Herein, we describe a new strategy for the preparation of thiazolothiazepine-based inhibitors of human immunodeficiency virus type-1 integrase (IN). The present method allows facile preparation of the title compounds in a single enantiomeric form starting from L-4-thiazolidinecarboxylic acid. This method could be easily extended to the synthesis of several analogs derived from optically active cyclic aminoacids. We also present a putative model showing the interaction between L- and D-isomers of compound I in the IN active site. A sensibly lower IC50 value was found for (-)-1 over racemic-1 in an anti-IN assay. (c) 2006 Elsevier SAS. All rights reserved.