A One-pot Synthesis Of Dibenzofurans From 6-Diazo-2-Cyclohexenones And Synthetic Studies Towards Aphanorphine And Chlorahololide A

This dissertation covers a one-pot synthesis of dibenzofurans from 6-diazo-2-cyclohexenones and synthetic studies towards Aphanorphine and Chlorahololide A. It includes three chapters.In Chapter 1, A One-Pot Synthesis of Dibenzofurans from 6-Diazo-2-Cyclohexenones is described. Dibenzofurans have attracted tremendous attention in both biological and material science owing to their pharmacological, electronic, and/or optical properties. We have developed a novel approach to rapidly construct dibenzofuran motifs from 6-diazo-2-cyclohexenones and ortho-haloiodobenzenes through Pd-catalyzed cross-coupling/aromatization followed by a Cu-catalyzed Ullmann coupling performed in a one-pot fashion. The new method is operationally simple, highly selective, and synthetically useful. A wide range of substrates are compatible for the transformation and the desired products have been obtained in good to excellent yields.Chapter 2 is focused on the synthetic studies towards Aphanorphine. Aphanorphine is a tricyclic alkaloid featuring a benzazepine skeleton, which was isolated from the fresh water blue-green alga Aphanizomenon Flos-Aquae along with other neurotoxins, such as saxitoxin and neosaxitoxin. One of the structural characteristics of the alkaloid is its possession of a quaternary carbon at the benzylic position. It has an interesting structural framework closely related to those of analgesics such as the natural narcotic morphine, pentazocine and eptazocine. Its potential pharmacological activities and highly rigid structure make aphanorphine an interesting target for synthesis and has received considerable attention. The total synthesis of(±)-Aphanorphine in 8 steps and 27.6% overall yield from the known amino alcohol and aldehyde highlighted by the aza-Cope/Mannich and intramolecular Friedel-Crafts reaction was discribed. In addition, an efficient alkyne aza-Cope-Mannich cyclization was also effective in the total synthesis of(±)-Aphanorphine in 8 steps and 30% overall yield between 2-hydroxy homopropargyl tosylamine and aldehyde in the presence of InCl3/AlCl3.Chapter 3 deals with the synthetic studies towards Chlorahololide A. Chlorahololide A, a highly complex lindenanetype sesquiterpenoid dimer, was first isolated by Yue and co-workers in 2007 from South China Chloranthus holostegius. Biogenetically, these unique dimers are supposed to be formed through a [4+2] cycloaddition process. Structurally, Chlorahololide A possess a novel polycyclic framework embedded with two cyclopropane rings bearing two adjacent angular methyl groups, and a highly congested cyclopentane along with an unusual trans-5/6 ring junction. Chlorahololide A contained eleven stereogenic centers, two of which are all-carbon quaternary centers. It exhibits potent and selective inhibition of the delayed rectifier(IK) K+ current with an IC50 of 10.9 μM. The obvious synthetic challenge posed by the Chlorahololide A, coupled with its impressive biological activity, have generated a significant interest from the synthetic community. Several distinct strategies have been applied to the construction of the core structure of the target compound, including(i) intermolecular Diels-Alder reaction,(ii) intermolecular Michael addition, and(iii) radical-alkene cyclization and so on. Unfortunately, none of them led to the completion of the total synthesis of this lindenanetype sesquiterpenoid dimer, and only unnatural Diels-Alder product and the analogues of natural product Cycloshizukaol were obtained.