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*).

Mediation of metal chelation in cysteine-derived tetramate systems

“…Esterication of L-cystine by thionyl chloride and simple alcohols occurred in quantitative yield, 39 although reaction with bulkier alcohols such as benzyl alcohol and p-methoxybenzyl alcohol was more limited and gave incomplete reaction, with starting material mostly being recovered. Acid-catalysed esteri-cation with p-TsOH monohydrate in toluene proved to be more reliable, 40,41 and was even better using cyclohexane as solvent, [42][43][44] giving diesters of L-cystine 6a-g which precipitated as their bis(p-toluenesulphonate) salts (Scheme 4). [45][46][47] Although widely used as starting materials for synthesising biologically relevant molecules, these systems have generally been incompletely characterised.…”

1H NMR spectroscopy in the presence of Mosher acid to rapidly determine the enantiomeric composition of amino acid benzyl esters, chirons susceptible to easy racemization

“…Surprisingly, the search for water-azeotroping solvents alternative to banned benzene, carbon tetrachloride and chloroform is very poorly exemplified and the assessment of the enantiomeric excess of the resulting benzyl ester almost completely neglected despite the well-known high susceptibility of amino acids, even more if esterified, to racemization (Matsuo et al 1967;Sato et al 1970;Bada 1972;Smith and Evans 1980;Dhaon et al 1982;Smith and Sivakua 1983). Proof is incautious replacement with high boiling toluene or benzyl alcohol leading, as we have demonstrated, to complete or partial racemization (Bolchi et al 2017a). Recently, we have reported the Fischer-Speier efficient preparation of several amino acid benzyl esters with very high enantiomeric excess in cyclohexane or in the green ether Me-THF at reflux (Bolchi et al 2017a;Bolchi et al 2018).…”

Antifouling and Antibacterial Properties Constructed by Quaternary Ammonium and Benzyl Ester Derived from Lysine Methacrylamide

“…To synthesize LysAAm–OBzl, the esterification of LysAAm with benzyl alcohol was carried out by imitating the esterification of amino acids with benzyl alcohol . First, LysAAm (40 mmol) and benzyl alcohol (200 mmol) were added into cyclohexane (160 mL).…”

“…To synthesize LysAAm− OBzl, the esterification of LysAAm with benzyl alcohol was carried out by imitating the esterification of amino acids with benzyl alcohol. 25 First, LysAAm (40 mmol) and benzyl alcohol (200 mmol) were added into cyclohexane (160 mL). Then, p-toluenesulfonic acid monohydrate (44 mmol), to stabilize the amino group for forming the p-toluenesulfonate salt, and 2,6-di-tert-butyl-p-cresol (0.5 mmol), to protect the vinyl group, were added into the above mixture.…”