36215-20-0Relevant articles and documents
Dramatic Effect of γ-Heteroatom Dienolate Substituents on Counterion Assisted Asymmetric Anionic Amino-Cope Reaction Cascades
Das, Pradipta,Delost, Michael D.,Qureshi, Munaum H.,Bao, Jianhua,Fell, Jason S.,Houk, Kendall N.,Njardarson, Jon T.
supporting information, p. 5793 - 5804 (2021/05/07)
We report a dramatic effect on product outcomes of the lithium ion enabled amino-Cope-like anionic asymmetric cascade when different γ-dienolate heteroatom substituents are employed. For dienolates with azide, thiomethyl, and trifluoromethylthiol substituents, a Mannich/amino-Cope/cyclization cascade ensues to form chiral cyclohexenone products with two new stereocenters in an anti-relationship. For fluoride-substituted nucleophiles, a Mannich/amino-Cope cascade proceeds to afford chiral acyclic products with two new stereocenters in a syn-relationship. Bromide- and chloride-substituted nucleophiles appear to proceed via the same pathway as the fluoride albeit with the added twist of a 3-exo-trig cyclization to yield chiral cyclopropane products with three stereocenters. When this same class of nucleophiles is substituted with a γ-nitro group, the Mannich-initiated cascade is now diverted to a β-lactam product instead of the amino-Cope pathway. These anionic asymmetric cascades are solvent- and counterion-dependent, with a lithium counterion being essential in combination with etheral solvents such as MTBE and CPME. By altering the geometry of the imine double bond from E to Z, the configurations at the R1 and X stereocenters are flipped. Mechanistic, computational, substituent, and counterion studies suggest that these cascades proceed via a common Mannich-product intermediate, which then proceeds via either a chair (X = N3, SMe, or SCF3) or boat-like (X = F, Cl, or Br) transition state to afford amino-Cope-like products or β-lactam in the case of X = NO2.
4-Aryl Pyrrolidines as a Novel Class of Orally Efficacious Antimalarial Agents. Part 1: Evaluation of 4-Aryl- N-benzylpyrrolidine-3-carboxamides
Meyers, Marvin J.,Liu, Jianguang,Xu, Jing,Leng, Fang,Guan, Jiantong,Liu, Zhijun,McNitt, Sarah A.,Qin, Limei,Dai, Linglin,Ma, Hongwei,Adah, Dickson,Zhao, Siting,Li, Xiaofen,Polino, Alex J.,Nasamu, Armiyaw S.,Goldberg, Daniel E.,Liu, Xiaorong,Lu, Yongzhi,Tu, Zhengchao,Chen, Xiaoping,Tortorella, Micky D.
supporting information, p. 3503 - 3512 (2019/03/29)
Identification of novel chemotypes with antimalarial efficacy is imperative to combat the rise of Plasmodium species resistant to current antimalarial drugs. We have used a hybrid target-phenotype approach to identify and evaluate novel chemotypes for malaria. In our search for drug-like aspartic protease inhibitors in publicly available phenotypic antimalarial databases, we identified GNF-Pf-4691, a 4-aryl-N-benzylpyrrolidine-3-carboxamide, as having a structure reminiscent of known inhibitors of aspartic proteases. Extensive profiling of the two terminal aryl rings revealed a structure-activity relationship in which relatively few substituents are tolerated at the benzylic position, but the 3-aryl position tolerates a range of hydrophobic groups and some heterocycles. Out of this effort, we identified (+)-54b (CWHM-1008) as a lead compound. 54b has EC50 values of 46 and 21 nM against drug-sensitive Plasmodium falciparum 3D7 and drug-resistant Dd2 strains, respectively. Furthermore, 54b has a long half-life in mice (4.4 h) and is orally efficacious in a mouse model of malaria (qd; ED99 ～ 30 mg/kg/day). Thus, the 4-aryl-N-benzylpyrrolidine-3-carboxamide chemotype is a promising novel chemotype for malaria drug discovery.
Novel multi-dentate phosphines for Pd-catalyzed alkoxycarbonylation of alkynes promoted by H2O additive
Yang, Da,Liu, Lei,Wang, Dong-Liang,Lu, Yong,Zhao, Xiao-Li,Liu, Ye
, p. 236 - 244 (2019/02/19)
A series of novel multi (bi-/tri-/tetra-)-dentate phosphines with good robustness against water and oxygen were synthesized and fully characterized. It was found that the developed ionic tri-dentate phosphine (L2′) enabled Pd-catalyzed alkoxycarbonylation of alkynes most efficiently while H2O was used as an additive instead of acid. As for L2′, its unique steric configuration with two types of potential P-P chelation modes (P?P distance of 4.31 ? and 4.36 ? respectively) to Pd-centre rendered the corresponding Pd-catalyst high activity and good stability for alkoxycarbonylation of alkynes. The in situ FT-IR analysis also verified that the formation and stability of Pd–H active species were greatly facilitated with the presence of L2′ as well as H2O additive. In addition, as an ionic phosphine, L2′ based PdCl2(MeCN)2 system immobilized in RTIL of [Bmim]NTf2 could be recycled for 7 runs without obvious activity loss or metal leaching.
Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections
Wei, Hanwen,Mao, Fei,Ni, Shuaishuai,Chen, Feifei,Li, Baoli,Qiu, Xiaoxia,Hu, Linghao,Wang, Manjiong,Zheng, Xinyu,Zhu, Jin,Lan, Lefu,Li, Jian
, p. 235 - 251 (2018/01/17)
Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H2O2 killing and human whole blood killing assays proved 21b could sensitize S. aureus to be killed under oxidative stress conditions. Notably, the murine study in vivo validated the efficacy of 21b against pigmented S. aureus Newman, vancomycin-intermediate S. aureus Mu50 and linezolid-resistant S. aureus NRS271.
A highly efficient Pd/CuI-catalyzed oxidative alkoxycarbonylation of α-olefins to unsaturated esters
Maffei, Mathias,Giacoia, Gabriele,Mancuso, Raffaella,Gabriele, Bartolo,Motti, Elena,Costa, Mirco,Della Ca’, Nicola
, p. 435 - 443 (2016/12/16)
A new protocol for the alkoxycarbonylation of α-olefins to the corresponding unsaturated esters has been developed. Differently substituted styrenes were selectively converted to cinnamate derivatives, via C[sbnd]H bond functionalization. Various palladium sources, including heterogeneous ones, in combination with CuI exhibited a high catalytic efficiency using oxygen as the most cheap oxidant. Monocarbonylated products were obtained in good yields and high chemoselectivity working with a low CO pressure (2 atm) and an excess of air (35 atm) avoiding in this way explosion risks. Commercial cinnamate derivatives were prepared in good to excellent yields by this very simple one-pot procedure.
An Abnormal N-Heterocyclic Carbene-Based Palladium Dimer: Aqueous Oxidative Heck Coupling under Ambient Temperature
Hota, Pradip Kumar,Vijaykumar, Gonela,Pariyar, Anand,Sau, Samaresh Chandra,Sen, Tamal K.,Mandal, Swadhin K.
, p. 3162 - 3170 (2015/11/03)
Herein we report the synthesis of a new abnormal N-heterocyclic carbene (aNHC)-based ligand and its use in synthesizing an acetate bridged C-H activated palladium dimer (1). In complex 1, the carbene ligand displays an abnormal mode of binding with the palladium(II) ion. We used complex 1 as a catalyst for the oxidative Heck coupling reaction of arylboronic acids with electron-deficient as well as electron-rich olefins at ambient temperature in water to produce selectively the β-arylated products in good to excellent yields.
Scope and Limitation of the Microwave-Assisted Catalytic Wittig Reaction
Hoffmann, Marcel,Deshmukh, Sunetra,Werner, Thomas
, p. 4532 - 4543 (2015/07/27)
We have developed a microwave-assisted catalytic Wittig reaction. In this paper, we give full account of the scope and limitations of this reaction. A screening of various commercially available phosphine oxides as precatalysts revealed Bu3P=O to be the most promising candidate. We tested 10 silanes for the in situ reduction of the phosphine oxide to generate Bu3P as the actual catalyst. Different epoxides were tested as masked bases. In this context, cyclohexene oxide as well as butylene oxide proved to be suitable. The reaction could be carried out at 125 C, but higher yields and E/Z selectivities were obtained at 150 °C. Under the optimised reaction conditions, more than 40 examples for the conversion of various aldehydes into the corresponding alkenes are reported. The products were obtained in yields of up to 88 with high E selectivities. Moreover, we also describe the further screening of several chiral phosphines as catalysts for the microwave-assisted enantioselective catalytic Wittig reaction. The scope and limitations of the microwave-assisted catalytic Wittig reaction have been evaluated with respect to the catalyst, silane, solvent, reaction conditions, and substrates.
Phospholane-catalyzed wittig reaction
Werner, Thomas,Hoffmann, Marcel,Deshmukh, Sunetra
, p. 3286 - 3295 (2015/05/20)
We identified 2-phenylisophosphindoline 2-oxide as a suitable and potentially tunable catalyst for the catalytic Wittig reaction of aldehydes with activated organohalides. This catalyst was obtained by a straightforward two-step synthesis. Trimethoxysilane proved to be an efficient reducing agent for the in situ generation and regeneration of the catalyst from the corresponding phosphane oxide. Sodium carbonate was identified as a suitable base for the transformation. It is noteworthy that the particle size of the sodium carbonate had a tremendous effect on the outcome of the reaction. Under the optimized reaction conditions, 23 aldehydes were converted into the corresponding alkenes in high isolated yields of up to 88%. Moreover, an asymmetric catalytic Wittig reaction was performed for the desymmetrization of a prochiral diketone.
First Microwave-Assisted Catalytic Wittig Reaction
Werner, Thomas,Hoffmann, Marcel,Deshmukh, Sunetra
supporting information, p. 6873 - 6876 (2016/02/19)
We introduce a novel catalytic Wittig reaction based on an inexpensive and readily available phosphane oxide as a precatalyst. The performance of the reaction under microwave irradiation led to significantly improved yields and reaction rates relative to those obtained under conventional heating. Moreover, herein we enclose the first example of the asymmetric catalytic Wittig reaction based on a chiral phosphane as the catalyst.
Palladium-catalyzed alkoxycarbonylation of terminal alkenes to produce α,β-unsaturated esters: The key role of acetonitrile as a ligand
Malkov, Andrei V.,Derrien, Nolwenn,Barlog, Maciej,Kocovsky, Pavel
supporting information, p. 4542 - 4547 (2014/05/06)
A mild protocol has been developed for the PdII-catalyzed alkoxycarbonylation of terminal olefins to produce α,β-unsaturated esters with a wide range of substrates. Key features are the use of MeCN as solvent (and/or ligand) to control the reactivity of the intermediate Pd complexes and the combination of CO with O2, which facilitates the CuII-mediated reoxidation of the Pd0 complex to Pd II and prevents double carbonylation. Acetonitrile is the key! A mild protocol has been developed for the PdII-catalyzed alkoxycarbonylation of terminal olefins to produce α,β-unsaturated esters with a wide range of substrates (see scheme). Key features are the use of MeCN as a solvent (and/or ligand) to control the reactivity of the intermediate Pd complexes and the combination of CO with O2, which facilitates the CuII-mediated reoxidation of Pd0 to PdII and prevents double carbonylation.
