First total synthesis of the biscarbazole alkaloid oxydimurrayafoline

Article abstract of DOI:10.1039/c2ob25842k

We report the first total synthesis of oxydimurrayafoline via nucleophilic substitution at the benzylic position at C-3 of the carbazole framework. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob25842k

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COMMUNICATION
First total synthesis of the biscarbazole alkaloid oxydimurrayafoline†‡
Carsten Börger, Micha P. Krahl, Margit Gruner, Olga Kataeva and Hans-Joachim Knölker*
Received 2nd May 2012, Accepted 23rd May 2012
DOI: 10.1039/c2ob25842k
We report the first total synthesis of oxydimurrayafoline via
nucleophilic substitution at the benzylic position at C-3 of the
carbazole framework.
A broad range of structurally diverse carbazole alkaloids has been
isolated from various natural sources.1 Their useful biological
activities induced the development of novel synthetic routes with
a special focus on methods using transition metals.2 We have
described an iron-mediated approach and a palladium-catalysed
approach to carbazoles, both of which have proven to be very
efficient for numerous applications in natural product syn-
thesis.3,4 Biscarbazoles are a class of carbazole alkaloids
in which two carbazole moieties are connected by different
linkages.1,5 In the present project, we aimed at the synthesis of
oxydimurrayafoline (1), a special biscarbazole connecting two
carbazole units via a benzylic ether linkage at the 3-position
(Fig. 1).
Oxydimurrayafoline (1) was isolated in 1987 by Furukawa
and co-workers from Murraya euchrestifolia Hayata as a colour-
less oil.6 So far, no synthesis of oxydimurrayafoline (1) has been
reported. In 2005, Rahman and Gray isolated from the stem bark
extract of Murraya koenigii 3,3′-[oxybis(methylene)]bis-
(9-methoxy-9H-carbazole) (2) which can be designated as iso-
oxydimurrayafoline.7 Isooxydimurrayafoline (2) showed potent
inhibitory activity against Gram-negative bacteria and fungi.7
Another structurally related biscarbazole alkaloid is murrafoline-F
(3), which was isolated in 1988 by Furukawa et al. from the
root bark of Murraya euchrestifolia Hayata.8 No synthetic
approach towards murrafoline-F (3) has been reported yet. The
biscarbazole alkaloid 1 obviously derives from the monomeric
1-methoxycarbazoles 4, a series of alkaloids which has been
found to have the carbon substituent at C-3 in all possible oxi-
dation states.1 The envisaged synthesis of oxydimurrayafoline
(1) should be feasible by etherification of the corresponding
monomeric carbazole building block koenoline (4b) (Scheme 1).
We decided to focus on mukonine (4e) as initial target carbazole
Fig. 1 Oxydimurrayafoline (1), isooxydimurrayafoline (2), murrafoline-F
(3), and the 1-methoxycarbazole alkaloids 4a–e.
Scheme 1 Retrosynthetic analysis of oxydimurrayafoline (1).
as the ester group can be easily reduced to provide koenoline
(4b). The synthesis of mukonine (4e) starting from commercially
available methyl 4-amino-3-methoxybenzoate (5) using our iron-
mediated approach was already reported more than 20 years
ago.9,10
Mukonine (4e) was isolated in 1978 by Chakraborty et al.
from Murraya koenigii and later also by Wu et al. from
Clausena excavata.11,12 A range of different synthetic routes to
mukonine (4e) has been reported.9–11,13 For the total synthesis of
Department Chemie, Technische Universität Dresden, Bergstrasse 66,
01069 Dresden, Germany. E-mail: hans-joachim.knoelker@tu-dresden.de;
Fax: +49 351-463-37030
†Part 102 of Transition Metals in Organic Synthesis; for Part 101,
see: ref. 4r.
‡Electronic supplementary information (ESI) available: 1H
and 13C NMR data of compounds 1, 4e, 14 and 16. CCDC 878261.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2ob25842k
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Scheme 2 Synthesis of mukonine (4e). Reagents and conditions: (a)
2.3 equiv. 5, MeCN, rt to 82 °C, 90 h, 68%; (b) very active MnO2, rt, 2
d, 71%; (c) 5 mol% Pd(OAc)2, 11 mol% SPhos, 0.9 equiv. 5, 1.3 equiv.
Cs2CO3, toluene, reflux, 40 h, 100%; (d) 10 mol% Pd(OAc)2, 10 mol%
K2CO3, PivOH, 115 °C, 14 h, 91%.
Scheme 3 Conversion of mukonine (4e) to the 3-chloromethyl-
carbazoles 12. Reagents and conditions: (a) a: 2 equiv. Boc2O, 1 equiv.
DMAP, MeCN, rt, 17 h, 97% 10a, b: 6.8 equiv. NaH, 3.4 equiv. TsCl,
THF, 0 °C to rt, 15 h, 96% 10b; (b) Et2O, −78 °C, a: 3.2 equiv.
DIBAL-H, 3.5 h, 100% 11a, b: 6 equiv. DIBAL-H, 4.5 h, 100% 11b;
(c) 3 equiv. EtiPr2N, CH2Cl2, a: 1.2 equiv. MsCl, 0 °C, 6.5 h, 90% 12a,
b: 2 equiv. MsCl, 0 °C to 5 °C, 7.5 h, 100% 12b.
mukonine (4e), our iron-mediated and our palladium-catalysed
synthesis can be both applied (Scheme 2). The iron complex salt
6 is prepared almost quantitatively by 1-azabutadiene-catalysed
complexation of cyclohexa-1,3-diene with pentacarbonyliron and
subsequent hydride abstraction with triphenylmethyl tetrafluoro-
borate.14,15 In an optimisation of our earlier approach,9,10 reac-
tion of 6 with the arylamine 5 afforded the iron complex 7 in
68% yield. Oxidative cyclisation of complex 7 using very active
manganese dioxide16 occurred with concomitant aromatisation
and demetalation to provide directly mukonine (4e) in 71%
yield. Alternatively, we have synthesised mukonine (4e) via our pal-
ladium-catalysed route.17 Using SPhos as ligand,18 the Buchwald–
Hartwig coupling of bromobenzene (8) with the arylamine
5 afforded quantitatively the diarylamine 9. Our conditions for
this coupling provided 9 in significantly higher yield than those
described by Fagnou et al., who obtained the diarylamine 9 in
76% yield using XPhos as ligand.13g On the other hand, our
original conditions for the palladium(II)-catalysed oxidative
cyclisation [20 mol% Pd(OAc)2, Cu(OAc)2, HOAc, reflux]4f pro-
vided mukonine (4e) only in 51% yield.17 Whereas, using
Fagnou’s conditions [10 mol% Pd(OAc)2, 10 mol% K2CO3,
PivOH, 110 °C] for this transformation, mukonine (4e) is
obtained in 91% yield.13g Thus, using our present conditions for
the Buchwald–Hartwig coupling and Fagnou’s conditions for the
oxidative cyclisation provides the best access to mukonine (4e)
(2 steps, 91% overall yield). The best previous routes have been
reported by Larock et al. (3 steps, 76% overall yield)13f and
Buchwald et al. (4 steps in 74% overall yield).13h The structural
assignment for mukonine (4e) was based on the spectroscopic
data, which are in full agreement with those reported in the
literature.§11
Fig. 2 Molecular structure of the chloromethylcarbazole 12b in the
crystal.
The structural assignment for the chloromethylcarbazole 12b
was confirmed by an X-ray crystal structure determination
(Fig. 2).¶ In 1978, Witiak and co-workers already described the
formation of a benzyl chloride by treatment of a benzylic
alcohol with mesyl chloride.19 An attempted Williamson ether
synthesis by deprotonation of the hydroxymethylcarbazole 11a
with sodium hydride and subsequent alkylation with chloro-
methylcarbazole 12a failed to provide the protected oxydimur-
rayafoline 13.
In view of the results described above, we decided to prepare
the mesylate of N-Boc-koenoline (11a) in the strict absence of
any nucleophile. Thus, compound 11a was treated with substoi-
chiometric amounts of methanesulfonic anhydride in the pres-
ence of N-ethyldiisopropylamine to provide directly the di-Boc-
oxydimurrayafoline 13 by reaction of 11a with the intermediate
mesylate (Scheme 4).
The nitrogen atom of mukonine (4e) was protected either by a
Boc group or a tosyl group to afford 10a and 10b, which on
reduction with DIBAL-H afforded the protected koenolines 11a
and 11b (Scheme 3). All attempts to convert the hydroxy group
to the corresponding mesylate group by reaction with methane-
sulfonyl chloride provided exclusively the chloromethyl-
carbazoles 12a and 12b. Obviously, the initially formed
mesylate is highly reactive and is prone to nucleophilic substi-
tution by the chloride ion which has been released.
5190 | Org. Biomol. Chem., 2012, 10, 5189–5193
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Scheme 5 Synthesis of 1-methoxy-2-(1-methoxy-9H-carbazol-3-
ylmethyl)-3-methyl-9H-carbazole (16). Reagents and conditions: (a)
KOH, H2O, MeOH, rt, 36 d, 78%; (b) 5 equiv. LiAlH4, Et2O, CH2Cl2,
rt, 18 h, 70%.
Scheme 4 Synthesis of oxydimurrayafoline (1). Reagents and con-
ditions: (a) 0.75 equiv. Ms2O, 3 equiv. EtiPr2N, CH2Cl2, 0 °C to rt,
15 h, 56% 13 and 24% 14; (b) KOH, H2O, MeOH, rt, 15 d, 86%.
compound 13. Thermal removal of the Boc group from N-Boc-
carbazoles requires temperatures of about 180 °C.20 However, at
140 °C complete decomposition of 13 occurred. Unfortunately,
13 is also not stable against strong acids, like trifluoroacetic acid.
Finally, treatment of di-Boc-oxydimurrayafoline 13 with
potassium hydroxide in aqueous methanol for 15 days at room
temperature provided oxydimurrayafoline (1). The spectroscopic
data of oxydimurrayafoline (1) are in good agreement with those
6
reported in the literature.k The 1H NMR spectrum of 1 has been
additionally compared with the original spectrum of the isolated
natural product, kindly provided by Professor Furukawa and
Professor Ito. Our approach leads to oxydimurrayafoline (1) in
six steps and 43% overall yield based on the arylamine 5.
Carbazoles are of interest due to their antibiotic activity
and the resulting pharmacological potential.1,21 However, the
biological activity of biscarbazoles has not been studied exten-
sively yet. Thus, we aimed at transforming compound 14 into
1-methoxy-2-(1-methoxy-9H-carbazol-3-ylmethyl)-3-methyl-9H-
carbazole (16) which represents an isomurrafoline-F (Scheme 5).
The structure of by-product 14 resulting from Friedel–Crafts
alkylation resembles that of murrafoline-F (3) but has a different
oxygenation pattern. Removal of the Boc groups using the reac-
tion conditions described above led to the deprotected biscarb-
azole 15. Reduction of 15 with lithium aluminium hydride
afforded the isomurrafoline-F 16.k
Fig. 3 NOESY spectrum of compound 14.
Under optimised conditions, the di-Boc-oxydimurrayafoline
13 was obtained in 56% yield along with compound 14 resulting
from Friedel–Crafts alkylation. Presumably, the intermediate
mesylate readily generates a benzylic cation. Thus, on treatment
of the hydroxymethylcarbazoles 11 with mesyl chloride, attack
of the liberated chloride ion as nucleophile leads to the chloro-
methylcarbazoles 12. The present conditions, generation of the
mesylate with substoichiometric amounts of methanesulfonic
anhydride in the absence of chloride ions, open up the possibility
of nucleophilic attack by the remaining benzylic alcohol 11a
to provide ether 13. Electrophilic substitution by attack of the
benzylic cation at C-2 of the carbazole nucleus of 11a affords
14. The structural assignment for 14 is supported by the spectro-
scopic data (1H NMR, 13C NMR, COSY and HSQC) and the
linkage is confirmed by the NOESY spectrum (Fig. 3 and ESI‡).
For completion of the synthesis of oxydimurrayafoline (1),
the two Boc protecting groups had to be removed from
Conclusions
In conclusion, via our palladium-catalysed approach we have
achieved a highly efficient access to mukonine (4e) in only two
steps and 91% overall yield. This represents the best current
route to mukonine (4e). Using mukonine (4e) as key inter-
mediate, we have completed the first total synthesis of oxydimur-
rayafoline (1) in six steps and 43% overall yield starting from
commercially available compounds.
We are indebted to Professor Hiroshi Furukawa and Professor
Chihiro Ito (Faculty of Pharmacy, Meijo University, Nagoya,
This journal is © The Royal Society of Chemistry 2012
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Japan) for providing the original 1H NMR spectrum of oxy-
dimurrayafoline. H.-J. K. is grateful to the Japan Society for Pro-
motion of Science (JSPS) for a fellowship. We thank the
Deutsche Forschungsgemeinschaft for financial support (grant
KN 240/16-1).
(b) D. P. Chakraborty, in The Alkaloids, ed. G. A. Cordell, Academic
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Notes and references
§Spectroscopic data for mukonine (4e): colourless crystals, mp
199–200 °C (lit.11: 195 °C); UV (MeOH): λ = 219 (sh), 236, 247, 267,
276, 310, 320, 335 (sh) nm; IR (ATR): ν = 3371, 3315, 3007, 2949,
2845, 1692, 1631, 1609, 1582, 1499, 1447, 1435, 1407, 1348, 1315,
1291, 1257, 1230, 1181, 1157, 1106, 1092, 1034, 1010, 989, 912, 880,
841, 756, 732, 683, 638 cm−1; H NMR (500 MHz, CDCl3): δ = 3.98
1
(s, 3 H), 4.06 (s, 3 H), 7.29 (ddd, J = 7.8 Hz, 6.3 Hz, 1.3 Hz, 1 H), 7.46
(m, 2 H), 7.60 (d, J = 1.4 Hz, 1 H), 8.10 (dd, J = 7.8 Hz, 0.9 Hz, 1 H),
8.48 (d, J = 0.9 Hz, 1 H), 8.49 (br s, 1 H); 13C NMR (125 MHz,
CDCl3): δ = 52.19 (CH3), 55.88 (CH3), 106.80 (CH), 111.37 (CH),
116.36 (CH), 120.42 (CH), 120.90 (CH), 122.03 (C), 123.72 (C),
123.87 (C), 126.49 (CH), 133.02 (C), 139.62 (C), 145.19 (C), 168.11
(CvO); MS (EI): m/z (%) = 255 (M+, 100), 240 (42), 224 (33), 212 (8),
196 (10), 181 (14), 153 (17), 126 (11), 112 (8); anal. calc. for
C15H13NO3: C 70.58, H 5.13, N 5.49; found: C 70.31, H 5.36, N 5.39.
¶Crystal data for 3-chloromethyl-1-methoxy-9-tosyl-9H-carbazole
(12b): C21H18ClNO3S, crystal size 0.42 × 0.28 × 0.15 mm3, M =
399.87 g mol−1, monoclinic, space group P21/c, λ = 0.71073 Å, a =
11.270(2), b = 12.954(2), c = 13.331(1) Å, β = 108.90(1)°, V =
1841.3(5) Å3, Z = 4, ρc = 1.442 g cm−3, μ = 0.343 mm−1, T = 198(2) K,
θ range = 3.18 to 27.03°, reflections collected: 64 231; independent:
4022 (Rint = 0.1037). The structure was solved by direct methods and
refined by full-matrix least-squares on F2; R1 = 0.0352, wR2 = 0.0728
[I > 2σ(I)]; maximal residual electron density: 0.235 e Å−3. CCDC
878261.
4 Palladium-catalysed synthesis, reviews: (a) H.-J. Knölker, Curr. Org.
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kSpectroscopic data for oxydimurrayafoline (1): colourless crystals, mp
114–115 °C (decomp.) (lit.6: oil); UV (MeOH): λ = 226, 243, 253, 260
(sh), 281, 291, 326, 338 nm; IR (ATR): ν = 3405, 3051, 2927, 2850,
2051, 1724, 1585, 1543, 1502, 1449, 1393, 1337, 1308, 1265, 1229,
5 (a) H. Furukawa, Trends Heterocycl. Chem., 1993, 3, 185; (b) S. Tasler
and G. Bringmann, Chem. Rec., 2002, 2, 115.
1
1134, 1104, 1035, 1012, 948, 835, 767, 745, 732, 665 cm−1; H NMR
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7 M. M. Rahman and A. I. Gray, Phytochemistry, 2005, 66, 1601.
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11 D. P. Chakraborty, P. Bhattacharyya, S. Roy, S. P. Bhattacharyya and
A. K. Biswas, Phytochemistry, 1978, 17, 834.
(500 MHz, CDCl3): δ = 4.01 (s, 6 H), 4.76 (s, 4 H), 6.98 (d, J = 0.7 Hz,
2 H), 7.23 (ddd, J = 8.2 Hz, 6.9 Hz, 1.3 Hz, 2 H), 7.41 (ddd, J = 8.2 Hz,
7.3 Hz, 0.9 Hz, 2 H), 7.47 (d, J = 8.1 Hz, 2 H), 7.69 (d, J = 0.7 Hz, 2
H), 8.04 (d, J = 7.8 Hz, 2 H), 8.28 (br s, 2 H); 13C NMR (125 MHz,
CDCl3): δ = 55.70 (2 CH3), 72.83 (2 CH2), 106.60 (2 CH), 111.14 (2
CH), 113.04 (2 CH), 119.57 (2 CH), 120.67 (2 CH), 123.75 (2 C),
124.09 (2 C), 125.83 (2 CH), 129.60 (2 C), 130.30 (2 C), 139.53 (2 C),
145.82 (2 C); ESI-MS (10 eV): m/z = 437 [M + H]+, 890 [2M + NH4]+.
Spectroscopic data for 1-methoxy-2-(1-methoxy-9H-carbazole-3-
ylmethyl)-3-methyl-9H-carbazole (16): colourless crystals, mp
49.5–50.5 °C; UV (MeOH): λ = 226, 235, 241, 250 (sh), 292, 328, 339,
382, 417 nm; IR (ATR): ν = 3412, 3055, 2920, 2851, 2056, 1918, 1711,
1617, 1587, 1500, 1453, 1392, 1337, 1308, 1255, 1229, 1132, 1104,
12 (a) T.-S. Wu, S.-C. Huang, P.-L. Wu and C.-M. Teng, Phytochemistry,
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955.
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P. Gonser and P. G. Jones, Synlett, 1994, 405; (c) H.-J. Knölker,
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1067, 1037, 1010, 943, 903, 870, 829, 766, 741, 629 cm−1 1H NMR
;
(500 MHz, acetone-d6): δ = 2.40 (s, 3 H), 3.91 (s, 3 H), 3.92 (s, 3 H),
4.42 (s, 2 H), 6.91 (s, 1 H), 7.07 (ddd, J = 7.9 Hz, 6.9 Hz, 0.9 Hz, 1 H),
7.16 (ddd, J = 7.9 Hz, 6.9 Hz, 0.9 Hz, 1 H), 7.31 (ddd, J = 8.2 Hz,
7.3 Hz, 1.3 Hz, 1 H), 7.37 (ddd, J = 8.5 Hz, 7.3 Hz, 1.3 Hz, 1 H),
7.41 (s, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.73
(s, 1 H), 7.90 (d, J = 7.9 Hz, 1 H), 8.06 (d, J = 7.6 Hz, 1 H), 10.21 (br s,
1 H), 10.35 (br s, 1 H); 13C NMR (125 MHz, acetone-d6): δ = 20.43
(CH3), 33.17 (CH2), 55.76 (CH3), 61.31 (CH3), 107.88 (CH), 111.97
(CH), 112.10 (CH), 112.35 (CH), 117.73 (CH), 119.43 (CH), 119.61
(CH), 120.76 (CH), 120.90 (CH), 124.15 (C), 124.42 (C), 124.46 (C),
124.89 (C), 126.03 (CH), 126.13 (CH), 129.36 (C), 129.81 (C), 130.10
(C), 132.69 (C), 133.50 (C), 141.04 (C), 141.27 (C), 144.85 (C), 146.68
(C); ESI-MS (10 eV): m/z = 421.2 [M + H]+, 858.5 [2M + NH4]+; MS
(EI): m/z (%) = 420 (M+, 100), 405 (12), 389 (8), 373 (7), 359 (5), 223
(8), 210 (7); HRMS: m/z calc. for C28H24N2O2 (M+): 420.1838; found:
420.1822.
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