Complexity-Driven Total Synthesis

在美国国家科学基金会化学部化学合成（SYN）项目的支持下，伊利诺伊大学厄巴纳-香槟分校（UIUC）化学系的大卫·萨拉（David Sarlah）正在研究构建复杂自然分子的创新策略。这项工作的显著特点是识别新的断开，从而在尽可能少的化学步骤中快速和受控地制备所需的分子结构。为了实现这一目标，一些未被开发的化学过程正在被评估并发展为通用方法，以提高有效合成具有不同结构复杂性水平的化合物的能力。这些研究的结果将对应用分子科学的许多不同领域产生积极影响，包括农用化学品、制药和材料科学。此外，该项目在概念上很有趣，有许多潜在的应用，使其非常适合各级科学家的教育。这笔拨款还将支持以科学、技术、工程和数学（STEM）为重点的广泛推广活动。这项工作的更广泛的影响包括在综合前沿的本科生和研究生的研究训练。此外，萨拉小组一直在领导一个外展项目，科学在行动（SIA），提供重要的动手科学教育在伊利诺伊州大香槟地区。通过SIA项目，该系的几个研究小组与当地教师合作，将科学经验带给儿童和低年级学生。这一建议的智力价值在于发展了几种策略，用于快速和受控地构建不同类型的复杂天然产物。通过探索过渡金属催化的环化和环异构化，Sarlah小组正在努力简化这些天然产物核心结构的获取，并以高度立体发散的方式进行。这些中间体将作为最后精加工的后期模板，形成多种天然产物，包括三萜、二甲基半萜和吲哚半萜，其中许多具有显著的生物学特性。作为这些研究的一部分，该团队正在努力利用未充分利用的镍催化环，以获得结构独特的一类去膜类化合物。利用收敛策略，环加合物可以迅速转化为结构上不同的鞘内酯或内酯。最后，一系列涉及具有挑战性的大环化、sp3-sp2醚化和立体选择性C-C键构建的策略将推动非规范氨基酸合成的发展，如强效抗生素达巴比汀。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 (SYN) program in the Chemistry Division of NSF, David Sarlah of the Department of Chemistry at the University of Illinois at Urbana-Champaign (UIUC) is studying innovative strategies for the construction of complex, naturally occurring molecules. The salient feature of the work is the identification of novel disconnections that lead to rapid and controlled preparation of desired molecular structures in as few chemical steps as possible. In pursuit of this goal, several underexplored chemical processes are being evaluated and developed into general methods to improve the ability to efficiently synthesize compounds with varying levels of structural complexity. The results of these studies will have a positive impact across many different fields of applied molecular sciences, including agrochemicals, pharmaceuticals, and materials science. Moreover, the project is conceptually interesting and has many potential applications, making it well suited for the education of scientists at all levels. This grant will also enable wide-ranging science, technology, engineering, and mathematics (STEM)-focused outreach activities. The broader impacts of this work include the research training of undergraduate and graduate students at the forefront of synthesis. Moreover, the Sarlah group has been leading an outreach program, Science in Action (SIA), that provides crucial hands-on science education in the greater Champaign, IL area. Through the SIA program, several research groups in the department, in collaboration with local teachers, are bringing science experiences to children and younger students.The intellectual merit of this proposal is the development of several strategies for the rapid and controlled construction of different types of complex natural products. By exploring transition metal-catalyzed cyclizations and cycloisomerizations, a range of terpenoid-based structures the Sarlah group is working to streamline access to these natural product core structures and do so in a highly stereodivergent manner. These intermediates will serve as late-stage templates for final elaboration to a diverse set of natural products, ranging from triterpenoids, merosesquiterpenes, and indolosesquiterpenes, many of which have notable biological properties. As part of these studies, the team is working to leverage an underutilized nickel-catalyzed annulation to access a structurally unique class of norcembranoids. Utilizing a convergent strategy, the cycloadduct can be rapidly converted towards structurally distinct scabrolides or ineleganolide. Finally, a series of strategies involving challenging macrocyclizations, sp3-sp2 etherifications, and stereoselective C-C bond constructions is planned to drive the development of noncanonical amino acid synthesis, as exemplified with the potent antibiotic darobactin.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.