Total Synthesis of Natural Hyacinthacine C-5 and Six Related Hyacinthacine C-5 Epimers

Abstract

The total synthesis of natural (+)-hyacinthacine C-5 was achieved, which allowed correction of its initially proposed structure, as well as six additional hyacinthacine C-type compounds. These compounds were readily accessible from two epimeric anti-1,2-amino alcohols. Keeping a common A-ring configuration, chemical manipulation occurred selectively on the B-ring of the hyacinthacine C-type products through methods of syn-dihydroxylation, S(N)2 ring-opening of a cyclic sulfate, and also employing either (R)- or (R,S)-alpha-methylallyl amine for the Petasis borono Mannich reaction. Our small analogue library was then assessed for its glycosidase inhibitory potency against a panel of glycosidases. (-)-6-Epi-hyacinthacine C-5 and (+)-7-epi-hyacinthacine C-5 (compound names are based on the corrected structure of hyacinthacine C5) proved most active, with inhibitory activities ranging between weak (IC50 = 130 mu M) and moderate (IC50 = 9.9 mu M) against the alpha-glucosidases of rat intestinal maltase, isomaltase, and sucrase, thus identifying potential new leads for future antidiabetic drug development.