New total synthesis and structure confirmation of putative (+)-hyacinthacine C3 and (+)-5-epi-hyacinthacine C3

Abstract

A unique synthesis of polyhydroxylated pyrrolizidine alkaloids, namely (+)-hyacinthacine C₃ and (+)-5-epi-hyacinthacine C₃ is presented. The strategy relies on a 1,3-dipolar cycloaddition of an L-mannose derived nitrone, which owing to its great syn-stereoselectivity builds up the majority of the required stereocenters. The following key steps include Wittig olefination and iodine-mediated aminocyclisation, that provide two epimeric pyrrolizidines with the appropriate configuration. As a result, structure and steric arrangement of the first synthetically prepared (+)-hyacinthacine C₃ are proved to be correct, clearly confirming the inconsistency with the stereochemistry assigned to the natural sample. With respect to the previously proven glycosidase inhibitory activities, the antiproliferative effect of (+)-hyacinthacine C₃ and (+)-5-epi-hyacinthacine C₃ was evaluated using several cell line models.