Acridone alkaloids comprise a large family of biologically active natural products ^[1],some of which display significant anticancer activity ^[2]. Chlorospermines A and B (1 and 2,Fig. 1) are two polycyclic acridone alkaloids recently isolated by Litaudon and co-workers from the stem bark of Glycosmis chlorosperma^[3]. The latter possesses remarkable inhibitory property against dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A),which is closely related to neuronal development and adult brain physiology. Although a number of acridone syntheses have been documented in literature ^{[4, 5, 6, 7, 8, 9, 10, 11]},they usually relied on Friedel-Crafts reactions which require strongly acidic conditions as well as electron-rich arene substrates. In order to build up a focused library of chlorospermine analogs for further biological evaluations,an efficient and modular approach to the tetracyclic core of chlorospermines is highly desired. This approach needs to be applicable to a wide range of substrates; thus,constructing the acridone core under neutral conditions would be optimal. The synthesis of multi-substituted arenes remains a remarkable challenge for modern organic chemistry ^{[12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24]}. Electrocyclization has proven to be a powerful tool for assembling functionalized ring systems,since Nicolaouet al.disclosed the elegant synthesis of endiandric acids ^{[25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43]}. Notably,multi-substituted arenes can be constructed in a highly efficient and convergent fashion,when 6pelectrocyclization is strategically combined with oxidative aromatization ^{[44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54]}. Recently,we have successfully applied such strategies to the syntheses of a series of natural products containing aromatic moieties,such as daphenylline ^[55],tubingensin A ^[56],xiamycin A,oridamycins A and B ^[57],rubriflordilactone A ^[58] and clostrubin ^[59]. Herein,we report a concise route toward the tetracyclic core of chlorospermines A and B using 6pelectrocyclization/aromatization as a key step.

Fig. 1

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Fig. 1. The structures of chlorospermines A and B.

All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions,unless otherwise noted. Tetrahydrofuran (THF) was distilled immediately before use from sodium-benzophenone ketyl. Methylene chloride (CH₂Cl₂) and triethylamine (Et₃N) were distilled from calcium hydride and stored under an argon atmosphere. Reagents were purchased at the highest commercial quality and used without further purification,unless otherwise stated. Solvents for chromatography were used as supplied by Titan chemical. Reactions were monitored by thin layer chromatography (TLC) carried out on S-2 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and aqueous ammonium cerium nitrate/ammonium molybdate or basic aqueous potassium permanganate as developing agent. E. Merck silica gel (60,particle size 0.040- 0.063 mm) was used for flash column chromatography. NMR spectra were recorded on Bruker AV-400 instrument and calibrated by using residual undeuterated chloroform (dH7.26) and CDCl₃ (dC 77.16) as internal references. IR spectra were recorded on a Thermo Scientific Nicolet 380 FT-IR spectrometer. High-resolution mass spectra (HRMS) were recorded on a Bruker APEXIII 7.0 Tesla ESI-FT.

The preparation of compound 3: To a stirred solution of known compound5(2.00 g,11.4 mmol) in DMF (10 mL) was added NIS (2.57 g,12.6 mmol) at 0℃. The reaction mixture was stirred at 22℃ for 1.5 h before it was diluted with EtOAc (80 mL). The resultant mixture was sequentially washed with saturated aq. Na2S2O3(20 mL) and brine (20 mL),and the organic phase was dried over anhydrous Na₂SO₄ and filtered. The solvent was evaporated under vacuum,and the crude iodide was dissolved in CH₂Cl₂(10 mL). To this solution were sequentially added TsCl (2.61 g,13.7 mmol),Et₃N (5.76 g,7.93 mL,57.0 mmol),and 4-DMAP (139 mg,1.14 mmol) at 0℃. The resultant mixture was allowed to warm to 22℃ and stirred at that temperature for 1 h before it was quenched with saturated aq. NaHCO₃(30 mL). The mixture so obtained was extracted with EtOAc (3×60 mL),and the combined organic phases were washed with brine (2×20 mL) and dried over anhydrous Na₂SO₄. After filtration and removal of the solvent under vacuum,the residue was subjected to flash column chromatography for purification using EtOAc/petroleum ether (1:5!1:1) as eluent to givea-iodoquinolone 3 (4.83 g,93% for the two steps) as a yellow foam (Scheme 1).3: IR (film,cm-¹ ):nmax 3063,2929,2843,1593,1560,1483,1263,1180,1037,812,870, 757,677,570; ¹HNMR (400 MHz,CDCl₃):δ9.09 (s,1H),7.93 (d,2H, J=8.1 Hz),7.57 (d,1H,J=8.6 Hz),7.45 (t,1H,J=8.2 Hz),7.40 (d, 2H,J=8.1 Hz),7.10 (d,1H,J=7.8 Hz),4.08 (s,3 H),2.50 (s,3H); ¹³C NMR (101 MHz,CDCl₃):δ155.99,155.09,154.48,146.16,141.03, 133.49,129.87,128.65,128.12,126.01,114.33,108.70,87.33, 56.08,21.67; HRMS (m/z ): [M+H]⁺ calcd. for C₁₇H₁₅O₄NIS⁺ 455.9761,found 455.9763.

Scheme 1

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Scheme 1.Synthesis of the tetracyclic core of chlorospermines A and B. Reagents and conditions: (a) NIS (1.1 equiv.),DMF,22℃,1.5 h; (b) TsCl (1.2 equiv.),Et3N (5.0 equiv.), 4-DMAP (10 mol%),CH2Cl2,22℃,1 h,93% for the two steps; (c) TBDPSCl (5.0 equiv.),imidazole (5.0 equiv.),DMF,22℃,1 h; (d)m-CPBA (1.3 equiv.),NaHCO3(1.3 equiv.), 22℃,5 h,87% for the two steps; (e) TMS-acetylene (4.5 equiv.),BuLi (3.0 equiv.),BF3·OEt2(3.0 equiv.),THF,-78℃,2 h; (f) TFA (0.5 equiv.),4 A˚ molecular sieves,CH2Cl2, 22℃,24 h; (g) K2CO3(2.0 equiv.),MeOH,22℃,2 h,53% for the three steps; (h) Pd(PPh3)2Cl2(5 mol%),CuI (5 mol%),Et3N (5.0 equiv.),3(1.0 equiv.),DMF,22℃,12 h,75%; (i) Pt(dvds) (5 mol%),(Et2CHO)Me2SiH (1.1 equiv.),CH2Cl2,22℃,10 h; (j) AgF (3.0 equiv.),THF/MeOH/water (500:250:1),22℃,3 h,41% for the two steps; (k) air,toluene, 125℃,3 h,56%

The preparation of compound 7: To a stirred solution of known β-hydroxy ketone 6(2.00 g,15.6 mmol) in DMF (1.0 mL) were sequentially added imidazole (5.31 g,78.0 mmol) and TBDPSCl (21.4 g,20.3 mL,78.0 mmol) at 0℃. The reaction mixture was allowed to warmed to 22℃ and stirred at that temperature for 1 h before it was quenched with saturated aq. NaHCO₃(30 mL). The resultant mixture was extracted with EtOAc (3×40 mL). The combined organic phases were washed with brine (50 mL),dried over anhydrous Na₂SO₄,and filtered. The solvent was evaporated under vacuum,and the residue was passed through a plug of silica with EtOAc/petroleum ether (1:20) to give the TBDPS ether as a colorless oil. This oil was dissolved in CH₂Cl₂ (15 mL). To this solution were sequentially added NaHCO₃(1.70 g,20.3 mmol) and m-CPBA (4.12 g,20.3 mmol,85 wt%) at 0℃. The reaction mixture was allowed to warm to 22℃ and stir at that temperature for 5 h before it was quenched with saturated aq. Na₂SO₃(50 mL). The resultant mixture was extracted with CH₂Cl₂(3×60 mL),and the combined organic phases were washed with brine (80 mL) and dried over anhydrous Na₂SO₄. After filtration and removal of the solvent under vacuum,the residue was purified by flash column chromatography with EtOAc/petroleum ether (1:10!1:5) to give lactone7(5.19 g,87% for the two steps) as a colorless oil (Scheme 1).7: IR (film,cm-¹ ): nmax3066,2959,2931,2857,1736,1474, 1429,1274,1114,1013,819,698; ¹HNMR (400 MHz,CDCl₃): d 7.70-7.65 (m,4H),7.48-7.44 (m,2H),7.42-7.38 (m,4H),3.78 (dd, 1H,J=6.0,5.0 Hz),2.61 (dd,1H,J=18.8,7.4 Hz),2.30 (dd,1H, J=18.8,7.0 Hz),1.81-1.76 (m,2H),1.42 (s,3H),1.31 (s,3H),1.08 (s, 9H); ¹³C NMR (101 MHz,CDCl₃):δ170.29,135.79,135.71,133.47, 132.60,130.03,129.96,127.78,127.68,84.24,71.35,27.47,26.95, 25.98,24.31,23.98,19.37; HRMS (m/z ): [M+H]⁺ calcd. for C₂₃H₃₁O₃Si⁺ 383.2037,found 383.2034.

The preparation of compound 4: To a stirred solution of (trimethylsilyl)acetylene (6.00 g,8.63 mL,61.0 mmol) in THF (120 mL) at-78℃ was added BuLi (17.0 mL,2.4 mol/L in hexane, 40.8 mmol). The resulting mixture was stirred at-78℃ for 15 min before BF₃·OEt₂ (5.79 g,5.03 mL,40.8 mmol) was added. The mixture so obtained was stirred at-78℃ for 30 min before a solution of 7 (5.19 g,13.6 mmol) in THF (18 mL) was added. The reaction mixture was stirred at -78℃ for 2 h before it was quenched with saturated aq. NH₄Cl (100 mL). The resultant mixture was extracted with EtOAc (3×80 mL). The combined organic phases were washed with brine and dried over anhydrous Na₂SO₄. After filtration and removal of the solvent under vacuum, the crude alcohol was dissolved in CH₂Cl₂(24 mL). To this solution were sequentially added 4 Å molecular sieves (3.40 g) and TFA (775 mg,520mL,6.80 mmol) at 0℃. The reaction mixture was stirred at 22℃ for 24 h before it was quenched with saturated aq. NaHCO₃(30 mL). The resultant mixture was extracted with CH₂Cl₂ (3×60 mL),and the combined organic phases were washed with brine (3×20 mL),dried over anhydrous Na₂SO₄,and filtered. The solvent was removed under vacuum,and the residue was dissolved in MeOH (30 mL). To this solution was added anhydrous K₂CO₃ (3.76 g,27.1 mmol) at 22℃. The resultant mixture was stirred at that temperature for 2 h before it was quenched with saturated aq. NH₄Cl (30 mL). The mixture so obtained was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine (2×50 mL) and dried over anhydrous Na₂SO₄. After filtration and removal of the solvent under vacuum,the residue was subjected to flash column chromatography for purification using EtOAc/petroleum ether (1:100) as eluent to give pyran 4 (2.81 g,53% for the three steps) as a colorless oil (Scheme 1).4:IR (film,cm-¹ ):nmax3286,3071,2934,2854,1640,1426,1313,1114, 837,742,703,617; ¹HNMR (400 MHz,CDCl₃):δ7.71-7.66 (m,4H), 7.47-7.43 (m,2H),7.41-7.37 (m,4H),5.02 (dd,1H,J=4.8,3.5 Hz), 3.68 (dd,1H,J=8.1,6.2 Hz),2.83 (s,1H),2.03-1.93 (m,2H),1.30 (s, 3H),1.29 (s,3H),1.07 (s,9H); ¹³C NMR (101 MHz,CDCl₃):δ136.04, 136.03,134.25,134.04,133.25,130.02,129.86,127.85,127.64, 106.66,79.46,78.16,75.05,71.51,28.75,27.11,26.22,19.50, 19.01; HRMS (m/z ): [M+Na]⁺ calcd. for C₂₅H₃₀NaO₂Si⁺ 413.1907, found 413.1902.

The preparation of compound 8: To a stirred solution of aiodoquinolone 3 (1.00 g,2.20 mmol) and pyran 4 (860 mg, 2.20 mmol) in DMF (3.0 mL) were sequentially added Pd(PPh₃)₂Cl₂ (77.2 mg,0.110 mmol),CuI (20.9 mg,0.110 mmol),and Et3N (1.12 g,1.54 mL,11.0 mmol) at 22℃. The reaction mixture was stirred at that temperature for 12 h before it was quenched with saturated aq. NaHCO₃ (10 mL). The mixture so obtained was extracted with EtOAc (3×30 mL). The combined organic phases were then washed with brine (50 mL),dried over anhydrous Na₂SO₄,and filtered. The solvent was removed under vacuum,and the residue was purified by flash column chromatography with EtOAc/petroleum ether (1:5!1:1) to give dieneyne 8(1.18 g,75%) as a pale yellow foam.8: IR (film,cm-¹ ):nmax3071,2959,2929, 2852,2215,1748,1593,1480,1382,1176,1111,903,757,703, 668; ¹HNMR (400 MHz,CDCl₃):δ8.86 (s,1H),7.84 (d,2H, J=8.4 Hz),7.72-7.68 (m,4H),7.57 (dd,1H,J=1.1,8.6 Hz),7.48- 7.39 (m,7H),7.24 (d,2H,J=8.4 Hz),7.07 (dd,1H,J=7.8,0.8 Hz), 5.01 (dd,1H,J=5.0,3.4 Hz),4.07 (s,3H),3.70 (dd,1H,J=8.4, 6.2 Hz),2.34 (s,3H),2.13-1.99 (m,2H),1.34 (s,3H),1.33 (s,3H), 1.08 (s,9H); ¹³C NMR (101 MHz,CDCl₃):δ155.28,153.32,151.86, 145.79,140.84,136.05,136.03,134.43,134.13,133.18,133.09, 130.08,130.01,129.93,128.84,128.21,127.89,127.69,124.34, 114.70,112.04,109.21,108.26,92.86,80.06,78.29,71.62,56.31, 29.18,27.11,26.43,21.87,19.50,18.79; HRMS (m/z ): [M+H]⁺ calcd. for C₄₂H₄₄O₆NSSi⁺ 718.2653,found 718.2646.

The preparation of compound 9: To a stirred solution of dieneyne 8(22.0 mg,0.0306 mmol) and (Et2CHO)Me2SiH (4.9 mg, 0.034 mmol) in CH₂Cl₂ (0.20 mL) was added Karstedt’s catalyst (30mL,0.05 mol/L in polydimethylsiloxane,0.0015 mmol) at 22℃. The reaction mixture was allowed to stir at 22℃ for 10 h before it was passed through a short plug of celite with Et2O (10 mL). The filtrate was concentrated under vacuum,and the residue (the crude mixture of two alkenylsilane regioisomers) was dissolved in THF/MeOH (1.5 mL,2:1). To this solution were sequentially added water (ca. 2mL) and AgF (11.6 mg, 0.0918 mmol) at 0℃. The reaction mixture was allowed to warm to 22℃ and stir at that temperature for 3 h in the dark before it was passed through a short plug of celite with EtOAc (15 mL). The filtrate was washed with saturated aq. NH₄Cl (2×3 mL) and dried over anhydrous Na₂SO₄. After removal of the solvent under vacuum,the residue was subjected to flash column chromatography for purification using Et3N/EtOAc/petroleum ether (1:20:80 then 3:100:200) as eluent to give cis-triene 9(9.0 mg,41% for the two steps) as a pale yellow oil. This compound is unstable and needs to be used for the next step immediately.9: IR (film,cm-¹ ): nmax3069,2929,2857,2220,1596,1483,1382,1177,1111,1054, 909,703,549; ¹HNMR (400 MHz,benzene-d6):δ9.01 (s,1H),7.98 (dd,1H,J=8.5,0.9 Hz),7.79-7.65 (m,7H),7.21-7.19 (m,4H),7.15- 7.12 (m,2H),6.55-6.53 (m,3H),5.96 (d,1H,J=12.2 Hz),5.31 (d, 1H,J=12.2 Hz),4.25 (dd,1H,J=5.2,3.1 Hz),3.55 (dd,1H,J=8.7, 5.8 Hz),3.51 (s,3H),1.98 (ddd,1H,J=17.8,8.7,3.1 Hz),1.88-1.77 (m,1H),1.75 (s,3H),1.21 (s,3H),1.07 (s,3H),0.90 (s,9H); the ¹³C NMR experiment was not performed because of the instability of the compound; HRMS (m/z ): [M+H]⁺ calcd. for C₄₂H₄₆O₆NSSi⁺ 720.2810,found 720.2800.

The preparation of compound10: A solution of cis-triene 9 (9.0 mg,0.0125 mmol) in toluene (9.0 mL) was heated to 125℃ and stirred at that temperature for 3 h under an air atmosphere before it was cooled to 22℃. The volatile was removed under vacuum,and the residue was purified by flash column chromatography with EtOAc/petroleum ether (1:5!1:2) to give tetracyclic acridone10(3.9 mg,56%) as a white foam. 10: IR (film, cm-¹ ):nmax3426,2926,2854,1620,1530,1441,1257,1111,1057, 816,763,700,611; ¹HNMR (400 MHz,CDCl₃): d8.70 (d,1H, J=8.9 Hz),8.52 (d,1H,J=7.6 Hz),7.76-7.73 (m,2H),7.65-7.63 (m, 2H),7.43 (s,1H),7.20-7.18 (m,3H),7.13-7.11 (m,3H),6.91 (t,1H, J=8.0 Hz),6.80 (d,1H,J=8.9 Hz),6.48 (dd,1H,J=7.8,1.0 Hz), 3.96 (dd,1H,J=7.2,5.6 Hz),3.32 (s,3H),2.33 (dd,1H,J=15.4, 7.2 Hz),2.24 (dd,1H,J=15.4,5.6 Hz),1.36 (s,3H),1.23 (s,3H), 1.12(s,9H); ¹³C NMR (101 MHz,CDCl₃):δ176.85,157.01,146.94, 139.52,136.27,136.20,134.63,133.40,131.48,130.40,130.03, 127.94,127.40,122.97,120.73,119.34,116.63,113.26,111.11, 103.42,77.74,71.41,55.38,27.16,26.51,25.84,20.71,19.57; HRMS (m/z ): [M+H]⁺ calcd. for C₃₅H₃₈O₄NSi⁺ 564.2565,found 564.2555. 3. Results and discussion

The synthesis commenced with the preparation of the two segments,a-iodoquinolone 3 and alkynylpyran 4. The former arose from known compound 5^[60]. Iodination with NIS afforded the corresponding 2-iodoenone,which further underwentN-protection (TsCl,Et3N,4-DAMP) to furnish 3 in 93% overall yield. It should be noted that the bromo counterpart ^[61] of 3 was much less reactive for the next Sonogashira coupling reaction and thus abandoned. The synthesis of the pyran segment took advantage of a Baeyer-Villiger oxidation. Silylation of β-hydroxy ketone 6 followed by treatment with m-CPBA under buffered conditions provided lactone7in 87% yield (two steps). This compound was exposed to lithiated TMS-acetelene in the presence of BF₃·OEt₂ to give an unstable lactol intermediate,which was dehydrated with TFA to generate a conjugate eneyne ^[62]. Desilylation with K₂CO₃/MeOH delivered 4 (53% yield for the three steps).

With the two segments in hand,we investigated the construction of the tetra-substituted arene. Compounds 3 and 4 were forged together through Sonogashira coupling (Pd(PPh₃)₂Cl₂,CuI, Et₃N) to afford dieneyne 8 in 75% yield. A number of conditions were examined for the transformation of 8 into the corresponding cis-triene9. Unfortunately,the partial hydrogenation with Lindlar catalyst lacked reproducibility,and Zn/Cu couple reduction ^[63] suffered low reactivity. The triene product 9 was found to be unstable and thus needed to be prepared under mild conditions and purified rapidly. To our delight,8 smoothly underwent Ptcatalyzed hydrosilylation [Pt(dvds),(Et2CHO)Me2SiH] to give a regioisomeric mixture of alkenylsilanes ^{[64, 65, 66]},which were then subjected to desilylation conditions ^{[67, 68, 69, 70]} (AgF,water) to form 9 in 41% overall yield. Finally,6pelectrocyclization/ aromatization occurred smoothly under thermal conditions (125℃) in the presence of air,to furnish tetracyclic acridone 10 in 56% yield. This compound may serve as a common intermediate for the synthesis of a series of chlorospermine analogs. 4. Conclusion

We have developed a convergent strategy to construct the tetracyclic core of chlorospermines A and B. The readily available building blocks are assembled together by Sonogashira coupling. Acis-triene intermediate was then prepared through a sequence of hydrosilylation/desilylation. A one pot 6p-electrocyclization/ aromatization process formed the tetra-substituted arene. Further studies toward the total synthesis of chlorospermines A and B and analogs thereof are currently underway.

Financial support was provided by Ministry of Science & Technology (No. 2013CB836900),National Natural Science Foundation of China (Nos. 21290180,21172235 and 21222202),and China Postdoctoral Science Foundation (No. 2014M561537,M.Y.).