Chiral mono-, di-, and tri-chloromethylphosphonates and phosphonothioates: preparation, absolute configuration, and the stereochemical course of their reaction with methoxide

Abstract

Enantiomerically pure (+)-(R)-O-ethyl S-methyl dichloromethylphosphonothioate, prepared using (–)-ephedrine as a chiral template, is further chlorinated to the trichloro analogue using BunLi–CCl4 and dechlorinated by hydrogenolysis via the monochloro analogue to the corresponding methyl -phosphonothioate of known configuration. With methoxide, the trichloro derivative gives P–C bond cleavage with inversion and the dichloro derivative gives P–S bond cleavage with retention of configuration. In the monochloro derivative P–S and P–O bond cleavages are competitive, P–S bond cleavage occurring with 70% inversion. Under similar reaction conditions P–S bond cleavage occurs stereospecifically with inversion of configuration in methylphosphonothioates. Methoxide treatment of (+)-(R)-ethyl isopropyl trichloromethylphosphonate results in P–C bond cleavage with inversion while (–)-(S)-ethyl phenyl dichloromethylphophonate loses the OPh group also with inversion. Possible reaction mechanisms are discussed.