An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds

• Published in: Chemistry : a European journal 2024-06, Vol.30 (32), p.e202401156-n/a
• Main Authors: Faghtmann, Jonas, Eugui, Macarena, Nygaard Lamhauge, Johannes, Sofie Pladsbjerg Andresen, Signe, Rask Østergaard, Anne, Bjerregaard Svenningsen, Esben, B. Poulsen, Thomas, Anker Jørgensen, Karl
• Format: Article
• Language: English
• Subjects: 3-oxidopyridinium betaine; Aldehydes; asymmetric catalysis; Betaines; Biological activity; Bone cancer; Cascade chemical reactions; cascade reaction; Cycloaddition; Enantiomers; hydroazulene; organocatalysis; Osteosarcoma; Osteosarcoma cells; Reagents; Sarcoma; Scaffolds
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202401156

A novel cascade reaction initiated by an enantioselective aminocatalysed 1,3‐dipolar [6+4] cycloaddition between catalytically generated trienamines and 3‐oxidopyridinium betaines is presented. The [6+4] cycloadduct spontaneously undergoes an intramolecular enamine‐mediated aldol, hydrolysis, and E1cb sequence, which ultimately affords a chiral hexahydroazulene framework. In this process, three new C−C bonds and three new stereocenters are formed, enabled by a formal unfolding of the pyridine moiety from the dipolar reagent. The hexahydroazulenes are formed with excellent diastereo‐, regio‐ and periselectivity (>20 : 1), up to 96 % ee, and yields up to 52 %. Synthetic elaborations of this scaffold were performed, providing access to a variety of functionalised hydroazulene compounds, of which some were found to display biological activity in U‐2OS osteosarcoma cells in cell painting assays. Organocatalysis opens up for a novel cascade reaction concept where 3‐oxidopyridinium betaines first undergo an enantioselective [6+4] cycloaddition with trienamines, followed by a spontaneously series of reactions to provide chiral hexahydraoazulenes, of which some show bioactivity.