An Efficient Method for the Preparation of Enantiomerically Pure N-Acylarylsulfonamides Having an Asymmetric Center at the α-Position: Condensation of Acid Chlorides and Arylsulfonamides Under Solid-Liquid Two-Phase Conditions

Abstract

A convenient synthetic method for the preparation of enantiomerically pure N-acylarylsulfonamides having an asymmetric center at the a-position of the carbonyl group is described. Chiral phenylacetic acids are first converted to the corresponding acid chlorides, which in turn are condensed with arylsulfonamides in the presence of powdered alkaline hydroxide in CH 2 Cl 2 , giving the corresponding N-acylarylsulfonamides with good optical and chemical yields. A more convenient one-pot procedure is also possible.N-Acylsulfonamides, forming a class of acidic functional groups, have been widely employed as carboxylic acid bioisosteres in medicinal chemistry. 1 They have similar pKa values to those of the corresponding carboxylic acids 2 and offer the possibility for a wide range of structural modifications. Acylation of sulfonamides with acid chlorides, 3 acid anhydrides 4 or reactive esters 5 have traditionally been used for the preparation of N-acylsulfonamides. 6 More recently, direct condensation of carboxylic acids and sulfonamides in the presence of condensing agents, such as carbonyldiimidazole (CDI), 7 2-chloro-Nmethylpyridinium iodide (CMPI) 8 or carbodiimides, 9 have also been employed for this purpose.During the course of development of our endotheline receptor antagonists, we found that N-acylarylsulfonamide (R)-4a is a potent endotheline-A receptor antagonist. 10 This compound has one asymmetric center at the a-position of the carbonyl group. In order to prepare (R)-4a, enantiomerically pure (R)-1a was allowed to react with arylsulfonamide 3 in the presence of various condensing agents (Scheme). Although these methods gave 4a in good to excellent yields, the product was completely or partially racemized in all cases. Acylation of 3 with the corresponding acid chloride (R)-2a in the presence of triethylamine also resulted in the racemized product (vide infra).The increasing importance of preparing the enantiomerically pure form of biologically active compounds in drug development studies 11 prompted us to survey a hitherto undocumented efficient method for the synthesis of chiral N-acylarylsulfonamide having an asymmetric center at the a-position of the carbonyl group. 12 In this paper, we describe a simple and economically feasible method for the preparation of 4 as a model of such chiral N-acylarylsulfonamides, which include the condensation of acid chloride 2, readily available from the corresponding optically active phenylacetic acid derivative 1, and arylsulfonamide 3 in the presence of powdered alkaline hydroxide in CH 2 Cl 2 . The product 4 thus obtained is enantiomerically pure enough for further elaboration.The results of the direct condensation of (R)-1a and 3 in the presence of condensing agents (route A) are summarized as Entries 1-6 in Table 1. Each reaction was carried out by reported methods. The optical purity of each of the starting materials and the products were determined by chiral HPLC analysis. The CDI method of Drummond and Johnson 7 resulted in good yield of 4a, but the product was ...

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