Abstract
Pectenotoxin-2 (1), isolated from the Japanese scallop Patinopecten Yessoensis and the dinoflagellate Dinophysis fortii as a causative toxin of the Diarrheic Shellfish Poisoning, is a polyether macrolide characterized by a 34-membered macrolactone, a non-anomeric [6,5]-spirocyclic acetal, a bicyclic acetal, three oxolanes, and a 6-membered cyclic hemiacetal. It exhibits potent cytotoxicity against several cancer cell lines due to its actin depolymerizing activity. Because the structural complexity and strong bioactivity attracted our attention, we initiated the program toward its total synthesis. In this symposium, we will describe the details of the recently finished total synthesis of pectenotoxin-2 (1) and its congeners, pectenotoxin-2b (3) and -2c (2). The synthesis of pectenotoxin-2 was performed by a convergent route starting from the Cl-C7, C8-C20, C21-C30, and C31-C40 segments. The C1 -C7 and C31-C40 segments were connected by esterification to form the left-half segment of 1. The C8-C20 segment was united with the C21-C30 segments with forming the bicyclic acetal moiety by a process including the sulfone coupling between the segments, oxidation to a ketone, desulfonylation with SmI2, and acetalization. The connection of the resulting C8-C30 (the right-half) with the left half by sulfone coupling was followed by the formation of an anomeric [6,5]-spirocyclic acetal. After several steps of functional group interconversion, the ring-closing olefin metathesis at C30-C31 successfully constructed pectenotoxin-2b (3). Finally, anomeric [6,5]-spirocyclic acetal 3 was converted to non-anomeric [6,5]-spirocyclic acetal 1 by a short-period treatment with aq-TFA in acetonitrile and to double-anomeric [6,6]-spirocyclic acetal 2 by a long-period exposure to the same acidic conditions. Synthetic pectenotoxin-2 (1) exhibited significant inhibition of the viability of HepG2 and Caco2. Synthetic pectenotoxin-2b (3) and -2c (2) also inhibited the viability, but with weaker IC50 values.
