Abstract
Artemisinin is an important drug to fight malaria. It is produced either by extraction or via a semisynthetic route involving enzyme engineering. A key intermediate to produce artemisinin by the enzymatic route is dihydroartemisinic aldehyde (DHAAl). However, control of the absolute configuration of the stereocenter α to the aldehyde is highly challenging. Herein we report a protocol that allows the diastereomeric enrichment of a mixture of (11R)/(11S)-DHAAl to the desired (11R)-DHAAl by utilizing a crystallization-induced diastereomer transformation induced by the Betti base. In addition, the Betti base can be quantitatively recovered and reused after the reaction.
Highlights
Half of the world population is at risk of malaria
In order to improve this ratio, a mixture of (11R)- and (11S)-dihydroartemisinic aldehyde (DHAAl) was treated with the (S)Betti base, which was identified as the correct enantiomer to access the desired diastereoenriched (11R)-DHAAl
Treatment of a 65:35 mixture of DHAAl diastereomers with (S)-1-(αaminobenzyl)-2-naphthol [(S)-2] in methanol for 4 h at room temperature led to the formation of a mixture of naphtho[1,2-e][1,3]oxazines (1′R,3′S,11R)-3 and (1′R,3′S,11S)-3 in a ratio of 72:28.16 When the reaction was performed on a 0.545 mmol scale, the yield of (1′R,3′S,11R)-3/ (1′R,3′S,11S)-3 was 63%, and when the reaction was performed on a larger scale (3.694 mmol), the yield of (1′R,3′S,11R)-3/ (1′R,3′S,11S)-3 was increased to 83%
Summary
Half of the world population is at risk of malaria. In 2017, around 435 000 deaths, mostly located in sub-Saharan African regions, were attributed to this disease.[1]. The world market price is highly volatile, ranging from US $250 to $1100 per kilogram.[2] To complement the natural production and narrow the market price fluctuation, a semisynthetic process based on isoprenoid fermentation has been developed.[3] This manufacturing route uses bioengineered microorganisms to produce advanced biosynthetic intermediates such as amorphadiene,[4] artemisinic acid,[3] and more recently dihydroartemisinic aldehyde (DHAAl)[5] (Scheme 1). The epimerization of the stereocenter α to the aldehyde presumably occurs through an imine/enamine equilibrium (Scheme 2)
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