β-selective glycosylation of 5-thioglucopyranose derivatives; syntheses of β-(1 → 6) linked 5′-thioglucopyranosyl disaccharides

Article abstract of DOI:10.1246/cl.2002.626

β-Stereoselctive and effective glycosylation with 5-thioglucopyranose was achieved by performing the reaction with pivaloyl- or benzoyl-protected glucopyranosyl trichloroacetimidates and BF₃OEt₂, a glycosyl activator, when C6-OH gluc

Full text of DOI:10.1246/cl.2002.626

626
Chemistry Letters 2002
ꢀ-Selective Glycosylation of 5-Thioglucopyranose Derivatives; Syntheses of ꢀ-(1 ! 6) Linked
50-Thioglucopyranosyl Disaccharides
Keiichiro Ohara,y Hiroko Matsuda,yy Masaru Hashimoto,Ãy;yy Kazuo Miyairi,y;yy and Toshikatsu Okunoy;yy
yFaculty of Agriculture and Life Science, Hirosaki University, 3 Bunkyou-Cho Hirosaki, Aomori 036-8561
yyThe United Graduate School of Agricultural Science, Iwate University, 3 Bunkyou-Cho Hirosaki, Aomori 036-8561
(Received February 21, 2002; CL-020169)
ꢀ-Stereoselctive and effective glycosylation with 5-thiogluco-
pyranose was achieved by performing the reaction with pivaloyl- or
benzoyl-protected glucopyranosyl trichloroacetimidates and
BF3OEt2, a glycosyl activator, when C6-OH glucopyranosyl or
galactopyranosyl derivatives were employed as acceptors.
Scheme 1. a) DHP, p-TsOH, CH2Cl2, (90%), b) NaOMe, MeOH (100%),
c) acyl chlorides, DMAP, pyridine, 45 ꢀC (IB-Cl; 74%, PivCl; 82%, BzCl;
In the last decade, carbohydrate analogues, carrying sulfur
98%), d) p-TsOH, MeOH, 50 ꢀC (R ¼ IB; 89%, R ¼ Piv; 73%, R ¼ Bz;
atoms in place of oxygens in their pyranose rings, have been
developed as potent glycosidase inhibitors1{3 and as probes to
investigate enzymatic cleavage of glycosidic linkages in detail.4
However, glycosylation reactions so far reported were ꢁ-stereo-
selective in most cases.1;5;6 Only a ꢀ-selective glycosylation has
been reported by utilizing galactosyl-transferase with UDP-5-
thiogalactose.7 We now for the first time disclose ꢀ-selective (up to
50 : 1 selectivity) chemical glycosylations with 6-OH pyranoses.
In the literature, 5-thioglucopyranosyl,1;3;8 5-thioarabino-
pyranosyl,2 and 5-thiofucopyranosyl trichloroacetimidates9 have
been reported to serve as successful glycosyl donors, providing ꢁ-
glycosides stereoselectively. Interestingly, all of those donors
carried acetyl protective groups at the C2-equatorial hydroxyl
position. According to the neighboring effects described in classic
carbohydrate chemistry, this should result in ꢀ-selective
glycosylation.10 We supposed that ꢀ-selective glycosylation could
be realized by choosing appropriate protective groups.
First, glycosyl trichloroacetimidates with a series of acyl
protective groups 3 (R ¼ isobutyryl, abbreviated as IB), 4 (R¼ Piv)
and 5 (R ¼ Bz) were synthesized from known 2,3,4,6-tetra-O-
acetyl-5-thioglucopyranose (1).1 After the anomeric hydroxyl
group was protected in a form of THP, all acetyl groups were
removed under basic methanolysis to yield tetraol 2 in 90% over two
steps. Re-acylations with acid chlorides, such as isobutyryl,
pivaloyl, or benzoyl chloride, were performed by slightly heating
at 45 ꢀC in pyridine with the addition of a catalytic amount of
DMAP. After the THP ether in the products was cleaved in acidic
methanol at 50 ꢀC, the C1-hydroxyl functionality was converted
into trichloroacetimidate to give donors 3–5 in good yields.11
Comparison of the coupling constants of the anomeric protons in 3–
85%) e) CCl3CN, DBU, 0 ꢀC (3; 77%, 4; 82%, 5; 72%).
(12%) (Run 5). Then, BF3OEt2 promoted reactions of the imidates
with various ester groups (3–5) were investigated. When the
reaction was performed with isobutyrate 3, the disaccharide was
only ꢀ-isomer 14ꢁ, but the yield was not practical (12%) (Run 6).
Reaction of pivaloate 4 with acceptors gluco-8, 9, and galacto-11
gave 15ꢁ 16ꢁ and 19ꢁ, respectively in good yields (68, 81 and 67%,
respectively). In particular, no 16ꢀ was detected by TLC.
Unfortunately, pivaloate esters of 16ꢁ could not be removed
cleanly as described below. It was found that benzoate 5 also had
promise as an inducer of ꢀ-selectivity. Treatment of 8, 9 and 11 with
BF3OEt2 afforded 17ꢁ, 18ꢁ and 20ꢁ in good yields and with
moderate stereoselectivity (ꢁ : ꢀ ¼ 1 : 5, 1 : 6 and 1 : 10, respec-
tively) (Run 10–12).12 The stereochemistry of those disaccharides
was determined based on their 1H-NMR spectra. Coupling
constants of the signals due to the C1’H of 17ꢀ (5.13 ppm), 18ꢀ
(5.10 ppm), and 20ꢀ (5.04 ppm) were 3.0, 3.4, and 2.4 Hz,
respectively, and showed that glycoside bonds newly formed have
ꢁ-stereochemistry. On the other hand, ꢀ-stereochemistry at the
C1’H in 17ꢁ, 18ꢁ, and 20ꢁ was also established by their large
coupling constants (17ꢁ : 7:8 Hz, 18ꢁ : 8:8 Hz, and 20ꢁ : 8:3 Hz).
Run 13–15 proved that TMSOTf, TfOH, or ZnCl2 were less
effective as glycosyl promoters (Run 13–15) than BF3OEt2.
Notably, reaction with TfOH gave 17ꢀ stereoselectively. Unfortu-
nately, this method seemed applicable only to primary alcohols
(Run 16, 17). A trace amount of 21ꢀ was obtained, when donor 5
was treated with 10 and BF3OEt2 was employed.
Finally, protective groups of disaccharides 15, 16, 18, and 19
were cleaved (Scheme 2). Treatment of 15ꢁ with sodium
methoxide in methanol proceeded smoothly to provide methyl 50-
thio-ꢁ-gentiobioside (22) in quantitative yield.13 In contrast, TLC
of the reaction mixture indicated it was a complex mixture. None of
23 was observed, when similar conditions were applied to p-
nitrophenyl glycoside 16ꢁ, protected as the pivaloate ester.
However, cleavage of benzoyl derivative 18ꢀ gave p-nitrophenyl
50-thio-ꢁ-gentiobioside 23 in 80% yield.13 Similarly, methyl 6-O-
(50-thio-ꢀ-glucopyranosyl)-ꢁ-galactopyranoside (24)13 was af-
forded from 20ꢁ under almost the same conditions as above.
Enzymatic reaction employing ꢀ-glycosidase revealed that
18ꢁ was not hydrolyzed at all under the conditions we employed (ꢀ-
glycosidase from almond, purchased from Sigma; 2.3 mg/mL, 18ꢁ;
˙
5 (3.4 Hz in all cases) with that of known compound 6 (3.2Hz),
prepared from 1, suggested that the trichloroacetimidate groups
were ꢁ-orientations.
In a previous report, reactions of acetate 6 with C6-OH acceptor
7 by TESOTf afforded ꢁ-glycosides predominantly (Run 1, in
Table 1).8 Our own experiment employing 6 with acceptor 8, gave
only ꢁ-isomer 13ꢀ under similar conditions (Run 2). Reactions
with TMSOTf or TfOH were not successful (Run 3, 4). In the case
of TfOH, anomerization at the C1 position of the acceptor occurred
during the reaction to give an inseparable mixture. However by
employing BF3OEt2, in place of TESOTf, the reaction afforded ꢀ-
glycoside 13ꢁ predominantly (ꢁ : ꢀ ¼ 1 : 1:5), albeit in low yield
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
627
Table 1. Glycosylation with donors 3–6 of acceptors 7–11
the other hand, Whistler et al., reported that methyl ꢁ- and ꢀ-5-
thiopyranosides are hydrolyzed at least 10 times faster than the
corresponding normal pyranosides.15 Also, Bennet et al., recently
determined those stabilities in detail employing methyl 5-
thiopyranosides or 5-thiopyranosyl fluorides.16 Thus, exploring
those differences between 50-thioglycoside and 50-oxoglycoside
seems to be interesting. Development of ꢀ-selective glycosylation
with secondary alcohols is under investigation in our group.
This work was supported by the Grant-in-Aid Scientific
Research (No. 12780434) from Ministry of Education Science,
Sports, and Culture of Japan.
References and Notes
1
2
3
4
S. Mehta and B. M. Pinto, Tetrahedron Lett., 33, 7675 (1992).
H. Hashimoto and M. Izumi, Tetrahedron Lett., 34, 4949 (1993).
M. Izumi, Y. Suhara, and Y. Ichikawa, J. Org. Chem., 63, 4811 (1998).
W. Thomas, S. Bjarne, S. Birte, and B. M. Pinto, Biochemistry, 39, 300
(2000).
5
6
H. Yuasa and H. Hashimoto, Trends in Glycoscience and Glycobiology,
13, 31 (2001).
O. Tsuruta, T. Takahara, H. Yuasa, and H. Hashimoto, The 76th Annual
Meeting of The Chemical Society of Japan, Yokohama, March 1999,
Abstr., No. 1A133.
7
8
9
H. Yuasa, O. Hindsgaul, and M. M. Palcic, J. Am. Chem. Soc., 114, 5891
(1992).
S. Mehta, K. L. Jordan, T. Weimar, U. C. Kreis, R. J. Batchelor, F. W. B.
Einstein, and B. M. Pinto, Tetrahedron Asymm., 5, 2367 (1994).
M. Izumi, O. Tsuruta, S. Harayama, and H. Hashimoto, J. Org. Chem.,
62, 992 (1997).
10 H. Paulsen, in ‘‘Modern Methods In Carbohydrate Synthesis,’’ ed. by
Shaheer H. Khan, Roger, O’Neil, Harwood Academic Publishers
GmbH, Amsterdam (1996), Vol. 1, Chap. p 1.
11 R. R. Schmidt and J. K.-H., in ‘‘Preparative Carbohydrate Chemistry,’’
ed. by S. Hanessian, Marcel Dekker, New York (1997), Chap. 6, p 283.
12 Typical experiment is as follows (Table 1 Run 8). Boron trifluoride
diethyl etherate (1.5 ꢂl, 11.8 ꢂmol) was added into a suspension of
donor 4 (16.5 mg, 24.4 ꢂmol), acceptor 9 (15.0 mg, 24.5 ꢂmol), and
molecular sieves 4A (50 mg) in CH2Cl2 (1.0 ml) at ꢁ78 ꢀC into the
mixture, which was allowed to warm to ꢁ40 ꢀC over 1 hr. After
triethylamine (10 ꢂL) was added, the mixture was filtrated and
concentrated. Silica gel column chromatography (hexane :
AcOEt ¼ 95 : 5) gave 16ꢁ (22.2 mg, 19.6 mmol, 81%). 1H-NMR
(CDCl3) ꢃ1.09, 1.11, 1.12, and 1.16 (each 9H, s), 3.08 (1H, ddd, 3.4, 5.4,
10.3 Hz), 3.70 (1H, dd, 7.3, 10.7 Hz), 3.89 (1H, dd, 2.4, 10.7 Hz), 4.04
(2H, m), 4.30 (1h, ddd, 2.4, 7.3, 10.3 Hz), 4.56 (1H, d, 8.8 Hz), 5.10 (1H,
t, 8.8 Hz), 5.25 (1H, t, 8.8 Hz), 5.29 (1H, t, 8.8, 10.3 Hz) 5.39 (1H, dd,
3.4, 10.3 Hz), 5.50 (1H, t, 10.3 Hz), 5.92 (1H, d, 3.4 Hz), 6.30 (1H, t,
10.3 Hz), 7.22–7.57 (11H), 7.85 (2H, dd, 1.5, 8.3 Hz), 7.90–7.96 (4H),
8.27 (2H, brd 9.3 Hz).
Ã1) See text. Ã2) Adducts were inseparable mixture, so that the yields were
estimated by 1H-NMR. Ã3) No isomer was detected by 1H-NMR nor TLC.
13 1H-NMR for 22–24 are as follows; 22: (D2O) ꢃ 2.81 (1H, ddd, 3.2, 6.0,
9.6 Hz), 3.18 (1H, t, 9.6 Hz), 3.29 (3H, s), 3.35 (1H, t, 9.6 Hz), 3.42 (1H,
dd, 3.7, 9.6Hz), 3.45 (1H, dd, 9.6, 10.3Hz), 3.52 (2H, t, 9.6 Hz), 3.65
(1H, ddd, 2.0, 4.9, 9.6 Hz), 3.71 (1H, dd, 6.0, 12.0 Hz), 3.76 (1H, dd, 4.9,
11.3 Hz), 3.80 (1H, dd, 3.2, 12.0 Hz), 3.95 (1H, dd, 2.0, 11.3 Hz), 4.50
(1H, d, 9.3 Hz), 4.65 (1H, d, 3.7 Hz); 23: (D2O) 2.69 (1H, ddd, 3.9, 6.3,
9.3 Hz), 3.08 (1H, t, 9.3 Hz), 3.34 (1H, t, 9.3 Hz), 3.40 (1H, t, 9.8 Hz),
3.42 (1H, t, 9.3 Hz), 3.60 (1H, dd, 6.3, 12.0 Hz), 3.65 (1H, dd, 3.4,
9.8 Hz), 3.66 (1H, dd, 3.9, 12.0 Hz), 3.74 (2H, m), 3.81 (1H, t, 9.8 Hz),
3.83 (1H, d, 12.0 Hz), 4.38 (1H, d, 9.3 Hz), 5.69 (1H, d, 3.4 Hz), 7.14
(2H, d, 9.3 Hz), 8.12 (2H, d, 9.3 Hz); 24: (C D OD) 2.78 (1H, ddd, 3.9,
3
Scheme 2.
6.3, 10.3 Hz), 3.18 (1H, t, 8.8 Hz), 3.41 (3H, s), 3.48 (1H, dd, 8.8,
10.3 Hz), 3.54 (1H, t, 8.8 Hz), 3.70(1H, dd, 3.4, 10.3 Hz), 3.72–3.83 (3H,
m), 3.87 (1H, d, 2.9 Hz), 3.88–3.99 (3H, m), 4.50 (1H, d, 8.8 Hz), 4.69
(1H, d, 3.9 Hz).
4.1 ꢂmol/mL, pH 5.0, 30 ꢀC). However, under these conditions,
70% of the ꢁ-p-nitrophenyl gentibioside was consumed in 100 min
to give ꢁ-p-nitrophenyl glucoside. Studies of the stability of ꢁ-50-
thioglucopyranosides have showed that ꢁ-50-thioanalogues were
much more stable than corresponding regular ꢁ-glucosides.14 On
14 H. Hashimoto, M. Kawanishi, and H. Yuasa, Chem. Eur. J., 2, 556
(1996).
15 R. L. Whistler and T. V. Es, J. Am. Chem. Soc., 28, 2303 (1963).
16 D. Indurugalla and A. J. Bennet, J. Am. Chem. Soc., 123, 10889 (2001).