130-95-0Relevant articles and documents
C?H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity
O' Donovan, Daniel H.,Aillard, Paul,Berger, Martin,de la Torre, Aurélien,Petkova, Desislava,Knittl-Frank, Christian,Geerdink, Danny,Kaiser, Marcel,Maulide, Nuno
, p. 10737 - 10741 (2018)
We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C?H activation and an aldol reaction, to unite the two heterocyclic moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (?)-quinine, the first synthesis of unnatural (+)-quinine, and also provides access to unprecedented C3-aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (?)-quinine both in vitro and in mice infected with Plasmodium berghei.
Total Asymmetric Synthesis of Quinine, Quinidine, and Analogues via Catalytic Enantioselective Cascade Transformations
Jiang, Yan,Deiana, Luca,Zhang, Kaiheng,Lin, Shuangzheng,Córdova, Armando
, p. 6016 - 6023 (2019)
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.
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.
METHOD FOR SCREENING SALTY-TASTE MODIFYING SUBSTANCE
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, (2018/04/19)
A method for screening an objective substance such as a salty-taste modifying substance is provided. It is identified by using a TMC6 protein whether a test substance is an objective substance such as a salty-taste modifying substance.
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
, 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
, 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.
Novel prodrugs with a spontaneous cleavable guanidine moiety
Hamada, Yoshio
supporting information, p. 1685 - 1689 (2016/07/29)
Water-soluble prodrug strategy is a practical alternative for improving the drug bioavailability of sparingly-soluble drugs with reduced drug efficacy. Many water-soluble prodrugs of sparingly-soluble drugs, such as the phosphate ester of a drug, have been reported. Recently, we described a novel water-soluble prodrug based on O–N intramolecular acyl migration. However, these prodrug approaches require a hydroxy group in the structure of their drugs, and other prodrug approaches are often restricted by the structure of the parent drugs. To develop prodrugs with no restriction in the structure, we focused on a decomposition reaction of arginine methyl ester. This reaction proceeds at room temperature under neutral conditions, and we applied this reaction to the prodrug strategy for drugs with an amino group. We designed and synthesized novel prodrugs of representative sparingly soluble drugs phenytoin and sulfathiazole. Phenytoin and sulfathiazole were obtained as stable salt that were converted to parent drugs under physiological conditions. Phenytoin prodrug 3 showed a short half-life (t1/2) of 13?min, whereas sulfathiazole prodrug 7 had a moderate t1/2of 40?min. Prodrugs 3 and 7 appear to be suitable for use as an injectable formulation and orally administered drug, respectively.
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.
