Methods for the synthesis of racemic and optically active title compounds are presented. Key step of these four-step procedures is the alkylation with 1-bromo-2-fluoroalkanes of glycine-ester-derived imines in anhydrous medium using lithium diisopropylamide as a base at low temperature or phase transfer catalyzed alkylation with 50% NaOH and triethylbenzylammoniumchloride as the phase transfer catalyst, respectively. Subsequent three-step deprotection gave the free acids in 13-33% overall yield. Deracemization ofγ-fluoro-α-aminobutyric acid methyl and ethyl esters withα-chymotrypsin was shown to give the (-)-enantiomers of the esters and (+)-γ-fluoro-α-aminobutyric acid in >98% ee, while from thetert-butylester the opposite stereochemical result was observed giving the (-)-acid with 88% ee. Optically activeγ-fluoro-α-amino acids were synthesized alternatively by phase transfer catalysis with N-benzyl-cinchonium chloride or using an auxiliary-directed asymmetric alkylation of the imine derived from (R)-(+)-camphor or (R)-(+)-2-hydroxypinan-3-one. These processes gave different enantiomers ofγ-fluoro-α-aminobutyric acid via a monomeric lithium enolate in the first or a dimeric lithium enolate in the second case, respectively. The enantiomeric excess can be improved by lithium/magnesium exchange.
Keywords: Amino acids / Fluorine / Chiral auxiliaries / 2-Hydroxy-3-pinanone / 1-Bromo-2-fluoroethane / 3-Bromo-2-fluoropropene (+)-(S)-2-Amino-4-fluorobutanoic acid (5a) (Ͼ 96% ee), its α-methylated derivative (+)-(S)-5b (85% ee), and (−)-(S)-2-amino-4-fluoro-4-pentenoic acid (10) (81% ee) were synthesized by diastereoselective alkylation in the presence of LDA at low temperatures. Alkylation of (+)-(R,R,R)-2-hydroxy-3-pinanone based imines of glycine tert-butyl ester 1a or alanine isopropyl ester 1b with 1-bromo-2-fluoroethane (2) or 3-bromo-2-fluoropropene (7), respectively, followed by step-
Summary. Versatile three-step procedures for syntheses of seven racemic 7-fluoro-a-amino acids are described.Alkylation of tert-butyl N-(diphenylmethylene)glycinate with 1-bromo-2-fluoroalkanes gave Nprotected aminoacid esters both in anhydrous medium using lithiumdiisopropylamide as base at low temperature or in a two phase system of 50% aqueous sodium hydroxide and methylene chloride with triethylbenzylammonium chloride as the phase transfer catalyst at room temperature. Subsequent two-step deprotection with citric acid and hydrochloric acid gave the title compounds in 13-33% overall yields.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.