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

通过高通量实验开发不对称烯烃氨基官能化

• 批准号: 2751716
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2751716
• 关键词: Development; asymmetric; olefin; amino; functionalizations

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.

胺是对我们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）。尽管具有这种相关性，但C-N键的形成仍然是一项具有挑战性的任务，需要满足选择性、效率和可持续性的严格要求，以便在该领域产生影响。获得这些分子的一种非常理想的方法是通过烯烃的直接胺化（2）。特别地，高度寻求能够实现胺和另一官能团在C-C双键上的伴随加成（总体氨基官能化）的方法，因为它们可以从丰富的原料中快速引入分子复杂性。然而，烯烃胺化和氨基官能化仍然是非常具有挑战性的，它们被列入所谓的“催化的十大挑战”（3）。在这里，我们提出了新的不对称多组分策略的发展，使用氮自由基和有机金属偶联伙伴的烯烃的氨基官能化在镍catalyst.Proposed催化循环：我们将开始研究的氧化还原Ni（I/II/III）-催化循环的发展，其中有机金属试剂将进行金属转移与Ni（I）-催化剂A。由于芳基/烷基-Ni（I）是强电子给体，因此B将引发贫电子芳氧基酰胺C的单电子还原。该步骤将产生R1-Ni（II）E和酰胺基自由基D，其将以马尔科夫尼科夫方式拦截烯烃。该自由基加成将产生β-氨基-自由基F，其将与E重组以提供R1-烷基-Ni（III）物质G。还原消除应该是容易的，并且将得到氨基官能化的产物H和起始Ni（I）-催化剂A。不对称归纳为了实现在这个氧化还原级联的不对称诱导，我们将探索使用手性配体（L*），结合后的镍催化剂可能能够控制该过程的立体化学结果。从机理上讲，关键的是：（a）最终的还原消除步骤（G->H）立体确定和（B）自由基金属转移步骤（F + E->G）可逆。如果碳自由基F是稳定的（例如苄基、烯丙基、α-C =O、α-O或-N），这将是可能的。为了便于确定最佳Ni-L* 组合和所有其他反应条件（溶剂、T、添加剂.），我们将利用GSK的自动化高通量设备。这种方法将加速该过程的实施，因为机器人平台将能够快速准确地筛选所有反应参数。该项目的这一部分将在位于斯蒂夫尼奇的GSK工厂进行博士生实习期间进行。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官能化。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保护的氮自由基前体，我们将能够在脱保护后获得相应的胺。生物催化：对β-取代酰胺的对映选择性方法也将与生物催化相结合进行研究。在这种情况下，我们将使用外消旋反应产物，并尝试通过酰胺酶的酰胺水解来实现动力学拆分。这一战略可能提供获得与制药部门有关的小分子-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. Chem. 2018，10，383。(2)Muller Chem.Rev.2008，108，3795。(3)北京大学新闻网. 2004，82，42.