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.

Biocatalyzed C−C Bond Formation for the Production of Alkaloids

“…It is worth emphasizing that the new STR mutant Val208Ala retained its enantioselectivity and thereby the 3α‐( S ) configuration was retained in the new strictosidine analogues obtained by this protein engineering method. Nevertheless, the recent findings by Pressnitz et al . reported an unexpected access to ( R )‐tetrahydro‐β‐carbolines.…”

“…STR‐ Rs ‐catalyzed transformation of commercially available methyl 4‐oxobutanoate and tryptamine led to the formation of Pictet‐Spengler product, which spontaneously converted to the lactam product ( R )‐1,2,5,6,11,11b‐Hexahydro‐3 H ‐indolizino[8, 7‐ b ]indol‐3‐one. Chemical reduction of this lactam produced ( R )‐harmicine with good yield of isolated product (62 %) and excellent enantioselectivity (>98 %) …”

“…The well‐known plasticity of few of the C−C bond forming enzymes is now being exploited. For instance, despite of the previously reported exclusive formation of S ‐configured products by STRs, the recently reported access to R ‐configured products will further strengthen the enzymatic toolbox for the synthesis of pharmaceutically important alkaloids . With advances in the protein engineering techniques, and discovery of novel enzymes, it can be anticipated that major bottlenecks, for instance, restricted scope of amine substrates for NCSs towards amines, issues related with scalability, can be tackled efficiently .…”

New Trends and Future Opportunities in the Enzymatic Formation of C−C, C−N, and C−O bonds

“…In 2018, Kroutil and co-workers used STR to prepare a number of alkyl substituted tetrahydro-β-carbolines with a high degree of stereoselectivity. [158] These substituted tetrahydro-βcarbolines are key intermediates in many bioactive molecules, including the alkaloid (R)-harmicine which displays potent anti-Leishmania activity. [159,160] Four native STRs originating from different organisms were initially chosen for screening; Catharanthus roseus (CrSTR), Ophiorrhiza pumila (OpSTR), Rauvolfia serpentine (RsSTR) along with the V208A variant of RvSTR.…”

Alkaloid diversification in the genus Palicourea (Rubiaceae: Palicoureeae) viewed from a (retro-)biogenetic perspective

“…Even biocatalyzed reactions with STR have been applied to synthesize carboline structures (e.g. Pressnitz et al 2018). However, in planta corresponding enzymes usually have a high rate of substrate specificity.…”