Synthetic Studies On The Marine Natural Product Of Ent-chromazonarol

ent-Chromazonarol, isolated from marine sponge Disidea pallescens, has been shown to have anticancer and antineoplastic activities and is a promising drug leading compound. The researches of this thesis were centered on the synthesis of the marine natural product of ent-chromazonarol as well as the synthetic studies on its analogues. Accordingly, the palladium-catalyzed carbene migratory insertion and reduction-isomerization of allylic alcohol have developed for the synthesis of ent-chromazonarol, 8-epi-19-methoxypuupehenol and 9-epi-pelorol. The main contents of this thesis are as follows:1. The synthesis of ent-chromazonarol. On one hand, the Mo OPH-promoted α-hydroxylation of sclareolide followed by an ester-to-hemiacetal conversion with DIBAL-H, an oxidative cleavage of the α-hydroxyl hemiacetal with sodium periodate, and a condensation with p-toluenesulfonyl hydrazide afforded the key intermediate of sesquiterpene N-tosylhydrazone. On the other hand, the hydroxyl protection of hydroquinone followed by iodination with N-iodosuccinimide gave the intermediate of iodo-dimethoxybenzene. Finally, the resulting intermediate of sesquiterpene N-tosylhydrazone and N-iodosuccinimide subsequently underent a Pd[PPh3]4-catalyzed carbene migratory insertion, a reduction-isomerization of allylic alcohol, a redox hydroxyl deprotection, and a BF3·Et2O-promoted intramolecular hydroalkoxylation to afford the marine natural product of ent-chromazonarol.2. The synthesis of 8-epi-19-methoxypuupehenol. The hydroxyl protection of benzene-1,2,4-triol followed by iodination with N-iodosuccinimide generated the intermediate of 1-iodo-2,4,5-trimethoxybenzene, which was coupled with the above intermediate of sesquiterpene N-tosylhydrazone by a Pd[PPh3]4-catalyzed carbene migratory insertion strategy to give an allylic alcohol. The reduction-isomerization of this allylic alcohol followed by a redox hydroxyl deprotection and a BF3·Et2O-promoted intramolecular hydroalkoxylation afforded 8-epi-19-methoxypuupehenol.3. The construction of the ring-CD skeleton of 9-epi-pelorol. Coupling of 1-iodo-2,3-dimethoxybenzene with the above intermediate of sesquiterpene N-tosylhydrazone by a Pd[PPh3]4-catalyzed carbene migratory insertion strategy afforded an allylic alcohol, which, in turn, underwent a intramolecular Friedel–Crafts alkylation reaction to afford the ring-CD skeleton of 9-epi-pelorol.It is note worthy that the palladium-catalyzed carbene migratory insertion strategy was used here for the first time for the synthesis of this kind of marine natural products, which might be an advantage in comparision to the reported tert-butyllithium-promoted nucleophilic addition strategy. The synthetic strategies in this thesis would find more applications for the syntheses of other members of this class of marine natural products as well as analogues for detailed structural-activity relationship studies.