The development of dearomative functionalizations and their use in the total synthesis of bioactive natural products

The dearomatization of aromatic compounds, some of the most abundant feedstock chemicals, has been heavily studied over the past century. Despite their widespread use, most methods for dearomatization do not result in the introduction of additional functionality. This dissertation describes the use of N-methyl-1,2,4-triazoline-3,5-dione (MTAD) in the development of various dearomative functionalization reactions as well as its use in the total synthesis of bioactive natural products. A total synthesis of the highly potent anticancer natural products, the Amaryllidaceae isocarbostyril alkaloids, was developed. The brevity and scalability of our synthesis was due to the development of a nickel-catalyzed asymmetric dearomative carboamination reaction, providing a stereodefined diene that provided facile access to the cyclitol core of these natural products. The utility of this dearomative functionalization reaction led us to explore similar types of reactivity, ultimately leading to the development of dearomative cyclopropanation, a dearomative Pauson-Khand reaction, and three different dearomative allylic substitution reactions — 1,4-hydroamination, trans-1,4- carboamination, and syn-1,2-diamination. We also explored the dearomative functionalization of heteroarenes and found that substituted pyridines were viable substrates. Dearomative dihydroxylation, diimide reduction, and epoxidation were all able to provide dearomatized products in synthetically useful yields. Further elaboration of these substrates was able to provide rapid access to substituted piperidines and piperidones.

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

2022

Author dc:creator

• Bingham, Tanner William

Contributors dc:contributor

• Sarlah, David
• Denmark, Scott E
• Hergenrother, Paul J
• White, Christina M

• Total Synthesis
• Scalability
• Dearomatization
• Aromatic Compounds
• MTAD
• Amaryllidaceae Isocarbostyril Alkaloids

Statement dc:rights

• Copyright 2022 Tanner Bingham

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/115652

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F115652