Asymmetric synthesis of azidotetrahydropyranols via Sharpless epoxidation

An approach to the synthesis of enantiomerically pure azidotetrahydropyranols 4 involving stereospecific reduction of propargylic alcohol 7 followed by Sharpless epoxidation of the resultant alllyic alcohols 8 and 12 is presented. Epoxide 10 undergoes ring opening with trimethyl orthoformate whereas epoxide 15 undergoes the expected ring opening with azide


Introduction
The use of enzymes in the synthesis of complex molecules has received much attention over the last 20 years.In particular, the employment of various aldolase enzymes in the synthesis of natural and non-natural carbohydrates has been demonstrated by a number of groups. 1 Our own contribution to this area (Scheme 1) involved a chemoenzymatic synthesis of β-homonojirimycin 1 via the rabbit muscle aldolase (RAMA) catalysed reaction of hemiacetal 2 with dihydroxyacetone phosphate to give azidoheptulose 3 followed by catalytic hydrogenation to give 1.The hemiacetal 2 was prepared as a single enantiomer by Sharpless epoxidation and during this work it was found that hemiacetals such as 2 are better substrates for RAMA than the corresponding open chain hydroxy-protected aldehydes.These results stand in contrast to the results obtained by Bednarski who investigated the use of natural hemiacetals as substrates for RAMA.They found that D-erythrose, D-ribose, D-arabinose and D-glucose are all very poor substrates for RAMA reacting at less than 1% of the rate of propanal. 3In order to further test our approach and to explore the rate enhamcement we had found with hemiacetals, we decided to prepare homologues of 2 based on the 4-azido-3-hydroxytetrahydropyranol system 4.If successful as substrates for RAMA, a new series of aza-sugar analogues could be prepared.

Result and Discussion
Our approach to the target molecules 4 was based on our previous synthesis of hemiacetals 2. This required a stereospecific synthesis of both the cisand trans-5-protected pent-2-ene-1,5diols (Scheme 2).Protection of 3-butynol 5 with t-butyldiphenylsilyl chloride following the procedure of Wipf 4 gave silyl ether 6 in 92% yield.Earlier studies using the t-butyldimethylsilyl protecting group had indicated that a more stable silyl ether was required to survive the subsequent synthetic steps intact.Generation of the acetylenic anion with n-butyllithium in THF at -23 °C followed by addition of dry paraformaldehyde 5 gave the monoprotected diol 7 in 86% yield.Reduction to the cis-alkene was first attempted using the conditions of Takano 6 involving Lindlar's catalyst and an excess of quinoline led to a 2:1 mixture of the cisand trans-alkenes.A non-stereospecific reduction of a propargylsilane has been reported previously 7 using a similar catalyst system.After a number of experiments, it was found that replacing the quinoline with pyridine gave the cis-alkene 8 in 96% yield as a single stereoisomer.The coupling constant for the alkene protons (10 Hz) confirmed the stereochemistry.
Sharpless epoxidation 8 of the cis-allylic alcohol 8 was carried out using (-)-diethyl tartrate under the usual conditions to give the epoxide 9 in excellent chemical yield.The optical purity of 9 was assessed by formation of the Mosher's ester (100% yield) and examination of the 19 F nmr spectrum.The major diastereoisomer showed a resonance at δ F -72.16 and the minor diastereoisomer a resonance at δ F -72.22.The relative integration was 88.5:11.5 indicating an enantiomeric excess of 77%.The absolute stereochemistry is assigned based on well-established precedent from the work of Sharpless. 9Oxidation of the epoxyalcohol 9 to the aldehyde 10 was best carried out using tetrapropylammonium perruthenate (TPAP) 10 with N-methylmorpholine-N-oxide as the stoichiometric oxidant to give the rather unstable aldehyde 10 in 80% yield.The next step in our synthesis involved the protection of the aldehyde as its dimethyl acetal in order to allow opening of the epoxide by azide at the 3-position, remote from the acetal. 2Treatment of epoxyaldehyde 10 with trimethylorthoformate in the presence of Amberlyst resin did not give the desired epoxyacetal but instead proceeded with ring opening of the epoxide by the methanol produced in the reaction to give the ether acetal 11 (scheme 3) in 86% yield.The assignment of this structure to the product was based on the appearance of an extra singlet at δ 3.39 in the 1 H nmr and a broad singlet at δ 2.4 corresponding to an OH proton.The FAB mass spectrum also showed a strong peak at m/z 455 corresponding to (M+Na) + and the infra-red spectrum confirmed the presence of an O-H group.Furthermore treatment with azide under conditions for opening the epoxide gave only starting material as would be expected for ether 11.Both the regio-and stereochemistry assigned to 11 is based on the expected site of reaction and the known mode of epoxide ring opening.We cannot exclude the possibility that the methanol ring opens the epoxide at C-2 although this seems unlikely on electronic grounds. 2 Scheme 2. Reagents: (i).TBDPS-Cl, imidazole, DMAP, DMF, 92%; (ii).n-BuLi, THF, -23 °C, then paraformaldehyde, 86%; (iii).H 2 , Pd/BaSO 4 , pyridine, 96%; (iv).(-)-diethyl tartarte, Ti(OiPr) 4 , tBuOOH, mol.sieves, CH 2 Cl 2 , 88%, 77% ee; (v).TPAP, NMMO, mol.sieves, CH 2 Cl 2 , 80%.
Faced with this unexpected result, we turned our attention to the trans-allylic alcohol.Reaction of propargyl alcohol 7 with lithium aluminium hydride gave the trans-allylic alcohol 12 in 76% yield.The two alkene protons overlap in the 1 H nmr and hence it was impossible to ascertain the stereochemistry from the coupling constants.Nevertheless, the spectral data were entirely consistent with the gross structure and it was clear from the data for cis-alcohol 8 that this was a stereoisomer.Sharpless epoxidation of trans-allylic alcohol 12 using (-)diethyl tartrate gave the epoxide 13 in 86% yield.The enantiomeric purity of 13 was again assessed by conversion into its Mosher's ester derivative.The 19 F nmr of the crude derivative showed two peaks at δ F -72.21 and -72.01 integrating in a ratio of 97.5:2.5 indicating an enantiomeric excess of 95%.In order to confirm this result, the racemic epoxide was prepared using m-chloroperoxybenzoic acid and its Mosher's derivative synthesised.The spectral data for this compound confirmed our assignment of the two resonances in the 19 F nmr.The stereochemistry assigned to 13 is based on literature precedent again.Oxidation to the aldehyde 14 proceeded smoothly using TPAP and NMMO in 80% and this somewhat unstable compound was reacted with trimethyl orthoformate to give the dimethyl acetal 15 in 85% yield.In the case of this diastereoisomeric epoxide, no ring opening of the epoxide was observed in contrast to the outcome of the same reaction on epoxyaldehyde 10.The epoxide was then ring opened using sodium azide in methanol/water to give azido alcohol 16 in 74% yield.Confirmation of the regiochemistry of ring opening was obtained by acetylation of the hydroxy group in 16 to give acetate 17.The 1 H nmr of 17 showed that the original multiplet assigned to the C-2 proton at δ 3.74-3.77had moved downfield to δ 5.12 and had become a dd.Meanwhile the ddd assigned to the C-3 proton moved from δ 3.86 (in 16) to δ 3.94 (in 17).This result agrees with the previous studies on the butane diol system. 2 The final steps in iii iv v vi the preparation of 4 simply involved hydrolysis of the acetal and removal of the silyl protecting group (scheme 5).This gave the [3S, 4S]-isomer of 4 as a mixture of anomers.Unfortunately, this anomeric mixture led to a very complex 1 H nmr with only the anomeric proton clearly visible as a doublet (J 5 Hz) at δ 5.00 for the major anomer and a broad singlet at δ 4.79 for the minor anomer.The ratio of the two anomers was 2.9:1.The 13 C nmr was more useful for characterisation but the hemiacetals were characterised by conversion into the methyl acetals 18.Although the 1 H nmr of the mixture of methyl acetals was considerably clearer it was not possible to derive the conformation of the tetrahydropyran ring owing to overlapping signals.However, for both anomers, the C-2 proton appeared as a doublet with J 3.6 and 2.9 Hz for major and minor anomer respectively indicating the C-3 hydroxy group is probably axial in both isomers.
In summary, we have been able to prepare one of the diastereoisomeric azido tetrahydropyranols for use in the RAMA-catalysed reaction with dihydroxyacetone phosphate but this route appears not to be general as was the case for the butane diol series. 4.To a cooled (0 ˚C) and stirring solution of 3butyn-1-ol (2.10 g, 30.0 mmol) in dry dichloromethane (60 ml) was added, tertbutyldiphenylsilyloxy chloride (8.52 g, 7.95 ml, 31.0 mmol) over a 10 minute period.Imidazole (2.86 g, 42.0 mmol) was then added in one portion followed by 4-dimethylaminopyridine (0.37 g, 3.00 mmol) and the resultant mixture stirred at RT overnight.The white precipitate produced was filtered through a sintered funnel and washed with cold dichloromethane (50 ml).The combined filtrates was then washed with a 1 M aqueous HCl solution (50 ml) and water (100 ml) successively.The organic layer dried and the solvent removed in vacuo and the residue purified