Lipase catalysis in the resolution of racemic intermediates of diltiazem synthesis in organic solvents (original) (raw)

1993, Journal of the Chemical Society, Perkin Transactions 1

The key intermediates of the diltiatem synthesis, methyl trans-3-(4-methoxyphenyl)glycidate 1 and methyl threo-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylthio) propionate 2, have been successfully resolved by using lipase catalysis in organic solvents. In the resolution of the glycidate 1, enzymatic enantioselectivity greatly depends on the solvent, tertiary alcohols leading to the highest optical purities of the products: e.e. close to 90% at 60% conversion for the unchanged (2R,3S)enantiomer and over 90% for the new (2S,3R)-ester, when the first 20% of the product is formed, can be obtained. Ester hydrolysis takes place simultaneously with ester alcoholysis. The enzymatic acylation of compound 2 with acid anhydrides or vinyl esters in THF tends to stop at 50% conversion, yielding the t w o enantiomers with an e.e. of the order of 100%. The enantiomers can be easily separated by flash chromatography. Dil t iazem , (+)-cis-(2 S, 3 S)-3-ace t O X~-5-[ 2-(dime t hy1amino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one 3 (Scheme l), is one of the most potent calcium-'c02Me ONo2 nitropheny1thio)propionate 2 and ester hydrolysis. Finally, acetylation and N-alkylation complete the synthesk6 An approach to optically active compound 3 usually involves either an asymmetric synthesis or a chemical or biocatalytic resolution of one of the key intermediates 1 or 2. The asymmetric Darzens c~ndensation,~*' the Sharpless asymmetric epoxidation * and a stereospecific synthesis through vicinal diols' have been successfully used to obtain optically active glycidate 1 or its derivative. The lipase-catalysed hydrolysis of ester 1 '