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A regioselective facile synthesis of furo[3,4-b]carbazolones: application to the total synthesis of mafaicheenamine E and claulansine D† Dipakranjan Mal* and Joyeeta Roy
Received 23rd March 2015, Accepted 28th April 2015
1-Hydroxycarbazole-2,3-dicarboxylates have been shown to undergo chemoselective reductive cyclization
DOI: 10.1039/c5ob00575b
the first total synthesis of claulansine D and mafaicheenamine E in 9 and 6 steps respectively. The other key steps of the syntheses are addition of an allylic indium reagent and CC double bond isomerization.
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to furo[3,4-b]carbazolones on reaction with LiAlH4. One of the furocarbazolones is utilized to accomplish
Introduction Carbazole alkaloids have occupied a central place in organic synthesis owing to their wide range of pharmacological and biological activities.1 The carbazole nucleus is present in many bioactive substances, some of which are marketed as drugs.1 The carbazole skeleton has also been explored as a building block of materials displaying optoelectronic properties because of their electron donating property. Polyvinylcarbazoles (PVK) have been extensively studied for their applications in photorefractive materials and xerography.2 Recently, carbazoles were investigated as scaffolds for organocatalysts.3 Consequently, there have been numerous reports on synthetic methods for construction of carbazole core. Nitrene insertion,4a electrocyclization,4b Diels–Alder reaction,4c–e benzannulation,4f– h photocyclization,4i and metal mediated reactions4j–o are typical strategies for the synthesis of this class of alkaloids. However, the regiochemical issue remains a key challenge in the synthesis of carbazole alkaloids despite the voluminous work for the carbazole core. Methods for the appropriate assembly of functional groups/substituents in the aromatic ring in a regiospecific manner are still limited.4 Furthermore, for the carbazole alkaloids with linearly fused lactone rings 1–7 (Fig. 1),5 there is no synthesis reported to date, barring a model study by Tilve et al. on furo[3,4-b]carbazolones.6 On the basis of our earlier studies in the field of carbazole synthesis,7 we reasoned that chemoselective reduction of a carbazole-2,3dicarboxylate would constitute a new synthetic approach for the fabrication of the linearly fused lactonic carbazole ring. Herein, we report the chemoselective reduction of 1-hydroxycarbazole-
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India. E-mail: [email protected]; Fax: +91 3222282252 † Electronic supplementary information (ESI) available: Copies of 1H, 13C NMR spectra for all the compounds. See DOI: 10.1039/c5ob00575b
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2,3-dicarboxylates to furocarbazolones as well as the first total synthesis of two natural products i.e. mafaicheenamine E (1) and claulansine D (2) employing addition of an allylic indium reagent and CC double bond isomerization as key steps.
Results and discussion The central theme of our plan is the assembly of the highly substituted carbazole core by anionic benzannulation (Scheme 1). For the synthesis of mafaicheenamine E (1), it was felt that furocarbazolone 9 would be a key precursor, which was thought to be obtainable from the tetrasubstituted carbazole 8. Chemoselective reduction of carbazole diesters As depicted in our retrosynthetic scheme, we decided to explore chemoselective reduction of 2,3-diester 8 for obtaining furocarbazolones 9. It is reported that a phenolic hydroxy group in phthalates is responsible for the preferential reduction of the adjacent ester function in the reduction with NaBH4 or DIBAL-H.8 This strategy has been utilized for the synthesis of naphthalene nuclei hericenone A,8b 6′-hydroxyjusticidin A,8c and aryl naphthalene lignans.8d,e In carbazole 8, both the esters are deactivated by the resonance effect of N and hydroxy groups. We anticipated that the directing effect of C1 oxygen co-ordinated metal hydride might be the predominating effect to result in selectivity. The carbazole diester 8 was prepared in 54% yield by annulation of MOM-protected furoindolone 10 with dimethyl maleate 11 using LDA.7 Under the conditions employed for the selective reduction of naphthalene diester i.e. NaBH4 in MeOH, or DIBAL (3 equiv.) in DCM, the carbazole diester 8 remained inert.8 However, with LAH (2 equiv.) in THF at room temperature, it produced furocarbazolone 9 in 64% yield after methylation of the crude product with K2CO3–CH3I. Both HSQC and HMBC experiments validated the structure of
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Fig. 1
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Structures of linear lactonic carbazoles.
Scheme 1
Retrosynthetic analysis of mafaicheenamine E (1).
furocarbazolone 9. The singlet at δ 8.36 corresponding to C4 showed correlation with the signal at δ 171.2 confirming the selective reduction of the C2 ester function. In order to establish the generality of the LAH reduction (13 to 16), we examined the reactivity of several other hydroxycarbazole-2,3-diesters (Table 1). When the similar reaction i.e. LAH reduction followed by exhaustive methylation was performed on carbazole 17, N-methylated furocarbazolone 19 was obtained in 50% yield. For further extension of this reduction strategy various furoindolones were prepared by following the usual sequence involving Japp–Klingemann reaction and Fischer indole synthesis.7 Keeping in mind the versatility of cross coupling reactions, 5-bromo and 5-chloro indole derivatives 20 and 21 were annulated with dimethyl maleate 11 to give 1-hydroxycarbazoles 22 (59% yield) and 23 (55% yield). Under the optimized conditions of LAH reduction, 1-hydroxycarbazoles 22 and 23 delivered expected furocarbazolones 24 and 25 in 65% and 58% yield respectively after methylation. During the reductions, Cl and Br substituents remained intact. Similarly, 5-carbomethoxyfuroindolone 26 underwent annulation with dimethyl maleate to give carbazole diester 27. Treatment of 27 with LAH followed by O-methylation gave furocarbazolone 28 in 55% yield. Of the three ester functions in 28, the one ortho to the phenolic OH group was selectively reduced. The structures of all furocarbazolones 24, 25 and 28
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correlate well with the chemical shift of the OMe proton at δ 4.10–4.13. The singlet due to the C4 proton appears at δ 8.36. To exemplify naphthalene diester, naphthoate 29,9 prepared from phthalide (30), was reduced with LAH under similar conditions. The reaction afforded 31, after methylation with K2CO3–CH3I. The NMR data of compound 31 were in conformity with literature values.10 Total synthesis of mafaicheenamine E (1) and claulansine D (2) For the elaboration of furocarbazolone 9 to the target molecule 1, chemoselective addition of an alkenyl Grignard reagent to carbazole 32 was planned. Furocarbazolone 9 was brominated with NBS in refluxing CCl4 to give 33 which was, without purification, hydrolyzed with dioxane–water to afford hydroxyfurocarbazolone 32 via concomitant deprotection of the MOM group. Unfortunately, furocarbazolone 32 resisted the planned reaction with 2-propenylmagnesium bromide in THF even under refluxing conditions as indicated by TLC. The use of excess Grignard reagent yielded a complex mixture of products. Next, we envisaged the reaction of methallylindium bromide with furocarbazolone 32. As expected, the reaction of 32 with methallylindium bromide generated in situ from methallyl bromide and indium metal furnished furocarbazole 34 in 92% yield.11 Gratifyingly, the isomerization of the methallyl group in 34 to the propenyl group could be effected
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Table 1
Entry no.
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Benzannulation of furoindolones with dimethyl maleate and LAH reduction of the resulting diestersa
Furoindolone/phthalide
Annulation producta (% yield)
Reduction productb (% yield)
1
2
3
4
5
6
Reagent and conditions: (a) dimethyl maleate 11, LDA, THF, −78 °C to rt, overnight; (b) (i) LAH (2 equiv.), THF, rt, 1 h; (ii) MeI (2 equiv.), K2CO3 (2 equiv.), acetone, 4–5 h. a
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Scheme 2 Total synthesis of mafaicheenamine E (1) and claulansine D (2). Reagents and conditions: (a) NBS, CCl4, AIBN, 85 °C, 2 h, 79%; (b) dioxane–water (2 : 1), reflux, 8 h, 75%; (c) methallyl bromide, In, DMF, 8 h, rt, 92%; (d) p-TSA, toluene, reflux, 16 h, 97%; (e) Boc2O, NEt3, ethyl acetate, rt, 3 h, 88%; (f ) OsO4, NMO, THF, water, rt, 9 h, 76%; (g) neat heating, 140 °C, 84%.
Scheme 3
Ring expansion with AlCl3. Reagents and conditions: (a) AlCl3, DCM, reflux, 1 h, 90%.
in 97% yield using p-toluenesulfonic acid in refluxing toluene leading to the completion of the total synthesis of the target alkaloid i.e. mafaicheenamine E (1) (Scheme 2).12 Attempted dihydroxylation of carbazole 1 with OsO4, NMO in THF : water did not afford claulansine D (2). Instead, it gave a complex mixture of products. Anticipating free NH group in furocarbazolone 1 was oxidised on treatment with NMO, it was protected as its Boc derivative with Boc-anhydride, triethylamine in ethyl acetate. The resulting furocarbazolone 35 was then subjected to the reaction with OsO4, NMO. It provided a diastereomeric mixture of 36. Neat heating of the sample 36 at 140 °C culminated in the total synthesis of (±) claulansine D (2). The diastereomeric mixture was purified by column chromatography to (±) furocarbazolone 2 and (±) nonnatural isomer 37 in a 2 : 1 ratio.
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In order to broaden the scope of the synthetic route, we considered an application of Mali’s rearrangement, i.e. phthalide to dihydroisocoumarin.13 When furocarbazolone 34 was treated with AlCl3 in dry DCM, chlorocarbazolone 38 was formed instead of the desired ring expanded product i.e. claulamine A (3). Further treatment of 38 with AlCl3 in dry DCM led to an intractable mixture of products (Scheme 3).
Conclusion We have shown that 1-hydroxycarbazole-2,3-dicarboxylates can be chemoselectively reduced to furo[3,4-b]carbazolones. Such a strategy was utilized to accomplish a short yet first total synthesis of mafaicheenamine E (1) and claulansine D (2). The
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other crucial steps were chemoselective addition of the organoindium reagent and CC double bond isomerization. Efforts towards the synthesis of claulansine A (6) and B (7) are underway.
extracts were washed few times with water (6 × 20 mL) followed by brine and dried (Na2SO4). The organic phase was concentrated under reduced pressure to yield the crude product which was purified by column chromatography on silica gel (EtOAc–hexane).
Experimental
General procedure for annulations of furoindolones (8, 17, 22, 23, 27)
All solvents for chromatography were distilled prior to use. All reactions with moisture-sensitive reagents were performed under an inert atmosphere. Solvents DMF, DCM, THF, MeOH, etc. were dried prior to use, according to the standard protocols. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica gel plates (60-F254). The products were purified by column chromatography on silica gel. Column chromatography was performed over silica gel (60–120 mesh) using hexane and ethyl acetate as eluents. NMR spectra were recorded with a 600 MHz (1H: 600 MHz, 13C: 150 MHz), 400 MHz (1H: 400 MHz, 13C: 100 MHz) and 200 MHz (1H: 200 MHz, 13C: 50 MHz) spectrometer. Splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet. Infrared spectra were recorded with FT-IR spectrophotometers and reported in cm−1. Melting points are uncorrected. Highresolution mass spectra were recorded with a mass spectrometer in positive ion mode. The phrase “usual work-up” refers to washing of the organic phase with water (2 × 1/4 the volume of the organic phase) and brine (1 × 1/4 the volume of the organic phase) and drying (Na2SO4), filtration, and concentration under reduced pressure. All known compounds are characterized by comparison of the 1H and 13C NMR data with those reported in the literature. Commercially available starting materials are used without further purification.
In a flame dried flask flushed with nitrogen, LDA was prepared by the addition of N,N-diisopropylamine (6.31 mmol) to a solution of n-BuLi (1.6 M in hexane) (5.68 mmol) in THF at −40 °C under a nitrogen atmosphere and stirred for 30 min at the same temperature. A solution of the furoindolone (1.42 mmol) in THF (10 mL) was then added dropwise. The reaction mixture was stirred at −78 °C for another 30 min. A solution of the Michael acceptor (1.73 mmol) in THF (10 mL) was added dropwise and further stirred at −78 °C for 1 h. The resulting mixture was allowed to warm slowly to room temperature and stirred overnight. The dark reddish brown solution was quenched with saturated ammonium chloride solution (10 mL). The resulting mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (30 mL) and worked up in the usual manner. The crude product was purified by column chromatography on silica gel to obtain a pure product.
General procedure for preparation of MOM-protected furoindolones (10, 20, 21, 26) To a stirred solution of substituted aniline (0.24 mol) in 5 N hydrochloric acid (125 mL) was added sodium nitrite (0.30 mol) in water (480 mL) at 0–5 °C. The diazonium salt solution was then slowly added to a solution of α-aceto-γ-butyrolactone (0.24 mol) in a 1 : 1 mixture of pyridine and water (250 mL) at 5 °C. After complete addition, the reaction mixture was stirred vigorously at rt for 1 h. Then it was filtered through a Buchner funnel and was dried under vacuum. The hydrazonolactone obtained was dissolved in 200 mL of acetic acid and 30 mL of trifluoroacetic acid and heated at reflux for 5 h. After completion of the reaction it was quenched using solid sodium bicarbonate and work-up was done in the usual manner. The solid obtained was recrystallized from a mixture of DMF and ethanol. Next, the furoindolone (9.28 mmol) was dissolved in dry DMF (10 mL), and NaH (14 mmol) was added to it at 0 °C and the solution was stirred for 20 min. CH3OCH2Cl (18.4 mmol) was then added to the solution at that temperature and stirring was continued at rt for 2–3 h. After the complete consumption of the starting material, the reaction mixture was extracted with EtOAc (60 mL) and the
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General procedure for LAH reduction and methylation (9, 19, 24, 25, 28, 31) The diester (0.58 mmol) was dissolved in THF (8 mL) at room temperature; lithium aluminium hydride (1.16 mmol) was added in parts. The reaction mixture was stirred at room temperature for another 1 h. On completion of the reaction, the contents were filtered through celite, concentrated under reduced pressure to obtain phthalide. The crude without further purification was dissolved in acetone (10 mL), and K2CO3 (2 equiv.) and MeI (2 equiv.) were added and stirring continued for 4–5 h. After completion of the reaction acetone was evaporated under reduced pressure and the usual work up was done using EtOAc and water. The crude was purified by column chromatography. 4-Methoxy-5-(methoxymethyl)-3,5-dihydro-1H-furo[3,4-b]carbazol-1-one (9). LAH reduction was done using the general procedure starting from compound 8 (500 mg, 1.45 mmol). Since the hydroxyl compound could not be purified totally, it was methylated using potassium carbonate and methyl iodide following the general procedure; yield 64% (275 mg, 0.92 mmol) over two steps; Rf = 0.4, in 1 : 4 ethyl acetate : hexane; mp 180–182 °C; IR (KBr, cm−1) νmax 2366, 1752, 1356, 1219, 1100, 773; 1H NMR (CDCl3, 400 MHz): δ 8.36 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.65–7.59 (m, 2H), 7.41 (t, J = 7.8 Hz, 1H), 6.02 (s, 2H), 5.58 (s, 2H), 4.13 (s, 3H), 3.37 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 171.2, 142.3, 140.2, 135.3, 131.9, 128.2, 127.6 (CH), 123.2, 121.4 (CH), 120.8 (CH), 119.1, 113.2 (CH), 110.4 (CH), 75.8 (CH2), 68.1 (CH2), 59.9 (CH3), 56.2 (CH3); HRMS (TOF MS ES+) m/z calcd for C17H16NO4 [M + H]+: 298.1079, found 298.1097.
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4-Methoxy-5-methyl-3,5-dihydro-1H-furo[3,4-b]carbazol-1-one (19). Dimethyl 1-hydroxy-9H-carbazole-2,3-dicarboxylate (17) obtained from the annulation of Boc-protected furoindolone (500 mg, 1.8 mmol) and dimethyl maleate (0.25 mL, 1.95 mmol) was subjected to sequential LAH reduction and methylation as shown in the general procedure. A solid (162 mg, 0.61 mmol) was obtained in 34% yield over two steps. Rf = 0.3, in 1 : 4 ethyl acetate : hexane; mp 184–186 °C; IR (KBr, cm−1) νmax 1751, 1584, 1460, 1341, 1219, 1102, 772; 1H NMR (CDCl3, 600 MHz): δ 8.30 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 5.46 (s, 2H), 4.14 (s, 3H), 4.03 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 171.3, 142.4, 139.5, 136.0, 131.9, 127.3, 127.1 (CH), 122.5, 120.5 (CH), 120.3 (CH), 117.5, 113.3 (CH), 109.1 (CH), 67.7 (CH2), 60.5 (CH3), 31.6 (CH3). HRMS (TOF MS ES+) m/z calcd for C16H14NO3 [M + H]+: 268.0974, found 268.0976. 7-Bromo-1,4-dihydro-4-methoxymethyl-3H-furo[3,4-b]indol3-one (20). This was prepared according to the general route as described for the preparation of MOM-protected furoindolones, starting from 4-bromoaniline. In the Japp–Klingemann step, 4-bromoaniline (27 mL, 0.24 mol), sodium nitrite (20 g, 0.3 mol) and α-aceto-γ-butyrolactone (31 g, 0.24 mol) were required. The furoindolone 20 (35 g, 0.12 mol) was obtained in 55% yield over three steps. Rf = 0.35, in 1 : 4 ethyl acetate : hexane; mp 158–160 °C; IR (KBr, cm−1) νmax 2398, 1748, 1340, 772; 1H NMR (CDCl3, 600 MHz): δ 7.80 (s, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 5.67 (s, 2H), 5.36 (s, 2H), 3.33 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 163.0, 142.4, 134.3, 130.0, 129.7 (CH), 123.7 (CH), 122.2, 115.3, 114.1 (CH), 74.5 (CH2), 66.8 (CH2), 56.3 (CH3); HRMS (TOF MS ES+) m/z calcd for C12H11NO3Br [M + H]+: 295.9922, found 295.9930. 7-Chloro-1,4-dihydro-4-methoxymethyl-3H-furo[3,4-b]indol3-one (21). This was prepared according to the general route as described for the preparation of MOM-protected furoindolones, starting from 4-chloroaniline. In the Japp–Klingemann step, 4-chloroaniline (21 mL, 0.24 mol), sodium nitrite (20 g, 0.3 mol) and α-aceto-γ-butyrolactone (31 g, 0.24 mol) were required. The furoindolone 21 (25 g, 0.10 mol) was obtained in 45% yield over three steps. Rf = 0.35, in 1 : 3 ethyl acetate : hexane; mp 160–162 °C; IR (KBr, cm−1) νmax 2363, 1734, 1339, 1219, 1062, 982, 772; 1H NMR (CDCl3, 600 MHz): δ 7.64 (s, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 10.2 Hz, 1H), 5.67 (s, 2H), 5.37 (s, 2H), 3.32 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 163.2, 142.3, 134.6, 130.3, 128.1, 127.4 (CH), 121.8, 120.7 (CH), 113.9 (CH), 74.5 (CH2), 67.0 (CH2), 56.5 (CH3); HRMS (TOF MS ES+) m/z calcd for C12H11NO3Cl [M + H]+: 252.0427, found 252.0420. Dimethyl 6-bromo-1-hydroxy-9-methoxymethyl-9H-carbazole-2,3-dicarboxylate (22). This was prepared from 20 (350 mg, 1.2 mmol) and dimethyl maleate 11 (0.2 mL, 1.54 mmol) in 59% yield (295 mg, 0.69 mmol) according to the general route for annulation. Rf = 0.45, in 1 : 4 ethyl acetate : hexane; mp 120–124 °C; IR (KBr, cm−1) νmax 2364, 1752, 1740, 1219, 1072, 985, 772; 1H NMR (CDCl3, 600 MHz): δ 11.45 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 6.00 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H),
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3.28 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.9, 169.8, 149.4, 140.9, 130.7 (CH), 129.5, 126.5, 126.1, 124.6, 123.7 (CH), 114.2, 112.9 (CH), 112.4 (CH), 107.7, 75.8 (CH2), 55.9 (CH3), 53.1 (CH3), 52.8 (CH3); HRMS (TOF MS ES+) m/z calcd for C18H17NO6Br [M + H]+: 422.0239, found 422.0230. Dimethyl 6-chloro-1-hydroxy-9-methoxymethyl-9H-carbazole2,3-dicarboxylate (23). This was prepared from 21 (300 mg, 1.19 mmol) and dimethyl maleate 11 (0.16 mL, 1.32 mmol) in 55% yield (250 mg, 0.65 mmol) according to the general route for annulation. Rf = 0.40 in 1 : 4 ethyl acetate : hexane; mp 110–115 °C; IR (KBr, cm−1) νmax 2870, 1769, 1732, 1680, 1421, 1132, 796; 1H NMR (CDCl3, 600 MHz): δ 11.53 (s, 1H), 8.02 (s, 1H), 7.76 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 7.2 Hz, 1.8, 1H), 6.11 (s, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 3.34 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.7, 169.9, 149.9, 140.7, 129.7, 128.3 (CH), 127.0, 126.7, 126.4, 124.2, 120.7 (CH), 113.0 (CH), 112.2 (CH), 107.8, 76.2 (CH2), 56.0 (CH3), 53.2 (CH3), 52.8 (CH3). 6-Bromo-10-methoxy-9-methoxymethyl-1,9-dihydro-2-oxa9-aza-cyclopenta[b]fluoren-3-one (24). It was prepared from compound 22 (200 mg, 0.48 mmol) according to the general route for LAH reduction as mentioned above. The crude was methylated using K2CO3 and MeI in acetone and was purified by column chromatography forming solid 24 in 65% (116 mg, 0.31 mmol) yield over two steps; Rf = 0.3, in 1 : 5 ethyl acetate : hexane; mp 201–205 °C; IR (KBr, cm−1) νmax 1762, 1588, 1455, 1219, 772; 1H NMR (CDCl3, 600 MHz): δ 8.30 (s, 1H), 8.21 (s, 1H), 7.63 (d, J = 10.2 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 5.97 (s, 2H), 5.58 (s, 2H), 4.10 (s, 3H), 3.33 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.9, 141.0, 140.5, 135.6, 132.4, 130.5 (CH), 127.1, 125.1, 123.7 (CH), 119.7, 114.4, 113.6 (CH), 112.1 (CH), 76.0 (CH2), 68.1 (CH2), 60.0 (CH3), 56.3 (CH3); HRMS (TOF MS ES+) m/z calcd for C17H15NO4Br [M + H]+: 376.0184, found 376.0180. 6-Chloro-10-methoxy-9-methoxymethyl-1,9-dihydro-2-oxa9-aza-cyclopenta[b]fluoren-3-one (25). This was prepared from compound 23 (200 mg, 0.53 mmol) according to the general route for LAH reduction as mentioned above. The crude was methylated using K2CO3 and MeI in acetone and was purified by column chromatography forming solid 25 in 58% (102 mg, 0.31 mmol) yield over two steps. Rf = 0.40, in 1 : 3 ethyl acetate : hexane; mp 192–195 °C; IR (KBr, cm−1) 1758, 1580, 1145, 772; 1H NMR (CDCl3, 600 MHz): δ 8.31 (s, 1H), 8.05 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 5.97 (s, 2H), 5.58 (s, 2H), 4.10 (s, 3H), 3.31 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.9, 140.7, 140.5, 135.8, 132.3, 127.8 (CH), 127.3, 127.2, 124.5, 120.7 (CH), 119.6, 113.6 (CH), 111.6 (CH), 76.1 (CH2), 68.1 (CH2), 60.0 (CH3), 56.3 (CH3); HRMS (TOF MS ES+) m/z calcd for C17H15NO4Cl [M + H]+: 332.0690, found 332.0679. Methyl 8-methoxymethyl-1-oxo-3,8-dihydro-1H-2-oxa-8-azacyclopenta[a]indene-5-carboxylate (26). This was prepared according to the general route as mentioned for the preparation of MOM-protected furoindolones, starting from methyl 4-amino-benzoate. In the Japp–Klingemann step, methyl 4-amino-benzoate (36 g, 0.24 mol), sodium nitrite (20 g,
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0.3 mol) and α-aceto-γ-butyrolactone (31 g, 0.24 mol) were required. The furoindolone 26 (30 g, 0.11 mol) was obtained in 47% yield over three steps. Rf = 0.40, in 1 : 2 ethyl acetate : hexane; mp 170–172 °C; IR (KBr, cm−1) νmax 2369, 1755, 1696, 1269, 1219, 1071, 988; 1H NMR (CDCl3, 600 MHz): δ 8.43 (s, 1H), 8.14 (dd, J = 7.8 Hz, 1.2 Hz 1H), 7.64 (d, J = 9 Hz, 1H), 5.71 (s, 2H), 5.43 (s, 2H), 3.95 (s, 3H), 3.34 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 167.0, 163.1, 146.1, 136.6, 130.6, 127.6 (CH), 124.2 (CH), 124.1, 120.5, 112.4 (CH), 74.7 (CH2), 67.0 (CH2), 56.5 (CH3), 52.3 (CH3). HRMS (TOF MS ES+) m/z calcd for C14H14NO5 [M + H]+: 276.0872, found 276.0880. Trimethyl 1-methoxy-9-methoxymethyl-9H-carbazole-2,3,6tricarboxylate (27). This was prepared according to the general route for annulation as mentioned previously from compound 26 (300 mg, 1.09 mmol) and dimethyl maleate 11 (0.16 mL, 1.32 mmol) in 62% yield (270 mg, 0.67 mmol). Rf = 0.6 in 1 : 5 ethyl acetate : hexane; mp 116–118 °C; IR (KBr, cm−1) νmax1725, 1707, 1660, 1320, 1279, 1197, 995, 773; 1H NMR (CDCl3, 600 MHz): δ 8.76 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.11 (s, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.35 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.5, 169.5, 167.1, 149.5, 144.6, 129.7, 129.0 (CH), 127.4, 127.0, 123.5 (CH), 123.1, 122.6, 112.8 (CH), 110.4 (CH), 107.8, 75.8 (CH2), 55.9 (CH3), 53.0 (CH3), 52.6 (CH3), 52.1 (CH3). HRMS (TOF MS ES+) m/z calcd for C20H19NO8Na [M + H]+: 424.1008, found 424.0994. Methyl 10-methoxy-9-methoxymethyl-3-oxo-3,9-dihydro-1H2-oxa-9-aza-cyclopenta-6-[b]fluorenecarboxylate (28). It was prepared from compound 27 (200 mg, 0.49 mmol) according to the general route for LAH reduction as mentioned above. The crude was methylated using K2CO3 and MeI in acetone and was purified by column chromatography forming solid 28 in 55% (97 mg, 0.27 mmol) yield over two steps; Rf = 0.2, in 1 : 5 ethyl acetate : hexane; mp 202–204 °C; IR (KBr, cm−1) νmax 1752, 1732, 1460, 1102; 1H NMR (CDCl3, 600 MHz): δ 8.79 (s, 1H), 8.36 (s, 1H), 8.24 (d, J = 9 Hz, 1H), 7.61 (d, J = 9 Hz, 1H), 6.01 (CH2), 5.58 (CH2), 4.13 (s, 3H), 4.00 (s, 3H), 3.35 (s, 3H); 13 C NMR (CDCl3, 150 MHz): δ 170.6, 167.1, 144.8, 140.4, 135.6, 132.2, 128.9 (CH), 127.9, 123.0 (CH), 119.9, 113.2 (CH), 110.5 (CH), 75.9 (CH2), 67.9 (CH2), 59.8 (CH3), 56.2 (CH3), 52.1 (CH3). HRMS (TOF MS ES+) m/z calcd for C19H18NO6 [M + H]+: 356.1134, found 356.1135. 4-Methoxy-3H-naphtho[2,3-c]furan-1-one (31). This was prepared in 60% yield (183 mg, 0.85 mmol) following the same sequence of reactions involving annulation of phthalide 30 (300 mg, 0.45 mmol) and subsequent reduction with LAH. IR (KBr, cm−1) νmax 2928, 2851, 2340, 1758, 772; 1H NMR (CDCl3, 600 MHz): δ 8.30 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 5.67 (s, 2H), 4.15 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.9, 150.1, 134.8, 129.8 (CH), 129.6, 128.6 (CH), 127.6 (CH), 124.4, 123.5, 122.8 (CH), 121.2 (CH), 68.7 (CH3), 59.6 (CH2). 1-Hydroxy-10-methoxy-1,9-dihydro-2-oxa-9-aza-cyclopenta[b]fluoren-3-one (32). Compound 9 (150 mg, 0.5 mmol) obtained was brominated using NBS (98 mg, 0.55 mmol), CCl4 (10 mL) under refluxing conditions. After completion of the reaction,
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the reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The monobrominated product without further purification was refluxed in dioxane : water (2 : 1). The dioxane was evaporated, and work up was done in the usual manner. The crude product was purified by column chromatography to furnish phthalaldehydic acid 32. Rf = 0.2 in 3 : 1 ethyl acetate : hexane; 1H NMR (DMSO-d6, 600 MHz): δ 11.89 (s, 1H), 8.34 (s, 1H), 8.27 (d, J = 6.6 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.22 (s, 3H);13C NMR (DMSO-d6, 150 MHz): δ 169.5, 141.2, 140.8, 136.2, 129.6, 127.3 (CH), 126.5, 122.8, 121.6 (CH), 120.2 (CH), 118.9, 112.5 (CH), 112.3 (CH), 96.9 (CH), 59.9 (CH3); HRMS (TOF MS ES+) m/z calcd for C15H12NO4 [M + H]+: 270.0766, found 270.0776. 10-Methoxy-1-(2-methallyl)-1,9-dihydro-2-oxa-9-aza-cyclopenta-[b]fluoren-3-one (34). To a suspension of indium metal (480 mg, 4.2 mmol) and sodium iodide (960 mg, 6.6 mmol) in dry DMF (15 mL), methallyl bromide (0.48 mL, 5.28 mmol) was added dropwise. The stirring was continued at room temperature until the metal dissolved completely to form a clear solution. To the allyl indium reagent generated as above, a solution of phthalaldehydic acid 32 (480 mg, 1.68 mmol) in DMF (9 ml) was added. The resulting reaction mixture was stirred for 8 h at room temperature. Then it was extracted with EtOAc (3 × 150 mL) and the extracts were worked up in the usual manner to give the crude product which was purified by column chromatography to furnish compound 34 in 92% yield (500 mg, 1.63 mmol). 1H NMR (CDCl3, 400 MHz): δ 8.55 (brs, 1H), 8.35 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.51–7.50 (m, 2H), 7.34–7.30 (m, 1H), 5.83 (dd, J = 6.4 Hz, J = 2.4 Hz, 1H), 4.90 (s, 2H), 4.09 (s, 3H), 3.03 (d, J = 14.8 Hz, 1H), 2.46–2.40 (m, 1H), 1.82 (s, 3H); 13C NMR (CDCl3, 50 MHz): δ 171.1, 140.7, 140.4, 138.9, 136.6, 135.5, 127.6 (CH), 127.5, 123.5, 121.1 (CH), 120.9 (CH), 119.08, 114.4 (CH2), 114.0 (CH), 111.5 (CH), 78.7 (CH), 60.5 (CH3), 42.1 (CH2), 23.3 (CH3); HRMS (TOF MS ES+) m/z calcd for C19H18NO3 [M + H]+: 308.1287, found 308.1300. Mafaicheenamine E (1). Compound 34 (300 mg, 0.97 mmol) was dissolved in dry toluene; p-toluene sulphonic acid (166 mg, 0.96 mmol) was added to it and heated overnight. No change could be detected on TLC analysis. After 16 h, the reaction mixture was concentrated in a vacuum, quenched with aqueous NaHCO3 and usual work-up was done with ethyl acetate. The crude product was purified by column chromatography to furnish compound 1 in 97% yield (290 mg, 0.94 mmol). 1H NMR (acetone-d6, 600 MHz): δ 10.94 (brs, 1H), 8.37 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 9.6 Hz, 1H), 5.22 (d, J = 9.6 Hz, 1H), 4.07 (s, 3H), 2.07 (s, 3H), 1.88 (s, 3H); 13C NMR (acetone-d6, 150 MHz) δ 170.0, 141.1, 139.7, 139.4, 136.8, 135.6, 127.1, 126.9, 123.1, 121.5, 121.5, 120.8, 120.0, 118.5, 112.9, 111.6, 75.9, 60.0, 25.0, 17.7. tert-Butyl 10-methoxy-1-(2-methyl-propenyl)-3-oxo-1,3-dihydro2-oxa-9-aza-cyclopenta[b]fluorene-9-carboxylate (35). Compound 1 (150 mg, 0.48 mmol) was dissolved in ethyl acetate (10 mL), and Boc-anhydride (1.5 equiv.), triethyl amine (1.5
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equiv.) and a pinch of DMAP were added. The reaction contents were stirred at rt for 3 h. After completion of the reaction, usual work up was done and the crude was purified by column chromatography to obtain a solid compound 35 in 88% yield (175 mg, 0.43 mmol). Rf = 0.6 in 1 : 6 ethyl acetate : hexane; 1H NMR (CDCl3, 600 MHz) δ 8.26 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 6.36 (d, J = 9.0 Hz, 1H), 5.16–5.14 (m, 1H), 3.82 (s, 3H), 2.02 (s, 3H), 1.85 (s, 3H), 1.74 (s, 9H); 13C NMR (CDCl3, 50 MHz): δ 170.6, 149.9, 143.3, 141.0, 140.7, 140.0, 134.7, 131.5, 128.4 (CH), 125.2, 123.7 (CH), 123.1, 120.5 (CH), 120.2 (CH), 115.1 (CH), 112.2 (CH), 84.9 (CH), 59.9 (CH), 28.1 (CH3), 26.0 (CH3), 18.9 (CH3). HRMS (TOF MS ES+) m/z calcd for C25H26NO5 [M + H]+: 408.1811, found 408.1819. Claulansine D (2). To a solution of 35 (100 mg, 0.24 mmol) in THF : water (3 : 2), OsO4 (0.05 M) (0.6 mL) and NMO (60 mg, 0.2 mmol) was added at rt. The reaction was stirred for another 8 h. After completion of the reaction as monitored by TLC analysis, the reaction was quenched with sodium sulphite and usual work up was done. Two diastereomers obtained were not separated by column chromatography. The mixture of diastereomers was obtained in 76% yield (82 mg, 0.18 mmol). The mixture was then neat heated to 140 °C till completion of the reaction, the product was then purified by column chromatography to give compound 2 in 55% yield (35 mg, 0.09 mmol) and the other diastereomer in 29% yield (18 mg, 0.05 mmol) in 2 : 1; Rf = 0.1, in 2 : 1 ethyl acetate : hexane; 1H NMR (DMSO-d6, 600 MHz): δ 11.80 (brs, 1H), 8.37 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.16 (s, 1H), 4.80 (d, J = 8.0 Hz, 1H), 4.79 (s, 1H), 4.06 (s, 3H), 3.89 (d, J = 7.5 Hz, 1H), 1.26 (s, 3H), 1.22 (s, 3H); 13C NMR (DMSO-d6, 150 MHz): δ 170.8, 140.8, 138.6, 136.3, 135.1, 126.7, 126.3, 122.6, 121.0, 119.6, 118.8, 112.7, 111.7, 77.6, 75.9, 71.6, 60.3, 28.5, 24.7. Non-natural Claulansine D (37). 1H NMR (DMSO-d6, 600 MHz): δ 11.76 (s, 1H), 8.37 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 5.97 (d, J = 5.4 Hz, 1H), 5.29 (d, J = 6.0 Hz, 1H), 4.30 (s, 1H), 4.11 (s, 3H), 3.6 (t, J = 4.8 Hz, 1H), 1.19 (s, 3H), 1.05 (s, 3H); 13C NMR (DMSO-d6, 150 MHz): δ 170.8, 141.2, 140.5, 136.7, 133.6, 127.2 (CH), 126.4, 123.0, 121.4 (CH), 120.1 (CH), 118.3, 113.1 (CH), 112.1 (CH), 81.6 (CH), 79.6 (CH), 72.2, 60.3 (CH3), 27.5 (CH3), 26.8 (CH3), HRMS (TOF MS ES+) m/z calcd for C19H19NO5Na [M + H]+: 364.1161, found 344.1145. 1-(2-Chloro-2-methyl-propyl)-10-methoxy-1,9-dihydro-2-oxa9-aza-cyclopenta[b]fluoren-3-one (38). Compound 34 (75 mg, 0.24 mmol) was dissolved in DCM (10 mL), and AlCl3 (10 mg, 0.06 mmol) was added and the mixture was refluxed for 8 h. After completion of the reaction, the reaction was worked up in the usual manner using DCM and water. The solid obtained was purified by column chromatography. Rf = 0.3 in 1 : 4 EtOAc : hexane; mp 186–190 °C; IR (KBr, cm−1) νmax 1756, 1370, 1240, 1019, 775; 1H NMR (CDCl3, 600 MHz) δ 8.62 (s, 1H), 8.38 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.54–7.53 (m, 2H), 7.34 (t, J = 7.8 Hz, 1H), 6.12 (d, J = 9 Hz, 1H), 4.14 (s, 3H), 2.95 (d, J = 9 Hz, 1H), 1.96–1.90 (m, 1H), 1.77 (s, 3H), 1.61 (s,
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3H);13C NMR (CDCl3, 50 MHz): δ 171.0, 140.4, 139.0, 136.9, 135.4, 127.6 (CH), 123.5, 121.2 (CH), 121.0 (CH), 118.7, 114.1 (CH), 111.5 (CH), 77.2 (CH), 70.1, 61.2 (CH3), 50.1 (CH2), 34.9 (CH3), 31.9 (CH3); HRMS (TOF MS ES+) m/z calcd for C19H19ClNO3 [M + H]+: 344.1053, found 344.1060.
Acknowledgements The authors are grateful to the Council of Scientific and Industrial Research (CSIR) and the Department of Science and Technology (DST) for financial support. JR is thankful to CSIR for a research fellowship. Financial support for Improvement of Science & Technology Infrastructure in Higher Educational Institutions by DST is also acknowledged.
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A regioselective facile synthesis of furo[3,4-b]carbazolones: application to the total synthesis of mafaicheenamine E and claulansine D† Dipakranjan Mal* and Joyeeta Roy
Received 23rd March 2015, Accepted 28th April 2015
1-Hydroxycarbazole-2,3-dicarboxylates have been shown to undergo chemoselective reductive cyclization
DOI: 10.1039/c5ob00575b
the first total synthesis of claulansine D and mafaicheenamine E in 9 and 6 steps respectively. The other key steps of the syntheses are addition of an allylic indium reagent and CC double bond isomerization.
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to furo[3,4-b]carbazolones on reaction with LiAlH4. One of the furocarbazolones is utilized to accomplish
Introduction Carbazole alkaloids have occupied a central place in organic synthesis owing to their wide range of pharmacological and biological activities.1 The carbazole nucleus is present in many bioactive substances, some of which are marketed as drugs.1 The carbazole skeleton has also been explored as a building block of materials displaying optoelectronic properties because of their electron donating property. Polyvinylcarbazoles (PVK) have been extensively studied for their applications in photorefractive materials and xerography.2 Recently, carbazoles were investigated as scaffolds for organocatalysts.3 Consequently, there have been numerous reports on synthetic methods for construction of carbazole core. Nitrene insertion,4a electrocyclization,4b Diels–Alder reaction,4c–e benzannulation,4f– h photocyclization,4i and metal mediated reactions4j–o are typical strategies for the synthesis of this class of alkaloids. However, the regiochemical issue remains a key challenge in the synthesis of carbazole alkaloids despite the voluminous work for the carbazole core. Methods for the appropriate assembly of functional groups/substituents in the aromatic ring in a regiospecific manner are still limited.4 Furthermore, for the carbazole alkaloids with linearly fused lactone rings 1–7 (Fig. 1),5 there is no synthesis reported to date, barring a model study by Tilve et al. on furo[3,4-b]carbazolones.6 On the basis of our earlier studies in the field of carbazole synthesis,7 we reasoned that chemoselective reduction of a carbazole-2,3dicarboxylate would constitute a new synthetic approach for the fabrication of the linearly fused lactonic carbazole ring. Herein, we report the chemoselective reduction of 1-hydroxycarbazole-
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India. E-mail: [email protected]; Fax: +91 3222282252 † Electronic supplementary information (ESI) available: Copies of 1H, 13C NMR spectra for all the compounds. See DOI: 10.1039/c5ob00575b
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2,3-dicarboxylates to furocarbazolones as well as the first total synthesis of two natural products i.e. mafaicheenamine E (1) and claulansine D (2) employing addition of an allylic indium reagent and CC double bond isomerization as key steps.
Results and discussion The central theme of our plan is the assembly of the highly substituted carbazole core by anionic benzannulation (Scheme 1). For the synthesis of mafaicheenamine E (1), it was felt that furocarbazolone 9 would be a key precursor, which was thought to be obtainable from the tetrasubstituted carbazole 8. Chemoselective reduction of carbazole diesters As depicted in our retrosynthetic scheme, we decided to explore chemoselective reduction of 2,3-diester 8 for obtaining furocarbazolones 9. It is reported that a phenolic hydroxy group in phthalates is responsible for the preferential reduction of the adjacent ester function in the reduction with NaBH4 or DIBAL-H.8 This strategy has been utilized for the synthesis of naphthalene nuclei hericenone A,8b 6′-hydroxyjusticidin A,8c and aryl naphthalene lignans.8d,e In carbazole 8, both the esters are deactivated by the resonance effect of N and hydroxy groups. We anticipated that the directing effect of C1 oxygen co-ordinated metal hydride might be the predominating effect to result in selectivity. The carbazole diester 8 was prepared in 54% yield by annulation of MOM-protected furoindolone 10 with dimethyl maleate 11 using LDA.7 Under the conditions employed for the selective reduction of naphthalene diester i.e. NaBH4 in MeOH, or DIBAL (3 equiv.) in DCM, the carbazole diester 8 remained inert.8 However, with LAH (2 equiv.) in THF at room temperature, it produced furocarbazolone 9 in 64% yield after methylation of the crude product with K2CO3–CH3I. Both HSQC and HMBC experiments validated the structure of
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Fig. 1
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Structures of linear lactonic carbazoles.
Scheme 1
Retrosynthetic analysis of mafaicheenamine E (1).
furocarbazolone 9. The singlet at δ 8.36 corresponding to C4 showed correlation with the signal at δ 171.2 confirming the selective reduction of the C2 ester function. In order to establish the generality of the LAH reduction (13 to 16), we examined the reactivity of several other hydroxycarbazole-2,3-diesters (Table 1). When the similar reaction i.e. LAH reduction followed by exhaustive methylation was performed on carbazole 17, N-methylated furocarbazolone 19 was obtained in 50% yield. For further extension of this reduction strategy various furoindolones were prepared by following the usual sequence involving Japp–Klingemann reaction and Fischer indole synthesis.7 Keeping in mind the versatility of cross coupling reactions, 5-bromo and 5-chloro indole derivatives 20 and 21 were annulated with dimethyl maleate 11 to give 1-hydroxycarbazoles 22 (59% yield) and 23 (55% yield). Under the optimized conditions of LAH reduction, 1-hydroxycarbazoles 22 and 23 delivered expected furocarbazolones 24 and 25 in 65% and 58% yield respectively after methylation. During the reductions, Cl and Br substituents remained intact. Similarly, 5-carbomethoxyfuroindolone 26 underwent annulation with dimethyl maleate to give carbazole diester 27. Treatment of 27 with LAH followed by O-methylation gave furocarbazolone 28 in 55% yield. Of the three ester functions in 28, the one ortho to the phenolic OH group was selectively reduced. The structures of all furocarbazolones 24, 25 and 28
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correlate well with the chemical shift of the OMe proton at δ 4.10–4.13. The singlet due to the C4 proton appears at δ 8.36. To exemplify naphthalene diester, naphthoate 29,9 prepared from phthalide (30), was reduced with LAH under similar conditions. The reaction afforded 31, after methylation with K2CO3–CH3I. The NMR data of compound 31 were in conformity with literature values.10 Total synthesis of mafaicheenamine E (1) and claulansine D (2) For the elaboration of furocarbazolone 9 to the target molecule 1, chemoselective addition of an alkenyl Grignard reagent to carbazole 32 was planned. Furocarbazolone 9 was brominated with NBS in refluxing CCl4 to give 33 which was, without purification, hydrolyzed with dioxane–water to afford hydroxyfurocarbazolone 32 via concomitant deprotection of the MOM group. Unfortunately, furocarbazolone 32 resisted the planned reaction with 2-propenylmagnesium bromide in THF even under refluxing conditions as indicated by TLC. The use of excess Grignard reagent yielded a complex mixture of products. Next, we envisaged the reaction of methallylindium bromide with furocarbazolone 32. As expected, the reaction of 32 with methallylindium bromide generated in situ from methallyl bromide and indium metal furnished furocarbazole 34 in 92% yield.11 Gratifyingly, the isomerization of the methallyl group in 34 to the propenyl group could be effected
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Table 1
Entry no.
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Benzannulation of furoindolones with dimethyl maleate and LAH reduction of the resulting diestersa
Furoindolone/phthalide
Annulation producta (% yield)
Reduction productb (% yield)
1
2
3
4
5
6
Reagent and conditions: (a) dimethyl maleate 11, LDA, THF, −78 °C to rt, overnight; (b) (i) LAH (2 equiv.), THF, rt, 1 h; (ii) MeI (2 equiv.), K2CO3 (2 equiv.), acetone, 4–5 h. a
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Scheme 2 Total synthesis of mafaicheenamine E (1) and claulansine D (2). Reagents and conditions: (a) NBS, CCl4, AIBN, 85 °C, 2 h, 79%; (b) dioxane–water (2 : 1), reflux, 8 h, 75%; (c) methallyl bromide, In, DMF, 8 h, rt, 92%; (d) p-TSA, toluene, reflux, 16 h, 97%; (e) Boc2O, NEt3, ethyl acetate, rt, 3 h, 88%; (f ) OsO4, NMO, THF, water, rt, 9 h, 76%; (g) neat heating, 140 °C, 84%.
Scheme 3
Ring expansion with AlCl3. Reagents and conditions: (a) AlCl3, DCM, reflux, 1 h, 90%.
in 97% yield using p-toluenesulfonic acid in refluxing toluene leading to the completion of the total synthesis of the target alkaloid i.e. mafaicheenamine E (1) (Scheme 2).12 Attempted dihydroxylation of carbazole 1 with OsO4, NMO in THF : water did not afford claulansine D (2). Instead, it gave a complex mixture of products. Anticipating free NH group in furocarbazolone 1 was oxidised on treatment with NMO, it was protected as its Boc derivative with Boc-anhydride, triethylamine in ethyl acetate. The resulting furocarbazolone 35 was then subjected to the reaction with OsO4, NMO. It provided a diastereomeric mixture of 36. Neat heating of the sample 36 at 140 °C culminated in the total synthesis of (±) claulansine D (2). The diastereomeric mixture was purified by column chromatography to (±) furocarbazolone 2 and (±) nonnatural isomer 37 in a 2 : 1 ratio.
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In order to broaden the scope of the synthetic route, we considered an application of Mali’s rearrangement, i.e. phthalide to dihydroisocoumarin.13 When furocarbazolone 34 was treated with AlCl3 in dry DCM, chlorocarbazolone 38 was formed instead of the desired ring expanded product i.e. claulamine A (3). Further treatment of 38 with AlCl3 in dry DCM led to an intractable mixture of products (Scheme 3).
Conclusion We have shown that 1-hydroxycarbazole-2,3-dicarboxylates can be chemoselectively reduced to furo[3,4-b]carbazolones. Such a strategy was utilized to accomplish a short yet first total synthesis of mafaicheenamine E (1) and claulansine D (2). The
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other crucial steps were chemoselective addition of the organoindium reagent and CC double bond isomerization. Efforts towards the synthesis of claulansine A (6) and B (7) are underway.
extracts were washed few times with water (6 × 20 mL) followed by brine and dried (Na2SO4). The organic phase was concentrated under reduced pressure to yield the crude product which was purified by column chromatography on silica gel (EtOAc–hexane).
Experimental
General procedure for annulations of furoindolones (8, 17, 22, 23, 27)
All solvents for chromatography were distilled prior to use. All reactions with moisture-sensitive reagents were performed under an inert atmosphere. Solvents DMF, DCM, THF, MeOH, etc. were dried prior to use, according to the standard protocols. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica gel plates (60-F254). The products were purified by column chromatography on silica gel. Column chromatography was performed over silica gel (60–120 mesh) using hexane and ethyl acetate as eluents. NMR spectra were recorded with a 600 MHz (1H: 600 MHz, 13C: 150 MHz), 400 MHz (1H: 400 MHz, 13C: 100 MHz) and 200 MHz (1H: 200 MHz, 13C: 50 MHz) spectrometer. Splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet. Infrared spectra were recorded with FT-IR spectrophotometers and reported in cm−1. Melting points are uncorrected. Highresolution mass spectra were recorded with a mass spectrometer in positive ion mode. The phrase “usual work-up” refers to washing of the organic phase with water (2 × 1/4 the volume of the organic phase) and brine (1 × 1/4 the volume of the organic phase) and drying (Na2SO4), filtration, and concentration under reduced pressure. All known compounds are characterized by comparison of the 1H and 13C NMR data with those reported in the literature. Commercially available starting materials are used without further purification.
In a flame dried flask flushed with nitrogen, LDA was prepared by the addition of N,N-diisopropylamine (6.31 mmol) to a solution of n-BuLi (1.6 M in hexane) (5.68 mmol) in THF at −40 °C under a nitrogen atmosphere and stirred for 30 min at the same temperature. A solution of the furoindolone (1.42 mmol) in THF (10 mL) was then added dropwise. The reaction mixture was stirred at −78 °C for another 30 min. A solution of the Michael acceptor (1.73 mmol) in THF (10 mL) was added dropwise and further stirred at −78 °C for 1 h. The resulting mixture was allowed to warm slowly to room temperature and stirred overnight. The dark reddish brown solution was quenched with saturated ammonium chloride solution (10 mL). The resulting mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (30 mL) and worked up in the usual manner. The crude product was purified by column chromatography on silica gel to obtain a pure product.
General procedure for preparation of MOM-protected furoindolones (10, 20, 21, 26) To a stirred solution of substituted aniline (0.24 mol) in 5 N hydrochloric acid (125 mL) was added sodium nitrite (0.30 mol) in water (480 mL) at 0–5 °C. The diazonium salt solution was then slowly added to a solution of α-aceto-γ-butyrolactone (0.24 mol) in a 1 : 1 mixture of pyridine and water (250 mL) at 5 °C. After complete addition, the reaction mixture was stirred vigorously at rt for 1 h. Then it was filtered through a Buchner funnel and was dried under vacuum. The hydrazonolactone obtained was dissolved in 200 mL of acetic acid and 30 mL of trifluoroacetic acid and heated at reflux for 5 h. After completion of the reaction it was quenched using solid sodium bicarbonate and work-up was done in the usual manner. The solid obtained was recrystallized from a mixture of DMF and ethanol. Next, the furoindolone (9.28 mmol) was dissolved in dry DMF (10 mL), and NaH (14 mmol) was added to it at 0 °C and the solution was stirred for 20 min. CH3OCH2Cl (18.4 mmol) was then added to the solution at that temperature and stirring was continued at rt for 2–3 h. After the complete consumption of the starting material, the reaction mixture was extracted with EtOAc (60 mL) and the
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General procedure for LAH reduction and methylation (9, 19, 24, 25, 28, 31) The diester (0.58 mmol) was dissolved in THF (8 mL) at room temperature; lithium aluminium hydride (1.16 mmol) was added in parts. The reaction mixture was stirred at room temperature for another 1 h. On completion of the reaction, the contents were filtered through celite, concentrated under reduced pressure to obtain phthalide. The crude without further purification was dissolved in acetone (10 mL), and K2CO3 (2 equiv.) and MeI (2 equiv.) were added and stirring continued for 4–5 h. After completion of the reaction acetone was evaporated under reduced pressure and the usual work up was done using EtOAc and water. The crude was purified by column chromatography. 4-Methoxy-5-(methoxymethyl)-3,5-dihydro-1H-furo[3,4-b]carbazol-1-one (9). LAH reduction was done using the general procedure starting from compound 8 (500 mg, 1.45 mmol). Since the hydroxyl compound could not be purified totally, it was methylated using potassium carbonate and methyl iodide following the general procedure; yield 64% (275 mg, 0.92 mmol) over two steps; Rf = 0.4, in 1 : 4 ethyl acetate : hexane; mp 180–182 °C; IR (KBr, cm−1) νmax 2366, 1752, 1356, 1219, 1100, 773; 1H NMR (CDCl3, 400 MHz): δ 8.36 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.65–7.59 (m, 2H), 7.41 (t, J = 7.8 Hz, 1H), 6.02 (s, 2H), 5.58 (s, 2H), 4.13 (s, 3H), 3.37 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 171.2, 142.3, 140.2, 135.3, 131.9, 128.2, 127.6 (CH), 123.2, 121.4 (CH), 120.8 (CH), 119.1, 113.2 (CH), 110.4 (CH), 75.8 (CH2), 68.1 (CH2), 59.9 (CH3), 56.2 (CH3); HRMS (TOF MS ES+) m/z calcd for C17H16NO4 [M + H]+: 298.1079, found 298.1097.
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4-Methoxy-5-methyl-3,5-dihydro-1H-furo[3,4-b]carbazol-1-one (19). Dimethyl 1-hydroxy-9H-carbazole-2,3-dicarboxylate (17) obtained from the annulation of Boc-protected furoindolone (500 mg, 1.8 mmol) and dimethyl maleate (0.25 mL, 1.95 mmol) was subjected to sequential LAH reduction and methylation as shown in the general procedure. A solid (162 mg, 0.61 mmol) was obtained in 34% yield over two steps. Rf = 0.3, in 1 : 4 ethyl acetate : hexane; mp 184–186 °C; IR (KBr, cm−1) νmax 1751, 1584, 1460, 1341, 1219, 1102, 772; 1H NMR (CDCl3, 600 MHz): δ 8.30 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 5.46 (s, 2H), 4.14 (s, 3H), 4.03 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 171.3, 142.4, 139.5, 136.0, 131.9, 127.3, 127.1 (CH), 122.5, 120.5 (CH), 120.3 (CH), 117.5, 113.3 (CH), 109.1 (CH), 67.7 (CH2), 60.5 (CH3), 31.6 (CH3). HRMS (TOF MS ES+) m/z calcd for C16H14NO3 [M + H]+: 268.0974, found 268.0976. 7-Bromo-1,4-dihydro-4-methoxymethyl-3H-furo[3,4-b]indol3-one (20). This was prepared according to the general route as described for the preparation of MOM-protected furoindolones, starting from 4-bromoaniline. In the Japp–Klingemann step, 4-bromoaniline (27 mL, 0.24 mol), sodium nitrite (20 g, 0.3 mol) and α-aceto-γ-butyrolactone (31 g, 0.24 mol) were required. The furoindolone 20 (35 g, 0.12 mol) was obtained in 55% yield over three steps. Rf = 0.35, in 1 : 4 ethyl acetate : hexane; mp 158–160 °C; IR (KBr, cm−1) νmax 2398, 1748, 1340, 772; 1H NMR (CDCl3, 600 MHz): δ 7.80 (s, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 5.67 (s, 2H), 5.36 (s, 2H), 3.33 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 163.0, 142.4, 134.3, 130.0, 129.7 (CH), 123.7 (CH), 122.2, 115.3, 114.1 (CH), 74.5 (CH2), 66.8 (CH2), 56.3 (CH3); HRMS (TOF MS ES+) m/z calcd for C12H11NO3Br [M + H]+: 295.9922, found 295.9930. 7-Chloro-1,4-dihydro-4-methoxymethyl-3H-furo[3,4-b]indol3-one (21). This was prepared according to the general route as described for the preparation of MOM-protected furoindolones, starting from 4-chloroaniline. In the Japp–Klingemann step, 4-chloroaniline (21 mL, 0.24 mol), sodium nitrite (20 g, 0.3 mol) and α-aceto-γ-butyrolactone (31 g, 0.24 mol) were required. The furoindolone 21 (25 g, 0.10 mol) was obtained in 45% yield over three steps. Rf = 0.35, in 1 : 3 ethyl acetate : hexane; mp 160–162 °C; IR (KBr, cm−1) νmax 2363, 1734, 1339, 1219, 1062, 982, 772; 1H NMR (CDCl3, 600 MHz): δ 7.64 (s, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 10.2 Hz, 1H), 5.67 (s, 2H), 5.37 (s, 2H), 3.32 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 163.2, 142.3, 134.6, 130.3, 128.1, 127.4 (CH), 121.8, 120.7 (CH), 113.9 (CH), 74.5 (CH2), 67.0 (CH2), 56.5 (CH3); HRMS (TOF MS ES+) m/z calcd for C12H11NO3Cl [M + H]+: 252.0427, found 252.0420. Dimethyl 6-bromo-1-hydroxy-9-methoxymethyl-9H-carbazole-2,3-dicarboxylate (22). This was prepared from 20 (350 mg, 1.2 mmol) and dimethyl maleate 11 (0.2 mL, 1.54 mmol) in 59% yield (295 mg, 0.69 mmol) according to the general route for annulation. Rf = 0.45, in 1 : 4 ethyl acetate : hexane; mp 120–124 °C; IR (KBr, cm−1) νmax 2364, 1752, 1740, 1219, 1072, 985, 772; 1H NMR (CDCl3, 600 MHz): δ 11.45 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 6.00 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H),
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3.28 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.9, 169.8, 149.4, 140.9, 130.7 (CH), 129.5, 126.5, 126.1, 124.6, 123.7 (CH), 114.2, 112.9 (CH), 112.4 (CH), 107.7, 75.8 (CH2), 55.9 (CH3), 53.1 (CH3), 52.8 (CH3); HRMS (TOF MS ES+) m/z calcd for C18H17NO6Br [M + H]+: 422.0239, found 422.0230. Dimethyl 6-chloro-1-hydroxy-9-methoxymethyl-9H-carbazole2,3-dicarboxylate (23). This was prepared from 21 (300 mg, 1.19 mmol) and dimethyl maleate 11 (0.16 mL, 1.32 mmol) in 55% yield (250 mg, 0.65 mmol) according to the general route for annulation. Rf = 0.40 in 1 : 4 ethyl acetate : hexane; mp 110–115 °C; IR (KBr, cm−1) νmax 2870, 1769, 1732, 1680, 1421, 1132, 796; 1H NMR (CDCl3, 600 MHz): δ 11.53 (s, 1H), 8.02 (s, 1H), 7.76 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 7.2 Hz, 1.8, 1H), 6.11 (s, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 3.34 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.7, 169.9, 149.9, 140.7, 129.7, 128.3 (CH), 127.0, 126.7, 126.4, 124.2, 120.7 (CH), 113.0 (CH), 112.2 (CH), 107.8, 76.2 (CH2), 56.0 (CH3), 53.2 (CH3), 52.8 (CH3). 6-Bromo-10-methoxy-9-methoxymethyl-1,9-dihydro-2-oxa9-aza-cyclopenta[b]fluoren-3-one (24). It was prepared from compound 22 (200 mg, 0.48 mmol) according to the general route for LAH reduction as mentioned above. The crude was methylated using K2CO3 and MeI in acetone and was purified by column chromatography forming solid 24 in 65% (116 mg, 0.31 mmol) yield over two steps; Rf = 0.3, in 1 : 5 ethyl acetate : hexane; mp 201–205 °C; IR (KBr, cm−1) νmax 1762, 1588, 1455, 1219, 772; 1H NMR (CDCl3, 600 MHz): δ 8.30 (s, 1H), 8.21 (s, 1H), 7.63 (d, J = 10.2 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 5.97 (s, 2H), 5.58 (s, 2H), 4.10 (s, 3H), 3.33 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.9, 141.0, 140.5, 135.6, 132.4, 130.5 (CH), 127.1, 125.1, 123.7 (CH), 119.7, 114.4, 113.6 (CH), 112.1 (CH), 76.0 (CH2), 68.1 (CH2), 60.0 (CH3), 56.3 (CH3); HRMS (TOF MS ES+) m/z calcd for C17H15NO4Br [M + H]+: 376.0184, found 376.0180. 6-Chloro-10-methoxy-9-methoxymethyl-1,9-dihydro-2-oxa9-aza-cyclopenta[b]fluoren-3-one (25). This was prepared from compound 23 (200 mg, 0.53 mmol) according to the general route for LAH reduction as mentioned above. The crude was methylated using K2CO3 and MeI in acetone and was purified by column chromatography forming solid 25 in 58% (102 mg, 0.31 mmol) yield over two steps. Rf = 0.40, in 1 : 3 ethyl acetate : hexane; mp 192–195 °C; IR (KBr, cm−1) 1758, 1580, 1145, 772; 1H NMR (CDCl3, 600 MHz): δ 8.31 (s, 1H), 8.05 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 5.97 (s, 2H), 5.58 (s, 2H), 4.10 (s, 3H), 3.31 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.9, 140.7, 140.5, 135.8, 132.3, 127.8 (CH), 127.3, 127.2, 124.5, 120.7 (CH), 119.6, 113.6 (CH), 111.6 (CH), 76.1 (CH2), 68.1 (CH2), 60.0 (CH3), 56.3 (CH3); HRMS (TOF MS ES+) m/z calcd for C17H15NO4Cl [M + H]+: 332.0690, found 332.0679. Methyl 8-methoxymethyl-1-oxo-3,8-dihydro-1H-2-oxa-8-azacyclopenta[a]indene-5-carboxylate (26). This was prepared according to the general route as mentioned for the preparation of MOM-protected furoindolones, starting from methyl 4-amino-benzoate. In the Japp–Klingemann step, methyl 4-amino-benzoate (36 g, 0.24 mol), sodium nitrite (20 g,
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0.3 mol) and α-aceto-γ-butyrolactone (31 g, 0.24 mol) were required. The furoindolone 26 (30 g, 0.11 mol) was obtained in 47% yield over three steps. Rf = 0.40, in 1 : 2 ethyl acetate : hexane; mp 170–172 °C; IR (KBr, cm−1) νmax 2369, 1755, 1696, 1269, 1219, 1071, 988; 1H NMR (CDCl3, 600 MHz): δ 8.43 (s, 1H), 8.14 (dd, J = 7.8 Hz, 1.2 Hz 1H), 7.64 (d, J = 9 Hz, 1H), 5.71 (s, 2H), 5.43 (s, 2H), 3.95 (s, 3H), 3.34 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 167.0, 163.1, 146.1, 136.6, 130.6, 127.6 (CH), 124.2 (CH), 124.1, 120.5, 112.4 (CH), 74.7 (CH2), 67.0 (CH2), 56.5 (CH3), 52.3 (CH3). HRMS (TOF MS ES+) m/z calcd for C14H14NO5 [M + H]+: 276.0872, found 276.0880. Trimethyl 1-methoxy-9-methoxymethyl-9H-carbazole-2,3,6tricarboxylate (27). This was prepared according to the general route for annulation as mentioned previously from compound 26 (300 mg, 1.09 mmol) and dimethyl maleate 11 (0.16 mL, 1.32 mmol) in 62% yield (270 mg, 0.67 mmol). Rf = 0.6 in 1 : 5 ethyl acetate : hexane; mp 116–118 °C; IR (KBr, cm−1) νmax1725, 1707, 1660, 1320, 1279, 1197, 995, 773; 1H NMR (CDCl3, 600 MHz): δ 8.76 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.11 (s, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.35 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.5, 169.5, 167.1, 149.5, 144.6, 129.7, 129.0 (CH), 127.4, 127.0, 123.5 (CH), 123.1, 122.6, 112.8 (CH), 110.4 (CH), 107.8, 75.8 (CH2), 55.9 (CH3), 53.0 (CH3), 52.6 (CH3), 52.1 (CH3). HRMS (TOF MS ES+) m/z calcd for C20H19NO8Na [M + H]+: 424.1008, found 424.0994. Methyl 10-methoxy-9-methoxymethyl-3-oxo-3,9-dihydro-1H2-oxa-9-aza-cyclopenta-6-[b]fluorenecarboxylate (28). It was prepared from compound 27 (200 mg, 0.49 mmol) according to the general route for LAH reduction as mentioned above. The crude was methylated using K2CO3 and MeI in acetone and was purified by column chromatography forming solid 28 in 55% (97 mg, 0.27 mmol) yield over two steps; Rf = 0.2, in 1 : 5 ethyl acetate : hexane; mp 202–204 °C; IR (KBr, cm−1) νmax 1752, 1732, 1460, 1102; 1H NMR (CDCl3, 600 MHz): δ 8.79 (s, 1H), 8.36 (s, 1H), 8.24 (d, J = 9 Hz, 1H), 7.61 (d, J = 9 Hz, 1H), 6.01 (CH2), 5.58 (CH2), 4.13 (s, 3H), 4.00 (s, 3H), 3.35 (s, 3H); 13 C NMR (CDCl3, 150 MHz): δ 170.6, 167.1, 144.8, 140.4, 135.6, 132.2, 128.9 (CH), 127.9, 123.0 (CH), 119.9, 113.2 (CH), 110.5 (CH), 75.9 (CH2), 67.9 (CH2), 59.8 (CH3), 56.2 (CH3), 52.1 (CH3). HRMS (TOF MS ES+) m/z calcd for C19H18NO6 [M + H]+: 356.1134, found 356.1135. 4-Methoxy-3H-naphtho[2,3-c]furan-1-one (31). This was prepared in 60% yield (183 mg, 0.85 mmol) following the same sequence of reactions involving annulation of phthalide 30 (300 mg, 0.45 mmol) and subsequent reduction with LAH. IR (KBr, cm−1) νmax 2928, 2851, 2340, 1758, 772; 1H NMR (CDCl3, 600 MHz): δ 8.30 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 5.67 (s, 2H), 4.15 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 170.9, 150.1, 134.8, 129.8 (CH), 129.6, 128.6 (CH), 127.6 (CH), 124.4, 123.5, 122.8 (CH), 121.2 (CH), 68.7 (CH3), 59.6 (CH2). 1-Hydroxy-10-methoxy-1,9-dihydro-2-oxa-9-aza-cyclopenta[b]fluoren-3-one (32). Compound 9 (150 mg, 0.5 mmol) obtained was brominated using NBS (98 mg, 0.55 mmol), CCl4 (10 mL) under refluxing conditions. After completion of the reaction,
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the reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The monobrominated product without further purification was refluxed in dioxane : water (2 : 1). The dioxane was evaporated, and work up was done in the usual manner. The crude product was purified by column chromatography to furnish phthalaldehydic acid 32. Rf = 0.2 in 3 : 1 ethyl acetate : hexane; 1H NMR (DMSO-d6, 600 MHz): δ 11.89 (s, 1H), 8.34 (s, 1H), 8.27 (d, J = 6.6 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.22 (s, 3H);13C NMR (DMSO-d6, 150 MHz): δ 169.5, 141.2, 140.8, 136.2, 129.6, 127.3 (CH), 126.5, 122.8, 121.6 (CH), 120.2 (CH), 118.9, 112.5 (CH), 112.3 (CH), 96.9 (CH), 59.9 (CH3); HRMS (TOF MS ES+) m/z calcd for C15H12NO4 [M + H]+: 270.0766, found 270.0776. 10-Methoxy-1-(2-methallyl)-1,9-dihydro-2-oxa-9-aza-cyclopenta-[b]fluoren-3-one (34). To a suspension of indium metal (480 mg, 4.2 mmol) and sodium iodide (960 mg, 6.6 mmol) in dry DMF (15 mL), methallyl bromide (0.48 mL, 5.28 mmol) was added dropwise. The stirring was continued at room temperature until the metal dissolved completely to form a clear solution. To the allyl indium reagent generated as above, a solution of phthalaldehydic acid 32 (480 mg, 1.68 mmol) in DMF (9 ml) was added. The resulting reaction mixture was stirred for 8 h at room temperature. Then it was extracted with EtOAc (3 × 150 mL) and the extracts were worked up in the usual manner to give the crude product which was purified by column chromatography to furnish compound 34 in 92% yield (500 mg, 1.63 mmol). 1H NMR (CDCl3, 400 MHz): δ 8.55 (brs, 1H), 8.35 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.51–7.50 (m, 2H), 7.34–7.30 (m, 1H), 5.83 (dd, J = 6.4 Hz, J = 2.4 Hz, 1H), 4.90 (s, 2H), 4.09 (s, 3H), 3.03 (d, J = 14.8 Hz, 1H), 2.46–2.40 (m, 1H), 1.82 (s, 3H); 13C NMR (CDCl3, 50 MHz): δ 171.1, 140.7, 140.4, 138.9, 136.6, 135.5, 127.6 (CH), 127.5, 123.5, 121.1 (CH), 120.9 (CH), 119.08, 114.4 (CH2), 114.0 (CH), 111.5 (CH), 78.7 (CH), 60.5 (CH3), 42.1 (CH2), 23.3 (CH3); HRMS (TOF MS ES+) m/z calcd for C19H18NO3 [M + H]+: 308.1287, found 308.1300. Mafaicheenamine E (1). Compound 34 (300 mg, 0.97 mmol) was dissolved in dry toluene; p-toluene sulphonic acid (166 mg, 0.96 mmol) was added to it and heated overnight. No change could be detected on TLC analysis. After 16 h, the reaction mixture was concentrated in a vacuum, quenched with aqueous NaHCO3 and usual work-up was done with ethyl acetate. The crude product was purified by column chromatography to furnish compound 1 in 97% yield (290 mg, 0.94 mmol). 1H NMR (acetone-d6, 600 MHz): δ 10.94 (brs, 1H), 8.37 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 9.6 Hz, 1H), 5.22 (d, J = 9.6 Hz, 1H), 4.07 (s, 3H), 2.07 (s, 3H), 1.88 (s, 3H); 13C NMR (acetone-d6, 150 MHz) δ 170.0, 141.1, 139.7, 139.4, 136.8, 135.6, 127.1, 126.9, 123.1, 121.5, 121.5, 120.8, 120.0, 118.5, 112.9, 111.6, 75.9, 60.0, 25.0, 17.7. tert-Butyl 10-methoxy-1-(2-methyl-propenyl)-3-oxo-1,3-dihydro2-oxa-9-aza-cyclopenta[b]fluorene-9-carboxylate (35). Compound 1 (150 mg, 0.48 mmol) was dissolved in ethyl acetate (10 mL), and Boc-anhydride (1.5 equiv.), triethyl amine (1.5
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equiv.) and a pinch of DMAP were added. The reaction contents were stirred at rt for 3 h. After completion of the reaction, usual work up was done and the crude was purified by column chromatography to obtain a solid compound 35 in 88% yield (175 mg, 0.43 mmol). Rf = 0.6 in 1 : 6 ethyl acetate : hexane; 1H NMR (CDCl3, 600 MHz) δ 8.26 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 6.36 (d, J = 9.0 Hz, 1H), 5.16–5.14 (m, 1H), 3.82 (s, 3H), 2.02 (s, 3H), 1.85 (s, 3H), 1.74 (s, 9H); 13C NMR (CDCl3, 50 MHz): δ 170.6, 149.9, 143.3, 141.0, 140.7, 140.0, 134.7, 131.5, 128.4 (CH), 125.2, 123.7 (CH), 123.1, 120.5 (CH), 120.2 (CH), 115.1 (CH), 112.2 (CH), 84.9 (CH), 59.9 (CH), 28.1 (CH3), 26.0 (CH3), 18.9 (CH3). HRMS (TOF MS ES+) m/z calcd for C25H26NO5 [M + H]+: 408.1811, found 408.1819. Claulansine D (2). To a solution of 35 (100 mg, 0.24 mmol) in THF : water (3 : 2), OsO4 (0.05 M) (0.6 mL) and NMO (60 mg, 0.2 mmol) was added at rt. The reaction was stirred for another 8 h. After completion of the reaction as monitored by TLC analysis, the reaction was quenched with sodium sulphite and usual work up was done. Two diastereomers obtained were not separated by column chromatography. The mixture of diastereomers was obtained in 76% yield (82 mg, 0.18 mmol). The mixture was then neat heated to 140 °C till completion of the reaction, the product was then purified by column chromatography to give compound 2 in 55% yield (35 mg, 0.09 mmol) and the other diastereomer in 29% yield (18 mg, 0.05 mmol) in 2 : 1; Rf = 0.1, in 2 : 1 ethyl acetate : hexane; 1H NMR (DMSO-d6, 600 MHz): δ 11.80 (brs, 1H), 8.37 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.16 (s, 1H), 4.80 (d, J = 8.0 Hz, 1H), 4.79 (s, 1H), 4.06 (s, 3H), 3.89 (d, J = 7.5 Hz, 1H), 1.26 (s, 3H), 1.22 (s, 3H); 13C NMR (DMSO-d6, 150 MHz): δ 170.8, 140.8, 138.6, 136.3, 135.1, 126.7, 126.3, 122.6, 121.0, 119.6, 118.8, 112.7, 111.7, 77.6, 75.9, 71.6, 60.3, 28.5, 24.7. Non-natural Claulansine D (37). 1H NMR (DMSO-d6, 600 MHz): δ 11.76 (s, 1H), 8.37 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 5.97 (d, J = 5.4 Hz, 1H), 5.29 (d, J = 6.0 Hz, 1H), 4.30 (s, 1H), 4.11 (s, 3H), 3.6 (t, J = 4.8 Hz, 1H), 1.19 (s, 3H), 1.05 (s, 3H); 13C NMR (DMSO-d6, 150 MHz): δ 170.8, 141.2, 140.5, 136.7, 133.6, 127.2 (CH), 126.4, 123.0, 121.4 (CH), 120.1 (CH), 118.3, 113.1 (CH), 112.1 (CH), 81.6 (CH), 79.6 (CH), 72.2, 60.3 (CH3), 27.5 (CH3), 26.8 (CH3), HRMS (TOF MS ES+) m/z calcd for C19H19NO5Na [M + H]+: 364.1161, found 344.1145. 1-(2-Chloro-2-methyl-propyl)-10-methoxy-1,9-dihydro-2-oxa9-aza-cyclopenta[b]fluoren-3-one (38). Compound 34 (75 mg, 0.24 mmol) was dissolved in DCM (10 mL), and AlCl3 (10 mg, 0.06 mmol) was added and the mixture was refluxed for 8 h. After completion of the reaction, the reaction was worked up in the usual manner using DCM and water. The solid obtained was purified by column chromatography. Rf = 0.3 in 1 : 4 EtOAc : hexane; mp 186–190 °C; IR (KBr, cm−1) νmax 1756, 1370, 1240, 1019, 775; 1H NMR (CDCl3, 600 MHz) δ 8.62 (s, 1H), 8.38 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.54–7.53 (m, 2H), 7.34 (t, J = 7.8 Hz, 1H), 6.12 (d, J = 9 Hz, 1H), 4.14 (s, 3H), 2.95 (d, J = 9 Hz, 1H), 1.96–1.90 (m, 1H), 1.77 (s, 3H), 1.61 (s,
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3H);13C NMR (CDCl3, 50 MHz): δ 171.0, 140.4, 139.0, 136.9, 135.4, 127.6 (CH), 123.5, 121.2 (CH), 121.0 (CH), 118.7, 114.1 (CH), 111.5 (CH), 77.2 (CH), 70.1, 61.2 (CH3), 50.1 (CH2), 34.9 (CH3), 31.9 (CH3); HRMS (TOF MS ES+) m/z calcd for C19H19ClNO3 [M + H]+: 344.1053, found 344.1060.
Acknowledgements The authors are grateful to the Council of Scientific and Industrial Research (CSIR) and the Department of Science and Technology (DST) for financial support. JR is thankful to CSIR for a research fellowship. Financial support for Improvement of Science & Technology Infrastructure in Higher Educational Institutions by DST is also acknowledged.
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