10.1016/S0040-4020(97)10286-1
The research details the first-time synthesis of (+)-Artemisinin and (+)-Deoxoartemisinin from Arteannuin B and Arteannuic Acid. The purpose of this study was to develop a short and efficient synthetic route leveraging prior art for the final photo-oxygenation/cyclization reaction, addressing the urgency in discovering novel antimalarial agents due to the emergence of chloroquine-resistant strains of Plasmodium falciparum. The researchers successfully established a synthetic link between Arteannuin B and Artemisinin, as well as a new route from readily available Arteannuic Acid, utilizing a novel oxidative lactonization reaction and a regioselective protection method. The study concluded that the yields for the photo-oxygenation reaction leading to Artemisinin were comparable to previous syntheses, with no observed "ene" products, likely due to the absence of axial allylic protons in their substrates. The yield for the photo-oxygenation to form Deoxoartemisinin was exceptionally high at 65%, attributed to the enhanced rate of cyclization and the absence of competing ene reactions. Key chemicals used in the process included Arteannuin B, Arteannuic Acid, singlet oxygen, Rose Bengal as a sensitizer, and various reagents for protection and deprotection steps, such as 1,2-bis(trimethylsilyloxy)ethane (BTSE), trimethylsilyltriflate (TMSOTf), and lithium aluminum hydride.
10.1016/S0040-4039(00)98789-6
The research aimed to efficiently synthesize (+)-8a,9-secoartemisinin 2, a ring-D cleaved, tricyclic analog of the potent antimalarial drug (+)-artemisinin 1. The purpose was to understand the molecular basis of action and the minimum structural requirements for high potency in this class of drugs, driven by the need for cost-effective and pharmacodynamically viable alternatives to combat resistant strains of Plasmodium falciparum. The methodology involved the use of vinylsilane ozonolysis to install crucial functional groups for the construction of the analog.
10.1002/cmdc.201000225
The research investigates the interaction between artemisinins, a class of compounds derived from the plant Artemisia annua and used in the treatment of malaria, and redox-active substrates such as leucomethylene blue and dihydroflavins. The study aims to understand the molecular mechanism by which artemisinins exert their antimalarial effects, particularly their ability to generate reactive oxygen species (ROS) and interfere with the redox balance within the malaria parasite. The researchers found that artemisinins can act as both one-electron transfer agents and two-electron acceptors, potentially disrupting the function of flavin cofactors in redox-active enzymes within the parasite. The chemicals used in the study include artemisinins, methylene blue, ascorbic acid, N-benzyldihydronicotinamide (BNAH), riboflavin, flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD), among others. The conclusions suggest that artemisinins may act as antimalarial drugs by perturbing the redox balance within the malaria parasite, and their selective potency may be due to differences in sensitivity between parasite and human glutathione reductase. This research provides insights into the potential mechanisms of artemisinin resistance in malaria parasites and could inform the development of new antimalarial drugs.
10.1016/S0040-4039(00)73532-5
The study explores innovative synthetic pathways for the production of (+)-Artemisinin, a sesquiterpene endoperoxide with significant antimalarial properties derived from traditional Chinese medicine. The researchers utilized (-)-menthol as the starting material and developed two synthetic routes involving key steps such as OH-assisted chemo- and stereoselective C-H functionalization and acid/base-induced ring opening. The synthesis involved several intermediate compounds, including enone 14, epoxide 15, secondary alcohol 16, and keto-alcohol 17, which were characterized using spectroscopic methods. The study successfully synthesized two useful precursors, (+)-artemisiol (2) and compound 5, which can be further converted into (+)-Artemisinin. The chemical transformations included Jones oxidation, acetylation, reduction, oxidation, and benzylation steps, among others. The study's innovative approach to C-H functionalization and ring opening provides valuable insights for the total synthesis of (+)-Artemisinin and its analogues, contributing to the global efforts in malaria treatment.
