Evolution of a Strategy for the Enantioselective Total Synthesis of (+)-Psiguadial B

(+)-Psiguadial
B is a diformyl phloroglucinol mero­terpenoid
that exhibits antiproliferative 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.