Methyl -4-chloro-3-hydroxybutanoate

To a solution of methyl 4-chloro-3-hydroxybutanoate (0.50 g, 3.3 mmol) in 62 ml tris-SO4 buffer (0.5 m, pH 7.5) NaCN was added (322 mg, 6.6 mmol), followed by addition of purified HheC-W249F halohydrin dehalogenase (15 mg in 3 ml buffer). The resulting mixture was stirred at ambient temperature (22 °C) for 5 h. 

All of these reactions may be repeated starting with methyl (2/ ,3f )-3-hydroxy-2-methylbutanoate (9a) which is obtained, as shown in Scheme 2, by the double deprotonation of methyl 3-hydroxybutanoate (2b) using lithium di-isopropylamide (LDA) to give the alkoxide-enolate (8) and alkylation with a methyl halide in THF at —After reduction with lithium aluminium hydride, tosyla-tion of the alcohol group and nucleophilic attack by lithium chloride, the (2f ,3f )-l-chloro-2-methyl-3-butanol (10) is available for the sequential metallation reactions and conversion to 1,4-diols or lactones. 

Synthesis of Methyl (S)-4-Chloro-3- and Methyl (S)-4-Cyano-3-hydroxybutanoate 199... 

S)-4-Chloro-3-hydroxybutanoic acid methyl ester 59 (Figure 16.16) is a key chiral intermediate in the total chemical synthesis of 60, a cholesterol antagonist that acts by inhibiting hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase [89,90]. The reduction of 4-chloro-3-oxobutanoic acid methyl ester 61 to (S)-59 has been demonstrated by cell suspensions of Geotrichum candidum SC 5469. In the biotransformation process, a reaction yield of 95% and EE of 96% were obtained for (S)-59 at 10 g/L substrate input. The EE of (S)-59 was increased to 98% by heat treatment of cell suspensions (55°C for 30 min) prior to conducting the bioreduction of 61 [91]. 

FIGURE 16.16 Anticholesterol drug 60. Preparation of (5)-4-chloro-3-hydroxybutanoic acid methyl ester 59. 

E. coli cells containing recombinant KER converts BAM into the (S)-form of methyl 4-bromo-3-hydroxybutanoate (BHBM) with 97.1% ee, and CAE into methyl (S)-4-chloro-3-hydroxybutanoate (CHBE) with 63.1% ee, indicating a little dissatisfied result for ee of produced chiral alcohols. 

---