Cchiral hydroxyalkyl sulfones

Chiral hydroxyalkyl sulfones are usually secondary alcohols and as such can be obtained in their non-racemic forms using general methods developed for these classes of compounds. Among the biocatalytic methods, two approaches were applied: microbiological reductions of the corresponding keto sulfones 5 and resolution of racemic hydroxyalkyl sulfones 6. In the former case, the earliest procedures utilized fermenting baker's yeast as the reducing agent,1011 which gave the products in high yields and with high enantiomeric excess. However, this method allowed to obtain only one enantiomer of a hydroxyalkyl sulfone - for P- and 7-hydroxyalkyl sulfones it is the (S)-enantiomer.1011'20'21 The same result was obtained using Corynebacterium equi22 and the fungus Aspergillus niger20'22 However, the (R)-enantiomers were produced during the reduction carried out with other fungi, namely Geotrichum candidum and, with somewhat inferior results, Mortierella isabellina (Equation 6).20 The ees of the products were strongly dependent on the length of the alkyl group R - the longer the chain the lower the ee value.10'21'23 The same influence was exerted by the phenyl group, although changing Baker's yeast for Saccharomyces kyokai 7 gave the opposite enantiomer, i.e. (R)-6, R = Ph.24

Another approach to the synthesis of chiral non-racemic hydroxyalkyl sul-fones used enzyme-catalysed kinetic resolution of racemic substrates. In the first attempt, Porcine pancreas lipase was applied to acylate racemic P, 7 and 8-hydroxyalkyl sulfones using trichloroethyl butyrate. Although both enantiomers of the products could be obtained, their enantiomeric excesses were only low to moderate.25 Recently, we have found that a stereoselective acetylation of racemic P-hydroxyalkyl sulfones can be successfully carried out using several lipases, among which CAL-B and lipase PS (AMANO) proved most efficient.26 Moreover, application of a dynamic kinetic resolution procedure, in which lipase-promoted kinetic resolution was combined with a concomitant ruthenium-catalysed27 racem-ization of the substrates, gave the corresponding P-acetoxyalkyl sulfones 8 in yields higher than 50% and with ees up to 99%. Also, in this case, the length of the alkyl chain proved crucial - only the compounds with the methyl or ethyl group attached to the stereogenic carbon atom were accepted by the enzymes. The acetates 8 were then quantitatively reduced to the corresponding ^-hydroxyalkyl sul-fones 7 by treatment with the borane/dimethyl sulfide complex (Equation 7, Table 1).26

Table 1

Dynamic kinetic resolution of ß-hydroxyalkyl sulfones

Entry Ar R Lipase Acetate 8 Alcohol 7

Table 1

Dynamic kinetic resolution of ß-hydroxyalkyl sulfones

Entry Ar R Lipase Acetate 8 Alcohol 7

(%)

MD (CHCl3)

Md (CHCl3)

(%)

1

Ph

Me

CAL-B

66

-1.0

-12.0

>99

2

Ph

Me

PS

64

-1.1

-11.8

>99

3

p-Tol

Me

CAL-B

79

-1.1

-11.6

>99

4

p-Tol

Me

PS

75

-0.9

-10.3

90

5

Ph

Et

CAL-B

42

-4.4

-9.2

>99

6

Ph

Et

PS

34

-4.4

-9.2

>99

a-Hydroxyalkyl sulfones 10 resemble a-hydroxyalkyl sulfides 3 (Equation 1) in the sense that they are unstable in their unprotected form. Therefore, the enzyme-promoted hydrolysis of the corresponding racemic O-acetyl derivatives 9 led to optically active unreacted substrates, while the resulting hydroxyalkyl sulfones 10 underwent decomposition to sulfinic acids and aldehydes. An attempt to achieve a dynamic kinetic resolution based on the assumed reaction of sulfinic acids with aldehydes and subsequent acetylation of the resulting hydroxyalkyl sulfones 10 (similar to the procedure shown in Equation 2) failed due to the lack of formation of the latter under the conditions applied (Equation 8).28 It should be added that such a formation was reported in an early literature as an easy and efficient process.29

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