Amines kinetic resolution

Studies of transaminases in kinetic resolution elucidated several benefits. Compared to asymmetric synthesis the equilibrium favors product formation if pyruvate is used as an amino acceptor. To get enantiopure amines, kinetic resolution is an acceptable choice with yields of 50%. Various (R)- and (S)-selective transaminases are well established nowadays, leading to enantiopure (S)- and (R)-amines, with high ee. Unfortunately product inhibition is one major disadvantage of kinetic resolution. If a critical concentration of product is achieved, the maximum conversion is prevented. Based on kinetic modeling in a previous study from Shin and Kim, the inhibitory effects were based on the strong binding of the product to the PLP cofactor. Consequently the binding of the amino acceptor is hindered, and conversion of the substrate is not possible [72]. 

A very interesting approach to optically active sulphoxides, based on a kinetic resolution in a Pummerer-type reaction with optically active a-phenylbutyric acid chloride 269 in the presence of /V,A -dimethyIaniline, was reported by Juge and Kagan332 (equation 149). In contrast to the asymmetric reductions discussed above, this procedure afforded the recovered sulphoxides in optical yields up to 70%. Chiral a, /1-unsaturated sulphoxides 270 were prepared via a kinetic resolution elaborated by Marchese and coworkers333. They found that elimination of HX from racemic /i-halogenosulphoxides 271 in the presence of chiral tertiary amines takes place in an asymmetric way leading to both sulphoxides 270 and 271, which are optically active (optical yields up to 20%) with opposite configurations at sulphur (equation 150). 

Table 1.3 Influence ofthe organic solvent on the enantioselectivity of the protease subtilisin in the kinetic resolution ofthe racemic amine (9) (expressed as the ratio ofthe initial rate of acylation of the pure enatiomers, Vs/vr).

The resolution of racemic ethyl 2-chloropropionate with aliphatic and aromatic amines using Candida cylindracea lipase (CCL) [28] was one of the first examples that showed the possibilities of this kind of processes for the resolution of racemic esters or the preparation of chiral amides in benign conditions. Normally, in these enzymatic aminolysis reactions the enzyme is selective toward the (S)-isomer of the ester. Recently, the resolution ofthis ester has been carried out through a dynamic kinetic resolution (DKR) via aminolysis catalyzed by encapsulated CCL in the presence of triphenylphosphonium chloride immobilized on Merrifield resin (Scheme 7.13). This process has allowed the preparation of (S)-amides with high isolated yields and good enantiomeric excesses [29]. 

Scheme 7.19 Dynamic kinetic resolution of primary amines.

Chiral Recognition. The use of chiral hosts to form diastereomeric inclusion compounds was mentioned above. But in some cases it is possible for a host to form an inclusion compound with one enantiomer of a racemic guest, but not the other. This is caUed chiral recognition. One enantiomer fits into the chiral host cavity, the other does not. More often, both diastereomers are formed, but one forms more rapidly than the other, so that if the guest is removed it is already partially resolved (this is a form of kinetic resolution, see category 6). An example is use of the chiral crown ether (53) partially to resolve the racemic amine salt (54). " When an aqueous solution of 54 was... 

Kinetic resolution of racemic allylic acetates has been accomplished via asymmetric dihydroxylation (p. 1051), and 2-oxoimidazolidine-4-carboxy-lates have been developed as new chiral auxiliaries for the kinetic resolution of amines. Reactions catalyzed by enzymes can be utilized for this kind of resolution. ... 

In the case of the ketone (12), a racemic mixture was converted to an optically active mixture (optical yield 46%) by treatment with the chiral base (13). This happened beeause 13 reacted with one enantiomer of 12 faster than with the other (an example of kinetic resolution). The enolate (14) must remain coordinated with the chiral amine, and it is the amine that reprotonates 14, not an added proton donor. 

This mechanism is the same as that of 19-23 the products differ only because tertiary amine oxides cannot be further oxidized. The mechanism with other peroxyacids is probably the same. Racemic (3-hydroxy tertiary amines have been resolved by oxidizing them with t-BuOOH and a chiral catalyst one enantiomer reacts faster than the other.This kinetic resolution gives products with enantiomeric excesses of > 90%. 

Aral S, Bellemin-Laponaz S, Fu GC (2001) Kinetic resolution of amines by a nonenzymatic acylation catalyst. Angew Chem Int Ed 40 234-236... 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

The first reductive kinetic resolution of racemic sulphoxides was reported by Balenovic and Bregant. They found that L-cysteine reacted with racemic sulphoxides to produce a mixture of L-cystine, sulphide and non-reduced optically active starting sulphoxide (equation 147). Mikojajczyk and Para reported that the reaction of optically active phosphonothioic acid 268 with racemic sulphoxides used in a 1 2 ratio gave the non-reduced optically active sulphoxides, however, with a low optical purity (equation 148). It is interesting to note that a clear relationship was found between the chirality of the reducing P-thioacid 268 and the recovered sulphoxide. Partial asymmetric reduction of racemic sulphoxides also occurs when a complex of LiAlH with chiral alcohols , as well as a mixture of formamidine sulphinic acid with chiral amines, are used as chiral reducing systems. ... 

If, according to a modified Horeau method (partial kinetic resolution of a racemate), an optically active carboxylic acid is treated with an excess of racemic amine or alcohol, the configuration of the carboxylic acid can be inferred from the optical rotation of the residual amine or alcohol [48]... 

This catalytic system can be used for the kinetic resolution of di-substituted 1-pyrrolines, for which high ee-values are achieved for both the amine and the recovered materials, especially when they are substituted in positions 2 and 5 (Table 6.6) [111]. Moreover, it should be noted that acyclic enamines are converted with high ee-values into their corresponding amines (89-98% ee Table 6.7), which is in sharp contrast to what is obtained for acyclic imines (vide supra) [112]. 

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]. 

Catalytic sol-gel lipase immobilizates were rapidly commercialized (by Fluka) after their invention in 1995 because of their remarkably stable activity in esterification reactions (and also in the kinetic resolution of chiral alcohols and amines) along with unique stability (residual activity of 70% even after 20 reaction cycles is common). The original procedure for the encapsulation produced by the fluoride-catalysed hydrolysis of mixtures of RSi(OCH3)3 and Si(OCH3)4 has been improved... 

Figure 5.19 Recycling experiments in the kinetic resolution of racemic amine using the sol-gel CaLB immobilizate prepared with 18-crown-6 as an additive. (Reproduced from ref. 30, with permission.)... 

The kinetic resolution of racemic trans ester 76a using catalytic amounts of chiral amine-borane 78 and di-f-butyl peroxide as initiator under pho-tolytic conditions at - 74 °C provided the enantioenriched (R,R) product in 74% ee after 52% consumption of the racemate [64-67]. For the ester 76b, (R,R) product in 97% ee was isolated after 75% consumption at -90°C (Scheme 20). 

Scheme 20 Chiral amine-borane catalyzed kinetic resolution...

B. Kinetic Resolution Using the Chiral-Amine-Catalyzed Thiol Addition... 

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