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 (2 R )-2- O -(4-nitrophenyl)sulfonyl-cyclohexyl lactic acid p -bromobenzylester 21 as a buidling block with improved crystallinity and stability is also described.