Update and Review,on‐resin chemical syntheses of aliphatic and vinylogous peptide boronic acids

The field of peptide boronic acid synthesis has witnessed significant advancements, driven by the unique properties and diverse applications of these fascinating molecules. Peptide boronic acids (PBAs), characterized by the presence of a boronic acid moiety within a peptide structure, have emerged as valuable tools in medicinal chemistry, materials science, and chemical biology. Research efforts have focused on developing efficient and versatile synthetic methodologies to access these compounds, leading to a range of innovative strategies.

One prominent approach involves solid-phase peptide synthesis (SPPS), a well-established technique for constructing peptide chains. The solid phase synthesis of C-terminal boronic acid peptides has been effectively achieved using commercially available resins, such as 1-glycerol polystyrene resin, yielding peptides with high efficiency. This method allows for the controlled assembly of amino acids and the subsequent introduction of the boronic acid functionality. Another significant development in solid-phase synthesis is the preparation of peptide β-aminoboronic acids on solid support, utilizing resins like 2-chlorotrityl resin. These strategies emphasize the importance of on-resin chemical syntheses of aliphatic and vinylogous peptide boronic acids, often employing transition metal-catalyzed late-stage functionalization.

Diversity-oriented synthesis has also played a crucial role in expanding the repertoire of accessible peptide-boronic acids. A new strategy for the diversity-oriented synthesis of peptide-boronic acids has been presented, utilizing 20 Fmoc-protected natural amino acids with orthogonal side-chain protection. Such approaches enable the rapid generation of libraries of peptide-boronic acids, facilitating the discovery of novel compounds with desired properties.

Beyond solid-phase methods, solution-phase strategies are also employed. For instance, late-stage hydroboration on the peptide backbone offers a powerful route to introduce boronic acid groups. This technique allows for the synthesis of aliphatic and vinylogous peptide boronic acids through transition metal-catalyzed reactions. Furthermore, the Miyaura borylation reaction stands out as a robust method for the synthesis of boronates via cross-coupling of borylation reagents with aryl and vinyl halides, which can be integrated into peptide synthesis workflows.

The catalytic power of boron-containing compounds has also been harnessed for peptide bond formation. Boronic acid catalysts are effective in facilitating peptide bond formation reactions between methyl esters derived from amino acids. Similarly, borinic acid catalysed peptide synthesis offers an efficient route to form peptide bonds with minimal racemization, a critical factor in maintaining peptide integrity. Alkane-gem-diboronic acids have emerged as versatile organoboron catalysts for dehydrative amidation of α-aminoacids, contributing to direct amide/peptide bond formation.

The unique properties of boronic acids, such as their ability to form reversible covalent complexes with diols and amines, lend themselves to interesting material applications. For example, boronic acid-modified phenylalanine dipeptide reversibly assembles into nanoribbon gels triggered by variations in pH, ionic strength, and polyols. This self-assembly behavior opens avenues for developing smart biomaterials and drug delivery systems.

In the realm of medicinal chemistry, peptide boronic acids have shown significant therapeutic potential. Two series of peptide-boronic acids as proteasome inhibitors were designed and synthesized, with many compounds exhibiting substantial antiproliferative activity against cancer cell lines. For the synthesis of the proteasome inhibitor prodrug 18, a dipeptidyl boronic acid was reacted with diethanolamine, demonstrating the utility of these compounds in drug development. The ability to synthesize boronopeptides through various methods is crucial for exploring their pharmacological profiles.

The fundamental chemistry of boric acid and its derivatives continues to be explored. Boron-assisted abiotic polypeptide synthesis highlights the role of boron esters in forming peptide bonds, releasing boric acid as a byproduct. Moreover, the engagement of boronic acids as carbon nucleophiles in reactions like the Passerini-type three-component coupling reaction enables the synthesis of novel organoboron compounds.

In summary, the peptide boronic acid synthesis landscape is rich with innovative methodologies, encompassing solid-phase and solution-phase strategies, catalytic approaches, and late-stage functionalization techniques. These advancements in peptide synthesis are not only expanding our understanding of boron chemistry but also paving the way for the development of novel therapeutics, advanced materials, and sophisticated biochemical tools. The ongoing research in this area promises further breakthroughs in harnessing the potential of boronic acids and their derivatives.