(±)-3,5-Bis(substitutedmethyl)pyrrolidines: Application to the Synthesis of Analogues of glycine-L-proline-L-glutamic Acid (GPE)

Abstract

Backiground: Alzheimer's disease is a fatal, complex, neurodegenerative disease over 46 million people live with dementia in the world characterized by the presence of plaques containing β-amyloid and neuronal loss. The GPE acts as a survival factor against β-amyloid insult in brain and suggests a possible new therapeutic strategy for the treatment of Central Nervous System injuries and neurodegenerative disorders. The structural simplicity of GPE makes it a suitable lead molecule for the development of new drugs that to cross the blood-brain barrier. Objective: With these aims in mind, we embarked on a synthetic program focused on the modification of the Lproline residue of GPE in order to investigate its importance on the neuroprotective activities. Method: The general synthetic strategy involved the preparation of several modified proline residues, which were subsequently coupled to N-Boc-glycine-OH and glutamic dimethyl ester hydrochloride. Results: the mixture of compounds 11 was obtained in good yields (72%) under these conditions, and this was readily separated by column chromatography and the components were identified by 1H and 13C NMR spectral, as well as by its EI HRMS. Conclusion: Compound (±)-8 was coupled with L-glutamic dimethyl ester hydrochloride gave a mixture of dipeptides 9a and 9b in a satisfactory yield. The use of T3P as coupling agent of the mixture 10a and 10b with Boc-glycine provided a new analogue of GPE, tripeptide 11, obtained with an overall yield of 65% from (±)-1.