Rozprawy doktorskie na temat „Organic synthesis, Catalysis, and methodology development”

A highly enantioselective acylation of silyl ketene acetals with acyl fluorides was developed to generate useful α,α-disubstituted butyrolactone products in high yield and excellent enantioselectivities. This transformation is promoted by an arylpyrrolidino thiourea catalyst and 4-pyrrolidinopyridine and represents the first example of enantioselective thiourea anion-binding catalysis with fluoride. Mechanistic investigations revealed both catalysts to be necessary for reaction to occur, suggesting the thiourea aids in the generation of the key N-acylpyridinium/fluoride ion pair. The outstanding hydrogen-bond-accepting ability of fluoride is likely important in this regard. In addition, a strong dependence on both the N-acylpyridinium counteranion and the substituents on the silicon group of the silyl ketene acetal were observed, highlighting the importance of the silicon-fluoride interaction. A cyclic oligomeric (salen)Co–OTf complex was used to catalyze a highly enantioselective addition of phenyl carbamate to meso-epoxides to afford protected trans-1,2-amino alcohols. The use of an oligomeric (salen)Co–OTf complex as the catalyst and aryl carbamates as nucleophiles was crucial to the development of this reaction protocol. This method is amenable to large-scale synthesis due to the low catalyst loadings and high concentration used, its operational simplicity, and the use of inexpensive, commercially-available starting materials. To demonstrate the synthetic utility of this protocol, optically pure trans-2-aminocyclohexanol hydrochloride and trans-2-aminocyclopentanol hydrochloride were prepared on a multigram scale using only 0.5 and 1 mol% catalyst loading, respectively.
Chemistry and Chemical Biology

Dans cette thèse les mécanismes de trois réactions catalysées par des complexes de palladium et de cuivre ont été étudiés en utilisant des méthodes expérimentales et théoriques. La première réaction est la synthèse d’amides à partir d’halogénoarènes, d’isonitriles et d’eau, qui est un exemple de couplage catalysé par le palladium impliquant l’insertion d’un isonitrile. Cette dernière molécule sert à la fois de ligand et de substrat, et son influence sur chaque étape du cycle catalytique a été mise en évidence. La deuxième réaction est l’ouverture des benzofuranes conduisant à des dérivés indoliques catalysée par des sels de palladium. Les conditions opératoires ont été optimisées et les étapes clés du mécanisme ont été élucidées.La dernière réaction étudiée, qui est le sujet principal de cette thèse, est l’addition d’amines sur des allènes catalysée par des sels de cuivre (hydroamination). La caractérisation des espèces catalytiques de cuivre(I) et l’étude théorique du mécanisme ont permis d’étendre cette réaction à différents substrats (allénamides, N-allénylazoles, N-allénylsulfamides) dans des conditions particulièrement douces et efficaces
In this thesis, the mechanism of three organic reactions catalyzed by palladium and copper complexes has been elucidated by the use of both experimental and theoretical methods. The first reaction is the synthesis of amides from haloarenes, isocyanides and water as an example of the broad family of palladium-catalyzed imidoylative couplings. Multiple roles of the isocyanide as both a ligand and a substrate in the different steps of the catalytic cycle have been disclosed. The second transformation is the palladium-catalyzed ring opening of benzofurans leading to indoles. Optimal conditions for this transformation have been found and the key aspects of its mechanism clarified. The last reaction, which is the main topic of this thesis, is the addition of amines to allenes catalyzed by copper salts (hydroamination). A characterization of the catalytically active copper(I) species and insight from theoretical calculations suggested how to extend this reaction to other substrates (allenamides, N-allenylazoles, N-allenylsulfonamides) under mild and efficient conditions

Thesis advisor: James P. Morken
This dissertation describes the development of various palladium-catalyzed syntheses of organoboron compounds with the 1,2-metallate shift of organoboron “ate” complexes as a common mechanistic feature. Chapter one discusses the history of the 1,2-metallate shift with a focus on reactions promoted by transition metals, followed by my work on the palladium-catalyzed, enantioselective, halide-tolerant conjunctive cross-coupling reaction to enable the use of Grignard reagents and arylbromides. Chapter two discusses the attempt to engage allylic electrophiles in the conjunctive cross-coupling reaction and the discovery and optimization of the vinylidenation reaction to access 1,1-disubstituted boryl alkenes. Unlike other palladium-catalyzed reactions that proceed by a 1,2-metallate shift, the vinylidenation proceeds by a β-hydride elimination rather than a reductive elimination as the final step in the catalytic cycle. Chapter three discusses the development of the enantioselective conjunctive cross-coupling of propargylic electrophiles to access enantioenriched β-boryl allenes. Methanol additive was found to improve both the yield and enantioselectivity of the reaction. 1H NMR studies show that methanol exchanges with the pinacol ligand on the boron “ate” complex
Thesis (PhD) — Boston College, 2020
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

The aim of this project was to utilize chiral cation-directed catalysis in the asymmetric synthesis of novel hererocycles. This goal was initially realized by the synthesis of azaindolines in high yields and enantioselectivities (Chapter 2). Extension of this methodology to substrates bearing two stereogenic centres was successful, although control over both diastereoselectivity and enantioselectivity in this process was modest. Finally the synthesis of heterocycles utilizing cation-directed rearrangement processes was examined, with proof of concept obtained for a novel asymmetric cyclization to form xanthenes.

A set of mild conditions for the pentafluorophenylation of carbonyl compounds employing copper-bisphosphine catalysis have been developed. The optimised conditions allow access to a wide range of pentafluorophenyl benzyl alcohols in high yields. The reaction of aliphatic aldehydes and particularly electrophilic ketones to give products in moderate yields is also disclosed. An investigation into the reactivity of β-fluoroalkyl-α ,β -unsaturated carbonyl compounds was conducted. Asymmetric copper hydride reduction of β -fluoroalkyl-α , β-unsaturated ketones was found to preferentially give the allylic alcohol product resulting from 1,2 attack in up to 62% ee. Reaction of β-fluoroalkyl-α , β-unsaturated esters under similar conditions gave the product of conjugate reduction in higher enantiomeric excess; up to 99% was observed. Rhodium-catalysed arylation of β -fluoroalkyl-α , β-unsaturated ketones was also found to give the product of direct carbonyl attack. Conditions for the racemic reaction are described along with those for the enantioselective reaction of methyl ketones in up to 74% ee. Ruthenium catalysed arylation of β-fluoroalkyl-α ,β -unsaturated aldehydes employing Me-Bipam as ligand gave the desired secondary allylic alcohols in good yields and good to excellent enantiomeric excesses (14 examples, 76-87% ee).

The synthesis of heterocycles using radical intermediates has become an important area of research in recent years. The aim of our research was to develop radical methodologies to construct heterocycles on solid-support. Tri-cyclic benzimidazole derivatives are desirable synthetic targets with a range of biological activity and are part of certain anti-tumour agents. Solid-supported radical reactions with substituted benzimidazoles were performed under different experimental conditions, including different solvents, three different resins (Wang, Merrifield and Rink) and different radical reagents. 4-Mercaptobenzoic acid moiety served as a traceless linker in radical ipso-substitution reactions of benzimidazole precursors attached to solid-support to construct tri-cyclic and tetracyclic benzimidazole adducts. The solution-phase radical ipso-substitution protocol was quite successfully translated onto solid-support.

In the following thesis, new methodologies towards the synthesis of a range of sulfonyl (-SO₂-) containing functional groups are documented. These methods utilise easy-to-handle sulfur dioxide surrogates, such as DABSO (vide infra), and exploit palladium catalysis as a new mechanistic protocol for the incorporation of the -SO2- unit. Chapter 1 is a literature review surveying sulfur dioxide in organic synthesis, the established uses of SO₂ surrogates and the importance of the sulfonyl moiety in chemistry. Palladium-catalysed (carbonylative) cross-couplings are also broadly discussed as they provide inspiration for, and mechanistic similarities with, the proposed chemistry. Chapter 2 describes a de novo synthesis of the sulfonamide functional group; a three-component and convergent methodology coupling (hetero)aryl and alkenyl halides with sulfur dioxide (provided by easy-to-handle surrogates such as DABSO) and hydrazine nucleophiles, is documented. This is achieved through the action of a readily available palladium catalytic system and is the first example of a metal-catalysed sulfonylative cross-coupling of halide based electrophiles. Chapter 3 presents a new method of generating (hetero)aryl and alkenyl sulfones. The ability of organometallic reagents to add to sulfur dioxide (supplied via DABSO) is applied to deliver the corresponding metal sulfinate salt. This in situ derived sulfinate is coupled with an (hetero)aryl or alkenyl (pseudo)halide using palladium catalysis to form the desired sulfone. An electronically modified XantPhos-type ligand was designed for the reaction in order to suppress unwanted aryl-aryl exchange. Chapter 4 documents the generation of (hetero)aryl and alkenyl sulfinates from the corresponding halide and DABSO through a palladium-catalysed sulfination protocol, obviating the need for organometallic reagents. A mild set of conditions using IPA as both a solvent and reductant together with a low loading of palladium catalyst offers an attractive route to sulfonyl compounds thanks to the in situ derived sulfinates being converted into a broad variety of functional groups via established onwards reactivity. Chapter 5 discusses the conclusion of the research and the potential for future work. Chapter 6 presents the experimental data.

Chemistry
Ph.D.
This thesis describes the synthesis of functionalized spiroligomers and their applications in metal binding, metal-mediated catalysis, and organocatalysis. By synthesizing a family of functionalized bis-amino acids achieved from reductive alkylation, the Schafmeister group has developed access to highly functionalized and shape programmable structures named “spiroligomers.” The rigid backbones of spiroligomers are good at organizing the orientations of functional groups on their side chains. This property enables them as promising candidates for catalysts. Firstly we synthesized a few spiroligomer dimers presenting metal-binding groups such as terpys and bipys. With the right orientation of metal binding groups controlled by adjusting the stereocenter of the spiroligomer, macrocyclic “square” complexes with metals were obtained. The crystal structures of these intriguing complexes were solved. This work rendered the first structurally, spectroscopically and electronically characterized metal-spiroligomer complexes as well as the first crystal structure of spiroligomer. Secondly, the question of whether metal-binding spiroligomers are able to catalyze certain reactions became our major concern. We developed a binuclear copper catalyst that could accelerate a phosphate ester rearrangement, and that demonstrated that when the two copper binding terpyridine groups were best able to approach each other, they accelerated the rearrangement more than 1,000 times faster than the background reaction. Other molecules that did not properly organize the two copper atoms demonstrate considerably slower reaction rates. At last, catalysts based on spiroligomers without metals are also of interests. By displaying two hydrophobic groups in various directions on a monomeric spiroligomer (also can be regarded as a proline derivative), we observed variable activities and enantioselectivities in the catalysis of asymmetric Michael addition (up to 94% ee at -40 °C for one organocatalyst).
Temple University--Theses

Total synthesis of the pyrrolizidine alkaloid NP25302: (+)-NP25302 is an unusual vinylogous urea containing pyrrolizidine alkaloid shown to exhibit cell adhesion inhibition. It was envisaged that this natural product could be accessed by a novel 5-endo-dig cyclisation to construct the pyrrolizidine core, and a Curtius rearrangement to install the vinylogous urea motif. This methodology was first tested on a model system, furnishing nor-NP25302 from L-proline in 12 steps and 9% overall yield. The total synthesis of (±)-NP25302 was completed in 9 steps and 26% overall yield from ethyl 2-nitropropionate using similar methodology. Studies into the stereospecificity of the Au(I)-catalysed cyclisation of monoallylic diols: During the synthesis of (+)-isoaltholactone in the Robertson group, the key Au(I)-catalysed cyclisation was observed to occur with some stereospecificity. Further investigations were therefore conducted into the stereochemical outcome of this reaction using stereodefined allylic alcohols, and from the combined results a mnemonic was proposed to predict the stereochemistry of the products of this reaction. Studies into the total synthesis of ascospiroketals A and B: Investigations were conducted into the total synthesis of the recently isolated natural products ascospiroketals A and B. A second generation synthesis was used to construct advanced intermediates 1 and 2.

Cette thèse décrit le développement de nouvelles méthodes de catalyse à l’or et au cuivre pour la synthèse de composés hétérocycliques et de produits trifluorométhylés.Dans un premier temps, une synthèse d’allènes trifluorométhylés par catalyse à l’or a été développée, dont l’étape clé est un transfert d’hydrure 1,5. Cette méthode donne accès de manière efficace et sélective à une large gamme d’allène perfluoroalkylés dont le potentiel synthétique a également été démontré.Le pouvoir catalytique de l’or a alors été utilisé dans une synthèse de 2H-1,3-oxazines reposant sur une cyclisation de type 6-endo d’azido alcynes. Cette méthode donne accès dans des conditions très douces à une gamme sans précédent d’oxazines polysubstituées avec d’excellents rendements.Dans un dernier temps, une méthode d’hydrofonctionnalisation radicalaire d’alcènols catalysée au cuivre. La stratégie impliquée repose sur une abstraction d’hydrogène 1,5, dans laquelle un groupement benzyloxy joue le rôle de donneur d’hydrogène
This manuscript presents the development of gold- and copper-catalyzed methods for the synthesis of heterocyclic compounds and trifluoromethylated products.Firstly, a gold-catalyzed synthesis of trifluoromethyl allenes was developed, relying on a 1,5 hydride shift. This method allows to access, in a very efficient and selective way, a large range of perfluoroalkylated allenes, of which the synthetic potential was also demonstrated.Afterwards, the catalytic power of gold was then used in a synthesis of 2H-1,3-oxazines, relying on a 6-endo type cyclization of azide-yne substrates. This methods allows to access, in very mild condition, an unprecedently large range of polysubstituted oxazines in excellent yields.Finally, a method for the copper-catalyzed radical hydrofunctionalization of alkenols was developed. The strategy involved relies on a 1,5 hydrogen abstraction, in which a benzyloxy moiety plays the role of the hydrogen donor

This thesis is divided into four separate parts with nucleophilic addition to aldehydes as the common feature in three of them. The first part deals with the investigation of the stereochemical induction and elucidation of the factors that dictate the p-facial selectivities in Mukaiyama aldol addition to a- and a,b-heteroatom substituted aldehydes. An explanation for the unexpected shift from 1,2-anti to 1,2-syn selectivity seen in the reaction when applying nucleophiles of different sizes in the addition to a-chloro aldehydes is offered. The next two parts describes the addition of 1,3-bis(silyl)propenes and C3 substituted 1,3-bis(silyl)propenes to aldehydes and the development of two highly stereoselective new methodologies for the construction of 1,3-dienes and 2,3,4,5-tetrasubstituted tetrahydrofuranes, respectively. The last part describes the attempts made towards the total synthesis of (±)-aspidophylline A, where the intention was to apply a domino carbopalladation-carbonylation reaction as the key step in the synthetic route.

QC 20130503

Cyclitols are cyclic compounds having hydroxyl groups which attached to different carbons on the ring. Cyclitols have attracted a great deal of attention for having diverse biological activities. Cyclic alcohols play an important role in biological processes such as inhibition of glycosidase, cellular recognition, and signal transduction. In addition to this, these compounds are very important molecules due to being capable of using while synthesizing natural products or pharmaceuticals. In this study, development of new methodology for the synthesis of bis-aminoinositol derivatives was aimed. The starting material, cis-diester, was synthesized from the Diels-Alder reaction of furan and maleic anhydride followed by reaction with MeOH. As a second key compound, trans-diester was obtained from the Diels-Alder reaction of furan and fumaryl chloride followed by esterification. The diester functionality in these two compounds was planned to be converted into the hydrazide upon treatment with hydrazine monohydrate. Before this reaction, double bond was protected via stereo selective oxidation reaction with m-CPBA due to preventing retro Diels-Alder reaction. Then, hydrazide functionality was converted into acyl azide through &beta
-nitroso hydrazide intermediate. Subsequent Curtius rearrangement reaction resulted in the formation of the isocyanate which was converted to the corresponding bis-urethane by treatment with MeOH. Attempt to cleave the oxa-bridge in urethane with sulfamic acid provided the unexpected tricyclic product 148. Furthermore, hydrolysis of isocyanate with aqueous HCl formed the diamine 156. However, O-bridge could not be opened with any reagents used for that of urethane derivative as described above. Then,the cis-diol 157 was synthesized to prevent the neighboring group participitation during the epoxide-opening reaction. Further ring-opening reactions are under investigation.

A synthetic investigation on the chemistry of cyclotryptamine derived natural products, with a particular focus on the synthesis of the trimeric-alkaloid, hodgkinsine. Methodology has been developed to tackle this complex natural product which utilises a desymmetrization approach; this strategy hinges on the development and applications of asymmetric C-N bond forming reactions. Chapter one examines elements of symmetry in natural products, looking in particular at the synthesis of compounds which contain cyclotryptamine functionality. Chapter two contains a brief review of enantioselective desymmetrization paying attention, if possible, on its application in the synthesis of natural products. In the remaining chapters we discuss our own progress and results in our pursuit of an efficient enantioselective total synthesis of hodgkinsine.

Nature’s biodiversity is complex and filled with beauty and wonder which are all observable on the macroscopic scale. This exquisiteness of nature’s intricacies are mirrored on the molecular level such that substances, large or small, are assembled to serve as signaling molecules, protective agents, and fundamental composites of higher-order frameworks for the operation and survival of life. Over the years, chemists have isolated and synthesized these molecules, known as natural products, to understand and evaluate their functions in biology and potential for medicinal applications. Although bioactive natural products demonstrate medicinal promise, poor pharmacological effects require further derivatization because semisynthesis is not sufficient to refine adverse pharmacokinetics. For some active molecules, isolation results in poor yields. In addition to small quantity isolation, many natural products, reflecting the immense complexity of biology itself, pose difficult synthetic challenges to organic chemists because of skeletal heterogeneity, stereochemical complexity, and substitution divergence. As a result of these synthetic obstacles to natural product utilization, improvements are needed in current chemical approaches, and new innovative methodologies for synthesis and chemical space exploration are necessary. Pharmaceutically relevant frameworks, natural products, and synthetic biologically active molecules are comprised of polycarbocyclic and heterocyclic scaffolds. Traditionally, cycloadditions, transannular transformations, and annulation reactions serve as powerful methods for polycyclic formation. In order to assemble diverse polycycles, donor-acceptor cyclopropanes are useful, versatile synthetic equivalents for C-C bond formations. By taking advantage of the strain within these unique, polarized systems, differing molecular architectures can be accessed directly to perform contemporary organic synthesis. Moreover, the donor-acceptor cyclopropanes initially utilized in these studies provided a fundamental basis for new methods to synthesize other relevant scaffolds. Unique, efficient, Lewis acid-catalyzed intramolecular cyclization strategies for the construction of functionalized polycycles using Friedel-Crafts-type alkylation sequences are presented to expand the reaction repertoire of the molecular architect. Generally, products were formed from commercially-available starting materials in high yields with broad scope. The methodologies were demonstrated to be modular, operationally simple, and amenable to different substitution patterns and functional groups to afford tetrahydroindolizines, heteroaromatic cyclohexenones, hydropyrido[1,2-a]indoles, pyrrolo[1,2-a]indoles, pyrrolo[3,2,1-ij]quinolines, pyrrolizines, and tetrahydrobenzo[ij]quinolizines. To demonstrate the utility of the methodologies devised, progress toward, (±)-rhazinicine, a natural product, is discussed. This dissertation is organized into six chapters: (1) an introduction, paradoxical stress and molecular strain’s utility in synthesis; (2) annulation reactions for the formation of heteroaromatic cyclohexenones; (3) hydropyrido[1,2-a]indole formation via an In(III)-catalyzed cyclopropane ring-opening/Friedel-Crafts alkylation sequence; (4) tetrahydroindolizine formation and progress toward the total synthesis of (±)-rhazinicine (5) pyrrolo[1,2-a]indole synthesis using a Michael-type Friedel-Crafts cyclization approach; and (6) a versatile protocol for the intramolecular formation of functionalized pyrrolo[3,2,1-ij]quinolines.

This thesis describes the development of nitro-Mannich/hydroamination cascade reactions for the synthesis of N-heterocycles, which are important motifs found in a variety of biologically active natural products and pharmaceuticals, such as atorvastatin (Lipitor®). Chapter 2 outlines the development of an efficient synthesis of 2,5-disubstituted pyrroles using a nitro-Mannich/hydroamination cascade. Starting from easily prepared N-protected imines and nitroalkyne substrates, a compatible combination of KOtBu (10 mol%) and AuCl3 (5 mol%) was used to afford the desired pyrrole products, after an alkene isomerisation/HNO2 elimination reaction sequence. Chapter 3 describes the extension of this methodology to the diastereo- and enantioselective synthesis of 1,2,3,4-tetrahydropyridine derivatives using a nitroalkyne substrate with an extended carbon chain. The sequential addition of a bifunctional Brønsted base/H-bond donor organocatalyst and a gold complex was found to facilitate the desired cascade reaction affording substituted 1,2,3,4-tetrahydropyridine products. We then established that highly substituted pyrrolidine compounds could be prepared by replacing the nitroalkyne substrate with a nitroallene substrate (Chapter 4). The combination of KOtBu (5 mol%) and a gold catalyst derived from Au(PPh3)Cl (10 mol%) and AgSbF6 (20 mol%) was found to give an efficient diastereoselective synthesis of pyrrolidine derivatives after an additional nitro group epimerisation step. In addition, the nitro-Mannich/hydroamination cascade using nitroallene substrates was developed into an enantioselective variant using the previously employed bifunctional Brønsted base/H-bond donor organocatalyst. This afforded enantioenriched pyrrolidine derivatives.

Enantiopure α-alkyl-substituted aldehydes are widely recognised as important building blocks in synthesis. Despite this, methods to prepare such substrates are limited. Strategically, asymmetric intermolecular S_N2 α-alkylation represents a highly straightforward transformation, but still remains an elusive feat. This thesis describes efforts to address this challenge, with attempted access to enantioenriched α-alkyl aldehydes by way of C-alkylation of chiral, non-racemic, hindered aldenamines using simple alkyl halides. Enamines derived from four types of auxiliary (a tropane, an oxazolidine, a pyrrolidine and a homotropane) have been prepared, and their alkylation profile examined. While the desired levels of asymmetric induction were not attained, use of the tropane and homotropane auxiliaries, which differ only by a single methylene group, interestingly, gave complimentary diastereocontrol during alkylation with EtI. The observed stereoselectivity is supported by density functional studies performed for ethylation of both enamines. Additionally, in the course of preparing the homotropane a highly efficient asymmetric synthesis of a homotropinone bearing gem-α-substitution has been developed.

This thesis is a dissertation to support the development of new domino pericyclic oxy-Cope/ene/Claisen/Diels-Alder reaction, diversity oriented synthesis of PPAPs scaffold via sequential one pot cascade reaction and ethyl aluminum sesquichloride catalyzed highly hindered Diels-Alder reaction. The first part concentrates on the domino pericyclic oxy-Cope/ene/Claisen/Diels-Alder reaction. As a result of this study, we have developed a general methodology for rapidly constructing complex diterpenes and discovered a thermal oxy-Cope/ene/Claisen/Claisen rearrangement, applied to the synthesis of trans decalin benzofurans. The second part involved the development of an efficient synthetic approach towards bicyclo[3.3.1]nonenone core found in many natural products, via a sequential Diels-Alder/gold(I)-catalyzed 6-endo-dig cyclization and its application to the synthesis of a diversified library of PPAPs. Finally, we have developed an efficient synthetic methodology for the formation of cyclohexene rings bearing quaternary carbon centers via an ethyl aluminum sesquichloride mediated highly hindered Diels-Alder reaction. This method solved an important problem encountered in the synthesis of many natural products including PPAPs. This methodology opened new opportunities in the total synthesis of PPAPs.

Thesis (Ph.D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2008.
Committee Chair: Weck, Marcus; Committee Member: Bunz, Uwe H. F.; Committee Member: Dickson, Robert M; Committee Member: Fahrni, Christoph J; Committee Member: Jones, Christopher W; Committee Member: Murthy, Niren.

Polycyclic Polyprenylated Acylphloroglucinols (PPAPs) are a vast family of natural products, which includes more than 200 members. They contain a stunningly complex molecular architecture which in most cases includes a bicyclo[3.3.1]nonane core. PPAPs have been of interest to the scientific community for their intricate structure, their powerful aid in treating many ailments and large portfolio of biological activities. More particularly, they have been of synthetic interest since 1999 with the first report of an approach to these complicated cores by Nicolaou. Herein, we present the first total synthesis of papuaforin A, papuaforin B, papuaforin C, hyperforin and the formal synthesis of nemorosone following a report by Simpkins and co-workers. We relied on a gold(I)-catalyzed carbocyclization for the construction of the core of this family of natural products. Ginkgolides are isolated from the ginko tree, Ginkgo biloba, a living fossil with records of its existence dating back 280 million years. For centuries, the plant and its extracts have been used extensively for their beneficial properties, especially in China, Japan and India. For example, extract Egb761, one of the most potent fraction, generates over $500 million a year alone. The ginkgolides possess a truly unique compact diterpene framework of six 5-membered rings with a high content oxygen. Eleven oxygens can be found in ginkgolide C for a core containing only 23 carbons. The ginkgolides also include a very unique feature: a tert-butyl group located on the most convoluted ring system: the B ring. Few groups have found success in limning a synthetic route to ginkgolides. Corey’s group was the first to achieve the total synthesis of ginkgolide B in 1987. He was also able to complete ginkgolide A a year later. Crimmins and co-workers also achieved the total synthesis of ginkgolide B a decade later in 1999. Herein, we present our new approach toward ginkgolides through a newly developed methodology for the α-allylation of ketones and the creation of highly hindered contiguous quaternary centers. The synthesis is still at an early stage but a synthetic pathway giving access to the ring B with all the key moieties has been extensively investigated.

Kyoto University (京都大学)
0048
新制・課程博士
博士(人間・環境学)
甲第21178号
人博第850号
新制||人||203(附属図書館)
29||人博||850(吉田南総合図書館)
京都大学大学院人間・環境学研究科相関環境学専攻
(主査)教授 吉田 寿雄, 教授 内本 喜晴, 教授 田部 勢津久
学位規則第4条第1項該当

Gold catalysis has attracted much attention within the chemical community in recent years, and its importance as a synthetic tool has only started to be uncovered. This thesis describes the development of a gold(I) catalyzed transformation and its application to the synthesis of a structurally unique Lycopodium alkaloid, Magellanine. Although there have been a few reports on the synthesis of the magellanane core to date, the approach described herein would represent a new and efficient strategy to construct the angularly fused tetracyclic core. The 5 exo dig/Prins reaction that would be the key step of the synthesis was first developed and studied on a model substrate, enabling the verification of the hypothesis that this transformation could indeed form the A and B rings of Magellanine and be applied to its synthesis. This reaction formed the tricyclic products in good yields and in good exo:endo ratios. The synthesis of Magellanine was undertaken, but problems of isomerization prevented the synthesis of the desired 5 exo dig/Prins substrate, which contained the C and D rings of Magellanine with a cis relationship at the ring junction. However, an almost identical substrate, save for a trans configuration between the C and D rings instead of the cis configuration, was prepared and served in further establishing the applicability of this methodology to the synthesis of Magellanine by successfully undergoing the 5-exo-dig/Prins reaction and generating the tetracyclic products. Studies of the steps following the key transformation were performed on the model substrate, allowing for the evaluation of these steps prior to their use in the synthesis. The results of the studies indicate a possible need to revisit the order in which the steps should be carried out. Promising solutions to the different obstacle encountered during the work are presented, demonstrating how the synthesis of Magellanine through a route featuring the 5-exo-dig/Prins cyclization is attainable.

En esta tesis se desarrolla una metodología general para la construcción tándem de manera asimétrica de importantes “building blocks” que se encuentran presentes en la estructuras de muchos productos naturales complejos y biológicamente activos, así como en compuestos de interés farmacológico significativo. Se ha desarrollado una metodología general para la síntesis del núcleo octahidroindolico utilizando materiales de partidas sencillos mediante (a) el tratamiento de un ß-ceto éster tert-butilico que presenta en su estructura un grupo amino monoprotegido y crotonaldehído en condiciones básicas mediante una secuencia tándem/domino one-pot de reacciones.1 Con el objetivo de simplificar las etapas de manipulación de la reacción se encontró que la utilización de una resina básica como el PS-BEMP aumenta el potencial y se obtiene de forma rápida y directa en un escaso número de pasos el sistema octahidroindólico. La utilización de diferentes aceptores de Michael sustituidos en las posiciones 2 y/o 3 permite la formación de una amplia gama de análogos de forma asimétrica con excelentes excesos enantioméricos y rendimientos moderados, otorgando una mayor robusteza a la metodología desarrollada. La aplicación a morfanos es diferente y requiere un cambio más sustancial ya que el átomo de N tosilado se incorpora en la unidad del aceptor de Michael ¿,ß-insaturado en lugar del ß-ceto ester como en el protocolo anterior para generar azabiciclos fusionados. (a) La metodología que se presenta para la obtención de sistemas de 2-azabiciclo[3.3.1]nonano (morfano) implica un proceso tándem basado en una reacción organocatalizada. La secuencia sintética, a partir de materiales de partida fácilmente disponibles, comporta la formación de tres nuevos enlaces: i) el primero en una reacción intermolecular de Michael que genera de manera organocatalizada y asimétrica un enlace C-C; ii) el segundo implica la formación de una ciclohexenona en medio básico completando una anelación de Robinson enantiocontrolada y iii) una reacción aza-Michael intramolecular para generar el sistema azabicíclico. Una nueva orientación de la reacción desarrollada anteriormente, permitió la formación de núcleos hidroisoquinolinicos presentes en el esqueleto pentacíclico yohimbinano. Esta vez, en lugar de una reacción aza-Michael se empleó una reacción de Pictet-Spengler. Tras la formación del enal (a través de una metátesis cruzada), la estructura pentacíclica fue generándose de manera espontánea por la naturaleza lábil y favorecida de la ciclación intramolecular permitiendo la obtención de la estructura deseada. El trabajo realizado en esta tesis, amplía el potencial de la reacción tándem inicialmente desarrollado y demuestra que es un proceso general que puede permitir la síntesis de diversos anillos de manera asimétrica.

Small-molecule libraries with enhanced structural diversity are of value in drug discovery campaigns where novel biologically active hits are desired. As such, multicomponent reactions (MCRs) have proven fruitful to enhance the molecular diversity of chemical collections and expedite forward progression of the drug discovery chain. Bicalutamide (Casodex), an anticancer drug, and Telaprevir (Incivek), an antiviral, are two examples of marketed drugs that can be synthesized using an MCR. The research topic of this dissertation involves the design, discovery, and development of novel MCRs and new combinations of MCRs with post-condensation modifications to generate over twenty-five new drug-like scaffolds in an operationally friendly, atom-economical, time- and cost-effective fashion. The developed chemical methodologies possess inherent 'iterative efficiency','high exploratory power', and 'bond forming efficiency' that allow them to quickly explore chemical space and navigate the 'hypothesis-synthesis-screening' loop that is key for a medicinal chemistry project. The prepared molecules were submitted to the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial screening against pathogens that are known to cause drug-resistance infections.

Chemistry
Ph.D.
All Strychnos and Aspidosperma alkaloids possess a core pyrrolo[2,3-d]carbazole ABCE tetracycle. In order to develop an efficient and divergent methodology for the synthesis of Strychnos alkaloids, a streamlined synthetic sequence to the ABCE tetracycle has been developed. It features a Mitsunobu activation of an N-hydroxyethyl gramine intermediate and subsequent intramolecular aza-Baylis-Hillman reaction. This method was first applied in the total synthesis of (±)-alstolucine B. Additional key steps in the synthesis included (1) chemoselective intermolecular and intramolecular Michael additions and (2) a Swern indoline oxidation. The second application of this method was in the first total synthesis of (-)-melotenine A, a novel rearranged Aspidosperma alkaloid with potent biological activity. Additional key steps in the synthesis included (1) a Piers annulation of a vinyl iodide and a methyl ketone to prepare the D ring and (2) a site-selective intermolecular vinylogous aldol reaction
Temple University--Theses

The thesis presents the construction of heterocyclic and carbocyclic rings using rhodium-catalyzed C-H bond activation followed by a tandem cyclization strategy. This involves the synthesis of heterocyclic compounds such as 1,2-benzothiazine using sulfoximine directed Rh(III)-catalyzed C-H activation and tandem [4+2] annulation with arylalkynyl silanes. A poly-heterocyclic furanone-fused 1,2-benzothiazine is synthesized using 4-hydroxy-2-alkynoate as a coupling partner using sulfoximine as a directing group by domino C-H activation, [4+2] annulation, and lactonization. The thesis also involves the synthesis of carbocycles such as furanone fused 1-naphthols by Rh(III)-catalyzed domino C-H activation, [4+2] annulation, and followed by lactonization using sulfoxonium ylide as a traceless carbenoid based directing group. In this Rh(III)-catalyzed C-H activation, sulfoxonium ylide is used as a directing group for the synthesis of 3-substituted indonone derivatives, which also involves a tandem [4+1] annulation. In this study, sulfoxonium ylide acts as a traceless directing group and internal oxidant. Therefore, external metal oxidants are not required, and the byproduct obtained is DMSO, which can be easily removed. Sulfoxonium ylide was also used as a directing group for the synthesis of 2H-cyclopropa[b]naphthalen-2-one carbocyclic scaffolds using allylates as coupling partners. This reaction proceeded via domino Rh(III)-catalyzed, [4+2] annulation, and cyclopropanation.
CSIR, SERB (EMR/2016/006358)

Substituted heterocycles are common building-blocks for biologically relevant molecules and represent challenging synthetic targets. Due to limited methods available for their preparation and derivatization, direct C-H functionalization protocols offer considerable advantages. Radical chemistry has shown great potential in this regard; however traditional approaches are unattractive due to poor selectivity and harsh reaction conditions. Visible light photoredox catalysis, on the other hand, is a mild alternative for alkyl radical generation and has proven its utility in organic synthesis. The work encompassed in this thesis details the efforts towards the development of practical photoredox-based functionalizations of heterocycles. Specific focus is placed upon overcoming obstacles pertaining to H-atom abstraction, back electron transfer, and redox strength of photocatalysts to achieve efficient C-Br bond reductions, amine oxidations, and C-C bond formations. In pursuit of these objectives, a C2-selective malonation of indoles and other electron-rich heteroarenes was accomplished in high yields using photocatalyst Ru(bpy)3Cl2, p-CH3OC6H4NPh, and blue LEDs as the light source. Use of a triarylamine over a trialkylamine suppressed H-atom abstraction and promoted C-C bond formation. Subsequent exploitation of the reductive quenching cycle of Ru(bpy)3Cl2 and use of Cl3CBr as an alternative oxidant led to an oxidative nucleophilic trapping of tetrahydroisoquinolines to provide a diverse set of analogues. Finally, photoredox catalysis was utilized for the creation of C-C bonds in the context of complex molecule synthesis. A variety of bromopyrroloindolines and indoles were coupled to furnish C3-C3' and C3-C2' bisindole alkaloids, which was successfully applied to the total synthesis of gliocladin C and related analogues. Moreover, fine-tuning of the redox cycle with photocatalyst Ir(ppy)2(dtbbpy)PF6 and LiB(cat)2 as the reductive quencher enabled the coupling less-reactive substrates and suppression of back electron transfer.

A number of oxygenated heterocycles have been described in nature as having a myriad of biological activities. Owing to these biological activities and their complex structure, these compounds are of interest to us and the preparation of selected oxygenated heterocycles is described in this thesis. Three main sections form this thesis, with each representing a class of oxygenated heterocycle. The first part of the thesis deals with pyranonaphthoquinone analogues where a model study was performed to construct the skeleton of the isochromane kalafungin. The synthesis of isochromane 6,9-dimethoxy-3,3a,5,9b-tetrahydro-2H-furo[3,2-c]isochromen-2-one was successfully achieved from commercially available 2,5-dihydroxybenzoic acid in an overall yield of 9.5%. The key steps employed in the synthesis of the isochromane were a cross metathesis reaction between (2-allyl-3,6-dimethoxyphenyl)methanol and ethyl acrylate to afford the α,β-unsaturated ester (E)-ethyl-4-(2-(hydroxymethyl)-3,6-dimethoxyphenyl)but-2-enoate which, after several synthetic steps, was converted to the isochromane via a radical induced lactonization using a hypervalent iodine reagent. The success of this route led us to the preparation of iscochromane (3aR, 5R, 9bR)-6,9-dimethoxy-5-methyl-3,3a,5,9b-tetrahydro-2Hfuro[ 3,2-c]isochromen-2-one. Our initial aim was to enzymatically resolve intermediate racemic alcohol 1-(2-allyl-3,6-dimethoxyphenyl)ethanol, however, the use of Candida antarctica lipase B (CALB) to facilitate the kinetic resolution was not as successful as we hoped. Therefore, using racemic alcohol 1-(2-allyl-3,6-dimethoxyphenyl)ethanol and the key reaction conditions developed in the model study of 6,9-dimethoxy-3,3a,5,9b-tetrahydro-2H-furo[3,2-c]isochromen-2-one, we successfully prepared isochromane (3aR, 5R, 9bR)-6,9-dimethoxy-5-methyl-3,3a,5,9btetrahydro 2H-furo[3,2-c]isochromen-2-one in an overall yield of 0.4%, albeit racemically. The second part of this thesis involved the use of nitroalkanes as precursors to spiroketals. In this section, we managed to successfully elucidate the mechanism of a novel Nef reaction previously described in our laboratories using three different substrates. The key steps involved during the elucidation of the mechanism were a Henry condensation reaction and a key modified Nef reaction. The preparation of the spiroketal skeleton of the griseusins was also attempted. The last part of this PhD thesis focused on the formation of angucycline analogues, specifically analogues related to the landomycins. We have successfully managed to prepare landomycin analogues tetraphene-7,12-dione, 3-methoxytetraphene-7,12-dione and 3,8-dimethoxytetraphene-7,12-dione. A Suzuki reaction followed by a Wittig reaction, isomerisation and final ring closing metathesis allowed for the smooth preparation of these analogues. The preparation of related analogues bearing seven-membered rings has also been achieved and is described.

Under the conditions of transfer hydrogenation employing ortho-cyclometallated iridium C,O-benzoate catalysts, selective silylallylation and CF₃-allylation were developed. In both cases, high levels of catalyst-directed enantioselectivity and diastereoselectivity were observed. Column chromatography was then tested as a new protocol to purify the iridium precatalyst; this single component precatalyst was proved to be more efficient to promote carbonyl crotylation reactions, both diastereo- and enantioselectivity were increased. Then, double asymmetric crotylation of 1,3-diols to deliver (pseudo-)C₂-symmetric adducts with exceptional level of enantioselectivity was devised. Implementation of this methodology and other hydrogenative C-C bond formations proved to be effective means for the preparation of two known polypropionate natural product fragments of C19-C25 of scytophycin C, C19-C27 of rifamycin S and the total synthesis of 6-deoxyerythronolide B.
text

Environmental protection is one of the greatest themes of the XXI century. For what concerns chemistry, in the early 1990’s, even before its current formal and exhaustive definition, given by Paul T. Anastas and John C. Warner in 1998, the term "green chemistry" starts to appear in the literature. Anastas and Warner formulated a list of 12 principles, that constitute the most complete definition of green chemistry. Herein, an effort towards the fulfillment of these principles is presented with respect to: 1) the development of a catalytic system based on hydrate ferric sulfate for the hydration of internal alkynes; 2) an approach to the synthesis of a new family of chiral phosphates for organocatalysis.

The use of sulfoxide ligands for transition metal catalyzed transformations has recently been brought to the forefront in organic chemistry. The synthesis of a series of tri- and disulfoxides will be presented, and their applications investigated. Their use in rhodium catalyzed 1,4-additions of phenylboronic acid to 2-cyclohexen-1-one result in enantioselectivities up to 80%. The incorporation of β-amino acid residues into polypeptides has resulted in new foldamers whose structures and enhanced stability provide interesting opportunities for new biological applications. A novel strategy for an iterative peptide synthesis involving β-amino acids will be proposed. Lastly, a hydroamidation-type strategy for the construction of β3-amino acids, or more specifically of β-(N-acylamino)acrylates, will be presented as preliminary work towards the goal of dipeptide synthesis.

A thesis submitted to the Faculty of Science, University of the Witwatersrand Johannesburg. In fulfilment of the requirements for the Degree of Doctor of Philosophy. March 2017
In this PhD thesis, we report for the first time, new methodology for the synthesis of angucycline antibiotic natural products. In particular, for the synthesis of 1,8-dihydroxy-3methyltetraphene-7,12-dione, commonly known as tetrangulol. We also report on the synthesis of 1,10,12-trimethoxy-8-methylbenzo[c]phenanthridine in our quest to synthesise phenanthroviridone from an intermediate product in the synthesis of tetrangulol. The Suzuki-Miyaura coupling reaction between 1,4,5-(trimethoxynaphthalen-2-yl)boronic acid and 2-iodo-3-methoxy-5-methylbenzaldehyde afforded intermediate, 3-methoxy-5methyl-2-(1,4,5-trimethoxynaphthalen-2-yl)benzaldehyde. Conversion of this benzaldehyde into the alkyne, 2-(2-ethynyl-6-methoxy-4-methylphenyl)-1,4,5-trimethoxynaphthalene was accomplished utilizing the Corey-Fuchs reaction. Exposure of the derived acetylene to a catalytic platinum(II)-mediated ring closure yielded the required tetracyclic aromatic product, 1,7,8,12-tetramethoxy-3-methyltetraphene which was converted into tetrangulol. Exposure of the related 3-methoxy-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-yl)benzaldehyde O-phenyl oxime to microwave irradiation in an ionic liquid yielded 1,10,12-trimethoxy-8methylbenzo[c]phenanthridine, instead of the desired natural product phenanthroviridone. We also report on the unexpected synthesis of the benzonaphthopyranone core found in other classes of angucycline antibiotics from oxygen analogs of 2-naphthylbenzyl alcohols when exposed to N-bromosuccinimide. Treatment of (2-(1,4-dimethoxynaphthalen-2yl)phenyl)methanol and related analogues with N-bromosuccinimide under an oxygen atmosphere afforded 12-methoxy-6H-dibenzo[c,h]chromen-6-one, 2-Methoxy-6Hbenzo[c]chromen-6-one and of 6H-benzo[c]chromen-6-one. An investigation into possible mechanisms for this transformation was also conducted.
LG2017

Reported herein is a brief summary of the history, properties, and applications of amine-boranes. The past methods devised for their preparation are described and the routes used to produce the compounds used in the work presented here are detailed. Building on prior synthetic approaches to amine-boranes, a new carbon dioxide mediated synthesis is presented. Proceeding through a monoacyloxyborane intermediate, the borane complexes of ammonia, primary, secondary, tertiary, and heteroaromatic amine are provided in 53-99% yields. Utilizing the amine-boranes obtained from the methods described, two divergent methods for direct amidation are introduced. The first uses amine-boranes as dual-purpose reagents, where the carboxylic acid is first activated by the borane moiety to form a triacyloxyborane-amine complex. This allows the delivery of the coordinated amine to form the amide products. A series of primary, secondary, and tertiary amides were prepared in 55-99% yields using this protocol, which displays a broad functional group tolerance. Extended from this dual-purpose methodology, a catalytic amidation is described. Utilizing ammonia-borane as a substoichiometric (10%) catalyst, a series of secondary and tertiary amide are prepared directly from carboxylic acids and amines in 59-99% yields, including amines containing typically borane reactive functionalities including alcohols, thiols, and alkenes. Amine-boranes are additionally used in two borylation methodologies. By reaction with n-butyl lithium, the amine-boranes are converted to the corresponding lithium aminoborohydrides, which upon reaction with a terminal alkyne provides the alkynyl borane-amine complexes in 65-98% yields. This process is compatible with both alkenes and internal alkynes, as well as a range of aprotic functionalities. A new strategy for aminoborane synthesis is also described and applied to the borylation of haloarenes. Activation of a series of amine-boranes with iodine produces the iodinated amine-borane, which undergoes dehydrohalogenation with an appropriate base to produce either monomeric or dimeric aminoboranes. Several aminoboranes were synthesized exclusively as the monomeric species, which due to their greater reactivity, were used directly in the synthesis of a series of aryl boronates in 65-99% yields.

The α-alkylation of ketones is a transformation of central importance to organic synthesis. Our lab recently introduced the N-amino cyclic carbamate (ACC) chiral auxiliaries for asymmetric ketone α-alkylation. ACCs provide significant advantages over existing asymmetric ketone alkylation methods as they are easy to introduce, both deprotonation and alkylation can be run at relatively mild temperatures, stereoselectivity of alkylation is excellent and auxiliary removal is facile. A unique feature of ACCs is their ability to control the regioselectivity of deprotonation through what we have termed Complex Induced Syn-Deprotonation. In what follows, we describe several projects relating to the development and synthetic application of ACCs.

An optimized synthesis of our most successful ACC auxiliary was developed, including an improved method for the formation of the key N-N hydrazide bond.

A detailed mechanistic investigation of four ACC auxiliaries was conducted, examining the regio- and stereoselectivity of the alkylations at the level of the ACC hydrazone. This work culminated in a theoretical study of ACC auxiliaries, conducted through a collaboration with the Houk Group at UCLA.

We also describe the use of ACCs in the development of the first method for the regiocontrolled asymmetric α,α-bisalkylation of ketones. The method proceeds in excellent yield and with >99:1 diastereoselectivity. This method was also extended to the asymmetric α,α,α',α'-tetraalkylation of ketones, enabled by the development of a mild, epimerization-free LDA-mediated isomerization of the α,α-bisalkylated ACC hydrazones.

Additionally, we discuss three synthetic applications of the ACC α,α-bisalkylation methodology. We report an asymmetric formal synthesis of (+)- and (-)-stigmolone, as well as two approaches to the polyketide fragment of the novel cyclic depsipeptide apratoxin D, which have led to the completion of the first asymmetric total synthesis of apratoxin D.

Dissertation

Indiana University-Purdue University Indianapolis (IUPUI)
The modification of brucine derivatives as chiral ligands and the use of a multifaceted chiral ligand, brucine diol, under different reaction conditions to produce various optical isomers is described. In Chapter 1, the generation of a number of brucine derivatives is described. Taking the advantage of brucine-diol’s excellent molecular recognition capability for multiple organic functional groups, we focused on the synthetic modifications of brucine-diol and the synthesis of brucine N-oxide. We also produced various brucine derivatives with different functional moieties in good yields and selectivities. In Chapter 2, we described the investigation of brucine N-oxide catalyzed Morita-Baylis-Hillman (MBH) reaction of alkyl/aryl ketones. Brucine N-oxide was used as a nucleophilic organic catalyst in the MBH reaction of alkyl vinyl ketone. In addition, asymmetric MBH reactions of alkyl vinyl ketones with aldehydes were investigated using a dual catalysis of brucine N-oxide and proline. In this dual catalyst system, proline was found to form iminium intermediates with electron-deficient aryl aldehydes, while the N-oxide activated vinyl ketones provided enolates through the conjugate addition. Our dual catalysis approach also allowed the development of MBH reaction of aryl vinyl ketones. In Chapter 3, brucine diol-copper complex catalyzed asymmetric conjugate addition of glycine (ket)imines to nitroalkenes is discussed. Stereodivergent catalytic asymmetric conjugate reactions for glycine (ket)imines with nitroalkenes were achieved using various chiral catalysts derived from a single chiral source, brucine diol. Both syn- and anti-conjugate addition products were obtained with high diastereoselectivity and enantioselectivity. In Chapter 4, enantiodivergent production of endo-pyrrolidines from glycine (ket)imines using brucine diol-copper complex is described. The [3+2] cycloaddition reaction of glycine imines and activated alkenes was performed to produce endo-pyrrolidines. The reversal of enantioselectivity was observed for endo-pyrrolidines between concerted and stepwise reaction pathways. The three new brucine derivatives produced in this study would potentially work as organocatalysts and chiral ligands with metal ion in asymmetric synthesis. The brucine diol-metal complex catalyzed reactions laid a good foundation for catalytic asymmetric reactions, where a single chiral source was used to control the absolute and the relative stereochemical outcomes of reactions. Understanding the molecular-level interactions between catalyst and substrates will provide insightful mechanistic details for the stereodivergent approaches in asymmetric catalysis.

L'azoto gioca un ruolo indispensabile per la vita sulla terra e per lo sviluppo degli esseri umani. Industrialmente, è necessario convertire l'azoto gassoso in ammoniaca (NH3) per la produzione di fertilizzanti, in modo da integrare la quantità di azoto fissata spontaneamente in natura. Attualmente, l'unica tecnologia di sintesi dell'ammoniaca su scala industriale è il processo sviluppato da Haber e Bosch all'inizio del XX secolo che utilizza N2 e H2 come gas di alimentazione. Tuttavia, il processo Haber-Bosch richiede condizioni molto drastiche, apparecchiature complesse e porta ad un elevato consumo energetico, operando inoltre a bassi tassi di conversione che non sono coerenti con le esigenze sempre crescenti di sviluppo economico e sociale. In alternativa al metodo Haber-Bosch, l'elettrocatalisi rappresenta una delle vie più promettenti che possono integrare l'elettricità prodotta da tecnologie di energia rinnovabile con la produzione di ammoniaca a temperatura ambiente e a pressione atmosferica. Una sfida specifica è legata allo sviluppo di nuovi elettrocatalizzatori/elettrodi con l'obiettivo di ottenere una produzione di ammoniaca a basso costo, su larga scala e delocalizzata sul territorio. Alla luce delle suddette questioni scientifiche fondamentali, questo lavoro di dottorato si concentra su tre aspetti principali legati alla reazione elettrocatalitica di riduzione dell'azoto (NRR): i) l’ingegneria e la progettazione dell'elettrocatalizzatore, ii) la progettazione dell'elettrodo e del dispositivo elettrochimico e iii) il miglioramento e l’ottimizzazione delle condizioni di reazione, per migliorarne le prestazioni nella sintesi dell'ammoniaca. La maggior parte delle attività di ricerca di questo dottorato, dalla sintesi e caratterizzazione dei materiali elettrocatalitici all'assemblaggio/collaudo degli elettrodi in dispositivi elettrochimici non convenzionali, sono state svolte presso il laboratorio CASPE (Laboratorio di Catalisi per la Produzione e l'Energia Sostenibile) dell'Università di Messina. Durante i tre anni, un periodo di 12 mesi è stato inoltre trascorso in cotutela con l'École supérieure de chimie, physique, électronique de Lyon (CPE Lyon), dove sono state studiate tecniche di sintesi avanzate per la preparazione di elettrocatalizzatori a base organometallica da utilizzare come elettrodi cataliticamente attivi nella NRR. La tesi di dottorato è organizzata in cinque capitoli principali. Il capitolo 1 si concentra sulle questioni di fissazione dell’azoto e sulla descrizione del processo industriale Haber-Bosch, con una panoramica sulle implicazioni generali relative al suo elevato fabbisogno energetico. Vengono poi presentati i metodi alternativi per la fissazione elettrochimica dell'azoto, con un'ampia descrizione dei vantaggi, legati alle condizioni più favorevoli (cioè temperatura ambiente e pressione atmosferica) e degli svantaggi, e discutendo gli elementi da sviluppare per una futura implementazione di questa tecnologia, includendo anche una descrizione del possibile meccanismo di reazione, ancora non del tutto chiaro in letteratura. Il capitolo 2, invece, si riferisce alla descrizione dei materiali elettrocatalitici sviluppati in questo lavoro di dottorato per la preparazione degli elettrodi: 1) i “Metal-Organic Frameworks” (MOF), una classe di materiali porosi molto promettenti per le loro caratteristiche peculiari di elevata superficie, proprietà adattabili, funzionalità organica e porosità, oltre che per la possibilità di creare specifici siti attivi catalitici grazie sia ai gruppi funzionali che ai centri ionici metallici; 2) i MXeni, una classe di materiali a base di carburi o nitruri metallici con struttura bidimensionale (2D), che hanno recentemente attirato un grande interesse per una vasta gamma di applicazioni, tra cui la catalisi e la fissazione di N2, per le loro proprietà uniche di conducibilità metallica e la natura idrofila delle superfici con terminali idrossilici o di ossigeno. Nei capitoli 3-5 vengono presentati e discussi i risultati sperimentali. Il capitolo 3 riguarda la preparazione di una serie di elettrodi di MOF a base di Fe (Fe@Zn/SIM-1) e il loro test nella NRR utilizzando un reattore trifasico avanzato, che lavora in fase gassosa. Questo nuovo dispositivo funziona a temperatura ambiente e a pressione atmosferica, e possiede il controelettrodo e l’elettrodo di riferimento immersi in una semicella anodica (dove avviene l'ossidazione di H2O a O2) contenente un elettrolita liquido (l'anolita), mentre la semicella catodica per la NRR opera in fase gassosa senza elettrolita liquido. Questo tipo di reattore elettrocatalitico è quindi molto diverso dai reattori elettrocatalitici convenzionali che operano in fase liquida, con il grande vantaggio di evitare problematiche legate alla bassa solubilità e al trasporto di N2 nell'elettrolita, e di permettere inoltre un più facile recupero dell'ammoniaca prodotta. I risultati ottenuti da questi test elettrocatalitici in fase gassosa sono stati molto utili per migliorare la progettazione degli elettrodi a base di MOF, evidenziando i limiti di questo tipo di materiali in termini di contenuto di N, stabilità e possibilità di preparare elettrocatalizzatori più avanzati mediante carbonizzazione. Un'ampia parte di questo capitolo è stata dedicata allo sviluppo di nuove strategie sperimentali per evitare i falsi positivi nella rilevazione dell'ammoniaca, che è uno degli argomenti più investigati negli ultimi due anni dai ricercatori che lavorano sulla NRR. Mentre in letteratura sono stati recentemente proposti protocolli molto accurati che utilizzano tecniche analitiche avanzate (basati sull’azoto marcato 15N), in questo lavoro viene invece suggerita una metodologia più semplice basata sull'analisi spettrofotometrica UV-visibile (accoppiata a test in bianco con gas inerti in luogo dell’azoto) che hanno permesso con successo di evitare contaminazioni da ammoniaca e identificare i falsi positivi, anche se tecniche analitiche più sofisticate sono sicuramente necessarie per confermare definitivamente la vera fonte di ammoniaca. Nel capitolo 4 viene presentata una serie di materiali MOF migliorati (MOF UiO-66-(COOH)2 a base di Fe o Fe e metalli alcalini), sintetizzati con la tecnica di reazione a scambio cationico per sostituire il protone dell'acido carbossilico con un catione di ferro. Rispetto ai materiali Fe@Zn/SIM-1, questa nuova classe di MOF è più stabile in acqua e non contiene atomi di azoto nella sua struttura. I risultati hanno dimostrato che il Fe@UiO-66-(COOH)2 ottenuto mediante l'80% di scambio cationico (con un contenuto effettivo di Fe di circa 8% in peso) è stato il miglior elettrocatalizzatore testato tra i vari materiali MOF a base di Fe sintetizzati. Le prestazioni nella NRR dipendono fortemente dal design della cella e dell'elettrodo. Più in dettaglio, è stato ottenuto un rendimento di ammoniaca di 1.19 μg•h-1•mgcat-2 con una configurazione di strati assemblati ed ordinati nel modo seguente: i) Nafion (la membrana), ii) MOF a base di Fe (l'elettrocatalizzatore), iii) il GDL (lo strato di diffusione gassosa a base di carbonio) e iv) un ulteriore strato di Fe-MOF. È stato anche esplorato l'effetto del voltaggio applicato, con un potenziale ottimale di -0.5 V vs RHE per massimizzare l'attività nella NRR e limitare la reazione collaterale di evoluzione dell'idrogeno. Inoltre, come attualmente utilizzato nei catalizzatori industriali per il processo Haber-Bosh, è stata studiata anche l'introduzione del potassio negli elettrocatalizzatori, al fine di facilitare il trasferimento di carica dagli ioni K- verso la superficie del catalizzatore a base di ferro, bilanciando il chemisorbimento dissociativo tra H2 e N2, e sopprimendo le reazioni collaterali, migliorandone così sia l'attività che la stabilità. I risultati ottenuti sono molto promettenti, anche se sono necessari ulteriori studi per migliorare le loro prestazioni nella NRR, per superare le limitazioni legate ai materiali MOF stessi, soprattutto a causa della loro bassa conducibilità e stabilità. Infine, il capitolo 5 si riferisce all'esplorazione di materiali avanzati, i MXeni (Ti3C2 MXeni), e al tentativo di sintetizzare una nanoarchitettura 3D partendo dalla loro forma bidimensionale. Per comprendere il ruolo della nanostruttura dei materiali MXeni nella NRR, “nanoribbons” (nano-nastri) di Ti3C2 sono stati trattati con KOH per ottenere una forma finale di strutture porose tridimensionali (3D). In particolare, l'obiettivo di questa parte di lavoro è stato quello di indagare come la conversione dei “nanoribbons” di Ti3C2 in strutture tridimensionali influenzi la reattività nella NRR condotta nel dispositivo elettrochimico in fase gassosa. È stata anche effettuata una caratterizzazione completa dei “nanoribbons” di MXeni (SEM, TEM, HRTEM, XRD, XPS e EDX). I risultati hanno mostrato che la nanostruttura tridimensionale porta ad un significativo miglioramento dell'attività di fissazione di N2 a causa della formazione di siti esposti di Ti-OH. È stata anche osservata una relazione lineare tra il tasso di formazione di ammoniaca e la quantità di ossigeno sulla superficie dei Ti3C2 MXeni.
Nitrogen plays an indispensable role for all life on earth and for the development of human beings. Industrially, nitrogen gas is converted to ammonia (NH3) and nitrogen-rich fertilisers to supplement the amount of nitrogen fixed spontaneously by nature. At present, the only industrial-scale ammonia synthesis technology is the process developed by Haber and Bosch in the early 20th century using gas phase N2 and H2 as the feeding gases. However, the Haber-Bosch process requires harsh conditions, complex equipment and high energy consumption, and operates with low conversion rates, which are inconsistent with economic and social growing development requirements. Compared to the Haber-Bosch method, electrocatalysis is one of the promising routes that can integrate electricity produced from renewable energy technologies for the production of ammonia at room temperature and ambient pressure. A specific challenge is related to the development of novel electrocatalysts/electrodes with the aim to achieve a low-cost, large-scale and delocalized production of ammonia. In view of the above key scientific issues, this PhD work focuses on three main aspects of the electrocatalytic nitrogen reduction reaction (NRR): i) engineering and design of the electrocatalyst, ii) electrode and cell design of the electrochemical device and iii) improvement and optimization of the reaction conditions, to enhance the performances of ammonia synthesis. Most of the research activities of this PhD work about synthesis and characterization of the electrocatalytic materials and assembling/testing of the electrodes in unconventional electrochemical devices were carried out at the laboratory CASPE (Laboratory of Catalysis for Sustainable Production and Energy) of the University of Messina. Moreover, during the three years, a period of 12 months was spent in cotutelle with the École supérieure de chimie, physique, électronique de Lyon (CPE Lyon), where advanced synthesis routes were explored for the preparation of organometallic-based electrocatalysts to be used as more active electrodes in NRR. The PhD thesis is organized in five main chapters. Chapter 1 focuses on N2 fixation issues and on describing the industrial Haber-Bosch process, with an overview of the general implications related to its high energy requirements. The alternative methods based on the electrochemical nitrogen fixation are then presented, with a wide description of pros and cons related to the milder conditions (i.e., room temperature and atmospheric pressure) and by discussing the elements to be developed for a future implementation of this technology, including a description of the possible reaction mechanism, which is still unclear in literature. Chapter 2, instead, refers to the electrocatalytic materials developed in this PhD work for the preparation of the electrodes: 1) the Metal-organic Frameworks (MOFs), a class of porous materials very promising for their peculiar characteristics of high surface area, tunable properties, organic functionality and porosity, as well as for the possibility of creating specific catalytic active sites thanks to both the functional groups and the metal ion centres; 2) the MXenes, a class of metal carbide or nitride materials with a two-dimensional (2D) structure, which have recently attracted a large interest for a broad range of applications, including catalysis and N2 fixation, for their unique properties of metallic conductivity and hydrophilic nature of the hydroxyl or oxygen terminated surfaces. In Chapters 3-5, the experimental results are presented and discussed. Chapter 3 concerns the preparation of a series of Fe-MOF-based (Fe@Zn/SIM-1) electrodes and their testing in NRR by using an advanced engineered three-phase reactor, working in gas-phase. This novel device operates at room temperature and atmospheric pressure, with counter and reference electrodes immersed into an anode half-cell (where the oxidation of H2O to O2 occurs) containing a liquid electrolyte (the anolyte), while the cathode half-cell for NRR operates in gas phase without a liquid electrolyte (electrolyte-less conditions). This type of electrocatalytic reactor is thus quite different from the conventional electrocatalytic reactors operating in liquid phase, with the main advantages of avoiding issues related to the low N2 solubility and transport in the electrolyte, and allowing an easier recovery of ammonia. The results obtained from these electrocatalytic tests in gas-phase were very useful to improve the design of the MOFs-based electrodes, evidencing the limits of these kinds of materials in terms of N content, stability and possibility to prepare more advanced electrocatalysts by carbonization. A wide part of this chapter was dedicated to the development of new experimental strategies for avoiding false positive in the detection of ammonia, which is one of the topics most studied from scientists working in NRR in the last two years. As accurate protocols were recently suggested in literature, also using advanced analytical techniques (i.e. using 15N labelled nitrogen), an easier methodology based on UV-visible spectrophotometric analysis (coupled with blank tests with inert gases) was suggested in this work to avoid ammonia contaminations and false positives, although more sophisticated analytical techniques may definitely confirm the real source of ammonia. In Chapter 4, a series of improved Fe-MOF-based materials (Fe-based and Fe-alkali metal-based MOF UiO-66-(COOH)2), synthesized by cation exchange reaction technique to replace the proton of carboxylic acid with an iron cation, are presented. With respect to Fe@Zn/SIM-1, this new class of MOFs are more stable in water and do not contain nitrogen atoms in their structure. Results evidenced that 80% cation exchange Fe@UiO-66-(COOH)2 (with an effective Fe content of around 8 wt.%) was the best electrocatalyst among the tested Fe-based MOF synthesized materials. The performances in NRR highly depended on cell and electrode design. More in detail, an ammonia yield of 1.19 μg•h-1•mgcat-2 was obtained with an assembling configuration of layers ordered as i) Nafion (the membrane), ii) Fe-based MOF (the electrocatalyst), iii) GDL (the carbon gas diffusion layer) and iv) a further layer of Fe-MOF. The effect of applied voltage was also explored, indicating an optimal voltage of -0.5 V vs. RHE to maximize activity in NRR and limiting the side hydrogen evolution reaction. Moreover, as currently used in the industrial catalysts for Haber-Bosh process, the introduction of potassium in the electrocatalysts was also investigated, in order to facilitate charge transfer from K- ions to the iron-based catalyst surface, balancing the dissociative chemisorption between H2 and N2, and suppressing side reactions, thus improving both activity and stability. These results were very promising, although a further experimentation is needed to improve their performances in NRR, to overcome limitations related to MOF materials themselves, majorly due to their low conductivity and stability. Finally, Chapter 5 refers to the exploration of advanced MXene materials (Ti3C2 MXene) and to the attempt of synthesizing a 3D nanoarchitecture starting from 2D-dimensional MXene-based catalysts. To understand the role of the nanostructure of MXene materials in NRR, Ti3C2 nanosheets were treated with KOH to obtain a final shape of three-dimensional (3D) porous frameworks nanoribbons. Specifically, the objective of this research was to investigate how the conversion of Ti3C2 nanosheets to 3D-like nanoribbons influence the NRR reactivity in the gas-phase electrochemical device. A full characterization of MXenes nanoribbons (SEM, TEM, HRTEM, XRD, XPS and EDX) was also presented. Results showed that the 3D-type nanostructure (nanoribbons) leads to a significant enhancement of the N2 fixation activity due to the formation of exposed Ti-OH sites. A linear relationship was observed between ammonia formation rate and amount of oxygen on the surface of Ti3C2 MXene.
L'azote joue un rôle indispensable pour toute vie sur terre et pour le développement des êtres humains. Industriellement, l'azote gazeux est converti en ammoniac (NH3) et en engrais riches en azote pour compléter la quantité d'azote fixée spontanément par la nature. À l'heure actuelle, la seule technologie de synthèse de l'ammoniac à l'échelle industrielle est le procédé mis au point par Haber et Bosch au début du XXe siècle, qui utilise les phases gazeuses N2 et H2. Cependant, le procédé Haber-Bosch nécessite des conditions difficiles, des équipements complexes et une consommation d'énergie élevée, et fonctionne avec de faibles taux de conversion, ce qui est incompatible avec les exigences d’un développement durable. Par rapport à la méthode Haber-Bosch, l'électrocatalyse est l'une des voies prometteuses qui permet d'intégrer l'électricité produite à partir de technologies d'énergies renouvelables pour la production d'ammoniac à température ambiante et à pression ambiante. Un défi spécifique est lié au développement de nouveaux électrocatalyseurs/électrodes dans le but de parvenir à une production d'ammoniac à faible coût, à grande échelle et délocalisée. Compte tenu ces défis scientifiques, ce travail de doctorat se concentre sur trois aspects principaux de la réaction électrocatalytique de réduction de l'azote (NRR) : i) ingénierie et conception de l'électrocatalyseur, ii) conception de l'électrode et de la cellule du dispositif électrochimique et iii) amélioration et optimisation des conditions de réaction, afin d'améliorer les performances de la synthèse de l'ammoniac. La plupart des activités de recherche de ce travail de doctorat sur la synthèse et la caractérisation des matériaux électrocatalytiques et l'assemblage/le test des électrodes dans des dispositifs électrochimiques non conventionnels ont été menées au laboratoire CASPE (Laboratory of Catalysis for Sustainable Production and Energy) de l'université de Messine. En outre, une période de 12 mois a été passée en cotutelle avec l'École supérieure de chimie, physique, électronique de Lyon (CPE Lyon), où des voies de synthèse avancées ont été explorées pour la préparation d'électrocatalyseurs à base de composés organométalliques qui ont été utilisés comme électrodes plus actives dans la RRN. Cette thèse de doctorat est organisée en cinq grands chapitres. Le chapitre 1 se concentre sur les questions de fixation de l'azote et sur la description du processus industriel de Haber-Bosch, avec un aperçu des implications générales liées à ses besoins élevés en énergie. Les méthodes alternatives basées sur la fixation électrochimique de l'azote sont ensuite présentées, avec une large description des avantages et des inconvénients liés aux conditions plus douces (c'est-à-dire la température ambiante et la pression atmosphérique) et en discutant des éléments à développer pour une future mise en œuvre de cette technologie, y compris une description du mécanisme de réaction possible, encore débattu dans la littérature. Le chapitre 2 fait référence aux matériaux électrocatalytiques développés pour la préparation des électrodes : 1) les matériaux hybrides organiques-inorganiques de type MOF, une classe de matériaux poreux très prometteurs pour leurs caractéristiques particulières de surface spécifique élevée et leurs propriétés ajustables ainsi que pour la possibilité de créer des sites catalytiques actifs spécifiques grâce aux groupes fonctionnels et aux centres d'ions métalliques ; 2) les MXènes, une classe de matériaux en carbure ou nitrure de métal à structure bidimensionnelle (2D), qui ont récemment suscité un grand intérêt pour un large éventail d'applications, notamment la catalyse et la fixation de N2, pour leurs propriétés uniques de conductivité métallique et de nature hydrophile des surfaces terminées par un hydroxyle ou un oxygène. Les chapitres 3 à 5 présentent et analysent les résultats expérimentaux. Le chapitre 3 concerne la préparation d'une série d'électrodes à base de Fe-MOF (Fe@Zn/SIM-1) et leur test dans la réaction NRR en utilisant un réacteur triphasé de pointe, fonctionnant en phase gazeuse. Ce nouveau dispositif fonctionne à température ambiante et à la pression atmosphérique, avec des électrodes de comptage et de référence immergées dans une demi-cellule anodique (où se produit l'oxydation de H2O en O2) contenant un électrolyte liquide (l'anolyte), tandis que la demi-cellule cathodique pour le NRR fonctionne en phase gazeuse sans électrolyte liquide. Ce type de réacteur électrocatalytique est donc très différent des réacteurs électrocatalytiques classiques fonctionnant en phase liquide, avec les principaux avantages d'éviter les problèmes liés à la faible solubilité et au transport de N2 dans l'électrolyte, et de permettre une récupération plus facile de l'ammoniac. Les résultats obtenus lors de ces essais électrocatalytiques en phase gazeuse ont été très utiles pour améliorer la conception des électrodes à base de MOFs, mettant en évidence les limites de ce type de matériaux en termes de teneur en N, de stabilité et de possibilité de préparer des électrocatalyseurs plus avancés par carbonisation. Une grande partie du chapitre 3 a été consacrée au développement de nouvelles stratégies expérimentales pour éviter les faux positifs dans la détection de l'ammoniac, qui est l'un des sujets les plus étudiés par les scientifiques travaillant dans la NRR ces deux dernières années. Comme des protocoles précis ont été récemment suggérés dans la littérature, utilisant également des techniques analytiques avancées (c'est-à-dire utilisant de l'azote marqué à 15N), une méthodologie plus facile basée sur l'analyse spectrophotométrique UV-visible (couplée à des essais à blanc avec des gaz inertes) a été suggérée dans ce travail pour éviter les contaminations par l'ammoniac et les faux positifs, bien que des techniques analytiques plus sophistiquées puissent définitivement confirmer la source réelle d'ammoniac. Dans le chapitre 4, une série de matériaux améliorés à base de Fe-MOF (incluant un dopage additionel par un métal alcalin du MOF UiO-66-(COOH)2), synthétisés par une technique de réaction d'échange de cations pour remplacer le proton de l'acide carboxylique par un cation de fer, sont présentés. En ce qui concerne le Fe@Zn/SIM-1, cette nouvelle classe de MOF est plus stable dans l'eau et ne contient pas d'atomes d'azote dans sa structure. Les résultats ont montré que l'échange cationique à 80 % Fe@UiO-66-(COOH)2 (avec une teneur effective en Fe d'environ 8 % en poids) était le meilleur électrocatalyseur parmi les matériaux synthétisés de MOF à base de Fe testés. Les performances du NRR dépendaient fortement de la conception de la cellule et de l'électrode. Plus en détail, un rendement en ammoniac de 1.19 μg•h-1•mgcat-2 a été obtenu avec une configuration d'assemblage de couches ordonnées comme i) Nafion (la membrane), ii) MOF à base de Fe (l'électrocatalyseur), iii) GDL (la couche de diffusion de gaz carbonique) et iv) une autre couche de Fe-MOF. L'effet de la tension appliquée a également été exploré, indiquant une tension optimale de -0,5 V par rapport à la RHE pour maximiser l'activité dans le NRR et limiter la réaction latérale d'évolution de l'hydrogène. En outre, comme c'est le cas actuellement dans les catalyseurs industriels pour le procédé Haber-Bosh, l'introduction de potassium dans les électrocatalyseurs a également été étudiée, afin de faciliter le transfert de charge des ions K- à la surface du catalyseur à base de fer, en équilibrant la chimisorption dissociative entre H2 et N2, et en supprimant les réactions secondaires, ce qui améliore à la fois l'activité et la stabilité. Ces résultats étaient très prometteurs, bien qu'une nouvelle expérimentation soit nécessaire pour améliorer leurs performances dans les NRR, afin de surmonter les limitations liées aux matériaux MOF eux-mêmes, principalement en raison de leur faible conductivité et de leur stabilité. Enfin, le chapitre 5 fait référence à l'exploration des matériaux avancés à base de MXène (Ti3C2 MXène) et à la tentative de synthèse d'une nanoarchitecture 3D à partir de catalyseurs à base de MXène en 2D. Pour comprendre le rôle de la nanostructure des matériaux à base de MXène dans la NRR, des nanofeuilles de Ti3C2 ont été traitées au KOH pour obtenir une forme finale de nanorubans à armature poreuse tridimensionnelle (3D). Plus précisément, l'objectif de cette recherche était d'étudier comment la conversion des nanofeuilles de Ti3C2 en nanorubans tridimensionnels influençait la réactivité du NRR dans le dispositif électrochimique en phase gazeuse. Une caractérisation complète des nanorubans MXenes (SEM, TEM, HRTEM, XRD, XPS et EDX) a également été présentée. Les résultats ont montré que la nanostructure de type 3D (nanorubans) conduit à une amélioration significative de l'activité de fixation du N2 en raison de la formation de sites Ti-OH exposés. Une relation linéaire a été observée entre le taux de formation d'ammoniac et la quantité d'oxygène à la surface du Ti3C2 MXene.