Cascade conversions

Later, a nickel-catalyzed cascade conversion of propargyl halides and propargyl alcohol into a pyrone in water was reported. The reaction involved a carbonylation by CO and a cyanation by KCN (Eq. 4.55).96 Recently, Gabriele et al. explored a facile synthesis of maleic acids by palladium catalyzed-oxidative carbonylation of terminal alkynes in aqueous DME (1,2-dimethoxyethane) (Eq. 4.56).97... 

The general concept of cascade conversions is demonstrated by a representative selection of illustrative bio-bio, chemo-chemo, and bio-chemo catalytic examples on a laboratory scale as well as on a pilot- or industrial-scale. 

Special attention is given to the integration of biocatalysis with chemocatalysis, i.e., the combined use of enzymatic with homogeneous and/or heterogeneous catalysis in cascade conversions. The complementary strength of these forms of catalysis offers novel opportunities for multi-step conversions in concert for the production of speciality chemicals and food ingredients. In particular, multi-catalytic process options for the conversion of renewable feedstock into chemicals will be discussed on the basis of several carbohydrate cascade processes that are beneficial for the environment. 

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. 

Fig. 13.3 The potential power of cascade conversions to overcome thermodynamic hurdles in multi-step syntheses. Dotted circles are compounds in the reaction medium, closed circles are isolated, pure compounds [3, 4].

Although beyond the scope of this chapter on cascade conversions, metabolic engineering of microorganisms promises to be a powerful means of converting part... 

Fig. 13.5 Relative trends of the various types of cascade conversions over the years [4],...

Fig. 13.6 A m ulti-enzyme one-pot example cascade conversion of glycerol into a heptose sugar through consecutive phosphorylation, oxidation, aldol reaction and dephosphorylation [11],...

Another interesting case is the one-pot four-enzyme cascade conversion of glycerol into a heptose sugar on gram scale [11], in which a pH switch method is applied to temporarily turn off one of the enzymes involved (Fig. 13.6). The four consecutive enzymatic conversion steps in one and the same reactor, without separation of intermediates, consist of ... 

An impressive one-pot six-step enzymatic synthesis of riboflavine from glucose on the laboratory scale has been reported with an overall yield of 35-50%. Six different enzymes are involved in the various synthesis steps, while two other enzymes take care for the in situ cofactor regenerations [12]. This example again shows that many more multi-enzyme cascade conversions will be developed in the near future, as a much greater variety of enzymes in sufficient amounts for organic synthetic purposes will become available through rapid developments in genomics and proteomics. 

Fig. 13.8 An early example of combined enzyme and metal catalysis the one-pot cascade conversion of glucose into mannitol [17, 18].

Table 13.1 Kinetics of three types of catalysis that are in concert in the one-pot glucose-to-mannitol bio-chemo cascade conversion [19].

Fig. 13.12 In situ aldehyde formation coupled with an aldol condensation as the starting point for further cascade conversions [29, 30].

Fig. 13.16 Merging reaction parameters of chemocatalysis (blank area) to that of biocatalysis (black area) to exploit fully the scope of bio-chemo cascade conversions.

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. 

Apart from new catalytic methods, cascade conversions require new process technologies, such as in situ product recovery, reactor design, and compartmental-ization. In the long term, part of the present-day stoichiometric chemistry as well as bio- and chemocatalytic conversions in multi-step syntheses will gradually be replaced by cascade catalysis in concert, and full fermentations by cell factory design, or combinations thereof (Fig. 13.17). 

Thanks are due to Michiel Makkee, who developed the combi-mannitol process in the 1980s at the Delft University of Technology, as well as to Rob Schoevaart, Ar-jan Siebum and Arjan van Wijk for their recent research efforts on other cascade conversions at Leiden University, as part of the IBOS Programme (Integration of Biosynthesis and Organic Synthesis) of Advanced Chemical Technologies for Sustainability (ACTS) with industrial support from Friesland Foods and DSM. 

Concerning cascade conversions, fruitful discussions with and the interest of Flerman van Bekkum (Delft University of Technology), Johan Lugtenburg (Leiden University), Joop Roels and Alle Bruggink (DSM) are gratefully acknowledged. 

The same as above holds for the (by-product) glycerol, a really challenging molecule for cascade conversions in water. 

It may be concluded that zeolite and ordered mesoporous materials offer many opportunities to operate in two- and multi-step organic cascade conversions. Some fine examples exist already. 

A combination of multiple catalysis (Fig. 8.1) operating simultaneously could diminish the time and yield losses, which are associated with isolation and purification. Cascade or tandem catalytic transformations possess significant challenges as the conditions for all individual transformations could be different moreover, there could be interactions between the catalytic species and the active sites of a particular catalyst, which are not necessarily beneficial. The rate of processes should be harmonized, otherwise one type of catalysis could be, for instance, substrate starved, thus diminishing the benefits of the multiple operation. A variety of cascade conversions have been reported in the literature involving combinations of heterogeneous, homogeneous, and enzymatic catalysts. 

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