Functionalised heterocycles remain the cornerstone of medicinal chemistry programmes. This project focuses on developing new metal catalysed coupling reactions for the synthesis of pharmaceutically relevant variants. The combination of mechanistically-guided reaction design, high-throughput experimentation (HTE), and data analysis, will be used to deliver optimal processes, and will be based on the use of heterocyclic sulfinates (and related reagents) as the coupling partners.

Molecules containing stereogenic phosphorous (V) atoms are commonplace in bioactive medicines and agrochemicals ranging from: antivirals, to cardiovascular treatments, to herbicides, yet their syntheses are often challenging, specific to the target molecule, and use stoichiometric amounts of non-recyclable chiral auxiliaries. This proposal aims to develop sustainable catalytic enantioselective routes to novel chiral phosphorous (V) building blocks and demonstrate their potential downstream broad scope applicability in medicinal and agrochemical research programs.

The introduction of saturation in the form of C_sp3-F into pharmaceutical candidates improves medicinal properties and increases the chance to reach the clinic. New chemistry will be developed for the conversion of alkyl chlorides or bromides into alkyl fluorides using safe and cost-effective alkali metal fluorides. More generally, the project will aim at reinventing the iconic Swartz reaction with extension to an enantioconvergent fluorination process applying synergistic asymmetric hydrogen bonding phase transfer catalysis.

New reaction manifolds are valuable for the synthesis of complex molecules. This project will focus on the development of radical-polar crossover reactions by employing visible light mediated energy transfer catalysis to generate complex three-dimensional heterocyclic scaffolds. The design of non-precious metal photocatalysts and metal free catalysts will be a key component of this project.

Polymers in liquid formulations are found in millions of everyday products, from paints to cosmetics. They also play a vital role in agriculture, including as key ingredients to control the delivery of agrochemicals. However, the way these polymers are made, used and disposed of is currently unsustainable. In collaboration with Syngenta, this project will investigate the utilisation of abundant natural carbohydrate feedstocks to produce degradable bio-based polymers, towards more sustainable materials for agricultural applications.

The design of new non-precious metal catalysts and organic catalysts is key to modern reaction innovation and sustainability. This project will involve, the design and synthesis of a new range of chiral organocatalysts bearing chiral heteroatoms. The new library of catalysts will be screened for a range of catalytic enantioselective synthetic organic transformations.

Air- and moisture-stable organozinc gels will be prepared using hexatriacontane encapsulation gel technology and used in Pd-catalysed sp³-sp² and sp²-sp² Negishi cross-coupling reactions. Off-the-shelf, stable gel capsules of organozinc reagents could transform the utility of such reagents in synthesis and cross-couplings, especially for reactions on an automated platform. Catalysis using earth-abundant metals (e.g. Co, Ni, Fe) will also be explored.

Resistance to pharmaceuticals, including anti-infectives and cancer drugs, and agrochemicals is a major global health problem. As highlighted by the 2016 O’Neill report, the situation with current antibiotics is perilous. Antibiotics are used on a massive scale in farming and medicine, hence we need sustainable routes for production of new antibiotics not susceptible to current resistance mechanisms. The project will involve the development of enzyme / enzyme inspired reactions for the efficient and sustainable preparation of new antibiotics. Late-stage modification of fermented natural products will be explored to efficiently generate structure activity relationship results, complementing efficient total synthesis approaches.

We will establish methods for the synthesis of novel, medicinally important bridged bicyclic hydrocarbon (BBH) scaffolds using late-stage oxygenation enabled by unspecific peroxygenase (UPO) enzymes. BBHs will be made using both known and new synthetic approaches, with methods selected that access scaffolds with maximum substituent diversity, and also sustainably. These will then be oxygenated using scalable and sustainable biocatalytic methods to produce novel BBH scaffolds for applications in drug discovery.

Established routes to BBHs will be used to generate suitable substrates to challenge the UPOs to start, and as the project develops, novel BBHs syntheses will also be explored; expertise in the Anderson group (Oxford) will be crucial in supporting these aspects. We will then explore their oxygenation using UPOs. Unsworth and Grogan (York) have a well-established collaboration exploring the selective UPO oxygenation of small organic molecules, and have ready access to large quantities of UPOs with proven efficacy in large scale biocatalysis. Substrate, chemo-, regio- and stereoselectivity of the biotransformations will all be explored; the discovery of highly enantioselective late-stage oxygenation methods is expected. The value of the newly oxygenated BBH scaffolds will be explored for utility in drug discovery with industry partners at MSD.

While hydrogen borrowing (HB) catalysis offers an attractive route for the construction of C-C bonds using alcohols and ketones, current methods rely upon expensive precious metal catalysts. This project will develop sustainable HB methods using earth-abundant metals (iron and cobalt), using a synergistic approach combining pre-catalyst development, reaction screening and mechanistic insight to achieve sustainable HB methods of practical synthetic use in both academia and industry.

Asymmetric cross-coupling technologies are powerful techniques that represent the state-of-the-art in the construction of chiral small molecules. Our laboratory has developed a series of Suzuki-type reactions which use commercially available and experimentally convenient boronic acids, but these reactions currently rely on using rhodium-based catalysts. This proposal aims to develop related methods which use non-precious metal as catalysts.

New (photo)catalytic methods will be developed to convert simple feedstock starting materials, such as carboxylic acids and amines, into valuable, complex, sulfonamide and sulfonimidamide building blocks. The control of stereochemistry will be an important consideration. An emphasis we be place on developing translatable methods, directly relevant for use in discovery chemistry.

There is significant interest in sp³-rich heterocyclic scaffolds for medicinal chemistry due to their success in proceeding through the drug development process. In this project, we will develop the Pd-catalysed sp³-sp² Suzuki-Miyaura cross-coupling of saturated heterocyclic organoborons with aryl/heteroaryl halides. This will provide a step-change in the way that 3D saturated nitrogen and oxygen heterocycles can be constructed, a limitation highlighted by the pharmaceutical industry.

Thiophene S,S-dioxides (TDOs) are convenient but underutilised building blocks in organic chemistry. This project will seek to develop new applications of TDOs in sustainable chemical synthesis. We will exploit their cycloaddition chemistry in the synthesis of carbo- and heterocyclic structures, where the sole byproduct is SO₂; this includes concise syntheses of alkaloid natural products, and other functionality-rich nitrogen containing building blocks. We will also study new aspects of TDO reactivity, such as radical- or photochemical-based transformations, as well as novel analogues of the TDO scaffold.