Acids, resolving agents, brucine

So, in a way, it is with quinine, known (29) since antiquity as a potent antimalarial. For chemists, the use of quinicine in 1854 in the first resolution of a racemate (1,3) marks a milestone Stereochemistry as we know it today made its debut in that year. In resolutions, quinine and its diastereomers proved to be safe to handle (compare the extreme toxicity of brucine or strychnine with that of quinine), versatile in their applications, and available in reasonably pure form. Little wonder that even today, 131 years after its first use as a resolving agent, quinine (and brucine) continues to be the chemical of choice when one is attempting a new resolution of a racemic acid (90). 

Crystallization-induced asymmetric transformation has already been described by Leuchs in 1913 during the resolution of 2-(2-carboxybenzyl)-l-indanone with brucine.34 In this case spontaneous racemization occurred. More recently researchers at Sanofi observed spontaneous racemization during the resolution of 3-cyano-3-(3,4-dichlorophenyl)propionic acid (7), most likely as a result of the basic resolving agent [>-(-)-N-1 n etli y I g I near nine [d-(-)-MGA] (8) (Scheme 7.6).35 The enantiopure cyano acid, obtained in 91% overall yield, is subsequently reduced to (+)-4-amino-3-(3,4-dichlorophenyl)-l-butanol (9), a key intermediate in the phase 2 synthesis of tachykinin antagonists. 

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. ... 

Note that the resolving agent is recovered unchanged after this procedure and can be reused repeatedly. Because of the need to obtain crystalline adducts which are readily broken down to their components again, the ionic salts formed between amines and acids, either carboxylic or sulphonic, are ideal for resolution. Thus even in the last century very many amines were resolved by formation of salts with, for example, tartaric acid (16) or camphorsulphonic acid (29), while organic acids were resolved with bases such as quinine, cinchonine and the highly toxic alkaloids brucine (36) and strychnine (37). Although reliable resolution methods have now been worked out for... 

Commercially available silica gel plates coated with acid or basic chiral selectors [o-galacturonic acid, l-(- -)-tartaric acid, L-lactic acid, (-)-brucine] were used for the separation of racemic ephedrine, atropine, neutral amino acids, and their 3-phenyl-2-thiohydantoins (PTH) derivatives. The use of amino acids as chiral selectors involved further possibilities of enantiomer separation owing to the simultaneous presence of basic and acidic groups. In fact, L-aspartic acid, L-lysine, L-histidine, L-arginine, and L-ser-ine resolved racemic alkaloids, (3-blockers, profens, some amino acids, and their Dns derivatives. Macrocyclic antibiotics [i.e., (-)-erythromycin and (-)-vancomycin] were also used as chiral agents for the separation of enantiomeric DNs amino acids. The mechanisms of chiral recognition was investigated by Aboul-Enein, El-Awady, and Heard they hypothesized that the formation of... 

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