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

A critical review of the state-of-the-art evidence in support of the mechanisms of glycosylation reactions is provided. Factors affecting the stability of putative oxocarbenium ions as intermediates at the SN1 end of the mechanistic continuum are first surveyed before the evidence, spectroscopic and indirect, for the existence of such species on the time scale of glycosylation reactions is presented. Current models for diastereoselectivity in nucleophilic attack on oxocarbenium ions are then described. Evidence in support of the intermediacy of activated covalent glycosyl donors is reviewed, before the influences of the structure of the nucleophile, of the solvent, of temperature, and of donor-acceptor hydrogen bonding on the mechanism of glycosylation reactions are surveyed. Studies on the kinetics of glycosylation reactions and the use of kinetic isotope effects for the determination of transition-state structure are presented, before computational models are finally surveyed. The review concludes with a critical appraisal of the state of the art.

Trifluoromethanesulfonate Anion as Nucleophile in Organic Chemistry.

Although the triflate ion is not generally perceived as a nucleophile, many examples of its behavior as such exist in the literature. This Synopsis presents an overview of such reactions, in which triflate may be either a stoichiometric or catalytic nucleophile, leading to the suggestion that nucleophilic catalysis by triflate may be more common than generally accepted, albeit hidden by the typical reactivity of organic triflates which complicates their observation as intermediates.

Further studies on cation clock reactions in glycosylation: observation of a configuration specific intramolecular sulfenyl transfer and isolation and characterization of a tricyclic acetal.

The use of the 2-O-(2-trimethylsilylmethallyl) group as intramolecular nucleophile and cation clock reaction in the glucopyranose series depends on the nature of the glycosyl donor. As previously reported, with trichloroacetimidates the anticipated intramolecular Sakurai reaction proceeds efficiently and is an effective clock, whereas with sulfoxides complications arise. The source of these complications is now shown to be an intramolecular sulfenyl transfer reaction between the tethered allylsilane and the activated sulfoxide. These results illustrate how a different unimolecular clock reaction may be required for a given cation when it is generated from different donors in order to avoid side reactions. The synthesis and cyclization of a 2-O-(3-hydroxypropyl) glucopyranosyl sulfoxide leading on activation to the formation of a trans-fused acetal is also described. The formation of this crystallographically-established trans-fused acetal is discussed in terms of the high effective concentration of the intramolecular nucleophile which leads to a high degree of a SN2 character in the displacement of the α-glucosyl triflate or at the level of the corresponding α-CIP. The possible use of such intramolecular alcohols as clock reactions and their limitations is discussed.

Cation Clock Reactions for the Determination of Relative Reaction Kinetics in Glycosylation Reactions: Applications to Gluco- and Mannopyranosyl Sulfoxide and Trichloroacetimidate Type Donors.

The development of a cation clock method based on the intramolecular Sakurai reaction for probing the concentration dependence of the nucleophile in glycosylation reactions is described. The method is developed for the sulfoxide and trichloroacetimidate glycosylation protocols. The method reveals that O-glycosylation reactions have stronger concentration dependencies than C-glycosylation reactions consistent with a more associative, S(N)2-like character. For the 4,6-O-benzylidene-directed mannosylation reaction a significant difference in concentration dependence is found for the formation of the ß- and α-anomers, suggesting a difference in mechanism and a rationale for the optimization of selectivity regardless of the type of donor employed. In the mannose series the cyclization reaction employed as clock results in the formation of cis and trans-fused oxabicyclo[4,4,0]decanes as products with the latter being strongly indicative of the involvement of a conformationally mobile transient glycosyl oxocarbenium ion. With identical protecting group arrays cyclization in the glucopyranose series is more rapid than in the mannopyranose manifold. The potential application of related clock reactions in other carbenium ion-based branches of organic synthesis is considered.

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

An overview of recent advances in glycosylation with particular emphasis on mechanism is presented. The mounting evidence for both the existence of glycosyl oxocarbenium ions as fleeting intermediates in some reactions, and the crucial role of the associated counterion in others is discussed. The extremes of the SN1 and SN2 manifolds for the glycosylation reaction are bridged by a continuum of mechanisms in which it appears likely that most examples are located.

Cation clock permits distinction between the mechanisms of α- and ß-O- and ß-C-glycosylation in the mannopyranose series: evidence for the existence of a mannopyranosyl oxocarbenium ion.

The use of a cationic cyclization reaction as a probe of the glycosylation mechanism has been developed and applied to the 4,6-O-benzylidene-protected mannopyranoside system. Cyclization results in the formation of both cis- and trans-fused tricyclic systems, invoking an intermediate glycosyl oxocarbenium ion reacting through a boat conformation. Competition reactions with isopropanol and trimethyl(methallyl)silane are interpreted as indicating that ß-O-mannosylation proceeds via an associative S(N)2-like mechanism, whereas α-O-mannosylation and ß-C-mannosylation are dissociative and S(N)1-like. Relative rate constants for reactions going via a common intermediate can be estimated.

Dissecting the mechanisms of a class of chemical glycosylation using primary ¹³C kinetic isotope effects.

Although arguably the most important reaction in glycoscience, chemical glycosylations are among the least well understood of organic chemical reactions, resulting in an unnecessarily high degree of empiricism and a brake on rational development in this critical area. To address this problem, primary (13)C kinetic isotope effects have now been determined for the formation of ß- and α-manno- and glucopyranosides using a natural abundance NMR method. In contrast to the common current assumption, for three of the four cases studied the experimental and computed values are indicative of associative displacement of the intermediate covalent glycosyl trifluoromethanesulfonates. For the formation of the α-mannopyranosides, the experimentally determined KIE differs significantly from that computed for an associative displacement, which is strongly suggestive of a dissociative mechanism that approaches the intermediacy of a glycosyl oxocarbenium ion. The application of analogous experiments to other glycosylation systems should shed further light on their mechanisms and thus assist in the design of better reactions conditions with improved stereoselectivity.

Influence of protecting groups on the anomeric equilibrium; case of the 4,6-O-benzylidene acetal in the mannopyranose series.

It is reported that the replacement of the 4- and 6-O-benzyl ethers in 2,3,4,6-tetra-O-benzyl-α,ß-mannopyranose by a 4,6-O-benzylidene acetal results in an increased population of the ß-anomer at equilibrium in CDCl(3) solution. The phenomenon is considered to arise from the lower steric bulk of the benzylidene acetal that, through diminished buttressing interactions, reduces steric interactions normally present in the ß-anomer.

2-Hydr-oxy-3,3-dimethyl-7-nitro-3,4-dihydro-isoquinolin-1(2H)-one.

In the title compound, C(11)H(12)N(2)O(4), a new hydroxamic acid which belonging to the isoquinole family, the heterocyclic ring adopts a half-chair conformation. The nitro group is essentially coplanar with the aromatic ring. Inter-molecular O-H⋯O hydrogen bonds assemble the mol-ecules around inversion centres to form pseudo-dimers.