Monoacetylation of carbohydrate diols via transesterification with ethyl acetate

Article abstract of DOI:10.1071/CH12518

Monoacetylation of secondary diols in protected monosaccharides was achieved with ethyl acetate as acyl donor and sodium tert-butoxide as a base. The regioseletivity of the reaction varied depending on the substrate. This new method provides a simple, fast, and efficient method to access selectively acetylated carbohydrates that is compatible with acid-sensitive protecting groups. CSIRO 2014.

Full text of DOI:10.1071/CH12518

CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 679–683
Communication
http://dx.doi.org/10.1071/CH12518
Monoacetylation of Carbohydrate Diols
via Transesterification with Ethyl Acetate
A
A B
,
A B
,
Xuyu Liu, Bernd Becker,
and Matthew A. Cooper
A
Institute for Molecular Bioscience, University of Queensland,
Brisbane, Queensland 4072, Australia.
B
Corresponding authors. Email: bbeckerr@gmail.com; m.cooper@uq.edu.au
Monoacetylation of secondary diols in protected monosaccharides was achieved with ethyl acetate as acyl donor and
sodium tert-butoxide as a base. The regioseletivity of the reaction varied depending on the substrate. This new method
provides a simple, fast, and efficient method to access selectively acetylated carbohydrates that is compatible with acid-
sensitive protecting groups.
Manuscript received: 21 November 2012.
Manuscript accepted: 2 January 2014.
Published online: 13 February 2014.
Ph
Ph
Ph
O
Oligosaccharides are essential in a variety of biological
processes but their chemical synthesis often requires several
protecting group transformations that can be time-consuming.
Therefore, simple, efficient, and selective protection of indi-
vidual hydroxyl groups in a monosaccharide is very useful for
the assembly of oligosaccharides. One of the most common
protecting groups used in carbohydrate chemistry is the acetate
group, with acetic anhydride[1] and acetyl chloride[2] being
the most common reagents, as presented in this discussion.
However, both reagents are often not selective and the need to
remove excess reagents after the reaction can be difficult in
some cases. Ethyl acetate (EtOAc) has been investigated as a
transesterification agent for the acetylation of alcohols under
a variety of conditions,[3] and an early example includes the
acetylation of sucrose.[4] Selective acetylation of various
monosaccharides with sodium hydride (NaH) has also been
reported,[5] but the selectivity of the reaction is limited to sys-
tems containing both primary and secondary hydroxyl groups;
moreover, only moderate yields are observed for primary acet-
ates. Although acetylation of alcohols with EtOAc using other
reagents, such as potassium carbonate,[6] phosphine reagents,[7]
acids or Lewis acids,[8] and alumina,[9] has been reported, the
procedures are either complicated or time-consuming, and their
application in carbohydrate chemistry has not been extensively
investigated.
O
O
O
1. base
O
O
2. EtOAc
ꢀ
O
O
O
Solvent
HO
HO
AcO
HO
AcO
HO
OMe
OMe
OMe
1
2a
2b
Scheme 1. Reaction of 1 with EtOAc as acetyl source.
determined by comparison of the integrals of the benzylidene-
and/or the thiomethyl or methoxy proton signals of the products
and the starting monosaccharide in the 1H NMR spectrum of the
reaction mixture after workup (see the Experimental section).
Although the reactions proceeded to provide exclusively
monoacetylated products, the yields were only moderate and
the observed regioselectivity was low. The use of bases with
larger steric substituents did not have a significant influence on
regioselectivity. The large differences in the steric properties of
sodium bis(trimethylsilyl)amide (NaHMDS) and NaH (Table 1,
entries 4 and 5), and those of sodium NaOtBu and NaH (Table 1,
entries 14 and 5) hardly affected the regioselectivity, presum-
ably because of a rapid equilibration between the anions of the 2-
and 3-hydroxyls in the carbohydrate ring. The highest conver-
sions of 1 to products 2a and 2b were obtained using NaH (62 %,
Table 1 entry 5) and NaOtBu (58 %, Table 1 entry 13). The use
of K2CO3 in EtOAc as solvent[6] also gave a reasonable yield of
2a and 2b (55 %, Table 1 entry 7), but the reaction was
significantly slower and required refluxing. To avoid potential
problems in larger scale reactions, owing to the production of
hydrogen gas, NaOtBu was chosen over NaH as a base for
further investigation.
To selectively introduce acetates in a manner com-
patible with acid sensitive groups, we selected methyl 4,6-O-
benzylidene-a-D-galactopyranoside 1 as a model and used
EtOAc as acetyl donor with various bases and dry solvents
(Scheme 1). The best results were obtained with N,N0-dimethyl-
formamide (DMF) and dimethyl sulfoxide (DMSO) as solvents,
and sodium hydride and sodium tert-butoxide (NaOtBu) as
bases (Table 1). No bis-acetylated products were observed.
All products in the crude reaction mixture were identified by
Various equivalents of EtOAc and NaOtBu, and reaction
times were investigated (Table 2). An excellent conversion of
1 was obtained with 100 equivalents of EtOAc and 0.5–1.5
equivalents of NaOtBu and 30 min reaction time (Table 2,
1
comparison with literature H NMR data or characterized by
NMR after purification, and used as reference for the analysis of
the crude reaction mixtures. The percentage conversion was
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

680
X. Liu, B. Becker, and M. A. Cooper
Table 1. Acetylation of 1 with EtOAcA and various bases
RT, room temperature
Entry
Base
Equiv. of base
Solvent
Time
Temperature
YieldB [%]
Ratio (2a : 2b)B
1
LDAC
1.8
1.2
1.2
1.2
1.2
1.2
10
THF
1 h
08C
08C
08C
08C
08C
08C
Reflux
RT
0
0
–
2
BuLi
THF
45 min
45 min
1 h
–
3
LiHMDS
NaHMDS
NaH
DMF
14
44
62
0
1 : 2.0
4
DMF
1 : 1.0
5
DMF
30 min
30 min
Overnight
30 min
1 h
1 : 1.1
6
DBU
DMF
–
7
K2CO3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
EtOAc
Toluene
CH2Cl2
Dioxane
THF
55
0
1 : 1.3
8
1.5
1.5
1.5
1.5
1.5
1.5
1.5
–
9
RT
0
–
10
11
12
13
14
1 h
RT
0
–
1 h
RT
0
–
EtOAc
DMSO
DMF
1 h
RT
0
–
30 min
30 min
RT
58
53
1 : 1.5
1 : 1.2
RT
A20 equivalents of EtOAc were used.
BDetermined by 1H NMR.
CLDA: lithium diisopropylamide.
Table 2. Optimization of Acetylation of 1 in DMSO at room temperature
Entry
Base
Equiv. of base
Equiv. of EtOAc
Time
YieldA [%]
Ratio (2a : 2b)B
1
NaOtBu
0.2
20
20
30 min
30 min
30 min
2 h
0
–
2
NaOtBu
0.5
64
1 : 1.1
1 : 1.5
1 : 1.4
1 : 1.7
1 : 1.1
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.4
1 : 1.9
1 : 1.4
1 : 1.8
1 : 1.5
3
NaOtBu
0.5
100
100
100
1.2
20
87 (75)
86C
85C
16
4
NaOtBu
0.5
5
NaOtBu
0.5
16 h
6
NaOtBu
1.5
30 min
30 min
30 min
30 min
30 min
30 min
30 min
30 min
30 min
7
NaOtBu
1.5
58
8
NaOtBu
1.5
100
150
20
82
9
NaOtBu
1.5
78
10
11
12
13
14
NaOtBu
5.0
15
LiOtBu
1.5
100
20
66
KOtBu
1.5
51
KOtBu
1.5
100
100
84
KOtBu (þ18-crown-6)
1.5 (2.7)
69
ADetermined by 1H NMR, isolated yields in brackets.
BDetermined by 1H NMR.
CBy-product(s) detected in 1H NMR spectrum.
Table 3. Acylation of 1 with various esters
iPr, isopropyl; Piv, pivaloyl
entries 3 and 8). Increasing equivalents of EtOAc (Table 2, entry
8 vs 9) and NaOtBu (Table 2, entries 2 and 7 vs 10) decreased the
yield. Generally, the reactions yielded only these two products
and the non-reacted starting material, however, by-products
were generated when longer reaction times were used (Table 2,
entries 4 and 5).
Different cations in the tert-butoxides were investigated and
had a noticeable effect on the yield of the reaction (Table 2).
Lithium tert-butoxide (LiOtBu) did not generate high yields
unlike sodium- and potassium tert-butoxide (Table 2, entry 11
vs 8 and 13). The addition of 18-crown-6 lowered the yield of
the reaction mediated by potassium tert-butoxide (Table 2,
entry 13 v. 14).
Ph
Ph
Ph
O
O
O
NaOtBu
ester
O
O
O
O
O
O
O
ꢀ
DMSO
HO
O
HO
O
HO
O
HO
OMe
OMe
OMe
R
R
2a R ꢁ Me
2c R ꢁ tBu
2b R ꢁ Me
2d R ꢁ tBu
Entry
Equiv.
of base
Ester
Time
YieldA
[%]
RatioA
(equiv.)
(2a,c : 2b,d)
As the base appeared to have limited effects on the regio-
selectivity of the reaction (Tables 1, 2), esters with various steric
properties were investigated as acylating agents (Table 3). The
use of bulkier esters led to lower yields and the regioselectivity
of the reactions did not change significantly compared with that
obtained with EtOAc. When purified 2a or 2b were subjected to
the optimized acetylation conditions, a mixture of both isomers
1
2
3
4
1.5
1.5
0.5
0.5
EtOAc (100)
iPrOAc (100)
EtOPiv (100)
EtOPiv (100)
30 min
30 min
30 min
48 h
82
69
39
44
1 : 1.5
1 : 1.8
1 : 1.3B
1 : 1.3B
ADetermined by 1H NMR.
BThe identities of the regioisomers were not clearly determined.

Monoacetylation of Carbohydrates
681
Table 4. NaOtBu-catalyzed acetylation of various diols
Entry
Substrate
YieldA [%]
Products[10–14],B
Ph
O
O
5
6
1
87 (75)
1 : 1.1C (2-OAc : 3-OAc)
O
HO
Ph
SMe
O
OH
O
O
HO
2
3
4
76 (65)
1 : 1.1 (2-OAc : 3-OAc)
1 : 2.1 (2-OAc : 3-OAc)
1 : 1.9 (2-OAc : 3-OAc)
HO
OMe
OH
O
O
Ph
O
7
HO
50
OMe
8
O
Ph
O
O
OMe
(51)
HO
HO
Ph
O
O
(75)D
1 : 1.1 (2-OAc : 3-OAc)
9
5
O
HO
OMe
OH
OBn
O
HO
10
6
7
.95 (80)
1 : 2.8 (4-OAc : 3-OAc)
1 : 2.6 (4-OAc : 6-OAc)
HO
BnO
OMe
OH
O
HO
BnO
11
12
.95
BnO
OMe
OH
O
HO
BnO
8
9
.95
.95
1 : 1.2 : 0.2 (4-OAc : 6-OAc : 4,6-di-OAc)
1.3 : 1.8 : 1 (1-OAc : 2-OAc : 1,2-di-OAc)
BnO
OMe
OH
OH
13
ADetermined by 1H NMR, isolated yield in brackets.
BRatios determined by 1H NMR.
CSee details in text for compound 5.
DBy-products from loss of benzylidene were observed.
were formed at the same ratio as that obtained when the reaction
was performed with 1 only. This indicated that an intramolecular
transesterification could occur under these conditions, limiting
the regioselectivity of the reaction.
To investigate the scope of this acetylation, a series of
monosaccharides with hydroxyl groups at various positions
were tested. Moderate-to-excellent conversions to monoacety-
lated products were achieved with all sugars (Table 4, entries
1–8). Better regioselectivity was observed in the monosacchar-
ides with primary hydroxyl groups, whereby acetylation
favoured the primary position when the secondary alcohol was
in an equatorial position (Table 4, entry 7). This selectivity was

682
X. Liu, B. Becker, and M. A. Cooper
diminished when an axial alcohol was present, with a small
proportion of bis-acetylated product also detected in this case
(Table 4, entry 8). However, no bis-acetylation was observed in
the other reactions (Table 4, entries 1–7). In contrast, under the
same conditions, acetylation of diol 13 was not regioselective
and a significant amount of the diacetylated product was also
generated (Table 4, entry 9). An unexpected side product was
observed (Table 4, entry 5), whereby a small amount of a
product with no benzylidene functionality was observed in the
NMR spectrum of the crude mixture. This side product was not
observed in the other reactions.
In conclusion, we report a simple, fast, and efficient method
for the monoacetylation of hexopyranosides with good yields,
using EtOAc in the presence of NaOtBu. Despite the limited
regioselectivity, this reaction is useful for the selective protec-
tion of individual monosaccharides as the regioisomers can be
generally easily separated by chromatography. This procedure
has potential for protecting group manipulations in oligosaccha-
ride synthesis.
the crude mixture to obtain pure 5 (2OAc) (116 mg, 36 %) and 5
(3OAc) (130 mg, 39 %).
5 (2OAc): dH (400 MHz, CDCl3) 7.48 (m, 2H), 7.36 (m, 3H),
5.50 (s, 1H), 4.90 (dd, J 9.5, 3.1, 1H), 4.43 (dd, J 3.5, 0.9, 1H),
4.35 (d, J 9.2, 1H), 4.35 (dd, J 12.3, 1.8, 1H), 4.10 (dd, J 9.6, 1H),
4.02 (dd, J 12.2, 1.7, 1H), 3.60 (dd, J 2.6, 1.7, 1H), 2.27 (s, 3H),
2.14 (s, 3H). dC (100 MHz, CDCl3) 170.96, 137.73, 129.13,
128.25, 126.27, 101.12, 85.20, 74.91, 73.78, 69.88, 69.20,
65.65, 21.11, 10.44. m/z 341.1053. HRMS Anal. Calc. for
C16H21O6S 341.1053. Found 341.1037.
5 (3OAc): dH (400 MHz, CDCl3) 7.48 (m, 2H), 7.39 (m, 3H),
5.55 (s, 1H), 5.21 (dd, J 9.6, 1H), 4.38 (dd, J 12.2, 1.9, 1H), 4.33
(d, J 10.1, 1H), 4.27 (dd, J 4.3, 1.5, 1H), 4.04 (dd, J 12.9, 1.8,
1H), 3.76 (ddd, J 9.1, 3.0, ,0.5, 1H), 3.57 (dd, J 2.6, 1.7, 1H),
2.24 (s, 3H), 2.14 (s, 3H). dC (100 MHz, CDCl3) 170.48, 137.37,
129.47, 128.40, 126.41, 101.64, 81.85, 75.70, 72.35, 69.94,
69.36, 69.19, 21.03, 10.40. m/z 363.0873. HRMS Anal. Calc.
for C16H20NaO6S 363.0873. Found 363.0880.
Acknowledgements
Experimental
XL thanks the University of Queensland (UQ) for a stipend as part of the
UQ Summer Research Scholarship Program. BB and MAC acknowledge
support of an NHMRC Australia Fellowship AF511105. The authors
are grateful for a donation of thiomethyl glycosides from Alchemia Ltd.
General Procedure
All solvents used were dry, as received from the supplier
(Sigma–Aldrich). To a stirred solution of pyranoside (1.0 mmol)
in DMSO (10 mL), NaOtBu was added (50 mg, 0.50 mmol), and
the mixture was stirred at room temperature. After 15 min,
EtOAc (10 mL, 100 mmol) was added dropwise. The reaction
was stirred for 30 min and then quenched with 10 % citric acid
solution (20 mL). The solution was extracted with EtOAc
(100 mL) and the organic layer was dried over MgSO4. After
filtration, the solvent was removed under reduced pressure. The
percentage conversion was determined by 1H NMR. Flash
chromatography was used to isolate the two isomers.
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