Total synthesis of cyanolide A in the absence of protecting groups, chiral auxiliaries, or premetalated carbon nucleophiles.

Abstract

Cyanolide A is a glycosidic 16-membered macrodiolide of C2 symmetry isolated from the Papua New Guinea cyanobacterium Lyungbya bouillonii[1] and is closely related in structure to the clavosolide family of natural products (Figure 1).[2] Cyanolide A exhibits potent molluscicidal activity (LC50 = 1.2 µm) against the water snail Biomphalaria glabrata,[1] a vector of the human parasitic disease schistosomiasis (also known as bilharziasis). Infecting more than 200 million people, schistosomiasis ranks second behind malaria among human parasitic diseases.[3] While drugs, most notably praziquantel,[4] exist to treat those infected, reinfection and the emergence of drug-resistant schistosomes are concerns.[5] Disease prevention by reducing or eliminating the population of infected water snails is more desirable.[6] The molluscicide niclosamide (bayluscide) was developed for this purpose and is utilized broadly.[7] However, it exhibits poor water solubility, is rather nonselective, adversely affects native fish, and is relatively expensive.[8] Hence, an authentic need for alternative molluscicidal agents persists, thus fueling efforts toward the synthesis of naturally occurring molluscicides.[9] Toward this end, cyanolide A has garnered significant attention from organic chemists, with several total and formal syntheses published since its isolation in 2010 (Figure 1).[10, 11] Herein, we report a total synthesis of cyanolide A in the absence of protecting groups, chiral auxiliaries, or premetalated C-nucleophiles in fewer than half the steps of any previous approach.