Synthesis of Chiral Tricyclic Pyrone Molecules via Palladium(0)‐Catalyzed Displacement Reactions of Chiral Tricyclic Pyrone Acetate With Azide or Amine

Abstract

AbstractTricyclic pyrone (TP) molecules have shown protection of MC65 neuroblastoma cells death induced by amyloid‐β proteins through SβC gene, a decrease of amyloid‐β peptide levels, and improvement of motor functions and memory in Alzheimer's disease mouse and rat models. Mechanistic studies suggest TP molecules modulate N‐methyl‐D‐aspartate receptor. A short synthesis of chiral TP analogs was sought using a Pd(0)‐catalyzed displacement of TP allylic acetate intermediate with sodium azide or substituted benzylamines. A three‐step sequence of reactions by the treatment of 2‐{(5aS,7S)‐3‐methyl‐1‐oxo‐1,5a,6,7,8,9‐hexahydropyrano[4,3‐b]chromen‐7‐yl}allyl acetate (9) with (Ph3P)4Pd and sodium azide, followed by reduction with Zn‐NH4OCHO and coupling with 3‐fluoro‐4‐hydroxybenzaldehyde and NaCNBH3 was found to give TP coupling molecule, (5aS,7S)‐7‐(1‐(3‐fluoro‐4‐hydroxybenzylamino)prop‐2‐en‐2‐yl)‐3‐methyl‐6,7,8,9‐tetrahydropyrano[4,3‐b]chromen‐1(5aH)‐one (2), in a good yield. An alternative shorter pathway – a two‐step sequence of reactions – by the displacement of 9 by 4‐(t‐butyldimethylsilyloxy)‐3‐fluoro‐benzylamine with a catalytic amount of (Ph3P)4Pd in THF followed by removal of the silyl ether protecting group gave 2, albeit in a lower chemical yield. The described syntheses should provide general procedures for the synthesis of a library of TP molecules for the discovery of anti‐Alzheimer drugs.