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Strictosidine synthase (STR1) catalyzes a Pictet–Spengler reaction (PSR) forming strictosidine, a likely biosynthetic key to all higher plant monoterpenoid indole alkaloids. Increasing the biocatalytic capacity of the enzyme may make it a powerful tool for generation of compound libraries with enhanced structural diversity and pharmaceutical activity. Herein two production routes of a rare class of azepino­[3,4,5-cd]-indoles are developed: a complementary STR1-dependent chemoenzymatic and stereoselectively chemical route to an epimeric 1H-azepino­[3,4,5-cd]­indolyl strictosidine or vincoside, respectively. Mechanisms of the asymmetric catalysis are proposed based on computational calculations and X-ray analysis of STR1-ligand complexes. Further chemoenzymatic manipulation of the complementary PSR products resulted in several diverse and complex azepino-indole alkaloids, in which two alkaloids with the epimeric center directs the discovered antimalaria activity: 4α­(S) with IC50 ≈ 3.4 μM, 4β­(R) with IC50 ≈ 6.1 μM. The chemoenzymatic synthesis may significantly extend the applications of the enantiospecific STR1-based PSR in the future.

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