Zn-catalyzed Enantio- and Diastereoselective Formal [4+2] Cycloaddition Involving Two Electron-Deficient Partners: Asymmetric Synthesis of Piperidines from 1-Azadienes and Nitroalkenes

• Published in: Journal of the American Chemical Society Vol. 137; no. 13; pp. 4445 - 4452
• Main Authors: Chu, John C. K., Dalton, Derek M., Rovis, Tomislav
• Format: Journal Article
• Language: English
• Published: 30-03-2015
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.5b00033

We report a catalytic asymmetric synthesis of piperidines through [4+2] cycloaddition of 1-azadienes and nitroalkenes. The reaction uses earth abundant Zn as catalyst, and is highly diastereo- and regio-selective. A novel BOPA ligand (F-BOPA) confers high reactivity and enantioselectivity in the process. The presence of
ortho
substitution on the arenes adjacent to the bis(oxazolines) was found to be particularly impactful, due to limiting the undesired coordination of 1-azadiene to the Lewis acid, and thus allowing the reaction to be carried out at lower temperature. A series of secondary kinetic isotope effect studies using a range of ligands implicates a stepwise mechanism for the transformation, involving an initial Michael-type addition of the imine to the nitroalkene followed by a cyclization event. The step-wise mechanism obviates the electronic requirement inherent to a concerted mechanism, explaining the successful cycloaddition between two electron-deficient partners.