Transition Metal-Catalyzed Reaction Development Toward the Synthesis of Alkaloids

在化学系化学合成项目的支持下，加州理工学院的Brian Stoltz教授正在研究新的方法，旨在促进制备具有抗癌特性的海洋化学物质。感兴趣的方法利用过渡金属催化剂的反应性，能够快速构建目标产品和相关生物活性物质中具有挑战性的分子框架。预计开发的合成工具将改善对一系列分子的获取，这些分子可以作为发现针对各种癌症类型的新疗法的平台。Stoltz教授和他的团队参与了广泛的教育和推广活动，旨在提高K-12学生对STEM（科学、技术、工程和数学）的兴趣，并扩大属于历史上代表性不足的群体的学生对科学学科的参与，该资助项目的更广泛影响延伸到对社会产生的效益。该奖项还将有助于支持Stoltz教授为改善加州理工学院化学与化学工程系的多样性、公平性和包容性所做的持续努力。吡咯亚胺醌类天然产物由于其结构的复杂性，为合成方法和策略的发展提供了动力，也由于与这类生物碱相关的广泛的生物活性，长期以来一直受到有机化学家的关注。尽管吡咯亚胺醌生物碱的价值已得到公认，但尚未实现对这些多环分子的足够快速和通用的方法，从而可以开发类似物和合成新的同族物。该资助项目的重点是开发两种钯催化方法，旨在解决这一缺陷，同时改善对其他重要靶分子的获取，即：(1)Larock/ Buchwald-Hartwig级联过程，促进双环和简单前体结构复杂性的快速增加，以及(2)过渡金属催化的螺旋环化反应。将进行具有代表性的吡罗亚胺醌的全合成，包括马芦胺A和F和血素酮B，以及其他吲哚生物碱，如吲哚内酰胺V，以证明所开发方法的效用并评价其适用范围。此外，第二种方法将更广泛地用于合成新型含杂原子的螺旋环，并对该技术的对映选择性变体进行研究。预计该资助项目将在过渡金属基有机合成实践中取得根本性进展，同时改善对一类生物碱的获取，这些生物碱是开发新的临床候选药物的先导化合物的潜在丰富来源。最后，值得注意的是，该奖项支持的研究为研究生提供了宝贵的培训机会，使他们能够在化学科学领域追求未来的职业生涯。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。

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Brian Stoltz of the California Institute of Technology is studying new methods designed to facilitate the preparation of marine-derived chemical substances with anticancer properties. The methods of interest leverage the reactivity of transition metal catalysts to enable rapid construction of the challenging molecular frameworks found within the targeted products and related bioactive substances. It is anticipated that the developed synthetic tools will improve access to a range of molecules that could serve as a platform for the discovery of novel therapeutics against a variety of cancer types. The broader impacts of the funded project extend to the benefits accrued to society as Professor Stoltz and his team engage in an extensive assortment of educational and outreach activities intended to promote interest in STEM (science, technology, engineering and mathematics) among K-12 students and to widen participation in scientific disciplines by students belonging to groups that have been historically underrepresented. The award will also help to support the ongoing efforts of Professor Stoltz to improve upon the diversity, equity, and inclusion landscape of the Division of Chemistry and Chemical Engineering at Caltech.Pyrroloiminoquinone natural products have been of longstanding interest to organic chemists because of their structural complexity, which provides a driving force for the development of synthetic methods and strategies, and also due to the broad range of biological activities associated with this alkaloid class. Notwithstanding the recognized value of pyrroloiminoquinone alkaloids, a sufficiently rapid and general approach to these polycyclic molecules that may enable analogue development and the synthesis of new congeners is as yet unrealized. The funded project focuses on the development of two palladium-catalyzed methods that are designed to address this deficiency while also improving access to other important target molecules, namely: (1) a Larock/Buchwald–Hartwig cascade process that facilitates biannulations and rapid increases in structural complexity from simple precursors, and (2) a transition metal-catalyzed spirocyclization reaction. The total synthesis of representative pyrroloiminoquinones, including makaluvamines A and F and sanguinone B, as well as other indole alkaloids, such as indolactam V, will be pursued to demonstrate the utility of the developed methods and to evaluate their scope. In addition, the second method will be studied more generally for the synthesis of novel heteroatom-containing spirocycles and enantioselective variants of this technology will be investigated. It is anticipated that the funded project will lead to fundamental advances in the practice of transition metal-based organic synthesis while improving access to a class of alkaloids that are a potentially rich source of lead compounds for the development of new clinical candidates. Finally, it is noted that the research supported by the award provides valuable training opportunities for graduate students to enable their pursuit of future careers in the chemical sciences.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.