Leveraging Main-Group Redox Catalysis for Enantioselective Alkene Difunctionalization

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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.