On the nature of the electronic effect of multiple hydroxyl groups in the 6-membered ring – the effects are additive but steric hindrance plays a role too

Abstract

Research during the last two decades has shown a remarkable directional component of the substituent effects of hydroxy groups, which has a profound effect on the properties of hydroxylated compounds such as carbohydrates. While the epimerisation of a single hydroxyl function is well studied the consequence of multiple epimerisations is more speculative. In this work the effect of three epimerisations was investigated. To this end epimeric 2-phenyl iminoxylitols that have a phenyl group as a conformational anchor and thus hydroxyl groups in the axial or equatorial position, respectively, were synthesized and their pK and conformation were studied. The results show that the large difference in the electronic effect between the axial and equatorial hydroxyls is partially cancelled by counteracting steric hindrance from 1,3-diaxial interactions. Hydrogen bonding does not appear to play any role in the electronic influence of the hydroxyl groups.

The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1–SN2 Interface

“…105 Finally, it was demonstrated that while the stabilizing ability of multiple axial hydroxyl groups for positive charge in piperidinium ions, and by extrapolation glycosyl oxocarbenium ions, is approximately additive, steric interactions between multiple axial groups eventually intervene to limit the effect. 106…”

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

“…Although steric effects are often decisive in determining the overall shape of a neutral molecule, in charged molecules electronic effects become more important and they may in fact outweigh steric effects. For example, protonated iminosugars, that is, carbohydrates having the endocyclic oxygen replaced by a nitrogen, may change their conformation to place their ring substituents in a sterically unfavourable (pseudo)‐axial orientation to stabilise the positive charge on the ring nitrogen . In line with these stereoelectronic effects, glycosyl donors that feature an “axial‐rich” substitution pattern, are generally more reactive than glycosyl donors equipped with equatorially disposed functional groups .…”

“…For example, protonatedi minosugars, that is, carbohydrates having the endocyclic oxygen replaced by an itrogen, may change their conformation to place their ring substituents in as terically unfavourable (pseudo)-axial orientation to stabilise the positive charge on the ring nitrogen. [5][6][7][8][9][10] In line with these stereoelectronic effects, glycosyl donors that feature an "axial-rich" substitution pattern, are generally more reactive than glycosyl donors equipped with equatorially disposed functional groups. [11][12][13] However,i ti se xtremelyc hallenging to understand-leta lone predict-what the overall effect of multiple ring substituents is on the reactivity of ap articularg lycosyl donor and as ar esult the effect on the stereoselectivity in ag lycosylation reaction.…”

“…Understanding these effects will enable the development of effective glycosylation methodologies and aid in the interpretation of the outcome of glycosylation reactions. We have studied the effect of C2‐fluoride and C2‐azide substituents, as well as C4‐carboxylic acid ester groups, as these functionalities are commonly employed in the assembly of fluorinated, cis ‐linked glycosamine‐containing or glycuronic acid‐featuring oligosaccharides, respectively …”

Determination of protonation states of iminosugar–enzyme complexes using photoinduced electron transfer

“…The p K a values of 6 , 12 and 15 of 5.15, 5.24 and 5.92 are rather low compared to 1 (p K a 6.7). This is caused by steric hindrance versus protonation in the tertiary amine, and the inductive effect from the aromatic system (the electron withdrawing influence of a benzyl group is 1.3 pH units 21 ), which is obviously larger when the chloroanthracene is closer to the amine.…”