Studies on the Total Synthesis of Aphidicolin

Lewis Alexander Thomas Allen

Thorpe Laboratory, Department of Chemistry, Imperial College London

October 2015

A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy, Imperial College London

Declaration

I hereby declare that all the work in this thesis is solely my own, except where explicitly stated and appropriately referenced. No part of this thesis has been submitted previously for a degree at this or any other academic institution.

Signed

Lewis A. T. Allen

The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work

Abstract

In this thesis further developments on the thermal cascade reaction discovered in the Parsons group have been made. The substrate scope has been increased to include the ketone linked 1,6-diynes, which had failed to cyclise in previous studies. Furthermore, variations on the precursor molecule have led to the cyclisation of nitrogen and sulphur analogues to provide the respective annulated pyrrole and thiophene products. The synthesis of these compounds using the Parsons-Board-Waters cyclisation had not been explored during earlier studies within the group.

The increased scope of the Parsons-Board-Waters cyclisation was applied to the total synthesis of the natural product (+)-aphidicolin. The development of model systems are described, with the importance of the ketone functionality being highlighted by the unsuccessful cyclisation of dioxolane protected precursors. Furthermore, the enantioselective synthesis of a key intermediate containing the required 1,3-diol functionality present in the natural product is reported. This will provide a route to future research on the application of the Parsons-Board-Waters cyclisation to (+)-aphidicolin.

Contents

Declaration ...... 2 Abstract ...... 3 Contents ...... 4 Acknowledgements ...... 6 List of Abbreviations ...... 7 Stereochemical Notations ...... 10 Summary of Thesis Chapters ...... 11 Introduction ...... 12 1.1 Natural product synthesis as a tool for discovery ...... 13 1.2 Parsons-Board-Waters reaction...... 14 1.3 Chemistry of Biradicals ...... 25 1.3.1 Bergmann Cyclisation ...... 25 1.3.2 Myers and Saito Cyclisation ...... 28 1.3.3 Schmittel Cyclisation ...... 33 1.3.4 Other Biradical Cyclisations ...... 35 1.4 Propargylic ene reactions ...... 37 1.5 Alkenyl Allene Intermediates in Synthesis ...... 41 1.6 Aphidicolin ...... 44 1.7 Previous Syntheses of Aphidicolin ...... 45 1.7.1 Trost ...... 45 1.7.2 McMurry ...... 47 1.7.3 Corey ...... 48 1.7.4 Van Tamelen ...... 50 1.7.5 Ireland ...... 52 1.7.6 Holton ...... 54 1.7.7 Tanis ...... 56 1.7.8 Itawa ...... 57 1.7.9 Toyota and Fukumoto ...... 59 1.7.10 Toyota and Ihara ...... 60 1.8 Project proposal ...... 62 Studies on the Parsons-Board-Waters Cyclisation ...... 65 2.1 Synthesis and cyclisation of the ketone linked 1,6-diyne 31 ...... 66 2.2 Synthesis and cyclisation of the ketone linked 1,7-diyne 272 ...... 68

2.3 Application of Microwave Synthesis ...... 70 2.4 Synthesis of Analogues of the Cyclisation Precursor 31 ...... 73 2.5 Synthesis of the Nitrogen Analogue 280 ...... 74 2.5.1 Approach to the N-methyl amine precursor 293 ...... 74 2.5.2 Synthesis and cyclisation of the N-tosyl amine precursor 307 ...... 77 2.6 Synthesis of the sulfur analogue 282 ...... 80 2.7 Concluding remarks on the methodological studies ...... 83 2.8 Future Applications ...... 86 Studies on the Total Synthesis of Aphidicolin ...... 87 3.1 The preparation of model systems ...... 88 3.1.1 Synthesis of the 1,6-diyne 263 ...... 89 3.1.2 Alternative synthesis of the 1,6-diyne 263 ...... 93 3.1.3 Lability of the trimethylsilyl group on eynone 337 ...... 94 3.1.4 Dioxolane cyclisation precursors ...... 95 3.1.5 Deprotection of dioxolane precursors ...... 98 3.1.6 The preparation of substrate 331 ...... 100 3.1.7 Synthesis and cyclisation of the substrate 333 ...... 103 3.1.8 Protection of the hexenol substrate 333 ...... 106 3.1.9 Synthesis of chiral substrates ...... 109 3.1.10 Future applications of these model studies ...... 111 3.2 The application of the Parsons-Board-Waters methodology to aphidicolin ...... 113 3.2.1 Diastereoselective approach to aldehyde 262 ...... 114 3.2.2 Organocuprate approach to the 1,3-diol 392 ...... 116 3.2.2.2 Alternative preparation of the phosphonate 402 ...... 120 3.2.3 Semi-pinacol rearrangement of epoxy alcohols ...... 123 3.2.4 Synthesis and rearrangement of the allylic alcohol 414 ...... 124 3.2.5 Synthesis and rearrangement of the silyl ether 417 ...... 125 3.2.7 Synthesis of the TIPS protected semi-pinacol substrate 423 ...... 128 3.2.8 Semi-pinacol rearrangement of the epoxy silyl ether 423...... 130 3.2.9 Tandem rearrangement and reduction of the epoxy silyl ether 423 ...... 134 3.2.10 Future studies on aphidicolin ...... 136 Experimental ...... 138 References ...... 230

Acknowledgements

First and foremost, I would like to thank Professor Parsons for providing me with the opportunity to pursue my doctoral studies in his group. Phil is both inspirational chemist and an excellent mentor. I will always be grateful for the kindness he has shown me by supporting my studies. I would also like to thank Drs. Alfred and Isabella Bader for their generous financial support to Professor Parsons.

I’m very grateful to the other members of the Parsons group who have provided me with invaluable support and company over the years. I would especially like to mention Lee who taught me when I was fresh out of the undergraduate labs. I would also like to thank Jason for his continuing support and Alex for his infuriating lunch time discussions. A special mention goes out to Ada, Daniel, and visiting Professor Kyungsoo Oh.

I am also thankful to Professor Donald Craig for his hospitality upon our arrival at Imperial College London. Professor Craig kindly offered to share valuable lab space with us, and his group was exceptionally accommodating during our transition from University of Sussex. Of course, a big thank you to the members of the Craig group I have known over the years, especially to the ever cheerful crew of Joe, Rich, and Toby.

Finally, I would like to acknowledge my family. To my parents, who have supported my education over many years now, thank you for always pushing me to continue with my studies. To my Brighton home, I would like to acknowledge those times that the Minley crew put me together again when I was burnout from work and commuting. Finally, I would like to thank my long suffering girlfriend Kerry for being so patient with me and understanding over these past three years.

List of Abbreviations

°C degree centigrade δ chemical shift 1,4-CHD 1,4-cyclohexadiene

[α]D specific optical rotation Å Ångström(s) Ac acetyl AIBN α,α′-azoisobutyronitrile aq aqueous AZADO 2-azaadamantane-N-oxyl Bn benzyl bp boiling point BTMSA bis(trimethylsilyl)acetylene n-Bu normal-butyl t-Bu tert-butyl CDI 1,1-carbonyldiimidazole CI chemical ionisation cm−1 wavenumbers CSA camphor-10-sulfonic acid DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DET diethyl tartrate DHP 3,4-dihydro-2H-pyran DIAD diisopropyl azodicarboxylate DIBAL-H diisobutylaluminum hydride DIPT diisopropyl tartrate DMAP 4-(dimethylamino)pyridine DME dimethoxyethane DMF N,N-dimethylformamide DMI 1,3-dimethyl-2-imidazolidinone DMPI Dess-Martin periodinane

DMS dimethyl sulfide DMSO dimethyl sulfoxide DNA deoxyribonucleic acid dr diastereomeric ratio ee enantiomeric excess eq equivalent(s) ES electrospray ionisation Et ethyl FVP flash vacuum pyrolysis g gram(s) hfc 3-(heptafluoropropylhydroxymethylene)-(+)-camphorate HMDS hexamethyldisilazane HMPA hexamethylphosphoramide hr hour(s) HRMS high resolution mass spectrometry Hz Hertz IR infrared J coupling constant LDA lithium diisopropylamide M mol dm-3 mCPBA meta-chloroperbenzoic acid Me methyl mg milligram(s) MHz megahertz min minute(s) mL millilitre(s) mmol millimole(s) MOMCl chloromethyl methyl ether Ms mesyl MW microwave MVK methyl vinyl ketone n normal NBS N-bromosuccinimide NME N-methylephedrine

NMO 4-methylmorpholine N-oxide p para Ph phenyl PCC pyridinium chlorochromate PDC pyridinium dichromate PMB 4-methoxybenzyl PPTS pyridinium p-toluenesulfonate pTSA para-toluenesulfonic acid

Rf retention factor R.T room temperature TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBHP tert-butyl hydroperoxide TBS tert-butyldimethylsilyl TDS tert-butyldiphenylsilyl Tf triflyl THF tetrahydrofuran TIPS triisopropylsilyl TLC thin layer chromatography TMEDA N,N,N′,N′-tetramethylethylenediamine TMS trimethylsilyl TPAP tetrapropylammonium perruthenate Ts tosyl X heteroatom or halide

Stereochemical Notations

The Maehr convention has been used in this report to indicate relative and absolute stereochemistry.1 Accordingly, solid and broken wedges represent absolute stereochemistry, while solid and broken lines represent racemates.

Summary of Thesis Chapters

In the introductory chapter of this thesis, an overview of the Parsons-Board-Waters cyclisation, mechanistically related cyclisations, and the historical approaches to (+)- aphidicolin will be provided.

In the second chapter, the extension of the Parsons-Board-Waters cyclisation methodology to include ketone linked 1,6-diynes, and the formation of annulated pyrrole and thiophene products will be described.

In the third chapter, the studies on the enantioselective total synthesis of (+)-aphidicolin, including the preparations of model systems will be discussed.

Finally in the fourth chapter, the preparations for the compounds synthesised during this research project will be described.

Chapter 1

Introduction

1.1 Natural product synthesis as a tool for discovery

Natural products display a vast array of distinct three dimensional structures. Analysis of these structures and prudent planning of a synthetic route is only part of the battle as the true complexity of the molecule may only become apparent during the research project. Well established reactions will occasionally fail leading to increased understanding and innovation in order to reach the target molecule; while newly developed methodology will be tested in a complex environment beyond the ideal substrates initially investigated. There therefore exists a synergistic relationship between natural product synthesis and methodological research. Yet these discoveries are not limited to organic synthesis as advances can directly impact medicine, biology, materials science, and physical chemistry.2

The synthesis of prostaglandin F2α by Corey is a strong example of this synergy between synthetic methodology and natural product synthesis. After completing a racemic approach,3 Corey developed the first asymmetric Diels-Alder reaction to overcome the challenge of the stereochemically defined cyclopentane core (Figure 1).4 This extrapolation of the existing methods opened up new possibilities for assembly of enantiopure molecules and informed further research into the use of chiral auxiliaries and chiral Lewis acids. Corey also developed his eponymous asymmetric reduction to address the challenge of forming the allylic alcohol entantioselectively.5,6 The methodology developed to address the structural challenges present in prostaglandin F2α represented significant additions to an organic chemist’s repertoire.

Figure 1: The chemical structure of prostaglandin F2α

1.2 Parsons-Board-Waters reaction

Discovered during studies towards the total synthesis of the antibiotic lactonamycin 5, the Parsons-Board-Waters reaction has been shown to provide a convenient route to a variety of heterocyclic compounds. The initial discovery was made when the amide 2 did not cyclise to provide the expected product 4 in the presence of tributyltin hydride and AIBN; instead the cyclisation unexpectedly yielded the lactam 3 in a 14% yield (Scheme 1).7 Thermal degradation studies of the substrate demonstrated that this cyclisation occurred in the absence of tributyltin radicals, with the lactam 3 isolated as the sole product in an improved yield of 50%.8

Reagents and Conditions: (a) AIBN, SnBu3H, benzene, reflux 14% of 3, 0% of 4; (b) toluene, reflux, 2 hr, 50% of 3, 0% of 4 Scheme 1: Boards’ unexpected cyclisation towards the synthesis of lactonamycin8

To build on this initial result, a second cyclisation substrate was prepared. It was found that the amide 6 cyclised in boiling toluene to the dihydroisobenzofuran 7 in a 38% yield, demonstrating the reaction can proceed without the formation of the dihydroanthracene substructure (Scheme 2).9

Reagents and Conditions: (a) toluene, reflux, 1 hr, 38% Scheme 2: Waters’ thermolysis of amide precursor 69

Following these initial results, an acid catalysed pathway was proposed to account for the transformation (Scheme 3).9 In this proposal, the cyclisation is promoted by anchimeric assistance from the lone pair on bromine to provide the diene 8. The bromonium ion is opened to give the tetracycle 9, which after loss of HBr furnished the observed product 3.

Scheme 3: Acid catalysed pathway

In order to investigate the acid catalysed pathway, the allyl ether 10 was synthesised. It was found that this substrate cyclised readily to provide the lactam 11 in a 92% yield, indicating that the bromoalkene is not essential to the mechanism (Scheme 4).8,10 It is notable that the yield of this process is markedly higher than for the bromoalkene substrates 2 and 6.

Reagents and Conditions: (a) toluene, reflux, 1 hr, 92% Scheme 4: Removal of the bromoalkene unit and cyclisation8,10

The low yield recorded for the bromoalkene substrates was rationalised to be the result of decomposition of either the substrate or product by hydrobromic acid produced during the reaction. In accordance with this hypothesis, it was found that inclusion of the acid trap epoxyhexane improved the yield of the reaction (Scheme 5).7,11 At this stage, the possibly of an acid catalysed process reliant on the bromoalkene moiety was discounted and new avenues were investigated.

Reagents and Conditions: (a) toluene, reflux, epoxyhexane, 1 hr, 76%; (b) toluene, reflux, epoxyhexane, 1 hr, 90% Scheme 5: Thermolysis of the precursors 2 and 6 in the presence of an acid trap7,11

While the bromoalkene was not found to be essential to the success of the cyclisation, the presence of a trimethylsilyl group on the terminus of the alkyne was found to be critical. Removal of the trimethylsilyl group from the precursor 6 provided the new amide precursor 12, which took thirteen hours to cyclise in boiling toluene (Scheme 6).7,8 It should be noted that this result is in direct comparison to 6 which cyclised in one hour.

Reagents and Conditions: (a) NaOMe, MeOH, DCM, 95%; (b) toluene, reflux, epoxyhexane, 13 hr, 97% Scheme 6: Role of the silyl group in cyclisation7,8

To investigate the importance of the propargylic position, the propargyl alcohol 2 was oxidised to the ketone 14. When the ketone 14 was heated in toluene, the lactam 15 was unexpectedly isolated in a 30% yield (Scheme 7).7

Reagents and Conditions: (a) toluene, reflux, 6 hr, 30% Scheme 7: The unexpected cyclisation of the propargylic ketone 237

A radical mechanism was proposed to account for this transformation (Scheme 8).7 In this mechanism, ketone 14 generates the biradical 16 under heating. The alkenyl radical then adds to carbonyl group to give, after tautomerization, intermediate 17. This intermediate would then fragment to provide the disubstituted alkyne 18, which upon loss of the acyl silane gives the observed product 15.

Scheme 8: The proposed radical pathway to account for the formation of the alkyne 15

Based on this proposed mechanism, it was hypothesised that in the absence of the carbonyl group the biradical intermediate may undergo a 5-exo-trig radical cyclisation onto the pendant alkene to form the diene 21. This new biradical intermediate may then undergo radical-radical recombination to provide the cyclisation product 22 (Scheme 9).9

Scheme 9: The proposed radical mechanism

However, when the propargylic position was blocked with a gem-dimethyl group, it was found that substrate 19 did not form the expected tricycle product 22, even after 72 hours in boiling toluene (Scheme 10).12 This result appears to demonstrate at least one hydrogen atom is necessary at that position for the cyclisation to progress.

Reagents and Conditions: (a) toluene, reflux, 72 hr Scheme 10: Failure to cyclise when there are no propargylic protons12

The deuterated substrate 23 offered further insight into the mechanism by showing that there is a deuteron shift from the propargylic position in the starting material to the allylic silane in the product (Scheme 8).7 This experiment also appeared to demonstrate a kinetic isotope effect as the reaction was significantly slowed by the incorporation of deuterium at the propargylic position.

Reagents and Conditions: (a) toluene, reflux, epoxyhexane, 3 hr, 94% Scheme 11: The observed 1,5-deuterium shift during the reaction7

The relationship between the amide functionality and the reactivity of the 1,6-diynes under thermal conditions was also examined. It was found that the ester 25 cyclised in boiling toluene to provide the expected dihydroisobenzofuran 26 in a 76% yield (Scheme 12).10 It should be noted however that the reaction duration increased dramatically from 1 hour for the amide to 52 hours for this example.

Reagents and Conditions: (a) toluene, reflux, epoxyhexane, 52 hr, 76% Scheme 12: Cyclisation of the ester linked 1,6-diyne 2510

Substitution was found to have a profound impact on the rate of reaction. For example, the isopropyl substituted ester 29 cyclised significantly faster than the ester 27 (Scheme 13).13 Similarly, both compounds, containing a dimethyl group in proximity to the ether link were shown to cyclise faster than the principle ester substrate 25 (Scheme 12). As previously demonstrated the effect on the rate of reaction is negligible when moving from the bromoalkene to the alkene (Scheme 4 and Scheme 5).

Reagents and Conditions: (a) toluene, reflux, 2 hr, 96 %; (b) toluene, reflux, 0.5 hr, 96% Scheme 13: The effect of substitution on the rate of cyclisation for ester substrates13

While the substrates containing an ester group between the alkynes provided the expected products, albeit with longer reaction times than the amide examples, it was found the ketone linked substrate 31 did not cyclise in boiling toluene (Scheme 14).14

Reagents and Conditions: (a) toluene, reflux, 24 hr Scheme 14: Attempted cyclisation of a ketone linked 1,6-diyne 3114

In order to expand the scope of the reaction, experiments were conducted where the alkene tether was either altered or removed (Scheme 15).13 When the tether was moved to the silyl group, a series of silicon containing heterocycles were synthesised. When dienophile was removed altogether, thermolysis of substrate 37 resulted in the synthesis of the (Z,Z)- exocyclic diene 38.14

Reagents and Conditions: (a) toluene, reflux, 16 hr, 38%; (b) toluene, reflux, 20 hr, 40%; (c) toluene, reflux, 4 hr, 61% Scheme 15: Relocation or removal of the alkene tether by Faggiani14 and Acvil13

In both of these examples, the structures of the products suggested that the reaction mechanism proceeds via an alkenyl allene intermediate. In the case of the exocyclic diene, the product 38 can be viewed clearly as the tautomer of the alkenyl allene 39 (Scheme 16).

Scheme 16: Tautomerism to provide (Z,Z)-exocyclic dienes

Given the experimental evidence collected so far, multiple pathways have been proposed to account for this transformation (Scheme 17).7

Scheme 17: Possible mechanistic routes for this transformation

Principally, the proposed mechanisms can be split into a concerted route and stepwise route:

(1) A concerted mechanism proceeding directly from the 1,6-diyne to a alkenyl allene 40 through a propargylic ene reaction. This intermediate would then participate in a Diels-Alder reaction with the pendant alkene to provide the product 24. The Diels- Alder chemistry of alkenyl allenes has been well documented.15

(2) A stepwise mechanism to provide the biradical intermediate 41. The biradical could either proceed to the alkenyl allene intermediate 40 directly, or abstract a deuteron to provide a further biradical intermediate 42. This further biradical intermediate could also form the alkenyl allene intermediate 40, or rearrange to provide intermediate 43 which can cyclise via a 5-exo-trig pathway, followed by radical-radical recombination to provide the tricyclic product.

As such, it is possible to draw a similarity here between this process and the ene reaction, first discovered by Alder16 in 1943. For a number of years, it has been noted that the ene reaction exists on a boundary between a concerted pericyclic reaction and a stepwise reaction, with specific examples supporting each pathway (Scheme 18).17–19 It is possible that the cyclisation discovered in the Parsons group may also exist on the boundary between these two pathways. For certain substrates the mechanism may follow a concerted propargylic ene pathway; whereas for other examples it may follow a stepwise route to the postulated biradical intermediate.

Scheme 18: The ene reaction

Despite this proposed ambiguity in the mechanistic understanding, the discussion of related processes to the Parsons-Board-Waters cyclisation has nevertheless been artificially divided into two camps - biradical and concerted processes. Furthermore, there will be a brief discussion of the use of alkenyl allenes in synthesis.

1.3 Chemistry of Biradicals

1.3.1 Bergmann Cyclisation Bergmann found that when the ene-diyne 48 was pyrolysed at 300 °C in a flow system deuterium exchanged between the acetylene and alkenyl positions (Scheme 19).20 At the lower temperature of 200 °C, this exchange was observed to provide a 1:1 mixture of 48 and 49.

Reagents and Conditions: Gas-phase pyrolysis at 300 °C for 30 seconds Scheme 19: Deuterium exchange between acetylene and alkenyl positions

Notably, the exchange was not observed for the trans isomer; furthermore, no single deuterium exchange products were observed, such as 50 and 51 (Scheme 20). Bergmann therefore proposed that the reaction is unimolecular, proceeding through an intermediate where C-1, C-3, C-4, and C-6 are equivalent.20

Reagents and Conditions: Gas-phase pyrolysis at 300 °C for 30 seconds Scheme 20: No single deuterium exchange products

Bergman’s proposal was confirmed when the ene-diyne 52 was heated in 2,6,10,14- tetramethylpentadecane resulting in quantitative formation of benzene (Scheme 21).20 In this example, hydrogen was abstracted from the hydrocarbon solvent, establishing that the intermediate is likely a biradical.

Reagents and Conditions: (a) 2,6,10,14-tetramethylpentadecane, 0.01 M Scheme 21: Formation of benzene via a biradical intermediate

Upon heating in carbon tetrachloride, p-dichlorobenzene was formed. Similarly benzyl alcohol and benzene were formed when heating in methanol, with no apparent formation of anisole – expected when operating under a dipolar mechanism.21 Both of these observations added further weight to Bergmann’s biradical proposal (Scheme 22).

Reagents and Conditions: (a) CCl4; (b) MeOH Scheme 22: Evidence of a biradical intermediate

22 Bergmann’s research gained new relevance upon the discovery of esperamicin A1 , I 23,24 25 calicheamicin γ1 and dynemicin which all feature an ene-diyne core structure. It was proposed that the significant cytotoxicity of these molecules was the result of the Bergmann cyclisation providing a highly reactive biradical intermediate capable of cleaving DNA strands.

Figure 2: The ene-diyne antibiotics

Due to the core structure, the mechanism for neocarzinostatin chromophore 126,27 however was less apparent. It was the abnormal structure of this molecule that prompted Myers to look at the possibility of ene-allenes undergoing thermal cyclisations.

1.3.2 Myers and Saito Cyclisation Following studies early conducted by Kappen and Goldberg,28 Myers proposed that the neocarzinostatin chromophore would cyclise to form a highly reactive biradical intermediate in the presence of methyl thioglycolate (Scheme 23).29

Reagents and Conditions: (a) methyl thioglycolate, MeOH, 30% Scheme 23: Myers’ proposed mechanism for the activation of neocarzinostatin chromophore

To investigate the formation of the unprecedented intermediate 62, Myers constructed the simple model system 64. When heated in 1,4-CHD, enyne-allene 64 cyclised to produce toluene and the two coupled products, 66 and 67 (Scheme 24).30

Reagents and Conditions: (a) 1,4-CHD, 0.003 M, Scheme 24: Cyclisation of 64 in 1,4-CHD

Myers also observed that the intermediate in the thermolysis of 64 could be trapped carbon tetrachloride, producing the aromatic chlorides 68 and 69 (Scheme 25).30

Reagents and Conditions: (a) CCl4, 100 °C Scheme 25: Cyclisation of 64 in carbon tetrachloride

Both of these transformations were accounted for by invoking the biradical intermediate 70. This would appear to support the earlier mechanistic proposal for the cyclisation of neocarzinostatin chromophore 60 to the biradical intermediate 62.

Scheme 26: Proposed biradical intermediate

However, when the enyne-allene was heated to 100 °C in methanol, methyl benzyl ether 71 was produced as the major product (Scheme 27). This result was unexpected as it indicates that a dipolar mechanism was in part in operation. The free radical products 72 and 73 were also produced during this reaction, although in reduced yields. Furthermore, in a later publication, it was observed that the related enyne-allene 74 produced the THF adduct 75 as the major product when heated in aqueous THF.31 These observations appeared to indicate that both radical and dipolar pathways are potentially in operation.

Reagents and Conditions: (a) MeOH, 100 °C; (b) 20% aqueous THF, 0.01M, 60°C Scheme 27: Trapping in methanol and aqueous THF

Myers concluded that the cyclisation does indeed produce the biradical intermediate 70, but that it has a high degree of polar character.31 This intermediate would then follow either a free radical or polar pathway depending on the reaction conditions – solvent acidity and the bond strength of the trapping agent.

In a publication the same year as Myers’ first report of a new Bergmann type cyclisation, Saito also disclosed that enyne-allenes can cyclise to provide new aromatic products.32 Saito had initially hypothesised that a Bergmann type cyclisation would occur under less forcing conditions if one of the acetylenes was replaced with allene, reducing the distance between the two reactive components. In order to investigate this proposal, Saito attempted to synthesise the enyne-allene 78 via a [2,3]-sigmatropic rearrangement from the propargylic phosphite 77. It was found however that the propargylic phosphite 77 instead formed two aromatic products when heated in carbon tetrachloride (Scheme 28).

Reagents and Conditions: (a) CCl4, 45 °C, 1.5 hr Scheme 28: Unsuccessful isolation of the allenyl phosphonate 78

The expected allenyl phosphonate 78 was not found in the crude mixture. To account for these observations, Saito proposed that the aromatic products were in fact formed from the highly reactive biradical intermediate 81, which in turn may be the product of the spontaneous cyclisation of the allenyl phosphonate 78 (Scheme 29).

Scheme 29: Saito’s proposed biradical intermediate

In order to examine this proposal more thoroughly, an isolatable enyne-allene was required. To this end, the allenylphosphine oxide 83 was synthesised from the propargyl alcohol 82. This particular enyne-allene, with an allenylphosphine oxide rather than allenyl phosphonate, was stable enough to be purified by column chromatography. When the allenylphosphine oxide 83 was then heated to 37 °C in the presence of 1,4-CHD, three new aromatic compounds were formed, confirming Saito’s hypothesis (Scheme 30).

Reagents and Conditions: (a) PCl(Ph)2, NEt3, hexane, −78 °C, 63%; (b) 1,4-CHD, benzene, 5 hr, 37 °C Scheme 30: Successful isolation and cyclisation of the allenyl phosphonate 92

Saito found that when the cyclisation was conducted in H2O/THF-d8 and there was complete incorporation of deuterium in the product (Scheme 31). However, no incorporation of deuterium was observed when the solvent mixture was changed to D2O/THF. These results appear to suggest that Saito’s substrates produce the free radical trapped products exclusively, in contrast to Myers’ observations.

Reagents and Conditions: 1:5 H2O/THF-d8, 60 °C, 28 % Scheme 31: Incorporation of deuterium

1.3.3 Schmittel Cyclisation In order to investigate the possibility of a Myers-Saito cyclisation initiated by electron transfer, Schmittel synthesised a series of enyne-allenes with high activation temperatures. These compounds contained bulky groups on alkyne to increase the thermal stability. During thermolysis, it was found however that these compounds cyclised in a novel fashion, C2-C6 rather than C1-C6, to provide indene products (Scheme 32).33

Reagents and Conditions: (a) 1,4-CHD, toluene, 50 °C, 57%; (b) 1,4-CHD, toluene, 84 °C, 76% Scheme 32: Schmittel cyclisation

When the substitution was altered to afford a tetrasubstituted allene, the cyclisation occurred at ambient temperature, precluding the isolation of the intermediate allene (Scheme 33).

Reagents and Conditions: (a) PClPh2, LDA, −78 °C; then 1,4-CHD, r.t, 63% Scheme 33: Substitution precludes isolation of the enyne-allene 102

Schmittel proposed a biradical intermediate to account for the product formation (Figure 3). However, in direct contrast to studies conducted on the Bergmann or Myers-Saito cyclisation, attempts to trap this postulated biradical intermediate failed.

Figure 3: Proposed biradical intermediate

In a series of computational investigations, it was postulated that this cyclisation may not always follow a biradical mechanism, as initially proposed by Schmittel.34–36 The computational studies by Engels suggested that depending on the terminal substituents the Schmittel cyclisation may follow either a concerted or stepwise route (Scheme 34).34 Engels’ study found that there was a shift from stepwise to concerted when moving from aryl to tert- butyl substitution on the alkyne. This mechanistic transition had been previously alluded to by poor correlation between computational studies and experimental results for tert-butyl substituted alkynes, when working within the biradical framework. Lipton and Singleton’s studies on the Schmittel cyclisation also point to a more complex mechanism than expected for this transformation.37

Scheme 34: Concerted and stepwise pathways for the Schmittel reaction

1.3.4 Other Biradical Cyclisations In 1999, Johnson and Kociolek reported an intriguing intramolecular cyclotrimerization process. They found that when the triyne 100 was heated under vacuum three new products were formed (Scheme 35).38

Reagents and Conditions: (a) 500-600 °C, 0.01 Torr, 35%, (1:5 101:102+103) Scheme 35: Johnson and Kociolek’s alkyne cyclotrimerization initiated by flash vapour pyrolysis

The authors proposed that the reaction followed a biradical pathway to provide the indan 101 (Scheme 36). The indan would then lose hydrogen to provide the observed product distribution shown in scheme 35.

Scheme 36: Johnson and Kociolek’s mechanistic proposal

Ley later demonstrated that the reaction temperature of this process could be significantly lowered by using a microwave reactor and introducing a heteroatom on the alkyne tether (Scheme 37).39 The length of the alkyne tether could even be increased with no appreciable loss of yield.

Reagents and Conditions: (a) DMF, MW, 200 °C, 1hr, 81%; (b) DMF, MW, 200 °C, 1hr, 80% Scheme 37: Ley’s alkyne cyclotrimerization initiated by microwave heating

The mechanism described in the publication begins with either biradical formation towards 109 or a formal [2+2] towards the Dewar benzene structure 110. Rearrangement, followed by fragmentation, would provide the biradical 113. This biradical would then lead towards the observed product 106 via the fully characterised intermediate 114.

Scheme 38: Ley’s mechanistic proposal

1.4 Propargylic ene reactions

Oppolzer documented the first example of a propargylic ene reaction in 1973.40 It was found that the propargyl amines 115 and 117 cyclised under thermal conditions to provide a pyrrolidine ring (Scheme 39). Since this initial publication by Oppolzer there have only been a few isolated reports of a propargylic ene reaction.

Reagents and Conditions: (a) 180 °C, 5 hr, 50%; (b) 210 °C, 2 hr, 43% Scheme 39: Oppolzer’s formation of pyrrolidine

In 2003, Pérez and Guitián discovered that a substrate in their palladium cyclisation studies decomposed at room temperature.41 Ketone 119 was found to undergo a propargylic ene reaction to give the vinyl-allene 120, observable by 1H NMR (Scheme 40). The alkenyl allene then reacted to provide the dimer and other decomposition products. Pérez and Guitián however failed to provide conclusive data in their publication to confirm this analysis.

Reagents and Conditions: (a) r.t, 7 hr Scheme 40: Pérez and Guitián’s decomposition of palladium cyclisation substrate under ambient conditions

The first example of an intermolecular propargylic ene reaction was reported in 2006 by Cheng.42 It was found that the arynes will undergo an ene reaction with a variety of alkynes at room temperature to give the corresponding phenylallenes (Scheme 41).

Reagents and Conditions: (a) KF, 18-crown-6, THF, r.t, 6 hr, 69%; (b) KF, 18-crown-6, THF, r.t, 6 hr, 52% Scheme 41: Intermolecular ene reaction involving an alkyne

During Roglans’ studies on rhodium catalysed [2+2+2] cyclisations, it was found that the rhodium catalytic system was unable to promote the cyclisation; instead of the expected aromatic compound 128, pyrrole 129 was isolated.43 Subsequent investigations found that when the macrocycle 127 was heated without catalyst, the tetracycle was formed in a 32% yield (Scheme 42).

Reagents and Conditions: (a) toluene, 30 hr, 32%, or toluene, 1,4-CHD, 6 days, 78% Scheme 42: Roglans [2+2+2] cyclisations

A radical mechanism was discounted following extensive EPR studies, leaving the authors to suggest a concerted process. In fact, the yield of the reaction was increased significantly by the introduction of 1,4-CHD.

Following the initial publications by Ley39 and Parsons8,10, Danheiser and co-workers reported a thermally promoted intermolecular formal [2+2+2] reaction with electron poor dienophiles (Scheme 43).44

Reagents and Conditions: (a) toluene, 160 °C, 21 hr, 94% Scheme 43: Danheiser’s intermolecular thermally promoted [2+2+2] cycloaddition

In a related publication, Danheiser also extended the cyclotrimerization methodology to the formation of substituted pyridines using a tethered nitrile (Scheme 44).45 In these examples, the presence of a nitrile group added an extra level ambiguity in the mechanism as both a propargylic ene reaction and propargylic cyano ene reaction are viable first steps towards the observed products.

Reagents and Conditions: (a) toluene, 160 °C, 21 hr, 71%; (b) (X = O) toluene, 210 °C, 6 hr, 0.01M, 35%; (X = NMe) toluene, 160 °C, 36 hr, 0.01M, 58% Scheme 44: Danheiser’s synthesis of pyridines via a [2+2+2] cycloaddition

To investigate the argument for the unprecedented propargylic cyano ene, the cyclisation of amide 139 was interrupted after 30 minutes in order to characterise the intermediates formed; this is compared to a minimum reaction duration of a day. It was found that the precursor 139 formed the enamine 140 after this brief heating time (Scheme 45).45

Reagents and Conditions: (a) toluene, 115 °C, 0.5 hr, 23% Scheme 45: Isolation of enamine 140 as evidence for the propargylic cyano ene reaction

The enamine 140 was found to cyclise with further heating to the expected tricyclic product 142, via tautomerization to the allenylimine 141 (Scheme 46). This observation appears to confirm the principle that Danheiser’s pyridine synthesis could begin with a propargylic cyano ene reaction. It is not clear however from this study whether the propargylic cyano ene pathway is the principle pathway to these products, or whether this is a minor pathway only in operation for this case because there are no protons to abstract for the propargylic ene pathway.

Scheme 46: Conversion of enamine 140 to the expected tricycle 142

1.5 Alkenyl Allene Intermediates in Synthesis

Alkenyl allenes are useful intermediates in the synthesis of complex molecules as they readily participate in Diels-Alder reactions. Notably, in each example of the previously discussed propargylic ene reactions, an alkenyl allene intermediate is described, with the exception of Oppolzer’s research, highlighting their relevance to the Parsons-Board-Waters cyclisation. In the most simple case, it has been shown that in the gas phase the simple alkenyl allene 143 will readily react to form dimerization and cycloisomerization products 144-150 (Scheme 47).15,46

Reagents and Conditions: (a) gas phase, 170 °C Scheme 47: Gas phase chemistry of a simple alkenyl allene

In the presence of a dienophile, alkenyl allenes will provide the [4+2]-cycloadduct. In this example, the simple alkenyl allene 143 reacted readily with the electron-deficient dienophile, 1,4-napthoquinone, to form the cycloadduct 151 (Scheme 48).47

Reagents and Conditions: (a) 1,4-naphthoquinone, EtOH, reflux, 10 mins, 64% Scheme 48: Diels-Alder reactions of alkenyl allenes

With unsymmetrical dieneophiles, the cycloaddition reaction proceeded regioselectivity (Scheme 49).48 In this case, the alkenyl allene 152 formed exclusively the two diastereomeric products 153 and 154 when heated with methyl vinyl ketone. The observed regioselectivities in Danheiser’s intramolecular work44 correlate well with this observation.

Reagents and Conditions: (a) MVK, 100 °C, 3hr, 50% Scheme 49: Diels-Alder reactions of alkenyl allenes

The dienophile may also be tethered to the alkenyl allene to provide rapid access to useful polycyclic intermediates in natural product synthesis. This approach has been used successfully to affect the total synthesis of (+)-compactin (Scheme 50).49 The advanced intermediate 155 reacted in an intermolecular fashion to form two diastereomers, which were immediately reduced to provide the respective alcohols 156 and 157.

Reagents and Conditions: (a) 140 °C, 1.25 hr; then LiB(sBu)3H, 84% Scheme 50: An approach to the total synthesis of (+)-compactin

A similar approach was used towards the total synthesis of (+)-sterpurene (Scheme 50).50 In this case however the alkenyl allene was formed in situ and cyclised at room temperature to provide the advanced tricyclic intermediate 161 in the homochiral form.

Reagents and Conditions: (a) PhSCl, Et3N, −78 °C, 2 hr; then R.T, 38 hr, 70% Scheme 50: An approach to the total synthesis of (+)-sterpurene

It is clear from these two brief examples concerning the application of alkenyl allenes to natural product synthesis that they can be exceedingly useful when constructing polycyclic systems.

1.6 Aphidicolin

Aphidicolin is a diterpenoid tetraol first isolated from Cephalosporium aphidicola Petch by Hesp in 1972.51,52 The molecule was also later isolated from Nigrospora sphaerica from which most current commercial supplies are derived.53 Aphidicolin demonstrates some very promising biological properties, including antitumor activity and antiviral activity.54–60 Despite these promising properties, research into the development of new drugs based on this structure has been inhibited by the poor water solubility. Analogues of aphidicolin, including 16-fluoroaphidicolin and aphidicolin-17-glycinate hydrochloride salt, however have shown greater promise for the development of new drugs.61

Figure 4: The chemical structure of (+)-aphidicolin

Aphidicolin features both a spiro bicyclo[3.2.1]octane substructure and six contiguous stereocentres - three of which are quaternary centres. Given the structural complexities of this molecule, it is no surprise that after the structural elucidation in 1972 the first enantioselective synthesis was not reported until 1987 by Holton.62 This is despite the initial independent reports of stereoselective approaches from both Trost63 and McMurry64 in 1979. The topologically related structures maritimol 168 and stemodin 169 have been subject to significantly less investigation, both biologically and chemically.65–67

Figure 5: The chemical structures of maritimol and stemodin

1.7 Previous Syntheses of Aphidicolin

1.7.1 Trost63 Trost’s synthesis of (±)-aphidicolin began with elaboration of the commercially available Kitahara enone68 170 to the diol 172. Hydrolysis of the ketal and protection of the diol provided the ketone 173, which was then treated with a sulphur ylide to give the oxaspirocyclopentane 174. The oxirane was opened and then converted to the cyclopropane 175, which after flash vacuum pyrolysis gave the enol ether 176. In the early stages of this approach Trost utilized his recently discovered cyclopentanone annulation methodology69 as a key step in his approach to the natural product.

Reagents and Conditions: (a) HOCH2CH2OH, TsOH, PhH, reflux, 79%; (b) Li, NH3, THF, t-BuOH, −78 °C;

then isoprene, NEt3, (CH3)3SiCl; (c) CH3Li, Et2O, R.T; then CH2O, −78 °C, 68% (over two steps); (d) LiAl(i-

C4H9)2(t-C4H9)H, hexane, heptane, Et2O, −78 °C, 99%; (e) 3N HCI, THF, 100%; (f) acetone, TsOH, reflux, + − 92%; (g) c-C3H5S Ph2BF4 , KOH, DMSO; (h) (i) (PhSe)2, NaBH4, DME, 60 °C; (ii)

CH3C[OSi(CH3)3]=NSi(CH3)3, NEt3, PhH, 60 °C, 56% (over three steps); (i) FVP, 610 °C, 97% Scheme 51: Trost’s synthesis of (±)-aphidicolin63

Unfortunately, this approach provided the product as a mixture of epimers (d.r: 2:1), with the desired compound present as the minor contribution. A two-step process however furnished the correct isomer as the sole product. The silyl enol ether 176 was alkylated and subjected to a hydroboration reaction to give the alcohol required for the synthesis of the final ring. Oxidation of alcohol 177 with PCC followed by basic workup in methanol provided the tetracycle 178. The known protected aphidicolin norketone 179 was formed via a Wolff- Kishner reduction. It was already known at the time that ketone 179 could be converted to the natural product via a three step sequence.52

Reagents and Conditions: (a) (i) Pd(OAc)2, CH3CN, 73%; (ii) Li, NH3, THF, t-BuOH; then silylation 82%; (b) n-BuLi, THF; then HMPA, allyl iodide, 85 °C; (c) thexylborane, diglyme, 0 °C; then NaOH, H2O2, 45 °C, 57%;

(d) PCC, NaOAc, DCM; then 2% KOH, CH3OH, 54%; (e) (i) DHP, TsOH, CHCI3; (ii) NH2NH2, KOH, triethylene glycol, 140 °C; then 220 °C 91% (f) 0.5% TsOH, (CH2)2CO, 78%; (g) PCC, NaOAc, DCM; then 2%

KOH, CH2OH, 87% Scheme 52: Trost’s synthesis of (±)-aphidicolin63

1.7.2 McMurry64 McMurry’s synthesis of (±)-aphidicolin shared a number of similarities with Trost’s approach. In particular, McMurry used Kitahara enone 17068 as the starting material for his synthetic sequence leading to the ketone 173, which also featured as an intermediate in Trost’s synthesis. Ketone 173 was alkylated and the resulting alkene oxidatively cleaved to give the diketone, which cyclised under basic conditions to the cyclopentenone 181. The enone 181 was reduced to the allylic alcohol, isolated as a single isomer, and then converted to the vinyl ether 182. Vapour phase pyrolysis provided the aldehyde 183 with the required stereochemistry for the final steps of the synthesis. The aldehyde was reduced and converted to the corresponding tosylate, which was then reacted with Collman’s reagent70 to give the known acetonide protected aphidicolin norketone 179.

Reagents and Conditions: (a) LDA, THF, and then methallyl iodide, 89%; (b) OsO4, NaIO4, H2O, dioxane,

86%; (c) NaH, t-amyl alcohol (trace), benzene, reflux, 95%; (d) LiAIH4, Et2O, 95%; (e) CH3CH2OCH=CH2,

Hg(OAc)2, reflux, 90%; (f) 360 °C, quartz tube, 20% (g) LiAIH4, THF; then p-TsCl, pyridine, 60%; (h)

Na2Fe(CO)4, N-methylpiperidone, 50 °C, 30% Scheme 53: McMurry’s synthesis of (±)-aphidicolin64

1.7.3 Corey71 Corey’s total synthesis of (±)-aphidicolin started with geranyl acetate which was readily converted to the protected alcohol 186. From the alcohol 186, the corresponding bromide was formed and immediately converted to enol phosphate ester 187, via the β-keto ester. This ester was treated with mercuric trifluoroacetate to give the bicycle 188. The hydroxyl group was introduced to provide a mixture of epimers, which were both oxidized and then selectively reduced to provide the desired diastereoisomer. The diol and the ketone were then protected, before the ester was reduced to the keto aldehyde 190, via the alcohol

Reagents and Conditions: (a) SeO2, EtOH, reflux; then NaBH4, 61%; (b) TBSCl, DMAP, NEt3, DCM, −20 °C; then K2CO3, MeOH, 0 °C, 90%; (c) (i) CH3SO2Cl, NEt3, DCM, −40 °C; (ii) LiBr, THF; (iii) methyl acetoacetate

lithium sodium salt, THF, 0 °C, 90% (over three steps); (d) NaH, diethylchlorophosphate, Et2O, 0 °C; (e)

mercuric trifluoroacetate, MeNO2, 0 °C; then NaCl, H2O, 60% (over two steps); (f) ethylene glycol, p-TsOH, benzene, reflux, 90%; (g) (i) NaBH4, DMF, O2; (ii) PDC, DCM; (iii) TBAF, THF, 0 °C; (iv) L-Selectride, THF,

−78 °C; (v) pivaladehyde, p-TsOH, DCM, 0 °C, 58% (over five steps); (h) (i) LiAlH4, Et2O; (ii) PDC, DCM;

(iii) acetone, H2O, HClO4, 90% (over two steps) Scheme 54: Corey’s synthesis of (±)-aphidicolin71

The keto aldehyde 190 was converted to the Robinson annulation product with MVK under basic conditions, and protected as the thioketal to furnish the ketone 191. Conversion of 191 to the required aldehyde 192 was accomplished using a four step homologation sequence devised by Corey for this particular sterically hindered ketone. Reduction, protection and hydrogenation provided the ketone 193, ready for the final stages of the synthesis. Finally, conversion of the protected alcohol to the tosylate, followed by internal alkylation formed the final ring of the core structure of aphidicolin. The reaction conditions were found to be highly selective in the formation of the desired enolate for the cyclisation. Conversion of the tetracycle 194 to (±)-aphidicolin had already been investigated by the Corey group.

Reagents and Conditions: (a) THF, t-BuOH, K2CO3, DBU, MVK; then pyrrolidinium acetate, THF, MeOH; (b) bis(trimethylsily1)propane-1,3-dithiol, CHCl3, ZnI2, 88%; (c) TMSCN, ZnI2, CHCl3, 40 °C, 97%; (d) DIBAL- + H, PhMe, 0 °C, 75%; (e) LiTMS, HMPA, −35 °C, 80%; (f) LiN(iPr)2, THF, HMPA; then H , 80%; (g) NaBH4,

EtOH, THF, −20 °C, (quant.); (h) TBSCl, DMAP, NEt3, CHCl3, 90%; (j) 1,3-diiodo-5,5-dimethylhydantoin,

acetone, THF, H2O, 86%; (k) H2, Pd/C, (no yield given); (l) desilylation, no conditions given (m) p-TsCl,

DMAP, NEt3, CHCl3, (no yield given); (n) 2-methyl-tetrahydrofuran, lithium di-tert-butylamide, −120 °C, 90%; Scheme 55: Corey’s synthesis of (±)-aphidicolin71

1.7.4 Van Tamelen72 Van Tamelen’s total synthesis of (±)-aphidicolin was heavily informed by the proposal for aphidicolin’s biogenesis. The diene 195, accessible from phenylgeranyl thioether, was converted to the allylic alcohol 196 via elimination of the 2,3-oxide. Subsequent epoxidation and protection of the allylic alcohol furnished the cyclisation precursor 197 as a single diastereoisomer. The epoxide 197 was treated with iron (III) chloride in toluene to give the cyclised product 198 in a yield of 12%. The yield of this step was reportedly diminished by the multiple HPLC separations necessary to provide the desired diastereoisomer as a pure compound. A Birch reduction and hydrolysis of the enol ether led to the enone 199, which was converted to the diene 200.

Reagents and Conditions: (a) NBS, THF-H2O, 0 °C; then K2CO3, MeOH, 33%; (b) LiN(Et)2, Et2O, reflux, 57%;

THF, −78 °C; (ii) 0.5M HCl, EtOH; (iii) CH2CO, TsOH, 55% (over three steps); (g) trisylhydrazine, TsOH, THF; then n-BuLi, TMEDA, hexane, −78 °C, 82% Scheme 56: Van Tamelen`s approach to (±)-aphidicolin72

The cycloaddition adduct 201 was formed when the diene was treated with maleic anhydride in refluxing benzene. Platinum mediated reduction of 201 to the carboxylic acid, followed by decarboxylation provided the olefin 202. Oxidation of the alkene with mCPBA, single electron reduction with sodium metal, and then formation of the mesylate furnished 203 as the required diastereoisomer. Alcohol 204, a known intermediate from Trost’s synthesis of (±)-aphidicolin, was isolated when mesylate 203 was heated in acetone.

Reagents and Conditions: (a) maleic anhydride, benzene, 80 °C, 86%; (b) Pt black, H2O, EtOH, 90%; (c)

Pb(OAc)4, O2, pyridine, 28%; (d) mCPBA, DCM, NaHCO3, 100%; (e) Na, benzene, 20%; (f) no experimental

data provided; (g) acetone, H2O, CaCO3, reflux, (no yield given) Scheme 57: Van Tamelen`s approach to (±)-aphidicolin72

1.7.5 Ireland73 Ireland’s total synthesis of (±)-aphidicolin started with the enone 205, accessible from the methoxysuberone.74 A hetero Diels-Alder reaction gave the ester 206 as the major diastereoisomer, which was easily separable from the minor component. The ester was converted to the olefin 207 ready for a Claisen rearrangement, which after the rearrangement and introduction of the oxime functionality provided the spirocyclic oxime 208, ready for the key step of this synthetic route. The spirocyclic oxime was converted to the diazo ketone, which during photolysis rearranged to the cyclobutanone 209. Purification of the crude cyclobutanone conveniently afforded the ketone 210 as the sole product.

Reagents and Conditions: (a) CH2=C(CO2CH3)CH2SiMe3, 125 °C, sealed tube, hydroquinone, 69%; (b) (i)

DIBAL-H, Et2O, −78 °C; (ii) Ph3P=CH2, THF, 95% (over two steps); (c) 150 °C, 7.5 hr, 84%; (d) no data available; (e) (i) NH2Cl, THF; (ii) λυ, Et2O, −73°C; then SiO2, petroleum ether, Et2O, 60% (over two steps); (f)

DIBAL-H, THF, −78 °C, 99%; (g) TBSCl, imidazole, DMF, 95%; (h) (i) OsO4, pyridine; then NaHSO3; (ii) 2,2- dimethoxypropane, p-TsOH; (iii) TBAF, THF, 92% Scheme 58: Ireland`s approach to (±)-aphidicolin73

Deoxygenation of intermediate 211 proceeded successfully via the phosphorodiamidate, which after deprotection of the ketal provided the ketone 212. The stereochemistry of cis fused decalin system was corrected by the reduction of the thioether 213 followed by trapping with trimethylsilyl chloride to afford the silyl enol ether 214. The silyl enol ether was then treated with methyl lithium and the enolate trapped formaldehyde. Further functional group manipulations provided (±)-aphidicolin.

Reagents and Conditions: (a) (i) n-BuLi, DME, TMEDA, Me2NPOCl2; then Me2NH; (ii) MeNH2, THF, t- + - BuOH, Li; then NH4Cl, 86% (over two steps); (b) PyridineH OTs , acetone, 95%; (c) no data available; (d)

(CH2O)x, C6H5SH, NEt3, EtOH, 78%; (e) Li, NH3, t-BuOH, THF; then TMSCl, NEt3, THF, 90%; (f) MeLi, THF, −78 °C; then HCHO (g) (i) 10% HOAc/THF; (ii) L-Selectride, THF, −78 °C; (iii) 10% aqueous HCI,

CH3OH, (49% over two steps) Scheme 59: Ireland`s approach to (±)-aphidicolin73

1.7.6 Holton62 Holton’s formal total synthesis began with a Michael reaction between 215 and the butenolide 216 to afford the enone 217 as a mixture of diastereoisomers - recrystallization provided the enone as the required single diastereoisomer. The newly formed lactone was first treated with vinyl lithium and then hydrofluoric acid to provide the diene 218. Under basic conditions, the diene cyclised, which after reductive desulfurization, gave the tricycle 219. Holton found that this entire sequence could be performed as a single synthetic operation to give 219 in an overall yield of 45% from the starting materials 215 and 216. For the next stages in the synthesis, the keto aldehyde 220 was synthesised from the tricycle 219.

Reagents and Conditions: (a) THF, −95 °C, 75% (d.r: 7.4:1); (b) vinyllithium; then HF, MeOH, 76%; (c) (i)

NaOMe, MeOH, H2O, 0 °C, (quant.); (ii) Zn, NH4Cl, 94%; (d) PPTS, benzene, 2-ethoxydioxolane, reflux; (e)

O3, CH2C12, −78 °C, DMS; (f) LiAlH4, THF; (g) TBSCl, DMAP, Et3N, DCM, −78 °C, 65% (over 4 steps) Scheme 60: Holton’s approach to (+)-aphidicolin62

With the key stereocentres in place, Holton turned his attention to the formation of the keto alcohol 223, a late stage intermediate in Corey’s racemic synthesis of aphidicolin. The spirocycle 221 was formed via a base catalysed Aldol condensation, followed by hydrogenation of the double bond and ketal exchange. Reduction of the enone with formaldehyde trapping provided the key intermediate 222. Diastereoselective reduction of the ketone formed the 1,3-diol, which was immediately converted to the acetonide 223. Following Corey’s procedure, the protected 1,3-diol 223 was converted to aphidicoline norketone 194, formally completing the first enantioselective route to (+)-aphidicolin.

Reagents and Conditions: (a) (i) t-BuOK, THF, t-BuOH, 0 °C; (ii) H2, 5% Pd/C, EtOH, NaOEt; (iii) 2-methyl-

2-ethyldioxolane, (HOCH2)2, p-TsOH, 0 °C, 90% (over three steps); (b) Li, NH3; then CH2O, 70%; (c) (i) L- selectride, THF, −78 °C; (ii) pivaldehyde, p-TsOH, HF, 0 °C, 85%; (d) (i) p-TsCl, DMAP, NEt3, CHCl3, (ii) 2- methyl-tetrahydrofuran, lithium di-tert-butylamide, −120 °C, 90% (over two steps) Scheme 61: Holton’s approach to (+)-aphidicolin62

1.7.7 Tanis75 Tanis’ formal total synthesis of (+)-aphidicolin started with the conversion of geraniol to the epoxide 225 via the Sharpless asymmetric epoxidation. Saponification, chlorination and coupling provided the furan 226 needed for the cyclisation. The Lewis acid mediated cyclisation proceed smoothly to afford the tricycle 227 as a single diastereoisomer in a 72% yield. The furan 228 was oxidised to yield the enone, which was reduced to the diketone 180. The conversion of 180 to aphidicolin had already been documented during McMurry’s racemic approach.64 This intermediate therefore completes the formal enantioselective synthesis of (+)-aphidicolin.

i Reagents and Conditions: (a) (i) PhCOCl; (ii) SeO2, TBHP, 70%; (b) L-DIPT, Ti(O Pr)4, TBHP, DCM 83%; (c)

PhCH2Br, NaH, 88%; (d) (i) NaOMe, MeOH, n-Bu4NI; (ii) n-BuLi, TsCl, LiCl, 84% (over two steps); (e) (3-

methylfuranyl)magnesium chloride, dilithium tetrachlorocuprate(II), 79%; (f) BF3.OEt2, benzene, DCM, n-

hexane, NEt3, −78 °C, 72%; (a) DMSO, (COCl)2, DCM, −78 °C; then NEt3, 97%; (b) (i) MgBr2, (ii) L- + selectride; (iii) LiAlH4, 89%, (dr: 8.5:1); (c) acetone, H , 93%; (d) (i) NBS, DMF; (ii) n-BuLi; then MeI, 65%

(over two steps); (e) mCPBA, 97%; (f) H2, Pd/C, 96% Scheme 62: Tanis’ approach to (+)-aphidicolin75

1.7.8 Itawa76–80 The Itawa’s formal total synthesis of (±)-aphidicolin began with the conversion of the dimethyl ketal 229 to the alcohol 230 via a three step sequence. The alcohol was converted to the mesylate which cyclised under the action of TMSOTf to give the spirocyclic compounds 231 and 232. The mixture was treated with t-BuOK furnishing the tricyclic enones 233 and 234, which were separable by chromatography. The enone 95 was accordingly transformed to the ketone 235 using standard techniques.

Reagents and Conditions: (a) p-TsOH, BnOH, n-hexane, 74%; (b) NaH, DMI, (BnO)2CH(CH2)3Br, THF, 82%;

BuOK, Et2O, 85%; (g) H2, Pd/C, AcOEt, 50 °C, 87%; (h) ethylene glycol, PPTS, benzene; then PCC, DCM, 97% Scheme 63: Itawa’s formal total synthesis of (±)-aphidicolin76–80

The enone 236 underwent an acid catalysed cyclisation to provide the final ring of the aphidicolin backbone. The tetracycle 237 was then converted to the isomeric enone 238 for the stereoselective installation of the 1,3-diol present in the parent molecule. In order to accomplish the final stages, Itawa turned to the studies conducted by Ireland.73 The silyl enol ether 239 was synthesised from the enone via the thioether. The enolate was then regenerated and trapped with formaldehyde. Finally selective reduction of the ketone and alterations to the protecting groups present furnished the ketone 179 previously formed by both Trost63 and McMurry64.

Reagents and Conditions: (a) LDA, PhSeBr, THF; then H2O2, pyridine, DCM; (b) Li, 2-(3-bromopropyl)-1,3- dioxolane, Et2O, 90%; (c) PCC, DCM, 82%; (d) Me2CuLi, Et2O, 84%; (e) p-TsOH, benzene, 83%; (f) LiAlH4,

THF, Et2O, 0 °C, 96%; (g) DMAP, acetic anhydride, DCM; then CrO3, DCM, −20 °C, 75%; (h) Pd(Ph3)4, n-

Bu3P, ammonium formate, CH3CN, 80%; (i) (CH2O)x, NEt3, PhSH, EtOH, reflux, 73%; (j) Na, NH3, THF, t-

BuOH, −78 °C; then TMSCl, NEt3, HMPA, THF, 55%; (k) MeLi, THF, CH2O, −78 °C, 76%; (l) L-Selectride, THF, −78 °C, 65%; (m) 5% HCl, THF, 40°C, 98%; (n) PPTS, 2,2-dimethoxypropane, 92% Scheme 64: Itawa’s formal total synthesis of (±)-aphidicolin76–80

1.7.9 Toyota and Fukumoto81–83 The Toyota and Fukumoto’s formal total synthesis of (±)-aphidicolin started with an aldol reaction between bromoacrolein and 240 to provide the allylic alcohol 241. The allylic alcohol was then cyclised under Heck conditions and protected as the ketal to give 242 and 243 as a 3:1 mixture of epimers. Conversion of this mixture to the alcohol 244 proceeded via a Claisen rearrangement and subsequent reduction of the aldehyde. Alcohol 244 was routinely converted to the triene, which upon heating to 230 °C cyclised to form the tetracycle 247 and 248 as a 3:1 mixture of epimers. Both epimers were transformed to the enone 238, a known intermediate from Itawa’s studies on aphidicolin.76–80

Reagents and Conditions: (a) LDA. THF, CH2CBrCHO, −78 °C, 89%; (b) Pd(OAc)2, P(o-tolyl)3, K2CO3,

CH3CN, reflux, 90%; (c) (HOCH2)2, PPTS, toluene, reflux, 89%; (d) (i) CH2=CHOEt, Hg(OCOCF3)2, reflux;

(ii) toluene, 140 °C, sealed tube; (iii) NaBH4. MeOH, 0 °C 82% (over three steps); (e) O2 PdCl2, CuCl, DMF- + - H2O, 40 °C, 70% (f) H2, 10% Pd/C, AcOEt, 82%; (a) Ph3P MeBr , n-BuLi, THF, reflux, 81%; (b) PCC, NaOAc, ® Florisil , DCM, 92%; (c) Ph2P(O)CH2CH=CH2, n-BuLi, HMPA, THF, −78 °C, 62%, (d) Methylene blue,

PhMe, 230 °C, sealed tube, 67% (d.r: 3:1); (e) (i) O2, hv, hematoporphyrin, Pyridine; (ii) NaI, AcOH, Et2O,

EtOH; (iii) MnO2, DCM, 81% (over three steps) Scheme 65: Toyota and Fukumoto’s synthesis of (±)-aphidicolin81–83

1.7.10 Toyota and Ihara84 Toyota and Ihara’s formal total synthesis of (±)-aphidicolin begins with the synthesis of the bridged ring system. The diene 249 cyclised in the presence of palladium (II) acetate to form the bridged ring system present in the natural product. Enone 250 was then converted to the acetonide via the epoxide. The Corey-Chaykovsky reaction provided both diastereoisomers as separable compounds, with the major diastereoisomer being the required isomer for the ring opening reaction.

Reagents and Conditions: (a) LDA, HMPA, THF, −78 °C; NCCO2Me, 93%; (b) LiAH4, THF; 10% HClO4,

THF; MOMCl, i-Pr2NEt, CH2Cl2, 76%; (c) LDA, HMPA, THF, −78 °C; TBSCl, 91%; (d) Pd(OAc)2 (5 mol%), + − DMSO, O2 (1 atm), 45 °C, 89%; (e) L-Selectride, THF, −78 °C, 93%; (f) Me2S (O)CH2 , THF, 89% (g) (i) 1M

KOH, dioxane, 100 °C; (ii) acetone, PPTS, reflux, 91% (over two steps); (h) O3, MeOH, −78 °C; then DMS,

96%; (i) LDA, HMPA, THF, −78 °C; CH2=CHCH2I, −78 °C, 92%; (j) dicyclohexylborane, THF; then NaOH,

H2O2, 0 °C, (no yield given) (k) TBSCl, imidazole, DMF, 0 °C, (no yield given) (l) NaBH4, MeOH, 86 %; (m)

(Imid)2C=S, DCM, reflux, 96%; (n) 250 °C, toluene, in stainless autoclave, 77% Scheme 66: Toyota and Ihara’s synthesis of (+)-aphidicolin84

Selective reduction of the double bond present in 253 proceeded smoothly to form, after further functional group manipulations, the benzyl ether 254 as a single diastereoisomer. The triene was 255 was heated to 230 °C to cleanly form the tetracycle 256. Notably, the cycloadduct is formed as a single isomer in this synthesis, rather than the mixture of diastereoisomers previously seen in the Toyota and Fukumoto synthesis.81–83 Reaction of 256 with formaldehyde and TBAF provided the keto alcohol 257 previously formed during Ireland’s total synthesis.73

Reagents and Conditions: (a) Bu4NF, THF, 100%; (b) H2, PtO2, MeOH, 100%; (c) NaH, BnBr, DMF, 75%; (d)

10% HClO4, THF, 45 °C; then acetone, p-TsOH, 53%; (e) (i) SO3.Py, DMSO, Et3N; then MeLi, Et2O, −78 °C; + - (ii) TPAP, NMO, 4 Å molecular sieves, DCM, 50% (over two steps); (f) Ph3P MeBr , n-BuLi, PhMe, 85%; (g)

Li, liquid NH3, 96%; (h) (i) SO3.Py, DMSO, Et3N, 83%; (ii) (EtO)2P(O)CH(Me)COMe, NaH, THF, 95%; (i)

TBSOTf, i-Pr2NEt, DCM, 93%; (j) 230 °C, toluene, in stainless autoclave, 75%; (k) CH2O, anhydrous Bu4NF, THF, 44% Scheme 67: Toyota and Ihara’s synthesis of (+)-aphidicolin84

1.8 Project proposal

As previously noted in the introduction, the ketone 31 did not cyclise to the anticipated product 32 (Scheme 68).14 This result is surprising when compared to the successful cyclisations of the amide and ester substrates, 6 and 25. It was decided that the initial stages of this project would focus on this anomalous result.

Reagents and Conditions: (a) toluene, reflux, epoxyhexane, 1 hr, 90%; (b) toluene, reflux, epoxyhexane, 52 hr, 76%; (c) toluene, reflux, 24 hr Scheme 68: Attempted cyclisation of a ketone linked 1,6-diyne 31

Provided the ketone linked 1,6-diyne 31 cyclised to the enone 32, the application of this methodology to the total synthesis of aphidicolin would be investigated. Our aim would be the synthesis of the protected aphidicolin norketone 179, a known intermediate en route aphidicolin (Scheme 69). 85,86

Scheme 69

Our retrosynthetic analysis of the protected aphidicolin norketone 179 led to the enone 259 (Scheme 70). In the forward sense, it is expected that the allyl silane present in 259 would react with acrolein to provide the tetracycle 258 through a Sakurai allylation followed by an adol reaction.87,88 Further manipulation of this tetracycle 258 would provide the norketone 179.

Scheme 70: Retrosynthesis of the aphidicolin norketone 179

The enone 259 would be accessible through methylation of the Parsons-Board-Waters cyclisation product 260, in turn accessible from the ketone precursor 261 (Scheme 71). The application of the cyclisation to this substrate would be the key reaction of this synthetic approach. The ketone 261 would be accessible from the aldehyde 262 and the dioxolane 263.

Scheme 71: Retrosynthesis of the advanced tricyclic intermediate 260

In the forward sense we expect that the cyclisation would provide the tricyclic compound 260 from the ketone 261, where the stereochemistry of the decalin ring is formed under substrate control (Scheme 72).

Scheme 72: Cyclisation of the ketone 261 to the tricyclic product 260

Chapter 2

Studies on the Parsons-Board-Waters Cyclisation

2.1 Synthesis and cyclisation of the ketone linked 1,6-diyne 31

During his doctoral studies in the Parsons group, Faggiani completed the synthesis of the ketone precursor 31 from the commercially available 4-pentynol and investigated its unsuccessful cyclisation.14 Since the procedural data for Faggiani’s route was not available at the start of our reinvestigation, an alternative approach to the ketone precursor was envisioned (Scheme 73).89 Formation of the alcohol 266 proceeded from the protected 4- petnynol 265 in 92% yield; this alcohol was then converted to the allyl ether 267. Deprotection of the TBS ether was accomplished using tetrabutylammonium fluoride, and the resulting alcohol was converted to the aldehyde 269 using the Swern oxidation.90 The aldehyde 269 was reacted with the lithium salt of trimethylsilyl acetylene and oxidised with Dess-Martin periodinane to provide the cyclisation precursor 31 in a yield of 78% over two steps.

Reagents and Conditions: (a) TBSCl, imidazole, DMAP, DCM, 95%; (b) n-BuLi, −78 °C; then paraformaldehyde, 92%; (c) NaH, 0 °C, then 2,3-dibromopropene, 65%; (d) TBAF, THF, 0 °C, 90%; (e)

(COCl)2, DMSO, DCM, −78 °C, then NEt3, 96%; (f) trimethylsilylacetylene, n-BuLi, THF −78 °C; then 269, 83%; (g) DMPI, DCM, 0 °C, 94% Scheme 73: Synthesis of the ketone cyclisation precursor 31

While conventional heating of the cyclisation substrate had failed in the earlier study by Faggiani,14 the cyclisation was nevertheless repeated under these conditions in order to confirm the result. After 72 hours in boiling toluene, the dihydroisobenzofuran 32 was unexpectedly isolated in a yield of 62% (Scheme 74). The cyclisation also provided the alkyne 270 as a by-product of the reaction. The by-product was proposed to be caused by the combination of the acidity of the glassware and prolonged heating time required for this substrate.

Reagents and Conditions: (a) epoxyhexane, toluene, 72 hr, 62% of 32 and 11% of 270 Scheme 74: Successful cyclisation of the ketone substrate 31

To provide unequivocal characterization of this novel compound, the cyclisation product 32 was desilylated with tetrabutylammonium fluoride in order to resolve overlapping peaks in the 1H NMR spectrum (Scheme 75). The product of this reaction was confidently identified as the enone 271.

Reagents and Conditions: TBAF, THF, −10 °C, 80% Scheme 75: Removal of the allylic silane with TBAF

It was proposed that the by-product 270 may cyclise to form the tricycle 271 in trace quantities during the reaction presented in scheme 74. Cyclisation of the isolated by-product 270 was attempted and the crude material compared to the known spectra of the tricycle 271. It was conclusively found that the desilylated material does not form the tricycle 271 (Scheme 76).

Reagents and Conditions: (b) toluene, reflux, epoxyhexane, 13 hr, 97%; (b) toluene, reflux, epoxyhexane, 72 hr Scheme 76: Role of the silyl group in cyclisation

2.2 Synthesis and cyclisation of the ketone linked 1,7-diyne 272

It was decided to investigate the synthesis and cyclisation of the homologue 272, in order to establish whether this reaction was specific to 1,6-diyne substrates (Scheme 77). Until this investigation only 1,6-diynes had been investigated during previous studies within the group.

Reagents and Conditions: (a) toluene, reflux, epoxyhexane Scheme 77: Proposed cyclisation of the 1,7-diyne 272

The 1,7-diyne 272 was prepared using the same route as for the 1,6-diyne 31 (Scheme 78). The synthesis began with the protection of 5-hexyn-1-ol as the TBS ether 275 and conversion of the propargyl alcohol 276. The allyl ether was formed and the TBS protecting group was removed to provide the alcohol 278. The alcohol was then oxidised using Swern conditions,90 the addition reaction completed and the resulting propargylic alcohol oxidised to the ketone 272.

Reagents and Conditions: (a) TBSCl, imidazole, DMAP, DCM, 92%; (b) n-BuLi, −78 °C; then para- formaldehyde, 97%; (c) NaH, 0 °C, then 2,3-dibromopropene, 53%; (d) TBAF, THF, 0 °C, 74 % (e) (COCl)2,

DMSO, −78 °C, then NEt3, 97%; (f) trimethylsilylacetylene, n-BuLi, −78 °C; then 279; (g) DMPI, 0 °C, DCM, 46% (over two steps) Scheme 78: Synthesis of the 1,7-diyne cyclisation precursor 272

After heating this substrate three days, the crude material showed no evidence of the characteristic furan peaks of 273 (Scheme 79).

Reagents and Conditions: (a) epoxyhexane, toluene, 3 days Scheme 79: Unsuccessful attempted cyclisation of the 1,7-diyne 272

2.3 Application of Microwave Synthesis

In order to optimize the cyclisation of 31 to 32, microwave conditions were investigated. It was our expressed hope that the shorter reaction time achievable by exceeding the normal boiling point of toluene would limit the formation of the by-product 270. Furthermore, it was hoped that these investigations into the application of microwave heating would allow for the cyclisation of more reluctant substrates, such as the 1,7-diyne 272, and aid others who were engaged with similar synthetic projects in the group.

Reagents and Conditions: (a) epoxyhexane, toluene, 62% of 32 and 11% of 270; (b) epoxyhexane, toluene Scheme 80: Summary of the thermal cyclisations investigated thus far

The shorter reaction time during microwave synthesis prevented the formation of the by- product 270, allowing us to isolate the tricycle 32 as the exclusive product (Scheme 81). Gradually increasing the temperature from 150 °C to 185 °C improved the yield of the process (Entries 1-3, Table 1). Alternative solvents were investigated, but no further improvement was made on the yield of the reaction (Entries 6-9, Table 1). Furthermore, the introduction of 1,4-CHD did not improve the yield as had previously been noted for the propargylic ene reaction by Roglans43 (Entry 4, Table 1).

Reagents and Conditions: (a) epoxyhexane, table 1 Scheme 81: Application of microwave synthesis

Entry Solvent Temp (°C) Time (h) Additive Yield (%)

1 toluene 150 4 - 26

2 toluene 175 4 - 59

3 toluene 185 2 - 72

4 toluene 185 2 1,4-CHD 66

5 toluene 185 2 THF 80

6 DMSO 185 1 - decomposition

7 DMF 185 1 - 68

7 DCE 185 2 - 66

9 acetonitrile 185 2 - 65

Table 1: Microwave conditions for the cyclisation 31

The newly investigated microwave conditions were applied to the cyclisation of the 1,7-diyne 272, which had previously been shown not to cyclise under standard thermal conditions. After 2 hours at 185 °C in a microwave reactor, no product was observed (Scheme 82).

Reagents and Conditions: (a) toluene, epoxyhexane, MW, 185 °C, 2hr Scheme 82: Microwave assisted cyclisation of 272

Following the unsuccessful cyclisation of the 1,7-diyne 272, DCE was reinvestigated as we were encouraged by both its volatility and its capacity to reach 200 °C in a microwave reactor. DCE had been initially discounted as the tricycle had been isolated in a 66% yield when heating to 185 °C. However, when the 1,6-diyne 31 was heated to 200 °C in DCE, the tricycle 32 was isolated in an improved yield of 81% (Scheme 83).

Reagents and Conditions: (a) DCE, epoxyhexane, MW, 185 °C, 66%; (b) DCE, epoxyhexane, MW, 200 °C, MW, 81% Scheme 83: Improved synthesis of the tricycle with DCE as the solvent

2.4 Synthesis of Analogues of the Cyclisation Precursor 31

With the optimized cyclisation in hand, we decided to investigate the synthesis of the nitrogen and sulphur analogues, 280 and 282. It was expected that the nitrogen and sulphur analogues would cyclise to form the annulated pyrrole 281 and the annulated thiophene 283 when heated under microwave conditions (Scheme 84).

Scheme 84: Predicted cyclisations of nitrogen and sulphur analogues

The synthesis of the dihydroisoindole structure is of particular interest as there are currently there are number of pharmaceuticals which are congeners of the isoindole structure. These congeners include the anticancer compound lenalidomide 284, the sedative (S)-pazinaclone 285, and the antiflammatory ampremilast 286 (Figure 6).

Figure 6: Biologically active congeners of isoindole

2.5 Synthesis of the Nitrogen Analogue 280

We proposed that the nitrogen containing cyclisation precursor 280 would be accessible from the amine 287 following the same approach documented for the oxygen containing cyclisation precursor 31 (Scheme 85).

Reagents and Conditions: (a) TBAF, THF; (b) Oxidation; (c) n-BuLi, trimethylsilylacetylene, THF; (d) Oxidation Scheme 85: Planned synthesis of the nitrogen thermolysis precursor 280

2.5.1 Approach to the N-methyl amine precursor 293 In order to rapidly access the amine 287, we turned our attention to the research conducted by Bieber et al. concerning the synthesis of propargylamines via a copper catalysed Mannich reaction (Scheme 86).91

Reagents and Conditions: (a) CuI, DMSO, 37% aq. formaldehyde, KHCO3, 20 hr, 93% Scheme 86: Bieber’s synthesis of propargylamines

Our proposal consisted of the application of this methodology to the synthesis of the amine 293 from the silyl protected alcohol 265 and the allylic amine 292 (Scheme 87). As the initial work conducted by Bieber used simple amines, we decided that it was prudent to investigate how this methodology would be affected by using the allylic amine 292.

Reagents and Conditions: (a) CuI, DMSO, 37% aq. formaldehyde, KHCO3 Scheme 87: Proposed synthesis of the tertiary amine 293

The allylic amine was synthesised by the slow addition of neat 2,3-dibromopropene to a cooled solution of aq. methylamine according to the procedure reported by Bottini.92 Despite multiple attempts, it was not possible to match the yield of 63% reported for a 3 mol scale by Bottini; instead the optimal yield was 22% on a smaller scale of 0.05 mol. The allylic amine 292 was reacted with phenylacetylene using the conditions described in Bieber’s research to furnish the propargyl amine 295 (Scheme 88). The propargyl amine however was produced in a markedly lower yield than reported for the less complex examples covered in the Bieber’s research.

Reagents and Conditions: (a) aq. MeNH2; then NaOH, 22%; (b) phenylacetylene, CuI, DMSO, 37% aq.

formaldehyde, KHCO3, 53% Scheme 88: Synthesis of the allylic amine 292 and application of Bieber’s methodology

Given these promising results, the methodology was applied directly to the synthesis of the protected alcohol 293. The previously synthesised protected pentynol 265 was reacted under these conditions to provide the allyl amine 293 in a yield of 51%. Deprotection of this intermediate provided the amino alcohol 296, ready for the final stages of this synthetic route (Scheme 89).

Reagents and Conditions: (a) CuI, DMSO, aq. formaldehyde, KHCO3, 51%; (b) TBAF, THF, 0 °C, 50% Scheme 89: Synthesis of alcohol 296

Oxidation of the amino alcohol 296 was more difficult than initially anticipated (Scheme 90). While the DMPI and PCC oxidations failed to form the required aldehyde, the Swern oxidation did provide trace amounts of the aldehyde 297, as shown by 1H NMR analysis. The failure of these methods should have perhaps been anticipated as decomposition has been previously reported in the literature when using a variety of oxidative agents on amino alcohols, including PCC and DMPI.93,94 A report concerning the successful application of the Swern oxidation to a variety of amino alcohols however had given us hope that this would be a viable synthetic pathway to the cyclisation precursor.95

Reagents and Conditions: (a) DMPI, DCM, 0 °C, 0%; (b) PCC, DCM, 0%; (c) (COCl)2, DMSO, DCM, −78 °C;

then NEt3, 11% Scheme 90: Oxidation of the amino alcohol 296

A paper published after our investigations reported a general method whereby amino alcohols can be reliably oxidised in air through the use of AZADO/copper catalysis (Scheme 91).96 This methodology could be applied to the future synthesis of the amino aldehyde 297.

Reagents and Conditions: (a) AZADO (3 mol%), CuCl (3 mol%), bpy (3 mol%), DMAP (6 mol%), MeCN, air, 3hr, 96% Scheme 91: Iwabuchi’s aerobic oxidation of amino alcohols

2.5.2 Synthesis and cyclisation of the N-tosyl amine precursor 307 An alternative approach based on the Gabriel synthesis97 was envisioned with a view to returning to Bieber’s propargyl amine synthesis later in the project (Scheme 92). This alternative entailed the conversion of the propargyl alcohol to the phthalimide protected amine 300. The phthalimide group would be removed and the primary amine reacted with 2,3-dibromopropene to provide the allylic amine 301. With the allylic amine in hand it would then be possible to protect this compound to the requirements of the cyclisation.

Scheme 92: Proposed synthesis of the allylic amine 301

Synthesis of the primary amine 302 began with the conversion of the propargyl alcohol 266 to the protected amine 300 under the Mitsunobu conditions. The phthalimide protecting group was then removed with hydrazine monohydrate to give the primary amine 302 (Scheme 93).

Reagents and Conditions: (a) DIAD, PPh3, THF, 0 °C; then phthalimide, 51%; (b) hydrazine monohydrate, THF, reflux, 97% Scheme 93: Synthesis of the amine 302

The primary amine was converted to the allylic amine 301 and then protected as the tosylate (Scheme 94). This approach did have the disadvantage of providing the diallylic amine 303 as a by-product of the reaction, eroding the overall yield of this synthetic sequence.

Reagents and Conditions: (a) 2,3-dibromopropene, K2CO3, THF, 47% of 301, 21% of 303; (b) TsCl, NEt3, 0 °C, 67% Scheme 94: Synthesis of tosyl amine 304

Following the same approach as for the oxygen containing substrate, the tosyl amine 304 was deprotected to provide the alcohol 305. The alcohol was oxidised to the aldehyde and then converted to the propargyl alcohol 306 in a yield of 56% over two steps. Oxidation with Dess-Martin periodinane provided the required cyclisation substrate 307.

Reagents and Conditions: (a) TBAF, THF, 81%; (b) (1) (COCl)2, DMSO, DCM, −78 °C; then NEt3; (2) n-BuLi, THF, trimethylsilylacetylene, −78 °C, 56% (over two steps); (c) DMPI, DCM, 70% Scheme 95: Synthesis of cyclisation precursor 307

Rewardingly, the tosyl amine precursor 307 was found to readily cyclise under microwave conditions to the expected dihydroisoindole 308 in a 61% yield (Scheme 96).

Reagents and Conditions: (a) DCE, epoxyhexane, 200 °C, 2 hr, 61% Scheme 96: Synthesis of dihydroisoindole 308

2.6 Synthesis of the sulfur analogue 282

We expected that the cyclisation precursor could be accessed from the previously synthesised propargyl alcohol 266, in a similar approach to the synthesis of the nitrogen analogue (Scheme 97). In order to install the key thioether functionality, the thioester 309 would be synthesised first using the Mitsunobu Reaction. This thioester would then be deprotected and alkylated in situ to provide the thioether 310. The allyl thioether would then be taken forward using the same chemistry that had been previously used for both the oxygen and nitrogen substrates.

Scheme 97: Proposed ynthesis of sulphur thermal precursor 282

Straightforward treatment of the propargyl alcohol 266 with thioacetic acid under Mitsunobu conditions gave the thioester 309 in a 70% yield. The thioacetate was then successfully converted to the bromoalkene 310 in a 62% yield (Scheme 98).

Reagents and Conditions: (a) DIAD, PPh3, thioacetic acid, THF, 0 °C, 70%; (b) MeOH, 2,3-dibromopropene,

K2CO3, 62% Scheme 98: Synthesis of thioether 310

The deprotection of the silyl ether 310 was attempted under standard conditions. Fortunately, the thio alcohol 311 was isolated as the only product (Scheme 99). It however appeared that this product was contaminated with a minor impurity which co-elutes with the alcohol during chromatography. Multiple purifications using various solvent mixtures did not alleviate the issue. Furthermore, the 1H NMR peak ratio remained constant regardless of the purification method or repeating the reaction with a different batch of the silyl ether.

Reagents and Conditions: (a) TBAF, THF, 0 °C, 80% Scheme 99: Deprotection of the silyl ether 310

Following the same route as for the previous thermal substrates in this research project, the thio alcohol 311 was oxidised to the aldehyde 312, and reacted with the lithium acetylide to provide the propargyl alcohol 313. The Swern oxidation was chosen for the final step of the precursor synthesis to avoid oxidising the thio ether moiety. When this transformation however was effected, the ketone 282 was isolated in a yield of 26%.

Reagents and Conditions: (a) (1) (COCl)2, DMSO, DCM, −78 °C; then NEt3; (2) n-BuLi, THF,

trimethylsilylacetylene, −78 °C, 50% (over two steps); (c) (COCl)2, DMSO, DCM, −78 °C; then NEt3, 26% Scheme 100: Synthesis of sulphur containing cyclisation precursor 282

Despite the low yield of the oxidation reaction, the route was seen through to its completion. The cyclisation was accomplished using the standard microwave conditions to provide the tricyclic compound 283 in a 58% yield (Scheme 101).

Reagents and Conditions: (a) DCE, epoxyhexane, 200 °C, 2 hr, 58% Scheme 101: Cyclisation of the sulphur precursor 282

2.7 Concluding remarks on the methodological studies

We are delighted to report the successful cyclisation of ketone linked 1,6-diynes following this reinvestigation. It is of particular note that the cyclisation took place over a far longer time period, 72 hours, than for the ester and amide examples.

Reagents and Conditions: (a) epoxyhexane, toluene, 72 hr, 62% Scheme 102: Successful cyclisation of the ketone substrate 31

To rationalise this, we turned to the work by Parker concerning the intramolecular Diels- Alder reaction of the amide and ester linked dienophiles 314-316 (Scheme 103).98 While the substrates 314 and 315 do not cyclise in refluxing benzene, the tertiary amide 316 will form the cycloaddition adduct 319 in a quantitative yield. Parker proposed that the precursors 314 and 315 do not adopt the required cisoid conformation when heated to 80 °C. Instead the diene and dienophile adopt a transoid relationship about the ester or secondary amide link, preventing the cycloaddition. The tertiary amide 316 however does have a population of the reactive cisoid conformer required to form the cycloadduct 319 under these conditions.

Reagents and Conditions: (a) benzene, reflux, 6 days; (b) benzene, reflux, 6 days, quant. Scheme 103: Parker’s intramolecular Diels-Alder studies

For the Parsons-Board-Waters cyclisation to progress, the alkyne units need to be in proximity, shown here as the cisoid relationship (Figure 7). The results for the ketone substrate 31 indicate that in boiling toluene there is a particularly small population of the cisoid conformer, as demonstrated by the particularly long reaction duration of 72 hours. In comparison, the amide 6 cyclises in less than one hour, indicating that there is a significantly higher population of the reactive cisoid conformer at this temperature relative to the ketone.

Figure 7: Conformers of the cyclisation precursors

Parker also described in her work the cyclisation of the diester 320 to the cycloadduct 321 (Scheme 104). Given the successful cyclisation of the diester 320 compared to the unsuccessful cyclisation of the ester 314 and secondary amide 315, we envisioned an extrapolation of this result to our investigations on the Parsons-Board-Waters cyclisation. In particular, we proposed that alternative linking groups for the 1,6-diyne may provide comparable or superior results to the amide 6, ester 25 and ketone 31 linked 1,6-diynes that have been previously researched by the group.

Reagents and Conditions: (a) benzene, reflux, 5 days, 40% Scheme 104: Parker’s intramolecular Diels-Alder studies

Following analysis of the synthetic routes for our studies on aphidicolin, it was proposed that a dioxolane group would be a useful alternative link for the 1,6-diyne. It was expected that the dioxolane precursor 322 would have a greater population of the reactive cisoid conformer when compared to the ketone 31, facilitating the cyclisation. Furthermore, the dioxolane group would protect the ketone from side reactions during synthetic transformations on the cyclisation products.

Scheme 105: Potential of the cyclisation dioxolane substrate

The dioxolane group would also help with the synthesis of precursor molecules for the studies on the synthesis of aphidicolin, as we expected the various precursor molecules to be built from the addition of the 1,6-diyne core 263 to a number of substituted aldehydes (Scheme 106). Provided the cyclisation of the dioxolane precursor 322 offered either comparable or superior results, the synthesis of the precursor molecules would be simplified by these investigations.

Scheme 106: Retrosynthesis of future propargyl alcohol substrates

2.8 Future Applications

The application of the investigated cyclisation in tandem with the Diels-Alder reaction may provide access to the steroidal backbone 328 (Scheme 107). In this process, the Parsons- Board-Waters cyclisation would provide a dihydroisobenzofuran intermediate 327, which would undergo a Diels-Alder reaction99 to provide the ether 328.

Scheme 107: Planned synthesis of the steroid core structure

Treatment of 328 with a source of fluoride would promote a fragmentation reaction to the diene, which would aromatize to 330 upon acidic workup (Scheme 108). Following a successful investigation of this proposal, analogues of the precursor molecule 326 would be synthesised as the steroid backbone is present in a number of small molecule therapies currently being used in modern medicine.100

Scheme 108: Fragmentation of the ether 328

Chapter 3

Studies on the Total Synthesis of Aphidicolin

3.1 The preparation of model systems

In order to investigate the application of this cyclisation methodology towards aphidicolin, we proposed the synthesis of two model systems, 331 and 333. The first substrate 331 would confirm the principle of the cyclisation. The second substrate would assess the impact of extending the chain length on the rate of reaction and product distribution.

Scheme 109: Model cyclisations

Both of the proposed models systems would be readily accessible from the dioxolane linked 1,6-diyne 263 (Scheme 110), which is also required for the synthesis of aphidicolin.

Scheme 110: Retrosynthesis of the model compounds

3.1.1 Synthesis of the 1,6-diyne 263 The retrosynthetic analysis of this key intermediate leads to the known Weinreb amide 338 (Scheme 111).

Scheme 111: Retrosynthesis of the diyne 263

This Weinreb amide 338 had been previously synthesised independently by Trost101 and Satyamurthi102 from the alkylation of N-methoxy-N-methylacetamide 339 and N-methoxy-N- methyl-2-phenylsulfonylacetamide 340 respectively (Scheme 112). In both examples, the starting amides, 339 and 340, were synthesised by the investigators. We hoped to develop a more intuitive and scalable approach to the amide 338 from the commercially available 4- pentynol.

Reagents and Conditions: (a) LDA, hexane, THF, −78 °C; then HMPA, propargyl bromide, 43%; (b) DMF,

K2CO3, propargyl bromide, 86%; (c) sodium amalgam, Na2HPO4, MeOH, 71% Scheme 112: Trost and Satyamurthi’s approaches to the Weinreb amide 338

In our approach, 4-pentynol 341 would be oxidised to 4-pentynoic acid 342 using the Jones oxidation, which in turn would be converted to the Weinreb amide 338. Treatment of the Weinreb amide with the lithium salt of trimethylsilylacetylene would provide the ketone 337. Protection of this ketone as the dioxolane would furnish the required intermediate for the synthesis of both the model systems and the natural product.

Reagents and Conditions: (a) Jones’ oxidation; (b) N,O-dimethylhydroxylamine hydrochloride, coupling agent;

Oxidation of 4-petnynol proceeded smoothly using the Jones oxidation to provide 4- pentynoic acid (Scheme 114).103 This routine transformation had already been reliably completed in a number of different syntheses.104,105

Reagents and Conditions: (a) CrO3, H2SO4, acetone, 85% Scheme 114: Oxidation of 4-pentynol using Jones’ Conditions

Oxidation of 4-pentynol was also accomplished using Zhao’s oxidation (Scheme 115).106 Zhao’s modification of the traditional stoichiometric chromium oxidation involves 1-2 mol% of chromium trioxide, with periodic acid as a co-oxidant. While Zhao’s oxidation is a safer alternative to the Jones’ oxidation, it was found to be less practical when conducted on larger scale (~120 mmol); we found that the periodic acid routinely crystallised from the wet acetonitrile solution while being added through a dropping funnel. Furthermore, the yield of this process was lower and less consistent than the traditional stoichiometric approach.

Reagents and Conditions: (a) 1-2 mol% CrO3, H5IO6, wet MeCN, 0 °C, 1hr, 50% Scheme 115: Oxidation of 4-pentynol using Zhao’s catalytic conditions

With the successful synthesis of 4-pentynoic acid, investigations into the synthesis of the Weinreb amide 338 were started. Our investigations began with the use of CDI in order to complete this transformation. Unfortunately, only trace quantities of the required amide were isolated when the reaction was conducted over two hours; this increased to an isolated yield of 20% when the mixture was left over 48 hours (Scheme 116). Before investigating alternative coupling agents, we decided to heat the mixture to reflux, allowing the amide to be isolated in an improved yield of 50%. Further optimization of this process, involving the use of other coupling agents, was delayed until the successful investigation of the later steps of this brief synthetic route.

Reagents and Conditions: (a) CDI, N,O-dimethylhydroxylamine hydrochloride, THF, 48 hr, 20%; (b) CDI, N,O-dimethylhydroxylamine hydrochloride, THF, reflux, 2 hr, 50% Scheme 116: Synthesis of the Weinreb amide 338

The Weinreb amide 338 was treated with lithium trimethylsilylacetylide to provide the eynone 337 in an isolated yield of 84% (Scheme 117). The yields however became inconsistent after the initial successful test reactions. Conversion of the amide to the product was observed, but the eynone was isolated in poor yield after workup and purification. We hypothesised that either the acid quench during work up or the acidic nature of silica had a damaging effect on the product. Neutral silica was used in an attempt to stem this loss of material, but with no success, suggesting that the acidic work up was indeed the issue. Analysis of the spectra of the crude material and mass recovery appeared to confirm this hypothesis. Accordingly, alternative routes to the eynone 337 were investigated.

Reagents and Conditions: (a) n-BuLi, trimethylsilylacetylene, −78 °C; then 338, 84% Scheme 117: Synthesis of the alkynone 337

With 337 in hand, the ketone functionality was protected as the corresponding dioxolane 263 (Scheme 118). This particular approach was chosen to avoid the use of protic acids, which may have a deleterious effect on the eynone 337. During column chromatography the product coeluted with 1,2-bis(trimethylsiloxy)ethane, which reduced the yields of subsequent reactions. The dioxolane 263 however could be separated from the reagent with ease by distillation under reduced pressure.

Reagents and Conditions: (a) (TMSOCH2)2, TMSOTf, DCM, −78 °C, 77% Scheme 118: Protection of the alkynone 337 as the ketal

3.1.2 Alternative synthesis of the 1,6-diyne 263 While the approach to the 1,6-diyne 263 through the Weinreb amide did provide some material for further research, it was not reliable. Alternatives were investigated so that the unreliable synthesis of this key intermediate did not inhibit further research. During the synthesis of the alcyopterosins, Witulski required the eynone 344 which was accessed through a Friedel–Crafts reaction between the acyl chloride 343 and BTMSA in the presence 107 of AlCl3 (Scheme 119). This approach was applied to the synthesis of our eynone 337.

Reagents and Conditions: (a) BTMSA, AlCl3, DCM, 0 °C, 94% Scheme 119: Witulski’s synthesis of the eynone 344

Pent-4-ynoyl chloride 345 was synthesised in 79% yield from the carboxylic acid 342 using oxalyl chloride with a catalytic quantity of DMF (Scheme 120). Treatment of the acyl chloride 345 with BTMSA and AlCl3 led to the formation of the ketone 337 (Scheme 120). Although the crude material was ostensibly pure by 1H NMR with excellent mass recovery, isolation of the pure product by column chromatography gave the product in a yield of only 25%. Purification of the crude compound by distillation however provided the desired product in 59% yield. Protection of the eynone 337 as the dioxolane 263 proceeded as previously described in scheme 118.

Reagents and Conditions: (a) (COCl)2, cat. DMF, DCM, 0 °C, 79%; (b) BTMSA, AlCl3, DCM, 0 °C, 59% Scheme 120: Alternative synthesis of the eynone 337

3.1.3 Lability of the trimethylsilyl group on eynone 337 In the Weinreb–Nahm ketone synthesis, we found that the yields varied greatly when the reaction was conducted on a larger scale, but no by-products were isolated during purification. Similarly, when the Friedel–Crafts approach was adopted, purification by chromatography of the crude material led to an isolated yield far below expectations, based upon crude mass recovery and purity of the crude material by 1H NMR. Furthermore, in this case it was noted that a faint second spot appeared once the alkyne 337 had eluted from the column. The fractions containing this faint spot however did not yield a compound once the solvent had been removed. Following these observations, it was proposed that the trimethylsilyl group on the eynone 337 was removed to provide the desilylated alkyne 346 either during work up or upon purification (Scheme 121). The desilylated alkyne was then removed under reduced pressure owing to its volatility, lowering the crude mass recovery.

Scheme 121: Removal of the trimethylsilyl group in the presence of silica or acid

Isobe found that during the synthesis of 8, 11-dideoxytetrodotoxin the trimethylsilyl group was unintentionally removed during the reduction of the eynone 347 (Scheme 122).108 After investigations, it was found that the eynone decomposed when stirring alone in MeOH, before the Luche reduction was carried out. The lability of this eynone 347 appears to support our proposal for the decomposition of 337 in the presence of weakly acidic media.

Reagents and Conditions: (a) NaBH4, CeCl3, MeOH, 0°C Scheme 122: Isobe’s observations on the lability of trimethylsilyl protected eynones

3.1.4 Dioxolane cyclisation precursors While considering the initial retrosynthetic analysis, it was proposed that the dioxolane group may help the thermal cyclisation by influencing the rotamer distribution in favour of the reactive conformer.109,110 This would also avoid the potential lability of the trimethylsilyl protected eynone intermediates, simplifying the synthesis of both the model systems and the aphidicolin core structure.

Reagents and Conditions: (a) n-BuLi, THF, −78 °C; then RCHO; (b) DCE, MW, 200 °C Scheme 123: Proposed cyclisations of dioxolane precursors 335 and 336

First, in order to assess whether the dioxolane 263 could be used as a plug in side chain, we opted to complete a model addition reaction (Scheme 124). The dioxolane was reacted with n-BuLi and the resulting acetylide with cyclohexanecarboxaldehyde to form the propargylic alcohol 351 in a 68% yield.

Reagents and Conditions: (a) n-BuLi, THF, −78°C; then cyclohexanecarboxaldehyde, 68% Scheme 124: Addition of the dioxolane 263 to an aldehyde

The dioxolane 263 was also used to revisit Bieber’s propargyl amine synthesis91 in order to rapidly access the cyclisation precursor 280. The dioxolane 263 reacted with the previously synthesised amine 292 as anticipated, forming the cyclisation precursor 352 in a 34% yield (Scheme 125). This approach significantly reduced the number of steps required to reach a dihydroisoindole precursor.

Reagents and Conditions: (a) CuI, DMSO, 37% aq. formaldehyde, 34% Scheme 125: Synthesis of the dioxolane protected cyclisation precursor 352

Unfortunately, the cyclisation precursor 352 was unchanged after two hours when heated in microwave reactor at 200 °C (Scheme 126). While the protecting group had been switched from a tosyl amine to a methyl amine, it was not identified as the culprit for this unsuccessful cyclisation; instead, the dioxolane protecting group was implicated as the problem.

Reagents and Conditions: (a) DCE, 200 °C Scheme 126: Failed cyclisation of the dioxolane protected cyclisation precursor 352

To evaluate this hypothesis, the previously synthesised ether precursor 31 was protected to provide the dioxolane 322 in a 72% yield (Scheme 127). This dioxolane substrate 322 offered a direct comparison to the successful cyclisation of the ketone 31 described at the start of this project.

Reagents and Conditions: (a) (TMSOCH2)2, TMSOTf, DCM, −78 °C; then NEt3 72% Scheme 127: Protection of the cyclisation substrate 31

When the dioxolane 322 was then heated to 200 °C in DCE for two hours, only trace quantities of the furan 323 were identified in the crude product. The significant reduction in yield however offered a concrete explanation for the poor conversion of the amine substrate 352 to the dihydroisoindole 353. These results throw doubt into our revised approach to the model systems presented in scheme 123, as we had hoped that the presence of the dioxolane protecting group would help the cyclisation, rather than hinder it.

Reagents and Conditions: (a) DCE, epoxyhexane, 200 °C, 10% by 1H NMR Scheme 128: Cyclisation of the dioxolane precursor 322

3.1.5 Deprotection of dioxolane precursors Protic conditions were initially investigated to deprotect the dioxolane 351. This is despite our earlier observations pointing to the potential lability of the TMS group for the product eynone 354 (Table 2).

Reagents and Conditions: (a) See Table 2 Scheme 129: Acidic deprotection of the model addition product 351

Entry Acid Solvent Temperature Yield (%)

1 pTSA acetone R.T N/R

2 pTSA acetone (dried) R.T N/R

3 CSA acetone R.T N/R

4 PPTS acetone R.T N/R

5 PPTS acetone 56 °C N/R

Table 2: Acidic deprotection of the model addition product 351

Surprisingly the acidic conditions investigated did not form the ketone 354. It has been previously observed that dioxolanes and the deprotected product can have the same retention factors by TLC. With this in mind, the results of these experiments were verified by 1H NMR and IR analysis of the crude material. It should be noted that although these conditions did not provide the ketone, the starting material was returned unchanged – no loss of the terminal silane.

While searching for alternative conditions, the report by Hu et al. concerning the neutral deprotection of dioxolanes using iodine in acetone came to our attention.111 When applied to our model system, the ketone 354 was formed in an isolated yield of 60% yield. This initial success was however improved to 80% by heating to 56 °C using a microwave reactor, shortening the reaction time to ten minutes from overnight (Scheme 130).

Reagents and Conditions: (a) I2, acetone, R.T, O/N, 60%; (a) I2, acetone, MW, 56 °C, 80% Scheme 130: Deprotection of the model addition product 351

While these conditions were successful for the deprotection of the model addition product 351, they would not remove the dioxolane group from the amine precursor 352, even at elevated temperatures (Scheme 131).

Reagents and Conditions: (a) I2, acetone, MW, 56 – 110 °C Scheme 131: Attempted deprotection of the dioxolane protected amine cyclisation precursor 352

Rather than continue with the investigations to optimize the synthesis of the amine precursors, our efforts became focused on the model systems described at the beginning of this section, alcohols 331 and 333 (Scheme 132).

Reagents and Conditions: (a) n-BuLi, THF, −78 °C; then aldehyde; (b) I2, acetone Scheme 132: Proposed syntheses of the model systems 331 and 333

3.1.6 The preparation of substrate 331 For the alcohol 331, the aldehyde 356 was needed. Reduction of the commercially available ester 358 was carried out to form the alcohol 359 (Scheme 133). Optimal conditions for the reduction were found to be DIBAL-H in toluene, which formed the alcohol in a yield of 91%. Oxidation of the pentenol 359 was accomplished using the Swern oxidation90 to provide the aldehyde 356 in an 82% yield.

Reagents and Conditions: (a) DIBAL-H, toluene, −78 °C, 91%; or LiAlH4, THF, 0°C, 59% (b) (COCl)2,

DMSO, DCM, −78 °C; then NEt3, 82% Scheme 133: Synthesis of 3,3-dimethylpent-4-en-1-al 356

100

The aldehyde 356 was added to the lithium acetylide of the dioxolane 263 to form the ketal 335 in a 73% yield (Scheme 134). Deprotection of the ketone gave the substrate 331 in a 76% yield, ready for the cyclisation.

Reagents and Conditions: (a) n-BuLi, THF, −78 °C; then 356, 73%; (b) I2, acetone, MW, 56 °C, 76% Scheme 134: Synthesis of the cyclisation precursor 331

It was found that upon heating in a microwave reactor, the alcohol 331 cyclised to the tricyclic enone 332 in a 73% yield (Scheme 135). The cis stereochemistry of the pentanone ring was established through the Karplus equation based on a coupling constant of 7 Hz.112 Unfortunately, we were not able to assign the relative stereochemistry of the TMS group from the spectroscopic data.

Reagents and Conditions: (a) DCE, 200 °C, 73% Scheme 135: Cyclisation of the precursor 331

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To provide a proposal for the relative stereochemistry of the TMS group in the cyclised product 332, we considered the work conducted in the group by Faggiani. As previously highlighted in the introduction, the propargyl alcohol 37 will form the (Z,Z)-exocyclic diene 38 when heated in boiling toluene (Scheme 136).14

Reagents and Conditions: (a) toluene, reflux, 4 hr, 61% Scheme 136: Synthesis of (Z,Z)-exocyclic diene 38

Based on this observation, it was proposed that the substrate 331 will first form the (Z,Z)- exocyclic diene 360 under microwave heating. The diene will then react in a Diels-Alder fashion to provide the tricyclic enone 332 with complete control over the relative stereochemistry (Scheme 137). This will provide the product 332 with TMS group cis to the cyclopentanone ring.

Reagents and Conditions: (a) DCE, 200 °C, 73% Scheme 137: Proposed structure of 332

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3.1.7 Synthesis and cyclisation of the substrate 333 In order to access the required hexenal 357, we decided to investigate a simple two-step homologation sequence to the hexenol 362 from the previously synthesised alcohol 359 (Scheme 138). Conversion of the alcohol 359 to the iodide 361 proceeded in a yield of 97%. Metal-halogen exchange followed by addition of para-formaldehyde should have formed the alcohol 362. Unfortunately, despite the promising 1H NMR and IR spectra of the crude material, the alcohol did not elute during column chromatography.

Reagents and Conditions: (a) pyridine, I2, PPh3, DCM 0 °C, 97%; (b) t-BuLi, THF, pentane, −78 °C; then para- formaldehyde Scheme 138: Attempted two-step homologation of 3,3-dimethylpent-4-en-1-ol 362

In order to successfully complete the synthesis of the aldehyde 357, we decided to avoid the formation of the hexenol 362. Looking towards a direct synthesis of the aldehyde, investigations focused on the possibility of forming the aldehyde 357 through an oxy-Cope rearrangement of the 1,5-hexadiene 365.113 Synthesis of the 1,5-hexadiene proceeded from the reaction between acrolein and the allyl bromide 364 in the presence of zinc.114 After optimization, we found that the neat alcohol 365 rearranged at 230 °C to the aldehyde 357 in a yield of 9% by 1H NMR (Scheme 139).

Reagents and Conditions: (a) Zn, sat. aq. NH4Cl, THF, 80%; (b) neat, MW, 230 °C, 2 hr, 9% Scheme 139: Oxy-Cope rearrangement

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Given the low yield of the oxy-Cope rearrangement, our focus was shifted to the anionic oxy- Cope115 as there is typically a rate enhancement on the order of 1010 to 1017 for the rearragnment.115 Based on the successful results documented during Paquette’s synthesis of Paclitaxel,116 the rearrangement was attempted with KHMDS, rather than the conventional KH (Scheme 140). Despite multiple attempts, aldehyde 357 was not isolated using this strategy. It was hypothesised that the lack of conformational rigidity significantly slowed the reaction, precluding the formation of 357.

Reagents and Conditions: (a) KHMDS, THF, 4 hr, −78 °C to 0 °C; (b) KHMDS, 18-crown-6 THF, 4 hr, −78 °C to 0 °C; (c) KHMDS, THF, 18-crown-6, 4 hr, 0°C to 50 °C Scheme 140: Anionic oxy-Cope rearrangement

Further investigations into the anionic oxy-Cope however were stopped, as an approach being developed in tandem had come to fruition (Scheme 141). In this successful approach, isobutyronitrile was deprotonated with LDA and then reacted with the dioxolane 366. The nitrile 367 was then reduced using DIBAL-H to give the aldehyde 368, which in turn was used to synthesise the olefin 369. Acid hydrolysis of the dioxolane protecting group revealed the aldehyde 357.

Reagents and Conditions: (a) LDA, isobutyronitrile, THF, −78 °C; then 366, 98%; (b) DIBAL-H, DCM, −78

°C, 82%; (c) methyltriphenylphosphonium bromide, n-BuLi, THF, 0 °C; then 368, 69%; (d) THF, H2O, AcOH, 67% Scheme 141: A successful approach to the hexenal 357

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With the aldehyde 357 in hand, the cyclisation substrate 333 was synthesised (Scheme 142). The cyclisation was attempted under standard conditions providing an unknown product as a single spot with a complex set of NMR spectra. The IR spectrum demonstrated a clear shift in the carbonyl peak from 1677 to 1700 cm-1, consistent with the shift observed for the cyclisation of the substrate 331 (1680 to 1695 cm-1). As cyclohexanone has been observed to -1 117 have an IR stretch of 1704 cm in CDCl3, we propose that the second carbonyl stretch lies concurrent with the enone stretch. The TMS group was observed to shift from δ = 0.25 ppm in 333 to δ = 0.14 and 0.09 ppm in the cyclisation product 334, consistent with upfield shift previously observed in the cyclisation of 331.

Reagents and Conditions: (a) n-BuLi, THF, −78 °C; then 358, 68%; (b) I2, acetone, MW, 56 °C, 65%; (c) DCE, MW, 200°C, 40% Scheme 142: Synthesis and attempted cyclisation of the precursor 333

It was our assessment that this unidentified product is a mixture of diastereoisomers of 334, making conclusive analysis difficult due to the overlapping peaks in the NMR spectra (Figure 8).

Figure 8: Possible stereoisomers of the expected cyclisation product 334

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3.1.8 Protection of the hexenol substrate 333 The multiple stereoisomers possible from the cyclisation of 333 and narrow range of chemical shifts made the spectral analysis particularly complex. It was hypothesised that removal of one of the stereocentres in the product will remove this roadblock to analysis. In order to achieve this, the cyclisation of the TBS protected substrate 370 was proposed (Scheme 143).

Reagents and Conditions: (a) TBSOTf, 2,6-lutidine, DCM, −78 °C Scheme 143: Protection and cyclisation of chiral propargyl alcohol substrates

Synthesis of the TBS silyl ether however proved to be more difficult that initially envisioned. Protection of the propargyl alcohol with TBSOTf and 2,6-lutidine provided the TBS silyl ether 370 as the sole crude product, with no evidence of unreacted starting material. Purification of this crude product by column chromatography led to the co-elution of both the desired product 370 and the terminal alkyne 372; 372 was not present in the crude material. Despite multiple purification attempts, it was not possible to separate the TBS ether 370 from the hydrolysed material 372.

Reagents and Conditions: TBSOTf, 2,6-lutidine, DCM, −78 °C, 54% (combined 370 and 372) Scheme 144: TBS protection of the precursor 333

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Surprised by this result, an alternative approach was adopted where the alcohol was protected before removal of the dioxolane protecting group. Protection of the alcohol 336 using the same conditions as for 333 provided the silyl ether 373 in 65% yield (Scheme 145). In direct comparison to the protection of 333, there was no indication of decomposition during purification.

Reagents and Conditions: TBSOTf, 2,6-lutidine, DCM, −78 °C, 65% Scheme 145: TBS protection of 326

Following the precedent set by earlier cyclisation substrates, deprotection of 373 was accomplished under microwave heating with iodine to form the ketone 370 as the sole product in the crude material (Scheme 146). Purification by column chromatography of the crude product again led to the co-elution of both 370 and the alkyne 372, even though the alkyne 372 was not present in the crude spectra.

Reagents and Conditions: I2, acetone, 56 °C, MW, 71% (combined 370 and 372) Scheme 146: Deprotection of the silyl ether 373

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The results of both strategies to ketone 370 indicate that TMS group is particularly sensitive to purification by column chromatography, using either regular silica or neutral silica. This result was unexpected, given the successful deprotection of 335 and 336 (Scheme 147). The only notable difference between the successful deprotection substrates and the substrate which decomposes on purification is the presence of a TBS protecting group on the propargyl alcohol. This line of investigation and the synthesis of chiral propargyl alcohols, presented briefly in the next section (3.1.9), were stopped following the unsuccessful isolation of 370 in order to focus on the aphidicolin cyclisation substrate 261.

Reagents and Conditions: (a) I2, acetone, 56 °C, MW, 76%; (b) I2, acetone, 56 °C, MW, 65%; (c) I2, acetone, 56 °C, MW, 71% (combined 370 and 372) Scheme 147

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3.1.9 Synthesis of chiral substrates At this time, investigations into the synthesis of chiral propargyl alcohol substrates were also underway. It was our expectation that protection of the homochiral alcohol followed by cyclisation, would form a homochiral allene intermediate, controlling the facial selectivity of the subsequent Diels-Alder reaction (Scheme 148).

Reagents and Conditions: (a) TBSOTf, 2,6-lutidine, DCM, −78 °C Scheme 148: Protection and cyclisation of chiral propargyl alcohol substrates

While investigating methods for the synthesis of propargyl alcohols as single enantiomers, Carreira's approach using zinc(II) triflate in the presence of optically pure N-methylephedrine came to our attention (Scheme 149).118

Reagents and Conditions: (a) Zn(OTf)2, (+)-NME, NEt3; then 374 and 375, 98% yield, 99% ee Scheme 149: Synthesis of the propargyl alcohol 376

109

Based on this approach, the synthesis (+)-351 in a 35% yield was successfully achieved from the reaction of 263 with cyclohexanecarboxaldehyde 375 under Carreira's conditions (Scheme 150). While initial attempts did not form the product, it was found that the commercial source of Zn(OTf)2 was of particular importance, as previously suggested by one of Carreira's research students.119 It is of note that other researchers have had issues utilizing Carreira's chiral propargyl alcohol synthesis with aliphatic alkynes.120–124

Reagents and Conditions: (a) Zn(OTf)2, (−)-NME, NEt3; then 375 and 326, 35% Scheme 150: Enantioselective synthesis of the propargyl alcohol (+)-351

Derivatization of (+)-351 was required in order to ascertain the enantiomeric excess of this reaction; (+)-351 was converted to the acetate (−)-377 in a 75% yield (Scheme 151). When subjected to chiral shift experiments with Eu(hfc)3, the enantiomeric excess of (−)-377 was determined to be 90%.

Reagents and Conditions: (a) Ac2O, NEt3, DMAP, DCM, 0 °C, 75% Scheme 151: Derivatization of (+)-351 to acetate (-)-377

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3.1.10 Future applications of these model studies Two new drimane sesquiterpenoids have been recently isolated from the extremophilic fungus Penicillium solutium that share a similar substructure to the compounds produced during the model studies (Figure 9).125 These new drimane sesquiterpenoids, known as berkedrimanes A and B, inhibit caspase-1 and -3 enzymes which are potential targets for therapies in a number of inflammatory diseases, including Alzheimer’s.126 The absolute stereochemistry of the berkedrimanes is not currently known, although the α-amino acid side chain has been confirmed as L-valine through degradation studies.

Figure 9: Berkedrimane A and B

Based on the model studies completed in this thesis, we propose that the cyclisation substrate 380 should be constructed with the aim of completing the synthesis of berkedrimanes A and B. Based on substrate control previously observed for Diels-Alder reactions,127,128 it is expected that the homochiral substrate 380 will cyclise to provide the lactone 381 as the major isomer (Scheme 151).

Reagents and Conditions: (a) DCE, 200 °C Scheme 151: Cyclisation of the propargyl alcohol 380

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The homochiral alcohol 384 has been previously synthesised in an 82% yield with an e.e of 95% by Ramachandran using the borane 383 (Scheme 152).129 Protection of the secondary alcohol, followed by deprotection of the PMB ether, and oxidation will provide the aldehyde 385, ready for the synthesis of the propargyl alcohol cyclisation substrate 380.

Reagents and Conditions: (a) Et2O, pentane, −100 °C; then NaOH, H2O2, 82%, e.e. 95% Scheme 152: Proposed synthesis of the aldehyde 385

Stereoselective methylation and then reduction of the tricycle 381 will yield the homoallylic alcohol 386, ready for epoxidation and esterification to form the advanced intermediate 387 (Scheme 153). The epoxide will then be opened with a source of fluoride to provide the allylic alcohol 388. From this common intermediate, deprotection and strategic use of deoxygenation protocols will provide either berkedrimane A 378 or berkedrimane B 379.

Reagents and Conditions: (a) KH, MeI, THF; (b) LiAlH4, THF; (c) VO(acac)2, t-BuOOH; (d) CDI, L-valine; (e) TBAF, THF Scheme 153: Proposal for the synthesis of Berkedrimane A and B from 381

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3.2 The application of the Parsons-Board-Waters methodology to aphidicolin

As previously stated in section 1.8, our approach to aphidicolin focuses on the application of the Parsons-Board-Waters methodology to the synthesis of the tricyclic intermediate 260 from the ketone precursor 261 (Scheme 72). With the successful extension of the Parsons- Board-Waters methodology to ketone linked 1,6-diynes, and the application of this chemistry to the model substrates described in the previous section, the synthesis of the ketone precursor 261 was investigated.

Scheme 72: Proposed cyclisation of the ketone 261 to the tricyclic product 260

Following the observations documented during the model studies, it is expected that addition of the previously synthesised 1,6-diyne 263 to the aldehyde 262 would form the ketone precursor 261, after removal of the dioxolane protecting group (Scheme 154). The next stage of our studies on aphidicolin focused on the synthesis of this key aldehyde 262.

Reagents and Conditions: (a) n-BuLi, THF, −78 °C; then 262; (b) I2, acetone, MW, 56 °C Scheme 154: Proposed synthesis of the ketone precursor 261

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3.2.1 Diastereoselective approach to aldehyde 262 Given the similarity in structure to our target aldehyde, a report by Takai and Utimoto concerning the synthesis of 1,3-diols was viewed with interest. In this report, the authors documented the diastereoselective synthesis of 1,3-diols from butadiene monoepoxide 390 and a series aldehydes in the presence of chromium(II) chloride (Scheme 155).130 Of particular note was the identical stereochemical relationship and comparable substitution patterns of the products, in combination with the high diastereomeric ratios and procedural simplicity.

Reagents and Conditions: (a) CrCl2, LiI, THF, 0 °C, 95%, dr: 98:2 Scheme 155: Takai and Utimoto’s stereoselective synthesis of 1,3-diols130

Following the precedent set by this report, it was hypothesised that the synthesis of the aldehyde 262 would be achieved from the 1,3-diol 392, which in turn would be accessible from the reaction between butadiene monoepoxide 390 and 382 using this methodology (Scheme 156). While an enantioselective route to the aldehyde 262 had initially been envisioned for this project, the possibility of forming the aldehyde in a diastereoselective fashion using only a few steps was an attractive proposition.

Scheme 156: Retrosynthesis of the aldehyde 262 using Takai and Utimoto’s chemistry

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To test this methodology, the aldehyde 382 was required. 1,3-Propane diol was protected to provide the benzyl ether 394 in a 40% yield and then oxidised under the Swern conditions90 to form 382 in a 93% yield (Scheme 157). With the aldehyde in hand, the application of Takai and Utimoto’s methodology was investigated. However despite our best efforts, treatment of the aldehyde 382 with butadiene monoepoxide 390 in the presence of CrCl2 did not form the expected 1,3-diol 392. From the 1H NMR spectrum of the crude product, it was possible to ascertain that 392 was not present as there was no evidence of the diagnostic vinyl peaks. After this initial attempt to synthesise the 1,3-diol in a diastereoselective fashion, it was decided to solely develop an enantioselective route, given the time remaining for this project.

Reagents and Conditions: (a) NaH, PMBCl, TBAI, 54%; (b) (COCl)2, DMSO, DCM, −78 °C; NEt3, 93%; (c)

382, CrCl2, LiI, THF, 0 °C Scheme 157: Synthesis of the aldehyde 382 and attempted stereoselective synthesis of the 1,3-diol 392

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3.2.2 Organocuprate approach to the 1,3-diol 392 In order to achieve the synthesis of the 1,3-diol 392 in an enantioselective fashion, we turned our attention to the work conducted by Kishi on the stereo- and regioselective opening of epoxy alcohols with organocuprates.131 Of particular relevance to our studies on aphidicolin was the report concerning the exclusive formation of the 1,3-diol 396 from the racemic epoxide 395 with divinylcuprate (Scheme 158).

Reagents and Conditions: (a) vinylmagnesium bromide, CuI, Et2O, −20 °C, 90% Scheme 158: Kishi’s synthesis of selective synthesis of the 1,3-diol 396

This approach was also applied to the synthesis of the enantioenriched 1,3-diol 398 during Ganem’s studies on the total synthesis of virgniamycin M.132 In this report the regioselective opening of the Sharpless asymmetric epoxidation product 397 was observed with dimethylcuprate (Scheme 159). Notably, the diol was formed as the exclusive product of the reaction in an 87% yield.

Reagents and Conditions: (a) Li(CH3)2Cu, Et2O, −20 °C, 87% Scheme 159: Ganem’s synthesis of the enantioenriched 1,3-diol 398

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Based upon these previous observations, it was proposed that synthesis of the 1,3-diol 392 would be achieved from the selective opening of the enantiopure epoxide 399, the product of a Sharpless asymmetric epoxidation reaction133 (Scheme 160). In principle, if a mixture of isomers is obtained, the regioselectivity of this process may be improved through selective use of solvents as it has previously been found that the combination of THF-DMEU favours the formation of 1,3-diols over the isomeric 1,2-diols.134

Reagents and Conditions: (a) vinylmagnesium bromide, CuI, Et2O, −20 °C, 90% Scheme 160: Proposed synthesis of the required 1,3-diol 392 from the enantiopure epoxide 399

The substrate for the asymmetric epoxidation, the allylic alcohol 400, would be accessible from the (Z)-allylic ester 401. Stereoselective synthesis of the (Z)-unsaturated ester 401 will be accomplished from the previously synthesised aldehyde 382 through either the Still- Gernnari modification of Horner–Wadsworth–Emmons reaction135 or the Ando modification of the Horner–Wadsworth–Emmons reaction.136,137

Scheme 161: Retrosynthesis of the epoxy alcohol 399

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3.2.2.1 Synthesis of the (Z)-unsaturated ester 401 The Horner-Wadsworth-Emmons (HWE) reaction typically provides an (E)-unsaturated ester product.138–140 However, there have been two notable modifications of this reaction that allow for the formation of the (Z)-unsaturated esters – the Still-Gernnari modification135 and the Ando modification136,137. In our synthetic studies, it was decided to attempt the Ando modification of the HWE reaction first as it does not require the use of the expensive and toxic 18-crown-6, while still providing excellent selectivity. While Ando’s early work focused on the synthesis of disubstituted (Z)-unsaturated esters,136 it was later found that this method could also be applied to the synthesis of trisubstituted (Z)-unsaturated esters by using ethyl 2-(diphenoxyphosphoryl)propanoate 402.137

Reagents and Conditions: (a) Triton B, benzaldehyde, THF, −78 °C, 100%, (Z:E) 91:9 Scheme 162: Ando’s (Z)-Selective Horner-Wadsworth-Emmons Reaction

Before investigating Ando’s modification of the HWE reaction, the PMB protection of 1,3- propanediol was revaluated as the conditions described earlier provided an impure product after chromatography. This impurity was not observable by 1H NMR, but dramatically influenced the yield of the Swern oxidation. As an alternative, chemoselective reduction of the acetal 404, formed by the condensation of p-anisaldehyde with 1,3-propanediol, provided the alcohol 394 (Scheme 163). This alternative route to the alcohol 394 was used exclusively to avoid the previously observed inconsistent oxidation yields.

Reagents and Conditions: (a) p-anisaldehyde, toluene, p-TsOH, 90%; (b) DIBAL-H, toluene, −10 °C, 86% Scheme 163: Revised synthesis of the alcohol 394

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Following the procedure reported by Ando, the required phosphonate 402 for the modified HWE reaction was synthesised in a two-step sequence from triethylphosphonoacetate 405 (Scheme 164).137 First, triethylphosphonoacetate 405 was chlorinated and then treated with phenol and triethylamine to give the diphenylphosphonate 406. Methylation of the 406 provided the Ando reagent in an overall yield of 16%, significantly lower than the overall yield of 40% reported in the original publication.137 One of the complications with this approach to 402 was the final purification step as the methylation reaction produced the permethylated phosphonate, as well as the desired compound 402, which had a similar retention factor. Furthermore, unreacted starting material was also present in the crude, which had a similar retention factor to 402. These issues with purification reduced the overall isolated yield of the process.

t Reagents and Conditions: (a) PCl5; then PhOH, NEt3, PhH, 39%; (b) BuOK, THF, −10 °C; then MeI, 40% Scheme 164: Synthesis of the Ando reagent 402

With the diphenylphosphonate 402 in hand, the Ando methodology was applied to the PMB protected aldehyde 382. The reaction conditions were taken from a later paper where the author used DBU in conjunction with sodium iodide to deprotonate the phosphonate 402.141 It was found that these conditions provided the desired (Z)-unsaturated ester 401 in a 67% yield (Scheme 165). The (E)-unsaturated ester was formed as a separable minor product of this reaction in an 11% yield, providing an E/Z ratio of 11:85.

Reagents and Conditions: (a) DBU, NaI, THF, −78 °C, 67% Scheme 165: Synthesis of the (Z)-unsaturated ester 401

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3.2.2.2 Alternative preparation of the phosphonate 402 As previously noted the overall yield for the synthesis of the phosphonate 402 was significantly lower than the yield reported by Ando.137 Furthermore, purification of the crude product by column chromatography was complicated by the similar retention factors of the starting material, product and permethylated by-product. For these reasons an alternative approach was envisioned where the methylation reaction was no longer necessary. To accomplish this, the substituted ethyl propionate 408 was successfully synthesised through a Michaelis–Arbuzov reaction142,143 between triethylphosphite and ethyl 2-bromopropionate (Scheme 166). Conversion of this propionate to the required diphenylphosphonate 402 was accomplished following the route previously described in scheme 164. This route vastly simplifies the purification steps, facilitating the synthesis of 402 on a 50 mmol scale.

Reagents and Conditions: (a) triethyl phosphite, 130 °C, 95%; (b) PCl5, 0 °C to 70 °C ; then PhOH, PhH, NEt3, 0 °C, 33% (over two steps) Scheme 166: Improved synthesis of the phosphonate 402

To further improve the synthesis, the direct reaction of diphenylphosphite with ethyl 2- bromopropionate in the presence of triethylamine was also attempted (Scheme 167). This approach however provided the required substituted propionate only in a yield of 9%. Given the operational simplicity of this procedure and the abundance of the starting materials, the reaction was subsequently attempted on a large scale, 100 mmol. This large scale reaction provided the product in a reduced yield of 3%.

Reagents and Conditions: (a) diphenylphosphite, NEt3, DCM, 9% Scheme 167: Attempted single step synthesis of the phosphonate 402

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3.2.2.3 Application of organocuprate chemistry to the synthesis of the 1,3-diol 392 The (Z)-unsaturated ester 401 was successfully reduced to the (Z)-allylic alcohol 400 required for studies on the Sharpless asymmetric epoxidation133 (Scheme 168). While initial studies only produced the epoxy alcohol 399 in a yield of 30-50%, it was found that increasing the overnight reaction temperature by 5 °C to −15 °C significantly improved the isolated yield. Unfortunately, it was not possible to determine the enantiomeric excess of this epoxy alcohol using lanthanide shift reagents; instead, it was necessary to synthesise the acetate derivative for analysis.

i t Reagents and Conditions: (a) DIBAL-H, toluene, −78 °C, 85%; (b) Ti(O Pr)4, (+)-DET, BuOOH, 4A sieves, −20 °C to −15 °C, DCM, 85% Scheme 168: Enantioselective synthesis of the epoxide 399

The racemic epoxy alcohol (±)-399 needed for calibration of the chiral shift experiments was synthesised from allylic alcohol 400 using MCPBA (Scheme 169). At this stage, it was confirmed that none of the 1H NMR peaks of the epoxy alcohol would resolve using the variety of lanthanide shift reagents readily available in the lab. The racemic acetate derivative (±)-409, synthesised from this epoxy alcohol (±)-399, was found to resolve well with

Eu(hfc)3. Specifically, it was found that the methyl of the acetate group split into two peaks with a relative ratio of 1:1 as expected for this racemic compound.

Reagents and Conditions: (a) MCPBA, NaHCO3, DCM, 0 °C, 66%; (b) Ac2O, NEt3, DMAP, DCM, 0 °C, 65% Scheme 169: Synthesis of the racemic epoxide (±)-399 and the acetate derivative (±)-409

121

With the successful resolution of acetate (±)-409 using Eu(hfc)3, the acetate of the enantiomerically enriched epoxide 399 was formed in order to ascertain the enantiomeric excess of the Sharpless asymmetric epoxidation reaction. When the chiral shift experiments were conducted, the enantiomeric ratio was found to be 93:7, corresponding to an ee of 86%.

Reagents and Conditions: (a) Ac2O, NEt3, DMAP, DCM, 0 °C, 74% Scheme 170: Synthesis of the homochiral acetate derivative 409

Treatment of the epoxy alcohol 399 with the organocuprate of vinylmagnesium bromide formed the 1,2-diol 410 exclusively in a yield of 23% (Scheme 171). Increasing the number of equivalents of the divinylcuprate improved the yield of the 1,2-diol, but did not produce any of the desired regioisomer 392. Protection of the diol 410 gave the ketal 411, confirming that the 1,2-diol had been formed. With zero evidence of the desired regioisomer 392, it was decided not pursue further investigations into the application of organocuprates on the stereoselective opening of this epoxy alcohol 399.

Reagents and Conditions: (a) CuI, vinylmagnesium bromide, THF, −20 °C, yields are given on the scheme; (b) 2,2-dimethoxypropane, PPTS, DCM, 88% Scheme 171: Opening of the epoxy alcohol 399 with divinylcuprate

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3.2.3 Semi-pinacol rearrangement of epoxy alcohols Suzuki, Tsuchihashi and Yamamoto found that when combined with the Sharpless asymmetric epoxidation the semi-pinacol rearrangement is a powerful tool in the asymmetric synthesis of aldol products (Scheme 172).144 The semi-pinacol rearrangement of epoxy alcohols and their related silyl ethers have since been used to produce asymmetric stereodefined quaternary carbon centres in a number of total syntheses.145–148

Reagents and Conditions: (a) BF3.OEt2, DCM, −78 °C, 85% Scheme 172: Suzuki, Tsuchihashi and Yamamoto’s studies on the semi-pinacol rearrangement

Given the failure of the organocuprate approach, a new strategy based on Suzuki, Tsuchihashi and Yamamoto’s studies was pursued. This proposal utilizes the previously synthesised enantiopure epoxide 399 formed during the Sharpless asymmetric epoxidation to form the epoxy alcohol 414. It was expected that the epoxy alcohol 414 would then rearrange stereospecifically to form the β-hydroxy aldehyde 415 (Scheme 173). Reduction of 415 would provide 392 with the correct stereochemistry required for our synthesis of aphidicolin.

Scheme 173: Proposed rearrangement of the allylic alcohol 414

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3.2.4 Synthesis and rearrangement of the allylic alcohol 414 The allylic alcohol 414 was synthesised via a two-step sequence from the epoxide 399 (Scheme 174). 399 was first oxidised to the aldehyde 416 using Swern conditions and then reacted with vinyl magnesium bromide to provide the required allylic alcohol 414. The allylic alcohol was isolated as a pair of separable diastereomers in a diastereomeric ratio of 1:1. At this stage, it was decided to keep the diastereomers separate in order to assess whether the stereochemistry of the alcohol would affect the rearrangement.

Reagents and Conditions: (a) (COCl)2, DMSO, NEt3, DCM, −78 °C, 96%; (b) vinylmagnesium bromide, THF, −20 °C, 83%, dr = 1:0.9 Scheme 174: Synthesis of the allylic alcohol 414

Treatment of the allylic alcohol 414 with boron trifluoride however did not yield the β- hydroxy aldehyde 415 as expected (Scheme 175). From the 1H NMR spectra, it was found that there was significant decomposition of the starting material under these conditions. In particular it was found that the peaks corresponding to the PMB protecting group were no longer present. Distillation of the BF3.Et2O and reduction of the reaction temperature did not improve the result. Furthermore, there was no discernible difference between the reactivity of the two isomers.

Reagents and Conditions: (a) BF3.Et2O, DCM, −50 °C; (b) BF3.Et2O, DCM, −78 °C Scheme 175: Semi Pinacol rearrangement of the allylic alcohol 414

124

3.2.5 Synthesis and rearrangement of the silyl ether 417

In order to examine the use of TiCl4 as the Lewis acid for this reaction it was necessary to synthesise the epoxy silyl ether 417. Initial investigations into the synthesis of 417 failed due to the use of TMSOTf; it been noted in the literature that the presence of the PMB protecting group precludes the use of TMSOTf due to exchange with the protecting group.149 Protection of the allylic alcohol 414 however was achieved by using an excess of TMSCl and imidazole in DCM (Scheme 176). Crucially, the two epimers of 414 needed to be protected separately as they were not separable by column chromatography after the TMS protection.

Reagents and Conditions: (a) TMSCl, imidazole, DCM, 95% Scheme 176: Synthesis of the TMS ether 417

Application of the semi-pinacol rearrangement to the silyl ether 417 failed to provide the product 415 for either epimer (Scheme 177). Similar to the attempted BF3.Et2O mediated rearrangement, there was no presence of either alkene or the aldehyde functionality in the 1H NMR and the integration of the aromatic peaks no longer had any correlation to the PMB protecting group. Encouragingly, the TMS group was no longer present in the crude spectra. It was hypothesised that the reaction conditions were incompatible with this particular protecting group strategy, given by the consistent decomposition under the action of Lewis acids.

Reagents and Conditions: (a) TiCl4, DCM, −78 °C Scheme 177: Semi Pinacol rearrangement of the trimethylsilyl ether 417

125

3.2.6 New protecting group strategy Following the unsuccessful application of the semi-pinacol rearrangement to the PMB protected substrate 414 and 417, it was hypothesised that the protecting group strategy that had been adopted may not be suitable for this reaction. Further investigation into the semi- pinacol rearrangement of epoxy silyl ethers revealed that Cha had used this approach in his synthesis of the (+)-asteltoxin 418.150 Cha et al. synthesised the bis-(tetrahydrofuran) core structure from the stereodefined tetrahydrofuran 420, which in turn was accessible from the hydroxy aldehyde 421 (Scheme 178).

Scheme 178: Cha’s retrosynthetic analysis of (+)-asteltoxin

The synthesis of the key intermediate 421 was accomplished via a semi-pinacol rearrangement of the silyl epoxy alcohol 422 with TiCl4 (Scheme 179). The authors found that the product 421 containing the key quaternary stereocenter was formed exclusively in a 96% yield. The β-hydroxy aldehyde was taken forward to successfully complete the synthesis the tetrahydrofuran core 420.

Reagents and Conditions: (a) TiCl4, DCM, −78 °C, 96% Scheme 179: Proposed rearrangement of the allylic alcohol 422

126

It was proposed that the successful synthesis of the 1,3-diol would in fact arise from the application of the semi pinacol rearrangement to the TIPS protected epoxy silyl ether 423 (Scheme 180), based on the success of Cha’s TIPS protected substrate 422. The success of this route would add credence to our proposal that the PMB protecting group is in fact unstable under these conditions.

Reagents and Conditions: (a) TiCl4, DCM, −78 °C; (b) NaBH4, MeOH Scheme 180: Proposed rearrangement of the epoxy silyl ether 423

Our attempt to synthesise the TIPS protected semi-pinacol substrate 423 directly from the PMB substrate 417 failed (Scheme 181). The deprotection of PMB ether under standard conditions151,152 failed to provide the alcohol 426. As there was very little lead material at this time, the synthesis of the epoxy silyl ether 423 was therefore attempted from 1,3-propanediol using the chemistry developed for the PMB protected substrate 417.

Reagents and Conditions: (a) DDQ, H2O, DCM, 0 °C; (b) TIPSCl, imidazole, DCM, DMAP Scheme 181: Unsuccesful protecting group exchange

127

3.2.7 Synthesis of the TIPS protected semi-pinacol substrate 423 It was expected that the previously disclosed route to the PMB protected semi-pinacol substrate 417 would be used with minimal modification. It was however decided to investigate the application of ozonolysis to the synthesis of the aldehyde 429, as previously this approach would have been incompatible with the PMB protecting group. In this alternative strategy, 3-buten-1-ol was protected as the corresponding silyl ether 428 in an 86% yield, and then ozonized to provide 429 in an overall yield of 84% (Scheme 182).

Reagents and Conditions: (a) TIPSCl, imidazole, DCM, 0 °C, 86%; (b) O3/O2, DCM MeOH, −78 °C; then DMS, R.T, 97% Scheme 182: Synthesis of the aldehyde 429

Treatment of the aldehyde 429 with the previously synthesised phosphonate 402 formed the (Z)-unsaturated ester 430 (Scheme 183). Unlike the PMB protected (Z)-unsaturated ester 401, the desired (Z)-unsaturated ester 430 was inseparable from the minor (E)-isomer. Reduction of ester 430 to the allylic alcohol 431 proceeded in an 80% yield. Unfortunately, like the unsaturated ester, 431 was still inseparable from the minor isomer.

Reagents and Conditions: (a) DBU, NaI, THF, −78 °C, 71%; (b) DIBAL-H, toluene, −78 °C, 80% Scheme 183: Synthesis of the (Z)-allylic alcohol 431

128

Sharpless asymmetric epoxidation of the allylic alcohol 431 formed the epoxy alcohol 432 (Scheme 184). Careful choice of chromatography solvents allowed for the separation of the epoxy alcohol 432 from the corresponding minor product stereoisomer present from the Ando modified HWE reaction, providing the epoxide 432 in an isolated yield of 83%.

i t Reagents and Conditions: (a) Ti(O Pr)4, (+)-DET, BuOOH, 4A sieves, −20 °C to −15 °C, DCM, 83% (432) Scheme 184: Enantioselective synthesis of the epoxide 432

Treatment of the epoxy alcohol 432 with acetic anhydride and triethylamine formed the acetate 434, which was subjected to a series of chiral shift experiments (Scheme 185). It was found that Eu(hfc)3 provided good separation of the acetate peaks for each enantiomer, allowing the enantiomeric excess to be determined as 88%.

Reagents and Conditions: (a) Ac2O, NEt3, DMAP, DCM, 0 °C, 71% Scheme 185: Synthesis of the homochiral acetate derivative 434

129

Oxidation of the epoxy alcohol 432, followed by the addition of the vinyl magnesium bromide to the crude product, formed the allylic alcohol 435 in a yield of 48% over two steps. The two epimers were separable and formed in a ratio of 1:1. The first epimer from the column will be referred to as 435a, and the more polar epimer referred to as 435b. Both epimers were subjected separately to TMS protection conditions to provide the epoxy silyl ether 423a from 435a, and 423b from 435b in a yield of 95% and 90% respectively.

Reagents and Conditions: (a) (COCl)2, DMSO, DCM, −78 °C; then NEt3; (b) vinylmagnesium bromide, THF, −20 °C, 48% (over two steps), dr = 1:1; (c) TMSCl, imidazole, DCM, 90-95% Scheme 186: Synthesis of the TIPS protected epoxy silyl ether 423

3.2.8 Semi-pinacol rearrangement of the epoxy silyl ether 423 With the semi-pinacol substrates 423a and 423b in hand, the rearrangement was attempted.

The rearrangement of the first substrate, 423a, with TiCl4 in DCM at −78 °C provided two new aldehyde products (Scheme 187). It was immediately found, however, that both unknown products were not stable on silica, and it was therefore not possible to purify the crude material to obtain pure samples of each aldehyde for further analysis.

1 Reagents and Conditions: (a) TiCl4, DCM, −78 °C, quantitative conversion by H NMR Scheme 187: Rearrangement of the epoxy silyl ether 423a

130

The second semi-pinacol substrate 423b provided exclusively the expected β-hydroxy aldehyde 436 under the same reactions conditions (Scheme 188). In this instance, it was possible to conclusively identify the product aldehyde 436 without purification of the crude material as the transformation was exceptionally clean. An isolated yield was again not possible due to the issues with purifying β-hydroxy aldehydes by column chromatography.

1 Reagents and Conditions: (a) TiCl4, DCM, −78 °C, quantitative conversion by H NMR Scheme 188: Rearrangement of the epoxy silyl ether 423b

By comparing the spectra of the crude β-hydroxy aldehyde 436 from this rearrangement of 423b (Scheme 188) with the unknown crude mixture (Scheme 187), it was possible to conclusively identify the presence of the expected product 436. After the first of the two unknowns had been identified, it was possible to conclude through further analysis that the second compound present in the crude mixture was in fact the diastereoisomer 437 (Scheme 189). The ratio of products was determined to be 2:1.

Reagents and Conditions: (a) TiCl4, DCM, −78 °C Scheme 189: Rearrangement of the epoxy silyl ether 423a

131

It has been noted previously in a letter by Suzuki and Tsuchihashi that cis semi-pinacol substrates do not necessarily rearrange stereospecifically, instead providing a mixture of diastereomeric products.153 In the case shown below, the trans substrate 438 rearranges cleanly to provide the keto alcohol 439 as the exclusive product in a yield of 85%; whereas the cis isomer provides a mixture of keto alcohol products, the expected product 441 in a 87% yield and the isomeric 439 in a 11% yield (Scheme 190).

Reagents and Conditions: (a) BF3.Et2O, DCM, −78 °C, 85%; (b) BF3.Et2O, DCM, −78 °C, 87% (441), 11% (439) Scheme 190: Reduced selectivity for substrate 440

In order for the toluene group to migrate stereospecifically, an antiperiplanar relationship between the migrating group bond and the epoxide bond is required. This would be the mechanism of formation for the products 439 and 441. For the formation of 439 from the cis substrate 440, this stereospecific migration pathway has not been followed. Suzuki and Tsuchihashi concluded that there is steric interaction between the substituents on the cis substrate that inhibits the molecule from adopting the required conformation for the migration, eroding the selectivity.153 We proposed that the epoxide 440 opens under the action of BF3.Et2O, forming a tertiary cationic intermediate 442, which can then be intercepted from either face by the tolyl migrating group to form 439 (Scheme 191).

Scheme 191: Loss of stereospecificity for the cis substrate 440

132

Based on this proposed mechanism, our reaction conditions were modified to improve the selectivity of the rearrangement (Scheme 192). Decreasing the reaction temperature was found to consistently produce more of the undesired isomer 437. The increased formation of 437 can be accounted for by a reduction in population of the conformer containing the required antiperiplanar relationship due to insufficient thermal energy to overcome the unfavourable steric interactions. It was reasoned that a reduction in solvent polarity would destabilise the deleterious formation of the cationic intermediate which leads to 437. Toluene was found to offer superior results to DCM, forming the products in an improved ratio of 86:14 (Entry 4, Table 3). Hexane offered comparable but slightly poorer results to toluene, forming the aldehydes in a ratio of 80:20. At this stage in the investigations, TiCl4 was being used as a 1M solution in DCM; to reduce the polarity of the reaction medium further, we opted to move to a freshly prepared 1M solution in toluene. Unfortunately, this provided products 436 and 437 in only a 34% yield by 1H NMR. Further investigations were suspended while the subsequent steps along this route were investigated.

Reagents and Conditions: (a) TiCl4, table 3 Scheme 192: Rearrangement of the epoxy silyl ether 423a

Temperature Reaction TiCl4 Ratio of products Conversion to Entry (°C) solvent solvent (436:437) aldehyde products 1 −78 DCM DCM 67:33 quant. 2 −90 DCM DCM 62:38 quant. 3 −100 DCM DCM 64:36 quant. 4 −78 toluene DCM 86:14 quant. 5 −78 hexane DCM 80:20 quant. 6 −78 toluene toluene 87:13 34%

Table 3: Reaction conditions for the rearrangement of the epoxy silyl ether 423a

133

3.2.9 Tandem rearrangement and reduction of the epoxy silyl ether 423 With the improved selectivity of the substrate 423b rearrangement to the aldehyde, it was decided to investigate a one pot procedure to provide the 1,3-diol 425 from the epoxy silyl ether substrates 423a and 423b. This investigation was prompted by the unsuccessful purification of the β-hydroxy aldehyde products using conventional and neutral silica. It was proposed that the addition of Et3SiH to the crude reaction mixture would reduce the aldehyde providing the 1,3-diol 425 in one step from the epoxy silyl ether 423 (Scheme 193).

Reagents and Conditions: (a) TiCl4, toluene, −78 °C; then Et3SiH Scheme 193: Proposed tandem rearrangement and reduction of the epoxy silyl ether 423

Encouragingly, we found that the epoxy silyl ether 423b underwent the rearrangement and concomitant reduction to provide the 1,3-diol 425 (Scheme 194). The tandem rearrangement and reduction was also completed on the mixture of epimers, 423a and 423b, to provide 425 in 40% yield with the inseparable diastereoisomer 443.

Reagents and Conditions: (a) TiCl4, DCM, −78 °C; then Et3SiH, 46%; (b) TiCl4, toluene, −78 °C; then Et3SiH, 40%, dr = 4:1 Scheme 194: Successful tandem rearrangement and reduction of the epoxy silyl ether 423

134

The yield of this process was lower than has been expected based upon crude mass recovery and purity by spectroscopic measures. To stem this perceived loss of material, the tandem rearrangement and reduction was repeated with the substrate 423b, and the crude 1,3-diol product was immediately protected as the dioxolane 444 (Scheme 195). This approach provided the product 444 in an overall yield of 60% from the epoxy silyl ether 423b.

Reagents and Conditions: (a) TiCl4, DCM, −78 °C; then Et3SiH; (b) 2,2-dimethoxypropane, PPTS, DCM, 60% (over two steps) Scheme 195: Protection of the crude 1,3-diol

When this approach was applied to the mixture of epimers, the dioxolanes 444 and 445 were isolated in a combined yield of 54% with a diastereomeric ratio of 9:1 (Scheme 196). The diastereomeric dioxolanes 444 and 445 were not separable by column chromatography, as had been expected, precluding the isolation of the desired dioxolane 444 as a single isomer.

Reagents and Conditions: (a) TiCl4, DCM, −78 °C; then Et3SiH; (b) 2,2-dimethoxypropane, PPTS, DCM, 54% (over two steps) Scheme 196: Protection of the crude 1,3-diol

135

3.2.10 Future studies on aphidicolin With the successful synthesis of the dioxolane 444, it is expected that the synthesis of the aphidicolin cyclisation precursor 261 will be easily accessed by following the chemistry investigated for the model systems (Scheme 197).

Reagents and Conditions: (a) TBAF, THF; (b) DMPI, DCM, 0 °C; (c) n-BuLi, 263, THF, −78 °C; then 262; (d)

I2, acetone, MW, 56 °C Scheme 197: Continuation of the route to the cyclisation precursor 261

After the cyclisation of the precursor 261 to the tricycle 260, the subsequent steps to aphidicolin will be investigated (Scheme 198). Conversion of the allyl silane 259 to the tetracycle 446 will be accomplished through a Hosomi–Sakurai reaction.87,88 Reduction of the double bond and carbonyl groups, followed by deprotection and oxidation will provide aphidicolin norketone 179.

(a) DCE, MW, 200 °C; (b) KH, MeI; (c) acrolein, Lewis acid; (d) TBSOTf, 2,6-lutidine; (e) H2, Pd/C; (f) Wolff- Kishner reduction; (g) DMPI Scheme 198

136

As an alternative, further studies on aphidicolin may proceed with the cyclisation of 447 to the tricycle 448 (Scheme 199). We expected that the cyclisation, operating under substrate control, will provide the product 448 with the correct decalin ring structure for the subsequent steps. This approach would dovetail with our proposed strategy to the berkedrimanes (Scheme 151),

Scheme 199: Cyclisation of 447

The tetracycle 449 will then be accessed from 448 following the approach detailed previously in scheme 198. Deprotection and oxidation of the chiral secondary alcohol, followed by conversion to the oxime will provide the selective oxidation substrate 450. Treatment of the oxime with palladium will promote oxidation of the equatorial methyl group to provide 451 (Scheme 200).154,155 451 will then be converted to the known aphidicolin norketone 179.

(a) PhI(OAc)2, Pd(OAc)2, AcOH, Ac2O Scheme 200: Selective oxidation of the tetracycle 450

137

Chapter 4

Experimental

138

General Experimental

Reaction Preparations Unless explicitly stated, commercially available reagents were used as received, after spectral analysis. All experiments were conducted under nitrogen and monitored using analytical thin layer chromatography. TLCs were carried out on Machery-Nagel glass backed plates with a 250µm layer of silica pre-coated with a fluorescent indicator. Visualization of TLC plates was accomplished by UV light (λ=254nm) and either potassium permanganate (KMnO4), vanillin or 2,4-Dinitrophenylhydrazine (Brady’s reagent). Reaction solvents were purified according to methods from the literature. Dichloromethane and triethylamine were distilled from calcium hydride. Tetrahydrofuran and diethyl ether were distilled from sodium with benzophenone as the indicator. Reaction glassware was dried in an oven prior to all reactions.

Chromatography Flash chromatography was carried out using silica gel (Geduran®, 40-63µm, Merck)

Spectrometry and Spectroscopy 1H NMR and 13C NMR were recorded on either a Bruker AV-400 spectrometer or a Brucker AV-500 spectrometer, where stated. Chemical shifts are reported in parts per million with the splittings noted as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and combinations thereof. Coupling constants (J) are recorded to the nearest 0.5Hz. Infrared Spectra were recorded using a Perkin-Elmer RX FT-IR spectrometer with the sample added as a thin film. Mass spectra were recorded using a Micromass AutoSpec-Q or Micromass Platform II instruments with the specific ionisation conditions noted before the data. Infrared spectra were obtained using a Perkin-Elmer Spectrum RX FTIR Optical rotations were recorded using a Perkin-Elmer 241 polarimeter with a 2.5cm cell. Specific rotations are quoted in °/dm/(g/cm3), with the temperature provided in superscript.

Microwave Reactions Microwave reactions were performed using a Biotage Initiator EXP Microwave System.

139

tert-Butyldimethyl(pent-4-ynyloxy)silane

To 4-pentyn-1-ol (12.5 g, 149 mmol) and imidazole (26.6 g, 391 mmol) in DCM (50 mL), tert-butyldimethylsilyl chloride was added in DCM (30 mL), followed by a catalytic amount of 4-(dimethylamino)pyridine (0.1 g, 0.8 mmol). The reaction was stirred overnight and then partitioned with water (50 mL). The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine, dried with sodium sulphate, filtered and reduced under vacuum. The crude material was then purified by column chromatography (5% EtOAc/hexane) to provide the title compound as a colourless oil (28 g, 142 mmol, 95%).

1 H NMR (400 MHz, CDCl3) δ 3.70 (t, J = 6 Hz, 2H, C-1), 2.27 (td, J = 7, 3 Hz, 2H, C-3), 1.93 (t, J = 2.5 Hz, 1H, C-5), 1.73 (tt, J = 7, 6 Hz, 2H, C-2), 0.89 (s, 9H, TBS), 0.06 (s, 6H, TBS) 13 C NMR (100 MHz, CDCl3) δ 84.4 (C-4), 68.3 (C-5), 61.6 (C-1), 31.7 (C-2), 26.1 (TBS), 18.5 (TBS), 15.0 (C-3) -5.20 (TBS) IR (neat, cm-1) 3310, 2954, 2931, 2858, 1472, 1253, 1103, 980, 832, 774, 628 + HRMS (CI+) m/z calculated for C11H23OSi [M+H] 199.1507, found 199.1507

Rf 0.62 (1:9 Et2O/hexane)

The experimental data are consistent with those presented in the literature.156

140

6-(tert-Butyldimethylsilyloxy)hex-2-yn-1-ol

To tert-butyldimethyl(pent-4-ynyloxy)silane (17 g, 86 mmol) in THF (400 mL) at −78 °C, n- BuLi (2.5 M in hexanes, 37.84 mL, 94.6 mmol) was added as drops. After stirring for 30 minutes at −78 °C, the reaction mixture was allowed to warm to −10 °C slowly over 20 minutes, before being cooled back to −78 °C at which point para-formaldehyde (4.1 g, 138 mmol) was added rapidly in one portion. The reaction mixture was then allowed to slowly warm to room temperature overnight. The reaction was quenched at 0 °C with aqueous ammonium chloride (200 mL), and the aqueous layer was extracted with ethyl acetate (3 × 200 mL). The organic extracts were washed with brine, dried with sodium sulphate, filtered and reduced under vacuum to provide the crude product. The crude product was then purified by column chromatography (25% EtOAc/hexane) to yield the title compound as colourless oil (18 g, 79 mmol, 92%).

1 H NMR (400 MHz, CDCl3) δ 4.24 (t, J = 2 Hz, 2H, C-1), 3.68 (t, J = 6 Hz, 2H, C-6), 2.30 (tt, J = 7, 2 Hz, 2H, C-4), 1.76 – 1.65 (m, 2H, C-5), 0.89 (s, 9H, TBS), 0.05 (s, 6H, TBS) 13 C NMR (CDCl3, 100MHz) δ 86.3 (C-2), 78.6 (C-3), 61.7 (C-6), 51.6 (C-1), 31.7 (C-5), 26.1 (TBS), 18.5 (TBS), 15.3 (C-4), -5.2 (TBS) IR (neat, cm-1) 3347, 2952, 2930, 2858, 1472, 1253, 1101, 1008, 834, 775 + HRMS (CI+) m/z calculated for C12H25O2Si [M+H] 229.1624, found 229.1617

Rf 0.34 (1:3 EtOAc/hexane)

The experimental data are consistent with those presented in the literature.156

141

(6-(2-Bromoallyloxy)hex-4-ynyloxy)(tert-butyl)dimethylsilane

To a stirring solution of sodium hydride (60% dispersion, 3.20 g, 81.16 mmol) in THF (180 mL) at 0 °C, 6-(tert-butyldimethylsilyloxy)hex-2-yn-1-ol (15.42 g, 67.63 mmol) in THF (45 mL) was added as drops. After one hour, 2,3-dibromopropene (80% technical grade, 8.5 mL, 67.63 mmol) was added as drops. The reaction medium was allowed to warm to room temperature over two hours, at which point an aqueous solution of K2CO3 (200 mL) was added portion wise. The layers were then partitioned and the aqueous extracted with ethyl acetate (3 × 200 mL). The combined organic layers were then washed with brine, dried over

MgSO4, filtered and reduced under vacuum. The crude product was purified by column chromatography (10% EtOAc/hexane) to give the title compound as a colourless oil (15 g, 44mmol, 65%).

1 H NMR: (400 MHz, CDCl3) δ 5.94 (q, J = 1.5 Hz, 1H, C-3’), 5.63 (dt, J = 2, 1 Hz, 1H, C- 3’), 4.21 – 4.15 (m, 4H, C-6 and C-1’), 3.68 (t, J = 6 Hz, 2H, C-1), 2.31 (tt, J = 7, 2 Hz, 2H, C-3), 1.72 (tt, J = 7, 6 Hz, 2H), C-2, 0.89 (s, 9H, TBS), 0.05 (s, 6H, TBS) 13 C NMR: (CDCl3, 100MHz) δ 129.0 (C-2’), 118.3 (C-3’), 87.6 (C-4), 75.4 (C-5), 73.3 (C- 1’), 61.7 (C-1), 57.9 (C-6), 31.7 (C-2), 26.1 (TBS), 18.5 (TBS), 15.4 (C-3), 14.3 (TBS), -5.2 (TBS) IR (neat, cm-1) 2952, 2930, 2857, 1468, 1253, 1087, 834, 774 79 + HRMS (CI+) m/z calculated for C15H28O2SiBr [M+H] 347.1042, found 347.1047

Rf 0.54 (1:3 Et2O/hexane)

142

6-(2-Bromoallyloxy)hex-4-yn-1-ol

Tetrabutylammonium fluoride (1.0 M in THF, 40.3 mL, 40.3 mmol) was added as drops to a stirring solution of (6-(2-bromoallyloxy)hex-4-ynyloxy)(tert-butyl)dimethylsilane (11.67 g, 33.6 mmol) in THF (340 mL) at 0°C. The cooling was removed and the reaction mixture was stirred for two hours at room temperature. Brine (200 mL) was added, and the solution was extracted with ethyl acetate (3 × 200 mL). The combined organic extracts were dried over

NaSO4, filtered, and reduced under reduced pressure. The crude product was purified by column chromatography (33% EtOAc/hexane) to provide the title compound as colourless oil (7.1 g, 30 mmol, 90%).

1 H NMR (400 MHz, CDCl3) δ 5.94 (q, J = 1.5 Hz, 1H, C-3’), 5.64 (dt, J = 2, 1 Hz, 1H, C-3’), 4.27 – 4.14 (m, 4H, C-6 and C-1’), 3.75 (t, J = 6 Hz, 2H, C-1), 2.36 (tt, J = 7, 2 Hz, 2H, C-3), 1.78 (tt, J = 7, 6 Hz, 2H, C-2) 13 C NMR (100 MHz, CDCl3) δ 128.9 (C-2’), 118.5 (C-3’), 87.0 (C-4), 75.9 (C-5), 73.4 (C- 1’), 61.8 (C-1), 57.9 (C-6), 31.3 (C-2), 15.5 (C-3) IR (Neat, cm-1) 3361, 2942, 2857, 1635, 1438, 1354, 1160, 1064, 905 668 79 + HRMS (CI+) m/z calculated for C9H17NO2Br [M+NH4] 250.0443, found 250.0441

Rf 0.21 (1:3 EtOAc/hexane)

143

6-(2-Bromoallyloxy)hex-4-ynal

To oxalyl chloride (0.9 mL, 10.3 mmol) in DCM (15 mL) at −78 °C, a solution of DMSO (1.3 mL, 19 mmol) in DCM (10 mL) was added as drops. The reaction mixture was stirred for 30 minutes before a solution of 6-(2-bromoallyloxy)hex-4-yn-1-ol (2 g, 8.6 mmol) in DCM (10 mL) was added as drops. The reaction mixture was again stirred for 30 minutes before the addition of triethylamine (6.2 mL, 43 mmol) as drops. Once the triethylamine had been added, the mixture was allowed to warm to room temperature over the course of an hour and quenched with NH4Cl (40 mL). The aqueous layer was then extracted with ethyl acetate

(3 × 50mL) and the combined organics washed with sequentially with 10% K2CO3 (50 mL), water (50 mL), 2 M HCl (50 mL) and finally brine (50 mL). The washed organics were then dried with magnesium sulphate, filtered and reduced under vacuum to provide the title compound as a pale yellow oil (1.9 g, 8.2 mmol, 96%). The crude product was used in the next step without further purification.

1 H NMR (CDCl3, 400MHz) δ 9.80 (t, J = 1 Hz, 1H, C-1), 5.93 (q, J = 1.5 Hz, 1H, C-3’), 5.64 (dt, J = 2, 1 Hz, 1H, C-3’), 4.21 – 4.12 (m, 4H, C-6 and C-1’), 2.69 (tt, J = 7, 1 Hz, 2H, C-2), 2.56 (ttd, J = 7, 2, 1 Hz, 2H, C-3) 13 C NMR: (CDCl3, 100MHz) δ 200.2 (C-1), 128.8 (C-2’), 118.6 (C-3’), 85.5 (C-4), 76.4 (C- 5), 73.4 (C-1’), 57.75 (C-6), 42.6 (C-2), 12.15 (C-3) IR (Neat, cm-1) 2904, 2852, 2729, 1725, 1633, 1356, 1075, 899, 666 79 + HRMS (CI+) m/z calculated for C9H15NO2Br [M+NH4] 248.0286, found 248.0267

Rf 0.40 (1:3 EtOAc/hexane)

144

8-(2-Bromoallyloxy)-1-(trimethylsilyl)octa-1,6-diyn-3-one

Dess-Martin periodinane (1.9 g, 4.5 mmol) was added in one portion to a cooled solution (−10 °C) of 8-(2-bromoallyloxy)-1-(trimethylsilyl)octa-1,6-diyn-3-ol (1 g, 3 mmol) in DCM

(100 mL). The mixture was stirred overnight before being quenched with saturated Na2S2O3 solution (100 mL). The layers were separated and the aqueous extracted with DCM (2 ×

100mL). The organic layers were combined, washed with NaHCO3, dried over sodium sulphate, filtered and reduced under vacuum. The crude material was purified by column chromatography (10% EtOAc/hexane) to provide the title compound (0.92 g, 2.8 mmol, 94%) as a colourless oil.

1 H NMR (400 MHz, CDCl3) δ 5.94 (q, J = 1.5 Hz, 1H, C-3’), 5.64 (dt, J = 2, 1 Hz, 1H, C-3’), 4.19 – 4.13 (m, 4H, C-8 and C-1’), 2.81 (t, J = 7 Hz, 2H, C-4), 2.57 (tt, J = 7, 2 Hz 2H, C-5), 0.25 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 185.2 (C-3), 128.8 (C-2’), 118.7 (C-3’), 101.5 (C-2), 99.1 (C- 1), 85.5 (C-6), 76.3 (C-7), 73.4 (C-1’), 57.7 (C-8), 44.1 (C4), 13.6 (C-5), -0.7 (TMS) IR (Neat, cm-1) 2960, 2905, 2856, 2156, 1678, 1252, 1108, 1079, 844, 761 79 + HRMS (ES+) m/z calculated for C14H20O2SiBr [M+H] 327.0416, found 327.0417

Rf 0.63 (1:3 EtOAc/hexane)

145

5-(Trimethylsilyl)-7,8-dihydro-4H-indeno[4,5-c]furan-6(5H)-one

8-(2-Bromoallyloxy)-1-(trimethylsilyl)octa-1,6-diyn-3-one (0.1 g, 0.3 mmol) and epoxyhexane were heated to reflux in toluene (15 mL) for 4 days. The reaction mixture was reduced in vacuum to colourless oil. The crude material was then purified by column chromatography (50% EtOAc/hexane) to give the title compound as a white crystalline solid (0.045 g, 0.18 mmol, 62%).

Alternatively: 8-(2-Bromoallyloxy)-1-(trimethylsilyl)octa-1,6-diyn-3-one (0.3 g, 0.9 mmol) and epoxyhexene in toluene (2 mL) were heated to 185 °C using a microwave reactor. After 2 hours, the volatiles were removed under vacuum to give a crystalline solid. The crude material was then purified by column chromatography (50% EtOAc/hexane) to provide the title compound as a white crystalline solid (0.16 g, 0.65 mmol, 72%)

1 H NMR (400 MHz, CDCl3) δ 7.62 – 7.49 (m, 1H, C-1), 7.19 (t, 1H, J = 2Hz, C-3), 2.91 – 2.67 (m, 4H, C-8 and C-4), 2.53 (t, J = 5 Hz, 2H, C-7), 2.34 – 2.29 (m, 1H, C-5), -0.14 (s, 9H, TMS). 13 C NMR (100 MHz, CDCl3) δ 206.8 (C-6), 156.4 (C-8a), 140.3 (C-5a), 138.5 (C-1), 137.7 (C-3), 122.4 (C-3a), 121.4 (C-8b), 35.0 (C-7), 25.6 (C-4 or C-8), 21.8 (C-5), 19.4 (C-4 or C- 8), -2.2 (TMS). IR (Neat, cm-1) 3134, 2948, 1680 (C=O), 1619, 1435, 1403, 1108, 1025, 831, 813, 755 + HRMS (ES+) m/z calculated for C14H19O2Si [M+H] 247.1154, found 247.1165

Melting Point: 107.1 °C − 110.4 °C (CHCl3)

Rf 0.3 (1:2 EtOAc/hexane)

146

8-(2-Bromoallyloxy)octa-1,6-diyn-3-one

8-(2-Bromoallyloxy)-1-(trimethylsilyl)octa-1,6-diyn-3-one (0.1 g, 0.3 mmol) and epoxyhexene were heated to reflux in toluene (15 mL) for 4 days. The reaction mixture was reduced in vacuum to colourless oil. The crude material was then purified by column chromatography (50% EtOAc/hexane) providing the title compound as a colourless oil (8 mg, 0.033 mmol, 11%).

1 H NMR (400 MHz, CDCl3) δ 5.95 – 5.92 (m, 1H, C-3’), 5.65 – 5.62 (m, 1H, C-3’), 4.24 – 4.06 (m, 4H, C-8 and C-1’), 3.27 (s, 1H, C-1), 2.84 (t, J = 7 Hz, 2H, C-4), 2.59 (tt, J = 7, 2 Hz, 2H, C-5) 13 C NMR (100 MHz, CDCl3) δ 184.8 (C-3), 128.8 (C-2’), 118.6 (C-3’), 85.1 (C-6), 81.1 (C- 2), 79.5 (C-1), 76.5 (C-7), 73.4 (C-1’), 57.7 (C-8), 44.2 (C-4), 13.5 (C-5) IR: (Neat, cm-1) 3263, 2887, 2092, 1681, 1358, 1077, 907, 673 79 + HRMS (CI+) m/z calculated for C11H15NO2Br [M+NH4] 272.0286, found 272.0291

Rf 0.54 (5:20 EtOAc/hexane)

147

7,8-Dihydro-4H-indeno[4,5-c]furan-6(5H)-one

To a solution of 5-(trimethylsilyl)-7,8-dihydro-4H-indeno[4,5-c]furan-6(5H)-one (45 mg, 0.18 mmol) in THF (6 mL) at 0 °C, TBAF (1 M in THF, 0.18 ml, 0.18 mmol) was added as drops. The solution was stirred for one hour at 0 °C, before warming to room temperature.

The reaction was then quenched with saturated NaHCO3 solution (10 mL, the layers separated, and the aqueous phase extracted with DCM (2 × 10mL). The organic extracts were washed with brine (20 mL), dried over magnesium sulphate, filtered and reduced under vacuum to provide the crude product as a yellow solid. The crude product was purified by column chromatography (25% ethyl acetate/hexane) to give the title compound as a white crystalline solid (25 mg, 0.14 mmol, 80%)

1 H NMR (400 MHz, CDCl3) δ 7.65 – 7.59 (m, 1H), 7.26 (d, J = 1.5 Hz, 1H), 2.85 – 2.77 (m, 2H, C-8), 2.71 (td, J = 7.5, 1.5 Hz, 2H, C-4), 2.60 – 2.52 (m, 2H, C-7), 2.47 (tt, J = 7.5, 2.5 Hz, 2H, C-5) 13 C NMR (100 MHz, CDCl3) δ 207.3 (C-6), 160.1 (C-8a), 139.0 (C-3), 138.2 (C-1), 137.1 (C-5a), 121.7 (C-3a or C-8b), 121.0 (C-3a or C-8b), 35.0 (C-7), 25.8 (C-8), 19.3 (C-5), 17.5 (C-4) IR (Neat, cm-1) 3084, 1676 (C=O), 1621, 1284, 1109, 1018, 838, 815, 616 + HRMS (EI+) m/z calculated for C11H10O2 [M] 174.0681, found 174.0680

Melting Point 141.6 – 144.1 °C (CHCl3)

Rf 0.21 (1:3 EtOAc/hexane)

148

tert-Butyl(hex-5-ynyloxy)dimethylsilane

To 5-hexyn-1-ol (2.5 g, 26 mmol) and imidazole (4.8 g, 70 mmol) in DCM (10 mL), tert- butyldimethylsilyl chloride (4.7 g, 31 mmol) in DCM (7 mL) was added, and the reaction was stirred overnight. Water (20 mL) was added, the layers were separated, and the aqueous was extracted with DCM (2 × 30 mL). The organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (5% Et2O/hexane) to provide the title compound as a colourless oil (5.1 g, 24 mmol, 92%)

1 H NMR (400 MHz, CDCl3) δ 3.67 – 3.59 (m, 2H, C-1), 2.26 – 2.18 (m, 2H, C-4), 1.94 (t, J = 2.5 Hz, 1H, C-6), 1.66 – 1.52 (m, 4H, C-2 and C-3), 0.89 (s, 9H, TBS), 0.05 (s, 6H, TBS) 13 C NMR (100 MHz, CDCl3) 84.7 (C-5), 68.4 (C-6), 62.8 (C-1), 32.0 (C-2 or C-3), 26.1 (TBS), 25.1 (C-2 or C-3), 18.5 (TBS), 18.4 (C-4), -5.15 (TBS) IR (Neat, cm-1) 3310, 2953, 2931, 2859, 1253, 1099, 833, 774 + HRMS (CI+) m/z calculated for C12H25OSi [M+H] 213.1675, found 213.1671

Rf 0.51 (2:20 Et2O/hexane)

The experimental data are consistent with those presented in the literature.157

149

7-(tert-Butyldimethylsilyloxy)hept-2-yn-1-ol

To tert-butyl(hex-5-ynyloxy)dimethylsilane (2g, 9.4 mmol) in THF (50 mL) at −78 °C, n- BuLi (2.5 M in hexanes, 4.7 mL, 10 mmol) was added as drops. Once the addition was complete the mixture was slowly raised to −10 °C, immediately cooled back to −78 °C, and para-formaldehyde (0.45 g, 15 mmol) was added in one portion. The mixture was allowed to warm to room temperature overnight. Sat. aq. NH4Cl (30 mL) was added, the layers separated and the aqueous extracted with EtOAc (3 × 50 mL). The organics were washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc/hexane) to provide the title compound as a colourless oil (2.2g, 9.1 mmol, 97%)

1 H NMR (400 MHz, CDCl3) δ 4.25 (dt, J = 5.5, 2 Hz, 2H, C-1), 3.67 – 3.59 (m, 2H, C-7), 2.24 (tt, J = 6.5, 2 Hz, 2H, C-4), 1.68 – 1.52 (m, 4H, C-5 and C-6), 1.49 (t, J = 6.0 Hz, 1H, ROH), 0.89 (s, 9H, TBS) 13 C NMR (101 MHz, CDCl3) δ 86.6 (C-2), 78.6 (C-3), 62.8 (C-7), 51.6 (C-1), 32.1 (C-5 or C- 6), 26.1 (TBS), 25.2 (C-5 or C-6), 18.7 (C-4), 18.5 (TBS), -5.1 (TBS) IR (Neat, cm-1) 3353, 2936, 2859, 1253, 1097, 1010, 834, 774 + HRMS (CI+) m/z calculated for C13H30NO2Si [M+NH4] 260.2046, found 260.2053

Rf 0.20 (5:20 EtOAc/hexane)

150

(7-(2-Bromoallyloxy)hept-5-ynyloxy)(tert-butyl)dimethylsilane

7-(tert-Butyldimethylsilyloxy)hept-2-yn-1-ol (2 g, 8.3 mmol) in THF (10 mL) was added to a stirring suspension of sodium hydride (60% dispersion, 0.4 g, 10 mmol) in THF (20 mL) at 0 °C. After one hour, 2,3-dibromopropene (80% technical grade, 1 mL, 8.3 mmol) was added, and the mixture was allowed to warm to room temperature. After a further two hours, 10% aq. K2CO3 solution (20 mL) was added. The layers were partitioned and the aqueous was extracted with EtOAc (3 × 20 mL). The organics were washed with brine (20 mL), dried over

MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (10% EtOAc/hexane) to provide the title compound as a colourless oil (1.6 g, 4.4 mmol, 53%).

1 H NMR (400 MHz, CDCl3) δ 5.95 (dq, J = 7.5, 1.5 Hz, 1H, C-3’), 5.64 (ddt, J = 7, 2, 1 Hz, 1H, C-3’), 4.27 – 4.11 (m, 4H, C-1’ and C-7), 3.67 – 3.59 (m, 2H, C-1), 2.30 – 2.21 (m, 2H, C-4), 1.68 – 1.51 (m, 4H, C-2 and C-3), 0.89 (s, 9H, TBS), 0.05 (s, 6H, TBS) 13 C NMR (100 MHz, CDCl3) δ 129.0 (C-2’), 118.4 (C-3’), 87.8 (C-6), 75.4 (C-5), 73.3 (C-7 or C-1’), 62.8 (C-1), 57.9 (C-7 or C-1’), 32.1 (C-2 or C-3), 26.1 (TBS), 25.2 (C-2 or C-3), 18.7 (C-4), 18.5 (TBS), -5.1 (TBS) IR (Neat, cm-1) 2952, 2929, 2857, 1253, 1083, 834, 774, 664 79 + HRMS (ES+) m/z calculated for C16H30O2Br Si [M+H] 361.1198, found 361.1197

Rf 0.45 (1:3 Et2O/hexane)

151

7-(2-Bromoallyloxy)hept-5-yn-1-ol

Tetrabutylammonium fluoride (1 M in THF, 3.2 mL, 3.2 mmol) was added to a solution of (7-(2-bromoallyloxy)hept-5-ynyloxy)(tert-butyl)dimethylsilane (0.98 g, 2.7 mmol) in THF (27 mL) at 0 °C. The mixture was warmed to room temperature and stirred for a further a 2 hours. Sat. aq. NH4Cl (20 mL) was added, the layers separated, and the aqueous was extracted with Et2O (3 × 20 mL). The organic extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (33% EtOAc/hexane) to give the title compound as a colourless oil (0.49 g, 2.0 mmol, 74%).

1 H NMR (400 MHz, CDCl3) δ 5.94 (q, J = 1.5 Hz, 1H, C-3’), 5.64 (dt, J = 2, 1 Hz, 1H, C-3’), 4.27 – 4.14 (m, 4H, C-1’ and C7), 3.68 (t, J = 6 Hz, 2H, C-1), 2.28 (tt, J = 7, 2 Hz, 2H, C-4), 1.74 – 1.55 (m, 4H, C-2 and C-3) 13 C NMR (100 MHz, CDCl3) δ 128.9 (C-2’), 118.4 (C-3’), 87.5 (C-6), 75.7 (C-5), 73.3 (C- 1’), 62.5 (C-1), 57.9 (C-7), 32.0 (C-2 or C-3), 25.0 (C-2 or C-3), 18.7 (C-4) IR (Neat, cm-1) 3356, 2938, 2862, 1635, 1070, 901 79 + HRMS (CI+) m/z calculated for C10H16O2Br [M+H] 247.0334, found 247.0359 Rf 0.11 (5:20 EtOAc/hexane)

152

7-(2-Bromoallyloxy)hepta-5-ynal

A solution of DMSO (0.16 mL, 2.2 mmol) in DCM (1 mL) was added as drops to oxalyl chloride (0.09 mL, 1.1 mmol) in DCM (1 mL) at −78 °C. The solution was stirred for 30 minutes, before the addition of 7-(2-bromoallyloxy)hept-5-yn-1-ol (175 mg, 0.71 mmol) in DCM (1 mL). After a further hour, triethylamine (0.82 mL, 5.7 mmol) was added, and the mixture was allowed to slowly warm to room temperature. Once at room temperature, water (5 mL) was added to quench the reaction. The biphasic mixture was partitioned and the aqueous extracted with DCM (3 × 5 mL). The organic extracts were washed with 2M HCl

(10 mL), sat. aq. NaHCO3 (2 × 10 mL), water (10 mL), and brine (10 mL). The washed organics were then dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound as a pale yellow oil (170 mg, 0.69 mmol, 97 %). The crude product was satisfactorily pure to be used in the next step without further purification.

1 H NMR (400 MHz, CHCl3) δ 9.81 (t, J = 1.5 Hz, 1H C-1), 5.94 (q, J = 1.5 Hz, 1H, C-3’), 5.67 – 5.61 (m, 1H, C-3’), 4.20 – 4.15 (m, 4H, C-1’ and C-7), 2.59 (td, J = 7, 1.5 Hz, 2H, C- 2), 2.32 (tt, J = 7, 2 Hz, 2H, C-4), 1.90 – 1.81 (m, 2H, C-3) 13 C NMR (125 MHz, CDCl3) δ 201.8 (C-1), 128.9 (C-2’), 118.5 (C-3’), 86.4 (C-6), 76.5 (C- 5), 73.4 (C-1’), 57.9 (C-7), 42.9 (C-2), 21.1 (C-3), 18.3 (C-4) IR (Neat, cm-1) 2921, 2853, 2726, 1722, 1357, 1079, 907 79 + HRMS (ES+) m/z calculated for C12H17NO2Br [M+CH3CNH] 286.0443, found 286.0439

Rf 0.38 (5:20 EtOAc/hexane)

153

9-(2-Bromoallyloxy)-1-(trimethylsilyl)nona-1,7-diyn-3-one

To a solution of trimethylsilylacetylene (0.22 mL, 1.6 mmol) in THF (6 mL) at −78 °C, n- BuLi (2.5 M in hexanes, 0.64 mL, 1.6 mmol) was added. The mixture was warmed to −10 °C after the addition was complete, and then cooled back down to −78 °C. 7-(2- bromoallyloxy)hepta-5-ynal (170 mg, 0.69 mmol) was added in THF (2 mL). After 30 minutes at −78 °C, the mixture was warmed to room temperature. Sat. aq. NH4Cl (10 mL) was added, the layers were separated, and the aqueous was extracted with EtOAc (3 ×10 mL).

The organics were washed with brine (10 mL), dried over MgSO4 and filtered. The organics were then concentrated under reduced pressure to provide the intermediate propargylic alcohol. Dess–Martin periodinane (300 mg, 0.72 mmol) was added to the crude propargyl alcohol in DCM (15 mL) at 0 °C, and the mixture was stirred overnight. The reaction mixture was diluted with Et2O (30 mL) and a 1:1 mixture (20 mL) of sat. aq. sodium thiosulfate and sat. aq. NaHCO3 was added. The layers were separated, and the aqueous extracted with Et2O

(20 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (10% EtOAc/hexane) to provide the title compound as a colourless oil (110 mg, 0.32 mmol, 46%).

1 H NMR (500 MHz, CDCl3) δ 5.95 (q, J = 1.5 Hz, 1H, C-3’), 5.64 (dt, J = 2, 1 Hz, 1H, C-3’), 4.21 – 4.16 (m, 4H, C-1’ and C-9), 2.70 (t, J = 7 Hz, 2H, C-4), 2.30 (tt, J = 7, 2 Hz, 2H, C-6), 1.87 (quintet, J = 7 Hz, 2H, C-5), 0.25 (s, 8H, TMS) 13 C NMR (125 MHz, CDCl3) δ 186.0 (C-3), 127.9 (C-2’), 117.6 (C-3’), 101.0 (C-2), 97.2 (C- 1), 85.5 (C-6), 75.4 (C-5), 72.4 (C-1’), 56.8 (C-9), 43.1 (C-4), 21.7 (C-5), 17.2 (C-6), -1.61 (TMS) IR (Neat, cm-1) 2960, 2902, 2855, 1675, 1111, 1080, 844, 761 79 + HRMS (ES+) m/z calculated for C15H21O2SiBr Na [M+H] 363.0392, found 363.0386

Rf 0.59 (5:20 EtOAc/hexane)

154

2-Bromo-N-methylprop-2-en-1-amine

2,3-Dibromopropene (5 mL, 50 mmol) was slowly added as drops via a dropping funnel to a vigorously stirring solution of MeNH2 (40% aq.) with a filled dry ice trap positioned in the spare neck. After one hour, NaOH (4g, 100mmol) and DCM (10 mL) were added. The biphasic mixture was separated and the DCM layer was dried over NaOH. Volatiles were removed by distillation and the crude material was purified by distillation to provide the title compound as a colourless oil (1.6g, 11 mmol, 22%)

1 H NMR (400 MHz, CDCl3) δ 5.77 (dt, J = 2, 1 Hz, 1H, C-3), 5.56 (d, J = 2 Hz, 1H, C-3), 3.41 (d, J = 1 Hz, 2H, C-1), 2.37 (s, 3H, NMe), 1.47 (br s, 1H, NH) 13 C NMR (100 MHz, CDCl3) δ 133.3 (C-2), 117.8 (C-3), 59.3 (C-1), 34.4 (NMe) IR (neat) 3297, 2937, 2798, 1632, 1450, 1095, 893, 735 79 + HRMS (ES+) m/z calculated for C4H9NBr [M+H] 149.9918, found 149.9913

The experimental data are consistent with those presented in the literature.158

155

(N-(2-Bromoallyl)-6-(tert-butyldimethylsilyloxy)-N-methylhex-2-yn-1-amine

Formalin (35 % aq, 2.4 mL) was added to a solution of 2-bromo-N-methylprop-2-en-1-amine (1.1 g, 7.3 mmol), tert-butyldimethyl(pent-4-ynyloxy)silane (1.2 g, 6.1 mmol) and CuI (24 mg, 0.24 mmol) in DMSO (12 mL). The reaction mixture was heated to 30 °C and maintained overnight. Once complete, the mixture was added to water (30 mL). Extracted with EtOAc (3 × 10 mL) followed by dried over MgSO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (5% − 10%

Et2O/hexane) to provide the title compound as a colourless oil (1.1g, 3.1 mmol, 51%)

1 H NMR (400 MHz, CDCl3) δ 5.86 (d, J = 2 Hz, 1H, C-3’), 5.59 (d, J = 2 Hz, 1H, C-3’), 3.70 (t, J = 6 Hz, 2H, C-6), 3.37 (t, J = 2 Hz, 2H, C-1), 3.25 (s, 2H, C-1’), 2.33 (s, 3H, NMe), 2.29 (tt, J = 7, 2 Hz, 2H, C-4), 1.72 (q, J = 6.5 Hz, 2H, C-5), 0.89 (s, 9H, TBS), 0.05 (s, 6H, TBS) 13 C NMR (100 MHz, CDCl3) δ 131.0 (C-2’), 119.3 (C-3’), 85.7 (C-3), 73.9 (C-2), 63.9 (C- 1’), 61.7 (C-6), 45.2 (C-1), 41.2 (NMe), 32.0 (C-5), 25.9 (TBS), 18.4 (TBS), 15.1 (C-4), -5.3 (TBS) IR (neat) 2954, 2932, 2960, 1632, 1471, 1257, 1104, 833, 776, 663 79 + HRMS (ES+) m/z calculated for C16H31NOBr Si [M+H] 360.1358, found 360.1359

Rf 0.13 (1:20 Et2O/hexane)

156

6-((2-Bromoallyl)(methyl)amino)hex-4-yn-1-ol

TBAF (1M in THF, 0.67 mL, 0.67 mmol) was added to a solution of (N-(2-Bromoallyl)-6- (tert-butyldimethylsilyloxy)-N-methylhex-2-yn-1-amine (200 mg, 0.56 mmol) in THF (6 mL) at 0 °C. The mixture was warmed to room temperature and saturated aq. NH4Cl (10 mL) was added. The layers were separated and the aqueous was extracted with EtOAc (3 × 10 mL).

The organic extracts were washed with brine, dried over MgSO4, filtered and reduced under vacuum. The crude product was then purified by column chromatography (50% EtOAc/hexane) to provide the title compound as a colourless oil (70 mg, 0.28 mmol, 50%)

1 H NMR (400 MHz, CDCl3) δ 5.87 – 5.84 (m, 1H, C-3’), 5.59 (d, J = 1.5 Hz, 1H, C-3’), 3.76 (t, J = 6.1 Hz, 2H, C-1), 3.37 (t, J = 2 Hz, 2H, C-6), 3.25 (d, J = 1 Hz, 2H, C-1’), 2.40 – 2.29 (m, 5H, C-3 and NMe), 1.83 – 1.71 (m, 2H, C-2), 1.52 (br s, 1H, ROH) 13 C NMR (100 MHz, CDCl3) δ 131.1 (C-2’), 119.6 (C-3’), 85.3 (C-4), 74.7 (C-5), 64.0 (C- 1’), 62.0 (C-1), 45.3 (C-6), 41.4 (NMe), 31.7 (C-3), 15.4 (C-2) IR (neat) 3341, 2944, 2870, 2797, 1630, 1433, 1327, 1115, 1032, 897, 839 79 + HRMS (ES+) m/z calculated for C10H17NOBr [M+H] 246.0494, found 246.0506; Rf 0.18 (1:3 EtOAc/hexane)

157

2-(6-(tert-Butyldimethylsilyloxy)hex-2-ynyl)isoindoline-1,3-dione

DIAD (2.1 mL, 10.4 mmol) was added to a solution of PPh3 (2.7 g, 10.4 mmol) in THF (20 mL) at 0 °C. After 30 minutes, a solution of 6-(tert-butyldimethylsilyloxy)hex-2-yn-1-ol (2 g, 8.8 mmol) and phthalimide (1.5 g, 10.4 mmol) in THF (20 mL) was added. The mixture was stirred overnight, before concentrating under reduced pressure. The crude material was purified by column chromatography (10 % Et2O/hexane) to provide the title compound as a colourless oil (1.6 g, 4.5 mmol, 51%).

1 H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 5.5, 3 Hz, 2H, Ar-H), 7.73 (dd, J = 5.5, 3 Hz, 2H, Ar-H), 4.42 (t, J = 2 Hz, 2H, C-1), 3.63 (t, J = 6 Hz, 2H, C-6), 2.22 (tt, J = 7, 2 Hz, 2H, C-4), 1.72 – 1.58 (m, 3H, C-5), 0.85 (s, 9H, TBS), 0.00 (s, 6H, TBS) 13 C NMR (100 MHz, CDCl3) δ 167.4 (C=O), 134.2 (CAr-H), 132.3 (CAr), 123.6 (CAr-H), 83.5 (C), 73.7 (C), 61.7 (C-6), 31.5 (C-5), 27.6 (C-1), 26.0 (TBS), 18.5 (TBS), 15.2 (C-4), - 5.2 (TBS) IR (neat) 2954, 2931, 2862, 1715, 1468, 1424, 1390, 1345, 1326, 1104, 1069, 835, 769, 727 + HRMS (ES+) m/z calculated for C20H28NO3Si [M+H] 358.1838, found 358.1838

Rf 0.18 (1:10 Et2O/hexane)

158

(6-(tert-Butyldimethylsilyloxy)hex-2-yn-1-amine

Hydrazine monohydrate (64-65%, 4.5 mL, 5.6 mmol) was added as drops to 2-(6-(tert- butyldimethylsilyloxy)hex-2-ynyl)isoindoline-1,3-dione (0.5 g, 1.4 mmol) in THF (14 mL). The reaction mixture was heated to reflux for one hour. Once complete by TLC, the mixture was cooled and H2O (20 mL) was added. The layers were separated and the aqueous extracted with Et2O (4 × 20 mL). The organic extracts were washed with brine, dried over

MgSO4, filtered and concentrated under reduced pressure to give the title compound as a colourless oil (310 mg, 1.36 mmol, 97%)

1 H NMR (400 MHz, CDCl3) δ 3.68 (t, J = 6 Hz, 2H, C-6), 3.39 (t, J = 2 Hz, 2H, C-1), 2.26

(tt, J = 7, 2.5 Hz, 2H, C-4), 1.76 – 1.64 (m, 2H, C-5), 1.50 (s, 2H, NH2), 0.89 (s, 9H, TBS), 0.05 (s, 6H, TBS) 13 C NMR (100 MHz, CDCl3) δ 82.4 (C-3), 81.1 (C-2), 61.8 (C-6), 32.0 (C-5), 31.9 (C-1), 26.1 (TBS), 18.5 (TBS), 15.3 (C-4), -5.2 (TBS) IR (neat) 2952, 2930, 2857, 1468, 1253, 1101, 964, 833, 774 + HRMS (ES+) m/z calculated for C12H26NOSi [M+H] 228.1784, found 228.1790

159

(N-(2-Bromoallyl)-6-(tert-butyldimethylsilyloxy)hex-2-yn-1-amine

2,3-Dibromopropene (0.22 mL, 2.2 mmol) and K2CO3 (300 mg, 2.2 mmol) were added to a solution of (6-(tert-Butyldimethylsilyloxy)hex-2-yn-1-amine (0.5 g, 2.2 mmol) in THF (22 mL). The reaction mixture was stirred overnight. Brine (20 mL) was added, the layers were separated, and the aqueous was extracted with EtOAc (2 × 30 mL). The organic extracts were dried over NaSO4, filtered and concentrated under reduced pressure to provide the crude product. The crude material was purified by column chromatography (10 % - 25 %

Et2O/hexane) to furnish the title compound as a colourless oil (360 mg, 1.04 mmol, 47 %)

1 H NMR (400 MHz, CDCl3) δ 5.82 (m, 1H, C-3’), 5.57 (d, J = 2 Hz, 1H, C-3’), 3.68 (t, J = 6 Hz, 2H, C-6), 3.53 (s, 2H, C-1’), 3.38 (t, J = 2 Hz, 2H, C-1), 2.27 (tt, J = 7, 2 Hz, 2H, C-4), 1.70 (tt, J = 7, 6 Hz, 2H, C-5), 1.34 – 1.22 (m, 1H, N-H), 0.89 (s, 9H, TBS), 0.05 (s, 6H, TBS) 13 C NMR (100 MHz, CDCl3) δ 132.5 (C-2’), 118.3 (C-3’), 83.9 (C-3), 77.4 (C-2), 61.8 (C-6), 56.3 (C-1’), 37.0 (C-1), 32.0 (C-5), 26.1 (TBS), 18.5 (TBS), 15.3 (C-4), -5.17 (TBS) IR (neat) 2952, 2930, 2857, 1630, 1463, 1253, 1100, 834, 774 79 + HRMS (ES+) m/z calculated for C15H29NOBr Si [M+H] 346.1202, found 346.1215

Rf 0.25 (1:9 Et2O/hexane)

160

N-(2-Bromoallyl)-N-(6-(tert-butyldimethylsilyloxy)hex-2-ynyl)-4- methylbenzenesulfonamide

p-Toluenesulfonyl chloride (236 mg, 1.2 mmol) was added in one portion to a solution of (N- (2-bromoallyl)-6-(tert-butyldimethylsilyloxy)hex-2-yn-1-amine (430 mg, 1.2 mmol) and triethylamine (0.17 mL, 1.2 mmol) in THF (3 mL) at 0 °C. Once stirred overnight, the mixture was concentrated under reduced pressure and the crude material dissolved in DCM

(10 mL). The DCM solution was washed with saturated aq. NaCO3 solution (2 × 10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (10 % Et2O/hexane) to yield to the title compound as a colourless oil (400 mg, 0.80 mmol, 67%)

1 H NMR (400 MHz, CDCl3) δ 7.79 – 7.67 (m, 2H, Ts), 7.32 – 7.27 (m, 2H, Ts), 5.94 (dd, J = 2, 1 Hz, 1H, C-3’), 5.66 (m, 1H, C-3’), 4.09 (t, J = 2.5 Hz, 2H, C-1), 4.03 (d, J = 1 Hz, 2H, C-1’), 3.51 (t, J = 6 Hz, 2H, C-6), 2.42 (s, 3H, Ts), 2.00 (tt, J = 7, 2 Hz, 2H, C-4), 1.45 (tt, J = 7, 6 Hz, 2H, C-5), 0.88 (s, 9H, TBS), 0.02 (s, 6H, TBS) 13 C NMR (100 MHz, CDCl3) δ 143.7 (Ts), 136.3 (Ts), 129.6 (Ts), 127.9 (Ts), 127.4 (C-2’), 120.0 (C-3’), 86.5 (C-3), 72.2 (C-2), 61.6 (C-6), 54.0 (C-1’), 36.9 (C-1), 31.6 (C-5), 26.1

(TBS), 21.7 (PhCH3), 18.5 (TBS), 15.1 (C-4), -5.2 (TBS) IR (neat) 2953, 2929, 2857, 1631, 1352, 1253, 1162, 1094, 900, 835, 766, 658 79 + HRMS (ES+) m/z calculated for C22H34NO3Br SSi [M+H] 500.1280, found 500.1290

Rf 0.21 (1:10 Et2O/hexane)

161

N-(2-Bromoallyl)-N-(6-hydroxyhex-2-ynyl)-4-methylbenzenesulfonamide

TBAF (1M in THF, 0.88 mL, 0.88 mmol) was added to a solution of N-(2-bromoallyl)-N-(6- (tert-butyldimethylsilyloxy)hex-2-ynyl)-4-methylbenzenesulfonamide (400 mg, 0.8 mmol) in THF (8 mL) at 0 °C. The mixture was then stirred for one hour at room temperature. Once complete, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (50 % EtOAc/hexane) to provide the title compound as a colourless oil (250 mg, 0.65 mmol, 81%)

1 H NMR (400 MHz, CDCl3) δ 7.82 – 7.65 (m, 2H, Ts), 7.37 – 7.27 (m, 2H, Ts), 5.95 – 5.93 (m, 1H, C-3’), 5.66 (dd, J = 2, 1 Hz, 1H, C-3’), 4.09 (t, J = 2 Hz, 2H, C-1), 4.04 (s, 2H, C-1’),

3.57 (t, J = 6 Hz, 2H, C-6), 2.43 (s, 3H, PhCH3), 2.11 – 2.02 (m, 2H, C-4), 1.53 (tt, J = 7, 6 Hz, 2H, C-5), 1.34 (s, 1H, R-OH) 13 C NMR (100 MHz, CDCl3) δ 143.8 (Ts), 136.2 (Ts), 129.6 (Ts), 127.9 (Ts), 127.3 (C-2’), 120.1 (C-3’), 86.0 (C-3), 72.8 (C-2), 61.53 (C-6), 54.02 (C-1’), 36.9 (C-1), 31.1 (C-5), 21.7

(PhCH3), 15.1 (C-4) IR (neat) 3451, 2922, 1347, 1158, 1092, 1063, 901, 811, 730, 657 79 + HRMS (ES+) m/z calculated for C16H20NO3NaBr S [M+Na] 408.0254, found 408.0245 Rf 0.25 (1:2 EtOAc/hexane)

162

(±)-N-(2-Bromoallyl)-N-(6-hydroxy-8-(trimethylsilyl)octa-2,7-diynyl)-4- methylbenzenesulfonamide

To oxalyl chloride (0.036 mL, 0.44 mmol) in DCM (1 mL) at −78 °C, DMSO (0.06 mL, 0.88 mmol) in DCM (1 mL) was added as drops. The mixture was stirred for 30 minutes before the addition of N-(2-bromoallyl)-N-(6-hydroxyhex-2-ynyl)-4-methylbenzenesulfonamide (115 mg, 0.29 mmol) in DCM (1 mL). After a further 30 minutes, triethylamine (0.33 mL, 2.3 mmol) was added as drops, maintaining the internal temperature at −78 °C. The reaction mixture was warmed to room temperature slowly over the course of an hour and then water (3 mL) was added. The layers were separated and the aqueous was extracted with DCM (2 ×

5 mL). The organic extracts were washed with NaHCO3 (2 × 5 mL), dried with MgSO4, filtered and concentrated under reduced pressure to provide the crude aldehyde (100 mg, 0.26 mmol). n-BuLi (2.5 M in hexanes, 0.22 mL, 0.57 mmol) was added to trimethylsilylacetylene (0.08 mL, 0.57 mmol) in THF (3 mL) at −78 °C. After 10 minutes, the cooling bath was removed the mixture was allowed to warm to −10 °C, before cooling being reapplied. The crude aldehyde (200 mg, 0.52 mmol) in THF (2 mL) was added to the mixture and the reaction was stirred for one hour at −78 °C, before warming to room temperature. The reaction was quenched with saturated aq. NH4Cl (10 mL). The layers were separated and the aqueous was extracted with EtOAc (3 × 10 mL). The organics were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound as a colourless oil (140 mg, 0.29 mmol, 56%)

163

1 H NMR (400 MHz, CDCl3) δ 7.78 – 7.70 (m, 2H, Ts), 7.35 – 7.27 (m, 2H, Ts), 5.95 – 5.93 (m, 1H, C-3’), 5.66 (dt, J = 2, 1 Hz, 1H, C-3’), 4.25 (dt, J = 7, 5.5 Hz, 1H, C-6), 4.08 (t, J = 2

Hz, 2H, C-1), 4.04 (s, 2H, C-1’), 2.44 (s, 3H, PhCH3), 2.20 – 2.04 (m, 2H, C-4), 1.80 (d, J = 5 Hz, 1H, R-OH), 1.69 – 1.54 (m, 2H, C-5), 0.18 (s, 9H, TMS). 13 C NMR (100 MHz, CDCl3) δ 143.9 (Ts), 136.2 (Ts), 129.7 (Ts), 127.9 (Ts), 127.3 (C-2’), 120.2 (C-3’), 105.8 (C-7), 90.3 (C-8), 85.5 (C-3), 73.0 (C-2), 61.6 (C-6), 54.1 (C-1’), 36.8

(C-1), 36.2 (C-5), 21.8 (PhCH3), 14.7 (C-4), 0.00 (TMS) IR (neat) 3486, 2959, 2921, 2851, 1349, 1251, 1160, 1092, 1066, 841, 757, 658 79 + HRMS (ES+) m/z calculated for C21H29NO3Br SSi [M+H] 482.0821, found 482.0810 Rf 0.31 (6:20 EtOAc/hexane)

164

(N-(2-Bromoallyl)-N-(6-oxo-8-(trimethylsilyl)octa-2,7-diynyl)-4- methylbenzenesulfonamide

Dess-Martin periodinane (60 mg, 0.14 mmol) was added to a solution of N-(2-bromoallyl)-N- (6-hydroxy-8-(trimethylsilyl)octa-2,7-diynyl)-4-methylbenzenesulfonamide (45 mg, 0.09 mmol) in DCM (2 mL) at 0 °C. The mixture was then stirred overnight. Et2O (10 mL) was added, followed by 10 mL of a 1:1 mixture of saturated aq. NaCO3 and saturated aq. sodium thiosulphate solution. The mixture was stirred for an hour. The layers were separated and the aqueous was extracted with Et2O (3 ×10 mL). The organics were dried over NaSO4, filtered and concentrated under reduced pressure to provide the title compound as a colourless oil (31 mg, 0.062 mmol, 70 %).

1 H NMR (400 MHz, CDCl3) δ 7.77 – 7.69 (m, 2H, Ts), 7.36 – 7.28 (m, 2H, Ts), 5.95 (q, J = 1.4 Hz, 1H, C-3’), 5.66 (dt, J = 1.8, 0.8 Hz, 1H, C-3’), 4.06 (t, J = 2.2 Hz, 2H, C-1), 4.02 (t, J

= 1.1 Hz, 4H, C-1’), 2.50 (t, J = 7 Hz, 2H, C-5), 2.44 (s, 3H, PhCH3), 2.24 (ddt, J = 9, 7, 2 Hz, 2H, C-4), 0.26 (s, 9H, TMS). 13 C NMR (100 MHz, CDCl3) δ 184.8 (C-6), 143.8 (Ts), 136.3 (Ts), 129.6 (Ts), 128.0 (Ts), 127.2 (C-2’), 120.4 (C-3’), 101.5 , 99.1 , 85.7, 84.5 (C-3), 73.2 (C-2), 54.1 (C-1’), 43.7 (C-5),

36.7 (C-1), 21.7 (PhCH3), 13.1 (C-4), -0.64 (TMS) IR (neat) 2962, 2914, 2152, 1677, 1350, 1252, 1161, 1107, 1094, 845, 758, 657 79 + HRMS (ES+) m/z calculated for C21H27NO3Br SSi [M+H] 480.0664, found 480.0667 Rf 0.29 (3:20 EtOAc/hexane)

165

2-Tosyl-5-(trimethylsilyl)-4,5,7,8-tetrahydrocyclopenta[e]isoindol-6(2H)-one

(N-(2-Bromoallyl)-N-(6-oxo-8-(trimethylsilyl)octa-2,7-diynyl)-4-methylbenzenesulfonamide (60 mg, 0.12 mmol) and 1,2-epoxyhexane (0.14 mL, 1.2 mmol) in DCE (1.2 mL) were heated to 200 °C for 2 hours using a microwave reactor. The mixture was then concentrated under reduced pressure and the residue purified by column chromatography (30 % EtOAc/hexane) to furnish the title compound as a pale yellow gum (29 mg, 0.073 mmol, 61%)

1 H NMR (400 MHz, CDCl3) δ 7.77 – 7.68 (m, 2H, Ts), 7.30 – 7.26 (m, 2H, Ts), 7.22 (d, J = 2 Hz, 1H, C-1), 6.88 (dt, J = 2, 1 Hz, 1H, C-3), 2.85 – 2.62 (m, 4H, C-4 and C-8), 2.51 (t, J =

5 Hz, 2H, C-7), 2.39 (s, 3H, PhCH3), 2.30 – 2.22 (m, 1H, C-5), -0.26 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 206.7 (C-6), 157.3 (C-8a), 145.3 (Ts), 140.5 (C-5a), 136.0 (Ts), 130.1 (Ts), 126.9 (Ts), 126.3 (3a or 8b), 124.9 (3a or 8b), 116.7 (C-1), 116.6 (C-3), 35.0

(C-7), 25.3 (C-4 or C-8), 21.7 (PhCH3), 21.6 (C-5), 21.2 (C-4 or C-8), -2.31 (TMS) IR (neat) 2953, 2924, 2852, 1685 (C=O), 1615, 1535, 1370, 1286, 1171, 1054, 841, 675 + HRMS (ES+) m/z calculated for C21H26NO3SSi [M+H] 400.1403, found 400.1400 Rf 0.36 (7:20 EtOAc/hexane)

166

S-6-(tert-Butyldimethylsilyloxy)hex-2-ynyl ethanethiolate

DIAD (1 mL, 5.7 mmol) was added to a solution of triphenylphosphine (1.5 g, 5.7 mmol) in THF (20 mL) at 0 °C. After 20 minutes, 6-(tert-butyldimethylsilyloxy)hex-2-yn-1-ol (1.3 g, 5.7 mmol) and thioacetic acid (0.4 mL, 5.7 mmol) in THF (10 mL) was added. After two hours, the mixture was concentrated under reduced pressure. The concentrated residue was purified by column chromatography (5 % Et2O/hexane) to provide the title compound as a colourless oil (1 g, 4 mmol, 70 %).

1 H NMR (400 MHz, CDCl3) δ 3.71 – 3.60 (m, 4H, C-1 and C-6), 2.34 (s, 3H, C-2’), 2.24 (tt, J = 7, 2.5 Hz, 2H, C-4), 1.67 (tt, J = 7, 6 Hz, 2H, C-5), 0.89 (s, 9H, TBS), 0.05 (s, 6H, TBS) 13 C NMR (100 MHz, CDCl3) δ 194.6 (C-1’), 83.2 (C-3), 74.6 (C-2), 61.7 (C-6), 31.7 (C-5), 30.3 (C-2’), 26.1 (TBS), 18.5 (TBS), 18.4 (C-1), 15.4 (C-4), -5.19 (TBS) IR (neat) 2953, 2929, 2857, 1697, 1132, 1101, 833, 774 + HRMS (ES+) m/z calculated for C14H27O2SSi [M+H] 287.1501, found 287.1495 Rf 0.72 (3:20 EtOAc/hexane)

167

(6-(2-Bromoallylthio)hex-4-ynyloxy)(tert-butyl)dimethylsilane

K2CO3 (1 g, 7.5 mmol) was added to a solution of S-6-(tert-butyldimethylsilyloxy)hex-2-ynyl ethanethiolate (750 mg, 3 mmol) in MeOH (30 mL). After one hour, the reaction was judged to be complete, and 2,3-dibromopropene (0.3 mL, 3 mmol) was added. After two hours, water (30 mL) and Et2O (50 mL) were added. The layers were separated and the aqueous was extracted with Et2O (3 × 50 mL). The ether extracts were washed with brine, dried over

MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (5 % Et2O/hexane) to provide the title compound as a colourless oil (670 mg, 1.85 mmol, 62 %)

1 H NMR (400 MHz, CDCl3) δ 5.83 (dt, J = 2, 1 Hz, 1H, C-3’), 5.55 (d, J = 1.5 Hz, 1H, C-3’), 3.68 (t, J = 6 Hz, 2H, C-1), 3.61 (d, J = 1 Hz, 2H, C-1’), 3.23 (t, J = 2.5 Hz, 2H, C-6), 2.29 (tt, J = 7, 2.5 Hz, 2H, C-3), 1.70 (tt, J = 7, 6 Hz, 2H, C-2), 0.89 (s, 9H, TBS), 0.05 (s, 6H, TBS) 13 C NMR (100 MHz, CDCl3) δ 128.9 (C-2’), 119.4 (C-3’), 84.0 (C-4), 75.1 (C-5), 61.8 (C-1), 41.3 (C-1’), 32.0 (C-2), 26.1 (TBS), 19.3(C-6), 18.5 (TBS), 15.4 (C-3), -5.2 (TBS) IR (neat) 2952, 2928, 2856, 1251, 1100, 833, 774 + HRMS (ES+) m/z calculated for C15H28OBrSSi [M+H] 363.0814, found 363.0808 Rf 0.6 (3:20 EtOAc/hexane)

168

6-(2-Bromoallylthio)hex-4-yn-1-ol

TBAF (1M in THF, 0.55 mL, 0.55 mmol) was added to a solution of (6-(2- bromoallylthio)hex-4-ynyloxy)(tert-butyl)dimethylsilane (180 mg, 0.5 mmol) in THF (5 mL) at 0 °C. The mixture was then stirred for three hours at room temperature. Once complete, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (40 % EtOAc/hexane) to provide the title compound as a colourless oil (100 mg, 0.4 mmol, 80%)

1 H NMR (400 MHz, CDCl3) δ 5.90 – 5.79 (m, 1H, C-3`), 5.55 (d, J = 1.5 Hz, 1H, C-3`), 3.75 (t, J = 6 Hz, 2H, C-1), 3.61 (d, J = 1 Hz, 2H, C-1`), 3.23 (t, J = 2.5 Hz, 2H, C-6), 2.33 (tdt, J = 6.5, 4.5, 2.5 Hz, 2H, C-3), 1.76 (tt, J = 7, 6 Hz, 2H, C-2) 13 C NMR (100 MHz, CDCl3) δ 128.7 (C-2`), 119.4 (C-3`), 86.4, 83.5, 80.6, 75.7, 61.9 (C-1), 41.4 (C-1`), 31.5 (C-2), 21.4, 19.27 (C-6), 15.6, 15.5 IR (neat) 3344, 2944, 1621, 1410, 1203, 1052, 895 + HRMS (ES+) m/z calculated for C9H14OBrS [M+H] 248.9943, found 248.9954 Rf 0.15 (3:20 EtOAc/hexane)

169

(±)-8-(2-Bromoallylthio)-1-(trimethylsilyl)octa-1,6-diyn-3-ol

To oxalyl chloride (0.1 mL, 1.2 mmol) in DCM (2 mL) at −78 °C, DMSO (0.16 mL, 2.4 mmol) in DCM (1 mL) was added as drops. The mixture was stirred for an hour before the addition of 6-(2-bromoallylthio)hex-4-yn-1-ol (200 mg, 0.8 mmol) in DCM (1 mL). After a further 30 minutes at −78 °C, triethylamine was added (0.9 mL, 6.4 mmol), and the mixture was allowed to warm to room temperature over the course of two hours. Water (5 mL) was added and the biphasic mixture separated. The aqueous was extracted with DCM (2 ×10 mL), and the combined organics were washed NaHCO3 (2 × 10 mL), dried with MgSO4, filtered and concentrated under reduced pressure to provide the crude aldehyde. To a solution of trimethylsilylacetylene (0.1 mL, 0.74 mmol) in THF (5 mL) at −78 °C, n-BuLi (2.3M in hexanes, 0.3 mL, 0.74 mmol) was added as drops. The mixture was stirred for one hour before the addition of the crude aldehyde in THF (3 mL). After one hour at −78 °C, the mixture was warmed to room temperature and saturated aq. NH4Cl (10 mL) was added. The biphasic mixture was separated and the aqueous layer extracted with EtOAc (3 × 10 mL). The organics were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound as a colourless oil (105 mg, 0.31 mmol, 39%).

1 H NMR (400 MHz, CDCl3) δ 5.84 (dt, J = 2, 1 Hz, 1H, C-3’), 5.56 (d, J = 2 Hz, 1H, C-3`), 4.51 (q, J = 6 Hz, 1H, C-3), 3.62 (d, J = 1 Hz, 2H, C-1’), 3.23 (t, J = 2.5 Hz, 2H, C-8), 2.49 – 2.33 (m, 2H, C-5), 1.97 – 1.84 (m, 2H, C-4), 1.57 – 1.49 (m, 1H, ROH), 0.18 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 128.9 (C-2`), 119.5 (C-3`), 105.9 (C-2), 90.3 (C-1), 83.0 (C- 6), 75.9 (C-7), 61.9 (C-3), 41.3 (C-1`), 36.6 (C-4), 19.3 (C-8), 15.0 (C-5), -0.0 (TMS) IR (neat) 3393, 2958, 1621, 1249, 1061, 896, 839, 759 + HRMS (ES+) m/z calculated for C14H22OBrSSi [M+H] 345.0339, found 345.0337 Rf 0.47 (3:20 EtOAc/hexane)

170

8-(2-Bromoallylthio)-1-(trimethylsilyl)octa-1,6-diyn-3-one

To oxalyl chloride (0.022 mL, 0.26 mmol) in DCM (1 mL) at −78 °C, DMSO (0.036 mL, 0.51 mmol) in DCM (0.5 mL) was added as drops. The mixture was stirred for one hour before the addition of 8-(2-bromoallylthio)-1-(trimethylsilyl)octa-1,6-diyn-3-ol (60 mg, 0.17 mmol) in DCM (0.5 mL). After a further 30 minutes at −78 °C, triethylamine was added (0.2 mL, 1.4 mmol), and the mixture was allowed to warm to room temperature. Water (3 mL) was added and the biphasic mixture separated. The aqueous was extracted with DCM ( 2 × 5 mL), and the combined organics were washed with NaHCO3 (2 × 5 mL), dried with MgSO4, filtered and concentrated under reduced pressure to provide the title compound as a pale yellow oil (15 mg, 0.043 mmol, 26%)

1 H NMR (400 MHz, CDCl3) δ 5.83 (dt, J = 2, 1 Hz, 1H, C-3`), 5.55 (d, J = 2 Hz, 1H, C-3`), 3.60 (d, J = 1 Hz, 2H, C-1`), 3.20 (t, J = 2.5 Hz, 2H, C-8), 2.79 (dd, J = 7.5, 6.5 Hz, 2H, C-4), 2.60 – 2.49 (m, 2H, C-5), 0.25 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 185.3 (C-3), 128.8 (C-2`), 119.6 (C-1`), 101.6 (C1 or C2), 99.1 (C1 or C2), 81.8 (C-6), 76.1 (C-7), 44.3 (C-4), 41.3 (C-1`), 19.1 (C-8), 13.7 (C-5), -0.6 (TMS) IR (neat) 2961, 2908, 1677, 1252, 1110, 846 + HRMS (ES+) m/z calculated for C9H14OBrS [M+H] 342.0109, no mass ion found Rf 0.7 (3:20 EtOAc/hexane)

171

5-(Trimethylsilyl)-7,8-dihydro-4H-indeno[5,4-c]thiophen-6(5H)-one

8-(2-bromoallylthio)-1-(trimethylsilyl)octa-1,6-diyn-3-one (15 mg, 0.043 mmol) and 1,2- epoxyhexane (0.05 mL, 0.4 mmol) in DCE (0.4 mL) were heated to 200 °C for 2 hours using a microwave reactor. The mixture was then concentrated under reduced pressure and the residue purified by column chromatography (15 % EtOAc/hexane) to furnish the title compound as a pale yellow gum (6.5 mg, 0.025 mmol, 58%)

1 H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 2.5 Hz, 1H, C-1), 6.93 (ddd, J = 2.5, 2, 0.5 Hz, 1H, C-3), 3.08 – 2.90 (m, 3H, C-8 and C-4), 2.81 – 2.74 (m, 1H, C-4), 2.57 (t, J = 5 Hz, 2H, C7), 2.33 (ddt, J = 8, 2.5, 1 Hz, 1H, C-5), -0.17 (s, 9H, TMS) 13 C NMR (125 MHz, CDCl3) δ 207.4 (C-6), 159.2 (C-8a), 140.3 (C-5a), 138.8 (C-3a or C- 8b), 136.7 (C-3a or C-8b), 121.6 (C-1), 119.4 (C-3), 35.2 (C-7), 26.1 (C-8), 25.3 (C-4), 22.2 (C-5), -2.3 (TMS) IR (neat) 2958, 2924, 1686 (C=O), 1603, 1350, 1250, 848 + HRMS (ES+) m/z calculated for C14H18OSSi [M+H] 262.0848, found 262.0846 Rf 0.15 (3:20 EtOAc/hexane)

172

4-Pentynoic acid

Jones reagent was freshly prepared from CrO3 (14 g), H2SO4 (12 mL) and water (100 mL). The jones reagent was added slowly to a solution of 4-pentyn-1-ol (7.7 mL, 83 mmol) in acetone (200 mL) at −5 °C until the orange colour persisted (90 mL of the Jones solution). After stirring for a further hour at 0 °C, the solution was allowed to warm to room temperature for a further 2 hours of stirring. The reaction mixture was quenched with isopropanol (100 mL) and stirred for 10 minutes, before volatiles were removed under vacuum. The aqueous residue was extracted with Et2O (3 × 200 mL) and the organic layer was then extracted with aq. 2M NaOH (2 × 200 mL). These aqueous extracts were then acidified with conc. HCl, and extracted with Et2O (6 × 200 mL). The organic extracts were then dried over MgSO4, filtered and reduced to provide the compound as off white amorphous solid (6.9 g, 70 mmol, 85%). The crude can either be recrystallized from pentane to provide white plates or used in the next reaction without further purification.

1 H NMR (400 MHz, CDCl3) δ 2.65 – 2.59 (m, 2H, C-2), 2.57 – 2.47 (m, 2H, C-3), 2.00 (t, J = 2.5 Hz, 1H, C-5) 13 C NMR (101 MHz, CDCl3) δ 177.8 (C-1), 82.2 (C-4), 69.4 (C-5), 33.2 (C-2), 14.2 (C-1) IR (neat, cm-1) 3500 – 2900 (broad peak), 1705, 1426, 1297, 1216, 897, 639 MS (CI+) m/z 135, 117, 97, 70 mp 56.5 °C – 58.3 °C (pentane) literature mp 57 °C – 58 °C (pet ether)159

The experimental data are consistent with those presented in the literature.160

173

N-Methoxy-N-methylpent-4-ynamide

To 4-pentynoic acid (0.3 g, 3.1 mmol) in THF (5 mL) at 0 °C, 1,1'-carbonyldiimidazole (0.55 g, 3.4 mmol) was added in portions. The reaction medium was allowed to warm to room temperature. After one hour, N,O-dimethylhydroxylamine hydrochloride (0.33 g, 3.4 mmol) was added in portions. The mixture was then heated to reflux for two hours, after which complete consumption of the starting material had been noted. Water (5 mL) was added and the mixture was partitioned. The aqueous portion was extracted with ethyl acetate (2 × 30mL) and the extracts dried over MgSO4. After filtration, the organic extracts were reduced under vacuum to give the crude product. Column chromatography (30% EtOAc/hexane) provided the title compound as a colourless oil (0.21 g, 1.5 mmol, 50%).

1 H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H, OMe), 3.22 (s, 3H, NMe), 2.72 (dd, J = 8.5, 6.5 Hz, 2H, C-2), 2.62 – 2.49 (m, 2H, C-3), 2.00 (t, J = 2.5 Hz, 1H, C-5) 13 C NMR (100 MHz, CDCl3) δ 172.5 (C-1), 83.6 (C-4), 68.8 (C-5), 61.4 (OMe), 32.3 (NMe), 31.3 (C-2), 14.0 (C-3) IR (neat, cm-1) 3276, 2970, 2939, 1658, 1423, 1387, 992, 642 + HRMS (ES+) m/z calculated for C7H12NO2 [M+H] 142.0868, found 142.0862

Rf: 0.20 (1:3 EtOAc/hexane)

The experimental data are consistent with those presented in the literature.101

174

Pent-4-ynoyl chloride

Oxalyl chloride (7.1 mL, 84 mmol) was added to a solution of 4-pentynoic acid (6.9 g, 70 mmol) and DMF (0.4 mL) in DCM (70 mL). The mixture was stirred for two hours, before the volatiles were removed under reduced pressure. The concentrated residue was twice dissolved in pentane (100 mL) and the solvent was decanted. The pentane washings were then concentrated under reduced pressure to provide the title compound as a red oil (7.2 g, 55 mmol, 79%).

1 H NMR (400 MHz, CDCl3) δ 3.13 (t, J = 7 Hz, 2H, C-2), 2.57 (td, J = 7, 2.5 Hz, 2H, C-3), 2.04 (t, J = 2.5 Hz, 1H, C-5) 13 C NMR (100 MHz, CDCl3) δ 172.2 (C-1), 80.4 (C-4), 70.3 (C-5), 45.6 (C-2), 14.7 (C-3) IR (neat, cm-1) 3300, 1789, 1403, 1043, 969, 900, 640 MS (CI+) m/z 135, 133, 97, 85, 83

The experimental data are consistent with those presented in the literature.161

175

1-(Trimethylsilyl)hepta-1,6-diyn-3-one

Aluminium trichloride (2.2 g, 17 mmol) was added in portions to a solution of pent-4-ynoyl chloride (2 g, 17 mmol) and bis(trimethylsilyl)acetylene (3.8 mL, 17 mmol) in DCM (40 mL) at 0 °C. The mixture was stirred for one hour at 0 °C after the addition, before a further hour at room temperature. The mixture was then poured onto 1M HCl (50 mL) cooled to −5 °C, and diluted with Et2O (60 mL). After stirring for 10 minutes, the biphasic mixture was separated and the aqueous extracted with Et2O (3 × 60 mL). The ether extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by distillation (110 – 120 °C, 12 mbar) to provide the title compound as a colourless oil (1.8 g, 10 mmol, 59%)

1 H NMR (400 MHz, CDCl3) δ 2.85 (t, 2H, C-4), 2.61 – 2.49 (m, 2H, C-5), 1.99 (t, J = 2.5 Hz, 1H, C-7), 0.26 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 185.1 (C-3), 101.5 (C-1 or C-2), 99.2 (C-1 or C-2), 82.3 (C- 6), 69.3 (C-7), 44.0 (C-4), 13.2 (C-5), -0.7 (TMS) IR (neat, cm-1) 2962, 1678, 1252, 1112, 845, 631 + HRMS (ES+) m/z calculated for C10H13OSi [M-H] 177.0736, found 177.0731

Rf 0.75 (1:3 EtOAc/hexane) bp 110 – 120 °C at 12 mbar

176

((2-(But-3-ynyl)-1,3-dioxolan-2-yl)ethynyl)trimethylsilane

1-(Trimethylsilyl)hepta-1,6-diyn-3-one (0.80 g, 4.5 mmol) in DCM (2 mL) was cooled to −78 °C, before the addition of 1,2-bis(trimethylsiloxy)ethane (2.2 mL, 9.0 mmol) and trimethylsilyl trifluoromethanesulfonate (0.10 mL, 0.50 mmol). The mixture was allowed to warm to room temperature over the course of 2 hours, after which the mixture was diluted with DCM (20 mL) and triethylamine (2.0 mL, 27 mmol) was added. The reaction mixture was partitioned with aqueous ammonium chloride (20 mL), and the aqueous layer extracted with DCM (2 × 20 mL). The combined organics was washed with brine, dried with sodium sulphate, filtered, and reduced under vacuum. The crude product was then purified by distillation (100 – 115 °C, 12 mbar) to provide the title compound (0.77 g, 3.5 mmol, 77%) as a colourless oil. The final product was contaminated with 1.5% of 1,2- bis(trimethylsiloxy)ethane by 1H NMR.

1 H NMR (400 MHz, CDCl3) δ 4.13 – 4.04 (m, 2H, C-5’ or C-4’), 4.01 – 3.93 (m, 2H, C-5’ or C-4’), 2.46 – 2.36 (m, 2H, C-2’’), 2.19 – 2.10 (m, 2H, C-1’’), 1.95 (t, J = 2.5 Hz, 1H, C-4’’), 0.17 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 102.0 (C-1, C-2 or C-2’), 101.8 (C-1, C-2 or C-2’), 89.5 (C-1, C-2 or C-2’), 83.8 (C-3’’), 68.3 (C-4’’), 64.9 (C-5’ and C-4’), 38.3 (C-1’’), 13.5 (C-2’’), -0.1 (TMS) IR (neat, cm-1) 3297, 2961, 2897, 1251, 1094, 843, 760 + HRMS (ES+) m/z calculated for C12H17O2Si [M-H] 221.0998, found 221.1017

Rf 0.71 (1:3 EtOAc/hexane)

177

(±)-1-Cyclohexyl-5-(2-((trimethylsilyl)ethynyl)-1,3-dioxolan-2-yl)pent-2-yn-1-ol

To ((2-(but-3-ynyl)-1,3-dioxolan-2-yl)ethynyl)trimethylsilane (0.5 g, 2.2 mmol) in THF (7 mL) at −78 °C, n-BuLi (2.5 M in hexanes, 0.88 mL, 2.2 mmol) was added as drops. The reaction mixture was stirred for 20 minutes at −78 °C, before being raised to −10 °C. The mixture was cooled to −78 °C and cyclohexanecarboxaldehyde (0.41 mL, 3.4 mmol) was added in THF (2 mL). The reaction mixture was warmed to room temperature over two hours, and quenched with saturated aqueous ammonium chloride (10 mL). The layers were separated and the aqueous was extracted with ethyl acetate (3 × 15 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (10% − 25% EtOAc/hexane) to give the title compound as a colourless oil (0.50 g, 1.5 mmol, 68 %).

1 H NMR (400 MHz, CDCl3) δ 4.13 (dt, J = 6, 2 Hz, 1H, C-1), 4.11 – 4.04 (m, 2H, C-4’ or C- 5’), 4.02 – 3.95 (m, 2H, C-4’ or C-5’), 2.50 – 2.40 (m, 2H, C-4), 2.19 – 2.10 (m, 2H, C-5), 1.90 – 1.63 (m, 5H, cyclohexyl), 1.58 – 1.44 (m, 1H, cyclohexyl), 1.34 – 0.98 (m, 5H, cyclohexyl), 0.19 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 102.0 (C-1’’, C-2’’ or C-2’), 101.8 (C-1’’, C-2’’ or C-2’), 89.3 (C-1’’ or C-2’’), 85.2 (C-3), 80.3 (C-2), 67.5 (C-1), 64.8 (C-4’ and C-5’), 44.4 (cyclohexyl), 38.5 (C-5), 28.7 (cyclohexyl), 28.2 (cyclohexyl), 26.5 (cyclohexyl), 26.0 (cyclohexyl), 26.0 (cyclohexyl), 13.8 (C-4), -0.1 (TMS) IR (neat, cm-1) 3442 (broad), 2925, 2853, 1250, 1092, 1030, 841, 760 + HRMS (ES+) m/z calculated for C19H31O3Si [M+H] 335.2042, found 335.2056

Rf 0.50 (1:4 EtOAc/hexane)

178

N-(2-Bromoallyl)-N-methyl-5-(2-((trimethylsilyl)ethynyl)-1,3-dioxolan-2-yl)pent-2-yn-1- amine

Formalin (35% aq, 0.2 mL) was added to a solution of ((2-(but-3-ynyl)-1,3-dioxolan-2- yl)ethynyl)trimethylsilane (111 mg, 0.5 mmol), 2-bromo-N-methylprop-2-en-1-amine (90 mg, 0.6 mmol), and Copper (I) iodide (2mg) in DMSO (1 mL). The mixture was heated to 30 °C and maintained overnight. Once complete the mixture was added to water (5 mL) and then extracted with with EtOAc (3 × 5 mL). The organic extracted were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to provide the title compound as a colourless oil (60 mg, 0.17 mmol, 34%).

1 H NMR (400 MHz, CDCl3) δ 5.85 (q, J = 1 Hz, 1H, C-3’’), 5.58 (d, J = 1.5 Hz, 1H, C-3’’), 4.14 – 3.92 (m, 4H, C-4’ and C-5’), 3.36 (t, J = 2 Hz, 2H, C-1), 3.24 (d, J = 1 Hz, 2H), 2.43 (ddt, J = 10.5, 8, 2 Hz, 2H, C-4), 2.32 (s, 3H, NMe), 2.18 – 2.09 (m, 2H, C-3), 0.17 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 131.2 (C-2’’), 119.5 (C-3’’), 102.0 (C), 101.9 (C), 89.4 (C), 85.1 (C-3), 74.1 (C-2), 64.9 (C-1’’), 64.0 (C-4’ and C-5’), 45.3 (C-1), 41.4 (NMe), 38.8 (C- 5), 13.8 (C-4), -0.08 (TMS) IR (neat, cm-1) 2964, 2898, 2799, 1634, 1251, 1091, 1033, 836, 761 + HRMS (ES+) m/z calculated for C17H27NO2BrSi [M+H] 384.0994, found 384.1006

Rf 0.51 (1:4 EtOAc/hexane)

179

((2-(5-(2-Bromoallyloxy)pent-3-ynyl)-1,3-dioxolan-2-yl)ethynyl)trimethylsilane

1,2-Bis(trimethylsiloxy)ethane (0.3 mL, 1.2 mmol) was added to a vigorously stirring solution of 8-(2-Bromoallyloxy)-1-(trimethylsilyl)octa-1,6-diyn-3-one (0.2 g, 0.6 mmol) in DCM (3 mL) at −78 °C. Trimethylsilyl trifluoromethanesulfonate (0.01 mL, 0.06 mmol) was added rapidly. The mixture was allowed to warm to room temperature slowly over the course of two hours. Once complete, the reaction mixture was diluted with DCM (20 mL) and triethylamine (0.4 mL, 3 mmol) was added. The reaction mixture was partitioned with sat. aq. ammonium chloride (20 mL) and the aqueous layer extracted with DCM (2 × 20 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (5%

Et2O/hexane) to provide the title compound as a colourless oil (0.16 g, 0.43 mmol, 72%).

1 H NMR (400 MHz, CDCl3) δ 5.94 (q, J = 1.5 Hz, 1H, C-3’’’), 5.64 (dt, J = 2, 1 Hz, 1H, C- 3’’’), 4.18 (dd, J = 2, 1 Hz, 4H, C-1’’’ and C-5’’), 4.10 – 4.03 (m, 2H, dioxolane), 4.01 – 3.94 (m, 2H, dioxolane), 2.51 – 2.41 (m, 2H, C-2’’), 2.20 – 2.09 (m, 2H, C-1’’), 0.18 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 129.0 (C-2’’’), 118.4 (C-3’’’), 102.0 (C-2’ or C-2), 101.87 (C-2’ or C-2), 89.5 (C-1), 86.9 (C-3’’), 75.3 (C-4’’), 73.3 (C-5’’ or C-1’’’), 64.9 (C-5’ and C- 4’), 57.9 (C-5’’ or C-1’’’), 38.4 (C-1’’), 13.9 (C-2’’), -0.1 (TMS) IR (neat, cm-1) 2959, 2897, 1251, 1092, 1034, 862, 844 + HRMS (CI+) m/z calculated for C16H24O3BrSi [M+H] 371.0678, found 371.0673 Rf 0.60 (1:3 EtOAc/hexane)

180

(±)-8-Cyclohexyl-8-hydroxy-1-(trimethylsilyl)octa-1,6-diyn-3-one

Iodine (16 mg, 0.06 mmol), 1-cyclohexyl-5-(2-((trimethylsilyl)ethynyl)-1,3-dioxolan-2- yl)pent-2-yn-1-ol (200 mg, 0.6 mmol) and acetone (3 mL) were heated to 56 °C in the microwave for 10 minutes. A 10% aq. solution of Na2S2O3 (8 mL) was added, and the mixture was concentrated under reduced pressure. The aqueous residue was diluted with water (20 mL) and subsequently extract with ethyl acetate (3 × 20 mL). The extracts were washed with brine (40 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (25% ethyl acetate – hexane) to give 8-cyclohexyl-8-hydroxy-1-(trimethylsilyl)octa-1,6-diyn-3-one as a colourless oil (0.1 g, 0.36 mmol, 60%).

1 H NMR (400 MHz, CDCl3) δ 4.11 (t, J = 5.5 Hz, 1H, C-8), 2.81 (t, J = 6.5 Hz, 2H, C-4), 2.63 – 2.51 (m, 2H, C-5), 1.87 – 1.62 (m, 5H, cyclohexyl), 1.53 – 1.44 (m, 1H, cyclohexyl), 1.33 – 0.95 (m, 5H, cyclohexyl), 0.25 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 185.4 (C-3), 101.6 (C-1 or C-2), 99.0 (C-1 or C-2), 83.9 (C- 6), 81.3 (C-7), 67.5 (C-8), 44.4 (C-4 or cyclohexyl), 44.3 (C-4 or cyclohexyl), 28.7 (cyclohexyl), 28.2 (cyclohexyl), 26.5 (cyclohexyl), 26.1 (cyclohexyl), 26.0 (cyclohexyl), 13.6 (C-5), -0.7 (TMS) IR (neat, cm-1) 3439 (broad), 2925, 2853, 1677, 1252, 1109, 843, 761 + HRMS (ES+) m/z calculated for C17H27O2Si [M+H] 291.1780, found 291.1792

Rf 0.46 (1:4 EtOAc/hexane)

181

3,3-Dimethylpent-4-en-1-ol

To methyl 3,3-dimethyl-4-pentenoate (12 mL, 75 mmol) in toluene (250 mL) at −78 °C, DIBAL-H (1M in hexanes, 170 mL, 170 mmol) was added as drops. The reaction mixture was stirred for 30 minutes at −78 °C before slowly warming to room temperature. Ethyl acetate was carefully added to quench the reaction, followed by a saturated solution of Rochelle’s salt in water (200 mL). The biphasic mixture was vigorously stirred overnight. Once the layers had separated, the aqueous layer was extracted with ethyl acetate (2 × 250 mL), and the organic extracts were washed with brine (250 mL). The washed extracts were dried with MgSO4, filtered, and concentrated under reduced pressure to provide the title compound as a colourless oil (7.8 g, 68 mmol, 91%).

1 H NMR (400 MHz, CDCl3) δ 5.83 (dd, J = 17.5, 11 Hz, 1H, C-4), 4.99 – 4.89 (m, 2H, C-5), 3.63 (t, J = 7 Hz, 2H, C-1), 1.60 (t, J = 7 Hz, 2H, C-2), 1.02 (s, 6H, 2 × Me) 13 C NMR (100 MHz, CDCl3) δ 148.3 (C-4), 110.9 (C-5), 60.2 (C-1), 45.2 (C-2), 35.9 (C-3),

27.2 (2 × Me) IR (neat, cm-1) 3327 (broad), 2963, 2933, 2878, 1365, 1055, 1003, 913 + HRMS (CI+) m/z calculated for C7H18NO [M+NH4] 132.1388, found 132.1392

Rf 0.32 (1:4 EtOAc/hexane)

The experimental data are consistent with those presented in the literature.162

182

3,3-Dimethylpent-4-en-1-al

To oxalyl chloride (3.3 mL, 39 mmol) in DCM (50 mL) at −78 °C, a solution of DMSO (5.6 mL, 79 mmol) in DCM (20 mL) was added as drops. After 30 minutes, 3,3 dimethylpent-4- en-1-ol (3 g, 26 mmol) was added in DCM (20 mL) to the reaction mixture. The mixture was stirred for a further 30 minutes, before the slow addition of triethylamine (30 mL, 210 mmol). Once the triethylamine had been added, the reaction was stirred for a further hour at −78 °C, before warming slowly to room temperature. Water (60 mL) was added to the reaction, mixture was separated, and the aqueous layer was extracted with DCM (2 × 80 mL). The combined organic were washed with 2M HCl (150 mL), water (150 mL), NaHCO3 (150 mL), and brine (150 mL). The washed extracts were dried with MgSO4, filtered, and concentrated under reduced pressure to provide the title compound as a pale yellow oil (2.4 g, 21 mmol, 82%). 3,3-Dimethylpent-4-en-1-al can be purified by distillation (45 °C at 40 mbar).

1 H NMR (400 MHz, CDCl3) δ 9.71 (t, J = 3 Hz, 1H, C-1), 5.97 – 5.85 (m, 1H, C-4), 5.06 – 4.95 (m, 2H, C-5), 2.34 (d, J = 3 Hz, 2H, C-2), 1.15 (s, 6H, 2 × Me) 13 C NMR (100 MHz, CDCl3) δ 203.4 (C-1), 146.4 (C-4), 112.0 (C-5), 54.8 (C-2), 36.1 (C-3), 27.5 (2 × Me) IR (neat, cm-1) 2962, 1718, 1002, 916, 681 + HRMS (CI+) m/z calculated for C7H16NO [M+NH4] 130.1232, found 130.1239

Rf 0.54 (1:4 EtOAc/hexane)

The experimental data are consistent with those presented in the literature.163

183

(±)-3,3-Dimethyl-9-(2-((trimethylsilylethynyl)-1,3-dioxolan-2-yl)non-1-en-6-yn-5-ol

To ((2-(but-3-ynyl)-1,3-dioxolan-2-yl)ethynyl)trimethylsilane (1 g, 4.5 mmol) in THF (10 mL) at −78 °C, n-BuLi (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added as drops. The reaction mixture was stirred for 20 minutes at −78 °C, before being raised to −10 °C. The mixture was cooled to −78 °C and 3,3-dimethylpent-4-en-1-al (0.61 g, 5.4 mmol) was added in THF (5 mL). The reaction mixture was stirred at −78 °C for 30 minutes, before warming slowly to room temperature over 2 hours. Saturated aqueous ammonium chloride (20 mL) was added slowly at 0 °C. The layers were separated, and the aqueous was extracted with ethyl acetate (3 × 20 mL). The organic extracts were washed with brine (30 mL), dried over

MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc/hexane) to give the title compound as a colourless oil (1.1 g, 3.3 mmol, 73%).

1 H NMR (400 MHz, CDCl3) δ 5.88 (dd, J = 17.5, 11 Hz, 1H, C-2), 5.03 – 4.91 (m, 2H, C-1), 4.39 (dtt, J = 7, 4.5, 2 Hz, 1H, C-5), 4.13 – 3.89 (m, 4H, dioxolane), 2.47 – 2.37 (m, 2H, C- 8), 2.16 – 2.06 (m, 2H, C-9), 1.84 – 1.69 (m, 3H, C-4 and OH), 1.08 (s, 3H, Me), 1.07 (s, 3H, Me), 0.17 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 148.2 (C-2), 111.4 (C-1), 102.0 (C-2’ or C-2’’), 101.9 (C-2’ or C-2’’), 89.4 (C-1’’), 84.4 (C-7), 82.3 (C-6), 64.9 (C-4’ and C-5’), 60.6 (C-5), 50.9 (C-4), 38.4 (C-9), 36.3 (C-3), 28.1 (Me), 26.5 (Me), 13.9 (C-8), -0.1 (TMS) IR (neat, cm-1) 3443, 2963, 2899, 1254, 1093, 1036, 843, 764 + HRMS (ES+) m/z calculated for C19H31O3Si [M+H] 335.2042, found 355.2061

Rf 0.28 (1:5 EtOAc/hexane)

184

(±)-8-Hydroxy-10,10-dimethyl-1-(trimethylsilyl)dodeca-11-en-1,6-diyn-3-one

Iodine (0.037 g, 0.15 mmol), 3,3-dimethyl-9-(2-((trimethylsilylethynyl)-1,3-dioxolan-2- yl)non-1-en-6-yn-5-ol (0.5 g, 1.5 mmol) and acetone (3 mL) were heated to 56 °C in the microwave for 10 minutes. A 5% aqueous solution of Na2S2O3 (10 mL) was added, and the mixture was concentrated under reduced pressure. The aqueous residue was diluted with water (10 mL) and extracted with DCM (2 × 30 mL). The organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc/hexane) to give the title compound as a colourless oil (0.33 g, 1.1 mmol, 76 %).

1 H NMR (400 MHz, CDCl3) δ 5.95 – 5.81 (m, 1H, C-11), 5.04 – 4.95 (m, 2H, C-12), 4.37 (dtt, J = 7, 5, 2 Hz, 1H, C-8), 2.83 – 2.75 (t, J = 7.5 Hz, 2H, C-4), 2.58 – 2.48 (m, 2H, C-5), 1.84 – 1.68 (m, 2H, C-9), 1.07 (s, 2H, Me), 1.06 (s, 2H, Me), 0.24 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 185.3 (C-3), 148.1 (C-11), 111.4 (C-12), 101.6 (C-2), 99.0 (C-1), 83.2 (C-6 or C-7), 82.9 (C-6 or C-7), 60.5 (C-8), 50.8 (C-9), 44.2 (C-4), 36.3 (C-10), 28.1 (Me), 26.5 (Me), 13.6 (C-5), −0.7 (TMS) IR (neat, cm-1) 3426, 2963, 1680, 1256, 1113, 845, 764 + HRMS (ES+) m/z calculated for C17H27O2Si [M+H] 291.1780, found 291.1789 Rf 0.35 (4:20 EtOAc/hexane)

185

(±)-3,3-Dimethyl-5-(trimethylsilyl)-3,3a,4,5,7,8-hexahydro as-indacene-1,6(2H, 8bH)- dione

8-Hydroxy-10,10-dimethyl-1-(trimethylsilyl)dodeca-11-en-1,6-diyn-3-one (140 mg, 0.48 mmol) was heated in DCE (4 mL) to 200 °C for two hours using a microwave reactor. The solvent was removed under reduced pressure to provide a pale yellow oil. The crude product was purified by column chromatography (10% − 15% EtOAc/hexane) to provide the title compound as a white non-crystalline solid (102 mg, 0.35 mmol, 73%).

1 H NMR (400 MHz, CDCl3) δ 3.24 (d, J = 7 Hz, 1H, C-8b), 3.18 – 3.04 (m, 1H, C-8), 2.62 – 2.48 (m, 1H, C-8), 2.39 (t, J = 4.5 Hz, 2H, C-7), 2.28 (d, J = 18.5 Hz, 1H, C-2), 2.17 – 2.03 (m, 4H, C-2, C-3a, C-4 and C-5), 1.30 (td, J = 13, 5.5 Hz, 1H, C-4), 1.17 (s, 3H, Me), 1.15 (s, 3H, Me), 0.02 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 214.6 (C-1), 207.4 (C-6), 164.0 (C-8a), 142.3 (C-5a), 52.5 (C- 8b), 49.1 (C-2), 44.6 (C-5), 36.5 (C-3), 35.01 (C-7), 29.9 (Me), 25.4 (C-4), 24.8 (Me), 21.66, −0.78 (TMS) IR (neat, cm-1) 2955, 2868, 1740, 1695, 1634, 1369, 1250, 844 + HRMS (ES+) m/z calculated for C17H27O2Si [M+H] 291.1780, found 291.1786 Rf: 0.20 (3:20 EtOAc/hexane)

186

5-Iodo-3,3-dimethylpent-1-ene

Pyridine (1.56 mL, 19.3 mmol), iodine (5.3 g, 21 mmol), and triphenylphosphine (5.5 g, 21 mmol) were added to a 0 °C solution of 3,3 dimethylpent-4-en-1-ol (2 g, 17.5 mmol) in DCM (140 mL). The mixture was slowly warmed to room temperature and stirred for 24 hours. The reaction was quenched with a 10% aqueous solution of Na2S2O3 (100 mL). The aqueous layer was separated and extracted with DCM (2 × 100 mL). The organic extracts were dried with

MgSO4, filtered, and reduced under vacuum. The crude product was purified by column chromatography (20% diethyl ether/hexane) to provide 5-iodo-3,3-dimethylpent-1-ene as a colourless oil (3.8 g, 17 mmol, 97%).

1 H NMR (400 MHz, CDCl3) δ 5.71 (dd, J = 17.5, 11 Hz, 1H, C-2), 4.99 (dd, J = 11, 1 Hz, 1H, C-1), 4.94 (dd, J = 17.5, 1 Hz, 1H, C-1), 3.11 – 3.02 (m, 2H, C-5), 2.02 – 1.92 (m, 2H, C-4), 1.00 (s, 6H, 2 × Me) 13 C NMR (101 MHz, CDCl3) δ 146.5 (C-2), 111.9 (C-1), 47.8 (C-4), 39.4 (C-3), 26.4 (2 × Me), 1.2 (C-5) IR (neat, cm-1) 2961, 2927, 2869, 1639, 1364, 1200, 1188, 1002, 913 + HRMS (EI+) m/z calculated for C7H13I [M] 224.0062, found 224.0064

Rf 0.8 (1:20 toluene/hexane)

187

(±)-6-Methylhepta-1,5-dien-3-ol

1-Bromo-3-methyl-2-butene (3.4 mL, 30 mmol) and freshly activated zinc (3 g, 45 mmol) were sequentially added to a solution of acrolein (1 mL, 15 mmol) in THF (3 mL) and sat. aq.

NH4Cl solution (15 mL). After 2 hours, the mixture was diluted with Et2O (40 mL) and filtered. Any remaining zinc was removed by carefully decanting the solvent, washing the zinc with further portions of Et2O where needed. The ether extracts were washed with brine

(100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc/hexane) to provide the title compound as a colourless oil (1.5 g, 12 mmol, 80%).

1 H NMR (400 MHz, CDCl3) δ 5.90 (ddd, J = 17, 11, 6 Hz, 1H, C-2), 5.25 (dt, J = 17, 1.5 Hz, 1H, C-1), 5.18 – 5.13 (m, 1H, C-5), 5.12 (dt, J = 10.5, 1 Hz, C-1), 4.13 (dq, J = 5, 2.5 Hz, 1H, C-3), 2.26 (ddt, J = 7.5, 6.5, 1 Hz, 2H, C-4), 1.74 (q, J = 1.5 Hz, 3H, Me), 1.67 – 1.63 (m, 4H, Me and OH) 13 C NMR (100 MHz, CDCl3) δ 140.8 (C-2), 135.7 (C-6), 119.4 (C-5), 114.7 (C-1), 72.8 (C- 3), 36.2 (C-4), 26.1 (Me), 18.2 (Me) IR (neat, cm-1) 3362, 2974, 2921, 1439, 1381, 1115, 1042, 991, 925 + HRMS (EI+) m/z calculated for C8H18NO [M+NH4] 144.1388, found 144.1381

Rf 0.48 (7:20 EtOAc/hexane)

The experimental data are consistent with those presented in the literature.164

188

1-Chloro-3-methylbut-2-ene

To hydrochloric acid (10 M, 16.5 mL, 174 mmol), 2-Methyl-3-buten-2-ol (5 g, 58 mmol) was added. The mixture was stirred rapidly for 15 minutes, before the addition of DCM (50 mL) and the layers were separated. The organic layer was washed with saturated NaHCO3 (50 mL), brine (50 mL), and dried over 4Å sieves. The solvent was removed to provide 1-chloro- 3-methylbut-2-ene as a colourless oil (5.9 g, 57 mmol, 98%).

1 H NMR (400 MHz, CDCl3) δ 5.44 (tdt, J = 8, 3, 1.5 Hz, 1H, C-2), 4.09 (d, J = 8 Hz, 2H, C- 1), 1.77 (d, J = 1.5 Hz, 3H, Me), 1.73 (d, J = 1.5 Hz, 3H, Me) 13 C NMR (101 MHz, CDCl3) δ 139.6 (C-3), 120.7 (C-2), 41.4 (C-1), 25.9 (Me), 17.8 (Me) IR (neat, cm-1) 2976, 2936, 1672, 1451, 1380, 1256, 843, 671 37 + HRMS (EI+) m/z calculated for C5H9Cl [M] 104.0393, found 104.0396

The experimental data are consistent with those presented in the literature.165

189

4-(1,3-Dioxolan-2-yl)-2,2-dimethylbutanenitrile

To diisopropylamine (2.2 mL, 15 mmol) in THF (25 mL) at 0 °C, n-BuLi (6 mL, 15 mmol, 2.5 M in hexanes) was added as drops. After stirring for 30 minutes, the mixture was cooled to −78 °C and isobutyronitrile (1.3 mL, 15 mmol) was added as drops. After 30 minutes, 2- (2-bromoethyl)-1,3-dioxolane (1.3 mL, 11 mmol) was added in THF (5 mL), and the mixture was stirred for a further hour. The cold bath was removed and the reaction mixture was allowed to warm to room temperature. Once at room temperature, saturated ammonium chloride (30 mL) was added. The biphasic mixture was separated, and the aqueous layer extracted with diethyl ether (3 × 30 mL). The organic extracts were washed with brine, dried over MgSO4, and reduced under vacuum to provide 4-(1,3-dioxolan-2-yl)-2,2- dimethylbutanenitrile as a pale yellow oil (1.85 g, 11 mmol, 98%).

1 H NMR (400 MHz, CDCl3) δ 4.90 (t, J = 4.5 Hz, 1H, C-2’), 4.01 – 3.92 (m, 2H, dioxolane), 3.91 – 3.81 (m, 2H, dioxolane), 1.89 – 1.80 (m, 2H, C-4), 1.69 – 1.61 (m, 2H, C-3), 1.34 (s, 6H, 2 × Me) 13 C NMR (100 MHz, CDCl3) δ 124.8 (C-1), 103.7 (C-2’), 65.1 (dioxolane), 34.9 (C-3), 32.1 (C-2), 29.8 (C-4), 26.7 (2 × Me) IR (neat, cm-1) 2978, 2887, 1474, 1410, 1136, 1035, 947, 873 + HRMS (ES+) m/z calculated for C9H16NO2 [M+H] 170.1181, found 170.1178 Rf 0.22 (2:3 EtOAc/hexane)

190

4-(1,3-Dioxolan-2-yl)-2,2-dimethylbutanal

DIBAL-H (1M in toluene, 53 mL, 53 mmol) was added as drops to a solution of 4-(1,3- dioxolan-2-yl)-2,2-dimethylbutanenitrile (6.4 g, 38 mmol) in DCM (190 mL) cooled to – 78 °C. The reaction mixture was stirred for 2 hours, and water (30 mL) was added to quench the excess DIBAL-H. The mixture was allowed to warm to room temperature, before the careful addition of a saturated aqueous solution of Rochelle’s Salt (200 mL). Once the mixture separated into two clear layers, the mixture was separated and the aqueous extracted with ethyl acetate (3 × 100 mL). The combined organic extracts were washed with brine (300 mL), dried over MgSO4, and reduced under vacuum to provide the crude product. The crude product was purified by column chromatography (25% ethyl acetate/hexane) to give the title compound as a colourless oil (5.2 g, 31 mmol, 82%).

1 H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H, C-1), 4.84 (td, J = 3, 1.5 Hz, 1H, C-2’), 3.99 – 3.91 (m, 2H, dioxolane), 3.89 – 3.81 (m, 2H. dioxolane), 1.58 – 1.56 (m, 4H, C-3 and C-4), 1.06 (s, 6H, 2 × Me) 13 C NMR (100 MHz, CDCl3) δ 206.1 (C-1), 104.4 (C-2’), 65.1 (dioxolane), 45.4 (C-2), 30.9 (C-4 or C-3), 28.8 (C-4 or C-3), 21.4 (2 × Me) IR (neat, cm-1) 2964, 2881, 1725, 1472, 1406, 1134, 1037, 877 + HRMS (ES+) m/z calculated for C9H17O3 [M+H] 173.1178, found 173.1187 Rf 0.18 (7:20 EtOAc/hexane)

191

2-(3,3-Dimethylpent-4-enyl)-1,3-dioxolane

To methyltriphenylphosphonium bromide (13 g, 37 mmol) in THF (130 mL) at 0 °C, n-BuLi (2.5 M in hexanes, 18 mL, 35 mmol) was added as drops. The mixture was stirred for 10 minutes at room temperature before being cooled back to 0 °C. 4-(1,3-Dioxolan-2-yl)-2,2- dimethylbutanal (5.2 g, 31 mmol) was added in THF (20 mL). The mixture was allowed to warm to room temperature over two hours. Water (100 mL) was added, the layers were separated, and the aqueous was extracted with Et2O (3 × 100 mL). The organic extracts were washed with brine (200 mL), dried over MgSO4, filter and concentrated under reduced pressure. The crude compound was purified by column chromatography (5% Et2O/hexane) to give the title compound as a colourless oil (3.6 g, 21 mmol, 69%).

1 H NMR (400 MHz, CDCl3) δ 5.74 (dd, J = 17, 11 Hz, 1H, C-4’), 4.94 – 4.88 (m, 2H, C-5’), 4.81 (t, J = 5 Hz, 1H, C-2), 4.00 – 3.92 (m, 2H, dioxolane), 3.89 – 3.80 (m, 2H, dioxolane), 1.64 – 1.55 (m, 2H), 1.43 – 1.36 (m, 2H), 0.99 (s, 6H, 2 × Me) 13 C NMR (101 MHz, CDCl3) δ 148.0 (C-4’), 110.9 (C-5’), 105.2 (C-2), 65.0 (dioxolane), 36.4 (C-3’), 29.4 (Me), 26.8 (Me) IR (neat, cm-1) 2958, 2875, 1640, 1409, 1132, 1034, 911 + HRMS (CI+) m/z calculated for C10H19O2 [M+H] 171.1385, found 171.1379

Rf: 0.18 (2:20 Et2O/hexane)

192

4,4-Dimethylhex-5-enal

2-(3,3-Dimethylpent-4-enyl)-1,3-dioxolane (2 g, 12 mmol) was dissolved in a mixture of

THF (32 mL), H2O (40 mL) and AcOH (20 mL) and then heated to reflux for two hours.

Once complete, the mixture was allowed to cool to room temperature and Et2O (60 mL) was added. The diluted mixture was quenched with sat. aq. NaHCO3 (50 mL). The biphasic mixture was partitioned and the aqueous was extracted with Et2O (2 × 50 mL). The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound as a colourless oil (1g, 8 mmol, 67%) which can be used without further purification.

1 H NMR (400 MHz, CDCl3) δ 9.76 (t, J = 1.5 Hz, 1H, C-1), 5.71 (dd, J = 17.5, 11 Hz, 1H, C- 5), 5.01 – 4.86 (m, 2H, C-6), 2.36 (td, 2H, J = 8, 1.5 Hz, C-2), 1.67 – 1.57 (m, 2H, C-3), 1.01 (s, 6H, 2 × Me) 13 C NMR (100 MHz, CDCl3) δ 202.9 (C-1), 147.2 (C-5), 111.8 (C-6), 40.0 (C-2), 36.3 (C-4), 34.1 (C-3), 26.7 (2 × Me) IR (neat, cm-1) 2961, 2932, 2872, 1724, 1413, 1364, 1004, 912 + HRMS (CI+) m/z calculated for C8H18NO [M+NH4] 144.1388, found 144.1382

Rf 0.27 (2:20 Et2O/hexane)

193

(±)-8,8-Dimethyl-1-(2-((trimethylsilyl)ethynyl)-1,3-dioxolan-2-yl)dec-9-en-3-yn-5-ol

To ((2-(but-3-ynyl)-1,3-dioxolan-2-yl)ethynyl)trimethylsilane (0.36 g, 1.6 mmol) in THF (5 mL) at −78 °C, n-BuLi (2.3 M in hexanes, 0.64 mL, 1.5 mmol) was added as drops. The reaction mixture was stirred for 30 minutes at −78 °C, and then 4,4-dimethylhex-5-enal (0.23 g, 1.8 mmol) was added in THF (3 mL). The reaction mixture was stirred at −78 °C for 1 hour, before warming slowly to room temperature over 2 hours. Sat. aq. NH4Cl (10 mL) was added and the biphasic mixture separated. The aqueous was extracted with EtOAc (3 × 10 mL). The organic extracts were washed with brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (15% EtOAc/hexane) to give the title compound as a colourless oil (0.36 g, 1.0 mmol, 68%).

1 H NMR (400 MHz, CDCl3) δ 5.83 – 5.68 (m, 1H, C-9), 4.97 – 4.87 (m, 2H, C-10), 4.32 – 4.26 (m, 1H, C-5), 4.13 – 4.04 (m, 2H, dioxolane), 4.03 – 3.91 (m, 2H, dioxolane), 2.48 – 2.39 (m, 2H, C-2), 2.17 – 2.08 (m, 2H, C-1), 1.71 (d, J = 5.5 Hz, 1H, OH), 1.66 – 1.54 (m, 2H, C-6), 1.47 – 1.35 (m, 2H, C-7), 1.00 (s, 6H, 2 × Me), 0.17 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 148.2 (C-9), 110.8 (C-10), 102.0 (C-2’ or C-2’’), 101.9 (C-2’ or C-2’’), 89.4 (C-1’’), 84.7 (C-3), 81.4 (C-4), 64.9 (dioxolane), 63.3 (C-5), 38.5 (C-1), 37.9 (C-7), 36.3 (C-8), 33.6 (C-6), 26.9 (Me), 26.9 (Me), 13.8 (C-2), −0.1 (TMS) IR (neat, cm-1) 3413, 2959, 2898, 1251, 1195, 1093, 1033, 842, 760 + HRMS (ES+) m/z calculated for C20H33O3Si [M+H] 349.2199, found 349.2209 Rf 0.37 (4:20 EtOAc/hexane)

194

(±)-8-Hydroxy-11,11-dimethyl-1-(trimethylsilyl)trideca-12-en-1,6-diyn-3-one

8,8-Dimethyl-1-(2-((trimethylsilyl)ethynyl)-1,3-dioxolan-2-yl)dec-9-en-3-yn-5-ol (0.25 g, 0.72 mmol) and iodine (0.018 g, 0.07 mmol) in acetone (4 mL) were heated to 56 °C for 10 minutes using a microwave reactor. The reaction mixture was diluted with DCM (15 mL) and quenched with sat. aq. Na2S2O3 solution (15 mL). The mixture was separated and the aqueous extracted with DCM (15 mL). The organic extracts were washed with brine (20 mL), dried over dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (15% EtOAc/hexane) to give the title compound as a colourless oil (0.14 g, 0.47 mmol, 65%).

1 H NMR (400 MHz, CDCl3) δ 5.75 (dd, J = 17, 11 Hz, 1H, C-12), 4.96 – 4.86 (m, 2H, C-13), 4.28 (td, J = 6.5, 3 Hz, 1H, C-8), 2.79 (t, J = 7.5 Hz, 2H, C-4), 2.55 (td, J = 7.5, 2 Hz, 2H, C- 5), 1.71 (d, J = 5.4 Hz, 1H, OH), 1.63 – 1.54 (m, 2H, C-9), 1.45 – 1.33 (m, 2H, C-8), 1.00 (s, 6H, 2 × Me), 0.25 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 185.3 (C-3), 148.1 (C-12), 110.9 (C-13), 101.6, 99.0, 83.3, 82.3, 63.2 (C-8), 44.3 (C-4), 37.8 (C-10), 36.3 (C-11), 33.5 (C-9), 26.9 (2 × Me), 13.6 (C-5), −0.7 (TMS) IR (neat, cm-1) 3404, 2959, 2868, 1677, 1253, 1109, 1013, 845, 762 + HRMS (ES+) m/z calculated for C18H28O2SiNa [M+H] 327.1756, found 327.1757 Rf 0.38 (4:20 EtOAc/hexane)

195

(±)-tert-Butyl(8,8-dimethyl-1-(2-((trimethylsilyl)ethynyl)-1,3-dioxolan-2-yl)dec-9-en-3- yn-5-yloxy)dimethylsilane

2,6-Lutidine (0.08 mL, 0.7 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.15 mL, 0.7 mmol) were added sequentially to a solution of 8,8-dimethyl-1-(2- ((trimethylsilyl)ethynyl)-1,3-dioxolan-2-yl)dec-9-en-3-yn-5-ol (250 mg, 0.7 mmol) in DCM (4 mL) cooled to −78 °C. The mixture was stirred for 30 minutes, before allowing it to slowly warm to 0 °C. The mixture was diluted with DCM (10 mL) and sat. aq. NH4Cl (10 mL) was added to quench the reaction. The layers were separated and the aqueous was extracted with DCM (2 × 10 mL). The dichloromethane extracts were dried over MgSO4, filtered and then concentrated under reduced pressure. The crude product was purified by column chromatography (10% Et2O/hexane) to provide the title compound as a colourless oil (210 mg, 0.46 mmol, 65%).

1 H NMR (400 MHz, CDCl3) δ 5.83 – 5.69 (m, 1H, C-9), 4.97 – 4.85 (m, 2H, C-10), 4.26 (tt, J = 6.5, 2.0 Hz, 1H, C-5), 4.14 – 4.03 (m, 2H, dioxolane), 4.02 – 3.92 (m, 2H, dioxolane), 2.46 – 2.38 (m, 2H, C-2), 2.16 – 2.08 (m, 2H, C-1), 1.61 – 1.51 (m, 2H, C-6), 1.48 – 1.29 (m, 2H, C-7), 0.98 (s, 6H, 2 × Me), 0.90 (s, 9H, TBS), 0.18 (s, 9H, TMS), 0.11 (s, 3H, TBS), 0.09 (s, 3H, TBS) 13 C NMR (100 MHz, CDCl3) δ 148.5 (C-9), 110.6 (C-10), 102.1 (C-2’ or C-2’’), 102.0 (C-2’ or C-2’’), 89.3 (C-1’’), 83.4 (C-3 or C-4), 82.1 (C-3 or C-4), 64.9 (dioxolane), 63.8 (C-5), 38.6 (C-1), 38.0 (C-7), 36.3 (C-8), 34.3 (C-6), 27.0 (Me), 26.0 (TBS), 18.5 (TBS), 13.9 (C-2), -0.1 (TMS), -4.2 (TBS), -4.8 (TBS) IR (neat, cm-1) 2957, 2930, 2857, 1251, 1090, 1034, 835, 775, 760 + HRMS (ES+) m/z calculated for C26H48O4Si2 [M+H2O] 480.3091, found 480.3094 Rf 0.17 (3:20 EtOAc/hexane)

196

(+)-1-Cyclohexyl-5-(2-((trimethylsilyl)ethynyl)-1,3-dioxolan-2-yl)pent-2-yn-1-ol

A flask containing zinc triflate (0.2g, 0.55mmol) and (−)-N-methylephedrine (0.11g, 0.6 mmol) was purged with N2 for 10 min. Toluene (1.5 mL) was added to the flask, followed swiftly by triethylamine (0.09 mL, 0.6 mmol), and the mixture stirred for two hours. The alkyne 263 was added in one portion, and after 20 minutes cyclohexanecarboxaldehyde was added. The mixture was then stirred overnight. The reaction was quenched with sat. aq.

NH4Cl soln. (5 mL), the biphasic mixture separated, and the aqueous layer extracted with

Et2O (3 × 5 mL). The combined organic extracts were washed with brine (10 mL), dried over

MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (5% Et2O/hexane) to provide the title compound as a colourless oil (0.06 g, 0.18 mmol, 36%). Spectroscopic data were identical to those reported for the racemic compound (351)

23 [α]D +6.7 (c 3.0, CHCl3) 90% ee as determined from 1H NMR chiral shift experiments of the acetate derivative

197

(±)-1-Cyclohexyl-5-(2-((trimethylsilyl)ethynyl)-1,3-dioxolan-2-yl)pent-2-ynyl acetate

Acetic anhydride (0.017 mL, 0.18 mmol) was added to a solution of (±)-1-cyclohexyl-5-(2- ((trimethylsilyl)ethynyl)-1,3-dioxolan-2-yl)pent-2-yn-1-ol (25 mg, 0.07 mmol), triethylamine (0.02 mL, 0.14 mmol) and DMAP (2 mg, 0.016 mmol) in DCM (0.4 mL) at 0 °C. After 30 minutes, the mixture was diluted with DCM (5 mL) and water (5 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (2 × 5 mL). The organics were dried over MgSO4, filtered, and concentrated under reduced pressure to provide the title compound as a colourless oil (20 mg, 0.054 mmol, 77%).

1 H NMR (400 MHz, CDCl3) δ 5.19 (dt, J = 6, 2 Hz, 1H, C-1), 4.10 – 4.03 (m, 2H, C-4’ or C- 5’), 4.00 – 3.92 (m, 2H, C-4’ or C-5’), 2.48 – 2.39 (m, 2H, C-4), 2.16 – 2.10 (m, 2H, C-5), 2.07 (s, 3H, OAc), 1.87 – 1.57 (m, 6H, cyclohexyl), 1.32 – 1.00 (m, 5H, cyclohexyl), 0.17 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 170.3 (OAc), 102.0 (C-1’’, C-2’’ or C-2’), 101.9 (C-1’’, C-2’’ or C-2’), 89.4 (C-1’’ or C-2’’), 85.8 (C-3), 76.7 (C-2), 68.9 (C-1), 64.9 (C-4’ and C-5’), 42.1 (cyclohexyl), 38.4 (C-5), 28.7 (cyclohexyl), 28.2 (cyclohexyl), 26.4 (cyclohexyl), 25.9 (cyclohexyl), 25.9 (cyclohexyl), 21.2 (OAc), 13.9 (C-4), -0.1 (TMS) IR (neat, cm-1) 2929, 2855, 1740, 1229, 1093, 977, 845, 760 + HRMS (ES+) m/z calculated for C21H32O4SiNa [M+Na] 399.1968, found 399.1978

Rf 0.55 (1:4 EtOAc/hexane)

198

(-)-1-Cyclohexyl-5-(2-((trimethylsilyl)ethynyl)-1,3-dioxolan-2-yl)pent-2-ynyl acetate

Acetic anhydride (0.028 mL, 0.3 mmol) was added to a solution of (+)-351 (40 mg, 0.12 mmol), triethylamine (0.034 mL, 0.24 mmol) and DMAP (3 mg, 0.02 mmol) in DCM (0.6 mL) at 0 °C. After 30 minutes, the mixture was diluted with DCM (5 mL) and water (5 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (2 × 5 mL). The organics were dried over MgSO4, filtered, and concentrated under reduced pressure to provide the title compound as a colourless oil (34 mg, 0.09 mmol, 75%). The Spectroscopic data were identical to those reported for the racemic compound (377).

1 90% ee as determined from H NMR chiral shift experiments (Eu(hfc)3) 23 [α]D −68 (c 2.0, CHCl3)

199

2-(4-Methoxyphenyl)-1,3-dioxane

A reaction flask was equipped with a dean stark apparatus attached to a condenser. In this flask, 1,3-propanediol (4.5 mL, 59 mmol) and p-anisaldehyde (7.2 mL, 59 mmol) were heated to reflux in toluene (10 mL) in the presence of p-TsOH (50 mg). After 3 hours, the toluene was removed under vacuum and the crude product was distilled under reduced pressure (180 °C, 11 mmbar) to give the title compound as a colourless oil (10.4 g, 53 mmol, 90%), which on exposure to air crystallised to a white solid.

1 H NMR (400 MHz, CDCl3) δ 7.45 – 7.36 (m, 2H, C-2’), 6.93 – 6.84 (m, 2H, C-3’), 5.46 (s, 1H, C-2), 4.28 – 4.22 (m, 2H, C-6), 4.04 – 3.82 (m, 2H, C-4), 3.80 (s, 3H, ArOMe), 2.28 – 2.15 (m, 2H, C-5), 1.47 – 1.40 (m, 1H, C-5) 13 C NMR (100 MHz, CDCl3) δ 160.1 (C-4’), 131.5 (C-1’), 127.4 (C-2’), 113.8 (C-3’), 101.7 (C-2), 67.5 (C-4), 55.4 (ArOMe), 25.9 (C-5) IR (neat, cm-1) 2955, 2863, 1613, 1518, 1237, 982, 819, 780, 627 + HRMS (ES+) m/z calculated for C11H15O3 [M+H] 195.1021, found 195.1016

Rf 0.8 (1:3 EtOAc/hexane)

200

3-(4-Methoxybenzyloxy)propan-1-ol

2-(4-methoxyphenyl)-1,3-dioxane (6.8 g, 35 mmol) in toluene (12 mL) at −10 °C was treated with DIBAL-H (1 M in hexanes, 44 mL, 44 mmol). The reaction was allowed to slowly warm to room temperature and it was stirred overnight, before the addition of toluene (10 mL). Rochelle’s salt (aq) (50 mL) was added to the reaction mixture at 0 °C. Once the layers had separated, the mixture was partitioned and the aqueous layer extracted with ethyl acetate

(3 × 50 mL). The organic layers were then washed with brine (50 mL), dried over MgSO4, filtered and reduced under vacuum to give the title product as a colourless oil (5.9 g, 30 mmol, 86%) which required no further purification.

1 H NMR: (400 MHz, CDCl3) δ 7.32 – 7.21 (m, 2H, C-2’), 6.92 – 6.83 (m, 2H, C-3’), 4.45 (s,

2H, ROCH2Ar), 3.30 (s, 3H, ArOMe), 3.76 (t, J = 5.5 Hz, 2H, C-1), 3.63 (t, J = 5.8 Hz, 2H, C-3), 2.56 (s, 1H, OH), 1.90 – 1.78 (m, 2H, C-2) 13 C NMR: (100 MHz, CDCl3) δ 159.4 (C-4’), 130.3 (C-1’), 129.4 (C-2’), 114.0 (C-3), 73.0

(ROCH2Ar), 69.2 (C-3), 62.0 (C-1), 55.4 (ArOMe), 32.2 (C-2) IR: (neat, cm-1) 3383, 2937, 2864, 1612, 1512, 1213, 1080, 1030, 819 + HRMS: (EI+) m/z calculated for C11H16O3 [M] 196.1099, found 196.1107

Rf: 0.10 (1:3 EtOAc/hexane)

201

3-(4-Methoxybenzyloxy)propanal

To oxalyl chloride (2.2 mL, 25 mmol) in DCM (20 mL) at −78 °C, DMSO (3.2 mL, 45 mmol) in DCM (10 mL) was added as drops. After 1 hour, 3-(4-methoxybenzyloxy)propan- 1-ol (2.0 g, 10 mmol) in DCM (10 mL) was added as drops. The reaction mixture was stirred for a further hour, after which triethylamine (11.6 mL, 80 mmol) was added as drops. Stirring was maintained for a further hour before the reaction temperature was allowed to slowly rise to room temperature. Water (50 mL) was added and the layers partitioned. The aqueous was extracted DCM (2 × 50 mL), and the extracts were washed sequentially with 10% K2CO3 (30 mL), water (30 mL), 1M HCl (30 mL), water (30 mL) and brine (30 mL). The organic layer was then dried over MgSO4, filtered and reduced under vacuum to provide the title compound as a pale yellow oil (1.8 g, 9.3 mmol, 93%). The crude material was used in the next reaction without further purification.

1 H NMR: (400 MHz, CDCl3) δ 9.78 (t, J = 2 Hz, 1H, C-1), 7.35 – 7.13 (m, 2H, C-2’), 6.98 –

6.80 (m, 2H, C-3’), 4.46 (s, 2H, ROCH2Ar), 3.80 (s, 3H, ArOMe), 3.80 – 3.76 (m, 2H, C-3), 2.68 (td, J = 6, 2 Hz, 2H, C-2) 13 C NMR: (100 MHz, CDCl3) δ 201.4 (C-1), 159.4 (Ar), 130.1 (Ar), 129.5 (Ar), 128.8 (Ar),

114.1 (Ar), 114.0 (Ar), 73.1 (ROCH2Ar), 63.7 (C-3), 55.4 (ArOMe), 44.0 (C-2) IR: (neat, cm-1) 2905, 2862, 1723, 1612, 1512, 1244, 1089, 1030, 818 + HRMS: (EI+) m/z calculated for C11H14O3 [M] 194.0943, found 194.0940

Rf: 0.35 (1:3 EtOAc/hexane)

202

Ethyl 2-(diphenoxyphosphoryl)acetate

Phosphorus pentachloride (23 g, 110 mmol) was added in portions to a vigorously stirring triethyl phosphonoacetate (8.8 mL, 45 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for an hour, before warming to 70 °C for four hours. The mixture was allowed to cool to room temperature and the volatiles were removed under reduced pressure (11 mbar) while warming slowly to 100 °C. The crude dichloride was used in the next step without further purification. To the dichloride in benzene (20 mL) at 0 °C, phenol (7.8 g, 83 mmol) in benzene (20 mL) was added, followed swiftly by triethylamine (14 mL, 100 mmol). After 1 hour at room temperature the mixture was diluted with EtOAc (60 mL) and washed sequentially with 1M

NaOH (3 × 40 mL) and brine (40 mL). The organics were dried with MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to furnish the title compound as a colourless oil (2.9 g, 9.4 mmol, 21%)

1 H NMR (400 MHz, CDCl3) δ 7.41 – 7.10 (m, 10H, OPh), 4.23 (qd, J = 7, 0.5 Hz, 2H, C-1’),

3.26 (d, J31P, 1H = 21.5 Hz, 2H, C-2), 1.28 (t, J = 7.1 Hz, 3H, C-2’) 13 C NMR (100 MHz, CDCl3) δ 165.0 (C-1), 164.9 (C-1), 150.2 (Ph), 150.1 (Ph), 123.0 (Ph), 125.7 (Ph), 125.6 (Ph), 120.8 (Ph), 120.8 (Ph), 62.1 (C-1’), 35.0 (C-2), 33.6 (C-2), 14.2 (C- 2’) 31 1 P NMR { H} (162 MHz, CDCl3) δ 12.7 IR: (neat, cm-1) 2985, 1735, 1591, 1487, 1278, 1184, 930, 761, 689 + HRMS: (ES+) m/z calculated for C16H18O5P [M+H] 321.0892, found 321.0897

Rf 0.30 (1:3 EtOAc/hexane)

203

(±)-Ethyl 2-(diethoxyphosphoryl) propanoate

Ethyl 2-bromopropionate (15.3 mL, 118 mmol) and triethylphosphite (21 mL, 118 mmol) were combined in a round bottom flask attached to a distillation apparatus. The stirring mixture was heated to 130 °C for 5 hours or until no more distillate was collected. The reaction was cooled to room temperature, placed under vacuum, and then slowly heated to 120 °C to remove unreacted starting materials. This distillation flask contained the title compound as a colourless oil (27 g, 112 mmol, 95 %).

1 H NMR (400 MHz, CDCl3) δ 4.29 – 4.04 (m, 6H, OCH2CH3), 3.02 (dqd, J31P, 1H = 23, J1H, 1H

= 7, 1 Hz, 1H, C-2), 1.43 (dd, J31P, 1H = 18, J1H, 1H = 7 Hz, 3H, C-3), 1.38 – 1.19 (m, 9H,

OCH2CH3) 13 C NMR (100 MHz, CDCl3) δ 169.9 (C-1), 169.9 (C-1), 62.8 (OCH2CH3), 62.8 (OCH2CH3),

61.5 (OCH2CH3), 40.2 (C-2), 38.9 (C-2), 16.6 (OCH2CH3), 16.5 (OCH2CH3), 14.3

(OCH2CH3), 11.9 (C-3), 11.8 (C-3) 31 1 P NMR { H} (162 MHz, CDCl3) δ 23.8 IR (neat, cm-1) 2984, 2942, 2911, 1733, 1247, 1046, 1018, 955, 795 + HRMS (ES+) m/z calculated for C9H20O5P [M+H] 239.1048, found 239.1052

Rf 0.2 (1:40 MeOH/DCM)

204

(±)-Ethyl 2-(diphenoxyphosphoryl)propanoate

To ethyl 2-(diethoxyphosphoryl)propanoate (10 g, 42 mmol) at 0 °C, PCl5 (22 g, 105 mmol) was added portion wise. After one hour at 0 °C, the thick mixture was warmed to room temperature. Following a further hour of stirring at room temperature, the reaction mixture was heated to 80 °C for 8 hours, at which point the volatiles were removed under vacuum (100 °C, 11 mmbar). The remaining faint orange oil was dissolved in THF (20 mL), cooled to −10 °C and treated with lithium phenoxide in THF (84 mmol). The reaction mixture was then stirred for 4 hours at room temperature, before the addition of ammonium chloride. The layers were partitioned and the aqueous layer extracted with ethyl acetate (3 × 50mL). The combined organics were then washed with brine, dried with MgSO4, filtered and reduced under vacuum to give the crude product as a colourless oil. The crude product was then purified using column chromatography (30% ethyl acetate/hexane) to give the title compound as a colourless oil (4.6 g, 14 mmol, 33%).

1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.25 (m, 4H, OPh), 7.25 – 7.09 (m, 6H, OPh), 4.23

(qdd, J = 7, 4, 0.5 Hz, 2H, C-1’), 3.37 (dq, J31P, 1H = 24, J1H, 1H = 7 Hz, 1H, C-2), 1.64 (dd,

J31P, 1H = 19, J1H, 1H = 7 Hz, 3H, C-3), 1.26 (t, J = 7 Hz, 3H, C-2’) 13 C NMR (100 MHz, CDCl3) δ 168.9 (C-1), 168.8 (C-1), 150.4 (OPh), 150.4 (OPh), 150.4 (OPh), 150.3 (OPh), 129.8 (OPh), 125.4 (OPh), 120.7 (OPh), 120.7 (OPh), 120.6 (OPh), 120.6 (OPh), 62.0 (C-1’), 40.4 (C-2), 39.0 (C-2), 14.2 (C-3’), 11.9 (C-3), 11.8 (C-3) 31 1 P NMR { H} (162 MHz, CDCl3) δ 16.8 IR (neat, cm-1) 2986, 1734, 1591, 1488, 1184, 1160, 927, 761, 688 + HRMS (ES+) m/z calculated for C17H20O5P [M+H] 335.1048, found 335.1047

Rf 0.25 (1:3 EtOAc/hexane)

205

(Z)-Ethyl 5-(4-methoxybenzyloxy)-2-methylpent-2-enoate

To ethyl 2-(diphenoxyphosphoryl) propanoate (1 g, 3 mmol) in THF (20 mL), sodium iodide (0.54 g, 3.6 mmol) and DBU (0.5 mL, 3.3 mmol) were added at 0 °C. The mixture was stirred for 30 minutes at 0 °C, before cooling to −78 °C and the addition of the crude aldehyde 141 in THF (10 mL). The mixture was stirred for 30 minutes at − 78 °C and then slowly warmed to room temperature. After stirring at room temperature for 30 minutes, the mixture was quenched with NH4Cl (aq). The layers were then partitioned and the aqueous layer extracted with ethyl acetate (3 × 30mL). The organics were then washed with water (30 mL), brine (30 mL), dried over MgSO4, and filtered. The dry organics were then reduced under vacuum and purified by column chromatography (10% ethyl acetate/hexane) to give the title compound as a colourless oil (0.54 g, 2 mmol, 67%).

1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.15 (m, 2H, PMB), 6.94 – 6.78 (m, 2H, PMB), 6.08 – 5.94 (m, 1H, C-3), 4.45 (s, 2H, PMB), 4.19 (q, J = 7 Hz, 2H, C-1’), 3.80 (s, 3H, PMB), 3.52 (t, J = 6.5 Hz, 2H, C-5), 2.77 (tdt, J = 6.5, 5, 1.5 Hz, 2H, C-4), 1.90 (q, J = 1.5 Hz, 3H, Me), 1.29 (t, J = 7.1 Hz, 1H, C-2’) 13 C NMR (100 MHz, CDCl3) δ 168.1 (C-1), 159.3 (PMB), 139.5 (C-3), 130.6 (PMB), 129.4 (PMB), 128.8 (C-2), 113.9 (PMB), 72.6 (PMB), 69.3 (C-5), 60.3 (C-1’), 55.4 (PMB), 30.3 (C-4), 20.8 (Me), 14.4 (C-2’) IR (neat, cm-1) 2947, 2857, 1708, 1512, 1243, 1091, 1031, 818, 755 + HRMS (ES+) m/z calculated for C16H22O4Na [M+Na] 301.1416, found 301.1403

Rf 0.5 (1:3 EtOAc/ hexane)

206

(Z)-5-(4-Methoxybenzyloxy)-2-methylpent-2-en-1-ol

To (Z)-ethyl 5-(4-methoxybenzyloxy)-2-methylpent-2-enoate (0.4 g, 1.4 mmol) in toluene (8 mL) at −78 °C, 1M DIBAL-H in hexane (3.2 mL, 3.2 mmol) was added as drops. The reaction medium was stirred at −78 °C for 30 minutes before being allowed to warm to room temperature over 2 hours. Sat. aq. Rochelle’s Salt (8 mL) was then added as drops at 0 °C. After vigorous stirring for 30 minutes, the phases were partitioned and the aqueous extracted with ethyl acetate (3 × 15 mL). The organic extracts were washed with brine (2 × 15ml), water (15 mL), dried over MgSO4, and filtered. The organics were then reduced under vacuum and purified by column chromatography (30% EtOAc/hexane) to provide the title compound as a colourless oil (0.28 g, 1.2 mmol, 85%).

1 H NMR (400 MHz, CDCl3) δ 7.29 – 7.18 (m, 2H, PMB), 6.92 – 6.81 (m, 2H, PMB), 5.31 (tq, J = 8, 1.5 Hz, 1H, C-3), 4.44 (s, 2H, PMB), 4.01 (s, 2H, C-1), 3.80 (d, J = 4 Hz, 3H, PMB), 3.43 (t, J = 6 Hz, 2H, C-5), 2.44 (d, J = 5.7 Hz, 1H, ROH), 2.37 – 2.30 (m, 2H, C-4), 1.82 (d, J = 1 Hz, 3H, Me) 13 C NMR (100 MHz, CDCl3) δ 159.4 (PMB), 138.2 (C-2), 130.0 (PMB), 129.6 (PMB), 128.7 (PMB), 124.7 (C-3), 114.1 (PMB), 113.9 (PMB), 73.0 (PMB), 69.02 (C-5), 61.4 (C-1), 55.4 (PMB), 28.5 (C-4), 22.4 (Me) IR (neat, cm-1) 3396, 2899, 1612, 1513, 1247, 1096, 1027 + HRMS (ES+) m/z calculated for C14H20O3Na [M+Na] 259.1310, found 259.1309

Rf 0.1 (1:3 EtOAc/hexane)

207

((2S,3R)-3-(2-(4-Methoxybenzyloxy)ethyl)-2-methyloxiran-2-yl)methanol

To (+)-Diethyl L-tartrate (0.043 mL, 0.25 mmol) in DCM (1 mL) with 4A sieves (100 mg) at i −20 °C, Ti(O Pr)4 (0.063 mL, 0.21 mmol) was added as drops in DCM (1 mL). After stirring for 20 minutes, (Z)-5-(4-Methoxybenzyloxy)-2-methylpent-2-en-1-ol (0.5 g, 2.1 mmol) was added as drops in DCM (1 mL). Stirring was maintained for a further 30 minutes, after which a 3.5M solution of tBuOOH in toluene (1.2 mL, 4.2 mmol) was added as drops. The reaction was then stirred for 3 hours at −35 °C and overnight at −15 °C. The mixture was quenched with 10% NaOH in bine stirred for a further hour, allowing the mixture to warm to room temperature. The mixture was then filtered through celite, washing the filter cake with DCM (3 × 10mL). The layers were partitioned and the aqueous extracted with DCM (3 × 10mL).

The organic extracts were washed with water (20 mL), brine (20 mL), dried over MgSO4, and filtered. The organics were reduced under vacuum and purified by column chromatography (40% ethyl acetate/hexane) to give the title compound as colourless oil (0.45 g, 1.8 mmol, 85%).

1 H NMR (400 MHz, CDCl3) δ 7.27 – 7.22 (m, 2H, PMB), 6.92 – 6.86 (m, 2H, PMB), 4.56 –

4.39 (m, 2H, PMB), 3.80 (s, 3H, PMB), 3.67 – 3.52 (m, 3H, C-2’ and CH2OH), 3.46 (dd, J =

12, 2.5 Hz, 1H, CH2OH), 3.27 (dd, J = 11, 2.5 Hz, 1H, ROH), 2.78 (dd, J = 10, 4 Hz, 1H, C- 3), 2.09 (dtd, J = 15, 4, 2.5 Hz, 1H, C-1’), 1.82 – 1.67 (m, 1H, C-1’), 1.42 (s, 3H, Me) 13 C NMR (100 MHz, CDCl3) δ 159.7 (PMB), 129.8 (PMB), 129.2 (PMB), 114.1 (PMB), 73.4

(PMB), 66.4 (C-2’), 64.2 (CH2OH), 62.5 (C-3), 60.6 (C-2), 55.4 (PMB), 29.2 (C-1’), 20.5 (Me) IR (neat, cm-1) 3425, 2965, 2926, 2865, 1612, 1513, 1245, 1085, 1030, 819 + HRMS (ES+) m/z calculated for C14H20O4Na [M+Na] 275.1259, found 275.1259 29 [α]D +18.09 (c 1.7, CHCl3)

Rf 0.22 (2:3 EtOAc/hexane)

208

((2S, 3R)-3-(2-(4-methoxybenzyloxy)ethyl)-2-methyloxiran-2-yl)methyl acetate

To a solution of ((2S,3R)-3-(2-(4-Methoxybenzyloxy)ethyl)-2-methyloxiran-2-yl)methanol (150 mg, 0.600 mmol), triethylamine (0.170 mL, 1.20 mmol) and DMAP (15 mg, 0.122 mmol) in DCM (3 mL) at 0 °C, acetic anhydride (0.150 mL, 1.59 mmol) was added in one portion. The reaction mixture was stirred for 30 minutes, before the addition of water (5 mL). The biphasic mixture was seperated and the aqueous was extracted with DCM (2 × 5 mL).

The organic phase was then dried over MgSO4, filtered and reduced under vacuum to provide the title compound as a colourless oil (130 mg, 0.44 mmol, 74%)

1 H NMR (400 MHz, CDCl3) δ 7.30 – 7.23 (m, 2H, PMB), 6.91 – 6.86 (m, 2H, PMB), 4.46 (d,

J = 1 Hz, 2H, PMB), 4.18 (d, J = 12 Hz, 1H, CH2OAc), 4.03 (d, J = 12 Hz, 1H, CH2OAc), 3.80 (s, 3H, PMB), 3.64 – 3.54 (m, 2H, C-2’), 2.98 (dd, J = 7, 5.5 Hz, 1H, C-3), 2.08 (s, 3H,

C(O)CH3), 1.97 – 1.75 (m, 2H, C-1’), 1.36 (s, 3H, Me) 13 C NMR (100 MHz, CDCl3) δ 170.9 (C=O), 159.4 (PMB), 130.4 (PMB), 129.4 (PMB),

114.0 (PMB), 72.9 (PMB), 67.0 (C-2’), 66.0 (CH2OAc), 61.9 (C-3), 58.5 (C-2), 55.4 (PMB),

29.2 (C-1’), 20.9 (C(O)CH3), 20.3 (Me) IR (neat, cm-1) 2932, 2860, 1739, 1454, 1234, 1032, 1091, 819 + HRMS (ES+) m/z calculated for C16H22O5Na [M+Na] 317.1365, found 317.1366 24 [α]D + 4.7 (c 5.3, CHCl3) ee 86%

Rf 0.29 (5:20 EtOAc/hexane)

209

((±)-3-(2-(4-Methoxybenzyloxy)ethyl)-2-methyloxiran-2-yl)methanol

To a stirring solution of (Z)-5-(4-Methoxybenzyloxy)-2-methylpent-2-en-1-ol (300 mg, 1.27 mmol) and NaHCO3 (117 mg, 1.4 mmol) in DCM (5 mL) at 0 °C, MCPBA (≤77 %, 311 mg, 1.4 mmol) was added as a solution in DCM (7 mL). The reaction mixture was then stirred for

2 hours. Saturated NaHCO3 (10 mL) was added as drops, the layers were separated, and the aqueous layer was extracted with DCM (2 × 15 mL). The organics were then washed with saturated NaHCO3 (20 mL), dried over MgSO4, filtered and reduced under vacuum to provide the racemic epoxide as a colourless oil (210 mg, 0.83 mmol, 66%). The spectral properties match those reported for the enantiopure compound

((±)-3-(2-(4-methoxybenzyloxy)ethyl)-2-methyloxiran-2-yl)methyl acetate

To a solution of ((±)-3-(2-(4-methoxybenzyloxy)ethyl)-2-methyloxiran-2-yl)methyl acetate (320 mg, 1.27 mmol), triethylamine (0.35 mL, 2.5 mmol) and DMAP (30 mg, 0.25 mmol) in DCM (6 mL) at 0 °C, acetic anhydride (0.3 mL, 3.2 mmol) was added in one portion. The reaction mixture was stirred for 30 minutes, before the addition of water (20 mL). The biphasic mixture was seperated and the aqueous was extracted with DCM (2 × 15 mL). The organic phase was then dried over MgSO4, filtered and reduced under vacuum to provide the title compound as a colourless oil (244 mg, 0.83 mmol, 65%). The spectral properties match those reported for the enantiopure compound

210

((2S, 3R)-3-(2-(4-methoxybenzyloxy)ethyl)-2-methylpent-4-ene-1,2-diol

To a stirred solution of copper iodide (4.6 g, 24 mmol) in THF (40 mL) at −20 °C, vinylmagnesium bromide (0.6M in hexanes, 80 mL, 48 mmol) was added as drops. After the addition was complete, ((2S,3R)-3-(2-(4-methoxybenzyloxy)ethyl)-2-methyloxiran-2- yl)methanol (1.5 g, 6.0 mmol) was added as drops in a solution of THF (20ml. The reaction was then stirred at −20 °C for a further 2 hours, before being allowed to slowly rise to −5 °C overnight. The mixture was quenched with 3% NH4OH/brine solution (50 mL) and warmed to room temperature over the course of an hour. The quenched mixture was then filtered through celite, the THF removed by rotary evaporation, and the aqueous residue was extracted with ethyl acetate (3 × 50 mL). The organic extracts were washed with brine (100 mL), dried over sodium sulphate, filtered and reduced under vacuum. The crude product was then purified by column chromatography (33% EtOAc/hexane to 50% EtOAc/hexane) to provide the title compound as a colourless oil (0.96 g, 54%).

1 H NMR (500 MHz, CDCl3) δ 7.25 – 7.22 (m, 2H, PMB), 6.91 – 6.83 (m, 2H, PMB), 5.70 (ddd, J = 17, 10, 9.5 Hz, 1H, C-4), 5.19 – 5.05 (m, 2H, C-5), 4.40 (AB q, J = 11.5 Hz, 2H, PMB), 3.79 (s, 3H, PMB), 3.56 (d, J = 11.5 Hz, 1H, C-1), 3.47 (ddd, J = 9, 7, 4.5 Hz, 1H, C- 1), 3.41 – 3.32 (m, 2H, C-2’), 2.64 (s, 1H, ROH), 2.51 (s, 1H, ROH), 2.35 (td, J = 10, 3 Hz, 1H, C-3), 1.84 (dddd, J = 14, 8.5, 7, 3 Hz, 1H, C-1’), 1.50 (dddd, J = 14, 11, 6, 4.5 Hz, 1H, C-1’), 1.08 (s, 3H, Me) 13 C NMR (126 MHz, CDCl3) δ 159.3 (PMB), 137.9 (C-4), 130.3 (PMB), 129.5 (PMB), 118.8 (C-5), 113.9 (PMB), 73.8 (PMB), 72.8 (C-3), 68.4 (C-2’), 68.1 (C-1), 55.4 (PMB), 48.0 (C- 3), 29.4 (C-1’), 21.1 (Me) IR (neat, cm-1) 3403, 2939, 2866, 1512, 1244, 1032, 915, 816 + HRMS (ES+) m/z calculated for C16H24O4Na [M+Na] 303.1572, found 303.1577 23 [α]D −5.8 (c 0.5, CHCl3)

Rf: 0.36 (25% EtOAc/hexane)

211

(R)-4-((R)-5-(4-methoxybenzyloxy)pent-1-en-3-yl)-2,2,4-trimethyl-1,3-dioxolane

To a stirred solution of (2S,3R)-5-(4-methoxybenzyloxy)-2-methyl-2-vinylpentane-1,3-diol (0.88 g, 3.1 mmol) in DCM (31 mL), 2,2-dimethoxypropane (0.76 mL, 6.2 mmol) and pyridinium p-toluenesulfonate (0.010 g, cat.) were added at room temperature. The reaction mixture was stirred overnight and subsequently quenched with NH4Cl (30 mL). The biphasic mixture was separated and the aqueous extracted with DCM (2 × 30 mL). The organic extracts were washed with brine (30 mL), dried over magnesium sulphate, filtered and reduced under vacuum. The crude acetonide was purified by column chromatography (25% ethyl acetate/hexane) to provide the title compound as a colourless oil (0.86 g, 2.7 mmol, 88%).

1 H NMR (400 MHz, CDCl3) δ 7.27 – 7.22 (m, 2H, C-2’’), 6.89 – 6.85 (m, 2H, C-3’’), 5.64 (ddd, J = 17, 10.5, 9.5 Hz, 1H, C-2), 5.14 (dd, J = 10.5, 2 Hz, 1H, C-1), 5.03 (ddd, J = 17, 2,

1 Hz, 1H, C-1), 4.40 (AB q, J = 11.5 Hz, 2H, ROCH2Ar), 3.90 (d, J = 8.5 Hz, 1H, C-5’), 3.80 (s, 3H), 3.68 (d, J = 8.5 Hz, 1H, C-5’), 3.46 (ddd, J = 9, 8, 4.5 Hz, 1H, C-5), 3.36 (ddd, J = 9, 8, 7 Hz, 1H, C-5), 2.29 (ddd, J = 12, 9, 2.5 Hz, 1H, C-3), 1.81 (dtd, J = 13.5, 8, 2.5 Hz, 1H, C-4), 1.49 (dddd, J = 13.5, 11.5, 7, 4.5 Hz, 1H, C-4), 1.40 (d, J = 0.9 Hz, 3H, Me), 1.38 (d, J = 0.8 Hz, 3H, Me) , 1.25 (s, 3H, Me) 13 C NMR (100 MHz, CDCl3) δ 159.3 (C-4’’), 137.7 (C-2), 130.8 (C-1’’), 129.4 (C-2’’),

119.0, 118.0 (C-1), 113.9 (C-3’’), 109.4 (C-2’), 82.9 (C-4’), 73.0 (C-5’), 72.7 (ROCH2Ar), 68.3 (C-5), 55.4 (ArOMe), 49.2 (C-3), 29.7 (C-4), 27.4 (Me), 26.9 (Me), 23.3 (Me) IR (neat, cm-1) 2982, 2935, 2864, 1512, 1368, 1245, 1095, 1055, 1036, 816 + HRMS (ES+) m/z calculated for C19H28O4Na [M+Na] 343.1885, found 343.1880 25 [α]D −13.6 (c 8.1, CHCl3)

Rf 0.34 (1:3 EtOAc/hexane)

212

1-((2S, 3R)-3-(2-(4-Methoxybenzyloxy)ethyl)-2-methyloxiran-2-yl)prop-2-en-1-ol

To a solution of oxalyl chloride (0.29 mL, 3.4 mmol) in DCM (6 mL) at −78 °C, DMSO (0.49 mL, 6.9 mmol) in DCM (1 mL) was added as drops. The mixture was stirred for 30 minutes before the addition of ((2S,3R)-3-(2-(4-Methoxybenzyloxy)ethyl)-2-methyloxiran-2- yl)methanol (500 mg, 2.3 mmol) in DCM (1 mL). After a further 30 minutes, triethylamine (2.7 mL, 18 mmol) was added as drops, maintaining the internal temperature at −78 °C. The reaction mixture was warmed to room temperature slowly over the course of an hour and then water (10 mL) was added. The layers were separated and the aqueous was extracted with

DCM (2 × 20 mL). The organic extracts were washed with NaHCO3 (2 × 20 mL), dried with

MgSO4, filtered and concentrated under reduced pressure to provide the crude aldehyde (480 mg, 2.2 mmol).

A solution of the crude aldehyde in THF (22 mL) was cooled to −20 °C and vinyl magnesium bromide was added (0.6 M in THF, 3.7 mL, 2.2 mmol). The reaction mixture was stirred for

2 hours. Saturated NH4Cl (20 mL) was added as drops, and the mixture was allowed to warm to room temperature. The layers were separated and the aqueous was extracted with DCM (3

× 20 mL). The organic extracts were washed with saturated NH4Cl (20 mL), dried over

MgSO4, filtered, concentrated under reduced pressure and purified by column chromatography (33 % EtOAc/hexane) to provide the allylic alcohol as separable epimers (dr = 1:1) (combined yield: 320 mg, 1.15 mmol, 50 % over two steps).

213

Epimer A:

1 H NMR (400 MHz, CDCl3) δ 7.29 – 7.20 (m, 2H, PMB), 6.93 – 6.84 (m, 2H, PMB), 5.93 (dddd, J = 17.5, 11, 5, 1 Hz, 1H, C-2), 5.41 (dt, J = 17.5, 2 Hz, 1H, C-3), 5.32 – 5.22 (m, 1H, C-3), 4.56 – 4.41 (m, 2H, PMB), 3.99 (dd, J = 2, 1 Hz, 1H, ROH), 3.94 (dq, J = 5, 2 Hz, 1H, C-1), 3.81 (s, 3H, PMB), 3.63 (ddd, J = 9.5, 4, 3.5 Hz, 1H, C-2’’), 3.54 (ddd, J = 12, 9.5, 2.5 Hz, 1H, C-2’’), 2.78 (dd, J = 10, 4 Hz, 1H, C-3’), 2.12 (dtd, J = 14.8, 3.6, 2.4 Hz, 1H, C-1’’), 1.84 (dddd, J = 14.5, 12, 10, 4 Hz, 1H, C-1’’), 1.27 (s, 3H, Me) 13 C NMR (100 MHz, CDCl3) δ 159.7 (PMB), 136.0 (C-2), 129.8 (PMB), 129.1 (PMB), 116.3 (C-3), 114.1 (PMB), 73.3 (PMB), 72.1 (C-1), 66.1 (C-2’’), 63.2 (C-3’), 62.3 (C-2’), 55.4 (PMB), 28.6 (C-1’’), 17.1 (Me) IR (neat, cm-1) 3431, 2967, 2926, 2866, 1612, 1513, 1246, 1082, 1033, 995, 819 + HRMS (ES+) m/z calculated for C16H22O4Na [M+Na] 301.1416, found 301.1421 23 [α]D −48 (c 5.5, CHCl3)

Rf 0.38 (1:2 EtOAc/hexane)

Epimer B:

1 H NMR (400 MHz, CDCl3) δ 7.31 – 7.20 (m, 2H, PMB), 6.93 – 6.84 (m, 2H, PMB), 5.86 (ddd, J = 17.5, 11, 5 Hz, 1H, C-2), 5.35 (dt, J = 17.5, 2 Hz, 1H, C-3), 5.20 (dt, J = 11, 1.5 Hz, 1H, C-3), 4.47 (d, J = 1 Hz, 2H, PMB), 4.08 (ddt, J = 5.5, 3.5, 1.5 Hz, 1H, C-1), 3.81 (s, 3H, PMB), 3.67 – 3.54 (m, 2H, C-2’’), 2.99 (dd, J = 7.5, 5 Hz, 1H, C-3’), 2.11 (d, J = 3.8 Hz, 1H, ROH), 2.02 (dddd, J = 14.5, 8, 6.5, 5 Hz, 2H, C-1’’), 1.82 (ddt, J = 14.5, 7.5, 5.5 Hz, 1H, C- 1’’), 1.29 (s, 3H, Me). 13 C NMR (100 MHz, CDCl3) δ 159.4 (PMB), 136.2 (C-2), 130.3 (PMB), 129.5 (PMB), 116.3 (C-3), 114.0 (PMB), 73.9 (C-1), 73.0 (PMB), 67.2 (C-2’’), 63.2 (C2’), 62.9 (C-3’), 55.4 (PMB), 29.1 (C-1’’), 17.0 (Me) IR (neat, cm-1) 3435, 2925, 2861, 1612, 1513, 1454, 1245, 1088, 1033, 993, 818 + HRMS (ES+) m/z calculated for C16H22O4Na [M+Na] 301.1416, found 301.1419 23 [α]D +56 (c 4.4, CHCl3)

Rf 0.23 (1:2 EtOAc/hexane)

214

(1-((2S, 3R)-3-(2-(4-Methoxybenzyloxy)ethyl)-2-methyloxiran-2- yl)allyloxy)trimethylsilane

The epimers of 414 were reacted separately as the protected products were inseparable by column chromatography.

Trimethylsilyl chloride (0.06 mL, 0.48 mmol) and imidazole (50 mg, 0.74 mmol) were added to a solution of (−)-414 (104 mg, 0.37 mmol) in DCM (4 mL) at 0 °C. The mixture was stirred overnight. Once complete, H2O (5 mL) was added, the layers were separated, and the aqueous layer was extracted with DCM (2 × 5 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure to provide the title compound as a colourless oil (120 mg, 0.35 mmol, 95%)

1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.22 (m, 2H, PMB), 6.93 – 6.84 (m, 2H, PMB), 5.92 (ddd, J = 17, 10.5, 5.5 Hz, 1H, C-2), 5.34 – 5.16 (m, 2H, C-3), 4.48 (d, J = 2 Hz, 2H, PMB), 3.91 (dt, J = 5.5, 1.5 Hz, 1H, C-1), 3.81 (s, 3H, PMB), 3.63 (ddd, J = 7.5, 6, 1.5 Hz, 2H, C- 2’’), 2.95 (dd, J = 8, 4 Hz, 1H, C-3’), 2.06 (dtd, J = 14, 7, 4 Hz, 1H, C-1’’), 1.77 (ddt, J = 14, 8, 6 Hz, 1H, C-1’’), 1.23 (s, 3H, Me), 0.09 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 159.4 (PMB), 137.8 (C-2), 130.5 (PMB), 129.5 (PMB), 116.3 (C-3), 114.0 (PMB), 73.4 (PMB), 73.0 (C-1), 67.7 (C-2’’), 62.7 (C-3’), 62.5 (C-2’), 55.4 (PMB), 29.0 (C-1’’), 17.4 (Me), 0.6 (TMS) IR (neat, cm-1) 2958, 2930, 2859, 1513, 1247, 1084, 876, 838, 751 + HRMS (ES+) m/z calculated for C19H30O4SiNa [M+Na] 373.1811, found 373.1811 24 [α]D −22 (c 3.2, CHCl3)

Rf 0.89 (1:2 EtOAc/hexane)

215

Trimethylsilyl chloride (0.06 mL, 0.48 mmol) and imidazole (50 mg, 0.74 mmol) were added to a solution of (+)-414 (100 mg, 0.36 mmol) in DCM (4 mL) at 0 °C. The mixture was stirred overnight. Once complete, H2O (5 mL) was added, the layers were separated, and the aqueous layer was extracted with DCM (2 × 5 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure to provide the title compound as a colourless oil (110 mg, 0.32 mmol, 89%)

1 H NMR (400 MHz, CDCl3) δ 7.34 – 7.22 (m, 2H, PMB), 6.93 – 6.81 (m, 2H, PMB), 5.80 (ddd, J = 17, 10.5, 4.5 Hz, 1H, C-2), 5.33 – 5.26 (m, 1H, C-3), 5.12 (dt, J = 10.5, 2 Hz, 1H, C-3), 4.47 (d, J = 1.5 Hz, 2H, PMB), 3.97 (dt, J = 4.5, 2 Hz, 1H, C-1), 3.81 (s, 3H, PMB), 3.69 – 3.56 (m, 2H, C-2’’), 2.90 (dd, J = 8, 4 Hz, 1H, C-3’), 2.00 (dddd, J = 14, 8, 7, 4 Hz, 1H, C-1’’), 1.75 (ddt, J = 14, 8, 6 Hz, 1H, C-1’’), 1.22 (s, 3H, Me), 0.14 (s, 9H, TMS) 13 C NMR (125 MHz, CDCl3) δ 159.4 (PMB), 137.2 (C-2), 130.4 (PMB), 129.5 (PMB), 115.6 (C-3), 114.0 (PMB), 75.0 (PMB), 73.0 (C-1), 67.6 (C-2’’), 63.0 (C-2’’), 61.7 (C-2’), 55.4 (PMB), 29.4 (C-1’’), 16.5 (Me), 0.3 (TMS) IR (neat, cm-1) 2956, 2929, 2861, 1513, 1248, 1085, 1034, 840, 732 + HRMS (ES+) m/z calculated for C19H30O4SiNa [M+Na] 373.1811, found 373.1800 23 [α]D +33 (c 0.6, CHCl3)

Rf 0.89 (1:2 EtOAc/hexane)

216

(But-3-enyloxy)triisopropylsilane

Triisopropylsilyl chloride (7.4 mL, 35 mmol) was added as drops to a solution of 3-buten-1- ol (2.5 g, 35 mmol) and imidazole (5.9 g, 88 mmol) in DCM (35 mL) at 0 °C. The mixture was stirred overnight, before the addition of saturated NH4Cl (40 mL). The biphasic mixture was separated and the aqueous was extracted with DCM (3 × 50 mL). The organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide the tile compound as a colourless oil (6.8 g, 30 mmol, 86%).

1 H NMR (400 MHz, CDCl3) δ 5.91 – 5.80 (m, 1H, C-3), 5.13 – 4.97 (m, 2H C-4), 3.73 (t, J = 7 Hz, 2H, C-1), 2.31 (qt, J = 7, 1.5 Hz, 2H, C-2), 1.16 – 0.98 (m, 21H, TIPS) 13 C NMR (100 MHz, CDCl3) δ 135.7 (C-3), 116.3 (C-4), 63.2 (C-1), 37.8 (C-2), 18.2 (TIPS), 12.2 (TIPS) IR (neat) 2942, 2893, 2866, 1464, 1384, 1102, 882, 680 + HRMS (CI+) m/z calculated for C13H29OSi [M+H] 229.1988, found 229.1991

The experimental data are consistent with those presented in the literature.166

217

3-(Triisopropylsilyloxy)propanal

(But-3-enyloxy)triisopropylsilane (6.8 g, 30 mmol) in DCM (30 mL) and MeOH (30 mL) at

−78 °C was treated with O3/O2. Once the solution became pale blue, the mixture was purged with nitrogen for 20 minutes, dimethylsulfide was added (25 mL), and allowed to warm to room temperature overnight. Saturated NaHCO3 soln. (50 mL) and hexane (200 mL) were added, and the layers were separated. The organics were washed with saturated NaHCO3 soln. (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide the aldehyde as a colourless oil (6.7 g, 29 mmol, 97%).

1 H NMR (400 MHz, CDCl3) δ 9.84 (t, J = 2 Hz, 1H, C-1), 4.08 (t, J = 6 Hz, 2H, C-3), 2.61 (td, J = 6, 2 Hz, 2H, C-2), 1.16 – 0.97 (m, 21H, TIPS) 13 C NMR (100 MHz, CDCl3) δ 202.4 (C-1), 58.1 (C-3), 46.9 (C-2), 18.1 (TIPS), 12.0 (TIPS) IR (neat) 2942, 2867, 2726, 1728, 1464, 1105, 881, 681 + HRMS (CI+) m/z calculated for C12H27O2Si [M+H] 231.1780, found 231.1786

Rf 0.25 (5% Et2O/hexane)

The experimental data are consistent with those presented in the literature.166

218

(Z)-Ethyl 2-methyl-5-(triisopropylsilyloxy)pent-2-enoate

Sodium iodide (3.1 g, 20 mmol) and DBU (2.8 mL, 19 mmol) were added to a solution of ethyl 2-(diphenoxyphosphoryl)propanoate (5.7 g, 17 mmol) in THF (65 mL) at 0 °C. The mixture was stirred for 30 minutes, before cooling to −78 °C. A solution of 3- (triisopropylsilyloxy)propanal (3.9 g, 17 mmol) in THF (20 mL) was added as drops. After an hour at −78 °C, the reaction mixture was warmed to slowly to room temperature and then saturated NH4Cl (50 mL) was added. The layers were separated and the aqueous was extracted with EtOAc (3 × 75 mL). The organics were dried over NaSO4, filtered, concentrated under reduced pressure, and purified by column chromatography to provide the title compound with the coeluting trans stereoisomer (cis/trans 86:14) as a colourless oil (3.8 g, 12.1 mmol, 71%).

1 H NMR (400 MHz, CDCl3) δ 6.06 (tq, J = 7, 1.5 Hz, 1H, C-3), 4.19 (q, J = 7 Hz, 2H, C-1’), 3.75 (t, J = 6.5 Hz, 2H, C-5), 2.74 – 2.67 (m, 2H, C-4), 1.91 (q, J = 1.5 Hz, 3H, Me), 1.30 (t, J = 7 Hz, 3H, C-2’), 1.16 – 0.98 (m, 21H, TIPS) 13 C NMR (100 MHz, CDCl3) δ 168.2 (C-1), 139.7 (C-3), 128.5 (C-2), 62.9 (C-5), 60.2 (C- 1’), 33.5 (C-4), 20.9 (Me), 18.2 (TIPS), 14.4 (C-2’), 12.2 (TIPS) IR (neat) 2942, 2866, 1715, 1210, 1101, 1055, 881, 681 + HRMS (ES+) m/z calculated for C17H35O3Si [M+H] 315.2355, found 315.2369

Rf 0.33 (1:40 Et2O/hexane)

219

(Z)-2-Methyl-5-(triisopropylsilyloxy)pent-2-en-1-ol

To a mixture of (Z)-2-methyl-5-(triisopropylsilyloxy)pent-2-en-1-ol (4.1 g, 13 mmol) in toluene (65 mL) at −78 °C, DIBAL-H (1M in hexane, 29 mL, 29 mmol) was added as drops. The reaction mixture was stirred at −78 °C for 30 minutes, before warming slowly to room temperature over the course of 2 hours. A saturated aqueous solution of Rochelle’s salt (70 mL) was added at 0 °C, and the cloudy mixture was stirred until the clear and two phases formed. The biphasic mixture was partioned and the aqueous extracted with EtOAc (3 × 50 mL). The organic extracts were washed with brine (100 mL), dried over NaSO4, filtered, and concentrated under reduced pressure. The crude compound was then purified by column chromatography to furnish the title compound as a colourless oil (2.8 g, 10.4 mmol, 80%). The desired stereoisomer coeluted with the minor trans allylic alcohol.

1 H NMR (400 MHz, CDCl3) δ 5.33 (td, J = 8, 2 Hz, 1H, C-3), 4.07 (d, J = 6 Hz, 2H, C-1), 3.69 (t, J = 6.0 Hz, 2H, C-5), 2.39 – 2.28 (m, 2H, C-4), 2.23 (t, J = 5.9 Hz, 1H, ROH), 1.82 (d, J = 1 Hz, 3H, Me), 1.17 – 0.97 (m, 21H, TIPS) 13 C NMR (100 MHz, CDCl3) δ 137.9 (C-2), 125.0 (C-3), 62.9 (C-5), 61.9 (C-1), 31.5 (C-4), 22.3 (Me), 18.1 (TIPS), 12.1 (TIPS) IR (neat) 3336, 2941, 2892, 2866, 1462, 1103, 1005, 882, 679, 656 + HRMS (ES+) m/z calculated for C15H33O2Si [M+H] 273.2250, found 273.2253 Rf 0.18 (2:20 EtOAc/hexane)

220

((2S,3R)-2-Methyl-3-(2-(triisopropylsilyloxy)ethyl)oxiran-2-yl)methanol

To a solution of (+)-diethyl L-tartrate (120 mg, 0.59 mmol) in DCM (6 mL) with 4Å i molecular sieves (0.5 g) at − 20 °C, Ti(O Pr)4 (0.14 mL, 0.49 mmol) was added as drops in DCM (4 mL). After 20 minutes (Z)-2-methyl-5-(triisopropylsilyloxy)pent-2-en-1-ol (1.4 g, 4.9 mmol) was added as drops in DCM (2 mL), and the mixture was stirred for a further 30 minutes. tBuOOH (4 M in toluene, 2.4 mL, 9.7 mmol) was added carefully to ensure that the reaction temperature stays at − 20 °C. The reaction was then stirred overnight. 10% NaOH in bine (15 mL) was added, allowing the mixture to warm to room temperature. The layers were partitioned and the aqueous extracted with DCM (3 × 15 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over MgSO4, and filtered. The organics were concentrated under reduced pressure, and purified by column chromatography (2%

Et2O/DCM) to provide the title compound as a colourless oil (1 g, 3.4 mmol, 83%).

1 H NMR (400 MHz, CDCl3) δ 3.97 – 3.78 (m, 2H, C-2’), 3.68 (dd, J = 12, 10 Hz, 1H,

CH2OH), 3.56 (dd, J = 12, 3.5 Hz, 1H, CH2OH), 2.96 (dd, J = 10, 3.5 Hz, 1H, ROH), 2.87 (dd, J = 9, 4 Hz, 1H, C-3), 2.09 – 1.98 (m, 1H, C-1’), 1.82 – 1.71 (m, 1H, C-1’), 1.44 (s, 3H, Me), 1.21 – 1.01 (m, 21H, TIPS) 13 C NMR (100 MHz, CDCl3) δ 64.7 (CH2OH), 62.7 (C-3), 60.9 (C-2), 60.8 (C-2’), 31.6 (C- 1’), 20.5 (Me), 18.1 (TIPS), 12.1 (TIPS) IR (neat) 3421, 2939, 2866, 1463, 1098, 880, 680, 656 + HRMS (ES+) m/z calculated for C15H33O3Si [M+H] 289.2199, found 289.2197 23 [α]D +21 (c 3.9, CHCl3)

Rf 0.39 (1:50 Et2O/DCM)

221

((2S,3R)-2-Methyl-3-(2-(triisopropylsilyloxy)ethyl)oxiran-2-yl)methyl acetate

Acetic anhydride (0.05 mL, 0.53 mmol) was added to a solution of ((2S,3R)-2-Methyl-3-(2- (triisopropylsilyloxy)ethyl)oxiran-2-yl)methanol (60 mg, 0.21 mmol), triethylamine (0.06 mL, 0.42 mmol) and DMAP (5 mg, 0.04 mmol) in DCM (1 mL) cooled to 0 °C. After 30 minutes, the mixture was added to a mixture of water (5 mL) and DCM (5 mL). The layers were separated and the organics were washed with brine (5 mL). The organics were dried over MgSO4, filtered, and concentrated under reduced pressure to provide the title compound as a colourless oil (49 mg, 0.15 mmol, 71%).

1 H NMR (400 MHz, CDCl3) δ 4.21 (d, J = 12 Hz, 1H, CH2OAc), 4.05 (d, J = 12 Hz, 1H,

CH2OAc), 3.86 (dd, J = 7, 5.5 Hz, 2H, C-2’), 3.03 (dd, J = 6.5, 6 Hz, 1H, C-3), 2.10 (s, 3H,

C(O)CH3), 1.89 – 1.74 (m, 2H, C-1’), 1.37 (s, 3H, Me), 1.16 – 1.01 (m, 21H, TIPS) 13 C NMR (101 MHz, CDCl3) δ 170.9 (C=O), 66.1 (CH2OAc), 62.0 (C-3), 60.7 (C-2’), 58.5

(C-2), 32.0 (C-1’), 20.9 (C(O)CH3), 20.3 (Me), 18.2 (TIPS), 12.1 (TIPS) IR (neat) 2943, 2866, 1744, 1463, 1382, 1229, 1098, 881, 680 + HRMS (ES+) m/z calculated for C17H35O4Si [M+H] 331.2305, found 331.2309 23 [α]D +4.9 (c 0.1, CHCl3) ee 88%

Rf 0.3 (1:20 Et2O/hex)

222

1-((2S,3R)-2-Methyl-3-(2-(triisopropylsilyloxy)ethyl)oxiran-2-yl)prop-2-en-1-ol

To a solution of oxalyl chloride (0.17 mL, 2.1 mmol) in DCM (4 mL) at −78 °C, DMSO (0.29 mL, 4.2 mmol) in DCM (1 mL) was added as drops. The mixture was stirred for 30 minutes before the addition of ((2S,3R)-3-(2-(4-Methoxybenzyloxy)ethyl)-2-methyloxiran-2- yl)methanol (400 mg, 1.4 mmol) in DCM (1 mL). After a further 30 minutes, triethylamine (1.6 mL, 11 mmol) was added as drops, maintaining the internal temperature at −78 °C. The reaction mixture was warmed to room temperature slowly over the course of an hour and then water (5 mL) was added. The layers were separated and the aqueous was extracted with DCM

(2 × 10 mL). The organic extracts were washed with NaHCO3 (2 × 10 mL), dried with

MgSO4, filtered and concentrated under reduced pressure to provide the crude aldehyde which was used without further purification.

A solution of the crude aldehyde in THF (14 mL) was cooled to −20 °C and vinyl magnesium bromide (1 M in THF, 1.4 mL, 1.4 mmol) was added. The reaction mixture was stirred for two hours. Saturated NH4Cl (15 mL) was added as drops, and the mixture was allowed to warm to room temperature. The layers were separated and the aqueous was extracted with

DCM (3 × 15 mL). The organic extracts were washed with saturated NH4Cl (20 mL), dried over MgSO4, filtered, concentrated under reduced pressure and purified by column chromatography (33 % EtOAc/hexane) to provide the allylic alcohol as separable epimers (d.r. 1:1) (combined yield: 210 mg, 0.67 mmol, 48% over two steps).

223

Epimer A:

1 H NMR (400 MHz, CDCl3) δ 5.95 (ddd, J = 17.5, 10.5, 5.5 Hz, 1H, C-2), 5.42 (dt, J = 17.5, 1.5 Hz, 1H, C-3), 5.27 (dt, J = 10.5, 1.5 Hz, 1H, C-3), 3.99 – 3.92 (m, 2H, C-1 and C-2’’), 3.84 (td, J = 10.5, 2.5 Hz, 1H, C-2’’), 3.52 (d, J = 1.5 Hz, 1H, ROH), 2.87 (dd, J = 9.5, 4 Hz, 1H, C-3’), 2.13 – 2.05 (m, 1H, C-1’’), 1.91 – 1.81 (m, 1H, C-1’’), 1.29 (s, 3H, Me), 1.21 – 1.04 (m, 21H, TIPS) 13 C NMR (100 MHz, CDCl3) δ 136.1 (C-2), 116.7 (C-3), 72.9 (C-1), 63.4 (C-3’), 62.5 (C-2’), 60.9 (C-2’’), 30.9 (C-1’’), 18.1 (TIPS), 17.4 (Me), 12.1 (TIPS) IR (neat, cm-1) 3443, 2939, 2867, 1382, 1096, 1070, 879, 681, 650 + HRMS (ES+) m/z calculated for C17H35O3Si [M+H] 315.2355, found 315.2369 301.1421 24 [α]D −24 (c 3.3, CHCl3)

Rf 0.37 (5:20 Et2O/hexane)

Epimer B:

1 H NMR (400 MHz, CDCl3) δ 5.89 (ddd, J = 17.5, 10.5, 5 Hz, 1H, C-2), 5.38 (dt, J = 17.5, 1.5 Hz, 1H, C-3), 5.24 (dt, J = 10.5, 1.5 Hz, 1H, C-3), 4.09 (ddt, J = 5, 3.5, 1.5 Hz, 1H, C-1), 3.94 – 3.82 (m, 2H, C-2’’), 3.05 (dd, J = 7.5, 5 Hz, 1H, C-3’), 2.09 (d, J = 3.5 Hz, 1H, ROH), 2.02 – 1.93 (m, 1H, C-1’’), 1.77 (ddt, J = 14, 7.5, 5 Hz, 1H, C-1’’), 1.30 (s, 3H, Me), 1.21 – 0.98 (m, 21H, TIPS) 13 C NMR (100 MHz, CDCl3) δ 136.3 (C-2), 116.4 (C-3), 74.0 (C-1), 63.2 (C-2’), 62.8 (C-3’), 61.0 (C-2’’), 31.8 (C-1’’), 18.1 (TIPS), 17.0 (Me), 12.1 (TIPS) IR (neat, cm-1) 3439, 2937, 2867, 1463, 1382, 1099, 993, 881, 750, 680 + HRMS (ES+) m/z calculated for C17H35O3Si [M+H] 315.2355, found 315.2360 24 [α]D +68 (c 1.7, CHCl3)

Rf 0.16 (5:20 Et2O/hexane)

224

Triisopropyl(2-((2R,3R)-3-methyl-3-(1-(trimethylsilyloxy)allyl)oxiran-2-yl)ethoxysilane

The epimers of 435 were reacted separately as the protected products were inseparable by column chromatography.

TMSCl (0.1 mL, 0.86 mmol) and imidazole (120 mg, 1.7 mmol) were added sequentially to a solution of (−)-435 (180 mg, 0.57 mmol) in DCM (6 mL) at 0 °C. The mixture was then stirred overnight. Water (5 mL) was added, the layers separated, and the aqueous layer was extracted with DCM (3 × 5 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure to provide the title compound as a colourless oil (210 mg, 0.54 mmol, 95%)

1 H NMR (400 MHz, CDCl3) δ 5.93 (ddd, J = 17, 10.5, 5.5 Hz, 1H, C-2’’), 5.29 (dt, J = 17, 1.5 Hz, 1H, C-3’’), 5.21 (dt, J = 10.5, 1.5 Hz, 1H, C-3’’), 3.95 – 3.85 (m, 3H, C-1 and C-1’’), 3.02 (dd, J = 8, 4 Hz, 1H, C-2’), 1.99 (dtd, J = 14, 7, 4 Hz, 1H, C-2), 1.80 – 1.68 (m, 1H, C- 2), 1.24 (s, 3H, Me), 1.16 – 1.02 (m, 21H, TIPS), 0.11 (s, 9H, TMS) 13 C NMR (101 MHz, CDCl3) δ 137.9 (C-2’’), 116.2 (C-3’’), 73.6 (C-1’’), 62.6 (C-2’), 62.5 (C-3’), 61.1 (C-1), 31.9 (C-2), 18.2 (TIPS), 17.5 (Me), 12.1 (TIPS), 0.6 (TMS) IR (neat, cm-1) 2946, 2867, 1252, 1098, 1075, 877, 840, 680 + HRMS (ES+) m/z calculated for C20H42O3Si2 [M+H] 387.2751, found 387.2761 301.1421 26 [α]D −20 (c 1.0, CHCl3)

Rf 0.75 (5:20 Et2O/hexane)

225

TMSCl (0.12 mL, 0.96 mmol) and imidazole (130 mg, 1.9 mmol) were added sequentially to a solution of (+)-435 (200 mg, 0.64 mmol) in DCM (6 mL) at 0 °C. The mixture was then stirred overnight. Water (5 mL) was added, the layers separated, and the aqueous layer was extracted with DCM (3 × 5 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure to provide the title compound as a colourless oil (220 mg, 0.58 mmol, 90%)

1 H NMR (400 MHz, CDCl3) δ 5.85 (ddd, J = 17, 10.5, 4.5 Hz, 1H, C-2’’), 5.38 – 5.28 (m, 1H, C-3’’), 5.16 (dt, J = 10.5, 2 Hz, 1H, C-3’’), 3.98 (dt, J = 4.5, 2 Hz, 1H, C-1’’), 3.92 – 3.86 (m, 2H, C-1), 2.94 (dd, J = 8, 4.5 Hz, 1H, C-2’), 1.94 (dddd, J = 14, 7.5, 7, 4.5 Hz, 1H, C-2), 1.78 – 1.66 (m, 1H, C-2), 1.22 (s, 3H, Me), 1.14 – 1.01 (m, 21H, TIPS), 0.15 (s, 9H, TMS) 13 C NMR (100 MHz, CDCl3) δ 137.3 (C-2’’), 115.4 (C-3’’), 75.1 (C-1’’), 62.9 (C-3’), 61.6 (C-2’), 61.2 (C-1), 32.2 (C-2), 18.2 (TIPS), 16.6 (Me), 12.1 (TIPS), 0.2 (TMS) + HRMS (ES+) m/z calculated for C20H43O3Si2 [M+H] 387.2751, found 387.2742 301.1421 26 [α]D +65 (c 1.0, CHCl3)

Rf 0.75 (5:20 Et2O/hexane)

226

(2R, 3R)-2-Methyl-5-(triisopropylsilyloxy)-2-vinylpentane-1,3-diol

TiCl4 (1M in DCM, 0.2 mL, 0.2 mmol) was added to a solution of (+)-423 (76 mg, 0.2 mmol) in DCM (4 mL) at −78 °C. After 5 minutes Et3SiH (0.1 mL, 0.6 mmol) was added in one portion, and the mixture was allowed to warm gradually to −50 °C. Once at −50 °C, the reaction was quenched with sat. aq. NH4Cl (5 mL), and the biphasic mixture was allowed to warm to room temperature. The organic layer was separated and the aqueous extracted with

DCM (3 × 5 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc/hexane) to provide the title compound as a single diastereoisomer (29 mg, 0.092 mmol, 46%).

Alternatively the rearrangement may be completed on the mixture of epimers:

TiCl4 (1M in DCM, 0.26 mL, 0.26 mmol) was added to a solution of 423 (100 mg, 0.26 mmol) in DCM (5 mL) at −78 °C. After 5 minutes Et3SiH (0.12 mL, 0.78 mmol) was added in one portion, and the mixture was allowed to warm gradually to −50 °C. Once at −50 °C, the reaction was quenched with sat. aq. NH4Cl (5 mL), and the biphasic mixture was allowed to warm to room temperature. The organic layer was separated and the aqueous extracted with DCM (3 × 5 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc/hexane) to provide the title compound in a diastereomeric ratio of 9:1 (33 mg, 0.1 mmol, 40%). The minor diastereoisomer is epimeric at C-2.

227

1 H NMR (400 MHz, CDCl3) δ 6.04 (dd, J = 18, 11 Hz, 1H, C-1’), 5.19 (dd, J = 11, 1.5 Hz, 1H, C-2’), 5.08 (dd, J = 18, 1.5 Hz, 1H, C-2’), 4.23 (d, J = 1.5 Hz, 1H), 4.02 (dt, J = 10, 4 Hz, 1H, C-5), 3.92 (dd, J = 10, 3 Hz, 1H, C-5), 3.89 – 3.84 (m, 1H, C-3), 3.68 (dd, J = 11, 6.5 Hz, 1H, C-1), 3.58 (dd, J = 11, 4.5 Hz, 1H, C-1), 3.10 – 3.03 (m, 1H, ROH), 1.77 – 1.57 (m, 3H, C4 and ROH), 1.14 – 1.02 (m, 21H, TIPS), 1.02 (s, 3H, Me). 13 C NMR (101 MHz, CDCl3) δ 140.5 (C-1’), 115.0 (C-2’), 79.8 (C-3), 70.2 (C-1), 64.4 (C-5),

45.1 (C-2), 33.5 (C-4), 18.6 (Me), 18.1 (TIPS), 11.9 (TIPS) IR (neat) 3382, 2946, 2869, 1463, 1249, 1090, 1069, 882, 840, 731 + HRMS (ES+) m/z calculated for C17H37O3Si [M+H] 317.2512, found 317.2527 24 [α]D +17 (c 3.0, CHCl3)

Rf 0.20 (5:20 Et2O/hexane)

228

Triisopropyl(2-((4R,5R)-2,2,5-trimethyl-5-vinyl-1,3-dioxan-4-yl)ethoxy)silane

PPTS (2mg, 0.01 mmol) was added to a solution of 2,2-dimethoxypropane (0.024 mL, 0.20 mmol) and (2R, 3R)-2-methyl-5-(triisopropylsilyloxy)-2-vinylpentane-1,3-diol (31 mg, 0.10 mmol) in DCM (1 mL), and the mixture was stirred overnight. The reaction mixture was diluted with DCM (5 mL), and sat. aq. NH4Cl solution (5 mL) was added. The layers were separated and the aqueous was extracted with DCM (2 × 5mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (5 % Et2O/hexane) to provide the title compound as a colourless oil (32 mg, 0.09 mmol, 90%)

1 H NMR (400 MHz, CDCl3) δ 6.38 (dd, J = 18, 11 Hz, 1H, C-1’’), 5.16 (dd, J = 11, 1.5 Hz, 1H, C-2’’), 5.08 (dd, J = 18, 1.5 Hz, 1H, C-2’’), 3.92 (dd, J = 10, 2 Hz, 1H, C-4’), 3.78 – 3.67 (m, 3H, C-6’ and C1), 3.46 (d, J = 11.5 Hz, 1H, C-6’), 1.67 – 1.58 (m, 1H, C-2), 1.45 (d, J = 1 Hz, 3H, Me), 1.41 (d, J = 1 Hz, 3H, Me), 1.40 – 1.35 (m, 1H, C-2), 1.06 – 1.03 (m, 21H, TIPS), 0.85 (s, 3H, Me) 13 C NMR (100 MHz, CDCl3) δ 140.2 (C-1’’), 113.9 (C-2’’), 98.9 (C-2’), 73.1 (C-4’), 71.2 (C-6’), 59.3 (C-1), 38.8 (C-5’), 33.7 (C-2), 29.7 (Me), 19.1 (Me), 18.2 (TIPS), 17.8 (Me), 12.1 (TIPS) IR (neat) 2942, 2866, 1463, 1380, 1099, 1064, 882, 753, 680 + HRMS (ES+) m/z calculated for C20H41O3Si [M+H] 357.2825, found 357.2938 23 [α]D +27 (c 1.0, CHCl3)

Rf 0.3 (1:20 Et2O/hexane)

229

Chapter 5

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