Chemocatalytic Reactions

A major aspect to be overcome in the integration of biocatalysis and chemocatalysis through cascade conversions is the lack of compatibility of the various procedures, both mutually for the many chemocatalytic reactions and between the chemocatalytic and biocatalytic conversions. This is in contrast to biocatalytic reactions, which are, by far, more mutually compatible and can be much more easily combined in a multi-step cascade, as will be shown below. 

Up to the late 1990s, combined multi-step chemo-chemo conversions were restricted to a few catalytic examples. Apparently, there has been little effort or interest in developing a toolkit of chemocatalytic reactions that are mutually compatible with respect to reaction conditions. Consequently, chemocatalysts have not yet reached the same level of mutual compatibility as biocatalysts. Some recent examples prove, however, the potential power of chemo-chemo catalytic cascades. 

Scheme 23.13 Biocatalytic-chemocatalytic reaction sequence to produce a-sinensal from trans-nerolidol. 1 Aspergillus niger sp., Aspergillus niger ATCC 9142, Rhodococcus rubropertinctus DSM 43197 2 chemical conversion steps...

As a first comparison of a chemocatalytic reaction with an analogous enzyme-catalyzed reaction, we discuss the hydrolysis of CO2 by H2O to give HCO3 by the enzyme carbonic anhydrase. The reaction steps involved in the enzyme catalyzed mechanism will be compared with the chemocatalytic steps involved in the hydrolysis of acetonitrile by a Zn + containing zeolite as discussed on page 186 in Chapter 4. Similarly to the zeolite, the interior of the enzyme is hydrophobic except for the region close to the Zn + center. Its structure is shown in Fig. 7.6. 

In this review, oxidations of sulfides to sulfoxides have been divided into three subsections (i) stoichiometric reactions, (ii) chemocatalytic reactions, and (hi) biocatalytic reactions. 

Because of their importance, various methods have been reported for the oxidation of tertiary amines to N-oxides. The oxidations of amines are discussed below under the following headings (i) stoichiometric reactions, (ii) chemocatalytic reactions, and (iii) biocatalytic reactions. Finally we provide some examples where N-oxides are generated in situ as catalytic oxotransfer species in catalytic transformations. 

A major advantage of biosynthesis is the fact that many enzymatic conversions have been evolved, working under almost the same reaction conditions. With the present knowledge of many biosynthetic pathways we now also have the heritage of many powerful bioconversions that, by far, work at ambient temperature and pressure and in aqueous medium. In other words, it is time to fully exploit biosynthetic procedures and the possibility of combining them with appropriate or new chemocatalytic transformations in a cascade mode of conversion. 

As mentioned above, combined catalytic conversions through combinations of chemocatalytic conversions are not well represented. Although the organic chemist has an extensive synthetic and catalytic toolkit, large differences in reaction conditions often hinder the combined use of tools in one-pot conversions or in a cascade mode without recovery steps. 

Apart from the impressive recent examples given above, however, there has been too little focus thus far on developing a toolkit of chemocatalytic conversions that are as mutually compatible as enzymatic reactions are in nature (presently there are great differences in solvent, temperature, sensitivity to air and moisture, reactants). This confirms in fact the main difference in approach between organic synthesis and biosynthesis organic synthesis employs a maximum diversity in reagents and conditions while biosynthesis exploits subtlety and selectivity from a small range of materials and conditions (Fig. 13.7). 

Full exploitation of cascade conversions by the true integration of biocatalytic and chemocatalytic procedures requires merging human s chemistry with nature s reaction conditions the latter impose a much stricter constraint with respect to reaction temperature, pressure and medium (Fig. 13.16). Consequently, a renaissance in the field of synthetic organic chemistry and catalysis is necessary to develop novel conversion processes that meet biocatalytic conditions. 

Strictly speaking a catalytic cascade process is one in which all of the catalysts (enzymes or chemocatalysts) are present in the reaction mixture from the outset. A one-pot process, on the other hand, is one in which several reactions are conducted sequentially in the same reaction vessel, without the isolation of intermediates. However, not all of the reactants or catalysts are necessarily present from the outset. Hence, a cascade process is by definition a one-pot process, but the converse is not necessarily true. Clearly a cascade process is a more elegant solution, but a one-pot process that is not, according to the strict definihon, a cascade reaction may have equal practical uhlity. In this chapter we shall be primarily concerned with enzymatic cascade processes, but the occasional chemocatalytic step may be included where relevant and sometimes a sequential one-pot procedure may slip through the net. 

Bio-Electrocatalytic and Chemocatalytic Reduction Reactions 7.6.1 Oxidation Catalysis... 

An important lesson to be learned from this exposition is that chemocatalytic systems adapt their state to the reaction mixture composition or rather the chemical potential of the gas phase to which they are exposed. To predict catalysis properly one therefore has also to be able to predict the state of the catalyst surface during reaction. 

However, in spite of aU these advantages, there are also some challenges ahead when developing chemoenzymatic one-pot processes. A major challenge is to achieve compatibility between the different types of classic chemical and chemocatalytic processes on one hand (which are often preferentially carried out in organic media) and enzyme catalysis (for which water is typically the reaction medium of choice) on the other. Furthermore, high conversions and yields of the individual steps are crucial as well in order to reduce the complexity of the finally resulting reaction mixture. 

To start with the first option of such a chemoenzymatic process sequence, namely initial biotransformation and subsequent chemocatalytic or classical chemical reaction(s), an early example from the Gijsen and Wong [40] already in 1995 demonstrated a one-pot process for the synthesis of a cyclitol, which is based on an initial enzymatic aldol reaction of aldehyde 37 with 0-monophosphorylated dihy-droxyacetone, followed by a subsequent spontaneous cyclization via intramolecular Horner-Wadsworth-Emmons olefination reaction (Scheme 19.14). Furthermore, the resulting functionalized cyclopentene derivative 39 was deprotected in situ in the presence of an added phosphatase. By means of this one-pot three-step process, the desired trihydroxylated cyclopentene derivative 40 was formed, which was then further transformed via acetylation into the desired product 41 with an overall yield of 71%. A closely related process represents the combination of an enzymatic aldol reaction with a subsequent nitroaldol reaction (Henry reaction). Examples for such a type of process were developed independently by the Wong [41] and Lemaire [42] groups. 

Selective oxidations are key reactions in many chemical syntheses of intermediates for drugs and natural products. Besides the huge number of available chemical oxidation catalysts, nature also offers a vast array of redox enzymes catalyzing the biological counterparts of most chemical redox transformations. Thus, the typically high selectivity of the enzymes is a key advantage in applying biocatalytic oxidation steps over chemocatalytic steps. 

Three-or-more-step bio-chemo cascades comprising different types of catalysts are rare, which is related to incompatibility of many chemocatalytic steps with enzymes in terms of reaction parameters such as substrates, solvents, pH, temperature, etc. 

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