Leveraging Main-Group Redox Catalysis for Enantioselective Alkene Difunctionalization

在化学系化学催化项目的支持下，伊利诺伊大学厄巴纳-香槟分校的斯科特·E·丹麦教授将进行研究，开发烯烃选择性去功能化的新方法。烯烃和其他不饱和化合物的加成是有机化学中最古老和最可靠的转化之一。然而，控制反应选择性仍然是一个挑战。越来越多的复杂天然产品、药物和农用化合物在立体形成中心含有邻近的氮和氧原子，突显了合成方法学的这一严重缺陷。这项建议通过一种基于机制的方法解决了设计对映体选择性去功能化过程所固有的挑战。计划的研究活动非常适合本科生、研究生和博士后同事的智力和实践培训。反应设计、开发和应用的相互作用代表了科学方法的精髓。向学生提出对计划实验结果的假设，他们必须学会收集和解释数据以证实或消除假设。这一活动的统一主题是发明挑战当前思维的新化学反应。UIUC圣埃尔莫·布雷迪暑期研究学者项目赞助的一名本科生实习生将得到支持。这个项目是一个为期10周的暑期研究项目，面向来自伊利诺伊大学化学系历史悠久的黑人学院的少数族裔学生(非洲裔美国人、西班牙裔美国人和美洲原住民)，以鼓励未来攻读博士学位。为了实现双键的区域功能化、非对映功能化和对映选择性功能化，引入了无数的反应，具有很好的通用性。然而，现有的绝大多数方法都使用过渡金属催化，如二羟基化和氨羟基化(Os)和二胺化(钯、铜)。尽管这些方法具有不可否认的实用性，但考虑到与金属污染相关的挑战，它们很少在工业上使用。这一提议旨在提供一种植根于主基团氧化还原催化的替代方法，其优点包括能够使用无害的氧化剂来驱动催化循环，以及Se(II)试剂对碳-碳双键的高亲和力。实现这一目标的可行路线图是为发展普遍适用和高选择性的烯烃双官能化构建机械/物理有机基础。本项目的总体目标分为三个具体目标：(1)催化，对映选择性1，2-二氨基化；(2)催化，对映选择性合成-1，2-羟胺；(3)催化，对映选择性合成-1，2-氨基化。对于每个具体目标，该小组将：(1)对催化反应进行详细的机理(动力学、光谱、结晶学、计算)研究，以了解目标反应实现高催化活性(周转频率和周转次数)的规则；(2)设计手性催化剂，为引入新的立体中心提供高立体选择性和高化学转化率；以及(3)展示各种底物类别的普遍性，这些底物类别代表了广泛有用的结构基序。该项目还支持UIUC圣埃尔莫·布雷迪暑期研究学者项目赞助下的一名本科生实习生。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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 Catalysis program in the Division of Chemistry, Professor Scott E. Denmark at the University of Illinois at Urbana-Champaign will conduct research to develop new methods for selective difunctionalizations of alkenes. Addition to alkenes and other unsaturated compounds is among the oldest and most reliable transformations in organic chemistry. However, controlling reaction selectivity remains a challenge. The growing number of complex natural products, pharmaceutical, and agrochemical compounds containing vicinal nitrogen and oxygen atoms at stereogenic centers underscores this critical deficiency in synthetic methodology. This proposal addresses the challenges inherent in the design of enantioselective difunctionalization processes through a mechanismbased approach. The research activities planned are ideal for the intellectual and practical training of undergraduates, graduate students, and postdoctoral coworkers. The interplay of reaction design, development and application represent the essence of the scientific method. Students are presented with hypotheses for the outcome of planned experiments and they must learn to collect and interpret data to substantiate or eliminate the hypothesis. The unifying theme of this activity is the invention of new chemical reactions that challenge current thinking. An undergraduate intern under the auspices of the St. Elmo Brady Summer Research Scholars Program at UIUC will be supported. This program is a 10-week summer research experience for underrepresented minority students (African American, Hispanic, Native Americans) from Historically Black Colleges at the University the Illinois Chemistry Department to encourage future enrollment in the PhD program. Countless reactions have been introduced to effect regio, diastereo and enantioselective functionalization of double bonds with good generality. However, the vast majority of the existing methods employ transition metal catalysis such as dihydroxylation and aminohydroxylation (osmium), and diamination (palladium, copper). Despite the undeniable utility of these methods, they are rarely employed industrially in view of the challenges associated with metal contamination. This proposal aims to provide an alternative approach that is rooted in Main Group redox catalysis the advantages of which include ability to use innocent oxidants to drive the catalytic cycle and the high affinity of Se(II) reagents for carbon-carbon double bonds. The actionable roadmap to achieve this goal is to construct the mechanistic/physical organic foundation for the development of generally applicable and highly selective alkene difunctionalization. The overall objective is divided into three Specific Aims of this project: (1) catalytic, enantioselective syn-1,2-diamination, (2) catalytic, enantioselective syn-1,2-oxyamination and (3) catalytic, enantioselective syn-1,2-carboamination. For each Specific Aim, the team will: (1) carry out detailed mechanistic (kinetic, spectroscopic, crystallographic, computational) investigations of the catalytic reactions to learn the rules for achieving high catalytic activity (turnover frequency and turnover number) for the target reactions (2) design chiral catalysts that will impart high stereoselectivity and high chemical conversion for the introduction of new stereocenters, and (3) demonstrate generality in a variety of substrate classes that represent broadly useful structural motifs. The project also supports an undergraduate intern under the auspices of the St. Elmo Brady Summer Research Scholars Program at UIUC.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.