The photoredox-catalysed generation and reaction of alkyl α-amino radicals for α-tertiary amine synthesis

This thesis comprises three projects focused on the synthesis of α-trialkyl-α-tertiary amines, exploiting photo-reductively generated alkyl α-amino radicals as intermediates. The first project describes the development of a multicomponent method for the photoredox-mediated synthesis of α-trialkyl α-tertiary amines (ATAs). This highly hindered scaffold is generated from primary amine, alkyl ketone and alkene feedstocks, via the single electron reduction of an in-situ formed imine, followed by 1,2-radical addition. The transformation was found to be broad-scoping with respect to all three components and its utility demonstrated in the single step synthesis of the blockbuster drug fingolimod. Mechanistic studies enabled a catalytic cycle to be proposed and highlighted the importance of a key 1,5-HAT process in driving the forward reaction. Subsequently, it was discovered that by employing a chiral amine as a starting material, stereochemical information could be transferred to the newly formed ATA. Further investigation highlighted phenylglycinol methyl ether as the optimal chiral amine transfer (CAT) reagent, which enabled the generation of a variety of enantioenriched ATAs. Computational studies supported a stereochemical model in which an intramolecular hydrogen-bond rigidifies the transition state of the enantiodetermining step, allowing an efficient relay of chiral information to the fully substituted centre. The final project describes efforts toward the total synthesis of the α-trialkyl-α-tertiary amine containing marine alkaloid, (±)-cylindricine C. Whilst attempts to incorporate the previously outlined methodology proved challenging, the synthesis of unnatural isomer, (±) 2,13-di-epi-cylindricine C, was achieved in an overall yield of 5.5% over 12 linear steps.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Harris, Georgia

Advisor dc:contributor.advisor

• Gaunt, Matthew

• Catalysis
• Organic Chemistry
• Photoredox
• Synthesis

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/327f8bb0-e8ad-465e-a238-2e1a9e449b8c/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.105907

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/364120