Date of Award

1-1-1996

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Abstract

Part one is the study of 13-carbaartemisinin analogs as potential antimalarial drugs. Based on knowledge of the artemisinin's chemistry, mode of action, and structure-activity relationship, we proposed 13-carba-10-deoxoartemisinin 6 as an orally active antimalarial. Thus, the total synthesis of 6 was carried out and completed in 12 steps with a yield of 2% starting with ($-$)isopulegol. More analogs were produced from an intermediate in the total synthesis sequence: two stereoisomers of 6, 13-carbaartemisinin, and five tricyclic analogs. In general, the 13-carba analogs showed lower in vitro biological activity than artemisinin 1, only a stereoisomer of 6 displayed comparable activity to that of 1. In order to gain an understanding about the obtained activity, the analogs were treated with FeBr$\sb2,$ a simulated condition for the heme-rich environment in malaria infected cells. Major products isolated from the FeBr$\sb2$ treatment were characterized by spectral data. In light of the crucial role played by the C-4 radical in delivering activity, and the structural information obtained from the FeBr$\sb2$-promoted rearrangement, an attempt was made to rationalize the displayed activity of the 13-carbaartemisinin analogs.Part two is the study of ketyl radical cyclizations. Under SmI$\sb2$/THF/HMPA/tBuOH conditions, nonactivated unsaturated ketones underwent regio- and stereoselective cyclizations to afford 5- and 6-membered rings. Crucial elements to the success of the cyclization are: (a) the HMPA/SmI$\sb2$ ratio needs to be at least 3:1; (b) the presence of a proton source is required; (c) the ketone substrate must be added to a premixed solution of SmI$\sb2$, HMPA and t-BuOH in THF; and (d) DMPU is substituted for HMPA in the case of very fast cyclizations. Mechanistic studies showed that there is no significant reversibility with the ketyl radical cyclization step. We suggested that two transition state (TS) species might exist for the cyclization step: a ketyl anion or a protonated ketyl, dependent primarily upon the acidity of the proton source. The chair-like TS model used in predicting product stereochemistry is discussed. Work on stereochemistry assignment and substrate preparation is also presented.

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