DEVELOPMENT OF PRACTICAL METHODS FOR ASYMMETRIC SYNTHESIS OF 1beta-METHYL ARBAPENEMS AS CANDIDATES FOR THE NEXT GENERATION OF ANTIBIOTICS

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Recently much attention has been focused on 1beta-methylcarbapenem antibiotics as the most promising candidates for the next generation of beta-lactam antibiotics. The main purpose of this project is to develop practical methods for asymmetric synthesis of the,1beta-methylcarbapenem key precursor.1. A highly stereocontrolled method has been developed for the asymmetric synthesis of the 1beta-methylcarbapenem key precursor from commercially available (R)-methyl beta-hydroxybutyrate. The key step is the aldol-type reaction of an achiral ketone Sn(II)-enolate with the chiral beta-acetoxy-beta-lactam intermediate which is easily accessible from the (R)-hydroxybutyrate via our previously-developed method.2. A new synthetic route to the 1beta-methylcarbapenem key precursor from easily available (S)-methyl beta-hydroxyisobutyrate has been developed which involves as a key step the chelation-controlled aldol reaction of (S)-3-benzyloxy-2-methylpropanal with the ketone silyl acetal of ethyl (trimethylsilyl)acetate.3. A novel, highly efficient approach to the 1beta-methylcarbapenem key precursor has been developed which employs the (R)-hydroxybutyrate and the (S)-hydroxyisobutyrate as the starting materials. The key steps are the chelation-controlled double-asymmetric aldol reaction and the N-C_4 cyclization of the stereochemically pure aldol product.4. A variety of 1beta-methylcarbapenem derivatives have been synthesized and their antibiotic activities have been evaluated.