Asymmetric Synthesis of a Pyrrolizidinone-Based hNK1 Antagonist through Reductive Ring Contraction of a Six-Membered Cyclic Nitronate

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.

Automated summary

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.