Influence of 3‐Thio Substituents on Benzylidene‐Directed Mannosylation. Isolation of a Bridged Pyridinium Ion and Effects of 3‐O‐Picolyl and 3‐S‐Picolyl Esters

Abstract

The influence on glycosyl selectivity of substituting oxygen for sulfur at the 3-position of 4,6-O-benzylidene-protected mannopyranosyl thioglycosides is reported and varies considerably according to the protecting group employed at the 3-position. The substitution of a thioether at the 3-position for the more usual 3-O-benzyl ether results in a significant loss of selectivity. The installation of a 3-S-picolinyl thioether results in a complex reaction mixture, from which a stable seven-membered bridged bicyclic pyridinium ion is isolated, while the corresponding 3-Opicolinyl ether affords a highly α-selective coupling reaction. A 3-O-picolyl ester provides excellent β-selectivity, while the analogous 3-S-picolyl thioester gives a highly α-selective reaction. The best β-selectivity is seen with a 3-deoxy-3-(2pyridinyldisulfanyl) system. These observations are discussed in terms of the influence of the various substituents on the central glycosyl triflate -ion pair equilibrium.

Detection and Characterization of Rapidly Equilibrating Glycosylation Reaction Intermediates Using Exchange NMR

“…The existence of this intermediate has long been debated but was never characterized. 5,65,14,55 However, the experiments reported herein now support the formation of 8 d as the chemical shift, triflate order, and glycosylation stereoselectivity all support its existence and role as a product-forming intermediate (Figure 7).…”

“…An example of this principle is neighboring group participation (NGP) of an acyl group at the C-2 position affording a bicyclic dioxolanium ion intermediate 3 that reacts in a stereospecific manner with a glycosyl acceptor to afford a 1,2- trans product (Figure A). − Extension of this principle to acyl functionalities positioned on the C-3, C-4, or C-6 hydroxyl groups via NGP has also been suggested to direct the stereoselectivity of glycosylation reactions. However, whether selectivity can be attributed to NGP of the acyl group or other stereoelectronic effects is a subject of much debate. − The second main strategy utilizes glycosyl donors that contain protecting groups that are less capable of neighboring group participation, e.g., benzyl ethers. In this case, the glycosyl cation is trapped by the promotor system counterion or a solvent additive to afford quasi- stable intermediates that can be displaced in an S N 2-like reaction pathway to afford a glycosylation product. − Most modern promotor systems give rise to the formation of glycosyl triflates and since these covalent adducts can exist in the α- ( 1 ) or β-form ( 6 ), reactions proceeding via these intermediates can in principle form the β- or α-product via an S N 2-like reaction pathway, respectively. , The nucleophilic displacement of α-glycosyl triflates 1 is likely to take place via an intermediate α-contact ion pair (CIP) 2 which maintains its stereochemical memory to form the β-product .…”

Can Side-Chain Conformation and Glycosylation Selectivity of Hexopyranosyl Donors Be Controlled with a Dummy Ligand?

“…Tables and provide illustrative examples of desulfurization with Raney nickel achieved concomitantly with hydrogenolysis of the benzyl groups. − The reactions were carried out in ethanol under 1 atm of hydrogen at room temperature and gave the desired products in good yields.…”

“…58 White amorphous solid. Adamantyl α-D-Glucopyranoside (39). Obtained from the deprotection of compound 27α (16.7 mg) using the general procedure for desulfurization eluting from silica gel with 10% MeOH in CH 2 Cl 2 to give 4.3 mg for a 64% yield.…”

Recent advances in stereoselective 1,2-cis-O-glycosylations

“…The protective group with hydrogen-bonding property such as picolinyl and picoloyl groups (Figure 2A2) (Pistorio et al, 2014;Alex et al, 2020) acts as the stereo-directing group for 1,2cis glycosylation (Loh, 2021;recent review, Khanam and Mandal, 2022), which can also be applied to selective βarabinofuranosylation and synthesis of natual prodiuct such as Tiacumicin B (Norsikian et al, 2020;Tresse et al, 2021). The direct intramolecular neighboring and remote group participation of these groups to glycosyl cation led to the trans-glycosylation of the substituents as well (Yasomanee and Demchenko, 2012;McMillan and Crich, 2022).…”