The first enantioselective total synthesis of the cytotoxic natural product (+)-psiguadial B is reported. Key features of the synthesis include (1) the enantioselective preparation of a key cyclobutane intermediate by a tandem Wolff rearrangement/asymmetric ketene addition, (2) a directed C(sp 3 )−H alkenylation reaction to strategically forge the C1−C2 bond, and (3) a ring-closing metathesis to build the bridging bicyclo[4.3.1]decane terpene framework.

A modular synthesis of enantioenriched polyfunctionalized cyclobutanes was developed and applied to the synthesis of (+)-rumphellaone A.

(+)-Psiguadial B is a diformyl phloroglucinol meroterpenoid that exhibits anti-proliferative activity against the HepG2 human hepatoma cancer cell line. This full account details the evolution of a strategy that culminated in the first enantioselective total synthesis of (+)-psiguadial B. A key feature of the synthesis is the construction of the trans-cyclobutane motif by a Wolff rearrangement with in situ catalytic, asymmetric trapping of the ketene. An investigation of the substrate scope of this method to prepare enantioenriched 8-aminoquinolinamides is disclosed. Three routes toward (+)-psiguadial B were evaluated that featured the following key steps: 1) an ortho-quinone methide hetero–Diels–Alder cycloaddition to prepare the chroman framework; 2) a Prins cyclization to form the bridging bicyclo[4.3.1]decane system, and 3) a modified Norrish–Yang cyclization to generate the chroman. Ultimately, the successful strategy employed a ring-closing metathesis to form the seven-membered ring and an intramolecular O-arylation reaction to complete the polycyclic framework of the natural product.