Resolving Structural Ambiguity through Total Synthesis: Evolution of a Synthetic Strategy for Secalosides A and B

Initial efforts were based on the use of our in-house methodologies to access the indane core of secalosides. These featured an asymmetric carbonyl-ene reaction, an intramolecular Heck cyclization, and <i>N</i>-heterocyclic carbene (NHC) chemistry.

However, these routes suffer from inefficient redox manipulations, poor selectivity, and undesired reactivity, hindering the preparation of the embedded indane core. The key to our revised route was a successful late-stage ring-contraction strategy that allowed for the concomitant formation of the highly strained ten-membered bis-lactone and the cyclopentane bearing the configurationally correct stereotriad. This transformation was achieved by tactical exploitation of macrocyclic character, which induced divergent reactivity from its acyclic variant, enabling an unusual transannular oxidative enolate coupling.