Pd-catalyzed site-selective C(sp2)-H radical acylation of phenylalanine containing peptides with aldehydes.

Marcos San Segundo,Arkaitz Correa

doi:10.1039/c9sc03425k

Marcos San Segundo, Arkaitz Correa

Open Access

https://doi.org/10.1039/c9sc03425k

Copy DOI

Abstract

The site-selective functionalization of C-H bonds within a peptide framework remains a challenging task of prime synthetic importance. Herein, the first Pd-catalyzed δ-C(sp2)-H acylation of Phe containing peptides with aldehydes is described. This oxidative coupling is distinguished by its site-specificity, tolerance of sensitive functional groups, scalability, and enantiospecificity and exhibits entire chemoselectivity for Phe motifs over other amino acid units. The compatibility of this dehydrogenative acylation platform with a number of oligopeptides of high structural complexity illustrates its ample opportunities for the late-stage peptide modification and bioconjugation.

Highlights

Driven by their enhanced biological activities and o en improved pharmacokinetics compared with their native counterparts, non-natural amino acids and peptides derived thereof have lately emerged as powerful scaffolds in proteomics and drug discovery.[1]
Just a few isolated examples for the modi cation of simple Phe units are known to date, but they have not been applied within a challenging peptide framework
This auxiliary was originally introduced by Daugulis[13] and has demonstrated superior directing abilities to enable a number of transformations in the realm of C–H activation, including a variety of C(sp3)–H modi cations of peptides.6a–c,8c–e A er systematic evaluation of all reaction parameters,[14] we found that the desired transformation was feasible and the corresponding acylated compound 3a was obtained in 79% yield when a combination of Pd(OAc)[2] as the catalyst, dicumyl peroxide (DCP) as the oxidant, Ag2CO3 as the additive, and DMF as the solvent was used (Table 1, entry 1)

Summary

Introduction

Driven by their enhanced biological activities and o en improved pharmacokinetics compared with their native counterparts, non-natural amino acids and peptides derived thereof have lately emerged as powerful scaffolds in proteomics and drug discovery.[1].

Results

Conclusion