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Studies in Palladium-Catalyzed Allylic Alkylation: Enantioselective Total Syntheses of Structurally Diverse Alkaloids

Citation

Pritchett, Beau Patrick (2017) Studies in Palladium-Catalyzed Allylic Alkylation: Enantioselective Total Syntheses of Structurally Diverse Alkaloids. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9ZG6Q9Q. http://resolver.caltech.edu/CaltechTHESIS:05232017-150306598

Abstract

Presented herein are three projects, all unified by the use of palladium-catalyzed, enantioconvergent, decarboxylative allylic alkylations to synthesize stereochemically rich, nitrogen-containing small molecules. The ubiquity of nitrogen in biologically active natural products and pharmaceutical ingredients necessitates perpetual exploration and development of relevant small molecules. Highly robust palladium-catalyzed allylic alkylation reactions of non-stabilized enolates enable the construction of sterically encumbered all-carbon quaternary and tetrasubstituted tertiary stereocenters present within such targets.

The successful development of a novel substrate class for palladium-catalyzed allylic alkylation, namely dihydropyrido[1,2-a]indolones (DHPIs), has enabled divergent syntheses of multiple monoterpene indole alkaloids. By setting the C20 quaternary stereocenter present within these alkaloids at an early stage in the synthesis, the remaining stereocenters can be forged with exquisite levels of control. Critical to the success of this work was the identification of highly tunable and predictable cyclizations between an indole and a C2-tethered iminium moiety. Regiodivergent cyclizations were used to complete the first catalytic enantioselective total synthesis of (–)-goniomitine, along with efficient formal syntheses of (+)-aspidospermidine and (–)-quebrachamine. Stereodivergent cyclization strategies were then employed in total syntheses of (+)-limaspermidine and (+)-kopsihainanine A. Synthetic efforts toward the highly caged Kopsia alkaloids (–)-kopsinine, (–)-kopsinilam, and (–)-kopsifoline G are also discussed.

Lastly, the synthesis of challenging alpha-quaternary Mannich-type products was accomplished through a simple, elegant inversion of strategy. The chiral building blocks made available by this technology bear significant potential in the realm of medicinal chemistry. Furthermore, this work enabled rapid total syntheses of (–)-isonitramine and (+)-sibirinine.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:total synthesis, palladium catalysis, monoterpene indole alkaloids, allylic alkylation, indole-iminium cyclization, enantioselective, aspidosperma alkaloids
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)
  • Davis, Mark E.
  • Grubbs, Robert H.
  • Stoltz, Brian M.
Defense Date:9 May 2017
Funders:
Funding AgencyGrant Number
National Institutes of Health (NIH)R01GM080269
National Science Foundation Graduate Research FellowshipDGE-1144469
Record Number:CaltechTHESIS:05232017-150306598
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:05232017-150306598
DOI:10.7907/Z9ZG6Q9Q
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1002/anie.201608138DOIArticle Adapted for Chapter 2
http://dx.doi.org/10.3987/COM-16-S(S)80DOIArticle Adapted for Appendix 1
http://dx.doi.org/10.1021/ja512124cDOIArticle Adapted for Chapter 4
ORCID:
AuthorORCID
Pritchett, Beau Patrick0000-0001-9922-9160
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:10195
Collection:CaltechTHESIS
Deposited By: Beau Pritchett
Deposited On:06 Jun 2017 17:45
Last Modified:08 Jun 2018 18:23

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