Seeking Innovation and Efficiency in Natural Product Synthesis

在化学系化学合成(SYN)项目的支持下，普林斯顿大学的埃里克·索伦森教授将开发新的合成方法，以合成具有建筑新奇和具有挑战性的支架的天然产品。在这些研究中建立的有机合成的思想和方法有可能有助于在化学/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。该项目旨在展示如何从简单的起始材料以相对较少的步骤形成环丁香烯内酯和古鲁瓦罗内酯类天然产品的复杂结构元素。索伦森教授和他的学生正在开发基于活性中间体的合成策略，这些中间体可能会被诱导经历级联的成键反应。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，并产生高效的实验室合成。这项研究有望产生新的成键反应，提供有关这些转化的范围和局限性的知识，并提供获得广泛的新分子结构的途径，其中一些有望具有治疗潜力。其他社会福利包括从非R1机构招募和参与暑期研究体验，教会学生如何处理有机合成中具有挑战性的问题，并帮助他们发现自己可以做科学。索伦森教授和他的学生将利用高能碳自由基、卡宾和有机金属物种在密集碳-碳键的受控结构中的反应性，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反应的基础上，直接生成环丁烯内酯天然产物四个环中的三个，他们将确定活性卡宾是否可以插入附近的碳-氢键，形成最后一个剩余的碳-碳键。如果它成功了，这种转变将产生有史以来最拥挤的碳-碳键之一，它是通过罗卡宾C-H插入反应构建的。在这个项目的过程中，还将开发一种在镍催化的酰化反应中捕获三级自由基的新反应，并将对Norrish-Yang光化学环化过程的能力有新的见解。此外，还将评估直接合成抗癌天然产物柯鲁瓦罗的可行性。这种方法的核心是对氧杂环进行创新的还原裂解，作为巴比尔环化的前奏，以建立具有挑战性的库瓦瓦罗环系和相对立体化学模式。在所有这些项目中，正在开发形成化学键的新方法和新想法，具有潜在的深远的科学影响。这一奖项反映了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 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.