Construction of Racemic and Enantiopure Biaryl Unnatural Amino Acid Derivatives via Pd(II)-Catalyzed Arylation of Unactivated Csp3−H Bonds

Abstract

We report the construction of racemic and enantiopure biaryl unnatural amino acid derivatives via the palladium-catalyzed stereoselective sp3 C−H activation and arylation of amino acid derivatives with iodobiaryls. The synthesis of biaryl motif installed (DL-), L- and D-amino acid derivatives including norvaline, phenylalanine, leucine, norleucine and 2-aminooctanoic acid with anti stereochemistry is reported. The synthesis of alanine derivatives with two biaryl motifs and aminoalkanoic acids with biaryl motifs is also shown. The C−H arylation of enantiopure carboxamides gave biaryl amino acid derivatives with good enantiopurity. Removal of the directing group 8-aminoquinoline, deprotection of the phthalimide moiety, and the preparation of biaryl amino acid derivatives containing free amino- and carboxylate groups are also reported. The stereochemistry (anti) of representative major diastereomers was unequivocally ascertained from X-ray structure analysis. Biaryl amino acids/peptides are important motifs in medicinal chemistry, and this work therefore represents a contribution towards enriching the library of biaryl amino acids.