Addition / C-C Bond Cleavage Reactions of Vinylogous Acyl Triflates and Their Application to Natural Product Synthesis David Mack Jones

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2010 Addition / C-C Bond Cleavage Reactions of Vinylogous Acyl Triflates and Their Application to Natural Product Synthesis David Mack Jones

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COLLEGE OF ARTS AND SCIENCES

ADDITION / C-C BOND CLEAVAGE REACTIONS OF VINYLOGOUS

ACYL TRIFLATES AND THEIR APPLICATION

TO NATURAL PRODUCT SYNTHESIS

DAVID MACK JONES

A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy

Degree Awarded: Spring Semester, 2010

The members of the committee approve the dissertation of David M. Jones defended on December 3, 2009.

______Gregory B. Dudley Professor Directing Dissertation

______Kenneth Taylor University Representative

______Jack Saltiel Committee Member

______D. Tyler McQuade Committee Member

______Kenneth Goldsby Committee Member

Approved: ______Joseph B. Schlenoff, Chair, Department of Chemistry and Biochemistry

The Graduate School has verified and approved the above-named committee members.

This manuscript is dedicated to my Mother and Father, without whom I would have been lost. Their constant and unwavering support has made all that I am, and all that I will be, possible.

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ACKNOWLEDGEMENTS

This body of work has been made possible not only through my hard work, but through the personal and academic support of many people. I would like acknowledge Professor Gregory Dudley. He was charged with the difficult task of not only providing challenging problems for me, his student, to explore, but also he had to provide an environment in which I could hone my own set of tools for future scientific endeavors. As a naïve 1st year graduate student I joined his research group and his constant guidance set me on the right path. As the years progressed he no longer provided answers, but only answered my questions with yet more questions. I remember being completely frustrated at the time with this tact. However now, in the waning moments of my graduate studies, I understand the role that a research advisor must play in the development of a Ph.D. student. I owe much to Dr. Dudley and I am very appreciative of his ability to change me from that naïve graduate student into the independent scientist that I have become today. I would also like to thank the members of the Dudley research group: Dr. Tim Briggs, who introduced me to lab techniques, and guided my early research; Dr. Shin Kamijo, who made my work possible through his early efforts; Dr. Doug Engel, who entered the lab at the same time as I and provided constant competition; Sami Tlais and Jingyue Yang, who often provided company late into the night in the lab; Marilda Lisboa, who provided several intermediates in my palmerolide research; and the rest of the members, past and present. I would like to acknowledge my family for providing constant support, financial and otherwise. Mom and Dad, you have truly been the foundation of my life. Although many times in grad school, you could not offer any advice to help me with my problems, you always made sure that I knew you would do anything in your power to help me. Amy, Laura, Ken, and your families, you have provided support to me in ways that you cannot even understand. I am thankful for your understanding of my inability to attend family gatherings, niece and nephew birthday parties, and other important milestones. Bamp, June, Grammy, and everyone else in the family, thank you. I would like to thank Kerri, a very big part of my life throughout graduate school; you have helped me through many difficult times. I would like to thank the Pritchard family for being like a second family to me. Thanks to Doug, Kerry, Phil, Chris, Antonio, Matt, Mike, Scott and all the other great friends in my life. I wish I had more space to mention all of those people that deserve recognition for supporting me in the generation of this manuscript, please forgive me for any omissions. Lastly, I would like to thank all of those who helped me edit this manuscript, without whom, this document would not have been possible: Kerry Gilmore, Sami Tlais, Marilda Lisboa, and Professor Dudley.

TABLE OF CONTENTS

List of Tables ...... ….. vi List of Figures ...... ….. vii List of Abbreviations ...... ….. xii Abstract ...... ….. xviii

1. INTRODUCTION: C-C BOND CLEAVAGE AND FRAGMENTATION REACTIONS IN ORGANIC SYNTHESIS...... 1

2. SYNTHESIS OF (Z)-6-HENEICOSEN-11-ONE: THE SEX PHEROMONE OF THE DOUGLAS-FIR TUSSOCK MOTH ..... ….. 13

The Doulas-Fir Tussock Moth ...... ….. 13 Synthesis of (Z)-6-Heneicosen-11-one ...... ….. 16 Experimental ...... ….. 21

3. A FRAGMENTATION / BENZANNULATION STRATEGY TO PROVIDE ACCESS TO BENZO-FUSED INDANES ...... 37

Introduction ...... ….. 37 The Alcyopterosins ...... ….. 37 Retrosynthetic Analysis of Alcyopterosin A ...... ….. 53 Exploring Gold and Copper Catalyzed Benzannulations .. .. 59 Experimental ...... ….. 70

4. SYNTHESIS OF THE EASTERN HEMISPHERE (C1-C15) OF PALMEROLIDE A ...... ….. 115

Introduction ...... ….. 115 The Melanoma Problem ...... ….. 116 Palmerolide A ...... ….. 121 Synthesis of the Eastern Hemisphere of Palmerolide A ... ….. 138 Experimental ...... ….. 145

5. RE-EXPLORING THE CLAISEN-TYPE CONDENSATIONS OF VINYLOGOUS ACYL TRIFLATES ...... ….. 170

New Insights into the Mechanism ...... ….. 170 Synthesis of -Ketophosphonates ...... ….. 177 Experimental ...... ….. 184

REFERENCES ...... ….. 202

BIOGRAPHICAL SKETCH ...... ….. 222

LIST OF TABLES

Table 1: Scope of Original Fragmentation Reaction with Respect to Nucleophiles ...... 11

Table 2: Grignard Triggered Fragmentation of 2 ...... 20

Table 3: DNA Binding Assay Performed by Iglesias et al...... 51

Table 4: Average Values (MG-MID) for In Vitro Antitumor Activity on the NCI 60-Cell Line Panel ...... 52

Table 5: Preliminary Screening of Benzannulation Reactions of Substrates 84a-f...... 65

Table 6: Selected Data from Nicolaou’s SAR Study (GI50 Values in M) .. 133

Table 7: Claisen-Type Condensation of Vinylogous Acyl Triflate 2 ...... 141

Table 8: Comparison of the Acidities of Several Acetophenone Phosphonate and Phosphine Oxide Derivatives in DMSO ...... 174

Table 9: Reactions of Vinylogous Acyl Triflates with 1.1 Equivalents of Dimethyl lithiomethylphosphonate (152b) ...... 180

Table 10: Fragmentation of VAT 2 Using 1.1 Equivalents of Various Phosphonate Derived Nucleophiles ...... 182

LIST OF FIGURES

Figure 1: Representative examples of the (1) Diels-Alder, (2) Michael Addition, (3) Evans Aldol, (4) and Sonogashira Cross Coupling Reactions in Synthesis ...... 2

Figure 2: Examples of Tandem Bond Forming / Bond Breaking Strategies in Organic Synthesis ...... 3

Figure 3: Examples of Transition Metal Catalyzed C-C Bond Cleavage Reactions in Synthesis ...... 4

Figure 4: Possible Mechanistic Pathways of Grob Fragmentations ...... 6

Figure 5: General Representation of the Wharton Fragmentation ...... 6

Figure 6: Wood and Njardarson’s Wharton fragmentation approach to CP-263,114 ...... 7

Figure 7: Base Promoted Eschenmoser-Tanabe Fragmentation Process...... 8

Figure 8: Mander’s Reduction-Epoxidation-Oxidation Solution for the Eschenmoser-Tanabe Fragmentation in the Synthesis of GB 13 ...... 9

Figure 9: Comparison of the Eschenmoser-Tanabe Fragmentation and Enone Formation from Vinylogous Acid Esters ...... 9

Figure 10: Mechanistic Hypothesis for the Fragmentation of Vinylogous Acyl Triflates ...... 12

Figure 11: (a)64 A Male Specimen of the Douglas-Fir Tussock Moth; (b)64 Distribution of Host Type Where Douglas-Fir Tussock Moth Has Been Found; (c) the DFTM Sex Pheromone...... 13

Figure 12: Smith’s Synthesis of the Sex Pheromone of the Douglas-Fir Tussock Moth ...... 17

Figure 13: Fetizon and Lazare’s Synthesis of Z6 ...... 17

Figure 14: Kocienski and Cernigliaro’s Synthesis of Moth Pheromone Z6 18

vii

Figure 15: Synthesis of (Z)-6-Heneicosen-11-one Using an ABC Strategy 21

Figure 16: Illudalane Skeleton and Alcyopterosin A ...... 38

Figure 17: Proposed Biosynthetic Pathway to the Illudalanes...... 38

Figure 18: (eq. 1) Proposed Decomposition of Stearodelicone (21) Upon Absorption on Silica Gel, and (eq. 2) the Observed Reactions of Ptaquiloside (23) in the Presence of Acid and/or Base ...... 40

Figure 19: Representative Sample of Illudalane Structures Isolated from A. paessleri and A. grandis ...... 41

Figure 20: Possible Traditional Reppe Reaction Involving Three Different Unsymmetrical Acetylenes ...... 42

Figure 21: Typical Solutions for Chemo- and Regioselective Cyclotrimerization of Alkynes ...... 43

Figure 22: Representative Examples of Sato’s One-Pot Metalative Reppe Reactions ...... 44

Figure 23: Sato’s Synthesis of Alcyopterosin A ...... 44

Figure 24: Key Steps in the Syntheses of Alcyopterosin E (28) (eq. 1) and Alcyopterosin I (30) by Witulski and Snyder (eq. 2)...... 46

Figure 25: Synthesis of Iglesias’ Key Intermediate ...... 47

Figure 26: Synthesis of Unnatural Alcyopterosin Analogs Performed by Iglesias et al ...... 48

Figure 27: Completion of Iglesias’ Synthesis of Alcyopterosin A...... 49

Figure 28: Compounds Known to Intercalate DNA...... 50

Figure 29: Retrosynthetic Analysis of Alcyopterosin A Using a Fragmentation / Benzannulation Approach ...... 54

Figure 30: AuCl3- and Cu(OTf)2-Catalyzed [4+2] Benzannulation Reactions Described by Asao and Yamamoto...... 55

Figure 31: Proposed Mechanism of the [4+2] Cycloaddition Reactions of 56 and 57 Catalyzed by AuCl3 and Cu(OTf)2 / CF2HCO2H… 56

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Figure 32: Intramolecular Lewis Acid-Catalyzed [4+2] Benzannulation Reactions Studied by Asao and Yamamoto ...... 57

Figure 33: Yamamoto’s Key Benzannulation in the Synthesis of (+)- Rubiginone B2 and (+)-Ochromycinone ...... 57

Figure 34: Contrast Between Known Benzannulations and Desired Benzannulation ...... 58

Figure 35: Comparison of Known Benzannulations and Those of a New Methodology...... 60

Figure 36: Originally Considered Reactions to Access Fragmentation Pre-nucleophile 77 ...... 61

Figure 37: Proposed Route to Benzannulation Substrates 84...... 62

Figure 38: Synthesis and Fragmentation Reaction of Aryltriazene 80...... 62

Figure 39: Synthesis of Benzannulation Substrates 84a-e...... 63

Figure 40: Synthesis of Benzannulation Substrate 84f...... 64

Figure 41: Direct Comparison of the Benzannulation Reactions of 84c and 84f ...... 66

Figure 42: Alternative Synthesis of Benzannulation Substrate 89 ...... 67

Figure 43: Benzannulation Reactions of Compound 89 ...... 68

Figure 44: Proposed Route to Vinyl Nucleophile 54 Using Negishi’s Z-Selective Bromoboration ...... 69

Figure 45: Several Chemotherapeutic Agents Used in the Treatment of Melanoma ...... 120

Figure 46: The Report Issued to Baker from the National Cancer Institute’s 60-Cell Line Panel Toxicity Assay for Palmerolide A181 ...... 123

Figure 47: Palmerolide A and Other Members of the Palmerolide Natural Products with Major Distinctions Highlighted in Red Ovals ...... 124

Figure 48: Palmerolide A and Strategic Disconnections...... 125

Figure 49: De Brabander’s Synthesis of the C16-C24 Fragment of . Palmerolide A ...... 126

Figure 50: De Brabander’s Synthesis of the C9-C15 Fragment of Palmerolide A ...... 126

Figure 51: De Brabander’s Synthesis of the C1-C8 Fragment of Palmerolide A ...... 127

Figure 52: Completion of De Brabander’s Synthesis of 109, a Diastereomer of Palmerolide A ...... 128

Figure 53: Synthesis of Nicolaou’s C16-C23 (112) and C8-C15 (116) Fragments ...... 129

Figure 54: Nicolaou’s Synthesis of C1-C8 Fragment of Palmerolide A ..... 130

Figure 55: Nicolaou’s End-Game Strategy for the Synthesis of 109 ...... 131

Figure 56: Key Analogs of Palmerolide A Developed by the Nicolaou Lab ...... 132

Figure 57: Key Reactions in Maier’s Formal Synthesis of Palmerolide A .. 135

Figure 58: Hall’s Asymmetric Crotylboration en Route to Palmerolide A’s C16-C24 Fragment ...... 136

Figure 59: Hall’s Unique Approach to Install the C7, C10, and C11 Stereocenters ...... 137

Figure 60: Brief Overview of the Addition / Bond Cleavage Reactions of Vinylogous Acyl Triflates ...... 139

Figure 61: Synthesis and Nucleophile-Triggered Decompositions of DHP Triflates ...... 140

Figure 62: Retrosynthetic Analysis of Palmerolide A Using a Fragmentation Approach ...... 140

Figure 63: Synthesis of the C1-C8 Olefination Reagent for the Synthesis of Palmerolide A ...... 142

Figure 64: Synthesis of Aldehyde 150, the C9-C15 Fragment of Palmerolide A ...... 143

Figure 65: Possible Michael Reaction of 155 ...... 144

Figure 66: Completion of the Eastern Hemisphere (C1-C15) Fragment Synthesis ...... 144 Figure 67: Mechanism of the Classical Claisen Condensation of Ethyl Acetate ...... 170

Figure 68: Proposed Mechanism for the Reaction Between 2 and 152a .. 171

Figure 69: Reported Claisen-Type Condensation Reactions of VAT 2 ..... 172

Figure 70: Observations Made During the Synthesis of the C1-C15 Fragment of Palmerolide A (Chapter 4) ...... 173

Figure 71: Proposed Fragmentation Reaction Pathway Between 2 and 166 ...... 175

Figure 72: Proposed Mechanism of the Reaction Between VAT 2 and 152 ...... 176

Figure 73: Common Methods for the Preparation of Phosphonates ...... 178

Figure 74: Synthesis of 180, an Analog of Phosphonate 178 ...... 181

LIST OF ABBREVIATIONS

ABC addition / C-C bond cleavage

Ac acetyl app apparent (spectral)

Aq aqueous

Ar aryl, argon

BAIB bis(acetoxy)iodobenzene (phenyliodonium diacetate)

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

Bn benzyl

BOLD bleomycin, vincristine, lomustine, and dacarbazine

Bt. Bacillus thuringiensis n-Bu normal butyl t-Bu tertiary butyl c centi oC degrees Celsius ca. circa (approximately)

Calcd calculated (in mass spectrometry)

CBS Corey-Bakshi-Shibata reagent

CD circular dichroism cf. confer (compare)

CI chemical ionization (in mass spectrometry)

CNS central nervous system

xii cod 1,5-cyclooctadiene

CSA camphor-10-sulfonic acid d doublet (spectral)

 heat, double bond location

 chemical shift, in parts per million relative to tetramethylsilane dba dibenzylideneacetone

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

DCE 1,2-dichloroethane

DCM dichloromethane

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

DEAD diethyl azodicarboxylate

DHP 5,6-dihydro-2-pyrone

DIBAL diisobutylaluminum hydride

DIPEA diisopropylethylamine

DMAP N,N-4-dimethylaminopyridine

DMP Dess-Martin periodinane

DMSO dimethylsulfoxide

DNA deoxyribonucleic acid dr diastereomeric ratio

DTFM Douglas-fir tussock moth

DTIC dacarbazine

E- entgegen or opposite (alkene geometry)

xiii

EDC-Cl 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ee enantiomeric excess e.g. exempli gratia (for example) eq equation

EI electron ionization (in mass spectrometry)

EPA United States Environmental Protection Agency equiv equivalent(s)

ESI electrospray ionization (in mass spectrometry)

Et ethyl et al. et alii (and the others)

EWG electron withdrawing group

FAB fast-atom bombardment (in mass spectrometry)

FT-IR Fourier-transformed infrared g gram(s) gem- geminal

GI50 half maximal growth inhibitory concentration h hour(s) ha hectares

Hex hexanes

HIV human immuno-deficiency virus

HPLC high-performance liquid chromatography

HRMS high-resolution mass spectrometry

HWE Horner-Wadsworth-Emmons

xiv

Hz hertz

IC50 half maximal inhibitory concentration i.e. id est (that is)

Ipc isopinocamphenyl

IR infrared

J coupling constant reported in hertz (in NMR spectroscopy)

 wavelength

L liter(s)

LC50 median lethal dose

LDA lithium diisopropylamide

LiHMDS lithium bis(trimethylsilyl)amide

 micro m multiplet (spectral), meter(s), milli m- meta-

M moles per liter, mega mCPBA m-chloroperbenzoic acid

Me methyl

MG-MID meangraph midpoint min minute(s)

MOM methoxymethyl mp melting point

Ms methanesulfonyl n nano

NCI United States National Cancer Institute

NMR nuclear magnetic resonance

Nuc nucleophile

OPP pyrophosphate p- para-

PCC pyridinium chlorochromate

Ph phenyl

Pin pinacolato

PMB p-methoxybenzyl ppm parts per million ppt precipitate

PPTS pyridinium p-toluenesulfonate i-Pr isopropyl q quartet (spectral)

RCM ring-closing metathesis ref reference retro retrograde r.t. room temperature s singlet (spectral)

SAR structure-activity relationship

SN2 substitution nucleophilic bimolecular t triplet (spectral)

TBAF tetrabutylammonium fluoride

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TBDPS tert-butyldiphenylsilyl

TBS tert-butyldimethylsilyl

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

TES triethylsilyl

Tf trifluoromethanesulfonyl

TFA trifluoroacetic acid

TGI total growth inhibitory concentration

THF tetrahydrofuran

TIPS triisopropylsilyl

TMS trimethylsilyl

TMZ temozolomide

Tol tolyl

Ts p-toluenesulfonyl

UV ultraviolet

VAT vinylogous acyl triflate

V-ATPases vacuolar adenosine triphosphatases wt. weight

Z- zasammen or together (alkene geometry)

xvii

ABSTRACT

This dissertation describes the synthetic utility of tandem addition / C-C bond cleavage reactions of vinylogous acyl triflates. The first chapter provides background into carbon-carbon bond breaking reactions that have been applied in organic synthesis and the preliminary data that allowed for the original work presented here. Chapter 2 explains the significance as well as the prior syntheses of a commercially important moth pheromone, (Z)-6-heneicosen-11-one. The second chapter culminates in the synthesis of the sex attractant through a fragmentation reaction made possible by the direct extension of the initial nucleophile-triggered fragmentation studies to include the use of Grignard reagents. Chapter 3 describes the application of the fragmentation method, coupled to a benzannulation reaction, to afford penta- and hexasubstituted indanes. This two step sequence provides the basis for future work directed toward the synthesis of alcyopterosin A, a known cytotoxic agent with possible biological applications. The current difficulties pertaining to the treatment of melanoma are discussed in Chapter 4. Recently, an exciting natural product that provides promising activity against this horrible cancer was discovered. Palmerolide A has the ability to kill melanoma cells selectively at low concentrations. The fragmentation method developed in these laboratories provides entry into a key fragment. The Claisen-type condensation reaction of vinylogous acyl triflates was expanded to the synthesis of a novel -ketophosphine oxide olefinating reagent, which allowed for the rapid synthesis of the eastern hemisphere (C1-C15) of this exciting natural product. Optimization of the Claisen-type condensation reaction to provide the -ketophosphine oxide reagent, led to the optimal reduction of the number of equivalents of the nucleophile. Intrigued by this, these reactions were explored in more detail. The results of this investigation are described in Chapter 5. The reduction in the number of equivalents of nucleophile, a key feature in these reactions, may be attributed to the ability of the phosphorus atom to form of an oxaphosphetane-like intermediate. As a result, new, potentially useful, - ketophosphonates were synthesized.

xviii

CHAPTER 1

INTRODUCTION: C-C BOND CLEAVAGE AND FRAGMENTATION REACTIONS IN ORGANIC SYNTHESIS

Synthetic organic chemistry has largely focused on the use of carbon-carbon bond forming reactions to assemble complex molecules. The means to install such bonds is of the utmost importance. There is a constant struggle to provide new carbon- carbon bond forming reactions that are tolerant to a diverse number of functional groups, as well as reactions that are both regio- and stereoselective. Discoveries of such reactions constantly expand the frontiers of organic chemistry. Tolerant and selective C-C bond forming reactions, such as the Diels-Alder,1-4 Michael addition,5-8 Evans aldol,9 and Sonogashira10-12 reactions were at the forefront of chemistry at the time of their discovery. These reactions have since been applied in the synthesis of numerous complex molecules (Figure 1). If not for the innovation of such reactions, the synthesis of many natural products would have proven to be a much more daunting challenge; they have changed the way chemists have approached natural product synthesis and have allowed the development of synthetic strategies which would have otherwise been impossible. The need to build up complexity quickly in synthesis requires bond forming reactions. Not surprisingly, C-C bond breaking reactions receive far less attention. However, these reactions often provide access to compounds that can be difficult to prepare through other methods. Some of the most useful C-C bond breaking reactions applied in organic synthesis are simply the reverse processes of C-C bond forming events similar to those mentioned above (the aldol,13,14 Diels-Alder,15,16 and Michael reactions,17,18 among others).

Diels-Alder Reaction From Boger's Synthesis of Rubrolone Aglycon19

O MeO OMe MeO OMe O N N H O (1) (2.5 equiv) O r.t., 45 min 97% H O O O O

Tandem Michael-Addition Reactions From Ihara's Synthesis of (± )-Longiborneol20

O LiHMDS (2 equiv) (2) THF O O o CO2Me -78 C, 1h, 3 then CO2Me CO2Me 0 oC, 3h 94%

1. Bu2BOTf, Et3N, O O -5 oC, DCM; then add O O OH (3) H O N O N 12

O 12 Ph Me Ph Me 2. MeOH, 30% H2O2 63%, 2 steps

Sonogashira Reaction in Paterson's Synthesis of Callipeltoside aglycon22

OTBS OTBS Me H Me

Me 1. Pd(Ph3P)2Cl2, CuI, Me O O (4) H + HN(i-Pr)2, EtOAc MeO H MeO MeO O O 2. TBAF, THF MeO O O 3. PPTS, CH3CN, H2O Me I Cl 54% over 3 steps Me Cl Callipeltoside aglycon

Figure 1: Representative examples of the (1) Diels-Alder, (2) Michael Addition, (3) Evans Aldol, and (4) Sonogashira Cross Coupling Reactions in Synthesis.

Often, reverse reactions are used in tandem with their forward counterparts to access complex molecules. Figure 2 provides some representative examples that

2 demonstrate the utility of retrograde reactions in organic synthesis. Jacobi and co- workers have utilized a Diels-Alder / retrograde Diels-Alder sequence to access (±)- Petasalbine (scheme 1).23 Jacobi took advantage of the reactivity of oxazoles as diene partners; after the cycloaddition reaction with a tethered alkyne, the heterocyclic intermediate underwent a retro-Diels-Alder to afford the required furan moiety. In 2005, Iwabuchi and co-workers synthesized cannabinoid receptor agonist (-)-CP55,940 using a modified-proline catalyzed aldol reaction to achieve stereocontrol, followed by a retro- aldol to generate the chiral cyclohexane carboskeleton (scheme 2).24

Jacobi's Key Diels-Alder/Retro-Diels-Alder Reaction in the Synthesis of (± )-Petasalbine

O N H N H O (1) O  Retro-Diels-Alder Me H OH Diels-Alder Me -HCN MeOH Me Me Me 84% Me Me OH (± )-Petasalbine

Iwabuchi's Aldol/Retro-Aldol Strategy in the Synthesis of (-)-CP55,940

TBDPSO O PO

N CO2H H N H O H MeCN, rt., 68% 68% (>99% de, 94% ee) O O O OH 2 steps (2) CHO

n-C6H13 O O OH OMe cat. TsOH OMe OH ethylene glycol xylene, reflux n-C H 6 13 49% n-C6H13 3 steps O OMOM 88% O O HO (-)-CP55,940 Figure 2: Examples of Tandem Bond Forming / Bond Breaking Strategies in Organic Synthesis.

Reactions such as the Cope rearrangement,25,26 as well as oxidative cleavages of olefins27 and diols,28 represent some traditional C-C bond cleavage reactions. Several new C-C bond breaking reactions have been made available through the advance of transition metal chemistry. Although transition metal-catalyzed C-C bond cleavage chemistry has made some headway in synthetic chemistry, many of these reactions are heavily dependent on the presence of either highly strained bonds (e.g. cyclopropane or cyclobutane moieties) or functional groups located about the reaction site capable of coordinating to the metal center (Figure 3, scheme 1).29-33 The evolution of metathesis catalysts has allowed for the development of ring opening metathesis reactions, yet another defining example of C-C bond cleavage reactions in synthetic chemistry (Figure 3, scheme 2).34-36

Murakami's Asymmetric Rhodium Catalyzed Synthesis of 3,4-Dihydrocoumarins Through Cleavage of a Cyclobutyl Intermediate37

R' O R' R [Rh(OH)(COD)]2 R -carbon elimination (R)-BINAP OH Toluene O ORh up to 92% and 95% ee (1) Rh Rh R' R' R' R R R 1,4-Rh shift "H+"

O O O O O O

Tandem Ring opening/Ring Closing Metathesis Strategy in Phillips' Synthesis of (± )-trans-Kumausyne38

PPh3 O Cl Ru O AcO Cl Ph H (2) O PPh3 O CH2Cl2, H2C=CH2, r.t. H H 83% H O Br (± )-trans-Kumausyne

Figure 3: Examples of Transition Metal Catalyzed C-C Bond Cleavage Reactions in Synthesis.

Throughout the 1950’s and 60’s, Grob and co-workers carried out investigations into heterolytic bond cleavage reactions of molecules consisting of various combinations of carbons and heteroatoms.39-43 These reactions produce three distinct fragments / products, and are thus referred to as Grob fragmentations. The three ―products‖ generated from the fragmentation are all included in the starting molecule with the general formula a—b—c—d—X (Figure 4). ―X‖ is referred to as the nucleofuge; leaving with the electron pair with which it was originally attached to the starting molecule, thus it becomes more negative. Prior to fragmentation, the nucleofugal fragment can be neutral (e.g. halide, sulfonate, or carboxylate) or charged (diazonium, oxonium, ammonium or sulfonium). The electrofuge, a—b, loses a bonding pair of electrons and becomes more positive. The electrofugal fragment is typically a carbonyl containing compound; however, carbon dioxide, olefins, dinitrogen, immonium-, carbonium-, and acylium ions have been generated as electrofuges. The central portion of the starting material, c—d, becomes the unsaturated fragment. The most commonly encountered unsaturated fragments are olefins, acetylenes, nitriles and imines. The most probable mechanistic pathway (Figure 4) of the Grob fragmentation is substrate dependent. Both steric and electronic properties of the substrate influence the nature by which the fragmentation takes place. Very narrow stereochemical requirements must be met in order to achieve proper orbital overlap for the one-step synchronous (concerted) mechanism to proceed. The transition state of the concerted process involves all five atoms, and thus, this mechanism is invoked usually in Grob fragmentations of conformationally rigid molecules. If necessary orbital overlap is insufficient or absent, the concerted process is not possible; in this case, a two-step process (usually cationic) must take place if the fragmentation is to occur. A two-step fragmentation pathway typically provides the possibility for side reactions (e.g. elimination), making fragmentations that proceed through stepwise mechanisms less useful.

(A) One-step synchronous: a b c d X b d + + a c X Electrofugal Unsaturated Nucleofugal fragment fragment fragment

Electrofuge Nucleofuge

(B) Two-step cationic:

- b d X b d a b + c d a c X a c

b d - a b d c d + X a c X c X

Figure 4: Possible Mechanistic Pathways of Grob Fragmentations.

P. S. Wharton pioneered the base-induced heterolytic fragmentation reaction of bicyclic-1,3-diol monosulfonate esters, now referred to as a Wharton fragmentation (Figure 5).44-47 Although the Wharton fragmentation falls into the category of a Grob fragmentation, it is a more specific term referring to the synthesis of alkenes from 1,3- diols. The most common substrates for the Wharton fragmentation are bicyclic-1,3- hydroxy monotosylates or monomesylates generated from unsymmetrical 1,3-diols.

OSO2R base n n OH O

Figure 5: General Representation of the Wharton Fragmentation.

The Wharton fragmentation is often employed for the synthesis of medium sized rings which are difficult to prepare. The rate of fragmentation depends both on the ring

6 strain of the bicycle and the concentration of the base. Typically strong, non- nucleophilic, bases (t-BuOK, NaH, dimsylsodium, etc.) are best for promoting the fragmentation. Alkenes from the Wharton fragmentation are generated stereospecifically from the bicyclic precursor. Wood and Njardarson successfully applied the Wharton fragmentation in their approach to the bicyclic core of CP-263,114 (Figure 6).48 The synthetic strategy outlined by Wood highlights the utility of the Wharton fragmentation, as the originally envisioned oxy-Cope rearrangement failed.

AcO MsCl, pyr AcO K2CO3, AcO DMAP MeOH Me Me Me OH OMs r.t. 95% 2 steps

Figure 6: Wood and Njardarson’s Wharton fragmentation approach to CP-263,114.

During the time Grob was describing the fragmentation reactions that now bear his name, Eschenmoser49,50 and Tanabe51,52 were independently exploring the ring opening reaction of ,-epoxyhydrazones. The Eschenmoser-Tanabe fragmentation process (Figure 7) is classified as a 7-centered Grob-type fragmentation process, yielding an electrofugal fragment (ketone) tethered to the unsaturated fragment (alkyne) and two nucleofugal fragments (N2 and typically an arylsulfinate).

H Base N N O Ts N Ts N TsNHNH R 2 R R O O -H2O O R' R' R'

Unsaturated Nucleofugal fragment fragments R N Ts N R' R Ts + NN + O R' O Nucleofugal fragment

Figure 7: Base Promoted Eschenmoser-Tanabe Fragmentation Process.

The substrates of the Eschenmoser-Tanabe fragmentation are typically prepared in a multistep sequence from ,-unsaturated ketones; first through the epoxidation of a cyclic enone, followed by a condensation reaction with tosyl hydrazide. The fragmentation is induced by treatment with acid or base in a protic medium induces fragmentation. Although the multistep sequence from cyclic enone to tethered keto- alkyne has found some application as a synthetic strategy through the years,53- 58,79,80,86,114,117 it remains largely pedagogical. The substrates required for the Eschenmoser-Tanabe process, epoxy hydrazones, can be difficult to prepare, as illustrated by Mander’s synthesis of the Galbulimima alkaloid GB 13.55 Direct epoxidation of the enone of the pentacyclic late-stage intermediate was unsuccessful. In an effort to obtain the necessary epoxy hydrazone, a reduction-epoxidation-oxidation sequence was performed (Figure 8). The possible difficulty in the synthesis of epoxy hydrazones and the protic medium (commonly ethanol or acetic acid) present potential drawbacks to the method.

1. LiAlH4, THF O H 2. mCPBA, DCM O H 3. DMP, NaHCO ; H 3 H H H MOMO H 4. p-NO2ArSO2NHNH2, MOMO H pyridine, EtOH, THF OMOM 59% OMOM 4 steps

Figure 8: Mander’s Reduction-Epoxidation-Oxidation Solution for the Eschenmoser- Tanabe Fragmentation in the Synthesis of GB 13.

Prior to the description of the Eschenmoser-Tanabe fragmentation process, Woods and Tucker described the reaction of vinylogous acid esters with phenylmagnesium bromide, providing cyclic enones.59 This method has been utilized in cyclic enones that are difficult to prepare using other methods.60 There is a marked similarity between the presumed intermediates of the Eschenmoser-Tanabe fragmentation and the synthesis of enones from vinylogous acid esters (Figure 9). Although there is a parallel between the intermediates A and B, they diverge in the manner by which they decompose.

The Eschenmoser-Tanabe Fragmentation

R' OH R' R' O R R O R NNTs - N2 NNHTs - TsH A

Enone Formation from Vinlogous Acid Esters

3 R OM 3 O 1 R R + R1 R3 M H3O R1 OR2 - R2OH OR2 O B

Figure 9: Comparison of the Eschenmoser-Tanabe Fragmentation and Enone Formation from Vinylogous Acid Esters.

In 2005, our lab sought to introduce an intermediate similar to B which would allow for a fragmentation similar to the Eschenmoser-Tanabe fragmentation under mild conditions in an aprotic solvent. Such a reaction would have important mechanistic implications and would provide a new tool in the synthesis of complex molecules. A crossover in the mechanistic pathway was envisioned to occur if the nucleofugacity of the –OR2 group in intermediate B were increased. Kamijo and Dudley carried out a preliminary investigation into a tandem carbanion addition / C-C bond cleavage reaction that provided tethered alkynyl ketones that are similar, yet regioisomeric, to those obtained by the Eschenmoser-Tanabe fragmentation.61 A change in the –OR2 group from alkoxy (enone formation, Figure 9) to trifluoromethanesulfonyloxy allowed for the desired crossover mechanism to take place both in an aprotic medium and under mild conditions (displayed in Table 1). Kamijo and Dudley found that the synthesis of vinylogous acyl triflates (2) was general and high yielding. Symmetric diketones such as 1 were converted into vinylogous acyl triflates (VATs), similar to 2, in nearly quantitative yields using a modified procedure.62 The fragmentation reaction was optimized for the addition of phenylmagnesium bromide, and ethereal solvents were found to provide the most suitable environment for the fragmentation. Table 1 summarizes the original scope of the fragmentation reaction with respect to nucleophiles explored by Kamijo and Dudley. Nucleophiles with electron donating groups had significant effect and accelerated the C- C bond cleavage process (entries 1—4 vs. entries 5—6), suggesting a transition state with significant carbonyl character. Aryl organolithium reagents were also found to trigger fragmentation more readily, presumably due to an increase in ionic character of the alkoxide intermediate (entries 7—9).

Table 1: Scope of Original Fragmentation Reaction with Respect to Nucleophiles.61,a

O 1 1.2 equiv Tf2O O R Me 2.0 equiv pyridine Me R1 M O Me CH2Cl2, 95-100% THF O OTf 1 2 3

entry R1__M conditions 3 yield (%)b

1 Ph—MgBr 0 oC to r.t. 3a 80c

o 2 p-MeO—C6H4—MgBr 0 C to r.t. 3b 86

o 3 m-MeO—C6H4—MgBr 0 C to r.t. 3c 57

o 4 o-MeO—C6H4—MgBr 0 C to r.t. 3d 34

o 5 p-Cl—C6H4—MgBr 0 — 60 C 3e 61

6 2-thienyl—MgBr 0 — 60 oC 3f 63

7 Ph—Li -78 oC to r.t. 3a 93c

o 8 m-MeO—C6H4—Li -78 C to r.t. 3g 78

o 9 o-MeO—C6H4—Li -78 C to r.t. 3h 57

10 Me—Li -78 oC to r.t. 3i 65 a 1 Typical procedure: enol triflate 2 (0.55 mmol) in 2 mL cold THF was treated with R —M (0.50 mmol). All reactions complete within 90 min. b Isolated yield. c Average of two runs.

The mechanistic hypothesis (Figure 10) that guided Kamijo and Dudley’s original studies has many interesting qualities as well as some guiding assumptions: (1) nucleophilic addition is fast and proceeds in a 1,2- fashion; (2) decomposition of intermediate C is the rate limiting step; (3) lithium triflate is extruded from C as a dissociated ion pair that subsequently recombines;63 (4) an increase in the ionic character of C promotes fragmentation; and (5) the stability of the resulting alkynyl ketone and the dissociated ion pair are reflected in the transition-state (concerted); however a two-step mechanism cannot be ruled out.

Li THFn R1 O R1 O R1 Li Me Me - LiOTf O Me THF OTf OTf fast slow 2 C 3

Figure 10: Mechanistic Hypothesis for the Fragmentation of Vinylogous Acyl Triflates.61

The fragmentation was found to be general with respect to the VAT, affording alkynyl ketones of varying tether lengths and substitution patterns. Having established a nucleophile-triggered fragmentation pathway of vinylogous acyl triflates under mild reaction conditions, the Dudley lab directed further efforts towards expanding the scope of the fragmentation reaction. This dissertation is focused on the development of this method as well as its uses as a strategy for obtaining complex intermediates capable for application in the synthesis of natural products. Since the discovery of this new reaction, we have demonstrated the value of vinylogous acyl triflates as useful tools in complex molecule synthesis.

CHAPTER 2

SYNTHESIS OF (Z)-6-HENEICOSEN-11-ONE: THE SEX PHEROMONE OF THE DOUGLAS-FIR TUSSOCK MOTH

The Douglas-Fir Tussock Moth

The Douglas-fir tussock moth (DFTM), Orgyia pseudotsugata seen in Figure 11a, is a major contributor to the defoliation of fir trees in the Pacific Northwest (Figure 11b). The populations of the DFTM typically remain stable; however they can explode, leading to significant defoliation.64 For instance, in 1974 a DFTM outbreak gave rise to the defoliation of 279,000 hectares (ha) of forest. The Environmental Protection Agency (EPA) allowed the use of DDT, an otherwise banned substance, on 161,000 ha of forest in order to contain the outbreak.65 The discovery of the sex pheromone (Figure 11c) of the DFTM in 1975,66 (Z)-6-Heneicosen-11-one (Z6) has played an integral role in the defense against such outbreaks.

(a) (b)

8 Z6

Figure 11: (a)64 A Male Specimen of the Douglas-Fir Tussock Moth; (b) 64 Distribution of Host Type Where Douglas-Fir Tussock Moth Has Been Found; (c) The DFTM sex pheromone.

Outbreaks in the population of the DFTM are typically short in duration, one to two years. The defoliation caused by outbreaks of the DFTM may result in complete tree death or in the top-kill of trees, which retards vegetation growth and may induce susceptibility of the tree to other pests. The defoliation of forestland caused by the DFTM also increases the risk and severity of forest fires. The preferred food source for the DFTM varies regionally, however the Douglas-fir is the dominant food source in most areas where they are found.67 The caterpillar larvae of the DFTM are the source of the defoliation. They are incapable of flight and are limited to the environment of the host tree. Newly hatched larvae feed on the current year’s foliage, as the larvae continue to grow, their demand for food increases and both new and old vegetation is consumed.68 After consuming copious amounts of vegetation, the larvae build their cocoon and pupation begins. Female moths emerge from their cocoon approximately 2 weeks later and mate soon after. Being unable to fly, the female moth is limited to the use of chemical communication in the form of pheromones to attract sexual partners. During the daylight hours of the male flight season, usually in the months from July to November, the females release their sex pheromone to signal potential mates. The females lay their eggs soon after mating and subsequently die.69 There are many natural controls by which the population of the DFTM is regulated. Eggs are preyed upon by small birds and parasitized by small wasp species. After hatching, the caterpillars are eaten by various predators such as birds, spiders and other insects. Carcelia yalensis, a parasitic fly species, is one of the primary foes of the DFTM larvae, laying eggs inside of the caterpillar, which then hatch and eat the caterpillar from within.70 When moth densities approach outbreak levels, there is a nuclear polyhedrosis virus that frequently infects many colonies of the moth. Once infected, a moth’s internal organs liquefy. The virus is spread throughout the colony when a diseased body ruptures and is spread on the surface of the vegetation, and is later ingested by other members of the species. Routinely, the virus is fatal and commonly spreads rampantly throughout the colony, thus resulting in outbreak suppression.71

When the natural means by which the DFTM populations are regulated become insufficient, outbreaks, and subsequent tree damage, may result. A well integrated management program must be maintained in order to handle population outbreaks and minimize destructive defoliation. The early detection of increasing populations is the foundation of any management program. Because the DFTM population produces only one generation per year, it is possible for outbreaks to be detected one to two years prior to any significant defoliation. Early detection of population outbreaks is made possible, primarily, through the annual monitoring of male populations. The males can be lured into traps baited with the sex attractant (Z6, Figure 11c) of their female counterparts, allowing for sampling to be performed.72 When an outbreak is perceived to be eminent, measures to suppress moth populations are determined through careful analysis of the potential threat to the forest. Most recently, biological insecticides have emerged as the preferred method for suppressing populations of the DFTM. Biological insecticides are regarded as environmentally benign, making them preferred over persistent chemical based alternatives. The two most common biological agents used to collapse populations of the DFTM are: Bacillus thuringiensis (Bt), marketed under several trade names (e.g. ThuricideTM from Bonide Products, Inc.), as well as the aforementioned tussock moth nucleopolyhedrosis virus (TM-Biocontrol-1, produced by the U.S. Forestry Service).73 These agents are very successful in decreasing the population of feeding larvae, however they are only used once outbreak population levels have been reached. As a result, significant defoliation remains possible. Pheromones have been used as species selective management agents.74 The sex pheromone of the DFTM offers a potentially new means of controlling moth populations at pre-outbreak levels through mating disruption.73,75,76 By spraying synthetic Z6, impregnated in controlled-release capsules, male moths become confused and unable to chemo-locate their female mating partners. By disrupting the mating habits of the DFTM, reductions in the number of caterpillars in the following year are likely. In 2005, the EPA has registered the use of Hercon® laminated plastic bio-flake formulation of Z6 for the control of tussock moths and other lepidopteran insects.77

Continued research will assist in providing the necessary data and determine the efficacy of Z6 as a mating disruption agent suitable for wide spread use.

Synthesis of (Z)-6-Heneiosen-11-one

Since its isolation and characterization by Smith, Daterman, and Davies in 1975,66 (Z)-6-heneicosen-11-one has arguably been the most important factor in the fight against severe defoliation by the DFTM. The use of Z6 in baited traps, allowing for population analysis and outbreak detection, and its potential for mating disruption lends credence to its commercial importance. There have been considerable efforts directed towards the synthesis of the DTFM sex pheromone.78-92 Most synthetic approaches to Z6 rely on one of two strategies: (1) elaboration of the moth pheromone through a series of steps that piece together the carbon back bone originating with the C11 carbonyl / protected-carbonyl through carbon-carbon bond forming reactions like the

SN2 reaction, or (2) beginning with a cyclic starting material and performing a ring- opening event to install the necessary carbons. The first synthesis78 of the sex attractant of the DFTM (Figure 12) exemplifies the first synthetic strategy. Smith and co-workers began their synthesis with the protection of aldehyde 4 as a dithiane. The dithiane (5) was then deprotonated with n-butyllithium, and the resulting anion was alkylated with 1-chloro-5-decyne. Subsequent deprotection and reduction of the ketone afforded alcohol 6. A syn-hydrogenation and oxidation provided Z6 in 44% over 6 steps.

1. n-BuLi; HS SH O Cl OH BF3 OEt2 S S 8 H 98% 8 H 2. CuO, CuCl 8 Acetone/H O 4 2 5 3. LiAlH 6 58% over 3 steps

1. H2, P-2 Ni O Ethylene Diamine 8 2. CrO3, pyridine 77% 2 steps Z6 Figure 12: Smith’s Synthesis of the Sex Pheromone of the Douglas-Fir Tussock Moth.

Fetizon and Lazare’s synthesis of the DFTM sex pheromone (Figure 13),81 in some ways, represents a hybrid of the strategies highlighted above. Their synthesis began with 2-hydroxytetrahydropyran (7). Although 7 is a cyclic starting material, hydroxy-aldehyde 8 is present in an equilibrium amount. Fetizon and Lazare took advantage of this equilibrium and olefinated the aldehyde using Wittig reagent 9 to install the Z-olefin of 10. Oxidation of alcohol 10, addition of n-decylmagnesium bromide, and oxidation of the resulting alcohol provided Z6 in short order (four steps) from a simple starting material in 51%.

OH Ph3P OH 1. CrO3, pyridine 9 2. n-C H MgBr O H 10 21 3. CrO , pyridine OH 60% 3 O 85% 3 steps 7 8 10

8 Z6

Figure 13: Fetizon and Lazare’s Synthesis of Z6.

In 1976, Kocienski and Cernigliaro published the synthesis of (Z)-6-heneicosen- 11-one (Figure 14);79 their synthesis exemplified the second strategy towards Z6, the

17 utilization of a ring-opening reaction. The ring opening reaction that Kocienski and Cernigliaro envisioned as providing efficient access to the moth pheromone was the Eschenmoser-Tanabe fragmentation49-52 (discussed in Chapter 1). Beginning with vinylogous acid ester 11, they performed the enone synthesis first described by Woods and Tucker.59 With all the necessary carbons installed, epoxidation of enone 12, followed by condensation with p-tosylhydrazide in an acetic acid / methylene chloride reaction medium provided tethered alkynyl-ketone 14. The alkyne was then hydrogenated using palladium on barium sulfate in methanol and pyridine. Z6 was synthesized in 4 steps from vinylogous acid ester 11 in 61% yield. Interestingly, there have been 2 other syntheses that have also applied an Eschenmoser-Tanabe fragmentation reaction similar to Kocienski and Cernigliaro to synthesize Z6.80,86

1. n-C H MgBr, OMe 10 21 O H O , NaOH, O Et O; 2 2 2 MeOH + O H3O 95% O 93% 6 6 11 12 13

O p-TsNHNH O 2 H2, Pd/BaSO4 8 AcOH/CH2Cl2 8 MeOH/Pyridine 71% 14 97% Z6

Figure 14: Kocienski and Cernigliaro’s Synthesis of Moth Pheromone Z6.

Having disclosed a preliminary study into the carbanion-triggered addition / C-C bond cleavage (ABC) fragmentation methodology (Chapter 1),61 our lab envisioned the synthesis of the sex pheromone of the Douglas-fir tussock moth to highlight our new method.93 The impetus for this endeavor was derived from the fact that alkyl Grignard nucleophiles were beyond the scope of our original report. Alkyl Grignards are often more accessible and, in many cases, more reasonably priced than the corresponding organolithiums; for instance: n-decylmagnesium chloride, needed for the synthesis of Z6, is commercially available, n-decyllithium is not; ethylmagnesium chloride is far

18 cheaper than ethyllithium ($36.40 / 100 mL of 2.0 M in Et2O vs. $77.80 / 100mL of 0.5 M in 9:1 benzene / cyclohexane, respectively).94 We therefore set out to optimize the reaction between VAT 2 and Grignard nucleophiles (Table 2). Aryl Grignard reagents (e.g., entry 1) were found to trigger fragmentation under our original conditions;61 however, alkyl Grignards were not competent partners (entry 2). A quick screening of the reaction medium (entries 2-4) revealed that toluene was the preferred solvent in our addition / fragmentation method using alkyl Grignards. The reaction of 2 in toluene with an ethereal solution of n-butylmagnesium chloride afforded the desired alkynyl ketone 3j (entry 4). Benzylmagnesium bromide provided 3k in 73% (entry 6), however branched alkyl Grignards (e.g., i-propylmagnesium chloride, entry 5) were significantly less efficient in the ABC process. The ability of n-decylmagnesium bromide, relevant for the synthesis of Z6, in the fragmentation reaction was explored; it was found to trigger the fragmentation of 2 (entry 7). In order to determine if toluene’s effect on the reaction involving Grignard nucleophiles was general, we reexamined phenylmagnesium bromide (entry 8), finding a modest and perhaps insignificant decrease in the yield as compared to THF (entry 1).

Table 2: Grignard Triggered Fragmentation of 2.a

O R1 M R1 Me O Me -78 oC to 60 oC OTf 2 3

Entry R1—M Solvent Product Yield (%)

1 PhMgBr THF 3a 80

2 n-BuMgCl THF 3j —c

d 3 n-BuMgCl Et2O 3j 24

4 n-BuMgCl Toluene 3j 63-83

5 i-PrMgCl Toluene 3k —c

6 BnMgBr Toluene 3l 73

7 n-decylMgBr Toluene 3m 58

8 PhMgBr Toluene 3a 71 a 1 o Solution of VAT 2 (1.1 equiv) treated with 1.0 equiv of R —M (in Et2O) at -78 C, warmed to r.t., and o b c then heated to 60 C for 30 min. Note that Et2O is present in each case. Product was not isolated in acceptable purity. d Reaction mixture was heated for 1 h at reflux; fragmentation was incomplete.

Having optimized the ABC reaction for alkyl Grignard reagents, we turned our attention to the synthesis of the (Z)-6-heneicosen-11-one (Figure 15). Vinylogous acyl triflate 15 was synthesized from 2-pentyl-1,3-cyclohexane dione95,96 using trifluoromethanesulfonic anhydride and pyridine by analogy to the procedure published by Kamijo and Dudley.61 Treatment of 15 with n-decylmagnesium bromide using our optimized conditions afforded tethered alkynyl ketone 16 in 80% yield. Subsequent hydrogenation of alkyne 16 provided Z6.79 Spectral data (1H NMR, 13C NMR. IR, and HRMS) for our synthetic sample was in accordance with literature reports.78-92

O n-decyl MgBr C10H21 5% Pd/BaSO4 O -78 oC to 60 oC H2, pyridine O C5H11 8 toluene, 2.5 h MeOH, 97% OTf 80% (ref. 77) 15 16 Z6

Figure 15: Synthesis of (Z)-6-Heneicosen-11-one Using an ABC Strategy.

Our synthesis is reminiscent of the Eschenmoser-Tanabe fragmentation approach applied by Kocienski and Cernigliaro79 (discussed above). For example, in their synthesis, vinylogous acid ester 11 was advanced to the moth pheromone in a four step sequence that featured the Eschenmoser-Tanabe reaction. By enhancing the nucleofugacity of the leaving group (methoxy of 11 vs. trifluoromethanesulfonyloxy of 15), we gained immediate access to the fragmentation product, streamlining the synthetic sequence. In summary, we extended the scope of our anion-triggered / C-C bond cleavage reaction of vinylogous acyl triflates to include alkyl Grignard reagents. We applied the ABC method to the synthesis of a commercially important natural product, (Z)-6- heneicosen-11-one, the sex pheromone of the Douglas-fir tussock moth. Within the context of our study, toluene proved to be a significantly more effective solvent than THF for alkyl Grignard-triggered fragmentation reactions. The following chapters will provide more insight into the development of our fragmentation method and its extension to other synthetic applications.

Experimental

General Information: 1H NMR and 13C NMR spectra were recorded on a Varian 300 (300 MHz) spectrometer, unless otherwise stated, using CDCl3 as the deuterated solvent. The chemical shifts () are reported in parts per million (ppm) relative to the residual chloroform peak (7.26 ppm for 1H NMR and 77.00 for 13C NMR). Coupling constants (J) are reported in Hertz

(Hz). IR spectra were recorded on a Perkin-Elmer FTIR paragon 1000 spectrometer using NaCl discs. Mass Spectra were recorded on a JEOL JMS600H spectrometer. All chemicals were used as received unless otherwise noted. Tetrahydrofuran (THF) and toluene were dried through a solvent purification system packed with alumina and molecular sieves under an Ar atmosphere. The Grignard solutions were titrated with a known amount of iodine dissolved in ether. The purifications of the compounds were performed by flash column chromatography using silica gel F-254 (230-499 mesh particle size).

Representative procedure for the reaction of vinylogous acyl triflates (2) with alkyl Grignard reagents (Table 2). To a toluene solution (2 mL) of n-BuMgCl (0.25 mL,

0.50 mmol; 2.0 M in Et2O) was added 2-methyl-3-(trifluoromethanesulfonyloxy)-2- cyclohexenone (2) (142 mg, 0.55 mmol) at -78 oC under an Ar atmosphere. The mixture was stirred at -78 oC for 10 min, at 0 oC for 10 min, at r.t. for 30 min, and then at 60 oC for 30 min. Half-saturated aqueous solution of NH4Cl was added to quench the reaction and the mixture was extracted with Et2O. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel using 1% EtOAc/Hex to 5% EtOAc/Hex to give 9-undecyn-5-one (3j) in 63% yield (52 mg).

1-Phenyl-5-heptynone (3a): See reference 61 for analytical data.

1 9-Undecyn-5-one (3j): Pale yellow oil; H NMR (300 MHz, CDCl3) (t, J = 7.3 Hz, 2H), 2.40 (quintet, J = 7.3 Hz, 2H), 2.15 (tq, J = 7.3, 2.5 Hz, 2H), 1.77 (t, J = 2.5 Hz, 3H), 1.73 (quintet, J = 7.3 Hz, 2H), 1.55 (quintet, J = 7.3 Hz, 2H), 1.30 (sextet, J = 7.3 13 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H); C NMR (75 MHz, CDCl3)  210.8, 78.2, 76.2, 42.6, 41.3, 25.9,22.8, 22.3, 18.1, 13.8, 3.4; IR (neat) 1713, 1454, 1410, 1371, 1216, 1126 -1 + cm ; HRMS (EI) Calcd for C11H18O (M ) 166.1357. Found 166.1357.

1 1-Phenyl-6-octyn-2-one (3l): Colorless oil; H NMR (300 MHz, CDCl3)  7.28-7.35 (m, 3H), 7.19-7.22 (s, 2H), 3.70 (s, 2H), 2.57 (t, J = 7.1Hz, 2H), 2.12 (tq, J = 7.1, 2.4 Hz,

13 2H), 1.74 (t, J = 2.4, 3H), 1.71 (quintet, J = 7.1, 2H); C NMR (75 MHz, CDCl3)  207.9, 134.2, 129.3, 128.6, 126.9, 78.1, 76.2, 50.1, 40.5, 22.8, 17.9, 3.3; IR (neat) 1713, 1602, -1 + 1495, 1453, 1367, 1093, 1031, 734, 700 cm ; HRMS (CI) Calcd for C14H17O ([M+H] ) 201.1279. Found 201.1276.

1 2-Heptadecyn-7-one (3m): Colorless oil; H NMR (300 MHz, CDCl3)  2.52 (t, J = 7.4 Hz, 2H), 2.40 (t, J = 7.4 Hz, 2H), 2.16 (tq, J = 7.0, 2.5 Hz, 2H), 1.77 (t, J = 2.5 Hz, 3H), 1.73, quintet, 7.0 Hz), 1.26 (m, 16H), 0.88 (t, J = 6.6 Hz). 13C NMR (Bruker 600 spectrometer, 150 MHz, CDCl3)  210.98, 78.31, 76.25, 43.00, 41.41, 31.89, 29.70, 29.57, 29.48, 29.36, 29.30, 29.28, 23.91, 22.67, 18.18, 14.09, 3.49; IR (neat) 1701, -1 + 1470, 1418, 1374, 1091, 793 cm ; HRMS (EI) Calcd for C17H30O (M ) 250.2297. Found 250.2296.

Synthesis of vinylogous acyl triflate 15: Prepared from 2-pentyl-1,3- cyclohexanedione92,93 using triflic anhydride and pyridine by analogy to Kamijo and 1 Dudley’s published procedure, see reference 61. H NMR (300 MHz, CDCl3)  2.75 (t, J = 6.2 Hz, 2H), 2.47 (t, J = 6.8, 2H), 2.32 (t, J = 7.6 Hz, 2H), 2.07 (app. quintet, J = 6.5 13 Hz, 2H), 1.22-1.42 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H); C NMR (75 Hz, CDCl3)  197.52, 161.66, 132.32, 118.22 (q, J = 319.9 Hz), 36.84, 31.72, 28.63, 27.95, 23.66, 22.23, 20.58, 13.83; IR (neat) 1693, 1659, 1417, 1347, 1215, 1140, 1040 cm-1; HRMS (CI) + Calcd for C12H18OSF3 ([M+H] ) 315.0878. Found 315.0893.

Synthesis of alkynyl ketone 16: To a stirred solution of vinylogous acyl triflate 15 (100 mg, 0.32 mmol) in toluene (3 mL) at -78 oC was added n-decylmagnesium bromide

(0.31 mL, 0.93 M in Et2O, 0.29 mmol). The reaction mixture was warmed to r.t. for 1 h, o heated to 60 C for 1.5 h, cooled to r.t., quenched with half-sat. NH4Cl solution (10 mL), and extracted with Et2O. The combined extracts were washed with H2O, dried over

MgSO4, concentrated and purified on silica gel (elution with 1% EtOAc/Hexanes) to afford alkynyl ketone 16 as an oil that solidified on standing; yielding 70 mg (80%). 1H

NMR (300 MHz, CDCl3) 2.52 (t, J = 7.3 Hz, 2H), 2.40 (t, J = 7.5 Hz, 2H), 2.08-2.23 (m, 4H), 1.74 (app. quintet, J = 7.0 Hz, 2H), 1.43-1.64 (m, 4H), 1.19-1.38 (m, 18H), 0.83-

13 0.95 (m, 6H); C NMR (75 Hz, CDCl3)  210.9, 81.1, 79.1, 43.0, 31.9, 29.6, 29.4, 29.3, 28.8, 23.9, 23.0, 22.6, 22.2, 18.7, 18.2, 14.1, 13.1; IR (neat) 1715, 1465, 1410, 1370, -1 + 1080, 720 cm ; HRMS (CI) Calcd for C21H39O ([M+H] ) 307.3001. Found 307.2999.

Synthesis of (Z)-6-heneicosen-11-one (Z6): The reduction was performed in similar manner to that presented in reference 77; note: the Pd/BaSO4 and pyridine must be stirred in methanol for approximately 30 min before addition of alkyne for best results. The following analytical data in accord with previous syntheses.76-90 1H NMR (500 MHz,

CDCl3) 5.37-5.41 (m, 2H), 2.35-2.41(m, 4H), 1.94-2.06 (m, 4H), 1.63 (app. quintet, J = 7.4 Hz, 2H), 1.21-1.37 (m, 22H), 0.85-0.90 (m, 6H); 13C NMR (Bruker 300 spectrometer,

75 Hz, CDCl3)  211.48, 130.96, 128.69, 42.90, 42.86, 42.82, 42.07; 31.97, 31.87, 29.55, 29.47, 29.40, 29.28, 27.19, 26.55, 23.88, 23.73, 22.66, 25.56, 14.09 (2 carbons); -1 + IR (neat) 3020, 1715, 1465, 1420, 1380 cm ; HRMS (CI) Calcd for C21H39O ([M+H] ) 309.3157. Found 309.3185.

1H NMR and 13C NMR spectra:

O Me

C10H21 O Me

OTf 15

C10H21

O C5H11

C10H21

O C5H11

C10H21 Z6 C5H21

CHAPTER 3

A FRAGMENTATION / BENZANNULATION STRATEGY TO PROVIDE ACCESS TO BENZO-FUSED INDANES

Introduction

This chapter provides a detailed study into gold and copper catalyzed benzannulation reactions of o-alkynyl aryl ketones bearing tethered acetylenes. The primary motivation for the aforementioned study is derived from a desire to apply the fragmentation reactions developed in the Dudley laboratory to an efficient synthesis of the alcyopterosins, a rare subclass of natural products. However, before tackling the synthesis of the alcyopterosins, a new methodology was required. A detailed background of the alcyopterosins, including previous synthetic strategies and biological importance, will provide the necessary context for the development of a new convergent synthetic strategy towards these natural products. Furthermore, a critical evaluation of benzannulation reactions similar to those envisioned necessary in our focused retrosynthesis will set the stage for the original work presented here. The goal of this work is to determine the optimal conditions governing intramolecular benzannulation reactions, while at the same time providing a method to prepare benzo-fused indanes. Our research has been designed to bridge the gap that exists between known benzannulation reactions and those which are required for our proposed synthesis. The results of this study will play a vital role in future synthesis of these natural products, new analogs, and other substituted indanes.

The Alcyopterosins

The illudalane sesquiterpenes,97 which include the alcyopterosins, represent a class of rarely encountered natural products. These secondary metabolites consist of

37 bicyclo[4.3.0]nonane carboskeleton as seen in Figure 16. In most cases the 6- membered ring is aromatic.

Illudalane Skeleton Alcyopterosin A

Figure 16: Illudalane Skeleton and Alcyopterosin A.

The biosynthesis of the illudalanes (Figure 17) originates from farnesyl pyrophosphate (17) via a humulene intermediate 18.98 The humulene intermediate is theorized to undergo cyclization to provide a protoilludane 19; a subsequent rearrangement could give rise to an illudane (20). From illudane intermediate 20, a bond cleavage reaction and aromatization would afford a molecule with the illudalane carboskeleton.

O O O P O P O O O 17 OPP 18

bond cleavage and H aromatization

19 20 Aromatic Illudalane Protoilludane Illudane Skeleton

Figure 17: Proposed Biosynthetic Pathway to the Illudalanes.

The chemistry of protoilludanes and illudanes has been studied by several researchers.99-105 Some members of these natural products have been found to be unstable under acidic or basic conditions, leading to the formation of aromatic illudalane

38 sesquiterpenes. Sterner and co-workers reported that the protoilludane stearodelicone (21) decomposes to illudalane 22 upon absorption onto silica gel (Figure 18, equation 1). The decomposition is presumably due to traces of acid in the silica gel resulting in the protonation of the enone, cleavage of the cyclobutyl moiety, and aromatization of the cyclohexyldienone.100 The degradation of ptaquiloside 23 (Figure 18, equation 2), the major illudane toxin isolated from the bracken fern, was examined by Saito and co-workers.101 The glycosidic bond of ptaquiloside is easily cleaved in the presence of acid or base. Upon cleavage of the glycosidic bond, the resulting alcohol is eliminated to produce bracken dienone (24). If acid is present the tertiary alcohol of 24 ionizes and the cyclopropyl ring undergoes heterolytic cleavage, resulting in the aromatization of the cyclohexadienyl moiety; the cation is thus trapped by water to produce 25. The fact that ptaquiloside and stearodelicone decompose to form illudalane-type products seems to support the likelihood of their biosynthesis from the protoilludanes and illudanes.

H O O O silica (1) gel

OR OR OR

21 22 R = stearoyl OH2

OH O H D-glucose O + HO (2) H /H2O HO O O OH - OH/H2O 25 (pH 8-11) OH OH OH H+/H O 23 O 2

D-glucose

24 Figure 18: (eq. 1) Proposed Decomposition of Stearodelicone (21) Upon Absorption on Silica Gel, and (eq. 2) the Observed Reactions of Ptaquiloside (23) in the Presence of Acid and/or Base.

The illudalanes are typically isolated from both fungi of the Basidomycotina subdivision105 and ferns of the Pteridaceae family.107 As rare as the illudalanes isolated from terrestrial sources are, the alcyopterosins are even more rare. This subclass of natural products represents the first illudalanes isolated from marine sources. The alcyopterosins were first isolated from a deep water soft coral species, Alcyonium paessleri, in sub-Antarctic waters by Palmero and co-workers in 2000.108 In 2009, Gavagnin and co-workers isolated several new members of the alcyopterosins from a different soft coral species, Alcyonium grandis.109 The alcyopterosins (Figure 19) have an aromatized six-membered ring, and almost all members have either a chlorine atom or a nitrate ester present on the ethylene side chain. Prior to the discovery of the alcyopterosins, there had never been a

40 natural nitrate ester secondary metabolite isolated from a marine source, despite the fact that nitrates are common solutes in seawater.108 Sulfates and phosphates, which are other common marine nutrients, are frequently observed in natural products isolated from marine organisms. The fact that the alcyopterosins have been isolated as nitrate esters makes them even more remarkable.

O OH

Cl O NO 2 O2NO O2NO O O 25 26 27 OH 28 O

HO O O 29 30 OH O2NO O2NO OH AcO HO Cl Cl

HO AcO

Cl O O

Figure 19: Representative Sample of Illudalane Structures Isolated from A. paessleri and A. grandis.

Several members of the illudalane sesquiterpenes possess some interesting biological activities; antimicrobial,99,110 cytotoxic,103,111 and antispasmodic activities112 being among them. Extracts containing members of the alcyopterosins have also been found to possess feeding-deterrent activity against a generalist Antarctic sea-star predator (Odontaster validus), implicating their chemical evolution as a defensive mechanism (further discussed in Chapter 4).109 Alcyopterosins A (25), C (26), and H (27), are cytotoxic towards the HT-29 (human colon carcinoma) cell line at 10 g/mL in

41 a preliminary in vitro test; and alcyopterosin E (28) has mild cytotoxicity (IC50 = 13.5 M) towards the Hep-2 (human larynx carcinoma) cell line.108 In addition, several synthetic analogs of the alcyopterosins show interesting DNA-binding properties (vide infra).113 The fact that the alcyopterosins are rarely observed as secondary metabolites, their unusual structure, and their potential biological applications, provides motivation to select them as synthetic targets. Since the initial report of their isolation and structural elucidation,108 there have been several synthetic efforts directed towards members of this sub-class of the illudalane sesquiterpenoids and several analogs.113-117 Most synthetic approaches to the alcyopterosin natural products include a convergent transition metal promoted cycloaddition reaction.114-117 Unsymmetrical polysubstituted aromatic rings are often difficult to prepare via sequential electrophilic aromatic substitution reactions. Such reactions often result in regioisomeric products that have to be separated. Therefore, several convergent aromatic annulations methods have been developed to solve this challenging problem. The next section will address the cyclotrimerization of alkynes and other aromatic annulation methods for assembly of the core arenes of the illudalane sesquiterpenes. The cyclotrimerization of acetylenes was first developed by Reppe in 1948.118 This method would be of particular value if selectivity could be obtained when performed on substituted acetylenes; for instance, when this method is applied for the synthesis of substituted aromatic compounds from three unsymmetrical acetylenes, 38 homo- and cross-coupled products are possible (Figure 20).

V X Y V U U W W Z Z U U

U W Y V V X X Y Y V W Metal U W Z X + + Catalyst V X X Plus 31 Other Isomers! V X Z U U W W W W

V Y X V X Y Z U Z

Figure 20: Traditional Reppe Reaction Involving Three Different Unsymmetrical Acetylenes.

Most of the recent solutions to the aforementioned issues associated with the cyclotrimerization of acetylenes rely on a limited number of strategies (Figure 21): (a) homo-coupling of acetylenes;119-125 (b) cross-coupling involving at least one symmetrical acetylene;126-129 or (c) cross-coupling of tethered alkynes.130-135

X X Y Y Y Y Metal Catalyst (a) X X X X Y Y

X X Y X Metal Catalyst X Y (b) X X Z Z X X

W W Y Y (c) n n Z X Z X Figure 21: Typical Solutions for Chemo- and Regioselective Cyclotrimerization of Alkynes.

In 2001, Fumie Sato published a preliminary investigation into a metalative Reppe reaction that allowed the use of three different unsymmetrical alkynes, one of which being ethynyl-p-tolylsulfone, to provide a functionalized metalated arene as a single isomer (Figure 22, equation 1).136 In the following year, Sato and co-workers expanded their metalative Reppe process to the synthesis of arenes metalated at the benzylic position. This extension was made possible by the replacement of the ethynylsulfone with propargyl bromide (Figure 22, equation 2).114 In either case, the + + metalated species could be trapped with a variety of electrophiles (e.g., H , D , I2), leading to the synthesis of some potentially valuable compounds.

CO Bu-t CO2Bu-t 2 CO2t-Bu Ti(O-i-Pr)4 / C6H13 SO2Tol C6H13 TiX3 2 i-PrMgCl (1) + Ti(O-i-Pr)2 -50 oC o H -50 C to r.t. C H C6H13 6 13 C6H13 C6H13

X = (O-i-Pr)2(O2STol)

SiMe3 MeSi3 SiMe3 Ti(O-i-Pr)4 / t-BuO2C CH2Br t-BuO C 2 i-PrMgCl 2 (2) + Ti(O-i-Pr)2 -50 oC o TiX H -50 C to r.t. 3 C H CO2t-Bu 6 13 C6H13 C6H13

X = (O-i-Pr)2Br

Figure 22: Representative Examples of Sato’s One-Pot Metalative Reppe Reactions.

The metalative Reppe reaction developed by Sato was also demonstrated to transform tethered alkynes, along with an external acetylene, to provide access to bicyclic arenes. The Sato laboratory utilized its new method to accomplish the first synthesis of alcyopterosin A (25) (Figure 23). The synthesis began with the reaction between acetylenic ester 31 and tethered diyne 32, to provide the substituted indane 33 in 73% yield after hydrolysis. Diyne 32 was synthesized in 6 steps from isophorone, featuring an Eschenmoser-Tanabe fragmentation (discussed in Chapter 1). The ethyl ester of 33 was manipulated through a reduction, oxidation, and olefination sequence to provide the ethylene side chain of 34. The olefin was then subjected to hydroboration- oxidation, followed by conversion of the resulting alcohol to a chloride using standard reaction conditions. The reaction sequence provided alcyopterosin A in 6 steps and 26% yield from diyne 32.

O 1. H2O2, NaOH O 2. TsNHNH2, AcOH

Isophorone 4-steps

CO Et Ti(O-i-Pr)4 / 2 Br i-PrMgCl; CO2Et + then H+ Me 73% 31 32 33

1. BH THF; 3 Cl 1. LiAlH4, 91% H2O2, NaOH, 67%

2. PCC, 96% 2. SOCl2, Pyridine 3. Ph3P=CH2, 86% 70% 34 25

Figure 23: Sato’s Synthesis of Alcyopterosin A.

Since Sato’s synthesis of alcyopterosin A, two other members of this subclass of natural products, alcyopterosins E and I (28 and 30, respectively) were synthesized using a transition metal-catalyzed [2+2+2] cycloaddition strategy.115,117 Witulski and co- workers completed the synthesis of alcyopterosin E115 (28) and confirmed the absolute configuration originally assigned by Palmero et al.108 From tethered triyne 35, they installed the tricyclic core (36) of alcyopterosin E in one synthetic operation using Wilkinson’s rhodium(I) catalyst (Figure 24, equation 1). Much like Sato’s synthesis, Witulski’s synthesis relied on the Eschenmoser-Tanabe fragmentation of isophorone to provide access to the gem-dimethyl moiety. Snyder and Jones provided the first synthesis of alcyopterosin I (30) in 2009 to highlighting their newly discovered intramolecular rhodium-catalyzed [2+2+2] cycloaddition reactions of diynes and enones.117 Cyclization precursor 37 was prepared through a sequential double bromide displacement of 1,4-dibromo-2-butyne, first with the enolate of ethyl isobutyrate, then with 3-pentynol. Conversion of the ethyl ester to the terminal enone of 37 was carried out through common organic transformations. The

45 cycloaddition reaction was carried out using Wilkinson’s catalyst, and a DDQ work-up produced the tricyclic core of alcyopterosin I in 71% yield (Figure 24, equation 2).

Isophorone

H H3C 10 mol % RhCl(PPh3)3, (1) H H CH Cl , 40 oC 2 2 O O O 72% OTs O OTs 35 36

O O O 1. RhCl(PPh3)3, PhCl, mW, 150 oC (2) EtO 2. DDQ, r.t. 71% 2 steps Ethyl Isobutyrate O O 37 38

Figure 24: Key Steps in the Syntheses of Alcyopterosin E (28) (eq. 1), and Alcyopterosin I (30) by Witulski and Snyder (eq. 2).

In contrast to the more academically attractive methods used to prepare the members of the alcyopterosins described above, Iglesias and co-workers presented a more conventional approach to alcyopterosin A and several unnatural analogs.113 In the course of Iglesias’ synthetic pathway, several compounds possessing the illudalane skeleton were obtained, allowing for structure-activity relationship (SAR) studies to be conducted. The Iglesias synthesis began with the construction of key intermediate 40 (Figure 25). Friedel-Crafts acylation of 4-bromo-m-xylene (38)—itself prepared through a bromination of m-xylene and purification—provided -chloroketone 39. Intermediate indanone 40 was obtained upon a subsequent acid promoted Nazarov reaction.

O O O

Cl Cl conc. H2SO4

AlCl3, CS2 Cl 67% 99% Br Br Br 38 39 40

Figure 25: Synthesis of Iglesias’ Key Intermediate.

Iglesias and co-workers employed intermediate 40 to synthesize a variety of analogs of the alcyopterosins (Figure 26). A reduction of the benzylic ketone of 40 provided bromoindane 41; another Friedel-Crafts acylation installed the necessary carbons for the ethylene side chain of the illudalane skeleton. With the -chloroketone 42 in hand, the synthesis of various side chain functionalities (compounds 43-47) was made possible through the use of several reduction methods. Compounds 45, 46, and 47 demonstrate an interesting divergence in reactivity; the reaction of -chloroketone 42 with excess sodium borohydride in refluxing ethanol provided three different analogs simply by increasing the reaction time. Compound 47, most similar to alcyopterosin A, was treated with lithium aluminum hydride to afford compound 48.

O O NaCNBH , 3 Cl Cl ZnI , DCE Cl 40 2 78% AlCl3, CS2 79% Br Br 41 42

R "conditions" LiAlH4 HO 47 67% Conditions: Br 48 (a) NaCNBH , ZnI , 3 2 43: R = CH Cl I 28% DCE, reflux 2 2 O (b) CuCl, NaBH , 4 44: R = CCH 24% EtOH, reflux 3 OH (c) NaBH , EtOH 4 45: R = CHCH Cl 43% reflux, 15 min 2 O (d) NaBH , EtOH, 4 46: R = HC CH 42% reflux, 4 h 2

(e) NaBH , EtOH, 4 47: R = CH CH OH 41% reflux, 16 h 2 2

Figure 26: Synthesis of Unnatural Alcyopterosin Analogs Performed by Iglesias et al.

Having synthesized several analogs lacking the gem-dimethyl substituents on the indane skeleton, Iglesias and co-workers turned their attention to the synthesis of alcyopterosin A (Figure 27). Double methylation of intermediate 40, followed by reduction of the ketone, generated compound 49. Friedel-Crafts acylation using chloroacetyl chloride and subsequent reduction provided analog 50. Alcyopterosin A (25) was obtained through the reduction of the arylbromide (providing 51) and conversion of the side-chain alcohol to the necessary chloride.

1. AlCl3, CS2 O O 1. MeI, NaH, Cl, 79% Toluene, 66% Cl HO

2. NaCNBH3, 2. NaBH4, EtOH, ZnI2, DCE reflux, 16 h Br 88% Br 42% Br 40 49 50

HO Cl LiAlH4 SOCl2, pyridine 69% 78%

51 25

Figure 27: Completion of Iglesias’ Synthesis of Alcyopterosin A.

The Iglesias laboratory, with numerous alcyopterosin analogs in hand, turned their attention to performing DNA binding experiments. The ability of the alcyopterosin analogs to bind to DNA was evaluated by measuring their hypochromic (decreased absorbance at 260 nm) and bathochromic (red-shift) effects on the UV absorbance spectrum of DNA.137 They validated their experiment through comparison of their test assays and known intercalating agents (m-AMSA, mitoxantrone, and bis-benzamide; Figure 28).

H H MeO N N SO2Me OH O HN OH HN

OH O HN OH N N H

m-AMSA Mitoxantrone

OH N N N N 3 H Cl NH N H bis-benzamide, Hoechst No. 33258

Figure 28: Compounds Known to Intercalate DNA.

The degree of interaction was expressed as a ratio between the final absorbance area after stirring the compound for 24 h with DNA (a24) and the initial absorbance area at max (a0). Values of 1 or higher indicate lack of affinity and values of 0 indicate complete binding. The results of the DNA binding affinity assay demonstrate that alcyopterosin A and various alcyopterosin analogs are potent DNA ligands (Table 3). The gem-dimethyl substitution modifies, only slightly, the DNA binding affinity of the compounds tested (47 vs. 50, and 48 vs. 51); whereas the ethylene side chain was of the utmost importance for DNA ligation (compounds 41 and 49 had very poor affinity for DNA). Perhaps most interesting was the fact that the presence of the bromine increased the degree of binding of the analogs containing the hydroxy-functionalized ethylene side chain (compounds 47, 48, 50, and 51).

Table 3: DNA Binding Assay Performed By Iglesias et al.113

Compound a24/a0 Compound a24/a0

41 0.90 49 0.87

42 0.12 50 0.40

43 0.16 51 0.71

44 0.26 25 0.38

45 0.69 Mxa 0.00

46 0.47 m-Ab 0.54

47 0.59 B-bc 0.57

48 0.89 a mitoxantrone; b m-AMSA; c bis-benzamide. O Cl HO HO Cl

Br Br Br 42 47 50 25

A preliminary test was then carried out by The National Cancer Institute (NCI). Compounds 44, 47, and 50 were evaluated in a three cell-line one dose pre-screen to determine if they possess any ability to inhibit the growth of tumor cells in vitro. The cell lines were MCF-7 (breast), NCI-H460 (lung), and SF-268 (CNS). Compounds found to reduce the growth of any of the three cell lines to 32% or less, when compared to untreated cells, were considered a positive in vitro lead. Compound 44 was found not to inhibit growth to any significant extent. Compound 50 was found to produce a 0% relative growth rate on all three cell lines, and compound 47 had the same effect on two of the cell lines (breast and lung). Analogs 47 and 50, having passed the first criterion for activity, were then subjected to further testing against a 60-cell line panel at varying concentrations (10-4 to

10-8 M). The cell lines consisted of subpanels representing melanoma, leukemia, and cancers of the breast, prostate, lung, colon, ovary, kidney, and brain. Dose-dependent responses were found for three different activity parameters: the molar concentration required to cause 50% growth inhibition (GI50), the concentration required to completely inhibit growth (TGI), and the concentration that leads to 50% cell death (LC50). The meangraph midpoints (MG-MID) correspond to the average sensitivity exhibited by the entire panel of cell lines to a specific compound. The comparison of the MG-MID and the activity against specific cell lines is often used to determine a compound’s selective activity. Compounds 47 and 50 demonstrated promising activities in the in vitro antitumor screening (Table 4). The concentrations that promoted cytostatic (MG-MID GI50) and cytotoxic (MG-MID LC50) effects for compounds 47 and 50 were found to have a marked difference (ca. 5-fold). The ability to selectively control cancer cell growth or induce cell death is an interesting trait observed for these natural product analogs.

Table 4: Average values (MG-MID) for in vitro antitumor activity on the NCI 60-Cell Line Panel

Compound MG-MIDa

b c d Log10GI50 (GI50) Log10TGI (TGI) Log10LC50 (LC50)

47 -4.77 (17 M) -4.40 (40 M) -4.12 (76 M)

50 -4.71 (19 M) -4.41 (39 M) -4.14 (72 M) a b MG-MID = meangraph midpoint, average across all cell lines tested. GI50 = concentration required to c d inhibit cell growth by 50%. TGI = concentration required to completely inhibit cell growth. LC50 = concentration required to kill 50% of tumor cells.

HO HO

Br Br 47 50

Nearly all members of the 60-cell line panel were found to be responsive to compound 50, whereas compound 47 was found to be more selective towards leukemia and cancers of lung, colon, and breast (GI50 < 15 M). The antitumor activity of compounds 47 and 50 observed by Iglesias support the findings that the gem-dimethyl substituents have little effect on DNA binding affinity as discussed above. The lack of the gem- dimethyl, on the contrary, produced an increase in the selectivity of compound 47’s ability to inhibit tumor growth. The studies performed by Iglesias and co-workers identified some new interesting anticancer leads as well as a straightforward approach to the alcyopterosins. Their research, and the studies conducted by the other researchers referenced above, have provided insight into the synthesis of compounds from this interesting subclass of natural products. As part of our lab’s research goals, ―to devise, develop, and apply new ideas in organic chemistry to the efficient synthesis of interesting molecules,‖138 we identified the alcyopterosin natural products as potential targets that could benefit from our fragmentation methodology. The remainder of this chapter will demonstrate the synthetic approach we devised to access these natural products and to provide the foundation for future synthetic efforts.

Retrosynthetic Analysis of Alcyopterosin A

In an effort to apply the carbanion-triggered fragmentation reaction of vinylogous acyl triflates (VATs) (discussed in the previous chapters) to the synthesis of additional natural products, we identified the alcyopterosins, specifically, alcyopterosin A, as potential targets. Our retrosynthetic analysis (Figure 29) began with bicyclic arene 52, which we envisioned gaining access to via an unprecedented benzannulation reaction of acyclic enediyne intermediate 53. Based on our previous work, we believed that a reaction between the metalated vinyl pre-nucleophile 54 and VAT 55 (derived from dimedone) would provide our key acyclic intermediate (53).

functional group benzannulation O manipulation Cl Z R Alcyopterosin A Z = COR, H (25) 52 53

X O fragmentation +

R OTf

54 55

Figure 29: Retrosynthetic Analysis to Alcyopterosin A Using a Fragmentation / Benzannulation Approach.

Our strategy to synthesize alcyopterosin A hinges upon two key synthetic transformations: (a) the fragmentation of vinylogous acyl triflate 55, and (b) the benzannulation of enediyne 53. The basis of the desired benzannulation reaction stems from the work of Yoshinori Yamamoto, Naoki Asao, and other members of the Yamamoto laboratory.139-142 The fragmentation reactions of vinylogous acyl triflates has been addressed in previous chapters. The following section will provide the relevant background of the Yamamoto / Asao methodology for benzannulation and significant questions that must first be addressed in order for the successful implementation of our strategy. In 2002, Yamamoto and co-workers published a preliminary communication regarding a regioselective AuCl3-catalyzed formal [4+2] cycloaddition reaction between o-alkynylbenzaldehydes (56) and alkynes (57) to produce naphthyl ketones (58 and 59) (Figure 30, equation 1).139 A more thorough full paper ensued the following year.140 The detailed study chronicled this benzannulation and also provided insight into a similar [4+2] benzannulation of o-alkynylbenzaldehydes (or enals) (60) and alkynes (57) using a copper catalyst. The copper catalyst system, in contrast to gold, produced debenzoylated arenes (61 and 62) (Figure 30, equation 2). Naphthalenes were

54 generated in most cases, but a few examples of simple benzene derivatives, derived from enals (as would be required for the synthesis of the alcyopterosins), were included. Similar benzannulation reactions have also been explored through the use of electrophilic iodine sources as stoichiometric reagents, however they fall outside the scope of this discussion.143,144

O 3 2 R3 R R H 3 mol % AuCl3 (1) + + R2 R3 DCE, 80 oC 2 R 1 R1 O R1 O R 58 59 56 57 R2 = EDG R2 = EWG major major

O 3 2 R3 R R H 5 mol % Cu(OTf)2 (2) + + R2 R3 1 equiv CF2HCO2H R2 DCE, 80 to 100 oC H H Ph 61 62 60 57 R2 = EDG R2 = EWG major major

Figure 30: AuCl3- and Cu(OTf)2-Catalyzed [4+2] Benzannulation Reactions Described By Asao and Yamamoto.

The proposed mechanisms of these benzannulation reactions are presented in Figure 31. Upon treatment with the Lewis acid, the soft -system of the alkyne 56 undergoes coordination to the Lewis acid (MLn: AuCl3 or Cu(OTf)2), enhancing the electrophilicity of the alkyne. Subsequent nucleophilic 6-endo-dig cyclization of the carbonyl oxygen onto the electron-deficient alkyne (as seen in 65) would form ate- complex 66. The [4+2] cycloaddition of 66 with alkyne 57 would form intermediate 68 via

67. In the case of AuCl3-catalysis, subsequent bond rearrangement (as shown in 69) would afford ketones 58 and 59 and regenerate the AuCl3. However, in the case of the

Cu(OTf)2 / CF2HCO2H system, protonolysis of the copper-carbon bond of 68, followed by the attack of the conjugate base on the oxocarbenium ion, would produce

55 intermediate 70. A retro-Diels-Alder reaction would then release a mixed anhydride and lead to the formation of products 61 and 62.

R1 O A H RX O RY H _ O 70 ML n R1 R1 A 56

RX RX RY H A = CF2HCO2H H H RY 61, 62 O O R1 1 O R O 58, 59 RX R1 X R1 R LnM Y R Y 65 LnM R L M 68 n 69 H RX O O

R1 RY ML n RX RY MLn 67 57 66 Figure 31: Proposed Mechanism of [4+2] Cycloaddition Reactions of 56 and 57 Catalyzed by AuCl3 and Cu(OTf)2 / CF2HCO2H.

Having successfully carried out intermolecular [4+2] benzannulation reactions, Yamamoto and co-workers turned their attention towards the synthesis of polycyclic naphthalene derivatives through the use of tethered alkyne dienophiles.142 The ―top- down approach‖ (Figure 32, equation 1), in which the tethered alkyne is linked through the carbonyl group, was found to convert compound 71 into naphthyl ketone 72 in high yields. Interestingly, the reaction was found to occur even in the absence of a Lewis acid at high temperatures, albeit in low yield (34% at 80 oC for 10 days). A related ―top- down‖ benzannulation (without the prepositioned benzene ring) is envisioned for our synthesis of alcyopterosin A. These examples, although limited, are therefore highly

56 relevant to our studies. The ―bottom-up approach‖ (Figure 32, equation 2), in which the tethered alkyne is linked through the aryl-alkyne group (73), provided corresponding polycyclic ketone 74 in yields ranging from 66 to 91%.

O R

AuX n-3 "Top-Down" (1) n 3 40 to 92%

Ph O R n = 3 and 4 71 R = Ph, Bu, H, TMS 72

O R

H AuX3 (2) "Bottom-Up" R 66 to 91% O 3 73 74 R = Ph, p-Tolyl, p-CF3C6H4, n-Bu, H, TIPS, (CH2)2OTIPS, I

Figure 32: Intramolecular Lewis Acid-Catalyzed [4+2] Benzannulation Reactions Studied by Asao and Yamamoto.

Yamamoto and co-workers applied the ―bottom-up‖ approach to the synthesis of (+)- ochromycinone and (+)-rubiginone B2 (Figure 33), demonstrating the power of these reactions in synthesis.145

OMe O O MeO O cat. AuX3

CHO OMe OMe OMe OMe OR O

R = OMe: (+)-rubiginone B2 R = OH: (+)-ochromycinone

Figure 33: Yamamoto’s Key Benzannulation in the Synthesis of (+)-Rubiginone B2 and (+)-Ochromycinone.

In their studies, Asao and Yamamoto provided few examples of intermolecular benzannulation reactions between alkynyl-enal substrates and alkynes (i.e. lacking the 139-142 prepositioned benzene backbone). Of these reactions, only the Cu(OTf)2 /

CF2HCO2H catalytic system were reported (Figure 34). Moreover, there were no reports of the intramolecular benzannulation reaction taking place when Cu(OTf)2 was used as the Lewis acid. The lack of such results prompts the questions: (1) Is AuCl3 capable of effectively inducing the benzannulation of dialkynyl-enones similar to 53, and (2) is the

Cu(OTf)2 / CF2HCO2H a competent catalyst system in inducing the intramolecular benzannulation reaction?

H 5 1 R 1 5 R + R R O Cu / H Few Examples (Only Intermolecular) R2 R2 R6 R6 R3 Yamamoto and Asao

Au Few Examples O (Only Benzo-Fused, Only Phenyl Ketones) R R Ph O Ph

O ? Needed for Synthesis of Alcyopterosin A

R Z 53 Z = COR, H 52 Figure 34: Contrast Between Known Benzannulations and Desired Benzannulation.

Using our fragmentation chemistry in conjunction with a new focused methodology, we could make considerable contributions to the Lewis acid-catalyzed intramolecular benzannulation reaction. We envisioned the ―top-down‖ approach, as outlined by Yamamoto and co-workers, as being well suited for the synthesis of

58 alcyopterosin A. Ultimately we would require entry into an indane system, as opposed to the benzo-fused indanes, potentially available via the Yamamoto / Asao methodology. The following section describes this new methodology, highlighting the use of fragmentation reactions to provide the needed monocyclic benzannulation precursors.

Exploring Gold and Copper Catalyzed Benzannulations

Prior to launching into the synthesis of alcyopterosin A, we sought to explore the ―top-down‖ intramolecular benzannulation in more detail. The substrates included in the previous study by Asao and Yamamoto only varied the substituent at the terminus of the tethered alkyne.142 An investigation into the effect of the substituents on the alkyne to which the Lewis acid coordinates is envisioned to provide valuable knowledge of the electronic requirements for benzannulation and catalyst selection, which may prove useful in the synthesis of alcyopterosin A (Figure 35). We chose to perform our study on benzo-fused systems for two reasons: (a) they would be most similar to those studied by Yamamoto and Asao, and (b) the substrates would be easier to prepare due to their inability to isomerize (e.g. E-, Z-isomerization). We believed that through the use of our fragmentation methodology we could provide access to the benzo fused substrates in short order.

AuX Asao and Yamamoto O 3 J. Org. Chem. 2005, 70, R 3682-3685. R Ph O Ph R = Ph, Bu, H, TMS

AuCl or Cu(OTf) O 3 2 Required for new focused methodology Me Me R O R R = p-MeOPh, Ph, t-Bu, n-Bu, TMS, p-CF Ph 3

Figure 35: Comparison of Known benzannulations and Those of a New Methodology.

This investigation would provide new knowledge into the steric and electronic requirements of the intramolecular gold and copper catalyzed benzannulation reactions, and allow access to new substituted benzo-fused indanes (polysubstituted naphthalenes). The results would thereby further the current understanding of these reactions as well as establish the ground work for future applications to alcyopterosin synthesis. We began our study by preparing the necessary substrates for the new benzannulation study. Initially we considered two different starting materials for the generation of o-alkynyl-haloarenes (77), which would serve as pre-nucleophiles for our fragmentation reaction: (a) 1,2-dibromobenzene (75); and (b) 2-bromoiodobenzene (76) (Figure 36). Upon further analysis, we identified some potential drawbacks in our initial strategy. Attempting a Sonogashira reaction between 75 and 1-hexyne using standard reaction conditions, we obtained an inseparable mixture of compounds 77 and 78 (ca. 35% yield, 1:1); similar results are not an uncommon occurance.146 Performing the Sonogashira reaction on dihaloarene 76 would provide a selective reaction because of

60 the increased reactivity of the iodide, however the cost of 76 makes it less attractive for use in a model study.

Br H R Br (a) Sonogashira Br coupling R R 75 77

R Br H R Br possible side product (b) 78 Sonogashira I coupling R 76

Figure 36: Originally Considered Reactions to Access Fragmentation Pre-nucleophile 77.

In an effort to circumvent the problems associated with the strategy outlined above, we identified 2-iodoaniline (79) as a potential alternative to the synthesis of benzannulation test substrates. The advantages to the use of 79 as a starting material would be three-fold: (a) 79 is intermediately priced (25 g/ $99.00) compared to 75 (25 g/ $74.10) and 76 (25 g/ $121.50);94 (b) the synthesis of iodotriazene 80147 would allow for a directed metalation reaction of an aryl iodide, rather than an aryl bromide (cf. 77), to provide nucleophile 81; and (c) triazene 82 could be converted into iodide 83 for the selective synthesis of benzannulation substrates 84 through a Sonogashira reaction (Figure 37). In effect, triazene 82 serves as a masked iodide that is also capable of directing metalation chemistry. Because of the fact that aryl iodides are more reactive than aryl bromides in both Sonogashira reactions and halogen-metal exchange reactions, coupled to the fact that our proposed halogen-metal exchange is envisioned to proceed through a directed metalation, we believed this strategy would provide a general and efficient approach to the synthesis of compounds similar to 84.

I O I Li HCl, NaNO2; R Li N + then R NH directed NH2 2 N R N3R2 N metalation OTf R 79 80 81 2

fragmentation "Conditions" H R O O O Sonogashira N3R2 I coupling R 82 83 84

Figure 37: Proposed Route to Benzannulation Substrates 84.

Our strategy proved very effective towards the synthesis of our model benzannulation substrates. Conversion of 79 to diethyl iodotriazene 80147 was carried out using standard conditions; first conversion of the arylamine to the diazonium salt, and then an in situ trapping of the diazonium with diethylamine. Halogen-metal exchange and subsequent fragmentation of vinylogous acyl triflate 2 provided triazene 82 in 82% over 2 steps (Figure 38).

I n-BuLi, Et2O I o HCl, NaNO2; -78 C; N O then Et2NH then 2, NH2 N Et 97% N -78 oC to r.t. N3Et2 Et 85% 79 80 82

Figure 38: Synthesis and Fragmentation Reaction of Aryltriazene 80.

Aryltriazenes, similar to 80 and 82, are bench stable and chromatographable; they have been used extensively in the synthesis of a large variety of phenylacetylene- based systems.148 Typically these aryltriazenes are converted to the corresponding iodoarene in high yields by heating in iodomethane at temperatures in excess of 100

62 oC.149 In the case of electron deficient aryltriazenes, decomposition of the triazene in iodomethane requires higher temperatures. The toxicity of iodomethane and the high temperatures and pressures required for the decomposition of aryltriazenes to iodoarenes prompted us to search out other methods for this transformation. We found reports in the literature that electron-deficient aryltriazenes undergo decomposition to afford iodoarenes in high yields upon treatment with sodium iodide and sulfonic acid cation exchange resins (H+ form) in dry acetonitrile at 75 oC; methanesulfonic acid and trifluoroacetic acid also provided the product in acceptable yields.150 Armed with this knowledge, we completed the synthesis of our model benzannulation substrates (Figure 39). Using slightly modified conditions, camphor-10- sulfonic acid (CSA) in place of the sulfonic acid exchange resin, aryltriazene 82 was converted to an aryl iodide 83. Sonogashira coupling reactions between various terminal acetylenes and aryl iodide 83 provided benzannulation precursors 84a-e.

10 equiv CSA 5 mol % PdCl2(PPh3)2, o 2 equiv NaI, 10 mol % CuI, Et3N, 50 C O 82 O o CH3CN, 75 C H R (ca. 75%) I R 83 84a: R = Ph 68% 84b: R = n-Bu 85% 84c: R = t-Bu 52% 84d: R = p-MeO-C6H4 60% 84e: R = TMS 80%

Figure 39: Synthesis of Benzannulation Substrates 84a-e.

The coupling reaction between 83 and an electron-deficient acetylene (R = p-

CF3-C6H4) did not proceed to any significant extent. In an effort to synthesize a substrate with an acetylene having an electronic deficiency, the trimethylsilyl (TMS) substituent of 84e was cleaved using a methanolic solution of potassium carbonate affording 85; a Sonogashira reaction was performed between 85 and 4- iodobenzotrifluoride to provide 84f in 85% yield (Figure 40).

5 mol % PdCl2(PPh3)2, o O K2CO3, MeOH 10 mol % CuI, Et3N, 50 C O O r.t., 92% CF3 85% TMS H 84e 85 I 84f CF3

Figure 40: Synthesis of Benzannulation Substrate 84f.

With a series of benzannulation substrates in hand similar to those prepared by

Yamamoto, ranging from electron-rich (R = p-MeO-C6H4, 84d) to electron-poor (R = p-

CF3-C6H4, 84f), we began to examine the benzannulation reaction using the AuCl3 and

Cu(OTf)2 / CF2HCO2H catalyst systems. The electron-neutral substrate included in our study (R = Ph, 84a) most resembles those examined by Yamamoto and Asao.142 However, only the gold catalyzed reaction was reported from their related studies. Table 5 summarizes the results obtained in the preliminary screening of benzannulation reactions. Substrates 84a (as suggested by the results of Yamamoto and Asao) and 84b provided promising reactivity when AuCl3-catalysis was employed. However, they provided a mixture of the decarbonylated / reduced product 87 and ketone products (86a and 86b, respectively) in the presence of the Cu(OTf)2 /

CF2HCO2H catalyst system (entries 1 and 2). Entries 4 and 5 demonstrate that the electronically rich alkynes (84d) and silylacetylenes (84e) are not competent benzannulation substrates in the presence of either catalytic system. Most interesting to our future synthetic efforts was the divergence in reactivity between substrates 84c and

84f; both substrates provided ketone products 86c and 86f in the presence of AuCl3, but when the Cu(OTf)2 / CF2HCO2H catalyst system was applied, the t-butylacetylene containing substrate (84c) provided reduced product 87 as the sole product and the electronically deficient acetylenic substrate (84f) provided only the ketone product (86f)

(entries 3 and 6, respectively). Thus, employing the Cu(OTf)2 / CF2HCO2H catalyst system, one can switch between the two reaction pathways by changing the acetylene substituent from t-butyl to p-CF3-C6H4. Likewise, in 84c (R = t-Bu) one can select

64 between the two products by simply changing the catalyst system from AuCl3 to

Cu(OTf)2 / CF2HCO2H.

Table 5: Preliminary Screening of Benzannulation Reactions of Substrates 84a-f.a

Catalyst O + DCE, 80 oC 1 to 1.5 h R O R H 84 86 87 Cu(OTf) / CF HCO H AuCl Catalystb 2 2 2 3 Systemc Entry R Substrate 86 Yield, %b 86 Yield, %d 87 Yield, %d

1 Ph 84a 86a 75 86a 65 87 23

2 n-Bu 84b 86c 70 86c 10 87 71

3 t-Bu 84c 86c 50 86c 0 87 71

e e e 4 p-MeO-C6H4 84d 86d 0 86d 0 87 0

e e e 5 Me3Si 84e 86e 0 86e 0 87 0

6 p-CF3-C6H4 84f 86f 76 86f 80 87 0 a b c Reactions performed on 10 mg scale for screening purposes. 5 mol % AuCl3. 5 mol % Cu(OTf)2, 1.0 d e equiv. CF2HCO2H. Isolated yields. No reaction was detected by TLC after 15 h, substrates were recovered.

After performing our preliminary study into the ―top-down‖ benzannulation reaction of Yamamoto on our series of test substrates, we chose to carry out the benzannulation of substrates 84c and 84f on a larger scale under the copper(II) catalysis conditions to confirm our preliminary results and provide more accurate yields. Indeed our results were confirmed: compound 84c provided the reduced product (87) in 88% yield (Figure 41, equation 1); whereas compound 84f lead to naphthyl ketone 86f in 89% yield (Figure 41, equation 2).

5 mol % Cu(OTf)2, 1.0 equiv. CF2HCO2H (1) O DCE, 80 oC 88% H 84c 87

5 mol % Cu(OTf)2, 1.0 equiv. CF2HCO2H (2) O DCE, 80 oC 89% O CF 3 CF3 84f 86f

Figure 41: Direct Comparison of the Benzannulation Reactions of 84c and 84f.

In an effort to demonstrate the ability of vinylogous acyl triflate 55 to undergo the desired fragmentation chemistry, as well as the ability of a substrate containing the gem-dimethyl on the alkyne tether to participate in the benzannulation reaction, we set out to synthesize a benzo-fused compound similar to 53 in our retrosynthetic analysis of alcyopterosin A (Figure 29). Due to the fact that vinylogous acyl triflate 55 was considered precious material,i we modified our synthetic approach (Figure 42). We began with a Sonogashira reaction between 3,3-dimethylbutyne and 2-iodo-aryltriazene 80, which provided an inseparable mixture of the desired compound 88 and unidentifiable byproducts. Conversion of the resulting o-alkynyl-aryltriazene into the corresponding iodoarene 88 was performed using our previously described conditions (see page 63). This reaction also provided an inseparable mixture that contained our desired product as the major component by 1H NMR. Performing halogen metal- exchange on the mixture containing iodoarene 88, followed by treatment with 1.0 equivalent of vinylogous acyl triflate 55 provided the desired product (89) in 61% yield (90% based on recovered triflate).

i Synthesized in 2 steps: (1) methylation of dimedone;151 and (2) subsequent triflation using standard 61 conditions from Kamijo and Dudley’s initial report.

1. PdCl2(PPh3)2, I o N3Et2 o n-BuLi, Et O, -78 C; CuI, Et3N, 50 C 2 O then O I H t-Bu 2. CSA, NaI, CH3CN 80 (ca. 82% over 2 steps) 88 OTf 89 55 61% (>90% brsm)

Figure 42: Alternative Synthesis of Benzannulation Substrate 89.

Compound 89 underwent the desired intramolecular [4+2] benzannulation reaction under either the gold or copper catalytic systems in 83 and 75%, respectively

(Figure 43). Much like our previous experiments, in the presence of the Cu(OTf)2 /

CF2HCO2H catalyst system compound 89 underwent benzannulation and decarbonylation to provide the substituted naphthalene derivative 90 (equation 1). The reaction of compound 89 in the presence of AuCl3 led to the formation of the naphthyl ketone product (91) (equation 2). Interestingly, the 1H NMR spectrum of ketone 91 suggests it exists as a racemic mixture of atropisomers.ii The gem-dimethyl groups are diastereotopic; each methyl group of the carbon bearing the gem-dimethyl can be distinguished and one of the adjacent methylene units of the partially saturated ring appears as an AB quartet (see page 113). We believe that the divergence in reactivity of compound 89 upon treatment with either the gold or copper catalyzed benzannulation conditions will prove useful, if it is observed when performed on acyclic intermediate 53, as in the synthesis of alcyopterosin A.

ii However a slow rotation about the arene-ketone bond on the NMR time scale cannot be ruled out.

5 mol % Cu(OTf)2, O 1.0 equiv. CF2HCO2H (1) DCE, 80 oC 83% H 89 90

5 mol % AuCl3, (2) O + DCE, 80 oC 75% O O 89

Figure 43: Benzannulation Reactions of Compound 89.

The newfound knowledge in the gold and copper benzannulation chemistry enables a new strategy for the synthesis of benzo-fused indanes. These benzannulation reactions contribute to the observations made by Yamamoto and Asao. In addition, the ability to obtain either the ketone or decarbonylated benzannulated products selectively, either through choice of catalyst or by altering the substrate, was previously unreported. This provides synthetic versatility in the synthesis of substituted indanes. For the Dudley lab, it is this flexibility that may be the key toward the future synthesis of alcyopterosin A. Our approach to benzo-fused indanes has incorporated the use of aryltriazenes for the synthesis of useful intermediates and the fragmentation of vinylogous acyl triflates. We have demonstrated the ability of vinylogous acyl triflates 2 and 55 to undergo fragmentation reactions to provide synthetically useful compounds. In regards to the synthesis of alcyopterosin A, a recently published study has provided the necessary method for the synthesis of vinyl nucleophile 54. Negishi and co-workers published the synthesis of various (Z)-2-alkynyl-vinyl iodides in a highly stereoselective fashion (≥98% Z) (Figure 44).152 Bromoboration of propyne and trapping

68 of the resulting vinyldibromoborane with pinacol diminishes the stereoisomerization of 92 to provide cyclic boronate 93. Compound 93 is stable to air for several days at room temperature without any change in the NMR spectrum. Negishi coupling of vinyl bromide 93 and the appropriate terminal acetylene, followed by subsequent exchange of the boronate for an iodide should provide access to 54 in high yield and selectivity.

H 1.1 equiv BBr3, O H BBr2 1.2 equiv pinacol CH2Cl2 H B O -78 oC to r.t., 2h o Me Br -78 C to r.t., 1h Me (85%, > 98% Z) Me Br 92 93

O Negishi 2 equiv I2, H I H B Coupling O 3 equiv NaOH Me H t-Bu Me THF-H2O, r.t. 54

Figure 44: Proposed Route to Vinyl Nucleophile 54 Using Negishi’s Z-Selective Bromoboration.

The detailed benzannulation studies presented above provide a firm foundation for future synthetic efforts. We have confirmed the ability of the Cu(OTf)2 / CF2HCO2H catalyst system to promote intramolecular benzannulation reaction. When coupled with the chemistry developed by Negishi, the results of this study pave the way for a convergent approach to access the alcyopterosins and various analogs thereof. The application of the fragmentation / benzannulation strategy to the synthesis of alcyopterosin A and analogs thereof is currently underway in the Dudley laboratory.

Experimental

General Information: 1H NMR and 13C NMR spectra were recorded on a Varian 300 (300 MHz), Bruker 400

(400 MHz), or Bruker 600 (600 MHz) spectrometer, using CDCl3 as the deuterated solvent. The chemical shifts () are reported in parts per million (ppm) relative to the residual chloroform peak (7.26 ppm for 1H NMR and 77.00 for 13C NMR). Coupling constants (J) are reported in Hertz (Hz). IR spectra were recorded on a Perkin-Elmer FT-IR spectrometer with diamond ATR accessory as thin film. Mass Spectra were recorded on a JEOL JMS600H spectrometer. Yields refer to isolated material judged to be > 95% pure by 1H NMR spectroscopy following silica gel chromatography, F-254 (230-499 mesh particle size). All chemicals were used as received unless otherwise noted. Acetonitrile (CH3CN) was distilled from calcium hydride (CaH2) and stored over molecular sieves. Diethyl ether (Et2O) was dried through a solvent purification system packed with alumina and molecular sieves under an Ar atmosphere. 1,2-Dichloroethane (DCE) was used as received with no further purification. Triethylamine and diethylamine were distilled from CaH2 and stored over KOH pellets. The n-butyllithium (n-BuLi) solutions were titrated with a known amount of menthol, using 1,10-phenanthroline as an indicator, in a solution of ether. All reactions were carried out under an inert argon atmosphere unless otherwise stated.

Synthesis of 3-trifluoromethanesulfonyloxy-2,5,5-trimethyl-2-cyclohexenone (55): Dimedone was methylated using iodomethane in a 5M aqueous KOH solution by analogy to a published procedure, see reference 150; the resulting 2,5,5-trimethyl-1,3- cyclohexanedione was converted to the corresponding triflate using triflic anhydride and pyridine by analogy to our published procedure, see reference 61. Clear oil; 1H NMR

(300 MHz, CDCl3) 2.57 (app. q, J = 2.0 Hz, 2H), 2.33 (s, 2H), 1.85 (t, J = 2.0 Hz, 3H), 13 1.09 (s, 6H); C NMR (75 MHz, CDCl3)  197.52, 160.47, 126.96, 118.24 (q, J = 319.7 Hz), 50.57, 42.48, 32.73, 27.86, 8.89; IR (neat) 1689, 1671, 1418, 1207, 1136, 1029, -1 + + 823 cm ; HRMS (EI ) Calcd for C10H13OSF3 (M ) 286.0487. Found 286.0490.

Synthesis of 3,3-diethyl-1-(2-iodophenyl)-triazene (80): To a solution of 2-iodoaniline (3 g, 13.7 mmol) in a minimal amount of acetonitrile (2 mL) was added ~6 g of ice, followed by dropwise addition of concentrated HCl (9.1 mL, 109.6 mmol). The solution was cooled to -10 oC and a solution of sodium nitrite (2.08 g, 30.14 mmol), in 33.3 mL of water—acetonitrile (3:1), was added slowly. The reaction mixture was stirred at -10 oC for 45 min. The solution of the generated diazonium salt was then transferred by cannula to a solution (1.4 L) of acetonitrile—water (3:1) containing freshly distilled diethylamine (14.2 mL, 137 mmol) and potassium carbonate (9.47 g, 68.5 mmol) at 0 oC. The resulting solution was allowed to warm upon stirring overnight. To the reaction mixture was added 500 mL of water, and the products extracted three times with 250 mL of ether. The combined extracts were washed with brine, dried with magnesium sulfate, and concentrated. The crude oil was purified by flash column chromatography using 10% EtOAc/Hex, providing iodotriazene 80 in 97% as a yellow oil (4.025 g). 1H

NMR (300 MHz, CDCl3) 7.84 (dd, J = 7.9, 1.2 Hz, 1H), 7.35 (dd, J = 8.0, 1.7 Hz, 1H), 7.29 (ddd, J = 8.0, 7.3, 1.2 Hz, 1H), 6.83 (ddd, J = 7.9, 7.3, 1.7 Hz, 1H), 3.80 (q, J = 7.2 13 Hz, 4H), 1.33 (t, J = 7.2 Hz, 6H); C NMR (100 MHz, CDCl3)  150.45, 139.06, 128.67, 126.52, 117.56, 96.61, 49.20, 42.16, 14.57, 11.14; IR (neat) 1577, 1561, 1457, 1399, -1 + + 1327, 1100, 749 cm ; HRMS (ESI ) Calcd for C10H15IN3 ([M+H] ) 304.0311. Found 304.0309.

Synthesis of 1-(2-(3,3-diethyl-1-triazo)phenyl)-1-oxo-5-heptyne (82): To a solution of iodotriazene 80 (2.0 g, 6.6 mmol) in diethyl ether (180 mL) at -78 oC was added n-BuLi (4.13 mL, 6.6 mmol, 1.6M solution in hexane) dropwise. The mixture was stirred at -78 oC for 30 min. To the solution was added triflate 2 (1.87 g, 7.26 mmol), as an ethereal solution (50 mL), dropwise. The solution was stirred at -78 oC for 15 min, 0 oC for 15 min, and at r.t. for 30 min. The reaction was then quenched with ½ sat. NH4Cl, extracted

2 times with Et2O, washed with H2O and brine, and dried with MgSO4. The concentrated solution provided a crude oil, which was purified by flash column chromatography using 1% EtOAc/Hex. The product (82) was isolated as a yellowish-brown oil in 85% yield 1 (1.59 g). H NMR (300 MHz, CDCl3)  7.48 (dd, J = 8.2, 1.0 Hz, 1H), 7.43 (dd, J = 7.6, 1.3 Hz, 1H), 7.37 (ddd, J = 8.2, 7.6, 1.5, 1H), 7.14 (dt, J = 7.6, 1.0 Hz, 1H), 3.77 (q, J =

7.0 Hz, 4H), 3.06 (t, J = 7.4 Hz, 2H), 2.19 (tq, J = 7.0, 2.5 Hz, 2H), 1.93-1.77 (app. quintet, J = 7.2 Hz, 2H), 1.74 (t, J = 2.5 Hz, 3H), 1.40-1.14 (broad multiplet, 6H); 13C

NMR (100 MHz, CDCl3)  206.36, 148.91, 135.12, 131.09, 127.96, 124.88, 118.14, 78.60, 75.95, 49.02, 43.48, 41.52, 23.84, 18.45, 14.46, 11.27, 3.47; IR (neat) 1674, -1 + + 1592, 1403, 1328, 1092, 757 cm ; HRMS (ESI ) Calcd for C17H24N3O ([M+H] ) 286.1919. Found 286.1915.

Representative procedure for the decomposition of aryl triazenes to provide aryl iodides and Synthesis of 1-(2-iodophenyl)-1-oxo-5-heptyne (83): To a solution of camphor-10-sulfonic acid (2.44 g, 10.5 mmol) and NaI (0.315 g, 2.1 mmol) in acetonitrile (25 mL) at 75 oC was added a solution of triazene 82 (300 mg, 1.05 mmol in 5 mL of acetonitrile) dropwise. The evolution of nitrogen was complete after 5 minutes of stirring at 75 oC. The mixture was cooled to r.t. and diluted with 25 mL of hexane. The product was extracted 5 times with hexane. The combined hexane layers were then dried with Na2SO4 and concentrated to provide a reddish oil. The crude material was then purified by flash column chromatography using hexane. The resulting red—brown oil (83) was not completely pure by 1H NMR, and was used in the next step without further purification (ca. 75% yield, >85% pure).

Representative procedure for the Sonogashira coupling reaction for the synthesis of compounds 84a-f and 88: To a solution of aryl iodide 83 (32 mg, 0.1 mmol) in triethylamine (1 mL) was added dichlorobis(triphenylphosphine)palladium (4 mg, 5 mol) and copper(I) iodide (2 mg, 10 mol). The heterogeneous solution was degassed using the freeze—pump—thaw method (5 times) and then warmed to room temperature. Hexyne (30 L, 0.22 mmol) was then added to the reaction mixture in one shot. The solution was then warmed to 50 oC and stirred for 3 h. The mixture was cooled to r.t., diluted with ether, and filtered through Celite™. The filter cake was washed three times with ether and the combined filtrates were concentrated. The crude product was then purified by flash column chromatography using pure hexanes up to 1% EtOAc/Hex, providing 84b as a pale yellow oil in 85% yield (22 mg).

1-(2-(2-phenylethynyl)phenyl)-5-heptyn-1-one (84a): Pale yellow oil; 1H NMR (300

MHz, CDCl3)  7.70 (dd, J = 7.5, 1.6 Hz, 1H), 7.63 (dd, J = 7.5, 1.5 Hz, 1H), 7.59-7.53 (m, 2H), 7.47 (dt, J = 7.5, 1.6 Hz, 1H), 7.40 (dt, J = 7.5, 1.5 Hz, 1H), 7.37-7.34 (m, 3H), 3.30 (t, J = 7.0 Hz), 2.26 (tq, J = 7.0, 2.5 Hz, 2H), 1.94 (quintet, J = 7.0, 2H), 1.69 (t, J = 13 2.5 Hz, 3H); C NMR (75 MHz, CDCl3)  202.64, 141.02, 133.74, 131.48, 130.86, 128.62, 128.36, 128.20, 122.83, 121.20, 94.57, 88.25, 78.30, 76.35, 40.99, 23.61, 18.29, 3.32; IR (neat) 2215, 1678, 1493, 1217, 753, 689 cm-1; HRMS (EI+) Calcd for + C21H18O (M ) 286.1358. Found 286.1353.

1-(2-(2-n-butylethynyl)phenyl)-5-heptyn-1-one (84b): Clear oil; 1H NMR (300 MHz,

CDCl3) 7.59 (dd, J = 7.6, 1.6 Hz, 1H), 7.47 (dd, J = 7.6, 1.5 Hz, 1H), 7.38, (dt, J = 7.6, 1.6 Hz, 1H), 7.32 (dt, J = 7.6, 1.5 Hz, 1H), 3.20 (t, J = 7.3 Hz, 2H), 2.46 (t, J = 7.0, 2H), 2.31-2.16 (m, 2H), 1.89 (quintet, J = 7.3 Hz, 2H), 1.76 (t, J = 2.5 Hz, 3H), 1.67-1.55 (m, 13 2H), 1.54 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); C NMR (75 MHz, CDCl3) 203.50, 141.45, 133.77, 127.82, 127.47, 121.93, 96.28, 79.39, 78.41, 76.13, 41.10, 30.52, 22.07, 18.32, -1 + + 13.57, 3.43; IR (neat) 2228, 1679, 1440, 758 cm ; HRMS (EI ) Calcd for C19H22O (M ) 266.1671. Found 266.1669.

1-(2-(2-t-butylethynyl)phenyl)-5-heptyn-1-one (84c): Clear oil; 1H NMR (300 MHz,

CDCl3) 7.60 (dd, J = 7.5, 1.5 Hz, 1 H), 7.46 (dd, J = 7.5, 1.5 Hz), 7.38 (dt, J = 7.5, 1.5 Hz, 1H), 7.31 (dt, J = 7.5, 1.5 Hz, 1H), 3.24 (t, J = 7.2 Hz, 2H), 2.24 (tq, J = 6.0, 2.5 Hz, 2H), 1.89 (quintet, J = 7.2 Hz, 2H), 1.76 (t, J = 2.5 Hz, 3H), 1.33 (s, 9H); 13C NMR (75

MHz, CDCl3)  203.52, 141.30, 133.62, 127.82, 127.48, 104.09, 78.39, 78.18, 76.14, 41.37, 30.58, 28.18, 23.63, 18.31, 3.45; IR (neat) 2235, 1679, 1362, 1273, 757 cm-1; + + HRMS (EI ) Calcd for C19H22O (M ) 266.1671. Found 266.1669.

1-(2-(2-(p-methoxyphenyl)ethynyl)phenyl)-5-heptyn-1-one (84d): Pale yellow oil; 1H

NMR (300 MHz, CDCl3)  7.69 (dd, J = 7.5, 1.2 Hz, 1H), 7.59 (dd, J = 7.5, 1.1 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.44 (dt, J = 7.5, 1.2 Hz, 1H), 7.36 (dt, J = 7.5, 1.1 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H), 3.29 (t, J = 7.3 Hz, 2H), 2.32-2.18 (m, 2H), 1.93 13 (app. quintet, J = 7.0 Hz, 2H), 1.69 (t, J = 2.4 Hz, 3H); C NMR (75 MHz, CDCl3) 

202.96, 159.94, 140.82, 133.57, 133.02, 130.87, 128.21, 127.85, 121.63, 114.96, 114.05, 94.84, 87.14, 78.37, 76.36, 55.28, 41.04, 23.66, 18.33, 3.37; IR (neat) 2212, -1 + + 1678, 1605, 151, 1247, 1028, 831, 758 cm ; HRMS (EI ) Calcd for C22H20O2 (M ) 316.1463. Found 316.1462.

1-(2-(2-trimethylsilylethynyl)phenyl)-5-heptyn-1-one (84e): Yellow oil; 1H NMR (300

MHz, CDCl3)  7.64-7.59 (m, 1H), 7.57-7.52 (m, 1H), 7.41 (dt, J = 7.4, 1.9 Hz, 1H), 7.37 (dt, J = 7.4, 1.7 Hz, 1H), 3.23 (t, J = 7.3 Hz, 2H), 2.42 (tq, J = 7.1, 2.5 Hz, 2H), 1.90 (quintet, J = 7.1 Hz, 2H), 1.76 (t, J = 2.5 Hz, 3H), 0.26 (s, 9H); 13C NMR (75 MHz,

CDCl3)  203.03, 141.81, 133.99, 130.61, 128.48, 127.88, 120.80, 103.53, 100.44, 78.30, 76.13, 41.17, 23.66, 18.27, 3.41, 0.39; IR (neat) 2157, 1682, 1249, 863, 840, 758 -1 + + cm ; HRMS (ESI ) Calcd for C18H22OSiNa ([M+Na] ) 305.1338. Found 305.1333.

1-(2-(2-(p-Trifluoromethylphenyl)ethynyl)phenyl)-5-heptyn-1-one (84f): Yellow oil; 1 H NMR (300 MHz, CDCl3)  7.74 (dd, J = 7.4, 1.5 Hz, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.65-7.58 (m, 3H), 7.50 (dt, J = 7.4, 1.6 Hz, 1H), 7.44 (dt, J = 7.4, 1.5 Hz, 1H), 3.24 (t, J = 7.3 Hz, 2H), 2.26 (tq, J = 7.0, 2.5 Hz, 2H), 1.94 (quintet, J = 7.0 Hz, 2H), 1.70 (t, J = 13 2.5 Hz, 3H); C NMR (150 MHz, CDCl3)  202.15, 141.14, 134.82, 131.05, 130.31 (q, 32.7 Hz), 128.78, 125.34 (q, 3.9 Hz), 123.88 (q, 270.9 Hz), 120.61, 92.74, 90.61, 78.28, 76.48, 40.77, 23.59, 18.31, 3.53; IR (neat) 1683, 1614, 1320, 1126, 1065, 824 cm-1; + + HRMS (EI ) Calcd for C22H17OF3 (M ) 354.1232. Found 354.1230.

Synthesis of 1-(2-ethynylphenyl)-5-heptyn-1-one (85): To a methanolic solution (2 mL) of trimethylsilylacetylene (84e) (136 mg, 0.48 mmol) was added potassium carbonate (100 mg, 0.72 mmol) at room temperature. The reaction mixture was stirred at room temperature until the starting material was no longer detected by TLC (ca. 30 min). The mixture was diluted with ether and water. The reaction was quenched with 1N

HCl until CO2 evolution was no longer observed. The product was extracted twice with

EtOAc. The combine organics were washed with water and brine, dried with Na2SO4, filtered and concentrated. The resulting crude oil was purified by flash column chromatography using 100% hexane up to 1% EtOAc/Hex, providing 85 as a clear oil in

1 94% yield (94 mg). H NMR (300 MHz, CDCl3)  7.69-7.63 (m, 1H), 7.63-7.56 (m, 1H), 7.48-7.38 (m, 2H), 3.35 (s, 1H), 3.18 (t, J = 7.1 Hz, 2H), 2.25 (tq, J = 7.1, 2.5 Hz), 1.91 13 (quintet, J = 7.1 Hz, 2H), 1.77 (t, J = 2.5 Hz, 3H); C NMR (150 MHz, CDCl3)  202.52, 141.92, 134.64, 130.85, 128.78, 120.04, 82.42, 82.24, 78.36, 76.32, 40.58, 23.51, -1 + 18.23, 3.44; IR (neat) 1687, 1440, 1225, 757 cm ; HRMS (EI ) Calcd for C15H13O ([M- H]+) 209.0967. Found 209.0964.

Representative procedure for the AuCl3—catalyzed benzannulation reaction: To a solution of AuCl3 (0.6 mg, 1.8 mol) in 100 L dichloroethane (DCE), obtained from a stock solution (6 mg/mL), was added an additional 200 L of DCE and diyne 84b (10 mg, 37 mol, in 200 L of DCE). The solution was then heated to 80 oC for 1.5 h. The mixture was cooled to r.t. and filtered through a plug of silica gel. The filtrate was concentrated and purified by flash column chromatography using 1% EtOAc/Hex , providing naphthyl ketone 86b in 70% yield (7 mg) as a clear oil.

(4-Methyl-2,3-dihydro-1H-cyclopenta[a]naphthalene-5-yl)-phenyl-methanone (86a): 1 H NMR (300 MHz, CDCl3)  7.85-7.80 (m, 2H), 7.61-7.53 (m, 1H), 7.50-7.38 (m, 3H), 7.34-7.26 (m, 1H), 3.35 (t, J = 7.5 Hz, 2H), 3.08 (t, J = 7.5 Hz, 2H), 2.30 (quintet, J = 7.5 13 Hz, 2H), 2.22 (s, 3H); C NMR (75 MHz, CDCl3)  200.88, 140.99, 140.41, 137.95, 134.73, 133.58, 130.30, 129.76, 129.55, 128.73, 125,50, 125.45, 125.26, 124.54; 32.63, 31.65, 23.89, 17.23; IR (neat) 1664, 1448, 1219, 884, 756, 717 cm-1; HRMS (EI+) Calcd + for C21H18O (M ) 286.1358. Found 286.1353. n-Butyl-(4-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalene-5-yl)-methanone 1 (86b): H NMR (300 MHz, CDCl3)  7.78 (dd, J = 7.8, 1.8 Hz, 1H), 7.55 (dd, J = 7.2, 1.8 Hz, 1H), 7.43-7.37 (m, 2H), 3.29 (t, J = 7.2 Hz, 2H), 3.04 (t, J = 7.8 Hz, 2H), 2.87 (t, J = 7.8 Hz, 2H), 2.31 (s, 3H), 2.26 (quintet, J = 7.8 Hz, 2H), 1.78 (quintet, J = 7.8 Hz), 1.44 13 (app. sextet, J = 7.6 Hz, 2H), 0.953 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3)  211.21, 141.03, 140.05, 137.75, 128.91, 128.87, 127.53, 125.57, 125.30, 124.74, 124.55, 45.65, 32.64, 31.59, 25.75, 23.87, 22.47, 16.91, 13.94; IR (neat) 1697, 1130, -1 + + 751 cm ; HRMS (EI ) Calcd for C19H22O (M ) 266.1671. Found 266.1670.

75 t-Butyl-(4-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalene-5-yl)-methanone (86c): 1 H NMR (300 MHz, CDCl3)  7.77 (dd, J = 7.6, 1.1 Hz, 1H), 7.53-7.33 (m, 3H), 3.29 (app. triplet, J = 7.8 Hz, 2H), 3.13-2.94 (m, 2H), 2.29 (s, 3H), 2.26 (app. quintet, J = 13 7.8Hz, 2H), 1.27 (s, 9H); C NMR (150 MHz, CDCl3)  219.07, 141.05, 139.42, 137.12, 129.31, 128.83, 127.46, 125.68, 129.19, 125.06, 124.66, 45.69, 32.71, 31.51, 28.09, 23.83, 18.34; IR (neat) 1688, 1276, 1261, 764, 749 cm-1; HRMS (EI+) Calcd for + C19H22O (M ) 266.1671. Found 266.1668.

(4-Methyl-2,3-dihydro-1H-cyclopenta[a]naphthalene-5-yl)-p-trifluoromethylphenyl- 1 methanone (86f): H NMR (300 MHz, CDCl3)  7.95 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.52-7.39 (m, 2H), 7.36-7.28 (m, 1H), 3.37 (t, J = 7.5 Hz, 2H), 3.10 (t, J = 7.5 Hz, 2H), 2.32 (quintet, J = 7.5 Hz, 2H), 2.22 (s, 3H); 13C NMR

(75 MHz, CDCl3)  199.80, 141.03, 140.47, 134.73 (q, J = 32.5 Hz), 133.78, 130.12, 129.99, 129.83, 128.82, 125.83 (q, J = 3.7 Hz), 125.72, 125.15, 124.71, 123.55 (q, J = 272.9 Hz), 32.60, 31.67, 23.84, 17.26; IR (neat) 1673, 1409, 1322, 1168, 1128, 1069 -1 + + cm ; HRMS (ESI ) Calcd for C22H17F3ONa ([M+Na] ) 377.1129. Found 377.1135.

Representative procedure for reactions performed with the Cu(OTf)2 / CF2HCO2H catalyst system: To a solution of Cu(OTf)2 (4 mg, 11 mol) and difluoroacetic acid (14 L, 0.22 mmol) in DCE, was added a solution of diyne 84c (58 mg, 0.22 mmol in 1 mL of DCE). The solution was heated to 80 oC and stirred for 40 min. The reaction mixture was cooled to r.t. and filtered through silica gel. The filtrate was concentrated; the resulting oil was purified by flash column chromatography using hexanes, providing naphthalene derivative 87 in 88% yield (35 mg).

1 4-Methyl-2,3-dihydro-1H-cyclopenta[a]naphthalene (87): H NMR (300 MHz, CDCl3)  7.78 (d, J = 7.3 Hz, 1H), 7.75 (d, J = 7.3 Hz, 1H), 7.47 (s, 1H), 7.46-7.35 (m, 2H), 3.28 (t, J = 7.5 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 2.43 (s, 3H), 2.26 (quintet, J = 7.5 Hz, 2H); 13 C NMR (150 MHz, CDCl3)  199.80, 141.03, 140.47, 134.73 (q, J = 32.5 Hz), 133.78, 130.12, 129.99, 129.83, 128.82, 125.83 (q, J = 3.7 Hz), 125.72, 125.15, 124.71, 123.55 (q, J = 272.9 Hz), 32.60, 31.67, 23.84, 17.26. 141.26, 139.08, 133.20, 132.86, 129.03,

127.62, 125.65, 124.87, 124.72, 124.24, 32.39, 31.32, 24.14, 19.76; IR (neat) 1595, -1 + + 1382, 1020, 872, 766, 743 cm ; HRMS (ESI ) Calcd for C14H14 (M ) 182.1096. Found 182.1094.

Synthesis of 1-(2-(2-t-butylethynyl)phenyl)-3,3-dimethyl-5-heptyn-1-one (89): Iodotriazene 80 was coupled to 3,3-dimethylbutyne using the same method as outlined above. The resulting alkynyl triazene was converted to the corresponding iodide under our modified conditions (see above). The product was purified by flash column chromatography providing 88 as the major component in an inseparable mixture of compounds. To a solution of the this mixture (165 mg, ~0.58 mmol) in diethyl ether (20 mL) was added n-BuLi (0.39 mL, 0.52 mmol, as a 1.31M solution in hexane) dropwise at -78 oC. The mixture was stirred for 30 min, at which time, an ethereal solution (5 mL) of triflate 55 (150 mg, 0.52 mmol) was added dropwise at -78 oC. The solution was stirred for 15 min at -78 oC, then at 0 oC, and finally at r.t. for 30 min. The reaction was quenched with ½ sat. ammonium chloride. The products were extracted with ether (2 times). The combined organic layers were washed with water and brine, dried with

MgSO4, filtered and concentrated. The resulting crude oil was purified by flash column chromatography using 1% EtOAc/Hex up to 5% EtOAc/Hex to provide diyne 89 in 61% 1 yield (94 mg); (>90% brsm). Clear oil; H NMR (300 MHz, CDCl3)  7.47 (dd, J = 7.4, 1.5 Hz, 1H), 7.43 (dd, J = 7.4, 1.5 Hz, 1H), 7.34 (dt, J = 7.4, 1.5 Hz, 1H), 7.29 (dt, J = 7.4, 1.5 Hz, 1H), 3.13 (s, 2H), 2.21 (q, J = 2.5 Hz, 2H), 1.75 (t, J = 2.5 Hz, 3H), 1.32 (s, 13 9H), 1.08 (s, 6H); C NMR (75 MHz, CDCl3)  204.27, 143.58, 133.39, 130.15, 127.41, 121.40, 103.72, 78,99, 77.50, 76.75, 76.49, 51.44, 34.58, 32.39, 30.65, 28.17, 27.14, -1 + + 3.48; IR (neat) 2359, 1684, 1472, 1362, 758 cm ; HRMS (EI ) Calcd for C21H26O (M ) 294.1984. Found 294.1984.

3,3,4-Trimethyl-2,3-dihydro-1H-cyclopenta[a]naphthalene (90): 1H NMR (300 MHz,

CDCl3)  7.76 (dd, J = 6.8, 2.5 Hz,1H), 7.70 (dd, J = 6.6, 2.5 Hz, 1H), 7.46 (s, 1H), 7.44- 13 7.34 (m, 2H), 3.08 (s, 2H), 2.86 (s, 2H), 1.26 (s, 6H); C NMR (75 MHz, CDCl3)  144.60, 142.46, 137.53, 137.41, 133.61, 131.99, 129.97, 129.09, 128.94, 128.41, 51.77,

50.61, 43.64, 34.16, 23.98; IR (neat) 1364, 872, 843, 743 cm-1; HRMS (EI+) Calcd for + C16H18 (M ) 210.1408. Found 210.1404. t-Butyl-(3,3,4-trimethyl-2,3-dihydro-1H-cyclopenta[a]naphthalene-5-yl)-methanone 1 (91): H NMR (300 MHz, CDCl3)  7.71 (dd, J = 7.8, 1.4 Hz, 1H), 7.47 (dd, J = 7.8, 1.3 Hz, 1H), 7.42 (dt, J = 7.8, 1.4 Hz, 1H), 7.36 (dt, J = 7.8, 1.4 Hz), 3.09 (s, 2H), 2.89 (d, J = 16.0 Hz, 1H), 2.80 (d, J = 16 Hz, 1H), 2.25 (s, 2H), 1.29 (s, 3H), 1.27 (s, 9H), 1.23 (s, 13 3H); C NMR (150 MHz, CDCl3)  219.15, 140.10, 128.55, 137.12, 129.29, 129.10, 127.68, 125.71, 125.13, 124.99, 124.54, 47.71, 46.40, 45.69, 39.25, 29.82, 29.79, -1 + 28.11, 18.25; IR (neat) 1685, 1463, 1102, 903, 738 cm ; HRMS (EI ) Calcd for C21H26O (M+) 294.1984. Found 294.1984.

1H NMR and 13C NMR Spectra:

OTf 55

N N N 80

N N N 82

84a

84b

84c

84d OMe

Si 84e

84f CF3

H 85

86a

100

86b

101

86b

102

86c

103

86c

104

86f CF3

105

86f CF3

106

107

108

109

110

111

112

113

114

CHAPTER 4

SYNTHESIS OF THE EASTERN HEMISPHERE (C1-C15) OF PALMEROLIDE A

Introduction

The goal of this work was to address the shortcomings of a previously reported fragmentation reaction in order to provide an efficient synthesis of the eastern hemisphere of palmerolide A. Palmerolide is an exciting natural product that possesses anti-cancer properties and selectively targets melanoma. This work will provide the basis for future synthetic efforts applied to the large scale synthesis of this natural product by the Dudley laboratory, including the expedient synthesis of the eastern hemisphere (C1-C15). The following chapter will highlight some of the deficiencies related to the treatment of the growing melanoma epidemic in western countries. There exists a need for new drugs that can selectively lead to cell death in melanoma tumors. The discovery of palmerolide A has provided a possible target that may ultimately lead to a better prognosis for patients that suffer from melanoma. Unfortunately, synthesis is the only means at present to obtain enough quantities of this natural product to perform further clinical studies. The examination of previous synthetic methods applied to the generation of palmerolide A draws attention to the fact that all approaches to this natural product have focused on a convergent process with the production of relatively few strategically generated C-C bonds in an effort to access the core structure. Thus, fragment synthesis is paramount to provide an efficient synthesis capable of producing quantities of palmerolide to support future biological studies. The eastern hemisphere contains three of the five stereocenters which are isolated by hydrocarbon regions. We envisioned our fragmentation strategy as being well suited for the synthesis of this C1-C15 fragment. However, an optimization of a known fragmentation reaction had to be improved prior to beginning this endeavor.

115

The Melanoma Problem

The skin is the largest organ of the human body. It is responsible for providing a protective barrier against infection and injury, and serves a key role in thermoregulation. The skin is composed of three distinct layers: the epidermis, the dermis, and the subcutis. For this discussion, the focus is on the epidermis, the most superficial layer of the skin. The dead cells at the surface are composed of squamous cells that have been flattened and keratinized; they provide the primary protective barrier for the body. Several types of cells exist below this outer most layer of the epidermis, including: Merkel cells (tactile receptors), Langerhans cells (antigen processing cells), keratinocytes, melanocytes and basal cells, among others.153 Melanocytes are responsible for the production of a pigment called melanin, which provides the skin with its color and protects the deeper layers of the skin from ultraviolet radiation. The sun stimulates the melanocytes to produce more melanin resulting in tanning of the skin. As do most cells, melanocytes grow, divide, and die. When these cells begin to divide and grow in an unregulated fashion, a melanoma tumor results. These tumors, as with all tumors, can either be benign (non-cancerous) or malignant (cancerous) in nature. Most melanocyte-derived tumors commonly develop in the skin, however, melanoma can develop anywhere melanocytes are found (e.g. the eye, meninges, digestive tract, and lymph nodes). Melanoma is one of the most common types of cancer. It is estimated that in 2009 alone, 68,720 adults in the United States will have been diagnosed with melanoma, resulting in 8,650 deaths.154 The prevalence of melanoma in Western countries increases every year. In the United States, Australia, and Europe, melanoma has been considered an epidemic cancer.155 In fact, the percentage of people developing melanoma in the United States has more than doubled in the past 30 years.156 People with fair skin are more susceptible towards developing melanoma, and white people develop melanoma at more than 10 times a higher rate than black people.154 Although the occurrence of this disease is more likely as individuals age,

116 melanoma has been detected at all age groups. People with personal and family histories of melanoma are at an increased risk, as are individuals with increased numbers of ordinary moles (benign clusters of melanocytes). Weakened immune systems, resulting from a number of conditions (e.g. HIV, different forms of cancer, or drugs prescribed following organ transplantation), increased exposure to ultraviolet radiation, and sunburns resulting in blistering are all thought to increase the likelihood of developing melanoma. However, it is not known why a person develops this type of cancer while others do not, and multiple factors probably give rise to melanoma tumors.156 The beginning signs and symptoms associated with melanoma often include, but are not limited to: changes in size, shape, color, or texture of an existing mole. Often times, these lesions have black or bluish-black areas, they are often referred to as ―ugly looking‖ moles. Leading cancer research advises self-examinations involving the so- called, ―ABCDE’s‖ of melanoma:153,154,156 Asymmetry, the shape of part of a mole does not match the other; Border irregularity, the edges are ragged, notched or blurred; Color, the color of the mole is not consistent, often shades of tan, brown, blue, pink, red, black, or white; and Diameter, the mole is larger than ¼ of an inch in diameter, larger than the size of a pencil eraser; and Evolution, mole has changed in size, shape, color, or has risen. Although these guidelines for self-examination are general signs of melanoma, some melanomas do not fit these rules. Only medical professionals can confirm the presence of melanoma. The onset of melanoma progresses through various stages of increasing severity. At stage 0, cells determined to be cancerous melanoma are found only in the most superficial layers of skin, and have not invaded any of the deeper tissues. Melanoma is considered to be stage I when the tumor is either no more than 1 mm in thickness and appears to be ulcerated, or between 1 to 2 mm thick and has no ulceration. Stage II melanoma is established when the tumor is between 1 to 2 mm thick and appears with ulceration. In stage I and stage II, the tumor may or may not have begun to penetrate into the deeper tissues of the skin. However, the cancerous cells cannot have spread to nearby lymph nodes. At stage III, the signs and symptoms of melanoma are progressively worse, the cancerous cells having spread (metastasized)

117 to nearby lymph nodes or other tissues just outside the original tumor. Finally stage IV melanoma refers to the condition resulting in the metastasis of cancerous melanoma cells to lymph nodes and/or tissues distant from the original tumor.156 Once metastasized, the development of a new tumor in the distant tissues ensues. If this occurs, the new tumor is still comprised of cancer cells originating from melanocytes, and the patient is said to have metastatic melanoma. The treatment of melanoma is usually carried out as a prescribed plan involving combinations of surgery, chemotherapy, biotherapy, and / or radiation therapy; these treatments are also integrated with a symptom management program (supportive care, or palliative care) due to the fact that many of the primary treatments are associated with negative side effects. Treatment plans are often case dependent and are based on the age and general health of the patient, as well as the severity of the cancer being treated.156 The surgical removal of the tumor is the most common practice for melanoma that is found in the superficial tissues, and is often accompanied by necessary skin grafts for larger tumors. Typically when surgery is performed the tumor and some of the surrounding normal tissue is removed for analysis to ensure removal of the cancer in its entirety. Surgery is also used for the removal of cancerous lymph nodes in the surrounding area of the original tumor. Although surgery is the most common treatment for melanoma, it is typically not effective in controlling melanoma that has spread to other areas of the body.153 Biotherapy (also referred to as immunotherapy) provides assistance to a person’s immune system, allowing for the body’s natural defenses to aid in fighting cancer. This type of therapy involves the use of proteins, small molecules, harmless bacterial microbes, and sometimes even weakened melanoma cells to initiate an immune response. Commonly used biotherapies are: injections of cytokines (proteins that activate the immune system) and injections of Interferon-alpha. Both cytokine proteins and Interferon-alpha are associated with flu-like side-effects that can be severe in some cases. This type of therapy is often utilized as an adjuvant therapy to limit the growth and metastasis of any remaining cancerous cells after surgery.153

118

Radiation therapy requires the use of high frequency electro-magnetic radiation to kill cancer cells and reduce the size of tumors. This type of therapy is typically not used to eradicate cancer, but prevent growth and metastasis. Radiation often results in general malaise of the patient, diarrhea, upset stomach, and skin irritation among other side effects. The use of radiation therapy is often reserved for those that have metastatic melanoma and recurrent melanoma.154 Chemotherapy is the use of chemicals to kill the cancerous cells selectively as opposed to healthy cells, and is often prescribed for more advanced cases of melanoma. Although there are many types of pharmacological agents used for the treatment of patients with stage III and IV melanoma, the prognosis for patients with metastatic cancer remains very poor; once the cancer has spread to organs and tissues distant from the originating tumor, the median overall survival rate is approximately 6 months.157 Despite vast research, the use of prescribed chemotherapeutic agents for the treatment of metastatic melanoma remains marginally beneficial. This form of cancer is one of the most chemo-resistant.158 Chemotherapy is often administered as single agents (Figure 45) such as: dacarbazine (DTIC), temozolomide (TMZ), cisplatin, carboplatin, carmustine, lomustine, docetaxel, and paclitaxel; DTIC and TMZ being the most common.158 In some cases the chemotherapy is administered as a combination of drugs / therapeutic agents: the Dartmouth Regimen (DTIC, carmustine, cisplatin, and tamoxifen), CVD (cisplatin, vinblastine, and DTIC), and BOLD (bleomycin, vincristine, lomustine, and DTIC) being representative examples.157 The fact that so many chemotherapeutic options are being used for the treatment of late stage melanoma, substantiates the claim that melanoma is a chemo-resistant type of cancer. Furthermore, 90 to 95% of patients with advanced melanoma do not survive more than three years, regardless of treatment modality.159

119

O H O N NH2 H C 3 N N O N N Cl NH O NH3 N N 3 Pt N Pt Cl NH3 O NH3 N CH3 N O O H2N CH3

Dacarbazine (DTIC) Temozolomide (TMZ) Cisplatin Carboplatin

O O Cl Cl Cl N N N N H H N N O O

Carmustine Lomustine

HO HO O O HO O O O H H O H H O NH O O O NH O O O O O O OH O OH O OH O OH O O O

Docetaxel Paclitaxel

Figure 45: Several Chemotherapeutic Agents Used in the Treatment of Melanoma.

The limited efficacy of treatment programs for metastatic cancer patients and the harsh side effects that accompany current cancer treatments provide researchers with the daunting task of finding effective alternatives to the drugs referenced above that will selectively target melanoma. This chapter highlights synthetic efforts towards an interesting new lead compound, palmerolide A, which possesses selective pharmacological activity towards melanoma cell lines. It describes a highly efficient and convergent method to generate the eastern hemisphere (C1-C15) of palmerolide A.

120

Palmerolide A

Chemical defense mechanisms are of the utmost importance in marine ecosystems.160-164 Sessile marine invertebrates, much like marine plants, are particularly susceptible to predation, fouling by settling larvae, diatoms, algae, and overgrowth by competing species for space and resources. Most research on the chemical ecology of marine invertebrate communities has focused on tropical regions because of their high levels of species diversity and density. Not surprisingly, members of these communities have evolved interesting chemical defenses.160 Many of the initial studies focusing on geographic patterns of chemical defense in marine invertebrates found that there was an inverse relationship between species chemically defended against predatory fish and latitude.165-167 This may be, in part, responsible for the focus of chemical ecology remaining on tropical locations, leaving benthic communities in the Antarctic to be relatively understudied. Another possible reason for the lack of research in the marine habitats of Antarctica is that it remains one of the least accessible marine environments. However, outside of the shallow waters, where anchor ice and ice scour dominate the landscape (< 33 m depth),168 exist diverse and stable communities of invertebrates.169 The Antarctic, cold adapted, marine ecosystem has been largely isolated for approximately 20 million years. Many of the marine organisms that are found in these communities emerged prior to the breakup of Gondwanaland and the movement of the continent to the pole; the biological isolation of the Antarctic marine ecosystem is perpetuated by the Antarctic Polar Front, an oceanic water current encircling the continent.170 The predation of fish on the sessile invertebrates is rather rare at higher latitudes, limiting the need for chemical defenses against vertebrate predators.171 However, predation in the Antarctic benthos is dominated by mobile invertebrates like sea stars.172 These waters harbor of some of the oldest, most environmentally and biologically stable marine environments, making them well suited for the evolution of chemical defense mechanisms against such predators.164 Indeed, the fact that the marine ecosystem around Antarctica is largely isolated from subtropical and temperate waters, in addition to the fact that mobile invertebrates control the predatory landscape of sessile

121 invertebrates, has led to an environment where interspecies chemical warfare plays a pivotal role in survival.173 The predation suppression exhibited by members of the alcyopterosins (discussed in Chapter 3) may be a representative example.109 For these reasons, natural products research in Antarctica has the potential to produce tantalizing leads for drug discovery and development. Although it is up to isolation chemists and marine ecologists to ascertain and characterize these compounds, it falls upon synthetic chemists to translate promising leads into viable drug development candidates. This responsibility is solely reserved for the synthetic community because of an international treaty that prohibits the exploitation of Antarctic resources for commercial development.174 Palmerolide A (94)175 was isolated by Bill Baker and co-workers from the Antarctic tunicate Synoicum adareanum. It represents one of the most exciting synthetic challenges in natural products organic chemistry today. Palmerolide A is a potent 175 inhibitor of vacuolar ATPase proton pumps (IC50 = 2 nM), which are highly expressed in metastatic cancer cells176 where they modulate pH. V-ATPases are also the target of several other interesting cytotoxic natural products including salicylihalamide A,177,178 179 180 bafilomycin A1, and oximidines. What’s more, palmerolide A was found to exhibit cytotoxicity three orders of magnitude greater towards the melanoma UACC-62 cell line 175 (LC50 = 18 nm) when compared to the rest of the NCI’s 60-cell line panel. Figure 46 depicts data from the report issued to Baker and co-workers from the NCI,181 the larger region highlighted in red shows the promising cytostatic activity demonstrated by palmerolide A (most notably against leukemia, colon, melanoma, renal and breast cancer). The smaller region highlighted in green provides the evidence of the natural product’s ability to kill melanoma cells selectively.

122

Figure 46: The Report Issued to Baker From the National Cancer Institute’s 60-Cell Line Panel Toxicity Assay for Palmerolide A.181

Baker and co-workers have since isolated several other members of the family of palmerolide natural products, some of which inhibits V-ATPase activity (Figure 47).181

123

Most notably, these compounds vary from the 94 in the position of the C8, C9 olefin (palmerolide A 94 vs. B, C, and H), and their enamide side chain (palmerolide A vs. D, E, F, and H); palmerolide E lacks the enamide moiety altogether.

O O

O 1 O N N 19 O 24 O 7 O HO OH O NH2 15 HO Palmerolide A (94) O 11 Palmerolide B V-ATPase (IC50 = 2 nM) O NH2 OSO3

O O

O O N N

O O OH OH HO Palmerolide C Palmerolide D O V-ATPase (IC50 = 150 nM) OH O NH2 O NH2 O O O

O O O N H O OH OH HO HO Palmerolide E O Palmerolide F O V-ATPase (IC50 = 6.5 M) V-ATPase (IC50 = 62.5 nM) O NH2 O NH2

O O

O O N O O NH OH O HO O NH2 HO O

Palmerolide E O NH Palmerolide H 2 OSO3 V-ATPase (IC50 = 10M)

Figure 47: Palmerolide A and Other Members of the Palmerolide Natural Products With Major Distinctions Highlighted in Red Ovals.181

124

This natural product has attracted several synthetic efforts182-188 due to its exciting biological activity and interesting structure. The chemical synthesis of palmerolide A requires one to address several independent challenges. Hydrocarbon regions isolate several stereocenters within the macrocyclic core, making it ideal for convergent fragment assembly strategies. Most synthetic approaches are focused on a few strategic bond disconnections: generation of the C15-C16 bond using a transition metal catalyzed coupling reaction, an esterification reaction to provide the C1-Oxygen bond, closure of the macrolide at the C8-C9 bond, and late stage enamide installation (Figure 48).

Esterification O

O 1 N 19 24 O 7 OH Enamide HO HWE or RCM Installation Coupling 15 O Reaction 11 O NH2 Palmerolide A (94)

Figure 48: Palmerolide A and Strategic Disconnections.

In 2007, the labs of Jef De Brabander181 and K. C. Nicolaou182 independently reported the total synthesis (and structural reassignment) of palmerolide A. The De Brabander synthesis began with a chiral vinylogous Mukaiyama aldol reaction between known vinylketene silyl N,O-acetal 95189 and aldehyde 96190 to provide alcohol 97 in a 13:1 diastereomeric ratio and 80% yield. A Mitsunobu inversion, followed by simultaneous reduction of the resulting benzoyl ester and chiral auxiliary, provided an aldehyde that was homologated using Ph3PCHCO2Me. This sequence provided the C16-C24 fragment of the palmerolide A (98), and contained the necessary stereochemistry at C19 and C20 as well as the 16,17 Z-olefin (Figure 49).

125

O O OH O OHC TiCl4, CH2Cl2 o O N N O -78 C + Me Me Me Me Me TBSO dr = 13:1 i-Pr I 80% I Me 95 96 97

O OH 1. PhCO2H, DEAD, Ph3P 2. DIBAL, CH2Cl2 Me 3. Ph3PCHCO2Me Me Me Me 61% over 3-steps I 98 Figure 49: De Brabander’s Synthesis of the C16-C24 Fragment of Palmerolide A.

De Brabander and co-workers began their synthesis of the C9-C15 fragment of palmerolide A with D-arabitol (99). The formation of a 1,3-benzylidene acetal and oxidative cleavage of the resulting 1,2-diol provided aldehyde 100.191 Conversion of aldehyde 100 to aldehyde 101 was carried out using a series of standard reactions. The condensation of aldehyde 101 with pinacol dichloromethylborane completed the synthesis of the C9-C15 fragment (Figure 50).192

1. Ph3PCHCO2Me OH 2. TIPSOTf, 2,6-Lutidine OTIPS HO OH TESO ref. 190 3. Pd/C, H , EtOAc OH O 2 HO 4. TESCl, imidizole TESO Ph O CHO 5. DIBAL, -78 oC HO OHC

99 100 101 81% over 5 steps

O PinB OTES O B RO CHCl2 R = TIPS CrCl2, LiI, r.t. OTES 84%

102 Figure 50: De Brabander’s Synthesis of the C9-C15 Fragment of Palmerolide A.

126

The synthesis of the C1-C8 fragment began with -valerolactone (103). Upon methanolysis and Swern oxidation, 103 was converted to aldehyde 104, and subsequently olefinated. The resulting t-butyl ester was hydrolyzed under acidic conditions and a Claisen-type condensation, using dimethyl methylphosphonate was carried out to afford the C1-C8 fragment (105) (Figure 51).

O O OHC 1. MeOH, H SO , 1. Ph3PCHCO2t-Bu 2 4 HO O reflux 2. TFA, CH2Cl2

2. Swern Oxidation 3. n-BuLi, (MeO)2P(O)Me, O Ref. 191 MeO O THF, -78 to 0 oC (MeO) P 72% 2 O 82% over 3 steps 103 104 105

Figure 51: De Brabander’s Synthesis of the C1-C8 Fragment of Palmerolide A.

Having synthesized the necessary fragments, vinyl iodide 98 and vinylboronate 102 were coupled through a Suzuki coupling reaction to provide 106. Subsequent Yamaguchi esterification194 of fragment 105 and 106, followed by cleavage of the triethysilyl ethers provided compound 107. A selective oxidation195 of the primary alcohol and an intramolecular Horner-Wadsworth-Emmons reaction (HWE)196 established the macrocyclic core of palmerolide A (108). The macrocycle was then transformed into 109 through a series of several steps: a CBS-reduction197 that provided the C7 stereochemistry (dr = 4:1); installation of the enamide via a Curtius rearrangement at C24, followed by addition of 2-methyl-propenylmagnesium bromide to the resulting isocyanate; carbamate synthesis at the C11 oxygen, and finally, global deprotection (Figure 52). The spectroscopic data of compound 109 proved to be inconsistent with the natural isolate. The De Brabander lab then carried out the same sequence of reactions utilizing the enantiomer of vinylboronate fragment 102 which provided a compound with the identical NMR spectrum to that of palmerolide A. However, the circular dichroism (CD) spectrum proved to be the mirror image to that of the natural product. De Brabander and co-workers had successfully completed the synthesis of the originally proposed compound as well as the unnatural enantiomer.

127

Their synthesis employed a relatively straightforward approach; notably a HWE macrocyclization, a selective vinylogous Mukaiyama aldol reaction, and a Curtius rearrangement reaction were utilized to provide the first synthesis of (-)-palmerolide A.

MeO2C cat. Pd(PPh ) , 1. Yamaguchi conditions, 3 4 105, 69% Tl2CO3, THF, H2O 98 + 102 79% RO o R = TIPS OTES 2. PPTS, MeOH, 0 C, 95%

OTES O 106 O

O O MeO C 2 O MeO2C 1. PhI(OAc) , TEMPO P(OMe) 2 O 2 2. K2CO3, 18-Crown-6, O RO PhMe, 60 oC RO R = TIPS OH R = TIPS 70% over 2 steps OH OH 107 108 O

O H N

O OH HO 18% over 9 steps O

O NH2 Diastereomer of Palmerolide A 109 Figure 52: Completion of De Brabander’s Synthesis of 109, a Diastereomer of Palmerolide A.

K. C. Nicolaou’s lab, having made the same disconnections as De Brabander, initiated their synthesis through the preparation of the C16-C23 (112) and C15-C8 (116) fragments (Figure 53).183 Nicolaou and co-workers, like De Brabander’s group, also utilized vinyl iodide 96 in their synthesis, however they chose to perform an Evans’ aldol reaction using imide 110 to set the C19 and C20 chiral centers (95% de), providing 111.197 The aldol reaction was followed by several standard reactions to reach the C16-

128

C23 fragment (112). The chiral centers at C10 and C11 were established through the reaction of aldehyde 113 (2 steps from 4-pentyn-1-ol)198 and [(Z)--(methoxy- methoxy)allyl]-(-)-diisopinocampheylborane (114),199 which afforded 115 upon desilylation in 74% yield (>95% de, >90% ee). Hydroxy acetylene 115 was converted to vinylstannane 116, first through carbamate installation,200 followed by a standard manipulation of the acetylene moiety.201

O O OH O O OTBS OH 96, n-Bu2BOTf, Et N O N O N 3 46% Bn Bn ( 95% de) 20% over 7 steps I I 110 111 112

TBS 1. MOMO 114 Bu3Sn MOM MOM O B[(-)-Ipc]2 O 2. K CO , MeOH CHO 2 3 O 74% OH 62% over 3 steps (>95% de, >90% ee) O NH2 113 115 116

Figure 53: The Synthesis of Nicolaou’s C16-C23 (112) and C8-C15 (116) Fragments.

TBS protected 5-hexene-1-ol (117) served as the starting material for the synthesis of Nicolaou’s C1-C8 fragment (120). Upon epoxidation and chiral resolution, using the Jacobsen method,202 117 was converted to 118 in 42% yield (>99 ee). Ring- opening of the epoxide using a sulfur ylide provided allylic alcohol 119, and a series of reactions (protection, deprotection, oxidation, olefination, and saponification) provided the acid fragment 120 in 59% from 119 (Figure 54).

129

TBSO TBSO TBSO 1. m-CPBA Me3S I 2. (R,R)-Jacobsen, n-BuLi OH Co(II), cat. AcOH, H2O O 42% (>99% ee) 117 over 2 steps 118 119

1. MOMCl, DIPEA, 85% HO2C 2. TBAF, 95% 3. DMP, NaHCO3, 95%

4. Ph3PCHCO2Me, 90% 5. KOH, 85% OMOM 120 Figure 54: Nicolaou’s Synthesis of the C1-C8 Fragment of Palmerolide A.

The Nicolaou lab, having each of the key fragments in hand, turned their attention towards the assemblage of the fragments and their elaboration into the originally proposed structure of palmerolide A (Figure 55). A Stille reaction203 between vinyl iodide 112 and vinylstannane 116, followed by a Yamaguchi esterification194 of the resulting alcohol and acid 120 provided cyclization precursor 121. Conversion of the allylic silyl ether into vinyl iodide 122 was carried out in a three step sequence: deprotection, oxidation, and olefination.204 Removal of the MOM protecting groups and a ring closing metathesis reaction35 led to the formation of the C8-C11 olefin and the macrocyclic core of palmerolide A (123). From vinyl iodide 123, enamide installation205 completed the synthesis of the proposed structure of palmerolide A (109). Having reached 109, Nicolaou came to the same conclusion as the De Brabander group: the originally proposed structure had been assigned incorrectly. Their synthetic scheme allowed for the synthesis of the naturally occurring enantiomer simply by inserting ent-116 and ent-120 into their already established route. They completed the synthesis of natural palmerolide A (94) with similar yields. Their product exhibited identical analytical data to those of the natural isolate, including the CD spectrum.

130

OTBS O 1. TBAF 1. cat. [Pd(dba)2], 2. DMP, NaHCO AsPh3, LiCl, 67% 3 112 + 116 2. Yamaguchi conditions, OR 3. CrCl2, CHI3 120, 61% RO R = MOM 63% (>95:5 E/Z) O

121 O NH2

O O I I O O

1. BF3 OEt2, 46% CuI, Cs2CO3 109 OR 35 OH 2. Grubbs II, 76% NH RO HO 2 R = MOM O O

O O NH2

122 O NH2 123

Figure 55: Nicolaou’s End-Game strategy for the Synthesis of 109.

Nicolaou’s synthesis of palmerolide A provided a very flexible route to the natural product.183 It allowed the Nicolaou lab to synthesize various isomers as well as some interesting analogs thereof.206,207 In the course of their research they performed some structure-activity relationship studies (SAR) studies, identifying some structural characteristics that influence cytotoxic activity. Figure 56 provides some representative examples of the analogs developed by Nicolaou.207

131

O O

O O H H N N

O O OH OH HO HO O

O NH2 OH Palmerolide A (94) 124

O O

O O H H N N O OH O HO O O O NH 2 O NH2 125 126

O O O O 127: R = 130: R = N Me N Me N R H H S O O 131: R = OH 128: R = N N HO H H O N O O O NH2 N 129 R = N 132: R = N H H

Figure 56: Key Analogs of Palmerolide A Developed by the Nicolaou Lab.

The synthetic analogs were tested for cytostatic activity against a panel of seven different cancer cell lines, including breast (MCF-7), melanoma (UACC-62), CNS (SF268), lung (NCI-H460), ovarian (1A9), Taxol-resistant ovarian (PTX22), and epothilone-resistant ovarian (A8) cells. The synthetic compounds tested were compared to Taxol, doxorubicin, and natural palmerolide A (94). Table 6 summarizes selected data (the less informative examples have been omitted).

132

Table 6: Selected Data from Nicolaou’s SAR Study (GI50 Values in M).

Cell Line Entry Compound UACC-62 MCF-7 SF268 NCI-H460 IA9 PTX22 A8

1 doxorubicin 0.294 + 0.141 0.056 + 0.005 0.129 + 0.048 0.008 + 0.001 0.033 + 0.007 0.201 + 0.049 0.051 + 0.017

2 Taxol 0.022 + 0.016 0.006 + 0.001 0.026 + 0.141 0.007 + 0.001 0.006 + 0.001 0.079 + 0.001 0.021 + 0.015

3 natural 94 0.057 + 0.007 0.040 + 0.007 0.030 + 0.012 0.010 + 0.001 0.038 + 0.003 0.066 + 0.007 0.018 + 0.003

4 synthetic 94 0.062 + 0.001 0.065 + 0.011 0.048 + 0.006 0.017 + 0.004 0.059 + 0.001 0.073 + 0.005 0.049 + 0.004

5 ent-94 8.077 + 0.194 6.260 + 0.171 9.475 + 0.593 6.589 + 0.054 >10 >10 8.844 + 1.301

6 109 >10 >10 >10 >10 >10 >10 >10

7 124 0.322 + 0.088 0.200 + 0.026 0.281 + 0.118 0.075 + 0.003 0.288 + 0.017 0.627 + 0.016 0.083 + 0.006

8 125 6.979 + 0.531 7.585 + 0.252 8.764 + 0.315 6.396 + 0.106 7.135 + 0.667 8.062 + 0.037 6.691 + 0.439

9 126 0.063 + 0.001 0.074 + 0.000 0.060 + 0.004 0.055 + 0.002 0.072 + 0.001 0.076 + 0.000 0.061 + 0.013

10 127 >10 >10 >10 7.291 + 0.137 7.774 + 1.094 >10 6.700 + 0.411

11 128 0.641 + 0.000 0.755 + 0.004 0.592 + 0.007 0.430 + 0.047 0.618 + 0.051 0.741 + 0.003 0.460 + 0.042

12 129 0.735 + 0.084 0.796 + 0.166 0.491 + 0.132 0.078 + 0.001 0.378 + 0.141 0.889 + 0.029 0.072 + 0.004

13 130 8.822 + 0.083 7.397 + 0.262 >10 3.796 + 0.306 7.944 + 0.430 >10 3.514 + 1.379

14 131 0.009 + 0.001 0.007 + 0.000 0.007 + 0.001 0.007 + 0.001 0.009 + 0.001 0.039 + 0.002 0.006 + 0.000

15 132 0.067 + 0.000 0.071 + 0.008 0.054 + 0.000 0.061 + 0.000 0.067 + 0.002 0.081 + 0.006 0.057 + 0.001

133

Several interesting discoveries resulted from the SAR studies performed by Nicolaou and co-workers. As expected, both the synthetic palmerolide A and the natural isolate demonstrated similarly potent activities across all cell lines tested, whereas the enantiomer was more than 100-fold less active (entries 3-5). The originally proposed diastereomer (compound 109) was practically inactive (entry 6). Removal of the carbamate moiety from C11 oxygen (compound 124) provided a mild decrease in activity (ca. 5-fold, entry 7). Their results also provided evidence that the C10 hydroxyl was necessary for reactivity (entry 8, compound 125). However, the compound lacking the C7 alcohol was comparable to palmerolide A (entry 9, compound 126). The enamide side chain also had a substantial effect on the ability of the analogs to inhibit the growth of the cancer cells examined. Replacing the isobutenyl group of palmerolide A with a methyl group decreased potency by more than two orders of magnitude, but when it was replaced by an isobutyl group, the analog retained most of its activity (entries 10 and 15, respectively). Polar aromatic enamide analogs of palmerolide A (compounds 128-130) retained some activity, but perhaps most interesting was the result of analog 131; this compound was found to have a 10-fold increase in the activity against some of the cell lines (entry 14). Several other groups have developed synthetic methods towards the synthesis of various fragments of palmerolide A, envisioning similar strategies to install the stereocenters and close the macrolide as De Brabander and Nicoloau,186-188 the labs of Maier184 and Hall185 provided some interesting alternatives. The Maier group provided a convergent synthesis of the C3-C15 fragment (134) beginning with ester 133 (from -valerolactone). They utilized a Noyori asymmetric hydrogenation208 to set the C7 stereocenter, a Sharpless asymmetric dihydroxylation209 to provide the C10 and C11 oxygens, and an Ohira-Bestmann reaction210 to install the unsaturation of the C14-C15 bond. The stereocenters of fragment 135 were generated analogously to Nicolaou’s synthesis of the similar fragment.184 An olefination reaction was carried out between fragments 134 and 135 establishing the C2-C3 bond (compound 136). After having attempted an intramolecular Stille reaction which resulted in E/Z mixture of the C14-C15 olefin, the macrolactone (137) was synthesized stereoselectively through an intramolecular Heck reaction.211 Maier converted 137

134 through a series of steps into Nicolaou’s late stage intermediate (123), completing the formal synthesis of palmerolide A (Figure 57).

H 3 O O OPMB MeO2C P(OEt)2 9% over 18 steps O 19 LiCl, i-Pr2NEt, 3 7 + 20 7 OTBS MeCN CO2Me 92% TBDPSO 133 O I 15 11 O NH2 R = TBDPS 135 134

O O MeO2C MeO C O 2 O

Pd(OAc)2, CsCO3, 123 OTBS Et3N, DMF OTBS I RO 81% RO 6 steps O O (ca. 34%)

O NH2 O NH2 R = TBDPS R = TBDPS 136 136

Figure 57: Key reactions in Maier’s Formal Synthesis of Palmerolide A.

The most recent synthesis, perhaps the most elegant, provided a route to palmerolide A that incorporated asymmetric catalysis as a key feature. Hall and co- workers185 applied an asymmetric E-crotylboration that had been developed in their lab to install the C19 and C20 stereocenters. The reaction involved aldehyde 96, and was 212 catalyzed by SnCl4, using a p-F-Vivol[7] ligand (137) in 95% yield and 90% ee (>95:5 dr). The resulting alcohol (138) was then carried into their C16-C24 fragment (139) (Figure 58).

135

O Bpin OH OH t-BuO2C 20 19 H 137 SnCl4 Na2CO3, 4 A MS, toluene, -78 oC, 60 h I I 95% (>95:5 dr, 90% ee) I 94 138 139

F F

137 (R,R)-p-F-Vivol[ 7] HO OH

Figure 58: Hall’s Asymmetric Crotylboration en Route to Palmerolide A’s C16-C24 Fragment.

The synthesis of the C1-C13 fragment (146) also employed a catalytic enantioselective reaction developed in the Hall lab; a two step hetero [4+2] cycloaddition / allylboration sequence involving 140 and enol ether 141 was used to set the C7 stereocenter.213 This was followed by an esterification using acid 143 to set up an unprecedented [3+3] B-Claisen-Ireland214 rearrangement, to provide both the C10 and C11 centers with the syn-configuration; subsequent oxidation and esterification led to the formation of 145 (55%, 142  145), which was thus converted to the fragment 146 (Figure 59).

136

Bpin (a) Jacobsen's HDA O OPMB catalyst (ref. 214) HO (1 mol %), BaO, THF, 14 h; 7 143 + Bpin O 3 OEt (b) 141, 2 h 10 O OEt EDC-Cl, DMAP, CH2Cl2 84% (96% ee) OH (10 equiv) 140 141 142

1a. LDA (2.1 equiv) OTMS 7 PMBO 1c. NaOAc, H2O2, Bpin o o 10 O 3 OEt THF, -78 C; THF, 0 C, 2 h Bpin O 2. CH N O 1b.TMSCl, Et3N, 2 2 PMBO pyranyl -100 oC, 2 h; -78 oC, 12 h; i-Pr2N 55% from 142 O 144 O 3 MeO 1

OPMB MeO 7 7 11 10 O 3 OEt OTIPS O OH TIPSO 10 145 B 11 OPMB 146

Figure 59: Hall’s Unique Approach to Install the C7, C10, and C11 Stereocenters.

Hall completed the macrolide of palmerolide A through the use of a B-alkyl Suzuki coupling reaction of vinyl iodide 139 and compound 146, followed by a saponification of the methyl ester and a Yamaguchi macrolactonization. Hall’s lab then installed the enamide by analogy to De Brabander’s Curtius rearrangement,182 selectively deprotected the PMB alcohol allowing for the installation of the carbamate moiety. Palmerolide A was realized upon deprotection of the silyl ethers. Hall’s route provided an aesthetically pleasing synthesis, incorporating three very interesting reactions to set the required stereochemistry, and obtained palmerolide A in 0.8% overall yield in 21 linear steps. Palmerolide A has generated a great deal of excitement in the synthetic community. Its promising biological activity and interesting structure have inspired numerous labs to select palmerolide as a target, either as a testing ground for

137 methodology, or to provide efficient synthetic strategies for the benefit of the research community at large. The efforts described above have provided instructive tools for the synthesis of the various fragments and the core macrolide. Notably, the use of aldehyde 94 has been incorporated into each of the syntheses for the creation of the C19 and C20 stereocenters. Moreover, the synthesis of the enamide side chain has involved either a Curtius rearrangement strategy or a copper-catalyzed reaction with a vinyl iodide. The next section will provide some details of our proposed synthesis of this promising natural product and recent developments in our fragmentation methodology. This chemistry has allowed us to devise and carry out a concise synthesis of the C1- C15 fragment of palmerolide A. Although there is still much work that needs to be done before reaching our goal of the total synthesis of palmerolide A, our chemistry provides new alternatives for the methods described above and contributes valuable information to the synthetic community.

Synthesis of the Eastern Hemisphere of Palmerolide A

Since the expansion of the carbanion-triggered fragmentation reactions of vinylogous acyl triflates to alkyl Grignard reagents,93 the scope of the reaction had been increased dramatically.216,217 As discussed in Chapter 1, the bond cleavage pathway is reminiscent of the Eschenmoser-Tanabe49-52 and related Grob-type fragmentations,39-43 but with a broader scope: the Eschenmoser-Tanabe fragmentation is limited to the synthesis of alkynyl ketones and aldehydes from cyclic enones, whereas vinylogous acyl triflates allow for the synthesis of a diverse range of carbonyl derivatives (Figure 60).217 The two step process—synthesis and fragmentation of vinylogous acyl triflates— enables the conversion of symmetric 1,3-diones into acyclic, differentially functionalized building blocks.

138

O R Me RM O Me

OTf 2

NHPh Ph CH2Ph Bu

O Me O Me O Me O Me

84% 93% 73% 76%

OEt MeO OMe P S S O O Me O Me O Me O Me

21% 74% 88% (needed for this study)

Figure 60: Brief Overview of the Addition / Bond Cleavage Reactions of Vinylogous Acyl Triflate 2.

Tummatorn and Dudley recently provided access to homopropargyl alcohols from -keto lactones (heterocyclic diones) through a related process (Figure 61).218 Conversion of heterocyclic diones (147) to the corresponding 5,6-dihydro-2-pyrone (DHP) triflates (148) occurs in excellent yields using a similar procedure to that of their carbocyclic analogs. Treatment of 148 with two equivalents of methyl Grignard in toluene at -78 oC, and subsequent warming, provides good to excellent yields of the corresponding homopropargyl alcohol 148 with retention of configuration.

139

O O 1 1 1 R o R 4 OH R O Tf2O, -78 C O MeMgBr (2.0 equiv) R 4 4 3 R Et3N, CH2Cl2 R o o R 3 O 3 OTf - 78 C to 60 C R R R2 R2 R2 >90% 73% to quant. 147 148 149

Figure 61: Synthesis and Nucleophile-Triggered Decomposition of DHP Triflates.

As stated above, palmerolide A is a natural product that is ideal for convergent fragment assembly strategies. As a logical consequence, the efficient synthesis of the key fragments becomes of a priority. We envisioned the bond cleavage methodology developed in our lab as being well suited for synthesis of palmerolide A’s key fragments. Our retrosynthetic analysis includes similar initial disconnections to those of De Brabander, Nicolaou, and Maier (Figure 62). For this discussion, the focus will remain on the eastern hemisphere (C1-C15) of palmerolide A. For the synthesis of this region, we imagined our C1-C8 fragments originating from vinylogous acyl triflate 2 through a Claisen-type fragmentation reaction using a phosphonate nucleophile, setting up an olefination of aldehyde 150 to form the C8-C9 bond.

O 7 H 3 N O 3 OTf O 20 19 2 7 O 16 OH 16 HO O 15 O PO CHO 10 10 PO 20 19 OTf 11 O NH2 11 OP 15 151 Palmerolide A (94) 150

Figure 62: Retrosynthetic Analysis of Palmerolide A Using a Fragmentation Approach.

140

The Claisen-type condensation of vinylogous acyl triflates216 was initially optimized by Kamijo and Dudley using the lithium enolate of acetophenone as the nucleophile trigger. As shown in Table 7, excess enolate (2.2 equiv) was required for complete conversion (entries 1 and 2). The direct extension of this methodology to the synthesis of -keto phosphonates was performed, but the anion of dimethyl methylphosphonate provided fragmentation product 153b in yields that were not practical for complex molecule synthesis (entry 3, Kamijo and Dudley). Reoptimizing this system for the preparation of olefination reagents revealed an advantage of the phosphine oxide over the phosphonate (entries 3 and 4, this work, Jones and Dudley). In contrast to enolate nucleophiles, the addition / bond cleavage reaction of a lithiated phosphine oxide required only 1.1 equivalents of the nucleophile (entry 2 vs. entry 5).

Table 7: Claisen-Type Condensations of Vinylogous Acyl Triflate 2.

O EWG Me [EWG CH2] Li THF O Me OTf

2 153

[EWG CH ] Equiv of Yield of entry 2 Li 153 (152) 152 153 OLi 1a 1.2 153a 56% Ph OLi 2a 2.2 153a 85% Ph O a 3 Li P OMe 2.2 153b 21% OMe O b 4 Li P Ph 2.2 153c 75% Ph O b 5 Li P Ph 1.1 153c 81-89% Ph a Reproduced from reference 216. b See Experimental information.

141

Having optimized the fragmentation reaction for the synthesis of olefination reagents, we turned our attention towards the synthesis of the C1-C18 portion (155) of palmerolide A (Figure 63). Lindlar hydrogenation of 153c reduced the alkyne to afford the corresponding Z-olefin (154), which was subjected to olefin-cross metathesis35 with ethyl acrylate. The best results for our metathesis reaction were obtained using 4 mol % of the Grubbs’ second generation catalyst and a substoichiometric amount (15 mol %) of titanium(IV) isopropoxide219,220 at 100 oC in a sealed tube as a solution in methylene chloride. Ti(Oi-Pr)4 is presumed to coordinate to the -ketophosphine oxide, preventing chelation to the ruthenium metal center which may inhibit metathesis.

O H2, Me 1. Tf2O, Pyridine 95-100% Pd(CaCO3-Pb) O O MeOH/pyridine O 2. Ph2P(O)CH2Li Ph P THF, -78 to 60 oC P 96% O Ph O Ph 81-89% Ph 1 154 153c

EtO2C Ethyl Acrylate, Grubbs' II (4 mol %) O Ti(Oi-Pr) , CH Cl P 4 2 2 Ph O 100 oC, 89% Ph 155 Figure 63: Synthesis of the C1-C8 Olefination Reagent for the Synthesis of Palmerolide A.

Synthesis of aldehyde partner 150 began with a Sharpless asymmetric dihydroxylation209 of ,-unsaturated ester 156 (Figure 64).221 The syn-diol (157) was obtained in 75% yield (99.6% ee), and was subsequently converted to acetonide 158 using acetone as the solvent (the reaction did not go to completion in CH2Cl2). Controlled ester reduction using diisobutylaluminum hydride provided aldehyde 150, which was used immediately in a Horner-Wittig olefination reaction (155 + 150  161).

142

O O AD-mix-, MeSO NH , HO 2,2-dimethoxypropane OEt 2 2 OEt H O, t-BuOH (1:1), 0 oC CSA, acetone 2 OH 75% (99.6% ee) 99% 156 157

O O O O OEt DIBAL H o O CH2Cl2, -78 C O (95-100%)

158 150

Figure 64: Synthesis of Aldehyde 150, the C9-C15 Fragment of Palmerolide A.

We investigated the coupling of fragments 155 and 150 to afford the 8,9-olefin employing several different conditions commonly used to perform olefination reactions, including: Ba(OH)2, DBU•LiCl (Masamune-Roush conditions), and t-BuOK. In each case, the desired product was not observed and a mysterious byproduct was observed. Although the 1H NMR spectrum was difficult to interpret, the vinyl protons of the enoate were no longer present. This caused us to be concerned with the potential for an intramolecular Michael addition reaction of the -ketophosphine oxide onto the tethered enoate (Figure 65). A common feature of all of these bases is that each is of intermediate basicity between the initial -ketophosphine oxide anion (159) and the enolate resulting from the undesired cyclization onto the enoate (160). The conjugate acid may therefore play a role in promoting a cyclization.

143

EtO EtO2C + EtO C EtO2C "H " 2 O - Ph P BH 2 Ph P Ph2P P 2 Ph O O O O O Ph H B 159 160

155 B: = Ba(OH)2, DBU LiCl (Masamune-Roush conditions), and t-BuOK

Figure 65: Possible Michael Addition Reaction of 155.

The combination of irreversible base (NaH) and a slight excess of aldehyde 150 provided the best results for our desired olefination, affording enone 161 in 89% yield (Figure 66). Following olefination, a CBS-reduction222 of enone 161 provided the C7 alcohol in 89% yield, albeit with only modest diastereoselectivity (ca. 75:25 dr). The selectivity is surprising in light of a similar CBS-reduction for which Chandrasekhar observed 97% de.187 On the other hand, our observations are in line with the 4:1 dr reported by De Brabander for the CBS-reduction at the C7 position of a macrocyclic precursor to palmerolide A.182 The stereoselective reduction of the C7 ketone remains an open challenge as we continue with our studies. TBS-protection of 162 under standard conditions furnished our C1-C15 fragment (163) of palmerolide A that will be utilized en route to the natural product.

EtO2C EtO2C

NaH (1.0 equiv) 1. (R)-CBS, THF THF, 0 oC; 89% (ca. 75:25 dr) 155 OR Then 150 (1.5 equiv), O 2. TBSOTf, 2,6-Lutidine O 0 oC to r.t., 89% O CH2Cl2, 94%

O O

161 162: R = H 163: R = TBS

Figure 66: Completion of the Eastern Hemisphere (C1-C15) Fragment Synthesis.

144

In summary, we have prepared 163, which comprises the eastern hemisphere (C1-C15) of palmerolide A, in 7 linear steps (approximately 42% overall yield) from unsymmetrical dione 1. The optimized addition / bond cleavage reaction (2  153c) provides efficient entry into a comparatively short synthesis of a C1-C8 olefination reagent for the convergent coupling with aldehyde 150. Aldehyde 150 is prepared in three steps and >99% ee from ester 156.221 This sequence highlights yet another example of the versatility of vinylogous acyl triflates in complex molecule synthesis, and demonstrates a marked improvement over our previously published Claisen-type condensations of 2.216 Chapter 5 will provide mechanistic insight into similar Claisen- type condensation reactions, as well as additional interesting olefination reagents.

Experimental

General information: 1 13 H NMR and C NMR spectra were recorded on a 300 MHz spectrometer using CDCl3 as the deuterated solvent. The chemical shifts () are reported in parts per million (ppm) 1 13 relative to the residual CHCl3 peak (7.26 ppm for H NMR and 77.0 ppm for C NMR) for all compounds. The coupling constants (J) are reported in Hertz (Hz). IR spectra were recorded on a Perkin-Elmer FT-IR spectrometer with diamond ATR accessory as thin film. Mass spectra were recorded using chemical ionization (CI), electron ionization (EI), or electrospray ionization (ESI). Melting points were taken on a MEL-TEMP melting point apparatus and are uncorrected. All optical rotation data was recorded at 25 oC on a Jasco P-2000 polarimeter with a 100 mm cell (concentration reported as g/100mL). Yields refer to isolated material judged to be ≥ 95% pure by 1H NMR spectroscopy following silica gel chromatography. All chemical were used as received unless otherwise stated. All solvents, solutions and liquid reagents were added via syringe. Tetrahydrofuran (THF) was purified by distillation over sodium and benzophenone.

Methylene chloride (CH2Cl2) was distilled from calcium hydride (CaH2). The n-BuLi solutions were titrated against a known amount menthol dissolved in tetrahydrofuran using 1,10-phenanthroline as the indicator. All reactions were carried out under an inert

145 nitrogen atmosphere unless otherwise stated. The purifications were performed by flash chromatography using silica gel F-254 (230-499 mesh particle size).

(2-Oxo-oct-6-ynyl)-diphenylphosphine oxide (153c): To a stirred solution of methyldiphenylphosphine oxide (201 mg, 0.92 mmol) in THF (50 mL) at –78 oC, was added n-BuLi (0.34 mL, 0.85 mmol), as a 2.5 M solution in hexane, dropwise. The reaction mixture was allowed to stir at –78 oC for 45 min, at which time vinylogous acyl triflate (VAT) 261 (200 mg, 0.77 mmol) was added dropwise. The reaction mixture was stirred at –78 oC for 15 min, 0 oC for 15 min, and finally room temperature for 45 min. The reaction mixture was quenched with a half-saturated aqueous solution of ammonium chloride. The product was extracted with CH2Cl2 (3 x 25 mL). The combined extracts were washed with sat. NaHCO3, sat. brine, and were dried with MgSO4. The dried organic solution was concentrated and purified by flash chromatography on silica gel (60% EtOAc/Hexanes) to give 225 mg (89%) of alkyne 153c as a white solid: mp = o 1 84 – 85 C; H NMR (300 MHz, CDCl3)  7.82 – 7.69 (m, 4H), 7.60 – 7.43 (m, 6H), 3.60 (d, J = 15.0, 2H), 2.76 (t, J = 7.0, 2H), 2.06 (tq, J = 7.0, 2.5, 2H), 1.74 (t, J = 2.5, 3H), 13 1.65 (quintet, J = 7.0, 2H); C NMR (75 MHz, CDCl3)  202.27, 132.03, 131.84 (d, J = 101.9), 130.71 (d, J = 9.8), 128.56 (d, J = 12.3), 78.03, 76.07, 46.94 (d, J = 56.9), 43.97, 22.48, 17.69, 3.28; IR (thin film) 1978, 1708, 1484, 1438, 1192 cm–1; HRMS (EI): Calcd + + for C20H21O2P [M ] 324.1279, found 324.1279.

((Z)-2-Oxo-oct-6-ene)-diphenylphosphine oxide (154): Palladium, 5 wt. % on calcium carbonate, poisoned with lead (820 mg) was stirred in methanol/pyridine (4:1, 50 mL), under an atmosphere of hydrogen. After 30 min, a solution of alkyne 153c (2.00 g, 6.17 mmol) in MeOH (2 mL) was added in one shot to the stirred palladium solution. The solution was stirred for 45 min. The reaction mixture was filtered through a pad of

Celite™ and the pad was washed with CH2Cl2 ~15 mL). The filtrate was concentrated and purified on silica gel by flash chromatography (50% EtOAc/Hexane) to afford 1.93 g (96%) of the product 154, containing the Z-olefin as a white solid: mp = 64 – 66 oC; 1H

NMR (300 MHz, CDCl3)  7.83 – 7.68 (m, 4H), 7.61 – 7.42 (m, 6H), 5.50 – 5.35 (m, 1H), 5.32 – 5.19 (m, 1H), 3.59 (d, J = 15.0, 2H), 2.65 (t, J = 7.2, 2H), 1.94 (q, J = 7.2, 2H),

146

13 1.60 – 1.49 (m, 5H); C NMR (75 MHz, CDCl3)  202.91, 132.19, 132.09 (d, J = 102.4), 130.91 (d, J = 9.8), 129.56, 128.73 (d, J = 12.3), 124.65, 47.15 (d, J = 56.6), 44.74, 25.90, 23.14, 12.74; IR (thin film) 1708, 1438, 1193, 1120 cm–1; HRMS (ESI): Calcd for + + C20H23O2PNa [M+Na ] 349.1333, found 349.1327.

((E)-ethyl-2-Oxo-oct-6-enoate)-diphenylphosphine oxide (155): To a solution of olefin 154 (1.00g, 3.06 mmol) and ethyl acrylate (1.33 mL, 12.24 mmol) in CH2Cl2 (30 mL) was added freshly distilled Ti(Oi-Pr)4 (120 L, 0.46 mmol), followed by Grubbs’ second generation catalyst (76 mg, 0.09 mmol). The reaction vessel was sealed with a Teflon screw-top with a rubber seal. The reaction mixture was placed in an oil bath heated to 100 oC and stirred for 20 min. The solution was cooled to room temperature and a second aliquot of Grubbs’ II catalyst was added (25 mg, 0.03 mmol). The reaction mixture was stirred and re-heated to 100 oC; after 10 min, it was cooled to room temp. and filtered through Celite™ and washed with CH2Cl2 (10 mL). The filtrate was concentrated and purified on silica gel by flash chromatography (60% EtOAc/Hexane, 80% EtOAc/Hexane) to provide 1.03 g (87%) of Horner-Wittig reagent 155 as a white o 1 solid: mp = 79 – 81 C; H NMR (300 MHz, CDCl3)  7.82 – 7.68 (m, 4H), 7.62 – 7.42 (m, 6H), 6.84 (dt, J = 15.7, 6.9, 1H), 5.75 (d, J = 15.6, 1H), 4.17 (q, J = 7.1, 2H), 3.58 (d, J = 14.9, 2H), 2.69 (t, J = 7.1, 2H), 2.09 (app. quartet, J = 6.6, 2H), 1.65 (quintet, J = 13 7.1, 2H), 1.28 (t, J = 7.1, 3H); C NMR (75 MHz, CDCl3)  202.19, 166.41, 147.94, 132.25, 131.90 (d, J = 102.4), 130.83 (d, J = 9.8), 128.74 (d, J = 12.3), 121.81, 60.09, 47.13 (d, J = 55.2), 44.30, 31.02, 21.48, 14.22; IR (thin film) 1709, 1653, 1438, 1187 cm- 1 + + ; HRMS (EI): Calcd for C22H25O4P [M ] 284.1490, found 384.1490.

(2R,3S)-2,3-dihydroxy-hept-6-ynoic ethyl ester (157). AD-mix-(30g, 1.6 g/mmol of olefin) and MeSO2NH2 (1.75g, 18.4mmol) were stirred in t-BuOH/H2O (1:1, 100 mL) at 0 oC for 1 hr. To the stirred heterogeneous solution was added a solution of the known compound 156,221 (E)--hept-2-en-6-ynoic ethyl ester (2.8 g, 18.4 mmol), in 24 mL of t- o BuOH/H2O (1:1) in one shot. The reaction mixture was stirred at 0 C for 24 h. To the o solution was added Na2SO3 (13.4 g, 106.7 mmol) at 0 C and stirred for an additional hour. The reaction mixture was diluted with CH2Cl2 (100 mL) and H2O (50 mL). Product

147 extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were washed with a saturated brine solution (150 mL), dried with Na2SO4, and concentrated under reduced pressure. The resulting oil was purified by flash chromatography on silica gel using 30% EtOAc/Hexanes to afford 2.57 g of diol 157 (75%, 99.6% ee as determined via chiral HPLC on a chiracel OD column after converting the diol to the dibenzoyl ester,223 using 2% isopropanol/hexanes as the eluent at a flow rate of 1.00 mL/hr; retention times (in o 25 minutes) of 79:30 (major) and 70.28 (minor)) as a white solid: mp = 50 - 51 C; []D = - o 1 31.7 (c = 6.7, CH2Cl2); H NMR (300 MHz, CDCl3)  4.31 (q, J = 7.1, 2H), 4.09 (d, J = 4.9, 1H), 4.06 (d, J = 6.3, 1H), 3.07 (d, J = 5.1, 1H), 2.39 (dt, J = 9.0, 2.7, 2H), 2.03 (d, J = 9.3, 1H), 2.00 (t, J = 2.7, 1H), 1.94 – 1.75 (m, 2H), 1.33 (t, J = 7.1, 3H); 13C NMR (75

MHz, CDCl3)  173.22, 83.47, 73.23, 71.15, 68.95, 62.05, 32.17, 14.83, 14.04; IR (thin -1 + film) 3444, 3291, 2111, 1732, 1214, 1118 cm ; HRMS (ESI): Calcd for C9H14O4Na [M+Na+] 209.0790, found 209.0796.

(4R,5S)-5-(3-butynyl)-2,2-dimethyl-[1,3]-dioxolane-4-carboxylic acid ethyl ester (158). To a stirred solution of diol 157 (500 mg, 2.68 mmol) in 10 mL acetone (HPLC grade) was added 2,2-dimethoxypropane (0.4 mL, 3.22 mmol) followed by camphor-10- sulfonic acid (CSA) (30 mg, 0.13 mmol). The solution was stirred for 24 hr at room temperature. The reaction was diluted with CH2Cl2 (10 mL) and then quenched with saturated NaHCO3 (20 mL). The product was extracted with CH2Cl2 (3 x 15 mL). The combined organic layers were washed with a saturated brine solution, dried with

MgSO4, and concentrated. The resulting oil was purified by flash chromatography on 25 silica gel (10% EtOAc/Hexanes) to afford 603 mg (>95%) of acetonide 158: []D = - o 1 23.5 (c = 4.5, CH2Cl2); H NMR (300 MHz, CDCl3)  4.30-4.20 (m, 3H), 4.16 (d, J = 7.6, 1H), 2.49 – 2.26 (m, 2H), 2.10 – 1.82 (m, 3H), 1.46 (s, 3H), 1.45 (s, 3H), 1.31 (t, J = 7.1, 13 3H); C NMR (75 MHz, CDCl3)  170.53, 110.98, 83.08, 78.71, 77.55, 68.86, 61.36, 32.47, 27.07, 25.61, 14.94, 14.12; IR (thin film) 3283, 2115, 1757, 1732, 1096 cm-1; + + HRMS (CI): Calcd for C12H19O4 [M ] 227.1283, found 227.1285.

(4R,5S)-5-(3-butynyl)-2,2-dimethyl-[1,3]-dioxolane-4-carboxaldehye (150). To a o solution of ethyl ester 158 (600 mg, 2.68 mmol) in CH2Cl2 (20 mL) at –78 C was added

148

DIBAL (4.02 mL), as a 1.0M solution in toluene, dropwise. The reaction mixture was allowed to stir at –78 oC for 1 hr. To the stirred solution was added 20 mL of a saturated aqueous solution of sodium, potassium tartrate and 1 mL of methanol dropwise at –78 oC. The reaction mixture was warmed to room temperature and stirred for approximately

2 hrs until the biphasic solution became clear. The product was extracted with Et2O (3 x

10 mL). The combined organic layers were dried with Na2SO4 and concentrated. The resulting oil was filtered through a plug of silica gel (10% EtOAc/Hex). The filtrate was concentrated, leaving 480 mg of a clear oil (>95% crude yield). The crude oil was then used immediately in the next reaction.

Horner-Wittig reaction to provide enone 161: To a solution of NaH, 60 wt. % in mineral oil, (70 mg, 1.75 mmol) in THF (15 mL) at 0 oC was added Horner-Wittig reagent 155 (673 mg, 1.75 mmol) at once. Upon stirring for 45min at 0 oC, aldehyde 150 (480 mg, 2.63 mmol) in 5 mL of THF was added in one shot. The reaction solution was subsequently stirred at 0 oC for 5 min (white ppt. began to form), and was warmed and stirred at room temperature for 1 hr. The reaction mixture was then diluted with Et2O (10 mL) and quenched with ½ sat. NH4Cl (20 mL). The product was extracted with Et2O (3 x

10 mL). The combined extracts were washed with sat. NaHCO3 (20 mL) followed by a wash with sat. brine (20 mL). The organics were dried with MgSO4 and concentrated. The crude yellowish oil was purified via flash chromatography on silica gel (10% EtOAc/Hexanes to 20% EtOAc/Hexane) to afford 540 mg (89%) of enone 161 as a clear 25 o 1 oil: []D = -12.5 (c = 3.9, CH2Cl2); H NMR (300 MHz, CDCl3)  6.93 (dt, J = 15.6, 6.9, 1H), 6.72 (dd, J = 15.8, 5.8, 1H), 6.37 (dd, J = 15.8, 1.3, 1H), 5.83 (dt, J = 15.6, 1.5, 1H), 4.26 – 4.12 (m, 3H), 3.87 (dt, J = 5.1, 4.8, 1H), 2.60 (t, J = 7.3, 2H), 2.47 – 2.28 (m, 2H), 2.28 – 2.18 (m, 2H), 1.98 (t, J = 2.5, 1H), 1.88 – 1.74 (m, 4H), 1.43 (s, 1H), 1.42 (s, 13 1H), 1.29 (t, J = 7.1, 3H); C NMR (75 MHz, CDCl3)  198.87, 166.40, 147.87, 141.28, 130.44, 122.02, 109.64, 83.06, 79.89, 78.96, 69.07, 60.14, 39.63, 31.24, 30.81, 27.12, 26.65, 21.92, 15.06, 14.18; IR (thin film) 3275, 1714, 1677, 1651, 1371 cm-1; HRMS + + (ESI): Calcd for C20H28O5Na [M+Na ] 371.1834, found 371.1830. (R)-CBS reduction to afford C7-alcohol (162): To a stirred solution enone 161 (200 mg, 0.57 mmol) in THF (50 mL) at -40 oC was added (R)-2-methyl-CBS-oxazaborolidine

149

(1.71 mL, 1.71 mmol), 1.0 M in toluene, dropwise. The reaction mixture was stirred for 30 min at –40 oC, at which time, borane-THF complex (1.14 mL, 1.14 mmol), 1.0 M in THF, was added dropwise. The solution was allowed to stir for an additional 45 min at – o o 40 C. The reaction was quenched with Et2O/MeOH (51 mL, 50:1) at –40 C, this was followed by a sat. NaHCO3 solution (80 mL) once the solution reached room temperature. The product was extracted with CH2Cl2 (3 x 35 mL), the organic layers were combined, washed with a sat. brine solution (100 mL) and dried with Na2SO4. The volatiles were evaporated and the crude oil purified by flash chromatography on silica gel (20% EtOAc/Hexane) to give 178 mg (89%) of allylic alcohol 162 as a mixture of diastereomers (3.2:1), resolved by chiral HPLC on a chiracel OD column with retention times (in minutes) of 17:02 (major) and 20:28 (minor) using 12 % isopropanol/hexanes 25 o as the eluent at a flow rate of 0.5mL/hr; isolated as a clear oil: []D = -4.9 (c = 4.2, 1 CH2Cl2); H NMR (300 MHz, CDCl3)  6.94 (dt, J = 15.6, 6.9, 1H), 5.91 – 5.77 (m, 2H), 5.67 (dd, J = 15.5, 7.5, 1H), 4.23 – 4.12 (m, 3H), 4.10 – 3.99 (m, 1H), 3.79 (dt, J = 7.1, 6.2, 1H), 2.44 – 2.28 (m, 2H), 2.28 – 2.16 (m, 2H), 1.97 (t, J = 2.6, 1H), 1.82 – 1.71 (m, 13 2H), 1.61-1.49 (m, 5H), 1.41 (s, 6H), 1.28 (t, J = 7.1, 3H); C NMR (75 MHz, CDCl3) 166.54, 148.59, 137.88, 126.96, 121.54, 108.70, 83.42, 81.25, 79.07, 71.35, 68.81, 60.08, 36.23, 31.84, 30.65, 27.10, 26.85, 23.69, 15.11, 14.15; IR (thin film) 3452, 3292, -1 + + 2115, 1714, 1370 cm ; HRMS (ESI): Calcd for C20H30O5Na [M+Na ] 373.1991, found 373.1984. t-Butyldimethylsilyl Ether 163: To a stirred solution of alcohol 162, resulting from the o CBS-reduction, (100 mg, 0.28 mmol) in CH2Cl2 (40 mL) at –78 C was added 2,6- lutidine (190 L, 1.68 mmol), followed by the dropwise addition of TBSOTf (190 L, 0.84 mmol). The reaction mixture was stirred at –78 oC for 30min. The reaction was o quenched with 20 mL of a saturated aqueous solution of NaHCO3 at –78 C. The heterogeneous mixture was warmed to room temperature and stirred for 10 min. The product was extracted with CH2Cl2 (3 x 15 mL). The combined organics were washed with brine (40 mL), dried with Na2SO4, and concentrated. The crude oil was purified by flash chromatography on silica gel (5% EtOAc/Hexanes) to give 122 mg (94%) of a 25 o 1 clear colorless oil, compound 163: []D = -10.2 (c = 4.1, CH2Cl2); H NMR (300 MHz,

150

CDCl3)  6.93 (dt, J = 15.5, 6.9 Hz, 1H), 5.86 – 5.69 (m, 2H), 5.56 (dd, J = 15.5, 7.4 Hz, 1H), 4.23 – 4.10 (m, 3H), 4.03 (t, J = 7.9 Hz, 1H), 3.78 (dt, J = 7.9, 4.0 Hz, 1H), 2.44 – 2.24 (m, 2H), 2.19 (q, J = 6.6, 2H), 1.95 (t, J = 2.4 Hz, 1H), 1.83 – 1.67 (m, 2H), 1.54 – 1.43 (m, 4H), 1.40 (s, 6H), 1.29 (t, J = 7.1, 3H), 0.89 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13 C NMR (75 MHz, CDCl3) 166.63, 148.85, 138.23, 126.61, 121.49, 108.73, 83.45, 81.40, 79.19, 72.33, 68.71, 60.11, 37.41, 32.08, 30.88, 27.20, 26.91, 25.83, 23.53, 18.17, 15.25, 14.25, -4.28, -4.76; IR (thin film) 3312, 2115, 1720, 1654, 1252 cm-1; + + HRMS (ESI): Calcd for C26H44O5SiNa [M+Na ] 487.2886, found 487.2855.

151

HPLC data for dihydroxylation of 156:

Det 166 dmj-III273px2

0.15 0.15

0.10 0.10 AU AU

0.05 0.05

0.00 0.00

154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 Minutes

Chiracel OD Column: (Standardized using products of both AD-mix- and AD-mix- dihydroxylations followed by dibenzoylation of the resulting diol).

Eluent = 2 % isopropanol/hexanes Flow rate = 1.00 mL/hr Detector wavelength = 240 nm Injection time = 84.67 min

2S,3R peak elution = 155.14 min 2R,3S peak elution = 164.16 min 2S,3R peak retention = 70:28 min 2R,3S peak retention = 79:30 min 2S,3R peak area = 45144 2R,3S peak area = 23068392 2S,3R peak % area = 0.03 2R,3S peak % area = 17.93

2S,3R : 2R,3S = 1 : 511 2R,3S = 99.6 % ee

152

HPLC data for CBS-reduction of 161:

Det 166 dmj-III250x2

0.25 0.25

0.20 0.20

0.15 0.15 AU AU

0.10 0.10

0.05 0.05

0.00 0.00

228 229 230 231 232 233 234 235 236 237 Minutes Chiracel OD Column: (Standardized using products of both (R)-CBS and (S)-CBS catalyzed reductions).

Eluent = 12 % isopropanol/hexanes Flow rate = 0.5 mL/hr Detector wavelength = 225 nm Injection time = 214.58 min

7S peak elution = 231.617 min 7R peak elution = 235.042 min 7S peak retention = 17:02 min 7R peak retention = 20:28 min 7S peak area = 10864911 7R peak area = 3371974 7S peak % area = 5.46 7R peak % area = 1.70

7S : 7R = 3.22 : 1

153

1H NMR and 13C NMR spectra:

O P Ph O Ph 153c

154

O P Ph O Ph 153c

155

O P Ph O Ph 154

156

O P Ph O Ph 154

157

EtO2C

O P Ph O Ph 155

158

EtO2C

O P Ph O Ph 155

159

O HO OEt

157

160

O HO OEt

157

161

O O OEt

158

162

O O OEt

158

163

EtO2C

O O

161

164

EtO2C

O O

161

165

EtO2C

OH O

162

166

EtO2C

OH O

162

167

EtO2C

OTBS O

163

168

EtO2C

OTBS O

163

169

CHAPTER 5

RE-EXPLORING THE CLAISEN-TYPE CONDENSATIONS OF VINYLOGOUS ACYL TRIFLATES

New Insights into the Mechanism

First reported in 1887,224 the Claisen condensation plays an important role in synthetic organic chemistry.225-228 The Claisen condensation involves the enolate of an ester undergoing a reversible nucleophilic addition / elimination reaction with another equivalent of ester in the presence of excess base. The reaction is driven to completion due to the irreversible deprotonation of the resulting -ketoester (Figure 67).

O O O O M additionO M O elimination OEt OEt OEt OEt EtO H

EtO M irreversible M + O O deprotonation O O "H3O " OEt OEt

EtOH Figure 67: Mechanism of the Classical Claisen Condensation of Ethyl Acetate.

As presented in previous chapters, our lab has been interested in the preparation of alkynyl ketones using the tandem addition / C-C bond cleavage reaction of vinylogous acyl triflates (VATs).61,93,216,217 This reaction was applied to the synthesis of an important moth pheromone natural product (Chapter 2)93 and provided access to substituted benzo-fused indanes (Chapter 3). The two-step conversion of cyclic diones to tethered alkynyl ketones has been shown to be general, affording a wide variety of differentially functionalized substrates.

170

Kamijo and Dudley were the first to examine the Claisen-type condensations of VATs. They provided insight into the mechanism of the reaction between the lithium enolate of acetophenone (152a) and VAT 2 (Figure 68).216 The stoichiometry played a pivotal role in the ability of the reaction to proceed to completion. Like the classical Claisen condensation, more than 2 equivalents of base (enolate) are needed to convert the starting material effectively to product. According to their postulated mechanism, the 1,2-addition of the enolate to VAT 2 proceeds reversibly, leading to intermediate 164. At elevated temperatures the fragmentation takes place, providing 1,3-diketone 153a. However, because the enolate addition is reversible, once 153a is formed, another equivalent of enolate (152a) deprotonates the -ketoester product. Thus, at least 2 equivalents of enolate are required for this reaction, one to undergo the addition and another for deprotonation.

OLi Ph O Ph O Li Ph 152a O O  O OTf -LiOTf OTf 2 164 153a

OLi Ph Ph Ph + O "H3O " O Li O O O Ph 165 153a

Figure 68: Proposed Mechanism for the Reaction Between 2 and 152a.

With this mechanistic model in mind, the investigation into the Claisen-type condensation reactions of VATs was carried out using the same protocol. Most of the nucleophiles examined in this reaction gave satisfactory results (Figure 69).216 The worst nucleophile in the series happened to be the anion of dimethyl

171 methylphosphonate, which gives rise to a potentially useful -ketophosphonate adduct (153b).

O [EWG-CH2] Li EWG (2.2 equiv) O THF OTf -78 oC to 60 oC 2 153 153b Ph Me OEt Me OMe MeO S O P O O O O O O O O O O

85% 42% 88% 53% 21%

Kamijo and Dudley, Org Lett. 2006, 8, 175-177

Figure 69: Reported Claisen-Type Condensation Reactions of VAT 2.

In 2007, our lab became interested in the synthesis of palmerolide A.175 Our synthetic plan called for the application of a tandem addition / C-C bond cleavage adduct similar to 153b. In order for this to be practical, the Claisen-type condensation reaction had to be a re-optimized for the synthesis of olefinating reagents similar to 153b. Changing the nucleophile from the lithium anion of dimethyl methylphosphonate to the lithium anion of methyldiphenylphosphine oxide (152c) afforded Horner-Wittig reagent 153c in the 70% yield range. Upon further optimization, we found that only 1.1 equivalents of the phosphine oxide nucleophile were necessary to convert VAT 2 effectively to the corresponding product 153c (Figure 70). This optimization culminated in the synthesis of the C1-C15 fragment of palmerolide A (Chapter 4).

172

Ph O Ph P O O Ph P Li Ph 152c O OTf THF -78 oC to 60 oC 2 153c 2.2 equiv of 152c = 69 - 75% 1.1 equiv of 152c = 81 -89%

Figure 70: Observations Made During the Synthesis of the C1-C15 Fragment of Palmerolide A (Chapter 4).

The ability to decrease the loading of the phosphine oxide nucleophile provided impetus for us to re-open the investigation into the Claisen-type condensation reactions of vinylogous acyl triflates. We initially hypothesized that the reactivity of the nucleophile has an important role in the reversibility of the addition step in the proposed mechanism. We postulated that if the reactivity of the nucleophile were sufficiently high, the reversibility of the initial addition step would be reduced. In addition, if the fragmentation step was significantly faster than that of the retro-addition, the concentration of the nucleophile (base) would be limited and would thus allow for the accumulation of fragmentation product. The pKa’s of some related pre-nucleophiles may provide insight into the relative reactivity of their corresponding anions in the addition / fragmentation reaction (Table 8).229 The data presented in Table 8 demonstrates the similarities in acidity between phosphonates and phosphine oxides as well as their significant difference compared to the acidity of the acetophenone derivatives. If the elevated pKa’s of phosphine oxides are representative of their relative reactivity, then the enhanced reactivity of the nucleophile might be responsible for the ability to lower the number of equivalents added.

173

Table 8: Comparison of the Acidities of Several Acetophenone, Phosphonate, and Phosphine Oxide Derivatives in DMSO.a

pKa

R O O O R EtO P R Ph P R Ph EtO Ph H 24.7 N/A N/A Ph 17.7 27.6 N/A CN 10.2 16.4 16.9 SPh 16.9 N/A 24.9 a pKa’s obtained from data presented in ref. 228.

To reiterate our previous observations, the Claisen-type ring opening of VAT 2 with the lithium enolate of acetophenone requires 2 equivalents of enolate, whereas the similar reaction involving the lithium anion of methyldiphenylphosphine oxide is best accomplished with 1 equivalent of the stabilized nucleophile. Having optimized the Claisen-type condensation of VATs for the acetophenone enolate (152a, Figure 68) and the anion of methyldiphenylphosphine oxide (152c, Figure 70), the next logical experiment to include in our new investigation was the addition of 1.1 equivalents of the enolate of ethyl acetate (166). Ethyl acetate was one of the best pre-nucleophiles in our earlier study, and it is intermediate in acidity between acetophenone and methyldiphenylphosphine (pKa of ethyl acetate in DMSO = 29.5).230 The reaction involving the enolate of ethyl acetate provided valuable data. When 1.1 equivalents of 166 were added to VAT 2, the desired fragmentation product (168) was obtained in 56% yield (Figure 71). This result was in line with our previous observation using 1.2 equiv. of the acetophenone enolate (152a) (56% yield).216 In this case, however, a previously unobserved byproduct was isolated (ca. 26% yield). We believe that the structure of this byproduct is that of alcohol 170. This byproduct proved to be unstable even at low temperatures (-15 oC). However, when immediately dissolved in THF, treated with excess NaH (approximately 3 equivalents) and heated to

174

60 oC for 30 min, this byproduct gave rise to the fragmentation product 168 in 78% yield, which provides support for our proposed structure (170). A revised mechanistic hypothesis is needed to account for the formation of - hydroxy ester 170. We envision an effectively irreversible addition of enolate 166 to VAT 2 to provide aldolate 167. In contrast to reactions using acetophenone, the retro-aldol of 167 (167  2) does not figure prominently in our observations. Intermediate 167 begins to undergo fragmentation upon warming, providing -ketoester 168. Subsequent deprotonation of the -ketoester by the alkoxide, not the enolate, occurs. Thus, two equivalents of base are still required for compete conversion of VAT 2 to 168. Although the isolation of byproduct 170 provides evidence for the proposed reaction pathway, a competing deprotonation of the -ketoester by the enolate resulting from a retro-addition cannot be ruled out.

OLi EtO O OEt O Li OEt 166 O O  O OTf OTf 2 167 168 EtO O Li O OEt OEt 167 + OTf O "H3O " O Li O 56% O

168 169 ca. 26% isolated EtO O separately treated with OH excess NaH proposed structure of THF, 78% isolated byproduct OTf 170

Figure 71: Proposed Fragmentation Reaction Pathway Between 2 and 166.

175

This new byproduct, tentatively assigned as 170, provided a more defined understanding of the reaction pathway, which enabled us to reconsider the reaction between phosphine oxide nucleophile 152c and vinylogous acyl triflates (Figure 72). We propose that the anion adds irreversibly at cold temperatures and the resulting oxy- anion coordinates to the phosphine oxide to provide intermediate 171. This intermediate is envisioned to resemble an oxaphosphetane intermediate, much like that formed during a Wittig olefination reaction.231-233 Such an intermediate would reduce the oxy- anion’s ability to deprotonate the -ketophosphine oxide product, and would reduce the possibility of a retro-addition, thus allowing for the use of one equivalent of nucleophile to consume the starting material. When the reaction mixture is subsequently warmed, the postulated oxaphosphetane-like intermediate collapses and provides the fragmentation product 153c, instead of undergoing the classical—retro-[2+2]— olefination reaction to provide 172 (not observed).

O O Ph O P Li Ph Li Ph Ph P Ph Ph P 152c O O  O OTf

2 171 153c

X (not observed) O _ P OTf Ph OLi Ph 172

Figure 72: Proposed Mechanism of the Reaction Between VAT 2 and 152c.

The results of the Claisen-type condensation reactions of VAT 2 and the various stabilized anions (cf. 152a, 152c, and 166) have provided us with a better understanding of their reaction mechanisms. Although it is not necessarily the reactivity of the nucleophile that determines the ability to use fewer equivalents, the isolation of

176 the alcohol intermediate 170 was very informative as to the intermediates involved in these reactions. The more detailed study of these reactions allowed for the expansion of the methodology to the synthesis of -ketophosphonates. -Ketophosphonates provide reactivity similar to -ketophosphine oxides (both are olefinating reagents), but the phosphonates provide some distinct advantages; they are cheaper, more widely available, and easier to work with than their phosphine oxide analogs. The next section addresses the conversion of VATs to novel phosphonate-based olefinating reagents.

Synthesis of -Ketophosphonates

The use of phosphonates in organic chemistry has revolutionized the synthesis of alkenes.231-244 The ability to generate E- and Z- alkenes selectively, the mild conditions required for reaction, and the ease of their synthesis provides the distinct advantages of phosphonates as olefination reagents over their phosphorane (Wittig reagents) or phosphine oxide (Horner-Wittig) counterparts. Common methods for the synthesis of phosphonates have relied on a two general strategies (Figure 73): (1) the Arbuzov reaction,245,246 which involves the alkylation of the corresponding trialkyl phosphite to prepare alkyl-, benzyl-, and allylphosphonates as well as phosphonate esters; or (2) a Claisen-type condensation between esters and a dialkyl methylphosphonates to prepare -ketophosphonates.247-251 Synthesis of - ketophosphonates using the Arbuzov reaction is also known, but one must recognize the potential for the competing Perkow reaction, which gives rise to enol phosphates.245

177

(1) Arbuzov Reaction

1 X OR1 2 OR O R H2CX R1O P 1 P R2 1 P 1 2 R O R O OR  R1O CH2R -R1X R1O

Trialkyl Phosphite Dialkyl Alkylphosphonate

R1 = 1o Alkyl R2 = Alkyl, Vinyl, Aryl, Ester

(2) Claisen-Type Condensation Reaction

O O O 1. Base, -78 oC 1 P 1 P R O Me R O R2 R1O O R1O 2. R2 OR3, -78 oC to r.t.

Base = n-BuLi, LDA, LiHMDS

Figure 73: Common Methods for the Preparation of Phosphonates.

The synthesis of -ketophosphonates was of particular interest to us. Having obtained a poor yield (21%) of phosphonate product 153c upon treating VAT 2 with 2.2 equivalents of dimethyl lithiomethylphosphonate (152b) under our original conditions,216 we were interested to determine if the conditions optimized for the lithiomethyldiphenylphosphine oxide (152c) nucleophile would provide increased yields of the -ketophosphonates. The use of lithiomethyldiphenylphosphine oxide as the nucleophile trigger provided excellent yields (up to 89%). However, the use of phosphonates for alkene synthesis is much more common.231,238,241 What’s more, the use of dimethyl methylphosphonate has a distinct advantage for large scale synthesis, its cost is far lower than that of methyldiphenylphosphine oxide (ca. 66 mmol / $1 vs. 1 mmol / $1, respectively).94 Table 9 summarizes the data resulting from the Claisen-type addition / bond cleavage reactions of various VATs and 1.1 equiv. of dimethyl lithiomethylphosphonate.

178

The reaction between VAT 2 and 1.1 equiv. of 152b proceeded in excellent yield (entry 1). This result was nearly a 5-fold increase compared to our previous report, in which 2.2 equivalents of nucleophile were used.216 VAT 173, which is similar to 2, but lacks the -methyl substituent, provided a messy reaction. Although the product was present in the 1H NMR spectrum, it could not be obtained in acceptable purity (entry 2). The vinylogous acyl triflates derived from dimedone and 1,3-cycloheptanedione (175 and 177, respectively) both provided their respective phosphonate products, 176 and 177, in acceptable yields. Interestingly, in the case of 175, an unstable byproduct was isolated (ca. 4%), whose 1H NMR spectrum is consistent with diene 179. Such a byproduct would support our proposed oxaphosphetane-like intermediate (cf. structure 171).

179

Table 9: Reactions of Vinylogous Acyl Triflates with 1.1 Equivalents of Dimethyl Lithiomethylphosphonate (152b).a

Entry VAT Product Yield, %b

MeO OMe O P O

1 O 97 OTf 2 153b MeO OMe O P O c 2 O — OTf 173 174 MeO OMe O P O d 3 O 41 OTf 175 176 MeO OMe O P O e 4 O 78 OTf 177 178 a Triflate (0.5 mmol) reacted with nucleophile (0.55 mmol, generated from 0.6 mmol of dimethyl methylphosphonate and 0.55 mmol n-BuLi) at -78 oC to 60 oC over 80 min. b Isolated yields. c Product detected by 1H NMR, however not obtained in acceptable purity, all attempts to purify failed. d Obtained a byproduct proposed to be diene 179. e decomposition of 177 was observed after purification and had to be used immediately.

O MeO P Li MeO OTf 152b 179

Vinylogous acyl triflates 173, 175, and 177, which lack the -methyl substituent, are relatively unstable when compared to their analog, VAT 2. Vinylogous acyl triflate 2 can be stored under an inert atmosphere for several months at -10 oC without any

180 observable decomposition by 1H NMR spectroscopy, whereas VATs 173 and 174 begin to discolor after 1 to 2 days. VAT 177 is even less stable; it began to decompose upon removal of solvent and had to be used immediately. In addition, 1,3-cycloheptanedione, the precursor to VAT 177, is extremely cost prohibitive (1 gram / $264.50, approximately 30 mol / $1).94 For these reasons, the two-step conversion from 1,3-cycloheptanedione to - ketophosphonate 178 is less than ideal. We desired an alternative strategy for accessing olefination reagents homologated tethered alkynes (cf. 178) using the KAPA acetylene zipper reaction.252 The KAPA acetylene zipper reaction rearranges internal alkynes to terminal alkynes. Rearrangement of phosphonate 153b was not effective (Figure 74, eq. 1), likely due to competing amidation of the phosphonate with 1,2-propanediamine. This technical problem was easily overcome by switching to the corresponding phosphine oxide (153c). Fragmentation of VAT 2 with lithiomethyldiphenylphosphine oxide provides 153c, and carrying out a subsequent KAPA zipper (alkyne isomerization) reaction provides Horner-Wittig reagent 180 (ca. 44% over two steps), an analog of phosphonate 178 (Figure 74, eq. 2).

OMe MeO OMe MeO P P O O 10 equiv KH (1) not observed O 1,3-Propanediamine, O 0 oC, 12 h 153c 178

O Ph Ph Ph Ph O Ph P Li P Ph P O 152c O 10 equiv KH (2) THF, -78 to 60 oC O 1,3-Propanediamine, O OTf 81-89% 0 oC, 12 h

2 (Chapter 4) 153c 180 49% Unoptimized

Figure 74: Synthesis of a 180, an Analog of Phosphonate 178.

181

Having demonstrated the ability to fragment various vinylogous acyl triflates to provide dimethyl -ketophosphonates, we turned our attention to determining if the fragmentation reaction could be expanded to the use of other phosphonate nucleophiles. Table 10 provides the results of this series of experiments.

Table 10: Fragmentation of VAT 2 Using 1.1 Equivalents of Various Phosphonate Derived Nucleophiles.a

entry Phosphonate Product Yield, %b

EtO OEt O Me P O EtO P Me 1 EtO O 94 181 182 EtO OEt O P Ph O EtO P Bn c 2 EtO O 70 183 184 EtO OEt O Ph P O EtO P Ph d,e 3 EtO O 0 185 186 OCH CF F3CH2CO 2 3 O P O F CH CO P 4 3 2 Me 0d,f F3CH2CO O 187 188 a Triflate 2 (0.50 mmol) reacted with nucleophile (0.55 mmol, generated from 0.6 mmol of phosphonate and 0.55 mmol of n-BuLi) in THF at -78 to 60 oC over 80 min. b Isolated yields. c Obtained byproduct, proposed to be 189 (ca. 8% yield). d decomposition of starting VAT 2 observed. e 20% recovered VAT 2. f 35% recovered VAT 2.

O Ph

OTf OTf 2 189

182

The reaction between VAT 2 and the anion of diethyl ethylphosphonate (181) proceeded cleanly in 94% yield (entry 1). This result is remarkable. In our previous studies of the Claisen-type condensation reactions, substitutions at the -position of the nucleophile led to decomposition of the starting VAT. In the case of the nucleophile derived from diethyl 2-phenylethylphosphonate (183) (entry 2), the phosphonate product 184 was obtained in 70% yield. This reaction provided an unstable byproduct consistent with an E/Z- mixture of dienes 189, in a roughly 1:1 ratio (ca. 8% yield). Again, alkene byproducts are consistent with a postulated oxaphosphetane-like intermediate (cf. 171, Figure 71). The more stabilized nucleophiles derived from phosphonates 185 and 187 failed to produce any discernable products, and small amounts of starting VAT 2 were recovered. In addition, to the electronic stabilization provided by the phenyl substituent, the increased steric profile may also inhibit the desired reaction with VAT 2. The anion of phosphonate 187, which would give rise to a Still-Gennari-type242 olefination reagent, is prone to homo-condensation,250 thus hampering its viability in Claisen-type condensation reactions. In summary, this work has provided valuable insight into the mechanism of the Claisen-type fragmentation of vinylogous acyl triflates. The observance of the suspected alcohol byproduct 170 allowed for a better understanding of the mechanism involving phosphine oxide derived nucleophiles. Ultimately, the results obtained during our synthesis of the C1-C15 fragment of palmerolide A allowed for the expansion of the method to the synthesis of -ketophosphonates and a better understanding of these reactions. The ability of the phosphorus atom to coordinate to the resulting alkoxyanion after addition, perhaps forming an oxaphosphetane-like intermediate, is a key feature. This coordination allows for the reduction in the equivalencies of nucleophile required and provides the desired reactivity. If correct, the proposed structure of the olefinated byproducts 179 and 189 would support the transient formation of a true oxaphosphetane intermediate. We have demonstrated throughout the course of our extensive research into the tandem nucleophilic addition / C-C bond cleavage reactions of vinylogous acyl triflates that this class of compounds can give rise to interesting and synthetically useful

183 compounds. Tethered alkynyl ketones, alkynyl -ketoesters, alkynyl -ketophosphine oxides, and now, through re-optimized conditions, alkynyl -ketophosphonates are available from these easily prepared VAT substrates. The synthetic utility of such compounds has been demonstrated in the preparation of (Z)-6-heneicosen-11-one (Chapter 2), penta- and hexasubstituted indanes (Chapter 3), and the C1-C15 fragment of palmerolide A (Chapter 4). The new addition described in this chapter has led to the synthesis of some potentially useful -ketophosphonates. Their utility in synthesis has yet to be explored. Future endeavors into the chemistry and application of vinylogous acyl triflates and these -ketophosphonates are currently underway in the Dudley laboratory.

Experimental

General information: 1H NMR and 13C NMR spectra were recorded on a Varian 300 MHz spectrometer or a

Bruker 600 MHz spectrometer using CDCl3 as the deuterated solvent. The chemical shifts () are reported in parts per million (ppm) relative to the residual CHCl3 peak (7.26 ppm for 1H NMR and 77.0 ppm for 13C NMR for all compounds. The coupling constants (J) are reported in Hertz (Hz). IR spectra were recorded on a Perkin-Elmer FT-IR spectrometer with diamond ATR accessory as thin film. Mass spectra were recorded using electron ionization (EI) or fast-atom bombardment (FAB) on a JEOL JMS600H spectrometer. Melting points were taken on a MEL-TEMP melting point apparatus and are uncorrected. Yields refer to isolated material judged to be ≥ 95% pure by 1H NMR spectroscopy following silica gel chromatography. All chemical were used as received unless otherwise stated. All solvents, solutions and liquid reagents were added via syringe. Tetrahydrofuran (THF) was purified by distillation over sodium and benzophenone. Methylene chloride (CH2Cl2) was distilled from calcium hydride (CaH2). The n-BuLi solutions were titrated against a known amount menthol dissolved in tetrahydrofuran using 1,10-phenanthroline as the indicator. All reactions were carried out under an inert nitrogen atmosphere unless otherwise stated. The purifications were

184 performed by flash chromatography using silica gel F-254 (230-499 mesh particle size). Vinylogous acyl triflates were prepared from the corresponding 1,3-dione according to our published procedure.61

Standard Procedure for the Claisen-type Condensation of the Vinylogous Acyl Triflates with Phosphonate Nucleophiles: To a THF solution (2 mL) of phosphonate 153b (0.6 mmol) was added n-BuLi (0.22 mL, 0.55 mmol; 2.5 M solution in hexanes) at -78 oC. After being stirred for 20 minutes at -78 oC, was added the vinylogous acyl triflate 2 (0.50 mmol) was added dropwise to the resulting solution. The mixture stirred at -78 oC for 10 min, at 0 oC for 10 min, at r.t. for 30 min, and 60 oC for 30 min; during the course of the reaction the solution changed from clear to yellow, and then a yellow to a reddish solution. The solution was diluted with 3 mL of Et2O. A half saturated aqueous NH4Cl solution was used to quench the reaction and the mixture was extracted 3 times with 5 mL portions of EtOAc. The combined organic layers were washed with 5 mL of NaHCO3(aq), 5 mL of saturated brine, dried with MgSO4, filtered and concentrated. The residual oil was purified on silica gel column chromatography (EtOAc/Hexanes = 10% - 40%) to afford 112 mg of -ketophosphonate 153b (97% yield).

Procedure for Converting -Ketophosphine Oxide 153c into -Ketophosphine Oxide 180 Through KAPA Zipper Reaction: To potassium hydride (307mg, 2.3 mmol; 30 % by wt.), freshly washed 3 times with hexane, was added 1,3-diaminopropane (2 mL). The heterogeneous mixture was stirred at room temperature for one hour; during which, the solution changed from clear to opaque orange/brown in appearance. The solution was then cooled to 0 oC and a solution of 153c (71 mg, 0.22 mmol; in 1 mL of 1,3-diaminopropane) was added dropwise. The reaction mixture stirred at 0 oC for approximately 12 hrs, at which time, it was quenched with 2 mL of water, followed by 2 mL of a sat. aqueous solution of ammonium chloride. The mixture was warmed to rt. and the product was extracted with EtOAc (3 x 5 mL). The combined organics were dried with MgSO4 and concentrated. The crude residue was purified by flash column chromatography on silica gel (EtOAc/Hexanes = 40 % to 50 %). 35 mg of 4 was obtained as a white solid (49% yield).

185

Analytical Data:

1 Ethyl 3-oxo-7-nonynoate (168): pale yellow oil; H NMR (300 MHz, CDCl3)  4.19 (q, J = 7.0 Hz, 2H), 3.45 (s, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.17 (tq, J = 6.8, 2.5 Hz, 2H), 1.76 (t, J = 2.5 Hz, 3H), 1.76 (app. quintet, J = 7.0 Hz, 2H) 1.28 (t, J = 7.0 Hz, 3H); 13C NMR

(75Hz, CDCl3)  202.35, 167.0, 77.9, 76.4, 61.2, 49.3, 41.6, 22.5, 17.8, 14.0, 3.3; IR (thin film) 1745, 1742, 1651, 1415, 1242, 1027 cm-1; HRMS (FAB) Calcd for + C11H16O3Na [M ] 219.0097. Found 219.0097. Spectroscopic data in consistent with previous report.216

Proposed Structure (170): yellow oil that quickly decomposed upon isolation; 1H NMR (300 MHz, CDCl3)  4.20 (q, J = 7.1 Hz, 2H), 3.84 (s, 1H), 2.77 (d, J = 15.4 Hz, 1H), 2.49 (d, J = 15.4 Hz, 1H), 2.41-2.30 (m, 2H), 1.99-1.67 (m, 7H), 1.29 (t, J = 7.1, 3H). Diagnostic peaks are circled.

1-(dimethylphosphonato)-2-oxo-6-octyne (153b): pale yellow oil; 1H NMR (300 MHz, CDCl3)  3.78 (d, J = 11 Hz, 6H), 3.10 (d, J = 22 Hz, 2H), 2.73 (t, J = 7.2 Hz, 2H), 2.16 (tq, J = 6.9, 2.5 Hz, 2H), 1.76 (t, J = 2.5 Hz, 3H), 1.75 (app. quintet, J = 7.0 Hz, 2H); 13C

NMR (75 MHz, CDCl3)  201.4, 78.0, 76.3, 52.9 (d, J = 6.5), 42.8, 41.3 (d, J = 128 Hz), 22.6, 17.8, 3.3; IR (thin film) 1712, 1449, 1254, 1025, 810 cm-1; HRMS (EI+) Calcd for + + C10H17O4P [M ] 232.0864. Found 232.0860. Spectroscopic data in consistent with previous report.216

1-(dimethylphosphonato)-4,4-dimethyl-2-oxo-6-heptyne (176): pale yellow oil; 1H

NMR (300 MHz, CDCl3)  3.78 (d, J = 11.3, 6H), 3.08 (d, J = 22.7 Hz, 1H), 2.67 (s, 1H), 2.28 (d, J = 2.5 Hz, 1H), 2.01 (t, J = 2.5 Hz, 1H), 1.09 (s, 3H); 13C NMR (75 MHz,

CDCl3)  200.90 (d, J = 5.8 Hz), 81.91, 70.45, 52.96 (d, J = 5.8 Hz) 52.72, 42.76 (d, J = 128.1 Hz), 33.34, 31.01, 26.79; IR (thin film) 1714, 1465, 1366, 1249, 1024, 811 cm-1; + + + HRMS (EI ) Calcd for C11H20O4P [[M+H] ] 247.1099. Found 247.1096.

186

1 1-(dimethylphosphonato)-2-oxo-7-nonyne (178): clear oil; H NMR (300 MHz, CDCl3) 3.76 (d, J = 11.2 Hz, 6H), 3.07 (d, J = 22.8 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H), 2.17 (dt, J = 7.0, 2.6 Hz, 2H), 1.92 (t, J = 2.6 Hz, 1H), 1.68 (app quintet, J = 7.6 Hz, 2H), 1.50 (app 13 quintet, J = 7.6 Hz, 2H); C NMR (75 MHz, CDCl3)  201.39 (d, J = 5.1 Hz, 1C), 83.88, 68.55, 52.98 (d, J = 4.5 Hz, 1C), 43.38, 41.25 (d, J = 128.3 Hz, 1C), 27.51, 22.35, 18.13; IR (thin film) 1712, 1456, 1249, 1021, 806 cm-1; HRMS (EI+) Calcd for + + C10H18O4P [[M+H] ] 233.0943. Found 233.0943.

Proposed structure (179): yellow oil that quickly decomposed; 1H NMR (300 MHz,

CDCl3)  6.19 (s, 1H), 5.03 (apparent doublet, J = 7.1 Hz, 2H), 2.24 (s, 2H), 2.08 (s, 2H), 0.99 (s, 6H). Diagnostic peaks are circled.

(2-oxo-7-octynyl)-diphenylphosphine oxide (180): white solid; mp = 68-71 oC; 1H

NMR (300 MHz, CDCl3)  7.95 – 7.66 (m, 4H), 7.66 – 7.34 (m, 5H), 3.58 (d, J = 15.0 Hz, 2H), 2.68 (t, J = 7.1 Hz, 2H), 2.12 (dt, J = 7.0, 2.5 Hz, 2H), 1.91 (t, J = 2.5 Hz, 1H), 1.66 – 1.50 (app. quintet, J = 7.2 Hz, 2H), 1.41 (app. quintet, J = 7.2 Hz, 2H); 13C NMR (150

MHz, CDCl3)  202.58 (d, J = 5.2 Hz), 132.27 (d, J = 2.9 Hz), 131.99 (d, J = 102.2 Hz), 130.92 (d, J = 5.2 Hz), 128.82 (d, J = 7.9 Hz), 84.06, 68.44, 47.14 (d, J = 56.1 Hz), 44.64, 29.70, 27.55, 22.35, 18.18; IR (thin film) 2232, 1709, 1438, 1187, 907, 725, 693 -1 + + + cm ; HRMS (EI ) Calcd for C20H21O2P [M ] 324.1279. Found 324.1282.

1 2-(diethylphosphonato)-3-oxo-7-nonyne (182): clear oil; H NMR (300 MHz, CDCl3)  4.20 – 4.03 (m, 4H), 3.22 (dq, J = 24.9, 7.1 Hz, 2H), 2.91 (dt, J = 18.0, 7.2 Hz, 1H), 2.65 (dt, J = 18.0, 7.1 Hz, 1H), 2.16 (m, 2H), 1.82 – 1.68 (m, 5H), 1.35 (m, 9H); 13C NMR (75

MHz, CDCl3)  205.43 (d, J = 3.9 Hz), 78.06, 75.97, 62.45 (d, J = 7.3 Hz), 62.35 (d, J = 7.7 Hz), 46.45 (d, J = 127.1 Hz), 41.72, 22.65, 17.79, 16.15 (d, J = 5.6 Hz), 10.75 (d, J = 6.4 Hz), 3.24; IR (thin film) 1713, 1448, 1245, 1048, 1018, 956, 791 cm-1; HRMS (EI+) + + Calcd for C13H23O2P [M ] 274.1334. Found 274.1338.

2-(diethylphosphonato)-3-oxo-1-phenyl-7-nonyne (184): clear colorless oil; 1H NMR

(300 MHz, CDCl3)  7.20 (m, 5H), 4.24 – 4.05 (m, 4H), 3.52 (ddd, J = 23.2, 11.3, 3.2 Hz,

187

1H), 3.30 (ddd, J = 13.6, 11.6, 7.4 Hz, 1H), 3.09 (ddd, J = 13.6, 10.6, 3.0 Hz, 1H), 2.75 (dt, J = 17.9, 7.1 Hz, 1H), 2.27 (dt, J = 17.9, 7.1 Hz, 1H), 1.98 (m, 2H), 1.72 (t, J = 2.5 13 Hz, 3H), 1.64 – 1.49 (m, 2H), 1.35 (m, 6H); C NMR (75 MHz, CDCl3)  204.72, 138.81 (d, J = 16.4 Hz), 128.46, 126.49, 78.06, 75.91, 62.76 (d, J = 6.6 Hz), 62.55 (d, J = 6.6 Hz), 54.37 (d, J = 123.9 Hz), 43.64, 32.30 (d, J = 3.9 Hz), 22.45, 17.68, 16.27 (d, J = 5.8 Hz), 3.29; IR (thin film) 1713, 1455, 1247, 1047, 1019, 960, 699 cm-1; HRMS (EI+) Calcd + + for C19H27O4P [M ] 350.1647. Found 350.1657.

Proposed Structure (189): yellow oil that quickly decomposed; 1H NMR (300 MHz,

CDCl3)  7.39 – 7.12 (m, 5H), 5.66 (dt, J = 70.5, 7.4 Hz, 1H), 3.55 (dd, J = 33.8, 7.5 Hz, 2H), 2.51 (s, 2H), 2.46 – 2.39 (m, 1H), 2.30 – 2.21 (m, 1H), 2.17 – 1.78 (m, 5H). Diagnostic peaks are circled.

188

1H NMR and 13C NMR Spectra:

EtO O

OTf 170 proposed

189

MeO OMe P O

176

190

MeO OMe P O

176

191

MeO OMe P O

178

192

MeO OMe P O

178

193

OTf 179 proposed

194

Ph Ph P O

180

195

Ph Ph P O

180

196

EtO OEt Me P O

182

197

EtO OEt Me P O

182

198

EtO OEt P Ph O

184

199

EtO OEt P Ph O

184

200

OTf 189 proposed

201

LIST OF REFERENCES

1. Diels, O.; Alder, K. Cause of the ―azo-ester‖ reaction. Ann. 1926, 450, 237-254.

2. Diels, O.; Alder, K. Synthesis in the hydroaromatic series. I. Addition of ―diene‖ hydrocarbons. Ann. 1928, 460, 98-122.

3. Diels, O.; Alder, K. Synthesis in the hydroaromatic series. V. -4-Tetrahydro-o-phthalic acid (reply to communication of E. H. Farmer and F. L. Warren: Properties of conjugated double bonds. (7)). Ber. 1929, 62B, 2087-2090.

4. Diels, O.; Alder, K.; Pries, P. Synthesis in the hydroaromatic series. IV. Addition of maleic anhydride to arylated dienes, trienes, and fulvenes. Ber. 1929, 62B, 2081-2087

5. Komnenos, T. The reaction of unsaturated aldehydes with malonic acid and ethyl malonate. Liebigs Ann. Chem. 1883, 218, 145-169.

6. Michael, A. J. Prakt. Chem./Chem.-Ztg. 1887, 35, 349.

7. Michael, A. Am. Chem. J. 1887, 9, 115.

8. Michael, A. Addition of sodium acetoacetate and sodium diethyl malonate to unsaturated acids. J. Prakt. Chem./Chem.-Ztg. 1994, 49, 20.

9. Evans, D. A.; Bartroli, J.; Shih, T. L. Enantioselective aldol condensations. 2. Erythro- selective chiral aldol condensations via boron enolates. J. Am. Chem. Soc. 1981, 103, 2127-2109.

10. Cassar, L. Synthesis of aryl- and vinyl-substituted acetylene derivatives by use of nickel and palladium complexes. J. Organomet. Chem. 1975, 93, 253-257.

11. Dieck, H. A., Heck, F. R. Palladium catalyzed synthesis of aryl, heterocyclic, and vinylic acetylene derivatives. J. Organomet. Chem. 1975, 93, 259-263.

12. Sonogashira, K.; Tohda, Y.; Hagihara, N. Convenient synthesis of acetylenes. Catalytic substitutions of acetylenic hydrogen with bromo alkenes, iodo arenes, and bromo pyridines. Tetrahedron Lett. 1975, 4467-4470.

13. Mukaiyama, T. The directed aldol reaction. Org. React. 1982, 28, 203-331.

14. Heathcock, C. H. The aldol reaction: acid and general base catalysis. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 133-238.

202

15. Rickborn, B. The retro-Diels-Alder reaction. Part I. C-C Dienophiles. Org. React.1998, 52, 1-393.

16. Sweger, R. W.; Czarnik, A. W. Retrograde Diels-Alder reactions. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 551-592.

17. Bergmann, E. D.; Ginsburg, D.; Pappo, R. The Michael reaction. Org. React. 1959, 10, 179-555.

18. Jung, M. E. Stabilized nucleophiles with electron deficient alkenes and alkynes. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 1-67.

19. Boger, D. L.; Ichikawa, S.; Jiang, H. Total synthesis of the rubrolone aglycon. J. Am. Chem. Soc. 2000, 122, 12169-12173.

20. Takasu, K.; Mizutani, S.; Noguchi, M.; Makita, K.; Ihara, M. Total synthesis of (+)- culmorin and (+)-longiborneol: an efficient construction of the tricycle[6.3.0.03,9]undecan-10-one by intramolecular double Michael addition. J. Org. Chem. 2000, 65, 4112-4119.

21. Furstner, A.; Ruiz-Caro, J.; Prinz, H.; Waldmann, H. Structure assignment, total synthesis, and evaluation of the phosphate modulating activity of glucolipsin A. J. Org. Chem. 2004, 69, 459-467.

22. Paterson, I.; Davies, R. D. M.; Marquez, R. Total synthesis of the callipeltoside aglycon. Angew. Chem., Int. Ed. Engl. 2001, 40, 603-607.

23. Jacobi, P. A; Craig, T. A.; Walker, D. G.; Arrick, B. A.; Frechette, R. F. Bis heteroannulation. 4. Facile synthesis of methylene acids, methylbutenolides, a- methyl- g-lactones, and related materials. Total synthesis of (+)-lingularone and (+)-petasalbine. J. Am. Chem. Soc. 1984, 106, 5585-5594.

24. Itagaki, N.; Sugahara, T.; Iwabuchi, Y. Expedient synthesis of potent cannabinoid receptor agonist (-)-CP55,940. Org. Lett. 2005, 7, 4181-4183.

25. Hill, R. K. Cope, oxy-Cope, and anionic oxy-Cope rearrangements. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds; Pergamon: Oxford, 1991; Vol. 5, pp 785-826.

26. Lutz, R. P. Catalysis of the Cope and Claisen rearrangements. Chem. Rev. 1984, 84, 205-247.

27. Lee, D. G.; Chen, T. Cleavage reactions. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon,: Oxford, 1991; Vol. 7, pp 541-591.

203

28. Shing, T. K. M. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, pp 703-717.

29. Hundlicky, T.; Reed, J. E. Rearrangement of vinylcyclopropanes and related systems. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 899-870.

30. Jun, C. –H. Transition metal-catalyzed carbon–carbon bond activation. Chem. Soc. Rev. 2004, 33, 610-618 and references therein.

31. Murakami, M.; Ito, Y. In Activation of Unreactive Bonds and Organic Synthesis; Murai, S., Ed.; Springer: Berlin, 1999; pp 97-129.

32. Jennings, P. W.; Johnson, L. L. Metallacyclobutane complexes of the group eight transition metals: synthesis, characterizations, and chemistry. Chem. Rev. 1994, 94, 2241-2290.

33. Tsuji, J. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E. –i., Ed.; Wiley: New York, 2002; Vol. 2. Pp 2643-2653.

34. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003.

35. Grubbs, R. H. Olefin metathesis. Tetrahedron 2004, 60, 7117-7140

36. Buchmeiser, M. R. Homogeneous metathesis polymerization by well-defined group VI and group VIII transition-metal alkylidenes: fundamentals and applications in the preparation of advanced materials. Chem. Rev. 2000, 100, 1565-1604.

37. Matsuda, T.; Shigeno, M.; Murakami, M. Asymmetric synthesis of 3,4-dihydrocoumarins by rhodium-catalyzed reaction of 3-(2-hydroxyphenyl)cyclobutanones. J. Am. Chem. Soc. 2007, 129, 12086-12087.

38. Chandler, C. L.; Phillips, A. J. A total synthesis of (±)-trans-kumausyne. Org. Lett. 2005, 7, 3493-3495.

39. Grob, C. A., Baumann, W. 1,4-Elimination reaction with simultaneous fragmentation. Helv. Chim. Acta 1955, 38, 594-610.

40. Grob, C. A. The principle of ethylogy in organic chemistry. Experientia 1957, 13, 126- 129.

41. Grob, C. A. Heterolytic fragmentation. A class of organic reactions. Angew. Chem., Int. Ed. Engl. 1967, 6, 1-15.

42. Grob, C. A. Mechanisms and stereochemistry of heterolytic fragmentation. Angew. Chem., Int. Ed. Engl. 1969, 8, 535-546.

204

43. Weyerstahl, P., Marschall, H. Fragmentation reactions. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, pp 1041- 1070.

44. Wharton, P. S. Stereospecific synthesis of 6-methyl-trans-5-cyclodecenone. J. Org. Chem. 1961, 26, 4781-4782.

45. Wharton, P. S.; Hiegel, G. A.; Coombs, R. V. trans-5-cyclododecenone. J. Org. Chem. 1963, 28, 3217-3219.

46. Wharton, P. S.; Hiegel, G. A. Fragmentation of 1,10-decalindiol monotosylate. J. Org. Chem. 1965, 30, 3254-3257.

47. Wharton, P. S.; Baird, M. D. Conformation and reactivity in the cis,trans-2,6- cyclodecadienyl system. J. Org. Chem. 1971, 36, 2932-2938.

48. Njardarson, J. T.; Wood, J. L. Evolution of the synthetic approach to CP-243,114. Org. Lett. 2001, 3, 2431-2434.

49. Eschenmoser, A.; Felix, D.; Ohloff, G. New fragmentation reaction of ,-unsaturated carbonyls. Synthesis of exaltone and rac-muscone from cyclododecanone. Helv. Chim. Acta 1967, 50, 708-713.

50. Felix, D.; Schreiber, J.; Ohloff, G. Eschenmoser, A. Synthetic Methods. 3. ,- Epoxyketone  alkynone fragmentation. I. Synthesis of exaltone and (+/-)-muscone from cyclododecanone. Helv. Chim. Acta 1971, 54, 2896-2912.

51. Tanabe, M.; Crowe, D. F.; Dehn, R. L. Novel fragmentation reaction of ,- epoxyketones. Synthesis of acetylenic ketones. Tetrahedron Lett. 1967, 3943-3946.

52. Tanabe, M.; Crowe, D. F.; Dehn, R. L.; Detre, G. Synthesis of secosteroid acetylenic ketones. Tetrahedron Lett. 1967, 3739-3743.

53. Murakami, Y.; Shindo, M.; Shishido, K. Enantiocontrolled synthesis of a chiral building block via diastereoselective ring-closing metathesis. Synlett 2005, 664-666.

54. Fehr, C.; Galindo, J.; Etter, O. An efficient enantioselective synthesis of (+)-(R,Z)-5- Muscenone and (-)-(R)-Muscone – an example of a kinetic resolution and enantioconvergent transformation. Eur. J. Org. Chem. 2004, 1953-1957.

55. Mander, L. N.; McLachlan, M. M. The total synthesis of the galbulimima alkaloid GB 13. J. Am. Chem. Soc. 2003, 125, 2400-2401.

56. Dai, W.; Katzenellenbogen, J. A. New approaches to the synthesis of alkyl-substituted enol lactone systems, inhibitors of serine protease elastase. J. Org. Chem. 1993, 58, 1900-1908.

205

57. Trost, B. M.; Chang, V. K. An approach to botrydianes: on the steric demands of a metal catalyzed enyne metathesis. Synthesis 1993, 824-832.

58. Gordon, D. M.; Danishefsky, S. J.; Schulte, G. K. Studies in the benzannulation of cycloalkynone: an approach to the synthesis of antibiotics containing the benz[a]anthracene core structure. J. Org. Chem. 1992, 57, 7052-7055.

59. Woods, G. F.; Tucker, I. W. The reaction of b-cyclohexanedione (dihydroresorcinol) and its ethyl enol ether with phenylmagnesium bromide. J. Am. Chem. Soc. 1948, 70, 2174- 2177.

60. Zimmerman, H. E.; Nesterov, E. E. An experimental and theoretical study of the type C enone rearrangement: mechanistic and exploratory organic photochemistry. J. Am. Chem. Soc. 2003, 125, 5422-5430.

61. Kamijo, S.; Dudley, G. B. A tandem carbanion addition/carbon-carbon bond cleavage yields alkynyl ketones. J. Am Chem. Soc. 2005, 127, 5028-5029.

62. Saito, Y.; Yamamoto, H.; Kageyama, H.; Nakamura, O.; Miyoshi, T.; Matsuoka, M. Investigation of the solution condition of lithium electrolyte solutions with LiCF3SO3 salt. J. Mater. Sci. 2000, 35, 809-812.

63. Hori, M.; Mori, M. Synthesis of heterocycles utilizing N2—TiCl4—Li—TMSCl. J. Org. Chem. 1995, 60, 1480-1481.

64. Wickman, B. E.; Mason, R. R.; Trostle, G. C. Douglas-fir tussock moth. Forest and Insect and Disease Leaflet 86; United States Department of Agricultural Forest Services, 1981.

65. Federal Register 39; 1974, no. 44, pp 8377-8381.

66. Smith, R. G.; Daterman, G. E.; Davies, G. D., Jr. Douglas-fir tussock moth pheromone identification and synthesis. Science 1975, 188, 63-64.

67. Beckwith, R. C. Influence of host foliage on the Douglas-fir tussock moth. Environ. Entomol. 1976, 5, 73-77.

68. Wickman, B. E. In The Douglas-Fir Tussock Moth: A Synthesis; Brooks, M. H.; Stark, R. W.; Campbell, R. W. Eds.; U.S. Forest Serv. Tech. Bull., 1978; Vol. 1585, pp 66-75.

69. Wickman, B. E.; Mason, R. R.; Paul, H. G. Flight, attraction, and mating behavior of the Douglas-fir tussock moth in Oregon. Environ. Entomol. 1975, 4, 405-408.

70. Torgerson, T. R. Identification of parasites of the Douglas-fir tussock moth based on adults, cocoons, and puparia. United States Department of Agriculture Forest Service

206

Research Paper; Pacific Northwest Forest and Range Experiment Station, 1977, PNW- 215; pp 28.

71. Evenden, J.; Jost, E. J. A report of the tussock moth control. United States Department of Agriculture: North Idaho, 1947; pp 51.

72. Daterman, G. E. In The Douglas-Fir Tussock Moth: A Synthesis; Brooks, M. H.; Stark, R. W.; Campbell, R. W. Eds.; U.S. Forest Serv. Tech. Bull., 1978; Vol. 1585, pp 902- 102.

73. Kelleher, K. Palmer Mountain Douglas-Fir Tussock Moth Control; United States Department of the Interior: Bureau of Land Management, Wenatchee Field Office, 2009, Project No. 09-0026; website: http://www.blm.gov/or/districts/spokane/plans/files/Palmer_Mtn_Tussock_Moth_EA_Fin al.pdf

74. Welter, S. C.; Pickel, C.; Millar, J. Cave, F.; Van Steenwyk, R. A; Dunley, J. Pheromone mating disruption offers selective management options for key pests. Calif. Agric. 2005, 59, 16-22.

75. Hulme, M.; Gray, T. G. Mating disruption of the Douglas-fir tussock moth (Lepidoptera: Lymantriidae) using a sprayable formulation of (Z)-6-heneicosen-11-one. Environ. Entomol. 1994, 23, 1097-1100.

76. Hulme, M.; Gray, T. G. Pheromone dosage on mating disruption of the Douglas-fir tussock moth. J. Entomol. Soc. B. C. 1997, 93, 99-104.

77. Environmental Protection Agency, Registration of Lepidopteran Pheromones Federal Register Notices, (Z)-6-Heneicosen-11-one (129060), 22 Jun 2005, website: http://www.epa.gov/pesticides/biopesticides/ingredients/fr_notices/frnotices_lep_pherom ones.htm#129060

78. Smith, R. G.; Davies, G. D., Jr.; Daterman, G. E. Synthesis of (Z)-6-heneicosen-11-one. Douglas-fir tussock moth sex attractant. J. Org. Chem. 1975, 40, 1593-1595.

79. Kocienski, P. J.; Cernigliaro, G. J. Pheromone synthesis. II. A synthesis of (Z)-6- heneicosen-11-one. The sex pheromone of the Doulas-fir tussock moth. J. Org. Chem. 1976, 41, 2927-2928.

80. Mori, K.; Uchida, M.; Matsui, M. Synthesis of aliphatic insect pheromones from alicyclic starting materials: (Z)-6-heneicosen-11-one and (Z)-8-dodecenyl acetate. Tetrahedron 1977, 33, 385-387.

81. Fetizon, M.; Lazare, C. A rapid and convenient synthesis of the sex pheromone of the Douglas-fir Lepidoptera Orgyia pseudotsugata. J. Chem. Soc., Perkin Trans. 1 1978, 842-844.

207

82. Akermark, B.; Ljungqvist, A. Eutectic potassium-sodium-aluminum chloride as a mild catalyst for ene reactions: simple synthesis of the sex pheromone from the Douglas-fir tussock moth. J. Org. Chem. 1978, 43, 4387-4388.

83. Trost. B. M.; Ornstein, P. L. A chemoselective desulfurization method via homogeneous nickel catalysis. Tetrahedron Lett. 1981, 22, 3464-3466.

84. Murata, Y.; Inomata, K.; Kinoshita, H.; Kotake, H. A convenient method for the synthesis of acyclic ketones. Synthesis of sex pheromone of Doulas-fir tussock moth. Bull. Chem. Soc. Jpn. 1983, 56, 2539-2540.

85. Reddy, G. B.; Mitra, R. B. Acetone dimethyl hydrazone: useful synthon for the synthesis of pheromones with keto and spiro ketal functions. Synth. Commun. 1983, 16, 1723- 1729.

86. Pramod, K.; Ramanathan, H.; Subba Rao, G. S. R. Strategic synthesis based on cylcohexadienes: preparation of 2-, 2,3-, and 2,4-substituted cyclohexenones; synthesis of (Z)-heneicosen-11-one. J. Chem. Soc., Perkin Trans. 1 1983, 7-10.

87. Sodeoka, M.; Shibasaki, M. New functions of (arene)tricarbonylchromium(0) complexes as hydrogenation catalysis: stereospecific semihydrogenation of alkynes and highly chemoselective hydrogenation of ,-unsaturated carbonyl compounds. J. Org. Chem. 1985, 50, 1147-1149.

88. Wenkert, E.; Ferreira, V. F.; Michelotti, E. L.; Tingoli, M. Synthesis of acyclic, cis olefinic pheromones by way of nickel-catalyzed Grignard reactions. J. Org. Chem. 1985, 50, 719-721.

89. Ballini, R. New and convenient synthesis of (Z)-6-heneicosen-11-one, the Douglas-fir tussock moth (Orgyia pseudotsugata) sex pheromone, and (Z)-non-6-en-2-one, the immediate precursor for the synthesis of brevicomin, the sex attractant of the western pine beetle Dentroctonus brevicomis. J. Chem. Soc. Perkin Trans. 1 1991, 1419-1421.

90. Stowell, J. C.; Polito, M. A. A .delta.-keto aldehyde synthesis: application to the preparation of the sex pheromone of the Douglas-fir tussock moth. J. Org. Chem. 1992, 57, 4560-4562.

91. White, J.; Whiteley, C. G. Use of organoboranes in the synthesis of pheromones: a convenient synthesis of (Z)-6-heneicosen-11-one and (Z)-5-undecen-11-one, pheromones of the Douglas-fir tussock moth and the bontebok, respectively. Synthesis 1993, 1141-1144.

92. Hayes, J. F.; Shipman, M.; Twin, H. Multicomponent reactions involving 2- methyleneaziridines: rapid synthesis of 1,3-disubstituted propanones. J. Org. Chem. 2002, 67, 935-942.

208

93. Jones, D. M.; Kamijo, S.; Dudley, G. B. Grignard-triggered fragmentation of vinylogous acyl triflates: synthesis of (Z)-6-heneicosen-11-one, the Douglas fir tussock moth sex pheromone. Synlett 2005, 936-938.

94. Prices Made Available from Sigma-Aldrich: http://www.sigmaaldrich.com/united- states.html.

95. Rosenmund, K. W.; Bach, H. Chem. Ber. 1961, 94, 2394.

96. Piers, E.; Grierson, J. R. Alkylation of 1,5-dimethoxy-1,4-cyclohexadiene. A convenient synthesis of 2-alkyl- and 2-alkenyl-1,3-cyclohexanediones. J. Org. Chem. 1977, 42, 3755-3757.

97. Fraga, B. M. Natural sesquiterpenoids. Nat. Prod. Rep. 2008, 25, 1180-1209.

98. Ayer, W. A.; McCaskill, R. H. The cybrodins, a new class of sesquiterpenes. Can. J. Chem. 1981, 59, 2150-2158.

99. Arnone, A.; Cardillo, R.; Di Modugno, V.; Nasini, G. Seconday mould metabolites. Part 29. Isolation and structure elucidation of candicansol, 3-epi-illudol and 1-O-acetyl-3-epi- illudol, novel sesquiterpenoids from Clitocybe candicans, and absolute configuration of 3-epi-illudol. J. Chem. Soc., Perkin Trans. 1 1989, 1995-2000.

100. Clericuzio, M.; Pan, F.; Han, F.; Pang, Z.; Sterner, O. Stearoyldelicone, an unstable protoilludane sesquiterpenoids from intact fruit bodies of Russula delica. Tetrahedron Lett. 1997, 38, 8237-8240.

101. Saito, K.; Nagao, T.; Matoba, M.; Koyama, K.; Natori, S.; Murakami, T.; Saiki, Y. Chemical assay of ptaquiloside, the carcinogen of Pteridium aquilinum, and the distribution of related compounds in the pteridaceae. Phytochemistry 1989, 28, 1605- 1611.

102. Hikino, H.; Takahashi, T.; Arihara, S.; Takemoto, T. Structure of Pteroside B, glycoside of Pteridium aquilinum var latiusculum. Chem. Pharm. Bull. 1970, 18, 1488-1489.

103. Yoshihira, K.; Fukuoka, M.; Kuroyanagi, M.; Natori, S. Chemical and toxicological studies on bracken fern, Pteridium aquilinum var. latiusculum. I. Introduction, extraction, and fractionation of constituents, and toxicological studies including carcinogenicity tests. Chem. Pharm. Bull. 1978, 26, 2346-2364.

104. Fukuoka, M.; Kuroyanagi, M.; Yoshihira, K.; Natori, S. Chemical and toxicological studies on bracken fern, Pteridium aquilinum var. latiusculum. II. Structures of pterosins, sesquiterpenes having 1-indanone skeleton. Chem. Pharm. Bull. 1978, 26, 2365-2385.

105. Yamada, K.; Ojika, M.; Kigoshi, H. Ptaquiloside, the major toxin of braken, and related terpene glycosides: chemistry, biology, and ecology. Nat. Prod. Rep. 2007, 24, 798-813.

209

106. Suzuki, S.; Muriayama, T.; Shiono, Y. Illudalane sesquiterpenoids, echinolactones A and B, from a mycelia culture of Echinodontium japonicum. Phytochemistry 2005, 66, 2329-2333.

107. Muriayama, T.; Tanaka, N. Prog. Chem. Org. Nat. Prod. 1988, 54, 1-355 and references therein.

108. Palmero, J. A.; Brasco, M. F. R.; Spagnuolo, C. Seldes, A. M. Illudalane sesquiterpenoids from the soft coral Alcyonium paessleri: the first natural nitrate esters. J. Org. Chem. 2000, 65, 4482-4486.

109. Carbone, M.; Nunez-Pons, L.; Castellucio, F.; Avila, C.; Gavagnin, M. Illudalane sesquiterpenoids of the alcyopterosin series from the Antarctic marine soft coral Alcyonium grandis. J. Nat. Prod. 2009, 72, 1357-1360.

110. Sengupta, P.; Sen, M.; Niyogi, S. K.; Pakrashi, S. C.; Ali, E. Isolation and structure of wallichoside, a novel pteroside from Pteris wallichiana. Phytochemistry 1976, 6, 995- 998.

111. Castillo, U. F.; Sakagama, Y.; Alonso-Amelot, M. Ojiva, M. Pteridanoside, the first protoilludane sesquiterpene glucoside as a toxic component of neotropical bracken fern Pteridium aquilinum var. caudatum. Tetrahedron 1999, 55, 12295-12300.

112. Sheridan, H.; Lemon, S.; Frankish, N.; McArdle, P.; Higgins, T.; James, J.; Bhandari, P. Synthesis and antispasmodic activity of nature and identical substituted indanes and analogs. Eur. J. Med. Chem. 1990, 25, 603-608.

113. Finkielsztein, L. M; Bruno, A. M.; Renou, S. G.; Iglesias, G. Y. M. Design, synthesis, and biological evaluation of alcyopterosin and illudalane derivatives as anticancer agents. Bioorg. Med. Chem. 2006, 14, 1863-1870.

114. Tanaka, R.; Nakano, Y.; Suzuki, D.; Urabe, H.; Sato, F. Selective preparation of benzyltitanium compounds by the metalative Reppe reaction. Its application to the first synthesis of alcyopterosin A. J. Am. Chem. Soc. 2002, 124, 9682-9683.

115. Witulski, B.; Zimmermann, A.; Gowans, N. D. First total synthesis of marine illudalane sesquiterpenoids alcyopterosin E. Chem. Comm. 2002, 2984-2985.

116. Nakao, Y.; Hirata, Y.; Ishihara, S.; Oda, S.; Yukawa, T.; Shirakawa, E.; Hiyama, T. Stannylative cycloaddition of enynes catalyzed by palladium-iminophosphine. J. Am. Chem. Soc. 2004, 126, 15650-15651.

117. Jones, A. L.; Snyder, J. K. Intramolecular rhodium-catalyzed [2+2+2] cyclizations of diynes with enones. J. Org. Chem. 2009, 74, 2907-2910.

210

118. Reppe, W.; Schweckendiek, W. J. Cyclisierende polymerization von acetylene. III. Benzol, benzolderivate und hydroaromatische verbindungen. Justus Liebigs Ann. Chem. 1948, 560, 104-116.

119. Saito, S.; Kawasaki, T.; Tsuboya, N.; Yamamoto, Y. Highly regioselective cyclotrimerization of 1-perfluoroalkynes catalyzed by nickel. J. Org. Chem. 2001, 66, 796-802.

120. Ozerov,O. V.; Patrick, B. O.; Ladipo, F. T. Highly regioselective [2+2+2] cycloaddition of terminal alkynes catalyzed by 6-arene complexes of titanium supported dimethylsilyl- bridged p-tert-butyl calyx[4]arene ligand. J. Am. Chem. Soc. 2000, 122, 6423-6431.

121. Ozerov, O. V.; Ladipo, F. T.; Patrick, B. O. Highly regioselective alkyne cyclotrimerization catalyzed by titanium complexes supported by proximally bridged p- tert-butyl calyx[4]arene ligand. J. Am. Chem. Soc. 1999, 121, 7941-7942.

122. Chio, K. S.; Park, M. K.; Han, B. H. J. Chem. Res. (S) 1998, 518-519.

123. Hill, J. E.; Balaich, G.; Fanwick, P. E.; Rothwell, I. P. The chemistry of titanacyclopentadiene rings supported by 2,6-diphenoxide ligation: stoichiometric and catalytic reactivity. Organometallics 1993, 12, 2911-2924.

124. Kataoka, Y.; Takai, K.; Oshima, K.; Utimoto, K. Selective reduction of alkynes to (Z)- alkenes via niobium- or tantalum-alkyne complexes. J. Org. Chem. 1992, 57, 1615- 1618.

125. Jhingan, A. K.; Maier, W. F. Homogeneous catalysis with a heterogeneous palladium catalyst. An effective method for the cyclotrimerization of alkynes. J. Org. Chem. 1987, 52, 1161-1165.

126. Mori, N.; Ikeda, S.; Odashima, K. Chemo- and regioselective cyclotrimerization of monoynes catalyzed by a nickel(0) and zinc(II) phenoxide system. Chem. Commun. 2001, 181-182.

127. Sato, Y.; Ohashi, K.; Mori, M. Synthesis of biaryls using nickel-catalyzed [2+2+2] co- cyclization. Tetrahedron Lett. 1999, 40, 5231-5234.

128. Takahashi, T.; Tsai, F.-Y.; Li, Y.; Nakajima, K.; Kotora, M. Carbon-carbon bond formation reaction of zirconacyclopentadienes with alkynes in the presence of Ni(II)- complexes. J. Am. Chem. Soc. 1999, 121, 11093-11100.

129. Takahashi, T.; Xi, Z.; Yamazaki, A.; Liu, Y.; Nakajima, K.; Kotora, M. Cycloaddition reaction of zirconacyclopentadienes to alkynes: highly selective formation of benzene derivatives from three different alkynes. J. Am. Chem. Soc. 1998, 120, 1672-1680.

211

130. Kotha, S.; Mohanraja, K.; Durani, S. Constrained phenallyl peptides via a [2+2+2]- cycloaddtition strategy. Chem. Commun. 2000, 1909-1910.

131. Witulski, B.; Stengel, T.; Fernandez-Hernandez, J. M. Chemo- and regioselective crossed alkyne cyclotrimerization of 1,6-diynes with terminal monoalkynes mediated by Grubbs’ catalyst or Wilkinson’s catalyst. Chem. Commun. 2000, 1965-1966.

132. Yamamoto, Y.; Ogawa, R.; Itoh, K. Highly chemo- and regioselective [2+2+2] cycloaddition of unsymmetrical 1,6-diynes with terminal alkynes catalyzed by Cp*Ru(cod)Cl under mild conditions. Chem. Commun. 2000, 549-550.

133. Witulski, B.; Stengel, T. Rhodium(I)-catalyzed [2+2+2] cycloadditions with N- functionalized 1-alkynyl amides: a conceptually new strategy for the regiospecific synthesis of indolines. Angew. Chem., Int. Ed. 1999, 38, 2426-2430.

134. Yamamoto, Y.; Nagata, A.; Itoh, K. Pd(0)-catalyzed [2+2+2] cycloaddition of dimethyl nona-2,7-diyne-1,9-dioate derivatives with dimethyl acetylendicarboxylate. Tetrahedron Lett. 1999, 40, 5035-5038.

135. Negishi,E.; Harring, L. S.; Owczarczyk, Z.; Mohamud, M. M.; Ay, M. Cyclic cascade carbopalladation reactions as a route to benzene and fulvene derivatives. Tetrahedron Lett. 1992, 33, 3253-3256.

136. Suzuki, D.; Urabe, H.; Sato, F. Metalative Reppe reaction. Organized assembly of acetylene molecules on titanium template leading to a new style of acetylene cyclotrimerization. J. Am. Chem. Soc. 2001, 123, 7925-7926.

137. Asis, S.; Bruno, A. M.; Martinez, A. R., Sevilla, M. V.; Gaozzo, C. H.; Romano, A. M.; Coussio, J. D.; Ciccia, G. Diarylsemicarbazones: synthesis, antineoplastic activity and topoisomerase I inhibition assay. Il Farmaco 1999, 54, 517-523.

138. Obtained from the Dudley Laboratory Research Webpage: http://www.chem.fsu.edu/dudley/overview.html

139. Asao, N.; Takahashi, K.; Lee, S.; Kashahara, T.; Yamamoto, Y. AuCl3-catalyzed benzannulation: synthesis of naphthyl ketone derivatives from o-alkynylbenzaldehydes with alkynes. J. Am. Chem. Soc. 2002, 124, 12650-12651.

140. Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. Lewis acid-catalyzed benzannulation via unprecedented [4+2] cycloaddition of o-alkynyl(oxo)benzenes and enynals with alkynes. J. Am. Chem. Soc. 2003, 125, 10921-10925.

141. Asao, N.; Aikawa, H.; Yamamoto, Y. AuBr3-catalyzed [4+2] benzannulation between an enynal unit and enol. J. Am. Chem. Soc. 2004, 126, 7458-7459.

212

142. Asao, N.; Sato, K.; Menggenbateer; Yamamoto, Y. AuBr3- and Cu(OTf)2-catalyzed intramolecular [4+2] cycloaddition of tethered alkynyl and alkenyl enynones and enynals: a new synthetic method for functionalized polycyclic hydrocarbons. J. Org. Chem. 2005, 70, 3682-3685.

143. Barluenga, J.; Vasquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. Regioselective synthesis of substituted naphthalenes: a novel de novo approach based on metal-free protocol for stepwise cycloaddition of o-alkynylbenzaldehyde derivatives with either alkynes or alkenes. Org. Lett. 2003, 5, 4121-4123.

144. Yue, D.; Ca, N. D.; Larock, R. C. Efficient syntheses of heterocycles and carbocycles by electrophilic cyclization of acetylenic aldehydes and ketones. Org. Lett. 2004, 6, 1581- 1584.

145. Sato, K.; Asao, N.; Yamamoto, Y. Efficient method for synthesis of angucyclinone antibiotics via gold-catalyzed intramolecular [4+2] benzannulation: enantioselective total synthesis of (+)-ochryomycinone and (+)-rubiginone B2. J. Org. Chem. 2005, 70, 8977- 8981.

146. Lemhadri, M.; Doucet, H.; Santelli, M. Sonogashira reaction of aryl halides with propiolaldehyde diethyl acetal catalyzed by a tetraphosphine/palladium complex. Tetrahedron 2005, 61, 9839-9847.

147. Kehoe, J. M.; Kiley, J. H.; English, J. J.; Johnson, C. A.; Peterson, R. C.; Haley, M. M. Carbon networks based on dehydrobenzoannulenes. 3. Synthesis of graphyne substructures. Org. Lett. 2000, 2, 969-972.

148. Kimball, D. B.; Haley, M. M. Triazenes: a versatile tool in organic synthesis. Angew. Chem. Int. Ed. 2002, 41, 3338-3351.

149. Moore, J. S.; Weinstein, E. J.; Wu, Z. A convenient masking group for aryl iodides. Tetrahedron Lett. 1991, 22, 2465-2466.

150. Satyamurthy, N.; Barrio, J. R. Cation exchange resin (hydrogen form) assisted decomposition of 1-aryl-3,3-dialkyltriazenes. A mild and efficient method for the synthesis of aryl iodides. J. Org. Chem. 1983, 48, 4396-4397.

151. Lertpibulpanya, D.; Marsden, S. P. Concise access to indolizidine and pyrroloasepine skeletal via intramolecular Schmidt reactions of azido 1,3-diketones. Org. Biomol. Chem. 2006, 4, 3498-3504.

152. Wang, C.; Tobrman, T.; Xu, Z.; Negishi, E. Highly regio- and stereoselective synthesis of (Z)-trisubstituted alkenes via propyne bromoboration and tandem Pd-catalyzed cross- coupling. Org. Lett. 2009, 11, 4092-4095.

213

153. American Cancer Society website review of melanoma: http://www.cancer.org/docroot/CRI/content/CRI_2_2_1X_What_is_melanoma_skin_can cer_50.asp?sitearea.

154. Cancer.netTM, oncologist-approved cancer information from the American Society of Clinical Oncology: http://www.cancer.net/patient/Cancer+Types/Melanoma?sectionTitle=Overview.

155. Tucker, M. A. Melanoma epidemiology. Hematol. Oncol. Clin. N. Am. 2009, 23, 383- 395.

156. National Cancer Institute, from the U.S. National Institutes of Health: http://www.cancer.gov/cancertopics/wyntk/melanoma/page1.

157. Atzpodien, J.; Morawek, L.; Fluck, M. Bleomycin, vinorelbine and trofosamide in relapsed stage IV cutaneous malignant melanoma patients. Cancer Chemother. Pharmacol. 2009, 64, 901-905.

158. Yang, A. S.; Chapman, P. B. The history and future of chemotherapy for melanoma. Hematol. Oncol. Clin. N. Am. 2009, 23, 583-597.

159. Bedikan, A. Y.; Papadopoulos, N. E.; Kim, K. B.; Hwe, W. –J.; Homsl, J.; Glass, M. R.; Cain, S.; Rudewicz, P.; Vernillet, L.; Hwe, P. A phase IB trial of intravenous INO-1001 plus oral temozolomide in subjects with unresurrectable stage—III or IV melanoma. Cancer Investigation 2009, 27, 756-763.

160. Bakus, B. J.; Targett, N. M.; Schulte, B. Chemical ecology of marine organisms: an overview. J. Chem. Ecol. 1986, 12, 951-987.

161. In Ecological roles of marine natural products. Paul, V. J., Ed.; Comstock: Ithaca, New York, 1992.

162. Pawlik, J. R. Marine invertebrate chemical defense. Chem. Rev. 1993, 93, 1911-1922.

163. Hay, M. E. Marine chemical ecology: what’s known and what’s next. J. Exp. Mar. Biol. Ecol. 1996, 200, 103-134.

164. McClintock, J. B.; Baker, B. J. A review of the chemical ecology of Antarctic marine invertebrates. Amer. Zool. 1997, 37, 329-342.

165. Bakus, G. J.; Green, G.; Toxicity in sponges and holothurians: a geographic pattern. Science 1974, 185, 951-953.

166. Green, G. Ecology of toxicity of marine sponges. Mar. Biol. 1977, 40, 207-215.

214

167. Bakus, G. J. Chemical defense mechanisms in the Great Barrier Reef, Australia. Science 1981, 211, 497-498.

168. Dayton, P. K; Robilliard, G. A.; DeVries, A. L. Anchor ice formation in McMurdo Sound, Antarctica and its biological effects. Science 1969, 163, 273-274.

169. Dayton, P. K.; Robilliard, G. A.; Paine, R. T.; Dayton, L. B. Biological accommodation in the benthic community at McMurdo Sound, Antarctica. Ecol. Monogr. 1974, 44, 105- 128.

170. Dayton, P. K.; Mordida, B. J.; Bacon, F. Polar marine communities. Amer. Zool. 1994, 34, 90-99.

171. Eastman, J. T. In Antarctic fish biology: evolution in a unique environment. Academic Press, Inc.: New York, 1993.

172. McClintock, J. B. Trophic biology of shallow-water Antarctic echinoderms. Mar. Ecol. Prog. Ser. 1994, 111, 191-202.

173. Amsler, C. D.; Iken, K. B.; McClintock, J. B.; Baker, B. J. In Marine Chemical Ecology, McClintock, J. B.; Baker, B. J. Eds.; CRC Press: Boca Raton, FL, 2001; 267-300.

174. Information available through the Antarctic Treaty Secretariat: http://www.ats.aq/.

175. Diyabalanage, T.; Amsler, C. D.; McClintock, J. B.; Baker, B. J. Palmerolide A, a cytotoxic macrolide from the Antarctic tunicate Synoicum adareanum. J. Am. Chem. Soc. 2006, 128, 5630-5631.

176. Martinez-Ziguilan, R.; Lynch, R. M.; Martinez, G. M.; Gillies, R. J. Am. J. Physiol. Cell Physiol. 1993, 265, C1015-C1029.

177. Boyd, M. R.; Farina, C.; Belfiore, P.; Gagliardi, S.; Kim, J. W.; Hayakawa, Y.; Beutler, J. A.; McKee, T. C.; Bowman, B. J.; Bowman, E. J. J. Pharmacol. Exper. Ther. 2001, 297, 114-120.

178. Xie, X. S.; Pardon, D.; Liao, X.; Wang, J. Roth, M. G.; De Brabander, J. K. Salicylihalamide A inhibits the V0 sector of the V-ATPase through a mechanism distinct from Bafilomycin A1. J. Biol. Chem. 2004, 279, 19755-19763.

179. Bowman, E. J.; Siebers, A.; Karlheinz, A. Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 7972-7976.

180. Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. Oximidines I and II: novel antitumor macrolides from Pseudomonas sp. J. Org. Chem. 1999, 64, 153-155.

215

181. Obtained through personal communications with Bill Baker.

182. Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. Total synthesis and structural revision of the marine metabolite palmerolide A. J. Am. Chem. Soc. 2007, 129, 6386- 6387.

183. Nicolaou, K. C.; Guduru, R.; Sun, Y. –P.; Banerji, B.; Chen, D. Y. –K. Total synthesis of the originally proposed and revised structure of palmerolide A. Angew. Chem. Int. Ed. 2007, 46, 5896-5900.

184. Jagel, J.; Maier, M. E. Formal synthesis of palmerolide A. Synthesis 2009, 2881-2892.

185. Penner, M.; Rauniyar, V.; Kaspar, L. T.; Hall, D. G. Catalytic asymmetric synthesis of palmerolide A via organoboron methodology. J. Am. Chem. Soc. 2009, 131, 14216- 14217.

186. Kaliappan, K.; Gowrisankar, P. Synthetic studies on the marine natural product, palmerolide A: synthesis of C1-C9 and C15-C21 fragments. Synlett 2007, 1537-1540.

187. Chandrasekhar, S.; Vijeender, K. Chandrasekhar, G.; Reddy, Ch. R. Towards the synthesis of palmerolide A: asymmetric synthesis of C1-C14 fragment. Tetrahedron: Asymmetry 2007, 18, 2473-2478.

188. Cantagrel, G.; Meyer, C.; Cossy, J. Synthetic studies towards the marine natural product palmerolide A: synthesis of the C3-C15 and C16-C23 fragments. Synlett 2007, 2983-2986.

189. Shirokawa, S. –i.; Kamiyama, M.; Nakamura, T.; Okada, M.; Nakazaki, A.; Hosokawa, S.; Kobayashi, S. Remote asymmetric induction with vinylketene N,O-acetal. J. Am. Chem. Soc. 2004, 126, 13604-13605.

190. Marshall, J.; Eidam, P. Diastereoselective additions of vinylzinc reagents to -chiral aldehydes. Org. Lett. 2004, 6, 445-448.

191. Urbansky, M.; Davis, C. E.; Surjan, J. D.; Coates, R. M. Synthesis of enantiopure 2-C- methyl-D-erythritol-4-phosphate and 2,4-cyclodiphosphate from D-arabitol. Org. Lett. 2004, 6, 135-138.

192. Takai, K.; Shinomiya, N.; Kai, A.; Saigo, K. Transformation of aldehydes into (E)-1- alkenylboronic esters with a germinal dichromium reagent derived from a dichloromethylboronic ester and CrCl2. Synlett 1995, 963-964.

193. Govoni, M.; Lim, H. D.; El-Atmioui, D.; Menge, W. M. P. B.; Timmerman, H.; Bakker, R. A.; Leurs, R.; De Esch, I. J. P. A chemical switch for the modulation of the functional activity of higher homologues of histamine on the human histamine H3 receptor: effects

216

of various substitutions at the primary amino function. J. Med. Chem. 2006, 49, 2549- 2557.

194. Inanaga, J.; Hirata, K.; Saeki, H.; Kastuki, T.; Yamaguchi, M. A rapid esterification by means of mixed anhydride and its application of large-ring lactonization. Bull. Chem. Soc. Jpn. 1979, 52, 1989-1993.

195. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. A versatile and highly selective hypervalent iodine (III)/2,2,6,6-tetramethyl-1-piperidinyloxy-mediated oxidation of alcohols to carbonyl compounds. J. Org. Chem. 1997, 62, 6974-6977.

196. Stork, G.; Nakamura, E. Large-ring lactones by internal ketophosphonate cyclizations. J. Org. Chem. 1979, 44, 4010-4011.

197. Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartrolli, J. M. Chiral enolate design. Pure Appl. Chem. 1981, 53, 1109-1127.

198. Makabe, h.;, Higuchi, M.; Konno, H.; Murai, M.; Miyoshi, H. Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin. Tetrahedron Lett. 2005, 46, 4671- 4675.

199. Brown, H. C.; Jadhav, P. K.; Bhat, K. S. Chiral synthesis via organoboranes. 13. A highly diastereoselective and enantioselective addition of [(Z)--alkoxyallyl]- diisopinocampheylboranes to aldehydes. J. Am. Chem. Soc. 1988, 110, 1535-1538.

200. Kocovsky, P. Carbamates: a method of synthesis and some synthetic applications. Tetrahedron Lett. 1986, 27, 5521-5524.

201. Boden, C. D. J.; Pattenden, G.; Ye, T. Palladium-catalyzed hydrostannylations of 1- bromoalkynes. A practical synthesis of (E)-1-stannylalk-1-enes. J. Chem. Soc., Perkin Trans. 1 1996, 2417-2419.

202. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. Highly selective hydrolytic kinetic resolution of terminal epoxides catalyzed by chiral (salen) Co(III) complexes. Practical synthesis of enantioenriched terminal epoxides and 1,2-diols. J. Am. Chem. Soc. 2002, 124, 1307- 1315.

203. Yin, L.; Liebscher, J. Carbon—carbon coupling reactions catalyzed by heterogeneous palladium catalysts. Chem. Rev. 2007, 107, 133-173.

204. Takai, K.; Utimoto, N. K. Simple and selective method for aldehydes  (E)-haloalkenes (RCH=CHX) conversion by means of a haloform-chromous chloride system. J. Am. Chem. Soc. 1986, 108, 7408-7410.

217

205. Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Copper-catalyzed coupling of amides and carbamates with vinyl halides. Org. Lett. 2003, 5, 3667-3669.

206. Nicolaou, K. C.; Sun, Y. –P.; Guduru, R.; Banerji, B.; Chen, D. Y. –K. Total synthesis of the original proposed structures of palmerolide A and isomers thereof. J. Am. Chem. Soc. 2008, 130, 3633-3644.

207. Nicolaou, K. C.; Leung, G. Y. C.; Dethe, D. H.; Guduru, R.; Sun, Y. –P.; Lim, C. S.; Chen, D. Y. –K. Chemical synthesis and biological evaluation of palmerolide A analogues.

208. Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. Asymmetric transfer hydrogenation of ,-acetylenic ketones. J. Am. Chem. Soc. 1997, 119, 8738-8739.

209. Kolb, H. C.; VanNieuwnhze, M. S.; Sharpless, K. B. Catalytic asymmetric dihydroxylation. Chem. Rev. 1994, 94, 2483-2547.

210. Roth, G. J.; Liepold, B.; Muller, S. G.; Bestmann, H. J. Further improvement of the synthesis of alkynes from aldehydes. Synthesis 2004, 59-62.

211. Negishi, E. –i. Bull. Chem. Soc. Transition metal-catalyzed organometallic reactions that have revolutionized organic synthesis. Bull. Chem. Soc. Jpn. 2007, 80, 233-257.

212. Rauniyar, V.; Hall. D. G. Rationally improved chiral Brønsted acid for catalytic enantioselective allylboration of aldehydes with an expanded reagent scope. J. Org. Chem. 2009, 74, 4236-4241.

213. Gao, X.; Hall, D. G. 3-Boronoacrolein as an exceptional heterodyne in the highly enantio- and diastereoselective Cr(III)-catalyzed three component [4+2]allylboration. J. Am. Chem. Soc. 2003, 125, 9308-9309.

214. Burke, S. D.; Fobare, W. F.; Pacofsky, G. J. Chelation control of enolate geometry. Acyclic diastereoselection via the enolate Claisen rearrangement. J. Org. Chem. 1983, 48, 5221-5228.

215. Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Highly enantio- and diastereoselective hetero-Diels-Alder reactions catalyzed by new chiral tridentate chromium(III) catalysts. Angew. Chem. Int. Ed. 1999, 38, 2398-2400.

216. Kamijo, S.; Dudley, G. B.; Claisen-type condensation of vinylogous acyl triflates. Org. Lett. 2006, 8, 175-177.

217. Kamijo, S. Dudley, G. B. Tandem nucleophilic addition/fragmentation reactions and synthetic versatility of vinylogous acyl triflates. J. Am. Chem. Soc. 2006, 128, 6499- 6507.

218

218. Tummatorn, J.; Dudley, G. B. Ring opening/fragmentation of dihydropyrones for the synthesis of homopropargyl alcohols. J. Am. Chem. Soc. 2008, 130, 5050-5051.

219. Furstner, A.; Langemann, K. Total synthesis of (+)-ricinelaidic acid lactone and (-) – gloesporone based on transition-metal-catalyzed C-C bond formations. J. Am. Chem. Soc. 1997, 119, 9130-9136.

220. Michaunt, A.; Boddaert, T.; Coquerel, Y.; Rodriguez, J. Reluctant cross-metathesis reactions: the highly beneficial effect of microwave irradiation. Synthesis 2007, 18, 2867-2871.

221. Prepared in two steps (one pot) from 4-pentynol (85% yield), see: Vatale, J. –M. One- pot selective oxidation/olefination of primary alcohols using TEMPO-BAIB system and stabilized phosphorus ylides. Tetrahedron Lett. 2006, 47, 715-718.

222. Corey, E. J.; Helal, C. J. Reduction of carbonyl compounds with chiral oxazaborolidine catalysts: a new paradigm for enantioselective catalysis and powerful new synthetic method. Angew. Chem. Int. Ed. 1998, 37, 1986-2012.

223. For a similar procedure, see: Kumar, P.; Naidu, V. Enantio- and diastereocontrolled total synthesis of (+)-boronolide. J. Org. Chem. 2006, 71, 3935-3941.

224. Claisen, L., Lowman, O. A new method for the synthesis of benzoyl acetic esters. Ber. 1887, 20, 651-654.

225. Davis, B. R.; Garratt, P. J. Acylation of esters, ketones, and nitriles. In Comprehensive Organic Synthesis; Trost, B. M.; Flemming, I. Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 795-863.

226. Hauser, C. R.; Hudson, D. E. Jr. Acetoacetic ester condensation and certain related reactions. Org. React. 1942, 1, 266-302.

227. Hauser, C. R.; Swamer, F. W.; Adams, J. T. 1,3,5-Triacetylbenzene. Org. React. 1954, 8, 59.

228. For Diekmann condensation see: Schaefer, J. P.; Bloomfield, J. J. Diekmann condensation (Including the Thorpe-Ziegler condensation). Org. React. 1967, 15, 1-203.

229. Bordwell, F. G. Equilibrium acidities in dimethyl sulfoxide solution. Acc. Chem. Res. 1988, 21, 456-463.

230. Zhang, X. –M.; Bordwell, F. G.; Van Der Puy, M.; Fried, H. E. Equilibrium acidities and hemolytic bond dissociation energies of the acidic C—H bonds in N-substituted trimethylammonium and pyridinium cations. J. Org. Chem. 1993, 58, 3060-3066.

219

231. Kelly, S. E. Alkene synthesis. In Comprehensive Organic Synthesis; Trost, B. M.; Flemming, I. Eds.; Pergamon: Oxford, 1991; Vol. 1, pp 729-818.

232. Maryanoff, B. E.; Reitz, A. B. The Wittig olefination and modifications involving phosphoryl-stabilized carbanions. Stereochemistry, mechanism, and selected synthetic aspects. Chem. Rev. 1989, 89, 863-927.

233. Vedejs, E.; Peterson, M. J. Stereochemistry and mechanism in the Wittig reaction. Top. Stereochem. 1994, 21, 1-157.

234. Boutagy, J.; Thomas, R. Olefin synthesis with organic phosphonate carbanions. Chem. Rev. 1974, 74, 87-99.

235. Heron, B. M. Heterocycles from intramolecular Wittig, Horner and Wadsworth-Emmons reactions. Heterocycles 1995, 41, 2357-2386.

236. Ernst, H.; Muenster, P. Carotenoid Synthesis. Wittig and Horner-Emmons reactions. Carotenoids 1996, 2, 307-310.

237. Lawrence, N. J. The Wittig reaction and related methods. Preparation of Alkenes 1996, 19-58.

238. Nicolaou, K. C.; Harter, M. W.; Gunzer, J. L.; Nadin, A. The Wittig and related reactions in natural products synthesis. Liebigs Annalen/Recueil 1997, 1283-1301.

239. Motoyoshiya, J. Recent developments in the Z-selective Horner-Wadsworth-Emmons reactions. Trends in Organic Chemistry 1998, 7, 63-73.

240. Minami, T.; Okauchi, T.; Kouni, R. -Phosphonovinyl carbanions in organic synthesis. Synthesis 2001, 349-357.

241. Prunet, J. Recent methods for the synthesis of (E)-alkene units in macrocyclic natural products. Angew. Chem. Int. Ed. 2003, 2, 2826-2830.

242. Still, W. C.; Gennari, C. Direct synthesis of Z-unsaturated esters. Tetrahedron Lett. 1983, 24, 4405-4408.

243. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Horner-Wadsworth-Emmons reaction: use of lithium chloride and an amine for base-sensitive compounds. Tetrahedron Lett. 1984, 25, 2183-2186.

244. Iorga, B.; Eymery, F.; Mouries, V.; Savignac, P. Phosphorylated aldehydes: preparation and synthetic uses. Tetrahedron 1998, 54, 14637-14677.

245. Arbuzov, B. A. Michaelis-Arbuzov and Perkow reactions. Pure Appl. Chem. 1964, 9, 307-353.

220

246. Bhattacharya, A. K.; Thyagarajan, G. Michaelis-Arbuzov rearrangement. Chem. Rev. 1981, 81, 415-430.

247. Recent Example: Somu, R. V.; Boshoff, J.; Quao, C.; Bennet, E. M.; Barry, C. E. Aldrich, C.C. Rationally designed nucleoside antibiotics that inhibit siderophore biosynthesis of Mycobacterium tuberculosis. J. Med. Chem. 2006, 49, 31-34.

248. Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. Regioselective synthesis of fluoroalkylated -aminophosphorus derivatives and aziridines from phosphorylated oximes and nucleophilic reagents. J. Org. Chem. 2006, 71, 6141-6148.

249. Wetermann, J.; Schneider, M.; Platzek, J.; Petrov, O. Practical synthesis of a heterocyclic immunosuppressive vitamin D analog. Org. Process Res. Dev. 2007, 11, 200-205.

250. Maloney, K. M.; Chung, J. Y. A general procedure for the preparation of - ketophosphonates. J. Org. Chem. 2009, 74, 7574-7576.

251. Milburn, R. R.; McRae, K.; Chan, J.; Tedrow, J.; Larsen, R.; Faul, M. A practical synthesis of -ketophosphonates. Tetrahedron Lett. 2009, 50, 870-872.

252. Yamashita, A.; Brown, C. A. Saline hydrides and superbases in organic reactions. IX. Acetylene zipper. Exceptionally facile contrathermodynamic multipositional isomerization of alkynes with potassium 3-aminopropylamide. J. Am. Chem. Soc. 1975, 97, 891-892.

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BIOGRAPHICAL SKETCH

Birth Place

Melrose, Massachusetts  February 3rd, 1981

Educational Background

Florida State University, Tallahassee, FL  August 2004 to December 2009  Ph.D. in Organic Chemistry (anticipated completion in December 2009)  Research Advisor: Professor Gregory B. Dudley

Barry University, Miami Shores, FL  August 1999 to December 2003  B.S. degree in Chemistry, B.S. degree in Biology – cum laude  Research Advisor: Professor Paul I. Higgs

The Canterbury School, Ft. Myers, FL  August 1995 to June 1999

Future Position

University of Pennsylvania, Philadelphia, PA  Beginning January 2010  Postdoctoral Research Associate  Under the supervision of Professor Amos B. Smith, III

Awards and Honors

 Gamma Sigma Epsilon, National Chemistry Honors Society (2002).  Polymer Chemist Societies Award for Outstanding Performance in Organic Chemistry (2002).  Outstanding Graduating Senior for Performance in Physical Sciences, Mathematics, and Computer Sciences, School of Arts and Sciences, Barry University (2003.  Golden Key, Graduate Student Honor Society (2007-2009).

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Publications

(2) Jones, D. M.; Dudley, G. B. Synthesis of the C1-C15 region of palmerolide A using a refined Claisen-type addition / bond cleavage methodology. Synlett, in press.

(1) Jones, D. M; Kamijo, S.; Dudley, G. B. Grignard triggered fragmentation of vinylogous acyl triflates: synthesis of (Z)-6-heneicosen-11-one, the Douglas-fir tussock moth. Synlett 2006, 936-938.

Presentations

(2) ―Organic Synthesis and Methodology: Towards the Illudalane Sesquiterpenoids.‖ Jones, D. M.; Dudley, G. B. Presented at the Florida Annual Meeting and Exposition (FAME), Orlando, FL, Summer 2007.

(1) ―Grignard triggered fragmentation of vinylogous acyl triflates: synthesis of (Z)-6- heneicosen-11-one, the Douglas-fir tussock moth.‖ Jones, D. M.; Kamijo, S.; Dudley, G. B. Presented at the 231st ACS Annual Meeting, Atlanta, GA, March 28th, 2006.

Posters

(2) ―An Addition / Fragmentation Approach to Palmerolide A.‖ Jones, D. M.; Jeong-Im, J.; Dudley, G. B. Presented at the Gordon Research Conference on Natural Products, Tilton, NH, July 26th-31st, 2009.

(1) ―Progress Towards Palmerolide A.‖ Jeong, J.; Jones, D. M.; Dudley, G. B. Presented at The 236th ACS National Meeting, Philadelphia, PA, August 17th-21st, 2008.

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