The direct and highly enantioselective synthesis of tetrahydroacridines was achieved through the phosphoric acid catalyzed addition of enamides to in situ generated ortho-quinone methide imines and subsequent elimination. This novel one-step process constitutes a very efficient, elegant, and selective synthetic approach to valuable N-heterocycles with a 1,4-dihydroquinoline motif. By subsequent highly diastereoselective hydrogenation and N-deprotection the reaction products were easily converted into free hexahydroacridines with a total of three new stereogenic centers.
Aza-Diels-Alder reactions (ADARs) are powerful processes that furnish N-heterocycles in a straightforward fashion. Intramolecular variants offer the additional possibility of generating bi- and polycyclic systems with high stereoselectivity. We report herein a novel Brønsted acid catalyzed process in which ortho-quinone methide imines tethered to the dienophile via the N substituent react in an intramolecular ADAR to form complex quinolizidines and oxazinoquinolines in a one-step process. The reactions proceed under very mild conditions, with very good yields and good to very good diastereo- and enantioselectivities. Furthermore, the process was extended to a domino reaction that efficiently combines substrate synthesis, ortho-quinone methide imine formation, and ADAR.
Prodigiosins (prodiginines) are a class of bacterial secondary metabolites with remarkable biological activities and color. In this study, optimized production, purification, and characterization of prodigiosin (PG) from easily accessible Serratia marcescens ATCC 27117 strain has been achieved to levels of 14 mg/L of culture within 24 h. Furthermore, environmentally friendly bromination of produced PG was used to afford both novel mono- and dibrominated derivatives of PG. PG and its Br derivatives showed anticancer potential with IC50 values range 0.62–17.00 µg/mL for all tested cancer cell lines and induction of apoptosis but low selectivity against healthy cell lines. All compounds did not affect Caenorhabditiselegans at concentrations up to 50 µg/mL. However, an improved toxicity profile of Br derivatives in comparison to parent PG was observed in vivo using zebrafish (Danio rerio) model system, when 10 µg/mL applied at 6 h post fertilization caused death rate of 100%, 30% and 0% by PG, PG-Br, and PG-Br2, respectively, which is a significant finding for further structural optimizations of bacterial prodigiosins. The drug-likeness of PG and its Br derivatives was examined, and the novel Br derivatives obey the Lipinski’s “rule of five”, with an exemption of being more lipophilic than PG, which still makes them good targets for further structural optimization.
Aza-Diels-Alder-Reaktionen (ADARs) sind leistungsfähige Prozesse zum schnellenu nd stereoselektiven Aufbau von Stickstoffheterocyclen. Intramolekulare Varianten bieten darüber hinaus die Mçglichkeit, bi-und polycyclische Ringsysteme in einem Schritt mit hoher Stereoselektivitätz u generieren. In dem hier entwickelten Brønsted-Säure-katalysierten Verfahren kçnnen nun erstmals ortho-Chinonmethidimine,d ie über den Iminsubstituenten an ein Dienophil gebunden sind, in einer enantioselektiven ADAR mit inversem Elektronenbedarf zu komplexen Chinolizidin-und Oxazinochinolin-Ringsystemen umgesetzt werden. Die Reaktionen laufen unter milden Bedingungen in sehr guten Ausbeuten und mit guten bis sehr guten Diastereo-und Enantioselektivitäten ab.D as Verfahren kann darüber hinaus zu einem Domino-Prozess erweitert werden, der Substratsynthese,o rtho-Chinonmethid-Bildung und ADAR effizient vereinigt.
Aza-Diels Alder reactions are straightforward processes in the construction of N-heterocycles, featuring inherent atom-economy and stereospecificity. Intramolecular strategies allow formation of bicyclic core structures with up to three stereocenters within a single step. Herein, this concept is combined with the chemistry of chiral Brønsted acid-bound ortho-quinone methide imines generating a range of interesting fused tetrahydro-quinolines in a diastereo- and enantioselective manner.
In this Account, we describe our journey leading to the discovery of a generally applicable Umpolung method for the α‐functionalization of ketones. Central to this reaction is the cyclic hypervalent fluoro iodane that is mostly known for various alkene functionalizations enabling for example the synthesis of fluoro-benzoxazepines, indoles, and ketones. During this work, we encountered α-functionalized ketones as minor side products. This observation prompted us to further investigate this reactivity thus revealing a directed umpolung of pyridyl ketones by the F-iodane. The key to success was unexpected non-covalent interaction between the nucleophile, substrate, and iodane.
1 Introduction
2 Cyclizations triggered by the Fluorination of Styrenes
3 Umpolung Reactions Facilitated by Hypervalent Iodanes
4 Discovering and Evolving an F-Iodane triggered Regioselective α-Functionalization of Carbonyl Compounds
5 First Investigations on the Nitrogen-Directed Umpolung
6 Conclusion
A broadly applicable phosphoric acid catalyzed, enantioselective reaction between in situ generated o‐quinone methide imines and enamides gives access to tetrahydroacridines and related fused N‐heterocycles.
Eine direkte,h oche nantioselektive Synthese von Tetrahydroacridinen gelang durchPhosphorsäure-katalysierte Addition von Enamiden an in situ erzeugte ortho-Chinonmethidimine mit nachfolgender Eliminierung.D iese neue, einstufige Methode erçffnet einen sehr effizienten, eleganten und selektiven Zugang zu wertvollen N-Heterocyclen mit einem 1,4-Dihydrochinolin-Motiv.D ie Reaktionsprodukte lassen sich anschließend direkt durchd iastereoselektive Hydrierung und N-Entschützung in freie Hexahydroacridine mit insgesamt drei neuen stereogenen Zentren überführen. Schema 1. Konzeption der N-Heterocyclen-Synthese.
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