First total synthesis of murrastifoline B and an improved route to murrastifoline F

Article abstract of DOI:10.1055/s-0033-1338621

We report the first total synthesis of murrastifoline B and an improved route to murrastifoline F using a twofold palladium-catalyzed Buchwald-Hartwig amination as key step. The monomeric carbazole and the biaryl precursor are also prepared via palladium-

Full text of DOI:10.1055/s-0033-1338621

LETTER
▌1381
lFettierr st Total Synthesis of Murrastifoline B and an Improved Route to Murrasti-
foline F
Total Synthesis of Murrastifoline B
Carsten Börger, 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: 17.03.2014; Accepted after revision: 31.03.2014
Me
Me
Abstract: We report the first total synthesis of murrastifoline B and
an improved route to murrastifoline F using a twofold palladium-
catalyzed Buchwald–Hartwig amination as key step. The mono-
meric carbazole and the biaryl precursor are also prepared via
palladium-catalyzed coupling reactions.
OMe
OMe
N
Me
N
Key words: alkaloids, catalysis, cyclization, natural products, pal-
ladium
N
N
OMe
MeO
H
H
murrastifoline A (1)
murrastifoline B (2)
Me
The broad range of biological activities observed for car-
bazole alkaloids induced a strong interest in this class of
R
compounds and the development of diverse synthetic
methods.1–4 However, only a few synthetic approaches
N
OMe
Me
N
3,5
OMe
have been reported for biscarbazole alkaloids. We have
developed an efficient palladium-catalyzed route to carba-
zole alkaloids which is also applicable to the synthesis of
H
murrayafoline A (4a) R = Me
mukonine (4b) R = COOMe
N
H
OMe
6
biscarbazoles. Recently, we have completed the total
murrastifoline F (3)
synthesis of murrastifoline A (1) using an Ullmann coup-
6
h
ling to form the C–N linkage (Figure 1). Herein, we de-
Figure 1 Murrastifoline A (1), murrastifoline B (2), murrastifoline
scribe the synthesis of the biscarbazole alkaloids F (3), and the 1-methoxycarbazole alkaloids 4a,b
murrastifoline B (2) and murrastifoline F (3) using a two-
fold Buchwald–Hartwig coupling of an appropriately
functionalized aminocarbazole and a bistriflate as key
step.
twofold Buchwald–Hartwig amination for the first time to
1
2
generate a carbazole framework. Using this method,
Chida et al. synthesized the biscarbazole alkaloid murras-
In 1990, Furukawa and co-workers isolated murrastifoline
13
tifoline A (1) in 2005.
B (2) from the stem bark of Murraya euchrestifolia Hay-
7
ata. Three years later, the same group isolated murrasti-
Me
8
foline F (3) from the root and stem bark of the same plant.
Me
OMe
In 2001, Bringmann et al. described the first synthesis of
H2N
murrastifoline F (3) by oxidizing murrayafoline A (4a) us-
ing lead(IV) acetate in 60% yield (22% over eight steps).
OMe
OTf
OTf
9
+
N
N
MeO
The simple 1-oxygenated carbazole alkaloids murrayafo-
Boc
1
0
11
line A (4a) and mukonine (4b) are precursors for these
biscarbazole alkaloids, not only for the proposed biosyn-
thesis but also for the chemical synthesis (vide infra).
N
MeO
H
murrastifoline B (2)
Me
5
6
For the synthesis of murrastifoline B (2) and murrastifo-
line F (3), we envisaged a twofold Buchwald–Hartwig
coupling of the bistriflate 5 with the appropriately substi-
tuted arylamines 6 and 7 to construct the second carbazole
framework (Scheme 1). In 2003, Nozaki et al. applied the
Me
OMe
H2N
Me
OMe
Me
OTf
OTf
N
+
N
OMe
Boc
N
H
OMe
murrastifoline F (3)
5
7
SYNLETT 2014, 25, 1381–1384
Advanced online publication: 03.04.2014
Scheme 1 Retrosynthetic analysis of murrastifoline B (2) and mur-
rastifoline F (3)
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338621; Art ID: ST-2014-B0236-L
Georg Thieme Verlag Stuttgart · New York
©

1382
C. Börger et al.
LETTER
The required aminocarbazoles 6 and 7 are available using tion of the carbazole nitrogen atom and subsequent cata-
our palladium-catalyzed approach to carbazoles. For the lytic hydrogenation provided the 3-aminocarbazole 6.
synthesis of 1-oxygenated carbazoles via double Buch- Twofold Buchwald–Hartwig coupling of 6 with the bistri-
wald–Hartwig coupling, two different biaryl precursors flate 5 in the presence of XantPhos [4,5-bis(diphe-
have been described in the literature.1 In their approach nylphosphino)-9,9-dimethylxanthene] following Nozaki’s
3,14
1
4
to murrastifoline A (1), Chida et al. described the dibromo protocol with concomitant cleavage of the Boc group
1
3
analogue of 5 which requires a six-step synthesis. The provided directly murrastifoline B (2). The spectroscopic
2
4
biaryl compound developed by Nozaki and co-workers is data of our synthetic murrastifoline B (2) are in full
7
accessible in only three steps but has an ester group in- agreement with those reported for the natural product. An
stead of the methyl substituent.14 However, we require a assignment of the H and C NMR data for 2 has been
methyl group at this position. Direct reduction of a methyl achieved by the following set of 2D NMR spectra: COSY,
carboxylate at C-3 of the carbazole to a methyl group is HSQC, HMBC, and NOESY (see Supporting Informa-
1
13
1
5,16
feasible,
but only if the nitrogen atom is unsubstitut- tion).
6
f
ed. Based on these considerations, we have prepared the
bistriflate 5 which is the methyl analogue of the biaryl
compound used by Nozaki.
O2N
O2N
a, b
c, d
NH2
2
-Bromo-6-methoxy-4-methylphenol (9) was prepared
N
H
OMe
MeO
from commercially available 5-bromovanillin (8) using
1
8
10
11
the procedure of Nazih and co-workers (Scheme 2). Su-
zuki–Miyaura coupling of compound 9 with 2-hydroxy-
phenylboronic acid under the conditions used by Nozaki
and co-workers for the ester analogue resulted in decom-
position. However using the conditions of Ganesh et al.,
the corresponding biphenyl is available in 95% yield.
Me
H2N
1
4
OMe
e
1
9
N
N
Subsequent reaction with triflic anhydride afforded the bi-
MeO
Boc
aryl bistriflate 5.
N
6
MeO
H
murrastifoline B (2)
OH
OH
Br
OMe
Br
OMe
OTf
OTf
Scheme 3 Synthesis of murrastifoline B (2). Reagents and condi-
a
b, c
tions: (a) PhBr (1.2 equiv), Pd(OAc) (6 mol%), SPhos (12 mol%),
2
Cs CO (1.4 equiv), toluene, reflux, 40 h, 100%; (b) Pd(OAc) (1.3
2
3
2
CHO
Me
Me
OMe
equiv), Cu(OAc) (2.5 equiv), AcOH, 117 °C, 40 h, 78%; (c) Boc O
2
2
8
9
5
(2 equiv), DMAP (1 equiv), MeCN, r.t., 20 h, 91%; (d) 10% Pd/C, H2,
EtOAc, r.t., 5 d, 100%; (e) 5 (1 equiv), 6 (1 equiv), Pd (dba) (20
2
3
Scheme 2 Synthesis of the biaryl 5. Reagents and conditions: (a)
N H (2 equiv), diethylene glycol, 110 °C, 15 min, then KOH (6
mol%), XantPhos (40 mol%), K PO (4.8 equiv), o-xylene, 130 °C,
3
4
2
4
64 h, 66%.
equiv), 150 °C, 2 h, 94%; (b) 2-hydroxyphenylboronic acid (1.5
equiv), Pd(PPh ) (7.5 mol%), K CO (3 equiv), DME, EtOH, H O,
3
4
2
3
2
1
30 °C, sealed tube, 16 h, 95%; (c) Tf O (3 equiv), pyridine (3 equiv), The synthesis of murrastifoline F (3) requires the Boc-
2
CH Cl , 0 °C to r.t., 3 h, 84%.
protected 4-amino-1-methoxy-3-methyl-9H-carbazole 7
for the twofold Buchwald–Hartwig amination with 5
2
2
(
Scheme 4). Thus, murrayafoline A (4a) appeared to rep-
Our approach to murrastifoline B (2) requires the 3-ami-
nocarbazole 6 as precursor for the twofold Buchwald–
resent a suitable intermediate. Murrayafoline A (4a) is
available in three steps and 79% overall yield via muko-
nine (4b) starting from the commercially available aryl-
Hartwig amination (Scheme 1). Buchwald–Hartwig
coupling17 of 2-methoxy-4-nitroaniline (10) with bromo-
6
g,h
amine 12.
Subsequent N-Boc protection of
benzene to the corresponding diarylamine and subsequent
murrayafoline A (4a) afforded carbazole 13. Nitration us-
ing clay-supported copper(II) nitrate (claycop) takes
oxidative cyclization led to the carbazole 11 (Scheme 3).
2
5
2
0
Using Fagnou’s protocol, we observed only decomposi-
tion of the diarylamine. Our original conditions for the
2
6
place at C-4, as observed previously in analogous cases.
Catalytic hydrogenation of the 4-nitrocarbazole afforded
the 4-aminocarbazole 7. Using Nozaki’s protocol, the
twofold Buchwald–Hartwig coupling of 7 and the bistri-
flate 5 with concomitant deprotection afforded directly
murrastifoline F (3). The spectroscopic data of murrasti-
palladium(II)-catalyzed oxidative cyclization,2
1,22
provid-
1
4
ed carbazole 11 in only 20% yield. Using two equivalents
of palladium(II) acetate in acetic acid at reflux, the condi-
tions reported by Åkermark et al. for the cyclization of
electron-deficient diarylamines,23 carbazole 11 was
2
7
foline F (3) are in agreement with those reported in the
literature.
formed in 58% yield. The best result (78% yield of carba-
zole 11) was obtained using only a slight excess of palla-
8
,9
dium(II) acetate in the presence of copper(II) acetate, In conclusion, our present approach, based on a twofold
conditions recently reported by us for the synthesis of 1,6- Buchwald–Hartwig coupling of an appropriately substi-
6
f
dioxygenated carbazoles bearing an ester group. Protec- tuted arylamine with the bistriflate 5, provides murrastifo-
Synlett 2014, 25, 1381–1384
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Murrastifoline B
1383
COOMe
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a, b
c, d
H2N
N
H
OMe
OMe
1
2
mukonine (4b)
Me
(
(
(
7) Ito, C.; Wu, T.-S.; Furukawa, H. Chem. Pharm. Bull. 1990,
3
8, 1143.
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Me
Me
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N
OMe
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N
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OMe
OMe
Boc
Boc
2
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N
H
1
3
7
OMe
3
murrastifoline F (3)
(
(
(
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Cs CO (1.4 equiv), toluene, reflux, 40 h, 100%; (b) Pd(OAc) (10
mol%), K CO (10 mol%), PivOH, 115 °C, 14 h, 91%; (c) LiAlH (3
1
7, 834.
2
12) Nozaki, K.; Takahashi, K.; Nakano, K.; Hiyama, T.; Tang,
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2
3
2
2
3
4
equiv), Et O, CH Cl , r.t., 4.5 h, 87%; (d) Boc O (4 equiv), DMAP (1
2
2
2
2
equiv), MeCN, r.t., 40 h, 91%; (e) claycop (250 mg/mmol), Ac O (5
2
equiv), Et O, r.t., 40 h, 96%; (f) 10% Pd/C, H , EtOAc, r.t., 7 d, 100%;
2
2
(
g) 5 (1 equiv), 7 (1.2 equiv), Pd (dba) (20 mol%), XantPhos (40
2 3
mol%), K PO (6 equiv), o-xylene, 120 °C, 4 d, 64%.
(14) Kuwahara, A.; Nakano, K.; Nozaki, K. J. Org. Chem. 2005,
0, 413.
3
4
7
(15) Chakraborty, D. P.; Roy, S.; Dutta, A. K. J. Indian Chem.
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murrastifoline F (3) in seven steps (44% overall yield).
(
(
2
005, 7, 3965. (b) Surry, D. S.; Buchwald, S. L. Angew.
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Supporting Information for this article is available online at
(
(
(
http://www.thieme-connect.com/ejournals/toc/synthesis. SnuIoipgfmr tooatrin guSIopi
n
nfo itrmart
References and Notes
(
1) Part 116 of Transition Metals in Organic Synthesis; for Part
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1
(
(
Schmidt, A. W.; Knölker, H.-J. Eur. J. Org. Chem. 2014,
submitted.
5
57.
(
2) (a) Chakraborty, D. P.; Roy, S. In Progress in the Chemistry
of Organic Natural Products; Vol. 57; Herz, W.; Grisebach,
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Wien, 1991, 71. (b) Chakraborty, D. P. In The Alkaloids;
Vol. 44; Cordell, G. A., Ed.; Academic Press: New York,
(
23) Åkermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E.
J. Org. Chem. 1975, 40, 1365.
24) Experimental Procedure for the Twofold Buchwald–
Hartwig Coupling to Murrastifoline B (2)
(
A solution of the aminocarbazole 6 (19.1 mg, 0.061 mmol),
the bistriflate 5 (30.2 mg, 0.061 mmol), Pd (dba) (11.2 mg,
1
993, 257.
3) (a) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102,
303. (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.
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03. (e) Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J. Chem.
2
3
(
0.012 mmol), XantPhos (14.1 mg, 0.024 mmol), and K PO4
3
4
(
(61.9 mg, 0.292 mmol) in o-xylene (3 mL) was heated at
130 °C for 64 h. The reaction mixture was diluted with
EtOAc and a sat. aq. solution of NH Cl was added. The
aqueous layer was separated and extracted three times with
EtOAc. The combined organic layers were washed with
4
(
2
Rev. 2012, 112, 3193.
brine and dried over MgSO . Removal of the solvent and
4
(4) (a) Bergman, J.; Pelcman, B. Pure Appl. Chem. 1990, 62,
purification of the residue by flash chromatography on silica
1
967. (b) Pindur, U. Chimia 1990, 44, 406. (c) Kawasaki, T.;
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d) Zhang, M. Adv. Synth. Catal. 2009, 351, 2243. (e) Roy,
gel (isohexane–EtOAc, 6:1) afforded murrastifoline B (2);
yield 16.4 mg (66%); colorless crystals; mp 58.5–59 °C (lit.7
(
oil). UV (MeOH): λ = 229 (sh), 242, 291, 335 nm. IR
J.; Jana, A. K.; Mal, D. Tetrahedron 2012, 68, 6099.
(ATR): ν = 3407, 3055, 2923, 2852, 1692, 1624, 1582, 1542,
(5) (a) Furukawa, H. Trends Heterocycl. Chem. 1993, 3, 185.
1
1
502, 1453, 1419, 1395, 1323, 1277, 1222, 1134, 1104,
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(
b) Tasler, S.; Bringmann, G. Chem. Rec. 2002, 2, 113.
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b) Knölker, H.-J. Chem. Lett. 2009, 38, 8. Recent
(
–1
1
cm . H NMR (600 MHz, acetone-d ): δ = 2.55 (s, 3 H),
6
(
3.63 (s, 3 H), 4.06 (s, 3 H), 6.89 (s, 1 H), 7.07 (d, J = 1.6 Hz,
applications: (c) Fuchsenberger, M.; Forke, R.; Knölker,
H.-J. Synlett 2011, 2056. (d) Gensch, T.; Rönnefahrt, M.;
Czerwonka, R.; Jäger, A.; Kataeva, O.; Bauer, I.; Knölker,
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1
H), 7.21–7.25 (m, 3 H), 7.35–7.37 (m, 1 H), 7.46 (ddd,
J = 8.3, 7.1, 1.2 Hz, 1 H), 7.66 (dd, J = 1.3, 0.8 Hz, 1 H),
7.68 (dt, J = 8.2, 0.8 Hz, 1 H), 7.84 (m, 1 H), 8.15–8.17 (m,
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1381–1384

1384
C. Börger et al.
LETTER
2
H), 10.61 (br s, 1 H). 13C NMR and DEPT (150 MHz,
(26) Knott, K. E.; Auschill, S.; Jäger, A.; Knölker, H.-J. Chem.
Commun. 2009, 1467.
acetone-d ): δ = 21.68 (CH ), 56.10 (CH ), 56.24 (CH ),
6
3
3
3
1
1
1
08.13 (CH), 110.82 (CH), 111.20 (CH), 112.30 (CH),
13.11 (CH), 113.36 (CH), 119.88 (CH), 120.16 (CH),
20.69 (CH), 121.29 (CH), 123.8 (C), 124.4 (C), 126.45
(27) Murrastifoline F (3)
9
Colorless crystals; 288–289 °C (lit. 289 °C). UV (MeOH):
λ = 227, 242 (sh), 260 (sh), 287 (sh), 351 nm. IR (ATR):
ν = 3055, 2923, 2852, 1653, 1592, 1500, 1460, 1444, 1395,
1318, 1281, 1227, 1192, 1170, 1104, 1072, 1041, 938, 822,
(CH), 126.56 (CH), 129.97 (C), 130.06 (C), 132.77 (C),
1
41.2 (C), 144.0 (C), 146.39 (C), 147.82 (C); 3 C signals are
+
–1 1
missing. ESI-MS (10 V): m/z = 407 [M + H] .
25) (a) Cornélis, A.; Lazlo, P. Synthesis 1985, 909. (b) Laszlo,
745, 695, 637, 606 cm . H NMR (300 MHz, CDCl ):
3
(
δ = 2.30 (s, 3 H), 2.40 (s, 3 H), 3.80 (s, 3 H), 3.91 (s, 3 H),
6.50–6.56 (m, 3 H), 6.69–6.82 (m, 4 H), 6.83 (s, 1 H), 6.94
(s, 1 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.53 (d, J = 7.6 Hz, 1 H),
P.; Pennetreau, P. J. Org. Chem. 1987, 52, 2407. (c) Gigante,
B.; Prazeres, A. O.; Marcelo-Curto, M. J.; Cornélis, A.;
Laszlo, P. J. Org. Chem. 1995, 60, 3445.
7.73 (d, J = 7.0 Hz, 1 H). ESI-MS (25 V): m/z = 438 [M +
+
NH ] .
4
Synlett 2014, 25, 1381–1384
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