Enantioselective support

Capillary Electrophoresis with Enantioselective Supporting Electrolytes... 

Most importantly, enantioselectivity benefits considerably from the use of water. This effect could be a result of water exerting a favourable influence on the cisoid - transoid equilibrium. Unfortunately, little is known of the factors that affect this equilibrium. Alternatively, and more likely, water enhances the efficiency of the arene - arene interactions. There is support for this observation"" . Since arene-arene interactions are held responsible for the enantioselectivify in many reactions involving chiral catalysts, we suggest that the enhancement of enantioselectivity by water might well be a general phenomenon. 

In cases where Noyori s reagent (see p. 102f.) and other enantioselective reducing agents are not successful, (+)- or (—)-chlorodiisopinocampheylborane (Ipc BCl) may help. This reagent reduces prochiral aryl and tert-alkyl ketones with exceptionally high enantiomeric excesses (J. Chandrasekharan, 1985 H.C. Brown, 1986). The initially formed boron moiety is usually removed hy precipitation with diethanolamine. Ipc2BCl has, for example, been applied to synthesize polymer-supported chiral epoxides with 90% e.e. from Merrifield resins (T. Antonsson, 1989). 

Enantioselective transport processes can be achieved either with solid or liquid membranes (Fig. 1-5). In this latter case, the liquid membrane can be supported by a porous rigid structure, or it can simply be an immiscible liquid phase between two solutions with the same character (aqueous or nonaqueous), origin and destination... 

In general, high selectivities can be obtained in liquid membrane systems. However, one disadvantage of this technique is that the enantiomer ratio in the permeate decreases rapidly when the feed stream is depleted in one enantiomer. Racemization of the feed would be an approach to tackle this problem or, alternatively, using a system containing the two opposite selectors, so that the feed stream remains virtually racemic [21]. Another potential drawback of supported enantioselective liquid membranes is the application on an industrial scale. Often a complex multistage process is required in order to achieve the desired purity of the product. This leads to a relatively complicated flow scheme and expensive process equipment for large-scale separations. 

As the main disadvantage of liquid membrane systems is the instability over a longer period of time, another approach would be to perform separation through a solid membrane [22]. Enantioselective polymer membranes typically consist of a nonse-lective porous support coated with a thin layer of an enantioselective polymer. This... 

As described above, the application of classical liquid- liquid extractions often results in extreme flow ratios. To avoid this, a completely symmetrical system has been developed at Akzo Nobel in the early 1990s [64, 65]. In this system, a supported liquid-membrane separates two miscible chiral liquids containing opposite chiral selectors (Fig. 5-13). When the two liquids flow countercurrently, any desired degree of separation can be achieved. As a result of the system being symmetrical, the racemic mixture to be separated must be added in the middle. Due to the fact that enantioselectivity usually is more pronounced in a nonaqueous environment, organic liquids are used as the chiral liquids and the membrane liquid is aqueous. In this case the chiral selector molecules are lipophilic in order to avoid transport across the liquid membrane. 

Polymer-supported amino alcohols and quaternary ammonium salts catalyze the enan-tioselective addition of dialkylzinc reagents to aldehydes (Table 31). When the quaternary ammonium salt F is used in hexane, it is in the solid state, and it catalyzes the alkylation of benzaldehyde with diethylzinc in good chemical yield and moderate enantioselectivity. On the other hand, when a mixture of dimethylformamide and hexane is used as solvent, the ammonium salt is soluble and no enantioselectivity is observed21. 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

Other metals can also be used as a catalytic species. For example, Feringa and coworkers <96TET3521> have reported on the epoxidation of unfunctionalized alkenes using dinuclear nickel(II) catalysts (i.e., 16). These slightly distorted square planar complexes show activity in biphasic systems with either sodium hypochlorite or t-butyl hydroperoxide as a terminal oxidant. No enantioselectivity is observed under these conditions, supporting the idea that radical processes are operative. In the case of hypochlorite, Feringa proposed the intermediacy of hypochlorite radical as the active species, which is generated in a catalytic cycle (Scheme 1). 

The first enantioselective synthesis of cis- and trans- 3-hydroxyflavanones is based on the Lewis-acid-catalysed reaction of phenylmethanethiol with chalcone epoxides <96CC2747>. Further support for the intermediacy of epoxides in the Algar-Flynn-Oyamada flavone synthesis has been provided by the isolation of epoxides in the corresponding preparation of 3-hydroxy-2-phenylquinol-4-ones <96JCS(P2)269>. 

A polymer-supported version of our optimal ligand was also developed [52]. Its preparation involves attachment of aziridine carbinols to polymer-bound triphenylchloromethane (Scheme 40). This polymer-bound ligand 53 was almost equally effective in the enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes with ee s ranging from 77-97% for the latter type of substrate [52]. It is of practical interest that this polymer-supported ligand could be reused without losing much of its efficiency. 

In the last 20 years a great deal of effort has been focused towards the immobilization of chiral catalysts [2] and disparate results have been obtained. In order to ensure the retention of the valuable chiral hgand, the most commonly used immobihzation method has been the creation of a covalent bond between the ligand and the support, which is usually a solid, hi many cases this strategy requires additional functionalization of the chiral hgand, and this change - together with the presence of the very bulky support - may produce unpredictable effects on the conformational preferences of the catalytic complex. This in turn affects the transition-state structures and thus the enantioselectivity of the process. 

The solids were used as catalysts in the benchmark cyclopropanation reaction between styrene and ethyl diazoacetate (Scheme 7). As far as the nature of the clay is concerned, laponite was foimd to be the best support for the catalytic complexes. The best enantioselectivity results (Table 7) were obtained with ligand 6b (69% ee in trans cyclopropanes and 64% ee in cis cyclopropanes) but the recovered solid showed a lower activity and enantioselectivity, which was attributed to partial loss of the chiral ligand from the support. In general, the use of the three chiral ligands led to enantioselectivity results that were intermediate between those obtained in homogeneous phase with CuCl2 and Cu(OTf)2 as catalyst precursors. This seemed to indicate that the sohd behaved as a counterion with an intermediate coordinating abihty to the copper centers. 

Table 7. As can be seen, both Dowex and Deloxan led to poor enantioselec-tivities, which further decreased after catalyst recovery. Better results, which are comparable with those obtained in homogeneous phase, were obtained with Nation (Table 7) [53], although it was necessary to carry out the reaction at 60 °C due to the low copper content in the soHd. This low copper level is a consequence of the low surface area of this polymer (< 0.02 m g ) and, for this reason, a nafion-silica nanocomposite was used as the support [53]. With this catalyst, the reaction took place at room temperature and with similar enantioselectivity (Table 7).

It seems reasonable to believe that this problem could be overcome by studying more coordinating ligands with the same structural features. Very recently, it has been demonstrated [56] that the use of iminobis(oxazolines) (Fig. 18) leads to better enantioselectivities and recoverable catalysts, both with laponite and nalion-silica supports (Table 8). Theoretical calculations are consistent with the stronger coordinating ability of iminobis(oxazolines) being the origin of these results [57]. 

It is concluded from these results that with this kind of non-C2 symmetric ligand (that led necessarily to poor enantioselectivities in homogeneous phase), it is possible to exploit support effects to change the trans/cis selectivity and to improve the enantioselectivity. This is demonstrated for the trans-cyclopropanes obtained with ligand 10a in styrene. Due to the relative disposition of the ester and phenyl groups in the transition state, support ef-... 

---