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In general, we have developed
methods that use ethyl pyroglutamate (5-oxoproline ethyl ester) as
a chiral template in organic synthesis.
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.
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.
We have
used pyroglutamate as a chiral template for
the synthesis of pyrrolizidine alkaloids.
Using
an acyloin condensation and
a silyl-cuprate strategy, we are developling an
asymmetric synthesis of castanospermine, using pyroglutamate as a chiral
template.
We are developing a Diels-Alder
stategy for the synthesis of pancratistatin, using
a phenacyl-oxazolone intermediate.
Our current research involves five general areas: (1) Development of new asymmetric synthetic methods. (2) Asymmetric synthesis of biologically important alkaloids. (3) Development of new reagents for determining enantiomeric composition of drugs. (4) Development of new AIDS drugs based on lactams. (5) Development of biologically important, lactam-based polymers.
The fundamental goal of our research is the development of new
synthetic
methodology. We are working
extensively in the areas of asymmetric Diels-Alder reactions and asymmetric
radical cyclizations. We developed a
facile route to N-dienyl lactams from glutamic acid and showed they undergo
Diels-Alder reactions with high
diastereoselectivity. We showed that allylic lactams derived from glutamic acid
can be cyclized with AIBN and
Bu3SnH to give pyrrolizidinones in high yield, with high diastereo- and
enantioselectivity. We then converted
pyroglutamate to a C5-alkenyl derivative, and functionalized nitrogen to allow
radical cyclization to another set of
pyrrolizidinone derivatives. These were converted to naturally occurring
pyrrolizidine alkaloids.
.
Most of this research involves refunctionalization of lactams, particularly ethyl pyroglutamate (1), easily prepared from L-glutamic acid. Using (1) as a chiral template and using synthetic methods developed in this lab, my group is pursuing the asymmetric synthesis of the anti-AIDS drug castanospermine (2) and the anti-cancer drug gephyrotoxin (3). Using a different lactam precursor, we are also working on an asymmetric synthesis of the anti-cancer drug pancratistatin, (4). The synthesis of these molecules has demanded development of several new synthetic methods, based on manipulation of pyroglutamate (1). The syntheses use a wide range of organic reactions, including the Diels-Alder reaction, radical cyclization, acyloin condensation, enolate condensations, Dieckmann cyclization, olefination reactions and organosilane-carbanion cyclizations. In addition, many functional group exchange reactions are employed, including oxidations, reductions, alkylations, halogenations, hydroxylations, epoxidations, etc. In other words, this is a typical synthetic organic laboratory.
The asymmetric synthesis of pancratistatin (4) uses a chiral
dihydrooxazoline and we are also using oxazolone
derivatives. Some our work is therefore characterized by the synthetic
manipulation of heterocycles. In this
particular case, the heterocycle "drives" the synthesis by setting the correct
stereochemistry in the Diels-Alder
cyclization used to make the 6-6-6 tricyclic ring system characteristic of (4).
The synthesis of castanospermine (2)
requires functionalization of the nitrogen of (1), using methods developed in
our labs. This leads to
lactam-diesters and lactam-aldehyde/esters that can be cyclized to the
indolizidine skeleton (the 5-6 fused ring
alkaloid skeleton seen in 2). The synthesis of gephyrotoxin (3) also uses (1)
but attaches a diene group to
nitrogen and refunctionalizes the ester group to an alkenyl group.
Intramolecular Diels-Alder cyclization leads to a
chiral nonracemic derivative that can be converted to (3).
.
Our work with pyroglutamate and its refunctionalization led to the synthesis of S-N-chloromethyl-5-methyl-2-pyrrolidinone (5), which can be coupled with chiral alcohols to give (6) and with chiral amines to give (7). Examining the proton NMR of (6) and (7) allows the determination of the percent-dr (diastereomeric ratio) of the alcohol or amine. The diastereotopic hydrogens (N-CH2-O or N-CH2-N) are the signals of interest. This analysis allows one to estimate the enantiomeric excess (ee) of the original alcohol or amine. In all cases examined to date, the diastereomer derived from the R-alcohol or amine is predictably distinguishable from the diastereomer derived from the S-alcohol or amine. Analysis by NMR therefore allows not only determination of the enantiomeric composition, but also which enantiomer is in excess. The limits of detectability by proton NMR are about 50 to 1, or the ability to see only 2% of the minor enantiomer. Since (5) does not have a strong chromophore, it shows a weak signal when UV detectors are used with HPLC. If the alcohol or amine bears a UV active group, however, very low levels of the minor enantiomer can be detected. We are currently working on methods to functionalize (5), allowing greater sensitivity in the analysis for all amines and alcohols so this technique can be used routinely with the UV detectors common to HPLC and GC. This will lead to a new analytical technique for identifying enantiomers and determining enantiomeric composition of anti-cancer drugs, anti-AIDS drugs, amino acids, and a variety of other pharmaceuticals.
We have recently begun a collaboration with the Institute of Macromolecular Chemistry in Prague, Czech Republic. We are synthesizing several functionalized lactams, many of which are key intermediates in the syntheses described above. The "monomers" will be converted to lactam homopolymers and also co-polymerized with acrylamides. The resulting polymers will be fully characterized, chemically and biologically. Since polymers of this general type have been important constituents of products ranging from contact lenses to pharmaceuticals, developing polymers with improved chemical, biological, and mechanical properties is the goal of this research. Polymers of this type have also been used in general drug-delivery systems and for "organ-directed" delivery of anti-cancer drugs. The properties of these new polymers will be examined with an eye to these future applications.
Although this research program encompass many different areas, in fact,
all the work is unified by the
relationship to lactams, particular chiral, nonracemic lactams. These
interesting molecules are a vehicle to many
different areas of chemistry: methods development, total synthesis, mechanistic
studies, polymers, rate studies.
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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