Research Interests of Michael B. Smith - University of Connecticut
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Description of Current Research Topics
Our current research involves five general areas
- Total synthesis of pancratistatin and related phenanthridone alkaloids
- Asymmetric synthesis of fused-ring alkaloids using a chiral lactam-ring-closing
metathesis strategy
- Asymmetric synthesis of sphingosine derivatives from a chiral lactam template
- Synthesis and identification of bacterial sphingolipids from dental disease. These
compounds are also found in plaques from atherosclerosis patients.
- Using conducting polymers as synthetic reagents, specifically for the environmentally
friendly oxidation of alcohols to aldehydes and ketones.
Pancratistatin (1) is a phenanthridone alkaloid with potent anticancer activity.
Our synthetic strategy uses an intermolecular Diels-Alder reaction such as the conversion
of 2 to 3 to set the requisite rings and stereochemistry.
Ring-closing metathesis using metal carbenes such as the Grubbs catalyst (4) is
a powerful new method for the synthesis of natural products. We previously prepared chiral
lactam 5 from glutamic acid, and used it as a template for the synthesis of fused
ring alkaloids. Combining the use of 4 and ring-closing metathesis gives us a
general method for the asymmetric synthesis of several biologically important alkaloids,
including castanospermine, mesembrine, gephyrotoxin, and stellettamide A.
We are working in collaboration with Professor Frank Nichols of the UCONN School of
Periodontology to identify bioactive lipids isolated from Porphyromonas gingivalis.
These lipids are tentatively identified as ceramides with unusual carbon chains relative to
mammalian ceramides. They induce a powerful inflammatory response in dental disease and the
same compounds have been identified in plaques from atherosclerosis patients. We are
synthesizing these ceramides in order to confirm their chemical structures and then provide
authentic samples to Prof. Nichols for further biological investigation.
By manipulating ethyl pyroglutamate (6), we can prepare 7, and oxidative cleavage
of the double bond to give 8, allows conversion to 9. This constitutes a general
asymmetric synthesis of several different ceramide derivatives, including those of bacterial
origin.
We have shown that the known conducting polymer 10 will oxidize alcohols such as benzyl
alcohol to the corresponding aldehyde (in this case benzaldehyde). The polymer can be recycled
to its oxidizing form by treatment with ferric chloride, making it reusable. Since we can
recycle the oxidizing agent and it does not contain toxic metals, this has the potential to be
an environmentally friendly oxidizing agent.
We are exploring the use of 10 and other conducting polymers as synthetic reagents in
collaboration with Professor Greg Sotzing of the UCONN Chemistry Department. This research will
also provide a tool to study the surface characteristics and reactivity of the polymers, with
the goal of designing polymers that will have reaction characteristics of our choice.
Previous Developments in our Research
- In general, we have developed
methods that use ethyl pyroglutamate (5-oxoproline ethyl ester) as
a chiral template in organic synthesis.
- We have
used pyroglutamate as a chiral template for
the synthesis of pyrrolizidine alkaloids.
- Pancratistatin is one member of the class
of dioxolophenanthridone
alkaloids. It has important anti-cancer activity, and many of this
class of alkaloids have important biological activity.
It is an interesting synthtic target. We are using a Diels-Alder strategy
for the synthesis of pancratistatin, using
a phenacyl-oxazolone intermediate. We have prepared both
the dienylbenzoic acid and oxazolone fragments. Problems
with forming the diene
unit were corrected using a lithium-halide exchange strategy. The two fragments were
coupled to give the requisite synthon. Heating gave the
Diels-Alder adduct, in moderate yield, but with the incorrect stereochemistry for the ring juncture. We are
examining the possiblity that the stereochemistry can be controlled by coordination of the
acyloxazolone unit with a Lewis acid.
- We have developed
a new NMR reagent for determining enantiomeric
composition of alcohols
and amines. There is no
kinetic resolution when 1-chloromethyl-5R-methyl-2-pyrrolidinone reacts
with alcohols or amines.
- In collaboration with Professor Shamil Latypov
from Kazan, Tartartan, Russian Federation,
a model has been developed
based on two major conformations of the alcohol adducts (G+ and G-).
The G- conformation is preferred and for substituents R1 and R2, when R2 is larger
(and has a higher priority by the Cahn-Ingold-Prelog selection rules) the "R"
alcohol adduct shows the "outer" AB quartet signals, with the "S" alcohol adduct
showing the "inner" AB quartet signals . This appears to be a general model.
- Castanospermine is a bicyclic alkaloid with important anti-viral
properties. We are attempting an asymmetric synthesis using 5S-vinyl-2-pyrrolidinone
as a chiral template. We will use
a silyl-cuprate strategy to set the hydroxyl unit at
C4 of the lactam unit [C1 of castanospermine].
- We have developed a practical
method for the N-alkylation of ethyl pyroglutamate
with functionalized alkyl halides.
- We have shown that organolithium
reagents react with ethyl pyroglutamate to give synthetically
useful ketones.
Additional information about my research and that of my colleagues
can be found at the homepage of
the Department of Chemistry
and information about the University of Connecticut can be found at the
homepage for the University of Connecticut.
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