Formal Synthesis of Palmerolide a Using Fragmentation Methodology Marilda Pereira Lisboa

Florida State University Libraries

Electronic Theses, Treatises and Dissertations The Graduate School

2013 Formal Synthesis of Palmerolide a Using Fragmentation Methodology Marilda Pereira Lisboa

Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected]

THE FLORIDA STATE UNIVERSITY

COLLEGE OF ARTS AND SCIENCES

FORMAL SYNTHESIS OF PALMEROLIDE A

USING FRAGMENTATION METHODOLOGY

MARILDA PEREIRA LISBOA

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, 2013

Marilda Pereira Lisboa defended this dissertation on April 1, 2013.

The members of the supervisory committee were:

Gregory B. Dudley

Professor Directing Dissertation

Akash Gunjan

University Representative

Igor V. Alabugin

Committee member

Lei Zhu

Committee member

Michael Shatruk

Committee member

The Graduate School has verified and approved the above-named committee members, and certifies that the dissertation has been approved in accordance with university requirements.

ACKNOWLEDGEMENTS

The PhD is definitely a life changing experience. I gained knowledge, I learned how to build knowledge and I exchanged knowledge with various people during this journey. Without a doubt, the person that helped me the most during the process was my advisor Dr Gregory

Dudley. I would like to thank Dr Dudley for all his support. In the beginning, I had no idea of how much I would learn from him, not only in the scientific level, but also in the personal level. I am grateful because I had the opportunity to work with a role model like Dr Dudley.

There are countless other people that help me during the last five years. Without listing their names, I just want to thank everyone for their contributions and friendship:

my friends from the Dudley lab,

my friends from the other labs,

my professors,

my students,

the staff from the Chemistry and Biochemistry Department,

the janitors,

my friends from UFMG in Brazil,

Fulbright and Capes,

my committee members,

and my family…

iii

TABLE OF CONTENTS

LIST OF TABLES ...... v

LIST OF FIGURES ...... vi

LIST OF ABBREVIATIONS ...... x

ABSTRACT ...... xiv

CHAPTER 1 - PALMEROLIDE A ...... 1

CHAPTER 2 - TOTAL SYNTHESES AND APPROACHES TOWARDS PALMEROLIDE A . 7

CHAPTER 3 - RING OPENING OF CYCLIC VINYLOGOUS ACYL TRIFLATES USING STABILIZED CARBANION NUCLEOPHILES ...... 41

CHAPTER 4 - FORMAL SYNTHESIS OF PALMEROLIDE A ...... 67

CHAPTER 5 - ENDEAVORS IN THE SYNTHESIS OF PALMEROLIDE A ...... 91

CHATER 6 - FUTURE DIRECTIONS ...... 112

APPENDIX A ...... 114

APPENDIX B ...... 121

APPENDIX C ...... 138

REFERENCES ...... 147

BIOGRAPHICAL SKETCH ...... 155

LIST OF TABLES

Table 1 - V-ATPase inhibition versus cytotoxicity of palmerolides A, D, E, F and G...... 3

Table 2 - Cytotoxicity of palmerolide A and some analogues...... 6

Table 3 - Overview of the synthetic sequences to palmerolide A...... 39

Table 4 - Reaction of vinylogous acyl triflates with 1.1 equiv of phosphonate ...... 55

LIST OF FIGURES

Figure 1 - Structure of palmerolides A-G...... 2

Figure 2 - First-generation of palmerolide A analogues...... 4

Figure 3 - Second-generation of palmerolide A analogues...... 6

Figure 4 - Retrosynthesis of proposed structure of palmerolide A...... 8

Figure 5 - Synthesis of fragment 29...... 8

Figure 6 - Preparation of fragments 30 and 31...... 9

Figure 7 - De Brabander synthesis of proposed structure 28 and ent-1...... 10

Figure 8 - Retrosynthesis of proposed structure of palmerolide A...... 11

Figure 9 - Synthesis of fragment 40...... 11

Figure 10 - Preparation of fragment 41...... 12

Figure 11 - Preparation of fragment 42...... 12

Figure 12 - Synthesis of proposed (28) and revised structure of palmerolide A (1)...... 13

Figure 13 - Improvements in the synthesis reported by Nicolaou/Chen...... 14

Figure 14 - Alternative macrocyclization strategies for the synthesis of palmerolide A...... 15

Figure 15 - Organoboron methodologies developed in Hall lab...... 16

Figure 16 - Retrosynthesis of palmerolide A by Hall and coworkers...... 17

Figure 17 - Synthesis of fragment 56...... 18

Figure 18 - Synthesis of fragment 57...... 19

Figure 19 - Completion of the synthesis of palmerolide A...... 19

Figure 20 - Retrosynthesis of palmerolide A by Maier group...... 20

Figure 21 - Preparation of fragments 81 and 82...... 21

Figure 22 - Preparation of fragment 69...... 21

Figure 23 - Completion of Maier formal synthesis...... 22

Figure 24 - Retrosyntheses of palmerolide A according to Prasad group...... 23

Figure 25 - Synthesis of fragment 40...... 24

Figure 26 - Synthesis of fragment 89...... 24

Figure 27 - Synthesis of the late intermediate 88 in Nicolaou/Chen synthesis...... 25

Figure 28 - Synthesis of fragment 90...... 25

Figure 29 - Synthesis of fragment 91...... 26

Figure 30 - Completion of the formal synthesis of palmerolide A...... 26

Figure 31 - Retrosynthesis of palmerolide A as reported by Kaliappan group...... 28

Figure 32 - Synthesis of fragment 111...... 28

Figure 33 - Synthesis of fragment 112...... 29

Figure 34 - Synthesis of fragment 113...... 30

Figure 35 - Completion of Kaliappan formal synthesis...... 30

Figure 36 - The C1-C14 fragment of palmerolide A by Chandrasekhar group...... 30

Figure 37 - Synthesis of the C1-C14 fragment of palmerolide A...... 31

Figure 38 - Retrosynthesis of palmerolide A according to Meyer/Cossy group...... 32

Figure 39 - Preparation of fragment 137...... 32

Figure 40 - Preparation of fragment 138...... 33

Figure 41 - Preparation of fragment 40...... 33

Figure 42 - Preparation of fragment C3-C15...... 33

Figure 43 - Fragment C3-C15 of palmerolide A...... 34

Figure 44 - Preparation of fragment C13-C21...... 34

Figure 45 - The C3-C14 fragment of palmerolide A by Baker group...... 35

Figure 46 - Preparation of fragment C3-C14...... 35

Figure 47 - Retrosynthetic analysis of palmerolide C and revised structure...... 36

Figure 48 - Preparation of fragments 165 and 167...... 37

vii

Figure 49 - Preparation of fragment 159...... 37

Figure 50 - Synthesis of the proposed structure of palmerolide C...... 38

Figure 51 - Prospective application to palmerolide A...... 41

Figure 52 - Mechanism of the classical Claisen condensation of ethyl acetate...... 42

Figure 53 - Fragmentation reactions...... 43

Figure 54 - Synthesis of VAT from a symmetrical dione...... 43

Figure 55 - VAT-Claisen reaction...... 44

Figure 56 - VAT-Claisen Reaction using lithium enolate of acetophenone...... 46

Figure 57 - Possible mechanistic pathways and deuterium-labeling experiment...... 47

Figure 58 - First report Claisen-type condensation reactions of VAT 177a...... 49

Figure 59 - Preparation of Horner-Wittig reagent 176f...... 50

Figure 60 - Proposed fragmentation reaction pathway between 177a and 192...... 50

Figure 61 - Crossover experiment with lithium enolate 195...... 52

Figure 62 - Proposed mechanism of the reaction between VAT 177a and 191...... 54

Figure 63 - Common methods for the preparation of phosphonates...... 54

Figure 64 - Byproducts 198b and 198c...... 56

Figure 65 - Synthesis of phosphonate 176i...... 57

Figure 66 - Synthesis of phosphonate 176m, an analogue of phosphonate 176i...... 58

Figure 67 - Proposed mechanism of the reaction between VAT 177 and phosphonates...... 59

Figure 68 - Retrosynthetic analysis: Identification of three key subunits for assembly to palmerolideA...... 68

Figure 69 - Synthesis of phosphonate 202...... 68

Figure 70 - Synthesis of aldehyde 203...... 69

Figure 71 - Synthesis of iodide 204...... 70

Figure 72 - Assembly of subunits 202, 203 and 204 to complete the formal synthesis of palmerolide A...... 71

viii

Figure 73 - Synthesis of Horner-Wadsworth-Emmons reagent 176a...... 91

Figure 74 - Synthesis of fragments 215 and 217...... 92

Figure 75 - Synthesis of fragment C1-C15 of palmerolide A...... 93

Figure 76 - Olefination reaction between phosphine oxide 215 and aldehyde 217...... 93

Figure 77 - Synthesis of new aldehyde fragment 203...... 94

Figure 78 - Synthesis of phosphonate 202 and enone 211...... 95

Figure 79 - (R)-CBS reduction of the C1-C15 fragment of palmerolide A...... 96

Figure 80 - CBS reduction of macrolactone 222 in the synthesis of palmerolide A...... 97

Figure 81 - Palmerolide A and targeted fragment C16-C24...... 97

Figure 82 - Convergent Negishi coupling for the preparation of aldehyde 229...... 98

Figure 83 - Homopropargylation by Grignard addition and Singaram’s method...... 99

Figure 84 - Unexpected carbometalation difficulties (top), and an unusual substitution reaction under identical conditions...... 100

Figure 85 - Synthesis of target C16-C24 fragment...... 100

Figure 86 - Attempts to convert aldehyde 238 to dienamide 239...... 101

Figure 87 - Model study applied to the macrocyclization event...... 102

Figure 88 - Alternative vinylogous aldol reaction...... 112

Figure 89 - Alternative macrocyclization by RCM...... 113

LIST OF ABBREVIATIONS

µM micromolar

Ac acetyl

AD-mix asymmetric dihydroxylation mixture

BBN borabicyclononane

BH3.THF borane tetrahydrofuran complex

Bn benzyl

Bz benzoyl

CBS Corey-Bakshi-Shibata

Cp cyclopentadienyl

CSA camphorsulfonic acid dba dibenzylideneacetone de diastereomeric excess

DEAD diethyl azodicarboxylate

DIPT diisopropyl tartrate

DMAP dimethylaminopyridine

DMEDA N, N-dimethylethylenediamine

DMF dimethylformamide

DMP Dess-Martin periodinane

DMS dimethylsulfide dr diastereomeric ratio

EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide

ee enantiomeric excess

EI electron impact ent enantiomer equiv equivalent

ESI electrospray ionization

EWG electron withdrawing group

FT fourier transform g gram

GI50 growth inhibition, 50%

HF.py hydrogen fluoride pyridine complex

HMDS hexamethyldisilazane

HMPA hexamethylphosphoramide

HRMS high-resolution mass spectroscopy

HWE Horner-Wadsworth-Emmons

IBX iodoxybenzoic acid

IC50 inhibitory concentration, 50%

Imid imidazole iPr isopropyl

IR infrared

KAPA potassium aminopropylamine

K-Selectride potassium tri-sec-butylborohydride

LAH lithium aluminum hydride

LC50 lethal concentration, 50%

LDA lithium diisopropylamide

M molar m-CPBA meta-chloroperbenzoic acid mg milligram

MHz megahertz mL milliliter mmol milimol

MOM methoxymethyl ether

MS molecular sieves

NBS N-bromosuccinimide

NCI National Cancer Institute nM nanomolar

NMR nuclear magnetic resonance

NOE nuclear overhauser effect

Ph phenyl

PKS polyketide synthase

PMB para-methoxybenzyl

PMP para-methoxyphenyl ppm parts per million

PPTS pyridinium para-toluenesulfonate

RCM ring-closing metathesis

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

ROESY rotating frame overhauser effect spectroscopy

xii

SI selectivity index

TBAF tetrabutylammonium fluoride

TBDPS tert-butyldiphenyl silyl

TBS tert-butyldimethylsilyl tBu tert-butyl

TCBC trichlorobenzoyl chloride

TEMPO tetramethylpiperidyl oxide

TES triethyl silyl

Tf triflate

THP tetrahydropyran

TIPS triisopropyl silyl

TLC thin-layer chromathography

TMS trimethylsilyl

Tr trityl or triphenylmethyl

Ts tosyl

VAT vinylogous acyl triflate

V-ATPase vacuolar adenosine triphosphatase

xiii

ABSTRACT

In this dissertation is described the formal synthesis of the natural product palmerolide A, using an addition/ fragmentation reaction of vinylogous acyl triflates developed in the Dudley

Lab. In the first chapter, the isolation and biological activity of palmerolide A and analogues are presented. Palmerolide A has promising biological activity relevant to melanoma research, and chemical synthesis is the only reliable source of the material. The second chapter contains a brief description of the reported syntheses of palmerolide A, as well as the various approaches towards this molecule and congeners. In chapter three, the fragmentation of vinylogous acyl triflates using stabilized carbanion nucleophiles is discussed. The mechanistic studies and the optimization that resulted in a practical synthesis of one of the fragments of palmerolide A are detailed. The formal synthesis of palmerolide A developed by the Dudley Lab and some tactical challenges are illustrated in chapter four. The next chapter includes several obstacles, efforts and the solutions that made possible the formal synthesis of this natural product. Future directions of the project are presented in chapter six. The synthesis of palmerolide A described in this thesis is the highest yielding synthesis reported to date.

xiv

CHAPTER 1

PALMEROLIDE A

Antarctic marine natural products offer exciting and underexplored opportunities for drug discovery. Antarctica is secluded from other continents by large distances, deep waters and marine currents, such that its ecosystem is isolated from the rest of the globe.1 The Antarctic marine fauna had to adapt to extreme local and cold environmental conditions.2 One way of adaptation is chemical defense. Sessile marine invertebrates, for instance, protect themselves from mobile predators and microorganisms via secondary metabolites.3 In this context, the study of this secluded location can lead to the isolation of unique compounds.4

The palmerolides (Figure 1) are a group of natural products isolated from the tunicate

Synoicum adareanum encountered in the cold shallow waters of Antarctica near Anvers Island.5,6

Palmerolide A (1) is a twenty-membered ring macrolide bearing an enamide side chain.

Palmerolide A is the most prominent member of this group, which is mainly due to its cytotoxicity. In the National Cancer Institute (NCI) sixty cell panel, palmerolide A targets melanoma (UACC-62, LC50 = 18 nM), colon cancer (HCC-2998, LC50 = 6.5 µM) and renal cancer cell lines (RXF 393, LC50 = 6.5 µM) selectively by three orders of magnitude when compared to the other cell lines in the panel.5 Moreover, palmerolide A is a vacuolar proton

7 ATP-ase (V-ATPase) inhibitor (IC50 = 2 nM) and is active in the NCI-s hollow fiber assay.

Some interesting structural features of palmerolide A, such as the carbamate and the vinyl amide moieties, led the Baker group to hypothesize a bacterial origin for this polyketide. The microbial community of the tunicate Synoicum adareanum was characterized using a single colony, however further studies are necessary to discriminate the free-living bacteria and the

associated populations. One finding that can support the possibility of bacteria producing palmerolide was the identification of polyketide synthase (PKS) genes, similar to bryostatin biosynthetic genes.8

Figure 1 - Structure of palmerolides A-G.

The cytotoxicity and selectivity of palmerolide A are important, because melanoma is an aggressive type of cancer, for which current chemotherapies are lacking.9 Melanoma occurs in the melanocytes, mainly in the skin, but can also appear in other pigmented tissues, like eye and intestines.10 The cancer of the skin is the most common type of cancer, and melanoma accounts for only 5% of the skin cancer cases. However, melanoma is responsible for the majority of skin cancer deaths.11 The incidence rates for melanoma have been rising for more than thirty years. In

2013, 76690 new cases and 9480 deaths from melanoma are estimated in the United States.10

Palmerolide A is a potent V-ATPase inhibitor. Some V-ATPase inhibitors like salicylihalamide A12 and the bafilomycins13 are known to possess cytotoxic activity. V-ATPases

are proton pumps present in the membranes of endosomes, lysosomes and secretory vesicles.

These enzymes play a major role in cancer metastasis because they are responsible for microenviroment acidification. Data show that the acidity of the tumor microenviroment is correlated to cancer progression and metastasis.14-17

Since the isolation of palmerolide A by Dr. Bill Baker and coworkers in 2006, the mechanism of action for the cytotoxicity of this natural product is not entirely understood. The discrepancy between V-ATPase inhibition and cytotoxicity among the palmerolides suggests an additional mechanism of action. Considering the biological activity among the palmerolides, palmerolide D is less potent towards V-ATPase (IC50 = 25 nM) than palmerolide A, but it presents greater cytotoxicity (UACC-62 LC50 = 2 nM). Also, palmerolide G is a very potent V-

ATPase inhibitor (IC50 = 7 nM), but it presents lower cytotoxicity (UACC-62 LC50 = 1200 nM) when compared to palmerolide A (Table 1).

Table 1 - V-ATPase inhibition versus cytotoxicity of palmerolides A, D, E, F and G. Palmerolide A Palmerolide D Palmerolide E Palmerolide F Palmerolide G V-ATPase 0.002 0.025 >10.000 0.063 0.007 (IC50, µM) UACC-62 0.024 0.002 5.000 0.758 1.207 (LC50, µM)

Additional biological studies are crucial to identify the molecular targets of palmerolide

A. For that, chemical synthesis is the best option to make available large amounts of palmerolide.

The accessibility of palmerolide A from natural sources is limited because it was isolated from the remote Antarctic continent. Moreover, Antarctica is protected by the Antarctic Treaty, which prohibits the commercial exploitation of the region.18

To date, three total syntheses19-22 and four formal syntheses23-28 of palmerolide A have been reported, as well as various synthetic approaches.29-35 One formal synthesis28 and two approaches come from the Dudley research group.36,37 Besides that, one synthesis of the proposed structure of palmerolide C was recently reported38. The earliest syntheses developed by

De Brabander19 and by the Nicolaou/Chen20 groups led to the stereochemistry reassignment of the natural product at the C7, C10 and C11 positions from R to S. Later in the same year, the

Baker group reported degradative studies on natural palmerolide A corroborating the reassignment.39

Figure 2 - First-generation of palmerolide A analogues.

In addition to that, the syntheses of various analogues were reported by the Nicolaou and

Chen groups and their structure-activity relationship was investigated.40,41 In the first report on the synthesis and biological evaluation of palmerolide A analogues (Figure 2), Nicolaou and

Chen observed the in vitro activity of palmerolide A derivatives against various cancer cell lines.

Natural palmerolide A, synthetic palmerolide A, taxol and doxorubicin were used as controls.

Based on previous findings on the correlation of enamide containing molecules and V-ATPase inhibitory activity,12 the enamide portion of the molecule was the main modification site (2-6).

Besides that, a series of diastereomers (8-10), compounds with deletions of carbamate (11-15) or hydroxyl groups (16 and 17), and the enantiomer of palmerolide A were synthesized and their biological activities assessed.

The results showed that natural (UACC-62 GI50 = 57 nM) and synthetic (UACC-62 GI50

= 62 nm) palmerolide A have comparable activity, while the enantiomer of palmerolide A showed a decrease of activity by 100-fold (UACC-62 GI50 = 8077 nM). Modifications in the side chain usually led to a decrease in activity, with the exception of the benzamide analogue 5 that was more potent (UACC-62 LC50 = 9 nM) and the saturated analogue 3 (UACC-62 GI50 = 67 nM) which showed similar activity when compared to palmerolide A. The diastereomers presented a large decrease in activity or no activity. The deletion of the carbamate group (12,

UACC-62 GI50 = 322 nM) or hydroxyl group at C10 (16, UACC-62 GI50 = 6979 nM) also decreased the activity. However, deletion of the hydroxyl group at C7 does not change the

40 activity significantly, (17, UACC-62 GI50 = 63 nM).

In 2011, the Chen group reported the synthesis and biological evaluation of a second- generation of analogues. Structural variations in the enamide side chain and in the C1-C8 fragment of various palmerolide derivatives (Figure 3), without the hydroxyl group at C7, were tested against a series of cancer cells and human melanocytes (HM-2). The human melanocytes cells were used to calculate the selectivity index (SI = GI50 HM-2/ GI50 UACC-62).

The results have shown that deletion of the enamide side chain afforded compounds with no activity, substitutions in the aromatic ring of the benzamide (18-22) and modifications in the

C1-C8 fragments decreased the activity (24-27). The benzamide analogue 23 (no OH at C7)

showed a small decrease in activity (UACC-62 GI50 = 55 nM) when compared to analogue 5

(UACC-62 GI50 = 9 nM). None of the analogues tested were more selective and potent than the benzamide analogue 5 (SI = 256.6) (Table 2).41

Figure 3 - Second-generation of palmerolide A analogues.

Table 2 - Cytotoxicity of palmerolide A and some analogues. UACC-62 (µM) HM-2 (µM) SI 1 0.061 ± 0.011 6.177 ± 1.272 101.3 5 0.009 ± 0.000 2.309 ± 1.269 256.6 17 0.076 ± 0.010 14.006 ± 4.589 184.3 23 0.055 ± 0.011 8.256 ± 2.222 150.1

In summary, the natural product palmerolide A and congeners are promising anticancer agents, and further biological studies are necessary to comprehend the cytotoxicity and selectivity of this group. However, the availability of material from natural sources is limited as a result of the remote isolation area and the Antarctic treaty. Accordingly, chemical synthesis is the best alternative to afford the palmerolides, and improvements are required for a more efficient synthetic sequence.

CHAPTER 2

TOTAL SYNTHESES AND APPROACHES TOWARDS PALMEROLIDE A

Palmerolide A was isolated in 2006. Since then, three total syntheses and four formal syntheses were achieved. Additionally, several synthetic approaches targeting this natural product, including one towards the synthesis of palmerolide C have been published. In this chapter, I present a review of the synthetic sequences reported to date, and categorized by research groups, excluding the ones developed within the Dudley Lab. I then conclude by contrasting the various strategies underlying the synthesis of palmerolide A.

The De Brabander group

One year after the disclosure of palmerolide A, the De Brabander group published the first synthesis of the proposed structure along with the enantiomer of this natural product.19 The proposed structure 28 was synthesized, but its physical properties and NMR spectra diverged from the data for natural palmerolide A. Noteworthy, a reevaluation of the NMR spectra and

Mosher ester analysis, led to the synthesis of the enantiomer of palmerolide A.

Specifically, the synthesis was accomplished by the coupling of three fragments (i.e. the vinyl iodide 29, the boronate 30 and the phosphonate 31). The fragments were connected by a

Suzuki cross-coupling, followed by a Yamaguchi esterification and finalized by a Horner-

Wadsworth-Emmons olefination to give the macrocyclic core. The enamide side chain was installed at the end of the sequence by a Curtius rearrangement (Figure 4).19

Figure 4 - Retrosynthesis of proposed structure of palmerolide A.

Vinyl iodide 29 was prepared using a vinylogous aldol reaction between silyl enol ether

32 and vinyl iodide 33. The anti-aldol product 34 was obtained in 80% yield and diastereomeric ratio (dr) of 13:1. In this reaction, the alkene at C21-C22 and the stereocenter at C20 were installed. The stereochemistry of the hydroxyl at C19 was inverted by Mitsunobu protocol in

66% yield. Thus, chiral auxiliary cleavage using DIBAL, followed by olefination, gave fragment

29 in 92% over the 2 steps (Figure 5).19

Figure 5 - Synthesis of fragment 29.

Fragment 30 was synthesized from D-arabitol, taking advantage of the chirality of the starting material to set stereocenters C10 and C11. The synthesis was achieved in eight steps in a sequence of protecting group manipulations and reduction-oxidation reactions. Fragment 31 was prepared in five steps from δ-valerolactone (Figure 6).19

Figure 6 - Preparation of fragments 30 and 31.

The macrocyclic core of the proposed structure of palmerolide A commenced with an intricate Suzuki coupling between vinyl iodide 29 and boronate 30 using Pd(PPh3)4 and Tl2CO3.

The diene product was obtained in 79% yield and connected to fragment 31 using Yamaguchi conditions (69% yield). Protecting group manipulations and selective oxidation gave an aldehyde. Subsequently, macrocyclization using Horner-Wadsworth.-Emmons olefination afforded product 36 in 70% yield over two steps. The alcohol at C11 was protected as a TMS silyl ether and (S)-CBS reduction of C7 gave an alcohol in 99% yield and 4:1 dr. Following the reduction, TBS ether installation and saponification gave a carboxylic acid, which was converted to an acyl azide in 92% yield. Curtius rearrangement followed by addition of 2-Me- propenylmagnesium bromide gave dienamide 39. Installation of the carbamate and deprotection afforded the proposed structure 28 (Figure 7).19

Unfortunately, the NMR spectra revealed that the proposed structure differed from the natural product. Accordingly, reanalysis of the original data suggested that C19 and C20 stereocenters might have been misassigned. Mosher ester analysis was used to assign the stereochemistry of the triad C7, C10 and C11, but C19 and C20 were assigned based on coupling constants, NOE and ROESY experiments. The spectra clearly showed that C19 and C20 have a syn relative configuration. However, the stereochemistry might have been assigned erroneously.

Thus, the De Brabander group decided to synthesize the C19 and C20 epimer of the proposed structure (i.e. the enantiomer of palmerolide A).

The enantiomer of palmerolide A was synthesized using the same sequence of reactions through the enantiomer of vinyl iodide 29 (yields in red/parentheses in figure 7). Notably, the

(S)-CBS reduction of C7 favored the opposite diastereomer and the product was obtained in 98% yield and 1:3 dr (mismatched case). Reduction with NaBH4 also favored the wrong stereochemistry at C7 (1:10 dr) confirming the substrate bias.19

Figure 7 - De Brabander synthesis of proposed structure 28 and ent-1.

The spectroscopic data for natural palmerolide A and the synthesized enantiomer were identical, except for the mirror image CD-spectra. The Mosher ester analysis of C7, C10 and C11 described in the isolation of palmerolide A was incorrect, the reagents were switched.39 As a result, the structure of the natural product was corrected.19,20,39

Nicolaou and Chen groups

The second total synthesis of palmerolide A was reported by the Nicolaou/Chen group in

2007.20 Nicolaou and Chen synthesized the proposed and revised structures of palmerolide A.

The retrosynthesis was also based in the assembling of three fragments (Figure 8). The fragments vinyl iodide 40, stannane 41, and acid 42 were coupled using a Stille coupling, followed by a

Yamaguchi esterification, then, ring-closing metathesis afforded the macrocyclic core. In the final step, the enamide in the side chain was installed.

Figure 8 - Retrosynthesis of proposed structure of palmerolide A.

The first fragment 40 was synthesized from oxazolidinone 43 and vinyl iodide 33 in a syn-selective aldol reaction in 46% and 95% de. Then, removal of the chiral auxiliary, olefination and protecting group manipulations gave vinyl iodide 40 (Figure 9).

Figure 9 - Synthesis of fragment 40.

The synthesis of the second fragment 41 began with the reaction of aldehyde 45 and an organoborane to give a monoprotected diol (>95% de and > 90% ee). After removal of TMS

protecting group, alcohol 46 was obtained in 74% yield over two steps. Hence, the carbamate and the vinyl stannane moieties were installed in three steps (62% yield) to afford fragment 41

(Figure 10).20

Figure 10 - Preparation of fragment 41.

Fragment 42 was prepared from alkene 47. A Jacobsen kinetic resolution converted the

+ - alkene into epoxide 48 in 42% yield (2 steps) and 99% ee. Epoxide opening with Me3S I afforded alcohol 49, setting the hydroxyl stereochemistry at C7. Five more steps converted alcohol 49 to carboxylic acid 42 (Figure 11).20

Figure 11 - Preparation of fragment 42.

Subsequently, fragments 40 and 41 were connected in a Stille coupling using Pd(dba)2 and AsPh3 in 67%. The third fragment 42 was coupled with alcohol 50 in a Yamaguchi esterification in 61% yield. Two steps later, a Takai olefination installed a vinyl iodide in the side chain in preparation for the enamide coupling at the end of the synthesis. The MOM protecting groups were removed using acidic conditions. Grubbs II catalyst promoted the cyclization of structure 52 in 76% yield and the enamide was installed using Buchwald protocol in 44% yield to give the proposed structure of palmerolide A.

Figure 12 - Synthesis of proposed (28) and revised structure of palmerolide A (1).

While the Nicolaou/ Chen team was completing the synthesis, they observed difference between the natural product and the synthetic material by NMR. Meanwhile, De Brabander reported a synthesis of palmerolide A. Grounded in this foundation work, the Nicolaou/Chen group synthesized the revised structure of palmerolide A using the same synthetic sequence presented in Figure 12 using ent-41 and ent-42 (yields in red/parentheses). This time, the synthetic and natural palmerolide A were identical.

After the first report, Nicolaou and Chen published a paper detailing the synthesis of the proposed structure, the 19-epimer, the 20-epimer, the 19,20-epimer and the revised structure of palmerolide A.21 A similar sequence of reactions, as described above in Figure 12, was used to prepare all the compounds along with some improvements. For example, a vinylogous anti-aldol reaction was used to prepare the vinyl iodide fragment 40 (Figure 13) replacing the previous aldol reaction (43→44, Figure 9). This modification decreased the number of steps and allowed for the preparation of other isomers. Besides that, the order of fragments coupling was alternated.

Initially, fragments 40 and 41 were connected in a Stille coupling followed by Yamaguchi esterification with fragment 42 (32% over 2 steps for the revised structure of palmerolide A).

Alternating the order of the reactions (1- Yamaguchi; 2- Stille), the yield increased to 55% over the 2 steps (Figure 13). The exchange of Cs2CO3 to K2CO3 was the last alteration performed in an attempt to increase the yield of the enamide coupling. However, only a small improvement was observed (46% to 51% yield).

Figure 13 - Improvements in the synthesis reported by Nicolaou/Chen.

Next, Nicolaou/Chen team explored different alternatives for the macrocyclization of the revised structure of palmerolide A (Figure 14). The options for the macrocyclization were: 1) a

Horner-Wadsworth-Emmons olefination (C2-C3 olefin) achieved in 73% yield; 2) a Stille coupling to connect C14-C15, which was not successful, giving a crude mixture that could not be purified; 3) a Yamaguchi macrolactonization accomplished in 81% yield; and 4) a Mitsunobu protocol, that gave the product in only 40% yield. Nicolaou/Chen group concluded that the

Yamaguchi lactonization and the Horner-Wadsworth-Emmons olefination are valuable options to the RCM in the construction of the macrocycle of palmerolide A.21

Later in 2008, Nicolaou and Chen published the synthesis and biological activity of various analogues of palmerolide A.40 Moreover, a second-generation of palmerolide A analogues were synthesized in 2011, and their biological activities studied by Chen group.41 The methods utilized for the synthesis of the analogues were equivalent to the previous reports.

Figure 14 - Alternative macrocyclization strategies for the synthesis of palmerolide A.

Hall group

The third total synthesis of palmerolide A was developed by the Hall group. Organoboron methods evolved by Hall and coworkers were used in the synthesis of this natural product.22

The catalytic enantioselective crotylboration of aldehydes was the first method utilized.

To this extent, Hall and colleagues published a series of articles on the theme.42-44 Various catalysts were designed to improve the yields and enantioselectivity of the crotyl- or allylboration. After optimization, the best results were achieved with p-F-Vivol (A - Figure 15).

A cycloheptyl derivative of this catalyst was used in the synthesis of palmerolide A to install the stereocenters C19 and C20 in the side chain. The second strategy used by Hall team in the

synthesis of palmerolide A was a [4+2] cycloaddition/allylboration sequence (B - Figure 15).45,46

The Jacobsen’s chromium (III) complex is the catalyst and the product can react with an aldehyde to afford α-hydroxyalkyl pyrans in good yields and high stereoselectivity. This methodology along with a Claisen rearrangement was used to set the stereocenters at C7, C10 and C11.

Figure 15 - Organoboron methodologies developed in Hall lab.

The Hall retrosynthetic approach to palmerolide A is depicted in Figure 16. The last step would be the enamide coupling in the side chain, following De Brabander’s end game. The coupling of two fragments 56 and 57, by Suzuki coupling and Yamaguchi macrolactonization, was thought to give the core of palmerolide A. Fragments 56 and 57 were envisioned based on asymmetric organoboron methodologies. Fragment 56 was prepared from the ring opening of pyran 58, which was synthesized from 59 in a Curtius rearrangement. The α-hydroxy pyran 59 was prepared using a [4+2] cycloaddition/allylboration strategy (Figure 16).22

The synthesis of fragment 56 started with an E-crotylboration of aldehyde 33 catalyzed by p-F-vivol[7].SnCl4 to give vinyl iodide 61 in 95% yield and 95:5 dr, with anti stereochemistry. The next step was the inversion of the stereochemistry at C19 (MeSO2Cl, Et3N;

then CsOAc). Then, a series of eight steps converted acetate 62 into fragment 56 in 44% yield

(Figure 17).

Figure 16 - Retrosynthesis of palmerolide A by Hall and coworkers.

The second fragment 57 was prepared from a [4+2]-cycloaddition between 3- boronoacrolein pinacolate 63 and ethyl vinyl ether 64. The Diels-Alder product 65 undergoes allylboration with aldehyde 63 to give α-hydroxyl pyrane 66 in 84% yield and 96% ee. The hydroxyl is acylated to give 67 in preparation for a Claisen-Ireland rearrangement. Then, reaction with LDA and TMSCl afforded an enolate, which gives the rearranged product through the chair-like transition state 68. In this process, the hydroxyl groups at C10 and C11 could be differentiated. Oxidation of C10 with retention of configuration and esterification gave pyran 69 in 55% over 4 steps. Differentially protected diol 70 was obtained in five further steps. Thus, ring opening and installation of the α,β-unsaturated ester gave fragment 57 (Figure 18).

Figure 17 - Synthesis of fragment 56.

Fragments 56 and 57 were coupled via Suzuki coupling in 50-77% yield. Subsequently, saponification and Yamaguchi macrolactonization gave the core of palmerolide in 66% yield over two steps. The synthesis was completed by a Curtius rearrangement to install the dienamide, carbamate formation and deprotection (6 steps, 11% yield) to give the natural product palmerolide A (Figure 19).

Figure 18 - Synthesis of fragment 57.

Figure 19 - Completion of the synthesis of palmerolide A.

The Maier Group

In 2007, the Maier group published a synthetic approach to the C3-C23 fragment of the proposed structure of palmerolide A.31 Two years later, in 2009, a formal synthesis of palmerolide A was reported using the same strategy.23 The Maier team prepared a late intermediate in Nicolaou/Chen synthesis. The retrosynthetic analysis relied in the coupling of

two fragments 73 and 74, which can be connected by a Horner-Wadsworth-Emmons olefination and a metal mediated cross-coupling reaction (Figure 20).

Figure 20 - Retrosynthesis of palmerolide A by Maier group.

The aldehyde fragment 74 was prepared from δ-valerolactone, the same starting material as in De Brabander synthesis. δ-Valerolactone underwent ring opening and alkynylation to give product 75. A Noyori asymmetric hydrogenation set the stereocenter at C7, then deprotection of the alkyne and protection of the hydroxyl group afforded 76. Reaction with acrolein gave the substrate for a Johnson-Claisen rearrangement 77. The rearrangement took place in the presence of triethyl orthoacetate and propionic acid to give, two steps later, enyne 78. Next, the stereocenters at C10 and C11 were installed in a Sharpless dihydroxylation and the alcohol at

C10 could be selectively protected as a TBDPS group providing alcohol 79. The carbamate was installed and deprotection/oxidation gave aldehyde 80, which was converted in four steps to alkene 81 or to tributylstannane 82 (Figure 21).

Figure 21 - Preparation of fragments 81 and 82.

The second fragment 73 was prepared using an aldol reaction between oxazolidinone 83 and vinyl iodide 33, strategy equivalent to Nicolaou/Chen synthesis, though, with increased yield of 72% (26% higher yield). Then, a sequence of seven steps resulted in fragment 73 (Figure 22).

Figure 22 - Preparation of fragment 69.

The vinyl iodide fragment 73 was coupled with fragment 81 to give terminal alkene 85, which could be converted to macrocycle 87 in a Heck reaction in 81% yield (only the E alkene was observed). Alternatively, fragment 73 was connected to aldehyde 82 to give tributylstannane

86, which could be used in a Stille coupling to afford macrocycle 87. However, the product was

obtained in 3:1 E/Z mixture. Isomerization of the double bond with iodine gave the E-alkene in

68-77% yield. Hence, the Heck reaction was more efficient than the Stille coupling in the macrocyclization. Macrolactone 87 was converted to the vinyl iodide intermediate 88 in the

Nicolaou/Chen synthesis in five more steps and 40% overall yield (Figure 23).

Figure 23 - Completion of Maier formal synthesis.

The Prasad Group

The first report by Prasad group was the synthesis of the C1-C18 fragment palmerolide A from tartaric acid.34 After that, the group published two formal syntheses of palmerolide A featuring different synthetic strategies.26,27 The first formal synthesis, released in 2011, was accomplished by the coupling of two fragments (40 and 89) using Yamaguchi and Heck macrocyclization. Fragment 40 was prepared by a Jung reaction. In the second formal synthesis, three fragments were assembled to form the macrocycle core. Fragments 40, 90 and 91 were

coupled by a Stille reaction, followed by Yamaguchi esterification and ring-closing metathesis.

Fragments 90 and 91 were prepared taking advantage of the chiral pool tartaric acid (Figure 24).

Figure 24 - Retrosyntheses of palmerolide A according to Prasad group.

Fragment 40 was common to the two formal syntheses reported by the group. The same fragment was used in the Nicolaou/Chen synthesis of palmerolide A, however, the Prasad group utilized a different strategy towards its preparation. The synthesis started with olefination of vinyl iodide 33 to give alcohol 92 in 68% yield over two steps. Then, Sharpless protocol gave epoxide 93, which was treated with TESOTf in the present of Hünigs base using Jung non-aldol conditions.47,48 The reaction set stereocenters C19 and C20. Olefination of the resulting aldehyde gave ester 94 in 60% over the two steps. Three more steps gave the desired fragment 40 (Figure

25).

Figure 25 - Synthesis of fragment 40.

Figure 26 - Synthesis of fragment 89.

In the initial formal synthesis of palmerolide A developed by Prasad team, the preparation of the fragment 89 started with TBS protection and NBS oxidation of furyl carbinol

95 to give aldehyde 96 in 47% over the two steps. Thus, a six-step sequence afforded enone 97 in

53% yield. Then, (R)-CBS reduction gave a mixture of separable diastereomers (7:3). The minor undesired diastereomer 98 was converted to the desired alcohol 99 under Mitsunobu conditions in 64% yield. Otherwise, reaction with NaBH4 gave a 1:1 mixture of diastereomers. The second fragment 89 was obtained five steps later in 65% yield (Figure 26).

Both fragments 40 and 89 were coupled in a Yamaguchi reaction in 91% yield and a

Heck macrocyclization in 60%. The Heck macrocyclization was used earlier in Maier formal

synthesis. Six more steps converted macrolide 97 into the late intermediate vinyl iodide 88 in

Nicolaou/Chen synthesis (Figure 27).26

The second formal synthesis involved the preparation of fragment 90. The known alcohol

102 derived from L-tartaric acid was converted to alkenol 103 in three steps. First, there was formation of a triflate, followed by reaction with 3-butenylmagnesium bromide and deprotection of the TBS ether using TBAF. Then, a sequence of four steps gave iodide 90 in 40% yield

(Figure 28).27

Figure 27 - Synthesis of the late intermediate 88 in Nicolaou/Chen synthesis.

Figure 28 - Synthesis of fragment 90.

The second fragment 91 started with a reaction between the bis-Weinreb amide of tartaric acid 104 with 3-butenylmagnesium bromide and reduction of the resulting ketone by K-

Selectride in 82% over two steps. The group utilized the same sequence in a previous publication.49 Protection of the hydroxyl group as a TBS ether gave alkene 105. The Weinreb amide was reduced using NaBH4 and installation of an alkyne using Bestmann-ohira reagent gave compound 106, which could be converted to tributylstannane 91 (Figure 29).

Figure 29 - Synthesis of fragment 91.

Figure 30 - Completion of the formal synthesis of palmerolide A.

With the three fragments in hand, they could couple vinyl iodide 40 and stannane 91 in a

Stille reaction in 71% yield (Figure 30). The primary alcohol was selectively converted to an iodide in two steps and Yamaguchi esterification with fragment 90 gave diiodide 108. Boord

elimination50 with zinc dust originated the diene 109 in 70% yield. Ring-closing metathesis using

Grubbs II, same strategy employed in Nicolaou/Chen synthesis, gave macrocycle 110 in 62% yield. Protection with MOMCl gave the macrolactone 101, which was published by Prasad team in their first formal synthesis of palmerolide A. With the synthesis of intermediate 101, the group accomplished the second formal synthesis of this natural product.

The Kaliappan group

In 2007, the Kaliappan group reported an approach to C1-C9 and C15-C21 fragments of the proposed structure of palmerolide A.29 Then, in 2010, Kaliappan and coworkers published a formal synthesis of palmerolide A.24 One year later, the group disclosed a full article detailing their findings and discussing the challenges related to the synthesis.25 The retrosynthetic analysis is presented in figure 31, and illustrates a ring-closing metathesis as the last event in the synthesis, which was also employed by Nicolaou/Chen and Prasad groups. The coupling of three fragments 111, 112 and 113 would afford the macrocyclic core of palmerolide A by a Julia-

Kocienski olefination, a Yamaguchi esterification and a ring-closing metathesis. The stereocenters at C19 and C20 were set by a Shimizu protocol; C10 and C11 were installed by a

Sharpless dihydroxylation and C7 by Jacobsen kinetic resolution.

The fragment 111 was synthesized from alcohol 114. Oxidation using IBX to form an aldehyde followed by olefination gave ester 115 in 85% yield. A sequence of reduction, oxidation, olefination and epoxidation using Sharpless conditions gave epoxide 116 in high ee.

The epoxide was opened by palladium-catalyzed hydrogenolysis to set the stereocenters C19 and

C20 in alcohol 117. This protocol, developed by Shimizu51 and coworkers, was employed as an alternative to the aldol reactions utilized in previous syntheses. Three steps further, addition of

vinyl Grignard to carbonyl compound 118, followed by acetylation gave diacetate 119, which was used in allylic rearrangement to provide alkene 120 as a mixture of isomers 1:7.5. The desired isomer could be purified after the selective deprotection of the primary alcohol. Then, oxidation gave aldehyde 111, precursor for the Julia-Kocienski olefination (Figure 32).

Figure 31 - Retrosynthesis of palmerolide A as reported by Kaliappan group.

Figure 32 - Synthesis of fragment 111.

The synthesis of the coupling partner for the Julia-Kocienski olefination, sulfone 112, started with mono-protected diol 121. Chlorination, Sharpless dihydroxylation and formation of the epoxide gave 122 in 62% yield over the three steps. The hydroxyl group was protected and

reaction with dimethylsulfonium ylide gave alcohol 123 in 75% yield. In this way, the diol C10 and C11 could be differentiated. The same approach with a TBS group at C11 was not successful. Four extra steps converted alcohol 123 to the sulfone fragment 112 (Figure 33).

Figure 33 - Synthesis of fragment 112.

The third fragment was prepared from Sharpless kinetic resolution of alcohol 124 to give the enantiomerically enriched alcohol 125 (95% ee) in 42% yield. In five additional steps the third fragment 113 was obtained (Figure 34).

The Julia-Kocienski olefination between fragments 111 and 112 was successful giving the diene product 126 in 80%. Alternative olefinations using inverted coupling partners (111 sulfone and 112 aldehyde) or with a ketone analogue of 111 were ineffective. The vinyl iodide in the side chain was inserted by a Takai olefination according to Nicolaou/Chen precedent. Next,

Yamaguchi conditions with fragment 113 gave ester 128. The carbamate was installed, the TIPS protecting groups were removed and ring-closing metathesis gave macrolactone 88.

Noteworthy, the ring-closing metathesis could not be accomplished with the TIPS protected starting material. Also, when PMB protecting groups were used to replace TIPS groups, the substrate could not be deprotected and the reaction resulted in decomposition of the starting material. Macrolide 88 is an advanced intermediate in the Nicolaou/Chen synthesis, concluding the formal synthesis of palmerolide A (Figure 35).

Figure 34 - Synthesis of fragment 113.

Figure 35 - Completion of Kaliappan formal synthesis.

The Chandrasekhar group

The Chandrasekhar group reported an approach to the C1-C14 portion of palmerolide A30

(Figure 36) showcasing of a methodology developed in the group, a deoxygenative rearrangement via allene to form a diene.52

Figure 36 - The C1-C14 fragment of palmerolide A by Chandrasekhar group.

Figure 37 - Synthesis of the C1-C14 fragment of palmerolide A.

The synthesis started with the alkynylation of aldehyde 131 producing the alcohol 132.

Then, reaction with triphenylphosphine produced diene 133 via an allene intermediate in 73% yield. Sharpless dihydroxylation gave a diol that was protected as an acetonide. Later, the stereocenter at C7 was installed using (R)-CBS in 90 % yield and 97% de. Some additional steps afforded the desired alcohol 130, which corresponds to the C1-C14 fragment of palmerolide A

(Figure 37).

The Meyer/Cossy Group

The Meyer/Cossy group developed an approach to the C3-C15 and C16-C23 fragments of palmerolide A.32 In their retrosynthetic analysis, the natural product could be obtained by the coupling of three fragments 40, 137 and 138. The three portions of the molecule would be combined by a nucleophilic addition of alkyne 138 to aldehyde 137, then a palladium catalyzed cross-coupling with fragment 40 and a ring-closing metathesis to form the C2-C3 bond (Figure

38).

The first fragment 137 was prepared from alcohol 139. Iodination and alkyne insertion afforded acetonide 140. Deprotection followed by selective protection of the primary alcohol gave 141 in 88% yield. The secondary alcohol was protected as a PMB and the primary alcohol converted to an aldehyde giving fragment 137 (Figure 39).

Figure 38 - Retrosynthesis of palmerolide A according to Meyer/Cossy group.

Figure 39 - Preparation of fragment 137.

The synthesis of the second fragment 138 started with acid 142, which was converted to a

Weinreb amide and alkynylated to form ketone 143. Noyori reduction and protecting group manipulations gave the alkyne fragment 138 (Figure 40).

The vinyl iodide fragment 40 (C16-C23) was also present in Nicolaou/Chen and Prasad syntheses of palmerolide A. Meyer/Cossy used similar synthetic strategy as Nicolaou/Chen.

However, the Meyer/Cossy fragment was obtained in two fewer steps due to the installation of a

Weinreb amide replacing the chiral auxiliary in vinyl iodide 44. The amide could be reduced to aldehyde 144, avoiding protection/deprotection of the hydroxyl group at C19.

Figure 40 - Preparation of fragment 138.

Fragments 137 and 138 were connected by nucleophilic addition of an alkynyl anion to aldehyde 137 producing diyne 145. Nevertheless, the alcohol group was formed during the addition in a 7:3 mixture of diastereomers. Subsequently, Dess-Martin periodinane oxidation gave a ketone that could be reduced by Noyori protocol in high diastereoselectivity. Next, the internal alkyne was reduced with Red-Al, the alcohol protected and the terminal alkyne uncovered, completing the synthesis of the second fragment C3-C15, 147.

Figure 41 - Preparation of fragment 40.

Figure 42 - Preparation of fragment C3-C15.

The Loh group

In 2012, the Loh group disclosed a synthesis of the C13-C21 fragment of palmerolide A

(Figure 43).35 A methodology developed by the Loh Lab was used to produce a 1,3-butadiene from the coupling of alkyl substituted alkenes and acrylates. Diene 148 was prepared from aldehyde 149 in five steps. The last step was the coupling between n-butyl acrylate and alkene

151. The yields and E/Z selectivity were improved by changing the protecting group in the primary alcohol to give acetate 148c in 69% yield and 80:20 E/Z (Figure 44).

Figure 43 - Fragment C3-C15 of palmerolide A.

Figure 44 - Preparation of fragment C13-C21.

The Baker group

The Baker Lab also contributed with an approach towards the synthesis of the natural product palmerolide A. The group reported the synthesis of C3-C14 fragment (152) using chiral pool (Figure 45).33

Figure 45 - The C3-C14 fragment of palmerolide A by Baker group.

Figure 46 - Preparation of fragment C3-C14.

The synthesis started with sugar derivatives 153 and 156. Alcohol 153 was monoprotected with a benzyl group, and then oxidation/olefination gave ester 154. Next, reduction, oxidation and olefination resulted in alkene 155. Alcohol 156 was protected with a benzyl group and the acetonide removed. The secondary alcohol was converted to an acetate group, and oxidation/olefination gave alkene 158. Alkenes 155 and 156 were coupled by a

Grubbs II-catalyzed cross-metathesis to give fragment 152 in 40% yield (Figure 46). Attempts to use Julia-Kocienski olefination to form the C8-C9 double bond were ineffective.

The Florence group

Florence and coworkers reported a total synthesis of the proposed structure of the natural product palmerolide C, a constitutional isomer of palmerolide A.38 After the synthesis, the NMR data of the synthesized material and the natural product were distinct and a revised structure was suggested. The synthetic approach involved the installation of the enamide in the side chain by

Buchwald protocol as the last event. Prior to that, two main fragments 159 and 160 afforded the macrolactone core by a Julia-Kocienski olefination and Yamaguchi macrolactonization. The fragments 159 and 160 were designed based in various aldol strategies (Figure 47).

The synthesis of the fragment 160 started with a (S)-proline catalyzed aldol reaction between acetonide 161 and aldehyde 162, giving the aldol adduct 163 in 44% yield and 96% ee.

Ester 157 was generated in seven steps and 39% yield. The ester was converted to a methyl ketone 158 via Weinreb amide in 93% yield. The C1-C6 fragment 167 was synthesized from monoprotected diol 166 in four steps and 53% overall yield (Figure 48).

Figure 47 - Retrosynthetic analysis of palmerolide C and revised structure.

Fragment 159 was synthesized from a Mosher ester derivative aldehyde 168. Olefination, reduction and oxidation gave aldehyde 169 that could be converted to vinyl iodide 170 by Takai olefination. Then, a vinylogous Mukaiyama aldol reaction converted aldehyde 170 into alcohol

171 in 70% and 6:1 dr. After that, four additional steps generated sulfone 159 (Figure 49).

Figure 48 - Preparation of fragments 165 and 167.

Figure 49 - Preparation of fragment 159.

Compounds 165 and 167 were connected by an aldol reaction to form alcohol 172, which could be eliminated to form the double bond between C6 and C7. The ketone was reduced under

Luche conditions to afford alcohol 173 in 94% yield and high diastereoselectivity. Few steps

later, aldehyde fragment 160 was coupled with fragment 159 in a Julia-Kocienski olefination to give 174 in 78% yield and 7:1 E/Z (Figure 50). Previously, Julia-Kocienski olefination of similar substrates in Kaliappan formal synthesis of palmerolide A was unsuccessful.

To conclude the synthesis of the proposed structure of palmerolide C, the Florence team used a Yamaguchi macrolactonization and Buchwald protocol to install the enamide in the side chain following Nicolaou/Chen tactic (Figure 50). However, the NMR data of the synthesized material and the natural product were dissimilar, suggesting the structural assignment of the natural product was wrong. Reassessment of the NMR spectra suggests that the stereochemistry at C9 and C10 were assigned erroneously. Specifically, the stereotriad C8, C9 and C10 observed in the natural product were most likely to be 8S, 9R, 10R, as a replacement for 8S, 9S, 10S in the initially proposed structure.

Figure 50 - Synthesis of the proposed structure of palmerolide C.

Summary

Collectively, the retrosynthetic strategy to disconnect the macrocyclic core of palmerolide A is similar throughout the total and formal syntheses reported for this natural product. The main features of the syntheses were summarized in Table 3. The formal synthesis developed by Dudley and coworkers (Chapter 4) is included.

Usually, three fragments were coupled to form the C8-C9 double bond, the C1-O ester and the C14- C15 or C15-C16 double bonds, except by Hall and Maier syntheses where two main fragments were used to assemble the macrocycle. Another variation pertains to the Horner-

Wadsworth-Emmons olefination, which is used by Hall group to form the C2-C3 double bond

(Table 3).

Table 3 - Overview of the synthetic sequences to palmerolide A. De Nicolaou/ Hall Maier Kaliappan Prasad Dudley Brabander Chen C1-C8 C1-C8 C1-C13 C3-C15 C1-C8 C1-C8 C1-C8 Fragments C9-C15 C9-C15 C14-C24 C16-C23-C2 C9-C14 C9-C15 C9-C15 C16-C24 C16-23 C15-23 C16-23 C16-C24 Suzuki Yamaguchi Suzuki HWE Julia Stille HWE Fragment (81%) (66%) (50-77%) (92%) (80%) (71%) (96%) coupling Yamaguchi Stille Yamaguchi Yamaguchi Yamaguchi (69%) (84%) (68%) (74%) (91%)

- Bond C8-C9 C8-C9 C1-O C15-C16 C8-C9 C8-C9 C15-C16 li HWE RCM Yamaguchi Heck RCM RCM Heck

tion Name 58% 81% 90% 81% 70% 62% 60% Cyc za Yield C7 (S)-CBS Jacobsen res B-Claisen Noyori red Jacobsen res tartaric acid NaBH4 C10 D-arabitol B-crotyl B-Claisen AD-mix-α AD-mix-α tartaric acid AD-mix-α C11 D-arabitol B-crotyl B-Claisen AD-mix-α AD-mix-α tartaric acid AD-mix-α Stereo centers C19 vinyl. aldol aldol B-crotyl aldol Shimizu Jung vinyl. aldol C20 vinyl. aldol aldol B-crotyl aldol Shimizu Jung vinyl. aldol Steps 22 18 26 27 26 24 22 Yield 0.06% 0.6% 0.7% 1% 0.4% 0.4% 1.4% Total

The most common macrocyclization events were a ring-closing metathesis (C8-C9) or

Heck reaction (C15-C16). Additionally, De Brabander used a Horner-Wadsworth-Emmons

macrocyclization (C8-C9) and Hall a Yamaguchi macrolactonization (Table 3). Nicolaou/Chen groups studied several tactics for the macrocyclization and they observed that the ring-closing metathesis, the Yamaguchi and the Horner-Wadsworth-Emmons were the highest yielding macrocyclization reactions.

The stereocenters at C19 and C20 were mainly installed by aldol or vinylogous aldol reactions. Other approaches used were a boron-crotylation by Hall, a Shimizu protocol by

Kaliappan and a Jung non-aldol reaction by Prasad. The diol at C10 and C11 were primarily installed by Sharpless dihydroxylation, organoboron methodologies or chiral pool (tartaric acid and D-arabitol). A variety of strategies were used to install C7 hydroxyl group, some reduction reactions (e.g. (S)-CBS, NaBH4, Noyori), Jacobsen kinetic resolution, organoboron/Claisen rearrangement and tartaric acid (Table 3).

The sensitive dienamide in the side chain was installed at a late stage. Two alternatives were used to synthesize the enamide, a Curtius rearrangement, first used by De Brabander and a

Buchwald protocol introduced by Nicolaou/Chen groups.

Overall, several synthetic approaches were reported on palmerolide A using similar disconnections. The unique features of the syntheses rely on the preparation of the fragments to assemble the macrolactone. However, the syntheses were achieved in low yield and can produce only limited amounts of palmerolide A and derivatives for biological studies. Therefore, taking into account the low availability of palmerolide A from natural sources, a more efficient synthesis is still needed. The synthesis developed in the Dudley Lab and ways to circumvent the current drawbacks and improve the effectiveness of the synthesis will be discussed in the following chapters.

CHAPTER 3

RING OPENING OF CYCLIC VINYLOGOUS ACYL TRIFLATES USING

STABILIZED CARBANION NUCLEOPHILES

Introduction

Since the isolation of palmerolide A, many laboratories became interested in the synthesis of this natural product. A methodology developed in the Dudley Lab was one of the reasons to pursue the synthesis of the palmerolide A. The Horner-Wadsworth-Emmons reagent

176a produced by the fragmentation of a vinylogous acyl triflate (177a) would be ideal for the synthesis of the C1-C8 fragment (Figure 51).53 In this chapter, the Claisen type condensation of vinylogous acyl triflates with carbanion nucleophiles will be described, as well as the efforts to optimize the reaction to afford -ketophosphonate 176a and analogues.54

Figure 51 - Prospective application to palmerolide A.

The Claisen condensation has been an important reaction in synthetic organic chemistry for over a century.55 In the classic Claisen condensation, an ester enolate nucleophile reacts with a carboxylic ester electrophile in a reversible addition and elimination sequence. The resulting

-keto ester is then subject to irreversible deprotonation at the α-position, which shifts equilibrium in favor of the condensation product (Figure 52).56-59 Ketone enolates, phosphonyl-

and sulfonyl-stabilized carbanions, and similar nucleophiles react with esters in an analogous fashion to provide -keto derivatives.55-59

Figure 52 - Mechanism of the classical Claisen condensation of ethyl acetate.

This report is focused on the use of a Grob-type heterolytic fragmentation pathway to drive formation of Claisen condensation-type products: -keto derivatives of ketones, esters, phosphonates, phosphine oxides, and sulfones. The classic addition and elimination of esters

(Claisen condensation) is replaced by the addition and fragmentation of vinylogous esters, specifically, cyclic vinylogous acyl triflates (VATs). Our lab has been exploring the synthetic utility of triggering Grob fragmentation reactions by nucleophilic addition to VATs.53,60,61 A broad range of nucleophiles react with cyclic VATs in an addition / bond cleavage process to provide acyclic alkynyl ketones (Figure 53, Equation 1). This reaction has been applied and extended to the synthesis of a moth pheromone, homopropargyl alcohols, and indane building blocks.62-64

The pivotal fragmentation process is related to the Eschenmoser–Tanabe reaction65-71

(179  180, Figure 53), but it is approached by nucleophilic addition to cyclic vinylogous esters by analogy to a related reaction that is known to provide cyclic enones (181  182, Figure

53).72,73 Consequently, ring opening of VATs provides products that are not accessible using the

Eschenmoser–Tanabe fragmentation, such as amides and homopropargyl alcohols.53,63 VATs are readily available in high yield from symmetrical diones (Figure 54). 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.53

Figure 53 - Fragmentation reactions.

Figure 54 - Synthesis of VAT from a symmetrical dione.

Recent contributions from other labs complement our on-going methodology and add to the growing arsenal of C–C bond cleavage reactions for production of valuable synthetic building blocks. The Williams lab recently expanded the utility of VATs to the synthesis of allenes, showing through elegant competition experiments and calculations that loss of triflate

and formation of the strong carbonyl bond can drive rapid formation of the higher energy cumulated allene π-system.74 Brewer and coworkers employed an analogous yet distinct addition and C–C bond cleavage process to prepare tethered alkynyl aldehydes,75,76 which are difficult to access using our method of hydride-triggered ring-opening of VATs.77

VAT-Claisen Reaction

Enolate nucleophiles trigger fragmentation of VATs in a process we call the VAT–

Claisen reaction (Figure 55). The VAT–Claisen reaction provides 1,3-dicarbonyl-type compounds through an addition and C–C bond cleavage process, as opposed to the traditional

Claisen condensation, which delivers 1,3-dicarbonyl-type compounds through addition and alkoxide elimination reaction of simple esters.

Figure 55 - VAT-Claisen reaction.

The success of the VAT-Claisen reaction is noteworthy for several reasons. Enolate addition to ketones (cf. 177a  184) is reversible and in many cases the equilibrium lies on the side of reactants. Moreover, α,-unsaturated ketones react with enolates typically via Michael

(1,4) addition, not 1,2-addition. Nonetheless, we observed products derived from 1,2-addition of enolates to VAT 177, followed upon warming by fragmentation to generate 1,3-dicarbonyl compounds. Preliminary observations were reported previously, and a more detailed study is reported herein.

Results and Discussion

The VAT–Claisen reaction is a key part of a two-step strategy for converting symmetric cyclic 1,3-diones (e.g., 183, Figure 54) into value-added acyclic building blocks comprising alkyne and carbonyl-activated methylene functionality. Such building blocks are valuable for a range of synthetic applications, as the alkyne and activated methylene can be processed in parallel by taking advantage of their complementary reactivity.36 These compounds are also valuable tools for synthetic methodology, especially for the development of intramolecular reactions for the synthesis of five-membered rings.78-81

Preliminary identification and analysis of the VAT–Claisen reaction. In our examination of the Claisen-type condensation reactions of VATs, we first studied the reaction of the lithium enolate of acetophenone.53 The stoichiometry of this reaction played a pivotal role in the ability of the reaction to proceed to completion. In analogy to the traditional Claisen condensation, which requires excess base, at least two equivalents of enolate nucleophile are necessary to drive the VAT–Claisen fragmentation of 177 to completion (Figure 56). The initial addition is conducted cold, with subsequent warming of the reaction mixture to promote fragmentation. Reaction of 2.2 equivalents of the lithium enolate of acetophenone with VAT

177a gave rise to 1,3-diketone 176b in 85% yield, whereas with only 1.2 equivalents of enolate the yield of 176b dropped to 56% and unreacted 177a was recovered. If the enolate (1.2 equiv) is supplemented with additional base (1.0 equiv of LiHMDS), then complete consumption of VAT

177a is observed and -diketone 176b is isolated in 78% yield.

Figure 56 - VAT-Claisen Reaction using lithium enolate of acetophenone.

Two mechanistic alternatives were initially considered to account for the need of two equivalents of enolate and/or base, and deuterium labelling helped differentiate between the two

(Figure 57). The first (path 1, cf. Figure 56), which we ultimately came to favor, parallels the addition and fragmentation pathway for the Grignard-triggered ring opening of VATs: direct 1,2- addition of the ketone enolate to VAT 177a provides tetrahedral intermediate aldolate D, which undergoes fragmentation upon warming to diketone E. The acidic methylene of diketone E is metalated as it forms in an acid/base reaction with excess enolate, which explains the need for two equivalents of enolate.

Specific concerns regarding the feasibility of this pathway prompted us to consider, evaluate, and ultimately discard an alternative mechanism (path 2). The first concern with path 1 was that ketone enolates typically add to α,-unsaturated ketones in a Michael (1,4) fashion, whereas the mechanism proposed in path 1 involves a direct 1,2-addition. Moreover, ketone aldolates typically undergo retro-aldol cleavage upon warming, and (unproductive) proton- transfer between the enolate and ketone often out-compete ketone aldol addition processes. In other words, we were initially sceptical as to the feasibility of path 1. Although general reactivity

trends do not necessarily translate to this specific system, we considered an alternative mechanism initiated by productive proton transfer between the enolate and VAT 177a (path 2).

Figure 57 - Possible mechanistic pathways and deuterium-labeling experiment.

The alternative mechanistic pathway starts with abstraction of the acidic α-proton of triflate 177a to form enolate G. Heterolytic fragmentation then would generate ketene intermediate H, analogous to the allene formation reported by Williams.74 Addition of another molecule of the lithium enolate of 189 and proton transfer would yield the most stable lithium enolate of the 1,3-diketone J through the intermediate I. Aqueous workup and keto-enol equilibrium in the presence of proton source would furnish the final product 176b.

A deuterium-labeling experiment (Figure 57, Equation 4) provided insight into the mechanistic pathway for the present Claisen-type condensation. We conducted the reaction using

VAT 177a and acetophenone-methyl-d3 (189-d3). The resultant products were the corresponding

1,3-diketone 176b without noticeable deuteration and recovery of 189-d3. These products are consistent with expectations based on path 1, and they are inconsistent with material that would be formed via path 2. Accordingly, we favored the mechanism outlined in path 1.

Preliminary Scope. With this mechanistic model in mind, we carried out the remainder of our initial experiments under the same protocol. Many of the nucleophiles examined gave satisfactory results, but not the anion of dimethyl methylphosphonate (190); Horner-Wadsworth-

Emmons reagent 176a was only isolated in 21% yield (Figure 58).53 This limitation was not inconsequential, as 176a promised to be an ideal starting material for a total synthesis of palmerolide A (Figure 51).5

We became interested in the synthesis of palmerolide A, in part because 176a maps conveniently onto the northwest region of the target molecule. However, the Claisen-type condensation reaction had to be re-optimized for the synthesis of olefinating reagents similar to

176a. Changing the nucleophile from the lithium anion of dimethyl methylphosphonate (190) to

the lithium anion of methyldiphenylphosphine oxide (191) afforded Horner-Wittig reagent 176f 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 177a effectively to the corresponding product 176f (Figure 59). This optimization culminated in the synthesis of the C1-

C15 fragment of palmerolide A.36

Figure 58 - First report Claisen-type condensation reactions of VAT 177a.

Refined mechanistic analysis. We reopened our investigation into the VAT-Claisen mechanism in order to gain a better understanding of the subtle balance of factors involved in determining optimal conditions. To reiterate our previous observations, the VAT-Claisen reaction of 177a with the lithium enolate of acetophenone requires 2 equivalents of enolate

(Figure 56), whereas the similar reaction involving the lithium anion of methyldiphenylphosphine oxide is best accomplished with 1 equivalent of the stabilized nucleophile (Figure 59).

The next logical experiment was reaction of VAT 177a with 1.1 equivalents of 192, the lithium enolate of ethyl acetate. Ethyl acetate was one of the best pre-nucleophiles in our earlier

study (177a  176d, 88% yield, Figure 58), and ester enolates are intermediate in acidity between ketones and phosphine oxides.82

Figure 59 - Preparation of Horner-Wittig reagent 176f.

Figure 60 - Proposed fragmentation reaction pathway between 177a and 192.

The enolate of ethyl acetate provided valuable data. When 1.1 equivalents of 192 were added to VAT 177a, the desired fragmentation product 176d was obtained in 56% yield (Figure

60). This result was in line with our previous observation using 1.2 equiv. of the acetophenone enolate (185) (56% yield, Figure 56).53 In this case, however, a previously unobserved byproduct was isolated, which we have tentatively identified as alcohol 195 (ca. 26% yield) based on its 1H

NMR spectrum. This byproduct proved to be unstable to storage, but when immediately

dissolved in THF, treated with excess NaH (approximately 3 equivalents) and heated to 60 °C for 30 min, this byproduct gave rise to the fragmentation product 176d in 78% yield, which provides support for our proposed structure (195).

A revised mechanistic hypothesis is needed to account for the formation of -hydroxy ester 195. Based on identification of aldol 195 after aqueous workup, we now consider aldolate

193 to be a persistent intermediate. In other words, ester enolate addition to 177a is not freely reversible. Aldolate 193 begins to undergo fragmentation upon warming, providing -ketoester

176d. When only one equivalent of enolate 192 is employed, the enolate is essentially consumed following addition to 177a and prior to fragmentation. Subsequent deprotonation of the - ketoester by the alkoxide, not the enolate, occurs. Aldol 195 does not undergo fragmentation, so full conversion to -keto ester 176d is not realized. Thus, two equivalents of base are still required for compete conversion of VAT 177a to 176d. Although the isolation of byproduct 195 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.

A crossover experiment confirms that ester enolate addition is only reversible to a limited degree (Figure 61). We generated what we presume to be a 1:1.8 mixture of aldolate 193 and the lithium enolate of methyl acetate (196) by treating aldol 195 with 2.8 equivalents of 196. The isolated fragmentation product mixture comprised ethyl and methyl esters 176d and 176g in an

88:12 ratio (as estimated by 1H NMR, 78% combined yield), indicating that retro-aldol reaction is occurring only to a minor extent. If the aldol addition were rapidly reversible, then we would expect to see a 35:65 ratio of 176d and 176g. If no retro-aldol reaction were occurring, then only ethyl ester 176d would be observed. Because both esters are detected with the ethyl ester as the major product, we conclude that enolate addition is reversible to a limited extent in this system.

Figure 61 - Crossover experiment with lithium enolate 195.

This more detailed understanding of the reaction pathway enabled us to reconsider the reaction between 1.0 equiv of phosphine oxide nucleophile 191 and VAT 177a (Figure 59).

Specifically, we must discard the assumption of an initial reversible addition of the phosphorus- stabilized anion to VAT 177a, but we must then rationalize why deprotonation of the product

-ketophosphine oxide does not occur (only 1 equiv of base is needed). The full conversion was realized with only one equivalent of nucleophile suggests that either the -ketophosphine oxide product (176f) is not acidic or the presumed intermediate oxy-anion (197) is not basic. We favor the latter alternative (Figure 62); the organolithium nucleophile adds irreversibly at cold temperatures, and the resulting oxy-anion coordinates to the phosphine oxide to provide intermediate 197. This intermediate is envisioned to resemble an oxaphosphetane intermediate, much like that formed during a Wittig olefination reaction.83,84,85 Such an intermediate would reduce the oxy-anion’s ability to deprotonate the -ketophosphine oxide product, and it 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 176f, instead of undergoing the classical retro-[2+2] pyrolysis reaction to provide dienyl triflate 198a (not observed).

The results of the Claisen-type condensation reactions of VAT 177a and the various stabilized anions (cf. 185, 191, and 196) provided a better understanding of the intricacies of the

VAT–Claisen reaction pathway. It is not solely the reactivity of the nucleophile that determines stoichiometry requirements, and the chemical properties of the aldolate-type intermediate (cf

186, 193, and 197) must be considered. Armed with new mechanistic insights, we expanded our methodology to the synthesis of various -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 analogues. The next section addresses the conversion of VATs to novel phosphonate-based olefinating reagents.

Synthesis of β-ketophosphonates using the VAT-Claisen reaction. The use of phosphonates in organic chemistry revolutionized the synthesis of alkenes.86-96 The ability to generate E- and Z- alkenes selectively, the mild conditions required for reaction, and the ease of their synthesis are distinct advantages of phosphonates as olefination reagents over their phosphorane (Wittig reagents) or phosphine oxide (Horner-Wittig) counterparts. Two general strategies are available for the synthesis of phosphonates (Figure 63): (1) the Arbuzov reaction,97,98 which involves the alkylation of the corresponding trialkyl phosphite to prepare alkyl-, benzyl-, and allylphosphonates as well as ester-derived phosphonates (Figure 62); or (2) a

Claisen-type condensation between esters and a dialkyl methylphosphonates to prepare - ketophosphonates (Figure 63).99-103 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.97

Figure 62 - Proposed mechanism of the reaction between VAT 177a and 191.

Figure 63 - 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 176a upon treating VAT 177a with 2.2 equivalents of dimethyl lithiomethylphosphonate (190) under our original conditions,53 we aimed to determine if the conditions optimized for the lithiomethyldiphenylphosphine oxide nucleophile (191) would provide increased yields of the -ketophosphonates. The use of lithiomethyldiphenylphosphine oxide as the nucleophile trigger provided excellent yields (up to 89%, Figure 59). However, the use of phosphonates for alkene synthesis is much more common.83,90,93 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. 75 mmol / $1 vs. 0.9 mmol / $1, respectively).104

Table 4 - Reaction of vinylogous acyl triflates with 1.1 equiv of phosphonatea

Table 4 summarizes the data resulting from the VAT–Claisen reactions of various VATs with 1.1 equiv of phosphonate-derived organolithium reagents. The reaction between VAT 177a and 1.1 equiv. of 190 proceeded in excellent yield (97%, entry 1). This result marks nearly a 5- fold increase in the yield of 176a compared to our previous report, in which 2.2 equivalents of nucleophile were used. The vinylogous acyl triflates derived from dimedone and 1,3- cycloheptanedione (177b and 177c, respectively) both provided their respective phosphonate products, 176g and 176h, in acceptable yields. Interestingly, in the case of 177b, an unstable byproduct was isolated (ca. 4%), whose 1H NMR spectrum is consistent with diene 198b (Figure

64). Such a byproduct would support our proposed oxaphosphetane-like intermediate (cf. structure 197, Figure 62).

Figure 64 - Byproducts 198b and 198c.

The reaction between VAT 177a and the anion of diethyl ethylphosphonate proceeded cleanly in 94% yield (entry 4). This result is remarkable. In our previous studies of the Claisen- type condensation reactions, substituents at the α-position of the nucleophile were linked to decomposition of the starting VAT. In the case of the nucleophile derived from diethyl 2- phenylethylphosphorane (entry 5), the phosphonate product 176k was obtained in 70% yield.

This reaction provided an unstable byproduct consistent with an E/Z- mixture of dienes 198c

(Figure 64), in a roughly 1:1 ratio (ca. 8% yield). Again, alkene byproducts are consistent with a postulated oxaphosphetane-like intermediate (Figure 62). The anion of bis(trifluoroethyl)- methylphosphonate (entry 6), which would give rise to a Still-Gennari-type94 olefination reagent,

is prone to homocondensation,102 thus hampering its viability in Claisen-type condensation reactions.

The stability of various VATs 177a-c deserves comment. Vinylogous acyl triflates 177b and 177c, which lack the α-methyl substituent, are relatively unstable when compared to their analogue, VAT 177a. Vinylogous acyl triflate 177a can be stored under an inert atmosphere for several months at -10 oC without any observable decomposition by 1H NMR spectroscopy, whereas VAT 177b begins to discolor after 1 to 2 days. VAT 177c 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 177c, is quite expensive (1 gram / $326.00, approximately 24 µmol / $1).104 For these reasons, the two-step conversion from 1,3- cycloheptanedione (199) to -ketophosphonate 176i (Figure 65) is less than ideal.

Figure 65 - Synthesis of phosphonate 176i.

We devised an alternative strategy for accessing Wittig-type reagents linked to alkynes by homologated tethers (>3 carbons, cf. 176i) using the KAPA acetylene zipper reaction.105 The

KAPA acetylene zipper reaction rearranges internal alkynes to terminal alkynes. Rearrangement of phosphonate 176e was not effective (Equation 5, Figure 66), 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 (176f). Fragmentation of VAT

177a with lithiomethyldiphenylphosphine oxide provides 176f (Figure 62), and carrying out a

subsequent KAPA zipper (alkyne isomerization) reaction provides Horner-Wittig reagent 176m

(Equation 6, Figure 66), an analogue of phosphonate 176i.

The proposed mechanism of the VAT–Claisen reaction of phosphonate-derived nucleophiles is illustrated in Figure 67. Addition of one equivalent of lithioalkylphosphonate to

VAT 177 generates -alkoxyphosphonate 200a and/or oxaphosphetane derivative 200b, depending on the extent of interaction between oxygen and phosphorus. One equiv of phosphonate nucleophile is necessary and sufficient for complete consumption of VAT 177.

Excess phosphonate nucleophile can react further with phosphonate intermediate 200a and/or

200b via the known phosphonate Claisen condensation.99-103 Therefore, use of excess phosphonate nucleophile would be detrimental, as observed in our earlier report.53 The required stoichiometry stands in contrast to enolate nucleophiles (cf. figures 56 and 60). Upon warming,

-alkoxyphosphonate 200a undergoes fragmentation to -keto phosphonate 176. Alternatively, pyrolysis of 200b can occur to generate cyclic dienyl triflate 198 in small amounts, especially as steric congestion increases in the system (Figure 67).

Figure 66 - Synthesis of phosphonate 176m, an analogue of phosphonate 176i.

In summary, we have identified, explored, and refined the VAT–Claisen reaction for the synthesis of alkynes tethered to 1,3-dicarbonyl-type structures. This methodology further enables the convenient two-step strategy for the synthesis of differentially functionalized acyclic keto alkynes from symmetrical cyclic diones. The full details disclosed in this work provide valuable insight into the mechanism of the VAT–Claisen reaction. The observance of the suspected alcohol byproduct 195 in reactions of VAT 177a with the lithium enolate of ethyl acetate allowed for a better understanding of the mechanism involving phosphine oxide derived nucleophiles. As is often the case, this is an example of natural products synthesis driving innovation in organic methodology: our interest in palmerolide encouraged us to reexamine a poor substrate and improve the scope of the earlier VAT-Claisen methodology. Ultimately, the results obtained from careful examination of various nucleophiles and VAT substrates provided a better understanding of these reactions and allowed for the expansion of the method to the synthesis of -ketophosphonates.

Figure 67 - Proposed mechanism of the reaction between VAT 177 and phosphonates.

We demonstrated throughout the course of our 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 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 the VAT–Claisen reaction has been demonstrated in the preparation of the

C1-C15 fragment of palmerolide A and the synthesis of some new and useful - ketophosphonates. Studies on the reactivity and synthetic utility of vinylogous acyl triflates continue in the Dudley laboratory.

Experimental Section

General Procedures. 1H NMR and 13C NMR spectra were recorded on a Varian 300

MHz spectrometer or a Bruker 400 or 600 MHz spectrometer using CDCl3 as the deuterated solvent. The chemical shifts (δ) are reported in parts per million (ppm) relative to the residual

1 13 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) (Appendix A). 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 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.60

Standard Procedure for the Claisen-Type Condensation of the Triflate (177a) with

Acetophenone. To a THF solution (2 mL) of acetophenone (0.14 mL, 1.2 mmol) was added

LiHMDS (1.0 M solution in THF, 1.1 mL, 1.1 mmol) at –78 °C under Ar atmosphere. After stirring for 30 min at –78 °C, 2-methyl-3-(trifluoromethanesulfonyloxy)-2-cyclohexenone (177a)

(93 μL, 0.50 mmol) was added to the resultant solution. The mixture was stirred at –78 °C for 10 min, at 0 °C for 10 min, at rt for 30 min, and then at 60 °C for 30 min. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with ether. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexanes/ether = 100/1 - 20/1) to give 1-phenyl-

1,3-dioxo-7-nonyne (176b) in 85% yield (96 mg).53

Standard Procedure for the Claisen-type Condensation of the Vinylogous Acyl

Triflates with Phosphonate Nucleophiles. To a THF solution (2 mL) of dimethyl methylphosphonate (0.6 mmol) was added n-BuLi (2.5 M solution in hexanes, 0.22 mL, 0.55 mmol) at –78 °C. After being stirred for 20 minutes at –78 C, a solution of vinylogous acyl triflate 177a (0.50 mmol) in THF was added dropwise to the resulting solution. The mixture stirred at –78 °C for 10 min, at 0 °C for 10 min, at r.t. for 30 min, and at 60 °C for 30 min; during the course of the reaction the solution changed from clear to yellow, and then from 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) and 5 mL of saturated aqueous NaCl, dried with MgSO4, filtered and concentrated. The residual oil was purified by silica gel column chromatography (gradient elution from 10% - 40%

EtOAc/Hexanes) to afford 112 mg of -ketophosphonate 176a (97% yield) as a pale yellow oil;

1 H NMR (300 MHz, CDCl3) δ 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,

13 2H); C NMR (75 MHz, CDCl3) δ 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.53

Characterization: Ethyl 3-oxo-7-nonynoate (176d): pale yellow oil; 1H NMR (300

MHz, CDCl3) δ 4.19 (q, J = 7.0 Hz, 2H), 3.45 (s, 2H), 2.67 (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);

13 C NMR (75Hz, CDCl3) δ 202.4, 167.0, 77.9, 76.4, 61.2, 49.3, 41.6, 22.5, 17.8, 14.0, 3.3; IR

-1 + (thin film) 1745, 1742, 1651, 1415, 1242, 1027 cm ; HRMS (FAB) Calcd for C11H16O3Na [M ]

219.0097. Found 219.0097. Spectroscopic data is consistent with previous report.53

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

NMR (300 MHz, CDCl3) δ γ.78 (d, J = 11.3, 6H), 3.08 (d, J = 22.7 Hz, 2H), 2.67 (s, 2H), 2.28

13 (d, J = 2.5 Hz, 2H), 2.01 (t, J = 2.5 Hz, 1H), 1.09 (s, 6H); C NMR (75 MHz, CDCl3) δ β00.90

(d, J = 5.8 Hz), 81.9, 70.5, 53.0 (d, J = 5.8 Hz), 52.7, 42.8 (d, J = 128.1 Hz), 33.3, 31.0, 26.8; IR

-1 + + (thin film) 1714, 1465, 1366, 1249, 1024, 811 cm ; HRMS (EI ) Calcd for C11H20O4P

[[M+H]+] 247.1099. Found 247.1096.

1-(dimethylphosphonato)-2-oxo-7-nonyne (176i): clear oil; 1H NMR (300 MHz,

CDCl3) δ 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 quintet,

13 J = 7.6 Hz, 2H); C NMR (75 MHz, CDCl3) δ 201.4 (d, J = 5.1 Hz, 1C), 83.9, 68.6, 53.0 (d, J =

4.5 Hz, 1C), 43.4, 41.3 (d, J = 128.3 Hz, 1C), 27.5, 22.4, 18.1; IR (thin film) 1712, 1456, 1249,

-1 + + + 1021, 806 cm ; HRMS (EI ) Calcd for C10H18O4P [[M+H] ] 233.0943. Found 233.0943.

2-(diethylphosphonato)-3-oxo-1-methyl-7-nonyne (176j): clear oil; 1H NMR (300

MHz, CDCl3) δ 4.20 – 4.03 (m, 4H), 3.22 (dq, J = 24.9, 7.1 Hz, 1H), 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) δ 205.43 (d, J = 3.9 Hz), 78.1, 76.0, 62.5 (d, J = 7.3 Hz), 62.4 (d, J = 7.7 Hz),

46.5 (d, J = 127.1 Hz), 41.7, 22.7, 17.8, 16.2 (d, J = 5.6 Hz), 10.75 (d, J = 6.4 Hz), 3.24; IR (thin

-1 + + + film) 1713, 1448, 1245, 1048, 1018, 956, 791 cm ; HRMS (EI ) Calcd for C13H23O2P [M ]

274.1334. Found 274.1338.

2-(diethylphosphonato)-3-oxo-1-phenyl-7-nonyne (176k): clear colorless oil; 1H NMR

(300 MHz, CDCl3) δ 7.20 (m, 5H), 4.24 – 4.05 (m, 4H), 3.52 (ddd, J = 23.2, 11.3, 3.2 Hz, 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 Hz, 3H), 1.64 – 1.49

13 (m, 2H), 1.35 (m, 6H); C NMR (75 MHz, CDCl3) δ 204.7, 138.8 (d, J = 16.4 Hz), 128.5, 126.5,

78.1, 75.91, 62.8 (d, J = 6.6 Hz), 62.6 (d, J = 6.6 Hz), 54.4 (d, J = 123.9 Hz), 43.6, 32.3 (d, J =

3.9 Hz), 22.5, 17.7, 16.3 (d, J = 5.8 Hz), 3.3; IR (thin film) 1713, 1455, 1247, 1047, 1019, 960,

-1 + + + 699 cm ; HRMS (EI ) Calcd for C19H27O4P [M ] 350.1647. Found 350.1657.

(2-Oxo-oct-6-ynyl)-diphenylphosphine oxide (176f): white solid: mp = 84 – 85 oC; 1H

NMR (300 MHz, CDCl3) δ 7.8β – 7.69 (m, 4H), 7.60 – 7.43 (m, 6H), 3.60 (d, J = 15.0, 2H), 2.76

(t, J = 7.1, 2H), 2.06 (tq, J = 7.0, 2.4, 2H), 1.74 (t, J = 2.5, 3H), 1.65 (p, J = 7.0, 2H); 13C NMR

(75 MHz, cdcl3) δ β0β.γ, 1γβ.0, 1γ1.8 (d, J = 101.9), 130.7 (d, J = 9.8), 128.6 (d, J = 12.3), 78.0,

76.1, 46.9 (d, J = 56.9), 44.0, 22.5, 17.7, 3.3; IR (thin film) 1978 (w), 1708, 1484, 1438, 1192

–1 + + cm ; HRMS (EI): calcd for C20H21O2P [M ] 324.1279, found 324.1279. Spectroscopic data is consistent with previous report.36

Proposed Structure (195): yellow oil that quickly decomposed upon isolation; 1H NMR

(300 MHz, CDCl3) δ 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).

Proposed structure (198b): yellow oil that quickly decomposed; 1H NMR (300 MHz,

CDCl3) δ 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).

Proposed Structure (198c): yellow oil that quickly decomposed; 1H NMR (300 MHz,

CDCl3) δ 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).

Procedure for Converting β-Ketophosphine Oxide 176f into β-Ketophosphine Oxide

176m 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 176f (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 NH4Cl. 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 176m was obtained as a white solid (49% yield). (2-oxo-7-octynyl)-diphenylphosphine oxide (176m): white solid; mp

o 1 = 68-71 C; H NMR (300 MHz, CDCl3) δ 7.95 – 7.66 (m, 4H), 7.66 – 7.34 (m, 6H), 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) δ 202.6 (d, J = 5.2 Hz), 132.3 (d, J = 2.9 Hz), 132.0 (d, J = 102.2 Hz), 130.9 (d, J

= 5.2 Hz), 129.0 (d, J = 7.9 Hz), 84.1, 68.4, 47.1 (d, J = 56.1 Hz), 44.6, 27.6, 22.4, 18.2; IR (thin

-1 + + + film) 2232, 1709, 1438, 1187, 907, 725, 693 cm ; HRMS (EI ) Calcd for C20H21O2P [M ]

324.1279. Found 324.1282.

Procedure for Crossover Experiment of Isolated Byproduct 195 with the Enolate of

MeOAc (196). To a THF solution (2 mL) of diisopropylamine (0.090 mL, 0.62 mmol) was added n-BuLi (0.28 mL, 0.59 mmol; 2.1 M solution in hexanes) at -78 oC. After being stirred for

20 minutes at -78 oC, MeOAc (0.05 mL, 0.62 mmol) was added dropwise to the resulting solution. After 30 min, the isolated byproduct 195 (73 mg, 0.211 mmol) was added dropwise.

The mixture was stirred at -78 oC for 20 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. 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 Et2O. The combined organic layers were washed with 5 mL of NaHCO3(aq) and 5 mL of saturated aqueous NaCl, dried with MgSO4, filtered and concentrated. The residual oil was purified by silica gel column

chromatography (EtOAc/Hexanes = 5%) to afford 26.8 mg (78% yield) of ethyl 3-oxo-7- nonynoate (176d) and 5 mg of a mixture 1:2 ratio of 176d and methyl 3-oxo-7-nonynoate

(176g), respectively. Methyl 3-oxo-7-nonynoate/ Ethyl 3-oxo-7-nonynoate (2:1 mixture)

1 (176d/176g): pale yellow oil; H NMR (400 MHz, CDCl3) δ 4.19 (q, J = 7.0 Hz, 2H), 3.74 (s,

3H), 3.47 (s, 2H), 3.45 (s, 2H), 2.67 (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).

CHAPTER 4

FORMAL SYNTHESIS OF PALMEROLIDE A

Macrolides from the palmerolide4-6,39 family of Antarctic marine natural products are important current targets for chemical synthesis. Preliminary cytotoxicity assays indicate that these compounds may be valuable for melanoma research, and chemical synthesis is likely the best option for producing a reliable supply of palmerolide A and congeners.18 Pioneering efforts from groups led by De Brabander19 and Nicolaou/Chen20 resulted in the total synthesis, structural reassignment, and several synthetic analogues21,40,41 of palmerolide A. Hall and coworkers elegantly leveraged organoboron chemistry to achieve a third total synthesis,22 and the Maier,23

Kaliappan,24 and Prasad26 labs have each formally completed synthetic routes to palmerolide A.

Several groups,29-37 including ours, have reported approaches to palmerolide A and, more recently, to palmerolide C.38 Collectively, these insightful studies are beginning to provide an understanding of how one might generate significant quantities of synthetic palmerolides, but no current synthetic route reportedly produces palmerolide A in greater than 1% overall yield.

The consensus synthetic strategy for palmerolide A involves the convergent assembly of key subunits, but the questions of which subunits and how best to assemble them remain open.

Here we disclose original, efficient, and stereoselective syntheses of key subunits 201, 202, and

203 (Figure 68). We have also assembled these subunits in good overall yield to provide macrolactone 200, a late-stage intermediate in the Hall synthesis.22 These studies move us significantly closer to the goal of developing a practical, scalable synthesis of palmerolide A; unresolved tactical challenges are presented.

Figure 68 - Retrosynthetic analysis: Identification of three key subunits for assembly to palmerolideA.

Figure 69 - Synthesis of phosphonate 202.

The synthesis of each of the three subunits is illustrated in Figures 69–71. For phosphonate 202 (Figure 69) we use nucleophile-triggered fragmentation of vinylogous acyl triflate 177a106 to prepare alkynyl ketone 176a on a multi-gram scale (98%, two steps).

Conversion of 176a into 202 is achieved by Lindlar semi-hydrogenation of the alkyne

(176a205, 90%), followed by Grubbs cross-metathesis (205202, 82%). The cross-metathesis

event optimally requires adding titanium tetraisopropoxide, which likely prevents the Lewis basic -keto phosphonate from binding to the ruthenium metal center and inhibiting metathesis.

Figure 70 - Synthesis of aldehyde 203.

The synthesis of aldehyde 203 (Figure 70) begins with Sharpless asymmetric dihydroxylation of known enoate 206,107 as we previously reported (75%, 99.6% ee).36 Here, the alkyne serves as a masked alkene to avoid potential regioselectivity problems in the dihydroxylation. After the diol is in place, Lindlar semi-hydrogenation reveals the terminal alkene (98%), and the diol is converted to the p-methoxyphenyl (PMP) methylidene acetal (98%) to give rise to ester 207. Treatment of 207 with excess DIBAL results in ester reduction, followed by reductive acetal ring-opening to give PMB-protected triol 208 (85%). The regioselective formation of 208 is consistent with internal coordination of the aluminum alkoxide

(from ester reduction) to the proximal acetal oxygen to guide the reductive ring-opening event

(cf. 207a).108 The primary alcohol of 208 is temporarily masked as a pivalate ester (93%), which is later removed using DIBAL after installing the secondary TIPS ether (92%, two steps). Dess–

Martin oxidation (95%) then affords aldehyde 203.

Figure 71 - Synthesis of iodide 204.

The third subunit, iodide 204 (Figure 71) is available using Kalesse’s new syn-selective variant of the Kobayashi vinylogous aldol reaction.109,110 Coupling of chiral (Z)-ketene

N,O-acetal 209 with iodo-aldehyde 33 in the presence of titanium tetrachloride provides 210

(69%). Many different tactics have been reported for controlling the C19-C20 stereochemistry, but this syn-selective vinylogous aldol reaction is perhaps ideal for the task at hand. N,O-Ketene acetal 209 is robust, easy to handle, and delivers the desired syn-isomer with excellent diastereoselectivity, making it a valuable building block for construction of the palmerolide side chain. Iodo-aldehyde 33, on the other hand, is unstable to storage, and it has a propensity to decompose even during the course of the reaction. We use excess 33 for the preparation of 210, but alternative solutions may be needed here. Homologation of 210 is achieved by DIBAL reduction of the imide and Wittig olefination of the resulting aldehyde to give subunit 204 (67%, two steps).

Our assembly of the three subunits is presented in Figure 72. Horner–Wadsworth–

Emmons (HWE) reaction of 202 and 203 was confounded by a tendency of phosphonate 202 to undergo base-mediated cyclization onto the tethered Michael acceptor (i.e., the unsaturated ester). Barium hydroxide111-116 effectively suppresses the Michael-type intramolecular cyclization of 202 in favor of the desired intermolecular HWE olefination of aldehyde 203 to give enone 211 in excellent yield (96%).

Figure 72 - Assembly of subunits 202, 203 and 204 to complete the formal synthesis of palmerolide A.

Borohydride reduction of 211 provides diastereomeric alcohols 212 and 213 (93%) in an approximately 1:1 ratio.19,26 These isomers are separable by chromatography on silica gel; the undesired isomer (213) can be converted into 212 by Mitsunobu inversion with p-nitrobenzoic acid (74%) and selective cleavage of the p-nitrobenzoate ester (in the presence of the ethyl ester) with sodium azide in methanol (84%).117 Attempts to produce 212 selectively using reagent control have not yet been successful, and we continue to seek a more practical solution to this challenge. Silylation and saponification of 212 gives acid 214, the C1–C15 section of palmerolide A.

Esterification of acid 214 with alcohol 204 using the Yamaguchi procedure (91%) is followed by Heck macrocyclization (59%) to provide 201. The Maier lab reported a similar Heck cyclization in the context of their formal synthesis of palmerolide A, and Hall and coworkers converted macrolactone 201 into the natural product in six additional steps (8% yield).

In summary, innovative routes to three key subunits (202, 203, and 204) have been developed, and these subunits have been assembled to produce 201, an advanced precursor of synthetic palmerolide A. We have prepared macrolactone 201 in 16% overall yield by a linear sequence of 16 steps from 4-pentynol, plus two auxiliary steps to invert alcohol 213212.

Diastereoselective C7 ketone reduction is perhaps the most overt challenge that remains to be addressed, and refinement of the protecting group strategy is also in order: late-stage cleavage of the PMB and TIPS ethers are reportedly inefficient (16% combined). Improvements in these two areas would impact the quantitative metrics (e.g., step-count and yield) associated with the efficiency of this route. A third challenge relates to the instability of iodo-aldehyde 33, which imposes practical constraints on the otherwise-ideal Kalesse vinylogous aldol reaction

(209210).

The remaining challenges not withstanding, this work marks a significant step towards the goal of providing cost-effective access to synthetic palmerolide A. Virtues of this formal synthesis include the nucleophile-triggered fragmentation (177a176a) en route to subunit 202, the efficient barium hydroxide-mediated HWE coupling (202+203211), a concise synthesis of subunit 204 by new vinylogous aldol chemistry, and facile annulation by the Yamaguchi / Heck sequence to deliver macrolactone 201. Efforts to resolve the issues outlined above and to generate useful quantities of synthetic palmerolide A are in progress.

Experimental Section

Methylene chloride was distilled from CaH2. All other solvents and reagents were used as obtained from commercial sources without further purification. Flash column chromatography was performed using EM Science silica gel 60 (43-60 micron mesh). Analytical and preparative

1 thin layer chromatography (TLC) were performed on EM Science silica gel 60 F254 plates. H and 13C NMR spectral data were recorded in a Bruker 400 or 600 MHz spectrometer using

CDCl3 as a solvent. The chemical shifts are reported in parts per million (ppm) relative to the

1 13 internal standard tetramethylsilane (0.0 ppm) for H NMR and CDCl3 (77.0 ppm) for C NMR

(Appendix B). Infrared spectral data were obtained using a Perkin-Elmer Spectrum 100 FT-IR spectrometer with diamond ATR accessory as thin film. All optical rotation data was recorded at

25 oC on a Jasco P-2000 polarimeter with a 100 mm cell (concentration reported as g/100 mL).

Synthesis of phosphonate 202

Phosphonate 176a - To a THF solution (170 mL) of dimethyl methylphosphonate (1.84 mL,

16.7 mmol) was added n-BuLi (1.6 M solution in hexanes, 9.6 mL, 15.3 mmol) at –78 °C. After being stirred for 20 minutes at –78 C, a solution of vinylogous acyl triflate 177a (3.58 g, 13.9 mmol) in THF was added dropwise to the resulting solution. The mixture stirred at –78 °C for 10 min, at 0 C for 10 min, at r.t. for 30 min, and at 60 °C for 30 min; during the course of the reaction the solution changed from clear to yellow. A half saturated aqueous NH4Cl solution was used to quench the reaction and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed with NaHCO3(aq) and brine, dried with MgSO4, filtered and concentrated. The residual oil was purified by silica gel column chromatography (gradient

elution from 80% - 100% EtOAc/Hexanes) to afford 3.23 g of β-ketophosphonate 176a

(quantitative yield) as a pale yellow oil. Spectroscopic data consistent with previous reports.53

(Z)-alkene 205. Palladium, 5 wt. % on calcium carbonate, poisoned with lead (258 mg) was stirred in methanol/pyridine (4:1, 15 mL), under an atmosphere of hydrogen. After 30min, a solution of alkyne 176a (500 mg, 2.15 mmol) in MeOH (2mL) was added in one shot to the stirred palladium solution. The reaction was then stirred for 1.5 h and filtered through a pad of

Celite™ and the pad was washed with CH2Cl2. The filtrate was then concentrated and purified on silica gel by flash chromatography (80% EtOAc/Hexane) to afford 450 mg (90%) of Z-olefin

1 205 as a light yellow oil. H NMR (400 MHz, CDCl3) δ 5.52-5.42 (m, 1H), 5.36-5.28 (m, 1H),

3.79 (s, 3H), 3.77 (s, 3H), 3.10 (d, J = 23 Hz, 2H), 2.60 (t, J = 7.3 Hz, 2H), 2.08-2.00 (m, 2H),

13 1.64 (quin, J = 7.3 Hz, 2H), 1.58 (d, J = 6.7 Hz, 3H). C NMR (100 MHz, CDCl3) δ β0β.1 (d, J

= 6.0 Hz), 129.4, 124.9, 53.1, 53.0, 43.5 (d, J = 1.5 Hz), 41.1 (d, J = 128 Hz), 25.8, 23.1, 12.7. IR

(thin film) 3014, 2956, 2856, 1713, 1416, 1405, 1370, 1249, 1024, 808, 701 cm-1; HRMS

+ + + (ESI+): calcd for C10H19O4PNa [M Na ] 257.09186, found 257.09190.

Horner-Wadsworth-Emmons Reagent 202 - To a solution of olefin 205 (450 mg, 1.92 mmol)

i and ethyl acrylate (0.963 mL, 5.8 mmol) in CH2Cl2 (19 mL) was added freshly distilled Ti(O Pr)4

(0.08 mL, 0.β9 mmol), followed by Grubbs’ second-generation catalyst (50 mg, 0.06 mmol). The reaction vessel was sealed with a Teflon screw-top with a rubber seal. The reaction was then placed in an oil bath heated to 100 oC and stirred for 20min. The reaction was then cooled to room temperature and a second aliquot of Grubbs’ second-generation catalyst was added (15 mg,

0.02 mmol). The reaction was stirred at 100 oC. After 10min, the reaction was cooled to room temperature and filtered through Celite™ and then washed with CH2Cl2. The filtrate was concentrated and then purified on silica gel by flash chromatography (60% EtOAc/Hexane, 80%

EtOAc/Hexane) to provide 460 mg (82%) of HWE reagent 202 as a yellow-brown oil; 1H NMR

(600 MHz, CDCl3) δ 6.91 (dt, Jtrans = 16 Hz , J = 7.0 Hz, 1H), 5.83 (d, Jtrans = 16 Hz, 1H), 4.18

(q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.09 (d, J = 23 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H),

13 2.22 (q, J = 7.0 Hz, 2H), 1.77 (quin, J = 7.0 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). C NMR (150

MHz, CDCl3) δ β01.0 (d, J = 6.0 Hz), 166.4, 147.7, 122.0, 60.1, 53.0 (d, J = 6 Hz), 42.9, 41.4 (d,

J = 127 Hz), 30.9, 21.5, 14.2. IR (thin film) 3479 (br), 2957, 1711, 1653, 1255, 1182, 1022, 807,

-1 + + + 730 cm ; HRMS (ESI+): calcd for C12H21O6PNa [M Na ] 315.09734, found 315.09835.

Synthesis of Aldehyde 203

Diol 206-1. AD-mix α (30g, 1.6g/mmol of olefin) and MeSO2NH2 (1.75g, 18.4mmol) were

t o stirred in BuOH/H2O (1:1, 100mL) at 0 C for 1hr. To the stirred heterogeneous solution was added a solution of the known compound, (E)-2-hept-2-en-6-ynoic ethyl ester (2.8g, 18.4mmol),

t o in 24mL of BuOH/H2O (1:1) in one shot. The reaction mixture was stirred at 0 C for 24h. To

o the reaction was then added Na2SO3 (13.4g, 106.7mmol) at 0 C and the solution was stirred for an additional hour. The reaction was then diluted with CH2Cl2 and H2O. Product extracted with

CH2Cl2 (3x). The combined organic extracts were washed with a saturated brine solution, dried with Na2SO4, and concentrated under reduced pressure. The resulting oil was then purified by flash chromatography on silica gel (30% EtOAc/Hexanes) to afford 2.57g (75%) of diol 206-1 as

o 25 1 a white solid: mp = 50 - 51 C; [α]D = -31.7 (c = 6.7, CH2Cl2); H NMR (300 MHz, CDCl3δ

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 (d,t, 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,

13 3H); C NMR (75 MHz, CDCl3) δ 17γ.ββ, 8γ.47, 7γ.βγ, 71.15, 68.95, 6β.05, γβ.17, 14.8γ,

14.04; IR (thin film) 3444 (br), 3291, 2111 (w), 1732, 1214, 1118 cm-1; HRMS (ESI): calcd for

+ + C9H14O4Na [M+Na ] 209.0790, found 209.0796.

Alkene 206-2. A mixture of palladium, 5 wt. % on calcium carbonate, poisoned with lead

(480mg), alkyne 206-1 (790 mg, 4.25 mmol) and quinoline (3 mL, 27 mmol) in CH2Cl2 (80 mL) was stirred for 1h under an atmosphere of hydrogen. The reaction was then filtered through a pad of Celite™ and the pad was washed with CH2Cl2. The product was extracted with HCl 1M solution (3 x 10 mL). The organic phase was dried with Na2SO4 and concentrated under reduced pressure. The resulting oil was purified on silica gel by flash chromatography (20 to 30%

25 EtOAc/Hexane) to afford 780 mg (98%) of alkene 206-2 as a light yellow oil: [α]D = -14.3 (c =

1 0.17, CH2Cl2); H NMR (400 MHz, CDCl3) δ 5.79-5.89 (m, 1H), 5.07 (dd, Jtrans= 17.1 Hz, Jgem=

1.6 Hz, 1H), 5.07 (br d, 1H), 4.28 (q, J = 7.1, 2H), 4.09 (br s, 1H), 3.92 (br s, 1H), 3.34 (br s,

13 1H), 2.35-2.12 (m, 3H), 1.64 -1.80 (m, 2H), 1.32 (t, J = 7.1, 3H) ; C NMR (100 MHz, CDCl3) δ

173.7, 138.0, 115.3, 73.4, 72.1, 62.3, 33.0, 30.1, 14.3. IR (thin film) cm–1 3307, 3071, 2960,

+ 2931, 2857, 1472, 1462, 1428, 1382, 110, 1045, 822, 738; HRMS (ESI): calcd for C9H16O4Na

[M+Na+] 211.09463, found 211.090502.

PMP acetal 207. To a stirred solution of diol 206-2 (1.05g, 5.6mmol) and 10-camphor sulfonic

acid (CSA) (65mg, 0.28mmol) in 15ml CH2Cl2 was added anisaldehyde dimethylacetal (2.02mL,

11.2mmol). After 4hr the reaction was quenched with NaHCO3 sat solution and extracted with

CH2Cl2 (3x). The combined organic layers were washed with a saturated brine solution, dried with Na2SO4, and concentrated. The resulting oil was then purified by flash chromatography on silica gel (1% EtOAc/Hexanes, 35g silica gel, 1.8inches column diameter) to afford 1676mg

25 1 (98%) of acetal 207: []D = -11.0 (c = 0.17, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.53 (d, J

= 8.7 Hz, .5H), 7.46 (d, J = 8.7 Hz, 1.5H), 6.78 (d, J = 8.7 Hz, 2H), 6.02 (s, 0.25H), 5.98 (s,

0.75H), 5.92-5.82 (m, 1H), 5.07 (dd, Jtrans= 17.1 Hz, Jgem= 1.5 Hz, 1H), 5.04 (br d, 1H), 4.37-

4.14 (m, 4H), 3.83 (s, 3H), 2.38-2.22 (m, 2H), 2.02-1.80 (m, 2H), 1.34 (t, J= 7.1 Hz, 3H ). 13C

NMR (100 MHz, CDCl3) δ 171.4, 170.4, 160.9, 160.8, 137.5, 137.4, 129.4, 128.7, 128.5, 115.6,

115.5, 113.9, 105.1, 104.4, 80.3, 79.7, 79.5, 78.9, 61.6, 55.5, 33.0, 32.5, 29.8, 14.4, 14.3. IR (thin film) 2937, 1753, 1733, 1614, 1518, 1247, 1171, 1089, 1029, 829 cm-1; HRMS (CI): calcd for

+ + + C17H22O5Na [M Na ] 329.13649, found 329.13605.

o Diol 208. To a solution of acetal 207 (1.67 g, 5.45mmol) in CH2Cl2 (130mL) at –78 C was added DIBAL-H (54.5mL), as a 1.0M solution in toluene, dropwise. The reaction was allowed to stir at –78 oC for 15min and transferred to the fridge (-13 ºC). After 5 days, 1.2L of a saturated aqueous solution of sodium, potassium tartrate and 3mL of methanol was added dropwise at 0 oC. The reaction was then warmed to room temperature and stirred for 4 h until the biphasic solution became clear. The product was extracted with EtOAc (5x). The combined organic layers were dried with MgSO4 and concentrated. The resulting oil was then purified by flash chromatography on silica gel (30% EtOAc/Hexanes and then 50% EtOAc/Hexanes) to afford

25 1 1.32mg (92% yield) of diol 208 as a colorless oil. []D = 26.6 (c = 0.14, CH2Cl2); H NMR

(400 MHz, CDCl3) δ 7.26 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 5.88-5.76 (m, 1H), 5.05

(dq, Jtrans= 17 Hz, Jgem= 3.4 Hz, J =1.64 Hz, 1H), 4.99 (dq, Jcis= 10.2 Hz, Jgem= 3.4 Hz, J =1.2

Hz, 1H), 4.61 (d, J = 11 Hz, 1H), 4.41 (d, J = 11 Hz, 1H), 3.81 (s, 3H), 3.72-3.57 (m, 3H), 3.52-

13 3.47 (m, 1H), 2.54 (bs, 1H), 2.25-2.10 (m, 3H), 1.82-1.64 (m, 2H). C NMR (100 MHz, CDCl3)

δ 159.5, 138.1, 130.0, 129.6, 115.1, 113.9, 78.8, 72.6, 72.0, 64.1, 29.4, 29.3. IR (thin film) 3397,

2933, 1612, 1513, 1463, 1245, 1075, 1031, 910, 820, 754 cm-1; HRMS (ESI+): calcd for

+ + + C15H22O4Na [M Na ] 289.14158, found 289.14095.

Pivaloyl ester 208-1. To a solution of diol 208 (740 mg, 2.81 mmol) in CH2Cl2 (20mL) at –78 oC was added pyridine (0.7 mL, 8.4 mmol) and trimethylacetyl chloride (0.6 mL, 4.8 mmol). The reaction was allowed to stir at –78 oC for 30 to 45 min until completion by TLC and quenched by

the addition of a saturated aqueous solution of sodium bicarbonate. The reaction mixture was then warmed to room temperature, extracted with CH2Cl2 (3x) and the combined organic layers dried with MgSO4 and concentrated. The resulting oil was then purified by flash chromatography on silica gel (10% EtOAc/Hexanes and then 20% EtOAc/Hexanes) to afford 913 mg (93% yield)

25 1 of pivaloyl ester 208-1 as a colorless oil. []D = 25 (c = 0.21, CH2Cl2); H NMR (400 MHz,

CDCl3) δ 7.25 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.85-5.75 (m, 1H), 5.03 (dq, Jtrans=

17 Hz, Jgem= 3.2 Hz, J =1.5 Hz, 1H), 5.10-4.96 (m, 1H), 4.57 (d, J = 11 Hz, 1H), 4.44 (d, J = 11

Hz, 1H), 4.17-4.08 (m, 2H), 3.79 (s, 3H), 3.48-3.42 (m, 1H), 2.52 (bs, 1H), 2.19-2.11 (m, 2H),

13 1.82-1.64 (m, 2H), 1.19 (s, 9H). C NMR (100 MHz, CDCl3) δ 178.4, 159.3, 137.9, 130.0,

129.5, 115.0, 113.8, 77.5, 72.0, 70.6, 65.2, 55.2, 38.7, 29.5, 29.2, 27.1. IR (thin film) 3487, 2959,

1727, 1612, 1513, 1480, 1462, 1283, 1247, 1157, 1033, 911, 820 cm-1; HRMS (ESI+): calcd for

+ + + C20H30O5Na [M Na ] 373.19909, found 373.19830.

Alcohol 208-2. To a solution of ester 208-1 (811 g, 2.31 mmol) in CH2Cl2 (4 mL) at room temperature was added 2,6-lutidine (1.65 mL, 13.9 mmol) and TIPSOTf (1.9 mL, 6.94 mmol).

The reaction was allowed to stir at room temperature for 1h, when a saturated aqueous solution of sodium bicarbonate was added to the reaction. The mixture was extracted with CH2Cl2 (3x) and the combined organic layers dried with MgSO4 and concentrated. The resulting oil was then purified by flash chromatography on silica gel (small column) (2% EtOAc/Hexanes) to afford the silyl ether (with impurity) as a colorless oil.

A solution of the silyl ether obtained above in 55 mL of CH2Cl2 was transferred to a 100 mL round-bottom flask. The solution was cooled to –78 oC and DIBAL-H (15.3 mL) was added as a

1.0M solution in toluene, dropwise. The reaction was allowed to warm to 0 oC. After 1h, 200 mL of a saturated aqueous solution of sodium, potassium tartrate and 10 mL of methanol was added dropwise at 0 oC. The reaction was then warmed to room temperature and stirred vigorously for

2h until the biphasic solution became clear. The product was extracted with EtOAc (3x). The combined organic layers were dried with MgSO4 and concentrated. The resulting oil was then purified by flash chromatography on silica gel (10% to 20% EtOAc/Hexanes) to afford 900 mg

25 (92% yield over the 2 steps) of alcohol 208-2 as a colorless oil. []D = -19 (c = 0.21, CH2Cl2);

1 H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.84-5.74 (m,

1H), 5.10-4.93 (m, 2H), 4.56 (d, J = 11 Hz, 1H), 4.48 (d, J = 11 Hz, 1H), 4.11-4.06 (m, 1H), 3.79

(s, 3H), 3.79-3.75 (m, 1H), 3.68-3.60 (m, 1H), 3.55 (qd, J = 10.0 Hz, J = 4.2 Hz, J = 2.2 Hz, 1H),

2.55 (bd, J = 4.8 Hz, 1H), 2.34-2.22 (m, 1H), 2.12-2.00 (m, 1H), 1.86-1.76 (m, 1H), 1.65-1.54

13 (m, 1H), 1.05 (s, 21H). C NMR (100 MHz, CDCl3) δ 159.4, 138.6, 130.2, 129.6, 114.8, 113.8,

81.1, 72.4, 70.3, 63.7, 55.2, 30.6, 28.0, 18.0, 17.9, 12.3. IR (thin film) 3476, 2866, 2492, 1612,

-1 + + + 1513, 1463, 1247, 1108, 1037, 882, 678 cm ; HRMS (ESI+): calcd for C24H42O4SiNa [M Na ]

445.27500, found 445.27446.

Aldehyde 203. Dess-Martin reagent (1100 mg, 2.6 mmol) was added to alcohol 208-2 (550 mg,

o 1.3 mmol) in CH2Cl2 (28 mL) at 0 C. Let stir until all the solids had dissolved and H2O (14 uL,

0.8 mmol) was added. The reaction mixture was warmed to rt and stirred for 1h. The reaction

was poured into a small plug of silica gel and purified by flash chromatography (20%

EtOAc/Hexanes) to yield aldehyde 203 as a colorless oil (520 mg, 95%). Aldehyde 203 was

25 1 immediately used in the next reaction. []D = -59 (c = 0.14, CH2Cl2); H NMR (400 MHz,

CDCl3) δ 9.76 (d, J = 1.7 Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.81-5.69

(m, 1H), 5.02-4.94 (m, 2H), 4.59 (d, J = 11 Hz, 1H), 4.53 (d, J = 11 Hz, 1H), 4.27 (dd, J = 4.9

Hz, J = 1.7 Hz, 1H), 3.80 (s, 3H), 3.55 (m, 1H), 2.29-2.19 (m, 1H), 2.12-2.00 (m, 1H), 1.92-1.82

13 (m, 1H), 1.59-1.48 (m, 1H), 1.04 (s, 21H). C NMR (100 MHz, CDCl3) δ 203.1, 159.4, 138.0,

130.2, 129.5, 115.1, 113.8, 79.9, 77.7, 72.2, 55.2, 30.1, 29.4, 17.9, 17.8, 12.2. IR (thin film)

2943, 2866, 1736, 1612, 1513, 1463, 1247, 881, 681 cm-1; HRMS (ESI+): calcd for

+ + + C24H40O4SiNa [M Na ] 443.25935, found 443.25845.

Synthesis of Vinyl Iodide 204

Syn-Aldol product 210. To a solution of aldehyde 33 (98 mg, 0.46 mmol) and TBS enol ether

209 (0.23 mmol, 90 mg) in CH2Cl2 (1.8 mL) at -78 ºC was added to a solution of TiCl4 1M in

CH2Cl2 (0.23 mL, 0.23 mmol). The reaction was stirred at the same temperature for 2 days.

Then, a solution of potassium sodium tartrate was added and the mixture stirred until all the solids have dissolved (1h). The reaction mixture was extracted with ethyl acetate, washed with a saturated solution of NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue purified by flash chromatography (10% to 20%

EtOAc/Hexanes) to yield syn-aldol product 210 as a colorless oil (77 mg, 69%). A minor diastereomer could be isolated during flash chromatography (ratio desired: undesired

1 25 1 diastereomer = 97:3 by H NMR). []D = 82 (c = 0.615, CHCl3); H NMR (400 MHz, CDCl3) δ

7.37-7.26 (m, 3H), 7.24-7.20 (m, 2H), 6.01 (bd, J = 0.8 Hz, 1H), 5.74 (dq, J = 10.1 Hz, J = 1.5

Hz, 1H), 4.72-4.64 (m, 1H), 4.26 (t, J = 9.0 Hz, 1H), 4.19 (dd, J = 9.0 Hz, J = 4.3 Hz, 1H), 3.72-

3.63 (m, 1H), 3.38 (dd, J = 13.4 Hz, J = 4.3 Hz, 1H), 2.85 (dd, J = 13.4 Hz, J = 9.3 Hz, 1H),

2.72-2.61 (m, 1H), 2.47 (dd, J = 13.0 Hz, J = 2.1 Hz, 1H), 2.24 (dd, J = 13.0 Hz, J = 9.9 Hz, 1H),

2.06 (d, J = 6.0 Hz, 1H), 1.96 (d, J = 1.5 Hz, 3H), 1.88 (d, J = 0.8 Hz, 3H), 1.09 (d, J = 6.8 Hz,

13 3H). C NMR (100 MHz, CDCl3) δ 171.6, 153.2, 145.1, 138.5, 135.0, 131.5, 129.4, 128.9,

127.4, 77.2, 72.7, 66.4, 55.6, 44.1, 38.7, 37.4, 24.0, 15.0, 14.2. IR (thin film) 3505 (br), 2961,

-1 + 2924, 1779, 1678, 1350, 1209, 1007, 702 cm ; HRMS (ESI+): calcd for C21H26O4NINa

[M+Na+] 506.08042, found 506.07959.

o Ester 204. To a solution of imide 210 (178 g, 0.368 mmol) in CH2Cl2 (4 mL) at –78 C was added DIBAL-H (0.92 mL, 0.92 mmol), as a 1.0M solution in toluene, dropwise. The reaction was allowed to stir at –78 oC. After 2h, 30 mL of a saturated aqueous solution of sodium potassium tartrate was added. The reaction was then warmed to room temperature and stirred for

2h until the biphasic solution became clear. The product was extracted with EtOAc (3x). The combined organic layers were dried with MgSO4 and concentrated. The resulting oil was used in the next reaction without further purification.

The aldehyde obtained in the previous step was dissolved in benzene (2 mL) and (tert- butoxycarbonyl-methylene)triphenylphosphorane (277 mg, 0.736 mmol) was added. The reaction was allowed to reflux for 2h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (10 to 20% EtOAc/Hexanes) to afford ester 210 (100 mg,

67% yield over the 2 steps) as a light yellow oil.

25 1 []D = +68 (c = 0.32, CHCl3); H NMR (400 MHz, CDCl3) δ 7.17 (dd, Jtrans = 15.7 Hz, J = 0.6

Hz, 1H), 6.01 (s, 1H), 5.76 (d, Jtrans = 15.7 Hz, 1H), 5.68 (d, J = 10.1 Hz, 1H), 3.59-3.53 (m,

1H), 2.65-2.50 (m, 1H), 2.39 (dd, J = 13.0 Hz, J = 0.9 Hz, 1H), 2.23 (dd, J = 13.0 Hz, J = 9.9 Hz,

1H), 1.86 (d, J = 0.6 Hz, 3H), 1.79 (d, J = 1.2 Hz, 3H), 1.62 (d, J = 4.0 Hz, 1H), 1.49 (s, 9H),

13 1.08 (d, J = 6.7 Hz, 3H). C NMR (100 MHz, CDCl3) δ 166.7, 148.1, 144.9, 142.3, 133.1, 118.5,

80.1, 77.3, 72.5, 45.3, 39.3, 28.1, 23.9, 16.2, 12.7. IR (thin film) 3440 (br), 2975, 2928, 1682,

-1 + 1620, 1367, 1314, 1147, 979, 847, 767, 670 cm ; HRMS (ESI+): calcd for C17H27O3INa

[M+Na+] 429.09026, found 429.08925.

Enone 211. Ba(OH)2.8 H2O (588 mg, 1.86 mmol) was added to a solution of aldehyde 203 (270 mg, 0.64 mmol) and HWE reagent 202 (385 mg, 1.28 mmol) in THF (17 mL) at room temperature. H2O (0.1 mL, 5.56 mmol) was added and the reaction was stirred at the same temperature overnight. The reaction was poured into a column with silica gel and purified by flash chromatography (10% EtOAc/Hexanes) to yield enone 211 as a colorless oil (361 mg,

96%). Note: When 1.5 equivalents of the HWE reagent 202 were used the product was obtained

25 1 in 86% yield over 2 steps (oxidation and olefination). []D = -72 (c = 0.14, CH2Cl2); H NMR

(400 MHz, CDCl3) δ 7.28 (d, J = 8.6 Hz, 2H), 7.00-6.86 (m, 2H), 6.90 (d, J = 8.6 Hz, 2H), 6.33

(dd, Jtrans = 16.0 Hz, J = 1.8 Hz, 1H), 5.85 (dt, Jtrans = 15.7 Hz, J = 1.6 Hz, 1H), 5.82-5.72 (m,

1H), 5.02-4.94 (m, 2H), 4.64-4.52 (m, 3H), 4.20 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.53 (qd, J =

10.0 Hz, J = 4.5 Hz, J = 2.3 Hz, 1H); 2.60 (t, J = 7.3 Hz, 2H), 2.30-2.19 (m, 3H), 2.11-1.99 (m,

1H), 1.80 (q, J = 7.3 Hz, 2H), 1.75-1.64 (m, 1H), 1.37-1.27 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H),

13 1.04 (s, 21H). C NMR (100 MHz, CDCl3) δ 199.4, 166.6, 159.4, 148.2, 146, 138.5, 130.4,

129.9, 129.6, 121.9, 114.9, 113.9, 80.9, 72.5, 71.7, 60.2, 55.3, 39.1, 31.4, 30.3, 28.7, 22.3, 18.0,

14.3, 12.3. IR (thin film) 2943, 2866, 1718, 1674, 1636, 1612, 1513, 1247, 1036, 981, 882, 681

-1 + + + cm ; HRMS (ESI+): calcd for C34H54O6SiNa [M Na ] 609.35873, found 609.35863.

Ester 212. To a solution of enone 211 (500 mg, 0.85 mmol) in methanol (10 mL) was added

NaBH4 (36 mg, 0.94 mmol) at room temperature. After 10 min, the reaction was complete as evidenced by TLC. Ethyl acetate (5 mL) was added to the reaction mixture and the solvent

o evaporated. EtOAc (10 mL) was added to the residue, the solution was cooled to 0 C and H2O was added until no reaction was observed. The organic layer was separated and the aqueous layer extracted with EtOAc (2x10 mL). The combined organic layers were dried over MgSO4 and concentrated. The product was obtained as a 1:1 (approximately) mixture of diastereomers in >

95% yield. The oil was purified by flash chromatography (15% EtOAc/Hexanes) to yield 1) undesired diastereomer 213 (197 mg, 39%), a mixture of the 2 diastereomers (75 mg, 15%) and

the desired diastereomer 212 (188 mg, 38%). The mixture (75 mg) was resubmitted to purification with the diastereomeric mixture obtained in a different experiment. Similar results were observed in the reaction of enone 211 with (R)-2-methyl-CBS-oxazaborolidine (3 equiv)

o and BH3-THF (2 equiv) in THF at -40 C.

25 1 Undesired diastereomer 213: []D = -32 (c = 6.76, CHCl3); H NMR (600 MHz, CDCl3) δ 7.26

(d, J = 9.0 Hz, 2H), 6.93 (dt, Jtrans = 15.7 Hz, 6.8 Hz, 1H), 6.90 (d, J = 9.0 Hz, 2H), 5.81 (dt,

Jtrans = 15.7Hz, J = 1.5 Hz, 1H), 5.80-5.69 (m, 3H), 4.99-4.92 (m, 2H), 4.57 (d, J = 11.2 Hz, 1H),

4.48 (d, J = 11.2 Hz, 1H), 4.44 (t, J = 4.6 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.15-4.10 (m, 1H),

3.80 (s, 3H), 3.43 (qd, J = 10.0 Hz, J = 4.5 Hz, J = 2.3 Hz, 1H); 2.26-2.18 (m, 3H), 2.08-1.99 (m,

1H), 1.75-1.68 (m, 1H), 1.63-1.45 (m, 5H), 1.46-1.35 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.04 (s,

13 21H). C NMR (150 MHz, CDCl3) δ 166.6, 159.2, 148.8, 138.8, 134.0, 130.7, 130.2, 129.4,

121.5, 114.6, 113.7, 81.3, 72.2, 72.1, 72.0, 60.1, 55.2, 36.5, 32.0, 30.3, 28.4, 23.8, 18.0, 14.2,

12.3. IR (thin film) 3439 (br), 2941, 2865, 1719, 1513, 1463, 1247, 1036, 882, 679 cm-1; HRMS

+ + + (ESI+): calcd for C34H56O6SiNa [M Na ] 611.37438, found 611.37453.

25 1 Desired diastereomer 212 []D = -33.6 (c = 5.01, CHCl3); H NMR (600 MHz, CDCl3) δ 7.26

(dd, J = 8.6 Hz, J = 0.8 Hz, 2H), 6.94 (dt, Jtrans = 15.7 Hz, J = 6.8 Hz, 1H), 6.87 (d, J = 8.6 Hz,

2H), 5.81 (dt, Jtrans = 15.7Hz, J = 1.4 Hz, 1H), 5.80-5.68 (m, 3H), 4.99-4.92 (m, 2H), 4.56 (d, J =

11.2 Hz, 1H), 4.48 (d, J = 11.2 Hz, 1H), 4.45 (t, J = 4.7 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.15-

4.10 (m, 1H), 3.80 (s, 3H), 3.43 (qd, J = 10.0 Hz, J = 4.5 Hz, J = 2.3 Hz, 1H); 2.26-2.18 (m,

3H), 2.08-2.00 (m, 1H), 1.81-1.74 (br s, 1H), 1.74-1.67 (m, 1H), 1.61-1.45 (m, 4H), 1.41-1.33

13 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.03 (s, 21H). C NMR (150 MHz, CDCl3) δ 166.6, 159.3,

148.8, 138.8, 134.1, 130.7, 130.2, 129.5, 121.5, 114.6, 113.8, 81.3, 72.2, 72.1, 71.9, 60.1, 55.3,

36.4, 32.0, 30.3, 28.4, 23.8, 18.1, 18.0, 14.2, 12.3. IR (thin film) 3427 (br), 2942, 2866, 1720,

-1 + + + 1513, 1463, 1247, 1036, 882, 680 cm ; HRMS (ESI+): calcd for C34H56O6SiNa [M Na ]

611.37438, found 611.37318.

Mitsunobu inversion. To a solution of alcohol 213 (125 mg, 0.21 mmol), PPh3 (167 mg, 0.64 mmol) and p-nitrobenzoic acid (106 mg, 0.64 mmol) in THF (1 mL) at 0ºC was added DEAD

40% solution in toluene (0.3 mL, 0.64 mmol). The reaction was allowed to warm to room temperature. After 2 h the reaction was quenched with water, NaHCO3 and extracted with

CH2Cl2 (3x). The combined organic layers were dried with MgSO4 and concentrated. The resulting oil was then purified by flash chromatography on silica gel (5 to 10% EtOAc/Hexanes) to yield p-nitrobenzoic ester as a colorless oil (116 mg, 74%). In a round bottom flask, the p- nitrobenzoic ester product (40 mg, 0.054 mmol) was dissolved in anhydrous methanol and sodium azide (35 mg, 0.54 mmol) was added. The reaction was stirred at 50 ºC for 2 days, and then, it was allowed to cool down to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (10 to 20%

EtOAc/Hexanes) to give alcohol 212 as a colorless oil (27 mg, 84%).

Acid 214. TIPSOTf (0.102 mL, 0.38 mmol) was added to a solution of alcohol 212 (185 mg,

0.31 mmol) and 2,6-lutidine (0.087 mL, 0.75 mmol) in CH2Cl2 (3 mL) at room temperature.

After stirring for 30 minutes at room temperature the reaction was complete. A saturated aqueous solution of NH4Cl was added. The phases were separated and the water layer was extracted 3 times with CH2Cl2. The combined organic layers were dried with MgSO4 and concentrated. The oil residue was purified in a small plug of silica by flash chromatography (5% EtOAc/Hexanes).

The product containing some impurities from TIPSOTf was transferred to a round-bottom flask, and then THF (6 mL), H2O (6 mL) and KOH (1217 mg, 21.7 mmol) were added to the reaction mixture. A reflux condenser was connected to the flask and the reaction was allowed to stir 12h at 100oC. HCl 1M was added to the reaction until pH 1. The solution was extracted with EtOAc

(5 times). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (5 to 20% EtOAc/Hexanes) to give acid 214

25 1 as a colorless oil (204 mg, 91% over the 2 steps). []D = -26 (c = 1.035, CHCl3); H NMR (600

MHz, CDCl3) δ 7.25 (d, J = 9.0 Hz, 2H), 7.04 (dt, Jtrans = 15.6 Hz, J = 6.8 Hz, 1H), 6.86 (d, J =

9.0 Hz, 2H), 5.82-5.64 (m, 4H), 4.99-4.90 (m, 2H), 4.57 (d, J = 11.4 Hz, 1H), 4.47 (d, J = 11.4

Hz, 1H), 4.46 (t, J = 4.6 Hz, 1H), 4.34-4.29 (m, 1H), 3.80 (s, 3H), 3.39 (ddd, J = 9.8 Hz, J = 4.6

Hz, J = 2.6 Hz, 1H); 2.26-2.16 (m, 3H), 2.07-1.98 (m, 1H), 1.71-1.64 (m, 1H), 1.60-1.42 (m,

13 4H), 1.41-1.33 (m,1H), 1.07-1.01 (m, 42H). C NMR (150 MHz, CDCl3) δ 171.6, 159.1, 152.1,

139.0, 130.4, 134.1, 129.2, 129.0, 120.6, 114.4, 113.7, 81.7, 72.8, 72.2, 72.0, 55.3, 38.1, 32.5,

30.4, 28.7, 22.7, 18.1, 18.1, 12.4. IR (thin film) 2942, 2865, 1697, 1513, 1463, 1246, 881, 678

-1 + + + cm ; HRMS (ESI+): calcd for C41H72O6Si2Na [M Na ] 739.47651, found 739.47340.

Vinyl iodide 214-1. To a solution of acid 214 (40 mg, 0.056 mmol) and triethylamine (0.013 mL, 0.09 mmol) in toluene (1 mL) was added trichlorobenzoyl chloride (0.009 mL, 0.056 mmol) dropwise at room temperature. After 1 h stirring the reaction mixture was added to a solution of alcohol 204 (17 mg, 0.043 mmol) and DMAP (8 mg, 0.064 mmol) in toluene (1 mL). During the addition the reaction mixture turned cloudy. After 1 hour the reaction was a yellow solution and the reaction was complete by TLC. A saturated solution of NH4Cl was added and the reaction mixture extracted with CH2Cl2 (3x). The combined organic layers were dried with Na2SO4. The solvent was removed under reduced pressure and the residue purified by flash chromatography

25 (2.5% EtOAc/Hexanes) to yield vinyl iodide 214-1 as a colorless oil (42 mg, 91%). []D = 16

1 (c = 0.725, CHCl3); H NMR (600 MHz, CDCl3) δ 7.25 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 15.5

Hz, 1H), 6.93 (dt, Jtrans = 15.6 Hz, J = 6.8 Hz, 1H), 6.86 (d, J = 9.0 Hz, 2H), 5.9 (s, 1H), 5.81-

5.66 (m, 5H), 5.64 (d, J = 10.1 Hz, 1H), 5.00-4.90 (m, 3H), 4.57 and 4.47 (ABq, JAB =11.4 Hz,

2H), 4.47-4.45 (m, 1H), 4.30-4.34 (m, 1H), 3.80 (s, 3H), 3.40 (ddd, J = 9.8 Hz, J = 4.6 Hz, J =

2.6 Hz, 1H); 2.81-2.73 (m, 1H), 2.34-2.44 (m, 2H), 2.26-2.14 (m, 3H), 2.08-1.99 (m, 1H), 1.83

(d, J = 0.6 Hz, 3H), 1.76 (d, J = 1.0 Hz, 3H), 1.72-1.54 (m, 4H), 1.51-1.44 (m,1H), 1.50 (s, 9H),

13 1.42-1.34 (m,1H), 1.05-1.02 (m, 42H), 1.00 (d, J = 6.7 Hz, 3H). C NMR (150 MHz, CDCl3) δ

166.6, 166.0, 159.1, 150.0, 147.9, 143.8, 140.9, 139.0, 134.1, 133.5, 131.1, 129.2, 128.9, 120.8,

118.9, 114.4, 113.6, 81.6, 80.2, 77.7, 74.0, 72.9, 72.2, 72.0, 55.3, 42.1, 38.2, 37.1, 32.4, 30.4,

28.6, 28.2, 24.1, 22.8, 18.2, 18.1, 16.4, 12.7, 12.4, 12.4. IR (thin film) 2942, 2866, 1713, 1620,

-1 + + + 1513, 1462, 1247, 1149, 978, 882, 678 cm ; HRMS (ESI+): calcd for C58H97O8ISi2Na [M Na ]

1127.56643, found 1127.56107.

Macrolactone 201. To a solution of vinyl iodide 214-1 (150 mg, 0.135 mmol) in DMF (15 mL) were added Cs2CO3 (75 mg, 0.23 mmol), Et3N (0.023 mL, 0.16 mmol) and Pd(OAc)2 (45 mg, 0.2 mmol). After stirring overnight at room temperature, the reaction mixture was quenched with water and extracted with EtOAc (5x). The combined organic layers were dried with MgSO4 and the solvent evaporated under reduced pressure. The residue purified by flash chromatography

(2.5% to 5% EtOAc/Hexanes) to yield macrolactone 201 as a light yellow solid (78 mg, 59%).

o 25 1 mp = 57 - 60 C; []D = -78 (c = 0.05, CHCl3); H NMR (600 MHz, CDCl3) δ 7.27 (d, J = 9

Hz, 2H), 7.21 (d, J = 16 Hz, 1H), 6.89 (d, J = 9 Hz, 2H), 6.79 (ddd, J = 5.5 Hz, J = 9 Hz, Jtrans =

15 Hz, 1H), 6.10 (dd, Jtrans = 15.7 Hz, J = 11 Hz, 1H), 5.75 (d, Jtrans = 16.0 Hz, 1H), 5.71 (d, Jtrans

= 16.0 Hz, 1H), 5.69-5.58 (m, 4H), 5.42 (ddd, J = 4.1 Hz, J = 10 Hz, Jtrans = 15 Hz, 1H), 4.96

(ddd, J = 2 Hz, J = 8 Hz, J = 11.5 Hz, 1H), 4.56 and 4.53 (ABq, JAB =11.6 Hz, 2H), 4.52-4.49

(m, 1H), 4.14-4.08 (m, 1H), 3.81 (s, 3H), 3.34 (ddd, J = 6 Hz, J = 4.5 Hz, J = 1.5 Hz, 1H); 2.79-

2.71 (m, 1H), 2.25-2.07 (m, 4H), 2.02 (dd, J = 13.5 Hz, J = 11.5 Hz, 1H), 1.92-1.84 (m, 1H),

1.78 (d, J = 1.0 Hz, 3H), 1.68 (s, 3H), 1.65-1.50 (m, 3H), 1.50 (s, 9H), 1.05-1.03 (m, 42H), 1.01

13 (d, J = 6.7 Hz, 3H). C NMR (150 MHz, CDCl3) δ 166.7, 166.1, 159.3, 149.3, 148.1, 141.7,

133.3, 133.0, 132.7, 131.3, 130.8, 129.5, 129.4, 128.4, 126.6, 120.6, 118.6, 113.8, 82.5, 80.1,

74.8, 73.6, 72.4, 70.5, 55.3, 43.9, 39.4, 37.9, 33.4, 30.9, 30.7, 28.2, 25.0, 18.2, 18.1, 18.1, 18.0,

16.8, 16.4, 12.7, 12.5, 12.3. IR (thin film) 2942, 2865, 1712, 1621, 1513, 1248, 1150, 977, 882,

-1 + + + 681 cm ; HRMS (ESI+): calcd for C58H96O8Si2Na [M Na ] 999.65414, found 999.65101.

CHAPTER 5

ENDEAVORS IN THE SYNTHESIS OF PALMEROLIDE A

In the synthesis of complex molecules, various challenges have to be addressed in order to accomplish the final goal. The difficulties encoutered during the formal synthesis of palmerolide A are described herein, as well as the solutions developed to overcome several issues.

Horner-Wadsworth-Emmons Reagent

The first challenge in the synthesis of palmerolide A was related to the preparation of the

Horner-Wadsworth-Emmons reagent 176a to afford the C1-C8 fragment (Figure 73).

Figure 73 - Synthesis of Horner-Wadsworth-Emmons reagent 176a.

The fragmentation reaction of vinylogous acyl triflates (VATs) using stabilized carbanions can generate olefinating reagents in a Claisen-type condensation reaction.53,54 Based on the fragmentation strategy, the desired Horner-Wadsworth-Emmons reagent was originally reported in very low yield (21%).53 After extensive optimization, this reaction was improved such that it now affords the same Horner-Wadsworth-Emmons in 97% yield. The initial 2.2 equivalents were replaced by 1.1 equivalents of nucleophile. The optimization and mechanistic insights were detailed in chapter 3.54

First-generation synthesis of the C1-C15 fragment of palmerolide A

A previous graduate student in the group, David Jones, was working on the synthesis of palmerolide A. In an attempt to improve the preparation of the Horner-Wadsworth-Emmons reagent 176a, he observed that the fragmentation of the vinylogous acyl triflate 177a afforded the Horner-Wittig reagent 176f in 75% yield, using 2.2 equivalents of nucleophile. After optimization, we observed that only 1.1 equivalents were necessary to afford the phosphine oxide 176f in 81-89% yield. This improvement resulted in the synthesis of 219, the C1-C15 fragment of palmerolide A (Figures 74 and 75).36

Figure 74 - Synthesis of fragments 215 and 217.

Thus, the Horner-Wittig reagent was converted to fragment 176f in two additional steps.

First, a Lindlar semi-hydrogenation gave a (Z)-alkene, and a cross-metathesis reaction using

Grubbs II catalyst afforded ester 215. Titanium isopropoxide was used as a Lewis acid to coordinate to the phosphonate Lewis base, releasing the ruthenium catalyst to react with the olefin.36

The C9-C15 aldehyde coupling partner was synthesized from ester 206, available in two steps from 4-pentynol.107 Sharpless dihydroxylation afforded a diol in 75% yield and 99.6% ee.

The diol was converted to an acetonide and DIBAL reduction gave aldehyde 217 (Figure 74).

Figure 75 - Synthesis of fragment C1-C15 of palmerolide A.

Figure 76 - Olefination reaction between phosphine oxide 215 and aldehyde 217.

The olefination of aldehyde 217 using Horner-Wittig reagent 215 was not commonplace.

The Horner-Wittig reagent 215 tends to undergo intramolecular Michael addition, in the presence of various bases, forming a six-membered ring (Figure 76, bottom). The use of one equivalent of sodium hydride along with excess aldehyde provided a reasonable solution to the problem, and the enone product 218 was obtained in 89% yield (Figure 76). The enone carbonyl was reduced by (R)-CBS reagent in 89% yield and modest diastereoselectivity (3:1 dr).

Protection of the resulting alcohol with a TBS group gave fragment 219, the C1-C15 of palmerolide A in 94% yield (Figure 75).36 The first-generation synthesis of the C1-C15 fragment was completed in seven steps from a symmetric dione in 41% overall yield.

Second-generation synthesis of C1-C15 fragment of palmerolide A

The first-generation of the C1-C15 fragment was modified in order to accomplish the synthesis of palmerolide A. Initially, the alkyne was converted to an alkene envisioning a Heck macrocyclization.23,26 The conversion was achieved by Lindlar semi-hydrogenation in the presence of six equivalents of quinoline to avoid over-reduction to the alkane. Furthermore, the secondary alcohols C10 and C11 were differentially protected. After extensive experimentation, the best conditions found were the formation of a PMP acetal 207 followed by DIBAL reductive ring opening (207 → 208). The primary aluminum alkoxide 207a can coordinate with the proximal oxygen, directing the acetal ring opening with high selectivity.108 Only one isomer was observed by NMR. Some additional steps converted 208 into the new aldehyde fragment 203

(Figure 77).28

Figure 77 - Synthesis of new aldehyde fragment 203.

The next event involved the olefination reaction of aldehyde 203 with the Horner-Wittig reagent 215. However, the reaction failed to give the desired product when the conditions previously reported (NaH, THF, 1.5 equivalents of aldehyde) were employed.36 Only the intramolecular Michael addition product was observed (Figure 78).

Figure 78 - Synthesis of phosphonate 202 and enone 211.

Alternatively, this olefination can in principle be accomplished using Horner-Wadsworth-

Emmons reagent 202, which was synthesized in two steps from phosphonate 176a (Figure 78).

However, attempts to couple aldehyde 203 and Horner-Wadsworth-Emmons 202 using NaH in

THF were also unsuccessful. A variety of conditions were tested, and only Ba(OH)2 in wet THF was able to suppress the intramolecular Michael addition reaction of the phosphonate.111-115 The enone product 211 was obtained in 96% yield (Figure 78).

Subsequently, the carbonyl at C7 was reduced using the (R)-CBS reagent and BH3.THF.

Unfortunately, no diastereoselectivity was observed during the reduction (~ 1:1 dr). The same conditions afforded a slightly higher selectivity during the synthesis of the first-generation of the

C1-C15 fragment, 3:1 dr (Figure 79).36 Congruent with our results, Prasad and coworkers

reported the (R)-CBS reduction of a similar fragment C1-C15 with low diastereoselectivity (7:3 dr).27

Figure 79 - (R)-CBS reduction of the C1-C15 fragment of palmerolide A.

In an effort to increase the selectivity, the reduction was carried out after the macrocyclization. However, the undesired diastereomer 223 was obtained as the major product

(1:3 dr). Employing the (S)-CBS reagent, only the undesired diastereomer 223 was observed.

These results are in accordance with the De Brabander synthesis of the ent-palmerolide A, in which the major isomer observed during the (S)-CBS-reduction of the macrolactone was the undesired one (Figure 80).19

Finally, the reduction of C7 in the formal synthesis of palmerolide A was accomplished by NaBH4. A 1:1 dr mixture was obtained and the undesired isomer was converted to the desired product in two steps, i.e. Mitsunobu protocol and sodium azide methanolysis (cf. figure 72).28

This solution enabled us to complete the formal synthesis, but the need to separate C7 diastereomers is anticipated to be problematic as we aim to prepare larger quantities of the natural product goal structure.

Figure 80 - CBS reduction of macrolactone 222 in the synthesis of palmerolide A.

First-generation synthesis of the vinyl iodide fragment

In 2012, we reported a convergent synthesis of the C16–C24 subunit of palmerolide A.37

Our strategy was unique given that all previous syntheses involved side chain fragments that either extend one carbon past, or end one carbon shy of C24. We also purposefully avoided the use of the potentially labile α,-unsaturated aldehyde 33 (Figure 81), which figures prominently in all but one of the previous synthetic approaches to palmerolide A.24

Figure 81 - Palmerolide A and targeted fragment C16-C24.

The first key step in the synthesis of the C16–C24 subunit 225 was a Negishi coupling118 between vinyl bromide 226119 and alkyl iodide 227120 (Figure 82), which were prepared by analogy to reported procedures. Negishi coupling, THP hydrolysis, and oxidation of the resulting alcohol provided aldehyde 229 in 57% overall yield.

Figure 82 - Convergent Negishi coupling for the preparation of aldehyde 229.

The next synthetic challenge was to set the C19-C20 syn-stereochemistry. Based on the

Felkin–Anh model, nucleophilic addition to chiral aldehyde 229 should favor the desired syn- diastereomer.121 However, steric differentiation between methyl and methylene is minimal, and substrate-controlled propargylation gave very poor diastereoselectivity (Figure 83).

We thus focused our attention on reagent- or catalyst-controlled asymmetric propargylation of aldehydes. Singaram’s propargylation emerged as our preferred choice (Figure

83) for its operational simplicity.122,123 Addition of aldehyde 229 to a THF solution of propargyl bromide, indium metal, and pyridine in the presence of (commercially available) amino alcohol

231 provided homopropargyl alcohol 230 in 93% yield (95:5 dr). Chiral ligand 231 was recovered in 94% yield and reused with identical results.

Figure 83 - Homopropargylation by Grignard addition and Singaram’s method.

Negishi–Wipf carbometalation / iodination124,125 was supposed to conclude the synthesis of the C16–C24 subunit (Figure 84), but unexpected complications arose. Standard conditions converted alkyne 230 into a complex mixture of products, one of which appeared to be the result of allylic substitution in which the TBDPS ether was replaced with a phenyl group. We repeated this experiment using alcohol 233, which lacks the alkyne moiety, and proceeded to isolate allylbenzene 234 in 36% yield. Further details and observations fall outside the current focus, but the phenyl group presumably comes from the TBDPS ether. Others have noted that silyl ethers can be problematic in this reaction,126,127,128 but we found no prior examples of this unusual allylic substitution.

After trying unsuccessfully to achieve the desired conversion by optimizing the experimental conditions, we changed the substrate (Figure 85). We removed the TBDPS ether, subjected diol 235 to carbometalation (optimally without adding water)124, and thus obtained iodides 236 and 237 in a 4:1 ratio. The minor product (237, from OHMe substitution, cf.

Figure 85) was easily separated from diol 236 using silica gel, and 236 was thus isolated in 60% yield. Selective protection of 236 gave TBS ether 225 in 85% yield, completing the synthesis of our target C16–C24 subunit.

Figure 84 - Unexpected carbometalation difficulties (top), and an unusual substitution reaction under identical conditions.

Figure 85 - Synthesis of target C16-C24 fragment.

The C16-C24 fragment 225 was prepared in seven steps and 27% overall yield from the known compounds 226 and 227, each of which was prepared in three steps. Next, we decided to investigate the installation of the enamide side chain using a model study. Numerous strategies

100

were explored in the attempt to install the dienamide; nonetheless, none of the conditions employed were successful.

For instance, a dienamide can be obtained by the coupling of either, an enol triflate or a tosylate electrophile with an amide nucleophile.129-131 All the conditions tested to form enols 240 afforded several isomers. Submitting the isomers to the coupling reaction with the amide was unsuccessful (Figure 86).

In another effort, the aldehyde 238 was converted to the dithiane 241. Isomerization of the double bond to the more stable allyl dithiane could afford the desired diene. Unfortunately, the diene observed in the isomerization reaction (LDA, HMPA, THF) was the terminal alkene

242 and not the desired one. The (Z)-isomer of dithiane 241 failed to give the desired diene, leading to decomposition of the starting material (Figure 86). In the meantime, Kalesse and coworkers reported a syn-selective vinylogous aldol reaction.109 Therefore, we decide to pursue the synthesis of a second-generation for the vinyl iodide fragment. The synthesis is detailed in chapter 4 (Figure 71).

Figure 86 - Attempts to convert aldehyde 238 to dienamide 239.

101

Macrocyclization

A model study was used to evaluate the macrocyclization reation. The Yamaguchi macrolactonization was tested with the C10, C11 acetonide system. The reaction afforded the macrocycle 244 in low yield (Figure 87). This result diverges from the Yamaguchi macrolactonization used by Hall in the total synthesis of palmerolide A, which was achieved in

90% yield.22

Figure 87 - Model study applied to the macrocyclization event.

The Heck macrocyclization, first reported by Maier and coworkers,23 was examined. The formation of the desired product was not observed. Subsequently, we decided to remove the acetonide and protect the alcohols with TBS groups. At this time, the Heck reaction gave the desired macrocycle 247 (Figure 87). The acetonide was detrimental to the macrocyclization event. Based on these results, the Heck macrocyclization was applyed to the formal synthesis of palmerolide A.28 All the challenges, detours and solutions described in this chapter resulted in

102

the most high-yielding synthesis of the natural product palmerolide A reported to date (cf table

3).28

Experimental Section

General Methods. All non-aqueous reactions were carried out under an inert atmosphere of nitrogen in oven-dried glassware. Air and moisture sensitive liquid reagents were added via a dry syringe or cannula. THF was dried over distilled sodium/benzophenone ketyl. Methylene chloride was distilled from CaH2. All other solvents and reagents were used as obtained from commercial sources without further purification. Flash column chromatography was performed using EM Science silica gel 60 (43-60 micron mesh). Analytical and preparative thin layer

1 13 chromatography (TLC) were performed on EM Science silica gel 60 F254 plates. H and C

NMR spectral data were recorded in a Bruker 400 or 600 MHz spectrometer using CDCl3 as a solvent. The chemical shifts are reported in parts per million (ppm) relative to the internal

1 13 standard tetramethylsilane (0.0 ppm) for H NMR and CDCl3 (77.0 ppm) for C NMR

(Appendix C). Infrared spectral data were obtained using a Perkin-Elmer Spectrum 100 FT-IR spectrometer with diamond ATR accessory as thin film. All optical rotation data was recorded at

25 oC on a Jasco P-2000 polarimeter with a 100 mm cell (concentration reported as g/100 mL).

Experimental Procedures

Ether 228. THF (8 mL) and iodide 227 (300 mg, 1.06 mmol) were added to flame dried

o o ZnCl2 (144 mg, 1.06 mmol). The mixture was cooled to -78 C and stirred for 15 min at -78 C.

103

tBuLi (1.7 M, 1.6 mL, 2.64 mmol) was added dropwise over 5 min and stirred for an additional

10 min at -78 oC. The yellow solution was then warmed to rt and then added dropwise via cannula to a flask containing Pd(PPh3)4 (61 mg, 52.8 umol) and bromide 226 (411 mg, 1.06 mmol) in THF (2 mL) at rt. The reaction was stirred overnight at rt. Et2O (10 mL) and H2O (10 mL) were added to the reaction mixture and the mixture was extracted with Et2O (3 X 20 mL).

The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10:90 Et2O/pentanes) to yield olefin

25 227 as a colorless oil (356 mg, 72%). [α]D = 1.44 (c = 0.26, CH2Cl2) IR (thin film) 3071, 2931,

-1 1 2856, 1668, 1589, 1473, 1428, 1111, 1032, 911, 821 cm ; H NMR (400 MHz, CDCl3)  7.68-

7.70 (m, 8H), 7.35-7.43 (m, 12H), 5.39 (t, J = 6.2 Hz, 2H), 4.54-4.56 (m, 2H), 4.22 (d, J = 6.2

Hz, 4H), 3.83-3.88 (m, 2H), 3.57-3.60 (m, 1H), 3.47-3.51 (m, 3H), 3.20-3.24 (m, 1H), 3.13-3.17

(m, 1 H), 2.15-2.20 (m, 1H), 2.08-2.12 (m, 1H), 1.67-1.94 (m, 8H), 1.50-1.62 (m, 9H), 1.43 (s,

6H), 1.04 (s, 18H), 0.89 (d, J = 6.0 Hz, 3H), 0.88 (d, J = 5.9 Hz, 3H); 13C NMR (100 MHz,

CDCl3)  135.6, 135.5, 135.4, 134.1, 129.5, 127.6, 125.8, 99.1, 98.8, 72.9, 72.8, 62.2, 62.1, 61.1,

44.1, 44.0, 31.5, 31.4, 30.8, 30.7, 19.6, 19.5, 19.2, 17.1, 17.0, 16.2, 16.1. HRMS (ESI): calcd for

C29H42O3SiNa [M+Na+] 489.2800, found 489.2797.

Alcohol 228a. Added TsOH (244 mg, 1.286 mmol) to ether 228 (200 mg, 0.429 mmol) in isopropanol (10 mL) at 0 oC. Let stir until all the solids had dissolved and mixture was warmed to rt and stirred for an additional 2 h. Triethylamine (0.5 mL) was added and the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (20:80 Et2O/pentanes) to yield alcohol 7 as a colorless oil (139 mg,

104

25 85%). [α]D = 3.77 (c = 0.29, CH2Cl2) IR (thin film) 3366 (br), 3071, 2930, 2857, 1667, 1590,

-1 1 1472, 1428, 1110, 1038, 736, 699 cm ; H NMR (400 MHz, CDCl3)  7.67-7.70 (m, 4H), 7.35-

7.42 (m, 8H), 5.42 (t, 1H), 4.22 (d, J = 6.2 Hz, 2H), 3.38-3.49 (m, 2H), 2.03-2.11 (m, 1H),

1.74-1.85 (m, 2H), 1.45 (s, 3H), 1.04 (s, 9H), 0.86 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz,

CDCl3)  136.1, 135.8, 134.2, 129.7, 127.8, 126.0, 68.5, 61.1, 44.2, 33.8, 27.0, 19.3, 16.8, 16.4.

HRMS (ESI): calcd for C24H34O2SiNa [M+Na+] 405.2225, found 405.2216.

Aldehyde 229. Added Dess-Martin reagent (1660 mg, 3.92 mmol) to alcohol 228 (750

o mg, 1.96 mmol) in CH2Cl2 (40 mL) at 0 C. Let stir until all the solids had dissolved and H2O

(22 uL, 1.25 mmol) was added. The reaction mixture was warmed to rt and stirred for 30 min.

The reaction was poured into a column with silica gel and purified by flash chromatography

(15:85 ethyl acetate/hexanes) to yield aldehyde 229 as a colorless oil (694 mg, 93%). Aldehyde

229 was immediately used in the next reaction. IR (thin film) 3072, 2960, 2930, 2857, 2711,

-1 1 1726, 1428, 1111, 1046, 823, 700 cm ; H NMR (400 MHz, CDCl3)  9.60 (s, 1H), 7.67-7.70

(m, 4H), 7.35-7.42 (m, 6H), 5.50-5.45 (m, 1H), 4.22 (d, J = 6.2 Hz, 2H), 2.38-2.52 (m, 2H), 1.96

(dd, J = 13.4 Hz, J = 7.8 Hz, 1H), 1.43 (s, 3H), 1.05 (s, 9H), 1.02 (d, J = 6.8 Hz, 3H); 13C NMR

(100 MHz, CDCl3)  204.9, 135.7, 134.1, 134.0, 133.6, 129.7, 127.8, 127.2, 61.1, 44.4, 40.6,

26.9, 19.3, 16.3, 13.3. HRMS (ESI): calcd for C24H32O2SiNa [M+Na+] 403.2069, found

403.2075.

105

Homopropargyl alcohol 230. An oven-dried 50 mL round bottom flask cooled under nitrogen was charged with (1R, 2S)-(-)-2-amino-1,2-diphenylethanol (844 mg, 3.94 mmol), indium powder (452 mg, 3.94 mmol) and THF (30 mL). The flask was purged with nitrogen and pyridine (0.β8 μL, γ.94 mmol) and propargyl bromide (0.47 μL, γ.94 mmol) were added to the flask. After stirring for 35 minutes at room temperature the flask was cooled to -78 oC and aldehyde 229 (500 mg, 1.31 mmol) was added dropwise. The reaction was allowed to warm to room temperature slowly overnight. After 16-20 h the reaction was quenched with HCl 1M (15 mL) and extracted with hexane/ ethyl ether 1:1 (2 x 15 mL). The combined organic layers were washed with HCl 1M, H2O and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (15:85 EtOAc/hexanes) to yield homopropargyl alcohol 229 as a colorless oil in a mixture of diastereomers (96:4 determined by

1H NMR) (553 mg, 93%). (1R, 2S)-(-)-2-amino-1,2-diphenylethanol was recovered by acid/base

25 extraction in 94% yield. [α]D = 10.8 (c = 0.14, CH2Cl2) IR (thin film) 3308, 3072, 2960, 2931,

-1 1 2857, 1472, 1462, 1428, 1383, 1111, 1045, 823, 738, 700 cm ; H NMR (400 MHz, CDCl3)

(major diastereomer)  7.67-7.71 (m, 4H), 7.35-7.42 (m, 6H), 5.41 (t, J = 6.0 Hz, 1H), 4.23 (d, J

= 6.0 Hz, 2H), 3.60-3.67 (m, 1H), 2.32-2.44 (m, 2H), 2.08-2.16 (m, 1H), 2.02-2.04 (m, 1H),

1.81-187 (m, 2H), 1.42 (s, 3H), 1.04 (s, 9H), 0.85 (d, J = 5.6 Hz, 3H); 13C NMR (100 MHz,

CDCl3)  135.9, 135.5, 134.4, 134.3, 129.8, 127.9, 126.7, 81.6, 72.7, 70.8, 61.3, 43.8, 35.1, 27.1,

25.2, 19.5, 16.3, 13.5. HRMS (ESI): calcd for C27H36O2SiNa [M+Na+] 443.2382, found

443.2404.

Mosher ester analysis of homopropargyl alcohol 230

106

S- and R-MTPA-esters from Mosher’s acid. To a stirred solution of alcohol 230 (10 mg, 0.022 mmol), S-(-)-α-methoxy-α-trifluoromethylphenylacetic acid (S-(-)-MTPA-OH) (26 mg, 0.11 mmol), and N,N-dicyclohexylcarbodiimide (23 mg, 0.11 mmol) in CH2Cl2 (1mL), was added

N,N-dimethylaminopyridine (13.5 mg, 0.11 mmol). The reaction was stirred at room temperature until consumption of the alcohol was observed by TLC analysis (20 h). The reaction was then filtered through Celite™ to remove most of the N,N-dicyclohexylurea . The crude oil containing 230-S was passed through a plug of silica gel and used without further purification for

NMR analysis. The same protocol was used to prepare the R-MTPA-ester of 229 with R-(+)-

MTPA-OH to give 229-R.

Stereochemistry assignment was confirmed based in Mosher, H. S. model.1

Proton δR (ppm)* δS (ppm)* δR - δS a 1.94 2.01 - 0.07 b 2.59 2.63 - 0.04

1 Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.

107

b' 2.46 2.54 - 0.08 e 0.85 0.77 + 0.08 h 5.34 5.30 + 0.04 i 4.21 4.19 + 0.02 1 * H NMR (600 MHz, CDCl3)

Alcohol 234. To a solution of [Cp2ZrCl2] (152 mg, 0.52 mmol) and trimethylaluminum

2M solution in hexanes (0.79 mL, 1.57 mmol) in CH2Cl2 was added water dropwise (9 μL, 0.5β mmol) carefully at -23oC. After 10 minutes, alcohol 233 (100 mg, 0.26 mmol) was slowly added to the mixture. After stirring for 35 minutes at -23oC the reaction was quenched with water (0.5 mL). At this point K2CO3 saturated solution was added (3.3 mL) and the mixture was allowed to warm to room temperature. The solution was extracted with CH2Cl2 (3x) and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography

25 on silica gel (15:85 EtOAc/hexanes) to yield alcohol 234 as a colorless oil (19 mg, 36%). [α]D

= -28.6 (c = 0.82, CH2Cl2) IR (thin film) 3288 (br), 2928, 2872, 1494, 1451, 1374, 1275, 1028,

-1 1 968, 745 cm ; H NMR (400 MHz, CDCl3)  7.26-7.30 (m, 2H), 7.16-7.19 (m, 3H), 5.35-5.40

(m, 1H), 3.40-3.52 (m, 2H), 3.37 (d, J = 7.3 Hz, 2H), 2.10-2.16 (m, 1H), 1.84-1.88 (m, 2H), 1.72

13 (s, 3H), 0.88 (d, J = 6.4 Hz, 3H); C NMR (100 MHz, CDCl3)  141.8, 135.0, 128.6, 128.5,

126.0, 125.1, 68.6, 44.4, 34.5, 33.9, 16.9, 16.3. HRMS (EI): calcd for C14H20O [M+Na+]

204.1514, found 204.1505.

108

Diol 235. To a solution of homopropargyl alcohol 230 (400 mg, 0.95 mmol) in 40 mL of

THF was added dropwise tetrabutylammonium fluoride 1.0 M solution in THF (1.9 mL, 1.9 mmol) at room temperature. After 2 hours, the reaction was quenched with water. The solution was extracted with CH2Cl2 (3x) and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30:70 EtOAc/hexanes) to yield diol

25 235 as a colorless oil (173 mg, 100%). [α]D = 13.2 (c = 1.04, CH2Cl2) IR (thin film) 3303,

-1 1 2965, 2918, 2118, 1667, 1430, 1381, 1266, 984 cm ; H NMR (600 MHz, CDCl3)  5.45 (t, J =

6.5 Hz, 1H), 4.12-4.20 (m, 2H), 3.65-3.70 (m, 1H), 2.33-2.44 (m, 2H), 2.11 (m, 1 H), 2.05 (t, J =

2.6 Hz, 1H), 1.87-1.93 (m, 2H), 1.66 (s, 3H), 0.87 (d, J = 6.4 Hz, 3H); 13C NMR (150 MHz,

CDCl3)  137.5, 125.6, 81.3, 72.1, 70.5, 59.2, 43.5, 34.6, 24.9, 15.9, 13.2. HRMS (ESI): calcd for C11H18O2Na [M+] 205.1204, found 205.1198.

Vinyl iodide 236. Trimethylaluminum 2M solution in hexanes (1.65 mL, 3.31 mmol) was added water dropwise to a solution of [Cp2ZrCl2] (321 mg, 1.10 mmol) in 5 mL of CH2Cl2 at room temperature. After stirring for 15 minutes, a solution of homopropargyl alcohol 235 (100 mg, 0.55 mmol) in 0.5 mL of CH2Cl2 was added dropwise to the reaction mixture. The reaction was left stirring for 2 days at room temperature when iodine (280 mg, 1.10 mmol) in 5 mL of

THF was added to the reaction mixture at -30oC. After 10 minutes, the reaction was allowed to warm to room temperature and let stirring for 1 hour. Then, a saturated solution of potassium sodium tartrate (400 mL) and 2 mL of MeOH were added to the yellow solution. After 2 hours

109

stirring at room temperature, the solution was extracted with ethyl acetate (6x). The organic phase was washed with brine, dried using MgSO4 and evaporated under reduced pressure to give a mixture of vinyl iodides 236/237 in 4:1 ratio. The residue was purified by flash column chromatography on silica gel (30:70 EtOAc/hexanes) to yield vinyl iodide 236 as a colorless oil

25 (107 mg, 60%). Vinyl iodide 236: [α]D = 17.8 (c = 3.15, CH2Cl2) IR (thin film) 3350 (br),

-1 1 2930, 1725, 1440, 1375, 1270, 1244, 1046, 981, 731 cm ; H NMR (400 MHz, CDCl3)  7.26-

7.30 (m, 2H), 7.16-7.19 (m, 3H), 5.35-5.40 (m, 1H), 3.40-3.52 (m, 2H), 3.37 (d, J = 7.3 Hz, 2H),

2.10-2.16 (m, 1H), 1.84-1.88 (m, 2H), 1.72 (s, 3H), 0.88 (d, J = 6.4 Hz, 3H); 13C NMR (100

MHz, CDCl3)  145.2, 137.5, 125.5, 70.9, 59.1, 44.7, 43.5, 35.3, 24.0, 16.0, 13.2. HRMS (EI): calcd for C12H21O2I [M+] 324.0587, found 324.0578.

25 Vinyl iodide 237: [α]D = 19.9 (c = 0.16, CH2Cl2) IR (thin film) 3455 (br), 2960, 2929, 1456,

-1 1 1377, 1271, 1143, 1048, 979, 760, 671 cm ; H NMR (400 MHz, CDCl3)  7.26-7.30 (m, 2H),

7.16-7.19 (m, 3H), 5.35-5.40 (m, 1H), 3.40-3.52 (m, 2H), 3.37 (d, J = 7.3 Hz, 2H), 2.10-2.16 (m,

13 1H), 1.84-1.88 (m, 2H), 1.72 (s, 3H), 0.88 (d, J = 6.4 Hz, 3H); C NMR (100 MHz, CDCl3) 

145.4, 132.5, 128.7, 71.2, 44.8, 43.7, 35.5, 24.0, 21.2, 15.6, 14.3, 13.3. HRMS (EI): calcd for

C13H23OI [M+] 322.0800, found 322.0794.

110

Vinyl iodide 225. To a solution of vinyl iodide 236 (20 mg, 0.062 mmol) in 3 mL of CH2Cl2 was added imidazole (8 mg, 0.124 mmol) and TBSCl (11 mg, 0.074 mmol) at room temperature.

The reaction mixture was stirred overnight and quenched with NH4Cl. The solution was extracted with CH2Cl2 (3x) and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (5:95 EtOAc/hexanes) to yield vinyl

25 iodide 225 as a colorless oil (23 mg, 85%). [α]D = 15.9 (c = 5.32, CH2Cl2) IR (thin film) 3467

(br), 2954, 2928, 2856, 1462, 1379, 1252, 1050, 832, 773, 666 cm-1; 1H NMR (400 MHz,

CDCl3)  6.00 (d, J = 7.3 Hz, 1H), 5.32-5.36 (m, 1H), 4.19 (d, J = 6.2 Hz, 2H), 3.62-3.68 (m,

1H), 2.28-2.40 (m,2H), 2.12-2.20 (m, 1H), 1.86 (d, J = 0.9 Hz, 3H), 1.68-1.78 (m, 2H), 1.60 (s,

3H), 1.47 (d, J = 4.1 Hz, 2H), 0.89 (s, 9H), 0.84 (d, J = 6.8 Hz, 3H), 0.06 (s, 6H); 13C NMR (100

MHz, CDCl3)  145.3, 135.1, 126.6, 71.3, 60.1, 44.7, 43.5, 35.5, 25.9, 24.0, 18.4, 16.1, 13.3, -

5.1. HRMS (ESI): calcd for C18H35O2ISiNa [M+Na+] 461.1348, found 461.1343.

111

CHAPTER 6

FUTURE DIRECTIONS

The formal synthesis of palmerolide A reported by the Dudley lab is the highest yielding synthetic sequence to date. However, key modifications would improve the yields and the scalability of the process and afford the natural product more efficiently.

Specifically, one of the weaknesses of the synthesis is the use of unstable aldehyde 33 in the preparation of the C16-C25 fragment. Due to the poor stability of the aldehyde, the vinylogous aldol reaction could not be performed on large scale. One alternative would be to replace vinyl iodide 33 with diene 248 (Figure 88). Preliminary results indicate or suggest that diene 248 is more stable than 33. The optimization of the vinylogous aldol reaction is underway in our lab.

Figure 88 - Alternative vinylogous aldol reaction.

A second shortcoming in our synthesis is the Heck macrocyclization, which was accomplished in only 59% yield.28 Moreover, if vinyl iodide 33 is replaced by diene 248 (Figure

88), then a new strategy must be adopted for the macrocyclization. Early studies involving a

112

ring-closing metathesis to form the C14-C15 bond are promising (Figure 89). Compared with reported syntheses, this ring-closing metathesis will be a new approach to afford the macrocyclic core of palmerolide A.

Figure 89 - Alternative macrocyclization by RCM.

Another concern is the deprotection of the C11 p-methoxybenzyl ether group at the end of the synthesis. In previous syntheses,22,23,25 this deprotection was challenging, possibly due to the presence of the dienes C14-C17 and C21-C24 in the molecule.132 Hall and coworkers used magnesium bromide diethyl etherate and dimethyl sulfide to deprotect the PMB in 50% yield.

22,132 A more labile protecting group like 2,6-dimethoxybenzyl ether133 could enhance the yield in this step. Future studies will test this hypothesis.

The last challenge to address is the reduction of the carbonyl at C7. The lack of diastereoselectivity during the reaction was observed in different syntheses. 22,26,28 Unfortunately, a viable alternative for this transformation is not foreseen. A stereoselective reduction of enones with similar diastereotopic faces is not available. A more efficient way to separate the diastereomers and invert the stereochemistry of the epi-C7 is desirable.

Provided that the challenges described above are addressed, an efficient and scalable synthesis of palmerolide A and analogues can be achieved for future biological studies.

113

APPENDIX A

1H NMR and 13C NMR SPECTRA (CHAPTER 3)

1 H NMR (300 MHz; CDCl3)

1 H NMR (400 MHz; CDCl3)

114

1 H NMR (300 MHz; CDCl3)

13 C NMR (75 MHz; CDCl3)

115

1 H NMR (300 MHz; CDCl3)

116

13 C NMR (75 MHz; CDCl3)

1 H NMR (300 MHz; CDCl3)

117

1 C NMR (75 MHz; CDCl3)

1 H NMR (300 MHz; CDCl3)

118

1 C NMR (75 MHz; CDCl3)

1 H NMR (300 MHz; CDCl3)

119

1 H NMR (300 MHz; CDCl3)

13 C NMR (75 MHz; CDCl3)

120

APPENDIX B

1H NMR and 13C NMR SPECTRA (CHAPTER 4)

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

121

1 H NMR (600 MHz; CDCl3)

13 C NMR (150 MHz; CDCl3)

122

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

123

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

124

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

125

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

126

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

127

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

128

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

129

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

130

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

131

1 H NMR (600 MHz; CDCl3)

13 C NMR (150 MHz; CDCl3)

132

1 H NMR (600 MHz; CDCl3)

13 C NMR (150 MHz; CDCl3)

133

1 H NMR (600 MHz; CDCl3)

13 C NMR (150 MHz; CDCl3)

134

1 H NMR (600 MHz; CDCl3)

13 C NMR (150 MHz; CDCl3)

135

1 H NMR (600 MHz; CDCl3)

22 1H NMR – 500 MHz reported by Hall, D. G. and coworkers

136

13 C NMR (150 MHz; CDCl3)

22 NMR – 127.5 MHz reported by Hall, D. G. and coworkers

137

APPENDIX C

1H NMR and 13C NMR SPECTRA (CHAPTER 5)

1 H NMR (400 MHz; CDCl3)

13 C NMR (400 MHz; CDCl3)

138

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

139

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

140

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

141

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

142

1 H NMR (600 MHz; CDCl3)

13 C NMR (150 MHz; CDCl3)

143

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

144

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

145

1 H NMR (400 MHz; CDCl3)

13 C NMR (100 MHz; CDCl3)

146

REFERENCES

1 Primo, C.; Vázquez, E. Antarctic ascidians: an isolated and homogeneous fauna. Polar Res. 2009, 28, 403-414.

2 Raguá-Gil, J. M.; Gutt, J.; Clarke, A.; Arntz, W. E. Antarctic shallow-water mega-epibenthos:shaped by circumpolar dispersion or local conditions? Mar. Biol. 2004, 144, 829-839.

3 McClintock, J. B.; Baker, B. J. A Review of the chemical ecology of antarctic marine invertebrates. Amer. Zool. 1997, 37, 329-342.

4 Lebar, M. D.; Heimbegner, J. L.; Baker, B. J. Cold-water marine natural products. Nat. Prod. Rep. 2007, 24, 774- 797.

5 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.

6 Noguez, J. H.; Diyabalanage, T.; Miyata, Y.; Xie, X.-S.; Valeriote, F. A.; Amsler, C. D.; McClintock, J. B.; Baker, B. J. Palmerolide macrolides from the Antarctic tunicate Synoicum adareanum. Bioorg. Med. Chem. 2011, 19, 6608- 6614.

7 Mi, Q.; Pezzuto, J. M.; Farnsworth, N. R.; Wani, M. C.; Kinghorn, A. D.; Swanson, S. M. Use of in vivo hollow fiber assay in natural products anticancer drug discovery. J. Nat. Prod. 2009, 72, 573-580.

8 Riesenfeld, C. S.; Murray, A. E.; Baker, B. J. Characterization of the microbial community and polyketide biosynthetic potential in the palmerolide-producing tunicate Synoicum adareanum. J. Nat. Prod. 2008, 71, 1812- 1818.

9 Bhatia, S.; Tykodi, S. S.; Thompson, J. A. Treatment of metastatic melanoma: an overview. Oncology 2009, 23, 488-496.

10 National Cancer Institute at the National Institutes of Health: http://www.cancer.gov/cancertopics/types/melanoma.

11 American cancer society. Melanoma skin cancer: http://www.cancer.org/cancer/skincancer- melanoma/detailedguide/melanoma-skin-cancer-key-statistics.

12 Xie, X.-S.; Padron, 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.

13 Bowman, E. J.; Siebers, A.; Altendorf, K. Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells. Proc. Natl. Acad. Sci. USA 1988, 85, 7972-7976.

14 Pérez-Sayáns, M.; Somoza-Martin, J. M.; Barros-Angueira, F.; Rey, J. M. G.; García-García, Abel. V-ATPase inhibitors and implication in cancer treatment. Cancer Treat. Rev. 2009, 35, 707-713.

15 Nishi, T.; Forgac, M. The vacuolar (H+)-ATPases – nature’s most versatile proton pumps. Nat. Rev.Mol. Cell. Biol. 2002, 3, 94-103.

16 Martinez-Zaguilan, R.; Lynch, R. M.; Martinez, G. M.; Gillies, R. J. Vacuolar ATP-ase are functionally expressed in plasma membranes of human tumor cells. Am. J. Physiol. Cell Physiol. 1993, 13, 779-808.

147

17 Beyenbach, K. W.; Wieczorek, H. The V-type H+ ATP-ase: molecular structure and function, physiological roles and regulation. J. Exp. Biol. 2006, 209, 577-589.

18 Information available through the Antarctic Treaty Secretariat: http://www.ats.aq/.

19 Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. Total synthesis and structure revision of the marine metabolite palmerolide A. J. J. Am. Chem. Soc. 2007, 129, 6386-6387.

20 Nicolaou, K. C.; Guduru, R.; Sun, Y.-P.; Banerji, B.; Chen, D. Y.-K. Total synthesis of the originally proposed and revised structures of palmerolide A. Angew. Chem. Int. Ed. 2007, 46, 5896-5900.

21 Nicolaou, K. C.; Sun, Y.-P.; Guduru, R.; Banerji, B.; Chen, D. Y.-K. Total synthesis of the originally proposed and revised structures of palmerolide A and isomers thereof. J. Am. Chem. Soc. 2008, 130, 3633-3644.

22 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.

23 Jägel, J.; Maier, M. E. Formal total synthesis of palmerolide A. Synthesis 2009, 17, 2881-2892.

24 Gowrisankar, P.; Pujari, S. A.; Kaliappan, K. P. A formal total synthesis of palmerolide A. Chem. Eur. J. 2010, 16, 5858-5862.

25 Pujari, S. A.; Gowrisankar, P.; Kaliappan, K. P. A Shimizu Non-aldol approach to the formal synthesis of palmerolide A. Chem. Asian J. 2011, 6, 3137-3151.

26 Prasad, K. R.; Pawar, A. B. Enantioselective formal synthesis of palmerolide A. Org. Lett. 2011, 13, 4252-4255.

27 Pawar, A. B.; Prasad, K. R. Formal total synthesis of palmerolide A. Chem. Eur. J. 2012, 18, 15202-15206.

28 Lisboa, M. P.; Jones, D. M.; Dudley, G. B. Formal synthesis of palmerolide A, featuring alkynogenic fragmentation and syn-selective vinylogous aldol chemistry. Org. Lett. 2013, 15, 886-889.

29 Kaliappan, K. P.; Gowrisankar, P. Synthetic studies on a marine natural product palmerolide A: synthesis of C1-9 and C15-21 fragments. Synlett 2007, 1537-1540.

30 Chandrasekhar, S.; Vijeender, K.; Chandrashekar, G.; Reddy, C. R. Towards the synthesis of palmerolide A: asymmetric synthesis of C1-C14 fragments. Tetrahedron: Asymmetry 2007, 18, 2473-2478.

31 Jägel, J.; Schmauder, A.; Binanzer, M.; Maier, M. E. A concise route to the C3-C23 fragment of the macrolide palmerolide A. Tetrahedron 2007, 63, 13006-13017.

32 Cantagrel, G.; Meyer, C.; Cossy, J. Synthetic studies toward the marine natural product palmerolide A synthesis of the C3-C15 and C16-C23 fragments. Synlett 2007, 2983-2986.

33 Lebar, M. D.; Baker, B. J. Synthesis of the C3-C14 fragment of palmerolide A using a chiral pool based strategy. Tetrahedron 2010, 66, 1557-1562.

34 Prasad, K. R.; Pawar, A. B. Stereoselective synthesis of C1-C18 region of palmerolide A from tartaric acid. Synlett 2010, 1093-1095.

35 Wen, Z.-K.; Xu, Y.-H.; Loh, T.-P. Palladium-catalyzed cross-coupling of unactivated alkenes with acrylates: application to the synthesis of the C13-C21 fragment of palmerolide A. Chem. Eur. J. 2012, 18, 13284-13287.

148

36 Jones, D. M.; Dudley, G. B. Synthesis of the C1-C15 region of palmerolide A using refined Claisen-type addition- bond cleavage methodology. Synlett 2010, 223-226.

37 Lisboa, M. P.; Jeong-Im, J. H.; Jones, D. M.; Dudley, G. B. Toward a new palmerolide assembly strategy: synthesis of C16-C24. Synlett 2012, 23, 1493-1496.

38 Florence, G. J.; Wlochal, J. Synthesis of the originally proposed structure of palmerolide C. Chem. Eur. J. 2012, 18, 14250-14254.

39 Lebar, M. D.; Baker, B. J. On the stereochemistry of palmerolide A. Tetrahedron Lett. 2007, 48, 8009-8010.

40 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. J. Am. Chem. Soc. 2008, 130, 10019-10023.

41 Ravu, V. R.; Leung, G. Y. C.; Lim, C. S.; Ng, S. Y.; Sum, R. J.; Chen, D. Y.-K. Chemical synthesis and biological evaluation of second-generation palmerolide analogues. Eur. J. Org. Chem. 2011, 3, 463-468.

42 Rauniyar, V.; Hall, D. G. Catalytic enantioselective and catalyst-controlled diastereofacial-selective additions of allyl- and crotylboronates to aldehydes using chiral BrØnsted acids. Angew. Chem. Int. Ed. 2006, 45, 2426-2428.

43 Rauniyar, V.; Zhai, H.; Hall, D. G. Catalytic enantioselective allyl- and crotylboration of aldehydes using chiral diol.SnCl4 complexes. Optimization, substrate scope and mechanistic investigations. J. Am. Chem. Soc. 2008, 130, 8481-8490.

44 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.

45 Gao, X.; Hall, D. G. 3-Boronoacrolein as an exceptional hetereodiene in the highly enantio- and diastereoselective Cr(III)-catalyzed three-component [4+2]/allylboration. J. Am. Chem. Soc. 2003, 125, 9308-9309.

46 Gao, X.; Hall, D. G. Deligny, M.; Fabre, A.; Carreaux, F.; Carboni, B. Catalytic enantioselective three-component hetero-[4+β] cycloaddition/allylboration approach to α-hydroxyalkyl pyran: scope, limitations, and mechanistic proposal. Chem.-Eur. J. 2006, 12, 3132-3142.

47 Jung, M. E.; D’Amico, D. C. Enantiospecific synthesis of all four diastereomers of 2-methyl-3- [(trialkylsilyl)oxy]alkanals: facile preparation of aldols by non-aldol chemistry. J. Am. Chem. Soc. 1993, 115, 12208-12209.

48 Jung, M. E.; D’Amico, D. C. Stereospecific formation of optically active 5-alkyl-4-methyl-3-[(trialkylsilyl)oxy]- 2-([(trialkylsilyl)oxy]-methyl)tetrahydrofurans via diastereoselective epoxidation and rearrangement of - [(trialkylsilyl)oxy]-2-alken-1-ols. J. Am. Chem. Soc. 1997, 119, 12150-12158.

49 Prasad, K. R.; Anbarasan, P. Enantiospecific synthesis of (-)-2-hydroxy-exo-brevicomin. Tetrahedron: Asymmetry 2006, 17, 850-853.

50 Swallen, L. C.; Boord, C. E. The synthesis of beta-bromo-alkyl ether and their use in further syntheses. J. Am. Chem. Soc. 1930, 52,651-660.

51 Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J. Palladium catalyzed selective hydrogenolysis of alkenyloxiranes with formic acid. Stereoselectivity and synthetic utility. J. Am. Chem. Soc. 1989, 111, 6280-6287.

149

52 Chandrasekhar, S.; Sultana, S. S. Stereoselective synthesis of the C1-C20 segment of the microsclerodermins A and B. Tetrahedron Lett. 2006, 47, 7255-7258.

53 Kamijo, S.; Dudley, G. B. Claisen-type condensation of vinylogous acyl triflates. Org. Lett. 2006, 8, 175-177.

54 Jones, D. M.; Lisboa, M. P.; Dudley, G. B. Ring opening of cyclic vinylogous acyl triflates using stabilized carbanion nucleophiles: Claisen condensation linked to carbon-carbon bond cleavage. J. Org. Chem. 2010, 75, 3260-3267.

55 Davis, B. R.; Garratt, P. J. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.2 pp 795-863.

56 Hauser, C. R. The general course of the Claisen type of condensation. J. Am. Chem. Soc.1938, 60, 1957-1959.

57 McElvain, S. M. Some observations on the acetoacetic ester condensation. J. Am. Chem. Soc. 1929, 51, 3124- 3130.

58 Roberts, D. C.; McElvain, S. M. The extent of the condensation of certain monosubstituted acetic esters. J. Am. Chem. Soc. 1937, 59, 2007-2008.

59 Nishimura, T.; Sunagawa, M.; Okajima, T.; Fukasawa, Y. Transition structures for the Dieckmann condensation. Tetrahedron Lett. 1997, 38, 7063-7066.

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

61 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.

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

63 Tummatorn, J.; Dudley, G. B. Ring opening / fragmentation of dihydropyrones for the synthesis of homopropargyl alcohols. J. Am. Chem. Soc. 2008, 130, 5050-5051.

64 Jones, D. M.; Dudley, G. B. An open-and-shut strategy: preparation of benzo-fused indanes by ring-opening of a vinylogous acyl triflate and metal-catalyzed Asao-Yamamoto benzannulation. Tetrahedron 2010, 66, 4860-4866.

65 Eschenmoser, A.; Felix, D. Ohloff, G. Eine neuartige fragmentierung cyclischer α,-ungesättigter carbonylsysteme; synthese von exalton und rac-muscon aus cyclododecanon vorläufige. Helv. Chim. Acta 1967, 50, 708-713.

66 Felix, D. Shreiber, J. Ohloff, G.; Eschenmoser, A. α--Epoxyketon → Alkinon-Fragmentierung I: Synthese von exalton und rac-muscon aus cyclododecanon über synthetische methoden. Helv. Chim. Acta 1971, 54, 2896-2912.

67 Tanabe, M.; Crowe, D. F.; Dehn, R. L.; Detre, G. A novel fragmentation reaction of α,-epoxyketones the synthesis of acetylenic ketones. Tetrahedron Lett. 1967, 40, 3943-3946.

68 Tanabe, M.; Crowe, D. F.; Dehn, R. L. Detre, G. The synthesis of secosteroid acetylenic ketones. Tetrahedron Lett. 1967, 38, 3739-3743.

150

69 Weyerstahl, P.; Marschall, H. Fragmentation Reactions. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Elmsford, NY, 1991; Vol.6, pp 1041-1070.

70 Grob, C. A.; Schiess, P. W. Heterolytic fragmentation. A class of organic reactions. Angew. Chem. Int. Ed. Engl. 1967, 6, 1-15.

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

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

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

74 Kolakowski, R. V.; Manpadi, M.; Zhang, Y.; Emge, T. J.; Williams, L. J. Allene synthesis via C-C fragmentation: Method and Mechanistic Insight. J. Am. Chem. Soc. 2009, 131, 12910-12911.

75 Draghici, C.; Brewer, M. Lewis acid promoted carbon-carbon bond cleavage of -siloxy--hydroxy-α-diazoesters. J. Am. Chem. Soc. 2008, 130, 3766-3767.

76 Bayir, A.; Draghici, C.; Brewer, M. Preparation of tethered aldehyde ynoates and ynones by ring fragmentation of cyclic -oxy--hydroxy-α-diazo carbonyls. J. Org. Chem. 2010, 75, 296–302.

77 Kamijo, S.; Dudley, G. B. Cyclic vinylogous triflate hemiacetals as new surrogates for alkynyl aldehydes. Tetrahedron Lett. 2006, 47, 5629-5632.

78 Kitagawa, O.; Suzuki, T.; Inoue, T.; Watanabe, Y.; Taguchi, T. Carbocyclization reaction of active methine compounds with unactivated alkenyl or alkynyl groups mediated by TiCl4-Et3N. J. Org. Chem. 1998, 63, 9470- 9475.

79 Nevado, C.; Cardenas, D. J.; Echavarren, A. M. Reaction of enol ethers with alkynes catalyzed by transition metals: 5-exo-dig versus 6-endo-dig cyclizations via cyclopropyl platinum or gold carbene complexes. Chem. Eur. J. 2003, 9, 2627-2635.

80 Hashimi, A. S. K.; Schwarz, L.; Choi, J. -H.; Frost, T. M. A new gold-catalyzed C-C bond formation. Angew. Chem. Int. Ed. 2000, 39, 2285-2288.

81 Itoh, Y.; Tsuji, H.; Yamagata, H. -I.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura, E. Efficient formation of ring structures utilizing multisite activation by Indium catalysis. J. Am. Chem. Soc. 2008, 130, 17161-17167.

82 Bordwell, F. G. Equilibrium acidities in dimethyl sulfoxide solution. Acc. Chem. Res. 1988, 21, 456-463.

83 Kelly, S. E. Alkene synthesis. In Comprehensive Organic Synthesis; Trost, B. M.; Flemming, I. Eds.; Pergamon: Oxford, 1991; Vol. 1, pp 729-818.

84 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.

85 Vedejs, E.; Peterson, M. J. Stereochemistry and mechanism in the Wittig reaction. Top. Stereochem. 1994, 21, 1- 157.

151

86 Boutagy, J.; Thomas, R. Olefin synthesis with organic phosphonate carbanions. Chem. Rev. 1974, 74, 87-99.

87 Heron, B. M. Heterocycles from intramolecular Wittig, Horner and Wadsworth-Emmons reactions. Heterocycles 1995, 41, 2357-2386.

88 Ernst, H.; Muenster, P. Carotenoid Synthesis. Wittig and Horner-Emmons reactions. Carotenoids 1996, 2, 307- 310.

89 Lawrence, N. J. The Wittig reaction and related methods. Preparation of alkenes; Oxford University Press: New York, 1996, pp 19-58.

90 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.

91 Motoyoshiya, J. Recent developments in the Z-selective Horner-Wadsworth-Emmons reactions. Trends in Organic Chemistry 1998, 7, 63-73.

92 Minami, T.; Okauchi, T.; Kouni, R. α-Phosphonyl carbanions in organic synthesis. Synthesis 2001, 349-357.

93 Prunet, J. Recent methods for the synthesis of (E)-alkene units in macrocyclic natural products. Angew. Chem. Int. Ed. 2003, 2, 2826-2830.

94 Still, W. C.; Gennari, C. Direct synthesis of Z-unsaturated esters. Tetrahedron Lett. 1983, 24, 4405-4408.

95 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.

96 Iorga, B.; Eymery, F.; Mouries, V.; Savignac, P. Phosphorylated aldehydes: preparation and synthetic uses. Tetrahedron 1998, 54, 14637-14677.

97 Arbuzov, B. A. Michaelis-Arbuzov and Perkow reactions. Pure Appl. Chem. 1964, 9, 307-353.

98 Bhattacharya, A. K.; Thyagarajan, G. Michaelis-Arbuzov rearrangement. Chem. Rev. 1981, 81, 415-430.

99 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.

100 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.

101 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.

102 Maloney, K. M. Chung, J. Y. A general procedure for the preparation of -ketophosphonates. J. Org. Chem. 2009, 74, 7574-7576.

103 Milburn, R. R.; McRae, K.; Chan, J.; Tedrow, J.; Larsen, R.; Faul, M. A practical synthesis of - ketophosphonates. Tetrahedron Lett. 2009, 50, 870-872.

104 Prices made available from Sigma-Aldrich: http://www.sigmaaldrich.com/united-states.html

152

105 Yamashita, A.; Brown, C. A. Saline hydrides and super bases 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.

106 Lisboa, M. P.; Hoang, T. T.; Dudley, G. B. Tandem nucleophilic addition / fragmentation of vinylogous acyl triflates: 2-methyl-2-(1-oxo-5-heptynyl)-1,3-dithiane. Org. Synth. 2011, 88, 353-363.

107 Vatèle, J. –M. One-pot selective oxidation/ olefination of primary alcohols using TEMPO-BAIB system and stabilized phosphorus ylides. Tetrahedron Lett. 2006, 47, 715-718.

108 Heapy, A. M.; Wagner, T. W.; Brimble, M. M. Synthesis of the FG fragment of pectenotoxins. Synlett 2007, 15, 2359-2362.

109 Symkenberg, G.; Kalesse, M. Syn-selective vinylogous Kobayashi aldol reaction. Org. Lett. 2012, 14, 1608-1611.

110 Mukaeda, Y.; Kato, T.; Hosokawa, S. Syn-selective vinylogous Kobayashi aldol reaction using the E,E- vinylketene silyl N,O-acetal. Org. Lett. 2012, 14, 5298-5301.

111 Alvarezibarra, C.; Arias. ; Banon, G,; Fernandez, M. J.; Rodriguez, M.; Sinisterra, V. J. An efficient and selective Wittig-Horner synthesis of acyclic α-enones with barium hydroxide as solid catalyst. J. Chem. Soc. Chem. Commun. 1987, 1509-1511.

112 Paterson, I.; Yeung, K. –S.; Smail, J. B. The Horner-Wadsworth-Emmons reaction in natural products synthesis: expedient construction of complex (E)-enones using barium hydroxide. Synlett 1993, 774-776.

113 Crimmins, M. T.; Shamszad, M.; Mattson, A. E. A highly convergent approach toward (-)-brevenal. Org. Lett. 2010, 12, 2614-2617.

114 Crimmins, M. T.; O’Brian, E. A. Enantioselective total synthesis of spirofungins A and B. Org. Lett. 2010, 12, 4416-4419.

115 Giannis, A.; Heretsch, P.; Sarli, V.; Stöẞel, A. Synthesis of cyclopamine using a biomimetic and diastereoselective approach Angew. Chem. Int. Ed. 2009, 48, 7911-7914.

116 Winbush, S. M.; Mergot, D. J.; Roush, W. R. Total synthesis of (-)-spinosin A: examination of structural features that govern the stereoselectivity of the transannular Diels-Alder reaction. J. Org. Chem. 2008, 73, 1818-1829.

117 Gómez-Vidal, J. A.; Forrester, M. T.; Silverman, R. B. Mild and selective sodium azide mediated cleavage of p- nitrobenzoic esters. Org. Lett. 2001, 3, 2477-2479.

118 King, A. O.; Okukado, N.; Negishi, E. I. Highly general stereo-, region-, and chemo-selective synthesis of terminal and internal conjugated enynes by the Pd-catalysed reaction of alkynylzinc reagents with alkenyl halides. J. Chem. Soc. Chem. Commun. 1977, 683-684.

119 Cheon, C. –G; Kim, W. –S.; Smith, A. B. III. A scalable route to trisubstituted (E)-vinyl bromides. Org Lett. 2005, 7, 3569-3572.

120 Sun, B.; Xu, X. General synthetic approach to bicycle[9.3.0]tetradecenone: a versatile intermediate to clavulactoneand clavirolides.Tetrahedron Lett. 2005, 46, 8431-8434.

121 Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of organic compounds; John Wiley and Sons: New York, NY, 1994.

153

122 Hirayama, L.; Dunham, K. K.; Singaram, B. Asymmetric indium-mediated synthesis of homopropargylic alcohols. Tetrahedron Lett. 2006, 47, 5173-5176.

123 Francais, A.; Leyva, A.; Etxebarria-J, G.; Ley, S. V. Total synthesis of the anti-apoptotic agents Iso- and Bongkrekic acids. Org. Lett. 2010, 12, 340-343.

124 Van Horn, D. E.; Negishi, E. Selective carbon-carbon bond formation via transition metal catalysts. 8. Controlled carbometalation. Reaction of acetylenes with organoalane-zirconocene dichloride complexes as a route to stereo- and region- defined trisubstituted olefins. J. Am. Chem. Soc. 1978, 100, 2252-2254.

125 Wipf, P.; Lim, S. Rapid carboalumination of alkynes in the presence of water. Angew. Chem. Int. Ed. Engl.1993, 32, 1068-1071.

126 Kallan, N. C.; Halcomb, R. L. Synthesis of the ring system of phomactin D using a Suzuki macrocyclization. Org. Lett. 2000, 2, 2687-2690.

127 Romero-Ortega, M. ; Colby, D. A.; Olivo, H. F. Synthesis of C1-C17 fragment of aurisides and callipeltosides. Tetrahedron Lett. 2002, 43, 6439-6441.

128 Quéron, E.; Lett, R. Synthetic studies on bafilomycin A1: stereoselective synthesis of the enantiopure C1-C11 fragment. Tetrahedron Lett. 2004, 45, 4527-4531.

129 Wallace, D. J.; Klauber, D. J.; Chen, C.-Y.; Volante, R. P. Palladium catalyzed amidation of enol triflates: a new synthesis of enamides. Org. Lett. 2003, 5, 4749-4752.

130 Klapars, A.; Campos, K. R,; Chen, C.-Y.; Volante, R. P. Preparation of enamides via palladium-catalyzed amidation of enol tosylates. Org. Lett. 2005, 7, 1185-1188.

131 Wallace, D. J.; Campos, K. R.; Shultz, C. S.; Klapars, A.; Zewge, D.; Crump, B. R.; Phenix, B. D.; McWilliams, J. C.; Krska, S.; Sun, Y.; Chen, C-Y.; Spindler, F. New efficient asymmetricsynthesis of taranabant, a CB1R inverse agonist for the treatment of obesity. Org. Process Res.Dev. 2009, 13, 84-90.

132 Onoda, T.; Shirai, R.; Iwasaki, S. A mild and selective deprotection of p-methoxybenzyl (PMB) ether by bromide diethyl etherate-methyl sulfide. Tetrahedron Lett. 1997, 38, 1443-1446.

133 Falck, J. R.; Barma, D. K.; Baati, R.; Mioskowski, C. Differential cleavage of arylmethyl ethers: reactivity of 2,6- dimethoxybenzyl ethers. Angew. Chem. Int. Ed. 2001, 40, 1281-1283.

154

BIOGRAPHICAL SKETCH

Educational Background

2008 - 2013 PhD in Organic Chemistry (anticipated completion May 2013) Department of Chemistry and Biochemistry Florida State University, FSU, Tallahassee, FL, USA Research Advisor: Dr. Gregory B. Dudley Fellowship: Fulbright / Capes

2005 - 2007 Master degree in Pharmaceutical Sciences Federal University of Minas Gerais, UFMG, Belo Horizonte, Brazil Thesis title: Synthesis of 3-O-[(undecen)-1-yl]-D-glucose Analogues and Investigation of their Antimalarial Activity Research Advisor: Dr. Ricardo José Alves Fellowship: Capes

2001 - 2005 B. A. degree in Pharmacy Federal University of Minas Gerais, UFMG, Belo Horizonte, Brazil

Undergraduate Training

2004 - 2005 Scientific Initiation. Synthesis of lactose derivatives for activity evaluation with Erythrina speciosa lectin.Federal University of Minas Gerais, UFMG, Belo Horizonte, Brazil. Fellowship: CNPq

2002 - 2004 Scientific Initiation. Synthesis and study of nitrogenated and sulfurated dendrimeric precursors, rationally planned, as new agents with anticancer and cytoprotector activities. Federal University of Minas Gerais, UFMG, Belo Horizonte, Brazil. Fellowship: CNPq

Publications

5. Lisboa, M. P.; Jones, D. M.; Dudley, G. B. Formal Synthesis of Palmerolide A. Org. Lett. 2013, 15, 886-889.

4. Lisboa, M. P.; Jeong-Im, J. H.; Jones, D. M.; Dudley, G. B. Toward a new palmerolide assembly strategy: synthesis of C16-C24. Synlett 2012, 23, 1493-1496.

3. Lisboa, M. P.; Hoang, T. T.; Dudley, G. B. Tandem Nucleophilic Addition/ Fragmentation of Vinylogous Acyl Triflates: 2-Methyl-2-(1-Oxo-5-Heptynyl)-1,3-Dithiane. Org. Synth. 2011, 88, 353-363.

155

2. Jones, D. M.; Lisboa, M. P.; Kamijo, S. Dudley, G. B. Ring opening of cyclic vinylogous acyl triflates using stabilized carbanion nucleophiles: Claisen condensation linked to carbon–carbon bond cleavage. J. Org. Chem. 2010, 75, 3260–3267.

1. Butera, A. P.; Souza Filho, J. D. S.; Prado, M. A. F.; Lisboa, M. P.; Alves, R. J. Synthesis of 4-(Methoxycarbonyl)phenyl -Lactoside Derivatives Modified at C(6) or C(6’), and Evaluation of Their Inhibitory Activity on Erythrina cristagalli Lectin-Mediated Hemagglutination. Helv. Chim. Acta 2009, 92, 176-187.

Teaching Experience

2012-2013 Florida State University, Tallahassee, FL, USA Teaching Assistant Organic Chemistry Recitation (CHM2210, CHM2211, CHM2200)

2008-2009 Florida State University, Tallahassee, FL, USA Teaching Assistant (General Chemistry Lab - CHM1046 L, Biochemistry Lab - BCH3023C, Organic Chemistry Lab - CHM2211L)

2007-2008 Vale do Rio Doce University (UNIVALE), Governador Valadares, MG, Brazil. Professor of Medicinal Chemistry – Pharmacy Professor of Analytical Chemistry – Pharmacy/ Chemistry

Research Presentations

Oral presentations

Lisboa, M. P.; Jones, D. M.; Dudley, G. B. Progress toward the total synthesis of palmerolide A. 244th ACS National Meeting and Exposition, Fall 2012, Philadelphia, PA; ORGN-310.

Lisboa, M. P.; Jones, D. M.; Jeong, J. H.; Dudley, G. B.(2009). Progress toward the total synthesis of palmerolide A. Florida Annual Meeting and Exposition 2009 (FAME). Orlando, FL.

Poster presentations

11. Lisboa, M. P.; Jones, D. M.; Dudley, G. B. (2012). Progress toward the total synthesis of palmerolide A. Graduate Research Symposium - Division of Organic Chemistry, Boulder, CO.

10. Lisboa, M. P.; Jones, D. M.; Dudley, G. B. (2012). Formal synthesis of palmerolide A. Gordon Research Conference - Organic Reaction and Processes. Smithfield, RI.

9. Lisboa, M. P.; Varotti, F. P.; Kretti, A. U.; Alves, R. J. (2008). Search for carbohydrate-based antimalarials: synthesis and evaluation of the antiplasmodial acitivity of 3-O-alkyl derivatives of th D- glucose. 4 Brazilian Symposium on Medicinal Chemistry. Porto de Galinhas, PE, Brazil.

156

8. Lisboa, M. P.; Alves, R. J. (2007). Synthesis of of potential antimalarial agents derivatives of th D-glucose. 30 Brazilian Chemical Society Meeting. Aguas de Lindoia, SP, Brazil.

7. Lisboa, M. P.; Alves, R. J. (2006). Synthesis of 3-O-[(undecen)-1-yl]-D-glicose analogues. XX Brazilian Chemical Society - MG Regional Meeting, São João Del Rei, MG, Brazil.

6. Lisboa, M. P.; Butera, A. P.; Alves, R. J.; Andrade, M. H. G.; Souza Filho, J. D.; Humberto, J. L. (2005). Aryl Lactosides and Investigation of their interactions with Erythrina speciosa lectin. XIV Scientific Initiation Week of UFMG, Belo Horizonte, MG, Brazil.

5. Lisboa, M. P.; Butera, A. P.; Alves, R. J.; Souza Filho, J. D.; Andrade, M. H. G. (2005). Synthesis of lactose derivatives and evaluation of their interactions with Erythrina speciosa lectin. 28th Brazilian Chemical Society Meeting, Poços de Caldas, MG, Brazil.

4. Lisboa, M. P.; Donnici, C. L.; Santos, V. M. R.; Oliveira, S. R. (2004). Synthesis of a new phosphorated and tiosubstituted compound with potential insecticide application. XIII Scientific Initiation Week of UFMG, Belo Horizonte, MG, Brazil.

3. Lisboa, M. P.; Donnici, C. L.; Porto, A. O.; Lima, G. M.; Araujo, M. H. (2003). Synthesis and complexation studies of organosulfurated compounds with heavy metals for environment and optic-electronic applications. XII Scientific Initiation Week of UFMG, Belo Horizonte, MG, Brazil.

2. Campana, P. R. V.; Lisboa, M. P.; Bento, S. F. V.; Donnici, C. L.; Bessa, A. H. F. B. E.; Montanari, C. A.; Araujo, M. H. (2002). Synthesis of new organosulfurated compounds for heavy metals complexes. XI Scientific Initiation Week of UFMG, Belo Horizonte, MG, Brazil.

1. Bento, S. F. V.; Lisboa, M. P.; Donnici, C. L.; Campana, P. R. V.; Montanari, C. A. (2002). Synthesis of organosulphurated compounds and heavy metals complexation studies. XVI Brazilian Chemical Society - MG Regional Meeting, Viçosa, MG, Brazil.

Awards

 Fulbright/Capes Doctoral Fellowship 2008-2012.

 Latin American and Caribbean Fellowship 2008-2012.

 Best poster presentation – Medicinal Chemistry Strategies in Drug Design. Lisboa, M. P.; Varotti, F. P.; Kretti, A. U.; Alves, R. J. (2008). Search for carbohydrate-based antimalarials: synthesis and evaluation of the antiplasmodial acitivity of 3-O-alkyl derivatives of D- glucose. 4th Brazilian Symposium on Medicinal Chemistry. Porto de Galinhas, PE, Brazil.

157

 Capes Fellowship - Master 2005-2007.

 CNPq Undergraduate Research Fellowship 2003-2005.

158