Chapter 1
Stereoselective Glycosylations - Additions to Oxocarbenium Ions

Bas Hagen, Stefan van der Vorm, Thomas Hansen, Gijs A. van der Marel, and Jeroen D.C. Codée

1.1 Introduction

Tremendous progress has been made in the construction of oligosaccharides, and many impressive examples of large and complex oligosaccharide total syntheses have appeared over the years [1]. At the same time, the exact mechanism underlying the union of two carbohydrate building blocks often remains obscure, and optimization of a glycosylation reaction can be a time- and labor-intensive process [2, 3]. This can be explained by the many variables that affect the outcome of a glycosylation reaction: the nature of both the donor and acceptor building blocks, solvent, activator and activation protocol, temperature, concentration, and even the presence and the type of molecular sieves. The large structural variety of carbohydrates leads to building blocks that differ significantly in reactivity, with respect to both the nucleophilicity of the acceptor molecule and the reactivity of the donor species. The reactivity of a donor is generally related to the capacity of the donor to accommodate developing positive charge at the anomeric center, upon expulsion of the anomeric leaving group. This also determines the amount of carbocation character in the transition state leading to the products. Most glycosylation reactions will feature characteristics of both SN1- and SN2-type pathways in the transition states leading to the products. It is now commonly accepted that the exact mechanism through which a glycosidic linkage is formed can be found somewhere in the continuum of reaction mechanisms that spans from a completely dissociative SN1 mechanism on one side to an associative SN2 pathway on the other side (Figure 1.1) [4-6]. On the SN1-side of the spectrum, glycosyl oxocarbenium ions are found as product-forming intermediates. On this outer limit of the reaction pathway continuum, the oxocarbenium ions will be separated from their counterions by solvent molecules (solvent-separated ion pairs, SSIPs), and there will be no influence of the counterion on the selectivity of the reaction. Moving toward the SN2 side of the spectrum contact (or close) ion pairs (CIPs) are encountered, and in reactions of these species, the counterion will have a role to play. Because glycosylation reactions generally occur in apolar solvents (dichloromethane is by far the most used one), ionic intermediates have very limited lifetimes, and activated donor species will primarily be present as a pool of covalent intermediates. The stability, lifetime, and reactivity of an oxocarbenium ion depend - besides the nature of the counterion - on the nature and orientation of the functional groups present on the carbohydrate ring. This chapter explores the role of oxocarbenium ions (and CIPs, featuring a glycosyl cation) in chemical glycosylation reactions. While it was previously often assumed that glycosylations, proceeding via an oxocarbenium ion intermediate, show poor stereoselectivity, it is now clear that oxocarbenium ions can be at the basis of stereoselective glycosylation events. The first part of this chapter deals with the stability, reactivity, and conformational behavior of glycosyl oxocarbenium ions, whereas the second part describes their intermediacy in the assembly of (complex) oligosaccharides.

Figure 1.1 Continuum of mechanisms to explain the stereochemical course of glycosylation reactions.

1.2 Stability, Reactivity, and Conformational Behavior of Glycosyl Oxocarbenium Ions

Amyes and Jencks have argued that glycosyl oxocarbenium ions have a short but significant lifetime in aqueous solution [7]. They further argued that in the presence of properly positioned counterions (such as those derived of expulsion of an aglycon), CIPs will rapidly collapse back to provide the covalent species and that the "first stable intermediate for a significant fraction of the reaction" should be the solvent-separated oxocarbenium ion. By extrapolation of these observations to apolar organic solvents, Sinnott reached the conclusion that intimate ion pairs have no real existence in an apolar environment, such as used for glycosylation reactions [8]. Hosoya et al. have studied CIPs by quantum mechanical calculations in dichloromethane as a solvent [9]. In these calculations, they have included four solvent molecules to accurately mimic the real-life situation. In many of the studied cases, CIPs turned out to be less stable than the corresponding solvent-separated ions, as will be described next [10]. Yoshida and coworkers have described that activation of thioglucoside 1 with a sulfonium salt activator, featuring the bulky nonnucleophilic tetrakis(pentafluorophenyl) borate counterion, in a continuous-flow microreactor, provides a reactive species (2) that has a lifetime on the order of a second (Scheme 1.1) [11]. They argued that this species was a glucosyl oxocarbenium ion, "somewhat stabilized" by the disulfide generated from the donor aglycon and the activator.

Scheme 1.1 Generation of glucosyl oxocarbenium ions in a continuous-flow microreactor.

The stability of a glycosyl oxocarbenium ion is largely influenced by the substituents on the carbohydrate ring. The electronegative substituents (primarily oxygen, but also nitrogen-based) have an overall destabilizing effect on the carbocation, and the destabilizing effect can be further enhanced by the presence of electron-withdrawing protecting groups, such as acyl functions. The exact position of the substituent on the ring and its orientation influence the stability of the anomeric cation. The combined influence of all substituents on the ring determines the reactivity of a glycosyl donor, and the extensive relative reactivity value (RRV) charts, drawn up by the Ley and Wong groups for a large panel of thioglycosides, clearly illustrate these functional group effects [12-14]. From these RRV tables, it is clear that the donor reactivity spectrum spans at least eight orders of magnitude. To investigate the influence of the carbohydrate ring substituents on the stereochemical outcome of a glycosylation reaction, Woerpel and coworkers have systematically studied C-glycosylation reactions of a set of furanosides and pyranosides, featuring a limited amount of ring substituents [15-20]. Their studies in the furanose series are summarized in Scheme 1.2a [15, 17]. As can be seen, the alkoxy groups at C2 and C3 have a strong influence on the stereochemical outcome of the reaction, where the alkoxy group at C5 appears to have less effect on the reaction. The presence of an alkoxy or alkyl group at C3 leads to the formation of the allylglycosides 11 and 12 with opposite stereoselectivity. Woerpel and coworkers have devised a model to account for these stereodirecting substituent effects that takes into account the equilibrium between two possible envelope oxocarbenium ion conformers (13 and 14, Scheme 1.2b) [17]. Attack on these oxocarbenium ion conformers by the nucleophile occurs from the "inside" of the envelopes, because this trajectory avoids unfavorable eclipsing interactions with the substituent at C2, and it leads, upon rehybridization of the anomeric carbon, to a fully staggered product (15 and 16), where attack on the "outside" would provide the furanose ring with an eclipsed C1-C2 constellation. The spatial orientation of the alkoxy groups influences the stability of the oxocarbenium ions. An alkoxy group at C3 can provide some stabilization of the carbocation when it takes up a pseudo-axial position. Stabilization of the oxocarbenium ion featuring a C2-alkoxy group is best achieved by placing the electronegative substituent in a pseudo-equatorial position to allow for the hyperconjugative stabilization by the properly oriented C2-H2 bond. Alkyl substituents at C3 prefer to adopt a pseudo-equatorial position because of steric reasons. With these spatial substituent preferences, the stereochemical outcome of the C-allylation reactions in Scheme 1.2 can be explained. Activation of the C3-benzyloxyfuranosyl acetate with SnBr4 can provide an oxocarbenium ion intermediate that preferentially adopts an E3 conformation, as in 14. Nucleophilic attack on this conformer takes place from the diastereotopic face that leads to the 1,3-cis product. In a similar vein, inside nucleophilic attack on the C2-benzyloxy furanosyl oxocarbenium ion E3 conformer, derived from furanosyl acetate 4, accounts for the stereochemical outcome of the C-allylation leading to product 9.

Scheme 1.2 (a) Diastereoselective C-allylations of furanosyl acetates. (b) "Inside" attack model.

To accurately gauge the combined effect of multiple substituents on a furanosyl ring, van Rijssel et al. [21, 22] used a quantum mechanical calculation method, originally developed by Rhoad and coworkers [23], to map the energy of furanosyl oxocarbenium ions related to the complete conformational space they can occupy. Energy maps for all four possible diastereoisomeric, fully decorated furanosyl oxocarbenium ions were generated revealing the lowest energy conformers for the ribo-, arabino-, xylo-, and lyxo-configured furanosyl oxocarbenium ions 17-21 (Scheme 1.3). It became apparent that the orientation of the C5-substituent, having a gg, gt, or...