Stereoselective Glycosylations-Additions to Oxocarbenium Ions

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. 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 contact or close ion pairs (CIPs) that features a glycosyl cation, in chemical glycosylation reactions. It deals with the stability, reactivity, and -conformational behavior of glycosyl oxocarbenium ions, and describes their intermediacy in the assembly of (complex) oligosaccharides. The chapter presents sophisticated and detailed DFT computational approaches to study glycosyl oxocarbenium ions. Where many anomeric triflates have been spectroscopically characterized, glycosyl oxocarbenium ions are too reactive to detect by straightforward NMR techniques. NMR spectroscopy has been used to characterize a multitude of covalent reactive intermediates such as anomeric triflates

Stereoselectivity of Conformationally Restricted Glucosazide Donors

Glycosylations of 4,6-tethered glucosazide donors with a panel of model acceptors revealed the effect of acceptor nucleophilicity on the stereoselectivity of these donors. The differences in reactivity among the donors were evaluated in competitive glycosylation reactions, and their relative reactivities were found to be reflected in the stereoselectivity in glycosylations with a set of fluorinated alcohols as well as carbohydrate acceptors. We found that the 2-azido-2-deoxy moiety is more β-directing than its C-2-<i>O</i>-benzyl counterpart, as a consequence of increased destabilization of anomeric charge development by the electron-withdrawing azide. Additional disarming groups further decreased the α-selectivity of the studied donors, whereas substitution of the 4,6-benzylidene acetal with a 4,6-di-<i>tert</i>-butyl silylidene led to a slight increase in α-selectivity. The C-2-dinitropyridone group was also explored as an alternative for the nonparticipating azide group, but this protecting group significantly increased β-selectivity. All studied donors exhibited the same acceptor-dependent selectivity trend, and good α-selectivity could be obtained with the weakest acceptors and most reactive donors

Acceptor reactivity in glycosylation reactions

The outcome of a glycosylation reaction critically depends on the reactivity of all reaction partners involved: The donor glycoside (the electrophile), the activator (that generally provides the leaving group on the activated donor species) and the glycosyl acceptor (the nucleophile). The influence of the donor on the outcome of a glycosylation reaction is well appreciated and documented. Differences in donor reactivity have led to the development of chemoselective glycosylation reactions and the reactivity of donor glycosides has been tuned to affect stereoselective glycosylation reactions. The quantification of donor reactivity has enabled the conception of streamlined one-pot glycosylation sequences. In contrast, although it has long been known that the nature and the reactivity of the nucleophile influence the outcome of a glycosylation, the knowledge of acceptor reactivity and insight into the consequences thereof are often circumstantial or anecdotal. This review documents how the reactivity impacts the glycosylation reaction outcome both in terms of chemical yield and stereoselectivity. The effect of acceptor nucleophilicity on the reaction mechanism is described and steric, conformational and electronic influences are outlined. Quantitative and computational approaches to comprehend acceptor nucleophilicity are assessed. The increasing insight into the stereoelectronic effects governing glycoside reactivity will eventually enable the conception of effective stereoselective glycosylation methodology that can be tuned to the reaction partners at hand

Furanosyl Oxocarbenium Ion Conformational Energy Landscape Maps as a Tool to Study the Glycosylation Stereoselectivity of 2-Azidofuranoses, 2-Fluorofuranoses and Methyl Furanosyl Uronates

The 3D shape of glycosyl oxocarbenium ions determines their stability and reactivity and the stereochemical course of SN1-reactions taking place on these reactive intermediates is dictated by the conformation of these species. The nature and configuration of functional groups on the carbohydrate ring effect the stability of glycosyl oxocarbenium ions and they control the overall shape of the cations. We here map the stereoelectronic substituent effects of the C2-azide, C2-fluoride and C4-carboxylic acid ester on the stability and reactivity of the complete suite of diastereoisomeric furanoses using a combined computational and experimental approach. Surprisingly all furanosyl donors studied react in a highly stereoselective manner to provide the 1,2-cis products, except for the reactions in the xylose series. The 1,2-cis selectivity in the ribo-, arabino- and lyxo-configured furanosides can be traced back to the lowest energy 3E or E3-conformers of the intermediate oxocarbenium ions. The lack of selectivity of the xylosyl donors is related to the occurrence of oxocarbenium ions, adopting other conformations.Bio-organic Synthesi

Mapping the effect of configuration and protecting group pattern on glycosyl acceptor reactivity

The reactivity of the acceptor alcohol can have a tremendous influence on the outcome of a glycosylation reaction, both in terms of yield and stereoselectivity. Through a systematic survey of 67 acceptor alcohols in glycosylation reactions with two glucosyl donors we here reveal how the reactivity of a carbohydrate acceptor depends on its configuration and substitution pattern. The study shows how the functional groups flanking the acceptor alcohol influence the reactivity of the alcohol and show that both the nature and relative orientation play an essential role. The empiric acceptor reactivity guidelines revealed here will aid in the rational optimization of glycosylation reactions and be an important tool in the assembly of oligosaccharides

Synthesis, Reactivity, and Stereoselectivity of 4-Thiofuranosides

Thiosugars, sugars that have their endocyclic oxygen substituted for a sulfur atom, have been used as stable bioisosteres of naturally occurring glycans because the thiosugar glycosydic linkage is supposed to be stabilized toward chemical and enzymatic hydrolysis. We have performed an in-depth investigation into the stability and reactivity of furanosyl thiacarbenium ions, by assessing all four diastereoisomeric thiofuranosides experimentally and computationally. We show that all furanosyl thiacarbenium ions react in a 1,2-cis-selective manner with triethylsilane, reminiscent of their oxo counterparts. The computed conformational space occupied by the thiacarbenium ions is strikingly similar to that of the corresponding furanosyl oxycarbenium ions, indicating that the stereoelectronic substituent effects governing the stability of furanosyl oxocarbenium ions and thiacarbenium ions are very similar. While the thio-ribo-furanose appears to be less reactive than its oxo counterpart, the thio-ara-, lyxo-, and xylo-furanosides appear to be more reactive than their oxygen equivalents. These differences are accounted for using the conformational preference of the donors and the carbocation intermediates. The lower reactivity of the thio-ribo furanosides in (Lewis) acid-mediated reactions and the similarity of the thia- and oxocarbenium ions make thio-ribo-furanosides excellent stabilized analogues of the naturally occurring ribo-furanose sugars

Anomeric Triflates vs Dioxanium ions: Different Product-Forming Intermediates from 1-Thiophenyl-2-O-Benzyl-3-O-Benzoyl-4,6-O-Benzylidene-Mannose and Glucose

Minimal structural differences in the structure of glycosyl donors can have a tremendous impact on their reactivity and the stereochemical outcome of their glycosylation reactions. It can be exceedingly hard to adequately account for the observed differences and our current understanding of the nature of different reactive intermediates and the reaction pathways in which these are involved often only allows for speculative explanations. Here we used the detection and characterization of fleeting reactive intermediates in combination with systematic glycosylation reactions to understand the disparate behavior of “benchmark” glycosylation systems involving benzylidene glucosyl and mannosyl donors. While these systems have been studied extensively, no satisfactory explanations are available for the differences observed between the 3-O-benzyl/benzoyl mannose and glucose donor systems. We report the use of in-depth computational studies to map the potential energy surfaces of the different reaction pathways available for these donors and through these we have discovered the underlying reasons for the disparate behavior of the seemingly very similar systems. Evidence has been provided for the intermediacy of benzylidene mannosyl 1,3-dioxanium ions while the formation of the analogous 1,3-glucosyl dioxanium ions is thwarted by a prohibitively strong flagpole interaction of the C-2-O-benzyl group with the C-5-proton in moving towards the transition state in which the glucose ring adopts a B2,5-conformation. This study provides a long-awaited explanation for the intermediacy of 1,3-dioxanium ions in the mannosyl system and an answer as to why these do not form from analogous glucosyl donors

Defining the S_N1 Side of Glycosylation Reactions:Stereoselectivity of Glycopyranosyl Cations

The broad application of well-defined synthetic oligosaccharides in glycobiology and glycobiotechnology is largely hampered by the lack of sufficient amounts of synthetic carbohydrate specimens. Insufficient knowledge of the glycosylation reaction mechanism thwarts the routine assembly of these materials. Glycosyl cations are key reactive intermediates in the glycosylation reaction, but their high reactivity and fleeting nature have precluded the determination of clear structure–reactivity-stereoselectivity principles for these species. We report a combined experimental and computational method that connects the stereoselectivity of oxocarbenium ions to the full ensemble of conformations these species can adopt, mapped in conformational energy landscapes (CEL), in a quantitative manner. The detailed description of stereoselective SN1-type glycosylation reactions firmly establishes glycosyl cations as true reaction intermediates and will enable the generation of new stereoselective glycosylation methodology.Bio-organic Synthesi