Catalytic C-H Activation of Aliphatic Amines

Lead Research Organisation: University of Cambridge
Department Name: Chemistry

Abstract

Aliphatic amines are central to the function of many biologically active molecules as evidenced by their prevalence in a large number of pharmaceutical agents. The groups appended to these nitrogen atoms are crucial in determining the physical properties of the amine and are linked to how well it interacts with a biological target.
Despite the apparent simplicity of the aliphatic amine motif, the number of general methods available for the synthesis of this important feature is surprisingly small. Methods such as reductive amination, alkylative tactics, hydroamination and transamination have met the demand for many years, however the development of new straightforward methods for the synthesis of complex systems is essential for the continued advance of synthesis. A systematic method for the synthesis of complex aliphatic amines would be valuable to practitioners of drug discovery, and a streamlined approach to these molecules could involve a catalytic process capable of transforming simple, readily available aliphatic amines into complex variants via selective functionalization of their C-H bonds.
Methods that enable the practical and selective functionalization of inert aliphatic C-H bonds have applications in fields that range from fine chemical production to drug discovery. Transition metal catalysis has emerged as a powerful tool to activate these traditionally unreactive C-H bonds. Several classes of functional group can direct C-H activation via a process called cyclometallation; coordination of the metal centre to a proximal Lewis basic atom steers the catalyst into position where the C-H bond can be cleaved. Reaction of the resulting C-metal bond with an external reagent leads to an overall transformation that sees a C-H bond converted into a versatile motif. Cyclometallation has led to a number of useful catalytic C-H functionalization processes that have expanded the chemists toolbox of available reactions; tailoring the electronic properties of directing functionalities has enabled cyclometallation in aliphatic hydrocarbons displaying carboxylic acid, hydroxyl groups, and derivatives of these motifs. Despite these advances, related transformations on aliphatic amines are rare and successful examples require the use of strongly electron withdrawing sulfonyl or bespoke directing groups to modulate the metal coordinating power of the nitrogen atom. As such, their synthetic intractability frequently precludes the wider application of strategic C-H bond activation in aliphatic amine systems.
The overarching aim of this proposal is to establish aliphatic amines as viable feedstock molecules for C-H activation using a novel activation strategy. This will provide distinct C-H disconnections that will form part of a C-H activation road map for synthesis. The aliphatic amine motif is so ubiquitous in pharmaceutically relevant molecules that it is considered a 'privileged' feature and so we will investigate how the multi-faceted C-H activation platform can be translated into viable applications that have impact drug discovery and development.

Planned Impact

Potential economic and societal impacts

Economic -

(1) the proposal will deliver a new platform methodology that directly addresses the preparation of a class of compounds (aliphatic amines) that are central to the pharmaceutical industry. In addition, the methodology can generate previously inaccessible variants of these important compounds that have unexplored physical and biological properties. In addition to providing a new synthetic platform methodology for us in the UK Pharma sector, we will also provide a people pipeline of trained researchers in the cutting edge, state-of-the-art synthetic chemistry.

(2) by providing samples of novel amines to other academic groups we create the possibility for others to use our advances to explore new areas of potential impact within their own fields of research

(3) spin out opportunities will be investigated in the areas of novel fragment compounds for building blocks, exploitation of preliminary results (eg the fingolimod project), resurrecting previously failed medicines. Discussions have already commenced with Cambridge Enterprise based on the preliminary studies undertaken.

(4) chemical re-purposing failed clinical candidates through late-stage modification could lead to new medicines. one successful compound could have a huge economic impact.

(5) Industry collaboration, secondment and steer will provide knowledge transfer

Societal

(1) there is a potential for the discover leads for new medicines from this project - each of the economic impacts 1-4 could also lead to the new ways to treat disease. the societal impact of these discoveries could be huge.

(2) knowledge transfer - through the various dissemination outlets (and others described in the impact summary) we will be able to have impact on chemists across the world who make amine containing molecules. Primarily, this will be realised in the pharmaceutical industry, but as the new science evolves, other application will be discovered. For example, some of the compounds we can make are analogs of polymerization initiators and their novel structures may lead to novel materials.

(3) educational - we are proposing to create a series of C-H activation 'infographics' to help inform pre-university (and undergraduates) about this important area.

Publications

10 25 50

publication icon
Cabrera-Pardo J (2017) Selective Palladium(II)-Catalyzed Carbonylation of Methylene ß-C-H Bonds in Aliphatic Amines in Angewandte Chemie International Edition

publication icon
Rodrigalvarez J (2019) Catalytic C(sp3)-H bond activation in tertiary alkylamines in Nature Chemistry

 
Description Strained ß-lactam rings are a key feature of penicillin and some other drugs. We designed a versatile route to these four-membered ring motifs through the palladium catalyzed coupling of carbon monoxide with secondary amines. The bulky carboxylate ligand appears to facilitate preliminary CO incorporation into a Pd anhydride, which is then attacked by the amine to set up ring closure via C-H activation. This approach broadens the substrate scope compared with a previous scheme in which C-H activation preceded CO insertion.
Exploitation Route We have demonstrated proof of concept on a continuous flow process for this reaction in collaboration with Professor Alexei Lapkin in Chemical Engineering
Sectors Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL http://science.sciencemag.org/content/354/6314/851
 
Description The problem is that it is impossible to know where this chemistry is used in industry becasue of the confidential nature of the research in industry (especially in pharma). Therefore, while I am aware of some of our work being used, by word of mouth, i do not know where or how. It has clearly influced academic research becuase work emanting from this grant is very highly cited.
First Year Of Impact 2018
Sector Chemicals
Impact Types Economic

 
Title Method for labelling nucleic acid 
Description Method to detect N6 methyl adenosine in DNA 
IP Reference PCT/EP2021/075252 
Protection Patent application published
Year Protection Granted 2021
Licensed Yes
Impact A method has been developed to target N6 methyl adenosine in DNA that may have implications for epigenetics and epitranscriptomics. Work is in an early stage but has been liscenced to Cambridge Epigenetix