This proposal describes the development of new reactions that can be used for the preparation of important classes of compounds including pyrrolidines, tetrahydrofurans, amino alcohols, diols, and diamines. Many of these molecules possess useful biological activity, and/or are important intermediates in the synthesis of more complex biologically active molecules. For example, the annonaceous acetogenin family of natural products contain substituted tetrahydrofuran units;members of this class of compounds exhibit a wide range of biological activities including antitumor, antimalarial, and antimicrobial. This family of molecules could be useful for the treatment of a variety of diseases including cancer and malaria. The substituted pyrrolidine alkaloids preussin and anisomycin have potent antifungal activity and also exhibit potentially useful antitumor activity. Diols, diamines, and amino alcohols are also found in a large number of biologically active compounds including the antibacterial agent discodermolide. The new reactions described in this proposal have a number of significant advantages over currently available methods for the synthesis of the compounds described above. The starting materials for the proposed reactions are simple and readily available, and the reactions lead to the formation of several different bonds and multiple stereocenters in single process. These new reactions are environmentally benign and will provide much shorter routes to the molecules described above, which will make important medicinal compounds more readily available at a lower cost than current technology allows. These new procedures will also allow for the synthesis of new derivatives of interesting, biologically active molecules which may lead to the discovery of new medicines and treatments for disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM071650-05S1
Application #
8046199
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Hagan, Ann A
Project Start
2005-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$76,788
Indirect Cost
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
Peterson, Luke J; Luo, Jingyi; Wolfe, John P (2017) Synthesis of Cyclic Guanidines Bearing N-Arylsulfonyl and N-Cyano Protecting Groups via Pd-Catalyzed Alkene Carboamination Reactions. Org Lett 19:2817-2820
Garlets, Zachary J; Silvi, Mattia; Wolfe, John P (2016) Synthesis of Cyclic Guanidines via Silver-Catalyzed Intramolecular Alkene Hydroamination Reactions of N-Allylguanidines. Org Lett 18:2331-4
White, Derick R; Wolfe, John P (2015) Synthesis of Polycyclic Nitrogen Heterocycles via Cascade Pd-Catalyzed Alkene Carboamination/Diels-Alder Reactions. Org Lett 17:2378-81
Hopkins, B A; Wolfe, J P (2014) Enantioselective Synthesis of Tetrahydroquinolines, Tetrahydroquinoxalines, and Tetrahydroisoquinolines via Pd-Catalyzed Alkene Carboamination Reactions. Chem Sci 5:4840-4844
Zavesky, Blane P; Babij, Nicholas R; Wolfe, John P (2014) Synthesis of substituted 2-aminoimidazoles via Pd-catalyzed alkyne carboamination reactions. Application to the synthesis of preclathridine natural products. Org Lett 16:4952-5
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
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
Schultz, Danielle M; Wolfe, John P (2011) Intramolecular alkene carboamination reactions for the synthesis of enantiomerically enriched tropane derivatives. Org Lett 13:2962-5
Mai, Duy N; Rosen, Brandon R; Wolfe, John P (2011) Enantioconvergent synthesis of (+)-aphanorphine via asymmetric Pd-catalyzed alkene carboamination. Org Lett 13:2932-5
Lemen, Georgia S; Wolfe, John P (2011) Cascade intramolecular N-arylation/intermolecular carboamination reactions for the construction of tricyclic heterocycles. Org Lett 13:3218-21

Showing the most recent 10 out of 37 publications