Quick and efficient access to diverse classes of biologically active lead compounds is an essential part of drug discovery. Heterocycles of different ring sizes and with different substitution patterns constitute extremely important structure classes (e.g. alkaloids) in the search for bioactivity. A contemporary challenge in organic synthesis is the mapping of new chemical spaces through tandem or cascade reactions in an atom economical fashion. Our strategy to access these biologically important heterocycles relies on a cyclization-triggered tandem addition to alkynes catalyzed by readily available alkynophilic coinage metals like copper, through an electrophilic activation of the enamine intermediate. Our tandem chemistry will enable us to generate biologically important N-heterocycles like cyclic aminoacids with a facility unmatched by previous methods. During our preliminary work, we synthesized various nitrogen heterocycles through an amination/alkynylation sequence and a tandem amination/cyanation in near quantitative yields, all in one pot. Our research plan will expand the scope of this strategy substantially. The major part of this proposal focuses on exploring the chemical space of these versatile tandem transformations by changing the components of the transformation and applying them to the synthesis of biologically important heterocycles. We plan to 1) explore nucleophiles in tandem sequences;2) develop an asymmetrical version;3) seek alternative roles for transient cyclic enamines. The proposed work is significant for the following reasons: first, having a functionalized group on the N-heterocycle will enable further transformations, resulting in more complex ring systems (Scheme 1). Second, one of the tenets of this proposal--transforming an enamine into a good electrophile--will shed light on the relatively obscure role of enamines as electrophiles. Third, beyond bringing about efficient ways to generate N-heterocycles of various ring sizes (5-7) and diverse carbon connectivities (fused, bridged, spiro), this work will produce scores of new compounds that will be screened by Eli Lilly in their drug discovery program for Alzheimer's disease, cancer, and diabetes.

Public Health Relevance

Nitrogen ring system of different ring sizes and with various substitution patterns constitute extremely important structure leads in the search for drug candidates. In this regard, alkaloids are representative examples. We have discovered a powerful strategy to access many important N-heterocycles, through a cyclization triggered tandem protocol that relies on a transition metal-catalyzed electrophilic activation of the enamine intermediate. The proposed work will furnish single-, fused- bridged- or spiro-heterocyclic systems, including biologically important unnatural cyclic aminoacids and fluorinated ring systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM101604-01
Application #
8290765
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2012-06-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$335,091
Indirect Cost
$109,091
Name
University of Louisville
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Okoromoba, Otome E; Han, Junbin; Hammond, Gerald B et al. (2014) Designer HF-based fluorination reagent: highly regioselective synthesis of fluoroalkenes and gem-difluoromethylene compounds from alkynes. J Am Chem Soc 136:14381-4
Han, Junbin; Lu, Zhichao; Hammond, Gerald B et al. (2014) Synthesis of Pyrrolidines and Pyrroles via Tandem Amination/Cyanation/Alkylation and Amination/Oxidation Sequences. European J Org Chem 2014:5786-5792