Matching Glycosyl Donor Reactivity to Sulfonate Leaving Group Ability Permits S_N2 Glycosylations

Abstract

Here we demonstrate that highly β-selective glycosylation reactions can be achieved when the electronics of a sulfonyl chloride activator and the reactivity of a glycosyl donor hemiacetal are matched. While these reactions are compatible with the acid- and base-sensitive protecting groups that are commonly used in oligosaccharide synthesis, these protecting groups are not relied upon to control selectivity. Instead, β-selectivity arises from the stereoinversion of an α-glycosyl arylsulfonate in an S N 2-like mechanism. Our mechanistic proposal is supported by NMR studies, kinetic isotope effect (KIE) measurements, and DFT calculations.

Versatile Glycosyl Sulfonates in β‐Selective C‐Glycosylation

“…Using Jacobsen and Kwan's modification of the Singleton procedure, we measured a KIE value of 1.029 for the reaction. This value is typical of S N 2‐like glycosylations, and is in line with values that have previously been reported by the Crich, Chan and Bennet, and our own groups …”

“…Nevertheless, we started our investigation of C‐glycosylation using acetophenone and perbenzylated glucose donor 1 a as the model system (Table ). On the basis of our previous studies, we opted to use 3,5‐bistrifluoromethylbenzenesulfonyl chloride (R= A ) as the promoter. We initially examined lithium and zinc enolates in order to minimize formation of the O‐alkylation product, but they proved to be ineffective nucleophiles (Entries 1–3).…”

Statistical Analysis of Glycosylation Reactions

“…However,w ithout these directing groups,t he development of glycosylation,e specially for 1,2-cis-glycoside, has been hampered by unpredictable stereoselectivity because the combination of donor and acceptor undergoes am echanism on the spectrum between the S N 1a nd S N 2p athways, and thus, leadingt oamixtureo fa-a nd b-glycosides. [6, 16c, 17] Figure 3d [17c-e] and Bennet [20] furthera pplied the cationic cyclization reactionand kinetic isotope effect (KIE) experiments to support such an S N 2-like mechanism.Because oxocarbenium ion 25 has as hort lifetime, since it is unstable and highly reactive, reports on 25 obtained through an S N 1-like mechanism are relatively few.…”

“…However, it is a very difficult process because glycosyl intermediates are usually acid labile and can easily decompose into side products [16c,d] . Recently, the comprehensive analysis of covalent intermediate 9 through low‐temperature NMR spectroscopy was reported by the groups of Crich, [16c, 17a–c] Yoshida, [19] Bennet, [20] Codée, [6, 21] and Asensio [22] . The in‐depth structural analysis of counterion 11 was further conducted by the groups of Seeberger, [12c, 23] Pagel, [12c, 23, 24] Codée [25] and Boltje [25, 26] through mass spectrometry in combination with collision‐induced dissociation (CID) and IR ion spectroscopy.…”

Single‐Step Glycosylations with 13C‐Labelled Sulfoxide Donors: A Low‐Temperature NMR Cartography of the Distinguishing Mechanistic Intermediates

“…These reactions involve the coupling of a glycosyl donor and an acceptor, and are the central transformation in saccharide synthesis. More recently, it has also become clear that a better understanding of the mechanistic aspects of the glycosylation process can contribute to its optimisation in terms of yield and stereoselectivity [5–11] . A case in point in this regard has been Crich's β‐mannosylation reaction, one of the best‐studied glycosylations to date [12, 13] .…”