1. Total Synthesis of Natural Hyacinthacine C5 and Six Related Hyacinthacine C5 Epimers
- Author
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Anthony W Carroll, Kongdech Savaspun, Stephen G. Pyne, Masako Hoshino, Atsushi Kato, and Anthony C. Willis
- Subjects
010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Total synthesis ,Stereoisomerism ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Structure–activity relationship ,Epimer ,Amine gas treating ,Maltase ,Mannich reaction ,Isomaltase - Abstract
The total synthesis of natural (+)-hyacinthacine C5 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, SN2 ring-opening of a cyclic sulfate, and also employing either ( R)- or ( R, S)-α-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 C5 and (+)-7- epi-hyacinthacine C5 (compound names are based on the corrected structure of hyacinthacine C5) proved most active, with inhibitory activities ranging between weak (IC50 = 130 μM) and moderate (IC50 = 9.9 μM) against the α-glucosidases of rat intestinal maltase, isomaltase, and sucrase, thus identifying potential new leads for future antidiabetic drug development.
- Published
- 2018