Nitrone and Alkyne Cascade Reactions for Regio‐ and Diastereoselective 1‐Pyrroline Synthesis

• Published in: Angewandte Chemie International Edition Vol. 60; no. 23; pp. 13089 - 13097
• Main Authors: Zhang, Guanqun, Alshreimi, Abdullah S., Alonso, Laura, Antar, Alan, Yu, Hsien‐Cheng, Islam, Shahidul M., Anderson, Laura L.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.06.2021; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: 1-pyrroline; Alkynes; Cascade chemical reactions; Chemistry; Chemistry, Multidisciplinary; Cycloaddition; cycloalkynes; dipolar cycloaddition; Divergence; nitrones; Physical Sciences; Science & Technology; sigmatropic rearrangement cascade; Stereoselectivity; nitrones; cycloalkynes; dipolar cycloaddition; 1-pyrroline; sigmatropic rearrangement cascade
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202101511

The synthesis of 1‐pyrrolines from N‐alkenylnitrones and alkynes has been explored as a retrosynthetic alternative to traditional approaches. These cascade reactions are formal [4+1] cycloadditions that proceed through a proposed dipolar cycloaddition and N‐alkenylisoxazoline [3,3′]‐sigmatropic rearrangement. A variety of cyclic alkynes and terminal alkynes have been shown to undergo the transformation with N‐alkenylnitrones under mild conditions to provide the corresponding spirocyclic and densely substituted 1‐pyrrolines with high regio‐ and diastereoselectivity. Mechanistic studies provide insight into the balance of steric and electronic effects that promote the cascade process and control the diastereo‐ and regioisomeric preferences of the 1‐pyrroline products. Diastereoselective derivatization of the 1‐pyrrolines prepared by the cascade reaction demonstrate the divergent synthetic utility of the new method. A formal [4+1] cascade reaction of N‐alkenylnitrones and alkynes has been developed for the regio‐ and stereoselective synthesis of densely substituted 1‐pyrrolines. This transformation provides a distinct disconnection strategy to access these heterocycles in comparison to traditional approaches. The scope, tolerance, and utility of the method are discussed, and mechanistic studies are examined to better understand reactivity and selectivity.