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Evolving Strategies Toward the Synthesis of Curcusone C

Citation

Wright, Austin Cameron (2020) Evolving Strategies Toward the Synthesis of Curcusone C. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/6FET-N212. https://resolver.caltech.edu/CaltechTHESIS:03272020-105741489

Abstract

Curcusone C is a tricyclic diterpenoid natural product possessing potent anti-cancer activities as well as a structurally unusual 2,3,7,8-tetrahydroazulene-1,4-dione skeleton. Herein, we report our evolving synthetic efforts toward the divergent total syntheses of ent-curcusone C and several structural congeners, which commenced with a Suzuki coupling of the peripheral carbon-based rings. Whereas the boronate partner was constructed from cyclopentenone, the halide partner could be elaborated from (S)-perillaldehyde. The alcohol coupling product was next esterified, then subjected to diazo transfer and cyclopropanation to produce a lactone. The resulting vinyl cyclopropane moiety was exposed to Kauffmann olefination conditions in order to form a divinylcyclopropane, which upon reductive lactone opening smoothly underwent a Cope rearrangement to establish the essential tricyclic core embedded in the curcusones.

Due to ongoing issues of scalability as well as unsatisfactory yields for the key cyclopropanation step, this route was ultimately abandoned, and an alternative strategy was devised which instead relied on a cross-electrophile coupling to join the peripheral rings. We further found that a central ring could be constructed via either Stetter annulation or ring-closing metathesis (RCM), accessing the tricyclic core of the curcusones in only 9 steps. Potential end-game strategies are further described.

We additionally report our experimental research into the acyl-amination of in situ-generated arynes using symmetrical imides. The difunctionalized aryl products could be further derivatized to synthetically useful indoles and quinolones via McMurray coupling and Camps cyclization, respectively.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Curcusone C, natural product total synthesis, cross-coupling, catalysis, organic chemistry, aryne insertion
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Stoltz, Brian M.
Thesis Committee:
  • Reisman, Sarah E. (chair)
  • Peters, Jonas C.
  • Ondrus, Alison E.
  • Stoltz, Brian M.
Defense Date:27 January 2020
Funders:
Funding AgencyGrant Number
NSF1800511
Record Number:CaltechTHESIS:03272020-105741489
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:03272020-105741489
DOI:10.7907/6FET-N212
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acs.orglett.9b03829DOIInformation relevant to Chapter 1.
https://doi.org/10.1039/C9SC04127CDOIInformation relevant to Chapter 1.
https://doi.org/10.1021/acs.orglett.6b00994DOIInformation relevant to Chapter 2.
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13665
Collection:CaltechTHESIS
Deposited By: Austin Wright
Deposited On:06 Apr 2020 21:21
Last Modified:13 Apr 2020 16:13

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