Achirality agents

The optical yield was found to be very sensitive to structural modifications of the achiral agent. For example, use of the more bulky FV or Bu substituents in the 3,5-positions of phenol resulted in lower optical yields. In some cases a reversal of the sense of asymmetric induction was observed. Systematic variation of reaction conditions using the best achiral component, 3,5-xylenol, established that optimum results were obtained in ether solvent at about - 15°C. There was also a minor but definite influence of the rate of addition of ketone as well as an effect of concentration on optical yield, with a slower rate being advantageous. The results of reduction of aryl alkyl ketones are shown in Table 9, along with comparative results of reduction with similar chiral auxiliary reagents. 

Catalytic Asymmetric Hydroboration. The hydroboration of olefins with catecholborane (an achiral hydroborating agent) is cataly2ed by cationic rhodium complexes with enantiomericaHy pure phosphines, eg, [Rh(cod)2]BE4BINAP, where cod is 1,5-cyclooctadiene and BINAP is... 

Derivatization with Optically Active Reagents and Separation on Achiral Columns. This method has been reviewed (65) a great number of homochiral derivatizing agents (HD A) are described together with many appHcations. An important group is the chloroformate HD As. The reaction of chloroformate HD As with racemic, amino-containing compounds yields carbamates, which are easily separated on conventional hplc columns, eg (66),... 

K.-M. Chu, S.-M. Sliieh, S.-H. Wu and O. Y.-P. Hu, Enantiomeric separation of a cardiotonic agent pimobendan and its major active metabolite, UD-CG 212 BS, by coupled achiral-cliiral normal-phase high-performance liquid chromatography , 7. Chromatogr. Sci 30 171-176(1992). 

The educt, a racemate, is derivatized before the separation with an agent which might be achiral or unichiral (Fig. 7-1), and afterwards is passed through a chromatographic system which is equipped with a stationary phase. This stationary phase may also be achiral or unichiral in nature. 

This strategy is the one most commonly used for the analytical determination of ena-tiopurity. A given racemate is reacted with a unichiral derivatizing agent, and the resulting pair of diastereomers is separated on an achiral stationary phase, in most of the cases on a reversed-phase type (Fig. 7-2). 

Let us assume that a given compound has a purity of 98 % ee, and that this compound is reacted with a derivatizing agent which has also a purity of 98 % ee. The two major compounds plus the minor impurities in the compound to be analyzed and the derivatizing agent will create a set of four diastereomers. Two pairs of diastereomers (-i-)-A(-i-)B and (-)-A(-)-B as well as (- )-A(-i-)-B and (-i-)-A(-)-B are enantiomeric pairs, and thus elute together on an achiral column. Therefore, a peak area of 98.011 % will be detected for (-i-)-A(-i-)-B, which leads to a purity of 96.03 % ee for (-i-)-A. This is a quite significant deviation from the true value for (-i-)-A. 

The complexation of achiral metal enolates by chiral additives, e.g., solvents or complexing agents could, in principle, lead to reagent-induced stereoselectivity. In an early investigation, the Reformatsky reaction of ethyl bromoacetate was performed in the presence of the bidentate ligand (—)-sparteine20. The enantioselectivity of this reaction varies over a wide range and depends on the carbonyl Compound, as shown with bcnzaldehyde and acetophenone. 

Asymmetric reduction with very high ee values has also been achieved with achiral reducing agents and optically active catalysts. The two most important... 

In the above cases, an optically active reducing agent or catalyst interacts with a prochiral substrate. Asymmetric reduction of ketones has also been achieved with an achiral reducing agent, if the ketone is complexed to an optically active transition metal Lewis acid. ... 

There are other stereochemical aspects to the reduction of aldehydes and ketones. If there is a chiral center to the carbonyl group, even an achiral reducing agent can give more of one diastereomer than of the other. Such diastereoselective reductions have been carried out with considerable success. In most such cases Cram s rule (p. 147) is followed, but exceptions are known. ... 

Chiral and achiral Jacobsen s catalysts exhibit similar diatereomeric excesses during the diastereoselective epoxidation of R-(+)-limonene using in situ prepared oxidizing agents. Therefore, the chiral center of the substrate appears to govern the chiral induction. In contrast, the chirality of the Jacobsen s catalyst appears to be responsible for the chiral induction when commercially available oxidants were used. 

Scheme 2.6 shows some examples of the use of chiral auxiliaries in the aldol and Mukaiyama reactions. The reaction in Entry 1 involves an achiral aldehyde and the chiral auxiliary is the only influence on the reaction diastereoselectivity, which is very high. The Z-boron enolate results in syn diastereoselectivity. Entry 2 has both an a-methyl and a (3-benzyloxy substituent in the aldehyde reactant. The 2,3-syn relationship arises from the Z-configuration of the enolate, and the 3,4-anti stereochemistry is determined by the stereocenters in the aldehyde. The product was isolated as an ester after methanolysis. Entry 3, which is very similar to Entry 2, was done on a 60-kg scale in a process development investigation for the potential antitumor agent (+)-discodermolide (see page 1244). 

Ferretti et al. (1988) used an amino column coupled to a derivatized amylose column (Chiralpak AS) operated in the reverse-phase mode to separate the enantiomers of the antifungal agent voriconazole from several chiral impurities and one achiral impurity. Three of the chiral impurities are the other enantiomer and corresponding diastereomers of voriconazole. More chiral impurities result from a chlorinated voriconazole. Additionally, this multidimensional method could baseline separate all but two of the chiral impurities into their respective enantiomers. These separations are shown in Figure 14.5. 

Ferretti, R., Gallinella, B., La, T.F., Zanitti, L. (1988). Direct resolution of a new antifungal agent, voriconazole(UK-109,496) and its potential impurities, by use of coupled achiral-chiral high-performance liquid chromatography. Chromatographia 47, 649-654. 

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