Catalytic Asymmetric Synthesis of Spiro[3.3]heptane‐Based Axially Chiral α‐Amino Acids

ABSTRACT Natural α‐amino acids are fundamental to virtually all forms of life, and their unnatural analogues are indispensable building blocks in synthetic chemistry and pharmaceutical science. Current research predominantly focuses on centrally chiral unnatural α‐amino acids, while α‐amino acids featuring other chirality types are yet to be disclosed. We therefore sought to expand the chemical space of α‐amino acids by introducing the concept of axially chiral α‐amino acid. Here, we rationally design a prochiral α‐amino acid substrate derived from a spiro[3.3]heptane scaffold, an emerging Fsp 3 ‐enriched isostere in medicinal chemistry, and subsequent catalytic asymmetric synthesis of axially chiral α‐amino acids is realized via a reductive amination enabled by chiral phosphoric acid catalysis. A wide array of spiro[3.3]heptane‐based axially chiral α‐amino acids are obtained in generally high yields and enantioselectivities, and are readily incorporated into complex peptides by both solution‐phase and solid‐phase peptide synthesis. As conformationally constrained L ‐lysine mimetics, these amino acids can enhance inhibitory activities against PD‐1/PD‐L1 and improve physicochemical properties. Experimental and computational studies elucidate the reaction mechanism, the origin of enantioselectivity, and the structural basis for the improved biological activities. This work expands the accessible chemical space of α‐amino acids and establishes valuable building blocks for complex peptide synthesis.