Dynamic resolution of α-haloacyl compounds in nucleophilic substitution has been recently developed as an asymmetric synthetic method for α-substituted carboxylic acids.
1While many chiral auxiliaries have successfully been used in the dynamic resolution, it is still highly desirable to develop a new chiral auxiliary for practical purposes. Tartaric acid derivatives are one of the most promising candidates for chiral auxiliary, as it is relatively inexpensive and readily available in both enantiomeric forms. However, so far it has not been used as a chiral auxiliary for the dynamic resolution of α-haloacyl compounds. In continuation of our ongoing efforts to develop efficient synthetic methods for dynamic resolution of α-haloacyl compounds, 2 we herein report the first example of L-tartaric acid-mediated asymmetric nucleophilic substitution for the preparation of 6-membered heterocycles containing 1,4-heteroatoms such as piperazin-2-ones, morpholin-2-ones, dihydroquinoxalinones and dihydrobenzoxazinones.Initial studies on L-tartaric acid-mediated dynamic resolution were performed with α-bromo ester 1a and dibenzylamine (Bn 2 NH) as shown in Scheme 1. A mixture of diastereomers of α-bromo ester 1a was readily prepared from diisopropyl L-tartrate in 79% yield by reacting it with α-bromo phenylacetic acid using DCC and DMAP. L-Tartaric acid-derived α-bromo ester 1a has two substitution sites and the two nucleophilic substitutions with dibenzylamine may show different stereoselectivity because the second substitution takes place under the influence of the first substitution. When the diastereomeric mixture of diisopropyl ester 1a was treated with tetrabutylammonium iodide (TBAI, 1.0 equiv), diisopropylethylamine (DIEA, 1.0 equiv) and dibenzylamine (2.5 equiv) in CH 2 Cl 2 at room temperature for 12 h, the disubstituted amino acid derivative 2a was produced in 85% yield. Also, mono-substituted amino acid derivative 3 was obtained in 30% yield when we carried out the substitution of diisopropyl ester (αRS)-1a with 1.0 equiv of dibenzylamine for 5 h. In order to determine the stereoselectivity of the substitutions, the chiral auxiliary was removed from the amino substituted products by reductive cleavage. Treatment of 2a with LiAlH 4 furnished enantioenriched N,N-dibenzyl 2-aminoalcohol (S)-4 with 94:6 enantiomeric ratio (er), while the reduction of 3 provided the amino alcohol (S)-4 with 91:9 er. The results imply that α-bromo ester 1a is dynamically resolved in the nucleophilic substitution and the second substitution with dibenzylamine is more stereoselective than the first substitution (91:9 er).A series of reactions were performed with diisopropyl ester 1a and dibenzylamine to assess the effect of solvent and temperature on yield and stereoselectivity as shown in Table 1, entries 1-7. Most of the solvents explored gave similar stereoselectivities such as 93:7 er in CH 3 CN, 93:7 er in ethyl acetate, 91:9 er in CHCl 3 , 90:10 er in THF and 92:8 er in DMF (entries 1-5). Variation of temperature did not significantly...
