Asymmetric radical cyclization leading to β-lactams: Stereoselective synthesis of chiral key intermediates for carbapenem antibiotics PS-5 and thienamycin

Article abstract of DOI:10.1016/0040-4020(95)00902-7

A stereoselective synthesis of β-lactams by 4-exo-trig radical cyclizations of N-[2,2-bis(phenylthio)ethenyl]-α-bromo amides bearing a chiral inductor on the nitrogen atom has been examined. Bromide 8, upon treatment with Bu₃SnH in the presence of AIBN in boiling benzene, gave a mixture of (4S)-2-azetidinone 12a and its (4R)-isomer 12b in a ratio of 71:29 and 69% combined yield. Similar treatment of α-bromobutanamide 11 with Bu₃SnH afforded trans-(4S)-2-azetidinone 17a as the major product along with its (4R)-isomer 17b (70:30, 77% combined yield). Compound 17a was converted into 24, a chiral key intermediate in the synthesis of (+)-PS-5 (25). The cyclization of bromide 28 bearing an additional stereogenic center [(S)-oxygen functionality] at the side chain proceeded with much higher (4S)-stereoselectivity to give azetidinone 29a as the major product together with its (4R)-isomer 29b in a ratio of 78:22 and 40% combined yield. Compound 29a was converted, via an inversion of the oxygen functionality, into 37, a chiral key intermediate in the synthesis of (+)-thienamycin (38). A possible explanation for the observed diastereoselectivity in radical cyclization is presented.