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

SusChEM：金属催化 P-立体杂环的不对称合成

• 批准号: 1562037
• 负责人: David Glueck
• 金额: $ 60万
• 依托单位: Dartmouth College
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1562037&HistoricalAwards=false
• 关键词: SusChEM; Metal; Catalyzed; Asymmetric; Synthesis

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.

化学系的化学催化计划支持达特茅斯学院的David S.Glueck教授研究制备手性磷立体中心膦的新方法。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业制造单一对映体药物。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方法。该项目还为研究生和本科生研究人员提供培训，并扩大未被充分代表的群体，特别是美洲原住民在化学、教育和研究方面的参与。这些结果在出版物和会议演讲中广泛传播，并被整合到推广计划中。金属催化的不对称合成用于制备单一对映体药物，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依赖于配体的催化选择性使得新型手性膦化合物和新的路线具有很高的价值。这一奖项的重点是P-立体生成膦，尽管它们在商业上取得了成功，但由于缺乏一般的合成方法，相对来说还没有被开发出来。手性膦通常是通过拆分或使用化学计量的手性助剂来制备的。催化不对称合成可以更经济地使用昂贵的手性试剂。扩大这类过程的范围并提高其选择性，使这类具有重要工业意义的化合物的这种不同寻常的方法更有价值。这项研究解决了这些问题，同时研究了催化中的两个基本主题：(1)富含地球的金属的使用和(2)正协同性。目标是P-立体生成的杂环，它们既可以作为配体，也可以作为其他P-立体生成膦的构筑块。报道了用铂族金属催化不对称合成P-立体发光性膦化合物的方法，它能诱导金属-磷化基团的快速金字塔反转，使其具有亲核性。Glueck教授和他的团队假设贵金属不是必需的，而是使用铜催化剂。它们较弱的金属-配位键可能会导致更快的配体取代和周转。为了制备P-立体合成杂环，他们假设分子内过程通过正协同作用在两个立体中心之间建立键导致更高的选择性。手性环氧化物中的碳立体中心用于P-C键形成合成磷烷的动态P-立体控制。两个P-立体中心的构型是同时控制的，因为它们连接在一起制造P-立体双膦。开展研究的学生接受无机、有机金属和有机化合物的合成和表征、反应的机理研究、催化以及向其他科学家和公众展示他们的结果方面的培训。

项目成果

Copper-Catalyzed Asymmetric Alkylation of Secondary Phosphines via Rapid Pyramidal Inversion in P-Stereogenic Cu–Phosphido Intermediates

• DOI: 10.1021/acs.organomet.2c00218
• 发表时间: 2022-06
• 期刊: Organometallics
• 影响因子: 2.8
• 作者: Sarah K. Gallant;Ryan M. Tipker;David S. Glueck

Rhodium-Catalyzed Asymmetric Dehydrocoupling: Enantioselective Synthesis of a P-Stereogenic Diphospholane with Mistake-Correcting Diastereoselectivity

铑催化的不对称脱氢偶联：具有纠错非对映选择性的对映体二磷烷的对映选择性合成

• DOI: 10.1021/acs.organomet.3c00188
• 发表时间: 2023
• 期刊: Organometallics
• 影响因子: 2.8
• 作者: Chachula, Sarah T.;Scheetz, Perry M.;Zureick, Andrew H.;Hughes, Russell P.;Glueck, David S.;Hernandez, Ritchie E.;Figueroa, Joshua S.;Rheingold, Arnold L.
• 通讯作者: Rheingold, Arnold L.

Configurational Lability at Tetrahedral Phosphorus: syn/anti ‐Isomerization of a P‐Stereogenic Phosphiranium Cation by Intramolecular Epimerization at Phosphorus

四面体磷的构型不稳定性：通过磷分子内差向异构化实现 P-立体磷鎓阳离子的顺/反异构化

• DOI: 10.1002/anie.202110753
• 发表时间: 2022
• 期刊: Angewandte Chemie International Edition
• 作者: Tipker, Ryan M.;Muldoon, Jake A.;Pham, Daniel H.;Varga, Balazs R.;Hughes, Russell P.;Glueck, David S.;Balaich, Gary J.;Rheingold, Arnold L.
• 通讯作者: Rheingold, Arnold L.