Synthesis Of The Key Intermediate Of Actinophyllic Acid

(–)-Actinophyllic acid is a new monoterpenoid indole alkaloid that was isolated from the leaves of Alstonia actinophylla, growing on the Cape York Peninsula, Queensland, Australia, by Carroll and co-workers in 2005. This unique indole alkaloid contains five continuous stereocenters and 1-azabicyclo[4.4.2] dodecane, 1-azabicyclo[4.2.1] nonane and octahydropyrrolo [1,2-a]azocine fragments. Its potent inhibition of activated thrombin-activatable fibrinolysis inhibitor(TAFIa) was expected to facilitate fibrinolysis. Therefore, total synthesis of actinophyllic acid could not only enrich indole alkaloid chemistry, but also pave the way for further studies on its biological activity. In this thesis, we focused on the synthetic studies toward(S)-3-(2,2-dimethyl-5-(3-methyl-1H-indol-2-yl)-1,3-dioxan-5-yl)pyrrolidin-2-one(77), which could serve as a key intermediate in the asymmetric total synthesis of actinophyllic acid.In this thesis,(R)-4-amino-2-hydroxybutanoic acid was used as the starting material, which underwent esterification, amidation reaction and protection of the hydroxyl group, providing the chiral building block 78. Compound 78 was converted to pyrrolidone 72 over five steps including protection of amide, deprotection of hydroxyl group, installation of a leaving group, a SN2 substitution by dimethyl malonate, followed by Krapcho decarboxylation. Next, a crucial aldol reaction between compound 72 and aldehyde 75 gave intermediate 87. A sequence of transformations involving oxidation, introduction of the hydroxymethyl group, nitro reduction, and removal of BOM protecting group finally led to the key intermediate 77 with the desired indole nuclei and C15 stereocenter. In summary, we have prepared the key intermediate(S)-3-(2,2-dimethyl-5-(3-methyl-1H-indol-2-yl)-1,3-dioxan-5-yl) pyrrolidin-2-one(77) in 19 longest linear steps and 2.08% overall yield, which set the stage for our ongoing asymmetric total synthesis of(–)-actinophyllic acid.