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Protecting-Group-Free Total Synthesis of Isoquinoline Alkaloids by Nickel-Catalyzed Annulation of o-Halobenzaldimine with an Alkyne as the Key Step



An efficient short total synthesis of benzo[c]phenanthridine alkaloids including oxyavicine, oxynitidine, and oxysanguinarine is described. Thus, N-methyl-o-bromobenzaldimines 1 bd undergo regioselective cyclization with 4-(benzo[d][1,3]dioxol-5-yl)but-3-yn-1-ol (2 b) in the presence of [Ni(cod)2] (cod=1,5-cyclooctadiene). In situ oxidation of the resultant isoquinolinium salts gives isoquinolinone derivatives 5 bd with benzo[d][1,3]dioxol-5-yl substitution at the C3 atom and a (CH2)2OH group at the C4 atom. Later, oxidation of the alcohol group in 5 bd to the aldehyde moiety followed by acid-catalyzed cyclization and dehydration completes the total syntheses to give oxyavicine, oxynitidine, and oxysanguinarine in 67, 65, and 60 % yields, respectively. The synthesis requires four steps from o-bromobenzaldehyde derivatives. Transformations of these alkaloids to the other alkaloids in this family are also discussed herein.