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


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.


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.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:(+)-psiguadial B; natural product total synthesis; trans-cyclobutane; Wolff rearrangement; asymmetric ketene addition; photochemistry
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Reisman, Sarah E.
Thesis Committee:
  • Stoltz, Brian M. (chair)
  • Reisman, Sarah E.
  • Peters, Jonas C.
  • Tirrell, David A.
  • Virgil, Scott C.
Defense Date:31 May 2017
Record Number:CaltechTHESIS:06052017-010024254
Persistent URL:
Related URLs:
URLURL TypeDescription from which portions of this thesis were adapted.
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:10274
Deposited By: Lauren Chapman
Deposited On:05 Jun 2017 23:45
Last Modified:04 Oct 2019 00:16

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