L-Lactate-mediated Dynamic Kinetic Resolution of α-Bromo Esters for Asymmetric Syntheses of α-Amino Acid Derivatives

Abstract

For asymmetric synthesis of α-substituted carboxylic acid derivatives, a variety of chiral auxiliaries have been used for the dynamic resolution of α-halo esters in nucleophilic substitution. 1 For example, L-lactamide-mediated dynamic kinetic resolution of α-bromo esters was successfully used for the asymmetric preparation of α-aryloxy carboxylic acids and oxazin-2-ones. 2 However, the application of Llactate as a chiral auxiliary was not effective for the dynamic resolution of α-halo esters. 3 In our continuous efforts to develop L-lactic acid as a chiral auxiliary for the dynamic resolution, we have recently found successful results with ethyl L-lactate. We herein report ethyl L-lactate-mediated dynamic kinetic resolution of α-bromo esters for the asymmetric preparation of α-amino acid derivatives.Treatment of racemic α-bromo-α-phenylacetic acid with ethyl L-lactate in the presence of DCC and DMAP provided α-bromo-α-phenyl ester (αRS)-1 with 50:50 diastereomeric ratio (dr) in 78% yield. When the diastereomeric mixture (αRS)-1 was treated with p-anisidine (p-MeOPhNH 2 , 1.5 equiv), tetrabutylammonium iodide (TBAI, 1.0 equiv) and diisopropylethylamine (DIEA, 1.0 equiv) in CH 2 Cl 2 at room temperature for 24 h, the amino acid derivative 2 was produced in 86% yield with 97:3 dr as shown in Scheme 1. Following removal of L-lactate chiral auxiliary with Et 3 N in MeOH gave methyl phenylglycinate (R)-3 with 97:3 enantiomeric ratio (er) in 65% yield. 4 These results imply that α-bromo stereogenic center is configurationally labile with respect to the rate of substitution and (αRS)-1 is dynamically resolved in the substitution with the amine nucleophile. In a solvent screen, the reactions in CHCl 3 , ether, n-hexane and THF provided (αR)-2 with the same dr as in CH 2 Cl 2 , while the lower selectivities of 92:8 dr and 93:7 dr were observed in the reactions in DMF and CH 3 CN, respectively.In order to understand the asymmetric reaction pathway, we carried out two reactions with α-bromo-α-phenyl ester 1 of 67:33 dr. When 1 of 67:33 dr was allowed to reach thermodynamic equilibrium in the presence of DIEA, the diastereomeric ratio of recovered 1 was determined to be 49:51 dr. The result indicates that the thermodynamic stabilities of two diastereomers are almost the same, ruling out dynamic thermodynamic resolution as a primary pathway. In the reaction of 1 (67:33 dr) with p-anisidine under the same condition, 2 was obtained with the same stereoselectivity (97:3 dr) as in the reaction of 1 with 50:50 dr. In other words, the dr of product 2 is not dependent on the initial dr of 1. These preliminary results indicate that the epimerization is sufficiently fast with respect to the rate of substitution and the primary pathway of the asymmetric induction is a dynamic kinetic resolution. 1

Supported Gold Nanoparticle-Catalyzed Selective Reduction of Multifunctional, Aromatic Nitro Precursors into Amines and Synthesis of 3,4-Dihydroquinoxalin-2-Ones

“…However, these methods required air-sensitive catalysts, toxic organic solvents, and several ligands. Few studies have also reported the nucleophilic substitution/cyclization of o -phenylendiamines with α-bromo-α-phenyl ester, α-sulfonyl epoxides or substituted trichloromethylcarbinols ( Scheme 2 ) [ 42 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. Recently, the hetero-Diels–Alder reaction of ketene enolates with ortho-benzoquinone diimides [ 68 , 69 ] and a photo-organocatalytic approach have been reported for the synthesis of substituted dihydroquinoxalinones [ 70 ] ( Scheme 2 ).…”

“…Nevertheless, several sequential steps involving protecting groups and specific pre-synthesized starting materials were required. the nucleophilic substitution/cyclization of o-phenylendiamines with α-bromo-α-phenyl ester, α-sulfonyl epoxides or substituted trichloromethylcarbinols (Scheme 2) [42,[64][65][66][67][68][69][70].…”