Michael-type addition to 2-nitrogalactal - A simple method to access 1,1-linked oligosaccharides

Article abstract of DOI:10.1055/s-2004-836059

Anomeric O-unprotected sugars add to 3,4,6-tri-O-benzyl-2-nitro-D-galactal to accomplish nitro group-containing 1,1-linked oligosaccharides in respectable yields with good selectivities. A 1:1 mixture of toluene and n-heptane has been found as the appropriate solvent system for these Michael-type additions. The nitro group-containing 1,1-linked oligosaccharides are easily convertible into interesting trehalosamine analogues.

Full text of DOI:10.1055/s-2004-836059

134
LETTER
Michael-Type Addition to 2-Nitrogalactal – A Simple Method to Access
1,1-Linked Oligosaccharides
1
, 1-Linked Oligo
e
saccharidesngarajan Balamurugan, Kandasamy Pachamuthu, Richard R. Schmidt*
Universität Konstanz, Fachbereich Chemie, Fach M 725, 78457 Konstanz, Germany
Fax +49(7531)883135; E-mail: Richard.Schmidt@uni-konstanz.de
Received 7 October 2004
symmetrical analogues of trehalosamine. Herein we
present our results on the Michael-type addition of ano-
meric O-unprotected sugars to 3,4,6-tri-O-benzyl-2-nitro-
D-galactal. The reaction is represented in Scheme 1 and
Abstract: Anomeric O-unprotected sugars add to 3,4,6-tri-O-ben-
zyl-2-nitro-D-galactal to accomplish nitro group-containing 1,1-
linked oligosaccharides in respectable yields with good selectivi-
ties. A 1:1 mixture of toluene and n-heptane has been found as the
appropriate solvent system for these Michael-type additions. The the results are compiled in Table 1.
nitro group-containing 1,1-linked oligosaccharides are easily con-
vertible into interesting trehalosamine analogues.
All reactions were carried out with easily accessible 3,4,6-
tri-O-benzyl-2-nitro-D-galactal 1.7f Potassium tert-butox-
ide was the base of choice as it worked well in our hands
for the Michael-type addition of various nucleophiles to 2-
nitroglycals.7 The required anomeric O-unprotected sug-
ars can be easily prepared. In a preliminary experiment, 1
was treated with equimolar quantities of 2,3,4-tri-O-
acetyl-6-O-benzyl-D-galactose (2) and potassium tert-bu-
toxide in toluene. The reaction yielded the desired 1,1-
linked disaccharide 2 in 46% yield. Out of the four possi-
ble diastereomers, only two were obtained, namely 2a and
2b. Hence, in accordance with the previous reports,7 ex-
clusive a-addition of the anomeric oxide of 2 to nitroga-
lactal 1 occurred followed by protonation from the b-side,
thus generating two new stereogenic centers with excel-
lent stereocontrol. The anomeric carbon of the anomeric
O-unprotected sugar part in the product was a 4:1 mixture
of a- (2a) and b-products (2b). The configuration of the
newly formed stereogenic centers were discerned from
the corresponding coupling constant values of the ano-
meric protons of 2a,b.8 With other anomeric O-unprotect-
Key words: Michael-type addition, 2-nitrogalactal, 1,1-linked
oligosaccharides, O-unprotected sugars, nitro group
1,1-Linked oligosaccharides occur as structural constitu-
ents in many organisms.1 Trehalosamines, amino group
containing 1,1-linked oligosaccharides, possess substan-
tial antimicrobial activity, thus they serve as promising
candidates for designing novel antibiotics and trehalase
inhibitors.2 Only a few reports have appeared in the liter-
ature on the synthesis of trehalosamines in general and
their non-symmetrical analogues in particular. They
mainly involve the glycosylation of anomeric O-unpro-
tected sugars with 1-halo sugars,3a–c oxyamination of 1,1-
linked pseudo glycals,3d,e selective displacement of hy-
droxyl functions in trehaloses with azide and subsequent
reduction,3f and enzymatic processes.3g Hence, efficient
methods are desirable to synthesize non-symmetrical
analogues of trehalosamine.
Glycals are extensively employed in the synthesis of oli- ed sugars such as 5 and 8, the yields of the products 5a and
gosaccharides and libraries thereof and of a variety of op- 8a,b were also less than 40%. Reactions carried out in
tically active products.4 Nitroglycals, in particular, THF were found to be even worse. In order to find out the
possess potential in the synthesis of glycoconjugates since cause for the low yields, in a separate experiment a mix-
D-glucosamine and D-galactosamine are frequently occur- ture of 1,1-disaccharides 2a and 2b was treated with po-
ring glycoconjugate constituents.5 Base assisted oxy- tassium tert-butoxide in toluene. This reaction clearly
Michael addition of d-lactols to acrylates has been report- revealed the reversible nature of the reaction under the re-
ed.6 Hence, it appeared that 2-nitroglycals could well action conditions. It in turn suggested reducing the polar-
serve as simple precursors for the synthesis of non- ity of the solvent so that the carbanion generated after the
Scheme 1 t-BuOK assisted synthesis of 1,1-linked oligosaccharides
SYNLETT 2005, No. 1, pp 0134–0138
0
5.
0
1.
2
0
0
5
Advanced online publication: 07.12.2004
DOI: 10.1055/s-2004-836059; Art ID: G40204ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,1-Linked Oligosaccharides
135
addition gets protonated quickly and the rate of the re- protected sugar part. It is interesting to note that the a/b ra-
verse reaction is decreased. In line with this suggestion, tio in the anomeric O-unprotected sugars is not sustained
the reaction of 1 with 2 in a 1:1 mixture of toluene and n- in the product; rather, it is dependent on the nature of the
heptane was found to be very clean and the yield of the substituent at its 2-position. For instance, when acetoxy
product was improved dramatically to 85%;8 the 2a/2b ra- and azido groups are in the equatorial position of carbon-
tio under these conditions was found to be 5:2. This result 2 (2, 3, and 6), the a-isomer is obtained predominantly
prompted a study with other anomeric O-unprotected even though, except 2, both 3 and 6 were mostly b-ano-
sugars as well.
mers, whereas 4 behaved differently. Compounds 7 and 8
with equatorial 2-dimethylmaleimido (DMMN) groups
resulted mostly in the b-isomer. However, tetra-O-acetyl-
mannose (5) with an axial 2-acetoxy group at C-2 gave ex-
clusively the a-anomer 5a. These observations are not a
surprise as the anomeric O-unprotected sugars are expect-
ed to undergo ring-opening and -closure under basic con-
dition and vary their anomer ratio. Thus, the reaction of 1
with 6 and 7 can be advantageously exploited to synthe-
size either a- or b-isomers of trehalosamine.
Different anomeric O-unprotected sugars 3–8 derived
from glucose, mannose, glucosamine and two disaccha-
rides were reacted with 1 under the new reaction
conditions to furnish the corresponding 1,1-linked oli-
gosaccharides in good yields (Table 1). Hence, this proto-
col can serve as a versatile method to synthesize 1,1-
linked oligosaccharides with different sugar components.
The configurations of the newly generated stereogenic
centers were assigned using NMR methods. Like 2, all the
anomeric O-unprotected sugars gave a mixture of a- and
b-anomers at the anomeric carbon of the anomeric O-un-
Table 1 Michael-Type Additions of Anomeric O-Unprotected Sugars to 3,4,6-Tri-O-benzyl-2-nitro-D-galactala
Sugar (a:b)
Time (h)
2
Products
Isolated yields (%)
a:b
85 (94)b
2.5:1
2 (a)
2a
2b
1
57 (84)b
4.5:1
3 (1:6.3)
3a
3b
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136
R. Balamurugan et al.
LETTER
Table 1 Michael-Type Additions of Anomeric O-Unprotected Sugars to 3,4,6-Tri-O-benzyl-2-nitro-D-galactala (continued)
Sugar (a:b)
Time (h)
2
Products
Isolated yields (%)
a:b
61 (95)b
1:1.7
4 (1:1.2)
4a
4b
5a
1
1
80 (95)b
single isomer
5 (6:1)
56 (72)b
3.2:1
6 (1:1.3)
6a
6b
2
62 (84)b
1:3.9
7 (b)
7a
7b
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LETTER
1,1-Linked Oligosaccharides
137
Table 1 Michael-Type Additions of Anomeric O-Unprotected Sugars to 3,4,6-Tri-O-benzyl-2-nitro-D-galactala (continued)
Sugar (a:b)
Time (h)
2
Products
Isolated yields (%)
a:b
68 (89)b
1:4.7
8 (1:5)
8a
8b
a For experimental details, see ref.8,
b Yields based on the consumed anomeric O-unprotected sugar.
Closely related anomeric O-alkylation of anomeric O-un- Due to the reversible nature of the anomeric ratio in the
protected sugars has been studied as it constitutes a con- nucleophiles 2–8 and of their oxy-Michael addition to 1,
venient and effective method to synthesize O-glycosides.9 the time-dependency of the a/b product ratio was further
Several factors such as the nature of base, solvent, sub- investigated with substrate 3. Aliquots taken from the re-
stituents, and temperature affect a/b selectivity. In this action mixture after 15 minutes, 1 hour, 2 hours, and 20
irreversible reaction, in a nonpolar solvent at room tem- hours were worked up and chromatographed; the a/b ratio
perature, the equatorial b-oxide has been found to be more of the product 3a,b was found by 1H NMR investigations
reactive than the axial a-oxide, thus furnishing mainly b- to be 3:1, 5:1, 8:1, and 8.6:1, respectively. In another set
glycosides. On the other hand, polar solvents and low re- of experiments, substrates 3 and 7 were treated with potas-
action temperatures led mainly to a-glycosides. In the sium tert-butoxide in the absence of 1 under otherwise
present study, in a nonpolar solvent system at 0 °C and af- identical conditions of the general procedure.8 The a/b ra-
ter 1–2 hours reaction time, independent of the anomeric tio of substrate 3 (a/b = 1:6.3) is reversed to 2.1:1 and
configuration of the starting material, in most cases the 2.5:1, respectively, after 10 minutes in toluene and 1 hour
thermodynamically more stable a-glycosides were ob- in a 1:1 toluene–n-heptane mixture. With substrate 7,
tained. Only for 7 and 8, having a bulky dimethylmaleim- from exclusive b-anomer, the a/b ratio is reduced to 1:11
ido group at C-2, and for 4 mainly the b-anomers were and 1:9.3, respectively, after 10 minutes in toluene and 1
received. Hence, these results are not in full agreement hour in a 1:1 toluene–n-heptane mixture. These experi-
with those found for irreversible anomeric O-alkylations, ments clearly show that a-glycoside formation (2a–8a) is
which were mainly investigated with primary alkylating favored for stereoelectronic reasons but it also requires
agents where also steric effects of the electrophile play a (slow) equilibration of the b-anomers 2–8 to the corre-
minor role. Rather the results obtained here resemble sponding a-anomers.
base-catalyzed trichloroacetonitrile addition to 1-O-un-
To show the usefulness of this method, the nitro group in
the 1,1-linked oligosaccharide 2a was reduced to the ami-
protected sugars where a-trichloroacetimidate formation
is thermodynamically favored.9a This view is also sup-
no group using Zn, HCl/HOAc7b in a THF–H2O mixture.
ported by the following investigations.
Subsequent acetylation gave the corresponding acetylated
trehalosamine derivative 9a in 70% yield over two steps
(Scheme 2).
Scheme 2 Conversion of 2a into trehalosamine analogue 9a
Synlett 2005, No. 1, 134–138 © Thieme Stuttgart · New York

138
R. Balamurugan et al.
LETTER
(4) (a) Collins, P. M.; Ferrier, F. J. Monosaccharides, Their
In conclusion, potassium tert-butoxide assisted Michael
addition of anomeric O-unprotected sugars to 3,4,6-tri-O-
benzyl-2-nitro-D-galactal (1) can be conveniently em-
ployed to prepare nitro group containing 1,1-linked
oligosaccharides bearing different sugar units. Addition to
2-nitrogalactal as Michael acceptor was stereoselective
leading only to a-galacto-configuration; anomerisation of
the nucleophiles, the 1-O-unprotected sugars, furnished in
most cases preferentially the a-anomer, hence a,a-1,1-
linked products were predominantly obtained. Further, it
has been demonstrated with an example that the nitro
group of the 1,1-linked oligosaccharide can be easily con-
verted into an amino group to access useful trehalosamine
analogues.
Chemistry and Their Roles in Natural Products; John Wiley
and Sons: Chichester, 1995, 317. (b) Lichtenthaler, F. W. In
Modern Synthetic Methods; Scheffold, R., Ed.; VCH:
Weinheim, 1992, 273. (c) Bols, M. Carbohydrate Building
Blocks; Wiley: New York, 1996, 49. (d) Danishefsky, S. J.;
Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35,
1380. (e) Izumi, M.; Ichikawa, Y. Tetrahedron Lett. 1998,
39, 2079.
(5) (a) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem.
Biochem. 1994, 50, 21. (b) Garg, H. G.; von dem Bruch, K.;
Kunz, H. Adv. Carbohydr. Chem. Biochem. 1994, 50, 277.
(6) (a) Schmidt, C. Diploma Thesis; University of Konstanz:
Germany, 1994. (b) Buchman, D. J.; Dixon, D. J.;
Hernandez-Juan, F. A. Org. Lett. 2004, 6, 1357.
(7) (a) Barroca, N.; Schmidt, R. R. Org. Lett. 2004, 6, 1551.
(b) Geiger, J.; Barroca, N.; Schmidt, R. R. Synlett 2004,
836. (c) Khodair, A. I.; Pachamuthu, K.; Schmidt, R. R.
Synthesis 2004, 53. (d) Khodair, A. I.; Winterfeld, G. A.;
Schmidt, R. R. Eur. J. Org. Chem. 2003, 1847.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. K. P. is grateful for an
Alexander von Humboldt Fellowship.
(e) Winterfeld, G. A.; Schmidt, R. R. Angew. Chem. Int. Ed.
2001, 40, 2654; Angew. Chem. 2001, 113, 2718. (f) Das, J.;
Schmidt, R. R. Eur. J. Org. Chem. 1998, 1609; and
references therein.
(8) General Procedure for the Michael-Type Addition:
To a solution of anomeric O-unprotected sugar (0.16 mmol)
in toluene (1 mL), t-BuOK (0.16 mmol) was added at 0 °C.
After 10 min, a solution of 1 (0.19 mmol) in toluene–n-
heptane mixture (1:2, 3 mL) was added to it. The reaction
mixture was stirred at the same temperature for the specific
period of time given in Table 1. Few drops of HOAc were
added to quench the reaction. It was taken in EtOAc, washed
with H2O, and sat. brine, dried over anhyd MgSO4, and
concentrated. Purification of the crude residue by
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chromatography on silica gel afforded the 1,1-linked
oligosaccharide. Selected 1H NMR data (250 MHz, CDCl3):
Compound 2a: d = 5.58 (J1,2 = 4.3 Hz, 1-Ha), 5.25 (J1,2 = 3.7
Hz, 1-Hb). Compound 2b: d = 5.50 (J1,2 = 4.1 Hz, 1-Ha), 4.56
(J1,2 = 8.3 Hz, 1-Hb). Compound 3a: d = 5.56 (J1,2 = 4.2 Hz,
1-Ha), 5.25 (J1,2 = 3.9 Hz, 1-Hb). Compound 3b: d = 5.49
(J1,2 = 4.2 Hz, 1-Ha), 4.60 (J1,2 = 8.1 Hz, 1-Hb). Compound
4a: d = 5.55 (J1,2 = 4.1 Hz, 1-Ha), 5.16 (J1,2 = 3.8 Hz, 1-Hb),
5.36 (J1,2 = 3.3 Hz, 1-Hc). Compound 4b: d = (J1,2 = 4.0 Hz,
1-Ha), 4.63 (J1,2 = 8.1 Hz, 1-Hb), 5.41 (J1,2 = 3.8 Hz, 1-Hc).
Compound 5a: d = 5.63 (J1,2 = 4.2 Hz, 1-Ha), 5.11 (J1,2 = 1.1
Hz, 1-Hb). Compound 6a: d = 5.60 (J1,2 = 4.2 Hz, 1-Ha), 5.21
(J1,2 = 3.9 Hz, 1-Hb). Compound 6b: d = 5.61 (J1,2 = 4.1 Hz,
1-Ha), 4.42 (J1,2 = 8.2 Hz, 1-Hb). Compound 7a: d = 5.63
(J1,2 = 4.1 Hz, 1-Ha), 5.41 (J1,2 = 4.1 Hz, 1-Hb). Compound
7b: d = 5.34 (J1,2 = 4.0 Hz, 1-Ha), 5.35 (J1,2 = 8.7 Hz, 1-Hb).
Compound 8a: d = 5.50 (J1,2 = 4.1 Hz, 1-Ha), 5.01 (J1,2 = 3.6
Hz, 1-Hb), 4.36 (J1,2 = 8.3 Hz, 1-Hc). Compound 8b: d = 5.29
(J1,2 = 4.1 Hz, 1-Ha), 5.08 (J1,2 = 8.2, 1-Hb), 4.51 (J1,2 = 8.0
Hz, 1-Hc). Compound 9a: d = 5.23 (J1,2 = 3.0 Hz, 1-Ha), 5.32
(J1,2 = 3.5 Hz, 1-Hb).
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Synlett 2005, No. 1, 134–138 © Thieme Stuttgart · New York