Diastereomeric complex

A variety of strategies have been devised to obtain chiral separations. Although the focus of this article is on chromatographicaHy based chiral separations, other methods include crystallisation and stereospecific ensymatic-catalysed synthesis or degradation. In crystallisation methods, racemic chiral ions are typically resolved by the addition of an optically pure counterion, thus forming diastereomeric complexes. 

Most chiral chromatographic separations are accompHshed using chromatographic stationary phases that incorporate a chiral selector. The chiral separation mechanisms are generally thought to involve the formation of transient diastereomeric complexes between the enantiomers and the stationary phase chiral ligand. Differences in the stabiHties of these complexes account for the differences in the retention observed for the two enantiomers. Often, the use of a... 

The dependence of chiral recognition on the formation of the diastereomeric complex imposes constraints on the proximity of the metal binding sites, usually either an hydroxy or an amine a to a carboxyHc acid, in the analyte. Principal advantages of this technique include the abiHty to assign configuration in the absence of standards, enantioresolve non aromatic analytes, use aqueous mobile phases, acquire a stationary phase with the opposite enantioselectivity, and predict the likelihood of successful chiral resolution for a given analyte based on a weU-understood chiral recognition mechanism. 

The principle of this method depends on the formation of a reversible diastereomeric complex between amino acid enantiomers and chiral addends, by coordination to metal, hydrogen bonding, or ion—ion mutual action, in the presence of metal ion if necessary. L-Proline (60), T.-phenylalanine (61),... 

The mechanism for the catalytic enantioselective carbo-Diels-Alder reaction of N-alkenoyl-l,3-oxazolidin-2-one 4 with, e.g., cyclopentadiene 2 catalyzed by chiral TADDOL-Ti(IV) complexes 6 has been the subject for several investigations and especially, the structure of the intermediate for the reaction has been subject to controversy. The coordination of 4 to 6 can give five diastereomeric complexes A, B], B2, C], and C2, as outlined in Fig. 8.8. 

As a unichiral additive which is mixed with the racemate of interest to form non-covalent diastereomeric complexes which can be distinguished by achiral techniques. 

The reversal of the stereoselectivity is attributed to the ability of chlorotrimethylsilane to trap the initially formed cuprate-enone complex, thereby suppressing equilibration of the diastereomeric complexes. The copper-catalyzed 1,4-addition of Grignard reagents to 5-substituted 2-cyclo-hexenone also proceeded with very high trans diastereoselectivity22. 

Thus, the enantiomeric contents in a pair of sulphoxides can be determined by the NMR chemical shifts in the methine or methylene protons in the two diastereomeric complexes which are stabilized by the hydrogen bond between the hydroxyl and the sulphinyl groups147-151 (Scheme 13). Similarly, the enantiomeric purity and absolute configurations of chiral sulphinate ester can be determined by measuring the H NMR shifts in the presence of the optically active alcohols152. 

Other methods involve isotopic dilution, kinetic resolution, relaxation rates of diastereomeric complexes, luminescence. ... 

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. 

The last several years have seen an enormous growth in the number and use of chiral stationary phases in liquid chromatography [742,780-791]. Some problems with the gas chromatographic approach are that the analyte must be volatile to be analyzed and larger-scale preparative separations are frequently difficult. For entropic reasons relatively high temperatures tend to minimize the stability differences between the diastereomeric complexes and racemization of the stationary phase over time may also occur. The upper temperature limit for phases such as Chirasil-Val is about 230 C and is established by the rate of racemization of the chiral centers and not by column bleed. Liquid chromatography should be s ior in the above... 

The resolution of enantiomers by liquid chromatography using chiral stationary phases is based on the formation of reversible diastereomeric complexes of different stability between the sample and stationary phase. Since the formation of the complexes is strongly dependent on the structure of the sample, there are no universal chiral stationary phases. The specific advantages of TLC for enantiomeric separations result from its low cost, convenience and speed (10,97,98). The main limitation, particularly with respect to column liquid chromatography, is the small number of phases currently available. 

The most widely used approach for the separation of enantiomers by TLC is based on a ligand exchange mechanism using commercially available reversed-phase plates impregnated with a solution of copper acetate and (2S,4R,2 RS)-4-hydroxy-l-(2-hydroxydodecyl)proline in optimized amounts. Figure 7.9 (10,97,98,107-109). Enantiomers are separated based on the differences in the stability of the diastereomeric complexes formed between the sample, copper, and the proline selector. As a consequence, a prime requirement for separation is that the seumple must be able to form complexes with copper. Such compounds include... 

Optically active (—)-(8R)-methylcanadine was stereoselectively synthesized through selective monocomplexation of (—)-canadine (26) to chromium tricarbonyl (240). Heating of chromium hexacarbonyl with 26 effected regioselective complexation of the D ring to give the diastereomeric complexes, which were treated with n-butyllithium and trimethylsilyl chloride to give the 11-trimethylsilyl derivative 475 (Scheme 97). Methylation of this complex with methyl iodide gave stereoselectively the 8-methyl derivative 476 by preferential alkylation from the opposite face to the bulky chromium... 

As mentioned above (Scheme 3), condensation of triallylborane and 3-methoxybut-l-yne led, after treatment with methanol, to 7-(l-methoxymethyl)-3-methoxy-3-borabicyclo[3.3.1]non-6-ene. Hydroboration-isomerization of the latter with a THF solution of diborane gave a THF complex of 2-methyl-1-boraadamantane 15 in 85% yield. Treatment of the latter with (S)-(—)-phenylethylamine gave a mixture of diastereomeric complexes ( ) 57 isolated as white, well-shaped crystals (Scheme 19) <2003MC121, B-2003MI97>. 

Chiral bis-(binaphthophosphole) (bis(BNP)) ligands have been used in the asymmetric hydroformylation of styrene. In solution, the free diphospholes display fluxional behavior. Consistent with their structure, the reaction of the bis(BNP) compounds with platinum(II) derivatives gives either cis chelate mononuclear complexes or trans phosphorus-bridged polynuclear derivatives. Coordination to platinum enhances the conformational stability of bis(BNP)s and diastereomeric complexes can be detected in solution. In the presence of SnCl2, the platinum complexes give rise to catalysts that exhibit remarkable activity in the hydroformylation of styrene. Under optimum conditions, reaction takes place with high branched selectivity (80-85%) and moderate enantio-selectivity (up to 45% ee). 

In theory, the two diastereomeric complexes will have different association constants. The evaluation of any chiral discrimination will depend upon measurement of the different proportions of the diastereoisomers formed. For example, nmr experiments have been successful in determining the degree of complex formation by each enantiomer. Alternatively, an extraction procedure has been employed this involves the interaction... 

The reaction of racemic Sb-chiral l-phenyl-2-trimethylsilylstibindole with the optically active ortho-palladated benzylamine derivative, di-p-chlorobis (S)-2-[l-dimethylamino)ethyl]phenyl-C,N dipalladium, leads to diastereomeric complexes which were used for the separation of the enantiomers of the stibindoles.65 The molecular structures of the diastereomeric palladium complexes are depicted in Fig. 4. 

Complexation with Chiral Metal Complexes. This idea was first suggested by Feibush et al.44 The separation is realized by the dynamic formation of diastereomeric complexes between gaseous chiral molecules and the chiral stationary phase in the coordination sphere of metal complexes. A few typical examples of metal complexes used in chiral stationary phase chromatography are presented in Figure 1-13.45... 

K. Le Barbu, F. Lahmani, and A. Zehnacker Rentien, Formation of hydrogen bonded structures in jet cooled complexes of a chiral chromophore studied by IR/UV double resonance spoctroscopy Diastereomeric complexes of 2 naphthyl 1 ethanol with 2 amino 1 pro panol., /. Phys. Chem. A 106, 6271 6278 (2002). 

The results reviewed in this section demonstrate that chiral recognition in complexes between chiral crown ethers and racemic ammonium salts and vice versa occurs both in polar and in apolar solvents. The maximum values of 2.9 found for the enantiomeric distribution constants correspond to a difference in free energy of the two diastereomeric complexes of 0.6 kcal mol-1. 

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