Asymmetric transformation kinetic resolution Dynamic

The asymmetric processes discussed so far in this chapter have focused on reactions that create non-racemic, chiral products from achiral reagents by selective reaction at one prochiral face or position over the other. However, these principles can also be applied to reactions that separate enantiomers of an existing racemic mixture, channel both enantiomers of such a mixture to a single enantiomeric product, or that select between reaction at one of two diastereotopic functional groups in an achiral substrate. These reactions are also synthetically valuable and are called kinetic resolutions, dynamic kinetic resolutions, and desymmetrizations. An understanding of these reactions draws from the principles established so far in this chapter, but they also require some additional principles to be established that apply in a specific way to these classes of asymmetric transformations. Thus, the remainder of Chapter 14 introduces the fundamentals of these classes of asymmetric catalysis. 

Other principal techniques for the preparation of one special enantiomer are kinetic resolution, dynamic kinetic resolution, and dynamic kinetic asymmetric transformations. 

The complete transformation of a racemic mixture into a single enantiomer is one of the challenging goals in asymmetric synthesis. We have developed metal-enzyme combinations for the dynamic kinetic resolution (DKR) of racemic primary amines. This procedure employs a heterogeneous palladium catalyst, Pd/A10(0H), as the racemization catalyst, Candida antarctica lipase B immobilized on acrylic resin (CAL-B) as the resolution catalyst and ethyl acetate or methoxymethylacetate as the acyl donor. Benzylic and aliphatic primary amines and one amino acid amide have been efficiently resolved with good yields (85—99 %) and high optical purities (97—99 %). The racemization catalyst was recyclable and could be reused for the DKR without activity loss at least 10 times. 

Figure 2b shows the other extreme, whereby the rate of epimerization is fast relative to the rate of substitution. In this case, Curtin-Hammett kinetics apply, and the product ratio is determined by AAG. In the specific case of organolithium enantiomers that are rendered diastereomeric by virtue of an external chiral ligand, such a process may be termed a dynamic kinetic resolution. Both of these processes are also known by the more general term asymmetric transformation One should be careful to restrict the term resolution to a separation (either physical or dynamic) of enantiomers. An asymmetric transformation may also afford dynamic separation of equilibrating diastereomers, but such a process is not a resolution. "... 

Asymmetric Transformations by Coupled Enzyme and Metal Catalysis Dynamic Kinetic Resolution... 

The integration of a catalyzed kinetic enantiomer resolution and concurrent racemization is known as a dynamic kinetic resolution (DKR). This asymmetric transformation can provide a theoretical 100% yield without any requirement for enantiomer separation. Enzymes have been used most commonly as the resolving catalysts and precious metals as the racemizing catalysts. Most examples involve racemic secondary alcohols, but an increasing number of chiral amine enzyme DKRs are being reported. Reetz, in 1996, first reported the DKR of rac-2-methylbenzylamine using Candida antarctica lipase B and vinyl acetate with palladium on carbon as the racemization catalyst [20]. The reaction was carried out at 50°C over 8 days to give the (S)-amide in 99% ee and 64% yield. Rather surpris-... 

M. J. Kim, Y. Ahn, and J. Park, Dynamic kinetic resolutions and asymmetric transformations by enzymes couples with metal catalysis, Curr. Opin. Biotechnol. 2002, 13, 578-587. 

Dynamic kinetic asymmetric transformation Dynamic kinetic resolution... 

Scheme 7.8. Asymmetric reduction of chiral P-keto esters may be used in an asymmetric transformation of the first kind (dynamic kinetic resolution) [78],...

Aryl alcohols are competent nucleophiles in the palladium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of racemic MBH derivatives. As an extension of this strategy, the palladium-catalyzed intramolecular DYKAT of MBH adducts was further explored. As shown in Scheme 4.96, reactions were carried out in dioxane at 25 °C with chiral ligand affording 300 in up to 45% yields and 98% ee via a highly selective kinetic resolution interestingly, when reactions were performed at 80 °C, up to 94% yield with 91% ee of 300 was obtained by the DYKAT process. 

A very recent paper described the first examples of asymmetric Suzuki coupling reactions of unactivated alkyl halides.These transformations take advantage of the fact that oxidative addition of secondary alkyl halides to Ni(0) proceeds through radical intermediates. This leads to scrambling of stereochemistry when achiral catalysts are employed, but can be exploited to achieve dynamic kinetic resolution with chiral catalysts. For example, use of a catalyst composed of Ni(COD)2 and chiral 1,2-diamine ligand 55 for the coupling of 52 with 53 gave 54 in 78% yield and 90% ee. 

Kejrwords Dynamic kinetic asymmetric transformation (DYKAT) Dynamic kinetic resolution (DKR) Hydrogenation Imine reduction Ketone reduction Mechanism of carbonyl reduction Mechanism of imine reduction Mechanism of dUiydrogen activation Ruthenium catalysis Shvo s catalyst Transfer hydrogenation... 

Kim, M.-J., Ahn, Y., Park, J. Dynamic kinetic resolution and asymmetric transformations by enzyme-metal combination. In Biocatalysis in the Pharmaceutical and Biotechnology Industries (ed. Patel, R.N.), 2007, CRC Press, Boca Raton, FL, 249-272. 

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