A5061305059- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Asymmetric Hydrogenation and Catalysis
- Catalytic C–H Functionalization Methods
- Chemical Synthesis and Analysis
- Asymmetric Synthesis and Catalysis
- Surface Chemistry and Catalysis
- Catalytic Cross-Coupling Reactions
- Innovative Microfluidic and Catalytic Techniques Innovation
- Biochemical and Molecular Research
- Synthesis and Catalytic Reactions
- Chemical Synthesis and Reactions
- HIV/AIDS drug development and treatment
- Organometallic Complex Synthesis and Catalysis
- Carbon dioxide utilization in catalysis
- Cyclopropane Reaction Mechanisms
- Advanced Synthetic Organic Chemistry
- Synthetic Organic Chemistry Methods
- Hepatitis C virus research
- Catalysis for Biomass Conversion
- Carbohydrate Chemistry and Synthesis
- Nanomaterials for catalytic reactions
- Computational Drug Discovery Methods
- Crystallography and molecular interactions
- Oxidative Organic Chemistry Reactions
Merck & Co., Inc., Rahway, NJ, USA (United States)
2015-2024
University of Illinois Chicago
2017-2023
Merck Institute for Science Education
2021
Princeton University
2014-2016
MSD (UK) Limited (United Kingdom)
2012-2013
University of Chicago
2004-2005
Breaking through the milligram floor When chemists synthesize compounds, threshold for success is at least a of product. This has been true decades—even though biochemical assays have long since descended into microgram territory—and results in part from constraints characterization methods. Buitrago Santanilla et al. present an automated dosing and protocol optimizing chemical reaction conditions on scale. allowed them to screen numerous base ligand combinations catalytic C-N bond-forming...
Overarching principles for salting-out extraction are long-established but poorly disseminated. We highlight the opportunity more widespread application of this technique using Hofmeister series as a foundational basis choosing right salt. The power approach is exemplified by aqueous workup highly water-soluble nucleoside in which use sodium sulfate allowed high recoveries without relying on back extraction.
Asymmetric hydrogenation of alkenes is one the most widely used methods for preparation single enantiomer compounds, especially in pharmaceutical and agrochemical industries. For more than four decades, precious metal complexes containing rhodium, iridium, ruthenium have been predominantly as catalysts. Here, we report rapid evaluation libraries chiral phosphine ligands with a set simple cobalt precursors. From these studies, base precatalysts discovered functionalized unfunctionalized...
Large arrays of hypothesis-driven, rationally designed experiments are powerful tools for solving complex chemical problems. Conceptual and practical aspects high-throughput experimentation discussed. A case study in the application to a key synthetic step drug discovery program subsequent optimization first large scale synthesis candidate is exemplified.
ConspectusThe structural complexity of pharmaceuticals presents a significant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made apply them complex drug intermediates. The use high-throughput experimentation (HTE) techniques offers means overcome this fundamental by facilitating the rational exploration large arrays catalysts and reaction conditions in time- material-efficient manner. Initial forays into HTE our...
Identifying catalyst activation modes that exploit one-electron chemistry and overcome associated deactivation pathways will be transformative for developing first-row transition metal catalysts with performance equal or, ideally, superior to precious metals. Here we describe a zinc-activation method compatible high-throughput reaction discovery identified scores of cobalt-phosphine combinations the asymmetric hydrogenation functionalized alkenes. An optimized prepared from (R,R)-Ph-BPE...
The asymmetric hydrogenation of cyclic alkenes lacking coordinating functionality with a C1-symmetric bis(imino)pyridine cobalt catalyst is described and has been applied to the synthesis important substructures found in natural products biologically active compounds. High activities enantioselectivities were observed substituted benzo-fused five-, six-, seven-membered alkenes. stereochemical outcome was dependent on both ring size exo/endo disposition. Deuterium labeling experiments support...
A highly active and enantioselective phosphine-nickel catalyst for the asymmetric hydrogenation of α,β-unsaturated esters has been discovered. The coordination chemistry catalytic behavior nickel halide, acetate, mixed halide-acetate with chiral bidentate phosphines have explored deuterium labeling studies, method continuous variation, nonlinear kinetic measurements provided mechanistic understanding. Activation molecular hydrogen by a trimeric (Me–DuPhos)3Ni3(OAc)5I complex was established...
Tied up nicely: A novel tandem reaction involving an intramolecular Heck with subsequent functionalization of unactivated CH bond to generate spiro-fused indane-oxindoles is described (see scheme; PMB=p-methoxybenzyl).
The unique reactivity of sulfoxonium ylides as a carbene source is described for variety X-H bond insertions, taking advantage simple, commercially available iridium catalyst. This method has applications in both intra- and intermolecular reactivity, including practical ring-expansion strategy lactams. safety stability recommend them preferable surrogates to traditional diazo ketones esters.
MK-7655 (1) is a β-lactamase inhibitor in clinical trials as combination therapy for the treatment of bacterial infection resistant to β-lactam antibiotics. Its unusual structural challenges have inspired rapid synthesis featuring an iridium-catalyzed N-H insertion and series late stage transformations designed around reactivity labile bicyclo[3.2.1]urea at core target.
The asymmetric hydrogenation of α,β-unsaturated carboxylic acids using readily prepared bis(phosphine) cobalt(0) 1,5-cyclooctadiene precatalysts is described. Di-, tri-, and tetra-substituted acrylic acid derivatives with various substitution patterns as well dehydro-α-amino were hydrogenated high yields enantioselectivities, affording chiral including Naproxen, (S)-Flurbiprofen, a d-DOPA precursor. Turnover numbers up to 200 routinely obtained. Compatibility common organic functional groups...
We report a concise, enantio- and diastereoselective route to novel nonsymmetrically substituted N-protected β,β-diaryl-α-amino acids esters, through the asymmetric hydrogenation of tetrasubstituted olefins, some most challenging examples in field. Stereoselective generation an E- or Z-enol tosylate, when combined with stereoretentive Suzuki-Miyaura cross-coupling enantioselective catalyzed by (NBD)2RhBF4 Josiphos ligand, allows for full control over two vicinal stereogenic centers. High...
The collaborative total synthesis of darobactin A, a recently isolated antibiotic that selectively targets Gram-negative bacteria, has been accomplished in convergent fashion with longest linear sequence 16 steps from d-Garner's aldehyde and l-serine. Scalable routes toward three non-canonical amino acids were developed to enable the synthesis. closure bismacrocycle was realized through sequential, halogen-selective Larock indole syntheses, where proper order cyclizations proved crucial for...
Using microscale high-throughput experimentation, an efficient, earth-abundant iron phenanthroline complex was discovered to catalyze the reductive cyclization of ortho-nitrostyrenes into indoles via nitrosoarene reactive intermediates. This method requires only 1 mol % Fe(OAc)2 and 4,7-(MeO)2phen uses phenylsilane as a convenient terminal reductant. The scope limitations were illustrated with 21 examples, investigation kinetics reaction revealed first-order behavior in catalyst silane...
The activity of bis(phosphine) iron dialkyl complexes for the asymmetric hydrogenation alkenes has been evaluated. High-throughput experimentation was used to identify suitable iron–phosphine combinations using displacement pyridine from py2Fe(CH2SiMe3)2 precatalyst formation. Preparative-scale synthesis a family also achieved both ligand substitution and salt metathesis methods. Each isolated organometallic established as tetrahedral hence high-spin ferrous compound, determined by Mössbauer...
The development of a concise asymmetric synthesis the antiviral candidate letermovir is reported, proceeding in >60% yield over total seven steps from commercially available materials. Key to effectiveness this process novel cinchonidine-based PTC-catalyzed aza-Michael reaction configure single stereocenter.
The mechanism of the asymmetric hydrogenation prochiral enamides by well-defined, neutral bis(phosphine) cobalt(0) and cobalt(II) precatalysts has been explored using(R,R)-iPrDuPhos ((R,R)-iPrDuPhos = (+)-1,2-bis[(2R,5R)-2,5-diisopropylphospholano]benzene) as a representative chiral ligand. A series (R,R)-(iPrDuPhos)Co(enamide) (enamide methyl-2-acetamidoacrylate (MAA), methyl(Z)-α-acetamidocinnamate (MAC), methyl(Z)-acetamido(4-fluorophenyl)acrylate (4FMAC)) complexes (1-MAA, 1-MAC,...
The cobalt-catalyzed asymmetric hydrogenation of dehydro-sitagliptin was studied and applied to the synthesis sitagliptin (Januvia). Catalyst discovery efforts were accelerated by application a general method for cationic bis(phosphine) cobalt η6-arene complexes. One-electron oxidation cobalt(II) dialkyl complexes in presence arenes furnished corresponding, bench-stable precatalysts, [(P–P)Co(η6-C6H6)][BAr4F]. Asymmetric utilized 0.5 mol % optimal catalyst,...
α- and β-substitution of dihydrocinnamates has been shown to increase the biological activity various drug candidates. Recently, we identified enantio- diastereopure α-methyl-β-cyclopropyldihydrocinnamates be important pharmacophores in one our discovery programs endeavored devise an asymmetric hydrogenation strategy improve access this valuable framework. We used high throughput experimentation define stereoconvergent Suzuki-Miyaura cross-coupling conditions affording...
Verknotet: Eine neuartige Tandemsequenz aus intramolekularer Heck-Reaktion und anschließender Funktionalisierung einer nichtaktivierten C-H-Bindung ergibt spirocyclisch verknüpfte Indan-Oxindole (siehe Schema; PMB=p-Methoxybenzyl). Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2008/z800549_s.pdf or from author. Please note: The publisher not responsible content functionality of any supporting supplied by authors. Any queries...
The development of a protecting group-free, 2-step synthesis 5-amino-2-hydroxymethyltetrahydropyran 1a from biorenewable Cyrene™ is described which renders access to BTK-inhibitor nemtabrutinib (2) more efficient and sustainable.
This manuscript describes a mild, functional group tolerant, and metal-free C-H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide coupling in one pot. demonstrates significant expansion of the accessible chemical space azole-2-amides, compared previously known methodologies. Key described reactivity is use silyl triflate reagents, which serve as reaction mediators deprotonation stabilizers (otherwise unstable) azole carboxylic acid intermediates. A...
A library of iridium and rhodium phosphine catalysts have been screened for the double-asymmetric hydrogenation 2,6-di-(1-phenylethenyl)-4-methylaniline to produce C2-symmetric aniline precursor N-heterocyclic carbenoid CuIPhEt. The best catalyst produced desired enantiomer in 98.6% selectivity. This rare example a highly selective 1,1-diaryl olefin enables four-step asymmetric synthesis phenylethyl imidazolium ion (IPhEt) from p-toluidine phenylacetylene its conversion hydrosilylation