Is acyl migration to the aglycon avoidable in 2-acyl assisted glycosylation reactions?

Abstract

This report unequivocally separates orthoester formation from acyl transfer for the first time and indicates possible routes to eliminate 2-O-acyl transfer during glycosylation reactions. Experimental evidence is shown that acyl transfer from 2-O-acyl-3,4,6-tri-O-benzyl-D-galactopyranose-derived glycosyl donors decreases in the order formyl > acetyl > pivaloyl. The 2-O-benzoyl derivatives are more variable, in some cases transferring easily, and in others not at all. Density functional theory (DFT) calculations of the structure and energetics of dioxolenium ion and related intermediates suggest that a proton transfer pathway from the nucleophile to O-2 provides an explanation for the observed trends. These DFT calculations of the proton transfer pathway support a mechanism in which a relay molecule is involved. Further DFT calculations used a constraint based on linear combinations of six bond lengths to establish the sequence of bond breaking and bond forming. The calculated anomeric carbon to former carbonyl oxygen bond that breaks during acyl transfer is the longest in the formyl case and shortest in those that exhibit little or no acyl transfer. Rotation about the aromatic to carbonyl Ph-C(=O) bond is different from the alkyl series. Analysis of this proposed TS led to the postulate that 2,6-substitution may hinder rotation even more. Thus, the 2,6-dimethylbenzoyl analogue was synthesized and it does not transfer directly or by rearrangement of its readily formed orthoester. DFT calculations suggested that 2,6-dimethoxybenzoyl should also not transfer easily. Experimentally, this proved to be the case and this new 2-O-acyl protecting group cleaves at 50°C with a 1 mol/L solution of LiOH in methanol. Thus, a calculated transition state has led to a prototype of a protecting group that solves a major problem in oligosaccharide synthesis. Résumé: Dans ce travail, on sépare sans équivoque et pour la première fois la formation d'orthoester des transferts d'acyles et on suggère des voies possibles pour éliminer le transfert de 2-O-acyle lors des réactions de glycosylation. On présente des données expérimentales montrant que le transfert d'acyle de donneurs glycosyles dérivés du 2-O-acyl-3,4,6-tri-O-benzyl-D-galactopyranose diminue dans l'ordre formyle > acétyle > pivaloyle. Les dérivés 2-O-benzoyles sont plus variables; dans certains cas, le transfert se fait facilement alors que dans d'autres il ne se fait pas du tout.Des calculs basés sur la théorie de la densité fonctionnelle (THF) de la structure et des énergies de l'ion dioxolénium et d'intermédiaires apparentés suggèrent qu'un transfert de proton du nucléophile vers O-2 s'avère la meilleure explication pour les tendances observées. Ces calculs de THF de la voie de transfert de proton appuient un mécanisme dans lequel une molécule relais serait impliquée. Des calculs supplémentaires de THF ont été réalisés en appliquant une contrainte basée sur des combinaisons linéaires de six longueurs de liaisons pour déterminer la séquence de bris et de formation de la lia...

Rapid Assembly of Oligosaccharides: A Highly Convergent Strategy for the Assembly of a Glycosylated Amino Acid Derived from PSGL-1

“…It is well known that the use of C-2 benzoyl esters will suppress ortho-ester formation, however, this protecting group is not compatible with glycopeptide synthesis because the rather strong basic conditions required for its removal47 will result in β-elimination of the O -glycopeptide linkage. It has been shown that a 2,5-di-fluoro-benzoyl esters (dFBz) is an efficient neighboring group participant that suppresses ortho-ester formation 48,49.…”

Conformational Pathways of Saturated Six-Membered Rings. A Static and Dynamical Density Functional Study

“…9 Our previous studies of the neighboring group-assisted glycosylation reactions, by quantum chemistry calculations, revealed that, in some cases, the relative energies of pyranose conformations determine the transition states between crucial steps. 10,11 Our previous studies also suggest that chemical modification of the rigidity of the pyranose ring controls the stereochemistry and determines the product distribution. 10,12,13 Our present goal is the complete characterization of the conformational potential energy surface of pyranoses.…”

Palladium-catalysed reactions of 6-halogeno-1,1′-binaphthyl derivatives. A detailed investigation of structure/reactivity and structure/selectivity relationships

“…23 Besides, according to our own results, other 2-hydroxy-2 0 -pivaloyloxy-1,1 0 -binaphthyl derivatives without a halide group, such as 6-nitro-2-hydroxy-2 0 -pivaloyloxy-1,1 0 -binaphthyl, 14 do not undergo isomerisation in the presence of a palladium catalyst under similar conditions.…”