Synthesis and use of glycosyl phosphates as glycosyl donors.

Article abstract of DOI:10.1021/ol9905452

Differentially protected glycosyl phosphates prepared by a straightforward synthesis from glycal precursors are used as powerful glycosyl donors. Activation of beta-glycosyl phosphates by TMSOTf at -78 degrees C achieves the selective formation of beta-gl

Full text of DOI:10.1021/ol9905452

ORGANIC
LETTERS
1999
Vol. 1, No. 2
211-214
Synthesis and Use of Glycosyl
Phosphates as Glycosyl Donors
Obadiah J. Plante, Rodrigo B. Andrade, and Peter H. Seeberger*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
seeberg@mit.edu
Received March 30, 1999
ABSTRACT
Differentially protected glycosyl phosphates prepared by a straightforward synthesis from glycal precursors are used as powerful glycosyl
donors. Activation of â-glycosyl phosphates by TMSOTf at −78 °C achieves the selective formation of â-glycosidic linkages in excellent yields
with complete stereoselectivity. Reaction with thiols results in the conversion of glycosyl phosphates into thioglycosides in nearly quantitative
yield. An orthogonal coupling strategy using glycosyl phosphate donors and thioethyl glycoside acceptors allows for the rapid synthesis of
a trisaccharide.
Complex glycoconjugates have been implicated in many
cell-cell recognition events important in inflammation,
immune response, and tumor metastasis.1,2 Much effort has
been devoted to the development of novel, powerful glyco-
sylation reactions to facilitate access to defined synthetic
oligosaccharide and glycoconjugate structures.3 A wide range
of anomeric groups, including most notably trichloro-
acetimidates,4 thioethyl glycosides,5 glycosyl sulfoxides,6
fluorides,7 and pentenyl glycosides8 have been explored as
glycosyl donors. While these methods have proven very
useful for the installation of a variety of glycosidic linkages,
they still suffer in many cases from lengthy syntheses, long
reaction times, and the use of toxic activating agents. Thus,
the need for the development of new, easily accessible
glycosylating agents which may be coupled selectively and
in high yield using nontoxic activators persists.
In biosynthesis, glycosyl transferases make use of glycosyl
phosphates in the form of nucleotide diphosphate sugars (e.g.
UDP-Glc) for the construction of glycosidic linkages.9 To
study these enzymatic reactions, a number of synthetic
approaches for the preparation of glycosyl phosphates have
been developed.10 While several phosphate analogues, in-
cluding phosphites,11 phosphoramidates,12 and phosphoro-
dithioates,13 have been employed as glycosyl donors in
(1) For reviews see: (a) Varki, A. Glycobiology 1993, 3, 97. (b) Lee,
Y. C.; Lee, R. T. Acc. Chem. Res. 1995, 28, 322.
(2) Chambers, W. H.; Brisette-Storkus, C. S. Chem. Biol. 1995, 2, 429.
(3) For a review see: Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93,
1503.
(4) For a review see: Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem.
Biochem. 1994, 50, 21.
(9) Heidlas, J. E.; Williams, K. W.; Whitesides, G. M. Acc. Chem. Res.
1992, 25, 307.
(10) (a) Inage, M.; Chaki, H.; Kusumoto, S.; Shiba, T. Chem. Lett. 1982,
1281. (b) Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1984, 680. (c)
Pale, P.; Whitesides, G. M. J. Org. Chem. 1991, 56, 4547. (d) Sabesan, S.;
Niera, S. Carbohydr. Res. 1992, 223, 169. (e) Sim, M. M.; Kondo, H.;
Wong, C.-H. J. Am. Chem. Soc. 1993, 115, 2260. (f) Boons, G.-J.; Burton,
A.; Wyatt, P. Synlett 1996, 310.
(5) For a review see: Garegg, P. J. AdV. Carbohydr. Chem. Biochem.
1997, 52, 179.
(6) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc.
1989, 111, 6881.
(7) Mukaiyama, T.; Murai, Y.; Shoda, S. Chem. Lett. 1981, 431.
(8) Fraser-Reid, B.; Konradsson, P.; Mootoo, D. R.; Udodong, U. J.
Chem. Soc., Chem. Commun. 1988, 823.
(11) Kondo, H.; Aoki, S.; Ichikawa, Y.; Halcomb, R. L.; Ritzen, H.;
Wong, C.-H. J. Org. Chem. 1994, 59, 864.
(12) Hashimoto, S.; Sakamoto, H.; Honda, T.; Abe, H.; Nakamura, S.;
Ikegami, S. Tetrahedron Lett. 1997, 38, 8969.
(13) Plante, O. J.; Seeberger, P. H. J. Org. Chem. 1998, 63, 9150.
10.1021/ol9905452 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/29/1999

oligosaccharide synthesis, glycosyl phosphates have received
surprisingly little attention for this application.14
weeks without decomposition. The phosphates 1â, 2â, and
5â, however, were more difficult to handle, as they decom-
posed upon prolonged exposure to silica gel. Butyl phos-
phates proved more stable than benzyl phosphates and were
easier to handle. Filtration through a short plug of silica gel
yielded the pure desired compounds in all cases. Even these
less stable â-phosphates could be stored at -20 °C for several
weeks without decomposition.
After having established a straightforward synthetic route
for the preparation of differentially protected glycosyl
phosphates, we evaluated the performance of these com-
pounds as donors in glycosylation reactions. Anomeric
â-phosphates served as powerful donors in the high-yielding,
selective formation of â-glycosidic linkages in only 10 min
upon activation with trimethylsilyl triflate (TMSOTf) at -78
°C (Table 2). Participation of the protecting group in the C2
position was not required for the selective formation of
â-glycosidic linkages, as the C2-TES protected donor 8â
yielded exclusively the desired â-disaccharide 16, although
the TES group was lost during the reaction. While primary
and hindered secondary alcohols such as the C2 hydroxyl
could be coupled in very good yields, tertiary acceptors failed
to react. Efficient conversion of glycosyl phosphate 2â into
the corresponding thioethyl glycoside 17 was achieved by
coupling with ethanethiol.
We now report the efficient synthesis of glycosyl phos-
phates from glycals and their use as powerful glycosyl donors
in the high-yielding and completely selective construction
of â-glycosidic linkages requiring very short reaction times.
A three step, “one-pot” procedure was used to selectively
prepare a variety of differentially protected glycosyl phos-
phates (Table 1). Conversion of a glycal into the 1,2-
Table 1. Synthesis of Glycosyl Phosphates from Glycal
Precursors15
entry R1
R2
R3
R4 R5 R6 solvent yield, % â:R
1
Bn
H
OBn Bn Piv Bn CH2Cl2
74
71
84
65
59
60
57
65
70
75
71
79
10:1a
1:10
17:1
11:1
1:4
THF
toluene
2
Bn
H
OBn Bn Piv Bu CH2Cl2
THF
toluene
8:1
3
4
5
6
7
8
Bn
OBn
H
H
Bn Piv Bu CH2Cl2
4:1
The more stable R-phosphates could also serve as glycosyl
donors upon activation with TMSOTf but required higher
temperatures for efficient activation. While no reaction was
observed at -78 °C, donor 2R was activated at -20 °C and
coupled to galactosyl acceptor 9 to yield 87% of the desired
â-disaccharide 13 within 10 min (Table 2). Couplings to
more hindered acceptors and to thiols were also accomplished
in good yields.
TIPS
TIPS
TBS
Bn
OBn Bn Piv Bn CH2Cl2
OBn Bn Piv Bu THF
OPiv Piv Piv Bu CH2Cl2
OYb Bn TES Bu CH2Cl2
OBn Bn TES Bu THF
1:0
H
1:1
H
1:0
H
1:0
Bn
H
2:1
a When the reaction was carried out at 0 °C, a ratio of 4:1 (â:R) was
observed. b Y ) 2,3,4,6-tetra-O-benzyl-â-D-galactopyranoside-(1f4)-.
Exclusive formation of â-glycosides using a nonparticipat-
ing group in C2 suggests that, upon activation of the
phosphate by TMSOTf, an anomeric triflate or a close ion
pair of an oxonium ion intermediate is formed. Anomeric
triflates have been proposed as intermediates in the formation
of â-mannosides from thioglycosides by Crich.17
Since thioethyl glycosides were completely stable under
the conditions used to activate â-glycosyl phosphates, we
investigated an orthogonal coupling strategy employing both
anhydrosugar by epoxidation with dimethyldioxirane (DMDO)
was followed by opening of the epoxide with a phosphoric
acid at -78 °C and protection of the generated C2 hydroxyl
group at 0 °C. We13 and others16 have recently described
the synthesis of anomeric phosphate derivatives using 1,2-
anhydrosugars. A strong solvent dependence for the ratio of
R- and â-glycosyl phosphates prepared by this method was
observed. While reactions in toluene and dichloromethane
produced preferentially â-phosphates, reactions in THF
resulted almost exclusively in R-phosphates (Table 1). Using
this approach, differentially protected glucosyl (1, 2, 4-6,
8), galactosyl (3), and lactosyl phosphates (7) were prepared.
Introduction of participating groups in the C2 position by
acylation proved straightforward and high-yielding. Silylation
of the C2 hydroxyl to install a nonparticipating TES group
was also feasible, while introduction of a C2 TBS group
failed. Efforts to equip the C2 position with a benzyl ether
protecting group did not meet with success but rather resulted
in the isolation of benzyl C2 phosphate glycosides. Similar
results had previously been observed in the dithiophosphate
series.13
Scheme 1. Orthogonal Glycosylation Strategy Using Glycosyl
Phosphates and Thioethyl Glycosides
All R-phosphates as well as the C2-silyl â-glycosyl
phosphates 7 and 8â were completely stable to silica column
chromatography and could be stored at 4 °C for several
212
Org. Lett., Vol. 1, No. 2, 1999

Table 2. Glycosylations with Glycosyl Phosphates and Trimethylsilyl Triflatea
a Glycosylations were carried out with 1.2 equiv of donor, 1.0 equiv of acceptor, and 1.2 equiv of TMSOTf in dichloromethane at -78 °C. b The reaction
was carried out at -20 °C.
glycosyl phosphates and thioethyl glycosides (Scheme 1).
Thioethyl mannoglycoside 12 served as glycosyl acceptor
in the reaction with glycosyl phosphate 2â to yield 83% of
disaccharide 18. Without any further manipulations, 18 was
used as a glycosyl donor and coupled to glycal acceptor 19
under previously described coupling conditions.18 The glycal
double bond of trisaccharide 20 allows for further elongation
by the glycal assembly method.19
In summary, we have described the efficient synthesis of
differentially protected glycosyl phosphates from glycals. We
have further demonstrated that R- and â-glycosyl phosphates
serve as powerful glycosyl donors in the formation of
â-glycosidic linkages in high yield and with complete
stereoselectivity. Efficient conversion of glycosyl phosphates
into thioethyl glycosides was also achieved. Additionally,
glycosyl phosphates and thioethyl glycosides were employed
in the synthesis of a trisaccharide using an orthogonal
glycosylation scheme, thus minimizing tedious protecting
group manipulations. Efforts to employ glycosyl phosphates
in the construction of other glycosidic linkages as well as in
(14) (a) Hashimoto, S.; Honda, T.; Ikegami, S. J. Chem. Soc., Chem.
Commun. 1989, 685. (b) Boger, D. L.; Honda, T. J. Am. Chem. Soc. 1994,
116, 5647. (c) Duynstee, H. I.; Wijsam, E. R.; van der Marel, G. A.; van
Boom, J. H. Synlett, 1996, 313. (d) Bohm, G.; Waldmann, H. Liebigs Ann.
Chem. 1996, 613.
(15) General procedure: 1.0 equiv of glycal, 1.5 equiv of 0.08 M
dimethyldioxirane, 1.10 equiv of dialkyl phosphate, 1.5 equiv of pivaloyl
chloride and 3.0 equiv of DMAP. All steps were carried out in dichlo-
romethane unless noted otherwise.
(16) Timmers, C. M.; van Straten, N. C. R.; van der Marel, G. A.; van
Boom, J. H. J. Carbohydr. Chem. 1998, 17, 471.
(17) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435.
(18) Seeberger, P. H.; Eckhardt, M.; Gutteridge, C.; Danishefsky, S. J.
J. Am. Chem. Soc. 1997, 119, 10064.
(19) For a review see: Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1380.
Org. Lett., Vol. 1, No. 2, 1999
213

the solid support synthesis of oligosaccharides are currently
underway and will be reported in due course.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data,
including 1H, 13C, and 31P NMR spectral data for all described
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the Depart-
ment of Chemistry at the Massachusetts Institute of Technol-
ogy, from the Kenneth M. Gordon Scholarship Fund
(Fellowship for O.J.P.), and from the NSF (Predoctoral
Fellowship for R.B.A.) is gratefully acknowledged.
OL9905452
214
Org. Lett., Vol. 1, No. 2, 1999