Total synthesis of new lipocarbazoles isolated from the actinomycete tsukamurella pseudospumae acta 1857

Article abstract of DOI:10.1055/s-0029-1217815

New lipocarbazoles were synthesized by a sequence of three palladium-mediated coupling reactions and an improved protecting group strategy.

Full text of DOI:10.1055/s-0029-1217815

LETTER
2483
Total Synthesis of New Lipocarbazoles Isolated from the Actinomycete
Tsukamurella pseudospumae Acta 18571
Total
S
ynthesis of
n
N
ew Lipoca
n
rbazoles e Hänchen, Roderich D. Süssmuth*
Fakultät II – Institut für Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623 Berlin, Germany
Fax +49(30)31479651; E-mail: suessmuth@chem.tu-berlin.de
Received 19 May 2009
carbazole alkaloids carazostatin (2)5 and antiostatin A4
(3),6 which are free-radical scavengers and can act as po-
tent antioxidants against lipid peroxidation.7 In contrast to
these natural products the lipocarbazoles 1a–c have com-
paratively long, saturated and unsaturated, alkyl chains.
Because of the amphiphilic character of these structures
they were suspected to be associated with the foaming ob-
served during the fermentation of the strain. All lipocarba-
zoles characterized thus far have the same heterocyclic
core structure and differ only in the type of the alkyl chain.
Abstract: New lipocarbazoles were synthesized by a sequence of
three palladium-mediated coupling reactions and an improved pro-
tecting group strategy.
Key words: heterocycles, cross-coupling, total synthesis, hydro-
boration, natural products
Carbazole alkaloids represent an important class of N-het-
erocyclic natural products. They can be isolated mostly
from sources like higher plants or bacteria and exhibit
therefore a high structural diversity as well as a broad
range of interesting biological activities.2 Recently, we
isolated a novel class of carbazoles from the fermentation
foam of the actinomycete Tsukamurella pseudospumae
Acta 1875.3 This strain was found in activated sludge
foam of sewage plants and is described as agent of foam-
ing thus causing heavy operational problems.4
The construction of the carbazole framework was intense-
ly studied over decades amongst others by the group of
Knölker et al.2 They developed efficient synthetic routes
based on transition-metal-mediated coupling reactions of
arylamines which found application in many total synthe-
ses of natural occurring carbazole alkaloids.8 According-
ly, and in order to obtain a rapid and variable synthetic
access to various alkyl-chain-substituted lipocarbazoles
we decided to build up the core structure first using a
sequence of palladium-mediated Buchwald–Hartwig
The lipocarbazoles A4, A3, and A2 (1a–c, Figure 1) show
high structural analogy to the well-known 3-oxygenated
OH
OH
OH
OH
Me
Me
Me
Me
N
N
N
N
H
H
H
H
2
O
Me
OH
HN
Me
N
H
1a
1b
1c
3
Figure 1 Lipocarbazoles A4 (1a), A3 (1b), A2 (1c), carazostatin (2), and antiostatin A4 (3)
SYNLETT 2009, No. 15, pp 2483–2486
x
x
.x
x
.2
0
0
9
Advanced online publication: 17.08.2009
DOI: 10.1055/s-0029-1217815; Art ID: G15709ST
© Georg Thieme Verlag Stuttgart · New York

2484
A. Hänchen, R. D. Süssmuth
LETTER
coupling and oxidative cyclization reactions (Scheme 1).9 acid (12b), and linolic acid (12c), respectively.16 The
Introduction of the alkyl chains in a late step of the syn- yields for this conversion were only moderate, but partic-
thesis was realized by a palladium-catalyzed Suzuki– ularly for the unsaturated alkyl chains a rapid access was
Miyaura reaction.10
desired as well as that the configuration of the double
bonds remained intact during the reaction. The alkenes
13a–c were further converted into the alkyl boron com-
pounds 6a–c using 9-borabicyclo[3.3.1]nonane (9-BBN-
H).17
oxidative cyclization
OH
OMe
Me
+
Me
OTf H2N
N
a
b
Suzuki–Miyaura
coupling
H
Alkyl
13a–c
Alkyl
Alkyl
6a–c
Br
5
+
4
B
COOH
Alkyl
12a–c
Buchwald–Hartwig
coupling
1a–c
Scheme 3 Preparation of alkyl boron compounds 6a–c. Reagents
and conditions: (a) Pb(OAc)4 (1.5 equiv), Cu(OAc)2 (0.15 equiv),
pyridine, benzene, 80 °C, 2 h (40% for 13a and 13b, 34% for 13c);
(b) 9-BBN-H, THF, 0 °C to r.t., 4 h, in situ.
B
Alkyl
6a–c
Scheme 1 Retrosynthetic strategy for lipocarbazoles8d
Phenyltriflate (4) was easily obtained in one step from
phenol (14, Scheme 4).18 Coupling of triflate 4 with aryl-
amine 5 was realized by a Buchwald–Hartwig reaction in
the presence of 5 mol% palladium(II) acetate, ( )-2,2¢-
bis(diphenylphosphino)-1,1¢-binaphthyl (BINAP) as
ligand and cesium carbonate as a base.9a,19 Oxidative cy-
clization of the diarylamine 15 turned out to be the most
challenging step of the synthesis. Various reaction condi-
tions using only catalytic amounts of palladium(II) acetate
and copper(II) acetate as reoxidants were tested,9c,d,20 but
the use of stoichiometric amounts of palladium(II) acetate
yielded the best results.9a,b,21 Having the carbazole core 16
in hands, we proceeded synthesizing the different lipocar-
bazoles. Hence a Suzuki–Miyaura cross-coupling reac-
tion of 16 with one of the in situ generated alkyl boron
compounds 6a–c in the presence of [1,1¢-bis(diphenyl-
phosphino)ferrocene]dichloropalladium(II) [PdCl2(dppf)]
was chosen.17 In the ultimate step of the total synthesis the
methyl ether protecting group was removed under mild
conditions without affecting the double bonds of the li-
pocarbazole precursors 17b and 17c using 9-iodo-borabi-
cyclo[3.3.1]nonane (9-I-9-BBN).22 In contrast to the
For the synthesis of arylamine 5 we conformed to the
reaction sequence previously described by Knölker et al.9a
However, for some synthetic steps alternative reagents
were used. First, 2-bromo-6-nitrotoluene (7), as cheap
starting material, was reduced to arylamine 8 using SnCl2
(instead of the more toxic N2H4·H2O) with nearly quanti-
tative yield within a reaction time of one hour.11 Subse-
quently phenol 9 could be obtained in a two-step
procedure.12 Thus, 3-bromo-2-methylaniline (8) was con-
verted into a stable aryl diazonium salt using NOBF4
which could be hydrolyzed with diluted H2SO4 at 60 °C to
yield phenol 9. In the next step the hydroxy group was
protected as methyl ether using MeI.13 The subsequent
nitration of the aromatic core with claycop14 gave two
isomeric nitro derivatives which could easily be separated
by flash chromatography.15 Similarly to the first step, re-
duction of 11 finally gave the desired arylamine 5 in near-
ly quantitative yield (Scheme 2).
NO2
Me
NH2
Me
OH
Me
a
b
c
Br
7
Br
8
Br
9
OMe
a
b
c
OMe
Me
OMe
OMe
Me
OH
OTf
N
H
Me
d
e
Br
14
4
15
O2N
Me
H2N
OMe
OMe
Br
Br
11
Br
5
d
e
10
1a–c
Me
Me
Scheme 2 Preparation of arylamine 5. Reagents and conditions:9a
(a) SnCl2·H2O, EtOH, 70 °C, 2 h (98%); (b) (1) NOBF4, CH2Cl2,
0 °C, 4 h; (2) 0.01 M H2SO4, 60 °C, 1 h (70%); (c) MeI, KOH,
DMSO, r.t., 1.5 h (98%); (d) claycop, Ac2O, hexane, r.t., 1 h (30%);
(e) SnCl2·H2O, EtOH, 70 °C, 1 h (99%).
N
H
N
H
Br
16
17a–c
Alkyl
Scheme 4 Preparation of lipocarbazoles 1a–c. Reagents and condi-
tions: (a) Tf2O, pyridine, CH2Cl2, 0 °C to r.t., 15 min (79%); (b)
Pd(OAc)2 (5 mol%), BINAP (7.5 mol%), Cs2CO3, toluene, 100 °C,
24 h (66%); (c) Pd(OAc)2 (1 equiv), AcOH, 100 °C, 24 h (39%); (d)
6a–c, PdCl2(dppf) (5 mol%), 3 N NaOH, THF, 65 °C, 1 h (75% for
17a, 74% for 17b, 68% for 17c); (e) 9-I-9-BBN, hexane, r.t., 5 min
(86% for 1a, 67% for 1b, 60% for 1c).
In parallel, the precursors for the different alkyl chains
with a terminal double bond 13a–c (Scheme 3) were syn-
thesized by oxidative decarboxylation using the corre-
sponding fatty acids, which are stearic acid (12a), oelic
Synlett 2009, No. 15, 2483–2486 © Thieme Stuttgart · New York

LETTER
Total Synthesis of New Lipocarbazoles
2485
(5) (a) Kato, S.; Kawai, H.; Kawasaki, T.; Toda, Y.; Urata, T.;
Hayakawa, Y. J. Antibiot. 1989, 12, 1879. (b) Jackson,
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H.-J. Chem. Commun. 2009, 12, 1467.
synthesis of carbazomadurin A and B reported by Knölker
et al.,9a,b no intermediate change of the phenolic protecting
group during the synthetic route is needed to prevent side
reactions with the double bonds present in the alkyl chains
of carbazoles 17b and 17c in the final deprotection step.
13
The analytical data (1H NMR, C NMR and MS) of the
lipocarbazoles were in full agreement with those de-
scribed for the isolated natural products.3,23–25 Further-
more, the proposed configurations and positions of the
double bonds in the alkyl chains of lipocarbazoles A4, A3,
and A2 (1a–c) could be confirmed.
(7) Kato, S.; Kawasaki, T.; Urata, T.; Mochizuki, J. J. Antibiot.
1989, 12, 1859.
In surface-tension measurements for lipocarbazole 1a us-
ing the hanging-drop technique, no surface activity could
be measured for the single compound. Thus no direct con-
nection to previously observed foaming could be verified.
As described for carazostatin (2), lipocarbazoles 1a and
1b show remarkable antioxidant activity.3 With regard to
this antioxidant activity, the biological function of these
compounds might be scavenging of radicals in biological
membranes.
(8) (a) Knölker, H.-J. Curr. Org. Synth. 2004, 1, 309.
(b) Agarwal, S.; Cämmerer, S.; Filali, S.; Fröhner, W.;
Knöll, J.; Krahl, M. P.; Reddy, K. R.; Knölker, H.-J. Curr.
Org. Chem. 2005, 9, 1601. (c) Choi, T. A.; Czerwonka, R.;
Forke, R.; Jäger, A.; Knöll, J.; Krahl, M. P.; Krause, T.;
Reddy, K. R.; Franzblau, S. G.; Knölker, H.-J. Med. Chem.
Res. 2008, 17, 374. (d) Knölker, H.-J. Chem. Lett. 2009, 38,
8.
(9) (a) Knölker, H.-J.; Knöll, J. Chem. Commun. 2003, 1170.
(b) Knöll, J.; Knölker, H.-J. Synlett 2006, 651. (c) Krahl,
M. P.; Jäger, A.; Krause, T.; Knölker, H.-J. Org. Biomol.
Chem. 2006, 4, 3215. (d) Forke, R.; Krahl, M. P.; Krause,
T.; Schlechtingen, G.; Knölker, H.-J. Synlett 2007, 268.
(e) Gruner, K. K.; Knölker, H.-J. Org. Biomol. Chem. 2008,
6, 3902.
(10) Forke, R.; Jäger, A.; Knölker, H.-J. Org. Biomol. Chem.
2008, 6, 2481.
(11) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839.
(12) (a) Hagemann, H. DE 2927938, 1981. (b) Boduszek, B.;
Shine, H. J. J. Am. Chem. Soc. 1988, 110, 3247.
(13) Johnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35,
2169.
(14) Laszlo, P.; Pennetreau, P. J. Org. Chem. 1987, 52, 2407.
(15) Gigante, B.; Prazeres, O.; Marcelo-Curto, M. J. J. Org.
Chem. 1995, 60, 3445.
(16) Boland, W.; Jaenicke, L. Liebigs Ann. Chem. 1981, 92.
(17) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.;
Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
(b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(c) Miyaura, N. Top. Curr. Chem. 2002, 219, 11.
(18) Thompson, A. L. S.; Kabalka, G. W.; Akula, M. R.;
Huffman, J. W. Synthesis 2005, 547.
In conclusion, the lipocarbazoles 1a–c could be synthe-
sized using three palladium-mediated coupling reactions.
The reaction sequence gives rapid access to a wide range
of derivatives with different alkyl chains. Additionally, by
use of total synthesis the proposed structure for the natural
products isolated from Tsukamurella pseudospumae Acta
1875 including the correct conformation of the double
bonds in the alkyl side chains was confirmed.
Acknowledgment
We grateful acknowledge financial support from the European
Commission (project ACTINOGEN, 6th framework, grant
LSHM-CT-2004-005224) and the Deutsche Forschungsgemein-
schaft (Cluster of Excellence ‘Unifying Concepts in Catalysis’
coordinated by the Technische Universität Berlin. We also thank
the Fonds der Chemischen Industrie for financial support of Anne
Hänchen and Professor Hans-Peter Fiedler for cooperation on this
project.
(19) (a) Abman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38,
6363. (b) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37,
2046. (c) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
2002, 219, 131.
References and Notes
(1) Article 50 in the series ‘Biosynthetic Capacities of
Actinomycetes’.
(20) (a) Knölker, H.-J.; O’Sullivan, N. Tetrahedron 1994, 50,
10893. (b) Knölker, H.-J.; Reddy, K. R.; Wagner, A.
Tetrahedron Lett. 1998, 39, 8267. (c) Ferreire, I. C. F. R.;
Queiroz, M.-J. R. P.; Kirsch, G. Tetrahedron 2002, 58,
7943. (d) Würtz, S.; Rakshit, S.; Neumann, J. J.; Dröge, T.;
Glorius, F. Angew. Chem. Int. Ed. 2008, 47, 7230.
(21) (a) Åkermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E.
J. Org. Chem. 1975, 40, 1365. (b) Mandal, A. B.; Delgado,
F.; Tamariz, J. Synlett 1998, 87.
(22) Fürstner, A.; Seidel, G. J. Org. Chem. 1997, 62, 2332.
(23) Spectral Data for Lipocarbazole A4 (1a)
IR (neat): n = 3466, 3388, 2920, 2849, 1500, 1466, 1436,
1311, 1233, 1147, 1064, 830, 772, 738 cm–1. 1H NMR (400
MHz, DMSO-d6): d = 10.65 (s, 1 H), 8.78 (s, 1 H), 7.87–7.85
(d, J = 8.0 Hz, 1 H), 7.41–7.39 (d, J = 8.0 Hz, 1 H), 7.28–
7.24 (t, J = 8.0 Hz, 1 H), 7.26 (s, 1 H), 7.04–7.00 (t, J = 8.0
Hz, 1 H), 2.88–2.84 (t, J = 8.0 Hz, 2 H), 2.22 (s, 3 H), 1.57–
(2) (a) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102,
4303. (b) Knölker, H.-J. Top. Curr. Chem. 2005, 244, 115.
(c) Knölker, H.-J.; Reddy, K. R. In The Alkaloids, Vol. 65;
Cordell, G. A., Ed.; Academic Press: Amsterdam, 2008, 1–
430.
(3) Schneider, K.; Nachtigall, J.; Hänchen, A.; Nicholson, G.;
Goodfellow, M.; Süssmuth, R. D.; Fiedler, H.-P. J. Nat.
Prod. 2009, submitted.
(4) Nam, S.; Kim, W.; Chun, J.; Goodfellow, M. Int. J. Syst.
Evolut. Microbiol. 2004, 54, 1209.
Synlett 2009, No. 15, 2483–2486 © Thieme Stuttgart · New York

2486
A. Hänchen, R. D. Süssmuth
LETTER
1.50 (m, 2 H), 1.45–1.38 (m, 2 H), 1.23 (br s, 13 × 2 H),
0.86–0.82 (t, J = 8.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
DMSO-d6): d = 148.93, 139.97, 133.24, 124.36, 123.95,
122.73, 121.30, 119.64, 119.48, 117.48, 110.75, 101.87,
31.32, 29.36, 29.33, 29.14, 29.12, 29.05, 28.73, 28.12,
22.13, 13.97, 12.17 ppm. MS (EI): m/z (%) = 435 (100), 267
(10), 210 (38), 167 (4), 97 (3), 83 (4), 69 (5), 57 (7). HRMS
(EI): m/z calcd for C30H45NO [M]+: 435.3501; found:
435.3500.
28.77, 28.67, 28.19, 26.67, 26.65, 22.17, 14.02, 12.07 ppm.
MS (EI): m/z (%) = 433 (94), 210 (100), 196 (6), 180 (12),
167 (11), 97 (3), 83 (4), 69 (5), 57 (8), 55 (9). HRMS (EI):
m/z calcd for C30H43NO [M]+: 433.3345; found: 433.3342.
(25) Spectral Data for Lipocarbazole A2 (1c)
IR (neat): n = 3471, 3381, 3009, 2924, 2853, 1593, 1499,
1461, 1436, 1311, 1230, 1146, 1062, 831, 772, 739 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.65 (s, 1 H), 8.79 (s,
1 H), 7.87–7.85 (d, J = 8.0 Hz, 1 H), 7.41–7.39 (d, J = 8.0
Hz, 1 H), 7.28–7.24 (t, J = 8.0 Hz, 1 H), 7.26 (s, 1 H), 7.04–
7.00 (t, J = 8.0 Hz, 1 H), 5.37–5.25 (4 × 1H), 2.89–2.85 (t,
J = 8.0 Hz, 2 H), 2.74–2.70 (t, J = 8.0 Hz, 2 H), 2.22 (s, 3 H),
2.00–1.97 (m, 2 × 2 H), 1.57–1.50 (m, 2 H), 1.46–1.39 (m, 2
H), 1.30–1.21 (m, 6 × 2 H), 0.85–0.81 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 148.93, 139.96,
133.24, 129.72, 127.77, 127.73, 124.37, 123.94, 122.72,
121.30, 119.63, 119.49, 117.50, 110.75, 101.88, 30.89,
29.33, 29.30, 29.07, 28.95, 28.73, 28.10, 26.63, 26.61,
25.23, 21.97, 13.91, 11.99. MS (EI): m/z (%) = 431 (58), 210
(100), 196 (9), 180 (15), 167 (17), 91 (5). HRMS (EI): m/z
calcd for C30H45NO [M]+: 431.3188; found: 431.3191.
(24) Spectral Data for Lipocarbazole A3 (1b)
IR (neat): n = 3471, 3382, 2923, 2853, 1593, 1500, 1461,
1436, 1311, 1231, 1146, 1062, 831, 772, 739 cm–1. 1H NMR
(400 MHz, DMSO-d6): d = 10.65 (s, 1 H), 8.79 (s, 1 H),
7.87–7.85 (d, J = 8.0 Hz, 1 H), 7.41–7.39 (d, J = 8.0 Hz, 1
H), 7.28–7.24 (t, J = 8.0 Hz, 1 H), 7.26 (s, 1 H), 7.04–7.00
(t, J = 8.0 Hz, 1 H), 5.35–5.27 (2 × 1 H), 2.89–2.85 (t, J =
8.0 Hz, 2 H), 2.22 (s, 3 H), 1.98–1.94 (m, 2 × 2 H), 1.57–
1.50 (m, 2 H), 1.46–1.39 (m, 2 H), 1.29–1.21 (m, 9 × 2 H),
0.85–0.81 (t, J = 8.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
DMSO-d6): d = 149.00, 140.04, 133.31, 129.74, 129.71,
124.46, 124.02, 122.80, 121.37, 119.71, 119.57, 117.58,
110.83, 101.96, 31.36, 29.37, 29.22, 29.17, 29.01, 28.90,
Synlett 2009, No. 15, 2483–2486 © Thieme Stuttgart · New York

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