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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.
Angewandte Chemie (International Ed. in English)
|September 5, 2020
Summary
A novel synthesis of (-)-Finerenone, a drug for type 2 diabetes and chronic kidney disease, was developed. This 6-step process utilizes an enantioselective hydrogenation of a naphthyridine core, achieving high yield and enantioselectivity.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Catalysis
Background:
- (-)-Finerenone is a nonsteroidal mineralocorticoid receptor antagonist.
- It is in phase III clinical trials for chronic kidney disease in type 2 diabetes.
- The drug features an unusual dihydronaphthyridine core.
Purpose of the Study:
- To report a novel 6-step synthesis of (-)-Finerenone.
- To address challenges in synthesizing the dihydronaphthyridine core, including atropisomerism.
- To achieve high yield and enantioselectivity in the synthesis.
Main Methods:
- Enantioselective partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst and a Hantzsch ester.
- Conversion of intrinsic kinetic resolution to kinetic dynamic resolution at elevated temperature.
- Density Functional Theory (DFT) calculations to elucidate selectivity.
Main Results:
- A 6-step synthesis of (-)-Finerenone was successfully developed.
- High yield and high enantioselectivity were achieved through kinetic dynamic resolution.
- The origin of selectivity was explained using DFT calculations.
Conclusions:
- A practical and efficient synthesis for (-)-Finerenone has been established.
- The developed method overcomes challenges associated with atropisomers.
- This synthesis provides a viable route for the production of (-)-Finerenone.
Keywords:
MR antagonistsenantioselective synthesispartial transfer hydrogenationpharmaceutical moleculeMore Related Videos
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