Dynamic kinetic resolution chiral compounds

Fig. 32.28 Examples of bioactive compounds and chiral diphosphines obtainable by BlNAP-Ru-catalyzed hydrogenation via dynamic kinetic resolution.

Enzymes may be used either directly for chiral synthesis of the desired enantiomer of the amino acid itself or of a derivative from which it can readily be prepared, or for kinetic resolution. Resolution of a racemate may remove the unwanted enantiomer, leaving the intended product untouched, or else the reaction may release the desired enantiomer from a racemic precursor. In either case the apparent disadvantage is that the process on its own can only yield up to 50% of the target compound. However, in a number of processes the enzyme-catalyzed kinetic resolution is combined with a second process that re-racemizes the unwanted enantiomer. This may be chemical or enzymatic, and in the latter case, the combination of two simultaneous enzymatic reactions can produce a smooth dynamic kinetic resolution leading to 100% yield. 

Dynamic kinetic resolution is an excellent methodology to prepare enantiomeri-cally pure compounds and, in this context, chiral 4-(dimethylammo)pyridine (DMAP) iron and ruthenium " complexes have been reported to catalyze the... 

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. 

The combination of Ru complex-catalyzed stereomutation of secondary alcohols with enzyme-catalyzed enantioselective acylation is an efficient procedure to obtain chiral acyloxy compounds with excellent optical purity from a variety of racemic secondary alcohols via dynamic kinetic resolution [112]. 

The stereoselective hydrogenation of a-monosubstituted (3-keto carboxylates and phosphonates through dynamic kinetic resolution has been applied to the synthesis of a wide variety of useful bioactive compounds as well as some chiral diphosphines (Figure 1.16) [lc,20,162b,c,179,243,246,250,252], The stereogenic center determined by the BINAP-Ru... 

Figure 1.16. Examples of biologically active compounds and chiral diphosphines obtainable viaBINAP-Ru catalyzed hydrogenation through dynamic kinetic resolution.

The resolution of racemic compounds mediated by enzymes has become a valuable tool for the synthesis of chiral intermediates. In most cases, however, only one enantiomer of the intermediate is required for the next step in the synthesis thus, the unwanted isomer must be either discarded or racemized for reuse in the enzymatic resolution process. Dynamic kinetic resolution is one way of avoiding this problem the unwanted enantiomer is racemized during the selective enzymatic process and serves as fresh starting material in the resolution. 

In this chapter, we attempt to review the current state of the art in the applications of cinchona alkaloids and their derivatives as chiral organocatalysts in these research fields. In the first section, the results obtained using the cinchona-catalyzed desymmetrization of different types of weso-compounds, such as weso-cyclic anhydrides, meso-diols, meso-endoperoxides, weso-phospholene derivatives, and prochiral ketones, as depicted in Scheme 11.1, are reviewed. Then, the cinchona-catalyzed (dynamic) kinetic resolution of racemic anhydrides, azlactones and sulfinyl chlorides affording enantioenriched a-hydroxy esters, and N-protected a-amino esters and sulftnates, respectively, is discussed (Schemes 11.2 and 11.3). 

The product class of enantiomerically pure amines is of considerable importance in both pharmaceutical and agrochemical applications. For instance, enantiopure aryl-alkyl amines are utilized for the synthesis of intermediates for pharmaceutically active compounds such as amphetamines and antihistamines. Several chemical as well as biotransformation methods for the asymmetric synthesis/dynamic kinetic resolution [29] or separation of enantiomers of chiral amines have been described. These are illustrated in Scheme 4.5 for (S)-a-methylbenzylamine [30]. 

Dynamic kinetic resolution (DKR) is an important and useful method to generate enantiomerically pure compounds from racemic substrates [87]. In this case, an in situ racemization of slow reacting enantiomer of chiral alcohol has been successfully carried out by metal-enzyme catalyst where metal complex acts as a racem-izing catalyst (Scheme 10.6) [88]. The racemization was found to be more efficient... 

Aldol donors bearing chiral auxiliaries include cii-l-)V-tosylamino-2-indanyl esters (ami-selective with TiCyf-Pr NEt) and (-)-bis(2,2,2-trifluoroethyl) menthoxycarbonyl)methylphosphonate. A dynamic kinetic resolution of racemic a-amino aldehydes is realized during their reaction with the latter compound. 

By modification of the reaction condition, biaryl lactones could be efficiently reduced to the corresponding biaryl products by this cobalt-catalyzed system. Various axially chiral biaryl compounds were obtained with high ee values (80-93% ee) by the atmpo-enantioselective borohydride reduction with the dynamic kinetic resolution of biaryl lactones in the presence of EtOH and l-(2-pyridinyl)ethanol (eq 39). 

Dynamic Kinetic Resolution. Another typical acid-catalysed reaction is the racemisation of chiral alcohols, due to inversion at the chiral carbon. This can actually be made use of in the formation of enantiopure compounds, by dynamic kinetic resolution using an enzyme, such as a lipase, that catalyses enantioseleetive esterification in an organic medium. By coupling zeolite Beta-catalysed intereonversion of benzylic alcohol enantiomers with enzyme-catalysed esterifieation of only one of the enantiomeric alcohols, almost complete eon version to enantiopure ester ean be achieved. ... 

In contrast to the Rh-catalyzed asymmetric intramolecular direct C—H bond functionalization reactions described above, their asymmetric inter-molecular variants have been rarely explored. In 2000, Murai and co-workers reported a Rh-catalyzed intermolecular asymmetric C—H activation/olefin coupling reaction of achiral biaryl pyridine (132) or isoquinoline derivatives to deliver axially chiral biaryls (133) (Scheme 5.46a). Although both the efficiency (up to 37% yield) and the enantioselectivity (up to 49% ee) of the reaction were only moderate, this protocol provided an alternative method for the synthesis of optically active biaryl compounds. To some extent, this reaction was similar to a formal dynamic kinetic resolution. The two atropisomers of the biaryl starting materials could interconvert with each other freely due to a low inversion energy barrier. A properly chosen chiral catalyst could react preferentially with one atropisomer. The increased steric bulkiness of the final alkylated products can prevent the epimerization and the biaryl compounds possessing a stable axial chirality are established. However, due to the relatively low efficiency of the catalyst, the yields of the desired products are generally low and the starting materials can be recovered (Scheme 5.46b). 

The Kabachnik-Fields reaction is a three-component hydrophosphonylation of imines formed in the reaction mixture from carbonyl compounds and amines [75]. In 2008, List and coworkers reported on such a reaction catalyzed by chiral phosphoric acids that combines a dynamic kinetic resolution with the concomitant generation of a new stereogenic center (Scheme 42.30). The resolution is possible when chiral racemic aldehydes 135 are used. This is because the imine formed in the first step of the reaction is in equilibrium with its achiral enamine tautomer, thereby racemizing the starting material continuously. Since one of the two enantiomers is selectively activated by the chiral phosphoric acid catalyst, the addition of phosphite 136 affords the exclusive formation of one diastereomer. All phos-phonate products 137 were obtained with good yields and moderate to excellent diastereo- and enantioselectivity [76]. 

Three routes to enantiopure compounds using hydrolase-catalyzed reactions, (a) Kinetic resolution starts with racemic substrate and converts one enantiomer into product. This separation yields one enantiomer as the product alcohol and one as the starting acetate, both with a maximum yield of 50%. (b) Desymmetrization of a prochiral compound transforms one of prochiral groups to yield a chiral product with a maximum yield of 100%. (c) A dynamic kinetic resolution combines rapid racemization of racemic starting material with a hydrolase catalyzed acylation of one enantiomer. The maximum yield is 100%. 

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