Abstract
Pinnatoxin A, a marine-derived macrocycle originating from a bivalve within the shellfish Pinna muricata and Pinna attenuata, was first isolated in 1995 by Uemura and has been a target of several synthetic studies due to its intriguing structure and bioactivity. Key features of this natural product are 14 chiral centers, a 6,7-spiroimine ring, 5,6-bicyclo ketal ring, and a 6,5,6-trispiroketal ring. The most notable features of the A-G 6,7-spirobicyclic ring structure is its chiral, quaternary center at its center, and the imine moiety incorporated into the A ring which has been found to be stable under mildly acidic conditions. The quaternary chiral center in synthetic chemistry is also noted to be one of the most difficult to form with high diastereoselectivity.
Herein a stereoselective synthesis of the A-G ring of Pinnatoxin A is described. The synthesis relies on a key step involving a cascade [3,3]-sigmatropic Claisen rearrangement followed by a Mislow-Evans rearrangement that forms the central quaternary chiral center with excellent diastereoselectivity in one step. This tandem rearrangement not only builds the A-G rings chiral core but also succeeds in functionalizing the G ring for further modification towards Pinnatoxin A’s total synthesis. In addition to the synthesis, a second key â-alkyl cross coupling is described using a palladium catalyzed Suzuki-Miyaura protocol in preparation for the tandem rearrangement. Also presented is evidence for the need to obtain the correct stereochemistry in incorporation of the E-F rings for formation of the imine to occur. Overall the A-G ring of Pinnatoxin A is synthesized with its longest linear sequence of 23 steps.
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