Development of a Synthetic Strategy Toward Trans-Cyclobutane-Containing Natural Products: Enantioselective Total Synthesis of (+)-Psiguadial B

Citation

Chapman, Lauren Marie (2017) Development of a Synthetic Strategy Toward Trans-Cyclobutane-Containing Natural Products: Enantioselective Total Synthesis of (+)-Psiguadial B. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z90G3H5M. https://resolver.caltech.edu/CaltechTHESIS:06052017-010024254

Abstract

Trans-cyclobutane-containing meroterpenoids are a structurally intriguing class of natural products with a diverse array of pharmacologically interesting properties. Herein, the development of a synthetic strategy for de novo construction of the trans-cyclobutane motif is described, which has enabled the first enantioselective total synthesis of the cytotoxic natural product, (+)-psiguadial B. Specifically, we have developed a photochemical Wolff rearrangement with tandem catalytic, asymmetric addition to a ketene generated in situ. To our knowledge, this work represents the first example of this methodology used to prepare enantioenriched amides. A palladium-catalyzed, directed C(sp³)–H alkenylation reaction is used to quickly build molecular complexity, and two distinct epimerization strategies permit access to either enantiomer of the natural product from a single enantiomer of organocatalyst.

In the course of this work, three different synthetic routes toward (+)-psiguadial B were investigated and each is discussed. These studies have led to the execution of several challenging key transformations, including an ortho-quinone methide hetero–Diels–Alder cycloaddition with a cyclohexanone-derived enol ether, a vinyl sulfide-mediated Prins cyclization, and a modified Norrish–Yang cyclization. Ultimately, the successful synthetic strategy was realized by employing a ring-closing metathesis to form the strained, 7-membered terpene framework, and a late-stage benzylic oxidation/arylation strategy to complete the core of the natural product. Finally, in an effort to apply these key strategy concepts in the context of other bioactive trans-cyclobutane-containing natural products, initial results toward a concise total synthesis of (+)-rumphellaone A are presented.

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