A NOVEL-APPROACH TO CEPHALOSPORINS FROM ALLENYLAZETIDINONES - A NEW CYCLIZATION STRATEGY VIA TANDEM CUPRATE ADDITION-SULFENYLATION

An efficient approach to the synthesis of 3-substituted cephems bearin g carbon-based substituents of choice at the C(3) position from inexpe nsive penicillins is described. The strategy involves the synthesis of an allenylazetidinone from penicillin sulfoxide followed by the addit ion of an organocuprate at low temperature. Organocuprates undergo 1,4 -conjugate addition at the central allenic carbon of the allenylazetid inone to form a carbon-carbon bond which is followed by ring closure v ia an intramolecular sulfenylation reaction. The chemistry has been ap plied to the synthesis of a variety of 3-substituted cephems bearing s ubstituents such as alkyl, cycloalkyl, aryl, alkenyl, and allyl. Precu rsors to the synthesis of important antibiotics, i.e., Cefadroxil, Cef ixime, and Cefzil, are also available from this novel approach. The me thodology is not limited to carbon-based 3-substituted cephems, but pr ovides access to some 3-norcephalosporins as well.