SULFUR-DIRECTED REGIOSELECTIVE RADICAL CYCLIZATION LEADING TO BETA-LACTAMS - FORMAL SYNTHESIS OF (+ -)-PS-5 AND (+)-THIENAMYCIN/

A new method for the synthesis of beta-lactams by tributyltin hydride (Bu(3)SnH)-mediated radical cyclizations of N-ethenyl-alpha-bromo amid es bearing sulfur-substituent(s) at the terminus of the N-vinylic bond is described. N-[2-(Phenylthio)ethenyl]-alpha-bromoacetamide (11), up on treatment with Bu(3)SnH in the presence of azobis(isobutyronitrile) (AIBN) in boiling toluene, underwent radical cyclization in a 4-exo-t rig manner to give beta-lactam 13, but in low yield (22%), whereas N-[ 2,2-bis(phenylthio)ethenyl] congener 23 cyclized with a high degree of efficiency to give beta-lactam 25 and a partially desulfurized lactam 13 in 70% combined yield. The effectiveness of the 4-exo cyclization of 23 can be explained in terms of the high stability of the intermedi ate of radical 19b. Similar treatment of alpha-bromobutanamide 24 with Bu(3)SnH afforded, in 58% yield, beta-lactam 26, which was transforme d, via aldehyde 31, into the key intermediate 35 for the synthesis of( +/-)-PS-5 (36). 1,2-Asymmetric induction in radical cyclizations leadi ng to beta-lactams was then examined. Cyclization of cetoxy-2-bromo-N- [2-(phenylthio)ethenyl]butanamide (38) proceeded with no diastereosele ctivity to give beta-lactams 40a and 40b in approximately equal amount s. However, 2,2-bis(phenylthio) congener 39 provided (3R,4R)-2-azetidi none 41a and its (3S,4S)-isomer 41b in a ratio of ca. 2:1. Similarly, (2R,3S)-butanamide 47 afforded 48a as a major product. Saponification of 48a followed by partial desulfurization of 49 gave alcohol 50, whic h was then subjected to Mitsunobu inversion to afford 52. This compoun d was converted into the key intermediate 56 for the synthesis of (+)- thienamycin (58). Reversibility of the radical cyclization leading to the beta-lactams is discussed.