On-Demand Complex Peptide Synthesis: An Aspirational (and Elusive?) Goal for Peptide Synthesis

Peptide synthesis is a truly interdisciplinary tool, familiar to a broad group of scientists who do not otherwise overlap scientifically. For this reason, some may perceive even complex peptide synthesis to be a "solved problem", while others might argue that immense opportunity remains untapped or simply inaccessible. At the extreme of complexity, what might a concise assessment of the state-of-the-art in peptide synthesis look like? As one of the most practiced forms of synthetic chemistry by chemists and non-chemists alike, what restrictions remain that constrain access to chemical space? Using popular terminology, what forms of peptide synthesis are appropriately termed "on-demand"? The purpose of this Perspective is to appraise synthetic access to complex peptides, particularly those containing unnatural α-amino amides. Several case studies in complex peptide synthesis are summarized here, each selected to characterize the challenges attendant to unnatural α-amino amide synthesis. As peptidic molecules find increasing value in therapeutic development, especially in clinical applications, their impact will ultimately be determined by efficient preparative methods.