Total synthesis of bioactive natural products: Darobactin A and nimbolide

Ryffel, David

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https://hdl.handle.net/2142/125754 Copy

Description

Title

Total synthesis of bioactive natural products: Darobactin A and nimbolide

Author(s)

Ryffel, David

Issue Date

2024-06-26

Director of Research (if dissertation) or Advisor (if thesis)

Sarlah, David

Doctoral Committee Chair(s)

Sarlah, David

Committee Member(s)

• White, M Christina
• Burke, Martin D
• Mitchell, Douglas A

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Total Synthesis
• Bioactive Compounds

Language

eng

Abstract

Natural products are important to the field of organic chemistry because they represent some of the most difficult synthetic challenges that face the field. Historically, many widely utilized reactions have been developed in the proving ground of total synthesis. Furthermore, many leaders of the field have been trained in laboratories that engage in total synthesis. Still, total synthesis remains relevant in the modern era of organic chemistry as increasingly complex natural products are isolated in even lower isolation yields. Additionally, these molecules oftentimes demonstrate unprecedented biological activities. To best capitalize on these unique structures, we must develop synthetic routes to these molecules while at the same time continuing to expand what is possible in the field of reaction discovery. The first chapter of this document describes the development of a synthetic route towards darobactin A, a recently discovered Gram-negative antibiotic. Our collaborative efforts towards darobactin A led to the development of novel approaches to unnatural amino acid derivatives and a halogen selective Larock macrocyclization. Furthermore, we found that the order of forming the two indole-containing macrocycles was crucial to delivering the desired atropisomer of the eastern macrocycle. Finally, a one-pot deprotection protocol was implemented to complete the first total synthesis of darobactin A in 16 steps longest linear sequence. The second chapter of this document describes the development of a synthetic route towards nimbolide, a potent anticancer agent. As part of these investigations, we have developed a palladium-mediated borylative Heck reaction to quickly access both diastereomers of a trans-decalin system that contains oxidation at the C4-position (nimbolide numbering). Selective oxidative manipulations were employed to avoid decarboxylation and provide a handle for introduction of the ester fragment on the B-ring. Finally, etherification, reductive cyclization, and lactonization will afford the natural product in a concise sequence.

Graduation Semester

2024-08

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/125754

Copyright and License Information

Copyright 2024 David Ryffel

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