Modular, Scalable Total Synthesis of Neopetromin

Abstract

The first total synthesis of neopetromin, featuring the highly strained Tyr C-6-to-Trp N-1’ linkage, is hereby reported. This modular synthetic strategy, employing C—H arylation and Larock macrocyclization, offers a novel approach to the synthesis of various RiPPs natural product families.

Keywords

Total synthesis / Natural product / Biaryl cyclic peptides / RiPPs / C—H activation / Larock macrocyclization / Scalable synthesis

References

[1] (a)Nguyen, T. Q. N.; Tooh, Y. W.; Sugiyama, R.; Nguyen, T. P. D.; Purushothaman, M.; Leow, L. C.; Hanif, K.; Yong, R. H. S.; Agatha, I.; Winnerdy, F. R.; Gugger, M.; Phan, A. T.; Morinaka, B. I. Post-Translational Formation of Strained Cyclophanes in Bacteria. Nat. Chem. 2020,12,1042–1053;b)Phan, C.-S.; Morinaka, B. I. Bacterial Cyclophane-Containing RiPPs from Radical SAM Enzymes. Nat. Prod. Rep. 2024,41,708–720;c)Zeng, M.; Tao, J.; Xu, S.; Bai, X.; Zhang, H. Marine Organisms as a Prolific Source of Bioactive Depsipeptides. Mar. Drugs 2023,21,120–141;

[2] (a)An, J. S.; Lee, H.; Kim, H.; Woo, S.; Nam, H.; Lee, J.; Lee, J. Y.; Nam, S.-J.; Lee, S. K.; Oh, K.-B.; Kim, S.; Oh, D.-C. Discovery and Biosynthesis of Cihunamides, Macrocyclic Antibacterial RiPPs with a Unique C-N Linkage Formed by CYP450 Catalysis. Angew. Chem. Int. Ed. 2023,62,e202300998;b)Imai, Y.; Meyer, K. J.; Iinishi, A.; Favre-Godal, Q.; Green, R.; Manuse, S.; Caboni, M.; Mori, M.; Niles, S.; Ghiglieri, M.; Honrao, C.; Ma, X.; Guo, J. J.; Makriyannis, A.; Linares-Otoya, L.; Böhringer, N.; Wuisan, Z. G.; Kaur, H.; Wu, R.; Mateus, A.; Typas, A.; Savitski, M. M.; Espinoza, J. L.; O’Rourke, A.; Nelson, K. E.; Hiller, S.; Noinaj, N.; Schäberle, T. F.; D’Onofrio, A.; Lewis, K. A New Antibiotic Selectively Kills Gram-Negative Pathogens. Nature 2019,576,459–464.

[3] He, B.-B.; Liu, J.; Cheng, Z.; Liu, R.; Zhong, Z.; Gao, Y.; Liu, H.; Song, Z.-M.; Tian, Y.; Li, Y.-X. Bacterial Cytochrome P450 Catalyzed Post-Translational Macrocyclization of Ribosomal Peptides. Angew. Chem. Int. Ed. 2023,62,e202311533.

[4] Saito, S.; Atsumi, K.; Zhou, T.; Fukaya, K.; Urabe, D.; Oku, N.; Karim, M. R. U.; Komaki, H.; Igarashi, Y. A Cyclopeptide and Three Oligomycin-Class Polyketides Produced by an Underexplored Actinomycete of the Genus Pseudosporangium. Beilstein J. Org. Chem. 2020,16,1100–1110.

[5] Yu, L.; Nagata, Y.; Nakamura, H. Atroposelective Total Synthesis of Cihunamide B. J. Am. Chem. Soc. 2024,146,2549–2555.

[6] (a)Ogawa, H.; Nakamura, H. Atroposelective total synthesis of strecintide 839. Tetrahedron Chem. 2024,11,100084;b)Ogawa, H.; Yu, L.; Li, S.; Nagata, Y.; Chan, T. K.; Matsuda, Y.; Liu, J.; Li, Y.-X.; Nakamura, H. Modular, Atroposelective Total Synthesis of Micitide 982. ChemRxiv 2024,c)Zhang, J.; Yu, L.; Ogawa, H.; Nagata, Y.; Nakamura, H. Modular, Scalable Total Synthesis of Lapparbin with a Noncanonical Biaryl Linkage. Angew. Chem. Int. Ed. 2024,e202409987.

[7] Hitora, Y.; El-Desoky, A. H.; Sadahiro, Y.; Sejiyama, A.; Kinoshita, A.; Ise, Y.; Angkouw, E. D.; Mangindaan, R. E. P.; Higaki, T.; Tsukamoto, S. Neopetromin, a Cyclic Tripeptide with a C-N Cross-Link, from the Marine Sponge Neopetrosia sp., That Causes Vacuole Fragmentation in Tobacco BY-2 Cells. J. Nat. Prod. 2024,87,1197–1202.

[8] Wyche, T. P.; Ruzzini, A. C.; Schwab, L.; Currie, C. R.; Clardy, J. Tryptorubin A: A Polycyclic Peptide from a Fungus-Derived Streptomycete. J. Am. Chem. Soc. 2017,139,12899–12902.

[9] Saad, H.; Majer, T.; Bhattarai, K.; Lampe, S.; Nguyen, D. T.; Kramer, M.; Straetener, J.; Brötz-Oesterhelt, H.; Mitchell, D. A.; Gross, H. Bioinformatics-Guided Discovery of Biaryl-Linked Lasso Peptides. Chem. Sci. 2023,14,13176–13183.

[10] Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Total Synthesis Reveals Atypical Atropisomerism in a Small-Molecule Natural Product, Tryptorubin A. Science 2020,367,458–463.

[11] (a)Garfunkle, J.; Kimball, F. S.; Trzupek, J. D.; Takizawa, S.; Shimamura, H.; Tomishima, M.; Boger, D. L. Total Synthesis of Chloropeptin II (Complestatin) and Chloropeptin I. J. Am. Chem. Soc. 2009,131,16036–16038;b)Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Catalytic Asymmetric Total Synthesis of (-)-Galanthamine and (–)-Lycoramine. Angew. Chem. Int. Ed. 2015,54,6255–6259;c)Liu, H.; Zhang, X.; Shan, D.; Pitchakuntla, M.; Ma, Y.; Jia, Y. Total Syntheses of Festuclavine, Pyroclavine, Costaclavine, Epi-Costaclavine, Pibocin A, 9-Deacetoxyfumigaclavine C, Fumigaclavine G, and Dihydrosetoclavine. Org. Lett. 2017,19,3323–3326;d)Shan, D.; Gao, Y.; Jia, Y. Intramolecular Larock Indole Synthesis: Preparation of 3, 4-Fused Tricyclic Indoles and Total Synthesis of Fargesine. Angew. Chem. Int. Ed. 2013,52,4902–4905;e)Holman, K. R.; Stanko, A. M.; Reisman, S. E. Palladium-Catalyzed Cascade Cyclizations Involving C-C and C-X Bond Formation: Strategic Applications in Natural Product Synthesis. Chem. Soc. Rev. 2021,50,7891–7908;f)Breazzano, S. P.; Poudel, Y. B.; Boger, D. L. A Pd(0)-Mediated Indole (Macro)Cyclization Reaction. J. Am. Chem. Soc. 2013,135,1600–1606;g)Schneider, F.; Guo, Y.; Lin, Y.-C.; Eberle, K. J.; Chiodi, D.; Greene, J. A.; Lu, C.; Baran, P. S. Total Synthesis of Dynobactin A. J. Am. Chem. Soc. 2024,146,6444–6448;h)Lin, Y.-C.; Schneider, F.; Eberle, K. J.; Chiodi, D.; Nakamura, H.; Reisberg, S. H.; Chen, J.; Saito, M.; Baran, P. S. Atroposelective Total Synthesis of Darobactin A. J. Am. Chem. Soc. 2022,144,14458–14462;i)Nesic, M.; Ryffel, D. B.; Maturano, J.; Shevlin, M.; Pollack, S. R.; Gauthier, D. R., Jr; Trigo-Mouriño, P.; Zhang, L.-K.; Schultz, D. M.; McCabe Dunn, J. M.; Campeau, L.-C.; Patel, N. R.; Petrone, D. A.; Sarlah, D. Total Synthesis of Darobactin A. J. Am. Chem. Soc. 2022,144,14026–14030;j)Isley, N. A.; Endo, Y.; Wu, Z.-C.; Covington, B. C.; Bushin, L. B.; Seyedsayamdost, M. R.; Boger, D. L. Total Synthesis and Stereochemical Assignment of Streptide. J. Am. Chem. Soc. 2019,141,17361–17369.

RIGHTS & PERMISSIONS

2024 The Authors. Published by SIOC, CAS, Shanghai and Wiley-VCH GmbH