Chemoenzymatic routes

An efficient chemoenzymatic route for the synthesis of optically active substituted indolines has been recently developed (Scheme 7.27), and also the alkoxycarbonyla-tion process is more efficient than the acylation reaction. Different lipases have been tested in the alkoxycarbonylation of these secondary amines, GALA being found to be the best biocatalyst for 2-substituted-indolines, and CALB for 3-methylindoline. The combination of lipases with a variety of allyl carbonates and TBME as solvent has allowed the isolation of the carbamate and amine derivatives in a high level of enantiopurity [51]. 

A novel chemoenzymatic route to polyester polyurethanes was developed without employing highly toxic isocyanate intermediates. First, diurethane diols were prepared from cyclic carbonates and primary diamines, which were subsequently polymerized with dicarboxylic acids and glycols by using lipase CA as catalyst, yielding the polyurethanes under mild reaction conditions. 

Archelas A, R Furstoss (1992) Synthesis of optically pure pityol—a pheromone of the bark beetle Pityophtho-rus pityographus—using a chemoenzymatic route. Tetrahedron Lett 33 5241-5242. 

Kohli, R.M., Burke, M.D., Tao, J. and Walsh, C.T. (2003) Chemoenzymatic route to macrocyclic hybrid peptide/ polyketide-like molecules. Journal of the American Chemical Society, 125, 7160-7161. 

Chemoenzymatic Routes to Enantiomerically Pure Amino Acids and Amines... 

The use of this kind of lyases has been exploited in organic synthesis by several groups using (R)-and (S)-oxynitrilases for the synthesis of a great variety of organic compounds. A representative example of the utility of this reaction in the synthesis of pharmaceuticals is the preparation of adrenergic bronchodilators [51]. Scheme 10.22 shows a chemoenzymatic route to (R)-terbutaline. 

Fig. 3 Chemoenzymatic routes to crosslinked macrolactones. Left enzymatic polymerization of a-methylenemacrolides and subsequent vinyl polymerization [10]. Right Enzymatically synthesized highly crystalline poly(ambrettolide) before and after thermal crosslinking [11]...

The reactive open-chain substrate 29 with the natural D-threo configuration was prepared along a chemoenzymatic route by making use of the common constitutional and stereochemical relationship which substrates of transaldolase share with those of transketolase. Thus, the R-configured 2-hydroxyaldehyde 28 was chain-extended under transketolase catalysis in the presence of 20 as ketol donor to yield the desired aldol. By this approach, several transaldolases could indeed be shown to display different levels of kinetic stereoselectivity. 

The chemoenzymatic route afforded a dramatic improvement in process efficiency compared to the first-generation process. This was reflected in the E factor which decreased 7-fold, from 86 to 12, and the substantial reduction in organic solvent usage resulting from a largely aqueous reaction medium. 

Figure 5.16 The Du Pont chemoenzymatic route to glycolic acid.

Combining whole-cell biocatalysis and radical polymerization, researchers at Imperial Chemical Industries (ICI) published a chemoenzymatic route to high-molecular-weight poly(phenylene) [86], This polymer is used in the fibers and coatings industry. However, since it is practically insoluble, the challenge was to make a soluble polymer precursor that could first be coated or spun, and only then converted to poly(phenylene). The ICI process starts from benzene, which is oxidized by Pseudomonas putida cells to cyclohexa-3,5-diene-l,2-diol (see Figure 5.17). The... 

Figure 5.17 The ICI chemoenzymatic route to poly(phenylene) uses genetically altered Pseudomonas putida cells, which consume benzene and excrete the dihydrodiol monomer.

Figure 5.29 Chemoenzymatic route to (S)-lysine, starting from cyclohexanol.

The four-step synthesis of a, -diaminocaprolactam shown in Figure 5.29 is part ofa chemoenzymatic route to (S)-lysine, an essential amino add in our diet [135], The racemic caprolactam (azepan-2-one) product is then hydrolyzed selectively to (S)-lysine, using an immobilized (S)-hydrolase enzyme. 

Figure 24.6. A proposed four-step chemoenzymatic route to the synthesis of enantio-pure MLM type asymmetrically structured TAGs.

The market volume of L-phenylalanine (L-Phe) has rapidly increased in recent years to 14 kt in 2002, according to an authorative estimate [86], which is mainly due to the commercial success of the artificial sweetener aspartame. L-Phe has been produced by a number of chemoenzymatic routes in the past [87] (see Fig. 8.14) and many more have been developed [88] but never commercialized. Fermentation of L-Phe is now so efficient that it has rendered all of the chemoenzymatic procedures obsolete. 

Grunewald J, Sieber SA, Mahlert C, Linne U, Marahiel MA. Synthesis and derivatization of daptomycin a chemoenzymatic route... 

Subtilisin Carlsberg, a laundry enzyme, is extraordinarily cheap and stable even at extreme concentrations of substrate and salt at elevated temperature. A major disadvantage of this chemoenzymatic route was the fact that no racemization procedure for the unwanted (R)-enantiomer [(R)-3] could be established [40]. 

A few synthetic applications for obtaining biologically active compounds have been described, based on the use of these bacterial enzymes. For instance, the pheromone (S)-frontalin was synthesized in five steps in 94% ee (but rather low overall yield) via a chemoenzymatic route implying epoxide resolution using lyophilized cells oi Rhodococcus equi [189] (Fig. 16). 

A big factor for the success of the process was the close similarity of the substrate to the natural substrates of Subtilisin Carlsberg, an enzyme with extraordinary properties. Since cheap commercial sources for this enzyme were available on the market, the enzyme could be discarded. A major disadvantage of the present chemoenzymatic route was the fact that no satisfactory racemization procedure for the unwanted enantiomer (R)-2 could be established due to elimination and/or hydrolysis side reactions. 

Similarly, a chemoenzymatic route was used to generate sLe" -substituted glycopep-tides to elucidate the critical binding epitope of PSGL-1, the physiological ligand for P-selectin (81). In a P-selectin inhibition assay, macrocyclic sLex analog exhibits a dramatic enhancement (100 times) relative to sLe"" (82). 

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