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- Title
An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds.
- Authors
Faghtmann, Jonas; Eugui, Macarena; Nygaard Lamhauge, Johannes; Sofie Pladsbjerg Andresen, Signe; Rask Østergaard, Anne; Bjerregaard Svenningsen, Esben; B. Poulsen, Thomas; Anker Jørgensen, Karl
- Abstract
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.
- Subjects
OSTEOSARCOMA; MOIETIES (Chemistry); HYDROLYSIS; PYRIDINE; ORGANOCATALYSIS; BETAINE; RING formation (Chemistry)
- Publication
Chemistry - A European Journal, 2024, Vol 30, Issue 32, p1
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.202401156