Dearomative Alkaloid Synthesis

在化学系化学合成计划(SYN)的支持下，佛罗里达州立大学(FSU)的乔尔·M·史密斯(Joel M.Smith)将研究更有效的方法来制备复杂的生物活性天然产物。靶分子的结构复杂性仍然是分子构建的一个重大挑战。这为发明和实施新的合成战略和战术来组装这些重要的分子支架提供了机会。为此，我们将使用原料起始材料作为廉价和可延展的构建块，以快速构建一些更具挑战性的自然界分子结构。在这笔赠款下开发的化学不仅将有利于我们的科学目标，而且将为其他从业者提供一个新的技术平台，供他们在构建重要的氮分子时使用。此外，FSU的课程和更广泛的塔拉哈西地区都将强调化学的影响。将向毕业生和本科生提供一门新课程，其中将包括化学和制药行业从业者的演讲。此外，为中小学生提供的实验室演示和活动将突出化学在日常生活中的作用(例如，穿着牛仔服装的深蓝色)。这些研究和教育努力旨在激发人们对分子结构艺术的兴趣，并为在年轻学生中推广科学提供一个基础平台。哌啶环是市售药物成分中最常见的杂环，也是许多生物活性生物碱中常见的亚结构。乔尔·史密斯和他的FSU团队对从吡啶(它们的芳香族同系物)控制合成各种复杂的稠合哌啶感兴趣。吡啶的受控官能化既具有氧化还原经济的诸多优势，也充满了带来精确的区域化学和立体化学结果的挑战。史密斯实验室开发了一个可延展的脱芳构化反应平台，利用该平台可以获得各种生物碱，包括来自螺杆菌、唐古托林、马钱子和甘露糖胺家族的生物碱。这些合成目标中的许多以前从未被访问过。对这种水平的分子多样性有一个统一的方法是这种方法的特点。克服这些合成挑战将为化学反应提供新的途径，并推动基于吡啶体系的战略方法在建筑上新颖和复杂的天然产品支架领域的发展。如果成功，这些生物碱天然产物的拟议区域和立体控制条目将允许进一步研究它们的生物活性，并允许将一系列有趣的片段纳入社区的以多样性为导向的合成(DOS)努力。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 program (SYN) in the Division of Chemistry (CHE), Joel M. Smith of Florida State University (FSU) will study more efficient ways to prepare complex biologically active natural products. The structural complexity of the target molecules still poses a significant challenge for molecular construction. This provides an opportunity for inventing and implementing novel synthetic strategies and tactics to assemble these important molecular scaffolds. To this end, we will use feedstock starting materials as cheap and malleable building blocks to quickly build some of nature’s more challenging molecular architectures. The chemistry developed under this grant will not only benefit our scientific goals, but will provide a novel technological platform for other practitioners to exploit when building important nitrogenous molecules. Additionally, the impact of chemistry will be emphasized both in the curriculum at FSU and in the broader Tallahassee area. A new course will be made available to both graduates and undergraduates that will incorporate talks from practitioners in the chemical and pharmaceutical industries. Furthermore, laboratory demonstrations and activities for primary and secondary students will highlight the role chemistry has on everyday life (e.g. indigo in denim clothing). These research and educational endeavors aim to inspire both interest in the art of molecular construction and provide a foundational platform for the promotion of science in young students. The piperidine ring is the most prevalent heterocycle in marketed pharmaceutical ingredients and is a common substructure in many biologically active alkaloids. Joel Smith and his FSU team are interested in the controlled synthesis of a variety of complex fused piperidines from pyridines, their aromatic congeners. The controlled functionalization of pyridines is endowed with as many advantages for redox economy as much as it is fraught with challenges with imbuing precise regiochemical and stereochemical outcomes. The Smith Lab has developed a malleable dearomatization reactivity platform with which to access various alkaloids including those from the aspidosperma, tangutorine, strychnos, and manzamine families. Many of these synthetic targets have never been accessed previously. Having a unified approach to this level of molecular diversity is distinguishing feature of this approach. Surmounting these synthetic challenges will provide for new avenues in chemical reactivity, and advance the area of pyridinium-system-based strategic approaches to architecturally novel and complex natural product scaffolds. If successful, the proposed regio- and stereocontrolled entries into these alkaloid natural products will permit the further study of their biological activity and allow for the inclusion of a collection of interesting fragments in diversity-oriented synthesis (DOS) endeavors in the community.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.