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Progress toward the synthesis of (+)-zoanthenol and the development of an asymmetric Tsuji allylation reaction

Citation

Behenna, Douglas C (2007) Progress toward the synthesis of (+)-zoanthenol and the development of an asymmetric Tsuji allylation reaction. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-10312006-164725

Abstract

The stereoselective synthesis of all carbon quaternary stereocenters is an important problem in synthetic chemistry due to their common occurrence in bioactive compounds. The zoanthamine class of marine natural products highlights the challenge in constructing such stereocenters. After a summary of the isolation, structure determination, and biological activities of the zoanthamine natural products, published approaches toward their chemical synthesis are reviewed.

Synthetic strategies toward the carbocyclic portion of zoanthenol focus on the synthesis of the three challenging quaternary stereocenters located on the central C ring. An unusual acid-mediated SN' cyclization of a nucleophilic arene with an allylic alcohol forms the B ring and diastereoselectively constructs the benzylic C(12) quaternary stereocenter. However, difficulties with late-stage installation of the remaining C(9) quaternary stereocenter compelled the use of C ring synthons containing the vicinal C(9) and C(22) stereocenters installed at an early stage in the synthesis. Desymmetrization of a meso-anhydride containing vicinal quaternary stereocenters accomplishes this goal in an enantioselective fashion. Several C ring synthons bearing the vicinal quaternary stereocenters are elaborated with A ring fragments, and several methods for the formation of the C(11)-C(12) bond in these systems are explored. Ultimately, a radical conjugate addition strategy provides the carbocyclic core of zoanthenol with the correct relative configuration of all three quaternary stereocenters.

These efforts toward the synthesis of zoanthenol highlight the difficulty in generating enantioenriched alpha-quaternary cycloalkanones derived from ketones with multiple acidic alpha-hydrogens. The first direct catalytic enantioselective access to such products is achieved by the application of chiral bidentate phosphinooxazoline (PHOX) ligands to Tsuji’s non-enantioselective allylation reactions. Cyclic allyl enol carbonates, silyl enol ethers, and allyl beta-ketoesters all provide uniformly excellent yields and high enantioselectivity in the reaction. The limitations on the substrate scope of the reaction are discussed. Preliminary studies into the mechanism of these allylation reactions with prochiral enolate fragments suggest that they occur by a different mechanism than the outer-sphere nucleophilic attack commonly proposed in the alkylation of prochiral allyl fragments.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Asymmetric Allylation; Asymmetric Catalysis; Decarboxylative Allylation; Total Synthesis; Zoanthamine Alkaloids; Zoanthenol
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Awards:The Herbert Newby McCoy Award, 2007
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Stoltz, Brian M.
Thesis Committee:
  • Bercaw, John E. (chair)
  • Stoltz, Brian M.
  • Grubbs, Robert H.
  • Goddard, William A., III
Defense Date:6 November 2006
Record Number:CaltechETD:etd-10312006-164725
Persistent URL:http://resolver.caltech.edu/CaltechETD:etd-10312006-164725
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5258
Collection:CaltechTHESIS
Deposited By: Imported from ETD-db
Deposited On:27 Nov 2006
Last Modified:08 Mar 2013 19:12

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