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

胺是对我们的社会至关重要的含氮分子，因为它们与药物、农用化学品和散装化学品有关(1)。尽管有这种相关性，但碳-氮键的形成仍然是一项具有挑战性的任务，必须满足选择性、效率和可持续性的严格要求，才能在实地产生影响。获得这些分子的一种非常理想的方式是通过烯烃的直接胺化(2)。特别是，能够在C-C双键上实现胺和另一种官能团的伴随加成的方法，即整个氨基官能化，因为它们可以迅速从丰富的原料中引入分子复杂性。然而，烯烃胺化和氨基功能化仍然是非常具有挑战性的，它们被列为所谓的“催化十大挑战”(3)。建议的催化循环：我们将首先研究氧化还原Ni(I/II/III)-催化循环的发展，其中有机金属试剂将在Ni(I)-催化剂上发生转金属反应。由于芳基/烷基-Ni(I)是强电子供体，B将引发贫电子芳氧胺C的单电子还原，这一步骤将生成以Markovnikov方式截留烯烃的R1-Ni(II)E和AMIDyl D。该自由基加成反应将生成β-氨基自由基F，它将与E重新结合，得到R_1-烷基-Ni(III)物种G。还原消除应该是容易的，并且将得到氨基功能化的产物H和起始的Ni(I)-催化剂A。为了在这个氧化还原级联反应中实现不对称诱导，我们将探索使用手性配体(L*)，当结合时，镍催化剂可能能够控制该过程的立体化学结果。从力学上讲，关键是：(A)最终还原消除步骤(G-&>H)立体测定和(B)自由基转金属步骤(F--&>G)可逆。如果碳基F是稳定的(例如，苄基、烯丙基、α-C=O、α-O或-N)，这是可能的。为了便于确定最佳的镍-L*组合和所有其他反应条件(溶剂、温度、添加剂……)，我们将利用葛兰素史克的自动化高通量设施。这种方法将加快该过程的实施，因为机器人平台将能够快速和准确地筛选所有反应参数。该项目的这一部分将在史蒂芬葛兰素史克的博士学位植入期间进行。范围：根据所使用的有机金属试剂和氮自由基取代模式，我们将能够获得广泛的氨基功能化。这可能包括氨基芳基化、乙烯基化和烷基化。通过使用N-Boc/CBZ保护的氮自由基前驱体，我们将能够在脱保护时提供获得相应胺的途径。生物催化：还将结合生物催化研究β取代酰胺的对映选择性方法。在这种情况下，我们将使用外消旋反应产物，并试图通过酰胺水解酰胺酶来实现动力学拆分。这一战略可能提供获得与制药部门相关的小分子蛋白质结合物的途径。该项目的这一部分将在MIB进行。(1)Blakemore NAT。化学。2018年，10383。(2)Muller Chem.2008年版，108,3795版。(3)Borman Chem。英语。新闻。2004年，82，42。

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.