Leveraging Main-Group Redox Catalysis for Enantioselective Alkene Difunctionalization

在化学系化学催化项目的支持下，伊利诺伊大学香槟分校的Scott E. Denmark教授将开展研究，开发烯烃选择性双官能化的新方法。烯烃和其他不饱和化合物的加法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物、药物和农用化合物在立体中心含有邻近的氮和氧原子，这突出了合成方法的这一严重缺陷。该建议通过基于机制的方法解决了对映选择性双功能化过程设计中固有的挑战。计划的研究活动对本科生、研究生和博士后同事的智力和实践训练是理想的。反应设计、开发和应用的相互作用是科学方法的本质。学生们被提出了对计划实验结果的假设，他们必须学会收集和解释数据来证实或消除假设。这个活动的统一主题是发明新的化学反应，挑战当前的思维。在伊利诺伊大学洛杉矶分校圣埃尔莫·布雷迪暑期研究学者项目的支持下，将支持一名本科生实习生。这个项目是一个为期10周的暑期研究经历，面向来自伊利诺伊大学化学系历史上的黑人学院的少数族裔学生（非裔美国人、西班牙裔美国人、印第安人），以鼓励未来攻读博士学位。无数的反应被引入来影响双键的区域、非映和对映选择性功能化，具有良好的通用性。然而，绝大多数现有的方法采用过渡金属催化，如二羟基化和氨基羟基化（锇）和二胺化（钯，铜）。尽管这些方法具有不可否认的效用，但由于与金属污染有关的挑战，它们很少在工业上使用。本提案旨在提供一种基于Main基团氧化还原催化的替代方法，其优点包括使用无害氧化剂驱动催化循环的能力以及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奠定机械/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syn1,2 -二胺化；(2)催化，对映选择性syn1,2 -氧胺化；(3)催化，对映选择性syn1,2 -碳胺化。对于每个特定目标，团队将：(1)对催化反应进行详细的机理（动力学、光谱学、晶体学、计算学）研究，以了解实现目标反应高催化活性（周转频率和周转数）的规则；(2)设计具有高立体选择性和高化学转化率的手性催化剂，以引入新的立体中心；(3)在代表广泛有用的结构基序的各种基材类别中展示普遍性。该项目还支持一名本科生实习生，该实习生由UIUC的圣埃尔莫·布雷迪暑期研究学者计划赞助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.