Reverse Orthogonal Oligosaccharide Synthesis

A just published Advance Article in Chemical Communications from Prof. Alexei Demchenko at the Univ of Missouri-St. Louis describes a strategy for oligosaccharide construction using what they term a reverse orthogonal strategy.  As we have noted here in F-Blog, and as most chemists know, the synthesis of oligosaccharides is not trivial.  The number of different monomer units, protections and deprotections, and stereocenters makes oligosaccharides much more difficult than peptides or oligonuceotides.

Various strategies have evolved including linear methods, one-pot strategies, and orthogonal activation strategies.  The linear methods are generally high yielding, but suffer from the number of steps required.  The one-pot strategies are nice due to the speed and ease of synthesis but requires access to a large number of glycosyl donors and acceptors and knowledge of the relative reactivities of them all.  The orthogonal activation approach also shortens the synthesis relative to the linear approach, but suffers from decreasing yields in the glycosylation as the oligosaccharide gets larger.  Demchenko proposes a different approach, the reverse orthogonal approach.  Scheme 1 from the paper is reproduced below which shows the linear strategy, the orthogonal approach, and their reverse orthogonal approach.

The reverse orthogonal approach basically uses orthogonal protecting groups on the glycosyl acceptor rather than orthogonal activating groups on the glycosyl donor.  The deprotection of the proper hydroxyl group is conducted in situ followed by addition of the glycosyl donor which has an orthogonal protecting group.  Selective deprotection of the second protecting group and addition of the next glycosyl donor elongates the oligosaccharide.  By alternating the two orthogonal protecting groups on each glycosyl donor they could construct oligosaccharides using only slight excesses (1.0-1.2 equiv) of glycosyl donor while maintaining yields in the 70-80% range for each glysosylation.  I won’t go into the details of the chemistry, but will leave that up to the interested reader to investigate.

So this is F-Blog, where does fluorous fit in?  The author’s concluding statement is “It is expected that the reverse orthogonal strategy will be also beneficial for oligosaccharide assembly using polymer, fluorous, ionic liquid, and nanoporous gold supports.”  The acknowledgement of fluorous supported oligosaccharide synthesis is great.  It’s good to see that people are recognizing the role of fluorous methods in this challenging field.  The author’s are correct, that fluorous tags could be implemented in this type of strategy.  In reading the experimentals within the Supplementary Information, the researchers used column chromatography after each glycosylation.  Replace that with a fluorous solid phase extraction (FSPE) or even a fluorous liquid-liquid extraction (FLLE) and the entire process gets streamlined even more.

Of course, one could say the same thing about the other supports as well, right?  Not exactly.  The polymer supported versions generally require large excesses (3-5 equiv) of the non-supported reagent.  Often times the monomers in oligosaccharide synthesis aren’t trivial to make either, so large excesses are a real drawback which is in direct contrast to peptide chemistry.  In addition, the experimental in this paper requires monitoring of the in situ deprotection then addition of the glycosyl donor.  Pretty tough to monitor reactions on solid phase.  No problem on fluorous phase which is complete solution phase chemistry.

Ionic liquids as tags is an interesting method and there have been some nice reports.  In general they seem to require more equivalents of donor (2-3 equiv) than fluorous methods.  The biggest problem with ionic liquids is that they are polar tags and deprotected carbohydrates are polar also, so you don’t have orthogonality in your phase separation.  This is in contrast to fluorous tags which are orthogonal to both polar and non-polar phases.

As has been demonstrated by many independent research groups, fluorous tags and oligosaccharide chemistry make a great combination, no matter what strategies are used; linear, one-pot, etc.  It’ll be interesting to see if reverse orthogonal strategies can be added to that list in the future.

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