Functional group tolerance in organocatalytic regioselective acylation of carbohydrates

Article abstract of DOI:10.1021/jo901569v

(Chemical Equation Presented) Organocatalytic regioselective acylation of mono- and disaccaharides with various functionalized acid anhydrides has been developed. Acylation of octyl β-D-glucopyranoside with acid anhydrides derived from R-amino acids, cinnamic acid, and gallic acid took place at C(4)-OH with 67-94% regioselectivity in the presence of catalyst 1. Regioselective acylation of disaccharides with functionalized acid anhydrides was also achieved with 78-94% selectivity. Especially, a disaccharide with seven free hydroxy groups (X = OH, R′ = H) underwent acylation at C(4)-OH with 78% regioselectivity in the presence of 1. Thus, functional group tolerance in the regioselective acylation catalyzed by 1 was found to be high.

Full text of DOI:10.1021/jo901569v

pubs.acs.org/joc
SCHEME 1. Organocatalytic One-Step Process (a) and Conven-
tional Protection/Deprotection Procedure(b) for the Preparation of
Functional Group Tolerance in Organocatalytic
Regioselective Acylation of Carbohydrates
Octyl 4-O-Isobutyryl-β-D-glucopyranoside
Yoshihiro Ueda, Wataru Muramatsu, Kenji Mishiro,
Takumi Furuta, and Takeo Kawabata*
Institute for Chemical Research, Kyoto University, Uji,
Kyoto 611-0011, Japan
kawabata@scl.kyoto-u.ac.jp
Received July 28, 2009
acylation of carbohydrates has been know to often proceed
on the primary hydroxy group at C-6.3 On the other hand,
chemoselective acylation of a secondary hydroxy group in
the presence of a primary hydroxy group is much more
difficult. Yoshida and co-workers reported the chemoselec-
tive acylation of a secondary hydroxy group at C(4) of octyl
R-D-glucopyranoside in 61% selectivity with an acetic anhy-
dride-DMAP system, where diacylation was minimized by
the use of less (0.70 equiv) acetic anhydride.4 Griswold and
Miller reported an excellent approach to the selective intro-
duction of an acetyl group at a secondary hydroxy group of
octyl β-D-glucopyranoside by using peptide-based chiral
catalysts.5 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. Recently, Onomura and co-workers reported Sn(IV)-
catalyzed highly regioselective benzoylation of monosac-
charides.6 We also reported an organocatalytic one-step
procedure for the chemo- and regioselective acylation of a
secondary hydroxy group of monosaccharides.7 With orga-
nocatalyst 1,8 acylation of the secondary hydroxy group
at C(4) of octyl β-D-glucopyranoside proceeded in up to
>99% selectivity in the presence of a primary hydroxy group
at C(6) and two other secondary hydroxy groups at C(2)
and C(3) (Scheme 1a). The same molecular transformation
could be alternatively achieved by conventional protection/
deprotection procedure via five steps in 46% overall yield
(Scheme 1b). Thus, development of this process is expected
to minimize the number of steps for functionalization of
Organocatalytic regioselective acylation of mono- and
disaccaharides with various functionalized acid anhydrides
has been developed. Acylation of octyl β-D-glucopyrano-
side with acid anhydrides derived from R-amino acids,
cinnamic acid, and gallic acid took place at C(4)-OH with
67-94% regioselectivity in the presence of catalyst 1.
Regioselective acylation of disaccharides with functiona-
lized acid anhydrides was also achieved with 78-94%
selectivity. Especially, a disaccharide with seven free
hydroxy groups (X = OH, R0 = H) underwent acylation
at C(4)-OH with 78% regioselectivity in the presence of 1.
Thus, functional group tolerance in the regioselective
acylation catalyzed by 1 was found to be high.
Nonenzymatic regioselective functionalization of carbo-
hydrates has been a fundamental challenge in current or-
ganic synthesis.1 Kattnig and Albert reported a convenient
method for the selective monoacylation of octyl β-D-gluco-
pyranoside with a typical acylation catalyst, 4-dimethylami-
nopyridine (DMAP), and acetyl chloride to give the 6-O-
acetate in 85% selectivity in 73% yield.2 Since the primary
hydroxy group at C-6 has the highest intrinsic reactivity, the
selective introduction of an acyl group at C(6)-OH of
carbohydrates is a reasonable consequence. Enzymatic
(3) (a) Therisod, M.; Klibanov, A. M. J. Am. Chem. Soc. 1987, 109, 3977–
3981. (b) Riva, S.; Chopineau, J.; Kieboom, A. P. G.; Klivanov, A. M. J. Am.
€
Chem. Soc. 1988, 110, 584–589. (c) Bjorkling, F.; Godtfredsen, S. E.; Kirk, O.
J. Chem. Soc. Chem. Commun. 1989, 934–935.
(4) (a) Kurahashi, T.; Mizutani, T.; Yoshida, J. J. Chem. Soc., Perkin
Trans. 1 1999, 465–473. (b) Kurahashi, T.; Mizutani, T.; Yoshida, J.
Tetrahedron 2002, 58, 8669–8677.
(5) Griswold, K. S.; Miller, S. J. Tetrahedron 2003, 59, 8869–8875.
(6) Demizu, Y.; Kubo, Y.; Miyoshi, H.; Maki, T.; Matsumura, Y.;
Moriyama, N.; Onomura, O. Org. Lett. 2008, 10, 5075–5077.
(7) Kawabata, T.; Muramatsu, W.; Nishio, T.; Shibata, T.; Schedel, H.
J. Am. Chem. Soc. 2007, 129, 12890–12895.
† Dedicated to Prof. Kaoru Fuji on the occasion of his 70th birthday.
(1) For an example, see: Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Kulkarni,
S. S.; Huang, Y.-W.; Lee, C.-C.; Chang, K.-L.; Hung, S.-C. Nature 2007, 446,
896–899.
(8) Catalyst 1 is commercially available from Wako Pure Chemical
Industries, Ltd.
(2) Kattnig, E.; Albert, M. Org. Lett. 2004, 6, 945–948.
8802 J. Org. Chem. 2009, 74, 8802–8805
Published on Web 10/15/2009
DOI: 10.1021/jo901569v
r
2009 American Chemical Society

Ueda et al.
JOCNote
TABLE 1. Regioselectivity Profiles of Acylation of 2 with Anhydride 3a
regioselectivityb
mono-
entry catalyst solvent acylate (%)
6-O:4-O:
3-O:2-O
diacylate
(%)
FIGURE 1. Catalytic regioselective introduction of functionalized
acyl groups into carbohydrates.
1
2
3
4
5
6
DMAP CHCl3
38
81
68
70
44
45
43:19:37:1
21:73:6:0
29:58:13:0
20:73:5:1
44:28:21:8
61:10:19:10
23
12
15
13
30
30
1
4
1
1
1
CHCl3
CHCl3
toluene
THF
carbohydrates. However, this protocol has been limited to
the acylation of monosaccharides with nonfunctionalized
acid anhydrides such as isobutyric anhydride and acetic
anhydride. We therefore examined the functional group
tolerance in the present process. Here, we describe the scope
of the organocatalytic regioselective acylation of mono- and
disaccaharides with various functionalized acid anhydrides
(Figure 1).
DMF
aThe reactions were carried out with a substrate concentration of 0.1
M. bPercent regioselectivity among four monoacylates.
Carbohydrates are involved in a wide range of intercellular
processes including infection, metastasis, differentiation,
and regulation of signaling, and so on.9 To clarify the mecha-
nisms of these events and to develop new therapeutics,
chemical synthesis of carbohydrates is indispensable. How-
ever, multistep protection/deprotection procedures are usu-
ally required for their synthesis because of the lack of a direct
method for the chemo- and regioselective manipulation of
one of the multiple hydroxy groups of carbohydrates.10
However, we have developed an organocatalytic one-step
procedure for the chemo- and regioselective acylation of
glucose derivatives.7 We further examined regioselective
introduction of functionalized acyl groups into various
carbohydrates. At first, acylation of octyl β-D-glucopyrano-
side (2) with acid anhydride 3 derived from phenylalanine
was examined (Table 1). The expected products, sugar-
amino acid hybrids, have been known to show ACE inhibitory
activity and also to be candidates for an artificial sweetner.11
Acid anhydride 3 was prepared from N-Cbz-phenylalanine
and triphosgene. Regioselectivity profiles of acylation of 2 with
DMAP and catalysts 1 and 4 were investigated.12,13 Treatment
of 2 with 10 mol % of DMAP in CHCl3 at 20 °C for 24 h gave
four monoacylates, the 6-O-, 4-O-, 3-O-, and 2-O-acylates, in a
ratio of 43:19:37:1 in a combined yield of 38% together with
23% of diacylates (entry 1). Thus, totally random acylation
took place by DMAP catalysis. In contrast, glucose derivative
2 underwent acylation preferentially on the secondary hydroxy
group at C(4) (58-73% regioselectivity among monoacylates)
even in the presence of a free primary hydroxy group at C(6) by
treatment with C2-symmetric chiral PPYs 1 and 4 (entries 2
and 3). As previously observed in the acylation of 2 with
isobutyric anhydride,7 catalyst 1 with an L-tryptophan sub-
structure showed better selectivity than catalyst 4 with a
D-tryptophan substructure. Analysis of the products was un-
ambiguously performed by careful investigation of 1H NMR
and COSY spectrum of the mixture of four monoacylates with
an authentic sample of the pure 4-O-acylate of 2, which was
obtained via conventional protection/deprotection sequences
(see Supporting Information).
(9) Doores, K. J.; Gamblin, D. P.; Davis, B. G. Chem.-Eur. J. 2006, 12,
656–665.
(10) Bartolozzi, A.; Seeberger, P. H. Curr. Opin. Struct. Biol. 2001, 11,
587–592.
(11) (a) Lohith, K.; Vijayakumar, G. R.; Somashekar, B. R.; Divakar, S.
Eur. J. Med. Chem. 2006, 41, 1059–1072. (b) Tamura, M.; Shoji, M.;
Nakatsuka, T.; Kinomura, K.; Okai, H.; Fukui, S. Agric. Biol. Chem.
1985, 49, 2579–2586.
(12) For our previous reports on chiral PPY analogues, see: (a) Kawa-
bata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119,
3169–3170. (b) Kawabata, T.; Yamamoto, K.; Momose, Y.; Nagaoka, Y.;
Yoshida, H.; Fuji, K. Chem. Commun. 2001, 2700–2701. (c) Kawabata, T.;
Stragies, R.; Fukaya, T.; Fuji, K. Chirality 2003, 15, 71–76. (d) Kawabata, T.;
Stragies, R.; Fukaya, T.; Nagaoka, Y.; Schedel, H.; Fuji, K. Tetrahedron
Lett. 2003, 44, 1545–1548.
(13) For chiral PPY and DMAP analogues for asymmetric synthesis, see:
(a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809–1810. (b) Ruble, J.
C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230–7231. (c) Ruble, J. C.; Latham, H.
A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492–1493. (d) Ruble, J. C.; Fu, G.
C. J. Am. Chem. Soc. 1998, 120, 11532–11533. (e) Naraku, G.; Shimamoto,
N.; Hanamoto, T.; Inanaga, J. Enantiomer 2000, 5, 135–138. (f) Ie, Y.; Fu, G.
C. Chem. Commun. 2000, 119–120. (g) Spivey, A. C.; Fekner, T.; Spey, S. E. J.
Org. Chem. 2000, 65, 3154–3155. (h) Spivey, A. C.; Maddaford, A.; Fekner,
T.; Redgrave, A. J.; Frampton, C. S. J. Chem. Soc., Perkin Trans. 1 2000,
3460–3468. (i) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int.
Ed. 2001, 40, 234–236. (k) Priem, G.; Anson, M. S.; Macdonald, S. J. F.;
Pelotier, B.; Campbell, I. B. Tetrahedron Lett. 2002, 43, 6001–6003. (k) Kim,
K.-S.; Park, S.-H.; Chang, H.-J.; Kim, K. S. Chem. Lett. 2002, 1114–1115. (l)
Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368–
13369. (m) Tabanella, S.; Valanocogne, I.; Jackson, R. F. W. Org. Biomol.
Chem. 2003, 1, 4254–4261. (n) Priem, G.; Pelotier, B.; Macdonald, S. J. F.;
Anson, M. S.; Campbell, I. B. J. Org. Chem. 2003, 68, 3844–3848. (o)
Pelotier, B.; Priem, G.; Campbell, I. B.; Macdonald, S. J. F.; Anson, M. S.
Synlett 2003, 679–683. (p) Spivey, A. C.; Leese, D. P.; Zhu, F.; Davey, S. G.;
Jarvest, R. L. Tetrahedron 2004, 60, 4513–4525. (q) Yamada, S.; Misono, T.;
Iwai, Y. Tetrahedron Lett. 2005, 46, 2239–2242. (r) Yamada, S.; Misono, T.;
Iwai, Y.; Masumizu, A.; Akiyama, Y. J. Org. Chem. 2006, 71, 6872–6880. (s)
Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 14264–14265. (t) Wurz, R.
P. Chem. Rev. 2007, 107, 5570–5595. (u) Duffey, T. A.; Shaw, S. A.; Vedejs, E.
J. Am. Chem. Soc. 2009, 131, 14–15.
We then investigated the solvent effects on the regioselec-
tivity of acylation with catalyst 1 (Table 1, entries 4-6).
Toluene, THF, and DMF were investigated in addition to
CHCl3. The polarity of the solvents roughly correlated with
the chemo- and regioselectivity of acylation. The highest
selectivity (73%) for 4-O-acylation was observed in the less
polar solvents toluene and CHCl3 (entries 2 and 4), whereas
J. Org. Chem. Vol. 74, No. 22, 2009 8803

Ueda et al.
JOCNote
TABLE 2. Effects of Temperature and Concentration on Regioselec-
tivity of 1-Catalyzed Acylation of 2
TABLE 3. Catalytic Regioselective Acylation of 2 with Functionalized
Acid Anhydrides
regioselectivitya
mono- regioselectivitya
T
concn
(M)
mono-
acylate (%)
6-O:4-O:
3-O:2-O
diacylate
(%)
T
concn
t
acylate
6-O:4-O:
3-O:2-O
diacylate
(%)
entry (°C)
entry (RCO)2O (°C) (M) (h) (%)
1
2
3
4
5
20
0
0.1
0.1
0.1
0.02
0.07
0.07
0.2
0.1
0.1
81
89
88
93
90
88
89
86
85
89
21:73:6:0
8:91:2:0
6:93:1:0
5:94:1:0
6:93:1:0
6:93:1:0
7:91:2:0
5:94:1:0
5:94:1:0
9:89:2:0
12
8
10
2
1
2
3
4
5
6
7
3
5
6
7
8
9
10
-20 0.02 24
-20 0.07 24
-50 0.07 24
-20 0.07 24
-50 0.07 24
-30 0.1
-50 0.05 165
93
82
75
76
76
88
78
5:94:1:0
8:88:4:0
1:86:13:0
27:70:3:6
23:67:10:0
3:94:3:0
2
10
17
10
15
6
-20
-20
-20
7
6b -20
96
7
8
9
-20
-30
-40
8
9
10
8
11:87:2:0
aPercent regioselectivity among four monoacylates.
10 -50
0.1
aPercent regioselectivity among four monoacylates. b1 mol % of
catalyst 1 was used.
acylation of the primary hydroxy group was predominant
(61%) in a polar solvent, DMF (entry 6). The observed
solvent effects indicate that the driving force for selective 4-
O-acylation may involve H-bonding between the substrate
and the catalyst. Another interesting phenomenon is that a
higher ratio of 4-O-acylation is associated with a higher yield
for monoacylation (entries 1-6). This implies that acylation
of the secondary hydroxy group at C-4 would proceed in an
accelerative manner. The tendency is consistent with our
previous observation that competitive acylation of a 1:1
mixture of 2 and 2-phenylethanol in the presence of 1
afforded the 4-O-isobutyrate of 2 exclusively.7 This tendency
indicate that catalyst 1 promotes accelerated acylation of the
secondary hydroxy group at C(4) of 2.
yields for monoacylation (entries 1-5). This protocol was
applied to regioselective introduction of cinnamoyl and gal-
loyl groups into carbohydrates because carbohydrates with
cinnamoyl and/or galloyl substructures have been frequently
found in biologically active glycosides.14,15 Treatment of 2
with cinnamic anhydride (9) in the presence of 10 mol % of 1
gave the 4-O-acylate with 94% regioselectivity and 88%
yield for monoacylation (entry 6). Similary, regioselective
galloylation was achieved by the use of catalyst 1 to give the
4-O-acylate with 87% regioselectivity and 78% yield for
monoacylation (entry 7). In these acylation reactions, ana-
lysis of regioselectivity was unambiguously performed by
1
careful investigation of H NMR of the mixture of mono-
Temperature effects were next investigated (Table 2). A
decrease in the reaction temperature to 0 °C increased the
regioselectivity for 4-O-acylation to 91% (entry 2). Further
decrease in the temperature at -40 °C increased the regios-
electivity up to 94% (entry 9). However, acylation at -50 °C
resulted in a small decrease in the regioselectivity to 89%,
probably due to the poor solubility of the substrate and
catalyst at the low temperature (entry 10). Effects of the con-
centration were next investigated in the acylation at -20 °C
(entries 3-5 and 7). Decrease in the concentration in-
creased the regioselectivity and the yield for monoacylation.
Treatment of 2 with 10 mol % of catalyst 1 and 1.1 equiv of
3 in CHCl3 at -20 °C at the concentration of 0.02 M gave the
4-O-acylate in 94% regioselectivity and 91% yield for mono-
acylation together with 2% formation of the diacylates
(entry 4). With only 1 mol % of catalyst 1, regioselective
acylation at C(4)-OH proceeded with 93% selectivity and
88% yield for monoacylation (entry 6).
acylates by comparison with an authentic sample of the
major acylate, which was obtained in a pure form by HPLC
separation of the mixture of the monoacylates or obtained
independently by conventional protection/deprotection se-
quences (see Supporting Information).
The protocol was applied to the regioselective acylation of
disaccharides. Acylation of Glc-Glc disaccharide 11 with iso-
butyric anhydride proceeded to give the 4-O-isobutyrate 12
with 94% regioselectivity and 94% yield for monoacylation
(Scheme 2a). Similarly, N-Cbz-protected phenyalanine ester
13 and cinnamoyl ester 14 were directly prepared from 11
with 83% and 85% regioselectivity, respectively (Scheme 2, b
and c). Azide-substituted disaccharide 15 and GlcNCbz-Glc
derivative 17 underwent acylation on treatment with isobutyric
anhydride in the presence of 10 mol % of 1 to give 16 with 93%
regioselectivity and 92% yield for monoacylation and 18
(14) (a) Chang, H.-T.; Tu, P.-F. Helv. Chim. Acta 2007, 90, 944–950.
(b) Li, R.-T.; Li, J.-T.; Wang, J.-K.; Han, Q.-B.; Zhu, Z.-Y.; Sun, H.-D.
Chem. Pharm. Bull. 2008, 56, 592–594. (c) Sigstad, E. E.; Cuenca, M. R.;
The optimized reaction conditions were applied to the
regioselective acylation of 2 with acid anhydrides derived
from various amino acids (Table 3, entries 1-5). Acylation
of 2 with acid anhydrides derived from L-phenylalanine, D-
phenyalanine, L-tryptophan, L-alanine, and glycine pro-
ceeded in the presence of 10 mol % of catalyst 1 to give the
4-O-acylates with 67-94% regioselectivity and 76-93%
ꢀ
Catalan, C. A. N.; Gedris, T. E.; Herz, W. Phytochemitsry 1999, 50, 835–838.
(15) Acylates of carbohydrates have been found to show different biolo-
gical activities depending on the position and structure of the acyl groups;
see: (a) Guiard, J.; Collmann, A.; Gilleron, M.; Mori, L.; De Libero, G.;
Prandi, J.; Puzo, G. Angew. Chem., Int. Ed. 2008, 47, 9734–9738. (b) Aich, U.;
Campbell, C. T.; Elmouelhi, N.; Weier, C. A.; Sampathkumar, S.-G.; Choi,
S. S.; Yarema, K. J. ACS Chem. Biol. 2008, 3, 230–240.
8804 J. Org. Chem. Vol. 74, No. 22, 2009

Ueda et al.
JOCNote
SCHEME 2. Catalytic Regioselective Acylation of Disaccharide 11
FIGURE 2. Functional group (blue circles) tolerance in molecular
recognition via hydrogen bonding (yellow rectangles).
Experimental Section
General Procedure for Catalytic Regioselective Acylation. A
sugar substrate (1.0 equiv), catalyst (10 mol %), and 2,4,6-
collidine (1.5 equiv) were dissolved in CHCl3 at 20 °C. After the
mixture was cooled to the temperature specified in Tables 1-3
and Schemes 2 and 3, an acid anhydride (1.1 equiv) was
added to the mixture. The resulting mixture was stirred at the
temperature for the period indicated in Tables 1-3 and
Schemes 2 and 3. The reaction was quenched with saturated
aq NH4Cl and extracted with AcOEt. The organic layer was
washed with water and brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by SiO2 column
chromatography or preparative SiO2 TLC to give the acylated
products.
SCHEME 3. Catalytic Regioselective Acylation of Disaccharides
15, 17, and 19
Octyl 4-O-((S)-2-Benzyloxycarbonylamino-3-phenylpropanoyl)-
β-D-glucopyranoside (Table 1). Colorless crystals (AcOEt/hexane);
mp140-142 °C; [R]20D -41 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.42-7.13 (m, 10H), 5.30 (d, J = 6.8 Hz, 1H), 5.06
(ABq, JAB = 12.0 Hz, ΔνAB = 16.5 Hz, 2H), 4.86 (t, J = 9.2 Hz,
1H), 4.46 (q, J = 6.8 Hz, 1H), 4.28 (d, J = 7.6 Hz, 1H), 3.87 (dt,
J = 9.2, 7.2 Hz, 1H), 3.68 (br s, 1H), 3.65 (t, J = 9.6 Hz, 1H), 3.51
(dt, J = 9.2, 7.2 Hz, 1H), 3.45 (t, J = 8.4 Hz, 1H), 3.42-3.32 (m,
1H), 3.30-3.20 (m, 2H), 3.15-3.00 (m, 2H), 2.10 (br s, 1H),
1.68-1.56 (m, 2H), 1.40-1.18 (m, 10H), 0.88 (t, J = 6.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 171.74, 156.24, 135.72, 135.22,
129.21, 128.85, 128.58, 128.39, 128.30, 127.45, 102.50, 74.25, 73.56,
73.45, 72.35, 70.38, 67.48, 61.19, 55.76, 37.35, 31.78, 29.56, 29.36,
29.18, 25.89, 22.62, 14.08; IR (KBr) 3573, 3487, 3340, 1730, 1706,
1536 cm-1; MS (EI) m/z (rel intensity) 573 (Mþ, 0.1), 443 (2), 300
(10), 120 (15), 91 (100); HRMS calcd for C31H43O9N 573.2955,
found 573.2938.
with 89% regioselectivity and 83% yield for monoacylation,
respectively (Scheme 3). We finally examined regioselective
acylation of disaccharide 19 with seven free hydroxy groups.
Acylation of 19 was sluggish even in the presence of catalyst 1
probably due to the poor solubility of 19 in CHCl3. Treatment
of 19 with 1.1 equivalents of isobutyric anhydride in the
presence of 30 mol % of catalyst 1 in CHCl3 at -20 °C gave
20 with 78% regioselectivity and 36% yield for monoacylation
together with diacylates (27%) and 40% recovery of starting
material. Although the chemical yield was far from satisfactory,
regioselective acylation of a particular secondary hydroxy
group out of seven hydroxy groups in different microenviron-
ments appears surprisingly refined.
The 4-O-acylates of the glucose moiety were universally
obtained as the major acylate in the acylation of various
carbohydrates with various functionalized acid anhydrides.
Thus, functional group tolerance in the present process was
found to be high. This seems surprising to us because the
hydrogen-bonding interactions between C(6)- and C(3)-OH
of the glucose moiety and the catalyst (Figure 2, yellow
rectangles), which was proposed to be responsible for the
selective 4-O-acylation,7 are supposed to be specifically
operative even in the presence of many other hydrogen bond
donors and acceptors (blue circles).
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.
Supporting Information Available: Experimental methods,
characterization data for all new compounds, and copies of
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 22, 2009 8805