Strategy-Guided Syntheses of Complex Natural Products

在美国国家科学基金会化学部化学合成（SYN）项目的支持下，克里斯托弗·D·加州大学欧文分校（UCI）化学系的Vanderwal正在开发用于组装结构复杂的天然分子的创新方法。这项工作的基本主题是战略性地使用现成的分子构建模块，以尽可能少的化学操作获得目标天然产品的复杂结构。在这样做的过程中，现有的化学方法将在非常具有挑战性的情况下被推到极限，并且预计将发现快速构建复杂分子结构的新策略。这些研究的结果将对受益于化学合成的许多应用科学领域产生积极影响，包括药物开发和材料科学。这笔赠款还将允许外展活动，以中学生从服务不足的社区从事校园内的科学实验，并同时了解大学的经验。 Vanderwal集团将进一步参与当地社区大学学生的导师工作，使他们能够获得第一次实验室研究经验。 这些研究的核心在于开发几种策略，用于快速组装几种有趣的天然产物的复杂分子结构。首先，由其他化学家通过冗长的序列合成的复杂的多环生物碱阿替尼定将通过一个简洁和高度收敛的设计来靶向，该设计旨在通过一个短的多键形成序列将两个同样复杂的片段结合起来。第二，二氢-β-沉香呋喃-一组超过500立体化学复杂，高度氧化的萜类化合物，具有许多有趣的生物学特性-将组装在一个有效的方式开始从一个高度氧化的B-环，这本身将通过立体选择性苯还原或不对称狄尔斯-阿尔德化学的新应用程序访问。最后，有效的和选择性的抗胰腺肿瘤药物阿鲁替胺将通过一种新的分子内环加成反应合成，这也将推动新的反应性的发展。这项工作的更广泛的影响包括本科生和研究生的特殊研究培训。该基金还支持UCI-LEAPS计划，该计划让当地中学生在大学化学和物理实验室进行为期一天的体验，以及UC-SCC计划，该计划支持当地社区大学生在UCI化学实验室实习。该奖项反映了NSF的法定使命，并通过使用基金会的智力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, Professor Christopher D. Vanderwal of the Department of Chemistry at UC Irvine (UCI) is developing innovative approaches for the assembly of structurally complex naturally occurring molecules. The underlying theme of the work is the strategic use of readily available molecular building blocks to arrive at the complex architectures of the targeted natural products in as few chemical operations as possible. In so doing, existing chemical methods will be pushed to their limits by their use in very challenging contexts, and new strategies for rapidly building complicated molecular architectures are expected to be uncovered. The results of these studies will positively impact the many areas of applied science that benefit from chemical synthesis, including pharmaceutical development and materials science. This grant will also permit outreach activities to middle school students from underserved communities to engage in scientific experiments on-campus, and simultaneously learn about the college experience. The Vanderwal group will further engage in the mentorship of local community college students and enable them to have their first laboratory research experiences. The core of these research studies lie in the development of several strategies for the rapid assembly of the complex molecular architectures of several interesting natural products. First, the complex polycyclic alkaloid arcutinidine, which has been synthesized via lengthy sequences by other chemists, will be targeted via a concise and highly convergent design that seeks to unite two equally complex pieces via a short multiple-bond-forming sequence. Second, the dihydro-beta-agarofurans—a group of over 500 stereochemically complex, highly oxygenated terpenoids with many interesting biological properties—will be assembled in an efficient manner starting from a highly oxidized B-ring, which itself will be accessed via novel applications of either stereoselective benzene reductions or asymmetric Diels–Alder chemistry. Finally, the potent and selective anti-pancreatic-tumor agent aleutianamine will be synthesized by a novel intramolecular cycloaddition reaction, which will also drive the development of new reactivity. The broader impacts of this work include the exceptional research training for undergraduate and graduate students. This grant also supports the UCI-LEAPS program that brings in local middle school students for day-long experiences in university chemistry and physics laboratories, and the UC-SCC program that supports the internship of local community college students in chemistry labs at UCI.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.