Direct access to spirocycles by Pd/WingPhos-catalyzed enantioselective cycloaddition of 1,3-enynes

Xiaoguang Li,Zhihui Shao,Yuhua Deng,Zheng Wang,Long Li,Shan Wang,Pengfei Luo,Fangzhi Peng,Ran Wang

doi:10.1038/s41467-021-25981-x

Xiaoguang Li, Zhihui Shao + Show 7 more

Open Access

https://doi.org/10.1038/s41467-021-25981-x

Copy DOI

Abstract

Spirocycles play an important role in drug discovery and development. The direct, catalytic, and enantioselective synthesis of spirocycles from readily available starting materials and in an atom economic manner remains a highly sought-after task in organic synthesis. Herein, an enantioselective Pd-hydride-catalyzed cycloaddition method for the synthesis of spirocyclic compounds directly from two classes of commonly available starting materials, 1,3-enynes and cyclic carbon−hydrogen (C−H) bonds, is reported. The reactions employ a chiral Pd/WingPhos catalyst to both suppress the formation of bis-allenyl by-products and control the stereoselectivity. 1,3-Enynes are used as dielectrophilic four-carbon units in the cycloaddition reactions, which also enables an enyne substrate-directed enantioselectivity switch with good levels of stereocontrol. The present spirocycle synthesis tolerates a broad range of functional groups of 1,3-enyne substrates, including alcohols, esters, nitriles, halides, and olefins. A variety of diverse cyclic nucleophiles, including pharmaceutically important heterocycles and carbocycles, can be flexibly incorporated with spiro scaffolds.

Highlights

Spirocyclic scaffolds are widely present in numerous natural products and biologically active compounds[1,2,3,4,5,6,7]
As our continuous interest in asymmetric cycloadditions[40,41,42,43,44,45,46], we explored the possibility of transition-metal hydride-based cycloaddition strategy for the direct catalytic asymmetric spirocycle synthesis
We report the successful development of Pd-hydride catalyzed cycloaddition of 1,3-enynes employing P-chiral WingPhos as the ligand that enables the direct, atom-economical, and enantioselective synthesis of spirocycles from two classes of commonly available starting materials (Fig. 1a)

Summary

Introduction

Spirocyclic scaffolds are widely present in numerous natural products and biologically active compounds[1,2,3,4,5,6,7]. Despite considerable progress in the asymmetric synthesis of spirocycles, the methods that are direct, catalytic, enantioselective, and atom economic[19] and that rely on the use of commonly available starting materials are in high need. The direct addition of enols/enolates to unactivated unsaturated hydrocarbons (hydroalkylation) with catalysis by transition-metal hydrides (MH) has been attracting increasing attention as an atomeconomical strategy for the C–C bond formation. Transition-metal-hydride-catalyzed asymmetric annulative double hydroalkylation sequences of unactivated unsaturated hydrocarbons with enols/enolates are scarce. We report the successful development of Pd-hydride catalyzed cycloaddition of 1,3-enynes employing P-chiral WingPhos as the ligand that enables the direct, atom-economical, and enantioselective synthesis of spirocycles from two classes of commonly available starting materials (Fig. 1a). WingPhos, R = anthryl (P-chiral ligand) atom economy two classes of commonly available starting materials diverse valuable spirocycles

Methods

Results

Conclusion