HETEROCYCLES

Short Paper | Special issue | Vol. 84, No. 2, 2012, pp. 1325-1334
Received, 30th June, 2011, Accepted, 5th August, 2011, Published online, 8th August, 2011.
DOI: 10.3987/COM-11-S(P)67

■ Synthetic Studies on Paspaline: Lewis Acid-Mediated Sequential Construction of A-E Ring Skeleton

Kentaro Okano, Yu Yoshii, and Hidetoshi Tokuyama*

Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan

Abstract

The common pentacyclic skeleton of indole diterpene alkaloids, paspaline and its derivatives was constructed by a sequential reaction. The appropriate choice of the protecting group on the indole nitrogen was critical for the formation of bis(methylthio)allylic alcohol, which then underwent sulfonium ion formation and intramolecular electrophilic C-C-bond formation at the indole 3-position.

Since a number of indole alkaloids have potent bioactivities, synthetic studies on this class of natural products have been the subject of intense research in organic synthesis. Among them, a family of indole diterpenes containing paspaline,1 paspalicine,2 and paspalinine3 has attracted a great deal of interest from the synthetic community because of their unique structure and significant bioactivity.4 Despite numerous synthetic efforts, however, few efficient synthetic strategies are available for construction of the common pentacyclic A to E ring skeleton including an indole nucleus. To date, a limited number of total syntheses of these alkaloids have been reported.5 In this paper, we described a novel strategy for construction of the core pentacyclic framework of these compounds.

Considering an introduction of the angular methyl group at the later stage of synthesis, we selected pentacyclic indole 2 as a model compound in this synthetic study (Scheme 2). For formation of the cyclopentenone ring, we planned to examine the intramolecular electrophilic aromatic substitution reaction of sulfonium ion 4. Thus, sulfonium ion 4 would be generated by acidic treatment of bis(methylthio)allylic alcohol 5, which was developed by Junjappa and Ila as an α,β-unsaturated acylium ion equivalent.6 Bis(methylthio)allylic alcohol 5, the precursor of sulfonium ion 4, would be readily assembled by 1,2-addition of 2-lithioindole (6) to ketene dithioacetal 7.

We set out the research by preparation of ketene dithioacetal 7 from decalone 8 according to Paquette’s protocol6b (Scheme 3). Thus, ketone 8, which was derived from Wieland-Miescher ketone by the known four-step sequence,7 was converted to lithium enolate in the presence of excess base. The desired ketene dithioacetal 7 was obtained by successive treatment with carbon disulfide and iodomethane.

Then, we attempted to introduce an indole unit at the carbonyl group of 7. Unfortunately, however, the reaction between 2-lithiated N-phenylsulfonylindole (9) and ketone 7 resulted in formation of a totally unexpected product 10 in low yield (Scheme 4). The structure of product 10 was established by extensive NMR analysis.8

The plausible reaction mechanism for the formation of 10 is depicted in Scheme 5. After 1,2-addition of 2-lithioindole 11 to ketene dithioacetal 7, intramolecular migration of the phenylsulfonyl group to the proximal lithium alkoxide took place to provide sulfonate 13. Then, elimination of sulfonate and cyclization of the resulting zwitter ion 15 led to the pentacyclic product 10.

At this point we considered that a more robust protective group on the indole nitrogen should be necessary to circumvent the undesired reaction. With these considerations, we examined the reaction using N-methylindole9 (16a) (Scheme 6). Thus, 1,2-addition of 2-lithio-N-methylindole to 7 proceeded smoothly to give tertiary alcohol 17a as a single isomer.10 Upon treatment with trifluoroborane etherate, the tertiary alcohol 17a underwent the expected cyclization reaction at the indole 3-position quite smoothly at –78 °C to furnish the desired pentacyclic compound 18a. Finally, removal of the dithioacetal with aqueous silver nitrate provided enone 19a in high overall yield (75% from 16a). The structure of 19a was unambiguously identified by X-ray crystallography11 (Figure 1). The three-step sequence was also able to convert MOM-protected indole 16b12 to the corresponding pentacyclic compound 19b in moderate yield.13

In conclusion, we have established a synthetic strategy for construction of the pentacyclic indole skeleton, starting from 1,2-addition of 2-lithioindole to β,β-bis(methylthio)enone and the subsequent one-pot sequential reaction including acid-mediated generation of sulfonium ion and intramolecular electrophilic aromatic substitution at the indole 3-position. This strategy would provide rapid access to a cyclopentenone ring fused to indole, which is a common structure motif in the indole diterpene hybrid molecules. Further synthetic studies towards natural products are currently under investigation.

EXPERIMENTAL
General
All moisture or air sensitive reactions were carried out under a positive atmosphere of argon in dried glassware. Materials were obtained from commercial suppliers and used without further purification unless otherwise mentioned. Anhydrous THF, Et2O, and CH2Cl2 were purchased from Kanto Chemical Co. Inc. Anhydrous toluene, MeCN, acetone, DMF, and DMSO were purchased from Wako Pure Chemical Industries. Flash column chromatography was performed on Silica Gel 60N (Kanto, spherical neutral, 40-50 µm) using the indicated solvent. Preparative TLC was performed on Merck 60 F254 glass plates precoated with a 0.50 mm thickness of silica gel. Analytical TLC was performed on Merck 60 F254 glass plates precoated with a 0.25 mm thickness of silica gel. IR spectra were measured on SHIMADZU FTIR-8300 spectrometer. NMR spectra were recorded on a Varian Gemini 2000 spectrometer, a JNM-AL400 spectrometer and a GX500 spectrometer with tetramethylsilane or chloroform as an internal standard. Mass spectra were recorded on a JEOL JMS-DX-303 or a JMS-AX-500 spectrometers.
rac-(4aR,8aS)-2-(Bis(methylthio)methylene)-8a-methyloctahydronaphthalen-1(2H)-one (7).
A flame-dried 10-mL two-necked round-bottomed flask equipped with a magnetic stirring bar was charged with 8 (50.5 mg, 304 µmol) and dry THF (0.7 mL) under argon atmosphere. To the solution were added LHMDS in THF (1.60 M, 400 µL, 640 µmol) and HMPA (120 µL, 691 µmol) at –78 °C, respectively. The resulting orange solution was stirred at –78 °C for 1 h, and carbon disulfide (40.0 µL, 665 µmol) was added to the solution at –78 °C. The resulting red solution was stirred at –78 °C for 1.5 h, after which time TLC (hexanes-EtOAc = 5:1) indicated complete consumption of 8. To the solution was added MeI (90.0 µL, 1.45 mmol) at –78 °C. The resulting mixture was stirred at –78 °C for 20 min and was then warmed to rt. The reaction mixture was stirred for 1 h, after which time the excess reagent was quenched by saturated aqueous ammonium chloride, and the resulting mixture was extracted with Et2O three times. The combined organic extracts were washed twice with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (hexanes- EtOAc = 20:1) to afford 7 (71.7 mg, 265 µmol, 88%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.37–3.29 (m, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 1.73–1.06 (m, 12H), 0.98 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 207.5, 143.6, 138.0, 48.8, 45.0, 33.7, 32.5, 28.0, 27.9, 25.9, 21.2, 17.7, 17.0, 14.0; IR (neat, cm–1): 2924, 2856, 1695, 1452, 1435, 1267, 1258, 1016, 868; LRMS-EI (m/z) 270 (M+); HRMS-EI (m/z) calcd. for C14H22OS2, 270.1111; found, 270.1110.
Compound 10.
A flame-dried 30-mL two-necked round-bottomed flask equipped with a magnetic stirring bar was charged with 9 (121 mg, 468 µmol) and dry THF (2.0 mL) under argon atmosphere. The flask was cooled to –78 °C. To the flask was added n-BuLi (1.54 M in n-hexane, 150 µL, 231 µmol). The resulting mixture was stirred at –78 °C for 17 min and warmed to 0 °C for 20 min. The resulting yellow solution was cooled to –78 °C for 25 min and to the mixture was added a solution of 7 (22.0 mg, 81.3 µmol) in THF (2.0 mL). The resulting mixture was stirred at –78 °C for 5 min, then warmed to rt for 20 min, after which time TLC (hexanes-CH2Cl2 = 1:1) indicated complete consumption of 7. To the flask was added saturated aqueous ammonium chloride. The mixture was extracted with Et2O three times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by preparative TLC (hexanes-CH2Cl2 = 4:1) to afford 10 (10.1 mg, 21.1 µmol, 26%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, 1H, J = 8.4 Hz), 7.56 (d, 1H, J = 8.0 Hz) 7.17 (ddd, 1H, J = 8.4, 7.2, 1.2 Hz), 7.08 (ddd, 1H, J = 8.0, 7.2, 0.8 Hz), 6.16 (s, 1H), 2.62–2.52 (m, 1H), 2.49–2.36 (m, 1H), 2.28–2.22 (m, 1H), 1.86–1.78 (m, 1H), 1.73–1.31 (m, 15H), 1.23 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 143.7, 142.8, 140.0, 133.3, 133.2. 121.5, 121.4, 120.0, 110.7, 93.2, 78.1, 44.4, 37.2, 35.7, 30.3, 27.8, 26.7, 25.2, 22.0, 21.6, 19.0, 12.0; IR (neat, cm–1): 2928, 2855, 1448, 1335, 1304, 1217, 1150, 746; LRMS-EI (m/z) 369 (M+); HRMS-EI (m/z) calcd. for C22H27NS2, 369.1585; found, 368.1516.
rac-(1R,4aR,8aS)-2-(Bis(methylthio)methylene)-8a-methyl-1-(1-methyl-1H-indol-2-yl)-decahydro-naphthalen-1-ol (17a)
A flame-dried 50-mL two-necked round-bottomed flask equipped with a magnetic stirring bar was charged with 16a (129 mg, 983 µmol) and dry THF (4.0 mL) under argon atmosphere. The flask was cooled to –78 °C. To the flask was added n-BuLi (1.54 M in n-hexane, 530 µL, 816 µmol). The resulting mixture was stirred at –78 °C for 5 min and warmed to rt for 15 min. The resulting white suspension was cooled to –78 °C for 10 min and to the mixture was added 7 (101 mg, 375 µmol). The resulting mixture was stirred at –78 °C for 5 min, then warmed to rt for 10 min, after which time TLC (hexanes-CH2Cl2 = 1:1) indicated complete consumption of 7. To the flask was added saturated aqueous ammonium chloride. The mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford crude 17a (235 mg) as a yellow oil. The residue was purified by silica gel column chromatography (hexanes-CH2Cl2 = 7:3) to provide 17a (118 mg, 294 µmol, 78%, yield is based on 7) as a yellow amorphous. Physical data of pure 17a: 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 1H, J = 8.4 Hz), 7.31 (d, 1H, J = 8.4 Hz), 7.18 (ddd, 1H, J = 8.4, 7.2, 1.2 Hz), 7.07 (dd, 1H, J = 8.4, 7.2 Hz), 6.51 (s, 1H), 6.44 (s, 1H), 3.98 (s, 3H), 3.34 (ddd, 1H, J = 16.8, 6.8, 2.4 Hz), 2.41 (ddd, 1H, J = 16.8, 11.6, 7.2 Hz), 2.26 (s, 3H), 2.18–2.05 (m, 1H), 2.03 (s, 3H), 1.95–1.81 (m, 1H), 1.63–1.28 (m, 7H), 1.27–0.97 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 154.2, 141.5, 137.5, 126.73, 126.68, 121.1, 120.0, 119.2, 108.9, 103.3, 84.3, 45.2, 36.9, 32.9, 32.7, 32.0, 29.5, 28.3, 25.7, 22.0, 16.8, 16.3, 14.9; IR (neat, cm–1): 3360, 2926, 2862, 1464, 1350, 1327, 1312, 1234, 1217, 748; LRMS-EI (m/z) 401 (M+); HRMS-EI (m/z) calcd. for C23H31NOS2, 401.1847; found, 401.1838.
rac-Dithioacetal compound (18a).
A flame-dried 50-mL two-necked round-bottomed flask equipped with a magnetic stirring bar was charged with 17a (27.5 mg, 68.5 µmol) and dry CH2Cl2 (3.0 mL) under argon atmosphere. To the solution was added boron trifluoride etherate (35.0 µL, 284 µmol) dropwise at –78 °C. The resulting mixture was stirred at –78 °C for 10 min, then warmed to rt for 15 min, after which time TLC (hexanes-CH2Cl2 = 1:1) indicated complete consumption of 17a. The excess reagent was quenched with saturated aqueous ammonium chloride, and the mixture was extracted with CH2Cl2 three times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and filtered. The filtrate was concentrated under reduced pressure to afford crude 18a (27.1 mg) as an orange oil, which was used for the next reaction without further purification. Physical data of pure 18a: 1H NMR (400 MHz, CDCl3): δ 7.75–7.66 (m, 1H), 7.35–7.27 (m, 1H), 7.21–7.08 (m, 2H), 3.94 (s, 3H), 2.63–2.35 (m, 3H), 1.95–1.15 (m, 19H); 13C NMR (100 MHz, CDCl3): δ 147.2, 146.4, 141.7, 141.3, 122.7, 121.6, 120.13, 120.07, 118.2, 110.0, 58.6, 46.3, 37.5, 36.0, 34.5, 28.3, 26.6, 25.6, 24.0, 21.9, 18.3, 13.3, 13.0; IR (neat, cm–1): 2922, 2856, 1701, 1612, 1582, 1470, 1431, 1271, 1217, 1161, 1040, 791, 754; LRMS-EI (m/z) 383 (M+); HRMS-EI (m/z) calcd. for C23H29NS2, 383.1741; found, 383.1736.
rac-Pentacyclic indole (19a).
A 50-mL round-bottomed flask equipped with a magnetic stirring bar was charged with crude 18a (27.1 mg) and AgNO3 (110 mg, 648 µmol). To the flask was added 1,4-dioxane-H2O (2:1 = 6.0 mL). The reaction mixture was stirred for 20 min, after which time TLC (CH2Cl2) indicated complete consumption of 18a. The reaction was quenched with H2O and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The organic solvents were removed under reduced pressure to give a crude product, which was purified by preparative TLC (CH2Cl2) to afford pure 19a (20.0 mg, 65.5 µmol, 96% over 2 steps) as a red solid. 1H NMR (400 MHz, CDCl3): δ 7.58 (d, 1H, J = 8.0 Hz), 7.17 (d, 1H, J = 8.4 Hz), 7.14 (ddd, 1H, J = 8.0, 7.2, 1.2 Hz), 7.04 (ddd, 1H, J = 8.4, 7.2, 1.2 Hz), 3.86 (s, 3H), 2.38–2.28 (m, 1H), 2.22–2.07 (m, 2H), 1.83–1.75 (m, 1H), 1.73–1.57 (m, 2H), 1.55–1.30 (m, 7H), 1.21 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.5, 161.5, 150.8, 142.2, 141.9, 137.4, 123.4, 122.7, 120.8, 118.8, 110.7, 46.0, 35.64, 35.59, 34.6, 28.0, 26.4, 24.8, 22.2, 21.5, 16.5; IR (neat, cm–1): 2930, 2858, 1693, 1611, 1472, 1456, 1408, 1042, 746; LRMS-EI (m/z) 305 (M+); HRMS-EI (m/z) calcd. for C21H23NO, 305.1780; found, 305.1783.
rac-(1R,4aR,8aS)-2-(Bis(methylthio)methylene)-1-(1-(methoxymethyl)-1H-indol-2-yl)-8a-methyldeca-hydronaphthalen-1-ol (17b).
A flame-dried 30-mL two-necked round-bottomed flask equipped with a magnetic stirring bar was charged with 16b (171 mg, 595 µmol) and dry THF (6.0 mL) under argon atmosphere. The flask was cooled to –78 °C. To the flask was added n-BuLi (1.54 M in n-hexane, 424 µL, 655 µmol). The resulting mixture was stirred at –78 °C for 10 min and to the mixture was added a solution of 7 (193 mg, 714 µmol) in THF (2.0 mL). The resulting mixture was stirred at –78 °C for 5 min, then warmed to 0 °C for 20 min, after which time TLC (hexanes-CH2Cl2 = 1:1) indicated complete consumption of 16b. To the flask was added water. The mixture was extracted with EtOAc three times. The combined organic extracts were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford crude 17b as yellow oil. The residue was purified by recrystallization (hexanes-EtOAc) to afford 17b (213 mg, 494 µmol, 83%) as a white amorphous. 1H NMR (400 MHz, CDCl3): δ 7.53 (d, 1H, J = 7.2 Hz), 7.47 (d, 1H, J = 7.2 Hz), 7.25–7.15 (m, 1H), 7.10 (dd, 1H, J = 7.2, 7.2 Hz), 6.64 (s, 1H), 6.35 (s, 1H), 6.18 (d, 1H, J = 10.0 Hz), 5.50 (d, 1H, J = 10.0 Hz), 3.40 (ddd, 1H, J = 18.4, 7.6, 2.4 Hz), 3.32 (s, 3H), 2.56 (ddd, 1H, J = 19.2, 10.8, 8.4 Hz), 2.27 (s, 3H), 1.96–1.73 (m, 5H), 1.63–0.80 (m, 13H); 13C NMR (100 MHz, CDCl3): δ 154.2, 142.6, 138.0, 128.7, 127.1, 121.8, 120.2, 120.1, 109.7, 105.1, 83.8, 75.9, 56.0, 44.1, 35.6, 33.1, 31.3, 29.7, 27.1, 25.4, 22.0, 17.2, 16.1, 15.4; IR (neat, cm–1): 3358, 2922, 2858, 1458, 1346, 1302, 1169, 1065, 910, 754, 735; LRMS-FAB (m/z) 431 (M+); HRMS-FAB (m/z) calcd. for C24H33NO2S2, 431.1953; found, 431.1952.
rac-Dithioacetal compound (18b).
A flame-dried 30-mL two-necked round-bottomed flask equipped with a magnetic stirring bar was charged with 17b (20.6 mg, 47.8 µmol) and dry CH2Cl2 (5.0 mL) under argon atmosphere. To the solution was added boron trifluoride etherate (30.0 µL, 243 µmol) dropwise at –78 °C. After 4 h, the reaction was quenched with MeOH/CH2Cl2 (1:10, 5.0 mL) and the resulting mixture was let warm to room temperature. Water was then added to the resulting mixture and the mixture was extracted twice with CH2Cl2. The combined organic extracts were dried over anhydrous sodium sulfate, and filtered. The organic solvents were removed under reduced pressure to give a crude product, which was purified by preparative TLC (CH2Cl2-hexanes = 2:3) to afford pure 18b (13.1 mg, 31.7 µmol, 66%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.77–7.70 (m, 1H), 7.49–7.42 (m, 1H), 7.22–7.13 (m, 2H), 5.63 (d, 1H, J = 10.8 Hz), 5.60 (d, 1H, J = 10.8 Hz), 3.27 (s, 3H), 2.63–2.53 (m, 1H), 2.52–2.41 (m, 1H), 2.34–2.26 (m, 1H), 1.82–1.76 (m, 4H) 1.73–1.31 (m, 12H), 1.25 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 147.4, 145.9, 142.4, 141.7, 123.8, 123.2, 121.0, 121.0, 118.4, 110.8, 76.1, 58.2, 55.5, 46.2, 37.2, 36.3, 28.4, 26.6, 25.5, 23.8, 21.9, 18.2, 13.1, 12.7; IR (neat, cm–1): 2924, 2856, 1448, 1377, 1340, 1186, 1105, 1076, 961, 916, 743; LRMS-EI (m/z) 413 (M+); HRMS-EI (m/z) calcd. for C24H31NOS2, 413.1847; found, 413.1857.
rac-Pentacyclic indole (19b).
A 10-mL round-bottomed flask equipped with a magnetic stirring bar was charged with 18b (13.1 mg, 31.7 µmol) and AgNO3 (16.2 mg, 95.1 µmol). To the flask was added 1,4-dioxane-H2O (1:1 = 1.0 mL). The reaction mixture was stirred for 1.5 h, after which time TLC (hexanes-EtOAc = 4:1) indicated complete consumption of 18b. The reaction was quenched with H2O and the aqueous layer was extracted with EtOAc three times. The combined organic extracts were dried over anhydrous sodium sulfate, and filtered. The organic solvents were removed under reduced pressure to give a crude product, which was purified by preparative TLC (hexanes-EtOAc = 4:1) to afford pure 19b (9.2 mg, 27 µmol, 86%, 57% over 2 steps) as a red oil. 1H NMR (400 MHz, CDCl3): δ 7.60 (d, 1H, J = 8.0 Hz), 7.34 (d, 1H, J = 8.0 Hz), 7.16 (ddd, 1H, J = 8.0, 7.2, 1.2 Hz), 7.07 (ddd, 1H, J = 8.0, 7.2, 1.0 Hz), 5.53 (d, 1H, J = 11.2 Hz), 5.48 (d, 1H, J = 11.2 Hz), 3.36 (s, 3H), 2.39–2.28 (m, 1H), 2.24–2.05 (m, 2H), 1.83–1.75 (m, 1H), 1.73–1.59 (m, 2H), 1.52–1.29 (m, 7H), 1.22 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.3, 160.6, 151.9, 142.2, 136.6, 123.7, 122.7, 121.6, 119.0, 111.7, 111.3, 76.1, 56.1, 45.9, 36.1, 35.8, 28.2, 26.5, 24.8, 22.1, 21.6, 16.9; IR (neat, cm–1): 2929, 2858, 1699, 1454, 1427, 1391, 1114, 1082, 1036, 748; LRMS-EI (m/z) 335 (M+); HRMS-EI (m/z) calcd. for C22H25NO2, 335.1885; found, 335.1880.

ACKNOWLEDGEMENTS
This work was financially supported by the Ministry of Education, Culture, Sports, Science, and Technology, Japan, the KAKENHI, a Grant-in-Aid for Scientific Research (B) (20390003), the Cabinet Office, Government of Japan through its “Funding Program for Next Generation World-Leading Researchers, Tohoku University Global COE program ‘International Center of Research and Education for Molecular Complex Chemistry’, and an Emergency Fund from Astellas Foundation for Research on Metabolic Disorders. We also appreciated Dr. Chizuko Kabuto for her kind assistance for X-ray crystallographic analysis.

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11. Crystal data for 19a C12H23NO: MW = 305.40, orthorhombic, a = 7.7989(4), b = 16.8310(7), c = 24.1167(12) Å, β = 90 °, V = 3165.6(3) Å3, T = 173 K, space group Pnaa (no. 56), Z = 8, µ(MoKα) = 0.78 cm–1, Dcalc = 1.282 g/cm–3. A total of 28499 reflections were measured, of which 3599 (Rint = 0.110) reflections were used for analysis. The structure was refined to a goodness of fit (GOF) of 1.129 and the final residuals were R = 0.066 and wR = 0.151. Crystallographic data of 19a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-829556. Copies of the date can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB1 1EZ, UK (fax:+44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
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