Lactone Reduction Using Samarium Diiodide: Biocatalysis, Radical

Home , Lactone

Lactone Reduction Using Samarium

Diiodide: Biocatalysis, Radical Cyclisations

and Ester Migration

A thesis submitted to the University of Manchester

for the degree of Doctor of Philosophy (PhD) in the

Faculty of Science and Engineering

2019

Charlotte V Morrill

School of Chemistry

Table of Contents

Abbreviations 4 Abstract 6 Declaration 7 Copyright statement 8 Acknowledgements 9 1. Introduction 10 1.1. Introduction to Samarium Diiodide 10

1.2. Activation of Carbonyls by SmI2 10 1.3. Activation of Carboxylic Acid Derivatives 11 1.3.1. Reduction of Aromatic Carboxylic Acid Derivatives 11 1.3.2. Reduction of Aliphatic Carboxylic Acid Derivatives 12 1.3.2.1. Mechanism of Lactone Reduction 13 1.3.2.2. Ring-Size Selectivity in Lactone Reductions 14 1.3.3. Reductive Radical Cyclisations of Carboxylic Acid Derivatives 16 1.3.3.1. Monocyclisations of Six-Membered Lactones 16 1.3.3.2. Cyclisations of Seven-Membered Lactones 19 1.3.3.3. Lactone Cyclisation Cascades 20

1.3.4. Activation of Other Carboxylic Acid Derivative by SmI2 22 1.3.4.1. Reduction of Carboxylic Acid Derivatives 22 1.3.4.2. Cyclisations of Carboxylic Acid Derivatives 23 1.3.5. Role of Additives 26

1.4. Enantioselective Cyclisation Reactions Using SmI2 28

2. SmI2-Mediated Reductive Radical Cyclisations of Five-Membered Lactones 30 2.1. Project Proposal 30 2.2. Optimisation of the Cyclisation 30 2.3. Scope of the Cyclisation 32 2.4. Cyclisation Mechanism and Rationale for Diastereoselectivity 34 2.5. Summary 35

3. Biocatalytic Conversion of Cyclic Ketones Bearing α-Quaternary Stereocentres to Lactones in an Enantioselective Radical Approach to Medium-Sized Carbocycles 36 3.1. Project Proposal 36 3.2. The Biocatalytic Baeyer-Villiger Reaction 37 3.2.1. Substrate Scope 38 3.2.2. Cofactor Regeneration Systems 39 3.3. Development of the BVMO-mediated Oxidation of Cyclic Ketones Bearing α- Quaternary Stereocentres 41 3.3.1. Synthesis of Racemic Starting Materials 41 3.3.2. Expression and Purification of Cyclohexanone Monooxygenase 42 3.3.3. Initial Biotransformations Using Model Substrates 43 3.3.4. Scope of the Biotransformation 44 3.3.5. Determination of Absolute Configuration 48

3.3.6. Computational Modelling Using CHMORhodo 50

3.4. SmI2-Mediated Cyclisations of Enantiomerically Enriched Substrates 51

3.4.1. Cyclisation of Enantiomerically Enriched Lactones Using

SmI2-H2O via a Carbonyl-Alkene Coupling 51 3.4.2. Cyclisation of Enantiomerically Enriched Ketone Substrates

Using SmI2-HMPA via a Ketone-Alkene Coupling 52 3.5. Summary 54

4. SmI2-Mediated 1,4-Ester Migration in Lactone Substrates 56 4.1. Project Proposal 56 4.2. Synthesis of Starting Materials 56 4.3. Initial Investigations of the Lactone Cyclisation 58 4.4. Identification of Unknown Compound 119 60 4.5. Optimisation of the 1,4-Ester Migration 61 4.6. Scope of the Transformation 63 4.6.1. Scope with Respect to the R Substituent 63 4.6.2. Scope with Respect to the Styrenyl Aromatic Substituent 65 4.7. Development of a One-Pot Procedure 69 4.8. Mechanism of the 1,4-Ester Migration 71 4.9. Rationale for the Origin of Diastereoselectivity 75 4.10. Summary 76

5. Overall Summary and Future Work 77 5.1. Summary 77 5.2. Future Work 79 5.2.1. Biocatalytic Baeyer-Villiger Reaction 79

5.2.2. SmI2-Mediated 1,4-Ester Migration 80 5.2.3. Biocatalytic Processes for the Construction of Lactone Substrates

for Reactions with SmI2 81

6. Experimental Section 84 6.1. General Information 84 6.2. Preparation of Samarium Diiodide 85 6.3. Protein Production and Purification 85 6.4. CHMO Sequence 86 6.5. CHMO Modelling 86 6.6. Experimental Data 87

6.6.1. Experimental Data for SmI2-Mediated Reductive Radical Cyclisations of Five-Membered Lactones 87 6.6.2. Experimental Data for Biocatalytic Conversion of Cyclic Ketones Bearing α-Quaternary Stereocentres to Lactones in an Enantioselective Radical Approach to Medium-Sized Carbocycles 100

6.6.3. Experimental Data for SmI2-Mediated 1,4-Ester Migration in Lactone Substrates 149

7. References 194

Word count 49024

Abbreviations

ADH alcohol dehydrogenase

APCI atmospheric pressure chemical ionisation

BLAST basic local alignment search tool

BV Baeyer-Villiger

BVMO Baeyer-Villiger monooxygenase

CDMO cyclododecanone monooxygenase

CHMO cyclohexanone monooxygenase

CPMO cyclopentanone monooxygenase

Cy cyclohexyl dba dibenzylideneacetone

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

DMP Dess-Martin periodinane dr diastereoisomeric ratio ee enantiomeric excess eq. equivalents er enantiomeric ratio

ES electrospray

FAD flavin adenine dinucleotide

G6PDH glucose-6-phosphate dehydrogenase

GC gas chromatography

GDH glucose dehydrogenase h hours

HFIP 1,1,1,3,3,3-hexafluoro-2-propanol

HG(II) Hoveyda-Grubbs second generation catalyst

HMPA hexamethylphosphoramide

HPLC high performance liquid chromatography

HRMS high resolution mass spectrometry

IPTG isopropyl-β-D-thiogalactoside

IR infrared

LB lysogeny broth mCPBA meta-chloroperoxybenzoic acid min minutes mp melting point

MWCO molecular weight cut off

NADP+ nicotinamide adenine dinucleotide phosphate

NADPH nicotinamide adenine dinucleotide phosphate (reduced form)

NMR nuclear magnetic resonance nOe nuclear Overhauser effect

PHOX phosphinooxazoline ppm parts per million pTSA para-toluenesulfonic acid rac racemic rpm revolutions per minute rt room temperature

SCE standard carbon electrode

SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis

SET single electron transfer

TBDMS tert-butyl dimethyl silyl

Tf trifluoromethylsulfonate

THF tetrahydrofuran

THP tetrahydropyran

TTN total turnover number

Abstract

Samarium diiodide (SmI2, Kagan’s reagent) has shown itself to be a highly versatile reducing agent since its introduction to the synthetic community in 1977. Although SmI2 was initially thought to be unable to reduce carboxylic acid derivatives, the discovery and development of the SmI2-H2O reagent system has rendered such reactivity possible and has opened new avenues for exploration.

The reductive cyclisation of six-membered lactone substrates has previously been reported by the Procter group. Herein, the analogous cyclisations of five-membered lactones, substrates which exhibit lower reactivity towards Sm(II), are described. By the use of appropriate additives, such lactones can be used to access substituted cyclohexanone motifs through diastereoselective radical cyclisation.

A synthetic route towards enantiomerically enriched cycloheptan- and cyclooctanols, structural motifs present in various biologically relevant molecules, is also disclosed. The strategy exploits Baeyer-Villiger monooxygenase-mediated biocatalysis in order to access lactone substrates with high enantioenrichment. A kinetic resolution process which transforms cyclic ketones bearing α-quaternary stereocentres into the corresponding lactones has been developed. The products of the kinetic resolution are suitable substrates for diastereoselective Sm(II)-mediated cyclisations. Overall the process gives access to diverse enantiomerically enriched carbocyclic scaffolds from simple racemic starting materials.

Finally, a novel reactivity mode of Sm(II) is reported, with the development of a 1,4-ester migration. The reaction proceeds through an unusual radical species formed at an acyclic ester moiety, rather than at the lactone carbonyl as observed in previous work. The reactivity appears to be determined by the conformation of the lactone substrate, where an alkyl substituent at the 5-position plays a key role in determining lactone conformation and thus the course of the reaction.

Declaration

No portion of the work referred to in this thesis has been submitted in support of an application for another degree or qualification of this or any other university or other institute of learning.

Part of this work has been published in peer-reviewed journals:

X. Just-Baringo, C. Morrill, D. J. Procter Tetrahedron, 2017, 72, 7691.

C. Morrill, C. Jensen, X. Just-Baringo, G. Grogan, N. J. Turner, D. J. Procter Angew. Chem. Int. Ed. 2018, 57, 3692.

H-M. Huang, M. Garduño-Castro, C. Morrill, D. J. Procter, Chem. Soc. Rev. 2019, 48, 4626.

The author of this thesis (including any appendices and/or schedules to this thesis) owns certain copyright or related rights in it (the “Copyright”) and s/he has given The University of Manchester certain rights to use such Copyright, including for administrative purposes.

Copies of this thesis, either in full or in extracts and whether in hard or electronic copy, may be made only in accordance with the Copyright, Designs and Patents Act 1988 (as amended) and regulations issued under it or, where appropriate, in accordance with licensing agreements which the University has from time to time. This page must form part of any such copies made.

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Acknowledgements

First and foremost, I would like to thank David for the opportunity to carry out my PhD in his group. Thank you for your support and guidance throughout my studies. Working in your group has been a truly fantastic experience and I feel incredibly lucky to have had such an excellent supervisor. I would also like to thank my co-supervisor Nick for the chance to work as part of such an eminent team, and for continued support throughout my PhD.

It has been a pleasure to work alongside so many talented people who have made the last four years so memorable. Thank you to all of the members of the Procter group, past and present, for making the lab such a great place to work: Monse, Ilma, Kay, Greg, Fabien, Min, Soumitra, Srimanta, Zhen, Quentin, Dong, Tung, Dean, Masanori, Raphael, Niklas, Aron, Miles, Andrea, Huanming, Jessica, Xavi, Nico, Jose, Pablo, Sam, Irem, Tao, Jiajie, Philipp, Jessica, Alex, Vaclav, Mateusz, Becky and Craig. Thank you for being both excellent colleagues and friends. Thank you to my friends in other groups in the building, including the Greaney group for being a pleasure to share the lab with. I am grateful to have met so many wonderful people during my time here. Kay, Monse and Ilma; thank you for being such amazing friends, for sharing the ups and downs and for always being there for me. Thank you to everybody who has taken the time to proofread my thesis, for many helpful comments and improvements.

Thank you to the people whom I have had the pleasure of working with during my PhD. I would particularly like to thank Xavi, for being such a fantastic teacher with endless patience. I was incredibly fortunate to be able to learn from such an excellent chemist with incredible expertise in samarium chemistry. Thank you to Chantel for teaching me so many new skills, as well as making the MIB a welcoming place to work. Ilma and Niklas, thank you for your persistence, enthusiasm and hard work.

Manchester has been a brilliant place to work over the past years. Many thanks to the analytical and technical staff at the University, who have always provided fantastic services and assistance when needed. Thank you also to other staff in the building, who have made this a friendly and welcoming place to work. I would like to gratefully acknowledge the BBSRC for funding my PhD studies, as well as the SCI for a travel bursary.

Thank you to my friends outside of chemistry, particularly to Caroline, for keeping me happy and motivated throughout my studies. Last but not least, thank you to my family for always supporting, encouraging and believing in me.

1. Introduction 1.1. Introduction to Samarium Diiodide

Samarium diiodide (SmI2, Kagan’s reagent) is a reductive single electron transfer (SET) reagent.[1,2] The reagent, used in the form of a deep blue solution in THF, is commercially

[3] available or easily prepared from samarium metal and an oxidant, such as I2 or CH2I2. Since its introduction into the synthetic community in 1977, it has been widely used for the mediation of various radical and anionic processes.[4–7]

Typically, SmI2 exhibits the desirable trait that its reactions are highly chemo-, regio- and diastereoselective. Key to its utility is the ability to tune its reactivity through the use of additives. Lewis bases, proton sources and inorganic species have been widely used as

[8] additives in processes mediated by SmI2, having a profound effect on reactivity. Additives may be used to tune the redox potential of the reagent. For example, the reduction potential of SmI2 in THF, found to be -1.33 V vs an Ag/AgNO3 reference electrode, can be increased to

[9] -2.05 V in the presence of 4 equivalents of HMPA. This tunability makes SmI2 a versatile and useful reagent to the synthetic chemist, giving a broad scope of possible reactivity. The reagent has been used to mediate a range of functional group transformations including dehalogenation,[10,11] reduction of electron deficient alkenes,[12,13] N-X bond reductions[14–16] and reduction of sulfoxide/sulfone groups.[17,18]

The mild conditions that are employed, the broad scope of reactivity and the high diastereoselectivities that can be achieved using SmI2 make it a desirable tool for complex molecule synthesis. The reagent has been successfully employed in the total syntheses of several biologically relevant molecules, including tumour-promoter phorbol[5,19] and various routes towards the anti-cancer agent Taxol.[20–22]

1.2. Activation of Carbonyls by SmI2

The single electron reduction of the carbonyl group of either an aldehyde or ketone, forming

[4,23] a ketyl radical, is a well-studied phenomena in the chemistry of SmI2. The fate of the radical that is formed depends on the conditions and substrates employed in the reaction. Following the initial electron transfer to form the ketyl radical intermediate, a second electron transfer and protonation can lead to direct reduction of the carbonyl to the alcohol product. Alternatively, the radical can be trapped by reaction with an appropriate radical acceptor, such as an alkene or a carbonyl, to form new carbon-carbon bonds (figure 1).[24]

Figure 1: Reactivity pathways of ketyl radicals formed by reduction of a carbonyl by SmI2

Ketyl radicals formed using SmI2 have been extensively exploited for the construction of carbon-carbon bonds in pinacol couplings[25] and carbonyl-alkene couplings.[26,27] Such reactions generally exhibit good selectivities and can be performed under mild conditions. Recent efforts have focused on the use of this methodology to construct complex motifs by cascade cyclisations involving multiple bond forming events. This is exemplified in the key step in a total synthesis by Procter et al of (+)-pleuromutilin, a natural product with antibacterial properties, in which a dialdehyde cascade was used to access the complex core of the natural product in a single reaction step (figure 2). The cascade process proceeded in excellent yield, with exquisite sequence control and diastereoselectivity.[28,29]

Figure 2: Application of a ketyl radical cyclisation cascade in the construction of the core of the natural product pleuromutilin mediated by SmI2

1.3. Activation of Carboxylic Acid Derivatives by SmI2 1.3.1. Reduction of Aromatic Carboxylic Acid Derivatives

The seminal work on the reduction of carboxylic acid derivatives using SmI2 was reported in

[30] 1993 by Kamochi and Kudo. By using SmI2 with H2O as an additive, a range of aromatic esters, carboxylic acids, nitriles and amides could be reduced to the corresponding alcohols

11 and amines in good yields (figure 3). Aliphatic carboxylic acid derivatives were found to be unreactive in this system.

Figure 3: First report of the reduction of aromatic carboxylic acid derivatives by the SmI2-H2O reagent system

1.3.2. Reduction of Aliphatic Carboxylic Acid Derivatives

In Kagan’s seminal paper, it was stated that carboxylic acid derivatives lay outside of the

[1] synthetic reach of reactions that could be mediated by SmI2. Given this generally accepted view, in 2003 Procter and co-workers made the surprising observation that triol 16 was formed as a byproduct during the expected formation of spirolactone 15 (figure 4).[31,32] The reaction used an excess of SmI2 and employed H2O as an additive. Although the reduction of aryl carboxylic acid derivatives had been previously reported, this represented the first observation of an aliphatic carboxylic acid derivative being activated by SmI2.

Figure 4: Initial observation of aliphatic lactone reduction in the expected formation of spirolactone 15

Following this discovery, the feasibility of the lactone reduction was studied further. It was found that by using H2O as an additive, a general method for the reduction of six-membered lactones could be achieved. The reaction exhibited chemoselectivity for the six-membered lactone; substrates bearing an acyclic ester could be employed (18c), with complete selectivity for lactone reduction observed. The corresponding diols could be obtained from the process in good yields (figure 5).[32,33]

Figure 5: Reduction of six-membered lactone substrates to diols by SmI2-H2O, selected examples

1.3.2.1. Mechanism of Lactone Reduction

The lactone reduction is thought to proceed by an initial reversible electron transfer from Sm(II) to the lactone carbonyl (figure 6). This generates intermediate I, in which the radical that is formed can be stabilised by an anomeric effect involving the lone pair of the neighbouring oxygen atom. In order for the reduction to proceed, the subsequent protonation and second electron transfer must outcompete back-electron transfer to the metal. This would generate intermediate III, which can be quenched by the proton source to give lactol species IV, which is in equilibrium with hydroxyaldehyde V. Reduction of the carbonyl gives VI, which can then be further reduced and protonated to deliver the diol product 18. The overall process requires four electrons and four proton transfers.[33]

Figure 6: Proposed mechanism of six-membered lactone reduction by SmI2-H2O

1.3.2.2. Ring-Size Selectivity in Lactone Reductions

Interestingly, lactone reduction by SmI2-H2O exhibits a strong selectivity for the reduction of six-membered lactones over lactones of other ring sizes.[33] This was probed by mechanistic studies, in which competitive reductions of lactones of varying ring sizes were performed (figure 7). Substrate 19, bearing both a five- and six-membered lactone, was smoothly reduced to diol 20 with no reduction of the five-membered lactone observed. Additionally, in a competition experiment involving a 1:1 mixture of six-membered lactone 22 and seven- membered lactone 21, reduction of the six-membered lactone preferentially occurred.

Figure 7: Mechanistic studies to probe the ring size selectivity in lactone reductions by SmI2-H2O

In order to investigate this phenomenon, lactols 24 and 26 were submitted to the reduction conditions (figure 8). In both cases, reduction of the lactol to the diol was observed in good yield. This suggests that the origin of the ring-size selectivity can be attributed to the initial electron transfer from SmI2 to the lactone substrate.

Figure 8: Reduction of five- and six-membered lactols by SmI2-H2O

Based on these experiments, it was proposed that the ring-size selectivity of the lactone reduction is a result of the reversibility of the first electron transfer. In six-membered lactones, the first radical intermediate that is formed (intermediate I, figure 6) is stabilised by an anomeric effect from neighbouring oxygen lone pairs. In six-membered rings, this effect is more pronounced than in other ring sizes of greater flexibility. This facilitates the second electron transfer, meaning that reduction of these substrates is more feasible. The effect of the proposed anomeric stabilisation was probed using a competition experiment.

Lactones 28 and 29 were exposed to the SmI2-H2O reduction conditions (figure 9). Diol 30 was formed smoothly, whilst lactone 28 was completely recovered. Due to the constraints of the bicyclic system in 28, the intermediate radical species would be unable to adopt the

Figure 9: Investigation of the anomeric effect in the reduction of six-membered lactones

15 chair conformation which is necessary for the anomeric stabilisation to occur, meaning that reduction of 29 is favoured.

The reversibility of the first electron transfer was illustrated using radical clock experiments.[34] Substrates 31 and 33, bearing a cyclopropyl ring adjacent to the lactone carbonyl (figure 10) were utilised. The lactones could undergo ring-opening of the cyclopropyl unit. This indicates that electron transfer to the lactone carbonyl can occur, but is reversible; if subsequent steps are not sufficiently favourable, back-electron transfer occurs and no productive chemistry is observed. In the case of substrates 31 and 33, rapid opening of the cyclopropyl ring occurs before back-electron transfer, hence ring-opened products 32 and 34 are formed.

Figure 10: Radical clock experiments supporting the reversibility of the first electron transfer from SmI2 to the lactone carbonyl

1.3.3. Reductive Radical Cyclisations of Carboxylic Acid Derivatives 1.3.3.1. Monocyclisations of Six-Membered Lactones

Following the development of a successful method for the reduction of lactones using SmI2, it was proposed that the intermediate radical that is formed could be intercepted by an appropriate radical acceptor, in order to access cyclisation products. It was considered that an alkene tether would be an appropriate group to induce cyclisation of the acyl radical.

Following preliminary studies on the feasibility of the cyclisation, it was proposed that an internal Lewis basic moiety in the lactone substrate could be used to stabilise intermediates and prevent over-reduction by coordination to Sm(III). To this end, substrates 35, bearing an

16 ester group at the 2-position, were identified as substrates for the cyclisation (figure 11). Under optimised conditions, lactones 35 could undergo 5-exo-trig cyclisation to the corresponding cyclopentanones 36.[33] In the case of the substrates bearing a fused aromatic (36e), the hemiketal product was isolated.

Figure 11: Cyclisation of six-membered lactone substrates bearing an alkenyl tether at the 2-position

Analogous to the mechanism for lactone reduction, the mechanism of the cyclisation begins with single electron transfer from Sm(II) to the substrate to generate intermediate I (figure 12). In order for the reaction to proceed, the 5-exo-trig cyclisation must proceed before either back-electron transfer or a second electron transfer can occur, the latter of which would result in direct lactone reduction. The ester group is thought to play several roles; it promotes reduction by coordinating to SmI2 and delivering the reagent; it stabilises the resultant ketyl radical anion by coordination to Sm(III), and; it stabilises the tetrahedral intermediate formed after cyclisation by coordination to Sm(III). Rapid 5-exo-trig cyclisation onto the radical acceptor generates intermediate II. It is proposed that diastereoselectivity arises from electronic effects that favour anti cyclisations. Following protonation, hemiketal intermediate III is formed. Coordination of the ester to Sm(III) is thought to prevent collapse

17 to the cyclopentanone and over-reduction to the cyclopentanol – the hemiketal is stable until workup, when the desired product is delivered.

Figure 12: Mechanism of the cyclisation of lactones bearing a tether at the 2-position

Subsequently, the cyclisation of lactones bearing an alkenyl tether at the 5-position was studied. It was found that these substrates were also suitable for cyclisation reactions mediated by SmI2. Six-membered lactones 37 could undergo reductive cyclisations to give the corresponding cycloheptanols 38 (figure 13). Oxidation delivered hemiketal products 39 in good yields.[35,36]

Figure 13: Cyclisations of six-membered lactones bearing alkenyl tethers at the 5-position mediated by SmI2-H2O

The mechanism of the reaction is similar to that of the cyclisations of lactones described previously (vide supra). The initial reversible electron transfer to the lactone substrate generates radical intermediate I. As the transition state for cyclisation requires the tether to adopt an axial position, it is beneficial to have a substituent other than H in the R1 position, as this increases the stability of the chair conformation that is required. 5-Exo-trig cyclisation delivers hemiketal II, which is in equilibrium with its open form III. The ketone is prone to rapid reduction to diol 38, which is the observed product of the cyclisation. The major diastereoisomer is thought to arise from the transition state in which the alkene adopts an endo-orientation relative to the ring.

Figure 14: Cyclisations of lactone substrates bearing an alkenyl tether at the 5-position to deliver cycloheptanols

This reactivity could be extended further to include the cyclisations of lactones with allenyl and alkynyl tethers.

1.3.3.2. Cyclisations of Seven-Membered Lactones

In addition to the cyclisation of six-membered lactones, similar reactivity could be achieved using analogous seven-membered lactones to achieve the construction of cyclooctanols.[37] The reaction proceeds through a mechanism analogous to that discussed previously. A range

19 of functional groups were tolerated and products could be accessed in good yields and diastereoselectivities (figure 15).

Figure 15: Cyclisation of seven-membered lactones to deliver cyclooctanol products

1.3.3.3. Lactone Cyclisation Cascades

Lactone substrates have been successfully used in cyclisation cascades, which deliver complex bicyclic products.[35,36] In the monocyclisations described above, following the cyclisation event the resultant radical was reduced to the anion and quenched by a proton source. As the intermediate that is formed contains a carbonyl at the ketone oxidation level, this is then reduced by additional equivalents of SmI2. A cascade process was designed in which the second ketyl radicals, formed from ketone intermediates, could instead be trapped by a second cyclisation event using another radical acceptor (figure 16). The cascades exhibited a strong ‘right then left’ sequence integrity to deliver the products in good yield and with moderate diastereocontrol. Calculations showed that the sequence selectivity could be attributed to the relative activation energies of the two competing cyclisation steps.

Figure 16: Cyclisation cascade of six-membered lactone bearing two radical acceptors to give bicyclic products

Interestingly, the relative configuration of the lactone starting material had a significant effect on the reactivity of the system. The cis isomer of lactone 45 was found to undergo the desired cascade process. In contrast, trans-45 delivered cyclopentanol product 47 as a mixture of diastereoisomers under the same reaction conditions (figure 17). Cyclisation from trans-45 is unfeasible due to the high-energy intermediate that would be required; cyclisation would have to occur from a chair-type transition state with both alkyl tethers in the axial positions.

Figure 17: Contrasting reactivity in the cyclisations of cis- and trans-lactones

The cyclisation cascades could also be extended to include challenging 5-exo/6-exo cyclisations, delivering carbo[5.4.0]bicyclic products.[38] The reaction proceeded in modest yields, giving access to the cascade products as single diastereoisomers.

1.3.4. Activation of Other Carboxylic Acid Derivatives By SmI2 1.3.4.1. Reduction of Carboxylic Acid Derivatives

A key advantage of SmI2 is the capacity to tune the reactivity of the reagent by using various additives. It was discovered that the synthetic reach of the carboxylic acid reduction process could be extended when an amine was used as an additive. The use of the SmI2-H2O-NEt3 reagent system enabled the reduction of unactivated esters, a functional group which is thought to be unreactive in the presence of SmI2-H2O alone (figure 18). The primary alcohol products could be formed in high yields.[39]

Figure 18: Reduction of unactivated acyclic esters by SmI2-H2O-NEt3

Furthermore, the SmI2-H2O-NEt3 reagent was found to be generally applicable for the reduction of other functional groups which were previously thought to be beyond the scope

[40] [41] [42] of SmI2, including carboxylic acids, nitriles, and amides (figure 19). The reductions proceed with high efficiency, via acyl-type or imidoyl-type radical intermediates, following the initial electron transfer from SmI2. In the case of the reduction of amides, complete selectivity for C-N bond cleavage over C-O cleavage is observed, and alcohol products are delivered. Mechanistic studies suggest that the selectivity is controlled by coordination of samarium to the Lewis basic nitrogen moiety during the course of the reaction, which facilitates electron transfer and controls the course of the cleavage.

In addition, the reduction of other cyclic carboxylic acid derivatives, Meldrum’s acids[43] and

[44] barbituric acids could be achieved using the SmI2-H2O system.

Figure 19: Reductions of carboxylic acid derivatives using SmI2-H2O-NEt3

1.3.4.2. Cyclisations of Carboxylic Acid Derivatives

Similarly to the cyclisation reactions of lactones described in section 1.3.3. (vide supra), the radical intermediates that are formed during the reactions of other carboxylic acid

[45] derivatives with SmI2 have also been exploited in cyclisations and cyclisation cascades. For example, the radicals formed by electron transfer to the amide-type carbonyl of barbituric acids could be intercepted by appropriate tethers to form complex medicinally relevant polycyclic barbiturate scaffolds 57 (figure 20).[46–50] The reaction involves stereocontrolled formation of up to five stereocentres in a single step. By adding acid to the reaction after completion of the cyclisation, elimination products could be formed. Interestingly, the use of lithium bromide as an additional additive extended the scope of the reaction, enabling the formation of products bearing quaternary centres (57d, e). Flowers and co-workers have proposed that using LiBr as an additive forms SmBr2 in situ, which has a higher reduction

[51] potential (-0.90 V vs SCE for SmI2, -1.55 V vs SCE for SmBr2).

Figure 20: Cyclisation of the amide-type carbonyls of barbituric acids, giving access to complex polycyclic scaffolds aLiBr (20 eq.) used

Additionally, the cyclisation of cyclic imides to form 2-azabicycles was reported by Shi and Szostak (figure 21).[52] The reaction proceeds through the formation of an aminoketyl radical,

Figure 21: Cyclisations of imidyl-type radicals formed by the SmI2-mediated reduction of imides

24 which undergoes cyclisation onto an alkene. The procedure was successful using both five- and six-membered cyclic imides and constructed the desired products with high diastereocontrol.

Following the success of the cyclisations of cyclic esters reported by Procter, the group of Wang reported the samarium-mediated intramolecular coupling of acyclic esters with alkenes to generate 2-(2-hydroxyalkyl)cyclopropanols.[53] The reaction employed allylsamarium bromide, acting as a SET reagent rather than a nucleophile, and used H2O and HMPA as additives. Following electron transfer to the ester carbonyl, 5-exo-trig cyclisation gave intermediate II. An anionic 3-exo-trig cyclisation of IV furnished the cyclopropane products 61 in good yields but typically with modest diastereoselectivities.

Figure 22: Radical/anionic cyclisation cascade of acyclic esters mediated by allylSmBr-H2O-HMPA

Subsequently, the same group reported a further ester cyclisation which constructed 2-(2- hydroxethyl)bicyclo[2.1.1]hexan-1-ols, using CuCl2•2H2O as an additional additive (figure 23).[54] By including an allyl group adjacent to the ester moiety, the terminal radical species II could undergo a second 5-exo-trig cyclisation to afford intermediate III. Intramolecular

25 nucleophilic addition furnished the product, which could be obtained with excellent diastereocontrol.

Figure 23: Cyclisation of acyclic esters with alkenes using allylSmBr-H2O-HMPA

1.3.5. Role of Additives

It has been reported that the use of H2O as an additive is crucial for the reductive transformations of carboxylic acid derivatives by SmI2. Mechanistic and kinetic studies have been used to probe the role of the additive in such reactions, and conclude that it has multiple parts to play.

Water exhibits a high affinity for SmI2 and will displace THF molecules from the inner coordination sphere.[55] Prasad andFlowers reported that the addition of 500 equivalents of

H2O to SmI2 resulted in a thermodynamic increase in reduction potential from -0.89 to -1.3 V (vs SCE in THF), generating a reductant capable of reducing a wider range of functional groups.[55]

Studies have shown that the concentration of water can have a profound effect on the

[34] chemoselectivity of SmI2-mediated reactions. At low concentrations of H2O, the reduction of lactones bearing an alkenyl acceptor is favoured over cyclisation (figure 24). This is consistent with the generation of a thermodynamically stronger reductant by the addition of H2O. At higher concentrations of water (>3.0 M) the rate of reduction is dramatically decreased, and cyclisation is favoured. This indicates that when water is used in high concentrations, it saturates the coordination sphere of Sm(II). Coordination to the substrate and inner sphere reduction of the ketyl-radical intermediate is thus disfavoured and the cyclisation event is promoted.[56,57] These results suggest that the fate of the radical intermediate formed by initial electron transfer from SmI2 is governed by thermodynamic control of the second electron transfer step, this being the postulated rate determining step of the reaction.

Entry H2O (eq.) 65:66 Reaction rate [107 x M-1 s-1] 1 25 >98:2 >21.3 2 200 97:3 14.3 3 1600 42:58 0.39 4 6400 22:78 0.25

Figure 24: Effect of H2O concentration on the reduction/cyclisation of lactone substrates (selected examples); reaction rate shown refers to the reduction of lactone 64 to diol 65

Additionally, the additive has been shown to affect the reaction by stabilising the radical intermediates. This was exemplified by the reaction of lactone 67, which bears a radical- stabilising phenyl substituent at the 5-position, with varying concentrations of water and

SmI2 (figure 25). Direct reduction of the lactone would give diol 68, analogous to the substrates described previously (vide supra). At low concentrations of water, this was found to be the preferred pathway and 68 was formed as the major product. Alternatively, if the ketyl-radical intermediate was sufficiently long-lived to allow radical fragmentation, the substrate could undergo C-O bond scission to give acid 69. This was observed at higher concentrations of H2O, suggesting that water plays a crucial role in the stabilisation of the radical intermediates.

Figure 25: Effect of water concentration on stability of radicals formed from lactone 67

The addition of NEt3 to the SmI2-H2O reagent results in an even greater increase in reduction potential, up to -2.8 V vs SCE. Studies to elucidate the role of the additive have shown that the amine is able to deprotonate a molecule of water that is coordinated to Sm(II), generating a formal negative charge at oxygen. This gives the reagent its high redox potential, meaning that it can act as a general reagent system for the reduction of a broad range of carboxylic acid derivatives.[58]

Hexamethylphosphoramide (HMPA) has been observed to have a significant enhancement

[10] on the rate of SmI2-mediated reductions. This additive also increases the reduction potential of SmI2, up to -1.75 V vs SCE. Studies by Flowers indicate that the addition of HMPA displaces THF that is bound to the metal, with four HMPA ligands bound to Sm(II) in

[59] solution. The additive has been shown to accelerate reactions of SmI2 and extend the reactivity of the reagent to previously inert functional groups.[60]

1.4. Enantioselective Cyclisation Reactions Using SmI2

The high reactivity of radical intermediates renders the enforcement of enantiocontrol in such reactions highly challenging. As a result, reports of enantioselective C-C bond formation reactions mediated by SmI2 are extremely scarce, with examples generally being limited in

[61,62] scope and yield. The efficient enantioselective cyclisation of ketyl radicals using SmI2 was reported by Procter and co-workers (figure 26).[63] The process employs a chiral ligand 72 and uses methanol as a proton source. The substrates are β-keto esters, with the ester group playing a crucial role in binding to Sm(III) in the transition state. The reaction shows broad scope with respect to cyclisations and cyclisation cascades and exhibits high diastereo- and enantioselectivities.

Figure 26: Enantioselective cyclisations and cyclisation cascades from samarium ketyl radicals

2. SmI2-Mediated Reductive Radical Cyclisations of Five-Membered Lactones 2.1. Project proposal

As discussed in chapter 1.3.3., the reductive cyclisation of six- and seven-membered lactone substrates has previously been reported by the Procter group.[35,37] It was proposed that this reactivity could be extended in order to achieve the analogous cyclisation of five-membered lactone substrates.

Given that the first electron transfer from SmI2 to lactone substrates is reversible, the second electron transfer is thought to be the rate determining step of such reactions. In the case of six-membered lactones, the intermediate radical anionic species are stabilised by interactions with the lone pairs of the endo- and exocyclic oxygen atoms. This interaction is known to be most pronounced in six-membered rings, therefore increasing the stability of the intermediates and facilitating the second electron transfer (section 1.3.2., vide supra).[33] In five-membered rings, which are more conformationally flexible, this effect is decreased, resulting in inhibition of the transformation by competitive back electron transfer. The reduction of five-membered lactones to the corresponding diols is therefore inefficient. Despite this, it was proposed that the intermediate radical could be intercepted by use of an appropriate radical acceptor to generate cyclisation products (figure 27).

Figure 27: Proposed pathway for the cyclisation of 5-membered lactones

2.2. Optimisation of the Cyclisation

The optimisation of the cyclisation reaction was investigated using lactone 73a as the model substrate (figure 28). Pleasingly, initial studies indicated that the desired cyclisation product

74a could be obtained using SmI2-H2O, in moderate conversion and with moderate diastereoselectivity in the cyclisation step; a mixture of diastereoisomers occurred from the

30 final reduction event, giving a 1:1 diastereoisomeric mixture at this postion. Trace amounts of acyclic diol 75, resulting from lactone reduction, were also observed. The optimisation commenced with the variation of the number of equivalents of H2O; increasing the amount of the additive led to decreased conversion and diastereocontrol, in addition to increasing the amount of the undesired diol (entries 1-4). The use of NEt3 as an additive increased the reaction conversion, however lowered the selectivity (entries 5-10). Using HMPA as an additive for the reaction proved to be beneficial. As the amount of HMPA was increased, a concurrent increase in the diastereoisomeric ratio was observed (entries 11-14). The optimal conditions were reached using 64 equivalents of HMPA and 800 equivalents of H2O, which could deliver the product in good conversion and diastereoselectivity (entry 14).

Entry H2O (eq.) Additive 73a (%) Conversion (%) (eq.) 74a (dr) 75 1 800 – 34 65 (88:12) 1 2 1600 – 33 63 (88:12) 4 3 2400 – 33 57 (81:19) 9 4 3200 – 58 33 (74:26) 9 5 800 NEt3 (60) – 97 (74:26) 3 6 800 NEt3 (30) – 86 (71:29) 14 7 800 NEt3 (15) – 94 (72:28) 6 8 800 NEt3 (8) – 86 (77:23) 14 9 800 NEt3 (4) 24 69 (79:21) 7 10 800 NEt3 (1) 44 53 (86:14) 3 11 800 HMPA (8) 16 81 (88:12) 3 12 800 HMPA (16) 5 93 (87:13) 2 13 800 HMPA (32) 36 64 (90:10) – 14 800 HMPA (64) 21 79 (92:8) –

Figure 28: Optimisation of the cyclisation of 5-membered lactone 73a – reactions performed by Dr Xavier Just-Baringo; diastereoisomeric ratios were determined by 1H NMR analysis of the crude reaction mixture and refer to the diastereoselectivity of the cyclisation event

2.3. Scope of the Cyclisation

Following the optimisation studies, the scope of the cyclisation was investigated. A range of lactones was synthesised by cross metathesis of lactone 76 with various substituted styrenes (figure 29). Moderate to good yields were obtained in all cases, with exclusive formation of the E isomer. The efficiency of the reaction was curtailed by the formation of (substituted) stilbene products. Additionally, as the reaction is reversible, significant amounts of starting material were recovered in some cases.[64]

Figure 29: Synthesis of 5-membered lactones by cross-metathesis

Cyclisations of lactones 73 were performed using both SmI2-H2O and SmI2-H2O-HMPA reagent systems. Issues of reproducibility were encountered in the reaction without the use of HMPA. This could be due to the longer reaction time associated with this system, leading to inconsistency due to the background decay of the Sm(II) reagent.

Lactones 73 underwent cyclisation to form diols 74 in moderate to good conversions and yields in all cases. Substitution was tolerated at all positions on the aromatic ring, with those bearing a substituent at the ortho position exhibiting the highest diastereoselectivities.

Comparing the two reagent systems, the use of HMPA led to higher conversion and diastereoselectivity in all cases.

Following cyclisation and analysis of the crude 1H NMR data, the crude diol product was oxidised using DMP to generate the cyclohexanones 77 (figure 30). This simplified the diastereoisomeric mixtures and aided purification. The relative stereochemistry of the major isomer was confirmed by X-ray crystallographic analysis of products 77a and 77b.

Figure 30: Scope of the cyclisation. Conditions A: SmI2 (8.0 eq.), H2O (800 eq.), THF, rt; Conditions B: SmI2 (8.0 a b 1 eq.), H2O (800 eq.), HMPA (64.0 eq.) THF, rt; Isolated yield Conversion determined by H NMR analysis of the crude reaction mixture

2.4. Cyclisation Mechanism and Rationale for Diastereoselectivity

The cyclisation is proposed to proceed through the formation of radical species I, formed by the initial reversible electron transfer from SmI2 to the substrate. Before back electron transfer to the metal can occur, the radical is intercepted by the alkene tether, leading to the formation of intermediate II via a 5-exo-trig cyclisation. This species then undergoes further electron transfer and protonation steps, leading to the generation of the desired product 74 which can be oxidised to give 77.

Figure 31: Proposed mechanism of the cyclisation

The relative stereochemistry of the major product of the cyclisation was determined by X- ray crystallographic analysis of compounds 77a and 77b (figure 32).

Figure 32: X-ray structures of 74a and 74b, showing the relative stereochemistry of the cyclisation products

It was observed that using HMPA as an additive generated the cyclisation products with increased conversion and diastereoselectivity. In addition to its ability to increase the reduction potential of SmI2, investigations into the role of HMPA as an additive have

34 indicated that the ability of HMPA to sequester Sm(II) may lead to an acceleration in the cyclisation event. This allows the formation of a dissociated ion pair I’, generating a species which is more likely to undergo the carbon-carbon bond formation event (figure 33).[65]

The enhancement in selectivity that is observed in the cyclisation with HMPA may be attributed to the increased steric bulk that is associated with the resultant Sm(III) species; the increased steric crowding in the reactive intermediates results in a greater degree of diastereocontrol in the cyclisation.

Figure 33: Suggested role of HMPA in the cyclisation

2.5. Summary

The scope of cyclisation reactions of lactone substrates using SmI2 has been extended to include five-membered lactones.[66] The issue of the lower reactivity of five-membered lactones in comparison with their six- and seven-membered counterparts was circumvented by the use of HMPA as an additive, which generates a Sm(II) reagent that gives rise to reactive intermediates that undergo a more facile and more selective cyclisation.

The reaction has been tested using several lactone substrates bearing substituted aromatics. Substitution was tolerated at all positions of the aromatic ring and a range of functional groups were compatible with the reaction. This methodology represents a route to the diastereoselective construction of substituted cyclohexanone substrates.

3. Biocatalytic Conversion of Cyclic Ketones Bearing α-Quaternary Stereocentres to Lactones in an Enantioselective Radical Approach to Medium-Sized Carbocycles 3.1. Project Proposal

Reductive radical cyclisation reactions mediated by SmI2 can be used to construct cycloalkanol motifs from lactone precursors through C-C bond formation (section 1.3.). Such reactions proceed diastereoselectively, however, inducing enantiocontrol remains challenging. As a result, reports of efficient asymmetric transformations mediated by SmI2 remain scarce.[63]

Cyclisation of lactones can generate cycloheptan- and cyclooctan-1,4-diols, structural motifs which are generally difficult to construct by radical methods. Such scaffolds are present in a range of biologically relevant molecules (figure 34),[67–76] and this drives the desire for the development of a method to access the motif in enantiomerically enriched form.

Figure 34: Biologically relevant molecules containing seven- and eight-membered cycloalkanol motifs

Biocatalysis offers a means by which to catalyse transformations with exquisite levels of chemo-, regio- and enantioselectivity, making it an attractive prospect for synthetic organic chemistry.[77–82] The scope of reactivity that can be achieved using enzymatic catalysts, however, is currently limited when compared with traditional synthetic organic reagents and small molecule catalysts. In order to exploit the advantages of both processes, it is desirable to integrate biocatalysts into reaction sequences with organic reagents, allowing access to a broad range of enantiomerically enriched scaffolds.

It was proposed that the lactone precursors for SmI2-H2O-mediated cyclisations could be accessed using a biocatalytic Baeyer-Villiger reaction, starting from racemic cyclic ketones (figure 35). Due to the challenge of synthesising products bearing fully-substituted stereocentres, ketones bearing an α-quaternary centre were targeted.

Figure 35: Proposed reaction sequence integrating biocatalytic Baeyer-Villiger oxidations with SmI2-H2O- mediated radical cyclisations

3.2. The Biocatalytic Baeyer-Villiger Reaction

The Baeyer-Villiger reaction, first reported in 1899,[83] is an oxidation reaction involving the transformation of a ketone into an ester or lactone by insertion of an oxygen atom adjacent to the carbonyl. Typically performed using peracids, the generally accepted mechanism of the reaction proceeds through a Criegee tetrahedral intermediate,[84] formed by nucleophilic attack of the peroxo species to the carbonyl. The reaction proceeds with retention of stereochemistry and predictable regioselectivity.

Asymmetric variants of the Baeyer-Villiger reaction using small molecule catalysts have been developed using metal-based[85–88] and organocatalysts.[89–92] Efficient examples with high enantioselectivities are generally limited to the transformation of cyclobutanones, which are particularly active substrates due to the favourable release of ring strain upon oxidation.[93]

The enzymatic equivalent of the Baeyer-Villiger reaction is catalysed by a family of flavin- dependent enzymes known as Baeyer-Villiger Monooxygenases (BVMOs).[94–98] The mechanism of the reaction is believed to be analogous to the chemical mechanism, using atmospheric oxygen as the oxidant and producing water as a byproduct (figure 36). Flavin species I, which is tightly bound by the enzyme, accepts hydride from cofactor NADPH to generate the reduced species II, with a corresponding oxidation of NADPH to NADP+. Flavin- oxygen adduct III is the active catalytic species, being the means of oxygen transfer to the substrate through the Criegee intermediate IV. Following rearrangement and release of the

37 lactone product, hydroxy-flavin species V can eliminate a molecule of water to regenerate flavin I and close the catalytic cycle.[99]

Figure 36: Mechanism of the BVMO-mediated Baeyer-Villiger reaction of cyclohexanone

3.2.1. Substrate Scope

The diversity of BVMO-producing strains and broad substrate acceptance make this class of enzyme of great interest for organic synthesis. BVMOs have been used from a wide variety of microorganisms to oxidise a diverse range of natural and non-natural substrates.[94] Given that the BV reaction proceeds with strict retention of stereochemistry, the high enantioselectivities that are observed indicate that the enzyme preferentially transforms one enantiomer of the racemic starting material, leaving the other unreacted.

Cyclohexanone Monooxygenase from Acinetobacter Calcoaceticus, one of the prototypical BVMOs, has been shown to have a broad substrate scope with respect to cyclic ketones.[100] In an investigation of the kinetic resolution of a range of 2-alkyl substituted cyclic ketones using CHMOAcineto from Bakers’ Yeast, almost all E values for the process were found to be in

38 excess of 200. Enantiomeric ratio E is equal to the relative ratio of the second order rate constants for the reactions of the individual substrate enantiomers and can be used to define enzyme selectivity; an E > 30 is required for a kinetic resolution to be preparatively viable. The exception to this high selectivity was seen for the reaction of 2-methylcyclohexanone, which had an E value of 10. This was deduced to be due to the size of the methyl substituent being too small to completely enforce the stereochemical discrimination.[101]

R Yield 82 ee (%) Yield 81’ ee (%) E (%) (%) Me – (R) – 50 (S) 49 10 Et 35 (R) >98 40 (S) 95 >200 nPr 33 (R) 92 27 (S) 97 >200 iPr 23 (S) 96 21 (R) >98 >200 nBu 32 (R) 98 30 (S) >98 >200 Allyl 29 (S) >98 30 (R) >98 >200

Figure 37: Selected examples from the substrate scope of CHMOAcineto

Despite the abundance of reports on the reaction of ketone substrates bearing a tertiary centre at the α-position, the biocatalytic oxidation of substrates bearing a quaternary centre at this position has yet to be explored.[102]

3.2.2. Cofactor Regeneration Systems

As shown in the catalytic cycle (figure 36), BVMOs require the use of a cofactor as a source of hydride. Generally, this is NADPH, which undergoes oxidation to NADP+ during the course of the reaction. Due to the high cost of the cofactor, its use in stoichiometric quantities would be economically prohibitive.

When using a whole cell biocatalyst, external regeneration systems are not required as natural recycling systems will turn over the cofactor. In the use of biocatalysts for organic

39 synthesis, however, it is often desirable to use the enzyme in its isolated form. This is due to the fact that the whole cell microorganism is likely to contain contaminating enzyme residues which can catalyse unwanted side reactions, thus reducing the yield of the desired product. When using an isolated enzyme, it is necessary to use a cofactor recycling system. This is typically achieved by adding a second enzyme into the reaction mixture which reduces NADP+ to NADPH at the expense of a cheaper sacrificial substrate, which acts as a hydride donor.

A commonly used cofactor recycling system is the glucose-6-phosphate/G6PDH pairing (figure 38).[103] The activated sugar glucose-6-phosphate I acts as the sacrificial donor, being oxidised to glucose-6-phosphonolactone II by the enzyme. Spontaneous hydrolysis forms the corresponding gluconate III, which renders the reaction irreversible and drives the equilibrium. An analogous system using glucose/GDH is also frequently used, and is preferable due to the low cost of the sacrificial substrate. Furthermore, the high stability of this enzyme means that it may catalyse 40000 turnovers of substrate with no loss of enzymatic activity.[104]

Figure 38: Glucose-6-phosphate regeneration system for the turnover of the NADPH cofactor in BVMO biocatalysis using an isolated enzyme

3.3. Development of the BVMO-Mediated Oxidation of Cyclic Ketones Bearing α-Quaternary Stereocentres 3.3.1. Synthesis of Racemic Starting Materials

Cyclic ketones 91-94 were identified as the model substrates for the initial investigation of the biocatalytic Baeyer-Villiger reaction. Oxidation of the five- and six-membered ketones would result in the formation of six- and seven-membered lactone products, which are suitable substrates for the SmI2-H2O-mediated cyclisations. It is desirable to include the styrene motif on the alkenyl tether, as this can give stabilisation to the radical intermediates that are formed during the reaction and thus promote cyclisation.

Ketones 91 and 92 were synthesised in 3 steps from commercially available diacids 85 and 86, firstly by a Fischer esterification, followed by a Dieckmann condensation and a Tsuji-Trost type palladium-catalysed decarboxylation (figure 39). Cross metathesis with styrene furnished ketones 93a and 94a.

Figure 39: Synthesis of cyclic ketone starting materials for use in initial investigations of the biocatalytic BV reaction

The Fischer esterification proceeded for both substrates in almost quantitative yield and did not require purification. The Dieckmann condensation and alkylation step again proceeded smoothly, with the crude reaction mixture after workup being used directly in the following

41 step. The Tsuji-Trost decarboxylation proceeded for both substrates 89 and 90 on large scale and in moderate yields, following purification by distillation. Products 93a and 94a could again be accessed in moderate yields from the cross metathesis step.

3.3.2. Expression and Purification of Cyclohexanone Monooxygenase

Given that the substrate scope with respect to cyclic ketones bearing an α-tertiary stereocentre had been extensively studied using CHMO from Acinetobacter Calcoaceticus, it was proposed to begin investigations of the BV reaction using this enzyme. The protein is composed of 543 amino acids and has a molecular weight of 60936.8 Daltons. The enzyme was expressed in E. Coli from a pET-28a vector containing the CHMO gene. Expression from the pET-28a vector gives rise to an N-terminal His6 tag, allowing isolation of the purified protein using HisTrap Ni2+ affinity chromatography.

The purity of the protein was assessed using SDS-PAGE gel analysis (figure 40) and was found to be of sufficient purity for use in biotransformations, at a concentration following purification of 0.73 mg mL-1.

1 2 3 4 5 6 7 8 9 10 11 12

Figure 40: SDS-PAGE analysis showing the purity of CHMOAcineto following purification; 1 Protein ladder; 2 Flow through; 3–16 Fractions containing purified CHMO collected from the HisTrap column

3.3.3. Initial Biotransformations Using Model Substrates

Biotransformations were performed on an analytical scale, using standard reaction conditions. As the isolated enzyme was used, a glucose/GDH pairing was chosen as the recycling system for the NADPH cofactor. The reactions were performed in 100 mM Tris/HCl buffer at pH 7.0, with 10 vol% of ethanol, used to solubilise the organic substrates in the aqueous reaction media. A substrate concentration of 1 mg mL-1 was used, with CHMO at a concentration of 0.5 mg mL-1. The reactions were run for 24 h, with shaking in a shaker incubator maintaining a temperature of 25 °C. The resulting crude reaction mixture was analysed directly using chiral GC.

To our delight, six-membered ketone 91 underwent an exquisite kinetic resolution process; the product was formed in 50% conversion and >99% ee. For this substrate, the total turnover number (TTN) of the enzyme was 1580. Ketone 93a was similarly efficiently transformed to the lactone in 47% conversion and with high enantioselectivity (figure 41). This result was somewhat surprising, given the lack of precedent in the literature for substrates bearing such a bulky tether. Five-membered ketones 92 and 94a were also accepted by the enzyme, although they gave rise to lower enantioselectivities. Reactions were performed both on an analytical (1 mg) and semi-preparative (6 mg) scale.

Following the success of the initial biotransformations using isolated enzyme, the transformation was also attempted using the whole cell biocatalyst. This resulted in greatly

1 mg scale 6 mg scale

Conversion er Conversion er

91 50 >99:1 50 >99:1

93a 47 >99:1 49 >99:1

92 48 89:11 36 95:5

94a 59 86:14 57 91:9

Figure 41: Initial biotransformations using model substrates. Conversion was determined by GC analysis of the crude reaction mixture; er values were determined by chiral-stationary-phase GC analysis and refer to the lactone product.

43 reduced conversion to the desired product. It is thought that this could be due to the increased difficulty of the substrate in penetrating the cell to reach the active site. Additionally, variation of enzyme concentration was attempted, however this gave inferior results. It was therefore decided to use the initial conditions in order to explore the scope of the reaction.

3.3.4. Scope of the Biotransformation

In order to explore the scope of the substrates that could be accepted by the enzyme, a range of ketones was synthesised by cross metathesis of parent ketones 91 and 92 with different styrenes. Five- and six-membered ketones were produced in moderate yields (figure 42).

Figure 42: Synthesis of ketone substrates by cross metathesis

Firstly, six-membered ketone substrates 91, 93 were subjected to the biotransformation on an analytical scale (figure 43). In all cases impeccable enantioselectivity was observed. Aryl substituents bearing substitution at all positions on the aromatic ring were tolerated, as was functionality including halogens, trifluoromethyl and methyl groups. E values for the process for all substrates were in excess of 200, indicating highly synthetically useful procedures. For substrates bearing larger substituents (95f, g) the observed conversions were lower, suggesting that these substrates are less well accommodated into the active site of the enzyme due to steric bulk. Subsequent to the assessment of the efficiency of the biotransformations on analytical scale, reactions of the most successful substrates were

Figure 43: Biotransformations of six-membered ketones to seven-membered lactones aConversion determined by GC or 1H NMR spectroscopy bIsolated yield; er values were determined by chiral-stationary-phase GC or HPLC analysis in comparison with authentic racemic materials

45 performed on a preparative scale, and the products could be isolated by silica gel column chromatography.

In order to probe the limits of substrate acceptance by the enzyme, six-membered ketone 96 was synthesised, containing a larger ethyl substituent at the α-quaternary centre. Under the standard conditions of the biotransformation, this substrate showed little conversion (3%) to the desired product 97, although the product was formed with high enantioselectivity. This indicates that substituents larger than a methyl group cannot be efficiently accommodated at this position. This observation is in line with literature precedent; in the scope of ketone substrates bearing a tertiary centre at this position, low enantioselectivity was observed only for 2-methylcyclohexanone, suggesting that larger alkyl groups cannot adopt the required arrangement in the active site of the enzyme for the opposite enantiomer to form.[101]

Figure 44: Biotransformation of six-membered ketone 96 bearing an ethyl substituent; conversion was determined by GC analysis of the crude reaction mixture; ee value was determined by chiral-stationary-phase GC analysis in comparison with authentic racemic material.

In addition to the six-membered ketones, the oxidation of five-membered ketones 92, 94 was also investigated (figure 45). In this case, the substrates could also be transformed by the enzyme, however, lower enantioselectivity was observed. In some cases (98b, c, h), E values are indicative of viable procedures, with moderate to good conversions observed. In the instance of substrates bearing bulky side chains, little to no conversion was observed.

The decrease in stereochemical discrimination for cyclopentanone substrates in comparison to analogous cyclohexyl substrates is consistent with literature observations regarding the oxidation of similar tertiary substituted ketones.[105] It is proposed that this may be rationalised by analysis of the conformation of the substrates within the enzyme active site. For cyclohexanone substrates, the substrates exhibit a high preference for conformations in which the large side chain adopts an equatorial arrangement. In cyclopentanones, the energy

46 barrier between alternate conformations is much lower. This makes the energy difference between conformations in which substituents occupy pseudoaxial and pseudoequatorial positions lower, meaning that both conformations are accessible and may be adopted by the substrate during catalysis.

Figure 45: Biotransformations of five-membered ketones to six-membered lactones aConversion determined by GC or 1H NMR spectroscopy bIsolated yield; er values were determined by chiral-stationary-phase GC or HPLC analysis in comparison with authentic racemic materials

The biocatalytic BV reaction was also explored in relation to seven-membered ketone substrate 99 (figure 46). This reaction did not exhibit any conversion to the lactone product 100. Such structures, an eight-membered lactone with two alkyl substituents at the 7- position, are unreported in the literature.

Figure 46: Attempted oxidation of a seven-membered ketone substrate

The biotransformation was completely regio- and chemo-selective; no competing epoxidation of the alkene was observed. This illustrates a significant advantage of the biocatalytic BV reaction, when compared to the chemical process using peracids. When the BV oxidation of ketone 93a was attempted using mCPBA, a mixture of products was formed (figure 47). In addition to unreacted starting material, both lactone and ketone epoxidation products were formed. A small amount of the desired lactone could be isolated.

Figure 47: Baeyer-Villiger oxidation of ketone 93a using mCPBA. Conversions determined by analysis of the crude 1H NMR spectrum, isolated yields are shown in brackets

3.3.5. Determination of Absolute Configuration

The absolute stereochemistry of lactone 95a could be determined by comparison with [α]D literature values, showing that the (R)-enantiomer was preferentially formed. Substrates bearing the styryl motif were unreported in enantiomerically enriched form, therefore the absolute stereochemistry of products was determined by the independent synthesis of enantiomerically enriched standards.

In order to access enantiomerically enriched samples of the desired lactone, β-keto ester 89, accessed as described in figure 39, was subjected to an enantioselective Tsuji-Trost decarboxylative allylation, following the procedure of Stoltz.[106] Using a chiral (S)-tBuPHOX ligand, the (S)-enantiomer of the ketone could be accessed in 84% ee. Chemical Baeyer- Villiger oxidation gave access to lactone (S)-95a, which could then be used to synthesise substrates (S)-95b and (S)-95c by cross metathesis (figure 48).

With enantiomerically enriched lactones of known configuration in hand, the absolute stereochemistry of the products from the biotransformations could be determined. Comparison of the HPLC traces showed that the products were of opposite stereochemistry, therefore showing that the lactones produced in the biotransformation have an (R) absolute configuration. The HPLC comparison was performed for substrates 95b and 95c and the stereochemistry of other substrates was inferred from these findings.

Figure 48: Synthesis of enantiomerically enriched standards for determination of absolute configuration using an asymmetric Tsuji-Trost decarboxylative allylation; er determined using chiral-stationary-phase GC analysis in comparison with authentic racemic material.

3.3.6. Computational Modelling using CHMORhodo

Given that the transformation of ketone substrates bearing an α-quaternary centre has not been previously reported, the use of computational modelling was employed in order to gain insight into the arrangement of the substrate in the active site. Despite being one of the prototypical BVMOs, a crystal structure for CHMO from Acinetobacter Calcoaceticus has not been reported.

Protein BLAST analysis of CHMOAcineto indicated that a related enzyme, CHMO from Rhodococcus sp. HI-31, shares a 55% amino acid sequence identity. The crystal structure of

CHMORhodo has been determined in complex with ε-caprolactone, the product of the Baeyer- Villiger oxidation of cyclohexanone.[107] The majority of residues in the active site are conserved between the two enzymes, meaning that this enzyme can be used as a model for

[108] CHMOAcineto, as previously reported by Reetz.

The computational modelling investigated the arrangement of the lactone product 95a in the active site immediately after catalysis. An in silico docking experiment was performed using both enantiomers of the lactone substrate in the two possible ‘flipped’ conformations. The (R)-enantiomer, the observed experimental product of the reaction, could be accommodated in the active site. The lactone sits directly beneath the enzyme-bound FAD residue, directing the alkenyl substituent into a hydrophobic pocket formed by side chains L435, F505 and F432. In particular, F432 has been found to have significant influence on enantioselectivity of CHMOAcineto reactions through mutation; replacing this residue with serine showed reversal of enantioselectivity in the desymmetrisation of 4-substituted cyclohexanone substrates.[109] This conformation also demonstrates how the enzyme is able to accommodate the bulky aromatic substituents on the tether. All other possible arrangements of the substrate in the active site resulted in steric clashes.

When comparing (R)-95a with ε-caprolactone, the lactone carbonyl superimposes well in the two structures, sitting at a distance of 3.3 Å from the ribose 1-hydroxyl. It is also 2.7 Å from the side chain of R327, which is proposed to stabilise the oxyanion of the Criegee intermediate that is formed during catalysis.

[110] Figure 49: Model of CHMOAcineto in complex with lactone product (R)-95a created using Autodock-Vina. Backbone and side chains of the enzyme are shown in light blue, carbon atoms of FAD, NADP+ and 95a are shown in grey, green and yellow respectively. Selected interactions are shown in black with distances indicated in Angstroms. Computational studies performed by Professor Gideon Grogan.

3.4. SmI2-Mediated Cyclisations of Enantiomerically Enriched Substrates

3.4.1. Cyclisation of Enantiomerically Enriched Lactones Using SmI2-H2O via a carbonyl-alkene coupling

As shown in figures 43 and 45, the biotransformations could be performed on both analytical and preparative scale. No loss of conversion or enantioselectivity was observed upon scale- up and the lactone products could be isolated by column chromatography. The most successful substrates from the biotransformations were selected for use in the SmI2- mediated cyclisation reactions.

Lactones 95, 98 were isolated and subjected to SmI2-H2O cyclisation conditions to generate diols 103 (figure 50). In order to simplify diastereoisomeric mixtures and aid purification, the crude diols were oxidised to the hemiketals 104 using Dess-Martin periodinane. The reactions proceeded with good diastereoselectivity, and enantioenrichment was retained from starting materials to products, allowing access to the desired medium-sized cycloalkanol motifs in enantiomerically enriched form.

Figure 50: Reductive radical cyclisations of enantioenriched lactones to generate medium-sized carbocycles; isolated yields shown; er values were determined by chiral-stationary-phase HPLC analysis in comparison with authentic racemic materials; ee values refer to the major diastereoisomer.

3.4.2. Cyclisation of Enantiomerically Enriched Ketone Substrates Using

SmI2-HMPA via a ketone-alkene coupling

Kinetic resolution processes exhibit the drawback that the maximum yield of the process is capped at 50%; one enantiomer of the substrate is preferentially accepted by the enzyme, and the other is left unreacted. In the case of an efficient kinetic resolution process, such as that which is reported here, it is possible to obtain the remaining starting material in enantioenriched form.

The ketone starting material from biocatalytic BV kinetic resolution can be easily isolated by column chromatography. In examples where the conversion is approaching 50%, this material is also significantly enantiomerically enriched (figure 51).

Figure 51: Enantiomerically enriched ketones isolated from the enzymatic kinetic resolution

It was proposed that the recovered ketone could be used in an alternative SmI2-mediated transformation, thus allowing the kinetic resolution to be used as part of a divergent approach to different product architectures. It was initially suggested that the recovered ketone could undergo a diastereoselective reduction, to generate the enriched cycloalkanol. Investigations commenced with racemic ketone 93a using various alcohols as proton sources in cosolvent quantities (entries 1 and 2). This gave the expected reduction product 105 in low to moderate conversions, as the major component of a mixture. The other isolable product of the reactions was identified as cyclobutanol 106a, formed by the cyclisation of the ketyl radical onto the alkene acceptor in a 4-exo-trig fashion. Having identified this product, we sought conditions which were optimal for its formation (figure 52).

The use of tBuOH as an additive resulted in almost complete recovery of unreacted starting material. Using MeOH increased the conversion, and gave the cyclobutanol as the minor

Entry SmI2 ROH (eq.) Additive Conditions Conversion 105:106a (eq.) (eq.) (%) 1 3 tBuOH (1:4 in THF) – rt <5 – 2 3 MeOH (1:4 in THF) – rt 46 82:18

3 4 MeOH (1:4 in THF) – rt 42 83:17 4 3 H2O (300) – rt 100 60:40 5 3 MeOH (3) HMPA (12) rt 100 56:44 6 3 MeOH (3) HMPA (12) -78 °C 100 20:80 7 3 H2O (3) HMPA (12) -78 °C 100 45:55 8 3 – HMPA (12) -78 °C 100 4:96

Figure 52: Optimisation of the formation of cyclobutanol 106 from ketone 105. Conversions determined by 1H NMR spectroscopy.

53 component of the crude reaction mixture. Increasing the equivalents of SmI2 used (entry 3) did not improve the result. When H2O was used, the conversion was improved and the amount of the desired product 106a was increased (entry 4).

Employing HMPA as an additive promoted the cyclisation and led to an increased proportion of the desired product. Performing the reaction at low temperature improved this further, leading to optimal conditions (entry 8) that allowed the cyclobutanol to be isolated in good yield (84%).

Using the optimal conditions, the recovered ketones (S)-93 were cyclised to give cyclobutanols 106 in enantiomerically enriched form (figure 53). As for the lactone cyclisations, the products were obtained without loss of enantioenrichment. The products could be isolated in good yields, as single diastereoisomers. The relative stereochemistry of the product was confirmed by nOe analysis.

Figure 53: Construction of enantiomerically enriched cyclobutanols using recovered ketones from the kinetic resolution; ee values determined using chiral-stationary-phase HPLC analysis in comparison with authentic racemic materials.

3.5. Summary

Despite the abundance of literature relating to the study of cyclohexanone monooxygenase from Acinetobacter Calcoaceticus, a prototypical Baeyer-Villiger monooxygenase, the transformation of cyclic ketone substrates bearing an α-quaternary centre had not yet been explored. It has been demonstrated in this work that such a transformation is possible and

54 that five- and six-membered ketones can be transformed into the corresponding six- and seven-membered lactones in a kinetic resolution process. Conversions range from moderate to excellent, with exquisite enantioselectivity observed in the case of six-membered ketones.

Computational modelling using CHMORhodo supported the experimental observation for the preferential formation of the (R)-enantiomer of the lactone product. The model of the substrate using the enzyme crystal structure provided insight into the arrangement of the active site residues during catalysis, as well as showing how the enzyme is able to tolerate bulky substituents.

The biotransformations could be performed on both analytical and preparative scale. The lactone products could be isolated in high enantiomeric excess, in addition to the recovered enriched ketone starting material. Both substrates could be subjected to reductive radical cyclisations mediated by samarium diiodide. The lactones underwent cyclisation using SmI2-

H2O to give enantiomerically enriched medium-sized carbocycles. By employing a different

SmI2 reagent system, enantiomerically enriched cyclobutanol motifs could be constructed from the recovered ketone. Overall, the process allows construction of diverse, enantiomerically enriched biologically relevant scaffolds from simple racemic starting materials using a combination of biocatalysis and a chemical reagent.[111]

Figure 54: Divergent approach to different enantiomerically enriched cyclic architectures using biocatalytic kinetic resolution in combination with SmI2-mediated cyclisations

4. SmI2-Mediated 1,4-Ester Migration in Lactone Substrates 4.1. Project Proposal

The development of one-pot processes, in which multiple chemical steps occur in the same reaction vessel, is a desirable pursuit in organic synthesis. Such processes decrease the time, cost and waste associated with the synthesis of complex molecules.

To this end, we envisaged an SmI2-mediated process which, starting from simple malonates, would generate complex cyclopentanone substrates in a single step. The reaction would proceed via an initial reduction of the ketone in the malonate substrate to generate an alcohol. Diastereoselective lactonisation would then generate the lactone, which would undergo a radical cyclisation onto the alkene acceptor, forming a hemiketal intermediate. Following carbon-oxygen bond cleavage, the desired product would be furnished (figure 55).

Figure 55: Proposed cascade reaction from malonates to decorated cyclopentanones mediated by SmI2

Building on our previous work on the integration of biocatalysis with SmI2, it was envisaged that the initial reduction step could be performed enzymatically using an alcohol dehydrogenase (ADH). This would introduce enantioenrichment into the products, with the control of subsequent stereochemistry based on the initial enantioselective reduction step.

4.2. Synthesis of Starting Materials

In order to investigate the viability of the SmI2-mediated cyclisation step, lactone 111 was first synthesised and isolated (figure 56). Malonate 109 was produced in two simple steps from commercially available dimethyl malonate. An alkylation using sodium hydride and 4- bromo-1-butene gave 108 in moderate yield on large scale. A Michael addition with methyl vinyl ketone gave desired product 109.

Several alcohols were investigated in the Sm(II)-mediated ketone reduction, with H2O giving the most efficient transformation. The reduction proceeded with quantitative conversion and the crude diol was lactonised using a substoichiometric amount of acid. The crude 1H NMR spectrum indicated that the lactone was formed as a 4:1 mixture of diastereoisomers. The major diastereoisomer could be isolated in good yield.

Figure 56: Synthesis of starting materials for investigation of the lactone cyclisation

In accordance with literature precedence, the major diastereoisomer from the acid-catalysed lactonisation was deduced to be that shown in figure 57.[112] Hydrogen bonding between the oxygen atoms encloses a decalin-type conformation, as shown in intermediate I. The alkyl group at the 2-position of the lactone lies in the axial position due to the greater stability of the trans junction that is formed. This transition state leads to the stereochemistry shown in 111, where the alkyl substituents at the 2- and 5-positions of the lactone are in a cis relative

57 configuration. X-ray crystallographic analysis obtained later indicated that the lactone preferentially adopts a half-boat conformation (vide infra).[113]

Figure 57: Predicted relative stereochemistry of the major diastereoisomer of the lactonisation

4.3. Initial Investigations of the Lactone Cyclisation

Studies began using lactone 111. Cyclisations of similar substrates have been previously reported in the Procter group, thus initial trials commenced with the optimised conditions

[33] previously described. Using 5 equivalents of SmI2 and 500 equivalents of water resulted in a complex reaction mixture (figure 58). The desired cyclopentanone product was not observed, however cyclopentanol 113 could be isolated, resulting from over-reduction of the cyclopentanone 112. The major product isolated from the reaction was diol 114, the product of direct lactone reduction.

Figure 58: Initial studies on the cyclisation of lactone 111 using SmI2-H2O

It was proposed that using an alkenyl radical acceptor incorporating an aryl substituent would promote cyclisation as a more stable benzylic radical would form upon cyclisation. This strategy had proved successful in the group’s previous studies. To this end, substrate

115a was synthesised by cross metathesis of malonate 109 with styrene (figure 59). This was then subjected to the SmI2-H2O-mediated ketone reduction and lactonisation, to give lactone 116a in 3.2:1 dr. The major diastereoisomer could again be isolated in diastereoisomerically pure form.

Figure 59: Synthesis of cyclisation substrate 116a using cross metathesis

Upon exposure of lactone 116a to the conditions described in figure 58, a complex mixture of unidentifiable products was formed. As the complexity of the product mixture was thought to be caused by over-reduction by excess SmI2 – the desired cyclisation being a two electron process – the number of equivalents of reagent used was reduced. When using 2.2 equivalents of SmI2 and 220 equivalents of H2O, the desired cyclisation product 117 could be isolated in 31% yield, in addition to small amounts of the cyclopentanol product of over- reduction (figure 60).

Figure 60: Cyclisation of lactone 116a to give cyclopentanone 117

Reducing the amount of SmI2 further to just 2 equivalents eliminated the formation of cyclopentanol 118. In this case, 117 could be observed by 1H NMR spectroscopy but was not isolated. Additionally, a second major product was identified in the NMR spectrum, which could be isolated in 33% yield as a 1:1 mixture of diastereoisomers (figure 61).

Figure 61: Formation of unknown product 119 from the SmI2-H2O reaction

4.4. Identification of Unknown Compound 119

Unknown compound 119 was obtained from the SmI2-H2O-mediated reaction as a 1:1 mixture of diastereoisomers. In order to elucidate the structure of the unknown species, the isolated compound was exposed to the same SmI2-H2O reaction conditions. No change was observed, indicating that the product formed was not an intermediate in the formation of cyclopentanone 117. Reduction of 119 using LiAlH4 gave open chain triol product 120 as a 1:1 mixture of diastereoisomers (figure 62).

Figure 62: Reduction of unknown compound 119 to triol 120 using LiAlH4

Based on these experiments, it was proposed that the structure of the unknown compound could be nine-membered lactone 121 (figure 63). Mechanistically, this may form from a common intermediate en route to cyclopentanone 117. The initial cyclisation generates the hemiketal species I, which could collapse by breaking the C-O bond to give the cyclopentanone, as observed in previous work. Alternatively, it was hypothesised that the C-C bond could break to form an enolate, which would then be protonated to give the nine- membered lactone. This structure appeared to be consistent with 1H NMR and accurate mass data.

Figure 63: Proposed structure of the unknown compound 119 and possible mechanism of formation

The proposed structure of the unknown compound was revised following X-ray crystallographic analysis. This confirmed the structure of the compound to be 119a, resulting from an overall 1,4-shift of the ester moiety. Crystallographic analysis of the more crystalline compound, where the phenyl ring bears a para-phenyl substituent, was used to shed light on the identity of 119 (vide infra).

Figure 64: Confirmed structure of compound 119a, determined by X-ray crystallography of a related compound

4.5. Optimisation of the 1,4-Ester Migration

As the formation of 119 represents unexplored reactivity in the chemistry of SmI2, the aims of the project were modified to optimise the ester migration over the formation of cyclisation product 117 (figure 65). Under the original reaction conditions, cyclopentanone 117 and lactone 119 were formed in a 1:1 ratio, as components of a complex reaction mixture. Reducing the number of equivalents of water (entries 2-3) was detrimental; product ratios stayed the same and the complexity of the reaction mixture increased.

Using HMPA as an additive had a positive effect (entries 4-6). The ratio of the desired product 119 was increased, additionally the formation of unknown byproducts was eliminated; 117

61 and 119, as well as unreacted starting material, were the only species discernible in the crude 1H NMR spectrum. To ensure complete conversion of starting material, the number of equivalents of SmI2 was increased to 2.5. In order to achieve selectivity for the desired product, 80 equivalents of HMPA had to be used (32 equivalents for each equivalent of SmI2).

Studies have previously shown that one molecule of SmI2 is coordinatively saturated by four molecules of HMPA.[114] The large excess that is used here is thus undesirable; the toxicity of the reagent makes its use prohibitive in large quantities. It was hypothesised that there could be competition between HMPA and H2O for ligation to the Sm(II) centre. Therefore, the number of equivalents of water used was decreased. The desired effect was observed, and by reducing the number of equivalents of H2O to 16, the amount of HMPA could concomitantly be reduced to 10 equivalents (4 equivalents for each mol of SmI2) (entry 13).

Entry SmI2 ROH (eq.) HMPA Conditions Conversion 119a:117 dr of (eq.) (eq.) (%) 119a

1 2.0 H2O (200) – rt 1:1 – 2 2.0 H2O (100) – rt 0.8:1 – 3 2.0 H2O (25) – rt 1:1 – 4 2.0 H2O (200) 16.0 rt 1.4:1 – 5 2.0 H2O (200) 32.0 rt 2.3:1 – 6 2.0 H2O (200) 64.0 rt 81 3:1 1:1 7 2.5 H2O (250) 80.0 rt 100 3:1 1:1 8 2.5 H2O (125) 80.0 rt 100 3.6:1 1:1 9 2.5 H2O (64) 80.0 rt 83 2.4:1 1:1 10 2.5 – 80.0 rt 50 – – 11 2.5 H2O (64) 40.0 rt 50 3.6:1 1:1 12 2.5 H2O (32) 20.0 rt 100 3.7:1 1:1 13 2.5 H2O (16) 10.0 rt 100 4.2:1 1:1 14 2.5 H2O (16) 10.0 -78 °C 100 (76) 11.5:1 3:1 15 2.5 MeOH (16) 10.0 -78 °C 100 7.2:1 3:1 16 2.5 HFIP (16) 10.0 -78 °C 100 14:1 1:1 17 2.5 iPrOH (16) 10.0 -78 °C 67 5.4:1 – 18 2.5 Ethylene 10.0 -78 °C 52 6.2:1 – glycol (16)

Figure 65: Optimisation of the SmI2-mediated 1,4-ester migration

The optimal conditions were reached by performing the reaction at -78 °C, resulting in almost complete selectivity for the formation of the desired product (entry 14). 119a could be isolated in 76% yield, as a 3:1 mixture of diastereoisomers.

Surprisingly, in contrast to previous reports of the activation of SmI2 for the reduction of carboxylic acid derivatives (section 1.3., vide supra), alcohols other than water could also be used to perform the reaction (entries 15-18), although the processes were less efficient than when H2O was used.

4.6. Scope of the Transformation 4.6.1. Scope with respect to the R Substituent

Initially, the scope of the transformation was investigated by variation of the substituent at the 5-position of the lactone ring. It was hypothesised that using a larger substituent at this position would induce greater diastereoselectivity in the lactonisation step as a result of greater energy differences between the two possible chair conformations. The reaction sequence described in figure 59 was modified to access the products with greater efficiency; cross metathesis of malonate 108 gave 125, which could be used as a general starting material for Michael additions with a range of vinyl ketones.

Vinyl ketones 124 were synthesised from the corresponding aldehydes by addition of vinyl Grignard, followed by oxidation. The crude vinyl ketone products were used directly in the Michael addition reactions due to their instability to silica gel column chromatography and susceptibility to decomposition. Conditions for the Michael addition were altered slightly depending on the electrophilicity of the Michael acceptor.

Figure 66: Synthesis of vinyl ketones 124 from aldehydes 122

As expected, a general trend was observed; lactonisation becomes more diastereoselective as the steric bulk of the R substituent is increased. Lactone products 116 could be formed in

63 moderate to good yields (figure 67). This process was found to be unsuccessful when the R group used was aromatic. Using a phenyl group at this position was incompatible with the reduction step and a complex mixture of products was formed.

Figure 67: Synthesis of substrates with variation of the R component at the 5-position of the lactone ring. aReactions performed by Ilma Amalina

The lactone substrates were exposed to the optimal conditions for the reductive rearrangement process. The reaction proved to be tolerant of variation at this position, with products formed in moderate to good yields in all cases. Two diastereoisomers were observed and isolated as an inseparable mixture. The transformation shows complete diastereoselectivity with respect to the carbon-carbon bond forming event of the ester migration. Diastereomeric ratios shown relate to the stereochemistry alpha to the lactone carbonyl, determined by the final protonation event. When water is used as the proton source for the reaction, the final product is furnished in 3:1 dr. Using other proton sources gives different degrees of selectivity; for example, using HFIP as a proton source delivers the product in 1:1 dr (figure 65, entry 16). This provides evidence that the diastereoselectivity is set during the final protonation step; the proton source must be involved in the step in which stereochemistry is determined. Additionally, disorder in the X-ray crystal structure around the 2-position of the lactone provides further support that the diastereoisomeric mixture consists of isomers differing in stereochemistry at this centre.

Figure 68: Scope of the 1,4-ester migration mediated by SmI2-H2O-HMPA with respect to the alkyl substituent. aReactions performed by Ilma Amalina.

4.6.2. Scope with respect to the Styrenyl Aromatic Substituent

In order to extend the scope of the process further, the variation of the aromatic styrene partner was next explored. Starting materials could be synthesised by cross metathesis of malonate 126 with various substituted styrenes (figure 69). Products 127 were obtained in moderate yields and could be used to access lactones 128.

Figure 69: Synthesis of substrates with variation of the aromatic substituent. aReactions performed by Ilma Amalina

At this point, the relative stereochemistry of the major diastereoisomer of the lactonisation was confirmed by X-ray crystallographic analysis (figure 70). The major diastereoisomer of 128f was isolated and could be crystallised. The observed relative stereochemistry is in line with the predicted transition structure for the lactonisation, where the two larger alkyl substituents are in a cis relative configuration. Both larger substituents lie in the equatorial positions in a half-boat conformation of the lactone. The switch from a chair conformation

Figure 70: X-ray crystal structure of 128f, showing the relative stereochemistry of the major diastereoisomer; comparison of possible conformations of lactone 128

66 to the half-boat conformation relieves unfavourable 1,3-diaxial interactions caused by the alkyl chain at the 2-position of the lactone.

Lactones bearing substituents in a cis arrangement, as is the case here, have been reported to preferentially adopt the half-boat conformation. For example, Simpson et al reported the crystal structure of a valerolactone substrate bearing three substituents in a cis arrangement (figure 71).[115] The lactone ring exists in a half-boat conformation in this substrate. Computational studies by Sundin and co-orkers have shown that, despite the half-chair configuration generally being the most stable for six-membered lactones, the half-boat conformation is relatively low-lying in energy, making it accessible. As both alkyl substituents at the 2- and 5-positions of the ring can lie equatorial in this conformation, it is generally favoured for lactones bearing substituents with a cis relationship.[113,116]

Figure 71: Crystal structure of lactone 129, showing the lactone ring in a half-boat configuration

With the lactone substrates 128 in hand, the SmI2-mediated ester migration was investigated (figure 72). The reaction was found to tolerate functionality at all positions of the aryl ring. Both electron-rich and electron-deficient functional groups could be incorporated with little variation in reaction efficiency.

Figure 72: Scope of the 1,4-ester migration mediated by SmI2-H2O-HMPA with respect to the aromatic substituent; aReactions performed by Ilma Amalina

The structure and relative stereochemistry of the product was determined by X-ray crystallographic analysis of 130h (figure 73).

Figure 73: X-ray crystal structure of 130h, showing the structure and relative stereochemistry of the major diastereoisomer

4.7. Development of a One-Pot Procedure

It was envisaged that the products 119 could be accessed in a one-pot procedure from malonates 115, as the ketone reduction and ester migration are both mediated by SmI2. Attempts were made to optimise a procedure whereby the reduction, lactonisation and migration could occur in a cascade fashion in a single reaction vessel.

The two SmI2-mediated steps require different reaction conditions in the sequential procedure; more equivalents of water were required in the initial reduction step, as well as it being performed at room temperature – requirements that were known to have a detrimental effect on the selectivity of the subsequent reductive migration. Initial investigations focused on altering the conditions of the reduction step so that they could be compatible with the migration. The process was attempted using malonate 115a (figure 74).

Entry H2O HMPA (eq.) Conversion (%) (eq.) 1 250 - 100 2 125 - 66 3 64 - 43 4 32 - 30 5 16 10 63 6 32 20 100

Figure 74: Optimisation of ketone reduction for the one-pot procedure

Reducing the number of equivalents of water led to decreasing conversion and starting material was recovered (entries 1-3). Introducing HMPA into the reaction mixture increased the efficiency of the process and complete conversion to the alcohol could be achieved.

Following the development of the compatible conditions for the reduction, the resultant alcohol next needed to be lactonised in situ. Firstly, the reaction was simply left to stir at room temperature under the reaction conditions after decolourisation. No conversion to the lactone was observed in this case after 24 h. Heating the reaction mixture was also unsuccessful. It was discovered that the lactonisation of the isolated alcohol could proceed using Sm(OTf)3. Adding this reagent to the reaction mixture after decolourisation again did not induce lactonisation.

In an attempt to circumvent the difficulties of inducing lactonisation, substrate 132 bearing a diphenyl malonate motif that is more susceptible to lactonisation was targeted. It was envisaged that the greater electrophilicity of the phenyl ester would encourage lactone formation. The precursor was accessed in 3 steps from malonate 115a, albeit in low overall yield (figure 75).

Figure 75: Synthesis of diphenyl malonate 132

Diphenyl malonate 132 was employed in the reduction. Under the conditions described in figure 73, a complex mixture of products was observed by crude 1H NMR spectroscopy. In order to isolate the lactone, the reaction was performed using the standard conditions used in the sequential process (figure 76). In this case the product could be obtained, but in a lower yield in comparison with that obtained using the corresponding methyl ester substrate. Peaks could be observed in the crude 1H NMR spectrum that were indicative of the formation of a primary alcohol adjacent to a methylene group. This suggests that reduction of the phenyl esters competes with reduction of the ketone, resulting in a lower yield of the desired product. It was therefore decided that the diphenyl ester substrate would not be suitable for use in the reaction. Efforts to develop the one-pot process have so far been unsuccessful.

Figure 76: Reduction and lactonisation of diphenyl malonate 132

4.8. Mechanism of the Reductive 1,4-Ester Migration

In contrast to the reactivity reported in previous work, in which cyclisation occurs involving a radical formed from the lactone carbonyl, the 1,4-ester migration appears to arise from cyclisation of a radical species formed from the ester functionality. A proposed mechanism for the reaction is shown in figure 77. Under the reaction conditions, electron transfer from Sm(II) to substrate 116 leads to the formation of ester radical I. 5-Exo-trig cyclisation onto the radical acceptor gives rise to spirocyclic intermediate II, which collapses to give the enolate III. Subsequent protonation to preferentially form the more stable anti- diastereoisomeric product completes the sequence.

Figure 77: Proposed mechanism for the SmI2-mediated formation of 119 from lactone 116

The cyclisation of radicals derived from the lactone carbonyl groups of six-membered lactone substrates bearing an alkenyl tether at the 2-position has been previously reported by the Procter group.[33] In the previously reported work, the lactone substrates do not have any

Figure 78: Cyclisation of six-membered lactones without substitution at the 5-position[33]

substitution, or bear two equivalent substituents, at the 5-position and provide cyclopentanone products. The cyclisation is thought to proceed through axial radical I (figure 78) and an anti-transition state.[117]

In the case of the substrates used in this work, it seems likely that the lactone is more stable in the half-boat conformation. Previous studies by the Procter group have shown that lactones which adopt a chair conformation can be reduced by SmI2 due to anomeric stabilisation of the radical intermediate by the lone pair of the adjacent ring oxygen atom.[33] In a boat conformation, this effect cannot occur as the orbitals cannot adopt the required geometry. Consequently, the radical is less stable and back electron transfer to Sm(III) occurs before further reactivity can take place. Thus, lactones that adopt a boat conformation are unreactive under SmI2 conditions. Instead, products arising from electron transfer to the acyclic ester carbonyl are observed.

Figure 79: Possible explanation for the apparent lack of reactivity of the lactone carbonyls in C5 alkyl lactones

When the reaction is performed at room temperature in the absence of HMPA, products 117 and 119 are formed in a 1:1 ratio. Under these conditions, the pathway to access both products must be feasible, suggesting that it is possible for the lactone to adopt both the chair and boat conformations. Using the optimised conditions, where HMPA is used as an additive and the reaction proceeds at -78 °C, almost exclusive formation of 119 is observed. This suggests that, at lower temperature, the system does not have sufficient energy to overcome the energy barrier to adopt the chair conformation that is required for reactivity to occur at the lactone carbonyl, therefore the boat conformation dominates and reactivity at the acyclic ester is observed.

Additional support for this hypothesis arises from the reactivity of the minor diastereoisomer 116a’ of the lactone starting material. This diastereoisomer was isolated and subjected to the reaction conditions, both unoptimised and optimised for the formation of the ester migration product. Under the optimised migration conditions, cyclopentanone 117 is formed in a higher proportion, when compared with the cyclisation of the major diastereoisomer (figure 80). This effect can be explained by considering the relative stabilities of the chair

Figure 80: Comparison of the reactivity of the major and minor diastereoisomers of lactone 116a and reactive chair conformations. Conditions A: SmI2 (2.0 eq.), H2O (200 eq.), THF, rt. Conditions B: SmI2 (2.5 eq.), H2O (16 eq.), HMPA (10 eq.), THF, -78 °C

73 transition states that are required to reach the cyclopentanone product from the two different diastereoisomers 116a and 116a’. Although both chair conformations suffer from unfavourable 1,3-diaxial interactions, the transition state arising from the minor diastereoisomer 116a’ would be of lower energy. In the major diastereoisomer, the R group in the 5-position of the lactone lies in an axial position in the chair conformation I; in the minor diastereoisomer it is equatorial, hence lowering the energy of conformation I’ and making it more accessible.

When substrate 134, the model substrate for the cyclisation in previous work, was subjected to the optimised conditions for the migration, a mixture of products was obtained. Cyclopentanone 135 and migration product 136 were observed in a 1:1 ratio in the crude 1H NMR and could be isolated in low yields (figure 81). This illustrates the crucial role that the substituent at the 5-position of the lactone, in addition to the reaction temperature and additives, has on the outcome of the reaction.

Figure 81: Reactivity of 134 under optimised conditions for cyclisation in previous work; reactivity of 134 under optimised conditions for the 1,4-ester migration in comparison to analogous substrate 116a with substitution at the 5-position

In order to probe the mechanism of the reaction further and to determine the significance of the lactone ring on the course of the reaction, acyclic substrates 125 and 137 were synthesised and used in the reaction (figure 82). In this case, the major product of the reaction was cyclopentanol 140 or 141. This results from cyclisation via radical species I to form intermediate II, an analogous intermediate to that formed in the cyclisation of lactones 116. In the case of 125 and 137, an alternative collapse of the intermediate occurs by extrusion of the ester methoxy group, rather than formation of the enolate. This can be attributed to the difference in stability of the resultant alkenes, whereby the cyclic tetrasubstituted alkene formed in the lactone substrates is more favourable. The ketone

138/139 that is formed is rapidly reduced by SmI2, hence cyclopentanol 140 or 141 is isolated.

Figure 82: Cyclisation of substrates 125 and 137 by SmI2-H2O-HMPA

Computational studies to further elucidate the mechanism of the reaction and the role of additives are currently ongoing. A possible alternative mechanism is suggested in figure 83, whereby reactivity does proceed from the lactone carbonyl. Following cyclisation from the radical onto the alkene acceptor, the hemiacetal could collapse to give alkoxide III. Lactonisation onto the ester group would give spirocyclic intermediate IV with elimination of a methoxy group, which could then attack the ketone carbonyl to give V. Collapse of this

75 intermediate by extrusion of the lactone enolate followed by protonation would generate product 119’. Although conformational analysis suggests that the major diastereoisomer that would result from this pathway would be different to the observed major product, further studies are needed to determine which mechanism is in operation.

Figure 83: Possible alternative mechanism leading to 119’ via cyclisation from the lactone carbonyl

4.9. Rationale for the Origin of Diastereoselectivity

The relative configuration of the major diastereoisomer of the cyclisation was confirmed by X-Ray crystallographic analysis of 130h (figure 73). The diastereoisomeric mixture arises at the 2-position of the lactone, controlled by the final protonation event. The ester migration event occurs with complete diastereocontrol.

The diastereoselectivity is set during the 5-exo-trig cyclisation. The observed stereochemistry can be explained by the transition structure shown in figure 84. Carbonyl-olefin radical couplings typically proceed though anti-transition states, in order to avoid unfavourable stereoelectronic interactions. In intermediate I, the OSmIII group is arranged anti to the radical acceptor and 5-exo-trig cyclisation occurs from this arrangement. Intermediate II then collapses to give the intermediate III with the experimentally observed stereochemistry. Subsequent protonation sets the stereochemistry at the final centre. Modest

76 diastereoselectivity is observed in this final step to preferentially generate the isomer in which both alkyl substituents are equatorial.

Figure 84: Possible origin of the diastereoselectivity of the 1,4-ester migration

4.10. Summary

A novel SmI2-H2O-HMPA-mediated 1,4-ester migration in lactone substrates has been developed. In contrast to previous work, radical cyclisation of an acyclic ester group, a group that is generally considered to be unreactive in SmI2 chemistry takes place. The reaction, which proceeds through the collapse of a spirocyclic intermediate, results in an overall hydrocarboxymethylation of an alkene. The scope of the process indicates that the reaction is tolerant of various alkyl and aromatic substituents, and the presence of several functional groups.

The reactivity reported here differs greatly from that reported previously for similar substrates. It was found that the alkyl substituent at the 5-postion of the lactone ring has a profound effect on the outcome of the reaction. Whereas cyclisation is favoured for substrates without this substitution, substrates described here exhibit a preference for ester migration. The difference in reactivity can attributed to the conformational preferences of the lactones, the radical anion intermediates and the barriers to their cyclisation.

5. Overall Summary and Future Work 5.1. Summary

Until recently, cyclisation reactions mediated by SmI2 were generally limited to processes involving ketyl radicals from ketone or aldehyde carbonyls. Given the accepted observation in Kagan’s seminal paper that carboxylic acid derivatives lay outside the reducing capabilities of SmI2, the discovery of the ability of the SmI2-H2O reagent to generate analogous ketyl radicals from the carbonyl group of carboxylic acid derivatives has opened up new avenues for exploration in this field of chemistry. Since the preliminary discovery of the feasibility of the activation of lactones using SmI2-H2O, reductions and cyclisation reactions of the unusual radicals that are formed have been developed to access a broad range of cyclisation products.[45] The Procter group has developed a variety of cyclisations and cyclisation cascades of precursors including lactones, Meldrum’s acids and barbituric acid derivatives.

The work described here extends our knowledge of the reactivity of lactone substrates in the presence of SmI2. Five-membered lactones, substrates which were previously thought to be unreactive to SmI2 conditions which can be used to activate analogous six-membered lactones, could be used to form radicals which could be exploited in cyclisation reactions. By optimisation of an appropriate reagent system, the transformation proceeded with broad functional group tolerance to furnish six-membered carbocycles in good yields and diastereoselectivities (figure 85).

Figure 85: Reductive cyclisations of five-membered lactones mediated by SmI2-H2O-HMPA

Samarium diiodide offers an excellent means by which to achieve diastereoselective transformations, due to its ability to chelate to Lewis basic sites and to organise transition states. Efficient asymmetric transformations of carboxylic acid derivatives, however, have remained elusive. In order to access enantiomerically enriched cyclisation products, BVMO

78 biocatalysis was identified as a desirable tool to produce cyclisation substrates for radical chemistry in an asymmetric fashion.

The scope of CHMO biocatalysis was extended to include substrates which bear a quaternary centre at the alpha position, a motif which had not been previously explored. The enzymatic transformation enabled access to the corresponding lactones in highly enantiomerically enriched form by an efficient kinetic resolution process.

Figure 86: Development of a biocatalytic Baeyer-Villiger kinetic resolution process for cyclic ketone substrates bearing an alpha-quaternary stereocentre

The biotransformation successfully gave access to substrates which could be exploited in

SmI2-mediated reductive cyclisations. Enantioenriched lactone products and enantioenriched recovered ketones could undergo cyclisations, giving access to six- and seven membered cycloalkanols as well as cyclobutanol motifs (figure 87). Overall, by combining a biocatalyst with chemical reagents the process allows the transformation of simple, racemic starting materials into diverse, enantiomerically enriched scaffolds.

Figure 87: Use of lactone products and recovered ketones in SmI2-mediated transformations to give diverse enantiomerically enriched scaffolds

Furthermore, unprecedented diastereoselective SmI2-mediated reductive 1,4-ester migrations have been observed. In contrast to previous work on similar lactone substrates, reactivity occurs at the less-reactive ester moiety; thus these studies are proposed to represent the first examples of the cyclisation of radicals derived from acyclic esters using

SmI2. The inclusion of a substituent at the 5-position of the lactone ring was found to be essential for the reactivity, given the constraints that it enforces on the conformation of the lactone. The reaction proceeds diastereoselectively with respect to the C-C bond forming event, with diastereoisomeric mixtures arising from the final protonation step. The scope of the process with respect to the alkyl and aryl substituents was investigated.

Figure 88: 1,4-ester migration of 6-membered lactone substrates

5.2. Future Work 5.2.1. Biocatalytic Baeyer-Villiger Reaction

The combination of the biocatalytic Baeyer-Villiger reaction with SmI2-mediated radical cyclisations gave access to enantiomerically enriched cyclooctanols, from seven-membered ketones, with exquisite enantioselectivity (>99% ee in all cases). The biotransformation was also shown to be applicable to the formation of six-membered lactones from five-membered cyclic ketones, although these substrates exhibited lower enantioselectivity and efficiency in the transformation. In order to address this, it would be desirable to explore the possibility of using an alternative biocatalyst, such as a Cyclopentanone Monooxygenase (CPMO).[118] Such biocatalysts have been reported, although they are less well studied than the related CHMO. The scope of the process with respect to the presence of α-quaternary stereocentres could be further investigated, which could give access to the cycloheptanol cyclisation products with greater efficiency and enantioselectivity.

As described, the scope of the enzymatic transformation is limited to a methyl group at the quaternary stereocentre – increasing the size of this substituent led to decreased conversion. It is possible that this could be improved by evolution of the biocatalyst, to expand the space

80 in the active site and allow it to accept more sterically demanding substrates. The lack of a crystal structure for the enzyme, however, could render the optimisation difficult, although this could be overcome using directed evolution.[109,119–121] Moreover, as the size of the group increases the difference in size between the two substituents at the quaternary centre lessens, making enantiodiscrimination more challenging. Mutating the enzyme to improve the substrate acceptance could therefore induce a decrease in the selectivity of the process.

5.2.2. SmI2-Mediated 1,4-Ester Migration

Efforts to expand the scope of the 1,4-ester migration process are currently ongoing. Whilst the scope of the aromatic and alkyl substituents has been found to be broad, further studies are necessary. The effect of varying the ester substituent (from a methyl ester to other ester groups) will be investigated to assess the generality of the migration process.

Further studies are required to shed light on the reaction mechanism. In order to distinguish between the two possible mechanisms, described in figures 77 and 83, labelling experiments will be used in order to track the fate of each of the carbonyl groups. Additionally, computational studies will be used to discern the mechanism and uncover the role of additives.

Additionally, further work is required on the development of a one-pot process, beginning from malonates 115 to directly synthesise migration products 119. As described in section

4.7. (vide supra), the reaction would proceed through the initial SmI2-mediated reduction, followed by in situ lactonisation and the subsequent migration step. The optimisation requires further screening in order to identify conditions which will perform the initial reduction step and also facilitate the lactonisation.

Figure 89: Access to 1,4-ester migration products 119 from malonates 115 in a one-pot procedure

Motivated by our previous work in combining biocatalysis with samarium(II) chemistry, it was proposed that an enzymatic reagent could be used to introduce enantioenrichment into the lactone products. An alcohol dehydrogenase (ADH) could be used to perform an enantioselective reduction of the ketone to the alcohol. Diastereoselective lactonisation followed by the 1,4-ester migration would give products 119 in enantiomerically enriched form (figure 90). Absolute stereochemistry would be set in the initial reduction step, which then controls formation of all subsequent stereochemistry. Ultimately, it is proposed that this reaction sequence could be developed into a one-pot procedure, in order to access the enantioenriched products in a single reaction vessel.

Figure 90: Proposed route to enantiomerically enriched 1,4-ester migration products from malonates by combining enzymatic catalysis with samarium(II) chemistry

5.2.3. Biocatalytic Processes for the Construction of Lactone Substrates for

Reactions with SmI2

Inspired by previous success in the integration of biocatalysis in reaction sequences involving

SmI2, future lines of research will seek to expand this field further. In particular, the construction of enantiomerically enriched lactones is of interest.

Cytochrome P450 oxidase enzymes are capable of the regio- and stereoselective hydroxylation of unactivated C-H bonds, through the reductive activation of molecular

82 oxygen by a heme cofactor within the active site.[122–124] An enzymatic hydroxylation could be used to introduce a hydroxyl group at the desired position in an enantioselective fashion, thus triggering diastereoselective lactonisation. Subsequent treatment of the enantioenriched lactone products would trigger radical cyclisations or ester migration processes (figure 91).

Figure 91: Proposed construction of lactone substrates using a P450 biocatalyst for use in SmI2-mediated transformations

An alternative approach towards lactone substrates could be achieved using enzymatic desymmetrisation. The oxidative cleavage of C=C bonds has previously been achieved using biocatalysts.[125–127] A biocatalyst could be used to discriminate between two alkenes in a prochiral substrate 143 (figure 92). Reduction of the resultant aldehyde, followed by lactonisation and cyclisation could be used to access substrates 147 in enantiomerically enriched form, possibly in a one-pot process.

Figure 92: Proposed reaction sequence for construction and cyclisation of lactone substrates by using biocatalytic alkene cleavage in combination with Sm(II)

Additionally, lactones bearing the alkenyl tether at the 5-position of the lactone ring could be accessed. Substrates 148 could be reduced enzymatically to give alcohols 149 (figure 93). Following lactonisation, these would be suitable substrates for Sm(II)-mediated cyclisations, giving an alternative route to access enantiomerically enriched cycloalkanols. This could be further extended to access cascade substrates by incorporating a second tether at the 2- position.[36]

Figure 93: Proposed construction of enantiomerically enriched cycloalkanols from biocatalytic reduction and Sm(II)-mediated cyclisations

6. Experimental section 6.1. General Information

Experiments (excluding biotransformations) were performed under an atmosphere of nitrogen using anhydrous solvents, unless otherwise stated. THF was freshly distilled before use. THF was distilled over sodium wire and benzophenone. All other solvents and reagents used were purchased from commercial suppliers and used according to relevant guidelines. The gene of Cyclohexanone Monooxygenase from Acinetobacter Calcoaceticus was supplied by GeneArt. 1H NMR spectra were obtained at room temperature on a Bruker 400 or 500 MHz spectrometer. 13C NMR were obtained at 101 or 126 MHz respectively. 19F NMR were obtained at 376 MHz. All NMR spectra were processed using Mestrenova© NMR software. Chemical shifts are reported in parts per million (ppm), relative to residual chloroform (δH = 7.27 and δC = 77.0) as internal standards, and coupling constants (J) are reported in Hz. Splitting patterns are reported as follows: singlet (s), doublet (d), triplet (t), quartet (q), heptet (hept), broad singlet (bs), double of doublets (dd), doublet of triplets (dt), doublet of quartets (dq), triplet of triplets (tt), quartet of doublets (qd), doublet of doublets of doublets (ddd), doublet of doublets of triplets (ddt), doublet of triplets of doublets (dtd), doublet of quartets of doublets (dqd), triplet of doublets of doublets (tdd), doublet of doublets of doublets of doublets (dddd) and multiplet (m). Column chromatography was carried out using 35 – 70 m, 60 Å silica gel. TLC analysis was carried out on aluminium sheets coated with silica gel 60 F254, 0.2 mm thickness and visualised using potassium permanganate solution and/or UV light at 254 nm. Mass spectra were obtained using positive and negative electrospray (ES±) or atmospheric pressure chemical ionisation (APCI) methodology. Infra‐red spectra were recorded as evaporated films or neat using a FT/IR spectrometer and values are reported in cm-1. Enantiomeric ratios were determined by chiral HPLC analysis (Agilent system equipped with a Phenomenex® Lux 5 µm Amylose–1 (4.6 x 250 mm), Chiralpak® 5 μm IA or Chiralcel® OD–H (4.6 x 250 mm) column using HPLC grade iPrOH/hexane) or by chiral GC analysis (Agilent system equipped with Beta DEXTM 120 (30 m x 0.25 mm) or ChiraSil® DEX CB (25m x 0.25 mm) column, injector temperature 250 °C) in comparison with authentic racemic materials.

Specific rotations were measured on a Rudolph Research Analytical Autopol I Automatic Polarimeter. Melting points were measured on a Stuart Scientific capillary melting point apparatus. Experimental data of compounds 115 h-j, 116h-j, 119h-j, 127 f-j, 128 f-j and 130 f-j, including X-ray crystallographic data, is reported in the thesis of Ilma Amalina.

[3] 6.2. Preparation of Samarium Diiodide (SmI2) Samarium diiodide was prepared as a 0.1 M solution in THF. A flask was charged with samarium metal (1.4 eq.) and 1,2–diiodoethane (1.0 eq.). The flask was flushed with N2 for 30 minutes before THF was added. The mixture was stirred at room temperature overnight to give a deep blue solution, which was allowed to settle for 1 hour before use. Concentration was determined by titration against cyclohexanone.

6.3. Protein Production and Purification Production and Purification of CHMO from Acinetobacter sp.NCIMB9871

The pET–28a vector containing the CHMO gene (1 μL) was added to E. Coli competent cell strain BL21 and was placed on ice for 20 minutes. The solution was heat shocked in a water bath (42 °C) for 45 seconds before cooling on ice for a further 2 minutes. LB media (1 mL) was added and the mixture was incubated at 37 °C for 90 minutes. The resulting mixture was then centrifuged (3 minutes, 5000 rpm) and the pellet was resuspended in supernatant (300 μL). The mixture was then spread between two kanamycin (30 μg mL–1) LB agar plates and incubated at 37 °C for 16 hours. The starter culture (5 mL) was added to LB media (500 mL) containing kanamycin

(500 μL) and the mixture was incubated at 37 °C with shaking at 200 rpm. Once the OD600nm had reached approximately 0.6 the cultures were induced with IPTG (1 mM) and incubated overnight at 25 °C, with shaking at 200 rpm. Cells were collected by centrifugation (15 min, 5000 rpm) and the supernatant was discarded. The resulting cell pellet was resuspended in 100 mM Tris/HCl buffer at pH 7.0 (100 mL). The cells were disrupted by sonication (4 °C, 20 second pulse, pulse off 20 seconds, 25 cycles) and the resulting suspension was centrifuged at 18000 rpm for 40 minutes. The resulting lysate was loaded onto a 5 mL His–Trap column (GE Healthcare). The His–tagged protein was purified by Ni2+ affinity chromatography by use of an AKTA purifier. Protein was eluted by increasing gradient of buffer imidazole concentration from 30 mM to 300 mM. Fractions containing protein were combined and centrifuged at 5000 rpm using a Centricon®

86 concentrator tube with 10 kDA MWCO. The protein was suspended in 100 mM Tris/HCl buffer at pH 7.0 to a concentration of approximately 1.5 mg mL–1, measured spectrophotometrically. The resulting protein was snap–frozen using liquid nitrogen and stored at –80 °C.

6.4. CHMO Sequence

MSQKMDFDAIVIGGGFGGLYAVKKLRDELELKVQAFDKATDVAGTWYWNRYPGALTDTETHLYCYSWDKE LLQSLEIKKKYVQGPDVRKYLQQVAEKHDLKKSYQFNTAVQSAHYNEADALWEVTTEYGDKYTARFLITA LGLLSAPNLPNIKGINQFKGELHHTSRWPDDVSFEGKRVGVIGTGSTGVQVITAVAPLAKHLTVFQRSAQ YSVPIGNDPLSEEDVKKIKDNYDKIWDGVWNSALAFGLNESTVPAMSVSAEERKAVFEKAWQTGGGFRFM FETFGDIATNMEANIEAQNFIKGKIAEIVKDPAIAQKLMPQDLYAKRPLCDSGYYNTFNRDNVRLEDVKA NPIVEITENGVKLENGDFVELDMLICATGFDAVDGNYVRMDIQGKNGLAMKDYWKEGPSSYMGVTVNNYP NMFMVLGPNGPFTNLPPSIESQVEWISDTIQYTVENNVESIEATKEAEEQWTQTCANIAEMTLFPKAQSW IFGANIPGKKNTVYFYLGGLKEYRSALANCKNHAYEGFDIQLQRSDIKQPANA

Uniprot sequence: P12015

6.5. CHMO Modelling

[128] The model of CHMOAcineto was created using the PHYRE server with the structure of

[107] CHMORhodo in its ‘tight’ conformation, in complex with epsilon–caprolactone (4RG3) as a model. Automated docking was performed using AUTODOCK VINA 1.1.2.[110] Coordinates for the (R)–lactone 95a were prepared using ACEDRG.[129] The appropriate pdbqt files for the monomeric model of CHMOAcineto and the ligand, (R)–lactone 95a were prepared in

AUTODOCK Tools. The active site of CHMOAcineto beneath the FAD coenzyme was described in a grid size of 28 Å × 28 Å × 26 Å (corresponding to x, y, z) with 0.375 Å spacing, centred around the catalytic centre at positions 15.04 Å × 1.64 Å × 24.06 Å (corresponding to x, y, z), and was generated using AutoGrid in the AUTODOCK Tools interface. The dockings were performed by Autodock–VINA, in which the posed dockings were below 2 Å r.m.s.d. Results generated by VINA were visualised in AUTODOCK Tools 1.5.6, where ligand conformations were assessed based upon lowest VINA energy.

6.6. Experimental Data

6.6.1. Experimental Data for SmI2–Mediated Reductive Radical Cyclisations of Five–Membered Lactones 5–Allyl–5–methyldihydrofuran–2(3H)–one (76)[130]

Zinc granules (3.5 g, 54 mmol, 1.5 eq.) were added to a solution of methyl levulinate (4.6 g, 36 mmol, 1.0 eq.) and allyl bromide (4.5 mL, 52 mmol, 1.5 eq.) in undried DMF (35 mL) under air at room temperature. After 10 minutes an exotherm was observed. The solution was allowed to cool to room temperature and was poured over saturated aqueous NH4Cl

(300 mL). Aqueous layers were extracted with Et2O (3 x 100 mL), combined aqueous layers were washed with LiCl solution (3 x 100 mL), brine (100 mL), dried (MgSO4) and concentrated. The crude product was purified by silica gel column chromatography (hexane/EtOAc, 85:15 to 8:2) to yield the title product as a pale yellow oil (4.4 g, 31 mmol, 88%). 1H NMR (400 MHz,

CDCl3) δ 1.40 (s, 3H, CH3), 1.90−2.02 (m, 1H, CHaHbCH2C(O)O), 2.09−2.23 (m, 1H,

CHaHbCH2C(O)O), 2.42 (d, J = 6.8 Hz, 2H, CH2CH=CH2), 2.58−2.67 (m, 2H, CH2C(O)O), 5.12−5.22

13 (m, 2H, CH2CH=CH2), 5.72−5.86 (m, 1H, CH2CH=CH2) ppm; C NMR (101 MHz, CDCl3) δ 26.1

(CH3), 29.1 (CH2CH2C(O)O), 32.1 (CH2CH2C(O)O), 45.2 (CH2CH=CH2), 85.9 (Cq), 119.8 (CH=CH2),

−1 132.0 (CH=CH2), 176.6 (C(O)) ppm; IR νmax (thin film, cm ): 3078, 2978, 2934, 1764 (C=O),

+ 1199, 1155, 1138, 939; HRMS calcd. for C8H12O2Na [M+Na] 163.0735, found 163.0742.

General procedure A: Hoveyda–Grubbs(II)–catalysed cross metathesis

(E)–5–Cinnamyl–5–methyldihydrofuran–2(3H)–one (73a)

To a solution of 5–allyl–5–methyldihydrofuran–2(3H)–one 76 (1.0 g, 7.1 mmol, 1.0 eq.) and

nd styrene (2.5 mL, 21 mmol, 3.0 eq.) in CH2Cl2 (9 mL) was added Hoveyda–Grubbs 2 generation catalyst (0.09 g, 0.14 mmol, 2 mol%). The reaction mixture was stirred at room

88 temperature under a slow stream of N2 for 15 h, then concentrated. Purification by silica gel column chromatography (hexane/EtOAc, 100:0 to 9:1 to 8:2) yielded the title compound as

1 a pale yellow oil (0.97 g, 4.4 mmol, 63%). H NMR (400 MHz, CDCl3) δ 1.46 (s, 3H, CH3),

1.96−2.06 (m, 1H, CHaHbCH2C(O)O), 2.16−2.26 (m, 1H, CHaHbCH2C(O)O), 2.52−2.69 (m, 4H,

CH2CO2 + CH2CH=CHAr), 6.19 (dt, J = 15.6, 7.6 Hz, 1H, CH=CHAr), 6.51 (d, J = 15.6 Hz, 1H,

13 CH=CHAr), 7.22−7.27 (m, 1H, ArCH), 7.29−7.39 (m, 4H, ArCH) ppm; C NMR (101 MHz, CDCl3)

δ 26.3 (CH3), 29.1 (CH2CH2C(O)O), 32.3 (CH2CH2C(O)O), 44.4 (CH2CH=CHAr), 86.3 (C), 123.4 (CH=CHAr), 126.2 (ArCH), 127.6 (ArCH), 128.6 (ArCH), 134.6 (CH=CHAr), 136.8 (ArC), 176.6

−1 (C(O)) ppm; IR νmax (thin film, cm ): 3027, 2974, 1763 (C=O), 1449, 1176, 939; HRMS calcd.

+ for C14H16O2Na [M+Na] 239.1048, found 239.1049.

(E)–5–(3–(2–Chlorophenyl)allyl)–5–methyldihydrofuran–2(3H)–one (73b)

Prepared according to general procedure A using 5–allyl–5–methyldihydrofuran–2(3H)–one 76 (0.10 g, 0.71 mmol, 1.0 eq.), 2–chlorostyrene (275 µL, 2.1 mmol, 3.0 eq.) and Hoveyda–

nd Grubbs 2 generation catalyst (0.009 mg, 0.014 mmol, 2 mol%) in CH2Cl2 (1.8 mL). Purification by silica gel column chromatography (hexane/EtOAc, 100:0 to 9:1) yielded the

1 title compound as a white solid (0.10 g, 0.41 mmol, 63%): mp (CH2Cl2) 48-50 °C. H NMR (400

MHz, CDCl3) δ 1.47 (s, 3H, CH3), 2.03 (ddd, J = 12.8, 9.6, 6.8 Hz, 1H, CHaHbCH2C(O)O), 2.23

(ddd, J = 12.8, 9.2, 8.0 Hz, 1H, CHaHbCH2C(O)O), 2.54–2.71 (m, 4H, CH2CO2 + CH2CH=CHAr), 6.18 (dt, J = 15.6, 7.6 Hz, 1H, CH=CHAr), 6.69 (d, J = 15.6 Hz, 1H, CH=CHAr), 7.16–7.26 (m, 2H, ArCH), 7.36 (dd, J = 7.6, 1.6 Hz, 1H, ArCH), 7.51 (td, J = 7.4, 1.8 Hz, 1H, ArCH) ppm; 13C NMR

(101 MHz, CDCl3) δ 26.3 (CH3), 29.1 (CH2C(O)O), 32.3 (CH2CH2C(O)O), 44.5 (CH2CH=CHAr),

86.1 (Cq), 126.5 (CH=CHAr), 126.8 (ArCH), 126.9 (ArCH), 128.6 (ArCH), 129.7 (ArCH), 130.8

−1 (CH=CHAr), 132.8 (ArC), 135.0 (ArCCl), 176.6 (C(O)O) ppm; IR νmax (thin film, cm ): 2931, 1754

+ (C=O), 1469, 1172, 1092; HRMS calcd. for C14H16O2Cl [M+H] 251.0833, found 251.0839.

(E)–5–(3–(2–Fluorophenyl)allyl–5–methyldihydrofuran–2(3H)–one (73c)

Prepared according to general procedure A using 5–allyl–5–methyldihydrofuran–2(3H)–one 76 (0.10 g, 0.71 mmol, 1.0 eq.), 2–fluorostyrene (255 µL, 2.1 mmol, 3.0 eq.) and Hoveyda–

nd Grubbs 2 generation catalyst (0.009 g, 0.014 mmol, 2 mol%) in CH2Cl2 (1.8 mL). Purification by silica gel column chromatography (hexane/EtOAc, 100:0 to 9:1) yielded the title

1 compound as a yellow oil (0.081 g, 0.34 mmol, 49%). H NMR (400 MHz, CDCl3) δ 1.44 (s, 3H,

CH3), 1.99 (ddd, J = 13.0, 9.4, 6.8 Hz, 1H, CHaHbCH2C(O)O), 2.19 (ddd, J = 13.0, 9.2, 8.0 Hz, 1H,

CHaHbCH2C(O)O), 2.52–2.68 (m, 4H, CH2CO2 + CH2CH=CHAr), 6.24 (dt, J = 15.8, 7.2 Hz, 1H, CH=CHAr), 6.63 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.01 (ddd, J = 10.8, 8.0, 1.0 Hz, 1H, ArCH), 7.08 (td, J = 8.0, 1.0 Hz, 1H, ArCH), 7.19 (m, 1H, ArCH), 7.41 (td, J = 8.0, 1.6 Hz, 1H, ArCH) ppm;

13 C NMR (101 MHz, CDCl3) δ 26.3 (CH3), 29.1 (CH2C(O)O), 32.3 (CH2CH2C(O)O), 44.8

(CH2CH=CHAr), 86.1 (Cq), 115.7 (d, J = 22.0 Hz, ArCH), 124.1 (d, J = 3.6 Hz, ArCH), 124.6 (d, J = 12.1 Hz, ArC), 126.2 (d, J = 4.0 Hz, CH=CHAr), 127.0 (d, J = 2.6 Hz, CH=CHAr), 127.3 (d, J = 3.7

Hz, ArCH), 128.9 (d, J = 8.3 Hz, ArCH), 160.0 (d, J = 247.4 Hz, ArCF), 176.6 (C(O)O) ppm; IR νmax

−1 (thin film, cm ): 2976, 1764 (C=O), 1486, 1227, 1184, 940; HRMS calcd. for C14H15O2FNa [M+Na]+ 257.0948, found 257.0951.

(E)–5–Methyl–5–(3–(4–(trifluoromethyl)phenyl)allyl)dihydrofuran–2(3H)–one (73d)

Prepared according to general procedure A using 5–allyl–5–methyldihydrofuran–2(3H)–one 76 (0.10 g, 0.71 mmol, 1.0 eq.), 4–(trifluoromethyl)styrene (315 µL, 2.1 mmol, 3.0 eq.) and

nd Hoveyda–Grubbs 2 generation catalyst (0.009 g, 0.014 mmol, 2 mol%) in CH2Cl2 (1.8 mL). Purification by silica gel column chromatography (hexane/EtOAc, 100:0 to 8:2) yielded the

1 title compound as a pale yellow oil (0.14 g, 0.49 mmol, 69%). H NMR (400 MHz, CDCl3) δ 1.46

(s, 3H, CH3), 1.99–2.08 (m, 1H, CHaHbCH2C(O)O), 2.20 (ddd, J = 13.2, 9.6, 7.6 Hz, 1H,

CHaHbCH2C(O)O), 2.54–2.71 (m, 4H, CH2CO2 + CH2CH=CHAr), 6.31 (dt, J = 15.8, 7.6 Hz, 1H,

CH=CHAr), 6.54 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.46 (d, J = 8.0 Hz, 2H, ArCH), 7.58 (d, J = 8.0 Hz,

13 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 26.2 (CH3), 29.1 (CH2C(O)O), 32.5 (CH2CH2C(O)O),

44.4 (CH2CH=CHAr), 86.0 (Cq), 124.2 (q, J = 270.2 Hz, CF3), 125.6 (q, J = 3.6 Hz, ArCH), 126.3

(CH=CHAr) 126.4 (ArCH), 129.5 (q, J = 32.3 Hz, ArCCF3), 133.3 (CH=CHAr), 140.3 (ArC), 176.5

−1 (C(O)O) ppm; IR νmax (thin film, cm ): 2978, 1766 (C=O), 1323, 1162, 1109, 1066; HRMS calcd.

+ for C15H19O2NF3 [M+NH4] 302.1362, found 302.1366.

(E)–5–Methyl–5–(3–(4–bromophenyl)allyl)dihydrofuran–2(3H)–one (73e)

Prepared according to general procedure A using 5–allyl–5–methyldihydrofuran–2(3H)–one 76 (0.10 g, 0.71 mmol, 1.0 eq.), 4–bromostyrene (280 µL, 2.1 mmol, 3.0 eq.) and Hoveyda–

nd Grubbs 2 generation catalyst (0.009 g, 0.014 mmol, 2 mol%) in CH2Cl2 (1.8 mL). The crude product was purified by silica gel column chromatography (hexane/EtOAc 100:0 to 9:1) yielded the title compound as a pale yellow oil (0.12 g, 0.56 mmol, 63%). 1H NMR (400 MHz,

CDCl3) δ 1.45 (s, 3H, CH3), 2.02 (ddd, J = 12.9, 9.6, 6.8 Hz, 1H, CHaHbCH2C(O)O), 2.20 (ddd,

J = 12.9, 9.4, 7.6 Hz, 1H, CHaHbCH2C(O)O), 2.52–2.71 (m, 4H, CH2CO2 + CH2CH=CHAr), 6.19 (dt, J = 15.6, 7.6 Hz, 1H, CH=CHAr), 6.44 (d, J = 15.6 Hz, 1H, CH=CHAr), 7.23 (d, J = 8.4 Hz, 2H,

13 ArCH), 7.44 (d, J = 8.4 Hz, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 26.2 (CH3), 29.1

(CH2C(O)O), 32.4 (CH2CH2C(O)O), 44.4 (CH2CH=CHAr), 86.1 (Cq), 121.3 (ArCBr), 124.3 (CH=CHAr), 127.7 (ArCH), 131.7 (ArCH), 133.4 (CH=CHAr), 135.7 (ArC), 176.6 (C(O)O) ppm;

−1 IR νmax (neat/cm ): 2975, 2932, 2905, 1758 (C=O), 1486, 1188, 1179, 938; HRMS calcd. for

+ C14H15O2BrNa [M+Na] 317.0153, found 317.0166.

(E)–5–Methyl–5–(3–(p–tolyl)allyl)dihydrofuran–2(3H)–one (73f)

Prepared according to general procedure A using 5–allyl–5–methyldihydrofuran–2(3H)–one 76 (0.10 g, 0.71 mmol, 1.0 eq.), 4–methylstyrene (285 µL, 2.1 mmol, 3.0 eq.) and Hoveyda–

nd Grubbs 2 generation catalyst (0.009 g, 0.014 mmol, 2 mol%) in CH2Cl2 (1.8 mL). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 9:1) yielded the title compound

1 as a pale yellow oil (0.087 g, 0.38 mmol, 53%). H NMR (400 MHz, CDCl3) δ 1.45 (s, 3H, CH3),

1.99 (ddd, J = 12.9, 9.4, 7.0 Hz, 1H, CHaHbCH2C(O)O), 2.21 (ddd, J = 12.9, 9.2, 7.8 Hz, 1H,

CHaHbCH2C(O)O), 2.34 (s, 3H, ArCH3), 2.48–2.70 (m, 4H, CH2CO2 + CH2CH=CHAr), 6.13 (dt, J = 15.8, 7.6 Hz, 1H, CH=CHAr), 6.47 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.13 (d, J = 8.0 Hz, 2H,

13 ArCH), 7.26 (d, J = 8.0 Hz, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 21.2 (ArCH3), 26.3

(CH3), 29.2 (CH2C(O)O), 32.3 (CH2CH2C(O)O), 44.4 (CH2CH=CHAr), 86.4 (Cq), 122.3 (CH=CHAr),

126.1 (ArCH), 129.3 (ArCH), 134.1 (ArCCH3), 134.4 (CH=CHAr), 137.4 (ArC), 176.7

−1 (C(O)O) ppm; IR νmax (neat/cm ): 2973, 2896, 1755 (C=O), 1191, 1013, 938; HRMS calcd. for

+ C15H18O2Na [M+Na] 253.1199, found 253.1200.

(E)–5–Methyl–5–(3–(m–tolyl)allyl)dihydrofuran–2(3H)–one (73g)

Prepared according to general procedure A using 5–allyl–5–methyldihydrofuran–2(3H)–one 76 (0.10 g, 0.71 mmol, 1.0 eq.), 3–methylstyrene (285 µL, 2.1 mmol, 3.0 eq.) and Hoveyda–

nd Grubbs 2 generation catalyst (0.009 g, 0.014 mmol, 2 mol%) in CH2Cl2 (1.8 mL). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 9:1) yielded the title compound

1 as a pale yellow oil (0.12 g, 0.53 mmol, 68%). H NMR (400 MHz, CDCl3) δ 1.46 (s, 3H, CH3),

2.00 (ddd, J = 12.9, 9.6, 7.0 Hz, 1H, CHaHbCH2C(O)O), 2.21 (ddd, J = 12.9, 9.2, 8.0 Hz, 1H,

CHaHbCH2C(O)O), 2.36 (s, 3H, ArCH3), 2.52–2.69 (m, 4H, CH2CO2 + CH2CH=CHAr), 6.18 (dt, J = 16.0, 7.2 Hz, 1H, CH=CHAr), 6.48 (d, J = 16.0 Hz, 1H, CH=CHAr), 7.07 (d, J = 7.2 Hz, 1H,

13 ArCH), 7.14–7.24 (m, 3H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 21.4 (ArCH3), 26.3 (CH3),

29.1 (CH2C(O)O), 32.3 (CH2CH2C(O)O), 44.4 (CH2CH=CHAr), 86.3 (Cq), 123.1 (CH=CHAr), 123.4

(ArCH), 126.8 (ArCH), 128.4 (ArCH), 128.5 (ArCH), 134.6 (CH=CHAr), 136.8 (ArCCH3), 138.2

−1 (ArC), 176.7 (C(O)O) ppm; IR νmax (neat/cm ): 2974, 1765 (C=O), 1454, 1177, 938; HRMS

+ calcd. for C15H19O2 [M+H] 231.1380, found 231.1381.

(E)–5–(3–(2,5–Dimethylphenyl)allyl)–5–methyldihydrofuran–2(3H)–one (73h)

Prepared according to general procedure A using 5–allyl–5–methyldihydrofuran–2(3H)–one 76 (0.10 g, 0.71 mmol, 1.0 eq.), 2,5–dimethylstyrene (313 µL, 2.14 mmol, 3.0 eq.) and

nd Hoveyda–Grubbs 2 generation catalyst (0.009 g, 0.014 mmol, 2 mol%) in CH2Cl2 (1.8 mL). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 9:1) yielded the

1 title compound as a dark brown oil (0.10 g, 0.42 mmol, 60%). H NMR (400 MHz, CDCl3) δ

1.47 (s, 3H, CH3), 1.97–2.07 (m, 1H, CHaHbCH2C(O)O), 2.19–2.28 (m, 1H, CHaHbCH2C(O)O),

2.30 (s, 3H, ArCH3), 2.32 (s, 3H, ArCH3), 2.55–2.71 (m, 4H, CH2CO2 + CH2CH=CHAr), 6.05 (dt, J = 15.6, 7.8 Hz, 1H, CH=CHAr), 6.48 (d, J = 15.6 Hz, 1H, CH=CHAr), 6.99 (d, J = 7.8 Hz, 1H,

13 ArCH), 7.04 (d, J = 7.8 Hz, 1H, ArCH), 7.23 (s, 1H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ

19.3 (ArCH3), 21.0 (ArCH3), 26.3 (CH3), 29.2 (CH2C(O)O), 32.3 (CH2CH2C(O)O), 44.7

(CH2CH=CHAr), 86.3 (Cq), 124.5 (CH=CHAr), 126.2 (ArCH), 128.3 (ArCH), 130.2 (ArCH), 132.1

(ArCCH3), 132.6 (CH=CHAr), 135.5 (ArCCH3), 135.8 (ArC), 176.7 (C(O)O) ppm; IR νmax

−1 + (neat/cm ): 2974, 2928, 1766 (C=O), 1455, 1177, 938; HRMS calcd. for C16H20O2Na [M+Na] 267.1361, found 267.1365.

(E)–5–Methyl–5–(3–(naphthalen–2–yl)allyl)dihydrofuran–2(3H)–one (73i)

Prepared according to general procedure A using 5–allyl–5–methyldihydrofuran–2(3H)–one 76 (0.10 g, 0.71 mmol, 1.0 eq.), 2–vinylnaphthalene (0.33 g, 2.1 mmol, 3.0 eq.) and Hoveyda–

nd Grubbs 2 generation catalyst (0.009 g, 0.014 mmol, 2 mol%) in CH2Cl2 (1.8 mL). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2 to 9:1) yielded the title compound as a yellow solid (0.087 g, 0.33 mmol, 46%). mp 91−93 °C. 1H NMR (400 MHz,

CDCl3) δ 1.49 (s, 3H, CH3), 2.03 (ddd, J = 12.8, 9.6, 6.8 Hz, 1H, CHaHbCH2C(O)O), 2.20–2.30 (m,

1H, CHaHbCH2C(O)O), 2.56–2.72 (m, 4H, CH2CO2 + CH2CH=CHAr), 6.32 (dt, J = 15.6, 7.6 Hz, 1H, CH=CHAr), 6.67 (d, J = 15.6 Hz, 1H, CH=CHAr), 7.41–7.50 (m, 2H, ArCH), 7.59 (dd, J = 8.4,

13 1.6 Hz, 1H, ArCH), 7.72 (s, 1H, ArCH), 7.76–7.83 (m, 3H, ArCH) ppm; C NMR (101 MHz, CDCl3)

δ 26.3 (CH3), 29.2 (CH2CH2C(O)O), 32.4 (CH2CH2C(O)O), 44.6 (CH2CH=CHAr), 86.3 (Cq), 123.4 (ArCH), 123.8 (CH=CHAr), 125.9 (ArCH), 126.0 (ArCH), 126.3 (ArCH), 127.7 (ArCH), 127.9 (ArCH), 128.3 (ArCH), 133.0 (ArC), 133.6 (ArC), 134.3 (ArC), 134.7 (CH=CHAr), 176.6 (C(O))

−1 ppm; IR νmax (neat/cm ): 2924, 1765 (C=O), 1455, 1185, 985, 936; HRMS calcd. for

+ C18H18O2Na [M+Na] 289.1204, found 289.1218.

General procedure B: SmI2–H2O–mediated lactone cyclisation followed by DMP oxidation

Rac–(2S,4R)–2–Benzyl–4–hydroxy–4–methylcyclohexan–1–one (77a)

To a solution of SmI2 (5.5 mL, 0.1 M in THF, 0.55 mmol, 8.0 eq.), H2O (1.0 mL, 56 mmol, 800 eq.) and HMPA (0.78 mL, 4.4 mmol, 64 eq.) was added (E)–5–cinnamyl–5– methyldihydrofuran–2(3H)–one 73a (0.018 g, 0.07 mmol, 1.0 eq.) in THF. The reaction was stirred at room temperature until decolourisation occurred. Rochelle’s salt saturated solution (5 mL) was added and the mixture was extracted with Et2O (3 x 5 mL) .The combined organic layers were washed with 1 M HCl (10 mL), saturated aqueous NaHCO3 (10 mL), brine

(10 mL), dried (MgSO4) and concentrated. The resulting crude diol was dissolved in CH2Cl2 (1 mL), the mixture was cooled to 0 C, and Dess–Martin Periodinane (0.045 g, 0.11 mmol, 1.5 eq.) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 h, then was quenched by addition of a 1:1 mixture of saturated aqueous

Na2S2O3/NaHCO3 (3 mL). The layers were separated and the aqueous was extracted with

CH2Cl2 (3 x 5 mL). The organic layers were dried (MgSO4) and concentrated. Purification by silica gel column chromatography (hexane/EtOAc 9:1 to 85:15) yielded the title product as an 11.4:1 mixture of diastereoisomers (0.026 mg, 0.12 mmol, 51%). The major

1 diastereoisomer was isolated as colourless crystals: mp (CH2Cl2) 79−81 °C. H NMR (400 MHz,

CDCl3) δ 1.29 (s, 3H, CH3), 1.52 (t, J = 13.4 Hz, 1H, CHaHbCHC(O)), 1.83 (td, J = 13.7, 4.6 Hz, 1H,

CHaHbCH2C(O)), 1.89−2.05 (m, 2H, CHaHbCHC(O) + CHaHbCH2C(O)), 2.27 (ddd, J = 13.7, 4.6, 2.2

Hz, 1H, CHaHbC(O)), 2.38 (dd, J = 14.1, 8.8 Hz, 1H, CHaHbAr), 2.83 (td, J = 13.7, 6.0 Hz, 1H,

CHaHbC(O)), 3.02−3.13 (m, 1H, CHC(O)), 3.27 (dd, J = 14.1, 4.6 Hz, 1H, CHaHbAr), 7.12−7.22

13 (m, 3H, ArCH), 7.24−7.31 (m, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 30.5 (CH3), 34.7

(CH2Ar), 37.4 (CH2CH2C(O)), 39.6 (CH2CH2C(O)), 45.3 (CCH2CH), 46.6 (CHC(O)), 69.1 (C), 126.0

−1 (ArCH), 128.3 (ArCH), 129.1 (ArCH), 140.1 (ArC), 212.5 (C(O)) ppm; IR νmax (neat/cm ): 3369

(O–H), 2965, 2935, 2918, 2852, 1686 (C=O), 1407, 1262, 1186; HRMS calcd. for C14H19O2 [M+H]+ 219.1380, found 219.1380.

Rac–(2S,4R)–2–(2–Chlorobenzyl)–4–hydroxy–4–methylcyclohexan–1–one (77b)

Prepared according to general procedure B using (E)–5–(3–(2–chlorophenyl)allyl)–5– methyldihydrofuran–2(3H)–one 73b (0.018 g, 0.07 mmol, 1.0 eq.), SmI2 (5.5 mL, 0.1 M in THF,

0.55 mmol, 8.0 eq.), H2O (1.0 mL, 56 mmol, 800 eq.) and HMPA (0.78 mL, 4.4 mmol, 64 eq.). The crude diol was then oxidised using Dess–Martin Periodinane (0.045 g, 0.105 mmol,

1.5 eq.) in CH2Cl2 (1 mL). The product was purified using silica gel column chromatography (hexane/EtOAc 9:1 to 85:15) to yield the title product as a >20:1 mixture of diastereoisomers (0.021 g, 0.083 mmol, 52%). The major diastereoisomer was isolated as colourless crystals:

1 mp 140−142 °C. H NMR (400 MHz, CDCl3) δ 1.31 (s, 3H, CH3), 1.62 (t, J = 13.4 Hz, 1H,

CHaHbCHC(O)), 1.80–1.96 (m, 2H, CHaHbCH2C(O) + CHaHbCHC(O)), 1.97−2.05 (m, 1H,

CHaHbCH2C(O)), 2.28 (ddd, J = 13.8, 4.6, 2.2 Hz, 1H, CHaHbC(O)), 2.54 (dd, J = 13.8, 8.6 Hz, 1H,

CHaHbAr), 2.84 (td, J = 13.8, 6.4 Hz, 1H, CHaHbC(O)), 3.15−3.25 (m, 1H, CHC(O)), 3.36 (dd,

J = 13.8, 5.4 Hz, 1H, CHaHbAr), 7.12−7.21 (m, 2H, ArCH), 7.24 (dd, J = 7.2, 2.0 Hz, 1H, ArCH),

13 7.34 (dd, J = 7.4, 1.8 Hz, 1H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 30.5 (CH3), 32.5 (CH2Ar),

37.4 (CH2CH2C(O)), 39.7 (CH2CH2C(O)), 45.0 (CCH2CH), 45.5 (CHC(O)), 69.2 (C), 126.6 (ArCH),

127.5 (ArCH), 129.5 (ArCH), 131.6 (ArCH), 134.2 (ArCCl), 137.8 (ArC), 212.2 (C(O)) ppm; IR νmax (neat/cm−1): 3385 (O–H), 2962, 2927, 1710 (C=O), 1470, 1436, 1132; HRMS calcd. for

+ C14H17O2ClNa [M+Na] 275.0809, found 275.0809.

Rac–(2S,4R)–2–(2–Fluorobenzyl)–4–hydroxy–4–methylcyclohexan–1–one (77c)

Prepared according to general procedure B using (E)–5–(3–(2–chlorophenyl)allyl)–5– methyldihydrofuran–2(3H)–one 73c (0.016 g, 0.07 mmol, 1.0 eq.), SmI2 (5.5 mL, 0.1 M in THF,

0.55 mmol, 8.0 eq.), H2O (1.0 mL, 56 mmol, 800 eq.) and HMPA (0.78 mL, 4.4 mmol, 64 eq.). The crude diol was then oxidised using Dess–Martin Periodinane (0.045 g, 0.11 mmol,

1.5 eq.) in CH2Cl2 (1 mL). The product was purified using silica gel column chromatography (hexane/EtOAc 9:1 to 85:15) to yield the title product as a 12.6:1 mixture of diastereoisomers (0.024 g, 0.10 mmol, 48%). The major diastereoisomer was isolated as a white solid: mp

1 69−72 °C. H NMR (400 MHz, CDCl3) δ 1.29 (s, 3H, CH3), 1.57 (t, J = 13.4 Hz, 1H, CHaHbCHC(O)),

1.78–2.07 (m, 3H, CHaHbCHC(O) + CH2CH2C(O)), 2.27 (ddd, J = 13.8, 4.6, 2.2 Hz, 1H,

CHaHbC(O)), 2.49 (dd, J = 13.9, 9.0 Hz, 1H, CHaHbAr), 2.82 (td, J = 13.8, 6.0 Hz, 1H, CHaHbC(O)),

3.05–3.16 (m, 1H, CHC(O)), 3.21 (dd, J = 13.9, 4.4 Hz, 1H, CHaHbAr), 6.96–7.09 (m, 2H, ArCH),

13 7.14–7.23 (m, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 28.0 (CH2Ar), 30.4 (CH3), 37.4

(CH2CH2C(O)), 39.6 (CH2CH2C(O)), 45.2 (CCH2CH), 45.4 (CHC(O)), 69.1 (C), 115.2 (d, J = 22.1 Hz, ArCH), 123.9 (d, J = 3.5 Hz, ArCH); 126.9 (d, J = 15.6 Hz, ArC); 127.8 (d, J = 8.0 Hz, ArCH), 131.6

−1 (d, J = 4.9 Hz, ArCH), 161.3 (d, J = 243.2 Hz, ArCF), 212.4 (C(O)) ppm; IR νmax (neat/cm ): 3352

+ (O–H), 2967, 2930, 1705 (C=O), 1490, 1228, 1112; HRMS calcd. for C14H17O2FNa [M+Na] 259.1110, found 259.1109.

Rac–(2S,4R)–4–Hydroxy–4–methyl–2–(4–(trifluoromethyl)benzyl)cyclohexan–1–one (77d)

Prepared according to general procedure B using (E)–5–methyl–5–(3–(4–

(trifluoromethyl)phenyl)allyl)dihydrofuran–2(3H)–one 73d (0.02 g, 0.07 mmol, 1.0 eq.), SmI2

(5.5 mL, 0.1 M in THF, 0.55 mmol, 8.0 eq.), H2O (1.0 mL, 56 mmol, 800 eq.) and HMPA (0.78 mL, 4.4 mmol, 64 eq.). The crude diol was then oxidised using Dess–Martin Periodinane

(0.045 g, 0.11 mmol, 1.5 eq.) in CH2Cl2 (1 mL). The product was purified using silica gel column

96 chromatography (hexane/EtOAc 9:1) to yield the title product as a 4.6:1 mixture of diastereoisomers (0.013 mg, 0.046 mmol, 65%). The major diastereoisomer could be isolated

1 as a colourless oil. H NMR (400 MHz, CDCl3) δ 1.31 (s, 3H, CH3), 1.54 (t, J = 13.2 Hz, 1H,

CHaHbCHC(O)), 1.79–2.07 (m, 3H, CH2CH2C(O) + CHaHbCHC(O)), 2.29 (ddd, J = 13.6, 4.8, 2.4 Hz,

1H, CHaHbC(O)), 2.41–2.50 (m, 1H, CHaHbAr), 2.83 (td, J = 14.0, 6.0 Hz, 1H, CHaHbC(O)), 3.05–

3.17 (m, 1H, CHC(O)), 3.28 (dd, J = 14.0, 5.2 Hz, 1H, CHaHbAr), 7.29 (d, J = 8.2 Hz, 2H, ArCH),

13 7.53 (d, J = 8.2 Hz, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 30.5 (CH3), 34.7 (CH2Ar), 37.4

(CH2CH2C(O)), 39.7 (CH2CH2C(O)), 45.4 (CCH2CH), 46.4 (CHC(O)), 69.2 (C), 125.3 (q, J = 3.8 Hz,

ArCH), 126.7 (q, J = 263.9 Hz, CF3), 129.5 (ArCH), 144.4 (ArC), 212.0 (C(O)) ppm, ArCCF3 not

−1 observed; IR νmax (neat/cm ): 3436 (O–H), 2928, 1707 (C=O), 1323, 1114, 1066; HRMS calcd.

− for C15H16O2F3 [M−H] 285.1102, found 285.1106.

Rac–(2S,4R)–2–(4–Bromobenzyl)–4–hydroxy–4–methylcyclohexan–1–one (77e)

Prepared according to general procedure B using (E)–5–methyl–5–(3–(4– bromophenyl)allyl)dihydrofuran–2(3H)–one 73e (0.021 g, 0.07 mmol, 1.0 eq.), SmI2 (5.5 mL,

0.1 M in THF, 0.55 mmol, 8.0 eq.), H2O (1.0 mL, 56 mmol, 800 eq.) and HMPA (0.78 mL, 4.4 mmol, 64 eq.). The crude diol was then oxidised using Dess–Martin Periodinane (0.045 g,

0.11 mmol, 1.5 eq.) in CH2Cl2 (1 mL). The product was purified using silica gel column chromatography (hexane/EtOAc 9:1) to yield the title product as an 8.9:1 mixture of diastereoisomers (0.017 g, 0.055 mmol, 79%). The major diastereoisomer could be isolated

1 as a white solid: mp (CH2Cl2) 113−115 °C. H NMR (400 MHz, CDCl3) δ 1.30 (s, 3H, CH3), 1.51

(t, J = 13.4 Hz, 1H, CHaHbCHC(O)), 1.78–2.04 (m, 3H, CHaHbCHC(O) + CH2CH2C(O)), 2.27 (ddd,

J = 13.7, 4.8, 2.4 Hz, 1H, CHaHbC(O)), 2.36 (dd, J = 14.0, 8.0 Hz, 1H, CHaHbAr), 2.82 (tdd,

J = 13.7, 6.2, 1.0 Hz, 1H, CHaHbC(O)), 2.99–3.10 (m, 1H, CHC(O)), 3.18 (dd, J = 14.0, 5.2 Hz, 1H,

13 CHaHbAr), 7.05 (d, J = 7.6 Hz, 2H, ArCH), 7.39 (d, J = 7.6 Hz, 2H, ArCH) ppm; C NMR (101 MHz,

CDCl3) δ 30.5 (CH3), 34.2 (CH2Ar), 37.4 (CH2CH2C(O)), 39.7 (CH2CH2C(O)), 45.3 (CCH2CH), 46.5 (CHC(O)), 69.2 (C), 119.8 (ArCBr), 130.9 (ArCH), 131.4 (ArCH), 139.1 (ArC), 212.2 (C(O)) ppm;

−1 IR νmax (neat/cm ): 3442 (O–H), 2964, 2927, 1704 (C=O), 1488, 1145, 1071, 1011; HRMS could not be obtained.

Rac–(2S,4R)–4–Hydroxy–4–methyl–2–(4–methylbenzyl)cyclohexan–1–one (77f)

Prepared according to general procedure B using (E)–5–methyl–5–(3–(p– tolyl)allyl)dihydrofuran–2(3H)–one 73f (0.016 g, 0.07 mmol, 1.0 eq.), SmI2 (5.5 mL, 0.1 M in

THF, 0.55 mmol, 8.0 eq.), H2O (1.0 mL, 56 mmol, 800 eq.) and HMPA (0.78 mL, 4.4 mmol, 64 eq.). The crude diol was then oxidised using Dess–Martin Periodinane (0.045 g,

0.11 mmol, 1.5 eq.) in CH2Cl2 (1 mL). The product was purified using silica gel column chromatography (hexane/EtOAc 9:1) to yield the title product as a 10.2:1 mixture of diastereoisomers (0.009 g, 0.038 mmol, 56%). The major diastereoisomer was isolated as a

1 white solid: mp 93−96 °C. H NMR (400 MHz, CDCl3) δ 1.29 (s, 3H, CH3), 1.52 (t, J = 13.4 Hz,

1H, CHaHbCHC(O)), 1.83 (td, J = 13.7, 4.8 Hz, 1H, CHaHbCH2C(O)), 1.89–2.04 (m, 2H,

CHaHbCHC(O) + CHaHbCH2C(O)), 2.27 (ddd, J = 13.7, 4.6, 2.2 Hz, 1H, CHaHbC(O)), 2.31–2.38 (m,

4H, ArCH3 + CHaHbAr), 2.82 (tdd, J = 13.7, 6.2, 1.0 Hz, 1H, CHaHbC(O)), 2.99–3.11 (m, 1H,

CHC(O)), 3.22 (dd, J = 14.4, 4.8 Hz, 1H, CHaHbAr), 7.05 (d, J = 8.0 Hz, 2H, ArCH), 7.09 (d, J =

13 8.0 Hz, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 21.0 (ArCH3), 30.5 (CH3), 34.3 (CH2Ar),

37.5 (CH2CH2C(O)), 39.6 (CH2CH2C(O)), 45.3 (CCH2CH), 46.6 (CHC(O)), 69.2 (C), 129.0

−1 (ArCH),129.0 (ArCH), 135.4 (ArC), 136.9 (ArC), 212.7 (C(O)) ppm; IR νmax (neat/cm ): 3441

+ (O-H), 2964, 2925, 1703 (C=O), 1515, 1144; HRMS calcd. for C15H20O2Na [M+Na] 255.1356, found 255.1348.

Rac–(2S,4R)–4–Hydroxy–4–methyl–2–(3–methylbenzyl)cyclohexan–1–one (77g)

Prepared according to general procedure B using (E)–5–methyl–5–(3–(m– tolyl)allyl)dihydrofuran–2(3H)–one 73g (0.016 g, 0.07 mmol, 1.0 eq.), SmI2 (5.5 mL, 0.1 M in

THF, 0.55 mmol, 8.0 eq.), H2O (1.0 mL, 56 mmol, 800 eq.) and HMPA (0.78 mL, 4.4 mmol, 64 eq.). The crude diol was then oxidised using Dess–Martin Periodinane (0.045 g,

0.11 mmol, 1.5 eq.) in CH2Cl2 (1 mL). The product was purified using silica gel column

98 chromatography (hexane/EtOAc 9:1 to 85:15) to yield the title product as a 9.9:1 mixture of diastereoisomers (0.029 g, 0.13 mmol, 58%). The major diastereoisomer was isolated as a

1 white solid: mp (CH2Cl2) 71−73 °C. H NMR (400 MHz, CDCl3) δ 1.30 (s, 3H, CH3), 1.52 (t,

J = 13.6 Hz, 1H, CHaHbCHC(O)), 1.84 (td, J = 13.9, 4.8 Hz, 1H, CHaHbCH2C(O)), 1.89–2.05 (m,

2H, CHaHbCHC(O) + CHaHbCH2C(O)), 2.24–2.37 (m, 5H, CHaHbC(O) + CHaHbAr + ArCH3), 2.83

(td, J = 13.9, 6.4 Hz, 1H, CHaHbC(O)), 3.01–3.12 (m, 1H, CHC(O)), 3.24 (dd, J = 14.2, 4,6 Hz, 1H,

CHaHbAr), 6.93–6.99 (m, 2H, ArCH), 7.01 (d, J = 7.4 Hz, 1H, ArCH), 7.17 (t, J = 7.4 Hz, 1H, ArCH)

13 ppm; C NMR (101 MHz, CDCl3) δ 21.4 (ArCH3), 30.5 (CH3), 34.6 (CH2Ar), 37.4 (CH2CH2C(O)),

39.6 (CH2CH2C(O)), 45.3 (CCH2CH), 46.6 (CHC(O)), 69.2 (C), 126.1 (ArCH), 126.7 (ArCH), 128.2

−1 (ArCH), 129.9 (ArCH), 137.9 (ArC), 140.0 (ArC), 212.7 (C(O)) ppm; IR νmax (neat/cm ): 3383

+ (O–H), 2965, 2930, 2853, 1686 (C=O), 1605, 1136; HRMS calcd. for C15H20O2Na [M+Na] 255.1361, found 255.1359.

Rac–(2S,4R)–2–(2,5–Dimethylbenzyl)–4–hydroxy–4–methylcyclohexan–1–one (77h)

Prepared according to general procedure B using (E)–5–(3–(2,5–dimethylphenyl)allyl)–5– methyldihydrofuran–2(3H)–one 73h (0.017 g, 0.07 mmol, 1.0 eq.), SmI2 (5.5 mL, 0.1 M in

THF, 0.55 mmol, 8.0 eq.), H2O (1.0 mL, 56 mmol, 800 eq.) and HMPA (0.78 mL, 4.4 mmol, 64 eq.). The crude diol was then oxidised using Dess–Martin Periodinane (0.045 g, 0.11 mmol, 1.5 eq.) in CH2Cl2 (1 mL). The product was purified using silica gel column chromatography (hexane/EtOAc 9:1) to yield the title product as a 7.2:1 mixture of diastereoisomers (0.007 g, 0.029 mmol, 41%). The major diastereoisomer could be isolated

1 as a colourless oil. H NMR (400 MHz, CDCl3) δ 1.31 (s, 3H, CH3), 1.57 (t, J = 13.2 Hz, 1H,

CHaHbCHC(O)), 1.85 (td, J = 13.9, 4.8 Hz, 1H, CHaHbCH2C(O)), 1.90–2.06 (m, 2H, CHaHbCHC(O)

+ CHaHbCH2C(O), 2.24 (s, 3H, ArCH3), 2.26–2.36 (m, 5H, ArCH3 + CHaHbC(O) + CHaHbAr), 2.84

(td, J = 13.9, 6.4 Hz, 1H, CHaHbC(O)), 2.99–3.11 (m, 1H, CHC(O)), 3.28 (dd, J = 14.2, 4.2 Hz, 1H,

13 CHaHbAr), 6.87–6.96 (m, 2H, ArCH), 7.03 (d, J = 7.6 Hz, 1H, ArCH) ppm; C NMR (101 MHz,

CDCl3) δ 19.1 (ArCH3), 21.0 (ArCH3), 30.5 (CH3), 31.7 (CH2Ar), 37.5 (CH2CH2C(O)), 39.7

(CH2CH2C(O)), 45.5 (CHC(O)), 45.5 (CCH2CH), 69.2 (C), 126.8 (ArCH), 130.2 (ArCH), 130.6

−1 (ArCH), 133. (ArC), 135.1 (ArC), 138.1 (ArC), 212.7 (C(O)) ppm; IR νmax (neat/cm ): 3441

+ (O–H), 2963, 2926, 1704 (C=O), 1454, 1234, 1143; HRMS calcd. for C16H22O2Na [M+Na] 269.1512, found 269.1505.

Rac–(2S,4R)–4–Hydroxy–4–methyl–2–(naphthalen–2–ylmethyl)cyclohexan–1–one (77i)

Prepared according to general procedure B using (E)–5–methyl–5–(3–(naphthalen–2– yl)allyl)dihydrofuran–2(3H)–one 73g (0.018 g, 0.07 mmol, 1.0 eq.), SmI2 (5.5 mL, 0.1 M in THF,

0.55 mmol, 8.0 eq.), H2O (1.0 mL, 56 mmol, 800 eq.) and HMPA (0.78 mL, 4.4 mmol, 64 eq.). The crude diol was then oxidised using Dess–Martin Periodinane (0.045 g, 0.11 mmol,

1.5 eq.) in CH2Cl2 (1 mL). The product was purified using silica gel column chromatography (hexane/EtOAc 9:1) to yield the title product as a 5.9:1 mixture of diastereoisomers (0.007 g, 0.026 mmol, 37%). The major diastereoisomer could be isolated as a colourless oil: 1H NMR

(400 MHz, CDCl3) δ 1.27 (s, 3H, CH3), 1.57 (t, J = 13.4 Hz, 1H, CHaHbCHC(O)), 1.85 (td, J = 13.8,

4.8 Hz, 1H, CHaHbCH2C(O)), 1.90–2.07 (m, 2H, CHaHbCHC(O) + CHaHbCH2C(O)), 2.30 (ddd,

J = 13.8, 4.6, 2.4 Hz, 1H, CHaHbC(O)), 2.56 (dd, J = 14.2, 9.0 Hz, 1H, CHaHbAr), 2.80–2.87 (m,

1H, CHaHbC(O)), 3.13–3.24 (m, 1H, CHC(O)), 3.43 (dd, J = 14.2, 4.6 Hz, 1H, CHaHbAr), 7.29– 7.35 (m, 1H, ArCH), 7.40–7.51 (m, 2H, ArCH), 7.60 (bs, 1H, ArCH), 7.75–7.84 (m, 3H, ArCH)

13 ppm; C NMR (101 MHz, CDCl3) δ 30.5 (CH3), 34.9 (CH2Ar), 37.5 (CH2CH2C(O)), 39.6

(CH2CH2C(O)), 45.3 (CCH2CH), 46.6 (CHC(O)), 69.2 (C), 125.2 (ArCH), 125.9 (ArCH), 127.4 (ArCH), 127.4 (ArCH), 127.6 (ArCH), 127.6 (ArCH), 128.0 (ArCH), 132.0 (ArC), 133.5 (ArC),

−1 137.6 (ArC), 212.5 (C(O)) ppm; IR νmax (neat/cm ): 3440 (O–H), 3051, 2964, 2928, 1707 (C=O),

+ 1236; HRMS calcd. for C18H20O2Na [M+Na] 291.1356, found 291.1348.

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6.6.2. Experimental Data for Biocatalytic Conversion of Cyclic Ketones Bearing α–Quaternary Stereocentres to Lactones in an Enantioselective Radical Approach to Medium–Sized Carbocycles

General procedure C: Fischer Esterification of Diacids

Diallyl pimelate (87)[131]

A flask connected to a Dean–Stark trap and a condenser was charged with pimelic acid (50 g, 312 mmol, 1.0 eq.). Toluene (156 mL) was added followed by allyl alcohol (64 mL, 937 mmol, 3.0 eq.) and then pTSA (0.30 g, 1.6 mmol, 0.005 eq.). The resulting suspension was stirred at 120 °C for 18 hours. The solution was allowed to reach room temperature, washed with

NaHCO3 saturated solution, brine, dried (MgSO4) and concentrated to yield the title product as a yellow oil (74.2 g, 295 mmol, 95%). 1H NMR (400 MHz, CDCl3) δ 1.34−1.41 (m, 2H,

C(O)CH2CH2CH2), 1.61−1.70 (m, 4H, C(O)CH2CH2), 2.33−2.37 (m, 4H, C(O)CH2CH2), 4.58 (dt,

J = 5.7, 1.3 Hz, 4H, C(O)OCH2), 5.24 (dq, J = 10.4, 1.4 Hz, 2H, CH=CHaHb), 5.32 (dq, J = 17.2,

13 1.4 Hz, 2H, CH=CHaHb), 5.92 (ddt, J = 17.2, 10.4, 5.7 Hz, 2H, CH=CH2) ppm; C NMR (101 MHz,

CDCl3) δ 24.5 (CH2), 28.5 (CH2), 34.0 (COCH2), 65.0 (C(O)OCH2), 118.2 (CH=CH2), 132.2

(CH=CH2), 173.2 (C(O)) ppm. Data is consistent with literature.

Diallyl adipate (88)[132]

Prepared according to general procedure C using adipic acid (46 g, 313 mmol, 1.0 eq.), allyl alcohol (64 mL, 939 mmol, 3.0 eq.) and p–TsOH.H2O (0.30 g, 1.6 mmol, 0.005 eq.) in toluene (156 mL) to yield the title product as a colourless oil (70 g, 310 mmol, 99%). 1H NMR

(400 MHz, CDCl3) δ 1.68−1.71 (m, 4H, C(O)CH2CH2), 2.36−2.39 (m, 4H, C(O)CH2), 4.59 (dt, J =

5.8, 1.4 Hz, 4H, C(O)OCH2), 5.24 (dq, J = 10.5, 1.3 Hz, 2H, CH=CHaHb), 5.32 (dq, J = 17.2, 1.5 Hz,

13 2H, CH=CHaHb), 5.92 (ddt, J = 17.2, 10.5, 5.7 Hz, 2H, CH=CH2) ppm; C NMR (101 MHz, CDCl3)

δ 24.3 (CH2), 33.8 (CH2), 65.1 (C(O)CH2), 118.3 (CH=CH2), 132.1 (CH=CH2), 172.9 (C(O)) ppm. Data is consistent with literature.

101

General procedure D: Dieckmann Condensation and Alkylation

Allyl 1–methyl–2–oxocyclohexane–1–carboxylate (89)[133]

A solution of diallyl pimelate 87 (20 g, 94% purity, 78 mmol, 1.0 eq.) in THF (13 mL) was added slowly to a suspension of sodium hydride (3.4 g, 60%, 86 mmol, 1.1 eq.) in THF (65 mL). The reaction was stirred at 40 °C for 18 h, then methyl iodide (6.3 mL, 102 mmol 1.3 eq.) was added and the reaction was stirred for a further 3 hours. The mixture was cooled to room temperature and H2O (16 mL) was added slowly. The solution was concentrated under vacuum and extracted with EtOAc (3 x 20 mL), washed with brine (15 mL), dried (MgSO4) and concentrated. The crude reaction mixture was used in the next step without further purification.

Allyl 1–methyl–2–oxocyclopentane–1–carboxylate (90)[134]

Prepared according to general procedure D using diallyl adipate 88 (18 g, 78 mmol, 1.0 eq.), sodium hydride (3.4 g, 60%, 86 mmol, 1.2 eq.) and methyl iodide (6.3 mL, 102 mmol, 1.3 eq.) in THF (78 mL). The crude reaction mixture was used in the following step without further purification.

General procedure E: Pd–Catalysed Decarboxylation of β–keto esters

2–Allyl–2–methylcyclohexan–1–one (91)[133]

The crude reaction mixture of allyl 1–methyl–2–oxocyclohexane–1–carboxylate 89

(78 mmol, 1.0 eq.) was added to THF (700 mL), followed by Pd2(dba)3 (3.6 g, 3.9 mmol,

5 mol%) and PPh3 (4.1 g, 16 mmol, 20 mol%). The resulting solution was stirred at 67 °C for

102

5 h. The mixture was cooled to room temperature and filtered through a plug of silica with the aid of Et2O. The crude product was distilled under vacuum (5 mBar, 70–110 °C) to yield

1 the title product as a colourless oil (6.4 g, 41 mmol, 53%). H NMR (400 MHz, CDCl3) δ 1.08

(s, 3H, CH3), 1.56−1.62 (m, 1H, CHaHbCH2CH2CH2C(O)), 1.72–1.87 (m, 5H,

CHaHbCH2CH2CH2C(O) + CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O)), 2.22–2.26 (m, 1H,

CHaHbCH=CH2), 2.35–2.41 (m, 3H, CHaHbCH=CH2 + CH2CH2CH2CH2C(O)), 5.03−5.07 (m, 2H,

13 CH2CH=CH2), 5.66−5.75 (m, 1H, CH2CH=CH2) ppm; C NMR (101 MHz, CDCl3) δ 21.1

(CH2CH2CH2CH2C(O)), 22.6 (CH3), 27.4 (CH2CH2CH2CH2C(O)), 38.6 (CH2CH2CH2CH2C(O)), 38.8

(CH2CH2CH2CH2C(O)), 42.0 (CH2CH=CH), 48.4 (C), 117.9 (CH2CH=CH2), 133.8 (CH2CH=CH2), 215.4 (C(O)) ppm.

2–Allyl–2–methylcyclopentan–1–one (92)[134]

Prepared according to general procedure E using the crude reaction mixture of allyl 1– methyl–2–oxocyclopentane–1–carboxylate 90 (6.4 g, 35 mmol 1.0 eq.), Pd2(dba)3 (1.6 g,

1.7 mmol, 5 mol%) and PPh3 (1.8 g, 7.0 mmol, 20 mol%) in THF (315 mL). The crude product was purified by silica gel column chromatography (hexane/EtOAc 97:3) to yield the title

1 product as a colourless oil (2.5 g, 18 mmol, 52%). H NMR (400 MHz, CDCl3) δ 1.01 (s, 3H,

CH3), 1.53−1.57 (m, 1H, CHaHbCH2CH2C(O)), 1.69–1.80 (m, 3H, CH2CH2CH2C(O) +

CHaHbCH2CH2C(O)), 1.94−2.20 (m, 4H, CH2CH2CH2CH2C(O) + CH2CH=CHAr), 4.88−4.95 (m, 2H,

13 CH2CH=CH2), 5.50−5.61 (m, 1H, CH2CH=CH2) ppm; C NMR (101 MHz, CDCl3) δ 18.7

(CH2CH2CH2C(O)), 21.8 (CH3), 35.1 (CH2CH2CH2C(O)), 37.7 (CH2CH2CH2C(O)), 40.1

(CH2CH=CHAr), 48.2 (C), 118.2 (CH2CH=CH2), 133.9 (CH2CH=CH2), 223.2 (C(O)). Data is consistent with literature.

2–Cinnamyl–2–methylcyclohexan–1–one (93a)

103

Prepared according to general procedure A using 2–allyl–2–methylcyclohexan–1–one 91 (2.0 g, 13 mmol 1.0 eq.), styrene (4.5 mL, 39 mmol 3.0 eq.) and Hoveyda–Grubbs 2nd

Generation catalyst (82 mg, 0.13 mmol, 1 mol%) in CH2Cl2. Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 9:1) yielded the title product as a pale yellow oil

1 (1.3 g, 5.6 mmol, 42%). H NMR (400 MHz, CDCl3) δ 1.14 (s, 3H, CH3), 1.64−1.87 (m, 6H,

CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O)), 2.39−2.48 (m, 4H,

CH2CH2CH2CH2C(O) + CH2CH=CHAr), 6.13 (dt, J = 15.8, 7.5 Hz, 1H, CH2CH=CHAr), 6.40 (d,

J = 15.6 Hz, 1H, CH2CH=CHAr), 7.19−7.23 (m, 1H, ArCH), 7.28−7.36 (m, 4H, ArCH) ppm;

13 C NMR (101 MHz, CDCl3) δ 21.1 (CH2CH2CH2CH2C(O)), 22.9 (CH3), 27.4 (CH2CH2CH2CH2C(O)),

38.6 (CH2CH2CH2CH2C(O)), 38.8 (CH2CH2CH2CH2C(O)), 41.2 (CH2CH=CHAr), 48.9 (C), 125.7

(CH2CH=CHAr), 126.1 (ArCH), 127.1 (ArCH), 128.5 (ArCH), 133.0 (ArC), 137.3 (CH2CH=CHAr),

–1 215.5 (C(O)) ppm; IR νmax (thin film, cm ): 2932, 1703 (C=O), 1449, 1424, 1122, 966; HRMS

+ calcd. for C16H20ONa [M+Na] 251.1406, found 251.1396.

(E)–2–(3–(4–Fluorophenyl)allyl)–2–methylcyclohexan–1–one (93b)

Prepared according to general procedure A using 2–allyl–2–methylcyclohexan–1–one 91 (200 mg, 1.3 mmol, 1.0 eq.), 4–fluorostyrene (0.47 mL, 3.9 mmol, 3.0 eq.) and Hoveyda– Grubbs 2nd Generation catalyst (8 mg, 0.013 mmol, 1 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a colourless oil

1 (125 mg, 0.51 mmol, 39%). H NMR (400 MHz, CDCl3) δ 1.14 (s, 3H, CH3), 1.67−1.87 (m, 6H,

CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O)), 2.37−2.50 (m, 4H,

CH2CH2CH2CH2C(O) + CH2CH=CHAr), 6.04 (dt, J = 15.7, 7.6 Hz, 1H, CH2CH=CHAr), 6.36 (d,

13 J = 15.7 Hz, CH2CH=CHAr), 6.96−7.00 (m, 2H, ArCH), 7.28−7.31 (m, 2H, ArCH); C NMR

(101 MHz, CDCl3) δ 21.1 (CH2CH2CH2CH2C(O)), 23.0 (CH3), 27.4 (CH2CH2CH2CH2C(O)), 38.7

(CH2CH2CH2CH2C(O)), 38.8 (CH2CH2CH2CH2C(O)), 41.2 (CH2CH=CHAr), 48.9 (C), 115.2 (d,

J = 21.5 Hz, ArCH), 125.5 (CH2CH=CHAr), 127.5 (d, J = 8.0 Hz, ArCH), 131.8 (CH2CH=CHAr),

–1 133.5 (ArC), 162.1 (d, J = 246.1 Hz, ArCF), 215.4 (C(O)) ppm; IR νmax (thin film, cm ): 2974,

19 1705 (C=O), 1508, 1226, 1157, 971; F NMR (376 MHz, CDCl3) δ –115.3 ppm; HRMS calcd.

+ for C16H23ONF [M+NH4] 264.1758, found 264.1761.

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(E)–2–Methyl–2–(3–(naphthalen–2–yl)allyl)cyclohexan–1–one (93c)

Prepared according to general procedure A using 2–allyl–2–methylcyclohexan–1–one 91 (200 mg, 1.3 mmol, 1.0 eq.), 2–vinylnapthalene (0.61 g, 3.9 mmol, 3.0 eq.) and Hoveyda– Grubbs 2nd Generation catalyst (8 mg, 0.013 mmol, 1 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 9:1) yielded the title product as a yellow solid

1 (144 mg, 0.52 mmol, 39%): mp (hexane) 66–68 °C. H NMR (400 MHz, CDCl3) δ 1.18 (s, 3H,

CH3), 1.64−1.90 (m, 6H, CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O)),

2.44−2.57 (m, 4H, CH2CH2CH2CH2C(O) + CH2CH=CHAr), 6.27 (dt, J = 15.7, 7.6 Hz, 1H,

CH2CH=CHAr), 6.57 (d, J = 15.7 Hz, 1H, CH2CH=CHAr), 7.40−7.57 (m, 2H, ArCH), 7.57 (d, J = 8.5 Hz, 1H, ArCH), 7.68 (s, 1H, ArCH), 7.78 (t, J = 9.2 Hz, 3H, ArCH); 13C NMR (101 MHz,

CDCl3) δ 21.1 (CH2CH2CH2CH2C(O)), 23.0 (CH3), 27.4 (CH2CH2CH2CH2C(O)), 38.6

(CH2CH2CH2CH2C(O)), 38.9 (CH2CH2CH2CH2C(O)), 41.4 (CH2CH=CHAr), 49.0 (C), 123.6 (ArCH),

125.6 (ArCH), 126.1 (ArCH), 126.2 (CH2CH=CHAr), 127.6 (ArCH), 127.8 (ArCH), 128.0 (ArCH),

132.8 (ArC), 133.1 (CH2CH=CHAr), 133.6 (ArC), 134.8 (ArC), 215.4 (C(O)) ppm; IR νmax (thin

–1 + film, cm ): 2932, 1702 (C=O), 1450, 1265, 1142, 962; HRMS calcd. for C20H22ONa [M+Na] 301.1563, found 301.1552.

(E)–2–(3–(3–Bromophenyl)allyl)–2–methylcyclohexan–1–one (93d)

Prepared according to general procedure A using 2–allyl–2–methylcyclohexan–1–one 91 (200 mg, 1.3 mmol, 1.0 eq.), 3–bromostyrene (0.51 mL, 3.9 mmol, 3.0 eq.) and Hoveyda– Grubbs 2nd Generation catalyst (8 mg, 0.013 mmol, 1 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a colourless oil

1 (232 mg, 0.76 mmol, 58%). H NMR (400 MHz, CDCl3) δ 1.14 (s, 3H, CH3), 1.65−1.87 (m, 6H,

CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O)), 2.37−2.50 (m, 4H,

CH2CH2CH2CH2C(O) + CH2CH=CHAr), 6.15 (dt, J = 15.8, 7.5 Hz, 1H, CH2CH=CHAr), 6.33 (d,

J = 15.8 Hz, 1H, CH2CH=CHAr), 7.16 (t, J = 7.7 Hz, 1H, ArCH), 7.24 (d, J = 7.7 Hz, 1H, ArCH),

105

13 7.36 (d, J = 7.8 Hz, 1H, ArCH), 7.48 (s, 1H, ArCH); C NMR (101 MHz, CDCl3) δ 21.1

(CH2CH2CH2CH2C(O)), 23.0 (CH3), 27.3 (CH2CH2CH2CH2C(O)), 38.6 (CH2CH2CH2CH2C(O)), 38.8

(CH2CH2CH2CH2C(O)), 41.2 (CH2CH=CHAr), 48.9 (C), 122.7 (ArCBr), 124.8 (CH2CH=CHAr), 127.7

(ArCH), 128.9 (ArCH), 130.0 (ArCH), 131.6 (CH2CH=CHAr), 139.6 (ArC), 215.2 (C(O)) ppm;

–1 IR νmax (thin film, cm ): 2973, 1732 (C=O), 1450, 1266, 1087, 1046, 879; HRMS calcd. for

+ C16H23ONBr [M+NH4] 324.0958, found 324.0961.

(E)–2–(3–(2–Chlorophenyl)allyl)–2–methylcyclohexan–1–one (93e)

Prepared according to general procedure A using 2–allyl–2–methylcyclohexan–1–one 91 (200 mg, 1.3 mmol, 1.0 eq.), 2–chlorostyrene (0.50 mL, 3.9 mmol, 3.0 eq.) and Hoveyda– Grubbs 2nd Generation catalyst (16 mg, 0.026 mmol, 2 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a pale yellow oil

1 (213 mg, 0.81 mmol, 62%). H NMR (400 MHz, CDCl3) δ 1.16 (s, 3H, CH3) 1.66−1.89 (m, 6H,

CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O)), 2.42−2.58 (m, 4H,

CH2CH2CH2CH2C(O) + CH2CH=CHAr), 6.11 (dt, J = 15.8, 7.8, 1H, CH2CH=CHAr), 6.78 (d, J = 15.8,

1H, CH2CH=CHAr), 7.13−7.22 (m, 2H, ArCH), 7.33 (dd, J = 7.8, 1.5 Hz, 1H, ArCH), 7.48 ((dd,

13 J = 7.8, 1.5 Hz, 1H, ArCH); C NMR (101 MHz, CDCl3) δ 21.1 (CH2CH2CH2CH2C(O)), 23.0 (CH3),

27.4 (CH2CH2CH2CH2C(O)), 38.8 (CH2CH2CH2CH2C(O)), 38.9 (CH2CH2CH2CH2C(O)), 41.4

(CH2CH=CHAr), 48.9 (C), 126.8 (ArCH), 126.9 (ArCH), 128.1 (ArCH), 128.9 (CH2CH=CHAr),

129.3 (CH2CH=CHAr), 129.5 (ArCH), 132.6 (ArCCl), 135.6 (ArC), 215.3 (C(O)) ppm; IR νmax (thin

–1 + film, cm ): 2933, 1703 (C=O), 1468, 1440, 1122, 967; HRMS calcd. for C16H20OCl [M+H] 263.1197, found 263.1198.

(E)–2–Methyl–2–(3–(4–(trifluoromethyl)phenyl)allyl)cyclohexan–1–one (93f)

106

Prepared according to general procedure A using 2–allyl–2–methylcyclohexan–1–one 91 (200 mg, 1.3 mmol, 1.0 eq.), 4–(trifluoromethyl)styrene (0.58 mL, 3.9 mmol, 3.0 eq.) and Hoveyda–Grubbs 2nd Generation catalyst (16 mg, 0.026 mmol, 2 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a pale

1 yellow oil (224 mg, 0.76 mmol, 58%). H NMR (400 MHz, CDCl3) δ 1.16 (s, 3H, CH3), 1.65−1.88

(m, 6H, CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O)), 2.37−2.53 (m, 4H,

CH2CH2CH2CH2C(O) + CH2CH=CHAr), 6.25 (dt, J = 15.8, 7.8 Hz, 1H, CH2CH=CHAr), 6.43 (d,

J = 15.8 Hz, 1H, CH2CH=CHAr), 7.43 (d, J = 8.3 Hz, 2H, ArCH), 7.54 (d, J = 8.3 Hz, 2H, ArCH)

13 ppm; C NMR (101 MHz, CDCl3) δ 21.1 (CH2CH2CH2CH2C(O)), 23.0 (CH3), 27.3

(CH2CH2CH2CH2C(O)), 38.7 (CH2CH2CH2CH2C(O)), 38.8 (CH2CH2CH2CH2C(O)), 41.4

(CH2CH=CHAr), 48.9 (C), 125.4 (q, J = 3.9 Hz, ArCH), 126.2 (ArCH), 128.9 (CH2CH=CHAr), 131.7

19 (CH2CH=CHAr), 140.8 (ArC), 215.1 (C(O)) ppm, ArCCF3 and ArCCF3 not observed; F NMR (376

–1 MHz, CDCl3) δ –62.5 ppm; IR νmax (thin film, cm ): 2935, 1704 (C=O), 1614, 1323, 1162, 1120,

+ 1067, 971; HRMS calcd. for C17H23ONF3 [M+NH4] 314.1726, found 314.1729.

(E)–2–Methyl–2–(3–(o–tolyl)allyl)cyclohexan–1–one (93g)

Prepared according to general procedure A using 2–allyl–2–methylcyclohexan–1–one 91 (200 mg, 1.3 mmol, 1.0 eq.), 2–methylstyrene (0.51 mL, 3.9 mmol, 3.0 eq.) and Hoveyda– Grubbs 2nd Generation catalyst (16 mg, 0.026 mmol, 2 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a yellow oil

1 (164 mg, 0.68 mmol, 52%). H NMR (400 MHz, CDCl3) δ 1.15 (s, 3H, CH3), 1.63−1.88 (m, 6H,

CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O)), 2.33 (s, 3H, ArCCH3),

2.40−2.55 (m, 4H, CH2CH2CH2CH2C(O) + CH2CH=CHAr), 5.98 (dt, J = 15.7, 8.0 Hz, 1H,

CH2CH=CHAr), 6.60 (d, J = 15.7 Hz, 1H, CH2CH=CHAr), 7.12−7.16 (m, 3H, ArCH), 7.38−7.40 (m,

13 1H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 19.8 (ArCCH3), 21.1 (CH2CH2CH2CH2C(O)), 22.9

(CH3), 27.4 (CH2CH2CH2CH2C(O)), 38.6 (CH2CH2CH2CH2C(O)), 38.8 (CH2CH2CH2CH2C(O)), 41.4

(CH2CH=CHAr), 48.9 (C), 125.8 (ArCH), 126.0 (ArCH), 127.1 (ArCH), 127.2 (CH2CH=CHAr),

130.1 (ArCH), 131.1 (CH2CH=CHAr), 135.0 (ArC), 136.7 (ArCCH3), 215.4 (C(O)) ppm; IR νmax

–1 + (thin film, cm ): 2931, 1703 (C=O), 1459, 1123, 967; HRMS calcd. for C17H23O [M+H] 243.1743, found 243.1748.

107

2–Cinnamyl–2–methylcyclopentan–1–one (94a)

Prepared according to general procedure A using 2–allyl–2–methylcyclopentan–1–one 92 (1.5 g, 11 mmol, 1.0 eq.), styrene (0.50 mL, 33 mmol, 3.0 eq.) and Hoveyda–Grubbs 2nd Generation catalyst (68 mg, 0.11 mmol, 1 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a pale yellow oil

1 (0.98 g, 4.6 mmol, 42%). H NMR (400 MHz, CDCl3) δ 1.07 (s, 3H, CH3), 1.72−1.77 (m, 1H,

CHaHbCH2CH2C(O)), 1.89−1.92 (m, 2H, CH2CH2CH2C(O)), 1.97−2.04 (m, 1H, CHaHbCH2CH2C(O)),

2.20−2.37 (m, 4H, CH2CH2CH2C(O) + CH2CH=CHAr), 6.12 (ddd, J = 15.7, 8.0, 7.3 Hz, 1H,

CH2CH=CHAr), 6.42 (d, J = 15.7 Hz, 1H, CH2CH=CHAr), 7.20−7.24 (m, 1H, ArCH), 7.29−7.37 (m,

13 4H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 18.8 (CH2CH2CH2C(O)), 22.1 (CH3), 35.2

(CH2CH2CH2C(O)), 37.8 (CH2CH2CH2C(O)), 40.2 (CH2CH=CHAr), 48.8 (C), 125.6 (CH2CH=CHAr),

126.1 (ArCH), 127.2 (ArCH), 128.5 (ArCH), 133.3 (CH2CH=CHAr), 137.3 (ArC), 222.7 (C(O))

–1 ppm; IR νmax (thin film, cm ) 2959, 1732 (C=O), 1449, 1161, 1060, 967; HRMS calcd. for

+ C15H19O [M+H] 215.1430, found 215.1425.

(E)–2–(3–(4–Fluorophenyl)allyl)–2–methylcyclopentan–1–one (94b)

Prepared according to general procedure A using 2–allyl–2–methylcyclopentan–1–one 92 (200 mg, 1.5 mmol, 1.0 eq.), 4–fluorostyrene (0.52 mL, 4.4 mmol, 3.0 eq.) and Hoveyda– Grubbs 2nd Generation catalyst (18 mg, 0.029 mmol, 2 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a yellow oil

1 (120 mg, 0.52 mmol, 36%). H NMR (400 MHz, CDCl3) δ 0.99 (s, 3H, CH3), 1.64−1.70 (m, 1H,

CHaHbCH2CH2C(O)), 1.82−1.96 (m, 3H, CH2CH2CH2C(O) + CHaHbCH2CH2C(O)) 2.10−2.30 (m, 4H,

CH2CH2CH2C(O) + CH2CH=CHAr), 5.95 (dt, J = 15.6, 7.6 Hz, 1H, CH2CH=CHAr), 6.30 (d, J =

15.6 Hz, 1H, CH2CH=CHAr), 6.91 (t, J = 8.6 Hz, 2H, ArCH), 7.23 (dd, J = 8.6, 5.4 Hz, 2H, ArCH)

13 ppm; C NMR (101 MHz, CDCl3) δ 18.7 (CH2CH2CH2C(O)), 22.1 (CH3), 35.3 (CH2CH2CH2C(O)),

37.7 (CH2CH2CH2C(O)), 40.1 (CH2CH=CHAr), 48.6 (C), 115.4 (d, J = 21.5 Hz, ArCH), 125.4 (d, J =

108

2.4 Hz, CH2CH=CHAr), 127.6 (d, J = 7.9 Hz, ArCH), 132.1 (CH2CH=CHAr), 133.5 (d, J = 3.1 Hz,

19 ArC), 162.1 (d, J = 247.5 Hz, ArCF), 223.1 (C(O)) ppm; F NMR (376 MHz, CDCl3) δ –115.1

–1 ppm; IR νmax (thin film, cm ): 2962, 1734 (C=O), 1600, 1508, 1227, 1158, 969; HRMS calcd.

+ for C15H18OF [M+H] 233.1336, found 233.1336.

(E)–2–Methyl–2–(3–(naphthalen–2–yl)allyl)cyclopentan–1–one (94c)

Prepared according to general procedure A using 2–allyl–2–methylcyclopentan–1–one 92 (200 mg, 1.5 mmol, 1.0 eq.), 2–vinylnapthalene (0.67 g, 4.4 mmol, 3.0 eq.) and Hoveyda– Grubbs 2nd Generation catalyst (18 mg, 0.029 mmol, 2 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a yellow solid

1 (126 mg, 0.48 mmol, 33%): mp (hexane) 42–44 °C. H NMR (400 MHz, CDCl3) δ 1.10 (s, 3H,

CH3), 1.74–1.81 (m, 1H, CHaHbCH2CH2C(O)), 1.90–1.95 (m, 2H, CH2CH2CH2C(O)), 2.03–2.09 (m,

1H, CHaHbCH2CH2C(O)), 2.20–2.43 (m, 4H, CH2CH2CH2C(O) + CH2CH=CHAr), 6.25 (dt, J = 15.7,

7.6 Hz, 1H, CH2CH=CHAr), 6.59 (d, J = 15.7 Hz, 1H, CH2CH=CHAr), 7.41–7.48 (m, 2H, ArCH), 7.58 (d, J = 8.5 Hz, 1H, ArCH), 7.69 (s, 1H, ArCH), 7.79 (t, J = 8.2 Hz, 3H, ArCH) ppm; 13C NMR

(101 MHz, CDCl3) δ 18.8 (CH2CH2CH2C(O)), 22.2 (CH3), 35.3 (CH2CH2CH2C(O)), 37.8

(CH2CH2CH2C(O)), 40.4 (CH2CH=CHAr), 48.9 (C), 123.6 (ArCH), 125.7 (ArCH), 125.7 (ArCH),

126.1 (CH2CH=CHAr), 126.2 (ArCH), 127.6 (ArCH), 127.9 (ArCH), 128.1 (ArCH), 132.8 (ArC),

–1 133.4 (CH2CH=CHAr), 133.6 (ArC), 134.8 (ArC), 223.2 (C(O)) ppm; IR νmax (thin film, cm ):

+ 2959, 1732 (C=O), 1454, 1161, 1060, 966; HRMS calcd. for C19H21O [M+H] 265.1587, found 265.1580.

(E)–2–(3–(3–Bromophenyl)allyl)–2–methylcyclopentan–1–one (94d)

Prepared according to general procedure A using 2–allyl–2–methylcyclopentan–1–one 92 (200 mg, 1.5 mmol, 1.0 eq.), 3–bromostyrene (0.52 mL, 4.4 mmol, 1.0 eq.) and Hoveyda–

109

Grubbs 2nd Generation catalyst (18 mg, 0.029 mmol, 2 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a yellow oil

1 (140 mg, 0.48 mmol, 33%). H NMR (400 MHz, CDCl3) δ 1.08 (s, 3H, CH3), 1.74−1.80 (m, 1H,

CHaHbCH2CH2C(O)), 1.88−2.04 (m, 3H, CH2CH2CH2C(O) + CHaHbCH2CH2C(O)), 2.19−2.40 (m,

4H, CH2CH2CH2C(O) + CH2CH=CHAr), 6.14 (dt, J = 15.7, 7.6 Hz, 1H, CH2CH=CHAr), 6.36 (d,

J = 15.7 Hz, 1H, CH2CH=CHAr), 7.18 (t, J = 7.8 Hz, 1H, ArCH), 7.26 (d, J = 7.8 Hz, 1H, ArCH),

13 7.36 (d, J = 7.8 Hz, 1H, ArCH), 7.51 (s, 1H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 18.7

(CH2CH2CH2C(O)), 22.1 (CH3), 35.3 (CH2CH2CH2C(O)), 37.7 (CH2CH2CH2C(O)), 40.1

(CH2CH=CHAr), 48.7 (C), 122.8 (ArCBr), 124.8 (ArCH), 127.4 (CH2CH=CHAr), 128.9 (ArCH),

130.0 (ArCH), 130.1 (ArCH), 131.9 (CH2CH=CHAr), 139.5 (ArC), 222.9 (C(O)) ppm; IR νmax (thin

–1 film, cm ): 2959, 1732 (C=O), 1561, 1471, 1161, 1070, 965; HRMS calcd. for C15H21ONBr

+ [M+NH4] 310.0801, found 310.0801.

(E)–2–(3–(2–Chlorophenyl)allyl)–2–methylcyclopentan–1–one (94e)

Prepared according to general procedure A using 2–allyl–2–methylcyclopentan–1–one 92 (200 mg, 1.5 mmol, 1.0 eq.), 2–chlorostyrene (0.52 mL, 4.4 mmol, 3.0 eq.) and Hoveyda– Grubbs 2nd Generation catalyst (18 mg, 0.029 mmol, 2 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a yellow solid

1 (253 mg, 1.0 mmol, 70%): mp (CH2Cl2) 36–38 °C. H NMR (400 MHz, CDCl3) δ 1.08 (s, 3H, CH3),

1.73−1.79 (m, 1H, CHaHbCH2CH2C(O)), 1.88−1.96 (m, 2H, CH2CH2CH2C(O)), 1.99−2.05 (m, 1H,

CHaHbCH2CH2C(O)), 2.21−2.39 (m, 4H, CH2CH2CH2C(O) + CH2CH=CHAr), 6.09 (dt, J = 15.6,

7.7 Hz, 1H, CH2CH=CHAr), 6.79 (d, J = 15.6 Hz, 1H, CH2CH=CHAr), 7.14−7.23 (m, 2H, ArCH),

13 7.34 (d, J = 7.6 Hz, 1H, ArCH), 7.49 (d, J = 7.8 Hz, 1H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ

18.7 (CH2CH2CH2C(O)), 22.1 (CH3), 35.3 (CH2CH2CH2C(O)), 37.7 (CH2CH2CH2C(O)), 40.3

(CH2CH=CHAr), 48.7 (C), 126.8 (ArCH), 126.8 (ArCH), 128.2 (ArCH), 128.8 (CH2CH=CHAr),

129.6 (ArCH), 129.6 (CH2CH=CHAr), 132.7 (ArCCl), 135.5 (ArC), 223.0 (C(O)) ppm; IR νmax (thin

–1 film, cm ): 2960, 1732 (C=O), 1469, 1440, 1162, 1033, 967; HRMS calcd. for C15H21ONCl

+ [M+NH4] 266.1306, found 266.1309.

110

(E)–2–Methyl–2–(3–(4–(trifluoromethyl)phenyl)allyl)cyclopentan–1–one (94f)

Prepared according to general procedure A using 2–allyl–2–methylcyclopentan–1–one 92 (200 mg, 1.5 mmol, 1.0 eq.), 4–(tifluoromethyl)styrene (0.52 mL, 4.4 mmol, 3.0 eq.) and Hoveyda–Grubbs 2nd Generation catalyst (18 mg, 0.029 mmol, 2 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a

1 yellow oil (123 mg, 0.44 mmol, 30%). H NMR (400 MHz, CDCl3) δ 1.08 (s, 3H, CH3), 1.74−1.80

(m, 1H, CHaHbCH2CH2C(O)), 1.87−2.03 (m, 3H, CH2CH2CH2C(O) + CHaHbCH2CH2C(O)),

2.18−2.40 (m, 4H, CH2CH2CH2C(O) + CH2CH=CHAr), 6.23 (dt, J = 15.7, 7.6 Hz, 1H,

CH2CH=CHAr), 6.45 (d, J = 15.7 Hz, 1H, CH2CH=CHAr), 7.44 (d, J = 8.1 Hz, 2H, ArCH), 7.55 (d,

13 J = 8.3 Hz, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 18.7 (CH2CH2CH2C(O)), 22.1 (CH3),

35.3 (CH2CH2CH2C(O)), 37.7 (CH2CH2CH2C(O)), 40.2 (CH2CH=CHAr), 48.7 (C), 122.9 (q, J =

32.6 Hz, ArCCF3), 125.5 (q, J = 3.9 Hz, ArCH), 126.2 (ArCH), 128.6 (CH2CH=CHAr), 132.1

19 (CH2CH=CHAr), 140.7 (ArC), 222.8 (C(O)) ppm, ArCCF3 not observed; F NMR (376 MHz,

–1 CDCl3) δ –62.5 ppm; IR νmax (thin film, cm ): 2966, 1732 (C=O), 1614, 1413, 1324, 1264, 1163,

+ 1122, 1066, 971; HRMS calcd. for C16H17OF3Na [M+Na] 305.1124, found 305.1114.

(E)–2–Methyl–2–(3–(o–tolyl)allyl)cyclopentan–1–one (94g)

Prepared according to general procedure A using 2–allyl–2–methylcyclopentan–1–one 92 (200 mg, 1.5 mmol, 1.0 eq.), 2–methylstyrene (0.52 mL, 4.4 mmol, 3.0 eq.) and Hoveyda– Grubbs 2nd Generation catalyst (18 mg, 0.029 mmol, 2 mol%). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 98:2) yielded the title product as a yellow oil

1 (180 mg, 0.79 mmol, 54%). H NMR (400 MHz, CDCl3) δ 1.08 (s, 3H, CH3), 1.72−1.78 (m, 1H,

CHaHbCH2CH2C(O)), 1.87−1.94 (m, 2H, CH2CH2CH2C(O)), 2.00−2.07 (m, 1H, CHaHbCH2CH2C(O)),

2.20−2.39 (m, 4H, CH2CH2CH2C(O) + CH2CH=CHAr), 2.34 (s, 3H, ArCCH3), 5.98 (dt, J = 15.5,

7.6 Hz, 1H, CH2CH=CHAr), 6.62 (d, J = 15.5 Hz, 1H, CH2CH=CHAr), 7.15−7.19 (m, 3H, ArCH),

13 7.39−7.41 (m, 1H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 18.8 (CH2CH2CH2C(O)), 19.8

111

(ArCCH3), 22.1 (CH3), 35.2 (CH2CH2CH2C(O)), 37.8 (CH2CH2CH2C(O)), 40.5 (CH2CH=CHAr), 48.8

(C), 125.6 (ArCH), 126.1 (ArCH), 127.0 (CH2CH=CHAr), 127.2 (ArCH), 130.2 (ArCH), 131.4

–1 (CH2CH=CHAr), 135.1 (ArCCH3), 136.6 (ArC), 223.2 (C(O)) ppm; IR νmax (thin film, cm ): 2959,

+ 1733 (C=O), 1456, 1161, 1060, 967; HRMS calcd. for C16H24ON [M+NH4] 246.1852, found 246.1851.

General procedure F: CHMO–Catalysed Biotransformations

(R)–7–Allyl–7–methyloxepan–2–one (95a)[37]

To a Falcon tube were added rac–91 (30 mg, 0.20 mmol, 1.0 eq.) in EtOH (2.25 mL), NADPH (11 mg, 0.015 mmol, 0.08 eq.), GDH (11 mg, 2.28 x 10–4 mmol, 0.1 mol%), glucose (225 mg, 1.2 mmol, 6.3 eq.), CHMO (11 mg, 1.86 x 10–4 mmol, 0.09 mol%) and Tris/HCl buffer (12.5 mL, pH 7.0, 100 mM). The reaction was incubated at 25°C with shaking at 250 rpm for 24 hours.

The mixture was extracted with EtOAc (3 x 10 mL), the organic layers were dried (MgSO4) and concentrated. Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil (16 mg, 0.089 mmol, 47%). 1H NMR (400 MHz,

CDCl3) δ 1.44 (s, 3H, CH3), 1.62–1.70 (m, 1H, CH2CH2CHaHbCH2C(O)O), 1.76–1.88 (m, 5H,

CH2CH2CHaHbCH2C(O)O + CH2CH2CH2CH2C(O)O + CH2CH2CH2CH2C(O)O), 2.41–2.64 (m, 2H,

CH2CH=CH2), 2.64–2.75 (m, 2H, CH2CH2CH2CH2C(O)O), 5.11–5.16 (m, 2H, CH2CH=CH2), 5.86

13 (ddt, J = 17.1, 10.1, 7.3 Hz, 1H, CH2CH=CH2) ppm; C NMR (101 MHz, CDCl3) δ 23.4

(CH2CH2CH2CH2C(O)O), 23.9 (CH2CH2CH2CH2C(O)O), 24.8 (CH3), 37.4 (CH2CH2CH2CH2C(O)O),

38.4 (CH2CH2CH2CH2C(O)O), 46.7 (CH2CH=CH2), 82.8 (C), 119.0 (CH2CH=CH2), 132.8

30 (CH2CH=CH2), 174.7 (C(O)O) ppm; Specific rotation [α]D –16.5 (c 1.2, CHCl3) for an

[135] 27 enantiomerically enriched sample of >99% e.e.; Lit [α]D +20.6 (c 3.46, hexane) for an enantiomerically enriched sampled of (S)–7–allyl–7–methyloxepan–2–one of 98% e.e.

Enantiomeric purity of (R)–95a was determined by GC analysis in comparison with authentic racemic material (>99:1 e.r. shown; ChiraSil® DEX CB 25 m x 0.25 mm column, 50 °C to 200 °C at a rate of 1 °C min–1, flow rate = 1.0 mL min–1).

112

rac–95a

(R)–95a

(R,E)–7–Cinnamyl–7–methyloxepan–2–one (95b)[37]

Prepared according to general procedure F using rac–93a (46 mg, 0.20 mmol, 1.0 eq.) in EtOH (2.25 mL), NADPH (11 mg, 0.015 mmol, 0.08 eq.), GDH (11 mg, 2.28 x 10–4 mmol, 0.1 mol%), glucose (225 mg, 1.2 mmol, 6.3 eq.), CHMO (11.2 mg, 1.86 x 10–4 mmol, 0.09 mol%) and Tris/HCl buffer (12.5 mL, pH 7.0, 100 mM). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil (20 mg, 0.08 mmol, 41%).

1 H NMR (400 MHz, CDCl3) δ 1.50 (s, 3H, CH3), 1.60–1.71 (m, 1H, CH2CH2CHaHbCH2C(O)O),

1.80–1.92 (m, 5H, CH2CH2CHaHbCH2C(O)O + CH2CH2CH2CH2C(O)O + CH2CH2CH2CH2C(O)O)),

2.57–2.82 (m, 4H, CH2CH=CHAr + CH2CH2CH2CH2C(O)O)), 6.28 (dt, J = 15.7, 7.6 Hz, 1H,

CH2CH=CHAr), 6.47 (d, J = 15.7 Hz, 1H, CH2CH=CHAr), 7.22–7.25 (m, 1H, ArCH), 7.32 (t,

13 J = 7.4 Hz, 2H, ArCH), 7.37–7.39 (m, 2H, ArCH) ppm; C NMR δ 23.4 (CH2CH2CH2CH2C(O)O),

113

24.0 (CH2CH2CH2CH2C(O)O), 24.7 (CH3), 37.4 (CH2CH2CH2CH2C(O)O), 38.6

(CH2CH2CH2CH2C(O)O), 46.4 (CH2CH=CHAr), 83.2 (C), 124.4 (CH2CH=CHAr), 126.2 (ArCH),

127.4 (ArCH), 128.6 (ArCH), 134.0 (CH2CH=CHAr), 137.1 (ArC), 174.8 (C(O)O) ppm; Specific

30 rotation [α]D –10.6 (c 1.4, CHCl3) for an enantiomerically enriched sample of >99% e.e.

Enantiomeric purity of (R)–95b was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown; Lux 5 μm Amylose–1 column, 80:20 hexanes:iPrOH, 1.0 mL min–1, 20 °C, 254 nm).

rac–95b

(R)–95b

Absolute stereochemistry was assigned by comparison with a sample of (S,E)–7–cinnamyl– 7–methyloxepan–2–one[131] (92:8 e.r. shown).

(S)–95b

114

The remaining starting material from the reaction could be isolated and was obtained as a pale yellow oil (18 mg, 0.079 mmol, 39%). Enantiomeric purity of (S)–93a was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown, Chiralpak® 5 μm IA column, 99.5:0.5 hexanes:iPrOH, 0.6 mL min–1, 20 °C, 254 nm).

rac–93a

(S)–93a

(R,E)–7–(3–(4–Fluorophenyl)allyl)–7–methyloxepan–2–one (95c)

Prepared according to general procedure F using rac–93b (49 mg, 0.20 mmol, 1.0 eq.) in EtOH (2.25 mL), NADPH (11 mg, 0.015 mmol, 0.08 eq.), GDH (11 mg, 2.28 x 10–4 mmol, 0.1 mol%), glucose (225 mg, 1.2 mmol, 6.3 eq.), CHMO (11 mg, 1.86 x 10–4 mmol, 0.09 mol%) and Tris/HCl buffer (12.5 mL, pH 7.0, 100 mM). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil (19 mg, 0.071 mmol, 32%).

1 H NMR (400 MHz, CDCl3) δ 1.49 (s, 3H, CH3), 1.65–1.71 (m, 1H, CH2CH2CHaHbCH2C(O)O)),

1.80–1.91 (m, 5H, CH2CH2CHaHbCH2C(O)O + CH2CH2CH2CH2C(O)O + CH2CH2CH2CH2C(O)O)),

115

2.54–2.79 (m, 4H, CH2CH=CHAr + CH2CH2CH2CH2C(O)O)), 6.20 (dt, J = 15.8, 8.2 Hz, 1H,

CH2CH=CHAr), 6.42 (d, J = 15.8 Hz, 1H, CH2CH=CHAr), 7.00 (t, J = 8.7 Hz, 2H, ArCH), 7.32–7.36

13 (m, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 23.4 (CH2CH2CH2CH2C(O)O), 24.0

(CH2CH2CH2CH2C(O)O), 24.7 (CH3), 37.4 (CH2CH2CH2CH2C(O)O), 38.7 (CH2CH2CH2CH2C(O)O),

46.4 (CH2CH=CHAr), 83.1 (C), 115.4 (d, J = 21.6 Hz, ArCH), 124.2 (d, J = 2.3 Hz, CH2CH=CHAr),

127.7 (d, J = 8.0 Hz, ArCH), 132.7 (CH2CH=CHAr), 133.3 (d, J = 3.1 Hz, ArC), 162.2 (d, J = 246.5

–1 Hz, ArCF), 174.8 (C(O)O) ppm; IR νmax (thin film, cm ): 2933, 1711 (C=O), 1507, 1333, 1224,

+ 1178, 1103, 1017; HRMS calcd. for C16H19O2FNa [M+Na] 285.1261, found 285.1255. Specific

30 rotation [α]D –11.5 (c 1.2, CHCl3) for an enantiomerically enriched sample of >99% e.e.

Enantiomeric purity of (R)–95c was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown; Lux 5 μm Amylose–1 column, 80:20 hexanes:iPrOH, 1.0 mL min–1, 20 °C, 254 nm).

rac–95c

(R)–95c

Absolute stereochemistry was assigned by comparison with a sample of (S,E)–7–(3–(4– fluorophenyl)allyl)–7–methyloxepan–2–one[131] (92:8 e.r. shown).

116

(S)–95c

(R,E)–7–Methyl–7–(3–(4–(trifluoromethyl)phenyl)allyl)oxepan–2–one (95d)[37]

Prepared according to general procedure F using rac–93f (59 mg, 0.20 mmol, 1.0 eq.) in EtOH (2.25 mL), NADPH (11 mg, 0.015 mmol, 0.08 eq.), GDH (11 mg, 2.28 x 10–4 mmol, 0.1 mol%), glucose (225 mg, 1.24 mmol, 6.3 eq.), CHMO (11 mg, 1.86 x 10–4 mmol, 0.09 mol%) and Tris/HCl buffer (12.75 mL, pH 7.0, 100 mM). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil (17 mg, 0.05 mmol, 27%).

1 H NMR (400 MHz, CDCl3) δ 1.51 (s, 3H, CH3), 1.65–1.70 (m, 1H, CH2CH2CHaHbCH2C(O)O),

1.81–1.92 (m, 5H, CH2CH2CHaHbCH2C(O)O + CH2CH2CH2CH2C(O)O + CH2CH2CH2CH2C(O)O),

2.57–2.82 (m, 4H, CH2CH=CHAr + CH2CH2CH2CH2C(O)O), 6.41 (dt, J = 16.0, 7.1 Hz, 1H,

CH2CH=CHAr), 6.50 (d, J = 16.0 Hz, 1H, CH2CH=CHAr), 7.47 (d, J = 8.2 Hz, 2H, ArCH), 7.56 (d,

13 J = 8.2 Hz, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 23.3 (CH2CH2CH2CH2C(O)O), 24.0

(CH2CH2CH2CH2C(O)O), 24.5 (CH3), 37.4 (CH2CH2CH2CH2C(O)O), 38.8 (CH2CH2CH2CH2C(O)O),

46.7 (CH2CH=CHAr), 82.9 (C), 125.5 (q, J = 3.9 Hz, ArCH), 126.3 (ArCH), 127.4 (CH2CH=CHAr),

132.6 (CH2CH=CHAr), 140.5 (ArC), 174.6 (C(O)O) ppm, ArCCF3 and ArCCF3 not observed.

30 Specific rotation [α]D –10.2 (c 0.6, CHCl3) for an enantiomerically enriched sample of >99% e.e.

Enantiomeric purity of (R)–95d was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown; Lux 5 μm Amylose–1 column, 85:15 hexanes:iPrOH, 0.7 mL min–1, 20 °C, 254 nm).

117

rac–95d

(R)–95d

(R,E)–7–(3–(2–Chlorophenyl)allyl)–7–methyloxepan–2–one (95e)[37]

Prepared according to general procedure F using rac–93e (52 mg, 0.20 mmol, 1.0 eq.) in EtOH (2.25 mL), NADPH (11 mg, 0.015 mmol, 0.08 eq.), GDH (11 mg, 2.28 x 10–4 mmol, 0.1 mol%), glucose (225 mg, 1.2 mmol, 6.3 eq.), CHMO (11 mg, 1.86 x 10–4 mmol, 0.09 mol%) and Tris/HCl buffer (12.5 mL, pH 7.0, 100 mM). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil (20 mg, 0.071 mmol, 26%).

1 H NMR (400 MHz, CDCl3) δ 1.53 (s, 3H, CH3), 1.65–1.73 (m, 1H, CH2CH2CHaHbCH2C(O)O)),

1.81–1.95 (m, 5H, CH2CH2CHaHbCH2C(O)O + CH2CH2CH2CH2C(O)O + CH2CH2CH2CH2C(O)O)),

2.62–2.83 (m, 4H, CH2CH=CHAr + CH2CH2CH2CH2C(O)O), 6.30 (dt, J = 15.7, 7.4 Hz, 1H,

CH2CH=CHAr), 6.86 (d, J = 15.9 Hz, 1H, CH2CH=CHAr), 7.19–7.26 (m, 2H, ArCH), 7.36 (dd,

13 J = 7.8, 1.5 Hz, 1H, ArCH), 7.56 (dd, J = 7.6, 1.7 Hz, 1H, ArCH) ppm; C NMR (101 MHz, CDCl3)

δ 23.4 (CH2CH2CH2CH2C(O)O), 24.0 (CH2CH2CH2CH2C(O)O), 24.8 (CH3), 37.4

118

(CH2CH2CH2CH2C(O)O), 38.7 (CH2CH2CH2CH2C(O)O), 46.5 (CH2CH=CHAr), 83.0 (C), 126.8

(ArCH), 126.9 (ArCH), 127.5 (CH2CH=CHAr), 128.4 (ArCH), 129.6 (ArCH), 130.2 (CH2CH=CHAr),

30 132.7 (ArCCl), 135.3 (ArC), 174.7 (C(O)O) ppm; Specific rotation [α]D +11.7 (c 0.9, CHCl3) for an enantiomerically enriched sample of >99% e.e.

Enantiomeric purity of (R)–95e was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown; Lux 5 μm Amylose–1 column, 80:20 hexanes:iPrOH, 1.0 mL min–1, 20 °C, 254 nm).

rac–95e

(R)–95e

(R,E)–7–(3–(3–Bromophenyl)allyl)–7–methyloxepan–2–one (95f)

Prepared according to general procedure F using rac–93d (61 mg, 0.20 mmol, 1.0 eq.) in EtOH (2.25 mL), NADPH (11 mg, 0.015 mmol, 0.08 eq.), GDH (11 mg, 2.28 x 10–4 mmol, 0.1 mol%), glucose (225 mg, 1.24 mmol, 6.3 eq.), CHMO (11 mg, 1.86 x 10–4 mmol, 0.09 mol%) and Tris/HCl buffer (12.5 mL, pH 7.0, 100 mM). Purification by silica gel column chromatography

119

(hexane/EtOAc 9:1) yielded the title product as a colourless oil (7 mg, 0.021 mmol, 11%).

1 H NMR (400 MHz, CDCl3) δ 1.49 (s, 3H, CH3), 1.65–1.70 (m, 1H, CH2CH2CHaHbCH2C(O)O)),

1.79–1.90 (m, 5H, CH2CH2CHaHbCH2C(O)O + CH2CH2CH2CH2C(O)O + CH2CH2CH2CH2C(O)O)),

2.55–2.81 (m, 4H, CH2CH=CHAr + CH2CH2CH2CH2C(O)O), 6.29 (dt, J = 15.8, 8.3 Hz, 1H,

CH2CH=CHAr), 6.39 (d, J = 15.8 Hz, 1H, CH2CH=CHAr), 7.17 (t, J = 8.0 Hz, 1H, ArCH), 7.28 (d, J = 8.3 Hz, 1H, ArCH), 7.35 (d, J = 7.8 Hz, 1H, ArCH), 7.52 (s, 1H, ArCH) ppm; 13C NMR (101 MHz,

CDCl3) δ 23.4 (CH2CH2CH2CH2C(O)O), 24.0 (CH2CH2CH2CH2C(O)O), 24.6 (CH3), 37.4

(CH2CH2CH2CH2C(O)O), 38.7 (CH2CH2CH2CH2C(O)O), 46.5 (CH2CH=CHAr), 82.9 (C), 122.8

(ArCBr), 124.9 (ArCH), 126.2 (CH2CH=CHAr), 129.1 (ArCH), 130.0 (ArCH), 130.2 (ArCH), 132.5

–1 (CH2CH=CHAr), 139.2 (ArC), 174.7 (C(O)O) ppm; IR νmax (thin film, cm ): 2933, 1711 (C=O),

+ 1590, 1471, 1289, 1178, 1109, 1017; HRMS calcd. for C16H19O2BrNa [M+Na] 345.0461, found

30 345.0454. Specific rotation [α]D –2.2 (c 0.6, CHCl3) for an enantiomerically enriched sample of >99% e.e.

Enantiomeric purity of (R)–95f was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown; Lux 5 μm Amylose–1 column, 80:20 hexanes:iPrOH, 1.0 mL/min, 20 °C, 254 nm).

rac–95f

(R)–95f

120

(R,E)–7–Methyl–7–(3–(naphthalen–2–yl)allyl)oxepan–2–one (95g)

Prepared according to general procedure F using rac–93c (6 mg, 0.02 mmol, 1.0 eq.), NADPH in EtOH (300 µL), NADPH (1.5 mg, 0.002 mmol, 0.08 eq.), GDH (1.5 mg, 3.04 x 10–5 mmol, 0.1 mol%), glucose (30 mg, 0.17 mmol, 6.3 eq.), CHMO (1.5 mg, 2.46 x 10–5 mmol, 0.09 mol%) and Tris/HCl buffer (2.7 mL, pH 7.0, 100 mM). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil (0.8 mg,

1 0.002 mmol, 13%). H NMR (400 MHz, CDCl3) δ 1.53 (s, 3H, CH3), 1.67–1.73 (m, 1H,

CH2CH2CHaHbCH2C(O)O)), 1.81–1.95 (m, 5H, CH2CH2CHaHbCH2C(O)O + CH2CH2CH2CH2C(O)O +

CH2CH2CH2CH2C(O)O)), 2.63–2.83 (m, 4H, CH2CH=CHAr + CH2CH2CH2CH2C(O)O), 6.41 (dt,

J = 15.8, 8.0 Hz, 1H, CH2CH=CHAr), 6.63 (d, J = 15.8 Hz, 1H, CH2CH=CHAr), 7.42–7.48 (m, 2H, ArCH), 7.61 (dd, J = 8.5, 1.3 Hz, 1H, ArCH), 7.72 (s, 1H, ArCH) 7.78–7.81 (m, 3H, ArCH) ppm;

13 C NMR (101 MHz, CDCl3) δ 23.4 (CH2CH2CH2CH2C(O)O), 24.0 (CH2CH2CH2CH2C(O)O), 24.7

(CH3), 37.4 (CH2CH2CH2CH2C(O)O), 38.6 (CH2CH2CH2CH2C(O)O), 46.6 (CH2CH=CHAr), 83.2 (C),

123.6 (ArCH), 124.9 (CH2CH=CHAr), 125.8 (ArCH), 125.9 (ArCH), 126.2 (ArCH), 127.6 (ArCH),

127.9 (ArCH), 128.2 (ArCH), 132.9 (ArC), 133.6 (ArC), 134.1 CH2CH=CHAr, 134.5 (ArC), 174.8

30 (C(O)O) ppm. Specific rotation [α]D +23.1 (c 0.14, CHCl3) for an enantiomerically enriched sample of >99% e.e.

Enantiomeric purity of (R)–95g was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown; Lux 5 μm Amylose–1 column, 80:20 hexanes:iPrOH, 1.0 mL min–1, 20 °C, 254 nm).

rac–95g

121

(R)–95g

(R,E)–7–Methyl–7–(3–(o–tolyl)allyl)oxepan–2–one (95h)

Prepared according to general procedure F using rac–93g (6 mg, 0.023 mmol, 1.0 eq.), NADPH in EtOH (300 µL), NADPH (1.5 mg, 0.002 mmol, 0.08 eq.), GDH (1.5 mg, 3.04 x 10–5 mmol, 0.1 mol%), glucose (30 mg, 0.17 mmol, 6.3 eq.), CHMO (1.5 mg, 2.46 x 10–5 mmol, 0.09 mol%) and Tris/HCl buffer (2.7 mL, pH 7.0, 100 mM). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil (1.4 mg,

1 0.006 mmol, 24%). H NMR (400 MHz, CDCl3) δ 1.51 (s, 3H, CH3) 1.66–1.72 (m, 1H,

CH2CH2CHaHbCH2C(O)O)),), 1.80–1.93 (m, 5H, CH2CH2CHaHbCH2C(O)O + CH2CH2CH2CH2C(O)O

+ CH2CH2CH2CH2C(O)O), 2.35 (s, 3H, ArCCH3), 2.61–2.82 (m, 4H, CH2CH=CHAr +

CH2CH2CH2CH2C(O)O), 6.13 (dt, J = 15.8, 7.5 Hz, 1H, CH2CH=CHAr), 6.68 (d, J = 15.8 Hz, 1H,

13 CH2CH=CHAr), 7.14–7.18 (m, 3H, ArCH), 7.43–7.45 (m, 1H, ArCH) ppm; C NMR (101 MHz,

CDCl3) δ 19.8 (ArCCH3), 23.4 (CH2CH2CH2CH2C(O)O), 24.0 (CH2CH2CH2CH2C(O)O), 24.9 (CH3),

37.4 (CH2CH2CH2CH2C(O)O), 38.6 (CH2CH2CH2CH2C(O)O) 46.5 (CH2CH=CHAr), 83.1 (C), 125.7

(ArCH), 125.8 (CH2CH=CHAr), 126.1 (ArCH), 127.4 (ArCH), 130.2 (ArCH), 132.0 (CH2CH=CHAr),

–1 135.1 (ArCCH3), 136.3 (ArC), 174.7 (C(O)O) ppm; IR νmax (thin film, cm ): 2932, 2860, 1711

+ (C=O), 1458, 1352, 1286, 1177, 1087, 1017; HRMS calcd. for C17H22O2Na [M+Na] 281.1512,

30 found 281.1503. Specific rotation [α]D –12.8 (c 0.1, CHCl3) for an enantiomerically enriched sample of >99% e.e.

122

Enantiomeric purity of (R)–95h was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown; Lux 5 μm Amylose–1 column, 85:15 hexanes:iPrOH, 0.7 mL min–1, 20 °C, 254 nm).

rac–95h

(R)–95h

Allyl 1–ethyl–2–oxocyclohexane–1–carboxylate (S1)

Prepared according to general procedure D using diallyl pimelate 87 (1.0 g, 4.1 mmol, 1.0 eq.), sodium hydride (0.18 g, 4.5 mmol, 1.1 eq.) and ethyl iodide (0.43 mL, 5.4 mmol, 1.3 eq.) in THF (3.6 mL). The crude reaction mixture was used in the following step without further purification.

123

2–Allyl–2–ethylcyclohexan–1–one (96)[136]

Prepared according to general procedure E using crude allyl 1–ethyl–2–oxocyclohexane–1– carboxylate S1 (0.61 g, 2.9 mmol, 1.0 eq.), Pd2(dba)3 (0.13 g, 0.15 mmol, 5 mol%), and PPh3 (0.15 g, 0.58 mmol, 20 mol%) in THF (26 mL). Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded the title product as a yellow oil (268 mg, 1.6

1 mmol, 56%). H NMR (400 MHz, CDCl3) 0.77 (t, J = 7.5 Hz, 3H, CH2CH3), 1.49 (apparent dq,

J = 14.8, 7.5 Hz, 1H, CHaHbCH3), 1.61–1.91 (m, 7H, CHaHbCH3 + CH2CH2CH2CH2C(O) +

CH2CH2CH2CH2C(O) + CH2CH2CH2CH2C(O)), 2.22–2.44 (m, 4H, CH2CH2CH2CH2C(O) +

13 CH2CH=CH2), 5.01–5.08 (m, 2H, CH2CH=CH2), 5.63–5.74 (m, 1H, CH2CH=CH2) ppm; C NMR

(101 MHz, CDCl3) δ 7.8 (CH2CH3), 20.8 (CH2CH2CH2CH2C(O)), 27.2 (CH2CH3), 27.3

(CH2CH2CH2CH2C(O)), 36.1 (CH2CH2CH2CH2C(O)), 38.5 (CH2CH=CH2), 39.2

(CH2CH2CH2CH2C(O)), 51.6 (C), 117.6 (CH2CH=CH2), 134.2 (CH2CH=CH2), 215.0 (C(O)) ppm.

(R)–7–Allyl–7–ethyloxepan–2–one (97)

Ketone rac–96 was subjected to the conditions in general procedure F using rac–96 (1 mg, 0.006 mmol, 1.0 eq.), in EtOH (50 µL), NADPH (0.25 mg, 3.36 x 10–4 mmol, 0.08 eq.), GDH (0.25 mg, 5.08 x 10–6 mmol, 0.1 mol%), glucose (0.5 mg, 0.003 mmol, 6.3 eq.), CHMO (0.25 mg, 4.10 x 10–6 mmol, 0.09 mol%) and Tris/HCl buffer (450 µL, pH 7.0, 100 mM). The reaction mixture was extracted with EtOAc (500 µL) and analysed directly by GC. 1H NMR

(400 MHz, CDCl3) δ 0.96 (t, J = 7.5 Hz, 3H, CH2CH3), 1.65–1.92 (m, 8H, CH2CH2CH2CH2C(O)O +

CH2CH2CH2CH2C(O)O + CH2CH2CH2CH2C(O)O + CH2CH3), 2.45–2.55 (m, 2H, CH2CH=CH2), 2.65–

2.75 (m, 2H, CH2CH2CH2CH2C(O)O), 5.12–5.17 (m, 2H, CH2CH=CH2), 5.78–5.88 (m, 1H,

13 CH2CH=CH2); C NMR (101 MHz, CDCl3) δ 7.7 (CH2CH3), 23.3 (CH2CH2CH2CH2C(O)O), 23.4

(CH2CH2CH2CH2C(O)O), 30.0 (CH2CH3), 36.2 (CH2CH2CH2CH2C(O)O), 37.4

(CH2CH2CH2CH2C(O)O), 42.3 (CH2CH=CH2), 85.1 (C), 118.8 (CH2CH=CH2), 132.7 (CH2CH=CH2),

124

–1 174.8 (C(O)O) ppm; IR νmax (thin film, cm ): 2923, 2851, 1703 (C=O), 1353, 1286, 1103 1008;

+ HRMS calcd. for C11H18O2Na [M+Na] : 205.1199, found 205.1200.

Reaction conversion and enantiomeric purity of (R)–97 were determined by GC analysis in comparison with authentic racemic material (3% conversion, >99:1 e.r. shown, ChiraSil® DEX CB 25 m x 0.25 mm column, 50 °C to 160 °C at a rate of 1 °C min–1, flow rate 1.0 mL min–1).

Racemic starting material rac–96

rac–97

125

Biotransformation

(R)– and (S)–96

(R)–97

(R)–6–Allyl–6–methyltetrahydro–2H–pyran–2–one (98a)[36]

Prepared according to general procedure F using rac–92 (1 mg, 0.006 mmol, 1.0 eq.) in EtOH (50 µL), NADPH (0.25 mg, 3.36 x 10–4 mmol, 0.08 eq.), GDH (0.25 mg, 5.08 x 10–6 mmol, 0.1 mol%), glucose (0.5 mg, 0.003 mmol, 6.3 eq.), CHMO (0.25 mg, 4.10 x 10–6 mmol, 0.09 mol%) and Tris/HCl buffer (450 µL, pH 7.0, 100 mM). The reaction mixture was extracted

1 with EtOAc (500 µL) and analysed directly by GC. H NMR (400 MHz, CDCl3) δ 1.38 (s, 3H,

CH3), 1.65–1.70 (m, 1H, CHaHbCH2CH2C(O)O), 1.78–1.92 (m, 3H, CHaHbCH2CH2C(O)O +

CH2CH2CH2C(O)O), 2.42–2.56 (m, 4H, CH2CH2CH2C(O)O) + CH2CH=CH2), 5.12–5.18 (m, 2H,

13 CH2CH=CH2), 5.80 (ddt, J = 17.1, 10.0, 7.3 Hz, 1H, CH2CH=CH2) ppm; C NMR (101 MHz, CDCl3)

δ 16.6 (CH2CH2CH2C(O)O), 26.4 (CH3), 29.4 (CH2CH2CH2C(O)O), 31.5 (CH2CH2CH2C(O)O), 46.2

(CH2CH=CH2) 83.7 (C), 119.4 (CH2CH=CH2) 132.4 (CH2CH=CH2) 171.2 (C(O)O) ppm.

Reaction conversion and enantiomeric purity of (R)–98a were determined by GC analysis in comparison with authentic racemic material (60% conversion, 86:14 e.r. shown, ChiraSil® DEX CB 25 m x 0.25 mm column, 100 °C to 150 °C at a rate of 1 °C min–1, flow rate 1.0 mL min–1).

126

rac–98a

Biotransformation

(R)– and (S)–92 (R)–98a

(R,E)–6–Cinnamyl–6–methyltetrahydro–2H–pyran–2–one (98b)[36]

Prepared according to general procedure F using rac–94a (43 mg, 0.20 mmol, 1.0 eq.) in EtOH (2.25 mL), NADPH (11 mg, 0.015 mmol, 0.08 eq.), GDH (11 mg, 2.28 x 10–4 mmol, 0.1 mol%),

127 glucose (225 mg, 1.2 mmol, 6.3 eq.), CHMO (11 mg, 1.86 x 10–4 mmol, 0.09 mol%) and Tris/HCl buffer (12.5 mL, pH 7.0, 100 mM). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil (17 mg, 0.074 mmol, 37%).

1 H NMR (400 MHz, CDCl3) δ 1.42 (s, 3H, CH3), 1.68–1.73 (m, 1H, CHaHbCH2CH2C(O)O), 1.84–

1.93 (m, 3H, CHaHbCH2CH2C(O)O + CH2CH2CH2C(O)O), 2.47–2.54 (m, 2H, CH2CH2CH2C(O)O),

2.58 (dd, J = 7.4, 1.1 Hz, 2H, CH2CH=CHAr), 6.21 (dt, J = 15.8, 7.5 Hz, 1H, CH2CH=CHAr), 6.48

(d, J = 15.9 Hz, 1H, CH2CH=CHAr), 7.22–7.26 (m, 1H, ArCH), 7.30–7.34 (m, 2H, ArCH), 7.36–

13 7.38 (m, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 16.6 (CH2CH2CH2C(O)O), 26.5 (CH3),

29.3 (CH2CH2CH2C(O)O), 31.6 (CH2CH2CH2C(O)O), 45.4 (CH2CH=CHAr), 84.0 (C), 123.8

(CH2CH=CHAr), 126.2 (ArCH), 127.5 (ArCH), 128.6 (ArCH), 134.3 (CH2CH=CHAr), 137.0 (ArC),

30 171.1 (C(O)O) ppm. Specific rotation [α]D +18.1 (c 0.9, CHCl3) for an enantiomerically enriched sample of 80% e.e.

Enantiomeric purity of (R)–98b was determined by HPLC analysis in comparison with authentic racemic material (90:10 e.r. shown; Lux 5 μm Amylose–1 column, 80:20 hexanes:iPrOH, 1.0 mL min–1, 20 °C, 254 nm).

rac–98b

(R)–98b

Absolute stereochemistry was assigned by comparison with a sample of (S,E)–6–cinnamyl– 6–methyltetrahydro–2H–pyran–2–one[131] (89:11 e.r. shown).

128

(S)–98b

(R,E)–6–(3–(4–Fluorophenyl)allyl)–6–methyltetrahydro–2H–pyran–2–one (98c)

Prepared according to general procedure F using rac–94b (46 mg, 0.20 mmol, 1.0 eq.) in EtOH (2.25 mL), NADPH (11 mg, 0.015 mmol, 0.08 eq.), GDH (11 mg, 2.28 x 10–4 mmol, 0.1 mol%), glucose (225 mg, 1.2 mmol, 6.3 eq.), CHMO (11 mg, 1.86 x 10–4 mmol, 0.09 mol%) and Tris/HCl buffer (12.5 mL, pH 7.0, 100 mM). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil (6 mg, 0.024 mmol, 12%).

1 H NMR (400 MHz, CDCl3) δ 1.41 (s, 3H, CH3), 1.68–1.74 (m, 1H, CHaHbCH2CH2C(O)O), 1.81

(m, 3H, CHaHbCH2CH2C(O)O + CH2CH2CH2C(O)O), 2.41–2.58 (m, 4H, CH2CH2CH2C(O)O) +

CH2CH=CHAr), 6.12 (dt, J = 15.6, 7.6 Hz, 1H, CH2CH=CHAr), 6.43 (d, J = 15.6 Hz, 1H,

13 CH2CH=CHAr), 6.99 (t, J = 8.6 Hz, 2H, ArCH), 7.32 (dd, J = 8.6, 5.6 Hz, 2H, ArCH) ppm; C NMR

(101 MHz, CDCl3) δ 16.5 (CH2CH2CH2C(O)O), 26.4 (CH3), 29.3 (CH2CH2CH2C(O)O), 31.7

(CH2CH2CH2C(O)O), 45.3 (CH2CH=CHAr), 83.9 (C), 115.4 (d, J = 21.6 Hz, ArCH), 123.5

(CH2CH=CHAr), 127.6 (d, J = 7.9 Hz, ArCH), 133.0 (CH2CH=CHAr), 133.1 (ArC), 160.9 (d, J =

19 246.6 Hz, ArCF), 171.1 (C(O)O) ppm; F NMR (376 MHz, CDCl3) δ –114.7 ppm; IR νmax (thin

–1 + film, cm ): 2940, 1722 (C=O), 1508, 1099, 1087, 1053;; HRMS calcd. for C15H17O2FNa [M+Na]

30 271.1105, found 271.1099. Specific rotation [α]D +22.6 (c 0.4, CHCl3) for an enantiomerically enriched sample of 97% e.e.

Enantiomeric purity of (R)–98c was determined by HPLC analysis in comparison with authentic racemic material (98.5:1.5 e.r. shown; Lux 5 μm Amylose–1 column, 80:20 hexanes:iPrOH, 1.0 mL min–1, 20 °C, 254 nm).

129

rac–98c

(R)–98c

Absolute stereochemistry was assigned by comparison with a sample of (S,E)–6–(3–(4– fluorophenyl)allyl)–6–methyltetrahydro–2H–pyran–2–one[131] (89:11 e.r. shown).

(S)–98c

(E)–6–Methyl–6–(3–(naphthalen–2–yl)allyl)tetrahydro–2H–pyran–2–one (98d)

130

Ketone rac–94c (6 mg, 0.023 mmol, 1.0 eq.), was exposed to the conditions of general procedure F using NADPH (1.5 mg, 0.002 mmol, 0.08 eq.), GDH (1.5 mg, 3.04 x 10–5 mmol, 0.1 mol%), glucose (30 mg, 0.167 mmol, 6.3 eq.), CHMO (1.5 mg, 2.46 x 10–5 mmol, 0.09 mol%) and Tris/HCl buffer (2.7 mL, pH 7.0, 100 mM). The crude reaction mixture was analysed by 1H NMR, no conversion to product was observed. Data for racemic standard:

1 H NMR (400 MHz, CDCl3) δ 1.45 (s, 3H, CH3), 1.72–1.76 (m, 1H, CHaHbCH2CH2C(O)O), 1.86–

1.96 (m, 3H, CHaHbCH2CH2C(O)O + CH2CH2CH2C(O)O), 2.46–2.65 (m, 4H, CH2CH2CH2C(O)O) +

CH2CH=CHAr), 6.34 (dt, J = 15.6, 7.6 Hz, 1H, CH2CH=CHAr), 6.64 (d, J = 15.8 Hz, 1H,

CH2CH=CHAr), 7.42–7.49 (m, 2H, ArCH), 7.59 (d, J = 8.5 Hz, 1H, ArCH), 7.72 (s, 1H, ArCH),

13 7.78–7.82 (m, 3H, ArCH); C NMR (101 MHz, CDCl3) δ 16.7 (CH2CH2CH2C(O)O), 26.6 (CH3),

29.4 (CH2CH2CH2C(O)O), 31.8 (CH2CH2CH2C(O)O), 45.6 (CH2CH=CHAr), 84.1 (C), 123.5 (ArCH),

124.3 (CH2CH=CHAr), 125.8 (ArCH), 125.9 (ArCH), 126.3 (ArCH), 127.7 (ArCH), 127.9 (ArCH),

128.2 (ArCH), 132.9 (ArC), 133.6 (ArC), 134.4 (CH2CH=CHAr), 134.5 (ArC), 171.2 (C(O)O) ppm;

–1 IR νmax (thin film, cm ): 3055, 2974, 1720 (C=O), 1506, 1380, 1253, 1089; HRMS calcd. for

+ C19H20O2Na [M+Na] 303.1358, found 303.1356.

(E)–6–(3–(3–Bromophenyl)allyl)–6–methyltetrahydro–2H–pyran–2–one (98e)

Ketone rac–94d (6 mg, 0.023 mmol, 1.0 eq.) was exposed to the conditions of general procedure F using NADPH (1.5 mg, 0.002 mmol, 0.08 eq.), GDH (1.5 mg, 3.04 x 10–5 mmol, 0.1 mol%), glucose (30 mg, 0.17 mmol, 6.3 eq.), CHMO (1.5 mg, 2.46 x 10–5 mmol, 0.09 mol%) and Tris/HCl buffer (2.7 mL, pH 7.0, 100 mM). The crude reaction mixture was analysed by 1H NMR, 2% conversion to product was observed, e.e. n.d. Data for racemic standard:

1 H NMR (400 MHz, CDCl3) δ 1.42 (s, 3H, CH3), 1.70–1.76 (m, 1H, CHaHbCH2CH2C(O)O), 1.83–

1.96 (m, 3H, CHaHbCH2CH2C(O)O + CH2CH2CH2C(O)O), 2.43–2.61 (m, 4H, CH2CH2CH2C(O)O) +

CH2CH=CHAr), 6.23 (dt, J = 15.8, 8.3 Hz, 1H, CH2CH=CHAr), 6.41 (d, J = 15.8 Hz, 1H,

CH2CH=CHAr), 7.18 (t, J = 7.8 Hz, 1H, ArCH), 7.27–7.29 (m, 1H, ArCH), 7.36 (d, J = 8.0 Hz, 1H,

13 ArCH), 7.52 (s, 1H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 16.6 (CH2CH2CH2C(O)O), 26.5

(CH3), 29.3 (CH2CH2CH2C(O)O), 31.8 (CH2CH2CH2C(O)O), 45.4 (CH2CH=CHAr), 83.8 (C), 127.8

(ArCBr), 124.9 (CH2CH=CHAr), 125.5 (ArCH), 129.1 (ArCH), 130.1 (ArCH), 130.3 (ArCH) 132.9

131

–1 (CH2CH=CHAr), 139.1 (ArC), 171.0 (C(O)O) ppm; IR νmax (thin film, cm ): 2933, 1710 (C=O),

+ 1469, 1440, 1333, 1290, 1101, 1017; HRMS calcd. for C15H17O2BrNa [M+Na] 331.0304, found 331.0306.

(R,E)–6–(3–(2–Chlorophenyl)allyl)–6–methyltetrahydro–2H–pyran–2–one (98f)[36]

Prepared according to general procedure F using rac–94e (1 mg, 0.006 mmol, 1.0 eq.) in EtOH (50 µL), NADPH (0.25 mg, 3.36 x 10–4 mmol, 0.08 eq.), GDH (0.25 mg, 5.08 x 10–6 mmol, 0.1 mol%), glucose (0.5 mg, 0.003 mmol, 6.3 eq.), CHMO (0.25 mg, 4.10 x 10–6 mmol, 0.09 mol%) and Tris/HCl buffer (450 µL, pH 7.0, 100 mM). The reaction mixture was extracted

1 with EtOAc (500 µL) and analysed directly by GC. H NMR (400 MHz, CDCl3) δ 1.43 (s, 3H,

CH3), 1.70–1.76 (m, 1H, CHaHbCH2CH2C(O)O), 1.83–1.96 (m, 3H, CHaHbCH2CH2C(O)O +

CH2CH2CH2C(O)O), 2.43–2.63 (m, 4H, CH2CH2CH2C(O)O) + CH2CH=CHAr), 6.19 (dt, J = 15.8,

7.8 Hz, 1H, CH2CH=CHAr), 6.85 (d, J = 15.8 Hz, 1H, CH2CH=CHAr), 7.16–7.24 (m, 2H, ArCH),

13 7.34 (d, J = 7.8 Hz, 1H, ArCH), 7.51 (d, J = 7.5 Hz, 1H, ArCH); C NMR (101 MHz, CDCl3) δ 16.6

(CH2CH2CH2C(O)O), 26.5 (CH3), 29.3 (CH2CH2CH2C(O)O), 31.8 (CH2CH2CH2C(O)O), 45.5

(CH2CH=CHAr), 83.8 (C), 126.8 (ArCH), 126.8 (ArCH), 126.9 (CH2CH=CHAr), 128.5 (ArCH),

129.6 (ArCH), 130.5 (CH2CH=CHAr), 132.7 (ArCCl), 135.1 (ArC) 171.1 (C(O)O) ppm. IR νmax (thin

–1 + film, cm ): 2917, 1721 (C=O), 1469, 1290, 1166, 1089; HRMS calcd. for C15H17O2ClNa [M+Na] 287.0809, found 287.0808.

Reaction conversion and enantiomeric purity of (R)–98f were determined by GC analysis in comparison with authentic racemic material (34% conversion, 86:14 e.r. shown, ChiraSil® DEX CB 25 m x 0.25 mm column, 50 °C to 200 °C at a rate of 1 °C min–1, flow rate 1.0 mL min–1).

132

rac–98f

Biotransformation

(R)–98f (R)– and (S)–94e

(E)–6–Methyl–6–(3–(4–(trifluoromethyl)phenyl)allyl)tetrahydro–2H–pyran–2–one (98g)

Ketone rac–94f (6 mg, 0.023 mmol, 1.0 eq.), was exposed to the conditions of general procedure F using NADPH (1.5 mg, 0.002 mmol, 0.08 eq.), GDH (1.5 mg, 3.04 x 10–5 mmol, 0.1 mol%), glucose (30 mg, 0.17 mmol, 6.3 eq.), CHMO (1.5 mg, 2.46 x 10–5 mmol, 0.09 mol%) and Tris/HCl buffer (2.7 mL, pH 7.0, 100 mM). The crude reaction mixture was analysed by 1H NMR, 4% conversion to product was observed, e.e. n.d. Data for racemic standard:

1 H NMR (400 MHz, CDCl3) δ 1.43 (s, 3H, CH3), 1.71–1.78 (m, 1H, CHaHbCH2CH2C(O)O), 1.83–

1.96 (m, 3H, CHaHbCH2CH2C(O)O + CH2CH2CH2C(O)O), 2.43–2.65 (m, 4H, CH2CH2CH2C(O)O) +

CH2CH=CHAr), 6.33 (dt, J = 15.8, 7.5 Hz, 1H, CH2CH=CHAr), 6.51 (d, J = 15.8 Hz, 1H,

133

13 CH2CH=CHAr), 7.46 (d, J = 8.0 Hz, 2H, ArCH), 7.56 (d, J = 8.3 Hz, 2H, ArCH); C NMR (101 MHz,

CDCl3) 16.6 (CH2CH2CH2C(O)O), 26.5 (CH3), 29.3 (CH2CH2CH2C(O)O), 31.9 (CH2CH2CH2C(O)O),

45.5 (CH2CH=CHAr), 83.7 (C), 125.5 (q, J = 271.9 Hz, ArCCF3), 125.6 (q, J = 3.9 Hz, ArCH), 126.4

(ArCH), 126.8 (CH2CH=CHAr), 129.4 (q, J = 32.5 Hz, CF3), 133.0 (CH2CH=CHAr), 140.4 (ArC),

19 –1 171.0 (C(O)O) ppm; F NMR (376 MHz, CDCl3) δ –62.5 ppm; IR νmax (thin film, cm ): 2925,

– 1721 (C=O), 1614, 1414, 1321, 1161, 1065; HRMS calcd. for C16H1O2F3 [M–H] 297.1108, found 297.1108.

(R,E)–6–Methyl–6–(3–(o–tolyl)allyl)tetrahydro–2H–pyran–2–one (98h)

Prepared according to general procedure F using rac–94g (1 mg, 0.006 mmol, 1.0 eq.) in EtOH (50 µL), NADPH (0.25 mg, 3.36 x 10–4 mmol, 0.08 eq.), GDH (0.25 mg, 5.08 x 10–6 mmol, 0.1 mol%), glucose (0.5 mg, 0.003 mmol, 6.3 eq.), CHMO (0.25 mg, 4.10 x 10–6 mmol, 0.09 mol%) and Tris/HCl buffer (450 µL, pH 7.0, 100 mM). The reaction mixture was extracted

1 with EtOAc (500 µL) and analysed directly by GC. H NMR (400 MHz, CDCl3) δ 1.44 (s, 3H,

CH3), 1.57–1.76 (m, 1H, CHaHbCH2CH2C(O)O), 1.85–1.94 (m, 3H, CHaHbCH2CH2C(O)O +

CH2CH2CH2C(O)O), 2.35 (s, 3H, ArCCH3), 2.43–2.62 (m, 4H CH2CH2CH2C(O)O) + CH2CH=CHAr),

6.07 (dt, J = 15.7, 7.5 Hz, 1H, CH2CH=CHAr), 6.69 (d, J = 15.7 Hz, 1H, CH2CH=CHAr), 7.14–7.18

13 (m, 3H, ArCH), 7.39–7.44 (m, 1H, ArCH); C NMR (101 MHz, CDCl3) 16.6 (CH2CH2CH2C(O)O),

19.8 (ArCCH3), 26.6 (CH3), 29.4 (CH2CH2CH2C(O)O), 31.7 (CH2CH2CH2C(O)O), 45.7

(CH2CH=CHAr), 84.0 (C), 125.2 (CH2CH=CHAr), 125.7 (ArCH), 126.1 (ArCH), 127.4 (ArCH),

130.3 (ArCH), 132.3 (CH2CH=CHAr), 135.1 (ArC), 136.2 (ArC), 171.2 (C(O)O) ppm; IR νmax (thin

–1 film, cm ): 2917, 1735 (C=O), 1685, 1293, 1256, 1088, 1053; HRMS calcd. for C16H20O2Na [M+Na]+ 267.1356, found 267.1349.

Reaction conversion and enantiomeric purity of (R)–98h were determined by GC analysis in comparison with authentic racemic material (39% conversion, 94:6 e.r. shown, ChiraSil® DEX CB 25 m x 0.25 mm column, 50 °C to 200 °C at a rate of 1 °C min–1, flow rate 1.0 mL min–1).

134

Racemic starting material rac–94g

Biotransformation

(R)–98h (R)– and (S)–94g

Allyl 2-oxocycloheptane-1-carboxylate (S2)[135]

To a suspension of NaH (2.7 g, 67 mmol, 2.5 eq.) in THF (35 mL) at 0 °C was added a solution of cycloheptanone (3.0 g, 27 mmol, 1.0 eq.) in THF (8 mL) dropwise over 15 minutes. The reaction was warmed to room temperature and diallyl carbonate (5.8 mL, 40 mmol, 1.5 eq.) was added and the reaction was stirred for 19 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (30 mL) and HCl was added until a pH of ~4 was reached. The

135 aqueous layers were extracted with EtOAc (7 x 50 mL), dried (MgSO4) and concentrated. The resulting crude product was used in the following step without further purification.

Allyl 1-methyl-2-oxocycloheptane-1-carboxylate (S3)[135]

To a suspension of K2CO3 (7.4 g, 54 mmol, 2.0 eq.) in acetone (36 mL) was added the crude product allyl 2-oxocycloheptane-1-carboxylate S2. Methyl iodide (3.3 mL, 54 mmol, 2.0 eq.) was added, the reaction was heated to 50 °C and stirred for 16 h. The reaction was cooled to room temperature and filtered and the solids were washed with acetone. The filtrate was concentrated and the crude product was used in the following step without further purification.

2-Allyl-2-methylcycloheptan-1-one (99)[135]

Prepared according to general procedure E using crude allyl 1-methyl-2-oxocycloheptane-1- carboxylate S3 (27 mmol, 1.0 eq.), Pd2(dba)3 (1.2 g, 1.3 mmol, 5 mol%) and PPh3 (1.4 g, 5.3 mmol, 20 mol%). Purification by Kugelrohr distillation (85 °C, 1 mBar) yielded the title

1 product as a pale yellow oil (2.3 g, 14 mmol, 52%). H NMR (CDCl3, 400 MHz) δ 1.05 (s, 3H,

CH3), 1.33–1.42 (m, 1H, C(O)CCHaHb), 1.45–1.80 (m, 7H, 3 x CH2 + C(O)CHaHb), 2.18 (dd,

J = 13.7, 7.7 Hz, 1H, CHaHbCH=CH2), 2.26 (dd, J = 13.7, 7.3 Hz, 1H, CHaHbCH=CH2), 2.40–2.48

(m, 1H, C(O)CHaHb), 2.61 (td, J = 11.0, 2.4 Hz, 1H, C(O)CHaHb), 4.98–5.10 (m, 2H, CH=CH2),

13 5.72 (ddt, J = 17.5, 10.2, 7.5 Hz, 1H, CH=CH2) ppm; C NMR (CDCl3, 101 MHz) δ 22.3 (CH3),

24.5 (CH2), 26.5 (CH2), 30.4 (CH2), 36.5 (C(O)CCH2), 40.6 (C(O)CH2), 43.6 (CH2CH=CH2), 50.9

(Cq), 117.9 (CH=CH2), 133.5 (CH=CH2), 217.2 (C(O)) ppm. Data is consistent with literature.

136

2–Methyl–2–((3–phenyloxiran–2–yl)methyl)cyclohexan–1–one (101) and 7–Methyl–7– ((3–phenyloxiran–2–yl)methyl)oxepan–2–one (102)

To a solution of ketone rac–93a (150 mg, 0.67 mmol, 1.0 eq.) and NaHCO3 (110 mg, 1.3 mmol,

2.0 eq.) in CH2Cl2 (2.5 mL) was added a solution of mCPBA (77%, 168 mg, 0.73 mmol, 1.1 eq.) in CH2Cl2 (2.5 mL). The reaction was stirred at room temperature for 15 h, then saturated aqueous NaHCO3 (5 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 x 5 mL), the organic extracts were combined, dried (MgSO4) and concentrated. The crude product mixture was purified by silica gel column chromatography (hexane/EtOAc 95:5) to yield a mixture of lactone and epoxide products.

2–Methyl–2–((3–phenyloxiran–2–yl)methyl)cyclohexan–1–one 101 was isolated as a colourless oil and as an 0.4:1 mixture of diastereoisomers (8 mg, 0.032 mmol, 6%). 1H NMR

(500 MHz, CDCl3) δ 1.24 (s, 3H, CH3 from major diastereoisomer), 1.28 (s, 3H, CH3 from minor diastereoisomer), 1.76–1.93 (m, 10.8H, CH2CH2CH2CH2C(O) from major diastereoisomer +

CH2CH2CH2CH2C(O) from major diastereoisomer + CH2CH2CH2CH2C(O) from major diastereoisomer + CH2CH(O)CH from major diastereoisomer + CH2CH2CH2CH2C(O) from minor diastereoisomer + CH2CH2CH2CH2C(O) from minor diastereoisomer +

CH2CH2CH2CH2C(O) from minor diastereoisomer + CHaHbCH(O)CH from minor diastereoisomer), 1.99 (dd, J = 14.4, 5.2 Hz, 0.4H, CHaHbCH(O)CH from minor diastereoisomer), 2.35–2.52 (m, 2.8H, CH2CH2CH2CH2C(O) from major diastereoisomer +

CH2CH2CH2CH2C(O) from minor diastereoisomer), 2.96–3.00 (m, 1.4H, CH2CH(O)CH from major diastereoisomer + CH2CH(O)CH from minor diastereoisomer), 3.57 (d, J = 2.1 Hz, 0.4H,

CH2CH(O)CH from major diastereoisomer), 3.59 (m, 0.4H, CH2CH(O)CH from minor

13 diastereoisomer), 7.24–7.35 (m, 7H, ArCH) ppm; C NMR (126 MHz, CDCl3) δ 21.1

(CH2CH2CH2CH2C(O) from major + minor diastereoisomers), 22.8 (CH3 from minor diastereoisomer), 23.4 (CH3 from major diastereoisomer), 27.5 (CH2CH2CH2CH2C(O) from major + minor diastereoisomer), 38.5 (CH2CH2CH2CH2C(O) from minor diastereoisomer), 38.6

(CH2CH2CH2CH2C(O) from major diastereoisomer), 39.2 (CH2CH2CH2CH2C(O) from major diastereoisomer), 39.5 (CH2CH2CH2CH2C(O) from minor diastereoisomer), 40.6 (CH2CH(O)CH from minor diastereoisomer), 40.8 (CH2CH(O)CH from major diastereoisomer), 48.1 (C from

137 major + minor diastereoisomer), 58.4 (CH2CH(O)CH from minor diastereoisomer), 58.6

(CH2CH(O)CH from major diastereoisomer), 59.7 (CH2CH(O)CH from major diastereoisomer),

59.8 (CH2CH(O)CH from minor diastereoisomer), 125.5 (ArCH from major + minor diastereoisomers), 128.1 (ArCH from major + minor diastereoisomer), 128.4 (ArCH from major diastereoisomer), 128.5 (ArCH from minor diastereoisomer), 214.9 (C(O) from major

–1 + minor diastereoisomer) ppm; IR νmax (thin film, cm ): 2932, 2863, 1703 (C=O), 1500, 1312,

+ 1124; HRMS calcd. for C16H20O2K [M+K] 283.1095, found 283.1087.

7–Methyl–7–((3–phenyloxiran–2–yl)methyl)oxepan–2–one 102 was isolated as a colourless oil as an 0.5:1 mixture of diastereoisomers (43 mg, 0.17 mmol, 25%). 1H NMR (400 MHz,

CDCl3) δ 1.57 (s, 3H, CH3 from major diastereoisomer), 1.63 (s, 1.5H, CH3 from minor diastereoisomer), 1.60–1.72 (m, 1.5H, CH2CH2CHaHbCH2C(O)O from major diastereoisomer +

CH2CH2CHaHbCH2C(O)O from minor diastereoisomer), 1.78–2.02 (m, 8H,

CHaHbCH2CH2CH2C(O)O from major diastereoisomer + CH2CH2CH2CH2C(O)O from major diastereoisomer + CH2CH2CHaHbCH2C(O)O from major diastereoisomer + CHaHbCH(O)CH from major diastereoisomer + CH2CH2CH2CH2C(O)O from minor diastereoisomer +

CH2CH2CH2CH2C(O)O from minor diastereoisomer + CH2CH2CHaHbCH2C(O)O from minor diastereoisomer + CHaHbCH(O)CH from minor diastereoisomer), 2.05–2.17 (m, 2H,

CHaHbCH2CH2CH2C(O)O from major diastereoisomer + CHaHbCH(O)CH from major diastereoisomer), 2.24 (dd, J = 14.4, 4.2 Hz, 0.5H, CHaHbCH(O)CH from minor diastereoisomer), 2.64–2.82 (m, 3H, CH2CH2CH2CH2C(O)O from major diastereoisomer +

CH2CH2CH2CH2C(O)O from minor diastereoisomer), 3.19–3.24 (m, 1.5H, CH2CH(O)CH from major diastereoisomer + CH2CH(O)CH from minor diastereoisomer), 3.64–3.65 (m, 1.5H,

CH2CH(O)CH from major diastereoisomer + CH2CH(O)CH from minor diastereoisomer) 7.26–

13 7.37 (m, 7.5H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 23.3 (CH2CH2CH2CH2C(O)O from major

+ minor diastereoisomer), 23.8 (CH2CH2CH2CH2C(O)O from minor diastereoisomer), 23.9

(CH2CH2CH2CH2C(O)O from major diastereoisomer), 24.4 (CH3 from minor diastereoisomer),

25.2 (CH3 from major diastereoisomer), 37.3 (CH2CH2CH2CH2C(O)O from major diastereoisomer), 37.4 (CH2CH2CH2CH2C(O)O from minor diastereoisomer), 38.6

(CH2CH2CH2CH2C(O)O from major diastereoisomer), 39.5 (CH2CH2CH2CH2C(O)O from minor diastereoisomer), 45.6 (CH2CH(O)CH from minor diastereoisomer), 45.9 (CH2CH(O)CH from major diastereoisomer), 58.0 (CH2CH(O)CH from major diastereoisomer), 58.1 (CH2CH(O)CH from minor diastereoisomer), 58.8 (CH2CH(O)CH from major + minor diastereoisomer), 82.3 (C from major diastereoisomer), 82.4 (C from minor diastereoisomer), 125.6 (ArCH from major + minor diastereoisomer), 128.2 (ArCH from major + minor diastereoisomer), 128.5

138

(ArCH from major + minor diastereoisomer), 137.0 (ArC from major + minor diastereoisomer), 174.3 (C(O)O from minor diastereoisomer), 174.4 (C(O)O from major

–1 diastereoisomer) ppm; IR νmax (thin film, cm ): 2930, 1713 (C=O), 1453, 1353, 1288, 1170,

+ 1017; HRMS calcd. for C16H20O3K [M+K] 299.1044, found 299.1037.

(1S,6R,8S)–8–Benzyl–6–methyl–9–oxabicyclo[4.2.1]nonan–1–ol (104a)[37]

Prepared according to general procedure B using SmI2 (4.6 mL, 0.1 M in THF, 0.46 mmol,

8.0 eq.), H2O (0.82 mL, 46 mmol, 800 eq.) and lactone (R)–95b (14 mg, 0.057 mmol, 1.0 eq.), followed by Dess–Martin Periodinane (36 mg, 0.086 mmol, 1.5 eq.) in CH2Cl2. Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded the title product as a 72:28 mixture of diastereoisomers (10 mg, 0.041 mmol, 73%). The major diastereoisomer could be

1 isolated and was obtained as a colourless oil. H NMR (400 MHz, CDCl3) δ 1.28 (s, 3H, CH3),

1.56–1.92 (m, 9H, CH2CH2CH2CH2COH + CH2CH2CH2CH2COH + CH2CH2CH2CH2COH +

CH2CH2CH2CHaHbCOH + CH2CHCH2Ar), 2.17–2.33 (m, 2H, CH2CH2CH2CHaHbCOH + CHCH2Ar),

2.57 (t, J = 12.1 Hz, 1H, CHaHbAr), 3.01 (dd, J = 12.3, 1.3 Hz, 1H, CHaHbAr), 7.15–7.23 (m, 3H,

13 ArCH), 7.28–7.33 (m, 2H, ArCH); C NMR (101 MHz, CDCl3) 22.4 (CH2CH2CH2CH2COH), 25.0

(CH2CH2CH2CH2COH), 31.1 (CH3), 36.0 (CH2Ar), 37.8 (CH2CH2CH2CH2COH), 41.8

(CH2CH2CH2CH2COH), 42.9 (CH2CHCH2Ar), 51.8 (CHCH2Ar), 78.9 (CH3CO), 107.9 (OCOH), 126.0

26 (ArCH), 128.4 (ArCH), 128.6 (ArCH), 140.7 (ArC) ppm; Specific rotation [α]D +12.6 (c 0.47,

CHCl3) for an enantiomerically enriched sample of >99% e.e.

Enantiomeric purity of (1S,6R,8S)–104a was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown; Lux 5 μm Amylose–1 column, 95:5 hexanes:iPrOH, 0.5 mL min–1, 20 °C, 210 nm).

139

rac–104a

(1S,6R,8S)–104a

(1S,6R,8S)–8–(4–fluorobenzyl)–6–methyl–9–oxabicyclo[4.2.1]nonan–1–ol (104b)

Prepared according to general procedure B using lactone (R)–95c (9 mg, 0.034 mmol, 1.0 eq.), SmI2 (2.7 mL, 0.1 M in THF, 0.27 mmol, 8.0 eq.) and H2O (0.49 mL, 27 mmol, 800 eq.), followed by Dess–Martin Periodinane (22 mg, 0.051 mmol, 1.5 eq.) in CH2Cl2 (0.48 mL). Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded the title product as a 75:25 mixture of diastereoisomers (7.8 mg, 0.03 mmol, 87%). 1H NMR (400 MHz,

CDCl3) δ 1.28 (s, 3H, CH3), 1.63–1.86 (m, 9H, CH2CH2CH2CH2COH + CH2CH2CH2CH2COH +

CH2CH2CH2CH2COH + CH2CH2CH2CHaHbCOH + CH2CHCH2Ar), 2.04–2.28 (m, 2H,

CH2CH2CH2CHaHbCOH + CHCH2Ar), 2.53 (t, J = 12.4 Hz, 1H, CHaHbAr), 2.97 (d, J = 12.4 Hz, 1H,

13 CHaHbAr), 6.96–7.00 (m, 2H, ArCH), 7.14–7.17 (m, 2H, ArCH); C NMR (101 MHz, CDCl3) δ

22.5 (CH2CH2CH2CH2COH), 25.0 (CH2CH2CH2CH2COH), 31.2 (CH3), 35.2 (CH2Ar), 37.9

(CH2CH2CH2CH2COH), 41.9 (CH2CH2CH2CH2COH), 42.9 (CH2CHCH2Ar), 52.0 (CHCH2Ar), 78.6

140

(CH3CO), 107.6 (OCOH), 115.2 (d, J = 21.1 Hz, ArCH), 129.9 (d, J = 7.8 Hz, ArCH), 133.4 (ArC),

19 –1 ArCF not observed; F NMR (376 MHz, CDCl3) δ –117.4 ppm; IR νmax (thin film, cm ): 3384

(O–H), 2963, 2829, 1643, 1498, 1365, 1241, 1145, 1090; HRMS calcd. for C16H21O2FNa

+ 26 [M+Na] 278.1418, found 287.1404; Specific rotation [α]D +26.3 (c 0.12, CHCl3) for an enantiomerically enriched sample of >99% e.e.

Enantiomeric purity of (1S,6R,8S)–104b was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown; Lux 5 μm Amylose–1 column, 98:2 hexanes:iPrOH, 0.5 mL min–1, 20 °C, 210 nm).

rac–104b

(1S,6R,8S)–104b

(1S,6R,8S)–8–(2–Chlorobenzyl)–6–methyl–9–oxabicyclo[4.2.1]nonan–1–ol (104c)[37]

Prepared according to general procedure B using lactone (R)–95e (15 mg, 0.054 mmol,

1.0 eq.), SmI2 (4.3 mL, 0.1 M in THF, 0.43 mmol, 8.0 eq.) and H2O (0.77 mL, 43 mmol, 800 eq.),

141 followed by Dess–Martin Periodinane (34 mg, 0.081 mmol, 1.5 eq.) in CH2Cl2 (0.75 mL). Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded the title product as an 80:20 mixture of diastereoisomers (11 mg, 0.038 mmol, 70%). The major diastereoisomer could be isolated and was obtained as a pale yellow oil. 1H NMR (400 MHz,

CDCl3) δ 1.27 (s, 3H, CH3), 1.55–1.93 (m, 9H, CH2CH2CH2CH2COH + CH2CH2CH2CH2COH +

CH2CH2CH2CH2COH + CH2CH2CH2CHaHbCOH + CH2CHCH2Ar), 2.17–2.21 (m, 1H,

CH2CH2CH2CHaHbCOH), 2.32–2.38 (m, 1H, CHCH2Ar), 2.75 (dd, J = 13.2, 11.2 Hz, 1H, CHaHbAr),

3.12 (dd, J = 13.2, 3.9 Hz, 1H, CHaHbAr), 7.15–7.26 (m, 3H, ArCH), 7.36 (dd, J = 7.5, 1.5 Hz, 1H,

13 ArCH); C NMR (101 MHz, CDCl3) δ 22.4 (CH2CH2CH2CH2COH), 25.1 (CH2CH2CH2CH2COH), 31.1

(CH3), 33.2 (CH2Ar), 37.6 (CH2CH2CH2CH2COH), 41.8 (CH2CH2CH2CH2COH), 42.2 (CH2CHCH2Ar),

50.4 (CHCH2Ar), 78.6 (CH3CO), 107.7 (OCOH), 126.8 (ArCH), 127.6 (ArCH), 129.7 (ArCH), 130.6

26 (ArCH), 133.9 (ArCCl), 138.3 (ArC) ppm; Specific rotation [α]D –4.9 (c 0.8, CHCl3) for an enantiomerically enriched sample of >99% e.e.

Enantiomeric purity of (1S,6R,8S)–104c was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown; Lux 5 μm Amylose–1 column, 85:15 hexanes:iPrOH, 0.3 mL min–1, 20 °C, 210 nm).

rac–104c

(1S,6R,8S)–104c

142

(1S,5R,7S)–7–Benzyl–5–methyl–8–oxabicyclo[3.2.1]octan–1–ol (104d)[36]

Prepared according to general procedure B using lactone (R)–98b (15 mg, 0.065 mmol,

1.0 eq.), SmI2, (5.2 mL, 0.1 M in THF, 0.52 mmol, 8.0 eq.) and H2O (0.93 mL, 52 mmol,

800 eq.), followed by Dess–Martin Periodinane (41 mg, 0.098 mmol, 1.5 eq.) in CH2Cl2

(0.91 mL). Purification by silica gel column chromatography (CHCl3/Et2O 98:2 to hexane/EtOAc 95:5) yielded the title product as a 75:25 mixture of diastereoisomers (8.7 mg,

1 0.037 mmol, 58%). H NMR (400 MHz, CDCl3) δ 1.31 (s, 3H, CH3), 1.38 (dd, J = 13.2, 5.1 Hz,

1H, CHaHbCHCH2Ar), 1.51 (dd, J = 12.9, 7.5 Hz, 1H, CHaHbCHCH2Ar), 1.62–1.68 (m, 2H,

CH2CH2CHaHbCOH + CH2CHaHbCH2COH), 1.79–2.00 (m, 4H, CH2CH2CH2COH +

CH2CH2CHaHbCOH + CH2CHaHbCH2COH), 2.32–2.36 (m, 1H, CHCH2Ar), 2.67 (dd, J = 13.4,

11.7 Hz, 1H, CHaHbAr), 2.95 (dd, J = 13.6, 4.3 Hz, 1H, CHaHbAr), 7.19–7.23 (m, 3H, ArCH), 7.28–

13 7.32 (m, 2H, ArCH); C NMR (101 MHz, CDCl3) δ 19.0 (CH2CH2CH2COH), 27.2 (CH3), 31.5

(CH2CH2CH2COH), 34.8 (CH2Ar), 35.6 (CH2CHCH2Ar), 39.5 (CH2CH2CH2COH), 50.9 (CHCH2Ar),

79.3 (CH3CO), 104.5 (OCOH), 126.0 (ArCH), 128.5 (ArCH), 128.5 (ArCH), 140.9 (ArC) ppm;

26 Specific rotation [α]D +42.4 (c 0.24, CHCl3) for an enantiomerically enriched sample of >99% e.e.

Enantiomeric purity of (1S,6R,8S)–104d was determined by GC analysis in comparison with authentic racemic material (90:10 e.r. shown, Beta DEXTM 120 30 m x 0.25 mm column, 50 °C to 200 °C at a rate of 1 °C min–1, flow rate 1.0 mL min–1).

rac–104d * minor diastereoisomer

* *

143

(1S,5R,7S)–104d * minor diastereoisomer

* *

(1S,6R,8S)–6–Methyl–8–(4–(trifluoromethyl)benzyl)–9–oxabicyclo[4.2.1]nonan–1–ol (104e)[37]

Prepared according to general procedure B using lactone (R)–95d (13 mg, 0.042 mmol,

1.0 eq.), SmI2 (3.3 mL, 0.1 M in THF, 0.33 mmol, 8.0 eq.) and H2O (0.59 mL, 33 mmol 800 eq.), followed by Dess–Martin Periodinane (21 mg, 0.049 mmol, 1.5 eq.) in CH2Cl2 (0.8 mL). Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded the title product as an 86:14 mixture of diastereoisomers (10 mg, 0.032 mmol, 76%). 1H NMR

(400 MHz, CDCl3) δ 1.28 (s, 3H, CH3), 1.53–1.88 (m, 9H, CH2CH2CH2CH2COH +

CH2CH2CH2CH2COH + CH2CH2CH2CH2COH + CH2CH2CH2CHaHbCOH + CH2CHCH2Ar), 2.13–2.18

(m, 1H, CH2CH2CH2CHaHbCOH), 2.27–2.36 (m, 1H, CHCH2Ar), 2.61 (dd, J = 13.1, 11.3 Hz, 1H,

CHaHbAr), 3.06 (dd, J = 13.2, 3.6 Hz, 1H, CHaHbAr), 7.31–7.36 (m, 2H, ArCH), 7.54–7.56 (m, 2H,

13 ArCH); C NMR (101 MHz, CDCl3) δ 22.4 (CH2CH2CH2CH2COH), 25.0 (CH2CH2CH2CH2COH), 31.1

(CH3), 35.9 (CH2Ar), 37.9 (CH2CH2CH2CH2COH), 41.8 (CH2CH2CH2CH2COH), 42.7 (CH2CHCH2Ar),

51.5 (CHCH2Ar), 78.9 (CH3CO), 107.7 (OCOH), 125.4 (q, J = 2.9 Hz, ArCH), 128.9 (ArCH), 129.1

19 (q, J = 32.3 Hz, ArCCF3), 144.9 (ArC), ArCCF3 not observed; F NMR (376 MHz, CDCl3) δ –62.3

144

26 ppm; Specific rotation [α]D –27.7 (c 1.1, CHCl3) for an enantiomerically enriched sample of >99% e.e

Enantiomeric purity of (1S,6R,8S)–104e was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown; Chiralcel OD–H column, 99:1 hexanes:iPrOH, 0.25 mL min–1, 20 °C, 220 nm).

rac–104e

(1S,6R,8S)–104e

General procedure G: SmI2–HMPA–mediated radical ketone cyclisation

(1S,6S,8R)–8–Benzyl–6–methylbicyclo[4.2.0]octan–1–ol (106a)

To a solution of SmI2 (1.7 mL, 0.1 M in THF, 0.17 mmol, 3.0 eq.) was added degassed HMPA (0.12 mL, 0.68 mmol, 12 eq.) at –78°C to generate a deep purple solution. The solution was stirred for 5 minutes before a solution of ketone (S)–93a (13 mg, 0.056 mmol, 1.0 eq.) in THF was added slowly. The reaction was allowed to warm to room temperature and stirred until

145 decolourisation occurred. A saturated aqueous solution of Rochelle’s salt (2 mL) was added and the aqueous layer was extracted with Et2O (3 x 2 mL). The organic layers were combined and washed with 1 M HCl (2 x 5 mL), NaHCO3 (3 mL) and NaCl (3 mL), dried (MgSO4) and concentrated. Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded the title product as a single diastereoisomer and as a pale yellow oil (11 mg, 0.48 mmol, 84%).

1 H NMR (500 MHz, CDCl3) δ 1.11 (s, 3H, CH3), 1.22–1.28 (m, 1H, CHaHbCH2CH2CH2COH), 1.32–

1.44 (m, 5H, CHaHbCH2CH2CH2COH + CH2CHaHbCH2CH2COH + CH2CH2CHaHbCH2COH +

CH2CHCH2Ar), 1.55–1.63 (m, 2H, CH2CHaHbCH2CH2COH + CH2CH2CHaHbCH2COH), 1.68–1.71

(m, 1H, CH2CH2CH2CHaHbCOH), 1.82–1.88 (m, 1H, CH2CH2CH2CHaHbCOH), 2.41–2.48 (m, 1H,

CHCH2Ar), 2.59 (dd, J = 13.9, 9.1 Hz, 1H, CHCHaHbAr), 2.85 (dd, J = 13.9, 6.0 Hz, 1H,

13 CHCHaHbAr), 7.16–7.20 (m, 3H, ArCH), 7.26–7.29 (m, 2H, ArCH); C NMR (126 MHz, CDCl3)

δ 20.3 (CH2CH2CH2CH2COH), 22.1 (CH2CH2CH2CH2COH), 23.4 (CH3), 30.6 (CH2CHCH2Ar), 30.9

(CH2CH2CH2CH2COH), 33.5 (CH2CH2CH2CH2COH), 35.5 (CHCH2Ar), 40.3 (CCH3), 46.9

(CHCH2Ar), 74.9 (COH), 125.7 (ArCH), 128.3 (ArCH), 128.5 (ArCH), 141.4 (ArC); IR νmax (thin

–1 + film, cm ): 3427 (O–H), 3026, 2926, 1494, 1453, 1062 989; HRMS calcd. for C16H22OK [M+K]

26 269.1302, found 269.1300; Specific rotation [α]D +27.7 (c 1.4, CHCl3) for an enantiomerically enriched sample of >99% e.e.

The relative stereochemistry of the product was assigned by nOe analysis:

Enantiomeric purity of (1S,6S,8R)–106a was determined by HPLC analysis in comparison with authentic racemic material (>99:1 e.r. shown, Lux 5 μm Amylose–1 column, 80:20 hexanes:iPrOH, 1 mL min–1, 20 °C, 220 nm).

rac–106a

146

(1S,6S,8R)–106a

(1S,6S,8S)–8–(2–Chlorobenzyl)–6–methylbicyclo[4.2.0]octan–1–ol (106b)

Prepared according to general procedure G using (S)–93e (19 mg, 0.072 mmol, 1.0 eq.), SmI2 (2.2 mL, 0.1 M in THF, 0.22 mmol, 3.0 eq.) and HMPA (0.15 mL, 0.87 mmol, 12 eq.). Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded the title

1 product as a pale yellow oil (14 mg, 0.053 mmol, 73%). H NMR (500 MHz, CDCl3) δ 1.12 (s,

3H, CH3), 1.21–1.43 (m, 6H, CH2CH2CH2CH2COH + CH2CH2CH2CH2COH + CH2CH2CH2CH2COH),

1.59–1.65 (m, 2H, CH2CH2CH2CH2COH), 1.70–1.74 (m, 1H, CHaHbCHCH2Ar), 1.83–1.89 (m, 1H,

CHaHbCHCH2Ar), 2.50 (qd, J = 9.2, 5.6 Hz, 1H, CHCH2Ar), 2.72 (dd, J = 14.2, 9.2 Hz, 1H,

CHCHaHbAr), 2.98 (dd, J = 14.2, 5.6 Hz, 1H, CHCHaHbAr), 7.12 (td, J = 7.6, 1.8 Hz, 1H, ArCH), 7.17 (t, J = 7.6 Hz, 1H, ArCH), 7.27–7.27 (m, 1H, ArCH), 7.33 (d, J = 7.6 Hz, 1H, ArCH); 13C NMR

(126 MHz, CDCl3) δ 20.4 (CH2CH2CH2CH2COH), 22.1 (CH2CH2CH2CH2COH), 23.4 (CH3), 30.4

(CH2CH2CH2CH2COH), 30.9 (CH2CHCH2Ar), 32.8 (CHCH2Ar), 33.5 (CH2CH2CH2CH2COH), 40.5

(CCH3), 45.3 (CHCH2Ar), 74.9 (COH), 126.6 (ArCH), 127.1 (ArCH), 129.4 (ArCH), 130.4 (ArCH),

–1 133.8 (ArCCl), 138.9 (ArC) ppm; IR νmax (thin film, cm ): 3430 (O–H), 2950, 2848, 1495, 1452,

+ 1077, 1020; HRMS calcd. for C16H21OClNa [M+Na] 287.1173, found 287.1167; Specific

27 rotation [α]D –30.7 (c 0.4, CHCl3) for an enantiomerically enriched sample of 74% e.e.

Enantiomeric purity of (1S,6S,8S)–106b was determined by HPLC analysis in comparison with authentic racemic material (87:13 e.r. shown, Lux 5 μm Amylose–1 column, 95:5 hexanes:iPrOH, 1 mL min–1, 20 °C, 220 nm).

147

rac–106b

(1S,6S,8R)–106b

(1S,5S,7R)–7–Benzyl–5–methylbicyclo[3.2.0]heptan–1–ol (106c)

Prepared according to general procedure G using (S)–94a (18 mg, 0.084 mmol, 1.0 eq.), SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol, 3.0 eq.) and HMPA (0.18 mL, 1.0 mmol, 12 eq.). Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded the title product as a

1 colourless oil (12 mg, 0.056 mmol, 66%). H NMR (400 MHz, CDCl3) δ 1.13 (s, 3H, CH3), 1.39–

1.64 (m, 5H, CH2CH2CH2COH + CH2CH2CH2COH + CHaHbCHCH2Ar), 1.65–1.84 (m, 2H,

CH2CH2CH2COH), 2.24 (dd, J = 13.4, 6.6 Hz, 1H, CHaHbCHCH2Ar), 2.46–2.55 (m, 1H, CHCH2Ar),

2.60 (dd, J = 13.6, 9.6 Hz, 1H, CHCHaHbAr), 2.86 (dd, J = 13.6, 5.6 Hz, 1H, CHCHaHbAr), 7.16–

13 7.21 (m, 3H, ArCH), 7.25–7.30 (m, 2H, ArCH); C NMR (101 MHz, CDCl3) δ 19.9 (CH3), 23.5

(CH2CH2CH2COH), 31.4 (CH2CH2CH2COH), 35.5 (CHCH2Ar), 35.6 (CH2CHCH2Ar), 38.3

(CH2CH2CH2COH), 44.2 (CHCH2Ar), 46.0 (CCH3), 83.7 (COH), 125.7 (ArCH), 128.3 (ArCH), 128.5

–1 (ArCH), 140.9 (ArC) ppm; IR νmax (thin film, cm ): 3455 (O–H), 2927, 2857, 1453, 1442, 1157,

148

+ 1051, 1040; HRMS calcd. for C15H20OK [M+K] 255.1146, found 255.1139; Specific rotation

27 [α]D –49.9 (c 1.0, CHCl3) for an enantiomerically enriched sample of 70% e.e.

Enantiomeric purity of (1S,5S,7R)–106c was determined by HPLC analysis in comparison with authentic racemic material (85:15 e.r. shown, Lux 5 μm Amylose–1 column, 95:5 hexanes:iPrOH, 1 mL min–1, 20 °C, 220 nm).

rac–106c

(1S,5S,7R)–106c

149

6.6.3. Experimental Data for SmI2–Mediated 1,4–Ester Migration in Lactone Substrates

Dimethyl 2–(but–3–en–1–yl)malonate (108)[137]

To a suspension of sodium hydride (1.1 g, 26 mmol, 1.2 eq.) in THF (90 mL) at 0 °C was added dropwise dimethyl malonate (3.0 mL, 26 mmol, 1.2 eq.). After stirring at this temperature for 30 minutes, 4–bromo–1–butene (2.2 mL, 22 mmol, 1.0 eq.) was added dropwise. The mixture was then heated to 67 °C for 19 h, and was then quenched by the addition of H2O (20 mL).

The mixture was diluted with Et2O (200 mL) and the organics were washed with H2O (50 mL) and brine (50 mL), dried (MgSO4) and concentrated. Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded the title product as a yellow oil (2.6 g,

1 14 mmol, 53%). H NMR (500 MHz, CDCl3) δ 1.98–2.06 (m, 2H, CHCH2CH2), 2.10 (t, J = 6.9 Hz,

2H, CHCH2CH2), 3.41 (t, J = 7.3 Hz, 1H, CHCO2Me), 3.75 (s, 6H, CO2CH3), 4.98–5.09 (m, 2H,

13 CH=CH2), 5.77 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H, CH=CH2) ppm; C NMR (101 MHz, CDCl3) δ 27.9

(CHCH2CH2), 31.2 (CHCH2CH2), 50.9 (CHCH2CH2), 52.5 (CO2CH3), 116.0 (CH2CH=CH2), 136.7

(CH2CH=CH2), 169.8 (CO2CH3) ppm. Data is consistent with literature.

General Procedure H: Michael Addition

Dimethyl 2–(but–3–en–1–yl)–2–(3–oxobutyl)malonate (109)[138]

To a suspension of sodium methoxide (0.35 g, 6.4 mmol, 1.2 eq.) in MeOH (6 mL) was added dimethyl 2–(but–3–en–1–yl)malonate 108 (1.0 g, 5.4 mmol, 1.0 eq.) in MeOH (5 mL). The mixture was stirred for 10 minutes and then methyl vinyl ketone (0.54 mL, 6.4 mmol, 1.2 eq.) was added. The reaction was stirred at room temperature for 16 h, then was quenched with

H2O (10 mL) and the organic solvent was removed under vacuum. The aqueous layer was

150 extracted with EtOAc (3 x 20 mL) and the organic layers were washed with brine (20 mL), dried (MgSO4) and concentrated. Purification by silica gel column chromatography (hexane/EtOAc 9:1 to 8:2) yielded the title product as a yellow oil (0.97 g, 3.8 mmol, 70%).

1 H NMR (500 MHz, CDCl3) δ 1.94–2.01 (m, 4H, CH2CH=CH2 + C(O)CH2CH2), 2.15 (s, 3H,

C(O)CH3), 2.16–2.20 (m, 2H, CH2CH2CH=CH2), 2.45 (dd, J = 8.8, 6.8 Hz, 2H, C(O)CH2), 3.73 (s,

6H, CO2CH3), 4.98 (dd, J = 10.0, 1.7 Hz, 1H, CH=CHaHb), 5.04 (dd, J = 17.1, 1.7 Hz, 1H,

13 CH=CHaHb), 5.71–5.81 (m, 1H, CH=CH2) ppm; C NMR (126 MHz, CDCl3) δ 26.7 (C(O)CH2CH2),

28.4 (CH2CH=CH2), 30.0 (C(O)CH3), 32.8 (C(O)CH2), 38.7 (CH2CH2CH=CH2), 52.5 (CO2CH3), 56.6

(Cq), 115.3 (CH=CH2), 137.2 (CH=CH2), 171.7 (CO2CH3), 207.2 (C(O)) ppm. Data is consistent with literature.

General Procedure I: Ketone reduction followed by lactonisation

Rac–Methyl (3R,6S)–3–(but–3–en–1–yl)–6–methyl–2–oxotetrahydro–2H–pyran–3– carboxylate (111)

To a solution of samarium diiodide (4.9 mL, 0.1 M in THF, 0.49 mmol, 2.5 eq.) and deionised water (0.88 mL, 49 mmol, 250 eq.) in THF was added a solution of dimethyl 2–(but–3–en–1– yl)–2–(3–oxobutyl)malonate 109 (50 mg, 0.20 mmol, 1.0 eq.) in THF (1 mL). The mixture was stirred at room temperature until decolourisation occurred, and then Rochelle’s saturated aqueous solution (5 mL) was added. The aqueous layer was extracted with Et2O (3 x 5 mL), the combined organic layers were washed with brine (5 mL), dried (MgSO4) and concentrated. The crude reaction mixture was dissolved in CH2Cl2 (4 mL) and para– toluenesulfonic acid (4 mg, 0.02 mmol, 10 mol%) was added. The mixture was stirred at room temperature for 16 h, then NaHCO3 (1 mL) was added. The aqueous layer was extracted with

CH2Cl2 (3 x 3 mL), the combined organic layers were dried (MgSO4) and concentrated. Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a 3.8:1 mixture of diastereoisomers (33 mg, 0.15 mmol, 75%). The major

1 diastereoisomer could be isolated and was obtained as a yellow oil. H NMR (500 MHz, CDCl3)

δ 1.37 (d, J = 6.2 Hz, 3H, CHCH3), 1.59–1.69 (m, 1H, CO2CHCHaHb), 1.80 (ddd, J = 13.9, 8.3, 5.1

Hz, 1H, CO2CHCH2CHaHb), 1.89–2.18 (m, 5H, CO2CHCHaHb + CH2CH2CH=CH2 + CH2CH2CH=CH2),

2.53 (dt, J = 13.9, 8.0 Hz, 1H, CO2CHCH2CHaHb), 3.78 (s, 3H, CO2CH3), 4.31-4.38 (m, 1H, CO2CH),

151

4.99 (d, J = 10.6 Hz, 1H, CH=CHaHb), 5.05 (dd, J = 16.3, 1.7 Hz, 1H, CH=CHaHb), 5.79 (ddt, J =

13 16.3, 10.6, 5.8 Hz, 1H, CH=CH2) ppm; C NMR (126 MHz, CDCl3) δ 21.4 (CHCH3), 26.9

(CO2CHCH2CH2), 27.7 (CO2CHCH2), 28.7 (CH2CH2CH=CH2), 35.6 (CH2CH2CH=CH2), 52.8 (Cq),

53.1 (CO2CH3), 74.8 (CO2CH), 115.3 (CH=CH2), 137.3 (CH=CH2), 170.8 (CO2CH), 171.8 (CO2CH3)

-1 ppm; IR vmax (thin film, cm ) = 2957, 1714 (C=O), 1411, 1259, 1014; HRMS calcd. for

+ C12H18O4Na [M+Na] 249.1097, found 249.1088.

Rac–Methyl (S)–2–((S)–3–hydroxybutyl)–2–(hydroxymethyl)hex–5–enoate (114)

Prepared according to general procedure B using rac–methyl (3R,6S)–3–(but–3–en–1–yl)–6– methyl–2–oxotetrahydro–2H–pyran–3–carboxylate 111 (21 mg, 0.093 mmol, 1.0 eq.), SmI2

(4.6 mL, 0.1 M in THF, 0.46 mmol, 5.0 eq.) and H2O (0.84 mL, 46 mmol, 500 eq.) in THF. Purification by silica gel column chromatography (hexane/EtOAc 1:1) yielded the title

1 compound as a colourless oil (11 mg, 0.048 mmol, 51%). H NMR (500 MHz, CDCl3) δ 1.20 (d,

J = 6.3 Hz, 3H, CHCH3), 1.30–1.49 (m, 2H, CH(OH)CH2CH2), 1.58–1.72 (m, 3H, CH(OH)CHaHb +

CH2CH2CH=CH2), 1.75–1.91 (m, 1H, CH(OH)CHaHb), 1.94–2.06 (m, 2H, CH2CH=CH2), 3.62–3.82

(m, 6H, CO2CH3 + CHOH + CH2OH), 4.96 (d, J = 10.2 Hz, 1H, CH=CHaHb), 5.02 (dd, J = 17.0,

2.3 Hz, 1H, CH=CHaHb), 5.78 (ddt, J = 17.0, 10.2, 6.4 Hz, 1H, CH=CH2) ppm, OH not observed;

13 C NMR (126 MHz, CDCl3) δ 23.6 (CHCH3), 28.5 (CH2CH=CH2), 28.8 (CH(OH)CH2), 32.6

(CH2CH2CH=CH2), 33.2 (CH(OH)CH2CH2), 50.6 (Cq), 51.9 (CO2CH3), 64.7 (CH2OH), 68.3 (CHOH),

-1 114.8 (CH=CH2), 138.1 (CH=CH2), 176.8 (CO2CH3) ppm; IR vmax (thin film, cm ) = 3412 (O-H),

+ 1729 (C=O), 1652, 1260, 1089, 1017; HRMS calcd. for C12H22O4Na [M+Na] 253.1410, found 253.1400.

152

General Procedure J: Grubbs I Cross Metathesis

Dimethyl (E)–2–(4–phenylbut–3–en–1–yl)malonate (125)

To a solution of dimethyl 2–(but–3–en–1–yl)malonate 108 (3.3 g, 18 mmol, 1.0 eq.) and styrene (6.1 mL, 53 mmol, 3.0 eq.) in degassed CH2Cl2 (68 mL) was added Grubbs I catalyst (0.36 g, 0.44 mmol, 5 mol%). The reaction was heated to 35 °C for 18 h, then concentrated. Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 8:2), followed by stirring overnight with decolourising charcoal, yielded the title product as a brown oil (2.2 g,

1 8.3 mmol, 43%). H NMR (400 MHz, CDCl3) δ 2.10 (dt, J = 7.5, 6.8 Hz, 2H, CHCH2CH2), 2.20–

2.36 (m, 2H, CHCH2CH2), 3.45 (t, J = 7.5 Hz, 1H, CHCH2), 3.74 (s, 6H, CO2CH3), 6.16 (dt, J = 15.8, 6.8 Hz, 1H, CH=CHAr), 6.41 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.22 (ddd, J = 9.2, 5.0, 2.8 Hz, 1H,

13 ArCH), 7.28–7.38 (m, 4H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 28.4 (CHCH2CH2), 30.6

(CHCH2CH2), 50.9 (CHCH2CH2), 53.4 (CO2CH3), 126.0 (ArCH), 127.1 (ArCH), 128.5 (CH=CHAr),

-1 128.5 (ArCH), 131.4 (CH=CHAr), 137.1 (ArC), 169.8 (CO2CH3) ppm; IR vmax (thin film, cm )

+ = 2952, 1731 (C=O), 1434, 1252, 1196, 1152; HRMS calcd. for C15H18O4Na [M+Na] 285.1097, found, 285.1090.

Dimethyl (E)–2–(3–oxobutyl)–2–(4–phenylbut–3–en–1–yl)malonate (115a)

Prepared according to general procedure H using dimethyl (E)–2–(4–phenylbut–3–en–1– yl)malonate 125 (1.6 g, 6.1 mmol, 1.0 eq.), methyl vinyl ketone (0.61 mL, 7.3 mmol, 1.2 eq.) and sodium methoxide (0.40 g, 7.3 mmol, 1.2 eq.) in MeOH (12 mL). Purification by silica gel column chromatography (hexane/EtOAc 8:2) yielded the title product as a yellow oil (1.2 g,

1 3.6 mmol, 60%). H NMR (400 MHz, CDCl3) δ 1.96–2.05 (m, 4H, CH2CH2C(O)CH3 +

153

CH2CH2C(O)CH3), 2.11 (s, 3H, CH2CH2C(O)CH3), 2.12–2.21 (m, 2H, CH2CH2CH=CHAr), 2.45–

2.39 (m, 2H, CH2CH2CH=CHAr), 3.68 (s, 6H, CO2CH3), 6.10 (dt, J = 15.9, 6.5 Hz, 1H, CH=CHAr), 6.35 (d, J = 15.9 Hz, 1H, CH=CHAr), 7.12–7.18 (m, 1H, ArCH), 7.20–7.25 (m, 2H, ArCH), 7.25–

13 7.29 (m, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 26.7 (CH2CH2CH=CHAr), 27.7

(CH2CH2C(O)CH3), 30.0 (CH2CH2C(O)CH3), 33.2 (CH2CH2CH=CH), 38.7 (CH2CH2C(O)CH3), 52.5

(CO2CH3), 56.6 (Cq), 125.9 (ArCH), 127.1 (ArCH), 128.5 (ArCH), 128.9 (CH=CHAr), 130.6

-1 (CH=CHAr), 137.4 (ArC), 171.7 (CO2CH3), 207.1 (CH2CH2C(O)CH3) ppm; IR vmax (thin film, cm )

+ = 2929, 2853, 1729 (C=O), 1447, 1221, 965; HRMS calcd. for C19H24O5Na [M+Na] 355.1516, found 355.1509.

Rac–methyl (3R,6S)–6–methyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H– pyran–3–carboxylate (116a)

Prepared according to general procedure I using dimethyl (E)–2–(3–oxobutyl)–2–(4– phenylbut–3–en–1–yl)malonate 115a (1.0 g, 3.0 mmol, 1.0 eq.), SmI2 (76 mL, 0.1 M in THF,

7.6 mmol, 2.5 eq.) and H2O (14 mL, 760 mmol, 250 eq.) in THF, followed by pTSA (30 mg,

0.15 mmol, 5 mol%) in CH2Cl2 (35 mL). Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded the title product as a 3.2:1 mixture of diastereoisomers (606 mg, 2.0 mmol, 66%). The major diastereoisomer could be isolated and was obtained as

1 a colourless oil. H NMR (500 MHz, CDCl3) δ 1.38 (d, J = 6.2 Hz, 3H, CO2CHCH3), 1.65 (ddt,

J = 14.1, 10.3, 8.0 Hz, 1H, CO2CHCHaHb), 1.84 (ddd, J = 13.9, 8.2, 5.0 Hz, 1H, C(O)CCHaHb),

1.98–2.06 (m, 2H, CO2CHCHaHb + CHaHbCH2CH=CHAr), 2.16 (ddd, J = 13.5, 11.3, 4.7 Hz, 1H,

CHaHbCH2CH=CHAr), 2.19–2.27 (m, 1H, CH2CHaHbCH=CHAr), 2.27–2.36 (m, 1H,

CH2CHaHbCH=CHAr), 2.56 (dt, J = 13.9, 8.2 Hz, 1H, C(O)CCHaHb), 3.79 (s, 3H, CO2CH3), 4.36

(dqd, J = 10.3, 6.2, 3.7 Hz, 1H, CO2CH), 6.18 (dt, J = 15.8, 6.6 Hz, 1H, CH=CHAr), 6.42 (d, J = 15.9 Hz, 1H, CH=CHAr), 7.18–7.23 (m, 1H, ArCH), 7.28–7.35 (m, 4H, ArCH) ppm; 13C NMR

(126 MHz, CDCl3) δ 21.4 (CO2CHCH3), 27.0 (CO2CHCH2), 27.8 (C(O)CCH2), 28.0

(CH2CH2CH=CHAr), 36.1 (CH2CH=CHAr), 52.8 (CO2CH3), 53.1 (Cq), 74.8 (CO2CH), 126.0 (ArCH),

127.1 (ArCH), 128.5 (ArCH), 129.1 (CH=CHAr), 130.7 (CH=CHAr), 137.5 (ArC), 170.8 (CO2CH),

-1 171.8 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2207, 1732 (C=O), 1434, 1260, 1065, 985;

+ HRMS calcd. for C18H22O4Na [M+Na] 325.1410, found 325.1397.

154

Rac–methyl (1S,3S)–3–benzyl–1–(3–hydroxybutyl)–2–oxocyclopentane–1–carboxylate (117)

Prepared according to a modified version of general procedure B using SmI2 (1.7 mL, 0.1 M in THF, 0.17 mmol, 2.5 eq.), H2O (0.30 mL, 17 mmol, 250 eq.) and rac–methyl (3R,6S)–6– methyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H–pyran–3–carboxylate 116a (20 mg, 0.066 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 8:2) yielded the title product as a colourless oil, as a 7:1 mixture of

1 diastereoisomers (5 mg, 0.016 mmol, 29%). H NMR (500 MHz, CDCl3) δ 1.15 (d, J = 6.2 Hz,

3H, CHCH3), 1.25–1.44 (m, 2H, CH3CH(OH)CH2), 1.51–1.64 (m, 2H, C(O)CHCHaHb +

C(O)CHCH2CHaHb), 1.86–1.94 (m, 2H, C(O)CHCHaHb + CH3CH(OH)CH2CHaHb), 2.05–2.11 (m,

1H, CH3CH(OH)CH2CHaHb), 2.36 (ddd, J = 13.4, 10.3, 7.2 Hz, 1H, C(O)CHCH2CHaHb) 2.61–2.71

(m, 2H, CHCH2Ar + CHCHaHbAr), 3.13 (dd, J = 13.4, 3.8 Hz, 1H, CHCHaHbAr), 3.68–3.74 (m, 1H,

CHOH), 3.71 (s, 3H, CO2CH3), 7.16–7.18 (m, 2H, ArCH), 7.20–7.23 (m, 1H, ArCH), 7.27–7.30

13 (m, 2H, ArCH) ppm, OH not observed; C NMR (126 MHz, CDCl3) δ 23.4 (CHCH3), 25.2

(CH3CH(OH)CH2CH2), 29.0 (C(O)CHCH2), 30.7 (C(O)CHCH2CH2), 34.0 (CH3CH(OH)CH2), 35.5

(CH2Ar), 50.9 (C(O)CH), 52.6 (CO2CH3), 59.9 (Cq), 67.9 (CHOH), 126.4 (ArCH), 128.4 (ArCH),

-1 129.2 (ArCH), 139.3 (ArC), 172.1 (CO2CH3), 214.5 (C(O)) ppm; IR vmax (thin film, cm ) = 2953,

+ 1728 (C=O), 1433, 1222, 1174, 966; HRMS calcd. for C18H25O4 [M+H] 305.1747, found 305.1744.

Rac–Methyl (1S,3S)–3–benzyl–2–hydroxy–1–(3–hydroxybutyl)cyclopentane–1– carboxylate (118)

Prepared according to general procedure B using SmI2 (0.34 mL, 0.1 M in THF, 0.034 mmol,

5.0 eq.), H2O (0.60 mL, 33 mmol, 500 eq.) and rac–methyl (3R,6S)–6–methyl–2–oxo–3–((E)– 4–phenylbut–3–en–1–yl)tetrahydro–2H–pyran–3–carboxylate 116a (20 mg, 0.066 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 9:1 to 1:1) yielded the title product as a colourless oil (6 mg, 0.019 mmol, 30%) as a single diastereoisomer.

155

1 H NMR (400 MHz, CDCl3) δ 1.18 (d, J = 6.2 Hz, 3H, CH(OH)CH3), 1.27–1.44 (m, 2H,

CH2CH(OH)CH3), 1.64–1.82 (m, 4H, CH2CHCH2Ar + CHaHbCH2CH(OH)CH3 + CHaHbCH2CHCH2Ar),

1.94 (ddd, J = 13.4, 10.8, 4.0 Hz, 1H, CHaHbCH2CH(OH)CH3), 2.18–2.33 (m, 2H,

CHaHbCH2CHCH2Ar + CHCH2Ar), 2.69 (dd, J = 13.7, 7.9 Hz, 1H, CHaHbAr), 2.88 (dd, J = 13.7,

7.6 Hz, 1H, CHaHbAr), 3.66 (s, 3H, CO2CH3), 3.71–3.81 (m, 1H, CH(OH)CH3), 4.24 (d, J = 3.8 Hz, 1H, CCH(OH)), 7.16–7.27 (m, 4H, ArCH), 7.27–7.32 (m, 1H, ArCH) ppm, OH not observed;

13 C NMR (101 MHz, CDCl3) δ 23.9 (CH(OH)CH3), 27.8 (CH(OH)CHCH2), 30.3

(CH2CH2CH(OH)CH3), 32.4 (CH(OH)CHCH2CH2), 35.0 (CH2CH(OH)CH3), 35.9 (CH2Ar), 45.3

(CHCH2Ar), 51.9 (CO2CH3), 59.4 (Cq), 68.6 (CH(OH)CH3), 76.4 (CH(OH)C), 125.8 (ArCH), 128.3

-1 (ArCH), 128.7 (ArCH), 141.5 (ArC), 176.9 (CO2CH3) ppm; IR vmax (thin film, cm ) = 3079 (O-H),

+ 2961, 1257, 1083, 1014; HRMS calcd. for C18H26O4Na [M+Na] 329.1723, found 329.1712.

2–Benzyl–5–(hydroxymethyl)nonane–1,8–diol (120)

To a solution of LiAlH4 (0.16 mL, 1.0 M in Et2O, 0.16 mmol, 4.0 eq.) in THF (0.3 mL) at 0 °C was added a solution of rac–methyl (R)–2–benzyl–4–((3S,6S)–6–methyl–2–oxotetrahydro– 2H–pyran–3–yl)butanoate 119a (12 mg, 0.039 mmol, 1.0 eq.) in THF (0.3 mL). The reaction was allowed to warm to room temperature and was stirred for 2 h. The reaction was quenched by the addition of H2O (2 mL), the aqueous layer was extracted with EtOAc (3 x

2 mL), the combined organic layers were dried (MgSO4) and concentrated. Purification by silica gel column chromatography (EtOAc) yielded the title product as a colourless oil and as

1 a 1:1 mixture of diastereoisomers (6.5 mg, 0.023 mmol, 59%). H NMR (400 MHz, CDCl3) δ

1.19 (d, J = 6.1 Hz, 3H, CH3), 1.25–1.53 (m, 9H, 4 x CH2 + CHCH2OH), 1.71–1.85 (m, 1H,

CHCH2Ar), 2.55–2.71 (m, 2H, CH2Ar), 3.44–3.64 (m, 4H, 2 x CH2OH), 3.72–3.82 (m, 1H, CHOH), 7.14–7.24 (m, 3H, ArCH), 7.28–7.34 (m, 2H, ArCH), OH not observed; 13C NMR (101 MHz,

CDCl3) δ 23.6 (CH3 from one diastereoisomer), 23.7 (CH3 from one diastereoisomer), 26.7

(CH2CH2CH(OH)CH3 from one diastereoisomer), 26.9 (CH2CH2CH(OH)CH3 from one diastereoisomer), 27.3 (CH2CHCH2Ar from one diastereoisomer), 27.5 (CH2CHCH2Ar from one diastereoisomer), 27.6 (CH2CH2CHCH2Ar from one diastereoisomer), 27.9 (CH2CH2CHCH2Ar from one diastereoisomer), 36.1 (CH2CH(OH)CH3 from one diastereoisomer), 36.2

156

(CH2CH(OH)CH3 from one diastereoisomer), 37.7 (CH2Ar from one diastereoisomer), 37.8

(CH2Ar from one diastereoisomer), 40.5 (CHCH2OH), 42.6 (CHCH2Ar from one diastereoisomer), 42.8 (CHCH2Ar from one diastereoisomer), 64.4 (CH2(OH)CHCH2Ar from one diastereoisomer), 64.6 (CH2(OH)CHCH2Ar from one diastereoisomer), 64.9 (CH2OH from one diastereoisomer), 65.0 (CH2OH from one diastereoisomer), 68.3 (CH(OH)CH3 from one diastereoisomer), 68.5 (CH(OH)CH3 from one diastereoisomer), 125.9 (ArCH), 128.3 (ArCH),

-1 129.2 (ArCH), 140.7 (ArC); IR vmax (thin film, cm ) = 3314 (O-H), 2924, 1454, 1264, 1029,

+ 948; HRMS calcd. for C17H28O3Na [M+Na] 303.1931, found 303.1916.

Dimethyl (E)–2–(3–oxopentyl)–2–(4–phenylbut–3–en–1–yl)malonate (115b)

Prepared according to general procedure H using dimethyl (E)–2–(4–phenylbut–3–en–1– yl)malonate 125 (300 mg, 1.1 mmol, 1.0 eq.), 1–penten–3–one (0.14 mL, 1.4 mmol, 1.2 eq.) and sodium methoxide (74 mg, 1.4 mmol, 1.2 eq.) in MeOH (2.5 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1 to 8:2) yielded the title product as a colourless

1 oil (280 mg, 0.81 mmol, 71%). H NMR (500 MHz, CDCl3) δ 1.06 (t, J = 7.3 Hz, 3H, C(O)CH2CH3),

2.06 (dd, J = 11.1, 5.1 Hz, 2H, CH2CH2CH=CHAr), 2.11–2.17 (m, 2H, CH2CH2CH=CHAr), 2.23 (t,

J = 7.8 Hz, 2H, CH2CH2C(O)CH2CH3), 2.41–2.46 (m, 4H, CH2CH2C(O)CH2CH3 +

CH2CH2C(O)CH2CH3), 3.73 (s, 6H, CO2CH3), 6.16 (dt, J = 16.1, 6.5 Hz, 1H, CH=CHAr), 6.40 (d, J = 16.1 Hz, 1H, CH=CHAr), 7.21 (t, J = 7.2 Hz, 1H, ArCH), 7.27–7.36 (m, 4H, ArCH) ppm;

13 C NMR (126 MHz, CDCl3) δ 7.8 (C(O)CH2CH3), 26.8 (CH2CH2C(O)CH2CH3), 27.7

(CH2CH2CH=CHAr), 33.2 (CH2CH2CH=CHAr), 36.0 (CH2CH2C(O)CH2CH3), 37.3

(CH2CH2C(O)CH2CH3), 52.5 (CO2CH3), 56.7 (Cq), 126.0 (ArCH), 127.1 (ArCH), 128.5 (ArCH),

129.0 (CH=CHAr), 130.6 (CH=CHAr), 137.4 (ArC), 171.7 (CO2CH3), 209.87 (CH2CH2C(O)CH2CH3)

-1 ppm; IR vmax (thin film, cm ) = 3053, 2186, 1732 (C=O), 1651, 1435, 1083; HRMS calcd. for

+ C20H26O5Na [M+Na] 369.1672, found 369.1657.

157

General procedure K: Grignard addition followed by DMP oxidation

1–Cyclohexylprop–2–en–1–one (124a)[139]

To a solution of cyclohexanecarboxaldehyde (1.2 mL, 10 mmol, 1.0 eq.) in THF (25 mL) was added dropwise vinyl magnesium bromide (11 mL, 1.0 M in THF, 11 mmol, 1.1 eq.) at –78 °C. After the addition was complete, the reaction was allowed to warm to room temperature and was stirred for 3 h. The reaction was quenched by the addition of NH4Cl saturated aqueous solution (10 mL), the aqueous layer was extracted with Et2O (3 x 20 mL), the combined organic layers were washed with brine (20 mL), dried (MgSO4) and concentrated.

The crude reaction mixture was dissolved in CH2Cl2 (38 mL), cooled to 0 °C, and Dess–Martin Periodinane (5.1 g, 12 mmol, 1.2 eq.) was added. The reaction was warmed to room temperature and stirred for 3 h. A 1:1 mixture of saturated aqueous Na2S2O3 and NaHCO3 (40 mL) was added, and the mixture was allowed to stir overnight. The aqueous layer was extracted with CH2Cl2 (3 x 20 mL), the combined organic layers were dried (MgSO4) and carefully concentrated to avoid loss of the volatile product. The crude product was used in

1 the following step without further purification. H NMR (400 MHz, CDCl3) δ 1.25–1.44 (m, 5H,

2.5 x CyCH2), 1.62–1.90 (m, 5H, 2.5 x CyCH2), 2.56–2.67 (m, 1H, CyCH), 5.76 (d, J = 10.4 Hz,

1H, CH=CHaHb), 6.26 (d, J = 17.5 Hz, 1H, CH=CHaHb), 6.44 (dd, J = 17.5, 10.5 Hz, 1H, CH=CH2) ppm. Data is consistent with literature.

Dimethyl (E)–2–(3–cyclohexyl–3–oxopropyl)–2–(4–phenylbut–3–en–1–yl)malonate (115c)

Prepared according to general procedure H using dimethyl (E)–2–(4–phenylbut–3–en–1– yl)malonate 125 (157 mg, 0.60 mmol, 1.0 eq.), 1–cyclohexylprop–2–en–1–one 124a (100 mg, 0.6 mmol, 1.0 eq.) and sodium methoxide (39 mg, 0.72 mmol, 1.2 eq.) in MeOH (1.3 mL) at

158

65 °C. Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded the title

1 product as a pale yellow oil (87 mg, 0.22 mmol, 36%). H NMR (500 MHz, CDCl3) δ 1.14–1.41

(m, 5H, 2.5 x CyCH2), 1.64–1.71 (m, 1H, 0.5 x CyCH2), 1.74–1.87 (m, 4H, 2 x CyCH2), 2.03–2.09

(m, 2H, CH2CH2CH=CHAr), 2.11–2.15 (m, 2H, CH2CH2CH=CHAr), 2.17–2.23 (m, 2H,

CH2CH2C(O)), 2.33 (tt, J = 11.2, 3.4 Hz, 1H, CyCH), 2.46 (dd, J = 8.9, 6.7 Hz, 2H, CH2CH2C(O)), 6.15 (dt, J = 15.8, 6.6 Hz, 1H, CH=CHAr), 6.40 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.18–7.24 (m, 1H,

13 ArCH), 7.28–7.35 (m, 4H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 25.7 (CyCH2), 25.8 (CyCH2),

26.8 (CH2CH2C(O)), 27.8 (CH2CH2CH=CHAr), 28.5 (CyCH2), 33.2 (CH2CH2CH=CHAr), 35.6

(CH2CH2C(O)), 50.9 (CyCH), 52.5 (CO2CH3), 56.7 (Cq), 126.0 (ArCH), 127.1 (ArCH), 128.5 (ArCH),

129.0 (CH=CHAr), 130.6 (CH=CHAr), 137.4 (ArC), 171.8 (CO2CH3), 212.5 (C(O)) ppm;

-1 IR vmax (thin film, cm ) = 2933, 1729 (C=O), 1451, 1240, 1196, 1163, 1124, 1090; HRMS calcd.

+ for C24H32O5Na [M+Na] 423.2142, found 423.2131.

4–Methylpent–1–en–3–one (124b)[140]

Prepared according to general procedure K using isobutyraldehyde (0.91 mL, 10 mmol,

1.0 eq.) and vinyl magnesium bromide (11 mL, 1.0 M in THF, 11 mmol, 1.1 eq.) in Et2O (25 mL) followed by DMP (5.1 g, 12 mmol, 1.2 eq.) in CH2Cl2 (38 mL). The crude product was used in

1 the following step without further purification. H NMR (300 MHz, CDCl3) δ 1.14 (d, J = 6.9 Hz,

6H, CH(CH3)2), 2.90 (hept, J = 6.9 Hz, 1H, CH(CH3)2), 5.78 (dd, J = 10.4, 1.6 Hz, 1H CH=CHaHb),

6.28 (dd, J = 17.5, 1.4 Hz, 1H, CH=CHaHb), 6.45 (dd, J = 17.5, 10.3 Hz, 1H, CH=CH2) ppm. Data is consistent with literature.

Dimethyl (E)–2–(4–methyl–3–oxopentyl)–2–(4–phenylbut–3–en–1–yl)malonate (115d)

159

Prepared according to general procedure H using dimethyl (E)–2–(4–phenylbut–3–en–1– yl)malonate 125 (392 mg, 1.5 mmol, 1.0 eq.), 4–methylpent–1–en–3–one 124b (220 mg, 2.2 mmol, 1.5 eq.) and sodium methoxide (121 mg, 2.2 mmol, 1.5 eq.) in methanol (3.5 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title

1 product as a colourless oil (248 mg, 0.69 mmol, 46%). H NMR (500 MHz, CDCl3) δ 1.10 (d, J =

7.0 Hz, 6H, CH(CH3)2), 2.04–2.09 (m, 2H, CH2CH2CH=CHAr), 2.11–2.18 (m, 2H,

CH2CH2CH=CHAr), 2.19–2.25 (m, 2H, CH2CH2C(O)), 2.45–2.51 (m, 2H, CH2CH2C(O)), 2.60

(hept, J = 7.0 Hz, 1H, CH(CH3)2), 3.73 (s, 6H, CO2CH3), 6.16 (dt, J = 15.8, 6.6 Hz, 1H, CH=CHAr), 6.40 (CH=CHAr), 7.17–7.25 (m, 1H, ArCH), 7.29–7.37 (m, 4H, ArCH) ppm; 13C NMR (101 MHz,

CDCl3) δ 18.3 (CH(CH3)2), 26.9 (CH2CH2C(O)), 27.8 (CH2CH2CH=CHAr), 33.3 (CH2CH2CH=CHAr),

35.4 (CH2CH2C(O)), 41.0 (CH(CH3)2), 52.5 (CO2CH3), 56.7 (Cq), 126.0 (ArCH), 127.1 (ArCH),

128.5 (ArCH), 129.0 (CH=CHAr), 130.6 (CH=CHAr), 137.4 (ArC), 171.7 (CO2CH3), 213.2 (C(O))

-1 ppm; IR vmax (thin film, cm ) = 2951, 1728 (C=O), 1683, 1597, 1447, 1196, 1174, 967; HRMS

+ calcd. for C21H28O5Na [M+Na] 383.1829, found 383.1816.

4,4–Dimethylpent–1–en–3–one (124c)[141]

Prepared according to general procedure K using pivaldehyde (1.1 mL, 10 mmol, 1.0 eq.) and vinyl magnesium bromide (11 mL, 1.0 M in THF, 11 mmol, 1.1 eq.) in Et2O (25 mL) followed by DMP (5.1 g, 12 mmol, 1.2 eq.) in CH2Cl2 (38 mL). The crude product was used in the

1 following step without further purification. H NMR (400 MHz, CDCl3) δ 1.18 (s, 9H, C(CH3)3),

5.67 (d, J = 10.3 Hz, 1H, CH=CHaHb), 6.36 (d, J = 16.9 Hz, 1H, CH=CHaHb), 6.82 (dd, J = 16.9,

10.3 Hz, 1H, CH=CH2) ppm. Data is consistent with literature.

Dimethyl (E)–2–(4,4–dimethyl–3–oxopentyl)–2–(4–phenylbut–3–en–1–yl)malonate (115e)

160

Prepared according to a modified version of general procedure H using dimethyl (E)–2–(4– phenylbut–3–en–1–yl)malonate 125 (351 mg, 1.3 mmol, 1.0 eq.), 4,4–dimethylpent–1–en–

3–one 124c (226 mg, 2.0 mmol, 1.5 eq.) and K2CO3 (272 mg, 2.0 mmol, 1.5 eq.) in 1,4–dioxane (3.4 mL) at 100 °C. Purification by silica gel column chromatography (hexane/EtOAc 9:1)

1 yielded the title product as a yellow oil (415 mg, 1.1 mmol, 83%). H NMR (400 MHz, CDCl3)

δ 1.14 (s, 9H, C(CH3)3), 2.03–2.11 (m, 2H, CH2CH2CH=CHAr), 2.11–2.23 (m, 4H,

CH2CH2CH=CHAr + CH2CH2C(O)), 2.46–2.53 (m, 2H, CH2CH2C(O)), 3.73 (s, 6H, CO2CH3), 6.16 (dt, J = 15.8, 6.6 Hz, 1H, CH=CHAr), 6.40 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.17–7.23 (m, 1H,

13 ArCH), 7.27–7.36 (m, 4H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 26.4 (C(CH3)3), 27.4

(CH2CH2C(O)), 27.8 (CH2CH2CH=CHAr), 31.5 CH2CH2C(O)), 33.3 (CH2CH2CH=CHAr), 44.3

(C(CH3)3), 52.5 (CO2CH3), 56.8 (Cq), 126.0 (ArCH), 127.1 (ArCH), 128.5 (ArCH), 129.1

(CH=CHAr), 130.6 (CH=CHAr), 137.4 (ArC), 171.8 (CO2CH3), 214.6 (C(O)) ppm; IR vmax (thin

-1 film, cm ) = 2973, 1732 (C=O), 1694, 1434, 1202, 1178, 967; HRMS calcd. for C22H30O5Na [M+Na]+ 397.1985, found 397.1974.

1–Phenylbut–3–en–2–one (124d)[142]

Prepared according to general procedure K using phenylacetaldehyde (1.2 g, 10 mmol, 1.0 eq.) and vinyl magnesium bromide (11 mL, 1.0 M in THF, 11 mmol, 1.1 eq.) in THF (25 mL) followed by DMP (5.1 g, 12 mmol, 1.2 eq.) in CH2Cl2 (38 mL). The crude product was used in

1 the following step without further purification. H NMR (400 MHz, CDCl3) δ 3.89 (s, 2H,

CH2Ar), 5.84 (dd, J = 10.2, 1.4 Hz, 1H, CH=CHaHb), 6.31 (dd, J = 17.6, 1.4 Hz, 1H, CH=CHaHb),

6.42 (dd, J = 17.6, 10.3 Hz, 1H, CH=CH2), 7.20–7.37 (m, 5H, ArCH). Data is consistent with literature.

Dimethyl (E)–2–(3–oxo–4–phenylbutyl)–2–(4–phenylbut–3–en–1–yl)malonate (115f)

161

Prepared according to general procedure H using dimethyl (E)–2–(4–phenylbut–3–en–1– yl)malonate 125 (420 mg, 1.6 mmol, 1.0 eq.), 1–phenylbut–3–en–2–one 124d (240 mg, 1.6 mmol, 1.0 eq.) and sodium methoxide (106 mg, 2.0 mmol, 1.2 eq.) in MeOH (3.5 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title

1 product as a yellow oil (277 mg, 0.68 mmol, 41%). H NMR (400 MHz, CDCl3) δ 1.97–2.04 (m,

2H, CH2CH2CH=CHAr), 2.05–2.13 (m, 2H, CH2CH2CH=CHAr), 2.17–2.23 (m, 2H, CH2CH2C(O)),

2.49 (dd, J = 8.8, 6.8 Hz, 2H, CH2CH2C(O)), 3.68 (s, 6H, CO2CH3), 3.70 (s, 2H, C(O)CH2Ph), 6.12 (dt, J = 15.8, 6.5 Hz, 1H, CH=CHAr), 6.36 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.13–7.37 (m, 10H,

13 ArCH) ppm; C NMR (101 MHz, CDCl3) δ 26.8 (CH2CH2C(O)), 27.7 (CH2CH2CH=CHAr), 33.1

(CH2CH2CH=CHAr), 37.0 (CH2CH2C(O)), 50.1 (C(O)CH2Ph), 52.5 (CO2CH3), 56.6 (Cq), 126.0 (ArCH), 127.1 (ArCH), 128.5 (ArCH), 128.5 (ArCH), 128.8 (ArCH), 128.9 (CH=CHAr), 129.4

(ArCH), 130.6 (CH=CHAr), 134.0 (ArC), 137.4 (ArC), 171.6 (CO2CH3), 206.8 (C(O)) ppm; IR

-1 vmax (thin film, cm ) = 2949, 1729 (C=O), 1495, 1454, 1202, 1118, 1072; HRMS calcd. for

+ C25H28O5Na [M+Na] 431.1829, found 431.1818.

5,5–Dimethylhex–1–en–3–one (124e)[143]

Prepared according to general procedure K using 3,3–dimethyl butyraldehyde (1.3 mL, 10 mmol, 1.0 eq.) and vinyl magnesium bromide (11 mL, 1.0 M in THF, 11 mmol, 1.1 eq.) in

THF (25 mL) followed by DMP (5.1 g, 12 mmol, 1.2 eq.) in CH2Cl2 (38 mL). The crude product

1 was used in the following step without further purification. H NMR (400 MHz, CDCl3) δ 1.05

(s, 9H, C(CH3)3), 2.49 (s, 2H, CH2C(CH3)3), 5.78 (d, J = 10.5 Hz, 1H, CH=CHaHb), 6.20 (d, J =

17.5 Hz, 1H, CH=CHaHb), 6.38 (d, J = 17.5, 10.5 Hz, 1H, CH=CH2) ppm. Data is consistent with literature.

Dimethyl (E)–2–(5,5–dimethyl–3–oxohexyl)–2–(4–phenylbut–3–en–1–yl)malonate (115g)

162

Prepared according to general procedure H using dimethyl (E)–2–(4–phenylbut–3–en–1– yl)malonate 125 (300 mg, 1.1 mmol 1.0 eq.), 5,5–dimethylhex–1–en–3–one 124e (173 mg, 1.4 mmol, 1.2 eq.) and sodium methoxide (0.074 g, 1.4 mmol, 1.2 eq.) in methanol (2.3 mL).

Purification by silica gel column chromatography (hexane/EtOAc 9:1 to CH2Cl2) yielded the

1 title product as a colourless oil (176 mg, 0.52 mmol, 40%). H NMR (400 MHz, CDCl3) δ 1.01

(s, 9H, C(CH3)3), 1.99–2.09 (m, 2H, CH2CH2CH=CHAr), 2.09–2.44 (m, 4H, CH2CH2CH=CHAr +

CH2CH2C(O)), 2.30 (s, 2H, C(O)CH2C(CH3)3), 2.41 (dd, J = 9.1, 6.4 Hz, 2H, CH2CH2C(O)), 3.73 (s,

6H, CO2CH3), 6.15 (dt, J = 15.9, 6.3 Hz, 1H, CH=CHAr), 6.39 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.17–

13 7.24 (m, 1H, ArCH), 7.28–7.36 (m, 4H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 26.7

(CH2CH2C(O)), 27.8 (CH2CH2CH=CHAr), 29.7 (C(CH3)3), 31.0 (C(CH3)3), 33.2 (CH2CH2CH=CHAr),

40.0 (CH2CH2C(O)), 52.5 (CO2CH3), 55.0 (C(O)CH2(C(CH3)3), 56.6 (Cq), 126.0 (ArCH), 127.1

(ArCH), 128.5 (ArCH), 129.0 (CH=CHAr), 130.6 (CH=CHAr), 137.4 (ArC), 171.7 (CO2CH3), 209.2

-1 (C(O)) ppm; IR vmax (thin film, cm ) = 2951, 1732 (C=O), 1447, 1363, 1247, 1225, 1174,

+ 1074; HRMS calcd. for C23H32O5Na [M+Na] 411.2142, found 411.2129.

Dimethyl 2–(but–3–en–1–yl)–2–(3–oxopentyl)malonate (126)

Prepared according to general procedure H using dimethyl 2–(but–3–en–1–yl)malonate 108 (3.4 g, 18 mmol, 1.0 eq.), 1–penten–3–one (2.2 mL, 22 mmol, 1.2 eq.) and sodium methoxide (1.2 g, 22 mmol, 1.2 eq.) in methanol (57 mL). Purification by silica gel column chromatography (PE/EtOAc 9:1) yielded the title product as a colourless oil (2.6 g, 9.7 mmol,

1 53%). H NMR (400 MHz, CDCl3) δ 1.06 (t, J = 7.3 Hz, 3H, C(O)CH2CH3), 1.93–2.01 (m, 4H,

CH2CH2CH=CH2 + CH2CH2CH=CH2), 2.16–2.23 (m, 2H, CH2CH2C(O)), 2.38–2.48 (m, 4H,

CH2CH2C(O) + C(O)CH2CH3), 3.72 (s, 6H, CO2CH3), 4.95–5.09 (m, 2H, CH=CH2), 5.71–5.84 (m,

13 1H, CH=CH2) ppm; C NMR (101 MHz, CDCl3) δ 7.8 (C(O)CH2CH3), 26.8 (CH2CH2C(O)), 28.4

(CH2CH2CH=CH), 32.8 (CH2CH2CH=CH), 36.0 (C(O)CH2CH3), 37.3 (CH2CH2C(O)), 52.5 (CO2CH3),

-1 115.2 (CH=CH2), 137.3 (CH=CH2), 171.7 (CO2CH3), 209.9 (C(O)) ppm; IR vmax (thin film, cm )

+ = 2953, 1729 (C=O), 1641, 1455, 1111, 1048, 1021; HRMS calcd. for C14H22O5Na [M+Na] 293.1359, found 293.1346.

163

Dimethyl (E)–2–(4–(4–bromophenyl)but–3–en–1–yl)–2–(3–oxopentyl)malonate (127a)

Prepared according to general procedure J using dimethyl 2–(but–3–en–1–yl)–2–(3– oxopentyl)malonate 126 (300 mg, 1.1 mmol, 1.0 eq.), 4–bromostyrene (0.43 mL, 3.3 mmol,

3.0 eq.) and Grubbs I catalyst (45 mg, 0.055 mmol, 5 mol%) in CH2Cl2 (4 mL). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 9:1) yielded the title product as a

1 colourless oil (147 mg, 0.35 mmol, 31%). H NMR (500 MHz, CDCl3) δ 1.06 (t, J = 7.4 Hz, 3H,

C(O)CH2CH3), 2.03–2.08 (m, 2H, CH2CH2CH=CH), 2.13 (dd, J = 9.8, 5.9 Hz, 2H, CH2CH2CH=CH),

2.22 (dd, J = 8.8, 6.8 Hz, 2H, CH2CH2C(O)), 2.40–2.46 (m, 4H, C(O)CH2CH3 + CH2CH2C(O)), 3.72

(s, 6H, CO2CH3), 6.14 (dt, J = 15.9, 6.5 Hz, 1H, CH=CHAr), 6.33 (d, J = 15.9 Hz, 1H, CH=CHAr),

13 7.19 (d, J = 8.2 Hz, 2H, ArCH), 7.41 (d, J = 8.2 Hz, 2H, ArCH) ppm; C NMR (126 MHz, CDCl3) δ

7.8 (C(O)CH2CH3), 26.8 (CH2CH2C(O)), 27.7 (CH2CH2CH=CH), 33.1 (CH2CH2CH=CH), 36.0

(C(O)CH2CH3), 37.3 (CH2CH2C(O)), 52.5 (CO2CH3), 56.6 (Cq), 120.8 (ArCBr), 127.5 (ArCH), 129.5

(CH=CHAr), 129.9 (CH=CHAr), 131.6 (ArCH), 136.4 (ArC), 171.7 (CO2CH3), 209.9 (C(O)) ppm;

-1 IR vmax (thin film, cm ) = 2940, 2043, 1729 (C=O), 1435, 1265, 1194, 1130; HRMS calcd. for

+ C20H25O5BrNa [M+Na] 447.0778, found 477.0765.

Dimethyl (E)–2–(4–(naphthalen–2–yl)but–3–en–1–yl)–2–(3–oxopentyl)malonate (127b)

164

Prepared according to general procedure J using dimethyl 2–(but–3–en–1–yl)–2–(3– oxopentyl)malonate 126 (230 mg, 0.85 mmol, 1.0 eq.), 2–vinylnapthalene (394 mg,

2.6 mmol, 3.0 eq.) and Grubbs I catalyst (35 mg, 0.043 mmol, 5 mol%) in CH2Cl2 (3.5 mL). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 9:1) yielded the

1 title product as a yellow solid oil (153 mg, 0.39 mmol, 45%). H NMR (500 MHz, CDCl3) δ 1.06

(t, J = 7.5 Hz, 3H, C(O)CH2CH3), 2.08–2.14 (m, 2H, CH2CH2CH=CH), 2.19–2.27 (m, 4H,

CH2CH2C(O) + CH2CH2CH=CH), 2.42–2.47 (m, 4H, C(O)CH2CH3 + CH2CH2C(O)), 3.73 (s, 6H,

CO2CH3), 6.29 (dt, J = 15.8, 6.6 Hz, 1H, CH=CHAr), 6.56 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.39– 7.52 (m, 2H, ArCH), 7.56 (dd, J = 9.1, 1.6 Hz, 1H, ArCH), 7.67 (s, 1H, ArCH), 7.78 (dd, J = 10.6,

13 8.5 Hz, 3H, ArCH) ppm; C NMR (126 MHz, CDCl3) δ 7.8 (C(O)CH2CH3), 26.8 (CH2CH2C(O)),

27.9 (CH2CH2CH=CH), 33.2 (CH2CH2CH=CH), 36.0 (C(O)CH2CH3), 37.4 (CH2CH2C(O)), 52.5

(CO2CH3), 56.7 (Cq), 123.4 (ArCH), 125.6 (ArCH), 126.0 (ArCH), 126.2 (ArCH), 127.6 (ArCH), 127.9 (ArCH), 128.1 (ArCH), 129.5 (CH=CHAr), 130.8 (CH=CHAr), 132.8 (ArC), 133.7 (ArC),

-1 134.9 (ArC), 171.8 (CO2CH3), 209.9 (C(O)) ppm; IR vmax (thin film, cm ) = 3061, 2166, 1732

+ (C=O), 1274, 1090; HRMS calcd. for C24H28O5Na [M+Na] 419.1829, found 419.1818.

Dimethyl (E)–2–(4–(2–fluorophenyl)but–3–en–1–yl)–2–(3–oxopentyl)malonate (127c)

Prepared according to general procedure J using dimethyl 2–(but–3–en–1–yl)–2–(3– oxopentyl)malonate 126 (250 mg, 0.92 mmol, 1.0 eq.), 2–fluorostyrene (0.33 mL, 3.0 mmol,

3.0 eq.) and Grubbs I catalyst (38 mg, 0.046 mmol, 5 mol%) in CH2Cl2 (4 mL). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 9:1) yielded the title product as a

1 yellow oil (151 mg, 0.41 mmol, 45%). H NMR (500 MHz, CDCl3) δ 1.06 (t, J = 7.3 Hz, 3H,

C(O)CH2CH3), 2.02–2.10 (m, 2H, CH2CH2CH=CH), 2.13–2.20 (m, 2H, CH2CH2CH=CH), 2.23 (dd,

J = 8.9, 6.7 Hz, 2H, CH2CH2C(O)), 2.41–2.47 (m, 4H, C(O)CH2CH3 + CH2CH2C(O)), 3.73 (s, 6H,

CO2CH3), 6.24 (dt, J = 16.0, 6.6 Hz, 1H, CH=CHAr), 6.54 (d, J = 16.0 Hz, 1H, CH=CHAr), 7.01 (ddd, J = 10.9, 7.8, 1.2 Hz, 1H, ArCH), 7.07 (td, J = 7.8, 1.2 Hz, 1H, ArCH), 7.18 (m, 1H, ArCH),

13 7.40 (td, J = 7.8, 1.8 Hz, 1H, ArCH) ppm; C NMR (126 MHz, CDCl3) δ 7.8 (C(O)CH2CH3), 26.8

165

(CH2CH2C(O)), 28.2 (CH2CH2CH=CH), 33.1 (CH2CH2CH=CH), 36.0 (C(O)CH2CH3), 37.3

(CH2CH2C(O)), 52.5 (CO2CH3), 56.7 (Cq), 115.7 (d, J = 22.3 Hz, ArCH), 123.1 (CH=CHAr), 124.0 (d, J = 12.2 Hz, ArCH), 125.1 (d, J = 12.2 Hz, ArCH), 127.1 (CH=CHAr), 128.3 (d, J = 8.4 Hz,

ArCH), 131.8 (d, J = 4.8 Hz, ArC), 160.0 (d, J = 248.5 Hz, ArCF), 171.7 (CO2CH3), 209.9 (C(O))

19 -1 ppm; F NMR (376 MHz, CDCl3) δ –118.6 ppm; IR vmax (thin film, cm ) = 2952, 1730 (C=O),

+ 1487, 1455, 1227, 1194, 1090; HRMS calcd. for C20H25O5FNa [M+Na] 387.1578, found 387.1561.

Dimethyl (E)–2–(4–(4–methoxyphenyl)but–3–en–1–yl)–2–(3–oxopentyl)malonate (127d)

Prepared according to general procedure J using dimethyl 2–(but–3–en–1–yl)–2–(3– oxopentyl)malonate 126 (250 mg, 0.92 mmol, 1.0 eq.), 4–methoxystyrene (0.39 mL,

3.0 mmol, 3.0 eq.) and Grubbs I catalyst (38 mg, 0.046 mmol, 5 mol%) in CH2Cl2 (4 mL). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 9:1) yielded the

1 title product as a brown oil (171 mg, 0.45 mmol, 49%). H NMR (400 MHz, CDCl3) δ 1.06 (t,

J = 7.4 Hz, 3H, C(O)CH2CH3), 2.00–2.07 (m, 2H, CH2CH2CH=CH), 2.09–2.15 (m, 2H,

CH2CH2CH=CH), 2.18–2.26 (m, 2H, CH2CH2C(O)), 2.38–2.46 (m, 4H, C(O)CH2CH3 +

CH2CH2C(O)), 3.72 (s, 6H, CO2CH3), 3.81 (s, 3H, ArOCH3), 6.00 (dt, J = 15.8, 6.5 Hz, 1H, CH=CHAr), 6.34 (d, J = 15.8 Hz, 1H, CH=CHAr), 6.84 (d, J = 8.7 Hz, 2H, ArCH), 7.26 (d, J = 8.7 Hz,

13 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 7.8 (C(O)CH2CH3), 26.8 (CH2CH2C(O)), 27.7

(CH2CH2CH=CH), 33.3 (CH2CH2CH=CH), 36.0 (C(O)CH2CH3), 37.4 (CH2CH2C(O)), 52.5 (CO2CH3),

55.3 (ArOCH3), 56.7 (Cq), 114.0 (ArCH), 126.8 (CH=CHAr), 127.1 (ArCH), 130.0 (CH=CHAr),

-1 130.3 (ArC), 158.8 (ArCOCH3) 171.8 (CO2CH3), 210.0 (C(O)) ppm; IR vmax (thin film, cm ) =

+ 2951, 1729 (C=O), 1607, 1511, 1246, 1176, 1032; HRMS calcd. for C21H28O6Na [M+Na] 399.1778, found 399.1764.

166

Dimethyl (E)–2–(4–(3–chlorophenyl)but–3–en–1–yl)–2–(3–oxopentyl)malonate (127e)

Prepared according to general procedure J using dimethyl 2–(but–3–en–1–yl)–2–(3– oxopentyl)malonate 126 (400 mg, 1.5 mmol, 1.0 eq.), 3–chlorostyrene (0.56 mL, 4.4 mmol,

3.0 eq.) and Grubbs I catalyst (61 mg, 0.074 mmol, 5 mol%) in CH2Cl2 (7 mL). Purification by silica gel column chromatography (hexane/EtOAc 100:0 to 9:1) yielded the title product as a

1 colourless oil (169 mg, 0.43 mmol, 29%). H NMR (400 MHz, CDCl3) δ 1.06 (t, J = 7.4 Hz, 3H,

C(O)CH2CH3), 2.01–2.09 (m, 2H, CH2CH2CH=CH), 2.13–2.17 (m, 2H, CH2CH2CH=CH), 2.22 (dd,

J = 8.9, 6.6 Hz, 2H, CH2CH2C(O)), 2.38–2.48 (m, 4H, C(O)CH2CH3 + CH2CH2C(O)), 3.73 (s, 6H,

CO2CH3), 6.17 (dt, J = 15.8, 6.5 Hz, 1H, CH=CHAr), 6.34 (d, J = 16.0 Hz, 1H, CH=CHAr), 7.15–

13 7.25 (m, 3H, ArCH), 7.32 (t, J = 1.8 Hz, 1H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 7.8

(C(O)CH2CH3), 26.8 (CCH2CH2C(O)), 27.7 (CH2CH2CH=CH), 33.1 (CH2CH2CH=CH), 36.0

(C(O)CH2CH3), 37.3 (CH2CH2C(O)), 52.5 (CO2CH3), 56.6 (Cq), 124.2 (ArCH), 126.0 (ArCH), 127.1 (ArCH), 129.4 (CH=CHAr), 129.7 (ArCH), 130.7 (CH=CHAr), 134.5 (ArCCl), 139.3 (ArC), 171.7

-1 (CO2CH3), 209.9 (C(O)) ppm; IR vmax (thin film, cm ) = 3012, 1732 (C=O), 1435, 1254, 1197,

+ 1117; HRMS calcd. for C20H25O5ClNa [M+Na] 403.1283, found 403.1273.

Rac–methyl (3R,6S)–6–ethyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H– pyran–3–carboxylate (116b)

Prepared according to general procedure I using dimethyl (E)–2–(3–oxopentyl)–2–(4– phenylbut–3–en–1–yl)malonate 115b (200 mg, 0.58 mmol, 1.0 eq.), SmI2 (14 mL, 0.1 M in

THF, 1.4 mmol, 2.5 eq.), and H2O (2.60 mL, 144 mmol, 250 eq.) in THF, followed by pTSA

(5.5 mg, 0.029 mmol, 5 mol%) in CH2Cl2 (5 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a white solid, as a 7.3:1

167

1 mixture of diastereoisomers (107 mg, 0.34 mmol, 58%). H NMR (400 MHz, CDCl3) δ 1.00 (t,

J = 7.5 Hz, 3H, CH2CH3), 1.58–1.88 (m, 4H, CH2CH3 + CO2CHCHaHb + C(O)CCHaHb), 1.95–2.07

(m, 2H, CO2CHCHaHb + CHaHbCH=CHAr), 2.10–2.37 (m, 3H, CHaHbCH=CHAr +

CH2CH2CH=CHAr), 2.55 (dt, J = 13.9, 8.0 Hz, C(O)CCHaHb), 3.79 (s, 3H, CO2CH3), 4.12 (dddd, J =

10.7, 6.8, 5.5, 3.9 Hz, 0.89H, CO2CH from major diastereoisomer), 4.23–4.30 (m, 0.11H,

CO2CH from minor diastereoisomer), 6.18 (dt, J = 15.8, 6.6 Hz, 1H, CH=CHAr), 6.42 (d, J = 16.0 Hz, 1H, CH=CHAr), 7.18–7.24 (m, 1H, ArCH), 7.28–7.38 (m, 4H, ArCH) ppm; 13C NMR

(101 MHz, CDCl3) δ 9.4 (CH2CH3), 25.5 (CO2CHCH2), 27.1 (C(O)CCH2), 28.1 (CH2CH2CH=CHAr),

28.6 (CH2CH3), 36.0 (CH2CH=CHAr), 53.0 (Cq), 53.1 (CO2CH3), 79.8 (CO2CH), 126.0 (ArCH),

127.1 (ArCH), 128.5 (ArCH), 129.1 (CH=CHAr), 130.7 (CH=CHAr), 137.5 (ArC), 170.9 (CO2CH),

-1 171.8 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2956, 2170, 1728 (C=O), 1446, 1265, 1124;

+ HRMS calcd. for C19H24O4Na [M+Na] 339.1567, found 339.1557.

Rac–methyl (3R,6R)–6–cyclohexyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro– 2H–pyran–3–carboxylate (116c)

Prepared according to general procedure I using dimethyl (E)–2–(3–cyclohexyl–3– oxopropyl)–2–(4–phenylbut–3–en–1–yl)malonate 115c (80 mg, 0.20 mmol, 1.0 eq.), SmI2

(5.0 mL, 0.1 M in THF, 0.50 mmol, 2.5 eq.), and H2O (0.90 mL, 50 mmol, 250 eq.) in THF, followed by pTSA (2 mg, 0.010 mmol, 5 mol%) in CH2Cl2 (1 mL) to give the title product as a 5.7:1 mixture of diastereoisomers. Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product (55 mg, 0.15 mmol, 74%). The major

1 diastereoisomer could be isolated and was obtained as a yellow oil. H NMR (400 MHz, CDCl3)

δ 0.98–1.25 (m, 4H, 2 x CyCH2), 1.50–1.58 (m, 1H, CyCH), 1.63–1.86 (m, 7H, CO2CHCHaHb +

C(O)CCHaHb + 2.5 x CyCH2), 1.90–2.04 (m, 3H, CO2CHCHaHb + CHaHbCH2CH=CHAr + 0.5 x

CyCH2), 2.10–2.38 (m, 3H, CH2CH2CH=CHAr + CHaHbCH2CH=CHAr), 2.53 (dt, J = 13.6, 8.0 Hz,

1H, C(O)CCHaHb), 3.78 (s, 3H, CO2CH3), 3.93 (ddd, J = 10.5, 6.2, 3.8 Hz, 1H, CO2CH), 6.18 (dt, J = 15.8, 6.5 Hz, 1H, CH=CHAr), 6.42 (d, J = 15.9 Hz, 1H, CH=CHAr), 7.19–7.24 (m, 1H, ArCH),

13 7.28–7.35 (m, 4H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 23.0 (CyCH2), 25.7 (CyCH2), 25.9

(CyCH2), 26.3 (CyCH2), 27.3 (C(O)CCH2), 28.0 (CyCH2), 28.1 (CH2CH2CH=CHAr), 28.3

168

(CO2CHCH2), 36.0 (CH2CH2CH=CHAr), 42.3 (CyCH), 53.0 (CO2CH3), 53.0 (Cq), 82.6 (CO2CH), 126.0 (ArCH), 127.1 (ArCH), 128.5 (ArCH), 129.2 (CH=CHAr), 130.7 (CH=CHAr), 137.5 (ArC),

-1 171.0 (CO2CH), 171.8 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2925, 2853, 1729 (C=O), 1447,

+ 1234, 1175, 966; HRMS calcd. for C23H30O4Na [M+Na] 393.2036, found 393.2019.

Rac–methyl (3R,6R)–6–isopropyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H– pyran–3–carboxylate (116d)

Prepared according to general procedure I using dimethyl (E)–2–(4–methyl–3–oxopentyl)–

2–(4–phenylbut–3–en–1–yl)malonate 115d (200 mg, 0.55 mmol, 1.0 eq.), SmI2 (134 mL,

0.1 M in THF, 1.4 mmol, 2.5 eq.), and H2O (2.5 mL, 139 mmol, 250 eq.) in THF, followed by pTSA (5.2 mg, 0.028 mmol, 5 mol%) in CH2Cl2 (5 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a white solid, as a 5.3:1

1 mixture of diastereoisomers (130 mg, 0.39 mmol, 72%). H NMR (400 MHz, CDCl3) δ 0.96 (d,

J = 6.8 Hz, 3H, CH(CH3)CH3), 1.01 (d, J = 6.7 Hz, 3H, CH(CH3)CH3), 1.69 (ddt, J = 13.7, 11.0,

8.1 Hz, 1H, CO2CHCHaHb), 1.79–1.91 (m, 2H, CH(CH3)2 + C(O)CCHaHb), 1.92–2.06 (m, 2H,

CO2CHCHaHb + CHaHbCH2CH=CHAr), 2.15 (td, J = 12.3, 11.6, 4.6 Hz, 1H, CHaHbCH2CH=CHAr),

2.23 (dtd, J = 11.5, 6.5, 3.1 Hz, 1H, CH2CHaHbCH=CHAr), 2.27–2.35 (m, 1H,

CH2CHaHbCH=CHAr), 2.54 (dt, J = 13.7, 8.0 Hz, 1H, C(O)CCHaHb), 3.78 (s, 3H, CO2CH3), 3.92

(ddd, J = 10.7, 6.1, 3.9 Hz, 0.84H, CO2CH from major diastereoisomer), 4.10–4.16 (m, 0.16H,

CO2CH from minor diastereoisomer), 6.18 (dt, J = 15.8, 6.6 Hz, 1H, CH=CHAr), 6.42 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.17–7.23 (m, 1H, ArCH), 7.28–7.34 (m, 4H, ArCH) ppm; 13C NMR

(126 MHz, CDCl3) δ 17.8 (CH(CH3)CH3), 17.9 (CH(CH3)CH3), 22.9 (CO2CHCH2), 27.2 (C(O)CCH2),

28.1 (CH2CH2CH=CHAr), 32.6 (CH(CH3)2), 36.0 (CH2CH=CHAr), 53.0 (CO2CH3), 53.1 (Cq), 83.1

(CO2CH), 126.0 (ArCH), 127.1 (ArCH), 128.5 (ArCH), 129.2 (CH=CHAr), 130.7 (CH=CHAr), 137.5

-1 (ArC), 171.0 (CO2CH), 171.8 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2963, 1727 (C=O), 1457,

+ 1247, 1192, 908, 731; HRMS calcd. for C20H26O4Na [M+Na] 353.1723, found 353.1711.

169

Rac–methyl (3R,6R)–6–(tert–butyl)–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro– 2H–pyran–3–carboxylate (116e)

Prepared according to general procedure I using dimethyl (E)–2–(4,4–dimethyl–3– oxopentyl)–2–(4–phenylbut–3–en–1–yl)malonate 115e (300 mg, 0.80 mmol, 1.0 eq.), SmI2

(20 mL, 0.1 M in THF, 2.0 mmol, 2.5 eq.), and H2O (2.6 mL, 200 mmol, 250 eq.) in THF, followed by pTSA (7.6 mg, 0.04 mmol, 5 mol%) in CH2Cl2 (8 mL) to give the title product as a 9.0:1 mixture of diastereoisomers. Purification by silica gel column chromatography

(hexane/EtOAc 9:1 to CH2Cl2) yielded the title product (69 mg, 0.20 mmol, 25%). The major

1 diastereoisomer could be isolated and was obtained as a yellow oil. H NMR (400 MHz, CDCl3)

δ 0.97 (s, 9H, C(CH3)3), 1.65–1.74, (m, 1H, CHaHbCHC(CH3)3), 1.82 (ddd, J = 13.8, 8.0, 4.2 Hz,

1H, C(O)CCHaHb), 1.88–2.05 (m, 2H, CHaHbCHC(CH3)3 + CHaHbCH2CH=CHAr), 2.11–2.37 (m, 3H,

CH2CH2CH=CHAr + CHaHbCH2CH=CHAr), 2.54 (dt, J = 13.8, 8.2 Hz, 1H, C(O)CCHaHb), 3.79 (s,

3H, CO2CH3), 3.82 (dd, J = 15.9, 6.5 Hz, 1H, CO2CH), 6.18 (dt, J = 15.9, 6.5 Hz, 1H, CH=CHAr), 6.42 (d, J = 15.9 Hz, 1H, CH=CHAr), 7.14–7.23 (m, 1H, ArCH), 7.28–7.36 (m, 4H, ArCH) ppm;

13 C NMR (101 MHz, CDCl3) δ 20.9 (CH2CHC(CH3)3), 25.3 (C(CH3)3), 27.4 (C(O)CCH2), 28.1

(CH2CH=CHAr), 34.2 (C(CH3)3), 36.0 (CH2CH2CH=CHAr), 52.8 (Cq), 53.0 (CO2CH3), 85.7 (CO2CH), 126.0 (ArCH), 127.1 (ArCH), 128.5 (ArCH), 129.2 (CH=CHAr), 130.7 (CH=CHAr), 137.5 (ArC),

-1 171.0 (CO2CH), 171.8 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2955, 1730 (C=O), 1447, 1250,

+ 1172, 965; HRMS calcd. for C21H28O4 [M+Na] 367.1880, found 367.1868.

Rac–methyl (3R,6R)–6–benzyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H– pyran–3–carboxylate (116f)

Prepared according to general procedure I using dimethyl (E)–2–(3–oxo–4–phenylbutyl)–2–

(4–phenylbut–3–en–1–yl)malonate 115f (200 mg, 0.49 mmol, 1.0 eq.), SmI2 (12 mL, 0.1 M in

THF, 1.2 mmol, 2.5 eq.), and H2O (2.2 mL, 122 mmol, 250 eq.) in THF, followed by pTSA

170

(4.7 mg, 0.025 mmol, 5 mol%) in CH2Cl2 (5 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil, as a 7.3:1

1 mixture of diastereoisomers (115 mg, 0.30 mmol, 62%). H NMR (400 MHz, CDCl3) δ 1.68

(ddt, J = 13.9, 10.5, 8.0 Hz, 1H, CO2CHCHaHb), 1.82 (ddd, J = 13.9, 7.8, 4.9 Hz, 1H, C(O)CCHaHb),

1.90–2.03 (m, 2H, CO2CHCHaHb + CHaHbCH2CH=CHAr), 2.05–2.34 (m, 3H, CHaHbCH2CH=CHAr

+ CH2CH2CH=CHAr), 2.48 (dt, J = 13.9, 7.9 Hz, 1H, C(O)CCHaHb), 2.88 (dd, J = 14.0, 6.8 Hz, 1H,

CHaHbAr), 3.09 (dd, J = 13.9, 5.7 Hz, 1H, CHaHbAr), 3.76 (s, 3H, CO2CH3), 4.45 (dddd, J = 10.5,

6.7, 5.8, 3.8 Hz, 0.88H, CO2CH from major diastereoisomer), 4.50–4.57 (m, 0.12H, CO2CH from minor diastereoisomer), 6.16 (dt, J = 15.8, 6.6 Hz, 1H, CH=CHAr), 6.40 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.18–7.26 (m, 4H, ArCH), 7.29–7.36 (m, 6H, ArCH) ppm; 13C NMR (101 MHz,

CDCl3) δ 25.2 (CO2CHCH2), 27.1 (C(O)CCH2), 28.0 (CH2CH2CH=CHAr), 36.0 (CH2CH2CH=CHAr),

41.7 (CH2Ar), 53.0 (Cq), 53.1 (CO2CH3), 79.1 (CO2CH), 126.0 (ArCH), 127.0 (ArCH), 127.1 (ArCH), 128.5 (ArCH), 129.1 (ArCH), 129.5 (CH=CHAr), (ArCH), 130.7 (CH=CHAr), 136.1 (ArC), 137.5

-1 (ArC), 170.4 (CO2CH), 171.7 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2950, 1732 (C=O), 1455,

+ 1365, 1163, 1103; HRMS calcd. for C24H26O4Na [M+Na] 401.1723, found 401.1709.

Rac–methyl (3R,6R)–6–neopentyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H– pyran–3–carboxylate (116g)

Prepared according to general procedure I using dimethyl (E)–2–(5,5–dimethyl–3– oxohexyl)–2–(4–phenylbut–3–en–1–yl)malonate 115f (150 mg, 0.39 mmol, 1.0 eq.), SmI2

(9.7 mL, 0.1 M in THF, 0.97 mmol, 2.5 eq.), and H2O (1.7 mL, 97 mmol, 250 eq.) in THF, followed by pTSA (3.7 mg, 0.02 mmol, 5 mol%) in CH2Cl2 (4 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil, as

1 a 8.6:1 mixture of diastereoisomers (113 mg, 0.32 mmol, 81%). H NMR (400 MHz, CDCl3) δ

0.96 (s, 9H, C(CH3)3), 1.36 (dd, J = 14.7, 2.7 Hz, 1H, CHaHbC(CH3)3), 1.62–1.82 (m, 3H,

CHaHbC(CH3)3 + C(O)CCHaHb + CO2CHCHaHb), 1.89–2.03 (m, 2H, CO2CHCHaHb +

CHaHbCH2CH=CHAr), 2.08–2.26 (m, 2H, CHaHbCH2CH=CHAr + CH2CHaHbCH=CHAr), 2.29–2.43

(m, 1H, CH2CHaHbCH=CHAr), 2.59 (ddd, J = 13.4, 8.7, 6.8 Hz, 1H, C(O)CCHaHb), 3.80 (s, 3H,

CO2CH3), 4.27 (dddd, J = 10.6, 7.9, 3.7, 2.7 Hz, 0.9H, CO2CH from major diastereoisomer), 4.42

(ddt, J = 11.1, 7.2, 3.5 Hz, 0.1H, CO2CH from minor diastereoisomer), 6.18 (dt, J = 15.9, 6.5 Hz,

171

1H, CH=CHAr), 6.42 (d, J = 15.9 Hz, 1H, CH=CHAr), 7.18–7.23 (m, 1H, ArCH), 7.28–7.35 (m,

13 4H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 27.0 (C(O)CCH2), 27.7 (CO2CHCH2), 28.1

(CH2CH2CH=CHAr), 29.9 (C(CH3)3), 30.1 (C(CH3)3), 36.0 (CH2CH2CH=CHAr), 48.9 (CH2C(CH3)3),

52.7 (CO2CH3) 53.0 (Cq), 75.8 (CO2CH), 126.0 (ArCH), 127.1 (ArCH), 128.5 (ArCH), 129.2

(CH=CHAr), 130.7 (CH=CHAr), 137.5 (ArC), 170.9 (CO2CH), 171.9 (CO2CH3) ppm; IR vmax (thin

-1 film, cm ) = 29116, 2184, 1728 (C=O), 1460, 1140, 1086, 1039; HRMS calcd. for C22H30O4Na [M+Na]+ 381.2036, found 381.2023.

Rac–methyl (3R,6S)–3–((E)–4–(4–bromophenyl)but–3–en–1–yl)–6–ethyl–2– oxotetrahydro–2H–pyran–3–carboxylate (128a)

Prepared according to general procedure I using dimethyl (E)–2–(4–(4–bromophenyl)but–3– en–1–yl)–2–(3–oxopentyl)malonate 127a (136 mg, 0.32 mmol, 1.0 eq.), SmI2 (8.0 mL, 0.1 M in THF, 0.80 mmol, 2.5 eq.), and H2O (1.4 mL, 80 mmol, 250 eq.) in THF, followed by pTSA

(3.0 mg, 0.016 mmol, 5 mol%) in CH2Cl2 (4 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil, as a 6.2:1

1 mixture of diastereoisomers (78 mg, 0.20 mmol, 62%). H NMR (400 MHz, CDCl3) δ 0.99 (t,

J = 7.5 Hz, 3H, CH2CH3), 1.52–1.86 (m, 4H, CH2CH3 + CO2CHCHaHb + C(O)CCHaHb), 1.94–2.06

(m, 2H, CO2CHCHaHb + CHaHbCH2CH=CHAr), 2.09–2.35 (m, 3H, CHaHbCH2CH=CHAr +

CH2CH=CHAr), 2.54 (dt, J = 13.9, 7.9 Hz, 1H, C(O)CCHaHb), 3.78 (s, 3H, CO2CH3), 4.02–4.20 (m,

0.9H, CO2CH from major diastereoisomer), 4.22–4.30 (m, 0.1H, CO2CH from minor diastereoisomer), 6.17 (dt, J = 15.8, 6.5 Hz, 1H, CH=CHAr), 6.36 (d, J = 15.9 Hz, 1H, CH=CHAr),

13 7.19 (d, J = 8.5 Hz, 2H, ArCH), 7.42 (d, J = 8.5 Hz, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ

9.4 (CH2CH3), 25.5 (CO2CHCH2), 27.1 (C(O)CCH2), 28.1 (CH2CH=CHAr), 28.6 (CH2CH3), 35.9

(CH2CH2CH=CHAr), 53.0 (CO2CH3), 53.1 (Cq), 79.8 (CO2CH), 120.7 (ArCBr), 127.5 (ArCH), 129.6

(CH=CHAr), 130.0 (CH=CHAr), 131.6 (ArCH), 136.4 (ArC), 170.8 (CO2CH), 171.8 (CO2CH3) ppm;

-1 IR vmax (thin film, cm ) = 2949, 1732 (C=O), 1455, 1385, 1250, 1039;HRMS calcd. for

+ C19H23O4BrNa [M+Na] 417.0672, found 417.0662.

172

Rac–methyl (3R,6S)–6–ethyl–3–((E)–4–(naphthalen–2–yl)but–3–en–1–yl)–2– oxotetrahydro–2H–pyran–3–carboxylate (128b)

Prepared according to general procedure I using dimethyl (E)–2–(4–(naphthalen–1–yl)but–

3–en–1–yl)–2–(3–oxopentyl)malonate 127b (120 mg, 0.29 mmol, 1.0 eq.), SmI2 (7.3 mL,

0.1 M in THF, 0.73 mmol, 2.5 eq.), and H2O (1.3 mL, 73 mmol, 250 eq.) in THF, followed by pTSA (2.8 mg, 0.015 mmol, 5 mol%) in CH2Cl2 (4 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as white crystals, as a 6.4:1

1 mixture of diastereoisomers (65 mg, 0.018 mmol, 61%). mp (CH2Cl2) 52–55 °C. H NMR

(CDCl3, 400 MHz) δ 1.01 (t, J = 7.5 Hz, 3H, CH2CH3), 1.61–1.81 (m, 3H, CH2CH3 + CO2CHCHaHb),

1.81–1.90 (m, 1H, C(O)CCHaHb), 1.98–2.13 (m, 2H, C(O)CCHaHb + CHaHbCH2CH=CHAr), 2.14–

2.45 (m, 3H, CHaHbCH2CH=CHAr + CH2CH=CHAr), 2.57 (dt, J = 14.0, 7.9 Hz, 1H, C(O)CCHaHb),

3.81 (s, 3H, CO2CH3), 4.14 (dddd, J = 10.6, 6.8, 5.5, 3.8 Hz, 0.85H, CO2CH from major diastereoisomer), 4.25–4.33 (m, 0.15H, CO2CH from minor diastereoisomer), 6.19 (dt, J = 15.8, 6.7 Hz, 1H, CH=CHAr), 6.81 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.11–7.25 (m, 4H, ArCH), 7.29 (s, 1H, ArCH), 7.35 (dd, J = 7.8, 1.5 Hz, 1H, ArCH), 7.50 (dd, J = 7.7, 1.5 Hz, 1H, ArCH) ppm; 13C

NMR (101 MHz, CDCl3) δ 9.4 (CH2CH3), 25.5 (CO2CHCH2), 27.1 (C(O)CCH2), 28.3 (CH2CH=CHAr),

28.6 (CH2CH3), 35.9 (CH2CH2CH=CHAr), 53.0 (CO2CH3), 53.1 (Cq), 79.8 (CO2CH), 126.7 (ArCH), 126.8 (ArCH), 126.9 (CH=CHAr), 126.9 (ArCH), 128.1 (ArCH), 128.2 (ArCH), 129.7 (ArCH), 129.6

(ArCH), 132.2 (CH=CHAr), 132.6 (ArC), 135.4 (ArC), 135.5 (ArC), 170.8 (CO2CH), 171.8

-1 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2951, 1728 (C=O), 1470, 1241, 1190, 1118,

+ 1032; HRMS calcd. for C23H26O4Na [M+Na] 389.1723, found 389.1710.

Rac–methyl (3R,6S)–6–ethyl–3–((E)–4–(2–fluorophenyl)but–3–en–1–yl)–2– oxotetrahydro–2H–pyran–3–carboxylate (128c)

Prepared according to general procedure I using dimethyl (E)–2–(4–(2–fluorophenyl)but–3– en–1–yl)–2–(3–oxopentyl)malonate 127c (100 mg, 0.27 mmol, 1.0 eq.), SmI2 (8.2 mL, 0.1 M

173 in THF, 0.82 mmol, 2.5 eq.), and H2O (1.5 mL, 82 mmol, 250 eq.) in THF, followed by pTSA

(2.6 mg, 0.014 mmol, 5 mol%) in CH2Cl2 (5 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil, as a 5.2:1

1 mixture of diastereoisomers (71 mg, 0.21 mmol, 79%). H NMR (500 MHz, CDCl3) δ 1.00 (t,

J = 7.5 Hz, 3H, CH2CH3), 1.59–1.70 (m, 2H, CHaHbCH3 + CO2CHCHaHb), 1.70–1.79 (m, 1H,

CHaHbCH3), 1.83 (ddd, J = 13.7, 8.2, 5.0 Hz, 1H, C(O)CCHaHb), 1.96–2.08 (m, 2H,

CHaHbCH2CH=CHAr + CO2CHCHaHb), 2.16 (ddd, J = 13.6, 11.4, 4.9 Hz, 1H, CHaHbCH2CH=CHAr),

2.21–2.30 (m, 1H, CH2CHaHbCH=CHAr), 2.31–2.39 (m, 1H, CH2CHaHbCH=CHAr), 2.55 (dt, J =

14.0, 8.0 Hz, 1H, C(O)CCHaHb), 3.79 (s, 3H, CO2CH3), 4.12 (dddd, J = 10.6, 6.8, 5.6, 3.8 Hz,

0.84H, CO2CH from major diastereoisomer), 4.26–4.33 (m, 0.16H, CO2CH from minor diastereoisomer), 6.26 (dt, J = 16.1, 6.8 Hz, 1H, CH=CHAr), 6.57 (d, J = 16.1 Hz, 1H, CH=CHAr), 7.01 (ddd, J = 10.9, 8.2, 1.3 Hz, 1H, ArCH), 7.07 (td, J = 7.4, 1.2 Hz, 1H, ArCH), 7.17 (tdd, J =

13 7.4, 5.1, 1.8 Hz, 1H, ArCH), 7.40 (td, J = 7.7, 1.8 Hz, 1H, ArCH) ppm; C NMR (126 MHz, CDCl3)

δ 9.4 (CH2CH3), 25.5 (CO2CHCH2), 27.0 (C(O)CCH2), 28.5 (CH2CH2CH=CHAr), 28.6 (CH2CH3),

35.9 (CH2CH2CH=CHAr), 53.0 (CO2CH3), 53.1 (Cq), 79.8 (CO2CH), 115.6 (d, J = 22.2 Hz, ArCH), 123.1 (CH=CHAr), 124.0 (d, J = 3.4 Hz, ArCH), 125.1 (d, J = 12.2 Hz, ArC), 127.1 (d, J = 4.0 Hz, ArCH), 128.3 (d, J = 8.4 Hz, ArCH), 131.9 (d, J = 4.0 Hz, CH=CHAr), 160.0 (d, J = 248.6 Hz, ArCF),

19 170.9 (CO2CH), 171.8 (CO2CH3) ppm; F NMR (376 MHz, CDCl3) δ –118.7 ppm; IR vmax (thin

-1 film, cm ) = 2950, 1727 (C=O), 1489, 1455, 1227, 1192, 1091; HRMS calcd. for C19H23O4FNa [M+Na]+ 357.1473, found 347.1458.

Rac–methyl (3R,6S)–6–ethyl–3–((E)–4–(4–methoxyphenyl)but–3–en–1–yl)–2– oxotetrahydro–2H–pyran–3–carboxylate (128d)

Prepared according to general procedure I using dimethyl (E)–2–(4–(4–methoxyphenyl)but–

3–en–1–yl)–2–(3–oxopentyl)malonate 127d (120 mg, 0.33 mmol, 1.0 eq.), SmI2 (9.9 mL, 0.1

M in THF, 0.99 mmol, 2.5 eq.), and H2O (1.8 mL, 99 mmol, 250 eq.) in THF, followed by pTSA

(3.1 mg, 0.017 mmol, 5 mol%) in CH2Cl2 (4 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a 4.2:1 mixture of diastereoisomers (83 mg, 0.24 mmol, 73%). The major diastereoisomer could be isolated and

1 was obtained as a colourless oil. H NMR (400 MHz, CDCl3) δ 0.99 (t, J = 7.5 Hz, 3H, CH2CH3),

174

1.59–1.70 (m, 2H, CHaHbCH3 + CO2CHCHaHb), 1.70–1.77 (m, 1H, CHaHbCH3), 1.78–1.87 (m, 1H,

C(O)CCHaHb), 1.96–2.05 (m, 2H, CHaHbCH2CH=CHAr + CO2CHCHaHb), 2.07–2.35 (m, 3H,

CHaHbCH2CH=CHAr + CH2CH2CH=CHAr), 2.55 (dt, J = 14.0, 8.0 Hz, 1H, C(O)CCHaHb), 3.78 (s,

3H, CO2CH3), 3.81 (s, 3H, ArOCH3), 4.11 (dddd, J = 10.6, 6.8, 5.5, 3.8 Hz, 1H, CO2CH), 6.03 (dt, J = 15.8, 6.6 Hz, 1H, CH=CHAr), 6.36 (d, J = 15.9 Hz, 1H, CH=CHAr), 6.84 (d, J = 8.0 Hz, 2H,

13 ArCH), 7.26 (d, J = 8.0 Hz, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 9.4 (CH2CH3), 25.5

(CO2CHCH2), 27.0 (C(O)CCH2), 28.0 (CH2CH2CH=CHAr), 28.6 (CH2CH3), 36.2 (CH2CH2CH=CHAr),

53.0 (Cq), 53.1 (CO2CH3), 55.3 (ArOCH3), 79.8 (CO2CH), 113.9 (ArCH), 127.0 (CH=CHAr), 127.1

(ArCH), 130.1 (CH=CHAr), 130.3 (ArC), 158.8 (ArCOCH3), 170.9 (CO2CH), 171.8 (CO2CH3); IR

-1 vmax (thin film, cm ) = 2951, 1727 (C=O), 1606, 1510, 1455, 1244, 1174, 1091, 1030; HRMS

+ calcd. for C20H26O5Na [M+Na] 369.1659, found 369.1658.

Rac–methyl (3R,6S)–3–((E)–4–(3–chlorophenyl)but–3–en–1–yl)–6–ethyl–2– oxotetrahydro–2H–pyran–3–carboxylate (128e)

Prepared according to general procedure I using dimethyl (E)–2–(4–(3–chlorophenyl)but–3– en–1–yl)–2–(3–oxopentyl)malonate 126e (130 mg, 0.33 mmol, 1.0 eq.), SmI2 (8.2 mL, 0.1 M in THF, 0.82 mmol, 2.5 eq.), and H2O (1.5 mL, 83 mmol, 250 eq.) in THF, followed by pTSA

(3.0 mg, 0.017 mmol, 5 mol%) in CH2Cl2 (5 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a 4.3:1 mixture of diastereoisomers (94 mg, 0.27 mmol, 81%). The major diastereoisomer could be isolated and

1 was obtained as a colourless oil. H NMR (400 MHz, CDCl3) δ 1.00 (t, J = 7.4 Hz, 3H, CH2CH3),

1.56–1.71 (m, 2H, CHaHbCH3 + CO2CHCHaHb), 1.70–1.89 (m, 2H, CHaHbCH3 + C(O)CCHaHb),

1.95–2.06 (m, 2H, CO2CHCHaHb + CHaHbCH2CH=CHAr), 2.14 (tdd, J = 11.3, 4.9, 1.8 Hz, 1H,

CHaHbCH2CH=CHAr), 2.19–2.26 (m, 1H, CH2CHaHbCH=CHAr), 2.27–2.37 (m, 1H,

CH2CHaHbCH=CHAr), 2.55 (ddd, J = 13.9, 8.9, 7.0 Hz, 1H, C(O)CCHaHb), 3.79 (s, 3H, CO2CH3),

4.06–4.17 (m, 1H, CO2CH), 6.20 (dt, J = 15.8, 6.5 Hz, 1H, CH=CHAr), 6.36 (d, J = 15.8 Hz, 1H,

13 CH=CHAr), 7.15–7.24 (m, 3H, ArCH), 7.27–7.33 (m, 1H, ArCH) ppm; C NMR (101 MHz, CDCl3)

δ 9.4 (CH2CH3), 25.5 (CO2CHCH2), 27.1 (C(O)CCH2), 28.0 (CH2CH2CH=CHAr), 28.6 (CH2CH3),

35.9 (CH2CH2CH=CHAr), 53.0 (Cq), 53.1 (CO2CH3), 79.8 (CO2CH), 124.2 (ArCH), 126.0 (ArCH), 127.0 (ArCH), 129.5 (CH=CHAr), 129.7 (ArCH), 130.8 (CH=CHAr), 134.5 (ArCCl), 139.4 (ArC),

175

-1 170.8 (CO2CH), 171.7 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2945, 1729 (C=O), 1455, 1272,

+ 1245, 1193, 1090; HRMS calcd. for C19H23O4ClNa [M+Na] 373.1177, found 373.1164.

General Procedure L: SmI2–H2O–HMPA–mediated ester migration Rac–methyl (R)–2–benzyl–4–((3S,6S)–6–methyl–2–oxotetrahydro–2H–pyran–3– yl)butanoate (119a)

To a solution of SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol, 2.5 eq.), HMPA (0.17 mL, 1.0 mmol,

10 eq.) and H2O (29 µL, 1.6 mmol, 16 eq.) at –78 °C was added a solution of rac–methyl (3R,6S)–6–methyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H–pyran–3– carboxylate 116a (30 mg, 0.10 mmol, 1.0 eq.) in THF (0.5 mL). The reaction was stirred at this temperature until decolourisation occurred, then saturated aqueous Rochelle’s salt solution

(5 mL) was added. The aqueous layer was extracted with Et2O (3 x 5 mL), the combined organic layers were washed with 1M HCl (2 x 5 mL), NaHCO3 (5 mL), brine (5 mL), dried

(MgSO4) and concentrated. Purification by silica gel column chromatography (hexane/EtOAc 85:15) yielded the title product as a colourless oil, as a 3:1 mixture of diastereoisomers

1 (23 mg, 0.076 mmol, 76%). H NMR (400 MHz, CDCl3) δ 1.35 (d, J = 6.2 Hz, 0.75H, CHCH3 from minor diastereoisomer), 1.36 (d, J = 6.3 Hz, 2.25H, CHCH3 from major diastereoisomer), 1.42–

1.65 (m, 4H, CO2CHCH2CHaHb + CO2CHCHaHb + CHaHbCH2CHCO2CH3 + CH2CHaHbCHCO2CH3),

1.68–1.80 (m, 1H, CH2CHaHbCHCO2CH3), 1.84–2.11 (m, 3H, CO2CHCHaHb + CHaHbCH2CHCO2CH3

+ CO2CHCH2CHaHb), 2.30 (dddd, J = 11.1, 8.1, 6.7, 4.5 Hz, 0.75H, CHCO2CH from major diastereoisomer), 2.41 (ddt, J = 10.0, 7.6, 3.7 Hz, 0.25H, CHCO2CH from minor diastereoisomer), 2.62–2.72 (m, 1H, CHCH2Ar), 2.78 (dd, J = 13.5, 6.6 Hz, 1H, CHCHaHbAr),

2.96 (dd, J = 13.5, 7.7 Hz, 1H, CHCHaHbAr), 3.61 (s, 3H, CO2CH3), 4.35-4.42 (m, 1H, CO2CH), 7.15 (dd, J = 6.9, 1.5 Hz, 2H, ArCH), 7.18–7.23 (m, 1H, ArCH), 7.24–7.30 (m, 2H, ArCH) ppm;

13 C NMR (101 MHz, CDCl3) δ 22.1 (CHCH3), 25.6 (CO2CHCH2CH2), 29.2 (CH2CH2CHCO2CH3),

29.7 (CH2CH2CHCO2CH3) 30.7 (CO2CHCH2), 38.5 (CH2Ar), 40.4 (CHCO2CH), 47.4 (CHCH2Ar),

51.5 (CO2CH3), 77.7 (CO2CH), 126.4 (ArCH), 128.4 (ArCH), 128.8 (ArCH), 139.0 (ArC), 173.4

-1 (CO2CH), 175.7 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2940, 1733 (C=O), 1435, 1162, 1098;

+ HRMS calcd. for C18H24O4Na [M+Na] 327.1567, found 327.1551.

176

Rac–methyl (R)–2–benzyl–4–((3S,6S)–6–ethyl–2–oxotetrahydro–2H–pyran–3– yl)butanoate (119b)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.), H2O (29 µL, 1.6 mmol, 16 eq.) and rac–methyl (3R,6S)–6–ethyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H–pyran–3– carboxylate 116b (32 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 85:15) yielded the title product as a colourless oil, as a 3:1

1 mixture of diastereoisomers (22 mg, 0.069 mmol, 69%). H NMR (500 MHz, CDCl3) δ 0.98 (t,

J = 7.5 Hz, 3H, CH2CH3), 1.36–1.79 (m, 7H, CH2CHCO2CH3 + CH2CH3 + CO2CHCHaHb +

CO2CHCH2CHaHb + CHaHbCH2CHCO2CH3), 1.83–2.08 (m, 3H, CO2CHCHaHb + CO2CHCH2CHaHb +

CHaHbCH2CHCO2CH3), 2.26–2.34 (m, 0.75H, CHCO2CH from major diastereoisomer), 2.37–

2.46 (m, 0.25H, CHCO2CH from minor diastereoisomer), 2.64–2.72 (m, 1H, CHCO2CH3), 2.76

(dd, J = 13.5, 6.9 Hz, 1H, CHaHbAr), 2.96 (dd, J = 13.6, 6.9 Hz, 1H, CHaHbAr), 3.61 (s, 3H,

CO2CH3), 4.14–4.22 (m, 1H, CO2CH), 7.13–7.16 (m, 2H, ArCH), 7.18–7.23 (m, 1H, ArCH), 7.25–

13 7.30 (m, 2H, ArCH) ppm; C NMR (126 MHz, CDCl3) δ 9.2 (CH2CH3), 25.5 (CH2CH2CHCO2CH3),

28.3 (CO2CHCH2CH2), 29.1 (CH2CH3), 29.2 (CH2CHCO2CH3), 29.8 (CO2CHCH2), 38.5 (CH2Ar),

40.8 (CHCO2CH), 47.4 (CHCO2CH3), 51.5 (CO2CH3), 82.3 (CO2CH), 126.4 (ArCH), 128.4 (ArCH),

-1 128.8 (ArCH), 139.1 (ArC), 173.5 (CO2CH), 175.8 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2942,

+ 1725 (C=O), 1435, 1371, 1246, 1163, 1090; HRMS calcd. for C19H26O4Na [M+Na] 341.1723, found 341.1708.

Rac–methyl (R)–2–benzyl–4–((3S,6R)–6–cyclohexyl–2–oxotetrahydro–2H–pyran–3– yl)butanoate (119c)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.), H2O (29 µL, 1.6 mmol, 16 eq.) and rac–methyl

177

(3R,6R)–6–cyclohexyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H–pyran–3– carboxylate 116c (37 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil, as a 3:1

1 mixture of diastereoisomers (27 mg, 0.072 mmol, 72%). H NMR (500 MHz, CDCl3) δ 1.00–

1.29 (m, 6H, 3 x CyCH2), 1.39–1.61 (m, 5H, CHaHbCHCO2CH3 + CO2CHCH2CHaHb + CyCH +

CyCH2), 1.64–1.81 (m, 5H, CO2CHCHaHb + CHaHbCH2CHCO2CH3 + CHaHbCHCO2CH3 + 0.5 x

CyCH2), 1.82–1.93 (m, 2H, CO2CHCHaHb + 0.5 x CyCH2), 1.94–2.06 (m, 2H, CO2CHCH2CHaHb +

CHaHbCH2CHCO2CH3), 2.22–2.32 (m, 0.75H, CHCO2CH from major diastereoisomer), 2.37–

2.45 (m, 0.25H, CHCO2CH from minor diastereoisomer), 2.64–2.71 (m, 1H, CHCO2CH3), 2.76

(dd, J = 13.6, 6.8 Hz, 1H, CHaHbAr), 2.96 (dd, J = 13.6, 8.0 Hz, 1H, CHaHbAr), 3.61 (s, 3H,

CO2CH3), 3.96–4.01 (m, 1H, CO2CH), 7.15 (d, J = 7.5 Hz, 2H, ArCH), 7.20 (dd, J = 8.6, 5.9 Hz,

13 1H, ArCH), 7.25–7.29 (m, 2H, ArCH) ppm; C NMR (126 MHz, CDCl3) δ 25.6 (CyCH2), 25.6

(CH2CH2CHCO2CH3), 25.9 (CyCH2), 26.0 (CyCH2), 26.3 (CyCH2), 28.0 (CyCH2), 28.1 (CO2CHCH2),

29.2 (CH2CHCO2CH3), 29.8 (CO2CHCH2CH2), 38.5 (CH2Ar), 41.0 (CHCO2CH), 42.8 (CyCH), 47.4

(CHCO2CH3), 51.5 (CO2CH3), 85.5 (CO2CH), 126.4 (ArCH), 128.4 (ArCH), 128.8 (ArCH), 139.0

-1 (ArC), 173.6 (CO2CH), 175.7 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2925, 2853, 1731 (C=O),

+ 1451, 1164; HRMS calcd. for C23H32O4Na [M+Na] 395.2193, found 395.2186.

Rac–methyl (R)–2–benzyl–4–((3S,6R)–6–isopropyl–2–oxotetrahydro–2H–pyran–3– yl)butanoate (119d)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.), H2O (29 µL, 1.6 mmol, 16 eq.) and rac–methyl (3R,6R)–6–isopropyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H–pyran–3– carboxylate 116d (33 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 85:15) yielded the title product as a colourless oil, as a 3:1

1 mixture of diastereoisomers (20 mg, 0.061 mmol, 61%). H NMR (500 MHz, CDCl3) δ 0.95 (d,

J = 6.9 Hz, 3H, CHCH3), 0.98 (d, J = 6.8 Hz, 3H, CHCH3), 1.41–1.67 (m, 4H, CO2CHCH2 +

CO2CHCH2CHaHb + CH2CHaHbCHCO2CH3), 1.69–1.78 (m, 1H, CH2CHaHbCHCO2CH3), 1.82–1.90

(m, 2H, CHaHbCH2CHCO2CH3 + CO2CHCH2CHaHb), 1.95–2.08 (m, 2H, CHaHbCH2CHCO2CH3 +

178

CH(CH3)2), 2.28 (dddd, J = 11.1, 8.2, 6.6, 4.5 Hz, 0.75H, CHCO2CH from major diastereoisomer), 2.37–2.47 (m, 0.25H, CHCO2CH from minor diastereoisomer), 2.65–2.71

(m, 1H, CHCH2Ar), 2.77 (dd, J = 13.6, 6.9 Hz, 1H, CHaHbAr), 2.96 (dd, J = 13.6, 8.1 Hz, 1H,

CHaHbAr), 3.61 (s, 3H, CO2CH3), 3.98 (ddd, J = 11.4, 6.2, 3.3 Hz, 0.25H, CO2CH from minor diastereoisomer), 4.03 (ddd, J = 11.5, 5.6, 3.1 Hz, 0.75H, CO2CH from major diastereoisomer), 7.12–7.17 (m, 2H, ArCH), 7.18–7.23 (m, 1H, ArCH), 7.25–7.31 (m, 2H, ArCH) ppm; 13C NMR

(126 MHz, CDCl3) δ 17.6 (CHCH3), 17.7 (CHCH3), 25.4 (CO2CHCH2CH2), 25.6 (CH2CH2CHCO2CH3)

29.2 (CH2CH2CHCO2CH3), 29.8 (CO2CHCH2), 32.9 (CH(CH3)2), 38.5 (CH2Ar), 40.9 (CHCO2CH),

47.4 (CHCH2Ar), 51.5 (CO2CH3), 86.0 (CO2CH), 126.4 (ArCH), 128.4 (ArCH), 128.9 (ArCH), 139.1

-1 (ArC), 173.6 (CO2CH), 175.8 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2955, 2924, 1731 (C=O),

+ 1453, 1245, 700; HRMS calcd. for C20H28O4Na [M+Na] 355.1880, found 355.1868.

Rac–methyl (R)–2–benzyl–4–((3S,6R)–6–(tert–butyl)–2–oxotetrahydro–2H–pyran–3– yl)butanoate (119e)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.), H2O (29 µL, 1.6 mmol, 16 eq.) and rac–methyl (3R,6R)–6–(tert–butyl)–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H–pyran–3– carboxylate 116e (34 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil, as a 1.8:1

1 mixture of diastereoisomers (25 mg, 0.073 mmol, 73%). H NMR (500 MHz, CDCl3) δ 0.95 (s,

9H, C(CH3)3), 1.38–1.62 (m, 4H, CO2CHCH2CHaHb + CO2CHCHaHb + CHaHbCH2CHCO2CH3 +

CH2CHaHbCHCO2CH3), 1.68–1.77 (m, 1H, CH2CHaHbCHCO2CH3), 1.86–1.93 (m, 1H,

CO2CHCHaHb), 1.96–2.02 (m, 2H, CO2CHCH2CHaHb + CHaHbCH2CHCO2CH3), 2.22–2.31 (m, 1H,

CHCO2CH), 2.68 (m, 1H, CHCH2Ar), 2.76 (dd, J = 13.6, 7.0 Hz, 1H, CHaHbAr), 2.97 (dd, J = 13.5,

8.0 Hz, 1H, CHaHbAr), 3.61 (s, 3H, CO2CH3), 3.91 (dd, J = 11.6, 3.1 Hz, 1H, CO2CH), 7.13–7.17 (m, 2H, ArCH), 7.21 (t, J = 7.4 Hz, 1H, ArCH), 7.26–7.31 (m, 2H, ArCH) ppm; 13C NMR (126 MHz,

CDCl3) δ 23.6 (CO2CHCH2), 25.4 (C(CH3)3), 25.6 (CO2CHCH2CH2), 29.2 (CH2CH2CHCO2CH3), 29.8

(CH2CH2CHCO2CH3), 34.5 (C(CH3)3), 38.5 (CH2Ar), 40.9 (CHCO2CH), 47.4 (CHCH2Ar), 51.5

(CO2CH3 from one diastereoisomer), 51.6 (CO2CH3 from one diastereoisomer), 88.7 (CO2CH

179 from one diastereoisomer), 88.8 (CO2CH from one diastereoisomer), 126.4 (ArCH), 128.4

(ArCH), 128.9 (ArCH), 139.1 (ArC), 173.7 (CO2CH), 175.8 (CO2CH3) ppm; IR vmax (thin film,

-1 + cm ) = 2954, 2871, 1731 (C=O), 1454, 1251, 1174, 1090; HRMS calcd. for C21H30O4Na [M+Na] 369.2036, found 369.2028.

Rac–methyl (R)–2–benzyl–4–((3S,6R)–6–benzyl–2–oxotetrahydro–2H–pyran–3– yl)butanoate (119f)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.), H2O (29 µL, 1.6 mmol, 16 eq.) and rac–methyl (3R,6R)–6–benzyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H–pyran–3– carboxylate 116f (38 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 85:15) yielded the title product as a colourless oil, as a 1:1

1 mixture of diastereoisomers (25 mg, 0.066 mmol, 66%). H NMR (500 MHz, CDCl3) δ 1.34–

1.77 (m, 5H, CH2CHCO2CH3 + CHaHbCH2CHCO2CH3 + CO2CHCHaHb + CO2CHCH2CHaHb), 1.81–

2.04 (m, 3H, CHaHbCH2CHCO2CH3 + CO2CHCHaHb + CO2CHCH2CHaHb), 2.23–2.31 (m, 0.5H,

CHCO2CH from one diastereoisomer), 2.34–2.44 (m, 0.5H, CHCO2CH from one diastereoisomer), 2.63–2.70 (m, 1H, CHCO2CH3), 2.77 (apparent td, J = 13.3, 8.6 Hz, 1H,

CH(CO2CH3)CHaHbAr), 2.85 (apparent td, J = 14.1, 7.2 Hz, 1H, CO2CHCHaHbAr), 2.95 (apparent dt, J = 13.4, 8.9 Hz, 1H, CH(CO2CH3)CHaHbAr), 3.08 (apparent dt, J = 13.4, 6.5 Hz, 1H,

CO2CHCHaHbAr), 3.60 (s, 3H, CO2CH3), 4.40 (m, 1H, CO2CH), 7.14 (d, J = 7.6 Hz, 2H, ArCH),

13 7.18–7.27 (m, 5H, ArCH), 7.27–7.34 (m, 3H, ArCH) ppm; C NMR (126 MHz, CDCl3) δ 25.4

(CH2CH2CHCO2CH3 from one diastereoisomer), 26.1 (CH2CH2CHCO2CH3 from one diastereoisomer), 28.0 (CO2CHCH2 from one diastereoisomer), 28.3 (CO2CHCH2 from one diastereoisomer), 29.2 (CH2CHCO2CH3), 29.7 (CO2CHCH2CH2), 38.0 (CHCO2CH from one diastereoisomer), 38.3 (CH(CO2CH3)CH2Ar from one diastereoisomer), 38.5

(CH(CO2CH3)CH2Ar from one diastereoisomer) 40.7 (CHCO2CH from one diastereoisomer),

41.6 (CO2CHCH2Ar from one diastereoisomer), 42.5 (CO2CHCH2Ar from one diastereoisomer),

47.4 (CHCO2CH3 from one diastereoisomer), 47.5 (CHCO2CH3 from one diastereoisomer),

51.5 (CO2CH3), 78.5 (CO2CH from one diastereoisomer), 81.6 (CO2CH from one diastereoisomer), 126.4 (ArCH from one diastereoisomer), 126.4 (ArCH from one

180 diastereoisomer), 126.8 (ArCH from one diastereoisomer), 126.8 (ArCH from one diastereoisomer), 128.4 (ArCH from one diastereoisomer), 128.4 (ArCH from one diastereoisomer), 128.5 (ArCH from one diastereoisomer), 128.6 (ArCH from one diastereoisomer), 128.8 (ArCH), 129.5 (ArCH from one diastereoisomer), 129.6 (ArCH from one diastereoisomer), 136.3 (ArC from one diastereoisomer), 136.6 (ArC from one diastereoisomer), 139.0 (ArC from one diastereoisomer), 139.1 (ArC from one diastereoisomer), 173.2 (CO2CH from one diastereoisomer), 174.8 (CO2CH from one diastereoisomer), 175.7 (CO2CH3 from one diastereoisomer), 175.7 (CO2CH3 from one

-1 diastereoisomer) ppm; IR vmax (thin film, cm ) = 2922, 1729 (C=O), 1454, 1375, 1251, 1164,

+ 1080; HRMS calcd. for C24H28O4Na [M+Na] 403.1880, found 403.1866.

Rac–methyl (R)–2–benzyl–4–((3S,6R)–6–neopentyl–2–oxotetrahydro–2H–pyran–3– yl)butanoate (119g)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.), H2O (29 µL, 1.6 mmol, 16 eq.) and rac–methyl (3R,6R)–6–neopentyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H–pyran–3– carboxylate 116g (36 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil, as a 1.5:1

1 mixture of diastereoisomers (23 mg, 0.064 mmol, 64%). H NMR (500 MHz, CDCl3) δ 0.97 (s,

9H, C(CH3)3), 1.32–1.79 (m, 7H, CH2C(CH3)3 + CO2CHCHaHb + CO2CHCH2CHaHb +

CH2CH2CHCO2CH3 + CH2CHaHbCHCO2CH3), 1.81–1.92 (m, 1.4H CO2CHCHaHb +

CH2CHaHbCHCO2CH3 from minor diastereoisomer), 1.93–2.10 (m, 1.6H, CO2CHCH2CHaHb +

CH2CHaHbCHCO2CH3 from major diastereoisomer), 2.24–2.32 (m, 0.4H, CHCO2CH from minor diastereoisomer), 2.39–2.46 (m, 0.6H, CHCO2CH from major diastereoisomer), 2.63–2.72 (m,

1H, CHCH2Ar), 2.78 (dd, J = 13.6, 6.7 Hz, 1H, CHaHbAr), 2.96 (apparent dt, J = 13.6, 8.0 Hz, 1H,

CHaHbAr), 3.61 (s, 3H, CO2CH3), 4.33–4.39 (m, 1H, CO2CH), 7.15 (dd, J = 7.2, 2.6 Hz, 2H, ArCH),

13 7.20 (m, 1H, ArCH), 7.25–7.31 (m, 2H, ArCH) ppm; C NMR (126 MHz, CDCl3) δ 25.7

(CO2CHCH2CH2), 28.3 (CO2CHCH2 from one diastereoisomer), 28.5 (CO2CHCH2 from one diastereoisomer), 29.2 (CH2CH2CHCO2CH3), 29.9 (C(CH3)3), 30.1 (CH2CH2CHCO2CH3 from one diastereoisomer), 30.1 (CH2CH2CHCO2CH3 from one diastereoisomer), 30.7

181

(CH2CH2CHCO2CH3 from one diastereoisomer), 37.8 (C(CH3)3), 38.2 (CH2Ar from one diastereoisomer), 38.5 (CH2Ar from one diastereoisomer), 40.4, (CHCO2CH), 47.4 (CHCH2Ar from one diastereoisomer), 47.6 (CHCH2Ar from one diastereoisomer), 49.0 (CH2C(CH3)3 from one diastereoisomer), 50.1 (CH2C(CH3)3 from one diastereoisomer), 51.5 (CO2CH3 from one diastereoisomer), 51.6 (CO2CH3 from one diastereoisomer), 75.4 (CO2CH from one diastereoisomer), 79.1 (CO2CH from one diastereoisomer), 126.4 (ArCH from one diastereoisomer), 126.4 (ArCH from one diastereoisomer), 128.4 (ArCH from one diastereoisomer), 128.4 (ArCH from one diastereoisomer), 128.4 (ArCH from one diastereoisomer), 128.5 (ArCH from one diastereoisomer), 139.0 (ArC from one diastereoisomer), 139.1 (ArC from one diastereoisomer), 173.3 (CO2CH from one diastereoisomer), 175.2 (CO2CH from one diastereoisomer), 175.7 (CO2CH3 from one

-1 diastereoisomer), 175.8 (CO2CH3 from one diastereoisomer) ppm; IR vmax (thin film, cm )

+ = 2949, 1728 (C=O), 1454, 1364, 1247, 1162, 1075; HRMS calcd. for C22H32O4Na [M+Na] 383.2193, found 383.2180.

Rac–methyl (R)–2–(4–bromobenzyl)–4–((3S,6S)–6–ethyl–2–oxotetrahydro–2H–pyran–3– yl)butanoate (130a)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.), H2O (29 µL, 1.6 mmol, 16 eq.) and rac–methyl (3R,6S)–3–((E)–4–(4–bromophenyl)but–3–en–1–yl)–6–ethyl–2–oxotetrahydro–2H–pyran– 3–carboxylate 128a (39 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil, as a 2.5:1

1 mixture of diastereoisomers (27 mg, 0.067 mmol, 67%). H NMR (500 MHz, CDCl3) δ 0.99 (t,

J = 7.5 Hz, 3H, CH2CH3), 1.44–1.66 (m, 5H, CH2CHCO2CH3 + CHaHbCH2CHCO2CH3 +

CO2CHCHaHbCH2 + CO2CHCH2CHaHb), 1.66–1.78 (m, 2H, CH2CH3), 1.81–2.09 (m, 3H,

CHaHbCH2CHCO2CH3 + CO2CHCHaHbCH2 + CO2CHCH2CHaHb), 2.27–2.35 (m, 0.71H, CHCO2CH from major diastereoisomer), 2.38–2.48 (m, 0.29H, CHCO2CH from minor diastereoisomer),

2.59–2.69 (m, 1H, CHCO2CH3), 2.73 (dd, J = 13.7, 6.4 Hz, 1H, CHaHbAr), 2.90 (dd, J = 13.7,

8.4 Hz, 1H, CHaHbAr), 3.61 (s, 3H, CO2CH3), 4.13–4.22 (m, 1H, CO2CH), 7.03 (d, J = 8.4 Hz, 2H,

13 ArCH), 7.40 (d, J = 8.4 Hz, 2H, ArCH) ppm; C NMR (126 MHz, CDCl3) δ 9.2 (CH2CH3), 25.6

182

(CH2CH2CHCO2CH3), 28.3 (CH2CH2CHCO2CH3), 29.1 (CH2CH3), 29.3 (CO2CHCH2CH2), 29.7

(CO2CHCH2CH2), 37.8 (CH2Ar), 40.8 (CHCO2CH), 47.3 (CHCH2Ar), 51.6 (CO2CH3), 82.6 (CO2CH),

120.3 (ArCBr), 130.6 (ArCH), 131.5 (ArCH), 138.0 (ArC), 173.4 (CO2CH), 175.4 (CO2CH3) ppm;

-1 IR vmax (thin film, cm ) = 2950, 2926, 1730 (C=O), 1488, 1246, 1193, 1102; HRMS calcd. for

+ C19H25O4BrNa [M+Na] 419.0828, found 419.0815.

Rac–methyl (R)–4–((3S,6S)–6–ethyl–2–oxotetrahydro–2H–pyran–3–yl)–2–(naphthalen–1– ylmethyl)butanoate (130b)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.), H2O (29 µL, 1.6 mmol, 16 eq.) and rac–methyl (3R,6S)–6–ethyl–3–((E)–4–(naphthalen–2–yl)but–3–en–1–yl)–2–oxotetrahydro–2H–pyran– 3–carboxylate 128b (37 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil, as a 2.7:1

1 mixture of diastereoisomers (23 mg, 0.062 mmol, 62%). H NMR (400 MHz, CDCl3) δ 0.95–

1.05 (m, 3H, CH2CH3), 1.40–1.85 (m, 7H, CH2CH3 + CH2CH2CHCO2CH3 + CO2CHCHaHb +

CO2CHCH2CHaHb + CHaHbCH2CHCO2CH3), 1.85–2.10 (m, 3H, CO2CHCHaHb + CO2CHCH2CHaHb +

CHaHbCH2CHCO2CH3), 2.26–2.35 (m, 0.73H, CHCO2CH from major diastereoisomer), 2.37–

2.48 (m, 0.27H, CHCO2CH from minor diastereoisomer), 2.75–2.84 (m, 1H, CHCH2Ar), 2.93

(dd, J = 13.6, 6.8 Hz, 1H, CHaHbAr), 3.14 (dd, J = 13.6, 7.9 Hz, 1H, CHaHbAr), 3.60 (s, 3H,

CO2CH3), 4.12–4.21 (m, 1H, CO2CH), 7.30 (dd, J = 8.4, 1.8 Hz, 1H, ArCH), 7.45 (tt, J = 6.8, 5.2 Hz, 2H, ArCH), 7.61 (d, J = 2.0 Hz, 1H, ArCH), 7.73–7.84 (m, 3H, ArCH) ppm; 13C NMR (101 MHz,

CDCl3) δ 9.2 (CH2CH3), 25.5 (CH2CH2CHCO2CH3), 28.3 (CO2CHCH2CH2), 29.1 (CH2CH3), 29.3

(CH2CH2CHCO2CH3), 29.8 (CO2CHCH2), 38.7 (CH2Ar), 40.8 (CHCO2CH), 47.4 (CHCH2Ar), 51.6

(CO2CH3), 82.6 (CO2CH), 125.5 (ArCH), 126.0 (ArCH), 127.2 (ArCH), 127.3 (ArCH), 127.6 (ArCH),

127.6 (ArCH), 128.1 (ArCH), 132.2 (ArC), 133.5 (ArC), 136.6 (ArC), 173.5 (CO2CH), 175.8

-1 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2953, 1729 (C=O), 1455, 1239, 1191, 1092, 963;

+ HRMS calcd. for C23H28O4Na [M+Na] 391.1880, found 391.1863.

183

Rac–methyl (R)–4–((3S,6S)–6–ethyl–2–oxotetrahydro–2H–pyran–3–yl)–2–(2– fluorobenzyl)butanoate (130c)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.), H2O (29 µL, 1.6 mmol, 16 eq.) and rac–methyl (3R,6S)–6–ethyl–3–((E)–4–(2–fluorophenyl)but–3–en–1–yl)–2–oxotetrahydro–2H–pyran– 3–carboxylate 128c (33 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil, as a 2.6:1

1 mixture of diastereoisomers (27 mg, 0.081 mmol, 81%). H NMR (400 MHz, CDCl3) δ 0.95–

1.04 (m, 3H, CH2CH3), 1.42–1.81 (m, 7H, CH2CH3 + CH2CH2CHCO2CH3 + CO2CHCHaHbCH2 +

CO2CHCH2CHaHb + CHaHbCH2CHCO2CH3), 1.83–2.11 (m, 3H, CO2CHCHaHbCH2 +

CO2CHCH2CHaHb + CHaHbCH2CHCO2CH3), 2.28–2.36 (m, 0.72H, CHCO2CH from major diastereoisomer), 2.39–2.49 (m, 0.28H, CHCO2CH from minor diastereoisomer), 2.69–2.78

(m, 1H, CHCO2CH3), 2.84–2.94 (m, 2H, CH2Ar), 3.61 (s, 3H, CO2CH3), 4.13–4.25 (m, 1H, CO2CH),

13 6.97–7.08 (m, 2H, ArCH), 7.10–7.25 (m, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 9.2

(CH2CH3), 25.6 (CH2CH2CHCO2CH3), 28.3 (CH2CH2CHCO2CH3), 29.1 (CH2CH3), 29.3

(CO2CHCH2CH2), 29.7 (CO2CHCH2CH2), 31.8 (d, J = 2.0 Hz, CH2Ar), 40.8 (CHCO2CH), 47.4

(CHCH2Ar), 51.6 (CO2CH3), 82.6 (CO2CH), 115.3 (d, J = 22.1 Hz, ArCH), 124.0 (d, J = 3.7 Hz, ArCH), 126.0 (d, J = 15.7 Hz, ArCH), 128.3 (d, J = 8.2 Hz, ArCH), 131.2 (d, J = 4.5 Hz, ArC), 161.2

19 (d, J = 245.2 Hz, ArCF), 173.5 (CO2CH), 175.5 (CO2CH3) ppm; F NMR (376 MHz, CDCl3) δ

-1 –118.0 ppm; IR vmax (thin film, cm ) = 2933, 1729 (C=O), 1492, 1372, 1229, 1163, 1105; HRMS

+ calcd. for C19H25O4FNa [M+Na] 359.1629, found 359.1614.

Rac–methyl (R)–4–((3S,6S)–6–ethyl–2–oxotetrahydro–2H–pyran–3–yl)–2–(4– methoxybenzyl)butanoate (130d)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.), H2O (29 µL, 1.6 mmol, 16 eq.) and rac–methyl

184

(3R,6S)–6–ethyl–3–((E)–4–(4–methoxyphenyl)but–3–en–1–yl)–2–oxotetrahydro–2H– pyran–3–carboxylate 128d (35 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 85:15) yielded the title product as a yellow oil, as a 3.7:1

1 mixture of diastereoisomers (22 mg, 0.063 mmol, 63%). H NMR (400 MHz, CDCl3) δ 0.92–

1.95 (m, 3H, CH2CH3), 1.41–1.76 (m, 7H, CH2CH3 + CO2CHCHaHb + CO2CHCH2CHaHb +

CHaHbCH2CHCO2CH3 + CH2CHCO2CH3), 1.84–2.01 (m, 3H, CO2CHCHaHb + CO2CHCH2CHaHb +

CHaHbCH2CHCO2CH3), 2.24–2.34 (m, 0.79H, CHCO2CH from major diastereoisomer), 2.38–

2.48 (m, 0.21H, CHCO2CH from minor diastereoisomer), 2.59–2.66 (m, 1H, CHCO2CH3), 2.71

(dd, J = 13.6, 6.8 Hz, 1H, CHaHbAr), 2.89 (dd, J = 13.6, 7.7 Hz, 1H, CHaHbAr), 3.61 (s, 3H,

CO2CH3), 3.78 (s, 3H, ArOCH3), 4.13–4.22 (m, 1H, CO2CH), 6.76–6.85 (m, 2H, ArCH), 6.98–7.13

13 (m, 2H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 9.2 (CH2CH3), 25.5 (CO2CHCH2CH2), 28.2

(CO2CHCH2), 29.1 (CH2CHCO2CH3), 29.2 (CH2CH3), 29.8 (CH2CH2CHCO2CH3), 37.6 (CH2Ar), 40.8

(CHCO2CH), 47.7 (CHCO2CH3), 51.5 (CO2CH3), 55.2 (ArOCH3), 82.6 (CO2CH), 113.8 (ArCH),

129.8 (ArCH), 131.1 (ArC), 158.2 (ArCOCH3), 173.5 (CO2CH), 175.8 (CO2CH3) ppm; IR vmax (thin

-1 film, cm ) = 2956, 2178, 1733 (C=O), 1443, 1271, 1217, 1193; HRMS calcd. for C20H28O5Na [M+Na]+ 371.1829, found 371.1815.

Rac–methyl (R)–2–(3–chlorobenzyl)–4–((3S,6S)–6–ethyl–2–oxotetrahydro–2H–pyran–3– yl)butanoate (130e)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.), H2O (29 µL, 1.6 mmol, 16 eq.) and rac–methyl (3R,6S)–3–((E)–4–(3–chlorophenyl)but–3–en–1–yl)–6–ethyl–2–oxotetrahydro–2H–pyran– 3–carboxylate 128e (35 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 85:15) yielded the title product as a yellow oil, as a 3.9:1

1 mixture of diastereoisomers (20 mg, 0.057 mmol, 57%). H NMR (400 MHz, CDCl3) δ 0.99 (t,

J = 7.5 Hz, 3H, CH2CH3), 1.46–1.79 (m, 7H, CH2CH3 + CO2CHCHaHb + CO2CHCH2CHaHb +

CHaHbCH2CHCO2CH3 + CH2CHCO2CH3), 1.83–2.08 (m, 3H, CO2CHCHaHb + CO2CHCH2CHaHb +

CHaHbCH2CHCO2CH3), 2.26–2.37 (m, 0.8H, CHCO2CH from major diastereoisomer), 2.39–2.48

(m, 0.2H, CHCO2CH from minor diastereoisomer), 2.62–2.69 (m, 1H, CHCO2CH3), 2.74 (dd,

J = 13.6, 6.6 Hz, 1H, CHaHbAr), 2.93 (dd, J = 13.6, 8.2 Hz, 1H, CHaHbAr), 3.62 (s, 3H, CO2CH3),

185

13 4.13–4.24 (m, 1H, CO2CH), 7.00–7.18 (m, 1H, ArCH), 7.13–7.24 (m, 3H, ArCH) ppm; C NMR

(101 MHz, CDCl3) δ 9.2 (CH2CH3), 25.6 (CH2CH2CHCO2CH3), 28.3 (CH2CH2CHCO2CH3), 29.1

(CH2CH3), 29.3 (CO2CHCH2CH2), 29.7 (CO2CHCH2), 38.0 (CH2Ar), 40.8 (CHCO2CH), 47.2

(CHCH2Ar), 51.6 (CO2CH3), 82.6 (CO2CH), 126.7 (ArCH), 127.0 (ArCH), 129.0 (ArCH), 129.7

(ArCH), 134.2 (ArCCl), 141.1 (ArC), 173.4 (CO2CH), 175.4 (CO2CH3) ppm; IR vmax (thin film,

-1 + cm ) = 2202, 1733 (C=O), 1538, 1422, 1264, 1089; HRMS calcd. for C19H25O4ClNa [M+Na] 375.1334, found 375.1319.

(E)–2–(3–Oxobutyl)–2–(4–phenylbut–3–en–1–yl)malonic acid (S4)

A solution of dimethyl (E)–2–(3–oxobutyl)–2–(4–phenylbut–3–en–1–yl)malonate 115a

(150 mg, 0.45 mmol, 1.0 eq.) and NaOH (0.77 mL, 2.0 M in H2O, 1.5 mmol, 3.3 eq.) was heated to 95 °C for 12 h. The reaction was then cooled to room temperature and extracted with hexane (3 mL). The aqueous layer was acidified to pH 1 using aq. HCl, and was extracted with

EtOAc (3 x 3 mL). The combined organic layers were dried (MgSO4) and concentrated. 1H NMR analysis indicated quantitative conversion to the title product and the crude product

1 mixture was used in the following step without further purification. H NMR (400 MHz, CDCl3)

δ 2.07–2.29 (m, 9H, C(O)CH2CH2 + CH=CHCH2 + CH=CHCH2CH2 + C(O)CH3), 2.55 (t, J = 7.7 Hz,

2H, C(O)CH2), 6.14 (dt, J = 15.8, 6.5 Hz, 1H, CH=CHAr), 6.40 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.15–7.26 (m, 2H, ArCH), 7.28–7.32 (m, 3H, ArCH), 10.44 (bs, 2H, C(O)OH) ppm.

(E)–2–(3–Oxobutyl)–2–(4–phenylbut–3–en–1–yl)malonyl dichloride (S5)

186

To a solution of the crude product mixture of (E)–2–(3–oxobutyl)–2–(4–phenylbut–3–en–1– yl)malonic acid S4 (134 mg, 0.45 mmol, 1.0 eq.) in CH2Cl2 (2 mL) was added oxalyl chloride (0.1 mL, 2.0 mmol, 4.4 eq.). The mixture was cooled to 0 °C and DMF (cat.) was added. After 5 minutes, the reaction was allowed to warm to room temperature and was stirred for a further 3 h then concentrated. 1H NMR analysis indicated full consumption of starting material and the crude product mixture was used directly in the following step.

Diphenyl (E)–2–(3–oxobutyl)–2–(4–phenylbut–3–en–1–yl)malonate (132)

The crude reaction mixture of (E)–2–(3–oxobutyl)–2–(4–phenylbut–3–en–1–yl)malonyl dichloride S5 (154 mg, 0.45 mmol, 1.0 eq.) was dissolved in CH2Cl2 (2.5 mL) and DMAP (6 mg, 0.05 mmol, 0.1 eq.) and phenol (107 mg, 1.14 mmol, 2.0 eq.) were added. The solution was cooled to 0 °C and NEt3 (0.14 mL, 1.1 mmol, 2.5 eq.) was added dropwise. The reaction was allowed to warm to room temperature and was stirred to 36 h. The reaction was quenched by the addition of H2O (1 mL) and the aqueous layer was extracted with EtOAc (3 x 3 mL).

The combined organic layers were washed with NaHCO3 (2 mL), dried (MgSO4) and concentrated. Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded

1 the title product as an orange oil (50 mg, 0.11 mmol, 24%). H NMR (400 MHz, CDCl3) δ 2.21

(s, 3H, CH3), 2.31–2.45 (m, 4H, CH2CH2CH=CHAr + CH2CH2CH=CHAr), 2.50 (dd, J = 8.6, 6.8 Hz,

2H, C(O)CH2CH2), 2.70 (dd, J = 8.6, 6.8 Hz, 2H, C(O)CH2CH2), 6.26 (dt, J = 15.8, 6.3 Hz, 1H, CH=CHAr), 6.50 (d, J = 15.8 Hz, 1H, CH=CHAr), 7.17–7.26 (m, 5H, ArCH), 7.28–7.43 (m, 10H,

13 ArCH) ppm; C NMR (101 MHz, CDCl3) δ 26.7 (C(O)CH2CH2), 27.9 (CH2CH2CH=CHAr), 30.1

(C(O)CH3), 33.4 (CH2CH2CH=CHAr), 38.6 (C(O)CH2CH2), 57.0 (Cq), 121.3 (ArCH), 126.1 (ArCH), 126.3 (ArCH), 127.3 (ArCH), 128.6 (ArCH), 128.6 (CH=CHAr), 129.7 (ArCH), 131.2 (CH=CHAr),

-1 137.3 (ArC), 150.4 (ArCO), 169.7 (CO2Ph), 206.8 (C(O)) ppm; IR vmax (thin film, cm ) = 2941,

+ 1749 (C=O), 1733 (C=O), 1492, 1194, 1163, 1099; HRMS calcd. for C29H28O5Na [M+Na] 479.1829, found 429.1819.

187

Rac–phenyl (3R,6S)–6–methyl–2–oxo–3–((E)–4–phenylbut–3–en–1–yl)tetrahydro–2H– pyran–3–carboxylate (133)

Prepared according to general procedure I using diphenyl (E)–2–(3–oxobutyl)–2–(4– phenylbut–3–en–1–yl)malonate 132 (45 mg, 0.099 mmol, 1.0 eq.), SmI2 (2.5 mL, 0.1 M in

THF, 0.25 mmol, 2.5 eq.) and H2O (0.44 mL, 25 mmol, 250 eq.) followed by pTSA (10 mg,

0.05 mmol, 5 mol%) in CH2Cl2 (12 mL). Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title product as a colourless oil as a 9:1 mixture of

1 diastereoisomers (18 mg, 0.049 mmol, 50%). H NMR (400 MHz, CDCl3) δ 1.44 (d, J = 6.2 Hz,

3H, CHCH3), 1.74 (ddt, J = 14.0, 10.6, 8.0 Hz, 1H, CO2CHCHaHb), 1.93–2.24 (m, 3H, CO2CHCHaHb

+ CO2CHCH2CHaHb + CHaHbCH2CH=CHAr), 2.28–2.56 (m, 3H, CH2CH2CH=CHAr +

CHaHbCH2CH=CHAr), 2.68 (dt, J = 14.0, 8.0 Hz, 1H, CO2CHCH2CHaHb), 4.55 (dtd, J = 12.4, 6.2,

3.1 Hz, 0.9H, CO2CH from major diastereoisomer), 4.87 (m, 0.1H, CO2CH from minor diastereoisomer), 6.23 (dt, J = 15.7, 6.4 Hz, 1H, CH=CHAr), 6.47 (d, J = 15.7 Hz, 1H, CH=CHAr),

13 7.04–7.27 (m, 4H, ArCH), 7.29–7.46 (m, 6H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 21.5

(CHCH3), 27.3 (CO2CHCH2CH2), 27.7 (CO2CHCH2), 28.1 (CH2CH2CH=CHAr), 36.0

(CH2CH2CH=CHAr), 75.4 (CO2CH), 121.1 (ArCH), 126.1 (ArCH), 126.4 (ArCH), 127.2 (ArCH), 128.5 (ArCH), 129.0 (CH=CHAr), 129.7 (ArCH), 130.9 (CH=CHAr), 137.1 (ArC), 150.4 (ArCO),

-1 169.9 (CO2CH), 170.2 (CO2Ph) ppm; IR vmax (thin film, cm ) = 2970, 1729 (C=O), 1645, 1260,

+ 1077, 1021; HRMS calcd. for C23H24O4Na [M+Na] 387.1567, found 387.1555.

Ethyl 2–oxotetrahydro–2H–pyran–3–carboxylate (S6)[33]

A solution of LDA was prepared by adding nBuLi (7.0 mL, 1.0 M in hexane, 11 mmol, 1.5 eq.) to DIPA (1.6 mL, 11 mmol, 1.5 eq.) in THF (30 mL) at –78 °C. The resulting mixture was stirred at this temperature for 1 h, then was warmed to 0 °C for 10 minutes and then cooled to –78 °C again. A solution of δ–valerolactone (0.69 mL, 7.5 mmol, 1.0 eq.) in THF (7.5 mL) was added via a syringe pump over a period of 30 minutes. The solution was maintained at this

188 temperature for 1 h, then was warmed to 0 °C for 10 minutes, before cooling again to –78 °C. Ethyl chloroformate (1.1 mL, 11 mmol, 1.5 eq.) was added and the reaction was allowed to warm to room temperature and was stirred for 14 h. The reaction was quenched by addition of saturated aqueous NH4Cl (5 mL), the aqeuous layer was extracted with EtOAc (3 x 15 mL), the combined organic layers were washed with brine (15 mL), dried (MgSO4) and concentrated. Purificaction by silica gel column chromatography (hexane/EtOAc 7:3) yielded

1 the title product as a yellow oil (0.55 g, 3.2 mmol, 42%). H NMR (400 MHz, CDCl3) δ 1.31 (t,

J = 7.1 Hz, 3H, CO2CH2CH3), 1.84–1.91 (m, 1H, C(O)CHCHaHb), 2.00 (ddd, J = 11.3, 6.4, 3.1 Hz,

1H, C(O)CHCHaHb), 2.13–2.22 (m, 1H, CO2CH2CHaHb), 2.23–2.33 (m, 1H, CO2CH2CHaHb), 3.56

(t, J = 7.9 Hz, 1H, CHCO2CH2), 4.20–4.30 (m, 2H, CH2CH3), 4.33–4.44 (m, 2H, CO2CH2CH2) ppm;

13 C NMR (101 MHz, CDCl3) 14.1 (CH2CH3), 20.9 (CHCH2CH2), 22.8 (CHCH2), 47.5 (CH), 61.6

(CO2CH2CH3), 69.6 (CO2CH), 167.7 (CO2CH2), 169.1 (CO2CH3) ppm. Data is consistent with literature.

(E)–(4–Bromobut–1–en–1–yl)benzene/((E)–(4–chlorobut–1–en–1–yl)benzene) (S7)[33]

To a solution of cyclopropyl magnesium bromide (16 mL, 0.5 M in THF, 8.0 mmol, 1.2 eq.) at 0 °C was added benzaldehyde (0.68 mL, 6.7 mmol, 1.0 eq.). After 15 minutes, acetyl chloride (0.57 mL, 8.0 mmol, 1.2 eq.) was added and the reaction was heated to 50 °C for 1 h. The reaction was then cooled to room temperature and concentrated. The crude residue was dissolved in a 1:1 mixture of H2O and Et2O (20 mL) and the organic layer was separated, the aqueous layer was extracted with Et2O (2 x 20 mL), the organic layers were combined, dried

(MgSO4) and concentrated. Purification by silica gel column chromatography (hexane) yielded the title product as a yellow oil, as an inseperable mixture of halides (5.7:1 Br:Cl)

1 (0.83 g, 3.4 mmol, 51%). H NMR (500 MHz, CDCl3) δ 2.70 (qd, J = 7.0, 1.5 Hz, 0.3H, CH2CH2Cl),

2.79 (qd, J = 7.0, 1.5 Hz, 1.7H, CH2CH2Br), 3.49 (t, J = 7.0 Hz, 1.7H, CH2Br), 3.64 (t, J = 7.0 Hz,

0.3H, CH2Cl), 6.21 (dt, J = 15.9, 7.0 Hz, 1H, CH=CHAr), 6.50 (d, J = 15.9 Hz, 1H, CH=CHAr), 7.22– 7.26 (m, 1H, ArCH), 7.32 (dd, J = 8.5, 7.2 Hz, 2H, ArCH), 7.38 (d, J = 7.2 Hz, 2H, ArCH) ppm; 13C

NMR (126 MHz, CDCl3) δ 32.3 (CH2Br), 36.3 (CH2CH2Br), 126.2 (ArCH), 126.7 (ArCH), 127.5 (ArCH), 128.6 (ArC), 132.7 (CH=CHAr), 137.0 (CH=CHAr) ppm. Data is consistent with literature.

189

Ethyl (E)–2–oxo–3–(4–phenylbut–3–en–1–yl)tetrahydro–2H–pyran–3–carboxylate (134)[33]

To a solution of NaH (0.12 g, 3.0 mmol, 1.2 eq.) in DMF (15 mL) at 0 °C was added a solution of ethyl 2–oxotetrahydro–2H–pyran–3–carboxylate S6 (431 mg, 2.50 mmol, 1.0 eq.) in DMF (7 mL). The reaction was heated to 60 °C for 1 h, then cooled to room temperature and (E)– (4–halobut–1–en–1–yl)benzene S7 (5.7:1 Br:Cl mixture of halides, 614 mg, 3.00 mmol, 1.2 eq.) was added. The reaction was again heated to 60 °C for a further 14 h, then was quenched with H2O (10 mL) and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with H2O (15 mL), dried (MgSO4) and concentrated. Purification by silica gel column chromatography (hexane/EtOAc 9:1) yielded the title

1 product as a colourless oil (0.45 g, 1.5 mmol, 59%). H NMR (400 MHz, CDCl3) δ 1.30 (t, J =

7.1 Hz, 3H, CH2CH3), 1.82–2.03 (m, 3H, CO2CH2CH2 + CHaHbCH2CH=CHAr), 2.06–2.15 (m, 2H,

CO2CH2CH2CH2), 2.18–2.29 (m, 1H, CHaHbCH=CHAr), 2.32–2.42 (m, 1H, CHaHbCH=CHAr),

2.43–2.53 (m, 1H, CHaHbCH2CH=CHAr), 4.19–4.37 (m, 4H, CH2CH3 + CO2CH2CH2), 6.18 (dt, J = 15.8, 6.7 Hz, 1H, CH=CHAr), 6.43 (d, J = 15.6 Hz, 1H, CH=CHAr), 7.16–7.27 (m, 1H, ArCH), 7.28–

13 7.37 (m, 4H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 14.1 (CH2CH3), 20.6 (CO2CH2CH2), 28.2

(CH2CH=CHAr), 28.2 (CH2CH2CH=CHAr), 36.0 (CO2CH2CH2CH2), 53.9 (Cq), 62.4 (CO2CH2CH3),

68.7 (CH2CH2), 126.0 (ArCH), 127.1 (ArCH), 128.4 (ArCH), 129.2 (CH=CHAr), 130.7 (CH=CHAr),

137.5 (ArC), 170.2 (CO2CH2CH2), 171.3 (CO2CH2CH3) ppm. Data is consistent with literature.

Ethyl 2-benzyl-4-(2-oxotetrahydro-2H-pyran-3-yl)butanoate (136) and rac-ethyl (1R,3R)-1- benzyl-3-(3-hydroxypropyl)-2-oxocyclopentane-1-carboxylate (135)[33]

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), H2O (29 µL, 1.6 mmol, 16.0 eq.), HMPA (0.17 mL, 1.0 mmol, 10.0 eq.) and ethyl (E)– 2–oxo–3–(4–phenylbut–3–en–1–yl)tetrahydro–2H–pyran–3–carboxylate 134 (30 mg,

190

0.10 mmol, 1.0 eq.) in THF. Purification by silica gel column chromatography (hexane/EtOAc 9:1 to 7:3) yielded title product ethyl 2-benzyl-4-(2-oxotetrahydro-2H-pyran-3-yl)butanoate 136 as a colourless oil, as a 1:1 mixture of diastereoisomers (6 mg, 0.02 mmol, 20%), as well as rac-ethyl (1R,3R)-1-benzyl-3-(3-hydroxypropyl)-2-oxocyclopentane-1-carboxylate 136 as a colourless oil, as a 5:1 mixture of diastereoisomers (5.0 mg, 0.016 mmol, 16%).

1 136 H NMR (500 MHz, CDCl3) δ 1.15 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 1.41–1.68 (m, 3H,

CO2CH2CHaHb + CO2CH2CH2CHaHb + CHaHbCHCO2CH2CH3), 1.69–1.80 (m, 1H,

CHaHbCHCO2CH2CH3), 1.82–1.92 (m, 3H, CO2CH2CHaHb + CH2CH2CHCO2CH2CH3), 2.01–2.11 (m,

1H, CO2CH2CH2CHaHb), 2.28–2.41 (m, 0.5H, CHCO2CH2CH2 from one diastereoisomer), 2.41–

2.48 (m, 0.5H, CHCO2CH2CH2 from one diastereoisomer), 2.61–2.72 (m, 1H, CHCO2CH2CH3),

2.75–2.83 (m, 1H, CHaHbAr), 2.89–2.99 (m, 1H, CHaHbAr), 4.06 (q, J = 7.1 Hz, 2H, CO2CH2CH3),

4.26–4.31 (m, 2H, CO2CH2CH2), 7.14–7.25 (m, 4H, ArCH), 7.28–7.37 (m, 1H, ArCH) ppm;

13 C NMR (126 MHz, CDCl3) δ 14.2 (CO2CH2CH3), 21.9 (CH2CH2CHCO2CH2CH3 from one diastereoisomer), 22.0 (CH2CH2CHCO2CH2CH3 from one diastereoisomer), 24.5

(CO2CH2CH2CH2), 28.8 (CO2CH2CH2 from one diastereoisomer), 29.2 (CO2CH2CH2 from one diastereoisomer), 29.4 (CH2CHCO2CH2CH3 from one diastereoisomer), 29.7

(CH2CHCO2CH2CH3 from one diastereoisomer), 38.4 (CH2Ar from one diastereoisomer), 38.7

(CH2Ar from one diastereoisomer), 39.4 (CHCO2CH2CH2), 47.5 (CHCO2CH2CH3 from one diastereoisomer), 47.6 (CHCO2CH2CH3 from one diastereoisomer), 60.3 (CO2CH2CH3), 68.2

(CO2CH2CH2 from one diastereoisomer), 68.3 (CO2CH2CH2 from one diastereoisomer), 126.4 (ArCH from one diastereoisomer), 128.4 (ArCH from one diastereoisomer), 128.5 (ArCH from one diastereoisomer), 128.5 (ArCH from one diastereoisomer), 128.9 (ArCH from one diastereoisomer), 129.1 (ArCH from one diastereoisomer), 139.1 (ArC from one diastereoisomer), 139.2 (ArC from one diastereoisomer), 175.3 (CO2CH2CH2), 175.9

-1 (CO2CH2CH3) ppm; IR vmax (thin film, cm ) = 2952, 2016, 1729 (C=O), 1457, 1171, 1081; HRMS

+ calcd. for C18H24O4Na [M+Na] 327.1567, found 327.1554.

1 135 H NMR (400 MHz, CDCl3) δ 1.24 (t, J = 7.1 Hz, 3H, CO2CH2CH3), 1.39–1.51 (m, 1H,

C(O)CCHaHb), 1.52–1.66 (m, 3H, C(O)CCHaHb + C(O)CHCHaHb + CHaHbCH2OH), 1.82 (dd,

J = 11.6, 9.4 Hz, 1H, CHaHbCH2OH), 1.92 (ddd, J = 13.3, 7.1, 3.4 Hz, 1H, CHaHbCH2CH2OH), 1.99–

2.14 (m, 1H, C(O)CHCHaHb), 2.37 (ddd, J = 13.3, 10.0, 7.1 Hz, 1H, CHaHbCH2CH2OH), 2.62 (dd,

J = 13.5, 9.0 Hz, 1H, CHaHbAr), 2.64–2.73 (m, 1H, C(O)CH), 3.14 (dd, J = 13.6, 4.0 Hz, 1H,

CHaHbAr), 3.54–3.64 (m, 2H, CH2OH), 4.17 (q, J = 7.1 Hz, 2H, CO2CH2CH3), 7.12–7.25 (m, 4H,

13 ArCH), 7.28–7.33 (m, 1H, ArCH) ppm; C NMR (101 MHz, CDCl3) δ 14.1 (CO2CH2CH3), 25.2

191

(C(O)CHCH2), 27.9 (C(O)CCH2), 29.0 (CH2CH2OH), 30.5 (CH2CH2CH2OH), 35.6 (CH2Ar), 50.8

(C(O)CH), 59.9 (Cq), 61.5 (CO2CH2CH3), 62.7 (CH2OH), 126.4 (ArCH), 128.5 (ArCH), 129.1

(ArCH), 139.4 (ArC), 171.6 (CO2CH2CH3), 214.6 (C(O)) ppm. Data is consistent with literature.

Dimethyl (E)–2–methyl–2–(4–phenylbut–3–en–1–yl)malonate (137)

To a solution of NaH (21 mg, 0.84 mmol, 1.2 eq.) in THF (0.3 mL) was added dropwise a solution of dimethyl (E)–2–(4–phenylbut–3–en–1–yl)malonate 125 (0.20 g, 0.76 mmol, 1.0 eq.) in THF (0.3 mL). After 30 minutes, methyl iodide (0.10 mL, 1.5 mmol, 2.0 eq.) was added and the reaction was stirred for a further 18 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (1 mL) and the aqueous layer was extracted with EtOAc

(3 x 3 mL). The combined organic layers were washed with brine (3 mL), dried (MgSO4) and concentrated. Purification by silica gel column chromatography (hexane/EtOAc 95:5) yielded

1 the title product as a colourless oil (118 mg, 0.430 mmol, 56%). H NMR (400 MHz, CDCl3) δ

1.48 (s, 3H, CCH3), 2.01–2.13 (m, 2H, CH2CH2CH=CHAr), 2.13–2.30 (m, 2H, CH2CH2CH=CHAr),

3.73 (s, 6H, CO2CH3), 6.18 (dt, J = 15.9, 6.6 Hz, 1H, CH=CHAr), 6.41 (d, J = 15.9 Hz, 1H,

13 CH=CHAr), 7.18–7.24 (m, 1H, ArCH), 7.28–7.36 (m, 4H, ArCH) ppm; C NMR (101 MHz, CDCl3)

δ 20.1 (CCH3), 28.0 (CH2CH2CH=CHAr), 35.2 (CH2CH2CH=CHAr), 52.5 (CO2CH3), 53.4 (Cq), 126.0 (ArCH), 127.0 (ArCH), 128.5 (ArCH), 129.4 (CH=CHAr), 130.5 (CH=CHAr), 137.5 (ArC), 172.7

-1 (CO2CH3) ppm; IR vmax (thin film, cm ) = 2997, 1732 (C=O), 1435, 1234, 1112, 966; HRMS

+ calcd. for C16H20O4Na [M+Na] 299.1254, found 299.1240.

Methyl 3–benzyl–2–hydroxycyclopentane–1–carboxylate (140)

Prepared according to general procedure L using SmI2 (2.5 mL, 0.1 M in THF, 0.25 mmol,

2.5 eq.), H2O (29 µL, 1.6 mmol, 16 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.) and (E)–2–(4–

192 phenylbut–3–en–1–yl)malonate 125 (26 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 9:1 to 7:3) yielded the title product as a colourless

1 oil, as a 1:1 mixture of diastereoisomers (10 mg, 0.042 mmol, 43%). H NMR (400 MHz, CDCl3)

δ 1.20–1.39 (m, 0.5H, CHaHbCHCH2Ar from one diastereoisomer), 1.51–1.66 (m, 0.5H,

CHaHbCHCH2Ar from one diastereoisomer), 1.71–1.86 (m, 1H, CHaHbCHCH2Ar from one diastereoisomer + CHaHbCHCO2CH3 from one diastereoisomer), 1.90–2.04 (m, 1.5H,

CHaHbCHCH2Ar from one diastereoisomer + CH2CHCO2CH3 from one diastereoisomer), 2.07–

2.16 (m, 0.5H, CHaHbCHCO2CH3 from one diastereoisomer), 2.22–2.37 (m, 1H, CHCH2Ar), 2.51

(dd, J = 13.7, 8.8 Hz, 0.5H, CHaHbAr from one diastereoisomer), 2.62 (dd, J = 13.8, 8.6 Hz,

0.5H, CHaHbAr from one diastereoisomer), 2.77–2.87 (m, 1H, CHaHbAr from one diastereoisomer + CHCO2CH3 from one diastereoisomer), 2.88–2.96 (m, 1H, CHaHbAr from one diastereoisomer + CHCO2CH3 from one diastereoisomer), 3.69 (s, 1.5H, CO2CH3 from one diastereoisomer), 3.73 (s, 1.5H, CO2CH3 from one diastereoisomer), 4.07 (t, J = 5.2 Hz, 0.5H, CHOH from one diastereoisomer), 4.30 (dd, J = 5.5, 3.7 Hz, 0.5H, CHOH from one diastereoisomer), 7.17–7.25 (m, 3H, ArCH), 7.28–7.33 (m, 2H, ArCH) ppm, OH not observed;

13 C NMR (101 MHz, CDCl3) δ 26.1 (CH2CHCO2CH3 from one diastereoisomer), 26.3

(CH2CHCO2CH3 from one diastereoisomer), 28.6 (CH2CHCH2Ar from one diastereoisomer),

28.9 (CH2CHCH2Ar from one diastereoisomer), 34.7 (CH2Ar from one diastereoisomer), 39.7

(CH2Ar from one diastereoisomer), 46.1 (CHCH2Ar from one diastereoisomer), 47.7

(CHCO2CH3 from one diastereoisomer), 48.3 (CHCH2Ar from one diastereoisomer), 51.8

(CO2CH3 from one diastereoisomer), 51.9 (CO2CH3 from one diastereoisomer), 52.5

(CHCO2CH3 from one diastereoisomer), 76.8 (CHOH from one diastereoisomer), 77.8 (CHOH from one diastereoisomer), 125.9 (ArCH from one diastereoisomer), 126.1 (ArCH from one diastereoisomer), 128.4 (ArCH from one diastereoisomer), 128.4 (ArCH from one diastereoisomer), 128.8 (ArCH from one diastereoisomer), 128.9 (ArCH from one diastereoisomer), 140.4 (ArC from one diastereoisomer), 141.2 (ArC from one diastereoisomer), 175.1 (CO2CH3 from one diastereoisomer), 175.4 (CO2CH3 from one

-1 diastereoisomer) ppm; IR vmax (thin film, cm ) = 3119 (O-H), 2950, 1716 (C=O), 1494, 1453,

+ 1250, 1169, 1051; HRMS calcd. for C14H28O3Na [M+Na] 257.1148, found 257.1137.

Methyl 3–benzyl–2–hydroxy–1–methylcyclopentane–1–carboxylate (141)

193

Prepared according to general procedure L using (2.5 mL, 0.1 M in THF, 0.25 mmol, 2.5 eq.),

H2O (29 µL, 1.6 mmol, 16 eq.), HMPA (0.17 mL, 1.0 mmol, 10 eq.) and dimethyl (E)–2–methyl– 2–(4–phenylbut–3–en–1–yl)malonate 137 (25 mg, 0.10 mmol, 1.0 eq.). Purification by silica gel column chromatography (hexane/EtOAc 8:2) yielded the title product as a colourless oil,

1 as a 4:1 mixture of diastereoisomers (5 mg, 0.02 mmol, 20%). H NMR (400 MHz, CDCl3) δ

1.30 (s, 3H, CCH3), 1.49–1.72 (m, 2H, CCH2CHaHb + CCHaHb), 1.72–1.88 (m, 1H, CCH2CHaHb),

2.18–2.32 (m, 1.6H, CCHaHb from major diastereoisomer + CHCH2Ar from major diastereoisomer), 2.32–2.45 (m, 0.4H, CCHaHb from minor diastereoisomer + CHCH2Ar from minor diastereoisomer), 2.66 (dd, J = 13.7, 8.1 Hz, 1H, CHaHbAr), 2.89 (dd, J = 13.7, 7.6 Hz,

1H, CHaHbAr), 3.66 (s, 2.4H, CO2CH3 from major diastereoisomer), 3.72 (s, 0.6H, CO2CH3 from minor diastereoisomer), 3.81–3.88 (m, 0.2H, CHOH from minor diastereoisomer), 4.15 (d, J = 4.6 Hz, 0.8H, CHOH from major diastereoisomer), 7.13–7.26 (m, 4H, ArCH), 7.27–7.32 (m, 1H,

13 ArCH) ppm, OH not observed; C NMR (101 MHz, CDCl3) δ 19.6 (CCH3), 28.2 (CCH2CH2), 33.3

(CCH2), 36.0 (CH2Ar), 45.6 (CHCH2Ar), 52.1 (CO2CH3), 54.9 (Cq), 78.1 (CHOH), 125.8 (ArCH),

-1 128.3 (ArCH), 128.7 (ArCH), 141.4 (ArC), 177.8 (CO2CH3) ppm; IR vmax (thin film, cm ) = 3205

+ (O-H), 2920, 1723 (C=O), 1455, 1158, 978; HRMS calcd. for C15H20O3Na [M+Na] 271.1305, found 271.1294.

194

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