2-aminophenols containing electron-withdrawing groups from N-aryl hydroxylamines

Reaction of substituted N-aryl hydroxylamines with methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride under basic conditions leads to the rearranged 2-aminophenols (45-94%). The overall reaction sequence can be performed using polymer-supported sulfonyl chloride resin allowing for the effective conversion of N-aryl hydroxylamines to the 2-aminophenols without the need for chromatography

The alpha-effect in cyclic secondary amines: new scaffolds for iminium ion accelerated transformations

Five-membered secondary amine heterocycles containing an α-heteroatom were prepared and shown to be ineffective as catalysts for the iminium ion catalysed Diels–Alder reaction between cinnamaldehyde and cyclopentadiene. Their six-membered counterparts proved to be highly active catalysts. In stark contrast, the catalytic activity observed when comparing the non α-heteroatom cyclic amines proline methyl ester and methyl pipecolinate showed the five-membered ring amine was significantly more active. Concurrent density functional theoretical calculations suggest a rationale for the observed trends in reactivity, highlighting that LUMO activation through an iminium ion intermediate plays a key role in catalytic activity

Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy

The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development

Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials

In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting

Entwicklung einer reversiblen Festphasensynthese

Die Festphasenchemie ist als Alternative zur klassischen Synthese in Lösung nicht mehr wegzudenken. Ein Problem liegt aber in der Charakterisierung und Reinigung von Intermediaten im Verlauf einer mehrstufigen Synthese. In der vorliegenden Arbeit werden diese Schwierigkeiten durch ein neues reversibles Verankerungskonzept behoben. Das Konzept der reversiblen Festphasensynthese beruht auf hydrophoben Wechselwirkungen zwischen einem Anker und der Festphase (Matrix). Das Ausmaß der Verankerung läßt sich durch die Polarität des Lösemittels steuern, wobei mit der Verwendung von Wasser die maximale Anbindung gegeben ist. Als Matrix wird hierbei auf kommerziell verfügbares und gut charakterisiertes „reversed phase“-Kieselgel zurückgegriffen. Als Anker dienen verschiedene N-alkylierte Acridonderivate. Dieses System erlaubt neben einfacher Handhabung die Wiedergewinnung der Festphase und des Ankers und stellt damit eine signifikante Verbesserung zur bisherigen Verfahrensweise da („green chemistry“). Durch die Fluoreszenzeigenschaften (Nachweisgrenze ca. 1 pmol/l) ermöglicht die Acridon-Teilstruktur ein einfaches und effizientes Detektieren der Verbindungen und Screening von Reaktionen durch DC. Das Konzept wurde auf verschiedene Reaktionen (z.B. 1,3-Dipolare Cycloadditionen, Barbier-Typ-Allylierungen, Aldol-Reaktionen, Pd-katalysierte Kreuzkupplungsreaktionen), die mit wässrigen Lösungen kompatibel sind, erfolgreich angewendet. Das Konzept erlaubt auch den Wechsel zwischen wässrigen (heterogenen) und organischen (homogenen) Bedingungen, wie am Beispiel der Malaprade-Reaktion gezeigt werden konnte. Somit werden die Vorzüge der Festphasensynthese mit denen der Synthese in Lösung kombiniert

Direct access to functionalized cyclic enones using Mannich, Morita-Baylis-Hillman and elimination reactions

A series of highly functionalized cyclic enones were obtained from Mannich, Morita-Baylis-Hiliman and elimination reaction with cyclic enones

Rearrangement strategies for aryl-heteroatom bond formation

A major interest in synthetic research is the controlled introduction and elaboration of new carbon-heteroatom bonds for the synthesis of arom. and heteroarom. products. Recently, C-H functionalization strategies have provided important contributions to the available methods. Although efficient and practical, the majority of these processes rely on activation with transition metals. The development of a metal-free methodol. to activate arom. rings would significantly augment the available methods and provide a valuable synthetic alternative. Within this talk we will present a versatile rearrangement strategy to access new aryl-heteroatom bonds through a formal metal-free C-H functionalization. The N-aryl hydroxylamine substrates for the rearrangement process (1) can easily be accessed from aryl halides via palladium and copper catalyzed coupling or from nitroarenes through a one-pot redn./protection sequence. Products accessed through this technol. provide fundamental building blocks for the prepn. of a variety of pharmacol. important heterocyclic scaffolds

Palladium catalyzed N-arylation of hydroxylamines

Over the past decade modified Ullmann couplings and palladium-catalyzed arylations of nitrogen contg. compds. (Buchwald-Hartwig aminations) have emerged as powerful tools in synthetic chem. Interestingly, despite their biol. and synthetic significance, only three reports of cross couplings of hydroxylamines have been disclosed. This lack of investigation is surprising as N-aryl hydroxylamines are valuable intermediates in the prepn. of important nitrogen heterocycles including indoles, isoxazolidines oxadiazolidinones and aziridines. Within the poster we present a mild and efficient palladium catalyzed method for the prepn. of N-aryl hydroxylamines. The scope and limitations of the procedure will be detailed and methods for the selective deprotection of both the N- and O-functionality described allowing full advantage of this important functional group to be revealed

Synthesis of benzoxazolones from nitroarenes or aryl halides

A simple and effective method for the preparation of benzoxazolones from nitroarenes or aryl halides is described. Partial reduction of a nitro group in the presence of a chloroformate followed by a microwave assisted rearrangement/ring closure sequence provides a convenient and practical procedure to prepare this important pharmacophore. Rearrangement precursors were also accessed from aryl halides through transition-metal catalyzed coupling