Bromofluorination of alkenes: 1‐bromo‐2‐fluoro‐2‐phenylpropane product: 1‐Bromo‐2‐fluoro‐2‐phenylpropane

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-

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.

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.

No abstract

(R)-(-)-2-Amino-4-fluorobutyric acid (4c) (32% ee) and six of its homologues 9 have been synthesized by diastereoselective alkylation (54-72% yield) of (R)-( +)-camphor-based glycine ester imines 1 with 1-bromo-2-fluoro-alkanes 6, at low temperature, followed by deprotection. Similarly 1-bromo-3-fluoropropane was used for the preparation of (R)-(-)-5-fluoronorvaline (4d) (42% ee). With 1-bromo-2-fluoropropane (6a) and its homologues (prepared by bromofluorination of 1-alkenes) partial resolution occurs in the alkylation step, yielding mixtures of four diastereomers. Using (R)-1-bromo-2-fluoro-4-methylpentane two diastereomeric alkylation products are formed (58% de). The overall yield of the threestep procedure vaned from 10%) to 32%.