A 14-step synthesis of (+)-cochlearol B is reported. This renoprotective meroterpenoid features a unique core structure containing a densely substituted cyclobutane ring with three stereocenters. Our strategy employed an organocatalytic Kabbe condensation in route to the key chromenyl triflate. A subsequent Catellani reaction incorporated the remaining carbon atoms featured in the skeleton of cochlearol B. An ensuing visible-light-mediated [2+2] photocycloaddition closed the cyclobutane and formed the central bicyclo-[3.2.0]heptane core. Notably, careful design and tuning of the Catellani and photocycloaddition reactions proved crucial in overcoming undesired reactivity, including cyclopropanation reactions and [4+2] cycloadditions.

Using nucleophilic, boron-based –CF2Ar reagents, we demonstrate three methods to form C–CF bonds: (1) nucleophilic aromatic substitution, (2) palladium catalyzed cross-coupling, and (3) nucleophilic substitution.

A 14-step synthesis of (+)-cochlearol B is reported. This renoprotective meroterpenoid features a unique core structure containing a densely substituted cyclobutane ring with three stereocenters. Our strategy employed an organocatalytic Kabbe condensation in route to the key chromenyl triflate. A subsequent Catellani reaction incorporated the remaining carbon atoms featured in the skeleton of cochlearol B. An ensuing visible-light-mediated [2+2] photocycloaddition closed the cyclobutane and formed the central bicyclo-[3.2.0]heptane core. Notably, careful design and tuning of the Catellani and photocycloaddition reactions proved crucial in overcoming undesired reactivity, including cyclopropanation reactions and [4+2] cycloadditions.

Since the first reports of their isolation, the meroterpenoids cochlearol A and B have attracted interest from the synthetic community for their unique structural features. This review describes the attempted and successful total syntheses of these natural products and provides a summary of the strategies developed in the years since their isolation.

The design of concise and efficient synthetic strategies to access naturally occurring, pharmaceutically active complex molecules is of utmost importance in current chemistry. It not only enables rapid access to these molecules and their analogues but also provides sufficient quantities for their biological evaluation. Identification of any symmetric or pseudosymmetric synthetic intermediates upon retrosynthetic bond disconnection of the target molecule holds the promise to significantly streamline the route towards the compound of interest. This review will highlight recent examples of successful natural product syntheses reported within the past five years that benefited from the recognition of symmetry elements during the retrosynthetic design.