A fundamentally new, simple, stereospecific synthesis of oligosaccharides containing the β-mannopyranosyl and β-rhamnopyranosyl linkage

Full text of DOI:10.1021/ja964021y

J. Am. Chem. Soc. 1997, 119, 2335-2336
2335
Table 1. Reaction Conditions Applied and Yields Obtained
Nua Elb
yield temp reaction
A Fundamentally New, Simple, Stereospecific
Synthesis of Oligosaccharides Containing the
â-Mannopyranosyl and â-Rhamnopyranosyl
Linkage
salt/
equiv
equiv equiv prod (%) solvent
(°C)
-5
25
time
7/4.5
7/4.5
11/4
11/3
11/6
11/6
11/6
12/5
12/6
5/1
9/1
5/1
5/1
9/1
9/1
9/1
5/1
9/1
8
10
13
13
18
18
18
14
19
88 DMF
78 DMF
40 DMF
57 CH3CN 25
40 DMF 25
52 DMAA 25
59 DMSO 25
75 CH3CN 25
80 min
2.5 h
CsF/6
CsF/6
0, 25 4 h, 10 h
Gyo¨rgy Hodosi* and Pavol Kova´cˇ
20 h
5 d
3 d
2 d
14 h
18 h
Bu4NF/1
NIDDK, Section on Carbohydrates, LMC
National Institutes of Health
Bethesda, Maryland 20892-0815
Bu4NF/1
CsF/6
67 DMF
25
ReceiVed NoVember 20, 1996
a Nucleophile. b Electrophile.
Table 2. Characteristic Data for Newly Synthesized Substancesa
The important role of oligosaccharides in biological pro-
cesses1 has been recognized for a long time. Consequently,
synthetic oligosaccharides have become indispensable probes
for the life sciences.2 Methods for the chemical synthesis of
oligosaccharides are based on a two-step process: The first
comprises activation of the anomeric center to generate a
glycosyl donor, and the second is its transfer to a glycosyl
acceptor. The stereochemical outcome of the reaction depends
on complex stereoelectronic effects as well as the presence or
absence of groups at O-2 in the glycosyl donor capable of
neighboring group participation.3 Except for rare cases, when
the coupling of a glycosyl donor and a glycosyl acceptor occurs
as an almost entirely SN2 process,4 the reaction of the glycosyl
donor involves the formation of the oxocarbenium ion (1). Thus,
the nonstereospecificity of glycosylation is virtually inherent
in the method.
b
I
II
I
II
[R]D
deg
δH-1
/
δH-1
δC-1
/
δC-1
/
compd mp (°C)
J
1,2 Hz /J1,2 Hz
J
C,H (Hz)
JC,H (Hz)
5
5.26/3.7
5.16/3.2
97.7
97.4
6c,d
8e
10
13
14
16
18e
19
150-151 +127 5.24/3.7 4.52/<1 97.2/172.7 99.1/157.8
+142 5.15/3.4 4.48/<1 96.9/170.0 100.2/158.0
+30 5.22/3.3 4.47/<1 97.0/175.9 101.1/158.3
+16 5.22/3.7 4.40/<1 96.9/175.7 100.9/158.6
+56 5.17/3.5 6.06/2.0 96.7/172.9 90.3/177.2
106-107 +104 5.13/3.6 4.58/<1 96.8/176.1 100.5/156.3
+83 5.12/3.7 4.50/<1 97.0/171.0 99.3/157.7
a Unless stated otherwise, the NMR spectra were measured at 300
(1H) and 75 (13C) Mz for solutions in CDCl3. b Optical rotations were
measured for solutions in CHCl3, c ≈ 1. c NMR spectra were measured
d
in C6D6. δHCO 7.58; δHCO 160.0. e Crystalized from ethanol.
constitutes a fundamentally new method for the glycosylation
of carbohydrates in that it does not involve the formation of
the oxocarbenium ion as an intermediate of the process, and
makes specific protection of hydroxyl groups in the glycosyl
donor unnecessary.7,8 Here, stereospecific formation of the 1,2-
cis-glycosidic linkage occurs because 1,2-O-stannylene acetals
of sugars favor the cis-arrangement around the anomeric center
(2, 3).9 Therefore, we propose to call the procedure “the
glycosylation Via locked anomeric configuration”. Accordingly,
when the stannylene derivatives10 prepared from L-rhamnose
or D-mannose were treated with carbohydrates bearing the
(trifluoromethyl)sulfonyl (triflyl) group, the 1,2-cis-oligosac-
charides11 formed could be isolated in 57-88% yields (Table
1).
Syntheses of 1,2-trans-linked oligosaccharides are relatively
easy, but not the highly stereoselective syntheses of their 1,2-
cis-linked counterparts. Most difficult are syntheses of â-man-
nosides and â-rhamnosides.5 Both the anomeric effect, which
favors the formation of the R-mannopyranosyl linkage, and the
formation of 1 during the transition state of the reaction are
largely responsible for this unfavorable situation. Efforts aimed
at overcoming these difficulties continue, and some new
approaches have recently been introduced.6 Nevertheless, there
is still a need for more efficient methods of glycosylation not
involving the formation of the oxocarbenium ion.
Reactions of 1,2-O-stannylene acetals of sugars with second-
ary triflates of carbohydrates occur, as expected, with inversion
of configuration at the activated center in the electrophile. Thus,
We have now discovered that 1,2-O-cis-stannylene acetals
of sugars are powerful nucleophiles capable of displacing, Via
the SN2 process, good leaving groups in carbohydrates. This
(7) 1-O-Alkylation with alkyl halides of 1,2-O-stannylene complexes has
been previously used to synthesize simple alkyl â-D-mannopyranosides (ref
8). Unlike the cases described herein, the stannylene complex used was
that of 3,4,6-tri-O-benzyl-D-mannose. Under the conditions described (ref
8), we have not observed (TLC) formation of oligosaccharides from 1,2-
O-stannylene complexes and nonanomeric halogeno sugars.
(8) (a) Dessinges, A.; Olesker, A.; Lukacs, G.; Thang, T. T. Carbohydr.
Res. 1984, 126, C6-C8. (b) Srivastava, V. K.; Schuerch, C. Tetrahedron
Lett. 1979, 3269-3272.
(9) (a) We verified this (ref 9b) by treatment of 1,2-O-stannylene acetals
of various sugars with acetic anhydride and isolation of the 1,2-O-cis-per-
O-acetyl derivatives in 85% to virtually theoretical yields. (b) Hodosi, G.;
Kova´cˇ, P. Abstracts, XVIII International Carbohydrate Symposium, Milano,
Italy, July 21-26, 1996; International Carbohydrate Organization: Milano,
Italy, 1966; p 394.
(10) The acetals are prepared as described in a typical experiment above.
Their solubility during the reaction is maintained by addition of a phase-
transfer salt (Table 1). The preferred solvent for glycosylation is acetonitrile.
However, the solubility of many stannylene acetals in it decreases, and the
reaction rate, particularly that of the much less reactive secondary triflates,
is impractically slow in that solvent. Therefore, we also used DMF, DMSO,
and DMAA (Table 1).
(1) Varki, A. Glycobiology 1993, 3, 97-130.
(2) Synthetic Oligosaccharides. Indispensable Probes in the Life Sciences;
Kova´cˇ, P., Ed.; American Chemical Society: Washington, DC, 1994; Vol.
560.
(3) (a) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212-
235. (b) Paulsen, H. Angew. Chem., Int. Ed. Engl., 1982, 21, 155-173. (c)
Schmidt, R. R. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: New York, 1991; Vol. 6; pp 33-64. (d) Khan, S. H.;
Hindsgaul, O. In Molecular Glycobiology; Fukuda, M., Hindsgaul, O., Eds.;
IRL Press: Oxford, 1994; pp 206-229.
(4) (a) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am.
Chem. Soc. 1975, 97, 4056-4062. (b) Paulsen, H.; Lockhof, O. Ber. Dtsch.
Chem. Ges. 1981, 114, 3102-3114. (c) Paulsen, H.; Lebuhn, R.; Lockhoff,
O. Carbohydr. Res. 1982, 103, C7-C11. (d) Garegg, P. J.; Ossowski, P.
Acta Chem. Scand. 1983, B37, 249-254. (e) Schmidt, R. R.; Reichrath,
M.; Moering, U. Chem. Ber. 1982, 115, 39-49.
(5) Baresi, F.; Hindsgaul, O. In Modern Methods in Carbohydrate
Synthesis; O’Neill, S. H. K. a. R. O., Ed.; Harwood Academic Publishers
GmbH: Amsterdam, 1996; Vol. 1, pp 251-276.
(6) (a) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 1087.
(b) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087-1088. (c) Baresi,
F.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 113, 9376. (d) Stork, G.; La
Clair, J. J. Am. Chem. Soc. 1996, 118, 247-248.
(11) (a) The stereochemistry of the newly formed glycosidic linkage was
deduced from the chemical shift for H-1II and from the JC-1,H-1, found in
the NMR spectra (Table 2). (b) All new compounds gave correct
microanalyses and/or exhibited 1H, 13C NMR, and mass spectral charac-
teristics in accord with their structures (cf, Table 2).
S0002-7863(96)04021-8 This article not subject to U.S. Copyright. Published 1997 by the American Chemical Society

2336 J. Am. Chem. Soc., Vol. 119, No. 9, 1997
Communications to the Editor
treatment of 7 with the known12 methyl 2,3,6-tri-O-benzoyl-4-
O-triflyl-D-galactopyranoside (9) gave the corresponding â-(1f4)-
linked disaccharide 10 in 78% yield. The best yield reported
thus far13 for the formation of the â-L-Rha-(1f4)-Glc linkage
was 43%.
Scheme 1a
a Conditions: (a) Bu2SnO, anhydrous MeOH, reflux, 2 h; BnBr,
DMF, CsF, 25 °C, 16 h, 84%. (b) Ac2O, AcOH, catalytic H2SO4, 25
°C, 3 h, 94%. (c) anhydrous MeOH, catalytic NaOMe, 25 °C, 3 h,
95%.
when each of the triflates 5 and 9 was treated with the 1,2-O-
stannylene acetal of 3-O-benzyl-D-mannose 12, obtained from
3-O-benzyl-D-mannose (22; Scheme 1),14 the â-(1f6)- and the
â-(1f4)-linked disaccharides 14 and 19 were obtained in the
respective yields of 75% and 67%.
Treatment in DMF of the much less reactive secondary triflate
9 with 11 gave the â-D-mannose-(1f4)-linked disaccharide 18
in 40% yield only. However, the reaction was very selective:
only traces of a byproduct (an analog of 15?) were formed. On
the other hand, the formation of the â-(1f4)-linked disaccharide
18 was very slow, and some of the starting material(s)
decomposed during the long reaction time. By changing the
solvent, the yield of 18 could be increased to 59% (Table 1). It
is worth noting that the same linkage was recently synthesized
Via a newly developed procedure,6d but in a yield of only
12%.15,16
Reactions of 7 in DMF were fast and gave virtually one
product. Conversely, the analogous acetal of D-mannose (11)
was much less reactive, and side reactions were observed during
the reaction time required for the conversion to be complete.
For example, formation of formates, such as 6, was observed
when DMF was the solvent (Table 1). Also, ether-linked
disaccharides, such as 15, were occasionally formed. The latter
was characterized Via the R-per-O-acetyl derivative 16.
A
In a typical experiment, a mixture of L-rhamnose (0.713 g,
3.92 mmol) and dibutyltin oxide (0.877 g, 3.52 mmol) in
anhydrous methanol (25 mL) was stirred at 60 °C until a clear
solution was obtained (∼1.5 h). CsF (0.714 g, 4.7 mmol) and
toluene (5 mL) were added, and the mixture was concentrated.
The residue, after having been kept at 50 °C, 0.2 Torr, for 2 h
to assure dryness, was dissolved in DMF (5 mL), molecular
sieves (4 Å, 0.5 g) were added, and the solution was cooled to
-5 °C. After addition of 5 (0.5 g, 0.79 mmol), the mixture
was stirred vigorously at -5 °C for 80 min, and concentrated.
The residue was triturated with acetonitrile, the resulting
suspension was filtered through a pad of Celite, solids were
washed with acetonitrile, and the combined filtrate was con-
centrated. Chromatography of the residue gave 8 (0.45 g, 88%).
Preliminary attempts to synthesize other oligosaccharides
containing 1,2-cis-glycosidic linkages (such as those containing
R-gluco- or R-galactopyranosyl linkages) from 1ax,2eq-O-stan-
nylene acetals indicate that those are much more complex
processes.
plausible explanation for the formation of 15 is the competitive
reaction at the equatorial O-3 in D-mannose whose reactivity,
compared to the O-3 in 11, was increased by the isomerization
of the acetal 11 (f 17) during the reaction. The side reactions
could be minimized by conducting the same reaction in
acetonitrile, but the reaction was much slower. Here, formation
of 6 could be completely eliminated, and 13 could be isolated
in 57% yield.
One of the outstanding features of the new method is that
specific blocking of hydroxyl groups in the glycosyl donor is
not required. Moreover, examples we have shown of the use
of the partially protected 1,2-O-stannylene acetal of D-mannose
(22) indicate the potential the new method offers for the
sequential construction of complex, higher oligosaccharides.
Acknowledgment. Authors dedicate this work to Professor Ja´nos
Kuszmann and thank Dr. Cornelis P. J. Glaudemans for his help and
keen interest.
Supporting Information Available: An experimental example for
preparation of compound 18 with analytical data (2 pages). See any
current masthead page for ordering and Internet access instructions.
The presumed isomerization 11 f 17 during the conversion
5 + 11 f 13 suggested that the yield of 13 could be improved
by the use of the 1,2-O-stannylene acetal of a 3-O-protected
D-mannose, where such isomerization cannot occur. Indeed,
JA964021Y
(12) Reed, L. A.; Goodman, L. Carbohydr. Res. 1981, 94, 91-99.
(13) van Steijn, A. M. P.; Kamerling, J. P.; Vliegenthart, J. F. G. J.
Carbohydr. Chem. 1992, 11, 665-689.
(14) 3-O-Benzyl-D-mannose was prepared as shown in the accompanying
formulas 20-22.
(15) A 77% yield of the same linkage was obtained in a different
laboratory (ref 16) by the internal aglycon delivery method. Since the method
described herein utilizes readily made acetals of unprotected sugars, the
yields achievable in these two ways cannot be fairly compared.
(16) Baresi, F.; Hindsgaul, O. Can. J. Chem. 1994, 72, 1447-1465.