Kinetic resolution reactions

Kinetic resolution reactions on C2-symmetric substrates have important applications. Desymmetrization is just one example of such a kinetic resolution reaction. Enzymatic desymmetrization is outlined in Scheme 8-1.5,6... 

Carbonylative kinetic resolution of a racemic mixture of trans-2,3-epoxybutane was also investigated by using the enantiomerically pure cobalt complex [(J ,J )-salcy]Al(thf)2 [Co(CO)4] (4) [28]. The carbonylation of the substrate at 30 °C for 4h (49% conversion) gave the corresponding cis-/3-lactone in 44% enantiomeric excess, and the relative ratio (kre ) of the rate constants for the consumption of the two enantiomers was estimated to be 3.8, whereas at 0 °C, kte = 4.1 (Scheme 6). This successful kinetic resolution reaction supports the proposed mechanism where cationic chiral Lewis acid coordinates and activates an epoxide. 

Pellissier, H., Recent developments in dynamic kinetic resolution. Tetrahedron, 2008, 64, 1563-1601 Turner, N.J., Enzyme catalysed deracemisation and dynamic kinetic resolution reactions. Curr. Opin. Chem. Biol., 2004, 8, 114-119 Gmber, C.C., Lavandera, I., Faber, K. and Kroutil, W., From a racemate to a single enantiomer deracemisation by stereoinversion. Adv. Synth. Catal., 2006, 348, 1789-1805 Pellissier, H., Dynamic kinetic resolution. Tetrahedron, 2003, 59, 8291-8327 Pmnies, O. and Backvall, J.-E., Combination of enzymes and metal catalysts. A powerful approach in asymmetric catalysis. Chem. Rev., 2003, 103, 3247-3261. 

The reversibility of hydrogen transfer reactions has been exploited for the racemi-zation of alcohols and amines. By coupling the racemization process with an enantioselective enzyme-catalyzed acylation reaction, it has been possible to achieve dynamic kinetic resolution reactions. The combination of lipases or... 

Turner, N. J. 2004. Enzyme catalyzed deracemization and dynamic kinetic resolution reactions. Curr. Op. Chem. Biol., 8(2), 114-119. 

The precatalyst used in these water-based kinetic resolution reactions is the cobalt Schiff-base complex 9.40. Its structural similarity to the asymmetric epoxidation catalysts 9.38A and 9.38B is to be noted. In the actual catalytic system 9.40 is activated with small amounts of acetic acid and air to give a cobalt(III) complex where CH3C02 and H20 are additional ligands. The mechanistic details of this reaction are as yet unknown. 

Keith, J. M. Larrow, J. R Jacobsen, E. N. Practical Considerations in Kinetic Resolution Reactions, Adv. Synth. Catal. 2001, 34, 5-26. 

This methodology has been extended successfully to polymer-supported chiral (salen)Co complexes [88] and to intramolecular kinetic resolution of epoxy alcohols (with (R,R)-L Co OAc)) [82]. The ceiling of 50 % yield in kinetic resolution reactions can be extended if the starting material undergoes racemization under the reaction conditions. This has been shown to be possible with epichlorohydrin in reaction with TMSN3, the dynamic kinetic resolution process affording now a 76 % product yield (97 % ee) and 12 % each of the dichloro and diazido products [89]. 

Hbhne et al. reported a substrate protection strategy that enhanced both the rate and the enantioselectivity of transaminase catalyzed kinetic resolution reactions [32]. The co transaminase catalyzed resolution of the pharmaceutically important syn thons 3 amino pyrrolidine 53 and 3 aminopiperidine 54 was imp roved by the addition of protecting groups to the substrate amines. Reaction rates were improved by up to 50 fold, and product ee was improved from 86 to 99% (Figure 14.23). 

Walsh and co-workers have developed a one-pot method for the synthesis of hydroxyepoxides via an initial synthesis of an allylic alcohol followed by an asymmetric epoxidation <05JOC1262,05JA14668,05JA16416>. This reaction provides an improvement in overall yields over the typical kinetic resolution reaction. The method involves an initial asymmetric addition to the aldehyde followed by a diastereoselective epoxidation reaction. 

In addition, the amino acylase process can be also applied in the production of other proteinogenic and non-proteinogenic L-amino acids such as L-valine and l-phenylalanine. It is worth noting that racemases have recently been developed by several companies which allow (in combination with the L-aminoacylases) an extension of the existing process towards a dynamic kinetic resolution reaction [10]. It should be mentioned that the same concept can be also applied for the synthesis of D-amino acids when using a D-aminoacylase as an enzyme. 

An unselective wheel A selective wheel S Values, Equations Yields Standard Kinetic Resolution Reactions... 

The s-values for the lipase route and the phosphine route were not the same, but this is less important than the rates of enantiomer consumption being equal. Hence the relative amounts of lipase and phosphine were adjusted so that the rates of enantiomer consumption were equal. At the end of the reaction, one enantiomer of alcohol is bound to the polymer and the other has formed an ester in solution. They may be separated by filtration. Both reactions have products of higher ee s than predicted for the simple kinetic resolution reactions at 50% conversion. Note that really quite different reagents were used to react with the two enantiomers. 

A dynamic kinetic resolution reaction involves the interconversion of the enantiomers of a starting material under conditions where one enantiomer is converted selectively into product. This principle is shown in Fig. 9-1, where a conventional kinetic resolution reaction and a dynamic kinetic resolution reaction are compared. In both cases enantiomer A reacts to form product B more quickly than enantiomer A. However, in the conventional kinetic resolution, enantiomer A is simply left behind as unreacted starting material. In the dynamic kinetic resolution, A and A are in equilibrium, which allows for the possibility that all of the starting material will be converted into product B. The reaction conditions must be chosen that whilst the starting material enantiomers (A/A ) undergo rapid equilibration (racemization), the product B must be inert to racemization. 

Dynamic kinetic resolution reactions are not limited to enzyme-catalyzed processes, and there are reviews available that consider all aspects of such reactions[1 31. 

In addition, reviews dealing with aspects of enzyme-catalyzed dynamic resolution and related processes such as stereoinversion and deracemisation have also been published[4 71. Details of the kinetic principles of dynamic kinetic resolution reactions have also been reported,7 9). Interestingly, a dynamic kinetic resolution reaction can provide a product with higher enantiomeric excess than the corresponding kinetic resolution. In a conventional kinetic resolution, the enantiomeric excess of the product often decreases as a function of conversion. This happens because as the reaction proceeds, the proportion of the preferred enantiomer of substrate decreases. Unless the enzyme is able to discriminate perfectly between the substrate enantiomers, it will catalyze the reaction of the less preferred enantiomer of substrate (the proportion of which grows as the reaction proceeds). However, in a dynamic kinetic resolution where the substrate enantiomers are interconverting rapidly, the ratio of substrate enantiomers will be constant at 1 1. Consequently, the enantiomeric excess of the product will not decrease as the reaction proceeds. 

Kellogg, Feringa and co-workers have achieved successful dynamic kinetic resolution reactions using cyclic hemiacetals as substrates[13, 14l The enzyme-catalyzed acetylation of 6-hydroxypyranone shown in Fig. 9-6 has been achieved with reasonable enantioselectivity with essentially complete conversion. The racemisation of the hemiacetal is presumed to proceed via reversible ring-opening of the pyranone1 1. The rate of reaction was found to greatly increase when the enzyme, lipase PS (Pseudomonas sp.) was immobilized on Hyflo Super Cell (HSC). 

Most substrates for enzyme-catalyzed kinetic resolution reactions do not undergo spontaneous racemization under conditions that are suitable for enzyme activity. One solution to this problem has been to design mild transition metal-catalyzed methods for in situ racemization 17. In order to achieve this goal, the racemisation method must be able to function without an adverse effect on the enzyme. Additionally, the enzyme must not inhibit the racemization method. 

In addition to in situ racemization of a-substituted carboxylic acid derivatives by deprotonation/reprotonation, a procedure involving halide exchange has been developed135, 361. Whilst the a-halo esters undergo racemization at a reasonable rate, the corresponding carboxylates are almost inert to racemization under the reaction conditions. Using immobilized phosphonium halide and CLEC (cross-linked enzyme crystals), a dynamic resolution procedure has been developed for the hydrolysis of a-bromo and a-chloro esters (Fig. 9-17). The enantiomeric excess in each case was similar to that achieved for simple kinetic resolution reactions using the same enzyme/substrate combinations. 

Pre-formed imino-esters have also been used as substrates for dynamic kinetic resolution reactions[42). The free amino acid precipitated from the reaction mixture as the reaction proceeded. 

NRKR non-reciprocal kinetic resolution (Section IV, A.l and Ref. 44), a kinetic resolution reaction such that the kinetic resolution in, say, the reaction of (+ )-A with ( + )-B, differs from that in the reaction of ( )-B with ( + )-A. 

The kinetic resolution reaction can be used for the asymmetric synthesis of chiral secondary allylic alcohols or their corresponding epoxides. The yield of either is, of course, limited to 50%, starting from the racemic allylic alcohol, but the methodology has found widespread use in organic synthesis. For example, epoxidation of the racemic allylic alcohol 54 gave the epoxide 55, used to prepare the anticoccidial antibiotic diolmycin A1 (5.63). ... 

The authors proposed a Zimmerman-Traxler type transition state 56 bearing a Z-enolate, which was based on the fact that mainly T) -haptomeric rhodium enolates exist after conjugate additions. Additionally, this concept could be extended to parallel kinetic resolution reactions with racemic unsymmetrically substituted diones. 

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