Total Synthesis Studies Of C₂₀-Diterpenoid Alkaloids

Diterpenoid alkaloids are the bioactive ingredients of medicinal plants from Aconitum,Consolidum,Delphinium,and Spiraea genera.To date,over 1,200 members of diterpenoid alkaloids have been isolated and characterized.The complex skeleton,diverse substitution types,and multiple chiral centers of the diterpenoid alkaloids have made them challenging targets to be synthesized.Based on the number of constituent carbons,these alkaloids can be categorized into C₁₈,C₁₉,and C₂₀0 classes.Among them,the C₂₀-diterpenoid alkaloids can be further classified into several types,depending on the characteristic bond linkages of the skeletons.With guan-fu base A,an antiarrhythmia agent approved in 2005 in China,as one of its distinguished members,the family of diterpenoid alkaloids exhibits a broad spectrum of biological activities,including acetylcholinesterase inhibition,de-addiction,anti-epileptiform,anti-inflammatory,and anti-cancer effects.The architectural complexity and notable biological profiles of the C₂₀-diterpenoid alkaloids have made them and their biogenetically relevant diterpenes highly pursued targets amongst the synthetic community from the 1960s,and a number of world-famous total synthesis groups,such as Professor Yong Qin of the Sichuan University,Professor Baran of the Scripps Institute,Professor Sarpong of the University of California,and Professor Gin of the University of Illinois,have made great contributions in this area.Current synthetic progress has been limited to the structurally simple alkaloids,such as atisine-,veatchine-,and napelline-type alkaloids.Nominine is the only member of the hetisine-type alkaloids to be synthesized prior to this work,and there is no total synthesis of hetsine-type alkaloids,although several groups have realized the assembly of the hetidine skeleton.The difficulties associated with the construction of the N–C6 and C14–C20 linkages that are not present in simpler congeners likely impede the synthetic progress toward the more complex hetisine-type members.In this thesis,the precursor 189 for the key 1,3-dipolar cycloaddition was prepared in a sequence of Stille coupling and other reactions starting from a cheap 3-methoxyphenylacetic acid.Subsequently,a new method of diastereoselective 1,3-dipolar cycloaddition of azomethine ylide to enone with an unusual regioselectivity has been developed.This 1,3-dipolar cycloaddition was employed as the key reaction for the assembly of the A/F/G/C tetracycle with the challenging N–C6 and C14–C20linkages already in place.An intramolecular nitrogen alkylation?E ring construction?,a Sm I₂-mediated free radical addition to the arene moiety without prior dearomatization?B ring construction?,and a diastereoselective aldol reaction?D ring construction?enabled the rapid access to the hetisine core.Finally,we completed the first total synthesis of hetisine type C₂₀-diterpenoid alkaloids?±?-spirasine IV and XI in 22 and 23total steps.Comparing to the hetisine-type C₂₀-diterpene alkaloids,hetidine-type C₂₀-diterpene alkaloids also possess the C14–C20 linkage in the skeleton,but no N–C6 linkage.Using the key intermediate 188a of A/F/G/C ring system with the N-C6 and C20-C14 linkages,we have obtained promising results of constructing hetidine skeleton by a strategy of breaking the N-C6 linkage.After extensive optimization of the conditions for the preparation of the easily enolizable precursor and the 1,3-dipolar cycloaddition,an enantioenriched tetracyclic compound can be prepared from chiral compound 212without chirality corrosion.The preparation of the chiral key tetracyclic compound188a has laid a solid foundation for the asymmetric total synthesis of various hetisine-and hetidine-type C₂₀-diterpene alkaloids.