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

• Published in: Nature communications Vol. 12; no. 1; pp. 5667 - 11
• Main Authors: Li, Long, Wang, Shan, Luo, Pengfei, Wang, Ran, Wang, Zheng, Li, Xiaoguang, Deng, Yuhua, Peng, Fangzhi, Shao, Zhihui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.09.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 639/638/403/933; 639/638/77/883; Alcohols; Alkenes; Atom economy; Carbon; Carbon cycle; Catalysis; Catalysts; Chemical synthesis; Cycloaddition; Enantiomers; Esters; Functional groups; Halides; Humanities and Social Sciences; multidisciplinary; Nitriles; Nucleophiles; Palladium; Science; Science (multidisciplinary); Stereoselectivity; Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25981-x

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. Spirocycles are traditionally difficult structures to synthesize due to the congested nature of the central atom. Here the authors show a method to synthesize quaternary carbon spirocycles in one step from 1,3-enynes and pyrazolidine-type heterocycles, both relatively unactivated structures, proceeding via palladium catalysis.