Parallel kinetic resolution

Although kinetic resolution is an established method for the preparation of chiral compounds, it requires a large difference in the rate constants of the enantiomers of the substrate in order to obtain the product and recovered starting material with 

The alternative approach to PKR using asymmetric HWE reactions, in which 

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Recently, Krische and co-workers developed an effective protocol for the catalytic desymmetrization and parallel kinetic resolution of enone-diones via tandem conjugate addition-aldol cyclization (Scheme 66).150 This transformation, involving enantioselective rhodium-catalyzed conjugate addition methodology, enabled the formation of two C-G bonds and four contiguous stereogenic centers from simple precursors with high diastereo- and enantiocontrol. 

The resolution of rac-20 represents a less common form of catalytic kinetic resolution (parallel kinetic resolution) [9]. In conventional kinetic resolution, one substrate enantiomer reacts preferably to leave behind the unreacted isomer in high optical purity (e.g., rac-18 (k)-19 in Scheme 4). In this instance, both starting material enantiomers undergo catalytic alkylation to give constitutional isomers. Since both enantiomers are consumed simultaneously, as the reaction proceeds, the amount of slow enantiomer (relative to the unreacted fast enantiomer) does not increase. Therefore, product ee remains high, even at relatively high conversions. 

Zirconocene-catalyzed kinetic resolution of dihydrofurans is also possible, as illustrated in Scheme 6.8 [18]. Unlike their six-membered ring counterparts, both of the heterocycle enantiomers react readily, albeit through distinctly different reaction pathways, to afford — with high diastereomeric and enantiomeric purities — constitutional isomers that are readily separable (the first example of parallel kinetic resolution involving an organome-tallic agent). A plausible reason for the difference in the reactivity pattern of pyrans and furans is that, in the latter class of compounds, both olefmic carbons are adjacent to a C—O bond C—Zr bond formation can take place at either end of the C—C 7T-system. The furan substrate and the (ebthi)Zr-alkene complex (R)-3 interact such that unfavorable... 

Finally, in 2001 Tanaka and Suemune described kinetic resolutions and parallel kinetic resolutions of dienals through the use of cationic and neutral Rh(l)/B1NAP complexes, respectively (Eqs. 17 and 18) [20-22]. 

If the 3-position is a tertiary, rather than a quaternary, stereocenter, Rh(I)/Tol-BINAP effects an intriguing parallel kinetic resolution - thus, one enantiomer of the substrate selectively undergoes hydroacylation to generate a cyclobutanone, while the other enantiomer is transformed into a cyclopentanone (Eq. 22) [24]. This observation is quite interesting, given the limited number of examples of parallel kinetic resolutions, particularly catalytic processes that involve carbon-carbon bond formation, and catalytic methods for the construction of cyclobutanones. 

Scheme 9. Desymmetrization and parallel kinetic resolution of cyclic anhydrides by (DHQD)2AQN...

These chiral acyl donors can be used for quite effective kinetic resolution of racemic secondary alcohols. For example, enantiomeric aryl alkyl ketones are es-terified by the acyl pyridinium ion 8 with selectivity factors in the range 12-53 [10], In combination with its pseudo-enantiomer 9, parallel kinetic resolution was performed [11], Under these conditions, methyl l-(l-naphthyl)ethanol was resolved with an effective selectivity factor > 125 [12]. Unfortunately, the acyl donors 8 and 9 must be preformed, and no simple catalytic version was reported. Furthermore, over-stoichiometric quantities of either MgBr2 or ZnCI2 are required to promote acyl transfer. In 2001, Vedejs and Rozners reported a catalytic parallel kinetic resolution of secondary alcohols (Scheme 12.3) [13]. 

Kinetic resolution relies on enantiospecific conversion of one enantiomer present in a racemic mixture while the other remains unchanged (except for parallel kinetic resolution in which both enantiomers are transformed but to different products). For secondary alcohols enantiospecific conversion might consist in oxidation of one enantiomer to a ketone while the other remains unchanged (Scheme 12.20). 

Most work on this subject is based on the use of alcohols as reagents in the presence of enantiomerically pure nucleophilic catalysts [1, 2]. This section is subdivided into four parts on the basis of classes of anhydride substrate and types of reaction performed (Scheme 13.1) - desymmetrization of prochiral cyclic anhydrides (Section 13.1.1) kinetic resolution of chiral, racemic anhydrides (Section 13.1.2) parallel kinetic resolution of chiral, racemic anhydrides (Section 13.1.3) and dynamic kinetic resolution of racemic anhydrides (Section 13.1.4). 

Parallel kinetic resolution of chiral, racemic anhydrides The term parallel kinetic resolution (PKR) implies that the two substrate enantiomers (Scheme 13.1, bottom... 

Parallel kinetic resolution of chiral, racemic anhydrides ... 

No examples of simple organocatalytic kinetic resolution of dicarboxylic acid anhydrides, e.g. by alcoholysis (Scheme 13.1, middle, X = CR2) seem to have been reported. This type of transformation requires that one anhydride enantiomer remains unchanged while the other is transformed to a mono-ester. Nucleophilic catalysts such as cinchona alkaloids have been shown to effect parallel kinetic resolution, that is, the two enantiomers of the anhydride are converted to regioiso-meric esters. This type of transformation is therefore discussed in Section 13.1.3. 

Parallel Kinetic Resolution of Chiral, Racemic Anhydrides... 

In 2001 Uozomi et al. reported that the (3-methyl)tetrahydrophthalic anhydride rac-21 undergoes parallel kinetic resolution when treated with methanol in the presence of the hydroxy proline derivative 13e (Scheme 13.10) [17]. The resulting esters 22 and 23 were formed with up to 80% ee, albeit at chemical yields of 12% and 29%, respectively. 

From these studies it has been shown that for a successful and efficient parallel kinetic resolution the following guidelines need to be adhered to a) derivatisation with two complementary chiral reagents have to occur without mutual interference [17] b) both reactions need to occur with similar but preferably equal rate and have complementary stereocontrol and c) afford distinct and easily separable products. 

Cu(OTf)2 (2mol%) is required (Equation (110)).183 The nature of the copper salt strongly influences the enantio-selectivity, and copper carboxylates proved to be especially efficient (Equation (lll)).184b It has been applied for an enantioselective synthesis of prostaglandin E methyl ester (Equation (112)),185 and can be used for the performance of a highly regiodivergent and catalytic parallel kinetic resolution.186... 

Parallel kinetic resolution (PKR), a concept that has been introduced for reactions where starting from a racemic mixture can allow the preparation of two different compounds at the same reaction rate [31], has been appHed for the separation of a mixture of P-D/L-deoxynucleosides. A practical synthesis of P-t-3 - and P-L-5 -0-levuHnyl-2 -deoxynucleosides has been described for the first time [32] through enzymatic acylation and/or hydrolysis processes. It is remarkable that the different behavior exhibited by PSL in the acylation of D- and L-nucleosides allows the parallel kinetic resolution of D/L nucleoside racemic mixtures. Scheme 10.12 shows a PKR of a 1 1 mixture of D and L nucleosides via an acylation reaction for furnishing easily separable compounds. This methodology would have tremendous potential for both research and industrial applications in the nucleic acid field. 

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