Special Issue on "Synthetic Carbohydrate Chemistry" J. Indian Chem. Soc., Vol. 97, February 2020, pp. 135-156 Aspects of chemical transglycosylations in modern glycoside synthesis† Anupama Das and N. Jayaraman* Department of Organic Chemistry, Indian Institute of Science, Bangalore- 560 012, India E-mail: [email protected] Manuscript received online 08 November 2019, revised and accepted 23 December 2019 Application of chemical methods forms as a powerful approach to achieve synthesis of custom-designed oligosaccharides. Chemical glycosylation methods continue to evolve till date even when the first such method dates back more than a century ago. The recent past has witnessed the emergence of the transglycosylations, wherein a preponderant O-glycoside acts as a glycosyl donor to afford yet another O-glycoside product bearing the newly introduced glycan/aglycan at the reducing end. Critical requirements of the aglycan portion of a glycoside donor are discussed, as also the mechanistic formulations based on a set of experimental observations. A critical review of the expanding facets of transglycosylations in the garb of modern glycosylation methods is presented herein. Keywords: Carbohydrates, conformations, glycosylations, oligosaccharides, oxocarbenium ion. 1. Introduction of the anomeric substituent as the leaving moiety. The re- Chemical glycosylations constitute to be one of the ma- sulting oxocarbenium ion acts as the reactive intermediate jor concurrent advancements in the general area in carbohy- to react with a glycosyl acceptor nucleophile and yield the drate chemistry1. Multiple hydroxyl groups containing sug- glycoside product. Chemical glycosylations to date practi- ars present a plethora of challenges at the outset, yet a judi- cally relied on the generation of the oxocarbenium ion as the cious underpinning of the reactivities of each hydroxyl groups intermediate. Although commendable efforts pertain to the also provides a facile route to implement chosen reactions recent reports of endocylic oxygen cleavage and on such sugar scaffolds. One of the earliest reactions of sug- anomerization as fruitful approaches to alter anomeric ste- 7 ars is the so-called glycosylation, particularly involving the reochemistry of glycosides . Significant advancements in chemical methods. Fischer glycosylation in 18952 and glycosylation started to emerge from late 1980’s, advancing Koenigs-Knorr glycosylation in 19013 continue to be hall-mark chemical methods to conduct glycosylations using a number reactions benefitting their applications in glycoside synthe- of reagents and reaction conditions. These advancements sis. Improvements on these very early methods add further helped not only to increase the arsenal of methods for values and these reactions are practiced rather routinely glycosylations under varying substrate conditions, but also through the improved chemical methods, examples of such to uncover the finer details of the glycosylation reactions. improvements are the Helferich condition in 1930’s4 and Further, elegant developments relating to glycosylation re- Hanessian-Banoub method5 of glycosylations, reported in actions to be conducted under solid-phase methods have 1977. A major change in the outlook of chemical emerged, leading to secure oligomeric glycosides in a facile 8 glycosylations can be attributed to the early establishing of manner and in a short duration . Excellent reviews on gen- thioglycosides as a versatile glycosyl donor by Lönn, and eral glycosylation reactions can be referred to many articles 9–11 Garegg and Fügedi in mid-1980’s6. An imminent understand- that appear in the recent years . ing is the control of chemical glycosylations under the Glycosylations in natural systems eminently adopt en- oxocarbenium or the glycosyl cation manifold, upon removal zymes as a source to catalyze the reaction, bringing together †Review. 135 J. Indian Chem. Soc., Vol. 97, February 2020 reactivities between the glycosyl donor and acceptor to af- being identified continuously. A major focus in glycosylation ford the glycoside. Glycosyl transferases and glycosyl hy- reactions is the generation of the oxocarbenium ion or glyco- drolases are two classes of enzymes that catalyze the syl cation intermediate from the glycosyl donor under the glycosylation reactions. Within these enzymes, requirements reaction conditions and the reactivity of this intermediate with of nucleotide factors in the case of glycosyl transferases, incoming alcohols as nucleophiles, leading to the glycoside and favorable thermodynamic equilibrium in the case of gly- bond formation. Generation of this intermediate with the es- cosyl hydrolases are stringent. Excellent reviews are referred timated lifetime of >2.5×10–12 s in aq. solution bears greater to read through the enzyme-mediated glycosylations12–14. relevance and importance in glycosylation reaction in gen- 15 A defining feature of chemical glycosylations is the ability eral . to generate the oxocarbenium ion as the reactive partner to Although the generation of the oxocarbenium ion forms react with acceptor nucleophile. Stringent requirements fur- the key step of a glycosylation, conformational preferences ther are the activator of the glycosyl donor, promoter of the of this species possess a crucial role in the stereochemical reaction, temperature, solvent, presence of molecular sieves outcome of the glycosylation, along with factors as that aris- and above all, the nature of protecting groups in the reactive ing from reactivities of individual hydroxyl moieties, protect- partners. Paulsen’s statement1 in 1982 that there is no single ing groups, reagents, promoters, temperature and solvent reagent or reaction condition that allow glycosylations on the polarity. Few salient aspects of these controls on glycosylation varieties of glycosyl donors and acceptors to secure assort- are discussed below briefly. ment of glycosides still stands largely true. Concerning the oxocarbenium ion generation in the pres- Within the preamble of the present article, chemical ence of triflate promoter, the work of Hosoya and co-workers transglycosylations are considered as a viable and fruitful demonstrates further that intermediate species in the form approach to conduct glycosylations, having the merits that of / contact ion pairs (CIP) (I, II and V) or solvent sepa- are otherwise un-available through other types of chemical rated ion pairs (SSIP) (III and IV) form and these species glycosylations. Herein, a transglycosylation refers to the re- equilibrate with one another in the solution phase between 16,17 actions wherein a glycosyl donor is an O-glycoside, which anomeric triflates 1a and 1b (Fig. 1) . reacts with the hydroxyl moiety in a glycosyl/aglycosyl ac- Inducing conformational constraints in the oxocarbenium ceptor and affords the newly formed O-glycoside. ion species through bicyclic formation: Inducing conforma- tional constraints onto the oxocarbenium ion species through 2.1. Relevance of oxocarbenium ion protecting groups, particularly benzylidene acetal, leads the Chemical glycosylations are warranted immensely, in or- species to be bicyclic in nature. This approach of conforma- der to secure homogeneous oligosaccharides and their con- tional constraints was systematically studied by Crich and jugates of biological importance. Chemical glycosylation co-workers, in order to ascertain the conformational equilib- methodologies are improved upon and newer methods are rium associated with the oxocarbenium ion. Among gluco- Fig. 1. Oxocarbenium ion equilibration in the CIP, SSIP and covalent forms in the presence of triflate promoter16,17. 136 Das et al.: Aspects of chemical transglycosylations in modern glycoside synthesis and mannopyranose derived oxocarbenium ions, having the oxocarbenium ion, the antiperiplanarity of the C2-O bond benzylidene acetal, the axial-orientation of the hydroxyl moi- would block the equatorial (-) face at C-1 anomeric carbon, ety in mannopyranose-derived intermediate species shifted thereby the axial (-) attack at C-1 carbon by the nucleo- the covalent triflate-CIP-SSIP equilibria towards the cova- phile become feasible, in the course of the formation of the lent intermediate, resulting in a high -selectivity of the gly- glycoside product with the chair conformation. Whereas cosidic bond. As a corollary, glucopyranose-derived mannosyl oxocarbenium ion species adopts B2,5 conforma- oxocarbenium ion species, having the equatorial hydroxyl tion and projects the C2-O bond in the -face, lying moiety at C-2 carbon, shifted the equilibrium far away from antiperiplanar to the bond. As a result, the nucleophilic at- the covalent triflate18. tack occurs through the -face, resulting in the glycoside 1 The stereoselectivity observed in the O- and C- with an initial S5 conformation (7). glycosylation of gluco- and mannopyranosides having 4,6- Blériot and co-workers used superacid HF/SbF5 on O-benzylidene moiety was evaluated by invoking the bent peracetate-protected 2-deoxy sugars 8 and 10, in an attempt bond model, advanced by Deslongchamps and co-workers19. to monitor the oxocarbenium formation (Scheme 1), during 4 The model predicts that H3 (Gluco-2) (Fig. 2) conformation the formation of the corresponding methyl glycosides 9 and evolves on the oxocarbenium ion having the gluco-configu- 1120,21. Under the conditions, the oxocarbenium ion was 1 13 ration, whereas that in manno-configured species is the B2,5 stable at room temperature, the corresponding H and C conformation