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教授正在研究旨在促进制备具有抗癌特性的海洋衍生化学物质的新方法。感兴趣的方法利用过渡金属催化剂的反应性，能够快速构建在目标产品和相关生物活性物质中发现的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多种癌症类型的新型疗法的平台。资助项目的更广泛的影响延伸到累积到社会的好处，因为教授Stoltz和他的团队从事广泛的教育和推广活动，旨在促进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。该奖项还将有助于支持Stoltz教授正在进行的努力，以改善加州理工学院化学与化学工程部的多样性，公平性和包容性景观。吡咯亚氨基醌天然产物由于其结构复杂性而长期受到有机化学家的关注，这为合成方法和策略的发展提供了动力，并且还由于与该生物碱类相关的广泛的生物活性。尽管吡咯亚氨基醌生物碱的公认价值，足够快速和通用的方法，这些多环分子，可以使类似物的开发和合成新的同系物尚未实现。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，同时也改善了对其他重要目标分子的获取，即：（1）Larock/Buchwald-Hartwig级联过程，促进简单前体的双环化和结构复杂性的快速增加，以及（2）过渡金属催化的螺环化反应。代表性的吡咯亚氨基醌，包括makaluvamines A和F和sanguinone B，以及其他吲哚生物碱，如吲哚内酰胺V的全合成，将被追求，以证明所开发的方法的效用，并评估其范围。此外，第二种方法将更普遍地研究用于合成新的含杂原子的螺环，并将研究该技术的对映选择性变体。预计资助的项目将导致过渡金属为基础的有机合成实践的根本性进展，同时改善获得一类生物碱，这是开发新的临床候选药物的潜在丰富的先导化合物来源。最后，值得注意的是，该奖项所支持的研究为研究生提供了宝贵的培训机会，使他们能够追求未来的职业生涯在化学科学。该奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。

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.