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

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

Volume: 15 Issue: 2

Author(s): Joana Ferreira da Costa, Xerardo Garcia-Mera, David Silva Poceiro and Olga Caamano*

Affiliation:

• Departamento de Quimica Organica, Facultade de Farmacia, Campus Vida s/n, Universidade de Santiago de Compostela, E-15782, Santiago de Compostela,Spain

Keywords: Proline derivatives, neuropeptides, GPE, azides, Staudinger–Vilarrasa coupling, synthesis.

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.

Cite this article as:

da Costa Ferreira Joana , Garcia-Mera Xerardo , Poceiro Silva David and Caamano Olga *, (±)-3,5-Bis(substitutedmethyl)pyrrolidines: Application to the Synthesis of Analogues of glycine-L-proline-L-glutamic Acid (GPE), Current Organic Synthesis 2018; 15 (2) . https://dx.doi.org/10.2174/1570179414666170821115323