Total Synthesis and Glycosidase Inhibition Studies of (–)‐Gabosine J and Its Derivatives

Abstract

Abstract The total syntheses of (–)‐gabosine J and its two gabosinol derivatives, the reduced forms of (–)‐gabosine J, were achieved by a chiral pool strategy that started from inexpensive and readily available D ‐mannitol. The desymmetrization of the C 2 ‐symmetric tri‐ O ‐isopropylidene mannitol through a H 2 SO 4 /silica mediated hydrolysis of one of the two terminal ketals and a ring‐closing methathesis (RCM) of the appropriately protected diene are the key steps in these syntheses. The preparation of (–)‐gabosine J, which involved simple steps as well as inexpensive and readily available reagents and starting material, was completed in 14 steps with an overall yield of 13 %. Similarly, gabosinol J‐α and gabosinol J‐β (two synthetic derivatives of gabosine J) were prepared in 13 steps in an overall yield of 11 and 6 %, respectively. A preliminary investigation into the biological activity of these compounds revealed that (–)‐gabosine J inhibits α‐mannosidase with an IC 50 of 260 μ M . Its reduced form gabosinol J‐α inhibits β‐galactosidase with an IC 50 of 600 μ M , and gabosinol J‐β inhibits β‐glucosidase. This is the first synthesis of a gabosine that employs mannitol as the starting material and the first report of the biological activity of gabosine J.