Kinetic Resolutions and Desymmetrisations

One does not immediately associate a reaction which generates sp1 carbon centres with asymmetric inductive capability, however the development of non-racemic catalysts such as 40, 41 and 42 (Fig. 6) has allowed the efficient synthesis of optically active alkenes via the kinetic resolution (KR) of dienes and the desymmetrisation of meso-alkenes via either RCM or ROM-CM. For a short review of asymmetric metathesis see Ref. [85]. 

Comparison of desymmetrisation and kinetic resolutions Mono esterification ofdiols Part VII - Hetero Diels-Alder Reactions... 

As we shall see further in Chapter 28, a kinetic resolution is the more rapid reaction of one enantiomer of starting material over the other. In the absence of anything fancy (like a dynamic kinetic resolution) they are limited to 50% yield of product (or starting material). But because a desymmetrisation starts with one achiral molecule (instead of a pair of enantiomers) this limitation is removed as are other complications we face in kinetic resolutions such as the build up of the wrong enantiomer which makes selectivity more difficult. However, it is worth noting that desymmetrisation and kinetic resolutions are brothers in the stereochemical world. 

Consider, for example, a hypothetical kinetic resolution of enantiomers (R) and (S)-239 by esterification of one of them. Compare this to the esterification and desymmetrisation of diol 241. In many ways, a desymmetrisation is a kinetic resolution but with the two enantiomers joined together in the same molecule. The features that make a reagent work well in a desymmetrisation, may well make it work in a kinetic resolution. Indeed, in Double Methods in Chapter 28 we see that this is the case. 

If a selective process can be applied twice then we might expect the quality of the resulting material to be very high. In the next example, the selective process is applied first to produce mostly a single enantiomer. When applied the second time, it removes the small amount of the wrong enantiomer that was produced the first time round In Chapter 25 we mentioned that desymmetrisations and kinetic resolutions were brothers. Both are used in each of the examples below. 

If the enhancement of enantiomeric excess did not impress you much (though it should, 99.96% is very difficult to achieve in one go ) perhaps an example where the ee is a bit lower after the first round will make the point more effectively. The bistriflate 82 contains a biaryl bond with restricted rotation so that replacing one of the triflates with something else will give us a chiral molecule (83a and 83b are enantiomers). As above, the first reaction is a desymmetrisation and the second reaction a kinetic resolution upon the products from the first. Both reactions are palladium mediated cross-couplings of an aryl triflate and phenyl Grignard. 

Kinetic resolution with racemisation Enzymes versus whole organisms Desymmetrisation with lipases Immobilised enzymes in desymmetrisation Polymer-supported reagents and enzymes Effects of amines on lipases and esterases Other acylating enzymes Enzymatic Oxidation... 

A tetrahydropyran that inhibits leukotriene biosynthesis Asymmetric synthesis of2-methyl-tetrahydropyran-4-one by kinetic resolution Part VI - Asymmetric Desymmetrisation of a Diels-Alder Adduct Ifetroban sodium a thromboxane receptor antagonist A laboratory synthesis starting with a Diels-Alder reaction Desymmetrisation of a symmetrical anhydride with a chiral Grignard reagent Laboratory and process routes compared Part VII - Asymmetric Synthesis of A Bicyclic 3-Lactone Lactacystin a naturalproteasome inhibitor... 

In addition to kinetic resolution processes, the previously described peptide-catalysed acylation reaction of alcohols can be applied to desymmetrisation of meso compounds. In 2005, Miller and coworkers published the desymmetrisation of prochiral glycerol derivatives via enantioselective acylation of one primaiy alcohol function. A (3-tum histidine-based pentapeptide was identified as the most promising catalyst from a peptide libraiy and afforded the monoacylated product with up to 97% enantiomeric excess. One year later Miller and Hansen successfully demonstrated the desymmetrisation of a meso bis-phenol compound, which was found to be challenging because of the large distance between the two OH groups as well as between the desired site of functionalisation and the prochiral stereogenic centre of the substrate. The nucleophilic N-methylhistidine containing peptide 9 was identified as a powerful tool for monoacylation via extensive libraiy... 

A number of other asymmetric enolate protonation reactions have been described using chiral proton sources in the synthesis of a-aryl cyclohexanones. These include the stoichiometric use of chiral diols [68] and a-sulfinyl alcohols [69]. Other catalytic approaches involve the use of a BlNAP-AgF complex with MeOH as the achiral proton source, [70] a chiral sulfonamide/achiral sulfonic acid system [71,72] and a cationic BINAP-Au complex which also was extended to acyclic tertiary a-aryl ketones [73]. Enantioenriched 2-aryl-cyclohexanones have also been accessed by oxidative kinetic resolution of secondary alcohols, kinetic resolution of racemic 2-arylcyclohexanones via an asymmetric Bayer-Villiger oxidation [74] and by arylation with diaryhodonium salts and desymmetrisation with a chiral Li-base [75]. 

Miller developed peptide-based iV-methylimidazole catalysts and applied them to acylative kinetic resolution of N-acylated amino alcohol 29 (Scheme 22.6). The p-hairpin secondary structure of the peptide backbone in catalysts 30 and 31 constitutes a unique environment for effective asymmetric induction. Acylative kinetic resolution of 29 with acetic anhydride in the presence of catalyst 31 proceeded with high s values (s = up to 51). The asymmetric acylation was further extended to remote asymmetric desymmetrisation of a o-symmetric nanometer-scale diol substrate, 32 (Scheme 22.7). Catalyst 33 enabled the enantiotopic hydrojq groups in 32 to be distinguished even though they are located 5.75 A from the prochiral stereogenic centre, and 9.79 A from each other. 

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