CHAPTER 3: PALLADIUM-CATALYSED CROSS COUPLINGS REACTIONS ON LEVOGLUCOSENONE AND APPLICATION TO THE SYNTHESIS OF CHIRAL γ- BUTYROLACTONES

INTRODUCTION

Levoglucosenone (6,8-dioxabicyclo[3.2.1]oct-2-en-4-one, 251, LGO, Figure 28) is obtained from the pyrolysis of acidified cellulose and has attracted interest as a chiral synthon since its characterisation by Halpern et al. in 1973.113 Being derived from a sugar, LGO is obtained enantiopure and contains two stereocentres and various synthetic handles that make it attractive for use in synthesis. The 1,6-anhydro bridge has the general effect of directing reactivity to the α- face of the ring, and thus provides control of stereochemical outcomes during derivatisation.114

Figure 28 Levoglucosenone (251)

The saturated derivative of LGO (dihydrolevoglucosenone, DHLGN) has also attracted interest as a potential solvent, being a dipolar aprotic amphiphilic compound with dipolarity similar to N- methylpyrrolidinone (NMP), DMF and sulfolane.115

Mechanism of LGO formation Halpern originally postulated that levoglucosenone was formed from levoglucosan (LGA, 1,6-β- D-anhydroglucopyranose, 252) under acidic conditions (Scheme 22). Levoglucosan was detected as a major product in the tar fractions of pyrolysis experiments on cellulose and was largely replaced by levoglucosenone when acid catalysis was employed.

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Scheme 38 The key step is the 1,2-hydride shift from 254 to form a more stable hydroxycarbenium ion at either C2 or C4. Proton abstraction then further dehydration yields LGO 251 or its regioisomer iso-LGO 259. The fact that no iso-LGO is observed was rationalised by suggesting that the C2 hydroxycarbenium ion 255 is stabilised in comparison to the C4 cation 257 by overlap of the empty p-orbital at C2 and the filled p-orbital of the oxygen at C6. Broido et al. demonstrated soon after though that although some LGO could be formed from LGA under acid-catalysed pyrolysis conditions, the predominant source of LGO was not from LGA but from another unidentified mechanism, due to much higher yields of LGO relative to the loss of LGA under varying conditions.116 More recently it has been determined computationally that the relative energies of the carbenium ions 255 and 257 generated from the hydride transfer are very similar, and therefore regiospecificity of this process would be likely to be low and expected to lead to formation of both isomers.117,118 Indeed, any mechanistic proposal would have to explain the complete lack of iso-LGO (or derivatives arising from further known thermal decomposition processes such as deformylation119).118

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Shafidazeh et al. proposed a mechanism starting with 1,4:3,6-dianhydro-α-D-pyranose (260, Scheme 39), a minor constituent in the pyrolysis of D-glucose and cellulose.120 It was demonstrated that LGO could be generated from the pyrolysis of 260 in the presence of phosphoric acid, and the mechanistic rationale explains the fact that no iso-LGO is observed (Scheme 39).

Scheme 39 Pathway A involves initial hydrolysis to give hemiacetal 261a in equilibrium with its aldehydo form 261b, which undergoes 2,3-elimination and anhydro bridge ring opening to give enol 262a. Dehydration of the tautomer 262b affords enone 263 which after ring closure to pyranose 264 and dehydration to form the 1,6-anhydro bridge gives LGO 251. There is some question though as to the origin of the H2O in the primary hydrolysis step. Alternatively in Pathway B, direct 2,3- elimination and anhydro ring opening gives enol 265, which undergoes an intramolecular transglycosylation to give the enol 266. Tautomerisation of 266 followed by dehydration gives

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LGO 251. The primary 2,3-elimination step seems unlikely though as the hydrogen at C2 is syn to the 3,6-anhydro bridge. An alternate hybrid mechanism is proposed in Scheme 40.

Scheme 40 The mechanism bears resemblance to that of Shafidazeh, however the initial step is carbocation formation as opposed to elimination, with subsequent 1,2-hydride shift from C2 to C3 giving hydroxycarbenium ion 268. The preferential H2-C3 hydride shift over the H4-C3 shift (which would ultimately lead to iso-LGO) is explained on the basis of a stereoelectronic argument in which the C2-H2 σ-orbital has better overlap with the empty p-orbital on C3 compared to the C4- H4 bond which in the boat conformation would have a dihedral angle approximating 90°. The exact mechanisms leading to the formation of LGO during cellulose pyrolysis still remains unclear and the matter is complicated by the extreme conditions which make rearrangements with high-energy barriers plausible in mechanistic considerations. Although interest in these processes is ongoing, intimate knowledge of the mechanisms does not necessarily equate to an ability to optimise the pyrolytic conditions to increase LGO selectivity in a practical sense. Optimisation will likely continue to occur through an iterative approach as opposed to rational design based on the mechanism.

Large-scale preparation of LGO The ability to produce LGO efficiently on a large-scale is essential for its use as a chiral synthon to become widespread. That it can be produced from highly abundant and biorenewable cellulosic or lignocellulosic material makes it highly attractive as a target for large-scale industrial preparation. The term lignocellulosic refers to any plant-based material containing no less than

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30% cellulose as well as the structural polymer lignin and includes but is not limited to materials such as paper, cardboard, wood chips and sawdust.121 Many methods of obtaining LGO from the pyrolysis of cellulosic materials are known including the use of microwave-assisted techniques,122 ionic liquids, 123 solid acid (such as sulfated zirconia) catalysis124 and in the polar solvent sulfolane, with or without acid-catalysis.125,126 Very recently a report has emerged of a rapid sulfuric acid-catalysed high-yielding conversion of cellulose to LGO in THF at 190-210 °C.127 This particular report contains the highest recorded yield for LGO from cellulose (51%) under the mildest conditions, however the process is extremely sensitive to cellulose loading and water content. Yields are found to decrease dramatically if cellulose loading exceeds 1% w/w and if non-anhydrous THF is used. Despite interest in its production, failure to scale up thermochemical processing has meant that historically LGO has had a high price despite the ready availability of lignocellulosic materials. Recently, an industrial-scale thermochemical processing plant based at Circa Group in Melbourne, Australia has been established, which utilises Kawamoto’s procedure of phosphoric acid-catalysed pyrolysis in sulfolane.121 The patented development of a screw reactor has enabled the separation of the solid char that forms during pyrolysis from the volatile organic compounds, and has largely solved the problem of scalability. The pilot plant is currently capable of producing approximately 1 tonne per year of LGO in 13-18% yield (based on microcrystalline cellulose as feedstock). The wider availability of LGO has caused a renaissance in interest and provided new opportunities to use this now abundant source of chirality in synthesis.

Use of LGO in organic synthesis

The development of new transformations which utilise LGO is crucial to make use of this biorenewable resource. Reactions previously reported on LGO directly include the reaction of the alkene with electrophiles,128,129 Diels-Alder chemistry,130 1,3-dipolar cycloadditions,131 and conjugate addition chemistry (Scheme 41).132,133-136

LGO has also served as a platform chemical in a host of syntheses of naturally occurring and synthetic products of biological interest including the cigarette beetle sex pheromone serricornin 279,137(+)-chloriolide 280,138 the antibacterial lipid phytosphingosine 281,139 the potent cytotoxin

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(-)-tetradotoxin 282,140 (-)-hongcongin 283,141 (+)-pelargonolactone 284,142 (-)-δ-multistriatin 285 and (+)-prelog djerassi lactonic acid 286143 (Figure 29).

Scheme 41

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Figure 29 Some natural products synthesised from LGO The Baeyer-Villiger oxidation of LGO generates chiral butyrolactones and was first investigated by Shafidazeh et al.144 The report originally misassigned the compound resulting from the oxidation of LGO with m-chloroperbenzoic acid as either orthoformate ester 287 or lactone 288, but the authors were unable to distinguish between the structures on the basis of NMR, UV or IR spectroscopy (Scheme 42).

Scheme 42

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The actual product of the oxidation was identified by Ebata et al. as the formate ester derivative of 5S-(hydroxymethyl)dihydrofuran-2(3H)-one 299, and this transformation was subsequently used extensively by the group to generate chiral substituted butyrolactones from LGO, including the naturally occurring eldanolide and whiskey lactone.134,145,146 A mechanism for the formation of the butyrolactone from 3-hexyl-substituted LGO 300 was proposed by Trahanovsky et al. implicating an unusual 1,3-C-O bond migration after protonation of an orthoformate intermediate 301 (Scheme 43).147

Scheme 43 An alternate mechanism is presented in Scheme 44 (represented for simplicity for the Baeyer- Villiger oxidation of DHLGN 305) that also implicates an orthoformate ester intermediate 306.

Scheme 44

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Pathway A and B represent decomposition of the orthoformate intermediate 306 eventually forming an 8- or 7-membered ring respectively (307 or 309). In Pathway A, the formate ester 308 of the lactone is formed, whereas Pathway B requires an external nucleophile and gives the alcohol 313 and a stoichiometric amount of formic acid or mixed anhydride depending on whether the nucleophile that attacks 309 is water or a carboxylic acid. More recently, enzyme-catalyzed Baeyer-Villiger type reactions have been reported on LGO and dihydrolevoglucosenone.148 Chiral butyrolactones are found in many flavour, fragrance149 and natural products,150-152 and LGO could be a useful starting material for their construction if additional methods for derivatisation of the bicyclic skeleton were available. Only two examples of palladium catalysis being used to derivatise LGO were found in the literature, namely a Stille coupling on 3-halo derivatives of LGO,153 as well as a Sonogashira coupling.154 Palladium catalysis seemed an appropriate and powerful means of conveniently generating a library of novel compounds based on LGO. Specifically, it was envisaged that palladium-catalysed Suzuki-Miyaura,155,156 Mizoroki- Heck157 and hydroarylation (also referred to as reductive Heck)158-162 reactions on LGO would give access to aryl glycals and ultimately chirally-substituted butyrolactones (Scheme 45). The current report describes the findings in this regard.

Scheme 45

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RESULTS AND DISCUSSION

Suzuki-Miyaura Reactions on 3-iodolevoglucosenone

The Suzuki-Miyaura (SM) reaction is a powerful palladium-catalysed carbon-carbon bond forming tool involving the coupling of an aryl or vinyl halide to an organoboron species (typically an aryl or vinyl boronic acid or boronate ester).163-165 Owing to the mild reaction conditions, broad functional group tolerance and ease of access to suitable alkyl/aryl halide and organoboron coupling partners, the SM reaction has emerged as one of the most popular transition metal- catalysed carbon-carbon bond forming processes over the past forty years, and together with Richard F. Heck and Ei-Ichi Negishi, Akira Suzuki was awarded a Nobel Prize in 2010 for its development and proliferation.166 The mechanism for the SM reaction is given in Scheme 46.

Scheme 46

The first step in the catalytic cycle is oxidative insertion of a ligated Pd(0) species 320 into the C- X bond. The ligands are generally bulky phosphines and the Pd(0) species are formed in-situ from

Pd(II) salts such as Pd(OAc)2 or PdCl2. The mineral base (such as hydroxide, alkoxide, acetate or carbonate) in the cycle has multiple roles as elucidated by Amatore et al.167 Its first role is to substitute the halide in 322 to give 323 which activates it for transmetallation. Its second role is to activate the boronic acid/ester 324 to produce a tetrahedral boronate species 325 with increased

83 nucleophilicity that is able to take part in the transmetallation step to yield 327. The base is also shown to accelerate the reductive elimination of 327, which furnishes the coupled product 328 and regenerates the palladium catalyst. Fluoride salts may be used in place of a base and are suitable for base-sensitive substrates,168 further expanding the scope of this versatile reaction. Furthermore, the use of fluoride can limit byproducts of protodeborylation.

In general, the rate-determining step is oxidative insertion in the case of an aryl/vinyl iodide, however transmetallation is found to be slower in the case of an aryl/vinyl bromide.169 No reports of Suzuki-Miyaura reactions using the known 3-iodolevoglucosenone142,154 were found in the literature despite this seeming a straightforward way to further functionalise LGO (Scheme 47).

Scheme 47

Iodination of LGO using I2/pyridine afforded 3-iodolevoglucosenone 314 in 96% yield and the product was simply isolated by filtration through a pad of silica gel followed by evaporation of volatiles and so could be performed on multi-gram scale. The SM reactions of 314 with a variety of boronic acids is presented in Table 6.

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a Entry RB(OH)2 Solvent Temp. Pd(OAc)2 Ligand Time Product Yield (oC) (mol%) (hr)

1 329a Tol. 110 5 PPh3 18 315a 66

2 329a Tol. 100 1 SPhos 18 315a 61

3 329b DMF 100 5 PPh3 0.5 315b 18

4 329b Tol. 110 5 P(o-tol)3 3 315b 43

5 329b Tol. 110 5 PPh3 3 315b 76

6 329b Tol. 100 1 SPhos 1.5 315b 85

7 329c Tol. 110 5 PPh3 2 315c 64

8 329c Tol. 100 1 SPhos 1.5 315c 89

9 329d DMF 100 5 P(o-tol)3 3 315d 49

10 329d Tol. 100 1 SPhos 3 315d 74

11b 329e Diox. 100 5 - 72 315e 0

13 329f Tol. 110 5 PPh3 18 315f 25

14 329f Tol. 100 1 SPhos 36 315f 27

15 329f Tol. 100 5 SPhos 24 315f 53

16 329g Tol 100 5 SPhos 16 315g 88 a b Reactions performed using 2 equiv Cs2CO3, with a 2:1 Pd:L ratio at a concentration of 20 mL/g. Pinacol boronate ester with 2 equiv CsF used and PdCl2(dppf) as catalyst. Table 6 Suzuki-Miyaura coupling reactions of iodide 314

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The reaction of phenylboronic acid 329a with 314 using Cs2CO3 as base with 5 mol% Pd(OAc)2 and triphenylphosphine as ligand provided the expected coupled product 315a in 66% yield (Table 6, entry 1). Following this success, these conditions were applied to the series of boronic acids shown in Table 6, which gave the coupled products in moderate to good yield (Table 6, entries 5, 7 and 12). As yields were somewhat lower than expected with significant byproducts of protodeborylation, alternative ligands and conditions were examined. Superior results were obtained using the Buchwald ligand SPhos (330a, Table 6)170 which allowed a reduction of the palladium loading to 1.0 mol% and gave clean reactions with excellent yields (Table 6, entries 6,8 and 10). SPhos represents a class of hindered biarylmonophosphine ligands that have exceptional activity in SM reactions.171 On the basis of computational studies and X-ray crystallographical insights, Barder et al. propose that their enhanced activity is due to the equilibrium being shifted from a bis-ligated Pd(0) complex (shown to have the crystalline conformation as that of 331a), to a more reactive monoligated species 331b that is stabilised by an interaction between palladium and the ipso-carbon of one of the aromatic rings as in 331c (Scheme 48).

Scheme 48 In slower reactions it was found that palladium loading had to be increased (entries 14 and 15) as prolonged reaction times led to decomposition of the starting material and products. In the case of the coupling of 314 with 2-fluorophenylboronic acid 329g, an excellent yield of the product was obtained when 5 mol% Pd(OAc)2 and 10 mol% SPhos were used (entry 15). Under these same conditions, coupling of the electron-poor 2-formylphenylboronic acid 329f with 314 provided the expected dicarbonyl product 315f in only moderate yield (entry 14).

Coupling of sp3 centres in SM reactions is considerably more challenging and generally requires 172 careful catalyst/ligand choice. PdCl2(dppf) (332, Figure 30) has been routinely employed for the coupling of primary alkyl boronic acids. Most methods utilising this catalyst with benzyl pinacol boronate ester require the presence of H2O which presumably hydrolyses the boronate ester to the more active boronic acid,171 which is not bench-stable in its pure form.173 These 86 conditions are not compatible with LGO as it is not base-stable in aqueous media. It was reasoned that CsF may be used in refluxing anhydrous dioxane which would activate the boronate ester without the need for hydrolysis, however monitoring the reaction by GCMS showed no reaction under these conditions, with extended reaction times leading only to the decomposition of the iodide 314. Dale et al. reported coupling of benzyl pinacol boronate ester with a 2-iodopyrazine under anhydrous conditions in DME,174 however replication of their conditions again lead to no observed conversion and only decomposition of the starting material.

Figure 30: [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 332 used in SM couplings of alkyl boronic acids

Structural Assignments for Suzuki-Miyaura Adducts Structural assignments for the SM adducts of arylboronic acids with 314 were made on the basis of 1H and 13C NMR spectroscopy as well as 2D COSY and HSQC NMR experiments. The features in the various NMR spectra for 315a-g were general and the structural assignment of the phenylboronic acid adduct 315a will be discussed as representative of this series of compounds. The assigned 1H and 13C NMR spectra for 315a are presented in

Figure 31. Suitable samples for X-Ray crystallographical analysis were obtained for 315a, 315b and 315d and the structures are presented in Figure 32-Figure 34.

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1 13 Figure 31 a) 300 MHz H b) 75 MHz C NMR spectra of 315a in CDCl3

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Figure 32 Molecular structures (50% probability ellipsoids) within the asymmetric unit for (1S,5R)-3-phenyl-6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one (315a).

Figure 33 View (50% probability ellipsoids) of the asymmetric unit for (1S,5R)-3- (benzo[d][1,3]dioxol-5-yl)-6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one (315b).

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Figure 34 View (50% probability ellipsoids) of the asymmetric unit for (1S,5R)-3-(2,3,4- trifluorophenyl)-6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one (315d).

Referring to Figure 31, the β-olefinic proton H2 in 315a appeared downfield at 7.24 ppm as a doublet due to a single coupling with the methine proton H1. H1 appeared as a dd signal due to coupling with H2 and H7. H7’ only has a single geminal coupling to H7 as there was a dihedral angle approaching 90° between this proton and the neighbouring H2 proton based on molecular modelling. This is consistent with the measured dihedral angle based on the crystal structure for 315a, which for the three conformers is between 87-89°. H7 produces the expected dd signal due to a geminal coupling with H7’ and H2. The acetallic H5 proton appeared as a singlet at 5.49 ppm and corresponds to the characteristic 13C ketal resonance at 101.6 ppm.

The single crystal X-ray crystal structure of 315a shows three distinct conformations in the solid state, which differ in the orientation of the phenyl ring. 315a-P represents an extended conjugated system in which all atoms in the system are coplanar. 315a-α and 315a-β show a twisting of the aromatic ring to avoid unfavourable steric interactions, with the proton closest in space to the carbonyl twisted towards the α- or β-face (based on designation for LGO) respectively. The absolute value of the C4-C3-C10-C15 torsion angles for 315a-α and 315a-β were measured as 43.8° and 40.8° respectively. The presence of the three conformers is likely due to solid-state packing effects. Similar deviations from a planar conjugated system were observed in the crystal structures of 315b and 315d (Figure 33 and Figure 34 respectively), with the C4-C3-C10-C15 torsion angles determined as 30.5° and 54.3° respectively.

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These results are the first reported SM reactions on 3-iodolevoglucosenone with the highly crystalline products being isolated in high yield and purity.

Mizoroki-Heck Reactions and hydroarylations of LGO The Mizoroki-Heck (MH) reaction (often shortened to simply the Heck reaction) was developed independently by Mizoroki and Heck in the 1970s and involves a palladium-catalysed coupling of an olefin with an iodide.175,176 The olefin is preferably electron-deficient, such as an α,β- unsaturated carbonyl, and the iodide is vinyl, aryl or benzyl (Scheme 49).177 As with the SM reaction the Pd(0) species is most commonly generated in-situ from Pd(II) salts and is ligated with bulky triaryl or trialkyl phosphines. The mechanism of the MH reaction is provided in Scheme 50.

Scheme 49

Scheme 50

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Similar to the SM reaction, the catalytic cycle begins with oxidative insertion of a ligated palladium(0) species 320 into a C-X bond, namely that of an aryl, vinyl or benzyl halide 334. This complex then coordinates the alkene 333 and undergoes a stereoselective syn-insertion to give 338 and/or 339. In an acyclic system, rotation followed by a syn-dehydropalladation of the organopalladium species 338 and/or 339 furnishes the coupled products 335 and/or 336 as well as a palladium hydride species 340 that undergoes a final reductive elimination to regenerate the Pd(0) catalyst. In related cyclic systems this syn-dehydropalladation is unable to occur due to geometric constraints, therefore formation of the final product from the organopalladium species 338 and/or 339 in these systems likely occurs via a base-catalysed E2 mechanism.178

Cabri et al. demonstrated that the regioselectivity of the Heck reaction is highly dependent on both olefinic and halide substrate.179 If the halide substrate is an iodide or bromide (chlorides are generally too unreactive), then unbranched adducts are generally favoured. In the case of styrenes, allylic alcohols, and α,β-unsaturated esters, amides or nitriles, substitution is shown to occur exclusively at the β-position if bromides and iodides are used as coupling partners. However, if a pseudohalide is used such as an aryl triflate, in tandem with a bidentate phosphine ligand, α-selectivity is increased, and in the case of N-vinylpyrollidinone, N-vinylamides and vinyl ethers, only branched α-adducts are observed. These outcomes were shown to be vastly independent of solvent, temperature and base used and the reaction outcomes are rationalised on the basis of different modes of coordination with the olefin leading to different organopalladium intermediates (Scheme 51).

Scheme 51 The lability of the Pd-OTf bond facilitates alkene insertion via disassociation of the anionic ligand as in Pathway B, generating a cationic organopalladium species 350. In contrast, a stronger Pd-halide bond means insertion occurs via disassociation of a neutral ligand is favoured as in Pathway A, forming a neutral organopalladium species 347.

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Indeed the cationic route Pathway B lends itself to asymmetric induction if a chiral bidentate phosphine ligand is used, with the first asymmetric MH reaction being reported by Hayashi and coworkers (Scheme 52),180,181 Asymmetric MH reactions are an area of ongoing interest.181

Scheme 52 It was envisaged that MH reactions on LGO would give primarily 2-aryldioxabicyclooctenes and that these might give appropriate substrates for conversion to chiral butyrolactones via Baeyer- Villiger oxidation. A known compounding factor in these reactions, especially in the case of cyclic enones, is that MH reactions compete with a palladium-catalysed hydroarylation (formal 158-161,182 conjugate addition) (Scheme 53).

Scheme 53 Initial detailed studies into palladium-catalysed hydroarylations were undertaken by Cacchi’s group, after they observed that α,β-unsaturated enones undergo a reaction with aryl iodides (which they were investigating as a safer alternative to aryl mercurials) in the presence of trialkylammonium formate and a catalytic amount of Pd(OAc)2(PPh3)2 to give conjugate addition-type products.159,161 It was noted that if tertiary amines were replaced by NaOAc or

NaHCO3, a preference for MH adducts was observed. They surmised that the trialkylammonium formate had roles as both proton source and reducing agent (Scheme 54).

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Scheme 54 Two distinct pathways were proposed to explain the observation of conjugate addition-type products. Pathway A involves the heterolytic cleavage of the Cα-Pd bond in 357 to give an intermediate enolate that is protonated by the trialkylammonium formate to give the Michael- type product 358 and a palladium(II) species 359 that is subsequently reduced by formic acid to regenerate the Pd(0) catalyst. Cacchi further suggested that the preference for heterolytic cleavage leading to saturated adducts over syn-dehydropalladation giving MH adducts when amine bases were used might arise from coordination of the amine to the organopalladium species in the transition state. This would confer greater anionic character at Cα that is stabilised by the neighbouring carbonyl. Pathway B involves coordination of the formate to 357 to give 360, with subsequent reduction giving a hydrido-Palladium(II) species 361. Reductive elimination then furnishes the product 358 and regenerates the Pd(0) species and reinitiates the catalytic cycle. 94

Namyslo et al. demonstrated that the carbopalladation product of rigid bicyclic alkenes represented by 362, that cannot undergo syn-dehydropalladation due to geometric constraints, could be trapped with deuteride generated from deutero-formic acid as well as by alkynes (Scheme 55).162

Scheme 55

With relevance to Cacchi’s mechanism, the product 364 must be formed by coordination of deutero-formate to Pd in 363, with subsequent reductive elimination yielding the norbornane with the deuterium substituted syn to the aryl group.

Mechanistic studies on acyclic systems by Friestad et al. suggested an initial buildup of MH adduct that was slowly reduced by the trialkylammonium species which is in equilibrium with the hydrido-palladium(II) complex formed after the syn-dehydropalladation step.182

Building on the work of Cacchi et al., de Vries et al. recently published experimental evidence identifying the role of the base in promoting either the MH reaction or hydroarylation in additions of aryl iodides to cyclic enones and chalcones using a Pd(0)-NHC complex.158 Under optimised reaction conditions, de Vries demonstrated that the use of tributylamine gave rise exclusively to hydroarylation products, while CsOPiv afforded only MH adducts. The key distinction in their mechanism is the coordination of the amine base to the organopalladium species 368 followed by hydride transfer to form an iminium ion 370 (Scheme 56).

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Scheme 56 Good evidence for the mechanism was obtained by the observation of products arising from further reactions involving the iminium ion 372 formed when tributylamine was used as base. Products arising from both hydrolysis of 372 as well as insertion of 376 leading to both arylketone 379 and styrene 380 were observed (Scheme 57).

Scheme 57 96

It was envisaged that variation of the reaction coordinates, particularly in terms of base, would provide ideal conditions for formation of either MH or hydroarylation products from LGO. This would be advantageous in that reduction of the MH adduct would be expected to be epimeric at C2 compared to the hydroarylation product, allowing for the selective tuning of stereochemistry at that position.

Mizoroki-Heck-Selective Reactions of LGO

A solvent and base optimisation study was conducted on the MH reaction of LGO and iodobenzene (Table 7).

a Entrya ArX Solvent Temp. Base Pd(OAc) Ligand Time Products Yield (°C) 2 (hr) (316:317) mol%

1 381a Tol. 110 Cs2CO3 5 P(o-tol)3 18 316a/317a 34 (ND)

2 381a Diox. 100 K3PO4 5 PPh3 18 316a/317a 37 (19:1)

3 381a Diox. 100 K3PO4 1 SPhos 5 316a/317a 65 (10:1)

4 381a Tol. 110 K3PO4 2.5 SPhos 48 316a/317a 60 (>20:1) 5 PhBr NMP 130 NaOAcb 0.005 - 18 316a/317a 24 (8:1)

6 381b Tol. 110 K3PO4 2.5 SPhos 12 316b/318b 52 (>20:1)

7 381c Tol. 110 K3PO4 2.5 SPhos 10 316c/317c 58 (>20:1)

8 381h Tol. 110 K3PO4 2.5 SPhos 10 316h/317h 57 (>20:1)

9 381i Tol. 110 K3PO4 2.5 SPhos 48 316i/317i 35 (>20:1) a Reactions performed at a concentration 20 mL/g LGO using a Pd:L ratio of 1:2 with 2 equiv. of base. b 1.05 equiv of NaOAc was used.

Table 7 Heck-selective reactions of LGO

The reaction catalysed by 5 mol% Pd(OAc)2, with P(o-tol)3 using Cs2CO3 as the base gave a low yield of 2-phenyl adduct 5a in toluene (entry 1). No products of cross-coupling were observed 97 when the reaction was conducted in DMF using Cs2CO3, the sensitivity of the substrate to amines generated by the base a likely cause for this outcome (not shown). The substrate LGO is sensitive to water in the presence of strong bases and it was found that yields were variable using

Cs2CO3 so alternatives were examined. De Vries published a homeopathic ligand-free procedure for MH reactions of aryl bromides with a range of olefins.183 Interestingly, these reaction conditions are most efficient at extremely low palladium loading (0.005 mol%), due to inhibition of the precipitation of Pd black that removes Pd from the catalytic cycle. The reaction is particular to aryl bromides, as due to the slower oxidative insertion step in comparison to aryl iodides, much of the Pd exists as less stable Pd(0) complexes. At higher concentrations these unstable complexes tend to aggregate and form inactive nanoclusters. Although high temperatures and the use of the toxic solvent NMP are required, reactions are generally short and proceed in excellent yield. The low amount of palladium required and the simplification of conventional MH conditions make it attractive in terms of industrial-scale processing. In the current study it was found that de Vries’ conditions gave only low yields which was attributed to the slow decomposition of LGO in NMP at 130 °C (Entry 5). Matsuda-Heck conditions were also explored in which an arenediazonium tetrafluoroborate salt 184,185 is used in place of an aryl halide. These “super electrophiles” allow facile oxidative insertion of palladium into the C-N2 bond, with subsequent extrusion of N2 furnishing a cationic Pd intermediate that reacts analogously to the neutral Pd species in the MH reaction. Due to the lability of the C-N2 bond, these reactions have the advantage of being able to be conducted at or near room temperature and are often faster than conventional MH reactions. They are also frequently done under base- and ligand-free conditions. The use of polar solvents such as

MeOH, THF, H2O and MeCN are essential to solvate the diazonium salt and stabilise the cationic Pd intermediate. Unfortunately, attempted Heck coupling in MeOH using phenyldiazonium tetrafluoroborate generated by oxidation of aniline with nitrous acid186 gave only products from methanol conjugate addition (not shown). Complete selectivity was achieved for the MH reaction of LGO at the expense of the hydroarylation with iodobenzene, SPhos and K3PO4 in toluene. The Heck reactions of electron rich aromatics proceeded more quickly than the electron poor aromatics and in better yield (entries 6,7 and 9). In all reactions, 0-3% of the 3-substituted products was also observed.

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Structural Assignments for Mizoroki-Heck Adducts Structural assignments for the MH adducts of arylhalides with LGO were made on the basis of 1H and 13C NMR spectroscopy as well as 2D COSY and HSQC NMR experiments. A single crystal X-ray structure was obtained for 316h and this is presented in Figure 35. The features in the various NMR spectra were general and the structural assignment of 316a will be discussed as representative of this series of compounds. The assigned 1H and 13C NMR spectra are presented in Figure 36.

The α-olefinic proton H3 at 6.31 ppm exhibited a fine 1.5 Hz 4J coupling across the C4 sp2 centre with the acetallic proton H5 at 5.41 ppm. The methine proton H1 did not couple with H7’ due to a dihedral angle approaching 90° between these atoms (based on simple molecular modelling) and appeared as a doublet due to a sole coupling with H7. The same effect was observed in the 1H NMR spectrum of 316h, and was consistent with the determined H7’- H1dihedral angle of 89.4° in its crystal structure. H7’ exhibited a single 6.8 Hz geminal coupling, and H7 produced the expected dd signal due to coupling with H7’ and H1. Similar to observations in relation to the solid-state structures of 315a, 315b and 315d, the crystal structure for 316h showed a slight twisting of the aromatic ring in relation to the plane of the enone to minimise eclipsing of the protons at C15/C3 and C11/C1. The C3-C2-C10-C15 torsion angle for this compound was determined as 26.7°.

Figure 35 View (50% probability ellipsoids) of the asymmetric unit for (1S,5R)-2-(p-Tolyl)- 6,8-dioxabicyclo[3.2.1]oct-2-en-4-one (316h)

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1 13 Figure 36 a) 300 MHz H and b) 75 MHz C NMR spectra of 316a in CDCl3

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Hydroarylation-Selective Reactions of LGO Optimising the reaction conditions to increase the selectivity towards hydroarylation products proved more challenging and these results are presented in Table 8.

Temp. Pd(OAc)2 Ligand Yield Entry ArX (oC) Base mol% (equiv) Time (hr) Products (316:317)

1 381a 90 Et3N 5 P(o-tol)3 4 316a/317a 83 (1:4)

2 381a 90 Et3N 5 PPh3 4 316a/317a 68 (1:4)

3 381a 110 DABCO 5 PPh3 18 316a/317a 73 (1:1)

4 381a 110 DIPEA 5 P(o-tol)3 18 316a/317a 32 (1:1.75)

5 381a 90 Et3N 5 SPhos 3 316a/317a 72 (1:3)

6 381a 110 BnEt2N 1 P(o-tol)3 2 316a/317a 71 (1:5.5)

7 381a 110 Bn3N 5 P(o-tol)3 18 316a/317a 25 (1:34)

8 381a 110 Bu3N 5 P(o-tol)3 4 316a/317a 55 (1:4)

b,c 9 381a 80 Bu3N 3 - 2 316a/317a 56 (1:7.7)

b,c 10 381a 80 BnEt2N 3 - 24 316a/317a 51 (1:7)

b,d 11 381a 80 BnEt2N 3 - 18 316a/317a 50 (1:9.8)

e 12 381b 110 BnEt2N 1 P(o-tol)3 12 316b/317b 90 (1:4)

13 381c 90 Et3N 5 P(o-tol)3 10 316c/317c 71 (1:2.2)

d 14 381c 110 BnEt2N 1 P(o-tol)3 2 316c/317c 69 (1:4)

15 381h 90 Et3N 5 P(o-tol)3 10 316h/317h 60 (1:2.5)

e 16 381h 110 BnEt2N 1 P(o-tol)3 4 316h/317h 70 (1:4)

17 381i 90 Et3N 5 P(o-tol)3 4 316i/317i 40 (1:>20)

e 18 381i 110 BnEt2N 1 P(o-tol)3 10 316i/317i 53 (1:>20) a Reactions performed at a concentration 20 mL/g LGO in DMF using a Pd:L ratio of 1:2 with 4.5 equiv. of base and b c 1.2 equiv. of aryliodide. Reactions performed on 1.0 mmol of 1 unless indicated. 0.50 mmol scale. [Pd(iPr)(NQ)2] d e was used in place of Pd(OAc)2. [Pd(Mes)(NQ)2] was used in place of Pd(OAc)2. 4.0 mmol scale. Table 8: Hydroarylation-selective reactions on LGO

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It was pleasing to note that all hydroarylation reactions proceeded with complete diastereoselectivty, with only the axially-substituted products observed. This was consistent with a mechanism in which the syn-insertion of the palladium(II) species following coordination occurs from the less sterically-crowded α-face of LGO.

The use of the base Et3N in DMF with aryl iodides gave good yields and moderate selectivity for hydroarylation (Table 8, entries 1 and 2). A small improvement was observed using the bulky tri- o-tolylphosphine ligand over triphenylphosphine (compare entries 1 and 2). The Pd(0)-NHC catalysts [Pd(Mes)(NQ)2] and [Pd(iPr)(NQ)2] (382 and 383 respectively, Figure 37) used for selective MH and hydroarylation reactions of a variety of enones by De Vries et al.158 gave good selectivity for hydroarylation. The reaction mixtures were complex however, and only moderate yields were obtained using LGO as a substrate (entries 9-11).

Figure 37 Pd(0)-NHC catalysts used for selective hydroarylation reactions Consistent with de Vries’ mechanism, the nature of the amine base was found to be crucial to reaction outcomes. The hindered base DIPEA had poor selectivity, probably due to a decreased coordination to the palladium center (entry 4). Interestingly, this base has been used with excellent results in the reductive Heck reactions reported recently by Zhou et al.187 The bicyclic base DABCO also had poor selectivity which was attributed to a slow hydride transfer to palladium (entry 3). It was reasoned that reducing the C-H bond strength to enhance hydride transfer with a benzylic amine could improve the selectivity towards the hydroarylation, so long as coordination to the palladium center was not affected. This hypothesis was tested using tribenzylamine 384 which gave excellent selectivity for the hydroarylation product, however this resulted in a moderately complex mixture and poor yield of product (entry 7). The GCMS trace of the crude reaction mixture showed the presence of dibenzylamine 386 as well as the Schiff base N-

102 benzylidenebenzylamine 387. The latter Schiff base was formed from the transfer of a second hydride from the byproduct dibenzylamine and the presence of both adducts are consistent with the mechanism proposed by De Vries.

Scheme 58

It is likely that the imine formed from the base was reacting with one of the palladated intermediates giving the complex reaction outcome. Reducing the number of benzyl groups by using benzyldiethylamine improved the selectivity over the trialkylamines and gave good selectivity for the hydroarylation products (compare entries 1, 6 and 8). When the cross-coupling of 251 with PhI using BnEt2N was performed in a sealed tube to trap volatile components and followed by GCMS, an 8:1 ratio, corrected using authentic standards, of the byproduct N-benzyl- N-ethylamine to diethylamine was observed. This outcome was contrary to original expectations, indicating that greater hydride transfer from the N-alkyl groups was taking place. It is reasoned that the improved selectivity observed with BnEt2N arises not from formation of a more stable iminium byproduct, but rather by improved coordination to the palladium centre that facilitates subsequent hydride transfer.

The optimised conditions with BnEt2N were then applied to a range of aryl iodides giving the hydroarylation products in improved yield and selectivity relative to the reactions with trialkylamines (entries 13-18). It is clear that selectivity is also highly dependent on the nature of the aryl iodide, and it is tentatively suggested that the activation or deactivation by substituents on the aromatic ring is the origin of the different selectivities observed. The more electron-rich aryl iodides 381b,c and h appeared to give poorer selectivity for hydroarylation compared to iodobenzene, while in contrast the electron -poor aryl iodide 381i gave excellent selectivity, with no products of the MH reaction observed by 1H NMR spectroscopy. The latter result may also be due to steric effects of the ortho-substituted ester substituent, and further experiments would be required to fully assert this argument.

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Structural Assignments of Hydroarylation Adducts The structural assignment of the hydroarylation adduct formed from methyl 2-iodobenzoate 381i and LGO (317i) will be discussed as being representative of this series of compounds. A single X-ray crystal structure for 317i was obtained (Figure 38) and features of the NMR spectra will be discussed in relation to this. The assigned 1H and 13C NMR spectra for 317i are provided in Figure 39 over.

Figure 38 View (50% probability ellipsoids) of the asymmetric unit for methyl 2- ((1S,2R,5R)-4-oxo-6,8-dioxabicyclo[3.2.1]octan-2-yl)benzoate (317i).

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1 13 Figure 39 a) 300 MHz H and b) 75 MHz C NMR spectra of 317i in CDCl3

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Referring to Figure 39a, the acetal proton of 317i appeared as a broadened singlet at 5.18 ppm due to a 4J coupling with the equatorial H3 proton across the sp2 centre. The signal for H3 appeared as a ddd, with a large geminal coupling of 16.8 Hz as well as two long-range couplings of 1.0 Hz. The other long-range coupling for this proton arises from interaction with H1 also seen in the 2D COSY NMR spectrum, which occurs along a slightly distorted W-path consistent with the crystal structure. No coupling was observed in the 1H NMR spectrum between the equatorial proton H3 and H2, consistent with simple molecular modelling of 317i as well as the dihedral angle between these two atoms from the crystal structure, which was determined to be 87.0°. As expected, the crystal structure indicates an axial aryl substituent and this is further evidenced by the gauche 8.8 Hz coupling between the axial proton at C3 and the neighbouring syn-H2 proton. H1 and H2 do not couple, and this is consistent with molecular modelling but not with the solid-state crystal structure for which a dihedral angle of 62.0° was observed between these atoms. This is likely due to differences in solid- and solution-state conformations. Unlike the SM or MH adducts, a small coupling of 0.9 Hz is observed between H7’ and H1, due to a slight distortion in the ring which makes the dihedral angle deviate from 90°. This is supported by the calculated dihedral angle from the X-ray crystal structure which was determined to be 98.0°

Reductions of Suzuki-Miyaura and Mizoroki-Heck Adducts

To convert the SM and MH adducts into substrates suitable for Baeyer-Villiger oxidation, a reduction of the olefin functionality in these compounds was undertaken. Reduction of the SM adducts was not straightforward. Under standard conditions using Pd/C or PdCl2 in EtOAc under an atmosphere of H2 at ambient pressure, the starting material 315a was recovered unchanged. Increased pressures up to 3 barr and extended reaction time of 48 hours did not alter the reaction outcomes. These results can be explained by the preferred conformation of the phenyl ring which twists to avoid unfavourable steric interactions, for which evidence was discussed previously (Figure 32-Figure 34). Combined with the anhydro-bridge in 315a, the accessibility of the alkene to the catalyst is reduced, and thus alternate methods were sought. Semmelhack et al. reported a conjugate reduction methodology in which a CuH species is generated in-situ from sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al™) or lithium trimethoxyaluminium hydride in the presence of copper(I) salts. In analogy to the related dialkyl cuprates,188 the CuH nucleophile selectively reacts at the β-position in an α,β-unsaturated enone, and under optimised conditions no 1,2-addition is observed. The reduction of the enone 315a 106 using a mixture of Red-Al/CuBr afforded the reduced product 389a in 69% yield, and no products of 1,2-addition were observed. These same conditions were then applied to 315b and 315c which afforded the reduced dioxabicyclo[3.2.1]octanes 389b and 389c in 61% and 54% yield respectively. The reductions of the SM adducts are summarised in Scheme 59.

Scheme 59 The structural assignments were based on an 11.9 Hz trans-diaxial H2-H3 coupling and were supported by a single crystal X-ray structure of 389a showing the equatorial reaction product (Figure 40).

Figure 40 A perspective view of the single crystal structure of 389a showing the equatorial phenyl substituent.

In each case, Michael-type addition of the hydride resulted in an enolate which was protonated from the face syn to the anhydro bridge to give the sterically-favourable equatorially-substituted compound (Scheme 60). Interestingly, the stereochemistry of 389a-c was opposite to that expected from hydrogenation.

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Scheme 60 Reduction of phenyl MH adduct 316a gave predominantly the expected C2-equatorial isomer 391 as well as 317a and the overreduced alcohol 392 (Scheme 61).

Scheme 61 Isolation of 391 free from 317a was possible by careful chromatography and characterisation of

391 was made in the basis of a trans-diaxial H3ax-H2 coupling. Characterisation of 392 was made on the basis of the disappearance of the carbonyl resonance in the 13C NMR spectrum and the observation of 12.8 Hz and 10.0 Hz trans-diaxial couplings for H3ax to H2 and H4 respectively. This reaction outcome demonstrates the versatility of palladium-catalysed cross- couplings with LGO, as the main product 391 is epimeric to the related hydroarylation product 317a at C2, allowing for a tuning of stereochemistry at this position by altering the conditions used in the palladium-catalysed cross-coupling.

Baeyer-Villiger Oxidations With a series of substituted LGO derivatives in hand, attention turned to their conversion to the corresponding δ-butyrolactones. Substituted LGO derivatives were thus treated with either m- CPBA or peracetic acid. In all Baeyer-Villiger oxidations, a mixture of alcohol and formate ester was formed and a second hydrolysis step using 1 N HCl in water/THF was required to convert all products through to the alcohols. The stereochemistry of the product was based on the starting material and can be predicted from the mechanism (previously discussed in relation to DHLGN in Scheme 44). No evidence for epimerisation was seen as all Baeyer-Villiger products were diastereomerically pure.

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Attempts to convert the SM cross-coupled product 315a to the unsaturated butenolide using m- CPBA catalysed by p-TSA gave only unreacted starting material. It is reasoned that the same steric hindrance encountered during hydrogenation of 315a similarly prevents nucleophilic attack at the carbonyl by the peroxide. The products of the conjugate reduction of the SM adducts 389a and 389c underwent a facile conversion to the butenolides 393a and 393c in good yield. The reaction of 389b with m-CPBA and catalytic p-TSA gave only a slow conversion to the lactone 393b, and even after one week 60% of 389b remained unreacted. A 50% yield for the lactone based on unreacted starting material was obtained in this instance, and these results are summarised in Scheme 62.

Scheme 62 Both unreduced MH adduct 316a and the saturated derivative 391 were efficiently oxidised to the corresponding lactones 394 and 395 in excellent yield (Scheme 63).

Scheme 63

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Oxidations of the hydroarylation products 317a, 317b, 317h and 317i were uneventful and afforded the substituted butyrolactones 396a,b,h, and i, the reactions proceeding in good yield (Scheme 64).

Scheme 64 The fact that 317a and its C2 epimer 391 undergo facile Baeyer-Villiger oxidation to the corresponding epimeric lactones demonstrates the utility of this protocol, as accessing these compounds as single enantiopure diastereomers by other means would likely prove difficult.

CONCLUSION

In this chapter, a series of reactions have been described that can be used to derivatise levoglucosenone affording chiral 2-aryl and 3-aryl substituted 6,8-dioxabicylo-[3.2.1]-octan-4- ones. These derivatives can be converted to δ-butyrolactones via Baeyer-Villiger oxidation and can potentially be used as synthons for the asymmetric construction of more complex molecules. The 2- and 3-aryl substituted lactones can be accessed from a biorenewable source without the need for low temperatures or air-sensitive organometallic reagents. New conditions are also described for a diastereoselective hydroarylation of LGO optimised with BnEt2N which may have applications in the addition of aryl iodides to other cycloalkenones. It is envisaged that this work will inspire new uses for the interesting chiral synthon LGO which is currently available in kilogram quantities and which may soon be available in bulk. Future work should aim to optimise the reduction conditions of the Heck adducts, and explore conditions allowing the coupling of sp3 centres. The next chapter details a report on the applications of these chiral butyrolactones to the synthesis of substituted cyclopropanes.

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CHAPTER 4: SYNTHESIS OF SUBSTITUTED CYCLOPROPANES FROM LEVOGLUCOSENONE

INTRODUCTION Levoglucosenone (LGO) is a versatile chiral synthon obtained from the pyrolysis of cellulose. The industrial production of LGO has recently been optimised to allow for production on multitonne per year scale, and may soon be available in bulk.121 For details of its production, general reactivity and uses in natural product synthesis see Chapter 3. This chapter expands the available methods for converting LGO into new chiral materials and synthons. The synthesis of both enantiomers of the GABAc receptor agonists trans-2-methylaminocyclopropane carboxylic acid (TAMP) and a general route to enantiopure cyclopropyl esters is also described.

Cyclopropyl rings are commonly encountered in biologically active natural and synthetic materials. In a medicinal and pharmaceutical context, their inherent ring strain leads to unique reactivity.189 For example, trans-2-phenylcyclopropylamine 397 is a potent inhibitor of monoamine oxidase (MAO), undergoing a 2-electron oxidation in vivo to give a cyclopropyl iminium ion 398 that reacts with the thiol of the cysteine residue in the enzyme (Scheme 65).190

Scheme 65 The cyclopropyl iminium ion is also implicated in the deactivation of aldehyde dehydrogenase (ALDH) by coprine 400, an unusual amino acid with a carbamate side chain isolated from inky cap mushrooms.191 The deactivation may also occur via a cyclopropanone intermediate 404, the end result being the formation of hemithioaminals 403 or acetals 406 with the thiol group of a cysteine residue (Scheme 66).

Scheme 66

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Ring strain in cyclopropanes means they can undergo a facile electrophilic ring opening. The glycoside ptaquiloside 407 is a compound isolated from bracken fern and has been identified as the origin of the plant’s carcinogenicity. The sugar unit of 407 is hydrolysed followed by elimination to give dieneone 408 which readily undergoes nucleophilic attack by N-7 on guanine or N-3 on adenine (Scheme 67). The driving force for the reaction is concomitant release of ring strain on the cyclopropane and formation of an aromatic ring. The covalently bound adducts subsequently cause DNA strand breaks.

Scheme 67 Cyclopropanes mimic the geometry and electronic distribution of olefins and have been shown to inhibit enzymes which utilise olefins.192,193 For example, enzymes that utilise phosphoenolpyruvate 411 are inhibited by its cyclopropyl analogue 412 (Figure 41).192

Figure 41 Phosphoenolpyruvate and its cyclopropyl analogue The enzyme dihydroxy-acid dehydratase produces enolic acids 413 as biosynthetic precursors to the amino acids valine and isoleucine in microorganisms and plants. They are effectively inhibited by their cyclopropyl analogues 414 which presumably mimic the transition state (Figure 42).193

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Figure 42 Enol acids and their cyclopropyl derivatives Conformational rigidity in cyclopropanes can also confer selective interactivity with biological targets. As an example Ohfune et al. synthesised the four diastereomers of L-2- (carboxycyclopropyl)glycine (CCG) 416a-d, cyclopropyl analogues of glutamic acid 415 that lock the conformation to mimic either its extended or folded form (Figure 43).194 They hypothesised that different glutamate receptors might prefer different orientations of glutamic acid at the active site. They found that CCG 416a and 416c were potent and selective agonists of metatrobic glutamate (mGluRs) and N-methyl-D-aspartic acid (NMDA) receptors respectively.

Figure 43 Cyclopropyl analogues of glutamic acid mimicking the extended and folded conformations Indeed, cyclopropyl acids and in particular cyclopropyl derivatives of amino acids are well represented in the medicinal chemistry literature.195-198 Constantino et al. found that simple disubstituted cyclopropane carboxylic acids represented by 417 were effective inhibitors of O- acetylserine sulfhydrylase, an enzyme crucial to the biosynthesis of cysteine in microorganisms (Figure 44).195 Docking studies demonstrated that the small molecules bind strongly to the active site via both hydrogen bonding of the acid and lipophilic interactions of the ester side chain and stabilised a closed, inactive form of the enzyme. The small molecules may form a platform for antibiotics against multidrug resistant pathogens.

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Figure 44 Cyclopropane carboxylic acids shown to be active inhibitors of O-acetylserine sulfhydrolase In 1986 Bonnaud et al. developed a series of 1-aryl-2-(aminomethyl)cyclopropane carboxylic acids, esters and carboxamides as potential antidepressants.196 Three amongst their compounds tested proved to have comparable or greater activity than the tricyclic antidepressants (TCAs) imipramine, chloripramine and desipramine (Figure 45).

Figure 45 Cyclopropanes developed by Bonnaud which have potent antidepressant activity in comparison with TCAs Compound 418 (milnacipran, marketed as Ixel, Savella, Dalcipran or Toledomin) passed clinical trials and is currently marketed for treatment of severe depression and fibromyalgia in several countries.199

Schwarz et al. synthesised a series of cyclopropyl β-amino acids as analogues of pregabilin 421 198 and gabapentin 422 (Figure 46). 421 and 422 are known potent binders to the α2-δ proteins of voltage-gated calcium ion channels in the brain, with anticonvulsant effects of interest in the treatment of epilepsy and neuropathic pain.200,201 The binding of the amino acid 424 in vitro was found to be comparable to 421 and 422, although poor transport across the blood-brain barrier was identified as a significant issue during in vivo tests.

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Figure 46 Anticonvulsants pregabalin and gabapentin and selected cyclopropane analogues synthesised by Schwarz198

With the prevalence of cyclopropane groups in bioactive compounds with diverse biological targets and modes of action, a variety of techniques have been developed for their synthesis. The classic Corey-Chaykovsky cylopropanation utilises a sulphur ylide such as 427 and an enone 428 with Michael addition and subsequent extrusion of a leaving group furnishing the cyclopropane 430 (Scheme 68).202

Scheme 68

Asymmetric induction can be achieved via the use of chiral sulphur ylides203 such as 432 and 433 and an elegant example of an enantioselective organocatalytic variant of the Corey cyclopropanation was published by Tand and coworkers with camphor-derived hydroxyl sulfonium ylides as the source of chirality.204 The authors found that either cyclopropane enantiomer 434 and 435 could be produced in up to 97% ee depending on the chirality of the ylide (Scheme 69). The reaction was also successful when 20 mol% of the sulfonium ylide was used in the cyclopropanation of chalcone in conjunction with phenyl allylic bromide (Scheme 70).

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Scheme 69

Scheme 70 The Corey-Chaykovsky reaction represents a class of cascade Michael-alkylations and this is a common approach used in cyclopropanation strategies. Nitronates can undergo facile Michael 205 addition to electron deficient olefins followed by cyclisation via an SRN1 or SN2 mechanism. The cyclopropane analogues of pregabilin and gabapentin described earlier were prepared by this method and a representative example giving cyclopropane 443 via 442 is shown in Scheme 71.

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Scheme 71 Recently Dieter et al. reported the 1,4 addition of organozincates formed from zinc bromide and Grignard reagents to racemic γ,δ-epoxy-α,β-enoates, enones, enesulfones and enamides shown by structure 444 to ultimately give 1,2,3-cyclopropanes 445 or 446 (Scheme 72).206 The reaction is remarkably regiospecific, with no byproducts of 1,2-addition observed and minimal byproducts resulting from nucleophilic addition of the organozincates to the epoxide ring. Furthermore, the diastereoselectivity of the reaction can be tuned by altering the solvent which gives different favourable conformers of the organozincates in solution.

Scheme 72

In addition, 2-halomalonates have also been demonstrated as efficient alkylidene transfer agents and Wang and coworkers recently reported a highly enantioselective organocatalytic cyclopropanation of α,β-unsaturated aldehydes using the trimethylsilyl ether of a bulky diphenyl prolinol 448.207 The enamine thus formed from the aldehyde and amino acid directs attack by bromomalonate 449 to the Si face of C3 in 447 (Scheme 73). A subsequent enamine type cyclopropanation through structure 460 then gives the cyclopropyl aldehyde 461. N-alkylation of the malonate is not observed due to the decreased electrophilicity of its preferred enol form.

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Scheme 73 Carbene transfer is another major class of cyclopropanation reactions, with the Simmons-Smith reaction being the most widely adopted.208 The reaction was historically performed with zinc- copper couple and diiodomethane, and Simmons proposed a butterfly-type intermediate 463 in order to explain the origin of the reaction’s regiospecificity. The carbene in general approaches from the less hindered face of the olefin 462 with conservation of the olefin’s configuration to give substituted cyclopropanes of type 464 (Scheme 74).208

Scheme 74 Further control of stereochemistry can be achieved with the presence of a hydroxyl at the allylic position in the olefin substrate that coordinates the zinc complex and accelerates the methylidene transfer while directing syn to the hydroxyl group.209-211 Modern Simmons-Smith reactions replace zinc-copper couple with the more reactive diethylzinc,212 and asymmetric variants of the Simmons-Smith reaction on allylic alcohols such as 466 are known using this reagent in conjunction with chiral ligands such as disulfonamides,213 dioxoborolanes.214 and more recently Al(salalen) compounds generated from the ligand 465 (Scheme 75).215

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Scheme 75 Charette’s asymmetric protocol using dioxoborolane 471 allowed for simultaneous construction of two cyclopropane units at a time in the benchmark enantioselective synthesis of the unusual natural product (+)-U-106305 469, a potent inhibitor of cholesteryl ester transferase protein that contains six cyclopropane units, five of which are contiguous.216 In the same year Barrett and co- workers published the enantiospecific synthesis of the antifungal agent FR-900848 470 utilising the same protocol. (Figure 47).217

Figure 47 (+)-U106305, FR-900848 and dioxoborolane ligand used in Charette’s asymmetric Simmons-Smith reactions Metal-carbenes such as 473 generated from the decomposition of diazo compounds 472 in the presence of transition metals also represent a class of versatile substrates for cyclopropanations

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(Scheme 76).218 As with Simmons-Smith carbene transfers, the reactions proceed with preservation of the configuration of the olefin through a metal-carbene-olefin complex 474.

Scheme 76 A little-used method for the construction of cyclopropanes, probably due to the inaccessibility of suitable starting materials, is the intramolecular 3-exo-tet cyclisation of 4,5-epoxyenolates (Scheme 77).219,220

Scheme 77 Tan et al. used this protocol in the construction of the key bicyclo[3.1.0]hexane scaffold in their enantiospecific synthesis of mGluR2/3 agonist 482 (Scheme 78).221

Scheme 78 120

Sá et el. recently reported using racemic γ,δ-epoxy malonates to prepare cyclopropane carboxamides under mild conditions with an amine base and the weak Lewis acid LiCl (Scheme 79).222

Scheme 79 There are several reports of both racemic223,224 and enantiopure225,226 epichlorohydrins and their analogues being used to generate cyclopropanes via cascade nucleophilic addition of a malonate to the terminal position of the epoxide ring followed by Payne rearrangement and carbocylisation (Scheme 80).

Scheme 80 A drawback to this method in asymmetric syntheses is the potential partial racemisation in the product lactone 491 due to competing SN2 displacement of the leaving group by the malonate nucleophile giving both enantiomers of 489 (Scheme 81).226

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Scheme 81 Pirrung’s initial experiments clearly showed that attack by pathway a is favoured if chloride is the leaving group (93% ee),224 but Burgess et al. demonstrated that using the pseudohalide triflate analogue results in a preference for path b giving the opposite enantiomeric series in 91% ee.225

4,5-Epoxyketones may also be used but are less reactive than the 4,5-valerates and γ,δ-epoxy malonates and generally require elevated temperatures and Lewis acids to promote intramolecular cyclopropanations over competing intermolecular processes such as aldol reactions.227

Ebata et al. demonstrated that a 4,5-epoxy valerate can be generated by ring-opening of the sulfonate derivative of (S)-(hydroxymethyl)butyrolactone (S)-493,146 which is derived efficiently from LGO in enantiopure form (see Chapter 3). Furthermore, the 4,5-epoxy valerates thus generated can be converted to the (R)-(hydroxmethyl)butyrolactone (R)-492 via acidic hydrolysis,228 thus providing simple access to both enantiomers of the epoxide 494. In the current work, it was envisaged that these enantiopure 4,5-epoxy valerates 494 would form suitable substrates for intramolecular carbocyclisations and give a general route to enantiopure disubstituted cyclopropanes from the biorenewable chiral synthon LGO (Scheme 82).

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Scheme 82 Additionally, the methods described in previous chapters for the palladium-catalysed Suzuki- Miyaura, Mizoroki-Heck and hydroarylation reactions of LGO could potentially be applied to the asymmetric synthesis of 1,1,2- and 1,2,3-trisubstituted cyclopropanes (Scheme 83).

Scheme 83 This chapter details the synthesis of di-and tri-substituted cyclopropanes from LGO and its derivatives as well as their conversion to known bioactive cyclopropyl amino acids.

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RESULTS AND DISCUSSION

Preparation and cyclopropanation of 4,5-epoxy esters Starting with 251, both enantiomers of epoxyvalerate 494 were synthesised as shown in Scheme 84. Hydrogenation of 251 and Baeyer-Villiger oxidation afforded hydroxymethylbutyrolactone (S)-492 in 91% overall yield for the two steps. Whereas Ebata reported that only 40% yield of butyrolactone (S)-492 was obtained if m-CPBA was used as oxidant,145 when catalysed by p- toluenesulfonic acid (p-TSA), the reaction afforded an excellent yield of (S)-492. Mesylation afforded (S)-493, and then reaction with 1.05 equivalents of sodium ethoxide in ethanol gave ethyl 4,5-epoxyvalerate (S)-494a in 58% yield for the 2 steps. Due to the volatility of ethyl epoxyvalerate (S)-494a, the bulkier cyclohexyl epoxyvalerate (S)-494b was also synthesised from (S)-493 with the lithium salt of cyclohexanol to simplify subsequent workups. The enantiomer (R)-494b was prepared by the cyclisation of epoxide (S)-494a to furnish the lactone (R)-492 which was treated as per its enantiomer to give (R)-494b.

Scheme 84 With the 4,5-epoxyvalerate series in hand, attention was turned to the intramolecular cyclopropanation, the results of which are presented in Table 9. In most cases yields were determined by 1H NMR spectroscopy with p-dimethoxybenzene or 1,3-diphenylbutadiene as standard.

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Entrya Solvent Substrate Temp. Yield 495 b (oC) (isolated) 1 THF (S)-494a 25 50 (nd) 2 THF (S)-494a -10 nd (36)

3 Et2O (S)-494a 25 36 (nd) 4c THF (S)-494a 25 47 (nd) 5 THF (S)-494a 50 46 (nd) 6 THF (S)-494b 25 53 (nd)d 7 THF (S)-494b 25 58 (50) 8e THF (S)-494b 25 38 (nd) 9 THF (S)-494b -78 0 (0) 10 THF (S)-494b -78 to 25 18 (nd) 11f THF (S)-494b -78 13(nd) 12g Toluene (S)-494b 80 30 (nd) 13 THF (S)-494b 50 65 (nd)

a Reactions were performed by the addition of 200 mg of epoxide to LiHMDS (1.2 equiv) in THF (15 mL) unless otherwise indicated. b Conversion determined by 1H NMR spectroscopy with 1,3-diphenylbutadiene or p- dimethoxybenzene as internal standard. c 1.2 equiv KHMDS was used. d 5 mL total solvent volume. e Inverse f g addition. 10 mol% BF3.Et2O. 1.0 equiv. of LiHMDS was used in toluene (15 mL).

Table 9: Base-promoted cyclopropanation reactions of (S)-494a and (S)-494b The hindered base LiHMDS gave the best results and temperature was found to be a key factor. At all temperatures except -78 °C the reaction proceeded rapidly, with all starting material having been consumed by the end of the addition of a solution of the epoxide to the base. The reaction was quenched with 10% w/w KH2PO3 followed by extraction or by addition of Amberlite® IRP-69 acidic exchange resin followed by filtration. Higher temperatures favoured intramolecular cyclisation with the best yield of 65% being obtained for the cyclisation of (S)- 494b in refluxing THF (entry 13). Attempts to increase the temperature further by performing

125 the reaction in toluene at 80 °C resulted in a lower yield of product (entry 12). Lowering the reaction temperature to -10 °C led to a complex mixture due to competing intermolecular processes (entry 2). In order to limit products of intermolecular coupling, the reaction were performed at high dilution (ca. 0.05 M), however using a higher concentration appeared to have little effect on yield (compare entries 1 and 6). Unsurprisingly, order of addition was crucial and the intramolecular reaction was favoured when the epoxide was added to a solution of LiHMDS, with inverse addition lowering the yield (Compare entries 1 and 8). At -78 °C, no reaction of the starting material was observed (entry 9). When the reaction was allowed to warm slowly from - 78 °C to room temperature, a complex mixture was obtained of which the desired cyclopropane was only a minor component (entry 11).

Only a single trans-diastereomer was isolated from the reactions and no other stereoisomers were visible in the crude 1H NMR spectrum. To exclude the possibility of formation of lactone (1S,5R)-499 from the cis-cyclopropyl isomer, which would be expected to be volatile and perhaps lost during workup, an authentic sample of (±)-3-oxabicyclo[3.1.0]hexan-2-one 499 was prepared. Briefly, but-2-en-1,4-diol was cyclopropanated using Zn/Cu couple and diiodomethane to give 501 then TEMPO/TCC oxidation afforded lactone 499 via 502b (Scheme 85). There was no evidence of 499 in any GCMS chromatograms obtained from crude reactions in Table 9.

Scheme 85 Spectroscopic data for cyclopropane (1S,2S)-495a was consistent with the literature.195 The assignment of (S)-495b could be made simply on the basis of coupling constants in the 1H NMR spectrum. Due to the unusual geometry of cyclopropanes, coupling of cis-protons are significantly larger (ca. 8-9 Hz) than trans-couplings and geminal couplings (both of which are approximately 4-6 Hz) and made structural assignment straightforward.229 Signals are typically shifted upfield relative to their acyclic analogues. The assigned 1H NMR spectrum of (1S,2S)- 495b is provided as reference in Figure 48.

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Figure 48 a) 500 MHz 1H NMR and b) 125 MHz 13C NMR spectra of (1S,2S)-495b in CDCl3 127

The methine proton of the cyclohexyl ester was assigned but due to the complexity generated from the overlapping signals of the multiple diastereotopic methylene protons of the cyclohexyl group, no effort was made to assign coupling constants. The methylene protons of the cyclopropane are distinguished as being anti or syn to the cyclohexyl ester and appear at 1.20 and 0.85 ppm. They were assigned based on chemical shift and supported by a correlation of these two peaks with the same carbon at 12.6 ppm in a HSQC experiment. An initial attempt to assign these protons specifically as anti or syn to the cyclohexyl ester group by a 2D ROESY experiment was unsuccessful with the only significant crosspeak observed being between these two protons. They were tentatively assigned by analogy to (1S,2S)-495a, in which significant crosspeaks in the ROESY spectrum were observed between H2-H3syn and H1-H3anti. As expected the two signals for these protons appear as a ddd with similar coupling patterns. They exhibit a small geminal coupling of 4.3 Hz and a single large cis-coupling (8.9 Hz for H3syn, 8.4

Hz for H3anti) as well as a smaller trans-coupling (4.5 for H3syn, 6.3 Hz for H2anti), consistent with the proposed structure. The relative chemical shifts of the other cyclopropane protons were assigned on the basis of a 2D COSY NMR experiment, however multiplicities of these signals were unable to be determined due to overlapping signals from the cyclohexane ring.

Preparation of (+)- and (-)-TAMP

To demonstrate the utility of LGO as a source of chiral cyclopropanes, a simple synthesis of both enantiomers of trans-2-methylaminocyclopropane carboxylic acid (TAMP 505) was devised.

Both (+)- and (-)-TAMP are partial agonists of GABAa receptors, ligand-gated ion channels which bind the neurotransmitter γ-aminobutryic acid (GABA).230 (+)-TAMP is also a potent

GABAc agonist, which demonstrates the sensitivity of these compounds’ observed activity to both conformational and stereochemical factors. Duke et al. suggest the ability of TAMP and its isomer cis-2-aminocyclopropanecarboxylic acid (CAMP) to bind competitively to GABAa and

GABAc receptors is a function of their ability to adopt the conformationally-locked analogues of the folded and extended forms of GABA.231

Taking alcohol (1S,2S)-495b through to (+)-TAMP (1S,2S)-505 was achieved by mesylation to (1S,2S)-503, substitution with azide to furnish (1S,2S)-504 and finally hydrogenation under acidic conditions to give the amino acid in 82% yield for the three steps. Attempted crystallisation of (1S,2S)-505 by vapour diffusion from methanol/diethyl ether unexpectedly gave pure methyl ester (1S,2S)-506. Spectroscopic and physical data for (1S,2S)-506 was in agreeance with the literature, with an observed specific optical rotation of +68.9 (lit. +65.5).232

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The enantiomer of (+)-TAMP was synthesised starting with epoxide (R)-494b which was treated with base to give cyclopropane (1R,2R)-495b in 40% yield. Conversion of cyclopropane (1R,2R)-495b through to (-)-TAMP (1R,2R)-505 proceeded in 79% combined yield via (1R,2R)- 503 and (1R,2R)-504. For ease of comparison, (1R,2R)-505 was also converted to the methyl ester (1R,2R)-506. It was found that the magnitude of the optical rotations had excellent agreement for the products as well as the intermediates indicating that epimerisation did not occur at any stage of the synthesis.

Figure 49 Preparation of trisubstituted cyclopropanes and formal synthesis of PCCG-4

Chapter 3 describes the syntheses of substituted butyrolactones from LGO using Mizoroki-Heck, Suzuki-Miyaura and palladium-mediated hydroarylation of either LGO or its 3-iododerivative followed by Baeyer-Villiger oxidation. In order to expand the scope of the cyclopropanation from LGO, the syntheses of 1,1,2- and 1,2,3-trisubstituted cyclopropanes using some of these lactone precursors was examined. Conversion of lactones 393a, 395 and 396a derived from palladium-catalysed cross-coupling adducts of LGO to their O-mesylate derivatives, followed by reaction with ethoxide in THF/ethanol afforded epoxy valerates 510, 511 and 512 in good yield (Scheme 86). 510 was isolated as a 1:1 mixture of diastereomers due to a base-promoted epimerisation at C2.

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Scheme 86 The reaction of phenyl-substituted epoxide 510 with LiHMDS was sluggish compared to other cyclopropanation reactions and afforded the trans-isomer 513 and lactone 514 formed from the cis-isomer (with trans and cis referring to the configuration of the ester and hydroxymethyl substituents) in a 29:6 isolated yield ratio (determined as 5:1 in the crude 1H NMR spectrum) (Scheme 87).

Scheme 87 Spectroscopic data for both 513233 and 514234 was consistent with the literature and the stereochemistry of 513 was further confirmed on the basis of crosspeaks in the ROESY spectrum between the phenyl group and the adjacent methylene resonance. The cyclisation of 511 under the optimised conditions afforded 515 in excellent yield and with complete diastereoselectivity for the trans-cyclopropane, with trans referring to configuration of

130 the ester and hydroxymethyl substituent (Scheme 88). A small amount of the O-silylated derivative 516 (10%) and traces of dimerised compound 517 arising from an intermolecular transesterification were also isolated from the reaction mixture.

Scheme 88 The silylated adduct 516 was readily converted to 515 by stirring in ethanolic HCl, confirming the structural assignment. Structural assignment of 515 was straightforward on the basis of coupling constants in its 1H NMR spectrum (Figure 50).

1 Figure 50 500 MHz H NMR spectrum of 515 in CDCl3 The cyclopropyl protons H2 and H1 appeared at 2.81 and 2.03 ppm respectively as dd signals. H2 has one large cis-coupling (9.3 Hz) and one large trans-coupling, whereas H1 has two small trans-couplings (5.3, 4.9 Hz), consistent with the structural assignment. The remaining

131 cyclopropyl proton appeared as a complex dddd signal due to coupling with H1 and H2 and the adjacent methylene protons at C5.

The C3 epimer of 511, 512, similarly underwent a facile cyclopropanation, although with opposite diastereoselectivity compared to 511, yielding the lactone 519 via the cis-cyclopropane 518 (cis being in reference to the hydroxymethyl and ester substituents) (Scheme 89).

Scheme 89 The synthesis of 519 from the decomposition of the diazo acetate derivative of cinnamyl alcohol in the presence of transition metal complexes is well established in the literature,218,234-241 and the spectroscopic data for 519 was consistent with these reports. Doyle and coworkers in particular have published widely on variations of dirhodium catalysts that allow for excellent asymmetric induction in the intramolecular cyclopropanation reaction of diazoacetates (Scheme 90).

Scheme 90 The protocol reported in this chapter for the synthesis of 519 is advantageous over the use of achiral diazo acetate derivatives, as the use of an enantiopure starting material mitigates the need to achieve asymmetric induction via specially designed chiral catalysts containing expensive rhodium.

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The vast difference in rates and yields of the base-promoted cyclisation of 511 and 512 compared to 510 was initially surprising. It is reasoned that this is perhaps evidence of a Thorpe- Ingold effect242,243 in which the bulky phenyl group compresses the angle between C2-C3-C4 and encourages the intramolecular cyclisation to occur. The opposing diastereoselectivities observed for the cyclisations of 511 and 512 are reasoned on the basis of simple steric arguments, in which the lithium enolate adopts a preferential geometry in the transition state that minimises interaction of the phenyl group and the enolate oxygen. This hypothesis is supported by DFT computations for the energies of the transition states in a vacuum performed in Spartan ’14244 at the B3LYP/631-G(d) level for the various approaches performed by Dr Ben Greatrex (Figure 51 and Table 10). It is reported that deprotonation of esters with LiHMDS in THF gives rise predominantly to enolates in the E-configuration,245,246 and computations are based on this geometry. The transition state geometries found are validated by the observation of a single imaginary IR frequency corresponding to the simultaneous bond- forming and bond-breaking step.

Figure 51 Transition state geometries for base-promoted cyclopropanation of 511 and 512

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Interatomic Rel. Energies Distances (Å) (kcal.mol-1) TS C2-C4 C4-O3

511TS1 2.074 1.922 0.0

511TS2 2.049 1.963 +5.79

512TS1 2.043 1.976 0.0

512TS2 2.069 1.949 +1.65

Table 10 Key bond distances and energies in 511TS1, 511TS2, 512TS1 and 512TS2 In line with expectations, the energy of the transition states in which O1 is on the same face as the phenyl ring are significantly higher. For the cyclisation of 511, proceeding through the more favourable transition state 511TS1 leads to the observed trans-product 515 (referring to the ester and hydroxymethyl substituents) with the phenyl substituent anti to the ester. For the cyclisation of 512, proceeding through transition state 512TS1 gives a cis-product (referring to the ester and hydroxymethyl substituents), again with the ester anti to the phenyl substituent, which spontaneously lactonises to give 519.

To demonstrate the utility of the 1,2,3-cyclopropane adduct derived efficiently from LGO, 515 was converted to its morpholinamide derivative 522 via base hydrolysis followed by coupling with PyBOP in 89% overall yield (Scheme 91).

Scheme 91

Cyclopropane 522 is a late-stage intermediate in Pellicciari’s synthesis of 2-(2’-carboxy-3’- phenylclopropyl)glycine (PCCG).247 The stereochemistry of 522 matches that of the cyclopropyl core of PCCG-IV (524), one of the sixteen possible stereoisomers of the phenylcyclopropyl amino acid. Pellicciari and coworkers demonstrated PCCG-IV to be a potent and selective antagonist of type-2 mGluR receptors (compared to other stereoisomers), suggesting that favourable interaction occurs at the active site due to the cyclopropyl analogue being 134 conformationally locked in the extended configuration of the parent amino acid receptor ligand. To complete their synthesis of PCCG-IV, 522 was oxidised by PCC to the aldehyde followed by stereospecific Strecker reaction with (R)-α-phenylglycinol and TMSCN to give the N-substituted

α-amino nitrile 523 that was then oxidatively cleaved with Pb(OAc)4 and hydrolysed under strongly acidic conditions to give PCCG-IV (524)(Scheme 92).

Scheme 92 CONCLUSION

The procedures described in this chapter yielded both enantiomers of the GABAc receptor agonist TAMP, with (+)-TAMP synthesised in 8 steps from LGO in 35% overall yield, and (-)- TAMP in 10 steps in 15% overall yield. It has also been shown that the products of palladium- catalysed cross coupling reactions on LGO are suitable substrates for conversion through to cyclopropyl esters via intramolecular ring-closure reactions. Of all the substrates for cyclopropanation, the 3-substituted epoxy valerate 511 gave the best results, undergoing cyclisation to the corresponding 1,2,3-trisubstituted cyclopropane in 91% yield with complete diastereoselectivity for the trans-isomer. For the intramolecular cyclisations of the C3 epimer 512, the diastereoselectivity was found to be completely reversed and this was explained on the basis of simple steric arguments and supported by computations on preferred transition state geometries. Work is currently underway to expand the series of trisubstituted cyclopropanes and apply this protocol to the synthesis of enantiopure biologically active cyclopropyl-substituted amino acids. The generation of enantiopure cyclopropanes using LGO is a viable option and has some advantages over the use of other cyclopropanation strategies. In particular, the fact that the other protocols only yield enantioenriched products and the current protocol does not rely on asymmetric induction via specialised chiral catalysts makes it highly attractive in terms of asymmetric synthesis.

135

CHAPTER 5: EXPERIMENTAL General Experimental

NMR spectra were recorded on a Bruker Avance 300 MHz, Bruker Avance III HD 500 MHz or

Agilent 600 MHz instrument. NMR experiments performed in D2O were referenced to internal 1 13 248 1,4-dioxane ( H 3.75 ppm, C 67.2 ppm) and spectra recorded in CDCl3, (CD3)2CO or C6D6 were referenced to residual solvent or Me4Si. FT-IR spectra were recorded on a PerkinElmer Spectrum 2 with a PIKE MIRacle ATR cell. Optical rotations were recorded with a Rudolph Analytical Instruments AutoPol I Automatic Polarimeter with cells of a 1 dm pathlength. LCMS data was acquired on a Varian LC-1200. GCMS data was acquired using an Agilent 7890A GC system coupled with an Agilent 5975C inert MSD. HRMS were recorded in positive ESI V mode (Source temperature 80 °C, desolvation temperature 150 °C, Capillary 2.5 kV). Solvents were dried using literature procedures.249 Melting points are uncorrected.

Experimental data for compounds in Chapter 1 General experimental. Trityl chloride was recrystallised from acetyl chloride, NHC 134 was synthesised using a literature procedure250 while other NHC catalysts were purchased from Strem Chemicals, Boston, USA. All other reagents are commercially available and were used as purchased.

General procedure for preparation of 1,6 and 1,5-di-O trityl alditols. To a solution of the alditol (1 equiv) in pyridine (5.5 mL/mmol) was added trityl chloride (2.2 equiv) and the mixture heated under reflux for 1.5 hours. The volatiles were removed under reduced pressure and the residue partitioned between DCM and sat. NaHCO3. The aqueous phase was extracted with DCM until no product remained in the aqueous layer (TLC) and the combined organic extracts washed with a further portion of saturated NaHCO3 before drying (Na2SO4) and concentrating under reduced pressure. The residue was either purified by flash chromatography or recrystallisation as stipulated.

General procedure for perbenzylation and permethylation of 94, 102, 118 and 123. To a solution of 1,6- or 1,5-di-O-trityl alditol (1 equiv) in THF (6 mL/mmol) under N2 was added either benzyl bromide (4.8 equiv for 1,6-di-O-trityl hexitols, 3.6 equiv for 1,5-di-O-trityl pentitols) or methyl iodide (4.8 equiv). A 60% oil dispersion of NaH (4.8 equiv) was added gradually and the mixture stirred for 6 hours and then heated under reflux overnight. If the 1 reaction was incomplete ( H NMR or TLC), Bu4NI (0.15 equiv) was added and the mixture 136 heated for a further hour before careful quenching with MeOH. The solvent was removed under reduced pressure and the residue partitioned between H2O/DCM. The organic phase was collected and washed with a further portion of H2O before being dried (Na2SO4) and concentrated under reduced pressure. Products were either purified by column chromatography or recrystallisation as specified.

General procedure A for detritylation of alditols 95, 103, 111. To a solution of the protected alditol 95, 103 or 111 (1 equiv) in 2:1 MeOH:DCM (15 mL/mmol) was added TFA (1.0 mL/mmol) and the mixture stirred overnight. The mixture was neutralised using saturated

NaHCO3 solution and after ensuring no acid remained, the organic phase was collected and the aqueous phase extracted twice with DCM. The combined organic extracts were washed with a further portion of saturated NaHCO3 before being dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (2:3 EtOAc/hexanes) to give the protected sugar.

General procedure B for detritylation of alditols 97, 105 and 113. To a solution of the protected alditol 97, 105 or 113 (1 equiv) in 1:1 DCM/MeOH (24 mL/mmol) was added p-

TSA.H2O (3.2 equiv) and the resulting mixture stirred for 18 hours. Solid Na2CO3 (3.3 equiv) was added and the mixture stirred for an additional 10 minutes before concentrating under reduced pressure. The residue was dissolved in DCM and insolubles removed by filtering through Celite. The volatiles were removed under reduced pressure and the residue purified by dry flash column chromatography (1:1 EtOAc/hexanes then 3:17 MeOH/EtOAc) to give the partially deprotected sugar.

General procedure for the Swern oxidation of diols 96, 98, 104, 106, 112, 114, 120 and 125. o To a solution of dry DMSO (4.8 equiv) in dry DCM (2.2 mL/mmol) at -78 C under N2 was added a solution of (COCl)2 (2.4 equiv) in dry DCM (1.1 mL/mmol) slowly via syringe, care being taken that during the addition the temperature of the solution did not rise above -60 oC. The solution was stirred for 10 minutes before a solution of diol (1 equiv) in dry DCM (10.8 mL/mmol) was added slowly via syringe, again taking care that solution temperature did not rise o above -60 C, and the mixture stirred for a further twenty minutes. Et3N (5 equiv) was added and the mixture stirred at below -60 oC for fifteen minutes before being allowed to come to room temperature (ca 1.5 hours). The solvent was removed under reduced pressure and the residue dissolved in diethyl ether then filtered. The filtrate was concentrated under reduced pressure affording the crude dialdehydes which were used without further purification.

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1,6-di-O-Trityl-D-mannitol (94).61 D-mannitol 93 (2.00g, 11.0 mmol) was treated as per the general method for tritylation and the product purified by flash column chromatography (2:3- 13:7 EtOAc/hexanes) to give 94 as a viscous pale yellow oil (7.10 g, 97%); 1H NMR (300 MHz,

CDCl3) δ 7.56–7.34 (m, 12H), 7.31–7.10 (m, 18H), 3.95 (dd, J = 5.9, 5.4 Hz, 2H), 3.83 (d, J = 13 5.9 Hz, 2H), 3.39–3.24 (m, 4H); C NMR (75 MHz, CDCl3) δ 143.7, 128.6, 127.9, 127.2, 87.04, 72.1, 70.6, 65.0; FT-IR (neat) 3402, 1489, 1447 cm-1; MS (ESI): 689.3 [M + Na]+.

1,6-di-O-Trityl-2,3,4,5-tetra-O-benzyl-D-mannitol (95).69 Tetrol 94 (3.00 g, 4.67 mmol) was treated as per the general method for perbenzylation and the product successively recrystallised from DCM/MeOH to give 95 as a colourless crystalline solid (4.34 g, 90%); 1H NMR (300 MHz,

CDCl3) δ 7.55–7.06 (m, 46H), 7.04–6.87 (m, 4H), 4.76 (d, J = 11.7 Hz, 2H), 4.45–4.31 (m, 6H), 4.31–4.21 (m, 2H), 3.86 (ddd, J = 6.5, 4.3, 2.3 Hz, 2H), 3.67 (dd, J = 10.5, 2.3 Hz, 2H), 3.34 (dd, 13 J = 10.5, 4.3 Hz, 2H); C NMR (75 MHz, CDCl3) δ 144.1, 138.8, 138.7, 128.8, 128.3, 127.9, 127.7, 127.4, 127.4, 127.30, 127.2, 126.9, 126.8, 86.6, 78.7, 77.9, 73.5, 71.6, 62.5; FT-IR (neat) 3030, 2940, 2881, 1105, 1073 cm-1; MS (ESI) 1049 [M + Na]+.

2,3,4,5-Tetra-O-benzyl-D-mannitol (96).71 95 (1.12 g, 1.10 mmol) was treated as per the general procedure A for detritylation to give 96 as a colourless syrup (510 mg, 86%); 1H NMR

(300 MHz, CDCl3) δ 7.40-7.09 (m, 20H), 4.78 (d, J = 11.4 Hz, 2H), 4.70-4.51 (m, 4H), 4.43 (d, J 13 = 11.6 Hz, 2H), 4.04-3.73 (m, 6H), 3.73-3.63 (m, 2H); C NMR (75 MHz, CDCl3) δ 138.5, 138.2, 128.6, 128.5, 128.0, 127.9, 127.8, 127.7, 79.9, 78.9, 74.5, 71.6, 60.5; MS (ESI) 565 [M + Na]+.

1,6-di-O-Trityl-2,3,4,5-Tetra-O-methyl-D-mannitol (97).61 Tetrol 94 (0.68 g, 1.0 mmol) was treated as per the general method for permethylation and purified by adsorption on silica followed by washing with hexanes and elution with EtOAc to give 97 as a rose solid (0.74 g, 1 100%); H NMR (300 MHz, CDCl3) δ 7.67-7.15 (m, 30H) 3.79 (br. d, J = 8.3 Hz, 2H) 3.60 (br. d, J = 10.1 Hz, 2H) 3.54 (s, 6H) 3.51-3.45 (m, 2H) 3.25 (s, 6H) 3.19 (dd, J = 10.1, 4.2 Hz, 2H); 13 C NMR (75 MHz, CDCl3) δ 144.2, 128.9, 127.8, 127.0, 86.8, 80.1, 79.3, 62.2, 60.5, 58.0; MS (ESI) 603 [M + Na]+.

2,3,4,5-Tetra-O-methyl-D-mannitol (98).61 97 (930 mg, 1.29 mmol) was treated as per the general procedure B for detritylation to give 98 as a white powder (230 mg, 75%); 1H NMR (300

MHz, CDCl3) δ 3.97 (dd, J = 11.9, 3.4 Hz, 2H) 3.71 (dd, J=11.9, 2.6 Hz, 2H) 3.56-3.49 (m, 4H) 13 3.46 (s, 6H) 3.41 (s, 6H) 3.38-3.31 (m, 2H); C NMR (75 MHz, CDCl3) δ 80.3, 78.9, 60.8, 58.9, 56.7; MS (ESI) 261 [M + Na]+ 499 [2M + Na]+. 138

2,3,4,5-Tetra-O-benzyl-D-manno-hexodialdose (99). 96 1.00 g, 1.86 mmol) was treated as per 29 the general method for Swern oxidations to give 99 as a pale yellow oil (0.99 g, 99%); [α]D -2.3 1 (c 4.4, DCM); H NMR (300 MHz, CDCl3) δ 9.70 (d, J = 1.3 Hz, 2H), 7.39-7.13 (m, 20H), 4.64 (d, J = 11.9 Hz, 2H), 4.60 (d, J = 11.4 Hz, 2H), 4.50 (d, J = 11.4 Hz, 2H), 4.42 (d, J = 11.9 Hz, 13 2H), 4.13 (br. s, 2H), 4.05 (br. s, 2H); C NMR (75 MHz, CDCl3) δ 200.0, 136.6, 136.5, 127.7, 127.6, 127.3, 127.2, 127.2, 127.1, 82.6, 79.4, 72.9, 71.7; FT-IR (neat) 2858, 1721 cm-1.

2,3,4,5-Tetra-O-methyl-D-manno-hexodialdose (100).61 98 (231 mg, 0.97 mmol) was treated as per the general method for Swern oxidations to give 100 as a yellow oil (225 mg, 99%); 1H

NMR (300 MHz, CDCl3) δ 9.58 (d, J = 1.6 Hz, 2H) 3.81-3.66 (m, 2H) 3.65-3.50 (m, 2H) 3.30 (s, 13 6H) 3.29 (s, 6H); C NMR (75 MHz, CDCl3). 200.8, 84.9, 81.5, 60.0, 58.4.

1,6- Di-O-trityl-D-sorbitol (102).65 D-sorbitol 101 (1.00g, 5.50 mmol) was treated as per the general method for tritylation and the product purified by flash column chromatography (1:1 EtOAc/hexanes) to give 102 as a viscous yellow syrup (3.41 g, 93%); 1H NMR (300 MHz,

CDCl3) δ 7.48-7.40 (m, 12H) 7.29-7.16 (m, 18H) 3.97-3.85 (m, 3H) 3.70-3.64 (m, 1H) 3.46-3.31 13 (m, 7H) 3.29-3.21 (m, 1H); C NMR (75 MHz, CDCl3) δ 143.6. 128.53, 128.5, 127.72, 127.7, 127.0, 126.9, 86.8, 73.4, 72.9, 71.5, 69.8, 65.0, 64.9, 60.2; FT-IR (neat) 3438, 3059, 3030, 2927, 2875, 1069 cm-1; MS (ESI) 689.3 [M + Na]+.

1,5-Di-O-trityl-2,3,4-tetra-O-benzyl-D-sorbitol (103).69 102 (1.13 g, 1.76 mmol) was treated as per the general method for perbenzylation and the product purified by column chromatography (1:9 EtOAc/hexanes) to give 103 as a viscous yellow syrup (1.70 g, 85%); 1H NMR (300 MHz,

CDCl3) δ 7.74-7.61 (m, 12H) 7.59-7.26 (m, 38H) 4.96 (d, J = 7.5 Hz, 1H) 4.92 (d, J = 7.2 Hz, 1H) 4.86-4.74 (m, 3H) 4.51-4.65 (m, 2H) 4.34 (d, J = 11.1 Hz, 1H) 4.31-4.25 (m, 1H) 4.24-4.17 (m, 1H) 4.15-4.01 (m, 2H) 3.84-3.75 (m, 1H) 3.65 (s, 1H) 3.56 (dd, J = 10.3, 5.0 Hz, 1H) 3.48 13 (dd, J = 10.0, 5.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 144.3, 144.2, 139.0, 138.9, 138.6, 129.07, 128.64, 128.6, 128.5, 128.4, 128.23, 128.2, 128.1, 128.0, 127.8, 127.5, 127.41, 127.36, 127.2, 127.15, 86.9, 96.8, 80.0, 79.6, 79.2, 78.6, 74.7, 74.0, 73.2, 72.2, 63.8, 63.0; FT-IR (neat) 3059, 3030, 2927, 2877, 1067 cm-1; MS (ESI) 1049 [M + Na]+.

2,3,4,5-tetra-O-benzyl-D-sorbitol (104).71 103 (3.35 g, 3.27 mmol) was treated as per the general procedure A for detritylation to give 104 as a colourless syrup (1.40 g, 79%); 1H NMR

(300 MHz, CDCl3) δ 7.53-7.06 (m, 20H) 4.83 (d, J = 11.1 Hz, 1H) 4.75 (d, J = 11.5 Hz, 1H) 4.72-4.61 (m, 4H) 4.53 (d, J = 11.7 Hz, 1H) 4.40 (d, J = 11.7 Hz, 1H) 4.03-3.67 (m, 7H) 3.65- 13 3.50 (m, 1H) 2.43 (br. s., 1H) 2.19 (br. s., 1H); C NMR (75 MHz, CDCl3) δ 138.2, 138.1, 139

128.6, 128.54, 128.5, 120.5, 128.4, 128.3, 128.1, 127.9, 127.88, 127.72, 79.7, 79.3, 78.9, 78.3, 74.7, 74.2, 72.9, 71.6, 61.7, 60.7; FT-IR (DCM) 3581, 3065, 3033, 2929, 2878, 1100 cm-1; MS (ESI) 565 [M + Na]+

1,6-di-O-Trityl-2,3,4,5-Tetra-O-methyl-D-sorbitol (105).65 102 (1.20 g, 1.80 mmol) was treated as per the general method for permethylation and the product purified by adsorption on silica followed by washing with hexanes and elution with EtOAc to give 105 as a gummy yellow 1 solid (1.25 g, 96%); H NMR (300 MHz, CDCl3) δ 7.62-7.12 (m, 30H) 3.55-3.64 (m, 2H) 3.53 (br. s, 3H) 3.52 (br. s, 3H) 3.47-3.37 (m, 6H) 3.36-3.29 (m, 1H) 3.18-3.07 (m, 2H) 2.90 (br. s, 13 3H); C NMR (75 MHz, CDCl3) δ 144.2, 144.1, 128.8, 127.8, 127.75, 127.0, 126.9, 86.7, 86.6, 81.7, 81.1, 80.8, 80.0, 63.5, 62.7, 60.5, 59.8, 59.1, 58.5; MS (ESI) 603 [M + Na]+.

2,3,4,5-Tetra-O-methyl-D-sorbitol (106).65 105 (914 mg, 1.26 mmol) was treated as per the general procedure B for detritylation to give 106 as a white powder (241 mg, 80%); 1H NMR 13 (300 MHz, CDCl3) δ 3.94-3.79 (m, 2H) 3.76-3.60 (m, 9H) 3.58-3.34 (m, 18H); C NMR (75

MHz, CDCl3) δ 81.3, 81.2, 81.0, 79.1, 61.6, 60.4, 60.2, 59.6, 58.7, 57.3; MS (ESI) 261 [M + Na]+, 499 [2M + Na]+.

2,3,4,5-Tetra-O-benzyl-D-sorbo-hexodialdose (107). 104 (2.04 g, 3.76 mmol) was treated as per the general method for Swern oxidations to give 107 as a pale yellow oil (1.70 g, 84%); 1H

NMR (300 MHz, CDCl3) δ 9.67 (s, 1H), 9.66 (d, J = 1.5 Hz, 1H), 7.37-7.14 (m, 20H), 4.82 (d, J = 11.7 Hz, 1H), 4.71 (br. d, J = 11.7 Hz, 1H), 4.57-4.43 (m, 4H), 4.53 (d, J = 11.7 Hz, 1H), 4.47 13 (d, J = 11.7 Hz, 1H), 4.09-4.04 (m, 2H), 4.01-3.94 (m, 2H); C NMR (75 MHz, CDCl3) δ 200.7, 199.8, 137.1, 137.0, 137.0 (2C), 128.4, 128.3, 128.2, 128.2, 128.0, 127.9, 127.9, 127.7, 83.4, 81.6, 79.5, 78.7, 74, 73.6, 72.9, 72.6 (4 masked Aryl C); FT-IR (neat) 3030, 2867, 1728 cm-1.

2,3,4,5-Tetra-O-methyl-D-sorbo-hexodialdose (108).65 106 (245 mg, 1.03 mmol) was treated as per the general method for Swern oxidations to give 108 as a pale yellow oil (212 mg, 88%); 1 H NMR (300 MHz, CDCl3) δ 9.72-9.50 (m, 2H) 3.77 (s, 1H) 3.73 (dd, J = 4.7, 1.9 Hz, 1 H) 3.66 (dd, J = 4.0 Hz, 1H) 3.60 (dd, J = 4.0 Hz, 1H) 3.40 (s, 3H) 3.37 (s, 3H) 3.34 (s, 3H) 3.21 (s, 13 3H); C NMR (75 MHz, CDCl3) δ 200.6, 199.7, 85.5, 88.0, 81.6, 80.2, 59.7, 59.5, 58.8, 58.6.

1,6-di-O-Trityl-D-galactitol (110).62 D-galactitol 109 (1.00 g, 5.50 mmol) was treated as per the general method for tritylation and the product successively recrystallised from DCM/hexanes 1 followed by EtOH to give 110 as a white powder (3.33 g, 91%); H NMR (300 MHz, CDCl3) δ 7.45-7.38 (m, 12H) 7.33-7.19 (m, 18H) 4.04-3.97 (m, 2H) 3.59 (s, 2H) 3.39 (dd, J = 9.8, 4.3 Hz,

140

13 2H) 3.26 (dd, J = 9.8, 6.0 Hz, 2H); C NMR (75 MHz, CDCl3) δ 148.6, 128.6, 128.0, 127.2, 87.3, 71.9, 69.2, 66.4; FT-IR (neat) 3379, 3022, 2944, 2877, 1074 cm-1; MS (ESI) 689.3 [M+Na]+.

1,6-di-O-Trityl-2,3,4,5-tetra-O-benzyl-D-galactitol (111). To a solution of 110 (1.13 g, 1.69 mmol) in THF (25 mL) were added BnBr (952 μL, 8.00 mmol) and NaH (253 mg, 10.5 mmol) and the mixture stirred for 24 hours. The reaction was carefully quenched with MeOH and the precipitate was collected by vacuum filtration. The solid was washed with H2O (50 mL) followed by MeOH (50 mL) then dried at the pump to yield 111 as a white powder (1.61 g, 1 81%); H NMR (300 MHz, CDCl3) δ 7.52-6.92 (m, 50H) 4.56-4.32 (m, 8H) 4.04-3.95 (m, 2H) 13 3.93-3.83 (m, 2H) 3.41-3.25 (m, 4H); C NMR (75 MHz, CDCl3) δ 144.1. 138.9, 128.7, 128.15, 128.1, 127.7, 127.6, 127.5, 127.2, 127.1, 126.9, 86.8, 79.0, 78.6, 73.5, 72.6, 63.9. FT-IR (neat) 3060, 2934, 2889, 1066 cm-1; MS (ESI) 1049.5 [M + Na]+; HRMS (ESI) m/z: [M + Na]+ Calcd for C72H66O6Na: 1049.4698; found 1049.4716.

2,3,4,5-Tetra-O-benzyl-D-galactitol (112).70 To a solution of 111 (0.50 g, 0.48 mmol) in toluene (30 mL) at 100 °C was slowly added MeOH (10 mL) then TFA (1.0 mL) and the mixture refluxed for 6 hours. The mixture was cooled to room temperature then poured onto a saturated solution of NaHCO3 (20 mL) and stirred for fifteen minutes. The organic phase was collected and the aqueous phase extracted again with toluene. Combined organic extracts were concentrated under reduced pressure and the residue purified by column chromatography (2:3- 1 1:1 EtOAc/hexanes) to yield 112 as a white powder (200 mg, 77%); H NMR (300 MHz, CDCl3) δ 7.44-7.17 (m, 20H) 4.81 - 4.63 (m, 8H) 4.03-3.96 (m, 2H) 3.92-3.74 (m, 6H) 2.54 (br. s., 2H); 13 C NMR (75 MHz, CDCl3) δ 138.5, 138.4, 128.42, 128.4 127.93, 127.9, 127.7, 80.3, 80.1, 74.3, 72.8, 66.5; FT-IR (neat) 3481, 3029, 2935, 2873, 1062 cm-1; MS (ESI) 565 [M + Na]+.

1,6-di-O-Trityl-2,3,4,5-Tetra-O-methyl-D-galactitol (113).62 110 (1.0 g, 1.5 mmol) was treated as per the general method for permethylation and the product purified by adsorption on silica followed by washing with hexane and elution with EtOAc to give 113 as a yellow solid 1 (0.90 82%); H NMR (300 MHz, CDCl3) δ 7.58-7.10 (m, 3H) 3.57 - 3.46 (m, 6H) 3.39 (s, 6H) 13 3.27-3.24 (m, 2H) 3.22 (s, 6H); C NMR (75 MHz, CDCl3) δ 144.1, 128.7, 17.8, 127.0, 87.2, 79.3, 79.1, 62.7, 60.6, 58.4; MS (ESI) 603 [M + Na]+.

2,3,4,5-Tetra-O-methyl-D-galactitol (114).62 113 (2.34 g, 3.24 mmol) was treated as per the general procedure B for detritylation to give 114 as a white powder (594 mg, 77%); 1H NMR

141

13 (300 MHz, CDCl3) δ 3.89-3.74 (m, 4H) 3.57-3.39 (m, 16H) 3.02 (br. s., 2H); C NMR (75 + + MHz, CDCl3) δ 81.0, 80.2, 60.8, 60.3, 57.9; MS (ESI) 261 [M + Na] 499 [2M + Na] .

2,3,4,5-Tetra-O-benzyl-D-galacto-hexodialdose (115). 112 (1.16 g, 2.14 mmol) was treated as per the general method for Swern oxidations to give 115 as a pale yellow oil (1.07 g, 93%); 1H

NMR (300 MHz, CDCl3) δ9.66 (s, 2H), 7.40-7.10 (m, 20H), 4.66 (br. d, J = 11.8 Hz, 2H), 4.49 (d, J = 11.8 Hz, 2H), 4.47 (d, J = 11.4 Hz, 2H), 4.34 (br. d, J = 11.4 Hz, 2H), 4.16-4.10 (m, 4H); 13 C NMR (75 MHz, CDCl3) δ 201.6, 137.0 (2C), 128.3, 128.2, 128.1, 128.1, 127.8, 127.7, 83.3, 78.3, 73.6, 73.2; FT-IR (neat) 3027, 2907, 2872, 1731, 1026 cm-1.

2,3,4,5-Tetra-O-methyl-D-galacto-hexodialdose (116).62 114 (1.00g, 4.22 mmol) was treated as per the general method for Swern oxidation to give 116 as a white powder (0.80 g, 81%); 1H 13 NMR (300 MHz, CDCl3) δ 9.77 (d, J = 1.3 Hz, 2H) 3.74 (br. s, 4H) 3.46 (s, 6H) 3.23 (s, 6H); C

NMR (75 MHz, CDCl3) δ 202.0, 85.4, 79.2, 60.0, 58.9.

1,5-Di-O-trityl-D-ribitol (118).66 D-ribitol 117 (1.00 g, 6.57 mmol) was treated as per the general method for tritylation and the product purified by recrystallisation from DCM/hexanes to 1 give a white powdery solid (3.34 g, 80%); H NMR (300 MHz, CDCl3) δ 7.48-7.42 (m, 12H) 7.39-7.18 (m, 18H) 3.77 (br. s., 3H) 3.48 (dd, J = 9.6, 3.6 Hz, 1H) 3.35 (dd, J = 9.6, 4.8 Hz, 2H) 13 2.99 (br. s., 2H) 2.91 (br. s., 1H); C NMR (75 MHz, CDCl3) δ 143.5, 128.5, 122.9, 127.2, 87.2, 73.3, 71.9, 65.0; FT-IR (neat) 3549, 3488, 3446, 2935, 1062 cm-1; MS (ESI) 659.3 [M + Na]+.

1,5-Di-O-trityl-2,3,4-tri-O-benzyl-D-ribitol (119).66 118 (224mg, 0.383 mmol) was treated as per the general method for perbenzylation and the product purified by flash column chromatography (1:9 EtOAc/hexanes) gave 119 as a viscous colourless syrup (223 mg, 70%); 1H

NMR (300 MHz, CDCl3) δ 7.55-6.73 (m, 45H) 4.70 (d, J = 11.5 Hz, 2H) 4.51 (d, J = 11.5 Hz, 2H) 4.46 (s, 2H) 3.96-3.83 (m, 3H) 3.43 (dd, J = 10.0, 2.8 Hz, 2H) 3.34 (dd, J = 10.0, 8.0 Hz, 13 2H); C NMR (75 MHz, CDCl3) δ 144.2, 138.8, 138.5, 128.9, 128.2, 128.0, 127.8, 127.7, 127.2, 126.0, 86.7, 79.3, 79.2, 73.4, 72.7, 64.2; FT-IR (neat) 3059, 3030, 2930, 2876, 1070 cm-1; MS (ESI) 929.4 [M + Na]+.

2,3,4-Tri-O-benzyl-D-ribitol (120).66 119 (105 mg, 0.116 mmol) was treated as per the general procedure A for detritylation to give 120 as a colourless syrup (40 mg, 82%); 1H NMR (300

MHz, CDCl3) δ 7.49-7.12 (m, 15H) 4.75 (s, 2H) 4.63 (s, 4H) 3.95 (t, J = 4.8 Hz, 1H) 3.86 - 3.63 13 (m, 6H); C NMR (75 MHz, CDCl3) δ 138.0, 137.9, 128.5, 128.2, 128.0, 127.9, 79.14, 79.1,

142

74.2, 72.2, 61.4; FT-IR (DCM) 3583, 3482, 3065, 3033, 2928, 2881, 1100 cm-1; MS (ESI) 445 [M + Na]+.

2,3,4-Tri-O-benzyl-D-ribo-pentodialdose (121). 120 (687 mg, 1.63 mmol) was treated as per the general method for Swern oxidations to give 121 as a tan oil (674 mg, 99%); 1H NMR (300

MHz, CDCl3) δ 9.43 (d, J = 1.1 Hz, 2H) 7.31-7.11 (m, 15H) 4.58 (d, J = 11.7 Hz, 2H) 4.52 (d, J 13 = 11.5 Hz, 2H) 4.42 (s, 2H) 4.10-3.88 (m, 3H); C NMR (75 MHz, CDCl3) δ 200.5, 128.52, 128.5, 128.1, 81.0, 79.8, 73.4, 72.4.

1,5-Di-O-trityl-D-xylitol (123). D-xylitol 122 (1.00 g, 6.57 mmol) was treated as per the general method for tritylation and the product purified by column chromatography (2:3-1:1

EtOAc/hexanes) to give a colourless syrup which crystallised after slow evaporation from CHCl3 1 (3.01 g, 72%); H NMR (300 MHz, CDCl3) δ 7.69-7.41 (m, 10H) 7.39-7.16 (m, 20H) 3.84 (br. s., 3H) 3.38 (dd, J = 9.6, 4.9 Hz, 2H) 3.30 (dd, J = 9.6, 5.8 Hz, 2H) 3.05 (br. s., 2H) 2.94 (d, J = 13 4.0 Hz, 1H); C NMR (75 MHz, CDCl3) δ 143.8, 128.73, 128.0, 127.75, 87.0, 72.4, 76.9, 65.0; FT-IR (neat) 3438, 3059, 3030, 2932, 2877, 1065 cm-1; MS (ESI) 659.2 [M + Na]+; HRMS (ESI) + m/z: [M + Na] Calcd for C43H40O5Na 659.2773; found 659.2798.

1,5-Di-O-trityl-2,3,4-tri-O-benzyl-D-xylitol (124). 123 (2.00 g, 3.14 mmol) was treated as per the general method for perbenzylation and the product purified by flash column chromatography (1:9 EtOAc/hexanes) to give 124 as a colourless oil which crystallised upon slow evaporation 1 from CHCl3 (1.80 g, 62%); H NMR (300 MHz, CDCl3) δ 7.72-7.12 (m, 45H) 4.90 (s, 2H) 4.57 (d, J = 11.3 Hz, 2H) 4.48 (t, J = 4.9 Hz, 1H) 4.32 (d, J = 11.5 Hz, 2H) 3.99-3.87 (m, 2H) 3.59 13 (dd, J = 9.8, 4.5 Hz, 2H) 3.30 (dd, J = 9.6, 4.3 Hz, 2H); C NMR (75 MHz, CDCl3) δ 144.1, 138.9, 136.8, 128.9, 128.6, 128.4, 128.2, 128.0, 127.6, 127.5, 127.2, 86.8, 80.0, 75.4, 73.1, 62.8; + + MS (ESI) 929.4 [M + Na] ; HRMS (ESI) m/z: [M + Na] Calcd for C64H58O5Na 929.4182; found 929.4172.

2,3,4-tri-O-benzyl-D-xylitol (125). 124 (1.7 g, 1.9 mmol) was treated as per the general procedure A for detritylation to give 125 as a colourless syrup (650 mg, 82%); 1H NMR (300

MHz, CDCl3) δ 7.48-7.11 (m, 15H) 4.72 (s, 2H) 4.66 (d, J = 11.9 Hz, 2H) 4.64 (d, J = 11.7 Hz, 13 2H) 3.86-3.69 (m, 5H) 3.68-3.58 (m, 2H) 2.37 (br. s., 2H); C NMR (75 MHz, CDCl3) δ 138.0, 137.9, 128.6, 128.5, 128.1, 128.0, 79.3, 79.1, 74.7, 72.8. 61.5. FT-IR (DCM) 3582, 3468, 3065, 3033, 2930, 2878, 1070 cm-1; MS (ESI) m/z 445 [M + Na]+.

143

2,3,4-Tri-O-benzyl-D-xylo-pentodialdose (126). 125 (628 mg, 1.49 mmol) was treated as per the general method for Swern oxidations to give 126 as a tan oil (616 mg, 99%); 1H NMR (300

MHz, CDCl3) δ 9.61 (s, 2H) 7.28-7.10 (m, 15H) 4.59 (d, J = 11.7 Hz, 2H) 4.49 (d, J = 11.7 Hz, 13 2H) 4.45 (s, 2H) 4.09 (t, J = 4.0 Hz, 1 H) 3.93 (d, J = 4.0 Hz, 2H); C NMR (75 MHz, CDCl3) δ 201.4, 128.5, 128.4, 128.3, 128.2, 80.9, 79.9, 73.8, 73.5.

General procedure for NHC-mediated carbocylisations of dialdehydes. To a suspension of precatalyst 134 (0.20 equiv) in DCE (5 mL) under N2 was added a solution of triethylamine in DCE (1.00 M, 0.15 equiv) and the mixture stirred for 10 minutes. A solution of dialdehyde (1 equiv) in DCE (50 mL/g) was then added and the mixture maintained at 25-60 °C as specified in Table 1-3 for 16-40 hours. The solvent was removed under reduced pressure and the residue taken up in a minimal volume of DCM then filtered through a bed of silica and washed through with 1:1 EtOAc/hexanes (ca. 20 mL) for reactions of 99, 107, 115 or neat EtOAc for 100 and 116. The products were further purified as specified.

(2S,3S,4R,5R,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-hydroxycyclohexanone (129). Purified by 30 column chromatography (3:7 EtOAc/hexanes) to give a light yellow syrup (550 mg, 54%); [α]D 1 -35.6 (c 5.9, DCM); H NMR (300 MHz, CDCl3) δ 7.57-6.96 (m, 20H), 4.86 (d, J = 11.7 Hz, 1H), 4.85 (d, J = 12.3 Hz, 1H), 4.75 (d, J = 11.7 Hz, 1H), 4.68 (d, J = 12.3 Hz, 1H), 4.63- 4.55 (m, 3H), 4.48 (d, J = 11.7 Hz, 1H), 4.44 (d, J = 12.3 Hz, 1H), 4.40 (d, J = 12.3 Hz, 1H), 3.95 (dd, 13 J = 3.8, 3.8 Hz, 1H), 3.82-3.72 (m, 2H), 3.53 (br. s, 1H); C NMR (75 MHz, CDCl3) δ 205.1, 138.5, 137.9, 137.8, 137.6, 128.6, 128.5, 128.45, 128.4, 128.38, 127.9, 127.89, 127.8, 127.7, 82.5, 80.5, 77.9, 76.6, 75.2, 73.8, 73.6, 73.5, 72.7 (3 masked Aryl C); FT-IR (neat) 3469, 3030, 2872, 1732, 1104, 1027, 1026 cm-1; MS (ESI) m/z 561 [M + Na]+; HRMS (ESI-TOF) m/z: [M + + Na] Calcd for C34H34O6Na 561.2253; found 561.2250.

(2S,3S,4R,5R,6R)-6-Hydroxy-2,3,4,5-tetramethoxycyclohexanone (130). Purified by column 32 chromatography (9:1 EtOAc/hexanes) to give a colourless syrup (115 mg, 62%); [α]D 30.0 (c 1 7.1, DCM); H NMR (600 MHz, CDCl3) δ 4.44 (d, J = 9.7 Hz, 1H), 4.30 (dd, J = 3.5, 1.5 Hz, 1H), 4.00 (dd, J = 4.1, 3.5 Hz, 1H), 3.89 (dd, J = 4.1, 2.9 Hz, 1H), 3.60 (s, 3H), 3.56 (s, 3H), 13 3.50 (s, 3H), 3.46 (s, 3H), 3.41 (dd, J = 9.7, 2.9 Hz, 1H); C NMR (150 MHz, CDCl3) δ 204.7, 84.4, 82.8, 79.3, 76.2, 75.8, 60.0, 59.9, 59.2, 58.9; FT-IR (neat) 3472, 2934, 2833, 1734 cm-1; + + MS (ESI) m/z 257 [M + Na] ; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C10H18O6Na 257.1001; found 257.0995.

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Typical procedure for the acetylation of hydroxyketones. To a solution of the hydroxyketone (0.10-0.20 mmol) in pyridine (1 mL) was added acetic anhydride (50 μL, 0.53 mmol) and the mixture stirred overnight. The solvent was removed by azeotropic distillation with toluene and the residue purified by flash chromatography (136, 146, 147, 158 1:3 to 3:7 EtOAc/hexanes; 137, 160 4:1 EtOAc/hexanes).

(2S,3S,4S,5S,6R)-6-Acetoxy-2,3,4,5-tetrakis(benzyloxy)cyclohexanone (136). Colourless 23 1 syrup (90 mg, 65%); [α]D -24.2 (c 1.2, DCM); H NMR (600 MHz, CDCl3) δ 7.45-7.18 (m, 18H), 7.17-7.10 (m, 2H), 5.62 (dd, J = 10.4, 1.0 Hz, 1H), 4.89 (d, J = 11.7 Hz, 1H), 4.74 (d, J = 12.9 Hz, 1H), 4.72 (d, J = 12.9 Hz, 1H), 4.64 (d, J = 12.3 Hz, 1H), 4.58 (d, J = 3.2, 1.0 Hz, 1H), 4.52 (d, J = 12.1 Hz, 1H), 4.50 (d, J = 12.3 Hz, 1H), 4.41 (d, J = 12.3 Hz, 1H), 4.40 (d, J = 12.3 Hz, 1H), 4.04 (dd, J = 10.4, 3.2 Hz, 1H), 3.94 (dd, J = 4.1, 3.2 Hz, 1H), 3.81 (dd, J = 4.1, 3.2 Hz, 13 1H), 2.18 (s, 3H); C NMR (75 MHz, CDCl3) δ 198.5, 169.9, 137.9, 137.8, 137.7, 128.45, 128.4, 128.3, 127.9, 127.85, 127.8, 127.7, 81.0, 78.9, 77.7, 77.6, 75.0, 73.8, 73.7, 73.6, 72.8, 29.7 (6 masked Aryl C); FT-IR (neat) 3030, 2871, 1742 cm-1; MS (ESI) m/z 581 [M + H]+, 603.2 + + [M + Na] ; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C36H36O7Na 603.2359; found 603.2360.

(2S,3S,4S,5S,6R)-6-Acetoxy-2,3,4,5-tetramethoxycyclohexanone (137). Crystalline solid (35 30 1 mg, 99%); mp 67-70 °C; [α]D 6.1 (c 0.33, DCM); H NMR (600 MHz, CDCl3) δ 5.46 (br d, J = 10.6 Hz, 1H), 4.27 (dd, J = 3.2, 0.9 Hz, 1H), 3.95 (dd, J = 4.1, 3.2 Hz, 1H), 3.91 (dd, J = 4.1, 2.9 Hz, 1H), 3.69 (dd, J = 10.6, 2.9 Hz, 1H), 3.60 (s, 3H), 3.48 (s, 3H), 3.46 (s, 3H), 3.45 (s, 3H), 13 2.18 (s, 3H); C NMR (150 MHz, CDCl3) δ 198.2, 169.9, 83.1, 80.8, 79.1, 77.4, 75.9, 60.0, 59.9, 59.3, 59.0, 20.7; FT-IR (neat) 2922, 2838, 1750, 1728 cm-1; MS (ESI) m/z 299 [M + Na]+; + HRMS (ESI-TOF) m/z: [M + Na] Calcd for C12H20O7Na 299.1107; found 299.1100.

(2R,3S,4R,5R,6S)-2,3,4,5-Tetrakis(benzyloxy)-6-hydroxycyclohexanone (138). Purified by column chromatography (3:7 EtOAc/hexane then 1:19 MeOH/toluene) to give a white solid (232 27 1 mg, 14%); mp 129-131°C; [α]D -6.7 (c 1.8, DCM); H NMR (600 MHz, CDCl3) δ 7.52-7.12 (m, 20H), 4.93 (d, J = 11.7 Hz, 1H), 4.90 (d, J = 10.6 Hz, 1H), 4.88 (d, J = 11.6 Hz, 1H), 4.86 (d, J = 10.6 Hz, 1H), 4.73 (d, J = 11.7 Hz, 1H), 4.73 (d, J = 11.7 Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H), 4.59 (d, J = 11.7 Hz, 1H), 4.20-4.16 (m, 2H), 4.14 (dd, J = 2.3, 2.3 Hz, 1H), 4.12 (dd, J = 8.8, 1.2 13 Hz, 1H), 3.80 (dd, J = 9.4, 2.3 Hz, 1H), 3.41 (d, J = 6.4 Hz, 1H); C NMR (150 MHz, CDCl3) δ 204.2, 138.4, 138.0, 137.9, 137.3, 128.5, 128.4, 128.3, 128.2, 128.14, 128.1, 127.93, 127.9, 127.7 (2C), 127.69, 127.6, 83.6, 82.5, 79.8, 77.9, 76.1, 74.9, 74.7, 73.6, 73.2; FT-IR (neat) 3430,

145

3030, 2867, 1734 cm-1; MS (ESI) m/z 561 [M + Na]+, 577.2 [M + K]+; HRMS (ESI-TOF) m/z: + [M + Na] Calcd for C34H34O6Na 561.2253; found 561.2247.

(2S,3S,4R,5S,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-hydroxycyclohexanone (144). Purified by column chromatography (3:7 EtOAc/hexane and 1:19 MeOH/toluene) to give a light yellow 28 1 syrup (463 mg, 27%); [α]D -40.4 (c 0.6, DCM); H NMR (600 MHz, CDCl3) δ 7.50-7.20 (m, 18H), 7.12-7.06 (m, 2H), 4.88 (d, J = 11.7 Hz, 1H), 4.73 (d, J = 12.3 Hz, 1H), 4.58-4.54 (m, 4H) 4.48-4.43 (m, 2H), 4.39 (d, J = 12.3 Hz, 1H), 4.36 (d, J = 12.3, 1H), 4.25-4.20 (m, 1H), 4.18- 13 4.13 (m, 1H), 3.80 (dd, J = 2.8, 2.8 Hz, 1H), 3.36 (br s, 1H); C NMR (75 MHz, CDCl3) δ 205.4, 138.0, 137.71, 137.7, 137.0, 128.5, 128.4, 128.3, 128.2, 128.0, 127.79, 127.75, 127.7, 127.6, 127.5, 82.2, 81.3, 80.3, 74.3, 73.6, 73.2, 73.0, 72.7, 72.3 (2 masked Aryl C); FT-IR (neat) 3429, 3030, 2871, 1731, 1069, 1026 cm-1; MS (ESI) m/z 561 [M + Na]+; HRMS (ESI-TOF) m/z: + [M + Na] Calcd for C34H34O6Na 561.2253; found 561.2261.

(2R,3S,4S,5S,6S)-6-Acetoxy-2,3,4,5-tetrakis(benzyloxy)cyclohexanone (146). Colourless 24 1 syrup (13 mg, 81%); [α]D -15.0 (c 0.53, EtOH); H NMR (600 MHz, CDCl3) δ 7.44-7.17 (m, 20H), 5.15 (d, J = 1.8 Hz, 1H, H6), 4.93 (d, J = 11.1 Hz, 1H), 4.90 (d, J = 10.5 Hz, 1H), 4.84 (d, J = 10.5 Hz, 1H), 4.81 (d, J = 12.1 Hz, 1H), 4.78 (d, J = 12.1 Hz, 1H), 4.72 (d, J = 11.7 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 4.55 (d, J = 11.1 Hz, 1H), 4.20 (dd, J = 9.1, 9.1 Hz, 1H, H3), 4.12 (dd, J = 2.3, 1.8 Hz, 1H, H5), 4.11 (br. d, J = 9.1 Hz, 1H, H2), 3.84 (dd, J = 9.1, 2.3 Hz, 1H, H4), 13 2.17 (s, 3H); C NMR (150 MHz, CDCl3) δ 197.6, 169.8, 138.4, 137.8, 137.75, 137.5, 128.5, 128.4, 128.3, 128.2, 128.19, 128.1, 128.0, 127.9, 127.85, 127.7, 127.66, 127.6, 83.9, 82.1, 80.0, 76.1, 75.8, 75.2, 74.1, 73.7, 73.2, 20.6; FT-IR (neat) 3030, 2921, 2864, 1758, 1739, 1095, 1074, 1025 cm-1; MS (ESI) m/z 581 [M + H]+, 603.2; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for

C36H36O7Na 603.2359; found 603.2341.

(2S,3S,4S,5R,6R)-6-Acetoxy-2,3,4,5-tetrakis(benzyloxy)cyclohexanone (147). Yellow syrup 34 1 (13 mg, 40%); [α]D -25.0 (c 0.60, EtOH); H NMR (600 MHz, CDCl3) δ 7.40-7.22 (m, 18H), 7.10-7.06 (m, 2H), 5.48 (d, J = 4.7 Hz, 1H), 4.92 (d, J = 11.7 Hz, 1H), 4.75 (d, J = 12.3 Hz, 1H), 4.59 (d, J = 12.5 Hz, 1H), 4.54 (d, J = 12.3 Hz, 1H), 4.54 (d, J = 12.5 Hz, 1H), 4.48 (br d, J = 4.1 Hz, 1H), 4.38 (d, J = 11.0 Hz, 1H), 4.35 (d, J = 11.0 Hz, 1H), 4.22-4.19 (m, 1H), 4.18-4.15 (m, 13 1H), 3.83 (dd, J = 2.9, 2.9 Hz, 1H), 2.20 (s, 3H); C NMR (75 MHz, CDCl3) δ 198.9, 170.0, 138.2, 137.8, 137.7,136.9, 128.6, 128.4, 128.24, 128.2, 127.9 (2C), 127.83, 127.8, 127.7, 127.6, 127.5, 80.9, 80.5, 80.2, 75.4, 73.5, 73.3, 73.0, 72.7, 72.5, 20.7 (1 masked Aryl C); FT-IR (neat)

146

3030, 2925, 2869, 1761, 1740, 1065, 1026 cm-1; MS (ESI) m/z 581 [M + H]+, 603 [M + Na]+; + HRMS (ESI-TOF) m/z: [M + Na] Calcd for C36H36O7Na 603.2359; found 603.2369.

(±)-(2R,3S,4R,5S,6S)-6-Acetoxy-2,3,4,5-tetrakis(benzyloxy)cyclohexanone (158). Colourless 1 syrup (14 mg, 17% from dialdehyde 115); H NMR (600 MHz, CDCl3) δ 7.45-7.41 (m, 2H), 7.34-7.22 (m, 16H), 7.11-7.06 (m, 2H), 5.61 (d, J = 2.6 Hz, 1H), 4.92 (d, J = 11.3 Hz, 1H), 4.83 (d, J = 11.9 Hz, 1H), 4.83 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 11.9 Hz, 1H), 4.58 (d, J = 10 Hz, 1H), 4.57 (d, J = 11.3 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.34 (d, J = 11.9 Hz, 1H), 3.98 (dd, J = 10.0, 2.9 Hz, 1H), 3.91 (dd, J = 3.8, 2.6 Hz, 1H), 3.84 (dd, J = 3.8, 13 2.9 Hz, 1H), 2.19 (s, 3H); C NMR (150 MHz, CDCl3) δ 198.8, 169.8, 138.3, 137.9, 137.6, 137.3, 128.5, 128.4, 128.3, 128.29, 128.05, 128.0, 127.95, 127.92, 127.9, 127.71, 127.67, 127.66, 83.6, 80.4, 76.7, 75.9, 74.7, 74.2, 73.9, 73.8, 73.4, 20.7; FT-IR (neat) 3030, 2869, 1741, 1227, 1103, 1043, 1026 cm-1; MS (ESI) m/z 603 [M + Na]+, 619 [M + K]+; HRMS (ESI) m/z: [M + + Na] Calcd for C36H36O7Na 603.2332; found 603.2337.

(±)-(2R,3S,4S,5R,6S)-6-Hydroxy-2,3,4,5-tetramethoxycyclohexanone (159). Purified by column chromatography (9:1 EtOAc/hexane) to give a colourless syrup (76 mg, 60%); 1H NMR

(600 MHz, CDCl3) δ 4.53 (dd, J = 3.9, 0.9 Hz, 1H), 4.14 (dd, J = 9.7, 0.9 Hz, 1H), 3.91 (dd, J = 3.9, 3.5 Hz, 1H), 3.87 (dd, J = 3.5, 3.2 Hz, 1H), 3.57 (s, 3H), 3.52 (dd, J = 9.7, 3.2 Hz, 1H), 3.52 13 (s, 3H), 3.51 (s, 3H), 3.43 (s, 3H); C NMR (150 MHz, CDCl3) δ 205.3, 85.0, 82.6, 79.6, 76.1, 74.3, 60.1, 59.7, 59.64, 59.6; FT-IR (neat) 3459, 2932, 2832, 1736, 1111, 1092, 1062 cm-1; MS + + (ESI) 257 [M + Na] ; HRMS (ESI) m/z: [M + Na] Calcd for C10H18O6Na 257.1001; found 257.0995.

(±)-(2R,3S,4R,5S,6S)-6-Acetoxy-2,3,4,5-tetramethoxycyclohexanone (160). Colourless syrup 1 (33 mg, 56%); H NMR (600 MHz, CDCl3) δ 5.53 (dd, J = 3.1, 0.9 Hz, 1H), 4.14 (br d, J = 10.0 Hz, 1H), 3.94 (dd, J = 3.8, 3.2 Hz, 1H), 3.89 (dd, J = 3.8, 3.2 Hz, 1H), 3.59 (s, 3H), 3.57 (dd, J = 10.0, 3.2 Hz, 1H), 3.53 (s, 3H), 3.52 (s, 3H), 3.46 (s, 3H), 2.20 (s, 3H); 13C NMR (150 MHz,

CDCl3) δ 198.5, 169.8, 85.2, 82.1, 78.2, 76.3, 75.9, 59.8, 59.72, 59.7 (2C), 20.7; FT-IR (neat) 2935, 2834, 1741, 1229, 1113, 1089, 1070, 1052 cm-1; MS (ESI) 299 [M + Na]+; HRMS (ESI) + m/z: Calcd for C12H20O7Na [M+Na] : 299.1107; found 299.1105.

(±)–(2R,3S,4S,5R,6R)-6-Hydroxy-2,3,4,5-tetramethoxycyclohexanone (161). Colourless syrup 1 (5 mg, 5%); H NMR (600 MHz, CDCl3) δ 4.44 (d, J = 8.5 Hz, 1H), 3.84 (d, J = 4.4 Hz, 1H), 3.82 (dd, J = 4.4, 2.6 Hz, 1H), 3.77 (dd, J = 9.1, 2.6 Hz, 1H), 3.63 (s, 3H), 3.54 (s, 3H), 3.43 (s, 13 3H), 3.42 (dd, J = 9.1, 8.5 Hz, 1H), 3.33 (s, 3H); C NMR (CDCl3, 150 MHz) δ 206.6, 84.7, 147

81.1, 80.3, 77.6, 76.1, 60.7, 59.0, 59.0, 58.2; FT-IR (DCM solution) 3492, 2941 2841, 1746, -1 + + 1103 cm ; MS (ESI) 257 [M + Na] ; HRMS (ESI) m/z: [M + Na] Calcd for C10H18O6Na 257.1001; found 257.0997. allo-Inositol (6).251 To a solution of hydroxyketone 128 (50 mg, 93 µmol) in EtOH (2 mL) was added NaBH4 (7 mg, 0.19 mmol) and the mixture heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue filtered through a plug of silica eluting with EtOAc. Following concentration, the residue was purified by column chromatography (50%

EtOAc/hexanes) and the main fraction (Rf 0.4) collected. The purified diol was taken up in EtOH

(2 mL), PdCl2 (1 mg) was added and the heterogeneous mixture stirred under an atmosphere of

H2 for 16 hours. The mixture was then filtered through Celite and washed though with a small portion of H2O. Removal of solvents gave the title compound as a crystalline solid (13 mg, 252 1 81%); mp 280 °C (dec); lit. 270-280 °C (dec); H NMR (300 MHz, D2O) δ 4.05-3.95 (m, 4H) 3.93-3.85 (m, 2H); FT-IR (neat) 3348 br., 2919 cm-1; MS (ESI) 203 [M + Na]+. epi-Inositol (5).253 A solution of hydroxyketone 144 (65 mg, 0.12 mmol) in EtOH (2 mL) was treated with NaBH4 (8 mg, 0.21 mmol) as per 128 to yield a crystalline solid (17 mg, 78%); mp 254 1 280 °C (dec.) lit. 305 °C; H NMR (300 MHz, D2O) δ 4.06 (dd, J = 3.1, 2.8 Hz, 2H), 3.83 (t, J = 9.9 Hz, 1H), 3.72 (t, J = 3.1 Hz, 1H), 3.47 (dd, J = 9.9, 2.8 Hz, 2H); 13C NMR (75 MHz, -1 CDCl3) δ 75.1, 72.4, 70.6, 67.4; FT-IR (neat) 3447, 3372, 3285, 3234, 2912 cm ; MS (ESI) m/z 203 [M + Na]+.

Experimental data for compounds in Chapter 2 (2S,3S,4S,5S,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-methanesulfonyloxycyclohexanone (169).

To a solution of hydroxyketone 129 (130 mg, 0.24 mmol) in DCM (2 mL) was added Et3N (68 µL, 0.49 mmol) then MsCl (37 µL, 0.48 mmol). The mixture was stirred overnight at which point the reaction was complete by TLC (1:4 EtOAc/hexanes). Concentration under reduced pressure and purification of the residue by column chromatography (1:3 EtOAc/hexanes) yielded 22 1 the mesylate 169 as a pale yellow syrup (120 mg, 81%); [α]D -37.8 (c 3.60, DCM); H NMR

(300 MHz, CDCl3) δ 7.43-7.19 (m, 18H), 7.16-7.03 (m, 2H), 5.41 (d, J = 10.0 Hz, 1H), 4.88 (d, J = 11.9 Hz, 1H), 4.74 (d, J = 11.7 Hz, 1H), 4.73 (d, J = 11.9 Hz, 1H), 4.67 (d, J = 12.4 Hz, 1H), 4.54-4.45 (m, 3H), 4.41 (d, J = 12.4 Hz, 1H), 4.37 (d, J = 12.4 Hz, 1H), 4.03 (dd, J = 10.0, 3.2 Hz, 1H), 3.88 (dd, J = 3.8, 3.8 Hz, 1H), 3.78 (dd, J = 3.8, 3.2 Hz, 1H), 3.21 (s, 3H); 13C NMR

(75 MHz, CDCl3) δ 198.2, 137.5, 137.4, 137.36, 137.3, 128.43, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.79, 127.7, 83.7, 80.7, 78.6, 77.2, 74.3, 73.8, 73.7, 73.6, 72.8, 39.4 (3 masked

148

Ar. C); FT-IR (neat) 3032, 1753, 1363, 1205, 1178, 1109 cm-1; MS (ESI) m/z 639.2 [M + Na]+; + HRMS (ESI) m/z: [M + Na] Calcd for C35H36O8NaS 639.2029; found 639.2055.

(2R/S,3S,4R,5R)-2-Azido-2,3,4,5-tetrakis(benzyloxy)cyclohexanone (171a/171b). To a solution of 169 (55 mg, 89 µmol) in DMF (2 mL) was added NaN3 (15 mg, 0.23 mmol) and the heterogenous mixture stirred overnight. The DMF was removed under reduced pressure (0.2 mbarr) and the 1:1 mixture of diastereomers was purified by column chromatography (3:17 EtOAc/hexanes) affording the title compounds 171a and 171b as colourless syrups (combined 29 1 yield 41 mg, 82%). Diastereomer 1: [α]D -43.1 (c 0.53, EtOH); H NMR (300 MHz, CDCl3) δ 7.50-7.18 (m, 20H), 5.11 (d, J = 11.5 Hz, 1H), 4.91 (d, J = 10.9 Hz, 1H), 4.79-4.53 (m, 6H), 4.29 (d, J = 8.5 Hz, 1H), 3.99-3.94 (m, 1H), 3.91 (dd, J = 8.5, 2.7 Hz, 1H), 2.70 (app. d, J = 3.8 Hz, 13 2H); C NMR (75 MHz, CDCl3) δ 199.8, 138.3, 137.9, 137.7, 137.66, 128.4, 128.36, 128.3, 128.2, 128.0, 127.83, 127.8, 127.7, 127.67, 95.8, 84.0, 80.0, 76.4, 73.5, 72.3, 71.5, 67.9, 40.4 (3 masked Ar. C); FT-IR (neat) 3032, 2927, 2122, 1748, 1178, 1096 cm-1; MS (ESI) m/z 586.2 [M + + + Na] ; HRMS (ESI) m/z: [M + Na] Calcd for C34H33N3O5Na 586.2318; found m/z 586.2322. 29 1 Diastereomer 2: [α]D -11.25 (c 0.26, EtOH); H NMR (300 MHz, CDCl3) δ 7.49-7.18 (m, 20H), 4.95-4.85 (m, 3H), 4.76-4.54 (m, 5H), 4.19 (d, J = 9.8 Hz, 1H), 4.05 (br. dd, J = 9.8, 3.2 13 Hz, 1H), 3.98-3.91 (m, 1H), 2.64 (app. d, J = 3.2 Hz, 2H); C NMR (75 MHz, CDCl3) δ 202.0, 138.4, 138.3, 138.2, 137.9, 128.4, 128.3, 128.0, 127.8, 127.7, 127.62, 127.6, 127.3, 101.4, 80.9, 79.7, 73.5, 73.4, 72.7, 71.5, 65.4, 41.0 (4 masked Ar. C); FT-IR (neat) 3035, 2923, 2132, 1745, 1155, 1096 cm-1; MS (ESI) m/z 586.2 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for

C34H33N3O5Na 586.2318; found m/z 586.2335.

(3S,4R,5R)-2,2,3,4,5-Pentakis(benzyloxy)cyclohexanone (220). To a solution of 169 (75 mg,

0.12 mmol) in benzyl alcohol (2 mL) was added Et3N (25 µL, 0.18 mmol) and the mixture stirred overnight. Concentration under reduced pressure (0.2 mmHg) and purification by column 28 chromatography (3:17 EtOAc/hexanes) gave 220 as a colourless syrup (50 mg, 65%); [α]D 1 +18.1 (c 0.72, DCM); H NMR (300 MHz, CDCl3) δ 7.49-7.16 (m, 25H), 5.04 (d, J = 12.1 Hz, 1H), 5.01 (d, J = 12.1 Hz, 1H), 4.93 (d, J = 11.1 Hz, 1H), 4.84 (d, J = 11.1 Hz, 1H), 4.78-4.59 (m, 6H), 4.27 (d, J = 8.7 Hz, 1H), 4.04-3.95 (m, 2H), 2.87 (dd, J = 13.0, 3.2 Hz, 1H), 2.73 (dd, J 13 = 13.0, 4.5 Hz, 1H); C NMR (75 MHz, CDCl3) δ 202.0, 138.7, 138.5, 138.4, 138.3. 138.0, 128.4, 128.35, 128.3, 128.27, 128.0, 127.9, 127.8, 127.7, 127.6, 127.56, 127.4, 102.4, 82.1, 79.9, 76.1, 73.5, 72.4, 71.5, 66.5, 65.6, 41.1 (4 masked Ar. C); FT-IR (neat) 3032, 1744, 1157, 1097

149

-1 + + cm ; MS (ESI) 651.3 [M + Na] ; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C41H40O6Na 651.2723; found 651.2749.

Synthesis of 220 from 138. To a solution of hydroxyketone 138 (53 mg, 98 µmmol) in DCM (1 mL) was added Et3N (30 µL, 0.21 mmol) then MsCl (15 µL, 0.19 mmol) and the mixture stirred overnight. Concentration of the mixture and subsequent purification by column chromatography (1:3 EtOAc/hexanes) gave mesylate 227 as a pale yellow syrup (40 mg, 66%); 1H NMR (300

MHz, CDCl3) δ 7.44-7.17 (m, 20H), 5.10 (dd, J = 2.5, 0.9 Hz, 1H), 4.91 (d, J = 11.3 Hz, 1H), 4.86 (d, J = 7.8 Hz, 1H), 4.86 (d, J = 7.8 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 4.57 (d, J = 11.3 Hz, 1H), 4.27 (dd, J = 2.5, 2.0 Hz, 1H), 4.18 (dd, J = 9.4, 9.4 Hz, 1H), 4.05 (dd, J = 9.4, 0.9 Hz, 1H), 3.81 (dd, J = 9.4, 13 2.0 Hz, 1H), 3.25 (s, 3H); C NMR (75 MHz, CDCl3) δ 197.6, 138.3, 137.55, 137.5, 137.2, 128.7, 128.54, 128.5, 128.35, 128.3, 128.2, 128.1, 128.0, 127.94, 127.9, 127.8, 127.7, 83.6, 81.8, 80.9, 79.5, 77.2, 76.1, 74.8, 74.0, 73.2, 39.8; FT-IR (neat) 3030, 2922, 2868, 1753, 1408, 1175 -1 + + cm ; MS (ESI) 639 [M + Na] ; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C35H36O8NaS 639.2029; found 639.2047. To a solution of 227 (15 mg, 24 µmol) in benzyl alcohol (1 mL) was added Et3N (5 µL, 36 µmol) and the mixture stirred for 4 hours at which point the reaction was complete by TLC (1:3 EtOAc/hexanes). Benzyl alcohol was removed by distillation under reduced pressure (0.2 mmHg) and subsequent purification of the residue by column chromatography (3:17 EtOAc/hexanes) afforded 220 as a colourless oil (10 mg, 65%) with spectroscopic properties identical to those described above.

(3S,4R,5S)-2,2,3,4,5-Pentakis(benzyloxy)cyclohexanone (228). To a solution of 144 (50 mg,

93 µmol) in DCM (2 mL) was added Et3N (26 µL, 0.186 mmol) then MsCl (14 µL, 0.18 mmol) and the mixture stirred for 2 hours at which point the reaction was complete by TLC (3:7 EtOAc/hexanes). DCM was removed under reduced pressure and the residue dissolved in EtOAc and filtered to remove Et3N.HCl. Concentration of the filtrate gave the crude mesylate as a syrup which was taken up in benzyl alcohol (2 mL), and Et3N (50 µL, 0.36 mmol) added. The mixture was stirred for 4 hours and then the volatiles were removed under reduced pressure (0.2 mmHg). Purification of the residue by flash column chromatography (1:9 EtOAc/hexanes) afforded 228 20 1 as a colourless syrup (10 mg, 17%); [α]D +24.4 (c 1.06, EtOH); H NMR (300 MHz, CDCl3) δ 7.42-7.15 (m, 25H), 5.00 (d, J = 12.4 Hz, 1H), 4.91 (d, J = 11.7 Hz, 1H), 4.88-4.78 (m, 4H), 4.70 (d, J = 11.1 Hz, 1H), 4.65-4.59 (m, 3H), 4.02 (dd, J = 7.9, 7.9 Hz, 1H), 3.75 (ddd, J = 11.5, 7.9, 5.8 Hz, 1H), 3.67 (d, J = 7.9 Hz, 1H), 3.04 (dd, J = 13.4, 11.5 Hz, 1H), 2.74 (dd, J = 13.4, 5.8

150

13 Hz, 1H); C NMR (75 MHz, CDCl3) δ 201.9, 138.4, 138.1, 138.0 (2C), 137.9, 129.7, 129.0, 128.5 128.4, 128.35, 128.3, 128.0, 127.8, 127.7, 127.65, 127.6, 127.5, 102.1, 83.4, 82.5, 76.8, 75.7, 75.2, 72.7, 66.4, 65.4, 42.3 (3 masked Ar. C); FT-IR (neat) 3030, 2927, 1441, 1089, 1070, 1028 cm-1; MS (ESI) 651.2 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for

C41H40O6Na: 651.2723; found 651.2729.

(±)-(3S,4S,5R)-2,2,3,4,5-Pentakis(benzyloxy)cyclohexanone (230). A solution of 157 (86 mg, 0.16 mmol) was treated as per the method for 169 to give mesylate 229 as a colourless syrup (97 1 mg, 99%); H NMR (300MHz, CDCl3) δ 7.50-7.16 (m, 18H), 7.06 (m, 2H), 5.57 (br. dd, J = 3.4, 0.9 Hz, 1H), 4.91 (d, J = 11.1 Hz, 1H), 4.79 (d, J = 11.9 Hz, 1H), 4.79 (d, J = 12.1 Hz, 1H), 4.67-4.46 (m, 5H), 4.33 (d, J = 12.1 Hz, 1H), 4.02 (dd, J = 3.8, 3.8 Hz, 1H), 3.98 (dd, J = 9.8, 3.4 13 Hz, 1H), 3.78 (dd, J = 3.8, 3.4 Hz, 1H), 3.25 (s, 3H); C NMR (75 MHz, CDCl3) δ 198.8, 138.1, 137.3 (2C), 137.1, 128.6, 128.5, 128.4, 128.38, 128.2, 128.0, 127.99, 127.81, 127.8, 83.5, 81.3, 80.0, 77.9, 74.6, 74.2, 74.1, 74.0, 73.98, 39.7 (3 masked Ar. C); FT-IR (neat) 3030, 2919, 1750, 1354, 1175, 1100 cm-1; MS (ESI) 639 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for

C35H36O8NaS 639.2029; found 639.2032. A solution of 229 (19 mg, 31 µmol) in benzyl alcohol (2 mL) was treated as per the method for 220 to give 230 as a colourless syrup (10 mg, 52%); 1H

NMR (300 MHz, CDCl3) δ 7.40-7.21 (m, 23H), 7.20-7.13 (m, 2H), 4.88-4.79 (m, 3H), 4.75-4.61 (m, 4H), 4.47 (d, J = 11.7 Hz, 1H), 4.32 (app. s, 2H), 4.24-4.10 (m, 3H), 2.86 (dd, J = 12.4, 4.9 13 Hz, 1H), 2.74 (dd, J = 12.4, 8.5 Hz, 1H) C NMR (75 MHz, CDCl3) δ 200.7, 138.3, 138.2, 137.7, 136.6, 128.5, 128.4, 128.3, 128.1, 127.93, 127.9, 127.8, 127.7, 127.53, 127.5, 127.4, 101.5, 81.6, 77.2, 76.4, 74.1, 73.4, 73.0, 64.5, 64.4, 42.8, (4 masked Ar. C); FT-IR (neat) 3030, 2923, 1744, 1096, 1070, 1027 cm-1; MS (ESI) m/z 651 [M + Na] +; HRMS (ESI-TOF) m/z: [M + + Na] Calcd for C41H40O6Na: 651.2723; found 651.2731.

(±)-(3S,4S,5R)-2,2,3,4,5-pentamethoxycyclohexanone (232). To a solution of 159 (60 mg, 0.26 mmol) in DCM (5 mL) was added Et3N (72 µL, 0.52 mmol) then MsCl (40 µL, 0.52 mmol) and the mixture stirred overnight at which point the reaction was complete by TLC (4:1 EtOAc/hexanes). Removal of the volatiles under reduced pressure and subsequent purification by column chromatography (4:1 EtOAc/hexanes) afforded mesylate 231 as a yellow syrup (55 1 mg, 61%); H NMR (300 MHz, CDCl3) δ 5.46 (br. d, J = 3.2 Hz, 1H), 4.09 (d, J = 9.8 Hz, 1H), 4.04 (dd, J = 4.3, 3.2 Hz, 1H), 3.89 (dd, J = 4.3, 3.2 Hz, 1H), 3.58 (s, 3H), 3.54 (dd, J = 9.8, 4.3 13 Hz, 1H), 3.53 (s, 3H), 3.51 (s, 3H), 3.45 (s, 3H), 3.25 (s, 3H); C NMR (75 MHz, CDCl3) δ 198.6, 85.1, 82.1, 81.4, 79.4, 76.2, 60.11, 60.1, 59.9, 59.6, 39.6; MS (ESI) m/z 335.1 [M + Na]+;

151

+ HRMS (ESI-TOF) m/z: [M + Na] Calcd for C11H20O8NaS 335.0777; found 335.0782. To a solution of 231 (50 mg, 0.14 mmol) in MeOH (2 mL) was added Et3N (80 µL, 0.57 mmol) and the mixture was stirred for two hours. Concentration under reduced pressure and subsequent purification by column chromatography (4:1 EtOAc/hexanes) gave 232 as a colourless oil (30 1 mg, 85%); H NMR (300 MHz, CDCl3) δ 3.85 (d, J = 2.1 Hz, 1H), 3.76 (dd, J = 9.2, 2.1 Hz, 1H), 3.69 (ddd, J = 9.8, 9.2, 5.3 Hz, 1H), 3.54 (s, 3H), 3.52 (s, 3H), 3.42 (s, 3H), 3.35 (s, 3H), 3.14 (s, 3H), 2.78 (dd, J = 13.6, 5.5 Hz, 1H), 2.44 (dd, J = 13.6, 9.8 Hz, 1H); 13C NMR (75 MHz,

CDCl3) δ 201.3, 100.8, 83.7, 77.5, 76.6, 60.8, 58.6, 58.0, 50.0, 49.2, 41.6; FT-IR (neat) 2938, 1743, 1192, 1111 cm-1, MS (ESI) m/z 271.1 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H20O6Na 271.1158; found 271.1154.

(3S,4R,5R)-2,2,3,4,5-Pentamethoxycyclohexanone (233). To a solution of hydroxyketone 130

(70 mg, 0.13 mmol) in DCM (2 mL) was added Et3N (100 µL, 0.72 mmol) then MsCl (50 µL, 0.65 mmol). The mixture was stirred overnight at which point the reaction was complete by TLC (4:1 EtOAc/hexanes). Solvent was removed by distillation under reduced pressure and the residue was taken up in EtOAc and insoluble materials removed by filtration. Concentration under reduced pressure gave the crude mesylate as a syrup which was used without further purification. The mesylate was taken up in MeOH (2 mL) and Et3N (100 µL, 0.72 mmol) added and the mixture stirred for 24 hours at which point the reaction was complete by 1H NMR. Concentration under reduced pressure and subsequent purification by column chromatography 24 (4:1 EtOAc/hexanes) gave 233 as a colourless syrup (20 mg, 27%); []D -9.2 (c 0.86, EtOH); 1 H NMR (300 MHz, CD3OD) δ 3.93 (ddd, J = 4.3, 3.0, 3.0 Hz, 1H), 3.77 (dd, J = 9.2, 3.0 Hz, 1H), 3.65 (d, J = 9.2 Hz, 1H), 3.60 (s, 3H), 3.56 (s, 3H), 3.45 (s, 3H), 3.39 (s, 3H), 3.33 (s, 3H), 13 2.78 (dd, J = 14.2, 3.0 Hz, 1H), 2.71 (dd, J = 14.2, 4.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 201.9, 100.4, 82.9, 82.8, 74.1, 61.0, 59.1, 57.2, 51.8, 51.1, 39.5; FT-IR (neat) 2938, 2834, 1742, 1109, 1075 cm-1; MS (ESI) 271 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for

C11H20O6Na 271.1158; found 271.1146.

(1R,2R,3R)-1,2,3-tri(benzyloxy)-1,2,3,4-tetrahydrophenazine (247). To a solution of 169 (33 mg, 54 µmol) in DCM (1 mL) was added o-phenylenediamine (23 mg, 0.21 mmol) then Et3N (30 µL, 0.21 mmol) and the mixture stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (1:4 20 1 EtOAc/hexanes) to give 247 as a pale yellow wax (25 mg, 54%); [α]D -23 (c 2.0, DCM); H

NMR (500MHz, CDCl3) δ 8.12-8.07 (m, 1H), 8.04-7.97 (m, 1H), 7.79-7.67 (m, 2H), 7.41-7.25

152

(m, 15H), 4.89 (d, J = 11.9 Hz, 1H), 4.86 (d, J = 4.3 Hz, 1H), 4.81-4.76 (m, 2H), 4.73 (d, J = 11.9 Hz, 1H), 4.69 (d, J = 12.2 Hz, 1H), 4.65 (d, J = 12.2 Hz, 1H), 4.45 (ddd, J = 1.7, 6.4, 9.2 Hz, 1H), 4.29 (dd, J = 4.3, 1.7 Hz, 1H), 3.53 (dd, J = 17.4, 9.2 Hz, 1 H), 3.48 (dd, J = 17.4, 6.4 13 Hz, 1H); C NMR (125 MHz, CDCl3) δ 151.9, 150.2, 142.0, 141.2, 138.3, 138.2, 138.1, 130.0, 129.2, 129.1, 128.5, 128.4, 128.33, 128.3, 127.8, 127.7, 127.65 (2C), 127.62, 78.1, 76.1, 73.1, 72.6, 72.3, 71.1, 34.6; FT-IR (neat) 3088, 3063, 3029, 2916, 1605, 1603 cm-1; MS (ESI) 503.2 [M + H]+ 525.2 [M + Na]+.

Experimental data for the compounds in Chapter 3

General Experimental. Cs2CO3 and K3PO4 were dried at 100 °C under vacuum and were used immediately. [Pd(Mes)(NQ)2], 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4- naphthoquinone)palladium(0) dimer (649736-75-4) and [Pd(Mes)(NQ)2], 1,3-Bis(2,4,6- trimethylphenyl)imidazol-2-ylidene (1,4-naphthoquinone)palladium(0) dimer (467220-49-1) were obtained from Sigma-Aldrich, St. Louis, USA.

Single crystal X-ray Crystallography. Single X-Ray crystallographical data was recorded and solved by Associate Professor Chris Sumby at the University of Adelaide. Single crystals were mounted in paratone-N oil on a plastic loop. X-ray diffraction data were collected at 150(2) K on an Oxford X-calibur single crystal diffractometer using Mo K radiation.255 Data sets were corrected for absorption using a multi-scan method, and structures were solved by direct methods using SHELXS-2014 and refined by full-matrix least squares on F2 by SHELXL- 2014,256-258 interfaced through the program X-Seed.259 In general, all non-hydrogen atoms were refined anisotropically and hydrogen atoms were included as invariants at geometrically estimated positions.

Table 11 in the Appendix of this thesis lists the X-ray experimental data and refinement parameters for the crystal structures.

Full details of the structure determinations have been deposited with the Cambridge Crystallographic Data Centre as CCDC 1412235-1412240 (315a, 315b, 315d, 316h, 317i, and 390a, respectively). Copies of this information may be obtained free of charge from The Director, CCDC, 12 Union Street, Cambridge CB2 1EZ, U.K. (fax, +44-1223-336-033; e-mail, [email protected]).

153

(1S,5R)-3-Iodo-6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one (314).129 To a solution of 251 (1.5 g,

11.9 mmol) in DCE (20 mL) was added I2 (4.2 g, 16.5 mmol) then pyridine (1.08 mL, 13.4 mmol) and the mixture stirred for 15 minutes. Toluene (20 mL) was added and the resulting suspension poured onto a 5 cm plug of silica and the product eluted using toluene. Concentration 1 of the filtrate gave 314 as a yellow crystalline solid (2.86 g, 96%); H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 4.9 Hz, 1H), 5.57 (s, 1H), 4.94 (dd, J = 4.9, 4.5 Hz, 1H), 3.88 (dd, J = 7.0, 4.5 Hz, 13 1H), 3.82 (d, J = 7.0 Hz, 1H); C NMR (75 MHz, CDCl3) δ 183.1, 155.7, 100.7, 99.7, 74.2, 66.5; FT-IR 3067, 2975, 2902, 1697 cm-1; MS (EI) 251.9 ([M]+, trace) 224.0 (100), 179.0 (16), 126.9 (15), 97.1 (31), 53.1 (14), 41.1 (13), 39.1 (19).

General procedure for Suzuki reactions with 314. To a stirred solution of 314 (250 mg, 0.99 mmol) in toluene (5 mL) under N2 were added arylboronic acid (1.5 equiv), phosphine (2-10 mol%), anhydrous Cs2CO3 (2.0 equiv) and Pd(OAc)2 (1-5 mol%) and the mixture heated to 90- 110 °C until complete by TLC (3:7 EtOAc/hexanes). The resulting mixture was washed with

H2O (10 mL) and the aqueous phase extracted with DCM (20 mL) then the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The products 315a-d, f, and g were purified by flash chromatography (1:3-7:13 EtOAc/hexanes and then further purified as specified.

(1S,5R)-3-Phenyl-6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one (315a). The general procedure performed using 314 (2.10 g, 8.33 mmol) afforded a product which was crystallised from 23 DCM/hexanes to give 315a as off-white crystals (1.12 g, 67%); mp 82-85 °C; [α]D -301 (c 1.53, 1 DCM); H NMR (300 MHz, CDCl3) δ 7.48-7.30 (m, 5H), 7.24 (d, J = 4.9 Hz, 1H), 5.49 (s, 1H), 5.12 (dd, J = 4.9, 4.5 Hz, 1H), 3.91 (dd, J = 7.0, 4.5 Hz, 1H), 3.81 (d, J = 7.0 Hz, 1H); 13C NMR

(75 MHz, CDCl3) δ 187.9, 143.1, 137.8, 133.1, 128.6, 128.2, 128.1, 101.6, 72.4, 66.5; FT-IR (neat) 3047, 2968, 2897, 1686 cm-1; MS (ESI) m/z 203.0 [M + H]+ 225.0 [M + Na]+; Anal Calcd for C12H10O3: C, 71.28; H, 4.98; Found: C, 71.53; H, 4.95.

(1S,5R)-3-(Benzo[d][1,3]dioxol-5-yl)-6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one (315b). The general procedure performed using 314 (250 mg, 0.99 mmol) afforded a product which 26 crystallised upon standing to give 315b as yellow crystals (208 mg, 85%); mp 129-131 °C; [α]D 1 -260 (c 1.43, DCM); H NMR (300 MHz, CDCl3) δ 7.17 (d, J = 5.1 Hz, 1H), 6.93-6.86 (m, 2H), 6.85-6.74 (m, 1H), 5.95 (s, 2H), 5.46 (s, 1H), 5.12 (dd, J = 5.1, 4.5 Hz, 1H), 3.92 (dd, J = 6.8, 4.5 13 Hz, 1H), 3.81 (d, J = 6.8 Hz, 1H); C NMR (75 MHz, CDCl3) δ 188.1, 148.1, 147.6, 142.0, 136.5, 127.1, 122.1, 108.7, 108.3, 101.7,101.3, 72.6, 66.7; FT-IR (neat) 3012, 2974, 2924, 1695 154 cm-1; MS (EI) m/z 246.1 ([M]+, 44), 215 (35), 173 (100), 131 (48), 116 (32), 115 (62), 103 (32);

Anal. Calcd for C13H10O5: C, 63.42; H, 4.09; Found C, 63.30; H, 4.05.

(1S,5R)-3-(4-Methoxyphenyl)-6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one (315c). The general procedure performed using 314 (250 mg, 0.99 mmol) afforded a product which was crystallised from hot diisopropyl ether to give 315c as colourless crystals (205 mg, 89%); mp 101-102 °C; 22 1 [α]D -264 (c 0.96, DCM); H NMR (300 MHz, CDCl3) δ 7.43-7.31 (m, 2H), 7.18 (d, J = 4.9 Hz, 1H), 6.96-6.82 (m, 2H), 5.47 (s, 1H), 5.11 (dd, J = 4.9, 4.6 Hz, 1H), 3.91 (dd, J = 6.8, 4.6 Hz, 13 1H), 3.81 (d, J = 6.8 Hz, 1H), 3.79 (s, 3H); C NMR (75 MHz, CDCl3) δ 188.3, 160.0, 141.5, 136.2, 129.4, 125.6, 113.8, 101.7, 72.6, 66.6, 55.2; FT-IR (neat) 3027, 3007, 2967, 2889, 2840, -1 + + 1688, 1602 cm ; MS (ESI) m/z 233 [M + H] , 255 [M + Na] ; Anal. Calcd for C13H12O4: C,

67.23; H, 5.21; Found C, 67.26; H, 5.26.

(1S,5R)-3-(2,3,4-Trifluorophenyl)-6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one (315d). The general procedure performed using iodide 314 (250 mg, 0.99 mmol) afforded a product which was crystallised from hot diisopropopyl ether to give 315d as colourless crystals (187 mg, 74%); mp 25 1 91-92 °C; [α]D -247 (c 1.10, DCM); H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 4.9 Hz, 1H), 7.07-6.92 (m, 2H), 5.49 (br. s, 1H), 5.17 (dd, J = 4.9, 4.7 Hz, 1H), 3.97 (dd, J = 6.9, 4.5 Hz, 1H), 13 3.89 (br. d, J = 6.9 Hz, 1H); C NMR (75 MHz, CDCl3) δ 186.3, 151.2 (ddd, JCF = 251.6, 9.9,

2.4 Hz), 149.1 (ddd, JCF = 252.4, 10.7, 3.2 Hz), 146.8, 140.0 (ddd, JCF = 252.2, 15.2, 15.2 Hz),

131.2, 124.6 (ddd, JCF = 7.6, 4.5, 4.5 Hz), 118.5 (dd, JCF = 12.0, 4.2 Hz), 111.9 (dd, JCF = 17.6, 3.6 Hz), 101.4, 72.2, 66.6; FT-IR (neat) 3101, 2996, 2961, 1704, 1507, 1469 cm-1; 13C NMR

(125 MHz, CDCl3) δ 186.3, 151.2 (ddd, JCF = 251.6, 9.9, 2.4 Hz), 149.1 (ddd, JCF = 252.4, 10.7,

3.2 Hz), 146.8, 140.0 (ddd, JCF = 252.2, 15.2, 15.2 Hz), 131.2, 124.6 (ddd, JCF = 7.6, 4.5, 4.5

Hz), 118.5 (dd, JCF = 12.0, 4.2 Hz), 111.9 (dd, JCF = 17.6, 3.6 Hz), 101.4, 72.2, 66.6. MS (EI) m/z 228.1 (M-CO, 50), 207.1 (40), 183.1 (100), 182.1 (65), 169 (43), 156 (47), 151 (45); Anal.

Calcd for C12H7F3O3: C, 56.26; H, 2.75; Found: C, 56.35; H, 2.66.

(1S,5R)-3-(2-Formylphenyl)-6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one (315f). The general procedure performed using 314 (250 mg, 0.99 mmol) afforded a product which was crystallised from hot diisopropyl ether to give 315f as bright orange crystals (120 mg, 53%); mp 150-151 °C; 20 1 [α]D -306 (c 2.67, DCM); H NMR (300 MHz, CDCl3) δ 9.86 (s, 1H), 7.90 (dd, J = 7.5, 1.5 Hz, 1H), 7.60 (ddd, J = 7.5, 7.5, 1.5 Hz, 1H), 7.53 (ddd, J = 7.5, 7.5, 1.1 Hz, 1H), 7.24-7.14 (m, 2H), 5.52 (s, 1H), 5.18 (dd, J = 4.7, 4.7 Hz, 1H), 4.00 (dd, J = 6.8, 4.7 Hz, 1H), 3.94 (d, J = 6.8 Hz, 13 1H); C NMR (75 MHz, CDCl3) δ 190.9, 187.1, 144.8, 137.2, 135.1, 134.7, 133.8, 130.7, 130.2, 155

129.2, 101.4, 72.3, 66.8; FT-IR (neat) 3010, 2974, 2844, 2761, 1692 (br.), 1601, 1591 cm-1; MS + + (ESI) m/z 231 [M + H] 253 [M + Na] ; Anal. Calcd for C13H10O4: C, 67.82; H, 4.38; Found: C, 67.65; H, 4.38.

(1S,5R)-3-(2-Fluorophenyl)-6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one (315g). The general procedure performed using 314 (250 mg, 0.99 mmol) afforded a product which was crystallised from hot diisopropyl ether to give 315g as a colourless crystalline solid (191 mg, 88%); mp 96- 16 1 97 °C; [α]D -300 (c 0.20, DCM); H NMR (500 MHz, CDCl3) δ 7.38-7.27 (m, 3H), 7.19-7.07 (m, 2H), 5.53 (s, 1H), 5.17 (dd, J = 4.7, 4.7 Hz, 1H), 3.98 (dd, J = 6.7, 4.7 Hz, 1H), 3.91 (d, J = 13 6.7 Hz, 1H); C NMR (125 MHz, CDCl3) δ 186.8, 160.0 (d, JCF = 248.9 Hz), 146.0 (d, JCF = 3.6

Hz), 132.6, 131.0 (d, JCF = 3.6 Hz), 130.4 (d, JCF = 8.2 Hz), 123.9 (d, JCF = 3.6 Hz), 120.9 (d, JCF

= 14.5 Hz), 115.8 (d, JCF = 22.7 Hz), 101.7, 72.3, 66.7; FT-IR (neat) 1698, 1485, 1214, 1108, -1 + 980, 884, 819, 765 cm ; MS (ESI) m/z 221.0 [M + H] ; Anal Calcd for C12H9FO3: C, 65.45, H, 4.12; Found: C, 65.21; H, 4.04.

General procedure for Heck reactions of 251. To a stirred solution of (-)-levoglucosenone 251

(252 mg, 2.0 mmol) under N2 in toluene (5 mL) were added aryl iodide (2.4 mmol), SPhos (16 mg, 0.04 mmol), anhydrous K3PO4 (4.0 mmol) and Pd(OAc)2 (4.4 mg, 0.02 mmol) and the mixture heated under reflux to 110 °C until the reaction was complete by TLC (3:7

EtOAc/hexanes). The resulting mixture was washed with H2O (10 mL) and the aqueous phase extracted with DCM (20 mL) then the combined organic extracts dried (MgSO4) and concentrated under reduced pressure. The products 316a-c,h and i were purified by flash chromatography (1:3 EtOAc/hexanes) and then further purified as specified.

(1S,5R)-2-Phenyl-6,8-dioxabicyclo[3.2.1]oct-2-en-4-one (316a). The general procedure for the Heck reaction of 251 (500 mg, 3.97 mmol) gave a product which was crystallised from 19 DCM/hexanes to give 316a as off-white crystals (483 mg, 60%); mp 98-100 °C; [α]D -384 (c 1 0.25, DCM); H NMR (300 MHz, CDCl3) δ 7.54-7.41 (m, 5H), 6.31 (d, J = 1.5 Hz, 1H), 5.51 (d, J = 5.0 Hz, 1H), 5.41 (d, J = 1.5 Hz, 1H), 4.04 (dd, J = 6.8, 5.0 Hz, 1H), 3.80 (d, J = 6.8 Hz, 1H); 13 C NMR (75 MHz, CDCl3) δ 189.4, 159.1, 133.8, 131.1, 129.4, 126.4, 120.5, 101.2, 74.0, 67.6; FT-IR (neat) 3030, 2961, 2922, 2886, 2852, 1683, 1258, 1110 cm-1; MS (EI) m/z 173 (M - HCO,

20), 157 (25), 129 (100), 128 (28), 115 (32), 101.8 (15); Anal. Calcd for C12H10O3: C, 71.28; H, 4.98; Found: C, 71.49; H, 4.78.

156

(1S,5R)-2-(Benzo[d][1,3]dioxol-5-yl)-6,8-dioxabicyclo[3.2.1]oct-2-en-4-one (316b). The general procedure for the Heck reaction of 251 (504 mg, 4.0 mmol) gave a product which was further crystallised from hot diisopropyl ether to give 316b as a yellow crystalline solid (612 mg, 20 1 62%); mp 147-149 °C; [α]D -412 (c 0.50, DCM); H NMR (300 MHz, CDCl3) δ 7.03 (dd, J = 8.2, 1.5 Hz, 1 H), 6.98 (d, J = 1.5 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.22 (br. d, J = 1.0 Hz, 1H), 6.05 (s, 2H), 5.47 (d, J = 5.0 Hz, 1H), 5.40 (s, 1H), 4.03 (dd, J = 6.6, 5.0 Hz, 1H), 3.77 (d, J = 13 6.6 Hz, 1H); C NMR (75 MHz ,CDCl3) δ 189.5, 158.5, 150.4, 148.8, 127.7, 121.3, 118.8, 108.9, 106.2, 101.9, 101.1, 73.8, 67.6; FT-IR (neat) 2985, 2901, 1668, 1504, 1490, 1254, 866 -1 + + cm ; MS (ESI) m/z 247.0 [M + H] 269.0 [M + Na] ; Anal. Calcd for C13H10O5: C, 63.42; H, 4.09; Found: C, 63.69; H, 3.94.

(1S,5R)-2-(4-Methoxyphenyl)-6,8-dioxabicyclo[3.2.1]oct-2-en-4-one (316c). The general procedure for the Heck reaction of 251 (250 mg, 1.98 mmol) gave a product which was recrystallised from hot diisopropyl ether to give 316c as colourless crystals (269 mg, 59%); mp 17 1 108-110 °C; [α]D -432 (c 0.44, DCM); H NMR (300 MHz, CDCl3) δ 7.57-7.35 (m, 2H), 7.07- 6.89 (m, 2H), 6.24 (br. dd, J = 1.3, 0.6 Hz, 1H), 5.51 (br d, J = 5.0 Hz, 1H), 5.39 (d, J = 1.3 Hz, 1H), 4.01 (dd, J = 6.6, 5.0 Hz, 1H), 3.84 (s, 3H), 3.75 (d, J = 6.6 Hz, 1H); 13C NMR (75 MHz,

CDCl3) δ 189.6, 162.1, 158.6, 128.0, 125.8, 118.2, 114.8, 101.2, 73.6, 67.5, 55.4; FT-IR (neat) 3054, 2992, 2981, 2844, 1669, 1587, 1109 cm-1; MS (ESI) m/z 233.1 [M + H]+ 255.1 [M + Na]+;

Anal. Calcd for C13H12O4: C, 67.23; H, 5.21; Found: C, 67.63; H, 5.33.

(1S,5R)-2-(p-Tolyl)-6,8-dioxabicyclo[3.2.1]oct-2-en-4-one (316h). The general procedure for the Heck reaction of 251 (250 mg, 1.98 mmol) gave 316h as colourless crystals (243 mg, 57%); 20 1 mp 99-100 °C; [α]D -410 (c 1.24, DCM); H NMR (300 MHz, CDCl3) δ 7.43-7.33 (m, 2H), 7.29-7.20 (m, 2H), 6.27 (br. d, J = 1.5 Hz, 1H), 5.50 (d, J = 5.0 Hz, 1H), 5.38 (d, J = 1.5 Hz, 1H), 4.01 (dd, J = 6.6, 5.0 Hz, 1H), 3.76 (d, J = 6.6 Hz, 1H), 2.37 (s, 3H); 13C NMR (75 MHz,

CDCl3) δ 189.5, 158.9, 141.8, 130.7, 129.9, 126.2, 119.2, 101.1, 73.7. 67.4, 21.3; FT-IR (neat) 3043, 2996, 2904, 1683, 1596, 1107 cm-1; MS (ESI) m/z 217.1 [M + H]+ 239.1 [M + Na]+; Anal.

Calcd for C13H12O3: C, 72.21; H, 5.59; Found: C, 72.47; H, 5.46.

Methyl 2-((1S,5R)-4-oxo-6,8-dioxabicyclo[3.2.1]oct-2-en-2yl)benzoate (316i). The general procedure for the Heck reaction of 251 (250 mg, 1.98 mmol) gave a product which was further crystallised from hot diisopropyl ether to give 316i as colourless crystals (181 mg, 35%); mp 21 1 149-150 °C; [α]D -447 (c 1.09, DCM); H NMR (300 MHz, CDCl3) δ 8.06 (ddd, J = 7.5, 1.5, 1.5 Hz, 1H), 7.57 (ddd, J = 7.5, 7.5, 1.5 Hz, 1H), 7.51 (ddd, J = 7.5, 1.5, 1.5 Hz, 1H), 7.18 (dd, J 157

= 7.5, 1.5 Hz, 1H), 5.90 (dd, J = 1.3, 0.6 Hz, 1H), 5.36 (d, J = 1.3 Hz, 1H), 5.04 (dd, J = 4.0, 0.6 13 Hz, 1H), 3.89 (s, 3H), 3.84-3.73 (m, 2H); C NMR (75 MHz, CDCl3) δ 188.9, 166.5, 163.9, 136.9, 133.0, 131.3, 130.1, 129.9, 128.7, 122.4, 101.1, 76.6, 66.6, 52.7; FT-IR (neat) 3010, 2957, 2922, 2851, 1707, 1693, 1265 cm-1; MS (ESI) m/z 261.1 [M + H]+ 283.1 [M + Na]+; Anal. Calcd for C14H12O5: C, 64.61; H, 4.65; Found: C, 64.26; H, 4.62.

General procedure for hydroarylation reactions of 251. To a stirred solution of (-)- levoglucosenone 251 (250 mg, 1.98 mmol) under N2 in DMF (5 mL) were added aryl iodide (1.2 equiv), tri-(o-tolyl)phosphine (2.0 mol%), benzyldiethylamine (4.5 equiv) and Pd(OAc)2 (1.0 mol%) and the mixture heated under reflux to 80-110 °C until the reaction was complete by TLC

(1:3 EtOAc/hexanes). The resulting mixture was washed with H2O (10 mL) and the aqueous phase extracted with DCM (20 mL) then the combined organic extracts dried (MgSO4) and concentrated under reduced pressure. The products 317a-c, h and i were purified by flash chromatography (EtOAc/toluene, 1:19) and then further purified as specified.

(1S,2R,5R)-2-Phenyl-6,8-dioxabicyclo[3.2.1]octan-4-one (317a).135 The general procedure for hydroarylation on 251 (1.0 g, 7.92 mmol) gave a mixture of 316a/317a 1:5.5 (1.11 g, 69%). A portion of the mixture (316a/317a 2:5, 0.50 g) was dissolved in EtOAc (5 mL) and stirred with

1.0 M KMnO4 (5 mL) for 3 hours. The biphasic mixture was filtered through silica, the filtrate concentrated under reduced pressure and crystallised from diisopropyl ether to give colourless 19 1 crystals of 317a (330 mg, 92% recovery); mp 104 °C, lit. 68 °C; [α]D -342 (c 0.33, DCM); H

NMR (300 MHz, CDCl3) δ 7.48-7.13 (m, 5H), 5.21 (s, 1H), 4.68 (br. d, J = 5.3 Hz, 1H), 4.18 (dd, J = 7.5, 1.0 Hz, 1H), 4.06 (dd, J = 7.5, 5.3 Hz, 1H), 3.44 (d, J = 8.7 Hz, 1H), 3.09 (dd, J = 13 16.8, 8.7 Hz, 1H), 2.60 (ddd, J = 16.8. 1.0, 1.0 Hz, 1H); C NMR (75 MHz, CDCl3) δ 200.3, 142.0, 128.8, 127.5, 127.3, 101.5, 78.1, 68.3, 46.6, 37.0; FT-IR (neat) 3028, 2951, 1741, 1716, 1110 cm-1; MS (EI) m/z 204.1 ([M]+, trace), 130.1 (100), 129.1 (74), 117.1 (86), 115.1 (81),

104.1 (29), 91.1 (37), 77.1 (28); Anal. Calcd for C12H12O3: C, 70.57; H, 5.92; Found: C, 70.35; H, 5.80.

(1S,2R,5R)-2-(Benzo[d][1,3]dioxol-5-yl)-6,8-dioxabicyclo[3.2.1]octan-4-one (317b). The general procedure for hydroarylation on 251 (0.50 g, 7.92 mmol) gave a mixture of 316b/317b 1:4 (0.80 g, 93%). An analytical sample of 317b was purified by careful flash chromatography 20 (1:19 EtOAc/toluene) to give colourless crystals; mp 128 °C (diisopropyl ether); [α]D -30.9 (c 1 0.51, DCM); H NMR (500 MHz, CDCl3) δ 6.80-6.71 (m, 2H), 6.67 (dd, J = 7.9, 0.9 Hz, 1H), 5.94 (s, 2H), 5.19 (s, 1H), 4.64 (d, J = 5.3 Hz, 1H), 4.15 (d, J = 7.4 Hz, 1H), 4.05 (dd, J = 7.4, 158

5.3 Hz, 1H), 3.37 (br d, J = 8.5 Hz, 1H), 3.06 (dd, J = 16.8, 8.5 Hz, 1H), 2.52 (br d, J = 16.8 Hz, 13 1H); C NMR (125 MHz, CDCl3) δ 200.2, 148.0, 146.8, 135.9, 120.6, 108.4, 108.0, 101.5, 101.1, 78.2, 68.3, 46.4, 37.4; FT-IR (neat) 2992, 2909, 2796, 1731, 1499, 1250, 906, 1109, 643 -1 + cm ; MS (ESI) m/z 271.1 [M + Na] ; Anal Calcd for C13H12O5: C, 62.90; H, 4.87; Found: C, 62.97; H, 4.90.

(1S,2R,5R)-2-(4-Methoxyphenyl)-6,8-dioxabicyclo[3.2.1]octan-4-one (317c). The general procedure for hydroarylation on 251 (1.0 g, 7.92 mmol) gave a mixture of 316c/317c 1:4 (1.29 g,

70%). The mixture was dissolved in dioxane (10 mL) and stirred with 1.0 M KMnO4 (10 mL) for 30 mins. The mixture was filtered through silica, eluted with EtOAc, the filtrate concentrated and the product purified by flash chromatography to give 317c as a crystalline solid (1.03 g, 56%); 21 1 mp 119-120 °C; [α]D -320 (c 0.51, DCM); H NMR (300 MHz, CDCl3) δ 7.21-7.08 (m, 2H), 6.92-6.81 (m, 2H), 5.19 (s, 1H), 4.63 (br. d, J = 5.2 Hz, 1H), 4.16 (d, J = 7.6 Hz, 1H), 4.04 (dd, J = 7.6, 5.2 Hz, 1H), 3.78 (s, 3H), 3.40 (d, J = 8.6 Hz, 1H), 3.07 (dd, J = 16.8, 8.6 Hz, 1H), 2.54 13 (dd, J = 16.8, 0.9 Hz, 1H); C NMR (75 MHz, CDCl3) δ 200.5, 158.7, 134.1, 128.5, 114.1, 101.5, 78.2, 68.2, 55.3, 45.9, 37.3; FT-IR (neat) 3061, 2983, 2836, 1753, 1730, 1697, 1510, -1 + 1244, 1109 cm ; MS (ESI) m/z 257.1 [M + Na] ; Anal Calcd for C13H14O4: C, 66.66, H, 6.02; Found: C, 66.40; H, 6.19.

(1S,2R,5R)-2-(p-Tolyl)-6,8-dioxabicyclo[3.2.1]octan-4-one (317h). The general procedure for hydroarylation on 251 (1.0 g, 7.92 mmol) gave a mixture of 316h/317h 1:3 (1.21 g, 70%). The mixture was dissolved in dioxane (10 mL) and stirred with 1.0 M KMnO4 (10 mL) for 30 minutes. The biphasic mixture was filtered through silica, eluted with EtOAc and the product was purified by flash chromatography (1:3 EtOAc/hexanes) to give colourless crystals of 317h 23 1 (940 mg, 54%); mp 91-93 °C; [α]D -340 (c 0.15, DCM); H NMR (300 MHz, CDCl3) δ 7.19- 7.05 (m, 4H), 5.19 (s, 1H), 4.65 (br. d, J = 5.2 Hz, 1H), 4.16 (dd, J = 7.7, 1.0 Hz, 1H), 4.04 (dd, J = 7.7, 5.2 Hz, 1H), 3.40 (d, J = 8.7 Hz, 1H), 3.06 (dd, J = 16.8, 8.7 Hz, 1H), 2.56 (ddd, J = 16.8, 13 1.0, 1.0 Hz, 1H), 2.33 (s, 3H); C NMR (75 MHz, CDCl3) δ 200.5, 139.0, 136.9, 129.4, 127.3, 101.5, 78.2, 68.2, 46.2, 37.1, 20.9; FT-IR (neat) 3047, 3000, 2954, 2924, 1737, 1721, 1111 cm-1; MS (EI) m/z 218.1 ([M]+, 8), 144.1 (53), 131.1 (85), 130.1 (22), 129.1 (100), 117.1 (24), 116.1

(20), 115.1 (38), 91.1 (37); Anal Calcd for C13H14O3: C, 71.54, H, 6.47; Found: C, 71.33; H, 6.26.

159

Methyl 2-((1S,2R,5R)-4-oxo-6,8-dioxabicyclo[3.2.1]octan-2-yl)benzoate (317i). The general procedure for hydroarylation on 251 (1.0 g, 7.92 mmol) and purification by flash 25 chromatography gave colourless crystals of 317i (1.11 g, 53%); mp 113-116 °C; [α]D -277 (c 1 0.57, DCM); H NMR (300 MHz, CDCl3) δ 7.94 (dd, J = 8.3, 1.5 Hz, 1H), 7.50 (ddd, J = 8.3, 7.0, 1.5 Hz, 1H), 7.38-7.28 (m, 2H), 5.18 (s, 1H), 4.80 (br. d, J = 5.2 Hz, 1H), 4.42 (d, J = 8.8 Hz, 1H), 4.22 (dd, J = 7.7, 0.9 Hz, 1H), 4.07 (dd, J = 7.7, 5.2 Hz, 1H), 3.87 (s, 3H), 3.07 (dd, J = 13 17.2, 8.8 Hz, 1H), 2.49 (ddd, J = 17.2, 0.9, 0.9 Hz, 1H); C NMR (75 MHz, CDCl3) δ 201.1, 167.7, 143.8, 132.6, 130.9, 128.8, 128.3, 127.0, 101.5, 77.7, 68.6, 52.1, 42.6, 37.0; FT-IR (neat) 3000, 2953, 2913, 1739, 1714, 1266, 1253, 1072 cm-1; MS (ESI) m/z 263.1 [M + H]+ 285.1 [M + + Na] ; Anal Calcd for C14H14O5: C, 64.12; H, 5.38; Found: C, 64.38; H, 5.30.

General procedure for the conjugate reduction of 315a, 315b and 315c. To a suspension of

CuBr (4 equiv.) in dry THF (20 mL) under N2 cooled to -5 °C was added a 60% w/w solution of sodium bis(2-methoxyethoxy) aluminium hydride (Red-Al) (4 equiv.) and the mixture stirred for 10 mins. The mixture was cooled to -65 °C and enone 315a, 315c or 315d (1 equiv.) was added and stirred at this temperature for 10 minutes then carefully quenched using methanol. The resulting mixture was filtered through a plug of silica and eluted with EtOAc. The filtrate was then concentrated under reduced pressure and the resulting mixture taken up in DCM (20 mL) and filtered through Celite. The volatiles were removed under reduced pressure and the residue purified by column chromatography (1:3 EtOAc/hexanes) giving 389a, 389b or 389c.

(1S,3S,4R)-3-Phenyl-6,8-dioxabicyclo[3.2.1]oct-4-one (389a). Treatment of 315a (106 mg, 0.52 mmol) as per the general method gave 389a as a white crystalline solid (74 mg, 69%); mp 33 1 138-145 °C (DCM/hexanes); [α]D -174 (c 1.08, DCM); H NMR (300 MHz, CDCl3, 25 °C) δ 7.42-7.23 (m, 3H), 7.20-7.10 (m, 2H), 5.29 (s, 1H), 4.85-4.73 (m, 1H), 4.20 (br. d, J = 7.2 Hz, 1H), 4.02 (ddd, J = 7.2, 5.4, 1.5 Hz, 1H), 3.96 (dd, J = 11.9, 7.9 Hz, 1H), 2.48 (dddd, J = 13.9, 13 11.9, 3.6, 1.5 Hz, 1H), 2.35 (dddd, J = 13.9, 7.9, 1.5, 0.6 Hz, 1H); C NMR (75 MHz, CDCl3, 25 °C) δ 199.8, 136.8, 128.9, 128.7, 127.5, 102.0, 73.5, 67.7, 47.8, 39.7; FT-IR (neat) 3028, 2952, 2920, 1731 cm-1; MS (ESI) m/z 205.0 [M + H]+ 227.0 [M + Na]+; HRMS calcd for [M + + Na] C12H12O3Na: 227.0679; found: 227.0680.

(1S,3S,5R)-3-(Benzo[d][1,3]dioxol-5-yl)-6,8-dioxabicyclo[3.2.1]octan-4-one (389b). Treatment of 315b (500 mg, 2.15 mmol) as per the general method gave 389b as a colourless 21 crystalline solid (306 mg, 61%); mp 122-126 °C (diisopropyl ether); [α]D -140 (c 0.35, DCM); 1 H NMR (500 MHz, CDCl3) δ 6.78 (d, J = 7.9 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 6.60 (dd, J = 160

7.9, 1.8 Hz, 1 H), 5.95 (s, 2H), 5.27 (br. s, 1H), 4.80 (dddd, J = 4.4, 3.4, 1.8, 0.8 Hz, 1H), 4.19 (dd, J = 7.5, 0.9 Hz, 1H), 4.03 (ddd, J = 7.5, 4.4, 1.4 Hz, 1 H), 3.89 (dd, J = 11.8, 7.9 Hz, 1H), 2.43 (dddd, J = 13.7, 11.8, 3,4, 1.4 Hz, 1H), 2.34 (dddd, J = 13.7, 7.9, 1.8, 0.9 Hz, 1H); 13C

NMR (75 MHz, CDCl3, 25 °C) δ 200.0, 148.0, 147.0, 130.4, 122.2, 109.1, 108.5, 101.9, 101.1, 73.5, 67.7, 47.6, 40.0; FT-IR (neat) 2974, 2931, 2891, 1731, 1614, 1231, 1100 cm-1; MS (ESI) + m/z 249.1 [M + H] ; Anal Calcd for C13H12O5: C, 62.90; H, 4.87; Found: C, 63.06; H, 4.65.

(1S,3S,5R)-3-(4-Methoxyphenyl)-6,8-dioxabicyclo[3.2.1]octan-4-one (389c). Treatment of 315c (260 mg, 1.06 mmol) as per the general method gave 389c as a colourless crystalline solid 22 1 (134 mg, 54%); mp 99-102 °C (diisopropyl ether); [α]D -152 (c 0.29, DCM); H NMR (300

MHz, CDCl3) δ 7.10-7.00 (m, 2H), 6.93-6.81 (m, 2H), 5.26 (s, 1H), 4.86-4.68 (m, 1H), 4.18 (br d, J = 7.2 Hz, 1H), 4.00 (ddd, J = 7.2, 5.8, 1.3 Hz, 1H), 3.91 (dd, J = 11.7, 7.9 Hz, 1H), 3.78 (s, 3H), 2.43 (dddd, J = 13.5, 11.7, 3.4, 1.3 Hz, 1H), 2.32 (dddd, J = 13.5, 7.9, 0.9, 0.9 Hz, 1H); 13C

NMR (75 MHz, CDCl3) δ 200.3, 158.8, 129.8, 128.7, 114.1, 101.8, 73.5, 67.6, 55.1, 46.9, 39.8; FT-IR (neat) 3036, 2985, 2952, 2931, 2840, 1731 1511, 1260, 1240, 1099 cm-1; MS (ESI) m/z + 235.1 [M + H] ; Anal Calcd for C13H14O4: C, 66.66; H, 6.02; Found: C, 66.70; H, 6.10.

(1S,2S,5R)-2-Phenyl-6,8-dioxabicyclo[3.2.1]octan-4-one (391). To a solution of 315a (202 mg, 1.0 mmol) in EtOAc (3 mL) was added 10% Pd/C (20 mg) and the mixture was stirred under an atmosphere of H2 overnight. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give a residue that was then purified by column chromatography (1:3- 1:1 EtOAc/hexanes) to give a 10:1 mixture of isomers 391 and 316a (166 mg, 81%) and alcohol 392 (30 mg, 15%). An analytical sample of 391 was obtained by careful chromatography; 391: 14 1 Crystalline solid; mp 83-86 °C; [α]D -77.9 (c 1.72, DCM); H NMR (500 MHz, CDCl3) δ 7.45- 7.36 (m, 2H), 7.35-7.29 (m, 1H), 7.28-7.21 (m, 2H), 5.18 (br. s, 1H), 4.79-4.72 (m, 1H), 4.14 (dd, J = 8.1, 1.1 Hz, 1H), 3.82 (br. ddd, J = 12.5, 5.9, 3.7 Hz, 1H), 3.78 (dddd, J = 8.1, 5.5, 0.9, 0.9 Hz, 1H), 3.03 (dd, J = 15.6, 12.5 Hz, 1H), 2.63 (dddd, J = 15.6, 5.9, 0.9, 0.9 Hz, 1 H); 13C

NMR (125 MHz, CDCl3) δ 200.1, 136.9, 129.1, 127.8, 127.4, 100.9, 78.0, 64.2, 46.0, 35.9; FT- IR (neat) 2989, 2917, 2852, 1735, 1599 cm-1; MS (ESI) m/z 227 [M + Na]+; HRMS calcd for [M + + Na] C12H12O3Na: 227.0679; found: 227.0677.

18 (1S,2S,4S,5R)-2-phenyl-6,8-dioxabicyclo[3.2.1]octan-4-ol (392). Colourless syrup; [α]D -50.4 1 (c 1.17, DCM); H NMR (500 MHz, CDCl3) δ 7.45-7.32 (m, 2H), 7.32-7.21 (m, 3H), 5.43 (br. s, 1H), 4.78-4.47 (m, 1H), 3.95 (dd, J = 7.6, 0.6 Hz, 1H), 3.85 (dddd, J = 10.0, 10.0, 5.8, 1.7 Hz, 1H), 3.68 (dd, J = 7.6, 5.2 Hz, 1H), 3.38 (ddd, J = 12.8, 4.0. 4.0 Hz, 1 H), 2.32 (ddddd, J = 12.8, 161

5.8, 4.0, 1.4, 1.4 Hz, 1H), 1.90 (ddd, J = 12.8, 10.0, 10.0 1H), 1.78 (d, J = 10 Hz, 1H); 13C NMR

(125 MHz, CDCl3) δ 138.6, 128.8, 127.5, 127.2, 102.5, 77.6, 69.5, 65.2, 42.7, 30.7; FT-IR (neat) 3481, 3090, 2981, 2932, 2949, 2866, 1602 cm-1; MS (ESI) m/z 229 [M + Na]+; HRMS calcd for + [M + Na] C12H14O3Na: 229.0835; found: 229.0835.

General procedure for the Baeyer-Villiger oxidation of 316a, 317a, 317c, 317h, 317i, 389a, 389c and 391. To a stirred solution of bicyclo[3.2.1]octane derivative (1 mmol) dissolved in DCM (3 mL) was added 32% peracetic acid (600 µL, 2.78 mmol) and the mixture stirred overnight. The reaction was quenched with 10% Pd/C (15 mg) and stirred for 20 minutes or until the evolution of O2 had ceased and a negative test for peroxides was obtained (starch/iodide). The mixture was then filtered through Celite, concentrated under reduced pressure and taken up in 1:1 THF/1M HCl (12 mL) and stirred for 3 hours. The volatiles were removed under reduced pressure and the residue purified by flash chromatography (1:1-7:3 EtOAc/hexanes).

(3S,5S)-5-(Hydroxymethyl)-3-phenyldihydrofuran-2(3H)-one (393a). Treatment of 389a (75 mg, 0.37 mmol) according to the general procedure gave a colourless oil that crystallised upon 20 1 standing (55 mg, 78%); mp 97-99 °C; [α]D +57.1 (c 0.98, DCM); H NMR (300 MHz, CDCl3) δ 7.47-7.16 (m, 5H), 4.77-4.67 (m, 1H), 4.04 (dd, J = 10.0, 8.2 Hz, 1H), 3.94 (br. d, J = 11.9 Hz, 1H), 3.69 (dd, J = 11.9, 2.8 Hz, 1H), 3.17 (br. s., 1H), 2.66 (ddd, J = 13.2, 10.0, 4.5 Hz, 1H), 13 2.43 (ddd, J = 13.2, 8.2, 8.2 Hz, 1H); C NMR (75 MHz, CDCl3) δ 178.3, 137.5, 128.9, 127.7, 127.5, 78.9, 64.1, 46.0, 32.6; FT-IR (neat) 3458, 3033, 2968, 1749, 1184, 1056, 1027 cm-1; MS + + (ESI) m/z 193.1 [M + H] , 215.1 [M + Na] ; Anal Calcd for C11H12O3: C, 68.74; H, 6.29; Found: C, 68.53; H, 6.46.

(3S,5S)-5-(Hydroxymethyl)-3-(Benzo[d][1,3]dioxol-5-yl)dihydrofuran-2(3H)-one (393b). To a solution of 389b (91 mg, 0.37 mmol) in DCM (1 mL) was added 70% m-chloroperbenzoic acid (99 mg, 0.40 mmol) then p-TSA (30 mg, 0.17 mmol) and the mixture stirred for 10 days. The 1H NMR spectrum of an aliquot of the reaction mixture showed 40% conversion of starting material to the desired lactone 393b and its formate ester derivative. The reaction mixture was quenched by pouring onto iron filings and the mixture stirred for 5 minutes until the evolution of O2 had ceased and a negative test for peroxides was obtained (starch/iodide). The mixture was then filtered through Celite, concentrated under reduced pressure and taken up in 1:1 THF/1M HCl (2 mL) and stirred for 3 hours. The volatiles were removed under reduced pressure and the residue purified by flash chromatography (7:3 EtOAc/hexanes) to give 393b as a colourless syrup (17 15 1 mg, 50% based on conversion of starting material); [α]D +45 (c 0.80, DCM); H NMR (500 162

MHz, CDCl3) δ 6.95-6.60 (m, 3H), 5.96 (s, 2H), 4.74 (dddd, J = 8.2, 4.6, 4.1, 3.1 Hz, 1H), 4.06- 3.89 (m, 2H), 3.74 (dd, J = 12.4, 4.1 Hz, 1H), 2.66 (ddd, J = 13.1, 9.8, 4.6 Hz, 1H), 2.43 (ddd, J 13 = 13.1, 8.2, 8.2 Hz, 1H), 2.12 (br. s., 1H); C NMR (125 MHz, CDCl3) δ 177.6, 148.2, 147.1, 131.0, 121.0, 108.6, 108.1, 101.2, 78.4, 64.5, 45.0, 32.7; FT-IR (neat) 3450, 2950, 2922, 2852, 1765, 1736, 1233, 1034 cm-1; MS (ESI) m/z 259.1 [M + Na]+; HRMS calcd for [M + Na]+

C12H12O5Na: 259.0577; found: 259.0573.

(3S,5S)-5-(Hydroxymethyl)-3-(4-methoxyphenyl)dihydrofuran-2(3H)-one (393c). Treatment of 389c (115 mg, 0.49 mmol) according to the general procedure gave 393c as a white crystalline 18 1 solid (69 mg, 63%); mp 90-93 °C (toluene); [α]D +42.4 (c 0.33, DCM); H NMR (500 MHz,

CDCl3) δ 7.23-7.14 (m, 2H), 6.95-6.82 (m, 2H), 4.73 (dddd, J = 8.0, 5.0, 4.7, 2.7 Hz, 1H), 4.06- 3.93 (m, 2H), 3.80 (s, 3H), 3.74 (ddd, J = 12.2, 6.3, 5.0 Hz, 1H), 2.65 (ddd, J = 13.2, 9.8, 4.7 Hz, 1H), 2.43 (ddd, J = 13.2, 8.0, 8.0 Hz, 1H), 2.07 (dd, J = 6.3, 6.3 Hz, 1H); 13C NMR (125 MHz,

CDCl3) δ 177.8, 159.0, 129.4, 128.7, 114.4, 78.4, 64.5, 55.3, 45.1, 32.7; FT-IR (neat) 3499, 3421, 3032, 3008, 2954, 2831, 1762, 1746, 1249, 1030 cm-1; MS (ESI) m/z 223.1 [M + H]+ + 245.0 [M + Na] ; Anal Calcd for C12H14O4: C, 64.85, H, 6.35; Found: C, 64.81; H, 6.40.

(S)-5-(Hydroxymethyl)-4-phenylfuran-2(5H)-one (394). Treatment of 316a (100 mg, 0.50 mmol) according to the general procedure gave 394 as a white crystalline solid (78 mg, 92%); o 17 1 mp 135 C (MeOH/Et2O); [α]D -172 (c 0.25, DCM); H NMR (500 MHz, CD3OD) δ 6.25-6.01 (m, 2H), 5.99-5.86 (m, 3H), 4.94 (s, 1H), 4.19 (br. dd, J = 3.8, 2.6 Hz, 1H), 2.51 (dd, J = 12.7, 13 2.6 Hz, 1H), 2.21 (dd, J = 12.7, 3.8 Hz, 1H); C NMR (125 MHz, CD3OD) δ 175.7, 167.4, 132.6, 131.6, 130.4, 128.8, 116.3, 85.3, 62.8; FT-IR (neat) 3393, 3110, 2932, 1723, 1707, 1614, -1 + + 1513 cm ; MS (ESI) m/z 191.1 [M + H] 213.1 [M + Na] ; Anal Calcd for C11H10O3: C, 69.46; H, 5.30; Found: C, 69.35; H, 5.24.

(4S,5S)-5-(hydroxymethyl)-4-phenyldihydrofuran-2(3H)-one (395). Treatment of 391 (442 mg, 2.16 mmol) according to the general procedure gave 395 as a crystalline solid (395 mg, 27 1 95%); mp 97-99 °C (tol.); [α]D +172 (c 1.01, CHCl3); H NMR (500 MHz, CDCl3) δ 7.42-7.34 (m, 2H), 7.34-7.28 (m, 1H), 7.28-7.21 (m, 2H), 4.80 (ddd, J = 7.6, 5.5, 3.7 Hz, 1H), 3.91 (ddd, J = 9.2, 8.2, 7.6 Hz, 1H), 3.53 (ddd, J = 12.5, 5.3, 3.7 Hz, 1H), 3.41 (br. ddd, J = 12.5, 5.3, 5.3 Hz, 1H), 3.02 (dd, J = 17.4, 8.2 Hz, 1H), 2.89 (dd, J = 17.4, 9.2 Hz, 1H), 1.86 (br. dd, J = 5.3, 5.3 13 Hz, 1H); C NMR (125 MHz, CDCl3) δ 176.5, 136.4, 128.9, 127.9, 127.6, 83.2, 62.2, 43.1, 34.5; FT-IR (neat) 3413, 3070, 3039, 2947, 1754, 1603 cm-1; MS (ESI) m/z 193.1 [M + H]+ 215.1 [M + Na]+. 163

(4R,5S)-5-(Hydroxymethyl)-4-phenyldihydrofuran-2(3H)-one (396a).260 Treatment of 317a (330 mg, 1.62 mmol) according to the general procedure afforded 396a as a straw oil that o 19 crystallised upon standing (279 mg, 90%); mp 89-91 C (diisopropyl ether); [α]D +41.6 (c 1 0.89, CHCl3); H NMR (300 MHz, CDCl3) δ 7.44-7.12 (m, 5H), 4.61-4.43 (m, 1H), 3.95 (d, J = 12.8 Hz, 1H), 3.80-3.55 (m, 2H), 3.03 (dd, J = 17.7. 9.0 Hz, 1H), 2.78 (dd, J = 17.7, 9.6 Hz, 1H), 13 2.35 (s, 1H); C NMR (125 MHz, CDCl3, 25 °C) δ = 176.1, 139.1, 129.1, 127.7, 127.2, 87.0, 61.9, 42.0, 37.2; FT-IR (neat) 3479, 3065, 3036, 2949, 2926, 1762, 1743 cm-1; MS (ESI) m/z 193.1 [M + H]+ 215.1 [M + Na]+.

(4R,5S)-5-(Hydroxymethyl)-4-(4-methoxyphenyl)dihydrofuran-2(3H)-one (396c). Treatment of 317c (184 mg, 0.79 mmol) according to the general procedure afforded 396c as a colourless o 20 oil that crystallised upon standing (116 mg, 66%); mp 92-93 C (IPA/Et2O); [α]D +22.7 (c 0.75, 1 DCM); H NMR (500 MHz, CDCl3) δ 7.22-7.14 (m, 2H), 6.98-6.83 (m, 2H), 4.50 (ddd, J = 8.2, 3.7, 2.4 Hz, 1H), 3.95 (dd, J = 12.8, 2.4 Hz, 1H), 3.81 (s, 3H), 3.71-3.59 (m, 2H), 3.00 (dd, J = 13 17.7, 9.2 Hz, 1H), 2.76 (dd, J = 17.7, 10.1 1H), 2.09 (br. s., 1H); C NMR (125 MHz, CDCl3) δ 175.8, 159.2, 130.7, 128.3, 114.6, 87.0, 61.9, 55.3, 41.4, 37.3; FT-IR (neat) 3441, 2963, 2910, -1 + 2840, 1757, 1733, 1610, 1029 cm ; MS (ESI) m/z 245.1 [M + Na] ; Anal Calcd for C12H14O4: C, 64.85, H, 6.35; found: C, 64.58; H, 6.22.

(4R,5S)-5-(Hydroxymethyl)-4-(p-tolyl)dihydrofuran-2(3H)-one (396h). Treatment of 317h (152 mg, 0.70 mmol) according to the general procedure afforded 396h as a colourless syrup 21 1 (110 mg, 77%); [α]D +29.2 (c 0.24, DCM); H NMR (500 MHz, CDCl3) δ 7.24-6.93 (m, 4H), 4.44 (ddd, J = 7.9, 4.0, 2.4 Hz, 1H), 3.86 (dd, J = 12.8, 2.4 Hz, 1H), 3.66-3.50 (m, 2H), 2.92 (dd, J = 17.7, 9.0 Hz, 1H), 2.68 (dd, J = 17.7, 9.8 Hz, 1H), 2.56 (br. s, 1H), 2.26 (s, 3H); 13C NMR

(125 MHz, CDCl3) δ 176.1, 137.5, 136.0, 129.8, 127.0, 87.1, 61.9, 41.6, 37.2, 20.9; FT-IR (neat) 3417, 3025, 2923, 2869. 1769, 1755, 1516 cm-1; MS (ESI) m/z 207.1 [M + H]+ 229.1 [M + Na]+; + HRMS calcd for [M + Na] C12H14O3Na: 229.0835; found: 229.0840.

Methyl 2-((2S,3R)-2-(hydroxymethyl)-5-oxotetrahydrofuran-3-yl)benzoate (396i). Treatment of 317i (152 mg, 0.58 mmol) according to the general procedure afforded 396i as a colourless 17 1 syrup (106 mg, 73%); [α]D +21.2 (c 0.33, DCM); H NMR (500 MHz, CDCl3, 25 °C) δ 7.90 (dd, J = 7.9, 1.2 Hz, 1H), 7.57 (ddd, J = 7.9, 7.7, 1.2 Hz, 1H), 7.44 (dd, J = 7.9, 0.9 Hz, 1H), 7.37 (ddd, J = 7.9, 7.7, 0.9 Hz, 1H), 4.59 (ddd, J = 6.9, 3.7, 2.7 Hz, 1H), 4.51 (ddd, J = 9.5, 7.3, 6.9 Hz, 1H), 4.00-3.87 (m, 1H), 3.93 (s, 3H), 3.82 (ddd, J = 12.1, 6.1, 4.8, 1H), 3.12 (dd, J = 18.0, 9.5 Hz, 1H), 2.94 (dd, J = 6.1, 6.1 Hz, 1H), 2.72 (dd, J = 18.0, 7.3, 1H); 13C NMR (125 MHz, 164

CDCl3) δ 176.2, 168.2, 141.5, 132.9, 130.9, 129.9, 127.4, 127.3, 87.0, 62.8, 52.5, 38.1, 37.4; FT- IR (neat) 3439, 2952, 1771, 1713, 1601, 1577 cm-1; MS (ESI) m/z 251.1 [M + H]+, 273.1 [M + + + Na] ; HRMS calcd for [M + Na] C13H14O5Na:273.0733; found: 273.0734.

Experimental data for compounds in Chapter 4 General Experimental. MeLi and BuLi solutions were titrated previous to use with diphenylacetic acid in THF.

(S)-5-(Hydroxymethyl)dihydrofuran-2(3H)-one ((S)-492).261 To a stirred solution of dihydrolevoglucosenone (4.0 g, 31.2 mmol) in DCM (50 mL) cooled using a water bath was added 70% m-chloroperbenzoic acid (11.5 g, 47 mmol) then p-TSA (800 mg, 5.0 mmol). The mixture was stirred for 16 hours and then the volatiles were removed under reduced pressure. To the residue was added 1 M HCl (20 mL) and the resulting solution stirred overnight. The mixture was filtered, the precipitate washed with water and the filtrate concentrated under reduced pressure. Purification of the residue by flash chromatography (ethyl acetate) to remove residual m-chloroperbenzoic acid afforded the title compound (3.07 g, 85%); [α]D +50.0 (c 1.0, CHCl3); 13 + C NMR (75 MHz, CDCl3) δ 177.8, 80.9, 64.0, 28.7, 23.2; MS (EI) m/z 116.1 ([M] , 0.5), 86 (12), 85 (100), 57 (10).

(S)-5-(Methanesulfonyloxymethyl)dihydrofuran-2(3H)-one ((S)-493).262 To a solution of (S)-

492 (5.08 g, 43.7 mmol) in DCM (50 mL) cooled using a water bath was added Et3N (9.2 mL, 66 mmol) then MsCl (4.7 mL, 61 mmol). The mixture was stirred for 3 hours then quenched with a saturated solution of NH4Cl and the DCM removed under reduced pressure. The aqueous layer was extracted twice with ethyl acetate then the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography 25 1 (ethyl acetate) to give (S)-493 as a yellow syrup (7.38 g, 87%); [α]D +33.3 (c 1.5, DCM); H

NMR (300 MHz, CDCl3) δ 4.88-4.71 (m, 1H), 4.43 (dd, J = 11.5, 3.0 Hz, 1H), 4.29 (dd, J = 11.5, 4.9 Hz, 1H), 3.07 (s, 3H), 2.67-2.52 (m, 2H), 2.47-2.32 (m, 1H), 2.23-2.06 (m, 1H); 13C - NMR (75 MHz, CDCl3) δ 176.0, 76.6, 69.7, 37.7, 27.9, 23.4; FT-IR (neat) 2940, 1769, 1164 cm 1; MS (EI) m/z 195.1 [M + H]+ 217.1 [M + Na]+.

(S)-Ethyl 3-(oxiran-2-yl)propanoate ((S)-494a).263,264 To a suspension of mesylate (S)-493 (1.80 g, 9.3 mmol) in dry EtOH (20 mL) was added solid sodium ethoxide (0.70 g, 10.2 mmol) and the mixture was stirred for 3 hours. The mixture was quenched with a saturated solution of

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NH4Cl and extracted three times with DCM. The combined organic extracts were dried (MgSO4) and the DCM distilled. The residue was filtered through a bed of silica eluting with 1:2 ethyl 22 acetate/hexanes and the filtrate concentrated to give a colourless oil (0.88g, 67%); [α]D -14.8 (c 1 1.35, CHCl3); H NMR (300 MHz, CDCl3) δ 4.14 (q, J = 7.0 Hz, 2H), 3.03-2.93 (m, 1H), 2.76 (dd, J = 4.4. 4.4 Hz, 1H), 2.50 (dd, J = 4.4, 2.8 Hz, 1H), 2.45 (dd, J = 7.5, 7.5 Hz, 2H), 2.02-1.89 13 (m, 1H), 1.84-1.72 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 172.7, 60.3, 51.0, 46.9, 30.3, 27.5, 14.0; FT-IR (neat) 2982, 1730, 1179 cm-1; MS (ESI) m/z 145.1 [M + H]+.

(S)-Cyclohexyl 3-(oxiran-2-yl)propanoate ((S)-494b). To cyclohexanol (1.25 g, 12.5 mmol) in dry THF (15 mL) cooled to -60 °C was slowly added a solution of MeLi in THF/cumene (0.83 M, 12.8 mL). The mixture was stirred for 10 minutes and then a solution of (S)-493 (1.73 g, 8.91 mmol) in dry THF (15 mL) was added and the mixture was allowed to come to room temperature over the course of an hour. The reaction was quenched with a saturated solution of

NH4Cl and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated and the residue purified by column chromatography (1:9 ethyl acetate/hexanes) to give (S)-494b 33 1 as a colourless oil (1.51 g, 84%); [α]D -11.8 (c 1.52, EtOH); H NMR (500MHz, CDCl3) δ 4.99-4.47 (m, 1H), 3.60 (dd, J = 11.4, 6.4 Hz, 1H), 3.50 (dd, J = 11.4, 6.9 Hz, 1H), 1.91-1.78 (m, 2H), 1.76-1.64 (m, 4H), 1.57-1.50 (m, 2H), 1.47-1.31 (m, 4H), 1.30-1.23 (m, 1H), 1.20 (ddd, J = 13 8.9, 4.5, 4.3 Hz, 1H), 0.85 (ddd, J = 8.4, 6.3, 4.3 Hz, 1H); C NMR (75 MHz ,CDCl3) δ 172.0, 72.5, 51.0, 46.8, 31.4, 30.6, 27.6, 25.2, 23.5; FT-IR (neat) 2934, 2858, 1727, 1176 cm-1; MS + + (ESI) m/z 221.1 [M + Na] ; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C11H18O3Na 221.1154; Found 221.1152.

(R)-5-(Hydroxymethyl)dihydrofuran-2(3H)-one ((R)-492).228 Trifluoroacetic acid (5 mL) was cooled to -10 oC and epoxide (S)-494a (1.25 g, 8.67 mmol) was added. The mixture was stirred at -10 °C for 20 minutes then diluted with toluene and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate) to give (R)-492 as a colourless 21 oil that was spectroscopically identical to (S)-492 (715 mg, 71%); [α]D -50.5 (c 1.5, CHCl3).

(R)-5-(Methanesulfonyloxymethyl)dihydrofuran-2(3H)-one ((R)-493). Methylhydroxy lactone (R)-492 (510 mg, 4.39 mmol) was treated as per the procedure for (S)-493 to give (R)- 23 493 which was spectroscopically identical to (S)-493 (762 mg, 89%); [α]D -30.0 (c 1.1, DCM).

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(R)-Cyclohexyl 3-(oxiran-2-yl)propanoate ((R)-494b). To cyclohexanol (870 mg, 8.65 mmol) in dry THF (10 mL) cooled to -60 °C was added a solution of n-butyl lithium in THF (1.6 M, 4.73 mL, 7.57 mmol) and the mixture stirred for 10 minutes. To this was added (R)-493 (1.05 g, 5.41 mmol) dissolved in THF (5mL) and the mixture was allowed to come to room temperature over the course of 1.5 hours. The mixture was quenched with a saturated solution of NH4Cl and extracted twice with ethyl acetate. The combined organic extracts were dried (MgSO4), concentrated under reduced pressure and the residue purified by column chromatography (1:9 ethyl acetate/hexanes) to give (R)-494b as a colourless oil that was spectroscopically identical to 22 (S)-494b (936 mg, 87%); [α]D +11.4 (c 1.32, EtOH).

(1S,2S)-Ethyl 2-(hydroxymethyl)cyclopropanecarboxylate ((1S,2S)-495a).195 A solution of LiHMDS in toluene (1 M, 1.82 mL) was added to THF (3.2 mL) and the mixture cooled to -5 °C. To this was slowly added a solution (S)-494a (0.220 g, 1.53 mmol) in THF (5 mL) over the course of 10 minutes. The mixture was quenched with 10% w/v NaH2PO4 (10 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure using a 20 °C water bath and the residue purified by column chromatography (1:1 ethyl acetate/hexanes) to give (1S,2S)-495a as a colourless oil (85 mg, 30 1 39%); [α]D +57.5 (c 0.8, DCM); H NMR (300 MHz, CDCl3) δ 4.11 (q, J = 7.0 Hz, 2H), 3.61 (dd, J = 11.3, 6.0 Hz, 1H), 3.47 (dd, J = 11.3, 6.8 Hz, 1H), 1.78-1.65 (m, 1H), 1.62 (br. s, 1H), 1.55 (app. td, J = 8.6, 4.3 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.22- 1.14 (m, 1H), 0.84 (ddd, J = 13 8.3, 6.2, 4.5 Hz, 1H); C NMR (75 MHz, CDCl3) δ 173.7, 64.6, 60.6, 24.2, 18.3, 14.2, 12.6; FT- IR (neat) 3424, 2981, 1721, 1177 cm-1; MS (EI) m/z 144.1 ([M]+, trace), 101.1 (36), 99.1 (73), 98.1 (43), 88.1 (64), 73.1 (100), 70.1 (39), 55.1 (98), 43.1 (27).

(1S,2S)-Cyclohexyl 2-(hydroxymethyl)cyclopropanecarboxylate ((1S,2S)-495b). Cyclohexyl ester (1S,2S)-494b (248 mg, 1.25 mmol) was treated as per the method for (1S,2S)-495a except that the reaction was performed at room temperature and the column eluent was 2:3 ethyl 32 acetate/hexanes to give (1S,2S)-495b as a colourless oil (123 mg, 50%); [α]D +51.5 (c 2.00, 1 EtOH); H NMR (300 MHz, CDCl3) δ 4.77-4.57 (m, 1H), 3.54 (dd, J = 11.5, 6.2 Hz, 1H), 3.43 (dd, J = 11.5, 6.4 Hz, 1H), 2.48 (br. s., 1H), 1.86-1.58 (m, 5H), 1.54-1.43 (m, 2H), 1.43-1.09 (m, 13 6H), 0.80 (ddd, J = 8.4, 6.2, 4.4 Hz, 1H); C NMR (75 MHz, CDCl3) δ 173.3, 72.7, 64.3, 31.5, 25.3, 24.0, 23.6, 18.6, 12.6; FT-IR (neat) 3420, 2934, 2858, 1719, 1175 cm-1; MS (ESI) 221.1

167

+ + [M + Na] ; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C11H18O3Na 221.1154; Found 221.1178.

(1R,2R)-Cyclohexyl 2-(hydroxymethyl)cyclopropanecarboxylate ((1R,2R)-495b). (R)-494b (936 mg, 4.72 mmol) was treated as per the method for (1S,2S)-495b to give (1R,2R)-495b as a 26 colourless oil that was spectroscopically identical to (1S,2S)-495b (376 mg, 40%); [α]D -47.6 (c 1.26, EtOH).

(1S,2S)-Cyclohexyl 2-(methanesulfonyloxymethyl)cyclopropanecarboxylate ((1S,2S)-503).

To a solution of (1S,2S)-495b (683 mg, 3.44 mmol) in DCM (10 mL) was added Et3N (720 µL, 5.17 mmol) then MsCl (380 µL, 4.82 mmol). The resulting mixture was stirred for 2 hours then quenched with a saturated solution of NH4Cl and extracted with ethyl acetate. The organic phase was dried (MgSO4) then concentrated under reduced pressure and the residue purified by column chromatography (3:7 ethyl acetate/hexanes) to give (1S,2S)-503 as a colourless syrup that 24 1 crystallised on standing (829 mg, 87%); mp 62-64 °C; [α]D +47.3 (c 1.1, EtOH); H NMR (300

MHz, CDCl3) δ 4.85-4.61 (m, 1H), 4.15 (dd, J = 11.1, 6.8 Hz, 1H), 4.07 (dd, J = 11.1, 7.2 Hz, 1H), 3.01 (s, 3H), 1.90-1.60 (m, 6H), 1.58-1.15 (m, 7H), 0.93 (ddd, J = 8.5, 5.8, 4.9 Hz, 1H); 13C

NMR (75 MHz, CDCl3) δ 171.9, 73.2, 71.5, 38.0, 31.5, 25.3, 23.7, 20.1, 19.4, 13.0; FT-IR (neat) 2944, 2861, 1710, 1161 cm-1; MS (ESI) m/z 277.1 [M + H]+ 299.1 [M + Na]+; HRMS (ESI-TOF) + m/z: [M + Na] Calcd for C12H20O5NaS 299.0929; Found 299.0923.

(1R,2R)-Cyclohexyl 2-(methanesulfonyloxymethyl)cyclopropanecarboxylate ((1R,2R)-503). (1R,2R)-495b (487 mg, 2.46 mmol) was treated as per the method for (1S,2S)-503 to give (1R,2R)-503 as a colourless oil that crystallised upon standing and was spectroscopically 30 identical to (1S,2S)-503 (623 mg 92%); [α]D -44.2 (c 0.63, EtOH).

(1S,2S)-Cyclohexyl 2-(azidomethyl)cyclopropanecarboxylate ((1S,2S)-504). To a solution of

(1S,2S)-503 (555 mg, 2.01 mmol) in DMF (10 mL) was added NaN3 (650 mg, 10.0 mmol) and the mixture stirred at 60 °C overnight. The mixture was diluted with ethyl acetate and washed with three portions of saturated NH4Cl. The organic layer was dried (MgSO4) and concentrated to give (1S,2S)-504 as a colourless oil which was used without further purification (425 mg, 29 1 95%); [α]D +40.8 (c 0.49, EtOH); H NMR (300MHz, CDCl3) δ 4.83-4.61 (m, 1H), 3.19 (app. d, J = 6.6 Hz, 2H), 1.89-1.61 (m, 5H), 1.59-1.14 (m, 8H), 0.85 (ddd, J = 8.5, 6.0, 4.7 Hz, 1H);

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13 C NMR (75 MHz, CDCl3) δ 172.4, 72.9, 53.2, 31.5, 25.3, 23.6, 20.4, 18.9, 13.0; FT-IR (neat) 2935, 2858, 2086, 1717, 1202, 1177 cm-1; MS (ESI) m/z 246.1 [M + Na]+. HRMS (ESI-TOF) + m/z: [M + Na] Calcd for C11H18N3O 224.1399; Found 224.1439.

(1R,2R)-Cyclohexyl 2-(azidomethyl)cyclopropanecarboxylate ((1R,2R)-504). (1R,2R)-503 (581 mg, 2.10 mmol) was treated as per the method for (1S,2S)-504 to give (1R,2R)-504 as a 26 colourless oil that was spectroscopically identical to (1S,2S)-504 (408 mg, 87%);[α]D -37.6 (c 2.74, EtOH).

(1S,2S)-Methyl 2-aminomethylcyclopropanecarboxylate hydrochloride ((1S,2S)-506).265 To a solution of (1S,2S)-9 (414 mg, 1.90 mmol) in 2:1 THF/2M HCl (9 mL) was added 5% Pd/C

(40 mg) and the mixture stirred overnight under an atmosphere of H2. The mixture was filtered through Celite and concentrated under reduced pressure then the residue was suspended in 2M HCl (5 mL) and stirred at 50 °C overnight. Removal of the volatiles under reduced pressure gave crude 2-aminomethylcyclopropanecarboxylate hydrochloride (1S,2S)-505 (278 mg, 99%) which was recrystallised by vapour diffusion from methanol/ether to give (1S,2S)-506 as translucent 24 1 crystals (208 mg, 74%); mp 188-192 °C; []D +68.9 (c 1.03, H2O); H NMR (300 MHz, D2O) δ 3.70 (s, 3H), 3.04 (dd, J = 13.4, 7.0 Hz, 1H), 2.95 (dd, J = 13.4, 7.9 Hz, 1H), 1.82 (ddd, J = 8.7, 4.7 4.7 Hz, 1H), 1.78-1.66 (m, 1H), 1.32 (ddd, J = 9.8, 4.7, 4.7 Hz, 1H), 1.09 (ddd, J = 8.7, 6.4, 13 4.7 Hz, 1H); C NMR (75 MHz, D2O) δ 176.5, 53.2, 42.8, 19.7, 19.5, 14.2; FT-IR (neat) 3423, 2924, 1717, 1208, 1170, 1153 cm-1; MS (ESI) m/z 116.0 [M]+.

(1R,2R)-Methyl 2-aminomethylcyclopropanecarboxylate hydrochloride ((1R,2R)-506).265 (1R,2R)-504 (344 mg, 1.54 mmol) was treated as per the method for (1S,2S)-506 to give (1R,2R)-506 as translucent crystals that were spectroscopically identical to (1S,2S)-11 (168 mg, 26 66%); [α]D -64.6 (c 0.43, EtOH).

(3S,5S)-5-(Methanesulfonyloxymethyl)-3-phenyldihydrofuran-2(3H)-one (507). To a solution of 393a (414 mg, 2.16 mmol) in DCM (5 mL) cooled in a water bath was added Et3N (0.45 mL, 3.2 mmol) then MsCl (0.23 mL, 3.0 mmol). The mixture stirred for 1.5 hours then quenched with saturated aqueous NH4Cl and extracted twice with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure and the residue purified by column chromatography (3:2 EtOAc/hexanes) to give 507 as a yellow syrup that 23 1 crystallised upon standing (591 mg, 100%); mp 102-104 °C; [α]D +50.8 (c 1.26, DCM); H

169

NMR (300MHz, CDCl3) δ 7.56-7.09 (m, 5H), 4.95-4.81 (m, 1H), 4.47 (dd, J = 11.5, 3.0 Hz, 1H), 4.36 (dd, J = 11.5, 4.5 Hz, 1H), 3.99 (dd, J = 9.8, 8.1 Hz, 1H), 3.09 (s, 3H), 2.67 (ddd, J = 13.5, 13 9.8, 4.9 Hz, 1H), 2.55 (ddd, J = 13.4, 8.2, 8.1 Hz, 1H); C NMR (75 MHz, CDCl3) δ 176.4, 136.6, 129.1, 127.9, 127.6, 74.8, 70.0, 45.2, 37.7, 32.5; FT-IR (neat) 3032, 2978, 1736, 1344, 1180, 1141 cm-1; MS (ESI) m/z 271.1 [M + H]+ 293.0 [M + Na]+; HRMS (ESI-TOF) m/z: [M + + Na] Calcd for C12H14O5NaS 293.0460; Found 293.0468.

(4R,5S)-5-(Methanesulfonyloxymethyl)-4-phenyldihydrofuran-2(3H)-one (508). To a solution of 396a (1.91 g, 9.94 mmol) was added Et3N (2.07 mL, 14.9 mmol) then MsCl (0.92 mL, 11.9 mmol) and the mixture stirred for 3 hours. The reaction was quenched with saturated

NaHCO3 and extracted twice with ethyl acetate. The combined organic extracts were dried

(MgSO4) and concentrated under reduced pressure and the residue purified by column chromatography (1:1 ethyl acetate/hexanes) to give 508 as a pale yellow syrup (2.62 g, 98%); 22 1 [α]D +47.4 (c 1.56, DCM); H NMR (500MHz, CDCl3) δ 7.38-7.30 (m, 2H), 7.29-7.23 (m, 1H), 7.22-7.16 (m, 2H), 4.61 (ddd, J = 8.1, 4.3, 2.4 Hz, 1H), 4.39 (dd, J = 11.9, 2.4 Hz, 1H), 4.26 (dd, J = 11.9, 4.3 Hz, 1H), 3.56 (ddd, J = 9.8, 9.2, 8.1 Hz, 1H), 3.01 (s, 3H), 2.97 (dd, J = 18.0, 9.2

Hz, 1H), 2.74 (dd, J = 18.0, 9.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 174.4, 137.8, 129.5, 128.3, 127.1, 83.0, 67.7, 42.7, 37.8, 36.7; FT-IR (neat) 3030, 2938, 1781, 1603, 1350, 1171 cm-1; MS (ESI) m/z 271.1 [M + H]+ 293.1 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for

C12H14O5NaS 293.0460; Found 293.0446.

(4S, 5S)-5-(methanesulfonyloxymethyl)-4-phenyldihydrofuran-2(3H)-one (509)

395 (245 mg, 1.28 mmol) was treated as per the method for 508 to give 509 as a crystalline solid 19 1 (281 mg, 82%); mp 137-139 °C (tol.); [α]D +152 (c 1.14, DCM) H NMR (500 MHz, CDCl3) δ 7.50-7.31 (m, 3H), 7.25-7.14 (m, 2H), 4.99 (ddd, J = 7.2, 6.4, 3.1 Hz, 1H), 4.09 (dd, J = 11.6, 3.1 Hz, 1H), 3.95 (br. ddd, J = 8.9, 7.2, 6.4 Hz, 1H), 3.91 (dd, J = 11.6, 6.4 Hz, 1H), 3.00 (dd, J = 13 17.7, 8.9 Hz, 1H), 2.93 (s, 3H), 2.92 (dd, J = 17.7, 6.4 Hz, 1H); C NMR (125 MHz, CDCl3) δ 175.3, 135.7, 129.4, 128.5, 127.5, 79.7, 68.5, 42.6, 37.5, 34.6; FT-IR (neat) 3032, 3015, 2961, 1766, 1763, 1600 cm-1; MS (ESI) m/z 271.1 [M + H]+ 293.0 [M + Na]+.

(R)-Ethyl 3-((S)-oxiran-2-yl)-3-phenylpropanoate (511). To a solution of 508 (2.60 g, 9.63 mmol) in 1:1 ethanol/THF (40 mL) was added sodium ethoxide (950 mg, 14.0 mmol) and the mixture stirred for 24 hours. The reaction was quenched with saturated NH4Cl and extracted twice with DCM. The combined organic extracts were dried (MgSO4) and concentrated and the residue purified by column chromatography (1:9 ethyl acetate/hexanes) to give 511 as a pale 170

13 1 yellow oil (1.72 g, 81%); [α]D -4.8 (c 2.70, DCM); H NMR (500MHz, CDCl3) δ 7.42-7.32 (m, 2H), 7.31-7.23 (m, 3H), 4.22-3.96 (m, 1H), 3.14 (ddd, J = 7.2, 3.7, 2.4 Hz, 1H), 3.01 (ddd, J = 8.9, 7.2, 6.1 Hz, 1 H), 2.92 (dd, J = 15.3, 6.1 Hz, 1H), 2.79 (dd, J = 15.3, 8.9 Hz, 1H), 2.77 (dd, J = 4.6, 3.7 Hz, 1H), 2.61 (dd, J = 4.6, 2.4 Hz, 1H), 1.17 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz,

CDCl3) δ 171.5, 139.8, 128.6, 127.7, 127.2, 60.4, 55.3, 46.9, 44.9, 37.6, 14.0; FT-IR (neat) 3063, 3030, 2981, 2927, 1729, 1602, 1251 cm-1; MS (ESI) m/z 221.1 [M + H]+ 243.1 [M + Na]+; + HRMS (ESI-TOF) m/z: [M + Na] Calcd for C13H16O3Na 243.0997; Found 243.1003.

(R)-ethyl 3-((S)-oxiran-2-yl)-3-phenylpropanoate (512)

509 (250 mg, 0.93 mmol) was treated as per the method for 511 to give 512 as a colourless oil 17 1 (136 mg, 66%); [α]D +11.0 (c 1.36, DCM); H NMR (500MHz, CDCl3)δ 7.39-7.31 (m, 2H), 7.30-7.20 (m, 3H), 4.18-4.03 (m, 2H), 3.32 (ddd, J = 7.6, 7.6, 5.6 Hz, 1H), 3.21 (ddd, J = 5.6, 4.0, 2.4 Hz, 1H), 2.78 (dd, J = 4.9, 4.0 Hz, 2H), 2.79 (dd, J = 15.6, 7.6 Hz, 1H), 2.68 (dd, J = 15.6, 7.6 Hz, 1H), 2.54 (dd, J = 4.9, 2.4 Hz, 1H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz,

CDCl3) δ 171.5, 139.5, 128.5, 127.9, 127.2, 60.5, 54.6, 45.9, 43.1, 36.9, 14.0; FT-IR (neat) 3067, 3032, 2981, 2923, 1731, 1602 cm-1; MS (ESI) m/z 243.0 [M + Na]+.

(1S,2S)-Ethyl 2-(hydroxymethyl)-1-phenylcyclopropanecarboxylate (513).233 To a stirred solution of 507 (455 mg, 1.68 mmol) in ethanol/THF (2:1, 15 mL) was added sodium ethoxide

(475 mg, 2.02 mmol). After 1 hour the reaction was neutralised with saturated NH4Cl and extracted twice with DCM. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure and the residue purified by column chromatography (1:9 ethyl acetate/hexanes) to give 510 as a 1:1 mixture of diastereomers (253 mg, 64%). A solution of LiHMDS in toluene (1.0 M, 712 µL) was added to THF (5 mL) and a portion of 510 (112 mg, 0.508 mmol) in THF (5 mL) added over the course of 10 minutes. The reaction was stirred for a further 20 minutes and then quenched with 10% w/v NaH2PO4 and extracted twice with DCM.

The combined organic extracts were dried (MgSO4) and concentrated and the residue purified by column chromatography (2:3 ethyl acetate/hexanes) to give 513 (33 mg, 29%) and 514 (5 mg, 16 1 6%); 513: [α]D +12.5 (c 0.24, DCM); H NMR (300 MHz, CDCl3) δ 7.57-7.01 (m, 5H), 4.25- 3.93 (m, 2H), 3.39 (dd, J = 11.7, 5.8 Hz, 1H), 3.18 (dd, J = 11.7, 7.9 Hz, 1 H), 2.18 (dddd, J = 9.2, 7.9, 6.6, 5.8 Hz, 1H), 1.70 (dd, J = 9.2, 4.5 Hz, 1H), 1.47 (br. s., 1H), 1.27 (dd, J = 6.6, 4.5 13 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3)173.8, 135.5, 131.0, 128.2, 127.4, 62.4, 61.1, 33.8, 29.5, 18.1, 14.1; MS (ESI) m/z 221.1 [M + H]+ 243.1 [M + Na]+. (1R,5S)-1- 234 1 phenyl-3-oxabicyclo[3.1.0]hexan-2-one 514: H NMR (300MHz, CDCl3) δ 7.80-6.86 (m, 5H),

171

4.47 (dd, J = 9.2, 4.7 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 2.55 (ddd, J = 7.9, 4.8, 4.7 Hz, 1H), 1.65 (dd, J = 7.9, 4.8 Hz, 1H), 1.58 (br. s., 1H), 1.36 (dd, J = 4.8, 4.8 Hz, 1H); 13C NMR δ 175.9, 134.1, 128.6, 128.3, 127.7, 68.0, 31.7, 25.1, 20.2; FT-IR (neat) 3060, 2973, 2907, 1758, 1602 cm-1; MS (ESI) m/z 175.0 [M + H]+ 197.0 [M + Na]+.

(1S,2S,3R)-Ethyl 2-(hydroxymethyl)-3-phenylcyclopropanecarboxylate (515). A solution of LiHMDS in THF (1 M, 2.40 mL) was added to THF (17.6 mL) and a solution of 511 (441 mg, 2.0 mmol) in THF (10 mL) was then added rapidly. At the end of the addition the reaction was immediately quenched with Amberlite® IRP-69 ion exchange resin and filtered through Celite. The filtrate was concentrated and the residue purified by column chromatography (1:9 ethyl acetate/hexanes) to give 515 (356 mg, 81%) as well as its O-trimethylsilyl ether derivative 516 17 1 (61 mg, 10%) as colourless syrups; 515: [α]D -150 (c 1.70, DCM); H NMR (500MHz, CDCl3) δ 7.26-7.20 (m, 2H), 7.20-7.10 (m, 3H), 4.10 (q, J = 7.2 Hz, 2H), 3.38 (dd, J = 7.0, 7.0 Hz, 1H), 3.35 (dd, J = 7.0, 7.0 Hz, 1H), 2.81 (dd, J = 9.3, 5.3 Hz, 1H), 2.04 (dd, J = 5.3, 4.9 Hz, 1H), 2.01 (dddd, J = 9.3, 7.0, 7.0, 4.9 Hz, 1H), 1.48 (br. s., 1H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (125

MHz, CDCl3) δ 173.0, 135.4, 128.7, 128.5, 126.9, 60.85, 60.8, 30.4, 30.0, 23.5, 14.2; FT-IR (neat) 3423, 3027, 2981, 1720, 1602, 1176 cm-1; MS (ESI) m/z 221.1 [M + H]+ 243.1 [M + + + Na] ; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C13H16O3Na 243.0997; Found 243.0988.

(1S,2S,3R)-Ethyl 2-(trimethylsilyloxymethyl)-3-phenylcyclopropanecarboxylate (516). 18 1 [α]D -92.2 (c 0.51, DCM); H NMR (500MHz, C6D6) δ 7.11-6.96 (m, 5H), 3.99 (q, J = 7.1 Hz, 2H), 3.31 (dd, J = 7.0, 7.0 Hz, 1H), 3.28 (dd, J = 7.0, 7.0 Hz, 1H), 2.98 (dd, J = 9.5, 5.2 Hz, 1H), 2.23 (dddd, J = 9.5, 7.0, 7.0, 4.9 Hz, 1H), 2.15 (dd, J = 5.2, 4.9 Hz, 1H), 0.98 (t, J = 7.2 Hz, 3H), -0.07 (s, 9H); FT-IR (neat) 3072, 3023, 2956, 2871, 1727, 1251, 1179 cm-1; 13C NMR (125

MHz, CDCl3) δ 173.2, 135.7, 129.0, 128.2, 126.7, 60.7, 60.5, 30.8, 30.0, 23.7, 14.2, -0.7; MS (ESI) m/z 293.1 [M + H]+ 315.1 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for

C16H24O3NaSi 315.1392; Found 315.1403.

(1R,5S,6S)-6-phenyl-3-oxabicyclo[3.1.0]hexan-2-one (519).241

512 (123 mg, 0.56 mmol) was treated as per the method for 515 to give 519 as a crystalline solid 17 1 (65 mg, 64%); mp 122-123 °C; [α]D +130 (c 0.50, CHCl3); H NMR (500MHz , CDCl3) δ 7.27-7.21 (m, 2H), 7.20-7.14 (m, 1H), 7.02-6.97 (m, 2H), 4.39 (dd, J = 9.5, 4.6 Hz, 1H), 4.34 (br. d, J = 9.5 Hz, 1H), 2.48-2.44 (m, 1H), 2.2 -2.23 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 174.9, 137.2, 128.7, 127.1, 125.9, 69.7, 29.3, 27.4, 26.1; FT-IR (neat) 3068, 2963, 2905, 1737, 1602 cm-1; MS (ESI) m/z 197.1 [M + Na]+. 172

((1S,2S,3R)-2-(hydroxymethyl)-3-phenylcyclopropyl)(morpholino)methanone (522).247 To a solution of 514 (67 mg, 0.30 mmol) in 1:1 THF/H2O (2 mL) was added NaOH (25 mg, 0.61 mmol) and the mixture heated for 20 minutes. A solution of HCl (1 M, 3 mL) was added and then the mixture concentrated under reduced pressure to give the crude carboxylic acid and NaCl. The residue was taken up in warm DCM (2 mL) and insoluble material removed by filtration. To the solution of the carboxylic acid were added morpholine (35 µL, 0.37 mmol), then PyBOP (190 mg, 0.37 mmol) and DIPEA (140 µL, 0.84 mmol) and the reaction mixture immediately applied to a column of silica and eluted with 3:17 methanol/ethyl acetate. Concentration of the appropriate fractions gave 522 as a colourless syrup (71 mg, 89%); 1H

NMR (500MHz ,CDCl3) δ 7.44-7.04 (m, 5H), 3.64 (br. s., 8H), 3.52 (dd, J = 11.6, 7.0 Hz, 1H), 3.30 (dd, J = 11.6, 7.3 Hz, 1H), 2.81 (dd, J = 9.6, 4.6 Hz, 1H), 2.64 (br. s., 1H), 2.18 (dd, J = 4.6, 13 4.6 Hz, 1H), 2.02 (dddd, J = 9.5, 7.3, 7.0, 4.6 Hz, 1H); C NMR (125 MHz, CDCl3) 170.5, 136.2, 128.6, 128.5, 126.8, 66.7 (2C), 60.8, 29.8, 29.3, 22.2.

173

Publications arising from work Stockton, K. P.; Greatrex, B. W.*; Taylor, D. K., Synthesis of allo- and epi-Inositol via the NHC-Catalyzed Carbocyclization of Carbohydrate-Derived Dialdehydes. J. Org. Chem 2014, 79, 5088-5096.

Stockton, K. P.; Glover, S. A.; Greatrex, B. W.*, Nucleophilic Trapping of Alkoxy-Stabilized Oxyallyl Systems Generated from Inosose 2-O-Mesylates. Synlett 2015, 26, 111-115.

Stockton, K.P.; Merritt C.J.; Sumby C.J., Greatrex, B.W.*, Palladium-Catalyzed Suzuki- Miyaura, Heck and Hydroarylation Reactions on (-)-Levoglucosenone and Application to the Synthesis of Chiral δ-Butyrolactones. European J. Org. Chem.. 2015 (manuscript accepted 4th September 2015).

Publications in preparation

Stockton, K.P.; Greatrex B.W.*, The synthesis of enantiopure cyclopropyl esters and both enantiomers of trans-2-(aminomethyl)cyclopropanecarboxylic acid (TAMP) from (-)- levoglucosenone.

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Appendix Compound 315a 315b 315d 316h 317i 390a

Empirical formula C12H10O3 C13H10O5 C12H7F3O3 C13H12O3 C14H14O5 C12H12O3 Formula weight 202.20 246.21 256.18 216.23 262.25 204.22 Crystal system Monoclinic Orthorhombic Monoclinic Orthorhombic Orthorhombic Monoclinic Space group P21 P212121 P21 P212121 P212121 P21 a (Å) 10.4550(2) 6.9964(2) 7.5899(3) 7.1651(3) 7.0634(6) 5.5440(2) b (Å) 9.4510(2) 9.3253(2) 6.9417(3) 8.1480(3) 10.2571(10) 12.6708(4) c (Å) 14.7548(3) 16.0267(4) 10.0031(3) 18.6623(7) 17.1587(14) 7.1607(3)  (º) 90 90 90 90 90 90  (º) 94.632(2) 90 100.865(3) 90 90 100.595(4)  (º) 90 90 90 90 90 90 Volume (Å3) 1453.16(5) 1045.64(5) 517.58(3) 1089.53(7) 1243.15(19) 494.44(3) Z 6 4 2 4 4 2 Density (calc.) (Mg/m3) 1.386 1.564 1.644 1.318 1.401 1.372 Absorption coefficient (mm-1) 0.100 0.122 0.152 0.093 0.107 0.098 F(000) 636 512 260 456 552 216 Crystal size (mm3) 0.55×0.43×0.21 0.61×0.42×0.29 0.86×0.58×0.31 0.57×0.40×0.27 0.56×0.22×0.10 0.53×0.40×0.33  range for data collection (º) 2.48 to 29.29 2.53 to 29.16 3.10 to 29.16 2.73 to 29.23 3.10 to 29.22 2.63 to 29.27 Reflections collected 27094 10977 9991 11846 9796 5764 Observed reflections [R(int)] 7020 [0.0380] 2545 [0.0323] 2499 [0.0337] 2683 [0.0300] 2980 [0.0396] 2294 [0.0496] Goodness-of-fit on F2 1.063 1.052 1.048 1.038 1.043 1.072 R1 [I>2(I)] 0.0469 0.0363 0.0344 0.0385 0.0418 0.0415 wR2 (all data) 0.1196 0.0859 0.0749 0.0915 0.0968 0.0930 Largest diff. peak and hole (e.Å-3) 0.372 and - 0.192 and - 0.225 and - 0.209 and - 0.252 and - 0.167 and - 0.232 0.314 0.212 0.229 0.273 0.199 Table 11 X-Ray Experimental data for 315a, 315b, 315d, 316h, 317i, and 390a from Chapter 3

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