A Strain-Promoted Divergent Chemical Steroidation Unveils Potent Anti-Inflammatory Pseudo-Steroidal Glycosides

• DOI: 10.1021/jacs.4c00537
• Publication Date: 2024-04-18T19:02:06Z
• Authors: Han Ding; Xiao-Lin Zhang; Aoxin Guo; Qian Ping Lee; Chao Cai; Ming Li; Hongzhi Cao; Xue-Wei Liu
• Keywords: Chemistry; 500; 540; Molecular structure; Non-steroidal

The development of novel agents with immunoregulatory effects is a keen way to combat the growing threat inflammatory storms global health. To synthesize pseudo-steroidal glycosides tethered by ether bonds promising immunomodulatory potential, we develop herein highly effective deoxygenative functionalization steroidal donor (steroidation) facilitated strain-release, leveraging cost-effective and readily available Sc(OTf)3 catalysis. This transformation produces transient steroid-3-yl carbocation which reacts O-, C-, N-, S-, P-nucleophiles generate structurally diverse steroid derivatives. DFT calculations were performed shed light on mechanistic details regioselectivity, underlying an acceptor-dependent steroidation mode. approach can be extended etherification sugar alcohols enable achievement diversity-oriented, pipeline-like synthesis in good excellent yields complete stereo- regiospecific control for anti-inflammatory agent discovery. Immunological studies have demonstrated that meticulously designed cholesteryl disaccharide significantly suppress interleukin-6 secretion macrophages, exhibiting up 99% inhibition rates compared negative control. These findings affirm potential as prospective category lead drugs.