Preparation of Pure Enantiomers

Chemists have developed an extensive set of specific chemical reactions for which the enantiomeric properties are well known. In many cases, the absolute structure of the target natural product is not known, so chemists make a variety of compounds with different R or S chiral centers and compare various chemical and physical measurements such as optical rotation or nuclear magnetic resonance spectroscopy (NMR) from the synthesized compound and the natural product to see if they are the same. A second common approach is to S)mthe-size racemic mixtures and develop a procedure to separate and 

FIGURE 5.20. The synthesis and structure of Ti(DET) (DET = diethyl ester of d-tartaric acid) and example of its use in asymmetric synthesis. 

For practical, legal, safety, environmental, and other reasons, the importance of producing enantiomerically pure pharmaceuticals, food additives, and other chemicals as opposed to racemic mixtures is increasing. In the 50 years since the thalidomide tragedy, scientists have been able to develop a much better understanding of the differences in the biological effects of individual enantiomers. This has led to the development of new techniques for the production and separation of chiral materials. This trend will certainly continue, and in the near future a pharmaceutical or food additive or agricultural product will probably be used as a racemic mixture only rarely. 

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One of the most actively investigated aspects of the biohydrolysis of carboxylic acid esters is enantioselectivity (for a definition of the various stereochemical terms used here, see [7], particularly its Sect. 1.5) for two reasons, one practical (preparation of pure enantiomers for various applications) and one fundamental (investigations on the structure and function of hydrolases). The synthetic and preparative aspects of enantioselective biocatalysis by hydrolases have been extensively investigated for biotechnology applications but are of only secondary interest in our context (e.g., [16-18], see Sect. 7.3.5). In contrast, the fundamental aspects of enantioselectivity in particular and of structure-metabolism relationships in general are central to our approach and are illustrated here with a number of selected examples. 

The resolution procedure applies to racemic organometallic esters and to the esters of a thianucleoside, for the preparation of pure enantiomers of an antiviral agent (2, 3 -dideoxy-5-fluoro-3 -thiacytidine) (eq 7). ... 

We then attempted purification of impure (.S )-144 by enantioselective HPLC. Fortunately, TBS derivative G was found to be separable by preparative HPLC on Chiralcel OD to give pure (S)-G. Deprotection of the TBS group of (S )-G under conventional conditions with TBAF caused partial racemization of (S)-144. However, treatment of (S )-G with dilute ethanolic hydrochloric acid at room temperature caused no appreciable racemization to give (.S )-144 (98.4% ee), [ah24 = -90.7 (acetone), in 40% yield. Similarly, (R)-144 was also synthesized by employing AD-mix-a instead of AD-mix-f) . (ft)-Cytosporone E (144 ), [a]o25 = +91.3 (acetone) could be obtained pure (>99% ee). As shown in the present case, use of preparative HPLC is becoming more and more important in the preparation of pure enantiomers. 

Not only covalent diastereomeric compounds but also diastereomeric non-covalent complexes differ in terms of their free energy. Non-covalent diastereomeric complexation is a more suitable technique for the preparation of pure enantiomers because the formation and destruction of non-covalent complexes are commonly more gentle and less laborious. 

New developments in chiral chromatography (more universal, easily available, stable, tailor-designed CSPs) and technology (recycling, displacement and especially, SMB) makes chromatography a valuable alternative to classical techniques for the preparation of pure enantiomers. 

The chromium-templated coupling of alkenyl- or arylcarbene, aUcyne and carbonyl ligands generates arene tricarbonylchromium complexes as primary benzannulation products which - based on their unsymmetric substitution pattern - bear a plane of chirality. Chiral arene complexes are powerful reagents in stereoselective synthesis however, the preparation of pure enantiomers is a lengthy and often tedious procedure, and thus diastereoselective benzannulation appears to be an attractive alternative. In order to lure the chromium fragment to one or the other face of the arene formed, chiral information may be incorporated in the carbene complex or the aUcyne. 

Hoong LK, Strange LE, Liotca DC, Koszalka GW, Bums CL, Schinazi RF Enzyme-mediated enantiosclective preparation of pure enantiomers of the anti-viral agent 2 r3 -dideoxy-5-flu-oro-3 thiacytidine (FTC) and related compouitds. ] OrgChem 1992 57 5563-5565. 

However, while the importance of chiral derivatives is increasing (especially in the field of organic electronics, where fullerenes present the more promising applications), the preparation of pure enantiomers has been based on the HPLC race-mate resolution or on the use of chiral starting materials. The noncoordinating character of fullerene double bonds has indeed hampered the use of most part of the available chiral methodologies based on the activation of electron-deficient olefins. 

A conceptually straightforward approach to the preparation of pure enantiomers of amino acids would be resolution of their diaslereomeric salts. Typically, the amine group is first protected as an amide and the resulting prodnct is then treated with an optically active amine, such as the inexpensive alkaloid brucine (Section 25-8 and margin). The two diastereomers formed can be separated by fractional crystallization. Unfortunately, in practice, this method can be tedious and can suffer from poor yields. 

Since the first separation of enantiomers by SMB chromatography, described in 1992 [95], the technique has been shown to be a perfect alternative for preparative chiral resolutions [10, 21, 96, 97]. Although the initial investment in the instrumentation is quite high - and often prohibitive for small companies - the savings in solvent consumption and human power, as well as the increase in productivity, result in reduced production costs [21, 94, 98]. Therefore, the technique would be specially suitable when large-scale productions (>100 g) of pure enantiomers are needed. Despite the fact that SMB can produce enantiomers at very high enantiomeric excesses, it is sometimes convenient to couple it with another separation... 

For preparative or semipreparative-scale enantiomer separations, the enantiose-lectivity and column saturation capacity are the critical factors determining the throughput of pure enantiomer that can be achieved. The above-described MICSPs are stable, they can be reproducibly synthesized, and they exhibit high selectivities - all of which are attractive features for such applications. However, most MICSPs have only moderate saturation capacities, and isocratic elution leads to excessive peak tailing which precludes many preparative applications. Nevertheless, with the L-PA MICSP described above, mobile phases can be chosen leading to acceptable resolution, saturation capacities and relatively short elution times also in the isocratic mode (Fig. 6-6). 

The use of lipase allows the hydrolysis to be used to prepare almost pure enantiomers. 

Optically Active Acids ami Esters. Enannoselcctive hydrolysis of esters of simple alcohols is a common method for the production of pure enantiomers of esters or Ihe corresponding acids. Lipases, esterases, and proteases accept a wide variety of esters and convert them to the corresponding acids, often in a highly cnantiosclectivc manner. Lipasc-cutulyzed kinetic resolutions are often practical for the preparation of optically active pharmaceuticals. 

Finally, the wide applicability and the experimental simplicity of the retro-Bingel reaction was evidenced in the isolation of pure enantiomers of C76, in the formation of methanofullerene compounds not accessible otherwise, such as ( )-75, and in the separation of constitutional isomers as well as of enantiomers of Cg4. The retro-cyclopropanation reaction seems to be generally selective, and still needs to be exploited in the preparation of unusual derivatives with controlled regiochemistry. 

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