Total synthesis of teixobactin and its stereoisomers

Abstract

Teixobactin is a depsipeptide natural product with potent antibiotic activity against a range of Gram-positive multi-drug resistant bacteria. Its composition features a unique L-allo-enduracididine (allo-End₁₀), three Iles_2/6/11 residues, and one D-allo-Ile₅ residue. Intrigued by the potential biological impact of the stereochemistry of these residues, we synthesized teixobactin and three of its stereoisomers carrying L-End₁₀, D-End₁₀ or D-allo-End₁₀. In addition, stereoisomers with D-allo-Ile shuffled to positions 2, 6 or 11 were prepared. Our synthetic strategy uses the combined methods of solution and solid phase peptide synthesis. The solution phase synthesis overcomes the racemization issue for ester coupling between Ile₁₁ and Thr₈. The solid phase synthesis improves efficiency and convergence. This method also allows the efficient preparation of fluorescent-labeled analogs of teixobactin.