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The Development of a Synthetic Strategy Toward Dihydrooxepine-Containing Epipolythiodiketopiperazines: Enantioselective Total Synthesis of (-)-Acetylaranotin and Related Investigations


Codelli, Julian Andrew (2014) The Development of a Synthetic Strategy Toward Dihydrooxepine-Containing Epipolythiodiketopiperazines: Enantioselective Total Synthesis of (-)-Acetylaranotin and Related Investigations. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9CR5RC4.


To the chemist, the epipolythiodiketopiperazine (ETP) fungal metabolites represent a fascinating family of natural products, not only for their unique structural elements, but also for the unusual modes by which they are hypothesized to exert their biological activities. Though efforts at the total synthesis of these molecules have led to an evolution of innovative synthetic methodologies and strategies, challenges remain—particularly with respect to acid-sensitive and highly oxygenated ETP structures, such as those containing one or more dihydrooxepine ring. As part of a broad research program targeting ETP natural products, we have developed a synthetic strategy towards dihydrooxepine-containing ETPs.

Herein, the enantioselective total synthesis of (–)-acetylaranotin is described. This represents the first total synthesis of any dihydrooxepine-containing ETP natural product. The key steps of the synthesis include an enantioselective azomethine ylide (1,3)-dipolar cycloaddition reaction to set the absolute and relative stereochemistry, a rhodium-catalyzed cycloisomerization/chloride elimination sequence to generate the dihydrooxepine moiety, and a stereoretentive diketopiperazine sulfenylation to install the epidisulfide.

Our strategy was extended to the synthesis of a small panel of epitetrathiodiketopiperazines, including the natural products SCH64877 and emethallicin C as well as analogs, which are currently being evaluated for biological activity. Furthermore, preliminary investigations into the synthesis of dihydrooxepine-containing macrocycles have been conducted, with a particular focus on the preparation of bis(ortho-methoxyaryl) ethers.

Finally, as part of our efforts to further explore interesting side reactions observed during synthetic studies toward acetylaranotin, a catalytic asymmetric double (1,3)-dipolar cycloaddition reaction was developed. This reaction provides access to highly substituted, enantioenriched pyrrolidizines from inexpensive, commercially available starting materials. Furthermore, the reactivity of diketopiperazine intermediates prepared en route to acetylaranotin toward aerobic oxidation was briefly explored.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:dihydrooxepine ; epidithiodiketopiperazine ; epipolythiodiketopiperazine ; natural product ; total synthesis
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.
Thesis Committee:
  • Stoltz, Brian M. (chair)
  • Bercaw, John E.
  • Tirrell, David A.
  • Reisman, Sarah E.
Defense Date:12 September 2013
Record Number:CaltechTHESIS:09172013-192454898
Persistent URL:
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URLURL TypeDescription adapted for Ch. 2 DOIArticle adapted for Ch. 4
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7958
Deposited By: Julian Codelli
Deposited On:06 Mar 2017 22:37
Last Modified:04 Oct 2019 00:02

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