Inclusion compounds, chiral separation

In normal phases HPLC (polar columns), the least polar component of the mobile phase have priority to be encapsulated in the CD cavity and cannot be easily replaced by another compound. The chiral separation is the result of the structure of the analyte and the competitive reactions between the stationary CDs and the components of the mobile phase. A mobile phase of water-organic hquid mixture is used in RP HPLC and the selectivity is the result of the formation of an inclusion complex of CDs with the hydrophobic part of the analyte. Sometimes, especially in some HPLC with polar organic phases, instead of the inclusion complexation, chiral separations are mainly dependent on the analyte interaction with secondary hydroxyl groups on the outer rim of the CD [31]. 

Amylose inclusion compounds, 14 168 Amylosic phases, for chiral separations, 6 88-89... 

Lelievre and Gareil (31) studied chiral separations of nonsteroidal anti-inflammatory drugs (carprofen, flurbiprofen, indoprofen, ketoprofen, naproxen, propafenone, and suprofen) and determined the acidity and inclusion complex formation constants of these chiral compounds with different neutral CDs (/3-CD, HP-/3-CD, DM-/3-CD, TM-/3-CD, and HP-y-CD). In... 

Chiral recognition. The use of chiral hosts to form diastereomeric inclusion compounds was mentioned above. But in some cases it is possible for a host to form an inclusion compound with one enantiomer of a racemic guest, but not the other. This is called chiral recognition. One enantiomer fits into the chiral host cavity, the other does not. More often, both diastereomers are formed, but one forms more rapidly than the other, so that if the guest is removed it is already partially resolved (this is a form of kinetic resolution, see category 6). An example is use of the chiral crown ether 42 partially to resolve the racemic amine salt 43.121 When an aqueous solution of 43 was mixed with a solution of optically active 42 in chloroform, and the layers separated, the chloroform layer contained about... 

Many types of chiral stationary phase are available. Pirkle columns contain a silica support with bonded aminopropyl groups used to bind a derivative of D-phenyl-glycine. These phases are relatively unstable and the selectivity coefficient is close to one. More recently, chiral separations have been performed on optically active resins or cyclodextrins (oligosaccharides) bonded to silica gel through a small hydrocarbon chain linker (Fig. 3.11). These cyclodextrins possess an internal cavity that is hydro-phobic while the external part is hydrophilic. These molecules allow the selective inclusion of a great variety of compounds that can form diastereoisomers at the surface of the chiral phase leading to reversible complexes. 

The inclusion of a separate chapter on catalysed cyclopropanation in this latest volume of the series is indicative of the very high level of activity in the area of metal catalysed reactions of diazo compounds. Excellent, reproducible catalytic systems, based mainly on rhodium, copper or palladium, are now readily available for cyclopropanation of a wide variety of alkenes. Both intermolecular and intramolecular reactions have been explored extensively in the synthesis of novel cyclopropanes including natural products. Major advances have been made in both regiocontrol and stereocontrol, the latter leading to the growing use of chiral catalysts for producing enantiopure cyclopropane derivatives. 

The first separation of enantiomers was achieved by Gil-Av, Feibush, and Charles-Siglerf using capillary GC. Separation of enantiomers using CSPs involves hydrogen bonding, coordination, and inclusion. Typical chiral selectors include modified CDs, deiivatized amino acids, and terpene-derived metal coordination compounds. The scope and limitations, applications, and mechanistic considerations of chiral separation by GC have been reviewed by Schuiig and Francotte. ° ... 

Recently an improvement in this separation technique was reported, which seemed to indicate that enantioselective inclusion in the lattices of chiral hosts could be employed on a large scale. [11] When crystalline hosts such as R,R)-(-)-S (m.p. 196 °C), [12] (/ ,/ )-(-)-9 (m.p. 165 °C), [12] and (5,5)-(-)-10 (m.p. 128 °C) are suspended in hexane or water, chiral guest molecules form the same inclusion compounds as from solution. This is by no means self-evident, since inclusion compounds have different crystal lattices than the pure host crystals. Thus crystal/liquid reactions occur, and phase rebuildings analogous to those observed in gas/solid reactions [13] must take place. Yet this suspension technique is more selective and more effective than the initially developed solution technique. Numerous racemic alcohols like 11, -hydroxy esters like 12, epoxy esters like 13, and epoxy ketones like 14 were stirred a few hours with appropriate hosts (suspensions of 8, 9, and 10) and formed 1 1 complexes that could be filtered off in yields of > 85 % and with ee values of > 97 % (the complex of 12 and 9 formed in hexane only 80% ee in one step). Recrystallization of the inclusion... 

It is essential that no covalent bonds are formed between host and guest molecules, as, e.g., when diastereomeric salts are used for separation. The differentiation of the enantiomers is effected only by the chiral (spatial) environment in the crystal or in the interior of the host molecule, respectively, whereby hydrogen bridges and dipol-dipol interactions may increase the stability of the inclusion compounds ( coordinato-clathrates ). The different energy constants of the diastereomeric host/guest inclusion compounds which result, e.g., in different solubilities, can be used to isolate one of the enantiomers. 

Whereas the separation of racemates in the case of urea and TOT was achieved only by a chiral crystal lattice of the achiral or racemic host, respectively, the optically active cyclodextrins, available from the chiral pool, are able to differentiate a chiral guest within their intramolecular cavity. Therefore, they do not necessarily need the crystal lattice to form inclusion compounds. The guest is encapsulated, while is is in solution, too, if the guest by size and shape fits into the cavity of the specific cyclodextrin molecule (a- (26), P- (27), or y-cyclodextrins). 

Xiong et al. also demonstrated that the chiral 2D framework [Cu(PPhj)(A,A( -(2-pyridyl-(4-pyridyl methyl)-amine)),5] C10 (9), with triangular cavities, synthesized from achiral components, [Cu(MeCN)j(PPh3)J[C10 ] and N,N -(2-pyridyl-(4-pyridyl methyl)-amine) can enantioselectively include 2-butanol [76]. Spontaneous resolution produced crystalline inclusion compound 91.5(2-butanol), which was structurally characterized. They manually separated the enantiomorphic forms of 91.5(2-butanol) according to their CD spectra in solid state and evacuated at 100°C to collect enantiopure 2-butanol. Although this work provides an economical route to enantioselective separation of racemic small diols, the separation... 

Modification of the mobile phase or the stationary phase leads to new methods or techniques. For instance, inclusion of silver ions from silver nitrate mainly in the stationary phase is used in argentation LC. This method enables a better separation of analytes containing one or more double bonds. The double bond forms a complex with the silver ion and this complex has greater retention, giving the possibility of differentiating the retention of compounds with double bond(s). Modification of the stationary phase with chiral compounds enables separation of the chiral compounds, which are of primary importance nowadays. This technique is called chiral separation. 

A broad range of macrocyclic compounds can be used as chiral selectors for enantioselective HPLC. Besides synthetic crown ethers, derivatized cyclodextrins and cyclic antibiotics are also used as chiral stationary phases. Enantiomer separation employing these compounds is often based on host-guest interactions [15], whereby the cyclic molecules form an inclusion compound or an association complex with the analyte. 

Native molecules are not used frequently for chiral separations because of the dense structure of the oligo- and polysaccharide chains (of which some are helical). Polysaccharides are often derivatized to increase their enantioselec-tivity by enlarging their cavities. This structural change is important because the cavities contribute to the enantiose-lectivity by inclusion of the compounds. Enantiomers are thus separated based on their different affinities (hydrogen bonds, dipole-, tt-tt-, and van der Waals interactions) for the chiral cavities of the saccharides. In Figure 52.11, the structures of amylose, dextran, and heparin, a few polysaccharide selectors, are shown. 

---