Total Synthesis of Natural Hyacinthacine C₅ and Six Related Hyacinthacine C₅ Epimers

Abstract

The total synthesis of natural (+)-hyacinthacine C 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, S2 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 C and (+)-7- epi-hyacinthacine C (compound names are based on the corrected structure of hyacinthacine C) proved most active, with inhibitory activities ranging between weak (IC = 130 μM) and moderate (IC = 9.9 μM) against the α-glucosidases of rat intestinal maltase, isomaltase, and sucrase, thus identifying potential new leads for future antidiabetic drug development.

Reactivity and Synthetic Applications of Multicomponent Petasis Reactions

“…Seven obtained hyacinthacine C 5 compounds were then evaluated as weak to moderate α-glycosidase inhibitors (9.9 to 130 μM). 207…”

The History of the Glycosidase Inhibiting Hyacinthacine C-type Alkaloids: From Discovery to Synthesis.

“…To date, fourteen of the natural hyacinthacines, A 1 , A 2 , A 3 , A 6 , A 7 , B 1 , B 2 , B 3 , B 4 , B 5 , B 7 , C 2 , C 3 and C 5 have been synthesized, along with their related epimers and enantiomers. [51][52][53][54][55][56][57][58][59][60][61][62][63][64] At this point, the authors note that an increasing number of reports suggest the confirmation of hyacinthacine A 5 through methods of total synthesis. [61,63,65] To the best of our knowledge, hyacinthacine A 5 has not yet been synthesized and although epimers of the structure have been reported, [66] the absolute configuration of the natural isolate is still yet to be confirmed.…”

“…To date, fourteen of the natural hyacinthacines, A 1 , A 2 , A 3 , A 6 , A 7 , B 1 , B 2 , B 3 , B 4 , B 5 , B 7 , C 2 , C 3 and C 5 have been synthesized, along with their related epimers and enantiomers [ 51 - 64 ]. At this point, the authors note that an increasing number of reports suggest the confirmation of hyacinthacine A 5 through methods of total synthesis [ 61 , 63 , 65 ].…”

“…Pyne and co-workers employed a flexible synthesis which is the latest addition towards accessing the hyacinthacine C-type alkaloids [ 64 ]. This synthetic work resulted in a total of seven hyacinthacine C-type analogues including the total synthesis of natural (+)-hyacinthacine C 5 141 and confirmed the hypothesis proposed by Goti et al that its true configuration is that of (+)-1- epi -hyacinthacine C 4 .…”

“… The total synthesis of (+)-5,6-di- epi -hyacinthacine C 5 130 , (‒)-5,7-di- epi -hyacinthacine C 5 133 , (+)-5- epi -hyacinthacine C 5 139 and (+)-1- epi -hyacinthacine C 4 141 [ 64 ]. …”