The availability of functionalized molecules is of preeminent importance in the fields of organic and medicinal chemistry and to the pharmaceutical and related industries. Not only should compounds be accessible, but also the means to readily and predictably modify them to change their properties and/or eliminate side effects is of tremendous significance. The chemistry that is proposed in this grant application involves the invention or accentuation of techniques to access molecules that contain basic nitrogen centers as key structural features. Our prior work in this field has been incorporated into the everyday repertoire of synthetic organic chemists and has greatly impacted the field of organic synthesis, particularly in drug discovery in the pharmaceutical industry. In addition, we are proposing work on the synthesis in enantiomerically pure (single handed) form of a wide variety of amines from extremely simple (alkene) precursors. Essentially all modern small molecule medicines must now be sold in single-handed forms and the successful accomplishment of this feat can add to the cost of the medicinal agent. Also included are new methods for the preparation of nitrogen heterocycles. In many ways, compounds of this type form the backbone of the pharmaceutical industry. We also propose to carry out mechanistic studies on all of the chemistry included. Further, information gained from this work will help to understand the mechanism of the processes that are being developed in order to increase the efficiency of the methods that we are developing. Overall, the successful realization of the chemistry proposed in this grant application will have a major impact on the ability of chemists and those in auxiliary fields to develop new medicinally important, sensor or biologically relevant compounds and materials that will move science forward.

Public Health Relevance

The chemistry we are proposing will improve access to compounds of importance in biomedical research in both academia and industry. The cross-coupling methods we are developing for carbon-nitrogen and carbon-oxygen bond formation are regularly used by those in discovery groups in the pharmaceutical industry for the preparation of new lead compounds. In addition, they allow for the constructions of analogues with increased potency and reduced side effects.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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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
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
Ingoglia, Bryan T; Buchwald, Stephen L (2017) Oxidative Addition Complexes as Precatalysts for Cross-Coupling Reactions Requiring Extremely Bulky Biarylphosphine Ligands. Org Lett 19:2853-2856

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