- Reductive Amination Revisited: Reduction of Aldimines with Trichlorosilane Catalyzed by Dimethylformamide─Functional Group Tolerance, Scope, and Limitations
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Aldimines, generated in situ from aliphatic, aromatic, and heteroaromatic aldehydes and aliphatic, aromatic, and heteroaromatic primary or secondary amines, can be reduced with trichlorosilane in the presence of dimethylformamide (DMF) as an organocatalys
- Campbell, Joanna L. P.,Davies, Christopher D.,Ho?ek, Jan,Ko?ovsky, Pavel,Kysilka, Ond?ej,Popov, Kirill K.,Pour, Milan
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p. 920 - 943
(2022/01/27)
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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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- 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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- Mechanistic investigations into the enantioselective Conia-ene reaction catalyzed by cinchona-derived amino urea pre-catalysts and CuI
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The enantioselective Coniaene cyclization of alkyne-tethered β-ketoesters is efficiently catalyzed by the combination of cinchona-derived amino-urea pre-catalysts and copper(I) salts. The reaction scope is broad and a series of substrates can be efficiently cyclized with high yields and enantioselectivities. Herein, we present a detailed mechanistic study based on experimental considerations and quantum mechanical calculations. Several variables, such as the nature of the organic pre-catalyst and the metal-ion source, have been thoroughly investigated. Kinetic studies, as well as kinetic isotope effects and deuterium labeling experiments have been used to gain further insights into the mechanism and prove the cooperative nature of the catalytic system. Our studies suggest that the rate-limiting step for the reaction involves the β-ketoester deprotonation and that the active species responsible for the enantiodeterming step is monomeric in amino-urea pre-catalyst. Computational studies provide a quantitative understanding of the observed stereoinduction and identify hydrogen bonding from the urea group as a crucial factor in determining the observed enantioselectivity.
- Sladojevich, Filippo,Fuentes De Arriba, ángel L.,Ortín, Irene,Yang, Ting,Ferrali, Alessandro,Paton, Robert S.,Dixon, Darren J.
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p. 14286 - 14295
(2015/03/30)
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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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experimental part
p. 264 - 280
(2012/07/17)
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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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- Deconstructing quinine. Part 1. Toward an understanding of the remarkable performance of cinchona alkaloids in asymmetric phase transfer catalysis
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A study of catalyst structure-activity/selectivity relationships for Cinchona alkaloid-based asymmetric phase transfer catalysis (APTC) is described. An array of substituent modifications at C(9) and the quinuclidine nitrogen were introduced to examine the role of steric and electronic effects on rate and selectivity. The synthesis of the catalysts began with manipulation of the C(9) hydroxyl group followed by alkylation of the quinuclidine nitrogen to generate the quaternary ammonium salt. Catalysts that contained large substituents attached to the quinuclidinium nitrogen were found to be the most selective and those in which the hydroxyl group was protected generally afforded faster catalysts. The presence of a polar group at C(9) significantly impacted catalyst activity. The Japan Institute of Heterocyclic Chemistry.
- Denmark, Scott E.,Weintraub, Robert C.
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scheme or table
p. 1527 - 1540
(2011/06/17)
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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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- Gamma-polymorph of a substituted pyrazoline, its preparation and use as medicaments
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The present invention relates to the γ-Polymorph of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide, methods for its preparation, medicaments comprising this compound as well as their use for the preparation of a medicament for the treatment of humans and animals.
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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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- 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 57-58
(2010/02/09)
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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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- 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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- 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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- Chiral rhodium-diphosphine catalyst capable of catalytic reduction of a tetramisole precursor to give a significant excess of the desired S-(-)isomer, levamisole
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A soluble, chiral, rhodium-containing catalyst which permits the catalytic reduction of prochiral 3-acyl-1-(2-alkoxyethyl)-4-phenyl-2-imidazolinones to chiral 3-acylimidazolidinones with a substantial excess of the desired S optical isomer. The 3-acylimidazolidinones may in turn be substantially converted to levamisole, and S isomer of tetramisole. The resolution of tetramisole to remove the R isomer is thus avoided.
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