Totalsynthesen von 5,6-Dihydrocineromycin B, Radicinol und 3-epi-Radicinol sowie Synthesen der vermeintlichen Strukturen von 3-Methoxy-3-epi-Radicinol und Orevactaene
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2016
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Totalsynthese und „late-stage“ Modifizierung von (‒)-5,6-Dihydrocineromycin B
(‒)-Dihydrocineromycin B (I, Schema 1) ist ein 14-gliedriges antibiotisches Makrolacton aus einer
Naturstofffamilie mit möglicherweise großem Potential zur Bekämpfung von Methicillin-resistentem
Staphylococcus aureus (MRSA). Der Mangel relevanter biologischer Daten für I und die ineffizienten
bekannten Möglichkeiten zum Aufbau der in polyketidischen Naturstoffen häufig vorkommenden
(E)-2-Methyl-2-but-2-en-1-ol Substruktur (blau) ermutigten uns eine neue Strategie zur Synthese
dieses Naturstoffs zu entwickeln. Unser Ansatz kombinierte ringschließende Alkinmetathese mit
einer regioselektiven Ru-katalysierten trans-Addition von Bu3SnH an das so erhaltene Zykloalkin III
und einer abschließenden Stille-Kupplung mit Iodmethan. Die vielseitigen
Verwendungsmöglichkeiten des Alkenylstannans II erlaubten neben der Synthese des Naturstoffs
auch die Herstellung zahlreicher Derivate.
Schema 1. Retrosynthetische Analyse von 5,6-Dihydrocineromycin B (I).
Goldkatalysierte Synthese von 4-Oxo-2-Pyronen
Die von Fürstner und Mitarbeitern zuvor entwickelte AuI-katalysierte Pyronsynthese ermöglicht den
einfachen Aufbau substituierter Pyrone unter bemerkenswert milden Bedingungen (Schema 2). Der
Aufbau des benötigten tert-Butylesters (VI) stellte sich jedoch für sterisch anspruchsvolle
Zyklisierungsvorläufer als problematisch heraus. Es war uns möglich zu zeigen, dass die analoge
Zyklisierung durch die Verwendung von 2-TMS-Ethanolestern (VII) durchgeführt werden kann,
welche sich einfacher darstellen lassen. Diese Modifikation der goldkatalysierten Pyronsynthese
wurde in den ersten Totalsynthesen von Radicinol (VIII), 3-epi-Radicinol (IX) und vermeintlichem
3-Methoxy-3-epi-Radicinol (X) eindrucksvoll zur Schau gestellt. Mithilfe einer Säure-mediierten SN2-
Substitution an C3 konnten die drei genannten Verbindungen aus der gemeinsamen Vorstufe XI
X
hergestellt werden. Bedauerlicherweise stimmen die gemessenen nicht mit den in der Literatur
veröffentlichten Daten für X überein, was eine falsche Strukturaufklärung nahelegt.
Schema 2. Vergleich der benutzten Ester in der goldkatalysierten Pyronsynthese und retrosynthetische Analyse von
Radicinol (VIII), 3-epi-Radicinol (IX) und 3-Methoxy-3-epi-Radicinol (X).
Darauffolgend wurde die Modifikation der goldkatalysierten Pyronsynthese als Schlüsselschritt in der
Synthese des hochkomplexen Orevactaene (XII, Schema 3) angewandt. Das sensitive Heptaen und
der hochoxidierte Bizyklus sowie die Nichtzuordnung der relativen Konfiguration von vier der sieben
stereogenen Zentren in der Literatur machten die Synthese reizvoll. Dies erforderte die Entwicklung
einer Strategie, die die individuelle Synthese jedes der 16 möglichen Diastereomere erlaubte. Daher
wurde eine hochkonvergente Route mit zwei aufeinanderfolgenden sp2–sp2 Kupplungsreaktionen zur
Verknüpfung der Fragmente XIII, XIV und XV entworfen. Die Synthese zweier möglicher
Diastereomere von Orevactaene (XII) konnte abgeschlossen werden. Allerdings zeigten die
gemessenen analytischen Daten, dass die Struktur des Bizyklus von Orevactaene (XII) vom
Isolationsteam grundlegend falsch zugeordnet wurde.
Schema 3. Retrosynthetische Analyse von Orevactaene (XII).
Total Synthesis and Late Stage Modification of (‒)-5,6-Dihydrocineromycin B (‒)-Dihydrocineromycin B (I, Scheme 1) is a 14-membered antibiotic macrolide, belonging to a family that exhibits potential for treatment against methicillin-resistant Staphylococcus aureus (MRSA). The lack of relevant biological data for I in particular and of efficient methods for the formation of the naturally abundant (E)-2-methyl-2-but-2-en-1-ol motif (blue) encouraged us to develop a new synthetic strategy. Our approach combined ring-closing alkyne metathesis to furnish cycloalkyne III, followed by a regioselective Ru-catalyzed trans-hydrostannation and the concluding Stille-coupling with methyl iodide. The versatility of vinyl-tributyltin intermediate II was demonstrated by late stage diversification that allowed various analogues of the natural product to be prepared. Scheme 1. Retrosynthetic anaylsis of 5,6-dihydrocineromycin B (I). Gold-Catalyzed 4-Oxo-2-Pyrone Synthesis Fürstner and coworkers previously developed a AuI-catalyzed cyclization which enabled facile synthesis of substituted pyrones under remarkably mild reaction conditions (Scheme 2). However, the preparation of sterically demanding cyclization precursors containing bulky tert-butyl ester (VI) was found to be challenging. We established that the analogous cyclization can be effected with the corresponding 2-TMS-ethanol-ester (VII) which is more readily prepared. This modification of the gold-catalyzed pyrone synthesis was applied to the first total syntheses of radicinol (VIII), 3-epiradicinol (IX), and putative 3-methoxy-3-epi-radicinol (X). Through acid-promoted SN2 reactions at C3 position of common intermediate XI, the three targets could be synthesized in a divergent fashion. Unfortunately, the analytical data of X did not match those reported in the isolation studies, which suggests structural misassignment in the original report. XII Scheme 2. a) Comparison of the used esters in the gold-catalyzed pyrone cyclization; b) Retrosynthetic analysis of radicinol (VIII), 3-epi-radicinol (IX) and 3-methoxy-3-epi-radicinol (X). Subsequently the gold-catalyzed pyrone synthesis was applied as a key step to prepare a highly complex natural product, Orevactaene (XII, Scheme 3). The sensitive heptaene and the highly oxidized bicyclic structure in the natural product renders its synthesis challenging. Furthermore, the lack of configurational assignment of four stereogenic centers in the literature called for a strategy that could allow the formation of all sixteen possible diastereoisomers. Therefore, by employing the highly convergent strategy, involving two late-stage sp2–sp2 cross-coupling reactions between fragments XIII, XIV, and XV, two stereoisomers of Orevactaene (XII) were synthesized. However, their analytical data did not support the proposed structure of XII, but rather indicate that the bicyclic structure was fundamentally misassigned by the isolation team. Scheme 3. Retrosynthetic analysis of orevactaene (XII).
Total Synthesis and Late Stage Modification of (‒)-5,6-Dihydrocineromycin B (‒)-Dihydrocineromycin B (I, Scheme 1) is a 14-membered antibiotic macrolide, belonging to a family that exhibits potential for treatment against methicillin-resistant Staphylococcus aureus (MRSA). The lack of relevant biological data for I in particular and of efficient methods for the formation of the naturally abundant (E)-2-methyl-2-but-2-en-1-ol motif (blue) encouraged us to develop a new synthetic strategy. Our approach combined ring-closing alkyne metathesis to furnish cycloalkyne III, followed by a regioselective Ru-catalyzed trans-hydrostannation and the concluding Stille-coupling with methyl iodide. The versatility of vinyl-tributyltin intermediate II was demonstrated by late stage diversification that allowed various analogues of the natural product to be prepared. Scheme 1. Retrosynthetic anaylsis of 5,6-dihydrocineromycin B (I). Gold-Catalyzed 4-Oxo-2-Pyrone Synthesis Fürstner and coworkers previously developed a AuI-catalyzed cyclization which enabled facile synthesis of substituted pyrones under remarkably mild reaction conditions (Scheme 2). However, the preparation of sterically demanding cyclization precursors containing bulky tert-butyl ester (VI) was found to be challenging. We established that the analogous cyclization can be effected with the corresponding 2-TMS-ethanol-ester (VII) which is more readily prepared. This modification of the gold-catalyzed pyrone synthesis was applied to the first total syntheses of radicinol (VIII), 3-epiradicinol (IX), and putative 3-methoxy-3-epi-radicinol (X). Through acid-promoted SN2 reactions at C3 position of common intermediate XI, the three targets could be synthesized in a divergent fashion. Unfortunately, the analytical data of X did not match those reported in the isolation studies, which suggests structural misassignment in the original report. XII Scheme 2. a) Comparison of the used esters in the gold-catalyzed pyrone cyclization; b) Retrosynthetic analysis of radicinol (VIII), 3-epi-radicinol (IX) and 3-methoxy-3-epi-radicinol (X). Subsequently the gold-catalyzed pyrone synthesis was applied as a key step to prepare a highly complex natural product, Orevactaene (XII, Scheme 3). The sensitive heptaene and the highly oxidized bicyclic structure in the natural product renders its synthesis challenging. Furthermore, the lack of configurational assignment of four stereogenic centers in the literature called for a strategy that could allow the formation of all sixteen possible diastereoisomers. Therefore, by employing the highly convergent strategy, involving two late-stage sp2–sp2 cross-coupling reactions between fragments XIII, XIV, and XV, two stereoisomers of Orevactaene (XII) were synthesized. However, their analytical data did not support the proposed structure of XII, but rather indicate that the bicyclic structure was fundamentally misassigned by the isolation team. Scheme 3. Retrosynthetic analysis of orevactaene (XII).
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Keywords
5,6-Dihydrocineromycin B, Radicinol, 3-epi-Radicinol, 3-Methoxy-3-epi-Radicinol, Orevactaene