Peptide Macrocyclization via Cu-catalyzed 1,3-Dipolar Cycloaddition of Azomethine Ylides

20 June 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Cyclic peptides are highly valued synthetic targets in organic and medicinal chemistry. The development of new synthetic methodologies for peptide macrocyclization, different from classical lactamization, is essential for the progress of the field. Herein, we report an efficient diastereoselective macrocyclization strategy for the synthesis of cyclic peptides using 1,3-dipolar cycloaddition of azomethine ylides. Linear precursors of different length and bearing diverse amino acids have shown to be compatible with this method (26 examples), giving good yields and almost complete diastereoselectivity. The DFT calculations suggest a stepwise mechanism in which Cu plays a key role in reagents preorganization.

Keywords

Peptides
Macrocyclization
dipolar cycloadditions
asymmetric synthesis

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