Enantioselective addition immobilized catalysts

Seebach has developed immobilization of TADDOL with a high degree of loading on porous silica gel and applications in enantioselective addition of Eq. 8.54. This catalyst leads to 85%... 

Seebach and co-workers copolymerized a dendritically modified TADDOL ligand with styrene (Figure 9). When associated with Ti(OiPr)4, the immobilized catalyst gave a very high ee (98%) for more than 20 runs in the enantioselective addition of diethylzinc to benzaldehyde95 96... 

The amino alcohol-catalyzed enantioselective addition of dialkylzincs to aldehydes, detailed in Chapter 5 (27), is accomplished with polymer catalysts containing DAIB, a camphor-derived auxiliary, and other chiral amino alcohols (28). Reactions that involve matrix isolation of the catalyst not only result in operational simplicity but also greatly facilitate understanding of the reaction mechanism. In solution, the catalytic chiral alkylzinc alkoxide derived from a dialkylzinc and DAIB exists primarily as dimer (27) however, when immobilized, its monomeric structure can be maintained. 

Soai et al. [62a] first reported the use of sihca gel or alumina as a heterogeneous support for chiral catalysts in the enantioselective addition of dialkylzincs to aldehydes. Chiral N-alkyhrorephedrines (R = Me, Et, n-Pr) were immobilized covalently on (3-chloropropyl)silyl-functionalized alumina or silica gel via a nucleophilic substitution. However, the catalytic activities and enantioselectivities were only moderate (24—59% ee) in comparison with those of homogeneous and polymer-... 

The immobilized catalyst (SiO2-[bmim]BF4-L-prohne, 70) displayed higher enantioselectivity (64% ee) with acceptable activity (51% yield) than the homogeneous conditions (60% ee, 62% yield) in the aldol reaction of acetone and benzaldehyde [71b]. Additionally, this system was even more efficient than the PEG-prohne-... 

Based on this concept, Seebach et al. developed the first example of TADDOL-cored dendrimers (Figure 4.41) immobilized in a PS matrix [116]. The resultant internally dendrimer-functionalized polymer beads were loaded with Ti(OiPr)4, leading to a new class of supported Ti-TADDOLate catalysts for the enantioselective addition of diethylzinc to benzaldehyde. Compared to the conventional insoluble polymer-supported Ti-TADDOLate catalysts, these heterogeneous dendrimer catalysts gave much higher catalytic activities, with turnover rates close to those of the soluble analogues. The polymer-supported dendrimer TADDOLs were recovered by simple phase separation and reused for at least 20 runs, with similar catalytic efficiency. 

A biocatalytic enantioselective addition of ammonia to a C=C bond of an afl-unsaturated compound, namely fumaric acid, makes the manufacture of L-aspar-tic acid, l-27, possible [30], This L-amino acid represents an important intermediate for the production of the artificial sweetener aspartame. The biocatalytic production process, which is applied on an industrial scale by, e.g., Kyowa Hakko Ko-gyo and Tanabe Seiyaku, is based on the use of an aspartate ammonia lyase [E.C.4.3.1.1] [31]. As a biocatalyst, an immobilized L-aspartate ammonia lyase from Escherichia coli [32, 33] as well as Brevibacterium flavum whole-cell catalysts [32 a, 34] have been applied successfully. 

The synthesis and characterization of a chiral amino-alcohol ((1R-2S)-ephedrine) immobilized on MCM-41 type mesoporous silicas (MTS Micelle Template Silicas) are described. The activity of these supported catalysts in the enantioselective addition of diethylzinc to benzaldehyde are reported, and compared with those obtained with the corresponding silica gel supported catalysts. The observed differences are discussed in terms of the nature of the grafting which depends on the support structure. 

Resin-bound amino alcohols also served to load diethyl zinc which then was employed in continuous flow additions to aromatic aldehydes [33]. Both diethyl zinc and p-chlorobenzaldehyde were added simultaneously at a slow rate under nitrogen into a cooled column loaded with functionalized polymer 6a, which afforded l-(p-chlorophenyl)-propanol with good enantiopurity (94% ee). The authors note that 58 mmol of the optically active alcohol were prepared in a continuous process by only employing 0.7 mmol of the immobilized catalyst. Similar results were reported for immobilized ephedrine, so it was concluded that continuous flow processes are often superior in efficiency and practicability compared to batch processes. In some cases, it was foimd that enantioselectivities were higher for convective flow processes than for the corresponding batch systems [34]. 

This approach has been extended to the conjugate addition of primary dialkylzincs to 2-aryl- and 2-heteroaryl-nitroolefins to obtain enantioenriched 2-arylamines. Dendritic styryl TADDOLs and polymer-bound Ti-TADDOLates have proved to be very practical chiral catalysts for the enantioselective addition of organozinc to aldehydes. Likewise, the immobilization of BfNOL by a cross-linking copolymerization of styryl derivatives has allowed several enantioselective Ti- and Al-Lewis acid-mediated additions to aldehydes. Dialkylzines obtained via an 1/Zn exchange or a B/Zn exchange have also been successfully used for the enantioselective additions to... 

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. 

There is one more report on the synthesis of a library of phosphorus ligands on solid phase. Waldmann et al. prepared a library of phosphoramidites on beads (Fig. 36.5), but these were only applied in enantioselective C-C-bond formation. In fact, as two ligands need to be bound to the catalyst, the use of an immobilized monodentate ligands should most likely be avoided unless the proximity between the ligands is sufficiently close. In addition, crosslinking by the metal may have a negative impact on the permeability of the polymer for the substrate. 

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