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

Abstract Herein, we report a full account of the evolution of a strategy that ultimately enabled the first total synthesis and definitive structural elucidation of secalosides A and B. The unambiguous structural assignment required the complex total syntheses of two proposed diastereomeric structures. 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 N-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. This strategy led to successful syntheses of both proposed structures and allowed for spectral data comparison with those of the natural secalosides, thereby resolving the long-standing ambiguity regarding the true structures of secalosides A and B.