(-) - Clau Analogues

Racemic clausenamide is pypyrrolinone natural product isolated from the aqueous extracts of the leaves of Clausena lansium (Lour) skeels, and exhibited nootropic activities in an array of varied biological tests. Both of its enantiomers were laterly prepared and the levo rotatory component was found to be the active isomer, which is now under Phase I clinical trial for its potential in treatment of Alzheimer's disease (AD). In order to study the action mechanism and the SAR of this agent, we finished the following work in this dissertation:(1) Six compounds, with one substituent less than the mother structure,(-)-clausenamide, were designed to detemine whether all these substituents are necessary for its biological activity.(2)6-Des-hydroxyl analogue(2) was synthesized in four steps, starting from (-)-clausenamide, with3-OH selective protection,6-OH elimination, hydrogenation as key steps. It was found in this investigation that the size of C3substituents would affect the migration of the double bond between C4,C5and C5,C6of clausenamide. Also starting from (-)-clausenamide, several attempts were made to furnish the synthesis of3-Des-hydroxyl analogue(3), and finally a successful approach to the target, using radical deoxygenation, was developed.(3)Based on Wolfgang's first synthesis of racemic clausenamide, the synthesis of optically pure (-)-6-dephenyl analogue (4) was accomplished by de novo synthesis using O-acetyl-(S)-mandelic acid as a resolution agent. The absolute configuration of the final product was determined transformation of this compound into kown enpiclausenamide, and comparaison of its optical rotation with the known data.(4) Two different routes to (-)-4-dephenyl clausenamide(5) were investigated. The one starting from D-pyroglutamic acid was proved to be successful.(5) The synthesis of (-)-N-demethyl derivative (6) was synthesized by the method previously developed by Dr. Xing-Zhou Li in our laboratory. (6) The synthesis of des-C5-substituent's analogue (7) was accomplished by de novo synthesis and resolved.