Organocatalytic [6+4] Cycloadditions via Zwitterionic Intermediates: Chemo‑, Regio‑, and Stereoselectivities

• Published in: Journal of the American Chemical Society Vol. 140; no. 42; pp. 13726 - 13735
• Main Authors: Yu, Peiyuan, He, Cyndi Qixin, Simon, Adam, Li, Wei, Mose, Rasmus, Thøgersen, Mathias Kirk, Jørgensen, Karl Anker, Houk, K. N
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.10.2018; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; DENSITY FUNCTIONALS; TROPONE; CORE; BUTADIENE; MECHANISMS; DIELS-ALDER REACTION
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.8b07575

The mechanisms and origins of chemo- and stereo­selectivities of the organocatalytic [6+4] cycloaddition between 2-cyclopentenone and tropone have been investigated by a combined computational and experimental study. In the presence of a cinchona alkaloid primary amine catalyst and an acid additive, 2-cyclopentenone forms a cross-dienamine intermediate that subsequently undergoes a stepwise [6+4] cycloaddition reaction via a zwitterionic intermediate. The rate-determining transition state features a strong hydrogen-bonding interaction between the tropone oxygen atom and the protonated quinuclidine directing the reaction course leading to a highly periselective [6+4] cycloaddition. The importance of the strong hydrogen-bonding interaction is also demonstrated by the influence of the concentration of the acid additive on the yields and enantio­selectivities of the reaction. The corresponding [4+2] cycloaddition reaction has a much higher energy barrier. The enantio­selectivity of the [6+4] cycloaddition originates from different repulsive hydrogen–hydrogen interactions that distinguish the diastereomeric transition states.