Total Synthesis of Aplydactone

Total Synthesis of Aplydactone

Author: Angewandte Chemie International Edition

Aplydactone (pictured) is an unusual brominated sesquiterpene isolated from the sea hare Aplysia dactylomela. Its tetracyclic ring system contains a highly strained [2]-ladderane (two fused four-membered rings). To date, two total syntheses and a formal synthesis have been reported by the groups of Trauner, Burns, and Snyder, respectively [1–3].

Yandong Zhang, Xiamen University, China, and colleagues have developed a conceptually different approach to this marine natural product by relying on a novel C–H functionalization step. The key transformations include: 1) a [2+2] photocycloaddition followed by a Wolff ring contraction to establish the 6-4-4 tricycle, 2) an unusual transannular C–H insertion to set up the bridged cyclohexanone ring and a quaternary stereocenter between two quaternary carbon atoms, and 3) a hydrogen-atom-transfer hydrogenation to furnish the brominated stereocenter.

A finely tuned conformation of the α-diazoketone precursor is key for the C–H insertion. This strategy enabled a protecting-group-free synthesis of aplydactone in 12 steps from a simple enone compound. An efficient synthesis of this complex molecule may allow further studies of its biomedical properties.


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