ably pure fluorous disaccharide 1112 was obtained in 69%
yield by the reaction of 9 with 3 equiv of the galactose
derivative 10 in the presence of trimethylsilyl trifluo-
romethanesulfonate (TMS-OTf) in ether, followed by FC72-
toluene extraction after a normal workup. The galactose
derivative 10 used in excess was obtained as the 1-hydroxyl
form of 10 from the toluene extract. Furthermore, we
confirmed the deprotection of the Bfp group in the usual
manner using NaOMe. After FC72-MeOH extraction, the
disaccharide 12 was obtained in 93% yield from the MeOH
layer, and the methyl ester 5b was obtained in 92% yield
from the FC72 layer. Treatment of the methyl ester 5b with
aqueous NaOH gave 6 that was able to be reused as the
fluorous protecting reagent.
glucose derivative 13 used in excess was obtained as the
1-hydroxyl form of 13 from the toluene extract. The tert-
butyldiphenylsilyl (TBDPS) group of 14 was removed by
treatment with HF-pyridine in THF to give the pure fluorous
glycosyl acceptor 15 that was extracted with FC72 by
partition between FC72, water, and toluene. The disaccharide
1
3
1
5 coupled with the glycosyl donor 13 under similar
13
Schmidt’s conditions to afford the crude trisaccharide 16,
which was extracted with FC72 by being partitioned between
FC72 and toluene. The analysis of the crude trisaccharide
1
1
6 by H NMR spectroscopy and TLC showed that it
contained the starting glycosyl acceptor 15 (22%). For
characterization of 16, the crude trisaccharide 16 was purified
14
by silica gel chromatography to provide pure 16 in 50%
To clarify the partition efficiency of the oligosaccharide
having the Bfp group as a fluorous tag, we synthesized the
longer chain oligosaccharide as shown in Scheme 3. The
15
yield. Treatment of pure 16 with HF-pyridine in THF gave
1
3
pure 17, which was extracted with FC72 by being
partitioned between FC72, water, and toluene. The coupling
of the trisaccharide 17 with 13 by a similar glycosylation
provided the tetrasaccharide 18, which was extracted with
toluene by being partitioned between FC72 and toluene. The
unreacted 17 was easily separated from 18 only by partition
between FC72 and toluene. The toluene extract containing
Scheme 3a
1
8 and the 1-hydroxyl form of 13 was treated with HF-
13
pyridine in THF to afford the tetrasaccharide 19, which
was extracted with FC72 by being partitioned between FC72
and toluene. The yield of 19 was 10% (two steps) from 17
and was dependent on the glycosylation step. Although the
tetrasaccharide 18 was not extracted with FC72 at all, the
deprotected tetrasaccharide 19 was easily extracted with
FC72 by three Bfp groups. To effectively extract longer
oligosaccharides, the development of other types of fluorous
15
16
protective groups and the use of fluorous silica gel are now
in progress.
In conclusion, the use of the Bfp group as a fluorous
protective group made it possible to synthesize a natural
oligosaccharide by minimal column chromatography puri-
fication. Each synthetic intermediate was able to be easily
purified by simple FC72-organic solvent extraction and
monitored as a single compound by NMR, mass spectros-
copy, and TLC in contrast to the solid phase synthesis. The
fluorous protecting reagent 6 (Bfp-OH) was able to be easily
prepared on a large scale. The Bfp group was readily
introduced to the carbohydrate hydroxyl functions, was
removed in high yield by the usual procedure, and was
recyclable after cleavage. With only three Bfp groups was
it possible to extract the derivative of the tetrasaccharide with
the FC72 phase. Further application to the synthesis of a
bioactive carbohydrate and glycoconjugate is now in progress.
a
Reagents and conditions: (a) TMS-OTf, molecular sieves (AW-
3
00), Et
2
O, 0 °C, 1 h; (b) HF-Py, THF, rt, 24 h; (c) 13 (8-20
equiv), TMS-OTf, molecular sieves (AW-300), Et
2
O, 0 °C, 1 h.
reaction of the fluorous glycosyl acceptor 9 with 5 equiv of
the glucose derivative 13 in the presence of TMS-OTf in
ether, followed by FC72-toluene extraction, afforded the
1
3
disaccharide 14 in 75% yield from the FC72 layer. The
1
(
12) For characterization of 11, the reasonably pure 11 (90% purity) was
(14) Compound 16: colorless oil, H NMR (400 MHz, CDCl3) δ ) 1.04
purified by silica gel chromatography to provide pure 11. Compound 11:
colorless oil, H NMR (400 MHz, CDCl3) δ ) 1.88 (m, 6H), 1.97 (s, 3H),
.04 (s, 3H), 2.06 (s, 3H), 2.10 (m, 6H), 2.13 (s, 3H), 2.56 (m, 18H), 3.41
s, 3H), 3.44 (m, 6H), 3.64 (m, 7H), 3.92 (m, 3H), 4.09 (m, 1H), 4.20 (m,
H), 4.45 (m, 1H), 4.74 (m, 1H), 5.05 (m, 1H), 5.22 (m, 4H), 5.41 (m,
(s, 9H), 1.88 (s, 3H), 1.90 (m, 6H), 1.93 (s, 3H), 1.98 (s, 6H), 2.05 (s, 3H),
2.06 (s, 3H), 2.08 (m, 6H), 2.56 (m, 13H), 2.72 (m, 5H), 3.39 (s, 3H), 3.43
(m, 7H), 3.54 (m, 8H), 3.72 (m, 3H), 3.92 (m, 2H), 4.07 (m, 1H), 4.50 (m,
2H), 4.74 (brs, 1H), 4.87-5.31 (m, 9H), 7.40 (m, 6H), 7.65 (m, 4H).
1
2
(
1
1
+
MALDI-TOF-MS: calcd for C122H103F102N3O28SiNa (M + Na ) 4046.5,
+
H). MALDI-TOF-MS: calcd for C96H71F102N3O21Na (M + Na ) 3562.2,
found 4045.1.
+
found 3561.1; calcd for C96H71F102N3O21K (M + K ) 3578.4, found 3577.2.
(15) Compounds 16 and 18 were obtained without complete optimization
of glycosidation conditions.
(
13) Compounds 14, 15, 16, 17, and 19 were not detected by TLC from
the toluene layer after three extractions with FC72. These results show that
these compounds were quantitatively extracted with FC72.
(16) Ryu, I.; Kreimermaan, S.; Niguma, T.; Minakata, S.; Komatsu, M.;
Luo, Z.; Curran, D. P. Tetrahedron Lett. 2001, 42, 947.
Org. Lett., Vol. 3, No. 24, 2001
3949