Enantioselective Construction of the Cycl[3.2.2]azine Core via Organocatalytic [12 + 2] Cycloadditions

• Published in: Journal of the American Chemical Society 2021-04, Vol.143 (16), p.6140-6151
• Main Authors: Jessen, Nicolaj Inunnguaq, Bertuzzi, Giulio, Bura, Maksimilian, Skipper, Mette Louise, Jørgensen, Karl Anker
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.1c00499

The first enantioselective [12 + 2] cycloaddition has been developed for the construction of a chiral cycl[3.2.2]­azine core, a tricyclic moiety with a central ring-junction nitrogen atom, by an operationally simple one-step organocatalytic process. The reaction concept builds upon aminocatalytically generated 12π-components derived from 5H-benzo­[a]­pyrrolizine-3-carbaldehydes reacting with different electron-deficient 2π-components and affording the complex scaffold of benzo­[a]­cycl­[3.2.2]­azine (indolizino­[3,4,5-ab]­isoindole) with excellent enantio- and diastereoselectivity in good yields. The developed reaction is robust toward diverse substituent patterns and has been extended to different classes of electron-deficient 2π-components by minor variations in reaction setup. The obtained [12 + 2] cycloadducts are electron-deficient in nature, and their reaction with nucleophiles have been demonstrated. The enantioselective [12 + 2] cycloaddition with α,β-unsaturated aldehydes as the electron-deficient 2π-components relies upon an unconventional, simple aminocatalyst. In order to understand the high stereoselectivity of the [12 + 2] cycloaddition for this simple catalyst, combined experimental and computational investigations were performed. The investigations point to activation of both the 5H-benzo­[a]­pyrrolizine-3-carbaldehyde and the α,β-unsaturated aldehyde by the aminocatalyst and that the reaction proceeds by a stepwise cycloaddition, where especially the ring-closure is crucial for the stereochemical outcome. For other electron-deficient 2π-components, such as α,β-unsaturated ketoesters and nitroolefins, a more sterically demanding aminocatalyst has been applied and the corresponding [12 + 2] cycloadducts are obtained with excellent stereoselectivity. The [12 + 2] cycloaddition with vinyl sulfones afforded fully unsaturated systems, which display photoluminescence properties and for which quantum yields have been evaluated.