first component in Huang-type, thioglycoside-based iterative
one-pot oligosaccharide syntheses and illustrate this principle
through the synthesis of a number of N-glycoyl R-sialoside-
based oligosaccharides of interest because of their potential
as markers for human tumors.8
Adapting the synthesis developed earlier for the prepara-
tion of 2,7 oxazolidinone 3 was converted to the N-
acetoxyacetimide derivative 4 in a straightforward manner
(Scheme 1).
interest in the matching of acceptor/donor pairs.10 The contrast
between a 3,4-diol and a 4-O-benzyl 3-ol in the galactopyranose
series is noteworthy but follows the established pattern in the
literature.6,7
A thiogalactosyl acceptor 6 was then prepared by standard
means (Supporting Information) and coupled to donor 4
under standard conditions resulting in the formation of
disaccharide 7 in excellent yield and selectivity (Scheme 2),
Scheme 2. Disaccharide Synthesis
Scheme 1. Donor Synthesis
A series of glycosylations were then conducted by combining
4 with the acceptor in a 2:1 dichloromethane/acetontrile mixture
at -78 °C before addition of N-iodosuccinimide and triflic acid,
leading to the results presented in Table 1, from which it is
thereby demonstrating viability of 4 in iterative one-pot
oligosaccharide syntheses.11
A series of four trisaccharides were then assembled by a one-
pot protocol in which a mixture of donor and the first acceptor
(1:1.15) and molecular sieves were cooled to -78 °C in a 2:1
dichloromethane/acetonitrile mixture before sequential addition
of N-iodosuccinimide (1.0 equiv) and triflic acid (0.5 equiv).
After stirring for 20 min at -78 °C, the second acceptor (1.5
equiv) was added, followed by further molecular sieves, NIS
(2.0 equiv), and triflic acid (0.5 equiv), and the reaction mixture
was allowed to come to 0 °C and maintained at that temperature
for 2 h before quenching (Scheme 3).12,13
Table 1. Exploratory Coupling Reactions with Donor 4
For selected examples, removal of the oxazolidinone group
was achieved by heating to 70 °C with aqueous ethanolic
(5) Indeed, previous strategies directed toward the one-pot synthesis of
sialylated oligosaccharides have necessitated the inclusion of the sialyl
moiety as part of a disaccharide, thereby circumventing the issue of the
low reactivity of sialic acid thioglycosides: Zhang, Z.; Niikura, K.; Huang,
X.-F.; Wong, C.-H Can. J. Chem. 2002, 80, 1051–1054.
(6) Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387–2391.
(7) Crich, D.; Li, W. J. Org. Chem. 2007, 72, 7794–7797.
(8) (a) Blixt, O.; Paulson, J. C. AdV. Synth. Catal. 2006, 345, 687–690.
(b) Malykh, Y. N.; Shaw, S. R. L. Biochimie 2001, 83, 623–634. (c) Varki,
A. Biochimie 2001, 63, 615–622. (d) Angata, T.; Varki, A. Chem. ReV.
2002, 102, 439–469.
(9) Stereochemical assignments were made on the basis of the 3JC1,H3ax
coupling constants: (a) Hori, H.; Nakajima, T.; Nishida, Y.; Ohrui, H.;
Meguro, H. Tetrahedron Lett. 1988, 29, 6317–6320. (b) Haverkamp, J.;
Spoormaker, T.; Dorland, L.; Vliegenthart, J. F. G.; Schauer, R. J. Am.
Chem. Soc. 1979, 101, 4851–4853. (c) Prytulla, S.; Lauterwein, J.;
Klessinger, M.; Thiem, J. Carbohydr. Res. 1991, 215, 345–349.
(10) (a) Spijker, N. M.; van Boeckel, C. A. A. Angew. Chem., Int. Ed.
1991, 30, 180–183. (b) Jayaprakash, K. N.; Chaudhuri, S. R.; Murty,
C. V. S. R.; Fraser-Reid, B. J. Org. Chem. 2007, 72, 5534–5545. (c) Cid,
M. B.; Alonso, I.; Alfonso, F.; Bonilla, J. B.; Lo´pez-Prados, J.; Mart´ın-
Lomas, M. Eur. J. Org. Chem. 2006, 394, 7–3959.
a Chemical shift and coupling constant reported for the major R-isomer.
b Not determined. Benzylation of 5dr gave 5er and enabled differentiation
of the two isomers in this otherwise unseparable mixture (see Supporting
Information). After saponification, the two anomers in this mixture could
be separated and characterized (see Supporting Information).
(11) The use of the phenylthio glycoside corresponding to 6 resulted in
lower yields and more complex reaction mixtures. For the relative reactivities
of substituted arylthio glycosides, see: Huang, L.; Wang, Z.; Huang, X.
Chem. Commun. 2004, 1960–1961.
apparent that donors 2 and 4 perform analogously under these
conditions.9 The dependence of coupling selectivity on the
acceptor alcohol is noteworthy in the context of the current
4034
Org. Lett., Vol. 10, No. 18, 2008