Synthetic Studies On Natural Products Applanatumol Z5,Mannolides And Longifolene Based On Diels-Alder Reaction

All-carbon quaternary carbon centers are widespread in natural products and drug molecules.The construction of quaternary carbon has always been a difficult and active area in organic synthetic chemistry.This dissertation was based on the one-step construction of double quaternary carbon by the Diels-Alder reaction,applanatumol Z5 and lingzhiol(containing 1,2-double quaternary carbon),mannolides A-C(containing 1,4-double quaternary carbon),longifolene(containing 1,5-double quaternary carbon)were selected as target molecules for the synthetic research.It was described in the following three chapters.Chapter 1 Synthetic studies on natural products Applanatumol Z5 and LingzhiolGanoderma meroterpenoids(GMs)has attracted chemist attention due to its unique structure and extensive biological activities.Among GMs,applanatumol Z5,lingzhiol and applanatumol C with special 5/5/6 rotary-door shaped and 1,2-double quaternary carbon structure were particularly representative.Applanatumol Z5 with weak against acetylcholinesterase activity and applanatumol C with COX-2 inhibitor effects were isolated from the fruit body of Ganoderma lucidum by Cheng' group.In addition,they isolated lingzhiol from Ganoderma lucidum that could activate the Nrf2/Keap1 enzyme activity in the glomerular mesangial cells of diabetic patients.Considering these three compounds had the same tricyclic framework,the Diels-Alder reaction was designed to construct two quaternary carbon frameworks in one step.So,we could complete the synthesis of these molecules efficiently.It was unexpectedly found that dithiolane and primary alcohols undergo an oxidative coupling by Pd/C and then deprotected to transform intermediates 1-14 into 1-11.Treatment tetrasubstituted dienophile 1-11 with Danishefsky diene(1-10)by Diels-Alder reaction constructed the rotary-door adjacent tricyclic ring system compound 1-16 in one step.Late stage,the diastereo-and regioselective carbonyl reduction led to achieve the total synthesis of applanatumol Z5 in 7 steps(5 pots)with 23% overall yield.Moreover,1-16 and applanatumol Z5 as key intermediates were attempted to synthesize applanatumol C and lingzhiol,respectively.Chapter 2 Synthetic studies on natural products Mannolides A-CMost of cephalotane-type diterpenoids are norditerpenoids with less than 20 carbons.For the first time,Yue's group isolated three new C20 cephalotane-type diterpenoids mannolides A-C from Cephalotaxus mannii Hook f.in Xishuangbanna in 2016.These new C20 skeleton could serve as the key biosynthetic intermediate for C19 norditerpenoids harringtonolide.Considering mannolides A-C had a novel and unique 1,4-double quaternary carbon structure,we chose Diels-Alder reaction to construct quaternary carbon center in one step and studied on the synthesis of these natural products.Starting from commercial available materials,we developed a novel strategy to synthesize polysubstituted phenol compound 2-61.This compound was treated with secondary alcohol 2-4 via the oxidative dearomatization to obtain 2-70 a,followed by intramolecular inverse-electron demand Diels-Alder reaction to construct the quaternary carbon center,and the selective Aldol reaction to obtain 2-81 a,The most critical continuous five stereocenters(two of which are all-carbon quaternary carbons)bowl-shaped core B/C/D ring system of mannolides A-C had been achieved The following investigation toward total synthesis of mannolides A-C was currently underway on the basis of present results in our laboratory.Chapter 3 Synthetic studies on natural product LongifoleneLongifolene,as a sesquiterpene was widely distributed in nature.Due to its unique activity and complicated structure,longifolene had attracted much more attention from the synthetic organic communities.Since it was isolated from Pinus longifolia in 1928 and the structure was unambiguously established by the Moffet's group in 1953,several groups had made great contributions to the total synthesis of this molecule.Here in,we used oxidative dearomatization/intramolecular inverse-electron demand D-A reaction to construct 1,4-double quaternary carbon and intramolecular selective desymmetric Aldol reaction to construct molecular skeleton efficiently.This desymmetric strategy could be utilized to complete the enantioselective synthesis.Late stage,1,5-double quaternary carbon would be obtained by ring expansion.The relevant researches were still in progress.