A stereoselective synthesis of the dihydroxyethylene dipeptide isostere, A-82768

Malaria, caused by Plasmodium sp , results in almost one million deaths and over 200 million new infections annually. The World Health Organization has recommended that artemisinin-based combination therapies be used for treatment of malaria. Artemisinin is a sesquiterpene lactone isolated from the plant Artemisia annua . However, the supply and price of artemisinin fluctuate greatly, and an alternative production method would be valuable to increase availability. We describe progress toward the goal of developing a supply of semisynthetic artemisinin based on production of the artemisinin precursor amorpha-4,11-diene by fermentation from engineered Saccharomyces cerevisiae , and its chemical conversion to dihydroartemisinic acid, which can be subsequently converted to artemisinin. Previous efforts to produce artemisinin precursors used S. cerevisiae S288C overexpressing selected genes of the mevalonate pathway [Ro et al. (2006) Nature 440:940–943]. We have now overexpressed every enzyme of the mevalonate pathway to ERG20 in S. cerevisiae CEN.PK2, and compared production to CEN.PK2 engineered identically to the previously engineered S288C strain. Overexpressing every enzyme of the mevalonate pathway doubled artemisinic acid production, however, amorpha-4,11-diene production was 10-fold higher than artemisinic acid. We therefore focused on amorpha-4,11-diene production. Development of fermentation processes for the reengineered CEN.PK2 amorpha-4,11-diene strain led to production of > 40 g/L product. A chemical process was developed to convert amorpha-4,11-diene to dihydroartemisinic acid, which could subsequently be converted to artemisinin. The strains and procedures described represent a complete process for production of semisynthetic artemisinin.

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“…5, compound 3), which is subsequently oxidized to dihydroartemisinic acid (Fig. 5, compound 4) with inexpensive inorganic reagents (26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin

Westfall

Pitera

Lenihan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

632

448

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“…166 The same reaction can also be carried out using a sol-gel-entrapped TEMPO. Reactions on a large scale have been described, 156,168,169 and continuousprocess oxidations have been devised. 170 Nitroxide-catalyzed bleach reactions have been considered and are likely used commercially on a large scale.…”

mentioning

confidence: 99%

Oxoammonium‐ and Nitroxide‐Catalyzed Oxidations of Alcohols

2009

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The discovery in 1959 of stable nitroxide‐based free radicals such as the prototypical 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO) led to their use as electron spin resonance (ESR) spin labels in chemistry, biomedicine, and materials science. These nitroxides are prepared by the oxidation of secondary amines that contain no hydrogen atoms on the alpha‐carbons. The unique redox properties of nitroxides enable their use as oxidants in organic synthesis. The varied preparation and uses of oxoammonium salts as stoichiometric oxidants for alcohols are one subject of this review. Oxoammonium ions as oxidants for alcohols have a number of advantages, for example, the method is heavy‐metal free and some of the reactions can be performed in water or aqueous mixtures. A few side reactions are associated with these oxidations. The most serious is the fast reaction of the oxoammonium ion with free amines The several ways these oxidation reactions can be carried out are discussed in detail. They are: Oxidations using stoichimetric quantities of preformed oxoammonium salts carried out in either acidic, neutral, or basic conditions; reactions in which stoichiometric quantities of oxoammonium salts are generated in situ by disproportionation of a nitroxide in the presence of a strong acid; nitroxide‐catalyzed oxidations using a secondary oxidant; efficient nitroxide‐catalyzed oxidations of primary alcohols to carboxylic acids; and oxidations of primary alcohols or hemiacetals that can lead to lactones.

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“…An SO 3 ·pyridine oxidation was utilized to oxidize alcohol 148 to the aldehyde followed by Grignard addition to generate secondary alcohol 149 (Scheme ), demonstrating that a sensitive epoxide functionality can tolerate the relatively mild oxidation conditions …”

Section: 12 Moffatt and Modified-moffatt Processesmentioning

confidence: 99%

“…It can be chemoselective for primary alcohols and is not prone to over-oxidation under the appropriate conditions. As shown in Scheme , oxidations of primary alcohols are straightforward using less than 1 mol % of TEMPO and aqueous sodium hypochlorite as the co-oxidant with sodium bicarbonate as a mild base. ,, The reaction is usually conducted under biphasic conditions using dichloromethane as the solvent and is suitable for sensitive substrates such as a prostaglandin analogue ( 293 ) . An additive, such as NaBr or KBr, may be used to accelerate the rate of the reaction in some cases.…”

Section: 13 Tempo-mediated Processesmentioning

confidence: 99%

“…Both achiral (magnesium monoperoxyphthalate, 88%) and chiral (Sharpless AE, 59%, 70% ee) epoxidations of Z-olefin 147 have been studied (Scheme 38). 60 Alcohol oxidation and addition of i-butylmagnesium chloride provided epoxy alcohol 149, which upon azide opening and reduction provided aminodiol 150. Resolution of this amine with tartaric acid provided enantiomerically homogeneous material (>99% ee).…”

Section: Non-asymmetric Epoxidationsmentioning

confidence: 99%

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