A Radical Approach to C-H Alkylation

Project: Research council

Description

Organic chemistry has transformed the way we live. It has allowed us to create molecules to treat disease, to grow crops to sustain our population, and to create high-tech materials used in modern technology. Organic molecules by their very nature contain dozens of C-H bonds which make up their hydrocarbon framework, but these are typically "inert" and unreactive. The field of C-H functionalisation aims to find ways of selectively replacing one or more of these C-H bonds with other chemical groups, allowing chemists to build up molecules in a much more efficient, cost-effective and sustainable fashion. Given the dramatic alterations of chemical and biological properties that can arise from the incorporation of simple aliphatic groups (e.g., Me, Et, i-Pr), the alkylation of C-H bonds is considered to be one of the most desirable substitutions from a structural-diversification viewpoint. However, despite some spectacular advances in this area, C-H alkylation is still not a routine disconnection in organic synthesis. In the case of C(sp3)-H bonds in aliphatic compounds, most solutions to the problem have relied upon hydrogen atom abstraction to generate alkyl radical intermediates, followed by trapping of these radicals with alkylating agents. As radicals alone do not possess the necessary reactivity to engage saturated alkyl electrophiles directly, transition metals such as nickel have been used to usher the radical intermediates into organometallic catalytic cycles. However, a reliance on transition metal catalysts to forge C(sp3)-C(sp3) linkages can lead to problems in a drug development setting, as these catalysts are prone to poisoning by the basic functionalities commonly encountered in 'drug-like' molecules (e.g., amines, certain heteroaromatics). Additionally, trace metal contamination is a serious concern in a pharmaceutical setting. For these reasons, a metal-free approach to C(sp3)-H bond alkylation could prove transformative in organic synthesis.

In this project, we will develop a conceptually-distinct approach to the catalytic alkylation of C(sp3)-H bonds - to install simple alkyl groups - that does not require organometallic catalysis. Given the recent industry call for methods that "tolerate nitrogen heteroatoms and (unprotected) polar functional groups", our efforts will be focused primarily on the C(sp3)-H alkylation of aliphatic amines. Mild, catalytic protocols for the substitution of alpha-C-H bonds in unprotected amines with simple alkyl groups are currently unknown, and the invention of robust procedures to effect these transformations would constitute a step-change in the synthesis of small molecule drugs. After all, two of the top ten most widely-used synthetic methods in medicinal chemistry (i.e., N-alkylation and reductive amination) are specifically used to target substituted amines, but both rely on C-N as opposed to C-C bond formation. Tellingly, the third most utilised reaction in the pharmaceutical industry is addition or removal of amine N-protecting groups (i.e., Boc), which inherently speaks to a paucity of synthetic methods compatible with unprotected amines. Given that over 80% of drugs or drug candidates contain amine functionality, it is clear that new and enabling synthetic methods to access complex amines in a scalable and sustainable fashion would have demonstrable impact upon the health and wellbeing of our society.
StatusNot started
Effective start/end date1/10/1930/09/21