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Research projects for Dr. Fitch Enantioselective activated-sulfur oxidation of alcohols. The oxidation of alcohols by activated sulfur reagents comes in a variety of flavors known under the names of Swern, Moffatt, and Corey-Kim. X Y- OH O S 1. H3C R1 CH3 2. Base R2 R1 R2 The reaction generally involves the treatment of primary or secondary alcohol with an activated sulfonium salt (usually derived from dimethyl sulfoxide, DMSO). Subsequent treatment with base gives the corresponding carbonyl aldehyde or ketone. Dr Fitch is interested in developing asymmetric variants of this reaction to resolve enantiomers of secondary alcohols. These compounds are important intermediates for the synthesis of complex natural products and drugs to treat disease. The general approach involves the use of chiral sulfoxides that, when activated, will react selectively with only one of the enantiomers of the chiral alcohol. This leaves the less reactive enantiomer behind. OH R2 X R3 S R1 H R4 + R3 R2 OH S R1 O H R4 Disfavored isomer is left behind R3 O R3 R4 Favored isomer gets oxidized R4 Enantioselective organometallic reactions. The metal mediated addition of carbon nucleophiles to carbonyl compounds is another common method for the preparation of alcohols. These reactions include the well known Grignard synthesis and the addition reactions of organolithium and organozinc reagents. Dr. Fitch is interested in the use of chiral metal complexes to catalyze these reactions, especially those involving lithium reagents. The first line of this work is to prepare chiral triamines from amino acids that can serve as ligands for the metal. This involves preparing a cyclic tripeptide and converting it to the triamine. Similar complexes have been used for enantioselective reactions with manganese and copper reagents. R' O 3 R' "R OH NH2 R' R' "R N R N R" Li R' N NH2 O 3 R' N R N Li OH R" R' N R" R' R" Synthesis and medicinal chemistry of natural products. Dr. Fitch is interested in many natural compounds, especially alkaloids (see below) that are derived from natural sources. In order to provide proof of structure and to prepare analogs for bioactivity studies, it is necessary to chemically synthesize the compounds. We use the tools of organic synthesis to prepare medicinally important compounds that are then evaluated biologically as potential biological probes or therapeutics. Two compounds that are of current interest are epiquinamide, a compound isolated from poison frogs, and derivatives of cytisine, a compound isolated from leguminous plants. O NH HN CH3 H N O N Epiquinamide Cytisine Both of these molecules are quinolizidine alkaloids with nicotinc receptor activity. Epiquinamide was isolated in 2003 from an Ecuadoran poison frog. We have synthesized three of the four possible diastereomers of the structure and are interested in developing a general annulation strategy for the general stereocontrolled synthesis of this class of molecules. Using this methodology, we plan to synthesize analogs of anagyrine (another quinolizidine alkaloid) by annulation of natural cytisine. O O EWG R N N N N N N From Cytisine Lupinine alkaloids Matrine alkaloids X Students involved in these projects will learn general synthetic methods as well as how to prepare chiral molecules and the measurement of enantiomeric excess. Isolation, structure elucidation, and pharmacology of neuroactive alkaloids. Dr. Fitch is interested in biologically active natural products. Especially of interest are compounds that are active at nicotinic acetylcholine receptors. These receptors are important mediators of communication within the nervous system. Compounds that act at these receptors may be important biological probes and potential drugs for the treatment of neurological diseases. Examples include the alkaloids cytisine and epiquinamide (above) as well as epibatidine, pumiliotoxins, sparteine, nicotine, and many others. HO Cl NH N CH3 N H N N N CH3 H R Epibatidine Pumiliotoxins Sparteine N Nicotine We use HPLC to analyze extracts of the materials and then collect the eluate in 96-well plates. We then analyze the biological activity of the fractions to identify promising compounds. Once active compounds are identified, we isolate the compounds to determine the structures. O HN CH3 H N Once the compounds have been isolated, we determine the biological activity using a variety of assays, including radioligand binding and functional fluorescence assays. Students working on this project will learn methods for isolation, chromatographic methods, and spectroscopic analysis, including mass spectrometry, NMR and IR spectroscopy.