ACCEPTED MANUSCRIPT
quantity of the target oligosaccharides is limited [8]. Although iterative one-pot synthesis of
oligosaccharides based on pre-activation of glycosyl donors has already been applied for the
synthesis of lipomannans, a tetramannoside with the same repeating structure is, to date, the only
example of this method [9,10].
We have already reported automated electrochemical assembly of carbohydrate building blocks
for the synthesis of the potential precursor of TMG-chitotriomycin tetrasaccharide by rational
optimization of carbohydrate building blocks based on DFT calculation, and electrochemical
measurements of their oxidation potentials [11-13]. Although α-glycosidic linkages of mannosides
are thermodynamically favorable and can be selectively constructed by the neighboring group
participation, it is important to optimize the carbohydrate building blocks which can be converted to
the corresponding storable glycosylation intermediates with reasonable reactivity for the subsequent
glycosylation with a free OH of glycosides. Here we report optimization of carbohydrate building
blocks for electrochemical automated solution-phase synthesis of oligomannosides with α-glycosidic
linkages and its application to the synthesis of GPI anchor oligosaccharides.
Results and Discussion
We initiated our study on the evaluation of carbohydrate building blocks by preparing a variety
of building blocks equipped with a neighboring group such as pivaloyl and acetyl groups at the
hydroxyl group of C-2 (2-OH) and/or C-6 (6-OH) (Figure 1). Building blocks 1a-c with a
neighboring group at 2-OH were easily accessible from the anomeric orthoester (See Supporting
Information), whereas other building blocks 2-5 were synthesized by the conventional manipulations
of protecting groups. Oxidation potentials of thus-obtained building blocks were measured by a
standard technique of linear sweep voltammetry (LSV) using a rotation-desk electrode (RDE) (Table
1). These oxidation potentials were compared with that of 4-fluorophenyl
2,3,4,6-tetra-O-benzyl-α-D-thiomannoside 2. Derivatization with an acetyl group at 2-OH increased
the oxidation potential about 0.09 V. On the other hand, in the case of pivaloyl and phosphate,
oxidation potentials were increased about 0.08 V and 0.11 V, respectively. Introduction of a pivaloyl
group to 6-OH showed comparatively less change in oxidation potential (1.64 V), whereas pivaloyl
functionalization of 2-OH as well as 6-OH increased the oxidation potential about 0.11 V. These
results suggest that a structurally similar protecting group causes slightly different electronic
behavior which influences the electrochemical oxidation. To get the a better understanding of this
phenomenon we performed DFT calculations (B3LYP/6-31G(d)). Statistical data obtained by these
calculations showed good correlation with oxidation potentials of glucosamine derivatives, however
potential differences did not completely fit those obtained by measurements, especially in building
blocks equipped with an acetyl or pivaloyl group at 2-OH. Therefore, further investigation is
required for better prediction of oxidation potentials based on theoretical calculations.
2