Total synthesis of pectenotoxin-2

Abstract

Pectenotoxin-2 (PTX2) is a shellfish toxin and has a non-anomeric spiroacetal, which is not stabilized by an anomeric effect. The selective construction of the non-anomeric spiroacetal has been a major problem in the synthesis of PTX2. Described herein is the stereoselective total synthesis of PTX2 via the isomerization of anomeric spiroacetal pectenotoxin-2b (PTX2b). The synthesis of PTX2b was achieved by a simple process including sulfone-mediated assembly of spirocyclic and bicyclic acetals and subsequent macrocyclization by ring-closing olefin metathesis. Finally, the selective construction of PTX2 was accomplished by the early termination of a dynamic transition process to equilibrium in the acid-catalyzed isomerization of anomeric PTX2b. [6,6]-Spiroacetal pectenotoxin-2c (PTX2c) was also synthesized from PTX2b. The cytotoxicity assay of the synthetic compounds against HepG2 and Caco2 cancer cells showed a potency of the order: PTX2PTX2b>PTX2c. A shellfish toxin: Non-anomeric spiroacetal pectenotoxin-2 was synthesized by the acidic isomerization of anomeric spiroacetal pectenotoxin-2b. In the isomerization step, [6,6]-spiroacetal pectenotoxin-2c was the major product at equilibrium. However, the early termination of a dynamic transition process to equilibrium in the step produced pectenotoxin-2 selectively. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.