485-19-8Relevant articles and documents
Laboratory-scale production of (S)-reticuline, an important intermediate of benzylisoquinoline alkaloids, using a bacterial-based method
Matsumura, Eitaro,Nakagawa, Akira,Tomabechi, Yusuke,Koyanagi, Takashi,Kumagai, Hidehiko,Yamamoto, Kenji,Katayama, Takane,Sato, Fumihiko,Minami, Hiromichi
, p. 396 - 402 (2017)
Benzylisoquinoline alkaloids (BIAs) are a group of plant secondary metabolites that have been identified as targets for drug discovery because of their diverse pharmaceutical activities. Well-known BIAs are relatively abundant in plants and have therefore been extensively studied. However, although unknown BIAs are also thought to have valuable activities, they are difficult to obtain because the raw materials are present at low abundance in nature. We have previously reported the fermentative production of an important intermediate (S)-reticuline from dopamine using Escherichia coli. However, the yield is typically limited. Here, we improved production efficiency by combining in vivo tetrahydropapaveroline production in E. coli with in vitro enzymatic synthesis of (S)-reticuline. Finally, 593 mg of pure (S)-reticuline was obtained from 1 L of the reaction mixture. Because this bacterial-based method is simple, it could be widely used for production of (S)-reticuline and related BIAs, thereby facilitating studies of BIAs for drug discovery.
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).
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
