Alkoxyallene-Based Stereodivergent Syntheses of (-)-Hyacinthacine B4 and of Putative Hyacinthacine C5 Epimers: Proposal of Hyacinthacine C5 Structure.

Abstract

Hyacinthacines are members of the class of polyhydroxylated pyrrolizidines exhibiting outstanding biological activity as glycosidases inhibitors. Their structural complexity is embodied in the densely functionalized core, possessing a series of contiguous stereogenic centers. In this synthetic study we report a route to the more complex congeners of this class of alkaloids exploiting the diastereoselective addition of an axially chiral lithiated alkoxyallene to an enantiopure cyclic nitrone. Our stereodivergent approach enabled the installation of the targeted configuration at the ring A by minimal synthetic manipulations and at ring B by using stage dependent selective functionalizations. The versatility and robustness of this methodology were demonstrated by the syntheses of (-)-hyacinthacine B4 and of two epimers of (+)-hyacinthacine C5, allowing a suggestion of the likely structure of the isolated natural product.