Editorial Cite This: J. Org. Chem. 2018, 83, 6826−6828
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Synthesis of Antibiotics and Related Molecules
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a polyketide-derived macrolide antibiotic, Ohba and Nakata report a sequential intramolecular Barbier-type reaction using 2,4,6-triisopropylphenyllithium followed by deoxygenation of the resulting anomeric hydroxyl group to access the macrocyclic aryl C-glycoside substructure of the natural product paecilomycin B.16 Pantin, Brimble, and Furkert describe the enantioselective synthesis of (−)-peniphenone A, a spiroketal natural product, by introducing the alpha-methyl beta-aryl ketone substructure, a structural motif shared with related natural products, via a Negishi cross-coupling between a chiral organozinc species and an aryl bromide. In this approach, they rely on a fascinating thermodynamic resolution at C10 during a critical spirocyclization reaction to access the desired natural product.17 One of the strengths of synthetic routes to natural products or natural product-like compounds is that, once established, they can be used to prepare analogues both to improve their pharmacological properties and to investigate their mode of action. For example, the Waldmann and Antonchick groups report the preparation of a library of 119 compounds inspired by natural pyrrolizidine alkaloids. Bioactivity screens demonstrated that this compound class exhibits activity against Plasmodium falciparum 3D7 and inhibits Hedgehog signaling.18 A similar type of campaign termed “motif-oriented” synthesis was used by Fürstner and colleagues to prepare a series of compounds inspired by nannocystin Ax.19 In silico docking studies of the related cyclodepsipeptide nannocystin A suggest that it binds to the eukaryotic translation elongation factor 1α. In addition to nannocystin Ax, 10 analogues were prepared, and their activity was evaluated, revealing key parts of the bioactive pharmacophore and demonstrating that a previous model may need refinement. In their synthetic strategy, a trisubstituted alkene with an allylic methyl ether, the motif of interest, inspired a late-stage sequence involving a molybdenum alkylidyne catalyzed ring-closing alkyne metathesis, followed by a ruthenium catalyzed hydroxyl-directed trans-hydrostannation of the resulting cycloalkyne to give a versatile intermediate for further derivatization. In another example, Herzon and coworkers provide a platform for rapid modification of (+)-pleuromutilin at various sites through application of Hartwig’s hydroxyl-directed iridium-catalyzed C−H silylation.20 The efficiency of their approach offers a practical means for rapid access to analogs for structure−activity relationship studies. Several contributions in this issue provide new insights into the biosynthesis of natural products. Minami and Oikawa demonstrate the total biosynthesis of the antiangiogenic agent (−)-terpestacin.21 The authors expressed a bifunctional terpene synthase, two cytochrome P450s, and a flavin-dependent oxidase in the heterologous host Aspergillus oryzae, which provided the desired natural product. This system is a promising production platform for genome mining for
atural products have long been a source of inspiration for organic chemists to develop new synthetic strategies and methodologies. Their societal value cannot be underestimated as the advent of antibiotics from natural sources has fundamentally changed how medicine is practiced. The high complexity of their structures has also instilled a sense of awe as to how these structures may have evolved. The remarkable advances in DNA sequencing of the past decade have provided an unprecedented opportunity to understand nature’s pathways to natural products and hence to compare synthetic and biosynthetic routes. We have enjoyed coediting this special issue of The Journal of Organic Chemistry that is focused on both synthetic and biosynthetic chemistry of natural products, with an emphasis on antibiotics. As described with representative examples below, this issue is a compendium that covers a wide spectrum of the chemistry of natural products, including synthetic methodology development, total chemical synthesis, biosynthetic studies, and analogue generation by either organic synthesis or biosynthetic pathway engineering. Several papers in this issue describe methods to prepare cyclic peptides and macrolides. These compounds have attracted much attention in both academia and industry as molecules that potentially can inhibit challenging drug targets such as protein−protein interactions.1−4 Furthermore, cyclic peptides exhibit an array of other activities. For instance, Inoue and co-workers show that WAP-8294A2 is a menaquinonetargeting antibiotic.5 The authors report its total synthesis and performed mode of action studies. Ichikawa’s laboratory illustrates the use of a solvent-dependent diastereodivergent Joullié−Ugi three-component reaction to access the antimicrobial cyclic depsipeptide plusbacin A3. In addition to macrocyclization using lactam or lactone structures, Nature also utilizes a large number of other cyclization strategies. One example is bottromycin, a ribosomally synthesized peptide that is post-translationally cyclized via an amidine linkage. Omura and Sunazuka and their co-workers confirmed the structure of several bottromycin congeners by total synthesis and report a series of analogues and their biological activities.6 They employ an efficient intermolecular amidination reaction to set the stage for a versatile macrocyclization via condensation of the Nterminal methyl proline and the C-terminal glycine. Although at present the great majority of technologies used to prepare cyclic peptides involve chemical reactions,7 biosynthetic strategies are finding increasing interest.8−12 For example, Zhang and coworkers applied the biosynthetic cyclization machinery to make analogs of teixobactin,13 a recently discovered antibiotic that has elicited much excitement as a potential lead compound for treatment of multidrug resistant bacteria.14 Gademann and co-workers describe the first total synthesis of the macrolide antibiotic fidaxomicin. In their synthesis, an ambitious ring-closing olefin metathesis reaction of a hexaene intermediate results in the macrocyclic structure of the natural product, a strategy they also apply to the first synthesis of the related natural macrolide tiacumicin A.15 In another example of © 2018 American Chemical Society
Special Issue: Synthesis of Antibiotics and Related Molecules Published: July 6, 2018 6826
DOI: 10.1021/acs.joc.8b01330 J. Org. Chem. 2018, 83, 6826−6828
The Journal of Organic Chemistry
Editorial
Notes
currently unknown natural products. Liu and co-workers describe the discovery of a new nonribosomal peptide cysteoamide.22 Analysis of the gene cluster provided key insights into the biosynthesis of this cyclic depsipeptide and demonstrated that an unusual cysteate contained within the compound is biosynthesized by a pyridoxal-phosphate dependent enzyme. This knowledge was then used to predict the gene clusters of other cysteate containing natural products. Vancomycin and teicoplanin are other examples of nonribosomal peptides that are used as drugs of last resort against antibiotic-resistant pathogens. They are members of the glycopeptide class of natural products and have fascinating structures with linkages between aromatic amino acids. Cryle and co-workers have reconstituted in vitro the activity of the P450 enzymes that introduce these cross-links and in this issue they investigate the substrate specificity of these enzymes.23 Inspired by Nature’s dimerization and rearrangement of oroidin-type alkaloids, Harran and co-workers devised a cascading auto-oxidation of a biproline derivative in the presence of guanidine free-base that affords a key spirocyclic intermediate in their synthesis of (−)-ageliferin.24 While much effort in the past two decades has focused on understanding the molecular transformations involved in the biosynthesis of natural products, more recently chemists have started to also focus on another type of organic chemistry in biology involving natural products: metabolism of natural products to generate derivatives that sometimes have completely different activities. Sometimes, these metabolic reactions are catalyzed by human enzymes and sometimes by enzymes produced by the microbiome. An example of the latter is reported by Crawford and co-workers who show that the commonly prescribed βlactams amoxicillin and ampicillin are metabolized by bacteria to produce compounds that activate innate immunity, whereas amoxicillin itself exhibits no such effects.25 Clearly, natural products remain an important pillar for organic chemistry, broadly defined. With the promise of genome mining delivering a large number of new structures to complement a perenially strong discovery effort focused on activity-based screens,26−29 it is clear that the future is bright.
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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Mohammad Movassaghi, Guest Editor Department of Chemistry, Massachusetts Institute of Technology
Wilfred A. van der Donk, Guest Editor
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REFERENCES
(1) Passioura, T.; Katoh, T.; Goto, Y.; Suga, H. Selection-based discovery of druglike macrocyclic peptides. Annu. Rev. Biochem. 2014, 83, 727. (2) Tsomaia, N. Peptide therapeutics: targeting the undruggable space. Eur. J. Med. Chem. 2015, 94, 459. (3) Zorzi, A.; Deyle, K.; Heinis, C. Cyclic peptide therapeutics: past, present and future. Curr. Opin. Chem. Biol. 2017, 38, 24. (4) Cyclic Peptides: from Bioorganic Synthesis to Applications; Koehnke, J., Naismith, J., van der Donk, W. A., Eds.; Royal Society of Chemistry: Cambridge, UK, 2018. (5) Itoh, H.; Tokumoto, K.; Kaji, T.; Paudel, A.; Panthee, S.; Hamamoto, H.; Sekimizu, K.; Inoue, M. Total Synthesis and Biological Mode of Action of WAP-8294A2: A Menaquinone-Targeting Antibiotic. J. Org. Chem. 2017, DOI: 10.1021/acs.joc.7b02318. (6) Yamada, T.; Yagita, M.; Kobayashi, Y.; Sennari, G.; Shimamura, H.; Matsui, H.; Horimatsu, Y.; Hanaki, H.; Hirose, T.; Omura, S.; Sunazuka, T. Synthesis and Evaluation of Antibacterial Activity of Bottromycin A2, B2, and other Analogs. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00045. (7) White, C. J.; Yudin, A. K. Contemporary strategies for peptide macrocyclization. Nat. Chem. 2011, 3, 509. (8) Walsh, C. T. Are highly morphed peptide frameworks lurking silently in microbial genomes valuable as next generation antibiotic scaffolds? Nat. Prod. Rep. 2017, 34, 687. (9) Walsh, C. T. Insights into the chemical logic and enzymatic machinery of NRPS assembly lines. Nat. Prod. Rep. 2016, 33, 127. (10) Kohli, R. M.; Walsh, C. T.; Burkart, M. D. Biomimetic synthesis and optimization of cyclic peptide antibiotics. Nature 2002, 418, 658. (11) Craik, D. J.; Du, J. Cyclotides as drug design scaffolds. Curr. Opin. Chem. Biol. 2017, 38, 8. (12) Yang, X.; Lennard, K. R.; He, C.; Walker, M. C.; Ball, A. T.; Doigneaux, C.; Tavassoli, A.; van der Donk, W. A. A lanthipeptide library used to identify a protein-protein interaction inhibitor. Nat. Chem. Biol. 2018, 14, 375. (13) Mandalapu, D.; Ji, X.; Chen, J.; Guo, C.; Liu, W.-Q.; Ding, W.; Zhou, J.; Zhang, Q. Thioesterase-mediated synthesis of teixobactin analogues: mechanism and substrate specificity. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.7b02462. (14) Ling, L. L.; Schneider, T.; Peoples, A. J.; Spoering, A. L.; Engels, I.; Conlon, B. P.; Mueller, A.; Schaberle, T. F.; Hughes, D. E.; Epstein, S.; Jones, M.; Lazarides, L.; Steadman, V. A.; Cohen, D. R.; Felix, C. R.; Fetterman, K. A.; Millett, W. P.; Nitti, A. G.; Zullo, A. M.; Chen, C.; Lewis, K. A new antibiotic kills pathogens without detectable resistance. Nature 2015, 517, 455. (15) Hattori, H.; Kaufmann, E.; Miyatake-Ondozabal, H.; Berg, R.; Gademann, K. Total Synthesis of Tiacumicin A. Total Synthesis, Relay Synthesis, and Degradation Studies of Fidaxomicin (Tiacumicin B, Lipiarmycin A3). J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00101. (16) Ohba, K.; Nakata, M. Convergent Total Synthesis of Paecilomycin B and 6′-epi-Paecilomycin B by a Barbier-Type Reaction Using 2,4,6-Triisopropylphenyllithium. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.7b03041. (17) Pantin, M.; Brimble, M. A.; Furkert, D. P. Total Synthesis of (−)-Peniphenone A. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.7b03231. (18) Jia, Z.-J.; Takayama, H.; Futamura, Y.; Aono, H.; Bauer, J.; Strohmann, C.; Antonchick, A.; Osada, H.; Waldmann, H. Catalytic Enantioselective Synthesis of a Pyrrolizidine-Alkaloid-Inspired Compound Collection with Antiplasmodial Activity. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.7b03202. (19) Fürstner, A.; Meng, Z.; Souillart, L.; Monks, B.; Huwyler, N.; Herrmann, J.; Müller, R. A “Motif-Oriented” Total Synthesis of
Department of Chemistry, University of Illinois at Urbana−Champaign and Howard Hughes Medical Institute
AUTHOR INFORMATION
ORCID
Mohammad Movassaghi: 0000-0003-3080-1063 Wilfred A. van der Donk: 0000-0002-5467-7071 6827
DOI: 10.1021/acs.joc.8b01330 J. Org. Chem. 2018, 83, 6826−6828
The Journal of Organic Chemistry
Editorial
Nannocystin Ax. Preparation and Biological Assessment of Analogues. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.7b02871. (20) Ma, X.; Kucera, R.; Goethe, O. F.; Murphy, S. K.; Herzon, S. B. Directed C−H Bond Oxidation of (+)-Pleuromeutilin. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00462. (21) Narita, K.; Minami, A.; Ozaki, T.; Liu, C.; Kodama, M.; Oikawa, H. Total biosynthesis of antiangiogenic agent (−)-terpestacin by artificial reconstitution of the biosynthetic machinery in Aspergillus oryzae. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.7b03220. (22) Wang, M.; Chen, D.; Zhao, Q.; Liu, W. Isolation, Structure Elucidation, and Biosynthesis of a Cysteate-Containing Non-ribosomal Peptide in Streptomyces lincolnensis. J. Org. Chem. 2018, DOI: 10.1021/ acs.joc.8b00044. (23) Schoppet, M.; Tailhades, J.; Kulkarni, K.; Cryle, M. Precursor manipulation in glycopeptide antibiotic biosynthesis: are β-amino acids compatible with the oxidative cyclization cascade? J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00418. (24) Ding, H.; Roberts, A. G.; Chiang, R.; Harran, P. G. Cascading Auto-oxidative Biproline Guanylations Form Optically Active Dispacamide Dimers and Permit an Eight-Step Synthesis of (−)-Ageliferin. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00631. (25) Oh, J.; Patel, J.; Park, H. B.; Crawford, J. β-lactam Biotransformations Activate Innate Immunity. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00241. (26) Bode, H. B.; Müller, R. The impact of bacterial genomics on natural product research. Angew. Chem., Int. Ed. 2005, 44, 6828. (27) Wilkinson, B.; Micklefield, J. Mining and engineering naturalproduct biosynthetic pathways. Nat. Chem. Biol. 2007, 3, 379. (28) Challis, G. L. Genome mining for novel natural product discovery. J. Med. Chem. 2008, 51, 2618. (29) Pye, C. R.; Bertin, M. J.; Lokey, R. S.; Gerwick, W. H.; Linington, R. G. Retrospective analysis of natural products provides insights for future discovery trends. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 5601.
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DOI: 10.1021/acs.joc.8b01330 J. Org. Chem. 2018, 83, 6826−6828
