Process Research of (<i>R</i>)-Cyclohexyl Lactic Acid and Related Building Blocks: A Comparative Study

Abstract

(S)-Cyclohexyl lactic acid is a component of the selective E-selectin inhibitor 2 ((S)-cHexLact-2-O-(3-Galβ(1→3)ddGlc(4→1)αFuc). We describe the evaluation of various synthetic routes to this building block: (A) diazotation of phenylalanine followed by phenyl ring hydrogenation; (B) phenyl ring hydrogenation of phenyl alanine followed by diazotation; (C) acidic hydrolysis of the cyanohydrin derived from phenylacetaldehyde, enantiomeric resolution of the resulting, racemic phenyl lactic acid via diasteromeric salt formation and phenyl ring hydrogenation; (D) enantioselective dihydroxylation of a cinnamate ester, followed by hydrogenation of the benzylic hydroxy group and the aromatic nucleus; (E) enantioselective biocatalytic reduction of phenylpyruvic acid, followed by phenyl ring hydrogenation. The development of (2R)-2-O-(4-nitrophenyl)sulfonyl-cyclohexyl lactic acid p-bromobenzylester 21 as a buidling block with improved crystallinity and stability is also described.