- C?H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity
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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.
- O' Donovan, Daniel H.,Aillard, Paul,Berger, Martin,de la Torre, Aurélien,Petkova, Desislava,Knittl-Frank, Christian,Geerdink, Danny,Kaiser, Marcel,Maulide, Nuno
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- Total Asymmetric Synthesis of Quinine, Quinidine, and Analogues via Catalytic Enantioselective Cascade Transformations
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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.
- Jiang, Yan,Deiana, Luca,Zhang, Kaiheng,Lin, Shuangzheng,Córdova, Armando
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Read Online
- Nickel-Catalyzed Dehydrogenation of N-Heterocycles Using Molecular Oxygen
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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.
- Banerjee, Debasis,Bera, Atanu,Bera, Sourajit
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supporting information
(2020/09/02)
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- METHOD FOR SCREENING SALTY-TASTE MODIFYING SUBSTANCE
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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.
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- Cellulose type chiral stationary phase based on reduced graphene oxide@silica gel for the enantiomer separation of chiral compounds
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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.
- Li, Yuanyuan,Li, Qiang,Zhu, Nan,Gao, Zhuxian,Ma, Yulong
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p. 996 - 1004
(2018/07/29)
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- Anti-Selective Asymmetric Nitro-Michael Reaction of Furanones: Diastereocontrol by Catalyst
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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).
- Sekikawa, Tohru,Kitaguchi, Takayuki,Kitaura, Hayato,Minami, Tatsuya,Hatanaka, Yasuo
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supporting information
p. 646 - 649
(2016/03/01)
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- Syn-selective nitro-Michael addition of furanones to β,β-disubstituted nitroalkenes catalyzed by epi-quinine derivatives
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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.
- Sekikawa, Tohru,Kitaura, Hayato,Kitaguchi, Takayuki,Minami, Tatsuya,Hatanaka, Yasuo
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supporting information
p. 2985 - 2989
(2016/07/06)
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- Novel prodrugs with a spontaneous cleavable guanidine moiety
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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.
- Hamada, Yoshio
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supporting information
p. 1685 - 1689
(2016/07/29)
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- Alkoxide coordination of iron(III) protoporphyrin IX by antimalarial quinoline methanols: A key interaction observed in the solid-state and solution
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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.
- Gildenhuys, Johandie,Sammy, Chandre J.,Müller, Ronel,Streltsov, Victor A.,Le Roex, Tanya,Kuter, David,De Villiers, Katherine A.
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supporting information
p. 16767 - 16777
(2015/10/06)
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- 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
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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.
- Wan, Jing-Wei,Ma, Xue-Bing,He, Rong-Xing,Li, Ming
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p. 557 - 560
(2014/05/06)
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- Enantioselective α-hydroxylation of β-keto esters catalyzed by cinchona alkaloid derivatives
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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.
- Wang, Yakun,Li, Zhi,Xiong, Ting,Zhao, Jingnan,Meng, Qingwei
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p. 2155 - 2160
(2014/11/08)
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- Relative to quinine and quinidine, their 9-epimers exhibit decreased cytostatic activity and altered heme binding but similar cytocidal activity versus Plasmodium falciparum
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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
- Gorka, Alexander P.,Sherlach, Katy S.,De Dios, Angel C.,Roepea, Paul D.
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p. 365 - 374
(2013/03/28)
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- Chiral benzisoselenazolones: Conformational analysis based on experimental and DFT calculated 77Se NMR
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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.
- Zielińska-B?ajet, Mariola,Boratyński, Przemys?aw J.,Palus, Jerzy,Skarzewski, Jacek
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p. 10223 - 10229
(2013/11/19)
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- Structure-reactivity study of O-tosyl Cinchona alkaloids in their new synthesis and in hydrolysis to 9-epibases. Unexpected formation of cinchonicine enol tosylate accelerated by microwave activation
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New methods for O-tosylation of the natural Cinchona alkaloids have been discovered as a biphasic processes with Bu3N as a catalyst. The optimized excess of tosyl chloride, necessary for transformation of each of the four alkaloids into O-tosyl derivative, decreases in the following order: quinine, quinidine, cinchonidine and cinchonine. The same decreasing order has been noticed for the hydrolysis rate of the appropriate tosylates to 9-epibases. Difficult conversion of O-tosylcinchonine in the hydrolytic medium of aqueous tartaric acid gives 9-epicinchonine together with parallel formation of cinchonicine enol tosylate. The latter product is obtained as the main when both cinchonine and cinchonidine tosylates react in the presence of salicylic acid under controlled microwave heating. On the basis of X-ray structure of the new alkene product, the stereoselective syn-E2 quinuclidine ring opening process, competing to the SN2 hydrolysis is postulated for this transformation. ARKAT-USA, Inc.
- Lipinska, Teodozja M.,Piechocka, Katarzyna,Denisiuk, Monika,Chmiel, Beata,Skorska-Stania, Agnieszka
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p. 264 - 280
(2012/07/17)
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- Stereochemistry of hydrophosphonylation of 9-aminoquinine Schiff bases
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Reaction of imines derived from 9-amino-deoxyquinine and p-chlorobenzaldehyde with diethyl phosphite was studied. Under the experimental conditions the addition to imine of 9S configuration proceeded with complete diastereoselectivity for 1″S and in 60% practical yield. In contrast, the imine of 9R configuration was much less reactive and gave only 22% of the 1:1 mixture of two 1″-epimers. The configuration of the newly created stereogenic centers were established using homo- and hetero-NOE NMR techniques and comparing the experimental and calculated (GIAO/DFT) spectra. Stereochemical models explaining the observed high diastereoselectivity of hydrophosphonylation in one case and its lack in the other were discussed. ARKAT-USA, Inc.
- Boratynski, Przemyslaw J.,Skarzewski, Jacek,Sidorowicz, Lukasz
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p. 204 - 215
(2013/09/24)
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- Easy access to 9-epimers of cinchona alkaloids: One-pot inversion by mitsunobu esterification-saponification
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Cinchona alkaloids were efficiently converted into their 9-epi diastereomers. The applied one-pot procedure was based on the Mitsunobu esterification with 4-nitrobenzoic acid followed by in situ saponification of the ester. This method requires only one column chromatography, easily separating the epi-isomer from the native alkaloid and the Mitsunobu byproducts. The procedure gives higher yields and is operationally simpler than the previously used stereoselective hydrolysis of the corresponding sulfonic acid esters. Georg Thieme Verlag Stuttgart New York.
- Sidorowicz, Lukasz,Skarzewski, Jacek
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p. 708 - 710
(2011/04/24)
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- Organocatalytic asymmetric synthesis of quinine and quinidine
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Quinine and quinidine were synthesized by a highly enantio- and stereoselective approach starting from a proline-catalyzed asymmetric cycloaldolization of benzyl bis(2-formylethyl)carbamate which gave a 70:30 mixture of (3R,4R)-N-Cbz-3-hydroxymethyl-4-hydroxypiperidine (96% ee) and its 4S-epimer (92% ee) in 94% yield after in situ NaBH4 reduction.
- Sarkar, Shaheen M.,Taira, Yuko,Nakano, Ayako,Takahashi, Keisuske,Ishihara, Jun,Hatakeyama, Susumi
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p. 923 - 927
(2011/03/20)
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- Selenophene-containing inhibitors of type IIA bacterial topoisomerases
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Figure Presented. We investigated compounds related to the previously reported antistaphyloccocal agent AVE6971 in an effort to attenuate inhibition of hERG potassium channel current that has been noted for this and related antibacterial drug classes. While most modifications of the original thiophene group compromised antibacterial activity, one selenophene analogue displayed (i) improved activity against the primary target enzyme DNA gyrase, (ii) similar activities against a panel of MRSA clinical isolates, and (iii) reduced hERG channel inhibition.
- Wiles, Jason A.,Phadke, Avinash S.,Bradbury, Barton J.,Pucci, Michael J.,Thanassi, Jane A.,Deshpande, Milind
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scheme or table
p. 3418 - 3425
(2011/06/27)
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- Practical and highly selective sulfur ylide mediated asymmetric epoxidations and aziridinations using an inexpensive, readily available chiral sulfide. Applications to the synthesis of quinine and quinidine
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(Chemical Presented) Heating one of the most abundant naturally occurring inorganic chemicals (elemental sulfur) with one of the most readily available homochiral molecules (limonene) gives a one-step synthesis of a chiral sulfide which exhibits outstanding selectivities in sulfur ylide mediated asymmetric epoxidations and aziridinations. In particular reactions of benzyl and allylic sulfonium salts with both aromatic and aliphatic aldehydes gave epoxides with perfect enantioselectivities and the highest diastereoselectivities reported to date. In addition reactions with imines gave aziridines again with the highest enantioselectivities and diastereoselectivities reported to date. The reactions are scaleable, and the sulfide can be reisolated in high yield. The epoxidation has been used as the key step in a convergent and stereoselective synthesis of each of the diastereoisomers of the cinchona alkaloids, quinine and quinidine. Copyright
- Illa, Ona,Arshad, Muhammad,Ros, Abel,McGarrigle, Eoghan M.,Aggarwal, Varinder K.
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supporting information; experimental part
p. 1828 - 1830
(2010/04/25)
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- Phase-Transfer catalysed enantioselective epoxidation of Estra-δ5(10),9(11)- diene using chiral ammonium salts derived from cinchona alkaloids
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A modified phase-transfer catalysed enantioselective epoxidation of estra-δ5(10),9(11)-diene, an important intermediate of anti-early pregnancy drug mifepristone 1, have been determined and investigated. Eight chiral ammonium salts (PTC A-H), used as phase-transfer catalysts, have been synthesized from cinchona alkaloids. Among them, PTC G and PTC H have exhibited satisfying catalytic activity to improve the ratio of α/β. epoxide up to 7:1.
- Yang, Ya-Xi,Li, Zheng,Chen, Guo-Rong,Li, Yuan-Chao
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experimental part
p. 163 - 167
(2010/09/03)
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- Clickable 9-azido-(9-deoxy)-Cinchona alkaloids: Synthesis and conformation
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The synthesis and conformational preferences of 9-azido-(9-deoxy)-Cinchona alkaloids constituting a novel class of Cinchona alkaloid derivatives of both natural and 9-epi configurations are described. One and two-step preparative syntheses of 9-azido-(9-deoxy)-Cinchona alkaloids have been developed, allowing for their easy access on a multigram scale. The stereochemical integrity of these azides has been confirmed from their circular dichroism and specific rotation data. The conformations of the 9-azido Cinchona alkaloids, deduced from both 1H NMR and DFT calculations, show that this class of Cinchona derivatives largely reflect the conformational preferences of the corresponding Cinchona bases; this strategy, therefore, offers a defined chiral and clickable scaffold.
- Kacprzak, Karol,Gierczyk, Blaej
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scheme or table
p. 2740 - 2745
(2011/02/23)
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- Synthesis of quinine and quinidine using sulfur ylide-mediated asymmetric epoxidation as a key step
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The epoxidation of meroquinene aldehyde with a chiral sulfur ylide as the key step in the synthesis of quinine and quinidine is described. The epoxidation reactions proceed under reagent control with high selectivity and good yield. The effect of sulfide and ylide substituents on the stereochemical outcome of the reaction is discussed.
- Arshad, Muhammad,Fernandez, M. Alejandro,McGarrigle, Eoghan M.,Aggarwal, Varinder K.
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experimental part
p. 1771 - 1776
(2010/10/19)
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- Organocatalytic activity of cinchona alkaloids: Which nitrogen is more nucleophilic?
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(Chemical Equation Presented) The cinchona alkaloids 1a-d react selectively at the quinuclidine ring with benzyl bromide and at the quinoline ring with benzhydrylium ions (diarylcarbenium ions). The kinetics of these reactions have been determined photometrically or conductimetrically and are compared with analogous reactions of quinuclidine and quinoline derivatives. Quantum chemical calculations [MP2/6-31+G(2d,p)//B3LYP/6-31G(d)] show that the products obtained by attack at the quinuclidine ring (Nsp3) of quinine are thermodynamically more stable when small alkylating agents (primary alkyl) are used, while the products arising from attack at the quinoline ring (N sp2) are more stable for bulkier electrophiles (Ar2CH). In some cases, rate and equilibrium constants for their reactions with benzhydrylium ions could be determined. These data gave access to the Marcus intrinsic barriers, which are approximately 20 kJ mol-1 lower for attack at the Nsp3-center than at the Nsp2-center.
- Baidya, Mahiuddin,Horn, Markus,Zipse, Hendrik,Mayr, Herbert
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supporting information; experimental part
p. 7157 - 7164
(2009/12/09)
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- Rabe rest in peace: Confirmation of the rabe-kindler conversion of d-quinotoxine into quinine: Experimental affirmation of the woodward-doering formal total synthesis of quinine
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(Chemical Equation Presented) Put to rest: The three-step conversion of d-quinotoxine into quinine, as originally reported by Rabe and Kindler in 1918, has been experimentally verified. This conversion serves to reaffirm the formal total synthesis of quin
- Smith, Aaron C.,Williams, Robert M.
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supporting information; experimental part
p. 1736 - 1740
(2009/02/06)
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- Reaction of quinidine acetate, epiquinidine and its acetate in superacid: Formation of gem-difluoro derivatives with or without rearrangement
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In HF-SbF5, quinidine 1a or its dihydrochloride cyclises previously obtained with usual acids. A similar reaction is observed in the presence of CCl4. Under similar conditions quinidine acetate 1b and epiquinidine acetate 2b dihydrochlorides both yield 10,10-difluoro derivatives epimeric at C-3, 6 and 7, and 9c and 10b, and a rearranged difluoro derivative 8b and 11b, respectively. Epiquinidine 2a leads to the expected analogues 10a and 11a and to a ketone 9a. Formation of gem-difluoro compounds implies chloro intermediates at C-10, precursors of α-chlorocarbenium ions, which are trapped by a fluoride ion and which lead by halogen exchange to the products.
- Debarge, Sébastien,Violeau, Bruno,Jouannetaud, Marie-Paule,Jacquesy, Jean-Claude,Cousson, Alain
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p. 662 - 671
(2007/10/03)
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- Simple enantiospecific synthesis of sulfides of Cinchona alkaloids
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The native and epi-Cinchona alkaloids were reacted with (ArS) 2/Bu3P in toluene at 65 °C to give the corresponding arylsulfanyl derivatives (15 examples, 31-75%) with complete inversion of configuration at 9-C stereogenic centers. Similar products were also obtained in the enantiospecific nucleophilic substitution of the 9-mesylates of alkaloids with sodium thiolates (4 examples, 73-84%) and no cinchona rearrangement was observed. The chiral thioethers obtained were preliminarily tested as N(sp 3), S-donating chiral ligands in the Pd-catalyzed allylic alkylation of dimethyl malonate with rac-1,3-diphenylprop-2-enyl acetate and gave the product with up to 78% ee. Georg Thieme Verlag Stuttgart.
- Zielinska-Blajet, Mariola,Kucharska, Malgorzata,Skarzewski, Jacek
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p. 1176 - 1182
(2007/10/03)
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- Improved synthesis of quinine alkaloids with the Teoc protective group
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TeocCl (Teoc: C(O)O(CH2)2TMS) generated in situ was conveniently used for trans-protection of the N-Bn piperidine intermediate to N-Teoc piperidine. Later, deprotection of the Teoc group and the subsequent quinuclidine ring formation was achieved with CsF in a domino fashion to afford the quinine alkaloids.
- Igarashi, Junji,Kobayashi, Yuichi
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p. 6381 - 6384
(2007/10/03)
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- Rearrangement or gem-difluorination of quinine and 9-epiquinine and their acetates in superacid
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In HF-SbF5, quinine 1a or its dihydrochloride rearranges into compound 3 (89%), the preferred conformation of the substrate favouring the observed cyclization. Under similar conditions epiquinine 2a dihydrochloride yields in equal amounts two 10,10-difluoro derivatives, epimeric at C-3. In this case, the more stable conformation of the substrate in which the benzylic hydroxyl group is 'exo' to the quinuclidyl moiety, prevents the cyclisation. Similarly acetates 1b and 2b give the corresponding 10,10-difluoro derivatives epimeric at C-3. Formation of gem-difluoro compounds implies the formation of chloro intermediates at C-10 followed by an hydride abstraction, yielding an α-chloronium ion. This one is trapped by a fluoride ion and leads to the product by halogen exchange.
- Debarge, Sébastien,Thibaudeau, Sébastien,Violeau, Bruno,Martin-Mingot, Agnès,Jouannetaud, Marie-Paule,Jacquesy, Jean-Claude,Cousson, Alain
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p. 2065 - 2073
(2007/10/03)
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- The First and Second Cinchona Rearrangement. Two Fundamental Transformations of Alkaloid Chemistry
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Stereochemistry, products, and driving forces of the "first and second Cinchona rearrangement" have been investigated and a unified theory is presented. The first cage expansion affords [3.2.2]azabicyclic α-amino ether and is formulated via a configurationally stable bridgehead iminium ion and quasiequatorial nucleophilic attack. The second cage expansion affords β-functionalized [3.2.2]azabicycles. In this case a nonclassical nitrogen-bridged cation is postulated to account for retention of configuration and potential reversibility of the cage expansion. The second rearrangement is favored for the so-called cinch bases (6′-R = H) in trifluoroethanol. Stereoelectronic factors, electron demand at C9, ground state conformation, and solvent type are crucial in all cases. A two-step protocol for preparing 9-epi-configured Cinchona alkaloids from 9-nat precursors is described.
- Franz, M. Heiko,Roeper, Stefanie,Wartchow, Rudolf,Hoffmann
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p. 2983 - 2991
(2007/10/03)
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- INHIBITORS OF FUNGAL INVASION
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This invention relates to various anti-fungall agents including agents that are inhibitors of fungal invasion.
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Drawing sheet 58
(2010/02/09)
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- Catalytic Asymmetric Total Syntheses of Quinine and Quinidine
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The catalytic, asymmetric syntheses of quinine and quinidine were achieved in 16 steps. The recently developed salen(Al)-catalyzed enantioselective Michael addition of methyl cyanoacetate served to set the crucial C4 stereocenter in 92% ee, and a late-stage asymmetric dihydroxylation was used to differentiate the common intermediate and access the two desired diastereomeric products with high selectivity. Copyright
- Raheem, Izzat T.,Goodman, Steven N.,Jacobsen, Eric N.
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p. 706 - 707
(2007/10/03)
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- Stereocontrolled synthesis of quinine and quinidine
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Disubstituted cyclopentene was prepared from cyclopentene monoacetate and transferred into disubstituted piperidine via oxidative cleavage of the olefin moiety followed by piperidine ring formation. The piperidine was then condensed at the side chain with a quinoline part to afford the olefin precursor of quinine. Finally, the olefin was converted into quinine through the corresponding epoxide. Quinidine was synthesized in a similar way.
- Igarashi, Junji,Katsukawa, Masahiro,Wang, Yong-Gang,Acharya, Hukum P.,Kobayashi, Yuichi
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p. 3783 - 3786
(2007/10/03)
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- Heterogeneous Enantioselective Hydrogenation of Activated Ketones Catalyzed by Modified Pt-Catalysts: A Systematic Structure-Selectivity Study
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A systematic structure-selectivity study was carried out for the enantioselective hydrogenation of activated ketones with chirally modified Pt/Al2O3 catalysts. For this, 18 modifiers containing an extended aromatic system able to form a strong adsorption complex with the Pt surface, and a suitable chiral group with an amino function capable to interact with the keto group of the substrate (HCd, Qd, HCn, Qn, and semi-synthetic derivatives, as well as synthetic analogues) were prepared and tested on 8 different activated ketones in AcOH and toluene under standard conditions. It was found that relatively small structural changes of the substrate and/or modifier structures strongly affected the enantioselectivity, and that no "best" modifier exists for all substrates. The highest ees for all substrates were obtained with quinuclidine-derived modifiers in combination with naphthalene or quinoline rings, either in AcOH (substrates 1-5 and 8, all carrying an sp3 carbon next to the keto group) or toluene (6 and 7, with an sp2 carbon next to the ketone). The presence and nature of the substituent R′ at the quinuclidine significantly affected the ee (positive and negative effects). Certain combinations of an aromatic system and an amino function were preferred: For the quinuclidine moiety, quinoline and to a somewhat lesser extent naphthalene were a better match, while for the pyrrolidinylmethyl group anthracene was better suited. Methylation of the OH group often had a positive effect for hydrogenations in AcOH but not in toluene. With the exception of 8, higher ees were obtained for the Cd/ Qn series [leading to (R)-products] than for the Cn/ Qd series [leading to (S)-products]. In several cases, opposite structure-selectivity trends were detected when comparing reactions in toluene and AcOH, indicating a significant influence of the solvent.
- Exner, Christian,Pfaltz, Andreas,Studer, Martin,Blaser, Hans-Ulrich
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p. 1253 - 1260
(2007/10/03)
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- The development of the first catalyzed reaction of ketenes and imines: Catalytic, asymmetric synthesis of β-lactams
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We report practical methodology for the catalytic, asymmetric synthesis of β-lactams resulting from the development of a catalyzed reaction of ketenes (or their derived zwitterionic enolates) and imines. The products of these asymmetric reactions can serve as precursors to a number of enzyme inhibitors and drug candidates as well as valuable synthetic intermediates. We present a detailed study of the mechanism of the β-lactam forming reaction with proton sponge as the stoichiometric base, including kinetics and isotopic labeling studies. Stereochemical models based on molecular mechanics (MM) calculations are also presented to account for the observed stereoregular sense of induction in our reactions and to provide a guidepost for the design of other catalyst systems.
- Taggi, Andrew E.,Hafez, Ahmed M.,Wack, Harald,Young, Brandon,Ferraris, Dana,Lectka, Thomas
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p. 6626 - 6635
(2007/10/03)
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- The first stereoselective total synthesis of quinine
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The first entirely stereoselective total synthesis of (-)-quinine is reported.
- Stork,Niu,Fujimoto,Koft,Balkovec,Tata,Dake
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p. 3239 - 3242
(2007/10/03)
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- Prodrugs for the therapy of tumors and inflammatory disorders
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Compounds of the formula Iglycosyl-Y[--C( Y)--X--] p --W(R) n --Z--C( Y)-active compound (I)are described which are suitable for the treatment of carcinomatous diseases, autoimmune diseases and chronic inflammatory diseases such as rheumatoid arthritis.
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- Structure and mechanism in cinchona alkaloid chemistry: Overturning a 50-year-old misconception
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Long-standing errors of the supposedly established literature, including textbooks and data bases have been corrected: The structure of the hetero- cinchona bases in the crystal and in solution (see scheme) and the mechanism of their formation from quinine and quinidine have been elucidated.
- Braje, Wilfried M.,Wartchow, Rudolf,Hoffmann, H. Martin R.
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p. 2539 - 2543
(2007/10/03)
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- Enantiomerically pure quinuclidine derivatives and methods for their production and use
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A process for cleaving cinchona alkaloids to a quinoline derivative and an enantiomerically pure, functionalized 1-azabicyclo(2.2.2)octane, includes treating a cinchona alkaloid with a complex metal hydride while simultaneously oxidizing by exposure to air in an ether or tetrahydrofuran. Enantiomerically pure 1-azabicyclo(2.2.2)octanes of the formula STR1 in which R is hydrogen, a straight-chain or branched alkoxycarbonyl group with 1 to 12 carbon atoms, a straight-chain or branched alkyl group with 1 to 12 carbon atoms, alkylated silyl groups, or a substituted phenyl or benzyl substituent, are also provided.
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- Enantioselektive Katalyse, 106 9-Amino(9-deoxy)cinchona-Alkaloide und Deren Derivate
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The stereospecific formation of 9-amino(9-deoxy)cinchona alkaloids with the configuration of the corresponding natural products was achieved by a sequence of reactions, including a substitution with inversion of configuration. Thus, the corresponding epi-alkaloids were reacted with hydrazoic acid, triphenylphosphine and diisopropyl azodicarboxylate followed by an in situ reduction of the intermediary azides. The configurations of the products were established by CD- and 1H-NMR-spectroscopy. Several amide, imine and amine derivatives were prepared from these amino-substituted alkaloids. Their ability to induce enantiomeric excess in asymmetric syntheses was tested.
- Brunner, H.,Buegler, J.
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- Heterocyclic amines useful in the therapy of asthma and imflammation of the respiratory tract
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Compounds of the formula STR1 wherein A, Y, X, B and D are described in the specification are disclosed. The compounds possess activity in treating asthma and other pathologies of the respiratory tract.
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- Optical resolution of threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)-propionic acid
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D(+)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid, an important intermediate in the synthesis of diltiazem hydrochloride, is obtained in better yields and high optical purity by a novel resolution process comprising the reaction of 2 moles of the (±) racemic acid with 1 mole of quinine and 1 mole of a base in a suitable polar solvent system to form a salt of the D(+) acid and quinine which precipitates; separating said salt and decomposing it with a strong base.
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- Detection and identification of side reactions of halogenated hydrocarbon solvents with amines of pharmaceutical interest by secondary processes to the neutralizations of sulphonphthaleinic dyes with these amines
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The neutralization reactions between amines and diprotic acid dyes in organic solvents generate {dye-, amineH+} and {dye2-, (amineH+)2} ion associates that show two absorption bands in the visible spectrum. An unidentified third absorption band; which appears with a high amine concentration, proves that halogenated hydrocarbon solvents (dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride) give side reactions with amines (atropine, tropine, quinine, ephedrine, and ajmaline) that generate a quaternary ammonium salt, N-halogenalkylammonium halide ({N+- RX,X-}). The molecular weight of the quaternary ammonium salt is the sum of the amine and that of the solvent. The {N+-RX,X-} ion associated reacts with {dye2-, (amineH+)2} by substitution reactions, forming {dye2-, amineH+, N+-RX} and {dye2-, (N+-RX)2} ion associates that justify the third absorption band. The amine-solvent side reactions are of first order with respect to the amine, being very slow processes with rate constant values from 399.4 h-1 (tropine-dichloromethane reaction) to 15.8 h-1 (atropine-1,2-dichloroethane reaction). Rate constants increase with the basicity of the amine measured in the halogenated hydrocarbons employed. Rate constants also increase with a reduction in the number of the halogen atoms present in the halogenated solvent. The new visible absorption band that appears in the amine-dye neutralization gives a quick colorimetric test to bring to light this kind of side reaction in these solvents.
- Gainza,Konyeaso,Asenjo
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p. 226 - 232
(2007/10/02)
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- Substitution reactions of benzethonium chloride with ion associates of bromocresol green - quinine and bromophenol blue - quinine in dichlormethane
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An excess concentration of base quinine (Q) reacts with a sulphonphthalein diacidic dye XH2, (bromocresol green, BCGH2, or bromophenol blue, BPBH2) in dichlormethane solution to form an ion associate (X(2-)(QH21+)2) of stoichiometry 1:2 (dye:amine).Benzethonium chloride (CIB) reacts with the 1:2 ion associate to form an ion associate (QH1+,X2-,B1+) and quinine hydrochloride ClQH(1+).This substitution reaction is a chemical equilibrium with formation constants of 1.50+/-0.67, 1.64+/-0.54, 1.07+/-0.29, 1.04+/-0.20, and 0.84+/-0.26 for BCG and 1.86+/-0.59, 1.47+/-0.23, 1.40+/-0.65, 1.13+/-0.37, and 1.11+/-0.27 for BPB at 283.16, 288.16, 293.16, 298.16, and 303.16 K respectively.The thermodynamic parameters determined by van't Hoff's equation are ΔH0 = -21.766+/-7.482 kJmol-1, ΔS0 = -73+/-51 Jmol-1K-1, and ΔG0 = -1.134+/-0.972 kJmol-1 for BCG and ΔH0 = -18.678+/-7.482 kJmol-1, ΔS0 = -61+/-26 Jmol-1K-1, ΔG0 = -0.916+/-0.401 kJmol-1 for BPB (ΔG0 at 293.16K; and ΔH0 and ΔS0 determined in the range 283-303K). Key words: bromocresol green-quinine-benzetonium, ion associate mixture, bromophenol blue-quinine-benzethonium, equilibrium constants, thermodynamic parameters.
- Gainza, Alberto Hernandez,Konyeaso, Roy Ikemefula
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p. 937 - 944
(2007/10/02)
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- STEREOSPECIFIC EPIMERIZATION, OXIDATION AND TOXINE REARRANGEMENT IN CINCHONA ALKALOIDS CATALYZED BY ACETIC ACID
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Glacial acetic acid catalyzed a novel stereospecific epimerization of chichona alkaloids at C-9.In the presence of water, acetic acid also catalyzed the known toxine rearrangement and oxidation to the corresponding 9-keto derivatives.Addition of acetic anhydride to acetic acid diminished oxidation and epimerization at C-9, and the main products were the results of hydramine fission.Only propionic acid but no other acids, effected similar but not identical transformations.Addition of small quantities of H2O2 or exclusion of oxygen produced quantitative oxidation and rearrangement products, respectively.The catalysis by aqueous solution of acetic acid, involves C-9-OH in the formation of a three-membered ring intermediate.On the other hand, with anhydrous acetic acid, the acetoxyl at C-9 participates in construction of a five-membered ring intermediate.In both cases the reaction appears to be intramolecular.Support for the proposed mechanisms was provided by the isolation of a quarternary salt derived from quinidine, the structure of which was also characterized by X-ray diffraction analysis.Aqueous acetic acid catalyzed the rearrangement of this salt to its corresponding toxine only, and neither oxidation nor epimerization could be observed under conditions employed for the natural alkaloids.
- Yanuka, Yehuda,Geryes, Artoul,Heller, Michael
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p. 911 - 922
(2007/10/02)
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- Enantiotopic-group Differentation. Catalytic Asymmetric Ring-opening of Prochiral Cyclic Acid Anhydrides with Methanol, using Cinchona Alkaloids
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Asymmetric ring-opening of prochiral acid anhydrides (1) with methanol has been achieved by a catalytic quantity of cinchona alkaloids (2).The product, the optically active half-ester (3), has been subjected to functional-group-selective reduction to give the optically active lactones (5).The reaction rate of the ring-opening and the extent of selectivity are dependent on the nature of the reaction medium, the polarity of solvent, and substrate concentration.By selecting the reaction conditions, an enantiometric excess of up to 70percent has been obtained.The kinetic isotope effect and other mechanistic investigations suggest that the reaction proceeds via general-base catalysis by the quinuclidine moiety of the base (2), and that the relative configuration of the C-9 hydroxy group with respect to the C-8 quinuclidine amino function determines the selectivity of the reaction.
- Hiratake, Jun,Inagaki, Minoru,Yamamoto, Yukio,Oda, Jun'ichi
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p. 1053 - 1058
(2007/10/02)
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- Dextro and levo-6-oxo-2-piperidinecarboxylic acid quinine salts
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A process for resolving mixtures of 6-oxo-2-piperidinecarboxylic acid enantiomers using quinine is disclosed.
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- Process for piperidine intermediates for quinine, quinidine and analogs thereof
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Quinine, quinidine and analogs thereof, are prepared by reacting a 4-quinolyllithium compound with a 4,5-erythro-5-ethyl(or vinyl)-quinuclidine-2ε -carboxaldehyde or the corresponding quinuclidine-2-carboxylic acid alkyl ester. Also described, inter alia, is the preparation of a 4,5-erythro-5-ethyl(or vinyl)-quinuclidine-2ε-carboxaldehyde, and a 4,5-crythro-5-ethyl(or vinyl)-quinuclidine-2ε -carboxylic acid and esters thereof. The end products are useful as antimalarial and antiarrhythmic agents.
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