Download Research projects for Dr

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.