Blaser reaction

Blaser and Spencer used aroyl halides in place of aryl halides, with aroyl chlorides being of specific interest as ubiquitous, relatively cheap compounds ( Blaser reaction ) [24], This latter reaction is normally conducted in aromatic solvents phosphines are not used here as catalyst ligands since they fully inhibit the reaction. In the same way, benzoic acid anhydrides can be used as the aryl source in combination with PdCl2 and catalytic amounts of NaBr [79]. In this reaction, one of the arenes is used in the coupling reaction by elimination of CO, whereas the other benzoate serves as the base. The benzoic acid thus formed can easily be recycled into the anhydride. The use of aryl and vinyl triflates according to Cacchi [25] and Stille [26] extends the scope of the Heck coupling to carbonyl compounds phenol derivatives act via triflate functionalization as synthetic equivalents of the aryl halides. The arylation of cyclic alkenes [27], electron-rich vinyl ethers [28], and allylic alcohols [29] is accessible through Heck reactions. Allylic alcohols yield C-C-saturated carbonyl compounds (aldehydes) for mechanistic reasons (y9-H elimination), as exemplified in eq. (6). 

Scheme 5.1 Four synthetic routes via A-via D to ethyl (R)-2-hydroxy-4-phenylbutyrate (HPB-Ester) according to Blaser eta/. (Figure 3 in reference [10]). In each route, one reaction is a reduction step which is performed using biochemical (A and B) and chemical (C and D) methods, respectively.

Blaser, H.-U., Indolese, A.,Naud, F. etal. (2004) Industrial R D on catalytic C—C and C—N coupling reactions apersonal account on goals, approaches and results. Advanced Synthesis and Catalysis, 346 (13-15), 1583-1598. 

F. Spindler, B. Pugin, H.-P. Jalett, H.-P. Buser, U. Pittelkow, H.-U Blaser, A Technically Useful Catalyst for the Homogeneous Enantioselective Hydrogenation of N-Aryl Imines A Case Study, in Catalysis of Organic Reactions (Ed. R. E. Maltz), Dekker, New York, 1996, pp. 153-168. 

Mayer C. Appenzeller U. Seelbach H. Achatz G. Oberkofler H. Breitenbach M. Blaser K. Crameri R Humoral and cell-mediated autoimmune reactions to human acidic ribosomal P2 protein in individuals sensitized to Aspergillus fumigatus P2 protein. J Exp Med 1999 189 1507-1512. 

In catalysis, adsorbed CO may retard some reactions such as olefin hydrogenation, fuel cell conversion, and enantioselective hydrogenation. For instance, Lercher and coworkers observed the deactivation of Pt/Si02 in the liquid-phase hydrogenation of crotonaldehyde, and ascribed this deactivation to the decomposition of crotonaldehyde on platinum surface to adsorbed CO [138]. Blaser and coworkers found that the addition of a small amount of formic acid decreases the rate of liquid-phase hydrogenation of ethyl pyruvate on cinchonidine-modified Pt/Al203 catalyst, which they explained as the decomposition of formic acid on the catalyst to adsorbed CO. Interestingly, the addition of acetic acid does not decrease the reaction rate, but whether acetic acid decomposes on the catalyst as formic acid does was not mentioned [139]. 

Rasch Angew. Chem. Int. Ed. Engl. 1994, 33, 2144. (c) H.-U. Blaser, B. Pugin In Chiral Reactions in Heterogeneous Catalysis,... 

H.U. Blaser, M. Lotz, F. Spindler, "Asymmetric Catalytic Hydrogenation Reactions with Ferrocene Based Diphosphine Ligands" in Handbook of Chiral Chemicals, 2nd Edition, D. J. Ager (Ed.), CRC Press, Boca Raton 2005... 

The turnover number is not used frequently in biocatalysis, possibly as the molar mass of the biocatalyst has to be known and taken into account to obtain a dimensionless number, but it is the decisive criterion, besides turnover frequency and selectivity, for evaluation of a catalyst in homogeneous (chemical) catalysis and is thus quoted in almost every pertinent article. Another reason for the low popularity of the turnover number in biocatalysis, apart from the challenge of dimensionality, is the focus on reusability of biocatalysts and the corresponding greater emphasis on performance over the catalyst lifetime instead of in one batch reaction as is common in homogeneous catalysis (Blaser, 2001). For biocatalyst lifetime evaluation, see Section 2.3.2.3. 

The asymmetric hydrogenation of aryl ketones is an important step in the synthesis of many pharmaceutical intermediates. Blaser and co-workers showed that Ru complexes with Fe-cyclopentadienyl sandwich complexes are good catalysts for this reaction [63]. Figure 1.26 shows the different substrates tested, along with the time, conversion, and substrate/catalyst ratio. Using these data, calculate the catalyst TON and TOF in each case. 

If a catalyst is an insoluble solid, that is, a heterogeneous catalyst, it can easily be separated by centrifugation or filtration. In contrast, if it is a homogeneous catalyst, dissolved in the reaction medium, this presents more of a problem. This offsets the major advantages of homogeneous catalysts, such as high activities and selectivities compared to their heterogeneous counterparts (see Table 7.1). However, as Blaser and Studer have pointed out [6], another solution is to develop a catalyst that, at least for economic reasons, does not need to be recycled. 

Appenzeller U, Mayer C, Menz G, Blaser K, Crameri R IgE-mediated reactions to autoantigens in allergic diseases. Int Arch Allergy Immimol 1999 118 193-196. 

Apeloig, Y., Bendikov, M., Yuzefovich, M., Nakash, M., Bravo-Zhivotovskii, D., Blaser, D., Boese, R. Novel Stable Silenes via a Sila-Peterson-type Reaction. Molecular Structure and Reactivity. J. Am. Chem. Soc. 1996, 118,12228-12229. 

Table 2.13 Important catalytic hydrogenation reactions, and preferred metal and solvent types. Source adapted from Blaser et al. [298].

Figure 2.51 Chemoselective hydrogenation of nitro groups with modified Pt catalysts developed by Solvias. Functional groups not converted are in blue. The boxed reaction is an example of chemoselective hydrogenation of a nitro group in the presence of an allyl ester. Source adapted from Blaser et al. [298, 299].

As a rule, the asymmetric catalytic reaction is part of a more extensive multi-step synthesis. This is particularly pronounced for the cases where the active substance is the goal of the development work (categories A and D), but also for the more simple intermediates described in B and C. This means that the catalytic step has to be integrated into the overall synthesis and therefore, the route selection is a very important phase of process development. Very detailed discussions of this aspect can be found, e.g., in the contributions of Wirz et al. (p. 385, 399), Netscher et al. (p. 71) or Caille et al. (p. 349). It is important to realize that the effectiveness of the catalytic step is only one, albeit often an important, factor but that it is the cost of the overall synthesis which is decisive for the final choice as to which route will be chosen. The comparison of competing routes is not always easy and different approaches can be found in the contributions of Blaser et al. (p. 91), Pes-ti and Anzalone (p. 365), or Singh et al. (p. 335). In some cases, the overall synthesis is actually designed around an effective enantioselective transformation as for example described for the metolachlor process by Blaser et al. (p. 55). This situation will become rarer when more catalysts with well described scope and limitations will be commercially accessible. 

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