Horeau principle

It was also found that the Padua reagent was useful for the oxidation of three isomeric bis(methylsulfmyl)benzenes with r-BuOOH, yielding the corresponding almost enantiopure bis-sulfoxides [64]. As mentioned above, the enantioselectivity of the first oxidation was enhanced (Horeau principle), because a minor amount of meso-disulfoxide was formed and separated from the chiral disulfoxide. It was reported that the Orsay reagent with cumyl hydroperoxide oxidized an /V-protected 2-.S -methylindole with moderate enantioselectivity, whereas the Padua protocol afforded the desired sulfoxide with 80% ee [65],... 

Introduction, steps 1 to 9, summary Some Principles Chiral auxiliaries The Horeau principle Popular Misconceptions Misuse of words... 

This method was successfully used8 to improve the enantiomeric excess of alcohol 76 from 92% ee to 99.6% ee. The combination of substrates that are already of quite good enantiomeric excess to give a product of even better ee is not uncommon and is sometimes referred to as the Horeau Principle.9... 

The authors of the above work specifically mention the Horeau principle but its operation k often less explicit. Take for example the production of acid 84 which can be produced in 90-92% ee by the reaction of optically pure diester 83 of hydrobenzoin 81 in a Diels-Alder reaction11... 

Figure 42.1 Schematic explanation of the Horeau principle and the product enantioen-richment within catalytic asymmetric MCRs. A three-component reaction in which the...

Horeau principle provides the mathematical foundation for rationahzing the enan-tioenrichment observed along successive catalytic cycles of asymmetric MCRs [7]. The simple calculations shown in Figure 42.1 reveal that this strategy can provide the major diastereomer of a chiral product that has two stereogenic centers with exquisite levels of enantiocontrol. This is despite combining two consecutive catalytic processes that might be only moderately selective (e.g., 80% ee + 80% ee = 97.5% ee). 

This example, although very interesting, could not exploit the full potential of an asymmetric MCR in which more than one catalytic event is under the control of the chiral organocatalysL There was poor control over the relative stereochemistry, although the Horeau principle (see Figine 42.1 and discussion thereof) calls for a higher overall stereoselectivity of the whole process. The low level of... 

In line with the previously discussed Horeau principle, the interaction between the chiral catalyst and the chiral intermediate, resulting from the first conjugated addition under iminium ion activation, induces a remarkable enanhoenrichment in the final enamine step. As a result, the chemistry shown in Schemes 42.10 and 42.11 afforded rapid access to acyclic complex products with enantiomeric excess... 

Horeau principle 1286,1294 Horner-Wadsworth-Emmons (HWE) sequence 1309 host-guest complexes 687 Houk-List transition state model 475, 477, 478... 

This type of procedure is referred to as a kinetic resolution since the enantiomers of the racemic substrate exhibit different rates of reaction with the optically active compound, i.e. the diastereomeric transition states that arise from differences in e.g. non-bonded interactions have different free energies. Horeau and Nouaille (1966) estimate that a rate difference corresponding to A AG of the order of 0 2 cal mol at 25°C could in principle be revealed by this method. 

What happens for a nonracemic mixture of enantiomers Is it possible to calculate the values of the chiral properties of the solution from knowledge of the properties of the enantiopure compound In principle, yes, on the condition that there is no autoassociation or aggregation in solution. Then, the observed properties will be simply the weighted combination of the properties of two enantiomers. A nice example of where this normal law may be broken was discovered by Horeau in 1967 it is the nonequivalence between enantiomeric excess (ee) and optical purity (op, with op = [a]exi/[ ]max) for 2,2-methylethyl-succinic acid. In chloroform op is inferior to ee, while in methanol op = ee. This was explained by the formation of diastereomeric aggregates in chloroform, while the solvation by methanol suppresses the autoassociation. 

In a different approach, fluorescence-based DNA microarrays are utilized (88). In a model study, chiral amino acids were used. Mixtures of a racemic amino acid are first subjected to acylation at the amino function with formation of A-Boc protected derivatives. The samples are then covalently attached to amine-functionalized glass slides in a spatially arrayed manner (Fig. 10). In a second step, the uncoupled surface amino functions are acylated exhaustively. The third step involves complete deprotection to afford the free amino function of the amino acid. Finally, in a fourth step, two pseudo-Qn nX. om.Qx c fluorescent probes are attached to the free amino groups on the surface of the array. An appreciable degree of kinetic resolution in the process of amide coupling is a requirement for the success of the ee assay (Horeau s principle). In the present case, the ee values are accessible by measuring the ratio of the relevant fluorescent intensities. About 8000 ee determinations are possible per day, precision amounting to +10% of the actual value ((S(S). Although it was not explicitly demonstrated that this ee assay can be used to evaluate enzymes (e.g., proteases), this should in fact be possible. So far this approach has not been extended to other types of substrates. 

There is an important difference between Horeau s and Heathcock s examples in that the aldol reaction generates two chirality elements in the bond-forming step. In principle, analysis of such a reaction requires evaluation of two aspects, i.e., the effect of double asymmetric induction on simple and induced diastereoselectivity. The aldol reaction is not particularly suited for this... 

Horeau published in 1982 a pioneering work on the use of mass spectrometry to evaluate the extent of KR in the esterification of racemic alcohols by a chiral anhydride. The principle was to label by deuterium one of the enantiomers of the alcohol and use it to prepare a pseudo-racemic mixture of the alcohol [102]. Mass spectrometry revealed which enantiomer reacted preferentially with the chiral reagent... 

Turning now to chemical methods used for stereochemical studies of carotenoids the modified Horeau method (32) has been successfully used to confirm the configuration of (2/ )- 3, 3-caroten-2-ol [(33), R=H] (38) and to establish the configuration of aleuriaxanthin (36) (34). However, no conclusive results could be obtained for plectaniaxanthin [(35), R = R =H] (28). In principle the Horeau method is based on partial resolution of racemic and meso a-phenylbutyric anhydride by means of an optically active secondary alcohol, which readts preferentially with one diastereomer. The unreacted anhydride is quantitatively determined by an appropriate procedure (32, 68, 94). 

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