Asymmetric Synthesis of (R)‐1‐Alkyl‐Substituted Tetrahydro‐ß‐carbolines Catalyzed by Strictosidine Synthases

Stereoselective methods for the synthesis of tetrahydro‐ß‐carbolines are of significant interest due to the broad spectrum of biological activity of the target molecules. In the plant kingdom, strictosidine synthases catalyze the C−C coupling through a Pictet–Spengler reaction of tryptamine and seco...

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Published in:Angewandte Chemie 2018-08, Vol.130 (33), p.10843-10847
Main Authors: Pressnitz, Desiree, Fischereder, Eva‐Maria, Pletz, Jakob, Kofler, Christina, Hammerer, Lucas, Hiebler, Katharina, Lechner, Horst, Richter, Nina, Eger, Elisabeth, Kroutil, Wolfgang
Format: Article
Language:English
Subjects:
Aldehydes
Aliphatic compounds
Asymmetric synthesis
Asymmetrische Katalyse
Biokatalyse
Biological activity
Chemical synthesis
Chemistry
Coupling (molecular)
Hand tools
Pictet-Spengler-Reaktion
Stereoselectivity
Strictosidin-Synthasen
Tetrahydro-β-carboline
Tryptamine
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Summary:Stereoselective methods for the synthesis of tetrahydro‐ß‐carbolines are of significant interest due to the broad spectrum of biological activity of the target molecules. In the plant kingdom, strictosidine synthases catalyze the C−C coupling through a Pictet–Spengler reaction of tryptamine and secologanin to exclusively form the (S)‐configured tetrahydro‐ß‐carboline (S)‐strictosidine. Investigating the biocatalytic Pictet–Spengler reaction of tryptamine with small‐molecular‐weight aliphatic aldehydes revealed that the strictosidine synthases give unexpectedly access to the (R)‐configured product. Developing an efficient expression method for the enzyme allowed the preparative transformation of various aldehydes, giving the products with up to >98 % ee. With this tool in hand, a chemoenzymatic two‐step synthesis of (R)‐harmicine was achieved, giving (R)‐harmicine in 67 % overall yield in optically pure form. Unerwartet: Strictosidin‐Synthasen setzen mehr Aldehydsubstrate um als bisher angenommen. So katalysieren sie Pictet‐Spengler‐Reaktionen von Tryptamin mit niedermolekularen Aldehyden, die überraschend nicht die natürlichen S‐konfigurierten Produkte, sondern die R‐konfigurierten Produkte in hohen Ausbeuten und mit bis zu 98 % ee liefern. Mithilfe dieser Methode gelang die Synthese von optisch reinem (R)‐Harmicin in zwei Stufen.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201803372