title: Structure-activity relationships of the antimalarial agent artemisinin. 3. Total synthesis of (+)-13-carbaartemisinin and related tetra- and tricyclic structures.
abstract: Provided by total synthesis, endoperoxides 18, 20, and 22 underwent intramolecular oxymercuration-demercuration leading respectively to formation of an isomeric tetracycle, (1aS, 3S, 5aS, 6R, 8aS, 9R, 12S)-10-deoxo-13-carbaartemisinin (19), (+)-10-deoxo-13-carbaartemisinin (21), and (+)-13-carbaartemisinin (4). Structure assignment to 19 and 21 was based on single-crystal X-ray crystallographic analysis. Tricyclic endoperoxide 20 was converted to methyl and benzyl ethers 23 and 24 and reduced to saturated analog 25 which was also converted to ethers 26 and 27. In vitro antimalarial screening of both tri- and tetracyclic analogs was conducted using the W-2 and D-6 clones of Plasmodium falciparum. Neither target 4 nor 21 displayed substantial antimalarial potency in vitro against P. falciparum, but the diastereomeric peroxide 19 possessed good antimalarial potency in vitro. Tricyclic analogs were uniformly impotent. Iron(II) bromide-promoted rearrangement of 21 gave, in 79% yield, the unique tetracyclic alcohol 35, while 19 provided ring-opened cyclohexanone 41 (39%) along with the tricyclic epoxide 42 (20%). Neither 41 nor 42 possessed in vitro antimalarial activity, suggesting that epoxide-like intermediates are not responsible for the mode of action of this subclass of antimalarials. Rearrangement of 10-deoxoartemisinin (43) with FeBr2 gave a major product (79%) not encountered in the rearrangement of artemisinin that resulted from unraveling of the tetracyclic system cyclohexanone 46. Minor amounts of 1,10-dideoxoartemisinin (49) (8%) were also produced in this reaction.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University 38677, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Avery
authors.forename: P
authors.initials: P
authors.lastname: Fan
authors.forename: J M
authors.initials: JM
authors.lastname: Karle
authors.forename: J D
authors.initials: JD
authors.lastname: Bonk
authors.forename: R
authors.initials: R
authors.lastname: Miller
authors.forename: D K
authors.initials: DK
authors.lastname: Goins
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: C099407:13-carbaartemisinin; D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C031327:artemisinin