Palladium(II)-catalysed total synthesis of naturally occurring pyrano[3,2-a]carbazole and pyrano[2,3-b]carbazole alkaloids†‡

Plants of the genera Murraya, Clausena and Glycosmis are the main terrestrial source for the isolation of carbazole alkaloids. Various species of these plants have been applied in Asian folk medicine for the treatment of numerous diseases. It is assumed that carbazole alkaloids play a central role in the pharmacological effect of the plant extracts because of their wide range of biological activities. Therefore, a variety of classical methods and new procedures using transition metals have been developed for the synthesis of carbazoles. We reported the application of iron-mediated and palladium(II)catalysed approaches for the synthesis of carbazole derivatives. Herein, we describe the application of our palladium(II)catalysed cyclisation of diarylamines to the synthesis of seven pyranocarbazole natural products: the pyrayafolines A–E (1–5), O-methylmurrayamine A (6) and O-methylmahanine (7) (Fig. 1). Pyrayafoline A (1) was first isolated by Furukawa and coworkers in 1986 from the stem bark of Murraya euchrestifolia Hayata collected in Taiwan. The structure was assigned based on the spectroscopic data and confirmed by synthesis. In 1991, the same group reported the isolation of the pyrayafolines B (2), C (3) and D (4) from the same natural source. In their studies, Furukawa et al. reported the O-methylation of natural pyrayafoline B–D (2–4) using diazomethane, and the total synthesis of O-methylpyrayafoline B and O-methylpyrayafoline C, which is equivalent to pyrayafoline A (1). The structural assignments for 2 and 3 were then confirmed by comparison of the spectroscopic data of the different O-methyl derivatives. Although pyrayafoline D (4) is chiral, the natural product did not show any optical rotation ([α]D = ±0, c 0.0013, MeOH). Pyrayafoline D (4) was also obtained by Itoigawa et al. from the leaves of Murraya koenigii collected in Bangladesh. In 1991, Furukawa and co-workers reported the isolation of pyrayafoline E (5) from the stem bark of Murraya euchrestifolia Hayata. The structural assignment for 5 was based solely on its spectroscopic data. As reported for pyrayafoline D (4), pyrayafoline E Fig. 1 Naturally occurring pyrano[3,2-a]carbazole and pyrano[2,3-b]carbazole alkaloids.


Introduction
Plants of the genera Murraya, Clausena and Glycosmis are the main terrestrial source for the isolation of carbazole alkaloids. 1 Various species of these plants have been applied in Asian folk medicine for the treatment of numerous diseases. It is assumed that carbazole alkaloids play a central role in the pharmacological effect of the plant extracts because of their wide range of biological activities. 2 Therefore, a variety of classical methods and new procedures using transition metals have been developed for the synthesis of carbazoles. 1,3 We reported the application of iron-mediated 4 and palladium(II)catalysed approaches for the synthesis of carbazole derivatives. 5 Herein, we describe the application of our palladium(II)catalysed cyclisation of diarylamines to the synthesis of seven pyranocarbazole natural products: the pyrayafolines A-E (1)(2)(3)(4)(5), O-methylmurrayamine A (6) and O-methylmahanine (7) (Fig. 1).
Pyrayafoline A (1) was first isolated by Furukawa and coworkers in 1986 from the stem bark of Murraya euchrestifolia Hayata collected in Taiwan. 6 The structure was assigned based on the spectroscopic data and confirmed by synthesis. In 1991, the same group reported the isolation of the pyrayafolines B (2), C (3) and D (4) from the same natural source. 7 In their studies, Furukawa et al. reported the O-methylation of natural pyrayafoline B-D (2-4) using diazomethane, and the total synthesis of O-methylpyrayafoline B and O-methylpyrayafoline C, which is equivalent to pyrayafoline A (1). The structural assignments for 2 and 3 were then confirmed by comparison of the spectroscopic data of the different O-methyl derivatives.
Although pyrayafoline D (4) is chiral, the natural product did not show any optical rotation ([α] D = ±0,c 0.0013,MeOH). Pyrayafoline D (4) was also obtained by Itoigawa et al. from the leaves of Murraya koenigii collected in Bangladesh. 8 In 1991, Furukawa and co-workers reported the isolation of pyrayafoline E (5) from the stem bark of Murraya euchrestifolia Hayata. 9 The structural assignment for 5 was based solely on its spectroscopic data. As reported for pyrayafoline D (4), pyrayafoline E (5) did not exhibit any optical rotation ([α] D = ±0,c 0.0007,CHCl 3 ). In the plant material which afforded pyrayafoline E (5), Furukawa and co-workers also identified pyrayafolines B-D (2-4) and other carbazole alkaloids. O-Methylmurrayamine A (6) was mentioned first in 1991 by Wu as a synthetic derivative of murrayamine A, which had been isolated from the leaves of Murraya euchrestifolia collected in Taiwan. 10 In 2003, Nakatani and co-workers described the isolation of O-methylmurrayamine A (6) from the leaves of Murraya koenigii collected in Malaysia. 11 In 2009, compound 6 was also isolated by Mukhapadhyay et al. from Murraya koenigii collected in India. 12 In 2011, we reported the first total synthesis of O-methylmurrayamine A (6) using an iron-mediated approach. 4c O-Methylmahanine (7) was mentioned first in 1972 by Kapil and co-workers as a synthetic derivative of Mahanine. 13 However, no spectroscopic data were disclosed. In 2003, Nakatani et al. described the first isolation of O-methylmahanine (7) from the leaves of Murraya koenigii collected in Malaysia. 11 O-Methylmahanine (7) was obtained as an optically active compound ([α] D = +3, c 0.10, CHCl 3 ). However, the absolute configuration has not been assigned. Not much is known about the biological activities of the compounds 1-7, except for pyrayafoline D (4) which has shown a promising cytotoxicity against a variety of cancer cell lines. 8,14 Results and discussion We have developed a synthesis for the natural products 1-7 from a common precursor using our palladium(II)-catalysed approach for the construction of the carbazole framework. Retrosynthetic analysis led to the orthogonally diprotected 2,7dihydroxycarbazole 8 as a relay compound (Scheme 1). The pyran ring was thought to be annulated at a later stage of the synthesis. Carbazole 8 should be available by a palladium(II)catalysed oxidative cyclisation of a corresponding diarylamine which can be obtained by the Buchwald-Hartwig amination 15 of meta-bromoanisole (9) and the arylamine 10.
The arylamine 10 16 was obtained from the nitrophenol 11 by formation of the triisopropylsilyl ether followed by reduction of the nitro group (Scheme 2). The Buchwald-Hartwig amination of m-bromoanisole (9) with the arylamine 10 using catalytic amounts of palladium(II) acetate and SPhos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) 15b as ligand led quantitatively to the diarylamine 12. Alternatively, compound 12 is available by Buchwald-Hartwig coupling of the silyl-protected bromocresol 14 and m-anisidine (96% yield). The best results for the oxidative cyclisation of the diarylamine 12 were achieved by heating in a microwave reactor in the presence of catalytic amounts of freshly recrystallised palladium(II) acetate and 2.5 equivalents of copper(II) acetate as reoxidant in pivalic acid. These reaction conditions afforded the orthogonally diprotected 2,7-dihydroxycarbazole 8 in 82% yield.
(Scheme 3). Annulation of the pyran ring was achieved by formation of the dimethylpropargyl ether using Godfrey's method 17 and subsequent thermally induced rearrangement of the resulting aryl propargyl ether. 18 Treatment of the 7-hydroxycarbazole 15 with methyl dimethylpropargyl carbonate (16) in the presence of 1,8-diazabicyclo[5.4.0]undec-1(8)ene (DBU) and catalytic amounts of copper(II) chloride followed by heating of the intermediate propargyl ether in toluene at reflux afforded a mixture of the protected pyranocarbazoles 17 and 18 in a ratio of 5.3 : 1 in favour of the pyrano-[3,2-a]carbazole 17. Both isomers were separated from each other by column chromatography and fully characterised by their spectroscopic data (see the Experimental section). The pyran ring formation results from a thermally induced sequence of an aryl-Claisen rearrangement followed by a 1,5hydrogen shift and electrocyclic ring closure (Scheme 4). 19 Pyran annulation following Casiraghi's method (reaction of 15 with prenal in the presence of titanium tetraisopropoxide in toluene at room temperature), 20 which proved to be superior in our previous study, 5k provided compound 17 only in up to 34% yield. Cleavage of the silyl ether of 17 afforded pyrayafoline C (3) in eight steps and 39% overall yield based on compound 11. Chemoselective O-methylation of pyrayafoline C (3) provided pyrayafoline A (1) in nine steps and 37% overall yield based on 11. The spectroscopic data of synthetic 1 and 3 are in agreement with those reported for the natural products. 6,7 The structure of pyrayafoline A (1) has been additionally confirmed by single-crystal X-ray analysis (Fig. 2). Pyrayafoline B (2) was obtained from the minor isomer 18 by cleavage of the silyl ether in eight steps and 6% overall yield based on 11. The spectroscopic data of our synthetic 2 are matching those reported by Furukawa et al. for the natural product. 7 The prenylated pyrayafolines D (4) and E (5) were synthesised from the diprotected carbazole 8 by reaction with a C 10 -building block (Scheme 5). Cleavage of the methyl ether of 8 and reaction of crude 7-hydroxycarbazole 15 with the carbonate 19 21 in the presence of DBU and catalytic amounts of copper(II) chloride followed by thermal rearrangement afforded the pyrano [3,2-a]carbazole 20 and the pyrano[2, 3-b]carbazole 21 in a ratio of 9.6 : 1. Both isomers were separated from each other by flash chromatography and fully characterised. Also in this case, application of Casiraghi's method for annulation of the pyran ring (reaction of 15 with citral in the presence of titanium tetraisopropoxide in toluene at room temperature) 20 was inferior (25% yield of carbazole 20). Cleavage of the silyl ether of the pyrano[3,2-a]carbazole 20 provided pyrayafoline D (4) in eight steps and 40% overall yield based on compound 11. Analogously, silyl ether cleavage of the pyrano[2, 3-b]carbazole 21 afforded pyrayafoline E (5) in eight steps and 3% overall yield based on 11. The spectroscopic data of synthetic 4 and 5 are in full agreement with those reported for the natural products. 7,9 For the synthesis of the carbazole alkaloids 6 and 7 with a pyran annulated at ring A, the silyl ether of the orthogonally diprotected 2,7-dihydroxycarbazole 8 was cleaved first to afford Scheme 3 Synthesis of pyrayafoline A-C (1-3). Reagents and conditions: (a) 2.0 equiv. BBr 3 , CH 2 Cl 2 , −78°C to rt; (b) 1. 2.0 equiv. 16, 2.0 equiv. DBU, 0.9 mol% CuCl 2 ·2H 2 O, MeCN, rt; 2. PhMe, reflux, 48% 17 and 9% 18 (three steps); (c) 1.5 equiv. TBAF, DMF, −10°C, 100%; (d) 1.3 equiv. NaH, 1.5 equiv. Me 2 SO 4 , THF, 0°C to rt, 93%; (e) 1.5 equiv. TBAF, DMF, −10°C, 78%.  (23) in the presence of titanium tetraisopropoxide in toluene (Casiraghi's method) 20 provided O-methylmurrayamine A (6). The present route leads to O-methylmurrayamine A (6) in a total number of six steps and 72% overall yield which is superior to our previous synthesis reported for this natural product. 4c The structure of 6 has been unambiguously confirmed by an X-ray crystal structure determination (Fig. 3). Reaction of the 2-hydroxycarbazole 22 with citral (24) and titanium tetraisopropoxide afforded O-methylmahanine (7) in six steps and 62% overall yield based on 11. The spectroscopic data of our synthetic carbazole alkaloids 6 and 7 are in full agreement with those reported in the literature. 10