Enantioselective Synthesis of Chiral 1,4-Diynes via Copper-Catalyzed Asymmetric Radical Alkynylation of Propargyl Chlorides

Abstract

Chiral 1,4-diynes serve as important synthetic building blocks; however, general and efficient catalytic asymmetric strategies for their direct assembly from readily available propargylic chlorides and alkynes remain underdeveloped. Herein, we report a copper-catalyzed enantioselective alkynylation of racemic propargyl chlorides with terminal alkynes, enabled by a Ugi's amine-based tridentate f-PNN ligand featuring planar chirality. The catalytic system under mild conditions affords a variety of enantioenriched 1,4-diynes in high yields and excellent enantioselectivities, with wide functional group tolerance. Preliminary mechanistic studies support that the reaction proceeds through a radical pathway, and density functional theory (DFT) calculations revealed the key noncovalent interactions between the ligand and substrate which are responsible for the high enantiocontrol. We have demonstrated that the enantioenriched 1,4-diynes can be converted into a variety of synthetic useful compounds, including a triazole, a terminal alkyne, a chiral compound with a tertiary chiral center bearing three all alkyl substituents, and enynes with controlled E/Z selectivity. Furthermore, we have successfully applied our method to the formal synthesis of a gonadotropin-releasing hormone (GnRH) antagonist.

Keywords

1,4-Diyne / Asymmetric / Alkynylation / Radical / Copper / Propargyl chloride / Catalysis / Tridentate f-PNN ligand

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