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

Abstract

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

Esterification and Etherification of Aliphatic Alcohols Enabled by Catalytic Strain-Release of Donor–Acceptor Cyclopropane

“…However, most current ring-opening reactions are intermolecular, and the synthetic utility of the intramolecular version is far less explored . Inspired by these elegant protocols and our established strain-release glycosylation and steroidation reactions utilizing the nucleophilic ring-opening property of DAC, readily activated by a Sc­(OTf) 3 catalyst, we conceived the possibility of achieving catalytic esterification or etherification involving the use of a mixed anhydride or a benzyl ether containing an ortho -2,2-dimethoxycarbonylcyclopropylbenzoyl (CCBz) group. The proposed activation path is depicted in Figure .…”