Complexity-Driven Total Synthesis

在国家科学基金会化学部化学合成(SYN)计划的支持下，伊利诺伊大学香槟分校(UIUC)化学系的David Sarlah正在研究构建复杂的自然分子的创新策略。这项工作的显著特点是识别出新的断链，从而在尽可能少的化学步骤中快速和可控地制备所需的分子结构。为了实现这一目标，正在对几个未被探索的化学过程进行评估，并将其发展成一般方法，以提高有效合成具有不同结构复杂程度的化合物的能力。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。这笔赠款还将支持广泛的以科学、技术、工程和数学(STEM)为重点的外联活动。这项工作的更广泛影响包括对处于综合前沿的本科生和研究生的研究培训。此外，Sarlah小组一直在领导一项名为科学在行动(SIA)的外联计划，该计划在伊利诺伊州大香槟地区提供重要的实践科学教育。通过SIA计划，该部门的几个研究小组与当地教师合作，为儿童和年幼的学生带来科学体验。这一建议的智力价值是为快速和可控地建造不同类型的复杂天然产品制定了几项战略。通过探索过渡金属催化的环化和环异构化反应，一系列基于萜类化合物的结构，Sarlah小组正在努力简化对这些天然产物核心结构的访问，并以高度立体分歧的方式这样做。这些中间体将作为最终精制的后期模板，用于一系列不同的天然产品，从三萜类、四萜类和吲哚类四萜，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得到充分利用的镍催化环化来获得一类结构独特的降分子类化合物。利用收敛策略，环加成物可以快速地转化为结构上不同的scabrolide或ineleganolide。最后，计划了一系列策略，包括挑战大环化、SP3-SP2醚化和立体选择性C-C键结构，以推动非规范氨基酸合成的发展，如强有力的抗生素达罗巴汀。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.