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.