Total Synthesis of Trabectedin, Lurbinectedin, and Renieramycin T

Open AccessCCS ChemistryRESEARCH ARTICLES29 Nov 2022Total Synthesis of Trabectedin, Lurbinectedin, and Renieramycin T Dong Li, Jiaolong Meng and Xuefeng Jiang Dong Li Shanghai Key Laboratory of Green Chemistry and Chemical Process, East China Normal University, Shanghai 200062 , Jiaolong Meng Shanghai Key Laboratory of Green Chemistry and Chemical Process, East China Normal University, Shanghai 200062 and Xuefeng Jiang *Corresponding author: E-mail Address: [email protected] Shanghai Key Laboratory of Green Chemistry and Chemical Process, East China Normal University, Shanghai 200062 State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071 https://doi.org/10.31635/ccschem.022.202202418 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Trabectedin and lurbinectedin are therapeutic antitumor pharmaceuticals approved by the Food and Drug Administration for treating soft tissue sarcomas and metastatic small cell lung cancer and have been facing synthesis challenges over the past three decades. In this report, the total synthesis of trabectedin, lurbinectedin, and renieramycin T were accomplished in 22–27 steps. The synthetic strategy features stereocontrolled Pictet–Spengler (PS) reaction leading to the multisubstituted tetrahydroisoquinoline fragment (DE ring), aldol condensation for C4–C10 bond formation, and a second PS cyclization with asymmetric oxomalonate for the fully substituted B ring, in which palladium complex-induced stereoselectivity is achieved via decarboxylative protonation anchoring the C1 stereocenter. The pentacyclic skeleton (A–E) was efficiently effectuated at a gram scale, displaying superior potential for further drug development. Download figure Download PowerPoint Introduction Trabectedin ( 1) is one of the most popular bistetrahydroisoquinoline natural products isolated from Caribbean tunicate Ecteinascidia turbinate,1,2 with an antiproliferative activity 10–1000-fold higher than taxol in vivo.3 It was approved by the Food and Drug Administration (FDA) for the treatment of soft tissue sarcoma and platinum-sensitive ovarian cancer in 2015.4,5 Lurbinectedin ( 2) is a synthetic derivative of trabectedin, approved by the FDA in 2020 as an orphan drug for the treatment of small cell lung cancer.6 Renieramycin T ( 3), with significant cytotoxicity against human cancer cell lines, was isolated in 2009 from Thai sponge Xestospongia sp. by Saito et al.7 The structures of these molecules feature a densely functionalized bistetrahydroisoquinoline skeleton (A–E ring) (Figure 1a), which harbors a fully substituted AB ring and a vertical DE ring. A fragile 10-membered sulfur-containing lactone is embedded in the trabectedin ( 1) and lurbinectedin ( 2) core region, and a highly sensitive benzylic C–S stereocenter at C4 and vulnerable hemiacetal amine stereocenter at C21 were observed. Notably, compared to 1 and 2, renieramycin T ( 3) possesses a high oxidation state E ring and unique angelic acid ester C1 side chain. Due to the demand and challenges of synthetic compounds, trabectedin has attracted significant attention from the chemistry community over the past three decades.8,9 Corey et al.10 achieved the first landmark total synthesis of trabectedin featuring an intermolecular Strecker reaction, C–S bond effectuating cyclization, and Pictet–Spengler (PS) reaction to forge a spiro ring. The groups of Fukuyama,11,12 Zhu,13 Danishefsky,14 Williams,15 and Chen16 accomplished three total syntheses along with several formal synthesis routes of trabectedin using remarkable strategies. Recently, Ma et al.17 reported the total synthesis of trabectedin and lurbinectedin, utilizing an elegant light-mediated C–H activation to assemble a benzo[1,3]dioxole motif. In addition, groups of Chen,18 Saito,19 Myers,20 Magnus,21 and Stoltz22 adopted enhanced strategies to synthesize renieramycin T, saframycin A, lemonomycinone, jorunnamycin A, jorumycin, and analogs of the bistetrahydroisoquinoline family, which inspired an efficient synthesis of the most-complex trabectedin. Figure 1 | (a) Trabectedin, lurbinectedin, and renieramycin T. (b) Strategy for the synthesis of trabectedin, lurbinectedin, and renieramycin T. Download figure Download PowerPoint Experimental Methods Experimental procedures, Supporting Information Schemes S1–S3, characterization of NMR spectra for all synthetic compounds, comparison of the synthetic natural products with isolated samples, and copies of NMR spectra are available in the Supporting Information. All reactions were carried out under a nitrogen atmosphere, unless otherwise stated. All chemicals were purchased commercially and used without further purification. Flash column chromatography was performed employing Qingdao Haiyang silica gel 60 (300–400 mesh). 1H and 13C NMR spectra were recorded on a Bruker-400, 500 spectrometer (Bruker, Saarbrücken, Saarland, Germany). Chemical shifts for 1H and 13C NMR spectra are reported in ppm (δ) relative to residual protium and carbon resonance in the solvent (chloroform-d: δ 7.26, 77.0 ppm). Results and Discussion Herein, we disclose an approach for the convergent total synthesis of trabectedin, lurbinectedin, and renieramycin T, with retrosynthetic analysis shown in Figure 1b. The formation of the bridged macrolactone after the synthesis of 1 and 2 was achieved via an in situ formation of ex-endo quinone methide/thio-Michael addition sequence from 4. Decarboxylative protonation bias of palladium complex 5 induced stereoselectivity of C1 in 4. An intermolecular PS reaction for the B ring of 6 was expected to take advantage of the highly active asymmetric oxomalonate 7, which enhanced the activity of imine intermediate and served as a precursor for subsequent C1 stereocenter construction. The fragments 9 and 10 were linked via intermolecular aldol condensation to form the C4–C10 bond of 8. Aldehyde 10 is readily obtained via PS cyclization with Garner aldehyde 1123 and amino alcohol 12.24 Our synthetic route commenced with the diastereoselective PS reaction between aldehyde 11 and amino alcohol 12. According to the protocol of Zhu et al.,13 tetrahydroisoquinoline product 13 with C11 (R)-selectivity was obtained in a yield of 94% on a 22-g scale (Scheme 1). The fully protected 14 was achieved in the following sequence: the introduction of an alloc group into a secondary amine, allylation of phenol, and acetylation of primary alcohol treated with acetic anhydride. Acetonylidene is deprotected via cerium chloride heptahydrate yielding alcohol 15. After Swern oxidation of 15, the aldehyde 10 was further condensed with phenol 9, which formed 16 with a 77% yield over two steps. Subsequently, 17 was obtained after deprotection via the Pd(PPh3)4/1,3-dimethylbarbituric acid (1,3-DMBA) system. Considering the benzylic hydroxy elimination in 17, we removed the benzylic hydroxyl group first using the combination of trifluoroacetic acid (TFA)/triethylsilane (TES), avoiding the distraction of the PS reaction for the next step. However, an intramolecular cyclization product 18 was formed by the attack of the protogenetic phenolic hydroxy group on C18. Among the acid sources evaluated, only boron trifluoride diethyl etherate afforded the desired dehydroxylation product, accompanied by compound 18 formation. To avoid the intramolecular cyclization, the phenol on C18 was protected using allyl bromide at room temperature affording 19 at an 80% yield. Boron trifluoride diethyl etherate-promoted dehydroxylation of 19 delivered the desired product with an 81% yield, and subsequent reductive amination afforded methylated product 20 at an 82% yield. Previously, asymmetric access to the fully substituted B ring met an insurmountable obstacle.13,17,25 First, the PS reaction with benzyloxyacetic aldehyde fragment 36 (Table 1, entry 1) failed due to the low activity of the imine intermediate and stable A-ring aromatic conjugated system resulting from the benzo-1,3-dioxole unit. Although the activated ethyl glyoxylate ( 37) delivered a ring-closed product with a good yield (Table 1, entry 4), an opposite configuration was displayed at C1. When diethyl ketomalonate ( 38)26–28 was used as the PS cyclization partner (Table 1, entry 5), the desired gem-ester was generated at an 87% yield. However, all attempts for retro-aldol decarboxylation generated complicated mixtures. Strikingly, PS cyclization with asymmetric oxomalonate 7 (Table 1, entry 6) achieved the B ring in a 1∶1 ratio with the C1 diastereomer at a 78% yield, which was subjected to palladium-catalyzed stereoselective decarboxylative protonation.29–31 Next, the protection of phenol on C5 and acetyl deprotection proceeded smoothly affording alcohol 21 in a 51% yield over four steps. The protecting group of the phenolic hydroxyl group is crucial for concise late-stage transformation towards 1, 2, and 3. Then, Swern oxidation of 21, followed by zinc chloride promoted the Strecker reaction and furnished pentacyclic skeleton 6 at a scale of 2 g. Scheme 1 | Construction of pentacyclic structure.aaConditions: (a) 11, AcOH, 4Å molecular sieves, DCM/TFE (7∶1), room temperature, 24 h, 94%; (b) AllocCl, DCM/NaHCO3 (aq.) (1∶1), room temperature, 1 h, 88%; (c) AllylBr, Cs2CO3, DMF, room temperature, 3 h, 85%; (d) DMAP, Pyridine/Ac2O (2∶1), room temperature, 30 min, 97%; (e) CeCl3·7H2O, MeCN, room temperature, 8 h, 93%; (f) (COCl)2, DMSO, −78 °C, 15 min, 15, −40 °C, 30 min; Et3N, room temperature, 15 min; (g) 9, MeMgCl (3 M in THF), THF, room temperature, 10 min then 9, room temperature, overnight, 77%, for the two steps; (h) Pd(PPh3)4, DMBA, DCM, room temperature, 8 h, 85%; (i) TFA, TES, 0 °C, 20 min, 68%; (j) AllylBr, K2CO3, acetone, room temperature, 24 h, 80%; (k) BF3·Et2O, TES, 0 °C, 30 min, 81%; (l) HCHO (36% in H2O), NaBH3CN, room temperature, 15 min; AcOH, room temperature, 1 h, 82%; (m) HBr (33% in AcOH), DCM, 0 °C, 2 h; (n) (Table 1); (o) MOMBr, NaH, THF, 0 °C, 15 min; (p) K2CO3, MeOH, room temperature, 2 h, 51%, for the four steps; (q) (COCl)2, DMSO, 15 min; 21, −78 °C, 1.5 h; Et3N, room temperature, 15 min; (r) TMSCN, ZnCl2 (1 M in Et2O), room temperature, 2 h, 65% for the two steps; (s) (Table 2). TFE, 2,2,2-trifluoroethanol; DMAP, 4-(dimethylamino)pyridine; TFA, trifluoroacetic acid; DMBA, dimethylbarbituric acid; TES, triethylsilane; MOMBr, bromomethyl methyl ether; TMSCN, trimethylsilyl cyanide; DBA, dimedone; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; THF, tetrahydrofuran. Download figure Download PowerPoint Table 1 | PS Cyclization for B-Ring. Entry Conditions Yield cis:trans 1 36, TFA, Toluene/TFE, 50 °C NR — 2 36, TFA/AcOH (4∶1), rt NR — 3 37, TFA, Toluene/TFE, 50 °C 47% Trans only 4 37, TFA, rt 80% Trans only 5 38, TFA/AcOH (6∶1), rt 87% — 6 7, TFA/AcOH (4∶1), rt 78% 1∶1 NR, no reaction; rt, room temperature; TFA, trifluoroacetic acid; TFE, 2,2,2-trifluoroethanol. The crucial decarboxylative protonation was tested for the C1 stereocenter introduction. The proton source of the π-allyl palladium complex scavenger was the key factor for stereoselective C1 formation (Table 2). Subjecting 6 to Pd(PPh3)4 and 1,3-DMBA in tetrahydrofuran (THF) at room temperature provided a mixture of desired isomer 22 and C1- epi -22 at a ratio of 1∶1 (Table 2, entry 1). Interestingly, a combination of Pd(PPh3)4 and dimedone (DBA) in THF efficiently afforded the desired product 22 as the sole configuration at an 88% yield (Table 2, entry 2). Stoltz et al.30,31 reported that excellent stereoselectivity can be obtained via adjusting the acidity of the organic proton donors. Compared with DBA, DMBA possesses faster protonation rate with stronger proton acidity, resulting in poor enol-type proton capture selectivity. Therefore, different pKa values between 1,3-DMBA (pKa = 4.7)32 and DBA (pKa = 5.2)33 accounted for the proton transfer rate of the C1 stereocenter. The conversion from 6 to 22 originated from allyl oxidative addition, followed by CO2 release affording Pd enolate. The π-allylpalladium complex bound to the tertiary amines shielded the upper face of 5. Therefore, the stereoselective protonation of C1 enolates was inclined to proceed from the bottom face. Similarly, the allyl ether group at C18 was removed to afford 22. However, when sodium p-toluenesulfinate/MeOH was applied (Table 2, entry 3), decarboxylation–allylation product 23 was isolated at a 32% yield in addition to 22. To select deallylation for further divergent synthesis, the sequence of reagent addition was reversed. Product 4 with allyl ether retention at C18 was achieved at a 72% yield when Pd(PPh3)4 and DBA were stirred for 15 min at room temperature, followed by the addition of substrate 6 (Table 2, entry 5).The exposed phenolic hydroxy group at C18 in 22 was required for subsequent oxidation reaction towards the synthesis of renieramycin T ( 3). In contrast, the preserved allyl ether in 4 is valuable in distinguishing the phenolic hydroxyl group at C5, concisely targeting the synthesis of trabectedin ( 1) and lurbinectedin ( 2). Table 2 | Construction of C1 Stereocenter. Entry Conditions 22 4 23 1a 1,3-DMBA, THF, rt C1 dr 1∶1, 85% — — 2a DBA, THF, rt 88% — — 3b TolSO2Na, MeOH, THF, rt 42% — 32% 4c DBA, THF, −20 °C then 6 11% 64% — 5c DBA, THF, rt then 6 — 72% — DBA, dimedone; DMBA, dimethylbarbituric acid; THF, tetrahydrofuran. Conditions: aPd(PPh3)4, proton source, 6, rt, 1 h. bPd(PPh3)4, TolSO2Na, 6, MeOH, rt, 1 h. cPd(PPh3)4, DBA, −20 °C or rt, 15 min; 6, rt, 1 h. Renieramycin T ( 3) was achieved from precursor 22, as summarized in Scheme 2. Ethyl ester was reduced by lithium borohydride, followed by oxidation from phenol to benzoquinone 24. A condensation between angelic acid and 24 in the presence of Yamaguchi's reagent yielded 25 at 78%. The final deprotection of the methyl ether group was carried out using zirconium tetrachloride at 0 °C for the synthesis of renieramycin T ( 3).7,18,19 Scheme 2 | Total synthesis of renieramycin T.aaConditions: (a) LiBH4, MeOH, THF, room temperature, 2 h, 88%; (b) Salcomine, O2 balloon, room temperature, 10 h, 90%; (c) angelic acid, 2,4,6-trichlorobenzoyl chloride, Et3N, DCM, 0 °C to room temperature, 3 h; 24, overnight, 78%; (d) ZrCl4, DCM, 0 °C, 1 h, 90%. Download figure Download PowerPoint The synthesis of trabectedin ( 1) and lurbinectedin ( 2) is shown in Scheme 3. Thus, 4 was subjected to selective deprotection using zirconium tetrachloride at 0 °C and then treated with lithium borohydride to form alcohol 26. The formation of 26 with benzeneseleninic anhydride in <15 min yielded α-hydroxyketone intermediate 27. Then, without purification, 27 was condensed with (R)-N-Alloc-S-Fm-Cys, leading to cyclized precursor 28. According to Corey's strategy,10 it was converted to 29 in a one-pot sequence with a 51% yield. After removal of alloc and allyl groups in 29, amine 30 was further converted to the corresponding α-ketoester 31 with a 52% yield. Finally, 31 was transformed into trabectedin ( 1) and lurbinectedin ( 2) via PS cyclization with 2-(3-hydroxy-4-methoxyphenyl)ethylamine hydrochloride salt 32 and 2-(5-methoxy-1H-indol-3-yl)ethanamine hydrochloride salt 33,10,17 followed by hydrolysis of the amino nitrile moiety ( Supporting Information Tables S1–S4). Scheme 3 | Total synthesis of trabectedin and lurbinectedin.aaConditions: (a) ZrCl4, DCM, 0 °C, 2 h; (b) LiBH4, MeOH, THF, room temperature, 2 h, 75% for the two steps; (c) (PhSeO)2O, DCM, −10 °C, 10 min; (d) (R)-N-Alloc-S-Fm-Cys, EDCI, DMAP, DCM, room temperature, 2 h, 64% for the two steps; (e) Tf2O, DMSO, −78 °C, 15 min; 28, −40 °C, 40 min; DIPEA, 0 °C 30 min; t-BuOH, 0 °C, 30 min; 2-tert-butyl-1,1,3,3-tetramethylguanidine, room temperature, 30 min; Ac2O, pyridine, room temperature, 20 min, 51%; (f) Pd(PPh3)4, Bu3SnH, AcOH, room temperature, 1 h, 85%; (g) 4-formal-1-methylpyridium benzenesulfonate, 30, room temperature, 4 h; DBU, 0 °C, 20 min; (COOH)2, room temperature, 40 min, 52%; (h) 32, NaOAc, EtOH, room temperature, 24 h, 91%; (i) 33, NaOAc, EtOH, 60 °C, 6 h, 88%; (j) AgNO3, MeCN/H2O (3∶2), 24 h, 85% (1), 92% (2). EDCI, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Tf2O, trifluoroacetic anhydride; DIPEA, N,N-diisopropylethylamine; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DMAP, 4-(dimethylamino)pyridine; DCM, dichloromethane. Download figure Download PowerPoint Conclusion The synthesis of trabectedin ( 1), lurbinectedin ( 2), and renieramycin T ( 3) were accomplished in a concise and practical manner. The key features of the strategy include a robust PS cyclization via asymmetric oxomalonate assembly of the B ring and palladium complex-induced stereoselectivity from decarboxylative protonation for the C1 chiral center. The basic chiral units and multisubstituted tetrahydroisoquinoline fragments were assembled on a decagram scale from readily available starting materials. This feasible strategy will set the stage for rapid access to pentacyclic skeleton analogs, facilitating further structure–activity relationship studies. Supporting Information Supporting Information is available and includes full synthetic sequences, experimental procedures, characterization data, and NMR spectra. Conflict of Interest There is no conflict of interest to report. Acknowledgments The authors are grateful for the financial support provided by National Science Foundation of China (grant nos. 22125103 and 21971065) and Science and Technology Commission of Shanghai Municipality (grant nos. 22JC1401000, 20XD1421500, and 20JC1416800). References 1. Rinehart K. L.; Holt T. G.; Fregeau N. L.; Keifer P. A.; Wilson G. R.; Perun T. J.; Sakai R.; Thompson A. G.; Stroh J. G.; Shield L. S.Bioactive Compounds from Aquatic and Terrestrial Sources.J. Nat. Prod.1990, 53, 771–792. Google Scholar 2. Rinehart K. L.; Holt T. G.; Fregeau N. L.; Stroh J. G.; Keifer P. A.; Sun F.; Li L. H.; Martin D. G.Ecteinascidins 729, 743, 745, 759A, 759B, and 770: Potent Antitumor Agents from the Caribbean Tunicate Ecteinascidia Turbinata.J. Org. 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Google Scholar H.; of an into a for Chem. 23, Google Scholar Information Chinese Chemical authors are grateful for the financial support provided by National Science Foundation of China (grant nos. 22125103 and 21971065) and Science and Technology Commission of Shanghai Municipality (grant nos. 22JC1401000, 20XD1421500, and 20JC1416800).