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Enantioselective Total Synthesis of (-)-Finerenone Using Asymmetric Transfer Hydrogenation
Andreas Lerchen1, Narasimhulu Gandhamsetty1, Elliot H E Farrar2
1School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
Abstract:
(-)-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.
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