Synthesis of N-acetylxylosamidoxime, a potential transition state analog inhibitor of glycosyltransferases

Article abstract of DOI:10.1016/S0040-4039(99)01964-4

The synthesis of a polyfunctionalized amidoxime is described involving condensation of hydroxylamine on a thioamide deriving from Boc-L-serine. This structure could be an efficient transition state like inhibitor of N- acetylglucosaminyltransferases, such

Full text of DOI:10.1016/S0040-4039(99)01964-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 299–301
Synthesis of N-acetylxylosamidoxime, a potential transition state
analog inhibitor of glycosyltransferases
Laurent Devel, Anne Vidal-Cros ∗ and Annie Thellend ∗
Laboratoire de Chimie Organique Biologique, Université P. et M. Curie Boite courrier 182, 4, Place Jussieu 75252,
Paris Cedex 05, France
Received 21 September 1999; accepted 15 October 1999
Abstract
The synthesis of a polyfunctionalized amidoxime is described involving condensation of hydroxylamine on a
thioamide deriving from Boc-L-serine. This structure could be an efficient transition state like inhibitor of N-
acetylglucosaminyltransferases, such as chitin synthase. © 2000 Published by Elsevier Science Ltd. All rights
reserved.
Various amidoxime, amidrazone and amidine derivatives of monosaccharide aldonolactams have
already been described.1 These molecules constitute powerful inhibitors of metabolically important gly-
cosyl hydrolases. Their inhibitory activity has been discussed in relation to the proposed oxocarbonium-
like transition state along the enzymatic hydrolysis pathway.2,3 The described derivatives exhibit roughly
similar affinities but differ greatly in stability, the amidoxime being the most stable one. This latter func-
tionality has been studied in the gluco, manno and galacto series. We turned our attention on molecules
possessing an acetamido function at position 2, to test whether the amidoxime functionality could confer
interesting properties towards N-acetylglucosamine-specific biosynthesis-glycosyltransferases.
Herein, we describe the synthesis of the N-acetylxylosamidoxime 12 in eleven steps starting from the
Garner’s synthon4 1 (Scheme 1).
After homologation of 1 into ester 2 by a Wittig reaction5 (87%) leading exclusively to the E stereomer,
chemoselective reduction by DIBAL-H at 0°C gave the allylic alcohol 3 (72%). Mesylation of the alcohol
followed by treatment with sodium azide gave allylic azide 4 in moderate yield (67%).
Since asymmetric dihydroxylation according to Sharpless was unsuccessful,6 the reaction was perfor-
med in non-asymmetric conditions and the resulting diastereomers 5a and 5b, obtained in a 55:45 ratio
(66%), were separated by crystallization.
After benzylation of the diol 5a in the presence of benzyl bromide (92%) and cleavage of the
oxazolidine using Dowex 50 W resin (72%), the alcohol 7 was cleanly oxidized with TEMPO7 and
the resulting acid esterified with diazomethane (51% overall yield).8
∗
Corresponding authors. E-mail: thellend@ccr.jussieu.fr; vidalc@ccr.jussieu.fr
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)01964-4

300
Scheme 1. (a) œ3P=CHCOOEt, THF reflux, 2 h; (b) DIBAL-H 20% wt in toluene, THF, 0°C, 1 h; (c) MsCl, Et3N, CH2Cl2, 0°C,
15 min then NaN3, DMF, rt, 12 h; (d) OsO4, MNO, H2O, tBuOH, THF, rt, 12 h; (e) BnBr, DMF then NaH, rt, 2 h; (f) DOWEX
50W (H+), MeOH, rt, 12 h; (g) NaHCO3 5% aq., KBr, TEMPO, NaOCl, acetone, 0°C, 1 h then CH2N2, MeOH; (h) Pd/CaCO3,
H2, MeOH, rt, 3 h; (i) Lawesson’s reagent, pyridine, toluene, reflux, 2 h; (j) TBDMSOTf, 2,6-lutidine, CH2Cl2, rt, 30 min then
MeOH, Ac2O, Bu4NF, rt, 12 h; (k) NH2OH.HCl, NaHCO3, MeOH reflux, 2 h
Reduction of azide 8 by Lindlar catalyst yielded the lactam 9 (86%), which was transformed into thio-
nolactam 10 by Lawesson’s reagent9 (75%). Use of classical Boc deprotection/reacetylation conditions10
led to degradation products. We thus established a modified version of Ohfune’s procedure,11 based
on trapping the amine formed in a protic solvent by acetic anhydride, and obtained the N-acetylated
thionolactam 11 (46% overall yield).
The amidoxime 12 was finally obtained by condensation of hydroxylamine (2 equivalents) on 11
(55%). This compound is derivatized in a specific manner such that further condensation on the
amidoxime hydroxyl function is possible. Such N-acetylglucosamidoxime analogs represent potential
transition state analog inhibitors of glycosyltransferases specific of N-acetylglucosamine derivatives,
among which chitin synthase.
Acknowledgements
We thank Dr. Y. Blériot for fruitful discussions.
References
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