The first enantioselective synthesis of the antihistamine agent clemastine, as its (S,S)-stereoisomer, has been achieved by ether formation between a proline-derived chloroethylpyrrolidine and an enantiomerically enriched tertiary alcohol. The tertiary alcohol was formed from the carbamate derivative of alpha-methyl-p-chlorobenzyl alcohol by invertive aryl migration on lithiation. The (S,S)-stereochemistry of the product confirms the invertive nature of the rearrangement.

We report a new mode of reactivity displayed by lithiated O-benzyl carbamates carrying an N-aryl substituent: upon lithiation, the N-aryl group is transferred cleanly from N to C. An arylation of the carbamate results, providing a route to alpha,alpha-arylated secondary or tertiary alcohols. We also report density functional theory calculations supporting the proposal that arylation proceeds through a dearomatizing attack on the aromatic ring, a significantly lower energy pathway than the 1,2-acyl transfer observed with related N-alkyl carbamates.

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RearrangementsO 0140 N to C Aryl Migration in Lithiated Carbamates: α-Arylation of Benzylic Alcohols. -(CLAYDEN*, J.; FARNABY, W.; GRAINGER, D. M.; HENNECKE, U.; MANCINELLI, M.; TETLOW, D. J.; HILLIER, I. H.; VINCENT, M. A.; J. Am. Chem. Soc. 131 (2009) 10, 3410-3411; Sch. Chem., Univ. Manchester, Manchester M13 9PL, UK; Eng.) -Nuesgen 29-036