Totalsynthesen von 5,6-Dihydrocineromycin B, Radicinol und 3-epi-Radicinol sowie Synthesen der vermeintlichen Strukturen von 3-Methoxy-3-epi-Radicinol und Orevactaene

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)

Dearomatization of electron poor six-membered N-heterocycles through [3+2] annulation with aminocyclopropanes

Many abundant and highly bioactive natural alkaloids contain an indolizidine skeleton. A simple, high yielding method to synthesize this scaffold from N-heterocycles was developed. A wide range of pyridines, quinolines and isoquinolines reacted with donor-acceptor (DA)-aminocyclopropanes via an ytterbium(III) catalyzed [3 + 2] annulation reaction to give tetrahydroindolizine derivatives. The products were obtained with high diastereoselectivities (dr > 20 : 1) as anti-isomers. Additionally, the formed aminals could be easily converted into secondary and tertiary amines through iminium formation followed by reduction or nucleophile addition. This transformation constitutes the first example of dearomatization of electron-poor six-membered heterocycles via [3 + 2] annulation with DA cyclopropanes

Cyclic Hypervalent Iodine Reagents for Azidation: Safer Reagents and Photoredox-Catalyzed Ring Expansion

Azides are building blocks of increasing importance in synthetic chemistry, chemical biology, and materials science. Azidobenziodoxolone (ABX, Zhdankin reagent) is a valuable azide source, but its safety profile has not been thoroughly established. Herein, we report a safety study of ABX, which shows its hazardous nature. We introduce two derivatives, tBu-ABX and ABZ (azidobenziodazolone), with a better safety profile, and use them in established photoredox- and metal-mediated azidations, and in a new ring-expansion of silylated cyclobutanols to give azidated cyclopentanones

A Short Access to the Skeleton of Elisabethin A and Formal Syntheses of Elisapterosin B and Colombiasin A

A short stereoselective synthesis of the Elisabethin A skeleton <b>4</b> is described, which opens a formal access to the diterpenes Elisapterosin B and Colombiasin A as well. Key reactions were an intermolecular <i>endo</i>-selective Diels–Alder reaction to generate the decalin part of the molecule, a chemo- and diastereoselective allylation of an aldehyde with allylzinc, a palladium ene annulation of the cyclopentane ring, and a novel sulfonium ylide induced fragmentation of a polycyclic ketone. Additional insights have been gained for the crucial epimerization at C-2

Cyclic Hypervalent Iodine Reagents for Azidation: Safer Reagents and Photoredox Catalyzed Ring Expansion

Azides are building blocks of increasing importance in synthetic chemistry, chemical biology and materials science. Azidobenziodoxolone (ABX, Zhdankin reagent) is a valuable azide source, but its safety profile has not been thoroughly established. Herein, we report a safety study of ABX, which shows its highly hazardous nature. We further introduce and study two derivatives, tBu-ABX and ABZ (azidobenziodazolone). ABZ displayed a similar reactivity but a better safety profile than ABX, and could be used in established photoredox- and metal-mediated azidation processes, as well as in a new ring-expansion of silylated cyclobutanols to give azidated cyclopentanones

Cyclic Hypervalent Iodine Reagents for Azidation: Safer Reagents and Photoredox Catalyzed Ring Expansion

Azides are building blocks of increasing importance in synthetic chemistry, chemical biology and materials science. Azidobenziodoxolone (ABX, Zhdankin reagent) is a valuable azide source, but its safety profile has not been thoroughly established. Herein, we report a safety study of ABX, which shows its highly hazardous nature. We further introduce and study two derivatives, <i>t</i>Bu-ABX and ABZ (azidobenziodazolone). ABZ displayed a similar reactivity but a better safety profile than ABX, and could be used in established photoredox- and metal-mediated azidation processes, as well as in a new ring-expansion of silylated cyclobutanols to give azidated cyclopentanones