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 b-d 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 b-d with benzo[d][1,3]dioxol-5-yl substitution at the C(3) atom and a (CH(2))(2)OH group at the C(4) atom. Later, oxidation of the alcohol group in 5 b-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.
Korivi
Rajendra Prasad
RP
Department of Chemistry, National Tsing Hua University, Hsinchu, 30013, Taiwan.
Cheng
Chien-Hong
CH
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000480:Alkynes / Q000737:chemistry*; D002384:Catalysis; D018360:Crystallography, X-Ray; D003500:Cyclization; D006846:Hydrocarbons, Halogenated / Q000737:chemistry*; D007097:Imines / Q000737:chemistry*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D009532:Nickel / Q000737:chemistry*; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000480:Alkynes; D006846:Hydrocarbons, Halogenated; D007097:Imines; D007546:Isoquinolines; D009532:Nickel