Synthesis of 3-Hydroxycephems from Penicillin G through Cyclization of Chlorinated 4-(Phenylsulfonylthio)-2-azetidinones Promoted by a BiCl3/Sn or TiCl4/Sn Bimetal Redox System

Abstract

A novel access to 3-hydroxycephems was attained from penicillin G via the C=C bond cleavage of 1-(1-alkoxycarbonyl-2-chloromethyl-2-propenyl)-4-(phenylsulfonylthio)-2-azetidinones by successive treatment with RuCl3/HIO4 and HIO4/CuSO4 and reductive cyclization of 1-(1-alkoxycarbonyl-3-chloro-2-hydroxy-1-propenyl)-4-(phenylsulfonylthio)-2-azetidinones on treatment with a newly devised BiCl3/Sn or TiCl4/Sn bimetal redox couple in DMF containing pyridine.

Synthesis of 2-exo-Methylenepenam and 3-Chloro-Δ3-cephem through a Sequential Reductive 1,2-Elimination/S−S Bond Fission or Chloride Ion-Addition/Cyclization of 3,4-Disubstituted 2-Butenoates in Metal Salt/Metal Combinations

“…The 3,4-disubstituted 2-butenoates 6 were easily prepared starting from penicillin (Scheme ). The transformation of the penicillin to enol 9 was performed by the reported procedures involving ene-type chlorination of azetidinone 7 , derived from penicillin, and subsequent oxidative cleavage of the terminal double bond of 8 . The enol 9 was then allowed to react with trifluoromethanesulfonic anhydride and triethylamine (1.5 molar equiv each) in dichloromethane at −78 °C for 1 h to afford 4-chloro-3-[[(trifluoromethyl)sulfonyl]oxy]-2-butenoate 6b (Y = OTf) (95%).…”

Synthesis of 3-Alkenyl- and 3-Arylalkyl-Δ3-cephems by Use of Terpyridine- or Bipyridine-Ligated Organocopper Species

“…Elemental analyses were performed on a Perkin-Elmer 2400 Series II CHNS/O analyzer. The 3-(chloromethyl)-Δ 3 -cephem 1 and organotins were prepared according to the reported procedures in the literature. Copper powder (200 mesh) was activated according to the literature before use .…”

Patent Review of Manufacturing Routes to Fifth-Generation Cephalosporin Drugs. Part 2, Ceftaroline Fosamil and Ceftobiprole Medocaril

“…Tanaka and co-workers have developed a route to 3-hydroxycepham that avoids an ozone oxidation (Scheme ). The penicillin derivative 23 was oxidized with RuO 2 and periodic acid to enol 24 , which was then ring-closed to enol 1f using BiCl 3 and tin …”