<p>N-Heterocycles are ubiquitous in biologically active natural products and pharmaceuticals. Yet, new syntheses and modifications of N-heterocycles are continually of interest for the purposes of expanding chemical space, finding quicker synthetic routes, better pharmaceuticals, and even new handles for molecular labeling. There are several iterations of molecular labeling; the decision of where to place the label is as important as of which visualization technique to emphasize. </p><p>Piperidine and indole are two of the most widely distributed N-heterocycles and thus were targeted for synthesis, functionalization, and labeling. The major functionalization of these scaffolds should include a nitrogen atom, while the inclusion of other groups will expand the utility of the method. Towards this goal, ease of synthesis and elimination of step-wise transformations are of the utmost concern. Here, the concept of electrophilic amination can be utilized as a way of introducing complex secondary and tertiary amines with minimal operations.</p><p>Molecular tags should be on or adjacent to an N-heterocycle as they are normally the motifs implicated at the binding site of enzymes and receptors. The labeling techniques should be useful to a chemical biologist, but should also in theory be useful to the medical community. The two types of labeling that are of interest to a chemist and a physician would be positron emission tomography (PET) and magnetic resonance imaging (MRI). </p><p>Coincidentally, the 3-positions of both piperidine and indole are historically difficult to access and modify. However, using electrophilic amination techniques, 3-functionalized piperidines can be synthesized in good yields from unsaturated amines. In the same manner, 3-labeled piperidines can be obtained; the piperidines can either be labeled with an azide for biochemical research or an 18F for PET imaging research. The novel electrophiles, N-benzenesulfonyloxyamides, can be reacted with indole in one of two ways: 3-amidation or 1-amidomethylation, depending on the exact reaction conditions. Lastly, a novel, hyperpolarizable 15N2-labeled diazirine has been developed as an exogenous and versatile tag for use in magnetic resonance imaging.</p> / Dissertation

Chiral quaternary centers possessing a bond to nitrogen are an important class of amine compounds, however, methods for their enantioselective preparation remain sparse. The focus of my graduate research described herein has been the development of a novel rhodium-catalyzed regio- and enantioselective allylic aryl amination of tertiary trichloroacetimidates for the synthesis of amine-bearing quaternary centers (also termed α,α-disubstituted amines). Prior to our work, allylic carbonates and acetates had been successfully utilized in transition-metal catalyzed substitution reactions with anilines for the asymmetric synthesis of tertiary centers. In contrast, these electrophiles have not proven useful in dynamic kinetic asymmetric transformations (DYKAT) that yield enantioenriched amine products, and no reports describing the asymmetric preparation of α,α-disubstituted allylic aryl amines via allylic substitution are noted. Many of the ideas for development of our rhodium-catalyzed amination method were based upon the findings of Overman where linear allylic trichloroacetimidates are utilized in [3,3]-sigmatropic rearrangements and substitution reactions by oxygen nucleophiles under palladium (II) catalysis. Our method diverges from this previous work by application of branched allylic trichloroacetimidates where the olefin component is mono-substituted, and the use of a transition-metal complex capable of facile oxidative addition to an intermediate organometallic complex. We hypothesized that bidentate chelation of these substrates at the imidate nitrogen and the relatively unimpeded olefin by a rhodium (I) complex would lead to rapid ionization to an activated complex and competent electrophile for substitution by neutral aniline nucleophiles. This premise was supported by many control studies and resulted in the development of a highly regioselective amination of branched allylic trichloroacetimidates for the operationally simple synthesis of α-substituted and α,α-disubstituted allylic aryl amines. Work followed utilizing chiral diene ligands that rendered the reaction enantioselective for preparation of enantioenriched tertiary and quaternary amine-containing centers. A highlight of these studies is the first example of DYKAT using a tertiary electrophile and an aryl amine nucleophile. The reaction is of broad substrate scope, is tolerant of varied functionality and substitution patterns on the nucleophilic partner, and solves regioselectivity issues often encountered with some substrate and aniline classes. I end by showing the synthetic utility of our rhodium-catalyzed reaction by applying this method to the synthesis of enantioenriched amino acids and construction of 7-membered nitrogen-containing heterocycles by a 2-step DYKAT amination and olefin hydroacylation sequence.

Porphyrins and their analogs are a class of chemically and biologically important compounds that have found a variety of applications in different fields such as catalysis, medicine, and materials. The physical, chemical, and biological dependence of the peripheral substituents of porphyrins on their properties has prompted great effort towards the synthesis of new porphyrins with different electronic, steric, and conformational environments. To this end, porphyrins have been prepared using a modular approach from bromo- and triflate synthons. These synthons underwent palladium-catalyzed cross-coupling with chiral amines, amides, alcohols, and boronic esters to create products that were tested for biological activity. Metalloporphyrins were screened as catalysts for cyclopropanation and C-H amination, yielding excellent results. By changing the porphyrin catalysts’ chiral groups, all four enantiomers could be produced in the cyclopropanation of styrene derivatives with ethyl diazoacetate (or t-butyl diazoacetate). Similarly, a variety of sultams were produced from benzenesulfonyl azides in high yields and high enantioselectivities using chiral cobalt porphyrins as catalysts. Porphyrins, metalloporphyrins, and the catalytic products generated were tested for activity in a variety of medicinal collaborations, namely as therapeutics for methicillin-resistant Staphylococcus aureus, Alzheimer’s disease, malaria, viral infections that include influenza and herpes, and cancer, as well as biological studies with ferrochelatase. They were also used in materials experiments with two different polymer groups.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Due to the prevalence of porphyrins and their derivatives in Nature, there is a wide interest in the synthesis, design and exploitation of their properties. Their electron delocalisation, and the ease with which the electronic system can be perturbed and manipulated, have meant that porphyrins have been investigated for applications in many avenues. Conjugated, multiporphyrin oligomers have been studied as light-harvesting system mimics, molecular wires and sensors. It has been predicted that the azo-linkage should enable superior porphyrin-to-porphyrin interaction. Preparation of an azo-linked bis(porphyrin) was approached by reacting protected hydrazines with bromoporphyrins. A series of mono- and bis-substituted porphyrinoids including novel diiminoporphodimethenes was synthesised using palladium-catalysed reactions, and spectroscopic, structural and redox properties of these products were investigated. The manner in which a bis-substituted product evolved from a mono-activated starting material was studied. The synthesis of these products was refined to produce each product selectively. These products display interesting redox properties, and several of them exhibit greatly red-shifted absorption spectra. The palladium-catalysed synthesis of primary and secondary aminoporphyrins, as well as a hydroxyporphyrin, from the reaction of bromoporphyrins with unsubstituted hydrazine was discovered and investigated. The synthesis of these products was optimised to yield each novel porphyrinoid selectively. Some of the electronic and structural properties of these products were studied, and the unique bis(porphyrin)secondary amine exhibited excitonic coupling between the macrocycles. A porphyrin dyad with an azo-linkage was isolated, and its synthesis was optimised, initially using palladium-catalysed homocoupling of aminoporphyrins, and then using copper catalysis. The synthesis of this "azoporphyrin" was optimised to obtain the desired dimers in high yields and the properties of these dimers were studied and contrasted with those of other conjugated porphyrin dimers. The absorption spectra exhibited greatly split Soret bands and intense, red-shifted Q-bands, while cyclic voltammetry showed a decrease in the HOMO-LUMO gap, indicative of extremely efficient porphyrin-porphyrin interaction. Two crystal structures of azoporphyrins were obtained, and the dihedral angle and the distance between the mean planes of the macrocycles were also significantly smaller than those found for the analogous (E)-ethene-linked dimers. A series of novel "head-to-tail" porphyrin dyads was also isolated and characterised, and these exhibited interesting spectral features, including very broad and red-shifted Q-bands and split Soret bands in their absorption spectra.

No description available.

Amine transaminases are enzymes that catalyze the mild and selective formation of primary amines, which are useful building blocks for biologically active compounds and natural products. In order to make the production of these kinds of compounds more efficient from both a practical and an environmental point of view, amine transaminases were incorporated into multi-step one-pot reactions. With this kind of methodology there is no need for isolation of intermediates, and thus unnecessary work-up steps can be omitted and formation of waste is prevented. Amine transaminases were successfully combined with other enzymes for multi-step synthesis of valuable products: With ketoreductases all four diastereomers of a 1,3-amino alcohol could be obtained, and the use of a lipase allowed for the synthesis of natural products in the form of capsaicinoids. Amine transaminases were also successfully combined with metal catalysts based on palladium or copper. This methodology allowed for the amination of alcohols and the synthesis of chiral amines such as the pharmaceutical compound Rivastigmine. These examples show that the use of amine transaminases in multi-step one-pot reactions is possible, and hopefully this concept can be further developed and applied to make industrial processes more sustainable and efficient in the future. / <p>QC 20170113</p>

The use of enzymes, nature´s own catalysts, both isolated or as whole cells to perform chemical transformations is called biocatalysis. As a complement to classical chemical catalysis, biocatalysis can be an environmentally friendly and more economical option in the production and synthesis of chemicals. Research on the application of amine transaminases in synthesis of chiral amines have exploded over the last two decades and interest from the industry is increasing. Amine transaminases are promising catalysts due to their ability to perform reductive amination of ketones with excellent enantioselectivity. For a process to be efficient, high substrate specificity of the applied enzyme is an important factor. A variant of Chromobacterium violaceum amine transaminase that was obtained through rational design has an increased specific activity toward (S)-1-phenylethylamine and a set of 4´-substituted acetophenones. This result makes this variant a promising catalyst for the asymmetric synthesis of similar amines. Amine transaminase catalyzed asymmetric synthesis of amines generally suffers from unfavorable equilibrium. Two methods that include spontaneous tautomerization and biocatalytic amidation for equilibrium displacement have therefore been developed. Efficient assays and screening methods are demanded for the discovery and development of novel amine transaminases. For this purpose, a sensitive fluorescence-based assay that holds promise as a high-throughput screening method was developed. One of the major obstacles for application of enzymes in industrial processes is the instability of the enzyme toward harsh conditions. The stability of Chromobacterium violaceum amine transaminase was investigated and improved using co-solvents and other additives. Co-lyophilization with surfactants was also applied to improve the performance of the same enzyme in organic solvents. / <p>QC 20161017</p>

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 1977 / Includes bibliographical references. / Ph. D. / Ph. D. Massachusetts Institute of Technology, Department of Chemistry

This diploma thesis dealt with the comparison of different methods of amination of polycaprolcatone in terms of their effectiveness for tissue engineering. A polycaprolactone membrane was prepared by an electrospinning method, which was subsequently modified by three different amination methods. Selected types of amination were plasma polymerization with cyclopropylamine monomer, hybrid modification using plasma and N-allylmethylamine monomer, and chemical amination using aminolysis with diaminohexane. Surface amines were subsequently characterized by electron scanning microscopy (SEM), X-ray photoelectron spectroscopy (XPS), attenuated total reflection infrared spectroscopy (ATR-FTIR) and contact angle measurement. A cell culture designated A375 (Human malignant melanoma cell lines A375® CRL-1619®) was cultured on the thus modified membranes, which was analyzed by optical microscopy, and a proliferation assay was performed by determining the relative amount of ATP. Based on the experimental results, we can confirm the success for all types of amination. In terms of efficiency for tissue engineering, the amination method by plasma polymerization with the monomer cyclopropylamine has the most satisfactory results.