A5017359346- Multicomponent Synthesis of Heterocycles
- Chemical Synthesis and Analysis
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical synthesis and alkaloids
- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Reactions
- Receptor Mechanisms and Signaling
- Synthesis and Biological Evaluation
- Alkaloids: synthesis and pharmacology
- Catalytic C–H Functionalization Methods
- Sulfur-Based Synthesis Techniques
- Chemokine receptors and signaling
- Synthesis and biological activity
- Click Chemistry and Applications
- Catalytic Cross-Coupling Reactions
- Synthetic Organic Chemistry Methods
- Synthesis and Characterization of Heterocyclic Compounds
- N-Heterocyclic Carbenes in Organic and Inorganic Chemistry
- Analytical Chemistry and Chromatography
- Quinazolinone synthesis and applications
- Computational Drug Discovery Methods
- Advanced Synthetic Organic Chemistry
- Synthesis of heterocyclic compounds
- Pharmacological Receptor Mechanisms and Effects
Vrije Universiteit Amsterdam
2013-2024
Luxembourg Institute of Health
2024
Amsterdam UMC Location Vrije Universiteit Amsterdam
2024
Friedrich Schiller University Jena
2024
University of Antwerp
2011
Centre for Human Drug Research
2006-2007
Hess (United States)
1999
A very short and efficient synthesis of the important drug candidate telaprevir, featuring a biocatalytic desymmetrization two multicomponent reactions as key steps, is presented. The classical issue lack stereoselectivity in Ugi- Passerini-type circumvented. atom economic convergent nature synthetic strategy require only limited use protective groups.
E=MCR2! The introduction of orthogonal functional groups in multicomponent reactions (MCRs) with unique solvent and functional-group compatibility enables their combination other one pot. resulting novel 5- 6CRs an unprecedented 8CR afford very complex products up to 80 % yields (see picture), nine new bond formations eleven diversity points a single reaction.
Palladium-catalyzed cross-coupling of a wide range substituted o-(pseudo)halobenzoates and hydrazines with isocyanide insertion followed by lactamization efficiently affords 4-aminophthalazin-1(2H)-ones that are difficult to obtain regioselectively classical methods.
Atypical chemokine receptor 3 (ACKR3), formerly referred to as CXCR7, is considered be an interesting drug target. In this study, we report on the synthesis, pharmacological characterization and radiolabeling of VUF15485, a new ACKR3 small-molecule agonist, that will serve important tool study <i>β</i>-arrestin-biased receptor. VUF15485 binds with nanomolar affinity (pIC<sub>50</sub> = 8.3) human ACKR3, measured in [<sup>125</sup>I]CXCL12 competition binding experiments. Moreover,...
Abstract Compared with the widespread use of carbonylative Pd‐catalyzed cross‐coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated intramolecular imidoylative N ‐(2‐bromoaryl)amidines, leading to 4‐aminoquinazolines. After thorough optimization reaction respect palladium source and loading, ligand, base, temperature, solvent, a small library 4‐aminoquinazolines was prepared determine scope this method. Various substituents...
We have combined the biocatalytic desymmetrization of 3,4-cis-substituted meso-pyrrolidines with an Ugi-type multicomponent reaction followed in situ by a Pictet-Spengler-type cyclization sequence for rapid asymmetric synthesis alkaloid-like polycyclic compounds.
Optimization of fragment hits toward high-affinity lead compounds is a crucial aspect fragment-based drug discovery (FBDD). In the current study, we have successfully optimized by growing into ligand-inducible subpocket binding site acetylcholine-binding protein (AChBP). This soluble homologue ligand domain (LBD) Cys-loop receptors. The optimization was monitored with X-ray structures complexes and systematic thermodynamic analyses using surface plasmon resonance (SPR) biosensor analysis...
A new synthetic approach to 4-aminopyrido[2,3-d]pyrimidines and 4-aminopyrido[3,2-d]pyrimidines based on palladium-catalyzed reaction of isocyanides with readily available N-(bromopyridyl)amidines is reported. The target heterocycles were obtained in generally good excellent yield. For the two regioisomeric pyrimidopyrimidines, we compared our involving oxidative addition analogous C–H activation protocol because both methods have been reported for synthesis 4-aminoquinazolines. We found...
In the wake of Covid-19 pandemic, it has become clear that global access to efficacious antiviral drugs will be critical combat future outbreaks SARS-CoV-2 or related viruses. The orally available main protease inhibitor nirmatrelvir proven an effective treatment option for Covid-19, especially in compromised patients. We report a new synthesis featuring highly enantioselective biocatalytic desymmetrization (>99% ee) and diastereoselective multicomponent reaction (>25:1 dr) as key steps. Our...
An efficient combination of MAO-N-catalyzed desymmetrization cyclic meso-amines with Ugi-Smiles multicomponent chemistry produced optically pure N-aryl proline amides. This method represents the first report a fully asymmetric process.
Abstract The interrupted Fischer indole synthesis of arylhydrazines and biocatalytically generated chiral bicyclic imines selectively affords either tetracyclic pyrroloindolines or tricyclic tryptamine analogues depending on the reaction conditions. We demonstrate that is compatible with a variety functional groups. products are obtained in high optical purity reasonable to good yield. present plausible mechanism explain observed outcome stoichiometry acid mediator. To synthetic utility our...
The developing fetus represents a highly sensitive period of exposure to endocrine disrupting compounds (EDCs). However, risk assessment EDCs is hampered by the lack data on direct in utero exposure. In this study, we developed robust analytical methodology for identification wide range known and unknown full-term amniotic fluid (AF). First, method extraction fractionation broad polar nonpolar was validated. Maximal recoveries reference minimal interference from matrix were achieved with...
An unforeseen twist in a seemingly trivial Bischler–Napieralski reaction led to the selective formation of an unexpected carbazole product. The proved be general, providing access range diversely substituted carbazoles from readily available substrates. Judicious variation substituents revealed complex cascade mechanism comprising no less than 10 elementary steps, that could diverted multiple ways toward various other derivatives.
E=MCR2! Orthogonale funktionelle Gruppen mit einzigartiger Kompatibilität Lösungsmitteln und anderen funktionellen ermöglichen die Kombination mehrerer Mehrkomponenten-Reaktionen in Eintopfprozessen. Die entsprechenden 5- 6CRs sowie eine neuartige 8CR liefern einer einzigen Reaktion bis zu 80 % Ausbeute sehr komplexe Produkte neun neuen Bindungen elf Diversitätspunkten (siehe Bild). Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents...
Abstract Diversity‐oriented synthesis : The multicomponent reaction of α‐isocyano amides, aldehydes or ketones, and amines affords N ‐(cyanomethyl)amides, presenting the fourth class products from this combination reagents (see scheme). scope is very broad various functional groups are tolerated. outcome can also be directed to formation 2 H ‐2‐imidazolines by Ag I catalysis. magnified image
Non-fused 3,6-dihydro-2H-1,3-thiazine-2-thiones constitute a so far rather unexplored class of compounds, with the latest report dating back more than two decades. Thiazine-2-thiones contain an endocyclic dithiocarbamate group, which is often found in pesticides, substrates for radical chemistry and synthetic intermediates towards thioureas amidines. We now multicomponent reaction (MCR) situ-generated 1-azadienes carbon disulfide. With this reaction, one-step protocol potentially interesting...
Abstract The combination of the recently developed multicomponent construction highly substituted 3,4‐dihydropyridones with subsequent allylation and intramolecular Heck‐type cyclization allows straightforward benzo[ a ]quinolizines, class polycyclic compounds that – despite their interesting pharmacological photochemical properties have little precedent in literature. After optimization individual steps, we used this reliable three‐step sequence to generate small library diversely...
A range of structurally diverse penta- and hexacyclic alkaloid-type compounds have been prepared in a two-step procedure from readily available starting materials. flexible N-acyliminium Pictet-Spengler reaction employing electron-rich β-arylethyl-amines, cinnamaldehyde derivatives, alkynoyl chlorides sets the stage for an intramolecular Diels-Alder cycloaddition. The complex polycyclic alkaloid-like are easily obtained reasonable to excellent yield reliable efficient sequence.
We describe the development of a high-resolution, noncontact fraction collector for liquid chromatography (LC) separations, allowing high-resolution fractionation in high-density well plates. The device is based on low-dead-volume solenoid valve operated at 1-30 Hz accurate collection fractions equal volume. was implemented modified autosampler resulting so-called FractioMate fractionator. influence supply voltage solvent release determined and effect frequency, flow rate, mobile phase...
A cobalt(II) mediated three-component synthesis of 5-substituted-N-sulfonyl-1,3,4-oxadiazol-2(3H)-imines using sulfonyl azides, N-isocyaniminotriphenylphosphorane (NIITP), and carboxylic acids has been developed. This one-pot tandem reaction starts with a nitrene transfer to NIITP, followed by addition the acid in situ formed carbodiimide subsequent intramolecular aza-Wittig reaction. Both steric constraints stoichiometry employed cobalt salt determine selectivity toward two products, i.e....
Abstract A practical two‐stage one‐pot synthesis of N‐substituted β‐amino alcohols using aldehydes and isocyanides as starting materials has been developed. This method features mild reaction conditions, broad scope, general tolerance functional groups. Based on a less common central carbon–carbon bond disconnection, this protocol complements traditional approaches that involve amines various carbon electrophiles (epoxides, α‐halo ketones, β‐halohydrins). Medicinally relevant products can be...
We present an Ugi multicomponent approach to explore the chemical space around Aspidosperma-type monoterpene indole alkaloids. By variation of isocyanide and carboxylic acid inputs we demonstrate rapid generation molecular diversity possibility introduce handles for further modification. The key three-component reaction showed full diastereoselectivity towards cis-fused ring system, which can be rationalized by DFT calculations that moreover indicate proceeds via a Passerini-type hydrogen...