Noncatalytic selective 6-O-acetylation of methyl 2,3-di-O-benzoyl-α-d-glucopyranoside with acetic acid and acetic anhydride

Article abstract of DOI:10.1007/s11172-020-3026-x

Noncatalytic acetylation of methyl 2,3-di-O-benzoyl-α-d-glucopyranoside with acetic acid or acetic anhydride proceeds regioselectively at the primary hydroxyl group and affords methyl 6-O-acetyl-2,3-di-O-benzoyl-α-d-glucopyranoside in good yield. The possibility of 6-O-acetylation should be taken into account when removing a 4,6-O-benzylidene protecting group with aqueous acetic acid at elevated temperature.

Full text of DOI:10.1007/s11172-020-3026-x

Russian Chemical Bulletin, International Edition, Vol. 69, No. 11, pp. 2228—2230, November, 2020
2228
Noncatalytic selective 6-O-acetylation
of methyl 2,3-di-O-benzoyl-α-D-glucopyranoside
with acetic acid and acetic anhydride
Y. E. Tsvetkov, M. L. Gening, and N. E. Nifantiev
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 8784. Е-mail: nen@ioc.ac.ru
Noncatalytic acetylation of methyl 2,3-di-O-benzoyl-α-D-glucopyranoside with acetic acid
or acetic anhydride proceeds regioselectively at the primary hydroxyl group and affords methyl
6-O-acetyl-2,3-di-O-benzoyl-α-D-glucopyranoside in good yield. The possibility of 6-O-acetyl-
ation should be taken into account when removing a 4,6-O-benzylidene protecting group with
aqueous acetic acid at elevated temperature.
Key words: acetic acid, acetic anhydride, methyl 2,3-di-O-benzoyl-α-D-glucopyranoside,
selective 6-O-acetylation.
The benzylidene group is widely used in synthetic
is capable of acetylating the primary hydroxy group in
4,6-diol 2.
organic chemistry for protection of 1,2- and 1,3-diols,
including protection of hydroxy groups at the C(4) and
C (6) atoms in hexopyranosides.1 The 4,6-O-benzylidene
group is usually removed by acid hydrolysis using dilute
strong acids (sulfuric, hydrochloric, p-toluenesulfonic
acid, etc.)1,2 or aqueous acetic acid upon heating.1,3—5
The advantage of the latter reagent is the simplicity of the
reaction mixture work-up, which consists in evaporation.
We also used the hydrolysis of benzylidene derivative 1
(see Ref. 6) with 80% aqueous AcOH to obtain 4,6-diol 2
(Scheme 1).
Considering this result, we studied the possibility of
noncatalytic selective 6-О-acetylation of diol 2 with acetic
acid, since our further goal was to obtain 6-acetate 3. This
compound is supposed to be used for the introduction of
an azide group at the C(4) atom with the formation of
4-azido-4-deoxygalactose derivative,7 a precursor for the
synthesis of containing 4-amino-4-deoxygalactose moiety
analogs of cyclic oligosaccharides obtained earlier,8 as well
as oligomeric blockers of bacterial adhesins,9 ion chan-
nels,10,11 and other molecular systems.12 In addition,
glucose derivatives selectively acetylated at the O(6) atom,
similar to compound 3, are convenient blocks for the
assembly of β-(1→6)-linear13 and β-(1→3),(1→6)-
branched14,15 oligoglucosides corresponding to the frag-
ments of β-glucans of the cell wall of fungi16,17 of the
genera Candida, Aspergillus, and others.
Scheme 1
Preliminary experiments showed that aqueous AcOH
(70—90%) at 80 °C in fact selectively acetylates diol 2 with
the formation of compound 3 as the main product. TLC
of the reaction mixture showed also the presence of minor
amounts of 4,6-diacetate 4 and 4-acetate 5 (Scheme 2).
The conversion degree of the starting diol 2 and the reac-
tion selectivity were practically independent of the con-
centration of AcOH used.
However, the low reaction rate (the degree of conver-
sion of 2 after 90 h was 75—80%) did not allow us to
consider the reaction with aqueous AcOH as a preparative
method for selective 6-O-acetylation. Therefore, further
we studied acetylation of 2 with anhydrous AcOH. The
reaction of 2 with glacial AcOH at 100 °C for 36 h gave
Reagents and conditions: 80% aq. АсОН, 50 °C, 48 h.
The reaction gave diol 2 in 80% yield, as well as
a product with higher chromatographic mobility, which,
according to the NMR spectra, was 6-acetate 3 (10%
yield). Therefore, aqueous AcOH at elevated temperatures
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2228—2230, November, 2020.
1066-5285/20/6911-2228 © 2020 Springer Science+Business Media LLC

Noncatalytic selective 6-O-acetylation
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 11, November, 2020
2229
Scheme 2
Reagents and conditions: АсОН, 100 °C, 36 h or Ас2О, 60 °C, 15 h or Ас2О, pyridine, CH2Cl2, 0 → 20 °C.
light or by spraying with a solution of orcinol (orcinol (180 mg)
in a mixture of water (85 mL), 85% phosphoric acid (10 mL), and
95% ethanol (5 mL)), followed by heating at ~150 °C. Column
chromatography was performed on Silica gel 60 (40—63 μm,
Merck). Optical rotation was measured on a JASCO P-2000
digital polarimeter (Japan) at 20—25 °C. NMR spectra were
recorded at 25 °C on a Bruker Avance 600 spectrometer in
deuterochloroform (CDCl3). Residual non-deuterated CHCl3
(δH 7.27) was used as an internal standard for 1Н NMR spectra,
the signal of CDCl3 (δC 77.0) was used as a reference for
13C NMR spectra. The signal assignment was carried out using
2D COSY and HSQC correlation NMR spectroscopy. The
electrospray ionization (ESI) high resolution mass spectrum was
recorded on a Bruker micrOTOF II instrument. Acetic acid of
reagent grade distilled over potassium permanganate was used
for acetylation.
Synthesis of compounds 2 and 3. A suspension of benzylidene
derivative 1 (3.90 g, 7.95 mmol) in 80% aq. АсОН (20 mL) was
stirred at 50 °C for 48 h (after ~30 h the reaction mixture became
homogeneous), AcOH was evaporated and coevaporated with
toluene (3×30 mL). The residue was chromatographed (tolu-
ene—EtOAc (4 : 1), then toluene—acetone (4 : 1→3 : 1)) to
obtain diol 2 (2.56 g, 80%) and 6-acetate 3 (0.37 g, 10%).
Methyl 2,3-di-О-benzoyl-α-D-glucopyranoside (2). A color-
less foam, Rf = 0.17 (toluene—EtOAc, 3 : 2), [α]D +146 (c 1,
EtOH) (Ref. 4: +155 (с 1, EtOH)). 1H NMR (600 МHz, CDCl3),
δ: 7.99—7.32 (m, 10 H, Ar); 5.77 (t, 1 H, Н(3), J = 9.7 Hz); 5.22
(dd, 1 Н, Н(2), J2,1 = 3.6 Hz, J2,3 = 10.1 Hz); 5.13 (d, 1 Н, Н(1),
J1,2 = 3.6 Hz); 4.00—3.91 (m, 3 Н, Н(4), 2 Н(6)); 3.89—3.84
(m, 1 Н, Н(5)); 3.43 (s, 3 Н, СН3О). 13С NMR (150 МHz,
CDCl3), δ: 167.3, 166.0 (PhCO), 133.4, 129.9, 129.8, 128.4 (Ar),
97.1 (C(1)), 74.1 (C(3)), 71.6 (C(2)), 71.3 (C(5)), 69.8 (C(4)),
62.0 (C(6)), 55.4 (CH3O).
good yield of 6-acetate 3 (72%), as well as compounds 4
and 5 in 15 and 6% yields, respectively. Thus, the reaction
with anhydrous AcOH showed a sufficiently high regio-
selectivity, which makes it suitable for 6-O-acetylation of
4,6-diols of the compound 2 type.
Acetic anhydride in the presence of basic or acidic
catalysts18,19, both homogeneous and heterogeneous, is
one of the most commonly used reagents in the acetylation
reaction. We studied the acetylation of diol 2 with acetic
anhydride in the absence of catalysts. The reaction of 2
with Ac2O at 60 °C for 15 h gave 6-acetate 3 and diacetate
4 in 83 and 15% yields, respectively. Carrying out this
reaction at 50 °C for 22 h leads to a slight decrease in the
yield of diacetate 4 (12%), while the yield of 3 remains
unchanged (83%). TLC showed that 4-acetate 5 is formed
in trace amounts in both cases.
For comparison, we carried out acetylation of 2 with
1.3 equiv of Ac2O in the presence of 2 equiv. of pyridine at
0 → 20 °C. This reaction turned out to be less regioselective
than the described above noncatalytic acetylation with AcOH
or Ac2O. As a result, 6-acetate 3, 4,6-diacetate 4, and 4-acet-
ate 5 were isolated in 64, 21, and 9% yields, respectively.
To sum up, acetic acid and acetic anhydride in the
absence of catalysts selectively acetylate the primary hy-
droxy group in methyl 2,3-di-O-benzoyl-α-D-gluco-
pyranoside, giving the corresponding 6-acetate in good
yield. The possibility of acetylation of C(6) hydroxy
group should be taken into account when removing the
4,6-O-benzylidene group with aqueous acetic acid at
elevated temperatures.
Methyl 6-О-acetyl-2,3-di-О-benzoyl-α-D-glucopyranoside
(3). A colorless syrup, Rf = 0.62 (toluene—EtOAc, 3 : 2),
[α]D +134 (с 1, CHCl3) (Ref. 25: [α]D +150.8 (с 1.2, CHCl3)).
1H NMR (600 МHz, CDCl3), δ: 8.01—7.34 (m, 10 Н, Ar); 5.76
(t, 1 Н, Н(3), J = 9.7 Hz); 5.27 (dd, 1 Н, Н(2), J2,1 = 3.6 Hz,
J2,3 = 10.1 Hz); 5.13 (d, 1 Н, Н(1), J1,2 = 3.6 Hz); 4.54 (dd, 1 Н,
Н(6а), J6a,5 = 4.6 Hz, J6a,6b = 12.3 Hz); 4.40 (dd, 1 Н, Н(6b),
J6b,5 = 2.4 Hz, J6b,6a = 12.3 Hz); 4.02—3.97 (m, 1 Н, Н(5));
3.82 (t, 1 H, Н(4), J = 9.5 Hz); 3.44 (s, 3 Н, СН3О); 2.16 (s, 3 Н,
СН3СО). 13С NMR (150 МHz, CDCl3), δ: 171.4 (CH3CO),
167.3, 165.9 (PhCO), 133.4, 133.3, 129.8, 128.4 (Ar), 97.1 (C(1)),
73.8 (C(3)), 71.2 (C(2)), 69.7 (C(5)), 69.5 (C(4)), 62.9 (C(6)), 55.4
(CH3O), 20.8 (CH3CO). The NMR spectroscopy data for com-
pound 3 are in good agreement with the data reported in the work.25
Synthesis of compounds 3, 4, and 5. Method А. A solution of
diol 2 (134 mg, 0.33 mmol) in glacial АсОН (2.5 mL) was
heated at 100 °C for 36 h, АсОН was evaporated and coevapo-
The efficiency of acetic acid and, in particular, acetic
anhydride as reagents for selective 6-O-acetylation is
superior to that of many reagents described in the litera-
ture, such as, for example, 1-acetoxybenzotriazole,20,21
1-acetylimidazole,22 and acetyl chloride in the presence
of pyridine23 or 2,4,6-collidine.24 Only in a few cases
(acetyl chloride in the presence of basic alumina18 and
acetic anhydride in the presence of 4 Å molecular sieves19
)
higher yields (~90%) of the products of selective 6-O-acetyl-
ation were achieved for substrates of similar structure.
Experimental
Thin layer chromatography was performed on Kieselgel 60
F254 silica gel plates (Merck), compounds were detected in UV

Tsvetkov et al.
2230
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 11, November, 2020
rated with toluene (3×5 mL). The residue was chromatographed
(toluene—EtOAc, 85 : 15 → 80 : 20 → 70 : 30) to obtain 6-acet-
ate 3 (106 mg, 72%) identical to that described above, diacetate
4 (25 mg, 15%), and 4-acetate 5 (9 mg, 6%).
5. P.-E. Jansson, J. Lindberg, G. Widmalm, Acta Chem. Scand.,
1993, 47, 711.
6. R. W. Jeanloz, D. A. Jeanloz, J. Am. Chem. Soc., 1957,
79, 2579.
7. S. Wu, L. Yang, W. Sun, L. Si, S. Xiao, Q. Wang, L. Dechoux,
S. Thorimbert, M. Sollogoub, D. Zhou, Y. Zhang, Eur. J.
Med. Chem., 2017, 130, 308.
8. M. L. Gening, D. V. Titov, A. A. Grachev, A. G. Gerbst,
O. N. Yudina, A. S. Shashkov, A. O. Chizhov, Y. E. Tsvetkov,
N. E. Nifantiev, Eur. J. Org. Chem., 2010, 2465.
9. M. L. Gening, D. V. Titov, S. Cecioni, A. Audfray, A. G.
Gerbst, Y. E. Tsvetkov, V. B. Krylov, A. Imberty, N. E. Nifan-
tiev, S. Vidal, Chem. Eur. J., 2013, 19, 9272.
10. T. Saha, A. Roy, M. L. Gening, D. V. Titov, A. G. Gerbst,
Y. E. Tsvetkov, N. E. Nifantiev, P. Talukdar, Chem. Commun.,
2014, 50, 5514.
11. A. Roy, T. Saha, M. L. Gening, D. V. Titov, A. G. Gerbst,
Y. E. Tsvetkov, N. E. Nifantiev, P. Talukdar, Chem. Eur. J.,
2015, 21, 17445.
12. V. P. Ananikov, D. B. Eremin, S. A. Yakukhnov, A. D. Dilman,
V. V. Levin, M. P. Egorov, S. S. Karlov, L. M. Kustov, A. L.
Tarasov, A. A. Greish, A. A. Shesterkina, A. M. Sakharov,
Z. N. Nysenko, A. B. Sheremetev, A. Yu. Stakheev, I. S.
Mashkovsky, A. Yu. Sukhorukov, S. L. Ioffe, A. O. Terent´ev,
V. A. Vil´, Y. V. Tomilov, R. A. Novikov, S. G. Zlotin, A. S.
Kucherenko, N. E. Ustyuzhanina, V. B. Krylov, Y. E. Tsvet-
kov, M. L. Gening, N. E. Nifantiev, Mendeleev Commun.,
2017, 27, 425.
13. D. V. Yashunsky, A. A. Karelin, Y. E. Tsvetkov, N. E. Nifan-
tiev, Carbohydr. Res., 2018, 455, 18.
14. D. V. Yashunsky, Y. E. Tsvetkov, N. E. Nifantiev, Russ. Chem.
Bull., 2015, 64, 2922.
15. D. V. Yashunsky, Y. E. Tsvetkov, N. E. Nifantiev, Carbohydr.
Res., 2016, 436, 25.
16. Yu. E. Tsvetkov, E. A. Khatuntseva, D. V. Yashunsky, N. E.
Nifantiev, Russ. Chem. Bull., 2015, 64, 990.
17. A. A. Karelin, Y. E. Tsvetkov, N. E. Nifantiev, Russ. Chem.
Rev., 2017, 86, 1073.
18. P. Tiwari, A. K. Misra, Carbohydr. Res., 2006, 341, 339 and
references cited therein.
19. M. Adinolfi, G. Barone, A. Iadonisi, M. Schiattarella,
Tetrahedron Lett., 2003, 44, 4661 and references cited therein.
20. L. Greffe, M. T. Jensen, F. Chang-Pi-Hin, S. Fruchard,
M. J. O´Donohue, B. Svensson, H. Driguez, Chem. Eur. J.,
2002, 8, 5447.
21. H.-M. Chen, S. G. Withers, Carbohydr. Res., 2018, 467, 33.
22. M. G. Tilbrook, R. V. Stick, S. J. Williams, Aust. J. Chem.,
1999, 52, 885.
Methyl 4,6-di-О-acetyl-2,3-di-О-benzoyl-α-D-glucopyr-
anoside (4). A colorless syrup, Rf = 0.69 (toluene—EtOAc, 3 : 2),
[α]D +132 (с 1, CHCl3) (Ref. 25: [α]D +127.9 (с 1, CHCl3)).
1H NMR (600 МHz, CDCl3), δ: 7.98—7.34 (m, 10 Н, Ar);
5.99—5.92 (m, 1 Н, Н(3)); 5.35 (t, 1 Н, H(4), J = 10.1 Hz);
5.23—5.18 (m, 2 Н, Н(1), Н(2)); 4.34 (dd, 1 Н, Н(6а), J6a,5
=
= 4.6 Hz, J6a,6b = 12.3 Hz); 4.18 (dd, 1 Н, Н(6b), J6b,5 = 2.2 Hz,
J6b,6a = 12.3 Hz); 4.16—4.11 (m, 1 Н, Н(5)); 3.44 (s, 3 Н, СН3О);
2.14, 1.95 (both s, 6 Н, 2 СН3СО). 13С NMR (150 МHz, CDCl3),
δ: 170.7, 169.5 (2 CH3CO), 165.8 (PhCO), 133.4, 133.3, 129.9,
129,7, 128.4 (Ar), 97.0 (C(1)), 71.8 (C(2)), 70.5 (C(3)), 68.3
(C(4)), 67.4 (C(5)), 62.0 (C(6)), 55.6 (CH3O), 20.8, 20.5
(2 CH3CO). The NMR spectroscopy data for compound 4 are
in good agreement with the data reported in the work.26
Methyl 4-О-acetyl-2,3-di-О-benzoyl-α-D-glucopyranoside (5).
A colorless syrup, Rf = 0.34 (toluene—EtOAc, 3 : 2), [α]D +144
(с 1, CHCl3). 1H NMR (600 МHz, CDCl3), δ: 7.99—7.35
(m, 10 Н, Ar); 6.03 (t, 1 H, H(3), J = 9.6 Hz); 5.30 (t, 1 H, H(4),
J = 9.9 Hz); 5.22 (d, 1 H, H(1), J1,2 = 3.6 Hz); 5.19 (dd, 1 H,
H(2), J2,3 = 9.6 Hz); 3.96—3.91 (m, 1 H, H(5)); 3.80 (dd, 1 H,
H(6a), J6a,5 = 2.2 Hz, J6a,6b = 12.7 Hz); 3.69 (dd, 1 H, H(6b),
J6b,5 = 4.1 Hz, J6b,6a = 12.7 Hz); 3.45 (s, 3 H, CH3O); 2.00 (s,
3 H, CH3CO). 13С NMR (150 МHz, CDCl3), δ: 170.6 (CH3CO),
166.1, 165.5 (2 PhCO), 133.4, 133.3, 129.9, 129.7, 128.4 (Ar),
97.0 (C(1)), 72.0 (C(2)), 70.2 (C(3)), 69.5 (C(5)), 68.8 (C(4)),
61.1 (C(6)), 55.6 (CH3O), 20.6 (CH3CO). MS (ESI), found m/z:
467.1304 [M + Na]+; calculated for С23H24NaO9 467.1313.
Method B. A solution of diol 2 (152 mg, 0.38 mmol) in Ас2О
(3 mL) was heated at 60 °C for 15 h, Ас2О was evaporated and
coevaporated with toluene (3×5 mL). Column chromatography
of the residue (toluene—EtOAc, 85 : 15 → 80 : 20) gave 6-acetate
3 (140 mg, 83%) and diacetate 4 (27 mg, 15%) identical to those
described above.
Method C. Pyridine (64 μL, 0.68 mmol) and Ас2О (42 μL,
0.44 mmol) were added to a solution of diol 2 (137 mg, 0.34 mmol)
in CH2Cl2 (3 mL) cooled with ice. The mixture was stirred at
4 °C for 2 h, then the temperature was raised to ambient within
3 h. After 16 h, MeOH (50 μL) was added, the reaction mixture
was diluted with chloroform (50 mL), washed with 1 M HCl and
water, and concentrated. Column chromatography of the residue
(toluene—EtOAc, 85 : 15 → 80 : 20 → 70 : 30) gave 6-acetate 3
(96 mg, 64%), 4,6-diacetate 4 (35 mg, 21%), and 4-acetate 5
(13 mg, 9%) identical to those described above.
This work was financially supported by the Russian
Science Foundation (Project No. 19-43-02023).
23. Q.-W. Liu, H.-C. Bin, J.-S. Yang, Org. Lett., 2013, 15, 3974.
24. S. Singh, Z. Su, M. Grossutti, F.-I. Auzanneau, Carbohydr.
Res., 2014, 390, 50.
25. T. Ziegler, M. Vollmer, S. Oberhoffner, E. Eckhardt, Liebigs
Ann. Chem., 1993, 255.
References
26. K.-i. Sato, N. Kubo, R. Takada, S. Sakuma, Bull. Chem. Soc.
Jpn, 1993, 66, 1156.
1. T. W. Greene, P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd ed., John Wiley & Sons, Inc., New York, 1999,
p. 217.
2. P. J. Kocieński, Protecting Groups, 3rd ed., Georg Thieme
Verlag, Stuttgart, 2005, p. 137.
3. E. B. Rodriguez, R. V. Stick, Austr. J. Chem., 1990, 43, 665.
4. M. von Itzstein, I. D. Jenkins, J. Chem. Soc., Perkin Trans. 1,
1986, 437.
Received June 15, 2020;
in revised form July 16, 2020;
accepted July 27, 2020