Dynamic Kinetic Resolution of L-Threonine-derived α-Bromo Esters for Asymmetric Synthesis of α-Amino Esters

Abstract

Many chiral alcohols have successfully been used as a chiral auxiliary for the dynamic resolution of -halo esters in nucleophilic substitution. 1 L-Threonine is a proteinogenic -amino acid that bears a chiral alcohol group. However, so far L-threonine has not been used as a chiral auxiliary for the dynamic resolution of -halo esters. We herein report the first example of L-threonine-mediated dynamic kinetic resolution of -bromo esters in nucleophilic substitution with various amine nucleophiles. Treatment of N-acetyl L-threonine isopropyl ester with racemic -bromo phenylacetic acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) provided -bromo ester (RS)-1 in 70% yield with about 50:50 diastereomeric ratio (dr). When the mixture of (S)-1 and (R)-1 was treated with p-anisidine (1.2 equiv), tetrabutylammonium iodide (TBAI, 1.0 equiv) and diisopropylethylamine (DIEA, 1.0 equiv) in CH2Cl2 at room temperature for 12 h, amino ester 8a was produced in 63% yield with 84:16 dr as shown in Table 1, entry 1. Also, six different N-protection groups of L-threonine were examined for the substitution with p-anisidine as shown in entries 2-7. The reactions of 2, 3, 4, and 7 bearing N-pivaloyl, N-Boc, Nbenzoyl, and N,N-dibenzyl groups gave slightly better drs ranging from 88:12 to 86:14, while the reactions of 5 and 6 bearing N-p-methoxybenzoyl and N-2-pyridinylcarbonyl groups gave lower drs compared to the reaction of 1. The dr and yield of the substitutions in Table 1 imply that -bromo carbon center is configurationally labile with respect to the rate of substitution and L-threonine-derived -bromo esters