A Facile Chemoenzymatic Approach: One‐Step Syntheses of Monoterpenoid Indole Alkaloids

Abstract

Facile chemoenzymatic syntheses of cytotoxic monoterpenoid indole alkaloids with novel skeletons and multiple chiral centers are described. Synthesis of these alkaloids was achieved by a simple one-step reaction using strictosidine and 12-aza-strictosidine as the key intermediates. Strictosidines were prepared by coupling of secologanin with tryptamine and 7-aza-tryptamine, respectively, using the immobilized recombinant Rauvolfia strictosidine synthase. A detailed stereochemical analysis is presented herein. The results provide an opportunity for a chemoenzymatic approach that leads to an increased diversification of complex alkaloids with improved structures and activities.

The Pictet–Spengler Reaction in Nature and in Organic Chemistry

“…In the likely presence of an excess of any primary amine (other nucleophiles have not yet been applied so far) closure of the E ring by a Michael addition takes place to deliver, after borohydride reduction, a diastereomeric mixture of each of the four N-analogous heteroyohimbines. [48,56] Scheme 5. Suggested mechanism of the strictosidine synthase catalyzed Pictet-Spengler reaction between tryptamine and secologanin, which generates the biosynthetic monoterpenoid indole alkaloid precursor 3a(S)-strictosidine enantioselectively.…”

“…Following optimized overexpression, [57] STR1 was used for the synthesis of azastrictosidine from 7-azatryptamine (Scheme 7). [56,58] Moreover, azastrictosidine has been used for the simple one-step chemical synthesis of a previously unknown lactam of azastrictosidine and for azanacycline under basic and acidic conditions, respectively. [56] Modification of the tryptamine unit by introducing a nitrogen atom in different positions should, therefore, ultimately result in a range of diverse and novel azaindole alkaloids.…”

“…Biomimetic, chemoenzymatic approach directed towards novel N-analogues of heteroyohimbines from strictosidine (SG = strictosidine glucosidase). [48,56] This "one-pot" chemoenzymatic approach has recently been simplified and extended for the generation of the new alkaloid aza-tetrahydroalstonine [56] by using recombinant and His 6 -tagged immobilized STR1 obtained from expression of its cDNA in E. coli. Following optimized overexpression, [57] STR1 was used for the synthesis of azastrictosidine from 7-azatryptamine (Scheme 7).…”

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

“…The latter serves as a central precursor of naturally occurring, biologically active indole alkaloids, thus the enzyme is located in the biosynthetic pathways at the central branching point of more than 2000 monoterpenoid indole alkaloids in higher plants, including some possessing extraordinary medicinal and therapeutic value 8. In general STRs have been reported to show a narrow substrate spectrum with respect to the aldehyde reactant, transforming only secologanin and close derivatives in most cases;7, 9 to the best of our knowledge, only one report indicated that simple non‐natural aliphatic aldehydes might also be accepted 10. Therefore, our aim was to investigate the substrate tolerance of STRs for non‐natural aldehydes.…”

Crystal Structure of Perakine Reductase, Founding Member of a Novel Aldo-Keto Reductase (AKR) Subfamily That Undergoes Unique Conformational Changes during NADPH Binding

“…Enzyme-catalyzed biosynthesis and chemo-enzymatic synthesis of pharmacologically active, plant-derived monoterpenoid indole alkaloids have attracted interest in recent years (1)(2)(3)(4)(5). A detailed knowledge of the participating enzymes is an indispensable requirement for further progress in this field.…”