Design and Asymmetric Synthesis of Unnatural Amino Acid Derivatives Showing Staircase and Orientational Chirality

Unnatural amino acid derivatives showcasing orientational and staircase chirality have been prepared by asymmetric synthesis and unambiguously confirmed by X-ray crystallography.

Abstract

Amino acids are basic building blocks of peptides and proteins, which play essential roles in biological processes. Unnatural chiral amino acids have been proven to be powerful in drug design and discovery. Meanwhile, chirality has gained significant attention in the scientific community since it has been showing a profound impact on chemical, biomedical, and materials sciences. So far, chiral amino acids have been primarily built on center chirality, which governed secondary, tertiary, and higher conformational structures of peptides and proteins. Here in this work, we demonstrate the design and asymmetric synthesis of unnatural amino acids with a staircase and several other chirality elements. The architecture of staircase chirality is characterized by two symmetrical phenyl rings anchored by a naphthyl pier, with the rings asymmetrically displaced due to the influence of chiral auxiliaries at their para positions. Notably, as proven by X-ray diffraction analysis, these staircase amino esters exhibit four distinct types of chirality: central, orientational, turbo, and staircase chirality, a chirality combination previously undocumented in the literature.

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