Carbene-catalyzed chirality-controlled site-selective acylation of saccharides

Abstract

Acylation stands as a fundamental process in both biological pathways and synthetic chemical reactions, with acylated saccharides and their derivatives holding diverse applications ranging from bioactive agents to synthetic building blocks. A longstanding objective in organic synthesis has been the site-selective acylation of saccharides without extensive pre-protection of alcohol units. In this study, we demonstrate that by simply altering the chirality of N-heterocyclic carbene (NHC) organic catalysts, the site-selectivity of saccharide acylation reactions can be effectively modulated. Our investigation reveals that this intriguing selectivity shift stems from a combination of factors, including chirality match/mismatch and inter- / intramolecular hydrogen bonding between the NHC catalyst and saccharide substrates. These findings provide valuable insights into catalyst design and reaction engineering, highlighting potential applications in glycoside analysis, such as fluorescent labelling, α/β identification, orthogonal reactions, and selective late-stage modifications.

Fig. 1. Overview of site-selective acylation on sugars.

a Significance of acylsugars. b Site selective modifications onto saccharides. c This work: carbene-controlled site-divergent acylation assisted by hydrogen bonding.

Fig. 2. Substrate scope for 3-OH and 2-OH selectivity.

The ratios referred to acylation on 2-OH:3-OH and were determined by ¹H NMR. ^aReactions were performed at 0  ^°C. ^bReactions were performed at r.t. ^cIt was also synthesized by other methods to verify our results (see Supplementary Information 4.2).

Fig. 3. Synthetic utilities and features.

a Selective synthesis of chaenomeloidin from Salicin. b Dual fluorescent labeling, c fluorescent labeling on glucosides over galactosides and α/β identification. d Orthogonal acylation on minimally protected saccharides.

Fig. 4. Mechanistic Investigation and proposed reaction pathway.

a and b DFT optimized transition state structures for the most favored TSs for each reaction using either NHC G for O3-selective acylation or NHC ent-G for O2-acylation; c NMR analysis; d Proposed mechanism.