Formal Synthesis of (±)-Platensimycin

Zou, Yuze; Chen, Chun-Hsing; Taylor, Christopher D.; Foxman, Bruce M.; Snider, Barry B.

doi:10.1021/ol070563g

Cited by 104 publications

(37 citation statements)

References 15 publications

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“…Finally, the unusual caged ring system forms hydrogen bonds with Thr270 and Ala309, but is otherwise rather solventexposed (Panel B, Figure 2). 24 Several total syntheses of platensimycin, [27][28][29] as well as a related natural product platencin, 30 have been reported. Additionally, analogues of platensimycin have been synthesised, [31][32][33][34][35] allowing the definition of structure-function relationships.…”

Section: Methodsmentioning

confidence: 99%

Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility

et al. 2014

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Martin Fisher, [a,b] Ramkrishna Basak, [a,b] Arnout P. Kalverda, [b] Colin W. G. Fishwick, [a,b] W. Bruce Turnbull [a,b] and Adam Nelson* [a,b] , An approach for designing bioactive small molecules has been developed in which de novo structure-based ligand design (SBLD) was focused on regions of chemical space accessible using a diversity-oriented synthetic approach. The approach was exploited in the design and synthesis of a focused library of platensimycin analogues in which the com plex bridged ring system was replaced with a series of alternative ring systems. The affinity of the resulting compounds for the C163Q mutant of FabF was determined using a WaterLOGSY competition binding assay. Several compounds had significantly improved affinity for the protein relative to a reference ligand. The integration of synthetic accessibility with ligand design enabled focus to be placed on synthetically-accessible regions of chemical space that were relevant to the target protein under investigation.

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Section: Methodsmentioning

confidence: 99%

Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility

et al. 2014

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“…Der nächste Ansatz zur Synthese des Platensimycin-Ketolids 310 kam aus der Gruppe von Snider, und obwohl 310 dabei in Form des Racemats entsteht, ist dies die effizienteste Herstellungsmethode, denn sie verläuft mit einer bemerkenswerten Gesamtausbeute von 32 % ausgehend vom Tetralon 338 (Schema 51). [223] Eine Birch-Reduktion [224] . [211] Schema 51.…”

Section: Angewandte Chemieunclassified

“…[211] Schema 51. Retrosynthetische Analyse (a) und Synthese (b) von (AE)-310 durch Radikalcyclisierung (Snider et al, 2007). [223] K. C. (Schema 52 b).…”

Section: Angewandte Chemieunclassified

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Fortschritte in der Chemie und Biologie natürlicher Antibiotika

et al. 2009

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Seit der bahnbrechenden Entdeckung von Penicillin wurde die Vielfalt natürlich vorkommender Moleküle ausgiebig hinsichtlich ihrer Eignung als Medikamente sowie zum Auffinden neuer Leitstrukturen beim Wirkstoffdesign untersucht. Die Suche nach Wirkstoffen, mit denen Infektionskrankheiten bekämpft werden können, war dabei von besonderem Interesse und verlief sehr erfolgreich. Die Erforschung der Antibiotika weist eindrucksvolle Entdeckungen und Geschichten über die Entwicklung von Wirkstoffen auf, von denen die große Mehrheit ihren Ursprung in Naturstoffen hat. Die Chemie und besonders die chemische Synthese haben eine bedeutende Rolle dabei gespielt, natürlich vorkommende Antibiotika und deren Derivate für die medizinische Anwendung bereitzustellen, und zweifellos werden diese Disziplinen auch künftig Schlüsseltechnologien sein. In dieser Übersicht stellen wir einige der bedeutendsten neueren Entwicklungen und Fortschritte in der Chemie, Biologie und Medizin natürlich vorkommender Antibiotika vor, wobei die Totalsynthese, das Design von Analoga und die biologische Bewertung von Molekülen mit neuartigen Wirkmechanismen im Vordergrund stehen.

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“…The first total synthesis of platensimycin as a racemic mixture was achieved by Nicolaou and co-workers 10. Since then, a number of formal syntheses targeting the same ketone intermediate ( 2 , Figure 1) in racemic or optically active forms have appeared in the literature 11–19. Syntheses and biological evaluation of several structural analogues have also been reported 20–23.…”

Section: Introductionmentioning

confidence: 99%

Total Synthesis of (−)-Platensimycin, a Novel Antibacterial Agent

Ghosh

2009

J. Org. Chem.

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An enantioselective synthesis of platensimycin, a novel antibiotic natural product that inhibits bacterial β-ketoacyl-(acyl-carrier-protein) synthase (FabF), is described. Our synthetic strategy for the construction of the oxatetracyclic core involved an intramolecular Diels-Alder reaction. Our preliminary studies provided a complex tetracyclic product, by first undergoing an interesting 1,5-hydride shift followed by a Diels-Alder reaction. Further optimization of the diene's electronic properties, by incorporation of a methoxy group, led to the oxatetracyclic core of platensimycin. The three required chiral centers, including two all-carbon quaternary chiral centers, were built in the intramolecular Diels-Alder step. The synthesis utilized natural (+)-carvone as the key chiral starting material, which determined the stereochemistry of the final product. The synthesis also featured an efficient Petasis olefination, a hydroboration sequence, a Gais's asymmetric Horner-WadsworthEmmons reaction, and a mercury salt catalyzed enol ether isomerization.

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Formal Synthesis of (±)-Platensimycin

Cited by 104 publications

References 15 publications

Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility

Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility

Fortschritte in der Chemie und Biologie natürlicher Antibiotika

Total Synthesis of (−)-Platensimycin, a Novel Antibacterial Agent

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