Quinone-catalyzed oxidative deformylation: synthesis of imines from amino alcohols.
ABSTRACT: A new method for imine synthesis by way of quinone-catalyzed oxidative deformylation of 1,2-amino alcohols is reported. A wide range of readily accessible amino alcohols and primary amines can be reacted to provide N-protected imine products. The methodology presented provides a novel organocatalytic approach for imine synthesis and demonstrates the synthetic versatility of quinone-catalyzed oxidative C-C bond cleavage.
Project description:Aminophenols can redox cycle through the corresponding quinone imines to generate ROS. The electrophilic quinone imine intermediate can react with protein thiols as a mechanism of immobilization in vivo. Here, we describe the previously unkown transimination of a quinone imine by lysine as an alternative anchoring mechanism. The redox properties of the condensation product remain largely unchanged because the only structural change to the redox nucleus is the addition of an alkyl substituent to the imine nitrogen. Transimination enables targeting of histone proteins since histones are lysine-rich but nearly devoid of cysteines. Consequently, quinone imines can be embedded in the nucleosome and may be expected to produce ROS in maximal proximity to the genome.
Project description:Detoxicating enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinone-like compounds. The protective role of the polymorphic NQO1 and NQO2 enzymes is especially of interest in the liver as the major site of drug bioactivation to chemically reactive drug metabolites. In the current study, we quantified the concentrations of NQO1 and NQO2 in 20 human liver donors and NQO1 and NQO2 activities with quinone-like drug metabolites. Hepatic NQO1 concentrations ranged from 8 to 213 nM. Using recombinant NQO1, we showed that low nM concentrations of NQO1 are sufficient to reduce synthetic amodiaquine and carbamazepine quinone-like metabolites in vitro. Hepatic NQO2 concentrations ranged from 2 to 31 ?M. NQO2 catalyzed the reduction of quinone-like metabolites derived from acetaminophen, clozapine, 4'-hydroxydiclofenac, mefenamic acid, amodiaquine, and carbamazepine. The reduction of the clozapine nitrenium ion supports association studies showing that NQO2 is a genetic risk factor for clozapine-induced agranulocytosis. The 5-hydroxydiclofenac quinone imine, which was previously shown to be reduced by NQO1, was not reduced by NQO2. Tacrine was identified as a potent NQO2 inhibitor and was applied to further confirm the catalytic activity of NQO2 in these assays. While the in vivo relevance of NQO2-catalyzed reduction of quinone-like metabolites remains to be established by identification of the physiologically relevant co-substrates, our results suggest an additional protective role of the NQO2 protein by non-enzymatic scavenging of quinone-like metabolites. Hepatic NQO1 activity in detoxication of quinone-like metabolites becomes especially important when other detoxication pathways are exhausted and NQO1 levels are induced.
Project description:The rhodium-catalyzed oxidative amidation of allylic alcohols and aldehydes is reported. In situ generated [(BINAP)Rh]BF4 catalyzes the one-pot isomerization/oxidative amidation of allylic alcohols or direct amidation of aldehydes using acetone or styrene as the hydrogen acceptor. The conditions are general, affording good to excellent yields with a wide array of amine and aniline nucleophiles, and chemoselective, other alcohols do not participate in the oxidation reaction. Utilization of biphasic conditions is critical, as they promote an equilibrium between the imine/enamine byproducts and the hemiaminal, which can undergo oxidation to the amide.
Project description:Many adverse drug reactions are thought to be caused by electrophilically reactive drug metabolites that conjugate to nucleophilic sites within DNA and proteins, causing cancer or toxic immune responses. Quinone species, including quinone-imines, quinone-methides, and imine-methides, are electrophilic Michael acceptors that are often highly reactive and comprise over 40% of all known reactive metabolites. Quinone metabolites are created by cytochromes P450 and peroxidases. For example, cytochromes P450 oxidize acetaminophen to N-acetyl-p-benzoquinone imine, which is electrophilically reactive and covalently binds to nucleophilic sites within proteins. This reactive quinone metabolite elicits a toxic immune response when acetaminophen exceeds a safe dose. Using a deep learning approach, this study reports the first published method for predicting quinone formation: the formation of a quinone species by metabolic oxidation. We model both one- and two-step quinone formation, enabling accurate quinone formation predictions in nonobvious cases. We predict atom pairs that form quinones with an AUC accuracy of 97.6%, and we identify molecules that form quinones with 88.2% AUC. By modeling the formation of quinones, one of the most common types of reactive metabolites, our method provides a rapid screening tool for a key drug toxicity risk. The XenoSite quinone formation model is available at http://swami.wustl.edu/xenosite/p/quinone .
Project description:Hydrogenation of 2-vinyl azines 1a-1e in the presence of N-arylsulfonyl imines 2a-2l at ambient temperature and pressure employing cationic rhodium catalysts ligated by tri-2-furylphosphine results in regioselective reductive coupling to furnish branched products of imine addition 3a-3v, which embody modest to high levels of syn-diastereoselectivity. Catalytic coupling of 6-bromo-2-vinylpyridine 1a to imine 2l under an atmosphere of elemental deuterium provides deuterio-3l, with deuterium exclusively at the former beta-position of the vinyl moiety. These data are consistent with a catalytic mechanism involving oxidative coupling of the vinyl azine and imine partners to furnish a cationic aza-rhodacyclopentane, which upon deuteriolytic cleavage releases the adduct and regenerates cationic rhodium(I) to close the catalytic cycle. These studies represent the first metal catalyzed reductive C-C couplings of vinyl azines.
Project description:Here, we have demonstrated visible light-emitting diode light-driven selective and efficient aerobic oxidation of primary/secondary alcohols to aldehydes/ketones and oxidative azo-coupling of anilines using biomass rice husk-derived chemically activated carbon sheet-supported copper-iron bimetallic hybrid nanomaterials (Cu x Fe1-x @RCAC) under oxidant and additive-free conditions. The catalytic activity of the Cu x Fe1-x @RCAC materials has been investigated for the oxidation of alcohols and anilines, and Cu0.9Fe0.1@RCAC was established as the best catalyst. Moreover, a tandem one-pot protocol has been developed for the sequential oxidation of alcohols followed by condensation to functionalized imidazole and imine derivatives in high isolated yields. The hybrid materials were highly robust and stable under the reaction conditions and were recovered simply by filtration and recycled up to 12th run without considerable loss in catalytic activity.
Project description:A new method for amino acid homologation by way of formal C-C bond functionalization is reported. This method utilizes a 2-step/1-pot protocol to convert ?-amino acids to their corresponding N-protected ?-amino esters through quinone-catalyzed oxidative decarboxylation/in situ Mukaiyama-Mannich addition. The scope and limitations of this chemistry are presented. This methodology provides an alternative to the classical Arndt-Eistert homologation for accessing ?-amino acid derivatives. The resulting N-protected amine products can be easily deprotected to afford the corresponding free amines.
Project description:The removal of 5-methyl-deoxycytidine (mdC) from promoter elements is associated with reactivation of the silenced corresponding genes. It takes place through an active demethylation process involving the oxidation of mdC to 5-hydroxymethyl-deoxycytidine (hmdC) and further on to 5-formyl-deoxycytidine (fdC) and 5-carboxy-deoxycytidine (cadC) with the help of ?-ketoglutarate-dependent Tet oxygenases. The next step can occur through the action of a glycosylase (TDG), which cleaves fdC out of the genome for replacement by dC. A second pathway is proposed to involve C-C bond cleavage that converts fdC directly into dC. A 6-aza-5-formyl-deoxycytidine (a-fdC) probe molecule was synthesized and fed to various somatic cell lines and induced mouse embryonic stem cells, together with a 2'-fluorinated fdC analogue (F-fdC). While deformylation of F-fdC was clearly observed in?vivo, it did not occur with a-fdC, thus suggesting that the C-C bond-cleaving deformylation is initiated by nucleophilic activation.
Project description:A highly regio- and diastereoselective synthesis of bicyclic pyrazolidinone derivatives by rhodium(II) acetate catalyzed [3 + 3]-annulation with enoldiazoacetates and azomethine imines has been achieved in high yield. A vinylogous reaction of the metal enol carbene with the azomethine imine initiates [3 + 3]-cycloaddition, whereas reaction at the carbene center effects N-N-cleavage of the azomethine imine.
Project description:In this communication, we report an asymmetric Friedel-Crafts reaction of indoles with imines catalyzed by a bifunctional cinchona alkaloid catalyst. This is the first efficient organocatalytic asymmetric Friedel-Crafts reaction of indoles with imines. This reaction is operationally simple and, unprecedentedly, affords high enantioselectivity for a wide range of indoles and both aryl and alkyl imines. This establishes a direct, convergent, and versatile approach to optically active 3-indolyl methanamines, a structural motif embedded in numerous indole alkaloids and synthetic indole derivatives.