Synthesis and beta-lactamase inhibitory activity of thiazolyl penam sulfones.

In our previous papers1»2), we described the structure-activity relationships of 6-(heterocyclyl)methylene penam sulfones (1) as a new class of /3-lactamase inhibitors and proposed a mechanism of enzyme inactivation for series 1. In continuation of these studies with series 1, we pursued the closely related structures in series 2, since they should follow a similar mechanistic pathway and should also act as good suicide inhibitors. Here, we report the syntheses of 2 and their synergy and /3-lactamase inhibition data. Preparation of the 6a-isomers in series 2 is illustrated in Scheme 1. Starting material, 6abromopenicillanate 3, is readily prepared by esterification of the corresponding acid3). Transmetallation of 6a-bromopenicillanate 3 by exchange with 1 eq of methylmagnesium bromide in THF at -78°C, followed by reaction with thiazole 2-carboxyaldehyde afforded a 55 %-yield of a separable 2: 1 mixture of diastereomers (6a,SR) 4 and (6a,$S) 5, respectively^. Compounds 4 and 5 were acylated using several reagents, e.g. acetic anhydride, benzoyl chloride, ethyl chloroformate, or methyl isocyanate, in the presence of pyridine in methylene chloride at room temperature to afford 6 and 7, respectively. The (6a,SR) fluoro derivative 6g was prepared in 55% yield by displacement reaction^ of the (6a,8$) hydroxy compound 5 with diethylaminosulfur trifluoride in methylene chloride. Removal of the protecting group was accomplished as indicated in Scheme 1 to give the final compounds 2. The corresponding 6/3-isomer was prepared via an aldol condensation as outlined in Scheme 2. 6,6-Dibromopenicillanate 8, prepared by esterification of the corresponding acid3) , reacted with 1 eq of methylmagnesium bromide, followed by reaction with thiazole 2-carboxyaldehyde, gave a mixture of hydroxy adducts. Acetylation of this mixture, followed by stereoselective reduction with tin hydride5), afforded a 95 :5 mixture of diastereomers (6/3,8i?) 9 and (6/5,8*S) 10. The major isomer 9 was isolated in 50% yield, starting from 8, as crystals, mp 185°C (dec), by recrystallization from ether. Hy-