Development of asymmetric olefin amino-functionalizations via high-throughput experimentations

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

Amines are nitrogen-containing molecules fundamental to our society due to their relevance as medicines, agrochemicals and also bulk chemicals (1). Despite this relevance the formation of C-N bonds is still a challenging task with stringent requirements of selectivity, efficiency and sustainability to be met in order to have an impact in the field.
A very desirable way of accessing these molecules is through the direct amination of olefins (2). In particular, methods able to achieve the concomitant addition of an amine and another functionality across a C-C double bond, an overall amino-functionalization, are highly sought after as they can rapidly introduce molecular complexity from abundant feedstocks. However, olefin amination and amino-functionalization are still very challenging and they are listed in the so-called "Ten Challenges for Catalysis" (3). Here, we propose the development of novel asymmetric multicomponent strategy for the amino-functionalization of olefins using nitrogen radicals and organometallic coupling partners under nickel catalysis.
Proposed Catalytic Cycle: We will start by studying the development of a redox Ni(I/II/III)-catalytic cycle where an organometallic reagent will undergo a transmetalation with a Ni(I)-catalyst A. As aryl/alkyl-Ni(I) are strong electron donors, B will trigger a single-electron reduction of the electron poor aryloxyamide C. This step will generate the R1-Ni(II) E and the amidyl radical D that will intercept the olefin in a Markovnikov fashion. This radical addition will generate the Beta-amino-radical F that will recombine with E to provide the R1-alkyl-Ni(III) species G. Reductive elimination is ought to be facile and will give the product of amino-functionalization H and the starting Ni(I)-catalyst A.
Asymmetric Induction. In order to achieve asymmetric induction in this redox cascade, we will explore the use of chiral ligands (L*) that upon binding the nickel-catalyst might be able to control the stereochemical outcome of the process. Mechanistically, it will be critical to have: (a) the final reductive elimination step (G->H) stereo-determining and (b) the radical transmetalation step (F + E->G) reversible. This will be possible if the carbon radical F is stabilised (e.g. benzylic, allylic, Alpha-C=O, Alpha-O or -N). To facilitate the identification of the optimum Ni-L* combinations and all other reaction conditions (solvent, T, additives...), we will take advantage of the automated high-throughput facilities at GSK. This approach will accelerate the implementation of the process as the robotic platform will enable the fast and accurate screening of all reaction parameters. This part of the project will be carried during the PhD placement at the GSK site in Stevenage.
Scope: Depending on the organometallic reagent used and the nitrogen-radical substitution pattern we will be able to access a broad range of amino-functionalizations. This might include amino-arylations, vinylations and alkylations. By using N-Boc/Cbz protected nitrogen radical precursors we will be able to provide access to the corresponding amines upon deprotection.
Biocatalysis: Enantioselective approaches towards Beta-substituted amides will also be studied in combination with biocatalysis. In this case, we will use the racemic reaction product and try to achieve kinetic resolution by amide hydrolysis with amidases enymes. This strategy might provide access to small molecule-protein conjugates of relevance to the pharmaceutical sector. This part of the project will be carried at the MIB.
References. (1) Blakemore Nat. Chem. 2018, 10, 383. (2) Muller Chem. Rev. 2008, 108, 3795. (3) Borman Chem. Eng. News. 2004, 82, 42.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S023755/1 01/04/2019 30/09/2027
2270214 Studentship EP/S023755/1 01/10/2019 30/09/2023 Lewis Caiger