Enantiomer selection

The binding sites of most enzymes and receptors are highly stereoselective in recognition and reaction with optical isomers (J, 2 ), which applies to natural substrates and synthetic drugs as well. The principle of enantiomer selectivity of enzymes and binding sites in general exists by virtue of the difference of free enthalpy in the interaction of two optical antipodes with the active site of an enzyme. As a consequence the active site by itself must be chiral because only formation of a diasteromeric association complex between substrate and active site can result in such an enthalpy difference. The building blocks of enzymes and receptors, the L-amino acid residues, therefore ultimately represent the basis of nature s enantiomer selectivity. 

The /-coordination polyhedra of the chiral zwitterions 81-84 in the crystal were found to be distorted trigonal bipyramids, with the two carbon-linked oxygen atoms in the axial positions. This is illustrated for 81 in Fig. 10. The crystals of 81-84 are built up by pairs of (A)- and (A)-enantiomers. Selected geometric parameters for these compounds are listed in Table XI. As can be seen from these data, the axial Si-O distances [1.749(2)-1.801(4) A] are significantly longer than the equatorial ones [1.683(2)-1.7182(14) A]. The Si-C distances are 1.866(6)-1.897(2) A. 

As demonstrated by single-crystal X-ray diffraction, the /-coordination polyhedra of 85-87 are distorted trigonal bipyramids, with each of the axial positions occupied by the oxygen atoms. This is shown for compound 86 in Fig. 11. In all cases, the crystals are formed from pairs of (A)- and (A)-enantiomers. Selected geometric parameters for 85-87 are listed in Table XIII. As can be seen from the Si-O [1.8004(10)-1.829(6) A], Si-N [1.741(7)-1.764(6) A], and Si-C distances [1.867(8)-1.915(2) A], the A/02N2C frameworks of 85-87 are built up by five normal covalent bonds and do not involve a bonding system in the sense of the 4+1 coordination usually observed for pentacoordinate silicon species with Si-N bonds. 

The chiral recognition of enantiomers can be of three types (i) desionoselective, (ii) ionoselective, or (iii) duoselective, in which only the non-dissociated, the dissociated or both forms (charged and uncharged), respectively, of the enantiomers selectively interact with the chiral selector. In the case of ionoselective and duoselective interactions, a reversal of the migration order of the enantiomers is theoretically possible by the appropriate selection of CD concentration and the pH of the BGE. The addition of organic modifier to the BGE can also change selectivity by modifying the solubility of the chiral selector and/or of the solute, the complex equilibrium, the conductivity of the BGE and the electroendos-motic flow (EOE) level. Several other factors, such as the temperature, the type and the concentration of the BGE, and the level of the EOE can influence the separation. 

Figure 3.25 Racemic dynamic combinatorial library targeting (-)-adenosine. Left Racemic porline containing dipeptide library building block. Middle Various enantiomeric oligomers formed through reversible hydrazone exchange. Right The SS enantiomer selected upon equilibration with (-)-adenosine.

As it is well known, enzyme catalyzed reactions can result in high enantiomer selectivity but the use of enzymes is limited by their properties and expressivity. However, enzymes have been utilized in some applications, such as the degradation of /7-chlorophenol [24] beeause of the small amount of enzyme needed under eontinuous flow. 

Performing a systematic comparison of lipase-catalyzed kinetic resolutions of several seeondaiy aleohols in continuous flow mode (Figure 7) and shake flask batch mode using immobilized and non-mobilized lipases was reported by Csajagi and eo-workers [25]. The results indieated that immobilized as well as lyophilized powder forms of liphases can be effeetively used in eontinuous flow mode kinetie resolutions of raeemic alcohols in non-aqueous solvent systems. The produetivity of the lipases was higher in continuous flow reactors than in batch mode systems, whereas the enantiomer selectivities were similar. 

Enantiomer-selective deactivation of racemic catalyts by a chiral deactivator affects the enantiomer-selective formation of a deactivated catalyst with low catalytic activity (Scheme 8.2). Therefore, it is crucial for a chiral deactivator to interact with one enantiomer of a racemic catalyst (Scheme 8.2a). As the chiral deactivator does not interact with the other enantiomer of racemic catalyst, the enantiomeri-cally enriched product can be obtained. Therefore, the level of enantiomeric excess (% ee) could not exceed that attained by the enantiopure catalyst. On the other hand, nonselective complexation of a chiral deactivator would equally and simultaneously deactivate both catalyst enantiomers, thereby yielding a racemic product (Scheme 8.2b). Although this strategy tends to use excess chiral poison relative to the amount of catalyst, it offers a significant advantage in reducing cost and synthetic difficulty since readily available racemic catalysts and often inexpensive chiral poisons are used. 

A similar enantiomer-selective activation has been observed for aldol " and hetero-Diels-Alder reactions.Asymmetric activation of (R)-9 by (/f)-BINOL is also effective in giving higher enantioselectivity (97% ee) than those by the parent (R)-9 (91% ee) in the aldol reaction of silyl enol ethers (Scheme 8.12a). Asymmetric activation of R)-9 by (/f)-BINOL is the key to provide higher enantioselectivity (84% ee) than those obtained by (R)-9 (5% ee) in the hetero-Diels-Alder reaction with Danishefsky s diene (Scheme 8.12b). Activation with (/ )-6-Br-BINOL gives lower yield (25%) and enantioselectivity (43% ee) than the one using (/f)-BINOL (50%, 84% ee). One can see that not only steric but also electronic factors are important in a chiral activator. 

Racemic alcohol Ketone product Main remaining enantiomer Selectivity /%... 

The catalyst exhibited high enantiomer selectivity in the reaction of the six-membered cyclic acetate roc-lab with KSAc on a 2.5 mmol scale. This led to the isolation of the thioacetate 19aa with 97% ee in 48% yield and the acetate ent-lab with >99% ee in 43% yield (entry 8). The reaction came to a practically complete halt after 51% conversion of the substrate. In order to determine the selectivity factor S, the kinetic resolution of roc-lab was repeated and the ee values of the acetate and thioacetate were monitored over the whole course of the reaction (Fig. 

The values given in column 3 of Table IV were obtained from the data in column 2 ((2) and (6)]. A comparison of the results for 14 and 15 indicates that the introduction of methyl groups at sites 4 and 5 (see 12), leading to central chirality R at both carbon atoms, is the main cause of enantiomer selectivity. This is in agreement with the only slightly different enantiomer selectivity of 16 relative to 15. As expected, the effect of 17 is reversed by 18. Although valinomycin 1 is chiral, no enantiomer selectivity was detectable (see Table IV). The potentiometrically determined enantiomer selectivity AEMF is correlated to the transport selectivity [(2), (6), (10), and (11)]... 

TABLE IV. Enantiomer Selectivity of Ligands 1 and 14 to 18 Determined by Poten-tiometry1 and by Electrodialysis1 ... 

Zapata-Sudo G etal Is comparative cardiotoxicity of S(-) andR(+) bupivacaine related to enantiomer-selective inhibition of L-type Ca2+ channels Anesth Analg 2001 92 496. [PMID 11159257]... 

The first example of kinetic resolution catalyzed by an organometallic compound was the partially enantiomer-selective polymerization of racemic propylene oxide induced with a diethylzinc optically active alcohol system (50). 

In the presence of chiral polymerization catalysts, enantiomeric monomers are consumed at different rates (Scheme 75). Enantiomer-selective polymerization of racemic propylene oxide catalyzed by a diethylzinc-(-f)-bomeol system is a classical example of such kinetic resolution H 176). The polymeric product has an [a]D of +7.4°. The mechanism... 

Scheme 126 shows the enantioselective cyclization of 1,3-dichloro-2-propanol to form partially resolved epichlorohydrin, which is achieved by combining small amounts of a chiral Schiff-base Co(II) complex and potassium carbonate (305). The same chiral Co(II) catalyst allows enantiomer-selective carbonation of propylene bromohydrin to afford propylene carbonate in fair chemical and optical yields (306). 

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