Crystallization, separation diastereoisomers

X-Ray studies on Na[(-)5 g-Co(ox)(aa)2],2H20 [aa = trans-iV-methyl-(S)-alaninate] confirm the RS configuration of the aa ligands and show the absolute configuration of the anion to be A. Fractional crystallization and column chromatography on D-lactose has been used to separate diastereoisomers of [Co(acac)2(L-Phe)] and [Co(acac)2(L-Val)]. The method was, however, unsuccessful for the corresponding L-Ala complex. ... 

The major sulfinamide diastereoisoraer (56) was obtained diastereoisomerically pure in 74% yield after crystallization (initial diastereoisomer ratio 90 10). Subsequent desulfurization, benzoylation, and stereoselective enolate hydroxylation (Scheme 4.30) gave an 86 14, syn anti mixture of the target diastereoisomers. Chromatographic separation of the product diastereoisomers afforded (2i ,3S)-(-)-(57), the methyl ester of the taxol C,j side chain, in 49% yield and > 93% ee. 

Hydrogenation removes the benzyl group, whose function was to prevent overalkylation. Next, HBr cleaves the ether and ester groups, and either catalytic or hydride reduction completes the synthesis of 6. Separation of diastereoisomers was achieved by fractional crystallization. 

The diastereoisomers have different physical properties. They have different melting and boiling points, solubilities, densities, refractive indices or adsorption coefficients. They can be easily separated, most often by fractional crystallization and adsorption. The enantiomers are not separated by these techniques. 

A large number of optically active square pyramidal organometallic complexes have been described. That shown in 9 is one of a pair of diastereoisomers that can be separated by fractional crystallization into (-I-) and ( —) rotating components. It is optically stable in... 

Quite a few complexes with the bidentate pentasulfido ligand are also known. The first reported was the homoleptic and optically active complex [Pt(85)3] (15) (53, 64, 65, 68, 69, 176). Brick-red (NH4)2[Pt(85)3] 2H20 is formed from the reaction of K2[PtCl6] with aqueous (NH4)28 solution. Addition of concentrated HCl results in the separation of maroon (NH4)2[Pt8i7] 2H20 (54). The [Pt(85)3] ion crystallizes from the solution as a racemate, which can be resolved by forming diastereoisomers. Upon crystallization, [Pt8,7] undergoes a second-order asymmetric transformation, so that the solid contains an excess of the (—) enantiomer (54). 

The mother liquor was concentrated to dryness after separation of the first fractio and the residue was crystallized from a mixture of ether and n-hexane (7 3) at -15°C. T1 crystals obtained were combined with the residue obtained after crystallization of 3. Tv consecutive crystallizations from the same solvent gave the second pure diastereoisomer ester 4 1.65 g, mp 72°-75°C, [ct]578 + 26.2° (c 1.8, CgHg). 

The N-sulfonyloxaziridines are an important class of selective, aprotic oxidizing reagents.12 Enantiomerically pure N-sulfonyloxaziridines have been used in the asymmetric oxidation of sulfides to sulfoxides (30-91% ee),13 selenides to selenoxides (8-9% ee),14 disulfides to thiosulfinates (2-13% ee),5 and in the asymmetric epoxidation of alkenes (19-65% ee).15-16 Oxidation of optically active sulfonimines (R S02N=CHAr) affords mixtures of N-sulfonyloxaziridine diastereoisomers requiring separation by crystallization and/or chromatography.13... 

For Cr, Mo, and W, these diastereoisomers could be separated by fractional crystallization into the (+)- and (-)-rotating components (71). Similarly, in the reaction of Mn(CO)sBr with the NN Schiff base (see Scheme 7), the two diastereoisomers of c-/s-(CO)3Mn(NN )Br, differing only in the manganese configuration, were formed and were resolved (72). 

Non-stereoselective reactions produce either a mixture of diastereoisomers or a racemic modification. Diastereoisomers exhibit different physical properties. Consequently, techniques utilizing these differences may be used to separate the isomers. The most common methods of separation are fractional crystallization and chromatography. 

Using a chiral auxiliary. The achiral substrate is combined with a pure enantiomer known as a chiral auxiliary to form a chiral intermediate. Treatment of this intermediate with a suitable reagent produces the new asymmetric centre. The chiral auxiliary causes, by steric or other means (see section 10.2.2), the reaction to favour the production of one of the possible stereoisomers in preference to the others. Completion of the reaction is followed by removal of the chiral auxiliary, which may be recovered and recycled, thereby cutting down development costs (Figure 10.10). An advantage of this approach is that where the reaction used to produce the new asymmetric centre has a poor stereoselectivity the two products of the reaction will be diastereoisomers, as they contain two different asymmetric centres. These diastereoisomers may be separated by crystallization or chromatography (see section 10.2.1) and the unwanted isomer discarded. 

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. 

The two diastereoisomers may have adequate crystallizing power and at the same time may differ considerably in crystalline character and/or in solubility in the available solvents. Such isomers are readily separated by simple fractional crystallization, and not infrequently the more soluble as well as the less soluble can be obtained pure. 

The product, mixed with charcoal, is filtered off and washed with 40% ethanol (60 ml.), the washings being discarded. The diastereoisomer is then extracted from the charcoal with successive portions of hot water (60°). The final wash portion should be colorless, and usually 300 ml. will suffice. The extract is evaporated to a volume of 50 ml., and on cooling in ice the pure diastereoisomer separates as orange-yellow crystals, [a]D = +103° the yield is 40 to 41 g. or 78 to 82% on the assumption of complete conversion to one isomer. Conversion to the iodide [a]D = +91° is effected as in the previous synthesis. The yield is 43 to 44 g. or 60 to 65%. 

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. 

Z-K[Co(enta)] 2H20. The diastereoisomer (2.0 g.) is suspended in 15 ml. of water in a mortar. Four grams of potassium iodide is added and the mixture triturated for 4 to.5 minutes. The insoluble iodide d-[Co(en)2(N02)2]I precipitates and is filtered. Eighteen milliliters of ethanol is added slowly to the filtrate with scratching of the sides of the vessel, and the levo salt separates as sparkling violet plates. This is allowed to stand for 3 or 4 minutes. Then more ethanol is gradually added until a total volume of 40 ml. has been added. The crystals are collected and washed with cold ethanol. Recrystallization is usually not necessary, but may be effected by dissolution in 15 ml. of warm water followed by the addition of 40 ml. of ethanol. The crystals obtained are washed with ethanol and acetone and air-dried. The yield is 1.2 g., or, if the whole of the diastereoisomer is used (2.6 g.), 1.5 g., representing a 75% yield. 

The isomers of [P glycinatotriethylenetetra-aminecobaltpii)]24 have been separated by a cation-exchange resin,303 and an X-ray investigation was performed on a crystal containing both the A-( — )589-(RR) and -(RS) diastereoisomers. 

Even more interesting is the addition of the (.S )-cnantiomcr of 2-amino-1-butanol, which itself forms a salt with (R)-mandelic acid. This salt has almost inhnite solubility. With this additive, the resolution of alaninol with (W)-mandelic acid results in the crystallization of an almost diastereoiso-merically pure salt, without incorporation of 2-amino-l-butanol. On use of this method enantiopure (R)-alaninol can be obtained after an additional recrystallization, without the need to separate the alaninol from the 2-amino-l-butanol. We call this procedure reverse Dutch Resolution, to indicate that the family mix remains in solution. Most likely in this case stereoselective nucleation inhibition plays a role by suppressing the nucleation of the (.S )-alaninol-(A )-mandclic acid diastereoisomer. 

Alternatively, diltiazem (30) has been prepared using the Evans auxiliary derivative 31 derived from L-valine (Scheme 23.7).55 After dehydration of the adduct from the condensation of 31 with anisaldehyde through the mesylate, the enol ether was formed with a Z E ratio of 4 1. This imide was then treated with 2-aminothiophenol in the presence of 0.1 equiv. 2-aminothiophenoxide with no change in the isomer ratio. The auxiliary was removed with trimethylaluminum, with concomitant formation of the lactam. After separation by crystallization, the correct diastereoisomer was converted to diltiazem in >99%ee. 

Distinction should be made at this time between diastereoisomers and enantiomers. The former are characterized by the presence of at least two closely associated asymmetric centers in the molecular structure, either of which can epimerize. Altogether then there are two pairs of enantiomers for a total of four stereochemically unique individuals. Diastereoisomers have different physical properties and as a result discriminations, and even separations, can be done relatively easily. Enantiomers on the other hand differ in only one physical property, i.e. the direction of rotation of polarized light. Reaction of an enantiomeric racemic mixture with a third chiral species will produce a mixture of diastereomers therefore facilitating their identification or their separation. Early examples of this were the separations done by fractional crystallization of salts produced by a derivatization reaction with, for example, the alkaloid (-)-brucine. Fractional crystallization would never seem to be an effective analytical method yet it was used with some success in a forensic sciences context to confirm the presence of (L)-cocaine by a carefully contrived microcrystalline test. The physical properties... 

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