Synthetic Approach to the Total Synthesis of Natural Marine Isoquinoline Alkaloid

外海鞘酸素是一种天然的海洋产品，从甲鱼外海鞘中发现，具有很强的抗肿瘤活性。其中，Et743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，在结构上与微生物红花素相关。由于它们的结构新颖多样，人们一直在寻找一种通用的方法来构建它们。摘要：1)从3-（4-甲氧基-3-甲基苯基甲基）-1-甲基- 2,5 -哌嗪二酮为原料，通过甲酰化和质子催化baeyer - villiger氧化，在早期引入了一个酚羟基，完成了ABC环模型的改进合成，该模型具有与果皮苷和萨弗拉苷相同的结构。2)完成了以2,3 -二羟基甲苯为原料，七步合成3-羟基-4-甲氧基-5-甲基苯甲醛衍生物的实际合成，并用于保护酚羟基作为异丙基。3)通过15步合成了苯甲醛衍生物的ABC环模型。总收益率为27%。我们有效地合成了一个关键的三环内酰胺中间体，在e环上有一个受保护的苯酚。目前，我们的实验室正在深入研究将这种方法应用于果皮酸天然产物的全合成。

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.