Carboxylic acids resolving reagents

A number of nonnatural amino acids were resolved into individual enantiomers on 0-9-(2,6-diisopropylphenylcarbamoyl)quinine-based CSPby Peter and coworkers [48,90,113,114] after derivatization with Sanger s reagent, chloroformates (DNZ-Cl, FMOC-Cl, Z-Cl), Boc-anhydride, or acyl chlorides (DNB-Cl, Ac-Cl, Bz-Cl). For example, the four stereoisomers of P-methylphenylalanine, P-methyltyrosine, P-methyltryptophan, and P-methyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid could be conveniently resolved as various A-derivatives [113]. The applicability spectrum of cinchonan carbamate CSPs comprises also P-amino carboxylic acid derivatives, which were, for example, investigated by Peter et al. [114]. A common trend in terms of elution order of DNP-derivatized P-amino acids was obeyed in the latter study On the utilized quinine carbamate-based CSP, the elution order was S before R for 2-aminobutyric acid, while it was R before S for the 3-amino acids having branched R substituents such as wo-butyl, iec-butyl, tert-butyl, cyclohexyl, or phenyl residues. 

Enantiomers of carboxylic acids may sometimes be separated by GC as methyl esters, but special derivatives are mostly prepared for this purpose. Ackman et al. [188] resolved enantiomers of isoprenoid fatty acids after their conversion into L-menthyl esters. The acids under analysis were chlorinated by refluxing with distilled freshly prepared thionyl chloride and the chlorides produced were treated with L-menthol in the presence of pyridine under strictly anhydrous conditions. GC separation was carried out in a capillary column coated with butanediol succinate polyester. Annett and Stumpf [189] made use of L-menthyloxycarbonyl derivatives for the separation of enantiomers of methyl esters of hydroxy acids. The derivatization reagent, L-menthyl chloroformate, was prepared by the reaction of L-menthol with phosgene, with cooling with ice. Diastereoisomers of different hydroxy acids were thus separated on 1.5% OV-210. 

Resolving Reagent for Carboxylic Acids and Other Types of Compounds. A large number of carboxylic acids have been resolved via their diastereomeric salts with (S)- or (7 )-a-methylbenzylamine (1). The ready availability of both enantiomers of (1) guarantees access to both enantiomers of the desired acid. Compounds (2)-(6) are representative examples of acids obtained in high enantiomeric purity. " Alternatively, racemic carboxylic acids have been resolved by covalent derivatization with (1) and separation of the resulting diastereomeric amides by physical means such as chromatography (eq 1) or fractional crystallization (eq 2). ... 

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. ... 

Most resolution is done on carboxylic acids and often, when a molecule does not contain a carboxyl group, it is converted to a carboxylic acid before resolution is attempted. However, the principle of conversion to diastereomers is not confined to carboxylic acids, and other functional groups may be coupled to an optically active reagent. Racemic bases can be converted to diastereomeric salts with active acids. Alcohols can be converted to diastereomeric esters, aldehydes to diastereomeric hydrazones, and so on. Amino alcohols have been resolved using boric acid and chiral... 

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. 

The underivatized cyclodextrins are rather unusual in their ability to function as water soluble chiral solvating agents. Enantiomeric resolution is observed in the NMR spectra of a wide range of water-soluble cationic and anionic substrates. Organic-soluble cyclodextrins are one of only a few reagents that can be used to enantiomerically resolve the spectra of hydrocarbons such as trisubstituted allenes, a-pinene, and aromatic hydrocarbons. Amines, alcohols, and carboxylic acids can also be resolved with organic-soluble cyclodextrins. 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

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