Studies of the thermal rearrangements of dispiro-1,2,4-Trioxanes

A series of α-alkoxy-3,6-dispiro-1,2,4-trioxanes have been synthesised by acid-catalysed perhydrolyses of α-alkoxy methylenecyclohexane oxides (provides ring A) to give selectively the corresponding 1-hydroperoxy-1-(hydroxymethyl)cyclohexanes followed by acid-catalysed condensation with an appropriate cycloalkanone (provides ring C). Analogous perhydrolyses catalysed by MoO2(acac)2 afforded mixtures of regioisomeric β-hydroxy hydroperoxides, albeit in overall increased yields. The resulting 1- (hydroperoxymethyl)-1-hydroxycyclohexanes allowed entry to the isomeric 3,5-dispiro- 1,2,4-trioxanes. X-ray crystallographic analysis of the isomeric dispiro-1,2,4-trioxanes revealed that (a) they originate from different diastereoisomers of the epoxide substrates, and (b) the 1,2,4-trioxane rings of the 3,5-isomers adopt distorted half-chair rather than chair conformations as a consequence of intramolecular 1,3-diaxial steric interactions. Modelling studies of the perhydrolysis process are in broad agreement with the regioselectivity of the acid-catalysed reactions, but suggest that the α-alkoxysubstituted epoxides can act as bidentate ligands which can adopt different binding modes to the Mo catalyst and hence provide alternative reaction pathways. Thermolysis of dilute solutions of the α-alkoxy-3,6-dispiro-1,2,4-trioxanes in decane afforded a variety of 13-, 14-, 15- and 20-membered fully ring-expanded keto lactones in high yield via stepwise, β-scission/radical recombination reactions in contrast to the partially ring-expanded oxalactones obtained previously from other 3,6-dispiro-1,2,4- trioxane derivatives. An investigation of substituent effects on the thermal rearrangement mechanisms of 3,6- dispiro-1,2,4-trioxanes using DFT calculations indicated that, after the initial O-O bond homolysis to form the corresponding oxy biradical, ring C generally opens significantly faster than the unsubstituted ring A because of the greater delocalisation of radical character into ring C. In these cases, the lowest rearrangement energy barrier links directly to the partially ring-expanded oxalactone product as observed experimentally. Methyl or methoxy substituents at the α-position of ring A render its ring opening by β- scission increasingly more competitive to that of ring C due to increased delocalisation of radical character onto the α-substituent, consistent with the ‘α-effect’. Methoxysubstituents are also noted to engage in close range interactions with the 1,2,4-trioxane ring. Since the energy barrier for ring A opening falls below that of ring C in the methoxy model, formation of the fully ring-expanded keto lactone becomes favoured.Engineering and Physical Sciences Research Council (EPSRC

Synthetic Methodologies for Intermolecular Radical Difunctionalizations of Alkenes and Application of Artemisinin in an Acrylamide Polymerization

An introduction is given to the topics of photoredox catalysis and intermolecular radical difunctionalizations of alkenes. Radical difunctionalizations transform C–C double (multiple) bonds by generating two new σ bonds in one reaction. Starting from general models in this research field, applications of α-carbonyl and acyl radicals are described. In addition, methodologies, which use the consecutive 1,2-addition of a radical as well as a nucleophile are addressed. An application of artemisinin as a radical co-initiator in acrylamide polymerizations in aqueous medium was developed. The assessment of reaction conditions, leading to the formation and characterization of polymer mixtures is described. Hydrochloric acid as well as iron species are used as co-initiators. Furthermore, results from an electron paramagnetic resonance (EPR) experiment with the initiator system were pointing towards the involvement of a by December 2020 unknown radical in the chemistry of artemisinin. A joined project is discussed, elaborating a method for Brønsted acid catalyzed γ-cyanoketone formations. The difunctionalization implements α-ketonyl radical formation from condensation of ketones with tert-butylhydroperoxide and methanesulfonyl cyanide. Contributions to learn about the application scope of formed γ-cyanoketones, subsequent transformations and from a noticed difference in diastereoselectivity compared to the previously reported γ-peroxyketone synthesis are described. An investigation of photoredox catalyzed alkene difunctionalization using a consecutive addition of acyl radicals and nucleophilic N-alkylindoles is summarized. In the Ir(ppy)3 catalyzed reaction, simple starting materials, namely aldehydes, N-alkylindoles and styrenes were employed. Moreover, a base is needed for successful product formation. The reaction is based on a Ir(III)/Ir(IV) catalytic cycle and tert-butyl perbenzoate as oxidant as well as precursor for tert-butoxyl radicals. Acyl radicals were generated by hydrogen atom transfer. Aryl as well as aliphatic aldehydes were suitable substrates. Investigations of the reaction scope, description of mechanistic indications and discussions in the scientific context are presented

Carbon Ligands

Homogeneous catalysis owes its success, in large part, to the development of a wide range of ligands with well-defined electronic and steric properties, which have thus made it possible to adjust the behavior of many organometallic complexes. However, ligands used in catalysis have long been centered on elements of group 15, and it is only more recently that carbon ligands have proved to be valuable alternatives with the emergence of cyclic diaminocarbenes (NHC).This Special Issue aims to provide a contemporary overview of the advances in carbon ligand chemistry from fundamental aspects to applications

Part A: Antimalarial agents modified at the C-16 position of artemisinin; Part B: Lead optimization of falcipain-2 and falcipain-3 inhibitors

Part A: Antimalarial Agents modified at the C-16 position of Artemisinin. Malaria is a widespread tropical and subtropical parasitic disease which is caused by malarial parasites and transmitted by the infected anopheles mosquitoe. The natural product artemisinin and its derivatives are currently considered the most effective drugs against drug resistant plasmodium falciparum. However, its undesired physicochemical proprieties have limited its usage. In order to improve its effectiveness, scientists around the world have developed novel methodology to synthesize artemisinin derivatives on different positions of the artemisinin skeleton. Previous work in our group has shown that many analogues modified at the C-16 of artemisinin had improved efficacy along with modified physicochemical proprieties. This work focuses on the synthesis of heteroatomic and heterocyclic derivatives of artemisinin with the emphasis on C-16 substituted triazole containing side-chains. Successful synthetic results and subsequent bioassay demonstrated that the compounds have modest antimalarial activity compared to artemisinin and improved water solubility. With these encouraging results in hand, further work is underway to tune the desired physicochemical properties so that plasma half-life and oral bioavailability will be improved. Part B: Lead Optimization of Falcipain-2 and Falcipain-3 Inhibitors. The expanding usage of artemisinin combination therapy casts concern about the potential development of drug resistance to this drug family, thus the search for new drug targets is always needed. Falcipain-2 (FP-II) and falcipain-3 (FP-III) are two cysteine proteases which malarial parasites utilize to degrade hemoglobin to obtain amino acids essential to the parasite. The inhibition of these two enzymes has been shown to have deadly effects on the protozoan life cycle. Recently published crystal structures of FP-II provided an outstanding opportunity for rational drug design and discovery. In the present study, structure-based optimization of virtual screening hits was carried out using scaffold hopping, docking and analogue synthesis. Unfortunately, the biological evaluation of the synthesized compounds against FP-II and FP-III indicated these compounds are inactive. However, the information gained from this exercise could aid further in optimization of this series of compounds

Synthesis and bioassay of rationally designed DXR inhibitors as potential antimalarial lead compounds

Globally, the eradication of malaria has been challenging due to the problem of resistance that past and currently available drugs exhibit. This is exacerbated by the inherent need for anti-malarial drugs to be affordable to the poverty-stricken majority that is primarily affected by this burden. This research has focused on the development of potential inhibitors of 1-deoxy-D- xylulose-5 phosphate reductoisomerase (DXR), an essential enzyme in the mevalonate- independent pathway for the biosynthesis of isoprenoids in Plasmodium falciparum. DXR mediates the isomerisation and reduction of 1-deoxy-D-xylulose-5-phosphate into 2-C- methyl-D-erithrytol 4-phosphate. This enzyme has been determined to be a target for the development of novel antimalarial agents and extensive molecular modelling has been undertaken to develop inhibitors that fit into the DXR active site. The in silico docking data have been used to inform the design and synthesis of various N-benzyl-substituted phosphoramidate ligands that were determined to have potential as novel substrate mimics of fosmidomycin, a known DXR inhibitor. Synthesis of the N-benzyl-substituted phosphoramidate ligands involved a nine-step sequence commencing from diethyl phosphoramidate. In all, some 40 compounds have been prepared, some of them new, and were fully characterized using NMR. Attention has also been given to the mass spectrometric fragmentation patterns exhibited by selected intermediates. Four of the final products were evaluated for in vitro antimalarial activity using a PLDH assay and exhibited IC50 values < 100 µM

Synthesis and Properties of Transition Metal Complexes of new 3,7-Diazabicyclo[3.3.1]nonane Derivatives

Das Ziel dieser Arbeit war die Entwicklung einer neuen Reihe 3,7-Diazabicyclo[3.3.1]nonan Derivate, wo nur elektronisch (5-substituierte Pyridine), sterisch (pyridin und 6-methyl substituierte Pyridine) und beide Effekte gleichzeitig (quinolin derivative) an dem Metallzentrum einwirken könnten. Die Synthese der substituierten 3,7 Diazabicyclo[3.3.1]nonanone erfolgt über eine zweifache Mannich-Reaktion. Im Verlauf dieser Arbeit konnten zahlreiche neue Derivate dargestellt werden. Der Zweck solcher Modifikationen waren neue Kupfer(II) und Eisen(II) komplexe zu synthetisieren, wo die Elektronische Eigenschaften des Metallzentrums (Redoxpotentiale) modifiziert werden könnten, so dass eine neue Familie effektive und stabile Katalysatoren für die Aziridinierung von Olefine mit PhINTS als Nitrenquelle, beziehungsweise für die selektive Oxidation von Olefine, erreichbar werden könnte

Application of Visible Light Mediated Photocatalysis in the Synthesis of Biologically Active Molecules

Im Rahmen der Arbeit wurde an zwei Projekten, einer Decarboxylierung und einer Endoperoxidsynthese, die Anwendbarkeit photokatalytischer Methoden zur Synthese biologisch aktiver Moleküle gezeigt. Durch Oxygenierung erhaltene bisher unbekannte Endoperoxide wurden auf ihre Aktivität gegen Malaria-Erreger getestet