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Chiral auxiliary-mediated dynamic resolution of α-halo esters has been known as an effective method for asymmetric synthesis of α-heteroatom substituted carboxylic acid derivatives.1 While the synthetic method can achieve a useful level of stereoselectivity, it is still of interest to find novel ways to utilize the dynamic resolution for practical synthesis. We have previously reported L-malate-mediated dynamic kinetic resolution of α-bromo esters with various aryl amines for asymmetric synthesis of N-aryl substituted amino acid derivatives.2 Herein we report our results on the extension of the methodology to various alkyl amines for practical asymmetric syntheses of morpholin-2-ones and piperazin-2-ones.Initial studies on L-malate-mediated dynamic kinetic resolution were performed with α-bromo esters 1a-b and dibenzylamine (Bn 2 NH) as shown in Scheme 1. When the diastereomeric mixture (1:1) of dimethyl ester (αRS)-1a was treated with tetrabutylammonium iodide (TBAI, 1.0 equiv), diisopropylethylamine (DIEA, 1.0 equiv) and dibenzylamine (1.5 equiv) in CH 2 Cl 2 at room temperature for 24 h, the amino acid derivative (αR)-2a was produced in 76% yield with 85:15 diastereomeric ratio (dr). Also, we examined the substitution of diisopropyl ester (αRS)-1b under the same reaction condition. The reaction of 1b gave amino acid derivative (αR)-2b with a slightly higher dr of 88:12 in 73% yield. Subsequent reductive cleavage of (αR)-2b using LiAlH 4 furnished the enantioenriched N,N-dibenzyl 2-aminoalcohol (R)-3 in 77% yield with 88:12 enantiomeric ratio (er). The results imply that α-bromo carbon center is configurationally labile and α-bromo esters 1a-b are dynamically resolved under the reaction condition.A series of reactions were examined with diisopropyl ester 1b and dibenzylamine to assess the effect of solvent and temperature on yield and selectivity as shown in Table 1.

A new and efficient method for the asymmetric synthesis of 3,4,6‐trisubstituted 2,5‐diketopiperazines has been developed. The dynamic kinetic resolution of L‐amino‐acid‐derived α‐bromo tertiary amides in the nucleophilic substitution reaction with p‐anisidine and a subsequent deprotection‐cyclization process provides rapid access to diverse cis‐2,5‐diketopiperazines 5a–5o and proline‐containing trans‐2,5‐diketopiperazines 5p–5t in enantiomerically pure form in 45–67 % overall yields.

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