Total synthesis, stereochemical assignment, and biological activity of chamuvarinin and structural analogues

摘要

A highly stereocontrolled synthesis of (+)-chamuvarinin has been completed in 1.5 % overall yield over 20 steps. The key fragment coupling reactions were the addition of alkyne 8 to aldehyde 7 (under Felkin-Anh control), followed by the two step activation/cyclization to close the C20-C23 2,5-cis-substituted tetrahydrofuran ring and a Julia-Kocienski olefination at C8-C9 to introduce the terminal butenolide. The inherent flexibility of our coupling strategy led to a streamlined synthesis with 17 steps in the longest sequence (2.2 % overall yield), in which the key bond couplings are reversed. In addition, a series of structural analogues of chamuvarinin have been prepared and screened for activity against HeLa cancer cell lines and both the bloodstream and insect forms of Trypanosoma brucei, the parasitic agent responsible for African sleeping sickness. A hive of activity: The total synthesis of the tetrahydropyran-containing acetogenin (+)-chamuvarinin has been completed through a modular coupling strategy utilizing key bond couplings at C8-C9 and C20-C21 (see figure). This enabled the unambiguous stereochemical assignment of the natural product. A revised synthetic approach provided material for biological studies and enabled access to analogue structures that displayed selective trypanocidal activity.