Divergent Diels-Alder Reactions in the Biosynthesis and Synthesis of Endiandric-Type Tetracycles: A Computational Study.

Endiandric acids and related polyketide natural products arise from polyene precursors and occur naturally as fused and bridged tetracycles. In some cases, the intramolecular Diels-Alder reactions that produce fused and bridged tetracycles result from a diene tether that may act as either a 4π or 2π component in the cycloaddition. To examine the preference for fused or bridged products, we applied density functional theory (using the M06-2X and B3LYP functionals) to reactants with various substituents for both fused and bridged transition states. Fused products were generally preferred except when disfavored by extreme steric hindrance (e.g., a tert-butyl group). These computational results are consistent with experimental data and suggest the existence of as-yet undiscovered natural products.