New total synthesis and structure confirmation of putative (+)-hyacinthacine C(3) and (+)-5-epi-hyacinthacine C(3)

A unique synthesis of polyhydroxylated pyrrolizidine alkaloids, namely (+)-hyacinthacine C(3) and (+)-5-epi-hyacinthacine C(3) 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 C(3) 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 C(3) and (+)-5-epi-hyacinthacine C(3) was evaluated using several cell line models.