Protecting-Group-Free Total Synthesis of Isoquinoline Alkaloids by Nickel-Catalyzed Annulation of o-Halobenzaidimine 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 1b-d undergo regioselective cyclization with 4-(benzo[d][1,3]dioxol-5-yl)but-3-yn-l-ol (2b) in the presence of [Ni(cod)(2)] (cod = 1,5-cyclooctadiene). In situ oxidation of the resultant isoquinolinium salts gives isoquinolinone derivatives 5b-d with benzo[d][1,3]dioxol-5-yl substitution at the C, atom and a (CH2)(2)OH group at the C-4 atom. Later, oxidation of the alcohol group in 5b-d 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.