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Enantioselective Total Synthesis of (-)-Finerenone Using Asymmetric Transfer Hydrogenation.

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.

SUBMITTER: Lerchen A

PROVIDER: S-EPMC7839499 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Enantioselective Total Synthesis of (-)-Finerenone Using Asymmetric Transfer Hydrogenation.

Lerchen Andreas A Gandhamsetty Narasimhulu N Farrar Elliot H E EHE Winter Nils N Platzek Johannes J Grayson Matthew N MN Aggarwal Varinder K VK

Angewandte Chemie (International ed. in English) 20201123 51

(-)-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 mixtur ...[more]

PMID: 32890415

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