Carbohydrate Reactivity: Glycosyl Cations out on Parole

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and synergistic control of a multitude New Hampshire 03755, USA. 4. Kassem, S., Lee, A. T. L., Leigh, D. A., Markevicius, A. & Solà, J. of processes in concert7. This systems e-mail: [email protected]; Nature Chem. 8, 138–143 (2016). 8 5. Su, X. & Aprahamian, I. Org. Lett. 13, 30–33 (2011). chemistry approach is destined to push Twitter: @aprahamian 6. Astumian, R. D. & Derényi, I. Eur. Biophys. J. the boundaries of what synthetic molecular 27, 474–489 (1998). machines can and will accomplish. ❐ References 7. Ray, D., Foy, J. T., Hughes, R. P. & Aprahamian, I. Nature Chem. 1. Feynman, R. P. Eng. Sci. 23, 22–36 (1960). 4, 757–762 (2012).

2. Gu, H., Chao, J., Xiao, S.-J. & Seeman, N. C. Nature 8. Nitschke, J. R. Nature 462, 736–738 (2009). Ivan Aprahamian is in the Department of 465, 202–205 (2010). Chemistry, Dartmouth College, Hanover, 3. Baum, R. Chem. Eng. News 81, 37–42 (2004). Published online: 21 December 2015

CARBOHYDRATE REACTIVITY Glycosyl cations out on parole The reactivity of glycosyl donors is often explained by invoking putative glycosyl cation intermediates but, until now, they have not been observed in the condensed phase. Luis Bohé and David Crich

3 ust as chemistry is the central science, glycosyl oxocarbenium ions . The field of On dissolution in the same HF/SbF5 carbohydrate chemistry is central to glycosyl oxocarbenium ions is therefore mixture, peracetyl-2-bromo-2-deoxy- Jglycoscience. Within carbohydrate at a similar level of development as that β-d-glucopyranose lost the anomeric chemistry there is arguably no reaction of carbenium ions in general in the 1960s acetate and afforded a triprotonated cation 4 more important than the formation of following Winstein’s seminal concept assigned to a H5 half-chair conformation glycosidic bonds — those between a sugar of the role of ion pairs in nucleophilic containing a loose unsymmetrical cyclic and a hydroxyl or other functional group of substitution4, but prior to the fundamental bromonium ion, whose presence was another molecule — known as glycosylation studies of Olah and co-workers that enabled revealed by the anomeric proton and or glycosidation. their observation by NMR spectroscopic carbon resonances of δ 8.36 and 198.1, In glycosylation a glycosyl donor methods in superacidic media. Now, respectively (Fig. 1c). reacts with a glycosyl acceptor, typically following closely on the heels of a poster Extension of the method to peracetyl- in the presence of a promoter, to form the by Akien and Subramanian5, Blériot and α-d-glucopyranose and peracetyl-2- glycosidic bond (Fig. 1a). The efficiency co-workers disclose in Nature Chemistry acetamido-2-deoxy-α-d-glucopyranose and stereoselectivity of this process is the generation, NMR spectroscopic gave spectra consistent with participation affected by a multitude of factors, not characterization, and preliminary by the neighbouring acetoxy or least the configuration and substitution reactions of free 2-deoxy and 2-bromo- acetamido groups and the formation pattern of the glycosyl donor. Such 2-deoxy glucopyranosyl oxocarbenium of fused dioxalenium and protonated factors are commonly considered to exert ions liberated from close proximity oxazolines such as have been previously their influence at the level of a putative with any counterion by the hydrofluoric characterized7. Attempted application intermediate glycosyl oxocarbenium acid–antimony pentafluoride (HF/SbF5) to peracetyl-2-azido-2-deoxy-β-d- ion — or glycosyl cation — in terms of superacidic medium6. glucopyranose only afforded a spectrum both reactivity and face selectivity. Indeed Blériot and co-workers report that consistent with protonation of the substrate this cation-centric model dominates to on dissolution in an approximately on each of the four acetate groups and the extent that the enormous majority of 4:1 mixture of HF and SbF5 at −40 °C, the azide moiety, without expulsion of the papers in the area omit any consideration 2-deoxy-β-d-glucopyranose tetraacetate anomeric acetate. This latter experiment of counterions, whether in the form of (lacking a strongly electron-withdrawing reveals the limits of the method, and more covalent intermediates, or contact (CIP) substituent at the two position) gave 1H importantly highlights the influence of or solvent separated (SSIP) ion pairs, and and 13C NMR spectra consistent with electron-withdrawing substituents on consider the oxocarbenium ion essentially conversion to the fully protonated form of the formation and stability of carbenium in a vacuum1. the tri-O-acetyl-2-deoxyglucopyranosyl and oxocarbenium ions. Indeed, it is the In recent years, however, this view has oxocarbenium ion as characterized multiplicity of electron-withdrawing been increasingly challenged as NMR by the anomeric proton and carbon substituents that explains the instability spectroscopic studies have failed to provide resonances with chemical shifts (δ) of of glycosyl oxocarbenium ions in contrast evidence for glycosyl oxocarbenium ions 8.89 and 229.1, respectively (Fig. 1b). with simple oxocarbenium ions, which in the condensed phase, despite the relative DFT calculations and coupling constant are well-known to be more stable than ease with which simple alkyl oxocarbenium analysis point to the preferential adoption analogous carbenium ions. ions are detected1,2. Moreover, it has of a 4E envelope conformation in which With the existence and structures of the been demonstrated that even relatively the three protonated substituents triprotonated triacetyl-2-deoxyglucosyl weakly nucleophilic counterions such as take up pseudoequatorial positions. oxocarbenium ion and its 2-bromo trifluoromethanesulfonate prefer to form Variable-temperature NMR spectroscopy congener established in HF/SbF5, attention covalently bound intermediates rather demonstrated the cation to be stable to was focused on their stereoselectivity than to exist in ion pairs with the putative at least 20 °C in the HF/SbF5 mixture. when quenched with either deuteride or

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a Global mechanism difference in conformation between the spectroscopically observed protonated X E O O O O promoter (PO) (PO) oxocarbenium ion in superacid media n E (PO)n n (PO) X X n X Y and putative oxocarbenium ions in Y Donor Activated donor Oxocarbenium ion Covalent neutral organic media urges caution in (CIP, SSIP or free) intermediate the use of the former as a predictor of the conformation and stereoselectivity of the ROH latter, unless Curtin–Hammett kinetic acceptor schemes are invoked. Finally, we return to the question O of the counterion and of covalent (PO)n OR intermediates and ion pairs reacting

Glycoside through SN2-like transition states. By their very design, experiments conducted in superacid media exclude participation b Tetraacetyl-2-deoxy-β-D-glucopyranose by external counterions. Caution must therefore be exercised in extrapolating HO the observation and characterization of OH O OAc 4 δC 229.1 glycosyl oxocarbenium ions in superacids OAc O 5,6 O c-C6D12 O by NMR spectroscopy , to explain the O HF/SbF5, –40 °C H AcO AcO O AcO OAc reactivity and selectivity of glycosyl donors AcO – AcOH OH δH 8.89 D in organic solution. Any such predictions 4 SbF6 Reduction product should take into account reaction kinetics Protonated triacetyl-2-deoxy 98:2 ax:eq D and computational work conducted with glucosyl oxocarbenium ion observed 4E conformation properly solvated counterions, both of which are increasingly available3,11. All told, the Article by Blériot and co-workers6 is ground-breaking and brings c Tetraacetyl-2-bromo-2-deoxy-β-D-glucopyranose the field of glycosyl oxocarbenium ions OH into line with that of other carbenium ions, δC 198.1 4 OAc of which they are a microcosm. As with OAc O δ O HF/SbF , –40 °C O OH c-C6D12 AcO O 5 O D carbenium ions in general, however, the AcO H AcO AcO OAc OH δ jury must remain out when it comes to – AcOH Br 5 O Br Br δH 8.36 Reduction product their intermediacy in substitution reactions 4 SbF6 4:96 ax:eq D to the exclusion of ion pairs and covalent intermediates. Glycosyl oxocarbenium ions Protonated triacetyl-2-bromo- 2-deoxyglucosyl oxocarbenium ion are effectively out on parole, but whether 4 observed H5 conformation they will remain free to roam at will must depend on further experimentation. ❐ Figure 1 | Oxocarbenium ions and their role in glycosylation. a, Global mechanism showing the location of oxocarbenium ions. b, Formation, structure and irreversible quenching of the fully protonated Luis Bohé is at the Institut de Chimie des triacetyl-2-deoxy-d-glucopyranosyl oxocarbenium ion. c, Formation, structure and irreversible quenching Substances Naturelles, 91190 Gif-sur-Yvette, of the fully protonated triacetyl-2-bromo-2-deoxy-d-glucopyranosyl oxocarbenium ion. France. David Crich is in the Department of Chemistry, Wayne State University, Detroit, Michigan 48202, USA. methanol. Thus, treatment of the 2-deoxy addition under the superacidic reaction e-mail: [email protected] oxocarbenium ion with cyclohexane-d12 conditions and necessarily raises questions afforded the corresponding reduced about the potential applicability of the References product with very high selectivity for method for stereoselective glycosidic 1. Bohé, L. & Crich, D. C. R. Chim. 14, 3–16 (2011). incorporation of deuterium in the bond formation. 2. Frihed, T. G., Bols, M. & Pedersen, C. M. Chem. Rev. 115, 4963–5013 (2015). axial position of the resulting 1-deoxy According to most current 3. Hosoya, T., Takano, T., Kosma, P. & Rosenau, T. J. Org. Chem. sugars as predicted on stereoelectronic hypotheses8–10, glycosyl oxocarbenium 79, 7889–7894 (2014). grounds for oxocarbenium ions adopting ions are predicted to adopt conformations 4. Winstein, S., Clippinger, E., Fainberg, A. H., Heck, R. the 4E envelope or neighbouring half- in organic solution which maximize the & Robinson, G. C. J. Am. Chem. Soc. 78, 328–335 (1956). 5. Akien, G. R. & Subramaniam, B. Generation and characterization 8,9 chair conformations . Conversely, number of pseudoaxial C–O bonds so of the pyranosyl and furanosyl oxocarbenium ions from the 2-bromo-2-deoxy oxocarbenium as to take advantage of through-space 2-deoxyaldoses. In 247th ACS National Meeting & Exhibition ion was attacked with high selectivity electrostatic stabilization of the positive CARB-96 (2014); http://go.nature.com/v67snk from the pseudoequatorial direction by charge at the anomeric center. The 6. Martin, A. et al. Nature Chem. 8, 186–191 (2016). 7. Crich, D., Dai, Z. & Gastaldi, S. J. Org. Chem. cyclohexane-d12, reflecting the importance fully protonated nature of the triacetyl- 64, 5224–5229 (1999). of the loosely bridging bromonium ion. 2-deoxyglucosyl oxocarbenium ion 8. Smith, D. M. & Woerpel, K. A. Org. Biomol. Chem. When methanol was employed as a precludes any such stabilization and 4, 1195–1201 (2006). nucleophile, a large excess was required results in the observed conformation that 9. Walvoort, M. T. C. et al. Carbohydr. Res. 345, 1252–1263 (2010). 10. Heuckendorff, M., Pedersen, C. M. & Bols, M. Chem. Eur. J. and selectivities were lower. This probably favours the pseudoequatorial placement 16, 13982–13994 (2010). reflects the reversible nature of the of the substituents. This fundamental 11. Adero, P. O. et al. J. Am. Chem. Soc. 137, 10336–10345 (2015).

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