SusChEM: Metal-Catalyzed Asymmetric Synthesis of P-Stereogenic Heterocycles

化学部的化学催化项目支持达特茅斯学院的David S. Glueck教授研究用手性磷立体中心制备膦的新方法。这种手性膦在不对称催化中很有用，不对称催化通常用于制药工业中制造单对映体药物。然而，由于缺乏通用的合成方法，手性膦配体的发展相对缓慢。该项目进一步改进了形成磷碳键和磷磷键的方法，为这一问题提供了新的和潜在有用的合成途径。该项目还为研究生和本科生研究人员提供培训，并扩大代表性不足的群体，特别是印第安人在化学、教育和研究方面的参与。研究结果在出版物和会议报告中广泛传播，并纳入推广计划。金属催化的不对称合成用于制备单对映体药物，通常需要手性膦配体。许多是已知的，但它们有限的结构多样性和配体依赖的催化选择性使得新型手性膦和新的途径有价值。该奖项的重点是p -立体膦，尽管它们在商业上取得了成功，但由于缺乏通用的合成方法，相对而言尚未得到开发。手性膦通常通过拆分或使用化学计量量的手性助剂制备。催化不对称合成允许更经济地使用昂贵的手性试剂。扩大这类过程的范围和提高其选择性，使这种不寻常的方法对一类工业上重要的化合物更有价值。该研究解决了这些问题，同时调查了催化的两个基本主题：(1)利用地球上丰富的金属和(2)正协同性。靶标是p -立体杂环，它既可以作为配体，也可以作为其他p -立体膦的组成部分。用铂族金属催化不对称合成了p -立体磷化氢，铂族金属磷化氢能在金属磷化基团中引起快速的锥体反转，使其具有亲核性。Glueck教授和他的团队假设不需要贵金属，而是使用铜催化剂。它们较弱的金属-配体键可能导致更快的配体取代和周转。为了制备p -立体杂环，他们假设分子内过程在两个立体中心之间形成键，通过正协同作用产生更高的选择性。手性环氧化合物中的碳立体中心用于形成P-C键合成磷烷的动态p立体控制。两个p -立体中心的构型在它们连接形成p -立体二膦时同时受到控制。从事这项研究的学生将接受以下方面的培训：无机、有机金属和有机化合物的合成和表征，它们的反应机理研究，催化，以及向其他科学家和公众展示结果。

The Chemical Catalysis Program of the Chemistry Division supports Professor David S. Glueck at Dartmouth College for research on new methods to prepare phosphines with a chiral phosphorus stereocenter. Such chiral phosphines are useful in asymmetric catalysis, which is commonly employed in the pharmaceutical industry to make single-enantiomer drugs. However, the development of chiral phosphines ligands has been relatively slow because of a lack of general synthetic methods. This project further improved the methods to form phosphorus-carbon and phosphorus-phosphorus bonds, providing new and potentially useful synthetic approaches to this problem. This project also provides training for graduate and undergraduate student researchers, and broadens the participation of underrepresented groups, especially Native Americans, in chemistry, education and research. The results are disseminated broadly in publications and conference presentations, and are integrated into outreach programs.Metal-catalyzed asymmetric synthesis, useful in the preparation of single-enantiomer drugs, often requires chiral phosphine ligands. Many are known, but their limited structural diversity and ligand-dependent selectivity in catalysis makes new types of chiral phosphines and new routes to them valuable. This award focuses on P-stereogenic phosphines, which despite their commercial success have been relatively unexplored because of a lack of general synthetic methods. Chiral phosphines are usually prepared either by resolution or by using a stoichiometric amount of a chiral auxiliary. Catalytic asymmetric synthesis allows more economical use of expensive chiral reagents. Expanding the scope and improving the selectivity of such processes make this unusual approach to a class of industrially important compounds more valuable. The research addresses these problems while investigating two fundamental topics in catalysis: (1) use of earth-abundant metals and (2) positive cooperativity. The targets are P-stereogenic heterocycles, which are useful both as ligands and as building blocks for other P-stereogenic phosphines. Catalytic asymmetric synthesis of P-stereogenic phosphines has been reported using platinum group metals, which induce rapid pyramidal inversion in the metal-phosphido groups and makes them nucleophilic. Professor Glueck and his group hypothesize that precious metals are not required and instead use copper catalysts. Their weaker metal-ligand bonds may result in faster ligand substitution and turnover. To prepare P-stereogenic heterocycles, they hypothesize that intramolecular processes to make bonds between two stereocenters result in higher selectivity via positive cooperativity. The carbon stereocenter in chiral epoxides are used for dynamic P-stereocontrol in synthesis of phosphiranes by P-C bond formation. The configurations of two P-stereocenters are controlled simultaneously as they are connected to make P-stereogenic diphosphines. Students who carry out the research receive training in synthesis and characterization of inorganic, organometallic, and organic compounds, mechanistic studies of their reactions, in catalysis, and in the presentation of their results both to other scientists and to the public.