Counterion-directed regioselective acetylation of octyl β-D-glucopyranoside

Article abstract of DOI:10.1021/ol0364935

(Equation presented) The DMAP-catalyzed acetylation of octyl β-D-glucopyranoside with a series of acetylating agents has been investigated. The nature of the counterion of the catalytic DMAP-acetyl complex dramatically influences the outcome of the reaction, indicating that the deprotonation of the transition state is controlling the reaction. Noncovalent interactions of the acetate ion with the substrate seem to direct the acetylation toward secondary hydroxyl groups.

Full text of DOI:10.1021/ol0364935

ORGANIC
LETTERS
2004
Vol. 6, No. 6
945-948
Counterion-Directed Regioselective
Acetylation of Octyl
â-D-Glucopyranoside
Egmont Kattnig and Martin Albert*
Institut fu¨r Organische Chemie, Technische UniVersita¨t Graz, A-8010 Graz, Austria
albert@orgc.tu-graz.ac.at
Received December 23, 2003
ABSTRACT
The DMAP-catalyzed acetylation of octyl â-D-glucopyranoside with a series of acetylating agents has been investigated. The nature of the
counterion of the catalytic DMAP-acetyl complex dramatically influences the outcome of the reaction, indicating that the deprotonation of the
transition state is controlling the reaction. Noncovalent interactions of the acetate ion with the substrate seem to direct the acetylation toward
secondary hydroxyl groups.
The regioselective manipulation of polyfunctional molecules
is one of the major challenges in organic chemistry.
Carbohydrates, as protagonists in the rising field of glyco-
biology, represent an excellent playground for studying
selective reactions. Due to the biological significance of this
important class of compounds, a strategy, which facilitates
a regioselective derivatization of sugars with minimal
preparative efforts, would be highly desirable.1
One of the most studied reactions is the acetylation of
alcohols. There are numerous reports on attempts to improve
the selectivity and efficiency of this transformation. After
the discovery of the beneficial role of DMAP (4-(dimethyl-
amino)pyridine) as a nucleophilic catalyst for this reaction,2
a series of equally or even more reactive nucleophilic
catalysts has been reported.3 The activation of the acylating
agent by Lewis acids represents an alternative to the basic/
nucleophilic catalysis. In addition to metal-based homoge-
neous catalysts4 some heterogeneous systems have been
found to be efficient, easily removable promoters for
acetylations.5
Currently, one of the major goals in the design of catalysts
consists of finding asymmetric derivatives, which allow for
an enantioselective acetylation of racemates. The main body
of work is related to the variation of the DMAP structure in
a chiral environment.6 Other systems are based on chiral
(3) (a) Steglich, W.; Ho¨fle, G. Tetrahedron Lett. 1970, 54, 4727-4730.
(b) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978, 34, 2069-
2076. (c) Heinrich, M. R.; Klisa, H. S.; Mayr, H.; Steglich, W.; Zipse, H.
Angew. Chem. 2003, 115, 4975-4977.
(4) For some recent examples see: (a) Orita, A.; Tanahashi, C.; Kakuda,
A.; Otera, J. Angew. Chem. 2000, 112, 2999-3001. (b) Karimi, B.; Maleki,
J. J. Org. Chem. 2003, 68, 4951-4954. (c) Zhao, H.; Pendri, A.; Greenwald,
R. B. J. Org. Chem. 1998, 63, 7559-7562.
(5) For some recent examples see: (a) Adinolfi, M.; Barone, G.;
Iaadonisi, A.; Schiattarella, M. Tetrahedron Lett. 2003, 44, 4661-4663.
(b) Reddy; B. M.; Sreekanth, P. M. Synth. Commun. 2002, 32, 2815-2819.
(c) Breton, G. W. J. Org. Chem. 1997, 62, 8952-8954. (d) Li, A.-X.; Li,
T.-S.; Ding, T.-H. Chem. Commun. 1997, 1389-1390.
(6) (a) Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H. J. Org. Chem.
1999, 64, 9430-9443. (b) Spivey, A. C.; Maddaford, A.; Leese, D. P.;
Redgrave, A. J. J. Chem. Soc., Perkin Trans. 1 2001, 1785-1794. (c)
Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem. 2000, 65, 3154-
3159. (d) Jeong, K.-S.; Kim, S.-H.; Park, H.-J.; Chang, K.-L.; Kim, K.-S.
(1) (a) Kurahashi, T.; Mizutani, T.; Yoshida, J.-i. J. Chem. Soc., Perkin
Trans. 1 1999, 465-473. (b) Moitessier, N.; Chapleur, Y. Tetrahedron Lett.
2003, 44, 1731-1735. (c) Oshima, K.; Aoyama, Y. J. Am. Chem. Soc. 1999,
121, 2315-2316. (d) Kurahashi, T.; Mizutani, T.; Yoshida, J.-i. Tetrahedron
2002, 58, 8669-8677. (e) Chung, M.-K.; Orlova, G.; Goddard, J. D.; Schlaf,
M.; Harris, R.; Beveridge, T. J.; White, G.; Hallett, F. R. J. Am. Chem.
Soc. 2002, 124, 10508-10518. (f) Hu, G.; Vasella, A. HelV. Chim. Acta
2003, 86, 4369-4391. (g) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org.
Chem. 1993, 58, 3791-3793.
(2) (a) Steglich, W.; Ho¨fle, G. Angew. Chem. 1969, 81, 1001. (b) Ho¨fle,
G.; Steglich, W.; Vorbru¨ggen H. Angew. Chem. 1978, 90, 602-615.
10.1021/ol0364935 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/14/2004

trialkyl phosphines,7 tertiary amines,8 or imidazoles.9 In
contrast to the large amount of literature dealing with
structural variations of catalysts for the acetylation there are
only a few reports that are (partly) concerned with the role
of the acetylating agent.2b,10 The commonly used acetyl
donors acetic anhydride and acetyl chloride, respectively, are
supposed to react with DMAP to build a covalent, ionic
intermediate (A, Figure 1). Subsequently, this reactive species
nucleophile to wider ion pairs should be facilitated. Ad-
ditionally, the acetate ion can act as a general base catalyst
by deprotonating the nucleophile in the transition state.
Though this explanation seems to be plausible no experi-
ments have been carried out to support this notion. Recently,
Yoshida et al. disclosed some surprising results on the
DMAP-catalyzed acetylation of different octyl glycopyrano-
sides.1a By using Ac2O in the presence of a heterogeneous
base (K2CO3), mainly the secondary hydroxyl groups at
positions 3 and 4 were acetylated, the primary group at C-6
remained almost unaffected. These contraintuitive results
were attributed to a complex hydrogen bond network and to
the catalytic activity of DMAP.
In this paper we want to communicate our results, which
indicate that the deprotonation of the transition state has a
pronounced impact on the reaction rate for primary and
secondary alcohols. Depending on the auxiliary base, the
relative reactivities of acetyl chloride and acetic anhydride
can be reversed, which was shown by kinetic measurements
with simple alcohols. Octyl â-D-glucopyranoside can be
acetylated with high selectivity either on the primary or on
secondary OH groups by using different acetylation agents
under otherwise identical conditions.
Figure 1. Mechanism of the DMAP-catalyzed acetylation.
reacts with the alcohol (B, Figure 1). Deprotonation of this
complex gives rise to the formation of the ester and
regenerates the catalyst. NMR and IR studies have shown
that the equilibrium of the reaction of acetyl chloride and
DMAP is shifted completely to the right, whereas acetic
anhydride only gives 5-10% of the corresponding ionic
complex (A) at room temperature.1b The concentration of
this active complex is believed to control the reaction rate
(Figure 1). However, it was noted by several groups that
DMAP-catalyzed acetylations with acetyl chloride as acetyl
To compare the reactivity of different acetylating agents,
we started a series of experiments with 1-propanol and
2-propanol. K2CO3 served as a heterogeneous or pyridine
as a homogeneous base in our experiments with CDCl3 as
solvent. DMAP was used as a catalyst in all cases. Acetyl
chloride, being the reagent with the highest carbonyl reactiv-
ity among the tested reagents, is converted very fast in the
presence of pyridine (2 equiv) as auxiliary base in CDCl3 as
solvent and 5 mol % of DMAP as catalyst. 1H NMR kinetics
indicate a half-life for the reaction with both 1-propanol as
well as 2-propanol of less than 10 s. In correlation with the
lower carbonyl reactivity, the reaction rate for acetic
anhydride was significantly slower for both 1- and 2-propanol
(t1/2 ) 11 and 120 min, respectively). With K2CO3 as the
heterogeneous, auxiliary base the relative order of reaction
rates was reVersed and the half-life times for both reactions
with acetyl chloride were rather slow (t1/2 ) 35 and 200 min).
This observed low reactivity is consistent with previous
reports (vide supra).2b,3a In contrast to that, the reactions with
acetic anhydride were considerably faster under these condi-
tions (t1/2 ) 3.2 and 18 min).11 Though these results, in view
of marked differences in carbonyl activity, might be surpris-
ing at first sight, the reversed reaction rates may be
contributed to the basicity of the counterion of the catalyti-
cally active ionic complex (A, Figure 1). In the presence of
a homogeneous base the deprotonation of the transition state
(B, Figure 1) can be performed by the auxiliary base or the
counterion. By using a base such as K2CO3, which is
insoluble in the reaction system, the deprotonation has to be
carried out by the acetate or chloride counterion. This implies
that the proton-transfer step influences the reaction rate. To
support this notion experiments with the labeled compounds
donor are slower than those with acetic anhydride.2b,3a
A
given explanation for that is based on structural differences
in catalytically active ion pairs. Mesomerically stabilized
anions such as acetates exist as wider ion pairs compared
to those with anions such as chloride. The attack of the
Chem. Lett. 2002, 1114. (e) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996,
61, 7230-7231. (f) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem.
Soc. 1997, 119, 1492-1493. (g) Ruble, J. C.; Tweddell, J.; Fu, G. C. J.
Org. Chem. 1998, 63, 2794-2795. (h) Fu, G. C. Acc. Chem. Res. 2000,
33, 412-420. (i) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am.
Chem. Soc. 1997, 119, 3169-3170. (j) Kawabata, T.; Yamamoto, K.;
Momose, Y.; Yoshida, H.; Nagaoka, Y.; Fuji, K. Chem. Commun. 2001,
2700-2701. (k) Priem, G.; Pelotier, B.; Macdonald, S. J. F.; Anson, M. S.;
Campbell, I. B. J. Org. Chem. 2003, 68, 3844-3848. (l) Vedejs, E.; Chen,
X. J. Am. Chem. Soc. 1996, 118, 1809-1810. (m) Kawabata, T.; Stragies,
R.; Fukaya, T.; Fuji, K. Chirality 2003, 15, 71-78. (n) Kawabata, T.;
Stragies, R.; Fukaya, T.; Nagaoka, Y.; Schedel, H.; Fuji, K. Tetrahedron
Lett. 2003, 44, 1545-1548. (o) Spivey, A. C.; Zhu, F.; Mitchell, M. B.;
Davey, S. G.; Jarvest, R. L. J. Org. Chem. 2003, 68, 7379-7385. (p) Shaw,
S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368-13369.
(7) (a) Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org. Chem. 1996, 61,
430. (b) Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 1999, 121, 5813-
5814.
(8) (a) Oriyama, T.; Hori, Y.; Imai, K.; Sasaki, R. Tetrahedron Lett.
1996, 37, 8543-8546. (b) Oriyama, T.; Imai, K.; Hosoya, T.; Sano, T.
Tetrahedron Lett. 1998, 39, 397-400. (c) Mizuta S.; Sadamori, M.;
Fujimoto, T.; Yamamoto, I. Angew. Chem. 2003, 115, 3505-3507.
(9) (a) Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus, P.
J., Jr.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638-11643. (b)
Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J. Chem. Commun. 2003,
1781-1785. (c) Vasbinder, M. M.; Jarvo, E. R.; Miller, S. J. Angew. Chem.,
Int. Ed. 2001, 40, 2824-2827 and references therein.
(11) In contrast to the acetylation with 2 equiv of pyridine (Table 1,
entry 2), the solvent environment is less polar, thereby accelerating the
reaction: see refs 2b and 10.
(10) Guibe-Jampel, E.; Le Corre, G.; Wakselman, M. Tetrahedron Lett.
1979, 20, 1157-1160.
946
Org. Lett., Vol. 6, No. 6, 2004

1-propanol-d1 and 2-propanol-d1 were conducted. Primary
kinetic isotope effects under basic conditions in the range
1.1-1.9 reflect the impact of the deprotonation step on the
reaction rate. Since primary kinetic isotope effects of >2
have to be expected for general base catalysis and of 1-1.5
for nucleophilic catalysis,12 no stringent conclusion about
the operating mechanism can be drawn.
employed. CH2Cl2 as a nonpolar solvent should allow
efficient intra- and intermolecular hydrogen bonding. Acetyl
group migrations could be avoided by careful temperature
control (0 °C) during the reaction.16 By using K2CO3 as
auxiliary base the results of Yoshida et al. could be
reproduced with minor deviations due to slightly varied
reaction conditions (Table 2, entry 1). However, AcCl gave,
Although acetyl cyanide is prone to homodimerization
under basic conditions,13 it can be used as an acetyl transfer
reagent under nucleophilic catalysis.14 Acetyl cyanide differs
from acetic anhydride and acetyl chloride, since the released
anion CN- represents a rather strong base with a pKa of 9.4
for the conjugated acid. As can be seen from Table 1, acetyl
Table 2. Product Distribution and Isolated Yields of the
Acetylation of Octyl â-D-Glucopyranoside under Varying
Conditions
Table 1. Experimental Half-Lives (t1/2 (min)) and Primary
Kinetic Isotope Effects (kD/kH in Parentheses) for the Reaction
of 1- and 2-Propanol with Three Different Acetylating Agents
conditionsa
Ac2O, K2CO3
Ac2O, pyridine
AcCN, K2CO3
AcCN, pyridine
AcCl, K2CO3
AcCl, pyridine
2-OAc 3-OAc 4-OAc 6-OAc yieldb
basea
Ac2O
AcCN
AcCl
1
2
3
4
5
6
7
8
0.50
0.57
0.15
0.16
0.17
0.12
0.44
0.48
0.46
0.23
0.08
0.08
0.03
0.03
0.25
0.18
0.04
0.20
0.77
0.76
0.74
0.85
0.25
0.34
47%
60%
44%
46%
44%
73%
59%
83%
1
2
3
4
5
6
1-propanol K2CO3
pyridine
3.2 (1.6) 1.3 (1.9)
35 (1.8)
11 (1.4)
30 (1.6)
18 (1.3)
1.0 (1.4)
1.5 (1.4)
n.d. (1.3)c 200 (1.3)
<0.2 (n.d.)b
none
33 (1.4)d
0.06
0.06
2-propanol K2CO3
pyridine 120 (1.6)
none 350 (1.3)
32 (1.1)
n.d. (1.2)c 120 (0.9)d
<0.2 (n.d.)b
AcOCO2tBu, K2CO3
AcOCO2tBu, pyridine
a 4 equiv of K2CO3 and 2 equiv of pyridine. b n.d. ) not determined;
a All reactions were performed in the presence of 5 mol % of DMAP
the reaction was too fast for an accurate determination of t1/2 (100%
conversion after 2 min). c The homodimerization of acetyl cyanide is faster
than the acetylation (the conversion does not exceed 40% in any case).
d Autocatalysis of the released HCl is assumed.
and 1 equiv. of auxiliary base. b The yield refers to isolated monoacetylated
sugars.
albeit in moderate yield, mainly the 6-acetate (entry 5). Since
both reactions have been conducted under the same reaction
conditions, the altered regioselectivity has to be attributed
to the counterions, assuming that a quaternary ammonium
salt (structure A, Figure 1) represents the reactive species in
both cases.
cyanide rapidly reacts with 1-propanol independent from the
base in use. Due to the unwanted homodimerization, the
preparative potential is narrowed; however, it underlines the
important role of the counterion for DMAP-catalyzed acety-
lations.
This effect has also been observed when pyridine was used
as a homogeneous base (entries 2 and 6). The reaction with
AcCl is fast and gives monoacetylated sugars in 73% yield,
with predominant formation (85%) of the 6-acetate. A
possible explanation for this phenomenon is given in Figure
2. In contrast to the chloride ion, the acetate ion can interact
This marked counterion effect prompted us to (re)-
investigate the reaction with a more complex substrate,
namely octyl â-D-glucopyranoside. Monosaccharidic glyco-
sides are endowed with three secondary hydroxyl groups of
comparable reactivity and one primary, slightly more reactive
OH group. Selective acetylation of the primary hydroxyl
group is supposed to be predominant.15 However, as dem-
onstrated by Yoshida et al. in a comprehensive study,1a the
hydroxyl groups at C-3 and C-4 preferentially react with
Ac2O in CHCl3 in the presence of DMAP and K2CO3 as
auxiliary base.
In our experiments, to accurately determine the product
distribution, mild (0 °C) reaction conditions and a stoichio-
metric amount (1.0 equiv) of the acetylating agents were
Figure 2. Directed acetylation of secondary OH groups.
(12) (a) Hubbard, P.; Brittain, W. J. J. Org. Chem. 1998, 63, 677-683.
(b) Butler, A. R.; Gold, V. J. Chem. Soc. 1961, 4362-4367. (c) Johnson,
S. L. J. Am. Chem. Soc. 1962, 84, 1729-1734.
(13) Tate, B. E.; Bartlett, P. D. J. Am. Chem. Soc. 1956, 78, 5575-
5580.
(14) Loukaci, A.; Kayser, O.; Bindseil, K.-U.; Siems, K.; Frevert, J.;
Abreu, P. M. J. Nat. Prod. 2000, 63, 52-56.
(15) Haines, A. H. AdV. Carbohydr. Chem. Biochem. 1976, 33, 11-
109.
with two OH groups by forming a noncovalently linked
cyclic transition state. The primary OH group directs the
deprotonation toward the secondary OH groups at positions
3 and 4. The deprotonation of the secondary OH groups in
Org. Lett., Vol. 6, No. 6, 2004
947

proximity is thereby facilitated. This is not possible for
chloride as counterion. To support this notion, AcCN was
submitted to the reaction with octyl â-D-glucopyranoside.
Similar to the chloride ion, cyanide should not be able to
direct the acetylation toward the secondary OH groups. A
pronounced selectivity for the primary OH group was found
under the applied conditions (entries 4 and 5). Contrarily,
acetyl tert-butyl carbonate,17 despite steric demands of the
released tert-butyl carbonate anion, preferentially acetylates
the secondary OH groups at position 3 and 4 with a ratio of
3 to 1 (entry 7).
A prerequisite for the participation of the counterion
consists of the formation of a quaternary ammonium salt.
Depending on the nature of the acylating agent and the
tertiary amine the formation of such a species is possible,
thereby enabling nucleophilic catalysis. Brittain et al. showed
by 1H NMR experiments that quinuclidine, though to a lesser
extent than DMAP, can give quaternary ammonium salts.12a
Pyridine, however, as a rather poor nucleophile does not give
such a reactive intermediate with Ac2O. By using the latter
as catalyst and auxiliary base (1.05 equiv), the reaction with
Ac2O was slow and the 6-acetate was formed as the major
product, indicating a general base catalysis of pyridine. By
using quinuclidine as catalyst (0.05 equiv), K2CO3 as
auxiliary base (1 equiv), and Ac2O as reagent the product
distribution was comparable to that obtained with DMAP
with 3- and 4-acetates as major products.
In the present study we have shown that the rate and the
selectivity of an acetylation reaction can be controlled by
the counterion of the acetylating agent under nucleophilic
catalysis. The team play of reagent, catalyst, and auxiliary
base is responsible for the outcome of the reaction. Further
studies dealing with other functional (e.g. chiral) counterions
will be reported in due course.
Acknowledgment. Prof. H. Ho¨nig and Prof. K. Dax are
thanked for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and selected spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) This was confirmed by 1H NMR monitoring of the reaction in
CDCl3.
(17) Yamamoto, Y.; Tarbell, D. S. J. Org. Chem. 1971, 36, 2954-2956.
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