Chiral-auxiliary direct separation

In recent years, for analytical purposes the direct approach has become the most popular. Therefore, only this approach will be discussed in the next sections. With the direct approach, the enantiomers are placed in a chiral environment, since only chiral molecules can distinguish between enantiomers. The separation of the enantiomers is based on the complex formation of labile diastereoisomers between the enantiomers and a chiral auxiliary, the so-called chiral selector. The separation can only be accomplished if the complexes possess different stability constants. The chiral selectors can be either chiral molecules that are bound to the chromatographic sorbent and thus form a CSP, or chiral molecules that are added to the mobile phase, called chiral mobile phase additives (CMPA). The combination of several chiral selectors in the mobile phase, and of chiral mobile and stationary phases is also feasible. 

Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by the use of various C-functionalized chiral nitrones in order to enforce enantioselec-tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as in the work of Merino et al. (40), that asymmetric induction is at best partial with dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot completely direct the addition to the nitrone. After poor results with menthol ester-and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-lidine 8a and its diastereomer 8b in near quantitative yield using the A-glycosyl... 

The integrals of the separated resonance absorptions provide a direct measure of the enantiomeric ratio from which the cc can be calculated. The chemical shift anisochrony of enantiomers (dR S<>) in the presence of a nonracemic chiral auxiliary compound is attributed to at least two contributions which are related to the geometry and stability of the resulting diastereomeric association complexes79 80 ... 

A highly versatile method for enantiomer analysis is based on the direct separation of enantiomeric mixtures on nonraceinic chiral stationary phases by gas chromatography (GC)6 123-12s. When a linearly responding achiral detection system is employed, comparison of the relative peak areas provides a precise measurement of the enantiomeric ratio from which the enantiomeric purity ee can be calculated. The enantiomeric ratio measured is independent of the enantiomeric purity of the chiral stationary phase. A low enantiomeric purity of the resolving agent, however, results in small separation factors a, while a racemic auxiliary will obviously not be able to distinguish enantiomers. 

After separation of the desired major diastereoisomer 154, the removal of the chiral auxiliary furnished vinyl compound 151 in enantiomerically pure form. The latter was directly converted to the 9-membered lactam 144 in 58% yield via a palladium-catalyzed carbonylation (10 atm CO, HCOOH, DME, 150°C). Removal of the methyl ester as previously described furnished (-)-rhazinilam. This elegant work constitutes the first asymmetric total synthesis of the natural product. 

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). 

We have just seen the theoretical importance of direct resolution by crystallization and the practical limitations of such a method. Moreover, for compounds that crystallize as racemic compounds this route is clearly not allowed. However, the use of a pure chiral auxiliary, leading to diasteromers with different physico-chemical properties, allows us to separate them by a variety of techniques and in particular fractional crystallization. We can schematize the process of formation and separation of the diastereomers in a simple way, as well as the recovery of the chiral auxiliary and the enantiomers (Scheme 2.3). 

Direct separation of enantiomers by chromatography Use of covalent chiral auxiliaries Stereoselective synthesis of individual enantiomers Separation of diastereoisomers by physical techniques Synthesis from chirality pool materials... 

Wulff has studied the use of chiral auxiliaries in the chromate ester (1, X = a chiral auxiliary) to control the absolute stereochemistry of the aryl chromium product 35. In the same disclosure he describes an attempt to control the chiral center adjacent to the ketone formed on electrocyclization. In his example, a pair of chromium carbene atropisomers 41 (only one shown) were prepared. These diastereomers were readily seperable on silica gel. It was shown that each diastereomeric atropisomer reacted stereospecifically with alkynes to produce a different diastereomer 42. Thus the chiral auxiliary allowed the separation of the atropisomers, but did not directly control the absolute stereochemistry adjacent to the ketone. Instead, the stereochemistry was determined by confining the chromium to one face of the indole in 41 by preventing rotation about the the carbene indole bond. 

With the increasing number of commercially available, extremely pure chiral auxiliaries, thin-layer chromatographic purity control via formation of diastereomers has gained increasing importance. In contrast to direct enantiomer separations, antipode separation via diastereomers usually is not achieved with chiral adsorbents however, enhanced diastereomer selectivity is also noted for asymmetric supports. The type of chiral reagent for formation of the diastereomer depends among other parameters on the structure—mono- or bifunctional—of the compound to be derivatized (see Table 7). 

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