Steric resolution

For a variety of reasons, analytical determination of one or both of the optical isomers is needed. The optical methods that have been traditionally used to determine the extent of optical rotation in racemic mixtures seldom have the required sensitivity. The case in point is a typical problem of peptide synthesis where the racemization of an optical isomer may occur during the chemical reaction, and where it is highly important to know accurately the extent of such racemization. The chromatographic approach to stereoselective analyses is quite attractive resolution of the antipodes, coupled with the sensitivity of the modem chromatographic techniques, makes this approach quite unique. 

The chromatographic separation of optical isomers has been an active area of research for many years. While much pioneering work in this area was primarily done using GC, the most recent emphasis seems to be on HPLC [172-174]. Yet, GC may still be preferred in certain directions of the field, as discussed below. Another dimension to stereospecific chromatographic investigations might be added through the development of sensitive detectors of optical activity [175]. 

A major disadvantage of the diastereoisomeric approach is that the optically-active reagents must be available in a very pure form otherwise multiple products result, as evidenced by peaks from all possible combinations. Although some differences in the boiling points of the formed diastereoisomers can be appreciable, capillary columns are still generally preferred. 

Obviously, a more attractive approach to steric resolution has been a direct separation of enantiomers on optically-active stationary phases. This approach. 

The major breakthrough in the GC enantiomer separation has been the work of Bayer and associates [23,76], who synthesized a silicone-based chiral phase, stable up to 240°C. As shown in Fig. 3.14, a racemic mixture of 19 protein amino acids can be separated [23] on a glass capillary column coated with Chirasil-Val, a chiral polysiloxane phase. The phase was synthesized through coupling L-valine-tert-butylamide to a copolymer of dimethylsiloxane and carboxyalkylmethylsiloxane. 

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An increasing number of laboratories are now involved with the chromatographic resolution of the optical isomers. Although the general aspects of steric resolution and the necessary derivatization approaches were already discussed in the previous sections of this chapter, it should be stressed here that the capabilities of such methods have been primarily demonstrated with amino acids and small peptides. In particular, the method of enantiomeric labeling (adding the unnatural enantiomers into the analyzed mixtures [480] as internal standards) may prove to be quite important in various biochemical studies. 

The empirical rule described above for the enantiofacial differentiation in AE of primary allylic alcohols also applies to secondary allylic alcohols. The new aspect that needs to be taken into consideration in this case is the steric hindrance arising from the presence of a substituent (R4) at the carbon bearing the hydroxy group (Figure 6.3). This substituent will interfere in the process of oxygen delivery, making the oxidation of one enantiomer much faster than the reaction of the other one. The phenomenon is so acute that in practice kinetic resolution is often achieved (Figure 6.4) [27]. 

The surface forces apparatus (SEA) can measure the interaction forces between two surfaces through a liquid [10,11]. The SEA consists of two curved, molecularly smooth mica surfaces made from sheets with a thickness of a few micrometers. These sheets are glued to quartz cylindrical lenses ( 10-mm radius of curvature) and mounted with then-axes perpendicular to each other. The distance is measured by a Fabry-Perot optical technique using multiple beam interference fringes. The distance resolution is 1-2 A and the force sensitivity is about 10 nN. With the SEA many fundamental interactions between surfaces in aqueous solutions and nonaqueous liquids have been identified and quantified. These include the van der Waals and electrostatic double-layer forces, oscillatory forces, repulsive hydration forces, attractive hydrophobic forces, steric interactions involving polymeric systems, and capillary and adhesion forces. Although cleaved mica is the most commonly used substrate material in the SEA, it can also be coated with thin films of materials with different chemical and physical properties [12]. 

The resolution of the overall reaction into steps implied by the steric effect (above) has been achieved" for the oxidation of isopropanol. In 97% aqueous acetic acid a rapid reaction, ic2 x 1.25x10 l.mole . sec (15 °C, p = 0.183 Af NaC104), which is unaffected by deuteration, precedes the oxidation. Evidence for an intermediate has been reported for the oxidation of 1,1,1-tri-fluoro-2-propanol at very high acidities . 

Use of the relatively small cyclopropane ring drastically reduces the potential for deleterious steric bulk effects and adds only a relatively small lipophilic increment to the partition coefficient of the drug. One of the clever elements of the rolicyprine synthesis itself is the reaction of d,l tranylcypromine (67) with L-5-pyrrolidone-2-carboxylic acid (derived from glutamic acid) to form a highly crystalline diastereomeric salt, thereby effecting resolution. Addition of dicyclohexylcarbodiimide activates the carboxyl group to nucleophilic attack by the primary amine thus forming the amide rolicyprine (68). 

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