Racemic mixture resolution auxiliaries

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... 

A wide variety of chiral sulfinyl substituents have been employed as chiral auxiliaries on both dienes162 and dienophiles163 in asymmetric Diels-Alder reactions. Carreno and colleagues164, for example, used Diels-Alder reactions of (Ss)-2-(p-tolylsulfinyl)-1,4-naphthoquinone (249) to separate racemic mixtures of a wide variety of diene ena-tiomers 250a and 250b via kinetic resolution and to obtain enantiomerically enriched... 

Like other methods of asymmetric synthesis, the solid-state ionic chiral auxiliary procedure has an advantage over Pasteur resolution in terms of chemical yield. The maximum amount of either enantiomer that can be obtained by resolution of a racemic mixture is 50%, and in practice the yield is often considerably less [47]. In contrast, the ionic chiral auxiliary approach affords a single enantiomer of the product, often in chemical and optical yields of well over 90%. Furthermore, either enantiomer can be obtained as desired by simply using one optical antipode or the other of the ionic chiral auxiliary. 

The resolution of the racemic mixture of modafinil acid 6 using thiazolidinethione 19 as the chiral auxiliary was achieved in 88% yield (Scheme 6) in the presence of DCC.33 Two diastereomeric intermediates 20 and 21 were easily separated by silica gel column chromatography and the absolute stereochemistry was assigned based on the single A-ray crystallographic analysis. Finally, the addition of ammonia to diastereomeric thiazolidinethione 20 yielded armodafinil 1. 

Even if the resolution of an amino acid is relatively easy, the synthesis of a racemic mixture when only one enantiomer is desired is wasteful, because half of the product cannot be used. Recently, considerable effort has been devoted to the development of methods that produce only the desired enantiomer by so-called asymmetric synthesis. As was discussed in Chapter 7, one enantiomer of a chiral product can be produced only in the presence of one enantiomer of another chiral compound. In some asymmetric syntheses a chiral reagent is employed. In others a compound called a chiral auxiliary is attached to the achiral starting material and used to induce the desired stereochemistry into the product. The chiral auxiliary is then removed and recycled. 

The biphosphole (370) has been obtained in enantiomerically pure form by spontaneous resolution in the crystallisation of a racemic mixture, without the use of chiral auxiliaries. A new approach to -functionalised phospholes is afforded by metallation at a methyl group of l-phenyl-3,4-dimethylphosphole(in which both phosphorus and the diene unit are protected by coordination to an iron carbonyl acceptor), followed by treatment with electrophiles, to give C-substituted products, e.g., (371). Copper(II) oxidation of the intermediate lith-iomethyl derivative leads to the formation of bridged systems, e.g., (372). ... 

In step X, a racemic product in the ratio 1 1 is isolated. In step X + 1, a chiral auxiliary is added to produce a diastereomeric salt that preferentially crystallizes out of solution and is isolated. In step X + 2, this salt is exposed to acidic or basic aqueous solution to liberate the free optically pure product that is finally collected. In this kind of resolution, half the mass of racemic product collected in step X is destined for waste. Therefore, the percent reaction yield for step X + 1 should be less than or equal to 50%. The reaction yields for steps X and X + 2 can be as high as 100%. The problem is that papers will report the percent yield for step 2 with a fraction that exceeds 50%. How can this be What authors have done is the following sleight of hand. The percent yield they report is not with respect to the starting mass of racemic mixture, but with respect to half its mass, that is, the half that will eventually be collected in step X + 2, assuming no losses along the way. Again, chemists have an... 

Section 2.2 deals with the classical resolution of racemic mixtures via formation of diastereomeric adducts with chiral auxiliaries or by chromatographic methods. 

The expression KR emphasizes that the racemic mixture undergoes a separation under a chiral influence in a kinetically controlled process. In principle, the word resolution refers to the isolation of one of the enantiomers of racemic mixture after a partial transformation of the initial mixture. If the reaction product is chiral, as in the esterification of a racemic alcohol, then the KR will afford a product with some enantiomeric excess. The full transformation of a racemic mixture by coupling with a chiral auxiliary will give a 1 1 mixture of diastereomers and is not considered as a KR process, unless the reaction is stopped at an intermediate stage, leaving some enantioenriched starting material. 

The knots based on neutral, purely organic molecules are obviously not prone to classical diastereomer resolution, and, while chromatographic methods were not suitable for the separation of the two enantiomers of the metal-templated trefoil knot, they have been proved successful in the amide-containing knots. As far as these knotted molecules are concerned, it must be noted that they incorporate classical stereogenic centers (carbon atoms), which makes them very different from the copper-based systems in terms of chirality. In the first instance, the separation of the two enantiomers of six different knots was achieved with a colunm that was not conunercially available (chiral-AD type). Trichloromethane was needed to obtain an optimal separation. The silica gel and the chiral stationary phase were covalently bound so that the material did not bleed out when the lipophilic eluent was used. Moreover, comparison of the experimental CD of the pure enantiomers of a knot with a theoretically calculated CD (based on X-ray structure and a fiiUy optimized AMI geometry) permitted assignment of the absolute configuration of this knot. The latter preparation of soluble knots based on substitution of the 5-position of the pyridine moieties in 13 afforded molecules that were soluble in solvents which could be used in commercially available chiral columns." On the other hand, the substitution of a racemic mixture of knots with chiral auxiliaries allows the separation of the diastereomeric product." ... 

Resolution of a racemic mixture was discovered by Pasteur in the last century. It remains an useful method to prepare enantiomerically pure compounds, although the yield in the desired enantiomw cannot exceed 50%. It is realized by the reaction of stoichiometric amounts of a chiral auxiliary which will produce a I I mixture of diastereomers, generally easy to separate. Removal of the chiral auxiliary graerates the desired enantiomer. A special case of resolution is one in which the racemic compound crystallizes as a conglomerate. Here, a chiral seed can propagate the production of... 

In racemic resolution processes a racemic mixture of the desired product is produced first. There are several techniques by which this mixture can be separated into its two enantiomers. A favorable option is to react the racemic mixture with another chiral compound to form diastereomers. The latter have different physicochemical properties and thus they can be separated, for example, by chromatographic or crystallization processes. After separation of the diasteromers the chiral auxiliary compound is split-off and separated to re-obtain the desired compound as pure enantiomer. In an alternative concept, called kinetic racemic resolution, the initial racemic mixture is reacted with a chiral reactant or in the presence of a chiral catalyst (e.g., an enzyme) and only one of the two enantiomers of the desired product is transformed into a new compound. The reacted and non-reacted enantiomers are usually easily separated. All processes of racemic resolution have the common disadvantage that both enantiomers, the desired and the undesired one, have to be synthesized initially. Consequently, half of the initial racemic mixture is the undesired enantiomer, which usually has no or very little commercial value. This problem is partialy solved by applying racemization processes in which after separation the pure wrong enantiomer is re-converted into the racemic mixture. The latter is then applied in another round of racemic resolution again to increase the final yield of the desired enantiomer. 

This method involves the chemists following a traditional synthetic route to make the compound, resulting in a racemic mixture. Then they separate the two enantiomers in a process called optical resolution. This involves using a pure enantiomer of another optically active compound (called a chiral auxiliary) that will react with one of the isomers in the mixture. The new product formed will now have different properties and so can be separated by physical means. For example, the solubility in a given solvent will differ so the unwanted enantiomer and the new product can be separated by fractional crystallisation. The new product is then converted back to the desired enantiomer in a simple reaction (e.g. by adding dilute alkali). 

Alternatively, (trimethylenemethane)iron complexes can be synthesized by disproportionation of tricarbonyl(2-methallyl)ironJ Enantiomerically pure tricarbonyl-(trimethylenemethane)iron complexes can be obtained by resolution of the racemic mixture via diastereomeric esters or amides. (5)-(-)-Ethyl lactate and (/ I)-(+)-a-methyl-benzylamine are employed as resolving reagents for this piupose. The chiral auxiliaries can be removed by a variety of reagents leaving the (trimethylenemethane)iron fragment unaffected. Treatment of both the corresponding Boc-protected amides and the chiral esters with diisobutylaluminum hydride (DIBAL) or methyllithium provides the primary or tertiary alcohols, respectively. Saponification of the ester with lithium hydroxide in methanol and subsequent acidification of the mixture affords the methyl ester. Treatment of the ester with triethylsilane leads to complete reduction of the functionality to leave a methyl group (Scheme 4—85). ... 

The main interest in (-)-encycloaddition processes to yield separable mixtures of diastereoisomeric urazoles. The non-destructive resolution of cyclooctatetraenes, which allows direct access to optically pure derivatives, is a typical illustration and has been amply demonstrated. Typically, (-)-enethyl acetate to afford a mixture of diastereoisomeric adducts, which can be separated by fractional recrystallization from ethyl acetate and hexane. HPLC is an alternative separation technique leading to both enantiomerically pure antipodes. The chiral auxiliary is subsequently removed by basic hydrolysis-manganese dioxide oxidation to afford the optically pure cyclooctatetraenes (eq 2). 

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