Asymmetric arylation of racemic allylic halides

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry

Abstract

Csp2-Csp2 cross-coupling reactions between arylboronic acid and aryl halides are widely used in both academia and industry and are strategically important in the development of new agrochemicals and pharmaceuticals. Csp2-Csp3 cross-coupling reactions have been developed, but enantioselective variations are rare and simply retaining the stereochemistry is a problem. The development of robust and widely applicable methods that form single enantiomer products is a major contemporary research goal. The research in Fletcher group focuses on the development of novel asymmetric synthesis methods. Previously the group has developed a novel reaction - dynamic kinetic asymmetric allylic arylation of racemic allylic halides using boronic acid nucleophiles and Rh catalysts. It employs dynamic kinetic resolution (DKR) - an elegant process to transform both enantiomers of reactant into a single enantiomer of product. DKR utilizes a centre of a particular molecule that can be easily epimerized so that the enantiomers can interconvert throughout the reaction process. At this point the catalyst can selectively lower the transition state energy of a single enantiomer, leading to almost 100% yield of one reaction pathway over the other. In this particular case, each of the enantiomers of the cyclic halide forms a complex with the rhodium catalyst. Due to presence of a chiral ligand on Rhodium, complex of one enantiomer reacts stereospecifically to give the product much faster than the other. The Rhodium intermediates are believed to undergo suprafacial 1,3-isomerisation between two different allyl species and if reductive elimination is rate-determining this would provide a mechanism for enantioselection. The advantages of the reaction include low catalyst loading of 1 mol% (the reaction can be easily scaled up to 4.0 mmol). The method uses readily available and inexpensive building blocks such as arylboronic acid reagents, which are relatively stable in air and have high atom economy. In addition, the reaction conditions are mild and a big variety of substituents on both cyclic allylic halides and arylboronic acids is tolerated hence the reaction is broadly applicable. The aim of my project is to apply the asymmetric alkylation method to a new set of substrates - linear allylic halides. Firstly, symmetrical (carrying the same substituent R on both sides of allylic halide) allylic halides will be tested for reactivity with Rhodium catalyst, chiral ligand and phenylboronic acid. The reaction will be optimised with respect to solvent, temperature, catalyst loading and reaction time. Next, substituents on allylic halide will be varied to determine any reactivity trends. Symmetrical starting materials (carrying the same substituent R on both sides of allylic halide) will be tackled first. Then allylic halides with two different groups will be tested. Here, the possibility of 1,3-shift could lead to a more complex mixture of products. The goal is to determine what factors facilitate the shift and how to avoid it to get a single enantiomer product. Provided the project is successful the impact would be immense as it would allow to create vast libraries of new compounds for drug screening and well as provide shorter and more efficient synthesis routes for existing drug molecules and other targets of biological significance. This project falls within the EPSRC Physical Sciences research area.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R513295/1 01/10/2018 30/09/2023
2124513 Studentship EP/R513295/1 01/10/2018 30/09/2021 Violeta Stojalnikova