Total synthesis of (±)-murrayazoline

Article abstract of DOI:10.1021/ol800602v

The total synthesis of (±)-murrayazoline (1) is described. The characteristic hexa-heterocyclic structure of 1 was constructed by a combination of the intramolecular Friedel-Crafts-type Michael addition and Pd-catalyzed C-O coupling reactions. The N-substituted carbazole component was synthesized in one pot by the double N-arylation of a sterically hindered amine with a dibromobiphenyl derivative.

Full text of DOI:10.1021/ol800602v

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1999-2002
Total Synthesis of (()-Murrayazoline
Akiko Ueno, Takafumi Kitawaki, and Noritaka Chida*
Department of Applied Chemistry, Keio UniVersity, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
chida@applc.keio.ac.jp
Received March 15, 2008
ABSTRACT
The total synthesis of (()-murrayazoline (1) is described. The characteristic hexa-heterocyclic structure of 1 was constructed by a combination
of the intramolecular Friedel-Crafts-type Michael addition and Pd-catalyzed C-O coupling reactions. The N-substituted carbazole component
was synthesized in one pot by the double N-arylation of a sterically hindered amine with a dibromobiphenyl derivative.
Murrayazoline (1, also known as curryangin and mahanim-
bidine) is a carbazole alkaloid isolated as a racemic or an
optically active compound from the genus Murraya.1 The
plants of the genus Murraya are shrubs belonging to
Rutaceae that have been used as a source of folk medicine
for the treatment of analgesia, local anesthesia, eczema,
rheumatism, and dropsy in Southern Asia,1c,d and murraya-
zoline and its related carbazole alkaloids have been reported
to show a potent antiplatelet aggregation activity.1e A struc-
tural elucidation study by spectral analyses revealed that
murrayazoline is a novel hexa-heterocyclic alkaloid com-
posed of N-substituted carbazole, dihydropyran, and cyclo-
hexane components.1 The unique structure of 1 was later
confirmed by a single-crystal X-ray analysis.2 Murrayazoline
is believed to be biologically synthesized from 2-hydroxy-
3-methylcarbazole and a monoterpene (C10) fragment via
mahanimbin (2), also isolated from the same plant, by the
action of the acid. Indeed, Dutta, Quasim, and Wadia reported
that when 2-hydroxy-3-methylcarbazole and citral were
treated with SnCl2, FeCl3,1b,3 or polyphosphoric acid, a
mixture containing some amount of 1 and 2 was obtained.3
In spite of its intriguing hexa-heterocyclic structure, which
is synthetically fascinating and challenging, no other synthetic
approaches to murrayazoline have appeared. In this paper,
we report the nonbiomimetic total synthesis of 1.
Recently, we reported the one-step construction of N-
substituted carbazoles by way of the palladium-catalyzed
double N-arylation reaction of various primary amines with
(3) Dutta, N. L.; Quasim, C.; Wadia, M. S. Indian J. Chem. 1969, 7,
1168
.
(4) (a) Kitawaki, T.; Hayashi, Y.; Chida, N. Heterocycles 2005, 65, 1561.
(b) Kitawaki, T.; Hayashi, Y.; Ueno, A.; Chida, N. Tetrahedron 2006, 62,
6792.
(5) (a) Nozaki, K.; Takahashi, K.; Nakano, K.; Hiyama, T.; Tang, H.-
Z.; Fujiki, M.; Yamaguchi, S.; Tamao, K Angew. Chem., Int. Ed. 2003, 42,
2051. (b) Kuwahara, A.; Nakano, K.; Nozaki, K. J. Org. Chem. 2005, 70,
413. (c) Nakano, K.; Hidehira, Y.; Takahashi, K.; Hiyama, T.; Nozaki, K.
Angew. Chem., Int. Ed. 2005, 44, 7136. (d) Kawaguchi, K.; Nakano, K.;
Nozaki, K J. Org. Chem. 2007, 72, 5119.
(6) (a) Muci, A. R.; Buchwald, S. L. In Topics in Current Chemistry;
Miyaura, N., Ed.; Springer-Verlag: Berlin, 2001; Vol. 219, pp 131-209.
(b) Hartwig, J. F. In Modern Arene Chemistry; Astruc, C., Ed.; Wiley-
VCH: Weinheim, 2002; pp 107-168. (c) Hartwig, J. F. Acc. Chem. Res.
1998, 31, 852. (d) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1158. (e) Strieter, E. R.; Blackmond, D. G.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 13978. (f) Huang, X.;
Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 6653. (g) Wolfe, J. P.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 1144. (h) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-L.;
Buchwald, S. L Acc. Chem. Res. 1998, 31, 805. (i) Hartwig, J. F. Angew.
Chem., Int. Ed. 1998, 37, 2046.
(1) Isolation of racemic murrayazoline: (a) Dutta, N. L.; Quasim, C.;
Wadia, M. S. Indian J. Chem. 1969, 7, 1061. (b) Kureel, S. P.; Dapil, R. S.;
Popli, S. P. Tetrahedron Lett. 1969, 3857. (c) Wu, T.-S.; Wang, M.-L.;
Wu, P.-L. Phytochemistry 1996, 43, 785. Isolation of (+)-murrayazoline,
see (d) Furukawa, H.; Wu, T.-S.; Ohta, T.; Kuoh, C.-S. Chem. Pharm. Bull
1985, 33, 4132. Biological activities of (+)-murrayazoline and related
carbazole alkaloids, see (e) Wu, T.-S.; Chan, Y.-Y.; Liou, M.-J.; Lin, F.-
W.; Shi, L.-S.; Chen, K.-T. Phytother. Res. 1998, 12, S80.
(2) Bordner, J.; Chakraborty, D. P.; Chowdhury, B. K.; Ganguli, S. N.;
Das, D. C.; Weinstein, B., Experientia 1972, 28, 1406. The absolute structure
of (+)-murrayazoline has not been determined.
10.1021/ol800602v CCC: $40.75
Published on Web 04/11/2008
2008 American Chemical Society

2,2′-dibromobiphenyl derivatives.4 The double N-arylation,
first developed by Nozaki and co-workers,5 is an important
extension of the Buchwald-Hartwig N-arylation reaction6
and proved to be an excellent protocol for the regioselective
construction of unsymmetrical multisubstituted carbazoles
in one step.4,5,7 The usefulness of the reaction has been
clearly shown by the efficient total syntheses of the carbazole
alkaloids mukonine5b and murrastifoline A,4 and the prepara-
tion of aza[7]helicene derivatives,5c π-conjugated hetero-
acenes,5d and dithieno[3,2-b:2′,3′-d]pyrroles.8
The synthesis of dibromobiphenyl 5 commenced from
commercially available 7 (Scheme 1). The O-tosylation of
Scheme 1. Preparation of Dibromobiphenyl 5
Our retrosynthetic analysis of 1, taking into account the
utilization of the double N-arylation, suggested that the
pentacyclic carbazole-cyclohexanone 3 would be a promis-
ing precursor (Figure 1). Compound 3 was expected to be
7, followed by the conventional iodination with N-iodosuc-
cinimide (NIS) gave 9 in 76% yield. The Suzuki-Miyaura
cross-coupling10 of 9 with 2-bromophenylboronic acid
cleanly afforded biphenyl 10 in 99% yield. Sandmeyer
reaction of 10 under standard conditions provided dibromo-
biphenyl 11 (85% yield). The O-Ts protecting group in 11
was removed by basic methanolylsis to give a phenol whose
O-methoxymethylation furnished 5 in 92% yield from 11.
The counterpart, the E-ring possessing a primary amine
function 6, was synthesized as shown in Scheme 2. Wittig
reaction of the known monothioacetal9 8, prepared from
cyclohexane 1,4-dione, with Ph3P ) CHOMe, followed by
Scheme 2. Preparation of E-Ring 6
Figure 1. Structures of murrayazoline (1) and mahanimbin (2) and
retrosynthetic analysis of 1. MOM ) -CH2OMe.
prepared by the intramolecular Friedel-Crafts-type Michael
addition of N-substituted carbazole 4. For the preparation
of 4, the double N-arylation reaction of amine 6 with
dibromobiphenyl derivative 5 was planned. The two requisite
fragments 5 and 6 were envisioned to be derived from
5-amino-2-methylphenol (7) and the known 1,5-dithiaspiro-
[5,5]unedecane-9-one9(8), respectively.
(7) For other approaches for the Pd-catalyzed one-step construction of
carbazoles, see: (a) Bedford, R. B.; Betham, M. J. Org. Chem. 2006, 71,
9403. (b) Watanabe, T.; Ueda, S.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H.
Chem. Commun. 2007, 4516. (c) Ackermann, L.; Althammer, A. Angew.
Chem., Int. Ed. 2007, 46, 1627. (d) Kitamura, Y.; Yoshikawa, S.; Furuta,
T.; Kan, T. Synlett 2008, 377
.
(8) Koeckelberghs, G.; De Cremer, L.; Vanormelingen, W.; Dehaen,
W.; Verbiest, T.; Persoons, A.; Samyn, C. Tetrahedron 2005, 61, 687.
2000
Org. Lett., Vol. 10, No. 10, 2008

acid hydrolysis afforded aldehyde 12 in 74% yield from 8.
The treatment of 12 with MeLi, followed by oxidation
afforded a methyl ketone, which was then reacted with MeLi
to give tertiary alcohol 13 in 64% yield. The reaction of 13
Scheme 4. Construction of the ABCDE Pentacyclic Structure
11
with TMSN3 in the presence of BF3·OEt2 and subsequent
deprotection of the thioacetal group afforded azide 14 (61%
for two steps). Ito-Saegusa oxidation of 14 cleanly provided
racemic cyclohexenone 15 in 84% yield. Protection of the
ketone carbonyl group as an ethylene ketal followed by
reduction of the azide function afforded amine 6 in 86% yield
from 15.
With both desired segments 5 and 6 in hand, the crucial
double N-arylation reaction was explored (Scheme 3). In our
Scheme 3
.
Construction of a Carbazole by the Double
N-Arylation of 6 with 5
Having completed the synthesis of the pentacyclic struc-
ture, we next turned our attention to the transformation of 3
into murrayazoline. Tebbe olefination of 3 gave exo-olefin
21 in 62% yield. For the construction of the dihydropyranyl
F-ring, compound 21 was treated with some Brønsted and
Lewis acids (H2SO4, CF3CO2H, and Sc(OTf)3); however,
under these acidic conditions, only decomposition of the
substrate was observed. The attempted halo-etherification
with NBS or I2 also resulted in a decomposition.13 The
treatment of 21 with other various electrophiles, such as
Hg(II) salts,14 Pd(II) salts,15 N-(phenylseleno)phthalimide,16
m-CPBA, and oxone-acetone,17 gave a complex mixture
of unidentified products, and the formation of the desired
compound 22 was not detected.
earlier study of the palladium-catalyzed double-N-arylation
of simple amines with 2,2′-dibromobiphenyl, it was revealed
that the use of Pd2(dba)3 as a palladium source, phosphine
186d as a ligand and NaO-t-Bu as a base gave acceptable
results when the sterically hindered aliphatic amine (tert-
butylamine) was employed.4 Actually, when a mixture of
amine 6 and biphenyl 5 in toluene was heated at 130 °C in
the presence of Pd2(dba)3, NaO-t-Bu, and ligand 18, the
double N-arylation successfully took place to provide the
desired N-substituted carbazole 17 in 59% yield. The use of
other ligands, 19 and 20,6c,e as anticipated, resulted in the
lower yields of 17.
The treatment of 17 with Sc(OTf)3 in dichloroethane and
H2O at 120 °C induced the deprotection of the ethylene ketal
group as well as the intramolecular Friedel-Crafts-type
Michael addition and the deprotection of the O-MOM group
to construct the D-ring, thus providing pentacyclic ketone 3
in 73% yield (Scheme 4).12In this reaction, the electrophilic
aromatic substitution exclusively occurred on the C-ring and
no formation of other isomers was observed; the electron-
donating substituents (O-MOM and methyl groups) increased
the reactivity of the C-ring to make the new C-C bond
between C-13b and C-13a, but not between C-7 and C-13a
(murrayazoline numbering).
(9) Rupp, H.; Schwarz, W.; Musso, H. Chem. Ber. 1983, 116, 2554.
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A. J. Organomet. Chem. 1999, 576, 147.
(11) Burkard, S.; Borschberg, H.-J. HelV. Chim. Acta 1989, 72, 254.
(12) For recent reports of Lewis acid-catalyzed Friedel-Crafts-type
Michael addition. See: (a) Zhuang, W.; Hansen, T.; Jørgensen; K, A. Chem.
Commun. 2001, 347. (b) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124,
9030. (c) Yamazaki, S.; Morikawa, S.; Iwata, Y.; Yamamoto, M.; Kuramoto,
K. Org. Biomol. Chem. 2004, 2, 3134. (d) Yamazaki, S.; Iwata, Y. J. Org.
Chem. 2006, 71, 739. (e) Kawatsura, M.; Aburatani, S.; Uenishi, J.
Tetrahedron 2007, 63, 4172. For the use of Sc(OTf)3 in Friedel-Crafts
alkylation, see: (f) Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S.-
I. J. Org. Chem. 1997, 62, 6997.
(13) (a) Taishi, T.; Takechi, S.; Mori, S. Tetrahedron Lett. 1998, 39,
4347. (b) Tanimoto, H.; Kato, T.; Chida, N. Tetrahedron Lett. 2007, 48,
6267.
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(b) Takao, H.; Wakabayashi, A.; Takahashi, K.; Imagawa, H.; Sugihara,
T.; Nishizawa, M. Tetrahedron Lett. 2004, 45, 1079.
(15) (a) Pealman, B. A.; McNamara, J. M.; Kishi, Y J. Am. Chem. Soc.
1981, 103, 4248. (b) Hosokawa, T.; Miyage, S.; Murahashi, S.; Sonoda, A
J. Org. Chem. 1978, 43, 2752. (c) Semmelhack, M. F.; Epa, W. R.
Tetrahedron Lett. 1993, 34, 7205.
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42, 4969. (b) Iwasaki, K.; Nakatani, M.; Katoh, T. Tetrahedron Lett. 2002,
43, 7937. (c) Nicolaou, K. C.; Petasis, N. A.; Claremon, D. A. Tetrahedron
1985, 41, 4835.
(17) (a) Ferraz, H. M. C.; Muzzi, M.; Wieira, T. O.; Viertler, H.
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Process Res. DeV 2002, 6, 405. and references therein.
Org. Lett., Vol. 10, No. 10, 2008
2001

zoline (1) was obtained in 80% yield.20 The H and 13C
1
These unsuccessful results led us to examine the intramo-
lecular C-O coupling of a tertiary alcohol function with an
aryl O-triflate moiety (Scheme 4 and Table 1). Thus, comp-
NMR, and MS data of the synthetic 1 were totally identical
to those of natural murrayazoline, kindly provided by
Professor Furukawa, and the melting point of the synthetic
1 (263-264 °C) showed good agreement with that reported
for the natural (()-murrayazoline (266 °C).1b
In summary, the total synthesis of (()-murrayazoline A
(1) has been accomplished. This nonbiomimetic synthesis
revealed that the double N-arylation is a powerful method
for the construction of structurally complex carbazoles. The
effective preparation of the hexa-heterocyclic structure in 1
by exploiting the intramolecular Friedel-Crafts-type Michael
addition and Bachwald-Hartwig C-O coupling reactions
would be applicable for the synthesis of natural products
possessing complex multicyclic structures.21
Table 1. Intramolecular C-O coupling of 24
Pd source (mol %)
liganda
base
yield (%)b
Pd(OAc)2 (100)
Pd(OAc)2 (100)
Pd(OAc)2 (100)
Pd(OAc)2 (20)
Pd(OAc)2 (100)
Pd2(dba)3 (100)
a
25
20
26
26
26
26
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
NRc
24
80
22
NR
29
Acknowledgment. We thank Professor Hiroshi Furukawa
(Meijo University, Nagoya, Japan) for providing us with the
spectral data and a sample of the natural murrayazoline.
Cs2CO3
Supporting Information Available: Experimental proce-
dures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL800602V
b Isolated yields after chromatographic purification. c No reaction.
(19) (a) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109.
(b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 10333. (c) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am.
Chem. Soc. 2000, 122, 10718. (d) Trraca, K. E.; Kuwabe, S.-I.; Buchwald,
S. L J. Am. Chem. Soc. 2000, 122, 12907. (e) Parrish, C. A.; Buchwald,
S. L. J. Org. Chem. 2001, 66, 2498. (f) Vorogushin, A. V.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 8146.
ound 3 was converted into its O-triflate derivative 23 in 94%
yield by the action of Tf2O, Et3N, and DMAP. The reaction
of 23 with MeMgBr in Et2O afforded tertiary alcohol 24 as
a single diastereomer in 72% yield from 3. Although the
Ullmann-type etherification of 24 (CuI, 1,10-phenanthroline,
Cs2CO3 in toluene)18 resulted in the decomposition of the
substrate, the palladium-catalyzed Buchwald-Hartwig
conditions5c,d,6a,c,i,19 were successful. Among the conditions
examined (Table 1) when 24 was treated with a stoichio-
metric amount of Pd(OAc)2, ligand 26,19e and CsCO3 in
toluene at 120 °C in a sealed tube for 20 h, (()-murraya-
(20) The severe steric hindrance due to the pentacyclic structure as well
as the electron-rich nature of the aryl moiety (C-ring) in 24 would be
responsible for the lower efficiency of the catalytic cycle in the C-O
coupling. Further screening of ligands might make this process catalytic.
For the development of a tunable ligand system in the Pd-catalyzed C-O
coupling reaction, see ref 19f.
(21) Chiral synthesis of 1 would be possible if cyclohexenone 15 could
be prepared in an optically active form. A study of an enantioselective
desymmetrization of 14 utilizing chiral lithium bases is underway. For recent
reports of enantioselective deprototation of ketones, see: (a) Rodeschini,
V.; Simpkins, N. S.; Wilson, C J. Org. Chem. 2007, 72, 4265. (b) Inoue,
M.; Lee, N.; Kasuya, S.; Sato, T.; Hirama, M.; Moriyama, M.; Fukuyama,
Y. J. Org. Chem. 2007, 72, 3065. (c) Toriyama, M.; Sugasawa, K.;
Motohashi, S.; Tokutake, N.; Koga, K. Chem. Pharm. Bull. 2001, 49, 468.
(18) (a) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org.
Lett. 2002, 4, 973. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
2002
Org. Lett., Vol. 10, No. 10, 2008