151841-47-3Relevant academic research and scientific papers
Deracemisation of benzylisoquinoline alkaloids employing monoamine oxidase variants
Schrittwieser, Joerg H.,Groenendaal, Bas,Willies, Simon C.,Ghislieri, Diego,Rowles, Ian,Resch, Verena,Sattler, Johann H.,Fischereder, Eva-Maria,Grischek, Barbara,Lienhart, Wolf-Dieter,Turner, Nicholas J.,Kroutil, Wolfgang
, p. 3657 - 3664 (2015/02/05)
Chemo-enzymatic deracemisation was applied to obtain the (S)-enantiomer of 1-benzylisoquinolines from the racemate in high isolated yield (up to 85%) and excellent optical purity (ee > 97%). The one-pot deracemisation protocol encompassed enantioselective oxidation by a monoamine oxidase (MAO-N) and concomitant reduction of the resulting iminium species by ammonia-borane. The challenge was the oxidation at the sterically demanding chiral centre. Recently developed variants of MAO-N, featuring an enlarged active-site pocket, turned out to be suitable biocatalysts for these substrates. In contrast to previous MAO-N variants, which preferentially converted the (S)-enantiomer, the MAO-N variant D11 used in the present study was found to oxidise all tested benzylisoquinoline substrates with (R)-enantiopreference. The structural determinants of enantioselectivity were investigated by means of protein-ligand docking simulations. The applicability of the deracemisation system was demonstrated on preparative scale (150 mg) for three benzylisoquinoline alkaloids (natural as well as non-natural), including the hypotensive and antispasmodic agent (S)-reticuline.
Inverting the regioselectivity of the berberine bridge enzyme by employing customized fluorine-containing substrates
Resch, Verena,Lechner, Horst,Schrittwieser, Joerg H.,Wallner, Silvia,Gruber, Karl,MacHeroux, Peter,Kroutil, Wolfgang
, p. 13173 - 13179 (2013/01/15)
Fluorine is commonly applied in pharmaceuticals to block the degradation of bioactive compounds at a specific site of the molecule. Blocking of the reaction center of the enzyme-catalyzed ring closure of 1,2,3,4- tetrahydrobenzylisoquinolines by a fluoro moiety allowed redirecting the berberine bridge enzyme (BBE)-catalyzed transformation of these compounds to give the formation of an alternative regioisomeric product namely 11-hydroxy-functionalized tetrahydroprotoberberines instead of the commonly formed 9-hydroxy-functionalized products. Alternative strategies to change the regioselectivity of the enzyme, such as protein engineering, were not applicable in this special case due to missing substrate-enzyme interactions. Medium engineering, as another possible strategy, had clear influence on the regioselectivity of the reaction pathway, but did not lead to perfect selectivity. Thus, only substrate tuning by introducing a fluoro moiety at one potential reactive carbon center switched the reaction to the formation of exclusively one regioisomer with perfect enantioselectivity. Custom-made substrates: Employing customized substrates with a fluoro atom at the normally preferred reaction site switched the regioselectivity of the berberine-bridged enzyme. With this strategy, it was possible to get access to (S)-11-hydroxy-functionalized berbines in an asymmetric fashion by using the wild-type enzyme (see scheme). Copyright
Biocatalytic oxidative C-C bond formation catalysed by the berberine bridge enzyme: Optimal reaction conditions
Resch, Verena,Schrittwieser, Joerg H.,Wallner, Silvia,MacHeroux, Peter,Kroutil, Wolfgang
experimental part, p. 2377 - 2383 (2011/10/19)
Berberine bridge enzyme (BBE) catalyses the oxidative formation of an intramolecular C-C bond using (S)-reticuline as the natural substrate to form (S)-scoulerine as the product. To allow application of the enzyme on a preparative scale for the synthesis
Biocatalytic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids
Schrittwieser, Joerg H.,Resch, Verena,Wallner, Silvia,Lienhart, Wolf-Dieter,Sattler, Johann H.,Resch, Jasmin,MacHeroux, Peter,Kroutil, Wolfgang
, p. 6703 - 6714 (2011/10/18)
A chemoenzymatic approach for the asymmetric total synthesis of the title compounds is described that employs an enantioselective oxidative C-C bond formation catalyzed by berberine bridge enzyme (BBE) in the asymmetric key step. This unique reaction yielded enantiomerically pure (R)-benzylisoquinoline derivatives and (S)-berbines such as the natural product (S)-scoulerine, a sedative and muscle relaxing agent. The racemic substrates rac-1 required for the biotransformation were prepared in 4-8 linear steps using either a Bischler-Napieralski cyclization or a C1-Cα alkylation approach. The chemoenzymatic synthesis was applied to the preparation of fourteen enantiomerically pure alkaloids, including the natural products (S)-scoulerine and (R)-reticuline, and gave overall yields of up to 20% over 5-9 linear steps.
Biocatalytic enantioselective oxidative C-C coupling by aerobic C-H activation
Schrittwieser, Joerg H.,Resch, Verena,Sattler, Johann H.,Lienhart, Wolf-Dieter,Durchschein, Katharina,Winkler, Andreas,Gruber, Karl,MacHeroux, Peter,Kroutil, Wolfgang
, p. 1068 - 1071 (2011/04/22)
Bridging the gap: The berberine bridge enzyme (BBE) was employed for the first preparative oxidative biocatalytic C-C coupling that leads to a new intramolecular bond. This unique transformation requires O2 as sole stoichiometric oxidant and gives access to novel optically pure (S)-berbine 2 and (R)-1-benzyl-1,2,3,4-tetrahydroisoquinoline 1 alkaloid derivatives by kinetic resolution.
