Glycosylation of the sixth residue in the sequence, Tyr-dThr/dAla-Gly-Phe-Leu-Ser-CONH₂, that has mixed binding affinity at the d- and µ-opioid receptors, provided glycopeptides with greater i.v. potency and in situ blood-brain barrier (BBB) permeability of the compounds. The glycosylated amino acids were prepared by direct glycosylation of the sugar acetates with a Schiff base in good yields using a Lewis acid as a promoter in dichloromethane/toluene. The use of the Schiff base for the first time in a direct sense in glycosylation is reported. Starting from L serine/threonine, the procedure is inexpensive and efficient alternative to previous methods. L-serine/threonine benzyl ester hydrochloride salts were reacted with diarylketimines in CH₃CN/CH₂Cl₂ at RT to form the Schiff bases in excellent yields. The benzophenone-derived Schiff bases exhibit ring-chain tautomerism as shown by NMR results in CDCl₃. These results further establish clearly, the positive inductive of the methoxy groups on the aromatic rings of the Schiff bases. The Schiff base, acting as an acceptor, was reacted with carbohydrate peracetate donors under BF₃•OEt₂ promotion at room temperature and in a microwave to provide amino acid glycosides in good yields. The difference in reactivity between a and b-carbohydrate peracetate donors towards the Schiff base is also illustrated.

Acknowledgement: We thank the Office of Naval Research (N00014-05-1-0807 & N00014-02-1-0471) and the National Science Foundation (CHE-607917) for support.