Regio- and enantioselective electrophilic aromatic substitution on drug-like molecules

化学学部的化学催化项目支持Gustafson教授的项目。古斯塔夫森教授是圣地亚哥州立大学化学系的一名教员。他正在开发新型的亲电芳香取代催化剂。这项研究计划的目标是设计新的催化剂，允许简单和复杂的芳香分子，包括药物和蛋白质的直接功能化。路易斯碱性基团能够激活亲电试剂，并且很容易结合到催化剂结构中，从而允许模块化催化剂设计。本项目处于催化、合成和物理有机化学的交叉点。因此，它非常适合各级科学家的教育。由于圣地亚哥州立大学独特而多样化的学生群体，古斯塔夫森教授的团队有能力为科学领域代表性不足的学生提供最高水平的教育和培训。涉及社区大学中代表性不足的学生的外展活动是该项目的一部分。路易斯碱可以催化激活多种亲电试剂进行亲电加成反应。Gustafson小组最近证明了路易斯碱，如硫脲和硫化氢，可以在非常温和的条件下催化芳香原料的卤化或磺化。初步的机理研究表明，这种化学反应是通过共价的卤-催化剂加合物进行的，催化剂的结构会影响反应的结果。拟议的研究包括深入的机理研究和开发新的催化剂，以将项目扩展到更复杂的系统。该提案力求回答三个主要问题：路易斯碱催化剂如何控制苯酚氯化的区域选择性，这种选择性是否可以扩展到其他类别的芳烃？其次，Lewis碱与Bronsted酸缀合如何催化杂环的轻度磺化反应，该反应是否可以扩展到肽，蛋白质和天然产物？此外，路易斯碱的变化会导致对其他类芳烃的化学选择性吗？最后，是否可以设计手性路易斯碱催化剂来实现对映选择性卤化和亚砜化？这一教育计划包括向当地社区大学中代表性不足的学生伸出援手，向他们介绍本科生可以获得的研究机会。这项拓展活动包括在当地社区大学的实践报告，向学生介绍丁烷构象分析背景下的计算化学。

The Chemical Catalysis Program of the Chemistry Division supports the project by Professor Gustafson. Professor Gustafson is a faculty member in the Department of Chemistry at San Diego State University. He is developing new classes of catalysts for electrophilic aromatic substitution. The goal of this research program is to design new catalysts that allow for the direct functionalization of both simple and complex aromatic molecules, including pharmaceuticals and proteins. Lewis basic groups are capable of activating electrophiles and are readily incorporated into catalyst structures, allowing for modular catalyst design. The project lies at the interface of catalytic, synthetic and physical organic chemistry. Therefore, it is well suited for the education of scientists at all levels. Professor Gustafson's group is well positioned to provide the highest level of education and training for students underrepresented in science due to San Diego State University's unique and diverse student population. Outreach activities involving underrepresented students at community colleges are part of the project. Lewis bases can catalytically activate diverse electrophiles towards electrophilic addition reactions. The Gustafson group has recently demonstrated that Lewis bases such as thioureas and phosphine sulfides can catalyze the halogenation or sulfenylation of aromatic feedstocks under very mild conditions. Preliminary mechanistic studies suggest this chemistry proceeds through a covalent halenium-catalyst adduct, and that the structure of the catalyst can influence the reaction outcome. The proposed research involves both in-depth mechanistic studies and the development of new catalysts to extend the project to more complex systems. There are three major questions this proposal strives to answer: How do Lewis base catalysts control the regioselectivity of phenol chlorination, and can this selectivity be extended to other classes of arenes? Second, how do Lewis bases conjugated to Bronsted acids catalyze the mild sulfenylation of heterocycles, and can this reaction be extended to peptides, proteins, and natural products? Furthermore, can changes in the Lewis base lead to chemoselectivity towards other classes of arenes? Finally, can chiral Lewis base catalysts be designed to effect enantioselective halogenation and sulfenylation? The educational plan includes outreach to underrepresented students at local community colleges to introduce them to research opportunities available to undergraduates. This outreach activity includes hands-on presentations at local community colleges that introduce students to computational chemistry in the context of the conformational analysis of butane.