Shunya Morita

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.