Solvent effect on the enantioselectivity

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. 

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). 

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... 

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... 

Narasaka reported that TADDOL-TiCl2 was able to catalyze asymmetric DA reaction of cyclopentadiene with oxazolidinone derivatives of acrylates in the presence of 4A MS [148]. A remarkable solvent effect on the enantioselectivity was observed, and high enantioselectivity was attained using mesitylene as the solvent. Cycloadditions to oxazolidinone derivatives of acrylates were also efficiently catalyzed by dendritic or polymer-supported TADDOL-Ti catalysts [149]. From the structural determination of the 3-(( )-3-cinnamoyl)-l,3-oxazolidin-2-one adduct, it can be deduced that the transition state involves binding of the dienophile to the titanium catalyst via the N-acyl-oxazolidinone [19a] (Scheme 14.59). The diastereo-and enantioselectivity of this type of catalyst are thus probably owing to both electronic and steric effects from TADDOL ligand. 

Katsuki reported a much more catalyst derived from the diol (143) and EtAlCh (Scheme 6.138) [166]. Interestingly, solvent effect on the enantioselectivity was remarkable. Thus, both enantioselectivities of the mdo-adduct were obtained just by changing THE solvent to toluene. Although this solvent effect was not explained, a linear relationship between the optical purity of (143) and the optical purity of cycloadduct for the reaction in THE was observed. In contrast, a negative nonlinear effect was observed in CH2CI2. These results likely suggested a monomeric catalyst... 

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]. 

However, high conversions (82-91%) and high enantioselectivities (up to 90% ee) could be obtained in the cycUzation of the ( )-trisubstitued olefin 64 catalyzed by complex 61d (Scheme 41). hi this reaction neither solvent nor temperature has a significant effect on the enantioselectivity. In the case of the corresponding (Z)-trisubstituted olefins, conversions are high, but enantioselectivities are lower (ee < 36%). 

The minimum amount of catalyst needed to obtain maximum selectivity was determined to be 5 mol%. Larger quantities had no effect. Consistent with other literature reports[17], very small quantities of water (5 mol% = 2.5 mg E O/g 3) lowered the selectivities (Table 11.6, entry 4). Water sensitivity required thorough drying of the equipment, the starting materials and the solvents. In the case of tetrahydrofuran, drying was achieved by using activated 5 A molecular sieves (KF titration >0.005%). On the other hand, solvents used for crystallization of the starting material (3), such as 2-propanol and acetonitrile showed little effect on the enantioselectivities of the reaction (entries 6 and 7). 

The investigation by Wolff and coworkers into the solvent effects of the enantioselectivity of chymotrypsin-catalyzed hydrolyses [87] raises another question. The research aimed at corroborating the results reported by Jones and Mehes [91] on... 

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. 

This binary solvent system provided complete miscibility of the phases over a broad range of reaction temperatures and avoided the use of water during the catalytic conversion, with its established negative effects on the enantioselectivity [41]. Phase separation after complete reaction was induced by the addition of small quantities of water, and the recycling of the catalyst could be readily achieved. Remarkably, attachment of the dendrimer to the BINAP system did not lead to a decrease in selectivity. 

Oxazaborolidine catalyzed reductions are generally performed in an aprotic solvent, such as dichloromethane, THF, or toluene. When the reactions are run in a Lewis basic solvent, such as THF, the solvent competes with the oxazaborolidine to complex with the borane, which can have an effect on the enantioselectivity and/or rate of the reaction. The solubility of the oxazaborolidine-borane complex can be the limiting factor for reactions run in toluene, although this problem has been circumvented by using oxazaborolidines with more lipophilic... 

A variety of solvents can been used ranging from benzene and dichlorometh-ane to more polar media hke THF or DMF. Sometimes the solvent strongly influences the rate and ee,but there are also reactions that are quite insensitive to the nature of the solvent. In allyhc substitutions with anionic nucleophiles, the counter ion can have a strong effect on the enantioselectivity. In the reaction of... 

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. 

It is well known that various parameters (e.g. solvent, pH, immobilization, chemical modification and temperature) can have an effect on the enantioselectivity of enzyme-catalysed processes. Most studies in this respect have been carried out on hydrolytic enzymes, especially lipases, esterases and proteases [28]. Recent reports, especially those involving non-hydrolytic enzymes, are discussed below. 

Enantiopreference of lipases and esterase toward secondary alcohols and the corresponding primary amines, (a) A general model showing the shape of the fast-reacting enantiomer. L represent a large substituent, while M represents a medium-sized substituent. This enantiomer reacts faster in both acylation and hydrolysis reactions, (b) Examples of well-resolved alcohols and amines show M substituents of a no more than a few carbons and significantly larger L substituents. The alcohol marked with the arrow reacts in the meso-diol. Solvent has little effect on the enantioselectivity of lipases and esterases because the substrate is buried. 

Solvent effect in the enantioselective hydrogenation of 2,2,2-trifluoroacetophenone on cinchonine-modified Pt/Al203 was studied in 10 different solvents. Application of strongly basic solvents inverted the sense of enantiodifferentiation from (5)-alcohol. 

---