Libraries of catalysts

Catalyst preparation. One library of catalysts, indicated below with the name Library 1, was prepared by wet impregnation to have a range of concentrations... 

Although the library of catalysts was actually very small, this combinatorial approach was shown to work surprisingly well. It remains to be seen if truly high throughput can be put into practice, which would require on-line methods for the detection and characterization of the particles bearing the polymers. 

We have discussed the structure and synthesis of the library of molecular catalysts for polymerization in Section 11.5.1. In the present section we want to take a closer look at the performance of the catalyst library and discuss the results obtained [87], The entire catalyst library was screened in a parallel autoclave bench with exchangeable autoclave cups and stirrers so as to remove the bottleneck of the entire workflow. Ethylene was the polymerizable monomer that was introduced as a gas, the molecular catalyst was dissolved in toluene and activated by methylalumoxane (MAO), the metal to MAO ratio was 5000. All reactions were carried out at 50°C at a total pressure of 10 bar. The activity of the catalysts was determined by measuring the gas uptake during the reaction and the weight of the obtained polymer. Figure 11.40 gives an overview of the catalytic performance of the entire library of catalysts prepared. It can clearly be seen that different metals display different activities. The following order can be observed for the activity of the different metals Fe(III) > Fe(II) > Cr(II) > Co(II) > Ni(II) > Cr(III). Apparently iron catalysts are far more active than any of the other central metal... 

Figure 11.40 Overview of the entire library of catalysts based on the metals Fe(ll) and (III), Ni(ll), Co(ll) and Cr(ll) and (III). The activity on the z axis is displayed as grams of polyethylene per millimole of catalyst per hour. The dicarbonyl backbones are visualized as color encoding the amine substituents are encoded as number on the y axis.

Uozumi has explored a series of (25, 4/ )-4-hydroxyproline-derived 2-aryl-6-hydroxy-hexahydro-lFf-pyrrolo[l,2-c]imidazolones as potential alternatives to cinchona alkaloid-based catalysts for the alcoholative ASD of meio-anhydrides (Fig. 16) [226]. Uozumi screened a small library of catalysts prepared by a four-step, two-pot reaction sequence from 4-hydroxyproline in combination with an aldehyde and an aniline. The most selective member, compound 67, mediated the methanolytic ASD of cw-hexahydrophthalic anhydride in 89% ee when employed at the 10 mol% level for 20 h at -25 °C in toluene [226]. 

In 1998, Jacobsen and Sigman demonstrated that peptide-based ligands, such as the one shown in Eq. (1), can be used to access optically enriched amino nitriles. The identity of the optimal catalyst was determined through examination of parallel libraries of catalyst candidates [2], Later, it was demonstrated that this protocol may be extended to additions to ketoimines, affording tertiary amino nitriles in high enantioselectivities [3]. 

In no time the concept of combinatorial chemistry has become a valuable tool in the process of drug discovery. The popularity of this approach is based on the possible synthesis and screening of libraries containing millions of compounds. In the field of asymmetric catalysis, combinatorial methods could help to discover new efficient catalysts as the number of possible metal-ligand combinations is immense. In an ideal case a substrate would be screened against a library of catalysts or a library of substrates against one catalyst to find out the most efficient conditions for the reaction in question. Up to now this has been essentially a utopian idea, but the first examples of the efficient detection of new catalysts and their reactions using combinatorial methods were recently described in the literature [1]. 

Figure 9.46 Monomer sets M1-M3 used in the synthesis of the SP peptidomimetic encoded library of catalysts L34.

TABLE 9.11 Efficiency of Library Individuals 9.129-9.134 from Screening of the SP Pool Encoded Peptidomimetic Library of Catalysts L34 as Acylation Catalysts... 

Different ligands and metal complexes can be combined in different ways to generate a library of catalysts. Since the reactions do not involve molecular hydrogen and are insensitive to air oxidation, it is a simple matter to set-up an experiment to screen catalysts against a substrate to find the most active and enantiose-lective for the reaction, and this is done conveniently using a robot. 

The number and the closely similar pfCa values of His residues made it difficult to assign the catalytic activity to specific residues. In a series of polypeptides histidines were partially replaced by the residues used in the sequence of SA-42 to form a library of catalysts derived from KO-42 but with less complexity [12, 23], Essentially, the catalytic site of KO-42 was divided into its components and analyzed. It was assumed that the sequence modifications had only minor effects on structure and that the rate constants of the resulting peptides could be directly compared. The peptide MN, closely related to KO-42 but with His-26, His-30 and His-34, reverted to the SA-42 residues Gin, Gin and Ala, catalyzed the reaction at pH 5.1 and 290 K with an efficiency that was less than 10% of that of the KO-42 catalyzed reaction. The peptide JN, in which His-11, His-15 and His-19 were reverted to Ala, Gin and Lys, exhibited a second-order rate constant that was 20% of that of KO-... 

The catalyst for cleavage of peptide deformylase was searched with a library of catalyst candidates synthesized by the Ugi reaction (Scheme 2) (134). In this multicomponent condensation reaction, the mixture of a carboxylic acid, an amine, an aldehyde, and an isocyanide produces an iV-acyl amino acid amide. The catalyst candidates, therefore, are iV-acylamino acid amides containing various polar and nonpolar pendants as well as the Co(III) complex of cyclen. The Co(III) complex of cyclen (135) was chosen as the proteolytic center in view of the results described in Section V.A. Cyclen with three secondary amines protected with ferf-butyloxycarbonyl (t-boc) groups was incorporated in either the carboxyl or the amine component of the Ugi reaction. Later, the t-boc groups were removed and Co(III) ion was inserted to the cyclen portion. 

Scheme 2. Synthesis of members of a chemical library of catalyst candidates for cleavage of peptide deformylase. (TFA =Trifluoroacetic acetic acid f-boc = tert-butyloxycarbonyl) [Adapted from Ref. (132).]...

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