Regioselective Benzoylation of 4,6-O-Benzylidene Acetals of Glycopyranosides in the Presence of Transition Metals

GRAPHICAL ABSTRACT Benzoylation of 4,6-O-benzylidene acetals of glycopyranosides by benzoic anhydride in acetonitrile in the presence of Cu(CF3COO)2 as a promoter gave 2-benzoates for α-D-glucopyranosides and α-D-mannopyranosides and 3-benzoates for β-D-galactopyranosides in good yields with high regioselectivity. Benzoylation of 4,6-O-benzylidene acetals of glycopyranosides of D-galactose and D-mannose by benzoyl chloride in the presence of MoO2(acac)2 as a catalyst in all studied cases led to regioselective 3-О-substitution.


RESULTS AND DISCUSSION
Earlier we found that regioselective acylation of glycopyranosides could be obtained by use of the salts of transition metals. In this case, molybdenum (V, VI) compounds [34,35] oriented substitution on 3-ОН in 2,3-and 3,4-cis-vicinal diols, but regioselectivity of acylation in the presence of copper (II) salts depended both on the configurations of the hydroxyl groups and on the configuration of the aglycone probably due to formation of intermediate complex glycosides with copper (II) ions. [36] In general, the causes that determine the differences in reactivity of the hydroxyl groups of carbohydrates in the acylation reactions are varied and may be because of steric and stereoelectronic effects, [37] as well as intramolecular hydrogen bonds. [38][39][40][41][42] In addition, regioselectivity may also be obtained by rearrangement of initially formed products to the most stable products. [43] The complexation of carbohydrates can change the ratio of these factors and, as a consequence, the reactivity of the hydroxyl groups.
In the present work we wanted to study the influence of Cu(CF 3 COO) 2 and MoO 2 (acac) 2 on regioselective benzoylation of 4,6-O-benzylidene acetals of glycopyranosides. The results of benzoylation of 4,6-O-benzylidene acetals of glycopyranosides in the presence of Cu(CF 3 COO) 2 are presented in Table 1.
Next, we explored the benzoylation of 4,6-O-benzylidene acetals of glycopyranosides in the presence of MoO 2 (acac) 2 . The results are presented in Table 2.
As can be seen from this table, using acetonitrile as solvent (entry 1 vs. 2 and 3) was preferable in the reaction. Table 2 also shows that 4,6-O-benzylidene derivatives of αand β-D-galactopyranoside and α-Dmannopyranoside demonstrated preferable reactivity for 3-ОН in comparison with 2-ОН in the benzoylation by benzoyl chloride even without a catalyst, but the reactions gave only moderate yields of 3-benzoate in the reaction mixture (entries 4, 6, 8, 10, and 12). The use of MoO 2 (acac) 2 as the catalyst in these cases greatly increased the yields of 3-O-benzoates in the reaction mixture along with increased regioselectivity. Similar results were obtained earlier [35] on the benzoylation of pyranosides by benzoyl chloride in the presence MoO 2 (acac) 2 . This was probably determined by the increase of the nucleophilicity of 3-OH after complexation with Mo(VI). Table 2 also shows that the benzoylation of methyl 4,6-O-benzylidene-α-D-glucopyranoside 1 both with and without a catalyst (entries 13 and 14, respectively) gave the same result with preferable formation of 2-O-benzoate. It indicates the absence of an intermediate complex of this acetal with molybdenum (VI).
In conclusion, we have found that using transition metal salts, Cu(CF 3 COO) 2 and MoO 2 (acac) 2 in particular, allowed the manipulation of reactivities of hydroxyl groups in 4,6-O-benzylidene acetals of glycopyranosides in their benzoylation with benzyoyl anhydride or chloride. This has provided an efficient method for monobenzoylation of these compounds in one step in good to excellent yields and high regioselectivity.

EXPERIMENTAL General Methods
Melting points were determined on a Boethius micro hot-stage apparatus and were uncorrected. Optical rotations were measured with a Perkin-Elmer model 141. Spectra 1 H and 13 C NMR were registered on a Bruker DPX-300 ( 1 H at 300 MHz and 13 C at 75 MHz). Chemical shifts (δ) are reported in ppm related to Me 4 Si. Positive mode HR LSI mass spectra were obtained on an Agilent Technology 6510 Q TOF LC/MS mass spectrometer (USA). The samples were dissolved in methanol (c 0.01 mg/mL). TLC was performed on silica gel L (5-40 μm; Chemapol) with hexane-acetone 7:3 as eluent. For detection, 10% sulfuric acid in ethanol at 130ºC was used. Column chromatography was performed on silica gel (100-160 μm; Chemapol).

as Promoter
A solution of acetal (0.25 mmol), benzoic anhydride (0.32 mmol), Cu(CF 3 COO) 2 (0.32 mmol), and 2,4,6-collidine (0.32 mmol) in acetonitrile (2 mL) was stirred at rt for 6 h. The reaction was monitored by TLC. Chloroform (20 mL) was added to the reaction mixture. The organic layer was washed with 2 N HCl, aq. NaHCO 3 , and water and was then concentrated to a small volume under reduced pressure at rt. The products were finally purified by flash chromatography on a column of silica gel using gradient acetone in hexane as eluents.