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Enantioselective Total Synthesis of (−)‐Finerenone Using Asymmetric Transfer Hydrogenation
Author(s) -
Lerchen Andreas,
Gandhamsetty Narasimhulu,
Farrar Elliot H. E.,
Winter Nils,
Platzek Johannes,
Grayson Matthew N.,
Aggarwal Varinder K.
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202011256
Subject(s) - enantioselective synthesis , kinetic resolution , transfer hydrogenation , acetophenone , chemistry , catalysis , combinatorial chemistry , organic chemistry , ruthenium
(−)‐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.