Pd-catalyzed site-selective C(sp²)–H chalcogenation of amino acids and peptides using a picolinamide auxiliary

Abstract

Chalcogenated amino acids/peptides are recently being considered therapeutic drug candidates. This report describes a handy synthetic method for the Pd-catalyzed picolinamide directed site-selective C(sp2)-H chalcogenation of α- amino acids and...

Pd-Catalyzed Picolinamide-Directed Late-Stage Chalcogenation of Tryptophan-Containing Peptides

“…Recently, our group reported picolinamidedirected site-selective chalcogenation of phenylalanine-containing amino acids and peptides with disulfides/diselenides under Pd-catalysis (Scheme 1a). 29 This method is incompatible with aliphatic disulfides, amino acids having free hydroxyl group, and requires the use of Na 2 CO 3 as base. In continuation of our studies on directed C−H functionalization, herein, we report a Pd-catalyzed late-stage C2-chalcogenation of tryptophan-containing peptides with disulfides/diselenides using picolinamide auxiliary (Scheme 1b).…”

“…32 The treatment of oxone with 3a and 4e delivered sulfones 6a and 6b, respectively, in good yields (Scheme 10). 29 Later, a gram scale reaction was conducted using 1a and 2f as model substrates (Scheme 11). The reaction of 1a with 2f under optimized conditions delivered the target sulfenyl peptide 3f in 66%.…”

“…All required materials were purchased from commercial suppliers and used without further purification. The compounds 2a – s were synthesized by following the literature reported procedure. ,− All the heating reactions were carried out over a magnetic stirrer with hot plate using heating blocks. Reactions were monitored by thin layer chromatography, visualized by UV and Ninhydrin.…”

“…The mixture was stirred for 2 h at room temperature. 29 After completion, the reaction mixture was extracted with ethyl acetate (3 × 10 mL) and washed with saturated brine. The organic layers were dried over anhydrous Na 2 SO 4 , filtered and evaporated under vacuo.…”

“…In the recent past, transition metal-catalyzed late-stage C–H bond functionalization via C–H bond activation has offered a reliable alternative over traditional approaches owing to their notable step economy and environmental sustainability. − In this realm, significant studies are documented at the C2 functionalization of tryptophan for versatile peptide modifications, as reported by Lavilla, Ackermann, , Fairlamb, and among others. − The C2-functionalization of tryptophan derivatives is well explored without a directing group harnessing the electron-rich nature of the indole ring or via the installation of various directing groups at indole nitrogen atom. ,− Moreover, the modification of phenylalanine and other aliphatic residues are also explored through the installation of picolinamide as directing group at the N -terminus of amino acid. − To our best knowledge, the late-stage C2-functionalization of tryptophan peptides using picolinamide directing group at the N -terminus of tryptophan is unexplored. Recently, our group reported picolinamide-directed site-selective chalcogenation of phenylalanine-containing amino acids and peptides with disulfides/diselenides under Pd-catalysis (Scheme a) . This method is incompatible with aliphatic disulfides, amino acids having free hydroxyl group, and requires the use of Na 2 CO 3 as base.…”