Cinchonidine based catalyst

In 2006, Ohkata and coworkers found that the natural cinchonidine (CD) functions as a Brans ted base catalyst (1 mol%) in the reaction between chloromethyl ketones 193 and (3-substituted methylidenemalononitriles 194 to furnish the corresponding tetrasubstituted trans-cyclopropanes 195 with enantioselectivities of up to 82% ee (Scheme 9.68) [62]. The 9-0H-protected derivatives provided almost no enantios-electivity, indicating that the hydrogen bonding is crucial for stereoinduction. 

Cinchonidine-derived catalyst 173 (10 mol%) has been also employed in the asymmettic synthesis of 4-alkytiden glutamic acid derivatives through a tandem conjugate addition-eUminalion reaction between the Schiff base of glycine tm-butyl ester and activated aUytic acetates under PTC conditions using CsOHH O as base [276]. The reaction, which is performed at -78°C in allows the preparation... 

The prototypical chiral bifunctional acid-base catalyst is quinine. Quinine, qninidine, cinchonine and cinchonidine all bear a basic tertiary amine group encased in a quinuclidine skeleton and an adjacent OH group capable of hydrogen bonding (Fig. 6.1). 

The hydrogenation of ehtyl pyurvate (EtPy) was carried out at 23 °C in a SS autoclave equipped with an injection chamber for separate introduction of the modifier Cinchonidine (CD) and Troger s base (TB) was used as modifiers. Different batches of EtPy, (Fluka) and Pt/Al203 catalysts (Engelhard E 4759, 5 %w Pt, Dpt = 25 %) were used. Experimental details incliding GC analysis can be found elsewhere [3,12]. The optical yield was calculated as e.e. = ([R]-[S])/([R]+[S]). The e.e. values were corrected for the amount of racemic product formed in minor amount in the reactor prior to the injection of CD. 

A characteristic feature of this solid-phase amino acid synthesis is the use of the phosphazene bases 53 and 54 for the PTC alkylation reaction [64, 65]. Because these compounds, which are soluble in organic media, do not react with alkyl halides, both alkyl halide and phosphazene bases can be added together at the start of the reaction, which is useful practically [65], Cinchonine and cinchonidine-derived salts, e.g. 25, were found to be very efficient catalysts. Under optimum conditions the alkylation proceeds with enantioselectivity in the range 51-99% ee, depending on the alkyl halide component [65], Seventeen different alkyl halides were tested. After subsequent hydrolysis with trifluoroacetic acid the corresponding free amino acids were obtained in high yield (often >90%). 

The use of Merrifield resin-bound alkaloid-based organocatalysts has also been reported [66-67]. The best results were obtained when attachment to the Merrifield resin was made via the hydroxy moiety of a (cinchonidine) alkaloid derivative [67]. The immobilization of alkaloid-derived catalysts on poly(ethylenglycol) (and modifications thereof) was also developed [68a, b]. Furthermore, asymmetric catalytic alkylations under micellar conditions were reported [68c],... 

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. 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

Dehmlow and coworkers screened several analogues of dnchona-based PTCs bearing an N-(9-anthracenylmethyl) group [17]. Especially, in the case of 2-isopropyl naphthoquinones, the nonnatural deazacinchonidine derivative catalyst 11 showed better results compared to those obtained with the natural cinchonidine-derived analogue 12, in terms of both the catalytic activity and the enantioselectivity (84% ee) in this reaction (Scheme 5.12). 

Asymmetric Michael additions can also be performed under phase-transfer conditions with an achiral base in the presence of a chiral quaternary ammonium salt as a phase-transfer agent. Conn and coworkers conducted the Michael addition of 2-propyl-l-indanone (13) to methyl vinyl ketone under biphasic conditions (aq 50% NaOH/toluene) using the cinchonine/cinchonidine-derived chiral phase-transfer catalysts (PTCs), 14a and 14b, as a catalyst (Scheme 9.5). However, only low to... 

A new kind of enantioselective [1,3]-proton transfer in aza-allylic systems was reported, namely, the N-benzylimines 30 were converted to the more thermodynamically favored N-benzylidene derivatives 31 as shown in Scheme 4. Among the chiral bases (i )-(-l-)-N,Ar-dimethyl-l-phenylethylamine, (li ,2S)-(-)-N-meth-ylephedrine, and (-)-cinchonidine employed as catalysts, only (-)-cinchonidine showed an asymmetric induction. A series of optically active 3-polyfluoroalkyl-P-amino acids 32, which are of great pharmaceutical interest, was prepared in 87 to 93% yields with ee s in the range of 15 to 36% [36]. 

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