Solvent effect on enantioselectivity

The second group of studies tries to explain the solvent effects on enantioselectivity by means of the contribution of substrate solvation to the energetics of the reaction [38], For instance, a theoretical model based on the thermodynamics of substrate solvation was developed [39]. However, this model, based on the determination of the desolvated portion of the substrate transition state by molecular modeling and on the calculation of the activity coefficient by UNIFAC, gave contradictory results. In fact, it was successful in predicting solvent effects on the enantio- and prochiral selectivity of y-chymotrypsin with racemic 3-hydroxy-2-phenylpropionate and 2-substituted 1,3-propanediols [39], whereas it failed in the case of subtilisin and racemic sec-phenetyl alcohol and traws-sobrerol [40]. That substrate solvation by the solvent can contribute to enzyme enantioselectivity was also claimed in the case of subtilisin-catalyzed resolution of secondary alcohols [41]. 

TABLE 7.3 Solvent Effect on Enantioselectivity Catalysis by Copper (L-abrine) as the Lewis Acid... 

In view of the predictive properties of the octanol-water partition coefficient, logP, in the description of enzymatic activity [79], this parameter has received much attention. However, as argued in an early but still authoritative review compiled by Carrea and coworkers [80], its usefulness in the correlation of solvent effects on enantioselectivity appears to be limited. The problem is exemplified by the entries in Figure... 

Applications of chirally modified titanium Lewis acids have been reported most cases use various acetal diols derived from tartrate as the chiral auxiliary26 33,31 90. Various methods of catalyst preparation are known, as well as the use of different types of dienes (open-chained, cyclopentadiene) and dienophiles (acroleins, acrylates, crotonates, fumarates and amides derived from oxazolidinone), including intramolecular cycloaddition30. Addition of 4 A molecular sieves can improve asymmetric induction31,34 (as observed with the Sharpless epoxidation, loc. cit 31 in ref 6) and shows remarkable solvent effects on enantioselectivity. This method has been applied to the asymmetric Diels-Alder cycloaddition of cyclopentadiene and open-chain dienes to acrylamides28, 35. 

Nitta, Y., Kobiro, K. (1995) Solvent effect on enantioselective hydrogenation of ( )-fl//7/ja-phenylcinnamic acid with cinchonidine-modified Palladium catalysts, Zeft 165-165. 

Furthermore, pronounced halide counterion effects and solvent effects on enantioselectivity were observed, thus supporting this hypothesized mechanism. 

Clearly, complete understanding of solvent effects on the enantioselectivity of Lewis-acid catalysed Diels-Alder reactions has to await future studies. For a more detailed mechanistic understanding of the origins of enantioselectivity, extension of the set of solvents as well as quantitative assessment of the strength of arene - arene interactions in these solvent will be of great help. 

Narasaka et al.16 reported that 53 catalyzes Diels-Alder reactions of 54-type substrates with diene in the presence of 4 A molecular sieves (Scheme 5-18). A remarkable solvent effect on the enantioselectivity is observed. High enantio-selectivity is attained using mesitylene as the solvent. As shown in Scheme 5-18, the reaction of 54a with isoprene proceeds smoothly in this solvent, affording product 55a with 92% ee. Other 3-(3-substituted acryloyl)-l,3-oxazolidin-2-ones 54b-d also give good results (75-91% ee) when reacted with cyclopentadiene. 

Catalyst 329, prepared from trimethylaluminum and 3,3/-bis(triphenylsily 1)-1,1 /-bi-2-naphthol, allowed the preparation of the endo cycloadduct (2S )-327 with 67% ee. The use of non-polar solvents raised the ee, but lowered the chemical yield213. Recently, it was reported that the reaction to form 327 exhibited autoinduction when mediated by catalyst 326214. This was attributed to a co-operative interaction of the cycloadduct with the catalyst, generating a more selective catalytic species. A wide variety of carbonyl ligands were tested for their co-operative effect on enantioselectivity. Sterically crowded aldehydes such as pivaldehyde provided the best results. Surprisingly, 1,3-dicarbonyl compounds were even more effective than monocarbonyl compounds. The asymmetric induction increased from 82 to 92% ee when di(l-adamantyl)-2,2-dimethylmalonate was added while at the same time the reaction temperature was allowed to increase by 80 °C, from -80 °C to 0°C. 

The solvent present in biphasic reactions can still have an effect on the enzyme even though the enzyme functions primarily in an aqueous microenvironment. A particularly dramatic example is the lipase AH (lipase from Burkholderia cepac/fl)-catalysed desym-metrization of prochiral 1,4-dihydropyridine dicarboxylic esters, where either enantiomer can be accessed in high enantioselectivity by using either water-saturated cyclohexane or diisopropyl ether (DIPE) respectively (Scheme 1.60). The acyl group used in acylation and deacylation can also have a dramatic effect on enantioselectivity. " ... 

Hirose, Y., Kariya, K., Sasaki, I., Kurono, Y., Ebiike, H. and Achiwa, K., Drastic solvent effect on lipase-catalysed enantioselective hydroloysis of prochiral 1,4-dihydropyridines. 

Column pressure usually has little effect on enantioselectivity in SFC. However, pressure affects the density of the mobile phase and thus retention factor [44]. Therefore, similar to a modifier gradient, pressure or density programming can be used in fast separation of complex samples [106]. Later et al. [51] used density/temperature programming in capillary SFC. Berger and Deye [107] demonstrated that, in packed column SFC, the effect of modifier on retention was more significant than that of pressure. They also showed that the enhanced solvent strength of polar solvent-modified fluid was nof due fo an increase in densify, caused by fhe addition of fhe liquid phase modifier, buf mainly due fo fhe change in composition. 

In this report the authors describe a surprising solvent effect on enantioselectivi-ties. Alcoholic solvents afford the opposite enantiomer using the same enantiomeric series of catalyst Eq. 9. This profound effect is presumably due to hydrogen bonding in the transition state on the nucleophilic enol and/or the carbonyl acceptor Eq. 10. These electrostatic interactions can be visualized with Models E and F. Although the enantioselectivity is reversed the values remain lower than when toluene is used. 

The generality of the solvent effect on the enantioselectivity was examined in the following examples using 1,3,5-trimethylbenzene (1,3,5-TMB) as the common solvent (under unoptimized reaction conditions). 

Despite the fact that solvent effects on enzyme enantioselectivity appear to resist our efforts to rationalize their outcome using commonly accepted solvent descriptors, the effects are certainly there. An impressive example is provided in a report on the successful resolution of ds/trans-( 1 R,5 R)-bicyclo[3.2.0]hept-6-ylidene-acetate ethyl esters, intermediates in the synthesis of GABA (y-aminobutyric acid) analogs, by the Pfizer Bio transformations and Global R D groups (Scheme 2.2) [136]. From a screening protocol, CaLB was identified as a reactive catalyst for the hydrolysis of the racemic mixture of / //-os lor enantiomers with approximately equal activity for the ds- and tmns-isomers and a rather modest (E = 2.7) preference for the /Z-(lR,5R)-enantiomers. Application of medium engineering resulted in a phenomenal increase in the enantioselectivity (addition of 40% acetone, E > 200), while the ds- and trans-isomers were still converted at an almost equal rate. 

H. Ebiike, and K. Achiwa, Drastic solvent effect on lipase-catalyzed enantioselective hydrolysis of prochiral 1,4-dihydropyridi-nes, Tetrahedron Lett. 1992, 33, 7157-7160. 

A detailed study of the effect of several reaction conditions was also conducted by the Kagan group [3], The nature of the solvent had a substantial effect on enantioselectivity. Compared with chloroform, much lower ee values were obtained with... 

Ir-f-binaphane complexes show good to excellent enantioselectivities but modest TONs and low TOFs for the hydrogenation of A -aryl imines with the general structure 27 (Table 15.3).14 The reaction has to be performed in poorly coordinating solvents such as dichloromethane and at a relatively high hydrogen pressure. As with the Ir-Josiphos catalysts, the best ee s are obtained with 2,6-disubstituted /V-aryl imines (Entries 1 and 2), whereas alkyl ketimines give low enantioselectivities (Entry 3). In some cases, the addition of I2 has a beneficial effect on enantioselectivity (Entries 4 and 5). 

Coupling attempts conducted with (R,S)-214 led to lower enantioselection upon C-C bond formation, an observation that points to the significant role played by the relative configuration (R,R) of the binaphthyl and ethylenediamine units in promoting asymmetric induction. This complex was found to be the most efficient among several different structural variations. Solvent effects on this transformation were also studied (Table 35), with toluene and chlorobenzene giving the best results. Low solubility of the catalyst (diethyl ether and diiso-... 

As with many catalytic systems, additives can play an important role. During optimization of the asymmetric rearrangement of cyclopentenyl tertiary ethers to chiral cyclohexenyl tertiary ethers, Hoveyda found a strong solvent effect on the enantioselectivity of the reaction using (97b). Lewis basic (see Lewis Acids Bases) additives were used to modify the catalyst since (97i) is Lewis acidic and coordination could change the equilibration of the Mo-alkyhdene isomers and, thus, could alter the enantioselectivity. Coordination of Lewis base to the metal center might also change the fit of the chiral pocket. Addition of 10 equiv (vs. substrate) of THF substantially increased the enantiomeric excess of the product in the model transformation (Table 10). ft was surmised that... 

Solvents effect equilibria and rates of reactions, which is not only important in synthesis and catalysis, but in other processes such as the rate of electron transfer. Thus far, the effect of chiral solvents on chiral recognition and enantioselective catalysis has not proven effective, but without further experiments, it is too early to draw any firm conclusions.10 There are many theories and rules relating to solvent effects on reactions, the majority developed with organic processes in mind, and discussions of these are not relevant here. Rather, the importance of solvent selection relevant to coordination chemistry will be illustrated with some key examples. 

The choice of the solvent had a significant effect on enantioselectivity and rate. MeOHCd/acetic acid and HCd/toluene are often the most effective modifier/ solvent combinations. 

Wynne D, Olmstead MM, Jessop PG. Supercritical and liquid solvent effects on the enantioselectivity of asymmetric cyclopropanation with tetrakis[l-[(4-tert-butylphenyl)sulfonyl]-(25)-pyrrolidinecarboxylate]dirhodium(II). J Am Chem... 

Since the formation of a chiral lithium alkoxide is likely to be involved in the asymmetric addition process, various ratios of the components (chiral ligand -BuLi 5a) were examined. The results of this study revealed a remarkable solvent effect on both efficiency and selectivity for -BuLi additions, and a dependence of the absolute configuration of the amine 6 on the solvent employed. The amino alcohols such as 7 and 8 gave only poor enantioselectivities in the butyl addition... 

Nitta, Y., Kubota, T., Okamoto, Y. (2004) Solvent effect on the structure sensitivity in enantioselective hydrogenation of alpha,beta-wnsatwaXed acids with modified palladium catalysts, J. Mol. Catal. A. Chem. 212, 155-159. 

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