Parallel enantiomeric excess

Enantiomeric or specific synthesis of cyanohydrin is influenced by the reaction medium, cyanide source, water content, buffer pH, enzyme, and temperature during the HNL-catalyzed reaction. To maximize the enantiomeric excess of the cyanohydrin product, care must be taken to minimize the parallel chemical (nonenzymatic) condensation and racemi-zation of products. 

Spectrophotometric assays can be used for the estimation of the enantiosel-ectivity of enzymatic reactions. Reetz and coworkers tested 48 mutants of a lipase produced by epPCR on a standard 96-well microtiter plate by incubating them in parallel with the pure R- and S-configured enantiomers of the substrate (R/S-4-nitrophenol esters) [10]. The proceeding of the enzyme catalyzed cleavage of the ester substrate was followed by UV absorption at 410 nm. Both reaction rates are then compared to estimate the enantiomeric excess (ee-value). They tested 1000 mutants in a first run, selecting 12 of them for development of a second generation. In this way they were able to increase the enantiomeric excess from 2% for the first mutants to 88% after four rounds of evolutive optimization. 

In parallel with the search for catalytic systems, an impressive amount of results in the field of enantioselective allylation has emerged (equation 8). The pioneering work of Marshall and Tang, using a chiral (acyloxy)borane 6 (CAB) system57, was followed by titanium-based catalysts 758 and 859-62 leading to various homoallylic alcohols with enantiomeric excess up to 98%. 

Figure 4 Enantiomeric excess (ee) obtained after irradiation of a racemic Cr(III)trisJ oxalato solution with unpolarized light at A = 695.5 nm, as a function of magnetic fielcL with an irradiation direction k either parallel or perpendicular to the magnetic field Bij Each point was obtained with a fresh racemic starting solution. (From Ref. 28.)...

The assymetric Strecker reaction of diverse imines, including aldimines as well as ketoimines, with HCN or TMSCN provides a direct access to various unnatural and natural amino acids in high enantiomeric excesses, using soluble or resin-linked non-metal Schiff bases the corresponding chiral catalysts are obtained and optimized by parallel combinatorial library synthesis [93]. A rather general asymmetric Strecker-type synthesis of various imines and a, 9-unsaturated derivatives is catalyzed by chiral bifunctional Lewis acid-Lewis base aluminum-containing complexes [94]. When chiral (salen)Al(III) complexes are employed for the hydrocyanation of aromatic substituted imines, excellent yields and enatio-selectivities are obtained [94]. 

Kinetic racemic resolution, as described in Section 4.2.5, suffers from the fact that the ratio of the substrate enantiomers to be resolved changes during the progress of the transformation. In order to circumvent low enantiomeric excess and low yields of the desired product, strategies hke dynamic kinetic resolution (DKR) [59] and parallel kinetic resolution [60] have been introduced. In the first case, racemization, for example, of the substrate is much faster than the undesired transformation of the slower reacting enantiomer, thus keeping an equal ratio of the substrate enantiomers during the whole process. Parallel kinetic resolution makes... 

Polymerised preformed [(N,N -dimethyl-l,2-diphenylethane diamine)2Rh] complex allows us to obtain enantioselective material. We have then shown that it is possible to imprint an optically pure template into the rhodium-organic matrix and to use the heterogeneous catalyst in asymmetric catalysis with an obvious template effect. The study of yield versus conversion graphs has shown that the mechanism occurs via two parallel reactions on the same site without any inter-conversion of the final products. Adjusting the cross-linker ratio at 50/50 allows us to find a compromise between activity and selectivity. Phenyl ethyl ketone (propiophenone) was reduced quantitatively in 2 days to (R)-l-phenyl propanol with 7tf% enantiomeric excess We have then shown that the imprinting effect is obvious for molecules related in structure to the template (propiophenone, 4 -trifluoromethyl acetophenone). It is not efficient if the structure of the substrate is too different to that of the template. 

A suitable catalyst for the synthesis of (R)-cyanohydrins is the enzyme (R)-oxynitrilase from bitter almonds. It catalyzes exclusively si-face addition of hydrogen cyanide to benzaldehyde or other aldehydes. A competing non-enzymatic parallel reaction lowers the enantiomeric excess of the product155, 56]. 

The method is particularly suited for high-throughput measurement of enantiomeric excess on a small (nano) scale. It is hence useful in the screening of a large number of candidate enantioselective catalysts in parallel tests. 

The obvious first test of methylene-bis(oxazolines) 6 was the copper-catalyzed cyclopropanation. Among the various derivatives that we had prepared (6 R = benzyl, c-alkyl, phenyl, tert-hutyl the bulky t rt-butyl-substituted derivative proved to be the most effective ligand, giving similarly high enantiomeric excesses as the semicorrin Ic (R = CMe20H) (Scheme 14) [25]. The same results were obtained by Masamune and coworkers in an independent parallel study [28]. More recently, Lowenthal and Masamune showed that the method works also well for certain trisubstituted and unsymmetrically disubstituted cis-olefins if the di-t rt-butyl-substituted ligand is replaced by structurally modified bis(oxazolines) [32]. 

The incorporation of N-phthaloyl amino acids into the dirhodium(II) platform afforded excellent asymmetric cyclopropanation catalysts [81b, 97]. In contrast to other phthaloyl catalysts [97], the X-ray crystal structure of Rh2(S-PTTL)4 (2), reported by Fox et al. revealed that the four phthalimido groups are situated on one face of the catalyst in a chiral crown structure (Figure 9.10) [93]. The four Bu- groups are directed on the other face of the catalyst, and aU C- Bu bonds are parallel to the Rh-Rh bond. Compound 2 exhibits high diastereoselectivity and yields for cyclopropanation with a-alkyl-a-diazoesters (Table 9.2, entry 2). The enantiomeric excess (ee) increases with the a-alkyl diazoester substituent size, and the highest 99% ee and 95% yield were achieved in the reaction of styrene with ethyl-2-diazo-5-methylhexanoate [93]. 

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