Transition metal complexes in organic synthesis. Part 65: Iron-mediated synthesis of carazostatin, a free radical scavenger from Streptomyces chromofuscus, and O-methylcarazostatin

Article abstract of DOI:10.1016/S0040-4020(02)01180-8

Highly efficient syntheses of the free radical scavenger carazostatin and its O-methyl derivative are described using cyclohexa-1,3-diene and 2-heptyl-4-methoxy-3-methylaniline as starting materials and iron-mediated oxidative cyclizations as key-steps.

Full text of DOI:10.1016/S0040-4020(02)01180-8

Tetrahedron 58 (2002) 8937–8945
Transition metal complexes in organic synthesis.
Part 65: Iron-mediated synthesis of carazostatin,
a free radical scavenger from Streptomyces chromofuscus,
and O-methylcarazostatinq
*
Hans-Joachim Knolker and Thomas Hopfmann
¨
¨ ¨
Institut fur Organische Chemie, Technische Universitat Dresden, Bergstrasse 66, 01069 Dresden, Germany
Received 23 July 2002; revised 2 September 2002; accepted 16 September 2002
Abstract—Highly efficient syntheses of the free radical scavenger carazostatin and its O-methyl derivative are described using cyclohexa-
1,3-diene and 2-heptyl-4-methoxy-3-methylaniline as starting materials and iron-mediated oxidative cyclizations as key-steps. q 2002
Elsevier Science Ltd. All rights reserved.
Many carbazole alkaloids with a broad range of useful
biological activities were obtained from natural sources.1
Kato isolated the free radical scavenger carazostatin from
Streptomyces chromofuscus and assigned the structure as
1-heptyl-3-hydroxy-2-methyl-9H-carbazole.2 Carazostatin
shows a strong inhibition of the lipid peroxidation induced
by free radicals and is more active than butylated
hydroxytoluene (BHT), a well-known antioxidant. In
liposomal membranes, carazostatin exhibits a stronger
antioxidant activity than a-tocopherol.3 It was found that
oxygen-derived free radicals are responsible for a variety of
diseases, e.g. myocardial and cerebral ischemia, arterio-
sclerosis, inflammation, and rheumatism.4,5 Free radicals
were also suggested to play a central role in senility and
cancer initiation.6 Thus, the isolation of free radical
scavengers from natural sources may provide novel lead
structures for the development of therapeutic agents against
these diseases.
Due to its promising biological activities, carazostatin
became an attractive target for organic synthesis.7 In recent
years, several new synthetic methodologies furnishing the
carbazole framework were described.1,8 We developed a
convergent synthesis of carbazole alkaloids using an iron-
mediated construction of the heterocyclic framework.9 Our
iron-mediated quinone imine cyclization was shown to be
especially useful for the synthesis of 3-hydroxycarbazoles.9,10
Therefore, we envisaged a total synthesis of the alkaloid
carazostatin based on the approach depicted in the retro-
synthesis (Scheme 1). The iron-mediated oxidative coupling
of cyclohexa-1,3-diene 1 and the fully substituted arylamine 2
provided a direct route to carazostatin.11 Herein, we describe
full details of this synthesis.
The azadiene-catalyzed complexation of cyclohexa-1,3-
diene 1 with pentacarbonyliron provides a simple and safe
access to tricarbonyl(h4-cyclohexa-1,3-diene)iron 3 even on
Scheme 1.
q For Part 64, see Ref. 9d.
Keywords: carazostatin; Diels–Alder reaction; cyclization.
*
Corresponding author. Fax: þ49-351-46337030; e-mail: hans-joachim.knoelker@chemie.tu-dresden.de
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01180-8

¨
H.-J. Knolker, T. Hopfmann / Tetrahedron 58 (2002) 8937–8945
8938
Scheme 2.
under our optimized reaction conditions. In this context, it is
interesting to note that, using ethyl phenylpropynoate as
dienophile the regioselectivity of the Diels–Alder cyclo-
addition with 1-methoxycyclohexa-1,3-diene 7 reverses, as
shown by us previously.14
The following 3 steps transform the methoxycarbonyl group
of compound 8 to the methyl group present in the natural
product. Reduction of the methyl ester 8 with lithium
aluminum hydride afforded quantitatively the benzyl
alcohol 10, which was converted to the benzylic bromide
Scheme 3.
Scheme 4.
large scale (Scheme 2).12 Complex 3 is converted to
tricarbonyl(h5-cyclohexadienylium)iron tetrafluoroborate 4
by hydride abstraction using triphenylcarbenium
tetrafluoroborate as originally described by Fischer.13
Thus, by this 2-step sequence the iron complex salt 4 is
available almost quantitatively on large scale.
11 by treatment with phosphorous tribromide (Scheme 5).
Reduction of the benzylic bromide 11 with lithium
aluminum hydride afforded after purification by flash
chromatography on silica gel, pure 3-heptyl-2-methyl-
anisole 12. Because of the clean course of the two former
reactions, the crude product was taken to the next
transformation in both cases. The benzylic bromide 11
turned out to be unstable and was submitted immediately to
the reduction. Thus, an overall yield of 85% was achieved
for the 3-step conversion of the Diels–Alder product 8 to
3-heptyl-2-methylanisole 12.
We projected to prepare the required arylamine 2 by Diels–
Alder reaction with an appropriate alkyne building block
analogous to our synthesis of hyellazole.14 The synthesis of
the alkyne was achieved by adaptation of literature
procedures.15 Deprotonation of 1-nonyne 5 with butyl-
lithium and quenching with methyl chloroformate afforded
methyl 2-decynoate 6 which could be used without further
purification (Scheme 3).
Nitration of 3-heptyl-2-methylanisole 12 with concentrated
nitric acid in dichloromethane at room temperature afforded
the desired 3-heptyl-2-methyl-4-nitroanisole 13 in 46%
yield along with 23% of 3-heptyl-2-methyl-6-nitroanisole.
The regiochemistry for both products was confirmed by
extensive NOE experiments (see Section 1). Catalytic
hydrogenation of the nitro derivative 13 provided 2-heptyl-
4-methoxy-3-methylaniline 2 (Scheme 5). Starting from
1-methoxycyclohexa-1,3-diene 7 the required arylamine 2
was obtained in 6 steps and 26% overall yield. The
The Diels–Alder reaction of 1-methoxycyclohexa-1,3-
diene 7 with methyl 2-decynoate 6 followed by retro-
Diels–Alder reaction with extrusion of ethylene provided
methyl 6-heptyl-2-methoxybenzoate 8 as the major product
(Scheme 4). Subba Rao reported that this procedure leads to
6-alkyl-2-methoxybenzoates.16 The regiochemistry in our
case was confirmed by COLOC spectra of compound 12 and
finally by conversion to the natural product (see below). An
optimization of the reaction conditions was achieved by
increasing the temperature to 200–2108C and extension of
the reaction time to 14 d (Table 1). Using this set of reaction
conditions, the desired product 8 was isolated in 84% yield
and methyl 2-heptyl-3-methoxybenzoate 9 in 5% yield.
Thus, in contrast to Subba Rao, we obtained the alternative
regioisomer of the cycloaddition as a by-product but only
Table 1. Reaction conditions and results of the Diels–Alder cycloaddition
T (8C)
t (d)
8, Yield (%)
9, Yield (%)
6, Yield (%)
130
200
150
200–210
3
6
14
14
39
60
79
84
–
–
48
35
Trace
–
Trace
5

¨
H.-J. Knolker, T. Hopfmann / Tetrahedron 58 (2002) 8937–8945
8939
Scheme 5.
advantages of the present route are the cheap starting
materials and the feasibility to perform all steps on a
multigram scale.
the N-alkylated arylamine (kinetic product) to the C-alkyl-
ated arylamine (thermodynamic product) have been
described earlier.18–20 In our iron-mediated quinone imine
cyclization, sequential chemoselective oxidations of 5-aryl-
substituted tricarbonyl(h4-cyclohexa-1,3-diene)iron com-
plexes are generally achieved using manganese dioxides
of different activity.10,14,21 Oxidation of complex 15 with
commercial manganese dioxide22 in dichloromethane at
room temperature led to the quinone imine 16. The
oxidative cyclization of compound 16 using Fatiadi’s very
active manganese dioxide23 provided the tricarbonyliron-
complexed 4b,8a-dihydrocarbazol-3-one 17 as dark yellow
crystals. The demetalation of complex 17 using trimethyl-
amine N-oxide24 proceeded at room temperature with
instantaneous tautomerization to carazostatin. All spectral
data (UV, IR, 1H NMR, 13C NMR, and MS) and the melting
The reaction of the arylamine 2 with the iron complex salt 4
afforded after 3 h in acetonitrile under reflux quantitatively
the iron complex 15 (Scheme 6). This electrophilic aromatic
substitution was monitored using thin-layer chromato-
graphy (TLC). After 1 min at room temperature a less
polar product, presumably the N-alkylated arylamine 14,
was formed. At reflux temperature, this intermediate
complex rearranged within 10 min to the final complex
15. The TLC analysis shows that both complexes have the
same Rf value but provide a different color on developing
the TLC plate with the ceric(IV) sulfate/phosphomolybdic
acid reagent.17,18 Related examples for rearrangements of
Scheme 6.

¨
H.-J. Knolker, T. Hopfmann / Tetrahedron 58 (2002) 8937–8945
8940
Scheme 7.
point of our synthetic carazostatin are in good agreement
with those reported for the natural product.2 The present
synthesis provides carazostatin via the iron-mediated
quinone imine cyclization in 4 steps and 45% overall
yield based on the iron complex salt 4.
carbazoles is the iron-mediated arylamine cyclization of the
arylamine-substituted tricarbonyl(h4-cyclohexa-1,3-diene)-
iron complexes. Using the appropriate oxidizing reagent,
this oxidative cyclization can be performed as a one-pot
reaction with concomitant aromatization and demetala-
tion.9,14 Thus, the iron-mediated arylamine cyclization
could be used for a shorter access to O-methylcarazostatin.
Oxidation of complex 15 with ferricenium hexafluoro-
phosphate in the presence of sodium carbonate in dichloro-
methane at room temperature provided a mixture of
O-methylcarazostatin and the 4b,8a-dihydrocarbazol-3-one
complex 17, which was not separable by chromatography.
Therefore, the crude product was treated with trimethyl-
amine N-oxide to demetalate complex 17 to carazostatin
(Scheme 8). Separation of the two products by flash
chromatography on silica gel provided O-methylcarazo-
statin in 53% yield and carazostatin in 33% yield. The
O-methylation of carazostatin as described above afforded
additional O-methylcarazostatin. In summary, the synthesis
via the iron-mediated arylamine cyclization leads to
O-methylcarazostatin in 3 steps and 82% overall yield
based on the iron complex salt 4. We noted already in our
synthesis of hyellazole and isohyellazole,14 that the iron-
mediated arylamine cyclization is clearly superior to the
iron-mediated quinone imine cyclization for the synthesis of
3-methoxycarbazoles, when using ferricenium hexafluoro-
phosphate in the presence of sodium carbonate as the
oxidizing agent.
O-Methylcarazostatin (1-heptyl-3-methoxy-2-methyl-9H-
carbazole), a non-natural derivative of carazostatin, could
be of pharmacological interest as well. Electrochemical
studies have shown that it is also more active than BHT as
antioxidant.7b We developed two different pathways to this
compound. The first uses the iron-mediated quinone imine
cyclization as described above and finally transforms
carazostatin to O-methylcarazostatin by chemoselective
O-methylation. The second utilizes the iron-mediated
arylamine cyclization of the tricarbonyliron complex 15.
The O-methylation of carazostatin with iodomethane and
potassium carbonate, previously described by Moody,7b
afforded after purification by flash chromatography on silica
gel and subsequent recrystallization from dichloromethane/
hexane pure O-methylcarazostatin in 89% yield (Scheme 7).
The N-methylated product could not be detected. Thus, the
route via the iron-mediated quinone imine cyclization
provides O-methylcarazostatin in 5 steps and 40% overall
yield based on the iron complex salt 4.
An alternative method for the synthesis of 3-methoxy-
Scheme 8.

¨
H.-J. Knolker, T. Hopfmann / Tetrahedron 58 (2002) 8937–8945
8941
1. Experimental
142.38 (C), 157.89 (C), 169.59 (CvO); the signal of one
CH2 group is missing due to overlapping with the signals of
the solvent; MS (208C): m/z (%)¼264 (Mþ, 65), 233 (41),
180 (30), 179 (16), 161 (100), 148 (10), 121 (15); HRMS:
calcd for C16H24O3 (Mþ): 264.1725, found: 264.1697.
1.1. General
All reactions were carried out using anhydrous and degassed
solvents under an inert gas atmosphere. Flash chromato-
graphy: Baker or Merck silica gel (0.03–0.06 mm). Melting
points: Bu¨chi 535. UV spectra: Perkin–Elmer Lambda 2
(UV/VIS spectrometer). IR spectra: Perkin–Elmer 882 and
Bruker IFS-88. H NMR and 13C NMR spectra: Bruker
WM-250 and AM-400; internal standard: the signal of the
deuterated solvent; coupling constants J in Hz. Mass
spectra: Finnigan MAT-90; ionization potential: 70 eV.
Compound 9. Yield: 360 mg (5%). IR (CCl ): n¼2953,
~
4
2929, 2857, 1728, 1582, 1460, 1434, 1253, 1100, 1065, 816,
771, 728, 665 cm21; 1H NMR (400 MHz, CDCl3): d¼0.88
(t, J¼6.9 Hz, 3H), 1.29–1.38 (m, 8H), 1.52 (m, 2H), 2.88
(m, 2H), 3.84 (s, 3H), 3.88 (s, 3H), 6.98 (br d, J¼8.2 Hz,
1H), 7.19 (t, J¼8.0 Hz, 1H), 7.35 (dd, J¼8.0, 1.0 Hz, 1H);
13C NMR and DEPT (100 MHz, CDCl3): d¼14.15 (CH3),
22.70 (CH2), 26.76 (CH2), 29.15 (CH2), 30.01 (CH2), 30.26
(CH2), 31.88 (CH2), 51.95 (CH3), 55.73 (CH3), 113.37
(CH), 121.85 (CH), 126.14 (CH), 131.51 (C), 133.14 (C),
157.84 (C), 168.68 (CvO); MS (208C): m/z (%)¼264 (Mþ,
64), 233 (25), 180 (29), 179 (100), 161 (26), 149 (17), 147
(12), 121 (11), 91 (19); HRMS: calcd for C16H24O3 (Mþ):
264.1725, found: 264.1721.
1
1.1.1. Methyl 2-decynoate (6). A 1.6 M solution of
n-butyllithium in hexane (66.2 mmol, 41.4 mL) was added
to a solution of 1-nonyne (5) (8.02 g, 64.6 mmol, 10.6 mL)
in diethyl ether (80 mL) at 2308C. The mixture was
warmed to room temperature over a period of 30 min and
cooled again to 2308C. Methyl chloroformate (8.44 g,
89.3 mmol, 6.9 mL) was added, the reaction mixture was
warmed to 258C, and stirred for additional 2 h at this
temperature. The mixture was poured into ice-water
(150 mL) and the layers were separated. The aqueous
layer was extracted with ether (4£50 mL) and the combined
organic layers were dried over sodium sulfate. The solvent
was removed in vacuo to provide methyl 2-decynoate (6) as
1.1.3. 6-Heptyl-2-methoxybenzyl alcohol (10). A suspen-
sion of lithium aluminum hydride (1.44 g, 37.9 mmol) in
diethyl ether (20 mL) was cooled to 2108C and a solution of
the benzoate 8 (6.67 g, 25.2 mmol) in diethyl ether (15 mL)
was added over a period of 20 min. The reaction mixture
was heated at reflux for 4 h, then quenched with ice-water,
and the resulting precipitate was dissolved with a small
amount of sulfuric acid (10%). The layers were separated
and the aqueous layer was extracted with ether (4£35 mL).
The combined organic layers were washed with a saturated
solution of sodium bicarbonate and dried over sodium
sulfate. The solvent was evaporated to afford the alcohol 10
a light yellow oil, yield: 11.1 g (94%). IR (film): n¼2931,
~
2857, 2238, 1713, 1664, 1602, 1433, 1377, 1327, 1255,
1211, 1163, 1069, 815, 781, 751, 724 cm21 1H NMR
;
(400 MHz, CDCl3): d¼0.87 (t, J¼6.8 Hz, 3H), 1.27 (m,
6H), 1.38 (m, 2H), 1.57 (quint, J¼7.2 Hz, 2H), 2.32 (t,
J¼7.2 Hz, 2H), 3.75 (s, 3H); 13C NMR and DEPT
(100 MHz, CDCl3): d¼14.02 (CH3), 18.62 (CH2), 22.56
(CH2), 27.49 (CH2), 28.66 (CH2), 28.76 (CH2), 31.59
(CH2), 52.52 (CH3), 72.79 (C), 89.95 (C), 154.27 (CvO);
MS (608C): m/z (%)¼181 (Mþ21, 1) 151 (81), 139 (35),
125 (26), 121 (34), 111 (29), 108 (35), 107 (28), 100 (80), 98
(21), 93 (47), 81 (67), 79 (100), 67 (47), 66 (33), 55 (53), 43
(55), 41 (52); HRMS: calcd for C11H17O2 (Mþ21):
181.1228, found: 181.1216.
as a colorless oil, yield: 5.96 g (100%). IR (film): n¼3436,
~
2926, 2857, 1736, 1598, 1584, 1465, 1437, 1376, 1314,
1263, 1198, 1178, 1112, 1088, 1005, 782, 745, 724 cm21
,
1H NMR (400 MHz, CDCl3): d¼0.88 (t, J¼6.9 Hz, 3H),
1.24–1.39 (m, 8H), 1.55 (m, 2H), 2.40 (br s, 1H), 2.67 (m,
2H), 3.86 (s, 3H), 4.73 (s, 2H), 6.76 (br d, J¼8.0 Hz, 1H),
6.81 (br d, J¼8.0 Hz, 1H), 7.19 (t, J¼8.0 Hz, 1H); 13C NMR
and DEPT (100 MHz, CDCl3): d¼14.10 (CH3), 22.65
(CH2), 29.16 (CH2), 29.61 (CH2), 31.83 (CH2), 32.16
(CH2), 33.24 (CH2), 55.42 (CH3), 57.41 (CH2), 108.03
(CH), 122.33 (CH), 126.82 (C), 128.51 (CH), 142.62 (C),
158.26 (C); MS (858C): m/z (%)¼236 (Mþ, 100), 218 (83),
161 (39), 152 (32), 147 (33), 137 (29), 136 (14), 135 (28),
134 (19), 123 (13), 122 (44), 121 (44), 93 (21), 91 (32), 83
(16), 81 (29), 79 (22), 77 (13); HRMS: calcd for C15H24O2
(Mþ): 236.1776, found: 236.1793.
1.1.2. Methyl 6-heptyl-2-methoxybenzoate (8) and
methyl 2-heptyl-3-methoxybenzoate (9). A mixture of
1-methoxycyclohexa-1,3-diene (7) (5.5 mL, content: 65%;
3.32 g, 30.1 mmol of 1,3-diene) and methyl 2-decynoate (6)
(5.49 g, 30.1 mmol) was heated in a sealed glass tube for
14 d at 200–2108C. The resulting yellow oil was subjected
to flash chromatography (hexane/EtOAc, 9:1) on silica gel
to provide as the less polar fraction methyl 2-heptyl-3-
methoxybenzoate (9) and as the more polar fraction methyl
6-heptyl-2-methoxybenzoate (8), both as colorless oils.
1.1.4. 6-Heptyl-2-methoxybenzyl bromide (11). Phos-
phorus tribromide (2.37 g, 8.74 mmol, 0.83 mL) was
added to a solution of alcohol 10 (5.96 g, 25.2 mmol) in
diethyl ether (30 mL) at 2408C over a period of 5 min and
the mixture was heated at reflux for 3 h. Additional
phosphorus tribromide (428 mg, 1.58 mmol, 0.15 mL) was
added and the reaction mixture was heated at reflux for
further 5 h. The cold mixture was poured on ice and the
layers were separated. The aqueous layer was extracted with
ether (5£30 mL) and the combined organic layers were
dried over sodium sulfate. Evaporation of the solvent in
vacuo at a temperature below 208C afforded bromide 11 as a
Compound 8. Yield: 6.68 g (84%). IR (film): n¼3071, 2929,
~
2857, 2021, 1931, 1734, 1583, 1468, 1431, 1376, 1269,
1187, 1107, 1074, 959, 826, 792, 748 cm21 1H NMR
;
(400 MHz, acetone-d6): d¼0.88 (t, J¼6.9 Hz, 3H), 1.29 (m,
8H), 1.57 (m, 2H), 2.52 (m, 2H), 3.79 (s, 3H), 3.82 (s, 3H),
6.86 (br d, J¼8.0 Hz, 1H), 6.89 (br d, J¼8.0 Hz, 1H), 7.30
(br t, J¼8.0 Hz, 1H); 13C NMR and DEPT (100 MHz,
acetone-d6): d¼15.00 (CH3), 23.95 (CH2), 30.75 (CH2),
32.67 (CH2), 33.15 (CH2), 34.64 (CH2), 52.70 (CH3), 56.79
(CH3), 110.12 (CH), 122.82 (CH), 125.55 (C), 131.67 (CH),
light yellow oil, yield: 7.06 g (93%). IR (film): n¼2955,
~

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H.-J. Knolker, T. Hopfmann / Tetrahedron 58 (2002) 8937–8945
8942
1
2926, 2854, 1599, 1585, 1473, 1440, 1314, 1268, 1217,
1143, 1067, 791, 747, 603, 540 cm21; 1H NMR (400 MHz,
CDCl3): d¼0.89 (t, J¼6.8 Hz, 3H), 1.28–1.42 (m, 8H), 1.64
(m, 2H), 2.70 (m, 2H), 3.88 (s, 3H), 4.67 (s, 2H), 6.73 (br d,
J¼8.0 Hz, 1H), 6.80 (br d, J¼8.0 Hz, 1H), 7.21 (t,
J¼8.0 Hz, 1H); 13C NMR and DEPT (100 MHz, CDCl3):
d¼14.13 (CH3), 22.68 (CH2), 25.80 (CH2), 29.20 (CH2),
29.71 (CH2), 31.08 (CH2), 31.82 (CH2), 32.53 (CH2), 55.80
(CH3), 108.39 (CH), 121.84 (CH), 123.97 (C), 129.50 (CH),
143.57 (C), 157.85 (C); MS (458C): m/z (%)¼300 (Mþ, 4.7),
298 (Mþ, 4.8), 219 (44), 135 (100), 95 (26), 81 (20), 67 (12),
55 (16); HRMS: calcd for C15H23OBr (Mþ): 298.0932,
found: 298.0921.
1344, 1317, 1268, 1119, 1086, 816, 806, 763 cm21; H
NMR (250 MHz, CDCl3): d¼0.87 (t, J¼6.7 Hz, 3H), 1.28–
1.43 (m, 8H), 1.57 (m, 2H), 2.21 (s, 3H), 2.78 (m, 2H), 3.87
(s, 3H), 6.72 (d, J¼9.1 Hz, 1H), 7.74 (d, J¼9.1 Hz, 1H); 1H
NMR NOE experiments (250 MHz, CDCl3): (1) irradiation
at 2.21, observed NOEs 1.57, 2.78; (2) irradiation at 2.78,
observed NOE’s 1.57, 2.21; (3) irradiation at 3.87, observed
NOE 6.72; (4) irradiation at 6.72, observed NOEs 3.87,
7.74; (5) irradiation at 7.74, observed NOE 6.72; 13C NMR
and DEPT (100 MHz, CDCl3): d¼11.61 (CH3), 14.09
(CH3), 22.63 (CH2), 28.95 (CH2), 29.49 (CH2), 29.58
(CH2), 29.97 (CH2), 31.81 (CH2), 55.81 (CH3), 107.19
(CH), 124.07 (CH), 126.73 (C), 137.71 (C), 143.89 (C),
160.73 (C); MS (308C): m/z (%)¼265 (Mþ, 20), 248 (100),
164 (9), 135 (11); HRMS: calcd for C15H23NO3 (Mþ):
265.1678, found: 265.1667.
1.1.5. 3-Heptyl-2-methylanisole (12). A solution of the
benzyl bromide 11 (7.06 g, 23.6 mmol) in diethyl ether
(15 mL) was added to a suspension of lithium aluminum
hydride (1.35 g, 35.6 mmol) in diethyl ether (20 mL) at
2308C over a period of 30 min. The reaction mixture was
heated at reflux for 15 h, then additional lithium aluminum
hydride (200 mg, 5.27 mmol) was added, and the mixture
was heated at reflux for further 3 h. The cold solution was
quenched with ice-water and the resulting precipitate was
dissolved with a small amount of sulfuric acid (10%). The
layers were separated and the aqueous layer was extracted
with ether (5£25 mL). The combined organic layers were
washed with a saturated solution of sodium bicarbonate and
dried over magnesium sulfate. The solvent was removed in
vacuo and the residue was subjected to flash chromato-
graphy (hexane/EtOAc, 5:1) on silica gel to provide the
anisole 12 as a colorless oil, yield: 4.73 g (91%). IR (film):
3-Heptyl-2-methyl-6-nitroanisole. Yellow oil, yield:
291 mg (23%). IR (film): n¼2929, 2857, 1588, 1522,
~
1
1468, 1410, 1353, 1256, 1110, 1067, 1003, 808 cm21; H
NMR (250 MHz, CDCl3): d¼0.88 (t, J¼6.7 Hz, 3H), 1.28–
1.42 (m, 8H), 1.55 (m, 2H), 2.27 (s, 3H), 2.62 (m, 2H), 3.86
(s, 3H), 6.98 (d, J¼8.4 Hz, 1H), 7.60 (d, J¼8.4 Hz, 1H); 1H
NMR NOE experiments (250 MHz, CDCl3): (1) irradiation
at 2.27, observed NOEs 1.55, 2.62, 3.86; (2) irradiation at
2.62, observed NOEs 1.55, 2.27, 6.98; (3) irradiation at
3.86, observed NOE 2.27; (4) irradiation at 6.98, observed
NOE’s 2.62, 7.60; (5) irradiation at 7.60, observed NOE
6.98; 13C NMR and DEPT (100 MHz, CDCl3): d¼11.90
(CH3), 14.07 (CH3), 22.62 (CH2), 29.11 (CH2), 29.52
(CH2), 29.84 (CH2), 31.75 (CH2), 33.98 (CH2), 61.98
(CH3), 122.34 (CH), 124.38 (CH), 132.33 (C), 141.99
(C), 149.11 (C), 151.83 (C); MS (258C): m/z (%)¼265
(Mþ, 100), 235 (20), 220 (11), 203 (11), 201 (18), 198 (38),
181 (70), 153 (19), 151 (30), 147 (16), 136 (15), 135 (32),
131 (16), 105 (12), 103 (22), 101 (37), 87 (14), 85 (48);
HRMS: calcd for C15H23NO3 (Mþ): 265.1678, found:
265.1652.
n¼2927, 2857, 1584, 1464, 1437, 1376, 1310, 1256, 1191,
~
1
1167, 1119, 1096, 775, 719 cm21; H NMR (250 MHz,
CDCl3): d¼0.88 (t, J¼6.7 Hz, 3H), 1.28–1.43 (m, 8H),
1.48–1.57 (m, 2H), 2.17 (s, 3H), 2.59 (m, 2H), 3.82 (s, 3H),
6.71 (br d, J¼7.9 Hz, 1H), 6.77 (br d, J¼7.9 Hz, 1H), 7.09
(t, J¼7.9 Hz, 1H); 13C NMR and DEPT (100 MHz, CDCl3):
d¼11.29 (CH3), 14.22 (CH3), 22.80 (CH2), 29.36 (CH2),
29.81 (CH2), 30.72 (CH2), 31.99 (CH2), 33.83 (CH2), 55.45
(CH3), 107.69 (CH), 121.58 (CH), 124.45 (C), 125.90 (CH),
142.55 (C), 157.77 (C); MS (408C): m/z (%)¼220 (Mþ, 52),
136 (100), 135 (29), 121 (13), 105 (14), 91 (5); HRMS:
calcd for C15H24O (Mþ): 220.1827, found: 220.1839.
1.1.7. 2-Heptyl-4-methoxy-3-methylaniline (2). Palladium
on carbon (10%, 85 mg) was added to a solution of the
nitrobenzene 13 (564 mg, 2.13 mmol) in methanol (16 mL).
This mixture was vigorously stirred under a hydrogen
atmosphere (800–900 Torr) until no further hydrogen
uptake was detected. The reaction mixture was filtered
over a short path of Celite (which was subsequently washed
with ethyl acetate) under an argon atmosphere and the
solvent was evaporated. Flash chromatography (hexane/
EtOAc, 5:1) of the residue on degassed silica gel afforded
the arylamine 2 as a colorless oil, yield: 396 mg (79%). IR
1.1.6. 3-Heptyl-2-methyl-4-nitroanisole (13) and 3-hep-
tyl-2-methyl-6-nitroanisole. Over a period of 40 min, nitric
acid (1.7 mL, content: 65%; 1.54 g, 24.4 mmol of acid) was
added to a solution of the anisole 12 (1.06 g, 4.81 mmol) in
dichloromethane (15 mL) at room temperature. During the
addition, a light stream of argon was passed through the
solution. After a reaction time of 1 h the mixture was poured
onto ice (30 g) and then neutralized by addition of a sat.
solution of sodium carbonate. The layers were separated and
the aqueous solution was extracted three times with ether.
The combined organic layers were dried over magnesium
sulfate and the solvent was removed in vacuo. Flash
chromatography (hexane/EtOAc, 7:1) of the residue on
silica gel afforded as the less polar fraction 3-heptyl-2-
methyl-6-nitroanisole and as the more polar fraction the
4-nitroanisole 13.
(film): n¼3446, 3365, 2954, 2926, 2871, 2855, 1620, 1483,
~
1468, 1439, 1377, 1315, 1257, 1219, 1165, 1117, 1085,
1015, 800, 724 cm21; 1H NMR (400 MHz, CDCl3): d¼0.89
(t, J¼6.8 Hz, 3H), 1.28–1.52 (m, 10H), 2.18 (s, 3H), 2.53
(m, 2H), 3.36 (br s, 2H), 3.75 (s, 3H), 6.54 (d, J¼8.6 Hz,
1H), 6.60 (d, J¼8.6 Hz, 1H); 13C NMR and DEPT
(100 MHz, CDCl3): d¼11.69 (CH3), 14.14 (CH3), 22.69
(CH2), 28.08 (CH2), 28.55 (CH2), 29.24 (CH2), 30.15
(CH2), 31.90 (CH2), 56.19 (CH3), 109.38 (CH), 113.39
(CH), 125.54 (C), 128.20 (C), 137.77 (C), 151.27 (C); MS
(208C): m/z (%)¼235 (Mþ, 100), 220 (26), 150 (45), 136
(15); HRMS: calcd for C15H25NO (Mþ): 235.1936, found:
235.1928.
Compound 13. Orange oil, yield: 586 mg (46%). IR (film):
n¼2956, 2928, 2856, 1603, 1580, 1519, 1468, 1438, 1378,
~

¨
H.-J. Knolker, T. Hopfmann / Tetrahedron 58 (2002) 8937–8945
8943
1.1.8. (1-4-h)-5-(2-Amino-3-heptyl-5-methoxy-4-methyl-
phenyl)cyclohexa-1,3-diene]tricarbonyliron (15). A sol-
ution of the arylamine 2 (145 mg, 0.616 mmol) and
tricarbonyl(h5-cyclohexadienylium)iron tetrafluoroborate
(4) (86 mg, 0.281 mmol) in degassed acetonitrile (10 mL)
was heated at reflux for 3 h. The solvent was evaporated in
vacuo and the crude product was subjected to flash
chromatography (hexane/EtOAc, 5:1) on silica gel to
provide the iron complex 15 as a red–orange waxy solid,
quinone imine complex 16 (90 mg, 0.206 mmol) in
dichloromethane (3 mL). The mixture was stirred at room
temperature for 25 min and then filtered over a short path of
silica gel/Celite, which was subsequently washed with ethyl
acetate several times. Evaporation of the solvent and flash
chromatography (hexane/EtOAc, 5:1) of the residue on
silica gel afforded the iron complex 17 as dark yellow
crystals, yield: 68 mg (78%), mp 95–988C. IR (drift):
n¼2956, 2925, 2856, 2057, 1981, 1953, 1939, 1931, 1656,
~
1626, 1601, 1458, 1371, 1301, 1286, 1264, 1171, 1142,
yield: 127 mg (100%). IR (film): n¼3463, 3383, 2927,
~
2855, 2043, 1966, 1621, 1600, 1464, 1420, 1377, 1257,
1
1128, 923, 871, 695, 649, 627 cm21; H NMR (400 MHz,
1
1225, 1193, 622, 563 cm21; H NMR (400 MHz, CDCl3):
CDCl3): d¼0.88 (t, J¼6.8 Hz, 3H), 1.25–1.36 (m, 8H), 1.47
(m, 2H), 1.99 (s, 3H), 2.63 (m, 2H), 3.10 (m, 1H), 3.47 (m,
2H), 4.92 (dd, J¼6.1, 4.5 Hz, 1H), 5.39 (m, 2H), 6.18 (d,
J¼1.8 Hz, 1H); 13C NMR and DEPT (100 MHz, CDCl3):
d¼11.98 (CH3), 14.07 (CH3), 22.60 (CH2), 27.83 (CH2),
29.12 (CH2), 29.16 (CH2), 29.74 (CH2), 31.78 (CH2), 45.01
(CH), 57.24 (CH), 59.13 (CH), 78.08 (CH), 85.10 (CH),
86.26 (CH), 122.29 (CH), 138.30 (C), 142.69 (C), 155.44
(C), 163.36 (CvN), 187.65 (CvO), 210.41 (3 CO); MS
(808C): m/z (%)¼435 (Mþ, 6), 407 (39), 351 (100), 349
(25), 307 (11), 295 (6), 293 (8), 281 (11), 267 (18); HRMS:
calcd for C23H25FeNO4 (Mþ): 435.1133, found: 435.1146.
d¼0.89 (t, J¼6.8 Hz, 3H), 1.28–1.48 (m, 10H), 1.61 (br d,
J¼15.2 Hz, 1H), 2.15 (s, 3H), 2.41 (ddd, J¼15.2, 11.1,
3.9 Hz, 1H), 2.52 (m, 2H), 3.18 (m, 2H), 3.33 (br s, 2H),
3.45 (dt, J¼11.1, 3.7 Hz, 1H), 3.78 (s, 3H), 5.52 (m, 2H),
6.60 (s, 1H); 13C NMR and DEPT (100 MHz, CDCl3):
d¼11.58 (CH3), 14.09 (CH3), 22.64 (CH2), 28.35 (2 CH2),
29.16 (CH2), 30.15 (CH2), 31.45 (CH2), 31.84 (CH2), 39.32
(CH), 56.49 (CH3), 60.24 (CH), 64.91 (CH), 84.84 (CH),
85.63 (CH), 107.99 (CH), 123.64 (C), 128.20 (C), 128.56
(C), 135.05 (C), 150.78 (C), 211.93 (3 CO); MS (808C): m/z
(%)¼453 (Mþ, 5), 425 (2), 397 (4), 369 (29), 367 (15), 313
(41), 312 (52), 311 (31), 289 (37), 235 (100), 220 (26), 151
(11), 150 (46), 136 (15), 85 (10); HRMS: calcd for
C24H31FeNO4 (Mþ): 453.1602, found: 453.1610.
1.1.11. Carazostatin (1-heptyl-3-hydroxy-2-methyl-9H-
carbazole). Trimethylamine N-oxide dihydrate (134 mg,
1.21 mmol) was added to a solution of the iron complex 17
(64 mg, 0.147 mmol) in acetone (5 mL) and the reaction
mixture was stirred for 14 h at room temperature. The
suspension was filtered over a short path of silica gel/Celite,
which was subsequently washed with ethyl acetate several
times. The solvent was evaporated and the residue was
subjected to flash chromatography (hexane/EtOAc, 6:1) on
silica gel to provide carazostatin as colorless crystals, yield:
32 mg (74%), mp 153–1558C (CH2Cl2/hexane) (Ref. 2
149–1528C; Ref. 7a,b 162–1638C from CH2Cl2/light
petroleum; Ref. 7c 159.5–160.58C; Ref. 7d,e 159–1608C
from CH2Cl2/light petroleum). UV (MeOH): l¼217, 233,
1.1.9. Tricarbonyl[(1-4-h)-5-(5-heptyl-6-imino-4-
methylcyclohexa-1,4-dien-3-onyl)cyclohexa-1,3-diene]-
iron (16). Commercial manganese dioxide22 (600 mg) was
added to a solution of the iron complex 15 (120 mg,
0.265 mmol) in dichloromethane (4 mL) and stirred for
30 min at room temperature. Additional manganese dioxide
(240 mg) was added and the reaction mixture was stirred at
room temperature for further 15 min. The mixture was
filtered over a short path of silica gel/Celite, which was
subsequently washed with ethyl acetate several times. The
filtrate was evaporated in vacuo and the red crude product
was subjected to flash chromatography (hexane/EtOAc, 5:1)
on silica gel to provide the quinone imine complex 16 as a
yellow–brown waxy solid, yield: 90 mg (78%). IR (film):
253, 264, 295 (sh), 302, 341, 350 nm; IR (drift): n¼3474,
~
3416, 3379, 2956, 2924, 2855, 1593, 1500, 1463, 1437,
1379, 1356, 1311, 1259, 1231, 1157, 1147, 1063, 832, 771,
753, 741, 659 cm21; 1H NMR (400 MHz, CDCl3): d¼0.89
(t, J¼6.8 Hz, 3H), 1.27–1.40 (m, 6H), 1.46 (m, 2H), 1.66
(m, 2H), 2.38 (s, 3H), 2.88 (t, J¼7.9 Hz, 2H), 4.58 (br s,
1H), 7.17 (br t, J¼7.8 Hz, 1H), 7.33 (s, 1H), 7.37 (br t,
J¼7.8 Hz, 1H), 7.42 (d, J¼8.0 Hz, 1H), 7.75 (br s, 1H), 7.93
(d, J¼7.8 Hz, 1H); 13C NMR and DEPT (100 MHz,
CDCl3): d¼11.98 (CH3), 14.12 (CH3), 22.68 (CH2), 28.78
(CH2), 29.32 (CH2), 29.53 (CH2), 30.00 (CH2), 31.86
(CH2), 102.96 (CH), 110.62 (CH), 118.89 (CH), 120.06
(CH), 120.79 (C), 121.37 (C), 123.66 (C), 124.12 (C),
125.24 (CH), 133.97 (C), 139.75 (C), 148.09 (C); MS
(908C): m/z (%)¼295 (Mþ, 100), 210 (55), 197 (4), 180 (5),
167 (6); HRMS: calcd for C20H25NO (Mþ): 295.1936,
found: 295.1928.
n¼3283, 2955, 2928, 2857, 2045, 1969, 1647, 1629, 1602,
~
1467, 1441, 1335, 1157, 1138, 1120, 878, 622, 618,
614 cm21
;
1H NMR (250 MHz, CDCl3): d¼0.89 (t,
J¼6.8 Hz, 3H), 1.28–1.46 (m, 11H), 1.98 (s) and 2.00 (s,
S3H), 2.31–2.51 (m) and 2.70 (m, S3H), 2.92 (m) and 3.04
(m, S1H), 3.14 (m, 1H), 3.31 (dt) and 3.89 (dt, J¼11.3,
3.5 Hz, S1H), 5.42–5.59 (m, 2H), 6.41 (s) and 6.49 (s,
S1H), 10.71 (br s) and 10.85 (br s, S1H); 13C NMR and
DEPT (100 MHz, CDCl3): (anti-imine stereoisomer)
d¼11.99 (CH3), 14.10 (CH3), 22.63 (CH2), 27.45 (CH2),
29.03 (CH2), 29.06 (CH2), 29.86 (CH2), 31.72 (CH2), 32.77
(CH2), 37.25 (CH), 60.46 (CH), 62.95 (CH), 84.86 (CH),
86.18 (CH), 127.09 (CH), 135.67 (C), 141.43 (C), 157.27
(C), 165.31 (CvN), 187.67 (CvO), 211.66 (3 CO); MS
(1058C): m/z (%)¼437 (Mþ, 0.4), 409 (6), 407 (10), 381
(19), 353 (52), 351 (100), 349 (10), 295 (10), 267 (30), 191
(20), 182 (8), 56 (8); HRMS: calcd for C23H27FeNO4 (Mþ):
437.1289, found: 437.1304.
1.2. O-Methylcarazostatin (1-heptyl-3-methoxy-2-
methyl-9H-carbazole)
1.2.1. By O-methylation of carazostatin. A mixture of
carazostatin (12.3 mg, 41.6 mmol), potassium carbonate
(115 mg, 0.832 mmol), and iodomethane (2.37 g,
16.7 mmol, 1.04 mL) in acetone (5 mL) was heated under
1.1.10. Tricarbonyl[(5-8-h)-4b,8a-dihydro-1-heptyl-2-
methyl-3H-carbazol-3-one]iron (17). Very active manga-
nese dioxide23 (440 mg) was added to a solution of the

¨
H.-J. Knolker, T. Hopfmann / Tetrahedron 58 (2002) 8937–8945
8944
reflux for 1 d. The solvent was removed in vacuo and the
residue was dissolved in diethyl ether (10 mL). The
suspension was filtered over a short path of silica gel/Celite,
which was subsequently washed with diethyl ether.
Evaporation of the solvent in vacuo and flash chromato-
graphy (hexane/EtOAc, 7:1) of the residue on silica gel
afforded O-methylcarazostatin as a colorless solid, which
was recrystallized from hexane/dichloromethane to obtain
colorless needles, yield: 11.5 mg (89%), mp 98–1018C
(hexane/CH2Cl2) (Ref. 7b 94–958C). UV (MeOH): l¼217,
233, 252, 263, 293 (sh), 301, 335, 350 nm; IR (drift):
are grateful to the BASF AG, Ludwigshafen, for a generous
gift of pentacarbonyliron.
References
1. (a) Bhattacharyya, P.; Chakraborty, D. P. Prog. Chem. Org.
Nat. Prod., Herz, W., Grisebach, H., Kirby, G. W., Eds.;
Springer: Wien, 1987; Vol. 52, p 159. (b) Chakraborty, D. P.;
Roy, S. Prog. Chem. Org. Nat. Prod., Herz, W., Grisebach, H.,
Kirby, G. W., Tamm, C., Eds.; Springer: Wien, 1991; Vol. 57,
p 71. (c) Chakraborty, D. P. The Alkaloids, Cordell, G. A., Ed.;
Academic: New York, 1993; Vol. 44, p 257.
n¼3424, 2923, 2855, 1611, 1583, 1494, 1452, 1426, 1307,
~
1269, 1256, 1225, 1207, 1161, 1147, 1125, 1113, 1099, 830,
769, 750, 744 cm21; 1H NMR (400 MHz, CDCl3): d¼0.88
(t, J¼6.8 Hz, 3H), 1.26–1.39 (m, 6H), 1.45 (m, 2H), 1.65
(m, 2H), 2.35 (s, 3H), 2.87 (t, J¼7.9 Hz, 2H), 3.94 (s, 3H),
7.18 (dt, J¼0.9, 7.8 Hz, 1H), 7.35 (dt, J¼1.1, 8.1 Hz, 1H),
7.37 (s, 1H), 7.42 (d, J¼8.1 Hz, 1H), 7.77 (br s, 1H), 7.99 (d,
J¼7.8 Hz, 1H); 13C NMR and DEPT (100 MHz, CDCl3):
d¼12.04 (CH3), 14.13 (CH3), 22.69 (CH2), 28.79 (CH2),
29.33 (CH2), 29.52 (CH2), 30.03 (CH2), 31.88 (CH2), 56.14
(CH3), 98.92 (CH), 110.65 (CH), 118.87 (CH), 119.83
(CH), 120.30 (C), 123.75 (C), 124.09 (C), 124.17 (C),
124.93 (CH), 133.68 (C), 139.52 (C), 152.68 (C); MS
(608C): m/z (%)¼309 (Mþ, 100), 294 (4), 224 (21), 210 (6),
180 (7); HRMS: calcd for C21H27NO (Mþ): 309.2093,
found: 309.2080.
2. Kato, S.; Kawai, H.; Kawasaki, T.; Toda, Y.; Urata, T.;
Hayakawa, Y. J. Antibiot. 1989, 42, 1879.
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4. (a) Palinski, W.; Rosenfeld, M. E.; Yla-Herttuala, S.; Gurtner,
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5. (a) Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.; Kato,
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1.2.2. Via the iron-mediated arylamine cyclization of
complex 15. Over a period of 30 min, four portions of
ferricenium hexafluorophosphate (4£18 mg, 54.4 mmol)
were added at room temperature to a solution of the iron
complex 15 (99 mg, 0.218 mmol) in dichloromethane
(60 mL). After a reaction time of 60 min, sodium carbonate
(237 mg, 2.24 mmol) was added. Additional oxidizing
reagent (6£72 mg, 0.218 mmol) was added after a reaction
time of 65, 80, 100, 130, 170, and 200 min. After a total
reaction time of 24 h the suspension was filtered over a short
path of silica gel/Celite, which was subsequently washed
with ethyl acetate. The solvent was evaporated and
ferrocene was removed in vacuo by sublimation. The
crude product (69 mg of a mixture of O-methylcarazostatin
and the iron complex 17) was dissolved in acetone (8 mL),
trimethylamine N-oxide dihydrate (60 mg, 0.540 mmol)
was added, and the reaction mixture was stirred at room
temperature for 1 d. Filtration of the reaction mixture over a
short path of silica gel/Celite with ethyl acetate, evaporation
of the solvent in vacuo, and flash chromatography
(hexane/EtOAc, 6:1) of the residue on silica gel afforded
as the less polar fraction, O-methylcarazostatin (yield:
35.6 mg, 53%) and as more polar fraction carazostatin
(yield: 21 mg, 33%), both as colorless solids. Carazostatin
was transformed to O-methylcarazostatin (19.6 mg, 89%
yield) in 1 step as described above. Total yield of
O-methylcarazostatin: 55.2 mg (82% based on 15). Spectral
data, see above.
6. Cerutti, P. A. Science 1985, 227, 375.
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¨
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¨
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¨ ¨
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993.
This work was supported by the Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie. We
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H.-J. Knolker, T. Hopfmann / Tetrahedron 58 (2002) 8937–8945
8945
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