Total synthesis of ryanodol.

Ryanodol (1) exists in nature in the form of the 1H-pyrrole-2-carboxylate ester derivative known as ryanodine, which is a potent modulator of the calcium release channel. The pentacyclic ABCDE-ring system of 1 is fabricated with eight oxy groups, three methyl groups, and one isopropyl group. All the eight tetrasubstituted stereocenters are concentrated within the 10-carbon ABDE framework. The total synthesis of this exceptionally complex molecule was achieved in 22 steps from the simple C2-symmetric tricycle 8. The synthetic route is based on installation of the seven stereogenic centers and formation of the four C-C bonds within the highly congested multicyclic format. The novel and flexible strategy developed here will enable the generation of chemical derivatives with different functional properties toward calcium release channels.