5-Substituted 1,2-Dihydroxyindolizidines and -Pyrrolizidines Related to Swainsonine: Synthesis and Inhibition Study

Abstract

Development of selective Golgi α-mannosidase II inhibitors possessing a modified swainsonine skeleton has recently become a popular field of study due to their great potential in suppressing metastasis. However, most of the studied modifications involve addition of a substituent on the bicycle which makes the synthesis rather complex as five stereogenic centres have to be generated. Inspired by our previously developed synthesis of (5S)-5-benzylswainsonines utilizing a fully stereoselective intramolecular reductive amination, we decided to further investigate the versatility of this strategy by preparing a small collection of simplified analogues bearing only two hydroxy groups, thus eliminating one of the stereogenic centres. This contribution reports a concise synthesis of 5-substituted 1,2-dihydroxyindolizidines and -pyrrolizidines whose key features include small number of steps, high yields and excellent stereoselectivity. The title compounds were also tested for inhibitory activity against a Golgi and a lysosomal α-mannosidase to assess the effects of the substituents, ring size and missing C8-hydroxyl on potency and selectivity.