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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM058160-17
Application #
8755679
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Cheung, Chi Wai; Buchwald, Stephen L (2014) Palladium-catalyzed hydroxylation of aryl and heteroaryl halides enabled by the use of a palladacycle precatalyst. J Org Chem 79:5351-8
Vinogradova, Ekaterina V; Müller, Peter; Buchwald, Stephen L (2014) Structural reevaluation of the electrophilic hypervalent iodine reagent for trifluoromethylthiolation supported by the crystalline sponge method for X-ray analysis. Angew Chem Int Ed Engl 53:3125-8
Zhu, Ye; Buchwald, Stephen L (2014) Ligand-controlled asymmetric arylation of aliphatic ?-amino anion equivalents. J Am Chem Soc 136:4500-3
Ernst, Johannes B; Tay, Nicholas E S; Jui, Nathan T et al. (2014) Regioselective synthesis of benzimidazolones via cascade C-N coupling of monosubstituted ureas. Org Lett 16:3844-6
Su, Mingjuan; Hoshiya, Naoyuki; Buchwald, Stephen L (2014) Palladium-catalyzed amination of unprotected five-membered heterocyclic bromides. Org Lett 16:832-5
Zhu, Shaolin; Buchwald, Stephen L (2014) Enantioselective CuH-catalyzed anti-Markovnikov hydroamination of 1,1-disubstituted alkenes. J Am Chem Soc 136:15913-6
Bruno, Nicholas C; Niljianskul, Nootaree; Buchwald, Stephen L (2014) N-substituted 2-aminobiphenylpalladium methanesulfonate precatalysts and their use in C-C and C-N cross-couplings. J Org Chem 79:4161-6
Park, Nathaniel H; Teverovskiy, Georgiy; Buchwald, Stephen L (2014) Development of an air-stable nickel precatalyst for the amination of aryl chlorides, sulfamates, mesylates, and triflates. Org Lett 16:220-3
Cheung, Chi Wai; Surry, David S; Buchwald, Stephen L (2013) Mild and highly selective palladium-catalyzed monoarylation of ammonia enabled by the use of bulky biarylphosphine ligands and palladacycle precatalysts. Org Lett 15:3734-7
DeBergh, J Robb; Niljianskul, Nootaree; Buchwald, Stephen L (2013) Synthesis of aryl sulfonamides via palladium-catalyzed chlorosulfonylation of arylboronic acids. J Am Chem Soc 135:10638-41

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