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.

Keywords: MR antagonists; enantioselective synthesis; partial transfer hydrogenation; pharmaceutical molecule.

Figure 1

Spironolactone, eplerenone, and finerenone as representative mineralocorticoid receptor antagonists.

Figure 2

Two strategies for the enantioselective synthesis of finerenone.

Scheme 1

Isolated yields are given. a) Ethyl iodide (2.0 equiv), Ag₂CO₃ (2.2 equiv), toluene, 115 °C, 16 hours. b) PivCl (1.5 equiv), NEt₃ (2.0 equiv), CH₂Cl₂, r.t. 48 hours. c) TMEDA (2.5 equiv), nBuLi (2.5 equiv), aldehyde (2.5 equiv), Et₂O/THF, −78 °C to r.t. d) Conc. HCl, dioxane/H₂O, 83 °C, 3 hours. e) (R)‐TRIP (10 mol %), acetoacetamide (3.0 equiv), 4 Å molecular sieves, toluene, 110 °C, 24 hours; ee of the product was determined by chiral SFC. f) DPP (20 mol %), acetoacetamide (3.0 equiv), 4 Å molecular sieves, toluene, 110 °C, 24 hours. g) HNO₃ (1.5 equiv), nBuOH, 100 °C, 3 hours. DPP=diphenyl phosphate; (R)‐TRIP=((R)‐3,3′‐bis(2,4,6‐triisopropylphenyl)‐1,1′‐binaphthyl‐2,2′‐diyl hydrogenphosphate).

Scheme 2

Isolated yields are given. The e.r. of (3) and (6) was determined by chiral SFC. a) Catalyst screening for partial transfer hydrogenation. b) Investigation of interconversion of atropisomers of starting material with temperature. c) Determination of the enantioselectivity in the reduction of the two separated atropisomers at different temperatures and calculations of the energy barriers. Computed ratios obtained by taking a Boltzmann weighting at 313 K over all conformers within 5 kcal mol⁻¹ of the lowest in free energy. d) Optimized conditions for partial transfer hydrogenation.

Scheme 3

C−H bond‐forming TSs calculated at the M06‐2X/6–311G(d,p)‐SMD(tetrahydrofuran)//B3LYP/6‐31G(d) level of theory. Red indicates position of OMe in reaction of disfavored atropisomer.