Resolving agents examples

This procedure is restricted mainly to aminodicarboxyhc acids or diaminocarboxyhc acids. In the case of neutral amino acids, the amino group or carboxyl group must be protected, eg, by A/-acylation, esterification, or amidation. This protection of the racemic amino acid and deprotection of the separated enantiomers add stages to the overall process. Furthermore, this procedure requires a stoichiometric quantity of the resolving agent, which is then difficult to recover efficiendy. Practical examples of resolution by this method have been pubUshed (50,51). 

Rate of complex formation between chiral alcohols and DBTA monohydrate in hexane suspension is quite slow (see Figure 1) and numerous separation steps are necessarry for isolation of the alcohol isomers (filtration of the diastereoisomeric complex then concentration of the solution, decomposition of the complex, separation of the resolving agent and the enantiomer, distillation of the product). To avoid these problems, alternative methods have been developed for complex forming resolution of secondary alcohols. In a very first example of solid phase one pot resolution [40] the number of separation steps was decreased radically. Another novel method [41] let us to increase the rate of complex forming reaction in melt. Finally, first examples of the application of supercritical fluids for enantiomer separation from a mixture of diastereoisomeric complexes and free enantiomers [42, 43] are discussed in this subchapter. 

There are only few examples for one pot resolution of racemates in the literature. [44, 45, 46], In these examples the solid complex forming resolving agent was mixed with the racemic liquid without any solvent and the enantiomers were separated by distillation. 

Many resolving agents derived from natural products have been used since the first discovery of the process, and they are still effective. Many examples are described in the literature.17,18 Synthetic resolving agents, such as a-methylbenzylamine, l-phenyl-2-(p-tolyl)ethylamine, and mandelic acid are very important ones, and widely used for the production of various optically active compounds. 

A variety of unsymmetrical optically active chelate ligands LL have been used as optically active resolving agents in square-pyramidal complexes of the type C5HsM(CO)2LL (M = Mo, W) giving partly cationic species (77-81) and partly neutral complexes (79, 82-91). The field of optically active square-pyramidal complexes has been reviewed (11, 92). All of the known examples are summarized in Table I. 

In Section III, it was shown that the introduction of an optically active resolving agent (S ) into a pair of enantiomers (R)/(S) gives two diaste-reoisomers (R.S1) and (S,S ) with different metal configurations. Instead of an optically active resolving agent (5 ), a racemic mixture of a chiral ligand (R )I(S ) can also be used. Then, not two, but four, isomers are formed two diastereoisomeric pairs of enantiomers (R,R ) and (5,5 ) as well as (R,S ) and (S,R ). An example is presented in Scheme 23,... 

Other resolving agents are readily prepared from inexpensive chiral starting materials such as glucose, aspartic acid, or glutamic acid. A literature example is the use of /V-methylglucamine 6, obtained by reductive amination of D-glucose, in the resolution of naproxen (Chapter 6).13... 

Other examples of application of this concept are presented in Table 7.2. It should be mentioned that the resolutions described in Table 7.2 intentionally are performed in nonoptimized conditions. Therefore, further improvement of the resolution efficiency should be possible when nucleation inhibitors are applied. The procedure clearly offers the opportunity to improve the outcome of a classical resolution without the need for stoichiometric mixtures of resolving agents. The original DR procedure as well as molecular modeling calculations32 can help in identifying efficient nucleation inhibitors. 

The resolution of racemic compounds through the formation of reversible diastereomer complexes is certainly an example of the generation of chirality upon association of an achiral solute (the racemate to be resolved) and a chiral solute (the resolving agent). Such interactions are normally considered solely from the separations point of view [11], and only rarely is CD used to follow the association mechanism. It is evident, however, that the spectroscopic method would be of great value to characterize the associated species. 

A number of inexact applications have been made, some of which have been discussed in detail. As an example, in some work (147) on diastereoisomeric salts of (+)bromocamphorsulphonicacid, (+)tartaricacid, and of other resolving agents, with complexes of the type [Co(en)2(a)]2+, comparisons were made where a is glycinate, L-alaninate, L-leucinate, and L-phenylalaninate, which may not be justified, as owing to the differences in steric requirements of the amino acid, there is no reason to believe that these less soluble diastereoisomers will be isomorphous. 

A further danger in this method is that crystallization procedures can be fairly arbitrary. For example, using (—)-strychnine as resolving agent,... 

The preceding example demonstrates the general view that the procedure most likely to alter the crystallization thermod)mamics of true race-mate systems will entail the formation of dissociable diastereomer species [50-54]. In most instances, these diastereomers are simple salts formed between proton donors and proton acceptors, or electron-pair donors and electron-pair acceptors. For example, the first resolving agents introduced for acidic enantiomers were alkaloid compounds, and hydroxyl acids were used for the resolution of basic enantiomers. This t) e of resolution procedure has been known since the time of Pasteur, and extensive tables of resolving agents and procedures are available [48,55,66]. 

As mentioned above, one of the limitations of using naturally occurring resolving agents is that only one enantiomer of the compound being resolved may be readily accessible by resolution. However, many examples have been described where brucine and some other alkaloid favor crystallization with opposite enantiomers of a given acid. For example, resolution of acid (6) with brucine yields the (+)-enantiomer, while cinchonidine provides material that is enriched in the (—)-enantiomerof the acid. Similarly, diacid (7) is resolved into its (—)-enantiomer by brucine and into its (+)-enantiomer by strychnine. The (+)-enantiomer of acid (8) can be obtained with brucine, while the (—)-enantiomer crystallizes with cinchonidine. Additional examples of the same phenomenon can be found in the literature. ... 

Reagent for the Resolution of Carboxylic Acids. Reagent (1) and its enantiomer have been used, although not as extensively as the more common (S)-a-Methylbenzylamine, as resolving agents for carboxylic acids via fractional crystallization of the corresponding diastereomeric salts. Examples of acids resolved this way include (2)-(6). Additional examples, such as man-delic, hydratopic, and a-aryloxypropionic acids, can be found in the literature. ... 

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