Artemisinic aldehyd

Experiments with and -labelled precursors provided unambiguous evidence, that there are several branch points in the biosynthesis of artemisinin. The most prominent sesquiterpene metabolites in sweet wormwood are, aside from artemisinin, artemisinic acid and arteannuin B, which branch off at the artemisinic aldehyde stage. [465]... 

DihyiJraaitc[Pg.4620]

Zhang YY, Teoh KH et al (2008) The molecular cloning of artemisinic aldehyde 11(13) reductase and its role in glandular trichome-dependent biosynthesis of artemisinin in Artemisia annua. J Biol Chem 283 21501-21508... 

A spectacular example of the combination of an ene reductase with other enzymatic activities is about the cascade biosynthesis of artemisinin 43 (Scheme 3.11), natural drug possessing the most rapid action against Plasmodium fcdciparum (malaria). Artemisinic acid, precursor of 43, has been produced biotedmologically on g-scale by means of an engineered yeast [68]. Then, the C(11)=C(13) bond reduction of artemisinic aldehyde 44 was catalyzed by the cloned Dbrl (double bond reductase 1) protein from Artemisia annua to yield the (llS)-dihydroartemisinic aldehyde 45 precursor. It is interesting to note that the stereochemical outcome of this ene reductase is opposite to that observed for the reduction of the very similar substrate 23 with OYEs [69]. 

Using various derivatives of artemisinic acid, the methodology onthned in Scheme 184 was extended to the synthesis of a nnmber of modified artemisinin-type tetracychc trioxanes. For example, the syntheses of 6,9-desdimethylartemisinin 586a , A-fi-hydroxyartemisinin , and C9-alkylated artemisinin analognes were reported . In some cases it is possible to avoid the lactonization step while preserving the ester fnnctionality and interrnpting the cychzation of aldehyde-peroxyhemiacetals of type 652, at the step of formation of tricyclic 5-hydroxy-1,2,4-trioxane . ... 

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. 

Artemisinic AlcohoUAAOH) CYPlAyj/CPR Arteitiisinic Aldehyde (AAA). CrPlAVI/CPR Ancmisinic Acid (AA)... 

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). 

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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