Resolutions kinetic

Kinetic resolution is the achievement of partial or complete resolution by viitue of unequal rates of reaction of the enantiomers in a racemate with a chiral catalyst [5]. The method usually forms two products one enantiomer does not react with the chiral catalyst or else it reacts very slowly whilst the other enantiomer reacts with the aid of the chiral catalyst to form a new product which may or may not be chiral. As a result two different compounds now make up the mixture and can be separated by conventional chromatographic techniques. One of the most widely applied examples of this technique is the Sharpless Kinetic Resolution. This asymmetric epoxidation of ally lie alcohols was reported by Sharpless in 1980 catalysed by a titanium (IV) tartrate complex in the presence of a hydroperoxide [6] and has been employed in a number of kinetic resolutions [7]. This reaction shows remarkable 

The production of enantiomerically enriched sulfoxides by kinetic resolution can arise in three different situations  

2 Asymmetric Synthesis of Allylic Sulfones and Allylic Sulfides and Kinetic Resolution of Allylic Esters 

4 Palladium-CatalYzed AllyHc Alkylation of Sulfur and Oxygen Nucleophiles 217 

Substrate Conv. [% Carbonate Yield [%] ee[%] Sulfone Yield [% ee[%] 

The limitation on the theoretical yield of a KR led to the development of methods to conduct kinetic resolutions in a fashion that allows the conversion of both enantiomers of the reactant into a single enantiomer of the product. D)mamic kinetic resolution (DKR) is one method that has accomplished tiiis goal. - -  

Comparison of a classical kinetic resolution with a dynamic kinetic resolution. In the dynamic kinetic resolution. I is an achiral intermediate or transition state. 

Example of Dynamic Kinetic Resolutions Dynamic Kinetic Resolution of 1,3-Dicarbonyl Compounds Through Asymmetric Hydrogenation 

DKR in the asymmetric reduction of a-substituted p-keto esters, illustrating the substrate racemization and the four possible diastereomeric products. 

The power of the rhodium(I)-catalyzed Alder-ene reaction is shown by a highly enan-tioselective kinetic resolution process [35]. The key result stems from an observation that a racemic mixture of 48, when treated with [Rh(COD)Cl]2 and ( )-BINAP, af forded roc49 (2i ,3S and 2S,3R, and not 2R,iR and 2S,3S Eq. (16). 

As stated earlier, this reaction did not match perfectly with the Curtain-Hammett postulate. The chiral Mo complex can select the favored face (either A or B) from L-C. However, facial selection of B-C on formation of the tr-complex (A or B) should be dictated by the orientation of the carbonate itself not by the chirality of the Mo complex. At the same time, we would expect the chiral Mo complex to 

Following the reaction with S,S-ligand 31, it was found that the S-carbonate (B-C-S) reacted first and gave the desired B-P with a very high S selectivity, f -carbonate (B-C-R) reacted ten times slower than S. When the reaction was terminated around 60% conversion with S,S-ligand 31, unreacted R-carbonate (B-C-R) was isolated from reaction mixture with 99% ee [24]. 

For mismatched carbonate (B-C-R) - decreasing [malonate] will increase ee - All malonate present initially 70% ee - Malonate added over six hours 92% ee - ee higher in toluene than THF due to much lower solubility of Na-malonate in toluene 

According to this equilibrium argument, the matched S-carbonate B-C-S should give a better branch to linear (B/L) ratio and enantiomeric excess if the nucleophilic substitution rate prior to Jt-allyl Mo conversion from complex A to B is increased, (see Table 2.7) For example, when the reaction was run at a higher concentration, [Malonate]0 0.6M rather than the typical -0.07 M, the ee of the product increases to 97% from 92%. 

The reaction equilibrium issues have become clearer, but the mechanism of the reaction and the real active catalytic complex were unknown. I nitially, we addressed these issues by measuring the reaction kinetics but the attempt did not lead us to a clear conclusion. 

In all the examples of stereoselective synthesis seen so far, at least one of the reactants (either the substrate or the reagent) is achiral. When two or more chiral reactants are expo- 

In the simplest case a racemic substrate is allowed to react with an enantiomerically pure compound, e.g., of (/ -configuration. The TS of the reactions leading to the (R,R)- and (RS)-isomers are diastereoisomerically related and differ in energy. Thus, different reaction rates can be expected for the two processes, and either by stopping the reaction before completion or by using a deficiency of the enantiomerically pure reagent, enrichment of the racemic mixture in the slower-reacting enantiomer can be obtained. 

This process, that resolves enantiomers on the basis of their different reaction rates, is called kinetic resolution [28], Conceptually it is similar to the reactions of Fig. 4, as the enantiomerically pure reagent (in this context, the kinetic resolving agent) differentiates between the two enantiomerically related molecules of the racemic substrate. Obviously, in the reactions of Fig. 4 it is one molecule that features the enantiomerically related entities (e.g., the two carbonyl faces of benzaldehyde) which are differentiated by the chiral non-racemic reagent. 

A few examples of kinetic resolutions are reported in Fig. 5. These have been selected among those reactions leading to the preparation of enantiomerically enriched compounds that do not feature a handle for classical resolutions. 

The hydroboration described in reaction A of Fig. 5 mainly occurs on the (R)-alkene and leaves the unreacted (,S)-oIefin having a 65% e.e. [29]. A similar level of stereoselection (70% e.e.) was estimated for the unreacted (R)-allenic sulfone recovered from the conjugate addition of half equivalent of (R)-a-methylbenzylamine to the racemic compound (reaction B) [30]. 

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Kinetic resolution (not as good as Sharp less asymmetric epoxldatlon)... 

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

Sharpless epoxidations can also be used to separate enantiomers of chiral allylic alcohols by kinetic resolution (V.S. Martin, 1981 K.B. Sharpless, 1983 B). In this procedure the epoxidation of the allylic alcohol is stopped at 50% conversion, and the desired alcohol is either enriched in the epoxide fraction or in the non-reacted allylic alcohol fraction. Examples are given in section 4.8.3. 

In the Sharpless epoxidation of divinylmethanols only one of four possible stereoisomers is selectively formed. In this special case the diastereotopic face selectivity of the Shaipless reagent may result in diastereomeric by-products rather than the enantiomeric one, e.g., for the L -(-(-)-DIPT-catalyzed epoxidation of (E)-a-(l-propenyl)cyclohexaneraethanol to [S(S)-, [R(S)-, [S(R)- and [R(R)-trans]-arate constants is 971 19 6 4 (see above S.L. Schreiber, 1987). This effect may strongly enhance the e.e. in addition to the kinetic resolution effect mentioned above, which finally reduces further the amount of the enantiomer formed. 

The 9 — 15 fragment was prepared by a similar route. Once again Sharpless kinetic resolution method was applied, but in the opposite sense, i.e., at 29% conversion a mixture of the racemic olefin educt with the virtually pure epoxide stereoisomer was obtained. On acid-catalysed epoxide opening and lactonization the stereocentre C-12 was inverted, and the pure dihydroxy lactone was isolated. This was methylated, protected as the acetonide, reduced to the lactol, protected by Wittig olefination and silylation, and finally ozonolysed to give the desired aldehyde. 

EinaHy, kinetic resolution of racemic olefins and aHenes can be achieved by hydroboration. The reaction of an olefin or aHene racemate with a deficient amount of an asymmetric hydroborating agent results in the preferential conversion of the more reactive enantiomer into the organoborane. The remaining unreacted substrate is enriched in the less reactive enantiomer. Optical purities in the range of 1—65% have been reported (471). 

Enzymatic hydrolysis of A/-acylamino acids by amino acylase and amino acid esters by Hpase or carboxy esterase (70) is one kind of kinetic resolution. Kinetic resolution is found in chemical synthesis such as by epoxidation of racemic allyl alcohol and asymmetric hydrogenation (71). New routes for amino acid manufacturing are anticipated. 

Quantitative Analysis of Selectivity. One of the principal synthetic values of enzymes stems from their unique enantioselectivity, ie, abihty to discriminate between enantiomers of a racemic pair. Detailed quantitative analysis of kinetic resolutions of enantiomers relating the extent of conversion of racemic substrate (c), enantiomeric excess (ee), and the enantiomeric ratio (E) has been described in an excellent series of articles (7,15,16). 

Fig. 1. Free-energy profile for a kinetic resolution depicted by equation 1 that follows Michaelis-Menten kinetics.

Enzyme-Catalyzed Asymmetric Synthesis. The extent of kinetic resolution of racemates is determined by differences in the reaction rates for the two enantiomers. At the end of the reaction the faster reacting enantiomer is transformed, leaving the slower reacting enantiomer unchanged. It is apparent that the maximum product yield of any kinetic resolution caimot exceed 50%. 

Kinetic Resolutions. From a practical standpoint the principal difference between formation of a chiral molecule by kinetic resolution of a racemate and formation by asymmetric synthesis is that in the former case the maximum theoretical yield of the chiral product is 50% based on a racemic starting material. In the latter case a maximum yield of 100% is possible. If the reactivity of two enantiomers is substantially different the reaction virtually stops at 50% conversion, and enantiomericaHy pure substrate and product may be obtained ia close to 50% yield. Convenientiy, the enantiomeric purity of the substrate and the product depends strongly on the degree of conversion so that even ia those instances where reactivity of enantiomers is not substantially different, a high purity material may be obtained by sacrificing the overall yield. 

The variety of enzyme-catalyzed kinetic resolutions of enantiomers reported ia recent years is enormous. Similar to asymmetric synthesis, enantioselective resolutions are carried out ia either hydrolytic or esterification—transesterification modes. Both modes have advantages and disadvantages. Hydrolytic resolutions that are carried out ia a predominantiy aqueous medium are usually faster and, as a consequence, require smaller quantities of enzymes. On the other hand, esterifications ia organic solvents are experimentally simpler procedures, aHowiag easy product isolation and reuse of the enzyme without immobilization. 

Lipase-catalyzed kinetic resolutions are often practical for the preparation of optically active pharmaceuticals (61). For example, suprofen [40828-46-4] (45), which is a nonsteroidal antiinflamatory dmg, can be resolved by Candida glindracea]i 2Lse in >95% ee at 49% conversion (61). Moreover, hpase-based processes for the resolution of naproxen [22204-53-1] and ibuprofen [15687-27-1] (61) have also been developed. 

Various racemic secondary alcohols with different substituents, eg, a-hydroxyester (60), are resolved by PFL neatly quantitatively (75). The effect of adjacent unsatuiation on enzyme-catalyzed kinetic resolutions was thoroughly studied for a series of aHyUc (61), propargyUc (62), and phenyl-substituted 2-aIkanols (76,77). Excellent selectivity was observed for (E)-aHyhc alcohols whereas (Z)-isomers showed poor selectivity (76). 

Another means of resolution depends on the difference in rates of reaction of two enantiomers with a chiral reagent. The transition-state energies for reaction of each enantiomer with one enantiomer of a chiral reagent will be different. This is because the transition states and intermediates (f -substrate... f -reactant) and (5-substrate... R-reactant) are diastereomeric. Kinetic resolution is the term used to describe the separation of enantiomers based on different reaction rates with an enantiomerically pure reagent. 

Fig. 2.6. Dependence of enanhomeric excess on relative rate of reaction and extent of conversion with a chiral reagent in kinetic resolution. [Reproduced from J. Am. Chem. Soc. 103 6237 (1981) by permission of the American Chemical Society.]...

As was the case for kinetic resolution of enantiomers, enzymes typically exhibit a high degree of selectivity toward enantiotopic reaction sites. Selective reactions of enaiitiotopic groups provide enantiomerically enriched products. Thus, the treatment of an achiral material containing two enantiotopic functional groups is a means of obtaining enantiomerically enriched material. Most successful examples reported to date have involved hydrolysis. Several examples are outlined in Scheme 2.11. 

Dihydronaphthalene is often used as a model olefin in the study of epoxidation catalysts, and very often gives product epoxides in unusually high ee s. In 1994, Jacobsen discovered in his study on the epoxidation of 1,2-dihydronaphthalene that the ee of the epoxide increases at the expense of the minor enantiomeric epoxide.Further investigation led to the finding that certain epoxides, especially cyclic aromatically conjugated epoxides, undergo kinetic resolution via benzylic hydroxylation up to a krei of 28 (Scheme 1.4.9). 

The first application of the Jacobsen-Katsuki epoxidation reaction to kinetic resolution of prochiral olefins was nicely displayed in the total synthesis of (+)-teretifolione B by Jacobsen in 1995. 

The AE reaction has been applied to a large number of diverse allylic alcohols. Illustration of the synthetic utility of substrates with a primary alcohol is presented by substitution pattern on the olefin and will follow the format used in previous reviews by Sharpless but with more current examples. Epoxidation of substrates bearing a chiral secondary alcohol is presented in the context of a kinetic resolution or a match versus mismatch with the chiral ligand. Epoxidation of substrates bearing a tertiary alcohol is not presented, as this class of substrate reacts extremely slowly. 

The application of the AE reaction to kinetic resolution of racemic allylic alcohols has been extensively used for the preparation of enantiomerically enriched alcohols and allyl epoxides. Allylic alcohol 48 was obtained via kinetic resolution of the racemic secondary alcohol and utilized in the synthesis of rhozoxin D. Epoxy alcohol 49 was obtained via kinetic resolution of the enantioenriched secondary allylic alcohol (93% ee). The product epoxy alcohol was a key intermediate in the synthesis of (-)-mitralactonine. Allylic alcohol 50 was prepared via kinetic resolution of the secondary alcohol and the product utilized in the synthesis of (+)-manoalide. The mono-tosylated 3-butene-1,2-diol is a useful C4 building block and was obtained in 45% yield and in 95% ee via kinetic resolution of the racemic starting material. 

Note that the maximum yield for a kinetic resolution is 50%. 

We have tecently discovered that pbospbotamidile 18 is also an excellent ligand for copper-catalyzed kinetic resolution of chital 2-cydobexenones fScheme 7.15). Chi-... 

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