Stereodivergent Approaches to Pd-Catalyzed Cross-Coupling Reactions

在化学系化学合成项目的支持下，纽约城市学院（CCNY）的Mark R. Biscoe教授正在研究所谓的“交叉偶联反应”，这是合成化学中重要的碳-碳键形成反应，与广泛的应用相关，包括制药，农业和材料化学。两种表面上具有相同组成和结构但互为镜像的分子可以引起非常不同的生物反应。因此，能够精确控制三维分子结构的合成方法对化学生物学和药物化学领域至关重要。本研究中正在开发的化学过程体现了一种通用策略，其中单个前体构建块可用于访问所需目标分子的镜像形式。达到这种水平的控制将需要在分子水平机制的基本理解方面取得进展，这些机制支持感兴趣的交叉偶联反应。从支持的研究中出现的新方法预计将广泛地用于立体选择性合成。Biscoe教授和他的同事团队所参与的一系列教育和推广活动扩大了项目的广泛影响，这些活动旨在增加参与科学和工程企业的学生的多样性。作为这些推广工作的一部分，Biscoe教授发起了CCNY和城市学院数学，科学和工程高中（HSMSE）之间的联合研究计划。这项努力的目标是创造一种途径，通过这种途径，高中生可以接触到前沿的学术研究，从而潜在地培养他们在科学相关领域追求未来职业的兴趣。根据该奖项，Biscoe团队将专注于研究和开发立体发散钯催化的由立体化学定义的宝石-二金属化烷基亲核试剂产生的交叉偶联反应。硼、锗和锡构成了对映体富集的宝石双金属亲核试剂中所含的主要金属基团，并且将研究获取这些多功能合成子的新方法以及它们在各种交叉偶联中的部署（例如，Suzuki-Miyaura和Stille反应）。设想立体定义的宝石-二金属化烷基亲核试剂在迭代立体特异性交叉耦合过程中的战略性应用将能够以可靠和通用的方式精确控制三维分子结构。由于烷基转移可以在立体构型保留或反转的情况下发生，因此将详细探讨从宝石-双金属物种进行金属转化的机理，以促进合成策略的发展，通过这种合成策略，可以从单个富集对映体前体获得所需交叉偶联产物的两个对映体。由于亲核试剂向钯的转移是交叉偶联反应催化循环的一个基本步骤，预计从这项工作中获得的新知识将导致碳-碳键立体选择性形成技术的重大进步。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Mark R. Biscoe of the City College of New York (CCNY) is studying so called 'cross-coupling reactions' that are important carbon-carbon bond forming reactions in synthetic chemistry, with relevance to a broad range of applications, including pharmaceutical, agricultural and materials chemistry. Two molecules that ostensibly have the same composition and structure but which are mirror images of each other, can elicit very different biological responses. Consequently, synthetic methods that enable precise control of three-dimensional molecular structure are essential to the fields of chemical biology and medicinal chemistry. The chemical processes under development in this research embody a versatile strategy wherein a single precursor building block can be used to access either mirror image form of a desired target molecule. Arriving at this level of control will require advances in the fundamental understanding of the molecular-level mechanisms that underpin the cross-coupling reactions of interest. The new methods emerging from the supported studies are anticipated to be broadly enabling for stereoselective synthesis. The broader impacts of the project are extended by a range of educational and outreach activities that Professor Biscoe and his team of coworkers are engaged in that are designed to increase the diversity of students participating in the science and engineering enterprise. As part of these outreach efforts, Professor Biscoe has initiated a joint research program between CCNY and the High School for Math, Science, and Engineering (HSMSE) of City College. The goal of this endeavor is to create a means through which high school students can gain exposure to cutting-edge academic research, thereby potentially fostering their interest in pursuing future careers in science-related fields.Under this award, the Biscoe team will be focused on the study and development of stereodivergent palladium-catalyzed cross-coupling reactions from stereochemically defined gem-dimetallated alkyl nucleophiles. Boron, germanium, and tin constitute the main group metals contained within the enantioenriched gem-dimetallated nucleophiles of interest and new methods to access these versatile synthons will be investigated alongside their deployment in a variety of cross-couplings (e.g., Suzuki-Miyaura and Stille reactions). It is envisioned that the strategic application of stereodefined gem-dimetallated alkyl nucleophiles in iterative stereospecific cross-coupling processes will enable precise control of three-dimensional molecular structure in a reliable and general manner. Because alkyl transfer can occur with retention or inversion of stereochemical configuration, the mechanism of the transmetallation step from the gem-dimetal species will be probed in detail to facilitate the development of synthetic tactics through which both enantiomers of a desired cross-coupling product can be accessed from a single enantioenriched precursor. Due to the fact that nucleophile transfer to palladium is a fundamental step in the catalytic cycle of cross-coupling reactions, it is anticipated that the new knowledge gained from this exercise will lead to significant advances in technology for the stereoselective formation of carbon-carbon bonds.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.