Man-Ki Cheung

C-10 Ester and Ether Derivatives of Dihydroartemisinin − 10-α Artesunate, Preparation of Authentic 10-β Artesunate, and of Other Ester and Ether Derivatives Bearing Potential Aromatic Intercalating Groups at C-10

Preparative and stereochemical aspects of reactions providing new C-10 ester and ether derivatives of the antimalarial drug dihydroartemisinin (DHA, 2) have been examined. β-Artesunate has been prepared for the first time, and has been differentiated from the antimalarial α-artesunate; the latter has been incorrectly designated as the β-epimer in Chemical Abstracts and some primary literature. New ester and ether derivatives bearing potential intercalating groups have been synthesised by means of the Schmidt, Mitsunobu and DCC coupling procedures, by acylation in the presence of DMAP, or by hydroxy activation with BF3 as catalyst. When the hydroxy group of DHA acts as a nucleophile towards activated carboxy groups in acylating agents or the DCC intermediate, α-esters are obtained exclusively. When the hydroxy group is activated for displacement by nucleophiles, as in the Schmidt or Mitsunobu procedures, β-esters and β-ethers are obtained either exclusively or predominantly. An exception is represented by the Mitsunobu procedure involving DHA and 1- and 2-naphthols, in which mixtures of epimers are obtained; however, exclusive formation of β-aryl ethers takes place when the Schmidt procedure is used, with activation of the intermediate trichloracetimidate by SnCl2. The latter method is therefore superior to patented procedures for the preparation of β-aryl ethers from nonbasic aryl alcohols without detectable rearrangement to C-aryl compounds. However, the Mitsunobu procedure is better when basic aromatic alcohols are used as nucleophiles. The formation of α-products in which the hydroxy group of DHA acts as a nucleophile is of biological significance in relation to enzyme-mediated Phase II glucuronidation of DHA, in which only the α-DHA glucuronide is formed.