Phenylglycine, resolution

Synthetic chiral adsorbents are usually prepared by tethering a chiral molecule to a silica surface. The attachment to the silica is through alkylsiloxy bonds. A study which demonstrates the technique reports the resolution of a number of aromatic compoimds on a 1- to 8-g scale. The adsorbent is a silica that has been derivatized with a chiral reagent. Specifically, hydroxyl groups on the silica surface are covalently boimd to a derivative of f -phenylglycine. A medium-pressure chromatography apparatus is used. The racemic mixture is passed through the column, and, when resolution is successful, the separated enantiomers are isolated as completely resolved fiactions. Scheme 2.5 shows some other examples of chiral stationary phases. 

Amino acid separations represent another specific application of the technology. Amino acids are important synthesis precursors - in particular for pharmaceuticals -such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Thus, amino acids represent an important class of compounds that can benefit from more efficient separations technology. 

The synthesis of a-amino acids by reaction of aldehydes or ketones with ammonia and hydrogen cyanide followed by hydrolysis of the resulting a-aminonitrile is called the Strecker synthesis. Enzymatic hydrolysis has been applied to the kinetic resolution of intermediate a-aminonitriles [90,91]. The hydrolysis of (rac)-phenylglycine nitrile... 

Molecules having only a sulfoxide function and no other acidic or basic site have been resolved through the intermediacy of metal complex formation. In 1934 Backer and Keuning resolved the cobalt complex of sulfoxide 5 using d-camphorsulfonic acid. More recently Cope and Caress applied the same technique to the resolution of ethyl p-tolyl sulfoxide (6). Sulfoxide 6 and optically active 1-phenylethylamine were used to form diastereomeric complexes i.e., (-1-)- and ( —)-trans-dichloro(ethyl p-tolyl sulfoxide) (1-phenylethylamine) platinum(II). Both enantiomers of 6 were obtained in optically pure form. Diastereomeric platinum complexes formed from racemic methyl phenyl (and three para-substituted phenyl) sulfoxides and d-N, N-dimethyl phenylglycine have been separated chromatographically on an analytical column L A nonaromatic example, cyclohexyl methyl sulfoxide, did not resolve. 

A two-step approach, involving repeated use of the same enzyme, has been reported for the resolution of rac-l-phenylethylamine 56a (Scheme 2.34). Penicillin acylase, from Alcaligenes faecalis, was initially used in aqueous medium with (R)-phenylglycine amide 67 as the acyl donor. Under these conditions, the enzyme catalyzed the enantioselective acylation of 56a at pH 10-11. The product amide 68 was insoluble, and was collected and re-exposed to the enzyme at pH below 7.5. This resulted in the cleavage of the phenylglycinyl substituent. Excellent conversions, E values and enantiomeric excesses were achieved [36]. 

Finally, it is noted that suitable enantiomers of helicenes have been applied as selector for non-helical compounds. The disodium salt of P-( +)-7,10-dicarboxy hexahelicene coated on silicagel was successfully used in resolving the N-(2,4-dinitro-phenyl)-a-amino acid esters. Good resolutions were found for alanine, isoleucine, valine, phenylalanine and phenylglycine 94). 

The applications of re-acidic chiral stationary phases include the resolution of a-blockers and /1-blockers, amines, arylacetamine, alkylcarbinols, hydantoins, barbiturates, naphthols, benzodiazapines, carboxylic acids, lactams, lactones, phthaldehydes selenoids, and phosphorus compounds. Hyun et al. [16] achieved a chiral resolution of a homologous series of iV-acyl-x-(l-naphthyl )cthylaminc on AA(3,5-dinitrobenzoyl-(i )-phenylglycine and N-(3,5 - dini tr o ben zoy I)-(,S ) -1 c u c ine CSPs. The authors used hexane-2-propanol (80 20, v/v) as the mobile phase. Similarly, the scope of re-basic CSPs comprises the chiral resolution of / -blockers, amino acids, amines, diamines, amino phosphonates, naphthols, benza-diazapines, carboxylic acids, hydroxy acids, dipeptides, tripeptides, diols,... 

FIGURE 5 Chromatograms of the chiral resolution of propranolol enantiomers on 3,5-dinitrobenzoyl-a-phenylglycine CSP using (a) n-dodecane and (b) -pentane as the major component of the mobile phases. (From Ref. 11.)... 

FIGURE 13 A comparison of the chiral resolution of 2-naphthyl amide derivatives of 2-aminooctane enantiomers on 3,5-dinitrobenzoyl phenylglycine CSP by HPLC and SFC using ( ) hexane-2-propanol (95 5, v/v), ( ) carbon dioxide-2-propanol (95 5, v/v), and ( ) carbon dioxide-2-propanol-water (95 4.8 0.2, v/v/v) as the mobile phases. (From Ref. 9.)... 

TABLE 3 Effect of Organic Modifiers and Sulfuric Acid on the Chiral Resolution of Leucine and Phenylglycine... 

In addition to the mobile phase composition, the effect of other parameters such as temperature, flow rate, pH, and structure of the analytes were also studied, but only a few reports were available in the literature. In 1995, Lin and Maddox [66] studied the effect of temperature on the chiral resolution of amino acids and esters. The temperature was varied from 5°C to 25°C and it was reported that the resolution improved at low temperature. Hyun et al. [48-50,67] carried out the effect of temperature on the chiral resolution of amino alcohols, amines, fluoroquinolones, and other drugs. Again, lowering of temperature resulted in better resolution. The effect of temperature on the chiral resolution of phenylalanine, phenylglycine, and 2-hydroxy-2-(4-hydroxy-phenyl)-ethyl amine is shown in Table 5 [50], which indicates an increase in retention factors at lower temperature, but the best separation occurred at 20°C. These experiments indicated the exothermic nature of chiral resolution on CCE-based CSPs. Lin and Maddox [66] also studied the effect of flow rate on the chiral resolution of... 

TABLE 5 Effect of Temperature on the Chiral Resolution of Phenylalanine, Phenylglycine, and 2-Hydroxy-2-(4-hydroxy-phenyl)-ethyl Amine... 

Theoretically, the procedure shown in Figure 14 can be effective for all of the combinations of preferentially resolvable less-soluble diastereomeric salts. However, practical activity of optically active material gradually decreases since resolution efficiency is not 100% in every process. In fact, yields of reciprocal resolution of ( )-phenylglycine (PG) and ( )-10-camphorsulfonic acid (CSA) gradually decreases as shown in Table 7. 

Table 7 Reciprocal resolution of ( )-phenylglycine (PG) and ( )-10-camphorsulfonic acid (CSA)...

By using this method, both substance (A) and resolving agent (B) can be resolved using a resolving agent composed of optically active and racemic form with a b ratio. Experimental results of the resolution of ( )-phenylglycine (PG) with 10-camphorsulfonic acid (CSA) (a b = 2 1) are shown below (Table 8). 

Watanabe, T., Hayashi, S., Ouchi, S., Senoo, S. (1973) Optical resolution of phenylglycine and camphorsulfonic acid, Jpn. Kokai Tokkyo Koho JP48-78137 Chem. Abstr. 80 71099 (1974). 

Based on their fluorination protocol, Cahard and co-workers have elaborated a convenient synthesis of a-fluoro-a-phenylglycin derivatives [18]. For example, upon reaction with reagent 24 racemic nitrile 23 was converted into the fluorinated derivative 25 with 94% enantiomeric excess. The corresponding ester derivatives of 23 gave rise to somewhat lower ees. This difference was contributed to the fact that a-lithiated nitriles can be in equilibrium with axial-chiral lithio ketene imines of low racemization barriers thus leading to a potential dynamic kinetic resolution. 

There are occasions when a resolution method can be useful. On the chemical side, this approach usually comes into play when small amounts of material are required and alternative methodology is under development. However, if a dynamic kinetic resolution can be achieved, then the approach can be very cost effective, as illustrated by D-phenylglycine (Chapters 7 and 25). In contrast,... 

Such an example is formed by the resolution of 4-hydroxyphenylglycine (Hpg) (Figure 7.8). Hpg cannot be resolved by (+)-camphor-10-sulfonic acid [(+)-Csa] and is, therefore, resolved on industrial scale with the more expensive and difficult to recycle (lR)-(+)-(endo,anti)-3-bromo-camphor-8-sulfonic acid. However, if racemic or (R)-phenylglycine (Phg) is added to the resolution of Hpg with (+)-Csa, co-resolution of both phenylglycines is possible. (R)-(-)-Hpg is incorporated in the crystal lattice of the (R)-(-)-Phg—(+)-Csa salt by partial replacement of (R)-(-)-Phg.27... 

FIGURE 7.8 Dutch Resolution of (R,S)-jt>-hydroxyphenylglycine with (+)-camphor-10-sulfonic acid and (R,S) or (R)-phenylglycine as a family member. 

---