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New Strategies for the Total Synthesis of Aza-Propellane Natural Products

Citation

Navarro, Raul (2014) New Strategies for the Total Synthesis of Aza-Propellane Natural Products. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/XQ0M-NT53. https://resolver.caltech.edu/CaltechTHESIS:12022013-141841545

Abstract

The propellane alkaloids comprise a large class of natural products that possess varying degrees of structural complexity and biological activity. The earliest of these to be isolated was acutumine, a chlorinated alkaloid that has been shown to exhibit selective T-cell cytotoxicity and antiamnesic properties. Alternatively, the hasubanan family of natural products has garnered considerable attention from the synthetic community in part due to its structural similarities to morphine. While these alkaloids have been the subject of numerous synthetic studies over the last forty years, very few enantioselective total syntheses have been reported to date.

As part of a research program directed towards the synthesis of various alkaloid natural products, we have developed a unified strategy for the preparation of the hasubanan and acutumine alkaloids. Specifically, a highly diastereoselective 1,2-addition of organometallic reagents to benzoquinone-derived tert-butanesulfinimines was established, which provides access to enantioenriched 4-aminocyclohexadienone products. This methodology enabled the enantioselective construction of functionalized dihydroindolones, which were found to undergo intramolecular Friedel-Crafts conjugate additions to furnish the propellane cores of several hasubanan alkaloids. As a result of these studies, the first enantioselective total syntheses of 8-demethoxyrunanine and cepharatines A, C, and D were accomplished in 9-11 steps from commercially available starting materials.

More recent efforts have focused on applying the sulfinimine methodology to the synthesis of a more structurally complex propellane alkaloid, acutumine. Extensive studies have determined that a properly functionalized dihydroindolone undergoes a photochemical [2+2] cycloaddition followed by a lactone fragmentation/Dieckmann cyclization to establish the carbocyclic framework of the natural product. The preparation of more appropriately oxidized propellane intermediates is currently under investigation, and is anticipated to facilitate our synthetic endeavors toward acutumine.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:propellanes, alkaloids, hasubanan, sulfinimine, acutumine
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Awards:Graduate Dean's Award for Outstanding Community Service, 2014
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Reisman, Sarah E.
Thesis Committee:
  • Stoltz, Brian M. (chair)
  • Gray, Harry B.
  • Hsieh-Wilson, Linda C.
  • Reisman, Sarah E.
Defense Date:31 October 2013
Funders:
Funding AgencyGrant Number
California Institute of TechnologyUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Gates Millenium Scholars ProgramUNSPECIFIED
National Institutes of Health1F31GM098025
National Science Foundation1057143
Record Number:CaltechTHESIS:12022013-141841545
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:12022013-141841545
DOI:10.7907/XQ0M-NT53
Related URLs:
URLURL TypeDescription
http://pubs.rsc.org/en/Content/ArticleLanding/SC/2011/C1SC00095KPublisherPublished Article: Chapter 2
http://onlinelibrary.wiley.com/doi/10.1002/anie.201104487/abstractPublisherPublished Article: Chapter 2
http://pubs.acs.org/doi/pdf/10.1021/ol3017963PublisherPublished Article: Chapter 4
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8034
Collection:CaltechTHESIS
Deposited By: Raul Navarro
Deposited On:16 Dec 2013 23:46
Last Modified:04 Oct 2019 00:03

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