Visible-light-mediated synthetic strategies for the synthesis of α-tertiary amine derivatives

The α-tertiary amine—a nitrogen atom with an α-carbon bearing three C–C bonds—is a motif that is widely prevalent in pharmaceutical materials and natural products. As a result of the fully substituted α-centre, compounds bearing this fragment have a high degree of structural complexity. This increased topological complexity has the result that α-tertiary amines often display physiochemical properties that make them ideal candidates for lead generation in medicinal chemistry campaigns. The importance of this structure is further underscored by the wide variety of chemistries that have been developed for the synthesis of compounds containing it. Despite the many excellent chemistries that have been reported, there are few that are modular, mild, and multicomponent in nature. As such, there remains a need to develop synthetic methodologies which rapidly deliver materials containing the α-tertiary amine motif. This thesis describes the development of two distinct, multicomponent approaches for the rapid assembly of these important materials from relatively simple precursors; both methods are made possible by the action of visible light and rely on imines as key intermediates. Following an introduction to polar, radical, and molecular rearrangement methodologies that generate α-tertiary amine derivatives, Chapter 4 describes the development of a synthetic methodology which delivers a highly important class of α-tertiary amine derivatives: α,α-dialkyl-amino acids. Facilitated by the action of visible light in combination with a silane reductant, this approach delivers a structurally and functionally rich range of α-tertiary amino acid derivatives from simple, readily available starting materials: primary amines, α-ketoesters and alkyl iodides. Chapter 5 describes the results of investigations into a visible-light-mediated protocol for the synthesis of all-alkyl α-tertiary amine derivatives; three simple components were coupled, furnishing functionally and structurally rich higher order amines containing a α-trialkyl α-tertiary amine motif. Irradiation with visible light and the action of a highly reducing photocatalyst facilitated a challenging reduction of an in situ formed dialkylimine delivering the corresponding α-amino radical, which was engaged with a range of olefin acceptors.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• Blackwell, John

Advisor dc:contributor.advisor

• Gaunt, Matthew

• Photochemistry
• Synthetic organic chemistry
• Photoredox catalysis
• Free radical chemistry
• Amine synthesis
• α-Tertiary amines

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/93099e36-8cdf-434a-b79e-02b6f440a707/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0003-2003-6660
0000-0002-7214-608X

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/331047