O-glycosyl trichloroacetimidates donors 1a-g containing
Fmoc protection and their use as glycosyl donors in solution
and on solid support.
glycosyl trichloroacetimidate 1b11 in 97% yield after filtration
on a small pad of silica.12 The reaction proved to be very
fast and clean. The same procedure applied to a similar
building block, namely, N-DMM-protected 4a, confirmed the
efficiency of this method. â-O-Glycosyl trichloroacetimidates
1a11 and 1b are of great interest for the construction of
carbohydrates of the lacto-series of glycosphingolipids and
of N-glycans.
These good results prompted us to investigate the compat-
ibility of our methodology with other protective groups. At
first, the synthesis of glucosamine derivatives 1c11 and 1e11
was investigated (Scheme 2). These compounds were
The main difficulty associated with the preparation of these
O-glycosyl trichloroacetimidates was to find conditions
compatible with the presence of this base sensitive group
all along the synthesis. Most of all, the last step of
introduction of the trichloroacetimidate moiety had to be
performed in basic conditions7b and seemed to be problem-
atic. However, the synthetic sequence described in Scheme
1 gave excellent results in all cases studied until now. For
Scheme 1a
Scheme 2a
a (a) FmocCl, DMAP, pyridine. (b) Excess HF‚pyridine, THF,
rt. (c) 0.1 equiv NaH, (1a) CH2Cl2/CCl3CN (1/1), (1b) CCl3CN,
rt.
all the building blocks prepared, we have chosen to use the
thexyldimethylsilyl group (TDS) to protect the anomeric
position. Thus the O-TDS-protected compounds (2a-g)8
were prepared. In all cases, the Fmoc group was introduced
using FmocCl with a catalytic amount of DMAP in pyridine
at room temperature in very good yields. To optimize the
desilylation step, N-DMM-protected9 glucosamine derivative
3a and the N-phthalimido derivative 3b were chosen as
models. The best results were obtained using an excess of
HF‚pyridine complex in THF at room temperature10 (92%).
Among the methods available to perform the formation of
the trichloroacetimidate function,7b the use of a catalytic
amount of NaH as the base seemed particularly attractive to
avoid the cleavage of the Fmoc group via â elimination.
Thus, in the presence of less than 0.1 equiv of NaH in
trichloroacetonitrile, alcohol 4b was converted into â-O-
a (a) FmocCl, DMAP, pyridine. (b) NaBH3CN, HCl‚Et2O, THF.
(c) Ac2O, pyridine. (d) Excess HF‚pyridine, THF, rt. (e) 0.1 equiv
NaH, CH2Cl2/CCl3CN (1/1), rt. (f) 2.5 equiv BzCl, pyridine.
synthesized using 2c as starting material. After linkage of
the Fmoc group to the O3 position (93% yield), the
benzylidene acetal function was regioselectively opened
using NaBH3CN and a solution of HCl‚Et2O13 to afford 3c
(11) NMR selected data for compounds 1a-g: 1H NMR (600 MHz,
CDCl3) δ 1a 6.23 (d, J1,2 ) 8.8 Hz, 1-Hâ); 1b 6.41 (d, J1,2 ) 8.4 Hz,
1-Hâ); 1c 6.38 (d, J1,2 ) 8.7 Hz, 1-Hâ); 1d 6.36 (d, J1,2 ) 8.7 Hz, 1-Hâ);
1e 6.54 (d, J1,2 ) 8.9 Hz, 1-Hâ); 1f 6.85 (d, J1,2 ) 3.4 Hz, 1-HR); 1g 6.40
(d, J1,2 ) 3.5 Hz, 1-HR).
(12) Typical Procedure. Compound 4b (115 mg, 0.16 mmol) was
dissolved in CCl3CN (3 mL) under Ar. Sodium hydride (0.1 equiv, 0.5
mg) was added to the solution, and after 10 min of stirring, a TLC analysis
showed a complete consumption of the starting material. The solution was
adsorbed on silica, and the solvents were evaporated in vacuo. The residue
was purified by flash chromatography (very small amount of silica) to afford
imidate 1b in a 97% yield.
(7) (a) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212. (b)
Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994, 50, 21.
(8) (a) For 2a and 2c see: Chiesa, V.; Schmidt, R. R. Eur. J. Org. Chem.,
accepted for publication. (b) For 2b see: Grathwohl, M. Diplomarbeit,
Universita¨t Konstanz, Germany, 1997. (c) For 2f see: Peter, J. Diplomarbeit,
Universita¨t Konstanz, Germany, 1994. (d) For 2g see: Knerr, L.; Roussel,
F.; Schmidt, R. R., unpublished results.
(9) Aly, M. R. E.; Castro-Palomino, J. C.; Ibrahim, E. I.; El-Ashry, E.
H.; Schmidt, R. R. Eur. J. Org. Chem. 1998, 2305.
(10) Trost, B. M.; Caldwell, C. G.; Murayama, E.; Heissler, D. J. Org.
Chem. 1983, 48, 3252.
(13) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108,
97.
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Org. Lett., Vol. 2, No. 20, 2000