Total Synthesis Of Diterpenoid Alkaloid Liangshanone

Napelline-type C₂₀-diterpenoid alkaloids are a group of important natural products,mainly found in the genus Aconitum.These molecules display a wide spectrum of pharmacological effects involving antiarrhythmic,anti-inflammatory,antinociceptive,and anxiolytic activities.The napelline alkaloids are structurally characterized by a congested hexacyclic framework,including an azabicyclo[3.3.1]nonane（A/E rings）,a bicycle[2.2.1] heptane（B/F rings）,and a bicycle[3.2.1]octane（C/D rings）units,as well as three all-carbon quaternary stereogenic centers at C4,C8,and C10.The above structural features make the total synthesis of napelline alkaloids extremely challenging.To date,the only known total synthesis of the representative compound,napelline,was achieved by the Wiesner group with over 45 steps.Due to the architectural complexity and notable biological profiles,developing a concise and efficient method to synthesize theses natural products is of significance.In this thesis,we concentrate on the total synthesis of liangshanone isolated from Aconitum liangshanium,aiming to develop an efficient synthesis strategy for the napelline alkaloids and lay a foundation for the investigation of their biological activities.This thesis consists of two parts: 1)a review on the recent progress in the total synthesis of C20-diterpenoid alkaloids;2)our studies leading to the total synthesis of liangshanone.Initial attempts at the OD/DA sequence on intermediate 212 derived from geraniol resulted in the formation of cycloadducts with the undesired configuration at C4.In a revised strategy,the desired tricycle 271 with the correct configuration at C4 was obtained from methyl crotonate by OD/DA sequence and late-stage diastereoselective α-methylation.Then,a tandem alkene cleavage/Mannich cyclization was used to construct A/B/E/F rings.After introducing anα-methoxycarbonyl group in ketone 210 to enhance the reactivity of C8,a Robinson-type annulation and an intramolecular aldol reaction were successfully employed as key steps to complete the hexacyclic backbone of liangshanone.Ultimately,we completed the first total synthesis of liangshanone in its racemic form with 29 steps.On the other hand,an approach of organocatalytic enantioselectiveα-hydroxymethylation was established,which allowed us to prepare an enantiomerically enriched tricyclic intermediate（+）-251 a that should enable asymmetric access to the target natural product.