Synthesis and HPLC enantioseparation of the cyclopropane analogue of valine (c₃Val)

Abstract

A new and efficient method is presented for the preparation of the N-Boc-protected cyclopropane analogue of valine, 1-(N-tert-butoxycarbonyl)amino-2,2-dimethylcyclopropanecarboxylic acid, both in racemic and enantiomerically pure forms. Cyclopropanation of the exocyclic double bond of 2-phenyl-4-isopropylidene-5(4H)-oxazolone with diazomethane followed by elaboration of the heterocyclic moiety provided multigram quantities of the racemic target compound. Subsequent HPLC resolution of a racemic precursor on a noncommercial chiral stationary phase has given access to enantiomerically pure products. Almost 1.5 g of the first-eluted enantiomer and 1.0 g of the second-eluted enantiomer have been isolated in optically pure form using a 150 x 20 mm ID column containing mixed 10-undecenoate/3,5-dimethylphenylcarbamate of cellulose covalently bonded to allylsilica gel with a mixture of hexanes/tert-butyl methyl ether/ethyl acetate as the mobile phase.

Access to Enantiomerically Pure cis‐ and trans‐β‐Phenylproline by High‐Performance Liquid Chromatography Resolution

“…These so‐called immobilized phases retain the advantages of coated polysaccharide‐based phases while being compatible with a wide variety of organic solvents, a feature of enormous value for preparative‐scale resolution. We have successfully applied such chiral stationary phases, either made at the laboratory (prior to their commercialization) or of the Chiralpak type, to the preparative HPLC resolution of non‐natural analogs of proline, valine, and phenylalanine with diverse structures.…”