Halide-Terminated N-Acyliminium Ion−Alkyne Cyclizations: A New Construction of Carbacephem Antibiotics

A series of 4-(3-alkynyl)azetidinones 13 was prepared from 4-(phenylsulfonyl)azetidine-2-one ( 9 ) and isopropyl glyoxylate hydrate. The 3-pentynyl ( 13a ) and 4-phenyl-3-butynyl ( 13b ) azetidinone acetates underwent 6-exo cyclization when treated with 3 equiv of SnCl 4 at 0 °C to provide 3-(1-chloroalkylidene)carbacephems 15a (65%) and 15b (33%) respectively. In contrast, the 3-butynyl ( 13d ) and 4-(trimethylsilyl)-3-butynyl ( 13c ) azetidinone acetates underwent 7-endo cyclization under similar conditions to give 1-azabicyclo[5.2.0]nonenes 14a (11%) and 14b (71%), respectively. Beginning with penicillin degradation product 18, the more elaborate 3-pentynyl azetidinone cyclization substrate 27 was prepared in seven steps. Exposure to 27 to 3 equiv of SnCl 4 in CH 2 Cl 2 at 0 °C for 6 h, followed by allowing the reaction mixture to warm to rt, provided the desired 3-(1-chloroethylidene)carbacephem 28 in 60% yield and high (>99%) enantiometric purity. Cleavage of the chloroethylidene group of 28 with ozone gave 3-hydroxy carbacephem 29 in 77% yield. Since this intermediate has been converted in three steps to loracarbef ( 3 ), a new formal total synthesis of this carbacephem antiboitic was concluded.