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Stereoretentive-Enantioconvergent Catalysis: A New Concept in Asymmetric Synthesis

Periodic Reporting for period 2 - SEC (Stereoretentive-Enantioconvergent Catalysis: A New Concept in Asymmetric Synthesis)

Reporting period: 2019-05-01 to 2020-10-31

The objective of this project is to experimentally establish a new concept in asymmetric synthesis: stereoretentive-enantioconvergent catalysis. The ability to synthesise chiral molecules in enantiopure form is vitally important, most recognisably for the pharmaceutical industry. This is because the molecules of life are chiral (e.g. D-sugars and L-amino acids) and enantiomers often interact very differently with living organisms. Classically, asymmetric synthesis utilising racemic substrates is limited to achieving a maximum yield of 50% (e.g. kinetic resolutions). Enantioconvergent catalysis avoids this limitation with both enantiomers of the starting material being converted into a single enantioenriched product, thanks to complex stereoablative or stereomutative de- racemisation processes. Stereoretentive-enantioconvergent catalysis will represent a completely new method for accessing enantiopure materials starting from racemic substrates and will therefore impact all areas of synthetic chemistry.

The overall objective of this project is to establish a conceptually new stereoretentive-dimerisation approach that results in both enantiomers of the starting material being incorporated into the product with no de-racemisation required. This new concept will prove highly valuable for the synthesis of small enantiopure building blocks, which will be of high value in many areas of synthesis, and also for more complex late-stage transformations in complex molecule synthesis. Several approaches will be pursued to demonstrate proof-of-principle, and applications in the synthesis of complex natural and unnatural products will then be used to demonstrate the potential of stereoretentive-enantioconvergent catalysis in target-orientated synthesis.
Work has been performed on developing stereoretentive-enantioconvergent catalytic methods for several reaction types. This has involved the synthesis of multiple racemic substrates, chiral catalysts and reagents. The inherent reactivity and selectivity of these different reactions have been investigated in detail. Several of these reactions have been determined to be unsuitable for further investigation, whilst others are being actively progressed. Key milestones have been reached, including the development of novel kinetic resolution methodology, which will be extended to develop enantioconvergent methods. Ultimately, this will lead to the first proof-of-principle results for stereoretentive-enantioconvergent catalysis.
This project is focused on developing a fundamentally new concept in the field of asymmetric synthesis. The progress made so far provides us with a strong foundation from which to build new reactions to acquire proof-of-principle results. When achieved this will represent a signifcant advancement for the field of asymmetric synthesis.