Design and synthesis of orthogonally protected monosaccharide
building
blocks are crucial for the preparation of well-defined oligosaccharides
in a stereo- and regiocontrolled manner. Selective introduction of
protecting groups to partially protected monosaccharides is nontrivial
due to the often unpredictable electronic, steric, and conformational
effects of the substituents. Abolished reactivity toward a commonly
used Lewis base-catalyzed acylation ofO-2 was observed
in conformationally restricted 4,6-O-benzylidene-3-O-Nap galactoside. Investigation of analogous systems, crystallographic
characterization, and quantum chemical calculations highlighted the
overlooked conformational and steric considerations, the combination
of which produces a unique passivity of the 2-OHnucleophile.
Evaluating the role of electrophile counterion and auxiliary base
in the acylation of the sterically crowded and conformationally restricted
galactoside system revealed an alternative Brønsted base-driven
reaction pathway via nucleophilic activation. Insights gained from
this model system were utilized to access the target galactoside intermediate
within the envisioned synthetic route. The acylation strategy described
herein can be implemented in future syntheses of key monomeric building
blocks with unique protecting group hierarchies.