Preparation of enantiopure methionine, arginine, tryptophan, and proline benzyl esters in green ethers by Fischer–Speier reaction

Abstract

The simplest way to prepare the tosylate salts of amino acid benzyl esters, whose enantiomers are very important synthetic intermediates, is treatment of amino acid with benzyl alcohol and p-toluenesulfonic acid in a refluxing water-azeotroping solvent (Fischer-Speier esterification). However, to this day, the literature proposes only hazardous solvents, such as benzene, carbon tetrachloride, and chloroform, which must be absolutely avoided, or solvents, such as toluene and benzyl alcohol, which cause racemization because of too high boiling water azeotropes. On the other hand, the alternative successful use of cyclohexane, which we have recently reported for several amino acid benzyl esters, is inapplicable or not very efficient for 'problematic' amino acid such as tryptophan, arginine, and methionine, for which, indeed, the simple Fischer-Speier esterification is not described or poorly exemplified in the literature. Therefore, more polar solvents, in particular the green ethers CPME, TAME, and Me-THF, were selected and first considered for the preparation of methionine benzyl ester, previously accomplished in cyclohexane with modest yield. After discarding CPME and TAME, because causing racemization and decomposing under acidic conditions, respectively, we focused on Me-THF. In this ether, the benzyl esters of Met, Arg, and Trp could be obtained in good yield and, as proved by chiral HPLC or H NMR analysis, enantiomerically pure. The procedure was successfully extended to proline benzyl ester, which could be prepared enantiomerically pure and in quantitative yield both in cyclohexane and in Me-THF, thus avoiding the recently reported use of carbon tetrachloride.

Modifications at C(5) of 2-(2-Pyrrolidinyl)-Substituted 1,4-Benzodioxane Elicit Potent α4β2 Nicotinic Acetylcholine Receptor Partial Agonism with High Selectivity over the α3β4 Subtype

“…The hydroxyl function was mesylated and the amine function was deprotected to give ( S , S )- 17a , ( S , S )- 17b , and ( S , S )- 17c and their epimers ( S , R )- 17a , ( S , R )- 17b , and ( S , R )- 17c . The subsequent cyclization of the three S , S stereoisomers by internal SN2 reaction afforded the pyrrolidinyl benzodioxanes ( S , R )- 18a , ( S , R )- 18b , and ( S , R )- 18c , which were N -methylated to the final products ( S , R )- 2a , ( S , R )- 2b , and ( S , R )- 2c with formaldehyde and NaBH 4 using Aquivion-Fe as a catalyst in the green ether CPME. , Identically, ( S , R )- 17a , ( S , R )- 17b , and ( S , R )- 17c were cyclized to ( S , S )- 18a , ( S , S )- 18b , and ( S , S )- 18c and then N -methylated to give ( S , S )- 2a , ( S , S )- 2b , and ( S , S )- 2c .…”

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

“…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). Differential scanning calorimetry investigations and development of chiral HPLC analytical methods specific for any amino acid benzyl ester allowed us to validate these new procedures and to discard unsuitable solvents such as toluene, but also as the high boiling ether CPME (Bolchi et al 2017a;Bolchi et al 2018;Bolchi et al 2017b).…”

“…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). Differential scanning calorimetry investigations and development of chiral HPLC analytical methods specific for any amino acid benzyl ester allowed us to validate these new procedures and to discard unsuitable solvents such as toluene, but also as the high boiling ether CPME (Bolchi et al 2017a;Bolchi et al 2018;Bolchi et al 2017b). NMR spectroscopy associated to the use of chiral auxiliaries can be alternative to chiral HPLC and its attractiveness is much higher if enantiodifferentiation is achieved by simply adding chiral solvating agents (CSA), which form rapidly reversible diastereomeric complexes with the two dissolved enantiomers of the analyte via noncovalent interactions and thus without need of any substrate derivatization (Wenzel and Chisholm 2011;Parker 1991;Seco et al 2004;Seco et al 2012;Perez-Trujillo et al 2013).…”

“…To our knowledge, such an approach has not been applied to amino acid benzyl esters before. The only example is the determination of the enantiomeric excess of L-arginine benzyl ester mono-ptoluenesulfonate we have recently reported together with its preparation by treatment with benzyl alcohol and ptoluenesulfonic acid in refluxing Me-THF (Bolchi et al 2018). Difficulty in desalifying the guanidine moiety without benzyl ester hydrolysis suggested us salification of the alpha-amino group with (R)--methoxy-trifluoromethylphenylacetic acid (Mosher acid, MTPA) (Dale et al 1969) and 1 H NMR analysis of the resulting benzyl ester tosylate (R)-Mosher carboxylate.…”

Efficient One‐Pot Reductive Aminations of Carbonyl Compounds with Aquivion‐Fe as a Recyclable Catalyst and Sodium Borohydride

“…[20] On our part, we needed a solvent stable under basic conditions, compatible with hydrides and, above all, apolar enough to avoid SB solubilisation and to exclude its reducing action during the DRA first stage. The choice, inspired by the recently reported replacement of banned solvents in L-amino acids esterification, [31][32][33] fell on the green ethers tert-amyl methyl ether (TAME), cyclopentyl methyl ether (CPME) and 2-methyl-tetrahydrofuran (Me-THF) and on pcymene, which is much less toxic than toluene. By the same protocol previously used in DCM, benzaldehyde was completely converted into benzylaniline and benzyl alcohol with a selectivity of 94 % in TAME, of 91 % in CPME, of 57 % in Me-THF and of 97 % in p-cymene.…”