Organic &Biomolecular Chemistry

PAPER

Cite this: DOI: 10.1039/c3ob40180d

Received 26th January 2013,Accepted 26th February 2013

DOI: 10.1039/c3ob40180d

www.rsc.org/obc

Concise total syntheses of (±)-noruleine and (±)-uleine†

Süleyman Patir*a and Erkan Ertürk*b

The first total synthesis of (±)-noruleine and a concise synthesis of (±)-uleine have been accomplished via

the DDQ mediated dehydrogenative cyclization of a tetrahydrocarbazole derivative bearing a non-substi-

tuted amide functionality to prepare the key azocino[4,3-b]indole precursor.

Introduction

The uleine-type alkaloids (e.g. 1–4) constitute an importantsubgroup of the Strychnos alkaloids which are characterized bythe presence of the 1,5-methanoazocino[4,3-b]indole moietybearing an ethyl group at the bridge carbon atom (Fig. 1).Uleine (2) was first isolated from Aspidosperma ulei Mgf bySchmutz and co-workers and its correct structure was proposedby Buchi and Warnhoft in the late 1950s.1a,b Similarly, nor-uleine (1) was also first isolated from Brazilian Aspidospermaspecies in 1965.1c After the isolation of uleine (2), differentpathways to its total synthesis were reported in a number ofpublications over a long span of time.2,3 However, it is surpris-ing to note that there has not been any report on the synthesisof (±)-noruleine (rac-1) up to now.

Syntheses of uleine-type alkaloids are somehow based onthe construction of a 1,5-methanoazocino[4,3-b]indole skele-ton, the key element of uleine and Strychnos alkaloids.4–6

Recently, we disclosed that the tetracyclic hexahydro-1,5-methanoazocino[4,3-b]indole derivatives (6) could be obtained

in high yields by reacting tetrahydrocarbazole derivatives7 car-rying a mono-substituted amide side chain (5) with DDQ(Scheme 1).6h This dehydrogenative cyclization reaction seemsto proceed via the formation of the vinylogous iminium cationI and the subsequent ring-closure reaction.8 In the context ofour studies on the synthesis of uleine group alkaloids,2e wereasoned that the DDQ-mediated construction of the 1,5-methanoazocino[4,3-b]indole skeleton could be a divergentapproach to the syntheses of uleine alkaloids starting from anappropriate tetrahydrocarbazole derivative carrying a non-sub-stituted amide side chain. Therefore, we herein would like toreport an effective route to the syntheses of racemic noruleine((±)-1) and racemic uleine ((±)-2).

Results and discussion

Recently, we described a multi-gram preparation of the car-boxylic acid 8.9 By reacting the useful carboxylic acid 8 with1,2-ethanedithiol in the presence of zinc(ıı) Lewis acid cata-lysts, the thioketal 9 was synthesized in 88% yield(Scheme 2).10 Somewhat but negligible cis–trans epimerizationtook place during the thioketalization of the trans-carboxylicacid 8. The N-methylamide 10 and the non-substituted amide11 were obtained in good yields by reacting the carboxylic acid9 with methylamine or aqueous ammonia in the presence ofethyl chloroformate as the coupling reagent, respectively.Then, the non-substituted amide 11 was converted into theazocino[4,3-b]indole compound 12 in 84% yield by treating itwith DDQ. The oxo compound 13 was then prepared in 74%yield by the oxidative dethioketalization of 12 with [bis(trifluoro-acetoxy)iodo]benzene [PhI(O2CCF3)2] in acetonitrile–water(9 : 1).11

Currently, synthesis of organic compounds without protec-tion and deprotection steps is of great importance due to theatom economy. Consequently, we planned a synthesis of theazocino[4,3-b]indole compound 13 without the dithiolane-protecting group starting from the keto-carboxylic acid 8(Scheme 3). Transformation of the carboxylic acid 8 into the

Fig. 1 Structure of uleine-type alkaloids.

†Electronic supplementary information (ESI) available: The NMR spectra of allsynthesized compounds as well as HR MS spectra of (±)-noruleine and(±)-uleine. See DOI: 10.1039/c3ob40180d

aDepartment of Chemistry Education, Faculty of Education, Hacettepe University,

06800 Beytepe, Ankara, Turkey. E-mail: patir@hacettepe.edu.trbChemistry Institute, TUBITAK Marmara Research Center, 41470 Gebze, Kocaeli,

Turkey. E-mail: erkan.erturk@tubitak.gov.tr; Fax: +90-262-641 2309;

Tel: +90-262-677 2993

This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem.

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non-substituted amide 14 took place in high yield (74%).However, the DDQ mediated dehydrogenative cyclization of 14giving the azocino[4,3-b]indole 13 proceeded in somewhatdiminished yield (45%) with regard to the dithiolane protectedcounterpart 11. It was interesting to observe that conversion ofthe amide 14 into 13 was stopped after reaching 50%, whichindicates that the Brønsted-acidic side product 7 could pre-clude the further conversion of 14. All attempts to enhance the

reaction yield by adding some buffer-like additives such asK2CO3 and K2HPO4 failed. It is noteworthy that the non-con-verted amide 14 could be recovered from the reaction mixtureafter purification.

Treatment of the keto-amide 13 with methyllithium in tetra-hydrofuran at 0 °C provided the corresponding alcohol IVwhich was subsequently converted into the methylidene-amide15 in 66% yield by adding trifluoroacetic acid as the dehydrat-ing agent into the reaction mixture (Scheme 4).2e Among thereducing agents that were tested for reduction of the amide 15,only sodium bis(2-methoxyethoxy)aluminum dihydride (Red-Al®)in tetrahydrofuran was found to be effective and noruleine((±)-1) was obtained in 34% yield. Thus, the first total synthesisof noruleine ((±)-1) was accomplished.

Finally, we anticipated that the methylidene-amide 15could also be useful for a sequential one-pot two-step synthesisof uleine ((±)-2). For this purpose, the methylidene-amide 15was first reduced with Red-Al® to noruleine ((±)-1) from whichuleine ((±)-2) was formed by reacting with methyl iodide in thepresence of K2CO3 via the methiodide formation and the base-catalyzed demethylation sequence (Scheme 5).

Scheme 1 Synthesis of hexahydro-1,5-methanoazocino[4,3-b]indole derivatives (6) from the tetrahydrocarbazole derivatives 5 mediated by DDQ.6h

Scheme 2 Synthesis of the azocino[4,3-b]indole derivative 13 via a protec-tion–deprotection strategy.

Scheme 3 Synthesis of the azocino[4,3-b]indole derivative 13 without protec-tion and deprotection steps.

Scheme 4 Synthesis of racemic noruleine ((±)-1).

Paper Organic & Biomolecular Chemistry

Org. Biomol. Chem. This journal is © The Royal Society of Chemistry 2013

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Conclusion

In conclusion, we have developed a DDQ-mediated synthesisstrategy to azocino[4,3-b]indoles from tetrahydrocarbazolesbearing a non-substituted amide functionality as the key stepfor the total syntheses of noruleine ((±)-1) and uleine ((±)-2). Tothe best of our knowledge, this work presents not only the firstreport on the total synthesis of noruleine ((±)-1) but also oneof the shortest and the most efficient routes to uleine ((±)-2).

Experimental sectionGeneral remarks

All reactions were carried out under an inert atmosphere of drynitrogen (N2) using oven-dried glassware. All synthetic com-pounds are in their racemic form. Tetrahydrofuran (THF) wasfreshly distilled under N2 from sodium–benzophenoneimmediately prior to use. Chloroform (CHCl3) and triethyl-amine (Et3N) were distilled under N2 from calcium hydride(CaH2). Dimethyl sulfoxide (DMSO) was dried over CaH2 anddistilled under reduced pressure. Acetone was dried over mag-nesium sulfate (MgSO4) and distilled under N2. Methanol(MeOH) was dried over magnesium (Mg) under N2 prior touse. 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ), 1,2-ethane-dithiol, zinc trifluoromethanesulfonate (Zn(OTf)2), zinc chlor-ide (ZnCl2), ethyl chloroformate, [bis(trifluoroacetoxy)iodo]-benzene and sodium bis(2-methoxyethoxy)aluminum hydride(Red-Al® 40% in toluene) were purchased from commercialsuppliers and used as received. Thin layer chromatography(TLC) was conducted on aluminum sheets that were pre-coatedwith silica gel SIL G/UV254 from MN GmbH & Co., in which thespots were visualized in UV-light (λ = 254 nm) and/or by stain-ing with phosphomolybdic acid. Chromatographic separationswere performed using silica gel (MN-silicagel 60, 230–400 mesh). All melting points were determined in an openglass capillary tube by means of a BÜCHI Melting PointB-540 apparatus and values are uncorrected. Infrared (FT-IR)spectra were recorded on a PerkinElmer Spectrum One FT-IRspectrometer, νmax in cm−1. Bands are characterized as broad(br), strong (s), medium (m), and weak (w). 1H and 13C NMRspectra were recorded on a 500 MHz NMR spectrometer at25 °C. Chemical shifts δ are reported in parts per million(ppm) relative to the residual protons in the NMR solvent(CHCl3: δ 7.26; DMSO-d6: δ 2.50) and carbon resonance of thesolvent (CDCl3: δ 77.00; DMSO-d6: δ 39.52). NMR peak multi-plicities are given as follows: s = singlet, d = doublet, t =

triplet, q = quartet, m = multiplet, br = broad. High resolutionelectrospray ionization mass spectra (HR-ESI-MS) wereobtained with MeOH on a Bruker micrOTOF-Q.

{3-β-Ethyl-2,3,4,9-tetrahydrospiro[1H-carbazole-1,2′(1,3)dithio-lane]2-yl}-acetic acid ((±)-9). The acid (±)-89 (10 g, 36.9 mmol),zinc trifluoromethanesulfonate (7.27 g, 20.0 mmol) and zincchloride (2.72 g, 20.0 mmol) were placed in a 500 mL oven-dried two-necked flask that was equipped with a magnetic stir-ring bar and a reflux condenser. The reaction flask was evacu-ated for 15 minutes and back-filled with dry N2. The solidmixture was dissolved by adding absolute chloroform (300 mL)to the reaction flask and 1,2-ethanedithiol (11.3 g, 10.1 ml,120.0 mmol) was added into the solution. The mixture wasrefluxed for 24 hours under a nitrogen atmosphere. After thereaction mixture was allowed to cool down to room tempera-ture, distilled water (200 mL) was added into the reactionflask. The organic layer was separated by using a separatingfunnel and dried over MgSO4. After all the volatile componentswere removed by rotary evaporation in vacuo, the residue waspurified by silica gel column chromatography eluting withEtOAc. After recrystallization from Et2O, 11.3 g of the dithio-lane-protected acid (±)-9 (32.5 mmol, 88%) were isolated as awhite solid. Mp: 226 °C; Rf = 0.82 (silica gel; EtOAc); FTIR(KBr): νmax (cm−1) 3439 (m), 3054 (m), 2968 (m), 2925 (m),2613 (w), 1698 (s), 1619 (w), 1456 (s), 1432 (s), 1403 (m), 1349(m), 1290 (s), 1231 (m), 1207 (m), 1174 (w), 1159 (m), 1130 (m),1101 (m), 1078 (w), 1013 (w), 977 (w), 950 (w), 925 (w), 907 (m),844 (m), 741 (s), 734 (s), 704 (w), 683 (w), 664 (w), 624 (w); 1HNMR (500 MHz, CDCl3): δ 1.04 (t, J = 7.3 Hz, 3H), 1.35–1.46 (m,1H), 1.76–1.82 (m, 1H), 1.82–1.91 (m, 1H), 2.37 (dd, J = 16.1,10.0 Hz, 1H), 2.69 (dd, J = 16.9, 7.8 Hz, 1H), 2.90 (td, J = 6.0,3.1 Hz, 1H), 3.01 (dd, J = 16.0, 5.2 Hz, 1H), 3.10 (dd, J = 16.8,3.1 Hz, 1H), 3.37–3.41 (m, 1H), 3.48–3.56 (m, 2H), 3.63–3.70(m, 1H), 7.08 (td, J = 5.0, 0.9 Hz, 1H), 7.18 (td, J = 5.1, 1.1 Hz,1H), 7.31 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 8.08 (s,1H); 13C NMR (APT, 125 MHz, CDCl3): δ 11.6 (CH3), 25.7 (CH2),26.1 (CH2), 35.7 (CH2), 41.2 (CH2), 42.0 (CH2), 42.4 (CH), 48.9(CH), 69.9 (C), 110.6 (C), 111.1 (CH), 118.8 (CH), 119.6 (CH),122.7 (CH), 127.2 (C), 136.7 (C), 136.8 (C), 179.1 (C); HRMS(ESI+): Calcd for C18H22NO2S2 ([M + H]+) 348.1092, found348.1104.

(N-Methyl){3-β-ethyl-2,3,4,9-tetrahydrospiro[1H-carbazole-1,2′(1,3)dithiolane]2-yl}-acetamide ((±)-10).6e The acid (±)-9(1 g, 2.88 mmol) was placed in a 100 mL oven-dried round-bottomed Schlenk flask equipped with a magnetic stirring bar.The reaction flask was evacuated for 15 minutes and back-filled with dry N2. The acid (±)-9 was dissolved by adding absol-ute chloroform (30 mL) into the reaction flask. After triethyl-amine (610 μL, 440 mg, 4.35 mmol) was added into thesolution, the reaction mixture was cooled to −5 °C and ethylchloroformate (423 μL, 480 mg, 4.40 mmol) was dropwiseadded into the reaction mixture under N2 by using a syringe.After the mixture was stirred at −5 °C for 2 h under N2, 10 mLof 40% aqueous methylamine solution (115 mmol MeNH2)were added into the reaction flask and the resulting mixturewas stirred at −5 °C for an additional 3 h. After the reaction

Scheme 5 Synthesis of racemic uleine ((±)-2).

Organic & Biomolecular Chemistry Paper

This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem.

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mixture was quenched with 10% K2CO3 (30 mL), the organiclayer was separated by using a separatory funnel and driedover MgSO4. After removing all the volatile components byrotary evaporation in vacuo, the residue was purified by silicagel column chromatography eluting with EtOAc–acetone–Et3N(75 : 25 : 7). Thus, the amide (±)-10 (0.70 g, 1.94 mmol, 67%)was obtained as a white solid. Mp: 225 °C; Rf = 0.81 (silica gel;EtOAc–acetone–Et3N, 75 : 25 : 7); FTIR (KBr): νmax (cm−1) 3445(m), 3318 (m), 3053 (w), 2956 (w), 2909 (w), 2837 (w), 1646 (s),1551 (m), 1456 (m), 1406 (w), 1347 (w), 1301 (w), 1282 (w),1253 (w), 1228 (w), 1154 (w), 1104 (w), 1011 (w), 930 (w), 905(w), 739 (s), 689 (w) 578 (w), 494 (w); 1H NMR (500 MHz,CDCl3): δ 0.94 (t, J = 7.2 Hz, 3H), 1.25–1.35 (m, 1H), 1.74–1.79(m, 2H), 2.28–2.35 (m, 2H), 2.78 (d, J = 4.8 Hz, 3H), 2.84–2.94(m, 3H), 3.29–3.33 (m, 1H), 3.40–3.46 (m, 2H), 3.57–3.61 (m,1H), 5.46 (br s, 1H), 7.00 (t, J = 7.2 Hz, 1H), 7.10 (t, J = 7.2 Hz,1H), 7.21 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 8.01 (br s,1H); 13C NMR (APT, 125 MHz, CDCl3): δ 10.8 (CH3), 24.5 (CH2),25.1 (CH2), 25.5 (CH3), 37.6 (CH2), 40.0 (CH2), 40.9 (CH2), 41.9(CH), 47.8 (CH), 69.1 (C), 109.6 (C), 110.0 (CH), 117.8 (CH),118.5 (CH), 121.6 (CH), 126.3 (C), 135.7 (C), 135.8 (C), 172.3(C); HRMS (ESI+): Calcd for C19H25N2OS2 ([M + H]+) 361.1408,found 361.1390.

{3-β-Ethyl-2,3,4,9-tetrahydrospiro[1H-carbazole-1,2′(1,3)dithio-lane]2-yl}-acetamide ((±)-11). The acid (±)-9 (3.0 g, 8.63 mmol)was placed in a 250 mL oven-dried round-bottomed Schlenkflask equipped with a magnetic stirring bar. The reaction flaskwas evacuated for 15 minutes and back-filled with dry N2. Theacid (±)-9 was dissolved by adding absolute chloroform(30 mL) into the reaction flask. After triethylamine (2.1 mL,1.51 g, 15.0 mmol) was added into the solution, the reactionmixture was cooled to −5 °C and ethyl chloroformate (1.43 mL,1.62 g, 15.0 mmol) was dropwise added into the reactionmixture under N2 by using a syringe. After the mixture wasstirred at −5 °C for 2 h under N2, 30 mL of 25% ammoniumhydroxide solution (190 mmol NH3) were added into the reac-tion flask and the resulting mixture was stirred at −5 °C for anadditional 2 h. After the reaction mixture was quenched with10% NaOH (50 mL), the organic layer was separated by using aseparatory funnel and dried over MgSO4. After removing all thevolatile components by rotary evaporation in vacuo, the residuewas crystallized from Et2O affording the amide (±)-11 (2.2 g,6.35 mmol, 74%) as a white solid. Mp: 257 °C (decomp); Rf =0.71 (silica gel; EtOAc–acetone–Et3N, 75 : 25 : 7); FTIR (KBr):νmax (cm

−1) 3468 (s), 3352 (s), 3255 (s), 3052 (w), 2967 (s), 2922(s), 2872 (s), 2849 (m), 2826 (m), 1914 (w), 1880 (w), 1663 (s),1588 (m), 1490 (w), 1458 (s), 1420 (s), 1400 (s), 1376 (m), 1351(m), 1331 (w), 1311 (s), 1277 (s), 1236 (s), 1220 (m), 1175 (w),1162 (m), 1147 (w), 1101 (m), 1074 (w), 1013 (w), 953 (w), 906(w), 889 (w), 868 (w), 858 (w), 842 (w), 792 (w), 755 (m), 741 (s),687 (w), 660 (w), 627 (w), 590 (w), 524 (w), 488 (w); 1H NMR(500 MHz, DMSO-d6): δ 0.96 (t, J = 7.2 Hz, 3H), 1.18–1.29 (m,1H), 1.61–1.66 (m, 1H), 1.72–1.78 (m, 1H), 2.17 (dd, J = 15.9,10.5 Hz, 1H), 2.41 (dd, J = 16.0, 8.7 Hz, 1H), 2.70 (t, J = 9.4 Hz,1H), 2.80 (d, J = 15.8 Hz, 1H), 2.91 (dd, J = 15.9, 4.9 Hz, 1H),3.20–3.36 (m, 1H), 3.47–3.54 (m, 1H), 3.59–3.64 (m, 1H),

3.82–3.88 (m, 1H), 6.79 (s, 1H), 6.95 (t, J = 5.0 Hz, 1H), 7.07 (td,J = 5.0, 1.0 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.38 (m, 2H), 10.61(s, 1H); 13C NMR (APT, 125 MHz, DMSO-d6): δ 11.7 (CH3), 25.2(CH2), 25.8 (CH2), 36.5 (CH2), 40.9 (CH2), 41.3 (CH2), 43.0(CH), 47.5 (CH), 69.6 (CH), 108.1 (C), 111.2 (CH), 118.2 (CH),118.4 (CH), 121.6 (CH), 126.0 (C), 136.8 (C), 138.7 (C), 174.2(C); HRMS (ESI+): Calcd for C18H22N2OS2Na ([M + Na]+)369.1071, found 369.1065.

12-Ethyl-6,6-[ethylenebis(sulfanediyl)]-1,2,3,4,5,6-hexahydro-1,5-methano-1H-azocino[4,3-b]indole-3-one ((±)-12). The amide(±)-11 (1.5 g, 4.33 mmol) was placed in a 100 mL oven-driedround-bottomed Schlenk flask equipped with a magnetic stir-ring bar. The reaction flask was evacuated for 15 minutes andback-filled with dry N2. The amide (±)-11 was dissolved byadding absolute THF (20 mL) into the reaction flask. DDQ(1.17 g, 5.15 mmol) was then added in one portion and theresulting reaction mixture was stirred at rt for 3 h under N2.After the reaction mixture was quenched with 10% NaOH(30 mL), the mixture was extracted with EtOAc (100 mL). Theseparated organic layer was dried over Na2SO4. After all thevolatile components were removed by rotary evaporationin vacuo, the residue was first purified by silica gel columnchromatography eluting with EtOAc–acetone–Et3N (75 : 25 : 7).Combined fractions containing the lactam (±)-12 were thenconcentrated by rotary evaporation in vacuo, crystallization ofwhich from Et2O yielded 1.25 g (3.63 mmol, 84%) of the titlecompound ((±)-12) as a white solid. Mp: 265 °C (decomp); Rf =0.60 (silica gel; EtOAc–acetone–Et3N, 75 : 25 : 7); FTIR (KBr):νmax (cm−1) 3175 (s), 3137 (s), 3055 (s), 2960 (s), 2920 (s),2868 (s), 1736 (m), 1647 (s), 1578 (m), 1552 (w), 1494 (m), 1475(m), 1456 (s), 1428 (m), 1401 (m), 1373 (s), 1344 (w), 1313 (m),1296 (m), 1281 (m), 1236 (s), 1191 (m), 1165 (m), 1149 (m),1141 (w), 1125 (m), 1108 (w), 1045 (w), 1021 (w), 1010 (m), 995(w), 958 (w), 923 (w), 907 (m), 856 (m), 800 (s), 779 (m), 738 (s),710 (m), 687 (m), 643 (m), 584 (m), 558 (w), 518 (m), 484 (m);1H NMR (500 MHz, DMSO-d6): δ 0.99 (t, J = 7.2 Hz, 3H),1.31–1.40 (m, 1H), 1.60–1.69 (m, 1H), 2.36–2.40 (m, 1H),2.69–2.87 (m, 3H), 3.42–3.48 (m, 2H), 3.67–3.72 (m, 2H), 4.32(br s, 1H), 6.98 (t, J = 7.1 Hz, 1H), 7.10 (t, J = 7.1 Hz, 1H), 7.32(d, J = 8.1 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 4.5 Hz,1H), 10.90 (s, 1H); 13C NMR (APT, 125 MHz, DMSO-d6): δ 12.5(CH3), 24.1 (CH2), 39.6 (CH2), 41.0 (CH2), 44.1 (CH), 44.8 (CH),45.8 (CH), 59.8 (C), 66.2 (CH2), 111.4 (CH), 113.3 (C), 118.6(CH), 118.7 (CH), 122.2 (CH), 124.9 (C), 134.2 (C), 136.8 (C),170.1 (C); HRMS (ESI+): Calcd for C18H21N2OS2 ([M + H]+)345.1095, found 345.1090.

12-Ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-1H-azocino[4,3-b]-indole-3,6-dione ((±)-13). The thioketal (±)-12 (0.8 g,2.32 mmol) was dissolved in 30 mL of CH3CN–H2O (9 : 1) in a100 mL round-bottomed flask. [Bis(trifluoroacetoxy)iodo]-benzene (3.0 g, 7.0 mmol) was added into the solution in oneportion and the resulting reaction mixture was stirred at rt for2 h. The reaction mixture was poured into 30 mL of 10%K2CO3 solution and extracted with CH2Cl2 (2 × 50 mL). Thecombined organic layers were dried over MgSO4. After all thevolatile components were removed by rotary evaporation

Paper Organic & Biomolecular Chemistry

Org. Biomol. Chem. This journal is © The Royal Society of Chemistry 2013

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in vacuo, the residue was purified by silica gel column chrom-atography eluting with EtOAc–acetone–Et3N (75 : 25 : 7). Theketone (±)-13 (0.46 g, 1.71 mmol, 74%) was obtained as a whitesolid. Mp: 253 °C (decomp); Rf = 0.55 (silica gel; EtOAc–acetone–Et3N, 75 : 25 : 7); FTIR (KBr): νmax (cm−1) 3210 (m),3081 (m), 2956 (m), 2925 (m), 2876 (w), 1663 (s), 1619 (s),1574 (w), 1540 (m), 1470 (m), 1436 (w), 1408 (m), 1376 (w),1362 (w), 1344 (w), 1331 (m), 1302 (w), 1250 (w), 1228 (s),1216 (m), 1188 (w), 1166 (m), 1151 (w), 1131 (w), 1111 (w),1090 (w), 1028 (w), 980 (w), 964 (w), 919 (m), 908 (w), 856 (w),834 (w), 811 (w), 779 (w), 740 (s), 651 (w), 615 (w), 524 (w),513 (w), 482 (m); 1H NMR (500 MHz, CDCl3): δ 0.93 (t, J =7.4 Hz, 3H), 1.33–1.51 (m, 2H), 2.50–2.57 (m, 2H), 2.92–3.04(m, 2H), 4.75 (s, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.37 (d, J = 8.2 Hz,1H), 7.38 (m, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.2 Hz,1H), 9.57 (s, 1H); 13C NMR (APT, 125 MHz, CDCl3): δ 11.9(CH3), 24.1 (CH2), 35.6 (CH2), 45.9 (CH), 46.0 (CH), 46.8 (CH),113.1 (CH), 120.1 (CH), 121.4 (CH), 124.4 (C), 127.7 (CH), 128.2(C), 128.6 (C), 138.3 (C), 170.8 (C), 191.1 (C); HRMS (ESI+):Calcd for C16H17N2O2 ([M + H]+) 269.1290, found 269.1293.

(3-β-Ethyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-acet-amide ((±)-14). The keto-carboxylic acid (±)-8 (5.0 g, 18.4 mmol)was placed in a 250 mL oven-dried round-bottomed Schlenkflask equipped with a magnetic stirring bar. The reaction flaskwas evacuated for 15 minutes and back-filled with dry N2. Theacid (±)-8 was dissolved by adding absolute chloroform(80 mL) into the reaction flask. After triethylamine (3.86 mL,2.8 g, 27.7 mmol) was added into the solution, the reactionmixture was cooled to −5 °C and ethyl chloroformate (2.64 mL,3.0 g, 27.7 mmol) was dropwise added into the reactionmixture under N2 by using a syringe. After the mixture wasstirred at −5 °C for 3 h under N2, 40 mL of 25% ammoniumhydroxide solution (257 mmol NH3) were added into the reac-tion flask and the resulting mixture was stirred at −5 °C for anadditional 2 h. Chloroform was evaporated under reducedpressure and the residue was washed with water. The precipi-tate was filtered, dried and recrystallized from EtOAc to obtainthe amide (±)-14 (3.9 g, 14.4 mmol, 78%) as a white solid. Mp:182 °C (decomp); Rf = 0.58 (silica gel; EtOAc–acetone–Et3N,75 : 25 : 7); FTIR (KBr): νmax (cm

−1) 3450 (s), 3268 (s), 3145 (m),3061 (m), 2959 (m), 2936 (w), 2879 (w), 2836 (w), 1686 (s),1643 (s), 1572 (m), 1546 (m), 1465 (m), 1414 (s), 1382 (m),1335 (m), 1249 (m), 1235 (m), 1205 (w), 1171 (m), 1142 (w),1031 (m), 992 (w), 963 (w), 921 (w), 800 (m), 756 (s), 741 (m),708 (m), 670 (w), 633 (w), 553 (m), 505 (m), 480 (m); 1H NMR(500 MHz, DMSO-d6): δ 0.94 (t, J = 7.4 Hz, 3H), 1.35–1.44 (m,1H), 1.52–1.60 (m, 1H), 2.15–2.22 (m, 1H), 2.49 (dd, J = 15.5,6.8 Hz, 1H), 2.58 (dd, J = 15.5, 4.8 Hz, 1H), 2.70 (dd, J = 16.6,8.2 Hz, 1H), 2.77–2.81 (m, 1H), 3.18 (dd, J = 16.7, 4.7 Hz, 1H),6.82 (s, 1H), 7.07 (td, J = 5.0, 0.6 Hz, 1H), 7.29 (td, J = 5.0,0.9 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H),11.54 (br s, 1H); 13C NMR (APT, 125 MHz, DMSO-d6): δ 11.0(CH3), 24.1 (CH2), 25.5 (CH2), 33.4 (CH2), 41.4 (CH), 48.5 (CH),112.8 (CH), 119.6 (CH), 121.1 (CH), 125.4 (C), 125.6 (C), 126.0(CH), 130.3 (C), 138.3 (C), 172.8 (C), 191.4 (C); HRMS (ESI+):Calcd for C16H17N2O2 ([M + H]+) 271.1447, found 271.1451.

12-Ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-1H-azocino[4,3-b]-indole-3,6-dione ((±)-13) from (±)-14. The keto-amide (±)-14(0.4 g, 1.48 mmol) was placed in a 100 mL oven-dried round-bottomed Schlenk flask equipped with a magnetic stirring bar.The reaction flask was evacuated for 15 minutes and back-filled with dry N2. The keto-amide (±)-14 was then dissolved byadding 40 mL of anhydrous THF–DMSO (1 : 1) mixture into thereaction flask. DDQ (0.4 g, 1.76 mmol, 1.20 eq.) was added inone portion and the resulting reaction mixture was stirred at50 °C for 22 h under N2. After the reaction mixture wasquenched with 10% NaOH (30 mL), the mixture was extractedwith EtOAc (100 mL). The separated organic layer was driedover Na2SO4. After all the volatile components were removed byrotary evaporation in vacuo, the residue was purified by silicagel column chromatography eluting with EtOAc–Et3N (10 : 1.5).In addition to the keto-lactam (±)-13 (0.18 g, 0.67 mmol, 45%)obtained as a white solid, the unreacted part of the startingketo-amide (±)-14 (0.17 g, 0.63 mmol, 43%) could also berecovered.

12-Ethyl-6-methylidene-1,2,3,4,5,6-hexahydro-1,5-methano-1H-azocino[4,3-b]indole-3-one ((±)-15). An oven-dried 100 mLSchlenk flask that was capped with a glass stopper andequipped with a magnetic stirring bar was evacuated underheating with a blow-drier for 15 min. After the flask wascooled down to room temperature, dry nitrogen was back-filled. The keto-lactam (±)-13 (2.0 g, 7.45 mmol) was placed inthe flask under a positive pressure of N2. After the flask wasagain evacuated for 15 min, dry nitrogen was back-filled andthe glass stopper was replaced with a rubber septum under apositive pressure of nitrogen. The keto-lactam (±)-13 was dis-solved by adding 30 mL of anhydrous THF and the mixturewas cooled to 0 °C. Methyllithium (10 mL of 3.0 M MeLi solu-tion in diethoxyethane, 30.0 mmol) was dropwise added byusing a syringe at 0 °C and the mixture was stirred at 0 °C for30 min. The reaction mixture was quenched by adding 50 mLof 10% NaOH solution and extracted with CH2Cl2 (100 mL).The organic layer was evaporated under reduced pressure andthe residue was dissolved in 50 mL CH2Cl2. To this solution,5 mL of trifluoroacetic acid was added and stirred at rt for 1 h.The reaction mixture was poured into 50 mL of 10% K2CO3

and extracted with CH2Cl2 (2 × 60 mL). Combined organiclayers were dried over MgSO4 and evaporated in vacuo. Theresidue was purified by silica gel column chromatographyeluting with EtOAc–acetone–Et3N (75 : 25 : 7) to yield the com-pound (±)-15 (1.3 g, 4.88 mmol, 66%). Mp: 220 °C (decomp);Rf = 0.60 (silica gel; EtOAc–acetone–Et3N, 75 : 25 : 7); FTIR(KBr): νmax (cm

−1) 3257 (s), 3073 (m), 2953 (m), 2916 (m), 2898(m), 2880 (m), 1647 (s), 1611 (s), 1580 (m), 1540 (w), 1498 (w),1472 (m), 1453 (m), 1429 (m), 1407 (m), 1377 (m), 1350 (w),1331 (m), 1320 (m), 1294 (w), 1269 (w), 1257 (w), 1235 (m),1199 (w), 1175 (w), 1127 (m), 1085 (w), 1041 (w), 1002 (w),975 (w), 953 (w), 921 (w), 908 (m), 871 (s), 852 (m), 832 (m),818 (w), 797 (m), 770 (w), 756 (w), 738 (s), 680 (m), 642 (m),619 (w), 586 (w), 561 (w), 536 (w), 494 (w), 474 (w); 1H NMR(500 MHz, DMSO-d6): δ 0.85 (t, J = 7.3 Hz, 3H), 1.11–1.19 (m,2H), 2.02–2.08 (m, 1H), 2.16–2.20 (m, 1H), 2.82 (dd, J = 18.2,

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7.9 Hz, 1H), 2.97 (br d, J = 7.1 Hz, 1H), 4.39 (s, 1H), 5.06 (s,1H), 5.52 (s, 1H), 7.00 (td, J = 5.0, 0.8 Hz, 1H), 7.12 (td, J = 5.0,1.0 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H),8.27 (d, J = 7.9 Hz, 1H), 11.25 (s, 1H); 13C NMR (APT, 125 MHz,DMSO-d6): δ 11.8 (CH3), 23.3 (CH2), 39.0 (CH), 40.6 (CH2), 42.3(CH), 45.8 (CH), 108.2 (CH2), 111.1 (CH), 115.3 (C), 118.8 (CH),118.9 (CH), 122.6 (CH), 125.8 (C), 130.9 (C), 136.9 (C), 139.2(C), 170.8 (C); HRMS (ESI+): Calcd for C17H19N2O ([M + H]+)267.1497, found 267.1495.

Noruleine ((±)-1).1c The lactam (±)-15 (0.3 g, 1.13 mmol, 1.00eq.) was placed in a 50 mL oven-dried round-bottomedSchlenk flask that was equipped with a magnetic stirring barand the flask was evacuated for 15 min and back-filled withN2. The lactam (±)-15 was dissolved by the addition of 15 mLabsolute THF with a syringe. Then, 2 mL of a 65% solution(w/w) of sodium bis(2-methoxyethoxy)aluminum dihydride intoluene (Red-Al®, 6.67 mmol, 6.00 eq.) was added into thesolution. The reaction mixture was stirred at 50 °C for 3 hunder N2, poured into brine (50 mL) and extracted with Et2O(2 × 50 mL). The combined organic layers were dried overNa2SO4 and evaporated in vacuo. The residue was purified bysilica gel column chromatography eluting with hexanes–EtOAc–Et3N–MeOH (4 : 4 : 2 : 2) to give (±)-noruleine (97 mg,0.384 mmol, 34%) as a pale white solid. Mp: 188–191 °C(decomp); Rf = 0.70 (silica gel; hexanes–EtOAc–Et3N–MeOH,4 : 4 : 2 : 2), 0.10 (silica gel; hexanes–EtOAc–MeOH, 4 : 4 : 2);FTIR (KBr): νmax (cm−1) 3421 (br m), 3067 (m), 3027 (m),2956 (s), 2918 (s), 2869 (s), 2766 (m), 1628 (m), 1610 (m),1537 (w), 1501 (w), 1451 (m), 1431 (m), 1368 (w), 1339 (w),1323 (m), 1293 (w), 1230 (m), 1117 (w), 1132 (w), 1100 (w),1083 (w), 1067 (m), 1053 (w), 1024 (w), 1008 (w), 992 (w),961 (w), 910 (w), 899 (w), 862 (m), 835 (m), 805 (m), 782 (w),737 (s), 673 (w), 656 (w), 625 (w), 595 (w), 583 (w), 484 (w); 1HNMR (500 MHz, CDCl3): δ 0.85 (t, J = 7.4 Hz, 3H), 1.11–1.18 (m,2H), 1.64–1.67 (m, 1H), 1.97–2.07 (m, 2H), 2.59 (td, J = 8.5,3.5 Hz, 1H), 2.60 (br s, 1H), 2.68 (ddd, J = 12.2, 5.6, 1.2 Hz, 1H),2.74 (d, J = 2.7 Hz, 1H), 4.37 (d, J = 2.1 Hz, 1H), 4.99 (s, 1H),5.28 (s, 1H), 7.10 (td, J = 5.0, 0.9 Hz, 1H), 7.19 (td, J = 5.1,1.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H),8.44 (br s, 1H); 13C NMR (APT, 125 MHz, CDCl3): δ 11.7 (CH3),24.6 (CH2), 34.8 (CH2), 37.3 (CH2), 40.5 (CH), 45.6 (CH), 49.3(CH), 106.9 (CH2), 110.9 (CH), 111.2 (C), 118.5 (CH), 119.7(CH), 122.9 (CH), 126.8 (C), 135.0 (C), 137.1 (C), 138.6 (C);HRMS (ESI+): Calcd for C17H21N2 ([M + H]+) 253.1705, found253.1696.

Uleine ((±)-2).2e The lactam (±)-15 (0.25 g, 0.93 mmol) wasplaced in a 50 mL oven-dried round-bottomed Schlenk flaskthat was equipped with a magnetic stirring bar and the flaskwas evacuated for 15 min and back-filled with N2. The lactam(±)-15 was dissolved by the addition of 15 mL absolute THFwith a syringe. Then, 2 mL of a 65% solution (w/w) of sodiumbis(2-methoxyethoxy)aluminum dihydride in toluene (Red-Al®,6.67 mmol) was added into the solution. The reaction mixturewas stirred at 50 °C for 3 h under N2. The mixture was pouredinto brine (50 mL) and extracted with Et2O (2 × 50 mL). Thecombined organic layers were dried over Na2SO4 and

evaporated in vacuo. The residue was dissolved in 10 mL of anacetone–MeOH mixture (1 : 1) and introduced into a 50 mLround-bottomed flask. After K2CO3 (1 g) and iodomethane(5 mL, 11.4 g, 80.0 mmol) were added into the solution, thereaction mixture was refluxed for 3 h. The mixture was pouredinto 50 mL brine and extracted with Et2O (50 mL). The organiclayer was dried over Na2SO4 and evaporated in vacuo. Columnchromatographic purification of the residue on silica geleluting with hexanes–EtOAc–Et3N–MeOH (4 : 4 : 2 : 2) yielded54 mg (0.205 mmol, 22%) of (±)-uleine as a pale white solid.Mp: 168 °C (decomp); Rf = 0.90 (silica gel; hexanes–EtOAc–Et3N–MeOH, 4 : 4 : 2 : 2); FTIR (KBr): νmax (cm−1) 3418 (w),3072 (m), 3073 (m), 2934 (s), 2869 (s), 2806 (m), 1629 (m),1609 (m), 1576 (w), 1536 (w), 1499 (w), 1462 (s), 1447 (s),1376 (w), 1352 (w), 1339 (w), 1320 (s), 1284 (m), 1242 (m),1226 (m), 1193 (w), 1166 (w), 1151 (m), 1123 (m), 1095 (m),1075 (w), 1042 (m), 1022 (w), 1009 (m), 977 (w), 937 (w),924 (w), 909 (w), 868 (m), 842 (m), 817 (w), 778 (m), 740 (s),653 (m), 619 (m), 589 (w), 564 (m), 523 (w), 488 (m); 1H NMR(600 MHz, CDCl3): δ 0.85 (t, J = 7.4 Hz, 3H), 1.10–1.14 (m, 2H),1.68–1.70 (m, 1H), 2.03–2.11 (m, 3H), 2.29 (s, 3H), 2.47–2.49(m, 1H), 2.69 (d, J = 2.7 Hz, 1H), 4.09 (d, J = 2.2 Hz, 1H), 4.99(s, 1H), 5.26 (s, 1H), 7.10 (td, J = 5.0, 1.0 Hz, 1H), 7.19 (td, J =5.0, 1.1 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 7.9 Hz,1H), 8.27 (br s, 1H); 13C NMR (APT, 150 MHz, CDCl3): δ 11.8(CH3), 24.4 (CH2), 34.7 (CH2), 39.5 (CH), 44.3 (CH), 46.1 (CH),46.3 (CH2), 55.6 (CH3), 106.8 (CH2), 107.7 (C), 110.7 (CH),119.5 (CH), 119.9 (CH), 122.7 (CH), 129.4 (C), 135.2 (C),136.6 (C), 138.7 (C); HRMS (ESI+): Calcd for C18H23N2

([M + H]+) 267.1861, found 267.1847.

Notes and references

1 For the isolation of uleine, see: (a) J. Schmutz, F. Hunzikerand R. Hirt, Helv. Chim. Acta, 1957, 40, 1189–1200. For thestructural elucidation of uleine, see: (b) G. Buchi andE. W. Warnhoft, J. Am. Chem. Soc., 1959, 81, 4433–4434. Forthe isolation of noruleine, see: (c) J. A. Joule, M. Ohashi,B. Gilbert and C. Djerassi, Tetrahedron, 1965, 21,1717–1734.

2 For the racemic total syntheses of uleine, see:(a) N. D. V. Wilson, A. Jackson, A. J. Gaskell and J. A. Joule,Chem. Commun., 1968, 584a; (b) A. Jackson,N. D. V. Wilson, A. J. Gaskell and J. A. Joule, J. Chem. Soc.C, 1969, 2738–2747; (c) G. Büchi, S. J. Gould and F. Näf,J. Am. Chem. Soc., 1971, 93, 2492–2501; (d) M. Schmitt andS. Blechert, Angew. Chem., Int. Ed. Engl., 1997, 36,1474–1476; (e) S. Patir and N. Uludag, Tetrahedron, 2009,65, 115–118.

3 For the chiral syntheses of uleine, see: (a) M. Saito,M. Kawamura, K. Hiroya and K. Ogasawara, Chem.Commun., 1997, 765–766; (b) M. Amat, M. Pérez, N. Llor,M. Martinelli, E. Molins and J. Bosch, Chem. Commun.,2004, 1602–1603; (c) M. Amat, M. Pérez, N. Llor,

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C. Escolano, F. J. Luque, E. Molins and J. Bosch, J. Org.Chem., 2004, 69, 8681–8693.

4 For the racemic syntheses of dasycarpidone, see:(a) L. J. Dolby and H. Biere, J. Am. Chem. Soc., 1968, 90,2699–2700; (b) Ref. 2b, A. Jackson, N. D. V. Wilson,A. J. Gaskell and J. A. Joule, J. Chem. Soc. (C), 1969, 2738–2747; (c) L. J. Dolby and H. Biere, J. Org. Chem., 1970, 35,3843–3845; (d) T. Kametani and T. Suzuki, Chem. Pharm.Bull., 1971, 19, 1424–1425; (e) T. Kametani and T. Suzuki,J. Org. Chem., 1971, 36, 1291–1293; (f ) J. Gracia,N. Casamitjana, J. Bonjoch and J. Bosch, J. Org. Chem.,1994, 59, 3939–3951.

5 For the chiral synthesis of dasycarpidone, see: ref. 3a,M. Saito, M. Kawamura, K. Hiroya and K. Ogasawara,Chem. Commun., 1997, 765–766.

6 For leading contributions on the construction of theazocino[4,3-b]indole skeleton, see: (a) M. Alvarez, R. Lavillaand J. Bosch, Tetrahedron Lett., 1987, 28, 4457–4460;(b) J. Bonjoch, J. Quirante, M. Rodriguez and J. Bosch,Tetrahedron, 1988, 44, 2087–2092; (c) D. Desmaele andJ. d’Angelo, Tetrahedron Lett., 1990, 31, 883–886;

(d) P. Magnus, N. L. Sear, C. S. Kim and N. Vicker, J. Org.Chem., 1992, 57, 70–78; (e) A. Diez, J. Castells, P. Forns,M. Rubiralta, D. S. Grierson, H.-P. Husson, X. Solans andM. Font-Bardia, Tetrahedron, 1994, 50, 6585–6602;(f ) S. Patir, Liebigs Ann., 1995, 1561–1562;(g) M.-L. Bennasar, T. Roca and D. García-Díaz, J. Org.Chem., 2008, 73, 9033–9039; (h) S. Patir and E. Ertürk,J. Org. Chem., 2011, 76, 335–338.

7 For an excellent review on carbazole alkaloids, see:A. W. Schmidt, K. R. Reddy and H.-J. Knölker, Chem. Rev.,2012, 112, 3193–3328.

8 (a) S. Shimizu, K. Ohori, T. Arai, H. Sasai and M. Shibasaki,J. Org. Chem., 1998, 63, 7547–7551; (b) H. Zhou, D. Han,X. Liao and J. M. Cook, Tetrahedron Lett., 2005, 46,4219–4224.

9 (a) N. Uludag, T. Hökelek and S. Patir, J. Heterocycl. Chem.,2006, 43, 585–591; (b) A. Uzgoren, N. Uludag, G. Okay andS. Patir, J. Heterocycl. Chem., 2009, 46, 1416–1419.

10 E. J. Corey and K. Shimoji, Tetrahedron Lett., 1983, 24,169–172.

11 G. Stork and K. Zhao, Tetrahedron Lett., 1989, 30, 287–290.

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