An official website of the United States government
A combination of DFT calculations and experiments is used to describe how the selection of a promoter can control the stereochemical outcome of glycosylation reactions with the deoxy sugar saccharosamine. Depending on the promoter, either α- or β-linked reactive intermediates are formed. These studies show that differential modes of activation lead to the formation of distinct intermediates that undergo highly selective reactions through an SN2-like mechanism.
more »
« less
This content will become publicly available on January 8, 2026
Contrasteric Glycosylations of Cotylenol and 1,2-Diols by Virtual Linker Selection
Many terpene glycosides exhibit contrasteric patterns of 1,2-diol glycosylation in which the more hindered alcohol bears a sugar; protection of the less hindered alcohol only increases steric repulsion. Here, we report a method for contrasteric glycosylation using a new sugar-linker that forms a cleavable, 10-membered ring with high efficiency, leading to syntheses of cotylenin E, J, and ISIR-050. Linker selection was aided by DFT calculations of side reactions and stereoselectivity, as well as conformational analyses using autoDFT, a Python script that converts SMILES strings to DFT-optimized conformational ensembles.
more »
« less
- Award ID(s):
- 2155228
- PAR ID:
- 10630954
- Publisher / Repository:
- American Chemical Society
- Date Published:
- Journal Name:
- Journal of the American Chemical Society
- Volume:
- 147
- Issue:
- 1
- ISSN:
- 0002-7863
- Page Range / eLocation ID:
- 1327 to 1333
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract While glycosyl triflates are frequently invoked as intermediates in many chemical glycosylation reactions, the chemistry of other glycosyl sulfonates remains comparatively underexplored. Given the reactivity of sulfonates can span several orders of magnitude, this represents an untapped resource for the development of stereoselective glycosylation reactions. This personal account describes our laboratories efforts to take advantage of this reactivity to develop β‐specific glycosylation reactions. Initial investigations led to the development of 2‐deoxy‐sugar tosylates as highly selective donors for β‐glycoside synthesis, an approach which has been used to great success by our group and others for the construction of deoxy‐sugar oligosaccharides and natural products. Subsequent studies demonstrate that “matching” the reactivity of the sulfonate to that of the sugar donor leads to highly selective SN2‐glycosylations with a range of substrates.more » « less
-
null (Ed.)Abstract Protein glycosylation, the enzymatic modification of amino acid sidechains with sugar moieties, plays critical roles in cellular function, human health, and biotechnology. However, studying and producing defined glycoproteins remains challenging. Cell-free glycoprotein synthesis systems, in which protein synthesis and glycosylation are performed in crude cell extracts, offer new approaches to address these challenges. Here, we review versatile, state-of-the-art systems for biomanufacturing glycoproteins in prokaryotic and eukaryotic cell-free systems with natural and synthetic N-linked glycosylation pathways. We discuss existing challenges and future opportunities in the use of cell-free systems for the design, manufacture, and study of glycoprotein biomedicines.more » « less
-
Carbohydrate molecules with an alpha-glycosylated carboxylic acid motif provide access to biologically relevant chemical space but are difficult to synthesize with high selectivity. To address this challenge, we report a mild and operationally simple protocol to synthesize a wide range of functionally and structurally diverse alpha-glycosylated carboxylic acids in good yields with high diastereoselectivity. While there is no apparent correlation between reaction conversion and the pKa of carboxylic acids, there is a notable trend in selectivity. Carboxylic acids with a pKa ranging from 4 to 5 exhibit high selectivity, whereas those with a pKa of 2.5 or lower do not display the same level of selectivity. Our strategy utilizes readily available 2,9-dibutyl-1,10-phenanthroline as an effective nucleophilic catalyst to displace a bromide leaving group from an activated sugar electrophile in a nucleophilic substitution reaction, forming phenanthrolinium intermediates. The attack of the carboxylic acid takes place from the alpha-face of the more reactive intermediate, resulting in the formation of alpha-glycosylated carboxylic acid. Previous calculations suggested that the hydroxyl group participates in the hydrogen bond interaction with the basic C2-oxygen of a sugar moiety and serves as a nucleophile to attack the C1-anomeric center. In contrast, our computational studies reveal that the carbonyl oxygen of the carboxylic acid serves as a nucleophile, with the carboxylic acid-OH forming a hydrogen bond with the basic C2-oxygen of the sugar moiety. This strong hydrogen bond (1.65 Å) interaction increases the nucleophilicity of the carbonyl oxygen of carboxylic acid and plays a critical role in the selectivity-determining step. In contrast, when alcohol acts as a nucleophile, this scenario is not possible since the -OH group of the alcohol interacts with the C2-oxygen and attacks the C1-anomeric carbon of the sugar moiety. This is also reflected in alcohol-OH's weak hydrogen bond (1.95 Å) interaction with the C2-oxygen. The O(C2)-HO (carboxylic acid) angle was measured to be 171° while the O(C2)-HO (alcohol) angle at 122° deviates from linearity, resulting in weak hydrogen bonding.more » « less
