Formation of β-glucosamine and β-mannose Linkages Using Glycosyl Phosphates

Article abstract of DOI:10.1021/ol006566+

Formula presented Glycosyl phosphates were examined for their utility in the synthesis of challenging glycosidic linkages. β-Glucosamine glycosides were formed preferentially and in good yield. β-Mannosides were constructed in high overall yield with mode

Full text of DOI:10.1021/ol006566+

ORGANIC
LETTERS
2000
Vol. 2, No. 24
3841-3843
Formation of â-Glucosamine and
â-Mannose Linkages Using Glycosyl
Phosphates
Obadiah J. Plante, Emma R. Palmacci, and Peter H. Seeberger*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
seeberg@mit.edu
Received September 8, 2000
ABSTRACT
Glycosyl phosphates were examined for their utility in the synthesis of challenging glycosidic linkages. â-Glucosamine glycosides were
formed preferentially and in good yield. â-Mannosides were constructed in high overall yield with modest anomeric selectivity. Interesting
solvent and conformational influences on the stereochemical outcome of the coupling reactions were observed.
The biological importance of carbohydrates and glycosylated
natural products1 has resulted in an increased focus on the
development of synthetic methods for the procurement of
pure oligosaccharides and glycoconjugates. The selective and
efficient installation of a variety of glycosidic linkages poses
a major challenge for synthetic chemists. Much effort has
been devoted to the development of glycosylation reactions
to facilitate access to synthetic carbohydrate structures.2
While many glycosidic linkages are now relatively straight-
forward to create, access to some glycosidic bonds remains
difficult. Complete stereoselectivity of trans-glycosidic bond
formation commonly relies on participating groups in the
C2 position. The installation of cis-glycosidic linkages where
participation is not feasible or trans-linkages in which a
nonparticipating C2 group is desired is more difficult to
control.
In nature, 2-amino glycosides are frequently encountered
(e.g., N-linked glycoproteins and blood group determinants).3
The construction of 2-amino â-glycosides commonly relies
on the N-phthalimido functionality as a C2 participating
group.4 Due to difficulty of removing the N-phthalimide
group, several other amine protecting groups have been
investigated. Azides represent an attractive class of protecting
groups since they are easily installed and removed.5,6
Furthermore, the lack of anchimeric assistance in C2 azido
donors could lead to glycosylating agents capable of
constructing either cis- or trans-glycosides. Currently, there
are few methods available for stereospecific glycosylation
using C2 azido donors.
(3) Hakomori, S.; Yongmin, Z. Chem. Biol. 1997, 4, 97.
(4) For a review, see: Debendham, J.; Rodebaugh, R.; Fraser-Reid, B.
Liebigs Ann./Recueil 1997, 791.
(5) (a) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996,
37, 6029. (b) Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M. HelV.
Chim. Acta 1991, 74, 2073. (c) Lemieux, R. U.; Ratcliffe, R. M. Can. J.
Chem. 1979, 57, 1244.
(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) For a review, see: Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93,
1503.
(6) Rosen, T.; Lico, I. M.; Chu, D. T. W. J. Org. Chem. 1988, 53, 1580.
10.1021/ol006566+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/10/2000

cis-Glycosidic â-mannosides are another class of glyco-
sides commonly found in nature as part of the core region
of N-linked glycoproteins.7 Steric inaccessibility of the â-face
of mannose due to the C2 axial substituent combined with
the anomeric effect favoring the thermodynamically more
stable R-anomer render this type of linkage one of the most
difficult to construct. Several approaches to the synthesis of
â-mannosides have been reported.8 Direct couplings using
mannosyl donors resulted in preferential formation of â-gly-
cosides only under heterogeneous conditions.9 Glycosylations
utilizing an intramolecular tether directly afforded the
â-mannosidic linkage by acceptor delivery to the top face
of the pyranose ring but necessitate multistep synthetic
procedures.10 More recently, conformationally constrained
mannosyl donors have been shown to give high â-selectiv-
ity.11
Initially, the direct formation of â-mannosidic linkages
using a nonconstrained glycosyl donor and different acceptors
was explored. Tetra-O-benzyl mannosyl phosphate 1 served
as donor in glycosylation reactions with monosaccharide
acceptors 5 and 7. Activation of 1 by TMSOTf at -78 °C
resulted in rapid glycosylation of the hindered acceptor 5 to
furnish disaccharide 6. Reaction with primary galactose
acceptor 7 afforded disaccharide 8. The selectivity of the
glycosylation reactions was strongly dependent on two
factors: the nature of the glycosyl acceptor and the solvent
used for the coupling reaction. In dichloromethane, the
desired â-mannoside 6â was preferentially formed (â: R )
3:1). When the less hindered C6 hydroxyl group of galactose
7 served as an acceptor, the R-linked disaccharide 8R was
obtained as the main product (â: R ) 1:1.6). In accordance
with prior results, the configuration of the acceptor moeity
was found to greatly influence the stereochemical outcome
of glycosylation.17
Glycosyl phosphates showed high â-selectivity in glycos-
ylations even when a nonparticipating group was present in
the C2 position.12,13 Encouraged by these findings, we
investigated protocols for the formation of â-mannosidic and
â-2-amino glucosidic linkages employing glycosyl phos-
phates.
A dramatic solvent effect was observed when the reaction
was carried out in acetonitrile.18 The selectivity of the
coupling reaction between donor 1 and acceptor 5 was
completely reversed in acetonitrile as disaccharide 6R was
preferentially obtained (â: R ) 1:5.5) (Table 1). Even for
A set of differentially protected glycosyl phosphates 1-4
(Figure 1) served as glycosylating agents in the coupling
Table 1. Formation of R- and â-Mannosides Using Phosphate
1
Figure 1. Phosphate-based glycosyl donors.
studies.14 These donors were prepared either by reaction of
the corresponding lactol precursors with a chlorophosphate15
or by reaction of dibutyl phosphate with the corresponding
1,2 anhydro sugar.16
the coupling of the less hindered acceptor 7, enhanced
R-selectivity was observed in acetonitrile (â: R ) 1:2.9).19
These experimental results may be rationalized by the initial
formation of either an anomeric R-triflate or a close ion pair
followed by SN2-type displacement by the acceptor nucleo-
phile to yield a â-disaccharide. Crich and co-workers reported
the existence of an R-triflate when glycosyl sulfoxides were
activated by triflic anhydride.17b,c In a participating solvent
such as acetonitrile, either a double displacement of the initial
anomeric triflate may occur or the close ion pair may be
(7) Merritt, J. R.; Naisang, E.; Fraser-Reid, B. J. Org. Chem. 1994, 59,
4443.
(8) For a review ,see: Gridley, J. J.; Osborn, H. M. I. J. Chem. Soc.,
Perkin Trans. 1 2000, 1471.
(9) Paulsen, H.; Lockhoff, O. Chem. Ber. 1981, 114, 3102.
(10) (a) Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 113, 9376.
(b) Stork, G.; Guncheol, K. J. Am. Chem. Soc. 1992, 114, 1087.
(11) Crich, D.; Sanxing, S. Tetrahedron 1998, 54, 8321.
(12) Plante, O. J.; Andrade, R. B.; Seeberger, P. H. Org. Lett. 1999, 1,
211.
(13) Hashimoto, S.; Honda, T.; Ikegami, S. J. Chem. Soc., Chem.
Commun. 1989, 11, 685.
(14) For the synthesis of 1, see: Sabesan, S.; Niera, S. Carbohydr. Res.
1992, 223, 169. For the synthesis of 2-4, see Supporting Information.
(15) Inagem, M.; Chaki, H.; Kusumoto, S.; Shiba, T. Chem.Lett. 1982,
1281.
(17) (a) Spijker, N. M.; van Boeckel, C. A. A. Angew. Chem., Int. Ed.
Engl. 1991, 30, 180. (b) Crich, D.; Sanxing, S. J. Am. Chem. Soc. 1998,
120, 435. (c) Crich, D.; Weiling, C. J. Org. Chem. 1999, 64, 4926.
(18) Schmidt, R. R.; Michel, J. J. Carbohydr. Chem. 1985, 4, 141.
(19) Wulff, G.; Rohle, G. Angew. Chem. 1974, 86, 173.
(16) Du, Y.; Kong, F. J. Carbohydr. Chem. 1995, 14, 341.
3842
Org. Lett., Vol. 2, No. 24, 2000

disrupted, thus resulting in the preferential formation of the
R-disaccharide.20 Efforts to obtain direct experimental evi-
dence for the formation of a triflate intermediate by low-
temperature NMR spectroscopy are in progress.
Table 3. Synthesis of R-Mannosides Using Glycosyl
Phosphate Donors
The influence of a nonparticipating, equatorial substituent
on the selectivity of glycosylation reactions was examined
by using C2 azido glycosyl phosphate donors. Activation of
glycosyl donor 2 with TMSOTf required higher temperatures
(-40 °C) and longer reaction times (2 h) than those for
mannose donor 1 (Table 2). Coupling of 2 to methyl
Table 2. Formation of R- and â-2-Azido Glucosides Using
Phosphate 2
into the mechanism of glycosyl phosphates activated by
TMSOTf are underway and should allow for further modi-
fication of the selectivity and potency of these donors.
glycoside 5 resulted preferentially in the formation of
â-linked disaccharide 9â in both dichloromethane and
acetonitrile (â: R ) 4:1). A strong preference for the
formation of the â-anomer (â: R ) 5:1) was again obtained
upon reaction of 2 with primary galactose acceptor 7,
resulting in a mixture of disaccharides 10R and 10â.
Interestingly, no solvent effect for couplings involving C2
azide donor 2 was observed.
Finally, we explored the use of mannosyl phosphates 3
and 4 for the formation of R-mannosidic linkages. In all
cases, only the desired R-isomer was obtained by virtue of
the participating pivaloyl group as expected.21 The reactions
were high-yielding, fast, and completely selective (Table 3).
In summary, we have described glycosyl phosphates as
useful donors in the synthesis of the challenging â-manno-
sidic and â-2-amino glucosidic linkages. Anomeric phos-
phates can be readily installed, require short reaction times,
and are compatible with a variety of protecting groups. The
stereoselectivity of the glycosylations involving mannosyl
phosphates is strongly influenced by solvent effects and by
the steric nature of the acceptor nucleophile. Investigations
Acknowledgment. Financial support from the donors of
the Petroleum Research Fund, administered by the American
Chemical Society (ACS-PRF 34649-G1), for partial support
of this research and the Mizutani Foundation for Glyco-
science, the Kenneth M. Gordon Scholarship Fund (Fellow-
ship for O.J.P.), the NIH (Biotechnology Training Grant for
O.J.P.), and Merck (Predoctoral Fellowship for E.R.P.) is
gratefully acknowledged.
Note Added in Proof: This Letter was inadvertantly
released ASAP on 11/10/00 before a final correction was
made. The last line of the first paragraph on the third page
should read “temperature NMR spectroscopy are in progress”.
The print and final Web version are correct.
Supporting Information Available: One additional
scheme along with detailed experimental procedures and
1
compound characterization data, including H, 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.
(20) Waldmann, H.; Bohm, G.; Schmid, U.; Rottele, H. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1944.
(21) Boger, D. L.; Honda, T. J. Am. Chem. Soc. 1994, 116, 5647.
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