Regioselective acylation of octyl β-D-glucopyranoside by chiral 4-pyrrolidinopyridine analogues

Article abstract of DOI:10.1055/s-2008-1032176

Chiral 4-pyrrolidinopyridine (PPY) analogues with dual functional side chains consisting of indole units have been prepared from trans-4-hydroxy-L- proline. Treatment of octyl β-D-glucopyranoside with isobutyric anhydride in the presence of the catalysts gave the 6-O-acylate as the major product via acylation of a primary hydroxyl group. On the other hand, the 4-O-acylate was obtained as the major product in 66% regioselectivity via acylation of the secondary hydroxyl group at C-4 on treatment of octyl β-D-glucopyranoside with isobutyric anhydride in the presence of a PPY catalyst. Use of isobutyryl chloride instead of isobutyric anhydride in the presence of the catalyst gave the 6-O-acylate in 87% regioselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032176

PAPER
747
Regioselective Acylation of Octyl b-D-Glucopyranoside by Chiral
4-Pyrrolidinopyridine Analogues
Regioselective
A
a
cylationo
k
f
O
ctyl
b
-
D
-
e
G
lucopyran
o
oside Kawabata,* Wataru Muramatsu, Tadashi Nishio, Takeshi Shibata, Yoshiharu Uruno, Roland Stragies
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
Fax +81(774)383197; E-mail: kawabata@scl.kyoto-u.ac.jp
Received 9 October 2007; revised 26 November 2007
Dedicated to the memory of the late Professor Yoshihiko Ito
asymmetric induction. We then investigated the chemose-
lectivity of acylation of meso-1,3-cyclohexanediol with
PPY and 1–3 (Table 1).4 Treatment of meso-1,3-cyclo-
hexanediol with isobutyric anhydride in the presence of
Abstract: Chiral 4-pyrrolidinopyridine (PPY) analogues with dual
functional side chains consisting of indole units have been prepared
from trans-4-hydroxy-L-proline. Treatment of octyl b-D-glucopyr-
anoside with isobutyric anhydride in the presence of the catalysts
gave the 6-O-acylate as the major product via acylation of a primary PPY gave the monoacylate and the diacylate in 35% and
hydroxyl group. On the other hand, the 4-O-acylate was obtained as
39% yield, respectively, together with 4% recovery (entry
the major product in 66% regioselectivity via acylation of the sec-
1). A similar tendency for mono- and diacylation was ob-
ondary hydroxyl group at C-4 on treatment of octyl b-D-glucopyra-
served in acylation with 1 (entry 2). On the other hand, the
noside with isobutyric anhydride in the presence of a PPY catalyst.
yield for monoacylation was slightly improved to 44%
Use of isobutyryl chloride instead of isobutyric anhydride in the
with 2, and further improved to 60% with 3 (entries 3 and
4). These observations might indicate that the indole units
in 2 and 3 could participate in the recognition of the 1,3-
diol substructure. This background prompted us to
develop PPY analogues 4–7 with dual functional side
chains consisting of indole units. Here, we describe the
preparation of chiral PPYs 4–7 and their use in the regio-
selective acylation of octyl b-D-glucopyranoside.
presence of the catalyst gave the 6-O-acylate in 87% regioselectiv-
ity.
Key words: regioselective acylation, nucleophilic catalyst, gluco-
pyranoside, chiral pyrrolidinopyridine, organocatalyst
We previously developed the chiral 4-pyrrolidinopyridine
(PPY) analogue 1, which could effectively catalyze acyla-
tive kinetic resolution of racemic diol and amino alcohol
derivatives with high enantioselectivity (Figure 1).1,2 We
further developed chiral PPY analogues 23 and 3.4 Al-
though chiral elements are not present in the catalytically
active pyridine ring in these nucleophilic catalysts, they
could promote enantioselective acylation via remote
While we assumed that two indole units in 3 could partic-
ipate in the substrate recognition, the indole unit in the C-
4 side chain of 3 was assumed to be located far from the
catalytically active pyridine nitrogen. Catalysts 4–7 were
designed with the expectation that the indole unit of the C-
4 side chain of catalysts would be located in proximity to
O
CbzHN
O
H
CO2Me
OH
H
4
N
H
CO2Me
N
N
N
N
O
H
NH
O
N
N
H
N
N
N
3
H
1
2
O
**
O
4
N
H
N
CO2Me
O
N
N
BocHN
HN
*
O
4: C*,C** = (S,S)
5: C*,C** = (R,S)
6: C*,C** = (S,R)
7: C*,C** = (R,R)
NH
Figure 1
SYNTHESIS 2008, No. 5, pp 0747–0753
x
x
.
x
x
.2
0
0
8
Advanced online publication: 18.02.2008
DOI: 10.1055/s-2008-1032176; Art ID: F18507SS
© Georg Thieme Verlag Stuttgart · New York

748
T. Kawabata et al.
PAPER
t-BuO
ii
Table 1 Acylation of meso-1,3-Cyclohexanediol with PPY Ana-
loguesa
HO
t-BuO
i
Ot-Bu
O
OH
OCOi-Pr
OCOi-Pr
N
catalyst (5 mol%)
(i-PrCO)2O (1.3 equiv)
OH
Ot-Bu
N
+
N
H
collidine (1.4 equiv)
CHCl3, 20 °C, 4 h
O
O
Cbz
OH
N
10
OH
monoacylate
OCOi-Pr
diacylate
9
HO
H
N
CO2Me
Entry
Catalyst
Monoacylate/diacylate/recovery (%)b
N
iii
iv
O
4–7
1
2
3
4
PPY
35:39:4
32:46:2
44:29:8
60:28:5
N
H
1
2
3
N
11
Scheme 1 Reagents and conditions: (i) (a) Z-Cl, NaOH, H2O; (b)
isobutene, conc. H2SO4, dioxane (53%); (ii) (a) H2, 10% Pd/C,
MeOH; (b) 4-bromopyridine hydrochloride, Pd(OAc)2, dppp,
Cs2CO3, toluene, 100 °C (65%); (iii) (a) SiO2, toluene, reflux; (b) H-
Trp-OMe, WSC·HCl, HOBt, NMM, DMSO–CH2Cl2 (70%); (c) TFA,
ethanedithiol, CH2Cl2 (67%); (iv) Boc-Trp-Pro-OH, HOBt, DIC,
DMF (47–92%).
a Data quoted from Kawabata et al.4
b Yields determined by 1H NMR with dibenzyl ether as an internal
standard.
the pyridine nitrogen due to the turn structure caused by
proline. Since the relative orientation of two of the indole
units was supposed to be linked to recognition of the sub-
strate, all possible stereoisomers of the dipeptides consist-
ing of proline and tryptophan were introduced at C-4 of
the pyrrolidine ring. Molecular modeling of the acylpyri-
dinium ion 8,5 generated from 4, was performed by
MacroModel (V. 9.0)/MCMM conformational searches
with the AMBER* force field (Figure 2). The calculated
structure indicated that the indole unit in the C-4 side
chain of 8 was in close proximity to the reactive acyl
group.
acid (TFA), gave 11 in 67% yield. Condensation of 11
with L,L-, D,L-, L,D-, D,D-Boc-Trp-Pro-OH, respectively,
in the presence of N,N¢-diisopropylcarbodiimide (DIC)
and N-hydroxybenzotriazole (HOBt) gave 4, 5, 6 and 7,
respectively, in 47–92% yields. We then investigated the
properties of catalysts 4–7 in the acylation of octyl b-D-
glucopyranoside.
Regioselective protection of carbohydrates and polyol
natural products is one of the major challenges in current
organic synthesis.8,9 Selective acylation of a primary hy-
droxyl group of alkyl b-D-glucopyranoside has been
achieved in ~100% regioselectivity by enzymatic pro-
cesses, however, concomitant diacylation was unavoid-
able.10 Kattnig and Albert reported that acylation of octyl
b-D-glucopyranoside with 4-dimethylaminopyridine
(DMAP) and acetyl chloride proceeded selectively on the
primary hydroxyl group to give the 6-O-acetate in 85%
selectivity in 73% yield.11 On the other hand, selective
acylation of a secondary hydroxyl group in the presence
of a free primary hydroxyl group has been known to be
difficult.12 Yoshida and coworkers reported regioselective
acylation of a secondary hydroxyl group at C-4 of octyl a-
D-glucopyranoside in 61% selectivity with an acetic anhy-
dride–DMAP system.13 Kattnig and Albert also reported
that acylation of octyl b-D-glucopyranoside with acetic
anhydride in the presence of DMAP and pyridine, gave
Catalysts 4–7, with dual functional side chains consisting
of two tryptophan substructures, were prepared
(Scheme 1). Thus, trans-4-hydroxy-L-proline was trans-
formed into the fully protected derivative 9 in 53% yield
according to a standard procedure.6 Hydrogenolysis of 9,
followed by coupling with 4-bromopyridine by Buch-
wald’s procedure,7 gave chiral PPY 10 in 65% yield. Se-
lective removal of the tert-butyl ester protecting group of
10, in the presence of tert-butyl ether, was achieved by
treatment with SiO2 in refluxing toluene. Condensation of
the resulting acid [activated using 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (WSC·HCl)]
with L-tryptophan methyl ester followed by removal of
the tert-butyl ether protecting group with trifluoroacetic
Figure 2 Acylpyridinium ion 8 and the most stable structure (stereo view) generated by Mocromodel (V. 9.0) with the AMBER* force field.
Synthesis 2008, No. 5, 747–753 © Thieme Stuttgart · New York

PAPER
Regioselective Acylation of Octyl b-D-Glucopyranoside
749
Table 2 Effects of Catalysts on the Regioselectivity of Acylation of Octyl b-D-Glucopyranosidea
catalyst (10 mol%)
(i-PrCO)2O (1.1 equiv)
i-PrCOO
HO
i-PrCOO
+
6
O
4
O
O
HO
HO
OC8H17
OC8H17
OC8H17
2
3
collidine (1.5 equiv)
toluene, 20 °C, 12 h
OH
i-PrCOO
monoacylate
diacylate
Entry
Catalyst
Monoacylate (%)
Regioselectivity (%)b
Diacylate (%)
Recovery (%)
6-O/4-O/3-O/2-O
1
2
3
4
5
DMAP
47
66
65
67
62
36:26:26:12
30:60:10:0
46:40:11:3
56:33:10:1
49:39:11:1
22
16
20
19
24
31
16
12
14
10
4
5
6
7
a The reactions were carried out with a substrate concentration of 0.08 M.
b Regioselectivity among four monoacylates.
the 3-O-acetate in 57% regioselectivity.11 Recently, We then investigated the effects of solvents, acylating
Griswold and Miller reported an excellent approach for agents and temperature on the regioselectivity of acyla-
the selective introduction of an acetyl group at a second- tion of octyl b-D-glucopyranoside with catalyst 4
ary hydroxyl group of octyl b-D-glucopyranoside with (Table 3). Chloroform, tetrahydrofuran (THF) and N,N-
peptide-based chiral catalysts;14 moderately selective 4- dimethylformamide (DMF) were examined in addition to
O-acylation was achieved, giving 6-, 4-, 3- and 2-O-acyl- toluene. Acylation in chloroform gave slightly higher se-
ates in a ratio of 22:58:11:9. Recently, we found highly lectivity (61%) for 4-O-acylation and slightly improved
chemo- and regioselective acylation of monosaccharides yield (71%) for monoacylation than in toluene (entries 1
catalyzed by C2-symmetric chiral PPY derivatives.15 In vs. 3). On the other hand, acylation in polar solvents such
this report, we describe the regioselectivity profile for the as THF and DMF gave the 6-O-acylate as the major prod-
acylation of octyl b-D-glucopyranoside with catalysts uct with low selectivity (entries 4 and 5). The observed
4–7.
solvent effects indicate that the driving force for 4-O-acy-
lation may involve H-bonding between the substrate and
the catalyst. Use of isobutyryl chloride instead of isobu-
tyric anhydride gave the 6-O-acylate in high regioselec-
tivity (87%) and in 77% yield for monoacylation (entry
6).17 Acylation with p-nitrophenyl isobutyrate gave the 6-
O-acylate as the major product in 65% regioselectivity
(entry 7). Acylation of octyl b-D-glucopyranoside with
isobutyric anhydride, in the presence of 4 in toluene at
0 °C, gave the highest regioselectivity (66%) for 4-O-acy-
lation (entry 2).
Isobutyric anhydride was employed as an acylating agent
because it has been known to show high selectivity in acy-
lative kinetic resolution of racemic alcohols1b due to the
high kcat/kuncat ratio.16 Acylation of octyl b-D-glucopyrano-
side was investigated with 10 mol% of catalysts and 1.1
mol equivalent of isobutyric anhydride (Table 2). Forma-
tion of the assigned products was unambiguously con-
firmed by comparison with authentic samples of 6-, 4-, 3-
and 2-O-isobutyryl octyl b-D-glucopyranosides, which
were independently prepared via conventional protec-
tion–deprotection sequences.15 With DMAP as a catalyst, It might be supposed that the acylation of C(4)-OH results
four monoacylates, 6-, 4-, 3- and 2-O-isobutyryl octyl b- from migration of the 6-O-acylate into the 4-O-acylate.
D-glucopyranosides, were obtained in a ratio of This possibility was investigated through treatment of the
36:26:26:12, respectively, in a combined yield of 47% to- 6-O-isobutyrate of octyl b-D-glucopyranoside with a C2-
gether with 22% of the diacylates and 31% recovery (en- symmetric chiral PPY derivative; in the presence of colli-
try 1). Thus, totally random acylation took place by dine and in the absence of isobutyric anhydride, the 6-O-
DMAP-catalysis. With catalysts 5–7, acylation took place isobutyrate was recovered in 99% yield and migration to
with a regioselectivity similar to that obtained using the 4-O-isobutyrate was not detected at all.15 This clearly
DMAP, giving the 6-O-acylate as the major product. On indicates that acylation of a secondary hydroxyl group at
the other hand, in the acylation with catalyst 4, the second- C-4 took place directly under the influence of the catalyst.
ary hydroxyl group at C-4 was predominantly acylated
In conclusion, we have developed chiral PPY analogues
(60%), even in the presence of a free primary hydroxyl
with dual functional side chains consisting of indole units.
group at C-6 (entry 2). These observations indicate that
Among them, catalyst 4 was found to be effective for the
regioselective acylation of the secondary hydroxyl group
at C-4 of octyl b-D-glucopyranoside, in the presence of a
free primary hydroxyl group at C-6.
the relative orientation of the two indole units of the cata-
lyst is critically involved in the selective acylation of one
out of the four hydroxyl groups of octyl b-D-glucopyrano-
sides.
Synthesis 2008, No. 5, 747–753 © Thieme Stuttgart · New York

750
T. Kawabata et al.
PAPER
Table 3 Effects of Solvents, Acylation Agents and Temperature on the Regioselectivity of Acylation of Octyl b-D-Glucopyranoside with 4a
4 (10 mol%)
i-PrCOX (1.1 equiv)
i-PrCOO
HO
i-PrCOO
6
O
4
O
O
HO
HO
+
OC8H17
OC8H17
OC8H17
diacylate
2
collidine (1.5 equiv)
solvent, 20 °C, 12 h
3
OH
i-PrCOO
monoacylate
Entry
Solvent
i-PrCOX
Monoacylate (%)
Regioselectivity (%)b
Diacylate (%)
Recovery (%)
6-O/4-O/3-O/2-O
1
2c
3
4
5
6
7
toluene
toluene
CHCl3
THF
(i-PrCO)2O
(i-PrCO)2O
(i-PrCO)2O
(i-PrCO)2O
(i-PrCO)2O
i-PrCOCl
66
69
71
69
60
77
48
30:60:10:0
25:66:9:0
22:61:17:0
37:22:34:7
41:14:34:11
87:9:4:0
16
20
18
18
24
11
6
16
10
10
13
15
10
41
DMF
toluene
toluene
i-PrCO2Npd
65:20:13:2
a The reactions in entries 1, 2, 6 and 7 and those in entries 3–5 were carried out with a substrate concentration of 0.08 M and 0.1 M, respectively.
b Regioselectivity among four monoacylates.
c The reaction was run at 0 °C for 24 h.
d p-Nitrophenyl ester.
HRMS: m/z calcd for C18H28N2O3: 320. 2100; found: 320.2115.
NMR spectra were obtained with a JEOL JMN 400 spectrometer,
chemical shifts are given in ppm units (TMS or CHCl3 as internal
standards at 0 ppm or 7.24 ppm, respectively). IR spectra were re-
corded with a JASCO FT/IR-300 spectrometer. Specific rotation
was measured with a Horiba SEPA-200 automatic digital polarim-
eter. MS spectra were recorded with a JEOL JMS-DX300 mass
spectrometer. TLC analysis and preparative TLC were performed
on commercial glass plates bearing a 0.25 mm layer and 0.5 mm
layer of Merck Kiesel-gel 60 F254, respectively. Silica gel chroma-
tography was carried out using Wakogel C-200, Fuji Silysia BW-
1277H or Nacalai Tesque Silica gel 60 (150–325 mesh). Anhydrous
solvents (THF, Et2O, hexane, CH2Cl2 and toluene; <50 ppm H2O
content) were purchased from Kanto Chemical Co., Inc. and used
without further treatment.
Methyl (S)-2-[(2S,4R)-4-Hydroxy-1-(pyridin-4-yl)pyrrolidine-
2-carboxamido]-3-(1H-indol-3-yl)propanoate (11)
A mixture of 10 (6.80 g, 21.2 mmol) and SiO2 (67 g) in toluene (200
mL) was heated under reflux for 12 h. After cooling to r.t., the mix-
ture was filtered, washed with NEt3–MeOH (5:95, 50 mL) and the
combined filtrate was evaporated in vacuo. To a solution of the res-
idue in DMSO–CH2Cl2 (2:1, 200 mL) were added L-tryptophan
methyl ester hydrochloride (11.8 g, 46.4 mmol), N-methylmorpho-
line (17.0 mL, 155 mmol), 1-hydroxybenzotriazole hydrate (5.00 g,
37.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (11.0 g, 61.9 mmol) at 0 °C. After stirring for 72 h at
r.t., the mixture was diluted with EtOAc (300 mL) and washed with
sat. aq NaHCO3 (2 × 50 mL) and brine (1 × 50 mL), dried over
Na2SO4, filtered and evaporated. The residue was purified by col-
umn chromatography (SiO2; EtOAc–MeOH, 9:1→5:1) to give a
pale-yellow foam (10.0 g). The foam was treated with 5%
ethanedithiol in TFA (30 mL) at r.t. for 6 h. After evaporation of the
solvent, the residue was diluted with CH2Cl2–EtOH (5:1, 200 mL)
and washed with sat. aq NaHCO3 (2 × 30 mL) and brine (1 × 30
mL), dried over Na2SO4, filtered and evaporated to give pale-yellow
solids which were recrystallized (MeOH–Et2O) to give pure 11.
tert-Butyl (2S,4R)-4-tert-Butoxy-1-(pyridin-4-yl)pyrrolidine-2-
carboxylate (10)
A mixture of 9 (31.9 g, 84.5 mmol)6 and 10% Pd/C (3.19 g) in
MeOH (300 mL) was stirred vigorously at r.t. under H2 for 12 h. The
mixture was filtered and washed with MeOH and the combined fil-
trate was evaporated in vacuo to give a colorless oil. A mixture of
the oil, 4-bromopyridine hydrochloride (26.5 g, 136 mmol),
Pd(OAc)2 (3.80 g, 17.0 mmol), 1,3-bis(diphenylphosphino)propane
(14.1 g, 34. 2 mmol) and Cs2CO3 (88.9 g, 273 mmol) in toluene (500
mL) was stirred with Ar bubbling for 15 min. The resulting mixture
was heated at reflux under Ar for 48 h. After cooling to r.t., the mix-
ture was filtered and washed with EtOAc. The combined filtrate
was washed with sat. aq NaHCO3 (2 × 50 mL) and brine (2 × 50
mL), dried over Na2SO4, filtered and evaporated. The residue was
purified by column chromatography (SiO2; EtOAc–hexane–Et3N,
50:50:5) to give 10.
Yield: 5.80 g (67%); colorless prisms; mp 217–220 °C; [a]D –62
20
(c 1.0, MeOH).
1H NMR (400 MHz, CDCl3–CD3OD): d = 7.92 (d, J = 6.8 Hz, 2 H),
7.46 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 1 H), 7.18 (td, J = 8.1,
1.2 Hz, 1 H), 7.09 (td, J = 8.1, 1.0 Hz, 1 H), 6.89 (s, 1 H), 6.15 (d,
J = 6.8 Hz, 1 H), 4.78 (dd, J = 7.3, 5.4 Hz, 1 H), 4.25 (quint, J = 5.1
Hz, 1 H), 4.12 (dd, J = 8.4, 6.1 Hz, 1 H), 3.71 (s, 1 H), 3.43–3.30
(m, 2 H), 3.22 (dd, J = 15.4, 7.3 Hz, 1 H), 3.10 (dd, J = 10.0, 4.4 Hz,
1 H), 2.30–2.22 (m, 1 H), 2.11–2.03 (m, 1 H).
Yield: 17.7 g (65%); [a]D20 –69 (c 1.0, MeOH).
1H NMR (CDCl3): d = 8.22 (d, J = 6.5 Hz, 2 H), 6.36 (d, J = 6.5 Hz,
2 H), 4.53 (quin, J = 7.2 Hz, 1 H), 4.23 (t, J = 5.9 Hz, 1 H), 3.70
(dd, J = 9.5, 7.2 Hz, 1 H), 3.19 (dd, J = 9.5, 6.0 Hz, 1 H), 2.25 (dd,
J = 7.2, 5.9 Hz, 2 H), 1.44 (s, 9 H), 1.22 (s, 9 H).
IR (KBr): 3294, 1741, 1667, 1601, 1520, 1227 cm–1.
MS (EI): m/z (%) = 408 (20) [M+], 279 (30), 256 (25), 163 (100),
145 (80), 130 (80).
HRMS: m/z calcd for C22H24N4O4: 408.1798; found: 408.1790.
MS (EI): m/z (%) = 320 (20) [M+], 219 (100), 163 (100), 145 (50).
Synthesis 2008, No. 5, 747–753 © Thieme Stuttgart · New York

PAPER
Regioselective Acylation of Octyl b-D-Glucopyranoside
751
(S)-{(3R,5S)-5-[(S)-3-(1H-indol-3-yl)-1-methoxy-1-oxopropan-
2-ylcarbamoyl]-1-(pyridin-4-yl)pyrrolidin-3-yl}-1-[(S)-2-(tert-
butoxycarbonylamino)-3-(1H-indol-3-yl)propanoyl]pyrroli-
dine-2-carboxylate (4)
To a solution of 11 (1.20 g, 2.94 mmol) and Boc-L-Trp-L-Pro-OH
(2.93 g, 7.34 mmol) in DMF (30 mL), were added N-methylmor-
pholine (0.97 mL, 8.81 mmol), N,N¢-diisopropylcarbodiimide (1.15
mL, 7.34 mmol) and DMAP (0.18 g, 1.47 mmol). The mixture was
stirred at r.t. for 4 d then hexane was added and the resulting super-
natant was decanted off. The remaining yellow oil was concentrated
in vacuo and the residue was purified by column chromatography
(SiO2; EtOAc–hexane–NH3 (25%), 84:16:2) to give 4, which was
further purified by recrystallization (2-propanol–Et2O).
(R)-{(3R,5S)-5-[(S)-3-(1H-indol-3-yl)-1-methoxy-1-oxopropan-
2-ylcarbamoyl]-1-(pyridin-4-yl)pyrrolidin-3-yl}-1-[(S)-2-(tert-
butoxycarbonylamino)-3-(1H-indol-3-yl)propanoyl]pyrroli-
dine-2-carboxylate (6)
Prepared from 11 and and Boc-L-Trp-D-Pro-OH, according to the
procedure for 4.
21
Yield: 92%; colorless crystals; 150–153 °C; [a]D +34 (c 1.0,
MeOH).
1H NMR (400 MHz, DMSO-d6): d (5:1 mixture of rotamers) = 11.0
(s, 1 H), 10.9 (s, 1 H), 8.90 (d, J = 8.2 Hz, 1/6H), 8.82 (d, J = 8.2
Hz, 5/6H), 7.95 (d, J = 6.1 Hz, 2 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.46
(d, J = 8.0 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz,
1 H), 7.21 (s, 1 H), 7.17 (s, 1 H), 7.10–6.90 (m, 1 H), 7.08 (t, J = 8.0
Hz, 1 H), 7.05 (t, J = 8.0 Hz, 1 H), 6.99 (t, J = 8.0 Hz, 1 H), 6.97 (t,
J = 8.0 Hz, 5/6H), 6.70 (m, 1/6H), 6.30–6.10 (m, 2 H), 5.40–5.20
(m, 1 H), 4.60–4.50 (m, 1 H), 4.42 (dd, J = 15.0, 7.5 Hz, 1 H), 4.40–
4.20 (m, 1 H), 4.20–4.00 (m, 1 H), 3.80–3.70 (m, 1 H), 3.63 (s,
3 H), 3.60–2.70 (m, 7 H), 2.45–2.20 (m, 1 H), 2.20–2.00 (m, 1 H),
1.90–1.40 (m, 4 H), 1.31 (s, 45/6H), 1.29 (s, 9/6H).
Yield: 1.29 g (55%); colorless crystals; mp 137–141 °C; [a]D21 –40
(c 1.0, MeOH).
1H NMR (400 MHz, DMSO-d6): d (5:1 mixture of rotamers) = 11.0
(s, 1 H), 10.9 (s, 1 H), 8.80 (d, J = 8.0 Hz, 1 H), 7.91 (d, J = 5.6 Hz,
2 H), 7.55 (d, J = 7.9 Hz, 1 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.38 (d,
J = 7.9 Hz, 1 H), 7.33 (d, J = 7.9 Hz, 1 H), 7.21 (s, 1 H), 7.18 (s,
1 H), 7.08 (t, J = 7.9 Hz, 1 H), 7.06 (t, J = 7.9 Hz, 1 H), 7.01–6.95
(m, 1 H), 6.99 (t, J = 7.9 Hz, 5/6H), 6.97 (t, J = 7.9 Hz, 5/6H), 6.92–
6.86 (m, 2/6H), 6.53 (d, J = 5.6 Hz, 1/6H), 6.21 (d, J = 5.6 Hz, 11/
6H), 5.35 (br s, 5/6H), 5.25 (br s, 1/6H), 4.57–4.50 (m, 1 H), 4.43–
4.21 (m, 3 H), 3.77 (dd, J = 11.1, 5.1 Hz, 1 H), 3.72–3.55 (m, 1 H),
3.63 (s, 15/6H), 3.62 (s, 3/6H), 3.55–3.35 (m, 2 H), 3.24 (dd,
J = 14.8, 4.6 Hz, 1 H), 3.08 (dd, J = 14.8, 9.7 Hz, 1 H), 2.98 (dd,
J = 14.8, 4.6 Hz, 1 H), 2.86 (dd, J = 14.8, 9.7 Hz, 1 H), 2.40–2.30
(m, 1 H), 2.25–2.00 (m, 2 H), 2.00–1.82 (m, 3 H), 1.36 (s, 9/6H),
1.29 (s, 45/6H).
IR (KBr): 3280, 1740, 1637, 1601, 1174 cm–1.
MS (FAB): m/z (%) = 792 (50) [MH+], 692 (30), 662 (20), 504 (40),
391 (100).
HRMS: m/z calcd for C43H50O8N7: 792.3721; found: 792.3710.
(R)-{(3R,5S)-5-[(S)-3-(1H-Indol-3-yl)-1-methoxy-1-oxopropan-
2-ylcarbamoyl]-1-(pyridin-4-yl)pyrrolidin-3-yl}-1-[(R)-2-(tert-
butoxycarbonylamino)-3-(1H-indol-3-yl)propanoyl]pyrroli-
dine-2-carboxylate (7)
Prepared from 11 and and Boc-D-Trp-D-Pro-OH according to the
procedure for 4.
IR (KBr): 3277, 1740, 1637, 1601, 1174 cm–1.
MS (FAB): m/z (%) = 792 (100) [MH+], 692 (10), 662 (30), 504
21
Yield: 83%; colorless crystals; mp 144–146 °C; [a]D –16 (c 1.0,
(20), 391 (40).
CH3OH).
HRMS: m/z calcd for C43H50O8N7: 792.3721; found: 792.3723.
1H NMR (400 MHz, DMSO-d6): d (7:1 mixture of rotamers) =
10.93 (s, 1 H), 10.86 (s, 1 H), 8.82 (d, J = 8.0 Hz, 1/8H), 8.73 (d,
J = 8.0 Hz, 7/8H), 7.94 (d, J = 6.1 Hz, 2/8H), 7.89 (d, J = 6.1 Hz,
14/8H), 7.55 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.38 (d,
J = 8.0 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.20 (s, 1 H), 7.16 (s,
1 H), 7.10–7.02 (m, 2 H), 7.00–6.95 (m, 1 H), 6.98 (t, J = 8.0 Hz,
2 H), 6.51 (d, J = 6.1 Hz, 2/8H), 6.17 (d, J = 6.1 Hz, 14/8H), 5.35
(br s, 7/8H), 5.29 (br s, 1/8H), 4.60–4.50 (m, 1 H), 4.45–4.20 (m,
3 H), 3.90–3.60 (m, 1 H), 3.63 (s, 21/8H), 3.61 (s, 3/8H), 3.55–3.30
(m, 3 H), 3.24 (dd, J = 14.8, 4.6 Hz, 1 H), 3.07 (dd, J = 14.8, 10.2
Hz, 1 H), 2.95 (dd, J = 14.8, 4.6 Hz, 1 H), 2.82 (dd, J = 14.8, 10.2
Hz, 1 H), 2.45–2.30 (m, 1 H), 2.25–2.00 (m, 2 H), 2.00–1.75 (m,
3 H), 1.32 (s, 9/8H), 1.29 (s, 63/8H).
(S)-{(3R,5S)-5-[(S)-3-(1H-indol-3-yl)-1-methoxy-1-oxopropan-
2-ylcarbamoyl]-1-(pyridin-4-yl)-pyrrolidin-3-yl}-1-[(R)-2-(tert-
butoxycarbonylamino)-3-(1H-indol-3-yl)propanoyl]pyrroli-
dine-2-carboxylate (5)
Prepared from 11 and and Boc-D-Trp-L-Pro-OH, according to the
procedure for 4.
21
Yield: 47%; colorless crystals; mp 143–146 °C; [a]D –72 (c 1.0,
MeOH).
1H NMR (400 MHz, DMSO-d6): d (5:1 mixture of rotamers) = 11.0
(s, 1 H), 10.8 (s, 1 H), 8.78 (d, J = 8.0 Hz, 1 H), 7.96 (d, J = 6.1 Hz,
10/6H), 7.85 (d, J = 6.1 Hz, 2/6H), 7.55 (d, J = 8.0 Hz, 1 H), 7.46
(d, J = 8.0 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz,
1 H), 7.21 (s, 1 H), 7.16 (s, 1 H), 7.08 (t, J = 8.0 Hz, 1 H), 7.05 (t,
J = 8.0 Hz, 1 H), 7.02–6.95 (m, 1 H), 6.99 (t, J = 8.0 Hz, 1 H), 6.97
(t, J = 8.0 Hz, 5/6H), 6.70 (m, 1/6H), 6.22 (d, J = 6.1 Hz, 10/6H),
5.95 (d, J = 6.1 Hz, 2/6H), 5.33 (br s, 1/6H), 5.27 (br s, 5/6H), 4.57–
4.50 (m, 1 H), 4.43 (dd, J = 15.0, 7.0 Hz, 1 H), 4.32–4.20 (m, 1 H),
4.20–4.00 (m, 1 H), 3.77–3.72 (m, 1 H), 3.62 (s, 3 H), 3.57–2.80
(m, 7 H), 2.40–2.20 (m, 1 H), 2.20–2.00 (m, 1 H), 1.90–1.60 (m,
3 H), 1.60–1.40 (m, 1 H), 1.32 (s, 45/6H), 1.27 (s, 9/6H).
IR (KBr): 3277, 1740, 1637, 1601, 1174 cm–1.
MS (FAB): m/z (%) = 792 (100) [MH+], 692 (10), 662 (20), 504
(20), 391 (40).
HRMS: m/z calcd for C43H50O8N7: 792.3721; found: 792.3710.
Regioselective Acylation of Octyl b-D-Glucopyranoside (Table
3, entry 2); Typical Procedure
Octyl b-D-glucopyranoside (58.5 mg, 0.20 mmol), 4 (15.8 mg, 20
mmol) and 2,4,6-collidine (40 mL, 0.30 mmol) were dissolved in
toluene (2.5 mL) at 20 °C. After cooling the solution to 0 °C, isobu-
tyric anhydride (36 mL, 0.22 mmol) was added and the solution was
stirred at 0 °C for 24 h. The reaction mixture was quenched with sat.
aq NH4Cl (5 mL) and extracted with EtOAc (3 × 30 mL). The or-
ganic layer was washed with H2O (1 × 10 mL) and brine (1 × 10
mL), dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by column chromatography (SiO2; EtOAc–
hexane, 30:70→100:0) to give diacylates (17.7 mg, 20%), octyl 6-
O-isobutyryl-b-D-glucopyranoside (12.3 mg, 17%) and a mixture of
IR (KBr): 3280, 1740, 1637, 1601, 1174 cm–1.
MS (FAB): m/z (%) = 792 (100) [MH+], 692 (40), 662 (20), 504
(30), 391 (70).
HRMS: m/z calcd for C43H50O8N7: 792.3721; found: 792.3710.
Synthesis 2008, No. 5, 747–753 © Thieme Stuttgart · New York

752
T. Kawabata et al.
PAPER
octyl 4-O-isobutyryl- and 3-O-isobutyryl-b-D-glucopyranoside
(88:12, 37.9 mg, 52%) and recovered starting material (5.6 mg,
10%). Identification of the regioisomeric products was unambigu-
ously made by comparison with pure regioisomers prepared inde-
pendently by a conventional protection–deprotection procedure.15
References
(1) (a) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am.
Chem. Soc. 1997, 119, 3169. (b) Kawabata, T.; Yamamoto,
K.; Momose, Y.; Nagaoka, Y.; Yoshida, H.; Fuji, K. Chem.
Commun. 2001, 2700.
The preparation and characterization of octyl 2-, 3-, 4- and 6-O-
isobutyryl-b-D-glucopyranosides has been previously described.15
Selected data for these are as follows.
(2) 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) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120,
11532. (e) Liang, J.; Ruble, J. C.; Fu, G. C. J. Org. Chem.
1998, 63, 3154. (f) Tao, B.; Ruble, J. C.; Hoic, D. A.; Fu, G.
C. J. Am. Chem. Soc. 1999, 121, 10452. (g) Ie, Y.; Fu, G. C.
Chem. Commun. 2000, 119. (h) Spivey, A. C.; Fekner, T.;
Spey, S. E. J. Org. Chem. 2000, 65, 3154. (i) Spivey, A. C.;
Maddaford, A.; Fekner, T.; Redgrave, A. J.; Frampton, C. S.
J. Chem. Soc., Perkin Trans. 1 2000, 3460. (j) Naraku, G.;
Shimomoto, N.; Hanamoto, T.; Inanaga, J. Enantiomer
2000, 5, 135. (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) Spivey, A. C.; Leese, D. P.; Zhu, F.; Davey,
S. G.; Jarvest, R. L. Tetrahedron 2004, 60, 4513. (t) Arp, F.
O.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 14264.
(3) Kawabata, T.; Stragies, R.; Fukaya, T.; Fuji, K. Chirality
2003, 15, 71.
Octyl 2-O-Isobutyryl-b-D-glucopyranosides
1H NMR (400 MHz, CDCl3): d = 4.74 (dd, J = 9.3, 8.0 Hz, 1 H),
4.43 (d, J = 8.0 Hz, 1 H), 4.34 (br s, 1 H), 3.99 (br s, 1/2H), 3.90–
3.80 (m, 2 H), 3.50 (dt, J = 9.7, 6.5 Hz, 1 H), 3.67 (br t, J = 9.2 Hz,
1 H), 3.59 (br t, J = 9.4 Hz, 1 H), 3.43 (dt, J = 9.7, 6.9 Hz, 1 H), 3.33
(dt, J = 9.2, 3.4 Hz, 1 H), 3.19 (br s, 1/2H), 2.60 (hept, J = 7.0 Hz,
1 H), 2.25 (br s, 1 H), 1.60–1.50 (m, 2 H), 1.30–1.22 (m, 10 H),
1.18 (d, J = 7.0 Hz, 6 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.09, 100.98, 77.23, 75.38,
73.73, 70.49, 70.18, 61.76, 34.09, 31.83, 29.56, 29.38, 29.24, 25.93,
22.65, 19.04, 18.81, 14.08.
Octyl 3-O-Isobutyryl-b-D-glucopyranosides
1H NMR (400 MHz, CDCl3): d = 4.90 (t, J = 9.3 Hz, 1 H), 4.37 (d,
J = 7.8 Hz, 1 H), 3.94–3.80 (m, 2 H), 3.90 (dt, J = 9.4, 6.8 Hz, 1 H),
3.67 (br t, J = 9.3 Hz, 1 H), 3.56 (dt, J = 9.4, 6.8 Hz, 1 H), 3.49 (br
t, J = 8.7 Hz, 1 H) 3.42 (ddd, J = 9.7, 4.6, 3.6 Hz, 1 H) 3.12 (br s,
1 H), 2.67 (hept, J = 7.0 Hz, 1 H), 2.52 (br s, 1 H), 1.81 (br s, 1 H),
1.65–1.59 (m, 2 H), 1.38–1.18 (m, 10 H), 1.22 (d, J = 7.0 Hz, 3 H),
1.21 (d, J = 7.0 Hz, 3 H), 0.88 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 178.96, 102.81, 78.03, 75.72,
72.20, 70.53, 69.79, 62.34, 34.15, 31.80, 29.61, 29.36, 29.22, 25.93,
22.64, 18.95, 18.92, 14.09.
Octyl 4-O-Isobutyryl-b-D-glucopyranosides
1H NMR (400 MHz, CDCl3): d = 4.85 (t, J = 9.7 Hz, 1 H), 4.32 (d,
J = 7.8 Hz, 1 H), 3.89 (dt, J = 9.4, 7.0 Hz, 1 H), 3.69 (t, J = 8.8 Hz,
2 H), 3.53 (dt, J = 9.4, 7.0 Hz, 1 H), 3.48–3.40 (m, 3 H), 2.65 (br s,
1 H), 2.62 (hept, J = 7.0 Hz, 1 H), 1.63 (quin, 7.0 Hz, 2 H), 1.40–
1.20 (m, 10 H), 1.19 (d, J = 7.0 Hz, 3 H), 1.19 (d, J = 7.0 Hz, 3 H),
0.88 (t, J = 6.9 Hz, 3 H).
(4) Kawabata, T.; Stragies, R.; Fukuya, T.; Nagaoka, Y.;
Schedel, H.; Fuji, K. Tetrahedron Lett. 2003, 44, 1545.
(5) The structure of the acylpyridinium ion is drawn as 8 with
the iminium +N=C substructure because of the reported
structure of several N-acyl-4-dialkylaminopydinium ions,
see: (a) Jones, P. G.; Linoh, K.; Blaschette, A.
13C NMR (100 MHz, CDCl3): d = 177.52, 102.59, 74.41, 74.23,
74.16, 70.60, 70.42, 61.46, 34.05, 31.83, 29.60, 29.41, 29.26, 25.93,
22.66, 19.00, 18.85, 14.10.
Z. Naturforsch. 1990, 45b, 267. (b) Lohse, C.; Hollenstein,
S.; Laube, T. Angew.Chem. Int. Ed. Engl. 1991, 30, 1656.
(c) Hollenstein, S.; Lohse, C.; Laube, T. Croat. Chem. Acta
1992, 65, 727. (d) Tao, B.; Ruble, J. C.; Hoic, D. A.; Fu, G.
C. J. Am.Chem. Soc. 1999, 121, 5091.
Octyl 6-O-Isobutyryl-b-D-glucopyranosides
1H NMR (400 MHz, CDCl3): d = 4.61 (br s, 1 H), 4.37 (dd, J = 12.1,
2.5 Hz, 1 H), 4.32 (dd, J = 12.1, 5.8 Hz, 1 H), 4.26 (d, J = 7.8 Hz,
1 H), 4.19 (m, 1 H), 3.84 (dt, J = 9.4, 7.0 Hz, 1 H), 3.76 (br s, 1 H),
3.57–3.48 (m, 1 H), 3.51 (dt, J = 9.4, 7.3 Hz, 1 H), 3.46 (dd, J = 5.8,
2.7 Hz, 1 H), 3.36 (t, J = 8.7 Hz, 2 H), 2.60 (hept, J = 7.0 Hz, 1 H),
1.64–1.58 (m, 2 H), 1.29–1.26 (m, 10 H), 1.18 (d, J = 7.0 Hz, 3 H),
1.17 (d, J = 7.0 Hz, 3 H), 0.88 (t, J = 6.8 Hz, 3 H).
(6) Trzeciak, A.; Bannwarth, W. Synthesis 1996, 1433.
(7) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240.
(8) Regioselective protection of glucose derivatives has been
reported, 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.
(9) Site-selective acylation of erythromycin has been
developed, see: Lewis, C. A.; Miller, S. J. Angew. Chem. Int.
Ed. 2006, 45, 5616.
13C NMR (100 MHz, CDCl3): d = 177.69, 102.59, 76.16, 73.89,
73.53, 70.37, 70.31, 63.52, 33.95, 31.84, 29.62, 29.41, 29.28,
25.92, 22.65, 19.03, 18.95, 14.09.
(10) (a) Therisod, M.; Klibanov, A. M. J. Am. Chem. Soc. 1987,
109, 3977. (b) Björkling, F.; Godtfredsen, S. E.; Kirk, O. J.
Chem. Soc., Chem. Commun. 1989, 934.
(11) Kattnig, E.; Albert, M. Org. Lett. 2004, 6, 945.
(12) We recently reported regioselective acylation of 6-O-
protected octyl b-D-glucopyranosides by DMAP catalysis,
see: Muramatsu, W.; Kawabata, T. Tetrahedron Lett. 2007,
48, 5031.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
(A) from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Synthesis 2008, No. 5, 747–753 © Thieme Stuttgart · New York

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Regioselective Acylation of Octyl b-D-Glucopyranoside
753
(13) (a) Kurahashi, T.; Mizutani, T.; Yoshida, J. J. Chem. Soc.,
Perkin Trans. 1 1999, 465. (b) Kurahashi, T.; Mizutani, T.;
Yoshida, J. Tetrahedron 2002, 58, 8669.
(14) Griswold, K. S.; Miller, S. J. Tetrahedron 2003, 59, 8869.
(15) See supporting information for: Kawabata, T.; Muramatsu,
W.; Nishio, T.; Shibata, T.; Schedel, H. J. Am. Chem. Soc.
2007, 129, 12890.
(16) Fischer, C. B.; Xu, S.; Zipse, H. Chem. Eur. J. 2006, 12,
5779.
(17) Reversal in regioselectivity of acylation depending on the
acylation agent was also reported by Kattnig and Albert, see
reference 11.
Synthesis 2008, No. 5, 747–753 © Thieme Stuttgart · New York