A catalytic one-step process for the chemo- and regioselective acylation of monosaccharides

Article abstract of DOI:10.1021/ja074882e

An organocatalytic method for the chemo- and regioselective acylation of monosaccharides has been developed. Treatment of octyl β-D-glucopyranoside with isobutyric anhydride in the presence of 10 mol % of a C₂- symmetric chiral 4-pyrrolidinopyridine catalyst (1) at -50°C gave the 4-O-isobutyryl derivative as the sole product in 98% yield. Thus, chemoselective acylation, favoring a secondary hydroxyl group in the presence of a free primary hydroxyl group, and regioselective acylation, favoring one of three secondary hydroxyl groups, took place with perfect selectivity. A competitive acylation between octyl β-D-glucopyranoside and a primary alcohol (2-phenylethanol) with 1.1 equiv of isobutyric anhydride in the presence of 1 gave the 4-O-isobutyrate of octyl β-D-glucopyranoside with 99% regioselectivity in 98% yield, which indicates that acylation of the secondary hydroxyl group at C(4) of the carbohydrate proceeds in an accelerative manner. A possible mechanism, involving multiple hydrogen-bonding between 1 and the monosaccharide, is proposed for the chemo- and regioselective acylation.

Full text of DOI:10.1021/ja074882e

Published on Web 09/29/2007
A Catalytic One-Step Process for the Chemo- and
Regioselective Acylation of Monosaccharides
Takeo Kawabata,* Wataru Muramatsu, Tadashi Nishio, Takeshi Shibata, and
Hartmut Schedel
Contribution from the Institute for Chemical Research, Kyoto UniVersity,
Uji, Kyoto 611-0011, Japan
Received July 3, 2007; E-mail: kawabata@scl.kyoto-u.ac.jp
Abstract: An organocatalytic method for the chemo- and regioselective acylation of monosaccharides has
been developed. Treatment of octyl â-D-glucopyranoside with isobutyric anhydride in the presence of 10
mol % of a C -symmetric chiral 4-pyrrolidinopyridine catalyst (1) at -50 °C gave the 4-O-isobutyryl derivative
2
as the sole product in 98% yield. Thus, chemoselective acylation, favoring a secondary hydroxyl group in
the presence of a free primary hydroxyl group, and regioselective acylation, favoring one of three secondary
hydroxyl groups, took place with perfect selectivity. A competitive acylation between octyl â-D-glucopyra-
noside and a primary alcohol (2-phenylethanol) with 1.1 equiv of isobutyric anhydride in the presence of 1
gave the 4-O-isobutyrate of octyl â-D-glucopyranoside with 99% regioselectivity in 98% yield, which indicates
that acylation of the secondary hydroxyl group at C(4) of the carbohydrate proceeds in an accelerative
manner. A possible mechanism, involving multiple hydrogen-bonding between 1 and the monosaccharide,
is proposed for the chemo- and regioselective acylation.
Introduction
C(4) of octyl R-D-glucopyranoside with 61% selectivity with
an acetic anhydride-DMAP system, where diacylation was
Carbohydrates play key roles in intercellular processes,
including infection, metastasis, differentiation, regulation of
signaling, and so on. In order to clarify the mechanisms of
these events and to develop new therapeutics, chemical synthesis
of carbohydrates is indispensable. However, synthetic methods
leading to carbohydrates have been relatively unexplored.
Multistep protection/deprotection procedures are usually required
for their synthesis because of the lack of a direct method for
the chemo- and regioselective manipulation of one of the
minimized by the use of less (0.70 equiv) acetic anhydride.6
Recently, Griswold and Miller reported an excellent approach
to the selective introduction of an acetyl group at a secondary
hydroxyl group of octyl â-D-glucopyranoside using peptide-
1
7
based chiral catalysts. Moderately selective 4-O-acylation has
been achieved in a ratio of 22:58:11:9 for 6-O-, 4-O-, 3-O-,
and 2-O-acylate, respectively, without the formation of diacy-
lates. Here we report an organocatalytic one-step procedure for
the chemo- and regioselective acylation of a secondary hydroxyl
2
multiple hydroxyl groups of carbohydrates. Selective acylation
8
of a primary hydroxyl group in the presence of three secondary
hydroxyl groups of octyl â-D-glucopyranoside has been achieved
with ∼100% chemoselectivity by enzymatic processes; however,
concomitant diacylation was unavoidable.3,4 Recently, Kattnig
and Albert reported a convenient method for the selective
monoacylation of octyl â-D-glucopyranoside with a typical
acylation catalyst, 4-(dimethylamino)pyridine (DMAP), and
group of monosaccharides. With an organocatalyst, acylation
of the secondary hydroxyl group at C(4) of octyl â-D-
glucopyranoside proceeded with up to >99% selectivity in the
presence of a primary hydroxyl group at C(6) and two other
secondary hydroxyl groups at C(2) and C(3) (Figure 1a).
Competitive acylation between the primary and secondary
hydroxyl groups usually takes place chemoselectively at the
acetyl chloride to give the 6-O-acetate with 85% selectivity in
9
primary one. On the other hand, with the present catalyst,
5
7
3% yield. Since the primary hydroxyl group at C(6) has the
chemoselective acylation, favoring of a secondary hydroxyl
group, and regioselective acylation, favoring one of three
secondary hydroxyl groups, took place with perfect selectivity.
The same molecular transformation could be achieved alterna-
highest intrinsic reactivity, the selective introduction of an acyl
group at C(6)-OH of carbohydrates is a reasonable conse-
quence. On the other hand, chemoselective acylation of a
secondary hydroxyl group in the presence of a primary hydroxyl
group is much more difficult. Yoshida and co-workers reported
the chemoselective acylation of a secondary hydroxyl group at
(
6) (a) Kurahashi, T.; Mizutani, T.; Yoshida, J. J. Chem. Soc., Perkin Trans.
1
1999, 465. (b) Kurahashi, T.; Mizutani, Tadashi.; Yoshida, J. Tetrahedron
2002, 58, 8669.
(
(
(
(
1) Doores, K. J.; Gamblin, D. P.; Davis, B. G. Chem.-Eur. J. 2006, 12, 656.
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(7) Griswold, K. S.; Miller, S. J. Tetrahedron 2003, 59, 8869.
(8) Site-selective acylation of erythromycin has recently been developed. See:
Lewis, C. A.; Miller, S. J. Angew. Chem., Int. Ed. 2006, 45, 5616.
(9) We recently reported regioselective acylation of 6-O-protected octyl â-D-
glucopyranosides by DMAP catalysis. See: Muramatsu, W.; Kawabata,
T. Tetrahedron Lett. 2007, 48, 5031.
1
989, 934.
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12890
9
J. AM. CHEM. SOC. 2007, 129, 12890-12895
10.1021/ja074882e CCC: $37.00 © 2007 American Chemical Society

Organocatalytic Selective Acylation of Monosaccharides
A R T I C L E S
Figure 1. (a) Catalytic one-step process and (b) conventional protection/
deprotection procedure for the preparation of octyl 4-O-isobutyryl-â-D-
glucopyranoside.
Figure 3. Design and structure of catalysts.
drates.12 The notion that tryptophan can be used as a carbohy-
drate recognition site is also suggested by the fact that two
tryptophan moieties are highly preserved in the substrate-
recognition site of a family of â-glucosidases. On the basis
of this hypothesis, we designed C2-symmetric chiral PPYs 1
and 2, each having two identical side chains, consisting of L-
and D-tryptophan, respectively (Figure 3). Octyl esters in 1
and 2 are employed to enhance the solubility of the catalysts in
nonpolar solvents, where H-bonding effects are stronger. In
addition to 1 and 2, catalysts 3 and 4, consisting of L- and
D-tyrosine, respectively, were also prepared because the phenol
substructure in tyrosine is expected to have properties similar
to those of the indole substructure in tryptophan.
1
3
1
4
Figure 2. Working hypothesis for selective acylation of a secondary
hydroxyl group in the presence of a primary hydroxyl group of a glucose
derivative.
tively by a conventional protection/deprotection procedure
involving five steps in 46% overall yield (Figure 1b).
Catalysts 1-4 were prepared from L-pyroglutamic acid in
six steps (see Supporting Information). The acylation of octyl
â-D-glucopyranoside was investigated with 10 mol % of catalyst
and 1.1 mol equiv of isobutyric anhydride in the presence of
Results and Discussion
We chose 4-pyrrolidinopyridine (PPY) as a catalytic center
for acylation because PPY is known to be one of the most
powerful catalysts for acylation of alcohols.10 It has been well
established that the reactive intermediates generated from PPY
and acid anhydrides are acylpyridinium ions.11 Figure 2 shows
a hypothetical picture of transition state molecular assembly
between an acylpyridinium ion and a carbohydrate substrate,
which enables the selective acylation of a secondary hydroxyl
group in the presence of a primary hydroxyl group. Since the
primary hydroxyl group at C(6) of carbohydrates is the most
reactive, it would preferentially form a H-bond with a H-bond
acceptor (e.g., an amide carbonyl group) of the catalyst. If
additional interactions of the hydroxyl groups at C(2) and/or
C(3) with functionality R of the catalyst are operative, the
combined effects of these attractive interactions would fix the
conformation of the carbohydrate, where the hydroxyl group at
C(4) is in close proximity to the reactive acyl group of the
acylpyridinium ion, so that it would be acylated selectively. We
chose tryptophan as a functional side chain of the catalyst
because its indole substructure is expected to be suitable for
H-bonding as well as for CH-π interaction with carbohydrates.
It has also been reported that pyrrole units (similar to indole
units) were used effectively as recognition sites for carbohy-
1
.5 mol equiv of collidine in toluene at 20 °C (Table 1).
Isobutyric anhydride was chosen as an acylating agent because
it shows high selectivity in the kinetic resolution of racemic
(
12) Vacca, A.; Nativi, C.; Cacciarini, M.; Pergoli, R.; Roelens, S. J. Am. Chem.
Soc. 2004, 126, 16456.
(13) Verdoucq, L.; Morini e´ re, J.; Bevan, D. R.; Esen, A.; Vasella, A.; Henrissat,
B.; Czjzek, M. J. Biol. Chem. 2004, 279, 31796.
(14) Chiral PPY and DMAP analogues have been developed for enantioselective
catalysis. See: (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809.
(
b) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230. (c) Ruble, J. C.;
Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492. (d) Kawabata,
T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169.
(e) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532. (f) Liang,
J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154. (g) Hodous, B.
L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637. (h) Ie, Y.;
Fu, G. C. Chem. Commun. 2000, 119. (i) Spivey, A. C.; Fekner, T.; Spey,
S. E. J. Org. Chem. 2000, 65, 3154. (j) Spivey, A. C.; Maddaford, A.;
Fekner, T.; Redgrave, A. J.; Frampton, C. S. J. Chem. Soc., Perkin Trans.
1
2000, 3460. (k) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem.,
Int. Ed. 2001, 40, 647. (l) Priem, G.; Anson, M. S.; Macdonald, S. J. F.;
Pelotier, B.; Campbell, I. B. Tetrahedron Lett. 2002, 43, 6001. (m) Kim,
K.-S.; Park, S.-H.; Chang, H.-J.; Kim, K. S. Chem. Lett. 2002, 1114. (n)
Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368.
(o) Spivey, A. C.; Zhu. F.; Mitchell, M. B.; Davey, S. G.; Jarvest, R. L. J.
Org. Chem. 2003, 68, 7379. (p) Tabanella, S.; Valanocogne, I.; Jackson,
R. F. W. Org. Biomol. Chem. 2003, 1, 4254. (q) Priem, G.; Pelotier, B.;
Macdonald, S. J. F.; Anson, M. S.; Campbell, I. B. J. Org. Chem. 2003,
68, 3844. (r) Pelotier, B.; Priem, G.; Campbell, I. B.; Macdonald, S. J. F.;
Anson, M. S. Synlett 2003, 679. (s) Kawabata, T.; Stragies, R.; Fukaya,
T.; Fuji, K. Chirality 2003, 15, 71. (t) Kawabata, T.; Stragies, R.; Fukuya,
T.; Nagaoka, Y.; Schedel, H.; Fuji, K. Tetrahedron Lett. 2003, 44, 1545.
(u) Spivey, A. C.; Leese, D. P.; Zhu, F.; Davey, S. G.; Jarvest, R. L.
Tetrahedron 2004, 60, 4513. (v) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc.
2006, 128, 14264.
(
10) Scriven, E. F. V. Chem. Soc. ReV. 1983, 12, 129.
(
11) H o¨ fle, G.; Steglich, W.; Vorbr u¨ ggen, H. Angew. Chem., Int. Ed. Engl. 1978,
1
7, 569.
J. AM. CHEM. SOC.
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VOL. 129, NO. 42, 2007 12891

A R T I C L E S
Kawabata et al.
Table 1. Effects of Catalysts on Regioselectivity of Acylation of
Octyl â-D-Glucopyranoside
implies that acylation of the secondary hydroxyl group at C(4)
would proceed in an accelerative manner (cf. Scheme 1c, below).
a
Having obtained promising results in the regioselective
acylation with 1 in CHCl3, we then investigated the temperature
effects (Table 3). A decrease in the reaction temperature to 0
°C increased the regioselectivity for 4-O-acylation to 98% (entry
2). With a decrease in catalyst loading to 1 mol % in the reaction
at 0 °C, the regioselectivity for 4-O-acylation decreased slightly
to 96% (entry 3). On the other hand, 1 mol % of catalyst was
effective for controlling the regioselectivity of acylation at -20
regioselectivityb
monoacylate
(%)
diacylate
(%)
recovery
(%)
entry
catalyst
6-O:4-O:3-O:2-O
1
2
3
4
5
DMAP
47
84
71
60
80
36:26:26:12
11:86:3:0
20:73:7:0
23:58:19:0
24:59:16:1
22
12
17
21
13
31
2
9
14
6
1
2
3
4
°
C and gave the 4-O-acylate and the 3-O-acylate in a 99:1 ratio
1
7
in a combined yield of 98% (entry 5). The reaction at -50
°C with 10 mol % of 1 showed perfect chemo- and regiose-
lectivity and gave the 4-O-acylate as the sole product in 98%
yield (entry 6). These strong temperature effects may indicate
a
The reactions were carried out with a substrate concentration of 0.08
M. b Regioselectivity (%) among four monoacylates.
Table 2. Effects of Solvents on Regioselectivity of Acylation of
a
q
Octyl â-D-Glucopyranoside with 1
the contribution of a large negative ∆S term for regioselective
acylation, which suggests multiple H-bonding in the transition
state of acylation (cf. Figure 5). Use of acetic anhydride instead
of isobutyric anhydride gave the 4-O-acetate in slightly dimin-
ished regioselectivity of 96% (entry 7). On the other hand, use
of isobutyryl chloride gave totally different results. The acylation
was sluggish (47% yield for monoacylation after 48 h at 0 °C),
and the major product was the 6-O-acylate with 60% regiose-
lectivity (entry 2 vs 8). The results indicate that the counteranion
of the acylpyridinium ion should significantly affect the
selectivity of acylation.
monoacylate
(%)
regioselectivityb
6-O:4-O:3-O:2-O
diacylate
(%)
recovery
(%)
entry
solvent
1
2
3
4
toluene
CHCl3
THF
84
90
51
46
11:86:3:0
4:91:5:0
27:51:22:0
63:12:24:1
12
4
28
26
2
3
16
21
DMF
a
The reaction in entry 1 and the reactions in entries 2-4 were carried
out with a substrate concentration of 0.08 and 0.1 M, respectively.
Regioselectivity (%) among four monoacylates.
Next, we investigated the scope of the regioselective acylation
of various monosaccharides catalyzed by 1. The results are
summarized in Figure 4. Acetylation (R ) CH3) of octyl â-D-
glucopyranoside with 1 mol % of 1 at -20 °C for 24 h gave
the 4-O-acetyl surrogate with 96% regioselectivity in 96% yield
for monoacylation (Figure 4a). Acylation of octyl â-D-thioglu-
copyranoside with isobutyric anhydride or acetic anhydride at
b
alcohols15 and also has a high kcat/kuncat ratio.16 Analysis of the
products was unambiguously performed by comparison with
authentic samples of octyl 6-O-, 4-O-, 3-O-, and 2-O-isobutyryl-
â-D-glucopyranosides, which were independently prepared via
conventional protection/deprotection sequences (see Supporting
Information). With DMAP as catalyst, four monoacylates, the
-
60 °C gave the 4-isobutyryl derivative with 97% regioselec-
tivity (92% yield for monoacylation) or the 4-acetyl derivative
with 95% regioselectivity (99% yield for monoacylation),
respectively (Figure 4b). The acylated thioglycosides are
expected to be used directly for glycosylation because thiogly-
cosides can be used as glycosyl donors. Acylation of octyl
R-D-glucopyranoside with isobutyric anhydride at 20 °C gave
the 4-O-isobutyryl surrogate as a major product but with a
largely diminished selectivity (54% regioselectivity and 75%
yield for monoacylation, Figure 4c). Acylation of octyl â-D-
mannopyranoside with isobutyric anhydride at -50 °C gave the
6
-O-, 4-O-, 3-O-, and 2-O-isobutyrates, were obtained in a ratio
of 36:26:26:12 in a combined yield of 47%, together with 22%
of diacylates and 31% recovery of starting material (entry 1).
Thus, totally random acylation took place by DMAP catalysis.
On the other hand, with C2-symmetric chiral PPYs 1-4, the
secondary hydroxyl group at C(4) was preferentially acylated
58-86% regioselectivity among monoacylates) in the presence
of a free primary hydroxyl group at C(6) (entries 2-5). The
highest selectivity (86%) for 4-O-acylation was observed with
1
8
(
1
, consisting of L-tryptophan.
We then investigated the solvent effects on the regioselectivity
4
-isobutyryl surrogate with 85% regioselectivity in 61% yield
for monoacylation (Figure 4d). Preferable acylation of the
secondary hydroxyl group at C(4) was observed in glucopyra-
nosides and in a mannopyranoside in which C(4)-OH is
of acylation with catalyst 1 (Table 2). CHCl3, THF, and DMF
were investigated in addition to toluene. The polarity of the
solvents roughly correlated with the chemo- and regioselectivity
of acylation. The highest selectivity (91%) for 4-O-acylation
was observed in a less-polar solvent, CHCl3 (entry 2), whereas
acylation of the primary hydroxyl group was predominant (63%)
in polar solvent, DMF (entry 4). The observed solvent effects
indicate that the driving force for selective 4-O-acylation may
involve H-bonding between a substrate and a catalyst and may
not significantly involve CH-π interaction. Another interesting
phenomenon is that a higher ratio of 4-O-acylation is associated
with a higher yield for monoacylation (entries 1-4). This
(
17) Experimental procedure for Table 3, entry 5: Octyl â-D-glucopyranoside
58.5 mg, 0.20 mmol), 1 (1.7 mg, 2.0 µmol), and 2,4,6-collidine (40 µL,
.30 mmol) were dissolved in CHCl (2.0 mL) at 20 °C. After the solution
(
0
3
was cooled at -20 °C, isobutyric anhydride (36 µL, 0.22 mmol) was added.
The resulting mixture was stirred at -20 °C for 24 h. The reaction mixture
was quenched with saturated aqueous NH
4
Cl solution and extracted with
O and brine, dried
over MgSO , filtered, and concentrated in vacuo. The residue was purified
ethyl acetate. The organic layer was washed with H
2
4
2
by SiO column chromatography (ethyl acetate/hexane ) 30:70 to 100:0)
to give a 99:1 mixture of octyl 4-O-isobutyryl-â-D-glucopyranoside and
octyl 3-O-isobutyryl-â-D-glucopyranoside in a combined yield of 98% (71
mg). Identification of the regioisomeric products was unambiguously
performed by the comparison with pure regioisomers prepared indepen-
dently by a conventional protection/deprotection procedure (see Supporting
Information).
(
15) Kawabata, T.; Yamamoto, K.; Momose, Y.; Nagaoka, Y.; Yoshida, H.;
Fuji, K. Chem. Commun. 2001, 2700.
16) Fischer, C. B.; Xu, S.; Zipse, H. Chem.-Eur. J. 2006, 12, 5779.
(18) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc. 1983,
105, 2430.
(
12892 J. AM. CHEM. SOC.
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Organocatalytic Selective Acylation of Monosaccharides
A R T I C L E S
Table 3. Effects of Temperature and Acylating Agents on Regioselectivity of Acylation of Octyl â-D-Glucopyranoside with 1 in CHCl3a
mol %
temp
C)
time
(h)
monoacylate
(%)
regioselectivityb
6-O:4-O:3-O:2-O
diacylate
(%)
recovery
(%)
entry
of 1
(
°
RCOX
1
2
3
4
5
6
7
8
10
10
1
10
1
10
1
10
20
0
0
-20
-20
-50
-20
0
(i-PrCO)2O
(i-PrCO)2O
(i-PrCO)2O
(i-PrCO)2O
(i-PrCO)2O
(i-PrCO)2O
Ac2O
12
12
12
12
24
38
24
48
90
97
97
98
98
98
96
47
4:91:5:0
0:98:2:0
2:96:2:0
0:99:1:0
0:99:1:0
0:>99:<1:0
0:96:4:0
60:35:5:0
4
2
2
0
0
0
4
13
3
0
1
0
0
0
0
19
i-PrCOCl
a
The reactions were carried out with a substrate concentration of 0.1 M. b Regioselectivity (%) among four monoacylates.
Figure 4. Regioselectivity profiles in acylation of carbohydrates with 10 mol % of 1/(RCO)2O/collidine/CHCl3 (1 Mol % of 1 was employed for (a),
RdCH3). R originates in the anhydride, (RCO)2O. The hydroxyl group predominantly acylated is shown as red colored OH, and the regioselectivity is
shown as a percentage among the four monoacylates. Yields shown are those for monoacylation. The reactions were carried out at the temperature and for
the time indicated in the parentheses.
equatorially oriented. On the other hand, acylation of octyl â-D-
galactopyranoside, whose C(4)-OH is axially oriented, took
place predominantly at the primary hydroxyl group at C(6)
Scheme 1. Mechanistic Investigation into Regioselectivity of
Acylation of Octyl â-D-Glucopyranosidea
(Figure 4e). This indicates that equatorial orientation is crucial
for the selective acylation of C(4)-OH.
We then investigated the mechanistic aspects to determine
the origin of the regioselectivity of acylation catalyzed by 1. It
might be supposed that the acylation of C(4)-OH is the result
of migration of the 6-O-acylate into the 4-O-acylate. To examine
this possibility, the 6-O-isobutyrate of octyl â-D-glucopyranoside
was independently prepared (see Supporting Information),# and
was treated under reaction conditions similar to those in entry
2
in Table 3, except that isobutyric anhydride was absent
(Scheme 1a). The 6-O-isobutyrate was recovered in 99% yield,
and no migration to the 4-O-isobutyrate was detected. This
clearly indicates that acylation of a secondary hydroxyl group
at C(4) took place directly under the influence of the catalyst.
Since we hypothesized that H-bonding between the primary
hydroxyl group at C(6) of the carbohydrate and the catalyst is
critical for regioselective acylation, the 6-OMe derivative was
prepared and treated under reaction conditions similar to those
in entry 4 in Table 3 (Scheme 1b). The 4-O-, 3-O-, and 2-O-
isobutyrates were obtained in a ratio of 31:67:2 in a combined
yield of 95%. Upon treatment of octyl â-D-glucopyranoside with
isobutyric anhydride in the presence of 10 mol % of DMAP in
CHCl3 at -20 °C, nonselective acylation took place to give
a
(a) Rearrangement of octyl 6-O-isobutyryl-â-D-glucopyranoside into
the 4-O-isobutyrate in the presence of 1 was not observed at all. (b)
Nonselective acylation of the 6-OMe derivative took place with 1. (c)
Competitive acylation between octyl â-D-glucopyranoside and 2-phenyle-
thanol in the presence of 1 gave the 4-O-isobutyrate of octyl â-D-
glucopyranoside with 99% regioselectivity. (d) Competitive acylation
between octyl â-D-glucopyranoside and racemic 1-phenyethanol in the
presence of 1 gave the 4-O-isobutyrate of octyl â-D-glucopyranoside with
6
-O-, 4-O-, 3-O-, and 2-isobutyrate in a ratio of 38:23:38:1 in
a combined yield of 69%. Accordingly, 1 behaves like a
nonselective catalyst, such as DMAP, when the primary
hydroxyl group at C(6) is protected. These results indicate that
H-bonding between the primary hydroxyl group at C(6) and
the catalyst is critical for the regioselectivity caused by 1 (cf.
Figure 5).
>
99% regioselectivity.
The effects of the functionality of the catalysts on the
regioselectivity of the acylation were investigated (Table 4).
J. AM. CHEM. SOC.
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VOL. 129, NO. 42, 2007 12893

A R T I C L E S
Kawabata et al.
Table 4. Effects of Catalysts on Regioselectivity of Acylation of
a
Octyl â-D-Glucopyranoside
monoacylate
(%)
regioselectivityb
6-O:4-O:3-O:2-O
diacylate
(%)
recovery
(%)
entry
catalyst
1
2
3
4
5
1
97
69
74
62
61
0:98:2:0
2
20
15
13
21
0
8
4
22
14
c
c
c
5
6
7
14:60:26:0
7:65:28:0
13:66:20:1
33:24:43:0
DMAP
a
The reactions were carried out with a substrate concentration of 0.1
M. b Regioselectivity (%) among four monoacylates. c Catalyst structures:
Figure 5. Proposed transition state model for the chemo- and regioselective
acylation of octyl â-D-glycopyranoside catalyzed by 1.
>
99% regioselectivity in 99% yield for monoacylation. The
existence of the primary or secondary alcohol did not affect
the selective acylation of the carbohydrate at all, indicating that
acylation of the secondary hydroxyl group at C(4) of the
carbohydrate with 1 proceeds in an accelerative manner. The
C2-symmetric structure of catalyst 1 seems to be important, since
approach of the carbohydrate substrate from the face of the C(2′)
side chain of the catalyst would lead to the transition state
structure shown in Figure 5, which is supposed to be identical
with that caused by the substrate approach from the face of the
C(5′) side chain. This notion was supported by the results of
the corresponding reaction with non-C2-symmetric catalyst 7
With catalyst 5 or 6, in which an indole substructure of 1 was
replaced by an N-methylindole or by 2-naphthyl, respectively,
acylation at the secondary hydroxyl group at C(4) was still
predominant, but with decreased regioselectivity (entries 2 and
3
). 4-O-Acylation took place predominantly throughout the
(Table 4, entry 4). Acylation of octyl â-D-glucopyranoside with
reactions with catalysts 1-6, which suggests that two amide
carbonyl groups at C(2′) and C(5′), common functionality in
these catalysts, seems essential for the selective acylation at
C(4)-OH. Comparison of the regioselectivity of acylation
catalyzed by 1 with that of acylation catalyzed by 5 indicates
that the indole NH of 1 seems to participate in increasing the
regioselectivity of acylation at C(4)-OH. On the basis of all
of these observations, we propose a possible transition state
assembly for the regioselective acylation of octyl â-D-glucopy-
ranoside with 1 (Figure 5). Since the primary hydroxyl group
at C(6) is the most reactive in the carbohydrate substrate, it
would preferentially form a H-bond with an amide carbonyl
that is likely to be the strongest H-bond accepter in the
acylpyridinium ion. As the result of the H-bonding, the indole
NH of the catalyst locates near C(3)-OH of the carbohydrate,
resulting in the formation of an additional H-bond between them.
The cooperative effects of the multiple H-bonding would fix
the conformation of the substrate at the transition state for
acylation, where the hydroxyl group at C(4) is in close proximity
to the reactive carbonyl group of the acylpyridinium ion,
resulting in the selective acylation of C(4)-OH in an accelera-
tive manner. The notion of accelerative acylation is supported
experimentally by the competitive acylation between octyl â-D-
glucopyranoside and a primary alcohol or a secondary alcohol
7
gave the 4-O-acylate as the major product but with decreased
regioselectivity of 66% (entry 1 vs 4). A substrate approaching
from the â-face (the face of the C(2′) side chain) of the
acylpyridinium ion generated from 7 would undergo selective
acylation at C(4)-OH, while a substrate approaching from the
less-hindered R-face (the C(5′) side chain is absent in 7) would
undergo nonselective acylation. As the result, the 4-O-acylate
was obtained as the major product but with diminished
regioselectivity in the acylation catalyzed by 7.
The transition state assembly shown in Figure 5 may
reasonably explain the difference in the regioselectivity profiles
of acylation of monosaccharides. In the case of octyl R-D-
glucopyranoside (Figure 4c), a transition state assembly as
shown in Figure 5 may be possible; however, it is somewhat
disfavored by the unfavorable interaction between an R-octyloxy
substituent at C(1) of the carbohydrate and the acylpyridinium
ion. Therefore, acylation of C(4)-OH of octyl R-D-glucopyra-
noside took place predominantly but with the diminished
regioselectivity of 54%. One difference between octyl â-D-
glucopyranoside (Figure 4a) and octyl â-D-mannopyranoside
(Figure 4d) is the orientation of the hydroxyl group at C(2).
Since the orientation of the hydroxyl group at C(2) does not
seem to significantly affect the transition state assembly, selec-
tive 4-O-acylation is also expected for the mannose derivative.
On the other hand, a transition state assembly as shown in Figure
5 is not possible with carbohydrates that have an axial hydroxyl
group at C(4). Accordingly, acylation of the galactose derivative
proceeded in a totally different manner and gave the 6-O-acylate
as a major product (Figure 4e), because of the intrinsically high
reactivity of the primary hydroxyl group of the carbohydrate.
(Scheme 1c,d). When a 1:1 mixture of octyl â-D-glucopyrano-
side and 2-phenylethanol was treated under conditions similar
to those in entry 4 in Table 3, the 4-O-isobutyrate of octyl â-D-
glucopyranoside was obtained with 99% regioselectivity in 98%
yield for monoacylation. Similary, competitive acylation be-
tween octyl â-D-glucopyranoside and racemic 1-phenylethanol
gave the 4-O-isobutyrate of octyl â-D-glucopyranoside with
12894 J. AM. CHEM. SOC.
9
VOL. 129, NO. 42, 2007

Organocatalytic Selective Acylation of Monosaccharides
A R T I C L E S
Conclusions
Acknowledgment. This work is supported by a Grant-in-Aid
for Scientific Research (A) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Organocatalytic chemo- and regioselective acylation of
monosaccharides has been developed. The present method
enables direct functionalization of one of the multiple hydroxyl
groups of octyl â-D-glucopyranosides with >99% selectivity
and in 98% yield. Accordingly, the development of the present
process greatly reduces the synthetic steps toward carbohydrates.
It also provides a novel strategy for the preferential function-
alization of a secondary hydroxyl group in the presence of a
free primary hydroxyl group.
Supporting Information Available: Preparation and charac-
terization of 1-7 and of octyl 6-O-, 4-O-, 3-O-, and 2-O-
isobutyryl-â-D-glucopyranosides. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA074882E
J. AM. CHEM. SOC.
9
VOL. 129, NO. 42, 2007 12895