ASYMMETRIC SYNTHESIS--STRUCTURE, STEREOCHEMISTRY AND NMR

在早期的工作中，我们开发了一种制备14-[2H]- artether和

In earlier work we developed a method for preparing 14-[2H]-arteether and have now employed that reaction sequence to prepare 14-[3H]-arteether. The 3H labeled arteether was used to study the mechanism of action of this group of antimalarial drugs. Infected and uninfected red blood cells were treated with labeled arteether, dihydroartemisinin and a third drug that also contains the same endoperoxide grouping. The same six proteins were found to react in infected cells, whereas none of the proteins in the uninfected red cells reacted with these compounds nor with a control, [3H]- desoxyarteether. These findings make it possible to identify, purify and study the structure and function of the reactive proteins. Diastereofacial additions of primary alcohols to the carbon-carbon double bond of anhydrodihydroartemisinin, catalyzed by triphenyl-phosphine hydrobromide, were employed to prepare a series of 11- epidihydroartemisinin derivatives. These additions enabled us to prepare previously unknown epimeric arteethers. The antimalarial activity of 11- epi-dihydroartemisinin was examined and found to be half as active as the isomer with the natural configuration at C-11. A study of minor reaction products as a function of the number of equivalents of alcohol employed, provided invaluable information on the mechanism of the reaction and on the stereochemistry of the reaction using Polarized c-Frontier Molecular Orbital Theory. Our study of the regio- and stereo-selectivity of Beauveria sulfurescens mediated hydroxylation of 1,4-disubstituted benzenes have shown that the beta-carbon of the alkyl side chain is selectively hydroxylated.