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Projekt Druckansicht

Neue synthetische Zugänge zu Polyketiden: Totalsynthese und Struktur-Aktivitätsbeziehungen der Naturstoffe Etnangien und Rhizopodin

Fachliche Zuordnung Organische Molekülchemie - Synthese, Charakterisierung
Förderung Förderung von 2008 bis 2013
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 67192531
 
Erstellungsjahr 2013

Zusammenfassung der Projektergebnisse

The polyketide natural products etnangien and rhizopodin are attractive study objects due to their extremely potent biological activities and their structurally unique and complex architectures. Within the etnangien part of this project the initially unknown stereochemistry of this labile polyene macrolide has been proposed by a combination of high field NMR-studies, molecular modelling, chemical methods and bioinformatics techniques. Novel synthetic methods were then developed, including diastereodivergent aldol methodology, an elaboration of a novel reagent for selective deprotection of silyl ethers, an extension of the Abiko-Masamune aldol methodology, a reliable protocol for Z-selective Stork-Zhao-Wittig olefinations and an effective procedures for 1,3-syn reductions of sterically hindered β -hydroxy ketones. Based on these methods, a first total synthesis of etnangien could be realized. This established unequivocally the relative and absolute configuration of this sensitive macrolide antibiotic. Key features of the expedient and modular synthesis include stereoselective substrate-controlled boron- and tinmediated aldol couplings to set the characteristic sequences of methyl and hydroxyl bearing stereogenic centers with high degrees of stereoselectivity and yield, an efficient Heck macrocyclization of a conformationally restricted substrate and a late-stage introduction of the labile side-chain. Finally, novel simplified analogues of the potent RNA polymerase inhibitor etnangien were designed, obtained by total synthesis and evaluated for antibacterial activity, demonstrating that a combination of the macrocycle and side chain is critical for full biological potential of these polyene macrolides. Along these lines novel hetero-bis-metallated alkenes with conjugated and isolated olefin subunits have been developed as versatile reagents to construct highly conjugated polyenes and stabilized olefinic analogues thereof. Within the rhizopodin part of this project the hitherto unknown absolute and relative configuration of this dimeric macrolide was assigned by J-based configurational analysis, NOE data, computational methods as well as chemical derivatization, in a similar fashion to the approach described for etnangien. Subsequently, efficient synthetic strategies were developed to access the characteristic structural features of this macrolide. These included a convergent synthesis of the central C8-C22 core using one of the first applications in complex target synthesis of a Krische allylation and a thiazolium catalyzed epoxyaldehyde transformation by Bode, extensive studies on substrate-controlled aldol reactions of hindered substrates, a highly a highly advantageous Heck reaction and a novel domino-concept for 1,3-anti-diol synthesis. Based on these efforts, a first total synthesis of rhizopodin was then effected by an expedient and modular synthesis involving a convergent assembly of three building blocks of similar complexity. Notable features of the convergent approach include a rapid assembly of the macrocycle by a site-directed sequential cross coupling strategy and a bidirectional attachment of the side-chains by means of a HWE coupling. Importantly, this route unequivocally confirms the full stereochemistry of this complex polyketide macrolide. Finally, a first set of simplified rhizopodin analogues were designed by computational methods, involving docking and redocking, synthesized by a modular strategy and biologically evaluated.

Projektbezogene Publikationen (Auswahl)

 
 

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