Doctor of Philosophy

dissertationThe Heck reaction is an important tool in target-directed syntheses, but its full potential has yet to be realized due to limited substrate compatibility. This limitation arises from poor behavior of the selectivity-determining steps of migratory insertion and -hydride elimination when using electronically nonbiased substrates. The inability to accommodate nonbiased alkenes is due to chemist's poor understanding of the controlling factors in these two key mechanistic steps. Herein are described Pd0 and PdII catalysts that exhibit unique selectivity in these electronically nonbiased molecular systems. Chapter 1 describes the use of an electrophilic PdII catalyst to install two identical aryl groups upon terminal aliphatic olefins. The use of the same system, with a different aryl source, led to the discovery that electrophilic PdII catalysts are capable of selectively delivering (E)-styrenyl products from electronically nonbiased olefins. Chapter 2 details optimization of the PdII system to selectively deliver traditionally inaccessible (E)-styrenyl products, and evaluation of substrate scope. Mechanistic experiments are performed, suggesting that the unique selectivity observed is attributable to the cationic nature of the catalyst, that the ligand on Pd is required for catalyst stability, and that the catalyst distinguishes between B-hydrogens on the basis of C-H bond strength. These findings are applied to rational design of a Pd0-catalyzed Heck reaction of similar substrates. The Pd0-catalyzed system exhibits greater functional group tolerance than the oxidative system, is operationally simple, and requires no added stabilizing ligand. The design and study of this reaction is the subject of Chapter 3. Mechanistic studies suggest that solvent choice is crucial in allowing the metal center to distinguish between - hydrogens on the basis of their relative hydridic nature. The insight gained in the work described in Chapters 2 and 3 allowed for the rational design of a system enabling enantioselective Heck reactions using acyclic substrates. This methodology, described in Chapter 4, was intended to deliver optically active -aryl ketones from allylic alcohol substrates. After establishing that the reaction performs as anticipated, it was applied to the unprecedented single-step enantioselective synthesis of y-aryl ketones, and aldehydes, and a d-aryl aldehyde

Site-Selective C−H Arylation of Primary Aliphatic Amines Enabled by a Catalytic Transient Directing Group

Transition-metal-catalysed direct C–H bond functionalization of aliphatic amines is of great importance in organic and medicinal chemistry research. Several methods have been developed for the direct sp3 C–H functionalization of secondary and tertiary aliphatic amines, but site-selective functionalization of primary aliphatic amines in remote positions remains a challenge. Here, we report the direct, highly site-selective γ-arylation of primary alkylamines via a palladium-catalysed C–H bond functionalization process on unactivated sp3 carbons. Using glyoxylic acid as an inexpensive, catalytic and transient directing group, a wide array of γ-arylated primary alkylamines were prepared without any protection or deprotection steps. This approach provides straightforward access to important structural motifs in organic and medicinal chemistry without the need for pre-functionalized substrates or stoichiometric directing groups and is demonstrated here in the synthesis of analogues of the immunomodulatory drug fingolimod directly from commercially available 2-amino-2-propylpropane-1,3-diol

Merging Metal Catalysis & DFT Studies toward the C-H Functionalization of a-Amino Carbonyl Compounds.

240 p.El principal objetivo de esta Tesis Doctoral consiste en el diseño de nuevos métodos catalíticos viafuncionalización de enlaces C¿H dirigidos a la modificación selectiva de aminoácidos y péptidos. Enparticular, se han desarrollado dos nuevas metodologías: una reacción de alcoxicarbonilación dederivados de Phe por activación de enlaces C(sp2)¿H catalizada por sales de Pd, y una reacción dehidroxilación de derivados de Tyr por funcionalización enlaces C(sp2)¿H catalizada por sales de Ru. Elmecanismo a través del cual ocurren dichos procesos se ha estudiado mediante cálculos computacionales.Así mismo, estudios de DFT han permitido elucidar el mecanismo a través del cual ocurren las reaccionesde CDC entre unidades de N-aril glicinas e indoles en presencia de sales de cobalto. En global, esta TesisDoctoral ha permitido avanzar en el desarrollo de nuevas estrategias sintéticas para modificarselectivamente biomoléculas de alto valor añadido

C–H Activation by Iron(III), Manganese(II) and Rhoda(III)electro Catalysis

While major progress was realized with noble transition metal catalysts, the employment of cost-effective and earth-abundant 3d metals has gained significant momentum during the last decade. As stoichiometric amounts of oxidants are often needed for the C–H activation, electricity has been identified as aninexpensive, economical, and environmental benign alternative for chemical redox equivalents. Thus, my projects have focused on both the earth-abundant 3d metals and resource-economic electrochemical C–H bond transformations. we achieved an expedient C–H functionalization of electron-rich benzyl and aryl amines by sustainable iron-catalysis with the assistance of a new fully substituted triazole TST directing group enabling C–H methylations, alkylations and arylations. We also developed a direct ortho-alkylation of pyridines by weak assistance of amides.A multifunctional and transformable Omethylamidoxime was designed to guarantee the reactivity and selectivity. The isolation of two C–H-activated rhodacycles offered the proof for sequence of the cascade C–H activation.In the last project, we have developed a bifurcated C–H cyclopropylation and dienylation of indoles by rhodaelectro-catalysis under aqueous conditions, avoiding the use of stoichiometric amounts of chemical oxidants

Recent advances in transition-metal-catalyzed, directed Aryl C-H/N-H cross coupling reactions

Amination and amidation of aryl compounds using a transition-metal-catalyzed cross-coupling reaction typically involves prefunctionalization or preoxidation of either partner. In recent years, a new class of transition-metal-catalyzed cross-dehydrogenative coupling reaction has been developed for the direct formation of aryl C–N bonds. This short review highlights the substantial progress made for ortho-C–N bond formation via transition-metal-catalyzed chelation-directed aryl C–H activation and gives an overview of the challenges that remain for directed meta- and para-selective reactions

Exploring C−H Functionalization Reactions with Theory and Experiment

C−H bond functionalization reactions are powerful, efficient, and potentially step-economic strategy for the construction of carbon−carbon and carbon−heteroatom bonds in organic synthesis. In recent years, novel Ni-catalyzed C−H bond functionalization reactions using N,N bidentate directing groups have been developed to selectively activate inert C−H bonds. However, the reaction mechanisms and origins of reactivity and selectivity of many of these organic transformations remain unclear. A detailed understanding of the molecular processes involved is essential for understanding and developing more efficient and diverse C−H functionalization reactions. Density functional theory (DFT) has emerged as a powerful tool to elucidate reaction mechanisms and intricate details of the elementary steps involved, and divergent reaction pathways in transition metal-catalyzed reactions. In this dissertation, the mechanisms of Ni-catalyzed C–H oxidative annulation, arylation, alkylation, benzylation and sulfenylation with N,N-bidentate directing groups are investigated using DFT calculations. Ni-catalyzed C–H functionalization reactions can be broadly divided into two distinct mechanistic steps: (i) C–H metalation (ii) C–C or C–heteroatom bond formation steps. Specifically, the C–H metalation may occur via either the concerted metalation-deprotonation (CMD) or σ-complex-assisted metathesis (σ-CAM) mechanism. The subsequent C–C and C–heteroatom bond formation steps may occur via closed-shell Ni(II) or Ni(IV) intermediates. Alternatively, radical pathways involving Ni(III) complexes are also possible. Our studies indicated that the reaction mechanism of Ni-catalyzed C–H functionalization is substrate-dependent. The mechanistic insights gained from the computational studies were employed to investigate a number of experimental phenomena including substituent effects on reactivity, chemo- and regioselectivity, ligand and directing group effects, and the effects of oxidants. Furthermore, a novel C(sp3)−H functionalization methodology was developed to synthesize biologically relevant vinyl sulfone-containing compounds of pharmacologically prevalent picolyl amides with allenic sulfones. The reaction conditions are mild. The starting materials can be prepared from readily available sources. The reaction has a broad functional group tolerance. Mechanistic studies suggested that the reaction likely operates via a rare pyridine-initiated and p-toluenesulfinate anion-mediated activation analogous to phosphine-triggered reactions and Padwa’s allenic sulfone chemistry

Metal-Catalyzed C(sp2)−H Functionalization Processes of Phenylalanine- and Tyrosine-Containing Peptides

The site-selective chemical diversification of biomolecules constitutes an unmet challenge of capital importance within medicinal chemistry and chemical biology. The functionalization of otherwise unreactive C-H bonds holds great promise for reducing the reliance on existing functional groups, thereby streamlining chemical syntheses. Over the last years, a myriad of peptide labelling techniques featuring metal-catalyzed C-H functionalization reactions have been developed. Despite the wealth of reports in the field, the site-selective modification of both phenylalanine (Phe) and tyrosine (Tyr) compounds upon metal catalysis remain comparatively overlooked. This review highlights these promising tagging strategies, which generally occur through the formation of challenging 6-membered metallacycles and enable the late-stage diversification of peptides in a tailored fashion.A. Correa is grateful to Ministerio de Ciencia e Innovacion (RTI2018-093721-B-I00, MCI/AEI/FEDER, UE) and Basque Government (IT1033-16) for financial support. He also kindly acknowledges the GEQO group of the RSEQ for the GEQO Young Research Award 2019. Likewise, he sincerely thanks all co-workers for their dedication and invaluable contribution

Metal–Ligand Interactions in Molecular Imprinting

Molecular imprinting enables the design of highly crosslinked polymeric materials that are able to mimic natural recognition processes. Molecularly imprinted polymers exhibit binding sites with tailored selectivity toward target structures ranging from inorganic ions to biomacromolecules and even viruses or living cells. The choice of the appropriate functional monomer, crosslinker, and the nature and specificity of template–monomer interactions are critical for a successful imprinting process. The use of a metal ion mediating the interaction between the monomer and template (acting as ligands) has proven to offer a higher fidelity of imprint, which modulates the molecularly imprinted polymers (MIPs) selectivity or to endow additional features to the polymer, such as stimuli-responsiveness, catalytic activity, etc. Furthermore, limitations in using nonpolar and aprotic solvents are overcome, allowing the use of more polar solvents and even aqueous solutions as imprinting media, opening new prospects toward the imprinting of biomacromolecules (proteins, DNA, RNA, antibodies, biological receptors, etc.). This chapter aims to outline the beneficial pairing of metal ions as coordination centers and various functional ligands in the molecular imprinting process, as well as to provide an up to date overview of the various applications in chemical sensing, separation processes (stationary phases and selective sorbents), drug delivery, and catalysis

New routes to planar chiral ligands and their use in asymmetric catalysis : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry at Massey University, Manawatū, New Zealand

This thesis contains 8 chapters detailing 3 optimised methods to synthesise [2.2]paracyclophane derivatives and our studies in the C-H activation field, namely selective remote β-C-H activation of cyclic amines, and enantioselective γ-C(sp³)-H functionalisation of cyclic amines, as well as a future direction. As the main focus of this thesis is on the development of novel planar chiral [2.2]paracyclophane derivatives, Chapter 1 starts with a brief description of [2.2]paracyclophane chemistry. A short introduction about the synthesis of key enantioenriched [2.2]paracyclophane derivatives is given. Finally, a short introduction of the recent applications of [2.2]paracyclophane-based ligands in asymmetric catalysis is also mentioned. Chapter 2 describes the synthesis of (RSp,SRP)-4-tert-butyl[2.2]paracyclophane phosphine oxide (SPO) and attempts to synthesise its asymmetric variant. Further, its synthetic utility is investigated, mainly in Suzuki-Miyaura cross-coupling, Buchwald-Hartwig amination, and Au(I)-catalysed cyclisation reactions. Additionally, a general route to the P-stereogenic [2.2]paracyclophane-derived phosphines via the reduction of tertiary phosphine oxides is reported. Chapter 3 mainly outlines attempts for β-C(sp³)-H activation of cyclic amine to target the shortest route of epibatidine moiety. A stepwise approach is mentioned. Firstly, a range of heteroatom-substituted secondary phosphine oxides (HASPOs) is evaluated to access (chiral) indolines via intramolecular C(sp³)-H activation. Next, an intramolecular C(sp³)-H activation of 7-azanorbornane, a core skeleton of epibatidine, is investigated. The third approach is mainly targeted for the directing-group-assisted intermolecular C(sp³)-H activation of 7-azanorbornane. Lastly, enantioselective γ-C(sp³)-H activation of N-cyclohexylpicolinamide using various chiral Brønsted acids, again targeting the epibatidine moiety by the late-stage cyclisation, is described. In a search for suitable planar chiral Brønsted acid, an optimised single-step protocol for the synthesis of [2.2]paracyclophanes carboxylic acid derivatives is reported in Chapter 4. This protocol proceeds via C(sp²)-H activation of chiral oxazolines and their coupling with bromo[2.2]paracyclophanes. Chapters 5 & 6 are related to pyridine sulfinates. Chapter 5 describes an attempted regioselective C-H functionalisation of aromatic acids via desulfitative coupling with pyridine-2-sulfinate. A detailed study with catalytic Pd(OAc)₂ and pre-formed palladacycle is mentioned. The effect of catalytic Pd(OAc)₂ on homo-coupling of pyridine-2-sulfinates is also investigated. The potential of sulfinates as nucleophilic coupling partners is investigated in Chapter 6. A novel methodology to synthesise pyridyl[2.2]paracyclophanes is described. The method involves desulfitative cross-coupling reactions between pyridine sulfinates and bromo[2.2]paracyclophanes. One of the interesting results of the desulfitative coupling with the unreactive (±)-4-bromo-5-amino[2.2]paracyclophane is also mentioned. Chapter 7 explains the future scope of the research work mentioned in this thesis. Finally, Chapter 8 describes the experimental procedures and characterisation of the synthesised compounds mentioned in Chapters 2 to 6

Highly Luminescent Lanthanide Chirality Probes

The chirality of biological systems can be probed using highly emissive lanthanide complexes with the aid of circularly polarised luminescence and emission spectroscopy. Such chirality probes can be synthesised through the incorporation of a remote chiral centre within the ligand framework, which can preferentially stabilise a particular stereoisomer giving an enantiopure complex of well-defined helicity. Alternatively, lanthanide chirality probes can be derived from achiral or dynamically racemic ligands, where the selective induction of a CPL signal can be monitored as a function of the nature and concentration of a selected chiral analyte. A series of chiral lanthanide complexes has been synthesised. Each complex is based on an amide substituted 1,4,7-triazacyclononane system derived from either R-(+) or S-(-)-α-methylbenzyl amine. The stereochemistry of the amide moiety controls the helicity of the complex, and one major diastereoisomer is formed for each lanthanide metal. The absolute stereochemistry of the major diastereoisomer was determined by X-ray crystallography (S-Δ-λλλ and R-Λ-δδδ). Inclusion of an aryl-alkynyl chromophore generated complexes that exhibited large extinction coefficients (up to 55,000 M-1 cm-1) and high quantum yields (up to 37%) in water. A second set of bright Eu (III) complexes has been prepared based on an achiral heptadentate ligand system, which vary in the nature of the pyridyl donor (phosphinate, carboxylate and amide). The binding of a number of chiral acids including lactate, mandelate and cyclohexylhydroxyacetate was monitored by a change in the emission spectrum and the induction of strong CPL. Empirical analysis of the ΔJ = 4 region of each of the Eu (III) complexes allows an assignment of the complex-anion adducts as R-Δ and S-Λ. Furthermore, variations in the sign and magnitude of CPL allow the enantiomeric purity of samples with unknown enantiomeric composition to be assessed. Finally, several dynamically racemic lanthanide chirality probes have been synthesised and characterised. Induced CPL has been assessed, which arises as a result of the change in complex constitution upon binding to important chiral biomolecules such as, sialic acid, O-phosphono-amino acids and peptides and oleoyl-L-lysophosphatidic acid (LPA). This work presents the first example of induced CPL in the detection of cancer biomarkers, sialic acid and LPA, and demonstrates the utility of this class of dynamically racemic Eu (III) complexes as chirality probes