Copper and rhodium catalyzed dynamic kinetic asymmetric transformations

The development of catalytic methods for asymmetric synthesis is one of the foremost achievements in chemistry. Asymmetric catalysis is a key technology in the efficient development of new medicines, fragrances, polymers, materials and catalysts. While many broadly useful methods for catalytic asymmetric oxidation and reduction exist, there are far fewer asymmetric methods for forming carbon-carbon bonds, which make up the framework of organic molecules.

Typically in asymmetric catalysis, prochiral (usually flat) starting materials are used and the catalyst selects one side of the starting material for a reaction that introduces chirality and selectively produces one enantiomer of product. Where an 'enantiomer' is a specific 3d orientation, often described as one "hand" where there are two possible hands, and the hands or enantiomers are non-superimposible mirror images of each other.

This project aims to develop new asymmetric reactions where racemic starting material (a 50:50 mixture of two enantiomers, or 'hands') is converted selectively into one enantiomer of a product at the same time that a new carbon-carbon bond forms. This is a much less straightforward process than using prochiral starting materials and there are only very few types of reaction that can use this strategy. However, as there are many more racemic than prochiral molecules, methods that use racemic starting materials would be very useful in asymmetric synthesis.

Catalytic asymmetric carbon-carbon bond forming methods that use racemic starting materials are known, but these are limited to the combination of a precious metal catalyst (palladium, iridium, etc.) and an especially stabilized reaction partner. Here we will develop new methods that don't require stabilized reaction partners. We will use nuclear magnetic resonance spectroscopy to study the new reactions and try to understand the chemical pathways that are occurring. We expect that the information from the spectroscopic studies will be very useful in designing additional reactions. Overall, these studies will provide important new ways to rapidly synthesize a wide range of molecules with a wide variety of uses.

Economic and societal benefits of this work will arise from the development of new methods in asymmetric catalysis and organic synthesis. These are key technologies in industries that are economically important to the UK. These technologies contribute to the development of new medicines, which is important to the health of many UK citizens.

Enantioselective catalysis has had tremendous impact on the chemical sciences. The methods proposed here represent new and broadly applicable methods for the catalytic asymmetric synthesis of C-C bonds, and fill a longstanding gap in the literature. The use of stabilized nucleophiles (pKa <25) in metal catalyzed AAA DYKAT reactions is now well established in catalysis and synthesis. The use of non-stabilized nucleophiles in such reactions is wrought with difficulties and remains a longstanding research goal. Despite the fact that it has been a high-profile challenge in the field for 20 years, there are no generally useful methods for using non-stabilized nucleophiles in DYKATs. This is truly remarkable as this topic has been the subject of extensive investigations by many leading groups around the world.

We will develop new DYKATs and aim to understand how these processes work. Our work aims to advance the rational design of new asymmetric transformations using simple chemical building blocks and is likely to open up new avenues of research. As mentioned in other sections of this proposal, the design of powerful asymmetric methods is relevant to the "Dial-a-molecule" Grand Challenge. The non-stabilized nucleophiles used in our preliminary results are considerably less reactive than traditional non-stabilized nucleophiles and this imparts considerable practical advantages over process that could be accomplished using traditional non-stabilized nucleophiles. These new reactions use readily available starting materials, and no extremely reactive, moisture sensitive, or pyrophoric premade organometallic reagents need to be prepared. These reactions work at room temperature or above rather than at cryogenic temperatures. This is highly unusual for asymmetric reactions with non-stabilized nucleophiles and of great practical significance, particularly when adopting processes to industrial scale. These processes also tolerate a wide variety of functional groups including heteroaromatic substrates. These factors combine to make these methods unusually (for catalytic asymmetric methods with non-stabilized nucleophiles) suitable for general use in academia and industry, and these methods should be widely adopted in many settings.

Preliminary mechanistic studies suggest that these copper and rhodium-catalysed DYKATs occur through entirely different mechanisms than previously reported DYKATs with palladium and iridium. Very little is known about the mechanism of any asymmetric copper-catalyzed reactions, but here we were able to demonstrate (through rigorous use of NMR spectroscopy) that the mechanism of asymmetric induction with Cu-catalysis involves highly dynamic allylic halide interconversion. Intriguingly, preliminary studies using a substituted allyl chloride suggest the Rh-catalyzed DYKATs occur through a different 'overall enantioselective inversion' mechanism. These insights promise to make our studies generally useful. DYKATs are no longer limited to the combination of a soft nucleophiles and an expensive metal capable of forming a pi-allyl-metal intermediate. Our observations open the door to using many new metal catalysts in DYKAT reactions.

Immediate beneficiaries are those that can directly use these methods: researchers in the field of asymmetric catalysis and organic synthesis. Many other scientists use these technologies in their research (materials scientists, supramolecular chemists, chemical biologists, etc.) and they may also benefit. Medicinal chemists, particularly those in the pharmaceutical industry, should be able to use these methods to access desired compounds.