As part of a research program focused on the development of new catalytic chemo-, regio-, and stereoselective synthetic methods for organic chemistry and pharmaceutical sciences, chemical methods based on cyclopropyl metal carbenes will be developed for the synthesis of highly functionalized cyclobutanes, pyrans, and other complex ring systems under mild catalytic conditions. The discovery of the novel reactivity of cyclopropyl metal carbenes, mediated by various transition metal catalysts, opens a broad range of mechanistically unique pathways and improves our fundamental understanding for the chemistry of cyclopropanes and metal carbenes.
In aim #1, we propose to develop: a) general methods for the preparation of aryl and alkyl substituted cyclopropyl diazo compounds and explore the chemo-, regio-, and stereoselectivity of the ring expansion of these diazo compounds in the presence of transition metal catalysts (e.g. dirhodium (II), copper (I), and silver (I));b) an enantioselective ring expansion reaction to prepare chiral cyclobutenes from meso diazo compounds;and c) general methods for the preparation of pyran derivatives.
In aim #2, we propose to develop a unified and flexible strategy for the diastereo- and enantioselective synthesis of chiral cyclobutanes based on methods we developed in preliminary study and methods proposed in aim #1. Natural products that we propose to accomplish here have broad biological activities, including antibiotics, antiviral agents, antimicrobial agents, analgesics, selective CYP inhibitors, and histamine H3 receptor antagonists.
In aim #3, we propose to expand the reactivity profile of cyclopropyl metal carbenes from the formation of cyclobutenes and 4H-pyrans via rearrangement to the formation of more complex ring systems via cycloadditions. Computational results from related systems were used to guide the design of several cycloaddition reactions. Transition metal catalysts were chosen for these cycloadditions based on their properties of being able to form metal carbenes, to catalyze cycloaddition reactions, and to cleave cyclopropane C-C bonds. These studies together will greatly increase the synthetic utility of cyclopropanes and metal carbenes and enable the discovery of previously unknown reactions of cyclopropanes and metal carbenes. The cumulative result of these aims is improved fundamental understanding of the chemistry of cyclopropanes and various metal carbenes and discovery of efficient methods that will find immediate utility in the synthesis of complex organic molecules.

Public Health Relevance

The outlined proposal provides access to important biologically active natural products and drug candidates rapidly, efficiently, and stereoselectively. Synthetic methods developed in this proposal are also flexible to make many potentially more potent analogs, which may cure human diseases more effectively.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088285-04
Application #
8301706
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2009-08-03
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$284,441
Indirect Cost
$88,421
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Li, Hui; Li, Xiaoxun; Wang, Hao-Yuan et al. (2014) Copper-catalyzed tandem annulation/arylation for the synthesis of diindolylmethanes from propargylic alcohols. Chem Commun (Camb) 50:12293-6
Schienebeck, Casi M; Li, Xiaoxun; Shu, Xing-Zhong et al. (2014) 3-Acyloxy-1,4-enyne: a New Five-carbon Synthon for Rhodium-Catalyzed (5+2) Cycloadditions. Pure Appl Chem 86:409-417
Liu, Na; Song, Wangze; Schienebeck, Casi M et al. (2014) Synthesis of Naturally Occurring Tropones and Tropolones. Tetrahedron 70:9281-9305
Winston-McPherson, Gabrielle N; Shu, Dongxu; Tang, Weiping (2014) Synthesis and biological evaluation of 2,3'-diindolylmethanes as agonists of aryl hydrocarbon receptor. Bioorg Med Chem Lett 24:4023-5
Xu, Xiufang; Liu, Peng; Shu, Xing-zhong et al. (2013) Rh-catalyzed (5+2) cycloadditions of 3-acyloxy-1,4-enynes and alkynes: computational study of mechanism, reactivity, and regioselectivity. J Am Chem Soc 135:9271-4
Liu, Renhe; Winston-McPherson, Gabrielle N; Yang, Zhong-Yue et al. (2013) Generation of rhodium(I) carbenes from ynamides and their reactions with alkynes and alkenes. J Am Chem Soc 135:8201-4
Schienebeck, Casi M; Robichaux, Patrick J; Li, Xiaoxun et al. (2013) Effect of ester on rhodium-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and alkynes. Chem Commun (Camb) 49:2616-8
Shu, Dongxu; Song, Wangze; Li, Xiaoxun et al. (2013) Rhodium- and platinum-catalyzed [4+3] cycloaddition with concomitant indole annulation: synthesis of cyclohepta[b]indoles. Angew Chem Int Ed Engl 52:3237-40
Liu, Renhe; Zhang, Min; Winston-McPherson, Gabrielle et al. (2013) Ring expansion of alkynyl cyclopropanes to highly substituted cyclobutenes via a N-sulfonyl-1,2,3-triazole intermediate. Chem Commun (Camb) 49:4376-8
Xu, Hua-Dong; Zhang, Ren-Wei; Li, Xiaoxun et al. (2013) Rhodium-catalyzed chemo- and regioselective cross-dimerization of two terminal alkynes. Org Lett 15:840-3

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