Dynamic Kinetic Resolution of Racemic Compounds

Cinchona-Based Organocatalysts for Desymmetrization of meso-Compounds and (Dynamic) Kinetic Resolution of Racemic Compounds... 

Scheme 11.3 Dynamic kinetic resolution of racemic compounds.

This chapter presented the current stage of development in the desymmetrization of mt >o-com pounds and (dynamic) kinetic resolution of racemic compounds in which cinchona alkaloids or their derivatives are used as organocatalysts. As shown in many of the examples discussed above, cinchona alkaloids and their derivatives effectively promote these reactions by either a monofunctional base (or nucleophile) catalysis or a bifunctional activation mechanism. Especially, the cinchona-catalyzed alcoholytic desymmetrization of cyclic anhydrides has already reached the level of large-scale synthetic practicability and, thus, has already been successfully applied to the synthesis of key intermediates for a variety of industrially interesting biologically active compounds. However, for other reactions, there is still room for improvement... 

Synthetically, in racemization has been shown to play an important role in biologi-cal 22 chemical dynamic kinetic resolution of carbonyl compounds . Generally, if the required in siturac mization is faster than the kinetic resolution (deriva-tization step), this process can allow the conversion of a racemic substrate into a single enantiomeric product in quantitative yield This strategy has found industrial application in the synthesis of Levobupivacaine , Bupivacaine and Roxiban . ... 

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). 

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. 

Dynamic kinetic resolution of racemates to obtain 100% yield of products with 100% ee is theoretically possible when the substrate racemizes but the product does not. Some examples are shown in this section. Deracemization reactions where racemic compounds are converted to enantiomerically pure form without changing the chemical structure will also be discussed. 

Akai, S. (2014). Dynamic kinetic resolution of racemic allylic alcohols via hydrolase-metal combo catalysis An effective method for the synthesis of optically active compounds. Chem. Lett., 43,746-754. 

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. 

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. 

Numerous biotranformation processes for fhe synthesis of amino acids have been described and for fhe purpose of this chapter, we have restricted the discussion to fhe unnatural amino acids fhat are not accessible by fermentation. For this class of amino acids, commercialized biotranformations are either based on asymmetric synthesis starting from a prochiral compound or on (dynamic) kinetic resolutions of a racemate. As an illustration the published processes for (R)- and (S)-tert-leucine are outlined in Scheme 4.4. Both stereoisomers of tert-leucine have been used for fhe synfhesis of peptides that serve as protease inhibitors acting against viral infections (e.g. Hepatitis C, HIV), bacterial infections, autoimmune diseases and cancer [27]. This particular amino acid is versatile in fhese applications since fhe tert-butyl moiety provides resistance against endogenous proteases and can enhance the binding affinity of fhe peptide to fhe target protease. 

Most commonly used biocataiytic kinetic resolutions of racemates often provide compounds with high EE, but the maximum theoretical yield of product is only 50%. The reaction mixture contains about a 50 50 mixture of reactant and product that possess only slight differences in physical properties (e.g., a hydrophobic alcohol and its acetate), and thus separation may be very difficult. These issues with kinetic resolutions can be addressed by employing a dynamic kinetic resolution process involving a biocatalyst or biocatalyst with metal-catalyzed in situ racemiza-tion [112-114]. 

Alternatively, they were also found to be good racemization catalysts. Iridium complexes, but also rhodium compounds, catalyzed the racemization step in the enzymatic dynamic kinetic resolution of secondary alcohols, and excellent results were reported for alkyl-aryl as well as dialkyl secondary alcohols. Finally, picolyl and pyridine functionalized N-heterocyclic carbene iridium complexes [(C N)Ir(Cp )Cl]Cl were moderately active catalysts for the polymerization of norbomene in the presence of methylaluminoxane as cocatalyst. ... 

Catalytic transformation based on combined enzyme and metal catalysis is described as a new class of methodology for the synthesis of enantiopure compounds. This approach is particularly useful for dynamic kinetic resolution in which enzymatic resolution is coupled with metal-catalyzed racemization for the conversion of a racemic substrate to a single enantiomeric product. 

After some early examples of bio-chemo combinations in the 1980s, there was then over a decade of silence , followed by clearly increasing interest from the mid-1990s in the field of dynamic kinetic resolution processes (i.e., chemocata-lyzed racemization combined with enantioselective enzymatic conversion, giving, in principle, 100% yield of an optically pure compound). 

This principle of a dynamic equilibrium between two compounds by one catalyst in combination with a selective conversion of one of those by a second catalyst is of great importance for the so-called 100% e.e.-100% yield synthesis of enantio-merically pure compounds from racemic starting materials. Over ten different examples of such dynamic kinetic resolution on a lab-scale have been reported [4], using the concomitant action of a chemocatalyst and a bio-catalyst (Fig. 13.10). Without such a combination of two catalysts in one reactor, either a maximum yield of only 50% can be obtained or separate recovery and racemization steps are required. 

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 (DKR) is an attractive protocol for the production of enantiopure compounds from racemic mixtures [45]. The concept of DKR is illustrated in Scheme 5.13. In many cases, DKRs are accomplished by the combination of enzymatic resolution and transition-metal-catalyzed racemization based on hydrogen transfer. Thus, the use of Cp Ir complexes as catalysts for racemization in DKR can be anticipated. 

It should be mentioned that the great majority of dynamic kinetic resolutions reported so far are carried out in organic solvents, whereas all cyclic deracemizations are conducted in aqueous media. Therefore, formally, this latter methodology would not fit the scope of this book, which is focused on the synthetic uses of enzymes in non-aqueous media. However, to fully present and discuss the applications and potentials of chemoenzymatic deracemization processes for the synthesis of enantiopure compounds, chemoenzymatic cyclic de-racemizations will also be briefly treated in this chapter, as well as a small number of other examples of enzymatic DKR performed in water. 

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. 

Highly stereoselective hydrogenation of racemic a-substituted P-keto esters via dynamic kinetic resolution [14,17] has been reported. Hydrogenation of a racemic a-amidomethyl substrate with the (-)-DTBM-SEGPHOS/Ru catalyst resulted in the 2S,3R alcohol in 99.4% ee (syn anti=99.3 0.7) (Scheme 22) [36]. The product was a key compound for an industrial synthesis of carbapenem antibi-... 

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]. 

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... 

Such conventional kinetic resolution reported above often provide an effective route to access to the enantiomerically pure/enriched compounds. However, the limitation of such process is that the resolution of two enantiomers will provide a maximum 50% yield of the enantiomerically pure materials. Such limitation can be overcome in several ways. Among these ways are the use of meso compounds or prochiral substrates,33 inversion of the stereochemistry (stereoinversion) of the unwanted enantiomer (the remaining unreacted substrate),34 racemization and recycling of the unwanted enantiomer and dynamic kinetic resolution (DKR).21... 

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