Synthesis of an Oxidation‐Stable Analogue of Cyclic Pyranopterin Monophosphate (cPMP)

Hilken, Stefan; Kaletta, Florian; Heinsch, Angela; Neudörfl, Jörg‐M.; Berkessel, Albrecht

doi:10.1002/ejoc.201301784

Cited by 5 publications

(4 citation statements)

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“…The fragile N8-C7-O moiety of the MPT can be oxidatively cleaved under acidic conditions, 11, 16 yielding a fully oxidized pyrazine ring, concomitantly opening the pyran ring by breaking the C7-O bond as in compound 2 . It is possible to reconstruct the N8-C7-O moiety by nucleophilic addition of the alcohol to an N-acetylated pyrazine ring, which can be formed by treating the pterin with chloroformate reagents e.g., benzyl chloroformate, 9H-fluoren-9-ylmethyl chloroformate (FMOC-Cl) that can subsequently be reduced by NaBH 3 CN.…”

Section: Resultsmentioning

confidence: 99%

“…10 Despite the biochemical interest, complete synthesis of this MPT remains a challenge that has compromised in-depth analyses of it properties, although progress has been made through years of efforts. [11][12][13][14][15] In recent years progress has been made particularly towards the syntheses of the precursor of the MPT cofactor 14,16 as well as coordination to Mo. 13 A general strategy to prepare the MPT is to functionalize a pterin molecule at the C-6 position to introduce a dithiolene functionality leading to a fully protected pterin moiety.…”

Section: Introductionmentioning

confidence: 99%

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A regioselective synthesis of the dephospho ditholene protected molybdopterin

et al. 2014

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The molybdopterin (MPT) is a complex molecule, made out of three distinctly different components. A retrosynthetic analysis provides a possible route for its synthesis that utilizes the coupling of a diamine with an osone analog. A regioselective condensation of the diamine with an osone affords the dephospho MPT, which has been characterized by NMR and IR spectroscopies, as well as high-resolution mass spectrometry.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A regioselective synthesis of the dephospho ditholene protected molybdopterin

et al. 2014

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“…Nucleophilic aromatic substitutions are an essential part of an organic chemist’s toolbox. − These reactions are key steps in the synthesis of various pharmaceutical compounds. Two recent examples are cyclic pyranopterin monophosphate (cPMP) analogues or 3,5-dinitrothiophene scaffolds used in the development of anticancer drugs. , Knowledge of the mechanism and energetics of nucleophilic aromatic substitution reactions has generated applications beyond their synthetic utility. For example, the susceptibility of electrophilic aromatic compounds to nucleophilic attack has been used to model their skin sensitization potential .…”

Section: Introductionmentioning

confidence: 99%

Influence of Solvation and Dynamics on the Mechanism and Kinetics of Nucleophilic Aromatic Substitution Reactions in Liquid Ammonia

et al. 2016

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The role of the solvent and the influence of dynamics on the kinetics and mechanism of the SNAr reaction of several halonitrobenzenes in liquid ammonia, using both static calculations and dynamic ab initio molecular dynamics simulations, are investigated. A combination of metadynamics and committor analysis methods reveals how this reaction can change from a concerted, one-step mechanism in gas phase to a stepwise pathway, involving a metastable Meisenheimer complex, in liquid ammonia. This clearly establishes, among others, the important role of the solvent and highlights the fact that accurately treating solvation is of crucial importance to correctly unravel the reaction mechanism. It is indeed shown that H-bond formation of the reacting NH3 with the solvent drastically reduces the barrier of NH3 addition. The halide elimination step, however, is greatly facilitated by proton transfer from the reacting NH3 to the solvent. Furthermore, the free energy surface strongly depends on the halide substituent and the number of electron-withdrawing nitro substituents.

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“…By using future advances of testing methods and by looking beyond a chemical's intended function only, environmental hazards can be minimized to allow chemicals to continue to provide vital functions to society. with a needle potential of 2500 V. The synthesis protocol was oriented on procedures described in literature (Hilken et al, 2014;Pahor et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Towards a Safe and Sustainable Future

van Dijk

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Human-made synthetic chemicals play a vital role in our society and economy, offering numerous benefits. However, their usage, production, and disposal have adverse environmental consequences, impacting both human and ecological health. Even though chemicals’ management improved over the last decades due to legislation, many issues related to chemical pollution still persist and additional mitigation options should be developed and implemented. This dissertation focussed on the identification and assessment of multiple mitigation options over the chemical life cycle -focussing on the design, registration, use and waste stages- in order to help reduce chemical emissions into the environment in a more comprehensive manner, thereby contributing to environmental policy ambitions. Chapter 2 underscores the importance of clear policy objectives to enhance chemicals and waste management. Key issues overlooked in European policy ambitions but vital for effective chemical management are identified, with a focus on providing guidance to decision-makers and scientists. In Chapter 3, focusses on the chemical design and production stage, contributing to the development of Safe and Sustainable chemicals. A systematic and computer-aided workflow is proposed and tested that can facilitate the design of chemicals for reduced environmental hazards whilst also taking sustainability parameters into account. Chapter 4 addresses the registration and market entry phase of chemicals, analysing risk assessment procedures for biocides, industrial chemicals, pesticides and medicines for human and veterinary use. Discrepancies in environmental protection goals and assessment strategies across these frameworks are identified, which result in inconsistent assessments and the continued marketing of banned substances. The chapter offers recommendations to harmonize registration frameworks and move towards a ‘one substance-one assessment’ approach. Chapter 5 focuses on identifying and replacing substances that are persistent, mobile, and toxic (PMT) or very persistent and very mobile (vPvM) in cosmetic products. PMT/vPvM substances were found in all product types. Case studies on the three most prevalent PMT/vPvM substances showed that all uses could be phased out as either the technical function of the substance is not necessary for the product performance, or because safer alternatives are available. Chapter 6 explores options for reducing chemical emissions during the waste stage, focussing on sewage treatment plants (STPs). An analysis of STPs across Europe showed that implementation of advanced treatment techniques, such as ozonation and activated carbon, can significantly reduce chemical flows released via STPs. Spatial disparities in treatment levels and the need for more stringent treatment near nature protection areas and water bodies with less than good ecological status are highlighted. The synthesis of findings from Chapters 3-6 emphasizes that options to reduce environmental emission of chemicals exist. However, given the expected increase in the diversity and use volume of chemicals, it is key to optimize and, when possible, reduce the wide variety of uses of the vast amount of chemicals. In other words, we must optimize the use of chemodiversity to move towards a safe and sustainable future. This transformation will require societal and institutional changes that strike a balance between the advantages of chemical use, innovation and the need for sustainability and safety.

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Synthesis of an Oxidation‐Stable Analogue of Cyclic Pyranopterin Monophosphate (cPMP)

Cited by 5 publications

References 52 publications

A regioselective synthesis of the dephospho ditholene protected molybdopterin

A regioselective synthesis of the dephospho ditholene protected molybdopterin

Influence of Solvation and Dynamics on the Mechanism and Kinetics of Nucleophilic Aromatic Substitution Reactions in Liquid Ammonia

Towards a Safe and Sustainable Future

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