C–C Cleavage/Cross-Coupling Approach for the Modular Synthesis of Medium-to-Large Sized Rings: Total Synthesis of Resorcylic Acid Lactone Natural Products

The chemical synthesis of medium (8-11 membered) and large sized (≥12 membered) cyclic systems is often challenging. The introduction of transannular strain and loss of degrees of freedom in forming macrocycles often result in poor reaction kinetics and thermodynamics (i.e., thermodynamically disfavored at equilibrium). To address these challenges, we herein report a strategy for the synthesis of medium-to-large sized rings, which leverages strain-release and metal templating through a palladium-mediated C-C cleavage/cross-coupling. By means of DOSY NMR techniques, we identified an undesired competing β-hydrogen elimination pathway, which was substrate dependent. Using a streamlined synthesis of the requisite precursors, our method enables the rapid generation of complex medium-to-large sized rings in a modular fashion through a C(sp²)-C(sp³) macrocyclization. The transformation enabled the short total synthesis of various resorcylic acid lactone (RAL) natural products and unnatural analogues of late-stage intermediates. A mechanistic proposal for the macrocyclization is supported by computational studies of the reaction using density functional theory.