Brucine alcohol resolution

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-... 

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... 

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 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... 

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... 

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. 

Resolution of Alcohols. Although not a well exploited use of brucine, a variety of secondary benzylic alcohols have been resolved by complexation and crystallization with brucine (eq 5). About a dozen alcohols were obtained in close to enantiomeric purity by this procedure. Also resolved by crystallization of their brucine inclusion complexes were a series of tertiary propargylic alcohols (eq 6). In this case, the enantiomer that does not crystallize with brucine can be obtained in almost complete optical purity from the mother liquors. 

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). 

Brucine has been used as an enantioselective catalyst in the kinetic resolution of alcohols. For example, an azirinylmethanol was reacted with 0.5 equiv of Acetic Anhydride in the presence of 25 mol % brucine. The resulting acetate was found to possess 24% ee (eq 13). ... 

One synthesis of cyclopentenone [80], requiring a resolution, involved initial ring contraction of phenol when treated with alkaline hypochlorite (49). Resolution of the resulting cis acid [85] was effected with brucine. The desired enantiomer [86] formed the more soluble brucine salt and was thus obtained from the mother liquors of the initial resolution. Oxidative decarboxylation with lead tetracetate, partial dechlorination with chro-mous chloride, and alcohol protection gave chloro enone [87]. Zinc-silver couple (50) dechlorinated [87] to the desired cyclopentenone [80]. 

A third approach to brefeldin A by Greene dealt with a version of the second synthesis designed to provide optically active 161, as shown in Scheme 1.39. Enantiomerically pure alcohol (S)-( -i- )-240, obtained via resolution of the derived phthalate mono ester with brucine, was acylated with acryloyl chloride to afford 241. Lewis acid promoted Diels-Alder reaction of 241 and cyclopentadiene then led to a 75% yield of diastereomers 242a (endo) and 242b (exo) in a 97 3 ratio. 

With modification, the aforesaid method can sometimes be applied to the resolution of a neutral compound. Such a resolution is accomplished by first converting the neutral compound into a derivative which can form a salt. Resolution of dl-octanol-2 is an example of the application of this modification. The racemic mixture of the alcohol is converted by treatment with phthalic anhydride into the acid phthalate. In the next step the acid phthalate is reacted with the naturally occurring laevorotatory base, brucine. Fractional crystallisation of the resulting mixture of the brucine salts yields the separated salts. Decomposition of the separated salts with hydrochloric acid removes brucine, and the two resulting acid phthalates are then hydrolysed with alkali to get the d- and 1-forms of octanol-2. 

Brucine is recommended as a convenient and effective reagent for the resolution of tertiary acetylenic alcohols. The evidence available to date indicates that the acetylenic alcohol must have two aryl groups, or one aryl group and one bulky alkyl group, attached to the hydroxyl-bearing carbon atom. The X ray crystal structure analysis of one such brucine complex was also reported. 

Simple alcohols with only one hydroxy function and one asymmetric carbon atom are classical chiral chemicals. While they are often commercially available, they are relatively expensive. Until recently, they were obtained mainly by resolution of the racemates using a reliable but not very convenient technique. Reaction of the racemic alcohol with phthalic acid anhydride gave the monoester of phthalic acid, which was resolved by salt formation with a chiral base, usually brucine, or occasionally also strychnine or cinchonidine. The methyl carbinols from 2-butanol 1 to 2-tridecanol were first obtained by this method1,2 and this was later extended to 3,3-dimethyl-2-butanol3. When crystallization of the diastereomeric salts was performed in the presence of triethylamine, some other methyl carbinols could also be resolved, such as... 

This resolution method was found to be appUcable to some cyanohydrins 15 and secondary alcohols 16. Very interestingly, the racemic cyanohydrins were converted into a pure optically active isomer in almost quantitative yield in the presence of 72 For example, when a solution of racemic l-cyano-2,2-dimethy 1-1-phenyl-propanol 15a) (1.0 g, 5.3 mmol) and 72 (2.1 g, 5.3 mmol) in methanol (2 ml) was kept in an uncapped flask for 24 h at room temperature, a brucine inclusion compound of 94% ee of +yi5a was obtained in quantitative yield, which upon decomposition gave 94% ee of - -)-15 a (1.0 g). Repeating inclusion formation of the 94 % ee containing (ri- )-75a (1.0 g) Avith 72(2.1 g) one more time yielded 100 % ee of (+)-15a [1.0 g, [a]jj -1- 15.9° (c 1.0 in MeOH)]. The process of the complete conversion of racemic cyanohydrin to one enantiomer consists of racemization of cyanohydrin through the equilibrium in Equation 1 and selective inclusion of one enantiomer in brucine... 

Simple secondary alcohols 16 are also easily resolved with brucine to give 100% ee of 16a [[ocJd 32.3° (c 1.0 in MeOH)] and 16b [[ [[, 34.4° (c 1.0 in MeOH)] However, in the cases of 15 and 16, a sterically bulky group such as t-Bu or CCI3 is necessary for efficient optical resolution. 

Optically active compds. A soln. of methyl d-/ -(phenyl-a-naphthyl-p-tolylmethoxy)-propionate (obtained by resolution of the corresponding acid with brucine) in dry ether added rapidly to a stirred 50%-NaH-mineral oil dispersion in ether, stirring continued 24-26 hrs., ice-cooled, and treated slowly with water d-phenyl-a-naphthyl-p-tolylcarbinol. Y 85%. - This is the final stage of a method for the resolution of alcohols. F. e. s. K. G. Rutherford, J. L. H. Batiste, and J. M. Pro-kipcak. Can. J. Chem. 47, 4073 (1969). 

ABSTRACT. Novel optical resolutions of guest compounds by inclusion complex formation with optically active host compound are reviewed Tertiary acetylenic alcohols, cyanohydrins, and secondary alcohols were resolved by complexation with alkaloids such as brucine or sparteine. Cycloalkanones, 2,3 -epoxycyclohexanones, and some other neutral compounds were resolved by complex formation with optically active diacetylenic diol. Mutual optical resolution of bis-g-naphthol and sulfoxides by complex formation was also reviewed. 

Optical Resolution of Tertiary Acetylenic Alcohols by Complex Formation with Brucine... 

We found that some tertiary acetylenic alcohols form a 1 1 complex with brucine, and that the acetylenic alcohols v ere easily resolved by utilizing the complexation. As an example, the experimental detail of the resolution of 1,1-di-methyl-2-phenyl-3-pentyn-2-ol is described. A solution... 

We also found that optically active sparteine can be used instead of brucine for the optical resolution of tertiary acetylenic alcohols and 2), and that sparteine can also be resolved by complexation with optically active acetylenic alcohols,5Efficiency of the optical resolution of acetylenic alcohols with sparteine was compared to that with brucine (Table 2), In some cases, optical resolution by complexation with sparteine is more efficient than that with brucine, and the use of the much less poisonous sparteine also has advantages over the use of the poisonous brucine. 

The method used for the optical resolution of acetylenic alcohols by complexation with brucine was found to be applicable to cyanohydrins ( ) 7 and some secondary alcohols ( ). Surprisingly, it was also found that racemic cyanohydrins are converted into one optically active isomer in yields of more than 50% in the presence of brucine. For example. When a solution of racemic (1.0 g) and an equimolar amount of brucine (2.1 g) in MeOH (2 ml) was kept in an uncapped flask at room temperature for 24 h, a brucine complex of (+) J crystallized out. Decomposition of the complex gave 100% ee (+)- in almost quantitative yield. This is not a simple optical resolution method but a novel preparation method of optically active cyanohydrins. This eantiomerization method can be applied to... 

Thusy Mills and Elliott (105) found that on crystallizing the brucine salt of JV-benzenesulfonyl-8-nitro-l-naphthylglycine (VIII) from two different solvents, acetone and methyl alcohol, an asymmetric transformation can be effected at will in two opposite senses. In effect, a novel type of resolution is achieved in this special case ... 

---