NHC-catalyzed external oxidative desymmetrization of pharmaceutically relevant dihydropyridines

The synthesis of 1,4-dihydropyridines (DHPs) was first published by A. Hantzsch in 1882 via a multicomponent approach. About 60 years later compounds of this class were found to exhibit pharmacological activities as analgesic, morphine agonist and antispasmodic and in 1975 they became the most important drugs used in the treatment of cardiovascular diseases when nifedipine (Adalat®) appeared on the market for the first time. More recently, NHC (N-Heterocyclic Carbene) catalysis has emerged as powerful tool in desymmetrization and resolution of alcohols via external and internal oxidation of Breslow intermediate. Thus, we envisioned the possibility to extend this approach directly to symmetric dialdehydes. Herein, we present a strategy for the synthesis of biologically relevant DHPs with high optical purity via NHC-catalyzed desymmetrization of 1,4- dihydropyridine-3,5-dicarbaldehyde. The Kharasch oxidant (DPQ) was found to be the best external oxidant in the process and a small library (18 entries) of DHPs was prepared. The reaction is robust and proceeds with good yield (up to 75%) and excellent enantioselectivity (up to 98%). Some synthetic elaboration of the compounds are presented as well.