Total synthesis of the cyclic monoterpenoid pyrano[3,2-a]carbazole alkaloids derived from 2-hydroxy-6-methylcarbazole

Article abstract of DOI:10.1039/c4ob01151a

The synthesis of seven pyrano[3,2-a]carbazole alkaloids has been achieved using their putative biogenetic precursor 2-hydroxy-6-methylcarbazole as key intermediate. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01151a

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Biomolecular Chemistry
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Total synthesis of the cyclic monoterpenoid
pyrano[3,2-a]carbazole alkaloids derived from
2-hydroxy-6-methylcarbazole†‡
Cite this: Org. Biomol. Chem., 2014,
12, 6490
Received 4th June 2014,
Accepted 7th July 2014
Cemena Gassner, Ronny Hesse, Arndt W. Schmidt and Hans-Joachim Knölker*
DOI: 10.1039/c4ob01151a
The synthesis of seven pyrano[3,2-a]carbazole alkaloids has been achieved using their putative biogenetic
www.rsc.org/obc
precursor 2-hydroxy-6-methylcarbazole as key intermediate.
Introduction
The research groups of Chakraborty, Furukawa, Ito and Wu
have isolated a wide range of biologically active carbazole alka-
loids from plants of the family Rutaceae (genera Murraya, Clau-
sena and Glycosmis).1,2 The pyrano[3,2-a]carbazoles, e.g. 1–9,
are an important subgroup of carbazole alkaloids which
exhibit diverse structural features (Fig. 1).2 In 1964, girinim-
bine (1) was among the first carbazole alkaloids which have
been isolated by Chakraborty et al. from terrestrial plants.3
Only two years later, the same group described the isolation of
the corresponding prenyl-substituted homologue mahanim-
bine (2).4 Biogenetically, both compounds derive from
2-hydroxy-3-methylcarbazole by fusion with either prenyl or
geranyl diphosphate.2 Originally, girinimbine was erroneously
assigned as structure 3,3a but subsequently it had to be re-
assigned as 1.3b,c,d Isogirinimbine (3) biogenetically could have
been formed from 2-hydroxy-6-methylcarbazole (10) and prenyl
diphosphate as C5 building block (Scheme 1). Interestingly,
although isogirinimbine (3) has not been found in nature so
far, the corresponding carbazole alkaloids 4–9 resulting from
fusion of 2-hydroxy-6-methylcarbazole (10) and geranyl diphos-
phate were isolated from natural sources.2 In 1970, Kapil et al.
isolated mahanimbicine [(+)-4] and bicyclomahanimbicine (6)
from Murraya koenigii.5 Subsequently, Crombie and Whiting
et al. proposed the correct structure for bicyclomahanimbicine
(6).6 It is interesting to note that also in 1970, Joshi et al.
obtained (−)-4 from the leaves of the same plant and named it
isomahanimbine,7 however, the absolute configuration was
not determined. The structures of 4 and 6 were supported by
synthesis.4c,d,5
Fig. 1 Naturally occurring pyrano[3,2-a]carbazole alkaloids 1–9.
Wu et al. isolated murrayamine-J (5),8 murrayamine-M (7)8
and murrayamine-G (8),9 from the leaves of Murraya euchresti-
folia. The hexacyclic pyrano[3,2-a]carbazole alkaloid isomurray-
azoline (9) was obtained in 1982 by Chakraborty et al. from the
stem bark of Murraya koenigii.10
We have developed diverse synthetic approaches to pyrano-
[3,2-a]carbazoles including girinimbine (1), mahanimbine (2),
pyrayafoline A–E and monoterpenoid pyrano[3,2-a]carbazole
alkaloids.11–14 Herein, we describe the synthesis of isogirinim-
bine (3), ( )-mahanimbicine [( )-isomahanimbine] [( )-4],
murrayamine-J (5) and the cyclic monoterpenoid pyrano[3,2-a]-
carbazole alkaloids 6–9, which biogenetically derive from
Department Chemie, Technische Universität Dresden, Bergstrasse 66, 01069 Dresden,
Germany. E-mail: hans-joachim.knoelker@tu-dresden.de; Fax: +49 351 463-37030
†Part 121 of Transition Metals in Organic Synthesis; for Part 120, see ref. 14c.
‡Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for all compounds. CCDC 1000251. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4ob01151a
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Scheme 1 Synthetic route to the pyrano[3,2-a]carbazoles 3–9.
2-hydroxy-6-methylcarbazole (10). Key steps of our approach
are an efficient construction of the carbazole 10 based on our
palladium-catalyzed route15 and a subsequent annulation of
either a C5 or a C10 building block (Scheme 1). The substi-
tution pattern present in compound 10 has been generated
previously in our synthesis of 7-oxygenated carbazole
alkaloids.16
Scheme 2 Synthesis of isogirinimbine (3). Reagents and conditions: (a)
1.3 equiv. 11, 5 mol% Pd(OAc)2, 10 mol% SPhos, 1.4 equiv. Cs2CO3,
toluene, reflux, 17.5 h, 98%; (b) 3 mol% Pd(OAc)2, 10 mol% K2CO3,
PivOH, 100 °C, 20.5 h, 89% 14 and ≤5% 15; (c) 1.9 equiv. BBr3, −78 °C to
rt, 2 h, 91%; (d) 1. 1.1 equiv. 16, 1.1 equiv. TFAA, 2.8 equiv. DBU, 0.2 mol%
Results and discussion
Buchwald–Hartwig coupling of p-toluidine (11) and m-bromo-
anisole (12) in the presence of SPhos (2-dicyclohexylphos-
phino-2′,6′-dimethoxybiphenyl)17 afforded the diarylamine 13 CuI, MeCN, −15 °C to rt, 6.5 h; 2. toluene, reflux, 23 h, 63% 3 and
≤3% 17.
(Scheme 2). Alternatively, compound 13 has been prepared
quantitatively on a 25 g scale by Buchwald–Hartwig coupling
of m-anisidine and p-bromotoluene (see Experimental
section).16 Palladium(II)-catalyzed oxidative cyclization of 13
provided the desired 2-methoxy-6-methylcarbazole (14)16 as
major product (89% yield) and up to 5% of glycoborine (15)18
as by-product. Cleavage of the methyl ether led to 2-hydroxy-6-
methylcarbazole (10). Formation of the dimethylpropargyl
ether via Godfrey’s method,19 followed by a thermally induced
sequence of Claisen rearrangement, 1,5-hydrogen shift and
electrocyclic ring closure20 provided isogirinimbine (3) in 63%
yield and as a by-product the furo[3,2-a]carbazole 17 in up to
3% yield. The structure of isogirinimbine (3) has been fully
supported by its spectroscopic data which confirm it as an
isomer of the natural product girinimbine (1). The 3-methyl-
regioisomer of 17 was obtained previously as by-product in our
synthesis of girinimbine (1).12
We envisaged ( )-mahanimbicine [( )-isomahanimbine]
[( )-4] as crucial intermediate for the synthesis of the formyl
derivative murrayamine-J (5) and the cyclic monoterpenoid
pyrano[3,2-a]carbazole alkaloids 6–9. Thus, we have developed
two alternative synthetic routes for the synthesis of ( )-4. The
Scheme 3 Synthesis of ( )-mahanimbicine [( )-4]. Reagents and con-
ditions: (a) 1. 1.5 equiv. 18, 2.0 equiv. DBU, 0.5 mol% CuI, MeCN, rt, 22 h;
2. toluene, reflux, 22.5 h, 49% ( )-4 and ≤5% 19.
( )-mahanimbicine [( )-4] in 49% yield along with the furo-
[3,2-a]carbazole 19 in up to 5% yield as by-product.
Alternatively, 2-methoxy-6-methylcarbazole (14) was initially
protected by transformation to the N-tosylcarbazole 20
first approach requires no protecting group (Scheme 3). Reac-
tion of 2-hydroxy-6-methylcarbazole (10) with the carbonate
1821 in the presence of catalytic amounts of copper(I) iodide
and subsequent thermally induced rearrangement provided
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Scheme 5 Synthesis of murrayamine-J (5), bicyclomahanimbicine (6)
and murrayamine-M (7). Reagents and conditions: (a) 8.0 equiv. DDQ,
MeOH–THF–water (10 : 1 : 1), rt, 6.25 h, 67%; (b) hν, toluene, rt, 14 d,
39%; (c) 6.6 equiv. DDQ, MeOH–THF–water (10 : 1 : 2), rt, 5 h, 51%.
genetic routes. Oxidation of ( )-mahanimbicine [( )-4] with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) afforded
murrayamine-J (5) (Scheme 5). Intramolecular [2 + 2] cyclo-
addition of [( )-4] led to bicyclomahanimbicine (6). Oxidation
of 6 with DDQ gave murrayamine-M (7).
For the Brønsted acid promoted cycloisomerization of
( )-mahanimbicine [( )-4], we took advantage of our previous
study on the conversion of mahanimbine (2) into cyclomaha-
nimbine and mahanimbidine.12 On treatment of ( )-4 with
one equivalent camphor-10-sulfonic acid (CSA) at room tem-
perature to 70 °C for 16 d, ( )-4 and rapidly formed 9 were both
completely converted into 8. Thus, murrayamine-G (8) was
obtained in 65% yield (Scheme 6, Table 1). Cycloisomerization
of ( )-mahanimbicine [( )-4] in the presence of catalytic
amounts of CSA in hexane at room temperature afforded in
70% yield a 1 : 1 mixture of 8 and 9 which after separation by
preparative HPLC led to pure isomurrayazoline (9). Our syn-
Scheme 4 Alternative route to ( )-mahanimbicine [( )-4]. Reagents
and conditions: (a) 4.1 equiv. NaH, 1.5 equiv. TsCl, THF, 0 °C to rt,
16.25 h, 80%; (b) 1. 3.0 equiv. BBr3, CH2Cl2, −78 °C to rt, 2.5 h; 2. 2.0
equiv. 18, 3.0 equiv. DBU, 0.5 mol% CuI, MeCN, rt, 22 h; 3. xylene, reflux,
27.5 h, 82% (3 steps, ratio 21/22 = 7.7 : 1); (c) 4.0 equiv. TBAF, THF, 75 °C,
6 h, 79% ( )-4 and 9% 23.
(Scheme 4). Cleavage of the methyl ether, copper-catalyzed
reaction with the carbonate 18 and thermal rearrangement led
in 82% yield to a mixture of the pyrano[3,2-a]carbazole 21 and
the pyrano[2,3-b]carbazole 22 in a ratio of 7.7 : 1. Finally,
removal of the tosyl group by treatment with tetrabutyl-
ammonium fluoride22 at elevated temperature provided
( )-mahanimbicine [( )-4].
Using the first approach (Scheme 3), ( )-mahanimbicine
[( )-4] is available in 5 steps and 40% overall yield based on
p-bromotoluene. Our second route (Scheme 4) leads to ( )-4 in
7 steps and 46% overall yield based on the same starting
material. It is interesting to note, that annulation of the pyran
ring with the carbonate 18 at 2-hydroxy-6-methylcarbazole (10)
provides the furo[3,2-a]carbazole 19 as by-product, whereas
annulation at the corresponding N-tosylcarbazole gives the
pyrano[2,3-b]carbazole 22 as by-product. This outcome is
explained by the steric demand of the tosyl group which sup-
presses the formation of N-tosyl-19 with the quaternary carbon
center in close proximity to the protecting group; instead
linear pyran annulation and thus formation of compound 22
is observed.
Using ( )-mahanimbicine [( )-4] as relay compound the
carbazole alkaloids 5–9 are accessible, following putative bio-
Scheme 6 Synthesis of murrayamine-G (8) and isomurrayazoline (9).
Reagents and conditions: see Table 1.
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used: s: singlet, d: doublet, t: triplet, m: multiplet and br:
broad. Mass spectra were recorded on a Finnigan MAT-95
spectrometer (electron impact, 70 eV) or by GC/MS-coupling
using an Agilent Technologies 6890 N GC System equipped
with a 5973 Mass Selective Detector (electron impact, 70 eV).
ESI-MS spectra were recorded on an Esquire LC with an ion
trap detector from Bruker. Positive and negative ions were
detected. Elemental analyses were measured on an EuroVector
EuroEA3000 elemental analyzer.
Table 1 Cycloisomerization of ( )-mahanimbicine [( )-4]
Reaction conditions
Yield
Ratio, 8 : 9
1.0 equiv. CSA, PhMe, rt to 70 °C, 16 d
8 mol% CSA, hexane, rt, 11.5 d
65% 8
70% 8, 9
—
1 : 1
thetic route leads to isomurrayazoline (9) in 8 steps and 16%
overall yield based on p-bromotoluene.
3-Methoxy-N-(4-methylphenyl)aniline (13). Method A: A solu-
tion of m-bromoanisole (12) (2.00 g, 10.7 mmol) in toluene
(5 mL) was added dropwise over a period of 5 h to a suspen-
sion of p-toluidine (11) (1.51 g, 14.1 mmol), palladium(II)
acetate (123 mg, 548 µmol), SPhos (440 mg, 1.07 mmol) and
caesium carbonate (4.90 g, 15.0 mmol) in toluene (18 mL) at
reflux and the mixture was heated at reflux for 12.5 h (total
reaction time: 17.5 h). After cooling to room temperature, the
mixture was filtered through a short pad of Celite (diethyl
ether) and the solvent was evaporated. Purification of the
residue by column chromatography on silica gel (pentane–
dichloromethane–ethyl acetate, 12 : 5 : 1) provided 3-methoxy-
N-(4-methylphenyl)aniline (13) as colourless solid, yield: 2.24 g
(98%), m.p. 68–70 °C. UV (MeOH): λ = 283 nm. IR (ATR): ν =
3365, 3000, 1596, 1512, 1492, 1463, 1438, 1389, 1324, 1302,
1283, 1256, 1237, 1198, 1158, 1107, 1032, 992, 951, 832, 774,
Conclusions
We have developed a highly efficient palladium-catalyzed route
to 2-hydroxy-6-methylcarbazole (10) (3 steps, 81% overall
yield). Using appropriate C5 or C10 building blocks, compound
10 has been transformed into isogirinimbine (3) and ( )-maha-
nimbicine [( )-4], respectively. ( )-Mahanimbicine [( )-4]
served as central intermediate for the synthesis of cyclic mono-
terpenoid pyrano[3,2-a]carbazole alkaloids and could be con-
verted into murrayamine-J (5), bicyclomahanimbicine (6),
murrayamine-M (7), murrayamine-G (8) and isomurrayazoline (9).
The spectroscopic data of the alkaloids were in full agreement
with those reported for the corresponding natural products.
For the compounds 3, 5 and 7–9 we have achieved the first
total synthesis. The present results emphasize the utility of our
synthetic methodology and demonstrate that for the first time
also the whole series of carbazole alkaloids which is isomeric
to girinimbine (1) and mahanimbine (2) is available by syn-
thesis on large scale. The biological properties of 3–9, e.g. their
potential anti-TB activity,23 are under further investigation.
1
753, 686, 649, 632 cm−1. H NMR (500 MHz, CDCl3): δ = 2.31
(s, 3 H), 3.77 (s, 3 H), 5.62 (br s, 1 H), 6.43–6.45 (m, 1 H),
6.58–6.60 (m, 2 H), 7.01–7.04 (m, 2 H), 7.09–7.11 (m, 2 H),
7.13–7.16 (m, 1 H). 13C NMR and DEPT (125 MHz, CDCl3): δ =
20.68 (CH3), 55.16 (CH3), 102.33 (CH), 105.43 (CH), 109.32
(CH), 119.36 (2 CH), 129.83 (2 CH), 130.03 (CH), 131.18 (C),
139.91 (C), 145.39 (C), 160.67 (C). EI-MS: m/z (%) = 213 (100)
[M+], 197 (4), 182 (4), 168 (4), 154 (5). HRMS: m/z calcd for
C14H15NO [M+]: 213.1154; found: 213.1158. Elemental analysis
calcd for C14H15NO: C 78.84, H 7.09, N 6.57; found: C 78.97,
H 7.08, N 6.40%.
Experimental
General methods
All reactions were carried out in oven-dried glassware using
Crystal data for 13: C14H15NO, M = 213.27 g mol−1, crystal
dry solvents under an argon atmosphere unless stated other- size: 0.50 × 0.40 × 0.10 mm3, monoclinic, space group P21/c,
wise. Acetonitrile, dichloromethane, tetrahydrofuran and a = 8.856(1) Å, b = 13.861(1) Å, c = 10.868(1) Å, β = 92.41(1)°,
toluene were dried using
a ,
solvent purification system V = 1332.9(2) Å3, Z = 4, ρcalcd = 1.063 g cm−3, μ = 0.067 mm−1
(MBraun-SPS). Palladium(II) acetate was recrystallized from T = 293(2) K, λ = 0.71073 Å, θ range 3.26–25.37°, 18 034 reflec-
glacial acetic acid. All other chemicals were used as received tions collected, 2165 independent reflections (Rint = 0.0280),
from commercial sources. Flash chromatography was per- 151 parameters. The structure was solved by direct methods
formed on a Büchi Sepacore system equipped with an UV and refined by full-matrix least-squares on F2; final R indices
monitor
using
silica
gel
from
Acros
Organics [I > 2σ(I)]: R1 = 0.0436, wR2 = 0.1205; maximal residual electron
(0.035–0.070 mm). Thin layer chromatography was performed density: 0.179 e Å−3 (Fig. S1‡) CCDC 1000251.
with TLC plates from Merck (60 F254) using UV-light for visua-
Method B: m-Anisidine (18.9 g, 153 mmol) was added por-
lization. Melting points were measured on a Gallenkamp MPD tionwise over a period of 3 h to a solution of p-bromotoluene
350 melting point apparatus. Ultraviolet spectra were recorded (20.0 g, 117 mol), caesium carbonate (45.7 g, 140 mmol), rac-
on a Perkin Elmer 25 UV/VIS spectrometer. Infrared spectra BINAP (3.61 g, 5.80 mmol) and palladium(II) acetate (1.53 g,
were recorded on a Thermo Nicolet Avatar 360 FT-IR spectro- 6.82 mmol) in toluene (80 mL) at reflux. The mixture was
meter using the ATR method (Attenuated Total Reflectance). heated at reflux for 13 h (total reaction time 16 h), then cooled
NMR spectra were recorded on Bruker Avance II 300, DRX 500 to room temperature, filtered over a short pad of silica gel and
and Avance III 600 spectrometers. Chemical shifts δ are Celite (diethyl ether), and the solvent was removed. Purifi-
reported in parts per million with the non-deuterated solvent cation of the residue by column chromatography on silica gel
as internal standard.24 The following abbreviations have been (petroleum ether–acetone, 15 : 1) provided the diarylamine 13
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as light yellow solid, yield: 25.4 g (100%). Spectroscopic data, 7.74 (s, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 8.32 (s, 1 H), 9.94 (br s,
see above.
1 H). 13C NMR and DEPT (125 MHz, acetone-d6): δ = 21.48 (CH3),
2-Methoxy-6-methylcarbazole (14) and glycoborine (5- 97.34 (CH), 109.06 (CH), 110.92 (CH), 117.03 (C), 119.78 (CH),
methoxy-3-methylcarbazole)
(15). Palladium(II)
acetate 121.46 (CH), 124.65 (C), 125.99 (CH), 128.42 (C), 139.17 (C),
(126 mg, 561 μmol) was added at 100 °C to a mixture of the 142.93 (C), 157.38 (C). EI-MS (70 eV): m/z (%) = 197 (100) [M+],
diarylamine 13 (4.02 g, 18.8 mmol), potassium carbonate 196 (55), 167 (7). HRMS: m/z calcd for C13H11NO [M+]: 197.0841;
(261 mg, 1.89 mmol) and pivalic acid (10.2 g) in a 50 mL test found: 197.0855.
tube. The mixture was heated and vigorously stirred at 100 °C
Isogirinimbine (3,3,8-trimethyl-3,11-dihydropyrano[3,2-a]-
for 20.5 h, then cooled to room temperature, diluted with ethyl carbazole) (3) and 1,1,7-trimethyl-2-methylene-1,10-dihydro-
acetate and washed with a saturated solution of potassium car- 2H-furo[3,2-a]carbazole (17). A solution of 2-methylbut-3-yn-
bonate, brine and water. The aqueous layers were extracted 2-ol (16) (54 µL, 47 mg, 0.56 mmol), DBU (114 µL, 116 mg, 762
with ethyl acetate. The combined organic layers were dried µmol) and trifluoroacetic anhydride (78 µL, 0.12 g, 0.56 mmol)
over sodium sulfate and the solvent was evaporated. Purifi- in acetonitrile (2 mL) was stirred at −15 °C for 90 min. The
cation of the residue by column chromatography on silica gel mixture was then added to a solution of 2-hydroxy-6-methylcarb-
(pentane–dichloromethane–ethyl acetate, gradient elution, azole (10) (100 mg, 507 µmol) and copper(I) iodide (0.2 mg,
119 : 1 : 0.2 to 29 : 1 : 0.2) provided 2-methoxy-6-methylcarb- 1 μmol) in acetonitrile (4 mL) and the mixture was stirred at
azole (14) as colourless solid, yield: 3.52 g (89%), m.p. −15 °C for 40 min. DBU (98 µL, 0.10 g, 0.66 mmol) was added
230–233 °C (ref. 16: 227–228 °C). For spectroscopic data, see and the mixture was stirred at −15 °C for 3 h and at room
ref. 16. Glycoborine (5-methoxy-3-methylcarbazole) (15) was temperature for 90 min. The mixture was washed twice with
obtained from the less polar fraction as by-product in up to water and brine and the solvent was evaporated. Toluene
5% yield, m.p. 138–140 °C (ref. 18a: 155–156 °C). UV (MeOH): (10 mL) was added to the residue, the solution was heated at
λ = 226, 238, 244, 254 (sh), 277 (sh), 287, 323, 337 mm. Fluo- reflux for 23 h and the solvent was evaporated. Purification of
rescence (MeOH): λex = 287 nm, λem = 345, 359 nm. IR (ATR): the residue by column chromatography on silica gel (petro-
ν = 3398, 3048, 3012, 2913, 2846, 1624, 1604, 1585, 1554, 1506, leum ether–dichloromethane, gradient elution, 99 : 1 to 3 : 1)
1473, 1453, 1438, 1388, 1345, 1314, 1294, 1258, 1225, 1178, provided isogirinimbine (3) as colourless solid, yield: 84.4 mg
1101, 1058, 973, 915, 879, 802, 781, 745, 716, 698, 620, 590, (63%), m.p. 186–187 °C. UV (MeOH): λ = 221 (sh), 237, 278
535 cm−1. 1H NMR (500 MHz, CDCl3): δ = 2.54 (s, 3 H), 4.09 (s, (sh), 289, 332, 337, 353 nm. Fluorescence (MeOH): λex
=
3 H), 6.67 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 7.21 (dd, 289 nm, λem = 362, 378 nm. IR (ATR): ν = 3415, 2969, 2919,
J = 8.2, 1.3 Hz, 1 H), 7.29 (d, J = 8.2 Hz, 1 H), 7.32 (t, J = 8.0 Hz, 2853, 1640, 1606, 1519, 1474, 1460, 1418, 1400, 1373, 1359,
1 H), 7.94 (br s, 1 H), 8.12 (d, J = 0.8 Hz, 1 H). 13C NMR and 1339, 1295, 1207, 1157, 1114, 1071, 1036, 898, 882, 859, 800,
DEPT (125 MHz, CDCl3): δ = 21.43 (CH3), 55.37 (CH3), 100.10 746, 721, 704, 652, 585, 578, 562, 540 cm−1
.
1H NMR
(CH), 103.48 (CH), 109.52 (CH), 112.40 (C), 122.77 (C), 122.89 (500 MHz, acetone-d6): δ = 1.44 (s, 6 H), 2.45 (s, 3 H), 5.76 (d, J
(CH), 126.16 (CH), 126.42 (CH), 128.86 (C), 136.82 (C), 141.16 = 9.8 Hz, 1 H), 6.63 (d, J = 8.4 Hz, 1 H), 6.90 (d, J = 9.8 Hz, 1 H),
(C), 156.19 (C). EI-MS (70 eV): m/z (%) = 211 (100) [M+], 7.11 (dd, J = 8.2, 1.1 Hz, 1 H), 7.30 (d, J = 8.2 Hz, 1 H), 7.76 (d, J
196 (27), 168 (68), 167 (19). Elemental analysis calcd for C14H13NO: = 0.6 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 10.25 (br s, 1 H). 13C
C 79.59, H 6.20, N 6.63; found: C 79.86, H 6.36, N 6.69%.
NMR and DEPT (125 MHz, acetone-d6): δ = 21.48 (CH3), 27.84
2-Hydroxy-6-methylcarbazole (10). A 1 M solution of boron (2 CH3), 76.48 (C), 105.66 (C), 109.71 (CH), 111.18 (CH), 118.18
tribromide in dichloromethane (1.00 mL, 1.00 mmol) was (C), 118.34 (CH), 119.98 (CH), 121.01 (CH), 124.70 (C), 126.42
added at −78 °C to a solution of 2-methoxy-6-methylcarbazole (CH), 128.88 (C), 129.99 (CH), 137.99 (C), 139.34 (C), 152.32
(14) (109 mg, 516 µmol) in dichloromethane (25 mL) and the (C). EI-MS: m/z (%) = 263 (28) [M+], 248 (100), 233 (5), 217 (4),
solution was stirred at −78 °C for 30 min. The cooling was 204 (9), 124 (14). HRMS: m/z calcd for C18H17NO [M+]:
removed and the mixture was stirred for 90 min. Methanol 263.1310; found: 263.1302.
(1 mL) was added at 0 °C and the mixture was washed with a
1,1,7-Trimethyl-2-methylene-1,10-dihydro-2H-furo[3,2-a]carb-
small amount of water. The aqueous layer was extracted once azole (17) was obtained as a by-product in up to 3% yield as col-
1
with diethyl ether, the combined organic layers were dried ourless oil. H NMR (300 MHz, acetone-d6): δ = 1.68 (s, 6 H),
over sodium sulfate and the solvent was evaporated. Purifi- 2.46 (s, 3 H), 4.35 (d, J = 2.6 Hz, 1 H), 4.61 (d, J = 2.6 Hz, 1 H),
cation of the residue by column chromatography on silica gel 6.80 (d, J = 8.3 Hz, 1 H), 7.14 (dd, J = 8.1, 1.0 Hz, 1 H), 7.32 (d,
(petroleum ether–acetone, 2 : 1) provided 2-hydroxy-6-methyl- J = 8.1 Hz, 1 H), 7.82 (d, J = 1.0 Hz, 1 H), 7.92, (d, J = 8.3 Hz,
carbazole (10) as colourless solid, yield: 93 mg (91%), 1 H), 10.21 (br s, 1 H). 13C NMR and DEPT (75 MHz, acetone-
m.p. 262–264 °C (ref. 5: 245 °C, decomp.). UV (MeOH): λ = 260, d6): δ = 21.46 (CH3), 28.69 (2 CH3), 44.78 (C), 82.07 (CH2),
305, 322 (sh), 335 (sh) nm. IR (ATR): ν = 3399, 3286, 2913, 105.52 (CH), 111.39 (CH), 116.22 (C), 120.02 (CH), 120.25 (C),
2855, 1617, 1508, 1488, 1461, 1416, 1343, 1308, 1295, 1275, 120.48 (CH), 124.56 (C), 126.83 (CH), 129.07 (C), 136.56 (C),
1218, 1158, 1134, 1106, 1036, 955, 937, 885, 836, 824, 805, 766, 139.62 (C), 155.55 (C), 173.56 (C). ESI-MS (−25 V): m/z = 262
1
730, 690, 652, 627 cm−1. H NMR (500 MHz, acetone-d6): δ = [(M − H)−].
2.45 (s, 3 H), 6.71 (dd, J = 8.4, 2.1 Hz, 1 H), 6.90 (d, J = 2.1 Hz,
Methyl 3,7-dimethyloct-6-en-1-yn-3-yl carbonate (18). A 0.5 M
1 H), 7.08 (dd, J = 8.2, 1.0 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), solution of ethynylmagnesium bromide in THF (51.0 mL,
6494 | Org. Biomol. Chem., 2014, 12, 6490–6499
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25.5 mmol) was added dropwise over a period of 15 min to a 6.64 (d, J = 9.8 Hz, 1 H), 6.72 (dd, J = 8.3, 0.5 Hz, 1 H), 7.14 (dd,
solution of 6-methylhept-5-en-2-one (2.94 mL, 2.52 g, J = 8.2, 1.1 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), 7.73 (s, 1 H), 7.74
20.0 mmol) in THF (20 mL) at −78 °C. The cooling was (d, J = 8.3 Hz, 1 H), 7.84 (br s, 1 H). 13C NMR and DEPT
removed and the mixture was stirred for 2.5 h. The mixture (125 MHz, CDCl3): δ = 17.63 (CH3), 21.44 (CH3), 22.73 (CH2),
was cooled to −78 °C, methyl chloroformate (3.06 mL, 3.74 g, 25.66 (CH3), 25.95 (CH3), 40.80 (CH2), 78.30 (C), 104.51 (C),
39.6 mmol) was added dropwise over a period of 5 min, the 109.44 (CH), 110.06 (CH), 117.30 (CH), 117.39 (C), 119.45 (CH),
cooling was removed and the mixture was stirred for 2 h. A 120.39 (CH), 124.11 (CH), 124.14 (C), 125.73 (CH), 128.65 (CH),
saturated aqueous solution of sodium hydrogencarbonate and 129.01 (C), 131.71 (C), 136.56 (C), 137.70 (C), 151.70 (C). EI-MS
diethyl ether were added, and the layers were separated. The (70 eV): m/z (%) = 331 (45) [M+], 288 (11), 248 (100), (10), 210
organic layer was washed with water and brine. The aqueous (51), 209 (36), 180 (17). Elemental analysis calcd for C23H25NO:
layers were extracted with diethyl ether, the combined organic C 83.34, H 7.60, N 4.23; found: C 83.59, H 7.88, N 4.23%.
layers were dried over sodium sulfate and the solvent was eva-
The furo[3,2-a]carbazole 19 was obtained as by-product in
1
porated. Purification of the residue by column chromatography up to 5% yield. H NMR (500 MHz, CDCl3): δ = 1.35 (s, 3 H),
on silica gel (pentane–diethyl ether, gradient elution, 100 : 1 to 1.47–1.53 (m, 1 H), 1.53 (s, 3 H), 1.64 (s, 3 H), 1.78 (ddd, J =
20 : 1) provided carbonate 18 as colourless liquid, yield: 3.68 g 13.4, 11.9, 4.6 Hz, 1 H), 1.90–1.98 (m, 1 H), 2.12 (ddd, J = 13.4,
(88%). IR (ATR): ν = 3287, 2959, 2923, 2853, 1754, 1699, 1684, 11.9, 4.8 Hz, 1 H), 2.51 (s, 3 H), 4.24 (d, J = 2.8 Hz, 1 H), 4.77
1651, 1635, 1441, 1376, 1338, 1257, 1165, 1114, 1074, 1022, 940, (d, J = 2.8 Hz, 1 H), 4.97 (m, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 7.17
1
884, 834, 790, 666, 631 cm−1. H NMR (500 MHz, CDCl3): δ = (dd, J = 8.2, 1.0 Hz, 1 H), 7.30 (d, J = 8.2 Hz, 1 H), 7.74 (m,
1.60 (s, 3 H), 1.66 (d, J = 0.8 Hz, 3 H), 1.70 (s, 3 H), 1.82 (ddd, J = 1 H), 7.77 (d, J = 1.0 Hz, 1 H), 7.83 (d, J = 8.3 Hz, 1 H). 13C NMR
13.6, 11.0, 5.9 Hz, 1 H), 1.96 (ddd, J = 13.6, 10.6, 6.0 Hz, 1 H), and DEPT (125 MHz, CDCl3): δ (ppm) = 17.61 (CH3), 21.58
2.11–2.23 (m, 2 H), 2.58 (s, 1 H), 3.75 (s, 3 H), 5.09 (m, 1 H). 13
C
(CH3), 24.21 (CH2), 25.70 (CH3), 28.65 (CH3), 41.95 (CH2),
NMR and DEPT (125 MHz, CDCl3): δ (ppm) = 17.57 (CH3), 22.79 48.39 (C), 82.67 (CH2), 102.61 (CH), 110.29 (CH), 113.24 (C),
(CH2), 25.59 (CH3), 26.17 (CH3), 41.17 (CH2), 54.29 (CH3), 73.85 119.47 (C), 119.67 (CH), 119.99 (CH), 123.52 (CH), 124.10 (C),
(CH), 76.78 (C), 83.03 (C), 122.85 (CH), 132.43 (C), 153.49 126.29 (CH), 129.40 (C), 132.30 (C), 135.74 (C), 137.95 (C),
(CvO). EI-MS (70 eV): m/z (%) = 210 (0.4) [M+], 151 (7), 119 155.63 (C), 170.22 (C).
(100), 105 (13), 91 (50), 69 (44). Elemental analysis calcd for
C12H18O3: C 68.54, H 8.63; found: C 68.38, H 8.93%.
2-Methoxy-6-methyl-9-tosylcarbazole (20). Sodium hydride
(539 mg of a 60% dispersion in mineral oil, 13.5 mmol) was
( )-Mahanimbicine [( )-isomahanimbine] [( )-4] and 1,7- added at 0 °C to a solution of 2-methoxy-6-methylcarbazole
dimethyl-2-methylene-1-(4-methylpent-3-en-1-yl)-1,10-dihydro- (14) (701 mg, 3.32 mmol) in THF (35 mL) and the mixture was
2H-furo[3,2-a]carbazole (19). Method A: A solution of 3,7- stirred at 0 °C for 1.25 h. p-Toluenesulfonyl chloride (949 mg,
dimethyloct-6-en-1-yn-3-yl methyl carbonate (18) (724 mg, 4.98 mmol) was added at 0 °C, the cooling was removed and
3.44 mmol) in acetonitrile (11.5 mL) was added at room temp- the mixture was stirred for 16.25 h. The mixture was diluted
erature over a period of 8 h to a solution of 2-hydroxy-6-methyl- with diethyl ether and washed with water and brine. The
carbazole (10) (453 mg, 2.30 mmol), DBU (0.69 mL, 0.70 g, aqueous layers were extracted with diethyl ether, the combined
4.6 mmol), and copper(I) iodide (2.3 mg, 12 µmol) in aceto- organic layers were dried over sodium sulfate and the solvent
nitrile (59 mL). The mixture was stirred at room temperature was evaporated. Purification of the residue by flash chromato-
for 14 h (total reaction time: 22 h). Diethyl ether was added graphy on silica gel (pentane–dichloromethane–ethyl, 70 : 5 : 1)
and the mixture was washed with a saturated aqueous solution provided 2-methoxy-6-methyl-9-tosylcarbazole (20) as colour-
of ammonium chloride and brine. The aqueous layers were less solid, yield: 969 mg (80%), m.p. 145–148 °C. UV (MeOH): λ
extracted with diethyl ether, the combined organic layers were = 224, 268, 296, 309, 326 nm. Fluorescence (MeOH): λex
=
dried over sodium sulfate, the solvent was evaporated and the 268 nm, λem = 396 nm. IR (ATR): ν = 3091, 2992, 2949, 2917,
residue was dried in vacuum. The crude product was dissolved 2831, 1622, 1580, 1493, 1477, 1453, 1361, 1299, 1280, 1253,
in toluene (40 mL), the solution was heated at reflux for 22.5 h 1190, 1167, 1147, 1130, 1090, 1044, 985, 938, 869, 842, 801,
1
and the solvent was evaporated. Purification of the residue by 777, 736, 705, 675 cm−1. H NMR (500 MHz, acetone-d6): δ =
column chromatography on silica gel (pentane–dichloro- 2.27 (s, 3 H), 2.43 (s, 3 H), 3.95 (s, 3 H), 7.01 (dd, J = 8.6,
methane–ethyl acetate, gradient elution, 294 : 5 : 1 to 69 : 5 : 1) 2.3 Hz, 1 H), 7.25–7.29 (m, 3 H), 7.73–7.77 (m, 3 H), 7.86 (d, J =
provided 10 (154 mg, 34%) and ( )-mahanimbicine [( )-4] as 2.3 Hz, 1 H), 7.90 (d, J = 8.6 Hz, 1 H), 8.14 (d, J = 8.5 Hz, 1 H).
colourless solid, yield: 372 mg (49%), m.p. 137–139 °C (ref. 5 13C NMR and DEPT (125 MHz, acetone-d6): δ = 21.21 (CH3),
and 7: 142 °C). UV (MeOH): λ = 238, 289, 335, 353 nm. Fluo- 21.35 (CH3), 56.07 (CH3), 100.72 (CH), 112.87 (CH), 115.55
rescence (MeOH): λex = 289 nm, λem = 361 nm. IR (ATR): ν = (CH), 120.43 (CH), 120.60 (C), 121.76 (CH), 127.38 (2 CH),
3428, 3409, 3012, 2968, 2916, 2856, 2727, 1639, 1608, 1517, 127.63 (C), 128.10 (CH), 130.73 (2 CH), 134.78 (C), 135.54 (C),
1473, 1454, 1419, 1402, 1374, 1338, 1297, 1223, 1208, 1190, 137.25 (C), 140.76 (C), 146.38 (C), 160.86 (C). EI-MS (70 eV):
1164, 1126, 1090, 1036, 945, 909, 882, 816, 798, 748, 719, 673, m/z (%) = 365 (65) [M+], 210 (100), 167 (26). HRMS: m/z calcd
584 cm−1. 1H NMR (500 MHz, CDCl3): δ = 1.45 (s, 3 H), 1.58 (s, for C21H19NO3S [M+]: 365.1086; found: 365.1099. Elemental
3 H), 1.66 (d, J = 0.8 Hz, 3 H), 1.70–1.82 (m, 2 H), 2.11–2.21 (m, analysis calcd for C21H19NO3S: C 69.02, H 5.24, N 3.83, S 8.77;
2 H), 2.50 (s, 3 H), 5.11 (m, 1 H), 5.66 (d, J = 9.8 Hz, 1 H), found: C 69.14, H 5.20, N 3.82, S 9.31%.
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N-Tosylmahanimbicine (21). A 1 M solution of boron tri- 2 H), 7.24 (d, J = 10.0 Hz, 1 H), 7.24 (m, 1 H), 7.52 (d, J = 0.7
bromide in dichloromethane (4.1 mL, 4.1 mmol) was added Hz, 1 H), 7.61 (d, J = 8.3 Hz, 1 H), 8.04 (d, J = 8.3 Hz, 1 H). 13C
dropwise at −78 °C to a solution of 2-methoxy-6-methyl-9-tosyl- NMR and DEPT (125 MHz, acetone-d6): δ (major isomer) =
carbazole (20) (502 mg, 1.37 mmol). The cooling was removed 17.66 (CH3), 21.23 (CH3), 21.27 (CH3), 23.37 (CH2), 25.83
and the mixture was stirred for 2.5 h. Methanol (4 mL) was (2 CH3), 40.99 (CH2), 78.40 (C), 115.19 (C), 115.89 (CH), 119.61
added, the mixture was diluted with diethyl ether, and washed (CH), 120.02 (CH), 121.02 (CH), 122.80 (CH), 124.49 (C), 124.97
with water and brine. The aqueous layer was extracted with (CH), 127.53 (CH), 127.82 (2 CH), 127.83 (CH), 129.73 (2 CH),
diethyl ether, the combined organic layers were dried over 130.55 (C), 132.08 (C), 133.15 (C), 136.34 (C), 138.19 (C), 139.75
sodium sulfate and the solvent was evaporated. Drying in (C), 145.67 (C), 154.82 (C). ESI-MS (+25 V): m/z (%) = 486.3
vacuum provided crude 2-hydroxy-6-methyl-9-tosylcarbazole [(M + H)+], 988.7 [(2M + NH4)+]. Elemental analysis calcd for
(539 mg) as light yellow solid, m.p. 166–168 °C.
C30H31NO3S: C 74.20, H 6.43, N 2.88, S 6.60; found: C 74.46,
2-Hydroxy-6-methyl-9-tosylcarbazole: UV (MeOH): λ = 222, H 6.68, N 2.97, S 6.49%.
244 (sh), 260, 267, 275, 297, 308 nm. Fluorescence (MeOH): λex
( )-Mahanimbicine [( )-isomahanimbine] [( )-4] and 2,10-
= 260 nm, λem = 381 nm. IR (ATR): ν = 3482, 3035, 2919, 1612, dihydro-2,7-dimethyl-2-(4-methylpent-3-enyl)pyrano[2,3-b]carb-
1558, 1499, 1442, 1398, 1346, 1296, 1268, 1215, 1186, 1161, azole (23). Method B: A 1 M solution of TBAF in THF (0.28 mL,
1114, 1088, 1027, 991, 952, 854, 811, 790, 739, 718, 701, 679, 0.28 mmol) was added at room temperature to a mixture of the
660, 604 cm−1 1H NMR (500 MHz, acetone-d6): δ = 2.28 (s, carbazoles 21 and 22 (68.7 mg, 141 µmol, ratio 21 : 22 = 7.7 : 1,
.
3 H), 2.42 (s, 3 H), 6.92 (dd, J = 8.5, 2.1 Hz, 1 H), 7.23–7.27 (m, see above). The mixture was irradiated in the microwave
3 H), 7.69–7.74 (m, 3 H), 7.81 (d, J = 2.4 Hz, 1 H), 7.82 (d, J = reactor at 300 W and 70 °C for 3 h and then at 75 °C for 2 h. A
8.2 Hz, 1 H), 8.11 (d, J = 8.5 Hz, 1 H), 8.80 (s, 1 H). 13C NMR 1 M solution of TBAF in THF (0.28 mL, 0.28 mmol) was added
and DEPT (125 MHz, acetone-d6): δ = 21.17 (CH3), 21.32 (CH3), and the mixture was irradiated in the microwave reactor at
102.55 (CH), 113.72 (CH), 115.44 (CH), 119.70 (C), 120.16 (CH), 300 W and 75 °C for 1 h. The mixture was diluted with diethyl
121.77 (CH), 127.28 (2 CH), 127.72 (CH), 127.87 (C), 130.66 ether, and washed first with an aqueous solution of
(2 CH), 134.62 (C), 135.64 (C), 137.09 (C), 140.90 (C), 146.26 ammonium chloride and then with brine. The aqueous layers
(C), 158.55 (C). EI-MS (70 eV): m/z (%) = 351 (79) [M+], 196 were extracted with diethyl ether, the combined organic layers
(100), 167 (12), 91 (5). HRMS: m/z calcd for C20H17NO3S [M+]: were dried over sodium sulfate and the solvent was evaporated.
351.0929; found: 351.0926. Elemental analysis calcd for Purification of the residue by column chromatography on
C20H17NO3S: C 68.36, H 4.88, N 3.99, S 9.12; found: C 68.55, H silica gel (pentane–dichloromethane–diethyl ether, gradient
4.86, N 3.94, S 9.78%.
elution, 119 : 1 : 0.2 to 14 : 1 : 0.2) provided ( )-mahanimbicine
A solution of 3,7-dimethyloct-6-en-1-yn-3-yl methyl carbon- [( )-4] as colourless solid (yield: 37.1 mg, 79%; spectroscopic
ate (18) (577 mg, 2.74 mmol) in acetonitrile (12 mL) was added data, see above) and 23 as light yellow solid, yield: 4.0 mg
1
over a period of 12 h at room temperature to a solution of the (9%). H-NMR (500 MHz, CDCl3): δ = 1.43 (s, 3 H), 1.57 (s, 3
crude 2-hydroxy-6-methyl-9-tosylcarbazole (539 mg), DBU H), 1.65 (s, 3 H), 1.67–1.80 (m, 2 H), 2.14–2.17 (m, 2 H), 2.49
(0.62 mL, 0.63 g, 4.1 mmol) and copper(I) iodide (1.3 mg, (s, 3 H), 5.10 (br t, J = 7.1 Hz, 1 H), 5.55 (d, J = 9.8 Hz, 1 H),
7 µmol) in acetonitrile (35 mL) and the mixture was stirred at 6.53 (d, J = 9.8 Hz, 1 H), 6.78 (s, 1 H), 7.12 (dd, J = 8.1, 1.1 Hz,
room temperature for 10 h (total reaction time 22 h). The 1 H), 7.23 (d, J = 8.1 Hz, 1 H), 7.57 (s, 1 H), 7.71 (br s, 1 H),
mixture was diluted with diethyl ether and washed with water, 7.82 (br s, 1 H).
10% aqueous HCl and brine. The aqueous layers were
Murrayamine-J (5). DDQ (109 mg, 480 µmol) was added at
extracted with diethyl ether, the combined organic layers were room temperature to a solution of ( )-mahanimbicine [( )-4]
dried over sodium sulfate, the solvent was evaporated and the (39.7 mg, 120 µmol) in methanol (20 mL), THF (2 mL) and
residue was dried in vacuum. The crude product was dissolved water (2 mL). The mixture was stirred at room temperature for
in xylenes (25 mL), the solution was heated at reflux for 27.5 h 2 h. DDQ (54.4 mg, 240 µmol) was added, the mixture was
and the solvent was evaporated. Purification of the residue by stirred for 1.5 h, an additional portion of DDQ (54.4 mg, 240
column chromatography on silica gel (pentane–dichloro- µmol) was added and the mixture was stirred at room tempera-
methane–ethyl acetate, gradient elution, 99 : 1 to 15 : 1) pro- ture for 2.75 h (total reaction time: 6.25 h). The mixture was
vided a mixture of N-tosylmahanimbicine (21) and compound diluted with diethyl ether and washed with 2 N aqueous
22, combined yield: 546 mg (82%), ratio of 21 : 22 = 7.7 : 1 NaOH, water and brine. The aqueous layers were extracted
(determined by 1H NMR integration). UV (MeOH): λ = 230, 266, with diethyl ether, the combined organic layers were dried
313 nm. Fluorescence (MeOH): λex = 266 nm, λem = 359, over sodium sulfate and the solvent was evaporated. Purifi-
419 nm. IR (ATR): ν = 2967, 2921, 2853, 1725, 1631, 1596, 1476, cation of the residue by column chromatography on silica gel
1451, 1398, 1368, 1272, 1172, 1086, 1035, 960, 918, 890, 810, (pentane–dichloromethane–ethyl acetate, gradient elution,
782, 749, 726, 703, 672, 662, 629, 575, 542 cm−1 1H NMR 1 : 0 : 0 to 13 : 5 : 1) provided murrayamine-J (5) as colourless
.
(500 MHz, acetone-d6): δ (major isomer) = 1.52 (s, 3 H), 1.58 (s, solid, yield: 27.9 mg (67%), m.p. 93–97 °C (ref. 8: oil). UV
3 H), 1.67 (s, 3 H), 1.80–1.90 (m, 2 H), 2.18–2.24 (m, 2 H), 2.21 (MeOH): λ = 246, 267, 311, 347 (sh) nm. Fluorescence (MeOH):
(s, 3 H), 2.39 (s, 3 H), 5.18 (m, 1 H), 5.80 (d, J = 10.0 Hz, 1 H), λex = 311 nm, λem = 350 nm. IR (ATR): ν = 3322, 3045, 2966,
6.88 (dd, J = 8.5, 0.7 Hz, 1 H), 7.00 (d, J = 8.2 Hz, 2 H), 7.08 (m, 2918, 2848, 2757, 1771, 1735, 1717, 1698, 1662, 1604, 1580,
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1508, 1474, 1462, 1415, 1393, 1343, 1320, 1278, 1224, 1176, column chromatography on silica gel (pentane–dichloro-
1121, 1085, 1031, 962, 895, 813, 784, 754, 721, 662, 629 cm−1
methane–ethyl acetate, gradient elution, 1 : 0 : 0 to 14 : 5 : 1)
.
1H NMR (600 MHz, CDCl3): δ = 1.46 (s, 3 H), 1.58 (s, 3 H), 1.66 provided murrayamine-M (7) as light yellow solid, yield: 15 mg
(s, 3 H), 1.71–1.83 (m, 2 H), 2.11–2.21 (m, 2 H), 5.10 (m, 1 H), (51%), m.p. 216–218 °C (ref. 8: oil). UV (MeOH): λ = 243, 255
5.71 (d, J = 9.8 Hz, 1 H), 6.67 (d, J = 9.8 Hz, 1 H), 6.81 (d, J = 8.4 (sh), 293, 329 (sh) nm. Fluorescence (MeOH): λex = 293 nm, λem
Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.89 = 368 nm. IR (ATR): ν = 3416, 3385, 2947, 2863, 1735, 1698,
(dd, J = 8.4, 1.4 Hz, 1 H), 8.35 (br s, 1 H), 8.46 (s, 1 H), 10.07 (s, 1673, 1654, 1605, 1572, 1508, 1474, 1458, 1414, 1318, 1220,
1 H). 13C NMR and DEPT (150 MHz, CDCl3): δ = 17.62 (CH3), 1182, 1151, 1114, 1088, 1021, 926, 891, 818, 787, 729, 686, 632,
22.70 (CH2), 25.65 (CH3), 26.05 (CH3), 40.88 (CH2), 78.69 (C), 610 cm−1. 1H NMR (500 MHz, CDCl3): δ = 0.78 (s, 3 H), 1.45 (s,
104.98 (C), 110.69 (CH), 110.91 (CH), 116.75 (CH), 117.07 (C), 3 H), 1.59 (s, 3 H), 1.66–1.78 (m, 3 H), 2.04–2.12 (m, 1 H), 2.54
120.85 (CH), 122.77 (CH), 123.93 (CH), 124.23 (C), 126.33 (CH), (m, 1 H), 2.74 (dd, J = 9.5, 7.7 Hz, 1 H), 3.30 (d, J = 9.5 Hz,
129.35 (C), 129.43 (CH), 131.85 (C), 136.75 (C), 143.42 (C), 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.82 (br
152.65 (C), 192.01 (CHO). EI-MS (70 eV): m/z (%) = 345 (33) s, 1 H), 7.85 (d, J = 8.5 Hz, 1 H), 7.88 (dd, J = 8.4, 1.6 Hz, 1 H),
[M+], 330 (4), 262 (100), 234 (4). HRMS: m/z calcd for 8.48 (m, 1 H), 10.07 (s, 1 H). 13C NMR and DEPT (125 MHz,
C23H23NO2 [M+]: 345.1729; found: 345.1731. Elemental ana- CDCl3): δ = 18.72 (CH3), 25.59 (CH2), 27.42 (CH3), 35.10 (CH3),
lysis calcd for C23H23NO2: C 79.97, H 6.71, N 4.05; found: 36.96 (CH), 37.66 (CH), 38.19 (CH2), 39.30 (C), 46.40 (CH),
C 79.22, H 6.94, N 4.14%.
83.88 (C), 107.17 (C), 110.68 (CH), 112.77 (CH), 116.48 (C),
Bicyclomahanimbicine (6). A solution of ( )-mahanimbicine 119.44 (CH), 122.88 (CH), 124.46 (C), 126.01 (CH), 129.32 (C),
[( )-4] (40.1 mg, 121 µmol) in toluene (40 mL) was placed in a 139.84 (C), 143.10 (C), 152.92 (C), 192.03 (CHO). EI-MS (70 eV):
water bath and irradiated using a daylight lamp (600 lm, m/z (%) = 345 (24) [M+], 262 (100), 233 (3), 204 (4). HRMS: m/z
6500 K) for 14 d under continuous stirring at room tempera- calcd for C23H23NO2 [M+]: 345.1729; found: 345.1746.
ture. Evaporation of the solvent and purification of the residue
Murrayamine G (8). A solution of ( )-mahanimbicine [( )-4]
by column chromatography on silica gel (pentane–dichloro- (63.8 mg, 193 μmol) and CSA (22.8 mg, 98.2 µmol) in toluene
methane–ethyl acetate, gradient elution, 120 : 1 : 0.2 to (9 mL) was stirred at room temperature for 6 d. An additional
23 : 1 : 0.2) provided bicyclomahanimbicine (6) as colourless portion of CSA (22.4 mg, 96.4 µmol) was added and the
solid, yield: 15.7 mg (39%), m.p. 224–225 °C (ref. 5: 218 °C, mixture was stirred at room temperature for 7 d and at 70 °C
decomp.). UV (MeOH): λ = 223, 242, 256, 261, 288 (sh), 304, for 3 d (total reaction time: 16 d). The mixture was diluted
322 (sh), 335 (sh) nm. Fluorescence (MeOH): λex = 242 nm, λem with diethyl ether and washed with an aqueous solution of
= 344, 359 nm. IR (ATR): ν = 3452, 3021, 2964, 2944, 2913, sodium hydrogencarbonate and brine. The aqueous layers
2856, 1711, 1609, 1508, 1483, 1454, 1415, 1381, 1365, 1339, were extracted with diethyl ether. Subsequently, the combined
1293, 1217, 1194, 1177, 1142, 1085, 1022, 976, 918, 873, 802, organic layers were dried over sodium sulfate and the solvent
1
766, 740, 672, 645, 589 cm−1. H NMR (500 MHz, CDCl3): δ = was evaporated. Purification of the residue by column
0.77 (s, 3 H), 1.45 (s, 3 H), 1.57 (s, 3 H), 1.63–1.76 (m, 3 H), chromatography on silica gel (pentane–dichloromethane–ethyl
2.07–2.14 (m, 1 H), 2.49–2.54 (m, 1 H), 2.50 (s, 3 H), 2.72 (dd, J = acetate, gradient elution, 60 : 1 : 0.2 to 17 : 1 : 0.2) provided
9.4, 7.7 Hz, 1 H), 3.28 (d, J = 9.4 Hz, 1 H), 6.77 (d, J = 8.4 Hz, 1 murrayamine-G (8) as colourless crystals, yield: 41.4 mg (65%),
H), 7.14 (dd, J = 8.2, 1.2 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), 7.40 m.p. 166–169 °C (ref. 9: 173–176 °C). (MeOH): λ = 219 (sh),
(br s, 1 H), 7.75 (s, 1 H), 7.76 (d, J = 8.4 Hz, 1 H). 13C NMR and 241, 257 (sh), 262, 307, 323 (sh) nm. Fluorescence (MeOH): λex
DEPT (125 MHz, CDCl3): δ = 18.53 (CH3), 21.42 (CH3), 25.61 = 307 nm, λem = 358 nm. IR (ATR): ν = 3463, 3074, 2963, 2920,
(CH2), 27.57 (CH3), 35.08 (CH3), 37.12 (CH), 37.65 (CH), 38.00 2862, 1613, 1519, 1481, 1445, 1420, 1378, 1312, 1297, 1217,
(CH2), 39.22 (C), 46.39 (CH), 83.54 (C), 106.48 (C), 109.99 (CH), 1172, 1159, 1100, 1027, 989, 963, 915, 888, 816, 798, 744, 658,
111.14 (CH), 116.62 (C), 118.94 (CH), 119.46 (CH), 124.35 (C), 621, 584, 559 cm−1 1H NMR (500 MHz, CDCl3): δ = 1.43 (s,
.
125.41 (CH), 128.88 (C), 137.46 (C), 139.64 (C), 151.85 (C). EI-MS 3 H), 1.48–1.50 (m, 1 H), 1.50 (s, 3 H), 1.61–1.67 (m, 2 H), 1.94
(70 eV): m/z (%) = 331 (30) [M+], 248 (100), 234 (3), 218 (2). (dt, J = 12.9, 3.1 Hz, 1 H), 2.03 (dd, J = 12.9, 2.7 Hz, 1 H), 2.11
HRMS: m/z calcd for C23H25NO [M+]: 331.1936; found: 331.1937. (dt, J = 9.3, 2.3 Hz, 1 H), 2.49 (s, 3 H), 2.58 (m, 1 H), 3.41 (m,
Murrayamine-M (7). DDQ (59 mg, 260 μmol) was added at 1 H), 4.73 (s, 1 H), 4.81 (t, J = 1.5 Hz, 1 H), 6.72 (d, J = 8.5 Hz,
0 °C to a solution of bicyclomahanimbicine (6) (28.3 mg, 1 H), 7.11 (dd, J = 8.1, 1.2 Hz, 1 H), 7.22 (d, J = 8.1 Hz, 1 H),
85.4 µmol) in methanol (10 mL), THF (1 mL) and water (2 mL). 7.70 (br s, 1 H), 7.71 (s, 1 H), 7.73 (d, J = 8.5 Hz, 1 H). 13C NMR
The cooling was removed and the mixture was stirred for 2 h at and DEPT (125 MHz, CDCl3): δ = 21.41 (CH3), 21.57 (CH3),
room temperature. DDQ (38.6 mg, 0.17 mmol) was added, the 23.00 (CH2), 28.89 (CH3), 35.95 (CH), 37.40 (CH2), 39.67 (CH2),
mixture was stirred for 1.5 h, an additional portion of DDQ 48.54 (CH), 74.08 (C), 105.67 (C), 108.70 (CH), 109.89 (CH),
(29 mg, 130 μmol) was added and the mixture was stirred for 112.09 (CH2), 115.36 (C), 119.08 (CH), 119.22 (CH), 124.40 (C),
1.5 h (total reaction time: 5 h). The mixture was diluted with 125.05 (CH), 128.65 (C), 137.60 (C), 140.08 (C), 149.89 (C),
diethyl ether and washed with 2 N aqueous NaOH, water and 155.17 (C). EI-MS (70 eV): m/z (%) = 331 (80) [M+], 316 (11), 248
brine. The aqueous layers were extracted with diethyl ether, (100), 210 (9). HRMS: m/z calcd for C23H25NO [M+]: 331.1936;
the combined organic layers were dried over sodium sulfate found: 331.1936. Elemental analysis calcd for C23H25NO:
and the solvent was evaporated. Purification of the residue by C 83.34, H 7.60, N 4.23; found: C 83.03, H 7.79, N 4.18%.
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Organic & Biomolecular Chemistry
Isomurrayazoline (9). A solution of ( )-mahanimbicine
p. 1; (b) A. W. Schmidt, K. R. Reddy and H.-J. Knölker,
Chem. Rev., 2012, 112, 3193.
[( )-4] (40.5 mg, 122 μmol) and CSA (2.3 mg, 10 µmol) in
hexane (12 mL) was stirred at room temperature for
11.5 d. The mixture was diluted with diethyl ether and washed
with an aqueous solution of sodium hydrogencarbonate and
brine. The aqueous layers were extracted with diethyl ether,
the combined organic layers were dried over sodium sulfate
and the solvent was evaporated. Purification of the residue by
column chromatography on silica gel (pentane–dichloro-
methane–ethyl acetate, gradient elution, 59 : 1 : 0.2 to
16 : 1 : 0.2) provided a mixture of murrayamine G (8) and iso-
murrayazoline (9) as colourless solid, yield: 28.4 mg (70%),
ratio of 8 : 9 = 1 : 1 (determined by the 1H NMR spectrum). The
two isomers were separated by preparative HPLC on a Grace
Vydac C8 column (208TP1050, 50 × 250 mm), gradient elution
with 55 mL min−1 (THF–H2O, 20–70% THF in 25 min) to
afford murrayamine-G (8) as colourless crystals (spectroscopic
data: see above) and isomurrayazoline (9) as colourless solid,
m.p. 224–227 °C (ref. 10: 269–270 °C). UV (MeOH): λ = 239
(sh), 246, 262 (sh), 307, 327 (sh), 340 (sh) nm. Fluorescence
(MeOH): λex = 246 nm, λem = 366 nm. IR (ATR): ν = 3047, 2965,
2922, 2900, 1631, 1592, 1446, 1416, 1347, 1307, 1288, 1221,
1204, 1180, 1152, 1134, 1087, 1068, 1037, 985, 941, 914, 882,
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1
855, 801, 787, 771, 744, 680, 625, 602, 593, 556 cm−1. H NMR
(500 MHz, CDCl3): δ = 0.13–0.21 (m, 1 H), 1.26–1.33 (m, 1 H),
1.28 (s, 3 H), 1.44 (s, 3 H), 1.47–1.54 (m, 1 H), 1.68 (ddd, J =
15.3, 6.8, 3.2 Hz, 1 H), 1.90 (s, 3 H), 1.90–1.93 (m, 1 H), 1.98
(ddd, J = 11.1, 5.5, 2.4 Hz, 1 H), 2.41 (ddd, J = 13.3, 5.3, 3.4 Hz,
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Phytochemistry, 1996, 41, 1433.
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43, 785.
1 H), 2.49 (s, 3 H), 3.29 (d, J = 4.6 Hz, 1 H), 6.64 (d, J = 8.2 Hz, 10 L. Bhattacharya, S. K. Roy and D. P. Chakraborty, Phyto-
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7.58 (d, J = 8.2 Hz, 1 H), 7.72 (m, 1 H). 13C-NMR and DEPT 11 (a) H.-J. Knölker and C. Hofmann, Tetrahedron Lett., 1996,
(125 MHz, CDCl3): δ = 21.31 (CH3), 21.70 (CH2), 22.91 (CH3),
28.12 (CH), 29.15 (CH3), 30.14 (CH3), 36.06 (CH2), 36.56 (CH2),
48.35 (CH), 60.47 (C), 76.26 (C), 107.73 (C), 108.87 (CH), 113.16
(CH), 114.51 (C), 119.00 (CH), 120.16 (CH), 124.10 (CH), 127.50
37, 7947; (b) K. K. Gruner and H.-J. Knölker, Org. Biomol.
Chem., 2008, 6, 3902; (c) K. K. Gruner, T. Hopfmann,
K. Matsumoto, A. Jäger, T. Katsuki and H.-J. Knölker, Org.
Biomol. Chem., 2011, 9, 2057.
(C), 128.82 (C), 138.92 (C), 144.32 (C), 156.37 (C). EI-MS (70 12 R. Hesse, K. K. Gruner, O. Kataeva, A. W. Schmidt and
eV): m/z (%) = 331 (99) [M+], 316 (100), 288 (15), 248 (63).
H.-J. Knölker, Chem. – Eur. J., 2013, 19, 14098.
Elemental analysis calcd for C23H25NO: C 83.34, H 7.60, N 13 V. P. Kumar, K. K. Gruner, O. Kataeva and H.-J. Knölker,
4.23; found: C 83.00, H 7.89, N 4.26%.
Angew. Chem., Int. Ed., 2013, 52, 11073.
14 (a) R. Hesse, A. Jäger, A. W. Schmidt and H.-J. Knölker, Org.
Biomol. Chem., 2014, 12, 3866; (b) K. K. Gruner, O. Kataeva,
A. W. Schmidt and H.-J. Knölker, Chem. – Eur. J., 2014, 20,
8536; (c) R. Hesse, O. Kataeva, A. W. Schmidt and
H.-J. Knölker, Chem. – Eur. J., 2014, 20, DOI: 10.1002/
chem.201403645.
Acknowledgements
We thank Micha P. Krahl for experimental support.
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