Fractional crystallization, resolution

Formate ion, bond lengths in, 757 electrostatic potential map of, 757 Formic acid, bond lengths in. 757 pKa of, 756 Formyl group, 697 p-Formyl benzoic acid, p/C, of, 760 Fourier-transform NMR spectroscopy (FT-NMR), 447-448 Fractional crystallization, resolution and, 307... 

Although the traditional method of separating the diastereomeric compounds generated in a resolution procedure is fractional crystallization, chromatographic procedures are now common and convenient. Diastereomeric compounds exhibit different adsorption... 

Another route to enantiomcrically pure iron-acyl complexes depends on a resolution of diastereomeric substituted iron-alkyl complexes16,17. Reaction of enantiomerically pure chloromethyl menthyl ether (6) with the anion of 5 provides the menthyloxymethyl complex 7. Photolysis of 7 in the presence of triphenylphosphane induces migratory insertion of carbon monoxide to provide a racemic mixture of the diastereomeric phosphane-substituted menthyloxymethyl complexes (-)-(/ )-8 and ( + )-( )-8 which are resolved by fractional crystallization. Treatment of either diastereomer (—)-(/J)-8 or ( I )-(.V)-8 with gaseous hydrogen chloride (see also Houben-Weyl, Vol 13/9a, p437) affords the enantiomeric chloromethyl complexes (-)-(R)-9 or (+ )-(S)-9 without epimerization of the iron center. 

It is well known that spontaneous resolution of a racemate may occur upon crystallization if a chiral molecule crystallizes as a conglomerate. With regard to sulphoxides, this phenomenon was observed for the first time in the case of methyl p-tolyl sulphoxide269. The optical rotation of a partially resolved sulphoxide (via /J-cyclodextrin inclusion complexes) was found to increase from [a]589 = + 11.5° (e.e. 8.1%) to [a]589 = +100.8 (e.e. 71.5%) after four fractional crystallizations from light petroleum ether. Later on, few optically active ketosulphoxides of low optical purity were converted into the pure enantiomers by fractional crystallization from ethyl ether-hexane270. This resolution by crystallization was also successful for racemic benzyl p-tolyl sulphoxide and t-butyl phenyl sulphoxide271. 

Although fractional crystallization has always been the most common method for the separation of diastereomers. When it can be used, binary-phase diagrams for the diastereomeric salts have been used to calculate the efficiency of optical resolution. However, its tediousness and the fact that it is limited to solids prompted a search for other methods. Fractional distillation has given only limited separation, but gas chromatography and preparative liquid chromatography have proved more useful and, in many cases, have supplanted fraetional crystallization, especially where the quantities to be resolved are small. 

Besides discovering this method of resolution, Pasteur also discovered the method of conversion to diastereomers and separation by fractional crystallization and the method of biochemical separation (and, by extension, kinetic resolution). 

Thus, racemic acid 12 (R = H) was obtained by [3+2] cycloaddition in 90-95% yield (Scheme 5.9) [28]. Its resolution into enantiomers could be achieved either by chiral preparative HPLC, or by fractional crystallization of its cinchonidine salts. Better results were obtained upon enzymatic kinetic resolution of its iso-butyl ester 12 (R = i-Bu) [29]. However, further work showed that racemic thiolester 13, which... 

Resolution of a racemic mixture is still a valuable method involving fractional crystallization [113], chiral stationary phase column chromatography [114] and kinetic resolutions. Katsuki and co-workers demonstrated the kinetic resolution of racemic allenes by way of enantiomer-differentiating catalytic oxidation (Scheme 4.73) [115]. Treatment of racemic allenes 283 with 1 equiv. of PhIO and 2 mol% of a chiral (sale-n)manganese(III) complex 284 in the presence of 4-phenylpyridine N-oxide resulted... 

The efficient resolution of /ra r-4,5-dihydroxy-l,2-dithiane into the two enantiomers in large quantities has been reported by the reaction of the racemic mixture with the amino acid iV-/-butoxycarbonyl-(5)-phenylalanine <1997TL7657>. By fractional crystallization, the (43, 53 )- and (4/J,5iJ)-esters were separated followed by hydrolysis, which provided the desired enantiomeric diols in excellent yield and >99% ee. These reactive diols provide isomerically pure analogs with interesting selectivity and therapeutic potential for example, 4,5-dihydroxy-l,2-dithiane derivatives have been reported to inhibit the replication of HIV-1 and HIV-2 (human immunodeficiency viruses). 

For resolution of the racemate 12 two different procedures can be applied 124 the en-antioselective enzymatic deacylation of chloroacetyl-DL-a-aminosuberic acid at pH 7.2 with Taka-acylase or the enantioselective salt precipitation of Z-dl-Asu-OH with D-tyrosine hydrazide according to the method of Vogler et alJ25 Complete enzymatic digestion is achieved in about ten days at 37 °C, and the optically pure L-enantiomer is obtained in 80% yield but the overall efficiency is lower than that of the chemical method. Fractional crystallization affords in good yields the Z-l-Asu-OH derivative 13 which is then used directly as a suitably protected intermediate in subsequent derivatization steps (see Scheme 6). Moreover, the recovery of the D-enantiomer from the mother liquors is also easy in this case. 

Synthesis (Pohland, 1953 1955 1963 janssen and Karel (Janssen)1956 Sullivan et al., 1963) In the Grignard reaction of 3-dimethylamino-2-methyl-1-phenyl-propan-lone with benzylmagnesium chloride 4-dimethylamino-3-methyl-1,2-diphenyl-butan-2-ol is formed. The preferred product is the a-diastereomer(75 % a-form, 15 % p-form). The a-form crystallizes and the diastereomeric p-form remains in solution, because of its better solubility. Racemic resolution to obtain the analgetically (+) enantiomer can be achieved on the pure a-Grignard product via fractional crystallization of the salts with D-camphorsulfonic acid. Alternatively the resolution can be achieved by treating the racemic mannich product 3-dimethylamino-2-methyl-1-phenyl-propan-1-one with (-)-dibenzoyltartaric acid in acetone as solvent. 

Note that these compounds are not enantiomers, but true diastereomers with different properties, and they may be separated by fractional crystallization. The asymmetric carbon atom has an 5 configuration in both diastereomers, but the chirality about the molybdenum atom is different. Thus the asymmetric carbon aids in the resolution of the molybdenum center, but its presence is not necessary for the complex to be chiral. It is merely necessary for the Schiff base to be unsymmetric, i.e., have one pyridine nitrogen and one imino nitrogen. If the bkJentate ligand had been ethylenediamine, bipyridine, or the oxalate ion, there would have been a mirror plane and no duality at the molybdenum. 

Azetidine-2-carboxylic acid (2) is commercially available. It is readily prepared as the racemate by refluxing 2,4-dibromobutyric acid ester with benzhydrylamine in acetonitrile. If benzyl 2,4-dibromobutyrate is treated with benzhydrylamine, the resulting benzyl TV-benz-hydryl-D,L-azetidine-2-carboxylate is hydrogenolytically processed to D,L-azetidine-2-car-boxylic acid in a one-step reaction. 101,107 Resolution of the racemate can be performed by the method of Vogler 108 via fractional crystallization of the Z-D,L-Aze-OH-H-Tyr-N2H3 salt thereby the salt of the D-imino acid precipitates first from methanol. 96 A stereoselective synthesis of A-tosyl-L-azetidine-2-carboxylic acid can be achieved by a two-step reaction from N-tosyl-L-homoserine lactone. 94 ... 

Racemic pipecolic acid (6) is obtained by ring closure of TV-alkylglycines by ionic 203 or radical 204 mechanisms. It also may be obtained by conversion of suitable substituents at the C2 of piperidine into the 2-carboxy group, e.g. hydrolysis of a nitrile group 205 or oxidation of a 1,2-dihydroxyethyl group. 206 Resolution of the racemic mixture can be carried out by fractional crystallization. 207-209 Enzymatic resolution of racemic pipecolic acid 210-213 or of synthetic intermediates 214 has been reported. 

The Z-protected derivative, again prepared by standard methods using benzyl chloroformate,t208 may serve in the case of racemic pipecolic acid for resolution into the pure enantiomers by fractional crystallization with L-tyrosine hydrazide/208 Acylation with N-protected pipecolic acid or of pipecolyl peptides is performed by standard procedures via the active ester methods, e.g. A-hydroxysuccinimide ester/121 by the mixed anhydride method, e.g. with isobutyl chloro-formate 95-114 or pivalic acid chloride/121 as well as by DCC/HOBt/118 In the synthesis on solid support, longer coupling times are required when compared to N-protected proline.1[235 ... 

Racemic piperazine-2-carboxylic acid (4-azapipecolic acid, 22) is obtained by hydrogenation of pyrazine carboxylic acid salts/236 For its enantiomeric resolution several methods have been described, e.g. fractional crystallization of its S-camphor-10-sulfonic add salt/236,237 fractional crystallization of l,4-dibenzylpiperazine-2-carboxylic add menthyl ester/238 or selective digestion of racemic piperazine-2-carboxylic add amide by leucine aminopeptidase/239 ... 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

A wide range of bidentates containing one or more asymmetric phosphorus or arsenic donor atoms is now available due to the exploitation of a resolution technique involving the fractional crystallization of pairs of diastereomeric complexes formed by the chiral bidentates with pal-ladium(II) complexes containing optically active dimethyl(a-methylbenzyl)amine or dimethyl(l-ethyl-a-naphthyl)amine. Indeed, in recent work the two enantiomer pairs of l-(methylphenyl-arsino)-2-(methylphenylphosphino)benzene, (29a) and (29b), have been separated and isolated as optically pure air-stable crystalline solids with [a]o values of 79° (R, R ) and 15.5° (R, S ). 95... 

Because the physical properties of enantiomers are identical, they seldom can be separated by simple physical methods, such as fractional crystallization or distillation. It is only under the influence of another chiral substance that enantiomers behave differently, and almost all methods of resolution of enantiomers are based upon this fact. We include here a discussion of the primary methods of resolution. 

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