Brucine separation

The d/-form was successfully resolved by treating its acid succinate with L-brucine, separating the brucine salts by fractional crystalli2Kition from acetone, decomposing the salts, and saponifying the acid succinates with ethanolic alkali (20). 

Caf,Tb,Tp,strychnine, brucine Separation by means of dynamic coating HPLC Corasil I or II, coated with 1.1% Poly G-300 1000x1 Heptane-Et0H(20 1), (10 1) sat. with stationary phase 4,7... 

This substance (dA, I A) contains a free carboxyl group and is treated in warm acetone solution with an equimolecular quantity of the optically active base brucine (IB) upon cooling, the brucine salt (dA, IB) separates out first in a moderately pure condition, whilst the brucine salt (lA, IB) remains in solution ... 

The latter upon decomposition with dilute hydrochloric acid yields laevo sec.-octyl hydrogen phthalate the crystalline brucine salt, when similarly treated, affords the dextro sec.-octyl hydrogen phthalate. These are reerystallised and separately hydrolysed with sodium hydroxide solution to yield pure I- and d-sec.-octyl alcohols ... 

Introduce 197 g. of anhydrous brucine or 215 g. of the air-dried dihydrate (4) into a warm solution of 139 g. of dZ-acc.-octyl hj drogen phthalate in 300 ml. of acetone and warm the mixture vmder reflux on a water bath until the solution is clear. Upon cooling, the brucine salt (dA, IB) separates as a crystalline solid. Filter this off on a sintered glass funnel, press it well to remove mother liquor, and wash it in the funnel with 125 ml. of acetone. Set the combined filtrate and washings (W) aside. Cover the crystals with acetone and add, slowly and with stirriug, a slight excess (to Congo red) of dilute hydrochloric acid (1 1 by volume about 60 ml.) if the solution becomes turbid before the introduction of... 

Strychnine, brucine Oxidation is performed with potassium dichromate solution This oxidizes brucine to the o-qumone which can then be separated chromatographically [17]... 

Dehydrocorydaline eontains four methoxyl groups. On reduetion it furnishes two stereoisomerides of eorydaline, m.p. 135°, and m.p. 158-9° (163-4° vac.), Spath) the latter ( 2f.9oeorydaline) by erj stallisation of the d-eamphorsulphonate can be partially separated into d- and Z-forms, the d-form of which is not identical with natural corydaline.The second isomeridc, m.p. 135°, has not been resolved into optically active components, but from the sulphonic acid the Z-compoiient has been isolated by crystallisation of the brucine salt, and this is taken to indicate that the inactive corydaline, m.p. 135°, is dZ-corydaliiie. °... 

Preparation. The mother liquors from strychnine manufacture are concentrated and the alkaloids precipitated as neutral oxalates. The precipitate is dried and extracted with dry alcohol in which the strychnine salt is the more soluble. The less soluble salt dissolved in water is decolorised with charcoal, the alkaloid regenerated with ammonia and purified by crystallisation as the sulphate. According to Saunders, pure brucine may be obtained by slow crystallisation from a solution of the pure hydrochloride in alcoholic ammonia. A method of separation depending on the greater solubility in water of strychnine hydriodide was employed by Shenstone, whilst others have made use of the sparing solubility of strychnine chromate for the removal of small quantities of this alkaloid from brucine. For a large scale process see Schwyzer. ... 

Dissolve about i gram of an organic base (brucine, strychnine, quinine, c.) in 10 c.c. of a mixture of equal volumes of concentrated hydrochloric acid and water. To the clear hot solution add excess of platinic chloride and let it cool. Yellow microscopic crystals of the chloroplatinate of the base separate. (If the chloroplatinate of the base is very soluble in water, such as aniline, it must be washed with strong hydrochloiic acid, pressed on a porous plate and dried in a vacuum-desiccator over solid caustic potash.)... 

Sulfoxides were first prepared in optically active form in 1926 by the classical technique of diastereomeric salt formation followed by separation of the diastereomers by recrystallization16 17. Sulfoxides 1 and 2 were treated with d-camphorsulfonic acid and brucine, respectively, to form the diastereomeric salts. These salts were separated by crystallization after which the sulfoxides were regenerated from the diastereomers by treatment with acid or base, as appropriate. Since then numerous sulfoxides, especially those bearing carboxyl groups, have been resolved using this general technique. 

Optically active (+)- and (—)-p-(/-propylmethylphenylstannyl) benzoic acids (56) and their methyl esters (57) were similarly prepared by Lequan four years later 38) (see Table 3). They are characterized by very low optical rotations. Furthermore, the diastereomeric brucine salts via which the acids were resolved, are characterized by almost identical NMR spectra that cannot be used to follow their separation so that no precise information is available about the optical purity of (56) and (57). 

The recemic mixture of an acid is separated by an optically active alkaloid like brucine, quinine or morphine. 

The replacement of the oxygen atom in sulfoxides by nitrogen leads to a new class of chiral sulfur compounds, namely, sulfimides, which recently have attracted considerable attention in connection with the stereochemistry of sulfoxide-sulfimide-sulfoximide conversion reactions and with the steric course of nucleophilic substitution at sulfur. The first examples of chiral sulfimides, 88 and 89, were prepared and resolved into enantiomers by Phillips (127,128) by means of the brucine and cinchonidine salts as early as 1927. In the same way, Kresze and Wustrow (129) were able to separate the enantiomers of other structurally related sulfimides. 

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. 

If 2-camphanyloxyacrylonitrile (15 R = C8H 02C00) is taken for cycloaddition, diastereoisomeric cycloadducts can be separated, and the basic system, 7-oxabicyclo-[2.2.1]hept-5-en-2-one 17, can be obtained in optically pure form [36]. Another way of obtaining enantiomeric ketones is based on crystallization of a brucine complex obtained from the corresponding cyanohydrines (see Sec. III). Ketone 17 can be converted [e.g., by cis-hydroxylation (—>18), protection of the diol system, and Baeyer-Villiger oxidation] to lactone 19, the opening of which leads to furanuronic acid 20. A new development in this field is based in cycloaddition between furan and 2-chloro- or 2-bromoacrolein in the presence of 5 mol% chiral oxazaborolidine 21 as catalyst [37],... 

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. 

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... 

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. 

The Worm of the alcohol can be obtained in 85-90% purity from the combined acetone and final methanol mother liquors by a rather laborious process of fractional crystallization aided by mechanical separation.137 140 Thus on long standing the acetone solution may deposit characteristic nodular aggregates of leaflets of nearly pure brucine 1-8-butyl phthalate, [a]n — 18.0° these are separated by filtration or decantation. The solution, upon concentration, may then yield more of the crude d-salt and then again the 1-salt. The method is tedious but gives rather good yields, especially when large quantities of material may be worked up in a leisurely fashion. 

To complete the total synthesis of the optically active form of veatchine, the successful resolution of the synthetic racemic ketone 244 was accomplished. Compound 244 was reduced stereoselectively with sodium boro-hydride to give the alcohol 248. The latter was heated with succinic anhydride and pyridine in xylene to yield the racemic half-ester 249. Treatment of 249 with brucine afforded the diastereoisomeric brucine salts, which were separated by fractional crystallization. The separated salts were decomposed... 

Distinction should be made at this time between diastereoisomers and enantiomers. The former are characterized by the presence of at least two closely associated asymmetric centers in the molecular structure, either of which can epimerize. Altogether then there are two pairs of enantiomers for a total of four stereochemically unique individuals. Diastereoisomers have different physical properties and as a result discriminations, and even separations, can be done relatively easily. Enantiomers on the other hand differ in only one physical property, i.e. the direction of rotation of polarized light. Reaction of an enantiomeric racemic mixture with a third chiral species will produce a mixture of diastereomers therefore facilitating their identification or their separation. Early examples of this were the separations done by fractional crystallization of salts produced by a derivatization reaction with, for example, the alkaloid (-)-brucine. Fractional crystallization would never seem to be an effective analytical method yet it was used with some success in a forensic sciences context to confirm the presence of (L)-cocaine by a carefully contrived microcrystalline test. The physical properties... 

In many cases, amino acids can be resolved by the methods we have already discussed (Section 5-16). If a racemic amino acid is converted to a salt with an optically pure chiral acid or base, two diastereomeric salts are formed. These salts can be separated by physical means such as selective crystallization or chromatography. Pure enantiomers are then regenerated from the separated diastereomeric salts. Strychnine and brucine are naturally occurring optically active bases, and tartaric acid is used as an optically active acid for resolving racemic mixtures. 

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