A5028770904- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Analysis
- Fluorine in Organic Chemistry
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Synthesis and Catalytic Reactions
- Radical Photochemical Reactions
- Asymmetric Hydrogenation and Catalysis
- Catalytic C–H Functionalization Methods
- Oxidative Organic Chemistry Reactions
- Synthesis and Reactions of Organic Compounds
- Computational Drug Discovery Methods
- Molecular spectroscopy and chirality
- Chemical Reactions and Isotopes
- Sulfur-Based Synthesis Techniques
- Chemical Reaction Mechanisms
- Carbohydrate Chemistry and Synthesis
- Synthetic Organic Chemistry Methods
- Click Chemistry and Applications
- Axial and Atropisomeric Chirality Synthesis
- Innovative Microfluidic and Catalytic Techniques Innovation
- Advanced Chemical Physics Studies
- Synthesis and Biological Evaluation
- Cancer therapeutics and mechanisms
- Advanced Synthetic Organic Chemistry
Merck & Co., Inc., Rahway, NJ, USA (United States)
2018-2025
University of California, Los Angeles
2009-2020
Merck Institute for Science Education
2020
University of St Andrews
2012-2015
University of California System
2014
Brandeis University
2014
Los Angeles City College
2014
Imperial College London
2011
Scripps Research Institute
2011
University of Oxford
2007-2010
ConspectusModern density functional theory and powerful contemporary computers have made it possible to explore complex reactions of value in organic synthesis. We describe recent explorations mechanisms origins stereoselectivities with calculations. The specific functionals basis sets that are routinely used computational studies organometallic our group described, followed by uncovered the stereocontrol catalyzed (1) vicinal diamines, including cinchona alkaloid-derived primary amines, (2)...
Shuffling nitrogen with a light push Manipulation of carbon–nitrogen rings is integral to the synthesis numerous pharmaceutical and agrochemical compounds. Jurczyk et al . report that photoexcitation carbonyl-substituted cyclic amines can shift from inside outside ring framework. The reaction appears proceed through 1,5-hydrogen electronically excited carbonyl, which sets in motion subsequent carbon–carbon bonding rearrangements. Several oxygen sulfur heterocycles were applicable as well....
Accessing hindered amines, particularly primary amines α to a fully substituted carbon center, is synthetically challenging. We report an electrochemical method access such starting from benchtop-stable iminium salts and cyanoheteroarenes. A wide variety of heterocycles (pyridine, pyrimidine, pyrazine, purine, azaindole) can be utilized in the cross-coupling reaction, including those with halide, trifluoromethyl, ester, amide, or ether group, heterocycle, unprotected alcohol alkyne....
Primary amines are an important structural motif in active pharmaceutical ingredients (APIs) and intermediates thereof, as well members of ligand libraries for either biological or catalytic applications. Many chemical methodologies exist amine synthesis, but the direct synthesis primary with a fully substituted α carbon center is underdeveloped area. We report method which utilizes photoredox catalysis to couple readily available O-benzoyl oximes cyanoarenes synthesize α-carbons. also...
The mechanisms and selectivities of the cycloadditions tropone to dimethylfulvene have been investigated with M06-2X B3LYP-D3 density functional theory (DFT) calculations quasi-classical direct molecular dynamics simulations. originally proposed reaction mechanism (Houk) involves a highly peri-, regio-, stereoselective [6F + 4T] cycloaddition [4π] [6π], followed by [1,5] hydrogen shift, and, finally, second [6 4] [6π] cyclopentadiene moiety [4π]. Paddon-Row Warrener an alternative mechanism:...
Organic electrosynthesis is a rapidly evolving field, providing powerful methods to assemble targets of interest in organic synthesis. Concerns around the scalability electrochemical remain biggest reason behind their scarce implementation manufacturing routes for pharmaceutical industry. To fill this gap, we report workflow describing key reaction parameters toward successful scale-up an electrosynthetic method from milligram kilogram scale. The used demonstrate our and flow setting was...
Employment of a combination an organophotoredox catalyst with Wilkinson's (Rh(PPh3)3Cl) has given rise to unprecedented method for hydrogen-isotope exchange (HIE) aliphatic C(sp3)-H bonds complex pharmaceuticals using T2 gas directly. catalyst, commonly used catalytic hydrogenations, was exploited as precatalyst activation D2 or and hydrogen atom transfer. In this combined methodology mechanistic study, we demonstrate that by coupling photocatalysis Rh catalysis, carbon-centered radicals...
The Diels−Alder reactions of a series silyloxydienes and silylated dienes with acyclic α,β-unsaturated ketones N-acyloxazolidinones have been investigated. endo/exo stereochemical outcome is strongly influenced by the substitution pattern reactants. High exo selectivity was observed when termini diene dienophile involved in shorter forming bonds were both substituted, while normal endo preference found otherwise. exo-selective asymmetric using Evans' oxazolidinone chiral auxiliary furnished...
The intramolecular aldol condensation of 4-substituted heptane-2,6-diones leads to chiral cyclohexenones. origins the enantioselectivities this reaction, disclosed by List et al. using a cinchona alkaloid-derived primary amine (cinchona amine) organocatalyst, have been determined with dispersion-corrected density functional theory (DFT). stereocontrol hinges on chair preference substrate–enamine intermediate and conformational preferences hydrogen-bonded nine-membered transition state...
Density functional theory (DFT) benchmark studies of 1H and 13C NMR chemical shifts often yield differing conclusions, likely due to non-optimal test molecules non-standardized data acquisition. To address this issue, we carefully selected measured for 50 structurally diverse small organic containing atoms from only the first two rows periodic table. Our dataset, DELTA50, was used calculate linear scaling factors evaluate accuracy 73 density functionals, 40 basis sets, 3 solvent models,...
An electrochemical, nickel-catalyzed reductive coupling of alkylpyridinium salts and aryl halides is reported. High-throughput experimentation (HTE) was employed for rapid reaction optimization evaluation a broad scope pharmaceutically relevant structurally diverse halides, including complex drug-like substrates. In addition, the transformation compatible with both primary secondary distinct conditions. Mechanistic insights were critical to enhance efficiency using salts. Systematic...
N -Cyano iminophosphoranes are synthesized using electrochemistry and evaluated as ligands in various nickel-catalysed reactions. The electronic structural properties of these were studied both computationally experimentally.
The origin of selectivity in the α-fluorination cyclic ketones catalyzed by cinchona alkaloid-derived primary amines is determined with density functional calculations. chair preference a seven-membered ring at fluorine transfer transition state key determining sense and level enantiofacial selectivity.
Derivatives of 4-hydroxyproline with a series hydrophobic groups in well-defined orientations have been tested as catalysts for the aldol reactions. All modified proline carry out intermolecular reaction water and provide high diastereoselectivity enantioselectivity. Modified prolines aromatic syn to carboxylic acid are better than those small (1a is 43.5 times faster 1f). Quantum mechanical calculations transition structures, TS-1a(water) TS-1f(water), that support hypothesis stabilizing...
Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types cancers. However, low overall response rates often hamper the broad utility potential these breakthrough therapies. Combination therapy strategies currently under intensive investigation in clinic, including combination PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report discovery a class heme-binding featuring unique amino-cyclobutarene motif, which was discovered...
A novel, highly diastereoselective, and metal-free synthesis of multisubstituted piperidines via an SN1 approach is reported in this study. The method allows for the preparation functionalized compounds with exceptional diastereomeric selectivities consistently reproducible yields. These are significant interest due to their remarkable biological activities toward influenza endonuclease.
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...
A combined experimental NMR and DFT computational analysis of molnupiravir, an orally dosed antiviral effective for treatment patients with COVID-19, determined that the molecule primarily exists as oxime tautomer both in solution solid state. Both Z E stereoisomers were observed various solvents, being major form, consistent calculations. An amine form was not detected directly, but results strongly suggest it transient intermediate responsible interconversion isomers solution. The...
The screening of chemical libraries is an essential starting point in the drug discovery process. While some researchers desire a more thorough targets against narrower scope molecules, it not uncommon for diverse sets to be favored during early stages discovery. However, cost burden associated with potential drawbacks if particular areas space are needlessly overrepresented. To facilitate triaged sampling and other collections we have developed Dedenser, tool downsampling clusters. Dedenser...
Experimental and computational studies probing the nature of intermediates in α-amination aldehydes catalyzed by prolinate salts support an enamine carboxylate intermediate stereodetermining step.
Quantum mechanical calculations reveal the origin of diastereo- and enantioselectivities aldol reactions between aldehydes catalyzed by histidine, differences related proline. A stereochemical model that explains both sense high levels experimentally observed stereoselectivity is proposed. The computations suggest imidazolium carboxylic acid functionalities histidine are viable hydrogen-bond donors can stabilize cyclic aldolization transition state. proposed to arise from minimization gauche...
A new pericyclic cascade is proposed for the chiral auxiliary-controlled synthesis of 3,3-disubstituted oxindoles from nitrones and ketenes. The remarkable acyclic 1,6-stereochemical induction, hitherto unexplained, rationalized by a stereoselective 3+2 cycloaddition step, which installs stereochemistry, chirality transfer step facilitated hetero-[3,3]-sigmatropic rearrangement (see picture; PG=protecting group). Detailed facts importance to specialist readers are published as "Supporting...
The origins of stereoselectivity the Nazarov reactions α-hydroxydivinylketones catalyzed by a vicinal thiourea-primary amine first reported Tius have been explored with density functional theory. electrocyclization transition structures in which thiourea group catalyst donates two hydrogen bonds to keto carbonyl reactant and primary accepts bond from hydroxyl modeled. enantiomeric structures, are conventionally described absolute sense conrotation dienone termini ("clockwise" or...