Enantioselective C–C bond synthesis catalysed by enzymes

Gebouw voor Scheikunde, Technische Universiteit Delft, Julianalaan 136, 2628 BL Delft, The Netherlands.
Chemical Society Reviews (Impact Factor: 30.43). 07/2005; 34(6):530-42. DOI: 10.1039/B412490A
Source: PubMed

ABSTRACT The enantioselective synthesis of C-C bonds is often the pivotal step of a synthesis. Nature has made a variety of versatile enzymes available that catalyse this type of reaction very selectively under mild conditions. Cyanohydrins, acyloins (alpha-hydroxy ketones), alpha-hydroxy acids and aldols (beta-hydroxy ketones) are very efficiently synthesised enantioselectively with the aid of C-C bond forming enzymes, which we discuss in this tutorial review. In the case of the alpha-hydroxy acids the applications of nitrilases in a synthetic dkr even allows a disconnection that has no enantioselective chemical equivalent.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Computational approaches could decrease the need for the laborious high-throughput experimental screening that is often required to improve enzymes by mutagenesis. Here we report that using multiple short molecular dynamics (MD) simulations makes it possible to accurately model enantioselectivity for large numbers of enzyme-substrate combinations at low computational costs. We chose four different haloalkane dehalogenases as model systems because of the availability of a large set of experimental data on the enantioselective conversion of 45 different substrates. To model the enantioselectivity, we quantified the frequency of occurrence of catalytically productive conformations (near attack conformations) for pairs of enantiomers during MD simulations. We found that the angle of nucleophilic attack that leads to carbon-halogen bond cleavage was a critical variable that limited the occurrence of productive conformations; enantiomers for which this angle reached values close to 180° were preferentially converted. A cluster of 20 - 40 very short (10 ps) MD simulations allowed adequate conformational sampling and resulted in much better agreement to experimental enantioselectivities than single long MD simulations (22 ns), while the computational costs were 50 - 100 fold lower. With single long MD simulations, the dynamics of enzyme-substrate complexes remained confined to a conformational subspace that rarely changed significantly, whereas with multiple short MD simulations a larger diversity of conformations of enzyme-substrate complexes was observed.
    Journal of Chemical Information and Modeling 06/2014; 54(7). DOI:10.1021/ci500126x · 4.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A domino addition-lactonization pathway has been applied to a dynamic covalent resolution protocol, leading to efficient oxathiazinanone formation as well as chiral discrimination. A new, double biocatalytic pathway has furthermore been proposed and evaluated where the initial product inhibition could be efficiently circumvented.
    Organic & Biomolecular Chemistry 04/2014; DOI:10.1039/c4ob00365a · 3.49 Impact Factor
  • Source