| The olefin of t-butyl 2-chloro-5-phenylpent-3-enoate (1) was reacted with osmium tetroxide in a stereocontrolled fashion to provide t-butyl 2-chloro-3,4-dihydroxy-5-phenylpentanoate (2) in 63% yield. X-ray crystallographic analysis of 2 established the three contiguous stereocenters as 2S, 3S, 4R. Thus the conversion of a γ-phenylseleno-α,β-alkenoate to an α-chloro-β,γ-alkenoate was assigned as a 1,3-syn process. A series of three α-chloro-β,γ-alkenenitriles was prepared in high yield and high enantiomeric excess. The Posner group's previously established enantioenriched allylic chloroester synthesis was extended to the chemoselective preparation of six different densely functionalized synthons. The one-step transformation of 17 → 36 represents a direct, facile, and highly stereoselective synthesis of a γ-alkyl-α,β-dihydroxy-γ-butyrolatone with the unusual replacement of the 2-CI in ester 17 by OH with retention of C-2 stereochemistry.;Twelve dehydroartemisinin (DART) thiazole derivatives were prepared and screened for in vitro Toxoplasma lytic cycle activity. Eleven (92%) were noncytotoxic to host cells while nine displayed effective inhibition of Toxoplasma growth, comparable in potency to artemether and >100 times more inhibitory than the currently employed trimethoprim. The thiazoles as a group were effective at inhibiting the growth of extracellular as well as intracellular parasites. Unexpectedly, two DART-thiazoles (76 and 77 ) were parasiticidal; both inhibited parasite replication irreversibly after parasite exposure to 10 μM of drug for 24 hours, whereas the standard trioxane drugs artemisinin and artemether were not. Several DART-thiazoles described here represent effective anti-Toxoplasma trioxanes as well as molecular probes for elucidating the mechanism of action of the DART class of artemisinin derivatives.;Sulfamates are a class of hydrolytically stable carbamate analogs with several pharmacological activities. Artemisinin dimer primary alcohol diethylcarbamate, when tested in a P. berghei murine model (with three mice), was curative at a dose of 3 × 30 mg/kg and prolonged the life of mice an average of 14 days at a dose of 3 × 10 mg/kg. The benzyl sulfamate of artemisinin primary alcohol was prepared in 22.6% yield from the primary alcohol. When the benzyl sulfamate variant was tested it was found to have only mild activity (7 days of life compared to five days for the vehicle only) in the assay. |
