Highly Efficient and Divergent Construction of Chiral γ-Phosphono-α-Amino Acids via Palladium-Catalyzed Alkylation of Unactivated C(sp³)–H Bonds

Abstract

Chiral γ-phosphono-α-amino acids play a crucial role in inhibitors of natural enzymes, as well as agonists and antagonists of metabotropic glutamate receptors. In this paper, an efficient and general protocol for the construction of chiral γ-phosphono-α-amino acids via Pd-catalyzed AQ-directed C­(sp3)–H alkylation of α-amino acid derivatives is developed. The reaction shows reactivity between methylene C­(sp3)–H bonds with phosphonated alkyl iodides with high yields, enantioselectivity, and diastereomeric ratios, which enables access to a wide range of challenging and important γ-phosphono-α-amino acids in large scale. Meanwhile, δ-phosphono-α-amino acid and δ-phosphono-propionic acid derivatives can also be successfully obtained. The derivatization reaction in the synthesis of l-AP4 and l-phosphinothricin highlight the applicability of this method.

Homogeneous Catalysis: A Powerful Technology for the Modification of Important Biomolecules

“…Recently, Yang and co‐workers developed an efficient synthesis of chiral γ‐phosphono‐α‐amino acids 156 through a palladium‐catalyzed aminoquinoline‐directed C(sp 3 )−H alkylation of α‐amino acid derivatives 154 (Scheme ) . The reaction of methylene C(sp 3 )−H bonds with phosphonated alkyl iodides 155 provided the products in high yields with high enantioselectivities, and diastereomeric ratios.…”

“…Recently,Y anga nd co-workers developed an efficient synthesis of chiral g-phosphono-a-amino acids 156 through ap alladium-catalyzed aminoquinoline-directedC (sp 3 )ÀHa lkylation of a-amino acid derivatives 154 (Scheme 45). [102] The reaction of methylene C(sp 3 )ÀHb onds with phosphonated alkyl iodides 155 provided the products in high yields with high enantioselectivities, and diastereomeric ratios. Mechanistically,i tw as proposed that the reaction may proceed through ar edox catalytic cycle that involved Pd II /Pd IV speciesa nd af ew intermediates.…”

Site‐Selective C–H Bond Activation/Functionalization of Alpha‐Amino Acids and Peptide‐Like Derivatives

“…The products were obtained in moderate to very good yields under especially mild conditions using Pd(OAc) 2 as catalyst and Ag 2 CO 3 as oxidant at room temperature. Additionally, the synthesis of chiral γ‐phosphono‐α‐amino acids was achieved by Yang and co‐workers (entry 7) . Phosphonate‐containing alkyl iodines could be coupled in the presence of Pd(TFA) 2 and AgCO 3 with the β‐C–H bond of alanine derivatives in good yields (up to 99 %).…”

Recent Advances on Amino Acid Modifications via C–H Functionalization and Decarboxylative Functionalization Strategies

“…Through the protocol they demonstrated an access to δ‐phosphono‐α‐amino acid and δ‐phosphonopropionic acid derivatives also. They applied the protocol for the synthesis of l ‐AP4 54 and l ‐phosphinothricin 55 …”