RUI: Synthesis of Isomeric Carbolines by Tandem Palladium Catalysis

NSF化学部的化学合成计划支持普罗维登斯学院化学和生物化学系Seann Mulcahy教授的研究。马尔卡西教授和他的本科生们正在开发一种新的方法来合成一类名为异构体碳氢化合物的有机化合物。众所周知，这些分子具有诱人的生物学特性，从神经化学效应到抗菌和抗癌活性。该项目的一个主要目标是使用含有钯元素的化合物作为催化剂，将这些分子从更简单的前体缝合在一个容器中。这种有效的化学过程将减少合成卡宾所需的时间、能量和资源。该项目进一步成为普罗维登斯学院本科生的培训工具，包括来自弱势背景的学生。该项目的范围超越了研究实验室，并被纳入本科生课程、夏季桥牌项目以及普罗维登斯公立学校的外展活动。所有参与这项工作的学生都在获得解决问题和批判性思维的技能，这是在所有级别的化学中取得成功所必需的。该项目涉及开发催化、一锅法合成具有重要生化功能(包括神经药理活性)的异构体α、β、伽马和增量-卡布林杂环。这项研究的特定靶点有可能成为研究大脑疾病的分子探针。这项工作的总体战略是使用单一的钯前驱体，它将催化两种机械上独特的转变。第一个目标是完成带有附加环的β-卡宾的合成。通过在同一烧瓶中进行串联的Sonogashira/[2+2+2]环化反应，这些分子就可以用一种“多任务”钯催化剂以原子经济的方式生成。第二个目标是为电子含量更高的α-卡宾异构体设计类似的策略。最终的科学目标是合成前体炔基腈和官能化的碘苯胺分子，导致伽马异构体和增量异构体。对每一类异构体的底物范围、催化效率和配体/溶剂效应进行了优化。在这项工作中，同样重要的是培养本科生成为更好的科学家。通过参与原创研究，本科生探索化学合成和催化的新领域。该项目还寻求招募代表人数不足的群体学习化学，无论是通过为新生提供的“夏季桥梁”研究体验，还是通过普罗维登斯公立学校的化学催化剂推广计划。

The Chemical Synthesis Program of the NSF Chemistry Division supports the research of Professor Seann Mulcahy in the Department of Chemistry and Biochemistry at Providence College. Professor Mulcahy and his undergraduate students are developing a new methodology for the synthesis of a class of organic compounds called isomeric carbolines. These molecules are known to have attractive biological properties, which range from neurochemical effects to antibacterial and anticancer activity. One major goal of this project is to use compounds containing the element, palladium, as a catalyst that will stitch together these molecules in a single vessel from simpler precursors. Such an efficient chemical process would reduce the time, energy, and resources needed for the synthesis of carbolines. The project further is serving as a training tool for undergraduate students at Providence College, including those students from disadvantaged backgrounds. The project's breadth reaches beyond the research laboratory and is being incorporated into the undergraduate curriculum, a summer bridge program, and outreach activities in Providence public schools. All of the students involved in this work are gaining problem solving and critical thinking skills that are needed for success in chemistry at all levels. This project involves the development of catalytic, one-pot procedures for the synthesis of isomeric alpha, beta, gamma and delta-carboline heterocycles that have important biochemical function including neuropharmacological activity. Specific targets of this research have potential as molecular probes for studying diseases of the brain. The overarching strategy in this work is the use of a single palladium precursor that will catalyze two mechanistically unique transformations. The first objective is to complete the synthesis of beta-carbolines which have an additional ring attached. By performing a tandem Sonogashira/[2+2+2] cyclization in the same flask, these molecules are created in an atom-economical way using a "multitasking" palladium catalyst. The second objective is to devise similar strategies for the more electron-rich alpha-carboline isomers. The final scientific objective is to synthesize precursor alkynylnitrile and functionalized iodoaniline molecules leading to the gamma- and delta-isomers. The substrate scope, catalytic efficiency, and ligand/solvent effects are optimized for each isomeric class. Equally important in this work is the training of undergraduate students to become better scientists. Through their involvement in original research, undergraduates explore new areas of chemical synthesis and catalysis. The project also seeks to recruit underrepresented groups to study chemistry, both through a "summer bridge" research experience for incoming students or the Catalysts for Chemistry outreach program in Providence public schools.