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A Propos of Glycosyl Cations and the Mechanism of Chemical Glycosylation; the Current State of The

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A Propos of Glycosyl Cations and the Mechanism of Chemical Glycosylation; the Current State of The Carbohydrate Research 403 (2015) 48–59 Contents lists available at ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres A propos of glycosyl cations and the mechanism of chemical glycosylation; the current state of the art ⇑ Luis Bohé a, David Crich b, a Centre de Recherche de Gif, CNRS, Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France b Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, MI 48202, USA article info abstract Article history: An overview of recent advances in glycosylation with particular emphasis on mechanism is presented. Received 25 April 2014 The mounting evidence for both the existence of glycosyl oxocarbenium ions as fleeting intermediates Received in revised form 16 June 2014 in some reactions, and the crucial role of the associated counterion in others is discussed. The extremes Accepted 19 June 2014 of the S 1 and S 2 manifolds for the glycosylation reaction are bridged by a continuum of mechanisms in Available online 1 July 2014 N N which it appears likely that most examples are located. Ó 2014 Elsevier Ltd. All rights reserved. Keywords: Oxocarbenium ions Counter ions Hydrogen bonding Kinetics 1. Introduction characteristics of one or the other of the two extremes without meeting the entire set of Ingoldian criteria that establish the In 2010, a propos of glycosyl cations and the mechanism of limiting mechanisms. chemical glycosylation, we surveyed critically the evidence for and against the existence of glycosyl oxocarbenium ions as inter- 2. Generation of glycosyl oxocarbenium ions and spectroscopic mediates in glycosylation reactions and discussed the influence evidence for them of a number of factors, including protecting groups, solvents, and additives on these reactions which are fundamental to glyco- Continuing their work on the generation of carbocations in 1 science. We concluded that ‘glycosyl cations are likely to have a organic solution at low temperature by direct and indirect electro- real existence in dichloromethane solution at low temperature lytic methods Yoshida and co-workers reported the activation of and that their observation only awaits the development of a suit- 4-fluorophenyl tetra-O-benzyl-b-D-thioglucopyranoside by elec- able ‘flash’ technique for their generation in the probe of an NMR trochemically generated tris(4-fluorophenyl)trisulfonium tetra- spectrometer’. In the update that follows we survey critically evi- kis(pentafluorophenyl)borate at a variety of temperatures below dence presented in the intervening four years for the transient À48 °C in dichloromethane in a flow system (Scheme 2). After a existence of glycosyl oxocarbenium ions in some glycosylation mixing time of 0.17 s the reaction mixture was combined with reactions, while stressing the important role of the counterion in methanol leading to the isolation of methyl tetra-O-benzylgluco- others. We begin by restating the general principle that glycosyla- pyranoside in high yield, leading the authors to suggest that ‘a gly- tion by nucleophilic substitution of a leaving group at the anomeric cosyl cation somewhat stabilized by the co-ordination of ArSSAr’ is center of a glycosyl donor by a glycosyl acceptor in the presence of formed by this process and that ‘the lifetime of the intermediate a promoter is best expressed in terms of a continuum of mecha- strongly depends on the temperature, and that the lifetime is on 2–4 5 nisms spanning the entire range from pure SN1, with a discrete the order of a second even at À78 °C’. glycosyl oxocarbenium ion intermediate, through to pure con- The electrochemical method for the activation of thioglyco- 6 certed SN2 reactions. Concrete examples of both extremes exist, sides, and especially the in situ generation of glycosyl triflates 1 as set out previously, but most O-glycosylations are probably best (using tetrabutyl ammonium triflate as supporting electrolyte), viewed as SN1-like or SN2-like, that is, having most of the has been developed into an iterative process enabling the one pot automated synthesis of oligosaccharides.7 ⇑ Corresponding author. Tel.: +1 3135776203. In spite of these advances and the inference of a glycosyl cation E-mail address: [email protected] (D. Crich). stabilized by co-ordination to a disulfide with a lifetime of seconds http://dx.doi.org/10.1016/j.carres.2014.06.020 0008-6215/Ó 2014 Elsevier Ltd. All rights reserved. L. Bohé, D. Crich / Carbohydrate Research 403 (2015) 48–59 49 O O PO PO X X β α-donor -donor activation activation O O O O X' O PO PO PO PO PO X' X' X' activated contact solvent-separated contact activated ion-pair ion pair ion-pair α-donor β-donor (CIP) (SSIP) (CIP) ROH ROH ROH ROH ROH ROH O O PO OR PO OR β-glycoside α-glycoside From From From From SN2 "SN1-like" "SN1-like" SN2 to to to to "SN2-like" SN1 SN1 "SN2-like" Scheme 1. A general glycosylation mechanism. – + 3. Computational work on glycosyl oxocarbenium ions ArS SAr + nBu4N B(C6F5)4 Satoh, Hünenberger, and their co-workers have conducted an CH2Cl2 extensive Quantum mechanical (QM) and molecular dynamics BnO (MD) study of the tetra-O-methyl glucopyranosyl oxocarbenium + – BnO O ion in complex with the triflate anion making use of distance con- ArS SAr B(C F ) + SAr 6 5 4 BnO straints to prevent collapse of the ion pair to the covalent tri- SAr BnO flates.11 They report that the conformation of the oxocarbenium ion is solvent dependent and that the predominant location of 0.038 M 0.115 M the counterion is conformation and thus solvent dependent. On in CH2Cl2 in CH2Cl2 flow rate flow rate this basis they formulate an alternative mechanism for glycosyla- 7.8 mL/min 20 mL/min tion and a rationale for stereoselectivity titled ‘the conformer and counter ion distribution hypothesis’. According to this hypothesis CH2Cl2, – 48 °C, 0.17 s the oxocarbenium ion preferentially adopts a B2,5 conformation in more polar solvents with the counterion most closely associated and sterically shielding the a-face; nucleophilic attack then takes BnO + – 4 O place preferentially on the b-face (Scheme 3). In vacuum the H3 BnO B(C6F5)4 BnO conformer is preferred, and because of the association of the coun- BnO terion with the b-face of this conformer it affords a-selective reac- tions (Scheme 3).11 The solvent dependent conformational change Scheme 2. Generation of a glycosyl cation equivalent by flow chemistry. of the oxocarbenium ion is attributed to increased stabilization of conformers with higher dipole moments by dielectric screening at À78 °C, we are unaware of any other published spectroscopic effects in the more polar solvents. detection of actual glycosyl oxocarbenium ions in organic solution Whitfield has discussed some of the difficulties associated with at the present time. However, and although details are not yet QM calculations of glycosylation reactions including apparent available, it has been reported recently that a protected fructofur- H-bonding of the incoming acceptor to oxygen atoms in the accep- anosyl oxocarbenium ion and protected 2-deoxypyranosyl tor, 1,6-anhydro formation, and the formation of complexes oxocarbenium ions have been generated in superacid media and between oxocarbenium ions and ether-type protecting groups.12 characterized at low temperature by NMR spectroscopy.8,9 The Preliminary attempts at the computational (QM) determination details of this work are eagerly anticipated. of transition states for the reaction of tetra-O-methyl a- and Evidence in support of the existence of conformationally equil- b-glucopyranosyl triflates with methanol have been reported.13 A ibrating sialyl oxocarbenium ions on the activation of the corre- lithium ion was included in the calculations at a fixed distance sponding thioglycosides with N-iodosuccinimide and triflic acid from the anomeric center so as to neutralize the charge on the in the absence of an acceptor alcohol has been provided by the departing triflate and prevent spontaneous collapse of any ion De Meo group; elimination to the glycal took place with loss of pairs.13 In spite of this artifact no ion pairs were identified as an axial or equatorial proton from C-3 as determined with the help minima in these calculations which employed a very restricted 10 of deuterium labeled isotopomers. number of explicit solvent molecules (CH2Cl2). All reactions 50 L. Bohé, D. Crich / Carbohydrate Research 403 (2015) 48–59 MeO Crich, Pratt, and their co-workers computed (QM) transition MeO O MeO states for the displacement of triflate from both anomers of MeO 4,6-O-benzylidene-2,3-di-O-methyl gluco- and mannopyranosyl 4 Nu 14 C1 triflates by isopropanol. In both series displacement of the a-triflate was found to take place via a B conformation of the – 2,5 TfO MeO pyranosyl ring, while that of the b-triflates involved the 4H OMe 3 OMe conformation of the ring. In each case the C1AOTf and C1AO(H)iPr (in vacuum) MeO O OMe MeO O OMe MeO + partial bonds at the transition states were 2.2 Å or longer, again 4 Nu H3 suggestive of exploded transition states (Fig. 1). Computed primary 13C kinetic isotope effects were in good agreement with experi- Nu mentally determined values for the three of the four cases thereby providing strong support for loosely associative mechanisms in Nu those cases. The single exception to the concordance between + MeO MeO experimental and calculated KIE values was that of the displace- O OMe (in CH3CN) OMe O ment of the b-mannosyl triflate, which, with an experimental pri- OMe OMe mary 13C KIE of 1.005 at 25 °C, is
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