Application Of Intramolecular Michael Addition To Asymmetric Total Synthesis Of Lycojapodine A,Lycoposerramine Y And Lycoposerramine-V

Lycopodium alkaloids are a structurally related,yet diverse group of natural alkaloids,which have attracted great attention of organic chemists due to their important biological activities and unique skeletal characteristics.In this paper,taking advantage of asymmetric total synthesis in structure elucidation and biological investigation,studies on asymmetric total synthesis of lycojapodine A,lycoposerramine-Y and lycoposerramine-V are focused.In our studies on total synthesis of lycojapodine A,desymmetrization was applied to prepare the common chiral methylated intermediate in lycopodium alkaloids.A variety of methods,including RCM reaction,intramolecular SN2 reaction,intramolecular addition of a terminal alkyne to the aldehyde,and ring-expansion reaction,were attempted to construct the aza heterocyclic nine-member ring,but all failed.Utilizing intramolecular Michael addition of a 2-piperidone derivative,two chiral spiro intermediates were obtained in a 1:1 ratio,whose configurations were elucidated by 2D NMR experiments.We also explored the intramolecular Michael addition and reductive-amination of a liner substance,and a reliable and efficient method was developed to construct the decahydroquinoline core of the lycopodium alkloids.Unfortunately,the stereochemistry of the product could not match that of natural lycojapodine A.In our studies on the total synthesis of lycoposerramine-Y,the ?,?-unsaturated Weinreb amide was found to be preferentially reacted with various Grignard reagent over the aliphatic Weinreb amide.Therefore a new strategy using different side chain in sequence was developed to prepare the precursor for next intramolecular Michael addition.Although the stereochemistry of the product from the intramolecular Michael addition was not consistent to nature lycoposerramine-Y again,the newly developed efficient method shows great potential to construct the chiral six-member ring of lycopodium alkaloids.We also investigated the tandem reaction combined with deprotection followed by intramolecular Michael addition,but the result was unsatisfactory.Using an asymmetric intramolecular Michael addition of the linear substance and a reductive amination,we finally achieved an asymmetric total synthesis of lycoposerramine-V and its diastereoisomer.