Scheme 4 One-pot procedure for the pentasaccharide. Reagents and
conditions: (a) (i) 3, TMSOTf, CH2Cl2, 270 uC, 1 h; (ii) 4, NIS/TfOH,
CH2Cl2, 250 to 210 uC, 2 h, 63%; (b) (i) PPh3, THF/H2O, r.t.; (ii)
NH2CH2CH2NH2, CH3CN–EtOH–toluene, 80 uC, 18 h; (iii) Py, Ac2O,
r.t.; (iv) 1 M NaOMe, MeOH, 2 days, four steps, 70%.
one pot (Scheme 4).3 Disaccharide 2 was activated with TMSOTf
to react exclusively with the C4 hydroxyl group of monosaccharide
3. Addition of disaccharide acceptor 4 to the reaction mixture,
followed by NIS/triflic acid to activate the thioglycosyl group of
the in situ formed trisaccharide completed the sequence. The fully
protected pentasaccharide 6 was obtained in 63% yield from two
disaccharides and one monosaccharide. Four deprotection steps
were required to liberate the target molecule of all masking
groups:12 reduction of the azide, removal of the N-phthaloyl
group, acetylation in pyridine and acetic anhydride and removal of
acetate esters and benzoate esters by exposure to sodium
methoxide in methanol provided pentasaccharide target 1 in 70%
yield over four steps.
Scheme 2 Preparation of disaccharide
2 and monosaccharide 3.
Reagents and conditions: (a) ref. 11; (b) (i) 70% HOAc, 40 uC; (ii) Py,
BzCl, CH2Cl2, 230 uC, 2 h, 75%; (c) Br2, CH2Cl2, 0 uC, 30 min; (d) 9,
AgOTf, sym-collidine, CH2Cl2, 230 uC, 4 h, 76%; (e) NBS, THF/H2O,
r.t., 90%; (f) CCl3CN, CH2Cl2, K2CO3, 0 uC to r.t., 78%; (g) Py, PivCl,
CH2Cl2, 82%.
The C2 N-phthalimido group drastically lowers the reactivity of
the C3 hydroxyl to yield mainly the 1–4 linked product.4,7
Galactosamine 15 was converted into the corresponding a-octyl
glycoside by heating with BF3?OEt28 to 70 uC for 3 h in octanol as
solvent (Scheme 3). The amine was converted into the correspond-
ing azide 17.9 Placement of a 4,6-benzylidene group by treatment
with benzaldehyde dimethyl acetal and a catalytic amount of
TsOH?H2O gave monosaccharide 18. Union of glycosyl building
block 19 and nucleophile 18 furnished initially the orthoester
before addition of more TMSOTf10 transformed the orthoester to
the desired disaccharide 20. Hydrolysis of the benzylidene group
yielded disaccharide diol 4.
Inhibition assays comparing different synthetic oligosaccharides
for their ability to inhibit the activity of cholesterol a-glucosyl-
transferase revealed that 1 was significantly more active than other
closely related carbohydrates. The IC50 was determined at
0.47 mM.2b
In summary, we have synthesized a pentasaccharide implicated
as a potent antibiotic against H. pylori. Key to this synthesis was
the one-pot glycosylation sequence to assemble the main
carbohydrate scaffold. The final product proved to be a good
inhibitor of cholesterol a-glucosytransferase. Further tests of the
antibiotic activity of the synthetic oligosaccharide in mice are
currently under way and will be reported in due course.
We thank the NIH (Grant PO1CA71932) for financial support.
We express our thanks to Dr J. Yu and H. Tao for 1H NMR and
13C NMR spectra.
With the three building blocks, 2–4, in hand, the key reaction
sequence en route to the target pentasaccharide was executed in
Notes and references
1 B. J. Marshall and J. R. Warren, Lancet, 1984, 1311–1315.
2 (a) M. Kawakubo, Y. Ito, Y. Okimura, M. Kobayashi, K. Sakur,
S. Kasama, M. N. Fukuda, M. Fukuda, T. Katsuyama and
J. Nakayama, Science, 2004, 305, 1003–1006; (b) H. Lee,
M. Kobayashi, P. Wang, J. Nakayama, P. H. Seeberger and
M. Fukuda, Biochem. Biophys. Res. Commun., 2006, 349,
1235–1241.
3 H. Yamada, T. Harada and T. Takahashi, J. Am. Chem. Soc., 1994,
116, 7919–7920.
4 T. Buskas and P. Konradsson, J. Carbohydr. Chem., 2000, 19,
25–51.
5 J. Linderg, S. C. Svensson, P. Pa˚hlsson and P. Konradsson,
Tetrahedron, 2002, 58, 5109–5117.
6 J. O. Kihlberg, D. A. Leigh and D. R. Bundle, J. Org. Chem., 1990, 55,
2860–2863.
Scheme 3 Synthesis of disaccharide 4. Reagents and conditions: (a)
BF3?OEt2, CH2Cl2, octanol, 70 uC, 2 h, 78%; (b) (i) 1 M NaOH, 120 uC,
12 h; (ii) TfN3, MeOH, K2CO3, CuSO4, CH2Cl2/H2O, r.t., overnight, two
steps 75%; (c) p-TsOH?H2O, dimethoxytoluene, CH3CN, 80%; (d) 19,
TMSOTf, CH2Cl2, 0 uC to r.t., 2 h, 83%; (e) 70% HOAc, 60 uC, 3 h, 78%.
1964 | Chem. Commun., 2007, 1963–1965
This journal is ß The Royal Society of Chemistry 2007