Defining the S_N1 Side of Glycosylation Reactions: Stereoselectivity of Glycopyranosyl Cations

Abstract

The broad application of well-defined synthetic oligosaccharides in glycobiology and glycobiotechnology is largely hampered by the lack of sufficient amounts of synthetic carbohydrate specimens. Insufficient knowledge of the glycosylation reaction mechanism thwarts the routine assembly of these materials. Glycosyl cations are key reactive intermediates in the glycosylation reaction, but their high reactivity and fleeting nature have precluded the determination of clear structure–reactivity-stereoselectivity principles for these species. We report a combined experimental and computational method that connects the stereoselectivity of oxocarbenium ions to the full ensemble of conformations these species can adopt, mapped in conformational energy landscapes (CEL), in a quantitative manner. The detailed description of stereoselective S N 1-type glycosylation reactions firmly establishes glycosyl cations as true reaction intermediates and will enable the generation of new stereoselective glycosylation methodology.

Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents

“…The stereoselectivity of this glycosylation can be accounted for by long-range participation 36 , 37 of the allyl carbamate, as well as the conformation of the intermediate oxocarbenium ion that can be substituted in a stereoselective manner on the α-face. 38 The yield of this glycosylation reaction (73%) compares favorably to the yields (50–60%) reported by Pearlman et al, who used glycal donors in combination with Brønsted acid catalysis. 39 The N -Alloc group in 15 was then removed using a catalytic amount of Pd(PPh 3 ) 4 and N , N -dimethylbarbituric acid (NDMBA) as the allyl scavenger.…”

Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions

“…To understand why some acetyl esters engage in LRP and lead to the formation of bicyclic dioxolenium ions from the parent oxocarbenium ions, while others do not, we computationally investigated their relative stability. We recently developed a DFT protocol to compute the relative energy of a large ensemble of oxocarbenium ion conformers, filling the complete conformational space these cations can occupy and plotted their relative energy to afford CEL maps 29,[39][40][41] . Employing this method, we are able to find low energy conformers and relevant (conformational) pathways a Glycosyl donors used for IRIS and in silico experiments b Glycosyl donors used for glycosylation reactions in solution which connect these on the CEL.…”

“…Although glycosyl cations have been characterized in superacid solution by nuclear magnetic resonance (NMR), protonation of the acetyl groups under these conditions prevents the assessment of their ability to engage in NGP and LRP 27,28 . This hampers our fundamental understanding of LRP and prevents its systematic development to advance stereoselective oligosaccharide synthesis [27][28][29][30] .…”

Synthesis of C‐Glycosyl Amino Acid Building Blocks Suitable for the Solid‐Phase Synthesis of Multivalent Glycopeptide Mimics

“…The preference for the formation of the α-product can be accounted for by the reactivity of the galactopyranosyl oxocarbenium ion. [38] Deacetylation of 15 with sodium methoxide and subsequent tritylation of the primary alcohol with TrtCl and Et 3 N, produced compound 16 as an inseparable α/ mixture. In this case, treatment with NBS did not result in a selective cyclization as both the αand the -compound underwent the cyclization at the same rate.…”