N-Heterocycles serve as a core to a many of biologically active pharmacophores. O f t h e 181 small molecule drugs that were approved by the FDA in the last 10 years, 51% i n c o r p o r a t e a 6 - m e m b e r e d N - h e t e r o c y cl e s t r u c t u r e. Of these 92 compounds, 25% comprise a pyridine, 22% comprise a pyrimidine, and 20% comprise a piperidine. Clearly, new and efficient methods to prepare N-heterocycles would have an enormous impact on the synthesis of current and future pharmaceuticals. To address the challenges of N-heterocycle synthesis, we chose to build a research program centered around the development of a general Ni-based cycloaddition catalyst system because 1) cycloaddition of unsaturated compounds, a reaction that provides an ideal, atom- efficient entry to ring systems, 2) mechanistically, heteroatom incorporation and concurrent inhibition of side product formation seemed more tangible for the Ni system;and 2) stoichiometric oxidative coupling reactions suggested that Ni may have a higher reactivity (and therefore more generality) than the traditional Co and existing Rh and Ru systems. We have since expanded our focus to include the development of new Fe based cycloaddition catalysts, which we have found to have complimentary reactivities compared to current catalytic systems. This proposal outlines our continuing efforts and encompasses the preparation N-heterocyclic compounds, not previously synthesized through cycloaddition chemistry, from environmentally friendly and readily available starting materials. Specifically, we seek 1) to expand Ni-catalyzed cycloadditions of azacyclobutanones, 2) develop new Fe cycloaddition catalysts for the preparation of pyrimidines, and 3) develop toolbox of catalysts that regioselectively couple alkynes and cyanamides to afford pyridines.

Public Health Relevance

N-Heterocycles serve as a core to a many of biologically active pharmacophores. O f t h e 181 small molecule drugs that were approved by the FDA in the last 10 years, 51% i n c o r p o r a t e a 6 - m e m b e r e d N - h e t e r o c y c l e s t r c t u r e. Of these 92 compounds, 25% comprise a pyridine, 22% comprise a pyrimidine, and 20% comprise a piperidine. Clearly, new and efficient methods to prepare N-heterocycles would have an enormous impact on the synthesis of current and future pharmaceuticals. As such, new, efficient methods to prepare N-heterocycles have a high impact on this important class of compounds. For example, piperidines are ubiquitous in natural products and pharmaceuticals. In general, the most prevalent way to prepare functionalized piperidines is to start from a piperidone precursor and utilize the carbonyl groups to install the desired functionality. Although this protocol is highly effective, only 2-piperidones and 4- piperidones are readily available starting materials. In contrast, access to 3-piperidones is practically non-existent. As such, medicinal chemists have been lacking an entire class of potential building- blocks. We recently discovered an efficient method for the preparation of 3-piperidones from a one-step Ni-catalyzed cycloaddition of azetidinones and alkynes. We believe development of this chemistry will have a significant impact on not only the synthesis of current, useful piperidine-type products but will also open up new areas of medicinal research. We have also discovered Fe catalysts that mediate cycloaddition chemistry to afford N-heterocyclic products. Furthermore, we have found that these Fe catalyst systems are even more versatile than traditional cycloaddition catalysts. Ultimately, we believe our efforts to develop new methods for N-heterocycle (3- piperidones, medium-ring azocines, pyrimidines, pyridines, etc.) preparation will significantly aid current pharmaceutical manufacturing.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM076125-06A1
Application #
8761930
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2005-09-30
Project End
2018-03-31
Budget Start
2014-07-15
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Utah
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Thakur, Ashish; Louie, Janis (2015) Advances in nickel-catalyzed cycloaddition reactions to construct carbocycles and heterocycles. Acc Chem Res 48:2354-65
Thakur, Ashish; Evangelista, Judah L; Kumar, Puneet et al. (2015) An in Situ Approach to Nickel-Catalyzed Cycloaddition of Alkynes and 3-Azetidinones. J Org Chem 80:9951-8
Kumar, Puneet; Thakur, Ashish; Hong, Xin et al. (2014) Ni(NHC)]-catalyzed cycloaddition of diynes and tropone: apparent enone cycloaddition involving an 8Ï€ insertion. J Am Chem Soc 136:17844-51
Staudaher, Nicholas D; Stolley, Ryan M; Louie, Janis (2014) Synthesis, mechanism of formation, and catalytic activity of Xantphos nickel π-complexes. Chem Commun (Camb) 50:15577-80
Stolley, Ryan M; Duong, Hung A; Louie, Janis (2013) Mechanistic Evaluation of the Ni(IPr)2-Catalyzed Cycloaddition of Alkynes and Nitriles to Afford Pyridines: Evidence for the Formation of a Key η (1)-Ni(IPr)2(RCN) Intermediate. Organometallics 32:4952-4960
Lane, Timothy K; Nguyen, Minh H; D'Souza, Brendan R et al. (2013) The iron-catalyzed construction of 2-aminopyrimidines from alkynenitriles and cyanamides. Chem Commun (Camb) 49:7735-7
Thakur, Ashish; Facer, Megan E; Louie, Janis (2013) Nickel-catalyzed cycloaddition of 1,3-dienes with 3-azetidinones and 3-oxetanones. Angew Chem Int Ed Engl 52:12161-5
Lane, Timothy K; D'Souza, Brendan R; Louie, Janis (2012) Iron-catalyzed formation of 2-aminopyridines from diynes and cyanamides. J Org Chem 77:7555-63
Kumar, Puneet; Zhang, Kainan; Louie, Janis (2012) An expeditious route to eight-membered heterocycles by nickel-catalyzed cycloaddition: low-temperature C(sp)2-C(sp)3 bond cleavage. Angew Chem Int Ed Engl 51:8602-6
Kumar, Puneet; Louie, Janis (2012) A single step approach to piperidines via Ni-catalyzed β-carbon elimination. Org Lett 14:2026-9

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