Quinidine derivative

A THF solution of 4-chlorobutylzinc iodide (7 mmol, 1.4 equiv) prepared in over 90% yield from 4-chloro-l-iodobutane [40 °C, 2h, then 23 °C, lOh] was added at —10 °C to a solution of CuCN 2LiCl (7 mmol) in THF (7 mL). After 5 min at 0°C, the yellow-green solution was cooled to —78°C and the 1-bromoalkyne 22 (925 mg, 5 mmol) in THF was slowly added. The reaction mixture was stirred for 18 h at —65 °C. After the usual workup and purification by flash chromatography (Si02, hexane), the pure enyne 23 was obtained (800 mg, 81% yield). 

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FIGURE 1.2 Structure and stereochemistry of commercially available cinchona alkaloid CSPs, marketed under trade name CHIRALPAK by chiral technologies europe. QN denotes quinine- and QD quinidine-derived and AX refers to their anion-exchanger capabilities vide infra). 

FIGURE 1.35 SLM process using O-9-(l-adamantylcarbamoyl)-10,ll-dihydro-ll-octadecylsulfinylquinme and corresponding quinidine derivative as chiral carriers for the preparative separation of enantiomers of Al-derivatized amino acids (e.g., DNB-Leu). (a) ftinciple of the carrier SLM process with carrier-mediated transport (top) and (nonstereoselective) nonspecific transport processes (bottom), (b) General experimental setup of the SLM production unit with two membrane modules, (c) Multistage SLM purification process. P, permeate QD/QN, membrane modnles snpported with quinidine-derived and quinine-derived chiral carriers. R, S, D, L refers to the respective enantiomers of the selectand (DNB-Leu). (Reproduced from A. Maximini et al., J. Membr. ScL, 276 221 (2006). With permission.)... 

Ultrapurification of 50 mmolL DNB-D,L-Leucine in a Cascade of Five Stages with Two Modules and Two Enantiomeric Carrier (Quinine and Quinidine Derivative with 5 vol% Polysiloxane-supported Carrier) Transmembrane Material Stream J, Enantioselectivity a, Enantiomer Excess ee, Purity, and Yield of DNB-D-Leucine... 

Fig. 1. Representative examples of recent generation of synthetic quinine or quinidine derivatives.

Ricci et al. [85] reported the use of a quinidine-derived chiral catalyst in the asymmetric addition of nitromethane to iV-Boc imine 40. At around the same time, S chans and co-workers used a dihydroquinidine-derive chiral thiourea DHQD-134 applicable to nitromethane and nitroethane 149 [86]. The application of nitroethane conveniently generates a tertiary stereogenic center in the P-nitroamine product 151. The methodology presented by Schaus is also applicable to novel... 

C9-epi-122 98% conv. (99% ee) after 30h, respectively (Figure 6.40). This structure-efficiency relationship supported the results already published by the Soos group for quinine- and quinidine-derived thioureas (Figure 6.39) [278]. C9-epimeric catalysts were found to be remarkably more efficient in terms of rate acceleration and stereoinduction than the analogs of natural cinchona alkaloid stereochemistry. This trend was also observed for the corresponding (thio)ureas derived from DHQD as shown by the experimental results in Figure 6.40 [279]. 

Quinidine. Derived from cinchona (anti- bark (minor alkaloid), the anti-malarial agent quinine being a major alkaloid... 

By a similar but solvent-free method Plaquevent et al. produced the Michael adduct 30 from 2-pentyl-2-cyclopentenone in 91% yield and with 90% ee, by use of the quinine-derived catalyst 31 (Scheme 4.10) [16], When the quinidine-derived ammonium salt 32 was employed, 80% of the enantiomeric product ent-30 was ob-... 

A detailed study of the effect of modified quinidine derivatives was conducted by the same group [103]. In particular the effects on enantioselectivity of several substituents at the C9 position and of catalyst conformation were investigated, with interesting results - the enantioselectivity was almost unaffected by the O-acyl substituent at the C9 carbon atom (Scheme 6.41). For example, use of catalysts 90, 91, and 92, which are based on structurally different acyl substituents, gave the product (1 R,2S)-( I )-89a with enantioselectivity in the narrow range 89-92% ee. The yields, however, differed substantially, and did not exceed 54%. Interestingly, a more rigid quinidine derivative resulted in complete reversal of enantioselectivity... 

The a-cyanoacetates 12 are optimal substrates for the approach outlined in Scheme 2.26 due to the low pKa of the a-proton. It has been reported that the quinidine-derived alkaloid /fisocupridine (/ -ICD) can catalyze the direct a-amination of a-cyanoacetates 12 (Eq. 4) and /fdicarbonyl compounds [10], probably by an enolate having a chiral /MCD-H+ counterion as the intermediate. The a-amination of a-cyanoacetates 12 with di-tert-butyl azodicarboxylate 2c is an efficient process that proceeds with only 0.5 mol% of /MCD. The expected products 13, having a stereogenic quaternary carbon center, were isolated in excellent yields and with excellent levels of enantioselectivity independently by the nature of the aryl-substituent in the a-cyanoacetates, while the / -dicarbonyl compounds give slightly lower enantioselectivty (83-90% ee). 

An important step in the development of asymmetric MBH reactions was the introduction of the quinidine-derived /Msocupreidine catalyst (/MCD) 44, by the Hatalceyama group [64, 65]. /MCD mediated the addition of acrylate 43 to a variety of aromatic and aliphatic aldehydes even at —55 °C in DMF, and afforded (R)-adducts in good yields (40-58%) and excellent enantioselectivity (ee up to 99%) (Table 5.3). The contribution of the 1,1,1,3,3,3-hexafluoroisopropyl acryl ester (HFIPA) to the reactivity of the system deserves comment. This ester displayed... 

M. Lammerhofer and W. Lindner, Quinince and quinidine derivatives as chiral selectors. Beush type chiral stationary phases for high performance liquid chromatography based on chincona carbamates and their applications as chiral anion exchanger, J. Chromatogr. 741 (1966), 33. 

The quinidine derivative hydroquinidine had some beneficial effects in 10 patients with myotonic dystrophy with slow saccadic eye movements, apathy, and hjrper-somnia (42,43). However, two patients had nausea and epigastric pain and withdrew while taking the active treatment. Although there were no cases of cardiac abnormalities, the authors raised the concern that in patients with myotonic dystrophy, who have a high frequency of cardiac disturbances, the risk of cardiac... 

Later, a dramatic jump in the ee values was achieved by the same research group by introducing the thiourea moiety at the 6 -position of 44 [22]. Using 10 mol% of the quinidine-derived catalyst 46, the highly enantioselective Henry reaction between nitromethane and the aromatic aldehydes (electron-rich, electron-deficient, and... 

In 2006, Deng and coworkers reported that quinine/quinidine-derived catalysts (64a,b) bearing a free OH group at the C6 -position and bulky phenanthryl moiety at the 9( Opposition quite efficiently promoted the Michael addition of the a-substituted P-ketoesters 65 to the a,P-unsaturated ketones 66 (Scheme 9.21) [18]. The reaction with as little as 1.0mol% of catalyst 64 afforded excellent stereoselectivity and chemical yields (up to 98% ee with quantitative yield) for a wide range of both donors and acceptors. 

In contrast to the oxidative deavage of the C10-C11-moiety, hydroboration followed by oxidation furnishes Cll-functionalized quinine and quinidine derivatives. As an illustration, only transformations in the quinidine series are shown (cf. Scheme 12.14). Cll-aldehyde 58 was obtained either upon direct oxidation of the borane species with PCC/Si02 or via an improved stepwise procedure including (i) oxidation with Me3NO-2 H20 to yield the terminal alcohol 57 and (ii) subsequent Dess-Martin oxidation [35], Oxidation and esterification of alcohol 57 using Jones reagent and MeOH/HCl gave the Cl 1-ester 59, which is a suitable precursor for the synthesis of cinchona alkaloid macrocycles (Scheme 12.15) [38],... 

Scheme 12.19 Quinuclidines as a simple helix. Helicity of l-azabicyclo[2.2.2]octane and twist sense of quinidine-derived oxazatwistanes.

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