Thanks to their structural similarity with pyrophosphate, gem-bisphosphonates (BPs) ensure specific bone targeting and are widely employed as drugs for the treatment of bone disorders like osteoporosis whose costs, every year, were estimated in €37 billion treating, affecting about 27.5 million people in Europe.[1] New recent studies demonstrated the cellular activity of nitrogen containing BP (N-BP) bearing long alkyl chain acting as potent inhibitors of specific enzymes thus leading to inactivation of osteoclasts that are the cells deputed to bone resorption. Despite of importance of enantiopure drugs in pharmacology, there is only one example of in vitro test on an enantiopure bisphosphonic acid. [2] Herein we present a straightforward synthesis of a β-substituted isatin bisphosphonates precursor on which asymmetric ketones condensation catalyzed by natural derived organocatalysts gave new N-BPs in high yield and high enantiomeric excess. Isatin BP precursor (IsBP) was obtained in high yield and purity by a simple Michael addition of isatin to vinylidenebisphosphonate tetraethylester (VBP). Aldol condensation of acetone on the carbonyl of the IsBP moiety was investigated using a wide range of natural derived organocatalyst, resulting in good yields and moderate e.e. using synthetic quinidine-thiourea catalyst. The optimized catalytic system was applied to a wide range of linear and cyclic aliphatic as well as aromatic ketones: six membered ring aliphatic ketones showed quantitative yields with a dramatic increase in e.e. as well as with electron rich acetophenones. Use of the pseudo-enantiomer quinine-thiourea catalyst allowed to obtain both enantiomeric form of the synthesized molecules. This efficient and versatile synthesis of BPs enabled the preparation of several enantioenriched BP tetraethyl esters that were deprotected removing the ester moieties [3] forming the corresponding bisphosphonic acids.

Highly Stereoselective Synthesis of Nitrogen Bisphosphonates: Organocatalytic Condensation on Osteoporosis Prodrugs

CHIMINAZZO, ANDREA;DE LUCA, LORENA;STRUKUL, Giorgio;SCARSO, Alessandro
2016

Abstract

Thanks to their structural similarity with pyrophosphate, gem-bisphosphonates (BPs) ensure specific bone targeting and are widely employed as drugs for the treatment of bone disorders like osteoporosis whose costs, every year, were estimated in €37 billion treating, affecting about 27.5 million people in Europe.[1] New recent studies demonstrated the cellular activity of nitrogen containing BP (N-BP) bearing long alkyl chain acting as potent inhibitors of specific enzymes thus leading to inactivation of osteoclasts that are the cells deputed to bone resorption. Despite of importance of enantiopure drugs in pharmacology, there is only one example of in vitro test on an enantiopure bisphosphonic acid. [2] Herein we present a straightforward synthesis of a β-substituted isatin bisphosphonates precursor on which asymmetric ketones condensation catalyzed by natural derived organocatalysts gave new N-BPs in high yield and high enantiomeric excess. Isatin BP precursor (IsBP) was obtained in high yield and purity by a simple Michael addition of isatin to vinylidenebisphosphonate tetraethylester (VBP). Aldol condensation of acetone on the carbonyl of the IsBP moiety was investigated using a wide range of natural derived organocatalyst, resulting in good yields and moderate e.e. using synthetic quinidine-thiourea catalyst. The optimized catalytic system was applied to a wide range of linear and cyclic aliphatic as well as aromatic ketones: six membered ring aliphatic ketones showed quantitative yields with a dramatic increase in e.e. as well as with electron rich acetophenones. Use of the pseudo-enantiomer quinine-thiourea catalyst allowed to obtain both enantiomeric form of the synthesized molecules. This efficient and versatile synthesis of BPs enabled the preparation of several enantioenriched BP tetraethyl esters that were deprotected removing the ester moieties [3] forming the corresponding bisphosphonic acids.
XIX Congresso Nazionale di Catalisi - GIC 2016
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10278/3681126
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