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

Abstract

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.

Biological Effects of a Simplified Synthetic Analogue of Ion‐Channel‐Forming Polytheonamide B on Plasma Membrane and Lysosomes

“…After synthesizing the protected amino acid components, the full solid‐phase total synthesis of 3 was realized by applying a strategy developed for the synthesis of 1 (see the Supporting Information) . Briefly, N‐terminal residues 1–11 and C‐terminal residues 12–48 were individually elongated on ChemMatrix resin using Fmoc chemistry through cycles of piperidine‐promoted Fmoc removal and amidation under microwave‐assisted conditions.…”

Tetrahydropyranyl: A Non‐aromatic, Mild‐Acid‐Labile Group for Hydroxyl Protection in Solid‐Phase Peptide Synthesis

“…Since the first synthesis of a tetrapeptide on a solid support in 1963, methodological advances in solid‐phase peptide synthesis (SPPS) have allowed the preparation of a vast number of complex peptides . Accordingly, a key factor in peptide science is amino acid side‐chain protection, a procedure used to prevent undesired side reactions.…”

Solid‐Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation

“…In fact, Fmoc‐based SPPS enables the routine synthesis of peptides with sizes up to 50 residues and for the manufacture of pharmaceuticals in hundred‐kilogram scales . Despite the remarkable advances in SPPS, when peptide molecules of interest contain components beyond the canonical 20 proteinogenic l ‐amino acids, their chemical synthesis poses formidable challenges …”