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The Synthesis and Late-Stage Diversification of the Cyanthiwigin Natural Product Core and Synthetic Insights Derived Therein

Citation

Kim, Kelly Eun-Jung (2017) The Synthesis and Late-Stage Diversification of the Cyanthiwigin Natural Product Core and Synthetic Insights Derived Therein. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9KP8046. http://resolver.caltech.edu/CaltechTHESIS:01202017-173233936

Abstract

Inspired by the therapeutic properties of many natural products and the ever-growing need for novel medicines, research programs for the late-stage diversification of complex molecular scaffolds have risen in popularity over the past few decades. In addition to generating a wide range of non-natural compounds for biological evaluation, these research efforts provide valuable synthetic insights into the preapration and reactivity of structurally intricate molecules. After a brief summary of the various strategies for late-stage diversification, examples of previous studies toward the derivatization of natural product-inspired scaffolds are highlighted.

A second-generation synthesis of the cyanthiwigin natural product core employing recently developed technologies is described. Re-optimization of the key double asymmetric catalytic alkylation transformation facilitates large-scale operations, and application of the aldehyde-selective Tsuji–Wacker oxidation enables productive recycling of an advanced intermediate. Together, these modifications expedite the preparation of the tricyclic cyanthiwigin framework on multi-gram scale.

The aldehyde-selective Tsuji–Wacker reaction is demonstrated to be effective for the oxidation of terminal alkenes bearing quaternary carbons at the allylic or homoallylic position. The synthetic utility of this method is extended through further transformation of the crude aldehyde products, permitting catalytic conversion of hindered terminal olefins to a variety of other synthetically useful functional groups.

With access to large quantities of the cyanthiwigin natural product core, a comparative study of various methods for intermolecular C–H oxidation was conducted. Examination of the reactivity of the cyanthiwigin framework under established conditions for allylic C–H acetoxylation, C–H hydroxylation, C–H amination, C–H azidation, and C–H chlorination reveals significant steric and electronic influences and suggests that functionalization is guided by innate reactivity within the substrate.

Finally, the preparation of several non-natural cyanthiwigin–gagunin hybrid molecules from the cyanthiwigin core is described. Preliminary studies toward the biological activities of synthetic intermediates are presented, and future directions for the synthesis of novel cyanthiwigin–gagunin hybrids are outlined.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:organic synthesis, natural products, natural product diversification, cyanthiwigin, C–H functionalization
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:
  • Grubbs, Robert H. (chair)
  • Stoltz, Brian M.
  • Gray, Harry B.
  • Reisman, Sarah E.
Defense Date:16 December 2016
Non-Caltech Author Email:mikyllek (AT) gmail.com
Funders:
Funding AgencyGrant Number
NSFCHE-1205646
Record Number:CaltechTHESIS:01202017-173233936
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:01202017-173233936
DOI:10.7907/Z9KP8046
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/acs.orglett.6b02962DOIArticle adapted for Ch. 2.
http://dx.doi.org/10.1021/jacs.6b08788DOIArticle adapted for Ch. 3.
http://dx.doi.org/10.1002/adsc.201500253DOIArticle relevant to Ch. 2.
ORCID:
AuthorORCID
Kim, Kelly Eun-Jung0000-0002-4132-2474
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:10019
Collection:CaltechTHESIS
Deposited By: Kelly Kim
Deposited On:01 Feb 2017 20:00
Last Modified:19 Mar 2018 20:53

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