Cinchonidine complex

Theoretical studies aimed at rationalizing the interaction between the chiral modifier and the pyruvate have been undertaken using quantum chemistry techniques, at both ab initio and semi-empirical levels, and molecular mechanics. The studies were based on the experimental observation that the quinuclidine nitrogen is the main interaction center between cinchonidine and the reactant pyruvate. This center can either act as a nucleophile or after protonation (protic solvent) as an electrophile. In a first step, NH3 and NH4 have been used as models of this reaction center, and the optimal structures and complexation energies of the pyruvate with NH3 and NHa, respectively, were calculated [40]. The pyruvate—NHa complex was found to be much more stable (by 25 kcal/mol) due to favorable electrostatic interaction, indicating that in acidic solvents the protonated cinchonidine will interact with the pyruvate. 

Figure 4. Side and top views of the energetically most favorable complexes formed between protonated cinchonidine and methyl pyruvate which would yield (R)-methyl lactate (left) and (S)-methyl lactate (right), respectively, upon hydrogenation. The complexes have been accomodated on a space filling model of platinum (111) surface in order to illustrate the space requirements of the adsorbed complexes. For the sake of clarity, in the side views the carbon atoms of the reactant are marked with a white square and the oxygen atoms with an o. Data taken from ref. [41].

The first approach applied for [cinchonidine (CD) - a-keto ester] complex was also unsuccessful. In the open conformation CD cannot provide the required steric shielding. In open form either the quinuclidine or the quinoline moiety of CD will interact with the substrate. It has already been demonstrated that the quinuclidine moiety has a crucial role both in the rate acceleration and the induction of ED [13]. 

Figure 2 The open fonn of cinchonidine-methyl pyruvate complex.

Hydrogenation of ethyl pyruvate in the presence of cinchonidine. In our previous studies [3, 4,14] variety of experimental data were obtained, which could not be explained by existing models [1,2] proposed earlier. These results are as follows [3,4,12] (i) the monotonic increase type behaviour of the optical yield - conversion dependencies, (ii) the complexity of the reaction kinetics, (iii) side reactions catalyzed by CD. It was also demonstrated that the enantio-differentiation can be induced if the modifier is injected into the reactor during racemic hydrogenation. 

FIGURE 1.16 Job plot for the complexes of 0-9-fert-butylcarbamoyl-6 -neopentoxy-cinchonidine selector and DNB-Leu enantiomers. Symbols /J-enantiomer ( ), 5-enantiomer (O)- The shifts of the most diagnostic H9 proton was monitored as function of increasing molar fractions X of DNB -Leu enantiomers and the total concentrations were 10 mM in methanol-rir. (Reproduced from N.M. Maier et al., J. Am. Chem. Soc., 124 8611 (2002). With permission.)... 

As much as the quinoline ring is concerned useful information on the existence or absence of ir-K-interactions with corresponding aromatic moieties in the selectands could indeed be derived by help of CIS of aromatic protons. Substantial upheld CIS in the range of AS = -0.24 to —0.37 ppm have been detected in the S -complex of DNB-Leu with the 0-9-tert-butylcarbamoyl-6 -neopentoxy-cinchonidine selector for the quinoline protons and the proton in para-position of the DNB group, while the corresponding / -complex was devoid of this effect [92], Essentially the same observation was made for the DNB-Ala-Ala selectand, but not for DNB-Ala-Ala-Ala,... 

Theoretical calculations proved that the reaction intermediate leading to R-ethyl lactate on cinchonidine-modified Pt(lll) is energetically more stable than the intermediate leading to the S-ethyl lactate [147], However, the catalytic system is complex and the formation and breaking of intermediates are transient, so it is certainly difficult to obtain direct information spectroscopically. It is therefore advisable to use simplified model systems and investigate each possible pairwise interaction among reactants, products, catalyst, chiral modifier, and solvent separately [147, 148]. In order to constitute these model systems, it is important to get initial inputs from specific catalytic phenomena. 

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. 

Metalloporphyrins have been used for the development of MIP for detection of a 9-ethyladenine nucleobase derivative [35]. With the increase of the template concentration, the bulk polymer exhibited a red shift in the absorbance spectra. This shift allowed for the quantitative detection of the template, which showed formation of a 1 1 monomer-template complex. Moreover, cinchonidine was imprinted using metalloporphyrin and MAA as the functional monomers [40]. The resulting MIP provided high selectivity against a diastereomer of the... 

Scheme 1 a The [2 + 2] cycloaddition product of prochiral trans 2-butene with Si dimers of the Si(100) surface leads to chiral adsorbate complexes, b Hydrogenation of prochiral a-keto esters over platinum is a heterogeneously catalyzed reaction leading to chiral alcohols. Using cinchonidin as chiral modifier makes this surface reaction enantioselective. In a similar fashion, TA-modified nickel is a highly enantioselective catalyst for /3-keto ester hydrogenation... 

More successful asymmetric reductions have been based on amine (particularly alkaloid) complexes of bis(dimethylglyoximato) cobalt(II), also known as cobaloxime(II) and represented Co(dmg)2 (compound VII). Cobaloxime-chiral amine complexes have been used to catalyze the hydrogenation of both olefinic and ketonic substrates (Fig. 24). It has been determined that hydroxyamine modifiers, for example, alkaloids such as quinine, quinidine, and cinchonidine, are most effective. The highest optical purity obtained thus far has been 71%, observed for reduction of benzil in benzene solution at 10° using quinine as the... 

Unfortunately, the immobilization of the alkaloid ligands did not result in the simultaneous immobilization of the osmium catalyst due to the weak binding of cinchonidine to the osmium complexes. In most studies, leaching of the osmium catalyst was reported and supplementation of the osmium catalyst was necessary after recovery of the immobilized chiral ligand. In other studies, the recycled ligands were used without further addition of the osmium catalyst resulting in reduced yields or longer reaction times. 

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... 

The 1,4-addition of 4-tert-butyl benzenethiol to 4-inethyl-4-phenyl-2,5-cyclohexanedienone catalyzed by cinchonidine is more complex as, in addition to a 1 1 adduct 9, the bis-addition product 10 is formed. The monoaddition product consists of trans- and cu-isomers in a 3 1 ratio with 17% ee and 52% ee, respectively (determined by 13C-NMR spectroscopy of the corresponding acetals with optically active alcohols)8. ... 

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