Neue synthetische Zugänge zu Polyketiden: Totalsynthese und Struktur-Aktivitätsbeziehungen der Naturstoffe Etnangien und Rhizopodin
Final Report Abstract
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.
Publications
- 2008. Configurational assignment of rhizopodin, an actin-binding macrolide from the myxobacterium Myxococcus stipitatus. Chemical Communications, Vol. 2008, Issue 41, pp. 5173-5175.
N. Horstmann, D. Menche
(See online at https://dx.doi.org/10.1039/B810405K) - 2008. Stereochemical Determination and Complex Biosynthetic Assembly of Etnangien, a Highly Potent RNA Polymerase Inhibitor from the Myxobacterium Sorangium Cellulosum. Journal of the American Chemical Society, Vol. 130. 2008, pp. 14234-14243.
D. Menche, F. Arikan, O. Perlova, N. Horstmann, W. Ahlbrecht, S. C. Wenzel, R. Jansen, H. Irschik, R. Müller
(See online at https://dx.doi.org/10.1021/ja804194c) - 2009. Selective Deprotection of Silyl Ethers with Sodium Periodate. Synthesis, Vol. 2009, Issue 11, pp. 1904-1908.
J. Li, D. Menche
(See online at https://dx.doi.org/10.1055/s-0028-1088062) - 2009. Total Synthesis of Etnangien. Journal of the American Chemical Society, Vol. 131. 2009, pp. 11678-11679.
P. Li, J. Li, F. Arikan, W. Ahlbrecht, M. Dieckmann, D. Menche
(See online at https://dx.doi.org/10.1021/ja9056163) - 2010. Design, Synthesis and Biological Evaluation of Simplified Analogues of the RNA Polymerase Inhibitor Etnangien. Bioorganic & Medicinal Chemistry Letters, Vol. 20. 2010, Issue 3, pp. 939–941.
D. Menche, P. Li, H. Irschik
(See online at https://dx.doi.org/10.1016/j.bmcl.2009.12.066) - Recent Advances in the Stereochemical Determination and Total Synthesis of Myxobacterial Polyketides. Synlett, Vol. 2010, Issue 20, pp. 2989-3007.
M. Kretschmer, D. Menche
(See online at https://dx.doi.org/10.1055/s-0030-1259070) - 2011. Modeling of Complex Polyketides: Stereochemical Determination by a Combination of Computational and NMR Methods. In: Modeling of Molecular Properties, ed. P. Comba, Wiley-VCH, 2011, pp. 397-411.
S. Dreisigacker, D. Menche
(See online at https://dx.doi.org/10.1002/9783527636402.ch24) - 2012. Efficient synthesis of diverse hetero-bis-metallated alkenes as modular reagents towards highly conjugated and isolated olefinic systems. Chemical Communications, Vol. 48. 2012, Issue 66, pp. 8267-8269.
M. Altendorfer, D. Menche
(See online at https://doi.org/10.1039/c2cc34052f) - 2012. Total Synthesis of Rhizopodin. Angew. Chem. 2012, 124, 5765–5768; Angewandte Chemie International Edition, Vol. 51. 2012, Issue 23, pp. 5667–5670.
M. Dieckmann, M. Kretschmer, P. Li, S. Rudolph, D. Herkommer, D. Menche
(See online at https://doi.org/10.1002/anie.201201946) - 2013. Modular Total Synthesis of Rhizopodin: A Highly Potent G-Actin Dimerizing Macrolide. Chemistry - A European Journal, Vol. 19. 2013, Issue 47, pp. 15993–16018.
M. Kretschmer, M. Dieckmann, P. Li, S. Rudolph, D. Herkommer, J. Troendlin, D. Menche
(See online at https://doi.org/10.1002/chem.201302197) - 2013. Stereoselective Synthesis of 1,3-anti Diols by an Ipc-mediated Domino Aldol-Coupling/ Reduction Sequence. Organic Letters, Vol. 15. 2013, Issue 1, pp. 228–231.
M. Dieckmann, D. Menche
(See online at https://doi.org/10.1021/ol3033303) - Stereochemistry and total synthesis of complex myxobacterial macrolides. Pure and Applied Chemistry, Vol. 85. 2013, Issue 6, pp. 1103-1120.
S. Essig, D. Menche
(See online at https://doi.org/10.1351/PAC-CON-12-09-12)
