L-Cinchonidine

Triethylamine Trimethylsilyl chloride Sodium iodide Palladium on carbon L-Cinchonidine Benzyl bromoacetate (trans)-4-Cyclohexyl-L-proline, hydrochloride... 

The PtySi02 catalyst EUROPT-l/cinchonidine modifier system has also been evaluated Tor substrates similar but different to [Pg.12]

MP 191° to 192,5°C, Two recrystallizations from aqueous ethanol gave the cinchonidine salt of the L-acid, MP 192,5° to 194°C. To the salt (2.9 g) in warm ethanol (50 ml) was added water (50 ml) and a slight excess (ca 10 ml) of N aqueous sodium hydroxide. The mixture was diluted with water, cooled, filtered from the precipitated base and the filtrate acidified with hydrochloric acid. Refluxing with 2 N ethanolic hydrogen chloride yielded p-nitro-N-phthaloyl-L-phenylalanine ethyl ester, according to U.S. Patent 3,032,585. 

The conjugate addition to acyclic enones is summarized in Table 5. The chiral hetero-cuprate derived from (S)-prolinol or cinchonidine produced products of low enantiomeric excess on treatment with chalcone (entries 3 and 4), while the cuprate from (S)-yV-methylpro-linol gave 64% ee (entry 6). Under more dilute conditions, 88% cc was obtained (entry 5). (2[Pg.909]

Apovincaminic acid ethylester was supplied by Richter Gedeon Co., (-)-dihydroapovincaminic acid ethyl ester was prepared according to the procedure described in (11). fSj-a, -diphcnyl-2-py rro 1 idincmethanol was synthesised as described (12). 2-benzylidene-l-benzosuberone was prepared as described in (13). Isophorone was supplied by Merck. Cinchonidine was purchased from Fluka. 

The most successful modifier is cinchonidine and its enantiomer cinchonine, but some work in expanding the repertoire of substrate/modifier/catalyst combinations has been reported (S)-(-)-l-(l-naphthyl)ethylamine or (//)-1 -(I -naphth T)eth Tamine for Pt/alumina [108,231], derivatives of cinchona alkaloid such as 10,11-dihydrocinchonidine [36,71], 2-phenyl-9-deoxy-10, 11-dihydrocinchonidine [55], and O-methyl-cinchonidine for Pt/alumina [133], ephedrine for Pd/alumina [107], (-)-dihydroapovincaminic acid ethyl ester (-)-DHVIN for Pd/TiOz [122], (-)-dihydrovinpocetine for Pt/alumina [42], chiral amines such as 1 -(1 -naphtln I)-2-(I -pyrro 1 idiny 1) ethanol, l-(9-anthracenyl)-2-(l-pyrrolidinyl)ethanol, l-(9-triptycenyl)-2-(l-pyrrol idi nyl)cthanol, (Z )-2-(l-pyrrolidinyl)-l-(l-naphthyl)ethanol for Pt/alumina [37,116], D- and L-histidine and methyl esters of d- and L-tryptophan for Pt/alumina [35], morphine alkaloids [113],... 

We have resolved racemic 5-methyl-2-cyclohexen-l-one by reaction in the presence of catalytic amounts of cinchonidine using a 1.5 L0 molar ratio of enone to thiophenol (excess enone) in benzene (55). The reaction (eq. [11]) was carried out at room temperature for 18 hr. The purified unreacted cyclohexenone had a rotation [a]2,578 of +47° (c = 1.0, CC14), indicating an optical purity of 59% and the S configuration. Thus the R isomer reacts faster with the thiophenol under these conditions. Sharpless (57) points out that even small differences in relative rate (e.g., 5-10) can provide useful amounts of a substance with high... 

Okamura and coworkers151 studied the base catalyzed Diels-Alder reactions between 3-hydroxy-2-pyrone (224) and chiral l,3-oxazolidin-2-one based acrylate derivatives. Catalysis of the reaction between 224 and 225 by triethylamine gave fair to good de values, somewhat dependent on the solvent system used (equation 63, Table 7). Addition of 5% of water to the solvent isopropanol, for example, increased the de of the endo adduct 226 substantially. When the amount of water was increased, however, the triethylamine catalyzed reaction became less endo and diastereofacially selective, a small amount of exo 227 being obtained. Replacing triethylamine by the chiral base cinchonidine also improved the de, but now independently of the solvent system used. 

Cervinka and co-workers have extensively investigated the asymmetric reduction of prochiral ketones with LAH modified with alkaloids and related amino alcohols. Most of this work has been reviewed in detail by Morrison and Mosher (1) and will not be discussed extensively here. Modification of LAH was effected with (-)-quinine (65), (- )-cinchonidine (66), (- )-ephedrine (67), (-)-A-ethyl-ephedrine (68), (-)- l-phenyl-2-dimethylaminoethanol (69), (+ )-quinidine (70), (+ )-cinchonine (71), and (+ )-pseudoephedrine (72). 

The next question is, what physicochemical parameters may influence the adsorption-desorption equilibrium We suspected that the difference with different solvents may be due to the fact that the solubilities of cinchonidine in different solvents are different, so we tested the solubilities of cinchonidine in 54 solvents, and found that if the initially established adsorption-desorption equilibrium is perturbed, that is beeause the solubility of einehonidine in that flushing solvent is relatively big (e.g., 12 g/L in diehloromethane). On the other hand, the adsorption-desorption equilibrium is not perturbed by cyclohexane, because the solubility of cinchonidine in cyclohexane is quite small (0.46 g/L). By plotting the measured cinchonidine solubility versus solvent polarity reported in the literature, nice volcano-like correlations ean be identified (Figure 18) [66]. This example shows that some empirical observations in enantioselective hydrogenation may be traeed baek to basie physieoehemieal properties sueh as the solubility of cinchonidine and the polarity of the solvent. 

This group of alkaloids has two structurally different a. The a of alkaloids found in the genus Cinchona (Ruhiaceae), such as quinine, quinidine, cinchonidine and cinchonine, is L-tryptophan. The j8 is tryptamine and the

[Pg.114]

Optica] resolution of these and related carboxylic acids were achieved using salt formation with alkaloids (strychnine, brucine, cinchonidine) 33,39,44 or with optically active amines [1-phenyl- or l-( 3-naphthyl)ethylamine]4o,44). The following rotations [a]D have been reported [8]paracyclophanecarboxylic acid (13) +18° (chloroform)441 [10]homologue (14) +80° (chloroform)39 and +67° (chloroform)40 its methyl-derivative (75) —28° (methanol)44 . Dioxa[10]paracyclophanecarboxylic acid (16) + 104° (ethanol)36 and bromo-dioxa[12]paracyclophanecarboxylic acid (79) —37° (acetone)33). 

Fig. 34. Investigation of the molecular interaction between adsorbed chiral modifier and KPL by MES 41. The modifiers were the following (a) CD and (b) A-methyl cinchonidine chloride. The KPL concentration was modulated (modulation period T = 180 s) between 0 and 5 x 10 mol/L in ( ILClz. The modifier concentration was 5 x 10 mol/L. The proposed model for the CD-KPL interaction is shown at the bottom (a). This hydrogen bonding interaction is prohibited when A-methyl-cinchonidine (b) is used as a chiral modifier instead of CD.

R)-1,1 -Bi-2-naphthol was prepared by resolution employing the N-benzylammonium chloride salt of (-)-cinchonidine to form separable diastereomeric clathrate complexes. Hu, Q-S. Vitharama, D. Pu, L. Tetrahedron Asymmetry 1995, 6, 2123. 

Most of the studies of Pt catalysts with cinchona alkaloids have focused on the hydrogenation of a-keto esters, especially ethyl pyruvate, as shown above, However, enantioselective hydrogenation of ketopantolactone and l-ethyl-4,4-dimethylpyrrolidine-2,3,5-trione is attainable with a Pt catalyst modified by cinchonidine, giving the corresponding R alcohols with 92% ee and 91% ee, respectively (Scheme 1.40) [213]. These reactions can be performed with an S/C of up to 237,000 [213a],... 

Cinchonine, cbz-L-Trp, Fmoc-L-Trp MAA, 4-VP/ EDMA S toluene/ dodecanol Cinchonine/ cinchonidine, cbz-rac-Trp, Fmoc-rac-Trp [157]... 

Marked solvent effects [<5(CDC13) — <5(DMSO)l on some of the l3C shifts in the spectrum of cinchonidine (erythro-senes) [302] but not in... 

Use of the preformed Z-silyl enol ether 18 results in quite substantial anti/syn selectivity (19 20 up to 20 1), with enantiomeric purity of the anti adducts reaching 99%. The chiral PT-catalyst 12 (Schemes 4.6 and 4.7) proved just as efficient in the conjugate addition of the N-benzhydrylidene glycine tert-butyl ester (22, Scheme 4.8) to acrylonitrile, affording the Michael adduct 23 in 85% yield and 91% ee [10]. This primary product was converted in three steps to L-ornithine [10]. The O-allylated cinchonidine derivative 21 was used in the conjugate addition of 22 to methyl acrylate, ethyl vinyl ketone, and cydohexenone (Scheme 4.8) [12]. The Michael-adducts 24-26 were obtained with high enantiomeric excess and, for cydohexenone as acceptor, with a remarkable (25 1) ratio of diastereomers (26, Scheme 4.8). In the last examples solid (base)-liquid (reactants) phase-transfer was applied. 

The cinchonidine-catalyzed addition of 4-tert-butylthiophenol reported by Wynberg and Hiemstra has also been used for kinetic resolution of racemic 5-methyl -2-cyclohexen-l-one At an enone/thiophenol ratio of 2 1, the remaining enone had an optical purity of 36% [54], A similar procedure was employed by Asaoka et al. for kinetic resolution of 5-trimethylsilyl-2-cyclohexen-l-one, affording 50% of the trans adduct (57% ee, enantiomerically pure after recrystallization) with 41% of the starting enone (59% ee) [55a]. 

To a solution of 39.4 g of ethyl 3- and 4-(4-chloro-l-oxobutyl)-a,a-dimethylphenylacetate dissolved in 800 mL of methanol and 200 mL of water was added 40 g of NaOH. The mixture was refluxed for one hour. The cooled mixture was then concentrated in vacuo. The concentrate was diluted with water and washed with 2 portions of EtOAc. The aqueous layer was acidified with concentrated HCI and extracted with 2 portions of EtOAc. The extracts were dried over MgS04, filtered, and concentrated in vacuo to afford 30.3 g of crude product. The crude product was dissolved in 600 mL of EtOAc, 38 g of cinchonidine was added, and the mixture was stirred overnight. The resulting solids were filtered and washed with EtOAc and sucked dry under a rubber dam to afford 25 g of a solid 4-(cyclopropyl-oxo-methyl)-a,a-dimethylphenylacetic acid. 

Production of enantiomerically pure a-arylpropanoic acids, also known as profens, is of critical importance to the pharmaceutical industry because they constitute a major class of antiinflammatory agents. One of the most practical approaches to preparing optically pure a-arylpropanoic acids is by resolution with chiral amines. Notable examples include brucine, quinidine, cinchonidine, morphine, ephedrine, and a-(l-naphthyl)ethylamine. For instance, (.Sj-a-methylbenzylaminc and... 

Spectra for the diastereoisomeric pairs quinine-quinidine, cinchonine-cinchonidine alkaloids are mirror images of each other and mixtures have been determined using CD detection [57]. Spectra for the pilocarpine-isopilocarpine pair were such low quality that they could be used only for qualitative distinction. CD detection combined with UV detection was used to measure enantiomeric excesses in mixtures of L-hyoscyamine and atropine, i.e. racemic hyoscyamine. This subject is returned to in greater depth later. 

The indium-induced Reformatsky reaction with stoichiometric amounts of chiral amino alcohols such as cinnco-nine and cinchonidine gives optically active /3-hydroxy esters with 40%-70% ee (Table 19). In contrast to the smooth reaction with uncomplexed indium-based Reformatsky reagents, ketones do not react with the complexed indium Reformatsky reagents. Other chiral ligands, including (—)-spartein, (—)-norephedrine, (+)-(l-methylpyrrolidin-2-yl)diphenylmethanol, (+)-Dibutyl tartrate and (+)-l,l -bi-2-naphthol, are not effective for this reaction.324... 

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