1316259-22-9Relevant academic research and scientific papers
Deracemization by simultaneous bio-oxidative kinetic resolution and stereoinversion
Schrittwieser, Joerg H.,Groenendaal, Bas,Resch, Verena,Ghislieri, Diego,Wallner, Silvia,Fischereder, Eva-Maria,Fuchs, Elisabeth,Grischek, Barbara,Sattler, Johann H.,MacHeroux, Peter,Turner, Nicholas J.,Kroutil, Wolfgang
supporting information, p. 3731 - 3734 (2014/04/17)
Deracemization, that is, the transformation of a racemate into a single product enantiomer with theoretically 100-% conversion and 100-% ee, is an appealing but also challenging option for asymmetric synthesis. Herein a novel chemo-enzymatic deracemization concept by a cascade is described: the pathway involves two enantioselective oxidation steps and one non-stereoselective reduction step, enabling stereoinversion and a simultaneous kinetic resolution. The concept was exemplified for the transformation of rac-benzylisoquinolines to optically pure (S)-berbines. The racemic substrates were transformed to optically pure products (ee>97-%) with up to 98-% conversion and up to 88-% yield of isolated product. From two make one: Chemo-enzymatic stereoinversion and enzymatic kinetic resolution have been combined in a simultaneous cascade process to transform racemic substrates (A, ent-A) into optically pure product P. The concept was exemplified for benzylisoquinolines rac-1 yielding optically pure berbines (S)-2. The reaction system comprised a monoamine oxidase (MAO-N), morpholine-borane, and the berberine bridge enzyme (BBE).
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.
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.
