis

Me 1. (COCl)2, DMSO, Me OH Et3N, CH2Cl2, H H -78 oC to rt OH H 8 H 8 PMBO PMBO O 2. NaBH , CeCl , O H 4 3 H TIPSO H BnO MeOH, 0 oC TIPSO H BnO 415 (53%) 414

Scheme 89. Recycling the C8 Epimer

128 newly-formed ring trans to the alcohol. 309 As a probe of the role of the C8 oxygen, alcohol 414 was protected as a silyl ether and subjected to Crabtree’s hydrogenation. In the event, no reaction was observed, even after several hours at ambient temperature. Whether responsible for a conformational or directing effect, the C8 hydroxyl is clearly important in this transformation. Oxidation 130 provided a ketone, which delivered a single diastereomer of tertiary alcohol 419 upon alkylation with methylmagnesium chloride (Scheme 91). Selective cleavage of the benzyl ether could be accomplished using lithium di-t-butylbiphenylide reduction or Raney nickel hydrogenation, 310 with the latter proving more amenable to larger scale.

Dess–Martin oxidation provided aldehyde 420 ,43 a one-carbon homologated variant

of aldehyde 395 . Aldehyde 420 was prepared in 18 steps and 9.8% overall yield,

Me Me H H + 6 OH [PCy3][COD][pyr.]Ir PF6- OH H H 8 PMBO o PMBO O H2,CH2Cl2, -50 C O H 94% H TIPSO H BnO TIPSO H BnO 414 416

Me Me

H + - H OTES [PCy3][COD][pyr.]Ir PF6 OTES H H PMBO H ,CH Cl PMBO O 2 2 2 O H H TIPSO H BnO TIPSO H BnO 417 418

Scheme 90. Diastereoselective Hydrogenation compared to 17 steps and 8.8% overall yield for aldehyde 395 . Highlights of this route include the discovery of novel reactivity for glycolate alkylation adducts, use of the more economical Swern oxidation 130 in place of Dess–Martin periodinane at two

129 points, 43 and more practical conditions for removal of the benzyl ether on large scale. 310 The practicality and efficiency of this route is underscored by the

preparation of 3.8 grams (7.2 mmol) of the B ring 420 in a single pass.

Me Me 1. (COCl)2, DMSO, H Me Et3N, CH2Cl2, OH OH o H -78 C to rt H PMBO PMBO O O H 2. MeMgCl, Et O, H H 2 TIPSO H BnO TIPSO BnO -78 oC 416 (84%) 419

Me Me 1. Raney Ni, H2, EtOH OH H B 2. Dess-Martin periodinane PMBO O (81%) H TIPSO 1 H O 420

Scheme 91. Completion of the Homologated B Ring

2. Formation of the BCDE Fragment

After preparing multigram quantities of B ring aldehyde 420 , this material was passed on to Dr. Patrick J. McDougall, who progressed the B ring aldehyde 420 and the E ring phosphonate 394 to BCDE fragment 421 . The route utilized was based

upon previous success forming BCDE fragment 422 in eleven steps from truncated

B ring 395 and truncated E ring 390 . The homologated cyclic ethers 420 and 394

were joined via a Horner–Wadsworth–Emmons olefination using aqueous barium

hydroxide (Scheme 92). 305,306 Cyclodehydration was accomplished using

Wilkinson’s catalyst, followed by heating with acid to give tricycle 424 in a single

pot. 311 Oxidation, ketalization, and reduction led to diol 422 in five steps. 214 This

route provided the BCDE tetracycle in four fewer steps from the B and E rings than

the previous strategy for the truncated fragments. 244

130 O MeO P Me MeO O OBn Me Me 24 OH H B H H Ba(OH) , THF, H O O 2 2 PMBO O 96% H TBSO E 1 H OBn TIPSO O H H 420 394

Me Me OH Me OBn (Ph P) RhCl, Me PhSiH; H H 3 3 2 B RO O H O H O PPTS, PhMe, 50 oC PMBO H E H OBn 92% TIPSO 423 R = TBS

Me Me Me Me OBn Me H Me OBn O O H 24 H B H H H C 5 steps H O PMBO O B C D O OBn H TBSO HO O E H E OBn O H H TIPSO H H H H H HO 1 424 421

Me Me H Me O H H OH H O B C D OH HO O O E H H H TIPSO H H

422

Scheme 92. Dr. McDougall's BCDE Formation

3. Formation of the GHIJ Fragment

The approach to the other half of brevetoxin A ( 303 ) was executed by J.

Lucas Zuccarello, Dr. Pamela A. Cleary, and Dr. Jon D. Parrish. Dr. Cleary designed a first generation synthesis of the G ring, 312 while Dr. Parrish formed the J ring in an expedient fashion. With these results, Luke Zuccarello progressed these

131 fragments, while optimizing each step, to the GHIJ fragment 425 (Figure 16). 243 A similar Horner–Wadsworth–Emmons olefination/cyclodehydration approach was successful in forming the tetracycle 425 . Additionally, tetracycle 426 was accessed to provide a substrate with less robust protecting groups on the J ring, for more facile removal at a later stage. Efforts are also underway to intercept Nicolaou’s silyl variant 342 .296,297

BnO BzO H OBn H OBz H O H O O H Me J O H Me J O I O O I O H H EtS H EtS H G O G O EtS H EtS H H H 425 426

TBSO H OTBDPS H O O H Me J O I O H EtS H G O EtS H H 342

Figure 16. GHIJ Fragments

F. Model Studies of F Ring Formation

Upon attempting to model Wittig and Horner–Wittig strategies for the formation of the F ring using E and G ring fragments, a plethora of obstacles were encountered. Oxidation of alcohol 427 ,43 an intermediate from the G ring

synthesis, 243 provided hemiketal 428 , with concomitant loss of the p-methoxybenzyl

protecting group, instead of the desired ketone 429 (Scheme 93). To impede this

cyclization so that we could access the ketal, we chose to install a cyclic constraint

on the opposite side of the G ring. Triol 430 was accessed by acidic deprotection of

132 both the silyl and p-methoxybenzyl protecting group, or by oxidative deprotection of the aryl ether, followed by fluoride-mediated removal of the silyl ether. The latter route was more reproducible, as the acidic conditions gave a ring-opened product

431 upon extended reaction time. Treatment of triol 430 with p-toluenesulfonyl

OTIPS OTIPS OTIPS

Me BnO Dess-Martin periodinane Me BnO Me H O BnO H H OPMB O O OPMB G CH2Cl2 82% O HO HO O 427 428 429 not observed

OTIPS HCl, MeOH, 65 oC OH 85% BnO Me or BnO Me HO H HO H H H O OPMB O OH OH BnO G 1. DDQ, CH2Cl2: HO H Me H HO H2O HO 431 2. n-Bu NF, THF 427 4 430 (93%)

Me BnO Me BnO H 1. Dess-Martin periodinane, H TsCl, Et N, O O OH 3 O CH2Cl2

CH2Cl2 HO 92% HO 2. p-TSA, MeOH, o CH(OMe)3, 65 C 430 432 (87%)

BnO Me 1. Pd(OH) ,H , O Me H 2 2 H O O MeOH O O G MeO 2. Dess-Martin MeO periodinane, MeO MeO pyr., CH Cl 433 2 2 434 (84%)

Scheme 93. G Ring Aldehyde for Model chloride caused spontaneous cyclization to give bicycle 432 . Oxidation provided the ketone, which was ketalized under acidic conditions to give dimethyl ketal 433 . Care

had to be taken when handling ketal 433 , as some slightly acidic solvents caused

133 elimination to occur. As a result, all NMR’s were taken in d 6-benzene. Finally, the benzyl ether was cleaved under hydrogenolysis conditions, and oxidation provided aldehyde 434 ,43 which we hoped to use in a Wittig or Horner–Wittig reaction.

The E ring model proved more difficult to work with. Diol 435 , an intermediate

from the E ring 394 synthesis, was obtained from Dr. McDougall. 214 Ring-closing metathesis afforded oxonene 436 (Scheme 94). 195,201 We hoped to install a good

leaving group on the primary alcohol, then protect the secondary alcohol. However,

tosylation of the primary alcohol of diol 436 led only to furan 437 . The diol was bis-

protected as triethylsilyl ethers and the primary silyl group was removed under acidic

conditions. Formation of the primary iodide led to facile cyclization to the previously

observed furan 437 , despite precedent in ladder toxin synthesis forming analogous

silyl protected 1,4-halohydrins in high yield. 254 We returned to diol 436 and

protected the primary alcohol as an ester, followed by protection of the secondary

alcohol as a silyl ether. Methanolysis of the acetate group was followed by formation

of the iodide 442 , which also formed furan 437 , though slower than the triethylsilyl

variant 440 . Attempts to form the phosphonium salt 443 led to mixtures of cyclization and deprotection products. These undesired cyclizations served to thwart our efforts at a phosphonium salt for the time being, so we pursued a phosphine oxide variant for a Horner–Wittig olefination. To that end, mesylation and subsequent phosphine oxide formation delivered oxonene 444 in 88% from alcohol

441 (Scheme 95). Unfortunately, the lithium enolate of phosphine oxide 444 and

aldehyde 434 did not react with one another, likely due to the size of the silyl ether

on the E ring 444 . So, ester 446 was protected with a methoxymethyl ether, and

134 TBSO Me H H OH TBSO Me 151,CH Cl , OH O 2 2 H H TsCl, Et3N, TBSO OH O 40 oC TBSO OH CH Cl E 2 2 92% 76%

435 436

TBSO Me TBSO Me H H H H OTs O O TBSO O TBSO OH

437 438 not observed

TBSO Me TBSO Me OH OH H H 1. TESCl, imid., H H O O PPh3, imid., DMAP, CH2Cl2 TBSO OH TBSO OTES I ,CH Cl 2. HF-pyr, THF 2 2 2 92% (73%) 436 439

TBSO Me TBSO Me H H I H H O spontaneous O TBSO OTES TBSO O

440 437

TBSO Me 1. Ac2O, Et3N,CH2Cl2 TBSO Me OH H H OH 2. TBSOTf, 2,-6-lut., H H o O CH2Cl2, -78 C O PPh3, imid., TBSO OH TBSO OTBS I , CH Cl 3. K CO , MeOH 2 2 2 2 3 78% (49%) 436 441

TBSO Me I- TBSO Me H H I + O H H PPh3 PPh3,CH3CN O TBSO OTBS TBSO OTBS 82 oC

442 443

Scheme 94. Attempted Phosphonium Salt Formation

135 TBSO Me O OH 1. MsCl, Et3N, TBSO Me H H o O CH2Cl2, 0 C H H P Ph O Ph TBSO OTBS TBSO OTBS 2. n-BuLi, PPh2, E THF, 0 oC; H O 441 2 2 444 (88%)

O TBSO Me P O Me 1. n-BuLi, THF, TBSO Me Me H H Ph H O H O Ph O -78 oc H H O O MeO TBSO OTBS G O E MeO TBSO MeO G 2. KH, DMF E MeO OTBS 434 444 445

TBSO Me TBSO Me H H OAc 1. MOMCl, i-Pr2NEt, H H OH 1. MsCl, Et3N, o O o O DMF, 60 C CH2Cl2, 0 C TBSO OH TBSO OMOM

2. K2CO3, MeOH 2. n-BuLi, PPh2, THF, 0 oC; (86%) 446 447 H2O2 (95%) O TBSO Me H H P Ph O Ph TBSO OMOM E

448

O TBSO Me P O Me 1. n-BuLi, THF, TBSO Me Me H H Ph H O H O Ph O -78 oc H H O O MeO TBSO OMOM G O E MeO TBSO MeO G 2. KH, DMF E MeO OMOM 434 448 449

Scheme 95. Attempted Horner–Wittig Olefinations deprotection of the acetate gave alcohol 447 . Formation of the phosphine oxide 448 proceeded as before, and again, the subsequent Horner–Wittig reaction was unsuccessful. Discouraged by the time we had invested into these models that were diverging more and more from our complex system, we set out to prepare the BCDE

136 phosphine oxide with a methoxypropyl protecting group and the GHIJ aldehyde, fitted with a dithioketal, to mimic Nicolaou’s olefination (Scheme 79). 296

G. Progressing the BCDE Fragment

1. Preparation of the BCDE Coupling Partner

Following the attempted modeling of the F ring formation, I undertook the task

of progressing the BCDE fragment 421 to some possible coupling partners for the

GHIJ tetracycles 342 , 425 , and 426 . After some deliberation, it was decided that p-

methoxybenzyl ethers would serve as useful protecting groups for the B ring diol

during the formation of the F ring. Bis-protection of diol 421 , and reduction of the more electron poor benzyl ethers provided E ring diol 450 (Scheme 96). In order to install a methoxypropyl protecting group on the secondary alcohol, it was necessary to transiently protect the primary alcohol. To that end, the primary ester was accessed, followed by preparation of the desired ketal 451 . Alkaline solvolysis of the primary acetate and subsequent formation of the mesylate proceeded uneventfully.

Formation of the phosphine oxide was successful; however, the oxidative workup also effected some hydrolysis of the acetal. Although the material could be reprotected, it was difficult to separate alcohol 452 from the excess diphenylphosphine oxide used in the reaction. To temporarily circumvent this difficulty, it was decided to form the acetal following synthesis of the phosphine oxide.

137 Me Me Me OBn H Me OH O Me H O Me H B H H 1. NaH, PMBBr, DMF HO C D O H H H O PMBO O H O 2. LiDBB, THF, -78 oC H E O HO H H OBn H H O H (83%) PMBO H H OH H 421 450

Me 1. K2CO3, MeOH Me OAc H Me 2. MsCl, Et3N, 1. Ac O, Et N, CH Cl O CH Cl , 0 oC 2 3 2 2 H H H 2 2 PMBO O MeO O Me 2. CH2=C(OMe)CH3, H O 3. n-BuLi, HPPh2, o H Me PPTS, 0 C PMBO H H O THF, 0 oC; H (73%) 451 H2O2 (81%)

Me O P Ph Me H O Me Ph H B H H PMBO C D O O H H O E PMBO H H OH H 452

Scheme 96. Unprotected Phosphine Oxide Synthesis

To access the desired phosphine oxide 453 using one additional step, the bis- silyl ether was prepared, followed by selective acidic deprotection of the primary silyl ether to give alcohol 454 (Scheme 97). Synthesis of the phosphine oxide 455 proceeded in quantitative yield over the two steps. This intermediate 455 represents a potential coupling partner for the GHIJ aldehydes 342 , 425 , and 426 . At this point, the silyl ether could be cleaved using fluoride, and the resultant alcohol could be used without purification and delivered desired phosphine oxide 453 in good yield.

Additionally, as a potential coupling partner for a Wittig reaction rather than a

Horner–Wittig olefination, phosphonium salt 456 was accessed in two steps from alcohol 454 . With each of the BCDE coupling partners 453 , 455 , and 456 , the stage was set to probe the most efficient method for accessing the F ring olefin.

138

Me 1. TBSOTf, Me Me OH H Me Me OH O 2,6-lut., H Me H H o O H CH2Cl2, 0 C PMBO O H H H O PMBO O H H O 2. HF-pyr, THF O PMBO H H OH H H O H (88%) PMBO H H OTBS 450 H 454

Me O Ph Me P 1. MsCl, Et3N, H Me Ph o O CH2Cl2, 0 C H H H 1. n-Bu4NF, THF PMBO O 2. n-BuLi, HPPh , O 2 H H O 2. CH2=C(OMe)CH3, THF, 0 oC; PMBO H H OTBS o H PPTS, 0 C H2O2 (85%) 455 (quant.)

Me O Ph Me H P O Me Ph H B H H PMBO C D O Me O OMe H H O E Me PMBO H H O H 453

Scheme 97. BCDE Phosphine Oxide Formation

Me Me OH Me I- H Me PPh + O 1. PPh3, imid., Me H Me 3 H B H H I , CH Cl O PMBO C D O 2 2 2 H B H H O PMBO C D O H O E O H H OTBS 2. PPh3, PMBO H H H O E H CH CN, PMBO H H OTBS 3 H 454 82 oC 456 (78%)

Scheme 98. Phosphonium Salt Formation

2. Analog Syntheses

Beyond the total synthesis of brevetoxin A ( 303 ), a second goal of this project involves accessing a variety of fragments and analogs of the brevetoxin structure that could provide further insight into the structure–activity relationships of this

139 molecule. To facilitate these efforts, a collaboration was established with the Baden laboratory at the University of North Carolina at Wilmington. The Baden group has examined the biological properties of the ladder toxins for over two decades. 289,313

As an initial group of molecules to assay, we hoped to pass along several BCDE

fragments. Oxidation of diol 421 delivered the A ring lactone, serving to form the

pentacycle 457 useful for assays, as well as model the late-stage A ring formation

(Scheme 99). 31 Oxidative deprotection of the benzyl ethers of pentacycle 457 was

unsuccessful. Reduction of the benzyl ethers of diol 421 proceeded in high yield to

give tetraol 458 . With these preliminary fragments in hand, diol 421 , pentacycle 457 ,

and tetraol 458 were sent to the Baden laboratory for testing, along with several

GHIJ analogs. Although these compounds have not delivered results of high

importance to date, they have paved the way for further collaboration in the hope of

better understanding the ladder toxins.

Me Me Me OBn H Me Me H OBn O O Me H B H H n-Pr4NRuO4, NMO, H C O B H H HO D O C D O O 4 A MS, CH Cl A O H H O 2 2 H O HO H E OBn 59% H E H O H H OBn H H 421 457 Me Me OBn OH Me H Me H O Me O Me H B H H LiDBB, THF, H B H H HO C D O HO C D O O o O H H O -78 C H H O HO H H E OBn HO H H E OH H 90% H 421 458

Scheme 99. Analog Syntheses

H. Union of the BCDE and GHIJ Fragments and Completion of Brevetoxin A

140 For the first attempt at coupling the BCDE and GHIJ fragments, phosphine oxide 453 and aldehyde 426 were chosen as substrates (Scheme 100). Use of n- butyllithium for the deprotonation of phosphine oxide 453 was difficult on small scale, as the resultant ylide was typically quenched by adventitious water prior to or during addition of aldehyde 426 . Since the use of superstoichiometric n-butyllithium would result in undesired alkylation and epimerization of aldehyde 426 , we chose to investigate the use of excess lithium diisoproplyamide for the deprotonation event.

To ensure that the ylide of fragment 453 was indeed formed, lithium diisopropylamide was added to the substrate resulting in a yellow solution; the ylide was quenched with deuterium oxide, and 1H NMR analysis of the resultant product

provided evidence for incorporation of deuterium in the phosphine oxide, confirming

that the ylide had been realized. Pushing forward, deprotonation of phosphine oxide

453 with lithium diisopropylamide followed by addition of a solution of aldehyde 426

provided a complex mixture of products. Inspection of the 1H NMR spectrum of each of these adducts led us to speculate that addition had occurred, however a significant portion of the material featured free hydroxyls resulting from benzoate ester cleavage. Elimination of each of the coupled alcohols provided a very low yield of what we believe to be alkene 459 . However, the difficulties encountered with the esters in the initial addition caused us to pursue this strategy using a GHIJ fragment with more robust protecting groups on the J ring, namely aldehyde 425 , possessing benzyl ethers in place of benzoate esters (Scheme 101).

141 Me O BzO Me P Ph H OBz H Me Ph H O O O J H B H H H Me C O O I O PMBO D Me H O OMe EtS H H H O E Me G O H PMBO H H O EtS H H 426 453 1. LiN(i-Pr) , THF, -78 oC <15% yield 2 2. KHMDS, DMF

Me HO Me H H Me O H O H B H H H Me J C O O I OH PMBO D EtS O H O EtS H H O H H E G O H PMBO H H OR H H

459 R = MOP

Scheme 100. Attempted Union of the Fragments

Future work will involve attempting the union of phosphine oxide 453 and aldehyde 425 , which we hope will allow the completion of the total synthesis of brevetoxin A ( 303 ) (Scheme 101). Following formation of diene 460 , we hope to effect deprotection of the acetal protecting group and form the mixed methoxyketal in one pot. These types of ring formations have previously been achieved with smaller rings. 314 Reduction of the resultant ketal should also result in deprotection of

the p-methoxybenzyl ethers to provide nonacycle 461 . Removal of the benzyl ethers

would then be followed by careful oxidation of the tetraol to deliver the A ring lactone

and J ring aldehyde in one step. Finally, treatment with Eschenmoser’s salt should

provide brevetoxin A ( 303)302

142 Me O BnO Ph H OBn Me H P O Me Ph H O O Me J H B H H H C O O I O PMBO D Me H O OMe EtS H H H O E Me G O H PMBO H H O EtS H H 453 425

1. LiN(i-Pr)2 2. KHMDS

Me BnO H Me H Me O H O H B H H H Me J C O O I OBn PMBO D EtS O H O EtS H H O H H E G O H PMBO H H OR H H

460 R = MOP

1. (F3C(O)O)2PhI 2. BF3-OEt2, Et3SiH

Me BnO Me H H Me O H O H B Me J C H H H HO D O O I O OBn F H H O H H H O E G O HO H H O H H H H

461

1. Na, NH3 2. Dess-Martin periodinane + - 3. CH2=N (Me)2I , Et3N

Me HO Me H H Me O H O B Me J H C H H H O D O O I O O A F H H O H H H O E G O O H H O H H H H

brevetoxin A (303)

Scheme 101. Proposed Completion of Brevetoxin A

I. Summary

143 In summary, a novel approach to the B ring 420 of brevetoxin A ( 303 ) has

been devised and executed to prepare multigram quantities of the oxocane. Novel

reactivity was discovered and exploited along this route, and several improvements

were made on the previous strategy. This material has been progressed to

tetracycle 421 , and portions of this supply have been carried forward to the phosphine oxides 453 and 455 and the phosphonium salt 456 (Scheme 97, 98).

Current efforts are directed at union of the BCDE and GHIJ fragments and the ultimate completion of brevetoxin A ( 303 ).

144

Chapter III

Experimental

A. Materials and Methods

Infrared (IR) spectra were obtained using a Jasco 460 Plus Fourier transform infrared spectrometer. Proton and carbon nuclear magnetic resonance ( 1H and 13 C

NMR) spectra were recorded on the following instruments: Bruker 400 ( 1H at 400

MHz; 13 C at 100 MHz) and Bruker 500 ( 1H at 500 MHz; 13 C at 125 MHz). Optical rotations were determined using a Jasco P1010 polarimeter. Thin layer chromatography (TLC) was conducted on silica gel F 254 TLC plates purchased from

Scientific Adsorbents, Inc. Flash column chromatography was carried out using

silica gel (32 to 63 m) purchased from Scientific Adsorbents, Inc. Diethyl ether

(Et 2O), tetrahydrofuran (THF), dichloromethane (CH 2Cl 2), and toluene were dried by

being passed through a column of neutral alumina under nitrogen immediately prior

to use. Alkylamines and benzene were distilled from calcium hydride immediately

prior to use. Chloroform was washed and distilled over phosphorous pentoxide

immediately prior to use. Dimethyl sulfoxide (DMSO) was distilled from calcium

hydride under reduced pressure and stored over 4 Å molecular sieves. Anhydrous

N,N-dimethylformamide (DMF) was purchased from Aldrich chemical company in 1L

Sure/Seal TM bottles. Acetic anhydride was distilled and stored under a blanket of

argon. Trifluoromethanesulfonic anhydride was distilled over phosphorous pentoxide immediately prior to use. All other reagents and solvents were used as received from the manufacturer. All air and water sensitive reactions were preformed in flasks flame dried under positive flow argon and conducted under an argon atmosphere. Davis oxaziridine was prepared via the condensation of benzaldehyde and benzenesulfonamide, followed by oxidation according to literature precedent. Pivaloyl chloride was distilled and stored over 4Å molecular sieves. Zinc borohydride was prepared by stirring a solution of zinc chloride (1.0 M in Et 2O) with

NaBH 4 for two days in Et 2O to prepare a 0.14M solution. Dess-Martin periodinane

was prepared according to literature procedures and stored at -20 ºC.

B. Procedures

Me BnO OH

Homoallylic alcohol 8. Into a flask equipped with a reflux condenser and an addition funnel was added freshly ground magnesium (10.55 g, 434.0 mmol). The flask and its contents were flame dried. 125 mL of THF and iodine (one crystal) were added to the flask. 2-bromopropene (50.00 g, 413.3 mmol) was added in 125 mL of THF to the addition funnel. Several drops of the 2-bromopropene solution were added to the flask via addition funnel and the solution was stirred until colorless. 350 mL of THF was added to the addition funnel and the solution was added dropwise to the flask. Following addition, 125 mL of THF was added to the flask, and the solution was stirred vigorously for 2 hours.

Into a flask equipped with an addition funnel and a low-temperature thermometer was added cuprous iodide (3.58 g, 18.8 mmol) in 375 mL of THF. The solution was cooled to –35 oC. The solution of 2-propenylmagnesium bromide was

146 transferred via cannula to the addition funnel and added dropwise to yield a yellow solution. ( R)-benzylglycidyl ether ( 5) (28.66 mL, 187.4 mmol) was added to the

addition funnel in 200 mL of THF. The epoxide was added dropwise, and the

solution was stirred at –35 oC for 1 hour. The reaction was quenched by the addition

of saturated aqueous NH 4Cl, and then warmed to room temperature. The resultant

mixture was filtered through celite, yielding a blue solution. The layers were

separated and the organic layer was washed with brine. The aqueous portions were

extracted twice with a 1:1 solution of EtOAc/hexanes. The organic layers were

combined, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash

column chromatography (25% EtOAc/Hexanes) provided 38.22 g (99%) of the

alcohol as a colorless oil.

O CO2H OBn Me

Glycolic acid 9. Into a flask equipped with an addition funnel was added sodium hydride (60% dispersion in mineral oil, 23.95 g, 598.6 mmol). The sodium hydride was rinsed with pentane three times, diluted in 100 mL of THF, and cooled to 0 °C. Bromoacetic acid (41.58 g, 299.3 mmol) was added to the addition funnel in

100 mL of THF and added dropwise to the flask. The solution was warmed to room temperature and stirred for 1 hour. The flask was again cooled to 0 oC, and the

previous secondary alcohol 8 (41.16 g, 199.5 mmol) was added to the addition funnel in 200 mL of DMF. The solution of alcohol was added to the flask dropwise.

Following addition, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was quenched by the addition of saturated aqueous NH 4Cl and diluted with diethyl ether. The solution was acidified to pH 3-4 by the addition of

147 10% H 2SO 4, then extracted. The organic layer was washed with brine, dried over

Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography

(10% then 25% EtOAc/Hexanes) provided 49.71 g (95%) of the acid as a colorless

1 oil: H NMR (400 MHz, CDCl 3) δ 1.75 (s, 3H), 2.13 (dd, J = 14.0, 6.0 Hz, 1H), 2.27

(dd, J = 14.0, 7.1 Hz, 1H), 3.48 (dd, J = 10.0, 8.5 Hz, 1H), 3.54 (dd, J = 10.1, 2.9 Hz,

1H), 3.71 (m, 1H), 4.10 (d, J = 17.3 Hz, 1H), 4.28 (d, J = 17.3 Hz, 1H), 4.59 (d, J =

12.0 Hz, 1H), 4.61 (d, J = 12.0 Hz, 1H), 4.77 (d, J = 0.8 Hz, 1H), 4.85 (dd, J = 1.6,

13 1.6 Hz, 1H), 7.29-7.39 (m, 5H); C NMR (100 MHz, CDCl 3) δ 22.6, 40.0, 68.2, 72.2,

73.6, 79.6, 114.3, 127.9, 128.1, 128.6, 136.7, 140.8, 172.2; IR (film) 3483 (br), 3201

-1 25 (br), 2917, 1733 (str), 1454, 1454, 1364, 1205, 1129 cm ; [ α] D = -25.0 (c = 1.30,

+ CH 2Cl 2); MS (electrospray ionization) calculated for C 15 H21 O4 [M + 1] : 265.14, found: 265.2.

S O O Me O N

Bn OBn

Oxazolidinethione glycolate 6. A flask was charged with the glycolic acid 9

(49.13 g, 185.9 mmol) and ( 4S )-4-benzyl-1,3-oxazolidine-2-thione (39.52 g, 204.5

o mmol) in 150 mL of CH 2Cl 2. The solution was cooled to 0 C.

Dicyclohexylcarbodiimide (38.35 g, 185.9 mmol), 4-dimethylaminopyridine (1.14 g,

9.33 mmol), and 35 mL of CH 2Cl 2 were added to the solution and the mixture was

warmed to room temperature. The yellow solution was stirred 4 hours, then cooled

o to 0 C, and filtered. The filtrate was washed with CH 2Cl 2. The combined organic portions were washed with saturated aqueous NaHCO 3, and the aqueous layer was extracted twice with CH 2Cl 2. The combined organic extracts were washed with

148 brine, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (25% EtOAc/Hexanes) provided 70.13 g (86%) of the glycolate as a

1 yellow oil: H NMR (400 MHz, CDCl 3) δ 1.81 (s, 3H), 2.31 (dd, J = 14.1, 6.7 Hz, 1H),

2.44 (dd, J = 14.3, 6.8 Hz, 1H), 2.64 (dd, J = 13.3, 10.2 Hz, 1H), 3.26 (dd, J = 13.3,

3.2 Hz, 1H), 3.64 (m, 2H), 3.93 (m, 1H), 4.23 (dd, J = 7.7, 7.7 Hz, 1H), 4.31 (dd, J =

9.3, 2.4 Hz, 1H), 4.54 (s, 2H), 4.79 (s, 1H), 4.83-4.90 (m, 1H), 4.83 (s, 1H), 5.23 (d, J

= 18.3 Hz, 1H), 5.34 (d, J = 18.3 Hz, 1H), 7.17-7.36 (m, 10H); 13 C NMR (100 MHz,

CDCl 3) δ 22.8, 37.3, 40.3, 59.8, 71.2, 71.9, 73.3, 73.5, 77.7, 113.1, 127.4, 127.5,

127.6, 128.4, 129.0, 129.4, 135.1, 138.1, 142.1, 171.4, 184.7; IR (film) 2924, 1712

-1 22 (str), 1361, 1324, 1206, 1124 cm ; [ α] D = +93 (c = 0.26, CH 2Cl 2); MS (electrospray

+ ionization) calculated for C 25 H30 NO 4S [M + 1] : 440.18, found: 440.3.

OH OH

Hex-5-ene-1,2-diol. Into a flask equipped with a mechanical stirrer, an

addition funnel, and a low temperature thermometer was added allylmagnesium

chloride (2.0 M in THF, 800.0 mL, 1.600 mol) and 800 mL of THF. The solution was

cooled to –20 oC. Glycidol (35.40 mL, 533.3 mmol) in 800 mL of THF was added dropwise via addition funnel keeping the temperature at –20 oC. The mixture was

o stirred 1 hour at –20 C, then quenched by the addition of saturated aqueous NH 4Cl.

The organic layer was washed with brine, and the combined aqueous extracts were

washed twice with 50% EtOAc/Hexanes. The combined organic extracts were dried

over Na 2SO 4 and concentrated in vacuo. Purification by flash column

149 chromatography (10% then 50% EtOAc/Hexanes) provided 57.16 g (93%) of the diol as a colorless oil.

O H

Pent-4-enal. Into a flask equipped with a mechanical stirrer was added hex-

5-ene-1,2-diol (65.31 g, 562.2 mmol), 800 mL of CH 2Cl 2, and 800 mL of water.

Sodium periodate (240.52 g, 1.1245 mol) was added to the biphasic solution which

was stirred for one hour. The reaction was quenched by the addition of saturated

aqueous NaHCO 3. The organic layer was washed twice with 10% Na 2S2O3 in water,

o then dried over Na 2SO 4. The volume was reduced to 100 mL in vacuo at 0 C.

Purification via distillation (bp: 96 oC, 760 mm Hg) gave 29.33 g (63%) of the aldehyde as a colorless liquid.

S O OH

O N O Me Bn OBn

Glycolate Aldol Adduct 11. Into a flask equipped with an addition funnel

was added glycolate 6 (28.63 g, 65.13 mmol) and 435 mL of CH 2Cl 2. The solution

was cooled to –78 oC and titanium tetrachloride (7.50 mL, 68.4 mmol) was added dropwise via addition funnel. The solution was stirred 10 minutes at –78 oC and N,

N-diisopropylethylamine (26.92 mL, 162.8 mmol) was added dropwise to give a

purple solution that was stirred at –78 oC for 2.5 hours. N-methylpyrrolidinone (6.57 mL, 68.3 mmol) was added to the solution via addition funnel and stirred for 10 minutes. 4- pentenal was added dropwise via addition funnel and stirred at –78 oC for 2 hours. The solution was warmed to –40 oC for 1 hour, then quenched by the

150 addition of half saturated aqueous NH 4Cl and warmed to room temperature. The aqueous layer was extracted twice with CH 2Cl 2, then the combined organic extracts

were dried over Na 2SO 4 and concentrated in vacuo. Purification by flash column

chromatography (20% then 50% EtOAc/Hexanes) provided 23.61 g (70%) of the

1 alcohol as a yellow oil: H NMR (400 MHz, CDCl 3) δ 1.67-1.78 (m, 2H), 1.80 (s, 3H),

2.01 (dd, J = 13.2, 11.1 Hz, 1H), 2.15 (ddd, J = 14.9 , 7.1, 7.1 Hz, 1H), 2.20-2.36 (m,

3H), 2.41 (dd, J = 14.0, 7.9 Hz, 1H), 3.20 (dd, J = 13.3, 2.8 Hz, 1H), 3.51 (dd, J =

10.3, 2.7 Hz, 1H), 3.68 (dd, J = 10.3, 7.6 Hz, 1H), 3.92-4.01 (m, 2H), 4.14 (dd, J =

9.4, 2.1 Hz, 1H), 4.19 (ddd, J = 9.3, 9.3, 9.3 Hz, 1H), 4.47 (d, J = 12.3 Hz, 1H), 4.53

(d, J = 12.3 Hz, 1H), 4.77 (m, 1H), 4.84 (s, 1H), 4.86 (s, 1H), 4.98 (d, J = 10.2 Hz,

1H), 5.05 (dd, J = 17.2, 1.5 Hz, 1H), 5.83 (dddd, J = 17.0, 10.3, 3.6, 3.6 Hz, 1H),

13 6.34 (d, J = 2.0 Hz, 1H), 7.08-7.35 (m, 10H); C NMR (100 MHz, CDCl 3) δ 22.6,

29.9, 33.2, 36.7, 40.7, 60.9, 70.6, 72.5, 73.1, 74.2, 78.7, 80.8, 114.0, 114.9, 127.22,

127.24, 127.5, 128.4, 128.9, 129.3, 135.6, 138.0, 138.1, 141.6, 172.2, 185.2; IR

-1 23 (film) 3458 (br), 2924, 1712 (str), 1446, 1361, 1324, 1206, 1128 cm ; [ α] D = +25 (c

+ = 0.43, CH 2Cl 2); MS (electrospray ionization) calculated for C 30 H38 NO 5S [M + 1] :

524.24, found: 524.3.

OBn Me

O HO

Dien diol 14. Into a flask equipped with an addtion funnel was added alcohol

11 (19.89 g, 38.01 mmol) in 380 mL of Et 2O. Methanol (3.08 mL, 76.0 mmol) was

151 o added, and the solution was cooled to 0 C. Lithium borohydride (2.0 M in Et 2O,

38.01 mL, 76.03 mmol) was added dropwise via addition funnel, and the solution

was stirred 1.5 hours at 0 oC. The reaction was quenched by the addition of aqueous NaOH (380 mL, 190 mmol) and stirred 15 minutes at room temperature.

The layers were separated and the aqueous was washed three times with Et 2O.

The combined organic extracts were dried over Na 2SO 4 and concentrated in vacuo.

Purification by flash column chromatography (20% EtOAc/Hexanes) gave 11.96 g

1 (95%) of the diol as a colorless oil: H NMR (400 MHz, CDCl 3) δ 1.51-1.60 (m, 2H),

1.75 (s, 3H), 2.08-2.19 (m, 2H), 2.26 (ddd, J = 14.4, 7.8, 7.8 Hz, 1H), 2.36 (dd, J =

14.0, 6.5 Hz, 1H), 2.72 (br s, 1H), 3.32 (m, 1H), 3.47 (dd, J = 10.0, 7.9 Hz, 1H), 3.56-

3.61 (m, 3H), 3.75 (br s, 1H), 3.77 (br s, 1H), 3.90 (dddd, J = 7.0, 7.0, 7.0, 2.6 Hz,

1H), 4.56 (s, 2H), 4.77 (s, 1H), 4.84 (s, 1H), 4.96 (ddd, J = 10.2, 1.9, 0.7 Hz, 1H),

5.03 (ddd, J = 17.1, 3.5, 1.6, 1H), 5.82 (dddd, J = 16.9, 10.2, 6.7, 6.7 Hz, 1H), 7.29-

13 7.38 (m, 5H); C NMR (100 MHz, CDCl 3) δ 22.7, 29.8, 32.5, 41.2, 62.7, 71.2, 72.9,

73.6, 76.7, 83.0, 114.0, 114.8, 127.9, 128.1, 128.6, 137.1, 138.3, 141.7; IR (film)

-1 24 3436 (br), 2921, 1641, 1454, 1092 cm ; [ α] D = -11 (c = 0.32, CH 2Cl 2); MS

+ (electrospray ionization) calculated for C 20 H30 O4Na [M + Na] : 357.20, found: 357.3.

OBn Me

O TBSO

TBSO

Diene 5. A flask was charged with the 1,3-diol 14 (11.96 g, 35.76 mmol) and 140 mL DMF. Imidazole (18.26 g, 268.2 mmol) and 4- dimethylaminopyridine (437 mg, 3.58 mmol) were added to the solution, followed by

152 tert -butyldimethylsilyl chloride (13.48 g, 89.40 mmol). The solution was warmed to

50 oC and stirred overnight. The reaction was quenched by the addtion of saturated aqueous NH 4Cl, cooled to room temperature, and diluted with Et2O. The layers

were separated, and the aqueous portion was washed twice with Et 2O. The

combined organic extracts were washed with brine, dried over Na 2SO 4, and

concentrated in vacuo. Purification by flash column chromatography (1%

EtOAc/Hexanes) provided 17.42 g (86%) of the diene as a colorless oil: 1H NMR

(400 MHz, CDCl 3) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.107 (s, 3H), 0.112 (s, 3H), 0.93 (s,

9H), 0.95 (s, 9H), 1.29 (dddd, J = 14.7, 9.9, 9.9, 5.0 Hz, 1H), 1.74-1.82 (m, 1H), 1.82

(s, 3H), 1.98 (m, 1H), 2.18-2.28 (m, 1H), 2.24 (dd, J = 13.8, 7.9 Hz, 1H), 2.39 (dd, J

= 13.8, 4.6 Hz, 1H), 3.45 (dd, J = 9.7, 6.2 Hz, 1H), 3.45-3.50 (m, 1H), 3.61 (dd, J =

10.6, 7.9 Hz, 1H), 3.69 (dd, J = 9.8, 4.6 Hz, 1H), 3.70-3.75 (m, 1H), 3.82-3.88 (m,

1H), 3.89 (dd, J = 10.6, 2.2 Hz, 1H), 4.59 (s, 2H), 4.82 (s, 1H), 4.85 (m, 1H), 4.98

(dd, J = 10.2, 1.9 Hz, 1H), 5.05 (ddd, J = 17.0, 3.3, 1.5 Hz, 1H), 5.85 (dddd, J = 16.9,

13 10.2, 6.6, 6.6 Hz, 1H), 7.27-7.37 (m, 5H); C NMR (100 MHz, CDCl 3) δ –5.5, -5.3, -

4.6, -4.3, 18.0, 18.2, 23.0, 25.8, 25.86, 25.92, 25.93, 30.6, 30.9, 41.4, 62.8, 71.9,

72.7, 73.2, 77.2, 83.3, 113.0, 114.3, 127.4, 127.5, 128.2, 138.6, 138.8, 142.6; IR

-1 24 (film) 2929, 1463, 1255, 1095 cm ; [ α] D = +35.7 (c = 1.24, CH 2Cl 2); MS

+ (electrospray ionization) calculated for C 32 H58 O4Si 2Na [M + Na] : 585.38, found:

585.5.

OBn Me

O TBSO

TBSO

153 Oxonene 18. Into a flask equipped with a reflux condenser was added diene

5 (16.56 g, 29.24 mmol) and 2.9 L CH 2Cl 2. The solution was brought to reflux for 30 minutes, followed by the addtion of Grubbs’ catalyst (1.25 g, 1.47 mmol) and stirring three hours at reflux. The solution was cooled to room temperature and concentrated in vacuo. Purification by flash column chromatography (1%

EtOAc/Hexanes) provided 15.53 g (99%) of the oxonene as a colorless oil: 1H NMR

(400 MHz, CDCl 3) δ 0.02 (s, 3H), 0.03 (s, 9H), 0.88 (s, 9H), 0.89 (s, 9H), 1.42 (dddd,

J = 3.9, 3.9, 13.5, 13.5 Hz, 1H), 1.73 (m, 1H), 1.79 (s, 3H), 1.86 (m, 1H), 1.98 (d, J =

14.02 Hz, 1H), 2.44 (dd, J = 14.2, 7.9 Hz, 1H), 2.81 (dddd, J = 13.2, 13.2, 13.2, 4.4

Hz , 1H), 3.29-3.35 (m, 2H), 3.38 (m, 1H), 3.54 (dd, J = 13.6, 8.9 Hz, 1H), 3.67 (dd, J

= 11.0, 8.5 Hz, 1H), 3.92 (dd, J = 11.1, 2.4 Hz, 1H), 3.96 (m, 1H), 4.56 (s, 2H), 5.34

13 (dd, J = 11.4, 5.3 Hz, 1H), 7.27-7.37 (m, 5H); C NMR (100 MHz, CDCl 3) δ –5.2, -

5.1, -4.8, 18.1, 18.3, 25.3, 25.8, 25.9, 26.0, 26.1, 32.2, 36.1, 61.8, 67.7, 73.0, 73.4,

77.9, 84.3, 126.1, 127.5, 127.6, 128.3, 134.7, 138.4; IR (film) 2928, 1471, 1254,

-1 24 1089 cm ; [ α] D = +33.6 (c = 1.16, CH 2Cl 2); MS (electrosray ionization) calculated

+ for C 30 H54 O4Si 2Na [M + Na] : 557.35, found: 557.4.

OH Me

O TBSO

TBSO

Primary alcohol 37. Into a flask equipped with a cold finger condenser,

cooled to –78 oC, and a stir bar was added oxonene 18 (4.03 g, 7.52 mmol) and 210

mL of THF. The solution was cooled to –78 oC, and 105 mL of ammonia was

condensed into the flask. Freshly cut sodium metal (3.46 g, 150 mmol) was added

154 to the solution yielding a blue color. After 15 minutes at –78 oC, the reaction was

quenched by the addition of saturated aqueous NH 4Cl. The ammonia was allowed to evaporate at room temperature, and the layers were separated. The aqueous portion was washed three times with Et 2O, dried over Na 2SO 4 and concentrated in

vacuo. Purification via flash column chromatography (5% EtOAc/Hexanes) gave

1 2.86 g (86%) of the alcohol as a colorless oil. H NMR (400 MHz, CDCl 3) δ 0.01 (s,

3H), 0.02 (s, 3H), 0.09 (s, 3H), 0.10 (s, 3H), 0.86 (s, 9H), 0.91 (s, 9H), 1.44 (m, 1H),

1.49 (d, J = 10.6 Hz, 1H), 1.70 (dddd, J = 13.8, 13.8, 5.3, 2.0 Hz, 1H), 1.78 (s, 3H),

1.90 (m, 1H), 2.39 (dd, J = 14.1, 9.9 Hz, 1H), 2.77 (dddd, J = 13.0, 13.0, 13.0, 5.4

Hz, 1H), 3.33 (m, 1H), 3.44-3.52 (m, 2H), 3.59 (m, 1H), 3.73 (dd, 10.0, 10.0 Hz, 1H),

3.88 (ddd, J = 6.6, 3.5, 3.5 Hz, 1H), 3.97 (ddd, J = 8.8, 3.2, 3.2 Hz, 1H), 4.01 (dd, J =

13 10.5, 2.1 Hz, 1H), 5.35 (dd, J = 11.8, 5.3 Hz, 1H); C NMR (100 MHz, CDCl 3) δ –

5.5, -5.3, -5.0, -4.9, 18.0, 18.5, 25.6, 25.78, 25.79, 26.0, 31.6, 35.0, 62.5, 67.7, 68.0,

-1 24 81.2, 85.8, 125.9, 133.9; IR (film) 3477 (br), 2929, 1463, 1255, 1089 cm ; [ α] D =

+26.9 (c = 2.44, CH 2Cl 2); MS (electrospray ionization) calculated for C 23 H48 O4Si 2Na

[M + Na] +: 467.30, found: 467.4.

O H Me O TBSO

TBSO

Aldehyde. A flask was charged with oxalyl chloride (2.0 M in CH 2Cl 2, 3.52

o mL, 7.04 mmol) and 40 mL of CH 2Cl 2 and cooled to –78 C. Dimethylsulfoxide (1.00

mL, 14.1 mmol) in 8 mL of CH 2Cl 2 was added dropwise, and the solution was stirred

2 minutes. The primary alcohol 37 (2.85 g, 6.40 mmol) and 16 mL CH 2Cl 2 were

155 added dropwise to the mixture and allowed to stir 30 minutes at –78 oC.

Triethylamine (4.46 mL, 32.0 mmol) was added dropwise and stirred 5 minutes at –

78 oC, followed by warming to 0 oC for 1 hour. The reaction was quenched by the addition of cold water. The organic portion was washed with cold saturated aqueous

NaHCO 3, then water. The combined aqueous portions were washed with CH 2Cl 2.

The combined organic extracts were then washed with brine, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (5%

EtOAc/Hexanes) provided 2.64 g (94%) of the aldehyde as a colorless oil: 1H NMR

(400 MHz, CDCl 3) δ 0.01 (s, 3H), 0.02 (s, 3H), 0.06 (m, 6H), 0.86 (s, 9H), 0.89 (s,

9H), 1.46 (dddd, J = 13.6, 13.6, 4.2, 4.2 Hz , 1H), 1.74-1.85 (m, 1H), 1.79 (s, 3H),

1.89 (m, 1H), 2.06 (d, J = 14.3 Hz, 1H), 2.50 (dd, J = 14.1, 10.2 Hz, 1H), 2.76 (dddd,

J = 13.1, 13.1, 13.1, 4.1 Hz, 1H), 3.49 (d, J = 10.0 Hz, 1H), 3.49-3.53 (m, 1H), 3.78

(dd, J = 10.9, 8.7 Hz, 1H), 3.89 (ddd, J = 10.3, 3.7, 3.7 Hz, 1H), 3.95 (dd, J = 16.5,

1.6 Hz, 1H), 5.39 (dd, J = 11.3, 5.3 Hz, 1H), 9.80 (s, 1H); 13 C NMR (100 MHz,

CDCl 3) δ –5.3, -5.1, -4.9, -4.7, 18.1, 18.3, 24.9, 25.8, 25.9, 32.5, 34.0, 62.3, 67.6,

83.6, 85.6, 127.5, 132.8, 204.5; IR (film) 2929, 1737 (str), 1473, 1254, 1086 cm -1;

24 [α] D = +84 (c = 0.48, CH 2Cl 2); MS (electrospray ionization) calculated for

+ C23 H46 O4Si 2Na [M + Na] : 443.28, found: 443.4.

Me OMe Me

O TBSO

TBSO

156 Enone. Into a flask equipped with a reflux condenser was added the aldehyde (2.70 g, 6.10 mmol), 60 mL of toluene, and 1-Methoxy-1-(triphenyl-l5- phosphanylidene)-propan-2-one ( 21) (6.37 g, 18.3 mmol). The solution was brought to reflux overnight, then cooled to room temperature. The mixture was concentrated in vacuo, then purified by flash column chromatography (5% EtOAc/Hexanes) to

1 provide 2.59 g (84%) of the enone as a colorless oil: H NMR (400 MHz, CDCl 3) δ

0.01 (s, 6H), 0.02 (s, 6H), 0.85 (s, 18H), 1.42 (dddd, J = 13.4, 13.4, 3.8, 3.8 Hz, 1H),

1.69 (d, J = 14.0 Hz, 1H), 1.70-1.78 (m, 1H), 1.79 (s, 3H), 1.85 (m, 1H), 2.42 (s, 3H),

2.71 (dd, J = 13.8, 9.1 Hz, 1H), 2.77 (dddd, J = 13.1, 13.1, 13.1, 4.5 Hz , 1H), 3.34

(dd, J = 5.9, 5.9 Hz, 1H), 3.62-3.68 (m, 1H), 3.64 (s, 3H), 3.91 (dd, J = 11.4, 2.2 Hz,

1H), 3.96 (ddd, J = 11.4, 3.7, 3.7 Hz, 1H), 4.21 (dd, J = 8.7, 8.7 Hz, 1H), 5.34 (dd, J

13 = 11.5, 5.4 Hz, 1H), 6.20 (d, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl 3) δ –5.2, -

5.04, -5.01, -4.97, 18.1, 18.2, 25.4, 25.79, 25.81, 25.86, 26.0, 32.2, 39.4, 59.7, 61.6,

74.2, 84.0, 126.3, 131.7, 134.1, 151.5, 195.0; IR (film) 2929, 1687 (str), 1471, 1253,

-1 24 1086 cm ; [ α] D = -48.6 (c = 1.46, CH 2Cl 2); MS (electrospray ionization) calculated

+ for C 27 H52 O5Si 2Na [M + Na] : 535.32, found: 535.5.

OMe Me

O TBSO

TBSO

Triene 38. A flask was charged with methylenetriphenylphosphine bromide

(6.59 g, 18.5 mmol) and 15 mL of THF and cooled to 0 oC. Potassium tert -butoxide

157 (1.0 M in THF, 14.8 mL, 14.8 mmol) was added to the heterogeneous mixture to give a yellow homogeneous solution. After stirring 30 minutes at 0 oC, the enone (1.89 g,

3.69 mmol) in 20 mL of THF was added dropwise and stirred 30 minutes at 0 oC.

The reaction was quenched by the addition of saturated aqueous NH 4Cl, warmed to room temperature, and diluted with Et 2O. The layers were separated and the aqueous portion was washed twice with Et 2O, dried over Na 2SO 4, and concentrated in vacuo. Purification via flash column chromatography (5% EtOAc/Hexanes) gave

1 1.63 g (87%) of the diene as a colorless oil: H NMR (400 MHz, CDCl 3) δ 0.03 (s,

3H), 0.038 (s, 3H), 0.045 (s, 3H), 0.06 (s, 3H), 0.87 (s, 9H), 0.89 (s, 9H), 1.43 (m,

1H), 1.72 (d, J = 14.1 Hz, 1H), 1.74 (m, 1H), 1.82 (s, 6H), 1.85 (m, 1H), 2.72 (dd, J =

14.1, 9.7 Hz, 1H), 2.84 (dddd, J = 13.0, 13.0, 13.0, 4.6 Hz, 1H), 3.39 (dd, J = 6.5, 4.7

Hz, 1H), 3.57 (s, 3H), 3.67 (dd, J = 11.2, 8.9 Hz, 1H), 3.95 (dd, J = 11.2, 2.1 Hz, 1H),

4.02 (ddd, J = 11.5, 3.6, 3.6 Hz, 1H), 4.19 (dd, J = 8.9, 8.9 Hz, 1H), 5.00 (s, 1H),

5.24 (d, J = 1.5 Hz, 1H), 5.30 (d, J = 8.6 Hz, 1H), 5.34 (dd, J = 11.4, 5.1 Hz, 1H); 13 C

NMR (100 MHz, CDCl 3) δ –5.1, -4.97, -4.96, -4.9, 18.2, 18.3, 19.6, 25.5, 25.9, 26.0,

26.3, 32.3, 40.3, 59.9, 61.8, 67.8, 74.5, 83.6, 113.4, 118.7, 125.9, 134.8, 137.2,

-1 24 154.6; IR (film) 2928, 1463, 1253, 1086 cm ; [ α] D = -31 (c = 0.38, CH 2Cl 2); MS

+ (electrospray ionization) calculated for C 28 H54 O4Si 2Na [M + Na] : 533.35, found:

533.5.

OMe Me

O HO

TBSO

158 Primary alcohol 40. A flask was charged with triene 38 (1.55 g, 3.03 mmol) and 30 mL of methanol. Ammonium fluoride (2.25 g, 60.6 mmol) was added to the solution and stirred overnight. The reaction was quenched by the addition of saturated aqueous NaHCO 3 and diluted with Et 2O. The layers were separated and the aqueous portion was washed twice with Et 2O. The combined organic extracts were dried over Na 2SO 4 and concentrated in vacuo. Purification by flash column

chromatography (5% EtOAc/Hexanes) provided 940 mg (79%) of the alcohol as a

colorless oil, as well as 240 mg (16%) of recovered starting diene: 1H NMR (400

MHz, CDCl 3) δ 0.06 (s, 3H), 0.07 (s, 3H), 0.88 (m, 9H), 1.49 (dddd, J = 14.5, 14.5,

6.0, 6.0 Hz, 1H), 1.72 (d, J = 14.2 Hz, 1H), 1.82 (s, 3H), 1.83 (s, 3H), 1.85-1.94 (m,

2H), 2.38 (dd, J = 7.8, 4.2 Hz, 1H), 2.65 (dd, J = 15.0, 10.5 Hz, 1H), 2.73 (m, 1H),

3.52-3.59 (m, 1H), 3.58 (s, 3H), 3.65 (m, 1H), 3.83 (ddd, 11.1, 7.9, 4.6 Hz, 1H), 4.10

(ddd, J = 11.5, 3.9, 3.9 Hz, 1H), 4.21 (dd, J = 9.1, 9.1 Hz, 1H), 5.04 (d, J = 0.5 Hz,

1H), 5.17 (d, J = 8.6 Hz, 1H), 5.27 (m, 1H), 5.37 (dd, J = 11.5, 5.3 Hz, 1H); 13 C NMR

(100 MHz, CDCl 3) δ –5.1, -4.9, 18.1, 19.8, 25.4, 25.8, 26.2, 31.8, 40.2, 59.9, 61.2,

68.7, 75.1, 81.4, 114.4, 117.2, 125.9, 134.6, 137.1, 155.7; IR (film) 3435 (br), 2928,

-1 22 1644, 1444, 1247, 1085 cm ; [ α] D = -13 (c = 0.31, CH 2Cl 2); MS (electrospray

+ ionization) calculated for C 22 H40 O4SiNa [M + Na] : 419.26, found: 419.3.

OMe Me

O O

TBSO

159 Aldehyde. A flask was charged with oxalyl chloride (2.0 M in CH 2Cl 2, 1.20

o mL, 2.40 mmol) and 15 mL of CH 2Cl 2 and cooled to –78 C. Dimethylsulfoxide (341

L, 4.80 mmol) in 3 mL of CH 2Cl 2 was added dropwise, and the solution was stirred

2 minutes. The primary alcohol 40 (865 mg, 2.18 mmol) and 6 mL of CH 2Cl 2 were

added dropwise to the mixture and allowed to stir 30 minutes at –78 oC.

Triethylamine (1.52 mL, 10.9 mmol) was added dropwise and stirred 5 minutes at –

78 oC followed by warming to 0 oC for 1 hour. The reaction was quenched by the

addition of cold water. The organic portion was washed with cold saturated aqueous

NaHCO 3, then water. The combined aqueous portions were washed with CH 2Cl 2.

The combined organic extracts were washed with brine, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (5%

EtOAc/Hexanes) provided 797 mg (93%) of the aldehyde as a colorless oil: 1H NMR

(400 MHz, CDCl 3) δ 0.09 (m, 6H), 0.89 (m, 9H), 1.57-1.77 (m, 3H), 1.81 (s, 3H), 1.82

(s, 3H), 1.87 (m, 1H), 2.69-2.81 (m, 2H), 3.54 (s, 3H), 4.09 (d, J = 4.8 Hz, 1H), 4.21-

4.27 (m, 1H), 4.23 (d, J = 9.0 Hz, 1H), 5.03 (d, J = 0.5 Hz, 1H), 5.24 (m, 1H), 5.30 (d,

J = 8.6 Hz, 1H), 5.35 (dd, J = 11.3, 5.6 Hz, 1H), 9.81 (s, 1H); 13 C NMR (100 MHz,

CDCl 3) δ –5.1, -4.8, 18.1, 19.7, 24.6, 25.7, 26.2, 33.9, 39.6, 59.8, 69.4, 74.8, 85.9,

114.3, 117.1, 126.0, 134.3, 137.0, 155.5, 202.5; IR (film) 2925, 1735 (str), 1462,

-1 22 1255, 1083 cm ; [ α] D = -11 (c = 0.33, CH 2Cl 2).

Me MeO H H Me O H H H O Me OTBS

160 Tricycle 41. Into a flask equipped with a reflux condenser was added the previous aldehyde (664 mg, 1.68 mmol), 17 mL of toluene, and 1-(Triphenyl-l5- phosphanylidene)-propan-2-one ( 28) (1.61 g, 5.05 mmol). The solution was brought to reflux overnight, then cooled to room temperature. The mixture was concentrated in vacuo, then purified by flash column chromatography (5% then 10%

EtOAc/Hexanes) provided 583 g (80%) of the ketone as a colorless oil: 1H NMR

o (400 MHz, C 6D6, 60 C) δ 0.007 (s, 3H), 0.011 (s, 3H), 0.89 (s, 9H), 1.56-1.65 (m,

1H), 1.62 (s, 3H), 1.84 (s, 3H), 1.86 (s, 3H), 1.87-2.02 (m, 3H), 2.12 (m, 1H), 2.29

(dd, J = 17.2, 6.5 Hz, 1H), 2.67 (m, 1H), 2.70 (d, J = 14.4 Hz, 1H), 2.89 (ddd, J = 6.9,

3.6, 3.6 Hz, 1H), 3.10 (m, 1H), 3.22 (m, 1H), 3.26 (s, 3H), 4.02 (dd, J = 8.4, 3.7 Hz,

1H), 4.20 (ddd, J = 10.4, 4.5, 4.5 Hz, 1H), 4.45 (ddd, J = 4.9, 2.5, 2.5 Hz, 1H), 5.49

13 o (m, 1H); C NMR (100 MHz, C 6D6, 60 C ) δ –4.8, -4.7, 16.2, 18.2, 23.0, 26.1, 27.6,

28.2, 28.5, 33.1, 39.0, 40.1, 41.2, 46.7, 56.7, 73.3, 80.4, 84.3, 113.3, 130.0, 131.2,

-1 22 149.1, 207.4; IR (film) 2927, 1712 (str), 1445, 1360, 1251, 1088 cm ; [ α] D = +40.8

+ (c = 1.10, CH 2Cl 2); MS (electrospray ionization) calculated for C 25 H43 O4Si [M + 1] :

435.29, found: 435.3.

Me MeO H H Me O H H H Me OTBS

Triene 42. A flask was charged with methylenetriphenylphosphine bromide

(2.30 g, 6.43 mmol) and 10 mL of THF. Potassium tert -butoxide (1.0 M in THF, 5.14

mL, 5.14 mmol) was added to the heterogeneous mixture to give a yellow

161 homogeneous solution. After stirring 30 minutes, ketone 41 (559 mg, 1.29 mmol) in

15 mL of THF was added dropwise and stirred 3 hours. The reaction was quenched by the addition of saturated aqueous NH 4Cl and diluted with Et 2O. The layers were

separated and the aqueous portion was washed twice with Et 2O, dried over Na 2SO 4, , and concentrated in vacuo. Purification via flash column chromatography (5%

EtOAc/Hexanes) gave 468 mg (85%) of the alkene as a colorless oil: 1H NMR (400

o MHz, C 6D6, 60 C) δ 0.016 (s, 3H), 0.022 (s, 3H), 0.93 (s, 9H), 1.58-1.68 (m, 1H),

1.65 (s, 3H), 1.75 (s, 3H), 1.81 (s, 3H), 1.90 (m, 1H), 2.04 (dd, J = 17.2, 5.6 Hz, 1H),

2.05-2.17 (m, 2H), 2.24 (dd, J = 7.1, 5.5 Hz, 1H), 2.60 (dd, J = 12.0, 6.1 Hz, 1H),

2.60-2.71 (m, 1H), 2.72 (d, J = 14.2 Hz, 1H), 2.82 (dd, J = 13.5, 6.4 Hz, 1H), 2.97

(m, 1H), 3.32 (s, 3H), 4.07-4.16 (m, 2H), 4.44 (m, 1H), 4.83 (m, 1H), 4.85 (m, 1H),

13 o 5.56 (m, 1H); C NMR (100 MHz, C 6D6, 60 C ) δ –4.8, -4.6, 16.1, 18.3, 21.3, 23.2,

26.2, 27.6, 33.0, 38.9, 40.7, 42.1, 43.0, 57.0, 73.7, 80.3, 84.6, 110.6, 114.8, 129.5,

-1 25 131.7, 148.6, 149.0; IR (film) 2928, 1706, 1644, 1452, 1254, 1086 cm ; [ α] D =

+22.3 (c = 1.32, CH 2Cl 2); MS (electrospray ionization) calculated for C 26 H45 O3Si [M +

1] +: 433.31, found: 433.4.

Me MeO H H Me O H H H Me OH

Secondary alcohol. A flask was charged with the previous alkene 42 (410 mg, 0.948 mmol) and 10 mL of THF. Tetrabutylammonium fluoride (1.0 M in THF,

1.90 mL, 1.90 mmol) was added to the solution and stirred 4 hours. Saturated

162 aqueous NH 4Cl was added and the solution was diluted with Et 2O. The layers were

separated and the aqueous portion was washed twice with Et 2O. The combined

organic extracts were dried over Na 2SO 4 and concentrated in vacuo. Purification via

flash column chromatography (10% EtOAc/Hexanes) provided 283 mg (95%) of the

1 o alcohol as a colorless oil: H NMR (400 MHz, C 6D6, 60 C) δ 1.60 (s, 3H), 1.61 (s,

3H), 1.71-1.85 (m, 2H), 1.79 (s, 3H), 1.90-2.08 (m, 4H), 2.11 (dd, J = 14.5, 3.9 Hz,

1H), 2.40 (ddd, J = 9.5, 9.5, 5.7 Hz, 1H), 2.69 (ddd, J = 10.2, 7.2, 2.6 Hz, 1H), 2.85-

2.92 (m, 2H), 3.07 (m, 1H), 3.30 (s, 3H), 3.70 (m, 1H), 4.16 (dd, J = 4.4, 2.7 Hz, 1H),

4.31 (ddd, J = 7.1, 3.5, 3.5 Hz, 1H), 4.78-4.82 (m, 2H), 5.67 (m, 1H); 13 C NMR (100

o MHz, C 6D6, 60 C ) δ 16.1, 19.9, 25.7, 28.2, 32.5, 35.4, 37.8, 42.6, 42.8, 44.3, 57.9,

73.4, 82.3, 85.9, 111.7, 115.7, 129.6, 134.3, 148.2, 150.0; IR (film) 3445 (br), 2918,

-1 25 1695, 1638, 1448, 1221, 1053 cm ; [ α] D = +100 (c = 0.67, CH 2Cl 2); MS

+ (electrospray ionization) calculated for C 20 H30 O3Na [M + Na] : 341.21, found: 341.4.

Me MeO H H Me O H H H Me O

Ketone 43. A flask was charged with the secondary alcohol (300 mg, 0.866 mmol) and 17 mL of CH 2Cl 2. Pyridine (351 L, 4.33 mmol) followed by Dess-Martin periodinane (735 mg, 1.73 mmol) were added to the solution and stirred 15 minutes.

The reaction was quenched by the addition of Na 2S2O3/NaHCO 3 (5:1 v:v) and the

layers were separated. The aqueous portion was washed twice with CH 2Cl 2 and the

combined organic extracts were dried over Na 2SO 4 and concentrated in vacuo.

163 Purification via flash column chromatography (10% EtOAc/Hexanes) gave 290 mg

1 (98%) of the ketone as a white solid: H NMR (400 MHz, CDCl 3) δ 1.64 (s, 6H), 1.78

(s, 3H), 1.93 (dd, J = 16.3, 4.6 Hz, 1H), 2.02 (dd, J = 14.4, 5.4 Hz, 1H), 2.05-2.18 (m,

2H), 2.24 (ddd, J = 11.2, 11.2, 4.7 Hz, 1H), 2.35 (ddd, J = 12.1, 12.1, 5.6 Hz, 1H),

2.51 (dd, J = 7.3, 7.3 Hz, 1H), 2.73 (d, J = 14.1 Hz, 1H), 2.82 (ddd, J = 12.4, 4.6, 4.6

Hz, 1H), 2.89 (dd, J = 11.8, 7.1 Hz, 1H), 3.10 (dddd, J = 12.2, 12.2, 12.2, 5.5 Hz,

1H), 3.49 (s, 3H), 4.06 (s, 1H), 4.30 (ddd, J = 8.0, 5.4, 3.3 Hz, 1H), 4.77 (s, 2H), 5.53

13 (dd, J = 10.8, 6.1 Hz, 1H); C NMR (100 MHz, CDCl 3) δ 15.9, 19.0, 26.0, 26.4, 35.1,

37.3, 41.3, 42.0, 42.1, 42.6, 58.6, 85.1, 87.7, 112.7, 117.2, 126.9, 134.3, 146.7,

-1 25 148.6, 214.0; IR (film) 3070, 1705 (str), 1448, 1202, 1119, 1032 cm ; [ α] D = -10.3

+ (c = 1.44, CH 2Cl 2); MS (electrospray ionization) calculated for C 20 H28 O3Na [M + Na] :

339.19, found: 339.3.

Me MeO H H Me O H H H OH Me O

Secondary alcohol 51. A flask containing the ketone 43 (280 mg, 0.885 mmol) in 20 mL of THF was cooled to -78 oC. Potassium hexamethyldisilazide (0.5

M in toluene) was added dropwise, and the solution was allowed to stir for one hour at -78 oC. Davis oxaziridine (278 mg, 1.062 mmol) was added in 10 mL of THF to

the enolate, and the solution was allowed to stir 45 minutes at -78 oC. The reaction was quenched by the addition of saturated aqueous NH 4Cl. The mixture was diluted

with Et 2O and the layers were separated. The aqueous portions were washed three

164 times with Et 2O, dried over Na 2SO 4 and concentrated in vacuo. Purification via flash

column chromatography (10% EtOAc/Hexanes) gave 245 mg (84%) of the alcohol

1 o as a white solid: H NMR (400 MHz, C 6D6, 60 C) δ 1.54 (s, 3H), 1.56 (s, 3H), 1.67

(s, 3H), 1.80 (dd, J = 16.5, 4.9 Hz, 1H), 1.95 (m, 1H), 2.03 (dd, J = 14.0, 8.3 Hz, 1H),

2.20-2.31 (m , 2H), 2.44 (m, 1H), 2.61 (dd, J = 6.3, 6.3 Hz, 1H), 2.76 (m, 1H), 3.03

(dd, J = 11.4, 7.6 Hz, 1H), 3.14 (br d, J = 9.6 Hz, 1H), 3.23 (s, 3H), 4.22 (ddd, J =

10.1, 10.1, 3.7 Hz, 1H), 4.30 (m, 1H), 4.59 (s, 1H), 4.74 (s, 1H), 4.78 (s, 1H), 5.30

13 o (dd, J = 7.5, 7.5 Hz, 1H); C NMR (100 MHz, C 6D6, 60 C ) δ 16.0, 19.5, 24.8, 34.9,

35.3, 39.9, 42.0, 42.8, 43.7, 57.8, 79.2, 83.6, 84.1, 112.7, 116.7, 121.8, 138.7,

-1 24 147.1, 149.0, 214.4; IR (film) 3419 (br), 2912, 1715 (str), 1447, 1051 cm ; [ α] D =

+55.3 (c = 6.50, CH 2Cl 2); MS (electrospray ionization) calculated for C 20 H28 O4 [M +

Na] +: 355.19, found: 355.3.

Me MeO H H Me O H H H OH Me HO Me

Diol 52. A flask was charged with methylmagnesium chloride (3.0 M in THF,

6.42 mL, 19.3 mmol) and 24 mL of THF. The solution was cooled to 0 oC and the ketone 51 (320 mg, 0.963 mmol) was added in 8 mL of THF dropwise. The solution was stirred 30 minutes, then quenched with saturated aqueous NH 4Cl, warmed to

room temperature, and diluted with Et 2O. The layers were separated and the aqueous portion was washed twice with Et 2O. The combined organic extracts were

dried over Na 2SO 4 and concentrated in vacuo. Purification via flash column

165 chromatography (20% EtOAc/ Hexanes) provided 278 mg (83%) of the alcohol as a

1 o white solid: H NMR (400 MHz, C 6D6, 60 C) δ 1.28 (s, 3H), 1.59 (s, 3H), 1.65 (s,

3H), 1.78 (s, 3H), 1.91 (dd, J = 16.8, 5.1 Hz, 1H), 1.99-2.09 (m, 2H), 2.13 (dd, J =

14.6, 4.4 Hz, 1H), 2.20-2.31 (m, 2H), 2.40 (ddd, J = 9.7, 9.7, 5.2 Hz, 1H), 2.56 (ddd,

J = 10.3, 7.4, 2.7 Hz, 1H), 2.76-2.85 (m, 2H), 3.12 (m, 1H), 3.29 (s, 3H), 3.51 (dd, J

= 7.5, 4.3 Hz, 1H), 4.13 (d, J = 2.6 Hz, 1H), 4.27 (ddd, J = 7.4, 4.4, 2.9 Hz, 1H), 4.83

13 o (s, 2H), 5.68 (dd, J = 10.7, 6.7 Hz, 1H); C NMR (100 MHz, C 6D6, 60 C) δ 16.0,

19.6, 24.3, 27.7, 35.1, 36.1, 38.0, 42.9, 43.4, 44.1, 58.0, 76.5, 77.4, 82.5, 87.5,

112.5, 115.8, 126.0, 135.9, 147.8, 149.7; IR (film) 3437 (br), 2910, 1445, 1376,

-1 24 1118, 1092, 1050 cm ; [ α] D = +82 (c = 0.34, CH 2Cl 2); MS (electrospray ionization)

+ calculated for C 21 H32 O4Na [M + Na] : 371.22, found: 371.4.

Me O H H Me O H H H OH Me HO Me

Ketone 53. A flask was charged with diol 52 (220 mg, 0.631 mmol), 10 mL of

CHCl 3, and 450 L of water. Hydrochloric acid (12 M, 450 L, 5.4 mmol) was added to the biphasic solution and stirred for 2 hours. The reaction was quenched by the slow addition of saturated aqueous NaHCO 3 and diluted with CH 2Cl 2. The layers

were separated and the aqueous portion was washed twice with CH 2Cl 2. The

combined organic extracts were dried over Na 2SO 4 and concentrated in vacuo.

Purification by flash column chromatography (20% EtOAc/Hexanes) gave 192 mg

(91%) of the ketone as a white solid and 16 mg (8%) of the ( 4S )-product ( #) as a

166 1 o colorless oil: H NMR (400 MHz, CDCl 3, 60 C) δ 1.06 (d, J = 6.6 Hz, 3H), 1.08 (s,

3H), 1.58 (ddd, J = 13.0, 13.0, 13.0 Hz, 1H), 1.69 (s, 3H), 1.89 (s, 3H), 1.88-1.99 (m,

2H), 2.08 (m, 1H), 2.33 (br s, 1H), 2.46 (ddd, J = 15.0, 12.3, 2.8 Hz, 1H), 2.48-2.60

(m, 2H), 2.63 (dd, J = 11.7, 7.6 Hz, 1H), 2.83-3.06 (m, 3H), 3.53 (br dd, J = 6.9, 6.9

Hz, 1H), 4.09 (s, 1H), 4.36 (ddd, J = 9.5, 3.2, 3.2 Hz, 1H), 4.86 (s, 2H), 5.76 (dd, J =

13 o 10.6, 6.3 Hz, 1H); C NMR (100 MHz, CDCl 3, 60 C) δ 14.5, 18.6, 24.4, 27.9, 35.9,

36.9, 39.3, 42.1, 46.8, 47.9, 54.4, 76.3, 77.0, 80.5, 89.2, 113.4, 125.0, 137.0, 146.3,

-1 22 210.9; IR (film) 3523 (br), 2925, 1705 (str), 1450, 1184, 1071 cm ; [ α] D = +35 (c =

+ 0.37, CH 2Cl 2); MS (electrospray ionization) calculated for C 20 H30 O4Na [M + Na] :

357.20, found: 357.3.

Me O H H Me O H H H OH Me HO Me

Ketone 54. Into a flask containing the previous ketone 53 (242 mg, 0.724 mmol) and 24 mL of methanol was added catalytic sodium hydride. After stirring 15 minutes, the reaction was quenched by the slow addition of saturated aqueous

NH 4Cl and diluted with Et 2O. The layers were separated and the aqueous portion

was washed twice with Et 2O. The combined organic extracts were dried over

Na 2SO 4 and concentrated in vacuo. Purification by flash column chromatography

(20% EtOAc/Hexanes) gave 103 mg (42%) of the ketone as a colorless oil and 139

1 o mg (58%) of the ( 4R )-product as a white solid: H NMR (400 MHz, CDCl 3, 60 C) δ

1.02 (d, J = 6.8 Hz, 3H), 1.21 (s, 3H), 1.62 (ddd, J = 14.2, 9.2, 5.5, Hz, 1H), 1.73 (s,

167 3H), 1.77 (s, 3H), 1.94-2.09 (m, 3H), 2.35-2.55 (m, 4H), 2.72-2.81 (m, 2H), 2.95

(ddd, J = 13.3, 11.4, 7.5 Hz, 1H), 3.04 (ddd, J = 7.6, 7.6, 7.6 Hz, 1H), 3.53 (dd, J =

7.4, 3.0 Hz, 1H), 3.77 (d, J = 5.7 Hz, 1H), 4.60 (m, 1H), 4.84 (s, 1H), 4.90 (s, 1H),

13 o 5.65 (dd, J = 10.7, 6.4 Hz, 1H); C NMR (100 MHz, CDCl 3, 60 C) δ 15.0, 20.2,

22.7, 27.9, 34.7, 34.8, 37.2, 40.2, 41.2, 45.0, 53.5, 76.1, 76.2, 77.2, 87.3, 112.1,

125.8, 134.5, 147.0, 211.9; IR (film) 3459 (br), 2930, 1710 (str), 1448, 1377, 1048

-1 21 cm ; [ α] D = +54 (c = 1.9, CH 2Cl 2); MS (electrospray ionization) calculated for

+ C20 H30 O4Na [M + Na] : 357.20, found: 357.3.

Me HO H H Me O

H H H MeOH Me HO

Triol. Into a flask charged with the ketone 54 (158 mg, 0.472 mmol) was

added 5 mL of THF. The solution was cooled to –78 oC and L-Selectride ® (1.0 M in

THF, 567 L, 0.567 mmol) dropwise. The reaction was stirred 10 minutes, then quenched by the addition of sodium hydroxide (3 M, 288 L, 0.864 mmol) and hydrogen peroxide (30%, 566 L, 5.184 mmol). The mixture was stirred three hours

at room temperature, then diluted with CH 2Cl 2. The layers were separated and the aqueous portions were washed twice with CH 2Cl 2. The combined organic extracts were dried over Na 2SO 4 and concentrated in vacuo. Purification by flash column

chromatography (50% EtOAc/Hexanes) gave 148 mg (94%) of the alcohol as a

1 o white solid: H NMR (400 MHz, CDCl 3, 60 C) δ 0.99 (d, J = 6.1 Hz, 3H)1.29 (s, 3H),

1.38 (m, 1H), 1.73 (s, 3H), 1.83 (s, 3H), 1.98 (dd, J = 14.6, 3.9 Hz, 1H), 2.06 (m, 1H),

168 2.13-2.28 (m, 3H), 2.61 (s, 2H), 2.78 (d, J = 14.4 Hz, 1H), 3.00 (ddd, J = 11.6, 8.2,

8.2, Hz, 1H), 3.65 (m, 1H), 3.78 (s, 1H), 3.92 (d, J = 7.0 Hz, 1H), 4.37 (d, J = 2.5 Hz,

1H), 4.75 (s, 1H), 4.84 (s, 1H), 5.64 (dd, J = 9.8, 7.0 Hz, 1H); 13 C NMR (100 MHz,

o CDCl 3, 60 C ) δ 16.9, 21.6, 22.9, 28.2, 28.4, 31.4, 34.4, 38.3, 39.5, 41.3, 45.5, 72.2,

75.9, 76.9, 79.8, 88.0, 110.7, 125.8, 134.2, 149.1; IR (film) 3382 (br), 2912, 1440,

-1 21 1366, 1052 cm ; [ α] D = +2.8 (c = 3.2, CH 2Cl 2); MS (electrospray ionization)

+ calculated for C 20 H32 O4Na [M + K] : 375.33, found: 375.2.

Me AcO H H Me O

H H H MeOAc Me HO

Diester 55. Into a flask containing the triol (122 mg, 0.363 mmol) in 10 mL of

CH 2Cl 2 was added triethylamine (253 L, 1.81 mmol) and 4-dimethylaminopyridine

(4.4 mg, 0.036 mmol). Acetic anhydride (103 L, 1.09 mmol) was added to the solution and stirred for firve hours. The reaction was quenched using saturated aqueous NH 4Cl and the layers were separated. The aqueous portions were washed twice with CH 2Cl 2, dried over Na 2SO 4 and concentrated in vacuo. Purification via flash column chromatography (20% EtOAc/Hexanes) gave 130 mg (85%) of the

1 o ester as a white solid: H NMR (400 MHz, CDCl 3, 60 C) δ 0.90 (d, J = 7.0 Hz, 3H),

1.24 (s, 3H), 1.47 (m, 1H), 1.63 (ddd, J = 13.5, 8.8, 4.1 Hz, 1H), 1.71 (s, 3H), 1.79 (s,

3H), 1.90 (dd, J = 14.8, 3.6 Hz, 1H), 1.91-2.08 (m, 2H), 2.04 (s, 3H), 2.07 (s, 3H),

2.25-2.34 (m, 2H), 2.61-2.68 (m, 2H), 2.77 (d, J = 14.9 Hz, 1H), 3.12 (ddd, J = 12.9,

11.5, 8.2 Hz, 1H), 3.90 (d, J = 6.4 Hz, 1H), 4.19 (d, J = 2.6 Hz, 1H), 4.75 (m 1H),

169 4.76 (s, 1H), 4.84 (s, 1H), 5.16 (dd, J = 4.1, 4.1 Hz, 1H), 5.70 (dd, J = 11.2, 6.0 Hz,

13 o 1H); C NMR (100 MHz, CDCl 3, 60 C ) δ 16.5, 20.9, 21.1, 21.3, 23.5, 28.3, 29.6,

29.8, 32.9, 37.9, 39.2, 42.1, 43.8, 73.7, 75.5, 78.7, 79.6, 87.6, 111.1, 125.2, 134.9,

148.3, 170.51, 170.54; IR (film) 3362 (br), 2933, 1734 (str), 1448, 1374, 1238 (str),

-1 22 1038 cm ; [ α] D = +18 (c = 3.1, CHCl 3); MS (electrospray ionization) calculated for

+ C24 H36 O6Na [M + Na] : 443.24, found: 443.3.

M AcO e H H Me O

H H H O Me HO MeA H c OH

Diol 56. A flask was charged with alkene 55 (16.1 mg, 38.3 mol) in 1 mL of

THF. (+)-Diisopinocampheylborane (33.1 mg, 115 mol) was added to the solution and allowed to stir 30 minutes. The reaction was quenched by the addition of 1 mL of water and sodium perborate tetrahydrate (53.0 mg, 345 mol) and allowed to stir for three hours, then diluted with brine and Et 2O. The layers were separated and the aqueous portion was washed twice with Et 2O, dried over Na 2SO 4, and concentrated in vacuo. Purification via flash column chromatography (10% then 30%

EtOAc/Hexanes) gave 12.3 mg (74%) of the diol as a colorless oil: 1H NMR (500

MHz, CDCl 3) δ 0.82 (d, J = 6.0 Hz, 3H), 8.87 (d, J = 6.9 Hz, 3H), 1.02 (m, 1H), 1.17

(m, 1H), 1.38 (s, 3H), 1.70-1.92 (m, 5H), 1.81 (s, 3H), 2.06 (m, 1H), 2.10 (s, 3H),

2.11 (s, 3H), 2.90 (br s, 1H), 2.46 (dd, J =10.3, 8.1 Hz, 1H), 2.69 (d, J = 14.8 Hz,

1H), 3.15 (ddd, J = 13.5, 11.5, 7.7 Hz, 1H), 3.53-3.62 (m, 3H), 3.87 (d, J = 10.7 Hz,

170 1H), 4.04 (s, 1H), 4.89 (d, J = 7.6 Hz, 1H), 5.18 (d, J = 3.3 Hz, 1H), 5.65 (dd, J =

13 10.3, 4.7 Hz, 1H); C NMR (125 MHz, CDCl 3) δ 14.2, 18.4, 21.2, 21.5, 21.8, 23.3,

24.7, 28.3, 29.4, 30.9, 32.5, 36.6, 38.0, 41.0, 45.7, 65.0, 73.8, 75.7, 77.8, 79.9, 88.7,

125.2, 133.9, 171.4, 171.6; IR (film) 3392 (br), 2926, 1735 (str), 1375, 1244 (str),

-1 21 1024 cm ; [ α] D = -11 (c = 0.40, CH 2Cl 2); MS (electrospray ionization) calculated for

+ C24 H38 O7Na [M + Na] : 461.25, found 461.4.

Me AcO H H Me O

H H H OAc Me O Me H

Asbestinin-12 (2). A flask charged with diol 56 (13.7 mg, 31.2 mol) in 1.6

o mL of CHCl 3 was cooled to 0 C. 2,6 lutidine (18.2 L, 0.156 mmol) followed by

trifluoromethanesulfonic anhydride (5.80 L, 34.4 mol) were added to the solution

and allowed to stir 30 minutes at 0 oC. The solution was warmed to room

temperature for 4 hours, then quenched via the addition of saturated aqueous

NH 4Cl. The mixture was diluted with CHCl 2 and the layers were separated. The aqueous portion was washed three times with CH 2Cl 2, dried over Na 2SO 4, and concentrated in vacuo. Purification via flash column chromatography (15%

EtOAc/Hexanes) gave 9.0 mg (69%) of asbestinin-12 as a colorless oil: 1H NMR

(400 MHz, CDCl 3) δ 0.88 (d, J = 7.1 Hz, 3H), 0.92 (d, J = 7.2 Hz, 3H), 1.00 (ddd, J =

13.4, 3.3, 1.7 Hz, 1H), 1.42 (s, 3H), 1.51 (ddd, J = 3.8, 3.8, 3.8 Hz, 1H), 1.62 (m,

2H), 1.79 (s, 3H), 1.85 (dd, J = 14.6, 4.5 Hz, 1H), 1.98 (ddd, J = 10.8, 3.1, 3.1 Hz,

1H), 2.02 (m, 1H), 2.10 (s, 3H), 2.12 (s, 3H), 2.26 (ddd, J = 11.0, 11.0, 11.0 Hz, 1H),

171 2.68 (d, J = 15.1 Hz, 1H), 3.19 (ddd, J = 13.8, 11.1, 7.4 Hz, 1H), 3.49 (dd, J = 13.3,

3.8 Hz, 1H), 3.85 (d, J = 13.1 Hz, 1H), 3.93 (d, J = 9.1 Hz, 1H), 4.10 (ddd, J = 3.4,

3.4, 3.4 Hz, 1H), 4.87 (d, J = 7.4 Hz, 1H), 5.28 (dd, J = 4.9, 2.9 Hz, 1H), 5.74 (dd, J =

13 10.8, 6.8 Hz, 1H); C NMR (125 MHz, CDCl 3) δ 10.8, 18.2, 19.3, 21.3, 21.6, 29.6,

31.3, 31.4, 33.4, 36.9, 37.6, 38.3, 40.8, 44.9, 67.8, 73.6, 76.7, 79.2, 81.7, 91.3,

126.7, 131.6, 170.8, 171.3; IR (film) 2926, 1737 (str), 1459, 1377, 1231, 1088 cm -1;

21 [α] D = -22 (c = 0.29, CHCl 3); MS (electrospray ionization) calculated for C 24 H36 O6

[M + Na] +: 443.24, found: 443.3.

Me MeO H H Me O H H H Me Me OH

Tertiary alcohol 44. A flask was charged with methylmag-nesium chloride

(3.0 M in THF, 3.47 mL, 10.4 mmol) and 70 mL of THF. The solution was cooled to

0 oC and the ketone 43 (659 mg, 2.08 mmol) was added in 35 mL of THF dropwise.

The solution was stirred 30 minutes, then quenched with saturated aqueous NH 4Cl,

warmed to room temperature, and diluted with Et 2O. The layers were separated and the aqueous portion was washed twice with Et 2O. The combined organic extracts were dried over Na 2SO 4 and concentrated in vacuo. Purification via flash column chromatography (10% EtOAc/ Hexanes) provided 678 mg (98%) of the alcohol as a

1 colorless oil: H NMR (400 MHz, CDCl 3) δ 0.95 (s, 3H), 1.66 (s, 3H), 1.69 (s, 3H),

1.69-1.79 (m, 1H), 1.85-1.96 (m, 2H), 1.90 (s, 3H), 2.00 (m, 1H), 2.17 (m, 2H), 2.28

(ddd, J = 11.2, 11.2, 4.5 Hz, 1H), 2.43 (dd, J = 11.7, 6.9 Hz, 1H), 2.75 (dd, J = 7.1,

172 7.1 Hz, 1H), 2.95 (d, J = 14.7 Hz, 1H), 3.07-3.24 (m, 2H), 3.52 (s, 3H), 3.87 (s, 1H),

4.18 (ddd, J = 8.6, 3.3, 3.3 Hz, 1H), 4.82 (s, 1H), 4.83 (m, 1H), 5.84 (dd, J = 10.9,

13 6.0 Hz, 1H) ; C NMR (100 MHz, CDCl 3) δ 15.8, 19.0, 27.1, 28.3, 28.9, 35.2, 36.7,

38.8, 41.8, 42.9, 45.0, 58.6, 75.3, 83.4, 89.4, 113.0, 116.7, 128.7, 136.5, 147.0,

-1 24 149.1; IR (film) 3511 (br), 2914, 1447, 1119, 1058 cm ; [ α] D = +74 (c = 0.42,

+ CH 2Cl 2); MS (electrospray ionization) calculated for C 21 H32 O3Na [M + Na] : 355.23, found: 355.3.

Me O H H Me O H H H Me Me OH

Ketone 45. A flask was charged with alcohol 44 (678 mg, 0.255 mmol), 20 mL of CHCl 3, and 2.5 mL of water. Hydrochloric acid (12 M, 2.50 mL, 30.0 mmol)

was added to the biphasic solution and stirred for 2 hours. The reaction was

quenched by the slow addition of saturated aqueous NaHCO 3. The layers were separated and the aqueous portion was washed twice with CH 2Cl 2. The combined organic extracts were dried over Na 2SO 4 and concentrated in vacuo. Purification by flash column chromatography (10% then 25% EtOAc/Hexanes) gave 562 mg (87%) of the ketone as a white solid and 58 mg (9%) of the ( 4S )-product ( #) as a colorless

1 oil: H NMR (400 MHz, CDCl 3) δ 0.90 (s, 3H), 1.07 (d, J = 6.6 Hz, 3H), 1.59 (dd, J =

25.8, 13.0 Hz, 1H), 1.69 (s, 3H), 1.71-1.78 (m, 1H), 1.85-2.03 (m, 4H), 1.93 (s, 3H),

2.48 (ddd, J = 12.3, 12.3, 2.8 Hz, 1H), 2.59 (dddd, J = 11.7, 11.7, 6.5, 6.5 Hz, 1H),

2.69 (dd, J = 12.0, 7.0 Hz, 1H), 2.91-2.97 (m, 2H), 3.07 (m, 1H), 3.13 (ddd, J = 11.9,

11.9, 6.4 Hz, 1H), 3.94 (s, 1H), 4.36 (ddd, J = 9.9, 3.1, 3.1 Hz, 1H), 4.86 (m, 2H),

173 13 5.83 (dd, J = 11.5, 5.4 Hz, 1H); C NMR (100 MHz, CDCl 3) δ 14.5, 18.5, 27.2, 28.4,

28.7, 35.2, 38.5, 39.0, 41.8, 46.0, 48.7, 54.1, 74.8, 80.5, 91.3, 113.4, 128.3, 136.6,

146.2, 211.7; IR (film) 3514 (br), 2928, 1702 (str), 1453, 1377, 1184, 1076 cm -1;

24 [α] D = +40 (c = 0.18, CH 2Cl 2); MS (electrospray ionization) calculated for

+ C20 H30 O3Na [M + Na] : 341.21, found: 341.3.

Me O H H Me O H H H Me Me OH

Ketone 46. Into a flask containing the previous ketone 45 (551 mg, 1.73

mmol) and 17 mL of methanol was added catalytic sodium hydride. After stirring 15

minutes, the reaction was quenched by the slow addition of saturated aqueous

NH 4Cl and diluted with Et 2O. The layers were separated and the aqueous portion

was washed twice with Et 2O. The combined organic extracts were dried over

Na 2SO 4 and concentrated in vacuo. Purification by flash column chromatography

(10% then 25% EtOAc/Hexanes) gave 246 mg (45%) of the ketone as a colorless oil and 303 mg (55%) of the ( 4R )-product ( #) as a white solid: 1H NMR (400 MHz,

CDCl 3) δ 1.09 (d, J = 6.8Hz, 3H), 1.14 (s, 3H), 1.59-1.71 (m, 2H), 1.77 (s, 3H), 1.80-

1.87 (m, 1H), 1.88 (s, 3H), 1.92-1.99 (m, 1H), 2.01 (dd, J = 14.8, 3.7 Hz, 1H), 2.11

(ddd, J = 13.9, 8.6, 7.1 Hz, 1H), 2.34 (s, 1H), 2.47 (ddd, J = 8.6, 8.6, 5.5 Hz, 1H),

2.58 (ddq, J = 21.7, 7.0, 7.0 Hz, 1H), 2.83 (ddd, J = 7.8, 7.8, 7.8 Hz, 1H), 2.84-2.93

(m, 2H), 3.02 (ddd, J = 8.1, 8.1, 4.6 Hz, 1H), 3.72 (d, J = 4.6 Hz, 1H), 4.58 (ddd, J =

6.3, 3.3, 3.3 Hz, 1H), 4.89 (d, J = 0.7 Hz, 1H), 4.92 (d, J = 1.3 Hz, 1H), 5.71 (dd, J =

174 13 11.3, 5.7 Hz, 1H); C NMR (100 MHz, CDCl 3) δ 15.5, 20.0, 25.3, 28.5, 28.9, 34.7,

36.5, 38.4, 40.7, 40.9, 45.9, 53.3, 74.7, 77.7, 89.1, 112.7, 129.2, 134.2, 146.9,

-1 24 212.9; IR (film) 3443 (br), 2928, 1710 (str), 1642, 1446, 1376, 1081 cm ; [ α] D =

+92 (c = 0.19, CH 2Cl 2); MS (electrospray ionization) calculated for C 20 H30 O3Na [M +

Na] +: 341.21, found: 341.4.

Me HO H H Me O H H H Me Me OH

Diol. Into a flask charged with the ketone 46 (523 mg, 1.64 mmol) was added

16 mL of THF. The solution was cooled to –78 oC and L-Selectride ® (1.0 M in THF,

1.97 mL, 1.97 mmol) dropwise. The reaction was stirred 10 minutes, then quenched by the addition of sodium hydroxide (3 M, 1.0 mL, 3.0 mmol) and hydrogen peroxide

(30%, 2.0 mL, 18 mmol). The mixture was stirred three hours at room temperature, then diluted with Et 2O. The layers were separated and the aqueous portions were washed twice with Et 2O. The combined organic extracts were dried over Na 2SO 4

and concentrated in vacuo. Purification by flash column chromatography (25%

EtOAc/Hexanes) gave 493 mg (94%) of the alcohol as a white solid: 1H NMR (400

o MHz, C 6D6, 60 C) δ 0.95 (d, J = 7.0 Hz, 3H), 1.19 (m, 1H), 1.28 (s, 3H), 1.33 (m,

2H), 1.56 (m, 1H), 1.64-1.73 (m, 2H), 1.70 (s, 3H), 1.75 (s, 3H), 1.77-1.94 (m, 2H),

1.89 (m, 1H), 2.19 (ddd, J = 7.8, 4.2, 4.2 Hz, 1H), 2.69-2.92 (m, 4H), 3.42 (s, 1H),

3.91 (d, J = 7.5 Hz, 1H), 4.24 (dd, J = 6.7, 3.8 Hz, 1H), 4.86 (s, 1H), 4.88 (d, J = 1.3

13 o Hz, 1H), 5.52 (dd, J = 11.0, 6.1 Hz, 1H); C NMR (100 MHz, C 6D6, 60 C ) δ 17.2,

175 22.0, 24.6, 28.4, 28.8, 29.7, 31.8, 38.5, 38.6, 39.8, 42.6, 45.9, 72.2, 74.7, 80.0, 89.5,

-1 25 110.6, 130.0, 132.3, 149.8; IR (film) 3329 (br), 2921, 1439, 1373, 1088 cm ; [ α] D =

+5.7 (c = 0.46, CH 2Cl 2); MS (electrospray ionization) calculated for C 20 H32 O3Na [M +

Na] +: 343.23, found: 343.3.

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

Ester 47. Into a flask containing the secondary alcohol (406 mg, 1.27 mmol)

in 26 mL of CH 2Cl 2 was added triethylamine (707 L, 5.07 mmol) and 4-

dimethylaminopyridine (16.0 mg, 0.127 mmol). Acetic anhydride (240 L, 2.53 mmol) was added to the solution and stirred overnight. The reaction was quenched using saturated aqueous NH 4Cl and the layers were separated. The aqueous

portions were washed twice with CH 2Cl 2, dried over Na 2SO 4 and concentrated in vacuo. Purification via flash column chromatography (25% EtOAc/Hexanes) gave

1 o 453 mg (99%) of the ester as a colorless oil: H NMR (400 MHz, C 6D6, 60 C) δ 0.87

(d, J = 7.0 Hz, 3H), 1.25 (s, 3H), 1.37 (ddd, J = 13.7, 6.2, 4.1 Hz, 1H), 1.50-1.69 (m,

4H), 1.66 (s, 3H), 1.67 (s, 3H), 1.74 (dd, J = 14.6, 3.9 Hz, 1H), 1.77-1.92 (m, 2H),

1.81 (s, 3H), 2.32 (ddd, J = 4.9, 4.9, 4.9 Hz, 1H), 2.66-2.78 (m, 3H), 2.89 (m, 1H),

3.88 (d, J = 6.6 Hz, 1H), 4.25 (dd, J = 7.0, 3.8 Hz, 1H), 4.83 (s, 1H), 4.85 (d, J = 1.3

Hz, 1H), 5.22 (dd, J = 5.1, 3.7 Hz, 1H), 5.51 (dd, J = 11.1, 6.0 Hz, 1H); 13 C NMR

o (100 MHz, C 6D6, 60 C ) δ 16.8, 20.7, 21.5, 24.9, 28.4, 29.7, 30.1, 30.2, 38.1, 38.8,

39.7, 43.0, 44.2, 73.8, 74.7, 79.7, 89.3, 111.1, 130.0, 132.6, 149.2, 170.0; IR (film)

176 -1 25 3465(br), 2924, 1737 (str), 1450, 1374, 1237, 1039 cm ; [ α] D = +42.2 (c = 1.32,

+ CH 2Cl 2); MS (electrospray ionization) calculated for C 22 H35 O4 [M + 1] : 363.25, found: 363.4.

Me AcO H H Me O H H H Me Me OTES

Diene 48. A flask was charged with ester 13 (64.0 mg, 0.176 mmol) in 2 mL

o of CH 2Cl 2 and cooled to 0 C. 2,6-lutidine (62 L, 0.53 mmol) and triethylsilyl trifluoromethanesulfonate (60 L, 0.27 mmol) were added sequentially and stirred for

1 hour at 0 oC. The reaction was quenched by the addition of saturated aqueous

NH 4Cl, warmed to room temperature and the layers were separated. The aqueous

portions were washed twice with CH 2Cl 2, dried over Na 2SO4 and concentrated in vacuo. Purification via flash column chromatography (5% EtOAc/Hexanes) gave 67

1 o mg (80%) of the alkene as a colorless oil: H NMR (400 MHz, C 6D6, 60 C) δ 0.62

(q, J = 7.8 Hz, 6H), 0.83 (d, J = 5.8 Hz, 3H), 1.00 (t, J = 7.9 Hz, 9H), 1.38 (ddd, J =

13.9, 3.1, 3.1 Hz, 1H), 1.55-1.65 (m, 2H), 1.57 (s, 3H), 1.71 (s, 3H), 1.73-1.89 (m,

4H), 1.79 (s, 3H), 1.86 (s, 3H), 2.20 (dd, J = 7.1, 4.6 Hz, 1H), 2.63 (d, J = 13.9 Hz,

1H), 2.68 (m, 1H), 2.96 (dd, J = 8.8, 8.8 Hz, 1H), 3.03 (d, J = 5.3 Hz, 1H), 3.97 (d, J

= 10.4 Hz, 1H), 4.08 (d, J = 1.63 Hz, 1H), 4.88 (s, 1H), 4.94 (m, 1H), 5.19 (m, 1H),

13 o 5.44 (dd, J = 10.6, 5.6 Hz, 1H); C NMR (100 MHz, C 6D6, 60 C ) δ 7.3, 7.5, 18.2,

20.7, 23.1, 23.5, 26.7, 28.5, 28.9, 29.5, 38.5, 39.2, 39.5, 41.4, 44.8, 74.1, 78.4, 79.4,

88.3, 110.1, 130.5, 130.9, 149.4, 170.5; IR (film) 2957, 1739 (str), 1462, 1373, 1235,

177 -1 23 1116, 1048 cm ; [ α] D = -33 (c = 0.43, CH 2Cl 2); MS (electrospray ionization)

+ calculated for C 28 H48 O4SiNa [M + Na] : 499.32, found: 499.4.

Me AcO H H Me O H H H Me Me OH HO

Diol 50. A flask was charged with diene 48 (10.4 mg, 21.8 mol) in 500 L of

THF. (+)-Diisopinocampheylborane (24.0 mg, 83.2 mol) was added to the solution and allowed to stir 30 minutes. The reaction was quenched by the addition of sodium hydroxide (3 M, 130 L, 0.390 mmol), then hydrogen peroxide (30%, 260 L,

2.29 mmol). The biphasic solution was stirred three hours, then diluted with brine

and Et 2O. The layers were separated and the aqueous portion was washed twice with Et 2O, dried over Na 2SO 4, and concentrated in vacuo. For purification purposes,

the product and isopinocampheol were carried on to the next reaction as a mixture.

In a separate experiment, purification via flash column chromatography (10%

1 EtOAc/Hexanes) gave the alcohol as a colorless oil: H NMR (400 MHz, CDCl 3) δ

0.59 (q, J = 7.8 Hz, 6H), 0.81 (d, J = 6.5 Hz, 3H), 0.94 (t, J = 7.9 Hz, 9 H), 1.01 (d, J

= 6.7 Hz, 3H), 1.22 (d, J = 15.3 Hz, 1H), 1.47 (s, 3H), 1.59-1.94 (m, 9H), 1.77 (s,

3H), 2.08-2.18 (m, 2H), 2.10 (s, 3H), 2.52 (ddd, J = 12.2, 12.2, 8.3 Hz, 1H), 2.66 (m,

2H), 3.41 (dd, J = 10.9, 5.3 Hz, 1H), 3.63 (m, 1H), 3.78 (d, J = 10.7 Hz, 1H), 3.93 (s,

13 1H), 5.14 (m, 1H), 5.48 (dd, J = 11.2, 5.9 Hz, 1H); C NMR (100 MHz, CDCl 3) δ 6.8,

6.9, 7.0, 15.8, 18.3, 21.2, 22.9, 26.7, 28.3, 28.5, 29.8, 32.9, 38.1, 38.7, 38.9, 44.4,

178 66.5, 73.9, 78.2, 78.8, 87.3, 130.0, 130.7, 171.4; IR (film) 3446 (br), 2957, 1737 (str),

-1 26 1457, 1374, 1237, 1137, 1117, 1043 cm ; [ α] D = +2.3 (c = 0.68, CH 2Cl 2); MS

+ (electrospray ionization) calculated for C 28 H50 O5SiNa [M + Na] : 517.33, found:

517.5.

Into a flask containing the alcohol 15 in 500 L of THF was added tetrabutylammonium fluoride (1.0 M in THF, 63 L, 63 mol). The solution was stirred 1 hour, then quenched by the addition of saturated aqueous NH 4Cl and

diluted with Et 2O. The layers were separated and the aqueous portion was washed three times with Et 2O, dried over Na 2SO 4, and concentrated in vacuo. Purification

via flash column chromatography (30% EtOAc/Hexanes) gave 5.1 mg (64% over two

1 steps) of the diol as a colorless oil: H NMR (500 MHz, CDCl 3) δ 0.82 (d, J = 6.0 Hz,

3H), 0.86-0.99 (m, 1H), 0.88 (d, J = 6.9 Hz, 3H), 1.17 (d, J = 9.8 Hz, 1H), 1.42 (s,

3H), 1.64 (dd, J = 13.9, 8.4 Hz, 1H), 1.75-1.85 (m, 6H), 1.79 (s, 3H), 1.93 (m, 1H),

2.09-2.13 (m, 1H), 2.10 (s, 3H), 2.34 (br s, 1H), 2.49 (dd, J = 8.7, 8.7 Hz, 1H), 2.60

(dd, J = 21.1, 11.0 Hz, 1H), 2.69 (d, J = 14.4 Hz, 1H), 3.46 (dd, J = 11.6, 5.5 Hz, 1H),

3.53 (dd, J = 11.5, 11.5 Hz, 1H), 3.78 (d, J = 10.2 Hz, 1H), 4.04 (s, 1H), 5.18 (d, J =

13 3.7 Hz, 1H), 5.52 (dd, J = 10.7, 5.5 Hz, 1H); C NMR (125 MHz, CDCl 3) δ 1.0, 14.1,

18.4, 21.2, 23.0, 28.4, 29.4, 29.7, 29.8, 30.9, 37.9, 38.1, 42.2, 45.7, 65.4, 74.0, 75.1,

79.9, 89.1, 130.1, 171.4; IR (film) 3355 (br), 2925, 1736 (str), 1455, 1381, 1237,

-1 26 1017 cm ; [ α] D = +33 (c = 0.39, CH 2Cl 2); MS (electrospray ionization) calculated

+ for C 22 H36 O5K [M + K] : 419.36, found: 419.4.

179 Me AcO H H Me O H H H Me Me O H

11-acetoxy-4-deoxyasbestinin D (1). A flask charged with diol 50 (8.9 mg,

24 mol) in 1.1 mL of THF was cooled to 0 oC. 2,6 lutidine (13.6 L, 0.117 mmol)

followed by trifluoromethanesulfonic anhydride (5.8 L, 34 mol) were added to the solution and allowed to stir 45 minutes at 0 oC. The solution was warmed to room temperature for 4 hours, then quenched via the addition of saturated aqueous

NH 4Cl. The mixture was diluted with Et 2O and the layers were separated. The

aqueous portion was washed three times with Et 2O, dried over Na 2SO 4, and concentrated in vacuo. Purification via flash column chromatography (10%

EtOAc/Hexanes) gave 5.5 mg (66%) of 11-acetoxy-4-deoxyasbestinin D as a

1 colorless oil: H NMR (500 MHz, CDCl 3) δ 0.91 (d, J = 7.1 Hz, 3H), 0.92 (d, J = 7.2

Hz, 3H), 1.01 (m, 1H), 1.35 (s, 3H), 1.52 (ddd, J = 13.5, 13.5, 9.7 Hz, 1H), 1.61 (m,

1H), 1.75 (s, 3H), 1.75 (m, 2H), 1.84-2.08 (m, 5H), 2.10 (s, 3H), 2.34 (ddd, J = 10.4,

10.4, 10.4 Hz, 1H), 2.50 (br d, J = 14.8 Hz, 1H), 2.55 (ddd, J = 14.5, 10.3, 4.8 Hz,

1H), 3.48 (dd, J = 13.2, 3.2 Hz, 1H), 3.86 (d, J = 15.2 Hz, 1H), 3.87 (d, J = 8.7 Hz,

1H), 4.10 (ddd, J = 5.5, 2.9, 2.9 Hz, 1H), 5.31 (dd, J = 5.1, 2.8 Hz, 1H), 5.47 (dd, J =

13 8.1, 8.1 Hz, 1H); C NMR (125 MHz, CDCl 3) δ 11.0, 17.9, 21.3, 23.4, 26.1, 28.9,

31.3, 31.5, 37.3, 37.5, 38.0, 38.5, 40.5, 45.8, 67.9, 73.5, 76.4, 81.0, 92.2, 128.7,

-1 26 130.8, 171.3; IR (film) 2926, 1737 (str), 1459, 1377, 1231, 1088 cm ; [ α] D = -15 (c

+ = 0.17, CHCl 3); MS (electrospray ionization) calculated for C 22 H35 O4 [M + 1] :

363.25, found: 363.2.

180 An authentic sample of 11-acetoxy-4-deoxyasbestinin D was provided by Dr.

Abimael D. Rodríguez (University of Puerto Rico, Río Piedras), 3 purified in the same manner as described above, and an optical rotation was obtained under identical

25 1 conditions: [ α] D = -15 (c = 0.10, CHCl 3). The H NMR (500 MHz, CDCl 3) spectrum

of the authentic sample also mirrored the synthetic material.

O O OPMB O N Me Me Me

Alkylation Adduct. Into a flask equipped with an addition funnel and a low- temperature thermometer was added sodum bis(trimethylsilyl)amide (0.78 M in toluene/THF, 321.86 mL, 251.05 mmol) and 400 mL of THF. The solution was cooled to –78 oC and glycolate 2 in 200 mL of THF was added dropwise via addition funnel keeping the temperature below –65 oC. The resultant solution was stirred 30 minutes at –78 oC, then methallyl iodide (90.66 mL, 836.8 mmol) was added

dropwise via addition funnel. The soludtion was stirred 5 minutes at –78 oC, then

warmed to –45 oC for 1 hour. The reaction was quenched by the addition of

saturated aqueous NH 4Cl, and then warmed to room temperature. The layers were

separated and the aqueous was extracted twice with EtOAc. The organic layers

were combined, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (10% then 20% EtOAc/Hexanes) provided 47.07 g (78%) of

1 the alkene as a yellow oil: H NMR (400 MHz, CDCl 3) δ 0.82 (d, J = 6.9 Hz, 3H),

0.87 (d, J = 7.0 Hz, 3H), 1.78 (s, 3H), 2.27 (m, 1H), 2.40 (dd, J = 13.9, 8.8 Hz, 1H),

2.51 (dd, J = 13.9, 4.0 Hz, 1H), 3.78 (s, 3H), 4.18 (m, 2H), 4.34 (m, 1H), 4.45 (AB,

181 JAB = 11.3 Hz, ν AB = 27.3 Hz, 2H), 4.82 (s, 2H), 5.26 (dd, J = 4.0, 8.8 Hz, 1H), 6.82

13 (d, J = 6.6 Hz, 2H), 7.24 (d, J = 6.7 Hz, 2H); C NMR (100 MHz, CDCl 3) δ 14.6,

17.7, 22.2, 28.3, 41.0, 55.1, 58.1, 63.8, 72.2, 75.4, 113.46, 113.52, 129.5, 129.8,

140.9, 153.4, 159.2, 172.7; IR (film) 2964, 2360, 1779 (str), 1709 (str), 1514 (str),

-1 21 1248 cm ; [ α] D = -75.0 (c = 2.75, CH 2Cl 2); MS (electrospray ionization) calculated

+ for C 20 H27 NO 5Na [M + Na] : 384.18, found: 384.2.

PMBO Me EtO O O

β-Keto Ester. Into a flask equipped with an addition funnel and a low

temperature thermometer was added diisopropylamine (50.52 mL, 360.5 mmol) and

285 mL of THF. The solution was cooled to 0 oC and n-butyl lithium (2.5 M in hexanes, 143.04 mL, 357.60 mmol) was added dropwise via addition funnel. After

10 minutes at 0 oC, the solution was cooled to –78 oC and ethyl acetate (35.21 mL,

360.5 mmol) was added dropwise via addition funnel and stirred for 1 hour. The alkene dissolved in 145 mL of THF was added dropwise and the reaction mixture was stirred 1 hour at –78 oC. The reaction was quenched by the addition of saturated aqueous NH 4Cl, and then warmed to room temperature. The layers were

separated and the aqueous was extracted twice with ethyl acetate. The organic

layers were combined, dried over Na 2SO 4, and concentrated in vacuo. Purification

by flash column chromatography (5% then 10% EtOAc/Hexanes) provided 38.31 g

1 (84%) of the ester as a colorless oil: H NMR (400 MHz, CDCl 3) δ β-keto ester 1.24

(t, J = 7.1 Hz, 3H), 1.72 (s, 3H), 2.34-2.47 (m, 2H), 3.55 (AB, JAB = 16.1 Hz, ν AB =

35.0 Hz, 2H), 3.78 (s, 3H), 4.03 (dd, J = 7.5, 5.5 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H),

182 4.47 (AB, JAB = 11.1 Hz, ν AB = 26.6 Hz, 2H), 4.78 (s, 1H), 4.84 (s, 1H), 6.86 (d, J =

8.6 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H); β-enol ester 1.30 (t, J = 7.1 Hz, 3H), 1.68 (s,

3H), 2.34-2.47 (m, 2H), 3.78 (s, 3H), 3.93 (dd, J = 8.1, 4.8 Hz, 1H), 4.21 (q, J = 7.1

Hz, 2H), 4.45 (AB, JAB = 11.4 Hz, ν AB = 100.3 Hz, 2H), 4.76 (s, 1H), 4.80 (s, 1H),

5.30 (s, 1H), 6.86 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 12.04 (s, 1H); 13 C

NMR (100 MHz, CDCl 3) δ 14.0, 14.1, 22.4, 39.9, 42.2, 44.7, 55.1, 60.1, 61.1, 71.2,

72.3, 82.8, 88.7, 113.2, 113.6, 113.7, 114.0, 129.1, 129.4, 129.5, 129.6, 140.5,

141.3, 159.2, 159.4, 167.2, 172.7, 176.8, 205.0; IR (film) 2980, 2938, 1747 (str),

-1 22 1719 (str), 1651, 1613 (str), 1515 (str), 1465, 1250 (str) cm ; [ α] D = -45.3 (c = 5.50,

+ CH 2Cl 2); MS (electrospray ionization) calculated for C 18 H24 O5Na [M + Na] : 343.15, found: 343.2.

PMBO Me HO OH

Diol. A flask equipped with an addition funnel was charged with lithium

aluminum hydride (9.08 g, 239 mmol) and 1.00 L of Et 2O. The suspension was

o cooled to 0 C and ester 3 (38.31 g, 119.6 mmol) in 200 mL of Et 2O was added dropwise. The solution was allowed to stir for 1 hour at 0 oC, then the reaction was

quenched by the slow addition of 9.08 mL of H 2O, 9.08 mL of 15% sodium hydroxide, and 18.16 mL of H 2O. After warming to room temperature, the

suspension was filtered through celite and the salts were washed with ethyl acetate.

The organic layers were dried over Na 2SO 4 and concentrated in vacuo. Purification

by flash column chromatography (40% EtOAc/Hexanes) provided 26.7 g (80%) of

183 the diol as a colorless oil: IR (film) 3390 (br), 2937, 1613, 1514 (str) cm -1; MS

+ (electrospray ionization) calculated for C 16 H24 O4Na [M + Na] : 303.16, found: 303.2.

PMBO Me TIPSO OH

Silyl Ether. A flask was charged with the diol (22.21 g, 79.22 mmol) and 320

mL of CH 2Cl 2. Imidazole (16.18 g, 237.7 mmol) and triisopropylsilyl chloride (18.63 mL, 87.14 mmol) were added sequentially. The solution was allowed to stir overnight, then quenched by the addition of saturated aqueous NH 4Cl. The layers

were separated, and the aqueous was washed twice with CH 2Cl 2. The organic

layers were combined, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (10% EtOAc/Hexanes) provided 34.59 g (100%) of the alcohol as a colorless oil: IR (film) 3492 (br), 2943 (str), 2866 (str), 1514, 1249

-1 + (str) cm ; MS (electrospray ionization) calculated for C 25 H44 O4SiNa [M + Na] :

459.29, found: 459.4.

PMBO Me TIPSO O

Ketone. A flask was charged with oxalyl chloride (2.0 M in CH 2Cl 2, 59.41 mL,

o 118.8 mmol) and 300 mL of CH 2Cl 2 and cooled to –78 C. Dimethylsulfoxide (14.06 mL, 198.02 mmol) in 75 mL of CH 2Cl 2 was added dropwise, and the solution was

stirred 2 minutes. The alcohol (34.59 g, 79.21 mmol) and 125 mL CH 2Cl 2 were

added dropwise to the mixture and allowed to stir 30 minutes at –78 oC.

Triethylamine (55.20 mL, 396.04 mmol) was added dropwise and stirred 5 minutes at –78 oC, followed by warming to room temperature for 1 hour. The reaction was

184 quenched by the addition of water. The organic portion was washed with saturated aqueous NaHCO 3, then water. The combined aqueous portions were washed with

CH 2Cl 2. The combined organic extracts were then washed with brine, dried over

Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography

(5% EtOAc/Hexanes) provided 34.43 g (100%) of the ketone as a colorless oil: 1H

NMR (400 MHz, CDCl 3) δ 1.05 (s, 21H), 1.71 (s, 3H), 2.3-2.43 (m, 2H), 2.67-2.82

(m, 2H), 3.77 (s, 3H), 3.93-4.02 (m, 3H), 4.45 (AB, JAB = 11.3 Hz, ν AB = 65.8 Hz,

2H), 4.77 (s, 1H), 4.81 (s, 1H), 6.85 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H); 13 C

NMR (100 MHz, CDCl 3) δ 11.7, 17.8, 22.3, 39.8, 40.6, 55.0, 58.5, 71.9, 83.2, 113.3,

113.6, 129.38, 129.42, 140.9, 159.2, 210.9; IR (film) 2043 (str), 2866 (str), 1719 (str),

-1 22 1613, 1514 (str), 1464, 1250 (str), 1099 (str) cm ; [ α] D = -24.1 (c = 5.45, CH 2Cl 2);

+ MS (electrospray ionization) calculated for C 25 H42 O4SiNa [M + Na] : 457.28, found:

457.3.

PMBO Me TIPSO OH

Alcohol. Into a flask equipped with an addition funnel and a low temperature

thermometer was added ketone 4 (35.96 g, 82.73 mmol) in 800 mL of Et 2O. The

o solution was cooled to –40 C and Zn(BH 4)2 (~0.14 M in Et 2O, 335 mL, 47 mmol) was added dropwise via addition funnel. The mixture was warmed to –25 oC and

stirred for 15 minutes. The reaction was quenched by the addition of 33.5 mL of

saturated aqueous NaCl. The mixture was warmed to room temperature, dried over

Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography

(5% EtOAc/Hexanes) provided 28.52 g (79%) of the alcohol as a colorless oil: 1H

185 NMR (400 MHz, CDCl 3) δ 1.08 (s, 21H), 1.71-1.84 (m, 2H), 1.77 (s, 3H), 2.25-2.37

(m, 2H), 3.36 (br s, 1H), 3.54-3.60 (m, 1H), 3.77 (s, 3H), 3.84-4.01 (m, 3H), 4.55 (s,

2H), 4.82 (s, 2H), 6.85 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H); 13 C NMR (100

MHz, CDCl 3) δ 11.7, 17.9, 22.9, 33.8, 38.9, 55.1, 62.7, 72.0, 72.8, 80.2, 112.8,

113.6, 129.4, 130.8, 142.8, 159.1; IR (film) 3493 (br), 2943 (str), 2866 (str), 1613,

-1 22 1514 (str), 1464, 1249 (str) cm ; [ α] D = +12 (c = 3.4, CH 2Cl 2); MS (electrospray

+ ionization) calculated for C 25 H44 O4SiNa [M + Na] : 459.29, found: 459.4.

PMBO Me TIPSO

O OH

Glycolic Acid. A flask equipped with an addition funnel was charged with

sodium hydride (60% dispersion in mineral oil, 6.59 g, 165 mmol). The solid was

rinsed with pentane three times, diluted in 55 mL of DMF, and cooled to 0 o C.

Bromoacetic acid (9.16 g, 65.9 mmol) in 25 mL of THF was added dropwise, then

allowed to stir 10 minutes. The alcohol 5 (23.97 g, 54.89 mmol) was added via addition funnel in 30 mL of THF, and the solution was warmed to room temperature and stirred overnight. The mixture was then cooled to 0 oC and quenched by the addition of saturated aqueous NH 4Cl and diluted with Et 2O. The layers were

separated, and the aqueous portion was extracted twice more using Et 2O. The combine organic layers were washed with brine, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (10% then 50%

EtOAc/Hexanes) provided 24.4 g (90%) of the acid as a yellow oil: 1H NMR (400

MHz, CDCl 3) δ 1.06 (s, 21H), 1.67 (m, 1H), 1.71 (s, 3H), 1.78 (m, 1H), 2.19 (dd, J =

186 14.4, 4.4 Hz, 1H), 2.36 (dd, J = 14.5, 8.3 Hz, 1H), 3.48 (ddd, J = 4.3, 4.3, 2.1 Hz,

1H), 3.77 (s, 3H), 3.77-3.88 (m, 3H), 4.22 (AB, JAB = 17.1 Hz, ν AB = 22.6 Hz, 2H),

4.55 (AB, JAB = 11.5 Hz, ν AB = 8.3 Hz, 2H), 4.79 (s, 1H), 4.81 (s, 1H), 6.84 (d, J =

13 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 10.80 (br s, 1H); C NMR (100 MHz, CDCl 3) δ

11.7, 17.8, 22.5, 33.6, 38.0, 54.9, 59.6, 68.1, 71.8, 78.3, 80.1, 113.0, 113.6, 129.5,

129.6, 142.0, 159.2, 173.4; IR (film) 3074 (br), 2943 (str), 2866 (str), 1763, 1732

-1 21 (str), 1613, 1514 (str), 1464, 1249 (str) cm ; [ α] D = +14 (c = 1.8, CH 2Cl 2); MS

+ (electrospray ionization) calculated for C 27 H46 O6SiK [M + K] : 533.41, found: 533.3. ii.) Acylation of the acid to yield glycolate 6

PMBO Me TIPSO

O Me Me

O N O O

Complex Glycolate. Into a flask fitted with an addition funnel was added the glycolic acid (24.36 g, 49.24 mmol) in 350 mL of THF. The solution was cooled to –

78 oC and triethylamine (7.55 mL, 54.2 mmol) was added to the solution, followed by dropwise addition of pivaloyl chloride (6.68 mL, 54.16 mL). The mixture was warmed to 0 oC and stirred for 1 hour, then cooled to –78 oC.

In a separate flask equipped with an addition funnel was added (4 S)-4-Isopropyl-

oxazolidin-2-one (8.27 g, 64.0 mmol) and 175 mL of THF. The solution was cooled

to –78 oC, and n-butyl lithium (2.3 M in hexanes, 25.69 mL, 59.09 mmol) was added

dropwise, and stirred for 30 minutes.

187 The lithiated oxazolidinone was then transferred via cannula into the mixed anhydride and the mixture was stirred for 1 hour at –78 oC followed by warming to 0 o C for 45 minutes. The reaction was quenched using saturated aqueous NH 4Cl,

then warmed to room temperature. The layers were separated and the aqueous

was washed twice with EtOAc. The combined organic layers were washed with

brine, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (10% then 20% EtOAc/Hexanes) provided 27.6 g (90%) of the

1 glycolate as a colorless oil: H NMR (400 MHz, CDCl 3) δ 0.83 (d, J = 6.9 Hz, 3H),

0.89 (d, J = 7.0 Hz, 3H), 1.05 (s, 21H), 1.68-1.78 (m, 1H), 1.73 (s, 3H), 1.85 (dddd, J

= 9.5, 9.5, 4.6, 4.6 Hz, 1H), 2.18 (dd, J = 14.5, 4.7 Hz, 1H), 2.34-2.43 (m, 2H), 3.72-

3.78 (m, 1H), 3.77 (s, 3H), 3.79-3.86 (m, 2H), 3.90 (ddd, J = 9.7, 9.7, 4.7 Hz, 1H),

4.17-4.23 (m, 2H), 4.36 (ddd, J = 7.9, 4.0, 4.0 Hz, 1H), 4.54 (AB, JAB = 11.2 Hz, ν AB

= 53.4 Hz, 2H), 4.77 (s, 2H), 4.78 (AB, JAB = 18.0 Hz, ν AB = 28.1 Hz, 2H), 6.83 (d, J

13 = 8.6 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H); C NMR (100 MHz, CDCl 3) δ 11.8, 14.5,

17.9, 22.8, 26.9, 28.1, 33.8, 38.9, 55.1, 58.0, 59.7, 64.1, 70.5, 71.7, 78.8, 79.2,

112.5, 113.5, 129.3, 130.8, 142.8, 153.8, 158.9, 170.0; IR (film) 2942, 2867, 1785

-1 25 (str), 1719 (str), 1613, 1514 (str), 1464, 1389, 1302, 1251 cm ; [ α] D = -18.7 (c =

+ 14.4, CH 2Cl 2); MS (electrospray ionization) calculated for C 33 H55 NO 7SiNa [M + Na] :

628.36, found: 628.3. e.) B fragment alcohol 7

188 PMBO Me TIPSO OBn O i-Pr O N

O O

Alkylation Adduct. A flask equipped with an addition funnel was charged with sodum bis(trimethylsilyl)amide (0.78 M in toluene/THF, 77.45 mL, 60.41 mmol) and 200 mL of THF. The solution was cooled to –78 oC and glycolate 6 (24.40 g,

40.27 mmol) in 200 mL of THF was added dropwise via addition funnel keeping the temperature below –65 oC. The resultant solution was stirred 1 hour at –78 oC.

In a separate flask, formaldehyde dibenzyl acetal (25.85 mL, 120.8 mmol) was

cooled to 0 oC, and iodotrimethylsilane(16.62 mL, 116.8 mmol) was added and allowed to stir 30 minutes.

The benzyl iodomethyl ether was then added to the enolate, and the solution was allowed to stir for 1 hour at –78 oC. The reaction was quenched by the addition of

saturated aqueous NH 4Cl, and then warmed to room temperature. The layers were

separated, and the aqueous was extracted twice with Et 2O. The organic layers were

combined, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash

column chromatography (5% then 10% EtOAc/Hexanes) provided 23.98 g (83%) of

1 the benzyl ether as a colorless oil: H NMR (400 MHz, CDCl 3) δ 0.66 (d, J = 6.9 Hz,

3H), 0.77 (d, J = 7.0 Hz, 3H), 1.04 (s, 21H), 1.60 (m, 1H), 1.73 (s, 3H), 1.82 (m, 1H),

2.17 (dd, J = 15.0, 3.8 Hz, 1H), 2.22 (m, 1H), 2.57 (dd, J = 14.7, 9.1 Hz, 1H), 3.52

(dd, J = 8.8, 8.8 Hz, 1H), 3.60 (ddd, J = 9.0, 3.7, 4.1 Hz, 1H), 3.70 (dd, J = 10.4, 4.0

Hz, 1H), 3.72 (s, 3H), 3.79 (dd, J = 4.4, 4.4 Hz, 1H), 3.83 (m, 2H), 3.88 (dd, J = 9.1,

189 3.0 Hz, 1H), 3.94 (m, 1H), 4.18 (ddd, J = 8.4, 3.2, 3.2 Hz, 1H), 4.47 (AB, JAB = 11.9

Hz, ν AB = 89.5 Hz, 2H), 4.55 (AB, JAB = 11.9 Hz, ν AB = 21.5 Hz, 2H), 4.80 (s, 2H),

5.58 (dd, J = 5.7, 4.1 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 7.17-7.30 (m, 7H); 13 C NMR

(100 MHz, CDCl 3) δ 11.6, 14.1, 17.3, 17.7, 22.6, 27.7, 34.6, 37.4, 54.7, 57.7, 59.8,

63.1, 71.0, 71.6, 72.9, 78.8, 79.4, 81.1, 111.9, 113.2, 127.0, 127.2, 127.8, 128.7,

130.5, 137.7, 142.9, 153.3, 158.7, 170.4; IR (film) 2942, 2866, 1780 (str), 1715,

-1 25 1514, 1388, 1248 (str) cm ; [ α] D = -34 (c = 1.9, CH 2Cl 2); MS (electrospray

+ ionization) calculated for C 41 H63 NO 8SiNa [M + Na] : 748.42, found: 748.4.

PMBO Me TIPSO

O OH BnO

Primary Alcohol. To a solution of the benzyl ether (21.55 g, 29.68 mmol)

o and methanol (1.81 mL, 44.52 mmol) in 300 mL of Et 2O at 0 C was added lithium borohydride (2.0M in THF, 22.26 mL, 44.52 mmol) dropwise via addition funnel.

After stirring for 1 hour at 0 oC, MeOH (1.81 mL, 44.52 mmol) was added. The

solution was quenched by the addition of saturated sodium potassium tartrate,

warmed to ambient temperature, and stirred for 2 hours. The layers were separated,

and the aqueous was extracted twice with Et 2O. The organic layers were combined,

dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column

chromatography (10% EtOAc/Hexanes) provided 15.28 g (86%) of the alcohol as a

1 colorless oil: H NMR (400 MHz, CDCl 3) δ 1.11 (s, 21H), 1.68 (m, 1H), 1.77 (s, 3H),

1.83 (m, 1H), 2.24 (dd, J = 14.6, 5.2 Hz, 1H), 2.46 (dd, J = 14.6, 8.5 Hz, 1H), 3.32

(br s, 1H), 3.54 (dd, J = 9.6, 6.0 Hz, 1H), 3.59-3.67 (m, 2H), 3.69 (ddd, J = 8.3, 4.3,

190 1.5 Hz, 1H), 3.75-3.88 (m, 4H), 3.78 (s, 3H), 4.02 (m, 1H), 4.55 (s, 2H), 4.58 (AB,

JAB = 11.5 Hz, ν AB = 25.5 Hz, 2H), 4.85 (s, 2H), 6.88 (d, J = 8.6 Hz, 2H), 7.27-7.39

13 (m, 7H) ); C NMR (100 MHz, CDCl 3) δ 11.8, 17.9, 22.7, 34.8, 38.0, 54.9, 59.6,

63.0, 70.2, 71.5, 73.1, 76.7, 79.1, 79.5, 112.6, 113.5, 127.2, 127.3, 128.1, 129.3,

130.0, 138.1, 142.5, 159.0; IR (film) 3450 (br), 2942 (str), 2865 (str), 1514, 1249,

-1 23 1093 (str) cm ; [ α] D = +17 (c = 4.7, CH 2Cl 2); MS (electrospray ionization)

+ calculated for C 35 H56 O6SiNa [M + Na] : 623.37, found: 623.3.

PMBO Me TIPSO

O O BnO

Aldehyde. A flask was charged with oxalyl chloride (2.0 M in CH 2Cl 2, 18.45

o mL, 36.89 mmol) and 150 mL of CH 2Cl 2 and cooled to –78 C. Dimethylsulfoxide

(4.37 mL, 61.49 mmol) in 30 mL of CH 2Cl 2 was added dropwise, and the solution was stirred 2 minutes. The alcohol 7 (14.78 g, 24.60 mmol) and 60 mL CH 2Cl 2 were added dropwise to the mixture and allowed to stir 30 minutes at –78 oC.

Triethylamine (17.14 mL, 123.0 mmol) was added dropwise and stirred 5 minutes at

–78 oC, followed by warming to room temperature for 1 hour. The reaction was quenched by the addition of water. The organic portion was washed with saturated aqueous NaHCO 3, then water. The combined aqueous portions were washed with

CH 2Cl 2. The combined organic extracts were then washed with brine, dried over

Na 2SO 4, and concentrated in vacuo. Purification by passing through a short plug of silica (10% EtOAc/Hexanes) provided 14.44 g (99%) of the aldehyde as a colorless

1 oil: H NMR (400 MHz, CDCl 3) δ 1.09 (s, 21H), 1.66-1.78 (m, 1H), 1.73 (s, 3H), 1.88

191 (m, 1H), 2.25 (dd, J = 14.4, 4.5 Hz, 1H), 2.44 (dd, J = 14.4, 8.3 Hz, 1H), 3.69 (ddd, J

= 8.2, 4.6, 1.7 Hz, 1H), 3.72-3.88 (m, 2H), 3.79 (s, 3H), 3.84-3.91 (m, 2H), 3.98 (m,

1H), 4.13 (ddd, J = 4.4, 4.4, 1.3 Hz, 1H), 4.53 (AB, JAB = 11.4 Hz, ν AB = 31.1 Hz,

2H), 4.55 (AB, JAB = 12.2 Hz, ν AB = 14.6 Hz, 2H), 4.80 (s,1H), 4.82 (s, 1H), 6.87 (d,

J = 6.8 Hz, 2H), 7.21-7.48 (m, 7H), 9.77 (d, J = 1.3 Hz, 1H); 13 C NMR (100 MHz,

CDCl 3) δ 11.9, 17.9, 22.7, 34.4, 38.7, 55.1, 59.7, 69.7, 71.4, 73.4, 78.7, 79.7, 84.6,

112.7, 113.6, 127.5, 127.6, 128.2, 129.3, 130.4, 137.7, 142.6, 159.0, 202.6; IR (film)

-1 23 2942 (str), 2865 (str), 1734 (str), 1613, 1514, 1463, 1249 (str), 1096 (str) cm ; [ α] D

= +4.0 (c = 1.9, CH 2Cl 2); MS (electrospray ionization) calculated for C 35 H54 O6SiNa

[M + Na] +: 621.36, found: 621.4.

H OH PMBO O H H OBn TIPSO

Diene. A flask fitted with an addition funnel and dry ice/acetone filled condenser was charged with freshly ground magnesium (3.65 g, 150 mmol) and the system was flame dried. The solid was suspended in 12 mL of THF, and one crystal of iodine was added to the suspension. Vinyl bromide (11.64 mL, 165 mmol) in 12 mL of THF was added dropwise via addition funnel until the mixture began to reflux.

The halide was added at a rate to maintain reflux until addition was complete. The solution was stirred for 30 minutes upon completion of addition, then diluted with 83 mL of THF.

In a separate flask equipped with an addition funnel, the previously prepared vinyl magnesium bromide (1.4 M in THF, 52.71 mL, 73.79 mmol) was added to 160 mL of

192 THF. The solution was cooled to 0 oC and the aldehyde (14.73 g, 24.60 mmol) was added dropwise via addition funnel. The solution was stirred for 5 minutes, then the reaction was quenched by the slow addition of saturated aqueous ammonium chloride. After dilution with Et 2O, the layers were separated, and the aqueous portion was extracted twice more with Et 2O. The organic layers were combined, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column

chromatography (10% EtOAc/Hexanes) provided 12.99 g (86%) of a colorless oil

consisting of a 3:1 inseparable mixture of alcohol epimers, favoring the configuration

shown: IR (film) 3437 (br), 2942 (str), 2866 (str), 1613, 1514 (str), 1463 (str), 1365,

1303, 1249 (str), 1093 cm -1; MS (electrospray ionization) calculated for

+ C37 H58 O6SiNa [M + Na] : 649.39, found: 649.4.

Me Me

H OH H H PMBO H PMBO OH O O H H H H OBn OBn TIPSO TIPSO

Oxocenes. A flask equipped with a reflux condenser was charged with the

diene (11.31 g, 18.06 mmol) in 1.800 L of CH 2Cl 2. The solution was refluxed for 30

minutes while purging the system with argon. The vessel was cooled to room

temperature and (Cl 2(PCy 3)(Imes)Ru=CHPh (765 mg, 0.903 mmol) was added. The

solution was stirred at reflux overnight, then cooled to room temperature.

Evaporation of the solvents and purification via flash column chromatography (10%

then 25% EtOAc/Hexanes) provided a separable mixture 5.58 g (52%) and 1.95 g

(19%%) of the oxocenes as a colorless oil: Major epimer: 1H NMR (400 MHz,

CDCl 3) δ 1.07 (s, 21H), 1.52 (dddd, J = 14.4, 9.8, 4.9, 4.9 Hz, 1H), 1.86 (s, 3H), 2.10

193 (m, 1H), 2.32 (d, J = 12.1 Hz, 1H), 2.67 (dd, J = 13.5, 2.9 Hz, 1H), 3.10 (br s, 1H),

3.43 (ddd, J = 8.8, 4.3, 4.3 Hz, 1H), 3.50 (m, 1H), 3.64 (m, 1H), 3.69-3.87 (m, 4H),

3.77 (s, 3H), 4.38 (m, 1H), 4.48 (AB, JAB = 11.1 Hz, ν AB = 122.3 Hz, 2H), 4.57 (AB,

JAB = 12.1 Hz, ν AB = 46.9 Hz, 2H), 5.46 (d, J = 4.4 Hz, 1H), 6.87 (d, J = 8.3 Hz, 2H),

13 7.25 (d, J = 8.5 Hz, 2H), 7.27-7.36 (m, 5H); C NMR (100 MHz, CDCl 3) δ 11.8, 17.8,

26.0, 31.8, 36.8, 54.87, 54.89, 70.7, 71.2, 71.9, 73.3, 77.5, 82.2, 82.6, 113.4,

127.46, 127.53, 128.2, 129.0, 129.7, 130.2, 134.7, 137.6, 158.9; IR (film) 3465 (br),

-1 21 2942, 2865, 1613, 1514 (str), 1464, 1302, 1249 cm ; [ α] D = +95.5 (c = 8.94

+ CH 2Cl 2); MS (electrospray ionization) calculated for C 35 H54 O6SiNa [M + Na] :

621.36, found: 621.3.

1 Minor epimer: H NMR (400 MHz, CDCl 3) δ 1.05 (s, 21H), 1.50 (m, 1H), 1.83 (s,

3H), 2.13 (m, 1H), 2.36 (dd, J = 13.5, 5.7 Hz, 1H), 2.73 (br s, 1H), 3.08 (d, J = 12.5

Hz, 1H), 3.40 (m, 1H), 3.54-3.72 (m, 4H), 3.76-3.86 (m, 2H), 3.81 (s, 3H), 4.38 (d, J

= 6.6 Hz, 1H), 4.48 (AB, JAB = 11.3 Hz, ν AB = 101.7 Hz, 2H), 4.54 (AB, JAB = 12.1

Hz, ν AB = 23.8 Hz, 2H), 5.56 (dd, J = 7.5, 1.1 Hz, 1H), 6.86 (d, J = 6.7 Hz, 2H),

13 7.21-7.38 (m, 7H); C NMR (100 MHz, CDCl 3) δ 12.0, 18.0, 26.8, 33.9, 37.1, 55.2,

59.9, 69.9, 71.0, 71.5, 73.7, 79.5, 80.3, 82.0, 113.7, 125.5, 127.72, 127.75, 128.4,

129.4, 130.4, 137.7, 139.3, 159.1; IR (film) 3445 (br), 2941, 2865, 1612, 1514, 1463,

-1 23 1248 cm ; [ α] D = +84 (c = 0.47 CH 2Cl 2); MS (electrospray ionization) calculated for

+ C35 H54 O6SiNa [M + Na] : 621.36, found: 621.4.

H O PMBO O H H OBn TIPSO

194 Enone. A flask was charged with oxalyl chloride (2.0 M in CH 2Cl 2, 2.91 mL,

o 5.81 mmol) and 25 mL of CH 2Cl 2 and cooled to –78 C. Dimethylsulfoxide (688 L,

9.69 mmol) in 5 mL of CH 2Cl 2 was added dropwise, and the solution was stirred 2 minutes. The alcohol (2.32 g, 3.87 mmol) and 10 mL CH 2Cl 2 were added dropwise

to the mixture and allowed to stir 30 minutes at –78 oC. Triethylamine (2.70 mL,

19.4 mmol) was added dropwise and stirred 5 minutes at –78 oC, followed by warming to room temperature for 1 hour. The reaction was quenched by the addition of water. The organic portion was washed with saturated aqueous

NaHCO 3, then water. The combined aqueous portions were washed with CH 2Cl 2.

The combined organic extracts were then washed with brine, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (10%

EtOAc/Hexanes) provided 1.47 g (64%) of the enone as a colorless oil: 1H NMR

(400 MHz, CDCl 3) δ 1.04 (s, 21H), 1.75 (m, 1H), 1.86 (m, 1H), 1.94 (s, 3H), 2.54 (d,

J = 16.7 Hz, 1H), 2.65 (dd, J = 16.8, 7.6, Hz, 1H), 3.50 (m, 1H), 3.67-3.76 (m, 2H),

3.79 (s, 3H), 3.82-3.92 (m, 3H), 4.24-4.31 (m, 2H), 4.47-4.58 (m, 3H), 5.80 (s, 1H),

6.88 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 7.24-7.35 (m, 5H); ); 13 C NMR (100

MHz, CDCl 3) δ 11.9, 18.0, 27.5, 35.8, 36.8, 55.17, 55.18, 59.9, 70.2, 72.3, 73.4,

78.5, 82.5, 87.2, 113.7, 126.0, 127.38, 127.42, 128.2, 129.4, 129.5, 138.1, 146.5,

-1 24 159.2, 203.4; IR (film) 2942, 2865, 1668, 1514, 1250 cm ; [ α] D = -7.5 (c = 2.4

+ CH 2Cl 2); MS (electrospray ionization) calculated for C 35 H52 O6SiNa [M + Na] :

619.34, found: 619.2.

The resultant enone 1.17 g (1.96 mmol) was dissolved in 10 mL of methanol and

cooled to 0 oC. Cerium chloride heptahydrate (740 mg, 1.96 mmol) was added,

195 followed by sodium borohydride (74 mg, 2.0 mmol). The solution was stirred for five minutes, then quenched by the addition of 1M HCl and diluted with Et 2O. After warming to room temperature, the layers were separated, and the aqueous fraction was extracted twice with Et 2O. The combined organic extracts were then washed with brine, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (10% EtOAc/Hexanes) provided 950 mg (82%) of oxocene

8 as a colorless oil.

Me H

H OH PMBO H O H H OBn TIPSO

Oxocane. To a solution of oxocene 8 (5.58 g, 9.32 mmol) in 93 mL of CH 2Cl 2

+ - was added Crabtree’s catalyst ([PCy 3][COD][Pyr]Ir PF 6 ; 188 mg, 0.233 mmol). The mixture was cooled to –50 oC and fitted with a hydrogen balloon. The flask was purged under vacuum and filled with hydrogen five times. The solution was allowed to stir overnight under an atmosphere of hydrogen. The balloon was removed and the solution was warmed to room temperature. Evaporation of the solvents and purification via flash column chromatography (10% EtOAc/Hexanes) provided 5.24 g

1 (94%) of the oxocane as a colorless oil: H NMR (400 MHz, CDCl 3) δ 1.03-1.14 (m,

24H), 1.55 (dddd, J = 13.8, 9.5, 4.6, 4.6 Hz, 1H), 1.67-1.81 (m, 2H), 1.83-2.02 (m,

3H), 2.08 (m, 1H), 2.96 (br s, 1H), 3.26 (ddd, J = 8.8, 8.8, 2.7 Hz, 1H), 3.63-3.72 (m,

2H), 3.72-3.80 (m, 3H), 3.78 (s, 3H), 3.82-3.87 (m, 2H), 4.44 (AB, J AB = 11.1 Hz,

ν AB = 84.2 Hz, 2H), 4.56 (AB, J AB = 12.0 Hz, ν AB = 32.8 Hz, 2H), 6.87 (d, J = 8.7

13 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.27-7.46 (m, 5H); C NMR (100 MHz, CDCl 3) δ

196 11.8, 17.9, 26.8, 27.7, 37.3, 40.1, 45.3, 55.0, 59.6, 70.6, 72.4, 73.0, 73.4, 81.5, 82.3,

83.0, 113.5, 127.5, 127.6, 128.3, 129.1, 130.4, 137.6, 158.9; IR (film) 3461 (br),

-1 21 2943, 2865, 1613, 1514, 1463, 1249 cm ; [ α] D = +38.0 (c = 8.10 CH 2Cl 2); MS

+ (electrospray ionization) calculated for C 35 H56 O6SiNa [M + Na] : 623.37, found:

623.3.

Me H

H O PMBO O H H OBn TIPSO

Ketone. A flask was charged with oxalyl chloride (2.0 M in CH 2Cl 2, 6.54 mL,

o 13.1 mmol) and 50 mL of CH 2Cl 2 and cooled to –78 C. Dimethylsulfoxide (1.55 mL,

21.8 mmol) in 10 mL of CH 2Cl 2 was added dropwise, and the solution was stirred 2

minutes. The oxocane (5.24 g, 8.72 mmol) and 20 mL CH 2Cl 2 were added dropwise

to the mixture and allowed to stir 30 minutes at –78 oC. Triethylamine (6.08 mL,

43.6 mmol) was added dropwise and stirred 5 minutes at –78 oC, followed by warming to room temperature for 1 hour. The reaction was quenched by the addition of water. The organic portion was washed with saturated aqueous

NaHCO 3, then water. The combined aqueous portions were washed with CH 2Cl 2.

The combined organic extracts were then washed with brine, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (10%

EtOAc/Hexanes) provided 4.94 g (95%) of the ketone as a colorless oil: 1H NMR

(400 MHz, CDCl 3) δ 0.96 (d, J = 6.7 Hz, 3H), 1.07 (s, 21H), 1.53 (ddd, J = 5.3, 11.9,

16.5 Hz, 1H), 1.77 (m, 1H), 1.84 (m, 1H), 1.95 (m, 1H), 2.23 (dd, J = 15.4, 9.1 Hz,

1H), 2.87 (dd, J = 15.4, 4.6 Hz, 1H), 2.98 (m, 1H), 3.43 (m, 1H), 3.67 (dd, J = 10.0,

197 2.6 Hz, 1H), 3.77 (m, 1H), 3.79 (s, 3H), 3.83-3.89 (m, 3H), 4.03 (dd, J = 4.3, 2.7 Hz,

1H), 4.42 (AB, , J AB = 11.8 Hz, ν AB = 46.5 Hz, 2H), 4.54 (AB, J AB = 12.3 Hz, ν AB =

22.3 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.24-7.35 (m, 5H);

13 C NMR (100 MHz, CDCl 3) δ 11.8, 17.9, 23.7, 27.6, 36.3, 37.3, 48.8, 55.0, 59.8,

69.6, 72.8, 73.3, 80.3, 80.8, 88.0, 113.6, 127.2, 127.3, 128.1, 129.1, 129.8, 138.0,

-1 23 159.0, 211.8; IR (film) 2940, 2865, 1699, 1514, 1457, 1248 cm ; [ α] D = -33 (c = 2.6

+ CH 2Cl 2); MS (electrospray ionization) calculated for C 35 H54 O6SiNa [M + Na] :

621.36, found: 621.4.

Me H

H OH PMBO Me O H H OBn TIPSO

Tertiary Alcohol. Into a flask equipped with an addition funnel was added methylmagnesium chloride (3.0 M in THF, 13.75 mL, 41.24 mmol) and 200 mL of

o E2O. The solution was cooled to –78 C, and ketone 10 (4.94 g, 8.25 mmol) in 200

mL of Et 2O was added dropwise via addition funnel. The mixture was allowed to stir

for 20 minutes at –78 oC. The reaction was quenched by the addition of saturated

aqueous ammonium chloride and allowed to warm to room temperature. The layers

were separated and the aqueous portion was extracted twice with EtOAc. The

combined organic extracts were then washed with brine, dried over Na 2SO 4, and

concentrated in vacuo. Purification by flash column chromatography (10%

EtOAc/Hexanes) provided 4.42 g (88%) of the alcohol as a colorless oil: 1H NMR

(400 MHz, CDCl 3) δ 1.04 (d, J = 6.4 Hz, 3H), 1.07 (s, 21H), 1.18 (s, 3H), 1.51-1.73

(m, 3H), 1.83-1.95 (m, 3H), 2.03 (m, 1H), 3.22 (m, 1H), 3.28 (br s, 1H), 3.62-3.69 (m,

198 3H), 3.73-3.87 (m, 3H), 3.80 (s, 3H), 4.44 (AB, J AB = 11.1 Hz, ν AB = 74.9 Hz, 2H),

4.52 (AB, J AB = 11.7 Hz, ν AB = 24.8 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 7.25 (d, J =

13 8.4 Hz, 2H), 7.27-7.37 (m, 5H); C NMR (100 MHz, CDCl 3) δ 11.9, 18.0, 21.8, 27.0,

27.6, 37.3, 41.5, 53.0, 55.1, 59.8, 70.7, 70.8, 73.6, 74.2, 82.0, 82.1, 82.9, 113.6,

127.6, 127.8, 128.4, 129.2, 130.5, 137.3, 159.0; IR (film) 3481 (br), 2943, 2865,

-1 22 1613, 1514, 1463, 1249 cm ; [ α] D = +42 (c = 1.9 CH 2Cl 2); MS (electrospray

+ ionization) calculated for C 36 H58 O6SiNa [M + Na] : 637.39, found: 637.3.

Me H

H OH PMBO Me O H H OH TIPSO

Primary Alcohol. To a solution containing tertiary alcohol (3.70 g, 6.01 mmol) in 120 mL of EtOH was added Raney Nickel (2800 slurry in H 2O, 18.76 mL).

The reaction flask was fitted with a hydrogen filled balloon. The flask was evacuated

under vacuum and filled with hydrogen. The procedure was repeated twice more,

and the reaction mixture was allowed to stir under an atmosphere of H 2 overnight.

The hydrogen balloon was removed and the suspension was filtered through celite.

The filtrate was washed several times with ethanol while ensuring that the solid was not allowed to become dry. The solvent was concentrated in vacuo and the product was purified by flash column chromatography (30% EtOAc/Hexanes) to provide 2.98

1 g (95%) of the diol as a colorless oil: H NMR (400 MHz, CDCl 3) δ 1.00 (d, J = 6.7

Hz, 3H), 1.07 (s, 21H), 1.15 (s, 3H), 1.51 (m, 1H), 1.56 (d, J = 12.9 Hz, 1H), 1.72 (m,

1H), 1.78-1.93 (m, 3H), 2.04 (m, 1H), 2.24 (br s, 1H), 3.17 (ddd, J = 8.4, 8.4, 2.7 Hz,

1H), 3.64 (m, 1H), 3.72-3.80 (m, 3H), 3.78 (s, 3H), 3.80-3.91 (m, 2H), 4.41 (AB, J AB

199 13 = 11.2 Hz, ν AB = 72.7 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H); C

NMR (100 MHz, CDCl 3) δ 11.9, 17.9, 21.7, 27.4, 27.5, 36.7, 41.0, 54.4, 55.1, 59.8,

63.3, 70.4, 74.3, 81.4, 82.4, 86.0, 113.6, 129.2, 130.4, 159.0; IR (film) 3389 (br),

-1 23 2944, 2866, 1613, 1514, 1463, 1384, 1302, 1249 cm ; [ α] D = +36 (c = 4.4 CH 2Cl 2);

+ MS (electrospray ionization) calculated for C 29 H52 O6SiNa [M + Na] : 547.34, found:

547.4.

Me H

H OH PMBO Me O H H O TIPSO

B Ring Aldehyde. To a solution of the diol (280 mg, 0.534 mmole) in 5 mL of

CH 2Cl 2 was added Dess-Martin periodinane (339 mg, 0.800 mmol). After stirring 1 hour at room temperature, the reaction was quenched via the addition of a 5:1 solution of saturated aqueous Na 2S2O3/NaHCO 3. The layers were separated and the aqueous layer was washed twice with CH 2Cl 2. The combined organic extracts were then dried over Na 2SO 4 and concentrated in vacuo. Purification by flash

column chromatography (25% EtOAc/Hexanes) provided 238 mg (85%) of the

1 aldehyde 11 as a colorless oil. H NMR (500 MHz, C 6D6) δ 9.88 (s, 1H), 7.22-7.19

(band, 2H), 6.83-6.80 (band, 2H), 4.39 (d, J = 11.5 Hz, 1H), 4.16 (d, J = 11.5 Hz,

1H), 4.05 (s, 1H), 3.93 (ddd, J = 5.0, 9.5, 9.5 Hz, 1H), 3.84 (ddd, J = 4.0, 7.0, 10.5

Hz, 1H), 3.76 (ddd, J = 2.5, 7.0, 9.5 Hz, 1H), 3.29 (s, 3H), 3.17 (m, 1H), 2.40 (s, 1H),

2.09 (dddd, J = 3.0, 7.0, 9.5, 9.5 Hz, 1H), 1.91-1.85 (band, 2H), 1.78 (ddd, J = 3.0,

3.0, 15.5 Hz, 1H), 1.66 (dddd, J = 3.5, 5.0, 9.0, 13.5 Hz, 1H), 1.51-1.42 (band, 2H),

1.17 (s, 3H), 1.12-1.04 (band, 21H), 0.89 (d, J = 6.5 Hz, 3H); 13 C NMR (125 MHz,

200 C6D6) δ 205.0, 159.7, 130.9, 129.41, 129.40, 128.5, 128.1, 127.9, 114.1, 89.9, 83.3,

82.3, 74.4, 70.8, 60.1, 54.7, 53.2, 41.2, 37.4, 27.8, 27.1, 22.9, 18.3, 18.2, 12.3; IR

(film) 3447, 2942, 2865, 1732, 1612, 1513, 1462, 1381, 1301, 1249, 1094 cm -1;

25 [α] D = +35 (c = 0.35, CH 2Cl 2); MS (electrospray ionization) calculated for

+ C29 H51 O6Si [M + H] : 523.35, found: 523.4.

Me OBn Me H O Me H H H PMBO O O H H O PMBO H H OBn H

BCDE Tetraaryl Ether. Into a flask containing a stir bar was added the diol

(87 mg, 0.13 mmol) in 3 mL of DMF. The mixture was cooled to 0 oC prior to addition of sodium hydride (60% dispersion in mineral oil, 26 mg, 0.64 mmol).

Freshly prepared p-methoxybenzyl bromide (57 L, 0.38 mmol) was added to the

solution. After stirring for 10 minutes at 0 oC, the reaction mixture was warmed to room temperature and allowed to stir for 14 hours. The reaction was quenched by the slow addition of saturated NH 4Cl, and diluted with Et 2O. The layers were

separated, and the aqueous portion was extracted three more times with Et 2O. The

organic layers were combined, dried over Na 2SO 4, and concentrated in vacuo.

Purification by flash column chromatography (25% EtOAc/Hexanes) provided 106

1 mg (91%) of the ether as a colorless oil: H NMR (400 MHz, CDCl 3) δ 0.95 (d, J =

6.6 Hz, 3H), 1.12 (s, 6H), 1.32-1.69 (m, 6 H), 1.70-2.02 (m, 5H), 2.04-2.26 (m, 3H),

2.33 (m, 1H), 2.44 (m, 2H), 2.56 (m, 1H), 2.87 (dd, J = 7.8, 7.8 Hz, 1H), 3.02 (dd, J =

9.3, 9.3 Hz, 1H), 3.28-3.58 (m, 11 H), 3.74 (s, 6H), 4.22-4.60 (m, 8H), 5.66 (m, 2H),

201 13 6.82 (m, 4H), 7.14-7.36 (m, 14H); C NMR (100 MHz, CDCl 3) δ 16.5, 21.0, 26.7,

28.0, 33.6, 34.2, 34.4, 34.6, 34.9, 42.3, 54.1, 55.1, 64.6, 66.4, 66.6, 68.9, 70.6, 71.2,

72.3, 72.7, 75.7, 80.7, 81.9, 82.1, 82.2, 82.3, 82.7, 82.9, 113.5, 113.6, 127.3, 127.4,

127.5, 127.7, 128.17, 128.23, 129.2, 129.4, 130.2, 130.5, 138.1, 138.3, 158.9,

-1 22 159.0; IR (film) 2954, 2925, 1609, 1516 (str), 1455, 1242 (str) cm ; [ α] D = -15 (c =

+ 0.73, CH 2Cl 2); MS (electrospray ionization) calculated for C 57 H74 O10 Na [M + Na] :

941.52, found: 941.6.

Me OH Me H O Me H H H PMBO O O H H O PMBO H H OH H

BCDE Diol. Preparation of LiDBB: A reaction vessel was charged with 4,4’- di-t-butylbiphenyl (3.17g, 11.9 mmol) and 10.8 mL of THF. Freshly cut lithium metal

(75 mg, 10.8 mmol) was added to the solution and the heterogenous mixture was placed in a sonicating bath. The solution was sonicated at 0 oC for two hours to

provide a 1.0 M solution of LiDBB.

To a flask equipped with a stir bar was added the BCDE ether (106 mg, 0.12 mmol)

and 5 mL of THF. The mixture was cooled to -78 oC, and the solution of LiDBB (3.0 mL, 3.0 mmol, 1.0 M in THF) was added. After stirring for 10 minutes at -78 oC, the

reaction was quenched by the addition of saturated NH 4Cl, diluted with Et 2O, and

warmed to room temperature. The layers were separated, and the aqueous portion

was extracted three more times with Et 2O. The organic layers were combined, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (25% to 75% EtOAc/Hexanes) provided 75 mg (89%) of the diol as

202 1 a colorless oil: H NMR (400 MHz, CDCl 3) δ 0.99 (d, J = 7.0 Hz, 3H), 1.15 (s, 3H),

1.18 (d, J = 7.4 Hz, 3H), 1.39-1.72 (m, 6 H), 1.73-2.02 (m, 5H), 2.10-2.27 (m, 3H),

2.35-2.87 (m, 6H), 2.91 (ddd J = 15.7, 12.1, 4.3 Hz, 1H), 3.06 (dd, J = 10.6, 10.6 Hz,

1H), 3.23-3.40 (m, 3H), 3.42-3.61 (m, 5H), 3.68-3.84 (m, 3 H), 3.784 (3, 3H), 3.789

(s, 3H), 4.39 (AB, JAB = 11.0 Hz, ν AB = 72.3 Hz, 2H), 4.41 (AB, JAB = 11.2 Hz, ν AB =

8.7 Hz, 2H), 5.73 (m, 2H), 6.85 (d, J = 2.9 Hz, 2H), 6.87 (d, J = 2.9 Hz, 2H), 7.22 (d,

13 J = 8.6 Hz, 2H), 7.26 (d, J = 11.6 Hz, 2H); C NMR (100 MHz, CDCl 3) δ 16.5, 21.4,

26.8, 28.1, 33.7, 34.5, 35.9, 36.1, 36.6, 42.4, 54.1, 55.2, 59.3, 64.9, 66.7, 68.9, 70.8,

72.4, 73.2, 75.9, 81.4, 82.05, 82.14, 82.3, 83.0, 86.4, 92.0, 113.6, 113.7, 127.7,

128.0, 129.3, 129.6, 130.3, 130.6, 159.0, 159.1; IR (film) 3395 (br), 2929, 1612,

-1 20 1514 (str), 1458, 1303, 1249 (str) cm ; [ α] D = 15 (c = 1.5, CH 2Cl 2); MS

+ (electrospray ionization) calculated for C 43 H62 O10 Na [M + Na] : 761.42, found:

761.5.

Me OTBS Me H O Me H H H PMBO O O H H O PMBO H H OTBS H

BCDE Bis Silyl Ether. To a round-bottomed flask equipped with a stir bar

was added the diol (62 mg, 0.092 mmol) in 5 mL CH 2Cl 2. The solution was cooled to

0 oC, and 2,6 lutidine (43 L, 0.37 mmol) was added, followed by t-butyldimethylsilyl trifluoromethanesulfonate (64 L, 0.28 mmol). The solution was stirred for 1 hour, then quenched by the addition of saturated NH 4Cl and warmed to room temperature.

The layers were separated, and the aqueous portion was extracted three more times

203 with CH 2Cl 2. The organic layers were combined, dried over Na 2SO 4, and

concentrated in vacuo. Purification by flash column chromatography (10%

EtOAc/Hexanes) provided 79 mg (96%) of the ether as a colorless oil: 1 H NMR (400

MHz, CDCl 3) δ 0.01 (s, 3H), 0.03 (s, 3H), 0.07 (s, 3H), 0.09 (s, 3H), 0.87 (s, 9H),

0.90 (s, 9H), 1.00 (d, J = 7 Hz, 3H), 1.15 (s, 3H), 1.16 (d, J = 7.3 Hz, 3H), 1.38-1.73

(m, 7H), 1.73-1.96 (m, 4H), 2.11-2.33 (m, 3H), 2.33-2.50 (m, 3H), 2.54 (m, 1H), 2.92

(ddd, J = 12.0, 9.8, 4.0 Hz, 1H), 3.07 (dd, J = 10.6, 10.6 Hz, 1H), 3.34-3.68 (m, 11H),

3.791 (s, 3H), 3.794 (s, 3H), 4.40 (AB, JAB = 11.0 Hz, ν AB = 72.6 Hz, 2H), 4.41 (AB,

JAB = 11.4 Hz, ν AB = 0.0 Hz, 2H), 5.66 (m, 2H), 6.85 (d, J = 3.7 Hz, 2H), 6.87 (d, J =

3.7 Hz, 2H), 7.22 (d, J = 9.4 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H); 13 C NMR (100 MHz,

CDCl 3) δ -5.54, -5.52, -4.9, -4.5, 16.5, 17.8, 18.0, 20.6, 25.67, 25.69, 26.7, 28.0,

33.6, 34.0, 34.2, 34.7, 37.4, 42.3, 54.1, 55.1, 58.5, 66.6, 69.0, 70.6, 72.3, 75.6, 75.7,

81.4, 82.1, 82.2, 82.9, 83.0, 113.5, 113.6, 126.1, 129.1, 129.2, 129.4, 130.2, 130.5,

158.9, 159.0; IR (film) 2955, 2928, 2855, 2360, 1613, 1514 (str), 1462, 1361, 1306,

-1 20 1250 (str) cm ; [ α] D = -14 (c = 1.5, CH 2Cl 2); MS (electrospray ionization) calculated

+ for C 55 H90 O10 Si 2Na [M + Na] : 989.60, found: 989.7.

Me OH Me H O Me H H H PMBO O O H H O PMBO H H OTBS H

BCDE Primary Alcohol. A reaction vessel with a stir bar was charged with

the bis silyl ether (66 mg, 0.068 mmol) in 3 mL of THF. Hydrogen fluoride-pyridine

(150 L, 65% hydrogen fluoride in pyridine) was added, and the solution was stirred

204 for 1.5 hours at room temperature. The reaction was quenched via the slow addition of saturated NaHCO 3 and diluted with Et 2O. The layers were separated, and the

aqueous portion was extracted three more times with Et 2O. The organic layers were combined, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash

column chromatography (25% EtOAc/Hexanes) provided 50 mg (86%) of the alcohol

as a colorless oil, along with 9 mg (14%) of the starting bis silyl ether: 1 H NMR (400

MHz, CDCl 3) δ 0.04 (s, 3H), 0.09 (s, 3H), 0.88 (s, 9H), 0.98 (d, J = 6.7 Hz, 3H), 1.14

(s, 3H), 1.19 (d, J = 7.5 Hz, 3H), 1.38-1.54 (m, 3H), 1.55-1.64 (m, 3H), 1.65-1.82 (m,

4H), 1.83-1.98 (m, 3H), 2.14 (m, 1H), 2.19-2.36 (m, 4H), 2.50 (m, 1H), 2.62 (m, 1H),

2.91 (dd, J = 8.6, 8.6 Hz, 1H), 3.06 (dd, J = 9.6, 9.6 Hz, 1H), 3.36 (m, 2H), 3.42-3.49

(m, 2H), 3.50-3.63 (m, 4h), 3.71 (m, 1H), 3.792 (s, 3H), 3.796 (s, 3H), 3.82 (m, 2H),

4.39 (AB, JAB = 11.0 Hz, ν AB = 74.0 Hz, 2H), 4.41 (AB, JAB = 11.5 Hz, ν AB = 7.5 Hz,

2H), 5.68 (m, 2H), 6.85 (d, J = 3.1 Hz, 2H), 6.87 (d, J = 3.1 Hz, 2H), 7.22 (d, J = 8.4

13 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H); C NMR (100 MHz, CDCl 3) δ -4.8, -4.3, 16.6,

17.9, 21.3, 25.8, 26.8, 28.1, 33.7, 34.7, 35.1, 35.5, 42.4, 54.2, 55.23, 55.24, 60.0,

66.8, 69.0, 70.8, 72.4, 73.8, 75.8, 82.2, 82.3, 82.4, 82.6, 83.0, 85.6, 113.6, 113.7,

126.8, 128.7, 129.3, 129.6, 130.3, 130.7, 159.0, 159.1; IR (film) 2956, 2929, 2853,

-1 20 1613, 1514 (str), 1463, 1303, 1250 (str), 1173 cm ; [ α] D = 1.8 (c = 0.84, CH 2Cl 2);

+ MS (electrospray ionization) calculated for C 55 H94 NO 10 Si 2 [M + NH 4] : 870.56, found: 870.6.

205 Me O P Ph Me H Ph O Me H H H PMBO O O H H O PMBO H H OTBS H

BCDE Silyl Protected Phosphine Oxide. The previously prepared alcohol

(26 mg, 0.030 mmol) in 1 mL CH 2Cl 2 was added to a flask with a stir bar. The solution was cooled to 0 oC, and triethylamine (17 L, 0.12 mmol) was added,

followed by methanesulfonyl chloride (5.0 L, 0.061 mmol). The solution was stirred

for 15 minutes, then quenched by the addition of saturated NH 4Cl and warmed to

room temperature. The layers were separated, and the aqueous portion was

extracted three more times with CH 2Cl 2. The organic layers were combined, dried

over Na 2SO 4, and concentrated in vacuo. Purification by flash column chromatography (25% EtOAc/Hexanes) provided 28 mg (100%) of the mesylate as a colorless oil.

Prepartion of lithium diphenylphosphide: To a reaction vessel with a stir bar was added diphenylphosphine (165 L, 0.948 mmol) in 2.5 mL of THF. The solution was

cooled to 0 oC, and n-butyllithium (652 L, 1.043 mmol, 1.6 M in hexanes) was added, resulting in a bright red solution. The mixture was warmed to room temperature and stirred for 30 minutes.

The previously prepared mesylate (28 mg, 0.030 mmol) was added to a flask in 1 mL of THF and 50 L of hexamethylphosphoramide. The solution was cooled to 0 oC, and the lithium diphenylphosphide (800 L, 0.304 mmol, 0.38 M in THF) was

added until a red color persisted for several minutes. The reaction was quenched

via the addition of 1 mL of water, then 100 L of 30% H 2O2 were added to the

206 solution and warmed to room temperature. After dilution with Et 2O, 10% Na 2S2O3

was used to wash the organic layer. The aqueous layer was extracted five times

further with Et 2O. The organic layers were combined, dried over Na2SO 4, and

concentrated in vacuo. Purification by flash column chromatography (50%

EtOAc/Hexanes) provided 29 mg (94%) of the phosphine oxide as a colorless semi-

1 solid: H NMR (400 MHz, CDCl 3) δ -0.05 (s, 3H), 0.04 (s, 3H), 0.83 (s, 9H), 0.97 (d, J

= 7.4 Hz, 3H), 0.98 (s, 3H), 1.14 (s, 3H), 1.26 (dd, J = 6.4, 6.4 Hz, 1H), 1.38-1.56 (m,

4 H), 1.56-1.73 (m, 3H), 1.74-1.95 (m, 6H), 2.08-2.37 (m, 5H), 2.44 (m, 1H), 2.61 (m,

1H), 2.89 (dd, J = 7.8 Hz, 1H), 3.06 (dd J = 10.4 Hz, 1H), 3.24-3.40 (m, 4H), 3.44 (dd

J = 11.0, 4.5 Hz, 1H), 3.50-3.61 (m, 3H), 3.68 (br s, 1H), 3.79 (s, 6H), 4.39 (AB, JAB =

11.0 Hz, ν AB = 72.3 Hz, 2H), 4.41 (AB, JAB = 12.7 Hz, ν AB = 0.0 Hz, 2H), 5.67 (m,

2H), 6.86 (d, J = 7.9 Hz, 4H), 7.23 (d, J = 7.7 Hz, 2H), 7.26 (d, J = 6.7 Hz, 2H), 7.41-

13 7.55 (m, 6H), 7.73 (m, 4H); C NMR (100 MHz, CDCl 3) δ -4.7, -4.3, 16.5, 17.9, 21.2,

24.7, 24.8, 25.8, 26.9, 28.1, 33.7, 34.7, 35.2, 36.0, 42.5, 54.2, 55.23, 55.25, 66.7,

69.0, 70.8, 72.4, 73.4, 75.9, 82.2, 82.36, 82.39, 83.0, 113.6, 113.7, 127.0, 128.48,

128.54, 128.6, 128.7, 129.3, 129.6, 130.3, 130.7, 130.8, 130.9, 131.0, 131.6, 131.7,

-1 20 159.0, 159.1; IR (film) 2952, 2925, 2855, 1516 (str), 1451, 1245 (str) cm ; [ α] D =

5.8 (c = 0.68, CH2Cl 2); MS (electrospray ionization) calculated for C 61 H86 O10 PSi [M +

1] +: 1037.57, found: 1037.6.

Me O P Ph Me H Ph O Me H H H PMBO O Me O OMe H H O Me PMBO H H O H

207 BCDE Acetal Protected Phosphine Oxide. A reaction vessel with a stir bar was charged with the silyl protected phosphine oxide (56 mg, 0.055 mmol) in 2 mL of THF. Tetrabutylammonium fluoride (163 L, 0.163 mmol, 1.0 M in THF) was added, and the solution was stirred for three hours at room temperature. The reaction was then concentrated in vacuo.

The crude hydroxyphosphine oxide from the previous step was dissolved in 3 mL of

2-methoxypropene in a reaction vessel with a stir bar at 0 oC. Pyridinium p- toluenesulfonate (50 mg, 0.20 mmol) was added, and the mixture was stirred for 1 hour. The reaction was quenched via the slow addition of saturated NaHCO 3, then

warmed to room temperature. The mixture was extracted five times with CH 2Cl 2, dried over Na 2SO 4, and concentrated in vacuo. Purification by flash column

chromatography (100% EtOAc then 100% Acetone) provided 48 mg (90%) of the

1 phosphine oxide as a pale white semi-solid: H NMR (400 MHz, C 6D6) δ 0.96 (d, J =

7.4 Hz, 3H), 1.08 (d, J = 7.4 Hz, 3H), 1.22 (s, 3H), 1.27 (s, 3H), 1.28 (s, 3H), 1.38

(m, 1H), 1.52 (m, 1H), 1.65-1.90 (m, 8H), 1.98 (m, 2H), 2.12 (m, 2H), 2.26-2.55 (m,

6H), 2.62 (dd, J = 12.3, 12.3 Hz, 1H), 2.79 (ddd, J = 12.1, 9.1, 4.3 Hz, 1H), 2.96-3.09

(m, 2H), 3.13 (s, 3H), 3.29 (s, 3H), 3.31 (s, 3H), 3.42-3.57 (m, 4H), 3.58-3.76 (m,

4H), 3.96 (dd, J = 4.4, 4.4 Hz, 1H), 4.31 (AB, JAB = 11.4 Hz, ν AB = 100.0 Hz, 2H),

4.36 (s, 2H), 5.89 (ddd, J = 10.5, 10.5, 6.5 Hz, 1H), 6.00 (ddd, J = 10.8, 10.8, 7.3 Hz,

1H), 6.78 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 7.02 (m, 6H), 7.20 (d, J = 8.5

13 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.81 (m, 4H); C NMR (100 MHz, C 6D6) δ 16.8,

22.4, 25.2, 25.4, 27.1, 28.3, 29.4, 29.5, 34.5, 35.2, 36.1, 37.0, 42.7, 49.2, 54.7, 54.9,

66.8, 69.7, 70.8, 72.8, 73.4, 75.9, 82.0, 82.3, 82.4, 82.7, 83.5, 127.2, 127.9, 128.1,

208 128.3, 128.5, 128.6, 128.66, 128.75, 129.66, 129.70, 131.0, 131.08, 131.10, 131.15,

131.19, 131.3, 131.4; IR (film) 2929, 2862, 1514, 1463, 1439, 1249, 1180 cm -1;

20 [α] D = 18 (c = 0.61, CH 2Cl 2); MS (electrospray ionization) calculated for

+ C59 H79 O11 PNa [M + Na] : 1017.53, found: 1017.6.

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