A5040767670- Catalytic C–H Functionalization Methods
- Catalytic Cross-Coupling Reactions
- Chemical synthesis and alkaloids
- Cyclization and Aryne Chemistry
- Crystallization and Solubility Studies
- Asymmetric Hydrogenation and Catalysis
- X-ray Diffraction in Crystallography
- Catalytic Alkyne Reactions
- Synthetic Organic Chemistry Methods
- Asymmetric Synthesis and Catalysis
- Synthesis and Catalytic Reactions
- Microbial Natural Products and Biosynthesis
- Plant and fungal interactions
- Synthesis and Biological Activity
- Marine Sponges and Natural Products
- N-Heterocyclic Carbenes in Organic and Inorganic Chemistry
- Sulfur-Based Synthesis Techniques
- Chemical Synthesis and Reactions
- Cyclopropane Reaction Mechanisms
- Axial and Atropisomeric Chirality Synthesis
- Synthesis of Indole Derivatives
- Peptidase Inhibition and Analysis
- Protist diversity and phylogeny
- Enzyme Catalysis and Immobilization
- Cancer-related gene regulation
Merck & Co., Inc., Rahway, NJ, USA (United States)
2021-2025
Leibniz University Hannover
2015-2017
University of Toronto
2009-2012
Davenport University
2011
York University
2008
Keele University
2007
Domino reactions possess the ability to generate complexity from simple starting materials. Disclosed is a strategy for domino direct arylation/N-arylation facile construction of diverse phenanthridine derivatives (see scheme; TMS=trimethylsilyl, TBDMS=tert-butyldimethylsilyl).
They all fall down: The value of domino processes can be greatly enhanced when the possibility exists for one to selectively diverge from a common intermediate. In preliminary studies dual reactivity aryl-palladium intermediates is exploited. A diverse array fluorene and phenanthrene derivatives were synthesized in rapid efficient manner (see scheme).
The highly strained 2H-azirine ring system has been the source of considerable theoretical and synthetic work. reaction these heterocycles with transition metals documented to give rise opening subsequent formation varied heterocycles. An interesting domino is described wherein bicyclic alkene, norbornene, mediates 2H-azirines aryl iodides under palladium catalysis provide indole or polycyclic dihydroimidazole
The use of aryl triflates as reaction partners in a palladium-catalyzed domino direct arylation/N-arylation provides great advantage due to the availability starting materials. Furthermore, it allows expedient access biologically interesting benzo[c]phenanthridine alkaloids.
A general and high yielding annulation strategy for the synthesis of various carbo- heterocycles, based on an intramolecular aryne ene reaction is described. It was found that geometry olefin crucial to success reaction, with exclusive migration trans-allylic-H taking place. Furthermore, electronic nature be important reaction. Deuterium labeling studies DFT calculations provided insight into mechanism. The data suggests a concerted asynchronous transition state, resembling nucleophilic...
Abstract Increasing the fraction of sp3 character in lead compounds has been shown to increase their drug-likeness by improving potency, selectivity, and physicochemical properties. Azabicyclo[2.1.1]hexanes have recently garnered much interest synthetic community as pyrrolidine analogues for interesting biological properties stereoelectronic effects. During course our optimization N-heteroaryl LRRK2 inhibitors, we discovered that this unique bicyclic system leads improvements solubility...
High yielding, room temperature cross couplings of unactivated alkyl bromides and aryl bromides/chlorides with alkyl-9-BBN reagents has been achieved using an NHC-based catalyst (Pd-PEPPSI-IPr) via a general, functional-group tolerant easily implemented protocol.
A palladium-catalyzed crossed biaryl coupling/reduction sequence enables the formation of meta-substituted biaryls via solvent-mediated arylpalladium(II) reduction. Isotope labeling studies determined that decomposition 1,2-dimethoxyethane (DME) is indeed involved in reductive process.
Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is negative immune regulator of T cell receptor (TCR) and B signaling that primarily expressed in hematopoietic cells. Accordingly, it has been reported HPK1 loss-of-function kinase-dead syngeneic mouse models shows enhanced cytokine production as well tumor growth inhibition vivo, supporting its value an immunotherapeutic target. Herein, we present the structurally enabled discovery novel, potent, selective...
Abstract Enorm steigern lässt sich der Nutzen von Dominoprozessen, wenn ausgehend einem gemeinsamen Intermediat eine selektive Gabelung möglich ist. Hier werden erste Untersuchungen zur dualen Reaktivität Aryl‐Palladium‐Intermediaten beschrieben. Eine Vielzahl an Fluoren‐ und Phenanthrenderivaten wurde schnell effizient erhalten (siehe Schema). magnified image
Although the chemistry of arynes is well developed, some challenges still remain. The ene reaction has not gained widespread use in synthesis as a result poor yields and selectivity. A general, high yielding selective intramolecular aryne-ene described providing various benzofused carbo- heterocycles. Mechanistic data presented, rationale for resulting stereochemistry discussed.
A catalyst selection method for the optimization of an asymmetric, vinylogous Mukaiyama aldol reaction is described. large library commercially available and synthetically accessible copper–bis(oxazoline) catalysts was constructed in silico. Conformer-dependent, grid-based descriptors were calculated each catalyst, defining a chemical feature space suitable machine learning. Selection diverse subset produced initial training set 26 new bis(oxazoline) ligands that synthesized tested...
In Dominoreaktionen lässt sich Komplexität ausgehend von einfachen Materialien erzeugen. Hier wird eine Strategie für die einfache Synthese einer Vielzahl an Phenanthridinderivaten durch Dominoreaktion aus direkter Arylierung und N-Arylierung vorgestellt (siehe Schema; TMS=Trimethylsilyl, TBDMS=tert-Butyldimethylsilyl). Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not copy-edited or typeset. They made...
Inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization novel series potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type ATP-competitive physicochemical properties were integrated with CNS drug-like through combination structure-based drug...
Abstract The polyketide, 20‐deoxy elansolid B1, was prepared by a convergent strategy that relied on putative biomimetic intramolecular Diels–Alder cycloaddition (IMDA) via vinylic p ‐quinone methide intermediate to furnish the key tetrahydroindane unit. ( Z , E )‐configured triene unit constructed Pd‐catalyzed Suzuki–Miyaura and Stille cross‐coupling reactions without isomerization of any olefinic double bonds. Formation ‐methide quinone under basic conditions subsequent Michael addition...
Examples of stereoselective reactions aryne intermediates are rare in the literature. A nickel-catalyzed [2+2+2] cycloaddition 1,6-enynes with is reported. Excellent stereoselectivities were observed when a substituent adjacent to olefin moiety resulting trans- stereochemistry products. This reaction capable generating much complexity from simple and readily available starting materials. Furthermore, products possess synthetic handle which poises them for further modifications.
A combination of mutasynthesis using a mutant strain A. pretiosum blocked in the biosynthesis amino-hydroxybenzoic acid (AHBA) and semisynthesis relying on Stille cross-coupling step provided access to new ansamitocin derivatives which one was attached by thermolabile linker nanostructured iron oxide particles. When exposed an oscillating electromagnetic field resulting oxide/ansamitocin conjugate 19 heats up aqueous suspension derivative 16 is released means retro-Diels-Alder reaction. It...
The elansolids A1/A2 and B1–B3 are secondary metabolites formed by the gliding bacterium Chitinophaga sancti. They show antibacterial activity against Gram-positive bacteria. It has been proposed that biosynthesis of tetrahydroindane unit involves an intramolecular Diels–Alder cycloaddition (IMDA). To study biosynthetic proposal, influence oxygen functionality at C-20, regiochemistry allylic alcohol precursor, nature phenol group were investigated. C-20 a profound effect on outcome this...
In the context of a PRMT5 inhibitor program, we describe our efforts to develop flexible and robust strategy access tetrahydrofuro[3,4-b]furan nucleoside analogues. Ultimately, it was found that Wolfe type carboetherification from an alkenol derived d-glucofuranose diacetonide capable furnishing B-ring installing desired heteroaryl group in single step. Using this approach, key intermediate 1.3-A delivered on gram scale 62% yield 9.1:1 dr favor S-isomer. After deprotection 1.3-A, late-stage...
A catalyst selection method for the optimization of an asymmetric, vinylogous Mukaiyama aldol reaction is described. large library commercially available and synthetically accessible copper-bis(oxazoline) catalysts was constructed in silico. Conformer-dependent, grid-based descriptors were calculated each catalyst, defining a chemical feature space suitable machine learning. Selection diverse subset produced initial training set 26 novel bis(oxazoline) ligands which synthesized tested...
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The synthesis of a key spiroamine building block for medicinal chemistry program is described. Key innovations were regioselective epoxide ring opening and late-stage Pictet–Spengler reaction that was quickly optimized using Design Experiments.
Abstract If a substituent is present adjacent to the olefin moiety, good excellent trans‐selectivity in product formation observed.
Reported is the synthesis of phenanthridines 3 and benzo[c]phenanthridines 6 via a methodology previously developed by Catellani (N. Della Ca', E. Motti, M. Catellani Adv. Synth. Catal. 2008, 350, 2513) Lautens (D. A. Candito, Angew. Chem. Int. Ed. 2009, 48, 6713) coupling aryl triflates 1 4 instead halides with imines 2 5. The palladium-catalyzed domino direct arylation/N-arylation includes crucial presence norbornene proceeds from both EWG- EDGbearing various or N-silyl aldimines This was...