Separation of Chiral Epoxide Enantiomers

The competitive adsorption isotherms were determined experimentally for the separation of chiral epoxide enantiomers at 25 °C by the adsorption-desorption method [37]. A mass balance allows the knowledge of the concentration of each component retained in the particle, q, in equilibrium with the feed concentration, < In fact includes both the adsorbed phase concentration and the concentration in the fluid inside pores. This overall retained concentration is used to be consistent with the models presented for the SMB simulations based on homogeneous particles. The bed porosity was taken as = 0.4 since the total porosity was measured as Ej = 0.67 and the particle porosity of microcrystalline cellulose triacetate is p = 0.45 [38]. This procedure provides one point of the adsorption isotherm for each component (Cp q. The determination of the complete isotherm will require a set of experiments using different feed concentrations. To support the measured isotherms, a dynamic method of frontal chromatography is implemented based on the analysis of the response curves to a step change in feed concentration (adsorption) followed by the desorption of the column with pure eluent. It is well known that often the selectivity factor decreases with the increase of the concentration of chiral species and therefore the linear -i- Langmuir competitive isotherm was used ... 

The second system studied was the separation of the chiral epoxide enantiomers (la,2,7,7a-tetrahydro-3-methoxynaphth-(2,3b)-oxirane Sandoz Pharma) used as an intermediate in the enantioselective synthesis of optically active drugs. The SMB has been used to carry out this chiral separation [27, 34, 35]. The separation can be performed using microcrystalline cellulose triacetate as stationary phase with an average particle diameter greater than 45 )tm. The eluent used was pure methanol. A... 

In order to broaden the capabilities of the Pirkle concept, both polar and polarizable groups were introduced into the molecule. The most popular of this type of chiral stationary phase are the (R,R) Whelk-01 and the (S,S)Whelk-01 phases, the structures of which are shown below. These phases are more versatile and have a wider field of application than the phases previously described. The phases are covalently bonded to the silica and so they can be used with almost any type of solvent. However, they have been found to operate most effectively in the normal phase mode. It should be noted that the polarizable character of the aromatic ring is essential for the stationary phase to function well. As the Pirkle phases are generally available in both the (R) and (S) configurations, the reversal of the elution order of a pair of enantiomers is possible. This stationary phase was originally designed for the separation of the Naproxen enantiomers but has found a wide application to the separation of epoxides, alcohols, diols, amides, imides and carbamates. 

Sharpless epoxidations can also be used to separate enantiomers of chiral allylic alcohols by kinetic resolution (V.S. Martin, 1981 K.B. Sharpless, 1983 B). In this procedure the epoxidation of the allylic alcohol is stopped at 50% conversion, and the desired alcohol is either enriched in the epoxide fraction or in the non-reacted allylic alcohol fraction. Examples are given in section 4.8.3. 

A noteworthy feature of the Sharpless Asymmetric Epoxidation (SAE) is that kinetic resolution of racemic mixtures of chiral secondary allylic alcohols can be achieved, because the chiral catalyst reacts much faster with one enantiomer than with the other. A mixture of resolved product and resolved starting material results which can usually be separated chromatographically. Unfortunately, for reasons that are not yet fully understood, the AD is much less effective at kinetic resolution than the SAE. 

Kinetic resolution.l33 Since enantiomers react with chiral compounds at different rates, it is sometimes possible to effect a partial separation by stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed on p. 102. An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane,134 since alkenes do not easily lend themselves to conversion to diastereomers if no other functional groups are present. Another example is the resolution of allylic alcohols such as 45 with one enantiomer of a chiral epoxidizing agent (see 5-36).135 In the case of 45 the discrimination was extreme. One enantiomer was converted to the epoxide and the other was not, the rate ratio (hence the selectivity factor)... 

Optically active diisopinocamphenylborane can be used to resolve racemic olefins. The reagent adds to one enantiomer, and the other is unchanged. Optical purities on the order of 37-65% are possible. Chiral ally lie alcohols can be resolved with chiral epoxidizing agents derived from tartrate complexes of titanium. One enantiomer is epoxidized and the other is not. Thus, die two alcohol enantiomers can be separated, one as the unsaturated alcohol and one as the epoxy alcohol. Use of die other tartrate isomer reverses die stereoselectivity. Selectivities on die order of >100 are possible with this method. As in any kinetic resolution, however, only one enantiomer can be recovered. The other is converted to a different chiral product. 

Peters et al. [143] used a valine-based chiral selector as the template molecule to prepare monolithic capillaries. These capillaries were used to successfully separate enantiomers of N-(3,5-dinitrobenzoyl)leucine. However, they found that the hydrophobicity of the monomers had a direct effect on the resolution and efficiency of the capillaries. The peaks tailed drastically due to reverse-phase interactions between the enantiomers and the monolith. They found that increasing the hydrophilicity of the monolith by the hydrolysis of the epoxide functionalities of the glycidyl methacrylate moieties resulted in a much more efficient separation. 

A so far still unsolved problem is the direct enantioselective epoxidation of simple terminal olefins. For example the epoxidation of propylene that was achieved with a 41% ee almost twenty years ago by Strukul and his coworkers using Pt/diphosphine complexes is still unsurpassed. Unfortunately such low ee s are of no practical interest. The problem was circumvented by Jacobsen using hydrolytic kinetic resolution of racemic epoxides (Equation 26) and is practised on a multi 100 kg scale at Chirex. The strategy used is to stereose-lectively open the oxirane ring of a racemic chiral epoxide leaving the other enantiomer intact. Reactions are carried out to a 50% maximum conversion. The catalyst belongs to the metal-salen class described above and can be recycled. The products are separated by fractional distillation. 

Determination of the degree and indeed the sense of enantioselection in these reactions is now easily achieved using complexation capillary gas chromatography20. Several chiral liquid phases based on metallic chelates of (1 / )-8-(ethylidene)-3-(heptafluorobutanoyl)camphorate 4 have been developed20 that serve admirably to separate the enantiomers of a wide variety of volatile epoxides, ketals and acetals. 

Epoxidation of the cis alkene A from two different sides of the double bond affords two cis epoxides in the last step—a racemic mixture of two enantiomers. Thus, half of the product is the desired pheromone disparlure, but the other half is its biologically inactive enantiomer. Separating the desired from the undesired enantiomer is difficult and expensive, because both compounds have identical physical properties. A reaction that affords a chiral epoxide from an achiral precursor without forming a racemic mixture is discussed in Section 12.15. 

Resolution of Racemic Mixtures ofAllylic Alcohols.An important application of the SAE reaction is the kinetic resolution of racemic mixtures of secondary allylic alcohols. In this case, the chiral catalyst reacts faster with one enantiomer than with the other since the two transition states are diastereomeric. Thus, using 0.5 mole of r-BuOOH for each mole of racemic allylic alcohol, the faster-reacting enantiomer will consume the r-BuOOH to furnish the epoxide. This leaves behind the unreacted slower-reacting allylic alcohol in high enantiomeric excess, which is then separated from the epoxide via chromatography. 

Resolution of compounds made as diastereoisomeric mixtures The synthesis of Jacobsen s Mn(III) epoxidation catalyst by resolution Resolution with half an equivalent of resolving agent Physical Separation of Enantiomers Chromatography on chiral columns Resolution of triazole fungicides by HPLC A commercial drug separation by chiral HPLC Differential Crystallisation or Entrainment of Racemates Conglomerates and racemic compounds Typical procedure for differential crystallisation (entrainment) Conventional resolution ofL-methyl DOPA Resolution ofL-methyl DOPA by differential crystallisation Finding a differential crystallisation approach to fenfluramine Resolution with Racemisation... 

Pais, L.S. Loureiro, J.M. Rodrigues, A.E. Separation of enantiomers of a chiral epoxide by simulated moving bed chromatography. J. Chromatogr. A,... 

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