Rapid and scalable synthesis of innovative unnatural α,β or γ-amino acids functionalized with tertiary amines on their side-chains.

Séverine Schneider,Frédéric Bihel,Hussein Ftouni,Frédéric Simonin,Songlin Niu,Martine Schmitt

doi:10.1039/c5ob00828j

Séverine Schneider, Frédéric Bihel + Show 4 more

Open Access

https://doi.org/10.1039/c5ob00828j

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Abstract

We report a selective ruthenium catalyzed reduction of tertiary amides on the side chain of Fmoc-Gln-OtBu derivatives, leading to innovative unnatural α,β or γ-amino acids functionalized with tertiary amines. Rapid and scalable, this process allowed us to build a library of basic unnatural amino acids at the gram-scale and directly usable for liquid- or solid-phase peptide synthesis. The diversity of available tertiary amines allows us to modulate the physicochemical properties of the resulting amino acids, such as basicity or hydrophobicity.

Highlights

Peptides are the keystones of most vital processes, only a few peptide-based drugs were marketed in the 20th century
We have reported an efficient and selective metal-catalyzed amide reduction allowing the rapid production at the gramscale, of original unnatural basic α, β- or γ-amino acids, readily available for liquid- or solid-phase peptide synthesis
The mixture was stirred for 5 minutes, a solution of compound 1 (4.46 mmol, 1 equiv.) in 24 mL of THF was added, and the reaction mixture was stirred for 16 hours under air at 40 °C

Summary

Introduction

Peptides are the keystones of most vital processes, only a few peptide-based drugs were marketed in the 20th century. Unnatural amino acids were generated from natural amino acids through chemical modifications of this backbone (amine alkylation, backbone extension, cyclization or isosteric replacements).[2] Another great area of interest was the design of “non-natural” side chains, allowing the improvement of interactions between the peptide and its targeted protein. Regarding this aspect, a large diversity of side chains were developed, but non-natural amino acids bearing various aromatic side chains were more extensively reported.2d,3 In contrast, side chains bearing a basic amino group mimicking ornithine, lysine or arginine derivatives were less well reported

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