Le développement d’une nouvelle génération de catalyseurs dits biohybrides est basé sur l’association d’un complexe métallique et d’une protéine. D’un côté, le complexe métallique est responsable de l’activité catalytique ; de l’autre côté, la protéine protège le complexe métallique vis-à-vis de la dégradation en milieu aqueux et fournit également un environnement chiral propice à une catalyse énantiosélective. Ces catalyseurs fonctionnant de manière sélective en milieu aqueux s’inscrivent tout à fait dans les préceptes de la chimie verte.Une nouvelle famille de protéines artificielles, nommée αRep, a été récemment décrite. Toutes les protéines de la bibliothèque αRep présentent le même repliement en solénoïde incurvé, mais diffèrent à la fois en taille (nombre de motifs répétés) et dans la nature de 5 acides aminés par motif répété. Une surface variable est ainsi générée sur la surface concave du solénoïde. Ces protéines sont extrêmement stables et modifiables. La modularité de ces protéines ouvre la voie à un panel varié d’ingénierie des protéines, notamment la conception de catalyseurs artificiels.Au sein de la bibliothèque αRep, le variant αRep-A3 est une protéine homodimérique pour laquelle les surfaces concaves de chaque monomère génèrent une crevasse. Les résidus formant cette crevasse peuvent être modifiés sans affecter la structure tridimensionnelle de la protéine. Le but de cette thèse a été d’évaluer la capacité de la protéine αRep-A3 à procurer une architecture rigide pour l’incorporation de complexes de métaux de transition. Pour cela, différents ligands de métaux de transition (phénanthroline, terpyridine, porphyrine) ont été couplés covalemment à des variants de αRep-A3 à différentes positions. Des résultats encourageants concernant la réaction de Diels-Alder entre azachalcone et cyclopentadiène suggèrent que ce type d’architecture pourrait fournir une base intéressante pour la création de nouvelles classes de métalloenzymes entièrement artificielles. Des pistes pour l’amélioration des catalyseurs basés sur les αRep par des méthodes d’évolution dirigée sont alors avancées sur la base de ces résultats. / The development of a new generation of so-called biohybrid catalysts is based on the association of a metal complex and a protein. On the one hand, the metal complex is responsible for the catalytic activity; On the other hand, the protein protects the metal complex from degradation in aqueous medium and also provides a chiral environment conducive to enantioselective catalysis. These catalysts, which function selectively in an aqueous medium, fit perfectly into the precepts of green chemistry.A new family of artificial proteins, called αRep, has recently been described. All proteins in the αRep library exhibit the same curved solenoid folding, but differ in size (number of repeating units) and in the nature of 5 amino acids per repeat unit. A variable surface is thus generated on the concave surface of the solenoid. These proteins are extremely stable and modifiable. The modularity of these proteins paves the way for a varied panel of protein engineering, including the design of artificial catalysts.Within the αRep library, the variant αRep-A3 is a homodimeric protein for which the concave surfaces of each monomer generate a crevice. The residues forming this crevice can be modified without affecting the three-dimensional structure of the protein. The aim of this thesis has been to evaluate the ability of the αRep-A3 protein to provide a rigid scaffold for the incorporation of transition metal complexes. To this end, various transition metal ligands (phenanthroline, terpyridine, porphyrin) have been covalently coupled to variants of αRep-A3 at different positions. Encouraging results regarding the Diels-Alder reaction between azachalcone and cyclopentadiene suggest that this type of scaffold could provide an interesting basis for the creation of new classes of fully artificial metalloenzymes. From these results, lines of improvement for αRep-based catalysts by means of directed evolution are then advanced.

No description available.

En esta tesis doctoral se ha estudiado la reacción 1,3-dipolar con iluros de azometino y diferentes dipolarófilos para la síntesis de compuestos ópticamente activos, usando diferentes complejos metálicos compuestos por sales de plata y cobre y diversos ligandos quirales. También se ha estudiado la reacción 1,3-dipolar térmicamente para la funcionalización de grafeno, y posterior uso de dicha funcionalización como soporte de un complejo metálico, el cual fue empleado en catálisis heterogénea.

It has been previously shown that micelles formed from surfactants with chiral head groups serve to induce a chiral reaction medium, leading to enhanced enantioselectivities in the reaction products. This utilization of chiral surfactants will offer an economical alternative to traditional chial solvents while simultaneously reducing organic waste. We have successfully dimethlated S-leucinol in an 85% yield, and have synthesized a hydrocarbon-based surfactant with this molecule as a head group. We have also formed polymeric surfactants that have polydimethylsiloxane as the hydrophobic portion with the (S)-dimethylleucinol as a head group. Tests of the solubility of these surfactants have been conducted. We also have done a reduction of a ketone in 95% ethanol and 1.3%-4% (w/v) surfactants, resulting in ee. 5.4%-6.6%.

<p dir="ltr">Ring strain is the driving force for numerous ring-opening reactions of three- and four-membered heterocycles. By comparison, five-membered heterocycles lack this thermodynamic driving force. As a result, only a few methods exist for the ring-opening of five-membered heterocycles using transition metal catalysts. For unstrained and unactivated 2,5-dihydrofurans this is achieved via a β-O elimination process, wherein, gaining selectivity over a competing β-H elimination is challenging. We report a novel strategy for the asymmetric ring-opening of 2,5-dihydrofurans with dichloroalkenes utilizing an earth-abundant cobalt catalyst. We propose that the dichloroalkenes form reactive vinylidene intermediates with the chiral catalyst, followed by a [2+2] cycloaddition with the heterocyclic alkene. This cobaltacyclobutane exclusively undergoes an outer-sphere β-O elimination assisted by zinc halide. Alternative inner-sphere β-O and β-H elimination pathways are inaccessible from this four-membered metallacycle. This is followed by a transmetallation step to form a zinc metallacycle, which subsequently gives rise to homoallylic alcohols, upon quenching, with high diastero- and enantioselectivity. Additionally, the organozinc intermediate can be trapped in situ by various electrophiles for further derivatizations. DFT model predicts the origin of the high diastereo- as well as enantioselectivity observed in the reaction.</p><p dir="ltr">Furthermore, the cobaltacyclobutane intermediate serves as a dynamic platform, facilitating access to a diverse array of products depending on the alkene partners employed. Utilizing chiral allylic alcohols as alkene partners leads to the translation of stereochemical information enabling the stereospecific synthesis of both <i>E</i>- and <i>Z</i>-isomers of alkenes. Alkenes are important motifs found in various natural products and bioactive compounds. A catalytic approach for the precise control of the alkene geometry is highly valuable since the stereochemistry of alkenes plays a pivotal role in determining the properties of molecules. Our strategy provides access to organozinc dienes which could be functionalized further to form highly substituted 1,4-skipped dienes. Additionally, meso-diols can undergo a desymmetrizing β-O elimination from the cobaltacyclobutane intermediate yielding chiral cyclopentenols with contiguous stereocenters</p>

Thesis advisor: Marc M. Snapper / Thesis advisor: James J. Morken / This dissertation will present three main projects focusing on the catalytic enantioselective synthesis and stereospecific functionalization of tertiary alkylboronates. In the first project, acyl chlorides were incorporated as a new class of electrophile in conjunctive cross-coupling, from which, a variety of tertiary β-boryl amides were successfully synthesized with high enantioselectivity. The utility of the tertiary alkylboronates products was also demonstrated through several orthogonal functionalizations of the boronic ester group and amide groups. The project culminated in the enantioselective total synthesis of natural product (+)-adalinine that leveraged this newly developed methodology. In the second project, a conjunctive cross-coupling enabled ring closure was developed to synthesize tertiary alkylboronates residing on carbocyclic and heterocyclic scaffolds. A Phosphinooxazoline (Phox) ligand was identified as a non-expensive ligand that catalyzed the conjunctive cyclization reaction with high enantioselectivity. A Series of synthetically challenging enantimerically enriched spirocyclic and aryl bicyclic tertiary alkylboronates were efficiently generated using this method, and several cyclopentyl boronic esters with two continuous stereogenic centers were synthesized with high diastereoselectivity. In the third project, a Rh-catalyzed diboration reaction was successfully employed to diborate monosubstituted cyclobutenes with excellent enantioselectivity. The less sterically hindered secondary boronic ester units in the diboron products can be regioselectively functionalized using the newly developed tert-butyllithium activation-transmetallation strategy. As a result, a variety of stereochemically defined β-substituted cyclobutyl tertiary boronic esters were synthesized with high efficiency. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

No description available.

Enzymes are some of nature's most powerful tools in chemical processes. However, their molecular complexity makes them difficult to synthesize and complicates their application in traditional organic synthesis. Peptides, a building block of enzymes, can be rapidly synthesized and have been used as a possible alternative in achieving enzyme-like catalysis. However, most peptide-based catalysts are limited in reaction-scope and are unable to incorporate traditional organic catalysts. We have designed a helical peptide scaffold capable of being functionalized with a wide variety of organocatalysts as well as transition-metal based catalysts. In order to understand how the peptide structure effects reactivity and selectivity we designed and studied a helical peptide functionalized with enamine and thiourea catalysts for the conjugate addition reaction of a variety of nitroolefins to cyclohexanone. By rationally engineering the peptide backbone, we were able to achieve up to 95%ee. Our studies emphasized the crucial role the peptide secondary structure plays in this reaction and its potential to serve as a general catalytic platform for future reaction development. Progress particularly toward the development of peptide scaffolds capable of binding transition-metals and performing organometallic catalysis is also described. Peptides are promising motifs in therapeutics. They are more specific and are able to bind to a larger range of targets than small-molecule based drugs while also having lower immunogenicity than larger biologic-based drugs. However, their poor in vivo stability is problematic for their more widespread use. Peptide stapling has been shown to increase peptide stability by covalently linking two ends of the peptide. Squaric esters are commonly used in conjugation chemistry and have shown to selectively react with primary amine nucleophiles, such as those on lysine sidechains. However, their potential to act as peptide stapling reagents has remained unexplored. We have developed a method whereby helical peptides can be stapled with squaric methyl ester on-resin. Peptides can be stapled at the i+1, i+4, and i+7 positions in good yields. The staple is also stable under the highly acidic conditions used to cleave the peptides from resin. Circular dichroism studies show that the staple is able to increase peptide helicity when compared with an unstapled control.

No / The oligomerisation of L-amino acids by papain was studied in a mixer ball mill and in a planetary ball mill. The biocatalyst proved stable under the ball milling conditions providing the corresponding oligopeptides in good to excellent yields and with a variable degree of polymerisation. Both parameters were found to be dependent on the reaction conditions and on the nature of the amino acid (specifically on its side-chain size and hydrophobicity). In addition, the chemoenzymatic oligomerisation was demonstrated by utilising twin-screw extrusion technology, which allowed for a scalable continuous process. Finally, the synthesised oligo(L-Leu) 2b proved to be active as a catalyst in the Juliá–Colonna enantioselective epoxidation of chalcone derivatives. / We acknowledge RWTH Aachen University for support by the Distinguished Professorship Program funded by the Excellence Initiative of the German federal and state governments. We kindly acknowledge Marcus Frings and Plamena Staleva for the HPLC analysis of products 4a–c (RWTH Aachen University) and ASEP for the TGA analysis (Queen’s University Belfast). D. E. C. and S. L. J. acknowledge the agency EPSRC, grant no. EP/R019655/1. Part of this work was performed at the Center for Chemical Polymer Technology (CPT) unit of DWI, which was supported by the EU and the federal state of North Rhine-Westphalia (grant EFRE 30 00 883 02).

Understanding the supramolecular interactions governing the self-assembly of molecular building blocks upon surfaces is fundamental to the design of new devices such as sensors or catalysts. Successful heterogeneous enantioselective catalysts have relied upon the adsorption of ‘chiral modifiers’, usually chiral amino acids, onto reactive metal surfaces. One of the most researched examples is the hydrogenation of β-ketoesters using nickel-based catalysts. The stability of the chiral modifiers upon catalyst surfaces is a major obstacle to the industrial scale-up of this reaction. In this study, the replacement of conventional modifiers with porous, chiral and functionalised self-assembled networks is investigated. Perylene-3,4,9,10-tetracarboxylic diimide (PTCDI) and melamine (1,3,5-triazine,-2,4,6-triamine) have been shown to form hydrogen bonded networks on Ag-Si(111)√3x√3R30° in ultra-high vacuum (UHV) and Au(111) substrates in UHV and ambient conditions, these networks are capable of hosting guest molecules. These networks are investigated further in this study. In UHV, the behaviour of the components and network formation on Ni(111) is probed using scanning tunnelling microscopy (STM) and temperature-programmed desorption (TPD). The stability of the PTCDI-melamine network on Au(111) was analysed using TPD. Metal coordination interactions between each of the network components and nickel upon the Au(111) surface were examined by STM before testing the ability of the network to act as a template for metal growth. Finally, a number of polymerisation reactions are investigated with a view to replacing chiral modifiers with porous, chiral, functionalised covalent networks. Periodic covalent networks should possess the greater chemical and thermal stability required for more widespread use. In UHV and ambient conditions, STM is used to monitor the progress of surface-confined reactions on Au(111) and characterise the resultant covalent structures.