Experimental and Theoretical Evidence of Through-Space Electrostatic Stabilization of the Incipient Oxocarbenium Ion by an Axially Oriented Electronegative Substituent During Glycopyranoside Acetolysis

Miljković, Momčilo; Yeagley, David; Deslongchamps, and Pierre; Dory, Yves L.

doi:10.1021/jo970677d

Cited by 145 publications

(141 citation statements)

References 18 publications

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“…These findings are in agreement with the findings of Miljkovic et al [29,30] who studied the acetolysis of methyl 2,3,4,6-tetra-O-methyl-α-and β-D-gluco-and galactopyranosides and found that α-D-galactopyranoside acetolyzed ca. 20 times faster than α-D-glucopyranoside.…”

Section: Stereoelectronic Effects Of Substituents: Polyhydroxylated Psupporting

confidence: 93%

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Armed-Disarmed Concept in the Synthesis of Glycosidic Bond

Miljković

2013

Electrostatic and Stereoelectronic Effects in Carbohydrate Chemistry

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-Reid et al. reported [1] that n-pentenyl glycosides undergo chemospecific cleavage 1 ! 2 ! 3, with N-bromosuccinimide under conditions that leave a wide variety of other protecting groups unaffected ( Fig. 5.1).According to the proposed mechanism ( Fig. 5.1), the addition of water to the reaction mixture will lead to hydrolysis but the addition of alcohol or another sugar having a free hydroxyl group will lead to the formation of glycoside or a disaccharide. In the course of these studies, Fraser-Reid et al. [1] observed that sugar molecules having an acyloxy group at the C2 carbon (6 in Fig. 5.2) hydrolyzed much more slowly than if they had an alkoxy group (7 in Fig. 5.2). This observation suggested that the n-pentenyl glycoside could be made more or less reactive (it could be armed or disarmed) by the type of protecting group placed on the C2 oxygen.The ability of the C2 acyloxy group to disarm the n-pentenyl glycoside was rationalized as shown in Fig. 5.3. Thus, it can be assumed that the cyclic halonium ions 8 and 9 are formed reversibly [2] and that the electron density on the glycosidic oxygen is depleted in 2-O-acyl derivatives so that nucleophilic attack of this oxygen on the halonium ion is less favored than in the 2-O-alkyl counterpart 9. The reason for this is that the electron-withdrawing group at the C2 carbon makes the C2 carbon slightly positively charged so that the formation of another positive charge at the C1 carbon is not a favorable process [there cannot exist two positive charges on two neighboring carbons (C1 and C2) (Fig. 5.3).].Consequently, the armed glycosyl donors react with electrophiles faster than the disarmed ones, and therefore in a solution containing both an armed and disarmed glycosyl donor molecules, whereby disarmed glycosyl donor molecules have one free hydroxyl group, the reaction with an electrophile will result in crosscoupling and not self-coupling, i.e., an armed glycosyl donor will react with the disarmed one, whereas a disarmed donor will not react with itself [3] as illustrated in Fig. 5.5. The promoters for the activation of n-pentenyl group [4,5] are iodonium dicollidine perchlorate (IDCP) and N-iodosuccinimide/triethylsilyl triflate (NIS/Et 3 SiOTf).M. Miljkovic, Electrostatic and Stereoelectronic Effects in Carbohydrate Chemistry,

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Section: Stereoelectronic Effects Of Substituents: Polyhydroxylated Psupporting

confidence: 93%

“…20 times faster than α-D-glucopyranoside. The influence of the electronegativity of the C4 substituent upon the rate of acetolysis was examined [30] by comparing the C4-OCH 3 with the C4-OAc and C4-NHAc substituent (see also Chap. 3).…”

Section: Stereoelectronic Effects Of Substituents: Polyhydroxylated Pmentioning

confidence: 99%

Armed-Disarmed Concept in the Synthesis of Glycosidic Bond

Miljković

2013

Electrostatic and Stereoelectronic Effects in Carbohydrate Chemistry

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“…The higher reactivity of galactosides in comparison with glucosides has also been reported. 25,31,32 The higher reactivity of galactose might be explained by assuming that the formation of an oxonium intermediate is the rate-determining step in these reactions.…”

Section: Resultsmentioning

confidence: 99%

Anomeric distinction and oxonium ion formation in acetylated glycosides

Denekamp

Sandlers

2005

J. Mass Spectrom.

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Collision-induced dissociation of ammonium-cationized alpha and beta acetyl pyranosidic isomers were studied and stereochemical dependence of the reactivity towards elimination of acetic acid from the anomeric position was found. It is shown that isomers that contain trans diacetyloxy groups at positions 1 and 2 of the pyranoside are more reactive, allowing anomeric distinction according to the relative abundance of the oxocarbenium product ion of this reaction in the spectrum. The higher reactivity of trans isomers is rationalized by neighboring group assistance that is possible only in the trans configuration. DFT calculations indicate that the lesser energetic reaction path occurs in an ammonium-cationized trans diequatorial 2,3-diacetoxy tetrahydropyran that was used as a model in order to study this process theoretically. It is also found that the configuration at position 4 of the carbohydrate plays a major role in the rate of formation and stability of oxocarbenium ions.

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“…Such an intermediate is commonly observed in the hydrolysis of glycans. [52][53][54][55] Moreover, using undamaged 2ʹ-deoxyuridine and 2ʹ-deoxycytidine, clear evidence was obtained that the N-glycosidic bond hydrolysis is mediated by the oxocarbenium ion pathway. 13 Although there were data supporting the involvement of a Schiff base intermediate resulting from the rupture of C1ʹ-O4ʹ bond (Route B, Figure 1), 11,12 such a route is not considered to contribute to the deglycosylation process.…”

Section: Discussionmentioning

confidence: 99%

Reactivity of Damaged Pyrimidines: Formation of a Schiff Base Intermediate at the Glycosidic Bond of Saturated Dihydrouridine

et al. 2015

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DNA glycosylases catalyze the first step of the base excision repair (BER) pathway. The chemistry used by these enzymes for deglycosylation has been largely considered as the chemistry of the oxocarbenium ion, e.g., direct rupture of the C1'-N1 bond resulting in an oxocarbenium ion intermediate. Here we present mechanistic studies revealing the 2'-deoxyribose isomerization and subsequent deglycosylation processes in two pyrimidine lesions: 5,6-dihydro-2'-deoxyuridine (dHdU) and 5,6-dihydrothymidine (dHT), formed via ionizing radiation damage to 2'-deoxycytidine and thymidine, respectively, under anoxic conditions. Acid or heat treatment of these two lesions leads to the production of two pairs of C1' epimers containing a pyranose and a furanose, respectively, indicating that both lesions favor the rupture of the C1'-O4' bond, resulting in a Schiff base intermediate at the N-glycosidic bond. Such a Schiff base intermediate was trapped and characterized by either Pd-catalyzed hydrogenation or thiol-mediated addition reaction. In contrast, in undamaged 2'-deoxyuridine and thymidine, reactions at elevated temperatures lead to the release of nucleobases most likely via the traditional oxocarbenium ion pathway. DFT calculations further support the experimental findings, suggesting that the oxocarbenium ion intermediate is responsible for the deglycosylation process if the integrity of the pyrimidine ring is maintained, while the Schiff base intermediate is preferred if the C5═C6 bond is saturated. Currently, the oxocarbenium ion pathway is indicated to be solely responsible for the deglycosylation in BER enzymes, however our results suggest an alternative Schiff base mechanism which may be responsible for the repair of saturated pyrimidine damages.

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Experimental and Theoretical Evidence of Through-Space Electrostatic Stabilization of the Incipient Oxocarbenium Ion by an Axially Oriented Electronegative Substituent During Glycopyranoside Acetolysis

Cited by 145 publications

References 18 publications

Armed-Disarmed Concept in the Synthesis of Glycosidic Bond

Armed-Disarmed Concept in the Synthesis of Glycosidic Bond

Anomeric distinction and oxonium ion formation in acetylated glycosides

Reactivity of Damaged Pyrimidines: Formation of a Schiff Base Intermediate at the Glycosidic Bond of Saturated Dihydrouridine

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