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Total synthesis of cyanthiwigin natural products via double asymmetric catalytic alkylation and investigations into the nature of double asymmetric processes

Citation

Enquist, John Andrew (2011) Total synthesis of cyanthiwigin natural products via double asymmetric catalytic alkylation and investigations into the nature of double asymmetric processes. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:10122010-101531793

Abstract

Since the initial isolation of the cyathane molecules in 1970, considerable synthetic interest has been invested into the preparation of these diterpenoid natural products. Owing to the biological activity and intriguing molecular architecture of these compounds, the members of the cyathane family of natural products have emerged as appealing targets for total synthesis. After a brief summary of the isolation and bioactivity properties of these diterpene compounds, previous synthetic efforts toward these molecules are reviewed. A concise and versatile approach toward the preparation of the cyanthiwigin family of cyathane natural products is described. By leveraging a unique double asymmetric catalytic alkylation procedure it is possible to quickly establish two of the most critical stereocenters of the cyanthiwigin framework with high levels of selectivity and expediency. The synthesis additionally employs a tandem ring-opening and cross-metathesis reaction, and an aldehyde-olefin radical cyclization process, to rapidly arrive at the tricyclic cyathane core of the cyanthiwigin molecules. From this unifying intermediate, the preparation of cyanthiwigins B, F, and G are attained swiftly and without the need for protecting groups. The nature of double asymmetric transformations is investigated from a historical, mathematical, and experimental perspective. The initial findings of Langenbeck and Horeau concerning the enantioenriching effects of scalemic duplication are described, with a specific focus on the impact of this phenomenon on total synthesis. A thorough mathematical examination, based on the work of Kagan, is then presented for situations involving double asymmetric transformations of prochiral starting materials. Expressions relating the final quantities of the stereoisomeric products to the intermediary selectivity of each stereoselective process are presented based on these formulae. Finally, experiments designed to probe the selectivity of each stage of stereoselective bond construction in a double asymmetric process are presented. The compiled results are scrutinized in keeping with the previously derived equations, and these findings are analyzed to understand the nature of the double asymmetric processes in question.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Total Synthesis Cyanthiwigin Cyathane Double Asymmetric
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Awards:The Herbert Newby McCoy Award, 2011
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Stoltz, Brian M.
Thesis Committee:
  • Dervan, Peter B. (chair)
  • Reisman, Sarah E.
  • Grubbs, Robert H.
Defense Date:28 September 2010
Record Number:CaltechTHESIS:10122010-101531793
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:10122010-101531793
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6133
Collection:CaltechTHESIS
Deposited By: John Enquist
Deposited On:01 Nov 2010 20:53
Last Modified:01 May 2013 19:37

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