Efficient synthesis of 1β-methylcarbapenems based on the counter-attack strategy

Abstract

A seven-step efficient synthesis of 1β-methylcarbapenems 1 from the acetoxyazetidinone 6 is described. The Reformatsky reaction of 3-(2-bromopropionyl)-1,3-benzoxazinone 7 with compound 6 gave an adduct 8 in 96% yield with high β-selectivity (β:α= 92:8). Compound 8 was transformed in three steps into the side-chain thiol esters 12a–e in good yields. The chlorotrimethylsilane-mediated Dieckmann-type cyclisation of thioesters 12b–e followed by counter-attack of the liberated thiolate anion 18 yielded the C-2 alkylthio- or arylthio-substituted 1β-methylcarbapenems 19b–e in a one-pot procedure. The synthesis of 1β-methylcarbapenems 1 was demonstrated by a simple cleavage of the silyl ether and allyl ester of compound 19b to afford target compound 1b in high yield.