Studies in Meroterpenoid Synthesis

A thesis presented

Jonathan W. Lockner

The Scripps Research Institute Graduate Program

in partial fulfillment of the requirements

for the degree of

Doctor of Philosophy

in the subject of

Chemistry

for

The Scripps Research Institute

La Jolla, California

November 2011

UMI Number: 3507067

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Thesis Acceptance Form

Acknowledgements

As a high school student in Plainfield, Illinois, I had the benefit of learning chemistry from Mr. Hill. He supplemented my experience with “Semi-Micro Qualitative

Analysis” – allowing me to perform simple chemistry experiments after school. As an undergraduate at the University of Illinois at Urbana-Champaign, I had the opportunity to carry out synthetic organic chemistry research in the laboratory of Professor Robert M.

Coates. I am indebted to him, as well as Dr. Chad Davis (then a graduate student and my mentor), for their influence in setting me on the path of scientific research.

My first employment was at Pharmacia in Kalamazoo, Michigan. I benefited from the attention afforded me by Dr. Christina Harris, my supervisor during the short time we all enjoyed there prior to the “diaspora” that came with the Pfizer acquisition. I still have fond memories of discussing selected chapters of “Classics in Total Synthesis.”

I will never forget the morning we were working in the lab and learned (via internet) that a plane had crashed into the World Trade Center.

Despite the negative connotation that comes with Pfizer for its ruthless decade of acquisitions, I am supremely grateful for its bearing on my life. This boy from the

Midwest might never have ventured out to California, were it not for the invitation to transfer to the Pfizer site in La Jolla. I am indebted to Dr. Rob Kania and Bob Hoffman, who were my supervisors, and to Simon Planken, from whom I learned much while sharing a lab bay with him. A special thanks also goes to Dr. Steve Tanis, who was always willing to “shoot the s#$t” with me. It is rare to find an individual with both a towering intellect and yet a down-to-earth, approachable personality.

Given their co-location on adjacent mesas, I pressed the powers-that-be at Pfizer to participate in courses at The Scripps Research Institute. At one point, I visited

Professor Phil Baran in his office, and, for better or for worse, he asked me “So when are we going to see you in this lab?” I took him up on the veiled invitation, and took a huge pay cut, to become “a monk” (one of the many metaphors I would hear uttered by Phil in the years that ensued). Of the many valuable lessons I have learned from Phil over the past five years, certainly this list includes: Be willing to work really, really hard; Develop and maintain a “killer instinct”; Strive to be innovative and opportunistic; Expect dedication and quality from yourself and others, and good things will happen.

For everyone in the Baran Lab that had to put up with my moodiness, and my obsessive-compulsive nature – thank you for your patience. I think that graduate school, in its most stressful seasons, brought out the worst in me. Thanks for putting up with me.

A special thanks goes to Dr. Mike DeMartino, with whom I shared a hood during my first two years in the Baran Lab. Dr. Jeremy Richter was an indispensable source of reassurance in my most trying times. Dr. Kyle Eastman always provided an injection of energy and enthusiasm that I only wish could come naturally in me. Dr. Ke Chen was an incredible example of a hard worker, a generous lab mate, and fun office neighbor.

Thank you to the members of my thesis committee: Professor Jin-Quan Yu,

Professor Kim Janda, Professor Floyd Romesberg, and Professor Carlos Guerrero. All of you are tremendous examples of top-flight scientists, and it has been a privilege to be shepherded by you over the years.

During the summer of 2009, I served as a mentor for Marcus Bray, a student at

Torrey Pines High. During the summer of 2011, I served as a mentor for Sylvia Chen, an undergraduate research fellow from University of Wisconsin, Madison. What great perspective I gained from those experiences. I also thank those with whom I worked in a direct manner: Dr. Elena Petricci, Paul Hernandez, Rune Risgaard, and Dr. Darryl Dixon.

Without the various support facilities such as the NMR lab (Dee-Hua Huang,

Laura Pasternak) and the HRMS lab (Bill Webb and colleagues), research progress would be markedly slower. The Scripps Research Institute benefits immensely from these expertly run labs that allow the chemist to elucidate the constitution of molecules he prepares. Additionally, I am indebted to the skilled colleagues at UCSD’s X-ray lab, led by Professor Arnie Rheingold, who solved numerous crystal structures, thereby obviating the need for time-consuming multidimensional NMR experiments and data analysis.

Scientific research, and training of young scientists, would simply not be possible without the generous financial support of government and private agencies. I personally thank Amgen, Bristol-Myers Squibb, and Leo Pharma for their funding which enabled me to carry out my research in the Baran Lab.

To those friends outside the lab, whom I rarely saw while a graduate student working long hours: thank you for your patience and understanding. I thank the entire

Koinonia family, especially Jen Ernest, Sarah Kim, Theresa Abueg, Marieke Jones,

Nathan and Sarah Venzara, Nick Taylor, Kayla Weisman, Michele Fujioka, Paul Carter,

Derek and Lacey Joseph, Brandon and Ariane Fries, David and Gracie Rhoads.

Mom (Phyllis Vancas) – so much of who I am is because of you. Thank you for working three jobs while a single mother raising two sons. My older brother, Randy, and

6 sister-in-law Kelly, and nephews (Justin, Nathan, Logan) – you are all very precious to me! My step-mom, Mary – thank you for the Omaha Steaks care package every

Christmas! My younger brother, Aaron – be kind to your mother!

Thank you to my father-in-law and mother-in-law (Danny and Julie Cruz) for making me truly feel like a son. Birthday privilege is a wonderful tradition! I am honored to be a part of your family. Jonathan Cruz, Jennie, Gabby, and Zoe – I love you all very much! Ernie and Patti Orderica, and the rest of my extended family here in San

Diego – I look forward to more Friday Clubs, Easter Bonnets, Turkey Bowls! Don and

Kathy Knox – thank you for your support!

Alyssa Janine – amazing, beautiful, charismatic, delightful, expressive, fun, gregarious, hilarious, intelligent, joyful, kind, lovely, marvelous, naturally beautiful, optimistic, patient, quotable, resourceful, sweet, tender, unconditional, vivacious, witty, xenophilic, youthful, zany – you are all of these, and so much more. Thank you for saying “I do.” We made it. Your enduring and constant love and support is the reason I made it through with my wrists intact.

Table of Contents Acknowledgements ...... 4 Table of Contents ...... 8 List of Figures ...... 9 Abbreviations ...... 12 Abstract ...... 16 Chapter 1. Review of Meroterpenoids ...... 17 Chapter 2. Studies in Meroterpenoid Synthesis ...... 31 Chapter 3. Radical Chemistry Applied to Meroterpenoid Synthesis ...... 65 Experimental ...... 82 References ...... 198 Appendix A. Spectra ...... 207 Appendix B. X-ray Crystallographic Data ...... 305 Curriculum Vitae ...... 336

Table of Contents

List of Figures

Figure 1-1. Mori’s synthesis of hongoquercin B ...... 17 Figure 1-2. Kende’s synthesis of stachybotrylactam ...... 18 Figure 1-3. Katoh’s synthesis of kampanol ABCD ring system ...... 18 Figure 1-4. Mori’s synthesis of stypoldione ...... 18 Figure 1-5. Smith’s synthesis of pyripyropene E ...... 19 Figure 1-6. Gansäuer’s synthesis of zonarone ...... 19 Figure 1-7. Biogenetic diversity of tetraketide-sesquiterpene conjugate ...... 22 Figure 1-8. Andilesins, andibenins, anditomin, emervaridione, insuetolides ...... 23 Figure 1-9. Tropolactones, simplicissin, fumagatonins ...... 24 Figure 1-10. Austins...... 24 Figure 1-11. Berkeleys, miniolutelides, paraherquonin ...... 25 Figure 1-12. Preaustinoids, austinoneol ...... 26 Figure 1-13. Andrastins, penisimplicins ...... 26 Figure 1-14. Citreohybridones, atlantinones ...... 27 Figure 1-15. Isocitreohybridones ...... 28 Figure 1-16. Citreonigrins ...... 28 Figure 1-17. PC 3.3.22.D and others ...... 29 Figure 1-18. Dhilirolides ...... 29 Figure 1-19. Terretonins ...... 29 Figure 2-1. Pluripotency of tetraketide-sesquiterpenoid conjugate ...... 32 Figure 2-2. Starburst summary of approaches to simplicissin ...... 33 Figure 2-3. Intermolecular alkylative dearomatization ...... 34 Figure 2-4. Bismuth-mediated intermolecular alkylative dearomatization ...... 36 Figure 2-5. Orsellinate dearomatization using LTA or PIDA ...... 36 Figure 2-6. Orsellinate dearomatization using allylTMS with PIFA ...... 37 Figure 2-7. “Oxidative terpenylation” via silanes or stannanes ...... 37 Figure 2-8. Atratate and orsellinate dearomatizations (Tamaru’s method) ...... 38 Figure 2-9. Phenolic aldol and reductive Friedel−Crafts approaches ...... 39 Figure 2-10. Examination of Barluenga’s reductive coupling method ...... 40 Figure 2-11. Tsuji−Trost and π-allyl Stille approaches ...... 41 Figure 2-12. Retrosynthesis for “interrupted Danheiser” cascade ...... 42

Figure 2-13. Initial pursuit of “interrupted Danheiser” cascade ...... 43 Figure 2-14. Alkene position isomerization ...... 44 Figure 2-15. Butenolide substrate for “interrupted Danheiser” cascade ...... 44 Figure 2-16. Designing for desired dehydrochlorination ...... 45 Figure 2-17. Preparation of 6-phenylpyrone for “interrupted Danheiser” ...... 46 Figure 2-18. Hetero-Diels−Alder/Diels−Alder approach ...... 47 Figure 2-19. Paterno−Buchi strategy ...... 47 Figure 2-20. Peterson and Sonogashira/semi-reduction approaches ...... 48 Figure 2-21. [2,3]-thia-Sommelett approach ...... 49 Figure 2-22. Ether substrates for [1,3]-Claisen rearrangement ...... 50 Figure 2-23. Screening effort for [1,3]-Claisen rearrangement ...... 51 Figure 2-24. [3,3]-Claisen rearrangement and selenoetherification ...... 52 Figure 2-25. Investigation of "reverse prenyl" for [3,3]-Claisen ...... 53 Figure 2-26. para-Claisen rearrangements, and de-allylation ...... 53 Figure 2-27. Allyl as a surrogate for methyl (proof-of-principle) ...... 55 Figure 2-28. Chroman substrate for para-Claisen study ...... 55

Figure 2-29. Methallyl and prenyl ethers subjected to Yb(OTf)3 ...... 56 Figure 2-30. Retrosynthesis featuring a biomimetic cation-π cyclization ...... 57 Figure 2-31. Horner olefination approach to cyclization substrate ...... 57 Figure 2-32. Biellman coupling approach to cyclization substrate ...... 58 Figure 2-33. Direct cross-metathesis approach to cyclization substrate ...... 59 Figure 2-34. “Molecular deletions” allow cyclization without fragmentation ...... 60 Figure 2-35. Alkylation of vinylogous ester (Majetich) ...... 60 Figure 2-36. Rapid, convergent access to tetracyclic pyran ...... 61 Figure 2-37. Relationship between tetracycle and known meroterpenoids ...... 62 Figure 2-38. Examples of γ- and δ-lactone ring-opening ...... 62 Figure 2-39. Elaboration of pyran to other key intermediates ...... 63 Figure 3-1. Minisci-type reactivity for boronic acids and trifluoroborates ...... 65 Figure 3-2. Development of a “borono-Pschorr” reaction ...... 67 Figure 3-3. Pinacol boronate ester as latent radical precursor ...... 68 Figure 3-4. Tandem radical cyclization/BQ trap ...... 69 + 2− Figure 3-5. Oxyarylation of acrylonitrile using Ag /S2O8 ...... 70 Figure 3-6. Application of “terpenyl” trifluoroborate for radical coupling ...... 72 10

Figure 3-7. Examination of classic Minisci reaction ...... 73 Figure 3-8. Enone route to quinone-sesquiterpenoid target ...... 74 Figure 3-9. Enantiospecific route to ent-chromazonarol ...... 76 Figure 3-10. Divergent access via ent-chromazonarol ...... 78 Figure 3-11. Avarone via “friedo” rearrangement of ent-yahazunone ...... 79 Figure 3-12. Other quinones joined with terpene ...... 80 Figure 3-13. Quinones as orsellinate surrogates ...... 80

Abbreviations

Ac acetyl acac acetylacetonato (ligand)

AD asymmetric dihydroxylation

AIBN azobis(iso-butyronitrile)

9-BBN 9-borabicyclo[3.3.1]nonane

BDSB bromodiethylsulfide bromopentachloroantimonate t-BHP tert-butylhydroperoxide

BINOL 1,1’-binaphthalene-2,2’-diol

Boc tert-butyloxycarbonyl

BOM benzyloxymethyl

Bn benzyl brsm based on recovered starting material

CAN ceric ammonium nitrate

Cbz benzyloxycarbonyl

CDI 1,1’-carbonyldiimidazole

CM (olefin) cross-metathesis

Cp cyclopentadienyl m-CPBA meta-chloroperbenzoic acid

CSA 10-camphorsulfonic acid dba dibenzylideneacetone

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

DCB 1,2-dichlorobenzene

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

Δ (delta) heat (oil bath)

DEAD diethyl azodicarboxylate

DIAD diisopropyl azodicarboxylate

DIBAL-H diisobutylaluminum hydride

4-DMAP 4-dimethylaminopyridine

DMDO dimethyl dioxirane

DMF N,N’-dimethylformamide

DMP Dess−Martin periodinane

DMSO dimethylsulfoxide

DNPH (2,4-dinitrophenyl)hydrazine dppf 1,1’-bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane dr diastereomeric ratio

EDDA ethylenediamine-N,N’-diacetic acid fod tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedianato)

HG-1 Hoveyda−Grubbs 1st generation catalyst

HG-2 Hoveyda−Grubbs 2nd generation catalyst

HMDS hexamethyldisilazane

HMPA hexamethylphosphoric triamide

HMTA hexamethylenetetramine hν irradiation with light (visible or otherwise)

HWE Horner−Wadsworth−Emmons imid imidazole

Koser’s reagent hydroxy(tosyloxy)iodobenzene

LAH lithium aluminum hydride

LDA lithium di-iso-propylamide

Lindlar catalyst 5% Pd on CaCO3 poisoned with Pb

L-Selectride® lithium tri-(sec-butyl)borohydride

Mander’s reagent methyl cyanoformate

Meldrum’s acid 2,2-dimethyl-1,3-dioxane-4,6-dione

MOM methoxymethyl

MsCl methanesulfonyl chloride

MTO methyltrioxorhenium

µW microwave irradiation

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NCI National Cancer Institute

OAc acetate

OMs methanesulfonate

OTf trifluoromethanesulfonate

PIDA phenyliodine (III) diacetate

PIFA phenyliodine (III) bis(trifluoroacetate) polysulfone 1:1 copolymer of SO2 and methylidenecyclopentane

PPTS pyridinium para-toluenesulfonate

14 prenyl 3,3-dimethylallyl reverse prenyl 1,1-dimethylallyl

SAM S-adenosyl methionine

SEM [2-(trimethylsilyl)ethoxy]methyl

SET single electron transfer

))) sonication

SPhos 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl

TBAF tetrabutylammonium fluoride

TBDPS tert-butyldiphenylsilyl

TBS tert-butyldimethylsilyl

TEMPO 2,2,6,6-tetramethyl-1-piperdinyloxy free radical

TFA trifluoroacetic acid

TFAA trifluoroacetic acid anhydride

TIPS triisopropylsilyl

THF tetrahydrofuran

TMP 2,2,6,6-tetramethyl-4-piperidinol

TMS trimethylsilyl

TMSE (trimethylsilyl)ethyl p-TsCl para-toluenesulfonyl chloride p-TsOH para-toluenesulfonic acid

UHP urea hydrogen peroxide

XPhos 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl

Abstract

The term “meroterpenoids” refers to natural products that contain both terpenoid and non-terpenoid components. This term encompasses a massive body of naturally occurring organic molecules, diverse in molecular constitution and biological activity.

As methods for isolation and structure elucidation have grown in sophistication, so too have methods for the laboratory synthesis of many meroterpenoid targets.

Described herein are various strategies and tactics examined for the pursuit of meroterpenoid (polyketide-terpenoid) natural products. Chapter 1 provides a literature review of the relevant meroterpenoid natural products that were the subject of study for this thesis research. With simplicissin as its focal point, Chapter 2 provides a review of various approaches that were examined in an aim to gain a foothold into this as-yet unassailable fungal meroterpenoid metabolite family. Chapter 3 describes the application of Minisci-type reactivity of boronic acids to practical radical cyclizations, and the successful implementation of this method for the preparation of ent-chromazonarol (and analogs thereof). This convergent approach to meroterpenoid synthesis has the potential to be applied to other classes beyond the quinone-sesquiterpenoids, including the tetraketide-sesquiterpenoids described in Chapters 1 and 2.

This thesis work was carried out with the ultimate goal of devising a means for efficient synthetic access to this class of meroterpenoids. Along the way, a number of pitfalls were encountered, but valuable insight was gained which should enable further pursuit of this elusive natural product family.

Chapter 1. Review of Meroterpenoids

To set the stage for the work summarized herein, a selection of literature examples of meroterpenoid synthesis is provided. They are grouped into “convergent” and “biomimetic” strategies. The following is meant to be concise and didactic, in order to provide context for the research work chronicled in subsequent chapters.

Mori and colleagues described a convergent synthesis of hongoquercin B.1 In this case, the two halves are brought together via displacement of an allylic bromide. After pyran ring-closure and protecting group manipulations, the target was attained.

EtO2C Me CO2H Br HO Me CO2Et SEMO Me Me SEMO Me nBuLi + Me OSEM Me Me I CuCN Me O BnO THF Me Me OSEM BnO AcO Me Me Me Me hongoquercin B

Figure 1-1. Mori’s synthesis of hongoquercin B

Kende and colleagues reported a convergent synthesis of stachybotrylactam.2

Marriage of the two halves is accomplished via 1,2-addition of an aryllithium species to an aldehyde.3 After furan ring-closure, benzylic alcohol deoxygenation, protecting group manipulations, and elaboration of the amide moiety, the target was attained.

O CO2tBu HO CHO BnO NH Me BnO CO2tBu Me nBuLi HO + OBn Br Me Me O THF Me Me BnO OBn Me Me BnO HO Me Me Me Me stachybotrylactam

Figure 1-2. Kende’s synthesis of stachybotrylactam

Katoh and colleagues described a convergent synthesis of the kampanol ABCD ring system.4 Union is achieved via 1,4-addition of an aryl Grignard to an enone.

Subsequent Wittig olefination, pyran ring-closure, and protecting group manipulations, provide the tetracycle.

HO MOMO Me MOMO Mg O (CH2Br)2 + Me OBOM Me Br O TBSO Et2O Me Me Me OBOM TBSO AcO Me Me Me Me kampanol ABCD ring system

Figure 1-3. Katoh’s synthesis of kampanol ABCD ring system

Mori and colleagues described a convergent synthesis of stypoldione.5 Here, an aryl stannane and allylic acetate are employed in a π-allyl Stille coupling. After pyran ring-closure and protecting group manipulations, the target was attained.

Me OMOM Me OAc Me Me Pd(dba)2 Me Me OMOM LiCl Me Me Me BnO Me + DMF Me Me Me OMOM BnO HO Me3Sn Me Me Me Me Me O O OMOM stypoldione

Figure 1-4. Mori’s synthesis of stypoldione

Smith and colleagues described a biomimetic synthesis of pyripyropene E.6 The two halves are united via enolate alkylation, and then exposure to BF3OEt2 effects epoxypolyene cation-π cyclization. Treatment with DBU promotes condensation to furnish the pyrone ring, finishing the target.

N Br O O N N O Me Me LDA MeO2C + O O Me MeO2C THF−HMPA O Me O Me Me Me Me O O AcO Me Me Me Me pyripyropene E

Figure 1-5. Smith’s synthesis of pyripyropene E

Gansäuer and colleagues described a synthesis of zonarone.7 First, an aryl stannane and allylic acetate are brought together via π-allyl Stille coupling. Exposure of the epoxypolyene to Cp2TiCl effects reductive radical cyclization. Finally,

Barton−McCombie deoxygenation, followed by oxidative demethylation, affords the natural product.

MeO O OAc Me MeO Me Pd(dba)2; OMe O + Me Me O Cp TiCl Bu3Sn OMe 2 Me Me HO Me Me Me Me zonarone

Figure 1-6. Gansäuer’s synthesis of zonarone

This last example, zonarone, has received significant attention by synthetic chemists.8 Indeed, it resides within a meroterpenoid family (quinone-sesquiterpenoid) for which a variety of strategies and tactics have been successfully executed for their laboratory synthesis. In contrast, the tetraketide-sesquiterpenoid natural product family exemplified by simplicissin remains unscathed by practitioners of total synthesis. For anyone skilled in the art of organic synthesis, it is easy to appreciate the differing degree of complexity present in these two meroterpenoid families. Importantly, the all-carbon quaternary center, generated when fully substituted phenol is joined with a terpenoid species, significantly elevates the task of devising and executing a total synthesis. 19

In the following pages, brief treatments of the simplicissin family and the zonarone family of meroterpenoid natural products are provided. Interested readers are encouraged to consult the excellent reviews by Geris9 and by Marcos10 for more in-depth coverage of these natural products.

The term “meroterpenoids,” introduced by Sir John W. Cornforth nearly forty years ago, refers to naturally occurring substances that “contain terpenoid elements in their molecules, along with structures of different (Greek merus = part, partial, or fragment) biosynthetic origin.”11 This basic definition means that vast swaths of known compounds – from alkaloids to vitamins – can be classified as meroterpenoids. Such molecules have had immense value in calling forth the development of synthetic methods that render these targets more accessible and, in turn, allow for the identification, validation, and even development of certain meroterpenoid natural products as useful therapeutic agents. Indeed, chemists have already met the challenges posed by many meroterpenoids: vitamin B12, longithorone A, austalide B, to name a few. Two decades ago, Simpson limited the scope of the term “meroterpenoids” to “compounds of mixed polyketide-terpenoid origins.” This reduced-coverage definition is employed by others, and is used herein.

Technological advances have allowed isolation of naturally occurring small molecules from some of the most unusual locations, such as a toxic lake in the largest

Superfund site in the United States, and in frigid waters off the coast of Norway. With only miniscule quantities of these isolated compounds at their disposal, researchers are now able to perform structure elucidation and biological screening, thus confirming not

20 only the rich molecular complexity but also the exciting bioactivity that characterize these natural products.

For instance, two fungal meroterpenoids do well to illustrate these points.

Berkeleydione12 and tropolactone B13 have been isolated in quantities sufficient for biological screening, and both have been validated as inhibitors of cancer cell proliferation in vitro. Berkeleydione is selectively active against non-small cell lung cancer (NCI-H460, log10 GI50 of −6.40) and tropolactone B exhibits cytotoxicity against human colon cancer (HCT-116, IC50 of 10.9 µM). However, no cancer patient has any hope of ever being treated with such agents unless synthetic chemists rise to the challenge of devising practical and efficient means for their large-scale production. Indeed, when the National Institutes of Health developed its Roadmap for Medical Research, it found that the number one stumbling block for biological sciences is synthetic chemistry.14

To any practitioner of chemical synthesis, these molecules represent formidable challenges, their solution requiring significant ingenuity and creativity. Many research groups are undoubtedly prospecting these targets right now. At the same time, these molecules – and their therapeutic potential – have garnered considerable interest by a much wider audience, as evidenced by a 2007 article15 in Wired Magazine, and a 2007 article16 in The New York Times. As long as such compounds remain unassailable by chemical synthesis, organic chemistry is not a mature science.17

During the past four decades, numerous reports have emerged detailing the isolation of meroterpenoids from terrestrial and marine fungi (chiefly of the genera

Aspergillus and Penicillium). Feeding experiments using 2H, 13C, and 18O labeled substrates have substantiated speculations on their biogenesis.18 Union of a terpene

21 fragment (farnesyl pyrophosphate, FPP), with a polyketide moiety (dimethyl orsellinate,

2) sets the stage for a variety of intramolecular bond-forming processes. Further diversity is generated from downstream oxidations and skeletal rearrangements (Figure 1-7).

O H MeO C Me O 2 O O (*from SAM) Me O H Me * * Me Me Me Me O O Me Me O RO Me Me Me O O O O O O HO H bis-methyl-tetraketide 1 Me Me Me Me simplicissin (4) novofumigatonin (5)

Me O O AcO OH Me CO R Me OH * * 2 Me Me Me FPP Me Me OH O Me O Me OH Me Me O Me O O Me austin (6) CO2R Me Me orsellinate 2 3 O Me OMe O Me Me O O Me Me Me OAc HO Me Me Me O O H O OH O H O H Me O Me O O O O O Me H Me Me Me MeO Me Me andibenin B (9) berkeleydione (8) tropolactone B (7)

Figure 1-7. Biogenetic diversity of tetraketide-sesquiterpene conjugate

The earliest work documented the isolation and structure elucidation of austin19 and andibenin B20 in 1976. Thorough review of the literature (including theses21) indicates that well over ninety unique meroterpenoids (of this type) are produced by various species of fungus. Presumably, all of them derive from dienone 3, the initial tetraketide-sesquiterpenoid conjugate. Given that the isolation reports span the past four decades, and that new members of this growing family of natural products continue to be discovered, it is all the more striking that no synthetic chemist has come forward with a viable laboratory route. Figures 1-8 through 1-19 illustrate the architectural diversity

22 manifested by this family of natural products. Altogether, there are over ninety unique metabolites; twenty-three X-ray crystal structures have been reported in the literature.

A special comment is in order for the relationship between simplicissin and novofumigatonin (see Figure 1-9). Though it was not suggested in the isolation report for novofumigatonin, it is noteworthy to consider that simplicissin may indeed give rise to novofumigatonin through a cascade involving oxidative cleavage of the cross-conjugated cyclohexadienone ring.22 Some credence to this hypothesis can be found in much earlier work focused on the biosynthesis of penicillic acid.23 Additionally, a report by Cossy for oxidative cleavage using copper perchlorate and oxygen24 provides a stimulus for pursuing a conversion of simplicissin to novofumigatonin in a laboratory setting. DMDO may also prove useful in facilitating this transformation.25

Me O O Me O Me O Me Me Me Me H Me OH Me Me Me H

O H O O H O O H O O H O O O O O O O O O H H H H Me Me Me Me Me Me Me Me

andilesin A andilesin B andilesin C anditomin

O O O Me Me Me Me O Me Me Me H Me OH Me Me HO HO HO Me H O H O H O O O O O OH O O O O Me O O Me O O Me H Me Me Me Me Me andibenin A andibenin B andibenin C emervaridione

Me Me Me O O O OH Me H Me Me H O O O Me Me Me O O O O O O O H O H O H O O O H H H Me Me Me Me Me Me insuetolide A insuetolide B insuetolide C

Figure 1-8. Andilesins, andibenins, anditomin, emervaridione, insuetolides

Me Me Me CO2Me CO2Me CO2Me CO2Me Me O O O O Me OH OAc OH Me Me Me Me Me Me Me Me O O O O O H Me O H Me O H Me O H Me O O O O H H H H Me Me Me Me Me Me Me Me tropolactone A tropolactone B tropolactone C tropolactone D

H O O MeO C Me Me 2 O OAc O O H O Me Me O Me Me Me Me O O O O Me O Me O Me Me Me O O O O HO H H Me Me Me Me Me Me OAc simplicissin novofumigatonin fumigatonin

Figure 1-9. Tropolactones, simplicissin, fumagatonins

O Me Me O O Me O O Me O O HO AcO Me OH Me OH Me OH Me OH Me Me Me Me Me Me Me Me O O O O O O O O

O O Me O O Me O O Me O O Me Me Me Me Me

isoaustinone austinolide austinol austin

O Me Me O O Me O O Me O O HO AcO AcO OH H Me O O O Me Me Me Me O Me O Me O Me O O O O O OAc O O Me O O Me O O Me O O Me Me Me Me Me neoaustin dehydroaustinol dehydroaustin acetoxydehydroaustin

Figure 1-10. Austins

O Me O Me O Me Me Me OH Me OH OH O Me Me Me HO C O 2 Me Me O CO2Me O H CO2Me H Me H CO2Me HO O Me Me Me Me berkeleyone A berkeleyone B berkeleyone C O O O Me Me Me Me Me Me OH O OH OH Me Me OH Me O O O H H CO2Me CO2Me O CO2Me O Me H Me Me O O O Me Me Me Me Me Me berkeleytrione berkeleydione 22-epoxyberkeleydione

O O O Me Me Me Me O O O O O H H H O O O H O H O H O H H Me H O Me O Me O Me Me O O Me H O CO Me O Me Me CO2Me Me Me 2 Me Me berkeleyacetal A berkeleyacetal B berkeleyacetal C

O O Me Me O Me Me H O H O Me Me H O H O O H H O HO H OH O Me OH O O O Me Me O O O Me Me H O OH Me Me Me Me O OCO2Me CO2Me Me Me H Me miniolutelide A miniolutelide B paraherquonin

Figure 1-11. Berkeleys, miniolutelides, paraherquonin

O O O Me O Me Me Me Me Me Me Me OH OH OH OH Me O Me Me Me Me Me Me Me O O O CO Me CO Me CO Me 2 H CO2Me O H 2 O H 2 O O O H H H O O Me Me Me Me Me Me Me Me preaustinoid A preaustinoid A1 preaustinoid A2 preaustinoid A3

Me O H OH OH H OAc H OH Me Me Me Me

Me O Me Me O Me Me O Me Me O Me CO2Me H CO2Me H CO2Me H CO2Me O O O H H H O O Me Me Me Me Me Me Me Me preaustinoid B preaustinoid B1 preaustinoid B2 austinoneol

Figure 1-12. Preaustinoids, austinoneol

Me Me Me Me Me O Me O Me O Me O O HO Me Me Me Me Me Me Me Me Me Me

H OH H OH H OH H OH AcO OMe AcO OMe AcO OMe O OMe H O H O H O H O Me Me Me Me Me Me Me Me andrastin A andrastin B andrastin C andrastin D

O O Me Me Me Me OMe OMe Me Me Me Me O O O O H H H H H H O O O OAc O OAc Me Me OAc Me Me penisimplicin A penisimplicin B

Figure 1-13. Andrastins, penisimplicins

Me Me Me Me Me O Me O Me O Me O O O O O Me Me Me Me Me Me Me Me

O O O O OH OAc OMe OMe AcO OMe AcO OMe AcO OMe HO OMe H O H O H O H O Me Me Me Me Me Me Me Me citreohybridonol citreohybridone A citreohybridone B citreohybridone C

Me Me Me Me Me O Me O Me O Me O O O O O Me Me HO Me Me MeO Me Me Me Me

OAc OAc OAc OMe AcO OMe AcO OMe AcO OMe AcO OMe H O H O H O H O Me Me Me Me Me Me Me Me citreohybridone D citreohybridone E citreohybridone F citreohybridone G

Me Me Me Me OAc Me OAc Me OAc O O OH O OH Me Me Me Me O Me Me O OH O O O OMe O OAc O OMe AcO AcO O AcO H H H Me Me Me Me Me Me citreohybridone J citreohybridone K citreohybridone L

Me Me Me O Me O O O OH Me Me Me Me O O OH O OMe OMe H O H O Me Me Me Me atlantinone A atlantinone B

Figure 1-14. Citreohybridones, atlantinones

Me Me Me Me OAc Me OMe Me OMe O O O Me Me Me Me Me Me

O O O O O O AcO OMe AcO OMe HO OMe H O H O H O Me Me Me Me Me Me isocitreohybridone A isocitreohybridone B isocitreohybridone C

Me OMe Me OEt OMe Me Me HO Me O O O Me Me Me Me Me Me

O O O O O AcO OMe AcO OMe AcO OMe H O H O H O Me Me Me Me Me Me isocitreohybridone G isocitreohybridone H isocitreohybridone I

Me Me Me O Me O Me O O OH O Me O Me Me Me Me Me OH O O O O O O O AcO OMe AcO OMe AcO O OMe H O H O H Me Me Me Me Me Me citreohybriddione A citreohybriddione B citreohybriddione C

Figure 1-15. Isocitreohybridones

O O O Me Me Me

Me H OH Me H Me H Me Me Me Me Me OAc O O O O O O O O CO2Me O O O O O O OH O O Me Me Me Me Me Me citreonigrin A citreonigrin B citreonigrin C

O OH O Me Me Me Me O H O OH Me H Me Me Me Me O H O H O O O H CO Me O CO2Me Me 2 O Me CO2Me O O O O Me Me Me Me Me Me citreonigrin D citreonigrin E citreonigrin F

O O Me O Me O Me Me Me O Me O H H H O O O O HO H Me O H O H CO2Me Me O O Me O H O OH Me Me Me Me O O CO2Me Me Me Me Me H Me citreonigrin G citreonigrin H citreonigrin I

Figure 1-16. Citreonigrins

O O O Me Me Me Me Me Me H Me Me H Me O O O Me O Me OH O Me OH H O O O O O O O O CO2Me CO2Me MeO C O Me Me 2 Me Me Me Me PC 3.3.22.D PC 3.3.6.8.4.A PC 3.3.6.8.4.F

O Me O Me Me O O Me CO2Me Me OH H H O HO2C O Me Me O H O O O H O OH Me O CO2Me Me Me PC 3.3.6.6.3.A PC 3.3.6.6.3.B

Figure 1-17. PC 3.3.22.D and others

OH OH OH O Me Me Me Me Me Me Me O O O O O O O O O HO H OH Me Me Me Me Me O O Me O O O O O O O O O O O Me O Me O Me O O Me Me Me Me Me Me Me Me dhilirolide A dhilirolide B dhilirolide C dhilirolide D

Figure 1-18. Dhilirolides

O O O O Me Me Me Me Me Me Me Me OMe OMe OMe Me Me Me Me Me Me Me Me H O O O O O O O OH H H H OH H OH H O O O O O O O O O O O O OH Me Me OH Me Me OH Me Me O Me Me OH terretonin terretonin A terretonin B terretonin C

O O O Me Me Me Me Me Me OMe OH Me Me Me Me H Me Me H O O O O OH H H O H O O O O O OH O O OMe O O OMe Me Me O Me Me OH Me Me OH terretonin D terretonin E terretonin F

Figure 1-19. Terretonins

While the meroterpenoid family delineated in the preceding pages remains unscathed by practitioners of chemical synthesis, the quinone/hydroquinone meroterpenoid family has provided a valuable arena for showcasing a variety of tactics for molecule construction. Again, the interested reader is encouraged to consult the recent review by Marcos10 for more in-depth coverage. Their biosynthesis is operationally very similar to the tetraketide-sesquiterpenoid family delineated above.

Chapter 2. Studies in Meroterpenoid Synthesis

It was emphasized in the previous chapter that, for the tetraketide-sesquiterpenoid family of fungal secondary metabolites typified by simplicissin, these meroterpenoids remain unassailable by laboratory chemical synthesis. A significant portion of the thesis research described herein was directed at this problem.

Simply put, the objective was to render these targets readily attainable by chemical synthesis. Scalable chemical syntheses of these biologically active fungal metabolites would allow supplementary biological evaluations to proceed in earnest.

The key feature that characterizes these metabolites is the carbon−carbon bond that unites the terpenoid and polyketide fragments early in their biogenesis.

Incorporation experiments (using 2H, 13C, and 18O labeled substrates) confirm that the biosynthetic pathway involves enzyme-mediated farnesylation of a fully substituted polyketide phenol (1, Figure 2-1). The resulting dienone (2) is susceptible to a variety of intramolecular transformations, leading to further structural complexity. Andibenin B

(7), berkeleydione (8), and tropolactone B (9) each represent a distinctly different fate for this intermediate dienone (Figure 2-1).

It seemed prudent to designate the dienone intermediate our primary target, since it would enable selective entry into the constitutionally isomeric scaffolds manifested by these meroterpenoids. Not only did we want to secure ample quantities of this intermediate, but we also looked forward to investigating the factors that are responsible for particular intramolecular events. In the course of our work, it occurred to us that simplicissin26 (3) might serve as a suitable surrogate for our initial goal.

MeO2C MeO2C OH Me Me O

CO2H 1' 1' FPP Me Me Me OH Me Me 11 Me transferase; O Me O Me 9 Me Me Me cyclase 10 8 OH HO HO 3 1 2 Me Me Me Me simplicissin (3)

Diels−Alder ene etherification Me CO2Me O O Me O Me Me Me Me OH Me Me Me Me OH CO Me O Me 2 Me CO2Me O Me O O Me Me 4 5 6 Me Me Me Me

O Me Me CO Me O 2 Me Me OH Me Me Me OAc O HO Me O O O H CO Me Me Me 2 O O H O O Me O O O Me Me Me H Me Me Me andibenin B (7) berkeleydione (8) tropolactone B (9)

Figure 2-1. Pluripotency of tetraketide-sesquiterpenoid conjugate

Employing the “cyclase/oxidase” two-phase strategy for total synthesis, our attention was directed to the development of an efficient, gram-scale preparation of simplicissin (3), which is biogenetically related to 7, 8, and 9. Simplicissin (3) is a versatile natural “synthon” en route to more complex meroterpenoids, and it represents attainment of the “cyclase-phase” while avoiding premature entry into the “oxidase- phase.” It is anticipated that 3 (or, where suitable, ent-3 or 1’-epi-3) will give way to the more highly oxidized meroterpenoids through appropriate chemical maneuvers.

With simplicissin as our initial target, tactics were examined to forge the carbon−carbon bond between terpenoid and polyketide components. These tactics are summarized in “starburst” fashion (Figure 2-2). 32

CO2Me CO2Me Me OR CO2Me Me OR Me OR R Me R Me CHO OR R Me OR Me OMe X OR OH Me NaH, nBuLi, K2CO3 Bi(OTf)3, Sc(OTf)3 Me CO2Me Me aldol O alkylation Me OR O Me Friedel Crafts path a − R Me alkylation path l Me Me path b OR then cation-π MeO2C O OAc OMe path k Me path c solvolysis MeO2C CO2Me Me Me Me Me OR path j Me Me O path d O Me R Me Me cycloadditions carbene electrocyclizations OR HO path e Me path i NNHTs Me Me Peterson simplicissin Me Me Sonogashira/semireduction allyl iodonium CO2Me path h then 6π path f Me OR CO2Me path g IArX Me O R Me Me cross-metathesis π-allyl Pd, Rh, Fe OR Me Wittig, Horner, Biellman PIDA, TMSOTf Me PhIO, BF •OEt OMe then cation-π sigmatropy 3 2 OCO2R Me [1,3], [2,3], [3,3] CO2Me CO2Me Me O CO2Me Me OR Me Me Me Me OR Me Me R Me OMe R Me OR Me O O

Me Me

Figure 2-2. Starburst summary of approaches to simplicissin

Direct, intermolecular tactics

The key carbon−carbon bond is the one that unites the terpenoid and polyketide portions of the molecule, generation of which demands phenol dearomatization. Phenols are known to suffer dearomatization under a variety of conditions, and so we began our investigation by screening those methods precedented in the literature.

Direct, intermolecular alkylative dearomatization of phenols is a strategy that has received significant attention in recent years, and was recently reviewed by Porco.27 In fact, alkylative dearomatization of phenols has been known at least since the work of

Curtin in 1958.28 A modest (23%, unoptimized) yield could be achieved for C- prenylation of methyl atratate (10, Figure 2-3). However, exposure of various orsellinate derivatives (e.g., 12) to bases, followed by treatment with prenyl chloride or bromide, failed to produce desired cyclohexadienone.

Me OH O Me Me Me Me Me Cl Me Me NaH then H2, Pd/C 57%

Me OH Me OH Me Me Br Me Me

Me OH NaH, PhMe Me OH 23% CO2Me CO2Me 10 11

OH Me O Me Me Me Me Me Cl Me Me Me OMe NaH, NaOMe, Me OMe CO2Me nBuLi, TMEDA, CO2Me 12 NaH then H2, Pd/C 13

Figure 2-3. Intermolecular alkylative dearomatization

The method of Fráter29 (alkylation-reduction) was carried out using 2,6- dimethylphenol to afford the corresponding enone, but application of this protocol to the orsellinate phenol (e.g., 12) failed to afford desired product; instead, only starting 34 materials were recovered. Porco reported dearomatizing prenylation of acylphloroglucinol substrates (reverse-prenyl acetate, KHMDS, THF, 65 °C); presumably, the additional nucleophilicity conferred by the third phenolic oxygen facilitates this process, while the electron-withdrawing ester of orsellinate renders this phenolic substrate less reactive.

Since the seminal work of Barton on the use of organobismuth species for arylative dearomatization of phenols, other researchers have sought to further broaden the scope of this relatively benign element for mediating carbon−carbon bond formation.

Preparation and use of aryl, alkynyl, alkenyl bismuth species in organic synthesis is well precedented, but the preparation and use of alkyl or allyl bismuth reagents is unprecedented. For our purposes, we briefly examined whether BiCl3 or Bi(OTf)3 could promote the Friedel−Crafts-type union of an orsellinate with an allylic alcohol, based on a report by Matsunaga and Shibasaki.30 (See also Rueping.31) Using these conditions, direct substitution of the hydroxyl group of allylic alcohols32 has been achieved with sulfonamides, carboxamides, and carbamates. Employing the fully substituted phenol

(e.g., 12) as nucleophilic component, no desired product was obtained. By contrast, C- prenylation33 could be accomplished with substrates lacking substitution at a position ortho (or para) to the phenol hydroxyl substituent (e.g., 10).

Me Me Me Me Me OH Me

OH Bi(OTf)3 OH Me 54% Me

OH Me Me Me OH Me Me OH Me

Me OH Bi(OTf)3 Me OH CO2Me 41% CO2Me 10 11 OH O Me Me Me OH Me

Me OR BiCl3, Bi(OTf)3 Me OR CO2Me CO2Me 12 13

Figure 2-4. Bismuth-mediated intermolecular alkylative dearomatization

Although alkylative dearomatization could not be achieved under the conditions described thus far, it was possible to employ either lead(IV) tetraacetate or bisacetoxyiodobenzene for oxidative dearomatization, with complementary regioselectivity.34 The major product resulting from each is illustrated in Figure 2-5.

Further investigation was made into the use of hypervalent iodine reagents for alkylative dearomatization, the results of which will be summarized here. (Incidentally, Drochner35 has prepared atratate dimers using FeCl3, and others have utilized K3Fe(CN)6 for furfuric acid36 and for virensate.37)

O OH O Me Me Me OAc PhI(OAc)2 Me Me Pb(OAc)4 AcO Me

Me OH Me OH Me OH

CO2Me CO2Me CO2Me 15 14 16

Figure 2-5. Orsellinate dearomatization using LTA or PIDA

It has been shown by Canesi38, Quideau39, and others that allylsilane may be used in conjunction with a hypervalent iodine source to effect alkylative dearomatization of phenols. Thus, monobenzyl and monomethyl ethers of the orsellinate (17, Figure 2-6)

36 were subjected to bis(trifluoroacetoxy)iodobenzene and allyltrimethylsilane, and the cross-conjugated allyl dienone products (18) were isolated in modest yields. Thus, direct, intermolecular alkylative dearomatization is possible with this orsellinate system.

OR OR TMS Me Me Me Me

Me OH PIFA or PhIO Me O BF3•OEt2 CO2Me ~20% CO2Me 17 18

Figure 2-6. Orsellinate dearomatization using allylTMS with PIFA

Unfortunately, extension of this method to more complex “terpenyl silanes” (e.g.,

20, Figure 2-7) and “terpenyl stannanes” (e.g., 23) proved to be quite challenging.40 The requisite substrates (unprecedented in the literature) were difficult to prepare and purify.

Professor Ian Fairlamb, in email correspondence, described the challenges associated with their preparation.41 Furthermore, these substrates suffered from a propensity to afford elimination products (e.g., 21 and 24) during attempted “oxidative terpenylation” of the orsellinate phenol (25).

SiMe3 OTf Me TMSCH MgCl Me Me 2 Me Me Me Me Me + Me Pd(Ph3P)4 56% 19 20 21

Cl SnBu3 Me Me Me Me Me Me Bu3SnLi +

HO HO HO Me Me Me Me Me Me 22 23 24 OR terpenyl Me Me silane/stannane oxidative "terpenylation" Me OR PIFA or PhIO product(s) BF3•OEt2 CO2Me 25

Figure 2-7. “Oxidative terpenylation” via silanes or stannanes

In thinking about other direct, intermolecular tactics for joining the two components, a report by Tamaru42 came to light. This report showcased the use of allyl alcohols (triethylborane, Pd(Ph3P)4, toluene, 75 °C, 2 h) in a dearomatizing allylation of polyphenolic arenes. This method is predated by a conceptually similar protocol reported by Miura43 and exploited by Danishefsky44 in a total synthesis of garsubellin A. Whereas

Miura’s protocol utilizes allylic carbonates and Ti(OiPr)4, Tamaru’s protocol utilizes allylic alcohols and triethylborane. The reaction works well for phloroglucinols and other electron rich arenes such as furans and indoles. Indeed, subjection of methyl atratate (10), dimethyl orsellinate (14), or methyl ether variants (12 and 29) to the conditions of Tamaru affords allylated products (Figure 2-8).

O OH OH O Me Me Me OH Me Me Me OH

Me OMe Me OH Me OMe Et3B, Pd(Ph3P)4 Me O Et3B, Pd(Ph3P)4 CO2Me CO Me CO Me 2 CO2Me 2 10 26 12 28

OH O OMe OMe Me Me Me Me Me OH Me Me OH Me

Me OH Me O Me OH Me O Et3B, Pd(Ph3P)4 Et3B, Pd(Ph3P)4 CO2Me CO2Me CO2Me CO2Me 14 27 29 30

Figure 2-8. Atratate and orsellinate dearomatizations (Tamaru’s method)

Based on these results, one can draw two conclusions: a) the reaction seems to stop at a certain oxidation state; b) cross-conjugated dienones predominate. One might be able to render this transformation asymmetric by utilizing appropriate chiral phosphine ligands. As was the case with hypervalent iodine, this Et3B/Pd method failed to produce desired products when put to the test with more complex “terpenyl” alcohols. In general, attempts to generate electrophilic species were thwarted by the propensity of these

38 reactive intermediates to suffer elimination rather than substitution by the phenolic nucleophiles.

Continuing the effort to identify a suitable method for direct union of the terpenoid and polyketide moieties, we examined the so-called “phenolic aldol” condensation reaction (Figure 2-9). A variety of conditions were screened, based on reports in literature that describe this type of transformation. None were capable of producing the desired polyketide-terpenoid hybrid products (e.g., 32 and 33). Some reductive Friedel−Crafts conditions (e.g. Sc(OTf)3 with 1,3-propanediol) were screened, but these also failed to afford desired products.

CO2Me Me OH OH CHO Me Me Me + Me O Me OH Me CO2Me Me Me

10 31 Me Me 32 CO2Me Me O OH CHO Me Me Me Me Me + Me O Me OH Me CO2Me Me Me 14 31 33 Me Me

L-proline CaCl2 CSA Bu2Mg piperidinium acetate MeOH, Δ TFA EtMgBr EDDA DBU, Δ TFAA MgCl2 PhB(OH)2 K2CO3, Δ Sc(OTf)3 Ti(OEt)4

Figure 2-9. Phenolic aldol and reductive Friedel−Crafts approaches

An intriguing transformation reported by Barluenga45 prompted us to investigate the possibility of performing a metal-free reductive alkylation of an arylboronic acid with a terpenyl tosylhydrazone. To that end, drimenyl tosylhydrazone (34, Figure 2-10) was prepared, and successfully coupled with 3-chloro-4-methoxyphenylboronic acid (36) and with 3-pyridylboronic acid (37). Unfortunately, the analogous atratate-derived boronic

39 acid (39) proved to be a challenging substrate to prepare. Decomposition of the drimenyl tosylhydrazone (34) in the presence of methyl atratate (10, i.e. without B(OH)2 prefunctionalization) produced cycloheptatriene ring products, suggested by crude 1H

NMR data. Such a phenomenon is commonly known as a Büchner reaction, in which a benzenoid ring suffers carbene cyclopropanation and 6π-electrocyclization to afford to a seven-membered ring.

CO2Me NNHTs Ar Me OR Me Me Me ArB(OH) 2 Me Me OR K2CO3 38 Δ Me Me Me Me 34 35

CO2Me OMe Me OR N (HO)2B Cl (HO)2B 36 37 (HO)2B Me OR 39

Figure 2-10. Examination of Barluenga’s reductive coupling method

Under palladium-catalyzed allylic alkylation conditions,46 O-prenylation of the orsellinate phenol is observed. Notably, a mixture of SN2-type and SN2’-type products is obtained through the use of rhodium instead of palladium. However, extension of this tactic to more complex substrates (e.g. 40, Figure 2-11) proved untenable. Drimenyl carbonate (40) is a tetrasubstituted alkene, activation of which is generally difficult

(sterically prohibited access to the π-system and propensity to suffer β-hydride elimination). Moreover, phenols are not great nucleophiles, particularly when they bear an electron-withdrawing ester substituent.

MeO2C OH

OCO Me 2 CO2Me Tsuji−Trost (R = H) or Me Me Me Me OH Me π-allyl Stille (R = SnMe3); + OH Me R Me then Eu(fod)3 Me TBSO Me Me OH 40 41 TBSO Me Me 42

Figure 2-11. Tsuji−Trost and π-allyl Stille approaches

There are a few exceptions: Mori has utilized the conditions of Hegedus to accomplish a “quantitative” π-allyl Stille coupling in a total synthesis of stypoldione.5

Recently, Sorensen utilized a π-allyl Stille coupling in the total syntheses of guanacastepenes A and E.47 Cyclogeranyl acetate (with phenyltrimethyltin or with (2- furyl)trimethyltin) gave rise to arylated terpenes under these conditions; however, preparation of the atratate-derived stannane (41, R = SnMe3) proved to be a challenge.

In any case, the style of approach taken by the Baran Lab in natural product total synthesis campaigns is characterized by avoidance of protecting groups, non-strategic redox manipulations, and substrate prefunctionalization. Wherever possible, innate reactivity of molecules is to be exploited.

Cycloaddition strategies

Owing to the lack of success with the direct, intermolecular tactics we screened, we began to think “outside the box.” Decidedly less biomimetic strategies for securing a terpene-polyketide conjugate were pursued. Of the more wildly imaginative tactics we considered, the “interrupted Danheiser” approach seemed particularly attractive. In a normal Danheiser benzannulation,48 the penultimate intermediate is a cyclohexadienone, which undergoes facile tautomerization to the aromatic phenol. We reasoned that this cycloaddition/electrocyclization cascade could be extended to a setting in which R = Me

(i.e., 43, Figure 2-12) instead of R = H. The cascade would then be stifled (or interrupted) at the cyclohexadienone stage, unable to tautomerize.49 Our electrocyclization cascade (which we referred to as an “interrupted Danheiser”) was envisioned to terminate at farnesylated cyclohexadienone (43).

Me Me O O Me O O Me Me Me Me Me Me Me + Me R OMe OMe R R OMe Me OMe CO Me 6π 4π Me [2+2] 2 Me CO2Me Me Me CO2Me CO2Me 43 44 45 46 (R = farnesyl)

Figure 2-12. Retrosynthesis for “interrupted Danheiser” cascade

Thus, beginning with farnesol, we arrived at acid chloride 51 (Figure 2-13).

Treating 51 with 1-methoxypropyne (available from propionaldehyde50) in the presence of Et3N, we hoped to obtain cyclohexadienone 43. In the absence of base, alkyne and acid chloride do nothing; however, dehydrochlorination and [2+2] does occur under solvent-free conditions at elevated temperature (95 °C). Unfortunately, the planned electrocyclization cascade was stymied by undesired dehydrochlorination, generating exo methylene 52 instead of internal alkene 45. Although 51 readily engages in [2+2]

42 cycloaddition with 1-methoxypropyne,51 we were unable to isomerize vinyl cyclobutenone 52 to 45 in order to “jump-start” the 4π/6π electrocyclization cascade.

O O Me Me O Me OEt aq KOH Meldrum's acid Me R R Me R O EtOH TiCl4, pyridine O O Me Me Me O 47 48 49 (R = farnesyl) NaOMe

Me Me O Me Me Me R OMe COCl (COCl)2 CO2H R R

OMe Et3N CO Me CO2Me MeO2C Me 2 Me 52 51 50

Figure 2-13. Initial pursuit of “interrupted Danheiser” cascade

Obtention of exo-methylene 52 is an example of a kinetic acidity problem: the methyl group of 51 bears three acidic protons that are more sterically accessible, while the methine proton is sterically less accessible. As a consequence, deprotonation leads to an undesired vinyl ketene reactive intermediate. Attempts were made to ameliorate this kinetic acidity problem. A tertiary amine base is typically employed for the dehydrochlorination that initiates the cascade. Recently, it has been shown that the use of

52 catalytic Et3N along with stoichiometric K2CO3 can benefit the ketene formation step.

Attention was then turned to alkene position isomerization using the isolated vinyl cyclobutenone substrate (52, Figure 2-14). Unfortunately, screening efforts failed to identify any conditions capable of achieving the desired goal.

O O O Me Me Me Me R Me Me 4π/6π R R

Me Me OMe MeO C OMe MeO C OMe 2 2 CO Me 52 2 (R = farnesyl) 45 43 Pd/C RhH(CO)Cl)(Ph3P)3 Pd(Ph3P)4 polysulfone Pd(OAc)2 µW 250 °C Pd(CH3CN)2Cl2 HI

Figure 2-14. Alkene position isomerization

With this first iteration leading to a dead-end, we devised a second-generation substrate possessing a butenolide moiety (57, Figure 2-15). Such a modification was, in our view, a tolerable concession: andibenin B (7, Figure 2-1) possesses such γ-lactone connectivity. We also exchanged the farnesyl for a cinnamyl moiety with the anticipation that the latter would (1) provide a more durable scaffold for our continuing investigation of the projected cascade, (2) facilitate handling and purification on account of its UV handle, and (3) participate in a downstream cross-metathesis53 reaction to install the farnesyl moiety. Moreover, cinnamyl bromide ($2/gram, Acros) is much less expensive than farnesyl bromide. Despite all of these benefits, untoward dehydrochlorination still prevailed, and the resultant butenolide-cyclobutenone (58) proved to be recalcitrant under a variety of conditions typically employed for olefin position isomerization.

O O O NaCl, DMSO, Me Me H O, ; Me 2 Δ HO CO TMSE R OTMSE R 2 R OEt (COCl) ; 2 Cl O OEt CH N ; O 2 2 NaOMe O O HCl 53 54 55 (R = cinnamyl)

Me O Me Me Me Me R R COCl (COCl) R CO2H OMe 2 OMe O O O O Et3N O O 58 57 56

Figure 2-15. Butenolide substrate for “interrupted Danheiser” cascade

Before abandoning our “interrupted Danheiser” approach, we designed a substrate for which only desired dehydrochlorination is possible (59, Figure 2-16). Whereas the alkene and butenolide substrates (51 and 57) have protons that permit untoward dehydrochlorination, the pyrone scaffold (59) does not.

O Me Me COCl Me R R 20% Me CO2Me MeO2C OMe 51 52 (R = farnesyl)

Me Me O Me R COCl R

49% O OMe O O O 57 58 (R = cinnamyl) O Me H Me O Me Cl OMe

O Ph O O Ph Ph O Ph 59 60

Figure 2-16. Designing for desired dehydrochlorination

Metalloenamine alkylation of propionaldehyde provided the known aldehyde 61

(Figure 2-17). Corey−Fuchs dibromoolefination, followed by dehydrobromination and lithium-halogen exchange, yields a lithium acetylide, which is quenched with benzoyl chloride to furnish alkynone 63. This is treated with dimethyl malonate in the presence of a catalytic amount of K2CO3. Under these conditions, conjugate addition, isomerization, and lactonization proceed, and pyrone 64 is isolated in good yield.

Hydrolysis of the methyl ester is accomplished with Me3SnOH, and subsequent exposure to oxalyl chloride generates acid chloride 59. The yield for hydrolysis of the methyl ester

64 was diminished due to decarboxylation, so the corresponding TMSE ester was prepared, which can be deprotected using TBAF. Thus, the stage was set for dehydrochlorination and [2+2]/4π/6π cascade.

Me H Me H Me H CBr 4 Br nBuLi; CHO Ph3P PhCOCl Ph Br O Ph 61 Ph 62 63 Ph

CO2Me K2CO3 CO2Me Me H Me H Me H O CO2Me CO2H Cl (COCl)2 Me3SnOH O Ph O O O Ph Ph O O Ph Ph Ph 59 65 64

Figure 2-17. Preparation of 6-phenylpyrone for “interrupted Danheiser”

On paper, this 6-phenylpyrone (59) appeared to be a solution worth pursuing. It was recognized that downstream oxidative excision of benzaldehyde, for instance, would be required to further process the anticipated product of our “interrupted Danheiser” cascade. In spite of this, we reasoned that pyrone 59 would enable us to at least secure proof-of-principle. However, in practice, preparation of pyrone 59 proved to be a protracted endeavor, and was eventually abandoned.

Another type of cycloaddition strategy was examined. It is known that an aldehyde (e.g., 67, Figure 2-18) can be made to engage with a Brassard-type diene (e.g.,

66) in a hetero-Diels−Alder cycloaddition.54 The resulting dihydropyrone species can be converted to a pyrone, and then reacted with an alkyne for a pyrone-alkyne Diels−Alder cycloaddition. After electrocyclic rupture and expulsion of carbon dioxide, a cyclohexadienone is revealed. Thus, dihydropyrone 68 was prepared. Unfortunately, exposure of this substrate to base led only to ring opening to provide the dienyl carboxylic acid, thus precluding the intended pyrone-alkyne Diels−Alder cycloaddition.

Me Me Me MeO OTMS MeO O MeO CO H 66 OEt 2 EtAlCl O LDA + 2 O Me Me Me

Me Me Me Me Me Me 67 68 69

Figure 2-18. Hetero-Diels−Alder/Diels−Alder approach

Finally, in the area of cycloadditions, the possibility arose of carrying out a

Paterno−Buchi [2+2] cycloaddition followed by rearrangement of the oxetane intermediate.55 Toward this end, the terpenoid moiety bearing a suitably positioned alkene (70, Figure 2-19) was prepared, as was the tetrasubstituted 1,4-benzoquinone (71).

The former was obtained from drimenol via reductive deoxygenation with double-bond transposition.56 The latter was obtained from an atratate derivative via oxidation

57 (mCPBA; O2-salcomine). Incidentally, it was discovered that quinone 71 could also be produced via treatment of the orsellinate with Koser’s reagent. Addition of methylmagnesium bromide, and 1,2-migration58 of the methyl substituent would generate the all-carbon quaternary center. This process benefits from the reclamation of dienone

π-system conjugation and the relief of ring strain by rupture of the oxetane ring.

MeO2C O

Me MeO2C O Me Me Me O + Me Me Me OMe Me Me Me O OMe 70 71 72 Me Me

Figure 2-19. Paterno−Buchi strategy

Intramolecular rearrangements

Approaches featuring 6π-electrocyclization to forge the B-ring were briefly investigated (Figure 2-20). Two fragments – allylic silane 73 and α,β-unsaturated aldehyde 74 – were subjected to Peterson olefination conditions. Alternatively, known vinyl triflate59 75 was coupled with the enyne 76 (best prepared from 74 using lithiated

(diazomethyl)trimethylsilane) under Sonogashira conditions. Subsequent semi-reduction of the alkyne was carried out, with the expectation that the resulting triene 77 would undergo 6π-electrocyclization, forging the terpenyl B-ring. Unfortunately, complex mixtures were obtained.

MeO2C O Me Me O Me Me SiMe3 + MeO2C MeO2C O OMe O O Me Me Me 73 74 Me Me CHO Me Me 6π Me Me Me OMe Me OMe MeO2C O Me Me O O Me Me Me Me O O O + Me Me 77 Me Me 78 O OTf OMe Me Me Me 75 76

Figure 2-20. Peterson and Sonogashira/semi-reduction approaches

Intramolecular rearrangements can often enable highly efficient production of congested systems. One of our early investigations along these lines involved a [2,3]- thia-Sommelett rearrangement. This was actually inspired by the recognition that specific C-methylation events occur during orsellinate polyketide biogenesis (Figure 1-7).

A means for methylation in the biological setting is S-adenosyl methionine (SAM) in cooperation with a methyltransferase enzyme.

This type of [2,3]-rearrangement was examined using a model system (Figure 2-

21). Following known methods, albicanyl mesylate (79) was prepared in six steps from commercially available β-ionone. Displacement of the mesylate with 2-propanethiolate furnished thioether 80. Meanwhile, the orsellinate phenol (14) was obtained in two steps from commercially available methyl atratate. It was reasoned that treatment of thioether

80 with an electrophilic chlorine source (sulfuryl chloride or N-chlorosuccinimide) followed by phenol 14 would generate oxysulfonium chloride salt 82. Subsequent treatment with triethylamine or other base would furnish an oxysulfonium ylide, which would suffer [2,3]-rearrangement60 to provide dienone 83.

OH Me OH Me R CO2Me Cl iPr O Me CO Me 14, SO Cl iPr S 2 2 2 S O Me [2,3] Me Me Me Me Et3N Me − HCl Me Me

79, R = OSO2Me Me Me 83 80, R = SiPr Me Me 82 78% i Raney 81, R = S(O) Pr Ni

OH Me OH Me Me NCS; OH O o-cresol; CO2Me Me Me OH S S Et N Me Me Me CO Me 3 2 32% 14

Me Me 84

Figure 2-21. [2,3]-thia-Sommelett approach

However, only sulfoxides and dienes (via elimination) were isolated. To be sure that the reaction was conducted in an operationally sound manner, tetrahydrothiophene was joined with ortho-cresol in moderate yield, presumably according to the process delineated above. It is possible that the albicanyl thioether 79 suffers from significant

49 steric bulk that prohibits its engagement with the phenol nucleophile 14. Instead, the substrate suffers oxidation (via adventitious O2, H2O, or upon quench), affording 81.

A recent report by Yamamoto61 inspired an approach whereby the carbon−carbon bond between terpene and polyketide fragments would be forged via an abnormal [1,3]-

Claisen rearrangement.62 First, terpenyl aryl ether substrates (85 through 90, Figure 2-

22) were prepared by either alkylation (base, terpenyl halide) or Mitsunobu etherification.63 For 10,11-epoxyfarnesol, Sharpless asymmetric dihydroxylation was employed. However, due to observed complications with epoxide 86, a detour was pursued, involving carbonate 87, obtained via treatment of the 10,11-diol with 1,1’- carbonyldiimidazole. For preparation of 88, 89, and 90, epoxypolyene cyclizations

64 65 (ZrCl4 or EtAlCl2 ) afforded bicyclic terpenoid diols, with subsequent modifications performed according to Cuerva66. For the phenolic Mitsunobu reactions, it was found that high concentration and sonication67 were necessary to obtain useful yields.

CO2Me CO2Me CO2Me Me OH Me OH Me OH

Me Me Me O O O Me Me Me Me Me Me O

O Me Me Me Me Me O Me 85 86 O 87

CO2Me CO2Me CO2Me Me OH Me OH Me OH

Me Me Me Me O O O Me Me Me Me Me Me

HO HO HO Me Me Me Me Me Me 88 89 90

Figure 2-22. Ether substrates for [1,3]-Claisen rearrangement

The ether substrates (85 through 90) were exposed to FeCl36H2O in CH2Cl2, affording rearranged products in low to moderate yields. Less complex (e.g. 85) substrates fared better than the more complex (e.g. 88) substrates. Isolated yields were

50−60% for the former, and 0−16% for the latter. Elimination was once again the prevailing side reaction. It was found that maintaining the reaction at 0 °C inhibited reaction progress, but at room temperature the reaction proceeded.68 Seeking to improve the yield for [1,3]-rearrangement with drimenyl substrates (88 and 89), extensive screening was conducted in search of a result better than that afforded by FeCl36H2O

(Figure 2-23). None were found, although the “leaders of the pack” were: Fe(ClO4)3,

69 Fe(OTf)3, Bi(OTf)3, Sc(OTf)3, and Yb(OTf)3. Treatment of the desired [1,3]- rearrangement product 91 with Amberlyst 15 beads ostensibly resulted in spiro furan ring formation70 (evidenced by crude 1H NMR).

CO2Me Me OH MeO C 2 OH Me Me Conditions Me O Me Me OH Me ≤16% Me

HO HO Me Me 89 Me Me 91

FeCl3•6H2O AgBF4 Bi(OTf)3 FeCl3 AgOTf Cu(OTf)2 Fe(NO3)3 AgO2CCF3 Mg(OTf)2 Fe(ClO4)3 AgSbF6 Sc(OTf)3 Fe(OTf)3 AuCl3 Yb(OTf)3 Fe(acac)2 Ph3PAuCl Zn(OTf)2 K2CO3, Δ Ph3PAuOTf ZrCl4 HMDS, PhNEt2 ArP(tBu)2AuCl Amberlyst 15 Et3N, CaCl2•H2O NaAuCl4 Mont. K10 TFA LiClO4 Mont. KSF anisole µW [(allyl)PdCl]2 zeolite NaY toluene µW PdCl2(PhCN)2 Florisil DMF µW (dppf)PdCl2 NiCl2(Ph3P)2 1,2-DCB µW Pd2dba3 NiCl2(dppp) hν various [IrCl(C8H14)2]2 NiCl2(dppf) Δ various [Ir(OCH3)(C8H12)]2 Mo(CO)6

Figure 2-23. Screening effort for [1,3]-Claisen rearrangement

Early investigations of normal [3,3]-Claisen rearrangements were focused on obtention of ortho-Claisen71 rearrangement products. Allyl orsellinate ether 92 (Figure 2-

24) was rearranged; its properties (color, polarity, peaks in NMR) suggested a dienone species 93, but its structure (ortho or para Claisen?) remained elusive (asterisks denote possible alternatives). Further heating of the dienone species (6 h) resulted in a product that suggested cyclization (e.g., 94). Selenoetherification was employed in order to help pin down the constitution of the dienone product. A less polar substance was generated, and its identity as a phenylselenyl ether (e.g., 95) was substantiated by LRMS.

O O O Me Me Me Me 1,2-DCB Me * Me + Me µW 200 °C O Me OH Me * OH Me CO Me CO Me CO2Me 2 2 92 93 94 representative possibility; 1 product constitution not H NMR definitively determined PhSeCl δ 1.06 (d, 3 H)

RSM and/or deallyation: O less polar; Me LRMS 407 m/z H2O µW 160 °C Me SePh + (C20H22O4SeH ) Me3Al, H2O PhNEt W characteristic 2 µ Me O 1,2-DCB 150 °C selenium isotopic CO Me BCl3 2 distribution 95

Figure 2-24. [3,3]-Claisen rearrangement and selenoetherification

Reverse prenylated orsellinate ether 96 (Figure 2-25) was also prepared and subjected to rearrangement conditions. Circumstantial evidence suggested that rearrangement indeed took place. Upon letting the NMR sample stand for two days, a new substance emerged. Presumably, trace protic acid in the CDCl3 allowed for cyclization (TLC change in polarity, diagnostic peaks in 1H NMR). Subsequent treatment of this sample with diazomethane resulted in a change that is consistent with ring opening and methylation of the substrate (yellow color, more polar, 1H NMR).

Me Me Me Me Me Me

O O and/or O H+ Me Me Me Me Me Me

Me OH Me O Me O

CO2Me CO2Me CO2Me 96 97 98

Figure 2-25. Investigation of "reverse prenyl" for [3,3]-Claisen

Allyl orsellinate ether 99 (Figure 2-26) was also rearranged, the product bearing properties suggestive of a dienone species (color, polarity, peaks in NMR), but its structure also remained elusive. Quinkert72 has reported that dienones exhibit distinct

UV maxima (300 nm for 2,4-linear; 240 nm for 2,5-crossed). Considering that it might have been an ortho-Claisen product with hydroxyl and allyl moieties near each other, etherification was pursued. Upon treatment with BBr3, fragmentation was observed.

Ultimately, its constitution was confirmed as 100 by X-ray crystallographic analysis.

O OH O Me Me BBr Me Me Me Me Yb(OTf)3 3

µW 100 °C Me OMe Me OMe Me OMe 1,2-DCE CO Me 2 CO2Me CO2Me 60 min 101 99 100 [X-ray]

OMe Other conditions: OMe Me Me Me Yb(OTf)3 Me Bi(OTf)3 IrOTf 80% Cu(OTf)2 Y(OTf)3 Me O (100% brsm) Me O Eu(fod)3 H2O µW CO2Me Eu(OTf)3 PhNEt2 µW CO2Me 102 103 [X-ray]

Figure 2-26. para-Claisen rearrangements, and de-allylation

Cross-conjugated dienones are more stable as there is no risk of Diels−Alder dimerization (cf. their linearly-conjugated congeners). Moreover, cross-conjugated dienones (arising from para-Claisen rearrangement of allyl aryl ethers) were found to be the thermodynamic sinks for the substrates that were studied. Thus, this first allyl ether

53 substrate (99) produced an allyl dienone (100) that was useless for our purposes, but the second allyl ether substrate (102) afforded an allyl dienone (103) that warranted further attention. An indication of things to come, the prenyl variant (accessed from 103 via cross-metathesis) when subjected to BBr3 (in an attempt to demethylate) resulted in clean fragmentation.

Initially, the Claisen rearrangements were conducted using microwave irradiation

® ™ (Biotage Initiator ) in 1,2-dichlorobenzene at 200 °C. It was found that Yb(OTf)3 permitted reduction of reaction temperature to 100 °C (microwave). This also permitted the switch to a lower-boiling solvent (1,2-DCE). After 2 h in the microwave, the ortho-

Claisen intermediate (a minor constituent) could be isolated by silica gel chromatography, and then resubjected to the conditions, in order to afford more of the para-Claisen product (103). In this way, an optimized yield of 80% (100% brsm) was realized.

At some point, we investigated the notion of exploiting the allyl group as a surrogate for methyl. We had shown that the allyl group of 103 could be converted (via

Lemieux−Johnson oxidative cleavage and reductive decarbonylation using Wilkinson’s catalyst) to a methyl group (i.e., 105, Figure 2-27). As such, this constituted the latter half of a four-step process (O-allylation, para-Claisen, oxidative cleavage, reductive decarbonylation) for installation of a quaternary methyl group. This held some appeal when we were entertaining strategies for attaching a suitable atratate (rather than orsellinate) nucleophile to a terpenyl electrophile via an sp2−sp3 coupling reaction

(Tsuji−Trost, π-allyl Stille, Figure 2-11). Unfortunately, none of these proved to be tenable (vide supra). The abnormal Claisen approach (Figure 2-23, vide supra) offered

54 the best traction, but it was plagued with low and/or irreproducible yields, despite optimization efforts.

OMe OMe OMe Me Me Me OHC Me OsO Me [Rh] Me 4 Me

Me O NaIO4 Me O Me O

CO2Me CO2Me CO2Me 103 104 105

Figure 2-27. Allyl as a surrogate for methyl (proof-of-principle)

We wanted to examine the allyl-as-methyl surrogate tactic in a more complex setting. Because no substrates along the lines of 91 (Figure 2-23) were on hand in appreciable quantities, chroman 108 was prepared (Figure 2-28). Subjection to standard rearrangement conditions provided a product whose properties suggested it was either a linear- or cross-conjugated dienone (e.g., 109). However, isolation of this product, and heating in the microwave (in the absence of Yb(OTf3)) effected the reverse process! The material reverted to the original chroman allyl ether 108!

Me Me Me Me Me OH O O Me H Me DDQ Me 2 Me

Me OH Δ Pd/C Me OH Me OH CO2Me 11 106 CO2Me 107 CO2Me

Me Me Me Me Br

O Yb(OTf)3 O K2CO3 Me µW Me

Me O µW Me O

CO2Me CO2Me 109 108

Figure 2-28. Chroman substrate for para-Claisen study

In addition to the allyl group, both methallyl and prenyl were examined (Figure 2-

29). Methallyl ether 110 afforded cross-conjugated dienone 111, albeit less efficiently

(lower conversion after 2 h). Prenyl ether 112 gave quantitative de-prenylation upon

55 exposure to Yb(OTf)3 or Eu(fod)3. Interestingly, we found that, all else being equal,

Yb(OTf)3 favored para-Claisen, Bi(OTf)3 favored ortho-Claisen, and Cu(OTf)3 favored de-allylation. Without catalyst, rearrangement is extremely slow. Y(OTf)3, Eu(OTf)3, and Eu(fod)3 all provided comparable reaction profiles (as per TLC), but with lower conversion to product.

OMe Me OMe Me Me Me Me Yb(OTf)3

Me O Me O

CO2Me Me CO2Me 110 111 OMe OMe Eu(fod) Me Me 3 Me Me Me or

Me O Me Yb(OTf)3 Me OH

CO2Me CO2Me 112 29

Figure 2-29. Methallyl and prenyl ethers subjected to Yb(OTf)3

Biomimetic cation-π cyclizations

Since we had identified conditions for an efficient para-Claisen rearrangement to produce allyl dienone 103, we pursued “terpenyl chain elongation” as a route to simplicissin (Figure 2-30). It was hoped that a biomimetic cation-π cyclization could be achieved.

MeO C MeO C 2 O 2 O Me Me OMe Me Me Me Me Me Me

Me O Me OMe Me Me Me O

CO2Me HO 103 Me Me Me Me simplicissin 113

Figure 2-30. Retrosynthesis featuring a biomimetic cation-π cyclization

First, allyl dienone 103 was transformed into aldehyde 104 (Figure 2-31).

Subsequent Horner olefination (using a phosphonate derived from geranyl acetone) afforded a diastereomeric mixture of β-hydroxyphosphonates 114, which failed to eliminate. It is known that β-hydroxyphosphonates lacking electron-withdrawing substituents are resistant to elimination.

MeO C 2 O OMe OMe Me Me Me Me Me OHC Me Me

Me OMe Me O Me O Me

CO2Me CO2Me OH PO3Et2 103 104 Me Me 114

Figure 2-31. Horner olefination approach to cyclization substrate

An alternative elaboration of allyl dienone 103 proceeded as follows: (1) cross- metathesis with methacrolein to generate a 5:1 E:Z mixture of olefin isomers (70%), followed by (2) TsOH-catalyzed equilibration to furnish exclusively E-enal (99%), (3)

NaBH4 reduction (80%), and (4) conversion of the resulting allylic alcohol to allylic chloride 115 (MsCl, Et3N, then LiCl, 94%). The stage was now set for an allylic cross- coupling with a nucleophilic species ultimately derived from geraniol (Figure 2-32).

Biellman coupling, wherein known geranyl phenyl sulfone was reacted with 115, furnished cyclization substrate 116 (58%, 93% brsm). Conditions typically suitable for effecting reductive desulfonylation or cation-π cyclization invariably produced fragmentation products (e.g., 29 and 117).

MeO C 2 OH MeO C 2 O Me Me OMe OMe Me Me Cl Me Me Me 29 Me Me a - d Me e f OMe Me Me OMe + Me O Me O Me Me Me CO2Me 115 CO2Me 103 Me Me Me Me SO2Ph 117 Me SO Ph 116 Me Me 2 SO2Ph

Reagents and conditions: (a) methacrolein, HG-2, 70%; (b) BF3•OEt2 InBr3 TMSOK pTsOH, 99%; (c) NaBH4, 80%; (d) MsCl, Et3N, LiCl, 94%; EtAlCl2 HCl Raney Ni (e) geranyl phenyl sulfone, LHMDS, THF−HMPA, 58%; (f) Sc(OTf)3 TiCl4 Na/Hg various conditions, see right FeCl3•6H2O ZrCl4 SmI2

Figure 2-32. Biellman coupling approach to cyclization substrate

Concurrent with the Biellman coupling approach depicted above, we also pursued direct cross-metathesis. The requisite triene (118, Figure 2-33) and epoxydiene (not shown) are readily available from geranyl acetone. Cross-metathesis with 103 using

Grubbs ruthenium catalysts afforded the desired products (113; epoxide variant not shown) in low yields and as trisubstituted olefin geometric isomers. This tactic was further hampered by the promiscuity of the ruthenium catalysts, which led to mixtures of truncated cross-metathesis products. Farnesyl dienone substrate 113 even suffered fragmentation upon exposure to mild electrophilic reagents such as bromodiethylsulfonium bromopentachloroantimonate (BDSB).73

MeO C 2 OH MeO C 2 O Me Me OMe Me Me Me Me Me Me Me 29 Me a b OMe + Me OMe + Me O Me Me Me Me CO2Me Me 118 103 Me Me 113 119 Me Me

Reagents and conditions: (a) HG-2; (b) various Bi(OTf)3 BF3•OEt2 FeCl3•6H2O Sc(OTf)3 MeAlCl2 SnCl4 Yb(OTf)3 TiCl4 1.0 M HCl BDSB

Figure 2-33. Direct cross-metathesis approach to cyclization substrate

Although not explicitly depicted in Figures 2-32 and 2-33, the corresponding epoxide substrates were prepared in both cases. Glimpses of cyclization without fragmentation were rarely observed, for instance, with Yb(OTf)3. The substrates turn out to be too susceptible to fragmentation, producing a terpenyl cation species and a rearomatized polyketide. Thus, while this approach appears to be operative in meroterpenoid biogenesis, we were unable to mimic this transformation in the reaction flask. Incidentally, there have been other situations in which a designed biomimetic cation-π cyclization has failed: Pattenden’s pursuit of stypoldione;74 Mori’s failure with olefin cyclization reactions;1 Parker’s failure with Lewis acids, success with Hg.75

Rather than resorting to redox manipulations or protecting group installations, we reasoned that untoward fragmentation might be sidestepped by carrying out a few simple molecular deletions, so to speak. As a proof-of-principle, the allyl dienone 103 was

76 reduced (NaBH4, pyridine ), then decarboxylated (Figure 2-34). The allyl moiety of 120 served as a functional group handle to install the farnesyl (or epoxyfarnesyl) fragment via cross-metathesis with 118 or 121 (Figure 2-34), providing material to quickly address the

“molecular deletions” hypothesis.

73 6 Gratifyingly, exposure of 122 to BDSB or 123 to BF3OEt2 produced cyclized products; 1H NMR, TLC, and LCMS substantiated their identity (124 and 125, Figure 2-

34). Presumably, by performing these molecular deletions, the propensity for fragmentation was successfully mitigated.

Me Me O Me Me Zn, CH2Br2 Me O Me O Me Me TiCl 4 G-2 Me BDSB Me Me Me Me Me Me Me 118 OMe OMe 40 °C 23 C Me ° Me Br CO2Me NaBH 4 Me O Me Me Me Me Me O pyridine; 122 124 Me Me Me Me NaCl, H2O DMSO OMe OMe 150 °C Me O Me O 103 120 Me Me

G-2 Me BF3•OEt2 Me Me Me Me Me O Me Me OMe OMe 40 °C −78 °C O Ph3P=CH2 O O Me Me HO Me Me Me Me Me Me Me Me 121 123 125

Figure 2-34. “Molecular deletions” allow cyclization without fragmentation

It turns out that a close analog of the “reduced” allyl dienone 120 is known in the literature. Majetich had prepared vinylogous ester 126, and carried out alkylations using a functionalized allylic iodide (Figure 2-35).77

LDA OMe OMe THF−HMPA allylic iodide Me Me Me Me Me 6:1 dr 84% O Me O TMS Me 126

Figure 2-35. Alkylation of vinylogous ester (Majetich)

We prepared gram quantities of 126, and carried out alkylations with farnesyl bromide and with epoxyfarnesyl bromide (Figure 2-36). On the heels of our earlier proof-of-principle, we were confidently optimistic about the key cation-π cyclization for

60 the present substrates. For farnesyl substrate (not shown), BDSB or SnCl4 was used. For epoxyfarnesyl substrate 127, BF3OEt2 or EtAlCl2 was employed.

As anticipated, cyclization of these substrates was not accompanied by fragmentation. The major product obtained from cyclization of the epoxy substrate 127

65 using EtAlCl2 was tetracyclic pyran 128 (51%). Fortuitously, X-ray quality crystals were generated (overnight evaporation of the NMR CDCl3 sample), confirming this structure.

Figure 2-36. Rapid, convergent access to tetracyclic pyran

Excitement from this result was attenuated by the recognition that the C8,C9,C10- stereotriad in 128 does not directly correspond to any members of the meroterpenoid family being targeted. However, as Figure 2-37 illustrates, this readily accessible tetracycle (two steps from known materials) warranted further attention. In principle, 128 could give rise to dienone 129, which bears striking resemblance to simplicissin (3) and tropolactone D (9) (see Figure 2-1). In fact, it can be regarded as a constitutional isomer of simplicissin (3) differing only in two aspects: C3-OH stereochemistry and pyran versus furan ring architecture. Furthermore, chemoselective epoxidation would provide

130, a topologically distinct constitutional isomer of preaustinoid A. In order to capitalize on these observations, carbon−oxygen bond cleavage was required.

MeO O MeO O

Me O Me O Me O Me Me Me Me Me Me Me Me Me O 9 O O O 10 H 8 Me H Me H Me HO HO O Me Me 128 Me Me 129 Me Me 130

O Me Me O O Me Me OH Me Me Me Me OH OH O HO Me Me Me Me H OMe O O O H H O OMe OMe O O O O O Me H Me Me Me Me Me ent-berkeleydione ent-berkeleytrione preaustinoid A

Figure 2-37. Relationship between tetracycle and known meroterpenoids

Several precedents (Figure 2-38) gave us hope that the pyran ring could be opened, and the stereotriad fixed. Additionally, Yamamoto has shown the usefulness of diethylaluminum tetramethylpiperidine (Et2AlTMP) for opening of epoxides to furnish allylic alcohols. Possibly, ring-opened product(s) may be generated upon exposure of the pyran tetracycle to a strong Lewis acid (to tug on the oxygens), a strong base (to relieve the substrate of a proton), or a combination of the two.

O OH O HI, Pred Me O Me I Δ Me 25% Me

Me Me H H Me LDA O 68% CO2H O

CO Me O 2 Me aq NaOH O Me dioxane, Δ OH Me Me CH2N2 Me Me Me Me

Figure 2-38. Examples of γ- and δ-lactone ring-opening

Of the conditions screened (Figure 2-39), LDA and LiNEt2 appeared to produce signs of pyran ring opened product(s), as suggested by TLC and 1H NMR (new peaks at

~13.8 ppm and ~5.4 to 4.7 ppm). However, the results were not reproducible and the putative ring-opened products could not be isolated. Perhaps exposure to silica gel unwittingly led to re-closure?

We forged ahead, reasoning that if vinylogous ester 128 is resistant to ring opening, perhaps the dienone 131 (Figure 2-39, right side) would be more cooperative.

This pursuit involved no concession steps, as it would merely fashion the dienone in the process, getting us even closer to our ultimate goal. Enolate C-acylation using methyl cyanoformate, and dehydrogenation mediated by DDQ, afforded the cross-conjugated dienone tetracycle 131. Incidentally, other reagents failed to achieve dehydrogenation of this substrate.

CO2Me Me O Me O Me O Me Me Me Me Me NCCO Me; Me O TBSOTf; Me 2 Me O O Me mCPBA O Me Me DDQ Me TBSO HO MeO CO Me Me Me Me 2 132 128 Me Me 131

Amberlyst 15 BBr3 TBSOTf, 2,6-lutidine BBr3 PhSiMe3, I2 CSA FeCl3 TsOH BF3•OEt2 TBSOTf, 2,6-lutidine PPTS LiI, pyridine K2CO3 CeCl3, NaI TsOH Sc(OTf)3 MgBr2 KOH, 18-crown-6 FeCl3 PPTS Yb(OTf)3 ZnBr2 NaOH MgBr2 Et3OBF4, proton sponge HBr NaHMDS MgI2 DBU HCl LDA PI3 KOtBu H2SO4 Et2Al•TMP ZnBr2 NaOMe HOAc CAN HOAc LDA TFA H2, Pd/C TFA LiNEt2 TMSOTf, Et3N mCPBA TMSI

Figure 2-39. Elaboration of pyran to other key intermediates

With fresh hope, we set out to screen conditions again, including LDA and

LiNEt2. Unfortunately, only decomposition or recovered starting material were the results. Around this time, it came to our attention that the Snyder group at Columbia had

63 experienced similar difficulties with a ring-opening pursuit: “In no case, however, were we ever able to convert tetracyclic materials… into exocyclic alkenes, despite numerous attempts.”73

An alternative tactic was investigated (Figure 2-39, left side). We reasoned that epoxidation of the vinylogous ester 128 would provide an intermediate 132 possessing a

“trigger” for desired pyran carbon−oxygen bond scission. Recognizing that certain members of the meroterpenoid family (e.g. berkeleydione) possess this extra oxidation anyway, we thought that we could only stand to gain if this tactic worked in practice.

Unfortunately, this epoxide also proved recalcitrant to desired pyran ring-opening.

While we explored oxidative and isohypsic tactics for C8−O bond cleavage, we did not want to resort to reductive tactics (a concession). Nevertheless, such a pursuit might have looked like this: reduction of vinylogous ester 128 using DIBAL-H, then acidic opening to provide a cyclohexenone. Subsequently, γ-acylation with methyl cyanoformate and DDQ-mediated dehydrogenation would provide a cyclohexadienone.

After a brief foray into enyne cycloisomerization (not shown), an idea for radical chemistry emerged. We recognized the potential opportunity to utilize the mild oxidative radical conditions identified by our laboratory in the context of meroterpenoid synthesis.

It was becoming abundantly clear that the way to efficiently prepare meroterpenoids was to take a convergent approach – that is, unite prefabricated terpenyl and polyketide portions in a direct, oxidative heterocoupling process.

Chapter 3. Radical Chemistry Applied to Meroterpenoid Synthesis

In this chapter, our explorations in radical chemistry are recounted. First, several new reactions are described which exploit organoboronic acids and organotrifluoroborates as radical precursors, particularly upon exposure to the

+ 2− Ag /S2O8 oxidation system. Then, application of this method to the preparation of a number of quinone-sesquiterpenoid natural products is described.

Radical cyclizations have proven to be a valuable tactic widely employed in organic synthesis. Often, however, the appeal they exhibit in generating molecular complexity is attenuated by the drawback of using toxic tin species and inert (oxygen- free) reaction conditions. In the case of aryl-centered radicals, diazonium salts serve as one means for entry into radical processes, although their preparation and handling offsets their synthetic value. Among the recent developments aimed at circumventing such drawbacks, the recently discovered Minisci-type reactivity of organoboronic acids and trifluoroborates (Figure 3-1) addresses many of these. Indeed, the conditions involve the use of ubiquitous boronic acids, inexpensive inorganic salts (catalytic silver nitrate, stoichiometric potassium persulfate), can be performed in an open-flask without recourse to high temperatures, and can be safely conducted on gram-scale. In this chapter, the chemistry of aryl radicals derived from boronic acids and trifluoroborates is explored in an intramolecular setting.

O AgNO3 (0.2 equiv) ArB(OH)2 K2S2O8 (3 equiv) or or e- deficient heteroarene ArBF3K N Ar Ar or benzoquinone O

Figure 3-1. Minisci-type reactivity for boronic acids and trifluoroborates

The preparation of tricyclic scaffolds such as dibenzofurans and fluorenones has received significant attention, owing to their presence in natural products and compounds of medicinal interest. One of the earliest means for access to such molecules involves the radical-based method known as the Pschorr cyclization, which dates back to 1896. This powerful transformation relies upon an arenediazonium salt as a radical precursor, and typically employs superstoichiometric iron or copper salts for radical generation. Figure

3-2 illustrates the invention and scope of a “borono-Pschorr” reaction that obviates the need for potentially dangerous arenediazonium salt preparation. Additionally, this method complements Pd-mediated processes recently described by Harvey, Fagnou, and

Glorius. A variety of functional groups are tolerated, such as nitriles, esters, Lewis-basic heteroatoms, and products are obtained in synthetically useful yields. Concomitant benzylic oxidation is observed, and this can be exploited to increase step economy. For instance, fluorenone (7) was obtained from a diarylmethane precursor under the standard conditions.

AgNO3 (0.2 equiv) BF3K K2S2O8 (3 equiv)

X PhCF3−H2O (1:1) 60 °C, 60 min X

X = O, CH2, CHOH, C(O) X = O, C(O)

CF3 F CO2Me o OMe p

O O O O O 1 2 3 4 5a/5bc 73% (65%)b 69% 57% 65% 41% (5:1 p:o)

OMe CO2Me CN CF3

CF3 O O O O O 6 7 8 9 10 43% 30%d (41%)e 67% 77% (55%)e 61%

F F F from alkyltrifluoroborate N F N N and N

O O O O EtO2C 11 12 13 64% 14 15 71% b,e 60% 65% (50%) (1.4:1 13:14)

Figure 3-2. Development of a “borono-Pschorr” reaction

The boronic acid is installed onto the substrate through lithium-halogen exchange followed by borate trap, or by transition metal-mediated borylation. For a substrate bearing a pinacol boronate ester, conversion to the trifluoroborate salt is accomplished by treatment with aqueous KHF2 followed by repeated evaporation with MeOH−H2O (1:1 v/v) to azeotropically remove pinacol.

Given the durability of pinacol boronate esters under a variety of conditions, we secured (as proof-of-principle) three examples of fluorenone synthesis utilizing a bifunctional reagent, 2-formylphenylboronic acid pinacol ester (Figure 3-3). Direct addition of an aryl Grignard, followed by treatment with aqueous KHF2, provided radical

+ 2− cyclization precursors, which, upon exposure to Ag /S2O8 , furnished the corresponding fluorenones. Such a strategy can prove useful in situations where a masked radical

67 precursor is carried through subsequent steps and then unmasked for the radical cyclization step.

Bpin R THF, −40 °C; aq KHF ; CHO 2 + + 2- Ag /S2O8 R O XMg R = H, CN, F

Figure 3-3. Pinacol boronate ester as latent radical precursor

Vicinal olefin difunctionalization, in which multiple carbon−carbon bonds are forged in concert, is a valuable tactic for complexity generation in synthesis. Such a process is exemplified by the results in Figure 3-4. In this tandem radical cyclization/benzoquinone trap protocol, 5-exo, 6-exo, and 6-endo radical cyclizations are combined with an intermolecular radical capture. The trend in isolated yields (for products 16 through 23) suggests that increasing degrees of olefin substitution attenuate the efficiency of the tandem process. Importantly, this protocol stands in contradistinction to the more classic tributyltin hydride-based radical cyclization and the palladium-catalyzed Heck-type process, both of which were found to be incompatible with the use of benzoquinone in this context.

O BLn 1,4-benzoquinone AgNO3 (0.2 equiv) X K2S2O8 (3 equiv) O PhCF3−H2O (1:1) BL = B(OH) or BF K 60 C, 60 min n 2 3 ° X X = O, CH2

O O O

O O and O O 16/17a 18/19b 71% (5:1)d 61% (1:1)e O O O Me O Me O O O O O 20b 21b 22a 76% (60%)c 64% 54% O

Me O Me isolated from control O experiment in absence of O 1,4-benzoquinone O 24a 23b ~20% 30%

Figure 3-4. Tandem radical cyclization/BQ trap

Incidentally, we have isolated benzofuranone (24) in a control experiment (in the absence of 1,4-benzoquinone). In lieu of a competent radical trapping agent, oxygen from the air intercepts the radical intermediate. This, accompanied by benzylic C−H oxidation of the substrate, leads to oxidative carbon−carbon bond cleavage.

While the results described in this section demonstrate a capacity for performing open-flask radical cyclizations, it is important to note its limitations. Although high

2− chemoselectivity has been observed under these biphasic conditions, persulfate (S2O8 ) is a strong oxidizing agent and therefore motifs such as benzylic C−H bonds and vicinal diols may not be compatible. Radical ring closure and intermolecular radicophile capture must outpace the capture of oxygen (O2) or H-abstraction (either from an intramolecular

69 donor or from solvent). Such considerations must be taken into account when planning a

+ 2− reaction using the Ag /S2O8 system.

The mechanism by which an organoboronic acid gives rise to a reactive radical

+ 2− species upon exposure to Ag /S2O8 will be the subject of future work. The working

+ 2− − hypothesis involves 1) Ag -mediated decomposition of S2O8 to give SO4 , 2) attack at

− boron by SO4 , and 3) carbon−boron bond homolysis.

We emphasize that this open-air radical chemistry does not involve high temperatures and avoids the use of toxic and/or expensive metals. Additionally, this method circumvents recourse to potentially hazardous entities such as arenediazonium salts, and can be safely conducted on gram-scale. With the emergence of non-cryogenic and C−H borylation protocols to complement classic methods for preparing organoboron species, we anticipate increased use of boronic acids and trifluoroborates as radical precursors in synthesis.

A notable extension of vicinal difunctionalization using aryl boronic acids deserves brief mention. In a manner akin to that described by Heinrich, oxyarylation of acrylonitrile was accomplished (Figure 3-5). Importantly, this differs from Heinrich’s work in one significant aspect: the aryl radical donor used here is a boronic acid (instead of a diazonium salt). Further development of this method could provide a safe, effective means for the preparation of arylacetaldehydes (e.g., 27).

B(OH)2 TEMPO OTMP Zn OAc MeO aq HCl CHO + 2- + Ag /S2O8 CN AcOH, Ac2O CN MeO MeO THF MeO 50% 25 70% 26 27 CN

+ 2− Figure 3-5. Oxyarylation of acrylonitrile using Ag /S2O8

Application of boron-derived radical chemistry to meroterpenoid synthesis

Quinone/hydroquinone sesquiterpenes are chiefly found in marine organisms, and have attracted attention due to their structural diversity and biological activity.10, 78 These natural products consist of a drimane or rearranged drimane sesquiterpene attached to a quinone or hydroquinone moiety. In many instances, both antipodes are found in nature.79 Fenical reported the isolation of isozonarol in 1973 from the algae Dictyopteris undulata;80 Perez-Garcia reported the isolation of ent-isozonarol in 2005 from the sponge genus Dysidea.81 Similarly, chromazonarol,82 ent-chromazonarol, yahazunol,8b, 81 ent- yahazunol, isohyatellaquinone, and ent-isohyatellaquinone79 have been isolated.

Many researchers have been engaged in the total synthesis of these meroterpenoids. Seifert prepared zonarone and isozonarone from β-ionone.8b, c Mori prepared zonarol from geranylacetone.8d Others have utilized Weiland−Miescher ketone.

See also Katoh/Terashima (1,2-addition of protected hydroquinone: popolohuanone E83).

It is also worth noting that radical-based methods have previously been employed for alkylation of quinones. The most pertinent examples will be summarized here. In

1948, Fieser employed a Hooker oxidation (H2O2) in order to generate alkyl radicals in the presence of naphthoquinones.84 In the 1980s, Hudson employed Minisci conditions

+ 2− 85 (Ag /S2O8 ) in order to functionalize naphthoquinones. Similar conditions were cited in a 1990 Bayer patent86 for the alkylation of naphthoquinones. In 1999, Theodorakis disclosed a convergent strategy for terpene-quinone synthesis via Barton radical decarboxylation.87 Finally, in 2011, a practical method for arylation and alkylation of quinones using boronic acids and trifluoroborates was reported by Baran and co- workers.88

It is important to emphasize that, in the method of Theodorakis, the reductive conditions produce “thiolated” hydroquinones, which require two subsequent synthetic operations in order to arrive at the terpene-quinone final targets (Figure 3-6). Thus, a direct coupling process that requires neither protecting group manipulations nor redox corrections is desirable. In that vein, the recently disclosed method for quinone functionalization using boronic acids88 fit this bill.

N O O

CO2H S a O b O S 61% 70% N 28 29 30 (Theodorakis) c 99%

O HO

BF3K e O d OH

13% 90%

33 32 31 Reagents and conditions: (a) thiopyridine N-oxide, DCC, 61%; (b) 1,4-benzoquinone, CH2Cl2, hν, 0 °C, 70%; (c) Raney-Ni, 99%; (d) MnO2, 90%; (e) 1,4-benzoquinone, AgNO3, K2S2O8, PhCF3−H2O, 60 °C, 1 h, 13%;

Figure 3-6. Application of “terpenyl” trifluoroborate for radical coupling

We ultimately opted for a semi-synthetic approach, beginning with (+)- sclareolide. As will be described in subsequent pages, this approach allowed us to quickly establish proof-of-principle. It should be noted that it is possible to prepare either antipode of sclareolide (or allylic alcohol) via wholly synthetic means, according to established procedures.89

Now, given the precedent for alkylation of quinones using aliphatic carboxylic

+ 2− acids under Minisci conditions (Ag /S2O8 ), the obvious question arises. Might a

72 terpenyl carboxylic acid give rise to a radical species for direct capture by 1,4- benzoquinone? Hudson obtained yields of no better than 20% (for his purposes as a medicinal chemist, this was acceptable). Employing his protocol in the present context

(Figure 3-7) failed to produce better than trace quantities of 36. Thus, it appears, at least in this context, that the organotrifluoroborates serve as better radical precursors than the corresponding carboxylic acids. Furthermore, as will be described later in this chapter, organoboronic acids have been found to perform even better for Minisci-type coupling with benzoquinones.

O O CO2H O a OH b O OH < 2% 34 35 36 Reagents and conditions: (a) 3 M KOH, MeOH, reflux; (b) 1,4-benzoquinone, AgNO3, K2S2O8, PhCF3−H2O, 60 °C, 1 h, < 2%;

Figure 3-7. Examination of classic Minisci reaction

Our first route relied upon bicyclic enone 37,90 which we prepared from β-ionone.

Copper-mediated 1,4-borylation,91 followed by Wittig methylenation, furnished pinacol

+ 2− boronate ester 38. The presence of an alkene during the Ag /S2O8 step produced untoward byproducts on account of the reactive homoallylic radical species. [Other possible side products include T-T (T = terpene) homodimer, T-OOH (capture of O2), elimination to alkene, and over-oxidation of T-Q (e.g. at benzylic position), dehydration

(applicable to our second route)] To ameliorate this complication, the alkene 38 was subjected to Pt-catalyzed hydrogenation,92 then converted to the trifluoroborate 33.

Through this route, dihydrozonarone 32 was prepared (Figure 3-8). We surmised that if appreciable quantities of 32 could be prepared, it might be possible to access analogs

1 through oxidation chemistry (e.g. TFDO, SeO2, O2). It was found that degassing the 73 reaction mixture prior to the addition of K2S2O8 precluded formation of peroxyl species, and led to a 13% isolated yield of the terpene-quinone conjugate 32. Both CuCl2 and

Dess−Martin periodinane have recently been shown to produce reactive radical species from alkyl trifluoroborates;93 however, we were unable to use these oxidants to obtain any detectable amount of terpene-quinone adduct.

Bpin BF3K Q

O a, b c, d e

13% 37 38 33 32

(a) B2pin2, CuCl, KOAc, DMF; (b) Ph3PCH2, PhMe; (c) H2, Pt/C, MeOH; (d) KHF2, MeOH−H2O; + 2- (e) 1,4-benzoquinone, Ag /S2O8 , PhCF3−H2O, 60 °C.

Figure 3-8. Enone route to quinone-sesquiterpenoid target

Our second route relied upon allylic alcohol 41 (itself a fungal metabolite94).

Both (−)-sclareol95 and (+)-sclareolide96 (34) have been utilized in semisynthetic campaigns for a number of meroterpenoids. We opted for (+)-sclareolide, given its cost advantage ($50 versus $6 per gram). It should be noted that 41 has been previously prepared from (−)-sclareol; the alternative route described herein is more efficient (fewer steps) and begins with less expensive (+)-sclareolide.

Cyclic boronic acid 42 (Figure 3-9) was prepared in five steps from (+)- sclareolide (34), a common feedstock in the perfume industry that can be purchased on kilogram scale. Exposure to DIBAL-H afforded lactol 39, according to the established procedure.96a, b Hypoiodite-mediated carbon−carbon bond cleavage97 under Suarez

98 conditions (I2, PIDA, hν) provided iodoformate 40. A two-step process for

99 dehydroiodination (AgF, pyridine ) and formate ester hydrolysis (K2CO3, MeOH) was found to provide the allylic alcohol 41 reliably and in good overall yield. Methods involving DBU, KOtBu, or K2CO3 (directly) all gave inferior results. Hydroboration of

74 allylic alcohol 41 using BH3THF provided 42 (and its diastereomer 43). In contrast to a report by Alvarez-Manzaneda,95c our observed diastereoselectivity for this hydroboration was only ~3:1. As such, chromatographic separation of diastereomers 42 and 43 was warranted. Although it is known that primary alkyl boronic acids undergo atmospheric oxidation,100 we found the cyclic boronic acids (42 and 43) to be sufficiently stable for handling and storage. Crystals were grown, and X-ray crystal structures were obtained, for both 42 and 43. Furthermore, we were delighted to find that boronic acid 42 performs better (than its trifluoroborate counterpart) in the radical coupling with 1,4-benzoquinone.

Notably, the synthetic sequence to prepare allylic alcohol 41 is readily scalable and requires no chromatography. The iodoformate 40 was quickly triturated with cold methanol, and the allylic alcohol 41 can be crystallized from hexanes95b (although 1H and

13C NMR routinely certified that the material was already sufficiently pure after aqueous work-up). Whereas Vlad95b accomplished a four-step synthesis of allylic alcohol 41 from

(−)-sclareol in an overall yield of 45%, Barrero95a in 54%, and Alvarez-Manzaneda95c in

64%, we have accomplished a four-step synthesis of allylic alcohol 41 from (+)- sclareolide (34) in an overall yield of 82% (50 mmol (+)-sclareolide afforded 41 mmol allylic alcohol).

Figure 3-9. Enantiospecific route to ent-chromazonarol

Exposure of 42 and 1,4-benzoquinone to silver nitrate and potassium persulfate in

PhCF3−H2O provided ent-chromazonarol (44) in 53% yield. Additionally, “hydroxy-ent- chromazonarol” (arising from concomitant benzylic oxidation) was isolated in ~15% yield.

The initial meroterpenoid 44, ent-chromazonarol, was readily transformed into a variety of naturally occurring metabolites. First, ent-yahazunol81 49 was obtained by treatment of 44 with SiO2-supported NaIO4 (furnishing ent-yahazunone 47) followed by

H2/Pd/C (or Na2S2O3 or Na2S2O4) in THF−H2O. Second, ent-zonarone 48 was obtained

96a by treatment of 47 with SOCl2 in pyridine. Third, ent-isozonarone 46 was obtained by dehydration of 47 under Mitsunobu conditions (or Martin’s sulfurane or Burgess reagent).95c Alkene position-isomerization (exo- to endocyclic) is possible with pTsOH in toluene at 50 °C.96a

Treatment of 44 with BCl3 furnished a ~6:1 mixture of isozonarol and zonarol.

Quinone reduction of ent-isozonarone 46 using Na2S2O3 (or Na2S2O4) in THF−H2O produced ent-isozonarol 45. The latter compound is a naturally occurring metabolite that

78c is cytotoxic (IC50 = 0.16 µM) in a mouse lymphoma cell line (P-388).

Further manipulations will be investigated (Figure 3-10). Exposure of ent- isozonarol 45 to acid furnishes ent-chromazonarol 44 as well as 8-epi-chromazonarol 56.

1 96b Alternatively, exposure of 44 to singlet oxygen ( O2) may provoke an ene reaction that

95c may enable access to ent-isochromazonarol 51. Other conditions (e.g. PCC in CH2Cl2 ) may favor benzylic oxidation of 44. Indeed, it is already known that benzylic oxidation

+ 2− is possible with Ag /S2O8 .

Importantly, all of the endpoints shown in Figure 3-10 are indeed naturally occurring substances. As is the case with other classes of natural products, both enantiomers of many terpene-quinone hybrids are found in nature.

HO HO HO

OH MeSO H OH OH 3 OH ??

avarol (52) ent-yahazunol (49) ent-zonarol (50)

Na2S2O3 Na2S2O3

O O O

O Ph3P O SOCl2 O DEAD OH pyridine

ent-isozonarone (46) ent-yahazunone (47) ent-zonarone (48)

Na2S2O3 OH OH HO

+ OH H O O

BCl3

ent-isozonarol (45) ent-chromazonarol (44) ent-isochromazonarol (51) 8-epi-chromazonarol (56)

Figure 3-10. Divergent access via ent-chromazonarol

In order to place this convergent strategy in context, it is useful to consider the work of Barrero, as well as the work of Yamamoto. In 1999, Barrero and co-workers101 disclosed a synthesis of ent-chromazonarol 44 from (−)-sclareol and hydroquinone. Bis- silyl protected bromohydroquinone and the aldehyde are brought together, after which deprotection steps are carried out in order to arrive at the final target. Also in 1999,

Yamamoto and co-workers61, 102 disclosed a synthesis of chromazonarol via enantioselective polyene cyclization involving Lewis acid-assisted chiral Bronsted acid catalysis. While the step-count and overall yield are superior to our approach (4 versus 6;

40% versus 31%), the modest 44% ee leaves much to be desired. Furthermore, the process described herein is scalable and requires no special chiral ligands.

The strategy we have developed is concise, scalable, and avoids recourse to both protecting group and redox manipulations. Several grams of ent-chromazonarol 44 have already been prepared by this method, and our lab continues to investigate the pluripotency of this strategic “hub.” Nine quinone-sesquiterpenoid natural products have already been attained, and many more are within reach.

One particularly intriguing target, avarone (53), could be generated by exposure of ent-yahazunone (47) to an appropriate protic or Lewis acid (Figure 3-11).

Biosynthetically, ionization initiates a “friedo” rearrangement, which is terminated by proton elimination. In fact, avarone (53) and avarol (52) represented the first “friedo” structures identified in sesquiterpenoid natural products.103 Additionally, ionization of ent-yahazunol (49) or a suitable derivative thereof may permit access to pelorol (54) via intramolecular Friedel−Crafts alkylation.96c

O O O

O O O OH

H H H ent-yahazunone (47) "friedo" avarone (53) rearrangement H2 Pd/C

HO HO HO OH

OH OH OH CO Me SnCl4 2

ent-yahazunol (49) pelorol (54)

Figure 3-11. Avarone via “friedo” rearrangement of ent-yahazunone

Besides the plethora of manipulations we envision for “pluripotent” ent- chromazonarol (44), we have already demonstrated another attractive feature of this approach to meroterpenoid synthesis: “borono-sclareolide” 42 can be united with other

79 quinones beyond the parent 1,4-benzoquinone. Other natural (and non-natural) targets can be prepared due to the convenient, modular nature of this approach.

OH R B quinone O O + 2− Ag /S2O8

42 55 O O O O OMe OMe

MeO O O O O

Figure 3-12. Other quinones joined with terpene

Finally, pursuit of the tetraketide-sesquiterpenoid metabolites (e.g. simplicissin) will continue, with the examination of orsellinate surrogates that can participate in the radical coupling process illustrated in this chapter. Ideally, one would prefer to generate a terpenyl radical in the presence of the orsellinate moiety, and the two would unite.

However, it has already been determined that exposure of the orsellinate to a variety of

+ 2− oxidation conditions (including Ag /S2O8 ) results in untoward degradation via quinone methide. There is clearly a significant barrier to entry due to the all-carbon quaternary center. Thus, orsellinate surrogates, such as those depicted in Figure 3-13, may prove useful in cracking the code presented by that meroterpenoid family.

O O Me OMe Me OMe

MeO2C Me Me Me O O 71 72

Figure 3-13. Quinones as orsellinate surrogates

Conclusions

Through the research effort described above, successful implementation of a radical-based method for meroterpenoid synthesis has been realized. Exploiting the

+ 2− behavior of organoboronic acids upon exposure to the Ag /S2O8 oxidant system, direct union of prefabricated “terpenyl” radicals with competent radicophiles such as 1,4- benzoquinone is possible. A six-step synthesis of ent-chromazonarol from (+)- sclareolide was accomplished. Importantly, this synthesis is scalable, allowing one to prepare multi-gram quantities of ent-chromazonarol within three days. The value of this six-step synthesis is significantly enhanced by the fact that ent-chromazonarol serves as a

“pluripotent” intermediate from which a variety of natural and unnatural meroterpenoid targets can be attained.

It is anticipated that extension of this tactic beyond “borono-sclareolide” as radical precursor and 1,4-benzoquinone as radicophile will reap a harvest of naturally occurring and novel scaffolds readily accessible by synthesis. Several future directions have already been mentioned above (e.g. Figures 3-12 and 3-13). Additionally, meroditerpenoids such as fascioquinols could be made via the method described herein.

Work described in Chapter 3 would not have been possible without the contributions of Rune Risgaard, Dr. Darryl Dixon, and Paul Hernandez. Rune Risgaard is responsible for preparation of a majority of substrates for the borono-Pschorr reaction

(Figure 3-2). Dr. Dixon prepared bifunctional substrates for fluorenone synthesis (Figure

3-3), and carried out several gram-scale reactions. Paul Hernandez aided us by preparing several substrates for tandem radical cyclization with quinone trap (Figure 3-4).

Experimental

General Experimental. All reactions were carried out under an inert nitrogen atmosphere with anhydrous solvents under anhydrous conditions, unless otherwise stated.

Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Dry dichloromethane (CH2Cl2), diethyl ether

(Et2O), methanol (MeOH), and tetrahydrofuran (THF) were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials, unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on 0.25 mm E. Merck silica plates (60F-254), using ultra violet (UV) light as visualizing agent and potassium permanganate (KMnO4) and heat, p-anisaldehyde in ethanol/aqueous H2SO4/CH3CO2H and heat, Seebach’s stain and heat, or dinitrophenylhydrazine (DNPH) and heat as developing agents. Preparative thin layer chromatography (PTLC) separations were carried out on 0.25 or 0.5 mm E. Merck silica plates (60F-254). Flash silica gel chromatography was performed using E. Merck silica gel (60, particle size 0.043−0.063 mm). Nuclear magnetic resonance (NMR) spectra were recorded on Bruker DRX-600,

DRX-500, AV-400, and Varian INOVA-399 instruments and calibrated using residual

1 undeuterated solvent as an internal reference (CHCl3 @ 7.26 ppm for H NMR, 77.16 ppm for 13C NMR). The following abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. High-resolution mass spectra (HRMS) were recorded on an Agilent LC/MSD

TOF mass spectrometer by electrospray ionization time of flight (ESI-TOF) reflectron experiments. Infra red (IR) spectra were recorded on a Perkin Elmer Spectrum BX FTIR spectrometer. Melting points were recorded on a Fisher-Johns 12-144 melting point apparatus and are uncorrected.

Me Me

S Me

Me Me

Isopropyl(((1S,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1- yl)methyl)sulfane (80).104 A suspension of sodium hydride (2.00 mmol, 60% dispersion in mineral oil) in anhydrous DMSO (2.4 mL) and anhydrous THF (2.4 mL) at room temperature was treated (dropwise!) with 2-propanethiol (2.10 mmol). This mixture was stirred under an argon balloon until gas evolution ceased. Meanwhile, a separate solution of albicanyl mesylate (79)105 (2.00 mmol) in anhydrous DMSO (2.2 mL) was prepared.

The resulting pale yellow solution was treated (dropwise!) with the homogeneous mixture of sodium 2-propanethiolate in DMSO/THF and stirred at room temperature for

7 h. The reaction was then diluted with Et2O, washed with saturated aqueous NaHCO3,

H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (19:1 à 2:1 hexanes/Et2O) afforded the title compound (437 mg,

78%) as a colorless oil. Rf = 0.25 (100% hexanes); IR (neat) νmax 2925, 1644, 1459, 1442,

-1 1 1382, 1365, 886 cm ; H NMR (400 MHz, CDCl3) δ 4.91 (bs, 1 H), 4.59 (bs, 1 H), 2.90

– 2.83 (m, 1 H), 2.68 – 2.58 (m, 2 H), 2.43 – 2.38 (m, 1 H), 2.08 – 2.00 (m, 1 H), 1.96 –

1.93 (m, 1 H), 1.79 – 1.69 (m, 2 H), 1.63 – 1.48 (m, 2 H), 1.43 – 1.38 (m, 1 H), 1.36 –

1.30 (m, 1 H), 1.27 (d, J = 5.5 Hz, 3 H), 1.25 (d, J = 6.2 Hz, 3 H), 1.24 − 1.10 (m, 3 H),

13 0.88 (s, 3 H), 0.81 (s, 3 H), 0.71 (s, 3 H); C NMR (150 MHz, CDCl3) δ 147.7, 107.8,

58.5, 55.3, 42.1, 40.2, 39.3, 37.9, 36.6, 33.8, 33.7, 26.5, 24.2, 23.7, 23.6, 21.9, 19.5, 14.6;

+ + HRMS (ESI-TOF) calcd. for C18H32SH [M + H ] 281.2297, found 281.2308.

Me Me

S+ O- Me

Me Me

(4aS,5S)-5-((Isopropylsulfinyl)methyl)-1,1,4a-trimethyl-6- methylenedecahydronaphthalene (81). In an attempt to effect a [2,3]-sigmatropic rearrangement via an intermediate oxysulfonium ylide species, a mixture of albicanyl isopropyl sulfide 80 (0.16 mmol) and phenol 14 (0.48 mmol, 3.0 equiv) in anhydrous

CH2Cl2 (0.5 mL) at −40 °C (CH3CN/CO2(s)) was treated with sulfuryl chloride (0.184 mmol, 1.15 equiv). The reaction mixture was stirred for 15 min at −40 °C and then treated (dropwise!) with a solution of Et3N (0.80 mmol, 5.0 equiv) in anhydrous CH2Cl2

(0.1 mL). The reaction was warmed to room temperature, diluted with CH2Cl2, washed with 5% aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo.

Purification by silica flash chromatography (100% CH2Cl2 à 15:1 CH2Cl2/acetone) afforded the title compound (40 mg, 84%) as a white solid; m.p. 56−58 °C; Rf = 0.51

(15:1 CH2Cl2/acetone); IR (neat) νmax 2928, 1645, 1460, 1442, 1387, 1365, 1048, 1038,

-1 1 1017, 885 cm ; H NMR (400 MHz, CDCl3) δ 4.94 (bs, 1 H, major diastereomer), 4.91

(bs, 1 H, minor diastereomer), 4.79 (bs, 1 H, major diastereomer), 4.41 (bs, 1 H, minor diastereomer), 2.94 – 2.90 (m, 1 H), 2.80 – 2.70 (m, 1 H), 2.69 – 2.61 (m, 1 H), 2.44 –

2.35 (m, 1 H), 2.15 – 2.05 (m, 1 H), 2.03 – 1.95 (m, 1 H), 1.78 – 1.71 (m, 1 H), 1.68 –

1.61 (m, 1 H), 1.58 – 1.47 (m, 1 H), 1.42 – 1.34 (m, 1 H), 1.31 – 1.26 (m, 6 H), 1.23 –

1.11 (m, 1 H), 0.87 (s, 3 H), 0.80 (s, 3 H), 0.73 (s, 3 H, major diastereomer), 0.72 (s, 3 H,

13 minor diastereomer); C NMR (150 MHz, CDCl3) δ 147.3, 147.1, 108.8, 107.9, 55.4,

55.0, 51.4, 51.2, 49.5, 49.0, 47.1, 45.8, 41.9, 41.9, 40.2, 39.6, 39.4, 38.9, 37.8, 37.6, 33.7,

33.6, 33.6, 24.1, 21.8, 21.7, 19.3, 19.3, 17.1, 16.1, 15.2, 14.5, 13.0; HRMS (ESI-TOF)

+ + calcd. for C18H32OSH [M + H ] 297.2247, found 297.2251.

OH OHC Me

Me OH CO2Me

Methyl 3-formyl-4,6-dihydroxy-2,5-dimethylbenzoate106 (S1). An oven-dried 500-mL round bottom flask was charged with a spin bar and TFA (150 mL), then cooled to 0 °C

(ice bath). Methyl atratate 10 (10.0 g, 51.0 mmol, 1.0 equiv, Sigma-Aldrich™, $211/kg) and HMTA (8.57 g, 61.2 mmol, 1.2 equiv) were added, and the resulting suspension was vigorously stirred at reflux (oil bath 90 °C) for 16 h. The TFA was removed in vacuo, and the amber residue was taken up in H2O (300 mL), then stirred at 60 °C for 6 h. The resulting orange suspension was filtered. The pale orange solid was washed with H2O

(20 mL) and then dried in vacuo. Recrystallization from hexanes afforded the title compound (9.4 g, 82%) as a white solid; m.p. 110−111 °C; Rf = 0.33 (10:1 hexanes/EtOAc, positive for DNPH stain); IR (neat) νmax 2958, 1636, 1607, 1421, 1305,

-1 1 1211, 1137, 807 cm ; H NMR (600 MHz, CDCl3) δ 13.12 (s, 1 H), 12.16 (s, 1 H), 10.27

13 (s, 1 H), 3.98 (s, 3 H), 2.76 (s, 3 H), 2.09 (s, 3 H); C NMR (150 MHz, CDCl3) δ 194.2,

172.0, 166.6, 166.0, 146.4, 113.6, 111.0, 106.9, 52.7, 16.5, 7.3; HRMS (ESI-TOF) calcd.

+ + for C11H12O5H [M + H ] 225.0757, found 225.0759.

OH Me Me

Me OH CO2Me

Methyl 2,4-dihydroxy-3,5,6-trimethylbenzoate106-107 (14). An oven-dried 250-mL round bottom flask was charged with a spin bar, aldehyde S1 (7.4 g, 33 mmol, 1.0 equiv),

Et3SiH (32 mL, 198 mmol, 6.0 equiv), and TFA (25 mL). The reaction mixture was vigorously stirred at room temperature under N2-balloon for 16 h. The reaction contents were poured into CH2Cl2−H2O (1:1 v/v, 800 mL), and the layers were separated. The aqueous layer was extracted with CH2Cl2 (200 mL). The organic layers were combined, washed with brine (2 × 200 mL), dried over MgSO4, filtered, and concentrated in vacuo.

The resulting off-white solid was triturated with hexanes. Purification by silica flash chromatography (10:1 à 4:1 hexanes/EtOAc) afforded the title compound (6.9 g, 99%) as a white solid; m.p. 92−93 °C; Rf = 0.36 (10:1 hexanes/EtOAc, negative for DNPH

-1 1 stain); IR (neat) νmax 2954, 1636, 1423, 1322, 1210, 1120, 1005, 800 cm ; H NMR (400

MHz, CDCl3) δ 11.45 (s, 1 H), 5.12 (s, 1 H), 3.93 (s, 3 H), 2.43 (s, 3 H), 2.14 (s, 3 H),

13 2.14 (s, 3 H); C NMR (150 MHz, CDCl3) δ 172.9, 159.7, 156.8, 137.7, 114.9, 107.4,

+ + 106.3, 52.0, 19.0, 12.0, 8.2; HRMS (ESI-TOF) calcd. for C11H14O4H [M + H ]

211.0965, found 211.0961.

O O Me Me

Me OH CO2Me

Methyl 4-(((allyloxy)carbonyl)oxy)-2-hydroxy-3,5,6-trimethylbenzoate (S2). A solution of phenol 14 (500 mg, 2.38 mmol, 1.0 equiv) in anhydrous THF (25 mL) at 0 °C

(ice bath) was treated with Et3N (0.33 mL, 2.38 mmol, 1.0 equiv), allyl chloroformate

(0.27 mL, 2.50 mmol, 1.05 equiv), and 4-DMAP (15 mg, 0.12 mmol, 0.05 equiv).

Immediately, the reaction became a thick white suspension. The ice bath was removed, and the reaction was allowed to warm to room temperature. After 5 h, the reaction contents were filtered through a pad of Celite. The solids were washed with THF, and the filtrate was concentrated in vacuo. Purification by silica flash chromatography (19:1 hexanes/EtOAc) afforded the title compound (410 mg, 59%) as a white solid; m.p. 64−66

°C; Rf = 0.25 (10:1 hexanes/EtOAc); IR (neat) νmax 2956, 1754, 1659, 1238, 1202, 1178,

-1 1 934, 803 cm ; H NMR (600 MHz, CDCl3) δ 11.04 (s, 1 H), 6.03 – 5.97 (m, 1 H), 5.44

(d, J = 17.2 Hz, 1 H), 5.34 (d, J = 10.4 Hz, 1 H), 4.75 (d, J = 5.7 Hz, 2 H), 3.96 (s, 3 H),

13 2.43 (s, 3 H), 2.09 (s, 3 H), 2.08 (s, 3 H); C NMR (150 MHz, CDCl3) δ 172.3, 158.9,

152.5, 152.0, 137.5, 131.2, 120.9, 119.7, 116.5, 111.7, 69.4, 52.4, 19.0, 12.7, 9.3; HRMS

+ + (ESI-TOF) calcd. for C15H18O6H [M + H ] 295.1176, found 295.1188.

O Me Me

Me OH CO2Me

Methyl 4-(allyloxy)-2-hydroxy-3,5,6-trimethylbenzoate (92). A solution of the known phenol 14 (500 mg, 2.38 mmol, 1.0 equiv) in anhydrous acetone (50 mL) at room 87 temperature was treated with allyl bromide (0.22 mL, 2.50 mmol, 1.05 equiv) and powdered, oven-dried K2CO3 (937 mg, 6.78 mmol, 2.85 equiv). The reaction mixture was stirred vigorously at reflux for 4 h. After cooling to room temperature, the reaction contents were filtered, and the filtrate was concentrated in vacuo. Purification by silica flash chromatography (25:1 hexanes/EtOAc) afforded the title compound (483 mg, 81%) as a white solid; m.p. 27−28 °C; Rf = 0.44 (10:1 hexanes/EtOAc); IR (neat) νmax 2952,

-1 1 1648, 1409, 1318, 1206, 1110, 980, 933, 805 cm ; H NMR (500 MHz, CDCl3) δ 11.05

(s, 1 H), 6.14 – 6.06 (m, 1 H), 5.43 (dq, J = 17.1, 1.6 Hz, 1 H), 5.28 (dq, J = 10.4, 1.3 Hz,

1 H), 4.26 (dt, J = 5.6, 1.5 Hz, 2 H), 3.94 (s, 3 H), 2.42 (s, 3 H), 2.17 (s, 3 H), 2.16 (s, 3

13 H); C NMR (125 MHz, CDCl3) δ 172.4, 160.2, 159.3, 137.3, 133.5, 122.0, 117.5,

+ 116.5, 109.5, 73.5, 52.0, 18.9, 12.8, 9.4; HRMS (ESI-TOF) calcd. for C14H18O4H [M +

H+] 251.1278, found 251.1284.

O Me Me

Me OMe CO2Me

Methyl 4-(allyloxy)-2-methoxy-3,5,6-trimethylbenzoate (99). A solution of the known phenol 12 (510 mg, 2.27 mmol, 1.0 equiv) in anhydrous acetone (50 mL) at room temperature was treated with allyl bromide (0.30 mL, 3.41 mmol, 1.5 equiv) and powdered, oven-dried K2CO3 (629 mg, 4.55 mmol, 2.0 equiv). The reaction mixture was stirred vigorously at reflux for 3 h. After cooling to room temperature, the reaction contents were filtered, and the filtrate was concentrated in vacuo. Purification by silica flash chromatography (10:1 à 4:1 hexanes/EtOAc) afforded the title compound (533 mg,

89%) as a colorless oil; Rf = 0.40 (4:1 hexanes/EtOAc); IR (neat) νmax 2949, 1729, 1325,

-1 1 1283, 1196, 1175, 1102, 988, 976, 735 cm ; H NMR (500 MHz, CDCl3) δ 6.13 – 6.06

(m, 1 H), 5.43 (dq, J = 17.2, 1.6 Hz, 1 H), 5.27 (dq, J = 10.4, 1.3 Hz, 1 H), 4.24 (dt, J =

5.5, 1.4 Hz, 1 H), 3.92 (s, 3 H), 3.74 (s, 3 H), 2.20 (s, 3 H), 2.16 (s, 3 H), 2.16 (s, 3 H);

13 C NMR (100 MHz, CDCl3) δ 169.4, 157.3, 153.8, 133.7, 132.5, 126.2, 125.3, 122.1,

+ 117.3, 73.4, 61.7, 52.1, 16.7, 12.5, 9.7; HRMS (ESI-TOF) calcd. for C15H20O4H [M +

H+] 265.1434, found 265.1438.

O Me Me

Me OMe

CO2Me

Methyl 1-allyl-2-methoxy-3,5,6-trimethyl-4-oxocyclohexa-2,5-dienecarboxylate

(100). A microwave vial was charged with a spin bar, allyl aryl ether 99 (200 mg, 0.76 mmol, 1.0 equiv), Yb(OTf)3H2O (236 mg, 0.38 mmol, 0.5 equiv), and 1,2- dichloroethane (2.5 mL). The vial was sealed, and heated in a Biotage Initiator at 100 °C for 2 h. The resulting golden amber solution was cooled to room temperature, diluted with H2O, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (10:1 à 4:1 hexanes/EtOAc) afforded the title compound (119 mg,

60%) as an off-white solid; X-ray (cyclohexane); m.p. 42−44 °C; Rf = 0.28 (4:1

-1 1 hexanes/EtOAc); IR (neat) νmax 2951, 1740, 1665, 1624, 1256, 1211, 1139, 752 cm ; H

NMR (400 MHz, CDCl3) δ 5.24 – 5.14 (m, 1 H), 4.98 (d, J = 16.9 Hz, 1 H), 4.90 (d, J =

10.1 Hz, 1 H), 3.83 (s, 3 H), 3.68 (s, 3 H), 2.94 (dd, J = 14.4, 6.8 Hz, 1 H), 2.79 (dd, J =

14.4, 7.4 Hz, 1 H), 1.93 (s, 3 H), 1.87 (s, 3 H), 1.80 (s, 3 H); 13C NMR (100 MHz,

CDCl3) δ 188.2, 171.2, 167.9, 143.8, 133.1, 131.4, 120.0, 118.6, 61.4, 59.4, 52.8, 37.0,

+ + 15.7, 11.8, 10.0; HRMS (ESI-TOF) calcd. for C15H20O4H [M + H ] 265.1434, found

265.1436.

OH Me Me

Me OMe CO2Me

Methyl 4-hydroxy-2-methoxy-3,5,6-trimethylbenzoate108 (101). A solution of the benzyl aryl ether (1.58 g, 5.02 mmol, 1.0 equiv) in EtOAc (25 mL) at room temperature was treated with 10% Pd/C (79 mg, 5 wt%). The reaction mixture was vigorously stirred at room temperature under H2-balloon for 6 h. The reaction contents were filtered to remove Pd/C, then concentrated in vacuo. Purification by silica flash chromatography

(4:1 hexanes/EtOAc) afforded the title compound (1.07 g, 96%) as a white solid; m.p.

77−78 °C; Rf = 0.30 (4:1 hexanes/EtOAc); IR (neat) νmax 3374, 2942, 1700, 1433, 1294,

-1 1 1211, 1182, 1104, 976, 733 cm ; H NMR (600 MHz, CDCl3) δ 4.96 (bs, 1 H), 3.90 (s, 3

13 H), 3.73 (s, 3 H), 2.16 (s, 3 H), 2.15 (s, 3 H), 2.12 (s, 3 H); C NMR (150 MHz, CDCl3)

δ 169.8, 153.8, 132.5, 121.8, 118.4, 114.2, 62.2, 52.3, 16.9, 11.8, 9.0; HRMS (ESI-TOF)

+ + calcd. for C12H16O4H [M + H ] 225.1121, found 225.1128.

OMe Me Me

Me OH CO2Me

Methyl 2-hydroxy-4-methoxy-3,5,6-trimethylbenzoate108-109 (29). A solution of the known phenol 14 (841 mg, 4.0 mmol, 1.0 equiv) in anhydrous acetone (48 mL) at room

90 temperature was treated with Me2SO4 (0.40 mL, 4.2 mmol, 1.05 equiv) and powdered, oven-dried K2CO3 (1.58 g, 11.4 mmol, 2.85 equiv). The reaction mixture was vigorously stirred at reflux for 5 h, then cooled to room temperature. The reaction was quenched with ice-cold 1 N HCl (150 mL) and extracted with Et2O. The organic layer was washed with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (20:1 à 4:1 hexanes/EtOAc) afforded the title compound

(734 mg, 82%) as a white solid; Rf = 0.40 (10:1 hexanes/EtOAc); IR (neat) νmax 2952,

-1 1 1653, 1318, 1114 cm ; H NMR (500 MHz, CDCl3) δ 11.05 (s, 1 H), 3.94 (s, 3 H), 3.69

13 (s, 3 H), 2.41 (s, 3 H), 2.17 (s, 3 H), 2.16 (s, 3 H); C NMR (125 MHz, CDCl3) δ 172.6,

161.5, 159.6, 137.5, 121.9, 116.5, 109.7, 60.2, 52.2, 19.0, 12.6, 9.2; HRMS (ESI-TOF)

+ + calcd. for C12H16O4H [M + H ] 225.1121, found 225.1128.

OMe Me Me

Me O CO2Me

Methyl 2-(allyloxy)-4-methoxy-3,5,6-trimethylbenzoate (102). A solution of phenol

29 (673 mg, 3.0 mmol, 1.0 equiv) in anhydrous acetone (36 mL) at room temperature was treated with allyl bromide (0.39 mL, 4.5 mmol, 1.5 equiv) and powdered, oven-dried

K2CO3 (1.04 g, 7.5 mmol, 2.5 equiv). The reaction mixture was vigorously stirred at reflux for 5 h, then cooled to room temperature. The reaction contents were filtered, washed with acetone, and the filtrate was concentrated in vacuo. Purification by silica flash chromatography (10:1 à 4:1 hexanes/EtOAc) afforded the title compound (766 mg,

96%) as a colorless oil; Rf = 0.35 (10:1 hexanes/EtOAc); IR (neat) νmax 2949, 1728, 1435,

-1 1 1326, 1282, 1199, 1172, 1104, 995 cm ; H NMR (400 MHz, CDCl3) δ 6.07 – 5.98 (m, 1

H), 5.37 (dq, J = 17.2, 1.6 Hz, 1 H), 5.23 (dq, J = 10.4, 1.3 Hz, 1 H), 4.36 (dt, J = 5.5, 1.5

Hz, 2 H), 3.88 (s, 3 H), 3.67 (s, 3 H), 2.19 (s, 3 H), 2.16 (s, 3 H), 2.16 (s, 3 H); 13C NMR

(100 MHz, CDCl3) δ 172.6, 161.5, 159.6, 137.5, 126.2, 125.3, 121.9, 116.5, 109.7, 73.4,

+ + 60.2, 52.2, 19.0, 12.6, 9.2; HRMS (ESI-TOF) calcd. for C15H20O4H [M + H ] 265.1434, found 265.1436.

OMe Me Me

Me O CO2Me Me

Methallyl ether (110). A solution of phenol 29 (306 mg, 1.36 mmol, 1.0 equiv) in anhydrous acetone (27 mL) was treated with methallyl bromide (0.21 mL, 2.05 mmol, 1.5 equiv) and powdered, oven-dried K2CO3 (377 mg, 2.73 mmol, 2.0 equiv). The reaction mixture was vigorously stirred at reflux for 18 h, then cooled to room temperature. The reaction contents were filtered, washed with acetone, and the filtrate was concentrated in vacuo. Purification by silica flash chromatography (20:1 à 10:1 hexanes/EtOAc) afforded the title compound (375 mg, 99%) as a colorless oil. Rf = 0.35 (10:1 hexanes/EtOAc); IR (neat) νmax 2949, 1730, 1435, 1327, 1283, 1199, 1173, 1106, 997

-1 1 cm ; H NMR (400 MHz, CDCl3) δ 5.09 (s, 1 H), 4.94 (s, 1 H), 4.23 (s, 2 H), 3.87 (s, 3

H), 3.67 (s, 3 H), 2.20 (s, 3 H), 2.16 (s, 3 H), 2.15 (s, 3H), 1.83 (s, 3 H); HRMS (ESI-

+ + TOF) calcd. for C16H22O4H [M + H ] 279.1591, found 279.1595.

OMe Me Me Me

Me O Me CO2Me

Methyl 4-methoxy-2,3,5-trimethyl-6-((3-methylbut-2-en-1-yl)oxy)benzoate (112). A solution of phenol 29 (100 mg, 0.445 mmol, 1.0 equiv) in anhydrous acetone (5.3 mL) was treated with 3,3-dimethylallyl bromide (78 µL, 0.669 mmol, 1.5 equiv) and powdered, oven-dried K2CO3 (154 mg, 1.113 mmol, 2.5 equiv). The reaction mixture was vigorously stirred at reflux for 5 h, then cooled to room temperature. The reaction contents were filtered, washed with acetone, and the filtrate was concentrated in vacuo.

Purification by silica flash chromatography (20:1 à 10:1 hexanes/EtOAc) afforded the title compound (128 mg, 99%) as a pale yellow oil. Rf = 0.35 (10:1 hexanes/EtOAc); IR

-1 1 (neat) νmax 2937, 1728, 1434, 1324, 1282, 1198, 1172, 1102, 995 cm ; H NMR (400

MHz, CDCl3) δ 5.51 – 5.47 (m, 1 H), 4.34 (d, J = 7.1 Hz, 2 H), 3.88 (s, 3 H), 3.66 (s, 3

H), 2.20 (s, 3 H), 2.16 (s, 3 H), 2.15 (s, 3 H), 1.77 (s, 3 H), 1.69 (s, 3 H); 13C NMR (100

MHz, CDCl3) δ 169.6, 158.4, 153.0, 138.0, 132.5, 125.9, 125.7, 122.3, 120.3, 71.3, 60.0,

+ + 52.2, 25.9, 18.0, 16.8, 12.3, 9.7; HRMS (ESI-TOF) calcd. for C17H24O4H [M + H ]

293.1747, found 293.1746.

OMe O Me

Me O CO2Me

1,4-quinone (71). In an attempt to carry out oxidative vinylation of an orsellinate phenol

29, the latter (22.4 mg, 0.1 mmol, 0.1 equiv) was dissolved in CH2Cl2 (3 mL) and treated with vinyltrimethylsilane (145 µL, 1.0 mmol, 10 equiv) and Koser’s reagent (392 mg, 1.0 mmol, 10 equiv) at room temperature. The yellow reaction mixture was stirred for 40 min, then diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (10:1 à 4:1

93 hexanes/EtOAc) afforded the title compound (15 mg, 67%) as a yellow-amber syrup; IR

-1 1 (neat) νmax 1740, 1657, 1228 cm ; H NMR (400 MHz, CDCl3) δ 3.99 (s, 3 H), 3.90 (s, 3

13 H), 2.02 (s, 3 H), 1.94 (s, 3 H); C NMR (100 MHz, CDCl3) δ 184.8, 183.0, 164.9,

155.9, 140.2, 136.9, 128.7, 61.1, 52.8, 13.1, 8.7; HRMS (ESI-TOF) calcd. for

+ + C11H12O5H [M + H ] 225.0757, found 225.0761.

OH Me

Me OH CO2Me

Methyl 3-allyl-4,6-dihydroxy-2,5-dimethylbenzoate (S3). A dry microwave vial with spin bar under argon balloon was charged with Pd(Ph3P)4 (29 mg, 0.025 mmol, 0.05 equiv) and methyl atratate 10 (98 mg, 0.50 mmol, 1.0 equiv). Anhydrous, degassed toluene (1.25 mL) was added, and the yellow-orange reaction mixture was treated successively with allyl alcohol (41 µL, 0.60 mmol, 1.2 equiv) and Et3B (1.0 M in hexanes, 1.2 mL, 1.2 mmol, 2.4 equiv). The reaction mixture gradually returned to a yellow color within about 5 min. After stirring at 75 °C for 2 h, the reaction was cooled to room temperature, diluted with EtOAc (15 mL), washed with 2 M aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (19:1 à 15:1 hexanes/EtOAc) afforded the title compound (73 mg, 62%) as a white solid; m.p. 72−74

°C; Rf = 0.33 (10:1 hexanes/EtOAc); IR (neat) νmax 3487, 2954, 1637, 1572, 1427, 1321,

-1 1 1184, 1096, 1051, 969, 904, 802 cm ; H NMR (400 MHz, CDCl3) δ 11.52 (s, 1 H), 5.99

– 5.90 (m, 1 H), 5.24 (s, 1 H), 5.06 (dt, J = 10.2, 1.6 Hz, 1 H), 4.97 (dt, J = 17.2, 1.5 Hz,

1 H), 3.93 (s, 3 H), 3.43 – 3.42 (m, 2 H), 2.42 (s, 3 H), 2.13 (s, 3 H); 13C NMR (100

MHz, CDCl3) δ 172.8, 160.4, 157.2, 137.9, 135.8, 116.6, 115.6, 108.3, 106.6, 77.4, 52.0,

+ + 30.6, 18.6, 8.2; HRMS (ESI-TOF) calcd. for C13H16O4H [M + H ] 237.1121, found

237.1123.

O Me

Me O CO2Me

Methyl 3,3,5-triallyl-2,5-dimethyl-4,6-dioxocyclohex-1-enecarboxylate (26). Using excess allyl alcohol, with Pd(Ph3P)4, Et3B, and methyl atratate 10, the title compound was isolated as a colorless oil; Rf = 0.35 (10:1 hexanes/EtOAc); IR (neat) νmax 2982, 1750,

-1 1 1713, 1667, 1637, 1434, 1220, 993, 917 cm ; H NMR (400 MHz, CDCl3) δ 5.80 – 5.70

(m, 1 H), 5.53 – 5.41 (m, 1 H), 5.35 – 5.24 (m, 1 H), 5.08 – 4.97 (m, 6 H), 3.73 (s, 3 H),

3.32 – 3.00 (m, 3 H), 2.77 – 2.42 (m, 3 H), 1.92 (s, 3 H), 1.21 (s, 3 H); 13C NMR (150

MHz, CDCl3) δ 206.3, 198.1, 169.5, 146.9, 135.0, 134.3, 131.8, 131.1, 121.0, 119.4,

115.9, 65.7, 60.6, 53.3, 43.3, 39.6, 31.1, 17.6, 16.8; HRMS (ESI-TOF) calcd. for

+ + C19H24O4H [M + H ] 317.1747, found 317.1745.

O Me Me

Me O CO2Me

Methyl 3,5-diallyl-2,3,5-trimethyl-4,6-dioxocyclohex-1-enecarboxylate (27). A dry microwave vial with spin bar under argon balloon was charged with Pd(Ph3P)4 (14.4 mg,

0.0125 mmol, 0.05 equiv) and methyl orsellinate 14 (53 mg, 0.25 mmol, 1.0 equiv).

Anhydrous, degassed toluene (0.63 mL) was added, and the yellow-orange reaction

95 mixture was treated successively with allyl alcohol (21 µL, 0.30 mmol, 1.2 equiv) and

Et3B (1.0 M in hexanes, 0.6 mL, 0.6 mmol, 2.4 equiv). The reaction mixture gradually returned to a yellow color within about 5 min. After stirring at 75 °C for 4 h, the reaction was cooled to room temperature, diluted with EtOAc (10 mL), washed with 2 M aqueous

HCl (5 mL), saturated aqueous NaHCO3 (5 mL), brine (5 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (19:1 à

15:1 hexanes/EtOAc) afforded the title compound (26 mg, 36%, mixture of diastereomers) as a colorless oil; Rf = 0.48 (10:1 hexanes/EtOAc); IR (neat) νmax 2954,

1748, 1712, 1665, 1638, 1222, 921 cm-1; data for major diastereomer: 1H NMR (600

MHz, CDCl3) δ 5.59 – 5.44 (m, 1 H), 5.41 – 5.24 (m, 1 H), 5.05 – 4.95 (m, 4 H), 3.71 (s,

3 H), 3.06 (dd, J = 14.0, 8.1 Hz, 1 H), 2.62 (dd, J = 14.0, 6.9 Hz, 1 H), 2.53 – 2.50 (m, 1

H), 2.43 (dd, J = 13.7, 7.2 Hz, 1 H), 1.91 (s, 3 H), 1.89 (s, 3 H), 1.20 (s, 3 H); 13C NMR

(150 MHz, CDCl3) δ 206.4, 198.7, 169.6, 145.1, 133.2, 132.0, 131.2, 120.7, 119.1, 65.6,

+ 60.6, 53.1, 43.4, 39.7, 17.7, 17.2, 12.7; HRMS (ESI-TOF) calcd. for C17H22O4H [M +

H+] 291.1591, found 291.1590.

Me OH Me Me

Me OH CO2Me

Methyl 2,4-dihydroxy-3,6-dimethyl-5-(3-methylbut-2-en-1-yl)benzoate (11). A dry microwave vial with spin bar under argon balloon was charged with Bi(OTf)3 (9.8 mg,

0.015 mmol, 0.05 equiv), KPF6 (2.8 mg, 0.015 mmol, 0.05 equiv), powdered drierite (45 mg), and 1,4-dioxane (1.0 mL). After stirring at room temperature for 10 min, methyl atratate 10 (118 mg, 0.6 mmol, 2.0 equiv) and 2-methyl-3-buten-2-ol (31 µL, 0.3 mmol,

1.0 equiv) were added. The reaction was stirred at room temperature for 60 min, then diluted with Et2O (5 mL). Silica gel (~3 g) was added, and the reaction contents were filtered, washed with Et2O, and concentrated in vacuo. Purification by silica flash chromatography (12:1 hexanes/EtOAc) afforded the title compound (32 mg, 41%) as colorless needles; Rf = 0.50 (5:1 hexanes/EtOAc); IR (neat) νmax 3485, 2955, 1638, 1570,

-1 1 1428, 1320, 1186, 1097, 1050, 968, 905 cm ; H NMR (500 MHz, CDCl3) δ 11.42 (s, 1

H), 5.48 (s, 1 H), 5.09 – 5.05 (m, 1 H), 3.92 (s, 3 H), 3.36 (d, J = 6.7 Hz, 2 H), 2.44 (s, 3

13 H), 2.12 (s, 3 H), 1.81 (s, 3 H), 1.73 (s, 3 H); C NMR (125 MHz, CDCl3) δ 172.8,

160.4, 157.2, 137.9, 135.8, 116.6, 115.6, 108.3, 106.6, 77.4, 52.0, 30.6, 18.6, 8.2.

Me Me

O Me

Me OH CO2Me

Methyl 7-hydroxy-2,2,5,8-tetramethyl-2H-chromene-6-carboxylate (106). A solution of the ortho-prenylated atratate 11 (150 mg, 0.57 mmol, 1.0 equiv) in benzene (14 mL) at room temperature was treated with DDQ (129 mg, 0.57 mmol, 1.0 equiv). The colorless solution immediately turned black. The reaction was stirred at reflux (oil bath 90 °C) for

2.5 h, then cooled to room temperature. The reaction contents were filtered through a pad of Celite, and the filtrate was concentrated in vacuo, affording the title compound (143

1 mg, 95%) as a red-brown syrup; Rf = 0.60 (10:1 hexanes/EtOAc); H NMR (500 MHz,

CDCl3) δ 11.72 (s, 1 H), 6.57 (d, J = 10.2 Hz, 1 H), 5.60 (d, J = 10.2 Hz, 1 H), 3.92 (s, 3

H), 2.44 (s, 3 H), 2.07 (s, 3 H), 1.41 (s, 6 H).

Me Me

O Me

Me OH CO2Me

Methyl 7-hydroxy-2,2,5,8-tetramethylchroman-6-carboxylate (107). A solution of the chromene 106 (142 mg, 0.54 mmol) in MeOH (20 mL) at room temperature was treated with 10% Pd/C (100 mg). The reaction mixture was vigorously stirred at room temperature under H2-balloon for 90 min. The reaction mixture was sparged with N2- balloon, filtered through a pad of Celite to remove catalyst, and the filtrate was concentrated in vacuo. Purification by silica flash chromatography (20:1 à 10:1 hexanes/EtOAc) afforded the title compound (77 mg, 51%) as a white solid; Rf = 0.40

1 (20:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 11.28 (s, 1 H), 3.92 (s, 3 H), 2.58

(t, J = 6.9 Hz, 2 H), 2.13 (s, 3 H), 2.06 (s, 3 H), 1.80 (t, J = 6.9 Hz, 2 H), 1.30 (s, 6 H).

Me Me

O Me

Me O CO2Me

Methyl 7-(allyloxy)-2,2,5,8-tetramethylchroman-6-carboxylate (108). A solution of the chroman 107 (72 mg, 0.27 mmol, 1.0 equiv) in acetone (3.5 mL) at room temperature was treated with allyl bromide (35 µL, 0.41 mmol, 1.5 equiv) and powdered, oven-dried

K2CO3 (94 mg, 0.68 mmol, 2.5 equiv). The reaction mixture was stirred at 55 °C for 16 h, then cooled to room temperature, filtered, and concentrated in vacuo. Purification by silica flash chromatography (20:1 hexanes/EtOAc) afforded the title compound (42 mg,

1 51%) as a colorless syrup; Rf = 0.20 (10:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3)

δ 6.09 – 5.99 (m, 1 H), 5.39 – 5.34 (m, 1 H), 5.23 – 5.20 (m, 1 H), 4.35 – 4.33 (m, 2 H),

3.87 (s, 3 H), 2.58 (t, J = 6.9 Hz, 2 H), 2.13 (s, 3 H), 2.06 (s, 3 H), 1.80 (t, J = 6.9 Hz, 2

13 H), 1.30 (s, 6 H); C NMR (125 MHz, CDCl3) δ 169.8, 153.9, 153.1, 134.1, 131.7,

120.8, 117.3, 117.1, 115.6, 75.3, 73.9, 52.2, 32.7, 26.8, 20.6, 16.0, 9.2.

Me Me O O Me Me Me O Me O

2,2-Dimethyl-5-((5E,9E)-3,6,10,14-tetramethylpentadeca-5,9,13-trien-2-ylidene)-1,3- dioxane-4,6-dione (49). A dry round-bottom flask with spin bar under argon balloon was charged with anhydrous THF (14.2 mL) and cooled to 0 °C (ice bath). Using a syringe pump, a solution of TiCl4 (1.0 M in CH2Cl2, 7.23 mL, 7.23 mmol, 2.0 equiv) was added dropwise over 45 min. The reaction mixture was treated with farnesyl butanone 48

(1.00 g, 3.62 mmol, 1.0 equiv) and Meldrum’s acid (522 mg, 3.62 mmol, 1.0 equiv).

Using a syringe pump, a solution of pyridine (1.17 mL, 14.47 mmol, 4.0 equiv) in anhydrous THF (2.4 mL) was added dropwise over 60 min. The ice bath was removed, and the reaction was stirred for 60 min. The reaction was quenched with H2O (1.8 mL) and Et2O (42 mL), washed with saturated aqueous NaHCO3 (7 mL), H2O (7 mL), and brine (7 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification of the resulting pale amber oil by silica flash chromatography (10:1 hexanes/EtOAc) afforded the title compound (1.33 g, 91%) as a nearly colorless oil. Rf = 0.30 (10:1 hexanes/EtOAc); IR (neat) νmax 2966, 2918, 2855, 1732, 1590, 1379, 1271, 1203, 1013,

-1 1 929, 806 cm ; H NMR (600 MHz, CDCl3) δ 5.08 (t, J = 6.2 Hz, 1 H), 5.05 (t, J = 6.8

Hz, 1 H), 5.00 (t, J = 7.0 Hz, 1 H), 4.01 – 3.95 (m, 1H), 2.31 (s, 3 H), 2.27 – 2.22 (m, 1

H), 2.19 – 2.13 (m, 1 H), 2.06 – 2.01 (m, 4 H), 1.97 – 1.91 (m, 4 H), 1.72 (s, 3 H), 1.70

(s, 3 H), 1.67 (s, 3 H), 1.60 (s, 3 H), 1.59 (s, 3 H), 1.57 (s, 3 H), 1.15 (d, J = 6.7 Hz, 3 H);

13 C NMR (150 MHz, CDCl3) δ 183.2, 161.6, 160.9, 137.8, 135.4, 131.4, 124.4, 123.9,

121.3, 116.9, 103.6, 68.1, 40.0, 39.8, 39.1, 33.4, 27.4, 26.9, 26.8, 26.7, 25.8, 18.4, 17.9,

+ + 17.8, 16.3, 16.1; HRMS (ESI-TOF) calcd. for C25H38O4Na [M + Na ] 425.2662, found

425.2669.

Me Me CO2Me Me Me CO2H

(2Z,6E,10E)-2-(Methoxycarbonyl)-3,4,7,11,15-pentamethylhexadeca-2,6,10,14- tetraenoic acid (50). A solution of alkylidene 49 (2.00 g, 4.97 mmol) in anhydrous

MeOH (7.5 mL) was treated with 25% NaOMe in MeOH (1.37 mL). The reaction was stirred at 65 °C for 3 h, then cooled to room temperature, diluted with Et2O, and quenched with 2 N aqueous HCl. The layers were separated, and the aqueous layer was extracted with Et2O. The organic layers were combined, washed with brine, dried over

Na2SO4, filtered, and concentrated in vacuo, affording the title compound (1.86 g, 99%, geometric mixture of half-esters) as a pale yellow oil. Rf = 0.80 (100% EtOAc); IR (neat)

-1 1 νmax 2966, 2917, 2854, 1729, 1697, 1434, 1254, 1218, 1049, 733 cm ; H NMR (500

MHz, CDCl3) δ 5.11 – 5.02 (m, 3 H), 3.78 (s, 3 H), 3.24 – 3.17 (m, 1 H), 2.16 – 2.03 (m,

6 H), 2.00 – 1.95 (m, 4 H), 1.98 (s, 3 H), 1.69 (s, 3 H), 1.60 (s, 3 H), 1.60 (s, 3 H), 1.59

13 (s, 3 H), 1.06 (d, J = 6.8 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 166.0, 164.9, 137.3,

100

135.2, 131.4, 124.6, 124.3, 121.5, 52.2, 39.9, 39.9, 33.0, 26.9, 26.8, 25.9, 18.0, 17.8, 16.1,

+ + 15.6; HRMS (ESI-TOF) calcd. for C23H36O4H [M + H ] 377.2686, found 377.2688.

Me Me O Me Me

OMe MeO2C

Methyl 2-methoxy-3-methyl-4-oxo-1-((5E,9E)-3,6,10,14-tetramethylpentadeca-

1,5,9,13-tetraen-2-yl)cyclobut-2-enecarboxylate (52). A microwave vial was charged with half-ester 50 (74 mg, 0.195 mmol, 1.0 equiv) and then azeotroped with benzene (2 ×

0.5 mL). Placed under an argon balloon, then added anhydrous benzene (1.5 mL) and a spin bar. The reaction solution was treated with (COCl)2 (51 µL, 0.586 mmol, 3.0 equiv) and stirred at room temperature for 2.5 h, then concentrated in vacuo. The resulting pale amber syrup was dissolved in anhydrous CH2Cl2 (1.5 mL), and treated with Et3N (82 µL,

0.586 mmol, 3.0 equiv) and 1-methoxypropyne (82 µL, 0.976 mmol, 5.0 equiv). The microwave vial was sealed, and the reaction was stirred at 50 °C (oil bath) for 24 h. After cooling to room temperature, the reaction was diluted with CH2Cl2, washed with H2O,

0.1 N aqueous HCl, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (3:1 hexanes/EtOAc) afforded the title compound (17 mg,

1 20%) as a yellow amber syrup; Rf = 0.15 (3:1 hexanes/EtOAc); H NMR (500 MHz,

CDCl3) δ 5.27 (t, J = 1.3 Hz, 1 H), 5.15 (t, J = 6.5 Hz, 1 H), 5.12 – 5.07 (m, 2 H), 4.95 (s,

1 H), 4.00 (s, 3 H), 3.95 (s, 3 H), 2.53 – 2.47 (m, 1 H), 2.23 – 2.17 (m, 1 H), 2.09 – 2.03

(m, 4 H), 2.00 – 1.95 (m, 4 H), 1.93 – 1.90 (m, 1 H), 1.83 (s, 3 H), 1.68 (s, 3 H), 1.59 (s,

13 3 H), 1.59 (s, 3 H), 1.58 (s, 3 H), 1.03 (d, J = 6.9 Hz, 3 H); C NMR (150 MHz, CDCl3)

101

δ 181.4, 158.7, 158.6, 145.1, 135.7, 135.0, 131.4, 124.6, 124.4, 123.7, 114.9, 106.9,

100.1, 56.4, 56.3, 40.0, 39.9, 38.5, 33.9, 29.9, 26.9, 26.8, 25.9, 18.3, 16.4, 7.2; LRMS

429.3

Me Me

Me O O O O O TMS

(5E,9E)-3,6,10,14-Tetramethyl-2-oxopentadeca-5,9,13-trien-1-yl (2-

(trimethylsilyl)ethyl) malonate (S4). A solution of chloromethyl ketone 54 (R = farnesyl) (175 mg, 0.563 mmol, 1.0 equiv) in DMF (14.1 mL) at room temperature was treated with malonate half-ester (575 mg, 2.81 mmol, 5.0 equiv) and powdered, oven- dried K2CO3 (389 mg, 2.81 mmol, 5.0 equiv). The reaction mixture was stirred for 3.5 h, then diluted with EtOAc, washed with H2O (3 × 10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (10:1 hexanes/EtOAc) afforded the title compound (47 mg, 17%) as a colorless syrup; Rf =

1 0.40 (6:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 5.11 – 5.05 (m, 3 H), 4.79 –

4.71 (m, 2 H), 4.26 – 4.23 (m, 2 H), 3.47 (s, 2 H), 2.64 – 2.57 (s, 1 H), 2.36 – 2.30 (s, 1

H), 2.13 – 1.95 (m, 9 H), 1.68 (s, 3 H), 1.60 (s, 3 H), 1.60 (s, 3 H), 1.59 (s, 3 H), 1.11 (d,

J = 6.9 Hz, 3 H), 1.04 – 1.01 (m, 2 H), 0.04 (s, 9 H).

102

Me TMS

Me Me O O Me

O O

2-(Trimethylsilyl)ethyl 2-oxo-4-((4E,8E)-5,9,13-trimethyltetradeca-4,8,12-trien-2-yl)-

2,5-dihydrofuran-3-carboxylate (55, R = farnesyl). A solution of acyloxymethyl ketone S4 (34 mg, 0.071 mmol, 1.0 equiv) in EtOH (0.7 mL) at 0 °C (ice bath) was treated with NaOEt (5.3 mg, 0.078 mmol, 1.1 equiv). The ice bath was removed, and the reaction was stirred for 80 min. The reaction contents were partitioned between Et2O and

0.5 M aqueous HCl, and the layers were separated. The aqueous layer was extracted with

Et2O (2 × 3 mL). The organic layers were combined, washed with brine, dried over

Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography

(10:1 hexanes/EtOAc) afforded the title compound (21 mg, 64%) as a colorless oil; Rf =

0.30 (6:1 hexanes/EtOAc); IR (neat) νmax 2955, 2917, 1773, 1713, 1249, 1023, 859, 836

-1 1 cm ; H NMR (500 MHz, CDCl3) δ 5.09 – 5.05 (m, 3 H), 4.83 – 4.74 (m, 2 H), 4.39 –

4.35 (m, 2 H), 3.68 – 3.61 (m, 1 H), 2.23 (t, J = 7.1 Hz, 2 H), 2.08 – 1.95 (m, 8 H), 1.67

(s, 3 H), 1.59 (s, 3 H), 1.59 (s, 3 H), 1.59 (s, 3 H), 1.19 (d, J = 7.0 Hz, 3 H), 1.14 – 1.10

+ + (m, 2 H), 0.06 (s, 9 H); HRMS (ESI-TOF) calcd. for C27H44O4SiH [M + H ] 461.3081, found 461.3083.

Me Me CO H Me 2

O O

103

2-Oxo-4-((4E,8E)-5,9,13-trimethyltetradeca-4,8,12-trien-2-yl)-2,5-dihydrofuran-3- carboxylic acid (56, R = farnesyl). A solution of TMSE ester 55 (R = farnesyl) (80 mg,

0.174 mmol, 1.0 equiv) in THF (11.6 mL) at 0 °C (ice bath) was treated with TBAF (1.0

M in THF, 1.74 mL, 1.74 mmol, 10 equiv). The ice bath was removed, and the reaction was stirred for 90 min. The reaction was then stirred at 30 °C for 2 h. The reaction was then stirred at room temperature for 90 min. The amber reaction solution was diluted with EtOAc (75 mL), washed with 1 N aqueous HCl (30 mL), H2O (30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (100% CH2Cl2, then 4:1 CH2Cl2/acetone) afforded the title compound

(47 mg, 75%) as a pale yellow syrup; Rf = 0.22 (4:1 CH2Cl2/acetone).

Me Me COCl Me

O O

2-Oxo-4-((4E,8E)-5,9,13-trimethyltetradeca-4,8,12-trien-2-yl)-2,5-dihydrofuran-3- carbonyl chloride (57). A solution of the carboxylic acid 56 (R = farnesyl) (60 mg,

0.166 mmol, 1.0 equiv) in benzene (0.24 mL) at 0 °C (ice bath) was treated with DMF

(catalytic, 1.6 µL) and (COCl)2 (15.2 µL, 0.175 mmol, 1.05 equiv). The ice bath was removed, and the reaction was stirred for 30 min. The spin bar was then removed, and the reaction contents were concentrated in vacuo, affording a dark red residue. The acid chloride was immediately carried onward to the [2+2] cycloaddition with 1- methoxypropyne.

104

Me Me

Me TMSO

Trimethyl(((5E,9E)-3,6,10,14-tetramethylpentadeca-1,5,9,13-tetraen-2-yl)oxy)silane

(S5). A 25-mL round bottom flask with spin bar was flame-dried and cooled under vacuum, then placed under argon balloon. The flask was charged with anhydrous THF (4 mL) and iPr2NH (0.17 mL, 1.19 mmol, 1.5 equiv). The solution was cooled to 0 °C (ice bath), then treated dropwise with nBuLi (2.5 M in hexanes, 0.45 mL, 1.11 mmol, 1.4 equiv). After 10 min at 0 °C, the solution was cooled to −78 °C. This LDA solution was treated with freshly distilled TMSCl (0.15 mL, 1.19 mmol, 1.5 equiv) followed by the methyl ketone 48 (220 mg, 0.80 mmol, 1.0 equiv). The reaction was stirred at −78 °C for

30 min, then gradually warmed to 0 °C. The reaction was quenched with cold H2O (4 mL), and the layers were separated. The aqueous layer was extracted with hexanes (2 ×

10 mL). The organic layers were combined, washed with saturated aqueous CuSO4 (5 mL), H2O (2.5 mL), brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo, affording the title compound (268 mg, 96%) as a colorless oil; Rf = 0.9 (10:1 hexanes/EtOAc). The silyl enol ether was immediately carried onward to chlorination using NCS.

Me Me

Me O Cl

105

(5E,9E)-1-Chloro-3,6,10,14-tetramethylpentadeca-5,9,13-trien-2-one (54, R = farnesyl). A solution of the silyl enol ether S5 (278 mg, 0.80 mmol, 1.0 equiv) in THF

(16 mL) under argon balloon at −78 °C was treated with powdered, oven-dried NaHCO3

(80 mg, 0.96 mmol, 1.2 equiv) followed by NCS (111 mg, 0.83 mmol, 1.04 equiv). The reaction was stirred at −78 °C for 2 h, then quenched with saturated aqueous NaHCO3

(25 mL), and the layers were separated. The aqueous layer was extracted with Et2O (2 ×

40 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (20:1 hexanes/EtOAc) afforded the title compound (168 mg, 68%) as a colorless oil; Rf = 0.50

(10:1 hexanes/EtOAc).

Me Me O Me Me

OMe O O

3-Methoxy-2-methyl-8-((4E,8E)-5,9,13-trimethyltetradeca-4,8,12-trien-2-yl)-6- oxaspiro[3.4]octa-2,7-diene-1,5-dione (58, R = farnesyl). A microwave vial was charged with the acid 56 (R = farnesyl) (41 mg, 0.11 mmol, 1.0 equiv) and then azeotroped with benzene (2 × 1 mL). Placed under an argon balloon, then added anhydrous benzene (1.5 mL) and a spin bar. The reaction solution was treated with

(COCl)2 (10 µL, 0.12 mmol, 1.05 equiv), stirred at room temperature for 2.5 h, then concentrated in vacuo. The resulting pale amber syrup was dissolved in anhydrous

CH2Cl2 (1.5 mL), and treated with Et3N (3.0 equiv) and 1-methoxypropyne (5.0 equiv).

The microwave vial was sealed, and the reaction was stirred at 50 °C (oil bath) for 24 h.

106

After cooling to room temperature, the reaction was diluted with CH2Cl2, washed with

H2O, 0.1 N aqueous HCl, dried over Na2SO4, filtered, and concentrated in vacuo.

Purification by silica flash chromatography (10:1 hexanes/EtOAc à 100% EtOAc) afforded the title compound (17 mg, 37%) as a yellow amber syrup; Rf = 0.15 (6:1 hexanes/EtOAc); LRMS 413.2

Me H

Ph CO2Me

(E)-Methyl 4-methyl-7-phenylhept-6-en-2-ynoate (S6). A 50-mL round bottom flask with spin bar was flame-dried and cooled under vacuum, then placed under argon balloon. The flask was charged with dibromide 62 (330 mg, 1.0 mmol, 1.0 equiv) and azeotroped with benzene. Anhydrous THF (7.7 mL) was added, and the solution was cooled to −78 °C, then treated with nBuLi (1.82 M in hexanes, 1.15 mL, 2.1 mmol, 2.1 equiv) and stirred for 15 min. Methyl chloroformate (155 µL, 2.0 mmol, 2.0 equiv) in anhydrous THF (1 mL) was added via cannula. The reaction mixture was stirred with warming to 0 °C, then to room temperature, over 2 h. The reaction was quenched with saturated aqueous NH4Cl (1.5 mL), extracted with Et2O, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (100:1 à 20:1 hexanes/EtOAc) afforded the title compound (208 mg, 91%) as a colorless oil. Rf = 0.33

-1 (20:1 hexanes/EtOAc); IR (neat) νmax 2975, 2232, 1709, 1433, 1247, 965, 741, 692 cm ;

1 H NMR (600 MHz, CDCl3) δ 7.37 (d, J = 7.3 Hz, 2 H), 7.31 (t, J = 7.6 Hz, 2 H), 7.22 (t,

J = 7.3 Hz, 1 H), 6.47 (d, J = 15.7 Hz, 1 H), 6.21 (dt, J = 15.9, 7.3 Hz, 1 H), 3.76 (s, 3 H),

2.73 (m, 1 H), 2.47 (m, 1 H), 2.40 (m, 1 H), 1.28 (d, J = 6.9 Hz, 3 H); 13C NMR (150

107

MHz, CDCl3) δ 154.4, 137.3, 132.9, 128.7, 127.5, 126.4, 126.3, 92.9, 73.5, 52.7, 39.3,

+ + 26.4, 19.5; HRMS (ESI-TOF) calcd. for C15H16O2H [M + H ] 229.1223, found

229.1224; LRMS 229.1

Me O Me

OMe O O

3-Methoxy-2-methyl-8-((4E,8E)-5,9,13-trimethyltetradeca-4,8,12-trien-2-yl)-6- oxaspiro[3.4]octa-2,7-diene-1,5-dione (58). A microwave vial was charged with the acid 56 (50 mg, 0.184 mmol, 1.0 equiv) and then azeotroped with benzene (2 × 1 mL).

Placed under an argon balloon, then added anhydrous CH2Cl2 (0.6 mL) and a spin bar.

The reaction solution was treated with DMF (catalytic, one drop) and (COCl)2 (48 µL,

0.551 mmol, 3.0 equiv), stirred at room temperature for 45 min, then concentrated in vacuo. The resulting pale amber syrup was dissolved in anhydrous CH2Cl2 (0.6 mL) and then transferred via cannula to a separate vial containing anhydrous CH2Cl2 (0.1 mL),

Et3N (1.3 µL, 0.009 mmol, 0.05 equiv), K2CO3 (25.4 mg, 0.184 mmol, 1.0 equiv), and 1- methoxypropyne (77 µL, 0.918 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 90 min, filtered through a Celite plug, rinsed with 4:1 hexanes/EtOAc, and concentrated in vacuo. Purification by silica flash chromatography

(4:1 hexanes/EtOAc) afforded the title compound (29 mg, 49%, 9:1 dr) as a colorless oil;

Rf = 0.50 (4:1 hexanes/EtOAc); IR (neat) νmax 2958, 1651, 1634, 1578, 1480, 1380, 946

-1 1 cm ; H NMR (600 MHz, CDCl3) δ 7.30 (d, J = 7.6 Hz, 2 H), 7.27 (t, J = 7.6 Hz, 2 H),

7.17 (t, J = 7.3 Hz, 1 H), 6.95 (s, 1 H), 6.39 (d, J = 15.8 Hz, 1 H), 6.19 (dt, J = 15.4, 7.3

108

Hz, 1 H), 4.05 (s, 3 H), 3.22 – 3.17 (m, 1 H), 2.75 (dt, J = 13.8, 6.7 Hz, 1 H), 2.51 (dt, J =

13 14.3, 7.6 Hz, 1 H), 1.92 (s, 3 H), 1.33 (d, J = 6.6 Hz, 3 H); C NMR (150 MHz, CDCl3)

δ 177.5, 159.1, 137.9, 132.1, 131.6, 129.4, 128.9, 128.6, 127.0, 126.1, 103.0, 57.1, 39.8,

+ + 30.8, 19.6, 7.4; HRMS (ESI-TOF) calcd. for C20H20O4H [M + H ] 325.1434, found

325.1440; LRMS 325.1

Me CO2H

O O

(E)-2-Oxo-6-phenyl-4-(5-phenylpent-4-en-2-yl)-2H-pyran-3-carboxylic acid (65). A

50-mL round bottom flask was charged with a spin bar, pyrone methyl ester 64 (426 mg,

1.14 mmol, 1.0 equiv), 1,2-DCE (11.4 mL), and Me3SnOH (2.06 g, 11.4 mmol, 10 equiv). The reaction mixture was stirred at 80 °C (oil bath) for 18 h, then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1 N aqueous HCl (3 × 10 mL), brine (1 × 10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (10:1 à 1:1 hexanes/EtOAc, then 1:1 hexanes/EtOAc spiked with 3% MeOH) afforded the title compound (218 mg, 53%) as a yellow solid; m.p. 55−57 °C; Rf = 0.20 (3:1 CH2Cl2/acetone); IR (neat) νmax 3027, 2928, 1729, 1494,

-1 1 1428, 734 cm ; H NMR (600 MHz, CDCl3) δ 13.07 (bs, 1 H), 7.91 (d, J = 7.1 Hz, 2 H),

7.59 (t, J = 7.6 Hz, 1 H), 7.54 (t, J = 8.0 Hz, 2 H), 7.32 – 7.24 (m, 3 H), 7.22 – 7.14 (m, 2

H), 7.04 (s, 1 H), 6.42 (d, J = 15.7 Hz, 1 H), 6.19 (dt, J = 15.5, 7.1 Hz, 1 H), 4.89 – 4.83

(m, 1 H), 2.59 (dt, J = 13.9, 6.9 Hz, 1 H), 2.50 (dt, J = 14.4, 7.6 Hz, 1 H), 2.36 (s, 1 H),

109

13 1.33 (d, J = 6.7 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 175.9, 166.4, 163.5, 162.1,

137.1, 132.9, 132.8, 129.7, 129.5, 128.7, 128.4, 127.5, 126.8, 126.7, 126.3, 109.2, 103.1,

+ + 39.8, 35.3, 19.3; HRMS (ESI-TOF) calcd. for C23H20O4H [M + H ] 361.1434, found

361.1425.

OMe Me

O O Me

Me Me

4-Methoxy-3-methyl-6-(((1S,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)methyl)-5,6-dihydro-2H-pyran-2-one (S7). A solution of the methylene homolog of albicanal (80 mg, 0.34 mmol, 1.0 equiv) in anhydrous CH2Cl2 (1.3 mL) at −78 °C was treated with Et2AlCl (1.0 M in hexanes, 375

µL, 0.38 mmol, 1.1 equiv). The reaction was stirred for 10 min, then treated with the

Brassard-type diene (173 mg, 0.75 mmol, 2.2 equiv). The reaction was stirred at −78 °C for 60 min, then warmed to room temperature. After 18 h, the reaction was cooled to 0

°C, treated with H2O, and extracted with Et2O (3 × 2 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (10:1 à 4:1 hexanes/EtOAc) afforded the title compound (70 mg,

60%) as a white solid; m.p. 97−99°C; X-ray; Rf = 0.20 (10:1 hexanes/EtOAc); IR (neat)

-1 1 νmax 2926, 1691, 1642, 1236, 1110, 734 cm ; H NMR (600 MHz, CDCl3) δ 4.82 (s, 1

H), 4.31 (s, 1 H), 3.77 (s, 3 H), 1.75 (s, 3 H), 0.87 (s, 3 H), 0.79 (s, 3 H), 0.66 (s, 3 H);

13 C NMR (150 MHz, CDCl3) δ 169.0, 165.4, 149.4, 105.9, 103.6, 73.4, 55.5, 55.0, 51.3,

110

42.0, 39.4, 38.7, 38.2, 33.7, 30.2, 29.8, 24.5, 21.8, 19.4, 14.7, 9.0; HRMS (ESI-TOF)

+ + calcd. for C22H34O3H [M + H ] 347.2581, found 347.2585.

OMe Me Me

Me O CO2Me

Methyl 3-allyl-4-methoxy-2,3,5-trimethyl-6-oxocyclohexa-1,4-dienecarboxylate

(103). A microwave vial was charged with a spin bar, allyl aryl ether 102 (264 mg, 1.0 mmol, 1.0 equiv), Yb(OTf)3H2O (310 mg, 0.5 mmol, 0.5 equiv), and 1,2-dichloroethane

(3.3 mL). The vial was sealed, and heated in a Biotage Initiator at 100 °C for 2 h. The resulting golden yellow solution was cooled to room temperature, diluted with H2O, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (10:1 à

1:1 hexanes/EtOAc) afforded the title compound (211 mg, 80%) as an off-white solid; m.p. 72−74°C; X-ray; Rf = 0.64 (1:1 hexanes/EtOAc); IR (neat) νmax 2955, 1733, 1658,

-1 1 1623, 1438, 1390, 1282, 1218, 1133, 978 cm ; H NMR (400 MHz, CDCl3) δ 5.32 – 5.28

(m, 1 H), 4.98 – 4.93 (m, 2 H), 3.90 (s, 3 H), 3.84 (s, 3 H), 2.75 – 2.70 (m, 1 H), 2.38 –

13 2.31 (m, 1 H), 1.94 (s, 3 H), 1.91 (s, 3 H), 1.33 (s, 3 H); C NMR (150 MHz, CDCl3) δ

184.7, 175.2, 167.9, 155.4, 133.8, 132.6, 119.5, 118.1, 62.0, 52.3, 48.3, 41.0, 23.5, 15.8,

+ + 9.8; HRMS (ESI-TOF) calcd. for C15H20O4H [M + H ] 265.1434, found 265.1444.

OMe Me OHC Me

Me O CO2Me

111

Methyl 4-methoxy-2,3,5-trimethyl-6-oxo-3-(2-oxoethyl)cyclohexa-1,4- dienecarboxylate (104). A solution of allyl dienone 103 (79.3 mg, 0.3 mmol, 1.0 equiv) in THF−H2O (2:1 v/v, 3 mL) was treated with NaIO4 (193 mg, 0.9 mmol, 3.0 equiv) and

OsO4 (2.5 wt% in tBuOH, 113 µL, 0.03 equiv) and stirred at room temperature for 13 h.

The reaction mixture was treated with saturated aqueous Na2S2O3 (1.5 mL) and saturated aqueous NaHCO3 (1.5 mL), then stirred for 30 min. The reaction mixture was extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (2:1 hexanes/EtOAc à 100% EtOAc) afforded the title compound (55 mg, 70%) as a

1 colorless oil. Rf = 0.20 (1:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 9.42 – 9.40

(m, 1 H), 3.92 (s, 3 H), 3.85 (s, 3 H), 3.03 – 2.97 (m, 1 H), 2.62 – 2.57 (m, 1 H), 1.98 (s,

13 3 H), 1.95 (s, 3 H), 1.41 (s, 3 H); C NMR (150 MHz, CDCl3) δ 184.7, 175.2, 167.9,

155.4, 133.8, 132.6, 119.5, 118.1, 62.0, 52.3, 48.3, 41.0, 23.5, 15.8, 9.8.

OMe Me Me Me

Me O CO2Me

Methyl 4-methoxy-2,3,3,5-tetramethyl-6-oxocyclohexa-1,4-dienecarboxylate (105).

A microwave vial was charged with a spin bar, aldehyde 104 (5 mg, 0.019 mmol, 1.0 equiv), and anhydrous toluene (0.5 mL), then degassed with argon while sonicating. The solution was treated with Wilkinson’s reagent (21 mg, 0.023 mmol, 1.2 equiv). The vial was sealed, and the reaction mixture was stirred at 110 °C (oil bath) for 15 h. The spin bar was removed, and toluene was removed in vacuo. Purification by silica flash chromatography (100% hexanes, then 2:1 hexanes/EtOAc) afforded the title compound

112

1 (3.5 mg, 78%) as an amber syrup; Rf = 0.48 (2:1 hexanes/EtOAc); H NMR (600 MHz,

13 CDCl3) δ 3.89 (s, 3 H), 3.86 (s, 3 H), 1.98 (s, 3 H), 1.90 (s, 3 H), 1.32 (s, 6 H); C NMR

(150 MHz, CDCl3) δ 184.6, 177.1, 168.1, 157.4, 131.8, 118.2, 62.0, 52.4, 44.0, 23.9,

16.0, 9.7; LRMS 239.1

OMe Me HO Me

Me O CO2Me

Methyl 3-(2-hydroxyethyl)-4-methoxy-2,3,5-trimethyl-6-oxocyclohexa-1,4- dienecarboxylate (S8). A solution of aldehyde 104 (122 mg, 0.46 mmol, 1.0 equiv) in

MeOH (1.5 mL) at 0 °C (ice bath) was treated with NaBH4 (17.3 mg, 0.46 mmol, 1.0 equiv) in four portions and then stirred for 10 min. The reaction was quenched by slow addition of saturated aqueous NH4Cl (0.2 mL) and then extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (1:1 hexanes/EtOAc à 100%

EtOAc) afforded the title compound (84 mg, 68%) as a colorless syrup. Rf = 0.50 (100%

1 EtOAc); H NMR (400 MHz, CDCl3) δ 3.93 (s, 3 H), 3.85 (s, 3 H), 3.40 – 3.31 (m, 2 H),

2.30 – 2.26 (m, 1 H), 1.98 (s, 3 H), 1.97 – 1.94 (m, 1 H), 1.93 (s, 3 H), 1.35 (s, 3 H).

OMe Me MsO Me

Me O CO2Me

Methyl 4-methoxy-2,3,5-trimethyl-3-(2-((methylsulfonyl)oxy)ethyl)-6-oxocyclohexa-

1,4-dienecarboxylate (S9). A solution of alcohol S8 (246 mg, 0.92 mmol, 1.0 equiv) in

113

CH2Cl2 (3.0 mL) at 0 °C (ice bath) was treated with Et3N (256 µL, 1.83 mmol, 2.0 equiv) followed by MsCl (78 µL, 1.01 mmol, 1.1 equiv). After 90 min at 0 °C, the reaction mixture was diluted with CH2Cl2 (20 mL), washed with 2 N HCl (3 mL), saturated aqueous NaHCO3 (3 mL), brine (3 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (1:1 hexanes/EtOAc) afforded the

1 title compound (267 mg, 84%) as a colorless syrup. Rf = 0.75 (100% EtOAc); H NMR

(400 MHz, CDCl3) δ 4.01 – 3.95 (m, 1 H), 3.96 (s, 3 H), 3.85 (s, 3 H), 3.84 – 3.80 (m, 1

H), 2.92 (s, 3 H), 2.48 – 2.42 (m, 1 H), 2.20 – 2.12 (m, 1 H), 1.98 (s, 3 H), 1.95 (m, 3 H),

1.38 (s, 3 H).

OMe Me I Me

Me O CO2Me

Methyl 3-(2-iodoethyl)-4-methoxy-2,3,5-trimethyl-6-oxocyclohexa-1,4- dienecarboxylate (S10). A solution of mesylate S9 (100 mg, 0.29 mmol, 1.0 equiv) in acetone (7.2 mL) at room temperature was treated with NaI (173 mg, 1.15 mmol, 4.0 equiv). The reaction mixture was stirred at reflux for 43 h. The reaction mixture was diluted with Et2O (30 mL), washed with H2O (2 × 20 mL), brine (20 mL), dried over

Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography

(2:1 hexanes/EtOAc) afforded the title compound (63 mg, 58%) as a white solid. Rf =

1 0.70 (1:1 hexanes/EtOAc); X-ray; H NMR (400 MHz, CDCl3) δ 3.92 (s, 3 H), 3.85 (s, 3

H), 2.71 – 2.55 (m, 3 H), 2.26 – 2.17 (m, 1 H), 1.94 (s, 3 H), 1.92 (m, 3 H), 1.33 (s, 3 H).

114

Me Me OH OMe Me Me Me

Et2O3P Me O CO2Me

β-Hydroxy phosphonate (114). A solution of the phosphonate (prepared from geranyl acetone, 13.3 mg, 1.0 equiv) in anhydrous THF (2.0 mL) at −78 °C was treated with nBuLi (2.5 M in hexanes, 1.0 equiv) and stirred for 20 min. The reaction was then treated with a solution of the dienone aldehyde 104 (11.2 mg, 1.0 equiv) in anhydrous

THF (0.5 mL). The resulting pale yellow solution was stirred at −78 °C for 60 min, then warmed to room temperature over 15 min. The reaction was quenched with saturated aqueous NH4Cl (five drops), the reaction contents were filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CHCl3, washed with H2O,

H2O/saturated aqueous Na2S2O3 (2:1 v/v), dried over Na2SO4, filtered, and concentrated in vacuo, providing a red-amber residue (24.9 mg). Analysis of the crude product by 1H

NMR and LCMS suggested the presence of β-hydroxyphosphonate as depicted above.

O N 2 OMe Me Me

Me O CO2Me

(E)-Methyl 4-methoxy-2,3,5-trimethyl-3-(3-(3-nitrophenyl)allyl)-6-oxocyclohexa-1,4- dienecarboxylate (S11). A dry microwave vial was charged with a spin bar, allyl dienone 103 (9.9 mg, 0.038 mmol, 1.0 equiv), anhydrous CH2Cl2 (0.75 mL), 3- nitrostyrene (56 mg, 0.38 mmol, 10.0 equiv), and Hoveyda−Grubbs 2nd generation catalyst (1.2 mg, 0.0019 mmol, 0.05 equiv). The vial was sealed, and the reaction was

115 stirred at 50 °C (oil bath) for 4 h. The reaction contents were loaded directly onto a pipet column (silica gel), and elution was carried out as follows: 1:1 CH2Cl2/hexanes, 100% hexanes, 10:1 à 2:1 hexanes/EtOAc, 100% EtOAc. The fractions corresponding to ~2:1 hexanes/EtOAc afforded the title compound (7 mg, 50%) as a colorless oil. Rf = 0.23

(2:1 hexanes/EtOAc); IR (neat) νmax 2951, 1735, 1660, 1627, 1527, 1349, 1218, 981, 734

-1 1 cm ; H NMR (600 MHz, CDCl3) δ 8.04 – 8.01 (m, 2 H), 7.53 (d, J = 7.8 Hz, 1 H), 7.42

(t, J = 7.9 Hz, 1 H), 6.40 (d, J = 15.8 Hz, 1 H), 5.83 – 5.78 (m, 1 H), 3.95 (s, 3 H), 3.84

(s, 3 H), 2.92 (ddd, J = 14.3, 7.6, 1.4 Hz, 1 H), 2.55 (ddd, J = 14.5, 7.1, 1.4 Hz, 1 H), 2.02

13 (s, 3 H), 1.91 (s, 3 H), 1.41 (s, 3 H); C NMR (150 MHz, CDCl3) δ 184.4, 174.8, 167.7,

154.8, 148.6, 138.7, 134.0, 131.8, 131.1, 129.6, 127.5, 122.2, 121.3, 119.7, 62.1, 52.4,

+ + 48.5, 40.1, 23.4, 16.0, 9.8; HRMS (ESI-TOF) calcd. for C21H23NO6H [M + H ]

386.1598, found 386.1593.

OMe Me Me

Me O CO2Me

(E)-Methyl 3-(3-(4-bromophenyl)allyl)-4-methoxy-2,3,5-trimethyl-6-oxocyclohexa-

1,4-dienecarboxylate (S12). A dry 10-mL round bottom flask was charged with a spin bar, allyl dienone 103 (25 mg, 0.095 mmol, 1.0 equiv), anhydrous CH2Cl2 (2.0 mL), 4- bromostyrene (173 mg, 0.95 mmol, 10.0 equiv), and Hoveyda−Grubbs 2nd generation catalyst (3.0 mg, 0.0048 mmol, 0.05 equiv). The reaction flask was equipped with a reflux condenser and N2-balloon, and the reaction was stirred at 40 °C (oil bath) for 11 h.

The reaction contents were loaded directly onto a pipet column (silica gel), and elution

116 was carried out as follows: 1:1 CH2Cl2/hexanes, 100% hexanes, 10:1 à 2:1 hexanes/EtOAc, 100% EtOAc. The appropriate fractions afforded the title compound (33 mg, 83%) as a colorless oil. Rf = 0.38 (2:1 hexanes/EtOAc); IR (neat) νmax 2949, 1734,

-1 1 1659, 1626, 1216, 1132, 980 cm ; H NMR (600 MHz, CDCl3) δ 7.35 (d, J = 8.4 Hz, 2

H), 7.05 (d, J = 8.4 Hz, 2 H), 6.28 (d, J = 16.0 Hz, 1 H), 5.66 – 5.61 (m, 1 H), 3.91 (s, 3

H), 3.82 (s, 3 H), 2.86 (ddd, J = 14.5, 7.6, 1.5 Hz, 1 H), 2.49 (ddd, J = 14.5, 7.0, 1.5 Hz, 1

13 H), 1.98 (s, 3 H), 1.89 (s, 3 H), 1.37 (s, 3 H); C NMR (150 MHz, CDCl3) δ 184.5,

175.1, 167.7, 155.1, 148.6, 135.8, 133.8, 132.0, 131.6, 127.8, 124.9, 121.2, 119.5, 62.0,

+ + 52.3, 48.4, 40.1, 23.4, 15.9, 9.7; HRMS (ESI-TOF) calcd. for C21H23BrO4H [M + H ]

419.0852, found 419.0857.

Me OMe Me Me Me Me O CO2Me

Methyl 4-methoxy-2,3,5-trimethyl-3-(3-methylbut-2-en-1-yl)-6-oxocyclohexa-1,4- dienecarboxylate (S13). A dry 10-mL round bottom flask was charged with a spin bar, allyl dienone 103 (26 mg, 0.1 mmol, 1.0 equiv), anhydrous CH2Cl2 (2.0 mL), 2-methyl-2- butene (1.33 mL), and Hoveyda−Grubbs 2nd generation catalyst (6.8 mg, 0.008 mmol,

0.08 equiv). The reaction flask was equipped with a reflux condenser and N2-balloon, and the reaction was stirred at 40 °C (oil bath) for 8 h. The reaction contents were loaded directly onto a pipet column (silica gel), and elution was carried out as follows: 100% hexanes, 4:1 hexanes/EtOAc. The appropriate fractions afforded the title compound (25

1 mg, 85%) as a pale amber oil. Rf = 0.20 (4:1 hexanes/EtOAc); H NMR (600 MHz,

CDCl3) δ 4.56 (tt, J = 6.6, 1.4 Hz, 1 H), 3.84 (s, 3 H), 3.84 (s, 3 H), 2.68 (dd, J = 15.3, 7.1

117

Hz, 1 H), 2.27 (dd, J = 15.3, 6.4 Hz, 1 H), 1.90 (s, 3 H), 1.89 (s, 3 H), 1.57 (d, J = 1.2 Hz,

13 3 H), 1.56 (s, 3 H), 1.32 (s, 3 H); C NMR (150 MHz, CDCl3) δ 184.8, 175.8, 168.0,

156.2, 134.7, 133.6, 119.7, 118.1, 61.7, 52.3, 48.1, 35.5, 25.8, 23.6, 18.3, 15.8, 9.8;

LRMS 293.1

Me OMe Me Me Me Me Me O CO2Me

Methyl 4-methoxy-2,3,5-trimethyl-6-oxo-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10- trien-1-yl)cyclohexa-1,4-dienecarboxylate (113). A dry 10-mL round bottom flask was charged with a spin bar, allyl dienone 103 (13.7 mg, 0.052 mmol, 1.0 equiv), anhydrous

nd CH2Cl2 (1.1 mL), triene (99.7 mg, 0.52 mmol, 10.0 equiv), and Hoveyda−Grubbs 2 generation catalyst (3.1 mg, 0.0036 mmol, 0.07 equiv). The reaction flask was equipped with a reflux condenser and N2-balloon, and the reaction was stirred at 40 °C (oil bath) for 4.5 h. The reaction contents were loaded directly onto a pipet column (silica gel), and elution was carried out as follows: 100% hexanes, 9:1 à 1:1 hexanes/EtOAc. The appropriate fractions afforded the title compound (9.9 mg, 45%) as a colorless oil. Rf =

-1 0.20 (4:1 hexanes/EtOAc); IR (neat) νmax 3454, 2950, 1735, 1659, 1619, 1218, 980 cm ;

1 H NMR (600 MHz, CDCl3) δ 5.14 – 5.05 (m, 2 H), 4.71 – 4.66 (m, 1 H), 3.90 (s, 3 H),

3.85 (s, 3 H), 2.72 – 2.64 (m, 1 H), 2.32 – 2.25 (m, 1 H), 2.14 − 1.95 (m, 4 H), 1.93 (s, 3

H), 1.91 (s, 3 H), 1.90 (s, 3 H), 1.72 − 1.67 (m, 2 H), 1.61 − 1.54 (m, 2 H), 1.59 (s, 3 H),

1.58 (s, 3 H), 1.34 (s, 3 H); LRMS 429.3 (M + H+)

118

Me O

Me OMe Me Me Me Me Me O CO2Me

Methyl 3-((2E,6E)-9-(3,3-dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dien-1-yl)-4- methoxy-2,3,5-trimethyl-6-oxocyclohexa-1,4-dienecarboxylate (S14). A dry microwave vial was charged with a spin bar, allyl dienone 103 (1.0 equiv), anhydrous

nd CH2Cl2 (0.4 mL), epoxydiene (2.0 equiv), and Grubbs 2 generation catalyst (0.06 equiv). The vial was sealed, and the reaction was stirred at 40 °C (oil bath) for 12 h. The reaction contents were loaded directly onto a pipet column (silica gel), and elution was carried out as follows: 9:1 à 1:1 hexanes/EtOAc. The appropriate fractions afforded the title compound (2 mg, 12%) as a colorless oil. Rf = 0.20 (4:1 hexanes/EtOAc); IR (neat)

-1 + νmax 2931, 1738, 1661, 1633, 1216, 983 cm ; LRMS 467.3 (M + Na )

OHC OMe Me Me Me Me O CO2Me

(E)-Methyl 4-methoxy-2,3,5-trimethyl-3-(3-methyl-4-oxobut-2-en-1-yl)-6- oxocyclohexa-1,4-dienecarboxylate (S15). A dry 25-mL round bottom flask was charged with a spin bar, allyl dienone 103 (347 mg, 1.31 mmol, 1.0 equiv), anhydrous

CH2Cl2 (2.0 mL), methacrolein (2.0 mL, 24.4 mmol, 18.6 equiv), and Hoveyda−Grubbs

2nd generation catalyst (49 mg, 0.08 mmol, 0.06 equiv). The reaction flask was equipped with a reflux condenser and argon balloon, and the reaction was stirred at 40 °C (oil bath) for 17 h. The spin bar was removed, and CH2Cl2 was removed in vacuo. Purification by

119 silica flash chromatography (100% CH2Cl2, 3:1 à 1:1 hexanes/EtOAc) afforded the title compound (280 mg, 70%, 5:1 E:Z mixture) as a pale brown syrup. This isomeric mixture

(275 mg, 0.90 mmol, 1.0 equiv) was dissolved in CH2Cl2 (9.0 mL) and treated with pTsOH (34 mg, 0.18 mmol, 0.2 equiv). The reaction mixture was stirred at room temperature under argon balloon for 16 h, then decanted into a separatory funnel. The pTsOH crystals were gently rinsed with additional solvent, and the liquid was decanted into the separatory funnel. The organic layer was washed with saturated aqueous

NaHCO3 (12 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (3:1 à 1:1 hexanes/EtOAc) afforded the title compound

(270 mg, 98%, >50:1 E:Z) as a pale greenish-gray solid; m.p. 84−86°C; Rf = 0.43 (1:1 hexanes/EtOAc); IR (neat) νmax 2956, 1726, 1682, 1659, 1630, 1361, 1280, 1219, 1033,

-1 1 975 cm ; H NMR (400 MHz, CDCl3) δ 9.26 (s, 1 H), 5.89 (t, J = 6.7 Hz, 1 H), 3.89 (s, 3

H), 3.85 (s, 3 H), 3.05 (dd, J = 16.5, 7.1 Hz, 1 H), 2.62 (dd, J = 16.5, 6.6 Hz, 1 H), 1.95

13 (s, 3 H), 1.93 (s, 3 H), 1.73 (s, 3 H), 1.44 (s, 3 H); C NMR (150 MHz, CDCl3) δ 194.7,

184.2, 174.2, 167.5, 154.2, 146.7, 141.3, 134.3, 119.9, 62.0, 52.5, 47.4, 35.6, 23.9, 15.8,

+ + 9.9, 9.8; HRMS (ESI-TOF) calcd. for C17H22O5H [M + H ] 307.1540, found 307.1545.

OMe HO Me Me Me Me O CO2Me

(E)-Methyl 3-(4-hydroxy-3-methylbut-2-en-1-yl)-4-methoxy-2,3,5-trimethyl-6- oxocyclohexa-1,4-dienecarboxylate (S16). A solution of aldehyde S15 (270 mg, 0.88 mmol, 1.0 equiv) in MeOH (14.7 mL) at 0 °C (ice bath) was treated with NaBH4 (100 mg, 2.64 mmol, 3.0 equiv) in one portion. The reaction mixture was stirred at 0 °C for 20

120 min. The reaction was quenched with saturated aqueous NaHCO3 (18 mL), then extracted with EtOAc (3 × 40 mL). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (1:1 à 1:4 hexanes/EtOAc) afforded the title compound

1 (218 mg, 80%) as a colorless syrup. Rf = 0.15 (1:1 hexanes/EtOAc); H NMR (500

MHz, CDCl3) δ 4.89 – 4.86 (m, 1 H), 3.88 (s, 3 H), 3.87 – 3.85 (m, 2 H), 3.84 (s, 3 H),

2.75 – 2.70 (m, 1 H), 2.37 – 2.33 (m, 1 H), 1.91 (s, 3 H), 1.91 (s, 3 H), 1.63 (s, 3 H), 1.37

13 (s, 3 H); C NMR (150 MHz, CDCl3) δ 184.7, 175.4, 168.1, 155.9, 138.4, 133.7, 119.8,

119.5, 68.6, 61.9, 52.5, 48.1, 35.1, 23.2, 16.0, 14.2, 9.8; LRMS 331.1 (M + Na+)

OMe Cl Me Me Me Me O CO2Me

(E)-Methyl 3-(4-chloro-3-methylbut-2-en-1-yl)-4-methoxy-2,3,5-trimethyl-6- oxocyclohexa-1,4-dienecarboxylate (115). A solution of alcohol S16 (218 mg, 0.71 mmol, 1.0 equiv) in CH2Cl2 (23.6 mL) at 0 °C (ice bath) was treated with Et3N (197 µL,

1.42 mmol, 2.0 equiv) followed by MsCl (110 µL, 1.42 mmol, 2.0 equiv). The reaction mixture was stirred with ice bath expiring for 40 h. TLC analysis indicated a mixture of mesylate (intermediate) and chloride (title compound). Anhydrous LiCl (30 mg, 0.71 mmol, 1.0 equiv) was added, and the reaction mixture was stirred for 3 h. The spin bar was removed, and CH2Cl2 was removed in vacuo. The residue was dissolved in EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (4:1 à 1:1 hexanes/EtOAc) afforded the title compound

(141 mg, 61%) as a colorless oil. Rf = 0.65 (1:1 hexanes/EtOAc); IR (neat) νmax 2950,

121

-1 1 1734, 1659, 1627, 1214, 980 cm ; H NMR (600 MHz, CDCl3) δ 4.96 (t, J = 6.8 Hz, 1

H), 3.88 – 3.87 (m, 2 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 2.75 (dd, J = 15.5, 7.4 Hz, 1 H),

2.33 (dd, J = 15.6, 6.2 Hz, 1 H), 1.91 (s, 3 H), 1.90 (s, 3 H), 1.71 (s, 3 H), 1.35 (s, 3 H);

13 C NMR (150 MHz, CDCl3) δ 184.5, 175.1, 167.8, 155.2, 134.9, 133.9, 124.3, 119.7,

61.8, 52.3, 51.8, 47.8, 35.2, 23.6, 15.8, 14.7, 9.8; HRMS (ESI-TOF) calcd. for

+ + C17H23ClO4H [M + H ] 327.1358, found 327.1369.

Me OMe Me Me Me PhO2S Me Me O CO2Me

Methyl 4-methoxy-2,3,5-trimethyl-6-oxo-3-((2E,6E)-3,7,11-trimethyl-5-

(phenylsulfonyl)dodeca-2,6,10-trien-1-yl)cyclohexa-1,4-dienecarboxylate (116). A solution of geranyl phenyl sulfone (28 mg, 0.1 mmol, 1.0 equiv) and allylic chloride 115

(33 mg, 0.1 mmol, 1.0 equiv) in anhydrous THF−HMPA (3:1 v/v, 0.5 mL) at −55 °C

(immersion cooler) was treated with nBuLi (2.5 M solution in hexanes, 50 µL, 0.125 mmol, 1.25 equiv). The red-amber reaction mixture was stirred at −55 °C for 12 h. The golden-yellow reaction mixture was quenched with ice-cold H2O and diluted with

EtOAc. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (3:1 à 1:1 hexanes/EtOAc) afforded the title compound (22 mg, 38%)

1 as a colorless syrup. Rf = 0.10 (3:1 hexanes/EtOAc); H NMR (600 MHz, CDCl3) δ 7.82

– 7.80 (m, 2 H), 7.61 (t, J = 7.4 Hz, 1 H), 7.51 (t, J = 7.2 Hz, 2 H), 5.02 – 4.99 (m, 1 H),

4.80 (dd, J = 16.0, 10.2 Hz, 1 H), 4.62 – 4.57 (m, 1 H), 3.83 (s, 3 H), 3.80 (s, 3 H), 2.80 −

122

2.76 (m, 1 H), 2.67 (ddd, J = 34.9, 15.7, 6.6 Hz, 1 H), 2.30 − 2.14 (m, 2 H), 1.89 (s, 3 H),

1.86 (s, 3 H), 1.68 (s, 3 H), 1.59 (s, 3 H), 1.54 (s, 3 H), 1.31 (s, 3 H); 13C NMR (150

MHz, CDCl3) δ 184.5, 175.5, 167.8, 155.7, 145.5, 137.8, 133.7, 133.6, 132.1, 129.4,

128.9, 123.7, 121.6, 119.9, 117.2, 63.6, 61.7, 52.3, 47.8, 39.9, 37.6, 35.2, 30.1, 26.4, 25.9,

+ + 24.0, 17.8, 16.9, 16.5, 15.8, 9.9; HRMS (ESI-TOF) calcd. for C33H44O6SH [M + H ]

569.2931, found 569.2906.

Me O

Me OMe Me Me Me PhO2S Me Me O CO2Me

Methyl 3-((2E,6E)-9-(3,3-dimethyloxiran-2-yl)-3,7-dimethyl-5-(phenylsulfonyl)nona-

2,6-dien-1-yl)-4-methoxy-2,3,5-trimethyl-6-oxocyclohexa-1,4-dienecarboxylate (S17).

A solution of the 6,7-epoxygeranyl phenyl sulfone (29 mg, 0.1 mmol, 1.0 equiv) and allylic chloride 115 (33 mg, 0.1 mmol, 1.0 equiv) in anhydrous THF−HMPA (3:1 v/v, 0.6 mL) at −40 °C (immersion cooler) was treated with LHMDS (0.5 M solution in THF,

0.20 mL, 0.1 mmol, 1.0 equiv). The red-amber reaction mixture was stirred for 20 min at

−40 °C and the color gradually faded to a pale yellow-amber. A separate flask was charged with NaH2PO4H2O (138 mg, 1.0 mmol) and H2O (1.0 mL), and cooled to 0 °C

(ice bath). Using a cannula, the reaction contents were transferred to the flask containing

1.0 M aqueous NaH2PO4 at 0 °C. The reaction contents were then transferred to a separatory funnel and extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (2:1 à 1:1 hexanes/EtOAc) afforded the title compound (34 mg,

123

1 58%) as a colorless oil. Rf = 0.40 (1:1 hexanes/EtOAc); H NMR (400 MHz, CDCl3) δ

7.79 (d, J = 7.5 Hz, 2 H), 7.61 (t, J = 7.3 Hz, 1 H), 7.50 (t, J = 7.4 Hz, 2 H), 4.87 – 4.81

(m, 1 H), 4.62 – 4.56 (m, 1 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 2.78 − 2.60 (m, 2 H), 2.29 −

2.10 (m, 2 H), 1.88 (s, 3 H), 1.85 (s, 3 H), 1.53 (s, 3 H), 1.30 (s, 3 H), 1.30 (s, 3 H), 1.25

13 (s, 3 H); C NMR (150 MHz, CDCl3) δ 184.5, 175.4, 167.7, 155.6, 144.8, 137.7, 133.7,

133.6, 129.4, 129.0, 121.6, 119.8, 117.7, 63.7, 63.5, 63.1, 61.8, 58.5, 52.3, 47.8, 37.7,

36.5, 35.2, 27.4, 25.0, 24.0, 18.8, 16.9, 16.5, 15.8, 9.9; LRMS 607.2 (M + Na+)

CO2Me Me OH

Me O Me Me

Me Me

Methyl 2-hydroxy-3,6-dimethyl-4-(((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1- yl)oxy)benzoate (85).110 A solution of methyl atratate 10 (908 mg, 4.63 mmol, 1.0 equiv) in acetone (46 mL) was treated with farnesyl bromide (1.32 g, 4.63 mmol, 1.0 equiv) and powdered, oven-dried K2CO3 (959 mg, 6.94 mmol, 1.5 equiv). The reaction mixture was stirred at 50 °C (oil bath) for 4 h, then cooled to room temperature. The reaction mixture was filtered through a Celite pad, rinsed with hexanes, and the filtrate was concentrated in vacuo. Purification by silica flash chromatography (19:1 à 4:1 hexanes/Et2O) afforded the title compound (1.30 g, 70%) as a white solid; Rf = 0.60 (10:1 hexanes/Et2O).

124

MeO C 2 OH Me Me

Me OH Me

Me Me

Methyl 2,4-dihydroxy-3,6-dimethyl-5-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-

1-yl)benzoate (S18). A microwave vial was charge with a spin bar, farnesyl aryl ether

85 (40 mg, 0.1 mmol, 1.0 equiv), and CH2Cl2 (2.0 mL). The solution was cooled to 0 °C

(ice bath) and treated with FeCl36H2O (81 mg, 0.3 mmol, 3.0 equiv) in one portion.

After 10 min, the ice bath was removed. The reaction was stirred for 60 min, then diluted with CH2Cl2 (8 mL), washed with saturated aqueous NaHCO3 (4 mL), dried over

Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography

(10:1 à 4:1 hexanes/Et2O) afforded the title compound (23 mg, 58%) as a colorless oil.

1 Rf = 0.30 (10:1 hexanes/Et2O); H NMR (400 MHz, CDCl3) δ 11.42 (s, 1 H), 5.49 (s, 1

H), 5.12 – 5.04 (m, 3 H), 3.92 (s, 3 H), 3.36 (d, J = 6.6 Hz, 2 H), 2.44 (s, 3 H), 2.12 (s, 3

H), 2.10 – 1.94 (m, 8 H), 1.81 (s, 3 H), 1.67 (s, 3 H), 1.58 (s, 6 H); HRMS (ESI-TOF)

+ + calcd. for C25H36O4H [M + H ] 401.2686, found 401.2677.

CO2Me Me OH

Me O Me Me O

Me Me

Methyl 4-(((2E,6E)-9-(3,3-dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dien-1-yl)oxy)-

2-hydroxy-3,6-dimethylbenzoate (86).110 A solution of methyl atratate 10 (39 mg, 0.2

125 mmol, 1.0 equiv) in acetone (2 mL) was treated with 10,11-epoxyfarnesyl bromide (60 mg, 0.2 mmol, 1.0 equiv) and powdered, oven-dried K2CO3 (41 mg, 0.3 mmol, 1.5 equiv). The reaction mixture was stirred at 50 °C (oil bath) for 60 min, then cooled to room temperature. The reaction mixture was filtered through a Celite pad, rinsed with hexanes, and the filtrate was concentrated in vacuo. Purification by silica flash chromatography (9:1 à 3:1 hexanes/EtOAc) afforded the title compound (62 mg, 75%) as a white solid; Rf = 0.15 (6:1 hexanes/Et2O).

CO2Me Me OH

Me O Me Me

O Me O Me O

Methyl 4-(((2E,6E)-9-(5,5-dimethyl-2-oxo-1,3-dioxolan-4-yl)-3,7-dimethylnona-2,6- dien-1-yl)oxy)-2-hydroxy-3,6-dimethylbenzoate (87).110 A solution of methyl atratate

10 (164 mg, 0.84 mmol, 2.0 equiv), 10,11-carbonate-farnesol (118 mg, 0.42 mmol, 1.0 equiv), and Ph3P (164 mg, 0.63 mmol, 1.5 equiv) in THF (10.5 mL) at 0 °C (ice bath) was treated dropwise with a solution of DEAD (40 wt% in toluene, 343 µL, 0.75 mmol,

1.8 equiv). The ice bath was removed after 10 min, and the reaction was stirred for 4 h.

The spin bar was removed, and the reaction contents were concentrated in vacuo.

Purification by silica flash chromatography (4:1 à 1:1 hexanes/Et2O) afforded the title compound (86 mg, 45%) as a white solid; m.p. 76−78 °C; Rf = 0.17 (3:1 hexanes/Et2O);

+ + HRMS (ESI-TOF) calcd. for C26H36O7H [M + H ] 461.2534, found 461.2537.

126

MeO C 2 OH Me Me

Me OH Me

O Me O Me O

Methyl 3-((2E,6E)-9-(5,5-dimethyl-2-oxo-1,3-dioxolan-4-yl)-3,7-dimethylnona-2,6- dien-1-yl)-4,6-dihydroxy-2,5-dimethylbenzoate (S19). A microwave vial was charge with a spin bar, 10,11-carbonate-farnesyl aryl ether 87 (56 mg, 0.12 mmol, 1.0 equiv), and CH2Cl2 (7.6 mL). The solution was cooled to 0 °C (ice bath) and treated with

FeCl36H2O (99 mg, 0.37 mmol, 3.0 equiv) in one portion. After 10 min, the ice bath was removed. The reaction was stirred for 60 min, then diluted with CH2Cl2 (10 mL), washed with saturated aqueous NaHCO3 (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (4:1 à 1:1 hexanes/Et2O) afforded the title compound (30 mg, 53%) as a colorless oil. Rf = 0.38

1 (1:1 hexanes/Et2O); H NMR (400 MHz, CDCl3) δ 11.42 (s, 1 H), 5.53 (s, 1 H), 5.13 (t, J

= 6.8 Hz, 1 H), 5.06 (t, J = 6.5 Hz, 1 H), 4.19 (dd, J = 10.0, 3.4 Hz, 1 H), 3.92 (s, 3 H),

3.36 (d, J = 6.5 Hz, 2 H), 2.62 (t, J = 6.9 Hz, 1 H), 2.43 (s, 3 H), 2.24 – 2.02 (m, 4 H),

2.12 (s, 3 H), 1.86 – 1.51 (m, 4 H), 1.80 (s, 3 H), 2.10 – 1.94 (m, 8 H), 1.59 (s, 3 H), 1.46

+ + (s, 3 H), 1.35 (s, 3 H); HRMS (ESI-TOF) calcd. for C26H36O7H [M + H ] 461.2534, found 461.2530.

OH Me Me

HO Me Me

127

3β-hydroxydrimenol (S20).111 The bicyclic keto aldehyde (225 mg, 0.96 mmol, 1.0 equiv) was dissolved in anhydrous MeOH (19.2 mL), cooled to 0 °C, and treated with

NaBH4 (73 mg, 1.92 mmol, 2.0 equiv). The reaction mixture was stirred at 0 °C for 30 min, then quenched with saturated aqueous NaHCO3, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (4:1 à 1:1 hexanes/EtOAc) afforded the title compound (219 mg, 96%) as a white solid; X-ray; Rf = 0.20 (2:1 hexanes/EtOAc).

OH Me Me

HO Me Me

3α-hydroxydrimenol (S21).112 The bicyclic keto aldehyde (500 mg, 2.13 mmol, 1.0 equiv) was dissolved in anhydrous THF (21 mL), cooled to −78 °C, and treated with L-

Selectride® (1.0 M, 21 mL, 21 mmol, 10 equiv). The reaction mixture was stirred at −78

°C for 2 h, diluted with MTBE, washed with 2 N aqueous HCl, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (4:1 à

1:1 hexanes/EtOAc) afforded the title compound (229 mg, 46%, ~9:1 3α:3β) as a white solid; Rf = 0.20 (1:1 hexanes/EtOAc); IR (neat) νmax 3218, 2964, 2933, 2876, 1453, 1375,

-1 + + 1193, 988, 722 cm ; HRMS (ESI-TOF) calcd. for C15H26O2Na [M + Na ] 261.1825, found 261.1824.

128

CO2Me Me OH

Me O Me Me

HO Me Me

Mitsunobu on 3β substrate (89). The diol S20 (115 mg, 0.48 mmol, 1.05 equiv) in anhydrous THF (0.2 mL) was treated with methyl atratate 10 (90 mg, 0.46 mmol, 1.00 equiv), Ph3P (126 mg, 0.48 mmol, 1.05 equiv), and DEAD (40 wt% in toluene, 219 µL,

0.48 mmol, 1.05 equiv). The reaction mixture was sonicated at room temperature for 30 min, then concentrated in vacuo. Purification by silica flash chromatography (4:1 à 1:1 hexanes/Et2O) afforded the title compound (49 mg, 25%) as a white solid; m.p. 52−54

°C; Rf = 0.41 (1:1 hexanes/Et2O); IR (neat) νmax 3401, 2936, 2869, 1650, 1276, 1119,

-1 1 803, 731 cm ; H NMR (400 MHz, CDCl3) δ 11.80 (s, 1 H), 6.33 (s, 1 H), 4.50 (d, J =

10.1 Hz, 1 H), 4.38 (d, J = 10.1 Hz, 1 H), 3.92 (s, 3 H), 3.28 (dd, J = 11.4, 4.5 Hz, 1 H),

2.53 (s, 3 H), 2.17 – 2.13 (m, 2 H), 2.06 (s, 3 H), 1.76 – 1.70 (m, 2 H), 1.67 (s, 3 H), 1.62

13 – 1.44 (m, 6 H), 1.04 (s, 3 H), 1.04 (s, 3 H), 0.83 (s, 3 H); C NMR (150 MHz, CDCl3) δ

172.7, 162.2, 161.4, 140.2, 135.6, 135.0, 111.2, 106.8, 105.4, 78.9, 64.2, 51.9, 50.8, 38.9,

37.9, 34.8, 34.1, 28.2, 27.8, 24.8, 20.9, 19.5, 18.7, 15.6, 8.3; HRMS (ESI-TOF) calcd. for

+ + C25H36O5H [M + H ] 417.2635, found 417.2647.

CO2Me Me OH

Me O Me Me

HO Me Me

129

Mitsunobu on 3α substrate (88). The diol S21 (229 mg, 1.0 equiv) in anhydrous THF

(0.4 mL) was treated with methyl atratate 10 (188 mg, 1.0 equiv), Ph3P (252 mg, 1.0 equiv), and DEAD (40 wt% in toluene, 0.44 mL, 1.0 equiv). The reaction mixture was sonicated at room temperature for 60 min, then concentrated in vacuo. Purification by silica flash chromatography (4:1 à 1:1 hexanes/Et2O) afforded the title compound (43 mg, 11%) as a colorless syrup; Rf = 0.20 (4:1 hexanes/EtOAc); LRMS 417.2

MeO C 2 OH Me Me

Me OH Me

HO Me Me

FeCl36H2O treatment (91). A dry microwave vial was charged with a spin bar and ether substrate 89 (6 mg, 1.0 equiv), then azeotroped with benzene (2 × 0.5 mL).

Anhydrous CH2Cl2 (0.9 mL) was added, and the solution was cooled to 0 °C (ice bath).

The reaction was treated with FeCl36H2O (12 mg, 3.0 equiv) in one portion, then stirred at 0 °C for 10 min. The ice bath was removed, and the reaction was stirred with warming to room temperature for 10 min. The reaction was quenched with saturated aqueous

NaHCO3 (1.0 mL), and the layers were separated. The organic layer was dried over

Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography

(2:1 à 1:1 hexanes/Et2O) afforded the title compound (1 mg, 16%) as a pale yellow residue; Rf = 0.10 (2:1 hexanes/Et2O); LRMS 417.2

130

MeO C 2 OH Me Me

Me O Me

HO Me Me

Spirocyclization (S22). A dry microwave vial was charged with a spin bar and substrate

91 (1 mg, 1 equiv), then azeotroped with benzene (2 × 0.5 mL). Anhydrous CH2Cl2 (0.2 mL) was added, followed by Amberlyst 15 beads (excess). The reaction mixture was stirred at room temperature for 60 min, then filtered through a cotton plug, and concentrated in vacuo. Purification by silica flash chromatography (10:1 à 1:1 hexanes/EtOAc) afforded the title compound (0.4 mg, ~40%) as a pale yellow residue.

1 Rf = 0.20 (4:1 hexanes/EtOAc); H NMR (600 MHz, CDCl3) δ 12.00, s, 1 H), 3.89 (s, 3

H), 3.21 (m, 1 H), 3.06 – 2.74 (AB quartet, J = 16 Hz, 2 H), 2.35 (s, 3 H), 2.08 (s, 3 H),

1.56 (s, 3 H), 1.04 (s, 3 H), 0.99 (s, 3 H), 0.82 (s, 3 H), 0.68 (d, J = 7.0 Hz, 3 H); LRMS

417.2

CO2Me Me OH

Me Me O Me Me

HO Me Me

Mitsunobu on 3β substrate with orsellinate (90). The diol S20 (50 mg, 0.21 mmol,

1.05 equiv) in anhydrous THF (0.2 mL) was treated with methyl orsellinate 14 (42 mg,

0.20 mmol, 1.00 equiv), Ph3P (55 mg, 0.21 mmol, 1.05 equiv), and DEAD (40 wt% in toluene, 95 µL, 0.21 mmol, 1.05 equiv). The reaction mixture was sonicated at room

131 temperature for 60 min, then concentrated in vacuo. Purification by silica flash chromatography (4:1 à 1:1 hexanes/Et2O) afforded the title compound (31 mg, 36%) as a white solid; m.p. 45−47 °C; Rf = 0.39 (1:1 hexanes/Et2O); IR (neat) νmax 3426, 2945,

2870, 1652, 1438, 1318, 1266, 1202, 1177, 1110, 960, 802, 736 cm-1; 1H NMR (400

MHz, CDCl3) δ 11.10 (s, 1 H), 4.43 (d, J = 11.4 Hz, 1 H), 4.33 (d, J = 11.4 Hz, 1 H), 3.94

(s, 3 H), 3.29 (dd, J = 11.2, 4.5 Hz, 1 H), 2.41 (s, 3 H), 2.18 (s, 3 H), 2.16 (s, 3 H), 2.13 –

2.02 (m, 2 H), 1.78 – 1.61 (m, 4 H), 1.60 – 1.50 (m, 4 H), 1.57 (s, 3 H), 1.07 (s, 3 H),

13 1.03 (s, 3 H), 0.84 (s, 3 H); C NMR (150 MHz, CDCl3) δ 172.7, 162.2, 159.6, 137.3,

137.1, 133.9, 122.0, 116.3, 109.1, 79.0, 69.9, 52.2, 50.9, 39.0, 38.0, 35.1, 34.2, 28.3, 27.8,

+ 21.1, 20.2, 19.1, 18.8, 15.6, 13.9, 8.3; HRMS (ESI-TOF) calcd. for C26H38O5Na [M +

Na+] 453.2611, found 453.2608.

OMe Me Me

Me O CO2Me

Reduction (S23).113 A dry round bottom flask was charged with a spin bar, anhydrous pyridine (15.4 mL), and NaBH4 (349 mg, 9.23 mmol, 2.0 equiv). The mixture was stirred at room temperature for 5 min, treated with allyl dienone 103 (1.22 g, 4.62 mmol, 1.0 equiv), and stirred at room temperature for 4.5 h. The reaction contents were partitioned between H2O and Et2O. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (9:1 à 3:1 hexanes/EtOAc) afforded the title compound (1.05 g, 85%) as a colorless oil; Rf = 0.65

-1 1 (2:1 hexanes/EtOAc); IR (neat) νmax 2975, 1741, 1656, 1608, 1220, 1090, 996 cm ; H

NMR (400 MHz, CDCl3) δ 5.82 – 5.72 (m, 1 H), 5.09 – 5.02 (m, 2 H), 3.87 (s, 3 H), 3.76

132

(s, 3 H), 3.47 (d, J = 13.3 Hz, 1 H), 2.40 – 2.25 (m, 3 H), 1.85 (s, 3 H), 1.23 (s, 3 H), 1.03

13 (d, J = 6.7 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 195.2, 179.4, 171.7, 134.9, 117.9,

117.7, 61.9, 57.8, 52.2, 44.5, 39.7, 39.4, 24.1, 13.4, 10.5; HRMS (ESI-TOF) calcd. for

+ + C15H22O4H [M + H ] 267.1591, found 267.1582.

OMe Me Me

Me O

Krapcho (120).114 A round bottom flask was charged with a spin bar, ester S23 (907 mg,

3.41 mmol, 1.0 equiv), DMSO (22.7 mL), H2O (1.23 mL, 68.1 mmol, 20 equiv), and

NaCl (239 mg, 4.09 mmol, 1.2 equiv). The flask was equipped with a reflux condenser, and the reaction was stirred at 150 °C (oil bath) for 90 min, then cooled to room temperature. The reaction contents were poured into saturated aqueous NaHCO3 (40 mL) and extracted with Et2O (3 × 25 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (9:1 à 2:1 hexanes/EtOAc) afforded the title compound

(490 mg, 69%) as a colorless oil; Rf = 0.47 (4:1 hexanes/EtOAc); IR (neat) νmax 2968,

-1 1 1658, 1609, 1322, 1221, 1094, 911 cm ; H NMR (400 MHz, CDCl3) δ 5.87 – 5.76 (m, 1

H), 5.08 – 5.00 (m, 2 H), 3.83 (s, 3 H), 2.38 – 2.19 (m, 4 H), 2.03 – 1.93 (m, 1 H), 1.81

13 (s, 3 H), 1.20 (s, 3 H), 1.02 (d, J = 6.9 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 200.1,

179.4, 135.1, 118.4, 117.3, 61.7, 44.4, 42.4, 39.1, 36.9, 23.7, 15.4, 10.3; HRMS (ESI-

+ + TOF) calcd. for C13H20O2H [M + H ] 209.1536, found 209.1529.

133

Me OMe Me Me Me Me Me O

3-Methoxy-2,4,5-trimethyl-4-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1- yl)cyclohex-2-enone (122). A dry 10-mL round bottom flask was charged with a spin bar, allyl enone 120 (10.4 mg, 0.05 mmol, 1.0 equiv), anhydrous CH2Cl2 (1.0 mL), triene

(96 mg, 0.50 mmol, 10.0 equiv), and Grubbs 2nd generation catalyst (3.0 mg, 0.0035 mmol, 0.07 equiv). The reaction flask was equipped with a reflux condenser and N2- balloon, and the reaction was stirred at 40 °C (oil bath) for 12 h. The reaction contents were loaded directly onto a pad of silica gel, and elution was carried out as follows:

100% hexanes, 10:1 à 4:1 hexanes/EtOAc, 100% EtOAc. The appropriate fractions afforded the title compound (11 mg, 57%, E:Z mixture) as a pale amber oil. Rf = 0.56

1 13 (4:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 7-030; C NMR (125 MHz,

+ + CDCl3) δ 7-030; HRMS (ESI-TOF) calcd. for C25H40O2H [M + H ] 373.3101, found

373.3103.

Me O Me Me Me OMe Me Br Me Me

BDSB cyclization (124). A dry microwave vial was charged with a spin bar, polyene

122 (1 mg), and anhydrous CH2Cl2 (0.1 mL). The reaction was treated with BDSB (1.5 mg, 1.0 equiv) at room temperature, and stirred for 75 min. The reaction mixture was quenched by the addition of 5% aqueous NaHCO3/5% aqueous Na2S2O3 (1:1 v/v, 0.2

134 mL), stirred for 15 min, diluted with H2O (1.0 mL), and extracted with CH2Cl2 (3 × 2 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in

1 vacuo. Rf = 0.43 (4:1 hexanes/EtOAc); crude H NMR (500 MHz, CDCl3) δ 4.48 (dd, J

= 10.0, 5.6 Hz, 1 H, diagnostic for C-3 bromide); LCMS (Multislow) retention time 8.5 min (major ion 451.3 m/z), consistent with title compound as depicted.

Me O

Me OMe Me Me Me Me Me O

4-((2E,6E)-9-(3,3-Dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dien-1-yl)-3-methoxy-

2,4,5-trimethylcyclohex-2-enone (123). A dry 10-mL round bottom flask was charged with a spin bar, allyl enone 120 (42 mg, 0.20 mmol, 1.0 equiv), anhydrous CH2Cl2 (2.0 mL), epoxy diene (208 mg, 1.00 mmol, 5.0 equiv), and Grubbs 2nd generation catalyst (12 mg, 0.014 mmol, 0.07 equiv). The reaction flask was equipped with a reflux condenser and N2-balloon, and the reaction was stirred at 40 °C (oil bath) for 7 h. The reaction contents were loaded directly onto a pad of silica gel, and elution was carried out as follows: 100% hexanes, 10:1 à 1:1 hexanes/EtOAc. The appropriate fractions afforded

1 the title compound (10 mg, 13%) as a pale amber oil; Rf = 0.25 (2:1 hexanes/Et2O); H

+ NMR (400 MHz, CDCl3) δ 7-040-3B; HRMS (ESI-TOF) calcd. for C25H40O3H [M +

H+] 389.3050, found 389.3057.

135

Me O Me Me Me OMe Me HO Me Me

BF3OEt2 cyclization (125). A dry microwave vial was charged with a spin bar, epoxypolyene 123 (1 mg, 1.0 equiv), and anhydrous CH2Cl2 (0.1 mL). The reaction was cooled to −78 °C, treated with BF3OEt2, and stirred for 90 min. The reaction was quenched with 5% aqueous NaHCO3, warmed to room temperature, extracted with

CH2Cl2, dried over Na2SO4, filtered, and concentrated in vacuo. Rf = 0.15 (1:1

1 hexanes/Et2O); crude H NMR (600 MHz, CDCl3) δ 3.20 (m, 1 H, diagnostic for C-3 alcohol); LRMS 389.3

Me OMe

Me Me O

3-Methoxy-2,5,6-trimethylcyclohex-2-enone (126). The title compound was prepared in three steps from commercially available 5-methylcyclohexane-1,3-dione according to

77, 115 procedures described by Majetich. The epimers are separable (PTLC, 100% Et2O); the less polar epimer is a tan solid, and the more polar epimer is an amber oil. An X-ray crystal structure was solved for the less polar epimer.

Me OMe Me Me Me O Me

Me Me

136

3-Methoxy-2,5,6-trimethyl-6-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1- yl)cyclohex-2-enone (S24). A 100-mL round bottom flask was charged with a spin bar, then flame-dried and cooled under vacuum. The flask was fitted with an argon balloon.

Anhydrous THF (4.2 mL) and iPr2NH (1.24 mL, 1.2 equiv) were added, and the solution was cooled to 0 °C. The solution was treated with nBuLi (2.5 M in hexanes, 1.15 equiv) dropwise via syringe, then stirred for 15 min at 0 °C. The solution was cooled to −78 °C, treated with Majetich ester 126 (1.23 g, 1.0 equiv) as a solution in THF−HMPA (4:1 v/v,

6.4 mL) via syringe pump over 90 min. The resulting yellow amber mixture was stirred at −78 °C for an additional 30 min, and treated with farnesyl bromide116 (2.30 g, 1.10 equiv) as a solution in THF (4.2 mL). The reaction mixture was stirred for 16 h with warming to room temperature. The reaction was quenched with saturated aqueous

NH4Cl. The spin bar was removed, and THF was removed in vacuo. The aqueous layer was extracted with Et2O. The organic layer was washed with brine, and the brine layer was back-extracted with Et2O. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (6:1 à

2:1 hexanes/Et2O) afforded the title compound (1.12 g, 41%, 3:1 dr) as a colorless oil; Rf

= 0.65 (1:1 hexanes/Et2O); IR (neat) νmax 2965, 2920, 2852, 1623, 1377, 1231, 1113, 992,

-1 1 736 cm ; H NMR (400 MHz, CDCl3) δ 5.09 (t, 1 H, J = 6.2 Hz), 4.92 (t, 1 H, J = 6.8

Hz), 3.79 (s, 3 H), 2.69 (t, J = 6.2 Hz, 1 H), 2.62 – 2.57 (m, 2 H), 2.27 − 1.85 (m, 6 H),

1.68 (s, 3 H), 1.63 − 1.59 (m, 2 H), 1.61 (s, 3 H), 1.58 (s, 3 H), 1.29 (s, 3 H), 1.25 (s, 3

13 H), 0.94 (d, J = 6.8 Hz, 3 H), 0.92 (s, 3 H); C NMR (100 MHz, CDCl3) δ 203.3, 168.9,

136.4, 134.1, 125.0, 121.0, 113.2, 64.4, 58.5, 55.0, 47.2, 40.1, 36.5, 34.4, 30.3, 27.7, 26.7,

137

+ + 25.1, 19.0, 18.5, 16.4, 15.8, 8.1; HRMS (ESI-TOF) calcd. for C25H40O2H [M + H ]

373.3106, found 373.3138.

Me OMe Me Me Me O O Me

Me Me

LDA alkylation (127). A 50-mL round bottom flask was charged with a spin bar, then flame-dried and cooled under vacuum. The flask was fitted with an argon balloon.

Anhydrous THF (2 mL) and iPr2NH (587 µL, 1.2 equiv) were added, and the solution was cooled to 0 °C. The solution was treated with nBuLi (2.5 M in hexanes, 1.15 equiv) dropwise via syringe, then stirred for 15 min at 0 °C. The solution was cooled to −78 °C, treated with Majetich ester 126 (584 mg, 1.0 equiv) as a solution in THF−HMPA (4:1 v/v, 3 mL) via syringe pump over 90 min. The resulting yellow amber mixture was stirred at −78 °C for an additional 30 min, and treated with epoxyfarnesyl bromide117

(1.15 g, 1.10 equiv) as a solution in THF (2 mL). The reaction mixture was stirred for 16 h with warming to room temperature, then quenched with saturated aqueous NH4Cl. The spin bar was removed, and THF was removed in vacuo. The aqueous layer was extracted with Et2O. The organic layer was washed with brine, and the brine layer was back- extracted with Et2O. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (9:1 à 2:1 hexanes/Et2O) afforded the title compound (950 mg, 70%, 3:1 dr) as a colorless oil; Rf =

-1 0.38 (4:1 hexanes/EtOAc); IR (neat) νmax 2961, 2924, 1624, 1377, 1233, 1115, 992 cm ;

1 H NMR (600 MHz, CDCl3) δ 5.09 (t, 1 H), 4.92 (t, 1 H), 3.79 (s, 3 H), 2.69 (t, J = 6.2

138

Hz, 1 H), 2.62 – 2.57 (m, 2 H), 2.27 − 1.85 (m, 6 H), 1.68 (s, 3 H), 1.63 − 1.59 (m, 2 H),

1.61 (s, 3 H), 1.58 (s, 3 H), 1.29 (s, 3 H), 1.25 (s, 3 H), 0.94 (d, J = 6.8 Hz, 3 H), 0.92 (s,

13 3 H); C NMR (150 MHz, CDCl3) δ 203.3, 168.9, 136.4, 134.1, 125.0, 121.0, 113.2,

64.4, 58.5, 55.0, 47.2, 40.1, 36.5, 34.4, 30.3, 27.7, 26.7, 25.1, 19.0, 18.5, 16.4, 15.8, 8.1;

+ + HRMS (ESI-TOF) calcd. for C25H40O3H [M + H ] 389.3050, found 389.3062; LRMS

389.3

Me O Me Me Me O Me HO Me Me

Treatment with EtAlCl2 (128). A dry 1000-mL round bottom flask was charged with a spin bar and the epoxide 127 (1.00 g, 2.57 mmol*, 1.0 equiv), then azeotroped with benzene (2 × 20 mL). The flask was fitted with an argon balloon. Anhydrous CH2Cl2

(400 mL) was added via cannula. The colorless solution was cooled to −78 °C, then treated with EtAlCl2 (1.0 M in hexanes, Sigma-Aldrich™, 12.9 mL, 5.0 equiv) via cannula dropwise over 20 min. The resulting pale yellow reaction was stirred at −78 °C for 3 h, then quenched with Et3N (7.7 mL, 55.3 mmol, 21.5 equiv). The dry ice-acetone bath was removed, and the reaction was treated with saturated aqueous Rochelle’s salt

(40 mL). The reaction mixture was allowed to warm to room temperature. The spin bar was removed, and CH2Cl2 was removed in vacuo. The aqueous layer was extracted with

EtOAc (3 × 50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (4:1 à 1:1 hexanes/EtOAc) afforded the title compound (340 mg, 35%, 51% adjusted for impurity

139 of starting material, which was contaminated* with Majetich ester 126) as a white solid; m.p. 73−75 °C; X-ray; Rf = 0.41 (1:1 hexanes/EtOAc); IR (neat) νmax 3474, 2934, 2869,

1735, 1660, 1616, 1392, 1202, 1121, 1091, 1044, 920, 726 cm-1; 1H NMR (600 MHz,

CDCl3) δ 3.27 (dd, J = 11.6, 4.5 Hz, 1 H), 2.35 − 2.24 (m, 2 H), 2.03 − 1.99 (m, 1 H),

1.82 − 1.79 (m, 1 H), 1.74 − 1.59 (m, 7 H), 1.66 (s, 3 H), 1.42 − 1.33 (m, 2 H), 1.17 (s, 3

H), 1.12 (s, 3 H), 1.10 − 1.00 (m, 2 H), 1.03 (s, 3 H), 0.93 (d, J = 6.8 Hz, 3 H), 0.80 (s, 3

13 H), 0.79 (s, 3 H); C NMR (150 MHz, CDCl3) δ 199.2, 175.8, 118.7, 82.2, 78.7, 55.4,

50.8, 42.3, 41.0, 39.0, 38.7, 38.0, 37.3, 36.6, 31.4, 28.2, 27.2, 22.1, 19.7, 19.0, 15.8, 15.5,

+ + 14.4, 8.3; HRMS (ESI-TOF) calcd. for C24H38O3H [M + H ] 375.2894, found 375.2908.

CO2Me Me O Me Me Me O Me

MeO2CO Me Me

Mander’s (S25).118 To a solution of LDA (0.264 mmol) in THF (0.4 mL) at −78 °C was added the tetracycle 128 (45 mg, 0.120 mmol) in THF (0.3 mL) dropwise via syringe.

The pale yellow reaction mixture was stirred for 30 min at −78 °C, then treated sequentially with HMPA (42 µL, 0.240 mmol) and methyl cyanoformate (21 µL, 0.264 mmol). The orange-amber reaction mixture was stirred for 15 min at −78 °C, then for 15 min at 0 °C. The reaction was quenched with ice water (0.5 mL) and extracted with Et2O

(2 × 5 mL). The combined organic layers were washed with brine (3 mL), dried over

Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography

(10:1 à 2:1 hexanes/EtOAc) afforded the title compound (40 mg, 68%) as a white foam;

1 Rf = 0.24 (4:1 hexanes/EtOAc); H NMR (600 MHz, CDCl3) δ 4.35 (dd, J = 11.6, 4.7 Hz,

140

1 H), 3.77 (s, 6 H), 3.25 (d, J = 12.9 Hz, 1 H), 2.40 − 2.34 (m, 1 H), 2.04 − 2.00 (m, 2 H),

1.85 − 1.62 (m, 6 H), 1.65 (s, 3 H), 1.45 − 1.37 (m, 3 H), 1.19 (s, 3 H), 1.14 (s, 3 H), 0.97

(s, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.86 (s, 3 H), 0.81 (s, 3 H); 13C NMR (150 MHz,

CDCl3) δ 193.8, 175.6, 171.7, 155.9, 118.2, 84.8, 82.6, 58.1, 55.5, 54.8, 52.3, 50.7, 41.1,

40.8, 38.2, 37.8, 36.9, 36.6, 31.2, 28.1, 23.5, 22.3, 20.1, 19.5, 16.5, 15.8, 12.7, 8.3;

LRMS 491.3

CO2Me Me O Me Me Me O Me

MeO2CO Me Me

DDQ treatment (131). A solution of the ester S25 (52 mg, 1.0 equiv) in 1,4-dioxane

(1.0 mL) at room temperature was treated with DDQ (45 mg, 2.0 equiv) and stirred at

110 °C (oil bath) for 2 h. The reaction mixture was cooled to room temperature, diluted with Et2O (20 mL), washed with 5% aqueous NaHCO3 (3 × 10 mL), H2O (10 mL), brine

(10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (6:1 à 2:1 hexanes/EtOAc) afforded the title compound (26 mg,

1 51%) as a white solid; Rf = 0.25 (2:1 hexanes/EtOAc); H NMR (600 MHz, CDCl3) δ

4.39 − 4.36 (m, 1 H), 3.87 (s, 3 H), 3.79 (s, 3 H), 1.95 (s, 3 H), 1.88 − 1.83 (m, 2 H), 1.82

− 1.75 (m, 1 H), 1.78 (s, 3 H), 1.65 − 1.54 (m, 2 H), 1.46 − 1.40 (m, 1 H), 1.42 (s, 3 H),

1.36 − 1.31 (m, 1 H), 1.31 − 1.26 (m, 1 H), 1.23 (d, J = 7.2 Hz, 3 H), 1.14 (s, 3 H), 0.99

13 (s, 3 H), 0.98 − 0.92 (m, 1 H), 0.87 (s, 3 H), 0.79 (s, 3 H); C NMR (150 MHz, CDCl3) δ

183.92, 171.56, 168.21, 157.42, 155.96, 132.23, 120.67, 84.76, 84.23, 55.58, 54.88,

141

52.51, 51.57, 41.80, 40.81, 38.28, 36.79, 28.98, 28.11, 27.62, 23.55, 21.41, 19.67, 16.46,

16.06, 15.61, 8.12; LRMS 489.3

CO2Me Me O Me Me Me O Me HO Me Me

Methanolysis of C3-carbonate (129). The carbonate 131 (10 mg, 0.02 mmol) was dissolved in MeOH (0.4 mL) and treated with K2CO3 (27 mg, 10 equiv). The reaction mixture was stirred at room temperature for 24 h, then partitioned between EtOAc (10 mL) and H2O (10 mL). The layers were separated, and the organic layer was dried over

Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography

(4:1 à 1:1 hexanes/EtOAc) afforded the title compound (7 mg, 54%) as a colorless film;

Rf = 0.30 (1:1 hexanes/EtOAc); IR (neat) νmax 3474, 2934, 1735, 1660, 1616, 1392, 1202,

-1 1 1121, 1044, 987, 726 cm ; H NMR (600 MHz, CDCl3) δ 3.87 (s, 3 H), 3.28 (dd, J =

11.6, 4.5 Hz, 1 H), 2.05 − 2.02 (m, 1 H), 1.95 (s, 3 H), 1.78 (s, 3 H), 1.41 (s, 3 H), 1.13

13 (s, 3 H), 1.03 (s, 3 H), 0.78 (s, 3 H), 0.76 (s, 3 H); C NMR (150 MHz, CDCl3) δ 183.8,

171.6, 168.1, 157.4, 132.1, 120.5, 84.4, 78.6, 55.4, 52.4, 51.6, 41.7, 40.9, 39.1, 37.4, 36.8,

28.9, 28.2, 27.6, 27.2, 21.3, 19.8, 15.9, 15.5, 15.4, 8.0; HRMS (ESI-TOF) calcd. for

+ + C26H38O5H [M + H ] 431.2792, found 431.2800.

142

CO2Me Me O Me Me Me O Me TBSO Me Me

TBS-protection of fully elaborated substrate (S26). A solution of the alcohol 129 (23 mg) in CH2Cl2 (0.2 mL) was treated with 2,6-lutidine (10 µL) and TBSOTf (18 µL).

After stirring for 30 min at room temperature, the reaction mixture was quenched with saturated aqueous NH4Cl (0.5 mL) and extracted with Et2O (3 × 2 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 (2 mL), brine (2 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (8:1 à 4:1 hexanes/EtOAc) afforded the title compound (89 mg, 73%) as a colorless oil; Rf = 0.45 (1:1 hexanes/Et2O); IR (neat) νmax 2951, 2932, 2856, 1736,

-1 1 1661, 1620, 1240, 1059, 834, 729 cm ; H NMR (400 MHz, CDCl3) δ 3.87 (s, 3 H), 3.24

(dd, J = 11.1, 4.9 Hz, 1 H), 2.37 − 2.30 (m, 1 H), 2.30 − 2.24 (m, 2 H), 2.19 − 2.12 (m, 3

H), 1.88 − 1.83 (m, 2 H), 1.82 − 1.75 (m, 1 H), 1.65 − 1.54 (m, 2 H), 1.46 − 1.40 (m, 1

H), 1.36 − 1.31 (m, 1 H), 1.31 − 1.26 (m, 1 H), 1.23 (d, J = 7.2 Hz, 3 H), 0.98 − 0.92 (m,

1 H), 0.91 − 0.88 (m, 9 H), 0.89 (s, 9 H), 0.83 (d, J = 6.9 Hz, 3 H), −0.05 (s, 6 H); 13C

NMR (150 MHz, CDCl3) δ 183.9, 171.7, 168.2, 157.4, 132.1, 120.5, 84.5, 79.1, 55.6,

52.4, 51.7, 41.8, 41.0, 39.6, 37.5, 36.8, 28.9, 28.6, 27.6, 26.0, 21.4, 20.0, 18.2, 16.0, 15.9,

+ + 15.5, 8.0, −3.6, −4.8; HRMS (ESI-TOF) calcd. for C32H52O5SiH [M + H ] 545.3657, found 545.3654.

143

Me O Me Me Me O Me TBSO Me Me

TBS-protection of C3-alcohol (S27). The alcohol 128 (94 mg, 1.0 equiv) was dissolved in CH2Cl2 (0.8 mL) and treated with 2,6-lutidine (47 µL, 1.6 equiv) and TBSOTf (86 µL,

1.5 equiv) at room temperature. After stirring for 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl. Extracted with Et2O (3 × 2 mL). The organic layers were combined, washed with saturated aqueous NaHCO3, brine, dried over

Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography

(2:1 à 1:1 hexanes/Et2O) afforded the title compound (89 mg, 73%) as a white solid. Rf

1 = 0.40 (1:1 hexanes/Et2O); H NMR (600 MHz, CDCl3) δ 2.37 − 2.30 (m, 1 H), 2.30 −

2.24 (m, 2 H), 2.19 − 2.12 (m, 3 H), 1.88 − 1.83 (m, 2 H), 1.82 − 1.75 (m, 1 H), 1.65 −

1.54 (m, 2 H), 1.46 − 1.40 (m, 1 H), 1.36 − 1.31 (m, 1 H), 1.31 − 1.26 (m, 1 H), 1.23 (d, J

= 7.2 Hz, 3 H), 0.98 − 0.92 (m, 1 H), 0.91 − 0.88 (m, 9 H), 0.83 (d, J = 6.9 Hz, 3 H); 13C

NMR (150 MHz, CDCl3) δ 183.9, 171.6, 168.2, 157.4, 156.0, 132.2, 120.7, 84.8, 84.2,

55.6, 54.9, 52.5, 51.6, 41.8, 40.8, 38.3, 36.8, 29.0, 28.1, 27.6, 23.6, 21.4, 19.7, 16.5, 16.1,

15.6, 8.1.

Me O Me Me Me O O Me TBSO Me Me

Epoxidation of vinylogous ester (132). The vinylogous ester S27 (68 mg, 1.0 equiv) was dissolved in CH2Cl2 (1.4 mL), cooled to 0 °C (ice bath), and treated with mCPBA

144

(24 mg, 1.0 equiv). The reaction mixture was stirred with warming to room temperature for 19 h. The reaction mixture was diluted with CH2Cl2, washed with saturated aqueous

NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (2:1 à 1:1 hexanes/Et2O) afforded the title compound (68 mg,

96%) as a white solid; m.p. 85−87 °C; Rf = 0.55 (1:1 hexanes/Et2O); Note: SM and Pdt are co-polar, but SM is UV-active, whereas pdt is not UV-active (stains with p-

-1 anisaldehyde); IR (neat) νmax 2950, 2934, 2855, 1712, 1094, 1072, 1061, 834, 772 cm ;

1 H NMR (400 MHz, CDCl3) δ 2.37 − 2.30 (m, 1 H), 2.30 − 2.24 (m, 2 H), 2.19 − 2.12

(m, 3 H), 1.88 − 1.83 (m, 2 H), 1.82 − 1.75 (m, 1 H), 1.65 − 1.54 (m, 2 H), 1.46 − 1.40

(m, 1 H), 1.36 − 1.31 (m, 1 H), 1.31 − 1.26 (m, 1 H), 1.23 (d, J = 7.2 Hz, 3 H), 0.98 −

0.92 (m, 1 H), 0.91 − 0.88 (m, 9 H), 0.83 (d, J = 6.9 Hz, 3 H); 13C NMR (150 MHz,

CDCl3) δ 183.9, 171.6, 168.2, 157.4, 156.0, 132.2, 120.7, 84.8, 84.2, 55.6, 54.9, 52.5,

51.6, 41.8, 40.8, 38.3, 36.8, 29.0, 28.1, 27.6, 23.6, 21.4, 19.7, 16.5, 16.1, 15.6, 8.1;

+ + HRMS (ESI-TOF) calcd. for C30H52O4SiH [M + H ] 505.3707, found 505.3719.

145

General Method for Chan−Evans−Lam coupling

A mixture of 2-iodophenol (220 mg, 1 mmol, 1 equiv), arylboronic acid (1.5 mmol, 1.5 equiv), anhydrous Cu(OAc)2 (218 mg, 1.2 mmol, 1.2 equiv), triethylamine (0.7 mL, 5 mmol, 5 equiv), pyridine (0.81 mL, 5 mmol, 5 equiv) and powdered 4 Å molecular sieves

(100 mg) in anhydrous CH2Cl2 (10 mL) was stirred at room temperature for 48 h. The reaction contents were filtered through a plug of silica gel and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (9:1 hexanes/EtOAc) afforded chromatographically and spectroscopically pure product.

I CF3 1-Iodo-2-(4-(trifluoromethyl)phenoxy)benzene (S1)

Using 2-iodophenol and 4-(trifluoromethyl)phenylboronic acid in a Chan−Evans−Lam coupling as described above, the title compound was obtained (90%) as a colorless oil; IR

(neat) νmax 3064, 1616, 1512, 1464, 1324, 1239, 1166, 1122, 1065, 1013, 837, 768, 743

-1 1 cm ; H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 7.9 Hz, 1.4 Hz, 1 H), 7.59 (d, J = 8.6

13 Hz, 2 H), 7.39 – 7.35 (m, 1 H), 7.03 – 6.97 (m, 4 H); C NMR (100 MHz, CDCl3) δ

160.0, 155.2, 140.4, 130.1, 127.4 (q, JCF = 3.8 Hz), 126.8, 121.2, 117.4, 89.9; quartet from CF3 and the quaternary carbon were not observed; HRMS (ESI-TOF) calcd. for

+ + C13H8F3IOH [M + H ] 362.9499, found 362.9485.

I F 1-(4-Fluorophenoxy)-2-iodobenzene (S2)

146

Using 2-iodophenol and 4-fluorophenylboronic acid in a Chan−Evans−Lam coupling as described above, the title compound was obtained (83%) as a colorless oil; IR (neat) νmax

3063, 1498, 1464, 1438, 1215, 1190, 1019, 847, 832, 816, 775, 749 cm-1; 1H NMR (400

MHz, CDCl3) δ 8.20 (dd, J = 7.9 Hz, 1.4 Hz, 1 H), 7.64 – 7.62 (m, 1 H), 7.38 (m, J = 8.6

Hz, 2 H), 7.29 (m, J = 9.2, 4.5 Hz, 2 H), 7.21 – 7.16 (m, 2 H); 13C NMR (100 MHz,

CDCl3) δ 160.3, 157.4 (d, JCF = 92.1 Hz), 152.8 (d, JCF = 2.7 Hz), 140.1, 129.9, 125.5,

120.2 (d, JCF = 8.2 Hz), 118.9, 116.6 (d, JCF = 23.4 Hz), 88.6; Did not ionize in HRMS

(ESI-TOF); GC/MS, M+ 314.

I COOMe

Methyl 4-(2-iodophenoxy)benzoate (S3)

Using 2-iodophenol and 4-(methoxycarbonyl)phenylboronic acid in a Chan−Evans−Lam coupling as described above, the title compound was obtained (71%) as a colorless oil; IR

(neat) νmax 2997, 2949, 1717, 1605, 1503, 1464, 1435, 1279, 1237, 1162, 1110, 1019,

-1 1 766, 753 cm ; H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.9 Hz, 2 H), 7.89 (d, J = 7.9

Hz, 1 H), 7.36 (td, J = 7.7 Hz, 0.6 Hz, 1 H), 7.03 (d, J = 8.1 Hz, 1 H), 6.98 – 6.92 (m,

13 3H), 3.90 (s, 3H); C NMR (100 MHz, CDCl3) δ 166.7, 161.2, 155.2, 140.3, 131.9,

+ 130.1, 126.8, 124.9, 121.4, 117.0, 90.0, 52.2; HRMS (ESI-TOF) calcd. for C14H11IO3H

[M + H+] 354.9826, found 354.98635.

1-Bromo-2-phenoxybenzene (S4)

147

To a suspension of NaOtBu (1.06 g, 11 mmol, 1.1 equiv) in THF (36 mL) was added 2- bromophenol (1.16 mL, 10 mmol, 1.0 equiv) at 0 °C. The reaction mixture was stirred at

0 °C for 15 min, and diphenyliodonium trifluoromethanesulfonate (5.16 g, 12 mmol, 1.2 equiv) was added in one portion. The reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was quenched with H2O at 0 °C, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (9:1 hexanes/EtOAc) afforded the title compound (33%) as a

1 colorless oil; H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 8.0 Hz, 1.6 Hz, 1 H), 7.33 –

7.29 (m, 2 H), 7.25 – 7.21 (m, 1 H), 7.10 – 7.06 (m, 1 H), 6.99 (td, J = 7.7 Hz, 1.5 Hz, 1

H), 6.95 − 6.92 (m, 3 H). See: Hu, J.; Koehmainen, E.; Knuutinen, J. Magn. Reson.

Chem. 2000, 38, 375–378.

O OMe

1-Bromo-2-(3-methoxyphenoxy)benzene (S5)

A mixture of copper(I) iodide (210 mg, 1.1 mmol, 0.1 equiv), Cs2CO3 (5.40 g, 16.5 mmol, 1.5 equiv), 3-methoxyphenol (1.64 g, 13.2 mmol, 1.2 equiv), 1,2-dibromobenzene

(2.59 g, 11 mmol, 1.0 equiv), and N,N-dimethylglycine (340 mg, 3.3 mmol, 0.3 equiv) in anhydrous 1,4-dioxane (44 mL) under an argon balloon was stirred at room temperature for 30 min and then at 115 °C overnight. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated in vacuo.

Purification by silica gel chromatography (9:1 hexanes/EtOAc) afforded the title compound (30%) as a colorless oil; Rf = 0.67 (4:1 hexanes/EtOAc); IR (neat) νmax 1604,

148

1594, 1578, 1486, 1468, 1261, 1226, 1135, 1044, 951, 844, 755 cm-1; 1H NMR (400

MHz, CDCl3) δ 7.64 – 7.61 (m, 1 H), 7.29 – 7.20 (m, 2 H), 7.04 – 6.99 (m, 2 H), 6.67 –

13 6.64 (m, 1 H), 6.55 − 6.51 (m, 2 H), 3.78 (s, 3 H); C NMR (150 MHz, CDCl3) δ 161.1,

158.2, 153.6, 133.6, 130.3, 128.8, 125.3, 121.1, 110.2, 109.1, 104.3, 55.5; HRMS (ESI-

+ + TOF) calcd. for C13H11BrO2H [M + H ] 279.0015, found 279.0005.

Br OMe

(2-Bromophenyl)(4-methoxyphenyl)methanone (S6)

A solution of 2-bromobenzoyl chloride (0.52 mL, 878 mg, 4 mmol) in CHCl3 (1.03 mL) was added at −15 °C to anhydrous aluminum chloride (572 mg, 1.04 mol) in CHCl3 (1.44 mL) and the resulting mixture stirred for 15 min at room temperature. Anisole (0.52 mL,

519 mg, 4.8 mmol, 1.2 equiv) in CHCl3 (0.4 mL) was then added dropwise, and the mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with 2 N aqueous HCl (1 mL), the layers were separated, and the aqueous layer was extracted with CHCl3 (3 × 2 mL). The organic layers were combined, washed with 2 N aqueous HCl (3 × 1 mL), saturated aqueous NaHCO3 (2 × 1 mL), brine (2 × 1 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was recrystallized from

MeOH to afford the title compound (880 mg, 76%) as a white solid; 1H NMR (400 MHz,

CDCl3) δ 7.79 (d, J = 8.8 Hz, 2 H), 7.63 (d, J = 7.6 Hz, 1 H), 7.43 – 7.39 (m, 1 H), 7.35 –

7.31 (m, 2 H), 6.94 (d, J = 8.8 Hz, 2 H), 3.87 (s, 3 H). See: Moorthy, J. N.; Samanta, S.

J. Org. Chem. 2007, 72, 9786−9789.

149

1-Benzyl-2-bromobenzene (S7)

A solution of 2-bromobenzylbromide (250 mg, 1.22 mmol) in benzene (3 mL) was treated with AlCl3 in THF (0.05 ml, 0.5 M) under argon balloon. The solution was refluxed for 5 h. The reaction mixture was extracted with Et2O (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (100% hexanes) afforded the title compound (200 mg, 81%) as a

1 colorless liquid; H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 8.0, 1.2 Hz, 1 H), 7.30 (t, J

= 7.2 Hz, 2 H), 7.24 − 7.19 (m, 4 H), 7.14 (dd, J = 7.7, 1.7 Hz, 1 H), 7.08 (td, J = 7.6, 1.7

Hz, 1 H), 4.13 (s, 2 H). See: Odedra, A.; Datta, S.; Liu, R.-S. J. Org. Chem. 2007, 72,

3289–3292.

General Methods for 1,2-addition followed by oxidation

Method A (iodoarenes)

A solution of iodoarene (1 mmol) in THF (10 mL) at −40 °C was treated with iPrMgCl

(2.3 M, 1.05 mmol, 1.05 equiv) in Et2O. After 1 h at −40 °C, 2-bromobenzaldehyde

(1.05 mmol, 1.05 equiv) was added. After stirring for 3 h, the reaction mixture was diluted with saturated aqueous NH4Cl (15 mL) and EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (100% hexanes à 4:1 hexanes/EtOAc) afforded the benzylic alcohol. This intermediate was dissolved in CH2Cl2 (4 mL) and treated with MnO2 (10.0

150 mmol, 10 equiv). The reaction mixture was stirred at room temperature overnight, filtered through Celite, and concentrated in vacuo. Purification by silica gel chromatography (100% hexanes à 4:1 hexanes/EtOAc) afforded chromatographically and spectroscopically pure product.

Method B (bromoarenes)

A solution of bromoarene (1 mmol) in THF (2.5 mL) at 0 °C was treated with iPrMgCl•LiCl (1.0 mL, 1 mmol, 1.0 M, 1 equiv) in THF dropwise. The reaction mixture was stirred at 0 °C for 2−3 h, then treated with a solution of 2-bromobenzaldehyde (0.9 mmol, 0.9 equiv) in THF (0.5 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (100% hexanes à 4:1 hexanes/EtOAc) afforded the benzylic alcohol.

This intermediate was dissolved in CH2Cl2 (4 mL) and treated with MnO2 (10.0 mmol, 10 equiv). The reaction mixture was stirred at room temperature overnight, filtered through

Celite, and concentrated in vacuo. Purification by silica gel chromatography (100% hexanes à 4:1 hexanes/EtOAc) afforded chromatographically and spectroscopically pure product.

Method C (fluoroarenes)

A solution of fluoroarene (1 mmol, 1.0 equiv) in THF (1 mL) at −78 °C was treated dropwise with nBuLi in hexanes (1.0 mmol, 1 equiv). The solution was stirred for 30

151 min, then treated with 2-bromobenzaldehyde (1.0 mmol) in THF (1 mL) at −78 °C. The solution was stirred at −78 °C for 30 min, then allowed to warm to 0 °C before quenching with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (100% hexanes à 4:1 hexanes/EtOAc) afforded the benzylic alcohol.

This intermediate was dissolved in CH2Cl2 (4 mL) and treated with MnO2 (10.0 mmol, 10 equiv). The mixture was stirred at room temperature overnight, filtered through Celite, and concentrated in vacuo. Purification by silica gel chromatography (100% hexanes à

4:1 hexanes/EtOAc) afforded chromatographically and spectroscopically pure product.

Br COOMe

Methyl 4-(2-bromobenzoyl)benzoate (S8)

Method A. Yield: 85% as a white solid; m.p. 63 °C; IR (neat) νmax 3057, 3001, 2952,

-1 1 1720, 1674, 1434, 1271, 1245, 1104, 928, 764, 731 cm ; H NMR (400 MHz, CDCl3) δ

8.09 (d, J = 8.3 Hz, 2 H), 7.83 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 7.8 Hz, 1 H), 7.43 – 7.33

13 (m, 3 H), 3.91 (s, 3 H); C NMR (100 MHz, CDCl3) δ 195.4, 166.3, 140.2, 139.6, 134.5,

133.5, 131.8, 130.1, 130.0, 129.4, 127.6, 119.7, 52.7; HRMS (ESI-TOF) calcd. for

+ + C15H11BrO3H [M + H ] 318.9964, found 318.9976.

Br CN

4-(2-Bromobenzoyl)benzonitrile (S9)

152

Method B. Yield: 60% as a white solid; m.p. 116 °C; IR (neat) νmax 3063, 2924, 2231,

1676, 1588, 1429, 1310, 1283, 1249, 929, 855, 753, 677 cm-1; 1H NMR (400 MHz,

CDCl3) δ 7.89 (d, J = 8.3 Hz, 2 H), 7.76 (d, J = 8.3 Hz, 2 H), 7.66 (d, J = 7.8 Hz, 1 H),

13 7.48 – 7.35 (m, 3 H); C NMR (100 MHz, CDCl3) δ 194.7, 139.6, 139.5, 133.6, 132.7,

132.2, 130.5, 129.5, 127.8, 119.7, 118.1, 117.0; HRMS (ESI-TOF) calcd. for

+ + C14H8BrNOH [M + H ] 285.9862, found 285.9861.

CF3

Br CF3

(3,5-Bis(trifluoromethyl)phenyl)(2-bromophenyl)methanone (S10)

Method B. Yield: 54% as a white solid; m.p. 68 °C; IR (neat) νmax 1686, 1379, 1278,

-1 1 1242, 1178, 1135, 911, 749, 681 cm ; H NMR (400 MHz, CDCl3) δ 8.24 (s, 2 H), 8.10

(s, 1 H), 7.70 (dd, J = 7.9, 1.1 Hz, 1 H), 7.52 – 7.39 (m, 3 H); 13C NMR (100 MHz,

CDCl3) δ 193.2, 138.8, 138.0, 133.8, 132.6 (q, JCF = 34.2 Hz), 132.6, 130.1 – 129.9 (m),

129.6, 128.0, 126.8 (dt, JCF = 7.4 Hz, 3.7 Hz), 123.0 (q, JCF = 271.6 Hz), 119.7; HRMS

+ + (ESI-TOF) calcd. for C15H7BrF6OH [M + H ] 396.9675, found 396.9660.

O F

Br F F

(2-Bromophenyl)(3,4,5-trifluorophenyl)methanone (S11)

Method C. Yield: 45% as a colorless oil; IR (neat) νmax 3076, 1676, 1618, 1588, 1508,

1470, 1430, 1297, 1281, 1204, 1150, 1072, 1055, 1040, 1026, 876, 848, 822, 778, 753,

153

-1 1 735, 679 cm ; H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.9 Hz, 1 H), 7.57 – 7.51 (m, 1

H), 7.45 – 7.36 (m, 3 H), 7.09 (tdd, J = 8.9 Hz, 6.7 Hz, 2.1 Hz, 1 H); 13C NMR (150

MHz, CDCl3) δ 191.5, 154.5 (ddd, JCF = 258.8 Hz, 10.1 Hz, 3.2 Hz), 151.3 (dt, JCF =

262.3 Hz, 10.8 Hz, 4.0 Hz) 141.6, 140.2 (dt, JCF = 253.9, 15.3 Hz), 134.3, 133.1, 130.1,

128.5, 125.9 (ddd, JCF = 13.3 Hz, 6.6 Hz, 2.4 Hz), 123.5 (ddd, JCF = 7.7 Hz, 3.7 Hz, 1.7

Hz), 120.2, 112.8 (dd, JCF = 17.8 Hz, 3.9 Hz); HRMS (ESI-TOF) calcd. for

+ + C13H6BrF3OH [M + H ] 314.9627, found 314.9624.

Br F

(2-Bromophenyl)(4-fluorophenyl)methanone (S12)

1 Method C. Yield: 68% as a colorless oil; H NMR (400 MHz, CDCl3) δ 7.86 – 7.82 (m, 2

H), 7.64 (s, 1 H), 7.43 (t, J = 7.4 Hz, 1 H), 7.39 – 7.32 (m, 2 H), 7.14 (t, J = 8.5 Hz, 2 H).

See: Bachmann, W. E.; Chu, E. J.-H. J. Am. Chem. Soc. 1935, 57, 1095–1097.

CF B(OH)2 3

(2-(4-(Trifluoromethyl)phenoxy)phenyl)boronic acid (S13)

According to the “in situ quench” method of Reider119, a solution of aryl iodide (530 mg,

1.67 mmol, 1.0 equiv, azeotroped with benzene 2 × 5 mL) and (iPrO)3B (0.46 mL, 2.01 mmol, 1.2 equiv, freshly distilled over sodium metal) in toluene−THF (4:1 v/v, 3.4 mL) at −78 °C under argon balloon was treated with nBuLi (0.84 mL, 2.4 M in hexanes, 1.2 equiv) dropwise via syringe pump over 30 min. The reaction mixture was stirred at −78

°C for an additional 30 min, then allowed to warm to −20 °C. The reaction mixture was

154 quenched by the addition of 2 N aqueous HCl (3 mL), and the mixture was allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried over

Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography

(4:1 hexanes/EtOAc) afforded the title compound (490 mg, 62%) as a white solid; m.p.

137–139 °C; Rf = 0.37 (4:1 hexanes/EtOAc); IR (neat) νmax 3527, 3374, 1604, 1478,

-1 1 1448, 1414, 1321, 1227, 1155, 1063, 855, 745 cm ; H NMR (600 MHz, CDCl3) δ 7.99

(d, J = 7.3 Hz, 1 H), 7.65 (d, J = 8.1 Hz, 2 H), 7.43 (t, J = 7.7 Hz, 1 H), 7.22 (t, J = 7.2

Hz, 1 H), 7.16 (d, J = 8.1 Hz, 2 H), 6.80 (d, J = 8.2 Hz, 1 H), 6.41 (s, 2 H); 13C NMR

(150 MHz, CDCl3) δ 162.0, 158.8, 137.4, 133.2, 127.6 (q, JCF = 3.7 Hz), 126.7 (q, JCF =

32.9 Hz), 124.4, 124.1 (q, JCF = 271.6 Hz), 119.7, 117.5; HRMS (ESI-TOF) calcd. for

+ + C13H10BF3O3H [M + H ] 283.0748, found 283.0745.

F B(OH)2

(2-(4-Fluorophenoxy)phenyl)boronic acid (S14)

According to the “in situ quench” method of Reider119, a solution of aryl iodide (250 mg,

0.80 mmol, 1.0 equiv, azeotroped with benzene 2 × 3 mL) and (iPrO)3B (0.22 mL, 0.96 mmol, 1.2 equiv, freshly distilled over sodium metal) in toluene−THF (4:1 v/v, 2.0 mL) at −78 °C under argon balloon was treated with nBuLi (0.37 mL, 2.4 M in hexanes, 1.1 equiv) dropwise via syringe pump over 30 min. The reaction mixture was stirred at −78

°C for an additional 30 min, then allowed to warm to −20 °C. The reaction mixture was quenched by the addition of 2 N aqueous HCl (1.5 mL), and the mixture was allowed to warm to room temperature. The layers were separated, and the aqueous layer was

155 extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried over

Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography

(4:1 hexanes/EtOAc) afforded the title compound (26 mg, 14%) as a white solid; m.p.

84–86 °C; Rf = 0.39 (4:1 hexanes/EtOAc); IR (neat) νmax 3402, 1601, 1503, 1479, 1446,

-1 1 1339, 1201, 1045, 850, 764 cm ; H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 7.2 Hz, 1

H), 7.36 (t, J = 7.8 Hz, 1 H), 7.13 (t, J = 7.2 Hz, 1 H), 7.12 – 7.06 (m, 4 H), 6.67 (d, J =

13 8.2 Hz, 1 H), 5.93 (s, 2 H); C NMR (150 MHz, CDCl3) δ 163.8, 160.6, 159.0, 151.2 (d,

JCF = 2.8 Hz), 137.2, 133.0, 123.2, 122.1, 122.1, 117.0, 116.8, 115.6; HRMS (ESI-TOF)

+ + calcd. for C12H10BFO3H [M + H ] 233.0780, found 233.0780.

CO Me B(OH)2 2

(2-(4-(Methoxycarbonyl)phenoxy)phenyl)boronic acid (S15)

A dry and nitrogen-flushed 10-mL flask equipped with a magnetic stirrer and a septum was charged with aryl iodide (245 mg, 0.69 mmol, 1 equiv) and (iPrO)3B (0.30 mL, 1.31 mmol, 1.9 equiv). THF was then added (1.4 mL). The reaction mixture was cooled to 0

°C, and iPrMgClLiCl (0.76 mL, 1.0 M in THF, 0.76 mmol, 1.1 equiv) was added dropwise over 5 min. The mixture was stirred for 30 min a 0 °C before 0.5 M HCl was added. The solution was stirred for 5 min and then diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 15 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo.

Purification by silica flash chromatography (4:1 hexanes/EtOAc) afforded the title compound (136 mg, 72%) as a white solid; m.p. 75–85 °C; Rf = 0.19 (4:1 hexanes/EtOAc); IR (neat) νmax 3377, 1719, 1603, 1478, 1444, 1432, 1275, 1214, 1163,

156

-1 1 875, 754, 693 cm ; H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 2 H), 7.97 (d, J =

7.1 Hz, 1 H), 7.40 (t, J = 8.6 Hz, 1 H), 7.19 (t, J = 7.2 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 2 H),

13 6.80 (d, J = 8.2 Hz, 1 H), 6.36 (s, 2 H), 3.91 (s, 3 H); C NMR (150 MHz, CDCl3) δ

166.5, 161.8, 160.0, 137.3, 133.0, 132.0, 131.8, 130.1, 124.3, 120.2, 119.0, 117.7, 117.3,

+ + 52.3; HRMS (ESI-TOF) calcd. for C14H13BO5H [M + H ] 273.0929, found 273.0922.

O OMe

B(OH)2

(2-(3-Methoxyphenoxy)phenyl)boronic acid (S16)

A solution of nBuLi in THF (1.24 mL, 2.3 M, 2.86 mmol, 1.05 equiv) was added dropwise to a solution of 1-bromo-2-(3-methoxyphenoxy)benzene (760 mg, 2.72 mmol) in anhydrous THF (9.5 mL) at −78 °C. The resulting mixture was stirred at −78 °C for

45 min and freshly distilled (Na) (iPrO)3B (1.57 mL, 6.8 mmol, 2.5 equiv) was added.

The mixture was stirred at −78 °C for 1 h and then at room temperature for a further 1 h.

Et2O (9 mL) and 1 M HCl (9 mL) were added at 0 °C. The mixture was stirred at 0 °C for 10 min, at room temperature for 1 h, and then extracted with Et2O. The combined organic extracts were washed with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (4:1 hexanes/EtOAc) afforded the title compound (400 mg, 64%) as a white solid; m.p. 71–74 °C; Rf = 0.29

(4:1 hexanes/EtOAc); IR (neat) νmax 3411, 1602, 1478, 1442, 1335, 1200, 1140, 1040,

-1 1 949, 850, 762, 685 cm ; H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 7.1 Hz, 1 H), 7.34 (d,

J = 7.7 Hz, 1 H), 7.27 – 7.23 (m, 1 H), 7.12 – 7.10 (m, 1 H), 6.76 – 6.73 (m, 2 H), 6.66 –

13 6.62 (m, 2 H), 6.22 (s, 2 H), 3.77 (s, 3 H); C NMR (150 MHz, CDCl3) δ 163.2, 161.2,

157

156.7, 137.0, 132.9, 130.6, 123.3, 116.5, 112.4, 110.6, 106.3, 55.6; HRMS (ESI-TOF)

+ + calcd. for C13H13BO4H [M + H ] 245.0980, found 245.0978.

General Method for Miyaura borylation followed by treatment with KHF2

A microwave vial was charged with PdCl2(CH3CN)2 (0.02 mmol), SPhos (0.08 mmol) and aryl halide (1.0 mmol), evacuated, and backfilled with argon. Anhydrous 1,4- dioxane (0.60 mL) was added via syringe, through the septum, followed by Et3N (0.21 mL, 1.5 mmol, 1.5 equiv) and pinacol borane (0.23 mL, 1.5 mmol, 1.5 equiv). The septum was exchanged for a microwave vial cap, and the reaction mixture was degassed with argon for 10 min. The reaction mixture was stirred at 110 °C until the aryl halide was consumed as determined by TLC (1−2 h). The mixture was filtered through a small plug of silica gel and concentrated in vacuo. Purification by silica gel chromatography

(100% hexanes à 4:1 hexanes/EtOAc) afforded the corresponding pinacol boronate ester. A concentrated solution of the pinacol boronate ester in MeOH (2 mL) at room temperature was treated with a saturated aqueous solution of KHF2 (4.5 M, 3 equiv). The mixture was stirred for 30 min. The solvent was removed in vacuo and pinacol was removed by evaporation (4 × 2 mL) from MeOH–H2O (1:1 v/v). The solid was dried thoroughly and extracted with acetone (3 × 5 mL) and then with hot acetone (1 × 5 mL).

The organic layer was filtered and evaporated to dryness. The crude product was washed with Et2O (3 × 2 mL) and recrystallized from acetone/Et2O to afford chromatographically and spectroscopically pure product.

158

BF3K OMe

Trifluoroborate (S17)

Yield: 40% (two steps) as a white solid; m.p. 179 °C; IR (neat) νmax 3628, 3052, 3007,

2936, 2841, 1709, 1654, 1593, 1509, 1290, 1253, 1178, 1150, 998, 946, 929, 846, 751,

-1 1 696 cm ; H NMR (400 MHz, (CD3)2CO) δ 7.73 (dd, J = 11.5, 8.4 Hz, 3 H), 7.28 (t, J =

7.3 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 6.98 (dd, J = 19.7, 8.1 Hz, 3 H), 3.88 (s, 3 H). 13C

NMR (100 MHz, (CD3)2CO) δ 201.7, 164.1, 144.1, 134.1 (q, JCF = 2.5 Hz), 133.4, 132.3,

+ 128.5, 126.4, 125.4, 113.9, 55.9; HRMS (ESI-TOF) calcd. for C15H14BO3 [M − F3K +

OMe]+ 253.1033, found 253.1032.

BF3K

Trifluoroborate (S18)

Yield: 54% (two steps) as a white solid; m.p. 170 °C; IR (neat) νmax 3627, 3058, 3025,

-1 1 2917, 2850, 1596, 1494, 1437, 1208, 953, 752, 700 cm ; H NMR (400 MHz, (CD3)2CO)

δ 7.59 – 7.55 (m, 1 H), 7.31 – 7.06 (m, 5 H), 6.95 – 6.78 (m, 3 H), 4.20 (s, 2 H); 13C

NMR (100 MHz, (CD3)2CO) δ 145.4, 144.9, 133.1 (q, JCF = 3.2 Hz), 130.4, 129.0, 128.6,

126.4, 125.7, 124.5, 41.1. Did not ionize in HRMS (ESI-TOF).

BF3K COOMe

Trifluoroborate (S19)

159

Yield: 30% (two steps) as a white solid; m.p. 234 °C; IR (neat) νmax 3627, 1723, 1666,

-1 1 1437, 1405, 1283, 1192, 1108, 951, 932, 753, 724 cm ; H NMR (400 MHz, CD3CN) δ

8.03 (d, J = 8.4 Hz, 2 H), 7.81 (d, J = 8.4 Hz, 2 H), 7.64 (d, J = 7.3 Hz, 1 H), 7.36 (t, J =

7.2 Hz, 1 H), 7.23 (t, J = 7.5 Hz, 1 H), 7.06 (d, J = 7.5 Hz, 1 H), 3.88 (s, 3 H); 13C NMR

(150 MHz, CD3CN): δ 202.3, 177.5, 167.1, 143.6, 142.7, 134.1, 133.7 (d, JCF = 2.2 Hz),

+ 130.9, 129.8, 129.1, 126.1, 52.9; HRMS (ESI-TOF) calcd. for C16H14BO4 [M − F3K +

OMe]+ 281.0985, found 281.0992.

BF3K CN

Trifluoroborate (S20)

Yield: 33% (two steps) as a white solid; m.p. 253 °C; IR (neat) νmax 3630, 3052, 2233,

1669, 1285, 1256, 1191, 1049, 950, 930, 858, 754, 709, 689 cm-1; 1H NMR (400 MHz,

CD3CN) δ 7.83 (d, J = 8.4 Hz, 2 H), 7.77 (d, J = 8.5 Hz, 2 H), 7.63 (d, J = 7.2 Hz, 1 H),

7.36 (t, J = 7.4 Hz, 1 H), 7.24 (t, J = 7.4 Hz, 1 H), 7.06 (d, J = 7.5 Hz, 1 H); 13C NMR

(150 MHz, CD3CN) δ 201.8, 143.2, 142.7, 133.7, 133.0, 131.2, 129.3, 126.3, 126.1,

− + 119.3, 116.0; HRMS (ESI-TOF) calcd. for C14H8BF3NO [M − K ] 274.0651, found

274.0659.

CF3

BF3K CF3

Trifluoroborate (S21)

160

Yield: 36% (two steps) as a white solid; m.p. 211 °C; IR (neat) νmax 3631, 3059, 1713,

1677, 1615, 1379, 1275, 1245, 1182, 1129, 1109, 1001, 948, 911, 753, 681 cm-1; 1H

NMR (400 MHz, (CD3)2CO) δ 8.24 (s, 2 H), 8.15 (s, 1 H), 7.66 (d, J = 7.4 Hz, 1 H), 7.32

(t, J = 7.3 Hz, 1 H), 7.21 (td, J = 7.4, 1.2 Hz, 1 H), 7.13 (d, J = 7.5 Hz, 1 H); 13C NMR

(150 MHz, (CD3)2CO) δ 199.6, 142.3, 141.7, 133.8 (q, JCF = 2.4 Hz), 131.6 (q, JCF = 33.4

Hz), 130.8 (q, JCF = 3.9 Hz), 129.5, 126.4, 126.3 (d, JCF = 2.6 Hz), 125.9 (dt, JCF = 7.7

+ Hz, 3.8 Hz), 124.3 (q, JCF = 272.0 Hz); HRMS (ESI-TOF) calcd. for C16H10BF6O2 [M −

+ F3K + OMe] 259.0678, found 259.0677.

O F

BF3K F F

Trifluoroborate (S22)

Yield: 40% (two steps) as a white solid; m.p. 263 °C; IR (neat) νmax 3059, 1681, 1509,

1630, 1509, 1463, 1308, 1270, 1194, 1059, 1016, 949, 923, 856, 831, 747, 688 cm-1; 1H

NMR (400 MHz, (CD3)2CO) δ 7.67 (d, J = 7.4 Hz, 1 H), 7.33 – 7.31 (m, 2 H), 7.17 (d, J

13 = 9.6 Hz, 3 H); C NMR (150 MHz, (CD3)2CO) δ 197.9, 153.6 (ddd, JCF = 252.5, 10.1,

2.6 Hz), 151.5 (ddd, JCF = 259.5, 10.3, 3.8 Hz), 144.5, 140.5 (dt, JCF = 248.8, 15.5 Hz),

134.0 (d, JCF = 3.0 Hz), 129.5, 128.0 – 127.9 (m), 127.2 (d, JCF = 9.0 Hz), 126.6, 125.9,

+ 112.2 (dd, JCF = 17.7, 4.2 Hz); HRMS (ESI-TOF) calcd. for C14H9BF3O2 [M − F3K +

OMe]+ 277.0650, found 277.0645.

BF3K F 161

Trifluoroborate (S23)

Yield: 29% (two steps) as a white solid; m.p. 207 °C; IR (neat) νmax 3634, 3054, 1662,

1596, 1504, 1286, 1258, 1232, 1193, 1149, 1103, 1050, 951, 931, 852, 752 cm-1; 1H

NMR (400 MHz, DMSO-d6) δ 7.68 (dd, J = 8.7, 5.8 Hz, 2 H), 7.49 (d, J = 7.4 Hz, 1 H),

7.27 – 7.20 (m, 3 H), 7.16 (t, J = 7.4 Hz, 1 H), 6.93 (d, J = 7.5 Hz, 1 H); 13C NMR (150

MHz; DMSO-d6) δ 199.4, 164.4 (d, JCF = 250.0 Hz), 143.0, 135.1, 132.5, 132.4, 127.4,

+ 125.1, 124.5, 114.8 (d, JCF = 21.8 Hz); HRMS (ESI-TOF) calcd. for C14H11BFO2 [M −

+ F3K + OMe] 241.0833, found 241.0829.

BF3K O

Trifluoroborate (S24)

To the bromide (159 mg, 0.61 mmol) in a microwave reaction vial equipped with a stir bar was added bis(pinacolato)diboron (308 mg, 1.21 mmol), anhydrous KOAc (179 mg,

1.82 mmol). The vial was sealed with a septum, and anhydrous 1,4-dioxane (2.5 mL) was added under argon balloon. The reaction mixture was degassed by bubbling with argon while sonicating for 10 min. PdCl2(dppf)CH2Cl2 (25 mg, 0.03 mmol) was then quickly added followed by an additional 5 min of degassing. The septum was then quickly replaced with a Teflon rupture disk under a blanket of argon. The reaction mixture was stirred at 100 °C in an oil bath for 17 h. The reaction mixture was then cooled to room temperature, filtered through a Celite plug, and concentrated in vacuo.

The crude product was purified via flash column chromatography on silica gel eluting with 50% EtOAc/hexanes. The boronate ester (contaminated with

162 bis(pinacolato)diboron) was then dissolved in MeOH (2 mL) followed by the addition of saturated aqueous KHF2 (~4.5 M, 0.4 mL) and stirred for 30 min. The reaction mixture was then concentrated on the rotovap. Pinacol was then azeotropically removed by dissolving the crude BF3K salt in MeOH/H2O (1:1 v/v, 3 mL) and concentrating on the rotary evaporator a total of four times followed by drying under high-vacuum for 1 h.

The BF3K salt was rinsed with hot acetone (5 × 10 mL) and concentrated to yield a pale yellow foam. The foam was then dissolved in a minimal amount of acetone and crystallized with Et2O at 0 °C, yielding the title compound (43%) as a white solid; m.p.

-1 1 160–162 °C; IR (neat) νmax 3060, 1674, 1582, 1416, 1188, 945, 926 cm ; H NMR (600

MHz, (CD3)2CO) δ 8.85 (d, J = 2.1 Hz, 1 H), 8.65 (dd, J = 4.8, 1.8 Hz, 1 H), 8.01 – 7.98

(m, 1 H), 7.67 (d, J = 7.4 Hz, 1 H), 7.39 (dd, J = 5.0 Hz, 1 H), 7.29 (t, J = 7.4 Hz, 1 H),

13 7.17 (t, J = 7.4 Hz, 1 H), 7.05 (d, J = 7.5 Hz, 1 H); C NMR (125 MHz, (CD3)2CO) δ

201.8, 153.3, 152.1, 143.3, 137.8, 134.7, 134.0, 129.0, 126.2, 125.9, 123.8; HRMS (ESI-

TOF) calcd. for C12H8BF3KNO 289.0288 (did not ionize). See: Harrowven, D. C.;

Sutton, B. J.; Coulton, S. Org. Biomol. Chem. 2003, 1, 4047–4057. (bromide)

BF3K

N N EtOOC

Heterocycle alkyltrifluoroborate (S25)

To a solution of 2-(4-bromobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (131.5 mg,

0.5 mmol) in CH3CN (1 ml) was added ethyl 1H-pyrazole-4-carboxylate (210 mg, 1.5 mmol, 3 equiv) and K2CO3 (345 mg, 2.5 mmol, 5 equiv). The reaction mixture was

163 stirred at 90 °C for 2 h. The crude product was partitioned between EtOAc and H2O.

The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo.

Purification by silica gel chromatography (100% hexanes à 1:1 hexanes/EtOAc) afforded the pinacol boronate ester (110 mg, 0.59 mmol). A concentrated solution of the pinacol boronate ester (90 mg, 0.28 mmol) in MeOH at room temperature was treated with a solution of saturated aqueous KHF2 (0.20 mL, 4.5 M, 0.92 mmol, 3.3 equiv). The solution was stirred for 15 min. The solvent was removed in vacuo and pinacol was removed by serial evaporation (4 × 1 mL) from MeOH–H2O (1:1 v/v). The crude product was extracted with acetone (4 × 2 mL), then hot acetone (2 mL), filtered, and concentrated in vacuo. The solid was washed with Et2O and recrystallized from acetone/Et2O to afford the title compound (80 mg, 53 % two steps) as a white solid; m.p.

138 °C; IR (neat) νmax 3564, 3132, 2981, 2929 1708, 1554, 1410, 1219, 1113, 1088,

-1 1 1028, 983, 938, 843, 767, 722 cm ; H NMR (400 MHz, (CD3)2CO) δ 7.95 (s, 1 H), 7.62

(s, 1 H), 4.07 (q, J = 7.1 Hz, 2 H), 3.97 (t, J = 7.3 Hz, 2 H), 1.66 (quintet, J = 7.4 Hz, 2

H), 1.15 – 1.09 (m, 5 H), 0.03 (dq, J = 14.9 Hz, 7.2 Hz, 2 H); 13C NMR (100 MHz,

(CD3)2CO) δ 163.4, 140.8, 133.4, 115.0, 60.2, 53.4, 34.2, 23.2 (d, JCF = 2.4 Hz), 14.7;

Did not ionize in HRMS (ESI-TOF).

Standard Procedure for “borono-Pschorr” cyclization

To a solution of boronic acid or trifluoroborate (0.1 mmol, 1.0 equiv) in trifluorotoluene

(0.5 mL) and water (0.48 mL) was added silver(I) nitrate (20 µL, 1 M, 0.02 mmol, 0.2 equiv). Potassium persulfate (81.1 mg, 0.3 mmol, 3.0 equiv) was then added in one

164 portion and the reaction mixture was stirred vigorously at 60 °C for 1 h. The mixture was extracted with EtOAc (5 ×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (100% hexanes à 4:1 hexanes/EtOAc) afforded chromatographically and spectroscopically pure product.

CF3

2-(Trifluoromethyl)dibenzo[b,d]furan (1)

Yield: 73% (gram-scale: 65%) as a white solid; m.p. 97 °C; IR (neat) νmax 2922, 1453,

1352, 1334, 1319, 1274, 1164, 1105, 1053, 898, 826, 770, 754 cm-1; 1H NMR (400 MHz,

CDCl3) δ 8.24 (s, 1 H), 8.00 (d, J = 7.5 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.67 – 7.61

13 (m, 2 H), 7.53 (t, J = 7.3 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 1 H); C NMR (150 MHz, CDCl3)

δ 158.5, 157.7, 129.1, 126.2 (q, JCF = 32.3 Hz), 125.4 (q, JCF = 271.9 Hz,), 125.4, 125.1

(q, JCF = 3.6 Hz), 124.2, 124.2, 121.8, 119.2 (q, JCF = 4.0 Hz), 112.9, 112.8; Did not ionize in HRMS (ESI-TOF).

2-Fluorodibenzo[b,d]furan (2)

1 Yield: 69%; H NMR (400 MHz; CDCl3) δ 7.92 (d, J = 7.7 Hz, 1 H), 7.62 – 7.56 (m, 2

H), 7.52 – 7.46 (m, 2 H), 7.37 – 7.33 (m, 1 H), 7.17 (td, J = 9.0, 2.7 Hz, 1 H). See: J. Am.

Chem. Soc. 2009, 131, 4194–4195.

165

COOMe

Methyl dibenzo[b,d]furan-2-carboxylate (3)

1 Yield: 57%; H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 1.4 Hz, 1 H), 8.19 (dd, J = 8.6

Hz, 1.7 Hz, 1 H), 8.01 (d, J = 7.7 Hz, 1 H), 7.61 – 7.59 (m, 2 H), 7.51 (td, J = 7.8, 1.1 Hz,

1 H), 7.42 – 7.38 (m, 1 H), 3.99 (s, 3 H). See: Org. Lett. 2004, 6, 3739–3742.

Dibenzo[b,d]furan (4)

1 Yield: 65%; H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.7 Hz, 1 H), 7.58 (d, J = 8.2 Hz,

1 H), 7.47 (t, J = 7.7 Hz, 1 H), 7.35 (t, J = 7.5 Hz, 1 H). See: J. Am. Chem. Soc. 2009,

131, 4194–4195.

MeO

OMe

O O

1-Methoxydibenzo[b,d]furan (5a) and 3-methoxydibenzo[b,d]furan (5b)

Yield: 41%, inseparable mixture (5:1 para:ortho); major isomer (5a): 1H NMR (400

MHz, CDCl3) δ 8.14 (d, J = 7.6 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.42 (dt, J = 7.7, 1.4

Hz, 1 H), 7.39 (t, J = 7.7 Hz, 1 H), 7.34 (dt, J = 7.7, 1.4 Hz, 1 H), 7.21 (d, J = 2.4 Hz, 1

H), 6.80 (d, J = 8.4 Hz, 1 H), 4.06 (s, 3 H). See: Oliveira, A. M. A. G.; Raposo, M. M.

166

M.; Oliveira-Campos, A. M. F.; Griffiths, J.; Machado, A. E. H. Helv. Chim. Acta 2003,

86, 2900–2907.

OMe

3-Methoxy-9H-fluoren-9-one (6)

1 Yield: 43%; H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 7.8, 3.2 Hz, 2 H), 7.50 – 7.45

(m, 2 H), 7.30 (td, J = 7.0, 0.6 Hz, 1 H), 7.03 (d, J = 1.9 Hz, 1 H), 6.75 (dd, J = 8.1, 1.5

Hz, 1 H), 3.92 (s, 3 H). See: Moorthy, J. N.; Samanta, S. J. Org. Chem. 2007, 72,

9786−9789.

Fluorenone (7)

1 Yield: 30% as a yellow solid from CH2 and 41% from CHOH; H NMR (400 MHz,

CDCl3) δ 7.56 (d, J = 7.4 Hz, 2 H), 7.43 – 7.37 (m, 4 H), 7.20 (t, J = 7.2 Hz, 2 H). See:

Tilly, D.; Fu, J.; Zhao, B.; Alessi, M.; Castanet, A.-S.; Snieckus, V.; Mortier, J. Org. Lett.

2010, 12, 68–71.

COOMe

Methyl 9-oxo-9H-fluorene-3-carboxylate (8)

167

Yield: 67% as a yellow solid; m.p. 145 °C; IR (neat) νmax 3055, 2960, 1713, 1420, 1277,

-1 1247, 1189, 1102, 921, 728, 661 cm ; 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1 H), 7.98

(d, J = 7.6 Hz, 1 H), 7.69 (t, J = 7.4 Hz, 2 H), 7.59 (d, J = 7.4 Hz, 1 H), 7.53 (t, J = 7.4

13 Hz, 1 H), 7.33 (t, J = 7.4 Hz, 1 H), 3.97 (s, 3 H); C NMR (100 MHz, CDCl3) δ 193.2,

166.3, 144.6, 143.9, 137.6, 137.6, 135.7, 135.4, 134.3, 131.0, 129.8, 124.8, 124.2, 121.4,

+ + 121.0, 52.8; HRMS (ESI-TOF) calcd. for C15H10O3H [M + H ] 239.0703, found

239.0703. See: Harget, A. J.; Warren, K. D.; Yandle, J. R. J. Chem. Soc. B. 1968,

214−218.

9-Oxo-9H-fluorene-3-carbonitrile (9)

1 Yield: 77% from C(O) and 55% from CHOH; H NMR (400 MHz, (CD3)2CO) δ 8.19 (s,

1 H), 7.92 (d, J = 7.4 Hz, 1 H), 7.81 (q, J = 8.5 Hz, 2 H), 7.70 (t, J = 6.7 Hz, 2 H), 7.50 (t,

J = 7.5 Hz, 1 H). See: Harget, A. J.; Warren, K. D.; Yandle, J. R. J. Chem. Soc. B. 1968,

214−218.

CF3

F3C

2,4-Bis(trifluoromethyl)-9H-fluoren-9-one (10)

Yield: 61% as a yellow solid; m.p. 124 °C; IR (neat) νmax 3119, 2924, 1729, 1633, 1388,

-1 1 1292, 1275, 1247, 1155, 1140, 1118, 909, 743 cm ; H NMR (400 MHz, CDCl3) δ 8.10

168

(s, 1 H), 8.03 (s, 1 H), 7.93 (d, J = 7.7 Hz, 1 H), 7.81 (d, J = 7.4 Hz, 1 H), 7.63 (t, J = 7.7

13 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 1 H); C NMR (150 MHz, CDCl3) δ 191.4, 146.2, 141.2,

137.4, 136.7, 135.1, 132.4 (q, JCF = 34.1 Hz), 132.1, 129.4 − 129.2 (m), 126.2 (q, JCF =

5.5 Hz), 125.9, 125.7 (q, JCF = 34.6 Hz), 124.9 (q, JCF = 3.7 Hz), 123.8 (q, JCF = 273.2

Hz); Did not ionize in HRMS (ESI-TOF); GC/MS, M+ 316.

F F

2,3,4-Trifluoro-9H-fluoren-9-one (11)

Yield: 71% as a yellow solid; m.p. sublimes; IR (neat) νmax 3076, 1714, 1625, 1601,

-1 1 1506, 1464, 1249, 1090, 876, 801, 761, 738, 690 cm ; H NMR (400 MHz, DMSO-d6) δ

7.96 – 7.92 (m, 1 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.71 – 7.65 (m, 2 H), 7.46 (td, J = 7.5, 0.7

13 Hz, 1 H); C NMR (150 MHz, DMSO-d6) δ 189.0, 156.2 (dd, JCF = 256.5, 10.3 Hz),

149.6 – 147.7 (m), 142.9, 141.6 – 141.6 (m), 140.8 (dt, J = 250.9, 16.2 Hz), 137.0, 134.7,

131.6, 125.5, 123.3, 118.1 (d, JCF = 10.8 Hz), 108.6 (d, JCF = 21.3 Hz); HRMS (ESI-

+ + TOF) calcd. for C13H5F3OH [M + H ] 235.0365, found 235.0363.

3-Fluoro-9H-fluoren-9-one (12)

1 Yield: 65%; H NMR (400 MHz, CDCl3) δ 7.66 (m, J = 7.9, 5.4 Hz, 2 H), 7.51 (m, J =

6.3 Hz, 2 H), 7.36 – 7.32 (m, 1 H), 7.20 (dd, J = 8.3, 2.2 Hz, 1 H), 6.95 (td, J = 8.6, 2.2

169

Hz, 1 H). See: Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem.,

Int. Ed. 2008, 47, 9462−9465.

5H-Indeno[1,2-b]pyridin-5-one (13)

1 Major (Rf = 0.57 in 4:1 hexanes/EtOAc); H NMR (CDCl3, 400 MHz) δ 8.63 (d, J = 5.0

Hz, 1 H), 7.90 (d, J = 7.4 Hz, 1 H), 7.86 (d, J = 7.4 Hz, 1 H), 7.73 (d, J = 7.4 Hz, 1 H),

7.61 (t, J = 7.4 Hz, 1 H), 7.44 (t, J = 7.4 Hz, 1 H), 7.22 (d, J = 5.2 Hz, 1 H), 7.21 (d, J =

5.2 Hz, 1 H).

9H-Indeno[2,1-c]pyridin-9-one (14)

1 Minor (Rf = 0.34 in 4:1 hexanes/EtOAc); H NMR (CDCl3, 400 MHz) δ 8.87 (s, 1 H),

8.65 (d, J = 1.1 Hz, 1 H), 7.76 (d, J = 7.3 Hz, 1 H), 7.66 (d, J = 7.3 Hz, 1 H), 7.60 (t, J =

7.4 Hz, 1 H), 7.53 – 7.47 (m, 2 H). See: Stauffer, K. J.; Williams, P. D.; Selnick, H. G.;

Nantermet, P. G.; Newton, C. L.; Homnick, C. F.; Zrada, M. M.; Lewis, S. D.; Lucas, B.

J.; Krueger, J. A.; Pietrak, B. L.; Lyle, E. A.; Singh, R.; Miller-Stein, C.; White, R. B.;

Wong, B.; Wallace, A. A.; Sitko, G. R.; Cook, J. J.; Holahan, M. A.; Stranieri-Michener,

M.; Leonard, Y. M.; Lynch, Jr., J. J.; McMasters, D. R.; Yan, Y. J. Med. Chem. 2005, 48,

170

2282−2293.

N N EtOOC

Ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylate (15)

1 Yield: 60%; H NMR (400 MHz, CDCl3) δ 7.86 (s, 1 H), 4.27 (q, J = 7.1 Hz, 2 H), 4.15

(t, J = 6.1 Hz, 2 H), 3.06 (t, J = 6.4 Hz, 2 H), 2.07 – 2.01 (m, 2 H), 1.91 – 1.85 (m, 2 H),

1.33 (t, J = 7.1 Hz, 3 H). See: Allin, S. M.; Barton, W. R. S.; Bowman, W. R.; Bridge,

E.; Elsegood, M. R. J.; McInally, T.; McKee, V. Tetrahedron 2008, 64, 7745−7758.

BF3K

Potassium aryltrifluoroborate (S26)

A concentrated solution of 2-(allyloxyphenyl)boronic acid (1.50 g, 8.43 mmol) in MeOH

(10 mL) at room temperature was treated with a saturated aqueous solution of KHF2

(~4.5 M, 6 mL). Within 5 min, a white suspension was obtained. The spin bar was removed, and the suspension was concentrated in vacuo. The white solid was extracted with hot acetone, and the acetone layer was concentrated in vacuo, affording the title compound (750 mg, 40%) as a white solid; m.p. 215 °C; IR (neat) νmax 1192, 954, 927,

-1 1 734 cm ; H NMR (400 MHz, CD3CN) δ 7.42 (d, J = 6.5 Hz, 1 H), 7.10 (t, J = 7.5 Hz, 1

H), 6.81 (t, J = 7.2 Hz, 1 H), 6.78 (d, J = 8.2 Hz, 1 H), 6.13 – 6.04 (m, 1 H), 5.45 (d, J =

17.2 Hz, 1 H), 5.23 (d, J = 10.5 Hz, 1 H), 4.52 (d, J = 5.0 Hz, 2 H); 13C NMR (150 MHz,

CD3CN) δ 162.4, 135.6, 134.4 (q, JCF = 2.8 Hz), 128.1, 120.9, 117.8, 112.4, 69.4; HRMS

171

+ + (ESI-TOF) calcd. for C9H8BF3OH [M – KH + H ] 201.0693, found 201.0700. See:

Morgan, J.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. I 1993, 1673−1676. (boronic acid)

See: Barluenga, J.; Fañanás, F. J.; Sanz, R.; Marcos, C.; Trabada, M. Org. Lett. 2002, 4,

1587−1590. (bromide)

B(OH)2

(2-(But-3-en-1-yl)phenyl)boronic acid (S27)

According to the “in situ quench” method of Reider119, a solution of aryl bromide (495 mg, 2.20 mmol, 1.0 equiv, azeotroped with benzene 2 × 5 mL) and (iPrO)3B (0.54 mL,

2.20 mmol, 1.0 equiv, freshly distilled over sodium metal) in toluene−THF (4:1 v/v, 12 mL) at −78 °C under argon was treated with nBuLi (0.96 mL, 2.3 M in hexanes, 1.0 equiv) dropwise via syringe pump over 30 min. The reaction was mixture stirred at −78

°C for an additional 60 min, then allowed to warm to −20 °C. The reaction mixture was quenched by the addition of 2 N aqueous HCl (10 mL), and the mixture was allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with Et2O (2 × 20 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (12:1 à

3:1 hexanes/EtOAc) afforded the title compound (236 mg, 57%) as a white solid; m.p.

83−84 °C; Rf = 0.24 (3:1 hexanes/EtOAc); IR (neat) νmax 1596, 1441, 1334, 1292, 910,

-1 1 754, 690 cm ; H NMR (400 MHz, CDCl3) δ 8.22 (dd, J = 7.7, 1.4 Hz, 1 H), 7.49 (td, J =

7.6, 1.5 Hz, 1 H), 7.33 – 7.28 (m, 2 H), 5.99 – 5.89 (m, 1 H), 5.07 – 4.98 (m, 2 H), 3.32

13 (t, J = 7.9 Hz, 2 H), 2.51 – 2.45 (m, 2 H); C NMR (100 MHz, CDCl3) δ 150.5, 138.4,

+ 137.8, 132.4, 130.2, 125.6, 115.1, 37.2, 35.2; HRMS (ESI-TOF) calcd. for C10H13BO2H

172

[M + H+] 177.1081, found 177.1076. See: Molander, G. A.; Sandrock, D. L. J. Am.

Chem. Soc. 2008, 130, 15792−15793. (bromide)

B(OH)2

O Me

(2-((2-Methylallyl)oxy)phenyl)boronic acid (S28)

According to the “in situ quench” method of Reider119, a solution of aryl iodide (4.1 g,

14.96 mmol, 1.0 equiv, azeotroped with benzene 2 × 10 mL) and (iPrO)3B (4.6 mL,

17.95 mmol, 1.2 equiv, freshly distilled over sodium metal) in toluene−THF (4:1 v/v, 60 mL) at −78 °C under argon balloon was treated with nBuLi (7.80 mL, 2.3 M in hexanes,

1.2 equiv) dropwise via syringe pump over 30 min. The reaction mixture was stirred at

−78 °C for an additional 60 min, then allowed to warm to −20 °C. The reaction mixture was quenched by the addition of 2 N aqueous HCl (40 mL), and the mixture was allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with Et2O (2 × 60 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (10:1 à

2:1 hexanes/EtOAc) afforded the title compound (2.6 g, 81%) as a white solid; m.p.

51−52 °C (hexanes); Rf = 0.50 (3:1 hexanes/EtOAc); IR (neat) νmax 3400, 1600, 1447,

-1 1 1338, 1217, 1017, 758 cm ; H NMR (500 MHz, CDCl3) δ 7.85 (dd, J = 7.3, 1.6 Hz, 1

H), 7.44 – 7.40 (m, 1 H), 7.03 (t, J = 7.3 Hz, 1 H), 6.90 (d, J = 8.4 Hz, 1 H), 5.91 (s, 2 H),

5.11 – 5.10 (m, 1 H), 5.06 – 5.05 (m, 1 H), 4.55 (s, 2 H), 1.86 (s, 3 H); 13C NMR (125

MHz, CDCl3) δ 163.9, 140.1, 137.0, 132.9, 121.5, 114.3, 111.4, 72.4, 19.7; HRMS (ESI-

173

+ + TOF) calcd. for C10H13BO3H [M + H ] 193.1030, found 193.1035. See: Casaschi, A.;

Grigg, R.; Sansano, J. M. Tetrahedron 2000, 56, 7553−7560. (iodide)

B(OH)2

O Me

(E)-(2-(But-2-en-1-yloxy)phenyl)boronic acid (S29)

According to the “in situ quench” method of Reider119, a solution of aryl iodide (1.16 g,

4.23 mmol, 1.0 equiv, azeotroped with benzene 2 × 10 mL) and (iPrO)3B (1.04 mL, 4.44 mmol, 1.05 equiv, freshly distilled over sodium metal) in toluene−THF (4:1 v/v, 21 mL) at −78 °C under argon was treated with nBuLi (1.93 mL, 2.3 M in hexanes, 5.36 mmol,

1.05 equiv) dropwise via syringe pump over 30 min. The reaction was stirred at −78 °C for an additional 60 min, then allowed to warm to −20 °C. The reaction mixture was quenched by the addition of 2 N aqueous HCl (20 mL), and the mixture was allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with Et2O (2 × 40 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (10:1 à

2:1 hexanes/EtOAc) afforded the title compound (687 mg, 85%, 5:1 E:Z) as a white solid; m.p. 55−60 °C (hexanes); Rf = 0.48 (3:1 hexanes/EtOAc); IR (neat) νmax 3366, 1599,

-1 1 1446, 1341, 1221, 997, 968, 755 cm ; H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 7.3,

1.9 Hz, 1 H), 7.42 (ddd, J = 8.3, 7.4, 1.9 Hz, 1 H), 7.02 (td, J = 7.3, 0.8 Hz, 1 H), 6.90 (d,

J = 8.3 Hz, 1 H), 5.92 (s, 2 H), 5.94 – 5.71 (m, 2 H), 4.55 (d, J = 6.2 Hz, 2 H), 1.80 – 1.77

13 (m, 3 H); C NMR (100 MHz, CDCl3) δ 164.0, 137.0, 132.9, 132.2, 125.4, 121.4, 111.4,

+ + 69.4, 18.0; HRMS (ESI-TOF) calcd. for C10H13BO3H [M + H ] 193.1030, found

174

193.1033. See: Kita, Y.; Nambu, H.; Ramesh, N. G.; Anilkumar, G.; Matsugi, M. Org.

Lett. 2001, 3, 1157−1160. (iodide)

B(OH)2

(2-(But-3-en-1-yloxy)phenyl)boronic acid (S30)

According to the “in situ quench” method of Reider119, a solution of aryl bromide (1.34 g,

5.90 mmol, 1.0 equiv, azeotroped with benzene 2 × 5 mL) and (iPrO)3B (1.64 mL, 7.08 mmol, 1.2 equiv, freshly distilled over sodium metal) in toluene−THF (4:1 v/v, 12 mL) at

−78 °C under argon was treated with nBuLi (3.08 mL, 2.3 M in hexanes, 1.2 equiv) dropwise via syringe pump over 30 min. The reaction mixture was stirred at −78 °C for an additional 60 min, then allowed to warm to −20 °C. The reaction mixture was quenched by the addition of 2 N aqueous HCl (10 mL), and the mixture was allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with Et2O (2 × 20 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (10:1 à

3:1 hexanes/EtOAc) afforded the title compound (951 mg, 84%) as a white solid; m.p.

79−81 °C (hexanes); Rf = 0.45 (3:1 hexanes/EtOAc); IR (neat) νmax 3371, 1600, 1574,

-1 1 1449, 1343, 1225, 1052, 903, 761 cm ; H NMR (500 MHz, CDCl3) δ 7.87 (dd, J = 7.3,

1.5 Hz, 1 H), 7.45 – 7.40 (m, 1 H), 7.03 (t, J = 7.3 Hz, 1 H), 6.90 (d, J = 8.4 Hz, 1 H),

6.34 (s, 2 H), 5.93 – 5.85 (m, 1 H), 5.29 – 5.25 (m, 1 H), 5.23 – 5.20 (m, 1 H), 4.14 (t, J =

13 6.2 Hz, 2 H), 2.62 (q, J = 6.4 Hz, 2 H); C NMR (125 MHz, CDCl3) δ 163.9, 137.1,

+ 134.3, 132.9, 121.3, 118.3, 110.8, 67.0, 34.0; HRMS (ESI-TOF) calcd. for C10H13BO3H

175

[M + H+] 193.1030, found 193.1031. See: Shi, L.; Narula, C. K.; Mak, K. T.; Kao, L.;

Xu, Y.; Heck, R. F. J. Org. Chem. 1983, 48, 3894−3900. (bromide)

BF3K

Potassium aryltrifluoroborate (S31)

According to the method of Darses120, the arylboronic acid (192 mg, 1.0 mmol, 1.0 equiv) in MeOH (1.0 mL) at room temperature was treated with a saturated aqueous solution of KHF2 (~4.5 M, 0.7 mL, ~3.3 equiv). Within 5 min, a white suspension was obtained. The spin bar was removed, and the suspension was concentrated in vacuo. The white solid was extracted with hot acetone, and the acetone layer was concentrated in vacuo, affording the title compound (226 mg, 89%) as a white solid; m.p. 176−178 °C;

-1 1 IR (neat) νmax 1597, 1475, 1438, 1187, 935, 738 cm ; H NMR (400 MHz, CD3CN) δ

7.42 (d, J = 6.3 Hz, 1 H), 7.10 (td, J = 7.8, 1.9 Hz, 1 H), 6.82 – 6.79 (m, 2 H), 6.01 – 5.94

(m, 1 H), 5.19 – 5.14 (m, 1 H), 5.09 – 5.06 (m, 1 H), 3.99 (t, J = 7.1 Hz, 2 H), 2.48 (q, J =

13 7.0 Hz, 2 H); C NMR (150 MHz, CD3CN) δ 162.7, 136.3, 134.5 (q, JCF = 3.3 Hz),

+ 128.2, 121.0, 117.1, 112.9, 68.6, 34.5; HRMS (ESI-TOF) calcd. for C10H10BF3OH [M –

KH + H+] 215.0855, found 215.0868.

O Me Me

(E)-1-Iodo-2-((2-methylbut-2-en-1-yl)oxy)benzene (S32)

A solution of 2-iodophenol (1.10 g, 5.0 mmol, 1.0 equiv) and (E)-1-iodo-2-methylbut-2- ene (1.47 g, 7.5 mmol, 1.5 equiv) in acetone (5 mL) was treated with powdered, oven-

176 dried K2CO3 (6.5 mmol, 1.3 equiv). The reaction mixture was stirred at reflux for 3 h, then concentrated in vacuo. The residue was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (100% hexanes) afforded the title compound (1.36 g, 94%, 5:3 E:Z) as a colorless oil. Rf = 0.50 (20:1

-1 1 hexanes/Et2O); IR (neat) νmax 1581, 1469, 1437, 1274, 1241, 1016, 996, 743 cm ; H

NMR (400 MHz, CDCl3) δ 7.78 – 7.75 (m, 1 H), 7.30 – 7.24 (m, 1 H), 6.84 – 6.80 (m, 1

H), 6.72 – 7.67 (m, 1 H), 5.70 – 5.65 (m, 1 H), 4.44 (br s, 2 H), 1.88 – 1.54 (m, 6 H); 13C

NMR (100 MHz, CDCl3) δ 157.5, 139.5, 131.3, 129.4, 123.3, 122.5, 112.7, 86.9, 75.0,

+ + 13.8, 13.4; HRMS (ESI-TOF) calcd. for C11H13IONa [M + Na ] 310.9903, found

310.9889. See: Janusz, J. M.; Young, P. A.; Scherz, M. W.; Enzweiler, K.; Wu, L. I.;

Gan, L.; Pikul, S.; McDow-Dunham, K. L.; Johnson, C. R.; Senanayake, C. B.; Kellstein,

D. E.; Green, S. A.; Tulich, J. L.; Rosario-Jansen, T.; Magrisso, I. J.; Wehmeyer, K. R.;

Kuhlenbeck, D. L.; Eichhold, T. H.; Dobson, R. L. M. J. Med. Chem 1998, 41,

1124−1137. (similar substrate)

B(OH)2

O Me Me

(E)-(2-((2-Methylbut-2-en-1-yl)oxy)phenyl)boronic acid (S33)

According to the “in situ quench” method of Reider119, a solution of aryl iodide (1.09 g,

3.98 mmol, 1.0 equiv, azeotroped with benzene 2 × 10 mL) and (iPrO)3B (0.96 mL, 4.38 mmol, 1.1 equiv, freshly distilled over sodium metal) in toluene−THF (4:1 v/v, 19 mL) at

−78 °C under argon was treated with nBuLi (1.90 mL, 2.3 M in hexanes, 4.38 mmol, 1.1

177 equiv) dropwise via syringe pump over 30 min. The reaction mixture was stirred at −78

°C for an additional 60 min, then allowed to warm to −20 °C. The reaction mixture was quenched by the addition of 2 N aqueous HCl (15 mL), and the mixture was allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with Et2O (2 × 30 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (10:1 à

2:1 hexanes/EtOAc) afforded the title compound (653 mg, 68%, 5:3 E:Z) as a colorless oil; Rf = 0.42 (3:1 hexanes/EtOAc); IR (neat) νmax 3404, 1599, 1446, 1337, 1319, 1213,

-1 1 1133, 990, 756 cm ; H NMR (600 MHz, CDCl3) δ 7.87 – 7.84 (m, 1 H), 7.45 – 7.40 (m,

1 H), 7.05 – 6.90 (m, 2 H), 6.19 (s, 2 H), 5.69 – 5.57 (m, 1 H), 4.62 – 4.49 (m, 3 H), 1.85

13 – 1.63 (m, 7 H); C NMR (125 MHz, CDCl3) δ 164.2, 136.9, 132.9, 130.9, 125.2, 121.3,

+ + 111.4, 74.9, 21.7, 13.5; HRMS (ESI-TOF) calcd. for C11H15BO3H [M + H ] 207.1187, found 207.1190.

Standard Procedure for tandem radical cyclization/trap

To a solution of 1,4-benzoquinone (0.1 mmol, 1.0 equiv) in trifluorotoluene (0.5 mL) and water (0.5 mL) were added the arylboronic acid or trifluoroborate (0.15 mmol, 1.5 equiv), silver(I) nitrate (0.02 mmol, 0.2 equiv), and potassium persulfate (0.3 mmol, 3.0 equiv).

The reaction mixture was stirred vigorously at 60 °C for 60 min. The reaction mixture was diluted with EtOAc (3 mL) and washed with 5% aqueous NaHCO3 (3 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 3 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo.

178

Purification was performed by silica gel chromatography to yield chromatographically and spectroscopically pure product.

Compounds 16 and 17 were obtained as a 5:1 mixture in 71% yield, separable by silica gel chromatography. As such, they are described individually.

2-((2,3-Dihydrobenzofuran-3-yl)methyl)cyclohexa-2,5-diene-1,4-dione (16)

A yellow oil; Rf = 0.50 (100% CH2Cl2); IR (neat) νmax 3378, 2923, 1654, 1598, 1480,

-1 1 1452, 1226, 1194, 748 cm ; H NMR (400 MHz, CDCl3) δ 7.15 (t, J = 7.8 Hz, 1 H), 7.12

(d, J = 7.1 Hz, 1 H), 6.86 (t, J = 7.4 Hz, 1 H), 6.82 – 6.74 (m, 2 H), 6.80 (d, J = 7.1 Hz, 1

H), 6.45 (d, J = 1.0 Hz, 1 H), 4.56 (t, J = 8.8 Hz, 1 H), 4.24 (dd, J = 9.1, 5.0 Hz, 1 H),

3.71 – 3.64 (m, 1 H), 2.86 (dd, J = 14.2, 5.9 Hz, 1 H), 2.64 (dd, J= 14.2, 8.2 Hz, 1 H); 13C

NMR (150 MHz, CDCl3) δ 187.5, 187.4, 159.8, 146.1, 136.9, 136.6, 134.1, 129.3, 129.0,

+ + 124.6, 120.8, 110.0, 76.1, 40.6, 35.2; HRMS (ESI-TOF) calcd. for C15H12O3H [M + H ]

241.0859, found 241.0865.

2-(Benzofuran-3-ylmethyl)cyclohexa-2,5-diene-1,4-dione (17)

179

A yellow oil; Rf = 0.60 (100% CH2Cl2); IR (neat) νmax 3411, 3062, 1654, 1600, 1452,

-1 1 1289, 1184, 1095, 747 cm ; H NMR (400 MHz, CDCl3) δ 7.53 (s, 1 H), 7.50 (d, J = 8.2

Hz, 1 H), 7.42 (d, J = 7.8 Hz, 1 H), 7.31 (t, J = 7.1 Hz, 1 H), 7.23 (t, J = 7.1 Hz, 1 H),

6.81 (d, J = 10.1 Hz, 1 H), 6.72 (dd, J = 10.0, 2.5 Hz, 1 H), 6.47 – 6.45 (m, 1 H), 3.84 (br

13 s, 2 H); C NMR (150 MHz, CDCl3) δ 187.7, 187.3, 155.6, 146.8, 143.4, 136.8, 136.6,

133.2, 127.3, 124.8, 123.0, 119.5, 115.0, 111.9, 23.3; HRMS (ESI-TOF) calcd. for

+ + C15H10O3H [M + H ] 239.0703, found 239.0700.

O O

2-((2,3-Dihydro-1H-inden-1-yl)methyl)cyclohexa-2,5-diene-1,4-dione (18) and 2-

(1,2,3,4-Tetrahydronaphthalen-2-yl)cyclohexa-2,5-diene-1,4-dione (19)

An amber oil (1:1 mixture in 61% yield, inseparable by silica gel chromatography); Rf =

-1 1 0.70 (100% CH2Cl2); IR (neat) νmax 2929, 1654, 1598, 1293, 908, 750 cm ; H NMR

(600 MHz, CDCl3) δ 7.24 – 7.06 (m, 4 H), 6.81 – 6.78 (m, 1 H), 6.76 – 6.73 (m, 1 H),

6.58 (br s, 1 H), 3.40 – 3.36 (m, 0.5 H), 3.20 – 3.16 (m, 0.5 H), 3.01 – 2.89 (m, 2.5 H),

2.88 – 2.81 (m, 0.5 H), 2.71 (dd, J = Hz, 0.5 H), 2.46 (dd, J = 14.2, 9.6 Hz, 0.5 H), 2.24 –

2.18 (m, 0.5 H), 2.04 – 2.01 (m, 0.5 H), 1.77 – 1.65 (m, 1 H); 13C NMR (150 MHz,

CDCl3) δ 188.0, 187.8, 187.6, 187.1, 152.9, 148.0, 145.9, 143.8, 137.2, 136.9, 136.5,

136.2, 135.7, 135.2, 133.7, 131.3, 129.1, 129.0, 127.0, 126.4, 126.2, 126.0, 124.8, 123.8,

+ 43.4, 35.0, 35.0, 33.2, 31.9, 31.2, 29.0, 28.1; HRMS (ESI-TOF) calcd. for C16H14O2H

[M + H+] 239.1067, found 239.1071.

180

Me O

2-((3-Methyl-2,3-dihydrobenzofuran-3-yl)methyl)cyclohexa-2,5-diene-1,4-dione (20)

The standard procedure was followed with a reaction time of 60 min to provide the product (76%; gram scale: 60%) as a yellow-orange solid; m.p. 75−77 °C; Rf = 0.47 (4:1

-1 1 hexanes/EtOAc); IR (neat) νmax 2963, 1655, 1597, 1480, 1294, 976, 754 cm ; H NMR

(600 MHz, CDCl3) δ 7.13 (t, J = 7.7 Hz, 1 H), 7.09 (d, J = 7.3 Hz, 1 H), 6.92 (t, J = 7.4

Hz, 1 H), 6.73 – 6.70 (m, 2 H), 6.62 (dd, J = 10.0 Hz, 2.4 Hz, 1 H), 5.84 – 5.82 (m, 1 H),

4.38 (d, J = 8.8 Hz, 1 H), 4.01 (d, J = 9.0 Hz, 1 H), 2.95 (d, J = 12.6 Hz, 1 H), 2.39 (d, J

13 = 12.6 Hz, 1 H), 1.45 (s, 3 H); C NMR (150 MHz, CDCl3) δ 187.5, 187.2, 159.6, 144.9,

136.8, 136.2, 134.7, 132.8, 129.0, 122.9, 121.1, 110.2, 81.6, 46.9, 39.2, 24.4; HRMS

+ + (ESI-TOF) calcd. for C16H14O3H [M + H ] 255.1016, found 255.1020.

O Me

2-(1-(2,3-Dihydrobenzofuran-3-yl)ethyl)cyclohexa-2,5-diene-1,4-dione (21)

The standard procedure was followed with a reaction time of 60 min to provide the product (64%, 1:1 dr) as an amber oil; Rf = 0.60 (100% CH2Cl2); IR (neat) νmax 3382,

-1 1 1653, 1597, 1479, 1452, 1190, 749 cm ; H NMR (500 MHz, CDCl3) δ 7.18 – 7.13 (m, 3

H), 6.96 (d, J = 7.3 Hz, 1 H), 6.87 (t, J = 7.4 Hz, 1 H), 6.82 – 6.75 (m, 6 H), 6.73 – 6.71

(m, 1 H), 6.43 – 6.42 (m, 1 H), 6.30 (d, J = 1.8 Hz, 1 H), 4.58 (t, J = 9.0 Hz, 1 H), 4.40–

181

4.36 (m, 2 H), 4.33 – 4.30 (m, 1 H), 3.66 – 3.61 (m, 1 H), 3.58 – 3.54 (m, 1 H), 3.39 –

3.33 (m, 1 H), 3.23 – 3.17 (m, 1 H), 1.06 (d, J = 7.0 Hz, 3 H), 1.05 (d, J = 7.0 Hz, 3 H);

13 C NMR (150 MHz, CDCl3) δ 187.6, 187.6, 187.4, 187.1, 160.7, 160.3, 150.7, 150.6,

137.2, 137.2, 136.3, 136.2, 133.1, 132.4, 129.1, 129.1, 128.0, 126.9, 125.7, 124.8, 120.8,

120.3, 109.9, 109.9, 75.9, 73.3, 46.0, 45.1, 36.6, 35.6, 14.4, 13.9; HRMS (ESI-TOF)

+ + calcd. for C16H14O3Na [M + Na ] 277.0835, found 277.0839.

2-(Chroman-4-ylmethyl)cyclohexa-2,5-diene-1,4-dione (22)

The standard procedure was followed with a reaction time of 60 min to provide the product (54%) as an amber oil; Rf = 0.60 (100% CH2Cl2); IR (neat) νmax 2929, 1654,

-1 1 1489, 1292, 1223, 1067, 757 cm ; H NMR (600 MHz, CDCl3) δ 7.19 (d, J = 7.7 Hz, 1

H), 7.14 – 7.10 (m, 1 H), 6.88 (td, J = 7.5, 1.2 Hz, 1 H), 6.82 (dd, J = 8.2, 1.2 Hz, 1 H),

6.81 (d, J = 10.0 Hz, 1 H), 6.77 (dd, J = 10.1, 2.5 Hz, 1 H), 6.58 – 6.56 (m, 1 H), 4.20 –

4.18 (m, 2 H), 3.09 – 3.05 (m, 1 H), 3.00 (ddd, J = 13.7, 4.8, 1.3 Hz, 1 H), 2.57 – 2.53

13 (m, 1 H), 2.04 – 1.99 (m, 1 H), 1.74 – 1.70 (m, 1 H); C NMR (150 MHz, CDCl3) δ

187.6, 187.5, 154.5, 147.1, 137.0, 136.6, 134.5, 129.4, 128.1, 124.8, 120.5, 117.2, 62.8,

+ + 36.8, 32.8, 26.5; HRMS (ESI-TOF) calcd. for C16H14O3H [M + H ] 255.1016, found

255.1019.

182

O Me Me O

2-(1-(3-Methyl-2,3-dihydrobenzofuran-3-yl)ethyl)cyclohexa-2,5-diene-1,4-dione (23)

The standard procedure was followed with a reaction time of 60 min to provide the product (30%, 7:4 dr) as an amber oil; Rf = 0.60 (100% CH2Cl2); IR (neat) νmax 3396,

-1 1 2968, 1672, 1654, 1596, 1479, 1457, 1187, 1033, 753 cm ; H NMR (500 MHz, CDCl3)

δ 7.12 (t, J = 7.6 Hz, 1 H), 6.96 (d, J = 7.4 Hz, 1 H), 6.84 (t, J = 7.4 Hz, 1 H), 6.70 (d, J =

7.5 Hz, 1 H), 6.64 – 6.59 (m, 2 H), 6.42 (s, 1 H), 4.62 (d, J = 9.3 Hz, 1 H), 4.09 (d, J =

9.3 Hz, 1 H), 3.40 (q, J = 6.9 Hz, 1 H), 1.35 (s, 3 H), 1.11 (d, J = 7.1 Hz, 3 H); 13C NMR

(150 MHz, CDCl3) δ 187.4, 186.6, 159.8, 150.7, 136.8, 135.8, 135.8, 133.2, 129.0, 124.4,

+ 120.4, 110.0, 80.8, 49.1, 38.5, 24.6, 14.8; HRMS (ESI-TOF) calcd. for C17H16O3H [M +

H+] 269.1172, found 269.1182.

Benzofuran-3(2H)-one (24)

Isolated in a control experiment, following the standard procedure except omitting 1,4- benzoquinone. The title compound (~20% yield) was isolated using silica gel

1 chromatography and verified by spectral comparison: H NMR (600 MHz, CDCl3) δ 7.68

(d, J = 7.7 Hz, 1 H), 7.62 (t, J = 7.8 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 7.10 (t, J = 7.4

13 Hz, 1 H), 4.63 (s, 2 H); C NMR (150 MHz, CDCl3) δ 200.1, 174.2, 138.0, 124.2, 122.2,

121.3, 113.8, 74.8. See: Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org.

Chem. 2001, 66, 4333–4339.

183

Me Me O N CN MeO Me Me

3-(4-Methoxyphenyl)-2-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)propanenitrile (25)

4-Methoxyphenylboronic acid (46 mg, 0.3 mmol, 1.5 equiv) in CH2Cl2 (1.0 mL) and water (1.0 mL) was treated with TEMPO (31 mg, 0.2 mmol, 1.0 equiv), acrylonitrile (66

µL, 1.0 mmol, 5.0 equiv), silver(I) nitrate (6.8 mg, 0.04 mmol, 0.2 equiv), and potassium persulfate (162 mg, 0.6 mmol, 3.0 equiv). The reaction mixture was stirred vigorously at

23 °C for 90 min. The reaction was treated with ascorbic acid (106 mg, 0.6 mmol, 3.0 equiv) and stirred at 23 °C for 10 min. The reaction mixture was extracted with Et2O (3

× 3 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification was performed by silica gel chromatography (1:1

CH2Cl2/hexanes à 100% CH2Cl2) to yield the product (31 mg, 50%) as a pale yellow

1 residue; H NMR (500 MHz, CDCl3) δ 7.22 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2

H), 4.74 (t, J = 6.7 Hz, 1 H), 3.80 (s, 3 H), 3.13 – 3.05 (m, 2 H), 1.59 – 1.40 (m, 5 H),

1.35 – 1.31 (m, 1 H), 1.27 (s, 3 H), 1.13 (s, 3 H), 1.09 (s, 6 H); 13C NMR (125 MHz,

CDCl3) δ 159.1, 131.0, 127.9, 126.9, 119.4, 114.3, 114.1, 75.5, 61.2, 60.1, 55.4, 40.1,

40.0, 38.6, 34.1, 33.8, 20.7, 20.5, 17.1. See: Heinrich, M. R.; Wetzel, A.; Kirschstein, M.

Org. Lett. 2007, 9, 3833−3835.

184

Me O

Me Me

(8aS)-5,5,8a-Trimethyl-1-methyleneoctahydronaphthalen-2(1H)-one (37). This known compound was prepared from β-ionone (six steps) according to Pollini.90b The title compound is an amber oil; Rf = 0.40 (10:1 hexanes/EtOAc).

Me Me O Me B O Me Me O

Me Me

(1R,8aS)-5,5,8a-Trimethyl-1-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methyl)octahydronaphthal-en-2(1H)-one (S34). A dry 100-mL round bottom flask was charged with a spin bar, copper (I) chloride (544 mg, 5.5 mmol, 1.1 equiv, freshly recrystallized from dilute aqueous HCl), and potassium acetate (540 mg, 5.5 mmol, 1.1 equiv, oven-dried), evacuated, and back-filled with argon. Anhydrous DMF (30 mL) was added, and the resulting green-brown mixture was stirred vigorously at room temperature for 90 min under an argon balloon. Meanwhile, a recovery flask was charged with bis(pinacolato)diboron (1.40 g, 5.5 mmol, 1.1 equiv) and enone 37 (1.03 g, 5.0 mmol, 1.0 equiv), and then azeotroped with benzene (2 × 10 mL), evacuated, and back-filled with argon. Anhydrous DMF (6 mL) was added, and the resulting colorless solution was transferred via cannula to the reaction flask containing CuOAc in DMF, at which point the reaction mixture darkened in color. Additional DMF (3 mL) was used to rinse the recovery flask. The reaction was stirred at 50 °C (oil bath) for 16 h, then cooled to room temperature. The reaction was diluted with H2O (50 mL) and extracted with Et2O (2 × 75

185 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (20:1 à

4:1 hexanes/EtOAc) afforded the title compound (1.21 g, 72%) as an off-white solid; m.p. 60−62 °C (hexanes); Rf = 0.30 (8:1 hexanes/EtOAc); IR (neat) νmax 2944, 2927,

-1 + 1707, 1366, 1341, 1310, 1146, 968, 847 cm ; HRMS (ESI-TOF) calcd. for C20H35BO3H

[M + H+] 335.2752, found 335.2759.

Me Me O Me B O Me Me

Me Me

4,4,5,5-Tetramethyl-2-(((1S,8aR)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)methyl)-1,3,2-dioxaborolane (38). A dry 250- mL round bottom flask was charged with a spin bar and Ph3PMeBr (8.04 g, 22.5 mmol,

7.5 equiv), then azeotroped with benzene (2 × 30 mL), evacuated, and back-filled with argon. Anhydrous toluene (75 mL) was added, followed by NaNH2 (powder, 831 mg,

21.3 mmol, 7.1 equiv) rapidly in one portion. The flask was equipped with a reflux condenser and argon balloon. The reaction mixture was stirred vigorously at reflux (120

°C oil bath) for 3 h. The golden yellow suspension was then allowed to settle and cool to room temperature for 1 h. Meanwhile, a dry 250-mL round bottom flask was charged with ketone S34 (1.00 g, 3.0 mmol, 1.0 equiv), then azeotroped with benzene (1 × 10 mL), evacuated, and back-filled with argon. Anhydrous toluene (50 mL) was added via cannula. Using this cannula, the clear, golden yellow solution of Ph3P=CH2 in toluene was transferred to the flask containing a solution of ketone in toluene. The mixture was

186 heated at 80 °C (oil bath) for 3 h, then allowed to stand at room temperature overnight.

In the morning, the reaction contents were concentrated in vacuo to afford a pale yellow solid (~4 g). This crude material was triturated using distilled hexanes. The hexanes layer was concentrated in vacuo to afford a pale yellow oil. Purification by silica flash chromatography (20:1 à 10:1 hexanes/EtOAc) afforded the title compound (895 mg,

90%) as a colorless syrup; Rf = 0.60 (10:1 hexanes/EtOAc); IR (neat) νmax 2976, 2930,

-1 1 1369, 1342, 1315, 1146, 967, 884 cm ; H NMR (400 MHz, CDCl3) δ 4.68 (s, 1 H), 4.50

(s, 1 H), 2.35 (m, 1 H), 2.10 – 2.04 (m, 2 H), 1.68 (m, 1 H), 1.58 – 1.30 (m, 5 H), 1.21 (s,

6 H), 1.18 (s, 6 H), 1.14 (m, 2 H), 0.86 (s, 3 H), 0.80 (s, 3 H), 0.65 (s, 3 H); 13C NMR

(150 MHz, CDCl3) δ 151.9, 106.1, 82.9, 55.2, 52.6, 42.4, 39.4, 37.7, 33.8, 33.7, 24.9,

+ + 24.7, 24.3, 21.9, 19.5, 13.6, 8.6; HRMS (ESI-TOF) calcd. for C21H37BO2H [M + H ]

333.2959, found 333.2971.

Me O

Me Me

Cyclopropane BQ adduct (S35). A mixture of the alkene BF3K and 1,4-benzoquinone in PhCF3−H2O (1:1 v/v) was treated with AgNO3 and K2S2O8, then vigorously stirred at

60 °C (oil bath) for 60 min. The reaction mixture was cooled to room temperature, extracted with EtOAc (3 × 2 mL), dried over Na2SO4, filtered, and concentrated in vacuo.

Purification by PTLC (100% CH2Cl2) afforded the title compound (1.5 mg, 9%) as

1 yellow amber residue. H NMR (600 MHz, C6D6) δ 0.40 (diagnostic for cyclopropane);

13 C NMR (150 MHz, C6D6) δ 21 carbons (6 quinone and 15 terpene).

187

Me Me O Me B O Me Me Me

Me Me

4,4,5,5-Tetramethyl-2-(((1S,2S,8aR)-2,5,5,8a-tetramethyldecahydronaphthalen-1- yl)methyl)-1,3,2-dioxaborolane (S36). A solution of alkene 38 (245 mg, 0.74 mmol) in

MeOH (3 mL) was treated with 5% Pt/C (210 mg) and placed under H2-balloon. The reaction mixture was stirred at room temperature for 2 h, filtered through a pad of Celite, rinsed with EtOAc, and concentrated in vacuo. Purification by silica flash chromatography (100% EtOAc) afforded the title compound (234 mg, 95%) as a

1 colorless syrup; Rf = 0.45 (20:1 hexanes/EtOAc); IR (neat); H NMR (600 MHz, CDCl3)

δ 1.81 (m, 1 H), 1.22 (s, 12 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.83 (s, 3 H), 0.79 (s, 6 H), 0.75

13 (s, 1 H), 0.65 (m, 1 H), 0.40 (m, 1 H); C NMR (150 MHz, CDCl3) δ 82.9, 56.6, 54.9,

53.5, 49.9, 42.4, 42.3, 39.8, 39.5, 36.9, 34.9, 34.3, 33.7, 25.0, 24.9, 22.1, 22.0, 21.6, 19.1,

18.6, 17.7, 15.9, 15.6, 13.6.

BF3K Me Me

Me Me

Potassium organotrifluoroborate (33). A clear, colorless solution of pinacol boronate ester S36 (106 mg, 0.32 mmol) in MeOH (2 mL) at room temperature was treated with a saturated aqueous solution of KHF2 (0.3 mL, 1.35 mmol). The resulting white suspension was stirred at room temperature for 30 min. The spin bar was removed, and

188 the solvent was removed in vacuo. Pinacol was removed by serial evaporation from

MeOH−H2O (1:1 v/v, 4 × 2 mL) using a rotary evaporator (55 °C bath temperature). The residue was dried under high vacuum and then washed with Et2O, affording the title compound (51 mg, 54%) as a white solid; 1H NMR (500 MHz, acetone-d6) δ 2.12 (m, 1

H), 1.70 (m, 1 H), 1.53 (m, 3 H), 1.39 (m, 2 H), 1.31 (m, 3 H), 1.14 (m, 1 H), 0.88 (d, J =

6.8 Hz, 3 H), 0.84 (s, 3 H), 0.81 (s, 3 H), 0.80 (s, 3 H), 0.22 (m, 1 H), 0.11 (m, 1 H).

OOH Me Me

Me Me

(4aS,5S)-5-(Hydroperoxymethyl)-1,1,4a,6-tetramethyldecahydronaphthalene (S37).

This peroxide was isolated from the reaction of potassium organotrifluoroborate salt 33 with silver (I) nitrate and potassium persulfate in the absence of 1,4-benzoquinone.

O Me Me

Me Me

2-(((1S,2S,8aR)-2,5,5,8a-Tetramethyldecahydronaphthalen-1-yl)methyl)cyclohexa-

2,5-diene-1,4-dione (32). A microwave vial was charged with a spin bar, potassium organotrifluoroborate salt 33 (31.4 mg, 0.1 mmol, 1.0 equiv), 1,4-benzoquinone (10.8 mg, 0.1 mmol, 1.0 equiv), trifluorotoluene (0.5 mL), and water (0.5 mL). This yellow reaction mixture was briefly heated using a heat gun to obtain complete dissolution. The yellow solution was degassed using an argon balloon while sonicating for 10 min, then treated with silver (I) nitrate (3.4 mg, 0.02 mmol, 0.2 equiv) and potassium persulfate 189

(81.1 mg, 0.3 mmol, 3.0 equiv). The yellow reaction mixture was degassed for another 5 min, then vigorously stirred at 60 °C (oil bath) for 2 h. The reaction mixture was cooled to room temperature, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (8:1 hexanes/Et2O)

1 afforded the title compound (2.5 mg, 8%) as a yellow solid; Rf = 0.90 (100% CH2Cl2); H

NMR (600 MHz, CDCl3) δ 6.72 (m, 1 H), 6.70 (m, 1 H), 6.58 (m, 1 H), 2.68 (m, 1 H),

2.26 (m, 1 H).

Me O Me

Me Me

96a Lactol (39). A solution of (+)-sclareolide 34 (12.6 g, 50 mmol, 1.0 equiv) in CH2Cl2

(340 mL) at −78 °C was treated with DIBAL-H (1.0 M in hexanes, 60 mL, 60 mmol, 1.2 equiv) dropwise via syringe pump over 15 min. The reaction mixture was stirred at −78

°C for an additional 45 min, then carefully treated with H2O (30 mL) via syringe. The reaction mixture was stirred for 60 min with warming to room temperature, then diluted with CH2Cl2 (400 mL) and saturated aqueous Rochelle’s salt (400 mL). This biphasic mixture was vigorously stirred until the organic layer was clear, and then the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 × 150 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo, affording the title compound as a white solid; Rf = 0.40 (2:1 hexanes/EtOAc).

190

I Me OCHO Me

Me Me

Iodoformate via Suarez (40). A solution of lactol96a, 96c 39 (12.1 g, 48.0 mmol, 1.0 equiv) in benzene (480 mL) was treated with PIDA (21.6 g, 67.2 mmol, 1.4 equiv) and I2

(14.6 g, 57.6 mmol, 1.2 equiv). The purple reaction mixture was vigorously stirred at 70

°C (oil bath) with simultaneous irradiation using a 150-watt flood lamp for 60 min. The reaction mixture was cooled to room temperature, concentrated in vacuo to reduce volume, diluted with brine (300 mL), and extracted with EtOAc (3 × 150 mL). The organic layers were combined, washed with saturated aqueous Na2S2O3 (2 × 150 mL), brine (150 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was immediately diluted with anhydrous MeOH, swirled, and cooled in a −78 °C bath. The resulting white solid (16.0 g, 88%) was collected via filtration; m.p. = 52−54 °C; X-ray;

Rf = 0.85 (2:1 hexanes/EtOAc); IR (neat) νmax 2919, 2840, 1703, 1393, 1203, 1168, 1146,

-1 1 1122, 911, 769 cm ; H NMR (500 MHz, CDCl3) δ 8.02 (s, 1 H), 3.36 – 3.34 (m, 1 H),

3.13 – 3.10 (m, 1 H), 2.54 – 2.51 (m, 1 H), 2.49 – 2.45 (m, 1 H), 1.88 – 1.84 (m, 2 H),

1.73 – 1.70 (m, 1 H), 1.47 (s, 3 H), 0.81 (s, 3 H), 0.80 (s, 3 H), 0.79 (s, 3 H); 13C NMR

(125 MHz, CDCl3) δ 160.4, 88.5, 62.3, 55.4, 41.7, 41.0, 39.8, 39.1, 33.4, 33.3, 21.6, 20.5,

+ + 19.9, 18.5, 15.0, −2.1; HRMS (ESI-TOF) calcd. for C16H27IO2H [M + H ] 379.1128, found 379.0741.

Me OCHO Me

Me Me

191

Allylic formate via AgF in pyridine (S38). A solution of iodoformate 40 (15.9 g, 42.0 mmol, 1.0 equiv) in anhydrous pyridine (140 mL) at room temperature was treated with silver (I) fluoride (10.7 g, 84.0 mmol, 2.0 equiv). The reaction flask was wrapped with aluminum foil to protect from light. The reaction mixture was stirred at room temperature for 12 h, concentrated in vacuo to reduce volume, diluted with Et2O (400 mL), and filtered through a Celite pad to remove dark grey solid. The filter cake was rinsed with Et2O (150 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 (5:1 v/v, 300 mL), then washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated in vacuo, affording the title

1 compound (10.3 g, 98%) as a pale yellow syrup; Rf = 0.60 (6:1 hexanes/EtOAc); H

NMR (400 MHz, CDCl3) δ 8.14 (s, 1 H), 5.07 (s, 1 H), 5.02 (s, 1 H), 2.23 (dt, J = 13.2,

4.4 Hz, 1 H), 1.67 (s, 3 H), 1.13 (d, J = 0.8 Hz, 3 H), 0.89 (s, 3 H), 0.85 (s, 3 H); 13C

NMR (150 MHz, CDCl3) δ 161.2, 137.6, 107.7, 85.0, 51.1, 41.6, 39.2, 38.1, 33.3, 30.1,

23.8, 21.8, 19.5, 19.1.

Me Me OH

Me Me

(2R,8aS)-2,5,5,8a-Tetramethyl-1-methylenedecahydronaphthalen-2-ol (41).94 A solution of allylic formate S38 (10.3 g, 41.0 mmol, 1.0 equiv) in MeOH (680 mL) at 0 °C

(ice bath) was treated with powdered, oven-dried K2CO3 (6.8 g, 49.2 mmol, 1.2 equiv).

The ice bath was removed, and the reaction mixture was vigorously stirred for 2 h. The reaction mixture was concentrated in vacuo to reduce volume, diluted with Et2O (300 mL), washed with H2O (150 mL), and back-extracted with Et2O (100 mL). The organic

192 layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo, affording the title compound (9.1 g, 99%) as an ivory-white solid; Rf = 0.30 (6:1 hexanes/EtOAc);

1 H NMR (600 MHz, CDCl3) δ 5.22 (s, 1 H), 4.84 (s, 1 H), 2.04 − 1.99 (m, 1 H), 1.79

(dtd, J = 12.7, 3.3, 1.5 Hz, 1 H), 1.75 − 1.69 (m, 1 H), 1.66 (tt, J = 13.7, 3.5 Hz, 1 H),

1.54 (ddt, J = 14.4, 7.4, 3.7 Hz, 1 H), 1.41 (s, 3 H), 1.13 (td, J = 13.5, 4.3 Hz, 1 H), 1.09

(s, 3 H), 0.98 (dd, J = 11.8, 2.6 Hz, 1 H), 0.87 (s, 3 H), 0.85 (s, 3 H); 13C NMR (150

MHz, CDCl3) δ 166.8, 103.8, 73.5, 53.6, 44.4, 41.9, 40.2, 39.2, 34.0, 33.4, 30.7, 29.9,

22.5, 21.8, 20.4, 19.2.

BF3K Me Me OH

Me Me

Potassium organotrifluoroborate salt (S39). A solution of alkene 41 (67 mg, 0.3 mmol, 1.0 equiv) in THF (3 mL) at 0 °C was treated with borane dimethylsulfide complex (0.19 mL, 0.375 mmol, 1.25 equiv). The ice bath was removed, and the reaction mixture was stirred for 16 h. The reaction mixture was treated with Et3N (52 µL), MeOH

(30 µL), KHF2 (94 mg), H2O (0.5 mL), and stirred for 30 min. The spin bar was removed, and solvents were removed in vacuo. The residue was dried under high vacuum, extracted with hot acetone−MeOH (4:1 v/v), and the filtrate was concentrated in vacuo. Trituration with cold Et2O afforded the title compound (11 mg, 11%, ~3:1 dr) as

13 a white solid; C (CD3OD) small peak at ~23 ppm for C−B.

193

OH B Me O Me

Me Me

Borono-sclareolide (42). Major diastereomer: Allylic alcohol 41 (500 mg, 2.25 mmol,

1.00 equiv) in anhydrous THF (8 mL) at 0 °C was treated with BH3THF (1.0 M in THF,

3.0 mL, 3.0 mmol, 1.33 equiv) dropwise over ~1 min via syringe. The ice bath was removed, and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to 0 °C and carefully treated with H2O (~1 mL). The ice bath was removed, the reaction mixture was stirred for 45 min, then concentrated in vacuo. Purification by silica flash chromatography (8:1 à 2:1 hexanes/EtOAc) afforded the title compound (401 mg, 71%) as a white solid; m.p. 105−108 °C; X-ray; Rf = 0.35 (3:1 hexanes/EtOAc); IR (film) νmax

−1 1 3301, 2918, 1446, 1408, 1385, 1036, 932 cm ; H NMR (CDCl3, 600 MHz) 5.64 (s, 1

H), 1.97 – 1.92 (m, 1 H), 1.17 (s, 3 H), 0.86 (s, 3 H), 0.83 (s, 3 H), 0.81 (s, 3 H); HRMS

+ + (ESI-TOF) calcd. for C15H27BO2H [M + H ] 251.2177, found 251.2181.

OH B Me O Me

Me Me

Borono-sclareolide (43). Minor diastereomer: See procedure above. This diastereomer is less polar, also a white solid (~25% yield); m.p. 132−135 °C; X-ray; Rf = 0.45 (3:1

−1 hexanes/EtOAc); IR (film) νmax 3289, 2929, 1446, 1405, 1382, 1082, 1053, 900 cm ;

+ + HRMS (ESI-TOF) calcd. for C15H27BO2H [M + H ] 251.2177, found 251.2179.

194

ent-Chromazonarol (44).82b, 121 A mixture of cyclic boronic acid 42 (1.0 equiv), freshly sublimed 1,4-benzoquinone (1.0 equiv), and AgNO3 (0.2 equiv) in PhCF3 (100 mL) and

H2O (100 mL) was degassed using an argon balloon with simultaneous sonication for 10 min. The reaction mixture was treated with K2S2O8 (5.0 equiv) rapidly in one portion.

The reaction flask was resealed, fitted with an argon balloon, and vigorously stirred at 60

°C (oil bath) for 2 h. The reaction mixture was cooled, then extracted with EtOAc (3 ×

75 mL). The organic layers were combined, washed with brine (50 mL), dried over

Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography

(100% CH2Cl2) afforded the title compound (53%) as a pale red solid; Rf = 0.20 (100%

−1 CH2Cl2); IR (film) νmax 3380, 2925, 2866, 1493, 1450, 1232, 1216, 1127, 937, 791 cm ;

1 H NMR (CDCl3, 600 MHz) 6.64 – 6.60 (m, 1 H), 6.59 – 6.55 (m, 1 H), 6.55 – 6.53 (m, 1

H), 4.41 (s, 1 H), 2.59 – 2.55 (m, 2 H), 2.05 – 2.01 (m, 1 H), 1.17 (s, 3 H), 0.90 (s, 3 H),

13 0.88 (s, 3 H), 0.84 (s, 3 H); C NMR (CDCl3, 150 MHz) δ 148.7, 147.3, 123.4, 117.6,

115.9, 114.3, 76.8, 56.3, 52.2, 42.0, 41.2, 39.3, 36.9, 33.6, 33.3, 22.6, 21.8, 20.8, 19.9,

18.7, 15.0.

BCl3-mediated opening of ent-chromazonarol: initially produced ~6:1 ent- isozonarol:ent-zonarol, but then some material re-closed upon exposure to CDCl3 or SiO2 to give new products:

195

ent-Dihydro-isochromazonarol (S40). Least polar spot on TLC

8-epi-Chromazonarol (56). Second-least polar spot on TLC

ent-Zonarol (50). Co-polar with 45

ent-Isozonarol (45). Co-polar with 50

196

Tetrasubstituted alkene hydroquinone (S41). More polar than 45 and 50

OH OH

81 −1 1 ent-Yahazunol (49). Yellow oil; IR (film) νmax 3402, 2868, 1654, 1495 cm ; H NMR

(CDCl3, 600 MHz) δ 6.70 (d, J = 8.4 Hz, 1 H), 6.61 (d, J = 3.1 Hz, 1 H), 6.56 (dd, J =

8.4, 3.1 Hz, 1 H), 2.86 (dd, J = 15.2, 2.3 Hz, 1 H), 2.37 (dd, J = 15.2, 6.0 Hz, 1 H), 1.89

(ddd, J = 12.2, 3.3, 3.3 Hz, 1 H), 1.77 (m, 1 H), 1.69 (m, 1 H), 1.62 (dd, J = 6.0, 2.3 Hz, 1

H), 1.58 (m, 2 H), 1.40 (m, 1 H), 1.34 (m, 1 H), 1.31 (s, 3 H), 1.29 (m, 1 H), 1.05 (ddd, J

= 13.7, 13.3, 3.8 Hz, 1 H), 0.95 (m, 1 H), 0.93 (s, 1 H), 0.83 (s, 1 H), 0.80 (s, 1 H), 0.79

13 (m, 1 H); C NMR (CDCl3, 150 MHz) δ 149.3, 147.9, 130.2, 118.2, 117.2, 114.0, 76.1,

60.6, 55.7, 43.9, 41.5, 40.3, 39.8, 33.3, 33.1, 27.4, 24.7, 21.4, 20.4, 18.2, 15.4.

197

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97. Rigby, J. H.; Warshakoon, N. C.; Payen, A. J. J. Am. Chem. Soc. 1999, 121, 8237.

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99. (a) Horii, S.; Fukase, H.; Kameda, Y. Carbohydr. Res. 1985, 140, 185; (b) Sugiyama, H.; Sera, T.; Dannoue, Y.; Marumoto, R.; Saito, I. J. Am. Chem. Soc. 1991, 113, 2290.

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100. (a) Snyder, H. R.; Kuck, J. A.; Johnson, J. R. J. Am. Chem. Soc. 1938, 60, 105; (b) Torssell, K.; Larsson, E. N. V. Acta Chem. Scand. 1957, 11, 404.

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103. Minale, L. Pure Appl. Chem. 1976, 48, 7.

104. (a) Uenishi, J.; Hamada, M.; Takagi, T.; Yonemitsu, O. Heterocycles 2001, 54, 735; (b) Kinoshita, M.; Miyake, T.; Arima, Y.; Oguma, M.; Akita, H. Chem. Pharm. Bull. 2008, 56, 118.

105. Gavagnin, M.; Kulcitki, V.; Ungur, N.; Carbone, M.; Cimino, G. Eur. J. Org. Chem. 2005, 1816.

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107. (a) Elix, J. A.; Lajide, L. Aust. J. Chem. 1984, 37, 2153; (b) Gloer, J. B.; Soman, A. G.; Wicklow, D. T. J. Nat. Prod. 1999, 62, 386.

108. Elix, J. A.; Mahadevan, I.; Wardlaw, J. H.; Arvidsson, L.; Jorgensen, P. M. Aust. J. Chem. 1987, 40, 1581.

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205

115. Majetich, G.; Ringold, C. Heterocycles 1987, 25, 271.

116. (a) Corey, E. J.; Hahl, R. W. Tetrahedron Lett. 1989, 30, 3023; (b) Griffiths- Jones, C. M.; Knight, D. W. Tetrahedron 2010, 66, 4150.

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120. Darses, S.; Michaud, G.; Genet, J. P. Eur. J. Org. Chem. 1999, 1875.

121. (a) Djura, P.; Stierle, D. B.; Sullivan, B.; Faulkner, D. J. J. Org. Chem. 1980, 45, 1435; (b) Alvarez-Manzaneda, E. J.; Chahboun, R.; Cabrera, E.; Alvarez, E.; Haidour, A.; Ramos, J. M.; Alvarez-Manzaneda, R.; Hmamouchi, M.; Bouanou, H. J. Org. Chem. 2007, 72, 3332.

206

Appendix A. Spectra

207

208

e O M S e e M e M M e M

209

e O M S e e M e M M e M

210

e e M e M O M 2

O C O (100) e e M M

211

e e M e M O M 2

O C O (100) e e M M

212

e H M O e M 2 H O

C O (S1) e C H M O

213

e H M O e M 2 H O

C O (S1) e C H M O

214

e H M O e M

2 H O C O (14) e e M M

215

e H M O e M

2 H O C O (14) e e M M

216

3 CF

I O (S1)

217

3 CF

I O (S1)

218

I O (S2)

219

I O (S2)

220

COOMe

I O (S3)

221

COOMe

I O (S3)

222

e M O

r B O (S5)

223

e M O

r B O (S5)

224

COOMe

Br O (S8)

225

COOMe

Br O (S8)

226

Br O (S9)

227

Br O (S9)

228

3 CF 3 CF

Br O (S10)

229

3 CF 3 CF

Br O (S10)

230

F F F

Br O (S11)

231

F F F

Br O (S11)

232

3 F C 2 )

H O ( O B (S13)

233

3 F C 2 )

H O ( O B (S13)

234

F 2 )

H O ( O B (S14)

235

F 2 )

H O ( O B (S14)

236

e M 2 O C 2 )

H O ( O B (S15)

237

e M 2 O C 2 )

H O ( O B (S15)

238

e M O 2

) H O ( O B (S16)

239

e M O 2 )

H O ( O B (S16)

240

OMe

K 3 BF O (S19)

241

OMe

K 3 BF O (S19)

242

3 BF (S20)

243

K 3 BF (S20)

244

COOMe

K 3 BF O (S21)

245

COOMe

K 3 BF O (S21)

246

3 CF 3 CF

K 3 BF O (S23)

247

3 CF 3 CF

K 3 BF O (S23)

248

F F F

K 3 BF O (S24)

249

F F F

K 3 BF O (S24)

250

K 3 BF O (S25)

251

F K

3 BF O (S25)

252

O K 3 (S26) BF

253

O K 3 (S26) BF

254

K N 3 N BF (S27) EtOOC

255

K N 3 N BF (S27) EtOOC

256

3 CF

O (1)

257

3 CF

O (1)

258

3 CF

C 3 F O (10)

259

3 CF

C 3 F O (10)

260

F F

F O (11)

261

F F F

O (11)

262

K 3 F

B O (S28)

263

3 F B O (S28)

264

2 ) H

O ( B (S29)

265

2 ) H

O ( B (S29)

266

e 2 M ) H

O ( B O (S30)

267

e 2 M ) H

O ( B O (S30)

268

e M 2 )

H O ( B O (S31)

269

e M 2

) H O ( B O (S31)

270

2 ) H

O ( B O (S32)

271

2 ) H

O ( B O (S32)

272

3 F B O (S33)

273

3 F B O (S33)

274

e M e M

I O (S34)

275

e M e M

I O (S34)

276

e M e 2 M )

H O ( B O (S35)

277

e M e 2 M ) H

O ( B O (S35)

278

O O (16)

279

O O

O (16)

280

O O (17)

281

O O (17)

282

O O

O (18) and (19) O

283

O O

O (18) and (19) O

284

O O (20) e M

285

O O (20) e M

286

O O e (21) M

287

O O e (21) M

288

O O (22)

289

O O (22)

290

O O e e (23) M M

291

O O e (23) e M M

292

OCHO

I (40)

293

OCHO

I (40)

294

H O

(41)

295

H O

(41)

296

H O O B

(42)

297

H O O B

(42)

298

H O O B

(43)

299

H O O B

(43)

300

H O O

(44)

301

H O O

(44)

302

O H O

O (47)

303

O H O

O (47)

304

Appendix B. X-ray Crystallographic Data

Useless allyl dienone

Useful allyl dienone

Iodoethyl dienone

Hetero-Diels−Alder product

Drimenediol

Pyran tetracycle

Majetich ester (one of the epimers)

Diaryl ether boronic acid

Iodoformate

Undesired diastereomer of boronic acid

Desired diastereomer of boronic acid

Iso-sclareolide

305

306

X-ray ID: baran38

A colorless rod 0.16 x 0.10 x 0.08 mm in size was mounted on a Cryoloop with Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using phi and omega scans.

Crystal-to-detector distance was 60 mm and exposure time was 60 seconds per frame using a scan width of 2.0°. Data collection was 97.9% complete to 67.00° in q. A total of 8552 reflections were collected covering the indices, -9<=h<=11, -8<=k<=8, -

26<=l<=24. 2456 reflections were found to be symmetry independent, with an Rint of

0.0560. Indexing and unit cell refinement indicated a primitive, monoclinic lattice. The space group was found to be P2(1)/n (No. 14). The data were integrated using the Bruker

SAINT software program and scaled using the SADABS software program. Solution by direct methods (SIR-2004) produced a complete heavy-atom phasing model consistent with the proposed structure. All non-hydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-97). All hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-97.

307

Table 1. Crystal data and structure refinement for baran38. X-ray ID baran38 Sample/notebook ID JWL-2-278-2 Empirical formula C15 H20 O4 Formula weight 264.31 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 9.3123(6) Å a= 90°. b = 6.9548(5) Å b= 90.230(5)°. c = 21.6941(15) Å g = 90°. Volume 1405.01(17) Å3 Z 4 Density (calculated) 1.250 Mg/m3 Absorption coefficient 0.734 mm-1 F(000) 568 Crystal size 0.16 x 0.10 x 0.08 mm3 Crystal color/habit colorless rod Theta range for data collection 4.08 to 68.31°. Index ranges -9<=h<=11, -8<=k<=8, -26<=l<=24 Reflections collected 8552 Independent reflections 2456 [R(int) = 0.0560] Completeness to theta = 67.00° 97.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9436 and 0.8916 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2456 / 0 / 177 Goodness-of-fit on F2 1.021 Final R indices [I>2sigma(I)] R1 = 0.0489, wR2 = 0.1107 R indices (all data) R1 = 0.0803, wR2 = 0.1256 Largest diff. peak and hole 0.228 and -0.175 e.Å-3

308

309

Table 1. Crystal data and structure refinement for baran40. Identification code baran40 Empirical formula C14 H19 I O4 Formula weight 378.19 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 10.3613(15) Å α= 90°. b = 9.5978(14) Å β= 95.517(2)°. c = 15.860(2) Å γ = 90°. Volume 1569.9(4) Å3 Z 4 Density (calculated) 1.600 Mg/m3 Absorption coefficient 2.047 mm-1 F(000) 752 Crystal size 0.29 x 0.22 x 0.14 mm3 Theta range for data collection 2.25 to 25.60°. Index ranges -12<=h<=12, -11<=k<=10, -19<=l<=18 Reflections collected 16540 Independent reflections 2953 [R(int) = 0.0700] Completeness to theta = 25.00° 100.0 % Absorption correction Multi-scan Max. and min. transmission 0.7626 and 0.5883 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2953 / 0 / 172 Goodness-of-fit on F2 1.060 Final R indices [I>2sigma(I)] R1 = 0.0380, wR2 = 0.1044 R indices (all data) R1 = 0.0401, wR2 = 0.1059 Largest diff. peak and hole 1.280 and -0.940 e.Å-3

310

X-ray ID: baran52

A colorless block 0.12 x 0.10 x 0.10 mm in size was mounted on a Cryoloop with

Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using phi and omega scans. Crystal-to-detector distance was 60 mm and exposure time was 10 seconds per frame using a scan width of 2.0°. Data collection was 100.0% complete to 67.00° in q. A total of 23045 reflections were collected covering the indices, -15<=h<=15, -

11<=k<=9, -15<=l<=15. 2551 reflections were found to be symmetry independent, with an Rint of 0.0346. Indexing and unit cell refinement indicated a primitive, monoclinic lattice. The space group was found to be P2(1)/n (No. 14). The data were integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by direct methods (SIR-2004) produced a complete heavy-atom phasing model consistent with the proposed structure. All non-hydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-97). All hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-97.

311

312

Table 1. Crystal data and structure refinement for baran52. X-ray ID baran52 Sample/notebook ID JWL-3-138-1 Empirical formula C15 H20 O4 Formula weight 264.31 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 12.6993(4) Å a= 90°. b = 9.2324(3) Å b= 114.997(2)°. c = 13.1215(4) Å g = 90°. Volume 1394.32(8) Å3 Z 4 Density (calculated) 1.259 Mg/m3 Absorption coefficient 0.739 mm-1 F(000) 568 Crystal size 0.12 x 0.10 x 0.10 mm3 Crystal color/habit colorless block Theta range for data collection 4.06 to 68.39°. Index ranges -15<=h<=15, -11<=k<=9, -15<=l<=15 Reflections collected 23045 Independent reflections 2551 [R(int) = 0.0346] Completeness to theta = 67.00° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9297 and 0.9165 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2551 / 0 / 178 Goodness-of-fit on F2 1.153 Final R indices [I>2sigma(I)] R1 = 0.0672, wR2 = 0.1898 R indices (all data) R1 = 0.0737, wR2 = 0.1959 Extinction coefficient 0.0022(8) Largest diff. peak and hole 0.966 and -0.680 e.Å-3

313

314

Table 1. Crystal data and structure refinement for Baran117. Identification code baran117 Empirical formula C22 H34 O3 Formula weight 346.49 Temperature 150(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 24.950(5) Å a= 90.000(5)°. b = 6.828(5) Å b= 111.724(5)°. c = 24.944(5) Å g = 90.000(5)°. Volume 3948(3) Å3 Z 8 Density (calculated) 1.166 Mg/m3 Absorption coefficient 0.075 mm-1 F(000) 1520 Crystal size 0.26 x 0.14 x 0.12 mm3 Crystal color, habit Colorless Rod Theta range for data collection 1.65 to 27.51°. Index ranges -32<=h<=31, -8<=k<=8, -31<=l<=32 Reflections collected 29898 Independent reflections 8678 [R(int) = 0.0743] Completeness to theta = 25.00° 98.9 % Absorption correction Multi-scan Max. and min. transmission 0.9913 and 0.9809 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 8678 / 0 / 464 Goodness-of-fit on F2 1.010 Final R indices [I>2sigma(I)] R1 = 0.0627, wR2 = 0.1347 R indices (all data) R1 = 0.1048, wR2 = 0.1529 Extinction coefficient 0.0003(4) Largest diff. peak and hole 0.451 and -0.286 e.Å-3

315

316

Table 7. Crystal data and structure refinement for BARAN129. Identification code baran129 Empirical formula C15 H26 O2 Formula weight 238.36 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 7.5830(5) Å α= 77.453(3)° b = 10.8645(8) Å β= 81.188(3)° c = 17.4484(13) Å γ = 77.815(3)° Volume 1362.85(17) Å3 Z 4 Density (calculated) 1.162 g/cm3 Absorption coefficient 0.579 mm-1 F(000) 528 Crystal size 0.31 x 0.21 x 0.11 mm3 Theta range for data collection 4.24 to 65.02° Index ranges -8<=h<=8, -12<=k<=12, -20<=l<=17 Reflections collected 15796 Independent reflections 4322 [R(int) = 0.0217] Completeness to theta = 65.00° 96.4 % Absorption correction Multi-scan Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4322 / 0 / 315 Goodness-of-fit on F2 0.825 Final R indices [I>2sigma(I)] R1 = 0.0362, wR2 = 0.0999 R indices (all data) R1 = 0.0384, wR2 = 0.1023 Largest diff. peak and hole 0.229 and -0.338 e Å-3

317

318

Table 1. Crystal data and structure refinement for baran151. Identification code baran151 Empirical formula C24 H38 O3 Formula weight 374.54 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = 7.1439(5) Å α= 90° b = 10.9125(8) Å β= 93.317(5)° c = 13.6533(9) Å γ = 90° Volume 1062.60(13) Å3 Z 2 Density (calculated) 1.171 g/cm3 Absorption coefficient 0.582 mm-1 F(000) 412 Crystal size 0.24 x 0.18 x 0.10 mm3 Crystal color, habit Colorless rod Theta range for data collection 6.21 to 48.06° Index ranges -6<=h<=6, -10<=k<=10, -13<=l<=12 Reflections collected 3567 Independent reflections 1760 [R(int) = 0.0272] Completeness to theta = 48.06° 98.6 % Absorption correction Multi-scan Max. and min. transmission 0.9441 and 0.8729 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1760 / 1 / 251 Goodness-of-fit on F2 1.125 Final R indices [I>2sigma(I)] R1 = 0.0673, wR2 = 0.1874 R indices (all data) R1 = 0.0698, wR2 = 0.1891 Absolute structure parameter 0.0(7) Largest diff. peak and hole 0.365 and -0.215 e Å-3

319

320

Structure determination of baran152 with the Bruker SMART X2S benchtop crystallographic system

A colorless crystal of baran152 (JWL-6-062-2) with the dimensions of 0.13 mm x 0.22 mm x 0.48 mm mounted on a Mitegen Micromount was automatically centered on a

Bruker SMART X2S benchtop crystallographic system. Intensity measurements were performed using a monochromated (Doubly Curved Silicon Crystal) Mo-Kα-radiation

(0.71073 Å) from a sealed MicroFocus tube. Generator settings were 50 kV, 1 mA. Data collection temperature was -73°C. Data were acquired using three sets of Omega scans at different Phi settings. The frame width was 0.5° with an exposure time of 10.0 s. The detailed data collection strategy was as follows: Detector distance: 40 mm Detector swing angle (fixed 2 Theta): -20°.

APEX2 software was used for preliminary determination of the unit cell. Determination of integral intensities and unit cell refinement were performed using SAINT. Data was corrected for absorption using SADABS and structure was solved by direct methods. All non-hydrogen atoms were refined anisotropically by Fourier full matrix least squares on

F2. Hydrogen atoms on oxygen atoms O1 to O4 were found from a Fourier difference map and were allowed to refine while all other hydrogen atoms were placed in calculated positions on their parent atoms with appropriate riding models.

321

Table 1. Crystal data and structure refinement for BARAN152. (JWL-6-062-2) Identification code baran152 Empirical formula C15 H26 O2 Formula weight 238.36 Temperature 200(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 7.6349(12) Å α= 77.207(5)°. b = 10.998(2) Å β= 81.241(5)°. c = 17.588(3) Å γ = 77.840(6)°. Volume 1399.2(4) Å3 Z 4 Density (calculated) 1.131 Mg/m3 Absorption coefficient 0.073 mm-1 F(000) 528 Crystal size 0.40 x 0.18 x 0.12 mm3 Crystal color / habit colorless / block Theta range for data collection 2.46 to 25.03°. Index ranges -9<=h<=8, -13<=k<=13, -20<=l<=20 Reflections collected 13670 Independent reflections 4894 [R(int) = 0.0817] Completeness to theta = 25.00° 99.2 % Absorption correction multi-scan / sadabs Max. and min. transmission 0.9913 and 0.9716 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4894 / 0 / 331 Goodness-of-fit on F2 1.035 Final R indices [I>2sigma(I)] R1 = 0.0593, wR2 = 0.1380 R indices (all data) R1 = 0.0969, wR2 = 0.1543 Largest diff. peak and hole 0.218 and -0.199 e.Å-3

322

BARAN157 (code JWL-7-149-3) September 16,2010 Colorless crystal of JWL-7-149-3 was mounted on Mitogen mount with epoxy and data was collected at 200K with Bruker SMART X2S benchtop CCD instrument. Crystal structure was twinned and two components were found using CELLNOW and data was corrected for absorption using TWINABS. Direct methods was used to solve structure and all non-hydrogen atoms were refined as anisotropic by Fourier full matrix least squares on F2 and all hydrogen atoms were placed in calculated positions with appropriate riding models.

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Table 1. Crystal data and structure refinement for baran157. Identification code baran157 Empirical formula C10 H16 O2 Formula weight 168.23 Temperature 200(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 7.6728(19) Å a= 94.209(7)°. b = 7.7503(18) Å b= 96.586(7)°. c = 8.780(2) Å g = 109.281(7)°. Volume 486.1(2) Å3 Z 2 Density (calculated) 1.149 Mg/m3 Absorption coefficient 0.078 mm-1 F(000) 184 Crystal size 0.45 x 0.24 x 0.20 mm3 Crystal color / habit colorless / block Theta range for data collection 2.80 to 26.39°. Index ranges -9<=h<=9, -9<=k<=9, 0<=l<=10 Reflections collected 8099 Independent reflections 3683 [R(int) = 0.02620] Completeness to theta = 25.00° 98.5 % Absorption correction multi-scan / twinabs Max. and min. transmission 0.9845 and 0.9657 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2877 / 0 / 114 Goodness-of-fit on F2 1.021 Final R indices [I>2sigma(I)] R1 = 0.0557, wR2 = 0.1449 R indices (all data) R1 = 0.0716, wR2 = 0.1558 Largest diff. peak and hole0.461 and -0.189 e.Å-3

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Table 1. Crystal data and structure refinement for Baran230. Identification code JWL-1417-028 Empirical formula C14 H13 B O5 Formula weight 272.05 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 14.0840(7) Å a= 90°. b = 23.9935(13) Å b= 93.249(2)°. c = 7.7998(4) Å g = 90°. Volume 2631.5(2) Å3 Z 8 Density (calculated) 1.373 Mg/m3 Absorption coefficient 0.103 mm-1 F(000) 1136 Crystal size 0.47 x 0.35 x 0.23 mm3 Crystal color, habit Colorless Block Theta range for data collection 1.45 to 30.58°. Index ranges -20<=h<=16, -33<=k<=32, -10<=l<=10 Reflections collected 41030 Independent reflections 7897 [R(int) = 0.0344] Completeness to theta = 25.00° 99.8 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9767 and 0.9533 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 7897 / 0 / 367 Goodness-of-fit on F2 1.045 Final R indices [I>2sigma(I)] R1 = 0.0675, wR2 = 0.1860 R indices (all data) R1 = 0.0855, wR2 = 0.1973 Extinction coefficient not measured Largest diff. peak and hole 0.541 and -0.288 e.Å-3

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Table 1. Crystal data and structure refinement for baran231. Identification code baran231 Empirical formula C16 H27 I O2 Formula weight 378.28 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = 9.7979(9) Å α= 90° b = 5.9478(5) Å β= 94.9970(10)° c = 13.9756(12) Å γ = 90° Volume 811.35(12) Å3 Z 2 Density (calculated) 1.548 g/cm3 Absorption coefficient 1.971 mm-1 F(000) 384 Crystal size 0.42 x 0.36 x 0.09 mm3 Theta range for data collection 1.46 to 26.17° Index ranges -12<=h<=12, -7<=k<=7, -17<=l<=15 Reflections collected 8400 Independent reflections 3171 [R(int) = 0.0255] Completeness to theta = 25.00° 99.8 % Absorption correction Multi-scan Max. and min. transmission 0.8426 and 0.4915 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3171 / 1 / 176 Goodness-of-fit on F2 1.016 Final R indices [I>2sigma(I)] R1 = 0.0190, wR2 = 0.0463 R indices (all data) R1 = 0.0204, wR2 = 0.0473 Absolute structure parameter 0.011(18) Largest diff. peak and hole 0.516 and -0.418 e Å-3

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Table 1. Crystal data and structure refinement for Baran232. Identification code JWL-1417-076-3 Empirical formula C15 H27 B O2 Formula weight 250.18 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = 7.5496(2) Å a= 90°. b = 11.4129(3) Å b= 90°. c = 17.1245(4) Å g = 90°. Volume 1475.50(6) Å3 Z 4 Density (calculated) 1.126 Mg/m3 Absorption coefficient 0.546 mm-1 F(000) 552 Crystal size 0.35 x 0.31 x 0.22 mm3 Crystal color, habit Colorless Block Theta range for data collection 4.66 to 67.80°. Index ranges -8<=h<=9, -13<=k<=13, -20<=l<=20 Reflections collected 9953 Independent reflections 2640 [R(int) = 0.0438] Completeness to theta = 67.80° 99.3 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.8892 and 0.8318 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2640 / 0 / 168 Goodness-of-fit on F2 1.035 Final R indices [I>2sigma(I)] R1 = 0.0388, wR2 = 0.1012 R indices (all data) R1 = 0.0389, wR2 = 0.1013 Absolute structure parameter 0.2(2) Extinction coefficient not measured Largest diff. peak and hole 0.222 and -0.226 e.Å-3

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Table 1. Crystal data and structure refinement for Baran233. Identification code JWL-1417-076-2 Empirical formula C15 H27 B O2 Formula weight 250.18 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = 9.6783(10) Å a= 90°. b = 7.2752(7) Å b= 108.221(7)°. c = 10.8776(12) Å g = 90°. Volume 727.50(13) Å3 Z 2 Density (calculated) 1.142 Mg/m3 Absorption coefficient 0.554 mm-1 F(000) 276 Crystal size 0.25 x 0.15 x 0.08 mm3 Crystal color, habit Colorless Block Theta range for data collection 4.28 to 69.27°. Index ranges -11<=h<=11, -8<=k<=8, -12<=l<=12 Reflections collected 2171 Independent reflections 2171 [R(int) = 0.0446] Completeness to theta = 60.00° 92.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9570 and 0.8739 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2171 / 1 / 171 Goodness-of-fit on F2 1.024 Final R indices [I>2sigma(I)] R1 = 0.0538, wR2 = 0.1455 R indices (all data) R1 = 0.0549, wR2 = 0.1473 Absolute structure parameter 0.3(3) Extinction coefficient not measured Largest diff. peak and hole 0.292 and -0.283 e.Å-3

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Table 1. Crystal data and structure refinement for Baran238. Identification code DD Empirical formula C16 H26 O2 Formula weight 250.37 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = 6.12370(10) Å a= 90°. b = 11.3579(2) Å b= 90°. c = 19.8378(4) Å g = 90°. Volume 1379.77(4) Å3 Z 4 Density (calculated) 1.205 Mg/m3 Absorption coefficient 0.598 mm-1 F(000) 552 Crystal size 0.34 x 0.12 x 0.08 mm3 Crystal color, habit Colorless Rod Theta range for data collection 4.46 to 70.17°. Index ranges -7<=h<=7, -13<=k<=13, -21<=l<=24 Reflections collected 7828 Independent reflections 2498 [R(int) = 0.0272] Completeness to theta = 68.00° 98.8 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9537 and 0.8225 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2498 / 0 / 167 Goodness-of-fit on F2 1.023 Final R indices [I>2sigma(I)] R1 = 0.0370, wR2 = 0.0957 R indices (all data) R1 = 0.0372, wR2 = 0.0960 Absolute structure parameter 0.0(2) Extinction coefficient not measured Largest diff. peak and hole 0.266 and -0.222 e.Å-3

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Curriculum Vitae

Jonathan W. Lockner

Current Position: The Scripps Research Institute Department of Chemistry 10550 North Torrey Pines Road La Jolla, California 92037 Telephone: (858) 784-2532 Facsimile: (858) 784-2590 Email: [email protected]

Date/Place of Birth: 17 May 1979 / Joliet, IL, USA Citizenship: United States

Education 2011 – Present Post-Doctoral Associate Advisor: Professor Kim D. Janda The Scripps Research Institute, La Jolla, California

2006 – 2011 Ph.D. in Chemistry Advisor: Professor Phil S. Baran The Scripps Research Institute, La Jolla, California

1997 – 2001 B.S. in Chemistry Advisor: Professor Robert M. Coates University of Illinois, Urbana–Champaign, Illinois

1993 – 1997 High school graduation from Plainfield High School

Industrial Experience 2003 – 2006 Research Associate, Medicinal Chemistry Pfizer Global Research & Development, La Jolla, California 2001 – 2003 Research Associate, Medicinal Chemistry Pharmacia Corporation, Kalamazoo, Michigan

Teaching/Mentoring Experience • Teaching Assistant for Heterocyclic Chemistry (2009) • Mentor for Marcus Bray, Torrey Pines High School (2009) • Mentor for Rune Risgaard, visiting student from Denmark (2011) • Mentor for Sylvia Chen, visiting student from UW–Madison (2011)

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Awards • Bristol–Myers Squibb Graduate Fellowship, 2010 • Amgen Graduate Research Fellowship, 2009 • Harold G. Snyder Undergraduate Summer Research Fellowship, 2000 • Dean’s List Honors, 1999 – 2000 • International Paper Company Scholarship, 1998 • Plainfield Rotary Club Scholarship, 1997 • Carlan Surles Memorial Scholarship, 1997 • American Legion Good Citizen Medallion, 1997

Publications 1. Davis, C. E.; Bailey, J. L.; Lockner, J. W.; Coates, R. M. Regio- and Stereoselectivity of Diethylaluminum Azide Opening of Trisubstituted Epoxides and Conversion of the 3º Azidohydrin Adducts to Isoprenoid Aziridines. J. Org. Chem. 2003, 68, 75−82. 2. Lockner, J. W.; Dixon, D. D.; Risgaard, R.; Baran, P. S. Practical Radical Cyclizations with Arylboronic Acids and Trifluoroborates. Org. Lett. 2011, 13, 5628−5631. 3. Dixon, D. D.; Lockner, J. W.; Zhou, Q.; Baran, P. S. Scalable, Divergent Synthesis of Bioactive Meroterpenoids. Manuscript in preparation.

Book Manuscript Editing 1. Li, J. J. Triumph of the Heart: The Story of Statins, Oxford University Press, 2009 2. Li, J. J. Name Reactions, Springer, 4th edition, 2009 3. Hoffman, R. W. Elements of Synthesis Planning, Springer, 2009

Professional Activities 1. Toastmasters International, 2009 – Present 2. American Association for the Advancement of Science, 2007 – Present 3. American Chemical Society, 2002 – Present 4. American Chemical Society Legislative Action Network, 2002 – Present 5. Phi Eta Sigma Honor Society, 1998 – 2001

Research Presentations 1. University of Illinois Allerton Conference, Monticello, IL (October, 2000) 2. The Scripps Research Institute Symposium, San Diego, CA (September, 2007) 3. The Scripps Research Institute Symposium, San Diego, CA (September, 2008) 4. The Scripps Research Institute Symposium, San Diego, CA (September, 2009) 5. Bristol-Myers Squibb Chemistry Awards Symposium (April, 2011)

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