Olivanic acid analogues. Part 5. Synthesis of 3-alkylthio and 3-alkylsulphinyl analogues via Michael addition of thiols to 3-unsubstituted 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylates. X-Ray molecular structure of (2RS,3RS,5SR)-benzyl 3-ethylthio-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate and (2RS,3SR,5SR,6RS,1′RS)- and (2RS,3SR,5RS,6SR,1′SR)-benzyl 3-chloro-6-(1-hydroxyethyl)-7-oxo-3-[(SR)-phenylsulphinyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate

Abstract

Reaction of thiols with 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylates results in Michael addition to the double bond, producing in high yield 2-thio-substituted 1-azabicyclo[3.2.0]heptane-2-carboxylates; the major products such as the ethylthio adducts (5) and (7) are those of trans-addition to the double bond. Oxidation of these major adducts with iodobenzene dichloride in the presence of aqueous pyridine results in highly regio- and stereo-specific oxidation to α-chlorosulphoxides as in compounds (27) and (28); base-catalysed elimination produces the Δ²-unsaturated α- and β-sulphoxides (31) and (32). Oxidation of the thiol addition products with iodobenzene dichloride–pyridine under anhydrous conditions gives the Δ³-unsaturated isomers such as (35) and (36) rather than the α-chloro sulphide products; equilibration with base results in a mixture of the Δ³- and Δ²-isomers which can be separated. Deprotection gives the bioactive Δ²-sodium salts [e.g., (40)], while the corresponding Δ³-salts (38) and (39) show no antibacterial properties.