Synthetic, Computational, and Experimental Studies of a Class 3 Atropisomeric Alpha-Naphthyl Tropone

Atropisomerism is a stereochemical phenomenon that results from high configurational stability of chiral axes and is an important structural element in many functional molecules. Thus, understanding how different structural features can influence the stability of chiral axes can be an important consideration for molecular design. Recent studies have demonstrated that certain tropone-based chiral axes are significantly more stable than those of related benzenoids, likely a result of their relatively smaller external bond angles. The following manuscript explores this phenomenon through computational and experimental studies on a simple, class 3 atropisomeric alpha-naphthyl-substituted tropone (G‡ ~ 32 kcal/mol). Conditions were established for an atropselective Suzuki cross-coupling that enabled its asymmetric synthesis, and the absolute configuration of the compound was determined using vibrational circular dichroism. Based on computational modeling, we found that the alpha-naphthyl-substituted tropone has a lower rotational energy barrier than the phenol analog, which appears to arise from the puckering ability of the tropone. Despite the lower rotational energy barrier, the alpha-naphthyl-substituted tropone still displays high configurational stability. Thus, this new atropisomeric scaffold has the potential for incorporation into drug design and should support the development of new classes of ligands and catalysts for use in asymmetric synthesis.