Chemzyme

The tridentate ligands C, L and M are effective catalysts for the enantioselective addition of dialkylzincs to aromatic aldehydes16,17. In particular, ligands L and M qualify as members of the chemical enzyme (chemzyme) class of synthetic reagents17, since they function in a predictable, clear-cut mechanistic way. As demonstrated by X-ray diffraction, the actual catalyst is a monomeric zinc chelate 2 formed in toluene at 50 C by reaction of L or M with one equivalent of diethylzinc. 

Oxazaborolidine catalysts behave like an enzyme in the sense of binding with both ketone and borane, bringing them close enough to undergo reaction and releasing the product after the reaction. Thus these compounds are referred to as chemzymes by Corey.78 The oxazaborolidines listed in Figure 6-6 are representative catalysts for the asymmetric reduction of ketones to secondary alcohols. 

Reactions involving bimetallic catalysts, either homo-dinuclear or hetero-bimetallic complexes, and chemzymes were highlighted by Steinhagen and Helmchen96c in 1996. Some examples are discussed in Chapter 2. Among these examples, Shibasaki s reports have been of particular significance.97 Shibasaki s catalyst is illustrated as 130, which consists of one central metal M1 (La+3, Ba+2, or A1+3), three other metal ions (M2)+ [(M2)+ can be Li+, Na+, or K+], and three bidentated ligands, such as (R)- or (iS )-BINOL. The catalyst exhibits both Lewis acidic properties because of the existence of central metal and the Lewis basic properties because of the presence of the outer metal ions. 

Catalyst Design from Theoretical Principles Chemzymes for Peptide Synthesis from Theozyme Blueprints... 

Corey has discussed the similarities and differences between synthetic and biological catalysts, coined the term chemzymes for the former, and discussed the connections between these microscopic catalysts and macroscopic robots. See Corey, E J. New Enantiose-lective Routes to Biologically Interesting Compounds Pure Appl. Chem 1990, 62,1209-1216. 

Muller, C. Wang, L-H. Zipse, H. Enzymes, Abzymes, Chemzymes-Theozymes In Transition State Modeling for Catalysis Truhlar, D. G. Morokuma, K., Eds. ACS Symposium Series 721 American Chemical Society Washington, DC, 1999 pp 61-73. 

Since the first two approaches are very well known and exploited, and excellent reviews and books on the topic are available [1], we will deal only with some of the most recent findings in chemical catalysis -excluding the Sharpless asymmetric epoxidation and dihydroxylation, to which the whole of Chapter 10 is devoted. Synthetic catalysts which mimic the catalytic action of enzymes, known as chemzymes, will be also considered. 

As an example of non-enzymatic catalyst using oxazaborolidines [10], Corey and his associates have described an efficient synthesis of (-i-)-l(S),5(R),8(S)-8-phenyl-2-azabicyclo[3.3.0]octan-8-ol (2.) and its enantiomer. The B-methyloxazaborolidine derivatives (3) of these amino alcohols are excellent catalysts -or chemzymes- for the enantioselective reduction of a variety of achiral ketones to chiral secondary alcohols [11]. 

Grafting a modified cinchona alkaloid to hexagonal mesoporous molecular sieve SBA-15 afforded catalyst (27) with excellent activity. 1-Phenyl-1-propene was converted to the corresponding diol in 98% yield (98% ee), while trans-stilbene yielded the desired product in 97% yield (99% ee) [92]. Other examples in this field are the utilization of microencapsulated osmium tetroxide by Kobayashi [93] and the application of continuous dihydroxylation mns in chemzyme membrane reactors described by Woltinger [94]. 

Some researchers have begun to explore the possibihty of combining transition metal catalysts with a protein to generate novel synthetic chemzymes . The transition metal can potentially provide access to novel reaction chemistry with the protein providing the asymmetric environment required for stereoselective transformations. In a recent example from Reetz s group, directed evolution techniques were used to improve the enantioselectivity of a biotinylated metal catalyst linked to streptavidin (Scheme 2.19). The Asn49Val mutant of streptavidin was shown to catalyze the enantioselective hydrogenation of a-acetamidoacrylic acid ester 46 with moderate enantiomeric excess [21]. 

To use membrane filtration for residence time decoupling the molecular weight of the chemical catalyst has to be increased, for example, by binding the catalyst to a homogeneously soluble polymer [4]. This allows for separation of reactants and catalysts by size. Due to their similarity to biological catalysts, the term chemzyme (chemical enzyme) [5, 6] has been coined for these polymer-enlarged but still homogeneously soluble chemical catalysts (Fig. 3.1.2) [7]. 

In analogy to the enzyme membrane reactors (EMRs) [8], a chemzyme membrane reactor (CMR) is used to retain a polymer-enlarged chemical catalyst of this kind. Tremendous progress could be made in the recycling of polymer-enlarged catalysts (Fig. 3.1.3) by employing different types of catalysts for both the enan-tioselective C-C bond formation and redox reactions. 

Fig. 3.1.3 Total turnover numbers (ttn) for different types of chemzymes 1, a,a-diphenyl-L-prolinol chemzyme ...

The highest ttn published to our knowledge so far for chemzymes (in the sense of polymer-enlarged chemical catalysts) is found in the transfer hydrogenation process catalyzed by Gao-Noyori s catalyst bound to a siloxane polymer (Fig. 3.1.3, 4) [13, 14]. In this transfer hydrogenation acetophenone is reduced to (S)-phenyl-ethanol using isopropanol as hydrogen donor. The product is produced in a CMR with 91% ee at a space-time yield of 578 g L d the ttn for the catalyst is 2633. 

While a number of dendritic catalysts have been described, catalyst recyclization in most cases is an unsolved problem. Diaminopropyl-type dendrimers bearing Pd-phosphine complexes have been retained by ultra- or nanofiltration membranes, and the constructs have been used as catalysts for allylic substitution in a continuously operating chemzyme membrane reactor (CMR) (Brinkmann, 1999). Retention rates were found to be higher than 99.9%, resulting in a sixfold increase in the total turnover number (TTN) for the Pd catalyst. 

Table 18.3 Reactions and their performance data in a chemzyme membrane reactor (CMR).

D. Reichert, A. Kuhnle, H.-P. Krimmer and K. Drauz, Julia-Colonna asymmetric epoxidation in a continuously operated chemzyme membrane reactor, Synlett 2002, (5), 707-710. 

The enzyme membrane reactor (EMR) is an established mode for running continuous biocatalytic processes, ranging from laboratory units of 3 mL volume via pilot-scale units (0.5-500 L) to full-scale industrial units of several cubic meters volume and production capacities of hundreds of tons per year (Woltinger, 2001 Bommarius, 1996). The analogous chemzyme membrane reactor (CMR) concept, discussed in Chapter 18, Section 18.4.5, is based on the same principles as the EMR but is far less developed yet. 

Researchers at Degussa AG focused on an alternative means towards commercial application of the Julia-Colonna epoxidation [41]. Successful development was based on design of a continuous process in a chemzyme membrane reactor (CMR reactor). In this the epoxide and unconverted chalcone and oxidation reagent pass through the membrane whereas the polymer-enlarged organocatalyst is retained in the reactor by means of a nanofiltration membrane. The equipment used for this type of continuous epoxidation reaction is shown in Scheme 14.5 [41]. The chemzyme membrane reactor is based on the same continuous process concept as the efficient enzyme membrane reactor, which is already used for enzymatic a-amino acid resolution on an industrial scale at a production level of hundreds of tons per year [42]. 

Scheme 9. Continuously operated epoxidation process in a chemzyme mem-bran reactor (figure reprinted with permission form Tsogoeva et al. 2002. Copyright 2002 Georg Thieme Verlag, Stuttgart, New York)...

The chemzyme membrane reactor is based on the same continuous process concept as the efficient enzyme membrane reactor, which has already been applied for enzymatic a-amino acid resolution on industrial scale at a production level of hundreds of tons per year (Drauz and Waldmann 2002 Wandrey and I iaschcl 1979 Wandrey et al. 1981 Groger and Drauz 2004). 

Membrane and membrane reactors have not been used in the industrial practice but find some application as modern separation technique [26] or in laboratory work about the application of chemzymes [27] or for enzymatic syntheses [28],... 

Fluorous biphase organometallic catalysis is now a well-established area and provides a complementary approach to aqueous and ionic biphase organometallic catalysis [50]. Since each catalytic chemical reaction could have its own perfectly designed catalyst (the chemzyme), the possibility to select from biphase systems ranging from fluorous to aqueous systems provides a powerful portfolio for catalyst designers. 

Continuous application of chemzymes in a membrane reactor asymmetric transfer of hydrogenation of acetophenone. Adv Synth Catal 343(6-7) 711-720. 

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