Transition metals in organic synthesis, part 111: 1 first total synthesis and structural revision of antipathine A

Article abstract of DOI:10.1055/s-0033-1339655

We describe the first total synthesis of antipathine A and a revision of the original structural assignment. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339655

2102▌
LETTER
1
letter
Transition Metals in Organic Synthesis, Part 111: First Total Synthesis and
Structural Revision of Antipathine A
First Total Synthesis and Structural Revision of Antipathine A
Andreas Berndt, Margit Gruner, Arndt W. Schmidt, Hans-Joachim Knölker*
Department Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax +49(351)46337030; E-mail: hans-joachim.knoelker@tu-dresden.de
Received: 18.07.2013; Accepted: 01.08.2013
14Me
O
Abstract: We describe the first total synthesis of antipathine A and
a revision of the original structural assignment.
14Me
N
3
13
5
4
5
4
6
6
3
12
N
4b 4a
9
4b 4a
9
O
13
11
N
10
Me
Key words: alkaloids, catalysis, cyclisation, palladium
12
15
7
2
11N
10
7
2
8a
9a
8a
9a
8
1
8
1
N
O
N
Me
15
H
H
O
The structural diversity and the manifold biological activ-
ities of carbazole alkaloids have induced a strong interest
in isolation and total synthesis of new members of this
class of natural products.1–5 Important natural sources are,
for example, higher plants of the genera Murraya,
Clausena, and Glycosmis of the family Rutaceae. Apart from
classical procedures for construction of the carbazole
framework, several new procedures using transition met-
als have been developed. We described an iron-mediated
and a palladium-catalysed approach for the synthesis of
carbazoles.4,5
1
2
Figure 1 Originally reported (1)6 and revised structure (2) of antipa-
thine A
synthetic analysis of 3 following route A suggests bromo-
benzene (4) and 6-amino-1,3-dimethylquinazoline-2,4-
dione (5) as precursors, whereas route B leads to aniline
(6) and 6-bromo-1,3-dimethylquinazoline-2,4-dione (7).
The first approach (route A) starts from 2-amino-5-nitro-
benzoic acid (8, Scheme 2). Condensation of 8 with urea
afforded 6-nitroquinazoline-2,4-dione (9).8 Double N-
methylation of 9 using tetraethylammonium hydroxide
and dimethyl sulfate led to 1,3-dimethyl-6-nitroquinazo-
line-2,4-dione (10),9 which on catalytic hydrogenation
In 2009, Qi et al. isolated antipathine A, a new carbazole
alkaloid from the South China Sea black coral Antipathes
dichotoma.6 They postulated structure 1 for this natural
product (Figure 1). Due to the inherent high strain of the provided
6-amino-1,3-dimethylquinazoline-2,4-dione
1,3-bridged ring system, Hill et al. questioned the struc- (5). Buchwald–Hartwig amination of bromobenzene (4)
tural assignment for antipathine A.7 Based on the pub- with 5 using SPhos as ligand10 afforded 1,3-dimethyl-6-
phenylaminoquinazoline-2,4-dione (3). Using route A,
the diarylamine 3 is available in four steps and 45% over-
all yield.
lished spectroscopic data, we suggested structure 2 for
antipathine A and developed a synthetic access to this
compound using our methodology for carbazole construc-
tion (Scheme 1).
For the synthesis of diarylamine 3 via the alternative route
B we used 2-amino-5-bromobenzoic acid (11) as starting
material (Scheme 3). Condensation of compound 11 with
urea led to 6-bromoquinazoline-2,4-dione (12). Subse-
Compound 2 should be available by oxidative cyclisation
of the diarylamine 3. Two alternative routes have been
considered for the synthesis of this diarylamine. Retro-
Me
O
Me
N
N
O
N
Me
N
N
H
Me
N
H
2
O
O
3
A
B
Me
N
Me
N
O
O
+
+
N
N
Br
H2N
Me
NH2
Br
Me
O
O
4
5
6
7
Scheme 1 Retrosynthetic analysis of antipathine A (2)
SYNLETT 2013, 24, 2102–2106
Advanced online publication: 21.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339655; Art ID: ST-2013-B0671-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
First Total Synthesis and Structural Revision of Antipathine A
2103
amine 3. Following route B, compound 3 was obtained in
three steps and 66% overall yield.
Me
N
H
N
O
NH2
O
a
b
The palladium(II)-mediated oxidative cyclisation of com-
pound 3 in acetic acid solution led to the pyrimido[4,5-
c]carbazole-1,3-dione 13 as major product in 68% yield
(Scheme 3, Table 1).11 The desired pyrimido[5,4-b]carba-
zole-2,4-dione 2, presumably identical with antipathine
A, was isolated in only 3% yield. However, using pivalic
acid as solvent,5j,5k,12 the regioisomeric carbazoles 2 and
13 were obtained in 93% yield and a ratio of 1:3. Thus,
compound 2 could be isolated in 23% yield and fully char-
acterised by its spectroscopic data.13
N
NH
O2N
Me
O2N
COOH O2N
O
O
10
8
9
Me
Me
N
O
N
O
O
c
d
N
N
H2N
Me
N
H
Me
O
5
3
Me
Scheme 2 Route A to the diarylamine 3. Reagents and conditions:
(a) urea (15 equiv), 150 °C, 25 h, 70%; (b) Et4N+OH– (2.5 equiv),
Me2SO4 (4 equiv), H2O, r.t., 1 h, 60 °C, 1 h, 77%; (c) 17 wt% Pd/C
(10% Pd), H2, CH2Cl2–EtOAc (1:1), r.t., 45 min, 93%; (d) PhBr (4,
1.1 equiv), Pd(OAc)2 (5 mol%), SPhos (10 mol%), Cs2CO3 (1.4 equiv),
PhMe, 100 °C, 72 h, 89%.
8
N1
O
7
2
N3
4
6
N
H
Me
5
O
3
Pd(OAc)2
H
N
O
NH2
a
Me
N1
OAc
Me
N1
L
NH
8
5
8
Pd
L
O
Br
O
Br
COOH
7
7
6
2
2
O
N3
N3
4
4
6
12
11
N
Me
N
H
Me
5
H
O
L
Pd
O
Me
Me
N
OAc
14a
14b
N
O
O
c
b
N
N
Br
Me
N
Me
H
O
O
Me
N3
7
3
O
O
L
L
Me
N1
L
4
2
N1
Me
8
5
Pd
O
O
Pd
5
6
N
2
N3
7
Me
N
Me
O
O
4
N
6
8
Me
N
H
Me
N
H
7
d
N
O
Me
+
15a
– [Pd(0)]
15b
N
H
2
N
H
O
– [Pd(0)]
13
Me
N
O
Scheme 3 Route B to the diarylamine 3 and oxidative cyclisation.
Reagents and conditions: (a) urea (20 equiv), 150 °C, 25 h, 94%;
(b) Et4N+OH– (2.5 equiv), Me2SO4 (3 equiv), H2O, r.t., 1 h, 60 °C, 1
h, 83%; (c) 7 (1.1 equiv), PhNH2 (6, 1 equiv), Pd(OAc)2 (7 mol%),
SPhos (14 mol%), Cs2CO3 (1.4 equiv), PhMe, 100 °C, 71 h, 85%;
(d) Pd(OAc)2 (1.1 equiv), PivOH, 100 °C, 25 h, 23% 2, 70% 13.
14Me
N
O
O
N
Me
4
5
6
3
13
12
11 N
4b
4a
Me
10
15
7
2
9
8a
9a
8
1
N
H
N
H
2
O
13
quent twofold N-methylation to 6-bromo-1,3-dimethyl-
quinazoline-2,4-dione (7) followed by Buchwald–
Hartwig coupling with aniline (6) afforded the diaryl-
Scheme 4 Ortho-directed palladation by coordinative interaction of
the C=O at C4 to palladium and non-directed palladation (L = AcOH,
PivOH).
Table 1 Reaction Conditions for the Oxidative Cyclisation of 3
Reaction conditions
Yield of 2 (%)
Yield of 13 (%)
Yield of 3 (%)a
Pd(OAc)2 (1.1 equiv), AcOH, 100 °C, 2 h, Ar
Pd(OAc)2 (1.1 equiv), PivOH, 100 °C, 25 h, Ar
a Re-isolated starting material.
3
68
70
8
7
23
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2102–2106

2104
A. Berndt et al.
LETTER
Table 2 1H NMR Spectroscopic Data for Antipathine Aa
Table 3 13C NMR Spectroscopic Data for Antipathine Aa
Data (δ, ppm) reported
Our data (δ, ppm)
for antipathine A (2)
Data (δ, ppm) reported
Our data (δ, ppm)
for antipathine A (2)
for antipathine A6
for antipathine A6
3.57 (s)
15-H3
14-H3
6-H
3.57 (s)
15-H3
14-H3
6-H
28.4
30.9
C15 (CH3)
28.51
31.03
C15 (CH3)
3.66 (s)
3.66 (s)
C14 (CH3)
C4 (CH)
C2 (CH)
C8 (CH)
C4a
C14 (CH3)
C4 (CH)
C1 (CH)
C8 (CH)
C2
7.35 (t, J = 7.5 Hz)
7.60 (t, J = 7.5 Hz)
7.66 (d, J = 7.5 Hz)
8.14 (s)
7.35 (t, J = 7.4 Hz)
7.59 (t, J = 7.6 Hz),
7.66 (d, J = 8.2 Hz)
8.14 (s)
104.7
110.1
111.9
114.4
119.5
122.0
122.8
128.4
129.7
133.9
136.8
143.5
151.0
162.6
104.87
110.19
112.03
114.50
119.62
122.18
122.91
128.46
129.76
133.94
136.74
143.60
151.09
162.71
7-H
7-H
5-H
8-H
4-H
4-H
8.42 (d, J = 7.5 Hz)
8.66 (s)
8-H
8.41 (d, J = 7.8 Hz)
8.65 (s)
5-H
C6 (CH)
C5 (CH)
C4b
C6 (CH)
C5 (CH)
C4b
2-H
1-H
12.73 (br s)
N–H
12.72 (br s)
N–H
a H atoms marked in bold have been wrongly assigned before.6
C7 (CH)
C1
C7 (CH)
C4a
The strong preference for compound 13 appears to be sur-
prising, since the carbazole with the [c]-anellated pyrimi-
dinedione ring represents the sterically more congested
ring system. We assume that the C–H bond activation of
3 preferentially occurs in the position ortho to the carbon-
yl group via coordination of the oxygen to palladium.14
This directed palladation leads to complex 14b (Scheme
4). A second intramolecular C–H bond activation gener-
ates palladacycle 15b. Reductive elimination of 15b pro-
vides the pyrimido[4,5-c]carbazole-1,3-dione 13 which is
observed as major product of these cyclisations. We have
recently been able to isolate a palladacycle related to 15b
and demonstrated its reductive elimination to 4-substitut-
ed carbazoles.14g Nondirected palladation to complex 14a
followed by cyclopalladation to 15a and reductive elimi-
nation ultimately affords the pyrimido[5,4-b]carbazole-
2,4-dione 2. Alternatively, palladacycle 15a might also be
formed by initial electrophilic palladation of the phenyl
ring and subsequent cyclopalladation. Presumably, the in-
creased steric demand of the pivalate ligand relative to an
acetate ligand renders the nondirected palladation (metal-
lation at the more easily accessible position C7 or at the
phenyl ring) more competitive to the directed palladation
(metallation at C5). Using pivalic acid as solvent leads to
a cleaner course of the reaction,5j,5k,12 and the pathway via
complex 14a and palladacycle 15a leading to carbazole 2
is gaining importance relative to the route leading to iso-
mer 13.
C3
C3
C9a
C9a
C8a
C8a
C12 (C=O)
C10 (C=O)
C12 (C=O)
C10 (C=O)
a C atoms marked in bold have been wrongly assigned before.6
had to be reassigned: 2-H as 1-H, 5-H as 8-H, 8-H as 5-H,
C2 as C1, C4a as C2, and C1 as C4a (Table 2 and Table
3). Also some of the reported HMBC correlations were re-
vised (Table 4). The combined spectroscopic data unam-
biguously confirm that carbazole 2 represents the correct
structure for antipathine A.
In conclusion, we have developed a synthesis of carbazole
2 using a palladium-catalysed Buchwald–Hartwig cou-
pling and a palladium-mediated oxidative cyclisation as
key steps to construct the carbazole framework. Our ap-
proach provides carbazole 2 in four steps and 15% overall
yield based on 2-amino-5-bromobenzoic acid (11). The
spectroscopic data emphasise that the original structural
assignment needs revision and confirm that the structure
of our synthetic compound 2 is identical with natural
antipathine A.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
Careful analysis of the NMR data for our synthetic com-
pound 2 supported by COSY, NOESY, HMBC, and
r
t
iornat
1
HSQC experiments led to a full assignment for all H
NMR and 13C NMR signals (Table 2 and Table 3, Sup-
porting Information).13 Comparison of the spectroscopic
data for our compound 2 with those published by Qi et al.
References and Notes
(1) Part 110: Kumar, V. P.; Gruner, K. K.; Kataeva, O.; Knölker,
H.-J. Angew. Chem. Int. Ed. 2013, 52, doi:
1
for natural antipathine A revealed that several H NMR
10.1002/anie.201305993.
and 13C NMR signals have been wrongly assigned in the
original publication which led to the incorrect structure.6
In particular, the NMR signals for the following atoms
(2) For reviews, see: (a) Chakraborty, D. P.; Roy, S. In Progress
in the Chemistry of Organic Natural Products; Vol. 57;
Herz, W.; Grisebach, H.; Kirby, G. W.; Steglich, W.; Tamm,
Synlett 2013, 24, 2102–2106
© Georg Thieme Verlag Stuttgart · New York

LETTER
First Total Synthesis and Structural Revision of Antipathine A
2105
Table 4 Comparison of the Assignments for the HMBC Correlations Reported by Qi et al.6 for 1 with our Corresponding Assignments for the
Revised Structure of Antipathine A (2)a
14
Me
14 Me
O
5
4
N
3
13
6
3
5
4
N
6
12
4b 4a
O
13
4b 4a
11
N
12
Me
2
11N
10
7
15
10
9
N
7
2
9
N
8a
9a
8
1
8a
9a
Me
8
1
O
15
H
O
H
1
2
HMBC correlations (δ, ppm) reported by Qi et al.6
HMBC correlations (δ, ppm) observed by us
2-H/C1
2-H/C3
2-H/C10
4-H/C9a
4-H/C3
4-H/C4a
4-H/C4b
–
8.66/129.7
8.66/104.7
8.66/162.6
8.14/136.8
8.14/133.9
8.14/114.4
8.14/122.8
–
1-H/C4a
1-H/C3
1-H/C10
4-H/C9a
4-H/C3
8.65/129.76
8.65/133.94
8.65/162.71
8.14/136.74
8.14/133.94
8.14/114.50
8.14/122.91
8.14/110.19
8.14/162.71
7.66/122.91
7.66/119.62
7.35/122.91
7.35/112.03
7.35/128.46
–
4-H/C2
4-H/C4b
4-H/C1
–
–
4-H/C10
8-H/C4b
8-H/C6
5-H/C4b
–
7.66/122.8
–
6-H/C4b
6-H/C8
–
7.35/122.8
7.35/111.9
–
6-H/C4b
6-H/C8
6-H/C7
7-H/C8
7-H/C8a
–
7.60/111.9
7.60/143.5
–
–
7-H/C8a
7-H/C5
7.59/143.60
7.59/122.18
8.41/143.60
8.41/129.76
8.41/128.46
3.66/133.94
3.66/151.09
3.66/104.87
3.57/162.71
3.57/151.09
12.72/129.76
12.72/136.74
–
8-H/C8a
–
8.42/143.5
–
5-H/C8a
5-H/C4a
5-H/C7
14-H3/C3
14-H3/C12
14-H3/C4
15-H3/C10
15-H3/C12
N–H/C4a
N–H/C9a
–
–
–
14-H3/C3
14-H3/C12
–
3.66/133.9
3.66/151.0
–
15-H3/C10
15-H3/C12
N–H/C1
N–H/C9a
N–H/C8
N–H/C8a
–
3.57/162.6
3.57/151.0
12.73/129.7
12.73/136.8
12.73/111.9
12.73/143.5
–
N–H/C8a
N–H/C4b
12.72/143.60
12.72/122.91
a Signals marked in bold have not been assigned correctly before6 and have now been revised as shown.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2102–2106

2106
A. Berndt et al.
LETTER
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Light yellow solid; mp 307–309 °C. UV (MeOH): λ = 217,
257, 275 (sh), 334, 374, 392 nm. Fluorescence (MeOH):
λex = 257 nm, λem = 434, 518 nm. IR (ATR): ν = 3278, 3045,
2951, 2921, 2056, 2030, 2009, 1734, 1688, 1631, 1582,
1517, 1489, 1458, 1418, 1345, 1317, 1288, 1222, 1184,
1139, 1079, 1025, 987, 924, 862, 791, 742, 721, 698, 637,
606 cm–1. 1H NMR (500 MHz, C5D5N): δ = 3.56 (s, 3 H),
3.65 (s, 3 H), 7.32 (d, J = 8.9 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 1
H), 7.60 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H), 7.73 (d, J = 8.1 Hz,
1 H), 7.98 (d, J = 8.9 Hz, 1 H), 10.27 (d, J = 8.4 Hz, 1 H),
12.90 (br s, 1 H). 13C NMR (125 MHz, C5D5N): δ = 28.71
(CH3), 31.73 (CH3), 110.96 (C), 111.45 (CH), 112.49 (CH),
118.68 (CH), 119.26 (CH), 120.91 (C), 123.20 (C), 127.29
(CH), 129.22 (CH), 136.28 (C), 137.32 (C), 142.72 (C),
151.07 (C=O), 162.83 (C=O). MS (70 eV): m/z (%) = 279
(100) [M+], 222 (12), 221 (6), 194 (22), 193 (30), 167 (8),
166 (12), 139 (7). HRMS: m/z calcd for C16H13N3O2 [M+]:
279.1008; found: 279.0999.
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Trans. 1 1998, 173. (c) Knölker, H.-J.; Reddy, K. R.;
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H.-J.; Fröhner, W.; Reddy, K. R. Synthesis 2002, 557.
(e) Knölker, H.-J.; Reddy, K. R. Heterocycles 2003, 60,
1049. (f) Knölker, H.-J. Curr. Org. Synth. 2004, 1, 309.
(g) Krahl, M. P.; Jäger, A.; Krause, T.; Knölker, H.-J. Org.
Biomol. Chem. 2006, 4, 3215. (h) Forke, R.; Krahl, M. P.;
Krause, T.; Schlechtingen, G.; Knölker, H.-J. Synlett 2007,
268. (i) Börger, C.; Knölker, H.-J. Synlett 2008, 1698.
(j) Forke, R.; Jäger, A.; Knölker, H.-J. Org. Biomol. Chem.
2008, 6, 2481. (k) Forke, R.; Krahl, M. P.; Däbritz, F.; Jäger,
A.; Knölker, H.-J. Synlett 2008, 1870. (l) Knölker, H.-J.
Chem. Lett. 2009, 38, 8. (m) Gruner, K. K.; Knölker, H.-J.
Org. Biomol. Chem. 2008, 6, 3902. (n) Schmidt, M.;
Knölker, H.-J. Synlett 2009, 2421. (o) Fuchsenberger, M.;
Forke, R.; Knölker, H.-J. Synlett 2011, 2056. (p) Huet, L.;
Forke, R.; Jäger, A.; Knölker, H.-J. Synlett 2012, 23, 1230.
(q) Börger, C.; Krahl, M. P.; Gruner, M.; Kataeva, O.;
Knölker, H.-J. Org. Biomol. Chem. 2012, 10, 5189.
(r) Börger, C.; Knölker, H.-J. Tetrahedron 2012, 68, 6727.
(s) Börger, C.; Kataeva, O.; Knölker, H.-J. Org. Biomol.
Chem. 2012, 10, 7269. (t) Thomas, C.; Knölker, H.-J.
Tetrahedron Lett. 2013, 54, 591. (u) Hesse, R.; Gruner, K.
K.; Kataeva, O.; Schmidt, A. W.; Knölker, H.-J. Chem. Eur.
J. 2013, 19, in press; DOI: 10.1002/chem.201301792.
(6) Qi, S.-H.; Su, G.-C.; Wang, Y.-F.; Liu, Q.-Y.; Gao, C.-H.
Chem. Pharm. Bull. 2009, 57, 87.
(12) Liégault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou,
K. J. Org. Chem. 2008, 73, 5022.
(13) Spectroscopic Data for Antipathine A {1,3-Dimethyl-1H-
pyrimido[5,4-b]carbazole-2,4(3H,6H)-dione} (2)
Yellow solid; mp 342–344 °C. UV (MeOH): λ = 219, 260,
318 (sh), 327, 383, 398 nm. Fluorescence (MeOH):
λ
ex = 260 nm, λem = 448 nm. IR (ATR): ν = 3263, 3028,
2921, 2846, 1771, 1735, 1717, 1686, 1626, 1559, 1540,
1518, 1456, 1432, 1377, 1333, 1307, 1241, 1191, 1146,
1098, 1067, 1017, 965, 856, 834, 765, 742, 723, 706, 640
cm–1. 1H NMR (500 MHz, C5D5N): δ = 3.57 (s, 3 H), 3.66 (s,
3 H), 7.35 (t, J = 7.4 Hz, 1 H), 7.59 (t, J = 7.6 Hz, 1 H), 7.66
(d, J = 8.2 Hz, 1 H), 8.14 (s, 1 H), 8.41 (d, J = 7.8 Hz, 1 H),
8.65 (s, 1 H), 12.72 (br s, 1 H). 13C NMR (125 MHz, C5D5N):
δ = 28.51 (CH3), 31.03 (CH3), 104.87 (CH), 110.19 (CH),
112.03 (CH), 114.50 (C), 119.62 (CH), 122.18 (CH), 122.91
(C), 128.46 (CH), 129.76 (C), 133.94 (C), 136.74 (C),
143.60 (C), 151.09 (C=O), 162.71 (C=O). MS (70 eV): m/z
(%) = 279 (100) [M+], 222 (10), 221 (5), 194 (18), 193 (36),
192 (5), 167 (10), 166 (12), 139 (7). HRMS: m/z calcd for
C16H13N3O2 [M+]: 279.1008; found: 279.1001.
(14) For the use of carbonyl groups as directing groups in
palladium(II)-catalysed C–H functionalisations, see for
example: (a) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.;
Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416.
(b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-
N.; Lazareva, A. Synlett 2006, 3382. (c) Yu, J.-Q.; Giri, R.;
Chen, X. Org. Biomol. Chem. 2006, 4, 4041. (d) Brasche,
G.; García-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10,
2207. (e) Bedford, R. B.; Haddow, M. F.; Mitchell, C. J.;
Webster, R. L. Angew. Chem. Int. Ed. 2011, 50, 5524.
(f) Wang, X.; Leow, D.; Yu, J.-Q. J. Am. Chem. Soc. 2011,
133, 13864. (g) Gensch, T.; Rönnefahrt, M.; Czerwonka, R.;
Jäger, A.; Kataeva, O.; Bauer, I.; Knölker, H.-J. Chem. Eur.
J. 2012, 18, 770.
Synlett 2013, 24, 2102–2106
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