The ability to prepare highly functionalized molecules in a general and predictable way is central to organic synthesis and the backbone of drug discovery, development and scale-up. The chemistry that we are proposing involves the development of carbon-heteroatom and carbon- carbon bond formations. Our prior work is widely used throughout academia and industry for the preparation of complex molecules and has become mainstay processes for synthetic chemists. The invention of new methods will not only allow access to important compounds but also the means to be able to efficiently and selectively modify them, to change their properties and or/eliminate side effects. Included in our proposed work are palladium-catalyzed cross coupling methods for the formation of heterocyclic carbon-nitrogen bonds, carbon-oxygen bonds and carbon-fluorine bonds; copper-catalyzed methods for the highly regio-, diastereo-, and enantioselective synthesis of aliphatic amines; and copper-catalyzed methods for the asymmetric formation of carbon-carbon bonds. Mechanistic studies will be conducted to understand the fundamental features of these transformations and will guide us to advance the efficiency and utility of this work. The substrates we are targeting are ubiquitous structural components in pharmaceuticals, natural products, agrochemicals and sensors. The application of these new technologies for the preparation of highly functionalized and diverse compounds, which have previously been inaccessible, will have a great impact in a range of areas that are directly important to human health.
The chemistry we are proposing will improve access to compounds of importance in biomedical research in both academia and industry. The methods we have developed for carbon- heteroatom and carbon-carbon bond formation are regularly used by those in discovery and process groups in the pharmaceutical industry for the preparation of new biologically relevant compounds. The methods we are devising will allow for the construction of analogues with increased potency and reduced side effects.
|Dennis, Joseph M; White, Nicholas A; Liu, Richard Y et al. (2018) Breaking the Base Barrier: An Electron-Deficient Palladium Catalyst Enables the Use of a Common Soluble Base in C-N Coupling. J Am Chem Soc 140:4721-4725|
|Tsai, Erica Y; Liu, Richard Y; Yang, Yang et al. (2018) A Regio- and Enantioselective CuH-Catalyzed Ketone Allylation with Terminal Allenes. J Am Chem Soc 140:2007-2011|
|Liu, Richard Y; Buchwald, Stephen L (2018) Copper-Catalyzed Enantioselective Hydroamination of Alkenes. Organic Synth 95:80-96|
|Zhang, Hong; Ruiz-Castillo, Paula; Buchwald, Stephen L (2018) Palladium-Catalyzed C-O Cross-Coupling of Primary Alcohols. Org Lett 20:1580-1583|
|Kubota, Koji; Dai, Peng; Pentelute, Bradley L et al. (2018) Palladium Oxidative Addition Complexes for Peptide and Protein Cross-linking. J Am Chem Soc 140:3128-3133|
|Liu, Richard Y; Bae, Minwoo; Buchwald, Stephen L (2018) Mechanistic Insight Facilitates Discovery of a Mild and Efficient Copper-Catalyzed Dehydration of Primary Amides to Nitriles Using Hydrosilanes. J Am Chem Soc 140:1627-1631|
|Zhou, Yujing; Bandar, Jeffrey S; Liu, Richard Y et al. (2018) CuH-Catalyzed Asymmetric Reduction of ?,?-Unsaturated Carboxylic Acids to ?-Chiral Aldehydes. J Am Chem Soc 140:606-609|
|Ichikawa, Saki; Zhu, Shaolin; Buchwald, Stephen L (2018) A Modified System for the Synthesis of Enantioenriched N-Arylamines through Copper-Catalyzed Hydroamination. Angew Chem Int Ed Engl 57:8714-8718|
|Gribble Jr, Michael W; Guo, Sheng; Buchwald, Stephen L (2018) Asymmetric Cu-Catalyzed 1,4-Dearomatization of Pyridines and Pyridazines without Preactivation of the Heterocycle or Nucleophile. J Am Chem Soc 140:5057-5060|
|Zhou, Yujing; Engl, Oliver D; Bandar, Jeffrey S et al. (2018) CuH-Catalyzed Asymmetric Hydroamidation of Vinylarenes. Angew Chem Int Ed Engl 57:6672-6675|
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