THE INTRAMOLECULAR ALDOL CONDENSATION ROUTE TO FUSED BICYCLIC AND TRICYCLIC BETA-LACTAMS

Staudinger cycloaddition of activated acid chlorides to 1,3-ketoaldimi nes, prepared in quantitative yields from 1,3-ketoaldehydes and amino esters, gave in excellent yields cis-a-azetidinones, 6-8, having the a dequate functionality to obtain fused bi- and tricyclic beta-lactams. Reaction of compounds 6 with LHMDS at low temperature gave a single di astereomer of fused bicyclic compounds with a carbapenam or carbacefam skeleton. Treatment of diastereomeric cis-2-azetidinones, 7/8, in ana logous conditions resulted either in the exclusive cyclization of one of the two diastereomers to form tricyclic [4.n.m] (n = 5, 6; m = 5, 6 ) compounds, or in the cyclization of both diastereomers to form tricy clic [4.n.7] (n = 5, 6) 2-azetidinones. In all cases the cyclization s tep was totally stereoselective. Alternatively, trans-carbapenams and one example of a tricyclic system having a trans-2-azetidinone ring ha ve been obtained by using longer reaction times and higher temperature s. Epimerization at C3 of the 2-azetidinone nucleus occurs in these re action conditions to obtain a single diastereomer of the final product s. This approach to fused policyclic 2-azetidinones is one of the scar ce syntheses of this kind of compound making use of the aldol condensa tion.