An improved method for the preparation of 3-O-benzyl-6-O-pivaloyl-α-D-glucopyranose 1,2,4-orthopivalate

Article abstract of DOI:10.1016/S0008-6215(02)00085-X

The synthetic route to 3-O-benzyl-6-O-pivaloyl-α-D-glucopyranose 1,2,4-orthopivalate (1), which was previously established, was shortened by introducing two novel reactions, regioselective pivaloylation with dibutyltin oxide in toluene for the regioselective activation of hydroxyl groups, and intramolecular orthoesterification with benzenesulfonyl chloride and triethylamine in dichloromethane. Compound 1 was obtained in 58.8% overall yield from commercially available 1,2:5,6-di-O-isopropylidene-α-D-glucopyranose (2) via four reaction steps.

Full text of DOI:10.1016/S0008-6215(02)00085-X

Carbohydrate Research 337 (2002) 951–954
www.elsevier.com/locate/carres
Note
An improved method for the preparation of
3-O-benzyl-6-O-pivaloyl-a-D-glucopyranose 1,2,4-orthopivalate
Makoto Karakawa,* Fumiaki Nakatsubo
Di6ision of Forest and Biomaterials Science, Graduate School of Agriculture, Kyoto Uni6ersity, Sakyo-Ku, Kyoto 606-8502, Japan
Received 18 February 2002; accepted 14 March 2002
Abstract
The synthetic route to 3-O-benzyl-6-O-pivaloyl-a-
D
-glucopyranose 1,2,4-orthopivalate (1), which was previously established,
was shortened by introducing two novel reactions, regioselective pivaloylation with dibutyltin oxide in toluene for the
regioselective activation of hydroxyl groups, and intramolecular orthoesterification with benzenesulfonyl chloride and triethy-
lamine in dichloromethane. Compound 1 was obtained in 58.8% overall yield from commercially available 1,2:5,6-di-O-isopropy-
lidene-a-D-glucopyranose (2) via four reaction steps. © 2002 Elsevier Science Ltd. All rights reserved.
Keywords: 3-O-Benzyl-6-O-pivaloyl-a-D-glucopyranose 1,2,4-orthopivalate; Regioselective pivaloylation; Intramolecular orthoesterification; Cellu-
lose synthesis
There are many functionalized cellulose derivatives.
Hydroxypropyl cellulose has liquid crystal properties,1
methyl or carboxymethyl celluloses show thermore-
versible gelation,2 Na-cellulose sulfates have film-forming
properties and biological activities,2 and so on.
The structure and properties of partially functionalized
celluloses—from natural cellulose or from chemosynthe-
sis—are controlled by the degree of polymerization (DP),
the degree of substitution (DS), and the functionalization
pattern. The pattern of functionalization includes the
distribution within the anhydroglucose unit along the
polymer chain and between the chains. However, much
remains unknown about the relationship between the
molecular structures of cellulose derivatives and their
properties.
subsequent derivatization. Recently, a method for the
preparation of 3-O-substituted cellulose using the
thexyldimethylsilyl group was reported by Koschella et
al.,6 but other regioselectively substituted cellulose
derivatives, such as 2-O-, 3,6-di-O- or 2,6-di-O-substi-
tuted celluloses, could be scarcely prepared by their
methods.
On the other hand, synthesis of cellulose has been
reported starting from 3,6-di-O-benzyl-, and 3-O-benzyl-
6-O-pivaloyl-a- -glucopyranose 1,2,4-orthopivalate (1)
D
by a cationic ring-opening polymerization.7,8 The cellu-
lose derivatives obtained can be converted to other
regioselectively substituted celluloses. Particularly, 2-O-,
3,6-di-O- or 2,6-di-O-substituted celluloses can be pre-
pared from the synthetic cellulose intermediates, because
the two secondary hydroxyl groups at the C-2 and C-3
positions in the repeating anhydroglucose units on the
cellulose chain are already protected with ester and ether
groups, respectively, and both of which can be selectively
deprototected. Thus, chemically synthesized cellulose is
extremely useful.
For these studies, and for the molecular design of
advanced materials from cellulose, it is important to be
able to prepare regioselectively substituted cellulose
derivatives bearing desired functional groups on the
desired hydroxyl groups in the repeating anhydroglucose
units of the polymers.
At present, regioselectively 6-O- and 2,3-di-O-substi-
tuted cellulose derivatives3–5 have been prepared from
natural cellulose via tritylation at the 6-O-position with
3-O-Benzyl-6-O-pivaloyl-a-D-glucopyranose 1,2,4-or-
thopivalate (1), the starting monomer for the synthesis
of cellulose, is also a valuable compound for preparing
various other orthopivalate derivatives that lead to
regioselectively substituted celluloses, as described in our
previous report.9 Compound 1 has been synthesized from
the commercially available 1,2:5,6-di-O-isopropylidene-
* Corresponding author. Fax: +81-75-7536300.
E-mail
address:
karakawa@kais.kyoto-u.ac.jp
(M.
Karakawa).
0008-6215/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00085-X

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M. Karakawa, F. Nakatsubo / Carbohydrate Research 337 (2002) 951–954
a-
D
-glucopyranose (2) via eight reaction steps, i.e., ben-
for subsequent regioselective esterification or etherifica-
tion.13–19 On the other hand, the selectivity of the
pivaloylation reaction for compound 4 was found to be
accomplished at lower reaction temperatures, i.e., be-
low at least −10 °C from the results of our preliminary
experiments. Thus, benzene, which has been generally
used for azeotropic removal of water, is not a suitable
solvent for the preparation of a cyclic tin intermediate
with dibutyltin oxide, because the reaction mixture
solidifies during the subsequent pivaloylation, which is
carried out below −10 °C.
zylation, O-dediisopropylidenation, benzylidenation,
pivaloylation, debenzylidenation, selective pivaloyla-
tion, selective depivaloylation, and intramolecular
orthoesterification.8,10 However, the total yield of com-
pound 1 from compound 2 was low, about 19%. A
synthetic route to compound 1 that had fewer steps and
a greater overall yield is desired.
In this paper, an improved method for the prepara-
tion of compound 1 is described, and two novel reac-
tions are discussed.
Thus, the best regioselective pivaloylation reaction
was accomplished under the following reaction condi-
tions. Compound 4 was treated with two equivalents of
dibutyltin oxide in toluene at 105 °C to convert it into
the bisdibutylstannylene acetal intermediate (Fig. 1),
which was subsequently reacted with pivaloyl chloride
,
and pyridine in the presence of powdered 4 A molecu-
lar sieves at −10 °C to afford compound 5 in 80%
yield. The structure of compound 5 was confirmed by
General o6er6iew.—An improved synthetic route for
compound 1 is shown in Scheme 1. We describe here
two novel reactions, the first of which is the regioselec-
tive pivaloylation at the 2-O- and 6-O-positions of
1
comparison of its H NMR data with those reported
previously.10 Thus, pivaloylation occurred under these
conditions with high regioselectivity at the O-2 and O-6
of compound 4.
3-O-benzyl-
intramolecular orthoesterification of 3-O-benzyl-2,6-di-
O-pivaloyl- -glucopyranose (5).
D
-glucopyranose (4), and the second is the
D
Fig. 1. Plausible structure of the intermediate stannylene
acetal.
Scheme 1. Reagents and conditions: (a) PhCH2Br, NaH,
t-Bu4NI, THF, 0 °C, 5 h; (b) Dowex 50-W (H+), 1:3 EtOH–
H2O, reflux, 5 h, 93% (two steps); (c) PivCl, pyridine,
Bu2SnO, CH3Ph, 4 A MS, 105“ −10 °C, 2 h, 80%; (d)
BuSO2Cl, Et3N, CH2Cl2, rt“reflux, 1 h, 79%.
In this reaction, another important factor in obtain-
ing such high selectivity along with high yield is to use
more than two equivalents of dibutyltin oxide with
compound 4; otherwise, the high selectivity with high
yield is lost. Therefore, the structure of the dibutylstan-
nylene acetal intermediate is considered to be structure
6, shown in Fig. 1. Consequently, the selectivity for O-6
is probably explained by the normal preference of a
4,6-O-dibutylstannylene acetal to react at the primary
oxygen atom16 and that for O-2 by the preference of a
dibutylstannylene acetal cis-fused to a five-membered
ring to react at the equatorial oxygen atom.14 These
results provide further evidence that esters of pyranose
rings do not rearrange at room temperature under
stannylene acetal reaction conditions17 unlike those on
acyclic 1,2-diols.18,19
,
Regioselecti6e pi6aloylation.—Compound 4 was pre-
pared from commercially available 1,2:5,6-di-O-iso-
propylidene-a- -glucopyranose (2) by benzylation and
D
subsequent O-dediisopropylidenation with cation-ex-
change resin in 93% overall yield.
Regioselective pivaloylations of compound 4 with
pivaloyl chloride in pyridine11 or pyridine–chloroform
mixed solvent system were tried, but compound 5 was
not obtained, although 6-O- and 1,6-di-O-pivaloyl
derivatives were produced in 41 and 51% yield, respec-
tively. In diethyl ether solvent,12 6-O- and 1,6-di-O-pi-
valoyl derivatives were also produced about 60 and
30% yield, respectively, without compound 5.
Then, we examined the selective activation of hy-
droxyl groups for regioselective pivaloylation of com-
pound 4. Dibutyltin oxide is a useful reagent for the
selective activation of equatorial, cis-hydroxyl groups
Intramolecular orthoesterification.—Conventional in-
tramolecular orthoesterification of compound 5, con-
ducted by refluxing with N,N%-carbonyldiimidazole in a
large amount of benzene (1 g/130 mL) to avoid inter-
molecular reactions, yielded compound 1 in 58% yield.8

M. Karakawa, F. Nakatsubo / Carbohydrate Research 337 (2002) 951–954
953
afford compound 5 in high yield without having to use
a blocking–deblocking technique. A novel orthoesterifi-
cation reaction with benzenesulfonyl chloride and tri-
ethylamine enables us to synthesize compound 1 in high
yield. Consequently, compound 1 is obtained in 58.8%
overall yield from commercially available 1,2:5,6-di-O-
isopropylidene-a- -glucopyranose (2) via four reaction
D
steps.
1. Experimental
Scheme 2. Proposed reaction mechanism for orthoesterifica-
tion.
General methods.—1H and 13C NMR spectra were
taken with a Varian INOVA 300 FT-NMR instrument
(300 MHz) with tetramethylsilane (Me4Si) as the inter-
nal standard in chloroform-d. Chemical shifts (l) and
coupling constants (J) are given in value (ppm) and Hz,
respectively. Optical rotations were measured at 25 °C
using a JASCO Dip-1000 digital polarimeter. Products
were purified on a silica gel column chromatography
(Wakogel® C-200, Wako Pure Chemical Industries,
Ltd.). The standard workup for reaction mixtures con-
sisted of extraction with EtOAc, washing with brine,
drying over Na2SO4, and concentration of the organic
extract in vacuo.
In this reaction, the 1-O-carbonylimidazole group
may act as a leaving group for the orthoesterification
by dehydration.7,8 Then, we tried another reagent for
the dehydration of OH-1 in compound 5. Both N,N%-di-
cyclohexyl- and N,N%-diisopropylcarbodiimides, which
are popular reagents for ester and peptide synthe-
ses,20,21 were tried, but the expected 1 was not obtained.
The use of thionyl chloride and pyridine in toluene gave
compound 1 in 36% yield, but the starting material still
remained. Finally, three kinds of sulfonyl chlorides,
methane-, p-toluene-, and benzenesulfonyl chlorides,
were examined. The reaction with p-toluene- and ben-
zenesulfonyl chlorides produced compound 1 in 18 and
79% yields, respectively, although methanesulfonyl
chloride gave none of the product. Thus, benzenesul-
fonyl chloride was found to be the most suitable
reagent for the dehydration of OH-1 leading to the
formation of the orthopivalate 1.
Preparation of 3-O-benzyl-
a solution of 1,2:5,6-di-O-isopropylidene-a-
D
-glucopyranose (4).—To
-glucopy-
D
ranose (2, 50 g, 192 mmol) in THF (225 mL), 60% NaH
dispersed in mineral oil (9.22 g, 0.23 mol), and tetra-
butylammonium iodide (7.09 g, 19.2 mmol) were added
at 0 °C. Benzyl bromide (25.1 mL, 210 mmol) was then
added dropwise at 0 °C. The solution was stirred at rt
for 5 h. After addition of MeOH (1 mL), the reaction
mixture was worked up by the standard procedure. The
product was separated on a silica gel column (16 g,
40×30 mm) eluted with 1:19 EtOAc–hexane to give
compound 3 as a yellow oil (ca. 67 g, 100% recovery
yield). The oil was used for the subsequent step without
further purification.
Crude compound 3 (67 g, 192 mmol) and Dowex
50-W (H+) (cation-exchange resin, Dow Chemical Co.)
(27 g, wet weight) were stirred in 1:3 EtOH–water (200
mL) at reflux for 5 h. After the reaction was completed,
the reaction mixture was neutralized with NaOMe, and
then filtered. The solvent (EtOH) was removed under
reduced pressure. The residual water layer was washed
with EtOAc, and then the water was removed by
lyophilization to give compound 4 as a white solid (48.1
g, 93%), which was crystallized from EtOAc to give
colorless crystals: mp 123–125 °C, lit.22 134–135 °C;
[h]2D5 +16.2“ +44.1° (c 0.5, water), lit.22 +21.6“ +
43.2°; Anal. Calcd for C23H32O7: C, 57.77; H, 6.71.
Found: C, 57.49; H, 6.55.
1
The structure of compound 1 was determined by H
and 13C NMR spectroscopy. The spectral data for
compound 1 were completely identical with the litera-
ture data.8 Thus, novel orthoesterification conditions
were established.
The following reaction mechanism to form the or-
thoester is proposed as shown in Scheme 2. Initially,
benzenesulfonyl chloride reacts at the C-1 oxygen atom
to yield compound 7. The carbonyl oxygen atom at the
C-2 position attacks at the C-1 position from the a-side
to form a dioxacarbenium ion intermediate 9, either
directly from 7 or via intermediate 8, and then the
hydroxyl group at the C-4 position in compound 9
attacks the C-7 position, resulting in an intramolecular
cyclization to compound 1.
Thus, compound 1 can be synthesized from
D-glu-
cose in five steps. The present method gives a higher
yield of compound 1 via fewer steps than the conven-
tional process.8,10
We have improved the synthetic method for com-
pound 1 by introducing two novel reactions. Selective
pivaloylation at the 2-O- and 6-O-positions was accom-
plished via the dibutylstannylene acetal intermediate to
Preparation
of
3-O-benzyl-2,6-di-O-pi6aloyl-D-
glucopyranose (5).—Compound 4 (5.0 g, 18.5 mmol)

954
M. Karakawa, F. Nakatsubo / Carbohydrate Research 337 (2002) 951–954
Acknowledgements
and dibutyltin oxide (9.2 g, 37.0 mmol) in toluene (200
mL) were gradually heated to 105 °C until the reaction
mixture become homogeneous and clear. To the clear
This investigation was supported in part by a Grant-
in-Aid for Scientific Research from the Ministry of
Education, Science, and Culture of Japan (no.
11556031).
,
solution, powdered 4 A molecular sieves (4.0 g) were
added. The mixture was cooled to −10 °C. Pyridine
(3.95 mL, 48.8 mmol) was added, followed by the
dropwise addition of pivaloyl chloride (5.46 mL, 44.4
mmol) in toluene (36 mL). After 2 h, MeOH (0.75 mL)
was added. The solvent was removed to give a yellow
oil that was purified on a silica gel column (97 g,
40×180 mm) eluted with CH2Cl2, and then 1:2
EtOAc–hexane. The combined eluent was evaporated
to give compound 5 as a slightly yellow oil (6.5 g, 80%):
1H NMR (CDCl3): l 1.16–1.28 (broad s, 18 H, H-piv),
7.26–7.35 (m, 5 H, Ar).
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