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An Efficient Chemoenzymatic Synthesis of Dihydroartemisinic Aldehyde
Author(s) -
Demiray Melodi,
Tang Xiaoping,
Wirth Thomas,
Faraldos Juan A.,
Allemann Rudolf K.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201609557
Subject(s) - sesquiterpene , aldehyde , artemisia annua , terpene , chemistry , artemisinin , biosynthesis , atp synthase , biotransformation , stereochemistry , enzyme , biochemistry , organic chemistry , biology , plasmodium falciparum , catalysis , malaria , immunology
Artemisinin from the plant Artemisia annua is the most potent pharmaceutical for the treatment of malaria. In the plant, the sesquiterpene cyclase amorphadiene synthase, a cytochrome‐dependent CYP450, and an aldehyde reductase convert farnesyl diphosphate (FDP) into dihydroartemisinic aldehyde (DHAAl), which is a key intermediate in the biosynthesis of artemisinin and a semisynthetic precursor for its chemical synthesis. Here, we report a chemoenzymatic process that is able to deliver DHAAl using only the sesquiterpene synthase from a carefully designed hydroxylated FDP derivative. This process, which reverses the natural order of cyclization of FDP and oxidation of the sesquiterpene hydrocarbon, provides a significant improvement in the synthesis of DHAAl and demonstrates the potential of substrate engineering in the terpene synthase mediated synthesis of high‐value natural products.