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

Abstract

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.

Asymmetric Biocatalytic Synthesis of 1‐Aryltetrahydro‐β‐carbolines Enabled by “Substrate Walking”

“…Analysis of the optical purity of the obtained product 3 a revealed an ee of 99 % with ( R )‐configuration. This absolute configuration is in line with the previously observed stereochemical outcome of Rs STR‐catalysed Pictet–Spengler reactions of small aldehydes [10b] . Furthermore, the observed absolute configuration and the site of mutation that created space at the back of the active‐site pocket (V208A) to accommodate 2 a also support a substrate binding mode in which the indole ring of tryptamine points out of the active site, as previously suggested by computational studies [11] …”

“…Since Op STR proved to be a synthetically useful catalyst in a previous study, [10b] the initial mutations were performed using this scaffold. In a focused library 13 residues inside and around the active‐site pocket were addressed as well as additional residues identified by MD simulations (Table S7; see also Supporting Information „Selection of Sites for Mutagenesis“) [16, 17] .…”

Recent trends in biocatalysis

“…Different from the natural ( S )-strictosidine produced from tryptamine and secologanin, replacement of secologanin with several simple aliphatic aldehydes produced ( R )-1-alkyl-THBCs in medium to high optical purity by several STRs ( Scheme 4B ). 284 The STR-reaction was combined with a chemical reduction to achieve a facile two-step synthesis of ( R )-harmicine. The switch of enantioselectivity was explained as the inverted binding of short-chain aliphatic aldehydes in STR through a structural and computational study.…”

Enzymkatalysierte späte Modifizierungen: Besser spät als nie

“…[197] Diese Selektivitätseigenschaft konnte dann ausgenutzt werden, um einen Vorläufer ( 182) des (R)-Harmicins aus 178 und 180 zu synthetisieren. [198] 5. Selektiver enzymkatalysierter Aufbau von Amidbindungen…”