Enantiomers of mandelic acid

The enantiomerically pure (/ )- and (iS )-ketones are prepared from the corresponding enantiomer of mandelic acid by catalytic hydrogenation, treatment of the resulting hexahydroman-delic acid with ethyllithium, and subsequent introduction of the silyl protecting group33. 

Valko et al. (22) studied the separation of mandelic acid enantiomers with y-CD and calculated very low binding constants 2.8 and 2.4 M x for the d- and L-enantiomers, respectively. The weak binding of mandelic acid to y-CD was explained by the large size of the y-CD torus for such a small molecule as mandelic acid. Unlike the enantiomers of leucovorin and its active metabolite, for which weak binding was associated with low enantio-selective (19), fairly high enantioselectivity was found for weakly bonded enantiomers of mandelic acid with y-CD (KD/KL = 1.17). 

Table I. Capacity factors of solutes (kl), calculated capacity factors of their P>-CD complexes (kn.g nn) and stability constants (Kj of -CD complexes of cresoles, p-nitrocinnimic acids and enantiomers of mandelic acid, mephenytoin and hexobarbital. Stationary phase 10 pm LiChrosorb RP 18...

Table II. Capacity Factors k of Enantiomers of Mandelic Acid and its ChloroderivativesDetermined on LiChrosorb RP-18 Column with 1.44x10 M ft-CD Aqueous Solutions at Two Different pH ...

CyDs have been used as major chiral mobile phase additives (CMPAs) for enantio-separations in HPLC. The first application of 8-CyD as a CMPA in combination with an achiral reversed-phase material for HPLC enantioseparations was reported by Sybilska and co-workers in 1982 [27]. These authors could achieve partial resolution of the enantiomers of mandelic acid and derivatives. The CMPA method played an important role in HPLC enantioseparations before the development of effective chiral stationary phases (CSPs) but is now rarely used. The major disadvantage of this technique, together with difficulties associated with the isolation of resolved enantiomers, is the rather large consumption of chiral selector. 

The Schiff bases obtained by reaction of 4-methyl-2,6-diformylphenol with l- or D-phenylglycinol 52 (Fig. 16) were foimd to interact enantioselectively with the two enantiomers of mandelic acid on account of the appearance of a fluorescent component with a longer lifetime. A job plot of the complex formation, however, revealed a 2 3 guest host stoichiometry of the complex formed, thus suggesting an oligomeric form of the type reported in Fig. 16b. The good enantioselectivity observed (Ks/K = 4 for the (R,R)-sensor) also allowed these authors to calibrate the fluorescence response vs the enantiomeric compositions of mandelic acid in benzene solutions containing 10 " M of the sensor [81]. 

Pu and coworkers described the same type of effect on the BINOL derivative containing enantiomers of the 2-amino-1,2-diphenyIethanoI unit 55 upon interaction with enantiomers of mandelic acid in benzene. By using the (S)-sensor, (5)-mandelic acid induced precipitation and formation of a highly fluorescent suspension with an enhanced fluorescence intensity of 950 times. In contrast, (/ )-mandeIic acid did not... 

Figure 3.9 presents a scheme for separation of the enantiomers of mandelic acid. The specific rotation of optically pure (S)-(-)-mandelic acid is -158. Suppose that instead of isolating pure (S)-(-)-mandelic acid from this scheme, the sample is a mixture of enantiomers with a specific rotation of -134. For this sample, calculate the following ... 

The resolution of mandelic acid by way of its diastereomeric salts with the natural chiral base cinchonine is illustrated in Figure 3.9. Racemic mandelic acid and optically pure (+)-cinchonine (Cin) are dissolved in boiling water, giving a solution of a pair of diastereomeric salts. Diastereomers have different solubilities, and when the solution cools, the less soluble diastereomeric salt crystallizes. This salt is collected and purified by further recrystallization. The filtrates, richer in the more soluble diastereomeric salt, are concentrated to give this salt, which is also purified by further recrystallization. The purified diastereomeric salts are treated with aqueous HCl to precipitate the nearly pure enantiomers of mandelic acid. Cinchonine remains in the aqueous solution as its water-soluble hydrochloride salt. 

Draw both enantiomers of mandelic acid and label each stereogenic center as R or S. 

Both enantiomers of mandelic acid are commercially available and these are suitable resolving agents for a variety of functional groups, and often used to isolate chiral alcohols. A sequential use of (R)- and (5)-mandelic acid allowed resolution of racemic amino alcohols (Eq. 3.3) [22]. Subsequent extraction gave 90% recovery of the amino alcohols with 99% ee or better. Mandelic acid was recovered in 93% yield. 

Mughal RK, Davey RJ, Blagden N. Application of crystallization inhibitors to chiral separations. 1. Design of additives to discriminate between the racemic compound and the pure enantiomer of mandelic acid. Cryst. Growth Des. 2007 7 218 224. 

Masamune [91]. It is recognized as particularly relevant in the context of stereoselective aldol reactions. Masamune developed the chiral ketones (J )-and (S)-179, derived from each enantiomer of mandelic acid, to conduct dia-stereoselective aldol reactions with both achiral and chiral aldehydes (Scheme 4.19) [91-93]. Subsequent to aldol addition, desilylation and oxidative cleavage of the chiral controlling group provides a carboxylic acid. The synthesis of the macrolide aglycon 6-deoxyerythronolide B (187) showcases the use of these ketones and represents the first successful application of double asymmetric induction in the context of a complex target [91, 93, 94). 

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