Glycosylation with 2′-carboxybenzyl glycosides as glycosyl donors: Scope and application to the synthesis of a tetrasaccharide

Article abstract of DOI:10.1055/s-2003-40348

Glycosylation of 2′-carboxybenzyl (CB) 2,3,4,6-tetra-O-benzyl-α-D-mannopyranoside (3), CB 2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside (4), and CB 2,3-di-O-benzyl-4,6-O-benzylidene-β-D-glucopyranoside (5) as glycosyl donors with various glycosyl acceptors p

Full text of DOI:10.1055/s-2003-40348

LETTER
1311
Glycosylation with 2¢-Carboxybenzyl Glycosides as Glycosyl Donors:
Scope and Application to the Synthesis of a Tetrasaccharide
Glycosylation
w
ith
w
2
¢
-Carboxybenzy
a
l
G
lycoside
n
s
Soo Kim,* Sung Soo Kang, Yong Sung Seo, Hyo Jin Kim, Yong Joo Lee, Kyu-Sung Jeong
Department of Chemistry, Yonsei University, Seoul 120-749, Korea
Fax +82(2)3647050; E-mail: kwan@yonsei.ac.kr
Received 17 March 2003
Dedicated to the late Professor Ray Lemieux in admiration of his many seminal contributions to carbohydrate chemistry.
O
O
O
Abstract: Glycosylation of 2¢-carboxybenzyl (CB) 2,3,4,6-tetra-O-
benzyl-a-D-mannopyranoside (3), CB 2,3,4,6-tetra-O-benzyl-b-D-
glucopyranoside (4), and CB 2,3-di-O-benzyl-4,6-O-benzylidene-
b-D-glucopyranoside (5) as glycosyl donors with various glycosyl
acceptors provided corresponding disaccharides in high yields. The
present CB glycoside methodology was successfully applied to the
efficient construction of the tetrasaccharide 41.
O
O
O
Tf2O
O
O
O
DTBMP
OH
O
OTf
O
B
A
C
O
Key words: carbohydrates, oligosaccharide synthesis, glycosyla-
tions, CB glycosides, BCB glycosides
O
ROH
O
O
O
OR
OTf
OTf
G
B
OTf
D
F
E
28
Development of efficient and stereoselective glycosyla-
tion methodologies has been one of the major concerns
in synthetic organic chemistry in recent years due to the
biological significance of complex oligosaccharides and
glycoconjugates.1 Although several glycosylation meth-
odologies based on quite efficient glycosyl donors such as
thioglycosides,2 glycosyl sulfoxides,3 glycals,4 glycosyl
trichloroacetimidates,5 n-pentenyl glycosides,6 and glyco-
syl fluorides7 have been available, there still remains a
need for more efficient and generally applicable new gly-
cosylation methodologies. In fact, there have been recent
reports on development of new glycosylation methods
based on devising new glycosyl donors and employing
Scheme 1
tetrasaccharide employing the pair of the ‘latent’ 2¢-(ben-
zyloxycarbonyl)benzyl (BCB) glycoside and the ‘active’
CB glycoside.
The CB tetrabenzylmannoside 312 was prepared by selec-
tive hydrogenolysis of BCB tetrabenzylmannoside 2,
which was obtained from the known BCB mannoside 110
as shown in Scheme 2. The CB tetrabenzylglucoside 4
was prepared in an analogous fashion while the CB 4,6-O-
benzylideneglucoside 5 (Figure 1)was synthesized by the
new activation systems for existing glycosyl donors.8 We known procedure.10
have also recently reported the 2¢-carboxybenzyl (CB)9
BnO
OBn
O
glycoside A in Scheme 1 as a novel type of glycosyl do-
nors for the stereoselective b-mannopyranosylation10 and
2-deoxyglycosylation.11 Lactonization of the glycosyl
triflate C, which was derived from the CB glycoside A,
was the driving force for the facile generation of the oxo-
carbenium D for the glycosylation as shown in Scheme 1.
In our previous work, only the CB mannopyranoside hav-
ing the 4,6-O-benzylidene protective group has been sub-
jected to the glycosylation reaction and just two examples
of glycosylation with CB glucopyranosides have been re-
ported.10 Therefore, to explore the scope of this CB glyco-
side methodology, we further carried out glycosylation
reactions with new CB mannopyranosides and CB glu-
copyranosides. In addition, in order to demonstrate the
applicability of the CB glycoside methodology to oligo-
saccharide synthesis, we report the construction of a
HO
HO
HO
OH
O
OBn
O
BnO
BnO
BnO
b
a
BnO
BnO
OCB
OBCB
OBCB
2
3
1
c
O
CH2
BnO
BnO
BnO
OBn
O
BCB =
CB =
OBn
BnO
O
O
CH2
O
BnO
OH
BnO
OMe
15
Scheme 2 Reagents and conditions a) NaH, BnBr, DMF, r.t., 2 h,
80%; b) H2, Pd/C, NH4OAc, MeOH, r.t., 1 h, 94%; c) 3, DTBMP,
Tf2O, 4 Å MS, CH2Cl2, –78 ºC, 10 min, then 9, –78 ºC to 0 ºC, 3 h,
75%.
BnO
Ph
O
O
O
O
BnO
BnO
OCB
OCB
BnO
OBn
OBn
5
4
Synlett 2003, No. 9, Print: 11 07 2003.
Art Id.1437-2096,E;2003,0,09,1311,1314,ftx,en;S05103ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
Figure 1

1312
K. S. Kim et al.
LETTER
Glycosylation of the CB tetrabenzylmannoside 3 with the Table 1 Glycosylation of the CB Mannoside 3 as the Glycosyl
Donor under the Standard Condition (Condition A)a
glycosyl acceptors 6–11 was carried out under the stan-
dard reaction condition (condition A) by the following se-
Entry
1
Glycosyl Acceptor
Product
Yield (%) Ratio (a/b)
quence: (i) stirring the solution of 3 (60 mg, 1.0 equiv) and
2,6-di-t-butyl-4-methylpyridine (DTBMP, 2.4 equiv) in
the presence of 4A molecular sieves (MS) for 20 min at
room temperature in CH2Cl2 (8 mL), (ii) addition of Tf2O
(1.2 equiv) to this solution at –78 ºC and stirring the solu-
tion for 10 min, (iii) addition of the glycosyl acceptor (2.0
equiv) and stirring the reaction mixture for further 1 h at
–78 ºC and allowing to warm over 2 h to 0 ºC, and (iv)
quenching the reaction by addition of aqueous NaHCO3.
Glycosylation of CB mannoside 3 with primary alcohol
acceptors 6–8 gave the mixtures of a- and b-disaccharides
12–14 (Table 1, entries 1–3) while reaction of 3 with sec-
ondary alcohol acceptors 9–11 afforded exclusively a-di-
saccharides 15–17 in good yields (Scheme 2 and Table 1,
entries 3–6). This result indicates that not only 4,6-O-ben-
zylidene-protected CB mannosides but also CB manno-
sides with other protective groups are efficient mannosyl
donors.
12
87
91
65
1.3:1
1.1:1
1.6:1
HO
O
BzO
BzO
BzO
OMe
6
2
3
13
14
HO
BzO
BzO
OBz
O
OMe
7
8
OH
O
O
O
O O
4
15
75
a only
BnO
O
HO
BnO
BnO
BnO
BnO
BnO
OMe
O
O
O
9
BnO
O
OBn
OBn
OBn
O
5
6
16
17
73
77
a only
a only
BnO
OBn
OBn
O
HO
28
BnO
OMe
Figure 2
10
O
O
OH
O
Glycosylations of the CB tetrabenzylglucoside 4 and of
the CB 4,6-O-benzylideneglucoside 5 with various glyco-
syl acceptors were also carried out under the standard re-
action condition (condition A) as described above for the
CB mannoside 3. Reaction of the benzyl-protected glu-
cose donor 4 with the glycosyl acceptor 6 under the reac-
tion condition A afforded a mixture of a- and b-
disaccharides 18 in 76% yield along with the self-con-
densed ester 28 (Figure 2), which must be derived from
two molecules of the glycosyl donor 4, in 22% yield
(Table 2, entry 1). Glycosylation of 4 with other glycosyl
acceptors 7 and 11 gave also the mixtures of a- and b-dis-
accharides along with the self-condensed ester 28
(Table 2, entries 2 and 3). However, glycosylation of the
4,6-O-benzylidene-protected glucose donor 5 with glyco-
syl acceptors 6, 7, 9, and 11 afforded exclusively the a-
disaccharides 21, 22, 23, and 24, respectively, in high
yields but formation of the self-condensed ester was not
observed (Table 2, entries 4–7). It is noteworthy that gly-
cosylation of the 4,6-O-benzylidene-protected glucose
donor 5 provided only a-disaccharides regardless of what
kind of glycosyl acceptors were used, primary or second-
ary alcohols. In fact, it has been previously reported that
the selective a-glucopyranosylation could be achieved by
employing the 4,6-O-benzylidene-protected glycosyl sul-
foxides and thioglycosides as glycosyl donors.13
O
O
11
a To a solution of the donor were added sequentially Tf2O and then the
acceptor at –78 ºC.
which was generated by deprotonation of the CB glyco-
side A by DTBMP, and the oxocarbenium ion D or the C-
1 triflate intermediate E or F as shown in Scheme 1. Gen-
eration of a substantial amount of ester 28 led us to postu-
late that the conversion of the carboxylate B into C was
slower than the formation of D by the lactonization of C.
We envisaged that if the concentration of B was kept at a
minimum during glycosylation, the formation of the ester
28 would be suppressed. We, therefore, ran the glycosyla-
tion reaction with the reversal of the order of addition of
the reactants. Thus, glycosylation of the CB tetrabenzyl-
glucoside 4 with various glycosyl acceptors 6–11 was car-
ried out under the modified reaction condition (condition
B) by the following sequence: (i) stirring the solution of
the glycosyl acceptor (2 equiv) and DTBMP (2.4 equiv) in
the presence of 4Å MS for 20 min at room temperature in
CH2Cl2 (3 mL), (ii) addition of Tf2O (1.2 equiv) to this so-
lution at –78 ºC, (iii) addition of 4 (60 mg, 1.0 equiv) in
CH2Cl2 (4 mL) dropwise to this solution over a period of
10 min and stirring the reaction mixture for further 1 h at
Formation of the self-condensed ester 28 probably result-
ed from the coupling between the carboxylate anion B,
Synlett 2003, No. 9, 1311–1314 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Glycosylation with 2¢-Carboxybenzyl Glycosides
1313
Table 2 Glycosylation of the CB Glycosides 4 and 5 as Glycosyl Donors under the Standard Condition (Condition A)a
Entry
Donor
Acceptor
Product
18
Yield (%)
Ratio (a/b)
1:2
Ester 28 (%)
1
2
3
4
5
6
7
4
4
4
5
5
5
5
6
7
76
73
77
87
85
80
85
22
22
16
0
19
1:3
11
6
20
1:1
21
a only
a only
a only
a only
7
22
0
9
23
0
11
24
0
a To a solution of the donor were added sequentially Tf2O and then the acceptor at –78 ºC.
–78 ºC and allowing to warm over 2 h to 0 ºC, and (iv) the standard condition to afford exclusively the b-disac-
quenching the reaction by addition of aqueous NaHCO3. charide 37 in 91% yield and removal of the PMB group in
Glycosylation of 4 with 6 under the condition B provided 37 with DDQ gave the alcohol 38 as shown in Scheme 4.
exclusively the disaccharide 18 (a/b = 1:2.5) in 93% yield Again, it has been demonstrated that CB mannopyrano-
without formation of ester 28 (Table 3, entry 1). Reaction sides having the 4,6-O-benzylidene group and a C-2 non-
of 4 with other acceptors 7–11 under the condition B also participating group are extremely useful mannosyl donors
gave exclusively disaccharides in high yields without the for the stereoselective b-mannopyranosylation.
ester 28 (Table 3, entries 2–6).
Glycosylation of the ketone glycosyl donor 34 with accep-
Then we applied this CB glycoside methodology to the tor 36, on the other hand, was conducted under the differ-
synthesis of the protected tetrasaccharide 41, which we ent reaction condition in order to obtain the a-
designed as an analog of the tetrasaccharide repeating disaccharide 39 because the b-disaccharide was found to
unit of the O-antigen polysaccharide from the E. coli li- be the major product under the standard condition. Thus,
popolysaccharide. Monosaccharide building blocks 32, a solution of 34, 36, and DTBMP in the presence of 4A
34, and 36 were synthesized from a common starting MS was stirred at room temperature for 30 min and cooled
material 30, which was prepared by selective benzylation down to –40 ºC. Triflic anhydride was added to this solu-
of the diol 29 using dibutyltin oxide (Scheme 3). p-Me- tion and the reaction mixture was stirred for further 1 h at
thoxybenzylation of 30 and the subsequent selective –40 ºC and allowed to warm to 10 ºC to afforded a mixture
hydrogenolysis of 31 gave the CB glycoside 32. Oxida- of the a-disaccharide 39 and its anomeric b-disaccharide
tion of 30 with PDC and the hydrogenolysis of the result- (4:1) in 74% yield. The latent BCB disaccharide 39 was
ing ketone 33 afforded another CB glycoside 34. converted into the active CB disaccharide 40 by the selec-
Pivaloylation of 30 and the subsequent reductive cleavage tive debenzylation. Finally, the coupling of two disaccha-
of the benzylidene acetal 35 with borane-dibutylboron rides 40 and 38 was carried out by addition of Tf2O to a
triflate14 provided the alcohol 36. Glycosylation of the
glycosyl donor 32 and acceptor 30 was carried out under
OH
O
OH
O
OPMB
O
Ph
O
Ph
O
Ph
O
b
a
O
O
O
HO
BnO
BnO
Table 3 Glycosylation of the CB Glycoside 4 as the Glycosyl Do-
OBCB
d
OBCB
OR
nor under the Modified Condition (Condition B)a
30
29
31: R = BCB
32: R = CB
c
f
Entry
Acceptor
Product
18
Yield (%)
Ratio (a/b)
1:2.5
1
2
3
4
5
6
6
7
93
92
92
87
86
96
HO
BnO
BnO
OPiv
O
OPiv
O
Ph
O
O
BnO
Ph
O
O
BnO
O
g
19
1:2.3
O
OR
OBCB
OBCB
36
35
8
25
1:1.3
33: R = BCB
34: R = CB
e
9
26
1:1.6
Scheme 3 Reagents and conditions a) Bu2SnO, MeOH, reflux, 1 h,
then BnBr, DMF, 90 ºC, 3 h, 84%; b) PMBCl, NaH, DMF, r.t., 1.5 h,
83%; c) H2, Pd/C, NH4OAc, MeOH, r.t., 1 h, 91%; d) PDC, CH2Cl2,
4 Å MS, r.t., 8 h, 72%; e) same as c), 92%; f) PivCl, DMAP (cat.),
Et3N, CH2Cl2, r.t, 1 h, 86%; g) BH3, Bu2BOTf (cat.), THF, 0 ºC to r.t.,
1 h, then Et3N, 2 h, 88%.
10
11
27
1:1.2
20
1.4:1
a To a solution of the acceptor and Tf2O was added dropwise the do-
nor at –78 ºC.
Synlett 2003, No. 9, 1311–1314 ISSN 1234-567-89 © Thieme Stuttgart · New York

1314
K. S. Kim et al.
LETTER
(3) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am.
Chem. Soc. 1989, 111, 6881.
(4) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1380.
OR
O
Ph
O
O
O
BnO
a
+
32
30
Ph
O
O
O
BnO
(5) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem.
1994, 50, 21.
(6) Fraser-Reid, B.; Madsen, R. In Preparative Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker, Inc.: New
York, 1997, 339.
(7) Shimizu, M.; Togo, H.; Yokoyama, M. Synthesis 1998, 799.
(8) For recent examples of new glycosyl donors and activating
systems, see: (a) Plante, O. J.; Palmacci, E. R.; Andrade, R.
B.; Seeberger, P. H. J. Am. Chem. Soc. 2001, 123, 9545.
(b) Nguyen, H. M.; Chen, Y.; Duron, S. G.; Gin, D. Y. J. Am.
Chem. Soc. 2001, 123, 8766. (c) Hinklin, R. J.; Kiessling, L.
L. J. Am. Chem. Soc. 2001, 123, 3379. (d) Davis, B. J.;
Ward, S. J.; Rendle, P. M. Chem. Commun. 2001, 189.
(9) The 2¢-carboxybenzyl (CB) glycoside seems to be the more
appropriate name than the 2-(hydroxycarbonyl)benzyl
(HCB) glycoside, which was used in our earlier publication.
See, ref. 10
(10) Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J. J. Am.
Chem. Soc. 2001, 123, 8477.
(11) Kim, K. S.; Park, J.; Lee, Y. J.; Seo, Y. S. Angew. Chem. Int.
Ed. 2003, 42, 459.
(12) The compound 3 has been prepared previously by a different
method. See: Scheffler, G.; Schmidt, R. R. J. Org. Chem
1999, 64, 1319.
OBCB
37: R = PMB
38: R = H
b
Ph
O
O
O
O
BnO
c
OPiv
O
+
34
36
O
BnO
BnO
OR
39: R = BCB
40: R = CB
d
Ph
O
O
O
BnO
O
OPiv
O
O
BnO
BnO
e
O
O
+
40
38
Ph
O
O
BnO
Ph
O
O
O
BnO
O
41
OBCB
(13) For discussions on a-glucopyranosylation, see: Crich, D.;
Scheme 4 Reagents and conditions a) 32, DTBMP, Tf2O, 4 Å MS,
CH2Cl2, –78 ºC, 10 min, then 30, –78 ºC to 0 ºC, 3 h, 91%; b) DDQ,
CH2Cl2–H2O (18:1), r.t., 9 h, 83%; c) 34, 36, DTBMP, 4 Å MS,
CH2Cl2, –40 ºC, then Tf2O, –40 ºC to 0 ºC, 3 h, 74% (a/b = 4:1);
d) H2, Pd/C, NH4OAc, MeOH, r.t., 1 h, 87%; e) 38, 40, DTBMP, 4 Å
MS, CH2Cl2, –40 ºC, then Tf2O, –40 ºC to 0 ºC, 3 h, 75%.
Cai, W. J. Org. Chem. 1999, 64, 4926.
(14) Jiang, L.; Chan, T.-H. Tetrahedron Lett. 1998, 39, 355.
(15) A solution of 40 (32 mg, 0.035 mmol, 1.0 equiv), 38 (39 mg,
0.042 mmol, 1.2 equiv) and 2,6-di-tert-butyl-4-methyl-
pyridine (21 mg, 0.11 mmol, 3.0 equiv) in CH2Cl2 (5 mL) in
the presence of 4A molecular sieves was stirred for 30 min
at room temperature and cooled to –40 ºC, then Tf2O (8.8
mL, 0.055 mmol, 1.5 equiv) was added. The reaction mixture
was stirred at –40 ºC for further 1 h and allowed to warm
over 2 h to 0 °C. The reaction mixture was quenched with
saturated aqueous NaHCO3 and the organic phase was
washed with brine, dried (MgSO4), concentrated in vacuo.
The residue was purified by silica gel flash column
chromatography (33% ethyl acetate in hexane) to afford
compound 41 (44 mg, 75%): colorless oil, Rf = 0.37 (33%
ethyl acetate in hexane); [a]D20 = +46.3 (c 1.5, CHCl3); 1H
NMR (250 MHz, CDCl3) d 1.14 (s, 9 H), 3.38–3.47 (m, 2 H),
3.56–3.63 (m, 2 H), 3.69 (dd, J = 3.0 Hz, 5.0 Hz, 1 H), 3.83–
3.91 (m, 5 H), 4.00–4.11 (m, 5 H), 4.14 (dd, J = 2.5 Hz, 5.0
Hz, 1 H), 4.22–4.35 (m, 6 H), 4.39–4.47 (m, 2 H), 4.52–4.65
(m, 5 H), 4.70–4.82 (m, 5 H), 4.92 (d, J = 6.0 Hz, 1 H), 5.00–
5.12 (m, 3 H), 5.29 (m, 1 H), 5,33 (s, 2 H), 5.53 (s, 1 H), 5.59
(s, 1 H), 5.61 (s, 1 H), 7.06–7.55 (m, 46 H), 7.68 (dd, J = 3.7
Hz, 3.7 Hz, 1 H), 7.94 (d, J = 3.7 Hz, 1 H), 8.00 (d, J = 3.7
Hz, 1 H); 13C NMR (63 MHz, CDCl3) d 27.3, 39.0, 64.9,
66.7, 67.8, 68.1, 68.4, 68.6, 69.1, 69.6, 70.0, 70.8, 71.4, 72.7,
73.9, 74.4, 74.7, 76.7, 78.6, 80.1, 97.3, 98.0, 98.8, 100.9,
101.4, 101.5, 101.6, 125.8, 125.9, 126.0, 126.1, 127.3,
127.6, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.6,
129.0, 134.0, 137.7, 146.5, 166.7, 177.1, 194.6; Anal. Calcd
for C100H102O24: C, 71.16; H, 6.09. Found: C, 71.15; H, 6.11;
MALDI-TOF MS Calcd for 1725.7761 (M + K). Found
1725.7712.
stirred solution of the glycosyl donor 40, acceptor 38, and
DTBMP in the presence of 4 Å MS at –40 ºC to afford ex-
clusively the desired a-tetrasaccharide 4115 in 75% yield.
This result indicates that the participating group at C-2 is
working well in the CB glycosides and the present meth-
odology could be applied for the construction of more
complex important oligosaccharides.
In summary, we have shown that CB glycosides having
various protective groups can be employed as efficient
glycosyl donors and demonstrated the power of the CB
glycoside methodology in oligosaccharide synthesis by
presenting the efficient construction of a tetrasaccharide.
Acknowledgement
This work was support by a grant (2001-1-0064) from Yonsei
University.
References
(1) (a) Varki, A. Glycobiology 1993, 3, 97. (b) Dwek, R. A.
Chem. Rev. 1996, 96, 683.
(2) Garegg, P. J. Adv. Carbohydr. Chem. Biochem. 1997, 52,
179.
Synlett 2003, No. 9, 1311–1314 ISSN 1234-567-89 © Thieme Stuttgart · New York