Advances in the Development of Trifluoromethoxylation Reagents

This review provides a short summary of the traditional methods for synthesis of CF3-O-containing compounds, followed by a critical overview of known trifluoromethoxylating reagents, focusing on their preparation, synthetic generality and limitations

Stereoselective total syntheses of piericidins, the neuritogenic steroid withanolide A and the development of photolabile surface anchors

Stereoselective Total Syntheses of Piericidins, the Neuritogenic Steroid Withanolide A and the Development of Photolabile Surface Anchors This thesis includes a detailed description of the stereoselective synthesis of the neuritogenic steroid lactone withanolide A. Key for the successful total synthesis were mostly strategic considerations for the sequential order of the installment of the enone moiety. The total synthesis was achieved by a singlet oxygen Schenck ene-reaction, a Wharton transposition, a Corey-Seebach homologation and a vinylogous aldol reaction. Biological evaluation demonstrated neurite outgrowth, which further supports the potential neuritogenic role of this compound in traditional Indian medicine. In addition, the first total syntheses of the piericidin natural products JBIR-02 and Mer-A2026B, and related piericidins are reported. Key features of the unified synthetic strategy involved an Ir-catalyzed one pot C-H activation/oxidation procedure for the preparation of multiple hydroxypyridines, a vinylogous Mukaiyama aldol reaction and a Negishi cross-coupling of an advanced pyridine intermediate with the fully elaborated allylic side chain. Following the successful total synthesis, the absolute configurations of Mer-A2026B and JBIR-02 were established as (9R,10R). Further the development of a molecular surface modification platform based on biomimetic nitrocatechol derivatives is reported. This allowed for small molecule functionalization under mild aqueous conditions and efficient release triggered by light therefore uncaging a small molecule cargo on demand. Small molecules may be fluorescent marker as shown in the proof-of-principle study or bioactive small molecules for drug release. Keywords: Natural Products, Total Synthesis, Neurite Outgrowth, Photocleavable Surface Hybrids, Steroids, Piericidins, Retinoids and Bipyridine

Estudio de reacciones de acoplamiento en tándem en derivados de quinoleína

La síntesis de nuevos compuestos poliaromáticos mediante reacciones de acoplamiento cruzado es uno de los campos de investigación de nuevos materiales más prometedores debido a sus buenas propiedades electrónicas, ópticas, etc. Desde la segunda mitad del siglo XX, el coranuleno ha sido uno de estos materiales más estudiados debido a su peculiar estructura y a sus prometedoras propiedades. Sin embargo, se cree que se pueden mejorar estas propiedades mediante la derivatización del coranuleno con la sustitución de un átomo de carbono por uno de nitrógeno. Diversos derivados nitrogenados del coranuleno han sido sintetizados en los últimos años, pero no se ha conseguido aún la síntesis del azacoranuleno, la especie derivada del coranuleno con un átomo de nitrógeno en el borde exterior de su estructura. En este trabajo se han sintetizado y caracterizado varias especies derivadas de quinoleína y de 1,4-dimetilbenceno con el objetivo de sintetizar un derivado nitrogenado mediante reacciones de acoplamiento. Numerosos ensayos de acoplamiento con las mencionadas especies han sido realizados en el presente trabajo.New PAH’s synthesis through cross-coupling reactions is one of the most promising new materials research fields about due to their good electronic and optic properties. Since the 20th century second half the corannulene has been one of these most studied materials due to its peculiar structure and promising properties. However, it is believed that these properties may be improved by the derivatization of corannulene with the substitution of one of its carbon atoms by a nitrogen atom. Many nitrogen derivatives have been synthesized in the past years, but the synthesis of azacorannulene, the corannulene-derived species with a nitrogen atom at the outer edge of its structure, has not yet been achieved. In the present work, several quinoline and 1,4-dimethylbenzene derivatives have been synthesized and characterized, aiming the synthesis of nitrogen derivative. Moreover, several cross-coupling tests have been performed in the present work.Departamento de Química OrgánicaMáster en Técnicas Avanzadas en Química. Análisis y Control de Calidad Químico

Studies towards the synthesis of LL-Z1640-2 and spirocyclic systems

Resorcyclic acid lactones (RALs) are natural products, with some having been shown to be potent inhibitors of several protein kinases and mammalian cell proliferation and tumour growth in animals. LL-Z1640-2 (also known as 5Z-7-oxo-zeanol or C292) is a cis-enone RAL, isolated in 1978 from fungal broth and classified as an anti-protozoal agent. Later, in 1999, its cytokine releasing inhibiting activity was discovered, with subsequent data showing it could selectively and irreversibly inhibit transforming growth factor activating kinase-1 (TAK1) activity at low concentrations. It is also reported as having significant activity versus tumour necrosis factor-alpha (TNF-α) production in cells. This thesis documents and describes the work undertaken towards a total synthesis of the 14-membered macrocycle, LL-Z1640-2. The presence of two internal bonds and three stereogenic centres poses a challenge synthetically, but this has been effectively overcome with the development of a flexible, economic and efficient synthesis, beginning from the commercially available starting materials, methyl 2,4,6-trihydroxybenzoate and 2-deoxy-D-ribose. The original route relied on a Wittig olefination to introduce the E-double bond, with moderate selectivity and success. Later, an improved method was built upon, which utilised Grubbs mediated cross-metathesis to form the desired E-olefin in good yield and selectivity. Once the entire carbon framework had been established via a one-pot oxidation-Grignard adition of the appropriate alkyne unit, subsequent transformations enabled the formation of the seco-acid. This very successfully underwent Mitsunobu macrolactonisation, with complete inversion of the stereocentre, to afford the macrocyclic lactone. From this intermediate, the desired natural product LL-Z1640-2 could be generated in three steps. A number of natural products and biologically important compounds contain spirocyclic pyran and piperidines ring systems as part of their overall structures. In 1996, pinnaic acid and halichlorine were isolated from their respective marine natural sources. It was subsequently shown that they exhibited inhibitory activity towards certain biological substances and for this reason they became targets for total synthesis. Characterised by an azaspiro[4.5]decane ring system, the difficulty in achieving total syntheses of such compounds is immense. The aim of the project was to develop a concise method towards the generation of highly functionalised spirocyclic piperidine units. The regioselective aza-Achmatowicz oxidative rearrangement was used as the key step to rearrange α-amino furan building blocks into their respective enones. Importantly, this rearrangement was proven to be viable and to proceed with compounds possessing a terminal olefin, with no over-oxidation observed. This thesis also describes the investigation and efforts made into the production of more functionalised units, as well as studies into the synthesis of the cores of halichlorine and polymaxenolide, again using the aza-Achmatowicz and Achmatowicz rearrangement respectively

Promocijas darbs

Darbā veikti nesimetrisko λ3-jodānu un dažādu skābekļa un slāpekļa nukleofīlu mijiedarbības pētījumi. Balstoties uz iegūtajiem rezultātiem, sekmīgi izstrādātas viena reaktora secīgu daudzstadiju reakciju metodes C-H saites aktivēšanai/funkcionalizēšanai. Metožu pielietojums ir parādīts uz plaša substrātu klāsta. C-H Saišu funkcionalizēšanas pieeja balstās uz in situ ģenerētu nesimetrisku λ3-jodānu un dažādu nukleofīlu (acetātu, fenolātu, azīdu un plaša alifātisku un aromātisko amīnu) klāsta reakciju pārejas metālu (Pd, Cu) katalīzes apstākļos. Izstrādātas metodoloģijas pielietojums potenciālo zāļvielu “vēlīnai modificēšanai” parādīts antibakteriālā līdzekļa linezolīda sintēzē.Reactivity of unsymmetrical λ3-iodanes with various O- and N-nucleophiles was investigated and new sequential one-pot multi-step C-H bond functionalization approach has been developed. The new methodology is based on a regioselective reaction of the in situ generated unsymmetrical λ3-iodanes with a range of nucleophiles (acetates, phenolates, azides and various aliphatic and aromatic amines) in the presence of transition metal (Pd, Cu) catalysts. Suitability of the developed methodology for late-stage modification of the potential drug molecules was demonstrated in synthesis of antibacterial linezolid

Radical Chemistry-Based Advances in Biomodification, Ligand Design and 18F Fluorine Labeling

This work contains radical chemistry-based advances within three individual projects. First, a photoinduced radical arylation of tyrosine derivatives is developed and discussed. Second, advances in dopamine D4 receptor ligand design and further understandings of the extended binding pocket of the D4 receptor are presented. And third, a radical chlorodifluoromethylation strategy is applied for the synthesis of 2-chlorodifluoromethyl indoles, which are tested for radiochemical 18F labeling

Crystal engineering and bifunctionality in spin-crossover materials

This thesis focuses on crystal engineering metal salts of 2,2’:6’,2’’-terpyridine and 2,6-di(pyrazol-1’-yl)pyridine to tune and better understand the cooperative spin crossover in the solid state and incorporation of a second functionality towards bifunctional spin crossover materials. Chapter 1 can be considered an introduction to the phenomenon of spin crossover in first row transition metal complexes and outlines its discovery, recent developments and progression towards real-world application. Chaper 2 is a discussion of the methodology of synthetic efforts undertaken in the acquisition of the wealth of tris-chelating organic compounds whose coordination chemistry is the subject of later chapters. Chapter 3 details the spectroscopic, electrochemical and magnetic properties of cobalt(II) and iron(II) complexes of tris-azinyl analogues of 2,2’:6’,2’’-terpyridine in efforts towards tuning their electronic spin-equilibria. Chapter 4 presents a series of novel ruthenium(II) based materials exhibiting enhanced room temperature emission and their incorporation into an inert spin crossover host material. Retention of parent functionalities is screened for over an operable temperature regime. Chapter 5 concerns iron(II) complex salts of 2,6-di(pyrazol-1’-yl)pyridine derivatives, whose ligand backbones are modified in an attempt to tune the solid state spin crossover behaviour both electronically and sterically. Chapter 6 is an account of all synthetic procedures carried out during this work, their standard characterisation and details the instrumentation performed on all materials which are the subject of discussion in this thesis