Nucleophilic substitution of halogen in 4-halo genated derivatives of glutamic acid

Abstract

Previously, it was found that the reaction of dimethyl N-phthaloyl-4-bromoglutamate (1) with aniline derivatives proceeds diastereoselectively, affording the threoisomer as the major product. 2 Studying the factors determining the different reactivities of the diastereomers is of significant interest, because it might be useful for the synthesis of biologically active C(4)-derivatives of glutamic ac id) In addition, these compounds are used in mechanistic studies of enzymatic reactions. 4,5 In relation to these needs, we investigated the nucleophilic substitution of a halogen in 4-halogenated derivatives of glutamic acid. In the previous communication, 1 we proposed a mathematical model of the process and determined the rate constants for the reactions of the diastereomers of bromide 1 with p-anisidine in various solvents. It was shown that the reactions proceeded with the inversion of the configuration of C(4), and the mechanism of the substitution was close to the classical SN2. In the present work, the relative reactivities of diastereomers of bromide 1 and iodide 2 (a is threo, and b is erythro) in reactions with substituted anilines is studied (Scheme 1). Both the position of the substituent and its polarity were varied. The pseudo-first order rate constants k3 and k 4 and the parameter of diastereoselectively S = k4/k 3 of the reaction for diastereomers 1 and 2 were determined as previously described 1 in the presence of a 12-fold excess of the corresponding amine. The effect of polarity of para-substituents on the stereoselectivity was investigated in the following series: