Total Synthesis and Glycosidase Inhibition Studies of (–)‐Gabosine J and Its Derivatives
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 C2-symmetric tri-O-isopropylidene mannitol through a H2SO4/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 IC50 of 260 μM. Its reduced form gabosinol J-α inhibits β-galactosidase with an IC50 of 600 μM, 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.