Microbial synthesis of chiral intermediates for ß-3-receptor agonists

Chiral intermediates were prepared by biocatalytic processes for the chemical synthesis of ß-3-receptor agonists. These include: (i) the microbial reduction of 4-benzyloxy-3-methanesulfonylamino-2'-bromoacetophenone 1to the corresponding (R)-alcohol 2by Spingomonas paucimobilisSC 16113. In the biotransformation process, a reaction yield of >85% and an optical purity of 99.5% were obtained for the desired (R)-alcohol 2; (ii) the enzymatic resolution of racemic a-methyl phenylalanine amide, 3, and a-methyl-4-hydroxy-phenylalanine amide, 5, by amidase from Mycobacterium neoaurumATCC 25795 to prepare the corresponding (S)-amino acids 4and 6. Reaction yields of 49.9 and 49 M% (theoretical maximum yield 50 M%) and optical purities of 99 and 94% were obtained for the desired (S)-amino acids 4and 6, respectively; (iii) the asymmetric hydrolysis of methyl-(4-methoxyphenyl)-propanedioic acid, ethyl diester, 7, to the corresponding (S)-monoester 8by pig liver esterase. A reaction yield of 96 M% and an optical purity of 96% were obtained for (S)-monoester 8when reactions were carried out in a biphasic system containing 10% ethanol at 10°C.