Chiral resolution, considerations

See Section IV.1 for alternative methods of chiral resolution. Partial chemical hydrolysis of proteins and peptides with hot 6 M HC1, followed by enzymatic hydrolysis with pronase, leucine aminopeptidase and peptidyl D-amino acid hydrolase, avoids racemiza-tion of the amino acids281. The problems arising from optical rotation measurements of chiral purity were reviewed. Important considerations are the nonideal dependence of optical rotation on concentration and the effect of chiral impurities282. 

For the purposes of this treatise, the definition of asymmetric synthesis is a modification of that proposed by Morrison and Mosher [1] and as such will be applied to stereospecific reactions in which a prochiral unit in either an achiral or a chiral molecule is converted, by utility of other reagents and/or a catalytic antibody, into a chiral unit in such a manner that the stereoisomeric products are produced in an unequal manner. As such, the considerable body of work devoted to antibody-catalysis of stereoselective reactions including chiral resolutions, isomerizations and rearrangements are considered to be beyond the scope of this discussion. For information regarding these specific topics and more general information regarding the catalytic antibody field the following papers... 

The complex structures of proteins, which have different types of groups, loops and bridges, are responsible for the chiral resolution of racemic compounds. Therefore, a small change in the protein molecule results in a drastic change in enantioselectivity. A few reports are available that indicate that different protein structures are responsible for different chiral resolution capacities. One of the advantages of protein-based CSPs is that chiral chromatography is carried out under the reversed phase mode - that is, aqueous mobile phases are frequently used - and, therefore, there is considerable scope for optimizing chiral resolution. 

Catalytic kinetic resolution can be the method of choice for the preparation of enantioenriched materials, particularly when the racemate is inexpensive and readily available and direct asymmetric routes to the optically active compounds are lacking. However, several other criteria-induding catalyst selectivity, efficiency, and cost, stoichiometric reagent cost, waste generation, volumetric throughput, ease of product isolation, scalability, and the existence of viable alternatives from the chiral pool (or classical resolution)-must be taken into consideration as well... 

Enantioselective separation by supercritical fluid chromatography (SFC) has been a field of great progress since the first demonstration of a chiral separation by SFC in the 1980s. The unique properties of supercritical fluids make packed column SFC the most favorable choice for fast enantiomeric separation among all of the separation techniques. In this chapter, the effect of chiral stationary phases, modifiers, and additives on enantioseparation are discussed in terms of speed and resolution in SFC. Fundamental considerations and thermodynamic aspects are also presented. 

The concentration of the chiral selector, for instance, has considerable influence on the mobility and separation of the enantiomers. Optical resolution varies with the chiral selector concentration and reaches a maximum value at a given optimum concentration. Wren and Rowe proposed a model that describes the influence of the selector concentration on selectivity, and which was extended by Vigh s group ° by including the pH as a separation parameter for weak acidic enantiomers. The latter model shows that the chiral selectivity is determined by the complex s relative mobility, the CD concentration, the degree of dissociation... 

Like other methods of asymmetric synthesis, the solid-state ionic chiral auxiliary procedure has an advantage over Pasteur resolution in terms of chemical yield. The maximum amount of either enantiomer that can be obtained by resolution of a racemic mixture is 50%, and in practice the yield is often considerably less [47]. In contrast, the ionic chiral auxiliary approach affords a single enantiomer of the product, often in chemical and optical yields of well over 90%. Furthermore, either enantiomer can be obtained as desired by simply using one optical antipode or the other of the ionic chiral auxiliary. 

Enantiopure epoxides and vicinal diols are important versatile chiral building blocks for pharmaceuticals (Hanson, 1991). Their preparation has much in common and they may also be converted into one another. These chirons may be obtained both by asymmetric synthesis and resolution of racemic mixtures. When planning a synthetic strategy both enzymic and non-enzymic methods have to be taken into account. In recent years there has been considerable advance in non-enzymic methods as mentioned in part 2.1.1. Formation of epoxides and vicinal diols from aromatics is important for the break down of benzene compounds in nature (See part 2.6.5). 

At the end of the resolution it is essential that the optical purity of the product is checked using one of the methods described in Section A.3. In addition, routine consideration should be given to the possibility of racemizing the undesired enantiomer and recycling the material in a chirally economic way. 

Amines containing a chiral carbon atom in the aliphatic residue attached to the nitrogen atom are of considerable interest to the coordination chemist as, when coordinated, these ligands can induce chirality in the metal-ligand chromophore. The recent compilation27 on the methods of optical resolution of more than 1000 amines and amino alcohols (Chapter 20.3) is an excellent resource. 

This article is confined to organo-transition-metal compounds having chiral metal atoms whose optical activity has been demonstrated. Only those compounds are discussed in detail for which there is a choice with respect to the metal configuration and for which a separation or at least an enrichment of isomers with opposite metal configuration has been achieved. After the treatment of such topics as optical resolution, optical purity, optical stability, optical induction, stereochemistry of reactions, relative and absolute configurations, Table I (Section XVII) collects the information available for the compounds under consideration. 

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