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Convergent Synthetic Strategies toward Heterodimeric Bisindole Alkaloids and Polyoxygenated Diterpenoids


Reimann, Christopher Elias (2021) Convergent Synthetic Strategies toward Heterodimeric Bisindole Alkaloids and Polyoxygenated Diterpenoids. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/j1y9-g269.


Described herein are two projects in the field of natural product synthesis unified by their use of convergent strategies. An introduction into a relevant subclass of natural products, the bis(monoterpenoid) indole alkaloids, precedes our synthetic efforts. The molecules in this class are comprised of two monoterpenoid indole alkaloids conjoined by at least one carbon–carbon bond, and we review efforts to construct these dimers using semi-, partial, and total synthesis.

The account of our synthetic work begins with a detailed approach to the bis(monoterpenoid) indole alkaloid leucophyllidine. An enantioselective Pd-catalyzed decarboxylative allylic alkylation generates an α-quaternary-substituted lactam, which serves as a building block for both monomeric subunits. The northern fragment, eburnamonine, is constructed through a five-step sequence comprised of Fischer indole synthesis, Bischler–Napieralski cyclization, and diastereoselective hydrogenation. The southern fragment, eucophylline, is constructed through a ten-step formal synthesis comprised of a Friedländer quinoline synthesis, followed by two orthogonal C–H functionalizations that each displayed unexpected reactivity.

We then describe the evolution of a convergent coupling strategy to unify the two polycyclic fragments. While the "biomimetic" Friedel–Crafts and "bio-inspired" organometallic addition approaches failed, a Pd-catalyzed cross-coupling was ultimately successful in forging the key C–C bond. Extensive efforts to install the final stereogenic center with a variety of reducing agents were unsuccessful, and DFT modeling was utilized to probe the recalcitrant nature of the trisubstituted alkene. Preliminary investigations of a directed hydrogenation are then discussed.

Finally, we report an approach to the first total synthesis of the polyoxygenated diterpenoid (–)-scabrolide A. The route begins with the synthesis of an enantioenriched cyclopentendiol building block and an acyclic diyne from (R)-linalool and (R)-carvone, respectively. A Stieglich esterification and thermal [4+2] cycloaddition affords a tricylic intermediate bearing all 19 carbons observed in the natural product. The cycloheptenoid motif is installed through a photochemical [2+2]/fragmentation sequence, exploiting an unusual alkene protecting group strategy to counteract unexpected reactivity.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Total synthesis, natural products, alkaloids, diterpenoids
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:
  • Fu, Gregory C. (chair)
  • Stoltz, Brian M.
  • Ondrus, Alison E.
  • Reisman, Sarah E.
Defense Date:14 July 2020
Record Number:CaltechTHESIS:08052020-191152340
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for Chapter 4.
Reimann, Christopher Elias0000-0003-3274-7590
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13847
Deposited By: Christopher Reimann
Deposited On:15 Sep 2020 15:40
Last Modified:08 Nov 2023 00:39

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