Synthesis of glycosyl-1-phosphates via dehydrative glycosylation.

Article abstract of DOI:10.1021/ol006041h

[reaction: see text] Direct synthetic access to glycosyl-1-phosphates is accomplished with the dehydrative coupling of carbohydrate hemiacetals and dialkyl phosphates, employing dibenzothiophene-5-oxide and triflic anhydride. The procedure offers a new and versatile method for efficient preparation of a host of glycosyl-1-phosphates of variable structure with good control over anomeric selectivity.

Full text of DOI:10.1021/ol006041h

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2135-2138
Synthesis of Glycosyl-1-phosphates via
Dehydrative Glycosylation
Brian A. Garcia and David Y. Gin*
Department of Chemistry, UniVersity of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
gin@scs.uiuc.edu
Received May 10, 2000
ABSTRACT
Direct synthetic access to glycosyl-1-phosphates is accomplished with the dehydrative coupling of carbohydrate hemiacetals and dialkyl
phosphates, employing dibenzothiophene-5-oxide and triflic anhydride. The procedure offers a new and versatile method for efficient preparation
of a host of glycosyl-1-phosphates of variable structure with good control over anomeric selectivity.
Glycosyl-1-phosphates are key intermediates in the chemical
and biosynthesis of glycoconjugates. In the biosynthesis of
complex carbohydrates, the controlled enzymatic assembly
of oligosaccharides and glycoconjugates typically involves
glycosyl nucleoside diphosphates1 or glycosyl lipid diphos-
phates,2 which function as effective glycosyl donors in
glycosyl transferase catalyzed couplings. Moreover, glycosyl-
1-phosphates have been shown to be effective glycosyl
donors in Lewis acid catalyzed glycosylations3,4 and also
have been employed as useful biochemical probes.5 Because
of the importance of glycosyl-1-phosphates in both biology
and chemistry, the efficient synthesis of this class of
carbohydrate intermediates has attracted much attention.
Existing methods for the chemical synthesis of glycosyl-
1-phosphates have involved the use of selected well-
established glycosylation reactions employing nucleophilic
phosphate glycosyl acceptors and electrophilic glycosyl
donors such as glycosyl bromides,6-8 thioglycosides,9 gly-
cosyl trichloroacetimidates,10 and activated glycals.4,11 While
these methods have been shown to be effective in the
introduction of the C(1)-phosphate moiety with varying
degrees of anomeric selectivity, they must also entail
multistep procedures for the preparation of the appropriate
anomerically derivatized carbohydrate donors. Other strate-
gies include the stereoselective synthesis of more stable
glycosyl-1-phosphate precursors such as glycosyl-1-phos-
phites12,13 or glycosyl-1-phosphoramidates;14,15 however, ac-
cess to glycosyl-1-phosphates by these strategies can only
be accomplished with a subsequent oxidation step to generate
the anomeric phosphate functionality. In a complementary
method, nucleophilic hexopyranoses have also been coupled
with chlorophosphate reagents to provide access to this class
of carbohydrates.3,16,17
To date, there are no general and efficient methods for
glycosyl-1-phosphate synthesis via the direct dehydrative
(10) Schmidt, R. R.; Wegmann, B.; Jung, K.-H. Liebigs Ann. Chem. 1991,
121.
(11) Timmers, C. M.; van Straten, N. C. R.; van der Marel, G. A.; van
Boom, J. H. J. Carbohydr. Chem. 1998, 17, 471.
(12) Sim, M. M.; Kondo, H.; Wong, C.-H. J. Am. Chem. Soc. 1993,
115, 2260.
(1) Heidlas, J. E.; Williams, K. W.; Whitesides, G. M. Acc. Chem. Res.
1992, 25, 307.
(2) Imperiali, B.; O’Connor, S. E.; Hendrickson, T.; Kellenberger, C.
Pure Appl. Chem. 1999, 71, 777.
(3) Sabesan, S.; Neira, S. Carbohydr. Res. 1992, 223, 169.
(4) Plante, O. J.; Andrade, R. B.; Seeberger, P. H. Org. Lett. 1999, 1,
211.
(13) Mu¨ller, T.; Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1995, 34,
1328.
(5) Gibbs, B. S.; Coward, J. K. Bioorg. Med. Chem. 1999, 7, 441.
(6) Gokhale, U. B.; Hindsgaul, O.; Palcic, M. M. Can. J. Chem. 1990,
68, 1063.
(7) Roy, R.; Tropper, F. D.; Grand-Maˆıtre, C. Can. J. Chem. 1991, 69,
1462.
(8) Arlt, M.; Hindsgaul, O. J. Org. Chem. 1995, 60, 14.
(9) Veeneman, G. H.; Broxterman, H. J. G.; van der Marel, G. A.; van
Boom, J. H. Tetrahedron Lett. 1991, 32, 6175.
(14) Westerduin, P.; Veeneman, G. H.; Marugg, J. E.; van der Marel,
G. A.; van Boom, J. H. Tetrahedron Lett. 1986, 27, 1211.
(15) Hitchcock, S. A.; Eid, C. N.; Aikins, J. A.; Zia-Ebrahimi, M.;
Blaszczak, L. C. J. Am. Chem. Soc. 1998, 120, 1916.
(16) Nunez, H. A.; O’Connor, J. V.; Rosevear, P. R.; Barker, R. Can. J.
Chem. 1981, 59, 2086.
(17) Inage, M.; Chaki, H.; Kusumoto, S.; Shiba, T. Chem. Lett. 1982,
1281.
10.1021/ol006041h CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

coupling of carbohydrate hemiacetals and dialkyl phosphates
(Scheme 1) despite the potential advantages of such a
Scheme 1
strategy. The coupling process itself would be a one-pot
procedure that obviates the need for the preparation and
isolation of an anomerically derivatized glycosyl donor.
However, such a dehydration process must necessarily be
one in which unproductive side reactions, such as self-
condensation of the hemiacetal donor or of the phosphate
reagent, are minimized.
We present herein the first examples of direct dehydrative
glycosylation of nucleophilic dialkyl phosphate acceptors
with glycosyl-C(1)-hemiacetal donors for the facile prepara-
tion of glycosyl-1-phosphates (Figure 1). We have recently
established that activated sulfonium reagents, derived from
a diaryl sulfoxide and triflic anhydride, are effective activa-
tors of nucleophiles such as hemiacetals18 and glycal enol
ethers.19,20 Using the reagent combination of dibenzothiophene-
5-oxide (DBTO) and triflic anhydride, carbohydrate hemi-
acetals can be activated for the efficient one-pot synthesis
of glycosyl-1-phosphates. In this procedure, triflic anhydride
(1.4 equiv) is added to a solution of the hemiacetal donor 1
(1 equiv), DBTO (2 equiv), and the acid scavenger 2,4,6-
tri-tert-butylpyridine (TTBP, 5 equiv) in dichloromethane at
-78 °C. The solution is stirred at -45 °C for 1 h, and the
dialkyl phosphate acceptor (3 equiv) is then added. The
reaction mixture was stirred at -45 °C for 1 h, at 0 °C for
30 min, and then at 23 °C for 1 h before it was neutralized
with the addition of triethylamine (10 equiv). It was observed
that aqueous workup of the reaction mixture can lead to
significant hydrolysis of the anomeric phosphate moiety.
Thus, to minimize hydrolysis, the reaction solution is directly
concentrated, and the residue is purified by flash column
chromatography to afford the corresponding glycosyl-1-
phosphate product.
Figure 1. Glycosyl-1-phosphates derived from dehydrative gly-
cosylation.21
recent mechanistic studies of hemiacetal activation using
activated sulfoxides,22 it is likely that anomeric bond
formation proceeds via initial in situ generation of an
anomeric oxosulfonium or sulfurane species such as 15,
which functions as a potent carbohydrate electrophile.
The reaction protocol is straightforward and is amenable
to the preparation of a variety of glycosyl-1-phosphates with
high efficiency. Selectively protected gluco-, galacto-,
manno-, and xylopyranoses, as well as furanose donors, can
be readily transformed to their corresponding glycosyl-1-
phosphates, as exemplified by the direct glycosylation of
various dialkyl phosphates (Figure 1). On the basis of our
Of particular interest is the stereochemical outcome of the
coupling products depicted in Figure 1. In the examples
where the hemiacetal donors incorporate C(2)-acyl protective
groups, exclusive formation of 1,2-trans-glycosyl-1-phos-
phates is observed (3-8) as a result of neighboring group
(18) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997,
119, 7597.
(19) Di Bussolo, V.; Kim, Y.-J.; Gin, D. Y. J. Am. Chem. Soc. 1998,
120, 13515.
(20) Di Bussolo, V.; Liu, J.; Huffman, Jr., L. G.; Gin, D. Y. Angew.
Chem., Int. Ed. 2000, 39, 204.
2136
Org. Lett., Vol. 2, No. 14, 2000

participatory effects. Although the C(2)-acyl-participatory
effect is a well-known means for controlling anomeric
selectivity in the glycosylation of a variety of nucleophilic
acceptors, it has not always led to predictable anomeric
selectivity in the case of glycosyl-1-phosphate synthesis as
a result of the propensity of the anomeric phosphate ester to
anomerize. For example, in glycosylation reactions to form
glycosyl-1-phosphates in which the anomeric bond forming
event is acid catalyzed, variables such as reaction duration
and purity of the phosphate reagents have dramatic effects
on anomeric selectivity even in the presence of a C(2)-
participatory group.10,23 However, with this dehydrative
glycosylation protocol using TTBP as a mild acid scavenger,
complete 1,2-trans-selectivity is observed, and no post-
coupling anomerization is detected.
combination with BF3‚OEt2 did not lead to anomeric
equilibration.26
With this promising result, the BF3‚OEt2/2-chloropyridine
reagent combination was then incorporated into the dehy-
drative coupling procedure in the absence of TTBP with the
goal of achieving direct access to the R-glycosyl-1-phosphate
of 11-14 with good selectivity (Figure 2). In the event, triflic
Although the â-glucosyl-, â-galactosyl-, and â-xylosyl-
1-phosphates 3-8 can be stereoselectively accessed through
neighboring group participatory effects using the above-
mentioned protocol, complementary access to their corre-
sponding R-anomers by employing donors devoid of a C(2)-
acyl group was less successful (11-14). For these glycosyl
donors, the anomeric ratio of the glycosyl-1-phosphate
products appear to vary with the nature of the coupling
partners.24 As a result, efforts subsequently focused on
exploring methods for dehydrative phosphate glycosylation
that would proceed under thermodynamic control to access
the R-anomers of 11-14 with high selectivity. In preliminary
investigations (Scheme 2), it was found that treatment of a
Figure 2. Glycosyl-1-phosphates derived from dehydrative gly-
cosylation.
anhydride (1.4 equiv) is added to a solution of the hemiacetal
donor 1 (1 equiv), DBTO (2 equiv), and 2-chloropyridine
(5 equiv) in dichloromethane at -78 °C. As before, the
solution is stirred at -45 °C for 1 h, and the dialkyl
phosphate acceptor (3 equiv) is then added. The reaction
mixture was stirred at 23 °C for 1 h, and BF3‚OEt2 (1 equiv)
was introduced. After a further 1 h at 23 °C, the reaction is
neutralized with the addition of triethylamine (10 equiv). The
solution is concentrated, and the residue is purified by flash
column chromatography to afford the glycosyl-1-phosphate
with good selectivity for the thermodynamically favored
anomer (Figure 2).27
In summary, an efficient method for the preparation of
glycosyl-1-phosphates is reported. The procedure involves
the first examples of direct dehydrative coupling of carbo-
hydrate hemiacetals with dialkyl phosphates, mediated by
DBTO and Tf2O. This protocol offers a new and versatile
method for efficient access to a host of glycosyl-1-phosphates
of variable structure.
Scheme 2
â-rich anomeric mixture of dibenzylphosphoryl 2,3,4,6-tetra-
O-benzyl-D-glucopyranoside anomers (11â; 1:6.6, R:â) with
BF3‚OEt2 (0.5 equiv) and 2-chloropyridine (1 equiv) in
dichloromethane (23 °C, 1 h) led to its anomerization to
afford 11R (7.3:1, R:â) with minimal hydrolysis (<5%) of
the anomeric phosphate linkage.25 The presence of the mild
acid scavenger 2-chloropyridine is essential for the controlled
epimerization of the C(1)-phosphate. Attempts to anomerize
11 with BF3‚OEt2 alone led to rapid decomposition of 11,
and the use of a stronger acid scavenger such as TTBP in
(26) The effectiveness of 2-chloropyridine may be due to its possible
role as a nucleophile in the displacement of the anomeric phosphate moiety
to facilitate anomeric epimerization in the presence of BF3‚OEt2. For
evidence of the intermediacy of glycosyl-2-chloropyridinium species in this
dehydrative glycosylation reaction, see ref 22.
(27) Glycosylations to prepare C(2)-acyl-protected glycosyl-1-phosphates
such as 3 in the presence of 2-chloropyridine and BF‚OEt2 led to the
isolation of only 28% of 3â and 58% recovery of the hemiacetal donor.
The corresponding R-glycosyl phosphate was not deteced. It is likely that,
in the presence of 2-chloropyridine and BF‚OEt2, the C(2)-acyloxy group
promoted hydrolysis rather than epimerization of the anomeric phosphate
moiety during the reaction/purification process.
(21) For the preparation of 9, 10, and 12, Ph2SO was substituted for
DBTO to facilitate chromatographic purification of the product. Efficiencies
and stereoselectivities were to those of similar reactions with either sulfoxide
1
reagent as indicated by H NMR analysis of the crude reaction mixtures.
(22) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269.
(23) Inage, M.; Chaki, H.; Kusumoto, S.; Shiba, T. Tetrahedron Lett.
1981, 22, 2281.
(24) The use of mannopyranose donors led to high R-selectivity for the
product glycosides even in the absence of C(2)-neighboring group partici-
pants (i.e., 9 and 10).
1
(25) Determined by H NMR analysis of the reaction mixture.
Org. Lett., Vol. 2, No. 14, 2000
2137

Acknowledgment. This research was supported by the
National Institutes of Health (GM-58833), the Arnold and
Mabel Beckman Foundation (BYI), Glaxo Wellcome Inc.,
the Alfred P. Sloan Foundation, and the Research Corpora-
tion (Cottrell Scholars Program).
Supporting Information Available: Experimental details
and spectral/analytical data for the glycosylation products.
This material is free of charge via the Internet at
http://pubs.acs.org.
OL006041H
2138
Org. Lett., Vol. 2, No. 14, 2000