Highly Enantioselective Construction of Strained Spiro[2,3]hexanes through a Michael Addition/Ring Expansion/Cyclization Cascade

• Published in: Angewandte Chemie International Edition Vol. 59; no. 8; pp. 3058 - 3062
• Main Authors: Zhao, Chuan‐Gang, Feng, Zhi‐Tao, Xu, Guo‐Qiang, Gao, Ang, Chen, Jing‐Wei, Wang, Zhu‐Yin, Xu, Peng‐Fei
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 17.02.2020
• Subjects: asymmetric catalysis; cascade reactions; Chemistry; Chemistry, Multidisciplinary; organocatalysis; Physical Sciences; Science & Technology; spirocycles; synthetic methods; cascade reactions; organocatalysis; CATALYSIS; ACTIVATION; ASYMMETRIC-SYNTHESIS; CARBON; HYDROGEN-BOND; spirocycles; asymmetric catalysis; synthetic methods; STRATEGIES
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201912834

We herein report a general organocatalytic enantioselective strategy for the construction of highly strained spiro[2,3]hexane skeletons from methylenecyclopropanes and a broad selection of α,β‐unsaturated aldehydes. The reaction proceeds through a Michael addition followed by ring expansion of methylenecyclopropanes and nucleophilic attack of an enamine to realize the construction of spiro[2,3]hexanes. Key to the success of this approach are the utilization of an electron‐deficient difluoro‐substituted secondary amine catalyst and the intrinsic reactivity of methylenecyclopropanes. Round, like a circle in a spiral: Highly strained spiro[2,3]hexane skeletons are accessed from readily prepared starting materials through a Michael addition/ring expansion/cycloaddition cascade. The process does not require metals, proceeds through organocatalysis, can be carried out on a gram scale, and gives three continuous carbon stereocenters with good enantioselectivity and diastereoselectivity.