Highly efficient and enantioselective syntheses of (2S,3R)-3-alkyl- and alkenylglutamates from Fmoc-protected Garner's aldehyde

Abstract

A 6-step enantioselective synthesis of (2S,3R)-3-alkyl/alkenylglutamates, including the biologically significant amino acid, (2S,3R)-3-methylglutamate, protected for Fmoc SPPS, is reported. Overall yields range from 52-65%. Key to the success of these syntheses was the development of a high-yielding 2-step synthesis of Fmoc Garner's aldehyde followed by a Horner-Wadsworth-Emmons reaction to give the corresponding Fmoc Garner's enoate in a 94% yield. The diastereoselective 1,4-addition of lithium dialkylcuprates to the Fmoc Garner's enoate was explored. Significant decomposition occurred when using lithium diethylcuprate and conditions previously reported for the 1,4-addition of lithium dialkylcuprates to Boc or Cbz-protected Garner's enoate. An optimization study of this reaction resulted in a robust set of conditions that addressed the shortcomings of previously reported conditions. Under these conditions, highly diastereoselective (> 20:1 in most cases) 1,4-addition reactions of lithium dialkyl/dialkenylcuprates to the Fmoc Garner's enoate were achieved in 76-99% yield. The resulting 1,4-addition products were easily converted into the Fmoc-(2S,3R)-3-alkyl/alkenylglutamates in two steps.

Keywords: 1,4-Additions; Enantioselective synthesis; Organocuprates; Unusual amino acids.