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UBC Theses and Dissertations

Total synthesis of Veratrum alkaloids Nair, G. Vijayakumaran


A general method for the total synthesis of Veratrum alkaloids is outlined and its application to the synthesis of 5α,6-dihydroveratramine described. The condensation of 3β-acetoxy-5α-etiojerv-12(13)-en-17-one (80), a known compound available from the degradation of hecogenin or from total synthesis, with the lithio derivatives of appropriately substituted pyridines and subsequent elaboration of the coupled products is considered as a general scheme for synthesizing members of the Veratrum family. 2-Ethyl-5-methyl-3-hydroxypyridine (78) was chosen to provide the heterocyclic portion of 5α,6-dihydroveratramine (18). A synthesis of this material was achieved via 2-propionyl-4-methyl furan (122). Two independent routes were developed for the synthesis of 122 and these studies led to novel results on the electrophilic substitution of 3-methylfuran. Condensation of the lithio derivative of the methyl ether of 78 with the steroidal enone (80) followed by acetylation gave a mixture of two compounds. These were characterized as 30-acetoxy-23-methoxy-22,27-iminojerva-12(13),22,24,27-tetraen-17-ol (compound "A", 131) and 38-acetoxy-23-methoxy-22,27-iminojerv-12(13),14(15),16(17),22,24,27-hexaene (compound "B", 132). Compound "A" was subsequently converted to a D-ring aromatic compound isomeric with 132 (compound "C", 134). The stereochemical implications of these results are described. Methods for the reduction of the pyridine ring in 132 to the piperidine moiety present in 5α,6-dihydroveratramine are outlined. Catalytic hydrogenation of 132 in an acid-ethanol medium furnished 5α,6-dihydroveratramine which was identified by comparison with authentic sample. In view of the known conversions, the present work completes the formal total syntheses of veratramine, jervine, 11-deoxojervine and veratrobasine.

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