Abstract:
Thiazole heterocycles are widely found in natural products and future therapeutics.[1] Construction of macrocyclic peptides with thiazole heterocycles is a very effective strategy to improve the affinity, stability and permeability of peptide-based drugs.[2] Recently, we reported an novel approach that allows access to macrocyclic thiazol(in)e peptides directly from linear peptide precursors.[3] However, the lack of side chains limits potential application of this approach. Here we extend our synthetic methodology towards the use of common hydrophobic amino acid side chains adjacent to the thiazole heterocycle.
We first synthesize α-amino nitriles and then start assembling peptides, which introduces our synthesized amino nitrile at the C-terminal by constructing a Dawson linker while cleavage of the peptide from solid support. Hence, the addition of α-amino nitriles directly installs the C-terminal nitrile and hydrophobic side chain, followed by biocompatible macrocyclisation to the thiazoline and mild basic oxidation in air to the thiazole.[4,5]
Using X-ray crystal, we determined that the stereocentres of the amino nitrile do not change during synthesis. HPLC readily purified the macrocyclic thiazole peptides we synthesized using the above method, which was validated by NMR and HRMS.
Thus, we demonstrate a nitrile-aminothiol click reaction by N-terminal cysteine and C-terminal chiral α-amino nitriles. The reaction proceeds under biocompatible conditions, and the mild oxidation steps preserve the stereochemical integrity of the macrocyclic peptides.