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.