Of ecteinascidins

Model studies directed toward the synthesis of Ecteinascidin 743 employed an elegant Pictet-Spengler cyclization of phenethylamine 54 and the 1,2-dicarbonyl compound 55 to assemble the spiro tetrahydroisoquinoline 56 in a stereospecific fashion. " The silica-catalyzed condensation reaction provided 56 in excellent yield. 

Zewail-Foote, M. Hurley, L. H. Differential rates of reversibility of ecteinascidin 743-DNA covalent adducts from different sequences lead to migration to favored bonding sites. J. Am. Chem. Soc. 2001, 123, 6485-6495. 

Cuevas C, Perez M, Martm MJ, Chicharro JL, Femandez-Rivas C, Flores M, Francesch A, GaUego P, Zarzuelo M, de La Calle F, Garcia J, Polanco C, Rodriguez I, Manzanares I. (2000) Synthesis of ecteinascidin ET-743 and phthalascidin PT-650 from cyanosafracin. B Org Lett 2 2545-2548. 

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.

Martinez, E.J. Corey, E.J. (2000) A new, more efficioit, and effective process for the synthesis of a key pentacyclic intomediate fen- production of ecteinascidin and phtfaalascidin antitumor agents. Org. Lett., 2, 993-6. 

Seaman, F.C. Hurley, L.H. (1998) Molecular basis for the DNA sequence selectivity of ecteinascidin 736 and 743 evidence for the dominant role of direct readout via hydrogen bonding. J. Am. Chem. Soc., 120, 13028-41. 

Ecteinascidins 597 (154), 583 (155), 594 (158) and 596 (158) are putative biosynthetic precursors of ecteinascidins and were isolated from E. turbinata from the Caribbean [158]. A recent review on the chemistry and pharmacology of the ecteinascidins has been published [159]. 

Scheme 12.37. Synthesis of ecteinascidin 743 using a Ugi 4CR, by Fukuyama and co-workers [132] MOM = methoxymethyl, TBDPS = t-butyldi phenyl si lyl, Boc = t-butoxycarbonyl,...

Kerr, R. G. and Miranda, N. L., Biosynthetic studies of ecteinascidins in the marine tunicate Ectein-ascidia turbinata, J. Nat. Prod., 58, 1618, 1995. 

Yields of marine-derived natural products are invariably low and supply problems have delayed their development as useful pharmaceutical agents. For example, over 3000 kg of the sea squirt E. turbinata is required to produce 3 g of ecteinascidin-743,sufficient for just one cycle of treatment (113)and 1000 kg of B. neritina yields 1.5 gof biyostatin-1 (114). For-... 

Jin, W., Metobo, S., Wiiiiams, R. M. Synthetic Studies on Ecteinascidin-743 Constructing a Versatiie Pentacyciic intermediate for the Synthesis of Ecteinascidins and Saframycins. Org. Lett. 2003, 5, 2095-2098. 

Synthesis of ecteinascidin ET-743 and phthalascidin Pt-650 from cyanosafracin B. Org. Lett. 2000, 2, 2545-2548. 

Table 2. In vivo cytotoxicity of Ecteinascidins and Eudistomin K against P-388 leukemia, B-16 melanoma, Lewis Lung carcinoma xenograft (LL), M5076 ovarian sarcoma and MX-1 human mammary carcinoma xenograft, doses in pg/kg/day. ...

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]. 

Jimeno, J.M. Faircloth, G. Cameron, L. Meely, K. Vega, E. Gomez, A. Sousa-Faro, J.M.F. Rinehart, K. Progress in The Acquisition of New Marine-Derived Anticancer Compounds Development of Ecteinascidin-743 (ET-743). Drugs of the Future. 1996,21, 1155-1165. 

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]. 

Guanidine/guanidinium nitrate is a selective (5-deacetylation reagent in the presence of base labile protective groups [30]. Endo et al. reported the use of selective O-deacetylation in the synthesis of ecteinascidin 743 (99) [24] (Scheme 7.20). The two (5-acetates in 97 were cleanly deprotected in the presence of the A -Troc group by using guanidinium nitrate in methanol. 

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