Enantioselectivity solvent polarity

The enantioselective hydrogenation of a,p-unsaturated acids or esters, using 5wt% Pt/Al203 or Pd/Al203 commercial catalysts doped with cinchonidine (CD), was deeply investigated to evidence the specific activity of Pd or Pt and the role of the reaction parameters and solvent polarity. Finally, the steric and electronic effects of different substituent groups were also studied. 

One example of the use of 2D-NMR experiments in conformational analysis is the study of molecular interactions between cinchonidine and acetic acid [26]. These alkaloids are used as chiral auxiliaries in enantioselective hydrogenations, and the enantiomeric excess is dependent on solvent polarity, acetic acid being a good solvent This suggests that protonation and a preferred conformation play a role in achieving high enantioselectivities. With a combination of COSY-experiments, 3J coupling constants and NOESY experiments, it was shown that one conformer is preferred in acidic solutions. 

Typically, solvents are screened to identify one that gives optimal results. Assuming that the substrate and catalyst are soluble, solvent polarities varying from alkanes, aromatics, halogenated, ethers, acetonitrile, esters, alcohols, dipolar aprotic to water have been used. An example of this, using a ketone and the rhodium cp TsDPEN catalyst, is shown in Table 35.3. Further optimization of this reaction improved the enantiomeric excess to 98%. A second example involved the reduction of 4-fluoroacetophenone in this case the enantioselectivity was largely unaffected but the rate of reduction changed markedly with solvent. Development of this process improved the optical purity to 98.5% e.e. 

Collins and co-workers have also reported on an enantioselective catalytic Diels—Alder cycloaddition, in which zirconocene and titanocene bis(triflate) complexes were used as catalysts [104], The influence of the solvent polarity on the observed levels of stereoselectivity is noteworthy. For example, as shown in Scheme 6.34, with 108 as the catalyst, whereas in CH2C12 (1 mol% catalyst) the endo product was formed with 30% ee (30 1 endoxxo, 88% yield), in CH3N02 solution (5 mol% catalyst) the enantioselectivity was increased to 89% (7 1 endoxxo, 85% yield). Extensive 1H and 19F NMR studies further indicated that a mixture of metallocene—dienophile complexes was present in both solutions (-6 1 in CH2C12 and -2 1 in CH3N02, as shown in Scheme 6.34), and that most probably it was the minor complex isomer that was more reactive and led to the observed major enantiomer. For example, whereas nOe experiments led to ca. 5 % enhancement of the CpH proton signals of the same ring when Hb in the minor complex was irradiated, no enhancements were observed upon irradiation of Ha in the major complex. 

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. 

Correlation of Enantioselectivity with Solvent Polarity and Hydrophobicity... 

As an example of the use of SC-CO2 in an enzymatic reaction, the lipase-catalyzed esterification of oleic acid with racemic ( )-citronellol should be mentioned. At 31 °C and 8.4 MPa, the (—)-(5)-ester is formed enantioselectively in SC-CO2 with an optical purity of nearly 100% [924]. The reaction rate is enhanced by increasing pressure, i.e. by increasing the solvation capability or solvent polarity of SC-CO2. A linear correlation has been found between reaction rate and the solvatoehromie solvent polarity parameter 1(30) see Section 7.4 for the definition of t(30). 

As we have seen, the Diels-Alder reaction can be both stereoselective and regioselective. In some cases, the Diels-Alder reaction can be made enantioselective Solvent effects are important in such reactions. The role of reactant polarity on the course of the reaction has been examined. Most enantioselective Diels-Alder reactions have used a chiral dienophile (e.g., 199) and an achiral diene,along with a Lewis acid catalyst (see below). In such cases, addition of the diene to the two faces of 199 takes place at different rates, and 200 and 201 are formed in different amounts. An achiral compound A can be converted to a chiral compound by a chemical reaction with a compound B that is enantiopure. After the reaction, the resulting diastereomers can be separated, providing enantiopure compounds, each with a bond between molecule A and chiral compound B (a chiral auxiliary). Common chiral auxiliaries include chiral carboxylic acids, alcohols, or sultams. In the case illustrated, hydrolysis of the product removes the chiral R group, making it a chiral auxiliary in this reaction. Asymmetric Diels-Alder reactions have also been carried out with achiral dienes and dienophiles, but with an optically active catalyst. Many chiral catalysts... 

Fig. 12 Influence of different anions A on the enantioselectivity of catalyst 16 as a dependence on the solvent polarity in the hydrogenation of 1 b.

In the polar solvent, the [(MeCN)4Pd](BF4)2/DMSO system facilitates the generation of a cationic tetracoordinate intermediate (TC) due to the solvent polarity and weakly coordinating nature of BFj. The same levels of enantioselectivity obtained under the polar conditions regardless of the Pd(II) sources imply that the reaction proceeded via the identical intermediate TC in the Pd(OCOCF3)2/DMSO system. In the polar solvent, Pd(OCOCF3)2 associatively... 

Analogous to the pyruvates, the same decrease in ee with increasing solvent polarity was found in the enantioselective hydrogenation of ketopan-tolactone into pantolactone over Pt-alumina-Cnd catalyst (Schuerch et al. ). The most suitable solvent proved to be toluene ee 78%) but in acetic acid solution the strong increase of ee, which was observed in the case of pyruvates, was not seen and the optical yield of pantolactone reached only up to 35% (see results in Part 5.4.). 

Buergi and Baiker studied the influence of different solvents for the conformations of Cnd in the enantioselective hydrogenation of ketopanto-lactone. They claimed three conformations of Cnd at RT closed (1) , closed (2) and open (3) . The latter structure is the most stable in polar solvents and increases with solvent polarity, as suggested by experiments on the enantioselective hydrogenation to pantolactone with a maximal ee of 78% in toluene solution, which is the solvent with the lowest dielectric constant. The increase in dielectric constant in the series of cyclohexane, hexane, diethyl ether and THF, decreases ee up to 50% and in EtOH and water even to 15%, in accordance with a decrease in the population of the open (3) conformation of Cnd. 

Conjugate addition of the y-butyrolactam to enals was promoted by diphenyl-prolinol trimethylsilyl ether 12 via the iminium activation process (Scheme 32, second hne) [53]. A satisfactory level of enantioselectivity was generally observed irrespective of the solvent polarity, although the use of aqueous acetonitrile was superior for optimizing the chemical yield and enantioselectivity. In addition, acidic additives had apparent effects on the reaction profile and the highest diastereoselectivity was attained with 2-fluorobenzoic acid. The synthetic utility of this site- and stereoselective transformation was demonstrated in a series of product derivatizations, including the three-step synthesis of a cAMP-specific phosphodiesterase (PDE IV) inhibitor (Scheme 32, third hne). 

Lynam C, Diamond D (2005) Varying solvent polarity to tune the enantioselective quenching of a calixarene host J Mater Chem 15 307-314... 

---