First total synthesis of the whole series of the antiostatins A and B

Article abstract of DOI:10.1039/b821039j

The first synthesis of the whole antiostatin family is described by using an iron-mediated carbazole synthesis, regioselective nitration at C-4 and establishing 5-isobutyl-1-nitrobiuret as a reagent for introduction of the antiostatin B side chain at C-4.

Full text of DOI:10.1039/b821039j

Chemical Communications
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Number 12 | 28 March 2009 | Pages 1421–1584
ISSN 1359-7345
FEATURE ARTICLE
COMMUNICATION
Alessandra Lattanzi
Hans-Joachim Knölker et al.
α,α-Diarylprolinols: bifunctional
organocatalysts for asymmetric
synthesis
First total synthesis of the whole
series of the antiostatins A and B

COMMUNICATION
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First total synthesis of the whole series of the antiostatins A and Bw
¨ ¨
Kerstin E. Knott, Stefan Auschill, Anne Jager and Hans-Joachim Knolker*
Received (in Cambridge, UK) 25th November 2008, Accepted 19th December 2008
First published as an Advance Article on the web 20th January 2009
DOI: 10.1039/b821039j
The first synthesis of the whole antiostatin family is described by
using an iron-mediated carbazole synthesis, regioselective nitra-
tion at C-4 and establishing 5-isobutyl-1-nitrobiuret as a reagent
for introduction of the antiostatin B side chain at C-4.
Currently, carbazoles are of high interest due to their
pharmacological potential.1 In 1990, Seto et al. at the University
of Tokyo isolated the antiostatins A1 to A4 and B2 to B5 from
Streptomyces cyaneus 2007-SV1 (Fig. 1).2 They exhibit a strong
Fig. 1 Antiostatins A1–A4 and B2–B5.
inhibitory activity against free radical induced lipid peroxidation.
The antiostatins are structurally unique because of their nitrogen
substituent at C-4, which is part of an isobutylbiuret side chain
for the antiostatins B. So far, no synthesis has been reported for
any member of this family of carbazoles, despite synthetic efforts
by several groups in the field.3,4 In the present paper, we describe
the first total synthesis of all antiostatins.
Our strategy is based on the iron-mediated carbazole
synthesis.5 We decided to introduce the nitrogen substituent
at C-4 after completion of the carbazole ring system. Thus, a
monocyclic precursor was designed which is easily exploitable
for access to all different antiostatins by introduction of the
different alkyl side chains at C-1 using a Sonogashira–Hagihara
coupling (Scheme 1).
Scheme 1 Synthesis of the arylamines 9. Reagents and conditions:
(a) claycop, Ac2O, Et2O, rt, 1 h, 94%; (b) AlCl3, CH2Cl2, rt, 21 h,
96%; (c) Tf2O, Et3N, CH2Cl2, ꢀ20 1C, 97%; (d) cat. Pd(PPh3)2Cl2,
cat. CuI, H– ꢁ –R (7a–f), Bu4NI, CH3CN–Et3N (5 : 1), reflux, 3–5 h;
(e) 1–5 bar H2, 10% Pd/C, CH3OH–CH2Cl2 (or EtOAc), rt, 3–5 d;
yields for 8 and 9: Table 1.
Nitration of 2,6-dimethoxytoluene (3) followed by regio-
selective ether cleavage of 4 afforded the nitrophenol 5
(Scheme 1). Conversion to the aryl triflate 6 paved the
way for introduction of different alkyl chains at C-1 of the
carbazole nucleus.6 Except for 7b and 7f, all required alkynes
are commercially available. 6-Methylhept-1-yne (7f) was pre-
pared in two steps from 1-bromo-4-methylpentane.7 For the
stereogenic centre in the side chain of antiostatin A2 (1b), we
assumed an S configuration in analogy to other chiral
(Scheme 2, Table 1). Oxidative cyclization of 11 using an
excess of ferricenium hexafluorophosphate in the presence of
sodium carbonate led to the carbazoles 12.15 Direct nitration
at C-4 of the unprotected carbazoles 12 was limited. Thus,
nitration of 12d (NO2BF4 in THF at ꢀ50 to ꢀ20 1C, 64%)
afforded regioselectively 22d, an intermediate for antiostatin
B4 (2c) (see Scheme 5). However, after transformation to the
corresponding tert-butyl carbamates 13, nitration with
claycop provided the 4-nitrocarbazoles 14 in excellent yields.
Catalytic hydrogenation of 14a–d led to the 9-Boc-4-amino-
carbazole alkaloids: carbazoquinocin
A
and D,8,9 and
carbazomadurin B.10,11 Thus, (S)-3-methylpent-1-yne (7b) has
been prepared in three steps from commercial (S)-2-methyl-
butan-1-ol by oxidation with the Dess–Martin reagent12
and subsequent Corey–Fuchs homologation to the terminal
alkyne.13z Sonogashira–Hagihara coupling14 of aryl triflate 6
with the alkynes 7 led to the alkynylarenes 8, which on catalytic
hydrogenation provided the arylamines 9 (Table 1).
carbazoles 15a–d, the precursors for the antiostatin
A
series.
Electrophilic substitution of the arylamines 9 by reaction
with the iron complex salt 10 afforded the iron complexes 11
For the synthesis of the antiostatins A, the carbazoles 15a–d
were acetylated at the amino group to afford the acetamides
16a–d (Scheme 3). Conversion to 17a–d by thermal removal of
the Boc group16 and subsequent cleavage of the methyl ether
provided the antiostatins A1 to A4 (1a–d). The spectroscopic
data and melting points of the antiostatins A1 to A4 (1a–d)
were in good agreement with those reported for the natural
products by Seto et al.2y The 1H NMR spectrum of our
Department Chemie, Technische Universitat Dresden, Bergstrasse 66,
¨
01069 Dresden, Germany. E-mail: hans-joachim.knoelker@tu-dresden.de;
Fax: +49 (0)351 463 37030
w Electronic supplementary information (ESI) available: Copies of the
1H and 13C NMR spectra of all antiostatins. CCDC numbers
708519–708521. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b821039j
synthetic antiostatin A2 ((S)-1b), with [a]D20
= +5.0
ꢂc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 1467–1469 | 1467

(c 0.5, CHCl3), was identical to the spectrum obtained from an
authentic sample of the natural product (see ESIw), kindly
provided by Prof. Seto and Dr Shin-ya. Due to the small
amount available of the natural product (0.4 mg), the absolute
configuration of natural antiostatin A2 could not be
determined yet.
We have developed an efficient reagent for introduction
of the antiostatin B side chain at C-4. Nitration of biuret
(18) using the classical procedure reported by Thiele and
Uhlfelder in 1898 led to 1-nitrobiuret (19) (Scheme 4).17
Alkylation with isobutylamine by adaptation of literature
procedures gave 1-isobutylbiuret (20).18 A further nitration
finally provided 5-isobutyl-1-nitrobiuret (21), which has been
structurally confirmed by X-ray analysis (Fig. 2).z
For an access to antiostatin B series, the unprotected
4-aminocarbazoles were required. Removal of the Boc pro-
tecting group from the 9-Boc-4-nitrocarbazoles 14c–f provided
the unprotected 4-nitrocarbazoles 22c–f (Scheme 5). This
three-step route to the 4-nitrocarbazoles 22 proceeds in much
better overall yield compared to the direct nitration of the
carbazoles 12 (cf. above). Catalytic hydrogenation of the
4-nitrocarbazoles 22c–f led to the 4-aminocarbazoles 23c–f,
which have been structurally confirmed by an X-ray analysis
of 23d (Fig. 3).z Slow addition of a solution of 5-isobutyl-1-
nitrobiuret (21) in acetonitrile to a solution of the amino-
carbazoles 23c–f in acetonitrile at reflux afforded the
5-isobutyl-1-(carbazol-4-yl)biurets 24c–f. The structural assign-
ments have been unequivocally confirmed by an X-ray crystal
structure determination of O-methylantiostatin B4 (24d)
(Fig. 4).z Finally, cleavage of the ether provided the
antiostatins B2 to B5 (2a–d). The spectroscopic data of the
antiostatins B2 to B5 (2a–d) were in full agreement with
those reported for the natural products.2y
In conclusion, we have developed a highly efficient synthesis
of the whole series of the antiostatins A and B. Due to the
flexibility of our modular approach, we can introduce all the
different alkyl chains at C-1 via a palladium(0)-catalysed
coupling and, at the stage of an advanced precursor, focus
either on the antiostatins A or B. For the antiostatins B,
5-isobutyl-1-nitrobiuret has been devised as reagent for
elaboration of the isobutylbiuret side chain at C-4 by reaction
with the corresponding aminocarbazole.
Scheme 2 Synthesis of the 9-Boc-4-aminocarbazoles 15. Reagents and
conditions: (a) CH3CN, 82 1C, 1–2 h; (b) Cp2FePF6, Na2CO3, CH2Cl2,
rt, 3–5 d; (c) Boc2O, DMAP, CH3CN, rt, 20–24 h; (d) claycop, Ac2O,
Et2O, rt, 4.5–20 h; (e) 5 bar H2, 30% Pd/C, CH3OH–CH2Cl2, rt, 3–7 d;
yields: Table 1.
Scheme 3 Synthesis of the antiostatins A1–A4 (1a–d). Reagents and
conditions: (a) AcCl, Et3N, THF, 0 1C to reflux, 13–24 h, 81–97%; (b)
180 1C, 45 min, 100%; (c) BBr3, CH2Cl2, ꢀ78 to ꢀ20 1C, 6–24 h, 65–94%.
We are grateful to Prof. H. Seto and Dr K. Shin-ya for
providing us the files of the original 1H NMR spectra of
antiostatin A1 and B4, and for sending us the sample of natural
antiostatin A2. We thank the BASF, Ludwigshafen, for a gift
of pentacarbonyliron.
Scheme 4 Synthesis of 5-isobutyl-1-nitrobiuret (21). Reagents and
conditions: (a) conc. H2SO4, conc. HNO3, 0 1C to rt, 2 h, 51%;
(b) i-BuNH2, EtOH, rt, 2 h, then 150 1C until melt, 99%; (c) conc.
H2SO4, conc. HNO3, 0 1C, 2 h, 24% (after recrystallization from EtOH).
Table 1 Transformation of the aryl triflate 6 into the 9-Boc-4-nitrocarbazoles 14 and the 9-Boc-4-aminocarbazoles 15 via the iron-mediated
synthesisa
7
R
8, yield (%)
9, yield (%)
11, yield (%)
12, yield (%)
13, yield (%)
14, yield (%)
15, yield (%)
7a
7b
7c
7d
7e
7f
(CH2)2CH3
100
90
98
100
82
85
100
88
95
100
96
84
100
95
89
100
96
100
63
93
93
96
81
91
93
100
98
100
100
100
81
81
83
91
90
81
100
100
99
92
—
—
(S)-CH(CH3)CH2CH3
(CH2)2CH(CH3)2
(CH2)4CH3
(CH2)3CH3
(CH2)3CH(CH3)2
a
The 9-Boc-4-aminocarbazoles 15a–d have been applied as synthetic precursors for the antiostatins A1 to A4 (1a–d) (Scheme 3). The
9-Boc-4-nitrocarbazoles 14c–f have been applied as synthetic precursors for the antiostatins B2 to B5 (2a–d) (Scheme 5).
ꢂc
This journal is The Royal Society of Chemistry 2009
1468 | Chem. Commun., 2009, 1467–1469

y Selected data. Antiostatin A1 (1a): yellow solid, mp 190–192 1C; 1H
NMR (500 MHz, acetone-d6): d = 0.92 (t, J = 7.2 Hz, 3 H), 1.37–1.42 (m,
2 H), 1.43–1.51 (m, 2 H), 1.65–1.71 (m, 2 H), 2.41 (s, 3 H), 2.50 (s, 3 H),
3.00 (m, 2 H), 7.12 (t, J = 7.9 Hz, 1 H), 7.33 (t, J = 7.9 Hz, 1 H), 7.46
(d, J = 7.9 Hz, 1 H), 8.08 (s) and 8.10 (s, S 1 H), 8.16 (d, J = 7.9 Hz, 1 H),
9.72 (br s, 1 H), 10.21 (br s, 1 H). Antiostatin A2 ((S)-1b): mp
185 1C. Antiostatin A3 (1c): mp 191–192 1C. Antiostatin A4 (1d): mp
180–183 1C. Antiostatin B2 (2a): mp 119–120 1C. Antiostatin B3 (2b):
mp 119–120 1C. Antiostatin B4 (2c): Yellow solid, mp 117–120 1C; 1H
NMR (500 MHz, acetone-d6): d = 0.91 (t, J = 6.9 Hz, 3 H), 1.02 (d, J =
6.7 Hz, 6 H), 1.28–1.43 (m, 6 H), 1.48–1.54 (m, 2 H), 1.66–1.72 (m, 2 H),
1.90–1.95 (m, 1 H), 2.43 (s, 3 H), 3.02 (m, 2 H), 3.23 (t, J = 6.2 Hz, 2 H),
6.90 (br s, 1 H), 7.13 (t, J = 8.0 Hz, 1 H), 7.33–7.37 (m, 1 H), 7.48 (d, J =
8.0 Hz, 1 H), 8.27 (br s, 1 H), 8.44 (br d, J = 7.5 Hz, 1 H), 8.91 (br s, 1 H),
10.23 (br s, 1 H), 10.94 (br s, 1 H); 13C NMR and DEPT (125 MHz,
acetone-d6): d = 12.78 (CH3), 14.33 (CH3), 20.21 (2 CH3), 23.29 (CH2),
29.17 (CH2), 29.51 (CH), 30.05 (CH2), 30.47 (CH2), 30.57 (CH2), 32.64
(CH2), 47.58 (CH2), 111.45 (CH), 114.90 (C), 116.67 (C), 119.11 (CH),
121.99 (CH), 122.81 (C), 122.92 (C), 125.44 (CH), 125.52 (C), 134.71 (C),
140.84 (C), 142.99 (C), 154.73 (CQO), 155.99 (CQO). Antiostatin B5 (2d):
mp 92 1C.
Fig. 2 X-Ray structure of 5-isobutyl-1-nitrobiuret (21).
z Crystal data for 21: C6H12N4O4, Mr = 204.20 g molꢀ1, orthorhombic,
Pbca, l = 0.71073 A, a = 10.571(1), b = 6.448(1), c = 28.570(3) A,
V = 1947.4(4) A3, Z = 8, rcalcd = 1.393 g cmꢀ3, m = 0.117 mmꢀ1, T =
198(2) K, y range = 3.44–25.001, reflections collected: 13855, independent:
1543 (Rint = 0.0342), R1 = 0.0386, wR2 = 0.0919 [I 4 2s(I)]. Crystal
data for 23d: C21H28N2O, Mr = 324.45 g molꢀ1, monoclinic, P21/c, l =
0.71073 A, a = 15.921(3), b = 4.739(1), c = 26.736(5) A, b = 113.91(3)1,
V = 1844.1(6) A3, Z = 4, rcalcd = 1.169 g cmꢀ3, m = 0.072 mmꢀ1, T =
198(2) K, y range = 3.05–26.001, reflections collected: 27 882, indepen-
dent: 3615 (Rint = 0.0538), R1 = 0.0528, wR2 = 0.1061 [I 4 2I(I)].
Scheme 5 Synthesis of the antiostatins B2–B5 (2a–d). Reagents and
conditions: (a) 180 1C, 45 min, 100%; (b) 5 bar H2, 30% Pd/C, EtOAc,
rt, 3–5 d, 82–100%; (c) 21, CH3CN, reflux, 4.5–5 h, 83–91%; (d) BBr3,
CH2Cl2, ꢀ78 to 0 1C, 2–3.5 h, 74–94%.
Crystal data for 24d: C27H38N4O3, Mr = 466.61 g molꢀ1, hexagonal, R3,
ꢀ
l = 0.71073 A, a = 27.586(4), c = 19.842(4) A, V = 13077(4) A3,
Z = 18, rcalcd = 1.067 g cmꢀ3, m = 0.070 mmꢀ1, T = 198(2) K, y range
= 3.05–25.401, reflections collected: 53 022, independent: 5332 (Rint
=
0.0424), R1 = 0.0704, wR2 = 0.2044 [I 4 2I(I)]. The structures were
solved by direct methods and refined by full-matrix least-squares on F2.
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Notes and references
z Synthesis of (S)-3-methylpent-1-yne (7b): 1. (S)-2-methylbutan-1-ol,
Dess–Martin periodinane,12 CH2Cl2, rt, 50 min, 83% (S)-2-methylbutanal;
2. Corey–Fuchs procedure:13 (a) CBr4, Zn, PPh3, CH2Cl2, rt, 14 h, 77%;
(b) BuLi, THF, ꢀ78 1C, 1 h, then rt, 2.5 h, 50%.
ꢂc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 1467–1469 | 1469