Mild but efficient methods for stereoselective glycosylation with thioglycosides: Activation by [N-phenylselenophthalimide-Mg(ClO4)2] and [PhIO-Mg(ClO4)2]

Article abstract of DOI:10.1055/s-1998-1575

Combinations of N-phenylselenophthalimide (N-PSP) or iodosobenzene (PhIO) with Mg(ClO₄)₂ effectively promote glycosylation with thioglycosides under mild conditions. A 2,2,2-trichloroethoxycarbonyl group or trityl protecting group at

Full text of DOI:10.1055/s-1998-1575

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Mild but Efficient Methods for Stereoselective Glycosylation with Thioglycosides: Activation
by [N-Phenylselenophthalimide–Mg(ClO ) ] and [PhIO–Mg(ClO ) ]
4
2
4 2
Koichi Fukase,* Yoshihiko Nakai, Takeshi Kanoh, and Shoichi Kusumoto*
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560, Japan
Fax: +81 6 850 5419; E-mail: koichi@chem.sci.osaka-u.ac.jp
Received 19 September 1997
Abstract: Combinations of N-phenylselenophthalimide (N-PSP) or
iodosobenzene (PhIO) with Mg(ClO4)2 effectively promote
glycosylation with thioglycosides under mild conditions. A 2,2,2-
trichloroethoxycarbonyl group or trityl protecting group at the 6-
position increased α-selectivity on glycosylation with 2-O-benzylated
donors.
application to solid-phase synthesis of oligosaccharides, since the
selective glycosylation is effected at or even above room temperature.
Thioglycosides have been used as versatile glycosyl donors since they
are stable under various reaction conditions but can be selectively
activated by appropriate thiophilic reagents. We have focused on a
search for practically useful methods for mild but efficient activation of
thioglycosides, thereby attempting to avoid the use of strongly acidic
conditions. Until now we have described two methods for this purpose
and furnished stereoselective glycosylation. One was the reaction with a
combination of N-bromosuccinimide (NBS) and a catalytic amount of
Shimizu et al. recently reported that N-PSP promotes glycosylation with
thioglycosides when used in combination with TMSOTf but no
stereoselectivity was observed under their reaction conditions. In view
of the results of our NBS–strong acid salts system,2 we expected a
similar stereoselective reaction with the N-PSP reagent by the combined
use with a suitable salt.
6
1
,2
various salts of strong acids. The other utilized hypervalent iodine
reagents prepared from iodosobenzene (PhIO) and various acids.3 By
both methods glycosylation reactions proceed rapidly at low
temperature (usually around -20 °C) in high yields. But in certain cases,
particularly in the NBS-based reaction, the yields of α-glucosides were
not satisfactory because a side reaction to form glycosyl bromides from
,4
Among many strong acid salts tested, only Mg(ClO4)2 can promote
glycosylation in combination with N-PSP. This was in strong contrast to
the reaction with NBS where addition of most strong acid salts
dramatically enhanced the glycosylation. Mg(ClO ) works probably as
4 2
5
a mild Lewis acid catalyst which matches the reactivity of N-PSP.
the starting thioglycosides could not be avoided. To overcome such
disadvantage, we examined the use of other mild oxidants in
combination with metal perchlorates and found the following two pairs
to be very effective: combinations of either N-phenylselenophthalimide
Glycosylation reactions were carried out under a N atmosphere in ether
2
7
by the use of 1.5 equiv of N-PSP and 0.5 equiv of Mg(ClO ) against a
4
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donor. An excess (1.2 equiv or 1.6 equiv) of a donor was used against
the acceptor. As summarized in Table 1, the desired glycosides were
obtained in good yields in all cases, though the reaction rates were much
lower than those by NBS-strong acid salts. Glycosylation of the 6-OH
group of acceptor 6 with 2,3,4,6-tetra-O-benzyl S-phenyl thioglycoside
(
N-PSP) or PhIO with a weakly Lewis acidic salt, Mg(ClO ) , where
4 2
highly α-selective glycosylation was achieved particularly when an
appropriate protecting group was introduced at the 6-position of the
donor molecule. These reagents are expected to be advantageous for

January 1998
SYNLETT
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gave disaccharide 7 in good yield with moderate α-selectivity (entry
References and Notes
). α-Selectivity was improved by using 6-O-Troc thioglycosides 2 and
(
(
(
(
(
1) Fukase, K.; Hasuoka, A.; Kusumoto, S. Tetrahedron Lett. 1993,
by virtue of the influence of the Troc function (entry 2, 3).4
,9,10
Since
3
4, 2187.
the present glycosylation reaction proceeds under neutral conditions, we
attempted to employ an acid-sensitive trityl (Trt) group as a protecting
group. Interestingly, the 6-O-Trt survived and showed a more potent α-
directing effect than the 6-O-Troc group, probably owing to shielding of
the β-face of the anomeric cationic transition-state by the bulky 6-O-Trt
group (entry 4).
2) Fukase, K.; Hasuoka, A.; Kinoshita, I.; Aoki, Y.; Kusumoto, S.
Tetrahedron 1995, 51, 4923.
3) Fukase, K.; Hasuoka, A.; Kinoshita, I.; Kusumoto, S. Tetrahedron
Lett. 1992, 33, 7165.
4) Fukase, K.; Kinoshita, I.; Kanoh, T.; Hasuoka, A.; Kusumoto, S.
Tetrahedron 1996, 52, 3897.
The reaction of a more hindered, 4-hydroxy group-free acceptor 6 was
also effected by use of 1.6 equiv of 6-O-Troc thioglycosides 2, 3 and 6-
O-Trt thioglycoside 4 at slightly higher temperatures. The desired
disaccharides 10 and 11 were also obtained in good yields with high α-
selectivity (entry 5-7).
5) Combinations of NBS-LiClO4 and NBS-LiNO3 were found to
promote highly α-selective glucosylation with O-benzylated
thioglucosides as donors in ether. When these reagents were
applied to a donor possessing a 6-O-(2,2,2-trichloroethoxy-
carbonyl) (Troc) group which is known to favor α-
glycosylation,9 the corresponding α-glucosides were obtained
in sufficiently high stereoselectivity but the yields were low
because of the formation of the corresponding glycosyl bromide.
,10
(6) Shimizu, H.; Ito, Y.; Ogawa, T. Synlett 1994, 535.
(
7) When the amount of Mg(ClO ) was reduced to 0.25 equiv to the
4
2
donor, the reaction took a longer period (ca. 1.5 times) for
completion. But no such obvious difference in the reaction rate
was observed when the amount of the perchlorate was increased
from 0.5 to 1.0 equiv.
The above satisfactory results with Mg(ClO ) prompted us to attempt
4
2
the combination of PhIO–Mg(ClO ) . Fine tuning of the reactivity of
4
2
the reagents was expected to be possible through correct choice of the
(
8) General procedure: To a solution of a thioglycoside (180 µmol)
and an acceptor (150 µmol) in dry ether (2.0 ml) was added
molecular sieves 4A (200 mg) under a N2 atmosphere. To the
mixture were added N-PST (82 mg, 270 µmol) and Mg(ClO4)2
1
1
added salts. In fact, PhIO–Mg(ClO4)2 was capable of mild but
efficient activation of thioglycosides to result in highly α-selective
glycosylation. The reactions were carried out under conditions similar to
those described above for N-PSP–Mg(ClO ) ; by the use of 1.5 equiv of
4
2
(20 mg, 90 µmol), and the mixture was stirred at 25 °C for 1 day.
PhIO and 0.5 equiv of Mg(ClO4)2 against a donor under a N2
atmosphere in ether. As shown in Table 2, the 6-O-Troc group enhanced
α-selective glycosylation (entry 2, 3). The glycosylation of the hindered
Ethyl acetate and a saturated aqueous NaHCO3 solution were
added and molecular sieves 4A was removed by filtration. The
organic layer was washed with brine, dried over MgSO , and
4
4-OH-free acceptor 6 also proceeded in good yield (entry 3). α-
concentrated in vacuo. The residue was purified by silica-gel
column chromatography to give a product.
Selectivity was also enhanced by the 6-O-Trt group in this case, though
the yield of the disaccharide did not exceed 70% because of the partial
1
2
(9) Fukase, K.; Yoshimura, T.; Kotani, S.; Kusumoto, S. Bull. Chem.
Soc. Jpn. 1994, 67, 473.
cleavage of Trt group (entry 4) during the reaction.
As described, the combinations of N-PSP with Mg(ClO4)2 and PhIO
with Mg(ClO ) effectively promote glycosylation with thioglycosides.
(
10) Suda, Y.; Bird, K.; Shiyama, T.; Koshida, S.; Marques, D.;
4
2
Fukase, K.; Sobel, M.; Kusumoto, S. Tetrahedron Lett. 1996, 37,
α-Selective glycosidation was effected by virtue of 6-O-Troc or 6-O-Trt
groups of a 2-O-benzylated donor. The simple experimental procedure
and high stereoselectivity provide one of the most versatile method for
glycosylation. The glycosylation reactions proceed cleanly at room
temperature under mild and homogeneous conditions without serious
side-reactions.
1
053.
(11) In our previous study, α-selective glycosylation was effected in
ether by use of SnCl2-AgClO4, SnCl4-AgClO4, BiCl3-AgClO4,
and SbCl3-AgClO4 as catalysts.4 Lately, we found the
combination
of
PhIO
with
also effectively promotes α-selective
glycosylations with 2-O-benzylated donors. Part of the water of
crystallization in Ln(ClO ) •nH O must be removed by stirring
lanthanide
perchlorates
13
[
Ln(ClO ) •nH O]
4
3
2
Acknowledgments. The present work was financially supported in part
by Grants-in-Aid for Scientific Research No. 07680630 and on Priority
Areas Nos. 06240105 and 08245229 from the Ministry of Education,
Science and Culture, Japan.
4
3
2
the mixture of a donor, an acceptor, and Ln(ClO ) •nH O in the
4
3
2
presence of molecular sieves 4A for 3 h prior to the addition of
PhIO. Perchlorates of Yb, Ho, Gd, Er are more effective than
those of Pr, Ce, La, Eu. TMSCl-AgClO is also a good catalyst for
4
α-selective glycosylation.

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(
12) Previously, Houdier et al. reported that bulky 6-O-substituents
trimethylsilyl triflate was also shown to be effective. The α-
selectivity, as far as given in their paper, is lower than that in our
present work: Boons, G.-J.; Bowers, S; Coe, D. M. Tetrahedron
Lett. 1997, 38, 3773. Probably because of the cleavage of the Trt
group during the reaction, the yields of the glycosylation were
generally moderate in these papers.
such as Trt or t-butyldimethylsilyl groups increase significantly
the proportion of
α product in the iodonium dicollidine
perchlorate-promoted glycosylation with pent-5-enyl and
thioethyl glycosides: Houdier, S.; Vottero, P. J. A. Carbohydr.
Res. 1992, 232, 349. Recently, Boons et al. also reported that the
6
-O-Trt group in thioglycosides withstand glycosylation with N-
(
13) Glycosylation with glycosyl fluorides catalyzed by lanthanide
perchlorates: Kim, W.-S.; Hosono, S.; Sasai, H.; Shibasaki, M.
Tetrahedron Lett. 1995, 36, 4443.
iodosuccinimide (NIS) and a catalytic amount of triflic acid and
favors the formation of α-glycosides. A combination of NIS–