title: One-step preparation of enantiopure L- or D-amino acid benzyl esters avoiding the use of banned solvents.
abstract: The enantiomers of amino acid benzyl esters are very important synthetic intermediates. Many of them are currently prepared by treatment with benzyl alcohol and p-toluenesulfonic acid in refluxing benzene or carbon tetrachloride, to azeotropically remove water, and then precipitated as tosylate salt by adding diethyl ether. Here, we report a very efficient preparation of eight L- or D-amino acid benzyl esters (Ala, Phe, Tyr, Phg, Val, Leu, Lys, Ser), in which these highly hazardous solvents are dismissed using cyclohexane as a water azeotroping solvent and ethyl acetate to precipitate the tosylate salt. With some work-up modifications and lower yield, the procedure can be applied also to methionine. Chiral HPLC analysis shows that all the benzyl esters, including the highly racemizable ones such as those of phenylglycine, tyrosine and methionine, are formed enantiomerically pure under these new reaction conditions thus validating the solvents replacement. Contrariwise, toluene cannot be used in place of benzene or carbon tetrachloride because leading to partially or totally racemized amino acid benzyl esters depending on the polar effect of the amino acid α-side chain as expressed by Taft's substituent constant (σ*).
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione "Pietro Pratesi", Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione "Pietro Pratesi", Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bavo
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione "Pietro Pratesi", Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy. marco.pallavicini@unimi.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
mesh_terms: D000085:Acetates / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry*; D001593:Benzyl Compounds / Q000138:chemical synthesis*; D003510:Cyclohexanes / Q000737:chemistry; D004952:Esters / Q000138:chemical synthesis*; D055772:Green Chemistry Technology; D013237:Stereoisomerism
chemical_list: D000085:Acetates; D000596:Amino Acids; D001593:Benzyl Compounds; D003510:Cyclohexanes; D004952:Esters; C506365:Cyclohexane; C007650:ethyl acetate
keywords: Amino acid benzyl ester; Chiral HPLC; Cyclohexane; Racemization; Taft’s substituent constant; Toluene; Water azeotrope