Alcohols brucine

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... 

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 ... 

The filtrates from the decomposition of the brucine salts with dilute hydrochloride acid should be carefully preserved. The brucine Is recovered by the addition of an excess of dilute ammonia solution (1 4) if the solution becomes turbid before all the ammonia solution is added, introduce a little alcohol until the solution becomes clear. After several hours in an open beaker, filter oft the brucine, wash it well with cold water and dry it in the air. 

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-... 

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. ... 

Brucine crystallises from water or aqueous alcohol in monoclinic prisms containing 4H2O, m.p. 105° or 178° dry), [a]n — 119° to — 127° (CHCI3) or — 80-1° (EtOH). The alkaloid is slightly soluble in cold water fl in 320), more so in boiling water (1 in 150), very soluble in alcohol, chloroform, or amyl alcohol, sparingly soluble in ether (1 in 134). 

Struxine, C2iH3(,04N2, obtained by Schaefer from deteriorated nux-vomica seeds in about 0-1 per cent, yield, is regarded as a decomposition product of strychnine or brucine. It forms rhombic crystals from alcohol, is colourless, but becomes yellow on exposure to light and chars at 250°. It yields normal and acid salts, the latter only from excess of acid. With sulphuric acid it gives no coloration, but addition of potassium dichromate produces a yellow colour changing to green. 

The virtue of performing the PKR in an enantioselective manner has been extensively elaborated during the last decade. As a result, different powerful procedures were developed, spanning both auxiliary-based approaches and catalytic asymmetric reactions. For instance, the use of chiral N-oxides was reported by Kerr et al., who examined the effect of the chiral brucine N-oxide in the intermolecular PKR of propargylic alcohols and norbornadiene [59]. Under optimized conditions, ee values up to 78% at - 60 °C have been obtained (Eq. 10). Chiral sparteine N-oxides are also able to induce chirality, but the observed enantioselectivity was comparatively lower [60]. 

A range of chiral alkaloids have been screened for the asymmetric reduction of 2- and 4-acetyl pyridine [41] and results are given in Table 10.5. Brucine and strychnine give the highest enantiomeric excess in the pyridinylethanols produced. Reduction of 3-acetylpyridine however affords no optically active alcohol under all conditions employed. A further effect of the added alkaloid is to raise the yield of secondary alcohol at the expense of the pinacols relative to reactions where no alkaloid is present. The high enantiomeric excess found during reduction of 4 ... 

Strychnine.—Treat 0.5 gm. of brucine with 5 gm. of absolute alcohol at the ordinary temperature for one hour, with frequent shaking. Filter, transfer a portion of the undissolved substance to a watch glass, allow it to dry thereon, and then dissolve it in a few drops of concentrated sulphuric acid. To this solution add a small crystal of potassium dichromate. A play of colors, from blue through violet and. red into green, is evidence of the presence of strychnine. 

Quantitative Determination. — Dissolve 0.25 gm. of brucine in 50 cc. of 85 per cent alcohol, and titrate with decinormal hydrochloric acid, using laemoid as the indicator. At least 5.8 cc. of decinormal acid should be required to produce the red end-point. 

The most common method of resolving an alcohol is to convert it to a half-ester of a dicarboxylic acid, such as butanedioic (succinic) or 1,2-benzene-dicarboxylic (phthalic) acid, with the corresponding anhydride. The resulting half-ester has a free carboxyl function and may then be resolvable with a chiral base, usually brucine ... 

Brucine, C23H2604N2 + 4H20.—Colourless needles or prisms M.P. 168° sparingly soluble in water, readily soluble in alcohol and in chloroform [a]D = about — 120° (in CHCI3). 

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... 

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]. 

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

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. 

Pickard and Kenyon used brucine and acetone successfully for the initial resolution of the hydrogen phthalates of a series of alcohols of the type CH3—CHOH—R,50 in which R represents normal alkyl groups from ethyl to undecyl. The d-form of the phthalate formed the less... 

Working in this way it is possible to obtain fairly readily about 50-55% of the calculated amount of pure brucine d-s-butyl phthalate the yield depends on how long the fractionation is continued and how the mother liquors are handled (see below). When large quantities of alcohol are to be resolved it is convenient to unite the material from several runs at this stage. 

The d-s-butyl hydrogen phthalate and the corresponding pure alcohol may be obtained from the brucine salt by the general procedure previously described for the octyl hydrogen phthalates (p. 402). Pure d-s-butyl hydrogen phthalate has [a]D + 38.5° (c = 4, 95% ethanol). Alternatively, the process may be shortened considerably by treating the brucine salt directly with a small excess of dilute sodium hydroxide and distilling the alcohol with steam.138 The alcohol is extracted or is salted out with potassium carbonate, dried, and distilled b.p. 98°/750 mm. [ ]d + 10.83° (without solvent). 

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. 

The 1-alcohol also can be purified by fractionation of the cinchonidine salts of the hydrogen succinate.63 For this purpose the alcohol is recovered from the mother liquors of the brucine salt and converted to the hydrogen succinate by the general procedures previously outlined (p. 393). The oily succinate is oombined with one molecular proportion of cinchonidine in acetone. The very soluble cinchonidine Z-s-butyl succinate is purified by five or six crystallizations and then has m.p. 54-55° [a]D — 85° (c = 5, 95% ethanol). The alcohol is recovered from the pure salt in the usual way. 

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... 

This appeared to be supported by the findings of Ray and Palinchak [55] who resolved 9-nitro-2-benzoylfluorene with brucine. The brucine salt contained alcohol of crystallization and could probably be represented by the formula V ... 

Optically active 2-butanol is prepared by converting the alcohol into the acid phthalate ester, 2.01 mol of which are thoroughly mixed with 2.0 mol of brucine. The mixture is charged into a 6-1 erlenmeyer flask with 2 1 of acetone and refluxed for 24 h. The solid changes in appearance during the reflux period and is kept broken up so that the acetone can come in contact with all of the solid. The mixture is filtered hot and recrystallized two or three times from methanol. The brucine salt is hydrolysed with sodium hydroxide to give a high purity (+)-2-butanol. 

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