Preparation of enantiomerically pure phosphine oxides by nucleophilic displacement chemistry using oxazaphospholidines

Abstract

The synthesis of enantiomerically pure triaryl- and diarylvinyl-phosphine oxides from PCl3 by three sequential nucleophilic displacements at phosphorus is demonstrated. A single diastereoisomer of the P-chlorooxazaphospholidine 4 is treated with an arylmagnesium halide to effect displacement of chloride. The major stereoisomer is formed with retention of configuration. After oxidation to the phosphine oxide with tert-butyl hydroperoxide, a second Grignard reaction leads to regiospecific and stereospecific P–O ring cleavage so that a second aryl group is introduced with retention of configuration. For the final step, the P–N bond is subjected to acid-catalysed methanolysis, previously shown to occur with inversion of configuration, followed by P–OMe displacement with a third arylmagnesium halide. The overall yield of triarylphosphine oxide is up to 29% for the cited five steps. Simple methoxyaryl or 2-naphthyl residues are employed to demonstrate the methodology, which permits the multigram-scale preparation of this class of compound in 94% e.e. The stereochemical course of the nucleophilic displacements with arylmagnesium halides is consistent with a model in which the organomagnesium reagent is complexed to the oxo-group and attacks phosphorus cis-to it in a direction defined by both electronic and steric factors.