Intramolecular glycosylation under neutral conditions for synthesis of 1,4-linked disaccharides.

Article abstract of DOI:10.1021/ol006988j

[structure: see text]. A new method for intramolecular glycosylation, in which the donor and acceptor were linked via a 3,5-dinitrosalicylic acid derivative, was developed. Simply dissolving the tethered glycoside in CH3NO2 and warming to 40-60 degrees C

Full text of DOI:10.1021/ol006988j

ORGANIC
LETTERS
2001
Vol. 3, No. 5
687-690
Intramolecular Glycosylation under
Neutral Conditions for Synthesis of
1,4-Linked Disaccharides
Jane B. Laursen, Lars Petersen, and Knud J. Jensen*
Department of Chemistry, Technical UniVersity of Denmark, Building 201,
KemitorVet, DK-2800 Kgs. Lyngby, Denmark
okkj@pop.dtu.dk
Received December 18, 2000
ABSTRACT
A new method for intramolecular glycosylation, in which the donor and acceptor were linked via a 3,5-dinitrosalicylic acid derivative, was
developed. Simply dissolving the tethered glycoside in CH NO and warming to 40−60 °C led to formation of 1,4-linked disaccharides under
3
2
neutral, hence, exceptionally mild, conditions.
The increased interest in glycobiology1 has led to consider-
able efforts in the development of new techniques for general
and efficient glycosylations2 in the synthesis of biologically
active oligosaccharides. One way of directing the regio- and
stereochemical outcome of the glycosylation is to tether the
donor and acceptor moieties prior to an intramolecular
glycosylation.2c,3 Efficient and stereoselective formation of
1,6-linked disaccharides by intramolecular glycosylation has
often been reported, whereas reported techniques for glyco-
sylation of the more hindered and less reactive 4-OH are
rare and afford moderate yields and stereoselectivity.4 By
far most glycosylation techniques, whether intermolecular
or intramolecular, rely on Lewis acid activation of the
glycosyl donor prior to glycosylation.
While these aryl glycosides are stable upon storage at 5 °C
and stable for days in CH2Cl2 and other nonpolar solvents,
they become efficient glycosyl donors in polar, aprotic
solvents such as N-methylpyrrolidinone (NMP). Simple
alcohols, e.g., methanol, were glycosylated stereospecifically,
whereas more sterically hindered alcohols, e.g., monosac-
charides, were glycosylated with R-selectivity. We envisioned
(3) (a) Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 113, 9376-
9377. (b) Bols, M. J. Chem. Soc., Chem. Commun. 1992, 913-914. (c)
Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087-1088. (d) Behrendt,
M. E.; Schmidt, R. R. Tetrahedron Lett. 1993, 34, 6733-6736. (e) Bols,
M. J. Chem. Soc., Chem. Commun. 1993, 791. (f) Bols, M. Tetrahedron
1993, 49 (44), 10049-10060. (g) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1765-1767. (h) Ziegler, T.; Lau, R. Tetrahedron Lett. 1995,
36, 1417-1420. (i) Valverde, S.; Go´mez, A. M.; Hernandez, A.; Herrado´n,
B.; Lo´pez, J. C. J. Chem. Soc., Chem. Commun. 1995, 2005-2006. (j)
Iimori, T.; Shibazaki, T.; Ikegami, S. Tetrahedron Lett. 1996, 37, 2267-
2270. (k) Stork, G.; Clair, J. J. L. J. Am. Chem. Soc. 1996, 118, 247-248.
(l) Ziegler, T.; Ritter, A.; Hu¨rttlen, J. Tetrahedron Lett. 1997, 38, 3715-
3718. (m) Rubinstenn, G.; Mallet, J.-M.; Sinay¨, P. Tetrahedron Lett. 1998,
39, 3697-3700. (n) Ito, Y.; Ohnishi, T.; Ogawa, T.; Nakahara, Y. Synlett
1998, 1102-1104. (o) Ziegler, T.; Lemanski, G. Eur. J. Org. Chem. 1998,
163-170. (p) Mu¨ller, M.; Huchel, U.; Geyer, A.; Schmidt, R. R. J. Org.
Chem. 1999, 64, 6190-6201. (q) Scheffler, G.; Schmidt, R. R. J. Org. Chem.
1999, 64, 1319-1325.
Very recently,5 we have developed a method for inter-
molecular glycosylation under neutral conditions. In this
glycosylation technique, the anomeric leaving group is
methyl 3,5-dinitrosalicylate (DISAL) or its para regioisomer.
(1) (a) Varki, A. Glycobiology 1993, 3, 97-130. (b) Molecular Biology;
Fukuda, M., Hindsgaul, O., Eds.; IRL Press: Oxford, 1994. (c) Yarema,
K. J.; Bertozzi, C. R. Current Opin. Chem. Biol. 1998, 49-61.
(2) (a) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155-173.
(b) Schmidt, R. R. Angew. Chem. 1986, 98, 213-236. (c) Davis, B. G. J.
Chem. Soc., Perkin Trans. 1 2000, 2137-2160.
(4) Lemanski, G.; Ziegler, T. Tetrahedron 2000, 56, 563-579.
(5) (a) Petersen, L.; Jensen, K. J. 20th International Carbohydrate
Symposium, August 27-September 1, 2000, Hamburg, Poster B-193. (b)
Petersen, L.; Jensen, K. J. submitted.
10.1021/ol006988j CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/06/2001

that a modified DISAL glycosyl donor, in which the alcohol
esterified by the benzoic moiety is not methanol but the 6-OH
of a partially protected carbohydrate (Figure 1, A), would
5. Using a “double base” system5 with an excess of Li2CO3
to drain HF from the reaction and a substoichiometric amount
of DMAP to transfer protons to the insoluble base, 90% of
5 with an R/â ratio of 6:1 was obtained. Next, the protecting
group of the acceptor moiety was removed by treatment with
formic acid in Et2O-toluene to give the tethered glycoside
6 in 46% yield. This moderate yield was probably due to
partial hydrolysis of the aryl glycosidic bond during aqueous
workup and purification by column chromatography. Dis-
solving the R-anomer of 6 in NMP-CH3CN and warming
to 40 °C caused a rearrangement to give the desired acylated
2-hydroxyethyl glucopyranoside 7 in 39% yield with an R/â
ratio of 2.7:1.
Subsequently, the strategy was implemented for disaccha-
ride synthesis (Scheme 2). The partially protected glycosyl
Figure 1. Design for a new intramolecular glycosylation method.
EWG ) electron withdrawing group (e.g., NO2); R1, R2
)
protecting groups.
Scheme 2. Synthesis of 1,4-Linked Disaccharides by
Intramolecular Glycosylationa
allow intramolecular glycosyl transfer to 4-OH by a 1,9-
glycosyl shift (Figure 1, B).
Initially, studies on this new intramolecular glycosylation
strategy were carried out with ethylene glycol as a simple
model for a carbohydrate diol (Scheme 1). The linker
Scheme 1. Initial Studies of Intramolecular Glycosylationa
a Reagents: (a) i. (COCl)2 (1.0 equiv), DMF (0.1 equiv) in
CH2Cl2; ii. 2,6-lutidine (2.5 equiv); iii. 8 (1.0 equiv), overall 63%;
(b) 9 (1.2 equiv), 1,4-dimethylpiperazine (0.6 equiv) or DMAP (0.3
equiv), Li2CO3 (2.0 equiv), 4 or 10 (1.0 equiv) in CH2Cl2, see Table
1 for yields; (c) CH3NO2, 40 °C, 37% 13, 58% 14; (f) NaOMe,
MeOH, rt, 95% 15, 93% 16.
a Reagents: (a) i. (COCl)2 (1.0 equiv), DMF (0.1 equiv) in
CH2Cl2; ii. 2,6-lutidine (2.5 equiv); iii. 2 (1.1 equiv), overall 78%;
(b) 3 (1.2 equiv), DMAP (0.3 equiv), 4 (1.0 equiv), Li2CO3 (2.0
equiv) in CH2Cl2, 90%; (c) HCOOH, Et2O-toluene, 46%; (d)
NMP-CH3CN, 40 °C, 39%.
acceptor methyl 2,3-di-O-benzyl-R-D-glucopyranoside 8 was
esterified with 2-fluoro-3,5-dinitrobenzoic acid 1 to give the
O-6 benzoic ester 9 in 63% yield. The high regioselectivity
of the O-acylation obliterated the need for transient protection
of O-4. The “donors” 2,3,4,6-tetra-O-benzyl-D-glucopyranose
4 or 2,3,4,6-tetra-O-benzyl-D-mannopyranose 10 were at-
tached to the linker moiety by nucleophilic aromatic substitu-
tion to form the aryl glycosides 11 and 12, respectively. In
the “double base” system both DMAP and 1,4-dimethylpip-
erazine (DMP) were used as organic bases in substoichio-
metric amounts (Table 1). With DMP promotion the â-gly-
precursor, 2-fluoro-3,5-dinitrobenzoic acid 1,5 was attached
to the acceptor, trityl 2-hydroxyethyl ether 2,6 via an ester
bond, giving the corresponding benzoic ester 3 in 78% yield.
Reaction of 3 and 2,3,4,6-tetra-O-benzyl-D-glucopyranose 4
by nucleophilic aromatic substitution gave the aryl glycoside
(6) Hurd, C. D.; Filachione, E. M. J. Am. Chem. Soc. 1937, 59, 1949-
1952.
688
Org. Lett., Vol. 3, No. 5, 2001

whereas substitution of CH3NO2 for NMP, CH3CN, or THF
led to degradation of the aryl glycosides. The tethered aryl
glycosides were also subjected to Lewis acid conditions
(Table 2, entries 4-7). Yields of these reactions were lower
than those for the neutral glycosylations, and the R-selectivity
in the formation of mannoside 14 also decreased signifi-
cantly.
Table 1. Aryl Glycoside Formation by Nucleophilic Aromatic
Substitution on 9
donor moiety
base
DMAPb 75% 11 (2.4:1)
DMPc
80% 11 (<1:25)
DMAPb 75% 12 (4:1)
DMPc
60% 12 (<1:8)
yield (R/â)a
isolated yield (R/â)
4
4
10
10
67% 11 (1:9.5)
53% 12 (1:0)
The stereoselectivity of the glycosyl transfer reaction
changed for some donor/acceptor combinations in going from
basic through neutral to acidic conditions (Table 2). However,
the differences are too small to draw firm conclusions to
the differences in reaction pathways. We observed that upon
dissolution in CH3NO2 and other polar solvents, the tethered
glycosides slowly underwent in situ anomerization (5-15%
R from pure â) during glycosylation under neutral or basic
conditions. Finally, removal of the DISAL linker was
performed by Zemple´n deacylation, liberating the 6-OH of
disaccharides 15 and 16 in 95% and 93% yields, respectively.
a Yields and anomeric distributions are determined by peak areas in
analytical HPLC. b 0.3 equiv of DMAP, 5 h at room temperature. c 0.6 equiv
of DMP (1,4-dimethylpiperazine), 17 h at room temperature.
cosides were formed predominantly in all cases, whereas the
faster DMAP-promoted reaction led to formation of the
R-glycosides.
Previous experiments on DISAL glycosides had shown
that once the aryl glycoside is formed, it does not undergo
racemization under the reaction conditions.5 Similarly, we
found that the R/â ratio of the tethered glycosides was
constant throughout the DMAP-promoted reaction. We
speculate that DMP-promoted arylation predominantly gives
the â-glycoside by selective reaction of the more nucleophilic
â-alkoxide, while the faster DMAP-promoted arylation
presumably proceeds by reaction of the initially predomi-
nantly R-configured alkoxide. Yields of aryl glycosides 11
and 12 were in the range of 60-80% with both DMP and
DMAP promotion.
The tethered glycosides 11 and 12 were subjected to
conditions similar to those used in the model studies (Table
2), and it was rewarding to observe that they did indeed
undergo intramolecular transglycosylation to form the cor-
responding 1,4-linked disaccharides 13 and 14, respectively.
Under neutral conditions in CH3NO2 at 60 °C, the intramo-
lecular glycosylation reaction favored formation of â-gluco-
sides and R-mannosides. Yields of the glycosyl transfer
according to HPLC were 37% for the glucose derivative 13
(Table 2, entry 1) and 58% for the mannose derivative 14
(Table 2, entry 2), respectively. The latter was isolated in
49% yield with an anomeric distribution of R/â 3.7:1, the
starting material 12 having the anomeric distribution of R/â
1.3:1.
In crossover experiments, secondary alcohols, 1,2:5,6-di-
O-isopropylidene-R-D-glucofuranose or cyclohexanol, were
added as competing nucleophiles in equimolar amounts to
the glycosyl transfer reaction of 11 in CH3NO2. The
secondary alcohol 1,2:5,6-di-O-isopropylidene-R-D-gluco-
furanose, comparable in nucleophilicity to the 4-OH of the
tethered acceptor 11, did not give the corresponding inter-
molecular glycosylation product, as the only disaccharide
observed was formed by intramolecular glycosyl transfer.
However, the more reactive cyclohexanol gave the inter-
molecularly formed glycoside as the major product.7 This
indicated that the glycosylation, although not concerted, did
take place within the solvent cage unless a nucleophile
significantly better than the tethered acceptor was added to
the solvent.
To reveal if any hydrolysis of the tethered glycoside
occurred during HPLC analysis, a control experiment was
performed in which a large excess of MeOH was added to
the glycosyl transfer reaction of 12 after 41 h and prior to
preparation of HPLC samples. No methyl glycoside was
formed under these circumstances, indicating that all of the
tethered glycoside 12 had undergone the expected 1,9-
glycosyl shift, elimination, or hydrolysis prior to dilution in
MeOH.
Addition of base to the reaction mixtures in the intramo-
lecular glycosylation was detrimental (Table 2, entry 3),
Table 2. Screening of Conditions for Intramolecular Glycosylation
tethered
reaction
time
isolated yield
entry
glycoside (R/â)
promotera
solvent
temp, °C
hydrolysisb,c
yield (R/â)b
(R/â)
1
2
3
4
5
6
7
11 (0:1)
12 (1.3:1)
11 (0:1)
11 (0:1)
11 (0:1)
11 (0:1)
12 (1.3:1)
CH3NO2
CH3NO2
CH3NO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
60
40
60
-78 to 0
20
20
15 h
41 h
40 h
24 h
10 min
10 min
90 min
48%
15%
>50%
50%
75%
65%
37% 13 (1:1.7)
58% 14 (3.7:1)
<20% 13 (1:1.7)
27% 13 (2.1:1)
5% 13 (1:1.2)
10% 13 (1:1)
24% 13 (1:1.3)
49% 14 (3.7:1)
based
BF3‚OEt2
FeCl3
TMSOTf
BF3‚OEt2
20
58%
20% 14 (1:1)
a Bases: 3-5 equiv. Lewis acids: 2 equiv. b Yields, anomeric distributions, and hydrolysis are determined by peak areas in analytical HPLC. c Hydrolysis
of aryl glycosides 11 and 12 forming free 1-OH glycopyranoses and esters of 3,5-dinitrosalicylic acid. d 2,6-Di-tert-butyl-4-(dimethylamino)pyridine, 2,6-
lutidine, Et3N, or DIPEA.
Org. Lett., Vol. 3, No. 5, 2001
689

In conclusion, we have developed a new method for
intramolecular glycosylation of the 4-OH of D-glucose under
neutral, and, hence, extremely mild, conditions. Monosac-
charide donors and acceptors were 1,6-linked by a 3,5-
dinitrosalicylic acid moiety (DISAL) to form tethered
glycosides, which underwent intramolecular transglycosyl-
ation to give the expected 1,4-linked disaccharides via 1,9-
glycosyl shifts. Yields were somewhat reduced by competing
hydrolysis. Further modifications in the implementation of
this new concept for intramolecular glycosylation might
allow improvements in yields and stereochemical control.
Acknowledgment. We thank Novo Nordisk Training and
Research Program (J.B.L.), the Alfred Benzon Foundation
(K.J.J.), the Lundbeck Foundation (K.J.J.), and the Danish
Technical Science Research Council (K.J.J.) for financial
support of this work.
Supporting Information Available: General experimen-
tal procedures for synthesis of esters 3 and 9, aryl glycosides
5-6 and 11-12, and glycosides 7 and 13-16. Complete
analytical data for compounds 3, 5-7, 9, and 11-16. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) The ratio between the inter- and intramolecular glycosylation products
was 5.2:1 (cyclohexyl glycoside vs 13).
OL006988J
690
Org. Lett., Vol. 3, No. 5, 2001