A concise synthesis of C-glycosyl phosphate and phosphonate analogues of N-acetyl-α-D-glucosamine 1-phosphate

Article abstract of DOI:10.1016/S0040-4039(99)02277-7

An easy preparation of the C-glycosyl phosphate and phosphonate analogues of N-acetyl-α-D-glucosamine 1-phosphate is described. The readily available 3-(2'-acetamido-3',4',6'-tri-O-acetyl-2'-deoxy-α-D- glucopyranosyl)-1-propene 3 has been used as a common

Full text of DOI:10.1016/S0040-4039(99)02277-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1187–1189
A concise synthesis of C-glycosyl phosphate and phosphonate
analogues of N-acetyl-α-D-glucosamine 1-phosphate
Olivier Gaurat, Juan Xie ∗ and Jean-Marc Valéry
Laboratoire de Chimie des Glucides, Université Pierre et Marie Curie et CNRS, 4 place Jussieu, 75005 Paris, France
Received 9 November 1999; accepted 6 December 1999
Abstract
An easy preparation of the C-glycosyl phosphate and phosphonate analogues of N-acetyl-α-D-glucosamine
1-phosphate is described. The readily available 3-(20-acetamido-30,40,60-tri-O-acetyl-20-deoxy-α-D-
glucopyranosyl)-1-propene 3 has been used as a common intermediate. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: glycosyl phosphates; C-glycosyl phosphate; C-glycosyl phosphonate; amino C-glycosides.
Glycosyl phosphates are the main metabolic precursors and the key glycosylating agents in the
biosynthesis of glycoconjugates. Recently, the synthesis of hydrolytically stable C-glycosidic analogues
of glycosyl phosphates has attracted increasing attention because of the biological importance of these
phosphates.1
Among the anomeric sugar phosphates, the N-acetyl-α-D-glucosamine 1-phosphate (GlcNAc-1-P) is
of particular interest. It is known to be the key intermediate in the biosynthesis of N-linked glycoproteins,
and also the metabolic precursor of the bacterial cell-wall components teichoic acid and mureine. Despite
its important biological implication, only two synthetic analogues of GlcNAc-1-P have been reported.
Nicotra and co-workers synthesised the phosphonate isostere with a multi-step sequence by introducing
the amino function at the end of synthesis because of the difficulty encountered during the prepara-
tion of the corresponding amino C-glycosyl halides and their subsequent conversion to phosphonate.2
Junker and Fessner prepared the diethyl 2-(30,40,60-tri-O-acetyl-20-deoxy-20-trifluoroacetamido-α-D-
glucopyranosyl)ethane phosphonate by radical promoted C–C bond formation between diethyl vinyl-
phosphonate and the corresponding glycosyl bromide, in 44% yield.3 We are interested in the modi-
fication of GlcNAc-1-P and we describe here a new approach to the synthesis of related, homologous
C-ethylene phosphate and phosphonate sugars 1 and 2.
∗
Corresponding author. Fax: 33-1-44-27-55-13; e-mail: xie@ccr.jussieu.fr (J. Xie)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02277-7
tetl 16205

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Our strategy was to proceed from the known 3-(20-acetamido-30,40,6-tri-O-acetyl-20-deoxy-α-D-
glucopyranosyl)-1-propene 34,5 as shown in Scheme 1. The acetyl protecting group in 3 was first
transformed into benzyl ether thus affording compound 4. Oxidation (OsO4/NaIO4) of the allyl function,
followed by reduction of the so-obtained aldehyde then furnished alcohol 5 in good yield. Reaction of
6
5 with POCl3 afforded the protected phosphate 6. Removal of benzyl ether was realised by catalytic
hydrogenolysis, leading to the desired C-glycopyranosyl phosphate 17 in excellent yield.
Scheme 1. Reagents and conditions: (a) MeONa, MeOH, 0°C to rt; (b) NaH, BnBr, DMF, 94% for two steps; (c) OsO4, NaIO4,
THF/H2O, quant.; (d) NaBH4, CH2Cl2/MeOH, 75%; (e) POCl3, THF, Ar, 0°C to rt, then H2O, 93%; (f) H2, Pd/C, MeOH,
AcOH cat. quant.; (g) CBr4, PPh3, CH2Cl2, quant.; (h) P(OEt)3, 120°C, 91%; (i) TMSI, CCl4, 0°C to rt, quant.
Synthesis of the phosphonate analogue was achieved by conversion of alcohol 5 into bromide 7 with
CBr4/PPh3. The Arbuzov reaction with P(OEt)3 afforded 8 in 91% yield. Finally, treatment of 8 with
Me3SiI (20 equiv. in CCl4) led to the expected phosphonate 2.7
In conclusion, the preparation of C-glycosyl phosphate and phosphonate analogues of GlcNAc-1-
P could be efficiently accomplished from the readily available α-C-allyl glycoside of N-acetyl D-
glucosamine 3. Compounds 1 and 2 are versatile intermediates for the synthesis of inhibitors of N-acetyl
glycosaminyl transferases and might themselves exhibit inhibition towards these enzymes. Biological
evaluation of these new compounds towards various glycosyltransferases and further elaboration are
under way.
Acknowledgements
We gratefully thank the Ministère de l’Enseignement Superieur et de la Recherche (MESR) for a grant
to O.G., and CNRS (Program ‘Physique et Chimie du vivant’) for financial support.

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References
1. Nicotra, F. In Carbohydrate Mimics: Concepts and Methods; Chapleur, Y., Ed.; Wiley-VCH: Weinheim, Chichester, 1998;
pp. 67–85.
2. Casero, F.; Cipolla, L.; Lay, L.; Nicotra, F.; Panza, L.; Russo, G. J. Org. Chem. 1996, 61, 3428–3432.
3. Junker, H. D.; Fessner, W. D. Tetrahedron Lett. 1998, 39, 269–272.
4. Roe, B. A.; Boojamra, C. G.; Griggs, J. L.; Bertozzi, C. R. J. Org. Chem. 1996, 61, 6442–6445.
5. Cui, J.; Horton, D. Carbohydr. Res. 1998, 309, 319–330.
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7. Selected physical data: Compound 1, 1H NMR (250 MHz, D2O) δ=4.20 (ddd, 1H, J=11.5, 5.7 and 3.5 Hz, H-10), 3.95 (m,
3H, H-1, H-20), 3.82 (dd, 1H, J=12.0 and 2.1 Hz, H-60), 3.71 (dd, 1H, J=12.0 and 5.0 Hz, H-600), 3.70 (t, 1H, J=9.1 Hz, H-30),
3.55 (ddd, 1H, J=9.1, 5.0 and 2.1 Hz, H-50), 3.40 (t, 1H, J=9.1 Hz, H-40), 3.05 (m, 1H, H-2), 2.00 (s, 3H, Me), 1.85 (m, 1H,
H-2); 31P NMR (202.46 MHz, D2O) δ=2.82. Compound 2, 1H NMR (250 MHz, D2O) δ=4.05 (m, 1H, H-10), 3.95 (m, 1H,
H-20), 3.84 (dd, 1H, J=12.0 and 1.8 Hz, H-60), 3.71 (t, 1H, J=9.0 Hz, H-30), 3.69 (dd, 1H, J=12.0 and 5.0 Hz, H-600), 3.47
(ddd, 1H, J=9.0, 5.0 and 1.8 Hz, H-50), 3.36 (t, 1H, J=9.0 Hz, H-40), 1.91 (s, 3H, Me), 1.80 (m, 2H, H-2), 1.65 (m, 2H, H-1);
31P NMR (202.46 MHz, D2O) δ=32.04.