Probing the Influence of Protecting Groups on the Anomeric Equilibrium in Sialic Acid Glycosides with the Persistent Radical Effect

Abstract

A method for the investigation of the influence of protecting groups on the anomeric equilibrium in the sialic acid glycosides has been developed on the basis of the equilibration of O-sialyl hydroxylamines by reversible homolytic scission of the glycosidic bond following the dictates of the Fischer–Ingold persistent radical effect. It is found that a trans-fused 4O,5N-oxazolidinone group stabilizes the equatorial glycoside, i.e., reduces the anomeric effect, when compared to the 4O,5N-diacetyl protected systems. This effect is discussed in terms of the powerful electron-withdrawing nature of the oxazolidinone system, which in turn is a function of its strong dipole moment in the mean plane of the pyranose ring system. The new equilibration method displays a small solvent effect and is most pronounced in less polar media consistent with the anomeric effect in general. The unusual (for anomeric radicals) poor kinetic selectivity of anomeric sialyl radicals is discussed in terms of the planar π-type structure of these radicals and of competing 1,3-diaxial interactions in the diastereomeric transition states for trapping on the α- and β-faces of the radical.

Synthesis of Bridged Diketopiperazines by Using the Persistent Radical Effect and a Formal Synthesis of Bicyclomycin

“…Herein, we present a unified, practical, general, and conceptually new radical approach to diverse bridged DKPs. Central is the facile and reversible thermal bond homolysis of hitherto unknown alkoxyamines 8 to generate captodatively stabilized transient DKP radicals 10 and the persistent radical TEMPO ( 9 ; Scheme ) 18. This degenerative process confers a sufficiently long lifetime for radical 10 to undergo irreversible endo or exo cyclizations to pendant alkene units depending on the tether length and substitution pattern, thereby steering the equilibrium to the bridged DKP products.…”

“…Although the utility of the PRE was recognized from the onset in polymer research, its application in organic chemistry was neglected until Studers seminal studies adecade ago. [18] This degenerative process confers as ufficiently long lifetime for radical 10 to undergo irreversible endo or exo cyclizations to pendant alkene units depending on the tether length and substitution pattern, thereby steering the equilibrium to the bridged DKP products. [16] Given the importance of bridged DKPs and the recent growth of interest in three-dimensional heterocyclic architectures in medicinal chemistry, [1,17] methods that allow rapid access to diverse bridged DKP motives are highly desired.…”

Unique Stereoselective Homolytic C−O Bond Activation in Diketopiperazine‐Derived Alkoxyamines by Adjacent Amide Pyramidalization

“…Only sterically very crowded SG1‐derived alkoxyamines 9 equilibrated up to a 6:1 mixture if a 1:1 diastereomeric mixture or the individual diastereomers was heated at 100 °C. The most promising examples for directed isomerizations have so far proven to be cyclic sialic acid derived anomeric alkoxyamines 11 , recently reported by Crich, providing a 7:1 ratio of α/β anomers at 90 °C depending on the protecting groups . Alkoxyamines 11 are also interesting in that the nitroxide unit is attached to a natural product core structure, providing the bias, but it shows that a simple cyclic constraint as in 11 is not sufficient to induce complete isomerization.…”

“…The most promising examples for directed isomerizationsh ave so far provent o be cyclic sialic acid derived anomeric alkoxyamines 11,r ecently reported by Crich, providinga7:1r atio of a/b anomers at 90 8Cd epending on the protecting groups. [70,71] Alkoxyamines 11 are also interesting in that the nitroxide unit is attached to an atural product core structure, providing the bias, buti t shows that as imple cyclic constraint as in 11 is not sufficient to induce complete isomerization. However,c ombining the cyclic constraint with the strain induced by amide distortion in DKP alkoxyamines (Figure 10 B) provides the necessary driving force for au nidirectionalt hree-point redox-fueleds witching system based on central chirality (see Figure 9).…”

Synthese überbrückter Diketopiperazine mit Hilfe des persistenten Radikaleffekts und eine formale Synthese von Bicyclomycin

“…Wirpräsentieren hier einen praktischen, breit anwendbaren und konzeptionell neuen radikalischen Zugang zu vielfältigen überbrückten DKP.Z entral für den Erfolg ist die leichte und reversible Homolyse der bisher unbekannten Alkoxyamine 8 zur Erzeugung der captodativ stabilisierten, aber transienten DKP-Radikale 10 und des persistenten Radikals TEMPO (9, Schema 1). [18] Dieser degenerative Prozess verleiht dem Radikal 10 eine genügend lange Lebenszeit für irreversible,i n Abhängigkeit von der Spacerlänge und dem Substitutionsmuster mçgliche endo-o der exo-Cyclisierungen mit in den Vorstufen vorhandenen Alkeneinheiten. Damit wird das anfängliche Gleichgewicht zu den DKP-Produkten verschoben.…”