Enzymatic kinetic resolution racemic amines

Alternative synthetic approaches include enantioselective addition of the organometallic reagent to quinoline in the first step of the synthesis [16], the resolution of the racemic amines resulting from simple protonation of anions 1 (Scheme 2.1.5.1, Method C) by diastereomeric salts formation [17] or by enzymatic kinetic resolution [18], and the iridium-catalyzed enantioselective hydrogenation of 2-substituted quinolines [19]. All these methodologies would avoid the need for diastereomer separation later on, and give direct access to enantio-enriched QUINAPHOS derivatives bearing achiral or tropoisomeric diols. Current work in our laboratories is directed to the evaluation of these methods. 

Scheme 4.10 Enzymatic kinetic resolution of racemic amines.

It has been demonstrated that the combination of metal-catalysed racemisation and enzymatic kinetic resolution is a powerful method for the synthesis of optically active compounds from racemic alcohols and amines. There are many metal complexes active for racemisation, but the conditions for enzymatic acylation often limit the application of the metal complexes to DKR. In the case of DKR of alcohols, complementary catalyst systems are now available for the synthesis of both (R)- and (5)-esters. Thus, (R)-esters can be obtained by the combination of an R-selective lipase, such as CAL-B or LPS, and a racemisation catalyst, whereas the use of an A-selective protease, such as subtilisin, at room temperature provides (5)-esters. The DKR of alcohols can be achieved not only for simple alcohols but also for those bearing various additional functional groups. The DKR of alcohols has also been applied to the synthesis of chiral polymers and coupled to tandem reactions, producing various polycyclic compounds. 

The racemization of primary amines discussed in Sect. 4.2.3.2 was also combined with an enzymatic kinetic resolution of primary amines in a two-step manner (Scheme 34) [18]. CALB was used for the kinetic resolution. After the first resolution... 

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]. 

Dynamic kinetic resolution enables the limit of 50 % theoretical yield of kinetic resolution to be overcome. The application of lipase-catalyzed enzymatic resolution with in situ thiyl radical-mediated racemization enables the dynamic kinetic resolution of non-benzylic amines to be obtained. This protocol leads to (/f)-amides with high enantioselectivities. It can be applied either to the conversion of racemic mixtures or to the inversion of (5)-enantiomers. 

The enzymatically catalyzed kinetic resolution of amino alcohols has been established on the multi-ton scale by BASF [7] (Scheme 7.14). Initial studies gave poor selectivity for the unprotected alcohols, as the resolution of trows-2-aminocyclopen-tanol (racemic 28) gave the amine (S,S) 29 and the amide (R,R) 30 in 25% . When the hydroxy functionality was protected as an ether, then resolution of racemic benzyl ether 31 proceeds with high to the give the amine (S,S) 32 and the RR amide 33 with >99.5 and 93 % respectively [33, 34]. 

The dynamic kinetic resolution (DKR) of secondary alcohols and amines (Scheme 11.11) is a prominent, industrially relevant, example of chemo-enzymatic chemistry in which a racemic mixture is converted into one enantiomer in essentially 100% yield and in high ee. This is in sharp contrast to enzyme-catalyzed kinetic resolutions that afford the desired end-product in a yield of at most 50%, while 50% of the starting material remains unreacted. In DKR processes, hydrolases are typically employed as the enantioselective acylation catalyst (which can be either R or S selective) while a concurrent racemization process racemizes the remaining substrate via an optically inactive intermediate. This ensures that all starting material is converted into the desired end-product. The importance of optically pure secondary alcohols and amines for the pharmaceutical industry triggered the development of a number of approaches that enable the racemization of sec-alcohols and amines via their corresponding ketones and imines, respectively [42],... 

Scheme 19.9 Dynamic kinetic resolution of a secondary amine based on ruthenium-catalyzed racemization and enzymatic acylation.

Scheme 19.13 Dynamic kinetic resolution of cyclic P-amino acid derivatives based on amine-catalyzed racemization and enzymatic oxazinone hydrolysis.

The DKR procedure described above was improved by Meijer and coworkers in 2007 [87]. The protocol was improved both in terms of reaction time (26 h instead of 72 h) and the required amount of acyl donor (the excess acyl donor could be reduced to 1.1 equiv). This was accomplished using a more effective acyl donor isopropyl 2-methoxyacetate for the enzymatic acylation. CALB was used for the kinetic resolution, and the para-methoxyphenyl derivative of the Shvo catalyst was used for racemization (22). All the DKR reactions were performed under reduced pressure (750 mbar) to eliminate the isopropyl alcohol from the reaction mixture. The isopropyl alcohol can be oxidized to acetone, and the latter can in subsequent reaction steps form unwanted condensation products with the amine substrates. The revised protocol afforded the products with excellent selectivity (96-99% ee). The yields were slightly lower (56-80%) than those obtained with the Backvall protocol [86], mainly due to problems with purification. 

Acyl transferase enzymes have been widely used to synthesize chiral esters, amides, alcohols, and amines. In many cases, these conversions involve kinetic resolutions of alcohols, adds, esters, amines, and amides. Of course, since each enantiomer makes up half of the racemic mixture, kinetic resolutions can provide a maximum 50% yield. This limitation can be overcome by racemizing or inverting the configuration of the unreacted substrate during the enzymatic reaction. Such a scheme is referred to as a dynamic kinetic resolution and theoretically allows complete substrate conversion to product along with 100% chemical yield of a single product enantiomer. 

Deracemization of a number of pharmaceutically valuable building blocks has been carried out by biocatalytic processes. They include epoxides, alcohols, amines, and acids [12,14,190-192]. Dynamic kinetic resolution (DKR) involves the combination of an enantioselective transformation with an in situ racemization process so that, in principle, both enantiomers of the starting material can be converted to the product with a high yield and ee. The racemization step can be catalyzed either enzymatically by racemases or nonenz3nnatically by transition metals. 

Chiral amines have been attracting attention as an important composition, particularly for pharmaceutical products. The organic synthetic methods of optically active amine compounds have been developed through the traditional resolution of racemic amines with the formation of diastereomer salts using an optically active mandelic acid or tartaric acid. Enzymatic synthesis has mainly used lipase and S- or R-stereoselective amine transaminase (AT) [29-31] (Figure 19.7). Turner et al. successfully synthesized chiral (R)- and (S)-amines by kinetic resolution using a combination of stereoselective AT and d- or L-amino acid oxidase (AAOx) [32] (Figure 19.7). However, the theoretical yield of the products has been limited to 50% in the kinetic resolution. 

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