Resolving agents carboxylic acids

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). 

The six-position may be functionalized by electrophilic aromatic substitution. Either bromination (Br2/CH2Cl2/-5°) acetylation (acetyl chloride, aluminum chloride, nitrobenzene) " or chloromethylation (chloromethyl methyl ether, stannic chloride, -60°) " affords the 6,6 -disubstituted product. It should also be noted that treatment of the acetyl derivative with KOBr in THF affords the carboxylic acid in 84% yield. The brominated crown may then be metallated (n-BuLi) and treated with an electrophile to form a chain-extender. To this end, Cram has utilized both ethylene oxide " and dichlorodimethyl-silane in the conversion of bis-binaphthyl crowns into polymer-bound resolving agents. The acetylation/oxidation sequence is illustrated in Eq. (3.54). 

Nowadays, a variety of optically active amines and carboxylic acids are available as resolving agents.17,18... 

Let s consider how we might resolve a racemic mixture of (R)- and (,S )-bu(an-2-ol. We need a resolving agent that reacts with an alcohol and that is readily available in an enantiomerically pure state. A carboxylic acid combines with an alcohol to form an ester. Although we have not yet studied the chemistry of esters (Chapter 21), the following equation shows how an acid and an alcohol can combine with the loss of water to form an ester. 

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. ... 

If the interaction sites are not present in the solute, they must be added through derivatization. When derivatization is required, the standard approach is to convert an alcohol, amine, or carboxylic acid to an aromatic amide, urea, or carbamate. For example, amphetamine was resolved as its naphthoyl amide (21), a series of ot-methylaryl acetic acid antiinflammatory agents were resolved after conversion to their 1-naphthalenemethyl-amides (22), and aliphatic alcohols can be resolved as 3,5-dinitro-carbamates (23). Other derivatives such as oxazolidones (24) and oxazolidines (25) have also been used. 

Diastereomeric relationships provide the basis on which a number of important processes depend. Resolution is the separation of a mixture containing equal quantities of enantiomers (termed a racemate or racemic mixture) into its components. Separation is ordinarily effected by converting the mixture of enantiomers into a mixture of diastereomers by treatment with an optically active reagent (the resolving agent). Since the diastereomers will have different physical and chemical properties, they can be separated by conventional methods and the enantiomers regenerated in a subsequent step. An example of this method is shown in Scheme 2.2 for the resolution of a racemic carboxylic acid by way of diastereomeric salt formation using an optically active amine. The / -acid-/ -amine and S-acid-/ -amine salts are separated by fractional recrystallization, and the resolved carboxylic acid is freed from its amine salt by acidification. 

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