The automated synthesis of oligosachharides is a topic that we’ve devoted quite a bit of time on here at F-Blog. This is largely due to the efforts of Prof. Nicola Pohl’s group who have pioneered the use of fluorous tags in an automated setting.
Unlike DNA or peptide synthesis, the efficient automated synthesis of oligosaccharides has been difficult to achieve due to the increased complexity of oligosaccharides vs oligonucleotides and peptides. There are more monomer units, stereochemistry in the coupling reaction, additional protecting groups, linear vs. branched structures, etc. All of these factors increase the degree of difficulty, so even decades after the automated synthesis of peptides and DNA has been not only commercialized but commoditized, oligosaccharides remain unsolved. The relative inaccessibility of oligosaccharides has undoubtedly held back the study of oligosaccharides in biological systems compared to DNA, RNA, and proteins.
A new review in Angewandte Chemie from Hsu et al describes the latest efforts in automated oligosaccharide synthesis. The approaches include one-pot methods, chemoenzymatic syntheses, and phase supported methods. Fluorous tags and separations, primarily in the form of fluorous solid phase extraction (FSPE), has been used in each of these synthetic strategies. In addition to the actual synthesis, this new review also has sections on glycan microarrays and vaccine development using synthetic oligosaccharides. Fluorous immobilization of course has been shown to be an effective method for the formation of glycan arrays. This current paper then provides a good review of the field and places the contribution of fluorous methods in great context.
One of the little details that I found interesting is the authors’ characterization of the fluorous separation which they described as a “specific solvophobic interactions”. This is in contrast to most reports which use terms such a “fluorous affinity” or “fluorous-fluorous interactions.” Partitioning based on solvophobic effects is exactly the way that we like to describe fluorous separations, since there is no intermolecular forces between fluorous molecules that explain the partitioning observed. As Prof. Craig Wilcox once rhetorically asked me, “Which compound has a lower boiling point, perfluorohexane or hexane?” The answer is perfluorohexane which clearly indicates a lack of any intermolecular interactions or affinity which would explain the high partitioning observed. So solvophobicity is a great term to describe fluorous partitioning, because it’s the incompatibility of fluorous domains with aqueous or organic phases that drives the the molecules into the fluorous phase rather than any attraction. Push vs. pull, if you will. The addition of the word specific is great. It emphasizes that it’s not simply hydrophobic or lipophobic, but rather that the solvophobicity is beyond the usual phobicities that we’re accustomed to seeing.