Changing the nature of chemical synthesis through metal catalyzed C-H bond functionalization

Lead Research Organisation: University of Cambridge
Department Name: Chemistry

Abstract

Despite the changing face of science, the importance of synthesis - the ability to make molecules - has not diminished. To solve the increasingly complex synthetic problems posed by Nature, medicine and materials, we must question the dogma that defines what we know about making organic molecules. This proposal seeks to address the 'synthesis grand challenge' to develop a new blueprint for chemical synthesis that will revolutionize the way that molecules are made in response to societies needs. In contrast to conventional synthesis, that often requires numerous chemical operations to link two molecules together, we will activate traditionally inert, but ubiquitous, carbon-hydrogen (C-H) chemical bonds with metal catalysts and transform them directly into a useful chemical architecture thereby streamlining the synthesis of natural products, medicines and materials. This will impact broadly in academia, industry and across modern society, providing (a) better ways of making molecules, (b) cheaper medicines through accelerated drug discovery, (c) advances in materials and chemical biology through chemical modification of polymers and proteins, (d) potential advances in energy related research through understanding the mechanism of hydrocarbon oxidation, and (e) an enhanced chemistry knowledge base.

Planned Impact

The impact of this research programme arises from the development of a new blueprint for chemical synthesis that will revolutionize the way that molecules are made. In contrast to conventional synthesis strategies, the paradigm shifting research concepts of this proposal represent a major step-change from the chemist's current approach to molecule assembly. By using a metal catalyst to selectively transform specific C-H bonds in hydrocarbons directly into a useful chemical structure, we will make this traditionally unreactive and ubiquitous motif behave as a highly versatile functional group that will underpin efficient complex molecule synthesis. Chemical synthesis based on this concept will be Innovative, Green, and High value. The broader impact of this research will be felt across modern society because the molecules that make up everyday products such as medicines, plastics, chemical commodities and fuels are almost always derived from arene, alkene, or alkanes hydrocarbons. Therefore, the outputs from this research will provide (a) better ways of making molecules, that lead to (b) new & cheaper medicines through accelerated drug discovery, (c) advances in materials and chemical biology through chemical modification of macromolecules, (d) potential advances in energy related research through understanding the mechanism of hydrocarbon oxidation, and (e) an enhanced knowledge base that will underpin the future of the Britain's 'Chemical Economy'. The following will benefit from this research, and how will they benefit 1. Academic community Acquiring knowledge and skills through the development of new methods and theoretical advances related to the research. In particular students and PDRA's will see the biggest benefit 2. Industry Acquiring knowledge and skills through the development of new methods and theoretical advances related to the research. This will lead to faster ways to make medicines, more cost effective drug synthesis, new fine chemicals, new fuels and better energy efficiency 3. General Public The public will benefit from improved health, energy and quality of life as a result of this research, from cheaper medicines, new materials and fuels. 4. Those in Education Those in education will benefit from learning about paradigm shifting new research, inspire them to become tomorrow's scientists. 5. The UK's Economy Will see impact in the knowledge base through our research. Spin out companies will increase prosperity by creating jobs and new technology business. Leveraging funding from other agencies will be provide high value for money to the grant. What will be be done to ensure they benefit. Broad dissemination though high profile publication, conferences, meetings, workshops, scientific and popular media and public engagement. Consultancy with industry, collaboration with academia and industry will all be mechanism to implement the impact. Setting up a enterprise though spin-out companies and job creation will stimulate the economy. The training of the researchers will be the biggest driver to impact this research. This research will be paradigm shifting and its impact will affect many aspects of modern society. The PI is dedicated to ensuring that the research results in the maximum impact.

Publications

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

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Cahard E (2013) Copper-catalyzed intramolecular electrophilic carbofunctionalization of allylic amides. in Angewandte Chemie (International ed. in English)

 
Description Our early findings have resulted in a copper catalyzed enantioselective carbonyl arylation method. this is the first example of enolate derivative arylation that is enantioseelctive. We have also been able to develop new methods for CH activation in a range of molecules and use them to make the natural products and medicines that we laid out in the goals. e have also introduced a new enantioselective catalytic C-H activation reaction, as well as a series of C-H activation prcoesses for aliphatic amines.
Exploitation Route This will have significant impact in the pharmaceutical industry and in the academic community
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description our findings are being used in academic and industrial institutions. they are used to more efficiently make medicines. By this I mean that our methods have been used in industry to make molecules for biological assesment. However, due to the nature of their research it is impossible to know how or where they are used, other than by word of mouth, due to the proprierty nature of their research.
First Year Of Impact 2017
Sector Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Catalytic C-H activation of alilphatic amines
Amount £794,000 (GBP)
Funding ID EP/N031792/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2016 
End 09/2019
 
Description Development of Continuous Flow Processes for C-H activation 
Organisation University of Cambridge
Department Department of Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided the fundamentally chemistry expertise of C-H activation and preliminary mechanistic information. We worked with the student from Professor Lapkins groups to help them develop a process model that ultimately led to batch and continuous flow processes
Collaborator Contribution The student and Professor Lapkin provided the reaction engineering expertise, developed a process model and batch and flow reactors to perform the chemistry.
Impact Angew. Chem. Int. Ed., 2016, 128, 9024, Continuous-Flow Synthesis and Derivitization of Aziridines through Palladium-Catalyzed C(sp3)-H Activation DOI:10.1002/anie.201602483 Chemistry and Chemical Engineering
Start Year 2014