| The azaspirocycle skeleton exists in many bioactive natural products and has emerged as a research frontier in the field of synthetic chemistry for decades.The efficient construction of the azaspirocycle skeleton is of great interest for synthetic methodology and development of innovative drugs.Based on the novel reactivity of nitroso groups,this thesis focuses on the method development of novel ring formation to forge a general formation strategy for azaspirocycles and application in the synthesis of structurally intriguing natural products.Given by the previous work in this research group,a novel reactivity of the nitroso group was discovered and constituted the first part of the thesis.A conjugated diene-nitroso substrate was prepared and subjected to the proposed nitroso-Diels-Alder reaction.It was surprisingly that a nitroso-ene reaction product was obtained instead.This unprecedented reaction outcome encouraged us to explore diene substrates to access a variety of azaspiro skeletons with excellent regioselectivity and functional group tolerance.We not only completed the preparation of 1-azaspiro [5.5] undecane,but also constructed two types of azaspiro [4.5] decane.The current progress further enriches the reaction mode of nitroso-ene reaction and also provides a novel and general method for various azaspirocycle skeletons.Secondly,the given nitroso-ene reaction was adapted as a key reaction toward the total synthesis of alkaloid 3-demethoxyerythratidinone.Starting from the readily available vinyl bromide and substituted aryl boronate,Suzuki coupling proceeded smoothly to produce a diene-methyl ester which was readily converted into hydroxamic acid.After oxidation,the corresponding reactive nitroso species was carried out intramolecular nitroso-ene reaction to furnish the A-B-D ring skeleton of Erythrina alkaloids.The final formation of the C-ring was designed to be went through the 1,6-aza-Michael addition,and the total synthesis is currently pursued in this laboratory. |
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