Stereoselective synthesis and anticancer profile of C-alkyl pyrrolidine-diols with a sphingoid base-like backbone

Abstract

The chiron approach to pyrrolidine-containing isophytosphingosine base-like compounds 21.HCl-23.HCl was developed from the known d-glucofuranose template. The key step of the synthesis was a highly diastereoselective aza-Claisen rearrangement, which created the cornerstone of the target molecules carrying three consecutive stereocentres. Subsequent cross metathesis reaction allowed the installation of a long-chain unit. The five-membered ring formation was accomplished via an intramolecular SN2 process. A single crystal X-ray analysis of the key intermediates confirmed the (2R,3R,4R)- and (2S,3R,4R)-configuration seen in the final derivatives. A comparison of the cytotoxic activity of the novel sphingomimetics (21.HCl-23.HCl) with recently described analogues (compounds 61, 62 and their antipodes) revealed that their antiproliferative profile strongly depends on the stereochemistry of the pyrrolidine substituents as well as the length of the side chain unit. Moreover, with regard to their structure and recent literature findings, compound 22.HCl may possess β-GCase inhibitory activity.