A5014774420- Catalytic C–H Functionalization Methods
- Cyclopropane Reaction Mechanisms
- Radical Photochemical Reactions
- Fluorine in Organic Chemistry
- Oxidative Organic Chemistry Reactions
- Chemical Synthesis and Analysis
- Catalytic Alkyne Reactions
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Asymmetric Hydrogenation and Catalysis
- Click Chemistry and Applications
- Synthetic Organic Chemistry Methods
- Inorganic Fluorides and Related Compounds
- Chemical Reactions and Isotopes
- Synthesis and Reactions of Organic Compounds
- Crystallography and molecular interactions
- Catalytic Cross-Coupling Reactions
- Veterinary medicine and infectious diseases
- Protein Tyrosine Phosphatases
- Organoboron and organosilicon chemistry
- Adrenal and Paraganglionic Tumors
- 14-3-3 protein interactions
- Asymmetric Synthesis and Catalysis
- Sulfur-Based Synthesis Techniques
- Synthesis and Biological Evaluation
Merck & Co., Inc., Rahway, NJ, USA (United States)
2019-2024
Boston University
2024
Merck (Japan)
2022
Chinese Academy of Medical Sciences & Peking Union Medical College
2019
Peking Union Medical College Hospital
2019
Yale University
2014-2018
University of New Haven
2015-2018
Peking University
2012-2015
Beijing National Laboratory for Molecular Sciences
2012-2014
A general method for the hydropyridylation of unactivated alkenes is described. The transformation connects metal-mediated hydrogen atom transfer to and Minisci addition reactions. reaction proceeds under mild conditions with high site-selectivities allows construction tertiary quaternary centers from simple alkene starting materials.
The replacement of aryl rings with saturated carbocyclic structures has garnered significant interest in drug discovery due to the potential for improved pharmacokinetic properties upon substitution. In particular, 1,3-difunctionalized bicyclo[1.1.1]pentanes (BCPs) have been widely adopted as bioisosteres parasubstituted arene rings, appearing a number lead pharmaceutical candidates. However, despite value 2-substituted BCPs replacements ortho- or meta-substituted general and rapid syntheses...
Abstract Within a medicinal chemist's toolbox, one of the most effective strategies to improve overall properties biologically active compound is bioisosteric replacement. Ever since first example replacing benzene with bicyclo[1.1.1]pentane (BCP) group was published in late 1990s, [1] chemistry community has continually been expanding scope such phenyl replacements. Recent interest from academia focused on novel synthetic access C( sp 3 )‐rich bicyclic hydrocarbons expanded ring sizes....
Copper-catalyzed cross-coupling of N-tosylhydrazones with trialkylsilylethynes leads to the formation C(sp)-C(sp(3)) bonds. Cu carbene migratory insertion is proposed play key role in this transformation.
A general method for the selective hydrogenation of alkenyl halides to alkyl is described. Fluoro, chloro, bromo, iodo, and gem-dihaloalkenes are viable substrates transformation. The selectivity consistent with reduction by a hydrogen atom transfer pathway.
We report the first reductive coupling of unactivated alkenes with N-methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts under hydrogen atom transfer (HAT) conditions, an expanded scope for pyridinium salts. N-Methoxy are accessible in 1–2 steps from commercial arenes or arene N-oxides (25–99%). imidazolium three amines (50–85%). In total 36 discrete methoxyheteroarenium bearing electron-donating, electron-withdrawing, alkyl, aryl, halogen, haloalkyl substituents were...
The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, tert-butyl, and alkynyl fragments order improve physicochemical properties. However, bceause of the difficulty synthesis, most BCP analogues prepared only bear 1,3-"para"-substituents. We report first selective synthesis 2,2-difluorobicyclo[1.1.1]pentanes via difluorocarbene insertion into bicyclo[1.1.0]butanes. Moreover, this methodology should inspire future studies on other...
Abstract This Minireview focuses on selected topics in the syntheses of bicyclo[1.1.1]pentane (BCP) analogues. A brief historical introduction was included. The content covers various synthetic routes 1‐substituted and 1,3‐disubstituted BCPs. Selective examples synthetically useful building blocks are summarized for each category organic chemists’ medicinal reference. compare‐and‐contrast analysis is also applied to evaluate these demonstrate progress strategic functional group...
It is shown that the reduction of alkenes by hydrogen atom transfer provides selectivities are distinct from classical hydrogenation catalysts. The first alkene hydrobromination, hydroiodination, and hydroselenylation reactions proceed processes also reported.
Oncogenic mutations in the
Three's a crowd: Tri- and tetrasubstituted allyl allenes can be easily accessed by this Cu(I)-catalyzed three-component coupling reaction of N-tosylhydrazones, terminal alkynes, halides. The proceeds through mechanism involving copper carbene migratory insertion.
Ethyne is employed as coupling partner in copper-mediated cross-coupling reactions with N-tosylhydrazones and α-diazoacetate, leading to the development of a new synthetic method for terminal allenes. With this novel method, allenes were obtained good yields excellent functional group tolerance. Copper carbene migratory insertion proposed key step these transformations.
Compared to the abundance of methodologies accessing 1-substituted and 1,3-disubstuted bicyclo[1.1.1] pentanes (BCPs), synthetic accessibility BCPs with substitutions at methylene position has been limited. Herein, we report a selective synthesis 1-dialkylamino-2-alkylbicyclo[1.1.1]pentanes from prefunctionalized starting materials. We also achieved further functionalizations these 1,2-disubstituted developed compounds minimum necessity chromatographic purifications 1,3-dichloroacetone....
Carbohydrates constitute an important class of biologically relevant natural products. Among the synthetic glycomimetics, C-glycosides are particularly interesting due to their chemical and metabolic stability toward acidic enzymatic hydrolysis at anomeric position. The stereochemical outcomes traditional methodologies access rely heavily on substrate control. Herein, we report a novel strategy diverse with precise control position via formal functional group deletion, where both α-...
Bicyclo[1.1.1]pentanes (BCP's) have been applied in medicinal chemistry as bioisosteres for phenyl groups. In pursuit of novel BCP analogs, we reported the first synthesis 2,2‐difluorobicyclo[1.1.1]pentanes (BCP–F 2 ) 2019. Herein, detail extension our effort BCP‐F analogs.
Cobalt bis(acetylacetonate) is shown to mediate hydrogen atom transfer a broad range of functionalized alkenes; in situ oxidation the resulting alkylradical intermediates, followed by hydrolysis, provides expedient access ketones and esters. By modification alcohol solvent, different alkyl ester products may be obtained. The method compatible with number functional groups including alkenyl halides, sulfides, triflates, phosphonates mild practical alternative Tamao–Fleming vinylsilanes...
Antibiotics derived from the diterpene fungal metabolite (+)-pleuromutilin (1) are useful agents for treatment Gram-positive infections in humans and farm animals. Pleuromutilins elicit slow rates of resistance development minimal cross-resistance with existing antibiotics. Despite efforts aimed at producing new derivatives by semisynthesis, modification tricyclic core is underexplored, part due to a limited number functional group handles. Herein, we report methods selectively functionalize...
We describe the first general transition-metal-free synthesis of gem-diboromethyl-substituted bicyclo[1.1.1]pentane (BCP) and other related C(sp3)-rich carbocyclic benzene bioisosteres from their corresponding p-tosylhydrazones. These novel functionalized demonstrated unique reactivities toward palladium-catalyzed C(sp2)–C(sp3) cross couplings. The overall transformation can be applied to relatively complex substrates with potential utility in drug discovery.
Described herein is our effort toward achieving the decarboxylative functionalization of 2,2-difluorobicyclo[1.1.1]pentane (BCP-F2) building blocks. When compared with nonfluorinated bicyclo[1.1.1]pentane (BCP) analogues, we discovered divergent reactivities. This first successful coupling BCP-F2 blocks reported via photoredox mechanism.
We show that cobalt bis(acetylacetonate) [Co(acac)2], tert-butyl hydroperoxide (TBHP), and triethylsilane (Et3SiH) constitute an inexpensive, general, practical reagent combination to initiate a broad range of Markovnikov-selective alkene hydrofunctionalization reactions. These transformations are believed proceed by cobalt-mediated hydrogen atom transfer (HAT) the substrate, followed interception resulting alkyl radical intermediate with SOMOphile. In addition, we report first reductive...
We report our efforts toward achieving C(sp2)-C(sp3) coupling reactions with 2,2-difluorobicyclo[1.1.1]pentane (BCP-F2) building blocks. By comparing the reactivities of matching pairs bicyclo[1.1.1]pentane (BCP) and BCP-F2 analogues, we discovered that Barluenga reaction was only cross-coupling protocol translated well between two structural motifs in contrast to other reported protocols. In this chemistry, a bearing tosylhydrazone functional group is cross-coupled an arylboronic acid....
The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity. Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well-suited since the ring strain imparts high bond strength thus metabolic stability on its C–H bonds. Cubane is ideal bioisostere it provides closest geometric match to benzene. At present, however, all cubanes design, like almost...