56-54-2Relevant articles and documents
Nickel-Catalyzed Dehydrogenation of N-Heterocycles Using Molecular Oxygen
Banerjee, Debasis,Bera, Atanu,Bera, Sourajit
supporting information, (2020/09/02)
Herein, an efficient and selective nickel-catalyzed dehydrogenation of five- and six-membered N-heterocycles is presented. The transformation occurs in the presence of alkyl, alkoxy, chloro, free hydroxyl and primary amine, internal and terminal olefin, trifluoromethyl, and ester functional groups. Synthesis of an important ligand and the antimalarial drug quinine is demonstrated. Mechanistic studies revealed that the cyclic imine serves as the key intermediate for this stepwise transformation.
Total Asymmetric Synthesis of Quinine, Quinidine, and Analogues via Catalytic Enantioselective Cascade Transformations
Jiang, Yan,Deiana, Luca,Zhang, Kaiheng,Lin, Shuangzheng,Córdova, Armando
supporting information, p. 6016 - 6023 (2019/08/26)
A catalytic asymmetric strategy for the total synthesis of quinuclidine natural products, which includes the completed enantioselective synthesis of the classical targets quinine and quinidine is disclosed. It is based on catalytic asymmetric cascade transformations, which paves the road for the synthesis of both enantiomers of the crucial C4 stereocenter with high enantioselectivity (up to 99 % ee) in one pot. Next, developing a route to all possible stereoisomers of a common early-stage intermediate sets the stage for the total synthesis of different enantiomers or epimers of quinine, quinidine and analogues with high selectivity.
Cellulose type chiral stationary phase based on reduced graphene oxide@silica gel for the enantiomer separation of chiral compounds
Li, Yuanyuan,Li, Qiang,Zhu, Nan,Gao, Zhuxian,Ma, Yulong
, p. 996 - 1004 (2018/07/29)
The graphene oxide (GO) was covalently coupled to the surfaces of silica gel (SiO2) microspheres by amide bond to get the graphene oxide@silica gel (GO@SiO2). Then, the GO@SiO2 was reduced with hydrazine to the reduced graphene oxide@silica gel (rGO@SiO2), and the cellulose derivatives were physically coated on the surfaces of rGO@SiO2 to prepare a chiral stationary phase (CSP) for high performance liquid chromatography. Under the optimum experimental conditions, eight benzene-enriched enantiomers were separated completely, and the resolution of trans-stilbene oxide perfectly reached 4.83. Compared with the blank column of non-bonded rGO, the separation performance is better on the new CSP, which is due to the existence of rGO to produce special retention interaction with analytes, such as π-π stacking, hydrophobic effect, π-π electron-donor–acceptor interaction, and hydrogen bonding. Therefore, the obtained CSP shows special selectivity for benzene-enriched enantiomers, improves separation selectivity and efficiency, and rGO plays a synergistic effect with cellulose derivatives on enantioseparation.
Anti-Selective Asymmetric Nitro-Michael Reaction of Furanones: Diastereocontrol by Catalyst
Sekikawa, Tohru,Kitaguchi, Takayuki,Kitaura, Hayato,Minami, Tatsuya,Hatanaka, Yasuo
supporting information, p. 646 - 649 (2016/03/01)
Catalyst-controlled switching of diastereoselectivity from high syn-selectivity (>98/2 dr, syn) to anti-selectivity (up to 96/4 dr, anti) of the asymmetric nitro-Michael reaction of furanones is described. Anti-diastereoselectivity of the nitro-Michael reaction is very rare. With 0.1-5 mol % loadings of an epi-quinine catalyst, the reaction of 5-substituted 2(3H)-furanones with nitroalkenes smoothly proceeded to give the anti-Michael adducts in good yields (up to 95%) with excellent diastereo- and enantioselectivities (up to 96/4 dr, anti; up to 99% ee). DFT calculations support a model that accounts the high anti-diastereoselectivity. (Chemical Equation Presented).
Syn-selective nitro-Michael addition of furanones to β,β-disubstituted nitroalkenes catalyzed by epi-quinine derivatives
Sekikawa, Tohru,Kitaura, Hayato,Kitaguchi, Takayuki,Minami, Tatsuya,Hatanaka, Yasuo
supporting information, p. 2985 - 2989 (2016/07/06)
Epi-quinine-catalyzed asymmetric nitro-Michael addition of furanones to β,β,-disubstituted nitroalkenes is described. The reaction proceeded smoothly with 1-5 mol % loadings of epi-quinine catalysts at room temperature, giving the corresponding Michael adducts in high yields (72-93%) with extremely high diastereo- and enantioselectivities (>98/2 dr, syn major; 95-99% ee). This reaction provides an effective and straightforward method for constructing all-carbon quaternary stereogenic centers adjacent to oxygen-containing quaternary stereogenic centers.
Alkoxide coordination of iron(III) protoporphyrin IX by antimalarial quinoline methanols: A key interaction observed in the solid-state and solution
Gildenhuys, Johandie,Sammy, Chandre J.,Müller, Ronel,Streltsov, Victor A.,Le Roex, Tanya,Kuter, David,De Villiers, Katherine A.
, p. 16767 - 16777 (2015/10/06)
The quinoline methanol antimalarial drug mefloquine is a structural analogue of the Cinchona alkaloids, quinine and quinidine. We have elucidated the single crystal X-ray diffraction structure of the complexes formed between racemic erythro mefloquine and ferriprotoporphyrin IX (Fe(iii)PPIX) and show that alkoxide coordination is a key interaction in the solid-state. Mass spectrometry confirms the existence of coordination complexes of quinine, quinidine and mefloquine to Fe(iii)PPIX in acetonitrile. The length of the iron(iii)-O bond in the quinine and quinidine complexes as determined by Extended X-ray Absorption Fine Structure (EXAFS) spectroscopy unequivocally confirms that coordination of the quinoline methanol compounds to Fe(iii)PPIX occurs in non-aqueous aprotic solution via their benzylic alkoxide functional group. UV-visible spectrophotometric titrations of the low-spin bis-pyridyl-Fe(iii)PPIX complex with each of the quinoline methanol compounds results in the displacement of a single pyridine molecule and subsequent formation of a six-coordinate pyridine-Fe(iii)PPIX-drug complex. We propose that formation of the drug-Fe(iii)PPIX coordination complexes is favoured in a non-aqueous environment, such as that found in lipid bodies or membranes in the malaria parasite, and that their existence may contribute to the mechanism of haemozoin inhibition or other toxicity effects that lead ultimately to parasite death. In either case, coordination is a key interaction to be considered in the design of novel antimalarial drug candidates.
An easy route to exotic 9-epimers of 9-amino-(9-deoxy) cinchona alkaloids with (8S, 9R) and (8R, 9S)-configurations through two inversions of configuration
Wan, Jing-Wei,Ma, Xue-Bing,He, Rong-Xing,Li, Ming
, p. 557 - 560 (2014/05/06)
Four exotic chiral organocatalysts, 9-amino-(9-deoxy) cinchona alkaloids with (8S, 9R) and (8R, 9S)-configurations, were conveniently synthesized for the first time in 27-72% total yields through two conversions of configuration at the 9-stereogenic centers of commercially available cinchona alkaloids.
Enantioselective α-hydroxylation of β-keto esters catalyzed by cinchona alkaloid derivatives
Wang, Yakun,Li, Zhi,Xiong, Ting,Zhao, Jingnan,Meng, Qingwei
, p. 2155 - 2160 (2014/11/08)
A highly efficient α-hydroxylation of β-keto esters catalyzed by cupreidine in the presence of cumyl hydroperoxide (CHP) was achieved. The reaction was applied to a wide variety of β-keto esters to give products in high yields (up to 95%) with excellent enantioselectivities (up to 97% ee). The reaction had been successfully scaled up to a gram quantity and (S)-5-chloro-2-hydroxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate - the important intermediate of Indoxacarb were obtained in 96% yield with 86% ee. The enantiomeric excess could be improved to 99% by crystallization, and this method has prospect of industrial application for its advantages of enantioselectivity, ease of catalyst preparation and reclamation of catalyst. Georg Thieme Verlag Stuttgart. New York.
Relative to quinine and quinidine, their 9-epimers exhibit decreased cytostatic activity and altered heme binding but similar cytocidal activity versus Plasmodium falciparum
Gorka, Alexander P.,Sherlach, Katy S.,De Dios, Angel C.,Roepea, Paul D.
, p. 365 - 374 (2013/03/28)
The 9-epimers of quinine (QN) and quinidine (QD) are known to exhibit poor cytostatic potency against P. falciparum (Karle JM, Karle IL, Gerena L, Milhous WK, Antimicrob. Agents Chemother. 36:1538-1544, 1992). We synthesized 9-epi-QN (eQN) and 9-epi-QD (eQD) via Mitsunobu esterification-saponification and evaluated both cytostatic and cytocidal antimalarial activities. Relative to the cytostatic activity of QN and QD, we observed a large decrease in cytostatic activity (higher 50% inhibitory concentration [IC50s]) against QN-sensitive strain HB3, QN-resistant strain Dd2, and QN-hypersensitive strain K76I, consistent with previous work. However, we observed relatively small changes in cytocidal activity (the 50% lethal dose), similar to observations with chloroquine (CQ) analogues with a wide range of IC50s (see the accompanying paper [A. P. Gorka, J. N. Alumasa, K. S. Sherlach, L. M. Jacobs, K. B. Nickley, J. P. Brower, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:356-364, 2013]). Compared to QN and QD, the 9-epimers had significantly reduced hemozoin inhibition efficiency and did not affect pH-dependent aggregation of ferriprotoporphyrin IX (FPIX) heme. Magnetic susceptibility measurements showed that the 9-epimers perturb FPIX monomer-dimer equilibrium in favor of monomer, and UV-visible (VIS) titrations showed that eQN and eQD bind monomer with similar affinity relative to QN and QD. However, unique ring proton shifts in the presence of zinc(II) protoporphyrin IX (ZnPIX) indicate that binding of the 9-epimers to monomeric heme is via a distinct geometry. We isolated eQN- and eQD-FPIX complexes formed under aqueous conditions and analyzed them by mass, fluorescence, and UVVIS spectroscopies. The 9-epimers produced low-fluorescent adducts with a 2:1 stoichiometry (drug to FPIX) which did not survive electrospray ionization, in contrast to QN and QD complexes. The data offer important insight into the relevance of heme interactions as a drug target for cytostatic versus cytocidal dosages of quinoline antimalarial drugs and further elucidate a surprising structural diversity of quinoline antimalarial drug-heme complexes. Copyright
Chiral benzisoselenazolones: Conformational analysis based on experimental and DFT calculated 77Se NMR
Zielińska-B?ajet, Mariola,Boratyński, Przemys?aw J.,Palus, Jerzy,Skarzewski, Jacek
, p. 10223 - 10229 (2013/11/19)
A series of new enantiomeric N-substituted benzisoselenazol-3(2H)-ones were prepared from 2-(chloroseleno)benzoyl chloride and 9-amino-deoxyquinine (both 9-native and 9-epi) as well as the other chiral primary amines. The 77Se NMR parameters for the obtained benzisoselenazolones were measured and theoretically calculated at the DFT level of theory using B97-2 hybrid functional and cc-pVTZ basis set. The DFT 77Se chemical shifts for the lowest energy conformers were in agreement with the experimental data, while the conformers of higher energy showed markedly worse fit. Interestingly, the preferred conformation for 2-(1-arylalkyl)-benzisoselenazolones is the gauche type (Se-N-C-H≈±180), and it is in agreement with those observed in crystals (X-ray). The calculation predicts a much higher sensitivity for the 77Se chemical shift of the conformation than for the corresponding 13C data. In the 77Se NMR spectra of chiral benzisoselenazolones with added racemic or l-N-Boc-phenylglycine, chiral discrimination could not be observed mostly due to signal broadening. In the 1H NMR spectra, the benzisoselenazole derived from epi-9-amino-deoxyquinine induced splittings of the amino acid signals, thus allowing for discrimination of the enantiomers.
