CAREER: Development of Stereoselective Cu-Catalyzed Reductive Coupling Reactions

在化学系化学催化项目的支持下，弗吉尼亚联邦大学化学系的Joshua Sieber将研究和开发新的化学工具来合成胺类极性有机化合物。这些化合物在自然界中普遍存在，制药业利用和开发它们来研究生物过程，并为治疗人类疾病创造新的疗法。然而，这类化合物通常极难获得和合成。本研究的目标是开发新的合成工具，以便使用地球上丰富的铜金属基催化剂系统轻松获得这些重要的胺衍生有机化合物。还将进行研究，了解这些过程是如何工作的，以便不断提高这些新技术的效率。该职业计划的教育目标旨在通过使用合成有机化学框架的科学方法的实践培训，为化学科学前沿的职业招募和准备多样化的STEM（科学，技术，工程和数学）劳动力。这一目标将通过以下方式实现：1)通过互动式课堂参观和夏季在首席研究员实验室进行科学研究的机会，向里士满公立高中的学生介绍合成有机化学的职业生涯；2)在弗吉尼亚州立大学建立一个新的本科高级有机化学实验室，旨在为学生提供合成技能，以应用于化学工业职业。开发能够构建碳-碳键的合成方法是有机化学的核心。拥有C-C键形成反应的“工具箱”使合成化学家能够获得化学生物学、药物化学和材料科学中应用所需的许多分子有机靶标。本研究旨在开发新的立体选择性和区域发散性铜催化工艺，在单一反应步骤中在最终产物中引入多个杂原子基团，从而方便和直接地获得手性多（杂原子）化合物。研究的核心将包括在不对称铜催化下烯丙酰胺与醛和亚胺亲电试剂的还原偶联反应。这些工艺的发展有望：1)提高其他技术难以制备的分子结构的合成效率；2)允许将基本原料转化为在天然产物合成、化学生物学和手性催化剂设计中具有重要意义的广泛的富含对映体的手性构建块，以及3)提供机理见解，以帮助未来发展一般的立体选择性催化非极性（极性反转）过程。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 Catalysis program in the Division of Chemistry, Joshua Sieber of the Department of Chemistry at Virginia Commonwealth University (VCU) will investigate and develop new chemical tools to synthesize amine-derived polar organic compounds. These compounds are prevalent in nature, and the pharmaceutical industry uses and develops them to study biological processes and create new therapeutics for the treatment of human diseases. However, such compounds are often extremely difficult to access and synthesize. The goals of this research are to develop new synthetic tools to enable easy access to these important amine-derived organic compounds using earth-abundant copper metal-based catalyst systems. Studies will also be performed to understand how these processes work so that the efficiency of these new techniques can be continually improved. The educational objective of this CAREER proposal aims to recruit and prepare a diverse STEM (Science, Technology, Engineering and Mathematics) workforce for careers at the frontiers of the chemical sciences through hands-on training of the scientific method using the framework of synthetic organic chemistry. This goal will be achieved through: 1) introducing Richmond Public High School students to careers in synthetic organic chemistry through interactive classroom visits and opportunities to perform scientific research in the principal investigator’s laboratory in the summer, and 2) developing a new undergraduate advanced organic chemistry laboratory at VCU aimed at providing synthesis skills to students for applications to industrial careers in chemistry.Development of synthetic methodology to enable the construction of C–C bonds is at the core of organic chemistry. Having a “toolbox” of C–C bond-forming reactions enables the synthetic chemist to access many molecular organic targets desired for applications in chemical biology, medicinal chemistry and materials science. This proposal aims to develop new stereoselective and regiodivergent Cu-catalyzed processes to introduce multiple heteroatom-groups in the final product in a single reaction step to allow for convenient and straightforward access to chiral poly(heteroatom)-containing compounds. The core of the investigation will consist of the study of allenamides in asymmetric Cu-catalyzed reductive coupling reactions with aldehyde and imine electrophiles. Development of these processes is expected to: 1) improve the synthetic efficiency for the preparation of molecular architectures that are difficult to prepare by other techniques; 2) allow for the conversion of basic feedstocks to a wide range of enantio-enriched chiral building blocks of significance in natural product synthesis, chemical biology and chiral catalyst design, and 3) provide mechanistic insights to aid in the future development of general, stereoselective catalytic umpolung (polarity-reversed) processes.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.