The total synthesis of (-)-cyanthiwigin F by means of double catalytic enantioselective alkylation

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Abstract
The utility of a 'double catalytic enantioselective reaction' is demonstrated by the rapid protecting group-free synthesis of the diterpenoid (−)-cyanthiwigin F, a natural marine product originally isolated from the sea sponge Myrmekioderma styx. Double catalytic enantioselective reactions have the potential to construct stereochemically complex molecules in a single operation by creating several stereocentres at remote points within the same molecular scaffold. The key step in the nine-step synthesis of cyanthiwigin F is the conversion of a complicated mixture of racemic and meso diastereomers into a synthetically useful intermediate with exceptional enantiomeric excess. Double catalytic enantioselective transformations are powerful synthetic methods that can facilitate the construction of stereochemically-complex molecules in a single operation. In this paper, the use of a double stereoablative enantioselective alkylation reaction in a concise synthesis of the marine diterpenoid (−)-cyanthiwigin F is reported. The key step involves the conversion of a complicated mixture of racemic and meso diastereomers into a synthetically useful intermediate with exceptional enantiomeric excess. Double catalytic enantioselective transformations are powerful synthetic methods that can facilitate the construction of stereochemically complex molecules in a single operation1,2. In addition to generating two or more stereocentres in a single reaction, multiple asymmetric reactions also impart increased enantiomeric excess to the final product in comparison with the analogous single transformation3,4,5,6. Furthermore, multiple asymmetric operations have the potential to independently construct several stereocentres at remote points within the same molecular scaffold, rather than relying on pre-existing chiral centres that are proximal to the reactive site1. Despite the inherent benefits of multiple catalytic enantioselective reactions, their application to natural product total synthesis remains largely underutilized2. Here we report the use of a double stereoablative7 enantioselective alkylation reaction in a concise synthesis of the marine diterpenoid (-)-cyanthiwigin F (ref. 8). By employing a technique for independent, selective formation of two stereocentres in a single stereoconvergent operation, we demonstrate that a complicated mixture of racemic and meso diastereomers may be smoothly converted to a synthetically useful intermediate with exceptional enantiomeric excess. The stereochemical information generated by means of this catalytic transformation facilitates the easy and rapid completion of the total synthesis of this marine natural product.