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

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posted on 2018-05-04, 00:00 authored by Lauren M. Chapman, Jordan C. Beck, Caitlin R. Lacker, Linglin Wu, Sarah E. Reisman
(+)-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.