Research
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.
|
