SYNTHESIS AND POLYMERIZATION OF BENZYL (3R,4R)-3-METHYLMALOLACTONATE VIA ENZYMATIC PREPARATION OF THE CHIRAL PRECURSOR

beta-methylaspartate ammonia-lyase, EC 4.3.1.2, (beta-methylaspartase) from Clostridium tetanomorphum was used to produce a 40/60 molar rati o of (2S,3R) and (2S,3S)-3-methylaspartic acids, 2a and 2b, respective ly, from mesaconic acid 1 as substrate, on a large scale. To prepare ( 3R-4R)-3-methyl-4-(benzyloxycarbonyl)-2-oxetanone (benzyl 3-methylmalo lactonate) 6, 2a and 2b were transformed, in the first step, into 2-br omo-3-methylsuccinic acids a and 3b and separated. After three further steps, (2S,3S)-3a yielded the alpha,beta-substituted beta-lactone (3R -4R) 6 with a very high diastereoisomeric excess (>95% by chiral gas c hromatography). The corresponding crystalline polymer, poly[benzyl bet a-(2R,3S)-3-methylmalate] 8, prepared by an anionic ring opening polym erization, was highly isotactic as determined by C-13 NMR. Catalytic h ydrogenolysis of lactone 6 yielded (3R,4R)-3-methyl-4-carboxy-2-oxetan one (3-methylmalolactonic acid) 7, to which reactive, chiral, or bioac tive molecules can be attached through ester bonds leading to polymers with possible therapeutic applications. Because of the ability of bet a-methylaspartase to catalyse both syn- and anti-elimination of ammoni a from (2S,3RS)3-methylaspartic acid 2ab at different rates, the (2S,3 R)-stereoisomer 2a was retained and isolated for further reactions, Th ese results permit the use of the chemoenzymatic route for the prepara tion of both optically active and racemic polymers of S-methylmalic ac id with well-defined enantiomeric and diastereoisomeric compositions. (C) 1998 Wiley-l.iss, Inc.