Cinchonine, catalytic reaction

Although thiolacetic acid additions are free-radical reactions (60), it was found recently that the addition to electron-poor olefins can be base catalyzed (61) (eqs. [14], [15]). Thus the (S)-(-) adduct is obtained with an e.e. of 54% when cyclohexenone is treated with thiolacetic acid in benzene in the presence of catalytic amounts of cinchonine. The reaction appears to be quite general, although very high e.e. s (>80%) have not yet been achieved. 

The first example of a catalytic asymmetric Horner-Wadsworth-Emmons reaction was recently reported by Arai et al. [78]. It is based on the use of a chiral quaternary ammonium salt as a phase-transfer catalyst, 78, derived from cinchonine. Catalytic amounts (20 mol%) of organocatalyst 78 were initially used in the Homer-Wadsworth-Emmons reaction of ketone 75a with a variety of phospho-nates as a model reaction. The condensation products of type 77 were obtained in widely varying yields (from 15 to 89%) and the enantioselectivity of the product was low to moderate (< 43%). Although yields were usually low for methyl and ethyl phosphonates the best enantioselectivity was observed for these substrates (43 and 38% ee, respectively). In contrast higher yields were obtained with phosphonates with sterically more demanding ester groups, e.g. tert-butyl, but ee values were much lower. An overview of this reaction and the effect of the ester functionality is given in Scheme 13.40. 

The catalytic asymmetric Horner-Wadsworth-Emmons reaction was realized by use of the quaternary ammonium salts 7 derived from cinchonine as a phase transfer catalyst.1631 Thus, tert-butylcyclo-hexanone 85 reacted with triethyl phosphonoacet-ate 86 together with RbOH-H20 in the presence of the ammonium salts 7, and then the product 87 was isolated after reesterification by treatment with acidic ethanol, as shown in Scheme 27 Among the... 

The use of compounds with activated methylene protons (doubly activated) enables the use of a mild base during the Neber reaction to 277-azirines. Using ketoxime 4-toluenesulfonates of 3-oxocarboxylic esters 539 as starting materials and a catalytic quantity of chiral tertiary base for the reaction, moderate to high enantioselectivity (44-82% ee) was achieved (equation 240). This asymmetric conversion was observed for the three pairs of Cinchona alkaloids (Cinchonine/Cinchonidine, Quinine/Quinidine and Dihydro-quinine/Dihydroquinidine). When the pseudoenantiomers of the alkaloid bases were used, opposite enantioselectivity was observed in the reaction. This fact shows that the absolute configuration of the predominant azirine can be controlled by base selection. 

As mentioned in the previous section, nowadays, readily available and inexpensive cinchona alkaloids with pseudoenantiomeric forms, such as quinine and quinidine or cinchonine and cinchonidine, are among the most privileged chirality inducers in the area of asymmetric catalysis. The key feature responsible for their successful utility in catalysis is that they possess diverse chiral skeletons and are easily tunable for diverse types of reactions (Figure 1.2). The presence of the 1,2-aminoalcohol subunit containing the highly basic and bulky quinuclidine, which complements the proximal Lewis acidic hydroxyl function, is primarily responsible for their catalytic activity. 

Scheme 4.12 Catalytic asymmetric Strecker reaction of N-Js aldimines and ketoimines by activation of 2,2 -biphenol with cinchonine.

The hydrogenolysis/decarboxylation/asymmetric protonation reaction cascade of acyclic benzyl P-oxo-esters such as 47 catalyzed by Pd/C with H2 in the presence of a catalytic amount of cinchonine 43 afforded the (S)-ketone 48 with enantioselec-tivities up to 75% ee, similar to previous results obtained with other P-amino alcohols. The reaction was carried out at room temperature in a short reaction time [28]. The best solvent for both yield and ee was ethyl acetate, compared with acetonitrile and THF. Comparative performances of cinchona alkaloids with other commonly used P-aminoalcohols are displayed on Scheme 7.22. 

Access to optically active 2-fluoro-l-tetralone 53 was achieved using the same palladium-mediated cascade reaction [30]. The catalytic enantioseiective decarbox-ylative protonation of 2-fluoro benzyl P-keto ester 54 in the presence of 30 mol% of quinine 20 afforded enantioenriched (S)-tetralone 53 in 65% ee (Scheme 7.24). The reaction was very sensitive to the nature of the palladium catalyst used. Furthermore, a minor amount of defluorinated product was observed. Several other cinchona derivatives were tested including analogues of cinchonine described by Brunner in organocatalytic EDP (see Section 7.5.3), but these chiral inductors afforded low selectivities (<30% ee). 

Shortly later, Brunner demonstrated the uselessness of copper [34]. The reaction of hemimalonate 45a carried out at room temperature in THF with 10mol% of cinchonine 43 without copper afforded 46a with 34% ee (Scheme 7.26), comparable to that obtained with copper but with a higher reaction rate. Beside its chiral inducting effect, the alkaloid also has a catalytic role in the decarboxylation process since the substrate is perfectly stable at room temperature in the absence of base. 

Early studies on the catalytic asymmetric Michael reactions were conducted with readily available amines of natural origin as hsted in Fig. 4. (-)-Quinine (1) and (+)-quinidine (2) are pseudo-enantiomeric concerning the aza[2.2.2]bicyclooc-tane and quinohne moiety, and generally give the antipodes. The same situation holds for (-i-)-cinchonine (3) and (-)-cinchonidine (4) which are demethoxylat-ed derivatives of 1 and 2. 

The only other example of an enantioselective base-catalyzed Diels-Alder reaction is illustrated in Scheme 53. A hydroxypyrone (71) is the substrate which undergoes activation by a catalytic amount of cinchonine (69a, R=H), subsequently reacting with N-methylmaleimide to form the derived tricyclic adduct with good selectivity [141]. 

Asymmetric induction in Michael reactions. Wynberg and Helder have reported asymmetric syntheses of Michael adducts from inactive donors and methyl vinyl ketone in the presence of catalytic amounts of quinine and cinchonine. Enantiomeric ratios were affected by the solvent highest inductions were obtained in toluene and tetrachloromethane. Quinine and cinchonine favored different enantiomers of the adduct. The enantiomeric excess was determined in one case from PMR spectroscopy to be 68%. 

The reactions described above require a stoichiometric amount of a chiral Ug-and to obtain the products in optically active form. Shioiri and coworkers have reported a catalytic version of the enantioselective HWE reaction using phosphonoacetates. Various chiral quaternary ammonium salts were examined as phase-transfer catalysts, generating enantioselectivity in chiral a,P-unsatu-rated esters which ranged from 37% ee to 55% ee. The best result (55% ee) was obtained by using a quaternary ammonium salt derived from cinchonine and RbOH as a base [Eq. (26)] [75]. 

A multicomponent bifunctional catalytic system based on a titanium complex was also used for the efficient enantioselective cyanation of aldehydes with ethyl cyanoformate [221]. The catalyst was readily prepared by the reaction of Ti(O Pr)4 with (S)-6,6 -Br2BINOL in combination with cinchonine and (lR,2S)-(—)-N-methylephedrine. As shown in Scheme 14.91, the optimized catalyst combination (10 mol%) promotes the reaction smoothly to afford the desired cyanohydrins ethyl carbonates in moderate to excellent isolated yields (up to 95%) with high enantioselectivities (up to 94% ee). Although the mechanistic aspects... 

In 2011, Moreau, Greek and coworkers reported a multicatalytic process [6] merging two consecutive enamine catalytic cycles based on a Michael addition/a-amination cascade reaction [7]. The Michael addition of aldehydes to p-nitrostyrene followed by the electrophilic amination were catalyzed, respectively, by the diphenylprolinol silylether 5 and the 9-amino-(9-deoxy)-cpf-cinchonine 6 (Scheme 12.4), both previously described by Hayashi and coworkers [8] and Melchiorre and coworkers [9]. One interesting feature of this reaction is that diphenylprolinol silylether 5 can specifically catalyze the Michael addition, while 9-amino-(9-deoxy)-ep/-cinchonine 6 is required to promote the electrophilic amination. The Michael addition of propionaldehyde to p-nitrostyrene was achieved by using only 5 mol% of catalyst 5 in chloroform at 0 C. After completion of the reaction, dibenzyl azodicarboxylate (DEAD, 1.5 equiv), trifluoroacetic acid (15 mol%) and the second catalyst 6 (5 mol%) were added. The expected product 7 was obtained as a single diastereomer in good yield (80%) and with excellent enantioselectivity (ee 96%). Various nitroalkenes bearing electron-rich and electron-deficient aryl... 

The enantioselective decarboxylative protonation of aminomalonic acid derivatives has been also extensively investigated by Rouden et al. [17]. Their first contribution in this area aimed at preparing enantioenriched pipecoUc esters by decarboxylation of A7-acetyl piperidinohemimalonate 24 [17]. Among the different cinchona alkaloids investigated, the best result was obtained by means of 9-ep/-cinchonine-benzamide 19b, previously developed by Brunner [14, 16]. Pipecolic ester 25 was obtained in up to 52% ee when conducting the reaction in THF at room temperature for 24 h. Various bis-cinchona alkaloids such as (DHQDj AQN 26 or (DHQDj Pyr 27 were also evaluated providing modest enantiomeric excesses not exceeding 24% ee. Most of the results outlined in this study were obtained in the presence of a stoichiometric amount of the chiral base. The few attempts to carry out experiments under catalytic conditions seem to... 

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