Total Synthesis of Benthol A: The Nominal and the Actual Natural Product

Abstract

Abstract The total synthesis of the dinoflagellate-derived “super-carbon-chain compound” benthol A rigorously confirmed what the analysis of one of the required building blocks had forecasted, namely that the configuration of the secondary −OH group at C40 had been misassigned by the isolation team as the only one of a total of 35 stereogenic centers decorating the backbone of this polyol/polyether derivative. This conclusion bears implications because the original assignment had been solely based on computational data, which had resulted in a remarkably high score of 99.93% that was ultimately misleading. The multiconvergent blueprint underlying the successful approach accounts for the fact that alongest linear sequence of 32 steps sufficed to reach this intricate marine natural product. The inherent flexibility should also empower future studies aiming at a detailed mapping of the pharmacophore of this compound endowed with significant antiplasmodial activity.