Artemisinin Artemisinic alcohol

Scheme 8. Summary of the biosynthetic pathway to artemisinin through artemisinic alcohol in Artemisia annua.

Recently, further improved yeast systems were reported [395]. These included, among others, CYP71AV1 and an alcohol dehydrogenase and aldehyde dehydrogenase (Adhl and AldHl) from A. annua for the respective conversion of artemisinic alcohol and aldehyde [396]. Titers of artemisinic acid of up to 25 g L were achieved in fermentation experiments and could be further converted to artemisinin by means of classical chemistry or photochemistry [395]. This semisynthetic process is now used at Sanofi for the industrial production of artemisinin. 

Very recently, a further improved yeast system was reported, which induded, among other optimizations and besides CYP71AV1, an alcohol and aldehyde [119] dehydrogenases (ADHl and ALDHl) from A. annua for artemisinic alcohol and aldehyde conversion, respectively (Scheme 5.28). Artemisinic acid titers of up to 25gl i were achieved in fermentation set-up [120]. A process based on the developed artemisinic acid-producing yeast strain is now used for the industrial production of artemisinin at Sanofi (www.rsc.org/chemistryworld/2013/04/sanqfi-launches-malaria-drug-production). 

Ring-contracted artemisinins, exemplified by (286), are accessible from methyl dihydro-artemisinate (284) via the alcohol (285) (Scheme 42) <95TL4641>. 

Scheme 5.28 Cascade process in S. cerevisiae toward the artimisinin precursor artemisinic acid. Pathway engineering yields amorpha-4,n-diene via farnesyl pyrophosphate (FPP), and oxidations of amorphadiene are catalyzed by CYP71AV1 (redox partner protein not shown), alcohol dehydrogenase ADHl, and aldehyde dehydrogenase ALDHl. Artemisinin is synthesized in vitro from the produced artemisinic acid by established Synthetic chemistry. ADS, amorphadiene synthase.

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