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 amides bearing sulfur-substituent(s) at the terminus of the N-vinylic bond is described. N-[2-(Phenylthio)ethenyl]-alpha-bromoacetamide (11), upon treatment with Bu(3)SnH in the presence of azobis(isobutyronitrile) (AIBN) in boiling toluene, underwent radical cyclization in a 4-exo-trig 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 intermediate of radical 19b. Similar treatment of alpha-bromobutanamide 24 with Bu(3)SnH afforded, in 58% yield, beta-lactam 26, which was transformed, via aldehyde 31, into the key intermediate 35 for the synthesis of(+/-)-PS-5 (36). 1,2-Asymmetric induction in radical cyclizations leading to beta-lactams was then examined. Cyclization of (2S,3R)-3-acetoxy-2-bromo-N-[2-(phenylthio)ethenyl]butanamide (38) proceeded with no diastereoselectivity to give beta-lactams 40a and 40b in approximately equal amounts. However, 2,2-bis(phenylthio) congener 39 provided (3R,4R)-2-azetidinone 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, which was then subjected to Mitsunobu inversion to afford 52. This compound 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.