Armed–Disarmed Effects in Carbohydrate Chemistry: History, Synthetic and Mechanistic Studies

Abstract

This chapter begins with an account of the serendipitous events that led to the development of n-pentenyl glycosides (NPGs) as glycosyl donors, followed by the chance events that laid the foundation for the armed-disarmed strategy for oligosaccharide assembly. A key mechanistic issue for this strategy was that, although both armed and disarmed entities could function independently as glycosyl donors, when one was forced to compete with the other for one equivalent of a halonium ion, the disarmed partner was found to function as a glycosyl acceptor. The phenomenon was undoubtedly based on reactivity, but further insight came unexpectedly. Curiosity prompted an examination of how ω-alkenyl glycosides, other than n-pentenyl, would behave. Upon treatment with wet N-bromosuccinimide, allyl, butenyl, and hexenyl glucosides gave bromohydrins, whereas the pentenyl analog underwent oxidative hydrolysis to a hemiacetal. Although the answer was definitive, an in depth comparison of n-pentenyl and n-hexenyl glucosides was carried out which provided evidence in support of the transfer of cyclic bromonium ion between alkenes in a steady-state phenomenon. It was found that for two ω-alkenyl glycosides having a relative reactivity ratio of only 2.6:1, nondegenerate bromonium transfer enabled the faster reacting entity to be converted completely to product, while the slower reacting counterpart was recovered completely. This nuance suggests that in the armed/disarmed coupling, such a nondegenerate steady-state transfer is ultimately responsible for determining how the reactants are relegated to donor or acceptor roles.Development of chemoselective armed/disarmed coupling led to another phase in the sequence of serendipities. During experiments to glycosylate an acceptor diol, it was found that armed and disarmed donor's glycosylated different hydroxyl groups. This observation caused us to embark on studies of regioselective glycosylation. One of these studies showed that it is possible to activate selectively n-pentenyl orthoesters (NPOEs) over other n-pentenyl donors, and that this chemoselective process enables regioselective glycosylation. As a result, reaction partners can be so tuned that glycosylation of an acceptor with nine free hydroxyl groups by an n-pentenyl orthoester donor carrying two free hydroxyl groups is able to furnish a single product in 42% yield. Experiments such as the latter suggest that the donor favors a particular hydroxyl group, and/or that a particular hydroxyl favors the donor. Either option implies that the principle of reciprocal donor acceptor selectivity (RDAS) is in operation.Such examples of regioselective glycosylation provide an alternative to the traditional practice of multiple protection/deprotection events to ensure that the only free hydroxyl group among glycosyl partners is the one to be presented to the donor. By avoiding such protection/deprotections, there can be substantial savings of time and material - as well as nervous anxiety.

A propos of glycosyl cations and the mechanism of chemical glycosylation; the current state of the art

“…It is becoming increasingly apparent that protecting groups can significantly affect the reactivity through their influence on the conformation of the donor and/or the incipient glycosyl oxocarbenium ion in addition to their more widely appreciated 35 disarming effects arising from their electron-withdrawing ability. Extreme examples of this phenomenon are to be found in the super-armed donors reported by the Bols 36 and Yamada 37–38 groups employing multiple silyl ethers, whose high degree of reactivity is consistent with the enforcement of conformations containing multiple axial or pseudoaxial C-O known 39–41 to be capable of stabilizing oxocarbenium ions while at the same time providing differential steric shielding of the α- and β-faces.…”

“…Indeed, glycosyl bromides and glycosyl iodides are frequently stable isolable substances at room temperature in the absence of moisture (pKa of HBr and HI: −9, −9.5, respectively). 74 In this context it is pertinent to note that the pKa of triflic acid, one of the strongest acids known, is ~−12 74 and that, as covalently bound glycosyl triflates have been amply demonstrated, 34–35,37–38 any anion whose conjugate acid is less acidic than triflic acid will form observable covalent glycosyl adducts unless prevented from doing so by pervasive steric factors. Indeed, silver perchlorate is (HClO 4 pKa ~−10) 75 has been known since 1970 to form covalent glycosyl perchlorates on reaction with 3,4,6-tri- O -acetyl-2-chloro-2-deoxy gluco- and mannopyranosyl chloride.…”

Interplay of Protecting Groups and Side Chain Conformation in Glycopyranosides. Modulation of the Influence of Remote Substituents on Glycosylation?

“…6 The influence of protecting groups on the anomeric reactivity of glycosyl donors also is broadly appreciated, with the more electron-withdrawing (or disarming) esters retarding reaction rates compared to the less electron-withdrawing (or arming) ethers. 6−11 …”

Two‐Step Functionalization of Oligosaccharides Using Glycosyl Iodide and Trimethylene Oxide and Its Applications to Multivalent Glycoconjugates

“…Per- O -acetylated glycosyl iodides have been shown to survive aqueous extractions, column chromatography, and are even so stable that X-ray crystal structures have been obtained. [15] The “disarmed” [16] nature of ester-protected glycosyl iodides necessitates using a promoter (Lewis acids or metals) or heat to afford reasonable yields of the glycosylation products. In addition, C-2 ester-protected glycosyl donors often form orthoesters as a side reaction.…”