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A sustainable strategy for the assembly of Glypromate® and its structurally-related analogues by tandem sequential peptide coupling

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Abstract

This work describes an improved and greener methodology of solution-phase synthesis for the preparation of Glypromate® (glycyl-L-prolyl-L-glutamic acid, GPE), a potent neuropeptide for applications in neurodegenerative conditions such as Huntington's, Parkinson's and Alzheimer's diseases. This protocol comprises the assembly of the perbenzylated form of Glypromate® [Cbz-Gly-Pro-Glu(OBn)-OBn (5)] from L-proline. Following a tandem sequential peptide coupling strategy, two chemoselective peptide bonds are formed without the need for purifying the intermediates ensuing a one-pot fashion synthesis. EcoScale score and E-factor were selected as the green metrics to assess the environmental impact of the preparation of tripeptide 5 using this protocol. After optimization and application of greener conditions, intermediate 5 was obtained with 95% global yield and 99% purity (NMR, HRMS, and rp-HPLC), with excellent final EcoScale score of 75 out of 100 and global E-factor of 1.8. Glypromate® is achieved by removing N- and C-protecting groups by hydrogenolysis using Pd/C as the catalyst in 98% yield, avoiding chromatographic techniques. Moreover, the protocol ensures stereochemical integrity (determined by VT-NMR and rp-HPLC) and was also successfully applied for the preparation of structurally-related Glypromate® analogues with higher degree of molecular complexity compatible with functionalized amino acids with different side chains. For the first time a one-pot protocol for the assembly of tripeptides with the removal of protecting groups in the same reaction vessel is reported.

Graphical abstract: A sustainable strategy for the assembly of Glypromate® and its structurally-related analogues by tandem sequential peptide coupling

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Supplementary files

Article information


Submitted
12 Jan 2020
Accepted
20 Apr 2020
First published
24 Apr 2020

Green Chem., 2020, Advance Article
Article type
Paper

A sustainable strategy for the assembly of Glypromate® and its structurally-related analogues by tandem sequential peptide coupling

I. E. Sampaio-Dias, L. Pinto da Silva, S. G. Silva, X. García-Mera and J. E. Rodríguez-Borges, Green Chem., 2020, Advance Article , DOI: 10.1039/D0GC00143K

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