Solvent Effects in the Enantioselective Catalytic-Phase-Transfer Alkylation of Polymer-Supported Glycine–Iminetert-Butyl Ester: Asymmetric Solid-Phase Synthesis of (R)-α-Amino Acid Derivatives

Polymer-supported glycine-imine tert-butyl esters (3, 8) were prepared from Merrifield- or Wang-resin and used in the enantioselective synthesis of (R)-alpha-amino acid derivatives by using (S,S)-3,4,5-trifluorophenyl-NAS bromide (5) as the chiral phase-transfer catalyst. The chemical yields and enantioselectivities were found to be dramatically dependent upon the ratio of water to organic solvent. The optimal solvent was a mixture of toluene/chloroform/water (9:1:0.5). The catalytic enantioselective solid-phase phase-transfer alkylation of polymer-supported glycine-imine substrate 3 with various alkyl halides with the use of 50% aqueous CsOH in the optimal solvent system at 0 degrees C followed by hydrolysis and benzoylation afforded the corresponding (R)-N-benzoyl-alpha-amino acid tert-butyl esters 11 in 60-80% yield and with enantiomeric ratios (er) of 96.5:3.5 to 99.5:0.5. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007).