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Quaternary amino acids, in which the alpha-carbon that bears the amino and carboxyl groups also carries two carbon substituents, have an important role as modifiers of peptide conformation and bioactivity and as precursors of medicinally important compounds1,2. In contrast to enantioselective alkylation at this alpha-carbon, for which there are several methods3?8, general enantioselective introduction of an aryl substituent at the alpha-carbon is synthetically challenging9. Nonetheless, the resultant alpha-aryl amino acids and their derivatives are valuable precursors to bioactive molecules10,11. Here we describe the synthesis of quaternary alpha-aryl amino acids from enantiopure amino acid precursors by alpha-arylation without loss of stereochemical integrity. Our approach relies on the temporary formation of a second stereogenic centre in an N?-arylurea adduct12 of an imidazolidinone derivative6 of the precursor amino acid, and uses readily available enantiopure amino acids both as a precursor and as a source of asymmetry. It avoids the use of valuable transition metals, and enables arylation with electron-rich, electron-poor and heterocyclic substituents. Either enantiomer of the product can be formed from a single amino acid precursor. The method is practical and scalable, and provides the opportunity to produce alpha-arylated quaternary amino acids in multi-gram quantities.

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The four-electron reduction of CO2 in the presence of secondary aromatic amines is described for the first time to access aminals. Under metal-free hydrosilylation conditions, the four C-O bonds of CO2 are cleaved, and the organocatalysts are able to balance the reactivity of CO2 to promote the selective formation of two C-N and two C-H bonds. The methodology enables the formation of various symmetrical and unsymmetrical aminals.

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Anodic oxidation in methanol of N-methylcarbanilides with an alkoxy-group para to the nitrogen atom (I) gives the intramolecular cyclization products, N-methylbenzoxazolium perchlorates: no cyclization product is obtained in the electrolysis of the anilides in acetonitrile.The process of cyclization was investigated by cyclic voltammetry, controlled potential electrolysis, and open circuit relaxation experiments using an optically transparent glassy carbon electrode.In spectroelectrochemical experiments on 4′-methoxy-N-methylbenzanilides (Ib-d) in methanol, accumulation of a metastable intermediate has been demonstrated.A possible reaction sequence for the formation of the benzoxazolium salts is discussed.

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A copper-catalyzed oxidative dearomatization/spirocyclization of indole-2-carboxamides using tert-butyl hydroperoxide (TBHP) as the oxidant has been developed that provides rapid and efficient access to C2-spiro-pseudoindoxyls. Two of the sp2 C-H bonds are functionalized during the reaction process, and the reaction likely proceeds via the formation of a highly reactive 3H-indol-3-one intermediate followed by aromatic electrophilic substitution with the N-aryl ring of the amide moiety.

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A solvent-free Buchwald-Hartwig amination had been developed under high-speed ball-milling conditions, which afforded the desired products with moderate to high yields. The addition of sodium sulfate was found to be crucial for improving both the performance and the reproducibility. Comparative solvent-free stirring experiments implicated the importance of mechanical interaction for the transformation, and the inert gas was proved to be unnecessary for this amination.

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(Chemical Equation Presented) Selective metal-free amination and Diels-Alder reactions are described in the furan series, leading to polysubstituted anilines or to stable oxabicyclic adducts in high yield. Interestingly, anilines are conveniently prepared through a novel one-pot, two-step amination/Diels-Alder procedure from commercially available 5-bromo-2-furaldehyde.

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An easily accessible formamidinate ligand-bearing titanium complex initially synthesized by Eisen et al. is used as catalyst for intermolecular hydroaminoalkylation reactions of unactivated, sterically demanding 1,1- and 1,2-disubstituted alkenes and styrenes with secondary amines. The corresponding reactions, which have never been achieved with titanium catalysts before, take place with excellent regioselectivity (up to 99: 1) and in addition, corresponding reactions of 1,3-butadienes with N-methylbenzylamine are also described for the first time.

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Near-infrared (NIR) fluorescent probes based on the Foerster resonance energy transfer (FRET) mechanism have various practical advantages, and their molecular design is generally based on the use of NIR dark quenchers, which are nonfluorescent dyes, as cleavable FRET acceptors. However, few NIR dark quenchers can quench fluorescence in the Cy7 region (over 780 nm). Here, we describe Si-rhodamine-based NIR dark quenchers (SiNQs), which show broad absorption covering this region. They are nonfluorescent independently of solvent polarity and pH, probably due to free rotation of the bond between the N atom and the xanthene moiety. SiNQs can easily be structurally modified to tune their water-solubility and absorption spectra, enabling flexible design of appropriate FRET pair for various NIR fluorescent dyes. To demonstrate the usefulness of SiNQs, we designed and synthesized a NIR fluorescent probe for matrix metalloproteinase (MMP) activity using SiNQ780. This probe 1 could detect MMP activity in vitro, in cultured cells and in a tumor-bearing mouse, in which the tumor was clearly visualized, by NIR fluorescence. We believe SiNQs will be useful for the development of a wide range of practical NIR fluorescent probes. (Chemical Equation Presented).

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A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by eerie ammonium nitrate oxidation of substituted (2,5- dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4- ylamino)[1,4]benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.

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The synthesis and biological activity of 42 6-substituted-2,4- diaminopyrido[3,2-d]pyrimidines (2,4-diamino-8-deazafolate analogues) are reported. The compounds were synthesized in improved yields compared to previous classical analogues using modifications of procedures reported previously by us. Specifically, the S-phenyl-; mono-, di-, and trimethoxyphenyl-; and mono-, di-, and trichlorophenyl-substituted analogues with H or CH3 at the N10 position and methyl and trifluoromethyl phenyl ketone analogues with H, C0H3, and CH2C?CH at the N10 position were synthesized. The S10 and N10 alpha- and beta-naphthyl analogues along with the N10 CH3 analogues were also synthesized. These compounds were evaluated as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystis carinii (pc) and Toxoplasma gondii (tg); selectivity ratios were determined against rat liver (rl) DHFR as the mammalian reference enzyme. Against pcDHFR the IC50 values ranged from 0.038 x 10-6 M for 2,4-diamino-6-[(N-methyl-2′- naphthylamino)methyl]pyrido[3,2-d]pyrimidine (28) to 5.5 x 10-6 M for 2,4- diamino-6-[(2′,4′-dimethoxyanilino)methyl]pyrido[3,2-d]pyrimidine (15). N10 methylation in all instances increased potency. None of the analogues were selective for pcDHFR. Against tgDHFR the most potent analogue was 2,4- diamino-6-[(N-methylanilino)methyl]pyrido[3,2-d]pyrimidine (5) (IC50 0.0084 x 10-6 M) and the least potent was 2,4-diamino-6-[(2′- naphthylamino)methyl]-pyrido[3,2-d]pyrimidine (37) (IC50 0.16 x 10-6 M). N10 methylation afforded an increase in potency up to 10-fold. In contrast to pcDHFR, several of the 8-deaza analogues were significantly selective for tgDHFR, most notably 2,4-diamino-6-[(2′-chloro-N- methylanilino)methyl]pyrido[3,2-d]pyrimidine (13), 2,4-diamino-6-[(3′,4′,5′- trimethoxyanilino)methyl]pyrido-[3,2-d]pyrimidine (29), and 2,4-diamino-6- [(2′,4′,6′-trichloroanilino)methyl]pyrido[3,2-d]pyrimidine (32) which combined high potency at 10-8 M along with selectivities of 8.0, 5.0, and 12.4, respectively. The potency of these three analogues are comparable to the clinically used agent trimetrexate while their selectivities for tgDHFR are 17-43-fold better than trimetrexate.

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