Enantioselectivity selectivity factor

Both catalysts are especially suitable for the KR of benzylic alcohols (eq 1). Cl-PIQ is generally more catal)dically active and achieves good to excellent enantioselectivity (selectivity factors s in the 30-100 range), while BTM is much more enantioselective (s in the 100-350 range). Both propionic and isobutyric anhydrides have proved to be useful as achiral acyl donors in BTM-catalyzed acylations, the latter usually leading to higher enantios-electivities, but somewhat lower reaction rates. Cl-PIQ has been used primarily in combination with propionic anhydride. Chloroform is the solvent of choice in most cases. BTM-catalyzed reactions are sensitive to moisture (rapid catalyst deactivation) and, therefore, should be carried out in the presence of anhydrous Na2S04. 

A number of studies have recently been devoted to membrane applications [8, 100-102], Yoshikawa and co-workers developed an imprinting technique by casting membranes from a mixture of a Merrifield resin containing a grafted tetrapeptide and of linear co-polymers of acrylonitrile and styrene in the presence of amino acid derivatives as templates [103], The membranes were cast from a tetrahydrofuran (THF) solution and the template, usually N-protected d- or 1-tryptophan, removed by washing in more polar nonsolvents for the polymer (Fig. 6-17). Membrane applications using free amino acids revealed that only the imprinted membranes showed detectable permeation. Enantioselective electrodialysis with a maximum selectivity factor of ca. 7 could be reached, although this factor depended inversely on the flux rate [7]. Also, the transport mechanism in imprinted membranes is still poorly understood. 

The choice of the particular upward pathway in the kinetic resolution of rac-19, that is, the specific order of choosing the sites in ISM, appeared arbitrary. Indeed, the pathway B C D F E, without utilizing A, was the first one that was chosen, and it led to a spectacular increase in enantioselectivity (Figure 2.15). The final mutant, characterized by nine mutations, displays a selectivity factor of E=115 in the model reaction [23]. This result is all the more remarkable in that only 20000 clones were screened, which means that no attempt was made to fully cover the defined protein sequence space. Indeed, relatively small libraries were screened. The results indicate the efficiency of iterative CASTing and its superiority over other strategies such as repeating cycles of epPCR. 

If kinetic resolution is being studied, the ratio of pseudo-e nantiomers can be measured by MS, allowing for the determination of ee-values (and/or of selectivity factors E). The same applies to the reaction of pseudo prochiral compounds. This system has been used successfully in the directed evolution of enantioselective enzymes. However, it should work equally well in the case of asymmetric transition metal catalyzed reactions. In the original version about 1,000 ee-deter-minations were possible per day (Figure 6).94 The second-generation version based on an 8-channel multiplexed spray system enables about 10,000 samples to be handled per day, the sensitivity being 2% ee.96... 

Finally, Inanaga s contribution to the development of chiral 4-dialkylaminopyrid-ine based catalysts for enantioselective acyl transfer relied on the use of C -symmetric 4-PPY derivative 36 (Fig. 7) [130]. This compound was obtained in an enantiopure form by selective cleavage of a carbamate intermediate using Sml, and allowed the KR of various. yec-alcohols with selectivity factors ranging from y = 2.1 to 14. 

Enantioselective enzyme-catalyzed reactions may involve the transformation of a prochiral substrate into a chiral product, in which case the selectivity is measured by the enantiomeric excess (ee). The transformations can also involve kinetic resolution of racemic substrates, in which case enantioselectivity is measured by the selectivity factor E reflecting the relative rates of reaction of the R)- and (5)-enantiomer. 

The kinetic resolution of (5, 7 )-l-methoxy-2-propylacetate was investigated using various commercially available hydrolases. The agreement between the apparent selectivity factor app and the actual value true determined by GC turned out to be excellent at low enantioselectivity E — 1.4— 13), but less so at higher enantioselec-tivity (20% variation at E— 80). This limitation may cause problems when attempting to enhance enantioselectivity beyond E — 50. 

Kawabata et al. found that peptides 24a-c containing a 4-pyrrolidinopyridine (PPY) unit afford selectivity factors in the range 5.6-7.6 in the kinetic resolution of the N-acylated amino alcohol roc-26 with iso-butyric anhydride (Scheme 12.12) [30]. In further studies by Miller et al. the octapeptide 27 was identified as even more enantioselective [31], As shown in Scheme 12.13, selectivity factors as high as 51 were achieved. 

High enantiomeric excess in organocatalytic desymmetrization of meso-diols using chiral phosphines as nucleophilic catalysts was achieved for the first time by Vedejs et al. (Scheme 13.21) [36a], In this approach selectivity factors up to 5.5 were achieved when the C2-symmetric phospholane 42a was employed (application of chiral phosphines in the kinetic resolution of racemic secondary alcohols is discussed in Section 12.1). A later study compared the performance of the phos-pholanes 42b-d with that of the phosphabicyclooctanes 43a-c in the desymmetrization of meso-hydrobenzoin (Scheme 13.21) [36b], Improved enantioselectivity was observed for phospholanes 42b-d (86% for 42c) but reactions were usually slow. Currently the bicyclic compound 43a seems to be the best compromise between catalyst accessibility, reactivity, and enantioselectivity - the monobenzoate of hydrobenzoin has been obtained with a yield of 97% and up to 94% ee [36b]. 

In a interesting example of organocatalysis, Suzuki et al. studied the enantioselective acylation of secondary alcohols using chiral NHCs [11,12]. The approach was partly based on the work of Nolan and Hedrick who had independently reported NHC-catalyzed transesterifications [13,14]. The enantioselective acylation was subsequently improved by using more sterically hindered acylating agents such as diphenylacetate derivatives (Scheme 4), leading to selectivity factors (s = kn, ) of up to 80 [15,16]. 

Plots of selectivity factor (calculated using Equation 2 and the data from Table I) for mephenytoin and hexobarbital enantiomers versus CD concentration are shown in Figure 3 a,b (22) The profiles of relation oC vs [(3-CD] for these two compounds are different because two different factors determine resolution of their enantiomers difference in K- values for hexobarbital and difference in kl t ftnn values for mephenytoin. The latter case represents 5nuinteresting example the resolution of its enantiomers arises from the great differentiation in the adsorption of diastereoisomeric (3-CD complexes. The calculated selectivity factor for these complexes is ca 3 (see Table I). In this particular case selectivities of the two processes adsorption and com-plexation in the bulk mobile phase solution are opposite to each other enantioselectivity arising from selective adsorption dominating over differentiation in the solution. Unfortunately the stabilities of diastereoisomeric -CD mephenytoin complexes are relatively small and solubility of -CD in the mobile phase solution is rather limited. Therefore one cannot shift the comple-xation equilibrium... 

Hundreds of impressive examples of enantioselective lipase-catalysed reactions are known, including industrial processes as in the case of the BASF method of chiral amine production (Collins et al. 1997 Breuer et al. 2004 Schmid and Verger 1998). However, the classical problem of substrate acceptance or lack of enantioselectivity (or both) persists. We were able to meet this challenge in model studies regarding the hydrolytic kinetic resolution of the ester rac-1 with formation of carboxylic acid 2, catalysed by the lipase from Pseudomonas aeruginosa. The wild-type (WT) lipase is only slightly (S )-selective, the selectivity factor amounting to a mere E = 1.1 (Scheme 1). 

Lipases are the most frequently used enzymes in organic chemistry, catalyzing the hydrolysis of carboxylic acid esters or the reverse reaction in organic solvents [3,5,34,70]. The first example of directed evolution of an enantioselective enzyme according to the principle outlined in Fig. 11.2 concerns the hydrolytic kinetic resolution of the chiral ester 9 catalyzed by the bacterial lipase from Pseudomonas aeruginosa [8], This enzyme is composed of 285 amino acids [32]. It is an active catalyst for the model reaction, but enantioselectivity is poor (ee 5 % in favor of the (S)-acid 10 at about 50 % conversion) (Fig. 11.10) [71]. The selectivity factor E, which reflects the relative rate of the reactions of the (S)- and (R)-substrates, is only 1.1. 

In the same period, Deng and coworkers also reported that the racemic 5-alkyl l,3-dioxolane-2,4-diones 51 undergo kinetic resolution in the presence of alcohols (ethanol or allyl alcohol) and dimeric cinchona alkaloids such as (DHQD)2AQN (11, 10mol%) [42]. A range of 5-alkyl dioxolanes 51 were highly enantioselectively converted to the (R)-esters (R)-52 (selectivity factors up to 133) (Scheme 11.27). The hydrolysis of the reaction mixture converts the remaining (S)-53 to the (S)-acid (s)-53 that can be easily separated from the (R)-ester 52 by extraction (Scheme 11.27). 

With the water wheel it is not merely a question of one enantiomer reacting and the other one not. It is, rather, a question of one reacting quickly (kfast) and the other reacting slowly (ksk)W). We will see much more of something called the s value later. This is the selectivity factor and is quite simple s = kfast/ kslow or, in other words, the relative rate. Consider two enantiomers of an alcohol being enantioselectively acetylated by some means. One reacts fast and one more slowly. 

In situ preparation of imprinted polymer films on a QCM was performed using S-propranolol as the template [4]. A pre-polymerization mixture containing MAA, trimethylolpropane trimethacrylate (TRIM, a crosslinker), the template and acetonitrile (porogen) was poured on the electrode of the QCM and immediately covered by glass and polymerized by UV irradiation. A low amount of the crosslinker (about 40 % of total monomers) was used to prepare more flexible polymer, allowing the polymer to be stably adhered on the electrode. The sensor showed enantioselective response with a selectivity factor of 5, and the detectability of S-propranolol was 50 iM in acetonitrile. 

Palladium catalysts have found application in the oxidative kinetic resolution of secondary alcohols such as 1-phenylethanol. (—)-Sparteine, was used to obtain high levels of enantioselection however, it was found that the nature of the palladium source was critical in obtaining a high chemical selectivity factor Pd2(dba)3 proved superior to Pd(OAc)2 but not as effective as Pd(nbd)Cl2-The observed difference in reactivity, for various palladium catalysts, was attributed to subtle differences in the solubility of the palladium-precatalysts in toluene as well as their ability to complex with (—)-sparteine (eq 32). ... 

Ding et al. described the chiral separation of enantiomers of several dansyl-amino acids by HPLC in the reversed-phase mode. The natural logarithms of selectivity factors (In a) of all the investigated compounds depended linearly upon the reciprocal of temperature (1/T). For most processes of enantioseparation, enantioselectivity, a, decreased with increasing of temperature, and the processes of chiral recognition were enthalpy-controlled. It is very interesting that enantioselectivity, a, increased with increasing temperature for dansyl-threonine (Dns-Thr) at a... 

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