Synthesis of glycosyl phosphonates by Michael-type addition to 2-nitroglycals

Article abstract of DOI:10.1002/ejoc.200400266

A new synthetic strategy, which allows to synthesize both α- and β-anomers of 2-acetylaminoglycosyl phosphonate or exclusively β-anomer is described. The present strategy is a successful Michael-type addition of dimethyl hydrogen phosphonate to 2-nitrogly

Full text of DOI:10.1002/ejoc.200400266

SHORT COMMUNICATION
Synthesis of Glycosyl Phosphonates by Michael-Type Addition to
2-Nitroglycals
Kandasamy Pachamuthu,[a] Ignacio Figueroa-Perez,[a] Ibrahim A. I. Ali,[a] and
Richard R. Schmidt*[a]
Keywords: Carbohydrates / Nitroglycals / Michael addition / Phosphonates / Anomerisation
A new synthetic strategy, which allows to synthesize both
α- and β-anomers of 2-acetylaminoglycosyl phosphonate or
exclusively β-anomer is described. The present strategy is a
successful Michael-type addition of dimethyl hydrogen phos-
phonate to 2-nitroglycals.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
might help to study the function of the phosphate group.
Vasella et al.[4Ϫ6] described the synthesis of such a type
of nonisosteric glycosyl phosphonate analogues starting
from 2-azido-2-deoxy sugars, employing the trichloroaceti-
midate method. In continuation of our work on Michael-
type addition of various nucleophiles to 3,4,5-tri-O-benzyl-
2-nitroglycals,[7Ϫ14] we now wish to report a convenient syn-
thesis of such nonisosteric phosphonate analogues by
Michael-type addition of dimethyl hydrogen phosphonate
to 2-nitroglycals.
During the last several years there has been considerable
interest in the preparation and investigation of phosphonic
acids and their derivatives that might be considered to be
analogues of naturally occurring phosphates.[1] It is under-
stood that the carbonϪphosphorus bond is incapable of be-
ing hydrolyzed by the enzymes involved in phosphate cleav-
age. Thus, the use of phosphonic acids as analogues of
natural phosphates represents a systematic approach to
metabolic regulation, enhancement or inhibition studies.
Results and Discussion
A straightforward way to synthesize the desired phos-
phonate analogues is Michael-type addition of HPO(OMe)2
to 2-nitroglycals. The advantage of this method is mainly
due to the easy preparation of the starting material in high
yields and the convenient transformation of the nitro group
into the corresponding amino group and hence, into an acyl-
amino group. Treatment of 3,4,5-tri-O-benzyl-2-nitrogalac-
tal with HPO(OMe)2 in the presence of potassium tert-bu-
toxide in toluene yielded the corresponding glycosyl phos-
phonates 2 and 3 in the ratio of 1:1.2 in 82% yield. Careful
examination of the reaction revealed that the anomeric (α/
β) ratio varies with time. A ratio of 1:1.2 for α/β was ob-
served after 5 min at 0 °C, but after 2 h at the same reaction
temperature only the β-product was observed in 60% yield,
which indicates that the α-anomer was slowly transformed
under basic reaction conditions into the thermodynamically
more stable β-anomer presumably by ring opening to inter-
mediate A followed by ring closure (Scheme 1).
The outer surface of the outer membrane of Escherichia
coli and other Gram-negative bacteria is made up primarily
of lipid A, the hydrophobic anchor for lipopolysaccharides.
Lipid A is essentially a β-(1Ј-6)-linked -glucosamine disac-
charide carrying phosphate residues at C-1 and C-4Ј, and
several N- and O-bound long-chain acyl groups.[2] Lipid X
(I), a monosaccharide isolated from E. coli mutants, is a
biosynthetic precursor of Lipid A corresponding to the re-
ducing end.[3] Although it was identified in 1984, the func-
tion of the phosphate group at C-1 is not fully understood.
Therefore, synthesis of phosphonate analogues of type II
[a]
Department of Chemistry, University of Konstanz,
Fach M 725, 78457 Konstanz, Germany
Fax: (internat.) ϩ 49-7531-883135
E-mail: Richard.Schmidt@uni-konstanz.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2004, 3959Ϫ3961
DOI: 10.1002/ejoc.200400266
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3959

K. Pachamuthu, I. Figueroa-Perez, I. A. I. Ali, R. R. Schmidt
SHORT COMMUNICATION
Scheme 3. Michael-type addition of HPO(OMe)2 to 2-nitrorham-
nal 6
2 h, only product 8 was isolated in 55% yield (Scheme 3
and Table 1).
Scheme 1. Michael-type addition of HPO(OMe)2 to 2-nitro-
galactal 1
On the other hand, reaction of 2-nitroglucal 9 with
HPO(OMe)2 at 0 °C for 5 min yielded mannose-configured
α-anomer 10 and glucose-configured β-anomer 11 in a ratio
of 1:1.2 in 81% yield (Scheme 4 and Table 1). A prolonged
reaction time yielded only the β-anomer 11 in 80% yield, as
was the case for the galactal derivative. The structures of 10
1
The anomeric configuration is evident from the H and
13C NMR spectroscopic data. In the H NMR spectra, the
1
signal of 1-H of 2 appears at δ ϭ 4.7 ppm (3J1,2 ϭ 7.1 Hz)
and for 3 at δ ϭ 4.19 ppm (3J1,2 ϭ 10.2 Hz). In the 13C
NMR spectra, the C-1 signals for 2 and 3 appear at δ ϭ
70.6 and 73.5 ppm, respectively; the signal for the α-anomer
2 occurs at a higher field than that for the corresponding
β-anomer 3.
1
and 11 were deduced from their H and 13C NMR spectro-
1
scopic data. In the H NMR spectra of compound 10, the
signal for 1-H appears at δ ϭ 4.63 (3J1,2 ϭ 2.6 Hz) and in
the spectra of 11 at δ ϭ 4.18 ppm (3J1,2 ϭ 9.1 Hz), whereas
the signal for 3-H for 10 appears at δ ϭ 4.31 ppm (3J3,4
ϭ
8.3, 3J3,2 ϭ 5.1 Hz) and that for 11 at δ ϭ 4.22 ppm (3J3,4 ϭ
3J3,2 ϭ 9.1 Hz). Likewise, reaction of 2-nitromaltal 12 also
yielded the same result. After 5 min at 0 °C, the products
obtained were 13 and 14 in a ratio of 1:1.5, and after 2 h,
only β-gluco-configured 14 was found. All compounds were
characterized by spectral and analytical means.
By employing different weak bases and lowering the reac-
tion temperature, the same result was obtained. Reduction
of the nitro group in compounds 2 and 3 with the use of
platinized Raney nickel in ethanol yielded the correspond-
ing amines, which were acetylated to give the known com-
pounds 4 and 5 in 90 and 92% yield, respectively,[4] as
shown in Scheme 2. The spectroscopic data are identical to
literature values.[4]
Scheme 4. Michael-type addition of HPO(OMe)2 to 2-nitroglucals
9 and 12
Conclusion
Scheme 2. Conversion of 2-nitrogalactosyl phosphonate to 2-(ace-
tylamino)galactosyl phosphonate
In conclusion, an efficient and very simple method for
the synthesis of various glycosyl phosphonates by Michael-
Reaction of 2-nitrorhamnal 6 with HPO(OMe)2 at 0 °C type addition of HPO(OMe)2 to 2-nitroglycals in high
yielded the corresponding glycosyl phosphonates 7 and 8 in yields is described. Applications of this methodology to
5 min and with a ratio of 1:1.2 (α/β) in 80% yield. After synthesize various phosphonate analogues of glycosyl con-
Table 1. Results obtained with 2-nitroglycals 6, 9, and 12
Starting compound
Reaction time
Products
Yield [%]
Reaction time
Yield [%]
6
5 min
5 min
5 min
7 ϩ 8
10 ϩ 11
13 ϩ 14
81 (1:1.2)
80 (1:1.2)
80 (1:1.5)
2 h
2 h
2 h
55 (only 8)
80 (only 11)
80 (only 14)
9
12
3960
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 3959Ϫ3961

Glycosyl Phosphonates by Michael-Type Addition to 2-Nitroglycals
SHORT COMMUNICATION
the solvent yielded the corresponding amines, which were dissolved
in acetic anhydride (5 mL) and stirred overnight at room tempera-
ture. Evaporation of the acetic anhydride, followed by flash column
purification afforded the 2-acetylamino-2-deoxygalactosyl phos-
phonates 4 and 5.
jugates and glycopeptides are under progress in our labora-
tory.
Experimental Section
Supporting Information: Data for 2, 3, 7, 8, 10, 11, 13 and 14.
General Remarks: Solvents were purified according to standard
procedures. NMR spectroscopic measurements were performed at
22 °C with a Bruker DRX600 instrument. TMS or the resonance
of the deuterated solvent was used as internal standard. CDCl3
(δ ϭ 7.24 ppm) was used as external standard. MALDI mass spec-
tra were recorded with a Kratos Kompact Maldi 1 instrument, and
2,5-dihydroxybenzoic acid (DHB) or 6-aza-2-thiothymine (ATT)
were used as matrices. Optical rotations were measured with a
PerkinϪElmer polarimeter 241/MS in a 1-dm cell at 22 °C. Thin-
layer chromatography (TLC) was performed on Merck silica gel 60
F254 plastic plates or Merck amino phase glass plates. Compounds
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. K. P. is grateful for an
Alexander von Humboldt Fellowship.
[1]
R. Engel, Chem. Rev. 1977, 77, 349Ϫ367.
E. Th. Rietschel, H. Brade, L. Brade, W. Kaca, K. Kawahara,
[2]
B. Lindner, T. Lüderitz, T. Tomita, U. Schade, U. Seydel, U.
Zähringer, in Progress in Clinical and Biological Research (Eds.:
J. W. ten Cate, H. R. Büller, A. Sturk, J. Levin, Alan R. Liss),
Alan Liss, Inc., New York, 1985, vol. 189, pp. 31Ϫ45.
were visualized by treatment with
a
solution of
[3]
(NH4)6Mo7O24·4H2O (20 g) and Ce(SO4)2 (0.4 g) in 10% sulfuric
acid (400 mL). Flash chromatography was performed on J. T. Baker
silica gel 60 (0.040Ϫ0.063 mm) at a pressure of 0.3 bar.
E. T. Rietschel, H.-W. Wollenweber, H. Brade, in Handbook
of Endotoxin, Chemistry of Endotoxin (Ed.: E. Th. Rietschel),
Elsevier, Amsterdam, 1984, vol. 1, pp. 187Ϫ220.
[4]
K. Briner, A. Vasella, Helv. Chim. Acta 1987, 70, 1341Ϫ1356.
[5]
General Experimental Procedure for the Synthesis of 2, 3, 7, 8, 10,
11, 13 and 14: To a stirred solution of the 2-nitroglycal (1 mmol)
and HPO(OMe)2 (1.1 mmol) in dry toluene at 0 °C was added pot-
assium tert-butoxide (1 mmol), and the resulting solution was
stirred for 5 min. The solvent was then evaporated under reduced
pressure, followed by extraction of the residue with ethyl acetate,
washing of the combined extracts with dild. HCl, water, brine, and
drying with anhydrous MgSO4. After filtration, evaporation of the
solvent gave the corresponding glycosyl phosphonates; provided
are isolated yields.
R. Meuwly, A. Vasella, Helv. Chim. Acta 1986, 69, 25Ϫ34.
[6]
A. Vasella, R. Wyler, Helv. Chim. Acta 1991, 74, 451Ϫ463.
[7]
J. Das, R. R. Schmidt, Eur. J. Org. Chem. 1998, 1609Ϫ1612.
[8]
G. A. Winterfeld, Y. Ito, T. Ogawa, R. R. Schmidt, Eur. J. Org.
Chem. 1999, 1167Ϫ1171.
[9]
G. A. Winterfeld, R. R. Schmidt, Angew. Chem. 2001, 113,
2718Ϫ2721; Angew. Chem. Int. Ed. 2001, 40, 2654Ϫ2657.
K. Pachamuthu, A. Gupta, J. Das, R. R. Schmidt, Y. D. Van-
[10]
kar, Eur. J. Org. Chem. 2002, 1479Ϫ1483.
[11]
K. Pachamuthu, R. R. Schmidt, Synlett 2003, 1355Ϫ1357.
[12]
G. A. Winterfeld, A. I. Khodair, R. R. Schmidt, Eur. J. Org.
Chem. 2003, 1009Ϫ1021.
General Experimental Procedure for the Synthesis of 4 and 5: To a
stirred solution of freshly prepared Pt/Raney nickel (1 g) in ethanol
was added the phosphonate 2 or 3, and the mixture stirred under
hydrogen overnight. Filtration of the catalyst and evaporation of
[13]
A. I. Khodair, K. Pachamuthu, R. R. Schmidt, Synthesis
2004, 53Ϫ58.
[14]
J. Geiger, N. Barroca, R. R. Schmidt, Synlett 2004, 836Ϫ840.
Received April 19, 2004
Eur. J. Org. Chem. 2004, 3959Ϫ3961
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3961