Brucine, resolution

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. 

Sorbinil 282 is a compound of potential therapeutic interest, because it prevents or alleviates the chronic complications of diabetes mellitus, due to its ability to inhibit the enzyme aldose reductase. Sarges et al. prepared 282 and its enantiomer by the reaction sequence shown in Scheme 12.71, involving a brucine resolution of the racemic hydantoin precursor 284. " The free base of brucine forms a crystalline complex with 282, whereas the other enantiomer of 282 only forms a crystalline complex with brucine hydrochloride. Since this resolution technique does not work with certain congeners of sorbinil, a synthesis via an asymmetric induction sequence (Scheme 12.72) has also been developed that seems generically applicable to optically active spiro hydantoins. Both methodsrequired 2,3-dihydro-6-fluoro-47/-l-benzopyran-4-one 283 and the introduction of the amino acid functionality... 

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. ... 

The resolution of sec.-octyl alcohol was first described by Pickard and Kenyon. The method employed by these authors differed from the foregoing in the following respects. The brucine salt of sec.-octyl hydrogen phthalate was crystallized several times from acetone until it reached optical purity and was then decom-... 

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. 

COOH racemate resolution with brucine in isoproponol... 

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). 

Having accomplished the resolution, it was found, however, that only one brucine salt could be isolated and that it mutarotated rapidly in solution from an initial reading of [a]o+30 35 to a final activity of... 

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... 

One of the more salient points concerning an unBymmetrically substituted oxaoirane ring is that it has an asymmetric carbon atom and should be capable of resolution into optically active form. TV oxazirane (XIX) has in fact been partially resolved (o -S.d4 ) by treating it with the alkaloid brucine under the correct conditions i... 

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. 

Optically pure trans-2-phenylcyclohexanol can also be prepared by resolution of the phthalate esters using brucine to obtain the (-t-)-alcohol and strychnine to obtain the (-)-alcohol (after basic hydrolysis of their respective salts).11 Enzyme-catalyzed kinetic resolution of the acetate esters using pig liver esterase4 and pig liver acetone powder12 has been used to prepare both enantiomers of this chiral auxiliary. The hydroboration of 1-phenylcyclohexene with isopinocampheylborane has been reported to give the chiral auxiliary in 97% enantiomeric excess.13... 

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 of tert-acetylenic alcohols. Brucine forms stable 1 1 molecular complexes with only one enantiomer of several terr-acetylenic alcohols. In some liivorublc eases, complete resolution can be achieved by only one complexation in oilier eases, repetition of complexation is necessary for complete resolution. The complexes are decomposed by dilute HC1. Complexation involves a hydrogen bond between the OH group and the N atom of brucine in addition, the linearity of the acetylene group may be involved.1... 

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

The kinetic resolution of racemic alcohols is probably the most intensively studied aspect of organocatalysis, and its beginnings can be traced back to the 1930s [2, 3]. In these early attempts naturally occurring alkaloids such as (—)-brucine and (+)-quinidine were used as catalysts. Synthetic chiral tertiary amines also were introduced and examined, and enantiomeric excesses up to ca. 45% were achieved up to the early 1990s [4, 5]. 

In the optical resolution of cyanohydrins, it was first found that brucine (4) is a suitable host for the cyanohydrins which substituted with one aromatic group and one bulky alkyl group. In this case, not only a simple enantiomer separation of rac-cyanohydrin but also its transformation to one enantiomer occurred and one pure enantiomer was obtained in a yield of more than 100%. For example, when a solution of rac-l-cyano-2,2-dimethyl-l-phenylpropanol (61a) (1.0 g, 5.3 mmol) and 4 (2.1 g, 5.3 mmol) in MeOH (2 ml) was kept in a capped flask for 12 h, a 1 1 brucine complex of (+)-61a (2.08 g, 134%, mp 112-114 °C) separated out as colorless prisms. Decomposition of the complex with dil HC1 gave (+)-61a of 97% ee (0.67 g, 134%). From the filtrate, rac-61a (0.33 g, 33%) was obtained.273 The... 

Toda, F., and Tanaka, K. (1981) ANew Optical Resolution Method of Tertiary Acetylenic Alcohol Utilizing Complexation with Brucine, Tetrahedron Lett., 22, 4669-4672. 

Conversion of Racemic Cyanohydrin into One Optically Acrtive Iosmer in the Presence of Brucine, Chem. Lett., 661-664. b) Tanaka, K. and Toda, F. (1987) Chiral Recognition and Optical Resolution of Cyanohydrin by Complexation with Brucine, Nippon Kagaku Kaishi, 456-459. 

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