A5035747535- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Analysis
- Catalytic C–H Functionalization Methods
- Asymmetric Synthesis and Catalysis
- Microbial Natural Products and Biosynthesis
- Synthesis and Catalytic Reactions
- Synthetic Organic Chemistry Methods
- Asymmetric Hydrogenation and Catalysis
- Advanced biosensing and bioanalysis techniques
- Crystallography and molecular interactions
- Oxidative Organic Chemistry Reactions
- DNA and Nucleic Acid Chemistry
- Catalytic Cross-Coupling Reactions
- Click Chemistry and Applications
- Alkaloids: synthesis and pharmacology
- Cyclopropane Reaction Mechanisms
- RNA and protein synthesis mechanisms
- Sulfur-Based Synthesis Techniques
- Carbohydrate Chemistry and Synthesis
- Radical Photochemical Reactions
- Peptidase Inhibition and Analysis
- Cyclization and Aryne Chemistry
- Organoboron and organosilicon chemistry
- Erythrocyte Function and Pathophysiology
Scripps Institution of Oceanography
2019-2025
Scripps Research Institute
2010-2023
Torrey Pines Institute For Molecular Studies
2019-2022
Scripps (United States)
2022
University of California, San Diego
2007-2011
Philadelphia University
2010
Harvard University
2000
A nickel-catalyzed conjunctive cross-coupling between non-conjugated alkenes, aryl iodides, and alkylzinc reagents is reported. Excellent regiocontrol achieved utilizing an 8-aminoquinoline directing group that can be readily cleaved to unmask net β,γ-dicarbofunctionalized carboxylic acid products. Under optimized conditions, both terminal internal alkene substrates provided the corresponding alkyl/aryl difunctionalized products in moderate excellent yields. The methodology developed herein...
The development of an enantioselective allylic alcohol dichlorination catalyzed by dimeric cinchona alkaloid derivatives and employing aryl iododichlorides as chlorine sources is reported. Reaction optimization, exploration the substrate scope, a model for stereoinduction are presented.
Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice organic synthesis. After placing this work in proper historical context, Article reports development, full scope, a mechanistic picture for strikingly different way forging such functional groups. Thus, carboxylic acids, once converted redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other derivatives (to...
Abstract Facile synthesis of C‐terminal thioesters is integral to native chemical ligation (NCL) strategies for protein synthesis. We introduce a new method mild peptide activation, which leverages solid‐phase (SPPS) on an established resin linker and classical heterocyclic chemistry convert hydrazides into their corresponding via acyl pyrazole intermediate. Peptide hydrazides, synthesized trityl chloride resins, can be activated in solution with stoichiometric acetyl acetone (acac), readily...
DNA Encoded Libraries have proven immensely powerful tools for lead identification. The ability to screen billions of compounds at once has spurred increasing interest in DEL development and utilization. Although provides access libraries unprecedented size diversity, the idiosyncratic hydrophilic nature tag severely limits scope applicable chemistries. It is known that biomacromolecules can be reversibly, noncovalently adsorbed eluted from solid supports, this phenomenon been utilized...
Abstract Samariumdiiodid (SmI 2 ) hat nach seiner Einführung vor mehr als drei Jahrzehnten durch Henri Kagan zunehmend Verwendung in der chemischen Synthese gefunden. Dieses Ein‐Elektronen‐Reduktionsmittel ist besonders nützlich für C‐C‐Bindungsknüpfungen, wie sie unter anderem auch bei Totalsynthesen erforderlich sind. In diesem Aufsatz werden ausgewählte Anwendungsbeispiele von SmI Totalsynthese vorgestellt, wobei neuartige Umwandlungen und mechanistische Überlegungen hervorgehoben werden....
Significance Combinatorial synthesis via DNA encoded library (DEL) has evolved as a technology of great importance in drug discovery. However, the idiosyncratic aqueous, dilute, DNA-sensitive parameters and infinitesimal scale this system present new challenges for traditional organic reactions. A detailed protocol aiding transition from reactions to with DNA-bound molecules was developed using tactical combination kinetic analysis reaction screening. As an example, venerable Giese addition...
The emerging use of covalent ligands as chemical probes and drugs would benefit from an expanded repertoire cysteine-reactive electrophiles for efficient diverse targeting the proteome. Here we endogenous electrophile sensor mammalian cells, KEAP1-NRF2 pathway, to discover electrophilic fragments a reporter-based screen NRF2 activation. This strategy identified series 2-sulfonylpyridines that selectively react with biological thiols via nucleophilic aromatic substitution (SNAr). By tuning...
A method to achieve enantioselective 1,4-hydroboration of terminal and internal enynes access allenyl boronates under CuH catalysis is described. The reaction typically proceeds in a highly stereoselective manner tolerates an array synthetically useful functional groups. utility the enantioenriched boronate products demonstrated through several representative downstream derivatizations.
An asymmetric 1,2-dicarbofunctionalization of unactivated alkenes with aryl iodides and aryl/alkenylboronic esters under nickel/bioxazoline catalysis is disclosed. A wide array alkenyl nucleophiles are tolerated, furnishing the products in good yield high enantioselectivity. In addition to terminal alkenes, 1,2-disubstituted internal participate reaction, establishing two contiguous stereocenters diastereoselectivity moderate combination experimental computational techniques shed light on...
From the enediyne class of antitumor antibiotics, uncialamycin is among rarest and most potent, yet one structurally simpler, making it attractive for chemical synthesis potential applications in biology medicine. In this article we describe a streamlined practical enantioselective total that amenable to novel analogues renders natural product readily available biological drug development studies. Starting from hydroxy- or methoxyisatin, features Noyori reduction, Yamaguchi...
A two-step degradation–reconstruction approach to the carbon-14 radiolabeling of alkyl carboxylic acids is presented. Simple activation via redox-active ester formation was followed by nickel-mediated decarboxylative carboxylation afford a range complex compounds with ample isotopic incorporations for drug metabolism and pharmacokinetic studies. The practicality operational simplicity protocol were demonstrated its use in an industrial setting.
A palladium(II)-catalyzed enantioselective α-alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL-derived phosphoric acid as the source stereoinduction, and cleavable bidentate directing group appended to alkene control regioselectivity stabilize nucleopalladated alkylpalladium(II) intermediate in catalytic cycle. wide range were found be compatible under optimal conditions afford products bearing α,α-disubstituted α-amino-acid derivatives...
DNA-compatible C(sp<sup>3</sup>)–H activation reactions of aliphatic carboxylic acids, amides, and ketones were developed for efficient access to DEL synthesis.
Previously, we reported the creation of a semi-synthetic organism (SSO) that stores and retrieves increased information by virtue stably maintaining an unnatural base pair (UBP) in its DNA, transcribing corresponding nucleotides into codons anticodons mRNAs tRNAs, then using them to produce proteins containing noncanonical amino acids (ncAAs). Here report systematic extension effort optimize SSO exploring variety deoxy- ribonucleotide analogues. Importantly, this includes first vivo...
DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to of unprecedented size, their production has been hampered by idiosyncratic needs encoding tag relegating compatible chemistry dilute aqueous environments. Recently reversible adsorption solid support (RASS) demonstrated promising method expand reactivity using standard organic synthesis protocols. Here we demonstrate suite...
A flurry of recent research has centered on harnessing the power nickel catalysis in organic synthesis. These efforts have been bolstered by contemporaneous development well-defined (pre)catalysts with diverse structure and reactivity. In this report, we present ten different bench-stable, 18-electron, formally zero-valent nickel-olefin complexes that are competent pre-catalysts various reactions. Our investigation includes preparations novel, bench-stable Ni(COD)(L)...
Transthyretin (TTR) is a natively tetrameric thyroxine transporter found in blood and cerebrospinal fluid whose misfolding aggregation causes transthyretin amyloidosis. A rational drug design campaign identified the small molecule tafamidis (Vyndaqel/Vyndamax) as an effective stabilizer of native TTR fold, this inhibitor regulatory agency-approved for treatment Despite 50 years structural studies on triumph structure-based design, there remains notable dearth information available to...