Perfectly regioselective and sequential protection of glucopyranosides

Article abstract of DOI:10.1002/ejoc.200901393

A perfectly regioselective and sequential method for the preparation of orthogonally protected glucopyranosides has been developed. An acyl group was introduced at C(4)-OH by organocatalysis with >99% regioselectivity. TBDPS, Boc, and BOM groups were sequentially introduced into the 4O-acyl- glucopyranoside at C(6)-OH, C(2)-OH, and C(3)-OH, respectively, with ca. 100 % regioselectivity in each step.

Full text of DOI:10.1002/ejoc.200901393

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901393
Perfectly Regioselective and Sequential Protection of Glucopyranosides
Wataru Muramatsu,[a] Kenji Mishiro,[a] Yoshihiro Ueda,[a] Takumi Furuta,[a] and
Takeo Kawabata*[a]
Dedicated to Professor Emeritus Kaoru Fuji on the occasion of his 70th birthday
Keywords: Regioselectivity / Protecting groups / Organocatalysis / Carbohydrates / Sequential protection
A perfectly regioselective and sequential method for the
preparation of orthogonally protected glucopyranosides has
been developed. An acyl group was introduced at C(4)-OH
by organocatalysis with Ͼ99% regioselectivity. TBDPS, Boc,
and BOM groups were sequentially introduced into the 4-
O-acyl-glucopyranoside at C(6)-OH, C(2)-OH, and C(3)-OH,
respectively, with ca. 100% regioselectivity in each step.
derivatives has been reported.[4] Chemoselective acylation
of a secondary hydroxy group in the presence of a free pri-
mary hydroxy group is much more difficult. Kurahasi, Mi-
zutani, and Yoshida reported a pioneering example of
chemoselective acylation of a secondary hydroxy group at
C(4) with 61% selectivity in the presence of a free primary
hydroxy group at C(6) of octyl α--glucopyranoside.[5a]
They also reported the regioselective acylation of octyl β-
-glucopyranoside with functionalized DMAP derivatives,
which gave the 3-O-acetate with 49% regioselectivity.[5b]
Kattnig and Albert reported the regioselective 3-O-acyl-
ation of octyl β--glucopyranoside with 57% selectivity and
60% yield by treatment with acetic anhydride in the pres-
ence of DMAP, whereas 6-O-acylation took place predomi-
nantly by use of acetyl chloride in place of acetic anhy-
dride.[5c] Griswold and Miller reported an excellent ap-
proach to the selective introduction of an acetyl group at a
secondary hydroxy group of octyl β--glucopyranoside by
using peptide-based chiral catalysts. Selective 4-O-acylation
has been achieved with 58% regioselectivity.[5d] Recently,
Onomura and co-workers reported highly regioselective
benzoylation of monosaccharides catalyzed by Me2Sn-
Cl2.[5e,6]
Introduction
Regioselective manipulation of one of the multiple hy-
droxy groups of carbohydrates has been a fundamental
challenge in organic synthesis. We have developed an organ-
ocatalyst with functional side chains for substrate recogni-
tion, which enables the regioselective introduction of an
acyl group at C(4)-OH of glycopyranosides.[1] As a further
challenge, we report here a strategy for sequential introduc-
tion of protective groups into four hydroxy groups of glyco-
pyranosides in a highly regioselective manner for each step
(Scheme 1). This gives orthogonally protected glycopyrano-
sides, which are expected to be useful intermediates for the
synthesis of oligosaccharides of biological interests.[2]
Scheme 1. Preparation of an orthogonally protected glucose deriva-
tive by regioselective and sequential introduction of protective
groups.
Enzymatic regioselective acylation and deacylation of
carbohydrates have been extensively studied.[3] On the other
hand, development of the non-enzymatic surrogates have
been the focus of current organic synthesis. Regioselective
acylation of a particular secondary hydroxy group among
three secondary hydroxy groups of 6-O-protected glucose
Results and Discussion
We have reported an organocatalytic regioselective acyl-
ation of monosaccharides.[1] Acylation of the secondary hy-
droxy group at C(4) of octyl β--glucopyranoside pro-
ceeded with up to Ͼ99% 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 2). A possible
transition-state assembly for regioselective acylation of oc-
tyl β--glucopyranoside promoted by catalyst 1 is shown in
[a] Institute for Chemical Research, Kyoto University
Uji, Kyoto 611-0011, Japan
Fax: +81-774-38-3197
E-mail: kawabata@scl.kyoto-u.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901393.
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W. Muramatsu, K. Mishiro, Y. Ueda, T. Furuta, T. Kawabata
SHORT COMMUNICATION
Scheme 2. Regioselective and straightforward route to orthogonally protected glucose derivative 5.
Figure 1. Since the primary hydroxy group at C(6) is the
most reactive in the substrate, it would preferentially form
hydrogen bonds with an amide carbonyl group of the acylp-
yridinium ion generated from 1. As the result of the H-
bonding interaction, the indole NH group is located in the
proximity of C(3)-OH, resulting in the formation of an ad-
ditional hydrogen bond between them. The cooperative ef-
fects of two hydrogen bonds would fix the conformation of
the substrate at the transition state for acylation, where the
C(4)-OH group is in close proximity to the reactive car-
Figure 1. Possible transition-state model for the regioselective acyl-
ation of octyl β--glucopyranoside with catalyst 1.
bonyl group of the acylpyridinium ion, resulting in the se-
lective acylation at C(4)-OH. We planned to employ this
catalytic regioselective acylation as a key step for the prepa-
ration of orthogonally protected glucose derivatives by a tion, which gives the 4-O-isobutyryl- and 3-O-isobutyryl de-
synthetic strategy shown in Scheme 2. Once the acyl group rivatives in a 99:1 ratio.[1] A TBDPS group was introduced
was regioselectively introduced at the intrinsically less reac- selectively into the primary hydroxy group at C(6) of 2 by
tive C(4)-OH group by organocatalysis, sequential introduc- treatment with TBDPSCl in DMF at 0 °C to give silyl ether
tion of the protective groups, PG2, PG3, and PG4 onto 3 as the sole product in 98% yield. Regioselective introduc-
C(6)-OH, C(2)-OH, and C(3)-OH, respectively, would be tion of a protective group into the C(2)-OH group was then
possible based on the intrinsic reactivity order of the C(6)-, examined. We assumed that the C(3)-OH group is in a steri-
C(2)-, and C(3)-OH groups. The orthogonally protected cally more congested environment than the C(2)-OH group
glucose derivative thus formed may be a potentially useful because of the neighboring C(4)-OCOiPr group,[10] so that
intermediate for the synthesis of oligosaccharides because the use of bulky reagents was expected to give the corre-
each of the mono-ols with three different protective groups sponding 2-O-protected isomer preferentially. Selected ex-
would be readily obtained by its deprotection.
amples for the optimization of the 2-O-selective protection
The regioselective synthesis of orthogonally protected are shown in Table 1. Regioselective protection of 3 was ex-
glucose derivative 5 is shown in Scheme 2. Treatment of oc- amined with triphenylmethyl chloride (TrCl), di-
tyl β--glucopyranoside (1 g scale) with isobutyric anhy- phenylmethyl bromide (DPMBr), benzyloxymethyl chloride
dride[7,8] in the presence of 1 mol-% of catalyst 1[9] at –20 °C (BOMCl), and di-tert-butyl dicarbonate [(Boc)2O] (En-
in CHCl3 gave 4-O-isobutyryl derivative 2 with Ͼ99% re- tries 1–4). The reaction took place preferentially at C(2)-
gioselectivity and 99% yield. No trace of regioisomers was OH in each case. Since the use of (Boc)2O gave the most
detected. The observed regioselectivity was slightly better promising results, solvent effects on the regioselectivity of
than that of the corresponding 0.2 mmol (58 mg) scale reac- the reaction with (Boc)2O were investigated (Entries 4–7).
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Perfectly Regioselective and Sequential Protection of Glucopyranosides
Table 1. Regioselective protection of octyl 4-O-isobutyryl-6-O-TBDPS-β--glucopyranoside (3).
Entry
PG2-X[a]
Solvent
Temp. [°C]/Time [h]
Yield of 4A [%]
Yield of 4B [%]
1[b]
2[b]
3[c]
4[d]
5[d]
6[d]
7[d]
8[d]
TrCl
CHCl3
CHCl3
CHCl3
CHCl3
toluene
THF
20/168
20/168
20/24
0/12
0/12
0/12
53
64
84
95
91
96
98
98
ca. 0
ca. 0
12
4
6
2
2
DPMBr
BOMCl
(Boc)2O
(Boc)2O
(Boc)2O
(Boc)2O
(Boc)2O
CH2Cl2
CH2Cl2
0/12
–10/24
ca. 0
[a] 1.5 and 1.2 equiv. of reagents were used for Entries 1–2 and 3–8, respectively. [b] Run in the presence of 10 mol-% of PPY and
2.0 equiv. of collidine. [c] Run in the presence of 1.5 equiv. of iPr2NEt. [d] Run in the presence of 10 mol-% of PPY and 1.5 equiv. of
collidine.
Among the solvents examined, CH2Cl2 gave the highest re- yield. Hydrogenolysis, reduction with DIBAL-H, and desi-
gioselectivity (98:2, Entry 7). Introduction of a Boc group lylation of 5 gave the 3-, 4-, and 6-alcohols 4, 7, or 8, respec-
was achieved exclusively at the C(2)-OH group by treatment tively, in 96–99% yield.
of 3 with Boc2O in CH2Cl2 at –10 °C in the presence of 4-
The strategy for the sequential and regioselective intro-
pyrrolidinopyridine (PPY) and collidine (Entry 8 and duction of protective groups into octyl β--glucopyranoside
Scheme 2). Finally, orthogonally protected glucose deriva- was applied to the corresponding thioglycosides because
tive 5 was obtained in 99% yield by treatment of 4 with they can be used directly for glycosylation as glycosyl do-
BOMCl under reflux of CH2Cl2. Thus, a perfectly regiose- nors[11] (Scheme 4). Since we already know that the control
lective and straightforward route to 5 was developed start- of regioselectvity of acylation of octyl β--thioglucopyrano-
ing from octyl β--glucopyranoside in 94% overall yield.
side in the presence of 1 is more difficult than that of octyl
Glucose derivative 5 is expected to be a reasonable pre- β--glucopyranoside,[1] we employed more drastic reaction
cursor for mono-ols with three different protective groups, conditions than those used for the acylation of octyl β--
which have been used as intermediates for oligosaccharide glucopyranoside. Acylation of octyl β--thioglucopyrano-
synthesis.[2] Preparation of the mono-ols by chemoselective side with isobutyric anhydride was carried out at –60 °C
deprotection of 5 was examined (Scheme 3). Thermal re- with 3 mol-% of 1 to give 4-O-isobutyryl derivative 9 with
moval of the Boc group of 5 gave the 2-alcohol 6 in 98% 94% regioselectivity and 99% yield. Silylation of 9 gave 6-
O-TBDPS derivative 10 as the sole detectable isomer in
93% yield. Introduction of a Boc group into the C(2)-OH
Scheme 4. Regioselective and straightforward route to orthogonally
protected thioglycosides 12.
Scheme 3. Preparation of protected mono-ols 4 and 6–8 from 5.
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W. Muramatsu, K. Mishiro, Y. Ueda, T. Furuta, T. Kawabata
SHORT COMMUNICATION
group of 10 was achieved with 97% regioselectivity and sion of the configuration at the C(3)-OH group under Mit-
99% yield. Finally, a BOM group was introduced at the sunobu conditions, and also to protected azidoglycoside 20
C(3)-OH group of 11 to give 12 in 98% yield.
under conditions similar to those for 16 (Scheme 7). Simi-
Octyl β--thioglucopyranoside mono-ols with three dif- larly, azidoglycoside 21 was readily prepared from 15 in
ferent protective groups, 11 and 13–15, were readily ob-
tained from 12 (Scheme 5) according to similar methods
employed for the transformation of 5 to 4 and 6–8. Prepara-
tions of the 2-, 4-, and 6-alcohols, 13, 14, and 15 were ac-
complished in high yields according to the same procedures
for 6, 7, and 8, respectively. Removal of the BOM group at
the C(2)-OH group of 12 required slightly harsher condi-
tions [4 atm of hydrogen, 30 wt.-% of Pd(OH)2/C] to give
11 in 92% yield. Protected mono-ols 11 and 13–15 appear
to be potentially useful intermediates for oligosaccharide
synthesis. Additionally, they are useful for the modification
of natural glycosides. For example, the hydroxy group at
C(4) of 14 was transformed to an azide group by mesylation
followed by azide substitution to give azidoglycoside 16 in
70% yield with inversion of configuration (Scheme 6). Azi-
doglycosides are useful precursors for aminoglycosides[12]
and triazole-linked glycosides.[13,14] Azidoglycoside 16 was
readily converted to 4-amino-4-deoxyglucoside 17 and tri-
azole-linked glycoside 18 in 95% and 88% yield, respec-
tively. Protected glucose derivative 11 was readily converted
to fully protected allose derivative 19 in 66% yield by inver- 12.
Scheme 5. Preparation of protected mono-ols 11 and 13–15 from
Scheme 6. Preparation of aminoglycoside 17 and triazole-linked glycoside 18 from protected glucose mono-ol 14.
Scheme 7. Preparation of fully protected allose derivative 19 and azidoglycoside 20 from protected glucose mono-ol 11.
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Perfectly Regioselective and Sequential Protection of Glucopyranosides
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derivative 22 by rearrangement of the octylthio group in
64% yield.[15] Glycosyl azide 22 is expected to be a versatile
intermediate for the synthesis of oligosaccharides contain-
ing an N-glycosyltriazole linkage and also to be a protected
glycosyl donor under enzyme-catalyzed glycosidation.[16]
Fully protected galactose derivative 23 was also obtained
from 14 under Mitsunobu conditions in 62% yield, which
may be a potentially useful intermediate for the synthesis
of galactose-containing oligosaccharides.
[6]
[7]
Conclusions
We have developed a method for highly regioselective
and sequential introduction of four different protective
groups onto four hydroxy groups of glycopyranosides. Each
of the protective groups of the orthogonally protected gluc-
opyranosides was readily removed to give the correspond-
ing mono-ols with three different protective groups, which
are possible intermediates for the synthesis of natural and
modified oligosaccharides with structural diversity. This
method provides a new way for regioselective manipulation
of carbohydrates.
[8]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for all new
compounds.
[9]
For an excellent review on chiral PPY and DMAP analogues
in asymmetric synthesis, see: R. P. Wurz, Chem. Rev. 2007, 107,
5570–5595.
[10]
The C(4)-OCOiPr group is assumed to be located closer to the
C(3)-OH group due to the buttressing effect of the neighboring
bulky TBDPS group at C(6).
Acknowledgments
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This work was supported by a Grant-in-Aid for Scientific Research
(A) from the Ministry of Education, Culture, Sports, Science and
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Received: December 1, 2009
Published Online: January 12, 2010
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