Total Synthesis of Pinnatoxin A.

The first total synthesis of pinnatoxin A (1), a Ca2+-channel activator isolated in 1995 by Uemura and co-workers from the shellfish Pinna muricata, is reported. The synthetic plan was based on Uemura's biosynthetic proposal, and consists of an intramolecular Diels-Alder reaction for construction of the G-ring as well as the macrocycle, followed by imine formation to establish the 6, 7-spiro-ring system. During this investigation, factors controlling the stereochemistry of the BCD bis-spiroketal ring system were investigated, and the chemoselectivity and efficiency of the Ni (II) /Cr (II) -mediated coupling protocol were demonstrated. This synthesis has also established the absolute stereochemistry of natural pinnatoxin A as the antipode of structure 1.