Synthetic Approach to the Total Synthesis of Natural Marine Isoquinoline Alkaloid

外海鞘素是从外海鞘中发现的天然海洋产物，具有很强的抗肿瘤活性。其中，Et 743目前正在进行II期临床试验评估。它是一种四氢异喹啉衍生物，在结构上与微生物番红花黄素相关。由于其新颖和多样的结构，一直在寻找构建它们的一般方法。我们对制备具有挑战性结构特征的海鞘素的合成策略的结果总结如下：1）我们完成了ABC环模型化合物的改进合成，该化合物具有与海鞘素和番红花苷相同的结构。（4-甲氧基-3-甲基苯甲基）-1-甲基-2，5-哌嗪二酮，这在早期阶段通过脱乙酰化引入酚羟基，随后通过质子催化的Baeyer-Villiger氧化。2）我们完成了以2，3-二羟基甲苯为起始原料，经7步反应合成3-羟基-4-甲氧基-5-甲基苯甲醛衍生物的实际合成。3）我们成功地以苯甲醛衍生物为起始原料，经15步反应合成了ABC环模型海鞘素。4）我们成功地合成了一个关键的三环内酰胺中间体，其E-环上的酚被保护，并将其应用于海鞘素天然产物的全合成。

Ecteinascidins are natural marine products discovered from Ecteinascidia turbinate and which exhibit potent antitumor activity. Among of them, Et743 is currently being evaluated in phase II clinical trials. It is a tetrahydroisoquinoline derivative that is structurally related to microbial safracins. Because of their novel and diverse structure, a general approach to their construction has been sought.A summary of our results on a synthetic strategy for the preparation of ecteinascidins, which have challenging structural features, follows :1) We completed an improved synthesis of the ABC ring model of compound, which has a structure common to ecteinascidins and safracins From 3- (4-methoxy-3-methylphenylmethyl) -1-methyl-2, 5-piperazinedione, this introduces a phenolic hydroxy group at an early stage by formylation followed by proton-catalyzed Baeyer-Villigeroxidation.2) We are finishing the practical synthesis of 3-hydroxy-4-methoxy-5-methylbenzaldehyde derivative prepared in seven steps from 2, 3-dihydroxytoluene and used to protect the phenolic hydroxy functionality as an isopropyl group.3) We succeeded in a practical synthesis of the ABC ring model of ecteinascidins from benzaldehyde derivative in 15 steps. The overall yield was 27%.4) We have efficiently synthesized a key tricyclic lactam intermediate having a protected phenol in the E-ring.Application of this strategy to the total synthesis of ecteinascidin natural products is now being intensive investigation in our laboratories.