Total Synthesis of Ovafolinins A and B: Unique Polycyclic Benzoxepin Lignans through a Cascade Cyclization

Abstract

Ovafolinins A and B, isolated from Lyonia ovalifolia var. elliptica, are lignans that contain a unique bridged structure containing a penta‐ and tetracyclic benzoxepin and an aryl tetralin. We report the first total synthesis of these natural products in which an acyl‐Claisen rearrangement was initially utilized to construct the lignan backbone with correct relative stereochemistry. Judicious use of a bulky protecting group placed reactive moieties in the correct orientation, thereby resulting in a cascade reaction to form the bridged benzoxepin/aryl tetralin from a linear precursor in a single step. Modification of this route allowed the enantioselective synthesis of (+)‐ovafolinins A and B, which confirmed the absolute stereochemistry, and comparison of optical rotation suggests that these compounds are found as scalemic mixtures in nature.