DOI: 10.1002/chem.201400178

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& Alkaloid Synthesis

Catalytic Asymmetric Assembly of Octahydroindolones: Divergent Synthesis of Lycorine-type Amaryllidaceae Alkaloids (+)-a-Lycorane and (+)-Lycorine Zhongwen Sun, Mingtao Zhou, Xiang Li, Xueling Meng, Fangzhi Peng,* Hongbin Zhang, and Zhihui Shao*[a]

Abstract: We report the first catalytic asymmetric approach to octahydroindolones and a divergent enantioselective synthesis of perhydroindole alkaloids, as exemplified by lycorine-type Amaryllidaceae alkaloids (+)-a-lycorane and (+)-lycorine, from a common intermediate by using a highly con-

cise route. The assembly of octahydroindolones employs a catalytic enantioselective 1,4-conjugate addition of nitro dienynes, followed by a TsOH-catalyzed cascade synthesis of highly functionalized enones, and a diastereoselective intramolecular Michael addition.

Introduction Facile access to versatile building blocks or structural motifs, and divergent syntheses of structurally and stereochemically complex natural products, are among the most highly sought after tasks in synthetic chemistry. As part of ongoing studies on polycyclic alkaloid syntheses,[1] we noted a lack of methods for the assembly of octahydroindolones I, motifs common in natural-product chemistry[2] (Figure 1 a). Motivated by the notion that facile stereocontrolled access to octahydroindolones I should provide a distinct strategic point from which to direct efforts towards divergent syntheses of perhydroindole alkaloids, a structurally diverse group of natural products including some of the Stemonaceae and Amaryllidaceae alkaloids, we commenced studies on this topic. We envisioned that octahydroindolones I could be produced from rationally designed functionalized nitrocyclohexanes II, featuring a strategically positioned carbonyl group and an ester functionality (Figure 1 b). Nitrocyclohexanes are valuable building blocks for the synthesis of natural products and biologically active compounds. Therefore, numerous methods have been developed for the synthesis of functionalized nitrocyclohexanes.[3] However, these reported protocols are not applicable to the synthesis of II. To address the synthetic challenges posed by I and II, an enabling approach was devised. We envisioned that [a] Z. Sun,+ M. Zhou,+ X. Li,+ X. Meng, F. Peng, Prof. H. Zhang, Prof. Z. Shao Key Laboratory of Medicinal Chemistry for Natural Resource Ministry of Education, School of Chemical Science and Technology Yunnan University, Kunming, Yunnan 650091 (P.R. China) Fax: (+ 86) 871-65035538 E-mail: [email protected] [email protected] [+] These authors contributed equally to this work. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201400178. Chem. Eur. J. 2014, 20, 6112 – 6119

Figure 1. a) Octahydroindolones I and representative natural products. b) Working hypothesis for the construction of I.

II could be constructed through a diastereoselective intramolecular Michael addition from functionalized enones III, bearing a nitro group and an ester functionality (Figure 1 b). Despite the potential attractions of this method, an approach towards highly functionalized enones III has not yet been reported. Inspired by the lack of methods towards these highly functionalized enones, we very recently introduced conjugated nitro dienynes as a new class of Michael acceptors and developed a catalytic cascade reaction of 1,3-enynes, leading 6112

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Scheme 1. Recently developed catalytic cascade synthesis of highly functionalized enones.

to the required enantioenriched functionalized enones in good yields with high enantioselectivity (Scheme 1).[4] Herein, we report the first catalytic asymmetric approach to octahydroindolones and the divergent enantioselective synthesis of perhydroindole alkaloids, as exemplified by lycorine-type Amaryllidaceae alkaloids (+)-a-lycorane and (+)-lycorine from a common intermediate.

Results and Discussion The lycorine-type Amaryllidaceae alkaloids (Scheme 2) were selected as targets for probing the synthetic design outlined in Figure 1. Lycorine-type alkaloids are isolated from the Amarylli-

daceae species of plants,[5] and have been high-profile targets for chemical synthesis[6] and medicinal chemistry studies[7] owing to their intriguing molecular architectures and wide range of biological activities.[8] Structurally, the lycorine-type Amaryllidaceae alkaloids are characterized by a tetracyclic pyrrolo[d,e]phenanthridine (galanthan) framework. Stereochemically, most lycorine-type alkaloids have a trans B/C-ring junction. Our strategy is outlined in Scheme 2. The synthesis was designed with the intention of applying the methodology recently developed in our laboratory[4] to diastereo- and enantioselectively construct the octahydroindolone structural motif and developing a general route to lycorine-type Amaryllidaceae alkaloids. Chemically, the diverse substituents at C1 and C2 in the target alkaloids could be derived by manipulation of the “masked” carbonyl group in the common intermediate 1, which could be accessed from the masked octahydroindolone 2. Strategically, the logical disconnection of the C5 N bond of 2 would deliver key cyclohexanone intermediate 3, which could be generated by a diastereoselective intramolecular Michael addition of enone 4. A TsOH-catalyzed cascade of 5 and the 1,4-regioselective catalytic asymmetric conjugate addition[9] of conjugated nitro dienyne 6 with di-tert-butyl malonate could be considered for the formation of chiral enone 4. Although we anticipated that the proposed intramolecular Michael addition of enones (Scheme 2) could occur in the presence of a suitable base, the crucial relative stereochemical outcome remained to be explored. Thus, we initially decided to investigate the stereochemistry by using a model reaction. The results are summarized in Table 1. In the presence of TMG (1,1,3,3-tetramethylguanidine), enone 7 underwent a diastereoselective intramolecular Michael addition to give cyclohexanone 8 as the major diastereoisomer (entry 1). The relative configuration of 8 was assigned on the

Table 1. Study of the model reaction.[a]

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Base

Solvent

Yield [%][b]

d.r.[c]

1 2 3

TMG DBU KOH

CH2Cl2 CH2Cl2 EtOH

65 56 44

7:1 5:1 4:1

[a] The reaction was performed in the presence of base (1.0 equiv) at room temperature. [b] Isolated yield. [c] Determined by 1H NMR analysis.

Scheme 2. Structural motif-guided retrosynthetic analysis of the lycorinetype alkaloids. Chem. Eur. J. 2014, 20, 6112 – 6119

Entry

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Figure 2. Transition-state analysis of intramolecular Michael addition of 7.

basis of X-ray crystal structural analysis.[10] The stereoselective formation of 8 might be rationalized by considering a chairlike transition state TS-I, shown in Figure 2. After solving the stereochemical issue, we focused our attention on the stereocontrolled synthesis of octahydroindolones and lycorine-type Amaryllidaceae alkaloids. Two representative lycorine-type alkaloids, a-lycorane[11, 12, 3f, g] and (+)-lycorine,[13, 14] were selected as synthetic targets. Our efforts began with the synthesis of conjugated nitro dienyne 6 (Scheme 3). Vinyl bromide 9 underwent Sonogashira

Scheme 4. Catalytic asymmetric synthesis of functionalized cyclohexanone 3.

clohexanone 3[15] as a single diastereoisomer in 60 % yield after column chromatography. With a catalytic asymmetric approach to the desired cyclohexanones in hand, the synthesis of octahydroindolones was initiated (Scheme 5). Treatment of 3 with ethane-1,2-dithiol in

Scheme 3. Synthesis of conjugated nitro dienyne 6.

coupling with propargylic alcohol, leading to the corresponding alcohol, 10. Oxidation of the hydroxyl group of 10 with IBX (2-iodoxybenzoic acid) afforded enynal 11. Compound 11 underwent a Henry reaction with CH3NO2, followed by treatment with TFAA (trifluoroacetic anhydride) in the presence of Et3N, to produce the desired conjugated nitro dienyne 6 with complete stereoselectivity. The catalytic enantioselective synthesis of functionalized cyclohexanone 3 is outlined in Scheme 4. In the presence of chiral diamine–NiBr2 complex, the 1,4-conjugate addition of nitro dienyne 6 with di-tert-butyl malonate proceeded smoothly to provide enantioenriched 1,3-enyne 5 in 91 % yield with 93 % enantiomeric excess (ee). It is worth noting that 1,6- or 1,8-addition was not observed. Then, treatment of 1,3-enyne 5 with a catalytic amount of TsOH (20 mol %) directly led to compound 12 with complete regioselectivity. Compound 12 was then esterified to provide the desired enone 4 in good yield without loss of enantiomeric purity. Compound 4 underwent a stereoselective intramolecular Michael addition with a diastereomeric ratio (d.r.) of 6:1, providing the enantioenriched cyChem. Eur. J. 2014, 20, 6112 – 6119

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Scheme 5. Stereocontrolled construction of the “masked” octahydroindolones.

the presence of BF3·OEt2 afforded thioketal 13. Reduction of the nitro group of 13 with zinc powder in 10 % aq HCl/ethanol, followed by treatment with sodium methoxide, gave bicyclic lactam 14. Finally, reduction of 14 with LiAlH4 resulted in the formation of the masked octahydroindolone 2, which was further converted into the corresponding carbamate 15. With the key octahydroindolone in hand, the divergent synthesis of a-lycorane and lycorine was undertaken. The enantioselective synthesis of (+)-a-lycorane is shown in Scheme 6. Compound 15 was subjected to a Bischler–Napieralski reaction and afforded the desired compound 1. Then, 1 was converted into 16, which was reduced with LiAlH4 to afford (+)-a-lycorane. All of the spectroscopic data for synthetic (+)-a-lycorane

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Full Paper the total synthesis or formal synthesis of racemic lycorine,[13] only two asymmetric syntheses have been reported to date.[14] These syntheses employed a stoichiometric amount of chiral controls. Thus, our synthesis represents the first catalytic enantioselective approach to lycorine.

Conclusion

Scheme 6. Enantioselective total synthesis of (+)-a-lycorane.

were in accordance with the data reported previously.[11j] There are three elegant asymmetric total syntheses or formal syntheses of ( )-a-lycorane to date,[12, 3f, g] however, their applications to the synthesis of the more complex alkaloid, lycorine, remained unknown. In contrast, the strategically positioned carbonyl group featured in 3 provided a good handle to install the hydroxyl groups at the C1 and C2 positions and introduce the olefin functionality in lycorine. The enantioselective synthesis of (+)-lycorine is shown in Scheme 7. Treatment of common intermediate 1 with HgCl2

We have developed the first catalytic asymmetric approach to octahydroindolones, structural motifs common in natural-product chemistry. The method holds great potential for enantioselective syntheses of perhydroindole alkaloids. In this context, we used this protocol to develop a general route to lycorinetype Amaryllidaceae alkaloids, exemplified by (+)-a-lycorane (1.9 % overall yield from 9) and (+)-lycorine (1.1 % overall yield from 9), from a common intermediate on the basis of a highly concise route. The synthesis of octahydroindolones features the catalytic enantioselective 1,4-conjugate addition of nitro dienynes and the TsOH-catalyzed cascade synthesis of highly functionalized enones that we have recently developed.[4] Further application of this methodology to the enantioselective syntheses of other perhydroindole alkaloids are currently under way in our research group.

Experimental Section General methods 1

H NMR and 13C NMR spectra were recorded at 300 MHz and 400 MHz. Chemical shifts (d) are expressed in ppm, and J values are given in Hz. The enantiomeric excess was determined by chiral HPLC with n-hexane and isopropanol as eluents. High resolution mass spectrometry (HRMS) was recorded on a VG Auto Spec-3000 spectrometer. Optical rotations were measured on a JASCO DIP370 polarimeter. All chemicals and solvents were used as received without further purification unless otherwise stated. Flash column chromatography was performed on silica gel (230–400 mesh).

Ethyl 2-(2-nitro-5-oxo-3-phenylcyclohexyl)acetate (8)

Scheme 7. Enantioselective formal synthesis of (+)-lycorine.

gave ketone 17. Selective reduction of 17 with NaBH4/CeCl3 afforded alcohol 18 in high yield with 3:1 d.r. Subsequently, 18 was mesylated, followed by treatment with DBU (1,8diazabicyclo[5.4.0]undec-7-ene) to produce compound 20 with complete regioselectivity, and intercepting an advanced intermediate in the racemic synthesis of lycorine by Torssell and coworkers,[13b] thus completing the formal synthesis of (+)-lycorine. Although many elegant methods have been developed for Chem. Eur. J. 2014, 20, 6112 – 6119

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TMG (86 mg, 0.75 mmol) was added to a solution of compound 7 (229 mg, 0.75 mmol) in dry dichloromethane (10 mL). The reaction mixture was stirred at room temperature until the reaction was complete (monitored by TLC). The mixture was quenched with 1 n HCl and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether = 1:3) to afford 8 (149 mg, 65 %) as a white solid. 1H NMR (300 MHz, CDCl3): d = 7.30 (m, 3 H), 7.22 (m, 2 H), 5.20 (t, J = 5.1 Hz, 1 H), 4.09 (q, J = 6.9 Hz, 2 H), 3.93 (q, J = 6.6 Hz, 1 H), 3.03 (m, 1 H), 2.89 (m, 1 H), 2.80–2.51 (m, 4 H), 2.33 (m, 1 H), 1.20 ppm (t, J = 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3): d = 206.41, 170.33, 139.01, 129.33, 128.13, 127.18, 89.34, 61.13, 43.14, 42.82, 42.15, 34.97, 32.93, 14.06 ppm; HRMS: m/z calcd for C16H19NO5 : 305.1263 [M] + ; found: 305.1263 [M] + .

1-Methoxy-4-((1 E,5 E)-6-nitrohexa-1,5-dien-3-ynyl)benzene (10) [Pd(PPh3)4] (46 mg, 0.04 mmol, 0.004 equiv), CuI (25 mg, 0.13 mmol, 0.013 equiv), and propargylic alcohol (560 mg, 10 mmol) were

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Full Paper added to a solution of vinyl bromide 9 (2.26 g, 10 mmol) in dry diethylamine (25 mL) and the resulting mixture was stirred for 36 h at room temperature. The solvent was removed under reduced pressure, and the crude product was purified by flash silica gel chromatography (ethyl acetate/petroleum ether = 1:3) to give 10 (1.62 g, 80 %) as a light-yellow solid. 1H NMR (300 MHz, CDCl3): d = 6.72 (m, 4 H), 5.95 (m, 3 H), 4.43 (m, 2 H), 2.33 ppm (m, 1 H); 13 C NMR (75 MHz, CDCl3): d = 148.2, 148.1, 141.5, 130.6, 121.8, 108.4, 105.5, 105.2, 101.3, 89.1, 85.0, 51.6 ppm; HRMS: m/z calcd for C12H10O3 : 202.0623 [M] + ; found: 202.0630 [M] + .

crude was purified by flash silica gel chromatography (ethyl acetate/petroleum ether = 1:6) to give 5 (84 mg, 91 %) as a yellow 1 solid. [a]20 D = + 47.8 (c = 1.0 in CHCl3); H NMR (300 MHz, CDCl3): d = 6.81 (m, 1 H), 6.73 (m, 3 H), 5.98 (s, 2 H), 5.85 (dd, J = 16.2 Hz, J = 1.8 Hz, 1 H), 4.80–4.65 (m, 2 H), 4.01–3.98 (m, 1 H), 3.52 (d, J = 7.8 Hz, 1 H), 1.49 ppm (s, 18 H); 13C NMR (75 MHz, CDCl3): d = 166.1, 165.8, 148.3, 148.2, 142.0, 130.5, 121.7, 108.4, 105.2, 105.1, 101.3, 85.4, 84.6, 83.0, 82.9, 76.5, 55.0, 30.9, 27.9, 27.8 ppm; HRMS: m/z calcd for C24H29NO8 : 459.1893 [M] + ; found: 459.1896 [M] + ; HPLC (Chiralpak AD-H, isopropanol/n-hexane = 15:85, flow rate 0.8 mL min 1, l = 254 nm): tmajor = 28.726 min, tminor = 35.973 min.

(E)-5-(Benzo[d][1,3]dioxol-5-yl)pent-4-en-2-ynal (11) (R,E)-7-(Benzo[d][1,3]dioxol-5-yl)-3-(nitromethyl)-5-oxohept6-enoic acid (12)

IBX (1.68 g, 6 mmol, 1.2 equiv) was added to a solution of 10 (1.01 g, 5 mmol) in THF/DMSO (14 mL, VTHF/VDMSO = 6:1) and the resulting mixture was stirred for 8 h at room temperature. The organic layer was washed with saturated aqueous Na2S2O3 solution and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude was purified by flash silica gel chromatography (ethyl acetate/petroleum ether = 1:6) to give 11 ( 0.79 g, 79 %) as a yellow solid. 1 H NMR (300 MHz, CDCl3): d = 9.33 (s, 1 H), 7.18 (d, J = 16.2 Hz, 1 H), 6.91 (m, 2 H), 6.79 (d, J = 14.1 Hz, 1 H), 6.06 (dd, J = 16.2 Hz, J = 1.2 Hz, 1 H), 6.01 ppm (s, 2 H); 13C NMR (75 MHz, CDCl3): d = 176.6, 149.8, 148.9, 148.5, 129.5, 123.7, 108.6, 105.5, 102.5, 101.7, 95.9, 90.6 ppm; HRMS: m/z calcd for C12H8O3 200.0475 [M] + ; found: 200.0473 [M] + .

TsOH (38 mg, 0.2 equiv) was added to a solution of compound 5 (459 mg, 1 mmol) in toluene (20 mL). The reaction mixture was stirred for 6 h under reflux. After removal of solvent, the crude product was purified by silica gel chromatography (ethyl acetate/ petroleum ether = 1:1) to afford compound 12 (263 mg, 82 %) as 1 a yellow liquid. [a]20 D = + 10.8 (c = 1.0 in CHCl3); H NMR (300 MHz, CDCl3), d = 7.40 (d, J = 15.9 Hz, 1 H), 6.95 (m, 2 H), 6.73 (m, 1 H), 6.46 (d, J = 15.9 Hz, 1 H), 5.94 (s, 2 H), 4.55 (d, J = 6.0 Hz, 2 H), 3.07 (m, 1 H), 2.81 (d, J = 6.0 Hz, 2 H), 2.56 ppm (d, J = 6.3 Hz, 2 H); 13C NMR (75 MHz, CDCl3), d = 197.2, 176.4, 150.3, 148.5, 143.8, 128.4, 125.4, 123.6, 108.7, 106.6, 101.7, 77.6, 41.1, 35.1, 29.7 ppm; HRMS: m/z calcd for C15H15NO7: 321.0849 [M] + ; found: 321.0857 [M] + .

5-((1 E,5 E)-6-Nitrohexa-1,5-dien-3-ynyl)benzo[d][1,3]dioxole (6)

(R,E)-Ethyl 7-(benzo[d][1,3]dioxol-5-yl)-3-(nitromethyl)-5-oxohept-6-enoate (4)

A slurry of LiAlH4 (3.8 mg, 0.1 mmol, 0.1 equiv) in dry THF (4 mL) was stirred for 30 min at 0 8C, and then nitromethane (305 mg, 5 mmol, 5 equiv) was added. After 30 min, 11 (200 mg, 1 mmol) was added in one portion. The mixture was stirred until the reaction was complete (monitored by TLC). Then 1 n HCl was added and the reaction mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the nitro alcohol product, which was used without purification for the next step. Trifluoroacetic anhydride (198 mg, 0.945 mmol, 1.05 equiv) and triethylamine (190 mg, 1.89 mmol, 2.1 equiv) were added to a solution of the nitro alcohol (0.9 mmol, 1 equiv) in dry dichloromethane (3 mL) at 0 8C. The reaction mixture was stirred at 0 8C until the reaction was complete (monitored by TLC). Then, the organic layer was washed with saturated aqueous NH4Cl solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the crude was purified by flash silica gel chromatography (ethyl acetate/petroleum ether = 1:10) to give 6 (122 mg, 50 %) as a yellow solid. 1H NMR (300 MHz, CDCl3): d = 7.25 (m, 2 H), 7.04 (d, J = 16.2 Hz, 1 H), 6.92 (m, 1 H), 6.89 (m, 1 H), 6.79 (d, J = 8.1 Hz, 1 H), 6.13 (dd, J = 16.2 Hz, J = 2.1 Hz, 1 H), 6.01 ppm (s, 2 H); 13C NMR (75 MHz, CDCl3): d = 149.4, 148.5, 145.9, 144.8, 129.9, 123.2, 121.3, 108.6, 105.8, 105.4, 104.3, 101.6, 84.2 ppm; HRMS: m/z calcd for C13H9NO4 : 243.0532 [M] + ; found: 243.0523 [M] + .

Thionylchloride (95 mg, 0.8 mmol) was added to a solution of compound 12 (257 mg, 0.8 mmol) in absolute ethanol (10 mL). The reaction mixture was stirred for 3 h under reflux. The solvent was removed under reduced pressure, and the mixture was diluted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether = 1:4) to afford compound 4 (229 mg, 1 82 %) as a yellow liquid. [a]20 D = + 20.7 (c = 1.0 in CHCl3); H NMR (300 MHz, CDCl3): d = 7.48 (d, J = 15.9 Hz, 1 H), 7.05 (d, J = 6.3 Hz, 2 H), 6.83 (d, J = 8.4 Hz, 1 H), 6.54 (d, J = 16.2 Hz, 1 H), 6.04 (s, 2 H), 4.60 (d, J = 6.0 Hz, 2 H), 4.14 (q, J = 7.2 Hz, 2 H), 3.16 (m, 1 H), 2.89 (d, J = 6.3 Hz, 2 H), 2.57 (d, J = 6.3 Hz, 2 H), 1.26 ppm (t, J = 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3): d = 196.9, 171.2, 150.2, 148.5, 143.4, 128.6, 125.2, 123.8, 108.6, 106.6, 101.7, 77.8, 60.9, 41.2, 35.4, 30.1, 14.1 ppm; HRMS: m/z calcd for C17H19NO7: 349.1162 [M] + ; found: 349.1163 [M] + ; HPLC (Chiralpak AD-H, isopropanol/hexane = 25:75, flow rate 1.0 mL min 1, l = 254 nm): tminor = 25.471 min. tmajor = 27.483 min.

(S,E)-Di-tert-butyl 2-(6-(benzo[d][1,3]dioxol-5-yl)-1-nitrohex5-en-3-yn-2-yl)malonate (5) Di-tert-butyl malonate (65 mg, 0.3 mmol, 1.5 equiv) and nitro dienyne 6 (0.2 mmol) were added to a solution of catalyst NiBr2/2 l (5 mol %) in m-xylene (0.5 mL). The reaction mixture was stirred at room temperature until the reaction was complete (monitored by TLC). The solvent was removed under reduced pressure and the Chem. Eur. J. 2014, 20, 6112 – 6119

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Ethyl 2-((1 R,2S,3 R)-3-(benzo[d][1,3]dioxol-5-yl)-2-nitro-5-oxocyclohexyl)acetate (3) 1,1,3,3-Tetramethylguanidine (86 mg, 0.75 mmol) was added to a solution of compound 4 (262 mg, 0.75 mmol) in dry dichloromethane (10 mL). The reaction mixture was stirred at room temperature until the reaction was complete (monitored by TLC). The mixture was quenched with 1 n HCl and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether = 1:3) to afford 3 (147 mg, 60 %) as a yellow solid. [a]20 D = + 25.8 (c = 1.0 in CHCl3);

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H NMR (300 MHz, CDCl3): d = 6.67 (m, 1 H), 6.59 (m, 2 H), 5.89 (s, 2 H), 5.06 (m, 1 H), 4.02 (q, J = 7.2 Hz, 2 H), 3.73 (m, 1 H), 2.93 (m, 1 H), 2.76 (m, 1 H), 2.66–2.49 (m, 3 H), 2.28 (m, 1 H), 2.24 (m, 1 H), 1.14 ppm (t, J = 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3): d = 206.3, 170.4, 148.4, 147.4, 132.7, 120.6, 108.8, 107.5, 101.4, 89.6, 61.1, 43.2, 42.9, 42.1, 34.9, 32.9, 14.1 ppm; HRMS: m/z calcd for C17H19NO7: 349.1162 [M] + ; found: 349.1169 [M] + ; HPLC (Chiralcel OD-H, isopropanol/n-hexane = 25:75, flow rate 0.8 mL min 1, l = 220 nm): tmajor = 30.586 min, tminor = 34.880 min.

Ethyl 2-((7S,8S,9 R)-9-(benzo[d][1,3]dioxol-5-yl)-8-nitro-1,4dithiaspiro[4.5]decan-7-yl)acetate (13) Boron trifluoride etherate (170 mg, 0.12 mmol) was added to a solution of compound 3 (380 mg, 1.09 mmol) and 1,2-dithioethane (102 mg, 1.09 mmol) in dry dichloromethane (6 mL). The resulting solution was stirred at room temperature for 30 min. The mixture was diluted with ether and saturated aqueous NaHCO3 solution, and then the organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate/ petroleum ether = 1:4) to give 13 (356 mg, 77 %) as a white 1 powder. [a]20 D = + 2.6 (c = 1.0 in CHCl3); H NMR (300 MHz, CDCl3): d = 6.68 (m, 3 H), 5.94 (s, 2 H), 4.90 (dd, J = 17.4 Hz, J = 5.1 Hz, 1 H), 4.12 (m, 2 H), 3.40 (m, 1 H), 3.25 (m, 5 H), 2.90 (m, 1 H), 2.66 (m, 1 H), 2.38 (m, 3 H), 2.17 (m, 1 H), 1.25 ppm (t, J = 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3): d = 171.2, 148.0, 147.0, 133.1, 120.4, 108.6, 107.7, 101.1, 90.8, 64.2, 60.9, 50.1, 42.9, 41.8, 40.5, 37.8, 34.9, 33.6, 14.2 ppm; HRMS: m/z calcd for C19H23NO6S2 : 425.0967 [M] + ; found: 425.0953 [M] + .

(3 a’S,7’R,7 a’S)-7’-(Benzo[d][1,3]dioxol-5-yl)hexahydrospiro[[1,3]dithiolane-2,5’-indol]-2’(1’H)-one (14) Zinc power (161 mg, 2.47 mmol, 3.5 equiv) and 10 % HCl (2 mL) were added to a solution of compound 13 (300 mg, 0.706 mmol) in EtOH (10 mL), and the resulting solution was stirred at room temperature for 24 h. After filtration, the filtrate was evaporated under vacuum. Then 2 m NaOH was added and extracted with CH2Cl2. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, and the crude product was used for the next step without further purification. CH3ONa (3.52 mmol, 190 mg) was added to a solution of the crude product in CH3OH (5 mL), and the reaction mixture was stirred at room temperature for 24 h. After removal of solvent, the mixture was diluted with EtOAc and H2O. The organic layer was washed with brine and dried over Na2SO4. The organic layer was filtered and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ethyl acetate/petroleum ether = 2:1) to give 14 (172 mg, 70 %) as a white powder. [a]20 D = + 51.3 (c = 1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d = 6.57 (m, 3 H), 5.88 (s, 2 H), 5.53 (brs, 1 H), 3.31 (m, 1 H), 3.17 (m, 4 H), 2.68 (m, 3 H), 2.34 (m, 2 H), 2.08 ppm (m, 3 H); 13C NMR (75 MHz, CDCl3): d = 177.0, 148.2, 146.8, 135.3, 120.9, 108.6, 107.6, 101.1, 65.4, 59.1, 47.1, 46.9, 40.9, 40.3, 37.6, 35.5, 34.2 ppm; HRMS: m/z calcd for C17H19NO3S2 : 349.0806 [M] + ; found: 349.0799 [M] + .

(3 a’S,7’R,7 a’S)-Ethyl 7’-(benzo[d][1,3]dioxol-5yl)hexahydrospiro[[1,3]dithiolane-2,5’-indole]-1’(6’H)-carboxylate (15) LiAlH4 (74 mg, 1.95 mmol, 5 equiv) was added to a solution of 14 (136 mg, 0.39 mmol) in dry THF (5 mL) and the resulting solution was stirred under reflux for 12 h. 1 m NaOH was added. The reacChem. Eur. J. 2014, 20, 6112 – 6119

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tion mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure, and the crude product 2 was used for next step without further purification. Methyl chloroformate (51 mg, 0.468 mmol) was added to a solution of crude product 2 and triethylamine (59 mg, 0.585 mmol) in CH2Cl2 (5 mL) at 0 8C, and the resulting solution was stirred at room temperature for 6 h. The mixture was diluted with CH2Cl2. The organic layer was washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ethyl acetate/petroleum ether = 1:3) to give 15 (84 mg, 53 % (over two steps)) as a white powder. [a]20 D = + 16.5 (c = 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 6.62 (m, 2 H), 6.51 (m, 1 H), 5.82 (s, 2 H), 3.64 (m, 2 H), 3.20 (m, 4 H), 3.11 (m, 4 H), 2.66 (m, 1 H), 2.43 (m, 1 H), 2.20 (m, 3 H), 2.14 (m, 2 H), 0.76 ppm (t, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 155.5, 147.4, 146.0, 136.6, 121.5, 108.2, 107.9, 100.7, 65.7, 62.1, 60.6, 48.1, 44.9, 44.4, 40.7, 40.3, 39.7, 36.9, 26.7, 14.1 ppm; HRMS: m/z calcd for C20H25NO4S2 : 407.1225 [M] + ; found: 407.1234 [M] + .

(3aS,3a1S,12bR)-1,3,3a,4,5,12b-Hexahydrospiro[[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridine-2,2’-[1,3]dithiolan]7(3a1H)-one (1) A mixture of 15 (35 mg, 0.086 mmol) and POCl3 (1 mL) was heated at 90 8C for 16 h, and the mixture was slowly poured into cold water and basified (pH 11) with 8 % NaOH. The mixture was extracted with CH2Cl2 and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ethyl acetate/petroleum ether = 2:1) to give 1 (26 mg, 85 %) 1 H NMR as a white powder. [a]20 D = + 39.0 (c = 1.0 in CHCl3); (300 MHz, CDCl3): d = 7.39 (s, 1 H), 6.54 (s, 1 H), 5.92 (s, 2 H), 4.07 (m, 1 H), 3.48 (m, 1 H), 3.30 (m, 4 H), 3.16 (m, 1 H), 2.97 (m, 1 H), 2.67 (m, 1 H), 2.61 (m, 1 H), 2.34 (m, 1 H), 2.20 (m, 1 H), 2.03 (m, 1 H), 1.92 ppm (m, 2 H); 13C NMR (75 MHz, CDCl3): d = 162.9, 150.4, 146.5, 136.7, 125.2, 108.6, 103.6, 101.5, 65.2, 59.6, 45.7, 41.9, 41.8, 40.2, 38.9, 37.6, 37.3, 30.7 ppm; HRMS: m/z calcd for C18H19NO3S2 : 361.0806 [M] + ; found: 361.0806 [M] + .

(3 aR,3 a1S,12 bR)-3,3 a,3 a1,4,5,12 b-Hexahydro-1 H[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridin-7(2 H)-one (16) Raney Ni (200 mg) was added to a solution of 15 (30 mg, 0.083 mmol) in EtOH (4 mL) and the resulting solution was stirred under a hydrogen atmosphere at 60 8C for 60 h. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ethyl acetate/petroleum ether = 2:1) to give 16 (19 mg, 85 %) as a white powder. [a]20 D = + 150.0 (c = 1.0 in CHCl3); 1 H NMR (300 MHz, CDCl3): d = 7.45 (s, 1 H), 6.66 (s, 1 H), 5.98 (s, 2 H), 4.11 (dd, J = 11.7 Hz, J = 7.5 Hz, 1 H), 3.45 (dd, J = 12.6 Hz, J = 9.0 Hz, 1 H), 3.21 (m, 1 H), 2.64 (m, 1 H), 2.45 (m, 1 H), 2.12 (m, 1 H), 1.97 (m, 1 H), 1.82 (m, 1 H), 1.79–1.62 (m, 4 H), 1.34 ppm (m, 1 H); 13C NMR (75 MHz, CDCl3): d = 162.7, 149.9, 145.9, 137.9, 124.9, 108.1, 103.4, 101.0, 60.5, 45.2, 36.9, 36.7, 30.4, 25.1, 22.8, 20.4 ppm; HRMS: m/z calcd for C16H17NO3 : 271.1208 [M] + ; found: 271.1211 [M] + .

(+)-a-Lycorane LiAlH4 (11 mg, 0.275 mmol, 5 equiv) was added to a solution of 16 (15 mg, 0.055 mmol) in dry THF (5 mL) and the resulting solution

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Full Paper was stirred under reflux for 12 h. 1 m NaOH was added and extracted with CH2Cl2. The organic layer was washed with brine and dried over Na2SO4. The organic layer was filtered, and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ethyl acetate/triethylamine = 50:1) to give (+)-a-lycorane (11 mg, 80 %) as a white solid. [a]20 D = + 34.2 (c = 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3), d = 6.69 (s, 1 H), 6.64 (s, 1 H), 5.91 (s, 2 H), 4.27 (d, J = 14.8 Hz, 1 H), 3.74 (d, J = 14.8 Hz, 1 H), 3.40 (m, 1 H), 2.91 (m, 1 H), 2.70 (m, 1 H), 2.49 (brs, 1 H), 2.38 (m, 1 H), 2.25 (m, 1 H), 1.88 (m, 2 H), 1.68 (m, 3 H), 1.58 (m, 1 H), 1.22 ppm (m, 1 H); 13C NMR (100 MHz, CDCl3), d = 147.1, 145.9, 134.5, 126.7, 107.4, 104.5, 101.0, 65.1, 54.7, 54.2, 36.8, 34.0, 27.7, 25.7, 25.3, 20.7 ppm; HRMS: m/z calcd for C16H19NO2 : 257.1416 [M] + ; found: 257.1419 [M] + .

(3 aS,3 a1S,12 bR)-3,3 a,4,5-Tetrahydro-1 H-[1,3]dioxolo[4,5j]pyrrolo[3,2,1-de]phenanthridine-2,7(3 a1H,12 bH)-dione (17) HgCl2 (136 mg, 0.5 mmol, 5 equiv) was added to a solution of 1 (36 mg, 0.1 mmol) in 4 mL (CH3CN/H2O = 7:1) and the reaction mixture was stirred at 40 8C for 24 h. The mixture was extracted with AcOEt. The organic layer was washed with brine and dried over Na2SO4. The organic layer was filtered and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ethyl acetate/petroleum ether = 10:1) to give 17 (23 mg, 80 %) as a white powder. [a]20 D = + 121.0 (c = 1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d = 7.45 (s, 1 H), 6.52 (s, 1 H), 5.95 (s, 2 H), 4.17 (m, 1 H), 3.58 (m, 1 H), 3.17 (m, 2 H), 2.84 (dd, J = 15.6 Hz, J = 5.1 Hz, 1H), 2.63 (m, 2 H), 2.28 (m, 2 H), 2.12 (m, 1 H), 1.70 ppm (m, 1 H); 13C NMR (75 MHz, CDCl3): d = 209.3, 161.9, 150.8, 147.1, 134.7, 124.6, 108.8, 104.0, 101.7, 59.7, 44.9, 43.9, 38.8, 35.5, 34.9, 33.7 ppm; HRMS: m/z calcd for C16H15NO4 : 285.1001 [M] + ; found: 285.0994 [M] + .

The organic layer was washed brine and dried over Na2SO4. The mixture was filtered and concentrated under reduced pressure to give the product 19, which was used without purification for the next step. 1,8-diazabicyclo [5.4.0]undec-7-ene (41 mg, 0.278 mmol) and DMF (20 mg, 0.278 mmol) were added to a solution of compound 19 (18 mg) in dry toluene (2 mL) and the reaction mixture was stirred for 5 h under reflux. The mixture was poured into H2O and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ethyl acetate/petroleum ether = 2:1) to give 20 (7 mg, 50 % (over two steps)) as a white solid. [a]20 D = + 136.1 (c = 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.47 (s, 1 H), 6.67 (m, 1 H), 5.99 (s, 2 H), 5.85 (m, 2 H), 4.16 (m, 1 H), 3.62 (m, 1 H), 3.26 (m, 1 H), 2.88 (m, 1 H), 2.67 (m, 1 H), 2.50 (m, 1 H), 2.14 (m, 1 H), 2.00 (m, 1 H), 1.63 ppm (m, 1 H); 13C NMR (100 MHz, CDCl3): d = 162.8, 150.4, 146.5, 137.0, 127.9, 126.4, 125.1, 108.5, 103.9, 101.5, 59.6, 45.4, 39.2, 35.8, 31.4, 25.5 ppm; HRMS: m/z calcd for C16H15NO3 : 269.1052 [M] + ; found: 269.1053 [M] + .

Acknowledgements We gratefully acknowledge financial support from the NSFC (21162034, 21372193, 21362040), the Program for Changjiang Scholars and Innovative Research Team in University (IRT13095), the Doctoral Fund of Ministry of Education of China (20135301110002), and the Government of Yunnan Province (2012FB114, 2013 A026). We thank Prof. Baomin Wang at Dalian University of Technology for providing the chiral guanidine catalysts. Keywords: cascade reactions · conjugate additions · divergent total synthesis · enantioselective catalysis · octahydroindolones

(3 aS,3 a1S,12 bR)-2-Hydroxy-3,3 a,3 a1,4,5,12 b-hexahydro-1 H[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridin-7(2 H)-one (18) NaBH4 (5.6 mg, 0.147 mmol) was added to a solution of 17 (21 mg, 0.0737 mmol) and CeCl3 .7H2O (27 mg, 0.0737 mmol) in MeOH (1.0 mL) at 0 8C and the resulting solution was stirred at 0 8C for 10 min. The mixture was quenched with water and extracted with AcOEt. The organic layer was washed with brine and dried over Na2SO4. The organic layer was filtered, and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ethyl acetate/methanol = 10:1) to give 18 (20 mg, 95 %) as a white powder. [a]20 D = + 78.9 (c = 1.0 in CHCl3); 1 H NMR (400 MHz, CDCl3): d = 7.36 (s, 1 H), 6.54 (s, 0.29 H), 6.47 (s, 0.70 H), 5.92 (s, 2 H), 4.04 (m, 2 H), 3.40 (m, 0.29 H), 3.34 (m, 0.74 H), 3.18 (m, 1 H), 2.92 (m, 0.73 H), 2.59 (m, 0.58 H), 2.33 (m, 1.29 H), 1.91 (m, 3 H), 1.66 ppm (m, 4 H); 13C NMR (100 MHz, CDCl3): d = 162.9, 150.4, 146.4, 137.6, 125.0, 108.5, 108.4, 103.8, 103.6, 101.5, 66.6, 66.3, 60.2, 45.8, 45.6, 36.5, 35.5, 35.3, 34.3, 34.1, 33.7, 33.2, 32.2, 32.1, 31.1 ppm; HRMS: m/z calcd for C16H17NO4 : 287.1158 [M] + ; found: 287.1151 [M] + .

(3 aS,3 a1S,12 bR)-3 a1,4,5,12 b-Tetrahydro-1 H-[1,3]dioxolo[4,5j]pyrrolo[3,2,1-de]phenanthridin-7(3 aH)-one (20) Triethylamine (12 mg, 0.111 mmol) and methane sulfonyl chloride (13 mg, 0.111 mol) were added to a solution of compound 18 (16 mg, 0.0557 mmol) in dry dichloromethane (2 mL) and the resulting solution was stirred at 0 8C for 3 h. The mixture was diluted with dichloromethane and saturated aqueous NaHCO3 solution. Chem. Eur. J. 2014, 20, 6112 – 6119

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Received: January 16, 2014 Published online on April 3, 2014

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Catalytic asymmetric assembly of octahydroindolones: divergent synthesis of lycorine-type amaryllidaceae alkaloids (+)-α-lycorane and (+)-lycorine.

We report the first catalytic asymmetric approach to octahydroindolones and a divergent enantioselective synthesis of perhydroindole alkaloids, as exe...
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