Active Chemistry Cells, Biochemistry & Physiology

SELEC: Sulfur based linchpins for the selective coupling of electrophilic fragments

In plain English

AI plain-English summary

A single chemical trick could replace temperamental, hard-to-handle ingredients in drug manufacturing with stable, widely available alternatives. Pharmaceutical and agrochemical companies rely heavily on molecules made of two linked heterocycles—ring-shaped structures that are the workhorses of modern drug design. The standard way to build these is to couple a "nucleophilic" fragment (which donates electrons) with an "electrophilic" fragment (which accepts them). The problem is that the nucleophilic partner is often an organometallic reagent: reactive, air-sensitive, and difficult to make or store. This project proposes a workaround. Instead of forcing one fragment to act as a nucleophile, the researchers will use a sulfur-based "linchpin" molecule that allows two electrophilic fragments—such as commercially abundant heteroaryl halides—to be coupled directly. The linchpin forms a sulfinate intermediate in situ, then undergoes two sequential palladium- or palladium/copper-catalysed reactions to forge the final bond. If successful, this method (SELEC) would give chemists a practical, broad-scope tool to skip the problematic organometallic step. The immediate impact is on manufacturing efficiency: cheaper, more stable starting materials could streamline the synthesis of new drugs and crop-protection chemicals. This is fundamental synthetic chemistry—it does not treat a disease or fix a supply chain today—but it removes a bottleneck that quietly slows the development of many medicines people will take tomorrow.

View original technical description
Functionlized heterocyclic motifs are of crucial importance in the pharmaceutical and agrochemical industries, and in particular heterocycles linked to a second heterocycle are dominant motifs. The main method to access these types of molecules involves the cross-coupling of formally "nucleophilic" and "electrophilic" fragments, usually mediated by a transition metal catalyst. These reactions generally work well, but there are issues with accessing suitable "nucleophilic" fragments, which often involve organometallic reagents. In this proposal we will develop chemistry that allows the coupling of two formally electrophilic fragments, such as heteroaryl halides. These molecules have enormous commercial availability, thus making them attractive substrates. We will avoid the need of using organometallic reagents by developing sulfur-based linchpins that will mediate the coupling reactions, and will form sulfinate species in situ. The coupling processes will involve the sulfur-linchpin reagent undergoing two consecutive transition-metal catalysed reactions; these reactions will either both be catalysed by palladium, or will involve palladium and copper co-catalysis. We anticipate that the sulfur-mediated electrophilic couplings (SELEC) will be broad in scope and will provide a useful and practical method for the synthesis of functionalised heterocycles.

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Researchers

Michael Willis (Principal Investigator)Sandip Jadhav (Fellow)

Related Research

Grants with similar aims, by meaning.

Leveraging sulfinates for heterocycle cross-electrophile coupling
Metal-free couplings for molecules, materials and bioactive targets
Exploiting sulfinate coupling partners for the preparation of diversely functionalized heterocycles
Developing heterocylic sulfinates as general coupling partners in transition metal catalysed processes
Lighting up sulfur salts: a general platform for metal-free cross-coupling (S-EDA COUPLING)

Original classification

Fellowship

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