Kinetic resolution reactions 5 Values

An unselective wheel A selective wheel S Values, Equations Yields Standard Kinetic Resolution Reactions... 

The s-values for the lipase route and the phosphine route were not the same, but this is less important than the rates of enantiomer consumption being equal. Hence the relative amounts of lipase and phosphine were adjusted so that the rates of enantiomer consumption were equal. At the end of the reaction, one enantiomer of alcohol is bound to the polymer and the other has formed an ester in solution. They may be separated by filtration. Both reactions have products of higher ee s than predicted for the simple kinetic resolution reactions at 50% conversion. Note that really quite different reagents were used to react with the two enantiomers. 

Although several interesting nitrogen-centered nucleophiles have been developed with ARO reactions of epoxides (vide supra), kinetic resolutions with such reagents are unlikely to be of practical value for the recovery of enantioenriched terminal epoxides. This is due to the fact that these nucleophiles are too valuable to be discarded in a by-product of the resolution, are generally not atom-economical, and, particularly in the case of azide, may represent safety hazards. 

Furthermore, the same methodology was used for an approach towards enantiopure PGFla (2-46) through a catalytic kinetic resolution of racemic 2-43 using (S)-ALB (2-37) (Scheme 2.10) [14]. Reaction of 2-35, 2-36 and 2-43 in the presence of 2-37 led to 2-44 as a 12 1 mixture of diastereomers in 75 % yield (based on malonate 2-36). The transformation proceeds with excellent enantioselectivity thus, the enone 2-45 obtained from 2-44 shows an ee-value of 97 %. 

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... 

Chiral amines can also be produced using aminotransferases, either by kinetic resolution of the racemic amine or by asymmetric synthesis from the corresponding prochiral ketone. The reaction involves the transfer of an amino group, a proton and two electrons from a primary amine to a ketone, and proceeds via an intermediate imine adduct. A variety of chiral amines can be obtained with high to very high ee-values. Several transformations have been developed and can be carried out on a 100-kg scale [94]. 

Carbon dioxide is one of the most abundant carbon resources on earth. It reacts with an epoxide to give either a cyclic carbonate or a polycarbonate depending on the substrates and reaction conditions. Kinetic resolution of racemic propylene oxide is reported in the formation of both cyclic carbonate and polycarbonate. The fe ei value defined as ln[l-(conversion)(l+%ee)]/ln[l-(conversion)(l% ee)] reached 6.4 or 5.6 by using a Co(OTs)-salen complex with tetrabutylammonium chloride under neat propylene oxide or using a combination of a Co-salen complex and a chiral DMAP derivative in dichloromethane, respectively. 

The infrared radiation caused by the heat of reaction of an enantioselective enzyme-catalyzed transformation can be detected by modern photovoltaic infrared (IT)-thermographic cameras equipped with focal-plane array detectors. Specifically, in the lipase-catalyzed enantioselective acylation of racemic 1-phenylethanol (20), the (K)- and (S)-substrates were allowed to react separately in the wells of microtiter plates, the (7 )-alcohol showing hot spots in the IR-thermographic images (113,114). Thus, enantioselective enzymes can be identified in kinetic resolution. However, quantification has not been achieved thus far by this method, which means that only those mutants can be identified which have E values larger than 100 (113-115). 

The beneficial effect of the hydrophobicity of [BMIM]PFg was shown to extend to other enzymes a remarkably enhanced enantioselectivity was observed for lipases AK and Pseudomonas fluorescens for the kinetic resolution of racemic P-chiral hydroxymethanephosphinates (Scheme 31) (278). The ee values of the recovered alcohols and the acetates were about 80% when the enzymatic reactions were conducted in the hydrophobic [BMIMJPFg. In contrast, there was little enantioselectivity (<5%) observed with the enzymes in hydrophilic [BMIM]BF4. The lack of stereoselectivity in [BMIM]BF4 was attributed to the high miscibility of [BMIM]BF4 with water. The relatively hydrophilic ionic liquid is capable of stripping off the essential water from the enzyme surface, leading to insufficient hydration of the enzyme and a consequently strong influence on its performance (279). 

Hoft reported about the kinetic resolution of THPO (16b) by acylation catalyzed by different lipases (equation 12) °. Using lipases from Pseudomonas fluorescens, only low ee values were obtained even at high conversions of the hydroperoxide (best result after 96 hours with lipase PS conversion of 83% and ee of 37%). Better results were achieved by the same authors using pancreatin as a catalyst. With this lipase an ee of 96% could be obtained but only at high conversions (85%), so that the enantiomerically enriched (5 )-16b was isolated in poor yields (<20%). Unfortunately, this procedure was limited to secondary hydroperoxides. With tertiary 1-methyl-1-phenylpropyl hydroperoxide (17a) or 1-cyclohexyl-1-phenylethyl hydroperoxide (17b) no reaction was observed. The kinetic resolution of racemic hydroperoxides can also be achieved by chloroperoxidase (CPO) or Coprinus peroxidase (CiP) catalyzed enantioselective sulfoxidation of prochiral sulfides 22 with a racemic mixmre of chiral hydroperoxides. In 1992, Wong and coworkers and later Hoft and coworkers in 1995 ° investigated the CPO-catalyzed sulfoxidation with several chiral racemic hydroperoxides while the CiP-catalyzed kinetic resolution of phenylethyl hydroperoxide 16a was reported by Adam and coworkers (equation 13). The results are summarized in Table 4. 

With substrates 16b and 17a, Hoft and coworkers observed only low ee values of up to 4% for the hydroperoxides. On the other hand, phenyl ethyl hydroperoxide (16a) could be isolated in high enantiomeric excess of >99% from the CPO-catalyzed reaction. The observed enantioselectivities of the sulfoxides varied, depending on the conversion of the sulfide and the hydroperoxide used, being highest with 16a (92% ee). Unfortunately, the CPO-catalyzed resolution of chiral hydroperoxides is difficult on a preparative scale because of the high dilution necessary (0.5ttmolmL ). In the CiP-catalyzed kinetic resolution of 16a better results were obtained compared to the CPO-catalyzed reaction (see Table 5). 

The ee values of the sulfides 5aa and 5ba are significantly lower than those of the corresponding sulfones 2aa and 2ba. Kinetic resolution and substitution of the acyclic carbonates rac-3aa and roc-3ba with the thiol under the conditions used above proceeded with similar high selectivities and gave the carbonates ent-3aa and mt-3ba, respectively, and the sulfides 6aa and 6ba, respectively (entries 3 and 4). The reactions of the cyclic carbonates rac-laa and rac-lba went to 50%... 

All of the kinetic resolutions described above have been characterized in terms of yields and ee values of the recovered substrate and the product. In principle the efficiency of a kinetic resolution can also be described by the selectivity factor S [lu], the ratio of the rate constants for the reactions of the enantiomers of the substrate with the catalyst. For a Pd-catalyzed kinetic resolution of an allylic substrate obeying first-order kinetics in regard to the reaction of the substrate with the catalyst (unimolecularity) S can be calculated according to Eq. (1), which contains as variables the conversion (c) and the ee value of the substrate (ee ). 

The catalyst exhibited high enantiomer selectivity in the reaction of the six-membered cyclic acetate roc-lab with KSAc on a 2.5 mmol scale. This led to the isolation of the thioacetate 19aa with 97% ee in 48% yield and the acetate ent-lab with >99% ee in 43% yield (entry 8). The reaction came to a practically complete halt after 51% conversion of the substrate. In order to determine the selectivity factor S, the kinetic resolution of roc-lab was repeated and the ee values of the acetate and thioacetate were monitored over the whole course of the reaction (Fig. 

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