1. Preparation of 4′‐Spirocyclobutyl Nucleoside Analogues as Novel and Versatile Adenosine Scaffolds
- Author
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Ann Vos, Freija De Vleeschouwer, Tongfei Wu, Guido Verniest, Jan Willem Thuring, Weimei Sun, Jonas Verhoeven, Hanchu Kong, Vineet Pande, Kristof Van Hecke, Lieven Meerpoel, Faculty of Physical Education and Physical Therapy, Chemistry, and Department of Bio-engineering Sciences
- Subjects
enol ethers ,Reaction mechanism ,Adenosine ,Glycosylation ,spiro compounds ,Stereochemistry ,Carbohydrates ,010402 general chemistry ,01 natural sciences ,Catalysis ,cyclobutanones ,medicine ,Stepwise reaction ,cycloaddition ,Density Functional Theory ,SAM-mimetics ,chemistry.chemical_classification ,Cycloaddition Reaction ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Substrate (chemistry) ,Nucleosides ,Stereoisomerism ,Biological activity ,General Chemistry ,Furanose ,Cycloaddition ,Dichloroethylenes ,0104 chemical sciences ,chemistry ,Metals ,Thermodynamics ,Oxidation-Reduction ,Nucleoside ,medicine.drug - Abstract
Despite the large variety of modified nucleosides that have been reported, the preparation of constrained 4 '-spirocyclic adenosine analogues has received very little attention. We discovered that the [2+2]-cycloaddition of dichloroketene on readily available 4 '-exo-methylene furanose sugars efficiently results in the diastereoselective formation of novel 4 '-spirocyclobutanones. The reaction mechanism was investigated via density functional theory (DFT) and found to proceed either via a non-synchronous or stepwise reaction sequence, controlled by the stereochemistry at the 3 '-position of the sugar substrate. The obtained dichlorocyclobutanones were converted into nucleoside analogues, providing access to a novel class of chiral 4 '-spirocyclobutyl adenosine mimetics in eight steps from commercially available sugars. Assessment of the biological activity of designed 4 '-spirocyclic adenosine analogues identified potent inhibitors for protein methyltransferase target PRMT5.
- Published
- 2019