Light-Driven Multicomponent C-C Couplings: New Avenues to Bioactive Molecules

Synthetic chemistry lays at the heart of Science and Technology and has greatly enabled the development of important life-changing discoveries. For instance, the discovery of novel powerful medicines generally requires the study of a number of structural analogues of complex chemical structures. Traditionally, to construct these analogues, pairs of elementary molecular fragments are connected in a sequence of chemical steps to form new carbon-carbon (C-C) bonds. This enhances the complexity of the intermediates until the desired molecule is achieved. However, the variety of structures accessible is generally limited by the chemical space available and the time/resources required to achieve the desired compound, defining strict boundaries to chemists' imagination for the construction of the medicines of tomorrow.
In contrast to traditional pair assembly chemistry, this proposal introduces a novel visible-light driven process which allows the multicomponent assembly of complex molecular fragments in a single chemical step. Two new C-C bonds are formed in the process, one of which is a synthetically versatile double bond, useful moiety for further structure manipulation. The chemistry is triggered by an unprecedented redox generation of a phosphorus ylide from a phosphonium salt, which is used as a linchpin between the chemical fragments in this ambitious multicomponent C-C coupling.
The mild conditions required for this methodology will allow the rapid modification of complex bioactive molecules, generating myriad novel structural analogues for the creation of new medicines.
Complex molecules containing ubiquitous functional groups (i.e. carboxylic acids or alcohol/amine derivatives) and even simple sp3 C-H bonds would undergo the desired reactivity, defining a substantial scope for future applications.
The wide application of our methodology will be exemplified in the preparation of a suite of novel analogues of leelamine, a cheap and readily available molecule with anti-cancer activity, potentially providing novel powerful chemotherapeutics for the treatment of a challenging illness.

The chemical & pharmaceutical sector is the UK's second largest manufacturing industry, providing a £62.8 billion annual turnover (source European Chemical Industry Council: www.chemlandscape.cefic.org). Ensuring prompt access to novel chemical structures, as well as identifying new convenient routes to powerful drug candidates, are crucial to maintaining and enhancing the economic competitiveness of this sector. Generally, industry is most likely to use only a limited set of "trusted" robust and functional group tolerant reactions to construct novel drug candidates and structural analogues of relevant molecules. This defines strict boundaries to chemist's imagination to explore new chemical space and construct novel powerful structures.
The process detailed in this proposal will provide the UK pharmaceutical industry with a novel mild and robust multicomponent coupling to connect complex molecular fragments, enabling the rapid construction of myriad novel chemical architectures for the design of the pharmaceuticals, agrochemicals and materials of tomorrow, thereby creating substantial short- and long-term economic value.
In addition, by connecting three different fragments in a single chemical step, this multicomponent coupling will allow a drastic reduction of synthetic steps for the synthesis of complex molecules, reducing the need for hazardous chemicals and purification steps and using a sustainable form of energy (visible light) to carry out the coupling process. This will contribute towards the creation of a more environmentally benign and resource conscious chemical industry.
Our proposed methodology will be exploited to synthesise novel potential anti-cancer molecules, which could lead to the development of novel chemotherapeutics for an illness that is estimated to cost £15.3 billion to the UK government in 2021 (source NHS: https://www.nhs.uk/news/cancer/cancer-survival-rates-threatened-by-rising-cost/).
The methodology proposed would not only provide significant economic value, enhancing the competitiveness of the UK chemical and pharmaceutical industry, but could also provide a route for the treatment of challenging illnesses severely affecting our society.