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

Abstract Tricyclic 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 (Ph 3 P) 4 Pd and sodium azide, followed by reduction with Zn‐NH 4 OCHO and coupling with 3‐fluoro‐4‐hydroxybenzaldehyde and NaCNBH 3 was found to give TP coupling molecule, (5a S ,7 S )‐7‐(1‐(3‐fluoro‐4‐hydroxybenzylamino)prop‐2‐en‐2‐yl)‐3‐methyl‐6,7,8,9‐tetrahydropyrano[4,3‐b]chromen‐1(5a H )‐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 (Ph 3 P) 4 Pd 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.