Organic synthesis can have a dramatic impact on public health when strategies can be devised to prepare molecules with useful biological properties efficiently and in large quantity. Designing new reactions that allow for selective bond construction is essential to meet this objective. This proposal outlines plans for expanding upon my research group's studies in utilizing oxidative fragmentation reactions in creating new selective transformations, and highlights the unique role that electron transfer processes can play in the synthesis of complex molecules of biological interest. The projects have been selected to show the unique chemoselectivity and functional group compatibility of the reaction conditions and to demonstrate the manner in which oxidative cleavage reactions create opportunities for new synthetic strategies. Specific goals for this project include: Utilizing oxidatively-generated oxocarbenium ions as pendent Lewis acids to initiate cascade reactions involving epoxides in unique ways that will provide access to a significant portion of the natural product lactodehydrothyrsiferol. Developing an oxidative method to use carbon-hydrogen bond activation to form electrophiles. This approach will be useful in the synthesis of C-aryl glycosides and will be applied to the total synthesis of morinol A. The method will also be used to initiate cyclization reactions that result from nucleophilic additions into macrocyclic carbocations, leading to a total synthesis of the cytotoxin aspergillide C. Devising a chiral electroauxiliary that promotes oxidative carbon-hydrogen bond activation, resulting in the formation of an electrophile that engages in diastereoselective addition reactions. A wide range of nucleophilic groups should be compatible with this method, providing access to numerous stereochemically that could not previously be accessed through this protocol.

Public Health Relevance

The projects that are described in this proposal involve the use of electron transfer to prepare molecules that have important biological activities, such as destroying cancer cells and altering cell signalling sequences. These reactions will allow for efficient preparations of agents that optimize these activities and for the design of unique processes that can be used to prepare compounds that exhibit a wide range activities, making this research relevant to areas that transcend those that are defined in the proposal.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062924-09
Application #
8117049
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2002-08-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
9
Fiscal Year
2011
Total Cost
$273,398
Indirect Cost
Name
University of Pittsburgh
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Cui, Yubo; Villafane, Louis A; Clausen, Dane J et al. (2013) Bimolecular Coupling Reactions through Oxidatively Generated Aromatic Cations: Scope and Stereocontrol. Tetrahedron 69:7618-7626
Han, Xun; Floreancig, Paul E (2012) Synthesis of bridged inside-outside bicyclic ethers through oxidative transannular cyclization reactions. Org Lett 14:3808-11
Peh, GuangRong; Floreancig, Paul E (2012) Cyclopropane compatibility with oxidative carbocation formation: total synthesis of clavosolide A. Org Lett 14:5614-7
Cui, Yubo; Balachandran, Raghavan; Day, Billy W et al. (2012) Synthesis and biological evaluation of neopeltolide and analogs. J Org Chem 77:2225-35
Clausen, Dane J; Floreancig, Paul E (2012) Aromatic cations from oxidative carbon-hydrogen bond cleavage in bimolecular carbon-carbon bond forming reactions. J Org Chem 77:6574-82
Cui, Yubo; Floreancig, Paul E (2012) Synthesis of sulfur-containing heterocycles through oxidative carbon-hydrogen bond functionalization. Org Lett 14:1720-3
Clausen, Dane J; Wan, Shuangyi; Floreancig, Paul E (2011) Total synthesis of the protein phosphatase 2A inhibitor lactodehydrothyrsiferol. Angew Chem Int Ed Engl 50:5178-81
Liu, Lei; Floreancig, Paul E (2010) 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone-catalyzed reactions employing MnO2 as a stoichiometric oxidant. Org Lett 12:4686-9
Liu, Lei; Floreancig, Paul E (2010) Structurally and stereochemically diverse tetrahydropyran synthesis through oxidative C-H bond activation. Angew Chem Int Ed Engl 49:3069-72
Cui, Yubo; Tu, Wangyang; Floreancig, Paul E (2010) Total synthesis of neopeltolide and analogs. Tetrahedron 66:4867-4873

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