Isomerism racemic mixture resolution

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). 

Before 1940 optically active compounds could only be obtained in stereo-isomerically pure form by isolation from natural sources, by resolution of racemic mixtures, or by a few laboratory controlled enzymic reactions. Many of the chemical reactions described in this book lead to products which contain chiral centres, axes, or planes, but in which the isolated material is the optically inactive (racemic) form. This is a direct consequence of the fact that the reactants, reagents, or solvents are achiral or are themselves racemic. The following selection of reactions drawn from the text illustrate this statement they may be cross-referenced to the relevant discussion sections, namely (a) Section 5.4.1, p. 519, (b) Section 5.4.3, p.542, (c) Section 5.11.7, p.687, (d) Section 8.1.3, p. 1133, e) Section 5.2.4, p. 504 and (/) Section 5.4.2, p. 531. 

Additives that specifically interact with an analyte component are also very useful in altering the electrophoretic mobility of that component. For example, the addition of copper(II)-L-histidine (12) or copper(II)-aspartame (54) complexes to the buffer system allows racemic mixtures of derivatized amino acids to resolve into its component enantiomers. Similarly, cyclodextrins have proven to be useful additives for improving selectivity. Cyclodextrins are non-ionic cyclic polysaccharides of glucose with a shape like a hollow truncated torus. The cavity is relatively hydrophobic while the external faces are hydrophilic, with one edge of the torus containing chiral secondary hydroxyl groups (55). These substances form inclusion complexes with guest compounds that fit well into their cavity. The use of cyclodextrins has been successfully applied to the separation of isomeric compounds (56), and to the optical resolution of racemic amino acid derivatives (57). 

The number of enzymes for industrial synthetic applications is growing fast. Enzymatic synthesis can be performed under mild reaction conditions so that many problems of chemical synthesis like isomerization orracemization can be prevented. Furthermore, enzymes are highly specific and selective, especially for enantio- or regio-selective introduction of functional groups. For the preparation of chiral enantiopure compounds, the resolution of racemic mixtures by hydrolases is a well-established route, which has the advantage to be able to use enzymes free of coenzymes. Otherwise, only a maximum yield of 50% can be reached by the primary reaction and further steps of reracemization must follow to avoid loss of the undesired enantiomer. 

Figure 9 shows the examples of separations of racemic mixtures of methylphenobarbital and mephenytoin performed under optimal conditions available (37). It has been found that ( -CD complexation resuTts in a distinct enantioselectivity in the case of mephenytoin and barbiturates which have a chiral center in the pyrimidine ring. The resolution of barbiturate enantiomers is due to the different stabilities of their diastereo-isomeric -CD complexes, while the separation of mephenytoin enantiomers results from the difference in their adsorption on the RP phase. The latter case should be considered further. It has been already suggested (18) that the adsorption of CD complexes in which guest molecules are entirely immersed in the CD cavity is low on RP phases. The distinct adsorption arises from the part of the molecule which is outside the cavity. Taking into account this fact and the remarkable difference in the adsorption of -CD mephenytoin diastereoisomers one may conclude that a significant difference must exist between immersion of mephenytoin enantiomers in the -CD cavity. 

If the interconversion of the Jt-allyl intermediates 34 and 35 is much slower than nucleophihc attack, the product distribution depends on the nature of the substrate. In this case the two enantiomeric chiral substrates 30 and ent-30 are converted to the corresponding product enantiomers 36 and ent-36 with overall retention of configuration. Starting from a racemic mixture of 36 and ent-36, the two product enantiomers 36 and ent-36 are formed in a 1 1 ratio and, therefore, a chiral catalyst cannot induce enantioselectivity (except for kinetic resolution). However, the analogous reaction of the hnear, achiral substrate 31 can be rendered enantioselective if a chiral catalyst is used that adds preferentially to one of the enantiotopic faces of 31 to give either complex 34 or 35. In this case, the enantioselectivity is determined in the oxidative addition of the substrate to the catalyst while nucleophilic addition to the 7i-allyl intermediate is irrelevant for the enantiomeric excess of the overall reaction. The relative rates of k-O-k isomerization and the other processes shown in Scheme 15 strongly depend on... 

Spontaneous resolution of racemate occurs when it crystallizes forming the equimolar mechanical mixture of crystals, and each crystal contains only one of two enantiomers present in the racemic mixture i.e., crystallization gives equal quantities of enantiomorph crystals—a conglomerate. Employing this procedure, enantiopure or nearly enantiopure isomeric compounds can be often obtained from the conglomerate by sorting. In some cases, noncovalent interactions also can play a key role in the spontaneous resolution process. Spontaneous resolution has been demonstrated in a number of racemic bioactive compounds. For example, racemic methadone, a synthetic... 

Tius and co-workers elegantly applied a variant of the Nazarov reaction to the preparation of cyclopentenone prostaglandins (Scheme 19.39) [46]. Moreover, it was demonstrated that the chirality of non-racemic allenes is transferred to an sp3-hybridized carbon atom. Preparation of allenic morpholinoamide 214 and resolution of the enantiomers by chiral HPLC provided (-)- and (+)-214. Compound (-)-214 was exposed to the vinyllithium species 215 to afford a presumed intermediate which was not observed but spontaneously cyclized to give (+)- and (—)-216 as a 5 1 mixture. Compound (+)-216 was obtained with an 84% transfer of chiral information and (-)-216 was obtained in 64% ee. The lower enantiomeric excess of (—)-216 indicates that some Z to E isomerization took place. This was validated by the conversion of 216 to 217, where the absolute configuration was established. The stereochemical outcome of this reaction has been explained by conrotatory cyclization of 218 in which the distal group on the allene rotates away from the alkene to give 216. 

The synthesis of a mixture of two diastereoisomers of harringtonine has also been reported24 by esterifying cephalotaxine (9b) with the acid chloride (33) of racemic 4-benzyloxy-7,7-dimethyl-2-oxo-l-oxacycloheptane-4-carboxylic acid and converting the functionality of the acyl moiety into that of harringtonine. Isomerically pure harringtonine (9a) was made formally accessible by optical resolution of a hydroxy-acid precursor. 

Supercritical carbon dioxide is an apolar solvent, thus it is able to replace hexane during separation of the unreacted enantiomer from the diastereoisomeric complex containing reaction mixture. This idea was successfully applied in the complex forming resolution of tram-2-halogenocyclohexanols (35, 36, 37) and menthol (28). [42, 43] Diastereo-isomeric complex formation reaction was carried out in the mixture of the hexane solution of the racemic ligand and less then an equivalent amount of pulverised DBTA monohydrate. 

A method introduced by Velluz (1957) involves seeding of a supersaturated solution of a racemate (an equimolar mixture of d- and 1-isomers obtained in the last step of synthesis of a compound capable of showing optical isomerism) with crystals of the optically active isomer sought. Resolution of dl-chloramphenicol... 

Resolution of racemic permethric acid also yields the unwanted IS-isomers. Transformation of one enantiomer into its mirror image demands the fission of the C —C -bond of the cyclopropane-ring. The complete isomerization to the equilibrated racemic cis/trans-mixture occurs under influence of fight and sensitizer in the case of ester and salts [346] or in an ionic manner [347] for the acid, involving the intermittent formation of the anhydride 205 and the acyl cation 206 (Reaction scheme 131). 

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