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Progress Toward the Enantioselective Total Synthesis of Ineleganolide and the Polycyclic Norcembranoid Diterpenes and Construction of the Ineleganoloids

Citation

Craig, Robert Allen, II (2015) Progress Toward the Enantioselective Total Synthesis of Ineleganolide and the Polycyclic Norcembranoid Diterpenes and Construction of the Ineleganoloids. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z92B8VZ6. http://resolver.caltech.edu/CaltechTHESIS:05242015-134810426

Abstract

Ineleganolide, horiolide, kavaranolide, sinulochmodin C, scabrolide A, scabrolide B, and yonarolide are related polycyclic furanobutenolide norcembranoid natural products that exhibit potent biological activity, and feature highly oxygenate carbocyclic scaffolds with complex stereochemical frameworks. Herein, we describe a unified synthetic approach toward ineleganolide and the related furanobutenolide norcembranoids. Assembly of the tetracyclic scaffold of ineleganolide is accomplished in a convergent manner from (R)-carvone and an enantioenriched cis-1,3-cyclopentenediol fragment, which is constructed by a key enantioselective allylic alkylation. From the combined product of the two major fragments, we employ a tandem intramolecular cyclopropanation/Cope rearrangement to furnish the cycloheptene carbocyclic core characteristic of ineleganolide.

Synthetic manipulations of this carbocyclic core are extensively investigated; several constitutional isomers of ineleganolide are synthesized through these studies. Many approaches are explored to assist in the completion of the synthesis. Computational studies inform our understanding of the conformational bias of late-stage intermediates. The retroaldol-aldol carbocyclic isomerization from the core of ineleganolide to the core of sinulochmodin C is also investigated.

Additionally, our work on the (3 + 2) cycloadditions of heterocumulenes with donor–acceptor cyclopropanes and with N–H- and N–sulfonyl aziridines is disclosed. The exploration of substrate scope, reaction mechanism, and the enantiospecific formation of heterocyclic products in investigated.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:ineleganolide; ineleganoloid; cycloaddition; allylic alkylation; total synthesis; enantioselective; bioactive; antileukemic; furanocembranoid; norcembranoid; diterpene
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Awards:Graduate Deans’ Award For Outstanding Community Service, 2015
Thesis Availability:Restricted to Caltech community only
Research Advisor(s):
  • Stoltz, Brian M.
Thesis Committee:
  • Dervan, Peter B. (chair)
  • Reisman, Sarah E.
  • Grubbs, Robert H.
  • Stoltz, Brian M.
Defense Date:11 May 2015
Funders:
Funding AgencyGrant Number
National Cancer Institute/National Institutes of HealthF31A174359
Record Number:CaltechTHESIS:05242015-134810426
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:05242015-134810426
DOI:10.7907/Z92B8VZ6
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ol3027297DOIArticle adapted for chapter 2
http://dx.doi.org/10.1021/ol302494nDOIArticle adapted for chapter 5
http://dx.doi.org/10.1002/chem.201303699DOIArticle adapted for chapter 6
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8884
Collection:CaltechTHESIS
Deposited By: Robert Craig
Deposited On:07 Mar 2017 18:25
Last Modified:13 Sep 2017 23:38

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