The stereoselective construction of saturated heterocycles remains an important challenge in organic synthesis, as many biologically active natural molecules contain these subunits. Although the development of methods for the construction of heterocycles has been of longstanding interest, a number of important targets are difficult to generate in a stereoselective manner using existing transformations. In addition, many methods are not readily amenable to the preparation of numerous analogs from a single precursor. The long-term goal of our research program is to develop new reactions for the construction of enantiomerically enriched, biologically active heterocycles. The objectives of the research outlined in this proposal, which represent significant steps toward our long term goal, are to develop new alkene carboheterofunctionalization reactions for the synthesis of several specific classes of biologically relevant heterocycles, and to develop new catalysts for asymmetric carboheterofunctionalization reactions. These objectives will be achieved by pursuing three specific aims: (1) to develop new alkene carboheterofunctionalization reactions for the construction of complex bicyclic heterocycles;(2) to develop new asymmetric alkene carboheterofunctionalization reactions;and (3) to develop new alkene carboheterofunctionalization reactions for the enantioselective synthesis of molecules bearing acetal or aminal stereocenters. All three aims involve the invention of new types of Pd-catalyzed reactions of aryl/alkenyl halides with amines/alcohols bearing pendant alkenes. These reactions will form two bonds and two stereocenters in one step to generate the desired heterocycles in an efficient and stereoselective manner, and will be applied to the synthesis of biologically significant targets. The proposed studies are innovative because they will lead new strategy-level disconnections that can be applied to complex molecule synthesis by a variety of chemists in both industry and academia. In addition, these studies will extend the forefront of alkene carboheterofunctionalization processes, and will provide insight into factors that can be used to control asymmetric induction in this important class of transformations. The knowledge gained can be used for the future development of other new reactions. The proposed research is significant because the new transformations developed during these studies will provide facile access to important biologically active compounds that are difficult to generate with existing methods. This will broaden the range of heterocyclic building blocks available for use in medicinal chemistry/drug development. In addition, these new transformations will also allow for facile generation of analogs of interesting molecules, which can be used to optimize biological or pharmaceutical properties of lead compounds.

Public Health Relevance

The proposed research is relevant to public health, because these studies will lead to new methods for the synthesis of medicinally relevant compounds. These new synthetic methods will provide access to biologically active molecules that cannot be prepared using existing chemical transformations, which will be of great utility for the development of new pharmaceuticals that are beneficial to human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098314-03
Application #
8453445
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2011-09-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$269,068
Indirect Cost
$85,718
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Babij, Nicholas R; McKenna, Grace M; Fornwald, Ryan M et al. (2014) Stereocontrolled synthesis of bicyclic sulfamides via Pd-catalyzed alkene carboamination reactions. Control of 1,3-asymmetric induction by manipulating mechanistic pathways. Org Lett 16:3412-5
Alicea, Jeremiah; Wolfe, John P (2014) Synthesis of substituted tetrahydroindoloisoquinoline derivatives via intramolecular Pd-catalyzed alkene carboamination reactions. J Org Chem 79:4212-7
Babij, Nicholas R; Wolfe, John P (2013) Desymmetrization of meso-2,5-diallylpyrrolidinyl ureas through asymmetric palladium-catalyzed carboamination: stereocontrolled synthesis of bicyclic ureas. Angew Chem Int Ed Engl 52:9247-50
Zavesky, Blane P; Babij, Nicholas R; Fritz, Jonathan A et al. (2013) Synthesis of cyclic guanidines via Pd-catalyzed alkene carboamination. Org Lett 15:5420-3
Ward, Amanda F; Xu, Yan; Wolfe, John P (2012) Synthesis of chromans via Pd-catalyzed alkene carboetherification reactions. Chem Commun (Camb) 48:609-11
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