Construction Of Complex Fused And Bridged Bicycles Via Olefin Metathesis And Studies Toward Total Synthesis Of Pseudolaric Acid F

Ring system as one of the most important geometric structures of organic compounds has attracted intense interests of organic chemists for their construction.How to construct the ring skeletons concisely and effectively is always what chemists pursued,even though significant development has been achieved in this field.In the past few decades,transition-metal-catalyzed olefin metathesis(RCM)has quickly become one of the most versatile and powerful tools in organic synthesis.It has been widely used to construct the C-C double bonds and the rings.RCM reaction has become one of the key reactions for total synthesis of natural products and drugs.This dissertation aims to develop new methods for the construction of complex ring systems(include bridged rings and fused rings)via RCM reaction.and apply them to to the synthesis of the tricyclic skeleton of taxol and the diterpene pseudolaric acid F.There are many natural products which contain bicyclo[n.3.1]ring system.Because of the huge strain,it is very difficult to construct these skeletons,especially the bicyclo[5.3.1]ring systems(also known as 6-8 bridged bicycle).Now We have developed an efficient RCM approach for synthesis of bridged carbocyclic compounds via the substrate conformation control by a bulky TMS group.Specifically,by treatment with 5 mol%Hoveyda-Grubbs second generation catalyst and 1.0 equivalent Ti(OiPr)4 in refluxing CH2Cl2 for 4 hours,a series of the substituted cyclohexanols which contain two olefin side chains at C-1 and C-3 positions and a large silyl group at C-5 position could undergo RCM reactions to afford the corresponding bridged bicycles.We have two considerations about the introduction of a large silyl group:1)The sterically demanding silyl group would stabilize a productive conformation of RCM in which two olefin chains occuped di-axial positions,2)The silyl group could be removed or converted to useful functions in later stage.With the optical reaction condition in hand,we synthesized a couple of bridged bicycles,including bicyclo[3.2.1]octene,bicyclo[3.3.1]nonenes,bicyclo[4.3.1]decenes in good yields.Even though the medium-sized carbocycles(including 8/9-membered rings)have high ring strain,we have synthesized bicyclo[5.3.1]undecenes bearing a double bond at different positions of the newly forged bridge.Also,the hydroxyl group was protected with TMS group,RCM reaction was worked well in most cases.Furthermore,we also successfully constructed the highly strained 6-9 bridged compound through the same strategy,albeit in low yield.Starting from one of the 6-8 bridged bicycle compounds,we synthesized the tricycle skeleton of taxol via Fleming-Tamao oxidation,SeO2-oxidation in several steps.A lot of bioactive natural products contain fused bicyclic ring systems.The way to make the bicycle rings would significantly influence the overall synthetic efficiency of these natural products.We have developed a new method base on enyne metathesis(EYM)reaction to synthesize the fused bicyles.By treatment of 3 mol%Grubbs second generation catalyst under the atmosphere of ethylene in refluxing CH2CI2 for 4 hours,various enynes underwent the desired transformation to afford a series of fused bicyclic dienes with diverse functions.With this method,we can not only synthesize diverse fused[5-7]/[5-6]/[6-7]bicyclic compounds,but also make more complex tricycle compounds(including fused[6-7-5]/[6-6-7]/[6-7-6]tricyclic compounds)in good yield.To our delight,we can also synthesize the fused more challenging[5-8]/[6-8]bicyclic compounds by this method.The resulting diene products could be converted to the useful intermediates via 4-π electrocyclization,singlet oxygen addition reaction and so on.Starting from fused[5-7]bicyclic compound 3-ad,the tricyclic skeleton of pseudolaric acid F were constructed with two key reactions,singlet oxygen cycloaddition and radical cyclization.Pseudolaric acid F contains a trans-fused[5-7]bicyclic core(polyhydroazulene)and a bicyclo[3.2.1]lactone system bearing four contiguous stereocenters.Pseudolaric acid F has been identified as a potent antifungal,antifertility agent,also it displays significant activity against the HL-60 cell.Beginning with cyclopentanone.the fused[5-7]bicycle compound was constructed via newly developed EYM reaction.The enone intermediate was formed via singlet oxygen cycloaddition followed by peroxide rearrangement.The C-10 quaternary carbon center was constructed via radical cyclization.Finally,the functionalized tricylic skeleton of pseudolaric acid F was acquired through ozonolysis,oxidation and Ohira reaction.