Optical Resolution—Diastereoisomers

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

The use of sulfoximines in the syntheses of optically active compounds has been reported [429]. A remarkable ketone methylcnation with optical resolution was realized. A highly selective diastereofacial addition of an enantiopure sulfoximine to a racemic ketone, chromatographic separation of the two diastereoisomers and reductive cleavage yielded both enantiomers of p-panasinsene [430], isolated from the root of ginseng, a herb used in Chinese folk medicine. 

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. 

Optical resolutions of two a-alkoxycarboxylic acids (3a and 3b, Scheme 3) were accomplished with the neutral calcium salt of DBTA (DBTACa) in aqueous ethanol solution. [24] Preparation of the diastereoisomers is quite simple a stoichiometric mixture of DBTA monohydrate and calcium oxide had to solve in hot aqueous ethanol to form DBTACa salt and then racemic acid (3a or 3b) had to add into it. On cooling [Ca(H20)(f -3a)]DBTA.H20 or [Ca(H20)(S-3b)]DBTA.H20 cystallised. Free (S)-3a or (R)-3b was obtained from the corresponding filtrate. In the schemes and the formulas (6) or (R) stands for showing the configuration of the of the major enantiomer in the product. For example, (.S )-3a means that the isolated material contained the 6-isomer in excess, ee values are given in the Tables. 

Nemak, K., Acs M., Jaszay M.Zs., Kozma, D., and Fogassy, E. Study of die diastereoisomers formed between pipecolic acid N-alkylanilides and 2R,3R-tartaric acid or 0,0 -dibenzoyl-2R,3R-tartaric acid. Do the tartaric acids form molecular complexes instead of salts during optical resolutions , Tetrahedron 1996, 52, 1637-1642. 

After the preparation of diastereoisomers by introduction of an optically active resolving agent, the next problem in an optical resolution is to separate the diastereoisomers. It should be recalled that the components of a pair of diastereoisomers necessarily have very similar properties. They contain exactly the same ligands and differ only in their arrangement around the metal atom. Several separation techniques have been used, based either on the fact that diastereoisomers differ in solubility, or in retention time during chromatography. 

The optical resolution of racemates 22a, 25a, and 27a was carried out by chromatographic separation of their (4/ ,5S)-MPOT-amide derivatives 22b, 25b, and 27b. The absolute stereochemistry of each pure diastereoisomer was confirmed by comparing the physical data of its derivative with those of the authentic compound in each case. Thus, (4i ,5S)-MPOT (5) proved to be a satisfactory chiral reagent useful for analytical separation and optical resolution of racemic carboxylic acids and amino acids (85JCS(P1)2361). 

Kashiwabara et al. communicated optical resolution of (2-aminoethyl)-n-butylphenylphosphine and the preparation of the bis(acetylacetonato)colmlt011) complex containing the resolved aminophosphine. The resolved phosphine was allowed to react with tris(acetylacetonato)cobalt(III) in methanol solution in the presence of activated charcoal at room temperature. From the resulting solution a pair of diastereoisomers as shown in Fig. 1.6 was isolated by column chromatography using a SP-Sephadex C-25 ion exchanger and an aqueous solution of Na2[Sb2(rf-tart)2j. 

The possibility of preparation of crosslinked polymers with molecular recognition for a certain substance by polymerization in the presence of templates has been verified in many examples. Cavities in the polymer containing functional groups are thus obtained whose shape and whose arrangement of the functional groups corresponded to that of the template. The selectivity for the optical resolution of racemates and the separation of different diastereoisomers, configurational isomers, or metal ions was quite high. Separations have been performed in analytical and preparative scale. It was also possible to perform stereoselective reactions with the substrates bound inside of the cavities. 

Cram and his co-workers have reviewed in full their latest work on the use of host-guest complexes for the total optical resolution of amines and a-amino-ester salts. This important method can be used with both liquid-solid systems (host chemically bound to silica) and liquid-liquid systems, when the host is contained in the mobile phase and a racemic mixture of the guest is adsorbed on to the stationary phase.A neat trick for the resolution of a-amino-acids is to mix solutions of the racemic acid and racemic ephedrine and then seed the mixture with a pure diastereoisomer. In this way, only two of the four possible diastereoisomers crystallize out, in turn. ... 

A different non-classical approach to the resolution of sulphoxides was reported by Mikolajczyk and Drabowicz269-281. It is based on the fact that sulphinyl compounds very easily form inclusion complexes with /1-cyclodextrin. Since /1-cyclodextrin as the host molecule is chiral, its inclusion complexes with racemic guest substances used in an excess are mixtures of diastereoisomers that should be formed in unequal amounts. In this way a series of alkyl phenyl, alkyl p-tolyl and alkyl benzyl sulphoxides has been resolved. However, the optical purities of the partially resolved sulphoxides do not exceed 22% after... 

P-chiral dibenzophosphole oxide (52a) (Scheme 14) shows liquid crystalline behaviour [52], a property that is of interest in the area of electro-optical displays [53]. Chiral resolution of (52a) was achieved by column chromatographic separation of the diastereoisomers obtained following coordination of the o -benzophosphole (52b) to chiral cyclometallated palladium(II) complexes [52]. Notably, the presence of a stereogenic P-centre is sufficient to generate a chiral cholesteric phase. 

Optically active substances are preferentially adsorbed by some optically active adsorbent. Thus Broadly and Easty (1951) found wool and casein to adsorb (+) mandelic acid from its aqueous solution. Some workers also successfully carried out resolution without using an active adsorbent. The alumina was found to be suitable for resolving diastereoisomers of (-) menthyl ( ) mandelate. 

Since all the physical properties of two given enantiomers are the same in the absence of a chiral, or optically active, medium, their chromatographic resolution needs a different approach from the relatively simple separation of geometrical isomers, stereoisomers or positional isomers. Two methods are used. The older technique of indirect resolution, requires conversion of the enantiomers to diastereoisomers using a suitable chiral reagent, followed by separation of the diastereoisomers on a non-chiral GC or LC stationary phase. This technique has now been largely superseded by direct resolution, using either a chiral mobile phase (in LC) or a chiral stationary phase. A variety of types of chiral stationary phase have been developed for use in GC, LC and SFC(21 23). 

Enantiomers have identical physical and chemical properties to one another except the direction in which they rotate plane polarised light (clockwise or anticlockwise). They may be separated by interaction with a second chiral species. This gives two diastereoisomers (if the two chiral centres are the same we can describe the diastereoisomers as optically pure meso AA and the racemic or rac form which itself occurs as two pairs of enantiomers, AA and AA) which do differ in their physical properties e.g. have different NMR spectra, can be separated by achiral chromatography etc). For example, Scheme 3.1 shows the experimental resolution of [Co(en)3]3+ using tartrate. 

The most useful and general of all methods of resolution is that which involves combination of a racemic substance with an optically active reagent (a so-called resolving agent) to give two diastereoisomeric derivatives, one derived from each of the two active components. These diastereoisomers often may be separated by conventional fractional crystallization. Each isomer then is treated to regenerate the pure active component. 

Busch and Bailar1 obtained optically active solutions of one of the enantiomers of the ethylenediaminetetraacetato-cobaltate(III) ion by selective adsorption on optically active quartz and by fractional crystallization of the strychnine salt. More recently Dwyer, Gyarfas, and Mellor2 reported the complete resolution using d and Z-tris(ethylenediamine) cobalt(III) chloride. Precipitation of the diastereoisomers was effected by addition of ethanol to the aqueous solution. The volume of ethanol used was critical and often merely the potassium salt separated. 

The preparation of homochiral compounds by formation and separation of diastereoisomers or by kinetic resolution of racemates, at or near the end of a total synthesis, has been a method of choice. This avoids the possibility of racemization should chirality be introduced earlier. However, the costs are high because only half by weight of the homochiral compound is theoretically possible from the racemate unless the optical antipode can also be easily inverted to the desired product. Indeed, previous methods for producing levomethadone based on the classical resolution at the end, or at the penultimate stage of the synthesis, were costly and not very effective. Levomethadone hydrochloride has previously been marketed as L-Polamidon and Levadone16 but was subsequently withdrawn because of the high cost of production. 

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