A simple route towards peptide analogues containing substituted (S)- or (R)-tryptophans

We investigated the Lewis acid-promoted Friedel-Crafts alkylation of indole and substituted indoles with dehydroalanine-containing dipeptides R-Xaa-Dha-OR1. The reaction proceeded with modest to sufficient diastereoselectivity, and yields strongly varied depending on the Lewis acid selected. The substituent R1 of the ester group revealed some impact on the preferential formation of (S)-Trp or (R)-Trp. We exploited the reaction to prepare different peptides containing substituted tryptophans. To test the efficacy of this method for preparing biologically relevant compounds, we synthesized two unprecedented analogues of endomorphin-1, the endogenous agonist of the μ-opioid receptor, having either (S)- or (R)-2-methyltryptophan in position 3.

Dipeptides containing substituted (S)- or (R)-Trp were obtained by F-C alkylation of indoles with dipeptides Xaa-Dha. As a preliminary application, we prepared endomorphin-1 (H-Tyr-Pro-Trp-PheNH2) analogues with 2-MeTrp in position 3.