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Fragment Coupling Approach To C₁₉- AND C₂₀-Diterpenoid Alkaloids: Total Synthesis of (–)-Talatisamine, (–)-Liljestrandisine, and (–)-Liljestrandinine

Citation

Fastuca, Nicholas James (2022) Fragment Coupling Approach To C₁₉- AND C₂₀-Diterpenoid Alkaloids: Total Synthesis of (–)-Talatisamine, (–)-Liljestrandisine, and (–)-Liljestrandinine. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/vf11-jy04. https://resolver.caltech.edu/CaltechTHESIS:05292022-214045444

Abstract

A unified, convergent fragment coupling approach to the C₁₉- and C₂₀-diterpenoid alkaloid natural products is presented. The highly-caged aconitine, denudatine, and napelline cores are disconnected through the central B-ring cyclohexane to an A/E/F-ring fragment common to the structures all three subfamilies. 1,2-addition of an appropriate organometallic C/D-bicycle to an A/F-ring hydrindane epoxy ketone fragment followed by a Lewis acid-catalyzed semipinacol reaction couples the two fragments together and sets a key all-carbon quaternary center at C11. This strategy is realized in the synthesis of the C₁₉-aconitine core by using a [3.2.1]-bicyclooctene C/D-fragment as the nucleophile in the 1,2-addition. This C/D-fragment is prepared using a meta-photocycloaddition; this represents an alternative approach to the commonly employed biomimetic Wagner-Meerwein rearrangement of a [2.2.2]-bicyclooctane.

To complete the aconitine core, a radical cyclization cascade to form the E-ring piperidine and B-ring cyclohexane in a single step is investigated. N-centered radicals were evaluated to initiate the cascade via a 6-exo-trig cyclization. A neutral aminyl radical gave rise to an unexpected Hoffman-Löffler-Freytag type product resulting from 1,5-hydrogen atom transfer. Employing Lewis-acidic single electron reducing metal catalyst led to formation of the E-ring cyclized product, however the second cyclization to close the B-ring did not occur.

As an alternative approach, the E-ring was closed via an intramolecular aziridination. Treatment of this aziridine with acetyl bromide results in an aziridine-opened alkyl bromide product. This alkyl bromide is used as a functional group handle to form the final ring of the aconitine core. From there, the total synteheses of the C₁₉-diterpenoid alkaloids (–)-talatisamine, (–)-liljestrandisine, and (–)-liljestrandinine were completed in short order. These synthetic efforts led to revision of the proposed structure of (–)-liljestrandisine.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:diterpenoid; alkaloid; natural product; total synthesis; fragment-coupling
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Reisman, Sarah E.
Group:Reisman Group
Thesis Committee:
  • Stoltz, Brian M. (chair)
  • Fu, Gregory C.
  • Peters, Jonas C.
  • Reisman, Sarah E.
Defense Date:26 April 2022
Funders:
Funding AgencyGrant Number
NIHT32GM007616
Record Number:CaltechTHESIS:05292022-214045444
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:05292022-214045444
DOI:10.7907/vf11-jy04
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acscentsci.1c00540DOIArticle adapted for portions of Chapters 2–4.
https://doi.org/10.15227/orgsyn.097.0327DOIArticle adapted for a portion of Chapter 2.
ORCID:
AuthorORCID
Fastuca, Nicholas James0000-0003-4081-6031
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14650
Collection:CaltechTHESIS
Deposited By: Nicholas Fastuca
Deposited On:07 Jun 2022 15:35
Last Modified:13 Jul 2022 22:27

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