New Fluorous Protecting Group for Carbohydrate Synthesis

Protecting group chemistry is of vital importance in synthetic chemistry to ensure that reactions occur where and when you want during a synthesis.  The more functionality a target molecules has, the more protecting groups are needed.  The more protecting groups used, the more selective the conditions for removing them need to be to remove only the protecting groups you want removed.  The need and importance for different protecting groups is perhaps best illustrated by the standard reference in the field, Green’s Protective Groups in Organic Groups, the fourth edition of which is now over 1100 pages.

Researchers at Leiden University have now introduced a new fluorous protecting group for carbohydrate chemistry based on some earlier work they had conducted for peptide chemistry.  Back in 2003 they introduced the FMsc tag as a base labile N-terminal fluorous tag for solid supported peptide synthesis.  The FMsc tag was designed to be analogous to FMoc in its reactivity, while providing the benefit of being fluorous so that FSPE could be used to easily isolate the desired compound.  In this latest report, the researchers report the use of FMsc as a hydroxyl protecting group and the development of FPsc as a new fluorous protecting group.  As seen below, both are sulfonylethoxycarbonate based tags with the only difference being a ethyl spacer vs. a propyl spacer.

Their decision to use these sulfonyl tags was inspired by the increased use of FMoc tags as base labile protecting groups in carbohydrate chemistry.  They reasoned that the use of a similarly base labile group would result in a protecting group which was less sterically demanding.  They first described the use of Msc in carbohydrate chemistry in the presence of other commonly used protecting groups and found that it worked well.  They then attempted to use the FMsc in a similar fashion.

Unfortunately, they found that the FMsc was more labile than the Msc group. Too labile, in fact.  Presumably the electron withdrawing effect of the fluorous chain made the protons alpha to the sulfonyl too prone to beta elimination.  They therefore added another methylene group to form the PFsc and to further insulate the reactive portion of the molecule from the inductive effects of the fluorous group.  Now the desired reactivity was observed.  This is a commonly seen in fluorous chemistry.  Most times an ethylene unit is enough, but sometimes one needs to go to a propylene unit to make sure that the inductive effect is minimized enough.

Last week, we extensively described fluorous carbohydrate chemistry, so we won’t go into detail here, but the utility of the PFsc group was demonstrated by synthesizing a trisaccharide using fluorous solid phase extraction (FSPE) to purify intermediates and the final product.

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