Advances in the Chemistry of (−)‐D‐Swainsonine

Abstract

Abstract(−)‐D‐Swainsonine is an indolizidine alkaloid molecule with a fused piperidine and pyrrolidine ring system. It has been the first glycoprotein‐processing inhibitor to be selected for clinical testing as an anticancer drug. D‐Swainsonine is an effective inhibitor of both lysosomal α‐mannosidase and Golgi α‐mannosidase II. Lysosomal α‐mannosidase is involved in cellular degradation of polysaccharides, and Golgi α‐mannosidase is the key enzyme in processing asparagine‐linked glycoproteins. A nowadays challenge is to build up D‐swainsonine derivatives/analogues with high selectivity to Golgi α‐mannosidase II, in order to avoid metabolic issues associated with the drug. This review covers the last 18 years of literature in the synthesis of D‐swainsonine and substituted D‐swainsonines from common precursors. The work is organized in four main precursor structures, with the aim to assist in the choice of the synthetic methodology to introduce pertinent substituents at the D‐swainsonine core.