Catalytic activation of thioesters via nucleophilic acyl substitution

化学部的化学催化项目用这个奖项来支持Vladimir Birman教授的研究项目。伯曼教授是圣路易斯华盛顿大学化学系的一名教员。伯曼教授的研究兴趣围绕手性有机化合物：其结构以不同的镜像形式存在的化合物，称为对映体。同一化合物的两个对映体往往表现出不同的生物活性，这在手性药物的情况下变得至关重要。错误的药物对映体可能会降低药理学活性，甚至有毒。因此，开发以单对映体形式制备手性化合物的方法具有相当大的兴趣。选择性催化是Birman小组研究的主要焦点，是实现这一目标的一种经济且无浪费的方法。本项目旨在利用Birman的手性催化剂探索一个新的反应家族，该催化剂先前由Birman小组开发，目前被世界各地的许多研究人员使用。这些反应提供了获得新的手性化合物的途径，这些化合物可能会在药物开发和生物学研究中得到应用。伯曼教授的研究项目涵盖了合成有机化学的许多领域，适合教育各个层次的学生：参与研究的研究生，在伯曼实验室接受培训的本科生，以及在他的指导下参加高级有机实验室的学生。此外，伯曼教授在圣路易斯公立学校的外展活动旨在激发小学生对科学的兴趣。拟议项目的总体主题是刘易斯碱催化硫酯的对映选择性活化。具体来说，Birman小组正在开发一种不对称催化重排，将α， β -不饱和硫酯转化为两性离子烯醇酸酯，然后与亲电试剂形成正式的环加成。由此产生的带有几个立体中心的多环结构，有望在天然产物合成和药物化学中发挥重要作用。这些多环产物是其他合成方法难以获得的。此外，外消旋硫酯的对映选择性醇解也在静态和动态动力学解析模式下进行了探索。先前在伯曼实验室开发的基于脒的对映选择性酰化催化剂被用于实现这两种新的转化。与该研究项目相关的教育计划包括进一步发展华盛顿大学本科课程中的有机化学部分，并继续向圣路易斯公立学校的中小学生推广。

With this award, the Chemical Catalysis Program of the Chemistry Division supports the research program of Professor Vladimir Birman. Professor Birman is a faculty member in the Department of Chemistry at Washington University in Saint Louis. Prof. Birman's research interests revolve around chiral organic compounds: compounds whose structures exist as distinct mirror images called enantiomers. The two enantiomers of the same compound often display different biological activities, which becomes vitally important in the case of chiral pharmaceuticals. The wrong enantiomer of a drug may have reduced pharmacological activity or even be toxic. Therefore, there is considerable interest in developing methods for preparing chiral compounds in the form of single enantiomers. Selective catalysis, which is the main focus of research in the Birman group, is an economical and waste-free approach to accomplishing this goal. The present project aims to explore a new family of reactions using Birman's chiral catalysts, which previously were developed in the Birman group and are currently used by many researchers worldwide. These reactions provide access to new classes of chiral compounds that may find applications as drug development and biological studies. Prof. Birman's research program, which encompasses many areas of synthetic organic chemistry, is suited for educating students at all levels: graduate students involved in research, undergraduates receiving training in the Birman lab, and those students taking Advanced Organic Lab under his supervision. In addition, Professor Birman's outreach activities in the public schools of Saint Louis are designed to spark the interest of elementary school students in science. The overarching theme of the proposed project is the Lewis base-catalyzed enantioselective activation of thioesters. Specifically, the Birman group is developing an asymmetric catalytic rearrangement of alpha,beta-unsaturated thioesters into zwitterionic enolates, followed by a formal cycloaddition with pi-electrophiles. The resulting polycyclic structures, adorned with several stereocenters, are expected to be important in natural product synthesis and medicinal chemistry. These polycyclic products are difficult to access by other synthetic methods. In addition, the enantioselective alcoholysis of racemic thioesters is being explored, both in static and dynamic kinetic resolution mode. Amidine-based enantioselective acylation catalysts previously developed in the Birman laboratory are employed to achieve both of these new transformations. The educational plan associated with this research program includes further development of the organic chemistry component of the undergraduate curriculum at Washington University and continued outreach to elementary/middle school students in the public schools of Saint Louis.