4067-4070 N11-17.fm

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. 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. 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 (Bn2NH) 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 CH2Cl2 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 LiAlH4 furnished the enantioenriched N,N-dibenzyl 2aminoalcohol (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. Most of the solvents explored gave similar selectivities to give 2b with 87:13 dr in CH3CN, 85:15 dr in ethyl acetate, 88:12 dr in p-dioxane and 87:13 dr in THF. However, the selectivity was reduced in DMSO (entry 5) and the reaction was very slow in n-hexane. Decreasing reaction temperature reduced the rate of the reaction significantly with a lower selectivity of 84:16 dr while similar selectivity was observed at 40 °C (entries 7 and 8). Next, we examined five different alkyl amine nucleophiles to evaluate the scope of the dynamic kinetic resolution as shown in Table 2. The treatment of diisopropyl ester 1b with N-benzyl-2-phenethylamine for 24 h at room temperature gave 4 in 83% yield with 86:14 dr (entry 1). Notably, when cyclic secondary amine nucleophiles were used, the reactions gave much lower stereoselectivities (entries 2-3). Also, the reactions with two primary amines provided the products 7-8 with lower selectivities compared to the reactions with