A new chiral benzimidazolide is developed as a nonenzymatic acylating agent for enantioselective benzoylation of racemic alpha-amino esters. The process is highly efficient, which exhibits uniformly high enantioselectivity for alpha-amino esters with or without aryl substituents under mild reaction conditions. The chiral benzimidazolide is inexpensive and is easily accessible.

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An enantioselective synthesis of 3-arylphthalides was achieved using (S)-1-phenylethylamine as a chiral auxiliary. Reduction of chiral keto amides of 2-aroylbenzoic acids followed by acidcatalyzed lactonization yielded (S)-3-arylphthalides with 75-85% ee.Chiral 3-substituted phthalide moieties are found in a large number of natural products and biologically active compounds, such as 3-n-butylphthalide, (-)-hydrastine, (-)-narcotine), 1 (-)-typhaphthalide, 2 vermistatin, 3 alcyopterosin E, 4,5 and cytosporone E. 6 Some members of this group are cytotoxic (vermistatin, alcyopterosin E), antibacterial (cytosporone E), show anticonvulsant, 7 antiasthmatic 8 and antitumor properties, 9 increase the duration of anesthesia, 10 and exhibit cerebral anti-ischemic action (3-n-butylphthalide). 11 They also compose part of the structure of several complex alkaloids (e.g., the convulsant alkaloid bicuculline) 12 and serve as intermediates for their synthesis.The precise biological activity of 3-substituted phthalides is often crucially dependent on their configuration. Efficient and stereoselective synthetic routes to these products in enantiomerically pure form are therefore highly desirable.One of the approaches for the preparation of nonracemic 3-substituted phthalides involves enantioselective reduction of 2-acylbenzoic acids and their derivatives followed by lactonization. Noyori et al. introduced a BINAP-Ru(II) catalyzed enantioselective hydrogenation of 2-acylbenzoic esters giving a straightforward entry to optically active 3-substituted phthalides in very high enantioselectivity. 13 Brown et al. reported a convenient and general synthesis of chiral 3-substituted phthalides with equally high enantioselectivity via intramolecular asymmetric reduction of 2-acylbenzoic acids by diisopinocampheylborane and intermolecular asymmetric reduction of 2-acylbenzoates with (-)-B-chlorodiisopinocampheylborane. 14 Asymmetric transfer hydrogenation methodology using chiral Ru complexes has been employed for the preparation of 3-substituted phthalides. 15 In addition to the asymmetric reduction of 2-acylbenzoic acid derivatives, some other useful methodologies have been reported for the preparation of chiral 3-substituted phthalides. 16,17 A chiral auxiliary approach has been used effectively for the enantioselective synthesis of g-substituted-g-lactones by many groups, 18,19 including a contribution from our group. 20 The presence of the same basic structural unit in 3-substituted phthalides made us consider the chiral auxiliary approach for the synthesis of nonracemic 3-substituted phthalides. We initially carried out the synthesis of racemic 3-arylphthalides by reduction of 2-aroylbenzoates followed by acid-catalyzed lactonization. 21 It was reasoned that the use of a chiral auxiliary in the process would result in the formation of nonracemic 3-arylphthalides. It was also expected that the forced proximity between the prochiral centre and the chiral auxiliary would result in better stereoselectivity than in the previous series of s...

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Route. -An enantioselective synthesis of 3-arylphthalides (II) is achieved using (S)-phenylethylamine as a chiral auxiliary. Reduction of chiral ketoamides (I) followed by acid-catalyzed lactonization affords title compounds (II) in 75-85% enantioselectivity. -(KARNIK*, A. V.; KAMATH, S. S.; Synthesis 2008, 12, 1832-1834; Dep. Chem., Univ. Mumbai, Vidyanagari, Mumbai 400 098, India; Eng.) -M. Paetzel 43-116