Highly enantioselective approach to geminal bisphosphonates by organocatalyzed Michael-type addition of β-ketoesters

A valuable organocatalyzed protocol has been developed for the asymmetric synthesis of bisphosphonate derivatives, a class of pharmaceutically important molecules. Cheap and commercially available dihydroquinine effectively catalyzed conjugate additions of cyclic beta-ketoesters to ethylide-nebisphosphonate esters, leading to optically active geminal bisphosphonates, bearing an all-carbon substituted quaternary stereocenter, in high yields and enantioselectivities of up to 99% ee. Further elaborations of Michael adducts to the corresponding bisphosphonic acids or vinyl phosphonates have also been successfully performed, with conservation of optical purity.