Synthesis of the Nephritogenoside Trisaccharide Unit Using Phenyl
1-Thioglycopyranoside Sulfoxides as a Glycosyl Donor
Yali Wang, H ong Zhang, and Wolfgang Voelter*
Abteilung für Physikalische Biochemie des Physiologisch-chemischen Instituts
der Universität Tübingen, Hoppe-Seyler-Straße 4, D-72076 Tübingen
Z. Naturforsch. 48b, 1143 - 1145 (1993); received February 23, 1993
Polysaccharide Synthesis, Phenyl 1-Thioglycoside Sulfoxides
The nephritogenoside trisaccharide unit was synthesized under mild conditions using phenyl
1-thioglycopyranoside sulfoxides as glycosyl donors. In the coupling process neither thiophenyl nor trityl protecting groups are cleaved from the carbohydrate m oieties demonstrating
the utility o f this method also for oligosaccharide block syntheses.
In spite o f considerable progress in the synthesis
o f oligosaccharides has been achieved in recent
years [ 1 - 6 ], efficient glycosylation o f unreactive
hydroxyl groups still remains a significant prob­
lem [7], So, the glycosyl halides, used for the com ­
monly applied Koenigs-Knorr method have low
thermal stability and are sensitive to hydrolysis,
and glycosyl donors like glycosyl bromides or gly­
cosyl trichloroacetimidates with labile protecting
groups, like e .g . trityl, are difficult to synthesize
and do not allow coupling with such a protection.
Recently the phenyl 1-thioglycopyranoside sulfox­
ide method, an efficient, rapid and under mild con­
ditions to perform glycosylation procedure for un­
reactive substances was described [7], As this ap­
proach has so far not been applied for the
synthesis o f polysaccharides, we want to dem on­
strate its utility using the nephritogenoside trisac­
charide unit Glc(t* 1—m5)G1c(/? 1—>6 )-Glc [8] as a
test case.
The synthetic route to the trisaccharide is seen
from Scheme I. Triflic anhydride (Tf 20 ) and 2,6-
BnO — I
J—0
SOPh
kt7
(
PivO
BnO N ----OPiv
OBn
3b
3a
3a
Scheme I. a) T f,0 , D tBP, - 7 8 to 10 °C (87.6%); b) mCPBA, - 7 8 °C (98%); c) T f20 , DtBP, - 7 8 to 0 °C (72.8% ).
* Reprint requests to Prof. W. Voelter.
Verlag der Zeitschrift für Naturforschung,
D -72072 Tübingen
0 9 3 2 -0 7 7 6 /9 3 /0 8 0 0 - 1143/$ 01.00/0
di-terz-butylpyridine (DtBP) promoted the glyco­
sylation o f phenyl 2,3,4-tri-0-pivaloyl-l-thio-/?-D glucopyranoside ( 1 ) with phenyl 2,3,4,6-tetraO-benzyl-1-thio-/7-D-glucopyranoside
sulfoxide
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Y. W ang et al. • Synthesis o f the Nephritogenoside Trisaccharide Unit
1144
HO— |
TrtO
SOPh
+
Piv(
OPiv
I— o
OAc
< K >
aco
N— r
OAc
( 2 ) in toluene and produced the phenyl 1 -thioglycosides 3 a in 58.4% and 3b in 29.2% yield;
with m-chloroperoxybenzoic acid (mCPBA) the
phenyl 1-thioglycoside (3 a) was oxidized to the
sulfoxide 4 in 98% yield; in the presence o f Tf20
and DtBP l,2,3,4-tetra-0-acetyl-/?-D-glucopyranose (5) was coupled with 4 in dichloremethane to
give the trisaccharide derivative 6 in 73% yield.
In the presence o f two moles o f D tBP and one
mole o f Tf20 l,2,3,4-tetra-0-acetyl-/?-D-glucopyranose (5) was glycosylated with phenyl 2,3,4tri-O-pivaloyl- 6 -O-trityl-1 -thio-/?-D-glucopyranoside sulfoxide (7) to yield the protected disac­
charide derivative 8 in 80.6% yield, and during the
coupling process no cleavage o f the trityl group
was observed (Scheme II).
So, for the first time, glycosyl sulfoxides were
used as glycosyl donors for the synthesis o f poly­
saccharides. This method proves to be a rapid glycosylation method, leading to high yields. Under
the mild conditions used, neither thiophenyl nor
trityl residues are cleaved from the carbohydrate
moieties. The thiophenyl group can esealy be oxi­
dized to the sulfoxide leading to a glycosyl donor
ready for further coupling steps and the trityl
group and other sensitive protecting groups can
advantageously be used for temporary protection
in oligosaccharide block synthesis. G lycosyl sulf­
oxides might also become effective reagents for the
solid phase synthesis o f carbohydrate [9,10].
Experimental
Phenyl 2 ,3 ,4-tri-O -pivaloy 1-6-0- (2 ,3 ,4 ,6-tetra0 -b en zyl-a -D -g lu co p y ra n o syl)-l-th io -ß -D -g lu co pyranoside (3 a) and ph en yl 2 ,3 ,4-tri-O -pivaloyl6 - 0 - ( 2 ,3 ,4 ,6-tetra-O -ben zyl-ß-D -glu copyran o syl) 1-thio-ß-D -glucopyranoside (3b)
175 mg o f triflic anhydride (0.62 mmole) were
dissolved in 3 ml o f toluene, cooled to - 7 8 °C un­
der nitrogen atmosphere, and then 400 mg o f
phenyl
2,3,4,6-tetra-O -benzyl-1-thio-/?-D-gluco-
I*
Scheme II. a) Tf70 and D tBP (1 :2 ), - 7 8 to
0 °C, (80.6%).
pyranoside sulfoxide (2) (0.62 mmole) in 1.5 ml
toluene were added under stirring, and subse­
quently 118 mg o f 2 ,6 -f-butylpyridine (0.62
mmole) in 0.3 ml o f toluene were brought into the
reaction vessel. After increasing the temperature to
- 7 0 °C, 405 mg o f phenyl 2,3,4-tri-O-pivaloyll-thio-/?-D-glucopyranoside (1) (0.77 mmole) in
2 ml toluene were added and the mixture was al­
lowed to warm to 10 °C. Then, 3 ml o f a saturated
NaHCOj solution were added and the mixture was
poured into water (30 ml) and extracted with dichloromethane (3 * 20 ml) and washed with water
(2 x 3 0 ml), dried over N a 2S 0 4, filtered and evapo­
rated. Chromatography on a silica gel column
(dichloromethane/ethyl acetate 40:1) gave 435 mg
o f 3a and 218 mg o f 3b in 58.4%, respectively
29.2% yield. 3a: - F D - M S : m /z = 1047 (M). - !H
N M R (400 M Hz, CDC13): S = 7 .4 -7 .0 8 (m, 2 5 H,
aromatic), 5.24 (t, J = 9.1, 1 H), 4 .8 8 -3 .2 4 (m,
21 H, H a-l-H a- 6 , H b -l-H b - 6 , 4 * - C H ,P h ) , 1.09
(s, 9H , Piv), 1.08 (s, 9H , Piv), 1.00 (s, 9 H , Piv). ,3C N M R (100.6 MHz, CDC13): Ö = 175.6, 175.0,
174.9 (-C O C M e3), 137.5, 137A 136.7, 136.5 (Cq,
aromatic), 131.6-123.6 (aromatic), 95.8 (Ca-1),
85.7 (Cb-1), 80.6, 78.6, 76.3, 75.2, 74.2, 73.4, 72.1,
71.9, 71.8, 68.7, 68.2, 67.1, 67.0, 65.7 (Ca-2-Ca-6,
Cb-2-Cb-6, -C H ,P h ), 37.3 ( - C M e 3), 2 8 .6 -2 8 .2
( - C H 3). 3b: - F D - M S : m /z = 1047 (M ), 956
(M -C H 2Ph). - 'H N M R (400 M H z, CDC13): S =
7 .2 8 -6 .9 3 (m, 25H , aromatic), 5 .1 5 -3 .1 5 (m,
2 2 H, H a-l-H a- 6 , H b -l-H b - 6 , 4 x - C H ,P h ) , 1.06
(s, 9H , Piv), 1.00 (s, 9H , Piv), 0.96 (s, 9H , Piv). 13C N M R (100.6 MHz, CDC13) Ö = 177.0, 176.8,
176.4 (-C O C M e 3), 138.6, 138.4, 138.1, 138.0 (Cq,
aromatic), 131.6-123.6 (aromatic), 104.1 (Ca-1),
86.3 (Cb-1), 84.8, 82.5, 78.4, 77.9, 76.0, 75.2, 75.1,
75.0, 73.8, 73.6, 69.8, 69.1, 68.9, 68.9 (Ca-2-Ca-6,
Cb-2-Cb-6, -C H .P h ), 3 9 .0 -3 8 .9 ( - C M e 3), 2 7 .4 27.3 ( - C H 3).
P henyl 2 ,3 ,4 -tr i-0 -p iv a lo y l-6 -0 -(2 ,3,4 ,6 -tetra O -ben zyl-a-D -glu copyran osyl) -1 -thio-ß-D -glucopyranoside sulfoxide (4)
To 350 m f o f 3a (0.335 mmole), dissolved in 10
ml dichloromethane, 105 mg o f 55% mCPBA
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Y. W ang et al. • Synthesis o f the Nephritogenoside Trisaccharide Unit
(0.335 mmole) in 10 ml dichloromethane were ad­
ded under stirring and an atmosphere o f nitrogen.
Then the reaction mixture was allowed to warm to
10 °C and 2 ml o f a saturated N a H C 0 3 solution,
containing 5% N a 2S 0 3, were added under stirring.
The mixture was washed with water (3 * 20 ml) and
dried over N a 2S 0 4, filtered and evaporated. Chro­
matography with petroleum ether/ethyl acetate
(3:1) on a silica gel column gave 352.6 mg o f 4 in
98% yield.
1 ,2,3,4 -T e tra -O -a c ety 1 -6 -0 -(-2 ,3 ,4-tri-O -pivaloylß -D -g lu copyran osyl) - 6 -0 - ( 2 ,3 ,4 ,6-tetra-O -ben zyl(x-D -glucopyranosyl)-ß-D -glucopyranose ( 6 )
352.6 mg o f 4 (0.332 mmole) were dissolved in
2.5 ml dichloromethane and stirred at - 7 8 °C un­
der an atmosphere o f nitrogen, then 66.7 mg o f
DtBP (0.349 mmole) in 0.3 ml o f dichlormethane
and 98.7 mg o f triflic anhydride (0.349 mmole) in
0.4 ml dichloromethane were added and the mix­
ture was allowed to warm to - 6 5 °C. To this solu­
tion 130.5 mg o f l,2,3,4-tetra-0-acetyl-/?-D-glucopyranose (5) (0.371 mmole) in 0.3 ml o f dichloro­
methane were added and then the temperature was
increased to 0 °C. After additon o f 2 ml o f a satu­
rated N a H C 0 3 solution the reaction mixture was
poured into water (30 ml) and extracted with di­
chloromethane (3 x 2 0 ml). The combined extracts
were washed with water (2 x 3 0 ml), dried over
N a 2S 0 4, filtered and evaporated. Chromatogra­
phy with dichloromethane/ethyl acetate (40:1 2 0 : 1 ) on a silica gel column gave 310 mg o f 6 in
72.7% yield. - F D - M S : m /z = 1284, 1285 (M ). ‘H N M R (400 MHz, CDC13): S = 7 .2 8 -7 .0 9 (m,
2 0 H, aromatic) 5.56 (d, J - 8.2, 1 H, Hc-1), 5.21 —
3.33 (m, 2 8 H, H a-l-H a- 6 , H b -l-H b - 6 , Hc-2-Hc-6,
4 x -C H ,P h ) , 1.97 (s, 3 H, Ac), 1.93 (s, 3H , Ac),
1.90(s, 3H , Ac), 1.85 (s, 3H , Ac), 1.10 (s, 9H , Piv),
1.09 (s, 9H , Piv), 1.03 (s, 9H , Piv). - ,3C N M R
(100.6 M Hz, CDC13) Ö = 177.3, 176.8, 176.7
[1]
[2]
[3]
[4]
[5]
H. Paulsen, Angew. Chem. 94, 184 (1982).
R. R. Schmidt, Angew. Chem. 98, 213 (1986).
K. Krohn, Nachr. Chem. Tech. Lab. 35,9 3 0 (1987).
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46,103(1990).
[6] K. C. N icolaou, T. J. Caulfield, and R. D. Groneberg, Pure Appl. Chem. 63, 555 (1991).
1145
(-C O C M e 3), 170.2, 169.6, 169.4, 169.0 (-C O M e),
139.2, 138.8, 138.5, 138.2 (Cq, aromatic), 128.7127.8 (aromatic), 100.3 (Cb-1), 97.2 (Ca-1), 91.80
(Cc-1), 8 2 .2 -5 3 .6 (m, Ca-2-Ca-6, Cb-2-Cb-6,
Cc-2-Cc-6, -C H .P h ), 38.95 (-C M e 3), 27.3
( - C H 3), 20.8 ( - C 0 C H 3).
1.2.3.4 -T e tra -O -a c ety 1-6- ( 2 ,3 ,4-tri-O -pivaloyl6-trityl-ß-D -glucopyranosyl)-ß-D -glucopyranose (8 )
To
232 mg o f phenyl 2,3,4-tri-O-pivaloylsulfoxide (7)
(0.3 mmole), 132.6 mg o f DtBP (0.6 mmole) in
3 ml o f dichloromethane were added, stirred at
- 7 8 °C under an atmosphere o f nitrogen, and then
87.7 mg o f triflic anhydride (0.3 mmole) were
brought into the reaction vessel. After warming
to - 6 5 °C, 116 mg o f l,2,3,4-tetra-0-acetyl-/?-Dglucopyranose (5) (0.33 mmole) were added and
the mixture was allowed to warm to 0 °C. After
addition o f 2 ml o f a saturated N a H C 0 3 solution
the mixture was poured into 30 ml water and ex­
tracted with dichloromethane (3 x 2 0 ml). The
combined extracts were washed with water (2 x 30
ml), dried over N a 2S 0 4, filtered and evaporated.
Chromatography with dichloromethane/ethyl ace­
tate (30:1) on a silica gel column gave 240 mg o f 8
in the 80.6% yield. - F D - M S m /z = 1005 (M). ’H N M R (400 M Hz, CDC13): Ö = 7 .3 5 -7 .0 6 (m,
15H, aromatic), 5.64 (d, J = 9.1, 1 H, Hc-1), 5 .2 2 4.83 (m, 6 H), 4.55 (d, J = 8.1, 1 H, Hb-1), 4 .0 3.55 (m, 6 H), 1.93 (s, 3H , Ac), 1.91 (s, 3H , Ac),
1.90 (s, 3 H, Ac), 1.87 (s, 3 H, Ac), 1.05 (s, 9 H, Piv),
0.96 (s, 9H , Piv), 0.73 (s, 9H , Piv). - 13C N M R
(100.6 M Hz, CDC13): S = 177.5, 177.3, 176.8
(-C O C M e 3), 170.2, i69.9, 169.5, 168.8 (-C O M e),
143.8 (Cq, aromatic), 128.9-127.3 (aromatic),
100.6 (Cb-1), 91.9 (Cc-1), 91.8 (1 C, -C P h 3), 8 6 .8 61.7 (Cb-2-Cb-6, Cc-2-Cc-6), 3 9 .1 -3 8 .6 (- C M e 3),
2 7 .4 -2 7 .0 ( - C H 3), 2 1 .0 -2 0 .6 (-C O C H 3).
6 -trityl-l-thio-/?-D-glucopyranoside
[7] D. Kahne, S. Walker, Y. Cheng, and D. van Engen,
J. Am. Chem. Soc. 111,6881 (1989). *
[8] S. Shibata, T. Taketa, and Y. Natori, J. Biol. Chem.
263, 12483(1988).
[9] A. Malik, H. Bauer, J. Tschakert, and W. Voelter,
Chemiker-Zeitung 114, 371 (1990).
[10] Y. Wang, H. Zhang, and W. Voelter, in preparation.
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