Late-Stage C–H Acylation of Tyrosine-Containing Oligopeptides with Alcohols

The selective tagging of amino acids within a peptide framework while using atom-economical C–H counterparts poses an unmet challenge within peptide chemistry. Herein, we report a novel Pd-catalyzed late-stage C–H acylation of a collection of Tyr-containing peptides with alcohols. This water-compatible labeling technique is distinguished by its reliable scalability and features the use of ethanol as a renewable feedstock for the assembly of a variety of peptidomimetics.


4.-Pd-Catalyzed C(sp 2 )-H Acylation of Tyr-Containing Compounds
General Procedure A (Acetylation): A reaction tube containing a stirring bar was charged with the corresponding peptide (0.15 mmol) and Pd(OAc)2 (10 mol %). The reaction tube was then evacuated and back-filled with dry argon (this sequence was repeated up to three times). Then, a commercially available solution of tert-butyl hydroperoxide (70 wt % in water) (0.90 mmol), EtOH (3.75 mmol) and toluene (1 mL) were added by syringe under argon atmosphere. The reaction tube was next warmed up to the corresponding temperature in a heating block and stirred for 16 hours. The mixture was then allowed to warm to room temperature, diluted with EtOAc and washed with aq.
NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL), dried over MgSO4 and evaporated under vacuum. The resulting crude was then purified by column chromatography to afford the corresponding product.
General Procedure B: A reaction tube containing a stirring bar was charged with the corresponding peptide (0.15 mmol) and Pd(OAc)2 (10 mol %). The reaction tube was then evacuated and back-filled with dry argon (this sequence was repeated up to three times). Then, a commercially available solution of tert-butyl hydroperoxide (70 wt % in water) (0.90 mmol), the corresponding alcohol (0.75 mmol) and toluene (1 mL) were added by syringe under argon atmosphere. The reaction tube was next warmed up to the corresponding temperature in a heating block and stirred for 16 hours. The mixture was then allowed to warm to room temperature, diluted with EtOAc and washed with aq.
NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL), dried over MgSO4 and evaporated under vacuum. The resulting crude was then purified by column chromatography to afford the corresponding product.
General Procedure C: A reaction tube containing a stirring bar was charged with the corresponding peptide (0.15 mmol) and Pd(OAc)2 (10 mol %). The reaction tube was then evacuated and back-filled with dry argon (this sequence was repeated up to three S14 times). Then, a commercially available solution of tert-butyl hydroperoxide (70 wt % in water) (0.60 mmol), the corresponding benzyl alcohol (0.45 mmol) and toluene (1 mL) were added by syringe under argon atmosphere. The reaction tube was next warmed up to the corresponding temperature in a heating block and stirred for 16 hours. The mixture was then allowed to warm to room temperature, diluted with EtOAc and washed with aq.
NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL), dried over MgSO4 and evaporated under vacuum. The resulting crude was then purified by column chromatography to afford the corresponding product.