HETEROCYCLES

Paper | Special issue | Vol. 79, No. 1, 2009, pp. 955-965
Received, 16th October, 2008, Accepted, 27th November, 2008, Published online, 11th December, 2008.
DOI: 10.3987/COM-08-S(D)71

■ A New Synthetic Route to the 1-Oxygenated Carbazole Alkaloids, Mukonine and Clausine E (Clauzoline I)

Shigeo Tohyama, Tominari Choshi, Shuhei Azuma, Haruto Fujioka, and Satoshi Hibino*

Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

Abstract

A new synthesis of the 1-oxygenated 1,3-disubstituted carbazole alkaloids, mukonine (1a) and clausine (1f) is described. The construction of the carbazole framework is based on an allene-mediated electrocyclic reaction involving the indole 2,3-bond. The 1,3-disubstituted 1-oxygenated carbazoles 1a and 1f are derived from the 1,2,3-trisubstituted carbazole.

INTRODUCTION
Naturally occurring carbazole alkaloids display a wide variety of biological activities, such as antitumor, antibacterial, antimicrobial, and anti-inflammatory activities. An intensive effort has been directed toward their isolation, and total synthesis.1 The search for the biologically active compounds of Murraya and Clausena led to the discovery of a broad variety of carbazole alkaloids, including the 1-oxygenated 3-substituted carbazoles and 2-oxygenated 3-substituted carbazoles. Among them, the simple 1-oxygenated 3-substituted carbazole alkaloids, mukonine (1a) and clausine E (clauzoline I: 1f) have been isolated from Murraya koenigii1a,2 and Clausena excavata1,3,4 (and anisata), together with 1b~1e, 1g, and 1h (Scheme 1). Several excellent synthetic routes for their preparation have been reported.1,5
We have been working to develop the synthesis of a biologically active condensed heterocyclic compound based on a thermal electrocyclic reaction of either the 6π-electron system or the aza 6π-electron system.6 Recently, the total synthesis of 3-oxygenated or 3,4-dioxygenated polyfunctionalized carbazole alkaloids was developed by an allene-mediated electrocyclic reaction involving the indole 2,3-bond.7 Initially, we planned a short-step sequence toward a 1-oxyganated carbazole 1 based on a thermal electrocyclic reaction of 2,3-bisalkenylindole 2 6 (Scheme 1). However, it was difficult to prepare the precursor 2. Taking advantage of our recent efforts,7 we applied this methodology for the syntheses of mukonine (1a) and clausine (1f).

RESULTS AND DISCUSSION
In the present paper, we describe a new synthesis of the 1-oxygenated 3-substituted carbazoles, mukonine (1a) and clausine (1f), based on an alle4ne-mediated electrocyclic reaction of the 6π-electron system involving the indole 2,3-bond (Scheme 2). We chose methyl 3-[2-formyl-N-(methoxymethyl)- indole-3-yl]acrylate (5a) and ethyl 3-[2-formyl-N-(methoxymethyl)indole-3-yl]acrylate (5b) as starting materials.8 Nucleophilic addition reaction of 5a and 5b with lithium methoxyacetylide or ethoxyacetylide, (prepared from chloroacetaldehyde dimethyl acetal or chloroacetaldehyde diethyl acetal with lithium diethylamide in in situ),9 gave the propargyl alcohol 6a and 6b, respectively. Subsequent treatment of 6a and 6b with chloromethyl methyl ether (MOMCl) in CH2Cl2 at 50 o C afforded the propargyl ether 7a and 7b, respectively. An allene-mediated electrocyclic reaction of the propargyl ether 7a was carried out by tetrahydroammonium fluoride (TBAF) according to the reported procedure7b to give the 1,2,3-trisubstituted carbazole-3-methyl ester 8a in somewhat low yield.

As shown in Table 1, the propargyl ether 7b was subjected to a similar reaction using TBAF to yield the cyclized carbazoles 8b in moderate to good yields, together with the carbazole-3-carboxylic acid 8c (run 1-3). On the other hand, the same reaction of 7b using t-BuOk7 gave the exclusively carbazole-3-carboxylic acid 8c through a cyclization followed by a hydrolysis of the ester 8c (run 4, 5). The carbazole-3-carboxylic acid 8c was treated with MeI in the presence of hexamethylphosphoramide (HMPA) to proceed to the carbazole-3-methyl ester 8d. Oxidation of the alkoxymethyl group at the 2-position of carbazoles 8a and 8d with dichlorodicyanoquinone (DDQ) in CH2Cl2 provided the 2-formyl-1-hydroxycarbazole 9, derived from both compounds. The allover yield (42%) of 1-oxygenated carbazole 9 from 5b was greater than that of the methyl ester series 5a (5%).
For the synthesis of 1a and 1f (Scheme 3), alkylation of the 1-hydroxycarbazole 9 was carried out by MeI or benzyl bromide in the presence of K2CO3 at 0 oC to yield 1-methoxycarbazole 10a and 1-benzyloxycarbazole 10b, respectively. Baeyer-Villiger reaction of 10a and 10b with m-chloroperbenzoic acid (mCPBA) in the presence of potassium fluoride (KF)10 in CH2Cl2 afforded 2-hydroxycarbazoles 11a and 11b, respectively. Subsequent treatment of 11a and 11b with N-phenyl bistrifluoromethanesulfonylamide (Tf2NPh) in the presence of NaH gave triflates 12a and 12b, which were subjected to hydrogenolysis11 with 10% Pd-C and hydrogen gas to produce mukonine (1a) and clausine E (1f) along with debenzylation. The spectral and physical data of the obtained mukonine (1a) and clausine E (1f) were identified by comparison with those reported previously.12

CONCLUSION
In summary, 1,3-disubstituted 1-oxygenated carbazole alkaloids, mukonine (1a) and clausine E (1f) were newly synthesized by the construction of 1,2,3-trisubstituted 1-oxygenated carbazoles 8a and 8c based on an allene-mediated electrocyclic reaction involving the indole 2,3-bond, followed by removal of the alkoxymethyl group at the 2-position of 8a and 8c in four-steps. Although this synthetic route is a long process, this scheme can be applied to a synthesis of the other carbazole alkaloids 1b-1e, 1g, and 1h. In addition, we demonstrated that 2,3-disubstituted 2-oxygenated carbazole alkaloids such as mukonal and mukonidine1,3,5 can be derived from 1,2,3-trisubstituted carbazole 9.

EXPERIMENTAL
All melting points were measured with a Yanagimoto micro-melting point apparatus MP-500D and are uncorrected. IR spectra were recorded with ATR method using a Shimadzu FTIR-8000 spectrophotometer and Technologies DuraScop. 1H-NMR and 13C-NMR spectra were taken with a JEOL AL-300 instrument using tetramethylsilane as an internal standard. Mass spectra (MS) were determined with a Shimadzu QP5050 (EI) and JMS-700 (CI with isobutane) spectrometers by direct inlet system, respectively. Solvents were distilled by normal methods (THF dried over sodium benzophenone ketyl, CH2Cl2 dried over CaH2, DMF dried over CaH2). Silica gel 60PF254 (60-100 mesh, Merck Art 7744) was used for column chromatography.
Methyl 3-[2-formyl-N-(methoxymethyl)indol-3-yl]acrylate (5a)
A stirred mixture of 3-iodoindole (1 g, 3.17 mmol), methyl acrylate (0.57 mL, 6.3 mmol), Et3N (0.87 mL, 6.3 mmol), PPh3 (26 mg, 0.1 mmol), and Pd(OAc)2 (13.5 mg, 0.06 mmol) in DMF (45 mL) were heated at 100 oC for 1 h under Ar. After being cooled to ambient temperature, the reaction mixture was diluted with water, and the mixture was extracted with EtOAc. The EtOAc was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 20 g) using EtOAc-hexane (1:4 v/v) as an eluent to give the N-MOM-indole 5a8 (734 mg, 85%). mp 104-106 oC (EtOAc); IR (ATR)ν: 1697, 1647 cm-1; 1H-NMR (CDCl3)δ: 3.32 (3H, s), 3.86 (3H, s), 6.01 (2H, s), 6.69 (1H, d, J=16.0 Hz), 7.35 (1H, t, J=7.3 Hz), 7.52 (1H, t, J=7.3 Hz), 7.61 (1H, d, J=7.3 Hz), 8.01 (1H, d, J=7.3 Hz), 8.32 (1H, d, J=16.0 Hz), 10.38 (1H, s); MS m/z: 273 (M+).

Ethyl 3-[2-formyl-N-(methoxymethyl)indol-3-yl]acrylate (5b)
The same procedure as above was carried out using 3-iodoindole (1 g, 3.17 mmol) and ethyl acrylate (697 μL, 6.4 mmol) to give the N-MOM-indole 5b (830 mg, 91%). mp 83-85oC (EtOAc); IR (ATR)ν: 1709, 1631 cm-1; 1H-NMR (CDCl3)δ: 1.38 (3H, t, J=7.1 Hz), 3.31 (3H, s), 4.32 (2H, q, J=7.1 Hz), 6.01 (2H, s), 6.68 (1H, d, J=15.8 Hz), 7.43 (1H, t, J=7.3 Hz), 7.51 (1H, t, J=7.3 Hz), 7.54 (1H, d, J=7.3 Hz), 8.02 (1H, d, J=7.3 Hz), 8.31 (1H, d, J=15.8 Hz), 10.38 (1H, s); MS m/z: 287 (M+).

Methyl 3-[2-(1-hydroxy-3-methoxyprop-2-yn-1-yl)-N-(methoxymethyl)indol-3-yl]acrylate (6a)
Et2NH (3.59 mL, 34.69 mmol) was added to a solution of n-BuLi (2.59 mol/L in hexane, 12.1 mL, 31.22 mmol) in THF (27 mL) under cooling with ice-water. After stirring at the same temperature for 10 min, chloroacetaldehyde dimethyl acetal (1.19 mL, 10.41 mmol) was added to the reaction mixture at the same temperature for further 1.5 h. A solution of N-MOM-indole 5a (474 mg, 1.73 mmol) in THF (15 mL) was added to the reaction mixture at same temperature for further 1.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, and then extracted with EtOAc. The EtOAc was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 15 g) using EtOAc-hexane (3:7 v/v) as an eluent to give the oily propargyl alcohol 6a (274 mg, 48%). IR (ATR)ν: 2271, 1712 cm-1; 1H-NMR (CDCl3)δ: 3.35 (3H, s), 3.64 (1H, d, J=7.5 Hz), 3.82 (3H, s), 3.91 (3H, s), 5.63 (1H, d, J=11.0 Hz), 6.09 (1H, d, J=7.5 Hz), 6.13 (1H, d, J=11.0 Hz), 6.57 (1H, d, J=15.8 Hz), 7.27 (1H, t, J=7.2 Hz), 7.34 (1H, t, J=7.2 Hz), 7.52 (1H, d, J=7.2 Hz), 7.93 (1H, d, J=7.2 Hz), 8.09 (1H, d, J=15.8 Hz), MS m/z: 329 (M+). HR-MS m/z: 329.1270 (Calcd for C18H19NO5: 329.1263)

Ethyl 3-[2-(3-ethoxy-1-hydroxyprop-2-yn-1-yl)-N-(methoxymethyl)indol-3-yl]acrylate (6b)
The same procedure as above was carried out using N-MOM-indole 5b (753 mg, 2.62 mmol) and chloroacetaldehyde diethyl acetal (3.34 mL, 22.57 mmol) to give the oily propargyl alcohol 6b (817 mg, 87%). IR (ATR)ν: 2264, 1697 cm-1; 1H-NMR (CDCl3)δ: 1.33 (3H, t, J=7.1 Hz), 1.35 (3H, t, J=7.1 Hz), 3.33 (3H, s), 3.90 (1H, d, J=5.9 Hz), 4.12 (2H, q, J=7.1 Hz), 4.25 (2H, q, J=7.1 Hz), 5.65 (1H, d, J=11.0 Hz), 6.09 (1H, d, J=11.0 Hz), 6.11 (1H, d, J=5.9 Hz), 6.52 (1H, d, J=16.0 Hz), 7.25 (1H, t, J=7.6 Hz), 7.31 (1H, t, J=7.6 Hz), 7.51 (1H, d, J=7.6 Hz), 7.92 (1H, d, J=7.6 Hz), 8.08 (1H, d, J=16.0 Hz), MS m/z: 357 (M+). HR-MS m/z: 357.1585 (Calcd for C20H23NO5 : 357.1576).

Methyl 3-{2-[3-methoxy-1-(methoxymethyloxy)prop-2-yn-1-yl]-N-(methoxymethyl)indol-3-yl} acrylate (7a)
A solution of propargyl alcohol 6a (548 mg, 1.66 mmol), MOMCl (0.76 mL, 9.98 mmol), and i-Pr2NEt (2.29 mL, 13.31 mmol) in CH2Cl2 (15 mL) were heated at 50 oC for 3 h. After being cooled to ambient temperature, the reaction mixture was quenched with water, and then was extracted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 15 g) using EtOAc-hexane (3:7 v/v) as an eluent to give the oily propargyl ether 7a (264 mg, 40%). IR (ATR)ν: 2268, 1709 cm-1; 1H-NMR (CDCl3)δ: 3.34 (3H, s), 3.39 (3H, s), 3.82 (3H, s), 3.90 (3H, s), 4.58 (1H, d, J=6.6 Hz), 4.93 (1H, d, J=6.6 Hz), 5.75 (2H, s), 6.07 (1H, s), 6.55 (1H, d, J=15.8 Hz), 7.26 (1H, td, J=7.0, 1.2 Hz), 7.32 (1H, td, J=7.0, 1.2 Hz), 7.58 (1H, dd, J=7.0, 1.2 Hz), 7.92 (1H, dd, J=7.0, 1.2 Hz), 8.10 (1H, d, J=15.8 Hz), MS m/z: 373 (M+). HR-MS m/z: 373.1550 (Calcd for C20H23NO6 : 373.1525).

Ethyl 3-{2-[3-ethoxy-1-(methoxymethyloxy)prop-2-yn-1-yl]-N-(methoxymethyl)indol-3-yl}acrylate (7b)
The same procedure as above was carried out using propargyl alcohol 6b (595 mg, 1.67 mmol) to give the oily propargyl ether 7b (590 mg, 88%). IR (ATR)ν: 2264, 1716 cm-1; 1H-NMR (CDCl3)δ: 1.35 (3H×2, t, J=7.1 Hz), 3.34 (3H, s), 3.39, (3H, s), 4.13 (2H, q, J=7.1 Hz), 4.28 (2H, q, J=7.1 Hz), 4.58 (1H, d, J=7.0 Hz), 4.94 (1H, d, J=7.0 Hz), 5.77 (2H, d, J=1.8 Hz), 6.09 (1H, s), 6.55 (1H, d, J=16.0 Hz), 7.26 (1H, t, J=7.6 Hz), 7.32 (1H, t, J=7.6 Hz), 7.58 (1H, d, J=7.6 Hz), 7.94 (1H, d, J=7.6 Hz), 8.10 (1H, d, J=16.0 Hz), MS m/z: 401 (M+). HR-MS m/z: 401.1811 (Calcd for C22H27NO6 : 401.1838).

Methyl 2-(methoxymethyl)-N-(methoxymethyl)-1-(methoxymethyloxy)carbazole-3- carboxylate (8a)
TBAF (1M in THF, 3.29 mL, 3.29 mmol) was added to a solution of the propargyl ether 7a (246 mg, 0.66 mmol) in THF (10 mL), and then heated at 90 oC for 10 min. After being cooled to an ambient temperature, the reaction mixture was quenched with saturated aqueous NH4Cl solution, and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 10 g) using EtOAc-hexane (3:7 v/v) as an eluent to give the 2-methoxymethylcarbazole 8a (128 mg, 52%). mp 58-60 oC (Et2O-hexane); IR (ATR)ν: 1720 cm-1; 1H-NMR (CDCl3)δ: 3.30 (3H, s), 3.48 (3H, s), 3.60 (3H, s), 3.97, (3H, s), 4.97 (2H, s), 5.26 (2H, s), 6.07 (2H, s), 7.32 (1H, t, J=7.7 Hz), 7.52 (1H, t, J=7.7 Hz), 7.60 (1H, d, J=7.7 Hz), 8.08 (1H, d, J=7.7 Hz), 8.49 (1H, s), MS m/z: 373 (M+). HR-MS m/z: 373.1543 (Calcd for C20H23NO6 : 373.1525).

Ethyl 2-(ethoxymethyl)-N-(methoxymethyl)-1-(methoxy-methyloxy)carbazole-3-carboxylate (8b)
The same procedure as above was carried out using propargyl ether 7b (600 mg, 1.49 mmol) to give the 2-ethoxymethylcarbazole 8b (525 mg, 88%). mp 56-57 oC (Et2O-hexane); IR (ATR)ν: 1712 cm-1; 1H-NMR (CDCl3)δ: 1.25 (3H, t, J=7.0 Hz), 1.45 (3H, t, J=7.1 Hz), 3.28 (3H, s), 3.60, (3H, s), 3.64 (2H, q, J=7.0 Hz), 4.43 (2H, q, J=7.1 Hz), 5.00 (2H, s), 5.26 (2H, s), 6.05 (2H, s), 7.30 (1H, t, J=7.2 Hz), 7.50 (1H, t, J=7.2 Hz), 7.58 (1H, d, J=7.2 Hz), 8.07 (1H, d, J=7.2 Hz), 8.43 (1H, s), MS m/z: 401 (M+). HR-MS m/z: 401.1824 (Calcd for C22H27NO6 : 401.1838).

2-(Ethoxymethyl)-N-(methoxymethyl)-1-(methoxymethyloxy)carbazole-3-carboxylic acid (8c)
A solution of propargyl ether 7b (57 mg, 0.15 mmol) in THF (3 mL) was added to a solution of t-BuOK (86 mg, 0.76 mmol) in t-BuOH (3 mL), and then heated at 90 oC for 1 h. After being cooled to an ambient temperature, the reaction mixture was adjusted to pH 5 with AcOH, and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was recrystallized from CHCl3-hexane to give the carbazole-3-carboxylic acid 8c (52 mg, 98%). mp 138-139 oC (CHCl3-hexane) IR (ATR)ν: 2924, 1682 cm-1; 1H-NMR (CDCl3)δ: 1.33 (3H, t, J=7.1 Hz), 3.32 (3H, s), 3.61, (3H, s), 3.79 (2H, q, J=7.1 Hz), 4.99 (2H, s), 5.25 (2H, s), 6.03 (2H, s), 7.34 (1H, t, J=7.1 Hz), 7.54 (1H, t, J=7.1 Hz), 7.60 (1H, d, J=7.1 Hz), 8.10 (1H, d, J=7.1 Hz), 8.62 (1H, s), MS m/z: 373 (M+). HR-MS m/z: 373.1509 (Calcd for C20H23NO6 : 373.1525).

Methyl 2-(ethoxymethyl)-N-(methoxymethyl)-1-(methoxymethyloxy)carbazole-3-carboxylate (8d)
25% aqueous NaOH (1.1 mL, 6.74 mmol) solution was added to a solution of the carbazole-3-carboxylic acid 8c (629 mg, 1.68 mmol) in HMPA (15 mL) at rt, and then stirred at same temperature for 30 min. MeI (0.84 mL, 13.48 mmol) was added to a reaction mixture, and then stirred at the same temperature for further 1 h. The reaction mixture was adjusted to pH 5 with AcOH, and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 20 g) using EtOAc-hexane (1:4 v/v) as an eluent to give the oily 2-ethoxymethylcarbazole 8d (647 mg, 99%). IR (ATR)ν: 1726 cm-1; 1H-NMR (CDCl3)δ: 1.25 (3H, t, J=7.0 Hz), 3.29 (3H, s), 3.60 (3H, s), 3.65 (2H, q, J=7.0 Hz), 3.96, (3H, s), 5.00 (2H, s), 5.26 (2H, s), 6.05 (2H, s), 7.30 (1H, t, J=7.5 Hz), 7.50 (1H, t, J=7.5 Hz), 7.58 (1H, d, J=7.5 Hz), 8.06 (1H, d, J=7.5 Hz), 8.44 (1H, s), MS m/z: 387 (M+). HR-MS m/z: 387.1702 (Calcd for C21H25NO6 : 387.1682).

Methyl 2-formyl-1-hydroxycarbazole-3-carboxylate (9)
A solution of 2-methoxymethylcarbazole 8a (100 mg, 0.27 mmol), DDQ (122 mg, 0.54 mmol), and LiClO4 (28 mg, 0.27 mmol) in CH2Cl2/H2O (18:1) (10 mL) were heated at 60 oC for 24 h. After being cooled to ambient temperature, the reaction mixture was filtered though Celite pad. The filtrate was extracted with CH2Cl2. The organic layer was washed water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was used without purification. 6 M HCl (0.5 mL) and ethylene glycol (0.5 mL) were added to a solution of the residue in THF (4 mL), and then heated at 60oC for 7 h. After being cooled to ambient temperature, the reaction mixture was added water and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 5 g) using EtOAc-hexane (3:17 v/v) as an eluent to give the 2-formylcarbazole 9 (32 mg, 46%). mp 204-205 oC (Et2O-hexane); IR (ATR)ν: 3355, 1682, 1647 cm-1; 1H-NMR (CDCl3)δ: 4.01 (3H, s), 7.31-7.36 (1H, m), 7.55 (2H, br d, J=4.0 Hz), 8.11 (1H, d, J=7.3 Hz), 8.34 (1H, s), 8.85 (1H, br s), 10.84 (1H, s), 13.22 (1H, s), MS m/z: 269 (M+). HR-MS m/z: 269.0697 (Calcd for C15H11NO4 : 269.0688).

Methyl 2-formyl-1-hydroxycarbazole-3-carboxylate (9)
The same procedure as above was carried out using 2-ethoxymethylcarbazole 8d (200 mg, 0.52 mmol) to give the 2-formylcarbazole 9 (79 mg, 57%).

Methyl 2-formyl-1-methoxycarbazole-3-carboxylate (10a)
A mixture of 2-formylcarbazole 9 (39 mg, 0.14 mmol), MeI (9 μL, 0.14 mmol), and K2CO3 (20 mg, 0.14 mmol) in DMF (5 mL) was stirred at rt for 12 h. The reaction mixture was quenched with aqueous NH4Cl solution, and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 5 g) using EtOAc-hexane (1:4 v/v) as an eluent to give the 1-methoxycarbazole 10a (21 mg, 51%). mp 204-205 oC (EtOAc-hexane); IR (ATR)ν: 3240, 1682 cm-1; 1H-NMR (CDCl3)δ: 3.99 (3H, s), 4.10 (3H, s), 7.30-7.36 (1H, m), 7.53-7.55 (2H, m), 8.11 (1H, d, J=7.3 Hz), 8.42 (1H, s), 8.67 (1H, br s), 10.59 (1H, s), MS m/z: 283 (M+). HR-MS m/z: 283.0849 (Calcd for C16H13NO4 : 283.0845).

Methyl 1-benzyloxy-2-formylcarbazole-3-carboxylate (10b)
The same procedure as above was carried out using 2-formylcarbazole 9 (57 mg, 0.21 mmol) and benzyl bromide (25 μL, 0.21 mmol) to give the 1-benzyloxycarbazole 10b (59 mg, 78%). mp 128-129 oC (Et2O-hexane); IR (ATR)ν: 3545, 1678 cm-1; 1H-NMR (CDCl3)δ: 3.98 (3H, s), 5.23 (2H, s), 7.28 (1H, t, J=7.5 Hz), 7.35-7.50 (7H, m), 8.05 (1H, d, J=7.5 Hz), 8.30 (1H, br s), 8.39 (1H, s), 10.49 (1H, s), MS m/z: 359 (M+). HR-MS m/z: (Calcd for C22H17NO4 : 359.1158).

Methyl 1-methoxy-2-(trifluoromethanesulfonyloxy)carbazole-3-carboxylate (12a)
A solution of 1-methoxycarbazole 10a (47 mg, 0.17 mmol), mCPBA (382 mg, 1.66 mmol), and KF (193 mg, 3.32 mmol) in CH2Cl2 (10 mL) was stirred at rt for 1 h. The reaction mixture was purified by column chromatography (silica gel 5 g) using EtOAc-hexane (3:17 v/v) as an eluent to give crude 2-hydroxycarbazole 11a. A solution of 2-hydroxycarnazole in THF (3 mL) was added to a suspension of 60%NaH (11 mg, 0.28 mmol) in THF (3 mL) at -30 oC. After stirred at the same temperature for 0.5 h, the reaction mixture which was added Tf2NPh (47 mg, 0.13 mmol), was stirred at the same temperature for further 3 h. The reaction mixture was quenched with aqueous NH4Cl solution, and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 3 g) using EtOAc-hexane (3:17 v/v) as an eluent to give the oily triflate 12a (32 mg, 48%). IR (ATR)ν: 3320, 1709, 1358, 1120 cm-1; 1H-NMR (CDCl3)δ: 4.00 (3H, s), 4.09 (3H, s), 7.31-7.37 (1H, m), 7.52 (2H, br d, J=3.7 Hz), 8.10 (1H, d, J=7.7 Hz), 8.56 (1H, s), 8.58 (1H, br s), MS m/z: 403 (M+). HR-MS m/z: 403.0318 (Calcd for C16H12F3NO6S : 403.0337).

Mukonine (1a)
A suspension of triflate 11a (28 mg, 0.069 mmol) and 10%Pd-C (30 mg) in EtOH (2 mL) was stirred at rt for 6 h under hydrogen atmosphere. The reaction mixture was filtrated through Celite pad, and the Celite pad was washed EtOAc. The combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 3 g) using EtOAc-hexane (3:17 v/v) as an eluent to give the mukonine (1a) (13 mg, 73%). mp 197-198 ℃ (Et2O-hexane) (Lit.,5a mp 197-198 oC, Lit.,11a mp 195 oC and Lit.,11b mp 201 oC) ; IR (ATR)ν: 3316, 1693 cm-1; 1H-NMR (CDCl3)δ: 3.92 (3H, s), 4.07 (3H, s), 7.26 (1H, t, J=7.8 Hz), 7.45 (1H, t, J=7.8 Hz), 7.58 (1H, s), 7.63 (1H, d, J=7.8 Hz), 8.21 (1H, d, J=7.8 Hz), 8.47 (1H, s), 10.78 (1H, br s), MS m/z: 255 (M+). HR-MS m/z: 255.0876 (Calcd for C15H13NO3 : 255.0895).
Clausine E (1f)
A solution of 1-benzyloxycarbazole 10b (79 mg, 0.22 mmol), mCPBA (509 mg, 2.20 mmol), and KF (255 mg, 4.40 mmol) in CH2Cl2 (5 mL) was stirred at rt for 1 h. The reaction mixture was purified by column chromatography (silica gel 5 g) using EtOAc-hexane (1:19 v/v) as an eluent to give crude 2-hydroxycarbazole 11b. A solution of 2-hydroxycarbazole 11b in THF (3 mL) was added to a suspension of 60%NaH (18 mg, 0.44 mmol) in THF (3 mL) at -30 oC. After stirred at the same temperature for 0.5 h, the reaction mixture which was added Tf2NPh (79 mg, 0.22 mmol), was stirred at the same temperature for further 3 h. The reaction mixture was quenched with aqueous NH4Cl solution, and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 3 g) using EtOAc-hexane (1:9 v/v) as an eluent to give the crude triflate 12b. A suspension of the crude triflate 12b and 10%Pd-C (50 mg) in EtOH (2 mL) was stirred at rt for 6 h under hydrogen atmosphere. The reaction mixture was filtrated through Celite pad, and the Celite pad was washed with EtOAc. The combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 3 g) using EtOAc-hexane (3:7 v/v) as an eluent to give the clausine E (1f) (15 mg, 28%). mp 190-191 oC (Et2O-hexane) (Lit.,3a mp 218-220 oC and Lit.,11b mp 203 oC) ; IR (ATR)ν: 3347, 1655, 1631, 1601 cm-1; 1H-NMR (acetone-d6)δ: 3.88 (3H, s), 7.23 (1H, td, J=7.4, 1.1 Hz), 7.43 (1H, td, J=7.4, 1.1 Hz), 7.56 (1H, d, J=1.1 Hz), 7.61 (1H, dd, J=7.4, 1.1 Hz), 8.18 (1H, dd, J=7.4, 1.1 Hz), 8.38 (1H, d, J=1.1 Hz), 9.07 (1H, s), 10.64 (1H, br s), MS m/z: 241 (M+). HR-MS m/z: 241.0756 (Calcd for C14H11NO3 : 241.0739).

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