Asymmetric Hydrogenation Of Nicotine Alkaloids And Functionalization Of Dihydrobenzo[c]phenanthridines And Their Biological Activities

Recently,botanical pesticides have recevied increasing attention because of low toxicity,low residue and envionmental friendliness.As the typical botanical pesticides,nicotine and benzo[c]phenanthridines are widely distributed and have a broad spectrum of biological activities.For instance,nicotine has the relationship with the mechanism of Parkinson's disease,Alzheimer's disease and pain and benzo[c]phenanthridines also possess various biological activities such as antitumor,insecticidal,anti-inflammatory and so on.Firstly,this thesis reviews the biological activities and syntheses of these two alkaloids in latest progress,then a series of work about the methodology of the syntheses of nicotine and benzo[c]phenanthridines and their application both in the synthesis of natural products and the related biological activities has been carried out.The related work is mainly divided into two parts:The nicotine's part: based on the atom economy,operational simplicity and environmental friendliness,the method of asymmetric hydogenation to synthesize nicotine and its analogues is firstly proposed.To overcome the challenge posed by enantioselective hydrogenation of pyridyl-containing unsaturated N-heterocycles,a strategy we refer to as the “substituent-control strategy” has been developed.Specifically,by introducing a substituent at the position adjacent to the pyridine N atom,the coordination ability of the pyridine moiety could be greatly reduced and thus facilitate the asymmetric hydrogenation of pyridyl-containing unsaturated N-heterocycles.Chapter two mainly focus on the methodology of Iridium-catalyzed asymmetric hydrogenation of 2-pyridyl cyclic imines.Chiral spiro iridium/phosphine-oxazoline catalysts with iodine as the additive have been developed to facilitate this asymmetric hydrogenation in high efficiency.The asymmetric hydrogenation exhibits broad scope and provides a novel efficient method for preparation of chiral nitrogen-containing heterocycles.Chapter three maily aims at the total synthesis of the nicotinic natural products(S)-nicotine,(S)-pyridylnicotine,(S)-anabasine and(S)-noranabasamine based on the developed hydrogenation of 2-pyridyl cyclic imines.Then the bioassay of nicotine analogues demonstrates that some of them have the high insecticidal activity with Culex pipiens pallens and can be further investigated as lead compounds.For example,the LC50 of compound TM-9 and TM-24 reaches 0.0433 ?g·mL-1 and 0.1839 ?g·mL-1,respectively.The benzo[c]phenanthridine's part: based on the former work,an improved and generally applicable base-free methodology for the annulation reaction of azabicyclic alkenes with substituted methyl o-halobenzoates(I or Br)has been developed.The present strategy has shown broad functional group compatibility and provides an efficient construction of benzo[c]phenanthridine nucleus of both fully aromatized-type and partially hydrogenated-type ones.