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

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.