CAREER: Elucidating Isodiazene Reactivity with Anomeric Amide Reagents

在化学系化学合成项目的支持下，芝加哥大学的马克·莱文正在研究一种方法，这种方法可以从复杂的分子中去除单个氮原子，同时保持结构的其余部分不变。这种所谓的“分子编辑”技术为科学家提供了对现有化合物进行深刻改变的能力，它可能有助于设计和评估新的候选药物制剂、先进材料和对社会潜在有益的农用化学品。除了开发更有效的氮删除转化变体外，还将寻求对其微观机制的理解，以便为该过程的未来变体提供信息，并扩大其适用范围。资助项目的更广泛影响延伸到进行研究的研究生和本科生的多样化团队的培训和职业发展，其中许多人将继续成为科学，技术，工程和数学（STEM）劳动力的一部分。此外，在该奖项的支持下，莱文教授和芝加哥大学的一位同事继续致力于组织最近开幕的未来教师会议（FFC），该会议旨在为属于化学科学传统上代表性不足的群体的博士后提供成功导航学术就业市场所需的工具和知识。预计年度FFC将有助于改善学院未来的多样性，并有望促进高等教育的包容性。该资助项目侧重于从胺底物和异二氮酰胺试剂中原位生成异二氮，并详细研究这些活性中间体的后续转化，这些转化通常涉及分子氮的挤压。该项目的调查计划分为两个主题。首先，将开发改进的异头酰胺试剂，颠覆目前同类最佳试剂的已知分解模式，使更具挑战性的弱亲核胺底物能够成功参与。这一目标的挑战将通过一个系统的，计算辅助的实验结构-活性关系调查试剂来解决。第二个研究主题涉及对不同底物类别如何反应的微妙机制差异的检查，并利用这些发现来开发额外的综合有用的转化。更好地理解作为底物结构函数的异二氮烯分配规则将使更有效的氮缺失反应以及氮插入、周环重排和脱胺官能化反应得以发展。每种类型的过程都有有价值的应用，预计从这项研究中产生的新知识将导致分子编辑理论和实践的重要进展，并在一般的合成有机化学的更广泛领域。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 support of the Chemical Synthesis Program in the Division of Chemistry, Mark Levin of the University of Chicago is studying a process that allows for the excision of single nitrogen-atoms from complex molecules while leaving the rest of the structure intact. This so-called 'molecular editing' technique provides scientists with the capacity to effect profound changes to existing compounds and it may facilitate the design and evaluation of new candidate pharmaceutical agents, advanced materials, and agrochemicals of potential benefit to society. In addition to developing more efficient and effective variants of the nitrogen-deleting transformation of interest, an understanding of its microscopic mechanism will be sought to inform on future variants of the process and to expand upon its range of applicability. The broader impacts of the funded project extend to the training and career development of the diverse team of graduate and undergraduate students conducting the research, many of whom will go on to become a part of the science, technology, engineering, and mathematics (STEM) workforce. Also under the auspices of the award, Professor Levin and a colleague at the University of Chicago continue their commitment to organizing the recently inaugurated Future Faculty Conference (FFC), a meeting designed to empower postdoctoral fellows belonging to groups traditionally underrepresented in the chemical sciences with the tools and knowledge necessary to successfully navigate the academic job market. It is envisioned that the annual FFC will help to improve the future diversity of the academy with the expected ancillary benefit of promoting inclusivity in higher education.The funded project focuses on the in situ generation of isodiazenes from amine substrates and anomeric amide reagents and detailed study of the subsequent transformations of these reactive intermediates, which typically involve extrusion of molecular nitrogen. The investigational plan of the project is divided into two themes. In the first, the development of improved anomeric amide reagents that subvert known decomposition modes of current best-in-class reagents, will be pursued to enable more challenging, weakly nucleophilic amine substrates to be successfully engaged. The challenges of this aim will be addressed through a systematic, computation-aided experimental structure-activity relationship survey of the reagent. The second research theme concerns an examination of the subtle mechanistic differences between how separate substrate classes react and leveraging the findings to develop additional synthetically useful transformations. A better understanding of the rules governing the partitioning of the isodiazene as a function of substrate structure will enable more effective nitrogen deletion reactions to be developed as well as nitrogen insertion, pericyclic rearrangements, and deaminative functionalizations. Each type of process has valuable applications and it is anticipated that the new knowledge emanating from this research will lead to important advances to the theory and practice of molecular editing and to the wider field of synthetic organic chemistry in general.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.