Enantioselective Total Synthesis of (−)‐Finerenone Using Asymmetric Transfer Hydrogenation

(−)‐Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes. It contains an unusual dihydronaphthyridine core. We report a 6‐step synthesis of (−)‐finerenone, which features an enantioselective partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst with a Hantzsch ester. The process is complicated by the fact that the naphthyridine exists as a mixture of two atropisomers that react at different rates and with different selectivities. The intrinsic kinetic resolution was converted into a kinetic dynamic resolution at elevated temperature, which enabled us to obtain (−)‐finerenone in both high yield and high enantioselectivity. DFT calculations have revealed the origin of selectivity. A short 6‐step enantioselective synthesis of (−)‐finerenone is reported featuring a partial transfer hydrogenation of a naphthyridine ring. The naphthyridine existed in two atropisomeric forms that reacted at different rates and selectivities; however, at elevated temperature kinetic dynamic resolution occurred, enabling (−)‐finerenone to be obtained with high enantioselectivity.