Concise and Short Synthesis of Functionalized 5,6-Dihydropyridin-2-ones by Means of Palladium(0)-Catalyzed Cross-Coupling of Ketene Aminal Phosphates

Abstract

A concise and short synthetic entry to 5,6-dihydropyridin-2-one derivatives has been developed by means of palladium(0)-catalyzed cross-coupling of cyclic ketene aminal phosphates.γ-Secretase is a membrane-bound macromolecular complex comprised of Presenilin, Nicastrin, Pen-2 and Aph-1, which is responsible for the proteolytic processing of amyloid precursor protein to generate amyloid β (Aβ) peptides.Since the neurodegenerative disorder Alzheimer's disease (AD) is pathologically characterized by the extensive extracellular deposition of Aβ as senile plaques and intracellular deposition of tau proteins as neurofibrillary tangles in cerebral cortices, regulation of the Aβ levels by γ-secretase inhibitors is considered as mechanism-based therapeutics for AD. 1 We have previously reported the discovery of structurally novel γ-secretase inhibitors GS155 (1) and GS416 (2) from our in-house synthetic library of natural products intermediates (Figure 1). 2,3The common structural feature of these molecules is the 6-membered cyclic enone core arranged with two aromatic rings, which is important for displaying the sufficient inhibitory activity.It was envisioned that functionalized 5,6-dihydropyridin-2-one derivatives (3) would be interesting structural alternatives to GS155 and GS416 (1 and 2, respectively).