Dynamic resolution of racemates

SCHEME 10.6 Dynamic resolution of racemic UK-350,926 with (5)-(-)-l-phenylethylamine. S. Chal-lenger/Organic Process Research and Development/ACS/2005. 

Figure 1.3 Kinetic and dynamic resolution of racemic substrates...

No more encouraging enantiomeric excess values were obtained in the dynamic resolution of racemic 1-phenylethanol performed by acetylation in the presence of optically active polymers [poly(0--acryloylquinine) (2a), poly(N-benzyl-2-pyrrolidinylmethyl acrylate) (13) and poly(O-acryloyl-N-benzylephedrine) (17)]... 

In an altanate process, the enzymatic dynamic resolution of racemic amino add 82 was also demonstrated by combining amino add oxidase with chemical reduction. (J )-selective oxidation with Celite-immobilized (J )-amino add oxidase from T. variabilis expressed in E. coli in combination with chemical imine reduction with borane-ammonia gave a 75% in process yield and 100% ee of (S)-amino add 82a [147]. 

Scheme 9.20 Dynamic kinetic resolution of racemic epoxide...

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 of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions. Dynamic kinetic resolution of a-alkyl P-keto ester has been performed through enzymatic reduction. One isomer, out of the four possible products for the unselective reduction (Figure 8.38), can be selectively synthesized using biocatalyst, and by changing the biocatalyst or conditions, all of the isomers can be selectively synthesized [29]. 

The dynamic resolution of an aldehyde is shown in Figure 8.40. The racemization of starting aldehyde and enantioselective reduction of carbonyl group by baker s yeast resulted in the formation of chiral carbon centers. The enantiomeric excess value of the product was improved from 19 to 90% by changing the ester moiety from the isopropyl group to the neopentyl group [30a]. 

Another approach to the synthesis of chiral non-racemic hydroxyalkyl sulfones used enzyme-catalysed kinetic resolution of racemic substrates. In the first attempt. Porcine pancreas lipase was applied to acylate racemic (3, y and 8-hydroxyalkyl sulfones using trichloroethyl butyrate. Although both enantiomers of the products could be obtained, their enantiomeric excesses were only low to moderate. Recently, we have found that a stereoselective acetylation of racemic p-hydroxyalkyl sulfones can be successfully carried out using several lipases, among which CAL-B and lipase PS (AMANO) proved most efficient. Moreover, application of a dynamic kinetic resolution procedure, in which lipase-promoted kinetic resolution was combined with a concomitant ruthenium-catalysed racem-ization of the substrates, gave the corresponding p-acetoxyalkyl sulfones 8 in yields... 

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. 

Hydrogen transfer reactions are reversible, and recently this has been exploited extensively in racemization reactions in combination with kinetic resolutions of racemic alcohols. This resulted in dynamic kinetic resolutions, kinetic resolutions of 100% yield of the desired enantiopure compound [30]. The kinetic resolution is typically performed with an enzyme that converts one of the enantiomers of the racemic substrate and a hydrogen transfer catalyst that racemizes the remaining substrate (see also Scheme 20.31). Some 80 years after the first reports on transfer hydrogenations, these processes are well established in synthesis and are employed in ever-new fields of chemistry. 

In the realm of hydrolytic reactions, Jacobsen has applied his work with chiral salen complexes to advantage for the kinetic resolution of racemic epoxides. For example, the cobalt salen catalyst 59 gave the chiral bromohydrin 61 in excellent ee (>99%) and good yield (74%) from the racemic bromo-epoxide 60. The higher than 50% yield, unusual for a kinetic resolution, is attributed to a bromide-induced dynamic equilibrium with the dibromo alcohol 62, which allows for conversion of unused substrate into the active enantiomer <99JA6086>. Even the recalcitrant 2,2-disubstituted epoxides e.g., 64) succumbed to smooth kinetic resolution upon treatment with... 

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

Dynamic and Static Kinetic Resolution of Racemic a-Substituted... 

As described above, the catalyst comprising RuC12 complex with a strong base is effective for the asymmetric hydrogenation through dynamic kinetic resolution. However, it is not suitable for static kinetic resolution of racemic a-substi-tuted ketones because of the basic conditions. The newly devised frans-RuHfri1-BH4)[(R)-XylBINAP][(S,S)-DPEN] without any additional base allows one to... 

Fu and co-workers have also applied their planar chiral catalyst 9 to dynamic kinetic resolution of racemic azalactones [50], Azalactones 54 racemize under the reaction conditions, allowing all material to be funneled to optically pure product. Protected (S)-amino acids 55 are formed in excellent yields with moderate enantioselectivities (83-98% yield, 44-61% ee, see Scheme 11). Use of more sterically encumbered alcohols as nucleophiles increases enantioselectivities but reaction rates become slower. 

Enzymatic resolution of racemic secondary alcohols by enantiomer-selective acylation gives optically pure compounds with up to 50% yield [332], When this method is coupled with the principle of dynamic kinetic resolution (see Section 1.4.1.5), the theoretical yield increases to 100%. Thus a reaction system consisting of an achiral transition-metal catalyst for racemization, a suitable enzyme, acetophenone, and an acetyl donor allows the transformation of racemic 1-phenylethanol to the R acetates with an excellent ee (Scheme 1.93) [333]. The presence of one equiv. of acetophenone is necessary to promote the alcohol racemization catalyzed by the... 

Most work on this subject is based on the use of alcohols as reagents in the presence of enantiomerically pure nucleophilic catalysts [1, 2]. This section is subdivided into four parts on the basis of classes of anhydride substrate and types of reaction performed (Scheme 13.1) - desymmetrization of prochiral cyclic anhydrides (Section 13.1.1) kinetic resolution of chiral, racemic anhydrides (Section 13.1.2) parallel kinetic resolution of chiral, racemic anhydrides (Section 13.1.3) and dynamic kinetic resolution of racemic anhydrides (Section 13.1.4). 

The planar chiral DMAP derivative 79a proved successful also in the dynamic kinetic resolution of racemic azlactones by ring-opening with alcohols (Scheme... 

Akai S, Tanimoto K et al (2004) Lipase-catalyzed domino dynamic kinetic resolution of racemic 3-vinylcyclohex-2-en-l-ols/Intramolecular Diels-Alder reaction one-pot synthesis of optically active polysubstituted decalins. Angew Chem Int Ed 43 1407-1410... 

DYNAMIC KINETIC RESOLUTION OF RACEMIC KETONES THROUGH ASYMMETRIC REDUCTION... 

Amides of (S)-lactic acid have been used as chiral auxiliaries in the dynamic kinetic resolution of racemic ibuprofen (Scheme 23.9).56 The therapeutically effective (S)-isomer 33 was obtained in 80% yield, with complete recovery of the pyrrolidine-derived (S)-lactamide auxiliary 34. 

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