摘要：

J. CHEM. SOC. PERKIN TRANS. 1 1993 Microbial Generation of (2R.3S)-and (2S,3S)-Ethyl 2-Benzamidomethyl- 3-hydroxybutyrate, a Key Intermediate in the Synthesis of (3S,1'R)-3-(1'-Hydroxyethy1)azetid i n -Zone Claudio FugantP Simonetta LanaWj Stefan0 Servi,a Auro Tagliani,a Angelo Bedeschi and Giovanni Franceschib a Dipartimento di Chimica del Politecnico, Centro CNR per la Chimica delle Sostanze Organiche Naturali, Via Mancinelli 7, 20737 Milano, Italy Farmitalia-Carlo Erba R & D, Via Giovanni XXIII 23, 20014 Nerviano, Milano, Italy Microbial reduction of the carbonyl group of the substituted acetoacetate esters 3-6 affords directly, or after Ni-Raney desulfurization. the corresponding enantiomerically pure 3s carbinols of variable diastereoisomeric composition.These compounds are transformed into (3S.1'R) -3-(I '-hydroxyethyl) -azetidin-2-one, a useful intermediate in the synthesis of p-lactam antibiotics. Since the importance of P-lactam antibiotics is well recognized, a chiral intermediate such as (3R, 1'R)-4-acyloxy-3-(1'-hydroxy-ethyl)azetidin-2-one 1 possessing the stereochemical features required for their preparation is of considerable interest. Such key intermediates are currently accessible from various chiral synthons such as L-aspartic acid,2" 2-benzamidomethyl-3- hydroxybutyrate 2b and (3 R)-hydroxybutrate 2c or through synthetic sequences followed by classical resolution of the racemic intermediate. 2d Since functionalization of the p-lactam nucleus at position 4 in compound 2 can be effected by radical ~xidation,~compound 2 itself is, in fact, also to be considered as a key intermediate in the above mentioned synthetic path.Compound 2 can be considered as derived from a suitable open-chain mubstituted P-hydroxy ester of type 14, itself available from the keto ester of the corresponding structure. A recent patent report refers to the utility of ethyl (2RS,2S)-2- benzamidomethyl-3-hydroxybutyrate11, obtained by baker's yeast (BY) treatment of 3, in the synthesis of (3S,l'R)-3-(1'- hydroxyethyl)azetidin-2-one 2. Product 2 is actually obtained from 14, prepared from 11, the actual product of the microbial reduction, by inversion of configuration at C-3 through conver- sion in to e thy1 trans-(5S,6R)-6-rnethyl-2-phenyl- 5,6-di hydro -1,3-0xazine-5-carboxyate,followed by acid hydrolysis.The microbial reduction affords the required compound with R absolute configuration at C-3, the reverse of that in 2. %H0 1 2 Microbial reduction of P-keto esters has been extensively studied, the 3-hydroxy esters of both enantiomeric forms being obtained by appropriate substrate modification at both ends of the molecule, or making use of additives in order to direct competitive enzymatic reactions.' In the case of racemic a-substituted P-keto esters of various origin, the prediction of the course of the reaction is less obvious, incomplete enantio- and/or diastereo-selection usually being achieved. In this particular field, however, excellent results have been obtained by catalytic asymmetric reduction.6 With the aim of improving efficiency in obtaining 2, we have investigated the mode of microbial reduction of a series of potential precursors, and devised an approach alternative to the one reported for inversion of configuration, if required, of the hydroxy ester obtained. In the first instance we submitted 3 to the action of a set of growing microorganisms, including the two strains of Geotrichum candidum which reduce ethyl 3-oxobutyrate to (S)-and (R)-ethyl 3-hydroxybutyrate, respectively.8 Identification of the transformation products was achieved by HPLC on a chiral column 7 and direct comparison with authentic (2R,3S)- 12 and (2S,3S)-13, obtained from 3 by BY treatment,, and rac-11, prepared from 3 by NaBH, reduction.The steric outcome of the microbial reduction of 3 is reported in Table 1. Inspection of the results indicates that two enantiomerically pure diastereoisomers are obtained, all possessing the 3S configuration. In only a few instances enhanced syn and anti diaster

展开