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Research Synopsis:
The
major emphasis of our research is on chemistry and biology of
carbohydrates. While the biological and medicinal importance of complex
carbohydrates and glyco-conjugates have been widely recognized, many of the
molecular details of how these compounds mediate their functions remain to
be elucidated. This has rendered high demands for structurally well defined
pure carbohydrates and glyco-conjugates. Our research program is currently
focused on the development of novel methods for syntheses of biologically
active oligosaccharides.
1) One-pot
oligosaccharide synthesis: reactivity tuning by post-synthetic modification
of aglycon
One pot glycosylations refer to
glycosylation methodologies, where multiple sequential glycosylation
reactions are carried out in a single reaction flask to yield desired
oligosaccharides without time-consuming intermediate purifications.
Currently, the majority of one-pot oligosaccharide synthesis methods
rely on differential anomeric reactivities of glycosyl donors. The
success of a one-pot synthesis is critically dependent on the judicious
choices of building blocks with appropriate reactivities. Tuning of
anomeric reactivity has been primarily achieved by protective groups on
glycon so far. We have demonstrated that one-pot synthesis can be
accomplished through aglycon reactivity tuning, which significantly
broadens the reactivity window allowing one-pot synthesis of longer
oligosaccharides. Moreover, we have designed our synthetic routes so
that building blocks with multiple levels of reactivity can be divergently
derived from a common intermediate, thus greatly reducing the amount of
time necessary for building block preparation.
2) Iterative one-pot synthesis: a
reactivity independent one-pot method
In order to further streamline
oligosaccharide synthesis, we have explored the possibility of performing
one-pot synthesis without resorting to reactivity tuning. This can be
realized by pre-activating the glycosyl donor in the ABSENCE of the
acceptor to generate a reactive intermediate. Addition of an acceptor to
the reactive intermediate will yield an oligosaccharide. This process can
be repeated enabling rapid assembly of oligosaccharides without anomeric
reactivity adjustment.
The iterative
one-pot approach provides a new, powerful strategy for oligosaccharide
synthesis because it 1) does not depend on the careful selection and
placement of protective groups on the carbohydrate coupling partners to
influence anomeric reactivities; 2) does not require any purification,
protective group manipulation or aglycon leaving group adjustment on
intermediates, 3) does not require large excess of glycosyl donors, 4)
utilizes only a single method for all glycosidic bond formations, and 5) allows
facile monitoring of reaction progress. The iterative one-pot strategy
can be potentially developed into a fully automated solution based
method for oligosaccharide assembly complementing current automated solid
phase methodology.
3) Fluorous chemistry in
oligosaccharide synthesis
Traditional oligosaccharide
synthesis is a time-consuming process mainly due to tedious chromatographic
purification of multiple synthetic intermediates. Resin based
solid-phase carbohydrate syntheses can help alleviate this problem but it
suffers several disadvantages such as reduced reactivity, lack of a general
method for real time monitoring of the reaction and difficulty in
purification of attached intermediates. Recently, fluorous chemistry has
become an attractive alternative to solid-phase synthesis. A highly
fluorinated compound is readily separated from nonfluorinated substances by
either binary fluorous/organic phase extraction or solid phase extraction
(SPE) through fluorous silica gel. We are interested in applying fluorous
chemistry to oligosaccharide synthesis. Recently, we have synthesized a new,
almost odorless fluorous thiol, which is utilized to prepare highly
fluorinated thioglycosyl donors. These thioglycosides showed excellent
reactivities in glycosylation reactions. The fluorous chain, stable under
esterification, etherification, deacetylation, and glycosylation
conditions, allowed facile purification of the thioglycosides by
solid-phase extraction through fluorous silica gel. The fluorous thiol was
readily recycled.
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