Microwave-enhanced synthesis of new (-)-steganacin and (-)-steganone aza analogues

Article abstract of DOI:10.1021/ol052766f

A novel, microwave-enhanced, highly efficient protocol for the synthesis of hitherto unknown (-)-steganacin and (-)-steganone 7-aza analogues containing a 1,2,3-triazole ring has been presented. Microwave irradiation was found to be highly beneficial in promoting the Suzuki reaction and the 1,3-dipolar cycloaddition reaction to generate the highly strained medium-sized ring system of the title molecules.

Full text of DOI:10.1021/ol052766f

ORGANIC
LETTERS
2006
Vol. 8, No. 3
487-490
Microwave-Enhanced Synthesis of New
)-Steganacin and ( )-Steganone Aza
Analogues
(−
−
Tetyana Beryozkina, Prasad Appukkuttan, Nuria Mont, and Erik Van der Eycken*
Department of Chemistry, UniVersity of LeuVen, Celestijnenlaan 200F,
B-3001 HeVerlee, Belgium
erik.Vandereycken@chem.kuleuVen.be
Received November 15, 2005
ABSTRACT
A novel, microwave-enhanced, highly efficient protocol for the synthesis of hitherto unknown (−)-steganacin and (−)-steganone 7-aza analogues
containing a 1,2,3-triazole ring has been presented. Microwave irradiation was found to be highly beneficial in promoting the Suzuki reaction
and the 1,3-dipolar cycloaddition reaction to generate the highly strained medium-sized ring system of the title molecules.
Antileukemic bisbenzocyclooctadiene lignan lactones and
their aza analogues have attracted considerable synthetic
interest in recent years due to their high biological potential.
Naturally occurring lactones (-)-steganacin and (-)-stega-
none (Figure 1), isolated from Steganotaenia araliacea by
the biological potential and solving the problems associated
with stereoselection, Koga et al.3 proposed the synthesis of
unnatural (-)-steganacin 7-aza analogues. Some of them
have been shown to exhibit antitumor activity even higher
than the corresponding natural lignan lactones.
However, the chemistry of these potent 7-aza analogues
has scarcely been developed, as can be surmised from the
absence of related literature. Nonphenolic oxidative intramo-
lecular coupling4 has been demonstrated to be suitable for
selective generation of the key biaryl skeleton of the title
molecules. However, this synthetic methodology is quite
sensitive to the nature of the substituents on both aromatic
rings, as for example, the nonphenolic oxidative coupling
(1) Kupchan, S. M.; Britton, R. W.; Ziegler, M. F.; Gilmore, Ch. J.;
Restivo, R. J.; Bryan, R. F. J. Am. Chem. Soc. 1973, 95, 1335-1336.
(2) (a) Wang, R. W.; Rebhum, L. I.; Kupchan, S. M. Cancer Res. 1977,
37, 3071-3079. (b) Sackett, D. L. Pharmacol. Ther. 1993, 59, 163-228.
(c) Zavala, F.; Guenard, D.; Robin, J.-P.; Brown, E. J. Med. Chem. 1980,
23, 546-549.
Figure 1. (-)-Steganacin, (-)-steganone, and (-)-steganacin aza
analogues.
the late Prof. S. M. Kupchan,1 have been demonstrated to
possess significant in vivo activity against P-388 leukemia
in mice and in vitro activity against cells derived from human
carcinoma of the nasopharynx (KB).2 In view of increasing
(3) (a) Tomioka, K.; Kubota, Y.; Kawasaki, H.; Koga, K. Tetrahedron
Lett. 1989, 30, 2949-2952. (b) Kubota, Y.; Kawasaki, H.; Tomioka, K.;
Koga, K. Tetrahedron 1993, 49, 3081-3090.
(4) (a) Dhal, R.; Landais, Y.; Lebrun, A.; Lenain, V.; Robin, J. P.
Tetrahedron 1994, 50, 1153-1164. (b) Stang, P. J.; Zhdankin, V. V. Chem.
ReV. 1996, 96, 1123-1178. (c) Tohma, H.; Kita, Y. Top. Curr. Chem. 2003,
224, 209-248. (d) Reddy, P. P.; Chu, C.-Y.; Hwang, D.-R.; Wang, S.-K.;
Uang, B.-J. Coord. Chem. ReV. 2003, 237, 257-269 and references therein.
* To whom correspondence should be addressed. Tel: + 32 16 327406.
Fax: + 32 16 327990.
10.1021/ol052766f CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/13/2006

cannot be performed in the absence of electron-rich groups
on the participating aromatic rings. Attempts to generate
diversely functionalized analogues of the title molecules for
the purpose of biological screening are scarcely described
in the literature.5 Furthermore, to the best of our knowledge,
there has been no literature precedent related to the synthesis
and manipulations of the potent 7-aza analogues after the
pioneering work of Koga et al.3
rings in the target molecules will be hampered due to the
presumably high activation barrier of the reaction. As we
have demonstrated in previous work related to the synthesis
of natural product analogues containing difficultly obtainable
medium-sized ring systems,6b microwave irradiation could
greatly contribute to solve this problem.
We started our synthesis from the commercially available
3,4-dimethoxybenzyl alcohol (1) (Scheme 2). The regiose-
As part of our ongoing research focused on the microwave-
enhanced synthesis of medium-sized-ring natural product
analogues,6 we have developed a new strategy for the
synthesis of novel steganacin and steganone 7-aza analogues.
Herein, we wish to delineate the first total synthesis of such
analogues containing a 1,2,3-triazole ring. Our new approach
for the formation of a [1,5-a]azocine skeleton was based on
a microwave enhanced Suzuki-Miyaura cross-coupling
reaction7 in combination with microwave-enhanced “click
chemistry”.8 Furthermore, partially due to the increased
current interest in click chemistry, 1,2,3-triazole moieties are
emerging as powerful pharmacophores in their own right.9
As can be viewed from the retrosynthetic scheme (Scheme
1), the success of our protocol mainly depends on the
Scheme 2. Suzuki-Miyaura Reaction in the Synthesis of the
Key Biaryl Aldehyde 4
lective bromination of alcohol 1 was carried out with NBS
in CCl4 and afforded alcohol 2 in 70% yield. To minimize
problems associated with the cross-coupling reactions of
highly electron-rich halides with boronic acids bearing an
electron-withdrawing group, we decided to carry out the
Suzuki-Miyaura reaction under our previously optimized
microwave-irradiation conditions.6a However, attempts to
carry out the Suzuki-Miyaura cross-coupling between
alcohol 2 and (2-formylphenyl)boronic acid to generate the
required biaryl skeleton met with failure, due to the formation
of an inseparable mixture of biaryls together with traces of
hemi-acetals in a combined yield of 48% (Scheme 3). An
Scheme 1. Retrosynthetic Analysis
Suzuki-Miyaura cross-coupling reaction and the consecutive
heterocyclization resulting in the formation of an eight-
member ring fused with a 1,2,3-triazole ring.
The Huisgen 1,3-dipolar cycloaddition10 of azides and
alkynes is a fast and efficient approach for the synthesis of
1,2,3-triazoles. However, the generation of medium-sized
Scheme 3. Suzuki-Miyaura Reaction between Alcohol 2 and
(2-Formylphenyl)boronic Acid
(5) (a) Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc.
1987, 109, 5446-5452. (b) Magnus, P.; Schultz, J.; Gallagher, T. J. Am.
Chem. Soc. 1985, 107, 4984-4988. (c) Monovich, L. G.; Le Huerou, Y.;
Roenn, M.; Molander, G. A. J. Am. Chem. Soc. 2000, 122, 52-57. (d)
Kamikawa, K.; Watanabe, T.; Daimon, A.; Uemura, M. Tetrahedron 2000,
56, 2325-2337.
(6) (a) Appukkuttan, P.; Orts, A. B.; Chandran, R. P.; Goeman, J. L.;
Van der Eycken, J.; Dehaen, W.; Van der Eycken, E. Eur. J. Org. Chem.
2004, 3277-3285; (b) Appukkuttan, P.; Dehaen, W.; Van der Eycken, E.
Org. Lett. 2005, 7, 2723-2726.
(7) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-coupling Reactions; Wiley-
VCH: Weinheim, 1998; p 517. (c) Suzuki, A. J. Organomet. Chem. 1999,
576, 147-168. (d) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002,
58, 9633-9695 and references therein. (e) Leadbeater, N. E. Chem.
Commun. 2005, 23, 2881-2902. (f) Apukkuttan, P.; Van der Eycken, E.;
Dehaen, W. Synlett 2005, 127-133.
(8) (a) Punna, S.; Diaz, D. D.; Li, C.; Sharpless, K. B.; Fokin, V. V.;
Finn, M. G. Polym. Prepr. (Am. Chem. Soc., DiV. Polym. Chem.) 2004, 45,
778-779. (b) Kolb, H. C.; Sharpless, K. B. Drug DiscoV. Today 2003, 8,
1128-1137. (c) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.,
Int. Edit. 2001, 40, 2004-2021 and references therein. (d) Apukkuttan, P.;
Fokin, V. V.; Dehaen, W.; Van der Eycken, E. Org. Lett. 2004, 6, 4223-
4225. (e) Kaval, N.; Ermolat’ev, D.; Appukkuttan, P.; Dehaen, W.; Kappe,
C. O.; Van der Eycken, E. J. Comb. Chem. 2005, 7, 490-502.
intramolecular disproportionation reaction between the al-
cohol and aldehyde centers of the molecule occurred.
(9) (a) Biagi, G.; Calderone, V.; Giorgi, I.; Livi, O.; Martinotti, E.;
Martelli, A.; Nardi, A. Farmaco 2004, 59, 397-404. (b) Su, C.; Lee, L.-
X.; Yu, S.-H.; Shih, Y.-K.; Su, J.-C.; Li, F.-J.; Lai, C. Liq. Cryst. 2004, 31,
745-749. (c) Zhu, X.; Schmidt, R. R. J. Org. Chem. 2004, 69, 1081-
1085. (d) Olesen, P. H.; Sorensen, A. R.; Urso, B.; Kurtzhals, P.; Bowler,
A. N.; Ehrbar, U.; Hansen, B. F. J. Med. Chem. 2003, 46, 3333-3341. (e)
Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor,
P.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 1053-
1057 and references therein.
488
Org. Lett., Vol. 8, No. 3, 2006

Therefore, the alcohol 2 was protected as the correspond-
ing TBDMS derivative by treatment with tert-butyldimeth-
ylsilyl chloride (TBDMSCl) in DMF in the presence of 1H-
imidazole, and the resulting silyl ether 3 was isolated in an
excellent yield of 96% (Scheme 2). The Suzuki-Miyaura
reaction of 3 with (2-formylphenyl)boronic acid was then
carried out under microwave-enhanced conditions, though
several attempts furnished the biaryl compound 4 in unsat-
isfactory yields (Table 1, entries 1-10). Contrary to our
°C for 15 min (Table 1, entry 14). Reaction performed under
conventioal heating, in view of proving the superiority of
the microwave-enhanced experiments, resulted in a lower
42% yield at 102 °C in 3 h, where the proto-deboronation
product, benzaldehyde, was the major product.
The thus obtained biaryl aldehyde 4 was then transformed
into the corresponding propargylic alcohol 5 via nucleophillic
addition of phenylacetylene in the presence of n-BuLi
(Scheme 4). The desired product 5 was isolated in 77% yield
Table 1. Optimization Experiments for the Cross-Coupling of
TDDMS Ether 3 with (2-Formylphenyl)boronic Acida
Scheme 4. Formation of Propargylic Alcohol 5 and Further
Conversion into the Intermediates 6 and 7
time
T
yield
entry
base
NaHCO3 Pd(Ph3P)4
K3PO4 Pd(Ph3P)4
Cs2CO3 Pd(Ph3P)4
catalyst
solvent
(min) (°C) (%)
1
2
3
4
5
6
7
8
9
DMF-H2O (1:1) 10 150 35
n-BuOH
n-BuOH
15 125 42
15 125 36
15 125 44
15 100 46
15 150 20
15 125 31
30 125 21
K3PO4
K3PO4
K3PO4
(Ph3P)PdCl2 n-BuOH
Pd(Ph3P)4
Pd(Ph3P)4
n-BuOH
n-BuOH
n-BuOH
n-BuOH
NaHCO3 Pd(Ph3P)4
K3PO4
K3PO4
Pd(Ph3P)4
Ni(dppp)Cl2 n-BuOH
(Ph3P)PdCl2 PhCH3-H2O
(1:1)
15 125
15 120
0
0
10 K3PO4
11 K3PO4
12 K3PO4
Pd(Ph3P)4
dioxane-EtOH
(1:1)
dioxane-EtOH
(2:1)
dioxane-EtOH
(2:1)
dioxane-EtOH
(2:1)
dioxane-EtOH 180a 102 42
15 130 63
15 130 68
15 130 68
15 130 77
Pd(Ph3P)4
as a mixture of two diastereoisomers (3:2, based on 1H NMR
analysis), which were found to be inseparable. One part of
the mixture of diastereomeric alcohols 5 was converted into
the corresponding ketone 6 by oxidation with MnO2 in
CH2Cl2 in an excellent yield of 98%, to minimize the
stereochemical problems, and in view of generating the
hitherto unknown 7-aza-analogues of (-)-steganone.
The other part of the mixture was converted into the
corresponding diastereomeric mixture of acetyl derivative
7, to keep maximum semblance with (-)-Steganacin. Treat-
ment of 5 with AcCl in the presence of Et3N and a catalytic
amount of DMAP in CH2Cl2 resulted in the formation of 7
in 80% yield (1:1 mixture of diastereoisomers, based on 1H
NMR analysis). The difference in the diastereomeric ratio
of the C4 center, in comparison with the intermediate 5,
arises presumably from the increased steric crowding around
the biaryl axis.
13 NaHCO3 Pd(Ph3P)4
14 Cs2CO3 Pd(Ph3P)4
15 Cs2CO3 Pd(Ph3P)4
(2:1)
a All reactions were carried out on 0.5 mmol of bromide with 1.3 equiv
of boronic acid, 3.0 equiv of base, and 5 mol % of catalyst under microwave
irradiation conditions in 4 mL of solvent at a maximum power level of 150
W. All reactions were carried out using a ramp time of 2 min and a hold
time as indicated in the table. a Reaction was performed under conventional
heating.
previous results,6 reactions using NaHCO3 as base (Table 1,
entries 1,7), as well as using Ni(dppp)Cl2 (Table 1, entry 9)
as catalyst gave unexpectedly low yields or met with failure.
Increasing the reaction temperature to 150 °C (Table 1, entry
6) or the reaction time to 30 min (Table 1, entry 8) dimin-
ished the yield considerably. Decreasing the reaction tem-
perature to 100 °C (Table 1, entry 5) led to a moderate yield.
The best result (77% yield) was obtained using Cs2CO3 as
the base and Pd(Ph3P)4 as the catalyst in a 2:1 mixture of
dioxane and ethanol upon irradiation at a temperature of 130
The deprotection of the TBDMS group in 6 and 7,
resulting in the formation of the corresponding primary
alcohols 8 (Scheme 5) and 12, was performed at rt under
mild acidic conditions using a mixture of AcOH, THF, and
H2O (3:1:1). Alcohol 12 was isolated as a mixture of
1
diastereoisomers (55:45, based on H NMR analysis).
The formation of the target triazolo[1,5-a]azocin-4(13H)-
one 11 was accomplished starting from alcohol 8 using a
pseudo one-pot three-step reaction sequence: (1) Appel
bromination11 of alcohol 8 at rt, in the presence of CBr4 and
Ph3P afforded the corresponding bromo derivative 9; (2)
(10) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596-2599. (b) Wang, Q.; Chan, T. R.;
Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc.
2003, 125, 3192-3193. (c) Tornoe, C. W.; Christensen, C.; Meldal, M. J.
Org. Chem. 2002, 67, 3057-3064. (d) 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A.; Ed.; Wiley-Interscience: New York, 1984. (e) Gothelf, K. V.;
Jørgensen, K. A. Chem. ReV. 1998, 98, 863-909 and references therein.
(f) L’abbe, G. Chem. ReV. 1969, 69, 345-363.
(11) Appel, R. Angew. Chem, Int. Ed. Engl. 1975, 14, 801-811.
Org. Lett., Vol. 8, No. 3, 2006
489

7.0 software for molecular modeling) using energy minimi-
zation experiments. The high diastereomeric excess of this
cyclization could be explained in terms of the high ring strain
of the fused heterocyclic skeleton of the target molecule.
This was further confirmed by the high torsional energy of
the minor diastereomer 15-(R) (18.25 kcal/mol), in com-
parison with the 15-(S) (11.22 kcal/mol) (Figure 2).
Scheme 5. Intramolecular Heterocyclization of Intermediates
6 and 7 to the Targets 11 and 15
nucleophilic displacement of the bromo group with an azide
functionality using NaN3 in DMF at 80 °C under microwave-
enhanced conditions resulted in the formation of 10; and (3)
microwave-assisted Huisgen 1,3-dipolar cycloaddition of the
azide group to the acetylene fragment at 210 °C in o-di-
chlorobenzene as solvent (Scheme 5) yielded the desired
target 11 in 43% overall yield. The three steps were
performed in a consecutive manner, without the isolation of
any of the intermediates. It is noteworthy that this cyclization,
when carried out under conventional heating in refluxing
o-dichlorobenzene for 48 h, failed to furnish the product 11
and the starting azide 10 was found untouched.
Dibenzotriazolo[1,5-a]azocine 15 was obtained from al-
cohol 12 applying a similar procedure in an excellent overall
yield of 76%. It is noteworthy that the cyclization of the
azide 14 into the target triazolo[1,5-a]azocine 15 was possible
at a much lower temperature of 120 °C than for compound
11. This fact can be explained by the lower rigidity of the
eight-member ring of compound 15 compared to compound
11, resulting in a lower activation energy for the reaction.
The cyclization of 14 was found to be highly diastereose-
lective, generating the isomers 15 in a ratio of 9:1. However,
the isomers were found to be inseparable applying different
chromatographic separations including HPLC. The major
isomer was assigned to be diastereomer 15-(S) based on NOE
experiments and computational calculations (with SYBYL
Figure 2. Conformation of the diastereomers according to torsional
energy calculations and some indicative NOE-correlations.
In conclusion, we have developed a novel microwave-
enhanced synthetic protocol for the formation of new 7-aza
analogues of (-)-steganacin and (-)-steganone. The key
steps of this methodology, the Suzuki-Miyaura cross-
coupling and the Huisgen 1,3-dipolar cycloaddition reactions,
were performed under MW irradiation, which was found to
be highly beneficial in promoting these reactions. The
generated compounds are under current investigation to test
their anti-carcinogenic activity.
Acknowledgment. We thank the F.W.O. (Fund for
Scientific Research - Flanders (Belgium)) and University
of Leuven for financial support to the laboratory. We also
thank Prof. Dr. Wim Dehaen and Prof. Dr. Susan Toppet
for their valuable advice and Mr. Arnout Voet for his
assistance with the computational calculations.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for compounds
1-15. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL052766F
490
Org. Lett., Vol. 8, No. 3, 2006