Chemoenzymatic transformations

Chemical and Chemoenzymatic Transformations of Carbohydrates into Fine Chemicals and Chiral Building Blocks... 

Particularly facile is trifluoroacetylation of daunomycin, which can be achieved by action of ethyl trifluoroacetate in the presence of triethylamine or other basic catalyst. The product of this reaction has considerably reduced cytotoxicity, but it can be more easily accumulated in a cell because it is no longer a substrate for the Pgp efflux pump. Its lipophilic esters (products of acylation at C-14 primary hydroxyl group) became experimental antitumor drugs [120,121] and valrubicin (AT-trifluoroacetyl-H-O-valeroyldoxorubidn) was registered for use in bladder cancer treatment. A new method for preparation of the drug, which consists of efficient two-step chemoenzymatic transformation of Dox was disclosed recently [122]. 

Scheme 3 One-pot chemoenzymatic transformations employing a P-galactosidase and TcTS [36]...

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

A chemoenzymatic synthesis of di-, tetra-, and octavalent sialyl Lewis X ligands scaffolded on dendrimers has been reported (Scheme 67). 508 Hypervalent L-lysine cores with covalently attached 2-acetamido-2-deoxy-D-glucose residues were chemically prepared and enzymatically transformed into sialyl Lewis X-containing dendrimers using (3-(l— 4) ga-... 

Mostly the baker s yeast transketolase has been used so far to prepare several valuable ketose sugars and derivatives 141 (cf. Sect. 7). Recently, the transketolase was utilized in the key stereogenic transformation of racemic 2-hydroxybutyraldehyde 142 into the homochiral synthon 5,6-dideoxy-D-t/ireo-hexulose 110 for the chemoenzymatic synthesis of (+ )-exo-brevicomin 107 [314], Transketolase has also been applied for the in-situ generation of Ery4P (35) from Fru6P (38) in a multi-enzymatic synthesis of 34 (Scheme 5). 

Santaniello, E., Ciuffeda, P. and Alessandrini, L. (2007) Deaminating enzymes of the purine cyde as biocatalysts for chemoenzymatic synthesis and transformations of antiviral agents structurally related to purine nucleosides, in Biocatalysis in the Pharmaceutical and Biotechnology Industries (ed. R. Patel), CRC Press, Chapter 17. 

The examples given in Section 4.2 demonstrate that state-of-the-art biocatalytic transformations have reached an extraordinary level making them valuable and competitive methods for use in the pharmaceutical industry. Progress made in the fields of chemoenzymatic synthesis, molecular biology and reaction engineering will improve and enlarge the possible apphcations of biocataiysts even further. 

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