Total Synthesis Of Sarpagine- And Koumine- Type Indole Alkaloids And Hetidine-Type C₂₀-Diterpenoid Alkaloids

Total synthesis of natural products is an effective means to provide substantial quantities and structural diversities of both natural products and their derivatives for innovative drug research.To accomplish the total synthesis of alkaloids with significant biological activities and complex chemical structures,new methodologies and synthetic strategies have been developed in this thesis.Based on these progresses,asymmetric total synthesis of five sarpagine-type indole alkaloids,three koumine-type indole alkaloids,and two hetidine-type C₂₀-diterpenoid alkaloids has been achieved.The thesis consists of two parts as follow:Part 1:Total synthesis of sarpagine-and koumine-type indole alkaloids.Sarpagine-and koumine-type alkaloids belong to the monoterpene indole alkaloid family,and hundreds of members have been isolated mainly from the medicinal plants of Apocynaceae and Gelsemiaceae category.These types of alkaloids have complex cage-shaped scaffolds and multiple stereogenic carbon centers,therefore,are challenging synthetic targets for chemists.This thesis reports a collective and asymmetric total synthesis of sarpagine-type alkaloids and the biogenetically related koumine-type alkaloids.New methodologies and strategies developed in this thesis include:(1)new method of tandem sequential amine oxidation and cyclopropanol ring-opening cyclization to construct the indole-fused azabicyclo[3.3.1]nonane skeleton;(2)new method of a cooperative organo/metal-assisted ketone?-allenylation to construct the azabicyclo[2.2.2]octane skeleton;(3)a biomimetic Au-catalyzed indolyl dearomative addition to the allene unit to assemble the koumine cage scaffold.Using the aforementioned bridged skeleton-forming methods as key steps,we have finished concise total synthesis of five sarpagine-type indole alkaloids(i.e.vellosimine,normacusine B,trinervine,affinisine,and N_a-methyl-16-epipericyclivine)and three koumine-type indole alkaloids(i.e.koumimine,N-demethylkoumine,and koumine).This strategy could be adapted to synthesize other related natural products and their derivatives/analogues.Part 2:Total synthesis of hetidine-type C₂₀-diterpenoid alkaloids.The C₂₀-diterpenoid alkaloids have been isolated mainly from plants of Ranunculaceae family with traditional medicine use.As a consequence of their broad spectrum of important biological activities and complex cage-shaped structures,the C₂₀-diterpenoid alkaloids have received significant attention of synthetic chemists over decades.Members of the C₂₀-diterpenoid alkaloids,especially these of atisine-,hetisine-,denudatine-,and hetidine-type,have been successfully synthesized.In contrast,only two members of the hetidine-type C₂₀-diterpenoid alkaloids(i.e.septedine and 7-deoxyseptedine)have been conquered,despite considerable efforts having been made toward this type by several natural product total synthesis groups.On basis of our experience in total synthesis of hetisine-type C₂₀-diterpenoid alkaloids,using A/C/E/F tetracycle 2-77 as the key intermediate,a sequence of Rh-catalyzed dearomative cyclopropanation of the benzene ring and subsequent S_N2-like ring opening of the cyclopropane moiety was developed to stereospecifically install the challenging equatorial C7-OH group and to concurrently construct the B ring.This cyclopropanation strategy also allowed preparation of natural product analogues with unnatural functionalities at C7.Next,we used a reversible aldol reaction to construct the bicyclo[2.2.2]octane skeleton and thus completed assembly of the hetidine core.Finally,the first asymmetric total synthesis of hetidine-type C₂₀-diterpenoid alkaloids talassamine and talassimidine has been accomplished in 26 and 27 total steps,respectively.