Construction of C5‐Indole Unnatural Amino Acid Motifs via Diastereoselective Pd(II)‐Catalyzed β‐C(sp3)‐H Functionalization

Abstract

AbstractWe report the construction of C5‐indole unnatural amino acid derivatives via the diastereoselective Pd(II)‐catalyzed prochiral β‐C(sp3)‐H arylation of racemic (DL), and enantiopure L‐ and D‐carboxamides of amino acids with 5‐iodoindoles. Independently, indole‐based compounds and amino acid motifs are important small molecules in organic synthesis and drug discovery research. This report aimed to contribute to enriching the library of indole‐based unnatural amino acid derivatives. The synthesis of examples of C5‐indole motif‐installed amino acid derivatives comprising norvaline, phenylalanine, leucine, norleucine, 2‐aminooctanoic acid having anti‐stereochemistry was accomplished. The synthesis of the C5‐indole motif‐containing non‐α‐amino acid (aminoalkanoic acid) derivatives was also reported. The C−H arylation reactions of racemic and enantiopure carboxamides with 5‐iodoindoles afforded the corresponding indole unnatural amino acid derivatives with good diastereoselectivity (anti, dr>95 : 5 and enantiopurity (er up to 99 : 1). Removal of the directing group (8‐aminoquinoline), phthalimide group and preparation of indole amino acid esters and free amino group‐containing indole unnatural amino acid motifs were also shown. The utility of the methodology was shown by synthesizing indole motif‐containing pyrrolidone and peptide molecules. The stereochemistry of the major (anti) diastereomers was ascertained from the X‐ray structure of a representative compound.