Atropostatin: Design and Total Synthesis of an Atropisomeric Lactone–Atorvastatin Prodrug

Abstract

Atorvastatins play an important role in the inhibition of HMG-CoA reductase, an enzyme present in the liver that takes part in the biosynthesis of cholesterol. In this article, we report the total synthesis of a lactone–atorvastatin prodrug with additional atropisomeric features. Conformational and experimental studies of model compounds were designed to test the stability of the chiral axis. Docking calculations were performed to evaluate the constant inhibition of a library of atorvastatins. Full synthesis of the best candidate was achieved and thermally stable atropisomeric lactone–atorvastatin was obtained. The absolute configuration of the chiral axis of the atropisomers was assigned by means of chiroptical ECD spectroscopy coupled with TD-DFT calculations.

Keywords

• atropisomer
• atorvastatin
• atropostatin
• dynamic NMR
• docking calculations
• ECD