Racemic compounds dynamic resolution

Racemate resolution, 1, 2 Racemic compounds alcohols, 45 chirally labile, 75 computer simulation, 79 diphosphines, 26 dynamic resolution, 75 esters, 309... 

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 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. 

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... 

Epoxides are a familiar sight in the world of kinetic resolutions. As well as being made by kinetic resolution, racemic epoxides can themselves be the substrates in a kinetic resolution. For example, the use of cobalt-salen complexes - something we shall see again in the dynamic kinetic resolution section - can be used to mediate the formation of enantiomerically pure oxazolidinones.20 Enzymes can be used to react with one enantiomer of epoxide.21 And enzymes are a good way to kinetically resolve compounds and can work under surprising conditions - supercritical C02 for example22... 

The cationic complexes 24 and 25 were of low optical stability and racemization was observed after 6 hr. However, recent dynamic NMR studies have permitted the observation of chiral pentacoordinated species without resolution. The compounds are configurationally stable on the NMR time scale. The racemization of such species opens up the problem of permutational isomerization, which will be discussed in detail in Sect. V-C. 

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. 

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. 

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. 

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. 

Organosulfur chemistry is presently a particularly dynamic subject area. The stereochemical aspects of this field are surveyed by M. Mikojajczyk and J. Drabowicz. in the fifth chapter, entitled Qural Organosulfur Compounds. The synthesis, resolution, and application of a wide range of chiral sulfur compounds are described as are the determination of absolute configuration and of enantiomeric purity of these substances. A discussion of the dynamic stereochemistry of chiral sulfur compounds including racemization processes follows. Finally, nucleophilic substitution on and reaction of such compounds with electrophiles, their use in asymmetric synthesis, and asymmetric induction in the transfer of chirality from sulfur to other centers is discussed in a chapter that should be of interest to chemists in several disciplines, in particular synthetic and natural product chemistry. 

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. 

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