Synthetic Approaches to the Stereochemically ... - ACS Publications

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Chapter 5

Synthetic Approaches to the Stereochemically Complex Antitumor Drug Ecteinascidin-743: A Marine Natural Product by the Name Yondelis® or Trabectidin Plato A. Magriotis* Laboratory of Pharmaceutical Chemistry, Department of Pharmacy, University of Patras, Rio, 26504, Greece *E-mail: [email protected]

Ecteinascidin-743 (Et-743) isolated from the Caribbean tunicate Ecteinascidia turbinate, is arguably the most potent cytotoxin known as indicated by its evaluation against the National Cancer Institute’s human in vitro cell line panel including melanoma, non-small-cell lung, ovarian, renal, prostate, and breast cancers, demonstrating potencies ranging from 1 pM to 10 nM. In fact, the antiproliferative activity of Et-743 is greater than that of Taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1-3 orders of magnitude, propelling Yondelis or Trabectidin to become the first marine anticancer drug to be approved, intact, in the European Union (EU, October 2007) and more recently in the US as a first-line treatment for soft tissue sarcomas. It is also undergoing clinical trials for breast, prostate, ovarian, and pediatric sarcomas in other countries. The complexity of molecular architecture, the remarkable biological activities, and the restricted natural availability (1.0 g from about 1.0 ton of tunicate) made Et-743 an exceedingly attractive synthetic target for total synthesis. The successful approaches toward the total synthesis of Et-743 are reviewed in this article..

© 2017 American Chemical Society Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Introduction Ecteinascidin-743 (1), isolated from the Caribbean tunicate Ecteinascidia turbinate (1), is probably the most potent cytotoxin known as indicated by its evaluation against the National Cancer Institute’s human in vitro cell line panel including melanoma, non-small-cell lung, ovarian, renal, prostate, and breast cancers, demonstrating potencies ranging from 1 pM to 10 nM (2). In fact, the antiproliferative activity of Et-743 is greater than that of Taxol, Camptothecin, Adriamycin, Mitomycin C, Cisplatin, Bleomycin, and Etoposide by 1-3 orders of magnitude (3, 4). Its proposed, unique mechanism of action involves binding to the N2 position of guanine in the minor groove demonstrating a preference for sequences containing 5′-PuGC and 5′PyGC motifs. Subsequent alkylation of DNA, via an iminium ion intermediate generated from an intramolecular acid-catalyzed activation and dehydration of the carbinolamine functionality present in the all important piperazine ring (box a, 1), induces a curvature of the DNA toward the major groove that ultimately disrupts the binding of transcription factors involved in cell proliferation (1, 5–7).

Another way of looking at Et-743 structurally is that it consists of three fused tetrahydroisoquinoline rings, two of which (subunits A and B) provide the framework for covalent interaction within the minor groove of the DNA double helix (8). The third ring (subunit C) protrudes from the DNA duplex and interacts with adjacent nuclear proteins, an interaction that is thought to account for the cytotoxicity of Et-743. Specifically, the cytotoxicity of Et-743 appears to be associated with the DNA repair mechanism. In vitro studies have demonstrated inhibition of transcription-dependent nucleotide excision repair pathways and therefore inhibition of cell cycle progression leading to p53-independent apoptosis. The transcription-coupled nucleotide excision repair process (TC-NER) involves recognition of DNA damage and recruitment of various nucleases at the site of DNA damage. At micromolar concentrations, Et-743 has been shown tο trap these nucleases in a malfunctioning nuclease-(Et-743)-DNA adduct complex and thereby inducing irreparable single-strand breaks in the DNA. This is supported by the fact that mammalian cell lines deficient in TC-NER show resistance to Et-743 (9). The complexity of molecular architecture, the remarkable biological activities, and the restricted natural availability (1.0 g from about 1.0 ton of 62 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


tunicate) made 1 an exceedingly attractive target for total synthesis. Three total syntheses and two formal total syntheses have been reported by Corey (10), Fukuyama (11), Zhu (4), Danishefsky (12), and Williams (13), respectively. More specifically, Corey and co-workers reported the first total synthesis of 1 in 36 steps and an overall yield of 0.72% (10). A second-generation synthesis improved the overall yield to 2.04% but still required 36 steps (14). Subsequently, Fukuyama and co-workers achieved a total synthesis of 1 in 50 steps and 0.56% overall yield (11). Later, Zhu and co-workers reported a 31 step synthesis in 1.7% overall yield (4), while Danishefsky and co-workers reported a formal total synthesis via a pentacyclic compound that intercepted a late-stage intermediate of Fukuyama’s route (vide infra (12)). Finally, Williams and Fishlock reported another formal total synthesis in still more than 30 steps (13). A second generation, more efficient, and robust synthesis of the natural product was reported four years ago by Fukuyama (15). Despite these advancements in total synthetic approaches to 1, the clinical supply of this complex drug is semisynthetically derived from natural cyanosafracin B obtained by fermentation as described by PharmaMar researchers (16), and shown in eq 1.

Notably, the original Corey and co-workers total synthesis has been applied to the described above semisynthesis of 1 from cyanosafracin B. The analysis and discussion of the successful approaches toward the total synthesis of 1 will be based on the construction of its central piperazine ring ((17), structure 1, box a; see also Scheme 2 in reference (17)) which not only comprises both tetrahydroisoquinoline subunits A and B but also is considered a privileged pharmacophore in medicinal chemistry since it is more than frequently found in biologically active compounds across a number of therapeutic areas (18). Actually, a recent survey of more than a thousand orally administered drugs showed that about 6% of these contained a piperazine fragment (19).

Total Syntheses of 1: Construction of the Piperazine Subunit and Its Surrogates The first enantioselective total synthesis of 1, achieved by Corey and co-workers, featured an internal Mannich bisannulation for the construction of the central piperazine ring as shown in the conversion of 4 to 5 (Scheme 1) which was effected by treatment of 4 with DIBAL, KF, and 20 equiv of trifluoromethanesulfonic acid in that order. Selective trifluoromethanesulfonation of the least hindered phenolic hydroxyl of 5 was followed by: (1) selective silylation of the primary hydroxyl, (2) protection of the remaining phenolic 63 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


group as the MOM ether, (3) double deallylative deprotection, (4) reductive N-methylation, and (5) Stille methylation to provide 6 in 83% yield and set up the stage for the installation of the ten-membered lactone ring and the spiro tetrahydroisoquinoline subunit C that will be described in the next section dealing with the completion of the total syntheses of 1.

Scheme 1. Piperazine construction in Corey’s total synthesis. Interestingly, 4 was prepared by the union of hοmochiral tetrahydroisoquinoline lactone 2 and α-amino aldehyde 3 both of which the chirality was set by a catalytic enantioselective hydrogenation, for example the reduction of 7 to furnish 8 in 97% yield and 96% ee (eq 2). The conversion of 8 to 2 demonstrates a method for control of stereochemistry in the tetrahydroisoquinoline series (10).

The second enantioselective total synthesis of 1, accomplished by Fukuyama and co-workers in Japan, proceeded through the piperazine surrogate 12 made by an intramolecular Heck reaction of the cyclic enamide 11 which was in turn obtained from diketopiperazine 10 that was assembled in short order by the powerful Ugi four-component condensation reaction of homochiral fragments 7 and 8 as well as isocyanide 9 and acetaldehyde as shown in Scheme 2 (11). The chirality of aryl glycinol derivative 7 was set by the development of novel methodology (20), whereas that of 8 was installed by a similar catalytic 64 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


enantioselective hydrogenation as shown in eq 2. Finally, conversion of 12 to the pentacyclic intermediate 13 was realized in sixteen conventional steps (11).

Scheme 2. Piperazine construction in Fukuyama’s total synthesis. The third total synthesis of 1, achieved by Zhu and co-workers in France (4), was centred on piperazine 21 (Scheme 3) that was diastereoselectively prepared from homochiral Garner’s aldehyde 14 and L-3-hydroxy-4-methoxy-5-methyl phenylalanol (15) which in turn was efficiently made in eight steps based on Corey’s enantioselective alkylation of N-(diphenylmethylene) glycine tert-butyl ester with a 2-methyl catechol derivative (21). Specifically, condensation of 14 and 15 provided, under optimized conditions shown in Scheme 3, the desired tetrahydroisoquinoline 16 as the only isolable product at the expense of other regio- (C-19 vs C-15, Et-743 numbering) and diastereoisomers. Interestingly, the stereochemistry at C-11 was controlled solely by the absolute configuration of amino alcohol 15 since condensation of 15 and (R)-14 gave also the C-11-C-13 cis diastereomer in excellent yield. It seems reasonable to assume, therefore, that both C-11 and C-13 substituents adopt pseudoequatorial positions leading to the observed cis selectivity after ring closure. The coupling of 16 and 17 (1:1 ratio) furnished products 18 and 19 in good yield and 1:3 ratio respectively. The observed 50% de can be explained by a SN1 mechanism via an ortho-quinone methide intermediate (Scheme 3). Accordingly, acetate 19 was protected, deprotected, and advanced to tricyclic piperazine 21 via an intramolecular Strecker reaction of oxidized primary alcohol 20, a transformation that resembles the intermolecular conversion of 2+3 to 4 in Corey’s synthesis (Scheme 1). 65 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Scheme 3. Piperazine construction in Zhu’s total synthesis.

As mentioned above, the fourth reported total synthesis of 1 by Danishefsky and co-workers was typically a formal one since it defined the alcohol corresponding to acetate 13, an advanced intermediate in Fukuyama’s total synthesis of 1 (Scheme 2), as a milestone which was achieved by a novel vinylogous Pictet-Spengler cyclization employing an unusual o-hydroxystyrene moiety (vide infra (12)). Thus, coupling of tetrahydroisoquinoline 22, derived from Borchardt’s alcohol (12), and homochiral L-tyrosine derivative 23, the chirality of which was set by a catalytic enantioselective hydrogenation of the corresponding dehydro methyl ester (cf eq 2), under the agency of BOP-Cl afforded amide 24 in excellent yield (Scheme 4). After oxidative cleavage of the PMB group and dehydration of the benzylic alcohol, the primary alcohol was oxidized to the aldehyde 25 suitable for the crucial intramolecular/vinylogous Pictet-Spengler/Mannich cyclization that was effected by the action of difluoroacetic acid in benzene to deliver pentacyclic compound 26 (Scheme 4) including the piperazine surrogate pharmacophore. The fifth reported total synthesis of 1 by Williams and co-workers was a formal one as well (13), by virtue of the conversion of a pentacyclic compound 31 (Scheme 5) into a related intermediate which constitutes a formal total synthesis by relay through the Danishefsky (12) and then Fukuyama (11) syntheses, respectively (vide infra (13)).

66 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Scheme 4. Piperazine surrogate construction in Danishefsky’s total synthesis.

Scheme 5. Piperazine surrogate construction in Williams’ formal total synthesis.



Specifically, acylation of tetrahydroisoquinoline 27, constructed employing a novel radical cyclization of a glyoxalimine derived from Borchardt’s catachol and Garner’s aldehyde, with the N-Fmoc protected amino acid chloride 28 prepared utilizing the oxazinone template technology developed in the William’s laboratory (22), furnished amide 29 without epimerization (Scheme 5). Interestingly, the use of the N-Boc free acid with a variety of coupling agents (DCC, HOBt, HATU) all resulted in very sluggish reactions with poor isolated yields, as did the attempted use of the N-Boc acid fluoride. Removal of the acetonide and the TBS group from 29 was followed by Swern oxidation to yield the piperazinone derivative 30 which upon treatment with trifluoroacetic acid gave rise to 31 and 32 as an approximately 0.72:1 ortho: para mixture of regioisomers in 72% combined yield (Scheme 5). This synthetic approach has been recently applied to the total synthesis of the related marine natural product Renieramycin T (23). Fukuyama and co-workers described their second generation total synthesis of 1 starting from N,N′-diacetylated diketopiperazine 33 prepared from inexpensive L-glutamic acid as the source of chirality (15). Accordingly, Perkin condensation of 33 with aldehyde 34 proceeded regioselectively to give 35. Convrersion to 36 was highly diastereo-selective consisting of protection, hydrogenolysis, hydrazinolysis, and selective reduction (Scheme 6). Cyclizaton of the latter proceeded smoothly via the corresponding N-acyliminium ion to furnish 37 after bistriflation under basic conditions in good yield. Finally the key intermediate 38 including the piperazine surrogate was accessed uneventfully in excellent overall yield as shown in Scheme 6.

Scheme 6. Piperazine surrogate construction in second generation Fukuyama’s total synthesis.



Earlier, Kubo and co-workers had reported (24) the synthesis of tetrahydroisoquinoline A (1) including piperazine surrogate 45 starting from 1,4-diacetyl-2,5-piperazinedione (39) and aryl alehyde 40 (25). Specifically, condensation of 39 and 40, according to the procedure of Gallina and Liberatori (26), gave 3-arylidene-2,5-piperazinedione 41 in 74% yield (Scheme 7).

Scheme 7. Piperazine surrogate construction in Kubo’s synthetic approach.

Alkylation of 41 with 4-methoxybenzyl chloride followed by treatment with hydrazine hydrate, methylation, deprotection with TFA and concentrated H2SO4, as well as hydrogenation over 20% palladium hydroxide on carbon in ethanol, provided 42 in very good overall yield (Scheme 7). Protection of the phenol with benzyl bromide in DMF afforded the O-benzylated compound, which was then converted to the corresponding isopropyl carbamate. Deprotection of the latter by hydrogenolysis followed by bromination and chemoselective reduction with an excess of lithium-tert-butoxyaluminum hydride in THF, gave a diastereomeric mixture of alcohol 43 in excellent overall yield. Treatment of 43 with TFA delivered tricyclic compound 44 (96% yield). Carbamate hydrolysis of 44 followed by N-methylation and debromination achieved their final goal including the piperazine surrogate structure 45 (Scheme 7). The conversion of 45 to 1 has not been reported yet.



Completion of the Total Syntheses of 1 Completion of the first total synthesis of 1 was accomplished by Corey and co-workers in the following manner. Oxidation of phenol 6 (Scheme 1) with (PhSeO)2O effected position-selective angular hydroxylation to yield, after desilylation and esterification of the resulting primary hydroxyl function with (S)-N-((allyloxy)carbonyl)-S-(9-fluorenyl-methyl)cysteine, ester 46 in very good yield (Scheme 8). Compound 46 was then transformed in one flask to the bridged lactone 47 in 79% overall yield by the following remarkable operations: (1) reaction of 46 with the in situ-generated Swen reagent from excess triflic anhydride and DMSO at -40°C for 30 min to convert the tertiary hydroxyl group of 46 to the O-dimethylsulfonium derivative, (2) addition of i-Pr2NEt and warming to 0°C for 30 min to form the quinone methide by cycloelimination of the Swern type oxosulfonium ylide intermediate, (3) quenching with tert-butyl alcohol to destroy excess Swern reagent, (4) addition of excess N-tert-butyl-N′,N′,N′′,N′′-tetramethylguanidine to convert the 9-fluorenylmethyl thiolether to the thiolate ion and to promote nucleophilic addition of sulfur to the quinone methide and therefore generate the 10-membered lactone bridge, and (5) addition of excess Ac2O to acylate the resulting pnenoxide ion and generate 47 (Scheme 8).

Scheme 8. Completion of Corey’s total synthesis.

Finally, the N-((allyloxy)carbonyl) group of 47 was cleaved and the resulting α-amino lactone was oxidized to the corresponding α-keto lactone 48 with the methiodide of pyridine-4-carboxaldehyde. Reaction of 48 with 2-[3-hydroxy-4-methoxyphenyl]ethylamine in the presence of silica gel generated the spiro tetrahydroisoquinoline C (Structure 1) stereospecifically which was 70 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


then subjected to MOM cleavage and replacement of CN by OH to yield ecteinascidin-743 (1, Scheme 8). The last steps of the second total synthesis of 1, reported by Fukuyama (10) are described in Scheme 9. Thus, hydrolysis of acetate 13 (Scheme 2) and condensation of the resultant alcohol with L-cysteine derivative 49 furnished ester 50. Chemoselective hydrazinolysis of the thioacetate gave the thiol, which, upon exposure to TFA in 2,2,2-trifluoroethanol under high dilution conditions (0.009 M), smoothly underwent cyclization to the ten-membered sulfide 51 after acetylation of the phenol group. Cleavage of the Troc group and reductive alkylation afforded the corresponding N-methyl amine of which the alloc carbamate and allyl ether were simultaneously cleaved with palladium catalyst to give rise to aminophenol 52 that was biomimetically oxidized according to Corey and co-workers to the respective α-ketolactone. Pictet-Spengler reaction of the latter with amine hydrochloride salt 53 furnished ecteinascidin-770 (54, Structure 1). Finally, generation of the labile hemiaminal from the aminonitrile was effected with silver nitrate to provide ecteinascidin -743 (1, Scheme 9).

Scheme 9. Completion of Fukuyama’s total synthesis. The Zhu and co-workers total synthesis of 1 was accomplished from intermediate 21 (Scheme 3) by reduction of the ester function and subsequent acetylation of the resulting primary alcohol affording the respective acetate. O-Desilylation of the latter followed by Dess-Martin oxidation gave rise to the corresponding aldehyde the Pomerantz-Fritsch-type cyclization of which took place smoothly to provide polyheterocyclic compound 55 (Scheme 10) with concomitant removal of the phenolic MOM-protecting group. Although of no consequence, the cyclization is highly stereoselective (dr > 20:1) and the 71 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


configuration at C4 of the major isomer was tentatively assigned as S in analogy to the work of Fukuyama and co-workers (11, 15). Saponification of 55 followed by coupling of the resulting alcohol with R-Troc-(S-4,4′,4′′-trimethoxytrityl)cysteine (56) under standard conditions yielded 57 in excellent yield. Gratifyingly, by simply dissolving 57 in TFE containing 1% of TFA, the bridged macrocycle 58 was produced in good isolated yield after masking the phenol as the corresponding acetate. In this operationally simple experiment a complex reaction sequence involving S-trityl deprotection, 1,4-β elimination leading to ortho-quinone methide and macrocyclization via an intramolecular Michael addition occurred in a highly ordered manner to accomplish the key C-S bond-forming process. Simultaneous removal of N-Alloc and O-allyl functions under Guibé’s conditions (27) followed reductive N-methylation to produce 59 after removal ot the N-Troc protective group and biomimetic oxidation according to Corey’s protocol (Scheme 10).

Scheme 10. Completion of Zhu’s total synthesis. 72 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Pictet-Spengler reaction of 59 with 3-hydroxy-4-methoxy-phenethylamine (60) was followed by treatment with AgNO3 in MeCN/H2O to provide Ecteinascidin-743 (1) in excellent overall yield for these last two steps. The conversion of 26 (Scheme 4) in Danishefsky’s formal total synthesis of 1 to primary alcohol 67, corresponding to acetate 13 (Scheme 2) in Fukuyama’s total synthesis, was accomplished as described in Scheme 11 below. Specifically, protection of phenol 26 was followed by a McCluskey reaction (28) of the N-Me amine, thereby providing 61 after deprotection ot the TBS ether and reprotection with MOM-Cl. Treatment of the latter with dimethyldioxirane (DMDO) led to epoxidation of the C3-C4 double bond affording the presumed epoxide 62 which upon treatment with 5 equivalents of sodium cyanoborohydride, provided ketone 64 along with a alcohol 63 in a 6:1 ratio.

Scheme 11. Completion of Danishefsky’s formal total synthesis. 73 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Two mechanistic hypotheses were put forth to account for the formation of the ketone 64. One could envision a concerted rearrangement with hydride migration, from C4 to C3, to afford ketone 64. Alternatively, the nitrogen atom of the lactam could open the epoxide to produce amidonium alkoxide 65 (Scheme 12). This intermediate could then undergo 1,2-hydride migration to give 64 or competitive reduction by external hydride to provide 63. Apparently, this duality is in fact operating since recourse to a large excess of sodium cyanoborohydride led to alcohol 63 as the predominant product (Scheme 11). Finally, the two benzyl groups were removed giving rise to a triol which upon treatment with a 1:1 ate complex of n-BuLi and DIBAL-H underwent partial reduction of the lactam to provide oxazolidine 66, the phenol group of which was selectively protected as its allyl ether to furnish milestone aminonitrile 67 after exposure to KCN in acetic acid and deprotection of the MOM ether with TFA (12).

Scheme 12. Mechanistic hypotheses accounting for the formation of ketone 64.



As mentioned, the total synthesis of 1 by Williams and co-workers is also a formal one by virtue of the conversion of intermediate 31 (Scheme 5) to 61 (Scheme 11), an advanced intermediate in Danishefsky and co-workers total synthesis, which in turn was advanced to 67 (Scheme 11) corresponding to acetate 13 (Scheme 2) described in the Fukuyama and co-workers total synthesis (eq 3).

Finally, The second generation synthesis of Fukuyama and co-workers was completed as follows. After treatment of aromatic amine 68 with tert-butyl nitrite and BF3 etherate, the resulting diazonium salt was reacted with enamide 38 (Scheme 6) in the presence of a palladium catalyst to perform the crucial, intermolecular in this case, Heck reaction. As expected the reaction occurred exclusively from the less hindered face of the enamide to produce coupling product 69 (Scheme 13) with the desired stereo- and regiochemistry. It is noted that this intermolecular Heck reaction was carried out on a multigram scale in excellent yield. An osmium-mediated dihydroxylation of the resulting highly hindered double bond in 69 was accomplished by using K3[Fe(CN)6] as a co-oxidant in the presence of quinuclidine and methanesulfonamide (15). Oxidative cleavage of the resulting 1,2-diol with H5IO6 formed a dialdehyde which underwent facile hydration to afford 70 as a single isomer the stereochemistry of which could not be determined. Hydrogenolysis of the benzyl group in 70 gave the corrersponding phenol heating of which in m-xylene promoted liberation of the dialdehyde that was trapped intramolecularly by the electron-rich B-ring (1) to furnish aldehyde 71 as a 5:1 mixture of diastereomers. Subsequent reduction of 71 with Red-Al afforded an oxazolidine similar to 66 (Scheme 11) which was treated with KCN in acetic acid to produce aminonitrile 72 (Scheme 13). Condensation of the primary hydroxyl group in 72 with cysteine derivative 49 (Scheme 9) followed by selective cleavage of the S-acetyl group with hydrazine produced the respective thiol 73 which upon treatment with TFA led to the cyclic sulfide 74 after acetylation of the phenolic hydroxyl group. Eventually, 74 was transformed to 52 (Scheme 9) the conversion of which to 1 was described in the first synthesis of Fukuyama and co-workers (11).



Scheme 13. Completion of Fukuyama’s second generation total synthesis.

Conclusion and Outlook As discussed above, most of the synthetic approaches, that culminated in the total syntheses of 1 outlined, relied on the Mannich reaction for the construction of the critical for antitumor activity piperazine ring. The latter is actually the common section of the tetrahydroisoquinoline subunits A and B (Structure 1). A more direct synthetic approach to this central piperazine ring could be provided by the unprecedented DiAza Diels-Alder Reaction (DADAR) between a 4-trialkysilyloxy-2-azadiene and an appropriately substituted imine as an integral 76 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


part of our retrosynthetic analysis shown in Scheme 14. Research efforts toward the development of the first DADAR as well as the implementation of the latter analysis are ongoing in the author’s Pharmaceutical Chemistry Laboratory at the University of Patras.

Scheme 14. Magriotis’ retrosynthetic analysis of Ecteinascidin-743. It remains to be seen whether one or a combination of the synthetic approaches discussed in this chapter will in fact find any use, besides the Corey synthesis, in the commercial production of 1.

References 1.

Rinehart, K. L.; Holt, T. G.; Fregeou, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem. 1990, 55, 4512–4515. 2. Hedge, S.; Schmidt, M. Ann. Rep. Med. Chem. 2008, 43, 492–493. 3. Molinski, T. F.; Dalisay, D. S.; Lievens, S. L.; Saludes, J. P. Nat. Rev. Drug Discovery 2009, 8, 69–85. 4. Chen, J.; Chen, X.; Bois-Choussy, MN.; Zhu, J. J. Am. Chem. Soc. 2006, 128, 87–89. 5. Pommier, Y.; Kohlhagen, G.; Bailly, C.; Waring, M.; Mazumder, A.; Kohn, K. W. Biochemistry 1996, 35, 13303–13309. 6. Moore, B. M., II; Seaman, F. C.; Wheelhouse, R. T.; Hurley, L. H. J. Am. Chem. Soc. 1998, 126, 2490–2491. 7. Rinehart, K. L. Med. Drug Rev. 2000, 1–27. 8. Zewail-Foote, M.; Hurley, L. H. J. Med. Chem. 1999, 42, 2493–2497. 9. Zewail-Foote, M.; Li, V.-S.; Kohn, H.; Bears, D.; Guzman, M.; Hurley, L. H. Chem. Biol. 2001, 8, 1033–1049. 10. Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202–9203. 11. Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552–6554. 77 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


12. Zheng, S.; Chan, C.; Furuuchi, T.; Wright, B. J. D.; Zhou, B.; Guo, J.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2006, 45, 1754–1759. 13. Fishlock, D.; Williams, R. M. J. Org. Chem. 2008, 73, 9594–9600. 14. Martinez, E. J.; Corey, E. J. Org. Lett. 2000, 2, 993–996. 15. Kawagishi, F.; Toma, T.; Inui, T.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2013, 135, 13684–13687. 16. Cuevas, C.; Pérez, M.; Martin, M. J.; Chicharro, J. L.; Fernández-Rivas, C.; Flores, M.; Francesch, A.; Gallego, P.; Zarzuelo, M.; delaCalle, F.; Garcia, J.; Polanco, C.; Rodriguez, I.; Manzanares, I. Org. Lett. 2000, 2, 2545–2548. 17. Sakai, R.; Jares-Erijman, E. A.; Manzanares, I.; Silva Elipe, M. V.; Rinehart, K. L. J. Am. Chem. Soc. 1996, 118, 9017–9023. 18. Shaquiquzzaman, M.; Verma, G.; Marella, A.; Akhter, M.; Akhtar, W.; Khan, M. F.; Tasneem, S.; Alam, M. M. Eur. J. Med. Chem. 2015, 102, 487–529. 19. Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.; Robertson, D. H.; Savin, K. A.; Durst, G. L.; Hipskind, P. A. J. Med. Chem. 2004, 47, 224–232. 20. Thoma, S.; Endo, A.; Kan, T.; Fukuyama, T. Synlett 2001, 1179–1181. 21. De Paolis, M.; Chen, X.; Zhu, J. Synlett 2004, 729–731. 22. Jin, W.; Williams, R. M. Tetrahedron Lett. 2003, 44, 4635–4639. 23. Yokoya, M.; Toyoshima, R.; Suzuki, T.; Le, V. H.; Williams, R. M.; Saito, N. J. Org. Chem. 2016, 81, 4039–4047. 24. Saito, N.; Tachi, M.; Seki, R.-i.; KaMayachi, H.; Kubo, A. Chem. Pharm. Bull. 2000, 48, 1549–1557. 25. Saito, N.; Tachi, M.; Seki, R.-i.; Sugawara, Y.; Takeuchi, E.; Kubo, A. Synth. Commun. 2000, 30, 2407–2421. 26. Gallina, C.; Liberatori, A. Tetrahedron 1974, 30, 667–673. 27. Guibé, F. Tetrahedron 1998, 54, 2967–3042. 28. Hobson, J. D.; McCluskey, J. G. J. Chem. Soc. (C) 1967, 2015–2017.


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