The enantioselective synthesis of 1- and 3-amino-containing carbonyl compounds is an important area of chemical, biological, and pharmaceutical research since many relevant molecules contain these functionalities. Applications of methods to prepare these compounds could have a far reaching impact in the development of new medicinal agents for the treatment of a wide range of disease. Current methods to prepare carbonyls with 1- or 3-amine functionality tend to be limited in scope, stereoselectivity, and/or efficiency. In order to address these limitations, the goal of this research is to develop an asymmetric palladium- or nickel-catalyzed reaction to synthesize these molecules in an efficient manner directly from the parent carbonyl-containing starting material. Toward this end, this research plan seeks to use knowledge from catalytic asymmetric Pd- and Ni- catalyzed enolate and dienolate coupling reactions and apply these methods to the coupling with O-acyl and -sulfonyl oximes as electrophilic sources of nitrogen. These oximes are attractive due to their facile conversion to the free amine in the post-coupling products. The resulting amino-carbonyls will provide rapid access to a range of high-value building blocks important for the preparation of biologically-relevant molecules such as amino alcohols, diamines, non-canonical amino acids and peptides, pyrrolidines, and lactams. Furthermore, non-natural amino alcohols are valuable in chiral auxiliary and ligand design for asymmetric organic transformations. A focused development of reaction parameters will be pursued, including ligand/catalyst design, identification of a competent nitrogen electrophile, and exploration of base-free conditions with regard to enolate generation. Similar enolate couplings have shown substrate dependence on base, temperature, and solvent, and therefore these variables will also be addressed. Upon development of a successful coupling protocol, mechanistic studies will be conducted in order to gain insight into methods to further optimize reaction efficiency. The value of the transformations developed in this research plan will be demonstrated by their application to the total synthesis of selected pharmaceutical agents and analogues.

Public Health Relevance

Methods to efficiently prepare nitrogen-containing carbonyl compounds are of great interest since the resulting molecules serve as building blocks for the construction of pharmaceutical agents. This technology has applications in drug discovery research by providing a facile method to synthesize a variety of complex structures that may have previously been difficult to access using alternative methods. Preparation of potential drug candidates in a rapid fashion will accelerate the drug development process, resulting in therapeutics being made available to patients sooner.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04A-B (20))
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Fabian, Miles
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Parsons, Andrew T; Senecal, Todd D; Buchwald, Stephen L (2012) Iron(II)-catalyzed trifluoromethylation of potassium vinyltrifluoroborates. Angew Chem Int Ed Engl 51:2947-50
Senecal, Todd D; Parsons, Andrew T; Buchwald, Stephen L (2011) Room temperature aryl trifluoromethylation via copper-mediated oxidative cross-coupling. J Org Chem 76:1174-6
Parsons, Andrew T; Buchwald, Stephen L (2011) Copper-catalyzed trifluoromethylation of unactivated olefins. Angew Chem Int Ed Engl 50:9120-3