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

• Published in: European journal of organic chemistry 2021-07, Vol.2021 (25), p.3641-3656
• Main Authors: Banga, Shefali, Kaur, Ramandeep, Babu, Srinivasarao Arulananda
• Format: Article
• Language: English
• Subjects: Alanine; Amino acids; Aminoquinolines; C−H activation; Diastereoselectivity; Norleucine; Palladium; Peptides; Phenylalanine; Phthalimides; Stereochemistry; Stereoselectivity; Structural analysis; Synthesis; Synthetic methods; Unnatural amino acids
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202100683

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. The Pd‐catalyzed stereoselective sp3 C−H activation and arylation of various carboxamides of amino acids with iodobiaryls are reported. The synthesis of biaryl motif installed (DL‐), L‐ and D‐amino acid derivatives including norvaline, phenylalanine, leucine, norleucine, 2‐aminooctanoic acid (with anti stereochemistry), alanine and aminoalkanoic acids has been described.