Inhibition enantioselective

Z-W Guo, CJ Sih. Enantioselective inhibition a strategy for improving the enantio-selectivity of biocatalytic systems. J Am Chem Soc 111 6836-6841, 1989. 

Harman CA, Turman MV, Kozak KR, Marnett LJ, Smith WL, Garavito RM. Structural basis of enantioselective inhibition of cyclooxygenase-1 by S-alpha-substituted indomethacin ethanola-mides. J. Biol. Chem. 2007 282 28096-28105. 

COX-1 inhibition up to 100 yM in human blood (152,153). (Cyclic voltammetry and iron chelation measurements confirmed that this (methoxyalkyl)thiazole series is free from redox and iron-complexing properties. The series differs from redox and theiV-hydroxyurea series in that it demonstrates enantioselective inhibition of 5-LO both in vitro and in vivo (154). This was the first evidence of 5-LO inhibitors forming enantiospecific interactions with the enzyme. Thus, unlike the a-methyl-ene center in the Abbott N-hydroxyurea series, the stereoselectivity of these ligands indicates a close contact of the stereogenic center and active site of the protein. 

The enantiomerically pure tertiary bases dextro- and levomethorphan were used for the preparation of 2-aryloxy propionic acid derivatives 10 by increasing the selectivity dramatically based on the enantioselective inhibition of the slow reacting enantiomer. 

Enantioselective inhibition strategy for improving the enantioselectivity of biocatalytic systems... 

The enantioselective inhibition of enzymes by the addition of chiral amines functioning as noncompetitive inhibitors has been reported for lipases [288]. This phenomenon is discussed in Sect. 2.1.3.2. For the selectivity enhancement of dehydrogenase reactions via addition of enzyme inhibitors see Sect. 2.2.3. 

Enantioselective Inhibition of Lipases. The addition of weak chiral bases such as amines or aminoalcohols has been found to have a strong influence on the selectivity of Candida rugosa [288] and Pseudomonas sp. lipase [494]. The principle of this selectivity enhancement was elaborated as early as 1930 [495]. As shown in Scheme 2.72, the resolution of 2-aryloxypropionates by CRL proceeds with low to moderate selectivity in aqueous buffer alone. The addition of chiral bases of the morphinan-type to the medium led to a significant improvement of about one order of magnitude. 

Scheme 2.73 Selectivity enhancement of Pseudomonas sp. lipase by enantioselective inhibition...

A common strategy is to use an excess of the alcohol to prevent equilibrium conditions [66,133]. However, it has been found that by decreasing the heptanol concentration from 900 to 90 mM in esterification of 2-methyldecanoic acid catalyzed by lipase, the E value increased from 37 to 83 [134]. The alcohol was found to be an enantioselective inhibitor influencing (Vma )R and (Vmax)s differently. It has been suggested that an equimolar amount of alcohol is sufficient in these kinds of reactions to avoid a decrease in enantioselectivity [66]. The phenomenon of enantioselective inhibition by the alcohol has been suggested to be connected to the unique presence of the hydrophobic active site tunnel in... 

Nitrilases catalyze the synthetically important hydrolysis of nitriles with formation of the corresponding carboxylic acids [4]. Scientists at Diversa expanded the collection of nitrilases by metagenome panning [56]. Nevertheless, in numerous cases the usual limitations of enzyme catalysis become visible, including poor or only moderate enantioselectivity, limited activity (substrate acceptance), and/or product inhibition. Diversa also reported the first example of the directed evolution of an enantioselective nitrilase [20]. An additional limitation had to be overcome, which is sometimes ignored, when enzymes are used as catalysts in synthetic organic chemistry product inhibition and/or decreased enantioselectivity at high substrate concentrations [20]. 

A more recent study focused on the directed evolution of the co-transaminase from Vibrio fiuvialis JS17, specifically with the aim to eliminate product inhibition by aliphatic ketones while maintaining high enantioselectivity. This was achieved by screening 85 000 clones produced by epPCR [72]. 

Biocatalysis has emerged as an important tool for the enantioselective synthesis of chiral pharmaceutical intermediates and several review articles have been published in recent years [133-137]. For example, quinuclidinol is a common pharmacophore of neuromodulators acting on muscarinic receptors (Figure 6.50). (JJ)-Quinudidin-3-ol was prepared via Aspergillus melleus protease-mediated enantioselective hydrolysis of the racemic butyrate [54,138]. Calcium hydroxide served as a scavenger of butyric acid to prevent enzyme inhibition and the unwanted (R) enantiomer was racemized over Raney Co under hydrogen for recycling. 

An asymmetric variant of this reaction was developed using chiral Pd complex 111 with either silanes or disiloxanes [66-68]. Both relative and absolute stereochemistries were controlled in this system and good yields (60-85%) were obtained after oxidation (Eq. 18). Formation of the silane-containing product was inhibited by the presence of water due to competitive formation of the palladium hydrides and silanols [68]. The use of disiloxanes as reductants, however, provided expedient oxidation to the alcohol products without decreasing the isolated yields enantioselectivity was 5-15% lower in this more robust system [66]. Benzhydryldimethylsilane proved to be a good compromise between high yield and facile oxidation [66]. Palladium com-... 

When the desired reaction is not essential, creative thinking must be employed. Adding a selectable moiety may create derivatives of a natural substrate that allow for selection. Hwang et al. [41] used this approach to derive a screen for enantioselective hydrolases. By linking the antibiotic chloramphenicol to either the R- or, S -enantiomer of 2-phenylbutyric acid, they showed that Exiguobacterium acetylicum could hydrolyse the l -form (as the released chloramphenicol inhibited growth) but not the, S -form. However, one must be aware that activity on a derivative may not always correspond to the activity on the actual desired substrate. 

Vedejs et al. reported catalyst inhibition during a study on the enantioselective transfer hydrogenation of dihydro-isoquinolines using Noyori s catalyst (Scheme 44.2) [27]. Here, the problem is caused by the bidentate nature of the substrate. Whereas the bromo compound 1 a could be rapidly reduced, the tosylamide-sub-stituted compound lb could not be reduced, and although the problem could be alleviated somewhat by alkylation of the sulfmamide to 1 c, hydrogenation of this was still sluggish. Although the authors propose this to be a case of product... 

Scheme 44.3 Substrate inhibition in enantioselective transfer hydrogenation.

Researchers at Merck Co. [35] who, together with scientists from Solvias, had developed the enantioselective hydrogenation of unprotected enamine amides and esters [36], reported a more recent example of product inhibition. The product amine amide or ester was found to be an inhibitor of the catalyst, and indeed instances of catalyst poisoning by amines have been reported several times (see later). The authors also found an excellent solution to this problem the addition of BOC-anhydride to the hydrogenation reaction neatly reacts away all the amine to form the BOC-protected amine, whereas the enamine was left unreacted (Scheme 44.4). This addition resulted in a remarkable rate enhancement [35]. 

James et al. reported a case of product inhibition in the Rh-catalyzed enantioselective hydrogenation of N-phenyl benzaldehyde imine [37]. These authors were able to isolate the deactivated catalyst, and to obtain its X-ray structure, which showed, surprisingly, that it was a rhodium complex with the product bound through a rf-n-axene interaction (Scheme 44.5). More cases of inhibition via formation of metal arene complexes will be detailed in Section 44.5. 

Scheme 44.6 Overcoming inhibition by nitrile in enantioselective hydrogenation.

---