Journal
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
Volume 2022, Issue 41, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ejoc.202200796
Keywords
Asymmetric synthesis; Cycloaddition; hNK1 antagonists; Pyrrolizidinones; Reductive amination
Categories
Funding
- Council on grants of the President of the Russian Federation [MD-3478.2022.1.3]
- Ministry of Science and Higher Education of the Russian Federation [075-00697-22-00]
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A concise seven-step asymmetric synthesis method was developed for the synthesis of MSD's potent hNK(1) antagonist, which contains a pyrrolizidinone core bearing two fluorine-substituted aryl groups. The pyrrolizidinone unit was constructed by reductive recyclization of a properly functionalized cyclic nitronate, which was assembled by stereoselective [4+2]-cycloaddition. X-ray analysis confirmed the previously suggested configuration of the hNK(1) antagonist based on bioactivity data, and revealed multiple weak interactions involving fluorine atoms in the crystal structure.
A concise seven-step asymmetric synthesis of MSD's potent hNK(1) antagonist containing a pyrrolizidinone core bearing two fluorine-substituted aryl groups was developed. The pyrrolizidinone unit was constructed by reductive recyclization of a properly functionalized cyclic nitronate, which was assembled by stereoselective [4+2]-cycloaddition of a nitroalkene with a vinyl ether bearing a Whitesell's chiral auxiliary group. The configuration of the hNK(1) antagonist, which was previously suggested based on bioactivity data, was confirmed by X-ray analysis. The crystal structure features multiple weak interactions involving fluorine atoms that are also found in a complex with the hNK(1) receptor simulated by molecular docking.
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