gem-Bisphosphonates (BP) represent the most powerful class of drugs currently employed for the contrast of osteoporosis and other bone resorption related disorders. Although their clinical use dates back to 1960's, the structure of most common BP drugs is rather simple and share the presence of the gem-bisphosphonate moiety. Only a bunch of reports on the synthesis of chiral BPs have appeared in the literature and only one example has been tested. In most cases a stereogenic center in the γ position is created employing organocatalysis and only in one case on the β carbon using metal catalysis.
Herein we present a new synthetic procedure of chiral BPs starting from the enantioselective epoxidation of prochiral aryl substituted vinilydenbisphosphonate esters with hydrogen peroxide in the presence of chiral tertiary amines leading to valuable enantioenriched epoxides that can be easily further functionalized through ring opening in order to install specific functionalities. In particular sparteine turned out to be the best organocatalyst providing the corresponding epoxides with high yields and ee up to 95% well tolerating the presence of a wide range of substituents on the aryl moiety.