Stereoselective preparation of 10α- and 10β-aryl derivatives of dihydroartemisinin

Lewis acid-catalysed arylation of the 10β-benzoate and, less effectively, the 10α-benzoate of dihydroartemisinin [DHA] with activated aromatic compounds, including naphthalenes, stereoselectively, provides 10α-aryl derivatives including disubstituted naphthalene derivatives. 2-Methoxynaphthalene provides the 1-, rather than the 3-substituted derivative. In contrast, 10β-aryl derivatives are obtained stereoselectively from the 10β-bromide, generated in situ from trimethylsilyl bromide and the TMS ether of 10α-DHA, and the corresponding aryl Grignard reagents. The 10α-aryl compounds are shown by NMR spectroscopy and X-ray crystallographic analysis to possess a chair pyranose ring with equatorial aryl group, whereas the 10β-aryl derivatives have a twist-boat pyranose ring with equatorial aryl group. The stereochemistry of the Lewis acid-catalysed arylations, which is common to that observed for the Lewis acid-catalysed arylation of pyranosyl glycosides with axial anomeric leaving groups in general, may be rationalized in terms of axial attack from the α or si face of the half-chair oxonium ion intermediate. On the other hand, the Grignard reagents activate the axial bromide to elimination through complexation, and thereby the aryl nucleophile attacks the incipient oxonium ion from the β or re face.