Seeking Innovation and Efficiency in Natural Product Synthesis

寻求天然产物合成的创新和效率

• 批准号: 2102663
• 负责人: Erik Sorensen
• 金额: $ 50万
• 依托单位: Princeton University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2102663&HistoricalAwards=false
• 关键词: Seeking; Innovation; Efficiency; Natural; Product

With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Professor Erik Sorensen of Princeton University will develop new synthetic methods toward the synthesis of natural products that possess architecturally novel and challenging scaffolds. The ideas and methods of organic synthesis being established in these studies have the potential to contribute to broader advances at the chemistry/biology interface and in materials science and polymer chemistry. This project seeks to demonstrate how the intricate structural elements of the cyclobutastellettolide and curvularol classes of natural products may be formed in a relatively small number of steps from simple starting materials. Professor Sorensen and his students are developing synthetic strategies based upon reactive intermediates that may be induced to undergo cascades of bond-forming reactions. Such cascade processes are desirable because they directly form substantial fractions of the target compounds and yield laboratory syntheses that are efficient. This research is expected to produce new bond-forming reactions, provide knowledge about the scope and limitations of these transformations and provide access to a wide range of novel molecular structures, some of which are expected to have therapeutic potential. Additional societal benefits include the recruitment and participation of under-represented college students from non-R1 institutions in summer research experiences that teach students how to approach challenging problems in organic synthesis and help them to discover that they can do science. Professor Sorensen and his students will harness the reactivities of high-energy carbon radicals, carbenes, and organometallic species in controlled constructions of crowded carbon–carbon bonds, a longstanding problem in the field of organic synthesis. On the foundation of a powerful free radical cascade cyclization that directly generates three of the four rings of the cyclobutastellettolide natural products, they will determine if a reactive carbene can insert into a nearby carbon–hydrogen bond to form the last remaining carbon–carbon bond. Should it succeed, this transformation would produce one of the most crowded carbon–carbon bonds ever constructed via a rhodium carbene C–H insertion reaction. In the course of this project, a new reaction for trapping tertiary radicals in nickel-catalyzed acylations will also be developed and new insights into the capabilities of the Norrish-Yang photochemical cyclization process will be gained. The feasibility of a distinctly direct strategy for synthesizing the anticancer natural product curvularol will also be evaluated. At the heart of this approach is an innovative reductive cleavage of an oxetane heterocycle as a prelude to a Barbier cyclization to establish the challenging curvularol ring system and pattern of relative stereochemistry. In all of these undertakings, new methods and ideas for forming chemical bonds are being developed with potentially far-ranging scientific impact.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.

在化学系化学合成（SYN）项目的支持下，普林斯顿大学的Erik Sorensen教授将开发新的合成方法，以合成具有建筑新颖和具有挑战性的支架的天然产物。在这些研究中建立的有机合成的思想和方法有可能在化学/生物界面以及材料科学和聚合物化学方面取得更广泛的进展。该项目旨在证明环丁烯内酯和曲戊醇类天然产物的复杂结构元素是如何从简单的起始材料在相对较少的步骤中形成的。Sorensen教授和他的学生正在开发基于反应中间体的合成策略，这些中间体可能被诱导进行级联成键反应。这种级联过程是可取的，因为它们直接形成目标化合物的大部分，并产生有效的实验室合成。这项研究有望产生新的成键反应，提供关于这些转化的范围和局限性的知识，并提供广泛的新分子结构，其中一些有望具有治疗潜力。额外的社会效益包括招募和参与来自非r1机构的代表性不足的大学生参加夏季研究经验，教学生如何处理有机合成中的挑战性问题，并帮助他们发现他们可以做科学。Sorensen教授和他的学生将利用高能碳自由基、碳烯和有机金属物种的反应性来控制密集碳-碳键的结构，这是有机合成领域的一个长期问题。在一个强大的自由基级联环化的基础上，直接产生环丁烯酰胺天然产物的四个环中的三个环，他们将决定一个活性碳是否可以插入附近的碳氢键，形成最后一个剩余的碳碳键。如果成功的话，这种转变将产生有史以来通过碳铑碳氢插入反应构建的最密集的碳-碳键之一。在这个项目的过程中，还将开发一种新的反应来捕获镍催化的酰化中的叔自由基，并对Norrish-Yang光化学环化过程的能力有新的认识。还将评估合成抗癌天然产物曲vularol的直接策略的可行性。该方法的核心是对氧烷杂环进行创新性的还原裂解，作为Barbier环化的前奏，以建立具有挑战性的曲烷环体系和相对立体化学模式。在所有这些事业中，形成化学键的新方法和新想法正在发展，可能产生深远的科学影响。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。