A comparative study of the influence of some protecting groups on the reactivity of d-glucosamine acceptors with a galactofuranosyl donor
Introduction
Many oligosaccharides and glycoconjugates carry 4-linked N-acetylglucosamine moieties.1 It is well known that the low reactivity at this 4-position carrying protecting groups at O-3 and O-6 sometimes hampers the synthesis of these biologically important compounds in acceptable yields.2 This low reactivity has been attributed to steric factors and to the formation of a deactivating hydrogen bond in which the amido group is involved.2, 3 Recent observations that the amide group may itself be glycosylated by active species leading to O-glycosyl imidates provide a third explanation to the low reactivity of N-acetylglucosamine acceptors.4, 5 As a consequence, protection and synthetic strategies for the 2-amino moiety of d-glucosaminyl acceptors play a critical role in glycosylation reactions and post-glycosylation chemical manipulation to obtain target glycosides.6
To the best of our knowledge there are only two reports directed to assess the effect of N-protecting groups on the relative reactivity of glucosamine acceptors. In one of them, Crich and Dudkin3 determined, through a competitive experiment, the acceptor reactivity of the 4-OH group of N-acetyl, N-phthalimido (Phth) and 2-azido-2-deoxyglucose derivatives when coupled with a mannosyl sulfoxide activated with triflic anhydride. They demonstrated that, under these conditions, the azido acceptor is 10 times more reactive than the N-acetylglucosamine acceptor, whereas the Phth acceptor has an intermediate reactivity. In addition, these authors have also shown that N,N-diacetylglucosamine and N-acetyl-N-benzylglucosamine derivatives, with a reactivity comparable to that of the Phth acceptor, were not worthwhile because of the instability of the imide function in the N,N-diacetyl derivative under those conditions. Furthermore, the complicated NMR spectra obtained for the N-acetyl-N-benzyl derivative indicates instability also for this compound.
More recently, in a comparative study of the reactivity of the N-acetyl, N-Phth, and N-2,2,2-trichloroethoxycarbonyl (Troc)-protected glucosamine derivatives, Matta and co-workers7 showed that the N-Troc group afforded greater 4-OH reactivity than the N-Phth and N-acetylglucosamine acceptors when coupled with a galactopyranosyl imidate donor in a trimethylsilyl triflate (TMSOTf) promoted glycosylation. The 4-OH of tetrachlorophtaloyl8 and sulfonamide9 protected glucosamine derivatives appeared to have considerable potential as acceptor alcohols; however, the remarkable reactivity recently reported for the methyl glycosides of the N-acetyloxazolidinones (1a and 1b)10 suggested that these derivatives were the ideal acceptors for the synthesis of oligosaccharides carrying 4-linked N-acetylglucosamine moieties.
The high reactivity of 1a and 1b was demonstrated by a series of couplings with a range of thioglycosides and also with other glycosylation methods (i.e., Kahne’s sulfoxide method, Gin’s dehydrative coupling sequence, and Schmidt’s trichloroacetimidate protocol). In all cases glycopyranosyl donors were used.10
The recent discovery of furanoside components in a wide variety of natural products of biological significance11, 12, 13 prompted us to study the reactivity of some glucosamine derivative acceptors with a galactofuranosyl donor hoping to contribute to the synthesis of furanoside oligosaccharides, as modern methods are allowing such molecules to be isolated. It has been shown by de Lederkremer and co-workers14 that galactofuranosides are good donors even when coupled with N-acetylglucosamine derivatives. They found that the coupling of penta-O-benzoyl-d-galactofuranose (2a) with benzyl 2-acetamido-3,6-di-O-benzoyl-2-deoxy-α-d-glucopyranoside (3a), employing tin(IV) chloride as catalyst, gave the disaccharide 4a in 85% yield. They also found that the coupling of tetra-O-benzoyl trichloroacetimidate 2b with the glucosamine derivative 3b in the presence of TMSOTf gave 4b in 77% yield (Scheme 1). These disaccharides were shown to be the β-anomers on the basis of the small galactofuranose 1JCH anomeric coupling constant and by the C-1′13C NMR chemical shift.15
Herein we report some observations, through competitive experiments with a galactofuranosyl trichloroacetimidate donor that clearly establish the influence of the N-dimethylmaleoyl group and electron-withdrawing and electron-donating groups at O-3 and O-6 on the reactivity of the 4-OH group of d-glucosamine acceptors.
Section snippets
Results and discussion
The purpose of this work is to study the relative reactivity of acceptors 5, 6a, 6b, and 6c in competition with the highly reactive N-acetyloxazolidinone protected glucosamine 1a by coupling with trichloroacetimidate 2b. We considered it interesting to include in this study the N-dimethylmaleimido (DMM) glucosaminyl acceptors 6a, 6b, and 6c, not only because this protecting group removes the deactivating hydrogen bond as well as the tendency toward amide glycosylation, but also because, as was
General methods
Melting points were determined on an Electrothermal 9100 apparatus and are uncorrected. The 1H and 13C NMR spectra were recorded on a Bruker AC 200 spectrometer for CDCl3 solutions with Me4Si as internal standard. For the 2D and COSY experiments, Bruker standard software was employed. Mass spectra were measured using MALDI-TOF HRMS and HRFABMS at the UCR Mass Spectrometry Facility (Department of Chemistry, University of California Riverside, USA) and Kent Mass Spectrometry (Kent, UK). Optical
Acknowledgements
We thank Dr. Manuel González-Sierra for spectral determinations and Dr. Cristóbal López for helpful suggestions. We also thank Drs. Crich and Nikolaev for sending us the experimental details for the preparation of different compounds. Financial support from UNR, UBA, and CONICET and a fellowship (M.L.B.) are also acknowledged. M.I.C., C.A.S., and E.A.R. are Research Members of the National Research Council of Argentina (CONICET).
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