Brucine, resolution acids

The doubt on the origin of chirality was still perceptible in (31JA3519). Achiral N-arylpyrroles 311 and 312, as we can say now, were submitted to brucine resolution, an attempt affording optically inactive acids. Resolution of chiral N-arylpyrroles 313 and 314 failed due to the weakness of the carboxylic acid on the pyrrole ring. Nevertheless, it was stated that the optical isomerism in phenyl pyrroles probably resembles closely that in the diphenyl series. ... 

Two pieces of chemical evidence support the three-membered ring formulation. The bifunctional oxazirane prepared from glyoxal, tert-butylamine, and peracetic acid (6) can be obtained in two crystalline isomeric forms. According to the three-membered ring formula there should be two asymmetric carbon atoms which should allow the existence of meso and racemic forms. A partial optical resolution was carried out with 2-7i-propyl-3-methyl-3-isobutyloxazirane. Brucine was oxidized to the N-oxide with excess of the oxazirane. It was found that the unused oxazirane was optically active. 

Enantionmerically enriched pairs of /i-stannylated benzoic acids (+)/(—)-35 and (+)/(—)-36 were obtained by resolution with brucine or strychnine (Scheme 13)20. Again, neither the configuration nor the enantiomeric enrichment could be determined. 

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). 

The synthesis was then continued with both, the racemic diester and the pure enantiomer (-)-30a which was prepared by hydrolysis of the racemic diester, resolution of the corresponding acid via the brucine salt and reesterification. 

The bases generally employed in such resolutions have been natural alkaloids, such as strychnine, brucine, and ephedrine. These alkaloids are more complex than the general case shown in the figure, in that they contain several chiral centres (ephedrine is shown in Section 3.4.4). Tartaric acid (see Section 3.4.5) has been used as an optically active acid to separate racemic bases. Of course, not all materials contain acidic or basic groups that would lend themselves to this type of resolution. There are ways of introducing such groups, however, and a rather neat one is shown here. 

Optica] resolution of these and related carboxylic acids were achieved using salt formation with alkaloids (strychnine, brucine, cinchonidine) 33,39,44 or with optically active amines [1-phenyl- or l-( 3-naphthyl)ethylamine]4o,44). The following rotations [a]D have been reported [8]paracyclophanecarboxylic acid (13) +18° (chloroform)441 [10]homologue (14) +80° (chloroform)39 and +67° (chloroform)40 its methyl-derivative (75) —28° (methanol)44 . Dioxa[10]paracyclophanecarboxylic acid (16) + 104° (ethanol)36 and bromo-dioxa[12]paracyclophanecarboxylic acid (79) —37° (acetone)33). 

The optically active N-aminoindoline (265) has been applied to the asymmetric synthesis of a variety of a-amino acids (70JA2476, 2488). Starting from TV-benzoyl-1,2,3,4-tetrahy-droquinaldine (257), the chloro amide (258) was prepared by von Braun cleavage. Thermolysis converted (258) to the rrans-unsaturated amide (259) which was epoxidized. On base treatment the epoxide (260) underwent intramolecular nucleophilic displacement and amide hydrolysis to afford indoline (261) stereospecifically. Resolution of (261) was accomplished via the brucine salt of the N-o-carboxybenzoyl derivative (262). Alkaline hydrolysis, N-nitrosation and reduction yielded the levorotatory 1-aminoindoline (265). Reaction of... 

Resolution of chiral acids through the formation of diastereomeric salts requires adequate supplies of suitable chiral bases. Brucine, strychnine, and quinine frequently are used for this purpose because they are readily available, naturally occurring chiral bases. Simpler amines of synthetic origin, such as 2-amino-1-butanol, amphetamine, and 1-phenylethanamine, also can be used, but first they must be resolved themselves. 

Pasteur s original chemical method of resolution, which is still widely used at the present time, involves the formation of diastereoisomeric salts from racemic acids or bases by neutralisation with available optically pure bases or acids respectively. The required optically pure reactants are often available from natural sources and include tartaric, malic and mandelic acids, and alkaloids such as brucine, strychnine, morphine and quinine. Ideally, by appropriate choice of the resolving reagent, the diastereoisomeric salts are crystalline and have solubilities sufficiently different to permit the separation and ready purification of the less soluble salt by fractional crystallisation from a suitable solvent. The regeneration of the optically pure enantiomorph, and incidentally the recovery of the resolving reagent, normally presents no problems. 

RESOLUTION Brucine. a-Methoxy-a-trifluoromethylphenylacetic acid. RING EXPANSION ... 

Cellulose was the first sorbent for which the resolution of racemic amino acids was demonstrated [23]. From this beginning, derivatives such as microcrystalline triacetylcellulose and /3-cyclodextrin bonded to silica were developed. The most popular sorbent for the control of optical purity is a reversed-phase silica gel impregnated with a chiral selector (a proline derivative) and copper (II) ions. Separations are possible if the analytes of interest form chelate complexes with the copper ions such as D,L-Dopa and D.L-penicillamine [24], Silica gel has also been impregnated with (-) brucine for resolving enantiomeric mixtures of amino acids [25] and a number of amino alcohol adrenergic blockers were resolved with another chiral selector [26]. A worthwhile review on enantiomer separations by TLC has been published [27],... 

Acid Sulfates. Pasteur 6 and also Le Bel4 fractionated the cinchonine salts of the mixture of amyl hydrogen sulfates derived from fusel oil and effected a partial separation of the structurally isomeric alcohols. Krtiger 41 failed to resolve the alkaloid salts of the hydrogen sulfate of ethyl-n-propylcarbinol but Meth,42 after failures in other instances, finally effected a partial resolution of a-butyl hydrogen sulfate as the brucine salt. The method has proved to be impracticable for most alcohols 48 because the majority of alkyl hydrogen sulfates are unstable and inconvenient to handle. 

Procedures are given for (1) resolution by the use of a simple ester (2) resolution by crystallization of brucine salts of acid phthalates which are readily separated and (3) a similar resolution in which the separation of the diastereoisomeric salts is difficult. In addition to the preparations described in this chapter other instructive examples, showing various further modifications and helpful devices, may be found in references 53, 74, 76, 128, 69, and 125. 

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. 

Production of enantiomerically pure a-arylpropanoic acids, also known as profens, is of critical importance to the pharmaceutical industry because they constitute a major class of antiinflammatory agents. One of the most practical approaches to preparing optically pure a-arylpropanoic acids is by resolution with chiral amines. Notable examples include brucine, quinidine, cinchonidine, morphine, ephedrine, and a-(l-naphthyl)ethylamine. For instance, (.Sj-a-methylbenzylaminc and... 

Resolution of Acids. The number of acids resolved with brucine is too large to attempt to list even a small portion of them in this synopsis. An excellent tabulation of all published resolutions with brucine up to 1972 is available. Only a few representative examples will be described here (eqs 1-4). In all these cases, the resolved acids were obtained in high yield and with almost absolute enantiomeric purity. The solvents most frequently used for brucine resolutions are acetone and alcohol solvents. However, water, hexane, and others have also been used as cosolvents. 

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. ... 

A more traditional and general approach to the resolution of alcohols is the formation of the corresponding hemiphthalate or hemisuccinate esters, followed by resolution of these acidic derivatives with brucine or some other chiral base (eqs 7-9). 

Resolution of Sulfoxides. Although it can be considered as the resolution of an unique type of carboxylic acid, some racemic sulfoxides containing carboxyhc acids have been resolved via diastereomeric crystalline complexes with brucine (eq 11). ... 

Preparative Methods prepared by esterification of f-leucine with Isobutene and cone Sulfuric Acid (under pressure). Typical yields are 62-64% and 12-14% of recovered amino acid, t-Leucine itself is commercially available in racemic and optically pure forms. It can also be prepared by oxidation of pina-colone to trimethylpyruvic acid, followed by oxime formation and zinc reduction. Resolution of the iV-formyl derivative of t-leucine has been carried out using brucine. ... 

Although (maleic acid)Fe(C0)4 has a symmetry plane perpendicular to the plane of the double bond, (fumaric acid)Fe(C0)4 is clearly asymmetric and should thus be capable of resolution into its enantiomers (457). Accordingly, addition of the complex to a solution of brucine in acetone and crystallization of the diastereoisomeric salts followed by decomposition with hydrochloric acid yielded the two enantiomers having optical activities [a]ff —593 (acetone C, 0.848) and [a] f - -587 (acetone C, 0.921). Analyses and infrared spectra of individual enantiomers were identical to those of the racemic mixture. 

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