Classical kinetic resolution, racemic

The classical kinetic resolution of racemic substrate precursors allows only access to a theoretical 50% yield of the chiral ladone product, while the antipodal starting material remains unchanged in enantiomerically pure form. The regioseledivity for the enzymatic oxidation correlates to the chemical readion with preferred and exclusive migration of the more nucleophilic center (usually the higher substituted a-carbon). The majority of cydoketone converting BVMOs (in particular CHMOAdneto)... 

Figure 4.6 Classical kinetic resolution with subsequent reracemization of unconverted enantiomer Synthesis of pantoic acid from pantolactone applying a stirred-tank reactor, extraction module and racemization step...

Figure 4.7 Classical kinetic resolution synthesis of L-methionine from IV-acetyl-methionine applying an ultrafiltration-membrane reactor and crystallization step as well as racemization step...

In contrast to the asymmetrization of meso-epoxides, the kinetic resolution of racemic epoxides by whole fungal and bacterial cells has proven to be highly selective (see above). These biocatalysts supply both the unreacted epoxide enantiomer and the corresponding vidnal diol in high enantiomeric excess. This so-called classic kinetic resolution pattern of the biohydrolysis is often regarded as a major drawback since the theoretical chemical yield can never exceed 50% based on the racemic starting material. As a consequence, methods... 

Classical kinetic resolution of racemates is frequently employed for the preparation of enantiopure compounds. In order to circumvent the limitation... 

The first artificial catalysts for the BV oxidation of racemic cyclic ketones via classical kinetic resolutions were independently and almost simultaneously reported by Bolm et and Strukul and coworkers. b These studies produced chiral lactones in moderate ee using chiral Cu conplex 99 (Scheme 2.25 and diphosphane/Pt complex 111 (Scheme 2.26 as catalyst. 

As long as the a-substituent consists of an alkyl- or aryl-group, dynamic resolution is readily achieved, leading to chemical yields far beyond the 50% which would be the maximum for a classic kinetic resolution. However, in-sim racemization is not possible due to electronic reasons for a-hydroxy- [914], a-alkylthio- [899], ot-azido- [915], or a-acetylamino derivatives [916], which are subject to kinetic resolution. The same holds for substrates which are fully substituted at the a-posi-tion, due to the impossibility of form the corresponding enolate. 

Dynamic resolution of various sec-alcohols was achieved by coupling a Candida antarctica lipase-catalyzed acyl transfer to in-situ racemization based on a second-generation transition metal complex (Scheme 3.17) [237]. In accordance with the Kazlauskas rule (Scheme 2.49) (/ )-acetate esters were obtained in excellent optical purity and chemical yields were far beyond the 50% limit set for classical kinetic resolution. This strategy is highly flexible and is also applicable to mixtures of functional scc-alcohols [238-241] and rac- and mcso-diols [242, 243]. In order to access products of opposite configuration, the protease subtilisin, which shows opposite enantiopreference to that of lipases (Fig. 2.12), was employed in a dynamic transition-metal-protease combo-catalysis [244, 245]. 

Most recently, the combination of several (bio)catalytic steps onto each other in a cascade reaction [20] has resulted in the development of so-called deracemization techniques, which lead to the transformation of a racemate into a single stereoisomer as the sole product. In an economic sense, these methods are far superior to classic kinetic resolution, which provides two enantiomers each in 50% yield [21]. 

It is the combination of these twin goals that has led to the evolution of classical kinetic resolution into dynamic kinetic resolution (DKR). In such a process, it is possible in principle to obtain a quantitative yield of one of the enantiomers. Effectively, DKR combines the resolution step of kinetic resolution, with in situ equilibration or racemisation of the chirally labile substrate (Figure i.2). In DKR, the enantiomers of a racemic substrate are induced to equilibrate at a rate faster than that of the slow-reacting enantiomer in reaction with the chiral reagent (Curtin-Hammett kinetics). If the enantioselectivity is sufficient, then isolation of a highly enriched non-racemic product is possible with a theoretical yield of 100% based on the racemic substrate. 

Scheme 11 Various resolutions of racemic 5-methylcyclohexenone. (a) Classic kinetic resolution.

The chemoenzymatic DKR protocol combines the enzyme-catalyzed resolution of a racemic substrate with the in situ racemization of the less reactive enantiomer, thus, producing optically active products in up to quantitative yield. This is a significant improvement with respect to the maximum yield of 50% obtained in classic kinetic resolution (KR). However, certain requirements have to be fulfilled to achieve an efficient DKR 1) The substrate must racemize at least as fast as the subsequent enzymatic reaction (2) no product racemization has to occur under the reaction conditions and (3) the enzymatic reaction must be both irreversible and highly stereoselective. Given that the racemization rate is higher than the resolution rate, the aizyme... 

Catalytic kinetic resolution can be the method of choice for the preparation of enantioenriched materials, particularly when the racemate is inexpensive and readily available and direct asymmetric routes to the optically active compounds are lacking. However, several other criteria-induding catalyst selectivity, efficiency, and cost, stoichiometric reagent cost, waste generation, volumetric throughput, ease of product isolation, scalability, and the existence of viable alternatives from the chiral pool (or classical resolution)-must be taken into consideration as well... 

In carrying out kinetic resolution, these in the standard approach are limited to 50% yield regarding the racemate. However, different approaches were developed [28] to overcome this limitation. The classical standard solution is to reracemize the unconverted enantiomer. A more advanced solution is the establishment of a dynamic kinetic resolution that has considerably expanded the synthetic scope of chemical processes. Here, the unconverted enantiomer is, in contrast to the latter method, racemized in situ. A great number of novel enzymatic methods have been developed [29]. Within this chapter, process solutions for enzymatic resolutions of racemic mixtures will be highlighted. 

The catalytic RCM and kinetic resolution can be carried out in a single vessel as well. This is particularly important for the practical utility of the Zr-catalyzed resolution Because the best theoretical yield in a classical resolution is 50%, it is imperative that the racemic substrate is prepared readily (or 50% material loss will be too costly). In this instance, the racemic substrate is not only obtained efficiently, it is synthesized in a catalytic manner and need not even be isolated prior to the resolution. Two representative examples are illustrated in Scheme 4 [5a]. The tandem catalytic RCM, leading to rac-19 and its subsequent catalytic resolution proceeds with excellent efficiency the one-vessel, two-stage process... 

In one version, classical derivatization using a chiral reagent or NMR shift agent is simply parallelized and automated by the use of flow-through cells, with about 1400 ee measurements being possible per day with a precision of +5%. In the second embodiment, illustrated here in detail, a principle related to that of the MS system described in Section III.C is applied 98). Chiral or mexo-substrates are labeled to produce /. sewiio-enantiomers or psendo-meso-compo md that are then used in the actual screen. Application is thus restricted to kinetic resolution of racemates and... 

Classic resolntion has been performed by formation of diastereomeiic salts which could be separated. In a series of synthetic steps and when resolution is one step, it is of utmost importance that the correct chirality is introduced at an early stage. When a racemate is subject to enzyme catalysis, one enantiomer reacts faster than the other and this leads to kinetic resolution (Figure 2.2c). Results of hydrolysis using lipase B from Candida antarctica (CALB) and a range of C-3 secondary butanoates are shown in Table 2.1. 

In the presence of chiral polymerization catalysts, enantiomeric monomers are consumed at different rates (Scheme 75). Enantiomer-selective polymerization of racemic propylene oxide catalyzed by a diethylzinc-(-f)-bomeol system is a classical example of such kinetic resolution H 176). The polymeric product has an [a]D of +7.4°. The mechanism... 

Resolution of cheap racemic mixtures with enzymes is a common route to enantiomerically pure chemicals on an industrial scale. However, the yield with a classical resolution is limited to 50%. An in situ racemization of the undesired enantiomer, combined with the enzymatic kinetic resolution, gives rise to a dynamic kinetic resolution (DKR) that should in principle lead to a 100% yield in the desired isomer. In spite of several Ru and Pd homogeneous systems successfully combined with enzymes and successfully applied on industrial scale in DKR [71, 72], few metal-based heterogeneous catalysts active for alcohol racemization have been reported [19, 73, 74]. 

The preparation of homochiral compounds by formation and separation of diastereoisomers or by kinetic resolution of racemates, at or near the end of a total synthesis, has been a method of choice. This avoids the possibility of racemization should chirality be introduced earlier. However, the costs are high because only half by weight of the homochiral compound is theoretically possible from the racemate unless the optical antipode can also be easily inverted to the desired product. Indeed, previous methods for producing levomethadone based on the classical resolution at the end, or at the penultimate stage of the synthesis, were costly and not very effective. Levomethadone hydrochloride has previously been marketed as L-Polamidon and Levadone16 but was subsequently withdrawn because of the high cost of production. 

The most powerful approaches, which can be used with several different enzyme systems, lead to a single enantiomer as the product in high yield and do not rely on a classic resolution approach in which the unwanted enantiomer is discarded. These approaches include dynamic kinetic resolutions, der-acemizations, and asymmetric and desymmetrization reactions (49, 50). In some cases, a chemical catalyst may be available to recycle the unwanted isomer in the same reactor vide infra). It is sometimes possible to racemize the unwanted isomer of the substrate and then to perform the reaction again (51). 

In addition to stereoselective metalation, other methods have been applied for the synthesis of enantiomerically pure planar chiral compounds. Many racemic planar chiral amines and acids can be resolved by both classical and chromatographic techniques (see Sect. 4.3.1.1 for references on resolution procedures). Some enzymes have the remarkable ability to differentiate planar chiral compounds. For example, horse liver alcohol dehydrogenase (HLADH) catalyzes the oxidation of achiral ferrocene-1,2-dimethanol by NAD to (S)-2-hydroxymethyl-ferrocenealdehyde with 86% ee (Fig. 4-2la) and the reduction of ferrocene-1,2-dialdehyde by NADH to (I )-2-hydroxymethyl-ferrocenealdehyde with 94% ee (Fig. 4-2lb) [14]. Fermenting baker s yeast also reduces ferrocene-1,2-dialdehyde to (I )-2-hydroxymethyl-ferro-cenealdehyde [17]. HLADH has been used for a kinetic resolution of 2-methyl-ferrocenemethanol, giving 64% ee in the product, (S)-2-methyl-ferrocenealdehyde... 

For diene ligands which are prochiral, complexation results in the fonnation of a racemic mixture. Resolution of this racemic mixture has been accomplished via either classical methods , chromatographic separation on chiral stationary pliascs - or kinetic resolution . For certain acyclic or cyclic dienes possessing a pendent chiral center(s)... 

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