Discovery Of Bioactive Components Of Isodon Scoarius And Total Synthesis Of Rugosiformisin A

Diterpenoids from the genus Isodon have attracted much attention of organic chemists and biologists due to their diverse structures and potential medicinal value.From a synthetic perspective,the novel structures have inspired innovations and provided great challenges for synthetic chemists,and the effective use of modern techniques,which is combined with organic synthesis and medicinal chemistry for the discovery of more novel natural and“natural-product-like”compounds,has been one critical research aspect;from a pharmacological point of view,the ability to find new lead compounds from the abundant Isodon diterpenoids,constitutes one critical element and is a great challenge.Our group has focused on the phytochemical investigations of this genus over the last four decades and have achieved substantial progress.Based on this topic,this dissertation combined phytochemistry with organic synthesis,and are organized as follows:?1?the investigations on the chemical constituents and their bioactivities of the medicinal plant,Isodon scoparius;?2?the total synthesis of the novel natural diterpenoid,rugosiformisin A.Additionally,the Chapter 3 summarized the progress in the total synthesis of natural spiro compounds,which mainly focus on the synthetic methods for the construction of the spiro scaffold.Chapter 1 Discovery of Bioactive Components of Isodon scopariusPrevious phytochemical investigations of I.scoparius by our group led to the discovery of four novel diterpenoids,which were structurally quite different from those isolated from other Isodon plants.This finding promoted us to systematically investigate this special species collected in different regions.Therefore,we investigated the chemical constituents of I.scoparius?10 Kg?distributed at an altitude of about 3450 m in the Yulong snow mountain of Lijiang County,Yunnan Province.As a result,125 compounds?75 new ones?were obtained.Scopariusene A?1?possessed of a rare expanded seven-membered B-ring;scopariusol A?4?featured a unique ether linkage spanning C-1 and C-11;18-hydroxy-merrilliadione and2-hydroxy-merrilliadione?81 and 82?were rare rearranged abietane diterpenoids;scopariusosides A–J?69–78?were new diterpene glycosides.The above research further refleted the chemical diversity of the secondary metabolites of I.scoparius,and the great influence by the ecological environment.Most of the isolated diterpenoids were evaluated for their in vitro cytotoxicity against five human tumor cell lines,anti-inflammatory activity,and the autophagy-modulating activity.14compounds showed cytotoxic activity,among which 7 showed significant cytotoxicity;13 compounds showed significant inhibitory effects on the NO production in LPS-stimulated RAW264.7 cells.It is worth to mention that 11 diterpenoids without the?-exomethylene-cyclopentanone moiety,which could be responsible for the cytotoxicity,showed effects on the expression of LC3B.This finding provides an alternative opportunity for the biological study of diterpenoids from the genus Isodon.Chapter 2 Total Synthesis of Rugosiformisin ARugosiformisin A,a tricyclic diterpenoid containing a novel spiro-[5.6]ring system,was isolated from I.rugosiformis by our group and has been revealed to have inhibitory activity on arachidonic acid-induced platelets aggregation in rabbits.Based on its unique architecture and the potential biological properties,and for the further pharmaceutical chemistry and pharmacodynamics research,we initiated the total synthesis of rugosiformisin A.The 6/6/6 ring system has been constructed via the Pd?dppf?Cl₂-catalyzed Suzuki-Miyaura coupled reaction,the Iridium-catalyzed asymmetric allylic substitution,the Birch reduction and acid hydrolysis reaction and so on,and we proceeded to the construction of the most challenging spiro-[5.6]ring system.Chapter 3 Total Synthesis of Natural Spiro CompoundsThe spiro motif is becoming more prevalent as a template in asymmetric synthesis,drug discovery,and catalysts development.The asymmetric synthesis of product containing spiroatoms is extremely challenging,and it has attracted significant interest from synthetic community.To date,different strategies has been developed to achieve the total synthesis of natural spiro compounds.In this review,we summarise the construction methods for the spiro moiety,including semi-pinacol rearrangement,Aldol reaction,ring-closing metathesis,Diels-Alder reaction,acid and based promoted spirocyclization,Claisen rearrangement,radical cyclisation and alkylation reaction,and some representative examples have been provided.This section aims to emphasize the key steps for the total syntheses of natural spiro compounds,especially synthetic methods for the construction of the spiro moiety,and therefore,other chemical transformations will be discussed briefly.