7 research outputs found

    A semiempirical (am1) study of the reactivity of redox states of quin one-containing model systems for anthracycline pharmacophores, 1993

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    The reactivity of redox states of model systems for anthracycline pharmacophores were examined by the AM1 semiempirical approach. The redox states examined were quinone (Q), quinone radical anion (Q ), semiquinone radical (QH ), semiquinone anion (QH"), and hydroquinone (QH2), while the model systems were 1,4-benzoquinone (I), 1,4-naphthaquinone (II), hydroxy-naphthaquinone (III) and dihydroxy-naphthaquinone (IV), which are all part of the pharmacophores of several anthracyciines. The imine and/or diimine derivatives of 1,4-benzoquinone and dihydroxy-naphthaquinone were also investigated. The relative reactivity of Q, Q' , QH, QH, and QH2 were examined by utilizing absolute electronegativity and chemical hardness data. In all cases, Q' and QH were found to be the most reactive species suggesting that these redox states are probably the ones tnat transfer their electrons to molecular oxygen thereby generating reactive oxygen species. The imine and diimine analogs were shown to have higher reactivity. This strongly suggests that 5-iminodaunomycin, a C-5 imine derivative of daunomycin, which has been described as redox-incapacitated, should not be less reactive than daunomycin. Based on electronegativity data, there were no specific reactivity trend observed for redox states of the four quinone systems (l-IV); however, absolute hardness data suggested that Q" was the most reactive intermediate for all four systems. SOMO and LUMO energies, absolute electronegativities and chemical hardness values, and reaction enthalpies (for the electron attachment to Q) of 12 disubstituted naphthaquinones were also correlated with their experimental reduction potentials using a least squares analysis. When all 12 points were included, the correlation coefficients obtained were: 0.28 (SOMO energies), 0.40 (LUMO energies), 0.41 (absolute hardness), 0.53 (electronegativity), and 0.57 (reaction enthalpies). In all cases, exclusion of three points gave better correlations with coefficients in the range of 0.73-0.91. In general, SOMO and LUMO energies and reaction enthalpies decreased with increasing reduction potential and absolute hardness and electronegativity values increased with increasing reduction potential. Since experimental reduction potentials have been shown to correlate with antitumor activity, this study shows the various electronic properties considered in this study should also correlate with antitumor activity, and thus can be used to generate a data base for structure-activity correlations and for new drug design purposes

    Synthetic, Mechanistic and Theoretical Studies Related to the Kinamycin Antibiotics

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    The synthesis of an isosteric-isoelectronic analogue of prekinamycin, an N-cyanobenzo[b]carbazoloquinone 2.1, is described. The key steps include a Vilsmeier-Haack formylation, a regioselective bromination, a Buchwald-Hartwig cross-coupling, a palladium mediated oxidative cyclization and N-cyanation to furnish the target in fifteen steps in an overall yield of 1.6%. Subsequent bioactivity studies were conducted in which the cytotoxicity of various compounds on K562 cells, a human erythroleukemic cell line, revealed that the analogue had a similar bioactivity profile to prekinamycin. These results suggest that the diazo functionality may not be an absolute requirement for bioactivity. A study of the reactivity of nitric oxide with diphenyldiazomethane, kinamycin A and isoprekinamycin diacetate was undertaken. Three products were isolated from the reaction with diphenyldiazomethane: a nitrimine 3.7, benzophenone and, for the first time, dinitrodiphenylmethane 3.9. The source of the two nitrogens in the nitrimine and dinitrodiphenylmethane was elucidated through isotopic labeling experiments with 15N-labeled diphenyldiazomethane. Results suggest that two separate 1,3-dipolar cycloadditions generating two different 5-membered intermediates via two separate [3+2] cycloadditions, furnishing the nitrimine and benzophenone, are occurring. Subsequent theoretical studies reveal that the [3+2] cycloadditions are in accord with experimental results. Further calculations show that the proposed intermediates and transition state structures are in good agreement with the product distribution and isotopic labeling studies. The kinamycins were found to be unresponsive to NO exposure in which theoretical calculations reveal that the free energy of activation for the 1,3 dipolar cycloadditions is significantly higher for the natural products than for diphenyldiazomethane. A comprehensive theoretical study on the chemistry of the N-acetyl indole-2,3-quinodimethanes (N-Ac IQDM 5.1) at the DFT B3LYP 6-31 G(d) level is described. Investigation of amide conformations of N-Ac IQDM in which good agreement between experimental and theoretical results is shown. Subsequent studies addressing regioselectivity and stereoselectivity of Diels-Alder (DA) reactions are described. FMO theory does not provide a rationalization for the regioselectivity observed in DA reactions of N-Ac IQDM. Transition state calculations were carried out to probe the regioselectivity of DA reactions of this system. For acrolein, Δ‡G was found not to be predictive of regiochemistry as observed experimentally. However, the calculated barriers, Δ‡E and Δ‡H, are in qualitative agreement with experimental trends in which the major regioisomer is predicted to be C-2 DA adduct. Methacrolein and crotonaldehyde were also examined. On comparison to acrolein, Δ‡G predicts that both α-substitution (i.e. methacrolein) and β-substitution (i.e. crotonaldehyde) increases regioselectivity for the C-2 regioisomer. Furthermore, the Δ‡E and Δ‡H data sets for methacrolein predicts increased regioselectivity for the C-2 adduct; the Δ‡E and Δ‡H data sets for crotonaldehyde predicts decreased C-2 regioselectivity. Efforts towards the synthesis of tetrahydrofluorenes via DA reactions of ethyl 2,3-dimethylene-2,3-dihydro-1H-indene-1-carboxylate (6.20) and diethyl 2,3-dimethylene-2,3-dihydro-1H-indene-1,1-dicarboxylate (6.36) are described and were generated from the corresponding ethyl 2-(2-(1-acetoxybuta-2,3-dien-2-yl)phenyl)acetate (6.18) and the diethyl 2-(2-(1-acetoxybuta-2,3-dien-2-yl)phenyl)malonate (6.35), respectively. Employing various solvents and bases, the carboxylate 6.20 failed to provide the desired DA adduct with methyl acrylate. The malonate 6.35 was synthesized by carboxyalkylation followed by a Stille cross coupling reaction. DA reactions with methyl acrylate were carried out in which evidence of a DA adduct was observed in the 1H NMR spectrum but attempts of its purification proved futile. DA reactions with N-phenylmaleimide provided the corresponding DA adduct in 77% yield. Quantum chemical calculations reveal that the two dienes 6.20 and 6.36 have termini that are significantly different and would suggest that FMO interactions would be a determining factor in the regioselectivity of Diels-Alder cycloadditions. In the case of acrolein, inspection of the MO coefficients predicts that the C-2 cycloadducts would be the major regioisomer. TS calculations agree with the qualitative interpretation that FMO arguments provide

    Noncovalent Interactions of Silent Agonists Binding to the Nicotinic Acetylcholine Receptor -and- Investigation into Expanding the Substrate Scope and Improving the Efficiency of Organic Photochemical Protecting Groups

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    This dissertation describes two very different projects. The first project focuses on the binding of a silent agonist to a ligand gated ion channel. The second project focuses on the study of development of new longer wavelength photolabile protecting groups for use in a biological setting to enable the spatially and temporally controlled release of biologically active small molecules. Chapter I introduces ligand gated ion channels and in particular a model of agonist binding at the nicotinic acetylcholine receptor. In addition, the nonsense suppression methodology used to incorporate the non-canonical amino acids required to probe non-covalent binding interactions is detailed. The second chapter details the use of non-canonical amino acids to study the binding of silent agonist NS6740 at the nicotinic acetylcholine receptor α7 subunit and the discovery of a novel hydrogen bond that modulates silent agonist activity. Chapters III, IV and V focus on efforts to expand the scope of photolabile protecting groups towards designing longer wavelength derivatives. Chapter III introduces the topic of photoremovable protecting groups and details the mechanist background of a quinone methide based photochemical protecting group. The fourth chapter investigates the use of quinoline and quinolinium derivatives as photochemical quinone methide precursors. Two quinoline derivatives were found to form a quinone methide transient when irradiated. Quinolinium derivatives proved photostable, most likely due to the electron withdrawing nature of the quinolinium. The final chapter details efforts to improve the photochemical reaction efficiency of quinone photoreduction by using a radical decarboxylation strategy to trap the charge transfer state. Synthesis of two glycine containing quinone compounds is detailed and their photochemistry is evaluated. Both proved to be photostable.</p

    Visible Light-assisted Deconstruction/Refunctionalization of Strained and Unstrained N-Cycloalkylanilines

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    The exploitation of ring strain as a driving force to facilitate chemical reactions is a well-appreciated principle in organic chemistry. Of the strained carbocycles frequently explored in this respect, cyclopropane ring systems have drawn considerably more interest among synthetic chemists than their homolog, the cyclobutane ring systems, even though the strain energy of cyclobutane (26.7 kcal/mol) is similar to that of cyclopropane (27.5 kcal/mol). We have previously developed a [4+2] annulation reaction for the synthesis of aniline-substituted six-membered carbocycles under photoredox catalysis via the oxidative cleavage of N-cyclobutylanilines. The key reaction involved in this method is a ring-opening process of cyclobutylanilines via single-electron oxidation of the anilines under visible light photoredox conditions to presumably generate distonic radical cation intermediates which possess bimodal reactivity due to the presence of a nucleophilic carbon radical moiety (site Y) and an electrophilic iminium ion moiety (site X) that are spatially separated. We have hitherto successfully achieved orthogonal 1,4-difunctionalization of the two reactive sites by using phenyl allyl sulfone or α-CF3-styrene as radical acceptor to capture the radical at Y and TMSCN as nucleophile to intercept the iminium ion at X respectively. The first of the three works described in this dissertation further exploits isocyanides (or isonitriles)—“stereoelectronic chameleons” that exhibit dichotomous reactivity—as radical acceptors in the difunctionalization of the bimodal amine distonic radical cations to afford both symmetrical and unsymmetrical N-substituted 2,6-diaminopimelonitriles in poor to good yields. This represents the first-ever report of a successful synthetic methodology that exploits the ambivalent reactivities of both distonic radical cations and isocyanides.Again, we report the development of a novel methodology for the synthesis of aminoalkynes from various N-substituted cyclobutane substrates via a sequential visible-light-assisted ring-opening and distal alkynylation with alkynyl hypervalent iodine (III) reagents. An in situ-generated distonic radical cation intermediate possessing resonance-stabilized iminium ion site mediates the transformation of the substrates into various pharmaceutically important nitrogen heterocycles. This methodology constitutes only the second example of aminoalkyne synthesis employing the cycloalkylamine deconstruction/refunctionalization strategy. Finally, we report the first-ever aromatization-promoted, visible-light-assisted deconstructive functionalization of unstrained medium-to-large-sized cycloalkanones using diamines as an activator of the ring cleavage for the synthesis of remotely functionalized quinazolinones. The protocol features an amido radical-mediated C(sp3)-C(sp3) cleavage via an aromatization/radical acceptor-driven ring-opening synergy, without the involvement of transition metals, exogenous oxidants, or chelation assistance. In addition, the reaction exhibits a broad substrate scope, good to excellent product yields, and high regioselectivities

    Visible Light-assisted Deconstruction/Refunctionalization of Strained and Unstrained N-Cycloalkylanilines

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    The exploitation of ring strain as a driving force to facilitate chemical reactions is a well-appreciated principle in organic chemistry. Of the strained carbocycles frequently explored in this respect, cyclopropane ring systems have drawn considerably more interest among synthetic chemists than their homolog, the cyclobutane ring systems, even though the strain energy of cyclobutane (26.7 kcal/mol) is similar to that of cyclopropane (27.5 kcal/mol). We have previously developed a [4+2] annulation reaction for the synthesis of aniline-substituted six-membered carbocycles under photoredox catalysis via the oxidative cleavage of N-cyclobutylanilines. The key reaction involved in this method is a ring-opening process of cyclobutylanilines via single-electron oxidation of the anilines under visible light photoredox conditions to presumably generate distonic radical cation intermediates which possess bimodal reactivity due to the presence of a nucleophilic carbon radical moiety (site Y) and an electrophilic iminium ion moiety (site X) that are spatially separated. We have hitherto successfully achieved orthogonal 1,4-difunctionalization of the two reactive sites by using phenyl allyl sulfone or α-CF3-styrene as radical acceptor to capture the radical at Y and TMSCN as nucleophile to intercept the iminium ion at X respectively. The first of the three works described in this dissertation further exploits isocyanides (or isonitriles)—“stereoelectronic chameleons” that exhibit dichotomous reactivity—as radical acceptors in the difunctionalization of the bimodal amine distonic radical cations to afford both symmetrical and unsymmetrical N-substituted 2,6-diaminopimelonitriles in poor to good yields. This represents the first-ever report of a successful synthetic methodology that exploits the ambivalent reactivities of both distonic radical cations and isocyanides.Again, we report the development of a novel methodology for the synthesis of aminoalkynes from various N-substituted cyclobutane substrates via a sequential visible-light-assisted ring-opening and distal alkynylation with alkynyl hypervalent iodine (III) reagents. An in situ-generated distonic radical cation intermediate possessing resonance-stabilized iminium ion site mediates the transformation of the substrates into various pharmaceutically important nitrogen heterocycles. This methodology constitutes only the second example of aminoalkyne synthesis employing the cycloalkylamine deconstruction/refunctionalization strategy. Finally, we report the first-ever aromatization-promoted, visible-light-assisted deconstructive functionalization of unstrained medium-to-large-sized cycloalkanones using diamines as an activator of the ring cleavage for the synthesis of remotely functionalized quinazolinones. The protocol features an amido radical-mediated C(sp3)-C(sp3) cleavage via an aromatization/radical acceptor-driven ring-opening synergy, without the involvement of transition metals, exogenous oxidants, or chelation assistance. In addition, the reaction exhibits a broad substrate scope, good to excellent product yields, and high regioselectivities

    Summaries of FY 1997 Research in the Chemical Sciences

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    The objective of this program is to expand, through support of basic research, knowledge of various areas of chemistry, physics and chemical engineering with a goal of contributing to new or improved processes for developing and using domestic energy resources in an efficient and environmentally sound manner. Each team of the Division of Chemical Sciences, Fundamental Interactions and Molecular Processes, is divided into programs that cover the various disciplines. Disciplinary areas where research is supported include atomic, molecular, and optical physics; physical, inorganic, and organic chemistry; chemical energy, chemical physics; photochemistry; radiation chemistry; analytical chemistry; separations science; heavy element chemistry; chemical engineering sciences; and advanced battery research. However, traditional disciplinary boundaries should not be considered barriers, and multi-disciplinary efforts are encouraged. In addition, the program supports several major scientific user facilities. The following summaries describe the programs

    Potassium Organotrifluoroborates: Reliable Cross-Coupling Partners and Stepping Stones to Functionalized Azaborine Cores

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    The synthesis of enantioenriched, air-stable secondary alkylmetallic reagents has gained much attention over the past few years; however, competition between product-forming reductive elimination and β-hydride elimination has hindered their efficient cross-coupling. The paradigm of employing a hemilabile ligand to favor reductive elimination has been extended to include an array of amides and benzylic ethers. The synthesis of protected secondary benzylic alcohols through a cross-coupling reaction was explored. Potassium 1-(benzyloxy)alkyltrifluoroborates, synthesized through a diboration of aldehydes, serve as nucleophilic partners in a stereospecific Suzuki-Miyaura reaction, where the benzyl group serves as a stabilizing group to prevent β-hydride elimination. ^ An improved synthesis of potassium β-trifluoroboratoamides utilizing tetrahydroxydiboron and tetrakis(dimethylamino)diboron as greener, more atom-economical dibora sources was explored. Enantioenriched potassium β-trifluoroboratoamides were cross-coupled with aryl chlorides to afford β-arylated amines. In this coupling, the carbonyl of the amide serves as a stabilizing group to prevent β-hydride elimination. ^ The replacement of a C=C bond with an isoelectronic B-N unit within an aromatic system results in azaborines, a class of compounds with stability and aromaticity similar to the all-carbon parent. Based on the potential of azaborines in the fields of medicinal chemistry and materials science, methods for the synthesis and functionalization of azaborines could have an impact by increasing structural diversity and creating new chemical space. A convergent, modular synthesis of 2,1-borazaronaphthalenes was developed from 2-aminostyrenes and potassium organotrifluoroborates, providing a transition metal-free route to elaborated azaborines. ^ Functionalization of 2,1-borazaronaphthalenes was envisioned to build molecular complexity and demonstrate the stability of azaborines to various transformations. The first general method for the Suzuki-Miyaura cross-coupling of brominated azaborine with potassium (hetero)aryltrifluoroborates was developed to afford 3-(hetero)arylated-2,1-borazaronaphthalenes in high yield. ^ Whereas 3-bromo-2-aryl-2,1-borazaronaphthalenes undergo cross-coupling with an aryltrifluoroborate, 1-alkyl-2-aryl-3-bromo-2,1-borazaronaphthalenes undergo a self-arylation, in which the azaborine serves as both the electrophilic and nucleophilic species in the cross-coupling. A Kumada coupling with Grignard reagents provides access to the 1,2,3-trisubstituted 2,1-borazaronaphthalenes. ^ A nickel-catalyzed reductive coupling was explored with brominated 2,1-borazaronaphthalenes and alkyl iodides. This method demonstrates the inherent stability of azaborines to transition-metal catalysis and provides the first examples of C3 alkylated 2,1-borazaronaphthalenes. ^ ^Please refer to dissertation for diagrams
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