Torsten Linker

Hier wird das Design einer Anthracenyl–Naphthyl (ANT‐NAPH)‐Dyade und ihre Verwendung als lumineszierender 4‐Stufen Fotoschalter vorgestellt. Beide Segmente können unabhängig mit Singulett‐Sauerstoff reagieren, womit eine optische Rückmeldung unterbrochen wird. In der ursprünglichen Form reagiert der höher konjugierte ANT‐Teil deutlich schneller, womit die Stufe ANTO₂‐NAPH eingeschaltet wird. Dies wird durch Fluoreszenz des verbleibenden NAPH‐Teils signalisiert. Zur Herabsetzung seiner Reaktivität, wurde ANT mit zwei Pyridinringen substituiert. Damit wurden zu Anfang getrennt vorliegende ANT‐ und NAPH‐Einheiten untersucht und die Reaktivität quantifiziert. Mit Protonierung der Pyridine ist eine deutlich langsamere Reaktion von ANT zu beobachten. Unter den drei verfügbaren Pyridyl‐Isomeren verstärkt sich dieser Effekt entlang der Reihe meta. Beim ortho‐Isomer schaltet sich das Reaktivitätsverhältnis endgültig von ANT nach NAPH um. Anwendung dieses Konzeptes an einer Dyade erlaubt es nun die ANT‐NAPHO₂‐Stufe einzuschalten. Hier wird das Signal durch ANT‐Fluoreszenz gegeben. Damit wird die Sequenz aus Protonierung‐Oxygenierung‐Neutralisation zur einzigen Methode, um die nicht favorisierte Dyade‐Form ANT‐NAPHO₂ zu isolieren. Da in der Dyade die Chromophore ANT und NAPH direkt verbunden sind, folgt aus ihrer Kopplung eine nicht‐oxygenierte dritte Stufe, in der die Fluoreszenz der NAPH Einheit ausgelöscht und die der ANT Einheit verstärkt ist. Aus der Reaktion beider Teile zu ANTO₂‐NAPHO₂ folgt schließlich eine vierte Stufe, die „dunkle“ Form.

We present the design of an anthracenyl–naphthyl (ANT‐NAPH) dyad and its application as a luminescent 4‐stage photo switch. Both segments can individually react with singlet oxygen to switch off an optical response. In their initial form the larger ANT component reacts significantly faster and thus an ANTO₂‐NAPH stage is turned on, observed by optical response of the remaining NAPH. To reduce its reactivity, ANT is substituted with two pyridine rings. This concept is first investigated and quantified on ANT and NAPH as separated molecules. Upon protonation the reaction of ANT becomes significantly slower. For the three possible pyridyl isomers this effect increases along the order meta. With the pyridyl nitrogen in ortho position the reaction completely toggles from ANT to NAPH. Application of this concept on the dyad allows to turn on the ANT‐NAPHO₂ stage with optical response of the remaining ANT. The sequence of protonation‐oxygenation‐neutralization is thereby the only possible way to isolate the unfavored form ANT‐NAPHO₂. In the dyad ANT and NAPH are directly attached and their coupling constitutes a non‐oxygenated third stage, where the NAPH luminescence is quenched and ANT luminescence is enhanced. Reaction of both NAPH and ANT to ANTO₂‐NAPHO₂ constitutes the fourth dark stage.

The Birch reduction has found a renaissance during the last two decades. In this Synpacts article a short summary of selected recent synthetic applications will be provided. 1,4-Cyclohexadienes, which are formed by Birch reduction in one step, are suitable precursors for radical reactions and are used as surrogates for difficult-to-handle substances. Their rearomatization under acidic conditions offers easy access to selectively alkylated arenes. Additionally, the Birch reduction of benzoic acids and subsequent trapping afford spiro compounds in high yields. Very recently, it was shown that 1,3-cyclohexadienes are directly available by Birch reduction in a one-pot reaction as well.1 Introduction2 Rearomatizations3 Synthesis of Spiro Compounds4 Synthesis of 1,3-Cyclohexadienes5 Conclusion

Birch‐Reduktionen sind wohlbekannte Transformationen von Arenen, die für die Synthese von 1,4‐Cyclohexadienen in großem Maßstab angewandt werden. Wir beschreiben hier erste Reaktionen von Benzoesäuren in Gegenwart von Carbonylverbindungen, die Aldolprodukte in mäßigen bis guten Ausbeuten liefern. Mit Alkylaldehyden entstehen die erwarteten nichtkonjugierten Diene durch Reaktion in der α‐Position. Interessanterweise greifen die intermediär gebildeten Enolate Ketone und Arylaldehyde aus ihrer γ‐Position an, was sich durch sterische Hinderung erklären lässt. Dies ebnet den Weg für die Ein‐Topf‐Synthese von 1,3‐Cyclohexadienen, die durch klassische Birch‐Reduktionen nicht zugänglich sind. Unsere Methode ist auf Benzoe‐ sowie m‐ and p‐Toluylsäuren und verschiedene Carbonylverbindungen anwendbar, und mehr als 25 neue Produkte wurden in bis zu 93 % Ausbeute isoliert. Prochirale Arylaldehyde liefern Diastereomerengemische im Verhältnis von etwa 4 : 1, im Cyclohexadienring entstehen hingegen nur trans‐Isomere mit hoher Selektivität. Zudem sind die gebildeten 1,3‐Cyclohexadiene nützliche Vorläufer für weitere Umsetzungen, was wir anhand erster Beispiele zeigen konnten. So liefert die Aromatisierung Produkte einer formalen meta‐selektiven Friedel–Crafts‐Alkylierung, und vier neue Stereozentren werden hochselektiv durch Cycloaddition von Singulett‐Sauerstoff erzeugt.

Birch reductions are well‐known transformations of arenes, applied for large scale synthesis of 1,4‐cyclohexadienes. Herein, we describe first reactions of benzoic acids in the presence of carbonyl compounds, affording aldol products in moderate to high yields. Alkyl aldehydes give the expected nonconjugated dienes by reaction at the α‐position. Interestingly, the intermediately formed enolate attacks aryl aldehydes and ketones from its γ‐position, which can be explained by steric hindrance. This opens the door for the one‐pot synthesis of 1,3‐cyclohexadienes, which are not accessible by classical Birch reductions. Our method is applicable to benzoic, m‐ and p‐toluic acid and various carbonyl compounds, and more than 25 new products were isolated in up to 93 % yield. Prochiral aryl aldehydes afford diastereomeric mixtures in ratios of about 4 : 1, but in the cyclohexadiene ring only trans isomers are formed with high selectivity. Finally, the 1,3‐cyclohexadienes are suitable precursors for further transformations, which we have demonstrated in first examples. Thus, aromatization affords products of a formal meta selective Friedel–Crafts alkylation, and four new stereocenters were generated by cycloaddition of singlet oxygen with excellent selectivity.

Vinyl‐substituted carbohydrates have been synthesized from glycals derived from hexoses and pentoses. Key step is the radical reaction of xanthates in the presence of triethylborane, a non‐toxic reagent. The mechanism has been investigated by isolation of various side products, which speak for a reversibility of the cyclopropylmethyl radical ring‐opening. Compared to reactions with tributyltin hydride, higher regioselectivities in favor of the 2‐vinyl‐substituted sugars have been obtained. Yields are slightly lower with triethylborane, but all products have been isolated in analytically pure form. The new reaction is applicable to benzyl‐ and silyl‐protected carbohydrates, which makes free sugars accessible as well. Overall, more than 15 1,2‐dideoxy‐2‐vinyl carbohydrates have been synthesized from simple precursors in only few steps.

β-γ-unsaturated spirolactones are easily available by Birch reduction. We describe their photochemistry in the presence of or without carbonyl compounds. The spirolactones show a distinct absorption band at 230 nm, which is not present in other cyclohexadienes. We explain this behavior by an interaction of the double bonds with the carbonyl group through space, further proven by TDDFT calculations. This allows their direct excitation with UV-C light. Interestingly, we obtain only products of an oxa-di-π-methane rearrangement, hitherto unknown for lactones. This speaks for a reaction pathway starting from singlet states, confirmed by calculated relative energies of biradical intermediates. Although polymerization is the main side reaction, we were able to isolate tricyclic lactones in moderate yields in a pure form. In the presence of benzaldehyde or benzophenone, excitation with UV-B light was possible, leading to H-atom abstraction in the allylic position and formation of alcohols. With an electron-rich double bond, the Paternó–Büchi products were isolated as well. The different diastereomers were separated by column chromatography or HPLC. Their relative configurations were determined using NOESY measurements or X-ray structure analysis. Overall, β-γ-unsaturated spirolactones show a remarkably different photochemistry compared to other cyclohexadienes, affording new products in only a few steps.

Carbohydrates constitute one of the four key classes of biomacromolecules but have not been studied by 2D-IR spectroscopy so far. Similarly as for proteins, their chemical structure and the repetitive nature of native vibrational oscillators, combined with their huge structural diversity, lead to spectrally congested infrared spectra already for singlecarbohydrates. Biophysical studies are further impeded by the strong overlap between water modes and carbohydrates modes. Here, we demonstrate the application of the known vibrational reporter group thiocyanate (SCN) in glucose. In his first study, we are able to perform IR- and 2D-IR spectroscopy of β -glucose with SCN at C2 position, as proof of concept in chloroform. Upon improved synthesis and removal of all protecting groups we succeed to perform 2D-IR in H₂O. All experiments are compared to results of methyl-thiocyanate as reference sample. Overall we show that theconcept of using site-specific vibrational reporter groups can be transferred to carbohydrates.

Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of Leishmania tarentolae promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity. The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in Leishmania. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogP_OW larger than 3.5 and a polar surface area smaller than 100 Ų. The most effective compounds (IC₅₀ in LtP < 2 µM) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP. Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group. However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in Leishmania. The identified compound pairs are a good starting point for subsequent experiments in pathogenic Leishmania in vitro and in animal models.

Photodynamic therapy (PDT) is a mild but effective method to treat certain types of cancer upon irradiation with visible light. Here, three isomeric methylpyridinium alkynylanthracenes 1o─p were evaluated as sensitizers for PDT. Upon irradiation with blue or green light, all three compounds show the ability to initiate strand breaks of plasmid DNA. The mayor species responsible for cleavage is singlet oxygen (¹O₂) as confirmed by scavenging reagents. Only isomers 1m and 1p can be incorporated into HeLa cells, whereas isomer 1o cannot permeate through the membrane. While isomer 1m targets the cell nucleus, isomer 1p assembles in the cellular cytoplasm and impacts the cellular integrity. This is in accordance with a moderate toxicity of 1p in the dark, whereas 1m exhibits no dark toxicity. Both isomers are suitable as PDT reagents, with a CC₅₀ of 3 μm and 75 nm, for 1p and 1m, respectively. Thus, derivative 1m, which can be easily synthesized, becomes an interesting candidate for cancer therapy.