Thermodynamic resolution, stereoselection

If kepi, k-epi are much larger than the rates k, ki of substitution, the enantiomeric ratio Hepi-1 is similar to kxjk (path C, dynamic kinetic resolution . Both mechanisms are performing when the rates of the two steps are similar. Since rates and equilibrium are temperature-dependent, enhancement of stereoselectivities can be achieved by sophisticated protocols (see Section m.E). The equilibrium 6/epi-6 is determined by the difference of free energy A AG. This effective energy difference is enlarged if it can be coupled with a second order transformation such as the selective crystallization of one diastere-omer dynamic thermodynamic resolution ). In fact, this applies to the first successful (—)-sparteine-mediated deprotonation (Section FV.C.l). 

Kremer et al. [123] observed the hydrophobic pockets as the binding site on AGP protein. However, more than one binding site was reported. Haupt et al. [124] presented a retention model for the chiral resolution of uncharged solutes, felodipine, on AGP and the model has assumed the presence of two different stereoselective sites for different enantiomers. In another study, Waters et al. [125] carried out certain thermodynamic experiments for the determination of the mechanism of chiral resolution on AGP protein. The authors reported the two... 

Lipases have been extensively used for the kinetic resolution of racemic alcohols or carboxylic acids in organic solvents. Chiral alcohols are usually reacted with achiral activated esters (such as vinyl, isopropenyh and trichloroethyl esters) for shifting the equilibrium to the desired products and avoiding problems of reversibility. For the same reasons, chiral acids are often resolved by using acidolysis of esters. In both cases, the overall stereoselectivity is affected by the thermodynamic activity of water of water favors hydrolytic reactions leading to a decrease in the optical purity of the desired ester. Direct esterifications are therefore difficult to apply since water formed during the reaction may increase the o of the system, favors reversibiUty, and diminishes the overall stereoselectivity. 

The regio- and the stereoselectivity of proline-catalyzed a-electrophilic substitution of carbonyl compounds can therefore be successfully explained by the oxazolidinone model, although the diastereoselectivity of the aldol and Mannich reactions was not taken into account in Seebach s discussion. Moreover, the model also could explain the autoinductive effects observed by Blackmond in the proline-catalyzed nitroso aldol and a-amination reactions of aldehydes [29, 31], by simply assuming that the oxazolidinone product acts as a base in the rate-determining enamine formation step. Kinetic resolution of proline, leading to chirality amplification effects, would be accounted for by the greater thermodynamic stability of the matched oxazolidinone product. In fact, the formation of Seebach s oxazolidi-nones, rather than enamines or iminium ion intermediates, from ketones and proline in DMSO solution had been described by List et al. in 2004 [23], but they concluded that this was a parasitic equilibrium leading to an unproductive intermediate. On the other hand, the product oxazolidinone in the proline-catalyzed a-amination of... 

From Table 3.1 it can be seen that both monodentate (entries 1-24) and P,N-bidentate (entries 25 32) ligands can be prepared. Entry 33 depicts a polymer-bound diazaphospholidine, prepared by reaction of 4 with poly(p-hydr-oxystyrene). The stereoselectivity is often very high towards the thermodynamic anti epimer but sometimes significant amounts of the other epimer at the phosphorus atom are obtained (entries 9, 12, 13, 17, 21 and 32). The observed selectivity suggests that a dynamic kinetic resolution takes place during the reaction of 4 with alcohols or amines. ... 

The kinetic resolution of amines was exploited first with co-TAs since the reaction is thermodynamically favored using pyruvate as acceptor [21]. Unfortunately, the inherent maximum 50% yield limits the practical applications of this approach and, therefore, will nof be considered in fhis confribufion. Thus, the other methodologies (stereoselective synthesis and deracemization) are preferred since a theoretical yield of 100% is possible. The asymmefric amination allows fhe preparation of enantiomer-ically pure amines at the expense of an amine donor, usually an amine or an AA (Scheme 2.2b). On the other hand, the combination of two stereocomplementary co-TAs enables to establish a deracemization process (Scheme 2.2c). Deracemization strategies are recommended when amines are readily available or the corresponding carbonyl compounds lack stability. 

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