Organosulfur Compounds 21 Cchiral hydroxy sulfides and derivatives

Searching for a method of synthesis of enantiopure lamivudine 1, the compound having a monothioacetal stereogenic centre, Rayner et al. investigated a lipase-catalysed hydrolysis of various racemic a-acetoxysulfides 2. They found out that the reaction was both chemoselective (only the acetate group was hydrolysed with no detectable hydrolysis of the other ester moieties) and stereoselective. As a result of the kinetic resolution, enantiomerically enriched unreacted starting compounds were obtained. However, the hydrolysis products 3 were lost due to decomposition.4 In this way, the product yields could not exceed 50% (Equation 1). The product 2 (R = CH2CH(OEt)2) was finally transformed into lamivudine 1 and its 4-epimer.5

When a reverse procedure was applied, i.e. enzymatic acetylation of racemic 3, formed in situ from the appropriate aldehydes and thiols, the reaction proceeded under the conditions of dynamic kinetic resolution and gave enantiomerically enriched acetates 2 with 65-90% yields and with ees up to 95% (Equation 2).6 It must be mentioned that the addition of silica proved crucial, as in its absence no racemization of the initially formed substrates 3 occurred and the reaction stopped at the 50% conversion.

When a, (-diacetoxysulfides 2, R1 = AcOCH2, were subjected to enzymemediated hydrolysis under kinetic resolution conditions, a completely regioselec-tive for the primary acetyl group and highly enantioselective reaction occurred (Equation 3).7

In the compounds discussed above, the sulfur atom was attached directly to the stereogenic carbon atom. However, some structures that have remote sulfur moieties are also worth mentioning. The approach to their synthesis was based on the use of fermenting baker's yeast as the reducing agent of the keto group present in the substrate (for reviews see Refs. 8 and 9). In this way, a variety of P-hydroxyalkyl sulfides were obtained in reasonable to good yields and with good to excellent enantiomeric excesses (e.g. Equation 4), although a low concentration of the substrates had to be applied.10-13

P-Keto dithioacetals were similarly transformed to non-racemic (3-hydroxy derivatives (e.g. Equation 5).14-18 In general, the reaction rate and stereochemical outcome depended on the hydrocarbon chain length and the type of the substituents in the substrate.

C-chiral racemic 7-hydroxy sulfides were also resolved using PFL under kinetic resolution conditions. The products were transformed into optically active 3-(alkanesulfonyloxy)thiolane salts (Scheme 1).19a Similarly, 1,2-cyclic sulfite glycerol derivatives (cis and trans) were resolved into enantiomers via a Pseudomonas cepacia-catalysed acylation with vinyl butyrate. The E values depended on the solvent used and varied from 2 to 26.19b

Scheme 1

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