Research on Synthesis of Marine Natural Products Austrodoral,Siphonodictyal B,Liphagal and Strongylin A

Author:Wang Jun Li

Supervisor:wu yan chao


Degree Year:2018





Some natural products possessing pharmaceutical value are less in natural sources and degradable in isolating process,so the isolation of these natural products in large quantity is difficult,which limits the research of their bioactivities further.In order to develop concise and effective synthetic methods,rearrangement reactions to construct the carbon skeleton effectively and strategies for achieving the natural products’skeleton directly have been used in the synthetic route.The synthesis of austrodoral analogue has been achieved using pinancol rearrangement of alky shift selectively.The synthesis of siphonodictyal B has been realized based on the early presence of an aldehyde group instead of a late-stage introduction catalyzed by Pd(PPh3)4.The concise and effective synthesis of aureol has been attained through 1,2-rearrangement reactions.The above mentioned method of achieving natural products is more concise and effective comparing with the previous methods.The controlled pinacol rearrangement via hydride shift or alkyl shift has been developed,which was used as the key step in the syntheses of marine natural products,including austrodoral,austrodoric acid and 8-epi-11-nordriman-9-one.Firstly,the key synthon 3-1 has been attained using the ozonolysis and reduction of NaBH4 as the key steps.Then,natural products could be generated through alky shift or hydride shift of 1,2-diol rearrangements switched by controlling the loading of BF3·Et2O.Austrodoral was selectively generated using 5 mol%of BF3·Et2O undergoing the alky shift of 1,2-diol rearrangements to construct the skeleton structure,functional group and chiral centers in one step.In contrast,8-epi-11-nordriman-9-one was obtained as the sole product when the 1,2-diol rearrangement was performed in the presence of 2 equivalent BF3·Et2O.The progress undergoes the hydride shift of pinacol rearrangements to construct the functional group and chiral centers in one step.Finally,Jones oxidation of austrodoral afforded austrodoric acid through the conversion of aldehyde carbonyl to carboxylic acid.The synthesis of austrodoral has been finished in 56.5%yield and 7 steps using rearrangement of pinacol as key reaction.The effective synthesis of 8-epi-11-nordriman-9-one afforded the material for researching the new method to construct siphonodictyal B.The skeletal rearrangement reaction of 1,2-diol 3-1 was used as a probe for preparing the ketones through high regioselectively hydride shift of pinacol rearrangement.8-epi-11-Nordriman-9-one was obtained with 90%yield as the sole product when the piancol rearrangement was performed in the presence of 2 equivalent BF3·Et2O in dichloromethane stirred for 30 minutes at room temperature.Under the optimized reaction conditions,the study of the scope of substrates suitable via hydride shift of 1,2-diol rearrangements,including 20 compounds owing different functional groups,has been completed in the yield of 76%-97%.The synthesis of ketones has been developed through selectively hydride shift of 1,2-diol rearrangement,which possess many advantages such as concise reaction operation,high yields,wide substrate scope,and toleration of substituent groups.The synthesis of natural products,such as siphonodictyal B,liphagal and croallidicytals C/D,has been achieved by using palladium-catalyzed cross coupling reaction of hydrazone and benzaldehyde.The synthetic route of siphonodictyal B used the 8-epi-11-nordriman-9-one as an key synthon.Firstly,N-tosylhydrazone 5-13 has been prepared from 8-epi-11-nordriman-9-one through Wittig reaction,acid catalyzed isomerizatioin and condensation of aldehyde carbonyl with hydrizine.Then,the cross coupling reaction was carried out with N-tosylhydrazone 5-13 in the presence of Pd(PPh3)4 and K2CO3 affording the skeleton of natural product of Z/E configurations,containing the C-C double bond inΔ9,15 position and aldehyde group in aryl ring.The structure of E configurations could be achieved through the iodine-promoted isomerization of carbon double bond configuration in sunlight.Siphonondicytal B was achieved by the removal of isopropyl ether protecting groups from compound of E configuration.Liphagal could be synthesized via cascade reactions,including epoxidation,rearrangement of epoxide,aldol condensation,and benzofuran formation,in one-pot operation from siphonondicytal B.The treatment of siphonondicytal B with catalysts of NIS and PPh3 gave the mixture of corallidictyals C/D in the ratio of 8/10(croallidicytal C/croallidicytal D)through the carbon double bond addition reaction with phenolic hydroxyl group.The cascade synthetic method of achieving analogue of siphonodictyal B gave the higher yield comparing with reported methods.The research on synthesis of analogue of aureol has been carried out involving the strategies of the consequence of 1,2-hydride shift and 1,2-methyl shift mediated by BF3·Et2O and the cross-coupling reaction of iodine alkane with aryl Grignad reagent catalyzed by nickel.In order to complete the synthesis of natural product aureol,the key synthon 6-4 has been attained through skeleton rearrangements of compound 6-5undergoing consequence of 1,2-hydride shift and 1,2-methyl shift mediated by BF3·Et2O,which gave the construction of chiral centers and had no influence on the iodine group used for the coupling reaction.Then,dppfNiCl2 catalyzed cross-coupling reaction of synthon 6-4 with(2,5-dimethoxyphenyl)magnesium bromide afforded the natural product precursor.The formal synthesis of aureol could be achieved in 2 steps through deprotection of methyl groups and addition reaction of the OH group and carbon-carbon double bond.Moreover,the synthesis of strongylin A was studied through a palladium-catalyzed cross coupling reaction and BF3·Et2O mediated rearrangement reactions.Compound 6-22 was achieved under the cross-coupling reaction of N-tosylhydrazone 6-24 with iodide 6-23 and hydrogenation catalyzed by Pd/C.The natural product precursor6-20 was attained through consequence of 1,2-hydride shift and 1,2-methyl shift mediated by BF3·Et2O.For now,the synthesis of strongylin precursor A has not been attained.