Catalyst-free regioselective acetylation of primary hydroxy groups in partially protected and unprotected thioglycosides with acetic acid

Article abstract of DOI:10.1039/d0ra07360a

Highly regioselective acetylation of primary hydroxy groups in thioglycoside derivatives with gluco- and galacto-configurations was achieved by treatment with aqueous or anhydrous acetic acid (60-100% AcOH) at elevated temperatures (80-118 °C), avoiding c

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Catalyst-free regioselective acetylation of primary
hydroxy groups in partially protected and
unprotected thioglycosides with acetic acid†
Cite this: RSC Adv., 2020, 10, 36836
a
*
Polina I. Abronina,
Nelly N. Malysheva,a Alexander I. Zinin,a
Natalya G. Kolotyrkina,a Elena V. Stepanova
and Leonid O. Kononov
ab
a
*
Highly regioselective acetylation of primary hydroxy groups in thioglycoside derivatives with gluco- and
galacto-configurations was achieved by treatment with aqueous or anhydrous acetic acid (60–100%
AcOH) at elevated temperatures (80–118 ꢀC), avoiding complex, costly and time-consuming
manipulations with protective groups. Acetylation of both 4,6-O-benzylidene acetals and the
corresponding diols as well as the unprotected tetraol with AcOH was shown to lead selectively to
formation of 6-O-acetyl derivatives. For example, the treatment of phenyl 1-thio-b-D-glucopyranoside
with anhydrous AcOH at 80 ꢀC for 24 h gave the corresponding 6-O-acetylated derivative in 47% yield
(71% based on the reacted starting material) and unreacted starting tetraol in 34% yield, which can easily
be recovered by silica gel chromatography and reused in further acetylation.
Received 27th August 2020
Accepted 24th September 2020
DOI: 10.1039/d0ra07360a
rsc.li/rsc-advances
inuenced by the nature of counter-ion of acetylating agent and
reaction conditions.28 Based on these ndings, regioselective
Introduction
acetylation of diols and polyols using catalytic amounts of
acetate ion has been developed.29 Lewis acid catalysed removal
of 6-O-protective group in per-O-trimethylsilylated30,31 or ben-
zylated32,33 compounds with subsequent one-pot acetylation of
monosaccharides affording 6-O-acetylated fully protected
sugars has been described. A method involving N-acetylth-
iazolidine-2-thione34 as acetylation agent has also been devel-
oped. 1-Acetylimidazole was used for selective acetylation of the
primary hydroxy groups in derivatives of methyl glycosides in
1,2-dichloroethane at 80 ꢀC (ref. 35) or, more recently, in water
in the presence of tetramethylammonium hydroxide (TMAH).36
Highly selective but less accessible chiral organocatalysts37,38 for
direct acetylation have also been proposed. Recently, 6-O-acet-
ylation by migration of acetyl group from O-2 has been devel-
oped.39 Enzymatic acetylation40–42 has also been applied for the
selective introduction of acetyl groups at primary hydroxy
groups of sugars.
Acetylation at O-6 is common for carbohydrate low-molecular
weight metabolites in plants.43–47 Bacterial polysaccharides oen
contain 6-O-acetyl groups, which play a complex role in the
functional immune response.48–51 Hence, the development of
ways for selective acetylation of unprotected and partially pro-
tected carbohydrates would contribute greatly to the study of
naturally occurring carbohydrate molecules.
Regioselective synthesis is a prominent challenge in organic
chemistry and especially in carbohydrate chemistry since
carbohydrates contain several hydroxyl groups of similar reac-
tivity.1–5 Although primary hydroxy groups are generally
considered more reactive in esterication reaction,6,7 regiose-
lective acetylation of primary hydroxy groups in carbohydrates
is surprisingly complicated4 and is usually conducted using
specic catalysts and conditions.8,9 Disadvantages of many
known acetylation methods are related to the use of environ-
mentally toxic and expensive reagents.
Typical examples of selective 6-O-acetylation in mono-
saccharides include the use of EtOAc in combination with
acidic10,11 or basic12,13 catalysis, vinyl acetate and germanium
compounds as catalysts,14 acetic acid (AcOH) and uronium-
based coupling agents,15 1-acetyloxybenzotriazole16,17 as well as
acetyl chloride or acetic anhydride in the presence of bases,18–22
25
iodine,23 Al2O3 (ref. 24) or 4 A molecular sieves. Reactions
˚
employing organotin4,26 and organosilicon27 derivatives were
used for regioselective acetylation of carbohydrates. It was
noted that the selectivity of acetylation is dramatically
aN. K. Kochetkov Laboratory of Carbohydrate Chemistry, N. D. Zelinsky Institute of
Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation.
E-mail: Polina-Abronina@yandex.ru; leonid.kononov@gmail.com; kononov@ioc.ac.
ru; Web: https://carbohydrates.ru
The non-catalysed (auto-catalysed) acetylation of simple
alcohols is well-known.52–59 It has been extensively studied for
industrial purposes like reactive distillation,60,61 which is used
for esterication or for recovery of dilute acetic acid from
wastewater.62–65 However, only few examples of the use of this
bResearch School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic
University, Lenin avenue 30, Tomsk 634050, Russian Federation
† Electronic supplementary information (ESI) available: All experimental
procedures, characterisation data and copies of NMR spectra. See DOI:
10.1039/d0ra07360a
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Table 1 Acidic conditions used for removal of benzylidene acetal and
Results and discussion
acetylation of thioglycoside diols and tetraola
Cleavage of 4,6-O-benzylidene group by aqueous AcOH with
concomitant acetylation
Concentration of
AcOH (%, v/v)
Method
Temperatureb (ꢀC)
Time (h)
Selective cleavage of 4,6-O-benzylidene group68,69 in various
carbohydrate derivatives is commonly achieved by acidic
hydrolysis70 (heating with aq AcOH,71 treatment with triuoro-
acetic acid (TFA) in CH2Cl2–ethylene glycol72 or aq TFA in
CH2Cl2 (ref. 73 and 74)), which leads to formation of the cor-
responding 4,6-diol. This procedure is considered to be robust
and efficient and is widely used in protective group strategies.1,75
We have recently reported that the cleavage of 4,6-O-benzy-
lidene group in derivatives of b-congured ethyl 1-thio-b-D-gal-
actopyranoside with silyl (TIPS or TBDPS) groups at O-2 and O-3
with 80% aq AcOH (80 ꢀC, 1 h) gave the expected 4,6-diols in 68–
75% yields, while treatment with aq TFA in CH2Cl2 led to
pyranose ring contraction.76 To study the effect of anomeric
conguration on the result of treatment of benzylidene acetals
with acids, we synthesised ethyl 4,6-O-benzylidene-1-thio-a-D-
galactopyranoside (1) and the corresponding 2,3-O-TIPS (2) and
TBDPS (3) derivatives, starting from the known77 ethyl 1-thio-a-
D-galactopyranoside.
Surprisingly, the reaction of a-congured ethyl 4,6-O-benzy-
lidene-2,3-bis-O-triisopropylsilyl-1-thio-a-D-galactopyranoside
(2) with 80% aq AcOH under similar conditions was not
complete in 1–2 h. Aer 24 h of treatment with 80% aq AcOH at
80 ꢀC (method B, Table 1, Fig. 1) the formation of the expected
diol 4 (19%) was accompanied by considerable amounts (22%)
of 6-O-acetylated product 5. Besides, the minor 4-O-acetylated
product 7 and 6-O-acetylated thioglycoside 6 with a single TIPS
group at O-2 were also obtained.
A
B
C
D
E
F
G
H
I
60
80
80
80
80
100
24
24
24
24
24
2.5
2
100
100
100
100
100
60
130c,d
130c,d
130c,d
117c,e
117c,f
24
24
80
a
Aqueous or anhydrous AcOH, heating at indicated temperature. b Bath
temperature. c Reux. d Bp 118 ꢀC. e Bp 102 ꢀC. f Bp 105 ꢀC.
reaction for acetylation of carbohydrates are known. The
primary hydroxy group of several carbohydrates was selectively
esteried by treatment with 50% AcOH at 100 C for 24 h. For
ꢀ
example, aer removal of excess of AcOH in vacuo the syrup
containing unchanged D-glucose, 6-O-acetyl-D-glucose, and a di-
O-acetyl-D-glucose was obtained.66 The preparation of 6-O-acetyl-
D-glucose by esterication of D-glucose was also performed by
treatment with 75% AcOH at 100 ꢀC for 8 h.67 Preparative yields
of 6-O-acetylated products were moderate (10–30%).
Herein, we describe a method for regioselective acetylation
of primary hydroxyl group in glycosides using acetic acid as
single reagent in the absence of added catalyst. We focused on
regioselective acetylation of thioglycoside diols and tetraol with
60–100% (v/v) AcOH using Methods A–I (Table 1).
Unlike the cleavage of 4,6-O-benzylidene group in TIPS-
containing derivative 2, the treatment of thiogalactopyranoside
Fig. 1 Results of acetylation of TIPS-containing compounds 2, 4 and TBDPS-containing compound 3 according to method B. TIPS ¼ (i-Pr)3Si.
TBDPS ¼ t-BuPh2Si. See also Tables 1S and 2S in ESI.†
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3 with TBDPS groups at O-2 and O-3 under identical conditions
(according to method B) (Fig. 1) at the same concentration (c ¼
48 mmol Lꢁ1) gave diol 8 and 6-O-acetylated product 9 in 39 and
35% yields, respectively (Fig. 1). Apparently, the TBDPS groups
are more stable under acidic conditions than the TIPS groups. A
study of inuence of the concentration on the outcome of acet-
ylation revealed an additional formation of a minor amount of 4-
O-acetylated product 10 at higher and lower concentrations
(Fig. 1).
To check if the preferential formation of the product of O-
acetylation of primary hydroxy group is related to limited
solubility of extremely hydrophobic silyl-containing ethyl thio-
a-D-galactopyranosides 2–4 we tested the known ethyl 2,3-di-O-
benzyl-4,6-O-benzylidene-1-thio-b-D-galactopyranoside
(11)71
with less hydrophobic benzyl groups at O-2 and O-3 in the
reaction with acetic acid according to method B (Table 1) at two
similar yet different concentrations (c ¼ 58 and 68 mmol Lꢁ1
)
(Fig. 2). The yield of 6-O-acetylated thiogalactoside 14 was 41
and 43%, respectively. Diol 12 (ref. 71) was isolated in 36 and
30% yields, when the reaction was performed at 58 and
68 mmol Lꢁ1 of 11, respectively (Fig. 2). Besides, 4-O-acetylated
thiogalactoside 13 was also obtained.
Fig. 3 The yields of products 16–19 obtained from compounds 15–17
under acetylation conditions according to methods A–C. Concen-
tration of substrate (15, 16 or 17) c ¼ 20 mmol Lꢁ1. See also Table 4S in
ESI.†
Similar results were obtained in gluco-series. Thus, the
cleavage of benzylidene group in phenyl 2,3-di-O-benzyl-4,6-O-
benzylidene-1-thio-b-D-glucopyranoside (15) with 80% aq AcOH
at 80 ꢀC under conditions of method B (Table 1) gave diol 16 and
6-O-acetylated product 17 in 43 and 45% yields, respectively
(Fig. 3). 4-O-Acetylated thiogalactoside 18 was also isolated in
6% yield. A decrease in AcOH concentration to 60% led to the
expected decrease in the proportion of 6-O-acetylated product
17, which was obtained in 27% yield (Fig. 3) under conditions of
method A (Table 1).
at 80 C has been reported.78 The authors emphasise that the
ꢀ
presence of 4,6-O-benzylidene acetal is critical for the success of
the transformation; no acetylation occurs with the corre-
sponding 4,6-diols under identical conditions. In particular,
according to the authors,78 when diol 16 was treated with 60%
aq AcOH “no primary O-acetylation product could be identied
even aer 24 h” at 80 ꢀC (these conditions mirror conditions of
method A, Table 1). Our data do not support these ndings. In
our hands, aer the treatment of diol 16 with 60% aq AcOH at
ꢀ
80 C according to method A (Fig. 3) 6-O-acetylated product 17
Acetylation of 4,6-diols with aqueous AcOH
was isolated in 28% yield. Unreacted diol 16 was recovered in
51% yield. Besides, the minor amount of 4-O-acetylated thio-
glucoside 18 was isolated in 2% yield.
Recently, the transformation of mono- and oligosaccharide 4,6-
O-benzylidene acetals to the corresponding 6-O-acetyl deriva-
tives with free 4-hydroxy group by treatment with 60% aq AcOH
Note that the increase in concentration of AcOH to 80%
ꢀ
while keeping the temperature at 80 C (method B) for acety-
lation of diol 16 with gluco-conguration led to comparable
yield (30%) of 6-O-acetylated product 17 (Fig. 3). Similar results
were obtained in acetylation of diol 4 with galacto-conguration
under identical conditions (80% aq AcOH 80 ꢀC, method B),
which gave 6-O-acetylated thioglycoside 5 (32%) as well as the
product with acetyl group at O-4 (7, 6%) and 6-O-acetylated
thioglycoside 6 (9%) with a single TIPS group at O-2 (Fig. 1).
Esterication of alcohols with AcOH is known to be a reversible
process that occurs under thermodynamic control.52–59 Indeed,
when 6-O-acetylated product 17 was treated under the reaction
conditions (80% aq AcOH, 80 ꢀC, 24 h; method B) the parent diol
16 (24%) and 4-acetate 18 (4%) were isolated from the reaction
mixture in addition to the starting 6-acetate 17 (53%) (Fig. 3).
Acetylation of 4,6-diols with anhydrous AcOH
Fig. 2 The yields of products 11–14 after acetylation of compound 11
according to method B at different concentrations of substrate 11. See
also Table 3S in ESI.†
In accordance with this view on the mechanism of esterication
of alcohols with aqueous AcOH,52–59 the use of anhydrous AcOH
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shied the esterication equilibrium towards the formation of
acetylated products. Thus, the treatment of gluco-diol 16 with
anhydrous AcOH at 80 ꢀC according to method C (Fig. 3)
increased the yield of 6-O-acetylated product 17 (42%). Small
amounts of 4-O-acetylated (18, 4%) and 4,6-di-O-acetylated (19
(ref. 79), 3%) derivatives were also isolated. It should be noted
that unreacted diol 16 (35%) can be easily recovered by silica gel
chromatography and reused in further acetylation.
Thus, we demonstrated that not only 4,6-O-benzylidene
acetals (as claimed in ref. 78) but also the corresponding 4,6-
diols can form 6-O-acetylated thioglycosides by treatment with
aqueous or anhydrous AcOH. Importantly, the regioselectivity
of acetylation does not depend on conguration of mono-
saccharide: thioglycosides with both gluco- and galacto-cong-
urations (with equatorial and axial 4-OH, respectively) perform
equally well in the acetylation reactions.
Fig. 5 The effect of temperature on selectivity of acetylation. The
yields of acetylated derivatives 20–28 isolated after acetylation of
compound 20 with anhydrous AcOH at 80, 100 and 118 ꢀC according
to methods C, D, E, respectively. Concentration of 20 c ¼ 20 mmol
L
ꢁ1. See also Table 5S in ESI.†
Acetylation of tetraol with aqueous or anhydrous AcOH
Reux of tetraol 20 in more dilute AcOH solutions at ca.
The next step was to study if the found conditions for acetyla-
tion of carbohydrate diols with AcOH would be applicable for
carbohydrate derivatives with larger number of hydroxyl groups.
Treatment of unprotected phenyl 1-thio-b-D-glucopyranoside
(20)80 with anhydrous AcOH at 80 ꢀC for 24 h according to
method C (Fig. 4, 5) gave the corresponding 6-O-acetylated
derivative 21 in 47% yield and unreacted tetraol 20 in 34% yield
along with minor amounts of mono- (26) and diacetylated
derivatives 27 as well as 3,6-di-O-acetylated thioglycoside 22
(Fig. 4 and 5). This result is remarkable considering that the
unreacted starting tetraol 20 can easily be recovered by silica gel
chromatography and reused in further acetylation (thus making
the yield of 21 fairly practical – 71% based on the reacted
starting material). The only, although minor, drawback of this
method for selective acetylation is the incomplete conversion of
the starting tetraol 20 even aer the long reaction time.
100 ꢀC for 24 h was not very effective either (Fig. 4). The
conversion of tetraol 20 dropped to 50% in 60% AcOH (bp
ꢀ
102 C, method H) as did the yield of 6-O-acetylated derivative
21 (33%). Although the yield of 6-O-acetylated derivative 21
ꢀ
somewhat increased to 42% in 80% AcOH (bp 105 C, method
I), the amount of recovered tetraol 20 decreased to 19%.
Further increase in reaction temperature resulted in prefer-
ential formation of di-, tri- and tetraacetylated products 22–28
when tetraol 20 was treated with anhydrous AcOH at reux (bp
ꢀ
118 C) for 24 h according to method E (Fig. 4 and 5). Impor-
tantly, neither tetraol 20 nor monoacetate 21 were detected
under these conditions.
Variation of the reaction time (methods F and G) revealed
that the treatment of tetraol 20 with anhydrous AcOH at reux
according to method F allows the preparation of the 6-O-acety-
lated derivative 21 in 49% yield, virtually identical to that ach-
ieved (47%) under conditions of method C, but in much shorter
time (2.5 h vs. 24 h), albeit accompanied by a decrease in the
yield of unreacted starting tetraol 20 (20%).
Increasing the reaction temperature to 100 ꢀC (24 h, method
D) resulted in almost complete conversion of 20 (95%) and
a decrease in the yield of 6-O-acetylated derivative 21 to 34%.
Substantial amounts of di- and triacetylated products 27 and 28
in addition to minor amounts of monoacetylated derivative 26
Our data are in qualitative agreement with the known results
for the preparation of 6-O-acetyl-D-glucose by esterication of D-
ꢀ
were formed aer 24 h at 100 C (Fig. 4 and 5).
Fig. 4 The results of acetylation of compound 20 according to methods C–I. Concentration of 20 c ¼ 20 mmol Lꢁ1. See also Table 5S in ESI.†
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glucose with 50–75% AcOH at 100 ꢀC,66,67 although the yields 60%) to afford acetylated products 21–28. The yields of puried
achieved in our work are considerably higher. products are shown in Fig. 4 and 5 (see also Table 5S in ESI†).
Note that the highest yields of 6-O-acetylated derivatives See ESI† for the characterisation data and copies of NMR
achieved by esterication of tetraol (49%), 4,6-diols (42%) or spectra.
4,6-O-benzylidene derivatives (45%) by aqueous or anhydrous
AcOH are similar.
A possibility of esterication of carbohydrate alcohols by
aqueous or anhydrous AcOH should be considered seriously as
this reaction may constitute an important side process consid-
erably diminishing the yield of the target transformation per-
formed in the presence of AcOH.
Phenyl 6-O-acetyl-1-thio-b-D-glucopyranoside (21)
Method C. Yield 47% (71% based on the reacted starting
23
material). Rf ¼ 0.30 (light petroleum–EtOAc 1 : 9). [a]D ꢁ61.7
1
(c 2.0 in CHCl3). H NMR (300 MHz; CD3OD): d ¼ 2.04 (s, 3H,
CH3CO), 3.22 (dd, J2,3 ¼ 8.5 Hz, J2,1 ¼ 9.7 Hz, 1H, H-2), 3.24–3.33
(m, 1H, H-4), 3.40 (dd ꢃ t, Japp ¼ 8.8 Hz, 1H, H-3), 3.50 (ddd, J5,6b
¼ 2.2 Hz, J5,6a ¼ 6.6 Hz, J5,4 ¼ 9.8 Hz, 1H, H-5), 4.19 (dd, J6a,5
¼
Conclusions
6.6 Hz, J6a,6b ¼ 11.9 Hz, 1H, H-6a), 4.40 (dd, J6b,5 ¼ 2.2 Hz, J6b,6a
¼ 11.9 Hz, 1H, H-6b), 4.59 (d, J1,2 ¼ 9.7 Hz, 1H, H-1), 7.19–7.38
(m, 3H, PhS (H-3, H-4, H-5)), 7.45–7.61 (m, 2H, PhS (H-2, H-6));
13C NMR (75 MHz, MeOD): d ¼ 20.8 (CH3CO), 64.9 (C-6), 71.4 (C-
4), 73.7 (C-2), 79.0 (C-5), 79.4 (C-3), 89.0 (C-1), 128.5 (PhS (C-4)),
129.8 (PhS (C-3, C-5)), 133.0 (PhS (C-2, C-6)), 134.8 (PhS (C-1)),
172.7 (CO). HRMS (ESI): m/z calcd for C14H18O6S + Na+:
337.0716 [M + Na]+; found: 337.0715.
We have developed an efficient and green procedure for the
highly regioselective acetylation of primary hydroxy groups in
thioglycosides, which was achieved by treatment with aqueous
or anhydrous AcOH, avoiding complex, costly and time-
consuming manipulations with protective groups. To this
end, acetylation of thioglycoside derivatives with gluco- and
galacto-congurations at various temperatures (80–118 ꢀC) and
concentrations of AcOH (60–100%) was studied. Acetylation of
both 4,6-O-benzylidene acetals and the corresponding diols as
well as the unprotected tetraol with AcOH was shown to lead
selectively to formation of 6-O-acetyl derivatives. Unreacted
starting polyol can easily be recovered by silica gel chromatog-
Conflicts of interest
There are no conicts to declare.
raphy and reused in further acetylation, which is important Acknowledgements
from the preparative point of view.
This work was supported by the Russian Foundation for Basic
Research (Project No. 20-03-00465-a).
Experimental
General procedure for deprotection of benzylidene acetals 2,
3, 11, 15 and acetylation of alcohols 4, 16, 17
Notes and references
1 S. Oscarson, in The Organic Chemistry of Sugars, ed. D. E. Levy
To thioglycosides 2, 3, 4, 11, 15–17 (0.1–0.5 mmol) 60–100% (v/v)
AcOH was added and the reaction mixture (c ¼ 10–100 mmol
Lꢁ1) was stirred at T ꢀC according to methods A–C (Table 1).
Then the reaction mixture was diluted with CH2Cl2 (50 mL) and
washed with satd aq NaHCO3 (50 mL). The aqueous layer was
extracted with CH2Cl2 (2 ꢂ 5 mL) and the combined organic
extracts were ltered through a cotton wool plug, concentrated,
and dried in vacuo. The products were puried by silica gel
column chromatography in gradient of EtOAc in light petro-
leum (1 / 20%) for isolating of silyl (TBDPS or TIPS)-
containing thioglycosides 4–10 and in gradient of EtOAc in
light petroleum (5 / 60%) for isolating of benzyl-containing
thioglycosides 16–19. The yields of puried products are
shown in Fig. 1–3 (see also Tables 1S–4S in ESI†). See ESI† for
the characterisation data and copies of NMR spectra.
¨
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