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Palladium-Catalyzed Cascade Cyclizations in Natural Product Synthesis: Synthetic Studies of Noraugustamine and Falcatin A

Citation

Holman, Karli Rose (2022) Palladium-Catalyzed Cascade Cyclizations in Natural Product Synthesis: Synthetic Studies of Noraugustamine and Falcatin A. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/9r6z-tw08. https://resolver.caltech.edu/CaltechTHESIS:04292022-203100439

Abstract

Palladium-catalyzed cascade cyclizations present a powerful strategy for the rapid assembly of polycyclic skeletal frameworks, enabling the efficient synthesis of bioactive and structurally complex natural products. Herein, we review the field of palladium-catalyzed cascade cyclizations in natural product synthesis and describe our application of these transformations toward the total syntheses of noraugustamine and falcatin A.

Our approach to the Amaryllidaceae alkaloid noraugustamine was driven by the simultaneous disconnection of a C–C and a C–N bond, with the aim of forming both bonds and two of the target’s six rings in a single step. A radical cascade cyclization delivered noraugustamine but displayed poor regioselectivity for 6-exo-trig versus 7-endo-trig cyclization. Improved regioselectivity was achieved using a palladium-catalyzed Heck cyclization, leading to the development of a novel oxidative Heck/aza-Wacker cascade forming both of the desired bonds with good yield and selectivity. This transformation and the general lessons taken from this work should find broad utility in the design of cascade cyclizations toward alkaloids of similar complexity.

We also investigated a palladium-catalyzed carboetherification cascade toward the synthesis of the central five- and seven-membered rings of the myrsinane diterpene falcatin A. In this case, competitive C–O coupling, olefin insertion, and cyclopropanation hindered our efforts to develop the proposed transformation in a simplified model system. A stereoselective bromoetherification and a nickel-catalyzed Nozaki–Hiyama–Kishi reaction were ultimately successful, forming the targeted rings. Efforts to synthesize a fully elaborated cyclization substrate, translate the key steps from the model system, and complete the synthesis of falcatin A are ongoing.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:natural products; organic synthesis; transition metal catalysis; palladium-catalyzed cascades
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Not set
Research Advisor(s):
  • Reisman, Sarah E.
Group:Reisman Group
Thesis Committee:
  • Fu, Gregory C. (chair)
  • Reisman, Sarah E.
  • Stoltz, Brian M.
  • Hsieh-Wilson, Linda C.
Defense Date:25 April 2022
Funders:
Funding AgencyGrant Number
NSFCHE-1800536
National Defense Science and Engineering Graduate FellowshipUNSPECIFIED
NIHT32 GM07616
NSF Graduate Research FellowshipDGE-1144469
Heritage Medical Research Institute (HMRI)UNSPECIFIED
NIHR35GM118191
Record Number:CaltechTHESIS:04292022-203100439
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:04292022-203100439
DOI:10.7907/9r6z-tw08
Related URLs:
URLURL TypeDescription
http://doi.org/10.1039/D0CS01385DDOIpublication from which chapter 1 was adapted
http://doi.org/10.1021/acs.orglett.2c00948DOIpublication from which portions of chapter 2 were adapted
ORCID:
AuthorORCID
Holman, Karli Rose0000-0001-6424-9479
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14566
Collection:CaltechTHESIS
Deposited By: Karli Holman
Deposited On:23 May 2022 19:05
Last Modified:13 Jul 2022 22:37

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