Enantioselective Total Synthesis and Assignment of the Absolute

Article pubs.acs.org/joc

Cite This: J. Org. Chem. 2018, 83, 15136−15143

Enantioselective Total Synthesis and Assignment of the Absolute Configuration of the Furo[3,2‑a]carbazole Alkaloid Furoclausine‑B Benedikt Spindler,† Olga Kataeva,‡ and Hans-Joachim Knölker*,† †

Fakultät Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany A. M. Butlerov Chemistry Institute, Kazan Federal University, Kremlevskaya Str. 18, Kazan 420008 Russia

‡

J. Org. Chem. 2018.83:15136-15143. Downloaded from pubs.acs.org by YORK UNIV on 12/21/18. For personal use only.

S Supporting Information *

ABSTRACT: We describe the first enantioselective total synthesis and the assignment of the absolute configuration of the furo[3,2-a]carbazole alkaloid furoclausine-B. As key steps for our approach we used a palladium(II)-catalyzed double C−H-bond activation for the construction of the carbazole framework, a Shi epoxidation, and an intramolecular opening of the epoxide for annulation of the dihydrofuran moiety.

■

INTRODUCTION In Asian folk medicine, extracts of the terrestrial plants Clausena excavata and Murraya euchrestifolia have been used for the treatment of a wide variety of diseases and infections.1 Thus, the constituents of these extracts have attracted the interest of many scientists. Among the various carbazole alkaloids isolated from these plants, a comparatively small group is characterized by a furan annulated at the carbazole nucleus.2 So far, only a few furocarbazole alkaloids have been isolated from natural sources. The first furocarbazoles isolated from the root bark of the Taiwanese shrub Murraya euchrestifolia Hayata by Furukawa in 1990 were the furo[3,2a]carbazole furostifoline (1) and the furo[2,3-c]carbazole eustifoline-D (2) (Figure 1).3 In 1997, two further furo[3,2-a]carbazole alkaloids, furoclausine-A (3) and -B (4), were obtained by Wu and coworkers from the acetone extract of the root bark of Clausena excavata.4 Since then, more furocarbazole alkaloids have been isolated, for example, from plants of the genera Zanthoxylum and Lonicera.5,6 We reported the first total syntheses of

furostifoline (1) and furoclausine-A (3) in 1996 and 2004, respectively.7−9 In both syntheses, an iron-mediated construction of the carbazole framework was applied. Annulation of the furan was achieved by reaction of a phenol with bromoacetaldehyde diethylacetal and subsequent protoncatalyzed cyclization. In 2007, we reported the first total synthesis of eustifoline-D (2) using a palladium(II)-catalyzed oxidative cyclization to form the carbazole framework.10 Several alternative synthetic approaches toward furocarbazoles have been described.11,12 Because of the stereogenic center at the dihydrofuran ring, furoclausine-B (4) is a more challenging synthetic target and no synthesis for this natural product has been reported so far. Wu et al. isolated furoclausine-B (4) as an optically active compound. However, the absolute configuration of the natural product was not determined. Herein, we describe the first total synthesis of furoclausine-B (4) in racemic form and of both enantiomers. Moreover, we assign the absolute configuration for the natural product.

■

RESULTS AND DISCUSSION

Our approach to furoclausine-B (4) is based on construction of the carbazole framework by a palladium(II)-catalyzed oxidative cyclization of the corresponding diarylamine 5 (Scheme 1). Previously, we have applied this strategy to the total synthesis of a variety of carbazoles.13 The sterically demanding triisopropylsilyl (TIPS) protecting group of compound 5 should ensure that no alternative regioisomer is formed in the cyclization step.13 Late-stage oxidation of the methyl group should afford the aldehyde at C-4 of furoclausine-B (4). The diarylamine 5 would result from Buchwald−Hartwig coupling14 of the protected bromoarene 6 and the 4-amino-2,3dihydrobenzofuran 7. The chiral dihydrobenzofuran 7 can be obtained by Shi epoxidation of the o-prenylphenol 8 followed Received: September 19, 2018 Published: November 28, 2018

Figure 1. Naturally occurring furocarbazole alkaloids. © 2018 American Chemical Society

15136

DOI: 10.1021/acs.joc.8b02426 J. Org. Chem. 2018, 83, 15136−15143

Article

The Journal of Organic Chemistry

reduction of the nitro group afforded the allyl ether 12. Claisen rearrangement at 140 °C led to the prenylated nitrophenol 8. It is noteworthy that the best yields for compound 8 were provided when the reaction was carried out on a multigram scale. With the phenol 8, we studied the enantioselective epoxidation using the fructose-derived chiral Shi catalysts (Figure 2, Scheme 3). A sequence of enantioselective

Scheme 1. Retrosynthetic Analysis of Furoclausine-B (4)

Figure 2. Fructose-derived Shi catalysts 13, 14, and ent-14.

Scheme 3. Synthesis of the Dihydrobenzofurans 15, ent-15, and rac-15 by Epoxidation and Cyclizationa by ring closure. Compound 8 should derive from commercially available 2-methyl-5-nitrophenol (9). First, the prenylated nitrophenol 8 as a key intermediate for the annulation of the dihydrofuran moiety was required. Our initial approaches for prenylation of 9 (palladium(0)-catalyzed Tsuji−Trost reaction and subsequent rearrangement, sodiummediated direct alkylation as reported by Tanaka and coworkers,15 and directed ortho-lithiation followed by reaction with prenyl bromide as described by Pettus16) gave poor results. Using Godfrey’s method,17−19 in analogy to previous applications in pyranocarbazole synthesis,20−23 we introduced the prenyl group by O-propargylation, subsequent hydrogenation of the triple bond to a double bond, and Claisen rearrangement (Scheme 2). The nitrophenol 9 reacted smoothly with 2-methylbut-3-yn-2-yl trifluoroacetate, prepared in situ from the propargylic alcohol 10, to give the propargyl ether 11.20 Hydrogenation of the triple bond in the presence of Lindlar’s catalyst with careful reaction monitoring to prevent

a Reagents and conditions: (a) 0.64 equiv of 13, 3.8 mol % Bu4NHSO4, K2CO3/HOAc buffer, DMM/MeCN (2:1), 0 °C, then 4.8 equiv of oxone and aq. KOH over 2 h, 17% (10.5% ee); (b) 2.3 equiv of NEt3, 20 mol % DMAP, CH2Cl2, rt, 10 min, then 1.6 equiv of TIPSCl, rt, overnight, 95%; (c) (1) 0.64 equiv of 14, 3.8 mol % Bu4NHSO4, DMM/MeCN (2:1), K2CO3/HOAc buffer, 0 °C, then 4.8 equiv of oxone in aq. Na2EDTA and aq. KOH over 2 h; (2) 2.3 equiv of TBAF, THF, 0 °C, 1 h, 96% (over two steps; >99.9% ee); (d) (1) 0.64 equiv of ent-14, 3.8 mol % Bu4NHSO4, DMM/MeCN (2:1), K2CO3/HOAc buffer, 0 °C, then 4.8 equiv of oxone and aq. KOH over 2 h; (2) 2.3 equiv of TBAF, THF, 0 °C, 1 h, 99% (over two steps; >99.9% ee); (e) (1) 1.2 equiv of mCPBA, aq. NaHCO3, CHCl3, 0 °C, then 1.5 h rt; (2) 2.3 equiv of TBAF, THF, 0 °C, 1 h, 96% (two steps). DMM = dimethoxymethane. DMAP = 4-(N,Ndimethylamino)pyridine. TBAF = tetra-n-butylammonium fluoride.

Scheme 2. Synthesis of the Prenylated Nitrophenol 8a

epoxidation and intramolecular nucleophilic epoxide opening was successfully applied to similar compounds by Hamada and co-workers as well as by other groups.24−26 The Shi catalyst 13 is readily available from L-fructose.27,28 However, direct epoxidation of 8 using catalyst 13 followed by an in situ 5exo-tet ring closure provided the dihydrobenzofuran 15 in only poor yield and with low enantiomeric excess (10.5% ee). Obviously, a protection of the hydroxy group was required, and thus, the phenol 8 was transformed to the silyl ether 16. Asymmetric epoxidation of 16 with 13 as catalyst followed by treatment with TBAF afforded the dihydrobenzofuran 15 in 57% yield and 87% enantiomeric excess. Shi’s diacetate catalyst 14, which can be prepared in two steps from catalyst 13,29−31

a

Reagents and conditions: (a) (1) 1.0 equiv of 10, 1.3 equiv of DBU, 1.15 equiv of TFAA, MeCN, −10 °C, 40 min; (2) 1.0 equiv of 9, 0.1 mol % CuCl2·H2O, 1.3 equiv of DBU, MeCN, 1.13 equiv of 2methylbut-3-yn-2-yl trifluoroacetate, −10 °C, 60 min and overnight, rt, 92%; (b) 10 wt % Lindlar cat., 3.0 equiv of quinoline, 1 atm of H2, EtOAc, rt, 1 h, 87%; (c) xylenes, 140 °C, 1 h, 92%. DBU = 1,8diazabicyclo[5.4.0]undec-7-ene. TFAA = trifluoroacetic anhydride. 15137


Article


Scheme 4. Synthesis of Furoclausine-B (4) from 15a

was reported to provide generally better results in terms of yield and enantioselectivity.24,29,30 Indeed, asymmetric epoxidation of 16 using the diacetate 14 as catalyst and subsequent cleavage of the silyl ether afforded the virtually enantiopure (>99.9% ee) dihydrobenzofuran 15 in 96% yield. The X-ray crystal structure determination of compound 15 unequivocally confirmed the R configuration of the stereogenic center (see Supporting Information, Figure S7). The absolute stereochemistry of 15 as determined by X-ray analysis is consistent with the expected asymmetric induction resulting from the Shi expoxidation of 16.27,31 At the beginning of our study, the absolute configuration of the natural product was not known. Therefore, we also started the synthesis of the enantiomeric series (Scheme 3). Shi epoxidation of compound 16 using the D-fructose derived diacetate catalyst ent-14 under identical reaction conditions provided ent-15 in virtually enantiopure form (>99.9% ee) in 99% yield. For analytical purposes, we prepared the racemic compound rac-15 by epoxidation of 16 with meta-chloroperbenzoic acid and subsequent cyclization to the dihydrobenzofuran (Scheme 3). With the racemic dihydrobenzofuran rac-15, we achieved a baseline separation of the two enantiomers 15 and ent-15 by chiral HPLC (Figure 3; for

a

Reagents and conditions: (a) 10 mol % PtO2, 1 atm of H2, EtOAc, rt, overnight, 91%; (b) 1.12 equiv of 7, 1.0 equiv of 6, 6 mol % Pd(OAc)2, 11 mol % rac-BINAP, 1.33 equiv of Cs2CO3, toluene, 110 °C, overnight, 93%; (c) 9 mol % Pd(OAc)2, 2.5 equiv of Cu(OAc)2, AcOH, 130 °C, 30 min, 71%; (d) 3.3 equiv of DDQ, MeOH/THF/ H2O (16:3:1), −15 °C, 20 min, 58%; (e) 3.2 equiv of TBAF, cat. H 2 O, THF, −10 °C, 40 min, 91%. BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene. DDQ = 2,3-dichloro-5,6dicyanobenzoquinone.

sequence of steps as described in Scheme 4 for furoclausine-B (4) (Scheme 5). Since a baseline separation for racemic furoclausine-B (rac-4) could not be achieved by chiral HPLC (Figure 4), it is difficult to determine the enantiomeric purity of 4 precisely. However, the enantiomeric excess of ent-4 can be determined accurately. Since the natural enantiomer of

Figure 3. Chiral HPLC of the enantiomers of the dihydrobenzofurans, 15 and ent-15, and of the racemate rac-15.

Scheme 5. Syntheses of ent-Furoclausine-B (ent-4) and racFuroclausine-B (rac-4)a

details of the protocol for chiral HPLC, see the General Information of the Experimental Section). Thus, the enantiomeric purity for 15 and ent-15 could be confirmed by this method with high accuracy. Hydrogenation of 15 in the presence of catalytic amounts of platinum(IV) oxide provided the arylamine 7 (Scheme 4). Buchwald−Hartwig coupling of 7 with the bromoarene 623 led to the diarylamine 5 which on palladium(II)-catalyzed oxidative cyclization afforded the 1,2-dihydrofuro[3,2-a]carbazole 17 in 71% yield. Subsequent oxidation of compound 17 using dichlorodicyanobenzoquinone (DDQ) gave the aldehyde 18. Cleavage of the silyl protecting group with an excess of TBAF provided furoclausine-B (4) in 91% yield. Thus, the conversion of 15 into furoclausine-B (4) has been achieved in five steps and 32% overall yield. The analytical data of 4 were in good agreement with those reported for the natural product isolated by Wu and co-workers.4 Finally, we also synthesized the S-enantiomer of furoclausine-B (ent-4) and racemic furoclausine-B (rac-4) via the same

a

15138

Reagents and conditions: see steps a−e in Scheme 4. DOI: 10.1021/acs.joc.8b02426 J. Org. Chem. 2018, 83, 15136−15143

Article


coupling using an Agilent Technologies 6890 N GC System equipped with a 5973 Mass Selective Detector (electron impact, 70 eV). ESIMS spectra were recorded on an Esquire LC with an ion trap detector from Bruker. Positive and negative ions were detected. ESI-HRMS were recorded on an Agilent Technologies Q-TOF 6538. Elemental analyses were measured on a EuroVector EuroEA3000 elemental analyzer. X-ray crystal structure analysis was performed with a BrukerNonius Kappa CCD that was equipped with a 700 series Cryostream low-temperature device from Oxford Cryosystems. SHELXS-97,32 SADABS version 2.10,33 SHELXL-97,34 POV-Ray for Windows version 3.7.0.msvc10.win64, and ORTEP-3 for Windows35 were used as software. The enantiomeric excess was determined by analytical chiral HPLC using an Agilent Model 1100 with G1315B UV-DAD; column: reversed phase cellulose, 4.6 × 250 mm, Macherey Nagel Nucleocel delta-rp; isocratic elution with 60% of H2O and 40% of MeCN at 10 °C; flow rate: 0.7 mL min−1 for 15 and 0.3 mL min−1 for 4. Synthesis of Furoclausine-B (4). 2-((2-Methylbut-3-yn-2-yl)oxy)-4-nitrotoluene (11). 2-Methylbut-3-yn-2-ol (10) (6.31 g, 75.0 mmol) was dissolved in acetonitrile (45 mL), and the solution was cooled to −10 °C. After addition of 1,8-diazabicyclo[5.4.0]undec-7ene (DBU) (14.8 mL, 99.2 mmol, 1.3 equiv), trifluoroacetic anhydride (TFAA) (12.2 mL, 86.6 mmol, 1.15 equiv) was added over a period of 40 min via a syringe pump to the −10 °C cold solution. In a separate flask, 2-methyl-5-nitrophenol (9) (10.1 g, 66.0 mmol) and copper(II) chloride dihydrate (11.3 mg, 0.066 mmol, 0.1 mol %) were dissolved in acetonitrile (70 mL). After cooling to −10 °C, DBU (12.8 mL, 85.8 mmol, 1.3 equiv) was added slowly. Then, the previously prepared solution of 2-methylbut-3-yn-2-yl trifluoroacetate was added over 60 min via a dropping funnel while the temperature was kept at −10 °C. After the addition, the mixture was stirred at room temperature overnight. A complete conversion was confirmed by TLC, and the solvent was evaporated. The residue was taken up in toluene and washed with water. The aqueous layer was extracted twice with toluene, and the combined organic layers were washed three times with 2 M HCl, four times with a sat. aq. K2CO3 solution, and finally with brine. The solvent was evaporated, and the residual oil was cooled in order to induce crystallization. The solid was dried under vacuum to give 2-((2-methylbut-3-yn-2-yl)oxy)-4nitrotoluene (11) (13.3 g, 60.7 mmol, 92% yield) as light brown crystals; mp 64 °C. UV (MeOH) λmax 211, 228, 279, 324 (sh) nm. IR (ATR) ν 3271, 3231, 3088, 2982, 2931, 1590, 1510, 1486, 1340, 1326, 1245, 1227, 1179, 1131, 1090, 971, 866, 810, 739, 695, 671 cm−1. 1H NMR (600 MHz, CDCl3) δ 1.73 (s, 6 H), 2.29 (s, 3 H), 2.68 (s, 1 H), 7.27 (dd, J = 8.3, 0.8 Hz, 1 H), 7.80 (dd, J = 8.3, 2.3 Hz, 1 H), 8.37 (d, J = 2.3 Hz, 1 H). 13C{1H} NMR and DEPT (151 MHz, CDCl3) δ 17.3 (CH3), 29.7 (2 CH3), 73.1 (C), 75.3 (C), 84.9 (CH), 112.9 (CH), 117.0 (CH), 130.9 (CH), 138.3 (C), 146.7 (C), 154.3 (C). EIMS (70 eV) m/z 219 (8) [M]+, 204 (100), 174 (23), 158 (66). Anal. Calcd for C12H13NO3: C 65.74, H 5.98, N 6.39. Found: C 65.70, H 6.14, N 6.49. 2-((2-Methylbut-3-en-2-yl)oxy)-4-nitrotoluene (12). 2-((2-Methylbut-3-yn-2-yl)oxy)-4-nitrotoluene (11) (6.14 g, 28.0 mmol) was dissolved in ethyl acetate (120 mL), and Lindlar catalyst (614 mg, 10 wt %) and quinoline (9.8 mL, 83.5 mmol, 3.0 equiv) were added. The reaction mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature. The reaction was completed after 1 h as indicated by TLC. After filtration over Celite (ethyl acetate), the organic layer was washed three times with 2 M HCl, three times with sat. aq. NaHCO3, and with brine and was then dried (MgSO4). Evaporation of the solvent and purification of the crude product by column chromatography (silica gel; isohexane/ethyl acetate, 9:1) provided 2((2-methylbut-3-en-2-yl)oxy)-4-nitrotoluene (12) (5.38 g, 24.3 mmol, 87% yield) as a red liquid. 1H NMR (600 MHz, CDCl3) δ 1.54 (s, 6 H), 2.29 (s, 3 H), 5.25−5.31 (m, 2 H), 6.13 (dd, J = 17.7, 10.9 Hz, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 7.72 (dd, J = 8.3, 2.3 Hz, 1 H), 7.89 (d, J = 2.3 Hz, 1 H). 13C{1H} NMR and DEPT (151 MHz, CDCl3) δ 17.4 (CH3), 27.3 (2 CH3), 80.9 (C), 112.7 (CH), 114.8 (CH2), 116.2 (CH), 130.7 (CH), 138.1 (C), 143.5 (CH), 146.6 (C), 155.0 (C). ESIMS (−50 V) m/z 219.8 [M − H]−, 440.6 [2M − H]−.

Figure 4. Chiral HPLC of the enantiomers of furoclausine-B, 4 and ent-4, and of the racemate rac-4.

furoclausine-B (4) has a lower retention time than ent-4, minor impurities of the former are easily separated from the major enantiomer ent-4. The retention times of the pure enantiomers 4 and ent-4 perfectly fit those of the racemic mixture, thus assigning the enantiomers in the mixture. On the basis of the chiral HPLC, the enantiomeric excess for our synthetic furoclausine-B (4) and ent-furoclausine-B (ent-4) is >99.5%. A comparison of the values for the specific rotation found for our synthetic compounds 4 ([α]D20 −34.4) and ent-4 ([α]D20 +33.9) with that reported for the natural product 4 ([α]D −32.73)4 emphasizes the high enantiopurity of our products and confirms the fact that the stereogenic center of the natural product 4 has an R configuration.

■

CONCLUSIONS Using our approach to carbazoles consisting of Buchwald− Hartwig coupling and subsequent palladium(II)-catalyzed oxidative cyclization, we have completed the first total synthesis of furoclausine-B (4) and of its enantiomer ent-4. The natural product was obtained in 11 steps with 21% overall yield, and the absolute configuration at the stereogenic center could be assigned as R.

■

EXPERIMENTAL SECTION

General Information. All reactions were carried out in ovendried glassware with dry solvents under an argon atmosphere unless stated otherwise. Acetonitrile, dichloromethane, tetrahydrofuran, and toluene were dried using a solvent purification system (MBraun-SPS). Palladium acetate was recrystallized from glacial acetic acid. Other chemicals were used as received from commercial sources. Microwave irradiations were carried out in a CEM Discover microwave apparatus with a maximum power of 300 W and a maximum pressure of 20 bar. Flash chromatography was performed with silica gel from Acros Organics (0.035−0.070 mm). TLC was performed with TLC plates from Merck (60 F254) using UV light for visualization. Melting points were measured on a Gallenkamp MPD 350 melting point apparatus. UV spectra were recorded on a PerkinElmer 25 UV/vis spectrometer. Fluorescence spectra were measured on a Varian Cary Eclipse spectrometer. IR spectra were recorded on a Thermo Nicolet Avatar 360 FT-IR spectrometer by the ATR method (attenuated total reflectance). NMR spectra were recorded on Bruker Avance II 300, DRX 500, and Avance III 600 spectrometers. Chemical shifts δ are reported in parts per million with the signal for the solvent as the internal standard. Standard abbreviations were used to denote the multiplicities of the signals. Mass spectra were recorded by GC/MS15139


Article

The Journal of Organic Chemistry Anal. Calcd for C12H15NO3: C 65.14, H 6.83, N 6.33. Found: C 65.17, H 7.18, N 6.52. 6-Methyl-3-nitro-2-prenylphenol (8). 2-((2-Methylbut-3-en-2-yl)oxy)-4-nitrotoluene (12) (2.01 g, 9.1 mmol) was dissolved in xylenes (60 mL) and heated at 140 °C for 1 h under reflux. The reaction mixture was allowed to cool to room temperature, the solvent was evaporated, and the residue was purified by column chromatography (silica gel; isohexane/ethyl acetate, 9:1). The resulting oil was cooled to induce crystallization and thus afforded 6-methyl-3-nitro-2prenylphenol (8) (1.85 g, 8.4 mmol, 92% yield) as colorless crystals; mp 65−66 °C. UV (MeOH) λmax 242, 277, 326 (sh) nm. IR (ATR) ν 3437, 2982, 2964, 2911, 2854, 1602, 1576, 1559, 1522, 1462, 1443, 1417, 1327, 1263, 1225, 1172, 1153, 1017, 965, 936, 844, 813, 733, 631 cm−1. 1H NMR (500 MHz, CDCl3) δ 1.79 (d, J = 1.3 Hz, 3 H), 1.85 (s, 3 H), 2.28 (s, 3 H), 3.56 (d, J = 6.9 Hz, 2 H), 5.26 (ddt, J = 8.4, 5.5, 1.4 Hz, 1 H), 5.60 (s, 1 H), 7.09 (d, J = 8.5 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 1 H). 13C{1H} NMR and DEPT (126 MHz, CDCl3) δ 16.5 (CH3), 18.1 (CH3), 25.8 (CH2), 26.0 (CH3), 116.4 (CH), 120.2 (CH), 120.9 (C), 128.6 (CH), 130.4 (C), 136.8 (C), 149.0 (C), 154.0 (C). ESIMS (+10 V) m/z 222.0 [M + H]+, 239.0 [M + NH4]+; ESIMS (−50 V) m/z 219.8 [M − H]−, 440.7 [2M − H]−. Anal. Calcd for C12H15NO3: C 65.14, H 6.83, N 6.33. Found: C 65.51, H 6.78, N 6.29. 6-Methyl-2-prenyl-3-nitrophenyl triisopropylsilyl ether (16). 6Methyl-3-nitro-2-prenylphenol (8) (2.90 g, 13.1 mmol) and 4-(N,Ndimethylamino)pyridine (320 mg, 2.6 mmol, 0.2 equiv) were dissolved in dichloromethane (90 mL). Triethylamine (4.2 mL, 30.3 mmol, 2.3 equiv) was added and the reaction mixture was stirred at room temperature for 10 min, before triisopropylsilyl chloride (3.6 mL, 17 mmol, 1.3 equiv) was added dropwise. After stirring at room temperature overnight, another portion of triisopropylsilyl chloride (0.72 mL, 3.4 mmol, 0.26 equiv) was added and the reaction was stirred for an additional 5 h. After quenching with water, the layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed twice with a sat. aq. NH4Cl solution, with brine and then dried (MgSO4). Removal of the solvent and purification by column chromatography (silica gel; isohexane/ ethyl acetate, 9:1) provided 6-methyl-2-prenyl-3-nitrophenyl triisopropylsilyl ether (16) (4.71 g, 12.5 mmol, 95% yield) as a colorless solid; mp 60−61 °C. UV (MeOH) λmax 240, 274, 332 (sh) nm. IR (ATR) ν 2945, 2867, 1558, 1523, 1460, 1353, 1269 cm−1. 1H NMR (500 MHz, CDCl3) δ 1.09−1.14 (m, 18 H), 1.33 (quin, J = 7.6 Hz, 3 H), 1.64 (dd, J = 6.6, 0.9 Hz, 6 H), 2.32 (s, 3 H), 3.62 (d, J = 6.0 Hz, 2 H), 4.97 (tt, J = 6.3, 1.3 Hz, 1 H), 7.05 (d, J = 8.2 Hz, 1 H), 7.31 (d, J = 8.2 Hz, 1 H). 13C{1H} NMR and DEPT (126 MHz, CDCl3) δ 14.4 (3 CH), 18.1 (6 CH3), 18.6 (2 CH3), 25.5 (CH2), 25.6 (CH3), 117.4 (CH), 121.2 (CH), 127.3 (C), 128.5 (CH), 133.6 (C), 134.0 (C), 149.8 (C), 153.9 (C). ESIMS (+25 V) m/z 378.6 [M + H]+, 395.4 [M + NH4]+. Anal. Calcd for C21H35NO3Si: C 66.80, H 9.34, N 3.71. Found: C 67.11, H 9.67, N 3.67. (R)-2-(2-Hydroxypropan-2-yl)-7-methyl-4-nitro-2,3-dihydrobenzofuran (15). Nitrobenzene 16 (1.48 g, 3.92 mmol), ketone 14 (758 mg, 2.51 mmol, 64 mol %), and Bu4NHSO4 (50.1 mg, 0.15 mmol, 3.8 mol %) were dissolved in a mixture of dimethoxymethane and acetonitrile (2:1, 69 mL) under air. After cooling the mixture to 0 °C, a buffer solution (40 mL, 0.1 M K2CO3 in water and 0.08 M HOAc) was added. Under vigorous stirring, an aqueous 1.47 M solution of KOH (23 mL) and a solution of oxone (5.78 g, 18.8 mmol, 4.8 equiv) in aqueous Na2EDTA (40 mL, 4 × 10−4 M) were added via two different needles by syringe pump over 2 h. Subsequently, the reaction was stirred at 0 °C for two additional hours, quenched by addition of a sat. aq. NH4Cl solution, and the layers were separated. The aqueous layer was extracted three times with ethyl acetate, the combined organic layers were washed with brine, and dried (MgSO4). Evaporation of the solvent afforded the corresponding epoxide as crude product, which was used in the following reaction without further purification. The crude epoxide (1.72 g) was dissolved in THF (90 mL), the solution was cooled to 0 °C, and tetra-nbutylammonium fluoride (9 mL, 9 mmol, 1 M in THF) was added over a period of 1 h. The mixture was transferred to a separatory

funnel (EtOAc) and washed four times with brine. The organic layer was dried over MgSO4, and the solvent was evaporated. Purification of the crude product by column chromatography (silica gel; isohexane/ ethyl acetate, 5:1 to 5:2) provided the dihydrobenzofuran 15 (891 mg, 3.76 mmol, 96% yield over two steps, >99.9% ee as determined by chiral HPLC) as yellow crystals; mp 101−104 °C. [α]D20 −39.9 (c 1.0, MeOH). UV (MeOH) λmax 218, 243, 284, 346 nm. IR (ATR) ν 3541, 2971, 2926, 2863, 1600, 1508, 1340, 1312, 1207, 1150, 1124, 1057, 1037, 978, 935, 817, 744 cm−1. 1H NMR (600 MHz, CDCl3) δ 1.25 (s, 3 H), 1.38 (s, 3 H), 1.81 (br s, 1 H), 2.29 (s, 3 H), 3.64 (m, J = 9.4 Hz, 2 H), 4.71 (dd, J = 9.4, 8.7 Hz, 1 H), 7.06−7.10 (m, 1 H), 7.63 (d, J = 8.3 Hz, 1 H). 13C{1H} NMR and DEPT (151 MHz, CDCl3) δ 15.8 (CH3), 24.2 (CH3), 26.2 (CH3), 32.8 (CH2), 71.9 (C), 89.9 (CH), 116.1 (CH), 123.7 (C), 126.7 (C), 130.1 (CH), 143.5 (C), 159.6 (C). EIMS m/z 237 (10) [M]+, 162 (77), 131 (64), 59 (100), 43 (61). Anal. Calcd for C12H15NO4: C 60.75, H 6.37, N 5.90. Found: C 60.72, H 6.39, N 5.71. Crystallographic Data for the Dihydrobenzofuran 15. C12H15NO4; M = 237.25 g mol−1; crystal size 0.368 × 0.104 × 0.090 mm3; orthorhombic; space group P212121; a = 8.48940(10) Å, b = 11.0722(2) Å, c = 12.8612(2) Å; V = 1208.91(3) Å3; Z = 4; ρcalcd = 1.304 g cm−3; μ = 0.820 mm−1; λ = 1.54178 Å; T = 198(2) K; θ range = 5.271−68.218°; reflections collected 14656; independent reflections 2207 (Rint = 0.0243); 162 parameters. The structure was solved by direct methods and refined by full-matrix least-squares on F2; final R indices [I > 2σ(I)]: R1 = 0.0276, wR2 = 0.0763; maximal residual electron density 0.173 e Å−3; absolute structure (Flack parameter)36 χ = 0.09(3). CCDC 1866291 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Center. (S)-2-(2-Hydroxypropan-2-yl)-7-methyl-4-nitro-2,3-dihydrobenzofuran (ent-15). Using the corresponding ketone ent-14 as catalyst, the same procedure as described for 15 afforded ent-15 (99% yield over two steps, >99.9% ee as determined by chiral HPLC) as yellow crystals; mp 101−102 °C. [α]D20 +41.5 (c 1.0, MeOH). The further analytical data are in full agreement with those of 15. rac-2-(2-Hydroxypropan-2-yl)-7-methyl-4-nitro-2,3-dihydrobenzofuran (rac-15). Nitrobenzene 16 (7.51 g, 19.9 mmol) was dissolved in chloroform (120 mL) under air, and an aq. solution of NaHCO3 (40 mL, 0.5 M) was added. The mixture was cooled to 0 °C, and 3chloroperoxybenzoic acid (mCPBA) (4.10 g, 23.8 mmol, 1.2 equiv) was slowly added in small portions. After stirring for 1.5 h at room temperature, water was added to the mixture at 0 °C, the layers were separated, and the organic layer was washed with a sat. aq. Na2S2O3 solution, a sat. aq. NaHCO3 solution, water, and brine. Drying (MgSO4) and subsequent evaporation of the solvent provided the racemic epoxide as a red oil, which was used for the following transformation without further purification. The crude epoxide (7.53 g) was dissolved in THF (450 mL), the solution was cooled to 0 °C, and tetra-n-butylammonium fluoride (45 mL, 45 mmol, 1 M in THF) was added over a period of 1 h. The mixture was transferred to a separatory funnel (EtOAc) and washed four times with brine. The organic layer was dried over MgSO4, and the solvent was removed. Purification of the residue by column chromatography (silica gel; isohexane/ethyl acetate, 5:1 to 5:2) afforded the dihydrobenzofuran rac-15 (4.53 g, 19.1 mmol, 96% yield over two steps) as a yellow oil. The further analytical data are in full agreement with those of 15. (R)-4-Amino-2-(2-hydroxypropan-2-yl)-7-methyl-2,3-dihydrobenzofuran (7). Dihydrobenzofuran 15 (765 mg, 3.22 mmol) was dissolved in ethyl acetate (70 mL), and platinum(IV) oxide (70.6 mg, 0.31 mmol, 10 mol %) was added. The mixture was stirred overnight under a hydrogen atmosphere (1 atm). Complete conversion was monitored by TLC, the reaction mixture was filtered over a short pad of Celite (EtOAc), and the solvent was evaporated. Purification of the crude product by column chromatography (silica gel; isohexane/ethyl acetate, 1:2) provided the arylamine 7 (605 mg, 2.92 mmol, 91% yield) as a light brown oil. [α]D20 −62.7 (c 1.0, MeOH). UV (MeOH) λmax 211, 289 nm. IR (ATR) ν 3346, 2974, 2929, 2056, 2030, 2009, 1638, 1604, 1571, 1502, 1458, 1434, 1323, 1200, 1170, 1151, 1124, 1055, 969, 937, 862, 793 cm−1. 1H NMR (600 MHz, CDCl3) δ 1.22 15140


Article

The Journal of Organic Chemistry (s, 3 H), 1.35 (s, 3 H), 2.12 (s, 3 H), 2.96 (dd, J = 9.0, 4.1 Hz, 2 H), 3.43 (br s, 2 H), 4.62 (t, J = 9.0 Hz, 1 H), 6.16 (d, J = 7.9 Hz, 1 H), 6.75 (d, J = 7.9 Hz, 1 H). 13C{1H} NMR and DEPT (151 MHz, CDCl3) δ 14.7 (CH3), 24.1 (CH3), 26.3 (CH3), 28.6 (CH2), 72.0 (C), 89.1 (CH), 107.7 (CH), 109.8 (C), 111.4 (C), 130.1 (CH), 141.0 (C), 158.6 (C). EIMS m/z 207 (36) [M]+, 174 (24), 148 (100), 133 (27), 120 (45). HRMS m/z [M]+ calcd for C12H17NO2: 207.1259. Found: 207.1254. (S)-4-Amino-2-(2-hydroxypropan-2-yl)-7-methyl-2,3-dihydrobenzofuran (ent-7). Starting from the corresponding dihydrobenzofuran ent-15, the same procedure as described for 7 afforded ent-7 (96% yield) as a light brown oil. [α]D20 +66.0 (c 1.0, MeOH). The further analytical data are in full agreement with those of 7. rac-4-Amino-2-(2-hydroxypropan-2-yl)-7-methyl-2,3-dihydrobenzofuran (rac-7). Starting from the corresponding dihydrobenzofuran rac-15, the same procedure as that described for 7 afforded rac-7 (96% yield) as a light brown oil. The further analytical data are in full agreement with those of 7. (R)-2-(7-Methyl-4-((3-((triisopropylsilyl)oxy)phenyl)amino)-2,3dihydrobenzo-furan-2-yl)propan-2-ol (5). The arylamine 7 (128 mg, 0.62 mmol, 1.12 equiv), cesium carbonate (237 mg, 0.73 mmol, 1.33 equiv), palladium(II) acetate (7.2 mg, 0.032 mmol, 6 mol %), and racBINAP (38.3 mg, 0.062 mmol, 11 mol %) were dissolved in toluene (12 mL) and heated to 110 °C. Then, a solution of 3-bromophenyl triisopropylsilyl ether (6) (180 mg, 0.55 mmol, 1.0 equiv) in toluene (4.5 mL) was added dropwise to the refluxing mixture. The reaction mixture was stirred at 110 °C overnight and subsequently filtered through a short pad of Celite (EtOAc). Evaporation of the solvent and purification of the residue by column chromatography (silica gel; isohexane/ethyl acetate, 5:1) provided the diarylamine 5 (231 mg, 0.507 mmol, 93% yield) as a light brown oil. [α]D20 −56.7 (c 1.0, MeOH). UV (MeOH) λmax 215, 282 nm. IR (ATR) ν 3528, 3366, 2971, 2941, 2865, 1600, 1519, 1499, 1464, 1333, 1283, 1189, 1151, 1119, 1064, 1047, 986, 940, 883, 864, 834, 799, 771, 684, 641 cm−1. 1 H NMR (600 MHz, CDCl3) δ 1.09 (d, J = 7.2 Hz, 18 H), 1.21 (s, 3 H), 1.24 (spt, J = 7.9 Hz, 3 H), 1.33 (s, 3 H), 1.93 (s, 1 H), 2.17 (s, 3 H), 2.99 (d, J = 9.0 Hz, 2 H), 4.61 (t, J = 9.0 Hz, 1 H), 5.27 (s, 1 H), 6.42 (ddd, J = 7.9, 2.3, 1.1 Hz, 1 H), 6.49 (t, J = 1.9 Hz, 1 H), 6.51 (ddd, J = 7.9, 2.3, 0.8 Hz, 1 H), 6.64 (d, J = 8.3 Hz, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 7.06 (t, J = 7.9 Hz, 1 H). 13C{1H} NMR and DEPT (151 MHz, CDCl3) δ 12.8 (3 CH), 14.9 (CH3), 18.1 (6 CH3), 24.0 (CH3), 26.2 (CH3), 29.5 (CH2), 72.0 (C), 89.2 (CH), 109.2 (CH), 110.5 (CH), 111.1 (CH), 112.3 (CH), 113.1 (C), 116.6 (C), 129.92 (CH), 129.94 (CH), 137.5 (C), 144.8 (C), 157.2 (C), 158.9 (C). EIMS m/z 455 (100) [M+], 412 (22), 396 (50). Anal. Calcd for C27H41NO3Si: C 71.16, H 9.07, N 3.07. Found: C 71.47, H 9.34, N 3.06. (S)-2-(7-Methyl-4-((3-((triisopropylsilyl)oxy)phenyl)amino)-2,3dihydrobenzo-furan-2-yl)propan-2-ol (ent-5). Starting from the corresponding arylamine ent-7, the same procedure as that described for 5 afforded ent-5 (83% yield) as a light brown oil. [α]D20 +57.0 (c 1.0, MeOH). The further analytical data are in full agreement with those of 5. rac-2-(7-Methyl-4-((3-((triisopropylsilyl)oxy)phenyl)amino)-2,3dihydrobenzo-furan-2-yl)propan-2-ol (rac-5). Starting from the corresponding arylamine rac-7, the same procedure as that described for 5 afforded rac-5 (95% yield) as a light brown solid; mp 97−98 °C. The further analytical data are in full agreement with those of 5. (R)-2-(2-Hydroxypropan-2-yl)-4-methyl-8-((triisopropylsilyl)oxy)1,2-dihydro-10H-furo[3,2-a]carbazole (17). A mixture of the diarylamine 5 (101 mg, 0.22 mmol), palladium(II) acetate (2.6 mg, 0.01 mmol, 4.5 mol %), copper(II) acetate (101.4 mg, 0.56 mmol, 2.5 equiv), and acetic acid (1 mL) was heated to 130 °C under air for 15 min in a sealed vessel using a microwave reactor. Then, another portion of palladium(II) acetate (2.6 mg, 0.01 mmol, 4.5 mol %) was added and the mixture was stirred at 130 °C for an additional 15 min. The mixture was cooled to room temperature, diluted with diethyl ether, and washed three times with a sat. aq. solution of potassium carbonate. Subsequently, the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with brine and dried

(MgSO4), and the solvent was evaporated. Purification of the residue by column chromatography (silica gel; isohexane/ethyl acetate, 5:1) provided the carbazole 17 (70.9 mg, 0.156 mmol, 71% yield) as a light brown solid; mp 202−203.5 °C. [α]D20 −53.2 (c 1.0, MeOH). UV (MeOH) λmax 213, 240, 266, 312, 325 nm. Fluorescence (MeOH) λex 240 nm, λem 353 nm. IR (ATR) ν 3576, 3373, 2942, 2864, 1621, 1497, 1452, 1389, 1322, 1276, 1238, 1205, 1171, 1152, 1125, 1069, 970, 956, 884, 832, 805, 715, 688, 648 cm−1. 1H NMR (500 MHz, CDCl3) δ 1.11−1.13 (m, 18 H), 1.26 (s, 3 H), 1.29 (dq, J = 14.9, 7.3 Hz, 3 H), 1.40 (s, 3 H), 2.00 (s, 1 H), 2.35 (s, 3 H), 3.30 (td, J = 7.3, 0.9 Hz, 2 H), 4.74 (t, J = 8.7 Hz, 1 H), 6.76 (dd, J = 8.0, 1.4 Hz, 1 H), 6.87 (d, J = 1.9 Hz, 1 H), 7.52 (s, 1 H), 7.56 (s, 1 H), 7.71 (d, J = 8.5 Hz, 1 H). 13C{1H} NMR and DEPT (126 MHz, CDCl3) δ 12.8 (3 CH), 15.7 (CH3), 18.1 (6 CH3), 24.2 (CH3), 26.3 (CH3), 29.1 (CH2), 72.1 (C), 89.4 (CH), 101.7 (CH), 106.5 (C), 112.3 (C), 113.1 (CH), 118.1 (C), 118.4 (C), 119.6 (CH), 119.8 (CH), 135.1 (C), 140.9 (C), 154.1 (C), 157.1 (C). ESIMS (+25 V) m/z 454.5 [M + H]+, 924.0 [2M + NH4]+; ESIMS (−75 V) m/z 452.3 [M − H]−. Anal. Calcd for C27H39NO3Si: C 71.48, H 8.66, N 3.09. Found: C 71.67, H 9.06, N 3.06. (S)-2-(2-Hydroxypropan-2-yl)-4-methyl-8-((triisopropylsilyl)oxy)1,2-dihydro-10H-furo[3,2-a]carbazole (ent-17). Starting from the corresponding diarylamine ent-5, the same procedure as that described for 17 afforded ent-17 (69% yield) as a light brown solid; mp 201−202 °C. [α]D20 +57.6 (c 1.0, MeOH). The further analytical data are in full agreement with those of 17. rac-2-(2-Hydroxypropan-2-yl)-4-methyl-8-((triisopropylsilyl)oxy)1,2-dihydro-10H-furo[3,2-a]carbazole (rac-17). Starting from the corresponding diarylamine rac-5, the same procedure as that described for 17 afforded rac-17 (72% yield) as a light brown solid; mp 200−202 °C. The further analytical data are in full agreement with those of 17. (R)-2-(2-Hydroxypropan-2-yl)-8-((triisopropylsilyl)oxy)-1,2-dihydro-10H-furo[3,2-a]carbazole-4-carbaldehyde (18). The carbazole 17 (50.3 mg, 0.11 mmol) was dissolved in a mixture of methanol, THF, and water (20 mL, 16:3:1) under air and cooled to −15 °C. 2,3Dichloro-5,6-dicyanobenzoquinone (DDQ) (84.1 mg, 0.37 mmol, 3.3 equiv) was added in small portions, and the resulting mixture was stirred at −15 °C for 20 min. The mixture was diluted with diethyl ether and washed three times with 2 M NaOH and then with brine. The organic layer was dried over MgSO4, and the solvent was evaporated. Purification of the residue by column chromatography (silica gel; isohexane/ethyl acetate, 5:1 to 2:1) provided the aldehyde 18 (29.9 mg, 63.9 μmol, 58% yield) as a bright yellow solid; mp >230 °C (decomp.). [α]D20 −26.5 (c 0.8, MeOH). UV (MeOH) λmax 236, 252, 301, 324 (sh), 346 nm. Fluorescence (MeOH) λex 301 nm, λem 348, 526 nm. IR (ATR) ν 3198, 2942, 2866, 1665, 1623, 1592, 1504, 1466, 1444, 1325, 1224, 1158, 1075, 995, 964, 884, 834, 804, 679, 636 cm−1. 1H NMR (500 MHz, CDCl3) δ 1.12 (d, J = 7.3 Hz, 18 H), 1.26−1.33 (m, 6 H), 1.44 (s, 3 H), 2.03 (br s, 1 H), 3.26 (dd, J = 14.8, 9.5 Hz, 1 H), 3.35 (dd, J = 14.8, 8.5 Hz, 1 H), 4.90 (dd, J = 9.5, 8.5 Hz, 1 H), 6.82 (dd, J = 8.4, 2.0 Hz, 1 H), 6.88 (d, J = 1.9 Hz, 1 H), 7.78 (d, J = 8.2 Hz, 1 H), 7.88 (br s, 1 H), 8.21 (s, 1 H), 10.28 (s, 1 H). 13C{1H} NMR and DEPT (126 MHz, CDCl3) δ 12.9 (3 CH), 18.1 (6 CH3), 24.6 (CH3), 26.3 (CH3), 27.9 (CH2), 71.9 (C), 91.5 (CH), 102.1 (CH), 107.5 (C), 114.2 (C), 114.4 (CH), 118.1 (C), 118.9 (CH), 119.5 (C), 120.8 (CH), 141.1 (C), 141.7 (C), 155.4 (C), 161.2 (C), 188.4 (CHO). ESIMS (+25 V) m/z 468.4 [M + H]+; ESIMS (−75 V) m/z 466.0 [M − H]−. Anal. Calcd for C27H37NO4Si: C 69.34, H 7.97, N 2.99. Found: C 69.35, H 8.17, N 2.94. (S)-2-(2-Hydroxypropan-2-yl)-8-((triisopropylsilyl)oxy)-1,2-dihydro-10H-furo[3,2-a]carbazole-4-carbaldehyde (ent-18). Starting from the corresponding carbazole ent-17, the same procedure as that described for 18 afforded ent-18 (60% yield) as a bright yellow solid; mp >30 °C (decomp.). [α]D20 +22.1 (c 1.0, MeOH). The further analytical data are in full agreement with those of 18. rac-2-(2-Hydroxypropan-2-yl)-8-((triisopropylsilyl)oxy)-1,2-dihydro-10H-furo[3,2-a]carbazole-4-carbaldehyde (rac-18). Starting from the corresponding carbazole rac-17, the same procedure as that described for 18 afforded rac-18 (57% yield) as a light brown 15141



■

solid; mp 221−224 °C. The further analytical data are in full agreement with those of 18. Furoclausine-B (4). The aldehyde 18 (97.4 mg, 0.21 mmol) was dissolved in THF (25 mL). Then, water (0.01 mL) was added, the mixture was cooled to −10 °C, and TBAF (0.33 mL, 1 M in THF, 1.6 equiv) was added dropwise. After 20 min, another portion of TBAF (0.33 mL, 1 M in THF, 1.6 equiv) was added and stirring was continued at −10 °C for an additional 20 min. The reaction mixture was diluted with diethyl ether and transferred to a separatory funnel. Brine was added, the layers were separated, and the organic layer was washed twice with brine. The combined aqueous layers were extracted with diethyl ether, and the combined organic layers were dried over MgSO4. Removal of the solvent, purification of the residue by column chromatography (silica gel; isohexane/ethyl acetate/methanol, 30:70:1), and subsequent filtration through cotton provided furoclausine-B (4) (58.7 mg, 0.19 mmol, 91% yield, >99.5% ee as determined by chiral HPLC) as a bright yellow solid; mp >220 °C (decomp.). [α]D20 −34.4 (c 1.1, MeOH) (ref 4: [α]D −32.73, c 0.022, MeOH). UV (MeOH) λmax 236, 242 (sh), 252, 300, 322 (sh), 344 nm. Fluorescence (MeOH) λex 300 nm, λem 346, 542 nm. IR (ATR) ν 3198, 2942, 2866, 1665, 1623, 1592, 1504, 1466, 1444, 1325, 1224, 1158, 1075, 995, 964, 884, 834, 804, 679, 636 cm−1. 1H NMR (600 MHz, acetone-d6) δ 1.28 (s, 3 H), 1.35 (s, 3 H), 3.35−3.45 (m, 2 H), 3.77 (s, 1 H), 4.92 (dd, J = 9.5, 7.9 Hz, 1 H), 6.76 (dd, J = 8.2, 2.2 Hz, 1 H), 6.90 (d, J = 2.2 Hz, 1 H), 7.88 (d, J = 8.2 Hz, 1 H), 8.13 (s, 1 H), 8.44 (br s, 1 H), 10.26 (s, 1 H), 10.34 (br s, 1 H). 13C{1H} NMR and DEPT (151 MHz, acetone-d6) δ 25.8 (CH3), 26.0 (CH3), 28.5 (CH2), 71.6 (C), 92.3 (CH), 108.87 (CH), 108.92 (CH), 114.5 (C), 117.0 (CH), 117.7 (C), 117.8 (C), 120.1 (C), 121.6 (CH), 142.3 (C), 143.6 (C), 143.8 (C), 162.6 (C), 187.7 (CHO). ESIMS (+10 V) m/z 312.2 [M + H]+; ESIMS (−25 V) m/z 309.9 [M − H]−. Anal. Calcd for C18H17NO4: C 69.44 H, 5.50, N 4.50. Found: C 69.56, H 5.73, N 4.43. ent-Furoclausine-B (ent-4). Starting from the corresponding aldehyde ent-18, the same procedure as that described for 4 afforded ent-4 (90% yield, >99.5% ee as determined by chiral HPLC) as a bright yellow solid; mp > 220 °C (decomp.). [α]D20 +33.9 (c 1.0, MeOH). The further analytical data are in full agreement with those of 4. rac-Furoclausine-B (rac-4). Starting from the corresponding aldehyde rac-18, the same procedure as that described for 4 afforded rac-4 (87% yield) as a bright yellow solid; mp >220 °C (decomp.). The further analytical data are in full agreement with those of 4.

■

REFERENCES

(1) (a) Wu, T.-S.; Wang, M.-L.; Wu, P.-L. Seasonal Variations of Carbazole Alkaloids in Murraya euchrestifolia. Phytochemistry 1996, 43, 785−789. (b) Arbab, I. A.; Abdul, A. B.; Aspollah, M.; Abdullah, R.; Abdelwahab, S. I.; Mohan, S.; Abdelmageed, A. H. A. Clausena excavata Burm. f. (Rutaceae): A Review of Its Traditional Uses, Pharmacological and Phytochemical Properties. J. Med. Plants Res. 2011, 5, 7177−7184. (2) Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J. Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids. Chem. Rev. 2012, 112, 3193−3328. (3) Ito, C.; Furukawa, H. New Carbazole Alkaloids from Murraya euchrestifolia Hayata. Chem. Pharm. Bull. 1990, 38, 1548−1550. (4) Wu, T.-S.; Huang, S.-C.; Wu, P.-L. Pyrano- and Furocarbazole Alkaloids from the Root Bark of Clausena excavata. Heterocycles 1997, 45, 969−973. (5) Macías V, V. E.; Coy B, E. D.; Cuca, L. E. Novel Furocarbazole Alkaloids and Antibacterial Activity of Ethanol Extract from Zanthoxylum fagara (L.) Sargent. Rev. Colomb. Quim. 2010, 39, 333−341. (6) Khan, D.; Khan, S.; Badshah, S.; Ali, H.; Ullah, H.; Muhammad, Z.; Woodward, S. New Furocarbazole Alkaloids from Lonicera quinquelocularis. Nat. Prod. Res. 2016, 30, 74−78. (7) (a) Knölker, H.-J.; Fröhner, W. First Total Synthesis of Furostifoline. Tetrahedron Lett. 1996, 37, 9183−9186. (b) Knölker, H.-J.; Fröhner, W. Convergent Iron-Mediated Syntheses of the Furo[3,2-a]carbazole Alkaloid Furostifoline. Synthesis 2000, 2131− 2136. (8) Knö lker, H.-J.; Krahl, M. P. First Total Synthesis of Furoclausine-A. Synlett 2004, 528−530. (9) Krahl, M. P.; Schmidt, A. W.; Knölker, H.-J. Iron-Mediated Total Synthesis of Furoclausine-A. Heterocycles 2012, 86, 357−370. (10) Forke, R.; Krahl, M. P.; Krause, T.; Schlechtingen, G.; Knölker, H.-J. First Total Synthesis of Methyl 6-Methoxycarbazole-3carboxylate, Glycomaurrol, the Anti-TB Active Micromeline, and the Furo[2,3-c]carbazole Alkaloid Eustifoline-D. Synlett 2007, 0268− 0272. (11) Fröhner, W.; Krahl, M. P.; Reddy, K. R.; Knölker, H.-J. Synthetic Routes to Naturally Occurring Furocarbazoles. Heterocycles 2004, 63, 2393−2407. (12) Lebold, T. P.; Kerr, M. A. Total Synthesis of Eustifolines A−D and Glycomaurrol via a Divergent Diels−Alder Strategy. Org. Lett. 2007, 9, 1883−1886. (13) Brütting, C.; Hesse, R.; Jäger, A.; Kataeva, O.; Schmidt, A. W.; Knölker, H.-J. Synthesis of Glycoborine, Glybomine A and B, the Phytoalexin Carbalexin A and the β-Adrenoreceptor Antagonists Carazolol and Carvedilol. Chem. - Eur. J. 2016, 22, 16897−16911. (14) (a) Murci, A. R.; Buchwald, S. L. Practical Palladium Catalysts for C-N and C-O Bond Formation. Top. Curr. Chem. 2002, 219, 131− 209. (b) Surry, D. S.; Buchwald, S. L. Biaryl Phosphane Ligands in Palladium-Catalyzed Amination. Angew. Chem., Int. Ed. 2008, 47, 6338−6361. (c) Ruiz-Castillo, P.; Buchwald, S. L. Applications of Palladium-Catalyzed C−N Cross-Coupling Reactions. Chem. Rev. 2016, 116, 12564−12649. (15) Yamada, S.; Ono, F.; Katagiri, T.; Tanaka, J. The oIsoprenylation of Phenols in the Presence of Metallic Sodium. Bull. Chem. Soc. Jpn. 1977, 50, 750. (16) Hoarau, C.; Pettus, T. R. R. Strategies for the Preparation of Differentially Protected ortho-Prenylated Phenols. Synlett 2003, 127− 137. (17) Godfrey, J. D.; Mueller, R. H.; Sedergran, T. C.; Soundararajan, N.; Colandrea, V. J. Improved Synthesis of Aryl 1,1-Dimethylpropargyl Ethers. Tetrahedron Lett. 1994, 35, 6405−6408. (18) Iwai, I.; Ide, J. Ring Closure of Propargyl Ethers. Chem. Pharm. Bull. 1963, 11, 1042−1049. (19) Zsindely, J.; Schmid, H. Sigmatropische Umlagerungen von Arylpropargyläthern; Synthese von 1,5-Dimethyl-6-methylentricyclo[3,2,1,02,7]oct-3-en-8-on-Derivaten. Helv. Chim. Acta 1968, 51, 1510− 1514.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02426. 1

H and 13C NMR spectra of all compounds; chromatograms (chiral HPLC) of 15, ent-15, rac-15, 4, ent-4, and rac-4; details of the X-ray crystal structure determination of 15 (PDF)

■

Article

Crystallographic structure file for 15 (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Hans-Joachim Knölker: 0000-0002-9631-5239 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank Jakob Reimann for experimental support. 15142


Article

The Journal of Organic Chemistry (20) Puls, F.; Kataeva, O.; Knölker, H.-J. Synthesis of Euchrestifoline Using Iron- and Palladium-Catalyzed C−H Bond Activations. Eur. J. Org. Chem. 2018, 4272−4276. (21) Hesse, R.; Jäger, A.; Schmidt, A. W.; Knö lker, H.-J. Palladium(II)-Catalysed Total Synthesis of Naturally Occurring Pyrano[3,2-a]carbazole and Pyrano[2,3-b]carbazole Alkaloids. Org. Biomol. Chem. 2014, 12, 3866−3876. (22) Gassner, C.; Hesse, R.; Schmidt, A. W.; Knölker, H.-J. Total Synthesis of the Cyclic Monoterpenoid Pyrano[3,2-a]carbazole Alkaloids Derived from 2-Hydroxy-6-methylcarbazole. Org. Biomol. Chem. 2014, 12, 6490−6499. (23) Schuster, C.; Julich-Gruner, K. K.; Schnitzler, H.; Hesse, R.; Jäger, A.; Schmidt, A. W.; Knölker, H.-J. Total Syntheses of Murrayamine E, I, and K. J. Org. Chem. 2015, 80, 5666−5673. (24) Jiang, H.; Hamada, Y. Highly Enantioselective Synthesis of Angelmarin. Org. Biomol. Chem. 2009, 7, 4173−4176. (25) Ren, X.-D.; Zhao, N.; Xu, S.; Lü, H.-N.; Ma, S.-G.; Liu, Y.-B.; Li, Y.; Qu, J.; Yu, S.-S. Total Synthesis of Illicidione A and Illihendione A. Tetrahedron 2015, 71, 4821−4829. (26) Wang, W.; Xue, J.; Tian, T.; Jiao, Y.; Li, Y. The First Asymmetric Total Synthesis of (+)-Coriandrone A and B. Org. Biomol. Chem. 2013, 11, 6686−6690. (27) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. An Efficient Catalytic Asymmetric Epoxidation Method. J. Am. Chem. Soc. 1997, 119, 11224−11235. (28) Zhao, M.-X.; Shi, Y. Practical Synthesis of an L-FructoseDerived Ketone Catalyst for Asymmetric Epoxidation of Olefins. J. Org. Chem. 2006, 71, 5377−5379. (29) Wu, X.-Y.; She, X.; Shi, Y. Highly Enantioselective Epoxidation of α,β-Unsaturated Esters by Chiral Dioxirane. J. Am. Chem. Soc. 2002, 124, 8792−8793. (30) Nieto, N.; Molas, P.; Benet-Buchholz, J.; Vidal-Ferran, A. Practical Synthesis of Shi’s Diester Fructose Derivative for Catalytic Asymmetric Epoxidation of Alkenes. J. Org. Chem. 2005, 70, 10143− 10146. (31) Wang, B.; Wu, X.; Wong, O. A.; Nettles, B.; Zhao, M.; Chen, D.; Shi, Y. A Diacetate Ketone-Catalyzed Asymmetric Epoxidation of Olefins. J. Org. Chem. 2009, 74, 3986−3989. (32) Sheldrick, G. M. SHELXS-97, Programs for Crystal Structure Solution; University of Göttingen: Göttingen, Germany, 1997. (33) Sheldrick, G. M. SADABS, v. 2.10, Bruker/Siemens Area Detector Absorbtion Correction Program; Bruker AXS Inc.: Madison, WI, 2002. (34) Sheldrick, G. M. SHELXL-97, Programs for Crystal Structure Refinement; University of Göttingen: Göttingen, Germany, 1997. (35) Farrugia, L. J. ORTEP −3 for Windows - A Version of ORTEPIII with a Graphical User Interface (GUI). J. Appl. Crystallogr. 1997, 30, 565. (36) Flack, H. D. On Enantiomorph-Polarity Estimation. Acta Crystallogr., Sect. A: Found. Crystallogr. 1983, 39, 876−881.

15143


Enantioselective Total Synthesis and Assignment of the Absolute

Recommend Documents