A Multi-Component Strategy for the Synthesis of Complex Aliphatic Amines using Photo-redox Catalysis

Lead Research Organisation: University of Cambridge
Department Name: Chemistry


Alkylamines are ubiquitous amongst pharmaceuticals, small-molecule biological probes, natural products and pre-clinical candidates1. Despite their importance, amine synthesis is still dominated by two methods: N-alkylation and carbonyl reductive amination2. The increasing demand for 'sp3-rich' molecules in drug-discovery3 continues to drive development of practical catalytic methods to synthesize complex saturated alkylamines4-6. In particular, processes that transform diverse, readily-available feedstocks into structurally diverse sp3-rich architectures provides a strategic advantage in complex alkylamine synthesis. Here, we propose a multicomponent reductive photocatalytic technology that combines readily-available dialkylamines, carbonyls and radical acceptor feedstocks to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This process involves a visible-light-mediated reduction of in-situ generated iminium ions, selectively furnishing previously inaccessible alkyl-substituted alpha-amino radicals, which engage radical acceptors and lead to C(sp3)-C(sp3) bond formation. The potential of this operationally straightforward reaction suggests a broad functional group tolerance, could facilitate the synthesis of drug-like amines not readily accessible by other methods and would be amenable to late-stage functionalization applications, making it of interest in pharmaceutical research and other areas.

Planned Impact

Access to novel biologically active molecules to treat diseases continues to be a major bottleneck in the pharmaceutical and SME biotech industries, potentially costing many lives and many £millions per year in healthcare investment and loss in productivity. In 2016, the Pharmaceutical Industry's estimated annual global spend on research and development (R&D) was over $157 billion. At a national level, the pharmaceutical sector accounted for almost half of the UK's 2016 £16.5bn R&D expenditure, with £700 million invested in pre-clinical small molecule synthesis, and 995 pharmaceutical related enterprises (big pharma, SMEs, biotech & CROs) employing around 23,000 personnel in UK R&D. The impact of this sector and its output on the nation's productivity is indisputable and worthy of investment in new approaches and technologies to fuel further innovation and development. An increasing focus on precision medicine and genetic understanding of disease will lead to a dramatic increase in the number of potent and highly selective molecular targets; identifying genetically informed targets could double success rates in clinical development (Nat. Gen. 2015, 47, 856). A recent perspective described advances in organic synthesis as essential to the future of drug discovery (Nat. Chem. 2018, 10, 383). It has been suggested that increasing the saturated content (sp3 carbons) of pharmaceutical candidates could raise the chance of clinical success. There is an urgent need for new chemistry that generates non-planar polar aliphatic amine scaffolds to support the exploration of biologically relevant chemical space. Therefore, the development of new catalytic methods that rapidly assemble complex alkyl amines is a key challenge to the continued advance of synthetic medicinal chemistry and drug discovery. Increasing the saturated content (sp3 carbons) of pharmaceutical candidates has been suggested to increase the chance of clinical success. Given that alkylamines appear in approximately 35% of pharmaceuticals (& about 60% contain a TAA), then the chemists' ability to make novel variants of these functional molecules efficiently becomes critical. This work will also be important for the agrochemical, biotech, synthesis CRO's, as well as materials and fine chemical industries, all of which use TAAs. The research could be crucial to the future prosperity of UK Pharma & biotech, as well as addressing unmet health needs. The proposal has a good fit with the EPSRCs portfolio in healthcare technologies, manufacturing for the future & food security and sustainability through catalysis & synthesis. The highly educated and trained synthetic chemists produced through this research program will be able to translate the outputs of this research through their future careers in chemical research
Description We have disocvered new ways to make alkylamines stimulated by visible light activated catalysts. These catalysts stimulate the formation of a reactive intermediate that enables the coupling of multiple feedstocks to form very useful amines that are of particular relevance in medicinal chemistry.
Exploitation Route Chemists in industry are using this work to make proprietry molecules for their programmes. This has resulted from consulatncies and interactiing directly with chemists in industry.
Sectors Chemicals,Healthcare