Convenient access to halide ion-catalyzed α-glycosylation free from noxious fumes at the donor synthesis

Full text of DOI:10.1081/CAR-120016858

Journal of Carbohydrate Chemistry
ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: http://www.tandfonline.com/loi/lcar20
CONVENIENT ACCESS TO HALIDE ION-CATALYZED
α-GLYCOSYLATION FREE FROM NOXIOUS FUMES AT
THE DONOR SYNTHESIS
Yuko Shingu , Yoshihiro Nishida , Hirofumi Dohi , Kazuhiro Matsuda &
Kazukiyo Kobayashi
To cite this article: Yuko Shingu , Yoshihiro Nishida , Hirofumi Dohi , Kazuhiro Matsuda
& Kazukiyo Kobayashi (2002) CONVENIENT ACCESS TO HALIDE ION-CATALYZED α-
GLYCOSYLATION FREE FROM NOXIOUS FUMES AT THE DONOR SYNTHESIS, Journal of
Carbohydrate Chemistry, 21:6, 605-611
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 21, No. 6, pp. 605–611, 2002
COMMUNICATION
CONVENIENT ACCESS TO HALIDE ION-CATALYZED
a-GLYCOSYLATION FREE FROM NOXIOUS FUMES
AT THE DONOR SYNTHESIS
1
Yuko Shingu,1 Yoshihiro Nishida,1, Hirofumi Dohi,
*
Kazuhiro Matsuda,2 and Kazukiyo Kobayashi1,
*
1Department of Molecular Design and Engineering, Graduate School of
Engineering, Nagoya University, Chikusa-ku, Nagoya 464-8603, Japan
2Division of Virus Disease Research, National Cancer Research Institute,
Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan
Key Words: a-Glycosylation; Glycosyl bromide; Glycosyl glyceride
a-Selective glycosylation is a highly challenging and meaningful objective in carbohy-
drate chemistry.[1a-c] This is mainly because many biologically active oligosaccharides
and other glycoconjugates in nature carry an a-glycoside linkage at the non-reducing
terminal such as a-L-fucoside in sialyl LewisX antigens[2] and a-D-galactobioside in PK
antigens.[3a,b] However, a-glycosylation is not straightforward and requires optimization
of the glycosyl donors, promoters, solvents, and other reaction conditions. In this respect,
a halide ion-catalyzed a-glycosylation method proposed by Lemieux et al.[4] in 1975 has
provided one of the few definitive ways. a-Selectivity is nearly perfect for many acceptor
sugars so far examined as long as 2-O-benzyl glycosyl bromides are employed as
donors.[5a–d] Moreover, the method requires no heavy metal promoters or strong Lewis
acid catalysts. These properties are of high significance for large-scale production of
‘‘sugar-based’’ therapeutic agents and biochemical materials.
In our study on the structure and immunogenic activity of a-D-glucopyranosyl-sn-
glycerophospholipids (GGPLs) isolated from Mycoplasma fermentans,[6a,b] we applied
*
Corresponding authors.
605
DOI: 10.1081/CAR-120016858
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2002 by Marcel Dekker, Inc.

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606
SHINGU ET AL.
Scheme 1. Preparation of 2-O-benzyl glycosyl bromides 2. (a) Conventional bromination using
noxious fumes of HBr. (b) Our proposal for bromination using Ph3P/CBr4.
the Lemieux method to stereoselective syntheses of GGPL-I and GGPL-III to elucidate
their absolute structures.[7a,b] During this study, however, we experienced much trouble
at the stage of preparing the 2-O-benzyl glycosyl bromides. In particular, the use of
hydrogen bromide (HBr) from a steel tank requires special attention regarding noxious
fumes. Such experiences prompted us to eliminate the difficulty prior to employing the
excellent a-glycosylation methodology. In this paper, we describe a convenient access
to 6-O-acetyl-2,3,4-tri-O-benzyl-a-D-glucopyranosyl bromide leading to a one-pot a-gly-
cosylation reaction. The pathway allows us to perform a highly practical a-glycosylation
without suffering from the noxious fumes.
2-O-Benzyl glycosyl bromides 2 are highly labile and intolerant to purification on
silica gel columns and other purification processes. Therefore, 1-O-p-nitrobenzoyl su-
gars 1a[8] and 1-thio glycosides[9] have been popularly employed as donor precursors
(Scheme 1-a). Upon treatment of 1a with HBr gas in CH2Cl2, the glycosylbromide 2 is
produced and p-nitrobenzoic acid crystallizes from the solution. Though 1-thio gly-
Scheme 2. Convenient synthesis of the bromide donor 6 and its application for one pot
a-glycosylation.

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DONOR SYNTHESIS AND a-GLYCOSYLATION
607
cosides are convertible to glycosyl bromides without using HBr gas, this approach
seems to cause an analogous problem of malodorous thiols.[10] In the present study, we
expected that anomeric free (1-OH) sugars 1b might lead to the halide ion-catalytic
a-glycosylation effectively by the use of an appropriate brominating agent. Among
several candidates as brominating agents,[11,12a,b–14] we investigated triphenylpho-
sphine/ carbon tetrabromide[14] as a reagent for replacing the 1-OH group with 1-Br
(Scheme 1-b).
In order to examine the 1-bromination reaction, 6-O-acetyl–2,3,4-tri-O-benzyl-D-
glucopyranose 5 was prepared from methyl tetra-O-benzyl-D-glucopyranoside 3 avail-
able from D-glucose in our reported way (72% yield for two steps).[15] Regioselective
acetolysis of 3 cleaved the 1-O-Me and 6-O-Bn groups and afforded 4, which was
subjected to aminolysis by piperidine in THF to then give the 1-OH sugar 5 (Scheme 2).
The bromination reaction of 5 with PhP3 and CBr4 was optimized at room temperature
(15–20°C) by changing the solvents (CH2Cl2, toluene, THF, and diethyl ether) and the
molar ratio of the bromination agents (1.0 ꢀ 3.0 mol equiv). The reaction was mo-
nitored by TLC on silica gel (n-hexane/ethyl acetate) to show that the 1-OH sugar 5
was consumed completely within 3 h and converted to glycosyl bromide 6 when CBr4
Scheme 3. Application of 6 for one pot a-glycosylation to 3-O-a-D-glycosyl-sn-glycerides.

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608
SHINGU ET AL.
(3 mol equiv) and Ph3P (3 mol equiv) were used in CH2Cl2.a Addition of diethyl ether
caused precipitation of Ph3P O. Filtration followed by the evaporation of the solvent
gave 6-O-acetyl-2,3,4-tri-O-benzyl-a-D-glucosyl bromide 6 as a syrup.[16]
One-pot glycosylation was next examined for the reaction mixture without any
isolation processes for the bromide donor 6 and Ph3P O. Commercially available (S)-
glycidol 7 and 1,2-O-isopropylidene-sn-glycerol 10 were employed as glycosyl ac-
ceptors, taking their synthetic potential for GGPLs and other a-D-glycosyl-sn-glycerides
into account (Scheme 3).[7,17,18] When the glycosylation was conducted at room tem-
perature in the presence of tetraethylammonium bromide[4,5] (Et4NBr, 1.5 mol equiv)
and N,N,N’,N’-tetramethylurea (TMU, 10 mol equiv),[7] each of the glycosylated pro-
ducts 8 and 11 was isolated in satisfactory yieldsb (82% and 95%, respectively, based
1
on the amount of 1-OH sugar 5) after purification on silica gel column. Their H NMR
spectrac showed that both of the acceptors 7 and 10 permitted a-selective glycosylation
affording no b-isomer. These results have shown that none of the brominating agents
and possible side-products, including Ph3P O, affect the one-pot a-glycosylation
under the halide ion-catalytic conditions. On the other hand, the reaction of 10 was
found to cause epimerization at the glycerol moiety to give a mixture of two di-
astereomers 11a and 11b in ca. 3:2 ratio. Analogous isomerization was reported in
glycosylation reactions using heavy metal promoters and regulated by the addition of
an appropriate amine base.[17,18] In the present case, the epimerization is considered to
proceed via the formation of an oxonium cation complex stabilized under the halide
ion-catalytic conditions (Scheme 3-b). The addition of excess TMU could not avoid the
aThe 1-bromination reaction at room temperature was sluggish in toluene and not detected in THF
and diethyl ether in 2 h.
bIn these reactions, glycosyl bromide 6 was consumed completely for a-glycosylation without any
decomposition into 5. The low yield of 8 was ascribed to partial ring opening of the epoxide moiety
by a bromide anion during the reaction.
1
cSelected analytical date of compound 8: H NMR (500 MHz, CDCl3) dH7.40 ꢀ 7.23 (m, 5 H Â 3,
–CH2C6H5), 4.55 ꢀ 5.02 (dd, 2 H Â 3, –CH2C6H5), 4.87 (d, 1 H, J = 4.0 Hz, H-1), 4.26 (dd, 1 H,
J = 4.0 and 12.0 Hz, H-6S), 4.22 (dd, 1 H, J = 2.5 and 12.0 Hz, H-6R), 4.02 (t, 1 H, J = 9.0 and 9.5
Hz, H-3), 3.88 (m, 1 H, H-5), 3.76 (dd, 1 H, J = 3.5 and 12.0 Hz, glycidol H-3proR), 3.48 (dd, 1 H,
J = 6.0 and 12.0 Hz, glycidol H-3proS), 3.53 (dd, 1 H J = 3.5 and 9.5 Hz, H-2), 3.20 (m, 1 H,
glycidol H-2), 2.57 and 2.78 (dd, 1 H Â 2, J = 4.0 and J = 5.0, J = 3.0 and 5.0 Hz, glycidol H-1proR
or H-1proS), 1.99 (s, 3 H, –Ac); HR MS (FAB): m/z calcd for C32H36O8Na [M + Na + ] 571.2308;
found 571.2285. Compound 11a (major product): 1H NMR (500 MHz, CDCl3) dH 7.40 ꢀ 7.23 (m,
5 H Â 3, –CH2C6H5), 4.56 ꢀ l4.99 (dd, 2 H Â 3, –CH2C6H5), 4.83 (d, 1 H, J = 3.5 Hz, H-1), 4.35
(t, 1 H, J = 5.5 and 6.5 Hz, glycerol H-2), 4.20 ꢀ 4.28 (dd, 1 H Â 2 H-6), 3.98 (t, 1 H, J = 9.0 and
9.5 Hz, H-3), 3.85 (m, 1 H, H-5), 4.07 and 3.74 (dd, 1 H Â 2, J = 8.5 and 6.5, J = 6.0 and 8.0 Hz,
glycerol H-3proR or H-3proS), 3.60 and 3.55 (dd, 2 H, J = 6.0 and 10.5, J = 6.5 and 10.5 Hz, glycerol
H-1proR or H-1proS), 3.54 (dd, 1 H, J = 3.5 and 9.5 Hz, H-2), 3.47 (dd, 1 H, J = 9.0 and 10.0 Hz, H-4),
2.02 (s, 3 H, –Ac), 1.42 and 1.36 (s, 3 H Â 2, isopropyl). Compound 11b (minor product): 1H NMR
(500 MHz, CDCl3): dH7.40 ꢀ 7.23 (m, 15 H, –CH2C6H5), 4.56 ꢀ 4.99 (dd, 2 H Â 3, –CH2C6H5),
4.74 (d, 1 H, J = 3.5 Hz, H-1), 4.32 (t, 1 H, J = 5.5 and 6.5 Hz, glycerol H-2), 4.20 ꢀ 4.28 (dd, 1
H Â 2, H-6), 4.00 (t, 1 H, J = 9.0 and 9.5 Hz, H-3), 3.88 (m, 1 H, H-5), 4.07 and 3.78 (dd, 1 H Â 2,
J = 6.5 and 8.5, J = 5.5 and J = 8.0 Hz, glycerol H-3proR or H-3proS), 3.69 and 3.42 (dd, 1 H Â 2,
J = 6.0 and 10.5, J = 6.5 and 10.5 Hz, glycerol H-1proR or H-1proS), 3.54 (dd, 1 H, J = 3.5 and 9.5 Hz,
H-2), 3.48 (dd, 1 H, J = 9.0 and 10.0 Hz, H-4), 2.02 (s, 3 H, –Ac), 1.41 and 1.35 (s, 3 H Â 2,
isopropyl); HR MS (FAB): m/z calcd for C35H42O9Na [M + Na + ] 629.2727; found 629.2704.

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DONOR SYNTHESIS AND a-GLYCOSYLATION
609
epimerization. In any case, the use of (S)-glycidol 7 provides a more practical way
towards 3-O-a-D-glycosyl-sn-glycerides, since a fatty acid can be introduced in an SN2
fashion affording 9 regioselectively (Scheme 3-a).[7]
In conclusion, we have demonstrated a convenient access to 2-O-benzyl glucosyl
bromide 6 starting from D-glucose leading to one-pot halide ion-catalyzed a-gly-
cosylation. This approach has solved the difficulty in the chemical construction of a-D-
glucopyranosyl-sn-glycerides widely distributed in bacterial cell walls. We expect that
the present pathway will be extended to other glycosyl donors and acceptors to solve
many of difficulties encountered in a-glycosylation chemistry. Additional studies are in
progress in our group and will be reported elsewhere.
ACKNOWLEDGMENT
A part of this study is supported by a grant of the Ministry of Education & Science of
Japanese Government.
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Received June 4, 2002
Accepted September 9, 2002