Remote Electronic Effects by Ether Protecting Groups Fine-Tune Glycosyl Donor Reactivity

Abstract

It was established that para-substituted benzyl ether protecting groups affect the reactivity of glycosyl donors of the thioglycoside type with the N-iodosuccinimide/triflic acid promoter system. Having electron donating p-methoxybenzyl ether (PMB) groups increased the reactivity of the donor in comparison to having electron withdrawing p-chloro (PClB) or p-cyanobenzyl ether (PCNB) protecting groups, which decreased the reactivity of the glycosyl donor relative to the parent benzyl ether (Bn) protected glycosyl donor. These findings were used to perform the first armed-disarmed coupling between two benzylated glucosyl donors by tuning their reactivity. In addition, the present work describes a highly efficient palladium catalyzed multiple cyanation and methoxylation of p-chlorobenzyl protected thioglycosides. The results of this paper regarding both the different electron withdrawing properties of various benzyl ethers and the efficient and multiple protecting group transformations are applicable in general organic chemistry and not restricted to carbohydrate chemistry.

β‐Selective Glycosylation by Using O‐Aryl‐Protected Glycosyl Donors

“…Jensen and co-workersr eported the effect of para-substituted benzyl-type protecting groups on the reactivity of thioglycoside glycosyl donors. [15] They found that glycosyl donors that contained electron-donatings ubstituents showed higher reactivities than those that contained electron-withdrawing substituents, whereas the b-selectivity decreased following protection with substituted benzylg roups that contained electron-withdrawing groups.N otably,o ur resultse xhibited the opposite tendency,t hat is, the glycosyl donor that contained NP groups exhibited the highest b-selectivity.…”

Gold-catalyzed synthesis of α-D-glucosides using an o-ethynylphenyl β-D-1-thioglucoside donor

“…We reasoned that modifying this system might render this type of activation suitable for S N 2-type glycosylation and hence could circumvent those drawbacks (Scheme 2b). Firstly, we proposed to replace the donor benzyl protecting groups with more electron- withdrawing 4-chlorobenzyl groups (PCB), [39] aiming to inductively discourage the formation of oxocarbenium intermediate B . Secondly, we would employ (2-ethynylphenyl)thio group, which differs from Yu’s version by the absence of alkyne terminus substituent, as the latent leaving group to 1) decrease the steric hindrance around the sulfur in the activated donor A , which should discourage the expulsion of the benzothiophene, and 2) ensure a faster gold- catalyzed cyclization reaction.…”

On the Gluco/Manno Paradox: Practical α‐Glucosylations by NIS/TfOH Activation of 4,6‐O‐Tethered Thioglucoside Donors

“…In spite of the anomeric effect, highly α‐selective glucosylations are not easy to achieve. Contrary to Fischer glycosylation conditions with simple alcohols like methanol, glycosylation reactions leading to oligosaccharides are often conducted under kinetic control; the kinetic products of glucosylation are typically the equatorial product , . Several methods for selective synthesis of α‐glucosides have been developed over the years.…”

“…Contrary to Fischer glycosylation conditions with simple alcohols like methanol, glycosylation reactions leading to oligosaccharides are often conducted under kinetic control; the kinetic products of glucosylation are typically the equatorial product. [2,3] Several methods for selective synthesis of α-glucosides have been developed over the years. Among the most famous of these approaches are: i) in-situ anomerization by Lemieux [4] & Gervay-Hague, [5] ii) intermolecular aglycon delivery by Hindsgaul, Stork and Bols, [6] iii) the use of auxiliaries by Boons, Fairbanks and Turnbull, [7] iv) hydrogen bond-mediated aglycon delivery by Demchenko, [8] and v) the Crich α-glucosylation reaction.…”

“…The organic layer was dried with MgSO 4 , filtered and the solvents evaporated to dryness. The crude product was purified by flash column chromatography with pentane as eluent with a gradient of CH2 Cl 2 , giving the product as a clear syrup, yield 1.20 g, 81 % R f = 0.22 (pentane/EtOAc, 30:1). [α] D r.t. = -23 (c = 1, CHCl 3 ).…”