Total synthesis of bioactive natural products: Darobactin A and nimbolide

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Ryffel, David

Contributors dc:contributor

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

• Total Synthesis
• Bioactive Compounds

Statement dc:rights

• Copyright 2024 David Ryffel

Language dc:language

en, eng

Handle dc:identifier

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

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F125754