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 (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.