Synthetic Studies toward the Aphidicolin Family of Diterpenoid Natural Products

Herein, we report an investigation of several synthetic strategies to access the aphidicolin family of natural products. Some unsuccessful approaches include strategies featuring Diels-Alder cycloadditions, Cope rearrangement, divinyl cyclopropane-Cope rearrangement, and C-C cleavage "cut-and-sew" reactions. Separating key bond-forming and bond-breaking steps into a two-step "sew-and-cut" strategy, a penta-carbocycle containing the embedded aphidicolin core was synthesized using an intramolecular [2 + 2]-photocycloaddition reaction─the "sew" step─to obtain a "linear" cycloadduct. Additionally, a constitutional "crossed" isomer of this [2 + 2]-adduct was obtained in a condition-dependent manner, providing insight into factors that can be leveraged to alter [2 + 2]-selectivity for complex substrates. Future application of contemporary C-C cleavage methodologies to facilitate the "cut" step should afford a suitable common intermediate for the synthesis of many members of the aphidicolin family.