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Approaches to the Total Synthesis of Aplysiatoxin


Dussault, Patrick H. (1987) Approaches to the Total Synthesis of Aplysiatoxin. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/zta1-3f55.


Approaches to the synthesis of the polyacetate tumor promoter aplysiatoxin (1a) are described. The spiroketal framework was convergently constructed in a heteroatom Diels-Alder cyclization to afford spiroketal 11. The desired spirocenter stereochemistry was achieved, in a key reaction pitting steric strain against the anomeric effect, by acid-catalyzed isomerization of spiroketal 12 to spiroketal13. Subsequent manipulation furnished alcohols 16A and 16B, which were the starting materials for investigations into macrocyclization and introduction of the C-3 lactol. 16A and 16B were efficiently converted to macrolactones 23A and 23B. The macrolactones were deprotected and brominated to furnish 27A and 27B, representing both possible C-15 epimers of 3-desoxyaplysiatoxin methyl ether. Attempted removal of the phenol methyl ether proved impossible. Nuclear Overhauser effect difference spectra on 27B showed signal enhancements within the rigid spiroketal framework analogous to those observed in derivatives of the natural product. Attempted transannular remote oxidation of C-3 using a C-9 alkoxy radical derived from the nitrite ester of 16B afforded, as the predominant product, the C-9 ketone resulting from fragmentation of the initial alkoxy radical; an alternate route involving allylic oxidation of the C-3 hydroxyethyl sidechain of 16A or 16B also failed to functionalize the C-3 position. Circular dichroism (CD) spectra of 16A and 16B imply that alcohol 16B contains the natural (S) stereochemistry at the C-15 methyl ether.

[Chemical structures 1a, 11, 12, 13, 16A, 16B, 23A, 23B, 27A, and 27B. See abstract in scanned thesis for details.]

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Chemistry
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Ireland, Robert E. (advisor)
  • Dervan, Peter B. (co-advisor)
Thesis Committee:
  • Grubbs, Robert H. (chair)
  • Dervan, Peter B.
  • Chan, Sunney I.
  • Myers, Andrew G.
  • Ireland, Robert E.
Defense Date:26 November 1986
Funding AgencyGrant Number
Record Number:CaltechTHESIS:04122019-170707466
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11458
Deposited By: Mel Ray
Deposited On:15 Apr 2019 16:33
Last Modified:16 Apr 2021 22:30

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