Towards the Synthesis of the Emestrin Family of Natural Products

Home , Peroxy acid

Brendan James Fisher

ORCID: 0000-0003-0090-8951

Submitted in total fulfilment of the requirements of the degree of Doctor of Philosophy

September 2018

School of Chemistry

Bio21 Institute

The University of Melbourne

Abstract

A Cope rearrangement of a vinyl pyrrole epoxide (397) was utilised to form the dihydrooxepino[4,3-b]pyrrole core (398) of the emestrin family of natural products which involved the first examples of the dearomatisation of pyrrole in this type of rearrangement. It was found that an electron withdrawing ester substituent on the C2 position of the epoxide was essential for the [3,3]-rearrangement to occur. The vinyl pyrrole epoxides were synthesised in an efficient manner by a vinylogous Darzens reaction. Density functional calculations showed lower transition state energies for Cope rearrangements of epoxides with C2 esters when compared to the unsubstituted substrates which agreed with the observed experimental results. Silyl substituted vinyl bromide esters also participated in the Darzens reactions to give the desired vinyl pyrrole epoxides in good to excellent yields. Only the triethoxysilyl vinyl epoxide 313c underwent Cope rearrangement to provide the fully substituted emestrin core dihydrooxepine.

The anion derived from an aryl bromosulfone did not give the Darzens product but underwent a previously unobserved stereoselective trimerization to afford the cyclohexene 343 as a single diastereoisomer. A mechanistic rationale involving SN2’ additions, [3,3]-Cope rearrangements and a stereoselective intramolecular conjugate addition was proposed and this was supported by density functional theory (DFT) calculations.

A four-step total synthesis of biaryl ether natural product violaceic acid (11) is described. The steps include an SNAr reaction to afford the biaryl ether 136, tin chloride-mediated chemoselective reduction of the nitro group to amine 135. A Cu-mediated Sandmeyer reaction of 135 gave violaceic acid methyl ester 374 which is hydrolysed to give pure violaceic acid 11. An improved synthesis of the known biaryl iodide 119 is also described via a Sandmeyer reaction of amine 135.

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Declaration

This is to certify that:

i. The thesis comprises only my original work; ii. Due acknowledgement has been made in the text to all other material used; iii. The thesis is less than 100,000 words in length, exclusive of tables, bibliographies, appendices and footnotes.

Brendan James Fisher

Preface

The synthesis of the dihydrooxepino[4,3‑b]pyrrole core of the emestrin family of natural products via Cope rearrangement of vinyl pyrrole epoxides has been published in a scientific journal (Rizzacasa, M.; Fisher, B.; et al.; Org. Lett. 2015, 17 (24), pp 5998 – 6001) and has been presented at the Royal Australian Chemical Institute, Victorian Branch, 40th Annual Synthesis Symposium, The University of Melbourne, Melbourne, Victoria, Australia on December 4th 2015, the Gordon Research Conference for Heterocyclic Compounds, Salve Regina University, Rhode Island, USA on June 18th – 23rd 2017, and the Royal Australian Chemical Institute, Victorian Branch, 42nd Annual Synthesis Symposium, The University of Melbourne, Victoria, Australia on December 1st 2017.

The unprecedented stereoselective base-induced trimerization of an α-bromovinylsulfone has been published in a scientific journal (Rizzacasa, M.; Fisher, B.; et al.; Org. Biomol. Chem. 2017, 15, pp 5529 – 5534) and has been presented at the Gordon Research Conference for Heterocyclic Compounds, Salve Regina University, Rhode Island, USA on June 18th – 23rd 2017 and the Royal Australian Chemical Institute, Victorian Branch, 42nd Annual Synthesis Symposium, The University of Melbourne, Victoria, Australia on December 1st 2017.

The synthesis of violaceic acid has been published in a scientific journal (Cameron, A.; Fisher, B.; Rizzacasa, M.; Tetrahedron, 2018, 74, pp 1203 – 1206).

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Acknowledgements

I’d like to thank my supervisor Professor Mark Rizzacasa for all the help, guidance, support and opportunities given to me throughout my PhD. I’m so lucky that I chose a supervisor so willing to help and be engaged with their students’ learning process. You’re a fantastic supervisor, a brilliant chemist, but most importantly a great person.

Acknowledgements and thanks to the contributors to this project, particularly Dr Elizabeth Krenske for providing invaluable computational data that led to two of our publications, and Professor Jonathan White for obtaining many X-ray crystal structures. Thanks to Nick Fisk, Jess Hummel and Alex Cameron for laying the foundations of this project, as well as Angus Robertson, Young Ye and Romain LePage for helping me keep it afloat.

Thanks to the University of Melbourne for supporting me financially via the Melbourne Research Scholarship, and to the University and the G.I. Feutrill award for funding my visit to the Gordon Research Conference.

Thanks to the Bio21 Institute support staff and students for all the help and friendship. Hamish Grant and Sunnia Rajput were invaluable in the NMR facility, as was everybody in the Bio21 stores, particularly Nick, Alex, Peter and Johanna who were not only a great help but great friends.

Thank you to the Rizzacasa group members, both past and present. I’ve never met a brighter bunch of people and I’m so excited to see what all your futures hold in chemistry and beyond. Thanks for putting up with my mood swings and occasionally cleaning up the sintered glass funnels. Thanks to Gajan Santhakumar, Dayna Sturgess and Darran Loits for showing me the ropes in lab management.

Thanks to all family and friends for the help and support over the years, particularly those who helped us with the move. Special thanks to my parents for constantly supporting me throughout my education and providing me with many privileges for which I am so fortunate.

Finally, thank you to my partner Liv Burnett. There is no way I would have finished this project if it weren’t for your unwavering support and understanding. It’s truly the hardest thing I’ve ever done and knowing you’d be there for me at home to make me happy after a tough day kept me going more often than not. You’re the best.

I’d like to take this opportunity to dedicate this body of work to Barbara Phillips and Carlene Fisher, two people who were a tremendous support and inspiration to me throughout my life and PhD. I hope this will serve as a reminder of the place in time that it was written and serve to further inspire me later in life.

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Table of Contents

Abstract i

Declaration iv

Preface vi

Acknowledgements viii

Table of Contents ix

List of Figures xii

List of Schemes xiv

List of Tables xix

Glossary of Abbreviations xx

1. Introduction

1.1 Structure and activity of epipolythiodioxopiperazines (ETPs) 1

1.2 Structure and activity of emestrin (4) and related compounds 1

1.3 Structure and activity of aranotin (12) and related compounds 4

1.4 Biosynthesis of acetylaranotin (3) 5

1.5 Structure and activity of emethallicin A (24) and related compounds 6

1.6 Previous syntheses of dihydrooxepine containing ETPs 7

1.6.1 Clive and Peng’s synthesis of the tricyclic core of the emestrins 7

1.6.2 Reisman and coworkers’ total synthesis of acetylaranotin (3) 10

1.6.3 Reisman and coworkers’ total synthesis of acetylapoaranotin (15) 12

1.6.4 Tokuyama and coworkers’ total synthesis of acetylaranotin (3) 13

1.6.5 Tokuyama and coworkers’ total synthesis of MPC1001B (8) 16

1.7 Biaryl ether synthesis and background 17

1.8 Bibliography 20

2. Retrosynthesis and reaction background

2.1 Retrosynthetic analysis of emestrin-type natural products 24

2.2 Reaction background: Cope rearrangement 27

2.3 Reaction background: vinylogous Darzens reaction 31

2.4 Bibliography 33

3. Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

3.1 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrins via the Cope rearrangement of vinyl pyrrole epoxides 36

3.1.1 Synthesis of vinyl pyrrole epoxides 36

3.1.2 Synthesis of vinyl pyrrole epoxides by a vinylogous Darzens reaction 38

3.1.3 Cope rearrangements of vinyl pyrrole epoxides 42

3.1.4 Computational analyses of Cope rearrangements 47

3.1.5 Preliminary conclusions 49

3.2 Attempts to remove the ester functionality 50

3.3 Towards a synthesis of the fully substituted dihydrooxepine 58

3.3.1 Allylic oxidation approach 58

3.3.2 Extended Darzens reactions 58

3.3.3 Wittig approach 62

3.4 Bibliography 69

4. A novel vinyl sulfone trimerization

4.1 Synthesis of vinyl pyrrole epoxides with alternative electron-withdrawing groups 73

4.1.1 Synthesis of alternative electron-withdrawing groups 73

4.1.2 Darzens reaction with a bromocrotononitrile 73

4.1.3 Attempts to synthesise a sulfone epoxide via a Darzens reaction 74

4.2 A novel vinyl sulfone trimerization 76

4.2.1 Characterisation of vinyl sulfone by-product 76

4.2.2 Optimising the trimerisation reaction 81

4.2.3 Proposed mechanisms and computational analyses of transition states 84

4.3 Bibliography 90

5. Synthesis of Violaceic acid (11)

5.1 Biaryl ether coupling 92

5.2 Selective reduction of nitro 136 to amine 135 94

5.3 Sandmeyer hydroxylation and hydrolysis of violaceic acid methyl ester (374) 95

5.4 Attempted modifications of the original route 97

5.5 Formal synthesis of Violaceic acid (11) 99

5.6 Bibliography 101

6. Future work and conclusions

6.1 Synthesis of the tricyclic core of the emestrin family of natural products 104

6.2 Future work and revised route towards the tricyclic core of the emestrins 105

6.3 Conclusion 106

6.4 Bibliography 108

7. Experimental section

7.1 General experimental 110

7.2 Experimental methods 111

7.3 Bibliography 171

List of Figures

Figure 1.1 Generic structure of ETPs (1), structure of gliotoxin (2) and acetylaranotin (3).

Figure 1.2 Emestrin (4), aurantioemestrin (5), dethiosecoemestrin (6), MPC1001 (7) and its related compounds (8, 9, 10).

Figure 1.3 Aranotin (12) and related compounds isolated from Arachniotus aureus.

1 Figure 3.1 H NMR spectrum of vinyl pyrrole epoxide 191 (500 MHz, CDCl3).

1 Figure 3.2 H NMR spectrum of vinyl pyrrole epoxide 190 (400 MHz, CDCl3).

1 Figure 3.3 H NMR spectrum of vinyl pyrrole epoxide 205 (400 MHz, CDCl3).

Figure 3.4 1H NMR spectrum of the epoxide protons of vinyl pyrrole epoxide 215 (600 MHz,

CDCl3).

1 Figure 3.5 H NMR spectrum of the t-butyl dihydrooxepine 218 (400 MHz, CDCl3).

13 Figure 3.6 C NMR spectrum of the t-butyl dihydrooxepine 218 (101 MHz, CDCl3).

Figure 3.7 X-ray crystal structure of the t-butyl dihydrooxepine 218.

Figure 3.8 X-ray crystal structure of the TMSE dihydrooxepine 220.

1 Figure 3.9 H NMR spectrum of dihydrooxepine aldehyde 247 (400 MHz, CDCl3).

13 Figure 3.10 C NMR spectrum of dihydrooxepine aldehyde 247 (151 MHz, CDCl3).

1 Figure 3.11 H NMR spectrum of dihydrooxepine 257 (400 MHz, CDCl3).

Figure 3.12 COSY spectrum of dihydrooxepine 257.

Figure 3.13 X-ray crystal structure of vinyl pyrrole epoxide 313b.

Figure 3.14 Steric interference in Cope rearrangement of silylated vinyl pyrrole epoxides.

1 Figure 3.15 H NMR spectrum of furan epoxide 314 (600 MHz, CDCl3).

1 Figure 3.16 H NMR spectrum of dihydrooxepine 315 (400 MHz, CDCl3).

1 Figure 3.17 H NMR spectrum of dihydrooxepine 316c (600 MHz, CDCl3).

13 Figure 3.18 C NMR spectrum of dihydrooxepine 316c (151 MHz, CDCl3).

1 Figure 4.1 H NMR spectrum of cyclic sulfone by-product (400 MHz, CDCl3).

13 Figure 4.2 C NMR spectrum of vinyl sulfone by-product (400MHz, CDCl3).

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Figure 4.3 HSQC spectrum of vinyl sulfone by-product.

Figure 4.4 COSY spectrum of vinyl sulfone by-product.

Figure 4.5 Proposed structure for cyclic by-product with COSY proton assignments.

Figure 4.6 X-ray crystal structure of sulfone by-product 343.

1 Figure 4.7 H NMR spectrum of cyclohexene 347 (500 MHz, CDCl3).

1 Figure 4.8 H NMR spectrum of d-343 (400 MHz, CDCl3).

1 Figure 5.1 H NMR spectrum of synthetic violaceic acid 11 (400 MHz, d6-DMSO).

13 Figure 5.2 C NMR spectrum of synthetic violaceic acid 11 (400 MHz, d6-DMSO).

Figure 5.3 1H NMR comparison of violaceic acid 11 obtained via LiOH hydrolysis of 119 and the reported method (400 MHz, d6-DMSO).

13 Figure 6.1 C NMR spectrum of triketopiperazine 389 (126 MHz, CDCl3).

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List of Schemes

Scheme 1.1 Degradation pathway to violaceic acid (11) from emestrin (4).

Scheme 1.2 Biosynthetic pathway leading to acetylaranotin (3).

Scheme 1.3 Clive and Peng’s synthesis of intermediate 33.

Scheme 1.4 Synthesis of diketopiperazine fragment 37.

Scheme 1.5 Synthesis of key fragment 45.

Scheme 1.6 Asymmetric synthesis of the tricyclic core of the emestrins (53).

Scheme 1.7 Reisman and coworkers’ total synthesis of key acetylaranotin intermediate 63.

Scheme 1.8 Synthesis of acetylaronotin (3).

Scheme 1.9 Synthesis of cyclohexadiene intermediate 78.

Scheme 1.10 Synthesis of (-)-acetylapoaranotin (15) from cyclohexadiene 78 and tetrahydrooxepino[4,3-b]pyrrole 64.

Scheme 1.11 Tokuyama and coworkers’ synthesis of key intermediate 92.

Scheme 1.12 Tokuyama and coworkers’ synthesis of acetylaranotin (3).

Scheme 1.13 Tokuyama and coworkers’ synthesis of 15-membered macrocycle 102 from a common intermediate (94).

Scheme 1.14 Tokuyama and coworkers’ final steps in the total synthesis of MPC1001B (8).

Scheme 1.15 Proposed structures of violaceic acid (11) and degradation to 11 from emestrin (4) and dethiosecoemestrin (6).

Scheme 1.16 Synthesis of dimethoxy violaceic acid (100) and acetylviolaceic acid (112) from violaceic acid (11).

Scheme 1.17 Koide and coworkers’ total synthesis of violaceic acid (11).

Scheme 2.1 Retrosynthetic analysis of emestrin (4), auriantioemestrin (5) and dethiosecoemestrin (6).

Scheme 2.2 Retrosynthetic analysis of dihydrooxepine 121.

Scheme 2.3 Previous syntheses of the tetrahydrooxepino[4,3-b]pyrrole core.

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Scheme 2.4 Resonance contributors of electrophilic aromatic substitutions of 2-substituted pyrroles.

Scheme 2.5 Retrosynthesis of violaceic acid (11).

Scheme 2.6 Stereochemical outcomes of Cope rearrangements of meso- and rac-3,4- dimethylhexa-1,5-diene (137) via boat or chair-like transition states.

Scheme 2.7 Examples of Cope rearrangements.

Scheme 2.8 Cope rearrangements of trans-divinylepoxides.

Scheme 2.9 Cope rearrangements of divinyl epoxides.

Scheme 2.10 Darzens reactions for the synthesis of epoxides.

Scheme 2.11 Synthesis of a vinyl furan epoxide via a vinylogous Darzens reaction.

Scheme 2.12 Mechanism of a vinylogous Darzens reaction.

Scheme 3.1 Synthesis of vinyl pyrrole epoxides from trichloroacylpyrrole (132).

Scheme 3.2 The route to vinyl pyrrole epoxide 195 via a vinylogous Darzens reaction.

Scheme 3.3 Synthesis of the vinyl pyrrole epoxide 200 via a vinylogous Darzens reaction.

Scheme 3.4 Synthesis of the substituted vinyl pyrrole epoxide 205 via a vinylogous Darzens reaction.

Scheme 3.5 Darzens reaction to afford vinyl pyrrole epoxides 210 and 211.

Scheme 3.6 Darzens reaction using bromoester 212.

Scheme 3.7 Attempted asymmetric vinylogous Darzens reaction.

Scheme 3.8 Cope rearrangement of vinyl pyrrole epoxides to give dihydrooxepines.

Scheme 3.9 Proposed mechanism for acid-catalysed degradation of dihydrooxepine 217.

Scheme 3.10 Ester group influence on Cope rearrangements of vinyl pyrrole epoxides.

Scheme 3.11 Cope rearrangements of simple divinyl epoxides and their transition state energies.

Scheme 3.12 Resonance state contributors of Cope rearrangements.

Scheme 3.13 Model vinyl pyrrole epoxides, their transition states and energies when undergoing a Cope rearrangement.

Scheme 3.14 Potential reaction pathway for removal of the dihydrooxepine ester functionality.

Scheme 3.15 Attempted reduction of dihydrooxepine esters 218 and 221 to the corresponding aldehyde 247.

Scheme 3.16 Ruthenium-catalysed reductive decarboxylation of esters.

Scheme 3.17 Preparation of pyridinylmethyl ester 254 and attempted Darzens reaction.

Scheme 3.18 Preparation of dihydrooxepine 256 and attempted decarboxylation.

Scheme 3.19 Conversion of dihydrooxepine ester 220 to the acid 258 and aldehyde 247.

Scheme 3.20 Synthesis of brominated thioester 260, and attempted Darzens reaction between aldehyde 204 and thioester 260.

Scheme 3.21 Attempted decarboxylation of acid 258.

Scheme 3.22 Mechanism of the decarbonylation of aldehydes with Wilkinson’s catalyst (262).

Scheme 3.23 Iridium catalysed decarbonylation of aldehydes.

Scheme 3.24 Ir catalysed decarbonylation of the dihydrooxepine aldehyde 247.

Scheme 3.25 Riley oxidation of dihydrooxepine 220 and the hydrolysis products observed.

Scheme 3.26 Darzens reactions with -siloxy-α-bromocrotonate 273.

Scheme 3.27 Synthesis of -substituted bromocrotonates 273 and 283.

Scheme 3.28 Alternative pathway to extended allylbromo esters 288 and 283 for use in the Darzens reaction.

Scheme 3.29 Attempted Darzens reactions.

Scheme 3.30 General mechanism for the Fleming-Tamao oxidation and examples.

Scheme 3.31 Proposed synthesis of a dihydrooxepine alcohol 276 via the Fleming-Tamao oxidation of a silyl substituted dihydrooxepine 300.

Scheme 3.32 Attempted formation of the brominated ester 305.

Scheme 3.33 Attempted cross metathesis between alkenes and vinyl pyrrole epoxide 211.

Scheme 3.34 Synthesis of silylaldehydes.

Scheme 3.35 Wittig synthesis of silylbromoesters.

Scheme 3.36 Darzens reactions involving extended susbtrates 312a-d.

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Scheme 3.37 Darens reaction and Cope rearrangement of furaldehyde (178) with silylated ester 312b.

Scheme 3.38 Cope rearrangements of silylated vinyl pyrrole epoxides 313a-c.

Scheme 3.39 Failed Fleming-Tamao oxidations of triethoxysilyl dihydrooxepine 316c.

Scheme 4.1 Alternative electron-withdrawing groups in a Darzens reaction.

Scheme 4.2 Methods for the decyanation of alkyl and arylnitriles.

Scheme 4.3 Darzens reaction between aldehyde 204 and crotononitrile 324.

Scheme 4.4 Formation of α,β-epoxysulfones via the Darzens reaction between an α-halosulfone and a ketone.

Scheme 4.5 Removal of sulfones using sodium/mercury amalgam.

Scheme 4.6 Synthesis of the vinyl sulfones 336 and 337 from their sulfinic acid precursors 332 and 333.

Scheme 4.7 Synthesis of the vinyl bromo sulfones 340 and 341.

Scheme 4.8 Attempted Darzens reactions using aryl vinyl sulfones.

Scheme 4.9 Synthesis of cyclohexene 347 using p-chlorophenyl substrate 344.

Scheme 4.10 Experiments probing the mechanism of the trimerisation reaction.

Scheme 4.11 Formation of enolates 340a and 348a and alternative electrophile 348 from bromovinyl sulfone 340.

Scheme 4.12 Proposed mechanism involving SN2 reactions for the formation of cyclohexene 343.

Scheme 4.13 Proposed mechanism for the formation of cyclohexene 343 involving SN2’ reactions and Cope rearrangements.

Scheme 4.14 Calculated transition states for SN2 and SN2’ reactions (ΔG in kcal/mol).

Scheme 4.15 Calculated transition states for Cope rearrangements of diene 351 (ΔG in kcal/mol).

Scheme 4.16 Transition state energies for the cis- and trans cyclisation products of the cyclisation (ΔG in kcal/mol).

Scheme 4.17 Calculated structures for cyclohexene 343 and the C1’ epimer epi-343 (ΔG in kcal/mol).

Scheme 5.1 Ullman-type biaryl ether synthesis.

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Scheme 5.2 Attempted Buchwald and Ullman couplings.

Scheme 5.3 The SNAr reaction mechanism, previous synthesis of biaryl ether 373, and formation of violaceic acid biaryl ether precursor 136.

Scheme 5.4 Selective tin(II)-mediated reduction of the nitro group.

1 Scheme 5.5 Results of Sandmeyer hydroxylation using Cu2O and glycine as additives.

Scheme 5.6 Synthesis of violaceic acid (11).

Scheme 5.7 Attempted formation of boronate ester 379.

Scheme 5.8 Suzuki-Miyaura coupling of nitroarenes and attempted cross coupling of nitroarene 136.

Scheme 5.9 Iodination of amine 135.

Scheme 5.10 Conversion of biaryl iodide 119 to impure violaceic acid 11.

Scheme 6.1 Attempts to form a diketopiperazine through a peptide coupling reaction.

Scheme 6.2 Attempts towards a triketopiperazine pyrrole aldehyde.

Scheme 6.3 Proposed modified approach to the emestrins.

Scheme 6.4 The synthetic approach towards the emestrin family of natural products.

Scheme 6.5 An unprecedented stereoselective base-induced trimerization of an α-bromosulfone.

Scheme 6.6 Synthesis of violaceic acid (11) and formal synthesis of biaryl iodide 119.

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List of Tables

Table 3.1 Cope rearrangements of vinyl pyrrole epoxides.

Table 4.1 Optimisation of formation of cyclohexene 343.

Table 5.1 13C NMR chemical shifts comparison between synthetic and natural violaceic acid 11.

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Glossary of abbreviations

Ac2O = acetic anhydride Acac = acetylacetonate AcOH = acetic acid AIBN = azobisisobutyronitrile Alk = alkyl aq. = aqueous Ar = aryl ATP = adenosine triphosphate ATR = attenuated total reflectance B = base

B2pin2 = bis(pinacolato)diboron BDA = bisdethio-di(methylthio)-acetylaranotin BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl bipy = 2,2’-bipyridine Bn = benzyl Boc = tert-butyloxycarbonyl

Boc2O = boc anhydride (di-tert-butyl dicarbonate) BOP-Cl = bis(2-oxo-3-oxazolidinyl)phosphinic chloride BORSM = based on recovered starting material br = broad Cbz = carboxybenzyl CCR2 = C-C chemokine receptor type 2 cod = 1,5-cyclooctadiene COSY = correlation spectroscopy CSA = camphor sulfonic acid d = doublet dba = dibenzylideneacetone DBE = double bond equivalents DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DCC = N,N-dicyclohexylcarbodiimide DCE = dichloroethane

DFT = density functional theory DIAD = diisopropyl azodicarboxylate DIBAL = diisobutylaluminium hydride DIPA = diisopropylamine DKP = diketopiperazine DMAP = 4-(dimethylamino)pyridine DMDO = dimethyldioxirane DME = dimethoxyethane DMF = N,N-dimethylformamide DMP = Dess-Martin periodinane DMS = dimethyl sulfide DMSO = dimethyl sulfoxide DNA = deoxyribonucleic acid EDA = ethylenediamine EDCI = N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride ESI = electrospray ionisation EtOAc = ethyl acetate ETP = epipolythiodioxopiperazine EWG = electron-withdrawing group GSH = glutathione h = hours HG-II = Hoveyda-Grubbs catalyst 2nd generation HMDS = hexamethyldisilazane HMPA = hexamethylphosphoramide HOTT = S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium hexafluorophosphate HRMS = high resolution mass spectrometry HSQC = heteronuclear single quantum coherence spectroscopy

IC50 = half maximal inhibitory concentration ImH = imidazole IR = infrared

LD50 = median lethal dose LDA = lithium diisopropylamide

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LG = leaving group m = multiplet MCP = monocyte chemoattractant protein m-CPBA = meta-chloroperoxybenzoic acid MeCN = acetonitrile MEM = 2-methoxyethoxymethyl MES = 2-mercaptoethane sulfonate MIC = minimum inhibitory concentration min = minutes m.p. = melting point Ms = methanesulfonyl MS = mass spectrometry NBS = N-bromosuccinimide NCS = N-chlorosuccinimide

NEt3 = triethylamine NMP = N-methylpyrolidinone NMR = nuclear magnetic resonance NOESY = nuclear overhauser effect spectroscopy NOE = nuclear overhauser effect nor-AZADO = 9-azanoradamantane N-oxyl Nu = nucleophile O = oxidation OAc = acetate PBPB = pyridinium bromide perbromide Petrol = petroleum spirits Ph = phenyl PMB = para-methoxybenzyl ppm = parts per million p-TSA = para-toluenesulfonic acid pyr = pyridine q = quartet quant. = quantitative

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Red = reduction Rf = retardation factor RNA = ribonucleic acid rt = room temperature s = singlet

SN2 = bimolecular nucleophilic substitution

SN2’ = bimolecular nucleophilic conjugate substitution

SNAr = nucleophilic aromatic substitution SPhos = 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl Su = succinimide t = triplet TBAF = tetra-n-butylammonium fluoride tBuXPhos = 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl TBS = tert-butyl(dimethyl)silyl Teoc = 2-(trimethylsilyl)ethoxycarbonyl Tf = triflate (trifluoromethanesulfonate) TFA = trifluoroacetic acid TFAA = trifluoroacetic anhydride THF = tetrahydrofuran THP = tetrahydropyranyl TIPS = triisopropyl silyl TMS = trimethylsilyl TMSE = trimethylsilyl ethyl Tol = para-toluene Tr = trityl (triphenylmethyl) Ts = para-toluenesulfonate TS = transition state UHP = urea hydrogen peroxide

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Chapter 1 Introduction

1. Introduction

1.1 Structure and activity of epipolythiodioxopiperazines (ETPs)

Fungal secondary metabolites have been utilised as pharmaceutical agents for the treatment of a number of diseases, with notable examples being the statins and penicillin.1 In addition to their potent bioactivity, many natural products possess intriguing structural elements, which has captured the interest of synthetic organic chemists. An interesting family of fungal secondary metabolites are the epipolythiodioxopiperazines (ETPs) (Figure 1.1).2

Figure 1.1 Generic structure of ETPs (1), structure of gliotoxin (2) and acetylaranotin (3).2–4

ETPs (1) possess a sulfide bridged diketopiperazine (DKP) and other common structural features of ETPs include a tricyclic core as seen in gliotoxin (2), or a pentacyclic core with C2 symmetry with respect to the DKP as found in acetylaranotin (3).4 Gliotoxin (2) was the first ETP discovered and was isolated in 1936 from a Trichoderma fungus culture,5 its structure later confirmed in 1958.3 Gliotoxin (2) exhibits anti-viral,6 antitumour,7,8 and antifibrogenesis activity.9–11 A number of studies have shown that the sulfide bridge is integral to the bioactivity of ETPs, including gliotoxin (2).3,12 This unique ETP bioactivity is believed to be due to conjugation to proteins with thiol residues, generation of reactive oxygen species, and chelation to transition metals.2,13

1.2 Structure and activity of emestrin (4) and related compounds

A di(tetra)hydrooxepino[4,3-b]pyrrole ring system is often part of the tricyclic or pentacyclic core of ETP natural products. The emestrins are notable of this family of natural products with examples such as emestrin (4),14 aurantioemestrin (5),15 dethiosecoemestrin (6),16 and MPC1001 (7)17,18 (Figure 1.2).

Chapter 1 Introduction

Figure 1.2 Emestrin (4), aurantioemestrin (5), dethiosecoemestrin (6), MPC1001 (7) and its related compounds (8, 9, 10).14–18

Emestrin (4), aurantioemestrin (5) and dethiosecoemestrin (6) were first isolated from Emericella striata in 1986,14–16 whilst MPC1001 (7) and its analogues were isolated from Cladorrhinum sp. KY4922 in 2004.17,18 The emestrins share a common tricyclic di(tetra)hydrooxepino[4,3-b]pyrrole ring system fused to a di- or tri-ketopiperazine. An ester linked biaryl ether is also present which is derived from the biaryl ether natural product violaceic acid (11), isolated from Emericella violacea.16,19 The tetrahydrooxepino[4,3-b]pyrrole natural product Emestrin (4) contains a 15-membered macrocycle, whilst 5 and 6 do not and the tricyclic core of these compounds is a dihydrooxepino[4,3-b]pyrrole which lacks a disulfide bridge. MPC1001 (7) and its analogues differ mostly by the presence of hydroxyl substituents on the pyrrolidine and the 15-membered macrocycle. It is obvious that 5 and 6 are degradation products of emestrin (4) probably derived from a retro-aldol process followed by reductive desulfurization (Scheme 1.1).16

Chapter 1 Introduction

Scheme 1.1 Degradation pathway to violaceic acid (11) from emestrin (4).

Emestrin (4) displays antifungal activity against Giberella zeae and Penicillum expansum with minimum inhibitory concentration (MIC) values of 10 and 2.5 µg/mL respectively.14 Dethiosecoemestrin (5) also displays antibacterial activity against E. coli (10 µg/disc) while 4, 5 and MPC1001 (7) all display antibacterial activity against B. subtilus (2.5, 10 and 2.6 µg/disc

16 respectively). Emestrin (4) is toxic to mice with an LD50 value of 13.0 mg/kg, targeting the heart, liver and thymus20 and also inhibits ATP synthesis in mitochondria, resulting in inhibition of respiration via an uncoupling effect on oxidative phosphorylation.21 4 has also exhibited cytotoxicity towards HL-60 human promyelotic leukemia cells with an IC50 of 0.05 µg/mL, while causing DNA fragmentation at 0.1 µg/mL.22 7 showed remarkable antiproliferative activity towards human prostate cancer cell lines with an IC50 = 9.3 nM which is more than double the potency of clinical chemotherapeutic agents doxorubicin and mitomycin C.17

Herath et al.23 investigated the CCR2 (C-C chemokine receptor type 2) receptor antagonistic effect of several emestrin-type natural products. CCR2 antagonists show promise for the treatment of inflammatory diseases such as rheumatoid arthritis, multiple sclerosis and atherosclerosis.23 Emestrin natural products were shown to inhibit binding of MCP-1 to CCR2. MCP-1 is a C-C chemokine (chemotaxic cytokine) monocyte chemoattractant protein (MCP) which binds to the CCR2 receptors of monocytes, dendritic cells, natural killer cells and memory T cells, causing an immune response.24,25 C-C chemokines have two adjacent cysteines near their amino terminus,26 and ETP natural products have been shown to be active against

2,13 proteins with thiol residues. Emestrin (4), MPC1001 (7) and MPC1001D (10) exhibited IC50 values of 0.84, 0.82 and 0.78 µM against membrane Chinese hamster ovary cell line CCR2 respectively, and an IC50 of 5.4, 4.1 and 4.2 µM against whole cell human monocyte cell line CCR2 respectively.23 This study suggested that emestrins lacking the macrocyle or polysulfide bridge were significantly less active, while presence of a phenol or a methyl ether group on the biaryl ether made little difference.23 A number of synthetic CCR2 receptor antagonists have

Chapter 1 Introduction been described,25 however emestrin type compounds are the first natural products shown to exhibit CCR2 receptor antagonism.

1.3 Structure and activity of aranotin (12) and related compounds

In 1968, a class of ETPs were isolated from the Arachniotus aureus fungus, with the first example being aranotin (12) (Figure 1.3).27–29 These compounds are structurally related to the emestrins as they also possess a disulfide-bridged DKP linked to a tetrahydrooxepino[4,3- b]pyrrole tricyclic system but lack the violaceic acid (11) derived biaryl ether moiety. Interestingly acetylaranotin (3) and BDA (13) both contain C2 symmetry.27,28

Figure 1.3 Aranotin (12) and related compounds isolated from Arachniotus aureus.27–29

Acetylaranotin (3) has been shown to exhibit both antifungal activity against C. albicans, C. neoformans, M. canis, M. gypseum, T. tonsurans, T. robrum and antiviral activity against Coxsackie A-21 viral RNA polymerase at concentrations of 10 µg/mL,30 and has also been shown to inhibit viral RNA synthesis at concentrations below which affect normal cellular RNA synthesis.31 The related compound bisdethio-di(methylthio)-acetylaranotin (BDA) (13), which lacks the disulfide bridge exhibited no effect on viral RNA synthesis.31 13 has significantly lower antiviral activity than aranotin (12), acetylaranotin (3) and apoaranotin (14), which all inhibited poliovirus at concentrations of 1 µg/mL or less.27 Acetylaranotin (3) and BDA (13) have been shown to inhibit plant growth via a reduction in root elongation, with 3 being approximately 20 times more potent than 13. This suggests that the disulfide bridge is critical for ETP activity. Acetylaranotin (3) and acetylapoaranotin (15) also had an apoptosis-inducing

29 effect on colon cancer cell lines with IC50 values of 21.2 µM and 2 µM respectively.

1.4 Biosynthesis of acetylaranotin (3)

In 2013 Guo et al. elucidated the biosynthetic pathway for the key fungal metabolite acetylaranotin (3).33 Following work conducted by Boente et al34 and expanding on their comprehensive review of the biosynthetic routes to Aspergillus terreus secondary metabolites,35

Chapter 1 Introduction they were able to identify genes associated with production of 3, increase production of the compound, and perform genome-based deletion analyses to determine its origin (Scheme 1.2).

Scheme 1.2 Biosynthetic pathway leading to acetylaranotin (3).

Acetylaranotin (3) is derived from the amino acid phenylalanine (16)33 and the diketopiperazine ring (17) is formed by dimerisation of phenylalanine (16) catalysed by the non-ribosomal peptide synthase derived from the AtaP gene cluster. The diketopiperazine is oxidised to the diol 18 by a P450 monooxygenase derived from the AtaTC genome cluster. The sulfur atoms are introduced by the cysteine-containing tripeptide glutathione (GSH) mediated by the GSH S- transferase derived from the AtaIMG genome cluster. This could involve an N-acyl imine intermediate which undergoes nucleophilic attack from GSH.36 The glutamine and glycine residues are cleaved by a dipeptidase derived from the AtaJ genome cluster, and the dithiol 19 is revealed by peptide cleavage mediated by the C-S lyase derived from the AtaIMG genome cluster. Sulfhydryl oxidase (derived from the AtaTC genome cluster) mediated oxidation of the dithiol to the disulfide 20 then occurs. Oxidation by a cytochrome P450 monooxygenase derived from the AtaF gene cluster forms the benzene epoxide 21. Concomitant nucleophilic attack by the nitrogen of the diketopiperazine forms the pyrrolidine 22. Acetylation by an acetyltransferase derived from AtaH yields 23 and stepwise oxygen insertion effected by a

Chapter 1 Introduction benzoate p-hydroxylase derived from the AtaY gene cluster first affords the asymmetrical natural product acetylapoaranotin (15). The mechanism for this oxidation is yet to be confirmed,35 but is thought to occur via a Criegee-type mechanism.37,38 Oxidation of the cyclohexadiene 15 via the same benzoate p-hydroxylase gives the symmetrical natural product acetylaranotin (3).33

1.5 Structure and activity of emethallicin A (24) and related compounds

Figure 1.4 Structures of emethallicins A-D (24, 25, 26, 27).39–41

Another class of tetrahydrooxepino[4,3-b]pyrrole ETP containing natural products are the emethallicins which were first isolated from Emericella heterothallica.39–41 The emethallicins contain a pentacyclic core with a polythiodiketopiperazine. In the case of emethallicins A (24), B (25) and D (26) there is a tetrahydrooxepino[4,3-b]pyrrole present along with a pyrrolidine fused to a cyclohexadiene, both with different benzyl ester sidechains. Emethallicin C (27) is a C2 symmetric molecule with two tetrahydrooxepino[4,3-b]pyrrole systems.40 24, 25, and 26 were found to be potent antihistamines with IC50 values of 30 nM, 80 nM and 1.0 µM respectively.40 ETPs closely related to the emethallicins (lacking the dihydrooxepine ring) have also shown anti-viral and anti-malarial activity.42

Chapter 1 Introduction

1.6 Previous syntheses of dihydrooxepine containing ETPs

1.6.1 Clive and Peng’s asymmetric synthesis of the tricyclic core of the emestrins

Their structural complexity and unique biological profiles make the ETPs intriguing targets for total synthesis. In addition, their paucity in nature means that the production of multigram quantities of these natural products and their derivatives can only be accomplished through total synthesis.

Scheme 1.3 Clive and Peng’s synthesis of intermediate 33.

Clive and Peng reported a synthesis of the dihydrooxepino[4,3-b]pyrrole ring system of the emestrin-type natural products.43 This was later modified to incorporate the diketopiperazine ring system to afford an asymmetric synthesis of this fragment (Scheme 1.3).44 Stereochemical inversion of trans-4-hydroxy-L-proline (28) followed by formation of the hydrochloride salt gives 29, which then undergoes esterification to give 30. Acylation of the nitrogen then occurs after exposure to the acid chloride 31 (derived from N-methylglycine) to give the amide 32. Swern oxidation is then utilised to give the pyrollidinone 33 which is utilised further in Scheme 1.4.

Chapter 1 Introduction

Scheme 1.4 Synthesis of diketopiperazine fragment 37.

Pyrollidinone 33 is protected as the dimethyl ketal 34 before the methyl ester is reduced to the alcohol by action of CaCl2 and NaBH4. Hydrolysis then gives the pyrolidinone 35, which upon protection of the hydroxy group with a bulky silyl ether gives 36. Base-induced cyclisation then gives the diketopiperazine 37 in good yield as a tautomeric mixture.

Scheme 1.5 Synthesis of key fragment 45.

The bulky silyl ether protecting group of 37 directs the sulfenylation to give the trimethylsilyl ethyl (TMSE) sulfide 39 as a single diastereoisomer (Scheme 1.5). Reduction of the pyrollidinone with NaBH4 gave alcohol 40 which was protected as the tetrahydropyranyl (THP) ether, and the silyl ether was cleaved using TBAF to give alcohol 41. Swern oxidation furnished the aldehyde 42 which was epimerised to the desired isomer 43, likely under thermodynamic control, by treatment with DBU. Addition of (ethoxyvinyl)zinc (44) to the aldehyde then gave

Chapter 1 Introduction enol ether 45 as a mixture of diastereoisomeric alcohols which were utilised further in Scheme 1.6.

Scheme 1.6 Asymmetric synthesis of the tricyclic core of the emestrins (53).

The alcohol 45 was protected as the MEM ether 46, which upon exposure to PhSeCl gave the phenylselenylaldehyde 47 which was reduced using Zn(BH4)2 and the THP protecting group removed under acidic conditions to give diol 48. The alcohol was protected as a t- butyldimethylsilyl ether (49) and oxidation to the pyrolidinone followed by deprotection gave 50. Condensation with dimethylformamide dimethyl acetal gave 51 in a low 15% yield (70% based on recovered starting material). TFA-mediated conjugate addition and elimination followed by selenoxide elimination furnishes the tricyclic core of the emestrin-type natural products (53).44 This synthesis of the dihydrooxopine core of the emetrin natural products is lengthy (26 steps, 0.07%) and is yet to be utilised in a total synthesis.

Chapter 1 Introduction

1.6.2 Reisman and coworkers’ total synthesis of acetylaranotin (3)

Thus far, two total syntheses of acetylaranotin (3)45,46 have been reported as well as one of MPC1001B (8)47 and one of acetylapoaranotin (15).48 The first total synthesis of acetylaranotin (3) was reported by Reisman and coworkers and is shown in Scheme 1.7.46

Scheme 1.7 Reisman and coworkers’ total synthesis of key acetylaranotin intermediate 63.

Cinnamaldimine 54 was prepared from ethyl glycinate and cinnamaldehyde46 and exposed to t- butyl acrylate (55) in the presence of copper (I) iodide and the chiral ligand brucin-OL49 to give the endo-pyrrolidine via catalytic asymmetric (1,3)-dipolar cycloaddition. Cleavage of the t- butyl ester gave the TFA salt 56 which was enantioenriched to >98% after recrystallisation. The amine was protected as a trimethylsilylethyl carbamate (Teoc) with Teoc oxy-succinimide (Teoc-OSu) and ozonolysis of the alkene gave the lactol 57 in 77% yield over two steps. The lactol 57 was treated with ethynylmagnesium bromide (58) to yield the alkyne and in situ

Mitsonobu lactonization afforded the desired diastereisomer 59 in 76% yield. NaBH4 reduction gave the diol 60 which was subsequently silylated and the primary silyl ether selectively

Chapter 1 Introduction deprotected to give the alkynol intermediate 61. Oxidation with Dess-Martin periodinane (DMP) followed by NCS-mediated chlorination gave an α-chloroaldehyde which was reduced in situ with NaBH4 to 62. Cycloisomerisation mediated by a rhodium catalyst formed the chlorotetrahydrooxepine 63 in excellent yield.

Scheme 1.8 Synthesis of acetylaronotin (3).

Attempts to dimerise two identical monomers to give the dimeric structure of acetylaranotin were unsuccessful. Key intermediate 63 was instead used to produce two dihydrooxepine fragments (64, 66) which were coupled to give the basic dimeric structure (67) of acetylaranotin (Scheme 1.8). Exposure of 63 to TBAF gave the free amine, and base-induced elimination then gave dihydrooxepine 64. The same elimination was used to produce dihydrooxepine 65 which underwent hydrolysis to give the free acid 66. These products were then coupled using BOP-Cl mediated peptide coupling conditions to give 67 in good yield. Global deprotection and intramolecular cyclisation of 67 affords the C2-symmetric DKP 68. The tetrasulfide was then obtained via sequential exposure of 68 to NaHMDS and S8, giving the correct C-S bond stereochemistry as confirmed by X-ray crystallography. 68 was subsequently acetylated and

Chapter 1 Introduction exposed to mild reducing conditions to give acetylaranotin 3 (Scheme 1.8) in a total of 19 linear steps and 0.19% overall yield.46

1.6.3 Reisman and coworkers’ total synthesis of acetylapoaranotin (15)

Reisman and co-workers reported a similar synthetic approach for the synthesis of acetylapoaranotin (15),48 utilising the key intermediate 64 as well as the previously developed dipolar cycloaddition (Scheme 1.7), TBAF induced macrocycle ring closure and sulfenylation chemistry.46 The synthesis begins with formation of cyclohexadiene fragment 78 (Scheme 1.9).

Scheme 1.9 Synthesis of cyclohexadiene intermediate 78.

A Cu(I)/brucin-OL-catalysed dipolar cycloaddition between imine 54 and Weinreb amide 7046 gave pyrollidine 71. This was protected as the trimethylsilyl ethyl carbamate and exposed to chemoselective 1,2-addition of ethyl magnesium chloride to give 73. Ring-closing metathesis using second generation Hoveyda-Grubbs catalyst50 (HG-II) yielded the β,γ-unsaturated cyclohexenone 74 in good yield. Epoxidation with dimethyl dioxirane (75) (DMDO) followed by silica gel-induced ring cleavage formed the γ-hydroxy enone 76 as an inseparable mixture of diastereomers. This was protected as the TBS ether (77) and converted to the enol triflate, which was reduced via action of formic acid and palladium catalysis to yield the cyclohexadienol 78 in 8 steps.

Chapter 1 Introduction

Scheme 1.10 Synthesis of (-)-acetylapoaranotin (15) from cyclohexadiene 78 and tetrahydrooxepino[4,3-b]pyrrole 64.

The ethyl ester of cyclohexadiene 78 was saponified to the acid 79, which was coupled with the tetrahydrooxepino[4,3-b]pyrrole 64 to yield 80. Treatment with TBAF resulted in global desilylation and DKP formation to give the pentacycle 81. A similar protocol to that shown in Scheme 1.8 was employed to install the disulfide bridge,46 yielding (-)-acetyapoaranotin (15) in 14 steps and 0.17% overall yield.48

1.6.4 Tokuyama and coworkers’ total synthesis of acetylaranotin

Tokuyama and coworkers were also able to complete a total synthesis of 3 utilising carboxybenzyl (Cbz) protected tyrosine 82 as the starting material (Scheme 1.11).45

Chapter 1 Introduction

Scheme 1.11 Tokuyama and coworkers’ synthesis of key intermediate 92.

The protected tyrosine 82 was converted into the α,β-unsaturated ketone 83 via a previously

51–53 published oxidative cyclisation method using PhI(OAc)2. 83 is then converted to the mesylate and eliminated to give the β,γ-unsaturated ketone 84.51 The double bond was isomerised via the action of catalytic DBU, and the product subsequently epoxidised with hydrogen peroxide to give the α,β-epoxyketone 85 in excellent yield. Wharton rearrangement and Dess-Martin oxidation furnished the α,β-unsaturated ketone 86. This was converted to the dienol silyl ether 87 via action of TMSOTf and Hünig’s base. Subjection to Rubottom oxidation was shown to oxidise the β,γ double bond exclusively and upon exposure to acidic silica gel during workup gave the γ-hydroxyenone 89 as the sole product. The γ-hydroxyenone 89 was protected as the TBS ether and then subjected to a Bayer-Villiger oxidation using trifluoroacetic anhydride and urea hydrogen peroxide.54,55 This gave the lactone 91 in reasonable yield, with migration of the sp2 hybridised carbon over the more substituted sp3 carbon.45 Conversion of 91 to the enol triflate and palladium-catalysed reduction formed the dihydrooxepine 92 in 72% yield over two steps. This key intermediate was then used to form the pentacyclic core of acetylaranotin (Scheme 1.12).

Chapter 1 Introduction

Scheme 1.12 Tokuyama and coworkers’ synthesis of acetylaranotin (3).

Palladium-catalysed transfer hydrogenolysis conducted on oxepine 92 removed the Cbz protecting group to give the free amine 93. The same intermediate was also hydrolysed with KOH to give the acid 94 and coupling then furnished the amide 95 in good yield. To complete the synthesis, the DKP ring was formed via deprotection of the Cbz-carbamate to the amine which underwent spontaneous base-catalysed ring closure. The two TBS groups were then deprotected to give the diol 96 and hydroxyl stereocentres were inverted via oxidation/reduction sequence to give diol 68. The disulfide bridge was installed using the same method described by Reisman et al46 (Scheme 1.8) to yield acetylaranotin (3) in 0.13% yield over 22 total steps.45

Chapter 1 Introduction

1.6.5 Tokuyama and coworkers total synthesis of MPC1001B (8)

Tokuyama and coworkers reported the total synthesis MPC1001B (8) starting from the dihydrooxepine intermediate 94 utilised in the acetylaranotin synthesis (Scheme 1.13).47

Scheme 1.13 Tokuyama and coworkers’ synthesis of 15-membered macrocycle 102 from a common intermediate (94).

Dihydrooxepine 94 was converted into the diketopiperazine 99 by coupling with sarcosine methyl ester HCl (98) followed by removal of the Cbz protecting group and TBAF treatment to promote cyclisation. Oxidation and Luche reduction inverted the hydroxy-carbon stereocentre which was then coupled to the biaryl ether acid 100 using EDCI. The key step of this sequence was the intramolecular aldol reaction of 101 using TBAF as a mild base to form the 15- membered macrocycle 102, the structure of which was confirmed by single crystal X-ray crystallography. The resulting alcohol 102 possessed the incorrect stereochemistry which had to be inverted (Scheme 1.14).

Chapter 1 Introduction

Scheme 1.14 Tokuyama et al. final steps in the total synthesis of MPC1001B (8).

Conditions described by Nicolaou56 were used in an attempt to introduce sulfur however this resulted in retro-aldol opening of the macrocycle. Thus, alcohol 102 was oxidised to the ketone 103 to thwart this base-induced degradation pathway. Deprotonation and sulfenylation then proceeded smoothly by treatment with LiHMDS and 1-chloro-3-trityltrisulfane to give 104.57 The ketone was then reduced to the alcohol possessing the required configuration. Sodium 2- mercaptoethanesulfonate (106, MESNa) removed the trityl groups to give the corresponding dithiol. Subsequent treatment with oxygen formed the disulfide bridge and gave the natural product target 8 (26 steps overall, 0.4% yield).47

1.7 Biaryl ether synthesis and background

A key fragment present in the emestrin type natural products is the biaryl ether. In 1982, Yamazaki and Maebayashi isolated the non-toxic biaryl ether violaceic acid 11 from Emericella violacea and proposed the structures 107 and 108 as shown in Scheme 1.15.19 Seya et al. obtained violaceic acid (11) from the acidic culture filtrate of Emericella striata, and also showed that the natural product dethiosecoemestrin (6) slowly degraded to violaceic acid in an organic solvent such as methanol.16 11 is also formed by reduction, ozonolysis and hydrolysis of triacetate 110 obtained via acetylation of emestrin (4).14 Biaryl ether 11 has the same 13C NMR chemical shifts to that of the material isolated by Yamazaki and Maebayashi.14,19 The alternative

Chapter 1 Introduction structure 11 was therefore proposed for violaceic acid which was the same biaryl ether obtained by hydrolysis of the ester present in dethiosecoemestrin (Scheme 1.15).16

Scheme 1.15 Proposed structures of violaceic acid (107, 108, 11) and degradation to 11 from emestrin (4) and dethiosecoemestrin (6).14,19

The revised structure was also confirmed by NOESY analysis of dimethoxy violaceic acid 100 and acetylviolaceic acid 112 which were prepared from violaceic acid (11) (Scheme 1.16).14 The methoxy protons of dimethoxyviolaceic acid (100) both showed an NOE to an aromatic proton with doublet splitting (J = 8.4 Hz), which indicates the methyl ethers are ortho to this proton and therefore both para to an aldehyde or carboxylic acid. The methoxy protons of acetylviolaceic acid (112) showed an NOE to a vicinal aromatic proton with doublet splitting (J = 8.8 Hz), and when this proton was selectively irradiated, the 13C signal assigned to the carbon

Chapter 1 Introduction bearing the acid broadened, indicating the acid was para to this methoxy group, not the acetoxy group.14 Thus, originally proposed structure for violaceic acid was revised to 11.14

Scheme 1.16 Synthesis of dimethoxy violaceic acid (100) and acetylviolaceic acid (112) from violaceic acid (11).14

In 2017, Koide et al. published the first total synthesis of violaceic acid which served to confirm the structure of the natural product as 11 (Scheme 1.17).14,19,58 This began with NBS mediated bromination of 113 to give the bromide 114. Hydrolysis, diazotization and treatment with pyrrolidine afforded the triazine 116. An Ullman-type coupling with the phenol 117 then gave the biaryl ether 118 in good yield. Iodination59 followed by Pd catalysed hydroxylation58,60 yielded violaceic acid (11) in a 36% overall yield.

Scheme 1.17 Koide and coworkers’ total synthesis of violaceic acid (11).

Chapter 1 Introduction

1.8 Bibliography

(1) Keller, N. P.; Turner, G.; Bennett, J. W. Nat. Rev. Microbiol. 2005, 3 (12), 937–947. (2) Gardiner, D. M.; Waring, P.; Howlett, B. J. Microbiology 2005, 151, 1021–1032. (3) Bell, M. R.; Johnson, J. R.; Wildi, B. S.; Woodward, R. B. J. Am. Chem. Soc. 1958, 80 (4), 1001. (4) Nagarajan, R.; Huckstep, L. L.; Lively, D. H.; DeLong, D. C.; Marsh, M. M.; Neuss, N. J. Am. Chem. Soc. 1968, 90 (11), 2980–2982. (5) Weindling, R.; Emerson, O. H. Phytopathology 1936, 26, 1068–1070. (6) Trown, P. W.; Bilello, J. A. Antimicrob. Agents Chemother. 1972, 2 (4), 261–266. (7) Vigushin, D. M.; Mirsaidi, N.; Brooke, G.; Sun, C.; Pace, P.; Inman, L.; Moody, C. J.; Coombes, R. C. Med. Oncol. 2004, 21 (1), 21–30. (8) Van Der Pyl, D.; Yang, H.; Inokoshi, J.; Shiomi, K.; Takeshima, H.; Omura, S. J. Antibiot. (Tokyo). 1992, 45, 1802–1805. (9) Orr, J. G.; Leel, V.; Cameron, G. A.; Marek, C. J.; Haughton, E. L.; Elrick, L. J.; Trim, J. E.; Hawksworth, G. M.; Halestrap, A. P.; Wright, M. C. Hepatology 2004, 40 (1), 232– 242. (10) Dekel, R.; Zvibel, I.; Brill, S.; Brazovsky, E.; Halpern, Z.; Oren, R. Dig. Dis. Sci. 2003, 48 (8), 1642–1647. (11) Wright, M. C.; Issa, R.; Smart, D. E.; Trim, N.; Murray, G. I.; Primrose, J. N.; Arthur, M. J. P.; Iredale, J. P.; Mann, D. A. Gastroenterology 2001, 121 (3), 685–698. (12) Mullbacher, A.; Waring, P.; Tiwari-Palni, U.; Eichner, R. D. Mol. Immunol. 1986, 23 (2), 231–235. (13) Iwasa, E.; Hamashima, Y.; Sodeoka, M. Isr. J. Chem. 2011, 51 (3–4), 420–433. (14) Seya, H.; Nozawa, K.; Nakajima, S.; Ken-ichi, K.; Shun-ichi, U. J. Chem. Soc., Perkin Trans. 1 1986, 67 (5), 109–116. (15) Kawahara, N.; Nozawa, K.; Nakajima, S.; Kawai, K. J. Chem. Soc., Chem. Commun. 1986, 1495–1496. (16) Seya, H.; Nozawa, K.; Udagawa, S.; Nakajima, S.; Kawai, K. Chem. Pharm. Bull. 1986, 34 (6), 2411–2416. (17) Tsumagari, N.; Nakai, R.; Onodera, H.; Hasegawa, A.; Rayahu, E. S.; Ando, K.; Yamashita, Y. J. Antibiot. (Tokyo). 2004, 57 (8), 532–534. (18) Onodera, H.; Hasegawa, A.; Tsumagari, N.; Nakai, R. Org. Lett. 2004, 6 (22), 4101– 4104. (19) Yamazaki, M.; Maebayashi, Y. Chem. Pharm. Bull. 1982, 30 (2), 509–513. (20) Terao, K.; Ito, E.; Kawai, K. ichi; Nozawa, K.; Udagawa, S. Mycopathologia 1990, 112 (2), 71–79.

Chapter 1 Introduction

(21) Ishizaki, K.; Kawai, K.; Nakamura, T.; Hisada, K.; Nozawa, Y.; Kawai, K. Proc. Jpn. Assoc. Mycotoxicol. 1988, 28, 29–32. (22) Ueno, Y.; Umemori, K.; Niimi, E. ‐C; Tanuma, S. ‐I; Nagata, S.; Sugamata, M.; Ihara, T.; Sekijima, M.; Kawai, K. ‐I; Ueno, I.; et al. Nat. Toxins 1995, 3 (3), 129–137. (23) Herath, K. B.; Jayasuriya, H.; Ondeyka, J. G.; Polishook, J. D.; Bills, G. F.; Dombrowski, A. W.; Cabello, A.; Vicario, P. P.; Zweerink, H.; Guan, Z.; et al. J. Antibiot. (Tokyo). 2005, 58 (11), 686–694. (24) Conrad, S. M.; Strauss-Ayali, D.; Field, A. E.; Mack, M.; Mosser, D. M. Infect. Immun. 2007, 75 (2), 653–665. (25) Xia, M.; Sui, Z. Expert Opin. Ther. Pat. 2009, 19 (3), 295–303. (26) Laing, K. J.; Secombes, C. J. Dev. Comp. Immunol. 2004, 28 (5), 443–460. (27) Neuss, N.; Boeck, L. D.; Brannon, D. R.; Cline, J. C.; DeLong, D. C.; Gorman, M.; Huckstep, L. L.; Lively, D. H.; Mabe, J.; Marsh, M. M.; et al. Antimicrob. Agents Chemother. 1968, 8, 213–219. (28) Neuss, N.; Nagarajan, R.; Molloy, B. B.; Huckstep, L. L. Tetrahedron Lett. 1968, 9, 4467–4471. (29) Choi, E. J.; Park, J. S.; Kim, Y. J.; Jung, J. H.; Lee, J. K.; Kwon, H. C.; Yang, H. O. J. Appl. Microbiol. 2011, 110 (1), 304–313. (30) Murdock, K. C. J. Med. Chem. 1974, 17 (8), 827–835. (31) Miller, P. A.; Trown, P. W.; Fulmor, W. Biochem. Biophys. Res. Commun. 1968, 33 (2), 219–221. (32) Kamata, S.; Sakai, H.; Hirota, A. Agric. Biol. Chem. 1983, 47 (11), 2637–2638. (33) Guo, C.-J.; Yeh, H.-H.; Chiang, Y.-M.; Sanchez, J. F.; Chang, S.-L.; Bruno, K. S.; Wang, C. C. C. J. Am. Chem. Soc. 2013, 135 (19), 7205–7213. (34) Boente, M. I. P.; Kirby, G. W.; Robins, D. J. Chem. Commun. 1981, 1981 (12), 619–621. (35) Guo, C.-J.; Wang, C. C. C. Front. Microbiol. 2014, 5 (December), 717. (36) Kim, J.; Movassaghi, M. J. Am. Chem. Soc. 2010, 132 (41), 14376–14378. (37) Goodman, R. M.; Kishi, Y. J. Am. Chem. Soc. 1998, 120 (36), 9392–9393. (38) Goodman, R. M.; Kishi, Y. J. Org. Chem. 1994, 59 (18), 5125–5127. (39) Murakami, Y.; Ishii, H. Chem. Pharm. Bull. 1989, 37 (10), 2592–2595. (40) Kawahara, N.; Nozawa, K.; Yamazaki, M.; Nakajima, S.; Kawai, K. Chem. Pharm. Bull. 1990, 38 (1), 73–78. (41) Kawahara, N.; Nozawa, K.; Nakajima, S.; Kawai, K.; Yamazaki, M. J. Chem. Soc., Chem. Commun. 1989, 0, 951–952. (42) Nicolaou, K. C.; Lu, M.; Totokotsopoulos, S.; Heretsch, P.; Giguère, D.; Sun, Y. P.; Sarlah, D.; Nguyen, T. H.; Wolf, I. C.; Smee, D. F.; et al. J. Am. Chem. Soc. 2012, 134 (41), 17320–17332.

Chapter 1 Introduction

(43) Peng, J.; Clive, D. L. J. Org. Lett. 2007, 9 (15), 2939–2941. (44) Peng, J.; Clive, D. L. J. J. Org. Chem. 2009, 74, 513–519. (45) Fujiwara, H.; Kurogi, T.; Okaya, S.; Okano, K.; Tokuyama, H. Angew. Chemie 2012, 51 (52), 13062–13065. (46) Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2012, 134 (4), 1930–1933. (47) Kurogi, T.; Okaya, S.; Fujiwara, H.; Okano, K.; Tokuyama, H. Angew. Chem. Int. Ed. Engl. 2016, 55 (1), 283–287. (48) Wang, H.; Regan, C. J.; Codelli, J. A.; Romanato, P.; Puchlopek-Dermenci, A. L. A.; Reisman, S. E. Org. Lett. 2017, 19 (7), 1698–1701. (49) Kim, H. Y.; Shih, H. J.; Knabe, W. E.; Oh, K. Angew. Chemie - Int. Ed. 2009, 48 (40), 7420–7423. (50) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122 (34), 8168–8179. (51) Wipf, P.; Methot, J. L. Org. Lett. 2000, 2 (26), 4213–4216. (52) Wipf, P.; Kim, Y. Tetrahedron Lett. 1992, 33 (38), 5477–5480. (53) Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117 (45), 11106–11112. (54) Heaney, H. Top. Curr. Chem. 1993, 164, 1. (55) Newbold, A. Some Oxidation Reactions Utilizing Hydrogen Peroxide Adducts in Combination with Carboxylic Anhydrides, 1991. (56) Nicolaou, K. C.; Totokotsopoulos, S.; Giguère, D.; Sun, Y. P.; Sarlah, D. J. Am. Chem. Soc. 2011, 133 (21), 8150–8153. (57) Williams, C. R.; Britten, J. F.; Harpp, D. N. J. Org. Chem. 1994, 59 (4), 806–812. (58) Ando, S.; Burrows, J.; Koide, K. Org. Lett. 2017, 19 (5), 1116–1119. (59) Wu, Z.; Moore, J. S. Tetrahedron Lett. 1994, 35 (31), 5539–5542. (60) Vorogushin, A. V.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127 (22), 8146–8149.

Chapter 1 Introduction

Chapter 2 Retrosynthesis and reaction background

2. Retrosynthesis and reaction background

2.1 Retrosynthetic analysis of emestrin-type natural products

The focus of this project was to develop a novel approach to members of the ETP family of natural products containing the oxepino[4,3-b]pyrrole moiety. The primary targets are the emestrin family of natural products, but also includes natural products related to aranotin (12) and the emethallicins. One disadvantage of the previous syntheses of members of the ETP family of natural products is the numerous steps involving protecting group and redox manipulations,1 resulting in poor overall yields. Thus, preparation of adequate quantities of material for biological testing via these routes is not feasible. We envisioned a short, divergent approach to the entire emestrin family via a novel synthetic sequence (Scheme 2.1).

Scheme 2.1 Retrosynthetic analysis of emestrin (4), auriantioemestrin (5) and dethiosecoemestrin (6).

Chapter 2 Retrosynthesis and reaction background

Retrosynthetic analysis of 5 and 6 begins with the disconnection of the ester linkage between the tricyclic component and the biaryl ether (Scheme 2.1), which gives the retrons dihydrooxepino[4,3-b]pyrrole 121 fragment and violaceic acid 11. Key intermediate dihydrooxepine 121 could also be reduced and undergo an intramolecular aldol condensation to yield saturated pyrrolidine emestrins such as 4 (Scheme 2.1).2

Scheme 2.2 Retrosynthetic analysis of dihydrooxepine 121.

The dihydrooxepino[4,3-b]pyrrole 121 could be accessed via a [3,3] Cope rearrangement3 from vinyl pyrrole epoxide 125,4 which in turn could be synthesised from pyrrole aldehyde 126 by a vinylogous Darzens condensation.5,6 Alternatively, vinyl pyrrole epoxide 127 could be synthesised by a Wittig extension7 of aldehyde 128 which in turn could be obtained by oxidation of allylic alcohol 129. Allylic alcohol 129 is accessible by reduction of alkyne 130 which in turn could be synthesised via a Sonogashira coupling reaction with a halogenated pyrrole 131.8 Compared to the reported approaches to dihydrooexpines (Scheme 2.3), this approach would allow rapid formation of the ring system moiety found in the unsaturated emestrins such as dethiosecoemestrin (6).9,10

Chapter 2 Retrosynthesis and reaction background

Scheme 2.3 Previous syntheses of the tetrahydrooxepino[4,3-b]pyrrole core.9,10

For the synthesis of a substituted system which could afford the tricyclic core of the natural product including the DKP, commercially available trichloroacetylpyrrole (132) may also be used as a starting material. Electrophilic aromatic substitution of pyrroles usually occurs at the C2 position, affording 133, due to increased resonance stabilisation of the intermediate -complex. The electron withdrawing trichloroacetyl substituent destabilises the resonance contributor TS211 thereby favouring the C4 substituted product 134, as the bulky trichloroacyl group also sterically hinders C3 substitution (Scheme 2.4).

Scheme 2.4 Resonance contributors of electrophilic aromatic substitutions of 2-substituted pyrroles.

Violaceic acid (11) could be synthesised via a Sandmeyer reaction of biaryl amine 135,12 which in turn could be formed by the chemoselective reduction of nitroarene 136.13 This biaryl ether 135 could be synthesised from two commercially available substituted benzenes via an SNAr reaction (Scheme 2.5).14

Chapter 2 Retrosynthesis and reaction background

Scheme 2.5 Retrosynthesis of violaceic acid (11).

2.2 Reaction background: Cope rearrangement

A Cope rearrangement is a [3,3]-sigmatropic rearrangement of a 1,5-diene.15 Early studies16–18 suggested that these generally occur via a 6-membered, chair-like transition state. Roth and Doering reported the stereochemical outcomes of Cope rearrangements of both meso-3,4- dimethylhexa-1,5-diene (meso-137) and racemic 3,4-dimethylhexa-1,5-diene (racemic 137) which supported the proposed chair-like transition state involved in these rearrangements (Scheme 2.6).16

Scheme 2.6 Stereochemical outcomes of Cope rearrangements of meso- and rac-3,4- dimethylhexa-1,5-diene (137) via boat or chair-like transition states.

Chapter 2 Retrosynthesis and reaction background

For the reaction to proceed via a boat-like (or “roof-like”) transition state, the racemic mixture (racemic 137) will give exclusively cis,trans-octa-2,6-diene (cis,trans-138), whilst the meso compound (meso-137) would give a mixture of both cis,cis-138 and trans,trans-138. However, if the chair-like transition state is preferred, then the stereochemical outcome will be reversed. It was found that the meso compound (meso-137) rearranged to give cis,trans-octa-2,6-diene (cis,trans-138) as the major product whilst the racemic mixture afforded trans,trans-138 as the major isomer.16 Thus, these observed stereochemical outcomes supported the chair-like transition state, with a calculated difference in transition state energy of 5.7 kcal/mol between the chair- and boat-like transition states.16 The chair-like transition state also allows for substituents to occupy the preferable pseudo-equatorial positions.19

In 1963 Braun reported the Cope rearrangement of divinylepoxide 140 (formed via hydrolysis of divinylethylenecarboxylate 139) to give dihydrooxepine 141 (Scheme 2.7).3 Cope rearrangements of divinylcyclopropanes have also been described.20 Rearrangement of divinylchlorocyclopropane 142 gave cycloheptadiene 143 and rearrangement of arylvinyl cyclopropane 144 gave cycloheptene 146 after rapid rearomatization of the initially formed cycloheptadiene 145.21 However, vinyl furan epoxide 147 undergoes Cope rearrangement to form the dihydrooxepine 148, without rearomatisation to the furan (Scheme 2.7).22,23

Scheme 2.7 Examples of Cope rearrangements.

Chapter 2 Retrosynthesis and reaction background

Trans-1,2-divinyl cyclopropanes rearrange to give 1,4-cycloheptadienes in lower yields due to the fact that these must isomerise to the cis isomer via a biradical intermediate prior to Cope rearrangement.24 Vogel and Günther described the Cope rearrangement of trans-divinyl epoxide 149 to give dihydrooxepine 141 exclusively at high temperature.25 When the same reaction was repeated at a lower temperature, the major product was instead vinyldihydrofuran 150 (Scheme 2.8). White showed that trans-divinyl epoxides 155 and 156 undergo Cope rearrangement to give dihydrooxepines in much lower yield than cis-divinyl epoxides 151 and 152 (Scheme 2.8).26 It was found that the rearrangement occurs via isomerisation to cis-divinyl epoxides 151 and 152 through carbonyl ylide intermediates 157-160 (Scheme 2.8).26

Scheme 2.8 Cope rearrangements of trans-divinylepoxides.25,26

Chapter 2 Retrosynthesis and reaction background

Scheme 2.9 Cope rearrangements of divinyl epoxides.27

While most Cope rearrangements proceed via a 6-membered chair-like transition state, divinyl epoxides must proceed via a boatlike (skew) transition state since this conformation aligns the alkene termini correctly for rearrangement (Scheme 2.9).27 White and coworkers showed that E,E divinyl epoxide 161 undergoes rapid Cope rearrangement to form cis-dihydrooxepine 162 via the boat-like transition state TS6.27 The corresponding Z,E divinyl epoxide 163 rearranges 5 times slower than 161 via TS7 to form the trans-dihydrooxepine product 164.27 This can be explained by the fact that transition state TS7 suffers from a steric interaction between the epoxide and the TMS group. For the current approach, it is postulated that [3,3] sigmatropic Cope rearrangement of vinyl pyrrole epoxide 122 (Scheme 2.6) would allow simple access to the key intermediate 165 for the total synthesis of emestrin type natural products and would be the first example of a Cope rearrangement involving the de-aromatisation of pyrrole.

Chapter 2 Retrosynthesis and reaction background

2.3 Reaction background: vinylogous Darzens reaction

Scheme 2.10 Darzens reactions for the synthesis of epoxides.

A Darzens reaction is the condensation of a carbonyl compound with the anion derived from an α-halogenated carbonyl compound or sulfone to yield an oxirane.5,28 Early examples of the reaction involved the synthesis of glycidic esters from ketones,29,30 as well as the reaction of chloroacetamides with aldehydes and ketones (Scheme 2.10).31,32 The only example of a vinylogous Darzens reaction to afford a vinyl furan epoxide was reported by Hudlicky. This involved a reaction of the enolate derived from ethyl bromocrotonate 174 with 2-furaldehyde 176, and 3-furaldehyde 178, to give epoxides 177 and 179 respectively (Scheme 2.11).22

Scheme 2.11 Synthesis of a vinyl furan epoxide via a vinylogous Darzens reaction.22

Chapter 2 Retrosynthesis and reaction background

Scheme 2.12 Mechanism of a vinylogous Darzens reaction.1

The proposed mechanism for this reaction is shown in Scheme 2.12.1 Treatment of an E/Z mixture of the ester 174 with lithium diisopropylamide affords E(O) dienolate 181 as the major isomer. This dienolate reacts with an aldehyde, presumably via the 6-membered Zimmerman-Traxler33

22,34 chair-like transition state TS9, to give an aldol adduct 182. Subsequent intramolecular SN2 reaction then forms the cis-vinylepoxide 175.22 A similar vinylogous Darzens reaction could provide a viable and efficient synthetic route to vinyl pyrrole epoxides (Scheme 2.11). If successful, this could furnish the required cis-vinyl pyrrole epoxide required for the Cope rearrangement, allowing rapid access to the dihydrooxepine core of the emestrins and related dihydrooxepine natural products.

Chapter 2 Retrosynthesis and reaction background

2.4 Bibliography

(1) Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75 (14), 4657–4673. (2) Kurogi, T.; Okaya, S.; Fujiwara, H.; Okano, K.; Tokuyama, H. Angew. Chem. Int. Ed. Engl. 2016, 55 (1), 283–287. (3) Braun, A. J. Org. Chem. 1963, 55 (Viii), 214–215. (4) Clark, D. L.; Chou, W.; White, J. B. J. Org. Chem. 1990, 55, 3975–3977. (5) Ballester, M. Chem. Rev. 1955, 55 (2), 283–300. (6) Barbieri, G.; Hudlicky, T. J. Org. Chem. 1991, 56 (15), 4598–4600. (7) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 87 (9), 1318–1330. (8) Sonogashira, K. J. Organomet. Chem. 2002, 653 (1–2), 46–49. (9) Fujiwara, H.; Kurogi, T.; Okaya, S.; Okano, K.; Tokuyama, H. Angew. Chemie 2012, 51 (52), 13062–13065. (10) Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2012, 134 (4), 1930– 1933. (11) Patterson, J. M. Synthesis (Stuttg). 1976, 1976 (5), 281–304. (12) Cohen, T.; Dietz, A. G.; Miser, J. R. J. Org. Chem. 1977, 42 (12), 2053–2058. (13) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25 (8), 839–842. (14) Bunce, R. A.; Easton, K. M. Org. Prep. Proced. Int. 2004, 36 (1), 76–81. (15) Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441–444. (16) Doering, W. E.; Roth, W. R. Tetrahedron 1962, 18, 67–74. (17) Goldstein, M. J.; Benzon, M. S. J. Am. Chem. Soc. 1972, 94 (20), 7147–7149. (18) Morokuma, K.; Borden, W. T.; Hrovat, D. A. J. Am. Chem. Soc. 1988, 110 (13), 4474– 4475. (19) Shea, K. J.; Stoddard, G. J.; England, W. P.; Haffner, C. D. J. Am. Chem. Soc. 1992, 114 (7), 2635–2643. (20) Moss, R. A.; Munjal, R. C. Synthesis (Stuttg). 1979, 6, 425–427. (21) Marvell, E. N.; Lin, C. J. Am. Chem. Soc. 1978, 100 (3), 877–883. (22) Hudlicky, T.; Fleming, A.; Lovelace, T. Tetrahedron 1989, 45 (10), 3021–3037. (23) Balaban, A. T.; Oniciu, D. C.; Katritzky, A. R. Chem. Rev. 2004, 104 (5), 2777–2812. (24) Davies, H. M. L.; McAfee, M. J.; Oldenburg, C. E. M. J. Org. Chem. 1989, 54 (4), 930– 936. (25) Vogel, E.; Günther, H. Angew. Chem. Int. Ed. Engl. 1967, 6, 385–401. (26) Chou, W.; White, J. B. Tetrahedron Lett. 1991, 32 (52), 7637–7640. (27) Chou, W. N.; White, J. B.; Smith, W. B. J. Am. Chem. Soc. 1992, 114 (12), 4658–4667. (28) Vogt, F.; Tavares, F. Can. J. Chem. 1969, 47, 2875–2881.

Chapter 2 Retrosynthesis and reaction background

(29) Johnson, W. S.; Belew, J. S.; Chinn, L. J.; Hunt, R. H. J. Am. Chem. Soc. 1953, 75 (20), 4995–5001. (30) Bachelor, F. W.; Bansal, R. K. J. Org. Chem. 1969, 34 (11), 3600–3604. (31) Tung, C. C.; Speziale, A. J.; Frazier, H. W. J. Org. Chem. 1963, 28 (6), 1514–1521. (32) Speziale, A. J.; Frazier, H. W. J. Org. Chem. 1961, 26, 3176–3183. (33) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79 (8), 1920–1923. (34) Rathke, M. W.; Sullivan, D. Tetrahedron Lett. 1972, 13 (41), 4249–4252.

Chapter 2 Retrosynthesis and reaction background

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

3. Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

3.1 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrins via the Cope rearrangement of vinyl pyrrole epoxides

3.1.1 Synthesis of vinyl pyrrole epoxides

Scheme 3.1 Synthesis of vinyl pyrrole epoxides from trichloroacetylpyrrole (132).

The route to a vinyl pyrrole epoxide began with commercially available trichloroacetylpyrrole (132) which upon treatment with iodine in the presence of silver trifluoroacetate at 0 °C gave the iodide 182 as a single regioisomer (Scheme 3.1).1 Methanolysis with sodium methoxide in

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products methanol gave the methyl ester 183,1 which was used in a Sonogashira reaction with the THP protected propargyl alcohol2 184 to give the alkyne 185 in good yield. Partial reduction to the alkene 186 was achieved using H2 gas in the presence of P2 nickel (generated by reduction of nickel acetate with sodium borohydride) and ethylenediamine.3 Protection of the pyrrole nitrogen gave the Boc-carbamate 187. The THP protecting group was removed with camphor sulfonic acid in methanol to afford the allylic alcohol 188 in excellent yield.

Epoxidation of the allylic alcohol 188 was achieved with an approximately 0.1 M anhydrous solution of dimethyl dioxirane4,5 (75) in acetone and subsequent oxidation of the resultant epoxyalcohol with Dess-Martin periodinane in the presence of sodium bicarbonate gave the aldehyde 189 (Scheme 3.1). A Wittig extension using the stabilised ylide methyl 2- (triphenylphosphoranylidene)acetate gave the α,β unsaturated methyl ester 191 in a low yield. The structure was supported by key peaks in the 1H NMR spectrum including the pyrrole peaks at 7.30 ppm and 6.77 ppm, double bond protons at 6.58 ppm and 6.23 ppm, epoxide protons at 4.14 ppm and 3.72 ppm, and two methyl ester peaks at 3.85 ppm and 3.74 ppm (Figure 3.1). Condensation of aldehyde 189 with the unstabilised ylide derived from the reaction of methyltriphenylphosphonium bromide with potassium tert-butoxide produced the vinyl pyrrole epoxide 190 in a very low yield. The structure was supported by analogous key peaks in the 1H NMR to vinyl pyrrole epoxide 191, however the double bond is more shielded and the multiplet at 5.54 ppm represents two protons of the terminal alkene (Figure 3.2).

1 Figure 3.1 H NMR spectrum of vinyl pyrrole epoxide 191 (500 MHz, CDCl3).

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

1 Figure 3.2 H NMR spectrum of vinyl pyrrole epoxide 190 (400 MHz, CDCl3).

3.1.2 Synthesis of vinyl pyrrole epoxides by a vinylogous Darzens reaction

Scheme 3.2 The route to vinyl pyrrole epoxide 195 via a vinylogous Darzens reaction.

The synthesis of a vinyl pyrrole epoxide using a Darzens reaction began with pyrrole 123 (Scheme 3.2)6 which was converted into the TIPS compound 192 in excellent yield. This allows for substitution in the C4 position.7 Thus, Vilsmeier-Haack formylation furnished the desired C4 aldehyde 193 and also resulted in concomitant removal of the TIPS protecting group. Reprotection of the pyrrole then gave carbamate 194. The key Darzens reaction was effected by treatment of aldehyde 194 with the anion derived from known ethylbromocrotonate8 (174) in THF/HMPA9 solvent at -100 °C which afforded the pyrrole vinyl epoxide 195 in 67% yield after

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products purification. Stringent reaction conditions were required as the enolate derived from ethyl bromocrotonate is prone to self-condensation and decomposition.10

Scheme 3.3 Synthesis of the vinyl pyrrole epoxide 200 via a vinylogous Darzens reaction.

For the synthesis of a substituted system which could afford the natural product, the current study began with commercially available trichloroacetylpyrrole (132) as a starting material (Scheme

3.3). Rieche formylation of 132 in a mixture of CH2Cl2/CH3NO2 as the solvent at -40 °C formed 197 as the only regioisomer detected.11 The methyl ester 198 was then obtained in excellent yield via methanolysis with sodium methoxide in methanol. Protection of pyrrole nitrogen of 198 gave Boc-carbamate 199 and Darzens reaction using the same conditions as described above afforded the vinyl pyrrole epoxide 200 as a single diastereoisomer in a 67% yield.

Scheme 3.4 Synthesis of the substituted vinyl pyrrole epoxide 205 via a vinylogous Darzens reaction.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

A vinyl epoxide with a tert-butyl ester in the C2 position was also synthesised as shown in Scheme 3.4. The trichloroacetyl group in 197 was hydrolysed to the acid 201. Treatment of 201 with the isourea 202 gave the t-butyl ester 203 in good yield. Boc protection and subjection of 204 in a Darzens reaction with the anion derived from 174 gave the vinyl pyrrole epoxide 205 as a single stereoisomer in comparative yield. The structure of 205 was confirmed by diagnostic peaks in the 1H NMR spectrum (Figure 3.3), which are characteristic of all C2 substituted ester vinyl pyrrole epoxides described in this thesis. The vinylic protons resonate at 6.04 ppm (dd, J = 17 Hz and 11 Hz), 5.49 ppm (dd, J = 17 Hz and 1.5 Hz) and 5.41 ppm (dd, J = 11 Hz and 1.5 Hz), whilst the pyrrole protons occur at 7.17 ppm and 6.67 ppm (each d, J = 1.9 Hz), and the epoxide proton is observed at 4.19 ppm (s).

1 Figure 3.3 H NMR spectrum of vinyl pyrrole epoxide 205 (400 MHz, CDCl3).

The Darzens reactions were also conducted on the aldehydes 199 and 204 using the anion dervived from trimethylsilylethyl (TMSE) bromoester 209 to give the vinyl epoxides 210 and 211 in good yields. TMSE bromocrotonate 209 was synthesised via Steglich esterification12 of crotonic acid (206) with trimethylsilyl ethanol (207) followed by subsequent bromination and elimination based upon the method described by Hudlicky et al.13 (Scheme 3.5). TMSE esters can easily be deprotected with TBAF to afford the corresponding acids.14 The Darzens method proceeds in as few as 4 steps from trichloroacetylpyrrole to give vinyl pyrrole epoxides in up to 53% yield while the pathway to vinyl epoxides 190 and 191 require 9 linear steps and the yields are reduced to 3-10%.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.5 Darzens reaction to afford vinyl pyrrole epoxides 210 and 211.

The alternative methyl bromocrotonate ester 212 was also trialled in the Darzens reaction15 as it was envisaged that the methyl ester could also be easily removed to give the unsubstituted dihydrooxepine system. However, the enolate derived from the methyl ester 212 was less stable and the Darzens reaction proceeded to give the vinyl pyrrole epoxide 213 in a much lower yield (Scheme 3.6).

Scheme 3.6 Darzens reaction using bromoester 212.

An asymmetric version of the vinylogous Darzens reaction was also attempted. Hudlicky et al. reported the condensation of the anion formed from menthyl bromocrotonate 21416 with an α,β- unsaturated ketone to form a vinyl cyclopropane but there is little precendence for this reaction and the diastereoselectivity was not reported. A Darzens reaction between the enolate derived from the chiral ester 214 and the pyrrole aldehyde 204 gave the epoxides 215 in excellent yield but as an inseparable 1.2:1 mixture of diastereomers as evidenced by integration of the characteristic epoxide signals in the 1H NMR spectrum (Figure 3.4).

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.7 Attempted asymmetric vinylogous Darzens reaction.

Figure 3.4 1H NMR spectrum of the epoxide protons of vinyl pyrrole epoxide 215 (600 MHz,

CDCl3).

3.1.3 Cope rearrangements of vinyl pyrrole epoxides

Scheme 3.8 Cope rearrangement of vinyl pyrrole epoxides to give dihydrooxepines.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Table 3.1 Cope rearrangements of vinyl pyrrole epoxides (all reactions conducted at 150 °C in a sealed tube). Vinyl R1, R2, R3 Solvent Time (h) Product Yield (%) epoxide

190 H, H, CO2Me CCl4 1 Decomposition NA

191 H, CO2Me, CO2Me CCl4 1 Decomposition NA

196 CO2Et, H, H CCl4 3 216 46

200 CO2Et, H, CO2Me CCl4 2 217 83

205 CO2Et, H, CO2tBu CCl4 2 218 60

210 CO2TMSE, H, CO2Me CH3CN 1.5 219 86

211 CO2TMSE, H, CO2tBu PhCH3 2 220 67

213 CO2Me, H, CO2tBu PhCH3 2 221 72

With a range of vinyl pyrrole epoxides in hand, the Cope rearrangement of each was tested and the results of these can be seen in Table 3.1 and Scheme 3.8. The first two vinyl pyrrole epoxides tested were compounds 190 and 191. Heating each of these at 150° C in a sealed tube in carbon tetrachloride as a solvent resulted only in extensive decomposition. In the case of 191, there was evidence of ring opening of the epoxide however this could not be purified enough for full characterisation.

The epoxides obtained from the Darzens reactions were then tested in the Cope rearrangement. The epoxide tert-butyl ester 205 was heated to 150°C in a sealed tube, a new higher Rf spot was detected on TLC after 1 h. Further heating resulted in complete conversion to dihydrooxepine 218. The structure was confirmed by diagnostic peaks in the 1H NMR spectrum, which were characteristic of all dihydrooxepines described herein (Figure 3.5). The C5 diastereotopic protons at 2.29 and 3.20 ppm displayed coupling to both the C4 proton at 4.66 ppm and C6 proton at 6.39 ppm (dd, J = 9 Hz and 3 Hz), as well as to each other (J = 15 Hz), while the singlet at 6.13 represents the C9 enolic proton and the doublet at 6.66 represents the C2 pyrrolidine proton. The 13C NMR spectrum showed key peaks at 162.7, 160.5 and 152.6 ppm representing the three carbonyl carbons (Figure 3.6). The two tert-butyl groups are evident by key peaks at 81.9, 28.2 and 28.1 ppm representing the quaternary carbons and methyl groups respectively. The ethyl ester group is evident with key peaks at 61.8 and 14.2 ppm representing the methylene and methyl

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products groups respectively. The C4 carbon is seen at 61.2 ppm while the C5 carbon is seen at 33.9 ppm. The remaining 6 peaks representing the sp2 hybridised carbons are present at characteristic shifts between 142.6 and 113.3 ppm. The product obtained was crystalline allowing for further structural confirmation via a single crystal X-ray (Figure 3.7).

1 Figure 3.5 H NMR spectrum of the t-butyl dihydrooxepine 218 (400 MHz, CDCl3).

13 Figure 3.6 C NMR spectrum of the t-butyl dihydrooxepine 218 (101 MHz, CDCl3).

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Figure 3.7 X-ray crystal structure of the t-butyl dihydrooxepine 218.

All the Darzens adducts also underwent smooth [3,3]-rearrangement to form the dihydrooxepines in good to excellent yields (Table 3.1). Epoxide 196, which lacks an electron withdrawing ester on the pyrrole, proceeded in 46% yield to form dihydrooxepine 216, it is believed that purification by flash chromatography resulted in a substantial loss of material due to its instability on silica gel.6 The dihydrooxepine 217 was also slightly unstable and decomposed to the aldehyde 199 when exposed to silica gel. A proposed mechanism for this decomposition in shown in Scheme 3.9. Protonation of the more reactive oxepine enol and hydrolysis of the resultant oxonium ion 217a affords the cyclic hemiacetal 222, which undergoes acid-promoted ring opening to give the -ketoester 223. Deprotonation accompanied by elimination of 223 gives pyrrole aldehyde 199. Fortunately, dihydrooxepine 217 was crystalline and was obtained in a much higher yield than 216, possibly due to extra stability form the electron withdrawing ester on the dihydropyrrole ring.

Scheme 3.9 Proposed mechanism for acid-catalysed degradation of dihydrooxepine 217.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Due to the harmful biological effects of carbon tetrachloride and its restricted availability,17 alternate solvents were also tested for the Cope rearrangements. Acetonitrile18 was trialled as well as toluene due to its comparative dielectric constant to carbon tetrachloride.19,20 The Cope rearrangements of vinyl pyrrole epoxides containing the TMSE ester (210, 211) as well as the methyl ester derivative (213) all proceeded to give the dihydrooxepine products in good yield (Table 3.1). Dihydrooxepine 220 was crystalline and a single crystal X-ray crystal structure was obtained (Figure 3.8).

Figure 3.8 X-ray crystal structure of the TMSE dihydrooxepine 220.

These experimental results suggested that the presence of an ester substituent at C2 of the epoxide was important for the Cope rearrangement to proceed at or below 150°C to form a dihydrooxepine. Thus, the ester substituent appears to significantly lower the transition state energy for Cope rearrangement. Additionally, undesired ring opening of the epoxide is hindered by the ester group which destabilises the carbocation 225 intermediate. The absence of this ester appears to increase the activation energy of the Cope rearrangement in substrates such as 190 and 191 and perhaps favour the undesired ring-opening of the epoxide to give carbocation 228 (Scheme 3.10).

Scheme 3.10 Ester group influence on Cope rearrangements of vinyl pyrrole epoxides.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

3.1.4 Computational analyses of Cope rearrangements

Scheme 3.11 Cope rearrangements of simple divinyl epoxides and their transition state energies.

The transition state energies for Cope rearrangements of model divinyl epoxides were computed at the M06-2X/6-311+G(d,p) level of theory by collaborators* (Scheme 3.11).21–23 The calculated transition state energy for the [3,3]-sigmatropic Cope rearrangement of the unsubstituted divinyl epoxide (140) was 25.7 kcal/mol. π-Acceptors at the terminus of acyclic dienes generally raise the barrier for rearrangement due to loss of conjugation in the product (235) (Scheme 3.12).24 This is not the case for a divinyl epoxide (230), which is calculated to proceed three times faster at 150° C when compared to the unsubstituted system 140. This is likely due to a new transition state resonance contributor containing an extended conjugated π-system (TS19) (Scheme 3.12). π-acceptors on the epoxide have been shown to lower the transition state energy for Cope rearrangement of acyclic dienes25 due to stabilisation of the transition state through conjugation

* Computational analyses of these rearrangements were conducted by Dr Elizabeth Krenske (University of Queensland). Geometries were computed with M06-2X/6-311+G(d,p) in Gaussian 09, using the SMD implicit solvent model to simulate solvation in CCl4. The ultrafine integration grid was used. The computations employed restricted M06-2X (RM06-2X). In order to check for any diradical character, the transition states with reoptimized with unrestricted UM06-2X using the guess=(mix,always) keyword. The transition states thus obtained had identical energies to those from the RM06-2X calculations reported. For additional information see the supplementary information in Org. Lett. 2015, 17 (24), pp 5998–6001.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products between the π-acceptor on the epoxide and the developing double bond (TS13-15) (Scheme 3.12). This has been shown experimentally and computationally, with a reaction rate five times faster for 232 at 150° C when compared to the unsubstituted system 140.

Scheme 3.12 Resonance state contributors of Cope rearrangements.

Calculations on the transition states of the more substituted systems were then conducted on the simplified methyl ester and methyl carbamate derivatives (Scheme 3.13). The transition state energy of the Cope rearrangement for the substituted vinyl pyrrole epoxide 238 is higher than for the analogous divinyl epoxide 232. This may be due to the extra energy required to dearomatise pyrrole to undergo the [3,3] sigmatropic rearrangement. The unsubstituted system 240 shows an increase in transition state energy of 1.5 kCal/mol when compared to the substituted epoxide 238, translating to a reaction 5 times slower at 150° C. Surprisingly, 242, the α,β unsaturated ester at the terminus of the vinyl pyrrole epoxide, led to a 2.5 kCal/mol increase in transition state energy, which when compared to the substituted epoxide 238 translates to a 15 times slower reaction at 150° C. This discrepancy of the transition state energies between the pyrrole system 242 and the divinyl system 230 may be explained through an unfavourable electrostatic interaction in TS22 between the terminal ester and the carbamate which results in a much higher transition state energy than anticipated.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.13 Model vinyl pyrrole epoxides, their transition states and energies when undergoing a Cope rearrangement.

These computational results show that epoxides such as 238 with the ester substituent adjacent to the epoxide have lower transition state energy when compared to unsubstituted vinyl pyrrole epoxides such as 240 and 242, which agrees with the experimental results. Thus, vinyl pyrrole epoxides such as 238 participate in a [3,3]-sigmatropic rearrangement rather than decomposition due to the lower transition state energies.

3.1.5 Preliminary conclusions

The first Cope rearrangement of a vinyl pyrrole epoxide involving the dearomatisation of pyrrole to form a dihydrooxepine has been achieved. It has been shown experimentally and by computational studies that an ester substituent at the C2 position of the epoxide is key to facilitating these rearrangements. This methodology provides a short and high yielding pathway (5 steps, 46% yield) to the dihydrooxepine core of the emestrin family of natural products, starting from commercially available trichloroacetylpyrrole 132,22 which represents a great improvement on previous methods (13 steps, 8% yield26 and 12 steps, 5% yield27).

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

3.2 Attempts to remove the ester functionality

While the ester is crucial for the success of the Cope rearrangement, it needs to be removed to give the dihydrooxepine system found in the natural products. Removal of esters is not trivial and, in most cases, involve conversion first to an aldehyde or an acid for decarbonylation or decarboxylation respectively. This would require selective reduction of the C7 ester of 227 to the corresponding aldehyde 24528 or selective hydrolysis to the corresponding carboxylic acid 244 which may in turn be converted into an aldehyde (Scheme 3.14).

Scheme 3.14 Potential reaction pathway for removal of the dihydrooxepine ester functionality.

Unfortunately, DIBAL reduction of esters 218 and 22129 was attempted but both reactions resulted in decomposition of the dihydrooxepine (Scheme 3.15).

Scheme 3.15 Attempted reduction of dihydrooxepine esters 218 and 221 to the corresponding aldehyde 247.

Murai et al. reported the ruthenium-catalysed reductive decarboxylation of pyridinylmethyl esters (Scheme 3.16). While most examples were aromatic esters (248), several examples of decarboxylation of aliphatic (250, 251) and heteroaromatic esters were also reported.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.16 Ruthenium-catalysed reductive decarboxylation of esters.30

The corresponding pyridinylmethyl crotonate ester 254 was synthesised by esterification of the acid derived from TMSE bromocrotonate 209 with 2-pyridinemethanol (253) and this was subjected to the standard Darzens reaction (Scheme 3.17).

Scheme 3.17 Preparation of pyridinylmethyl ester 254 and attempted Darzens reaction.

The anion derived from the pyridinylmethyl ester failed to undergo the Darzens reaction with the aldehyde 204 so an alternative pathway to the dihydrooxepine was investigated (Scheme 3.18). Steglich esterification of the acid derived from TMSE ester 220 with 253 gave the pyridyl ester 255, however, exposure of this ester to ruthenium carbonyl mediated decarboxylation conditions30 only lead to decomposition of 256 (Scheme 3.18).

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.18 Preparation of dihydrooxepine 256 and attempted decarboxylation.

Reduction of the dihydrooxepines with a TMSE ester was then investigated (Scheme 3.19).14 Treatment of ester 220 with TBAF gave the acid 258 which was used without further purification in all subsequent experiments. Steglich esterification gave the thioester 259 in 69% yield over two steps and subsequent Fukuyama reduction of 259, with a higher catalyst loading and excess hydride than described,31 gave the aldehyde 247 in a 68% yield (Scheme 3.19). The structure of

+ aldehyde 247 was supported by mass spectrometry (HRMS calc. for C19H25NO6 [M + H] = 364.17601, found 364.17539), and 1D NMR spectroscopy with a 1H NMR singlet at 9.12 ppm for an aldehyde proton (Figure 3.9) and a key 13C NMR resonance at 186.9 ppm (Figure 3.10).

Scheme 3.19 Conversion of dihydrooxepine ester 220 to the acid 258 and aldehyde 247.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

1 Figure 3.9 H NMR spectrum of dihydrooxepine aldehyde 247 (400 MHz, CDCl3).

13 Figure 3.10 C NMR spectrum of dihydrooxepine aldehyde 247 (151 MHz, CDCl3).

The direct synthesis of thioester 259 from the aldehyde 204 was then investigated using the crotonic thioester 260. Formation of the thioester 260 was achieved by coupling of the acid derived from TMSE bromocrotonate 209 and ethanethiol. This thioester was then tested in the Darzens reaction under standard conditions using aldehyde 204 (Scheme 3.20). Unfortunately, the anion derived from the thioester failed to react with the aldehyde, yielding only starting material. This anion is probably less reactive than the corresponding ester due to the lower pKa of the -protons in thioesters compared to esters (16.9 for S-phenyl 2-phenylethanethioate and 18.7 for phenyl 2-phenylacetate).32

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.20 Synthesis of brominated thioester 260, and attempted Darzens reaction between aldehyde 204 and thioester 260.

With the key intermediates 258 and 247 in hand, approaches to decarboxylation and decarbonylation were investigated. Although there are many reported methods for decarboxylation in the literature,33–38 very few are analogous to the complex and sensitive system found in the substrates 258 and 247. Whilst Barton decarboxylation is an efficient method for decarboxylation, this would be challenging due to the radical that would need to form at the sp2 hybridised carbon.33–35 Microwave assisted copper catalysis is a milder method for decarboxylation of -unsaturated carboxylic acids but this has been mainly applied to aromatic acids. Unfortunately, microwave assisted copper catalysed decarboxylation38 failed (Scheme 3.21).

Scheme 3.21 Attempted decarboxylation of acid 258.38

Decarbonylation was then investigated as a potential route to desired dihydrooxepine 257. Wilkinson’s catalyst (262) can be used for the decarbonylation of aldehydes, however requires a stoichiometric amount of catalyst (Scheme 3.22).39,40 Mild decarbonylation of aromatic and α,β- unsaturated aldehydes has also been achieved using iridium catalysts (Scheme 3.23).41

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.22 Mechanism of the decarbonylation of aldehydes with Wilkinson’s catalyst (262).

Scheme 3.23 Iridium catalysed decarbonylation of aldehydes.

Scheme 3.24 Ir catalysed decarbonylation of the dihydrooxepine aldehyde 247.

Attempted decarbonylation of aldehyde 247 with Wilkinson’s catalyst (262) in refluxing toluene only resulted in decomposition. [RhCl(cod)]2-BINAP as the catalyst in o-dichlorobenzene as the solvent at 140 °C also resulted in decomposition.42 When the published procedure41 was followed with dimethoxyethane as a solvent and 2.5 mol % of [Ir(cod)Cl]2 catalyst only starting material resulted. When dioxane was used as a solvent at 101 °C, decarbonylation of the aldehyde occurred but only in very low yield (Scheme 3.24). The use of diglyme at a higher temperature (162 °C) was also trialled however this resulted in decomposition. The decarbonylation reaction was highly

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products irreproducible and it postulated that the active form of the catalyst, the IrCl(cod) monomer equivalent of 263, is very short-lived. This is supported by our experiments conducted on the decarbonylation of cinnamaldehyde (269), which was reported to give styrene (270) in a 79-99% yield,41 but in our hands gave 269 and 270 in a 2:1 ratio. The dihydrooxepine 257 could not be fully characterised due to the small amounts obtained (<2 mg) but the assigned structure of 257

+ was supported by mass spectrometry ([M + H] calc. for C18H25NO5 = 336.18110, found 336.18054) and analysis of the 1H and COSY NMR spectrum (Figures 3.11 and 3.12).

1 Figure 3.11 H NMR spectrum of dihydrooxepine 257 (400 MHz, CDCl3).

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Figure 3.12 COSY spectrum of dihydrooxepine 257.

The signals observed at 3.01 ppm and 2.20 ppm are at the characteristic chemical shift for the allylic protons of the dihydrooxepine (protons H6 and H7 respectively) and show a high degree of correlation to adjacent protons in the COSY spectrum (Figure 3.8). H5 was observed at 4.67 ppm is characteristic for the pyrrolidine proton and shows coupling only to the allylic protons in the COSY spectrum. The singlet at 6.12 ppm for H3 is characteristic of the pyrrolidine double bond proton and shows no coupling in the COSY spectrum. An aldehyde signal (Figure 3.5) is no longer present and the chemical shift for H4 has moved upfield indicative of the -vinylic proton of an enol ether (6.03 ppm to 4.85 ppm) (Figure 3.7). This proton exhibits coupling in the COSY spectrum to both the adjacent allylic protons (H6 and H7) as well as the α-vinylic proton of the enol ether at H2. Future work will involve optimisation of the decarbonylation reaction by screening more catalysts and solvents.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

3.3 Towards a synthesis of the fully substituted dihydrooxepine

3.3.1 Allylic oxidation approach

For the synthesis of the fully substituted dihydrooxepine of the emestrins allylic oxidation at C5 is required. Riley oxidation has been employed to oxidise the allylic position of α,β-unsaturated esters43 and this reaction was tested on dihydrooxepine 220 (Scheme 3.25).

Scheme 3.25 Riley oxidation of dihydrooxepine 220 and the hydrolysis products observed.

Unfortunately, the desired alcohol was not formed and only the hydrolysis products 271 and 272 were isolated.44 Previous reactions in which the dihydrooxepine was hydrolysed, the pyrrole aldehyde 204 is the major product, however in this case an α-keto ester is formed and the double bond from the dihydrooxepine undergoes a shift. This led us to believe that the dihydrooxepine did in fact undergo oxidation in the desired position, however the alcohol underwent elimination in the hydrolysis step. Addition of base (NaHCO3, NEt3 or iPr2NEt) to buffer the acidity of the reaction and hinder the hydrolysis only served to thwart the oxidation process (yielding only starting material) or gave only hydrolysis product 271. It is believed that the electron withdrawing ester substituent increases the lability of the dihydrooxepine ring, and this method may be more fruitful if the ester substituent may be removed prior to oxidation.

3.3.2 Extended Darzens reactions

To introduce the required oxygenation on the dihydrooxepine, several vinylogous Darzens reactions with -substituents were investigated which allow for the introduction of the additional substituent prior the Cope rearrangement. Hudlicky employed the Darzens reaction using the bromoester 273 to form vinyl furan epoxides from furaldehyde (178) in good yield (Scheme 3.26).13,45

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.26 Darzens reactions with -siloxy-α-bromocrotonate 273.

Both the TBS protected10 (273) and a benzyl protected crotonate (283) were synthesised as shown in Scheme 3.27. Borane reduction of the acid 278 and TBS protection gave 279 in good yield.46 One pot bromination and elimination then gave the bromocrotonate 273 in an 82% yield. Phosphine catalyzed addition of benzyl alcohol to ethyl but-2-ynoate (280) gave the alkene 28246,47 but bromination of this compound proved challenging due to both lack of reactivity and instability of the substrate. It was eventually found that bromination with Br2 in carbon tetrachloride followed by exposure to DBU gave the bromide 283 in good yield.

Scheme 3.27 Synthesis of -substituted bromocrotonates 273 and 283.

A Darzens precursor with a -alkyl substitutent was also synthesised. Ethyl (Z)-2- bromopentenoate was synthesised via a Wittig reaction using the known phosphonium ylide 286, prepared from ethyl bromoacetate (285) as shown in Scheme 3.28, and propanal (287).48,49 This Wittig approach to -unsaturated bromoesters was also utilised as a more efficient method of synthesising previously obtained benzyloxy ester 284. Aldehyde 288 was synthesised from solketal using a reported method50 and subjected to the Wittig reaction.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.28 Alternative pathway to extended allylbromo esters 288 and 283 for use in the Darzens reaction.

Scheme 3.29 Attempted Darzens reactions.

Unfortunately, none of the -substituted bromoesters participated in a Darzens reaction under the conditions described previously to give the vinyl pyrrole epoxide (Scheme 3.29). Hudlicky et al. described the propensity of the silyl ether 273 to undergo polymerisation at -100 °C via a proposed Brook rearrangement,13,51 which may have occurred when exposed to the conditions described in Scheme 3.29. The benzyl ether derivative 283 and propenoate ester 288 also failed to participate in the Darzens reaction with the aldehyde 204. Thus, it appears that the allylic anions are less reactive and/or undergo degradation rather than condensation with the somewhat unreactive pyrrole aldehyde.

It was then postulated that an alternative vinyl silane could be synthesised via a Darzens reaction and subsequently undergo a Cope rearrangement followed by conversion to the alcohol via a Fleming-Tamao oxidation,52–54 to afford the desired dihydrooxpine 276. Fleming-Tamao oxidation involves the use of a peroxy acid or hydrogen peroxide for the conversion of a phenylalkyl silane (295) to an alcohol (296) (Scheme 3.30).55–57 A silyl substituent could be introduced via a vinylogous Darzens reaction using a -silyl derivative of the bromocrotonate esters as utilised in previous Darzens reactions (Scheme 3.29). This precursor may prove more stable and less prone to self-condensation than the previously tested -substituted -unsaturated bromoesters.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.30 General mechanism for the Fleming-Tamao oxidation and examples.55–57

Scheme 3.31 Proposed synthesis of a dihydrooxepine alcohol 276 via the Fleming-Tamao oxidation of a silyl substituted dihydrooxepine 300.

An attempted synthesis of the requisite Cope precursor vinyl silane 299 began with a cross metathesis between allyltrimethylsilane (302) and methyl acrylate (303) to give the alkene 304 in quantitative yield,58,59 however subsequent bromination failed to provide the desired bromoester 305 (Scheme 3.32). The vinylogous alkylsilane derivative (308) of the vinyl pyrrole epoxide (211) could be synthesised via a cross metathesis approach. Thus, the vinyl silane 306 was tested along with a number of related substrates (Scheme 3.33).60,61 Unfortunately, this approach failed to yield

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products any substituted vinyl pyrrole epoxides. The low reactivity of the alkenes could be attributed to the steric bulk of the vinyl epoxide.

Scheme 3.32 Attempted formation of the brominated ester 305.

Scheme 3.33 Attempted cross metathesis between alkenes and vinyl pyrrole epoxide 211.

3.3.3 Wittig approach

The Wittig reaction for the synthesis of γ-silylated esters using the known ylide 285 (Scheme 3.28) was next examined.48,49 The aldehydes 310a-c were first synthesised via ozonolysis of the alkenes (Scheme 3.34).62,63 Allyltriethoxysilane (309c) and allyltriphenylsilane (309b) are both commercially available, while allyltriisopropylsilane (309a) was synthesised via addition of allyl magnesium bromide to chloro(triisopropyl)silane.62,63 Allyltrimethylsilane (309d) was unstable to ozonolysis due to competing desilylation. Allyldimethylphenylsilane (309e) was synthesised via Grignard addition of allyl bromide to chlorodimethylphenylsilane64 however exposure of this to ozone resulted in desilylation. The aldehyde was eventually synthesised by a Reformatsky

65 reaction and subsequent reduction to the alcohol 311 using LiAlH4. Subjection of alcohol 311 to Swern oxidation gave the aldehyde 310e in good yield.65,66 With these aldehydes in hand, the Wittig reaction was then tested (Scheme 3.35). Wittig reaction with the aldehydes 310a-c,e was successful but the triethoxy (312c) and dimethylphenylsilyl (312d) derivatives were considerably more susceptible to proto-desilylation upon exposure to silica gel.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.34 Synthesis of silylaldehydes.62–66

Scheme 3.35 Wittig synthesis of silylbromoesters.50,62

Scheme 3.36 Darzens reactions involving extended substrates 312a-c,e.

The above silyl allyl bromo esters were then tested in the Darzens reaction with pyrrole aldehyde 204 (Scheme 3.36). The anions derived from these esters did not undergo Darzens condensation at -100 °C but did readily react with aldehydes at -78 °C.45 Significant desilylation occurred when using the triethoxysilyl ester 313c which resulted in the formation of the known vinyl pyrrole epoxide22 205 in 32% yield alongside the desired silane 313c. The dimethylphenyl silane 312e

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products only gave a complex mixture of by-products whilst the triphenylsilyl ester 312b gave the highest yield thus far in any Darzens reaction and the crystalline product 313b was subjected to X-ray analysis (Figure 3.13).

Figure 3.13 X-ray crystal structure of vinyl pyrrole epoxide 313b.

The increased steric repulsion between the silyl substituent and pyrrole nitrogen protecting group could hinder the ability of these compounds to undergo the Cope rearrangement, as shown in Figure 3.14. For comparison, a silyldivinyl epoxide 314 derived from furan aldehyde 178 was synthesised and subjected to a Cope rearrangement (Scheme 3.37)

Figure 3.14 Steric interference in Cope rearrangement of silylated vinyl pyrrole epoxides.

Scheme 3.37 Darzens reaction and Cope rearrangement of furaldehyde (178) with silylated ester 312b.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

1 Figure 3.15 H NMR spectrum of furan epoxide 314 (600 MHz, CDCl3).

1 Figure 3.16 H NMR spectrum of dihydrooxepine 315 (400 MHz, CDCl3).

Aldehyde 178 underwent the Darzens reaction with ester 312b to give the divinyl epoxide 314 in good yield. The structure was confirmed by 1H NMR spectroscopy (Figure 3.15) which showed double bond signals at 6.60 ppm and 6.40 ppm showing a characteristic 18.8 Hz trans coupling, along with the epoxide singlet at 4.30 ppm. This was also supported by mass spectrometry (HRMS

+ calc. for C29H26O4Si [M + H] = 467.16786, found 467.16765). Prolonged heating at 180°C induced Cope rearrangement to give dihydroxepine 315 in 40% yield. The structure was confirmed by analysis of the 1H NMR spectrum (Figure 3.16) which showed a characteristic

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products doublet of doublets at  3.83 ppm (J = 8.9 and 5.0 Hz) representing the proton at C5, as well as a doublet (J = 9.3 Hz) at 6.35 ppm representing the proton at C6 of the dihydrooxepine. The vinyl pyrrole epoxides 313a-c were also heated in attempt to induce the Cope rearrangement (Scheme 3.38).

Scheme 3.38 Cope rearrangements of silylated vinyl pyrrole epoxides 313a-c.

1 Figure 3.17 H NMR spectrum of dihydrooxepine 316c (600 MHz, CDCl3).

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

13 Figure 3.18 C NMR spectrum of dihydrooxepine 316c (151 MHz, CDCl3).

The triphenylsilyl and triisopropylsilyl vinyl epoxide pyrrole derivatives 313a and 313b decomposed on prolonged heating however, the less bulky triethoxysilyl substrate 313c did undergo the Cope rearrangement when heated at 180°C overnight. The structure of the dihydrooxepine 316c was supported by analysis of the 1H NMR spectrum which showed a characteristic doublet of doublets at  3.22 ppm (J = 9.8 Hz and 3.9 Hz) representing the proton at C5, as well as a doublet at 6.48 ppm (J = 9.9 Hz) representing the proton at C6 (Figure 3.17). The 13C NMR spectrum also indicated the dihydrooxepine had formed due to the presence of two resonances at 29.7 and 33.9 ppm (Figure 3.18). This indicates the presence of two sp3 hybridised carbons not present in the vinyl pyrrole epoxide starting material, likely corresponding to the C4 and C5 carbons shielded due to their proximity to the silicon substituent. This was also supported

+ by mass spectrometry (HRMS calc. for C27H43NO10Si [M + H] = 570.27345, found 570.27304).

With the triethoxysilyl dihydrooxepine 316c in hand, it remained to test the Fleming-Tamao oxidation to the desired alcohol 276. A range of oxidants were trialled, shown in Scheme 3.39.53,54,67

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Scheme 3.39 Failed Fleming-Tamao oxidations of triethoxysilyl dihydrooxepine 316c.

Trimethylamine-N-oxide was tested under a range of temperatures using both KHF2 and a

53 combination of KF and KHCO3 however only decomposition was observed. H2O2 was also utilised as an oxidant however this also resulted in decomposition. It was postulated that anhydrous conditions using m-CPBA may furnish the desired alcohol,67 but this also resulted in decomposition. The ester group was shown to be problematic in other oxidations (see Scheme 3.25) and removal of this should allow for clean silyl oxidation. Further investigations are required to find conditions for this transformation.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

3.4 Bibliography

(1) Belanger, P. Tetrahedron Lett. 1979, 27, 2505–2508. (2) Córdova, A.; Lin, S.; Tseggai, A. Adv. Synth. Catal. 2012, 354 (7), 1363–1372. (3) Brown, C. A.; Ahuja, V. K. J. Chem. Soc. Chem. Commun. 1973, No. 15, 553–554. (4) Murray, R. W.; Singh, M. Org. Synth. 2003, 74, 91–96. (5) Taber, D. F.; Hassan, R.; DeMatteo, P. W.; Enquist, J. A. Org. Synth. 2013, 90, 350–357. (6) Hummel, J. Towards the Synthesis of the Core Structure in Dethiosecoemestrin, 2014. (7) Bober, A. E.; Proto, J. T.; Brummond, K. M. Org. Lett. 2017, 19 (7), 1500–1503. (8) Kakimoto, M.; Kai, M.; Kondo, K. Chem. Lett. 1982, 525–526. (9) Reich, H. J. J. Org. Chem. 2012, 77 (13), 5471–5491. (10) Hudlicky, T.; Fleming, A.; Lovelace, T. Tetrahedron 1989, 45 (10), 3021–3037. (11) Alonso Garrido, D. O.; Buldain, G.; Ojea, M. I.; Frydman, B. J. Org. Chem. 1988, 53 (2), 403–407. (12) Neises, B.; Steglich, W. Angew. Chemie Int. Ed. English 1978, 17 (7), 522–524. (13) Hudlicky, T.; Fleming, A.; Radesca, L. J. Am. Chem. Soc. 1989, 111 (17), 6691–6707. (14) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94 (17), 6190–6191. (15) Brenna, E.; Gatti, F. G.; Manfredi, A.; Monti, D.; Parmeggiani, F. Org. Process Res. Dev. 2012, 16 (2), 262–268. (16) Hudlicky, T.; Radesca, L.; Rigby, H. L. J. Org. Chem. 1987, 52, 4397–4399. (17) Manibusan, M. K.; Odin, M.; Eastmond, D. A. J. Environ. Sci. Heal. Part C 2007, 25 (3), 185–209. (18) Chou, W. N.; White, J. B.; Smith, W. B. J. Am. Chem. Soc. 1992, 114 (12), 4658–4667. (19) Mardolcar, U. V.; de Castro, C. A. N.; Santos, F. J. V. Fluid Phase Equilib. 1992, 79, 255– 264. (20) Van Loon, R.; Fuks, S.; Bellemans, A. Bull. Soc. Chim. Belges 1967, 76, 202–210. (21) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120 (1–3), 215–241. (22) Cameron, A.; Fisher, B.; Fisk, N.; Hummel, J.; White, J. M.; Krenske, E. H.; Rizzacasa, M. A. Org. Lett. 2015, 17 (24), 5998–6001. (23) Marenich, A. V; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113 (18), 6378– 6396. (24) Aviyente, V.; Houk, K. N. J. Phys. Chem. A 2001, 105 (2), 383–391. (25) Hrovat, D. A.; Beno, B. R.; Lange, H.; Yoo, H.; Houk, K. N.; Borden, W. T.; February, R. V; Re, V.; Recei, M.; August, V. J. Am. Chem. Soc. 1999, 121, 10529–10537. (26) Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2012, 134 (4), 1930– 1933. (27) Fujiwara, H.; Kurogi, T.; Okaya, S.; Okano, K.; Tokuyama, H. Angew. Chemie 2012, 51

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

(52), 13062–13065. (28) Clayden, J. .; Greeves, N. .; Warren, S. .; Wothers, P.; Clayden; Greeves; Warren; Wothers. Organic Chemistry, 1st ed.; Oxford University Press: New York, 2001. (29) Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962, 3 (14), 619–620. (30) Chatani, N.; Tatamidani, H.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 4849–4850. (31) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Lin, S. C.; Li, L.; Fukuyama, T. J. Braz. Chem. Soc. 1998, 9 (4), 381–387. (32) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218–4223. (33) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983, No. 18, 939–941. (34) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron Lett. 1983, 24 (45), 4979– 4982. (35) Ko, E. J.; Savage, G. P.; Williams, C. M.; Tsanaktsidis, J. Org. Lett. 2011, 13 (8), 1944– 1947. (36) Dickstein, J. S.; Curto, J. M.; Gutierrez, O.; Mulrooney, C. A.; Kozlowski, M. C. J. Org. Chem. 2013, 78 (10), 4744–4761. (37) Dickstein, J. S.; Mulrooney, C. a; O’Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Org. Lett. 2007, 9 (13), 2441–2444. (38) Goossen, L. J.; Manjolinho, F.; Khan, B. A.; Rodríguez, N. J. Org. Chem. 2009, 74 (6), 2620–2623. (39) Ohno, K.; Tsuji, J. J. Am. Chem. Soc. 1968, 90 (1), 99–107. (40) Doughty, D. H.; Pignolet, L. H. J. Am. Chem. Soc. 1978, 100 (22), 7083–7085. (41) Iwai, T.; Fujihara, T.; Tsuji, Y. Chem. Commun. 2008, No. 46, 6215–6217. (42) Morandi, B.; Carreira, E. M. Synlett 2009, 13, 2076–2078. (43) Matera, R.; Gabbanini, S.; Valvassori, A.; Triquigneaux, M.; Valgimigli, L. European J. Org. Chem. 2012, No. 20, 3841–3851. (44) Trachtenberg, E. N.; Nelson, C. H.; Carver, J. R. J. Org. Chem. 1970, 35 (5), 1653–1658. (45) Hudlicky, T.; Heard, J. N. E.; Fleming, A. J. Org. Chem. 1990, 55, 2570–2572. (46) Huelgas, G.; Mel, R.; Jim, J.; Cabrera-vivas, B. M.; Sansinenea, E.; Ortiz, A. Tetrahedron 2015, 71, 4590–4597. (47) Trost, B. M.; Li, C. J. J. Am. Chem. Soc. 1994, 116 (23), 10819–10820. (48) Gong, X.; Yang, H.; Liu, H.; Jiang, Y.; Zhao, Y.; Hua, F. Org. Lett. 2010, 12 (14), 3128– 3131. (49) Mao, Y.; Mathey, F. Org. Lett. 2012, 14 (4), 1162–1163. (50) Bouton, J.; Van Hecke, K.; Van Calenbergh, S. Tetrahedron 2017, 73 (30), 4307–4316. (51) Brook, A. G. Acc. Chem. Res. 1974, 7 (3), 77–84.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

(52) Fleming, I.; Hill, J. H. M.; Parker, D.; Waterson, D. J . Chem. Soc., Chem. Commun. J. Chem. S O C . Chem. Commun 1985, 3 (318), 318–321. (53) Sakurai, H.; Ando, M.; Kawada, N.; Sato, K.; Hosomi, A. Tetrahedron Lett. 1986, 27 (1), 75–76. (54) Sunderhaus, J. D.; Lam, H.; Dudley, G. B. Org. Lett. 2003, 5 (24), 4571–4573. (55) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc. Chem. Commun. 1984, No. 1, 29. (56) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics 1983, 2 (11), 1694–1696. (57) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52 (22), 7599–7662. (58) Ferrié, L.; Amans, D.; Reymond, S.; Bellosta, V.; Capdevielle, P.; Cossy, J. J. Organomet. Chem. 2006, 691 (24–25), 5456–5465. (59) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121 (4), 791–799. (60) Pietraszuk, C.; Marciniec, B.; Fischer, H. Organometallics 2000, 19, 913–917. (61) Pietraszuk, C.; Fischer, H.; Kujawa, M.; Marciniec, B. Tetrahedron Lett. 2001, 42 (6), 1175–1178. (62) Guptill, D. M.; Cohen, C. M.; Davies, H. M. L. Org. Lett. 2013, 15 (24), 6120–6123. (63) Robertson, J.; Hall, M. J.; Stafford, P. M.; Green, S. P. Org. Biomol. Chem. 2003, 1 (21), 3758–3767. (64) Chen, C.; Dugan, T. R.; Brennessel, W. W.; Weix, D. J.; Holland, P. L. J. Am. Chem. Soc. 2014, 136 (3), 945–955. (65) Fujio, M.; Uchida, M.; Okada, A.; Alam, M. A.; Fujiyama, R.; Siehl, H. U.; Tsuno, Y. Bull. Chem. Soc. Jpn. 2005, 78, 1834–1842. (66) Marti, G. Studies toward the Synthesis of Bafilomycin A₁ and Fusidilactone C. Ph D. Dissertation, Swiss Federal Institute of Technology Zurich (ETH), 2007. (67) Evans, P. A.; Baikstis, T.; Inglesby, P. A. Tetrahedron 2013, 69 (36), 7826–7830.

Chapter 3 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products

Chapter 4 A novel vinyl sulfone trimerization

4. A novel vinyl sulfone trimerization

4.1 Synthesis of vinyl pyrrole epoxides with alternative electron-withdrawing groups

4.1.1 Synthesis of alternative electron-withdrawing groups

Previous efforts to decarboxylate or decarbonylate the dihydrooxepine 319 have been met with limited success. Experimental and computational results demonstrated that the Cope rearrangement of vinyl pyrrole epoxides requires a C2 electron-withdrawing substituent to proceed at an appreciable rate. Thus, a Darzens reaction could be utilised to introduce an easily removable electron-withdrawing substituent alternative to the previously used esters (Scheme 4.1).

Scheme 4.1 Alternative electron-withdrawing groups in a Darzens reaction.

4.1.2 Darzens reaction with a bromocrotononitrile

One possibility is to utilise a nitrile as the electron-withdrawing group for a Darzens reaction as Chatani et al. have described the mild rhodium-catalysed reductive cleavage of carbon-nitrile bonds with hydrosilanes.1 While all examples involving the cleavage of carbon-nitrile bonds are aromatic or aliphatic (320),1 a similar protocol has been used for the rhodium-catalysed silylation of alkenyl nitriles (322),2 which could be modified for decyanation by substituting the disilane shown in Scheme 4.2 for a silane, although it was not discussed whether these conditions would preferentially reduce the alkene.3 The known bromo-crotononitrile 3244 was synthesised and subjected to the standard Darzens conditions with aldehyde 204 (Scheme 4.3).

Chapter 4 A novel vinyl sulfone trimerization

Scheme 4.2 Methods for the decyanation of alkyl and arylnitriles.

Scheme 4.3 Darzens reaction between aldehyde 204 and crotononitrile 324.

Unfortunately, the Darzens reaction failed to give the vinyl pyrrole epoxide product 325, and only starting material was recovered. It is probable that the anion could simply not be reactive enough or undergo unproductive self-condensation more readily than the ester analogues.

4.1.3 Attempts to synthesise a sulfone epoxide via a Darzens reaction

It was postulated that an aryl sulfone could also be used as an alternative electron-withdrawing group. Darzens reactions using arylsulfonylmethyl halides (172, 326) have been extensively studied (Scheme 4.4),5,6 however the use of a vinylogous anion derived from a vinylbromo sulfone in this reaction had not been described. Such a vinyl pyrrole epoxide could be elaborated to a dihydrooxepine via the Cope rearrangement and the aryl sulfone easily cleaved in a subsequent single step to unveil the desired dihydrooxepine system. A number of methods for cleaving a carbon-sulfone bond have been described, however some involve strongly basic conditions that may not be suitable for sensitive substrates.7–10 However, mild conditions such as sodium/mercury/aluminium amalgams could be applied for the removal of an aromatic sulfone (Scheme 4.5), although some methods have shown to concomitantly reduce double bonds or remove protective groups.11–15

Chapter 4 A novel vinyl sulfone trimerization

Scheme 4.4 Formation of α,β-epoxysulfones via the Darzens reaction between an α-halosulfone and a ketone.

Scheme 4.5 Removal of sulfones using sodium/mercury amalgam.

Scheme 4.6 Synthesis of the vinyl sulfones 336 and 337 from their sulfinic acid precursors 332 and 333.

The synthesis of various bromovinyl sulfones was then investigated. Yadav and co-workers have reported a simple one-step route to vinyl sulfones via reaction of sulfinic acids 332 and 333 with propylene oxide in water in the presence of a catalytic amount of lithium bromide (Scheme 4.6).16 Unfortunately, this method failed to give the desired vinyl sulfones and only resulted in the formation of the secondary alcohols 334 and 335. However, it was found that vinyl sulfones 336 and 337 could be synthesised in reasonable yield over two steps involving sufination and mesylation of the resultant secondary alcohols followed by base induced elimination. The reported bromination of vinyl sulfones with molecular bromine and pyridinium bromide perbromide (PBPB)17 was not successful as all the vinyl sulfones were inert to these conditions. The dibromides 338 and 339 were eventually formed by radical bromination18

Chapter 4 A novel vinyl sulfone trimerization

followed by elimination mediated by DBU19 to give vinylbromosulfones 340 and 341. With the bromo sulfones in hand, the Darzens reactions were then tested using the pyrrole aldehyde 204 (Scheme 4.8). Unfortunately, when the pyrrole aldehyde 204 was treated with the anions derived from 340 and 341 under the standard Darzens conditions only starting material was observed.

Scheme 4.7 Synthesis of the vinyl bromo sulfones 340 and 341.

Scheme 4.8 Attempted Darzens reactions using aryl vinyl sulfones.

4.2 A novel vinyl sulfone trimerization

4.2.1 Characterisation of vinyl sulfone by-product

When the pyrrole aldehyde 204 was treated with the anion derived from 340 at -78 °C using LiHMDS as a base, examination of the 1H NMR spectrum of the crude product was promising since clear signals corresponding to an isolated terminal alkene were present at 4.81 ppm (d, J = 17.5 Hz, 1H), 5.40 ppm (d, J = 11 Hz, 1H) and 6.54 ppm (dd, J = 17.5 and 11 Hz, 1H). Unfortunately, other signals did not correspond to the desired Darzens vinyl pyrrole epoxide product 342. The terminal alkene containing by-product was isolated by flash chromatography and extensive analyses of the 1H, 13C, HSQC and COSY NMR spectra as well as mass spectral analysis suggested the formation of a sulfone trimer with the molecular formula of

C30H30BrO6S3 in a 32% yield.

Chapter 4 A novel vinyl sulfone trimerization

1 Figure 4.1 H NMR spectrum of vinyl sulfone by-product (400 MHz, CDCl3).

The 1H NMR spectrum (Figure 4.1) of the product displays 6 sets of doublets in the aromatic region between 7.31 and 7.74 ppm integrating for two protons each, and all exhibiting characteristic 8.2-8.8 Hz J couplings for a para-disubstituted benzene. Along with two singlets at 2.43 (6H) and 2.45 ppm (3H) representing the para-methyl substituents, this indicated the presence of three p-toluene rings, likely bridged by a sulfone to the remaining structural features. The [M + H]+ peaks were found in the mass spectrum at 663.05419 and 665.05168 in a 1:1 ratio suggesting the presence of a single Br atom. This led to the hypothesis that three molecules of bromovinyl sulfone 340 had self-condensed, and the mass spectrum supported this

+ with a proposed molecular formula of C30H31BrO6S3 ([M +H] calc. = 663.04661, 665.04457). Accounting for the bromine and three p-toluene sulfones, the formula for the carbon skeleton becomes C9H10X4, indicating three remaining degrees of unsaturation.

13 Figure 4.2 C NMR spectrum of vinyl sulfone by-product (400MHz, CDCl3).

Chapter 4 A novel vinyl sulfone trimerization

Figure 4.3 HSQC spectrum of vinyl sulfone by-product.

Chapter 4 A novel vinyl sulfone trimerization

Analysis of the HSQC spectrum (Figure 4.3) revealed the presence of two sets of diastereotopic protons. The signals at 1.93 ppm and 2.77 ppm both correlated to a single peak in the 13C spectrum at 31.5 ppm, while the signals at 2.58 ppm and 2.97 ppm both correlated to a single peak at 24.9 ppm. The HSQC also supported the presence of a terminal double bond, with the

CH2 protons at 4.81 ppm and 5.40 ppm correlating to a single deshielded carbon signal at 122.0 ppm and the CH proton at 6.54 correlating to a signal at approximately 128.2 ppm. The HSQC also showed a correlation between the signal at 6.80 ppm and a deshielded carbon at 131.4 ppm, indicating this proton is likely part of an internal alkene. The proton at 6.11 ppm correlates to the carbon signal at 65.2 ppm indicating a proton attached to a deshielded sp3 hybridised carbon, postulated to contain one of or both a sulfone and bromine subsituent. The signal at 68.3 ppm in the 13C spectrum shows no correlation to a proton in the HSQC, indicating a deshielded sp3 hybridised quaternary carbon. Thus, NMR analysis shows there are two alkenes (2 DBE) and likely one ring (1 DBE) for a total of 3 degrees of unsaturation in the carbon skeleton.

Figure 4.4 COSY spectrum of vinyl sulfone by-product.

Chapter 4 A novel vinyl sulfone trimerization

The COSY spectrum (Figure 4.4) only showed correlation between the CH of the terminal alkene (H2) at 6.54 ppm and the adjacent CH2 signals (H4) at 4.81 ppm and 5.40 ppm, indicating the terminal alkene was adjacent to a quaternary carbon. The CH signal at 3.39 ppm (H5) showed a correlation to the diastereotopic protons at 2.58 ppm and 2.97 ppm (H6). This indicates this CH group was likely adjacent to two quaternary carbons and a CH2 group, given its chemical shift indicates it is relatively shielded and unlikely to be attached to a carbon atom bearing a sulfone or Br atom. The CH signal at 6.80 ppm (H1) showed a correlation to the other pair of diastereotopic protons at 1.93 ppm and 2.77 ppm (H7) indicating the internal alkene was adjacent to a CH2 group and one of the alkene carbons was quaternary, likely bearing a deshielding sulfone substituent.

Figure 4.5 Proposed structure for cyclic by-product with COSY proton assignments.

The data suggested that the cyclohexene 343 was the structure of the by-product. This assignment allows for all key structural features discussed in the assignment of the various 1D and 2D NMR spectra as well as the mass spectrum. One issue was the absence of coupling between H5 and H3 (3.39 ppm (dd) and 6.11 ppm (s) respectively) in the 1D 1H NMR or COSY spectrum. In addition, the assignment of stereochemistry was also not possible. Fortunately, a single X-ray crystal structure was obtained which confirmed the relative stereochemistry as shown in Figure 4.6.

Chapter 4 A novel vinyl sulfone trimerization

Figure 4.6 X-ray crystal structure of sulfone by-product 343.

As can been seen in Figure 4.6, the by-product obtained from the attempted Darzens reaction was a complex cyclohexene with three contiguous stereocentres produced as a single diastereoisomer by a novel trimerisation of the vinyl sulfone bromide 340. The lack of coupling observed between H3 and H5 can be explained by the observed dihedral angle between the protons in the X-ray structure which is close to 90°. None of the pyrrole aldehyde was involved in this process. This reaction was unprecedented and thus a further investigation of the scope and mechanism of this reaction was conducted.

4.2.2 Optimising the trimerisation reaction

A range of reaction conditions were tested to investigate the base and its stoichiometry (Table 4.1). The best yield (49%) obtained for the cyclic trisulfone 343 was with a sub-stoichiometric amount of LiHMDS as base (0.9 equivalents) and HMPA as a co-solvent (entry 3, Table 4.1). Interestingly, a stoichiometric amount of base (entry 4) resulted in a greatly reduced yield of cyclohexene 343, while an excess of base (entry 5) did not give any cyclohexene product. This shows that full deprotonation of 340 results in no cyclic product, meaning a protonated form of sulfone 343 acts as a reactive intermediate in the sequence. Unfortunately, all attempts to form the equivalent cyclohexene from the phenyl sulfone 341 failed. The phenyl sulfone was not very soluble in THF/HMPA at -78°C which may explain why this failed to undergo the trimerization, however even at higher temperatures, the phenyl derivative was unreactive.

Chapter 4 A novel vinyl sulfone trimerization

Table 4.1 Optimisation of formation of cyclohexene 343 (-78 °C in THF/HMPA, 2 h, * = no HMPA co-solvent). Yields based on 3 eq. of vinyl sulfone giving 1 eq. cyclohexene adduct.20

Entry Base Equivalents of base Yield (%) Yield based on recovered starting material (%) 1* LiHMDS 0.5 11 41 2 LiHMDS 0.8 30 37 3 LiHMDS 0.9 49 59 4 LiHMDS 1 17 23 5* LiHMDS 3 0 0 6 NaHMDS 0.9 0 NA 7* LDA 0.8 11 22 8* NaH 0.8 24 31

Scheme 4.9 Synthesis of cyclohexene 347 using p-chlorophenyl substrate 344.

The reaction was tested on bromo sulfone 346 which was obtained from the p- chlorophenylsulfinic acid sodium salt 344 (Scheme 4.9), and trimerisation occurred albeit in much lower yield than for the sulfone 340. The structure was confirmed by the key peaks in the 1H NMR (Figure 4.7) which matched cyclohexene 343, and by mass spectrometry ([M +H]+ calc. for C27H22BrCl3O6S3 = 722.89061, 724.88766, 726.88561, found 722.88966, 724.88698, 726.88397).

Chapter 4 A novel vinyl sulfone trimerization

1 Figure 4.7 H NMR spectrum of cyclohexene 347 (500 MHz, CDCl3).

To probe the mechanism of this reaction, a series of experiments were conducted and supplemented with computational studies.20 Treatment of vinylsulfone 340 with an excess of base followed by an acid quench produced the vinyl bromo sulfone 348 as the only product, suggesting a likely electrophile that can react with the anion of sulfone 340 (Scheme 4.10). When the trimerisation reaction was conducted under the optimised conditions followed by quenching with D2O the CH signal at 6.11 ppm integrated to 37% of the other 1H peaks (Figure 4.8). Thus, the cyclohexene d-343 had 63% deuterium incorporation in the position indicated (Scheme 4.10). This suggested that the final step of the sequence involves formation of the six membered ring via intramolecular cyclisation and protonation of the resultant anion to give the product. Thus, it appears that all three stereocentres are formed in the final stages of the reaction.

Scheme 4.10 Experiments probing the mechanism of the trimerisation reaction.

Chapter 4 A novel vinyl sulfone trimerization

1 Figure 4.8 H NMR spectrum of d-343 (400 MHz, CDCl3).

4.2.3 Proposed mechanisms and computational analyses of transition states

A sub-stoichiometric amount of base allows for an equilibrium to be established between the enolate 340a and its resonance form 348a, which can be quenched by protonation by 340 to form the alternative electrophile 348 (Scheme 4.11). Two possible mechanisms were postulated for the formation of the cyclohexene 343 from these reactive intermediates and density functional theory (DFT) calculations21,22 were conducted for each of the steps (Schemes 4.12- 4.17).*

Scheme 4.11 Formation of enolates 340a and 348a and alternative electrophile 348 from bromovinyl sulfone 340.

A possible mechanism for the formation of cyclohexene 343 (Scheme 4.12) begins with the - anion 340a which undergoes an SN2 reaction with the isomerised allylbromo sulfone 348

* Computational analyses of these mechanisms were conducted by Dr Elizabeth Krenske (University of Queensland). Density functional theory calculations were performed in Gaussian 09. Geometries were optimized with M06-2X/6-31G(d) in implicit tetrahydrofuran as modeled with the SMD solvent model. Vibrational frequency calculations at this level were performed to determine whether stationary points were minima or first-order saddle points and to obtain thermochemical quantities. Single-point energy calculations were subsequently performed with M06-2X/6-311+G(d,p) in SMD implicit tetrahydrofuran. The thermochemical corrections obtained from the M06-2X/6-31G(d) frequencies were added to the solution-phase M06-2X/6- 311+G(d,p) potential energies to give Gibbs free energies in solution, which are reported at a standard state of 298.15 K and 1 mol/L. For additional information see the supplementary information in Org. Biomol. Chem. 2017, pp 5529 – 5534.

Chapter 4 A novel vinyl sulfone trimerization

electrophile to produce the diene 349. Deprotonation of 349 gives anion 349a and a second SN2 attack of 348 forms the triene 350. Deprotonation to give anion 350a followed by a 6-exo-trig23 conjugate cyclisation forms the final C-C bond and two stereocentres and a protonation of the resultant anion 343a from the least hindered face yields the cyclohexene 343.

Scheme 4.12 Proposed mechanism involving SN2 reactions for the formation of cyclohexene 343.

Scheme 4.13 Proposed mechanism for the formation of cyclohexene 343 involving SN2’ reactions and Cope rearrangements.

Chapter 4 A novel vinyl sulfone trimerization

A second mechanistic rationale for the formation of cyclohexene 343 (Scheme 4.13) involved the alternative resonance form -anion 348a reacting with the allyl bromide 348 via SN2’ attack24 to afford the 1,5-diene 351. This is primed to then participate in a [3,3]-Cope rearrangement25 and the resultant product is then deprotonated to form the -anion 352 which can undergo a second SN2’ with 348 to yield the 1,5-diene 353. This can also undergo Cope rearrangement, and deprotonation gives the -anion 350a. A final 6-exo-trig conjugate-type cyclisation as proposed in the SN2 sequence above (Scheme 4.12) affords cyclohexene 343.

Scheme 4.14 Calculated transition states for SN2 and SN2’ reactions (ΔG in kcal/mol).

16 Calculations revealed that the rate of the SN2’ reaction was favoured by a factor of 8.16x10 at -

78 °C over the SN2 mode of attack This strongly supported the proposal that the first step of the sequence forms the 1,5-diene 351 via SN2’ attack and not the alternative 1,5-diene 349 via SN2 attack. The 1,5-diene 351 could then undergo a Cope rearrangement to furnish either the Z-diene (Z-352) or E-diene (E-352) that could subsequently undergo further deprotonation. Calculations suggest the rate of the Cope rearrangement that produces the Z isomer Z-352 was 2.44 x 104 times faster at -78 °C than the formation of the E-isomer E-352 (Scheme 4.15) which was

Chapter 4 A novel vinyl sulfone trimerization

attributed to the bulky aryl sulfone substituent preferring the equatorial orientation reflecting the

26 difference in A values of SO2Ar (2.94) and Br (0.48) substituents in cyclohexanes.

Scheme 4.15 Calculated transition states for Cope rearrangements of diene 351 (ΔG in kcal/mol).

A second SN2’ reaction as described in Scheme 4.13 followed by another Cope rearrangement then produced triene 350. Deprotonation of 350 gives the -anion 350a which can cyclise by an intramolecular conjugate addition into the highly electrophilic vinyl sulfone to afford the sulfone anion 343a. DFT studies suggested that formation of the observed trans product was favoured with a transition state energy difference of 4.7 kcal/mol (Scheme 4.16).

Chapter 4 A novel vinyl sulfone trimerization

Scheme 4.16 Transition state energies for the cis- and trans- cyclisation products of the cyclisation (ΔG in kcal/mol).

The final stereocentre is installed by protonation of carbanion 343a and this step is also completely stereoselective (Scheme 4.17). It was not possible to model the protonation of 343a, because the exact identity of the proton donor is unknown however, computations indicate that the experimentally observed product 343 is 4.9 kcal/mol more stable than the C1’-epimer (epi- 343). This result is consistent with a thermodynamically controlled protonation step, but it does not rule out the possibility that protonation leading to 343 is also kinetically favoured.

Scheme 4.17 Calculated structures for cyclohexene 343 and the C1’ epimer epi-343 (ΔG in kcal/mol).

Chapter 4 A novel vinyl sulfone trimerization

DFT calculations support the reaction sequence to form 343 from 340 proceeding by a series of

SN2’ additions and Cope rearrangements, followed by conjugate addition-cyclisation and protonation (Scheme 4.13).20 This is an unusual process not previously documented and appears to be somewhat substrate specific. The high degree of stereocontrol in a single transformation provides a complex synthetic intermediate.

Chapter 4 A novel vinyl sulfone trimerization

4.3 Bibliography

(1) Tobisu, M.; Nakamura, R.; Kita, Y.; Chatani, N. J. Am. Chem. Soc. 2009, 131 (9), 3174– 3175. (2) Kita, Y.; Tobisu, M.; Chatani, N. J. Synth. Org. Chem. Japan 2010, 68 (11), 1112–1122. (3) Nagai, Y. Org. Prep. Proced. Int. 1980, 12 (1–2), 13–48. (4) Li, W.; Li, J.; Wan, Z. K.; Wu, J.; Massefski, W. Org. Lett. 2007, 9 (22), 4607–4610. (5) Li, Z.; Jangra, H.; Chen, Q.; Mayer, P.; Ofial, A. R.; Zipse, H.; Mayr, H. J. Am. Chem. Soc. 2018, 140 (16), 5500–5515. (6) Vogt, F.; Tavares, F. Can. J. Chem. 1969, 47, 2875–2881. (7) Yoshio, U.; Sano, H.; Aoki, S.; Okawara, M. Tetrahedron Lett. 1981, 22 (28), 2675– 2678. (8) Semmelhack, M. F.; Keller, L.; Sato, T.; Spiess, E. J. Org. Chem. 1982, 47 (22), 4382– 4384. (9) Fabre, J. L.; Julia, M. Tetrahedron Lett. 1983, 24 (40), 4311–4314. (10) Sato, K.; Seiichi, I.; Onishi, A.; Uchida, N.; Minowa, N. J.C.S. Perkin I 1981, 761–769. (11) Nanda, S. Tetrahedron Lett. 2005, 46, 3661–3663. (12) Michael, J. P.; Koning, C. B. De; Malefetse, T. J.; Yillah, I. Org. Biomol. Chem. 2004, 2, 3510. (13) Muchowski, M.; Wu, Y. Tetrahedron Lett. 1994, 35 (11), 1639–1642. (14) Huang, D. F.; Shen, T. Y. Tetrahedron Lett. 1993, 34 (28), 4477–4480. (15) Nájera, C.; Yus, M. Tetrahedron 1999, 55 (35), 10547–10658. (16) Chawla, R.; Kapoor, R.; Singh, A. K.; Yadav, L. D. S. Green Chem. 2012, 14, 1308. (17) Philips, J. C.; Aregullin, M.; Oku, M.; Sierra, A. Tetrahedron Lett. 1974, 15 (47), 4157– 4160. (18) Chudasama, V.; Wilden, J. D. A Chem. Commun. 2008, No. 32, 3768. (19) Hudlicky, T.; Radesca, L.; Rigby, H. L. J. Org. Chem. 1987, 52, 4397–4399. (20) Fisher, B.; Lepage, R. J.; White, J. M.; Ye, Y.; Krenske, E. H.; Rizzacasa, M. A. Org. Biomol. Chem. 2017, 15, 5529–5534. (21) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120 (1–3), 215–241. (22) Marenich, A. V; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113 (18), 6378– 6396. (23) Baldwin, J. E. J. Chem. Soc. Chem. Commun. 1976, 734–736. (24) DeWolfe, R. H.; Young, W. G. Chem. Rev. 1956, 56 (4), 753–901. (25) Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441–444. (26) Juaristi, E.; Labastida, V.; Antúnez, S. J. Org. Chem. 2000, 65 (4), 969–973.

Chapter 4 A novel vinyl sulfone trimerization

Chapter 5 Synthesis of Violaceic acid

5. Synthesis of Violaceic acid (11)

5.1 Biaryl ether coupling

An early approach to the synthesis of violaceic acid1 involved Pd catalyzed cross coupling reactions to form the biaryl ether.2–5 Tokuyama et al. described a synthesis of a biaryl ether related to violaceic acid using an Ullmann-type coupling (Scheme 5.1) and similar couplings were also tested by Koide et al. in their synthesis of violaceic acid (Scheme 5.1).

Scheme 5.1 Ullmann-type biaryl ether synthesis.6,7

Copper catalyzed Ullmann-type coupling produced the related biaryl ether 111 in low yield6 but a palladium catalyzed Ullmann-type coupling was unsuccessful.7 It was hypothesized that the electron donating ortho methoxy substituent significantly hampers the reaction.7 Previous studies in the Rizzacasa group involving the formation of functionalised biaryl ethers that could be elaborated to violaceic acid via either Buchwald or Ullmann-type couplings were also not fruitful (Scheme 5.2).1

Chapter 5 Synthesis of Violaceic acid

Scheme 5.2 Attempted Buchwald and Ullmann couplings.1

These results are not surprising since these substrates are poor precursors for Buchwald coupling due to the electron donating ortho substituents and the ligand used.1,2 In addition, there is also limited precedent for the use of ortho substituted aryl halides for Ullmann couplings,3–5,7 so these approaches were not pursued. Therefore, an alternative route involving nucleophilic aromatic substitution between an ortho-fluoro-nitrobenzene and phenol was investigated (Scheme 5.3).8 This reaction proceeds via deprotonation of the phenol (371 or 117) to form the phenolate anion which undergoes nucleophilic attack at the carbon bearing the fluoro substituent. The resonance stabilized Meisenheimer intermediate (369)9 then eliminates the fluoride resulting in rearomatisation to furnish the biaryl ether.10

Chapter 5 Synthesis of Violaceic acid

10 8 Scheme 5.3 The SNAr reaction mechanism, previous synthesis of biaryl ether 373, and formation of violaceic acid biaryl ether precursor 136.1,8

Treatment of a mixture of commercially available phenol 117 and fluorobenzene 124 with NaH gave the desired biaryl ether 136 in excellent yield.1 Elaboration to the natural product violaceic acid then only required conversion of the nitro group to an alcohol and hydrolysis of the ester.

5.2 Selective reduction of nitro 136 to amine 135

There are a number of methods for converting the nitro group to a phenol via an amine.4,11 A significant challenge was the conversion of the nitro group to an amine without reduction of the aldehyde. A number of methods were previously tested including iron and palladium mediated reductions,12–15 but none were successful. Reduction of nitro compound 136 with tin(II) chloride in ethanol was highly chemoselective giving the corresponding amine 135 in 60%.1,16 Other methods such using mossy tin17 or dithionite18 as a reducing agent were ineffective and only resulted in starting material.

Scheme 5.4 Selective tin(II)-mediated reduction of the nitro group.

Chapter 5 Synthesis of Violaceic acid

5.3 Sandmeyer hydroxylation and hydrolysis of violaceic acid methyl ester (374)

Previous work utilized a Sandmeyer reaction to afford the methyl ester of violaceic acid1 based on a report by Cohen.11 Diazotization of amine 135 in the presence of fluoroboric acid and subsequent treatment with copper(II) nitrate and copper(II) oxide gave significant quantities of by-products 375 and 376, and very little of the desired phenol 374.

1 Scheme 5.5 Results of Sandmeyer hydroxylation using Cu2O and glycine as additives.

With glycine as an additive,19 the selectivity of the reaction significantly improved giving the phenol 374 in an improved yield and the amount of by-products were reduced.1 The glycine ligand increases the rate of hydroxylation of the aryl radical compared to the competing processes.1,19 Efforts to improve the yield of the desired phenol were not successful. Violaceic acid methyl ester 374 was then hydrolysed with aqueous lithium hydroxide to give violaceic acid (11) in good yield.

Scheme 5.6 Synthesis of violaceic acid (11).

Chapter 5 Synthesis of Violaceic acid

1 Figure 5.1 H NMR spectrum of synthetic violaceic acid 11 (400 MHz, d6-DMSO).

13 Figure 5.2 C NMR spectrum of synthetic violaceic acid 11 (101 MHz, d6-DMSO).

Chapter 5 Synthesis of Violaceic acid

Table 5.1 13C NMR chemical shifts comparison between synthetic and natural violaceic acid 11

(101 MHz, d6-DMSO.

Synthetic Violaceic acid 13C Natural Violaceic acid 13C 13C chemical shift chemical shifts (ppm) chemical shifts (ppm) difference (ppm) 191.21 190.61 0.6 166.98 166.44 0.54 154.88 154.32 0.56 154.24 153.79 0.45 145.12 144.65 0.47 144.69 144.27 0.42 129.28 128.83 0.45 128.43 127.83 0.6 126.67 126.17 0.5 123.68 123.22 0.46 119.40 118.81 0.59 119.13 118.75 0.38 117.61 117.09 0.52 113.07 112.59 0.48 56.46 55.95 0.51

The total synthesis of violaceic acid (11) was thereby completed in 4 steps with an 11% overall yield. The 1H NMR and 13C NMR spectra of the product was in accordance to those published by Seya et al. and Koide et al. with an average 13C NMR chemical shift difference of 0.50 ppm (Table 5.1, Figure 5.1).7,20

5.4 Attempted modifications of the original route

Aryl bromides can be converted into to phenols via a pinacolborane intermediate which in turn can be synthesized by a Pd catalysed cross coupling with pinacol borane (378).21,22 Bromination of the amine 135 using a reported method23 gave bromide 377 but borylation21 failed, possibly due to electronic effects present in the biaryl ether and no similar examples were reported (Scheme 5.7).21

Chapter 5 Synthesis of Violaceic acid

Scheme 5.7 Attempted formation of boronate ester 379.

Nakao et al. have described the Suzuki-Miyaura coupling of nitroarenes24 and this was applied to the direct coupling of a nitroarene 136 in hope to yield biaryl product 379 (Scheme 5.8).

Unfortunately, the nitroarene 136 failed to undergo coupling with B2pin2 (383) in place of an arylboronic acid.21,22 and the amine 135 was the only product formed.

Scheme 5.8 Suzuki-Miyaura coupling of nitroarenes24 and attempted cross coupling of nitroarene 136.

25 B2pin2 mediated reductions of nitroarenes had been reported by Wu et al. in 2016, suggesting that the observed reaction in Scheme 5.8 involved a similar nitroarene reduction without requiring Pd catalysis. This method was then optimized to determine whether it was an more efficient approach to the amine intermediate than the original tin(II) chloride reduction (Scheme 5.4). While these reactions proceeded to give the amine 135 smoothly as a single product, the yield was low and removing the excess B2pin2 was difficult, so this reduction offered no improvement on the SnCl2 mediated approach.

Chapter 5 Synthesis of Violaceic acid

Scheme 5.9 Borane reduction of nitroarene 136.25

5.5 Formal synthesis of Violaceic acid (11)

The synthesis of violaceic acid described above could also provide the known iodide7 which would constitute a short formal synthesis. Several methods for the Sandmeyer iodination26–28 of amine 135 were trialed however all resulted in significant unwanted proto-deazotization the product of which was difficult to separate from the iodide.

Scheme 5.9 Iodination of amine 135.29

A superior iodination reaction was found based on a reported procedure29 which involved formation of the ammonium tosylate salt followed by very slow addition of an aqueous solution of sodium nitrite and potassium iodide which gave biaryl iodide 119 in good yield (Scheme 5.9). Slow addition of the iodide solution was crucial in obtaining a high yield whilst avoiding proto- deazotization of the intermediate. The biaryl iodide was synthesized in 3 steps and 43% overall yield from the commercially available benzenes 117 and 124 which represents an improvement on the reported method (36% yield over 4 steps).7

As described in Chapter 1.7, it was reported7 that violaceic acid 11 could be formed in quantitative yield by palladium catalysed oxidation and concomitant hydrolysis of the iodide 119. However, when the conditions described were applied to the iodide 119, impure violaceic acid 11 was formed (Figure 5.3) in an estimated 50% yield (Scheme 5.10), and this could not be purified (when compared to that obtained in Scheme 5.6). Methylation of the impure sample gave the known methyl ester 111 in 40% yield over the two steps, suggesting that the original coupling was indeed inefficient. Therefore, the route described in this chapter allows access to pure violaceic acid in a reproducible yield when compared to the reported synthesis.7,30

Chapter 5 Synthesis of Violaceic acid

Scheme 5.10 Conversion of biaryl iodide 119 to impure violaceic acid 11.7

Figure 5.3 1H NMR comparison of violaceic acid 11 obtained via LiOH hydrolysis of 119 and

7 the reported method (400 MHz, d6-DMSO).

In conclusion, a 4 step total synthesis of violaceic acid 11 was been achieved in an 11% overall yield.30 In addition, an improved synthesis of known violaceic acid intermediate iodide 1197 was achieved in 3 steps and overall yield of 43% which is an improvement of the published approach (36% yield over 4 steps). The structure of violaceic acid 11 was therefore confirmed.7,31,32

100

Chapter 5 Synthesis of Violaceic acid

5.6 Bibliography

(1) Cameron, A. J. Studies Toward the Total Synthesis of Dethiosecoemestrin, Masters Thesis, University of Melbourne, 2015. (2) Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew. Chemie - Int. Ed. 2006, 45 (26), 4321–4326. (3) Cristau, H. J.; Cellier, P. P.; Hamada, S.; Spindler, J. F.; Taillefer, M. Org. Lett. 2004, 6 (6), 913–916. (4) Cai, Q.; Zou, B.; Ma, D. Angew. Chemie - Int. Ed. 2006, 45 (8), 1276–1279. (5) Niu, J.; Zhou, H.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2008, 73 (19), 7814–7817. (6) Kurogi, T.; Okaya, S.; Fujiwara, H.; Okano, K.; Tokuyama, H. Angew. Chem. Int. Ed. Engl. 2016, 55 (1), 283–287. (7) Ando, S.; Burrows, J.; Koide, K. Org. Lett. 2017, 19 (5), 1116–1119. (8) Bunce, R. A.; Easton, K. M. Org. Prep. Proced. Int. 2004, 36 (1), 76–81. (9) Meisenheimer, J. European J. Org. Chem. 1902, 323 (2), 205–246. (10) Goldstein, S. W.; Bill, A.; Dhuguru, J.; Ghoneim, O. J. Chem. Educ. 2017, 94 (9), 1388– 1390. (11) Cohen, T.; Dietz, A. G.; Miser, J. R. J. Org. Chem. 1977, 42 (12), 2053–2058. (12) Wulfman, D. S.; Cooper, C. F. Synthesis (Stuttg). 1978, 12, 924–925. (13) Channe Gowda, D.; Gowda, S. F Indian J. Chem. - Sect. B Org. Med. Chem. 2000, 39 (9), 709–711. (14) Weidner-Wells, M. A.; Ohemeng, K. A.; Nguyen, V. N.; Fraga-Spano, S.; Macielag, M. J.; Werblood, H. M.; Foleno, B. D.; Webb, G. C.; Barrett, J. F.; Hlasta, D. J. Bioorganic Med. Chem. Lett. 2001, 11 (12), 1545–1548. (15) Leslie, C. P.; Fabio, R. Di; Bonetti, F.; Borriello, M.; Braggio, S.; Forno, G. D.; Donati, D.; Falchi, A.; Ghirlanda, D.; Giovannini, R.; et al. Bioorganic Med. Chem. Lett. 2007, 17 (4), 1043–1046. (16) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 26 (11), 1362. (17) Rebstock, T. L.; Ball, C. D.; Hamner, C. L.; Sell, H. M. J. Am. Chem. Soc. 1956, 78 (22), 5831–5832. (18) Gorvin, J. H. J. Chem. Soc. 1949, 3304–3311. (19) Hanson, P.; Rowell, S. C.; Walton, P. H.; Timms, A. W. Org. Biomol. Chem. 2004, 2 (13), 1838–1855. (20) Seya, H.; Nozawa, K.; Nakajima, S.; Ken-ichi, K.; Shun-ichi, U. J. Chem. Soc., Perkin Trans. 1 1986, 67 (5), 109–116. (21) Birkett, S.; Ganame, D.; Hawkins, B. C.; Quach, T.; Rizzacasa, M. A. Org. Lett. 2011, 13 (8), 1964–1967.

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(22) Billingsley, K. L.; Buchwald, S. L. J. Org. Chem. 2008, 73 (14), 5589–5591. (23) McQuaid, K. M.; Long, J. Z.; Sames, D. Org. Lett. 2009, 11 (14), 2972–2975. (24) Yadav, M. R.; Nagaoka, M.; Kashihara, M.; Zhong, R.; Miyazaki, T.; Sakaki, S.; Nakao, Y. J. Am. Chem. Soc. 2017, 139 (28), 9423–9426. (25) Lu, H.; Geng, Z.; Li, J.; Zou, D.; Wu, Y.; Wu, Y. Org. Lett. 2016, 18, 2774–2776. (26) Ito, N.; Esaki, H.; Maesawa, T.; Imamiya, E.; Maegawa, T.; Sajiki, H. Bull. Chem. Soc. Jpn. 2008, 81 (2), 278–286. (27) Tietze, L. F.; Düfert, M. A.; Hungerland, T.; Oum, K.; Lenzer, T. Chem. - A Eur. J. 2011, 17 (30), 8452–8461. (28) Yang, K. S.; Budin, G.; Reiner, T.; Vinegoni, C.; Weissleder, R. Angew. Chemie - Int. Ed. 2012, 51 (27), 6598–6603. (29) Krasnokutskaya, A.; Semenischeva, N. I.; Filimonov, V. D.; Knochel, P. Synthesis (Stuttg). 2007, 1, 81–84. (30) Cameron, A.; Fisher, B.; Rizzacasa, M. A. Tetrahedron 2018, 74 (12), 1203–1206. (31) Yamazaki, M.; Maebayashi, Y. Chem. Pharm. Bull. 1982, 30 (2), 509–513. (32) Seya, H.; Nozawa, K.; Udagawa, S.; Nakajima, S.; Kawai, K. Chem. Pharm. Bull. 1986, 34 (6), 2411–2416.

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103

Chapter 6 Future work and conclusions

6. Future work and conclusions

6.1 Synthesis of the tricyclic core of the emestrin family of natural products

It may be useful to form a triketopiperazine pyrrole aldehyde and subsequently form the dihydrooxepine through the aforementioned Darzens reaction and Cope rearrangement. This avoids the use of protecting groups and thus the synthesis of the key dihydrooxepine pyrrole core would be shorter and more efficient. The diketopiperazine found in emestrin (4) could be formed through a peptide coupling protocol described by Negoro et al followed by a base mediated ring closure1 however all attempts to couple a range of pyrrole acids failed (Scheme 6.1.).

Scheme 6.1 Attempts to form a diketopiperazine through a peptide coupling reaction.

Scheme 6.2 Attempts towards a triketopiperazine pyrrole aldehyde.

Amide 388 was formed in quantitative yield and then subjected to acylation (Scheme 6.2.)2,3 which resulted in the formation of the triketopiperazine 389 directly. This was evidenced by the 13C NMR spectrum which contained three carbonyl resonances at 155.7, 155.2 and 148.0 ppm

+ (Figure 6.1) and the mass spectrum (HRMS calc. for C8H6N2O3 [M + H] = 179.04567, found

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Chapter 6 Future work and conclusions

179.04514). This highlights the difference in reactivity between pyrroles and pyrrolidines. Unfortunately, attempts to formylate this substrate via a Rieche or Vilsmeier-Haack reaction were both unsuccessful. The iodide gave the amide 390 in a lower yield and this was converted into the triketopiperazine 391 in a similar manner. This could serve as a precursor to the vinyl epoxide via a route similar to that described in chapter 3.1.1.

13 Figure 6.1 C NMR spectrum of triketopiperazine 389 (126 MHz, CDCl3).

6.2 Future work and revised route towards the tricyclic core of the emestrins

Future work will focus on the optimisation of the decarbonylative or decarboxylative route, with the potential to screen an array of catalysts in this reaction. A modified approach to the core of the emestrins with the triketopiperazine installed prior to the Darzens reaction and Cope rearrangement is shown in Scheme 6.3.

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Chapter 6 Future work and conclusions

Scheme 6.3 Proposed modified approach to the emestrins.

6.3 Conclusion

A dihydrooxepino[4,3-b]pyrrole analogue (398) of the emestrins can be synthesised in 46% yield in 5 steps (Scheme 6.4.) from commercially available trichloroacetylpyrrole as described in Chapter 3. The fully substituted system with a triethoxysilyl substituent was synthesised in 6 steps and 7% overall yield (Scheme 5.4, Chapter 3.3). The C2 ester on the epoxide was critical for a successful Cope rearrangement,4 however the removal of this functional group remains to be optimised.

Scheme 6.4 The synthetic approach towards the emestrin family of natural products.

Attempted Darzens reaction of the α-bromosulfone 340 resulted in the formation of the cyclic

5 product 343. This was formed by a series of SN2’ reactions and Cope rearrangements followed by cyclisation and protonation and this mechanism was supported by a series of experiments and DFT calculations (Scheme 6.6.).

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Chapter 6 Future work and conclusions

Scheme 6.5 An unprecedented stereoselective base-induced trimerization of an α-bromosulfone.

A 4 step synthesis of violaceic acid (11) was described starting from commercially available arenes 117 and 354.6 An improved formal synthesis of known biaryl iodide 1197 was also described which was converted into impure violaceic acid in low yield using published methods (Scheme 6.6).7

Scheme 6.6 Synthesis of violaceic acid (11) and formal synthesis of biaryl iodide 119.

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6.4 Bibliography (1) Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.; Kuromiya, A.; Komiya, M.; Suzuki, K.; Matsumoto, J. J. Med. Chem. 1998, 41, 4118–4129. (2) Tutino, F.; Papeo, G.; Quartieri, F. J. Heterocycl. Chem. 2010, 47, 112–117. (3) Overman, L. E.; Shin, Y. Org. Lett. 2007, 9 (2), 339–341. (4) Cameron, A.; Fisher, B.; Fisk, N.; Hummel, J.; White, J. M.; Krenske, E. H.; Rizzacasa, M. A. Org. Lett. 2015, 17 (24), 5998–6001. (5) Fisher, B.; Lepage, R. J.; White, J. M.; Ye, Y.; Krenske, E. H.; Rizzacasa, M. A. Org. Biomol. Chem. 2017, 15, 5529–5534. (6) Cameron, A.; Fisher, B.; Rizzacasa, M. A. Tetrahedron 2018, 74 (12), 1203–1206. (7) Ando, S.; Burrows, J.; Koide, K. Org. Lett. 2017, 19 (5), 1116–1119.

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Chapter 7 Experimental section

7. Experimental section

7.1 General experimental

Melting points were obtained with an EZ-Melt automated melting point apparatus and are uncorrected. Infrared spectra were obtained using a Perkin Elmer 1600 series spectrometer with an attenuated total reflectance (ATR) attachment using a diamond/ZnSe single bounce crystal. Proton nuclear magnetic resonance spectra (1H NMR, 400 MHz, 500 MHz and 600 MHz) and proton decoupled carbon nuclear magnetic resonance spectra (13C NMR, 101 MHz, 126 MHz, 151 MHz) were obtained in deuterochloroform at ambient temperature on Varian 400, Varian Inova 500 and Inova 600 instruments with residual chloroform as internal standard unless otherwise specified. Deuterochloroform used for all NMR spectra of epoxides and dihydrooxepines was dried and neutralised with K2CO3 and basic alumina. Chemical shifts are followed by multiplicity, coupling constant(s) (J, Hz), integration and assignments where possible. High resolution mass spectra (HRMS) were obtained by ionizing samples via electron spray ionisation (ESI) using a ThermoScientific OrbiTrap Infusion instrument.

Flash chromatography was carried out using Merck silica gel 60 according to a procedure described by Still.1 Analytical thin layer chromatography (TLC) was conducted on aluminium- backed 2mm thick silica gel 60 GF254 and chromatograms were visualised with short wave UV, a 12.6% w/v aq. solution of 20:3:0.75 K2CO3:KMnO4:NaOH or 20% w/w phosphomolybdic acid in ethanol. When used as a reaction solvent, THF, ether and CH2Cl2 were used dry from a solvent cartridge system (glass contour) where solvents were dried by passage through two packed columns of neutral alumina under argon. NEt3, toluene and acetonitrile were distilled from CaH. Methanol was distilled from magnesium methoxide. Diisopropylamine (DIPA) and hexamethyldisilazane (HMDS) were distilled from NaOH. Dry DMF and HMPA were obtained by storage over 4Å molecular sieves. Unless otherwise specified commercially available reagents were used as received. O-tert-butyl-N,N-diisopropylisourea (202) was prepared according to the procedure published by Ohwada et al.2 Dess-Martin periodinane (DMP) was prepared according to the procedure published by Ireland.3 Dimethyl dioxirane (DMDO) was prepared according to the procedures published by Murray and Taber.4,5 Ozone was generated using OzoneLab OL80W ozonation equipment.

The usual workup refers to extraction into the specified solvent (3x), washing when specified (all reactions involving HMPA were washed 3x with water), drying over anhydrous MgSO4 (unless otherwise specified), filtering through a sintered glass funnel and concentrating under reduced pressure. Petrol refers to petroleum ether 40 – 60 °C boiling range. Ether refers to diethyl ether. Brine refers to saturated aq. NaCl. Unless otherwise specified, reactions were conducted under

110

Chapter 7 Experimental section

either N2 or argon atmospheres in glassware which had been flame dried or oven dried at 150 °C. It should be noted that all Darzens reactions conducted on a scale above 700mg of pyrrole aldehyde (approx. 2.37 mmol) incurred a significant reduction in yield.

7.2 Experimental methods

2,2,2-Trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone6 (172)

Silver trifluoroacetate (3.7 g, 16.8 mmol) and iodine (3.95 g, 15.6 mmol) were added to a solution of 2-trichloroacetylpyrrole (3.0 g, 14.1 mmol) in chloroform (40 mL) at 0 °C and the solution was stirred at 0 °C for 4 h. The reaction was quenched with sat. Na2S2O3, separated and extracted with

CH2Cl2. The combined organic layers were washed with sat. Na2S2O3, brine and water, then dried, filtered and solvents were evaporated. The crude residue (4.69 g, 98%) was used in the next step without further purification, and the spectral data were in accordance with that reported.6

1 H NMR (400 MHz; CDCl3): δ 9.45-9.43 (br s, 1H, NH), 7.45-7.44 (m, 1H, ArH), 7.21-7.19 (m, 1H, ArH).

Methyl 4-iodo-1H-pyrrole-2-carboxylate6 (183)

Sodium (1.4 g, 60.9 mmol) was added to methanol (50 mL) at 0 °C and a solution of the iodide 182 in methanol (60 mL) was added. The solution was warmed to rt and stirred for 1 h, after which time the reaction was acidified with 10% aq. HCl and extracted with CH2Cl2. The combined organic extracts were dried, filtered and the solvents were evaporated. The crude residue was filtered through a plug of silica gel (20% EtOAc/petrol as eluent) to afford the methyl ester 183 (3.010 g, 83%) as a red solid. The spectral data were in accordance with that reported.6

1 H NMR (400 MHz; CDCl3): δ 9.84 (br s, 1H, NH), 7.00-6.98 (m, 2H, ArH), 3.84 (s, 3H, -

OCH3).

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Chapter 7 Experimental section

2-(Prop-2-yn-1-yloxy)tetrahydro-2H-pyran7 (184)

para-Toluenesulfonic acid (165 mg, 0.867 mmol) was added to a solution of propargyl alcohol

(5 mL, 86.7 mmol) in CH2Cl2 (10 mL). The solution was cooled to 0 °C and dihydropyran (8.3 mL, 91 mmol) was slowly added. The reaction mixture was stirred at rt for 1 h and quenched with saturated aq. NaHCO3. The organic layer was separated, and the aqueous layer was extracted further with dichloromethane. The combined organic extracts were washed with brine and dried

(Na2SO4), filtered and solvents were evaporated to give 184 (11.67 g, 96%) as a yellow oil. The spectral data were in accordance with that reported.7

1 H NMR (400 MHz; CDCl3): δ 4.82 (t, J = 3.4 Hz, 1H, -OCH(CH2)O-), 4.32-4.20 (m, 2H, -

CCH2), 3.84 (m, 1H, -CH2), 3.53 (m, 1H, -CH2), 2.41 (t, J = 2.4 Hz, 1H, -CCH), 1.65-1.53 (m,

6H, -CH2);

13 C NMR (101 MHz; CDCl3): δ 96.8, 79.8, 73.8, 62.0, 54.0, 30.2, 25.3, 19.0.

Methyl 4-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-1H-pyrrole-2-carboxylate (185)

To a solution of the iodide 183 (4.625 g, 18.33 mmol) in N,N-dimethylformamide (30 mL) was added alkyne 184 (5.14 g, 36.7 mmol), NEt3 (7.2 mL, 51.3 mmol), and bis(triphenylphosphine)palladium(II) dichloride (1.96 g, 2.79 mmol). The solution was stirred for 15 min at rt after which time CuI (524 mg, 2.75 mmol) was added. The solution was stirred for 16 h at rt then water was added, and the mixture was extracted with ether. The combined organic extracts were washed with water and brine, then dried, filtered and solvents were evaporated. The crude residue was purified using flash chromatography (20% - 100% EtOAc/petrol as eluent) to afford the alkyne 185 (2.94 g, 61%) as a brown oil.

IR νmax (film): 3284, 2947, 2869, 1704, 1567, 1490, 1439, 1380, 1363, 1346, 1324, 1266, 1202, 1184, 1154, 1115, 1076, 1055, 1024, 1015, 987, 944, 927 cm-1;

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Chapter 7 Experimental section

1 H NMR (400 MHz; CDCl3): δ 9.10 (br s, 1H, NH), 7.11 (dd, J = 2.9, 1.4 Hz, 1H, ArH), 6.94 (t,

J = 1.9 Hz, 1H, ArH), 4.88 (t, J = 3.4 Hz, 1H, -OCH(CH2)O-), 4.48 (d, J = 15.7 Hz, 1H, -OCH2C-

), 4.41 (d, J = 15.7 Hz, 1H, -OCH2C-), 3.87-3.91 (m, 1H, -CH2), 3.85 (s, 3H, -OCH3), 3.53-3.58

(m, 1H, -CH2), 1.72-1.86 (m, 2H, -CH2), 1.61-1.68 (m, 2H, -CH2), 1.51-1.56 (m, 2H, -CH2);

13 C NMR (101 MHz; CDCl3): δ 126.5, 122.5, 118.1, 117.5, 106.3, 96.8, 84.2, 79.7, 62.0, 54.9, 51.7, 30.3, 25.4, 19.0;

+ HRMS (ESI) calc. for C14H17NO4 [M + H] = 264.1191, found 264.1230.

(Z)-methyl 4-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-en-1-yl)-1H-pyrrole-2-carboxylate (186)

A suspension of Ni(OAc)2•4H2O (993 mg, 3.99 mmol) in EtOH (10 mL) was degassed and placed under an atmosphere of H2 gas. A 5% v/v solution of 2.5 M aq. NaOH in ethanol (4.3 mL) was added to NaBH4 (163 mg, 37.8 mmol) and this was degassed before adding to the suspension of

Ni(OAc)2•4H2O and the mixture turned black. Ethylenediamine (1.28 mL, 60.1 mmol) was added followed by a solution of the alkyne 185 (422 mg, 1.60 mmol) in degassed ethanol (10 mL). The resultant solution was stirred at rt for 2.5 h then filtered through a plug of silica gel and CeliteTM with EtOAc as an eluent. The residue was purified by flash chromatography (20% EtOAc/petrol as eluent) to give the alkene 186 (283 mg, 66%) as a yellow oil.

IR νmax (film): 3293, 2945, 2868, 1670, 1568, 1488, 1439, 1389, 1353, 1315, 1285, 1265, 1233, 1199, 1113, 1076, 1066, 1022, 999, 963, 903 cm-1;

1 H NMR (600 MHz; CDCl3): δ 9.73-9.68 (br s, 1H, NH), 6.93 (d, J = 1.2 Hz, 1H, ArH), 6.85 (d,

J = 1.4 Hz, 1H, ArH), 6.34 (d, J = 12 Hz, 1H, -CH=CH), 5.66-5.62 (m, 1H, -CH=CHCH2), 4.69

(t, J = 3.7 Hz, 1H, -OCH(CH2)O-), 4.49 (ddd, J = 13.0, 5.8, 1.1 Hz, 1H, -OCH2CH), 4.29 (ddd,

J = 13.0, 6.6, 1.0 Hz, 1H, -OCH2CH), 3.89 (ddd, J = 11.1, 8.1, 2.9 Hz, 1H, CH2), 3.82 (s, 3H, -

OCH3), 3.52-3.49 (m, 1H, -CH2), 1.85-1.80 (m, 1H, -CH2), 1.74-1.69 (m, 1H, -CH2), 1.62-1.49

(m, 4H, -CH2);

13 C NMR (151 MHz; CDCl3): δ 161.67, 125.5, 123.4, 123.08, 123.06, 122.4, 115.4, 98.3, 64.6, 62.3, 51.5, 30.7, 25.4, 19.5;

+ HRMS (ESI) calc. for C14H19NO4 [M + H] = 266.1387, found 266.1386.

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Chapter 7 Experimental section

(Z)-1-tert-butyl-2-methyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-en-1-yl)-1H- pyrrole-1,2-dicarboxylate (187)

To a solution of the alkene 186 (283 mg, 1.06 mmol) in CH2Cl2 (15 mL) at 0 °C was added di- tert-butyl dicarbonate (0.73 mL, 3.18 mmol) followed by a solution of 4-(dimethylamino)pyridine

(6.5 mg, 0.053 mmol) and i-Pr2NEt (1.1 mL, 6.32 mmol) in CH2Cl2 (5 mL) via cannula. The reaction mixture was stirred at 0 °C for 1.25 h and was then quenched with water. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and the solvents were evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as eluent) to afford the pyrrole 187 (387 mg, 100%) as a colourless oil.

IR νmax (film): 3447, 2946, 1726, 1478, 1437, 1394, 1370, 1327, 1281, 1256, 1232, 1156, 1075, 1032, 975, 906 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.27 (d, J = 1.8 Hz, 1H, ArH), 6.83 (d, J = 1.9 Hz, 1H, ArH),

6.27 (d, J = 11.7 Hz, 1H, -CH=CH), 5.76 (dt, J = 11.9, 6.0 Hz, 1H, -CH=CHCH2), 4.69 (t, J =

3.6 Hz, 1H, -OCH(CH2)O-), 4.47 (ddd, J = 13.1, 5.8, 1.8 Hz, 1H, -OCH2CH), 4.27 (ddd, J =

13.1, 6.7, 1.5 Hz, 1H, -OCH2CH), 3.84 (s, 3H, -OCH3), 1.89 – 1.81 (m, 2H, -CH2), 1.77 – 1.70

(m, 2H, -CH2), 1.65 – 1.59 (m, 2H, -CH2), 1.59 (s, 9H, t-Bu), 1.56-1.51 (m, 2H, -CH2);

13 C NMR (101 MHz; CDCl3): δ 161.2, 148.2, 128.0, 125.4, 122.3, 121.7, 121.1, 98.3, 85.0, 64.2, 62.4, 51.96, 51.95, 30.7, 25.4, 23.5, 19.5;

+ HRMS (ESI) calc. for C19H27NO6 [M + H] 366.1911, found 366.1906.

(Z)-1-tert-butyl 2-methyl 4-(3-hydroxyprop-1-en-1-yl)-1H-pyrrole-1,2-dicarboxylate (188)

To a solution of the alkene 187 (59 mg, 0.161 mmol) in methanol (10 mL) was added camphorsulfonic acid (11 mg, 0.047 mmol) and the solution was stirred for 1.5 h at rt. The reaction was quenched with saturated aq. NaHCO3 and the mixture was extracted with ether. The combined organic layers were dried, filtered and the solvents were evaporated to give 188 (97%, 44 mg) as a yellow oil which was used in the next step without further purification.

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Chapter 7 Experimental section

IR νmax (film): 3406, 2986, 2952, 1724, 1575, 1478, 1458, 1436, 1395, 1371, 1328, 1304, 1281, 1256, 1232, 1153, 1075, 1027, 953 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.25 (d, J = 1.8 Hz, 1H, ArH), 6.81 (d, J = 1.9 Hz, 1H, ArH),

6.25 (dd, J = 11.6, 0.3 Hz, 1H, -CH=CH), 5.78 (dt, J = 11.8, 6.0 Hz, 1H, -CH=CHCH2), 4.43

(dd, J = 6.3, 1.1 Hz, 2H, -OCH2CH), 3.85 (d, J = 0.5 Hz, 3H, -OCH3), 1.87 (br s, 1H, -OH), 1.58 (d, J = 0.4 Hz, 9H, t-Bu);

13 C NMR (126 MHz; CDCl3): δ 161.1, 148.1, 130.3, 125.43, 125.38, 121.9, 121.5, 120.9, 85.2, 59.9, 52.0, 27.6;

+ HRMS (ESI) calc. for C14H19NO5 [M + Na] 304.1155, found 304.1153.

1-tert-butyl 2-methyl 4-((2S,3R)-3-vinyloxiran-2-yl)-1H-pyrrole-1,2-dicarboxylate (190)

To a solution of the alkene 188 (119 mg, 0.423 mmol) in CH2Cl2 (10 mL) at 0 °C was added approximately 0.1 M solution of dimethyldioxirane in acetone until all starting material was consumed as indicated by TLC analysis. The solution was concentrated in vacuo to give the epoxide (100%, 126 mg) as a colourless oil.

1 H NMR (600 MHz; CDCl3): δ 7.24 (s, 1H, ArH), 6.73 (s, 1H, ArH), 3.93 (d, J = 4.0 Hz, 1H, -

CHAr), 3.80 (s, 3H, -OCH3), 3.64-3.55 (m, 2H, -CH2OH), 3.33 (q, J = 5.1 Hz, 1H, -CHCH2), 2.10 (br s, 1H, -OH), 1.54 (s, 9H, t-Bu);

13 C NMR (151 MHz; CDCl3): δ 161.0, 147.8, 125.4, 124.27, 124.24, 119.6, 119.0, 85.3, 77.2, 77.0, 76.8, 60.5, 58.3, 52.0, 27.6.

To a solution of the crude epoxide (126 mg, 0.423 mmol) in CH2Cl2 (10 mL) was added NaHCO3 (171 mg, 2.03 mmol) followed by Dess-Martin periodinane (180 mg, 0.424 mmol). The solution was stirred at rt for 45 min and was then quenched with saturated aq. Na2S2O3 and saturated aq.

NaHCO3. The solution was extracted with ether and the combined organic layers were washed with a saturated aq. NaHCO3 followed by saturated aq. Na2S2O3. The organic layer was dried

(Na2SO4), filtered and the solvents were evaporated to give the crude aldehyde (112 mg) which was used in the next step without additional purification. Methyltriphenylphosphonium bromide (757 mg, 2.12 mmol) was dissolved in THF (10 mL) and cooled to 0 °C before adding potassium

115

Chapter 7 Experimental section tert-butoxide (213 mg, 1.90 mmol). The solution was stirred for 45 min and was then cooled to - 78 °C and a solution of the aldehyde (112 mg) in THF (10 mL) was added via cannula. The solution was stirred at -78 °C for 1 h then quenched with saturated aq. NH4Cl and extracted with ether. The combined organic layers were washed with saturated aq. NH4Cl and brine, then dried

(Na2SO4), filtered and the solvents were evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as eluent) to give the vinyl epoxide 190 (14 mg, 11%) as a yellow oil.

IR νmax (film): 2983, 1751, 1730, 1480, 1436, 1395, 1371, 1324, 1302, 1281, 1250, 1226, 1156, 1076, 984, 938, 846 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.28 (d, J = 1.8 Hz, 1H, ArH), 6.78 (d, J = 1.9 Hz, 1H, ArH),

5.57-5.54 (m, 2H, -CH=CH2), 5.36 (dd, J = 7.2, 4.7 Hz, 1H, -CH=CH2), 4.03 (d, J = 4.1 Hz, 1H,

-CHAr), 3.84 (s, 3H, -OCH3), 3.60 (q, J = 3.7 Hz, 1H, -CHCH=CH2), 1.58 (s, 9H, t-Bu);

13 C NMR (101 MHz; CDCl3): δ 161.0, 147.9, 132.1, 125.3, 124.5, 121.9, 120.1, 119.4, 85.1, 59.4, 53.8, 52.0, 27.6;

+ HRMS (ESI) calc. for C15H19NO5 [M + Na] 316.1155, found 316.1152.

1-tert-butyl 2-methyl 4-((2S,3R)-3-((E)-3-methoxy-3-oxoprop-1-en-1-yl)oxiran-2-yl)-1H- pyrrole-1,2-dicarboxylate (191)

To a solution of the crude epoxide above (129 mg, 0.434 mmol) in CH2Cl2 (10 mL) was added

NaHCO3 (220 mg, 2.62 mmol) followed by Dess-Martin periodinane (224 mg, 0.528 mmol). The solution was stirred at rt for 1.5 h and was then quenched with a saturated aq. Na2S3O4 and saturated aq. NaHCO3. Ether was added, and the solution was stirred vigorously for an additional 90 min. The solution was extracted with ether and the combined organic extracts were washed with water, a 2M aq. solution of Na2S2O3 and saturated aq. NaHCO3, then dried (Na2SO4) and filtered. The solvents were evaporated to afford the crude aldehyde (124 mg) which was dissolved in CH2Cl2 (10mL). Methyl 2-(triphenylphosphoranylidene)acetate (290 mg, 0.868 mmol) was added and the solution was stirred for 50 min at rt. The solvents were evaporated, and the crude residue was purified by flash chromatography (20% EtOAc/petrol as the eluent) to afford the vinyl epoxide 191 (52 mg, 34%) as a yellow oil.

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Chapter 7 Experimental section

IR νmax (film): 3370, 2953, 1753, 1725, 1659, 1480, 1437, 1396, 1372, 1305, 1281, 1245, 1153, 1076, 1027, 978 cm-1;

1 H NMR (500 MHz; CDCl3): δ 7.30 (dd, J = 1.9, 0.7 Hz, 1H, ArH), 6.77 (d, J = 1.9 Hz, 1H,

ArH), 6.58 (dd, J = 15.7, 7.8 Hz, 1H, -CHCO2CH3), 6.23 (dd, J = 15.7, 0.7 Hz, 1H, -CH=CH),

4.14 (d, J = 4.0 Hz, 1H, -CHAr), 3.85 (s, 3H, -OCH3), 3.74 (s, 3H, -OCH3), 3.72 (ddd, J = 7.8, 4.1, 0.7 Hz, 1H, -CHCH=CH), 1.59 (s, 9H, t-Bu);

13 C NMR (126 MHz; CDCl3): δ 165.6, 160.9, 147.8, 141.2, 126.3, 125.7, 124.6, 118.96, 118.94, 85.3, 57.7, 54.6, 52.0, 51.8, 27.6;

+ HRMS (ESI) calc. for C17H21NO7 [M + Na] 374.1210, found 374.1203.

5-(2,2,2-trichloroacetyl)-1H-pyrrole-3-carbaldehyde (197)

Aldehyde 197 was prepared by the method published by Frydman et al.8 2-

(Trichloroacetyl)pyrrole (5.00 g, 23.56 mmol) was dissolved in CH2Cl2 (20 mL) before addition of nitromethane (20 mL) and aluminium trichloride (3.20 g, 28.27 mmol). Solution was cooled to

-40 °C before addition of dichloromethyl methyl ether (2.5 mL, 28.27 mmol) in CH2Cl2 (5 mL). The solution was stirred at -40 °C for 2.5 h after which it was poured into ice water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and solvents were evaporated. The crude solid was triturated with 10% EtOAc/petrol. Solvents were evaporated to afford the product 197 (4.68 g, 83%) as a grey solid. The spectral data were in accordance with the published compound.8

1 H NMR (400 MHz; CDCl3): δ 9.97 (br s, 1H, NH), 9.92 (s, 1H, CHO), 7.75 – 7.78 (m, 2H, ArH);

13 C NMR (101 MHz; CDCl3): δ 119.5, 124.3, 128.1, 130.6, 173.9, 185.3.

Methyl 4-formyl-1H-pyrrole-2-carboxylate (198)

The pyrrole aldehyde 198 was prepared by the method published by Barker et al.9 Sodium (100 mg, 4.35 mmol) was dissolved in methanol (13 mL) and pyrrole aldehyde 197 (500 mg, 2.08

117

Chapter 7 Experimental section mmol) was added. The solution was stirred at rt for 1.25 h before making acidic with 10% aq. HCl. The solution was extracted with ether (3 x 30 mL) and the combined organic layers were dried, filtered, and the solvents were evaporated to afford the product 198 (290 mg, 91%) as a pink solid. The spectral data were in accordance with the published compound.9

1 H NMR (400 MHz; CDCl3): δ 9.85 (s, 1H, CHO), 9.82 (br s, 1H, -OH), 7.58 – 7.57 (dd, J = 1.6

Hz, 3.6 Hz, 1H, ArH), 7.32 (t, J = 2 Hz, 1H, ArH), 3.90 (s, 3H, -OCH3);

13 C NMR (101 MHz; CDCl3): δ 52.1, 114.2, 115.7, 127.6, 128.4, 161.2, 185.6.

1-tert-butyl 2-methyl 4-formyl-1H-pyrrole-1,2-dicarboxylate (199)

To a solution of the pyrrole aldehyde 198 (290 mg, 1.89 mmol) in CH2Cl2 (10 mL) at 0 °C was added a solution of di-t-butyl dicarbonate (825 mg, 3.78 mmol) in CH2Cl2 (10 mL) via cannula. The solution was stirred for 10 min and a solution of 4-(dimethylamino)pyridine (29 mg, 0.237 mmol) and i-Pr2NEt (0.66 mL, 3.78 mmol) in CH2Cl2 (5 mL) was then added via cannula. The solution stirred at 0 °C for 2 h then quenched with water. The solution was extracted with EtOAc and the combined organic layers were washed with brine and dried (Na2SO4), filtered, and solvents were evaporated. The crude residue was filtered through a plug of silica gel with 25% EtOAc/petrol as the eluent to afford the pyrrole 199 (396 mg, 83%) as a yellow oil.

IR νmax (film): 2985, 1763, 1732, 1687, 1564, 1486, 1460, 1437, 1417, 1372, 1340, 1283, 1260, 1232, 1151, 1114, 1078, 954, 910 cm-1;

1 H NMR (600 MHz; CDCl3): δ 9.82 (s, 1H, CHO), 7.88 (d, J = 1.7 Hz, 1H, ArH), 7.17 (d, J =

1.6 Hz, 1H, ArH), 3.86 (s, 3H, -OCH3), 1.59 (s, 9H, t-Bu);

13 C NMR (151 MHz; CDCl3): δ 184.9, 160.6, 132.2, 126.2, 117.0, 110.0, 86.7, 85.1, 52.3, 27.55;

+ HRMS (ESI) calc. for C12H15NO5 [M + Na] 276.0842, found 276.0840.

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Chapter 7 Experimental section

Ethyl 2-bromobut-2-enoate10,11 (174)

A solution of Br2 (14 g, 87.6 mmol) in CH2Cl2 (5 mL) was added to a solution of ethyl crotonate

(10.9 mL, 87.6 mmol) in CH2Cl2 (15 mL) at 0 °C. and the solution was stirred at rt for 2 h then was cooled to 0 °C and 1,8-diazabicyclo[5.4.0]undec-7-ene (15 mL, 100.3 mmol) was added and the mixture was stirred for 45 min. Ether was added to the reaction and the solution was made acidic with 10% aq. HCl. The mixture was separated and washed with saturated aq. Na2S2O3, and the aqueous layer was further extracted with ether. The combined organic layers were washed with saturated aq. Na2S2O3 and water before being dried, filtered and the solvents were evaporated. The crude residue was filtered through a plug of silica gel with 10% EtOAc/petrol as the eluent to give the bromo crotonate ester 174 (8.41 g, 50%) in a 3:1 mixture of E:Z isomers as a yellow oil. The spectral data obtained was in accordance that reported.10,11

1 (Z-174): H NMR (400 MHz; CDCl3):  7.37 (q, J = 6.8 Hz, 1H, -CHCH3), 4.28 (q, J = 7.1 Hz,

2H, -CH2CH3), 2.04 (d, J = 7.5 Hz, 3H, -CHCH3), 1.33 (q, J = 7.0 Hz, 3H, -CH2CH3).

1 (E-174): H NMR (400 MHz; CDCl3):  6.76 (q, J = 7.5 Hz, 1H, -CHCH3), 4.28 (q, J = 7.1 Hz,

2H, -CH2CH3), 1.95 (d, J = 6.8 Hz, 3H, -CHCH3), 1.33 (q, J = 7.0 Hz, 3H, -CH2CH3).

1-tert-butyl-2-methyl-4-((2S,3R)-3-(ethoxycarbonyl)-3-vinyloxiran-2-yl)-1H-pyrrole-1,2- dicarboxylate (200)

A solution of n-BuLi in hexanes (2.0 M, 1.78 mL, 3.55 mmol) was added to a solution of i-Pr2NH (0.49 mL, 3.55 mmol) and HMPA (0.61 mL, 3.55 mmol) in THF (2.5 mL) at -78 °C then the mixture was warmed to rt and stirred for 15 min. The reaction was then cooled to -100 °C and a solution of ester 174 (681 mg, 3.55 mmol) in THF (2 mL) at -78 °C was transferred to the reaction via a cooled cannula. A solution of the aldehyde 199 (300 mg, 1.18 mmol) in THF (4 mL) at -78 °C was then added to the reaction via cooled cannula. The reaction mixture was stirred for 1.5 h at -100 °C and for 45 min at -78 °C and was then quenched with saturated aq. NH4Cl. The solution was warmed to rt before extracting with ether. The combined organic layers were washed with

119

Chapter 7 Experimental section

water and brine, dried (Na2SO4), filtered, and the solvents evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as eluent) to afford the vinyl epoxide 200 (316 mg, 73%) as a yellow oil.

IR νmax (film): 2983, 1726, 1585, 1479, 1459, 1436, 1394, 1370, 1327, 1306, 1276, 1255, 1232, 1152, 1075, 1045.6, 987, 951 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.24 (d, J = 1.7 Hz, 1H, ArH), 6.73 (d, J = 1.7 Hz, 1H, ArH),

6.05 (dd, J = 17.3, 10.9 Hz, 1H, -CH=CH2), 5.50 (dd, J = 17.3, 0.9 Hz, 1H, -CHCH2), 5.42 (dd,

J = 11.0, 0.9 Hz, 1H, -CHCH2), 4.27 (dq, J = 7.1, 2.0 Hz, 2H, -CH2CH3), 4.20 (s, 1H, -CHAr),

3.83 (s, 3H, -OCH3), 1.57 (s, 9H, t-Bu), 1.33 (t, J = 7.1 Hz, 3H, -CH2CH3);

13 C NMR (151 MHz; CDCl3): δ 168.8, 160.8, 147.8, 127.4, 125.5, 125.1, 120.5, 119.5, 117.8, 85.3, 62.9, 62.0, 59.4, 51.9, 27.5, 14.0;

+ HRMS (ESI) calc. for C18H23NO7 [M + Na] 388.1367, found 388.1368.

4-formyl-1H-pyrrole-2-carboxylic acid8 (201)

Pyrrole 197 (3.64 g, 15.14 mmol) was dissolved in 20% aq. NaOH (100 mL) and stirred under reflux for 1 h. The reaction was cooled then acidified with 10% aq. HCl. The solution was extracted with ether, dried, filtered and the solvents were evaporated. The crude residue (1.33 g, 63%) was used in the next step without further purification. The spectral data obtained was in accordance with that reported.8

1 H NMR (500 MHz; DMSO-d6)  12.50 (br s, 1H, -CO2H), 9.73 (s, 1H, CHO), 7.75 (s, 1H, ArH), 7.07 (s, 1H, ArH), 3.50 (br s, 1H, NH). tert-butyl 4-formyl-1H-pyrrole-2-carboxylate (203)

To a solution of the acid 201 (140 mg, 1.00 mmol) in CH2Cl2 (20 mL) was added O-tert-butyl- N,N-diisopropylisourea (202) (650 mg, 3.25 mmol). The solution was stirred for 18 h then filtered

120

Chapter 7 Experimental section

TM through a plug of Celite with CH2Cl2 as the eluent. The crude residue was purified by flash chromatography (20% EtOAc/petrol as eluent) to afford the pyrrole 203 (123 mg, 63%) as a yellow oil.

IR νmax (film): 3274, 2979, 1705, 1663, 1559, 1501, 1477, 1443, 1416, 1395, 1367, 1389, 1357, 1213, 1157, 1110, 986, 963, 849, 831, 760, 746, 734 cm-1;

1 H NMR (600 MHz; CDCl3): δ 9.83 (s, 1H, CHO), 9.52 (br s, 1H, NH), 7.51 (s, 1H, ArH), 7.23 (s, 1H, ArH), 1.56 (s, 9H, t-Bu);

13 C NMR (151 MHz; CDCl3): δ 185.9, 160.7, 128.5, 127.2, 126.4, 113.8, 82.2, 28.2;

+ HRMS calc. for C10H13NO3 [M + H] = 196.0968, found 196.0967.

Di-tert-butyl 4-formyl-1H-pyrrole-1,2-dicarboxylate (204)

To a solution of t-butyl ester 203 (123 mg, 0.626 mmol) in CH2Cl2 (5 mL) at 0 °C was added a solution of di-tert-butyl dicarbonate (410 mg, 1.88 mmol) in CH2Cl2 (10 mL) via cannula. The solution was stirred for 10 min and a solution of 4-(dimethylamino)pyridine (8 mg, 0.07 mmol) and i-Pr2NEt (0.33 mL, 1.9 mmol) in CH2Cl2 (5 mL) was then added via cannula. The solution stirred at 0 °C for 1.5 h then quenched with water. The solution was extracted with EtOAc and the combined organic layers were washed with water and brine, dried, filtered, and solvents were evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as eluent) to afford the pyrrole 204 (116 mg, 63%) as a yellow oil.

IR νmax (film): 2982, 1764, 1723, 1687, 1562, 1479, 1459, 1417, 1395, 1371, 1341, 1286, 1242, 1155, 1113, 1080, 1036, 910, 846, 823, 779, 732 cm-1;

1 H NMR (400 MHz; CDCl3): δ 9.82 (s, 1H, CHO), 7.84 (d, J = 1.8 Hz, 1H, ArH), 7.12 (d, J = 1.8 Hz, 1H, ArH), 1.60 (s, 9H, t-Bu), 1.55 (s, 9H, t-Bu);

13 C NMR (101 MHz; CDCl3): δ 185.1, 159.0, 147.4, 132.2, 128.9, 125.9, 116.5, 86.3, 82.1, 28.0, 27.6;

+ HRMS (ESI) calc. for C15H21NO5 [M+Na] 318.1312, found: 318.1310.

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Chapter 7 Experimental section

Di-tert-butyl-4-((2S,3R)-3-(ethoxycarbonyl)-3-vinyloxiran-2-yl)-1H-pyrrole-1,2- dicarboxylate (205)

A solution of n-BuLi in hexanes (1.1 M, 4.0 mL, 4.4 mmol) was added to a solution of i-Pr2NH (0.5 mL, 3.57 mmol) and HMPA (0.63 mL, 3.64 mmol) in THF (20 mL) at -78 °C and the solution was warmed to 0 °C. The reaction was then cooled to -100 °C and a solution of ester 174 (703 mg, 3.64 mmol) in THF (5 mL) was cooled to -78 °C and transferred to the reaction via a cooled cannula. A solution of the aldehyde 204 (308 mg, 1.08 mmol) in THF (5 mL) was cooled to -78 °C and transferred to the reaction via a cooled cannula. The reaction was stirred for 2 h at -100

°C and was then quenched with saturated aq. NH4Cl. The solution was warmed to rt before extracting with ether. The combined organic layers were washed with water and brine, dried

(Na2SO4), filtered, and the solvents evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as eluent) to afford the vinyl epoxide 205 (239 mg, 53%) as a yellow oil.

IR νmax (film): 2971, 1738, 1478, 1456, 1306, 1280, 1232, 1217, 1156, 1122, 1078, 1046, 987, 908, 849, 823, 776, 731, 676 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.17 (d, J = 1.9 Hz, 1H, ArH), 6.67 (d, J = 1.9 Hz, 1H, ArH),

6.04 (dd, J = 17.3, 10.9 Hz, 1H, -CH=CH2), 5.49 (dd, J = 17.3, 1.5 Hz, 1H, -CH=CH2), 5.41 (dd,

J = 10.9, 1.5 Hz, 1H, -CH=CH2), 4.31-4.23 (m, 2H, -CH2CH3), 1.57 (s, 9H, t-Bu), 1.53 (s, 9H, t-

Bu), 1.32 (d, J = 7.1 Hz, 3H, -CH2CH3);

13 C NMR (101 MHz; CDCl3): δ 169.0, 159.4, 147.9, 127.4, 127.1, 125.1, 120.5, 119.2, 117.4, 85.0, 81.4, 63.0, 62.1, 59.7, 28.1, 27.6, 14.1;

+ HRMS (ESI) calc. for C21H29NO7 [M + Na] 430.18362, found 430.18321.

2-(trimethylsilyl)ethyl but-2-enoate (208)

To a solution of crotonic acid (10.0 g, 116.2 mmol) in CH2Cl2 (100 mL) was added 2- (trimethylsilyl)ethanol (12.3 mL, 85.8 mmol) and 4-(dimethylamino)pyridine (1.05 g, 8.59

122

Chapter 7 Experimental section mmol). The solution was cooled to 0 °C and N,N'-dicyclohexylcarbodiimide (20.9 g, 101.3 mmol) was added. The solution was warmed to rt and stirred for 17 h. Pentane (50 mL) was added and

TM the suspension was filtered through a plug of Celite and washed with CH2Cl2. Purification on a plug of silica gel (20% EtOAc/petrol as eluent) afforded the ester 208 (14.4g, 92%) as a colourless oil.

IR νmax (film): 2953.4, 2856.4, 2119.8, 1718.4, 1659.4, 1146.1, 1378.3, 1310.8, 1294.1, 1262.0, 1249.8, 1173.4, 1102.0, 1061.2, 1044.3, 1004.5, 968.9, 937.3, 893.2, 857.6, 833.7, 763.7, 692.8, 666.4 cm-1;

1 H NMR (600 MHz; CDCl3): δ 6.94 (dq, J = 15.5, 6.9 Hz, 1H, -CHCH3), 5.82 (dq, J = 15.5, 1.7

Hz, 1H, -CH=CH), 4.22-4.19 (m, 2H, -OCH2), 1.86 (dd, J = 6.9, 1.7 Hz, 3H, -CHCH3), 1.01-0.98

(m, 2H, -CH2Si), 0.03 (s, 9H, -Si(CH3)3);

13 C NMR (151 MHz; CDCl3): δ 166.7, 144.1, 123.0, 62.2, 17.9, 17.3, -1.5;

+ HRMS calc. for C9H18O2Si [M + Na] = 209.09738, found 209.09656.

2-(trimethylsilyl)ethyl 2-bromobut-2-enoate (209)

A solution of bromine (3 g, 18.8 mmol) in CH2Cl2 (5 mL) was added to a solution of ester 208

(2.854 g, 15.32 mmol) in CH2Cl2 (5 mL) at 0 °C and the solution which was stirred for 2 h. 1,8- Diazabicyclo[5.4.0]undec-7-ene (2.75 mL, 18.38 mmol) was added and the solution was stirred for a further 90 min at 0 °C. Ether was added to the reaction which was then acidified with 10% aq. HCl. The biphasic mixture was separated, and the organic layer was washed with sat. aq.

Na2S2O3. The aqueous layer was further extracted with ether and the combined organic layers were washed with sat. aq. Na2S2O3 and water. The organic layer was dried and filtered through a plug of silica gel with ether as the eluent. The solvents were evaporated, and the crude residue was purified by flash chromatography (5% EtOAc/petrol as eluent) to afford a 5:1 mixture of the Z:E isomers of the brominated ester 209 (3.323g, 82%) as a yellow oil.

IR νmax (film): 2954.1, 2855.3, 1713.7, 1630.1, 1451.8, 1379.0, 1334.8, 1250.7, 1225.3, 1179.5, 1107.1, 1042.7, 970.3, 936.0, 859.1, 837.9, 739.8, 698.0, 667.7 cm-1;

1 (E-209): H NMR (600 MHz; CDCl3): δ 7.35 (q, J = 6.9 Hz, 1H, -CHCH3), 4.31-4.28 (m, 2H, -

OCH2), 1.93 (d, J = 6.9 Hz, 3H, -CHCH3), 1.09-1.06 (m, 2H, -CH2Si), 0.06 (s, 9H, -Si(CH3)3);

123

Chapter 7 Experimental section

1 (Z-209) H NMR (600 MHz; CDCl3): δ 6.74 (q, J = 7.5 Hz, 1H, -CHCH3), 4.31-4.28 (m, 2H, -

OCH2), 2.03 (d, J = 7.5 Hz, 3H, -CHCH3), 1.09-1.06 (m, 2H, -CH2Si), 0.06 (s, 9H, -Si(CH3)3);

13 C NMR (101 MHz; CDCl3): δ 163.1, 143.2, 140.9, 112.1, 64.4, 17.3, -1.5;

+ HRMS calc. for C19H17BrO2Si [M + Na] = 287.00789, 289.00584, found 287.19730, 289.00631.

1-tert-butyl 2-methyl 4-((2S,3R)-3-((2-(trimethylsilyl)ethoxy)carbonyl)-3-vinyloxiran-2-yl)- 1H-pyrrole-1,2-dicarboxylate (210)

A solution of n-BuLi in hexanes (2.46 M, 4.27 mL, 10.5 mmol) was added to a solution of iPr2NH (1.47 mL, 10.5 mmol) and HMPA (1.83 mL, 10.5 mmol) in THF (20 mL) at -78 °C, and the resultant mixture was warmed to rt. The reaction was then cooled to -100 °C and a solution of ester 209 (2.77 g, 10.5 mmol) in THF (5 mL) at -78 °C was transferred to the reaction via a cooled cannula. A solution of the aldehyde 199 (762 mg, 3.01 mmol) in THF (5 mL) at -78 °C was then added via a cooled cannula. The reaction mixture was stirred for 1.5 h at -100 °C and was then quenched with saturated aq. NH4Cl. The solution was warmed to rt then extracted with ether. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and the solvents evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as eluent) to afford the vinyl epoxide 210 (1.12 g, 85%) as a yellow oil.

IR νmax (film): 2955.3, 1728.1, 1479.2, 1436.4, 1394.7, 1371.1, 1307.4, 1251.0, 1233.6, 1154.4, 1076.4, 1042.8, 987.9, 935.0, 858.6, 839.1, 806.9, 774.7, 735.9, 702.3, 668.1 cm-1;

1 H NMR (500 MHz; CDCl3): δ 7.23 (t, J = 0.9 Hz, 1H, ArH), 6.73 (d, J = 1.9 Hz, 1H, ArH), 6.05

(dd, J = 17.3, 10.9 Hz, 1H, -CHCH2), 5.49 (dd, J = 17.3, 1.5 Hz, 1H, -CHCH2), 5.41 (dd, J =

10.9, 1.5 Hz, 1H, -CHCH2), 4.33-4.29 (m, 2H, -OCH2), 4.19 (s, 1H, -CHAr), 3.82 (s, 3H, -OCH3),

1.57 (s, 9H, t-Bu), 1.06 (ddd, J = 10.0, 7.1, 1.2 Hz, 2H, -CH2Si), 0.06 (s, 9H, -Si(CH3)3);

13 C NMR (151 MHz; CDCl3): δ 169.0, 160.9, 147.8, 127.5, 125.5, 125.1, 120.5, 119.6, 117.9, 85.3, 64.5, 63.0, 59.4, 52.0, 27.6, 17.3, -1.5;

+ HRMS calc. for C21H31NO7Si [M + Na] = 460.17675, found 460.17748.

124

Chapter 7 Experimental section

Di-tert-butyl 4-((2S,3R)-3-((2-(trimethylsilyl)ethoxy)carbonyl)-3-vinyloxiran-2-yl)-1H- pyrrole-1,2-dicarboxylate (211)

A solution of n-BuLi in hexanes (2.30 M, 3.61 mL, 8.30 mmol) was added to a solution of iPr2NH (1.16 mL, 8.30 mmol) and HMPA (1.44 mL, 8.30 mmol) in THF (5 mL) at -78 °C this was warmed to rt. The reaction was then cooled to -100 °C and a solution of ester 209 (2.201 g, 8.30 mmol) in THF (5 mL) at -78 °C was transferred to the reaction via a cooled cannula. A solution of the aldehyde (700 mg, 2.37 mmol) in THF (5 mL) at -78 °C was then added to the reaction via a cooled cannula. The reaction mixture was stirred for 1.5 h at -100 °C and was then quenched with saturated aq. NH4Cl. The solution was warmed to rt before extracting with ether. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and the solvents evaporated. The crude residue was purified by flash chromatography (7.5% EtOAc/petrol as eluent) to afford the vinyl epoxide 211 (969 mg, 85%) as a yellow oil.

IR νmax (film): 2954.2, 1720.1, 1579.9, 1478.0, 1458.5, 1412.0, 1393.7, 1369.0, 1339.4, 1282.6, 1249.5, 1152.3, 1094.7, 1074.3, 1040.2, 988.2, 933.1, 838.7, 775.9, 760.6, 697.8, 667.2 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.17 (s, 1H, ArH), 6.67 (s, 1H, ArH), 6.04 (ddd, J = 17.3, 10.9,

1.1 Hz, 1H, -CHCH2), 5.44 (dd, J = 34.9, 14.1 Hz, 2H, -CHCH2), 4.32-4.28 (m, 2H, -OCH2), 4.18

(s, 1H, -CHAr), 1.57 (s, 9H, t-Bu), 1.53 (s, 9H, t-Bu), 1.06 (t, J = 8.6 Hz, 2H, -CH2Si), 0.05 (d, J

= 1.2 Hz, 9H, -Si(CH3)3);

13 C NMR (151 MHz; CDCl3): δ 169.0, 159.4, 147.9, 127.5, 127.0, 125.0, 120.4, 119.2, 117.4, 84.9, 81.4, 64.4, 63.1, 59.6, 28.1, 27.6, 17.3, -1.6;

+ HRMS calc. for C24H37NO7Si [M + H] = 480.24175, found 480.24186.

Methyl 2-bromobut-2-enoate12 (212)

Br2 (8.0 g, 49.94 mmol) was added to a solution of methyl crotonate (5.3 mL, 49.9 mmol) in

CH2Cl2 (20 mL) at 0 °C. and the resultant solution was stirred at 0 °C for 45 min. 1,8- Diazabicyclo[5.4.0]undec-7-ene (9 mL, 59.93 mmol) was added dropwise and the reaction was

125

Chapter 7 Experimental section stirred at 0 °C for a further 1 h. Ether was added and the reaction was quenched with 10% aq. HCl. The mixture was separated and extracted further with ether. The combined organic layers were washed with saturated aq. Na2S2O3 and water, dried, filtered and the solvents were evaporated. The crude residue (7.70 g, 86%) was used in the next step without further purification. The spectral data were in accordance that reported.12

IR νmax (film): 3670.3, 2988.3, 2901.4, 1730.8, 1629.9, 1435.2, 1406.8, 1394.0, 1256.8, 1066.3, 1044.8, 888.5, 759.9, 739.3, 658.4;

1 H NMR (400 MHz; CDCl3): δ 7.38 (q, J = 6.9 Hz, 1H, -CHCH3), 3.82 (s, 3H, -OCH3), 1.94 (d,

J = 6.9 Hz, 3H, -CHCH3);

13 C NMR (101 MHz; CDCl3): δ 162.9, 141.6, 117.1, 53.1, 17.8;

+ HRMS calc. for C5H8BrO2 [M + H] = 178.97077, 180.96872, found 178.97033, 180.96813.

Di-tert-butyl 4-((2S,3R)-3-(methoxycarbonyl)-3-vinyloxiran-2-yl)-1H-pyrrole-1,2- dicarboxylate (213)

A solution of n-BuLi in hexanes (2.26 M, 1.24 mL, 2.809 mmol) was added to a solution of iPr2NH (394 µL, 2.81 mmol) and HMPA (519 µL, 2.809 mmol) in THF (2 mL) at -78 °C this was warmed to rt. The reaction was then cooled to -100 °C and a solution of ester 212 (503 mg, 2.809 mmol) in THF (2 mL) at -78 °C was transferred to the reaction via a cooled cannula. A solution of the aldehyde 204 (237 mg, 0.802 mmol) in THF (2 mL) at -78 °C was then added to the reaction via a cooled cannula. The reaction mixture was stirred for 2 h at -100 °C, then warmed to -78 °C for 1 h, then 0 °C for 30 min. The reaction was then quenched with saturated aq. NH4Cl and extracted with ether. The combined organic layers were washed with water and brine, dried

(Na2SO4), filtered, and the solvents evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as eluent) to afford the vinyl epoxide 213 (116 mg, 10%) as a yellow oil.

126

Chapter 7 Experimental section

IR νmax (film): 2981.9, 2980.6, 1723.3, 1719.5, 1584.2, 1478.7, 1457.7, 1437.5, 1394.1, 1369.9, 1305.4, 1279.4, 1243.5, 1239.7, 1151.8, 1123.0, 1075.9, 1046.5, 988.1, 936.5, 910.7, 905.9, 847.7, 822.9, 823.1, 794.2, 775.8, 737.7, 726.5, 717.4, 675.1 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.17 (s, 1H, ArH), 6.67 (d, J = 1.2 Hz, 1H, ArH), 6.04 (dd, J =

17.3, 10.9 Hz, 1H, -CHCH2), 5.50 (d, J = 17.3 Hz, 1H, -CHCH2), 5.42 (d, J = 11.0 Hz, 1H, -

CHCH2), 4.21 (s, 1H, -CHAr), 3.82 (s, 3H, -OCH3), 1.57 (s, 9H, t-Bu), 1.53 (s, 9H, t-Bu);

13 C NMR (101 MHz; CDCl3): δ 169.4, 159.4, 147.9, 127.3, 127.1, 125.1, 120.6, 119.1, 117.3, 85.0, 81.4, 63.0, 59.7, 52.8, 28.1, 27.6;

+ HRMS calc. for C20H27NO7 [M + Na] = 416.16852, found 416.16788.

(Z)-(1S,2R,5S)-2-isopropyl-5-methylcyclohexyl 2-bromobut-2-enoate13 (214)

To a solution of crotonic acid (820 mg, 10.1 mmol) dissolved in CH2Cl2 (10 mL) was added 10 drops of N,N-dimethylformamide followed by oxalyl chloride (1.29 mL, 15 mmol). The reaction was stirred at rt for 1.5 h before the solvent was evaporated to give crotonyl chloride. A solution of crotonyl chloride in THF (20 mL) was added to a solution of d-menthol (1.042 g, 6.67 mmol) in NEt3 (2.0 mL) at 0 °C and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.25 mL, 8.34 mmol) was then added. The reaction was stirred at 0 °C for 16 h before water and ether were added and the mixture was acidified with 10% aq. HCl. The mixture was further extracted with ether. The combined organic layers were washed with 10% aq. KOH, 10% aq. HCl and brine, before being dried and filtered through a plug of silica gel with ether as the eluent. The solvent was evaporated to afford the menthyl crotonate ester (1.345 g, 90%) which was used in the next step without further purification.

A solution of the above ester in CCl4 (2 mL) was cooled to 0 °C and a solution of Br2 (1.44 g,

9.01 mmol) in CCl4 (2 mL) was added via cannula. The solution was stirred at 0 °C for 1 h before the solvent was removed. The crude dibromide residue was redissolved in dimethoxyethane (10 mL) and cooled to 0 °C before adding 1,8-diazabicyclo[5.4.0]undec-7-ene (1.35 mL, 9.03 mmol). After 30 min, water and ether were added and the mixture was made acidic with 10% aq. HCl. The mixture was separated, washed with 10% aq. HCl, and extracted further with ether. The combined organic layers were washed with brine, dried, filtered and solvents were evaporated. The crude residue was purified by flash chromatography (2.5% EtOAc/petrol as eluent) to afford

127

Chapter 7 Experimental section menthyl bromocrotonate 214 (1.271 g, 63%) in a 2.4:1 mixture of E:Z isomers as a colourless oil. The spectral data obtained was identical to that reported.13

1 (Z-214): H NMR (600 MHz; CDCl3): δ 7.33 (q, J = 6.8 Hz, 1H, -C=CH), 4.78-4.73 (m, 1H, -

OCH), 2.04 (m, 2H, -CH2), 1.93 (d, J = 6.8 Hz, 3H, -C=CHCH3), 1.70-1.67 (m, 2H, -CH2), 1.51-

1.45 (m, 2H, -CH2), 0.91-0.88 (m, 7H, -CH3), 0.76 (t, J = 6.8 Hz, 3H, -CHCH3);

1 (E-214): H NMR (600 MHz; CDCl3): δ 6.70 (q, J = 7.5 Hz, 1H, -C=CH), 4.78-4.73 (m, 1H, -

OCH), 2.04 (m, 2H, -CH2), 2.01 (d, J = 7.5 Hz, 3H, -C=CHCH3), 1.70-1.67 (m, 2H, -CH2), 1.51-

1.45 (m, 2H, -CH2), 0.91-0.88 (m, 7H, -CH3), 0.76 (t, J = 6.8 Hz, 3H, -CHCH3).

Di-tert-butyl-4-((2S,3R)-3-((((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)-3- vinyloxiran-2-yl)-1H-pyrrole-1,2-dicarboxylate (215)

A solution of n-BuLi in hexanes (2.0 M, 773 µL, 1.70 mmol) was added to a solution of iPr2NH (238 µL, 1.70 mmol) and HMPA (296 µL, 1.70 mmol) in THF (3 mL) at -78 °C this was warmed to rt. The reaction was then cooled to -100 °C and a solution of ester 214 (515 mg, 1.70 mmol) in THF (3 mL) at -78 °C was transferred to the reaction via a cooled cannula. A solution of the aldehyde 204 (143 mg, 0.486 mmol) in THF (3 mL) at -78 °C was then added to the reaction via a cooled cannula. The reaction mixture was stirred for 1.5 h at -100 °C and was then quenched with saturated aq. NH4Cl. The solution was warmed to rt before extracting with ether. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and the solvents evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as the eluent) to afford the vinyl epoxides 215 as a 1:1 mixture of diastereoisomers (207 mg, 82%) as a yellow oil.

IR νmax (film): 2957.2, 2932.2, 2871.3, 1749.3, 1721.7, 1585.5, 1478.8, 1457.0, 1393.7, 1369.2, 1328.4, 1304.5, 1276.5, 1242.0, 1156.6, 1122.4, 1076.4, 1037.2, 983.0, 957.0, 913.1, 848.2, 822.8, 775.7, 757.6, 733.8, 676.7 cm-1;

1 H NMR (600 MHz; CDCl3): δ 7.16 (dd, J = 1.6, 0.9 Hz, 1H, ArH), 6.67-6.66 (m, 1H, ArH),

6.02 (dddd, J = 17.3, 10.9, 3.7, 0.6 Hz, 1H, -CH=CH2), 5.49-5.46 (m, 1H, -CH=CH2), 5.40-5.37

(m, 1H, -CH=CH2), 4.81-4.76 (m, 1H, -OCH), 4.13 (d, J = 8.5 Hz, 1H, -CHAr), 2.04-2.00 (m,

128

Chapter 7 Experimental section

1H, -CH2), 1.86-1.82 (m, 1H, -CH2), 1.70-1.66 (m, 3H, -CH2), 1.56 (s, 9H, t-Bu), 1.52 (s, 9H, t-

Bu), 1.18 (dd, J = 30.0, 0.6 Hz, 1H, -CH2), 1.08-1.00 (m, 3H, -CH2), 0.89 (s, 8H, -CH3), 0.77 (d,

J = 2.0 Hz, 3H, -CHCH3);

13 C NMR (101 MHz; CDCl3): δ 168.5, 159.5, 147.9, 127.63, 127.61, 127.55, 127.53, 127.06, 127.04, 125.12, 125.05, 120.46, 120.42, 120.39, 119.23, 119.19, 119.14, 117.52, 117.48, 85.0, 81.4, 76.2, 63.25, 63.19, 59.46, 59.37, 46.8, 40.6, 34.1, 31.4, 28.1, 27.6, 26.4, 26.2, 23.6, 23.3, 21.9, 20.75, 20.63, 16.5, 16.2;

+ HRMS calc. for C29H43NO7 [M + H] = 518.31178, found 518.31138.

(R)-1-tert-butyl 6-ethyl 2-methyl 8,8a-dihydro-1H-oxepino[4,3-b]pyrrole-1,2,6- tricarboxylate (217)

A solution of divinyl epoxide 205 (340 mg, 0.933 mmol) in degassed CCl4 (5 mL) in a pressure tube was heated and stirred at 150 °C for 2 h. The solvents were evaporated, and the crude residue was purified using flash chromatography (20% EtOAc/petrol as eluent) to afford the dihydrooxepine 217 (279 mg, 83%) as a colourless solid. m.p. 92.2 – 93.8 °C.

IR νmax (film): 2980, 1707, 1648, 1587, 1477, 1437, 1389, 1368, 1336, 1268, 1214, 1168, 1124, 1060, 1046, 979, 953, 938, 917 cm-1;

1 H NMR (500 MHz; CDCl3): δ 6.69 (d, J = 2.8 Hz, 1H, -NC=CH), 6.40 (dd, J = 9.5, 3.5 Hz, 1H,

-C=CHCH2), 6.18 (s, 1H, -C=CHO), 4.70 (dt, J = 9.1, 2.8 Hz, 1H, -NCH), 4.28 (q, J = 7.1 Hz,

2H, -CH2CH3), 3.83 (s, 3H, -OCH3), 3.21 (ddd, J = 15.2, 9.7, 3.0 Hz, 1H, -CHCH2), 2.31 (ddd, J

= 15.2, 9.2, 3.3 Hz, 1H, -CHCH2), 1.47 (s, 9H, t-Bu), 1.34 (t, J = 7.1 Hz, 3H, -CH2CH3);

13 C NMR (126 MHz; CDCl3): δ 162.64, 162.53, 152.5, 142.7, 135.2, 134.9, 126.6, 117.3, 113.2, 82.2, 61.8, 61.0, 52.2, 33.9, 28.1, 14.2;

+ HRMS (ESI) calc. for C18H24NO7 [M + H] 366.1547, found 366.1548.

129

Chapter 7 Experimental section

(R)-1,2-di-tert-butyl 6-ethyl 8,8a-dihydro-1H-oxepino[4,3-b]pyrrole-1,2,6-tricarboxylate (218)

A solution of the divinyl epoxide 205 (239 mg, 0.549 mmol) in degassed CCl4 (2 mL) in a pressure tube was heated and stirred to 150 °C for 1.5 h. The solvents were evaporated, the crude residue was recrystallised from petrol, and the mother liquor was purified using flash chromatography (10% EtOAc/petrol as the eluent) to afford the dihydrooxepine 218 (143 mg, 60%) as a colourless solid. m.p. 140.4-140.1 °C.

IR νmax (film): 2971, 1738, 1650, 1579, 1448, 1367, 1275, 1228, 1217, 1166, 1126, 1061, 1017, 896, 852, 770 cm-1;

1 H NMR (400 MHz; CDCl3): δ 6.66 (d, J = 2.8 Hz, 1H, -NC=CH), 6.39 (dd, J = 9.7, 3.2 Hz, 1H,

-C=CHCH2), 6.13 (s, 1H, -C=CHO), 4.66 (dt, J = 9.1, 2.9 Hz, 1H, -NCH), 4.27 (q, J = 7.1 Hz,

2H, - CH2CH3), 3.20 (ddd, J = 15.2, 9.7, 3.0 Hz, 1H, -CHCH2), 2.29 (ddd, J = 15.2, 9.2, 3.3 Hz,

1H, -CHCH2), 1.52 (s, 9H, t-Bu), 1.47 (s, 9H, t-Bu), 1.33 (t, J = 7.1 Hz, 3H, -CH2CH3);

13 C NMR (101 MHz; CDCl3): δ 162.7, 160.5, 152.6, 142.6, 136.9, 134.5, 126.8, 117.4, 113.3, 81.94, 81.87, 61.8, 61.2, 33.9, 28.15, 28.11, 14.2;

+ HRMS (ESI) calc. for C21H29NO7 [M + H] 408.2017, found 408.2014.

(R)-1-tert-butyl 2-methyl 6-(2-(trimethylsilyl)ethyl) 8,8a-dihydro-1H-oxepino[4,3- b]pyrrole-1,2,6-tricarboxylate (219)

A solution of divinyl epoxide 210 (141 mg, 0.323 mmol) in degassed acetonitrile (5 mL) was heated to 150 °C in a pressure tube with stirring. After 90 min the reaction was cooled, the solvent was evaporated, and the crude residue was filtered through a plug of silica with 10% EtOAc/petrol as the eluent to afford the dihydrooexpine 219 (122 mg, 86%) as a yellow oil.

IR νmax (film): 2954.4, 1715.8, 1436.8, 1369.6, 1337.1, 1249.7, 1151.0, 1124.4, 1063.9, 916.5, 836.0, 759.6, 731.1, 695.8 cm-1;

130

Chapter 7 Experimental section

1 H NMR (600 MHz; CDCl3): δ 6.66 (d, J = 2.7 Hz, 1H, -NC=CH), 6.37 (dd, J = 9.6, 3.0 Hz, 1H,

-C=CHCH2), 6.16 (s, 1H, -C=CHO), 4.68 (dt, J = 9.1, 2.5 Hz, 1H, -NCH), 4.29 (t, J = 8.5 Hz,

2H, -OCH2), 3.81 (s, 3H, -OCH3), 3.19 (ddd, J = 15.1, 9.8, 2.9 Hz, 1H, -CHCH2), 2.28 (ddd, J =

15.1, 9.3, 3.2 Hz, 1H, -CHCH2), 1.45 (s, 9H, t-Bu), 1.05 (t, J = 8.5 Hz, 2H, -CH2Si), 0.05 (s, 9H,

-Si(CH3)3);

13 C NMR (151 MHz; CDCl3): δ 162.7, 162.5, 152.5, 142.9, 135.2, 134.9, 126.5, 117.3, 113.0, 82.1, 64.2, 61.0, 52.1, 33.8, 28.0, 17.3, -1.6;

+ HRMS calc. for C21H31NO7Si [M + H] = 438.19480, found 438.19419.

(R)-1,2-di-tert-butyl 6-(2-(trimethylsilyl)ethyl) 8,8a-dihydro-1H-oxepino[4,3-b]pyrrole- 1,2,6-tricarboxylate (220)

A solution of divinyl epoxide 211 (336 mg, 0.701 mmol) in degassed toluene (3 mL) in a pressure tube was heated and stirred at 150 °C for 2 h. The solvents were evaporated, and the crude residue was purified using flash chromatography (10% EtOAc/petrol as eluent) to afford the dihydrooxepine 220 (458 mg, 67%) as a colourless solid. m.p. 118.9 - 120.6 °C.

IR νmax (film): 3670.6, 2978.1, 2901.4, 1722.8, 1649.3, 1578.6, 1453.9, 1393.8, 1368.8, 1338.1, 1252.1, 1220.1, 1169.0, 1125.9, 1066.0, 1057.4, 861.4, 839.4, 739.7, 702.7 cm-1;

1 H NMR (400 MHz; CDCl3): δ 6.65 (d, J = 2.7 Hz, 1H, -NC=CH), 6.37 (dd, J = 9.7, 3.2 Hz, 1H,

-C=CHCH2), 6.13 (s, 1H, -C=CHO), 4.66 (dt, J = 9.0, 2.6 Hz, 1H, -NCH), 4.30 (t, J = 8.5 Hz,

2H, -OCH2), 3.19 (ddd, J = 15.1, 9.8, 3.0 Hz, 1H, -CHCH2), 2.29 (ddd, J = 15.2, 9.2, 3.2 Hz, 1H,

-CHCH2), 1.52 (s, 9H, t-Bu), 1.47 (s, 9H, t-Bu), 1.06 (t, J = 8.5 Hz, 2H, -CH2Si), 0.05 (s, 9H, -

Si(CH3)3);

13 C NMR (101 MHz; CDCl3): δ 162.8, 160.5, 152.6, 142.8, 136.9, 134.5, 126.8, 117.4, 113.1, 81.92, 81.86, 64.2, 61.2, 33.9, 28.15, 28.11, 17.3, -1.5;

+ HRMS calc. for C24H37NO7Si [M + H] = 480.24175, found 480.24138.

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Chapter 7 Experimental section

(R)-1,2-di-tert-butyl 6-methyl 8,8a-dihydro-1H-oxepino[4,3-b]pyrrole-1,2,6-tricarboxylate (221)

A solution of divinyl epoxide 213 (116 mg, 0.295 mmol) in degassed toluene (3 mL) in a pressure tube was heated and stirred at 150 °C for 2 h. The solvents were evaporated, and the crude residue was purified using flash chromatography (20% EtOAc/petrol as the eluent) to afford the dihydrooxepine 220 (84 mg, 72%) as a yellow oil.

IR νmax (film): 2979.7, 1724.9, 1683.9, 1650.0, 1563.9, 1478.8, 1457.1, 1393.4, 1368.9, 1340.6, 1277.6, 1219.9, 1161.8, 1078.6, 849.6, 759.8 cm-1;

1 H NMR (400 MHz; CDCl3): δ 6.64 (d, J = 1.9 Hz, 1H, -NC=CH), 6.37 (dd, J = 9.5, 3.0 Hz, 1H,

- C=CHCH2), 6.11 (s, 1H, -C=CHO), 4.64 (dd, J = 6.7, 2.5 Hz, 1H, -NCH), 3.79 (s, 3H, -OCH3),

3.21-3.14 (m, 2H, -CHCH2), 2.30-2.24 (m, 2H, -CHCH2), 1.50 (d, J = 0.9 Hz, 9H, t-Bu), 1.45 (s, 9H, t-Bu);

13 C NMR (101 MHz; CDCl3): δ 163.2, 160.4, 152.5, 142.4, 137.0, 134.4, 126.9, 117.3, 113.6, 81.92, 81.85, 61.2, 52.7, 33.9, 28.12, 28.08;

+ HRMS calc. for C20H27NO7 [M + H] = 394.18658, found 394.18587.

Pyridin-2-ylmethyl 2-bromobut-2-enoate (254)

To a solution of the bromocrotonate ester 209 (1.00 g, 3.79 mmol) in THF (20 mL) was added

TBAF.3H2O (2.39 g, 7.58 mmol) and stirring for 1 h at rt. Ether and water were added before making acidic with 10% aq. HCl. The layers were separated, and the aqueous layer was extracted twice further with ether. The combined organic layers were then washed with water, dried, filtered and the solvents were evaporated. The crude acid was then dissolved in CH2Cl2 (15 mL) before adding 4-(dimethylamino)pyridine (46 mg, 0.379 mmol), 2-pyridinemethanol (402 µL, 4.17 mmol) and N,N'-dicyclohexylcarbodiimide (821 mg, 3.98 mmol). The solution was stirred for 1

TM h before filtering through Celite with CH2Cl2 and evaporating solvents. The crude residue was

132

Chapter 7 Experimental section purified by flash chromatography (10-20% EtOAc/petrol as eluent) to afford the ester 254 (564 mg, 58%) as a yellow oil.

IR νmax (film): 2941.2, 1723.6, 1629.4, 1593.5, 1573.9, 1476.5, 1437.7, 1374.5, 1265.4, 1241.7, 1150.2, 1108.4, 1046.5, 995.5, 909.6, 843.9, 763.8, 736.9 cm-1;

1 H NMR (500 MHz; CDCl3): δ 8.61 (d, J = 4.7 Hz, 1H, ArH), 7.73 (td, J = 7.7, 1.6 Hz, 1H, ArH),

7.50 (q, J = 6.9 Hz, 1H, -CHCH3), 7.42 (d, J = 7.8 Hz, 1H, ArH), 7.25 (dd, J = 7.5, 4.9 Hz, 1H,

ArH), 5.37 (s, 2H, -OCH2), 1.98 (d, J = 6.9 Hz, 3H, -CHCH3);

13 C NMR (126 MHz; CDCl3): δ 162.1, 155.4, 149.5, 142.4, 136.8, 122.9, 121.7, 117.0, 68.3, 18.0;

+ HRMS calc. for C10H10BrNO2 [M + H] = 255.9973, 257.9953, found 255.9970, 257.9944.

(R)-1,2-di-tert-butyl 6-(pyridin-2-ylmethyl) 8,8a-dihydro-1H-oxepino[4,3-b]pyrrole-1,2,6- tricarboxylate (256)

Dihydrooxepine 220 (577 mg, 1.20 mmol) was dissolved in THF (18 mL) before adding

TBAF.3H2O (760 mg, 2.41 mmol) and stirring at rt for 1.5 h. Ether and water were added before making acidic with 10% aq. HCl. The organic layer was separated, and the aqueous layer was extracted further with ether. The combined organic extracts were dried with Na2SO4, filtered and the solvents evaporated. The crude acid was carried through to the next step without further purification.

To a solution of the crude acid in CH2Cl2 (10 mL) was added 2-pyridinemethanol (130 µL, 1.35 mmol), 4-(dimethylamino)pyridine (18 mg, 0.147 mmol) followed by N,N’- dicyclohexylcarbodiimide (260 mg, 1.26 mmol). The solution stirred at rt for 1 h before then filtered through a plug of CeliteTM and the filtrate was concentrated. The crude residue was purified by flash chromatography (40% EtOAc/petrol as eluent) to afford the dihydrooxepine 256 (385 mg, 68% over two steps) as a colourless solid. m.p. 128.0 – 129.0 °C.

IR νmax (film): 2978.6, 2932.4, 1719.7, 1647.5, 1592.9, 1574.4, 1477.1, 1455.7, 1439.1, 1390.8, 1367.3, 1337.5, 1272.0, 1218.6, 1195.7, 1161.4, 1142.4, 1123.4, 1060.9, 1016.7, 913.7, 851.5, 814.1m, 796.7, 755.3, 729.3 cm-1;

133

Chapter 7 Experimental section

1 H NMR (600 MHz; CDCl3): δ 8.59 (d, J = 4.8 Hz, 1H, ArH), 7.71-7.69 (m, 1H, ArH), 7.36 (d, J = 7.8 Hz, 1H, ArH), 7.23 (dd, J = 7.3, 5.1 Hz, 1H, ArH), 6.66 (d, J = 2.8 Hz, 1H, -NC=CH),

6.47 (dd, J = 9.7, 3.2 Hz, 1H- C=CHCH2), 6.12 (s, 1H, -C=CHO), 5.34 (s, 2H, -OCH2), 4.68-4.66

(m, 1H, -NCH), 3.20 (ddd, J = 15.3, 9.7, 3.0 Hz, 1H, -CHCH2), 2.29 (ddd, J = 15.3, 9.2, 3.2 Hz,

1H, -CHCH2), 1.51 (s, 9H, t-Bu), 1.46 (s, 9H, t-Bu);

13 C NMR (151 MHz; CDCl3): δ 162.4, 160.5, 155.3, 152.6, 149.5, 142.3, 136.8, 134.5, 126.9, 123.0, 121.8, 117.3, 114.1, 81.98, 81.89, 67.7, 61.2, 34.0, 28.14, 28.10;

+ HRMS calc. for C25H30N2O7 [M + H] = 471.21313, found 471.21308.

(R)-di-tert-butyl-6-((ethylthio)carbonyl)-8,8a-dihydro-1H-oxepino[4,3-b]pyrrole-1,2- dicarboxylate (259)

To a solution of dihydrooxepine 220 (405 mg, 0.845 mmol) in THF (5 mL) was added

TBAF.3H2O (533 mg, 1.69 mmol) the solution was stirred at rt for 1.75 h. Ether and water were added before and the mixture was acidified with 10% aq. HCl. The organic layer was separated, and the aqueous layer was extracted twice further with ether. The combined organic extracts were dried (Na2SO4), filtered and the solvents evaporated. The crude acid 258 was carried through to the next step without further purification.

Ethanethiol (64 µL, 0.89 mmol), 4-(dimethylamino)pyridine (12 mg, 0.098 mmol) and N,N’- dicyclohexylcarbodiimide (171 mg, 0.831 mmol)were added to a solution of the crude acid in

TM CH2Cl2 (5 mL). The solution was stirred at rt for 1 h before filtering through a plug of Celite with CH2Cl2. The organic layer was washed with sat. NaHCO3, water and brine, then dried

(Na2SO4), filtered and the solvent evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as eluent) to afford the thioester 259 (247 mg, 69% over two steps) as a yellow oil.

IR νmax (film): 2978.6, 2933.2, 1715.6, 1672.9, 1637.1, 1577.8, 1477.9, 1456.6, 1391.3, 1367.7, 1352.3, 1325.7, 1272.8, 1257.4, 1218.6, 1198.2, 1156.9, 1111.3, 1080.9, 1048.5, 1017.0, 977.8, 913.5, 894.9, 853.5, 796.5, 767.8, 733.4, 687.5, 666.1 cm-1;

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Chapter 7 Experimental section

1 H NMR (400 MHz; CDCl3): δ 6.66 (d, J = 2.7 Hz, 1H, -NC=CH), 6.23 (dd, J = 9.5, 3.2 Hz, 1H,

-C=CHCH2), 6.11 (s, 1H, -C=CHO), 4.68 (dt, J = 9.2, 2.9 Hz, 1H, -NCH), 3.21 (ddd, J = 15.5,

9.5, 3.1 Hz, 1H, -CHCH2), 2.91 (q, J = 7.4 Hz, 2H, -CH2CH3), 2.27 (ddd, J = 15.5, 9.3, 3.2 Hz,

1H, -CHCH2), 1.53 (s, 9H, t-Bu), 1.47 (s, 9H, t-Bu), 1.27 (t, J = 7.4 Hz, 3H, -CH2CH3);

13 C NMR (101 MHz; CDCl3): δ 188.7, 160.5, 152.4, 147.7, 137.4, 134.1, 127.6, 116.8, 108.7, 82.0, 61.2, 33.5, 28.15, 28.10, 23.1, 14.3;

+ HRMS calc. for C21H29NO6S [M + H] = 424.17938, found 424.17857.

(R)-di-tert-butyl 6-formyl-8,8a-dihydro-1H-oxepino[4,3-b]pyrrole-1,2-dicarboxylate (247)

Thioester 259 (55 mg, 0.130 mmol) was dissolved in acetone (2 mL) before adding 5% palladium on carbon (1.0 Eq, 277 mg) and Et3SiH (104 µL, 0.650 mmol). The mixture was stirred at rt for 2.5 h before filtering through CeliteTM with acetone and evaporating the solvent. The crude residue was purified by flash chromatography (20% EtOAc/petrol as the eluent) to afford the aldehyde 247 (32 mg, 68%) as a yellow oil.

IR νmax (film): 2979.7, 2933.1, 1704.5, 1637.5, 1578.9, 1477.8, 1457.0, 1391.8, 1367.5, 1340.6, 1273.6, 1257.6, 1218.9, 1155.3, 1110.5, 1067.6, 1045.6, 1017.0, 985.1, 914.2, 895.3, 851.9, 815.1, 785.1, 766.1, 731.0 cm-1;

1 H NMR (400 MHz; CDCl3): δ 9.12 (s, 1H, -CHO), 6.70 (d, J = 2.7 Hz, 1H, -NC=CH), 6.14 (s,

1H, -C=CHO), 6.03 (dd, J = 9.3, 3.0 Hz, 1H, -C=CHCH2), 4.71 (dt, J = 9.1, 2.8 Hz, 1H, -NCH),

3.34 (ddd, J = 15.8, 9.3, 3.0 Hz, 1H, -CHCH2), 2.44 (ddd, J = 15.8, 9.2, 3.1 Hz, 1H, -CHCH2), 1.53 (s, 9H, t-Bu), 1.48 (s, 9H, t-Bu);

13 C NMR (151 MHz; CDCl3): δ 186.9, 160.3, 152.5, 151.0, 137.4, 134.4, 127.2, 123.9, 117.1, 82.19, 82.01, 61.1, 34.5, 28.12, 28.10;

+ HRMS calc. for C19H25NO6 [M + H] = 364.17601, found 364.17539.

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Chapter 7 Experimental section

(Z)-S-ethyl 2-bromobut-2-enethioate (260)

To a solution of the bromocrotonate ester 209 (2.00 g, 7.58 mmol) in THF (40 mL) was added

TBAF.3H2O (4.78 g, 15.16 mmol) and the resultant solution was stirred for 1 h at rt. Ether and water were added before making acidic with 10% aq. HCl. The layers were separated, and the aqueous layer was extracted twice further with ether. The combined organic layers were then washed with water, dried, filtered and the solvents were evaporated. The crude acid was then dissolved in CH2Cl2 (30 mL) before adding 4-(dimethylamino)pyridine (92 mg, 0.758 mmol), ethanethiol (600 µL, 8.32 mmol) and N,N'-dicyclohexylcarbodiimide (1.642 g, 7.958 mmol). The

TM solution was stirred for 1.5 h before filtering through Celite with CH2Cl2. The solution was then washed with sat. aq. NaHCO3, water and brine. The organic layer was then dried, filtered and the solvents were evaporated. The crude residue was purified by flash chromatography (2.5% EtOAc/petrol as eluent) to afford the thioester 260 (1.017 g, 64%) as a yellow oil.

IR νmax (film): 2929.9, 2854.4, 2117.0, 1710.1, 1655.3, 1609.6, 1562.6, 1519.5, 1449.4, 1375.2, 1359.7, 1346.2, 1299.1, 1267.2, 1227.3, 1132.5, 1105.8, 1074.8, 1045.0, 946.4, 891.2, 817.8, 754.2, 654.6 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.32 (q, J = 6.8 Hz, 1H, -CHCH3), 2.95 (q, J = 7.4 Hz, 2H, -

CH2CH3), 1.97 (d, J = 6.8 Hz, 3H, -CHCH3), 1.29 (t, J = 7.4 Hz, 3H, -CH2CH3);

13 C NMR (101 MHz; CDCl3): δ 187.8, 137.9, 125.0, 24.8, 17.7, 14.3;

+ HRMS calc. for C6H9BrOS [M + H] = 208.96357, 210.96153, found 208.6928, 210.6911.

(R)-di-tert-butyl 8,8a-dihydro-1H-oxepino[4,3-b]pyrrole-1,2-dicarboxylate (257)

Triphenylphosphine (2.4 mg, 9.15 µmol) was added to [IrCl(cod)]2 (3.0 mg, 4.47 µmol) in 1,4- dioxane (200 µL) and stirred at rt for 10 min. Dihydrooxepine aldehyde 247 (32 mg, 0.088 mmol) was added and the reaction was heated at reflux for 17 h. The mixture was then cooled, and ether and water were added. The biphasic mixture was separated, and the aqueous layer was extracted further with ether. The combined organic layers were washed with water and brine, before drying

136

Chapter 7 Experimental section

(Na2SO4), filtering and evaporating solvents. The crude residue was purified by column chromatography (10-20% EtOAc/petrol as the eluent) to afford the dihydrooxepine 257 (2.5 mg, 8%) as a colourless oil.

1 H NMR (400 MHz; CDCl3): δ 6.55 (d, J = 2.7 Hz, 1H, -C=CHO), 6.24 (dd, J = 7.9, 2.9 Hz, 1H, -CH=CHO), 6.12 (s, 1H, -NC=CH), 4.87-4.82 (m, 1H, -CH=CHO), 4.67 (dt, J = 9.2, 2.9 Hz, 1H,

-NCH), 3.01 (ddd, J = 14.3, 9.5, 3.1 Hz, 1H, -CHCH2), 2.24-2.16 (m, 1H, -CHCH2), 1.53 (s, 9H, t-Bu), 1.48 (s, 9H, t-Bu);

Insufficient material was obtained to gain full 13C NMR spectra.

13 Peaks observed in C NMR (101 MHz; CDCl3): δ 141.8, 135.7, 118.4, 104.2, 81.6, 62.3, 34.0, 28.17, 28.14;

+ HRMS calc. for C18H25NO5 [M + H] = 336.18110, found 336.18054.

(E)-di-tert-butyl-5-(3,4-dioxo-4-(2-(trimethylsilyl)ethoxy)but-1-en-1-yl)-4-formyl-1H- pyrrole-1,2-dicarboxylate (271)

(E)-tert-butyl 5-(3,4-dioxo-4-(2-(trimethylsilyl)ethoxy)but-1-en-1-yl)-4-formyl-1H-pyrrole- 2-carboxylate (272)

Selenium dioxide (24 mg, 0.216 mmol) was added to a solution of dihydrooxepine xx (50 mg, 0.104 mmol) in a 9:1 mixture of 1,4-dioxane/water (0.5 mL) and stirred at 80 °C for 16 h before.

The reaction was cooled to rt and water was added, and the mixture was extracted with CH2Cl2, dried (Na2SO4), filtered and the solvents were evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as eluent) to afford the hydrolysis product 271 (12 mg, 23%) as the major component and 272 as the minor component (6 mg, 15%).

271: IR νmax (film): 2981.3, 2955.8, 1774.8, 1719.6, 1683.2, 1606.1, 1541.6, 1477.2, 1460.1, 1424.9, 1393.3, 1371.3, 1281.5, 1250.7, 1236.1, 1075.8, 974.6, 912.7, 839.0, 763.4, 733.6, 697.6 cm-1;

137

Chapter 7 Experimental section

1 H NMR (500 MHz; CDCl3): δ 10.02 (s, 1H, CHO), 7.99 (dd, J = 16.2, 0.5 Hz, 1H, -CH=CH), 7.55 (dd, J = 16.2, 1.0 Hz, 1H, -CH=CH), 7.27 (d, J = 1.0 Hz, 1H, ArH), 4.45-4.41 (m, 2H, -

OCH2), 1.65 (s, 9H, t-Bu), 1.57 (s, 9H, t-Bu), 1.18-1.14 (m, 2H, -SiCH2), 0.09 (s, 9H, -Si(CH3)3);

13 C NMR (101 MHz; CDCl3): δ 184.9, 182.0, 161.5, 158.5, 147.8, 135.8, 132.1, 129.3, 126.6, 126.3, 117.7, 88.1, 82.8, 65.4, 28.4, 28.1, 27.4, 17.3, -1.6;

+ HRMS calc. for C24H35NO8Si [M + H] = 494.22102, found 494.22037.

272: IR νmax (film): 3675.4, 3314.7, 2982.1, 2358.6, 2327.2, 1714.8, 1677.4, 1370.0, 1251.9, 1157.1, 1066.0, 840.1, 739.3 cm-1;

1 H NMR (500 MHz; CDCl3): δ 10.08 (s, 1H, -CHO), 10.00 (br s, 1H, -NH), 8.20 (d, J = 16.4 Hz, 1H, -CH=CH), 7.41 (d, J = 16.3 Hz, 1H, -CH=CH), 7.27 (d, J = 2.2 Hz, 1H, ArH), 4.46-

4.42 (m, 2H, -OCH2), 1.60 (s, 9H, t-Bu), 1.20-1.16 (m, 2H, -SiCH2), 0.09 (s, 9H, -Si(CH3)3);

13 C NMR (101 MHz; CDCl3): δ 185.4, 181.9, 161.8, 159.4, 133.2, 132.8, 128.3, 127.7, 121.7, 117.1, 83.1, 65.4, 28.2, 17.4, -1.6;

+ HRMS calc. for C19H27NO6Si [M + H] = 394.16859, found 394.16789.

Ethyl 4-((tert-butyldimethylsilyl)oxy)but-2-enoate14 (279)

To a solution of fumaric acid monoethyl ester (3.0 g, 20.81 mmol) in THF (20 mL) at 0 °C was added slowly a 1.0 M solution of BH3 in THF (22 mL, 22 mmol) and the reaction was stirred at rt for 20 h. A 50% aq. solution of AcOH (6 mL) was added and the solvents were evaporated. The crude residue was redissolved in CH2Cl2 (30 mL) and TBSCl (3.31 g, 21.85 mmol) was added followed by NEt3 (3.2 mL, 21.85 mmol). The reaction was stirred at rt for 20 h before washing the reaction mixture with water, 10% aq. HCl and saturated aq. NaHCO3. The organic layer was dried, filtered and the solvent was evaporated. The crude residue (3.546 g, 70%) was used in subsequent steps without further purification. The spectral data were in accordance with that reported.14

1 H NMR (500 MHz; CDCl3): δ 7.00 (dt, J = 15.5, 3.4 Hz, 1H, -CH=CH), 6.10 (dt, J = 15.5, 2.3

Hz, 1H, -CH=CH), 4.35 (dd, J = 3.3, 2.4 Hz, 2H, -CHCH2), 4.21 (q, J = 7.1 Hz, 2H, -CH2CH3),

1.31 (t, J = 7.1 Hz, 3H, -CH2CH3), 0.93 (s, 9H, -tBu), 0.09 (s, 6H, -Si(CH3)2);

13 C NMR (126 MHz; CDCl3): δ 166.7, 147.3, 119.6, 62.2, 60.3, 25.8, 18.4, 14.3, -5.4.

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Chapter 7 Experimental section

Ethyl 2-bromo-4-((tert-butyldimethylsilyl)oxy)but-2-enoate15 (273)

To a solution of the silyl ether 279 (1.947 g, 7.975 mmol) in CCl4 (5 mL) at 0 °C was added a solution of Br2 (4.6 g, 28.71 mmol) in CCl4 (3 mL). The reaction was stirred at 0 °C for 1 h and then warmed to rt for 1 h. Ether was added, and the reaction was quenched with saturated aq.

Na2S2O3. The mixture was separated and extracted further with ether, and the combined organic layers were washed with saturated aq. Na2S2O3 and brine, then dried, filtered and the solvents were evaporated. The crude dibromide was dissolved in dimethoxyethane (20 mL) and cooled to 0 °C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.28 mL, 8.56 mmol) in dimethoxyethane (20 mL) was added and the reaction was stirred at 0 °C for 45 min. The reaction was filtered through a plug of CeliteTM with ether and the filtrate was then washed with 10% aq. HCl. The aqueous layer was extracted further with ether and the combined organic layers were washed with brine, then dried, filtered and the solvents were evaporated. The crude residue was purified by flash chromatography (5% EtOAc/petrol as eluent) to afford the bromo ester 273 as a 2.6:1 mixture of E/Z isomers (1.23 g, 48%) as a yellow oil. The spectral data were in accordance with that reported.15

1 (Z-273) H NMR (400 MHz; CDCl3): δ 7.38 (t, J = 4.9 Hz, 1H, -C=CH), 4.59 (d, J = 4.9 Hz, 2H,

-CHCH2), 4.27 (dq, J = 10.8, 7.1 Hz, 2H, -CH2CH3), 1.36-1.32 (t, J = 7.2 Hz, 3H, -CH2CH3),

0.90 (s, 9H, -tBu), 0.08 (s, 6H, -Si(CH3)2);

1 (E-273) H NMR (400 MHz; CDCl3): δ 6.84 (t, J = 4.9 Hz, 1H, -C=CH), 4.41 (d, J = 4.9 Hz,

2H, -CHCH2), 4.27 (dq, J = 10.8, 7.1 Hz, 2H, -CH2CH3), 1.36-1.32 (t, J = 7.2 Hz, 3H, -CH2CH3),

0.92 (s, 9H, -C(CH3)3), 0.10 (s, 6H, -Si(CH3)2).

(Z)-Ethyl 4-(benzyloxy)-2-bromobut-2-enoate (283)

A solution of ethyl 2-butynoate (2.10 mL, 18.01 mmol), benzyl alcohol (1.90 mL, 18.27 mmol), triphenylphosphine (235 mg, 0.892 mmol) and glacial acetic acid (205 µL, 3.57 mmol) in toluene (15 mL) was stirred under reflux for 19 h. Water was added to the cooled reaction and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and the solvents were evaporated. The crude residue was purified by flash chromatography (10%

139

Chapter 7 Experimental section

EtOAc/petrol as the eluent) to afford the known alkene14 282 (2.882 g, 73%) as a brown oil. The alkene (3.690 g, 16.72 mmol) was dissolved in carbon tetrachloride (4 mL) and cooled to 0 °C and shielded from light. A solution of Br2 (9.62 g, 60.19 mmol) in carbon tetrachloride (4 mL) was added to the alkene solution via cannula and the reaction was stirred at 0 °C for 1 h then warmed to rt for 2 h. Ether was added, and the reaction was quenched with saturated aq. Na2S2O3. The mixture was separated, and the aqueous layer was extracted further with ether. The combined organic layers were washed with saturated aq. Na2S2O3 and brine, then dried, filtered and the solvents were evaporated. The crude dibromide was dissolved in dimethoxyethane (20 mL) and cooled to 0 °C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (2.65 mL, 17.72 mmol) in dimethoxyethane (10 mL) was added to the solution via dropping funnel. The reaction was stirred for 3 h at 0 °C before filtering through a plug of CeliteTM with ether as the eluent. The mixture was then washed with 10% aq. HCl and the aqueous layer was extracted further with ether. The combined organic layers were washed with brine, dried, filtered and the solvents were evaporated. The crude residue was purified by flash chromatography (5% EtOAc/petrol as the eluent) to give the bromo ester 283 (2.339 g, 47%) as a yellow oil.

To a solution of solketal (2 mL, 16.09 mmol) in THF (10 mL) and N,N-dimethylformamide (3 mL). at 0 °C was added 60% NaH in mineral oil (840 mg, 20.9 mmol) and once bubbling ceased, benzyl bromide (2.3 mL, 19.30 mmol) was added. The reaction was stirred at rt for 2.5 h before water was added and the mixture was extracted with ether. The combined organic layers were washed with brine, dried, filtered and the solvents were evaporated. The crude material was dissolved in a 4:1 solution of AcOH/water (25 mL) and stirred at rt for 17 h. The solvents were evaporated, and the crude diol was dissolved in CH2Cl2 and cooled to 0 °C. NaIO4 (5.16 g, 24.14 mmol) in water (20 mL) was added and the solution was stirred at rt. After 4.5 h the reaction was separated and extracted further with CH2Cl2. The combined organic layers were dried (with

16 Na2SO4), filtered and the solvents were evaporated to give the known aldehyde 287. The crude aldehyde (16.09 mmol) was dissolved in CH2Cl2 (40 mL) before adding the ylide 285 (7.027 g, 16.45 mmol). The solution was stirred for 19 h at rt before the solvent was evaporated. The crude residue was purified by flash chromatography (5% EtOAc/petrol as the eluent) to afford the ester 283 (3.418 g, 71%) as a yellow oil.

IR νmax (film): 2982.6, 2862.9, 1728.6, 1634.7, 1497.1, 1454.7, 1366.8, 1258.3, 1230.2, 1093.6, 1039.0, 864.2, 734.6, 697.8 cm-1;

1 H NMR (500 MHz; CDCl3): δ 7.49 (t, J = 5.1 Hz, 1H, -C=CH), 7.38-7.32 (m, 5H, ArH), 4.58

(s, 2H, -OCH2), 4.32 – 4.29 (m, 4H, -CH2CH3, -CHCH2), 1.34 (t, J = 7.0 Hz, 3H, -CH2CH3);

13 C NMR (126 MHz; CDCl3): δ 161.7, 143.1, 137.4, 128.5, 127.98, 127.85, 115.7, 73.2, 69.9, 62.7, 14.1;

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Chapter 7 Experimental section

+ HRMS calc. for C13H15BrO3 [M + H] = 299.02828, 301.02624, found 299.02772, 301.02558.

Ethyl 2-bromo-2-(triphenylphosphoranylidene)acetate17,18 (285)

Ethyl bromoacetate (10 mL, 90.4 mmol) in EtOAc (30 mL) was added to a solution of triphenylphosphine (27 g, 113 mmol) in EtOAc (100 mL) at 0 °C and stirred at rt for 17 h. The reaction was filtered and the colourless solid was washed with ether and dried under vacuum. The colourless solid was dissolved in CH2Cl2 (50 mL) and a solution of NaOH (7.6 g, 181 mmol) in water (200 mL) was added and stirred for 30 min. The mixture was separated and extracted with

CH2Cl2 and the combined organic layers were dried, filtered and the solvent was evaporated. Br2

(12 g, 75 mmol) in CH2Cl2 (50 mL) was added to the crude ylide (25.46 g) in CH2Cl2 (100 mL) at 0 °C. The solution was warmed to rt and stirred for 20 h. The reaction was washed with water and saturated aq. NaHCO3, and the organic layer was dried (Na2SO4), filtered and the solvent was evaporated. The crude ylide was recrystallised from acetone/n-hexane (2:1) to afford the ylide 285 (22.74 g, 59%) as a yellow solid. The spectra obtained were identical to that reported.17

1 H NMR (400 MHz; CDCl3): δ 7.70-7.46 (m, 15H, ArH), 4.10-3.73 (br s, 2H, -CH2CH3), 1.25-

0.52 (br s, 3H, -CH2CH3).

Ethyl 2-bromopent-2-enoate (288)

Propionaldehyde (1.70 mL, 23.71 mmol) was added to a solution of ylide 285 (2.00 g, 4.68 mmol) in CH2Cl2 (10 mL) and stirred for 21 h at rt. The solvent was evaporated and the crude residue was purified by flash chromatography (5% EtOAc/petrol as the eluent) to afford the ester 288 (903 mg, 96%) in a 5:1 mixture of Z:E isomers as a colourless oil.

IR νmax (film): 2976.4, 2937.5, 1727.9, 1625.6, 1461.1, 1367.8, 1261.1, 1239.4, 1128.4, 1095.5, 1044.7, 976.2, 862.1, 745.3 cm-1;

1 (Z-288): H NMR (400 MHz; CDCl3): δ 7.27 (t, J = 6.8 Hz, 1H, -C=CH), 4.27 (q, J = 7.1 Hz,

2H, -CH2CH3), 2.35 (quintet, J = 7.5 Hz, 2H, -CHCH2), 1.33 (t, J = 7.1 Hz, 3H, -CH2CH3), 1.10

(t, J = 7.6 Hz, 3H, -CH2CH3);

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Chapter 7 Experimental section

1 (E-288): H NMR (400 MHz; CDCl3): δ 6.65 (t, J = 7.8 Hz, 1H, -C=CH), 4.27 (q, J = 7.1 Hz,

2H, -CH2CH3), 2.50 (quintet, J = 7.6 Hz, -CHCH2), 1.33 (t, J = 7.1 Hz, 3H, -CH2CH3), 1.10 (t, J

= 7.6 Hz, 3H, -CH2CH3);

13 C NMR (101 MHz; CDCl3): δ 162.5, 149.9, 147.4, 115.8, 62.3, 62.0, 25.5, 24.9, 14.15, 14.08, 13.2, 11.9;

+ HRMS calc. for C7H11BrO2 [M + H] = 207.00207, 209.00002, found 207.00163, 208.99962.

Methyl 4-(trimethylsilyl)but-2-enoate19 (304)

Hoveyda-Grubbs CatalystTM 2nd Generation20 (110 mg, 0.176) was added to a solution of methyl acrylate (952 µL, 10.5 mmol) and allyltrimethylsilane (556 µL, 3.50 mmol) in CH2Cl2 (10 mL)

TM and stirred at rt for 18 h. The reaction was filtered through a plug of Celite with CH2Cl2 and the solvent was evaporated. The crude residue was purified by flash chromatography (2.5% EtOAc/petrol as eluent) to afford the alkene 304 (603 mg, 100%) as a colourless oil. The spectra obtained were identical to that reported.19

1 H NMR (400 MHz; CDCl3): δ 7.05 (dt, J = 15.4, 8.9 Hz, 1H, -CH2CH=CH), 5.66 (d, J = 15.4

Hz, 1H, -CH=CH), 3.71 (s, 3H, -OCH3), 1.73 (d, J = 8.9 Hz, 2H, -SiCH2), 0.05 (s, 9H, -

Si(CH3)3);

13 C NMR (101 MHz; CDCl3): δ 167.3, 148.3, 118.5, 51.2, 24.9, -1.9.

Allyltriisopropylsilane21 (309a)

Mg turnings (1.51 g, 63 mmol) were activated by heating with a single crystal of iodine until a purple vapour appeared. The activated magnesium was cooled to rt before adding ether (10 mL) followed by dropwise addition of allyl bromide (5.2 mL, 60 mmol) in ether (15 mL) over 1 h. The reaction was stirred at rt for 90 min before adding a solution of TIPSCl (4.3 mL, 20 mmol) and flame-dried ZnCl2 (140 mg, 1 mmol) in THF (30 mL) and stirring at rt for 18 h. The reaction was cooled to 0 °C and quenched with water and 1M aq. HCl. The mixture was separated and washed with water, and the organic layer was dried, filtered and the solvent was evaporated. The crude residue was filtered through a plug of silica gel with n-hexanes as the eluent to afford

142

Chapter 7 Experimental section allyltriisopropylsilane 309a (3.83 g, 97%) as a colourless oil. The spectra obtained were identical to that reported.21,22

1 H NMR (500 MHz; CDCl3): δ 5.89 (ddd, J = 17.3, 8.7 Hz, 1H, -CH=CH2), 4.93 (d, J = 16.1

Hz, 1H, -CH=CH2), 4.82 (d, J = 9.9 Hz, 1H, -CH=CH2), 1.65 (d, J = 8.1 Hz, 2H, -SiCH2), 1.07 (s, 21H, iPr).

Allyldimethyl(phenyl)silane23 (309e)

Mg turnings (912 mg, 37.52 mmol) were activated by heating with a single crystal of iodine until a purple vapour appeared. The activated magnesium was cooled to rt before adding ether (5 mL) followed by dropwise addition of allyl bromide (3.09 mL, 35.73 mmol) in ether (10 mL) over 1 h. The reaction was stirred at rt for 3.5 h before adding a solution of chloro(dimethyl)phenyl silane

(2 mL, 11.91 mmol) and flame-dried ZnCl2 (81 mg, 0.6 mmol) in THF (20 mL) and stirring at rt for 19 h. The reaction was cooled to 0 °C and quenched with water and 1M aq. HCl. The mixture was separated and washed with water, and the organic layer was dried, filtered and the solvent was evaporated. The crude residue was filtered through a plug of silica gel with n-hexanes as the eluent to afford allyldimethyl(phenyl)silane 309e (1.855 g, 88%) as a colourless oil. The spectra obtained were identical to that reported.23

1 H NMR (600 MHz; CDCl3): δ 7.51 (t, J = 3.2 Hz, 2H, ArH), 7.35 (t, J = 2.4 Hz, 3H, ArH),

5.77 (dq, J = 17.4, 8.7 Hz, 1H, -CH=CH2), 4.87-4.83 (m, 2H, -CH=CH2), 1.75 (d, J = 8.0 Hz,

2H, -SiCH2), 0.27 (s, 6H, -Si(CH3)2);

13 C NMR (151 MHz; CDCl3): δ 138.6, 134.6, 133.6, 128.9, 127.7, 113.3, 23.6, -3.5.

2-(triisopropylsilyl)acetaldehyde (310a)

A solution of 309a (1.016 g, 5.12 mmol) in CH2Cl2 (20 mL) was cooled to -78 °C before a stream of ozone was bubbled through the solution. The reaction was deemed complete once the solution turned from colourless to blue, and a stream of argon was then bubbled through the solution until the blue colour dissipated. The solution was then warmed to rt before adding 90% aq. AcOH (20 mL) and zinc dust (402 mg, 6.15 mmol). The reaction was stirred for 2.5 h at rt before adding water and extracting with ether. The combined organic layers were first washed with water, then

143

Chapter 7 Experimental section

thoroughly with saturated aq. NaHCO3, and brine. The organic layer was then dried (Na2SO4), filtered, and the solvents evaporated to give the aldehyde 310a (1.014 g, 99%) as a colourless oil.

IR νmax (film): 2944.5, 2892.4, 2868.1, 1702.1, 1464.1, 1386.0, 1368.8, 1247.0, 1163.5, 1127.7, 1070.7, 1006.3, 907.3, 882.7, 786.4, 730.5, 676.9 cm-1;

1 H NMR (500 MHz; CDCl3): δ 9.80 (t, J = 4.4 Hz, 1H, -CHO), 2.32 (d, J = 4.4 Hz, 2H, -SiCH2),

1.09 (d, J = 5.5 Hz, 21H, iPr3).;

13 C NMR (101 MHz; CDCl3): δ 200.8, 33.1, 18.4, 11.4;

+ HRMS calc. for C11H24OSi [M + H] = 201.16747, found 201.16669.

2-(triphenylsilyl)acetaldehyde (310b)

A solution of allyltriphenylsilane (2.00 g, 6.66 mmol) in CH2Cl2 (30 mL) was cooled to -78 °C before a stream of ozone was bubbled through the solution. The reaction was deemed complete once the solution turned from colourless to blue, and a stream of argon was then bubbled through the solution until the blue colour dissipated. The solution was then warmed to rt before adding 90% aq. AcOH (20 mL) and zinc dust (514 mg, 8.00 mmol). The reaction was stirred for 3 h at rt before adding water and extracting with ether. The combined organic layers were then washed with water, saturated aq. NaHCO3, and brine. The organic layer was then dried, filtered, and the solvents evaporated to afford the aldehyde 310b (1.925 g, 95%) as a colourless solid. m.p. 97.8 – 99.0 °C.

IR νmax (film): 3070.1, 3049.3, 1703.3, 1589.0, 1568.0, 1487.0, 1428.2, 1388.7, 1332.8, 1306.9, 1261.9, 1190.0, 1157.5, 1132.2, 1111.2, 1067.5, 1012.4, 997.0, 914.4, 859.9, 791.9, 739.2, 697.9 cm-1;

1 H NMR (500 MHz; CDCl3): δ 9.72 (t, J = 4.2 Hz, 1H, -CHO), 7.57 (d, J = 7.9 Hz, 7H, ArH),

7.50-7.44 (m, 8H, ArH), 3.09 (d, J = 4.2 Hz, 2H, -SiCH2);

13 C NMR (101 MHz; CDCl3): δ 200.0, 135.5, 132.6, 130.2, 128.2, 36.6;

+ HRMS calc. for C20H18OSi [M + Na] = 325.10246, found 325.10170.

144

Chapter 7 Experimental section

2-(triethoxysilyl)acetaldehyde (310c)

A solution of allyltriethoxysilane (2.00 mL, 8.84 mmol) in CH2Cl2 (20 mL) was cooled to -78 °C before a stream of ozone was bubbled through the solution. The reaction was deemed complete once the solution turned from colourless to blue, and a stream of argon was then bubbled through the solution until the blue colour dissipated. The solution was then warmed to rt before adding 90% aq. AcOH (20 mL) and zinc dust (694 mg, 10.61 mmol). The reaction was stirred for 2 h at rt before adding water and extracting with ether. The combined organic layers were first washed with water, then thoroughly with a saturated aq. NaHCO3, and brine. The organic layer was then dried with Na2SO4, filtered, and the solvents evaporated to give the aldehyde 310c (1.769 g, 98%) as a colourless oil.

IR νmax (film): 3069.7, 3053.5, 3001.1, 1584.6, 1478.0, 1433.3, 1386.6, 1325.8, 1307.0, 1278.7, 1181.8, 1157.2, 1118.3, 1088.3, 1069.9, 1026.8, 998.3, 970.7, 906.9, 848.1, 793.1, 739.4, 722.1, 692.2 cm-1;

1 H NMR (500 MHz; CDCl3): δ 9.68 (t, J = 4.1 Hz, 1H, -CHO), 3.86 (t, J = 7.0 Hz, 6H, -CH2CH3),

2.35 (d, J = 4.1 Hz, 2H, -SiCH2), 1.25 (t, J = 7.0 Hz, 9H, -CH2CH3);

13 C NMR (126 MHz; CDCl3): δ 198.6, 59.0, 34.3, 18.1;

+ HRMS calc. for C8H18O4Si [M + H] = 207.10526, found 207.10464.

2-(dimethyl(phenyl)silyl)ethanol24 (311)

A solution of chlorodimethylphenylsilane (2 mL, 11.91 mmol) and ethyl bromoacetate (1.3 mL, 11.68 mmol) in THF (5 mL) was added to Zn (764 mg, 11.67 mmol) in THF (15 mL) at reflux over 15 min. The solution was stirred at reflux for 4 h before quenching with 10% aq. HCl. The mixture was extracted with ether and the combined organic layers were washed with saturated aq.

NH4Cl, saturated aq. NaHCO3 and brine, before being dried, filtered and the solvents were evaporated. The crude residue was purified by flash chromatography (5% EtOAc/petrol as the eluent) to give the α-silyl ester (2.107 g, 81%) as a colourless oil. The spectral data were in accordance with that reported.24

145

Chapter 7 Experimental section

1 H NMR (400 MHz; CDCl3): δ 7.53 (t, J = 3.5 Hz, 2H, ArH), 7.37 (d, J = 5.9 Hz, 3H, ArH), 4.03

(q, J = 7.1 Hz, 2H, -CH2CH3), 2.11 (s, 2H, -SiCH2), 1.16 (t, J = 7.1 Hz, 3H, -CH2CH3), 0.41 (s,

6H, -Si(CH3)2).

A solution of the α-silyl ester (2.60 g, 11.68 mmol) in ether (20 mL) was added to a mixture of

LiAlH4 (890 mg, 23.45 mmol) in ether (20 mL) at 0 °C. The reaction was warmed to rt and stirred for 2 h before quenching dropwise with 20% w/v aq. NaOH until the solution turned white.

Na2SO4 was added and the mixture was filtered, and the solvent was evaporated to give the alcohol 311 (1.734 g, quant. yield) as a colourless oil. The spectral data were in accordance with that reported.24

1 H NMR (400 MHz; CDCl3): δ 7.51 (dt, J = 4.8, 2.3 Hz, 2H, ArH), 7.36 (dd, J = 3.8, 2.0 Hz, 3H,

ArH), 3.74 (t, J = 8.3 Hz, 2H, -CH2OH), 1.21 (t, J = 8.3 Hz, 2H, -SiCH2), 0.31 (s, 6H, -Si(CH3)2).

2-(dimethyl(phenyl)silyl)acetaldehyde25 (310e)

A solution of dimethyl sulfoxide (1.82 mL, 25.56 mmol) in CH2Cl2 (5 mL) was added to a solution of oxalyl chloride (1.27 mL, 14.83 mmol) in CH2Cl2 (30 mL) at -78 °C and the solution was stirred at -78 °C for 45 min. A solution of alcohol 311 (1.897 g, 10.52 mmol) in CH2Cl2 was added and the solution was then stirred at -78 °C for a further 80 min. NEt3 (5.90 mL, 42.33 mmol) was then added and the solution was warmed to rt and stirred for 1 h. Ether was added and the reaction mixture was washed twice with 1M aq. HCl, and once with water. The aqueous layer was then extracted further with ether, and the combined organic layers were then washed with water and brine, dried, filtered and the solvents evaporated to afford the aldehyde 310e (1.696 g, 90%) as a yellow oil.

-1 IR νmax (film): 2957.2, 1703.2, 1427.9, 1253.0, 1117.6, 1063.5, 832.4, 790.1, 731.5, 699.5 cm ;

1 H NMR (400 MHz; CDCl3): δ 9.63 (t, J = 3.7 Hz, 1H, -CHO), 7.51 (s, 2H, ArH), 7.40 (d, J =

5.2 Hz, 3H, ArH), 2.49 (d, J = 4.0 Hz, 2H, -SiCH2), 0.43 (s, 6H, -Si(CH3)2);

13 C NMR (101 MHz; CDCl3): δ 200.4, 136.3, 133.4, 129.8, 128.1, 39.3, -2.6;

+ HRMS calc. for C10H14OSi [M + H] = 179.08922, found 179.08558.

146

Chapter 7 Experimental section

Ethyl 2-bromo-4-(triisopropylsilyl)but-2-enoate (312a)

Ylide 285 (2.30 g, 5.38 mmol) was added to a solution of aldehyde 310a (533 mg, 2.66 mmol) in

CH2Cl2 (20 mL) and the solution was stirred for 18 h at rt. The reaction was deemed incomplete by TLC and ylide (2.28 g, 5.34 mmol) was added and the reaction was heated at reflux for 5 h. The solvent was evaporated before redissolving in toluene and heating to reflux for 17 h. Solvent was evaporated, and the crude residue was purified by flash chromatography (2.5% EtOAc/petrol as the eluent) to afford the ester 312a (868 mg, 90%) as a yellow oil.

IR νmax (film): 2943.3, 2891.8, 2867.6, 1708.9, 1611.0, 1463.7, 1386.0, 1367.8, 1257.6, 1163.1, 1129.5, 1095.8, 1054.8, 1017.2, 998.5, 907.9, 882.4, 694.4, 659.1 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.50 (t, J = 9.0 Hz, 1H, -CHCH2), 4.25 (q, J = 7.1 Hz, 2H, -

CH2CH3), 1.99 (d, J = 9.0 Hz, 2H, -SiCH2), 1.31 (t, J = 7.1 Hz, 3H, -CH2CH3), 1.08 (s, 21H, iPr3);

13 C NMR (101 MHz; CDCl3): δ 162.7, 146.0, 113.0, 62.0, 18.53, 18.44, 14.2, 11.4;

+ HRMS calc. for C15H29BrO2Si [M + H] = 349.11984, 351.11780, found 349.11945, 351.11713.

Ethyl 2-bromo-4-(triphenylsilyl)but-2-enoate (312b)

Triphenylsilane aldehyde 310b (911 mg, 3.01 mmol) was added to a solution of ylide 285 (2.57 g, 6.02 mmol) in CH2Cl2 (25 mL) and stirred for 16 h at rt. The solvent was evaporated, and the crude residue was purified by flash chromatography (5% EtOAc/petrol as the eluent) to afford the ester 312b (1.02 g, 75%) as a colourless solid. m.p. 75 – 77 °C.

IR νmax (film): 3069.6, 3048.8, 2981.0, 1721.5, 1613.0, 1588.9, 1487.2, 1444.9, 1394.6, 1366.2, 1251.9, 1136.1, 1110.5, 1052.5, 997.9, 907.1, 861.6, 730.8, 712.2, 697.2 cm-1;

1 H NMR (500 MHz; CDCl3): δ 7.55 (dquintet, J = 6.6, 1.6 Hz, 6H, ArH), 7.49-7.44 (m, 4H,

ArH), 7.42-7.38 (m, 6H, ArH, -C=CH), 4.22 (q, J = 7.1 Hz, 2H, -CH2CH3), 2.77 (d, J = 8.7 Hz,

2H, -SiCH2), 1.28 (t, J = 7.1 Hz, 3H, -CH2CH3);

13 C NMR (126 MHz; CDCl3): δ 162.5, 143.3, 135.6, 133.2, 130.0, 128.1, 115.2, 62.1, 22.2, 14.2;

147

Chapter 7 Experimental section

+ HRMS calc. for C24H23BrO2Si [M + H] = 451.07289, 453.07085, found 451.07303, 453.07057.

Ethyl 2-bromo-4-(triethoxysilyl)but-2-enoate (312c)

Ylide 285 (3.49 g, 8.16 mmol) was added to a solution of aldehyde 310c (841 mg, 4.08 mmol) in

CH2Cl2 (10 mL) and the solution was stirred for 17 h at rt. The reaction was deemed incomplete and ylide (1.75 g, 4.10 mmol) was added and the reaction was heated at reflux for 5.5 h. Solvent was evaporated before redissolving the crude material in ether, filtering, and evaporating the solvent. This procedure was repeated before filtering rapidly through a plug of silica with 20% EtOAc/Pet as the eluent to afford the ester 312c (868 mg, 60%) as a yellow oil.

IR νmax (film): 2977.5, 2928.4, 2889.0, 1727.7, 1618.4, 1444.4, 1392.6, 1367.0, 1257.7, 1165.6, 1101.6, 1053.5, 962.8, 792.9, 738.7 cm-1;

1 H NMR (600 MHz; CDCl3): δ 7.38 (t, J = 8.8 Hz, 1H, -C=CH), 3.84 (t, J = 7.0 Hz, 6H, -

CH2CH3), 2.01 (d, J = 8.8 Hz, 2H, -SiCH2), 1.22 (t, J = 7.0 Hz, 9H, -CH2CH3);

13 C NMR (151 MHz; CDCl3): δ 162.5, 142.3, 114.8, 62.1, 58.9, 19.5, 18.1, 14.2;

+ HRMS calc. for C12H23BrO5Si [M + H] = 355.05764, 357.05559, found 355.05742, 357.05506.

Ethyl 2-bromo-4-(dimethyl(phenyl)silyl)but-2-enoate (312d)

Ylide 285 (8.13 g, 19.02 mmol) was added to a solution of the aldehyde 310e (1.696 mg, 9.51 mmol) in CH2Cl2 (40 mL) and stirred for 16 h at rt, then at reflux for 1 h. Solvent was evaporated before redissolving the crude material in ether, filtering, and evaporating the solvent. This procedure was repeated four times before purifying by flash chromatography (5% EtOAc/petrol as the eluent) to afford the ester 312d (284 mg, 9%) as a yellow oil.

IR νmax (film): 3070.2, 3052.3, 2959.2, 2900.9, 1724.2, 1612.6, 1428.0, 1367.9, 1253.8, 1118.7, 1054.1, 1027.5, 998.1, 908.0, 830.4, 790.3, 729.8, 669.6 cm-1;

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Chapter 7 Experimental section

1 H NMR (400 MHz; CDCl3): δ 7.52 (dd, J = 4.8, 2.5 Hz, 2H, ArH), 7.43 (t, J = 8.0 Hz, 1H, -

C=CH), 7.38 (d, J = 11.8 Hz, 3H, ArH), 4.25 (q, J = 7.2 Hz, 2H, -CH2CH3), 2.17 (d, J = 8.9 Hz,

2H, -SiCH2), 1.31 (t, J = 7.2 Hz, 3H, -CH2CH3), 0.38 (s, 6H, -Si(CH3)2);

13 C NMR (101 MHz; CDCl3): δ 162.7, 144.4, 137.2, 133.4, 129.5, 128.0, 113.7, 62.1, 24.9, 14.2, -2.8;

+ HRMS calc. for C14H19BrO2Si [M + H] = 327.04159, 329.03955, found 327.04105, 329.03885.

Di-tert-butyl 4-((2S,3R)-3-(ethoxycarbonyl)-3-((E)-2-(triisopropylsilyl)vinyl)oxiran-2-yl)- 1H-pyrrole-1,2-dicarboxylate (313a)

A solution of n-BuLi in hexanes (2.27 M , 350 µL, 0.796 mmol) was added to a solution of iPr2NH (112 µL, 0.796 mmol) and HMPA (138 µL, 0.796 mmol) in THF (2 mL) at -78 °C and the solution was warmed to rt. The reaction was then cooled to -78 °C and a solution of ester 312a (278 mg, 0.796 mmol) in THF (2 mL) was cooled to -78 °C and transferred to the reaction via a cooled cannula. A solution of the aldehyde 204 (67 mg, 0.227 mmol) in THF (1 mL) was cooled to -78 °C and transferred to the reaction via a cooled cannula. The reaction was stirred for 1 h at -78 °C and was then quenched with saturated aq. NH4Cl. The solution was warmed to rt before extracting with ether. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and the solvents evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as the eluent) to afford the vinyl epoxide 313a (103 g, 80%) as a yellow oil.

IR νmax (film): 2942.1, 2866.7, 1750.0, 1721.5, 1614.7, 1462.3, 1394.0, 1369.2, 1282.1, 1242.1, 1206.2, 1155.3, 1120.2, 1075.3, 1017.3, 995.6, 909.2, 882.6, 849.8, 823.2, 775.9, 757.7, 732.3, 678.8, 663.3 cm-1;

1 H NMR (600 MHz; CDCl3): δ 7.13 (dd, J = 1.3, 0.6 Hz, 1H, ArH), 6.61 (d, J = 1.9 Hz, 1H, ArH), 6.26 (d, J = 19.2 Hz, 1H, -CH=CH), 5.92 (d, J = 19.3 Hz, 1H, -CH=CH), 4.31-4.24 (m,

2H, -CH2CH3), 4.21 (s, 1H, -CHAr), 1.54 (s, 9H, t-Bu), 1.50 (s, 9H, t-Bu), 1.31 (d, J = 7.4 Hz,

3H, -SiCH(CH3)2), 0.93 (dd, J = 16.3, 7.2 Hz, 18H, -CH(CH3)2);

13 C NMR (101 MHz; CDCl3): δ 169.3, 159.4, 147.8, 135.5, 130.4, 127.2, 124.8, 118.8, 117.6, 84.8, 81.2, 64.0, 62.0, 60.0, 28.1, 27.6, 18.4, 14.1, 10.7;

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Chapter 7 Experimental section

+ HRMS calc. for C30H49NO7Si [M + H] = 564.33565, found 564.33500.

Di-tert-butyl-4-((2S,3R)-3-(ethoxycarbonyl)-3-((E)-2-(triphenylsilyl)vinyl)oxiran-2-yl)-1H- pyrrole-1,2-dicarboxylate (313b)

A solution of n-BuLi in hexanes (2.10 M , 378 µL, 0.793 mmol) was added to a solution of iPr2NH (111 µL, 0.793 mmol) and HMPA (138 µL, 0.793 mmol) in THF (5 mL) at -78 °C and the solution was warmed to rt. The reaction was then cooled to -78 °C and a solution of ester 312b (358 mg, 0.793 mmol) in THF (3 mL) was cooled to -78 °C and transferred to the reaction via a cooled cannula. A solution of the aldehyde 204 (67 mg, 0.227 mmol) in THF (2 mL) was cooled to -78 °C and transferred to the reaction via a cooled cannula. The reaction was stirred for 1.5 h at -78

°C and was then quenched with saturated aq. NH4Cl. The solution was warmed to rt before extracting with ether. The combined organic layers were washed with water and brine, dried

(Na2SO4), filtered, and the solvents evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as the eluent) to afford the vinyl epoxide 313b (139 mg, 92%) as a colourless solid. m.p. 164.8 – 166.8 °C.

IR νmax (film): 3069.7, 2980.3, 1748.7, 1721.6, 1588.6, 1478.2, 1457.9, 1428.8, 1393.7, 1369.1, 1282.2, 1241.9, 1199.9, 1154.1, 1111.9, 1075.1, 1047.5, 997.7, 910.9, 849.0, 823.0, 786.8, 737.9, 700.2 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.39-7.33 (m, 15H, PhH), 7.17 (s, 1H, ArH), 6.69 (s, 1H, ArH), 6.62 (d, J = 21.4 Hz, 1H, -CH=CH), 6.38 (d, J = 18.9 Hz, 1H, -CH=CH), 4.28 (s, 1H, -CHAr),

4.28-4.20 (m, 2H, -CH2CH3), 1.48 (d, J = 10.3 Hz, 18H, t-Bu), 1.31 (t, J = 6.0 Hz, 3H, -CH2CH3);

13 C NMR (101 MHz; CDCl3): δ 168.8, 159.4, 147.6, 139.7, 135.8, 135.0, 133.7, 130.23, 130.07, 129.6, 127.9, 127.3, 125.0, 118.9, 117.4, 84.8, 81.4, 64.1, 62.1, 60.2, 28.1, 27.6, 14.1;

+ HRMS calc. for C39H43NO7Si [M + H] = 666.28870, found 666.28854.

150

Chapter 7 Experimental section

Di-tert-butyl-4-((2S,3R)-3-(ethoxycarbonyl)-3-((E)-2-(triethoxysilyl)vinyl)oxiran-2-yl)-1H- pyrrole-1,2-dicarboxylate (313c)

A solution of n-BuLi in hexanes (2.79 M , 875 µL, 2.44 mmol) was added to a solution of iPr2NH (342 µL, 2.44 mmol) and HMPA (425 µL, 2.44 mmol) in THF (3 mL) at -78 °C and the solution was warmed to rt. The reaction was then cooled to -78 °C and a solution of ester 312c (868 mg, 2.44 mmol) in THF (3 mL) was cooled to -78 °C and transferred to the reaction via a cooled cannula. A solution of the aldehyde 204 (206 mg, 0.697 mmol) in THF (3 mL) was cooled to -78 °C and transferred to the reaction via a cooled cannula. The reaction mixture was stirred for 45 min at -78 °C and was then quenched with saturated aq. NH4Cl. The solution was warmed to rt before extracting with ether. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and the solvents evaporated. The crude residue was purified by flash chromatography (10% EtOAc/petrol as the eluent) to afford the vinyl epoxide 313c (154 mg, 39%) as a yellow oil and the vinyl epoxide 205 (91 mg, 32%).

IR νmax (film): 2978.1, 2931.4, 1750.4, 1723.0, 1618.9, 1586.4, 1479.4, 1458.3, 1393.6, 1369.6, 1282.2, 1244.0, 1203.5, 1157.7, 1101.1, 1076.0, 995.5, 961.6, 849.1, 822.5, 776.5, 734.2 cm-1;

1 H NMR (500 MHz; CDCl3): δ 7.17 (dd, J = 1.9, 0.8 Hz, 1H, ArH), 6.66-6.66 (m, 1H, ArH), 6.61 (d, J = 19.0 Hz, 1H, -CH=CH), 5.84 (d, J = 19.0 Hz, 1H, -CH=CH), 4.32-4.27 (m, 2H, -

CH2CH3), 4.25 (d, J = 0.5 Hz, 1H, -CHAr), 3.73-3.68 (m, 6H, -CH2CH3), 1.57 (s, 9H, t-Bu), 1.53

(s, 9H, t-Bu), 1.33 (t, J = 7.1 Hz, 3H, -CH2CH3), 1.17 (t, J = 7.0 Hz, 9H, -CH2CH3);

13 C NMR (101 MHz; CDCl3): δ 168.7, 159.3, 147.8, 139.6, 127.2, 125.4, 124.9, 118.8, 117.3, 85.0, 81.4, 63.8, 62.1, 60.3, 58.5, 28.1, 27.6, 18.1, 14.1;

+ HRMS calc. for C27H43NO10Si [M + H] = 570.27345, found 570.27286.

151

Chapter 7 Experimental section

(2R,3S)-ethyl 3-(furan-3-yl)-2-((E)-2-(triphenylsilyl)vinyl)oxirane-2-carboxylate (314)

A solution of n-BuLi in hexanes (2.27 M , 700 µL, 1.59 mmol) was added to a solution of iPr2NH (223 µL, 1.59 mmol) and HMPA (277 µL, 1.59 mmol) in THF (3 mL) at -78 °C and the solution was warmed to rt. The reaction was then cooled to -78 °C and a solution of ester 312b (720 mg, 1.59 mmol) in THF (2 mL) was cooled to -78 °C and transferred to the reaction via a cooled cannula. A solution of 3-furaldehyde 178 (39 µL, 0.456 mmol) in THF (2 mL) was cooled to -78 °C and transferred to the reaction via a cooled cannula. The reaction mixture was stirred for 2 h at -78 °C and was then quenched with saturated aq. NH4Cl. The solution was warmed to rt before extracting with ether. The combined organic layers were washed with water and brine, dried

(Na2SO4), filtered, and the solvents evaporated. The crude residue was purified by flash chromatography (7.5 - 10% EtOAc/petrol as the eluent) to afford the vinyl epoxide 314 (155 mg, 73%) as a colourless oil.

IR νmax (film): 3135.6, 3049.7, 3068.8, 2983.9, 1743.6, 1732.3, 1617.7, 1588.9, 1567.7, 1504.7, 1485.2, 1444.9, 1428.4, 1368.6, 1263.0, 1200.7, 1161.6, 1144.9, 1111.4, 1073.6, 1048.0, 1025.6, 997.7, 911.3, 874.8, 860.8, 833.9, 784.9, 738.4, 699.4, 665.8 cm-1;

1 H NMR (600 MHz; CDCl3): δ 7.40 (t, J = 7.8 Hz, 9H, ArH), 7.34 (t, J = 6.8 Hz, 8H, ArH), 6.60 (dd, J = 18.8, 2.7 Hz, 1H, -CH=CH), 6.40 (dd, J = 18.8, 2.7 Hz, 1H, -CH=CH), 6.28 (s, 1H, ArH),

4.30 (s, 1H, -CHAr), 4.23 (q, J = 7.1 Hz, 2H, -CH2CH3), 1.31 (t, J = 7.1 Hz, 3H, -CH2CH3);

13 C NMR (126 MHz; CDCl3): δ 168.9, 142.9, 141.9, 139.6, 135.9, 133.7, 130.0, 129.7, 127.9, 118.4, 109.9, 63.9, 62.1, 59.4, 14.1;

+ HRMS calc. for C29H26O4Si [M + H] = 467.16786, found 467.16765.

152

Chapter 7 Experimental section

(8R,8aS)-ethyl 8-(triphenylsilyl)-8,8a-dihydrofuro[3,2-c]oxepine-6-carboxylate (315)

A solution of the divinyl epoxide 314 (155 mg, 0.332 mmol) in degassed toluene (3 mL) in a pressure tube was heated and stirred at 180 °C for 15 h. The solvent was evaporated, and the crude residue was purified using flash chromatography (7.5% EtOAc/petrol as the eluent) to afford the dihydrooxepine 315 (62 mg, 40%) as a colourless oil.

IR νmax (film): 3070.6, 3049.1, 2998.7, 2937.8, 1726.6, 1637.3, 1581.6, 1486.4, 1428.5, 1371.1, 1274.3, 1219.0, 1176.1, 1109.3, 1058.5, 1024.2, 998.4, 967.9, 910.7, 855.7, 805.5, 786.1, 767.0, 739.9, 699.6, 662.3 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.63 (d, J = 7.4 Hz, 5H, ArH), 7.31 (t, J = 7.4 Hz, 7H, ArH), 7.18 (d, J = 7.4 Hz, 3H, ArH), 6.35 (d, J = 9.3 Hz, 1H, -CH), 6.00 (s, 1H, -CH), 5.77 (s, 1H, -CH),

5.65 (s, 1H, -CH), 4.91 (s, 1H, -CH), 4.17 (dd, J = 17.4, 7.2 Hz, 2H, -CH2CH3), 3.83 (dd, J = 8.9,

5.0 Hz, 1H, -SiCH), 1.23 (t, J = 7.1 Hz, 3H, -CH2CH3);

13 C NMR (101 MHz; CDCl3): δ 148.5, 136.4, 135.8, 134.9, 133.7, 129.5, 129.0, 128.2, 127.4, 125.3, 112.8, 103.4, 80.9, 61.5, 34.2, 14.1;

+ HRMS calc. for C29H26O4Si [M + H] = 467.16786, found 467.16736.

(8R,8aS)-1,2-di-tert-butyl 6-ethyl 8-(triethoxysilyl)-8,8a-dihydro-1H-oxepino[4,3-b]pyrrole- 1,2,6-tricarboxylate (316c)

A solution of the divinyl epoxide 313c (154 mg, 0.270 mmol) in degassed toluene (4 mL) in a pressure tube was heated and stirred at 180 °C for 16 h. The solvent was evaporated, and the crude residue was purified using flash chromatography (10% EtOAc/petrol as the eluent) to afford the dihydrooxepine 316c (62 mg, 40%) as a colourless oil.

IR νmax (film): 2978.3, 2932.4, 2889.9, 1723.8, 1653.3, 1579.0, 1479.1, 1457.9, 1391.8, 1368.3, 1339.7, 1267.1, 1214.7, 1163.5, 1103.5, 1078.7, 964.0, 850.1, 777.9, 730.2 cm-1;

153

Chapter 7 Experimental section

1 H NMR (600 MHz; CDCl3): δ 6.62 (s, 1H, -NC=CH), 6.48 (d, J = 9.9 Hz, 1H, -CHCH=CH),

6.16 (s, 1H, -C=CHO), 4.84 (s, 1H, -NCH), 4.24 (q, J = 7.1 Hz, 2H, -CH2CH3), 3.76 (dd, J =

11.9, 5.4 Hz, 6H, -CH2CH3), 3.22 (dd, J = 9.8, 3.9 Hz, 1H, -SiCH), 1.50 (s, 9H, t-Bu), 1.45 (s,

9H, t-Bu), 1.30 (t, J = 7.1 Hz, 3H, -CH2CH3), 1.15 (t, J = 7.0 Hz, 9H, -CH2CH3);

13 C NMR (151 MHz; CDCl3): δ 163.0, 160.2, 153.1, 140.5, 134.5, 129.7, 124.7, 119.4, 116.0, 81.6, 81.1, 62.1, 61.5, 58.8, 33.9, 29.7, 28.13, 28.12, 18.1, 14.2;

+ HRMS calc. for C27H43NO10Si [M + H] = 570.27345, found 570.27304.

(Z)-2-bromobut-2-enenitrile26 (324)

Br2 (2.0 g, 12.5 mmol) in CH2Cl2 (5 mL), followed by a 45% w/v solution of HBr in AcOH (0.061 mmol, 12 µL) was added to a solution of crotononitrile (1 mL, 12.28 mmol) in CH2Cl2 (10 mL) at 0 °C. The solution was stirred for 15 min before warming to rt and stirring for 2 h. Ether was added, and the reaction was quenched with saturated aq. Na2S2O3. The mixture was separated, and the organic layer was washed with brine, dried, filtered and the solvent was evaporated. The crude dibromide was dissolved in DMSO (20 mL) and heated to 80 °C for 1 h. The reaction was cooled before adding ether. The mixture was then washed with water and brine, and the organic layer was dried, filtered and the solvent was evaporated. The nitrile 324 was obtained quantitatively and used without further purification. The spectral data were in accordance with that reported.26

1 H NMR (400 MHz; CDCl3): δ 6.99 (q, J = 6.9 Hz, 1H, -CHCH3), 1.94 (d, J = 6.9 Hz, 3H, -

CHCH3).

1-tosylpropan-2-ol (334)

Propylene oxide (4.70 mL, 3.89 g, 67 mmol) and LiBr (485 mg, 5.58 mmol) were added to a solution of sodium p-toluene sulfinate (10.0 g, 56.1 mmol) in water (280 mL) and stirred at 85°C for 17 h. The mixture was cooled to rt, and then extracted with EtOAc. The combined organic layers were dried, filtered and solvents evaporated. The crude sulfonyl alcohol 334 (6.14 g) was

154

Chapter 7 Experimental section obtained as a colourless solid and carried through to the next step without further purification. m.p. 73.5 -73.8 °C.

IR νmax (film): 3494.1, 1597.9, 1453.6, 1401.0, 1299.8, 1286.2, 1183.4, 1139.7, 1085.0, 1043.6, 1018.6, 939.4, 877.9, 839.3, 818.6, 801.0, 769.6, 704.2, 665.5 cm-1;

1 H NMR (500 MHz; CDCl3): δ 7.82 (d, J = 8.2 Hz, 2H, ArH), 7.39 (d, J = 8.0 Hz, 2H, ArH),

4.34-4.28 (m, 1H, -CHOH), 3.44 (d, J = 1.3 Hz, 1H, -OH), 3.24-3.13 (m, 2H, -SO2CH2), 2.47 (s,

3H, ArCH3), 1.25 (d, J = 6.1 Hz, 3H, -CH3);

13 C NMR (101 MHz; CDCl3): δ 145.2, 136.1, 130.1, 127.9, 63.4, 62.4, 22.5, 21.6;

+ HRMS (ESI) calc. for C10H14O3S [M + H] = 215.07364, found 215.07357.

1-(phenylsulfonyl)propan-2-ol (335)

Propylene oxide (4.26 mL, 3.54 g, 61.0 mmol) and LiBr (530 mg, 6.10 mmol) were added to a solution of sodium benzene sulfinate (10.0 g, 60.9 mmol) in water (50 mL) and stirred at 85°C for 16 h. The mixture was cooled to rt, and then extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and solvents evaporated. The crude sulfonyl alcohol 335 (6.01 g) was carried through to the next step without further purification.

IR νmax (film): 3485.6, 1447.7, 1302.8, 1291.0, 1143.3, 1083.8, 1044.9, 999.0, 939.6, 877.1, 838.8, 790.2, 748.7, 719.5, 688.6 cm-1;

1 H NMR (500 MHz; CDCl3): δ 7.98-7.94 (m, 2H, ArH), 7.72-7.66 (m, 1H, ArH), 7.63-7.57 (m,

2H, ArH), 4.37-4.31 (m, 1H, -CHOH), 3.40 (s, 1H, -OH), 3.27-3.16 (m, 2H, -CH2), 1.26 (d, J =

6.4 Hz, 3H, -CH3);

13 C NMR (101 MHz; CDCl3): δ 134.1, 129.5, 128.8, 127.9, 63.3, 62.3, 22.5;

+ HRMS (ESI) calc. for C9H12O3S [M + H] = 201.05799, found 201.05815.

155

Chapter 7 Experimental section

(E)-1-methyl-4-(prop-1-en-1-ylsulfonyl)benzene (336)

Methanesulfonyl chloride (6.78 mL, 10.04 g, 87.69 mmol) was added to a solution of the crude sulfonyl alcohol 334 (5.733 g) in toluene (70 mL) at 0°C followed by the dropwise addition of

NEt3 (24 mL, 17.75 g, 175.41 mmol). The mixture was warmed to rt with stirring for 90 minutes, and then heated to 100°C for 90 min. The solution was cooled to rt before neutralising with 5% aq. HCl and extracting with ether. The combined organic layers were washed with brine, dried, filtered and solvents evaporated. The crude product was purified by flash column chromatography (20% EtOAc/petrol as the eluent) affording the alkene 336 (2.968 g, 43%) over 2 steps as a colourless solid. m.p. 98.6 – 99.6 °C.

IR νmax (film): 1640.6, 1594.0, 1494.9, 1440.0, 1387.6, 1309.9, 1300.8, 1284.2, 1141.1, 1106.3, 1085.1, 1046.2, 1018.1, 959.2, 819.8, 809.3, 739.8, 775.0, 723.2, 705.3, 661.6 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.75 (d, J = 8.1 Hz, 2H, ArH), 7.32 (d, J = 8.0 Hz, 2H, ArH),

6.94 (dq, J = 14.6, 7.2 Hz, 1H, -CH=CH), 6.33 (d, J = 15.0 Hz, 1H, -SO2CH), 2.43 (s, 3H, ArCH3),

1.91 (d, J = 6.9 Hz, 3H, -CH3);

13 C NMR (101 MHz; CDCl3): δ 144.2, 141.8, 137.7, 132.1, 129.8, 127.6, 21.6, 17.2;

+ HRMS (ESI) calc. for C10H12O2S [M + H] = 197.06308, found 197.06342.

(E)-(prop-1-en-1-ylsulfonyl)benzene (337)

Methanesulfonyl chloride (1.58 mL, 2,34 g, 20.44 mmol) was added to a solution of the crude sulfonyl alcohol 335 (1.241 g) in toluene (30 mL) at 0°C followed by the dropwise addition of

NEt3 (5.7 mL, 4.14 g, 40.88 mmol). The mixture was stirred at rt for 10 min before heating to 100 °C for 90 min. The solution was cooled to rt before neutralising with 5% aq. HCl and then extracted with ether. The combined organic layers were washed with brine, dried, filtered and solvents evaporated. The crude product was purified by flash column chromatography (20% EtOAc/petrol as eluent) to afford the alkene 337 (1.59 g, 35%) over 2 steps as a colourless solid. m.p. 69.2-70.0 °C.

156

Chapter 7 Experimental section

IR νmax (film): 1642.8, 1446.8, 1233.2, 1143.7, 1085.8, 1071.0, 1024.0, 999.1, 951.8, 811.7, 770.0, 750.9, 713.9, 687.9 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.88 (d, J = 7.3 Hz, 2H, ArH), 7.61 (t, J = 7.4 Hz, 1H, ArH), 7.54 (t, J = 7.5 Hz, 2H, ArH), 6.99 (dq, J = 14.7, 7.2 Hz, 1H, -CH=CH), 6.35 (d, J = 15.0 Hz, 1H, -

SO2CH), 1.93 (d, J = 6.9 Hz, 3H, -CH3);

13 C NMR (101 MHz; CDCl3): δ 142.5, 133.2, 131.8, 129.2, 127.6, 17.3;

+ HRMS (ESI) calc. for C9H10O2S [M + H] = 183.04743, found 183.04750.

1-((1-bromoprop-1-en-1-yl)sulfonyl)-4-methylbenzene (340)

Br2 (579 µL, 1.79 g, 11.2 mmol) and AIBN (92 mg, 0.56 mmol) in CCl4 (2 mL) was added to a solution of vinyl sulfone 336 (1.00 g, 5.61 mmol) in CCl4 (4 mL) and stirred at reflux for 3 h. The mixture was cooled to rt, quenched with saturated aq. Na2S2O3 and then extracted with ether. The combined organic layers were then washed with saturated aq. Na2S2O3 and brine, then dried, filtered and solvents evaporated. The crude sulfonyl dibromide 338 (2.02 g) and was carried through to the next step without further purification.

1,8-Diazabicyclo[5.4.0]undec-7-ene (1.01 mL, 1.03 g, 6.77 mmol) was added dropwise to a solution of crude sulfonyl dibromide 338 (2.02 g) in DME (30 mL) and stirred at 0°C for 1 h. The reaction mixture was raised to rt with stirring for 4 h. The mixture was filtered through a plug of CeliteTM with ether, then quenched with 10% aq. HCl. The mixture was separated, and the aqueous layer was further extracted with ether, then dried, filtered and solvents evaporated. The crude product was purified by flash chromatography (20% EtOAc/petrol as the eluent) to afford the bromide 340 (962 mg, 62%) over 2 steps as pale yellow crystals as a 5:1 mixture of Z/E isomers. m.p. 74.9 – 76.2 °C.

IR νmax (film): 2981.3, 1597.3, 1381.7, 1323.2, 1270.0, 1153.6, 1085.9, 955.3, 870.5, 812.7, 704.9, 663.4 cm-1;

1 (Z-340) H NMR (400 MHz; CDCl3): δ 7.81 (d, J = 8.2 Hz, 2H, ArH), 7.48 (q, J = 6.8 Hz, 1H, -

CHCH3), 7.34 (d, J = 8.1 Hz, 2H, ArH), 2.44 (s, 3H, ArCH3), 1.94 (d, J = 6.8 Hz, 3H, -CHCH3);

1 (E-340) H NMR (400 MHz; CDCl3): δ 7.85 (d, J = 8.2 Hz, 2H, ArH), 7.36 (d, J = 7.2 Hz, 2H,

ArH), 6.73 (q, J = 7.7 Hz, 1H, -CHCH3), 2.46 (s, 3H, ArCH3), 2.25 (d, J = 7.8 Hz, 3H, -CH3);

157

Chapter 7 Experimental section

13 C NMR (101 MHz; CDCl3): δ 145.0, 143.3, 139.4, 134.4, 129.76, 129.72, 129.0, 128.5, 125.4, 21.71, 21.68, 17.0, 16.6;

+ HRMS (ESI) calc. for C10H11BrO2S [M +Na] = 296.95553, found 296.95550.

(Z)-((1-bromoprop-1-en-1-yl)sulfonyl)benzene (341)

A solution of Br2 (0.996 mL, 3.09 g, 19.3 mmol) and AIBN (159 mg, 0.967 mmol) in CCl4 (2 mL) was added to a solution of vinyl sulfone 337 (1.59 g, 8.71 mmol) in CCl4 (8 mL) and stirred at reflux for 3 h. The mixture was cooled to rt and quenched with saturated aq. Na2S2O3 and then extracted with ether. The combined organic layers were then washed with saturated aq. Na2S2O3 and brine, then dried, filtered and solvents evaporated. The crude sulfonyl dibromide 339 (3.14 g) and was carried through to the next step without further purification.

1,8-Diazabicyclo[5.4.0]undec-7-ene (1.74 mL, 1.77 g, 11.6 mmol) was added dropwise to a solution of crude sulfonyl dibromide 341 (3.14 g) in DME (40 mL) and stirred briefly at 0°C. The reaction mixture was raised to rt with stirring for 3 h. The mixture was filtered through a plug of CeliteTM with ether, the organic extract was quenched with 10% aq. HCl. The organic layer was extracted with ether, dried, filtered and solvents evaporated. The crude product was purified by flash column chromatography (20% EtOAc/petrol as the eluent) to afford the bromide 341 (1.16 g, 51%) over 2 steps, as a colourless solid. m.p. 118.2 – 118.7 °C.

IR νmax (film): 1613.2, 1447.4, 1316.5, 1303.9, 1293.2, 1272.1, 1159.0, 1148.7, 1084.6, 1069.7, 869.1, 754.9, 722.8, 686.0 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.94 (d, J = 7.5 Hz, 2H, ArH), 7.66 (t, J = 7.4 Hz, 1H, ArH), 7.55

(t, J = 7.9 Hz, 2H, ArH), 7.51 (t, J = 7.2 Hz, 1H, -C=CH), 1.96 (d, J = 6.8 Hz, 3H, -CH3);

13 C NMR (101 MHz; CDCl3): δ 139.9, 137.4, 133.9, 129.05, 128.97, 125.0, 17.1;

+ HRMS (ESI) calc. for C9H9BrO2S [M +Na] = 282.93988, found 282.93974.

158

Chapter 7 Experimental section

4,4'-((4R,5S)-5-((S)-bromo(tosyl)methyl)-4-vinylcyclohex-1- enedisulfonyl)bis(methylbenzene) (343)

HMDS (137 µL, 106 mg, 0.654 mmol) was added to THF (1.5 mL) followed by HMPA (114 µL, 117 mg, 0.654 mmol) and cooled to -78 °C before adding a 2.46M solution of n-butyl lithium (266 µL, 0.654 mmol). The solution was then warmed to 0 °C and stirred for 10 minutes before cooling to -78 °C. A solution of vinyl bromo sulfone 340 (200 mg, 0.727 mmol) in THF (1.5 mL) was cooled to -78 °C and added to the LiHMDS solution via a cooled cannula. The reaction was stirred at -78 °C for 2 h before ether was added and the reaction was quenched with saturated aq.

NH4Cl. The suspension was warmed to rt before separating and further extracting the aqueous layer with ether. The combined organic layers were washed with water and brine before being dried, filtered, and solvents evaporated. The crude product was purified by flash chromatography (40% EtOAc/petrol as the eluent) to afford the cyclohexene 343 (79 mg, 49% yield) as a colourless solid as well as the starting material 340 (33 mg, 17%). 59% BORSM. m.p. 157 – 158 °C

IR νmax (film): 1595.6, 1317.8, 1302.2, 1288.3, 1151.0, 1084.7, 912.9, 814.8, 731.0, 707.0, 663.0 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.74 (d, J = 8.2 Hz, 2H, ArH), 7.70 (d, J = 8.3 Hz, 2H, ArH), 7.59 (d, J = 8.2 Hz, 2H, ArH), 7.37 (d, J = 8.2 Hz, 2H, ArH), 7.33 (d, J = 8.8 Hz, 2H, ArH), 7.31 (d, J = 8.6 Hz, 2H, ArH), 6.80 (t, J = 2.5 Hz, 1H, -C=CH), 6.54 (dd, J = 17.5, 11.0 Hz, 1H, -

CH=CH2), 6.11 (s, 1H, -CHBr), 5.40 (d, J = 11.0 Hz, 1H, -CH=CH2), 4.81 (d, J = 17.5 Hz, 1H, -

CH=CH2), 3.39 (dd, J = 10.7, 4.5 Hz, 1H, -CHCHBr), 2.97 (dd, J = 17.8, 4.0 Hz, 1H, -

CH2C(SO2Ar)), 2.77 (d, J = 18.8, Hz, 1H, -CH2C(SO2Ar)), 2.58-2.51 (m, 1H, -CH2C(SO2Ar)),

2.46 (s, 3H, ArCH3), 2.44 (s, 6H, ArCH3), 1.93 (dd, J = 18.5, 4.8 Hz, 1H, -CH2C(SO2Ar));

13 C NMR (101 MHz; CDCl3): δ 145.81, 145.78, 144.7, 139.4, 135.3, 132.6, 131.6, 131.4, 130.4, 129.96, 129.89, 129.64, 129.51, 129.41, 128.2, 122.0, 68.3, 65.2, 36.0, 31.5, 24.9, 21.79, 21.69, 21.67;

+ HRMS (ESI) calc. for C30H31BrO6S3 [M +H] = 663.04661, 665.04457, found 663.05419, 665.05168.

159

Chapter 7 Experimental section

(Z)-1-((1-bromoprop-1-en-1-yl)sulfonyl)-4-chlorobenzene (346)

Propylene oxide (390 µL, 324 mg, 5.57 mmol ) and LiBr (49 mg, 0.56 mmol) were added to a solution of sodium para-chlorobenzene sulfinate 344 (1.00 g, 5.05 mmol) in water (20 mL) and stirred to 85°C for 20 h. The mixture was cooled to rt, and then extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and solvents evaporated. The crude sulfonyl alcohol was (404 mg) was carried through to the next step without further purification.

Methanesulfonyl chloride (400 µL, 592 mg, 5.17 mmol) was added to a solution of the crude sulfonyl alcohol (404 mg) in toluene (20 mL) followed by the dropwise addition of NEt3 (1.45 mL, 1.053 g, 10.40 mmol). The mixture was stirred at rt for 50 min before heating to 100 °C for 90 min with stirring. The solution was cooled to rt before neutralising with 5% aq. HCl and then extracted with ether. The combined organic layers were washed with brine, dried, filtered and solvents evaporated. The crude product was purified by flash column chromatography (20% EtOAc/petrol as the eluent) to afford the alkene 345 (286 mg, 26%) over 2 steps as a yellow oil.

1 H NMR (400 MHz; CDCl3): δ 7.80 (d, J = 8.7 Hz, 2H, ArH), 7.50 (d, J = 8.7 Hz, 2H, ArH),

7.03-6.94 (m, 1H, -CH=CH), 6.32 (dd, J = 15.0, 1.6 Hz, 1H, -CHSO2), 1.92 (d, J = 6.9 Hz, 3H, -

CH3);

13 C NMR (101 MHz; CDCl3): δ 143.2, 139.9, 139.2, 131.5, 129.5, 129.1, 17.4.

Br2 (136 µL, 422 mg, 2.64 mmol) and AIBN (22 mg, 0.132 mmol) in CCl4 (1 mL) were added to a solution of vinyl sulfone 345 (286 mg, 1.32 mmol) in CCl4 (3 mL) and stirred at reflux for 3.5 h. The mixture was cooled to rt and quenched with saturated aq. Na2S2O3 and then extracted with ether. The combined organic layers were then washed with saturated aq. Na2S2O3 and brine, then dried, filtered and solvents evaporated. The crude sulfonyl dibromide (473 mg) was carried through to the next step without further purification.

1,8-Diazabicyclo[5.4.0]undec-7-ene (226 µL, 230 mg, 1.512 mmol) was added dropwise to a solution of crude sulfonyl dibromide (473 mg) in DME (10 mL) and stirred briefly at 0 °C. The reaction mixture was raised to rt with stirring for 2.5 h. The mixture was filtered through a plug of CeliteTM with ether, the organic extract was quenched with 10% aq. HCl. The organic layer was extracted with ether, dried, filtered and solvents evaporated. The crude product was purified

160

Chapter 7 Experimental section by flash column chromatography (20% EtOAc/petrol as the eluent) to afford the bromide 346 (129 mg, 33%) over 2 steps, as a colourless solid. m.p. 51.0 - 52.0 °C.

IR νmax (film): 1615.4, 1582.0, 1475.3, 1435.9, 1395.2, 1328.2, 1279.8, 1158.4, 1143.3, 1112.2, 1088.8, 1014.0, 952.2, 872.2, 827.8, 764.5, 754.7, 705.9, 670.5 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.87 (d, J = 7.5 Hz, 2H, ArH), 7.52 (q, J = 6.2 Hz, 1H, -CHCH3)

7.52 (d, J = 7.4 Hz, 2H, ArH), 1.96 (d, J = 6.2 Hz, 3H, -CHCH3);

13 C NMR (101 MHz; CDCl3): δ 140.8, 140.5, 135.9, 130.4, 129.4, 124.6, 17.1;

+ HRMS (ESI) calc. for C9H8BrClO2S [M +H] = 294.91953, 296.91746, 298.91453, found 294.91882, 296.91662, 298.91382.

4,4'-((4R,5S)-5-((S)-bromo((4-chlorophenyl)sulfonyl)methyl)-4-vinylcyclohex-1- enedisulfonyl)bis(chlorobenzene) (347)

HMDS (70 µL, 54 mg, 0.332 mmol) was added to THF (3 mL) followed by HMPA (58 µL, 60 mg, 0.332 mmol) and cooled to -78 °C before adding a 2.12M solution of n-butyl lithium (157 µL, 0.332 mmol). The solution was then warmed to 0 °C and stirred for 10 min before cooling to -78 °C. A solution of vinyl bromo sulfone 346 (109 mg, 0.369 mmol) in THF (2 mL) was cooled to -78 °C and added to the LiHMDS solution via a cooled cannula. The reaction was stirred at -

78 °C for 2.5 h before ether was added and the reaction was quenched with saturated aq. NH4Cl. The suspension was warmed to rt before separating and further extracting the aqueous layer with ether. The combined organic layers were washed with water and brine before being dried, filtered, and solvents evaporated. The crude product was purified by flash chromatography (40% EtOAc/petrol as the eluent) to afford the cyclohexene 347 (6 mg, 7%) as a yellow oil and the starting material 346 (43 mg, 39%). 11% BORSM.

IR νmax (film): 1736.4, 1582.1, 1475.5, 1395.5, 1320.1, 1280.2, 1152.4, 1089.8, 1013.5, 911.6, 829.1, 756.6, 733.9, 706.6 cm-1;

1 H NMR (500 MHz; CDCl3): δ 7.82-7.79 (m, 4H, ArH), 7.67 (d, J = 8.6 Hz, 2H, ArH), 7.57-

7.53 (m, 6H, ArH), 6.86 (t, J = 2.5 Hz, 1H, -C=CH), 6.51 (dd, J = 17.4, 11.0 Hz, 1H, -CH=CH2),

6.05 (s, 1H, -CHBr), 5.46 (d, J = 11.0 Hz, 1H, -CH=CH2), 4.86 (d, J = 17.5 Hz, 1H, -CH=CH2),

3.47 (dd, J = 10.4, 4.6 Hz, 1H, -CHCHBr), 2.97 (dd, J = 18.0, 4.1 Hz, 1H, -CH2C(SO2Ar)), 2.81

161

Chapter 7 Experimental section

(d, J = 18.2 Hz, 1H, -CH2C(SO2Ar)), 2.56 (t, J = 13.7 Hz, 1H, -CH2C(SO2Ar)), 2.03-1.98 (m, 1H,

-CH2C(SO2Ar));

13 C NMR (126 MHz; CDCl3): δ 141.83, 141.75, 140.6, 139.03, 139.02, 136.7, 133.9, 132.7, 132.1, 131.7, 131.1, 129.73, 129.65, 129.29, 129.25, 122.6, 68.5, 64.6, 35.7, 31.3, 25.0;

+ HRMS (ESI) calc. for C27H22BrCl3O6S3 [M +H] = 722.89061, 724.88766, 726.88561, found 722.88966, 724.88698, 726.88397.

1-((1-bromoallyl)sulfonyl)-4-methylbenzene (348)

HMDS (229 µL, 176 mg, 1.09 mmol) was added to THF (2 mL) followed by HMPA (190 µL, 195 mg, 1.09 mmol) and cooled to -78 °C before adding a 2.46M solution of n-butyl lithium (443 µL, 1.09 mmol). The solution was then warmed to 0 °C and stirred for 10 minutes before cooling to -78 °C. A solution of vinyl bromo sulfone 340 (100 mg, 0.363 mmol) in THF (1 mL) was cooled to -78 °C and added to the LiHMDS solution via a cooled cannula. The reaction was stirred at -78 °C for 20 min before ether was added and the reaction was quenched with 10% aq. HCl. The suspension was warmed to rt before separating and further extracting the aqueous layer with ether. The combined organic layers were washed with water and brine before being dried, filtered, and solvents evaporated. The crude product was purified by flash chromatography (20% EtOAc/petrol as the eluent) to give the isomerised alkene 348 (10 mg, 10%) as an orange oil.

IR νmax (film): 1595.6, 1448.9, 1414.4, 1381.2, 1325.2, 1305.1, 1290.7, 1218.8, 1185.3, 1150.0, 1084.4, 1018.5, 983.0, 943.5, 909.7, 815.4, 783.7, 710.9, 657.0 cm-1;

1 H NMR (500 MHz; CDCl3): δ 7.80 (d, J = 8.3 Hz, 2H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH),

5.98 (ddd, J = 16.8, 10.2, 8.9 Hz, 1H, -CH=CH2), 5.44-5.39 (m, 2H, -CH=CH2), 5.22 (d, J = 8.8

Hz, 1H, -CHBr), 2.47 (s, 3H, ArCH3);

13 C NMR (101 MHz; CDCl3): δ 145.8, 131.7, 130.2, 129.6, 128.7, 124.8, 64.9, 21.7;

+ HRMS (ESI) for C10H11BrO2S [M + H] = 274.97359 and 276.97154, found 274.97352 and 276.97154.

162

Chapter 7 Experimental section

Methyl 3-(5-formyl-2-nitrophenoxy)-4-methoxybenzoate (136)

A solution of methyl 3-hydroxy-4-methoxybenzoate 117 (1.6 g, 8.7 mmol) in DMF (10 mL) was added dropwise to a pentane-washed suspension of NaH (60% in mineral oil, 379 mg, 9.5 mmol) in DMF (10 mL) and stirred. at rt for 1 h. A solution of 3-fluoro-4-nitrobenzaldehyde 124 (1.1 g, 6.5 mmol) in DMF (10 mL) was then added dropwise to the solution and stirred at rt for 1 h. The reaction was quenched with saturated aq. NH4Cl and extracted with CH2Cl2. The combined organic layers were washed with 10% aq. HCl and brine, dried, filtered and the solvents were evaporated. The resultant yellow solid was purified by flash chromatography (30% EtOAc/Pet.) to afford 136 (2.05 g, 95%) as bright yellow crystals. m.p. 128.0 - 129.0 °C.

IR νmax (film): 2952, 2829, 1709, 1612, 1581, 1531, 1513, 1485, 1437, 1383, 1349, 1280, 1255, 1238, 842, 804, 764 cm-1;

1 H NMR (400 MHz; CDCl3): δ 9.93 (s, 1H, CHO), 8.05 (d, J = 8.2 Hz, 1H, ArH), 8.00 (d, J = 8.6 Hz, 1H, ArH), 7.82 (s, 1H, ArH), 7.64 (d, J = 8.2 Hz, 1H, ArH), 7.25 (d, J = 1.4 Hz, 2H,

ArH), 7.06 (d, J = 8.6 Hz, 1H, ArH), 3.89 (s, 3H, -OCH3), 3.84 (s, 3H, -OCH3);

13 C NMR (101 MHz; CDCl3): δ 189.8, 165.8, 155.1, 151.6, 142.1, 139.6, 129.2, 126.2, 123.6, 123.5, 117.6, 112.4, 56.2, 52.2;

+ HRMS (ESI): Calc. for C16H13NO7 [M+H] 332.07648, found 332.07646.

Methyl 3-(2-amino-5-formylphenoxy)-4-methoxybenzoate (135)

SnCl2.2H2O (340 mg, 1.51 mmol) was added to nitroarene 136 (100 mg, 0.302 mmol) in ethanol (2 mL) and stirred at 70 °C for 30 min. The reaction was cooled to rt and poured into ice water and made alkaline with 5% aq. NaHCO3. The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, dried, filtered and the solvents were evaporated. The crude material was then purified by flash chromatography (40% EtOAc/Pet.) to afford the biaryl amine 135 (55 mg, 60%) as an orange solid. m.p. 144.8 – 145.8 °C.

163

Chapter 7 Experimental section

IR νmax (film): 3363, 2928, 2850, 1713, 1673, 1611, 1592, 1570, 1512, 1438, 1275, 1229, 908, 765, 732 cm-1;

1 H NMR (400 MHz; CDCl3): δ 9.65 (s, 1H, CHO), 7.90 (dd, J = 8.6, 1.8 Hz, 1H, ArH), 7.66 (d, J = 1.8 Hz, 1H, ArH), 7.45 (dd, J = 8.1, 1.1 Hz, 1H, ArH), 7.13 (d, J = 1.0 Hz, 1H, ArH), 7.03

(d, J = 8.6 Hz, 1H, ArH), 6.83 (d, J = 8.1 Hz, 1H, ArH), 4.56 (s, 2H, -NH2), 3.89 (s, 3H, -OCH3),

3.86 (s, 3H, -OCH3);

13 C NMR (101 MHz; CDCl3): δ 190.1, 166.1, 155.0, 144.4, 143.9, 143.8, 128.5, 127.62, 127.60, 123.3, 121.9, 116.2, 114.4, 112.0, 56.1, 52.1;

+ HRMS (ESI): Calc. for C16H15NO5 [M+H] 302.10230, found 302.10230.

Methyl 3-(5-formyl-2-hydroxyphenoxy)-4-methoxybenzoate

Violaceic acid methyl ester (374)

48% HBF4 in water (86 µL, 0.47 mmol) was added to a solution of 135 (100 mg, 0.33 mmol) in acetonitrile (1.7 mL) at 0 °C. The resultant brown mixture was stirred at 0 °C for 15 min before tBuONO (99 µL, 0.83 mmol) was added and the reaction was stirred for 2 h at 0 °C. A solution of Cu(NO3)2 (2.4 g, 9.9 mmol) and glycine (1.49 g, 19.8 mmol) in water (50 mL) was then added followed by the addition of ascorbic acid (8 mg, 0.05 mmol). The resultant deep blue mixture was stirred for 20 h and extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and solvents were evaporated. Purification of the crude product by flash chromatography (30% EtOAc/Pet.) yielded 374 (22 mg, 22% yield) as a pale yellow gum.

IR νmax (film): 3362, 2928, 2852, 1716, 1690, 1603, 1511, 1439, 1276, 1210, 1180, 1132, 1113, 1022, 993, 905, 826, 805, 765, 733 cm-1;

1 H NMR (400 MHz; CDCl3): δ 9.75 (s, 1H, CHO), 7.94 (d, J = 8.5 Hz, 1H, ArH), 7.81 (s, 1H, ArH), 7.54 (d, J = 8.2 Hz, 1H, ArH), 7.26 (s, 1H, ArH), 7.14 (d, J = 8.2 Hz, 1H, ArH), 7.03 (d, J

= 8.6 Hz, 1H, ArH), 3.89 (s, 3H, -OCH3), 3.87 (s, 3H, -OCH3);

13 C NMR (101 MHz; CDCl3): δ 190.4, 165.9, 155.0, 152.5, 145.7, 143.4, 129.9, 128.48, 128.30, 123.5, 123.2, 116.1, 115.9, 112.1, 56.1, 52.2;

164

Chapter 7 Experimental section

+ HRMS (ESI): Calc. for C16H14O6 [M+H] 303.08686, found 303.08638.

Violaceic acid (11)

Violaceic acid methyl ester 374 was dissolved in THF (4 mL) and cooled to 0 °C before adding water (2 mL) and LiOH (11 mg, 0.463 mmol). The solution was stirred at rt for 16 h before adding water and EtOAc and making acidic with 10% aq. HCl. The resultant mixture was separated, and the aqueous layer was further extracted with EtOAc before washing the combined organic layers with water and brine. The organic layer was then dried (Na2SO4), filtered and the solvents were evaporated. The product 11 was obtained pure as a pale orange gum (22 mg, 85%).

IR νmax (film): 2925, 2851, 1684, 1602, 1512, 1439, 1274, 1212, 1181, 1136, 1114, 1022, 969, 825, 786, 768 cm-1;

1 H NMR (400 MHz; DMSO-d6): δ 9.71 (s, 1H, CHO), 7.73 (d, J = 8.4 Hz, 1H, ArH), 7.59 (dd, J = 8.3, 1.5 Hz, 1H, ArH), 7.26-7.22 (m, 3H, ArH), 7.11 (d, J = 8.2 Hz, 1H, ArH), 3.86 (s, 3H, -

OCH3);

13 C NMR (101 MHz; DMSO-d6): δ 191.2, 167.0, 154.9, 154.2, 145.1, 144.7, 129.3, 128.4, 126.7, 123.7, 119.4, 119.1, 117.6, 113.1, 56.5;

+ HRMS (ESI): Calcd for C15H12O6 [M+Na] 311.0532, found 311.0527.

Methyl 3-(2-bromo-5-formylphenoxy)-4-methoxybenzoate (377)

Biaryl amine 135 (52 mg, 0.173 mmol) in acetonitrile (2 mL) was added to a solution of copper (II) bromide (48 mg, 0.213 mmol) and iso-amyl nitrite (34 µL, 0.256 mmol) in acetonitrile (1 mL) at 0 °C and stirred at 0 °C for 1 h before warming to rt for 1 h. The solution was poured into 1 M aq. HCl and extracted with ether. The combined organic layers were washed with 1 M aq. HCl,

165

Chapter 7 Experimental section dried, filtered and the solvents were evaporated. The crude residue was filtered through a plug of silica with 25% EtOAc/petrol as the eluent to afford the biaryl bromide 377 (38 mg, 60%) as a pale orange-pink solid. m.p. 106.4 – 107.3 °C.

IR νmax (film): 2953.3, 2844.3, 1699.5, 1609.3, 1573.4, 1511.2, 1474.1, 1437.1, 1417.6, 1382.9, 1320.3, 1276.0, 1235.6, 1200.5, 1177.4, 1129.6, 1094.6, 1034.0, 1022.9, 994.2, 957.9, 906.3,

-1 825.2, 804.6, 786.6, 764.1, 729.9 cm ;

1 H NMR (400 MHz; CDCl3): δ 9.84 (s, 1H, CHO), 7.95 (d, J = 8.6 Hz, 1H, ArH), 7.81 (d, J = 7.7 Hz, 1H, ArH), 7.69 (s, 1H, ArH), 7.44 (d, J = 7.9 Hz, 1H, ArH), 7.12 (s, 1H, ArH), 7.06 (d,

J = 8.5 Hz, 1H, ArH), 3.87 (s, 6H, -OCH3);

13 C NMR (101 MHz; CDCl3): δ 190.6, 166.0, 155.23, 155.09, 143.1, 136.7, 134.4, 128.3, 125.4, 123.3, 122.7, 120.2, 115.8, 112.2, 56.1, 52.1;

+ HRMS calc. for C16H13BrO5 [M + H] = 365.00246, 367.00041, found 365.00182, 366.99982.

Methyl 3-(5-formyl-2-iodophenoxy)-4-methoxybenzoate (119)

p-TsOH.H2O (500 mg, 2.63 mmol) was added to a solution of biaryl amine 135 (264 mg, 0.876 mmol) in acetonitrile (4 mL) at -5 °C. Sodium nitrite (121 mg, 1.752 mmol) and potassium iodide (364 mg, 2.19 mmol) were dissolved in water (2 mL) and added dropwise to the solution over 45 min. The reaction was stirred at -5 °C for 45 min before warming to rt for 1.25 h. The reaction was then quenched with saturated aq. NaHCO3 and solid NaHSO3. The solution was extracted with EtOAc and the combined organic layers were washed with brine, dried, filtered and the solvents were evaporated. The crude material was purified by flash chromatography (25% EtOAc/Pet.) to yield the iodide 119 (275 mg, 76%) as a white solid. m.p. 117.6 – 118.4 °C.

IR νmax (film): 1700, 1609, 1580, 1568, 1511, 1467, 1413, 1381, 1321, 1278, 1234, 1200, 1177, 1131, 1094, 1020, 994, 804, 764 cm-1;

1 H NMR (400 MHz; CDCl3): δ 9.80 (s, 1H, CHO), 8.02 (d, J = 8.0 Hz, 1H, ArH), 7.92 (dd, J = 8.6, 2.0 Hz, 1H, ArH), 7.68 (d, J = 2.0 Hz, 1H, ArH), 7.26 (dd, J = 7.9, 1.7 Hz, 1H, ArH), 7.04

(d, J = 8.6 Hz, 1H, ArH), 6.99 (d, J = 1.6 Hz, 1H, ArH), 3.85 (s, 3H, -OCH3), 3.83 (s, 3H, -

OCH3);

166

Chapter 7 Experimental section

13 C NMR (101 MHz; CDCl3): δ 190.8, 166.0, 157.9, 155.2, 143.2, 140.6, 137.7, 128.4, 125.5, 123.3, 123.0, 114.4, 112.3, 95.3, 56.2, 52.1;

+ HRMS (ESI): Calc. for C16H13IO5 [M+H] 412.98804, found 412.98658.

Methyl 3-(5-formyl-2-methoxyphenoxy)-4-methoxybenzoate (111)

Biaryl iodide 119 (82 mg, 0.200 mmol), tBuXPhos (4.3 mg, 0.010 mmol), Pd2(dba)3 (5.5 mg, 0.006 mmol) and KOH (45 mg, 0.800 mmol) were dissolved in 1,4-dioxane (1 mL) and water (1 mL). The reaction mixture was stirred and heated to 100 °C for 17 h before cooling to rt, acidified with 10% aq. HCl and extracted with EtOAc. The combined organic layers were washed with brine and dried (Na2SO4), filtered and the solvents were evaporated. The crude residue was dissolved in 5 mL of N,N-dimethylformamide before adding K2CO3 (166 mg, 1.20 mmol) and iodomethane (74 µL, 1.20 mmol). The mixture was stirred at rt for 18 h before adding water and extracting with EtOAc. The combined organic layers were washed with water and brine before being dried (Na2SO4), filtered, and the solvents were evaporated. Purification of the crude product by flash chromatography (40% EtOAc/Pet. Ether) yielded 111 (26 mg, 41%) as a pale yellow oil.

IR νmax (film): 3079, 3009, 2952, 2842, 1714, 1688, 1604, 1577, 1509, 1459, 1435, 1394, 1318, 1268, 1224, 1204, 1177, 1132, 1120, 1096, 1021, 994, 961, 905, 805, 786, 764, 730 cm-1;

1 H NMR (400 MHz; CDCl3): δ 9.79 (s, 1H, CHO), 7.87 (dd, J = 8.6, 1.5 Hz, 1H, ArH), 7.62 (dd, J = 8.3, 1.4 Hz, 1H, ArH), 7.57 (d, J = 1.6 Hz, 1H, ArH), 7.26 (s, 1H, ArH), 7.10 (d, J = 8.4 Hz,

1H, ArH), 7.02 (d, J = 8.6 Hz, 1H, ArH), 3.97 (s, 3H, -OCH3), 3.89 (s, 3H, -OCH3), 3.84 (s, 3H,

-OCH3);

13 C NMR (101 MHz; CDCl3): δ 190.4, 166.2, 155.4, 154.7, 146.7, 144.3, 130.1, 128.0, 127.3, 123.1, 121.1, 116.9, 111.80, 111.81, 56.27, 56.08, 52.0;

+ HRMS (ESI): Calc. for C17H17O6 [M+H] 317.10251, found 317.10203.

167

Chapter 7 Experimental section

N-methyl-1H-pyrrole-2-carboxamide27 (388)

2.0 M methylamine in THF (17.8 mL, 35.3 mmol) was added to a solution of 2- trichloroacetylpyrrole 132 (3.06 g, 14.4 mmol) in acetonitrile (15 mL) and stirred at rt for 19 h. The solvents were evaporated, and the product 388 was collected in quantitative yield and was used without further purification. The spectral data obtained was in accordance with that reported.27

1 H NMR (400 MHz; CDCl3): δ 9.35 (br s, 1H, NH), 6.91 (d, J = 1.1 Hz, 1H, ArH), 6.51 (s, 1H,

ArH), 6.22 (q, J = 3.1 Hz, 1H, ArH), 5.83 (br s, 1H, -CONH), 2.98 (d, J = 4.9 Hz, 3H, -CH3).

2-methylpyrrolo[1,2-a]pyrazine-1,3,4(2H)-trione (389)

Ethyl chlorooxoacetate (1.03 mL, 9.22 mmol) followed by NEt3 (1.30 mL, 9.32 mmol) were added to a solution of amide 388 (572 mg, 4.61 mmol) in CH2Cl2 (30 mL) and stirred at rt for 3 h before heating to reflux for 1 h. The solution was cooled, and the solvent was evaporated. The crude residue was purified by flash chromatography (25% EtOAc/petrol as the eluent) and further purified by recrystallisation from CH2Cl2 in petroleum spirits to afford the triketopiperazine 389 (372 mg, 45%) as a yellow solid (m.p. 146.0 – 147.8 °C). Non-cyclised product was redissolved in CH2Cl2 (10 mL) and NEt3 (1.30 mL, 9.32 mmol) was added and the solution was heated to reflux for 1.25 h. The product was afforded in quantitative yield from the second batch.

IR νmax (film): 2979.7, 2946.3, 2603.9, 2531.8, 2497.1, 1736.8, 1557.5, 1475.4, 1445.0, 1397.6,

-1 1333.1, 1251.6, 1227.6, 1174.3, 1066.6, 1037.0, 963.0, 851.7, 807.8, 748.6, 666.9 cm ;

1 H NMR (600 MHz; CDCl3): δ 7.68 (t, J = 1.6 Hz, 1H, ArH), 7.34 (t, J = 1.6 Hz, 1H, ArH), 6.60

(d, J = 0.7 Hz, 1H, ArH), 3.40 (s, 3H, -CH3);

13 C NMR (126 MHz; CDCl3): δ 155.7, 155.2, 148.0, 123.6, 123.2, 122.9, 116.8, 27.1;

+ HRMS calc. for C8H6N2O3 [M + H] = 179.04567, found 179.04514.

168

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4-iodo-N-methyl-1H-pyrrole-2-carboxamide (390)

2.0 M methylamine in THF (5.9 mL, 11.78 mmol) was added to a solution of iodotrichloropyrrole 182 (1.64 g, 4.71 mmol) in acetonitrile (40 mL) and stirred at rt for 19 h. The solvents were evaporated and the crude residue was purified by flash chromatography (50% EtOAc/petrol as the eluent) to afford the amide 390 (702 mg, 60%) as a brown solid. m.p. 172.5-174.0 °C.

IR νmax (film): 3221, 2942, 1703, 1614, 1567, 1520, 1444, 1410, 1374, 1322, 1223, 1156, 1131, 1021, 950, 910, 827, 779, 731 cm-1;

1 H NMR (400 MHz; DMSO-d6): δ 11.72 (br s, 1H, NH), 8.01 (d, J = 4.0 Hz, 1H, ArH), 6.94 (s,

1H, ArH), 6.81 (br s, 1H, -CONH), 2.69 (d, J = 4.5 Hz, 3H, -CH3);

13 C NMR (101 MHz; DMSO-d6): δ 160.3, 128.8, 126.4, 116.31, 116.25, 60.8;

+ HRMS (ESI) calc. for C6H8IN2O [M+H] : 250.9676; found 250.9674.

7-iodo-2-methylpyrrolo[1,2-a]pyrazine-1,3,4(2H)-trione (391)

Ethyl chlorooxoacetate (260 µL, 2.32 mmol) followed by NEt3 (340 µL, 2.44 mmol) were added to a solution of pyrrole amide 390 (387 mg, 1.548 mmol) in CH2Cl2 (15 mL) and the solution was stirred at rt for 2 h. The solvents were evaporated and the crude residue was purified by flash chromatography (20% EtOAc/petrol as the eluent) to afford the triketopiperazine 391 (317 mg, 67%) as a yellow solid. m.p. 197.9 – 199.6 °C.

IR νmax (film): 3129.8, 2948.2, 1755.1, 1734.8, 1683.7, 1673.9, 1591.6, 1563.1, 1464.6, 1432.6, 1411.9, 1391.6, 1339.7, 1315.6, 1181.9, 1164.3, 1102.5, 1066.2, 988.7, 908.0, 801.4, 781.0, 739.3 cm-1;

1 H NMR (400 MHz; CDCl3): δ 7.78 (d, J = 1.5 Hz, 1H, ArH), 7.37 (d, J = 1.5 Hz, 1H, ArH),

3.39 (s, 3H, -CH3);

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Chapter 7 Experimental section

13 C NMR (101 MHz; CDCl3): δ 154.9, 154.1, 146.3, 128.8, 127.3, 124.7, 72.3, 27.2;

+ HRMS calc. for C8H5IN2O3 [M + H] = 304.94231, found 304.94159.

170

Chapter 7 Experimental section

7.3 Bibliography

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Minerva Access is the Institutional Repository of The University of Melbourne

Author/s: Fisher, Brendan

Title: Towards the synthesis of the emestrin family of natural products

Date: 2018

Persistent Link: http://hdl.handle.net/11343/217920

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