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

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Sampaio Dias, IE (Author) Other; Pinto da Silva, LP (Author) Other; Sandra G. Silva (Author) FCUP; Garcia Mera, X (Author) Other; Rodriguez Borges, JE (Author) FCUP

Journal

Title: Green Chemistry

Vol. 22

Pages: 3584-3596

ISSN: 1463-9262

Publisher: Royal Society of Chemistry

Indexing

ISI Web of Knowledge - 3 Citations

Scopus - 3 Citations

Other information

Authenticus ID: P-00S-BYA

DOI: 10.1039/d0gc00143k

Abstract (EN): This work describes an improved and greener methodology of solution-phase synthesis for the preparation of Glypromate (R) (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 (R) [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 (R) 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 (R) 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13