4-Alkyl-2-trichloromethyloxazolidin-5-ones: Valuable Precursors to Enantiomerically Pure C- and N-Protected α-Alkyl Prolines

An efficient, economical and enantioselective method for preparation of various mono-and diprotected a-substituted proline derivatives is described. The lithium enolate of known 2-trichlo- romethyloxazolidin-5-one 3b reacted with electrophiles to furnish the 4-alkyloxazolidinones 4a-d with high diastereoselectivity and in good yields. The oxazolidinones 4 represented versatile synthons that could be converted in a single step into useful proline peptido- mimetics. For example oxazolidinones 4a-d reacted with sodium methoxide by a novel mechanism that involved elimination of trichloromethyl anion from an intermediate tetrahedral adduct to af- ford N-formyl a-substituted proline methyl esters 5a-d. Alternative- ly acidic methanolysis of oxazolidinone 4a afforded the amino acid methyl ester hydrochloride 6. Hydrolysis of the N,O-acetal function of 4a could be effected under acidic conditions (6 N HCl, RT) to af- ford the free amino acid 1a after ion exchange chromatography. Our procedure represents a convenient and general route to a valuable class of peptidomimetics and should be welcomed by chemists pre- paring conformationally restricted peptides and other compounds.