TY - JOUR
T1 - Enantioselective Total Synthesis of (‐)‐Finerenone using Asymmetric Transfer Hydrogenation
AU - Aggarwal, Varinder Kumar
AU - Lerchen, Andreas
AU - Gandhamsetty, Narasimhulu
AU - Farrar, Elliot
AU - Winter, Nils
AU - Platzek, Johannes
AU - Grayson, Matthew
PY - 2020/12/14
Y1 - 2020/12/14
N2 - (−)‐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.
AB - (−)‐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.
U2 - 10.1002/anie.202011256
DO - 10.1002/anie.202011256
M3 - Article
VL - 51
SP - 23107
EP - 23111
JO - Angewandte Chemie-International Edition
JF - Angewandte Chemie-International Edition
SN - 1433-7851
IS - 57
ER -