Synthesis of optically active 3'-nor-type 1-oxacephems from 6-APA was described. R-Nitrobenzyl 7B-amino-3-chloro-7a-methoxy-l-oxa-3-cephem-4-carboxylate 39 was also prepared.
et al. 2a described that some 3-norcephalosporins showed antibacterial activity equivalent to naturally occurring cephalosporins, among which 7-(D-Z-amino-2_phenylacetamido)-3-chlor-3-cephem-4-carboxylic acid 1. (Cefaclor) 2b is found to have an antibacterial activity higher than Cefalexin 2 (X = Me), a widely used oral cephalosporin. It has been known that replacement of the sulfur atom at position 1 of the cephem nucleus with oxygen enhances the biological activity. 3a,b To date, however, there is no report on synthesis of an optically active 3'-nor-type 1-oxacephem nucleus except an ambiguous synthesis reported in the patent literature. 4 We have succeeded in synthesizing the 3-hydroxy-1-oxacephem nucleus and some 3'nor-type derivatives. 5 Our synthetic plan is to use the azetidinone propargyl ether 2 derived from 6-APA as the starting material and to apply the intramolecular Wittig reaction to an activated carboxylic acid for constructing the desired 3-hydroxy-1-oxacephem nucleus. 1, X=CI 2, X=Me NH, 0 3 C4CHPb -Preparation of azetidinone Lfrom C-APA has already been reported from our laboratories.5 Compound A6 prepared from 2 was selectively hydrogenated (Pd-C, CaC03, MeOH) to allylic ether 5 (98%), which was treated with mCPBA to give epoxide 5 (81.2%). An isomeric mixture of glycols 8 was obtained in 94% yield on treating 5 with HC104 in aqueous acetone followed by hydrolysis of the partially formed acetonide I. Oxidative cleavage of 8 with HI04 afforded aldehyde 2, which was subsequently submitted to further oxidation (Cr03, acetone) to the carboxylic acid 10 (92%). -The isopropylideneacetate moiety of methyl ester 117 -obtained from 10 (CH2N2, CH2C12) was converted into the triphenylphosphoranylideneacetate group by the procedure established in our laboratories, 8 involving ozonolysis and successive reduction (03, -78'C, CH2C12; then En, HOAc, -50°C to ambient temp) to a 1:l mixture of epimeric alcohols 12, chlorination of 12 (3 mol equiv SOC12, pyridine, CH2C12, O'C, 30 min) to a mixture of chlorides I3, and treatment with