Ecteinascidin total synthesis

Isocyanide-based MCR was also applied for the total synthesis studies of natural products containing piperazine substructure. For example, trabectedin (also known as ecteinascidin 743 or ET-743) is undergoing clinical trials for the treatment of breast, prostate, and pediatric sarcomas. Ecteinascidin 743 (2) is an extremely potent antitumor agent isolated from a marine tunicate, Ecteinascidia turbinate [12]. Eukuyama et al. developed the total synthesis of ecteinascidin 743 from a Ugi reaction [13]. The reaction of p-methoxyphenyl isocyanide 3 gave Ugi product 7, which was cyclized to DKP intermediate 8 (Scheme 1). 

Scheme 1 Ugi reaction as a central step in the total synthesis of Ecteinascidin 743 by Fukuyama et al.

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

Several other novel, structurally and mechanistically diverse marine natural products have entered various preclinical and clinical studies. One of these products is ecteinascidin-743 (89 ET-743), isolated from the tunicate Ecteinscidea turbinata (105, 106) and recently approved for the treatment of sarcoma in the European Union as the first direct-from-the-sea drug. Total synthesis and methods developed during the total synthesis allowed the preparation of a simpler analog phthalascidin (90) with comparable activities (107-109). 

Ecteinascidin 743 is an extremely potent antitumor agent isolated from a marine tunicate. The total synthesis of this natural product was realized in the laboratory of T. Fukuyama." To achieve the synthesis of the key dipeptide fragment, they utilized the Ugi four-component reaction. The transformation was carried out under mild conditions providing the product with excellent yield. 

The Passerini reaction and the Ugi reaction provide a-acyloxyamides and a-acet-amidoamides, respectively. Naturally, these reactions have been applied in the synthesis of peptides and cyclopeptides/cyclodepsipeptides [91]. Recently, the application of these reactions in the synthesis of heterocycles was reported. One of the most notable examples is Fukuyama and co-workers total synthesis of ecteinascidin 743 (Et 743) (148), a complex natural product recently commercialized as an anticancer drug (Scheme 5.46) [92]. Thus, reaction of the amine 149, the amino acid 150, 4-methoxyphenyl isocyanide (151) and acetaldehyde afforded the corresponding Ugi adduct 152 in 90% yield. After a series chemical transformations, 152 was ultimately converted to Et 743. The connection between the structure of Et 743 and the peptidic nature of Ugi adduct is not obvious, but with the deep insight of an experienced synthetic chemist, the non-trivial link can be drawn and be put into practice [93, 94]. 

The preclinical pharmacology of Et 729 has been reported [73]. The current clinical plan for the more available ecteinascidin, Et 743, calls for three 0.5 mg doses per patient [74]. Ecteinacidin 743 is currently in phase 1 clinical trials in three European countries and in the United States [68]. The ecteinascidins have currently been extracted from harvested tunicate. Some partial syntheses of the ecteinascidin structure have been reported [70, 75], and one enantioselective total synthesis of ecteinascidin 743 has been published [74]. 

Having now appended both tetrahydroisoquinoline systems onto the central C-ring piperazine, the only major synthetic objective remaining to complete the total synthesis of ecteinascidin 743 (1) was the formation of the ten-membered macrocyclic F-ring lactone through the envisioned biomimetic o-quinone methide capture. Before this operation could be explored, however, several func-... 

With most elements of ecteinascidin 743 (1) now in place, only a few steps remained before the total synthesis would hopefully be successfully concluded. Thus, following deallylation of 74... 

In 2002, another impressive total synthesis of ecteinascidin 743 (1) was completed by Professor Tohru Fukuyama and several of his coworkers at the University of Tokyo. A collection of the most instructive transformations from this insightful approach, based in part on previous efforts targeting members of the saframycins (cf. Scheme 1), are presented in Schemes 14 and 15. 

Scheme 15. Key features of Fukuyama s total synthesis of ecteinascidin 743 (1).

Among MCRs, the Ugi reaction is a powerful three- or four-component coupling reaction with isocyanide as one of the reactants to construct multiple bonds in complex molecules. Applications of Ugi reactions in total synthesis are rather rare. One of the most advanced examples is the use in the total synthesis of ecteinascidin 743 48 by Fukuyama and coworkers, as depicted in Scheme 6.5 [22]. 

SCHEME 6.5 Synthesis of key fragment 60 in the total synthesis of ecteinascidin 743 48, using the Ugi multicomponent reaction. 

Danishefsky and coworkers reported studies toward the total synthesis of tetrahydroisoquinoline alkaloid, ecteinascidin. The synthesis required a pentasubstituted E-ring system where they utilized the di-f-butylsilylene protecting group in the sequence to prepare the amino acid 42 (eq 15). In addition to above... 

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