DIASTEREOCONTROL VIA COSOLVENTS IN THE ZINC ESTER ENOLATE-IMINE CONDENSATION ROUTE TO BETA-LACTAMS

Strongly coordinating polar cosolvents influence the diastereoselectiv ity of the C-C coupling reaction of the chlorozinc enolate 1b of ethyl etramethyl-1-aza-2,5-disila-cyclopentane-1-acetate with N-alkyl and N -silyl imines in THF at -78 degrees C. The corresponding Lithium enola te 1a does not react with N-alkyl imines. Whereas DMSO and sulfolane d id not change the cis/trans ratio, the use of three equivalents NMP, T MU and DMPU led to a significant increase in the amount of cis-beta-la ctams formed. HMPA was found to be the best cosolvent in promoting the formation of the cis-diastereoisomer. Other reaction parameters were also shown to have small influences on the cis/trans ratio. When inste ad of LDA (2,4,6-triisopropylphenyl)lithium (TIP-Li) was used to depro tonate the ester, the formation of cis-p-lactams was slightly enhanced ; the enantioselectivity of the C-C coupling reaction was not influenc ed by the base. An extra equivalent of ZnCl2 in the reaction mixture a lso favored the formation of cis-beta-lactams. The change from trans- to cis-beta-lactams is discussed in terms of enolate aggregation equil ibria and competing transition states. Moreover, the (E)-(Z)-equilibri um of zinc enolate 1b is operative in the absence of a coordinating am ine, suggesting the intermediacy of an isomeric C-metallated species.