Comprehensive Strategies in the Synthesis of Noncanonical Cyclic Peptides Containing Biaryl-Bridged Linkages
- 1Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China, 999077
Abstract
CONSPECTUS: The development of synthetic methodologies for natural products and the establishment of chemical supply routes for complex compounds, which advanced significantly in the twentieth century, provided organic chemists in both academia and industry with considerable confidence and assurance. These achievements offered humanity a systematic framework and a degree of sustainability in the supply of complex organic molecules. Established synthetic strategies enabled access, to a certain extent, to diverse bioactive compounds such as terpenes, alkaloids, and peptides. The isolation of bioactive natural products has often been compared to the extraction of crude oil, and we are repeatedly taught that the major bioactive natural products or their core scaffolds have already been “almost completely isolated.” Yet such a sense of accomplishment is frequently illusory. In reality, isolation techniques for bioactive natural products have advanced dramatically over time, and reports of newly isolated bioactive compounds continue to appear with vigor. In recent decades, the rapid progress of genome mining since the early 2000s has enabled the computational analysis of genetic information to uncover novel bioactive substances with pharmaceutical potential. This technology revealed that many organisms harbor, within their genomes, numerous beneficial bioactive compounds that are not produced under conventional environmental conditions. Consequently, a surge of discoveries—akin to a gold rush—has been reported. Among these natural products are compounds with previously unknown and distinctive scaffolds, many of which lack established synthetic supply routes. Notable examples include cihunamide B, lapparbin, micitide 982, rubrin, scabrirubin CB-4, and cyctetryptomycin A, all of which represent recently isolated noncanonical cyclic peptides characterized by biaryl-bridged linkages. Most of these compounds were discovered through genome mining and are distinguished by rigid architectures in which two aromatic rings, such as tryptophan and tyrosine, are covalently linked within the cyclic peptide framework. The presence of multiple highly conjugated sp2 carbons imparts pronounced linearity to the cyclic peptide backbone, concomitantly increasing structural strain. As a result, conventional strategies for cyclic peptide synthesis—such as intramolecular amide coupling, intramolecular Ullmann coupling, or intramolecular oxidative cyclization—are inadequate for constructing these highly strained biarylbridged cyclic peptides. We have recently established a general modular synthetic approach for these noncanonical cyclic peptides, enabling their supply on the gram scale. Most notably, this methodology not only permits the synthesis of naturally occurring biaryl-bridged linkages but also allows the deliberate incorporation of diverse, artificially designed aromatic motifs into arbitrary peptide linkers. Within the vast genetic “ocean” encoded in microbial genomes, numerous cryptic natural products with unprecedented scaffolds are expected to remain undiscovered. The systematic synthetic strategy we present herein provides a general and coherent framework that enables access to these compound classes, which until now have been exclusively available through microbial biosynthesis. Moreover, recent advances in photochemical and electrochemical methodologies, particularly inexpensive and mild radical reactions, have proven to be highly effective approaches for the synthesis of these previously unexplored natural products. These cutting-edge single-electron processes are not merely substitutes for classical two-electron name reactions; rather, they have emerged as powerful tools for navigating the genomic “ocean” and uncovering new chemical space.
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BibTeX
@misc{nakamura2026comprehensive,
title = {{Comprehensive Strategies in the Synthesis of Noncanonical Cyclic Peptides Containing Biaryl-Bridged Linkages}},
author = {Hugh Nakamura},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008905/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008905/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Comprehensive Strategies in the Synthesis of Noncanonical Cyclic Peptides Containing Biaryl-Bridged Linkages
AU - Hugh Nakamura
PY - 2026
DA - 2026/09/16
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008905/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008905/v1
AB - CONSPECTUS: The development of synthetic methodologies for natural products and the establishment of chemical supply routes for complex compounds, which advanced significantly in the twentieth century, provided organic chemists in both academia and industry with considerable confidence and assurance. These achievements offered humanity a systematic framework and a degree of sustainability in the supply of complex organic molecules. Established synthetic strategies enabled access, to a certain extent, to diverse bioactive compounds such as terpenes, alkaloids, and peptides. The isolation of bioactive natural products has often been compared to the extraction of crude oil, and we are repeatedly taught that the major bioactive natural products or their core scaffolds have already been “almost completely isolated.” Yet such a sense of accomplishment is frequently illusory. In reality, isolation techniques for bioactive natural products have advanced dramatically over time, and reports of newly isolated bioactive compounds continue to appear with vigor. In recent decades, the rapid progress of genome mining since the early 2000s has enabled the computational analysis of genetic information to uncover novel bioactive substances with pharmaceutical potential. This technology revealed that many organisms harbor, within their genomes, numerous beneficial bioactive compounds that are not produced under conventional environmental conditions. Consequently, a surge of discoveries—akin to a gold rush—has been reported. Among these natural products are compounds with previously unknown and distinctive scaffolds, many of which lack established synthetic supply routes. Notable examples include cihunamide B, lapparbin, micitide 982, rubrin, scabrirubin CB-4, and cyctetryptomycin A, all of which represent recently isolated noncanonical cyclic peptides characterized by biaryl-bridged linkages. Most of these compounds were discovered through genome mining and are distinguished by rigid architectures in which two aromatic rings, such as tryptophan and tyrosine, are covalently linked within the cyclic peptide framework. The presence of multiple highly conjugated sp2 carbons imparts pronounced linearity to the cyclic peptide backbone, concomitantly increasing structural strain. As a result, conventional strategies for cyclic peptide synthesis—such as intramolecular amide coupling, intramolecular Ullmann coupling, or intramolecular oxidative cyclization—are inadequate for constructing these highly strained biarylbridged cyclic peptides. We have recently established a general modular synthetic approach for these noncanonical cyclic peptides, enabling their supply on the gram scale. Most notably, this methodology not only permits the synthesis of naturally occurring biaryl-bridged linkages but also allows the deliberate incorporation of diverse, artificially designed aromatic motifs into arbitrary peptide linkers. Within the vast genetic “ocean” encoded in microbial genomes, numerous cryptic natural products with unprecedented scaffolds are expected to remain undiscovered. The systematic synthetic strategy we present herein provides a general and coherent framework that enables access to these compound classes, which until now have been exclusively available through microbial biosynthesis. Moreover, recent advances in photochemical and electrochemical methodologies, particularly inexpensive and mild radical reactions, have proven to be highly effective approaches for the synthesis of these previously unexplored natural products. These cutting-edge single-electron processes are not merely substitutes for classical two-electron name reactions; rather, they have emerged as powerful tools for navigating the genomic “ocean” and uncovering new chemical space.
ER -