Diversity oriented microwave-assisted synthesis of (-)-steganacin aza-analogues

Article abstract of DOI:10.1021/jo801290j

(Chemical Equation Presented) A novel microwave-assisted, highly efficient protocol for the synthesis of hitherto unknown aza-analogues of (-)-Steganacin, a naturally occurring bisbenzocyclooctadiene lignan lactone with potent antileukemic and tubulin polymerization inhibitory activity, has been developed. Focused microwave irradiation is demonstrated to be highly beneficial in promoting the three crucial steps of the sequence to effect the final ring closure: the Suzuki-Miyaura reaction, Cu-mediated A₃-coupling, as well as the intramolecular Huisgen 1,3-dipolar cycloaddition.

Full text of DOI:10.1021/jo801290j

Diversity Oriented Microwave-Assisted Synthesis of (-)-Steganacin
Aza-Analogues
Nuria Mont,§,† Vaibhav Pravinchandra Mehta,† Prasad Appukkuttan,#,†
Tetyana Beryozkina,¶,† Suzzane Toppet,‡ Kristof Van Hecke,| Luc Van Meervelt,|
Arnout Voet, Marc DeMaeyer, and Erik Van der Eycken*,†
Laboratory for Organic & MicrowaVe-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke
UniVersiteit LeuVen, Celestijnenlaan 200F, B-3001, HeVerlee, LeuVen, Belgium, Department of Chemistry,
Katholieke UniVersiteit LeuVen, Celestijnenlaan 200F, B-3001, HeVerlee (LeuVen), Biomolecular
Architecture, Department of Chemistry, Katholieke UniVersiteit LeuVen, Celestijnenlaan 200F, B-3001,
HeVerlee (LeuVen), and Molecular and Structural Biology, Katholieke UniVersiteit LeuVen,
Celestijnenlaan 200D, B-3001 HeVerlee (LeuVen), Belgium
erik.Vandereycken@chem.kuleuVen.be
ReceiVed June 23, 2008
A novel microwave-assisted, highly efficient protocol for the synthesis of hitherto unknown aza-analogues
of (-)-Steganacin, a naturally occurring bisbenzocyclooctadiene lignan lactone with potent antileukemic
and tubulin polymerization inhibitory activity, has been developed. Focused microwave irradiation is
demonstrated to be highly beneficial in promoting the three crucial steps of the sequence to effect the
final ring closure: the Suzuki-Miyaura reaction, Cu-mediated A3-coupling, as well as the intramolecular
Huisgen 1,3-dipolar cycloaddition.
Introduction
(-)-Steganone and (-)-Steganacin, two bisbenzocycloocta-
diene lignan lactones isolated in 1973 by the late S. M. Kupchan
et al.,1 have attracted substantial synthetic interest owing to their
high biological potential (Figure 1). These naturally occurring
lignan lactones possess significant in ViVo activity against P-388
leukemia in mice and in Vitro activity against cells derived from
* Correspondening author.
FIGURE 1. (-)-Steganone and (-)-Steganacin aza-analogues.
† Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Department of Chemistry, Katholieke Universiteit Leuven.
§ Present Addresses: Prous Institute for Biomedical Research, Roger de Llu´ria,
118, 3-2, 08037 Barcelona, Spain.
a human nasopharynx (KB) carcinoma cell line.1 (-)-Steganacin
inhibits in vitro polymerization of microtubules by 50% at about
2 µM and also binds to the mammalian tubulin with an affinity
comparable to that of colchicine.2 In the light of the increased
demand for diversely functionalized structural analogues of the
title molecules for biological screening as well as to solve the
# Present address: Department of Chemistry, Ludwig-Maximilians-Universita¨t,
Butenandtstrasse 5-13, Building F, D-81377 Munich, Germany.
¶ Present address: Organic Chemistry Department, V.N. Karazin Kharkiv
National University, Svoboda sq. 4, 61077 Kharkiv, Ukraine.
‡ Department of Chemistry, Katholieke Universiteit Leuven.
| Biomolecular Architecture, Department of Chemistry, Katholieke Universiteit
Leuven.
Molecular and Structural Biology, Katholieke Universiteit Leuven.
(1) (a) Kupchan, S. M.; Britton, R. W.; Ziegler, M. F.; Gilmore, C. J.; Restivo,
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Rebhun, L. I.; Kupchan, S. M. Cancer Res. 1977, 37, 3071–3079. (c) Zavala,
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10.1021/jo801290j CCC: $40.75
Published on Web 08/28/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7509–7516 7509

Mont et al.
problems associated with stereoselectivity, Koga3 et al. proposed
the synthesis of unnatural (-)-Steganacin 7-aza-analogues.
Moreover, it was found that some of them exhibit in Vitro and
in ViVo antitumor activity even higher than the corresponding
natural lignan lactones.
structural unit as it is stable to metabolic transformations, such
as oxidation, reduction, and both basic and acidic hydrolysis.
Additionally, somewhat as a result of the increased current
interest in click chemistry, 1,2,3-triazole moieties are rising as
potent pharmacophores themselves.11 We now wish to report a
strategy for the synthesis of aza-analogues allowing the intro-
duction of five points of diversity in the system.
There have been a plethora of reported protocols on the synthesis
of these lignan lactones after the first total synthesis of (()-
Steganacin published in 1976 by Kende4 and of (()-Steganone
by Raphael.5 Since the generation of the biaryl backbone of the
title molecules was deemed to be the key step, several coupling
procedures have been investigated for this purpose, such as
nonphenolic oxidative intramolecular coupling using either
VOF3,4,6c,i,m,n,9 thallium,6l ruthenium,7a,c,d rhenium,7b manganese,7b
or cerium7b reagents. However, this synthetic approach is highly
sensitive to the nature of the substituents on both aromatic rings,
as biaryl formation does not occur in the absence of electron-rich
groups. Other strategies like photocyclization,5,6a,b,n,p SNAr
reaction,6a or Ullmann coupling2c,6c,e-h,j generally suffer from lower
yields as well as sensitive conditions and longer reaction times,
and are often associated with the problem of homodimerization.8
Even though the Suzuki-Miyaura reaction has been demonstrated
to be a viable method for the selective generation of the biaryl
skeleton of these compounds,6r,t,u,9b this mild and efficient cross-
coupling protocol has never been investigated for the generation
of more potent aza-analogues whose, synthesis has hardly been
explored.3a,b,10a,b
Results and Discussion
The synthesis of the proposed aza-analogues is based on
a Suzuki-Miyaura cross-coupling reaction to generate the
biaryl axis,9b,12 followed by an A3-coupling reaction13 and
subsequent ring closure applying “click chemistry”.14 These
three key reactions are performed upon microwave irradiation
(Scheme 1).
According to our previous investigations,10c our sequence
started from the commercially available methoxy-substituted
benzyl alcohols 1a (R1 ) H) and 1b (R1 ) OMe) which were
regioselectively brominated with NBS in CCl4 affording the
corresponding 2-bromoalcohols 2a,b in 70% and 74% yield,
respectively (Scheme 2).15 Subsequently, the alcohols 2a,b were
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We have recently reported an efficient, microwave-assisted
protocol for the synthesis of hitherto unknown triazole analogues
of (-)-Steganacin and (-)-Steganone, based on a combination
of Suzuki-Miyaura cross-coupling and Huisgen 1,3-dipolar
cycloaddition reaction.10c Although the 1,2,3-triazole moiety
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7510 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of (-)-Steganacin Aza-Analogues
SCHEME 1. Retrosynthetic Analysis
SCHEME 3. A3-Coupling of Biaryl Aldehyde 4aa
a Reagents and conditions: (a) phenylacetylene (2.0 equiv), piperidine
(1.5 equiv), CuCl (10 mol %), [bmim]PF6 (1 drop), dioxane, MW, 140 °C,
20 min, 60 W, 70%; (b) AcOH/THF/H2O (3:1:1), rt, 18 h, 82%.
SCHEME 2. Synthesis of the Biaryl Compounds 4a-ca
Initially, CuI was used in water as the sole solvent (Table 1,
entry 1) under microwave irradiation at 80 °C, following the
procedure described by Shi et al.13k However, the reaction met
with failure, since the corresponding imine was isolated as the
only product. Therefore, we attempted to perform the reaction
as a two-step process (Table 1, entry 2), following the procedure
described by Li et al.13y The imination was carried out
previously by reacting the aldehyde and the amine in DMF for
2 h at 60 °C. Then phenylacetylene and the catalyst, a mixture
of CuBr (30 mol %) and RuCl3 ·3H2O (3 mol%), were added
at rt. Disappointingly, as in the previous case, only the imine
was isolated after a reaction time of 20 h. However, when the
reaction was performed in a one-pot fashion upon microwave
irradiation with CuBr as catalyst in THF at a ceiling temperature
of 120 °C for 20 min (Table 1, entry 3), the desired propargyl
amine was isolated in a moderate yield of 56%, after chromato-
graphic purification. In view of improving the yield, we
investigated the use of 1,4-dioxane containing 0.1 mL of the
ionic liquid [bmim]PF613j using CuCl as catalyst (Table 1, entry
4). After 20 min of reaction time at a ceiling temperature of
150 °C, using a maximum irradiation power of 60 W, the desired
propargylamine was isolated in 67% yield. Increasing the
irradiation power to 150 W (Table 1, entry 5) resulted in a lower
yield of 60%. However, carrying out the reaction at 140 °C
with a maximum irradiation power of 60 W provided the amine
5 in 70% yield (Table 1, entry 6).
The deprotection of the benzylic alcohol of 5 (Scheme 3)
was attempted by applying a solution of 2 equiv of tetrabuty-
lammonium fluoride in THF at rt for 3 h. However, only starting
material was isolated. On the contrary, when 5 was treated
with a mixture of AcOH/THF/H2O (3:1:1) at rt for 18 h, a
diastereomeric mixture (55:45) of alcohol 6 was isolated in 82%
yield.
Next, the formation of the target compound 9 was attempted
by using our previously developed one-pot three-step reaction
sequence10c (Scheme 4): Appel bromination18 of alcohol 6 at rt
was carried out for the generation of the corresponding benzyl
bromide 7 followed by nucleophilic displacement of the bromide
with azide to generate the corresponding benzyl azide 8.
However, final microwave-assisted intramolecular Huisgen 1,3-
dipolar cycloaddition did not work and resulted in the formation
of a complex mixture presumably caused by an intramolecular
ring closure of the amine on the in situ generated bromide in 7,
followed by degradation. Alternative brominating procedures
using HBr (48% in water), HBr (33% in AcOH), PBr3, NBS +
PBr3, and TMSBr or strategies using SOCl2 or CH3SO2Cl met
with failure.
a Reagents and conditions: (a) NBS (1.0 equiv), CCl4, rt, 4 h, 70% (2a),
74% (2b); (b) TBS-Cl (1.3 equiv), 1H-imidazole (3.0 equiv), DMF, rt, 6 h,
96% (3a), 94% (3b); (c) 2-(formyl) phenyl boronic acid (1.3 equiv),
Pd(Ph3P)4 (5 mol %), Cs2CO3 (3.0 equiv), dioxane/2-PrOH (2:1), MW, 130
°C, 15 min, 150 W, 77% (4a), 80% (4b), 82% (4c).
protected as the corresponding TBS derivatives by treatment
with tert-butyldimethylsilyl chloride (TBS-Cl) in DMF in the
presence of 1H-imidazole,6g,15a,c and the resulting silyl ethers
3a,b were isolated in excellent yields of 96% and 94%,
respectively (Scheme 2). The Suzuki-Miyaura cross-coupling
reaction of the silyl ethers 3a,b with 2-formylphenylboronic acid
and 2-formyl-4-methoxyphenylboronic acid were carried out
under microwave irradiation conditions with dioxane/isopro-
panol (2:1) affording the corresponding biaryl intermediates
4a-c in yields of 77%, 80%, and 82%, respectively. Only trace
amounts of protodeboronation and homocoupling were detected.
Our next goal was the introduction of an additional point of
diversity applying an A3-coupling reaction. This is a multicom-
ponent reaction involving a suitable aldehyde, an amine, and
an alkyne, resulting in the formation of a propargylic amine.
Reppe16 performed the first example of A3-coupling in 1955
using a copper salt as catalyst. In recent years, several catalysts
have been used for this reaction, such as salts of Cu,13f,k,l,p,17
Ni,13a Ir,13c,n Au,13i Ag,13o,q Hg,13u as well as Cu in combination
with chiral ligands13g,s,w,x or ionic liquids.13h,m,t It has been
demonstrated that the reaction highly benefits from microwave
irradiation.13h,k,l As a proof of concept we investigated the A3-
coupling of aldehyde 4a with piperidine and phenylacetylene.
We chose to investigate simple Cu(I)-based catalytic systems
(Scheme 3).
(15) (a) Tennant, S.; Wege, D. J. Chem. Soc., Perkins Trans. 1 1989, 2089–
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To evaluate whether the amine is causing the problem, we
decided to decrease the nucleophilicity by converting it into
(18) Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801–811.
(19) Jing, W.; et.al. PCT Int. Appl. 1998, WO 9828268.
J. Org. Chem. Vol. 73, No. 19, 2008 7511

Mont et al.
TABLE 1. Optimization of the A3-Coupling of 4a, Using Microwave Irradiationa
yieldb c (%)
,
entry
4a:piperidine: PhCtCH
temp (°C)
time (min)
power (W)
150
solvent
catalyst (mol %)
CuI (15)
CuBr (30) RuCl3.3H2O (3)
CuBr (8)
CuCl (10)
CuCl (10)
1
1:1.3:1.6
1:1.2:1.2
1:1.2:1.2
1:1.5:2
1:1.5:2
1:1.5:2
80
rt
120
150
150
140
30
1200
20
20
20
H2O
DMF
THF
0d
2e
3
0d
150
60
150
60
56 (51:49)
67 (50:50)
60 (50:50)
70 (48:52)
f
f
f
4
5
6
dioxane + [bmim]PF6
dioxane + [bmim]PF6
dioxane + [bmim]PF6
20
CuCl (10)
a All reactions were carried out on a 1.0 mmol scale in 4 mL of solvent. b Yields are isolated yields of the diastereomeric mixtures. c Values in
parentheses indicate the diastereomeric ratios as determined by NMR spectroscopy. d Only imine was formed. e The reaction was performed in two
steps; the imination was performed previously in DMF at 60 °C for 2 h. f 0.1 mL of ionic liquid was used.
SCHEME 4. Attempt for the Synthesis of the Final Product 9a
a Reagents and conditions: (a) CBr4 (3.0 equiv), Ph3P (3.0 equiv), 0 °C to rt, 6 h; (b) NaN3 (3.0 equiv), DMF, MW, 80 °C, 20 min, 25 W; (c) DMF, MW,
120 °C, 15 min, 50 W.
SCHEME 5. Reinvestigation of the A3-Coupling of 4a with
Aniline As the Primary Aminea
imine followed by microwave-assisted reaction of phenylacety-
lene in the presence of CuBr (30 mol %) and RuCl3.3H2O (3
mol %) as the catalyst system (same conditions as in Table 1,
entry 2) also met with failure as the imine was isolated as the
sole product. However, microwave-assisted reaction of the
aldehyde 4a with 1.5 equiv of aniline and 3 equiv of pheny-
lacetylene in the presence of CuBr as the catalyst in THF at a
ceiling temperature of 120 °C for 15 min furnished the
propargylamine 10a in a moderate yield of 55% (Table 2, entry
3). When this reaction was carried out under solvent-free
conditions, the desired propargylamine was isolated in a good
yield of 65% (Table 2, entry 4). The yield could be further
improved up to 89% by lowering the temperature to 90 °C and
applying these solvent-free conditions (Table 2, entry 5). Further
lowering the temperature to 60 °C resulted in an incomplete
reaction as mainly imine was isolated (Table 2, entry 6).
a Reagents and conditions: (a) Phenylacetylene (3.0 equiv), aniline (1.5
equiv), CuBr (5 mol %), neat, MW, 90 °C, 15 min, 100 W.
TABLE 2. Reinvestigation of the A3-Coupling of 4a with Aniline
As Primary Aminea
4a:aniline: temp time power
entry PhC’CH (°C) (min) (W)
catalyst
(mol %)
yield
(%)b
solvent
1
1:1.5:2
140
20
60 dioxane +
[bmim]PF6
DMF
CuCl (10)
0d
c
2e
1:1.2:1.2 rt
1200
CuBr (30)
RuCl3 · 3H2O (3)
CuBr (5)
CuBr (5)
CuBr (5)
0d
In view of generating a small library of the target aza-
analogues, the A3-coupling reaction was performed by applying
a set of differently substituted anilines (R3), alkynes (R4), and
biaryl aldehydes (R1 and R2) (Table 3).
3
4
5
6
1:1.5:3
1:1.5:3
1:1.5:3
1:1.5:3
120
120
90
15 100 THF
55
65
15 100 neat
15 100 neat
15 100 neat
89
60
CuBr (5)
35f
In all cases, except when n-butylamine was used (Table 3,
entry 2), the A3-coupling worked well when aldehyde 4a and
phenylacetylene were involved, and the resulting compounds
were isolated in good to excellent yields of 73-89% (Table 3,
entries 1-8). Interestingly, the steric and electronic demands
imposed by the substituents of the anilines did not noticeably
influence the outcome of the reaction. In the case of n-bu-
tylamine, a moderate yield of 42% was obtained as a complex
reaction mixture was formed, hampering product isolation (Table
3, entry 2). This was not totally unexpected, as the literature
revealed a handful of examples where primary alkyl amines
were employed for A3-coupling,13f,h,i,x mostly resulting in low
yields. For further increasing diversity, various acetylenes were
investigated applying our optimized microwave-assisted A3-
coupling protocol. When 4a was reacted with 4-fluorophenyl
acetylene and 4-fluoroaniline, corresponding propargylamine 10i
was obtained in 82% yield. Upon reaction of trimethylsily-
lacetylene with aldehyde 4a and m-trifluoromethylaniline, the
corresponding propargylamine 10j was isolated in 82% yield
a All reactions were carried out on a 1.0 mmol scale in 4 mL of
solvent. b Yields are isolated yields of the diastereomeric mixtures. c 0.1
mL of ionic liquid was used. d Only imine was formed. e The reaction
was performed in two steps; the imination was previously performed in
DMF at 60 °C for 2 h. f Incomplete reaction.
the corresponding acetamide. However, to validate this concept,
a primary amine should be introduced during the A3-coupling
reaction. A careful literature survey revealed that in the case
where the A3-coupling is run with primary amines, mostly
(substituted) anilines are used.13f,j,m,w Therefore, as a proof of
concept, we chose aniline to reinvestigate the A3-coupling
reaction of aldehyde 4a with phenylacetylene (Scheme 5).
Initially, we applied the previously optimized reaction condi-
tions for the A3-coupling when piperidine was used as amine
(Table 2, entry 1). To our surprise, the reaction met with failure
as only the imine was recovered. An attempt to carry out
the coupling in two steps (Table 2, entry 2) by first forming the
7512 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of (-)-Steganacin Aza-Analogues
TABLE 3. A3-Coupling Reaction with Various Primary Amines
TABLE 4. Acylation of the Propargylamines 11a-m
for the Generation of Propargylamines 10a-l
entry compda
R1
R2
R3
R4
Ph
Ph
4-OMe-Ph Ph
R5 yield (%)b
temp
(°C)
yield
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11e
11f
11g
11h
11i
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
H
Ph
n-Bu
Me
75
70
78
72
78
75
76
74
73
75
76
78
96
entry compda
R1
R2
R3
R4
Ph
Ph
Ph
Ph
Ph
(%)b,c
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
10g
10h
10i
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4,5-OMe
H
Ph
90 89(51:49)
90 42(50:50)
60 73(48:52)
90 86(50:50)
90 87(58:42)
90 87(46:54)
90 89(65:35)
120 86(55:45)
90 82(55:45)
H
H
H
H
H
H
H
H
H
H
n-Bu
4-OMe-Ph
4-F-Ph
2-Me-Ph
3,4-di-Cl-Ph Ph
2-pyridine
3-Br-Ph
4-F-Ph
3-CF3-Ph
Ph
4-F-Ph
2-Me-Ph
Ph
Ph
3,4-diCl-Ph Ph
2-pyridine Ph
3-Br-Ph
3-CF3-Ph
4-F-Ph
Ph
Ph
Ph
Ph
4-F-Ph
9
TMS Me
4-F-Ph Me
Ph
Ph
Ph
10
11
12
13
11j
11k
11l
9
3,4,5-OMe H
Me
Me
CF3
10
11
12
10j
10k
10l
TMSd 120 82(49:51)
3,4,5-OMe OMe 3-CF3-Ph
Ph
Ph
Ph
90 81(51:49)
90 85(50:50)
c
11m 3,4-OMe
H
3,4,5-OMe OMe 3-CF3-Ph
a All reactions were carried out on 1.0 mmol scale in 4 mL of
CH3CN upon microwave irradiation (300 W, 30 min), using 2.5 equiv
of acetic anhydride. b Yields are isolated yields. c TFAA (2.5 equiv),
pyridine. TFAA ) trifluoroacetic anhydride.
a All reactions were carried out upon microwave irradiation (100 W,
15 min) on a 1.0 mmol scale with 3.0 equiv of alkyne, 1.5 equiv of
amine, and 5 mol % of CuBr. b Yields are isolated yields. c Values in
parentheses indicate the diastereomeric ratio of the product obtained as
determined by NMR; d TMS ) trimethylsilyl.
SCHEME 8. Deprotection of the Hydroxyl Group in
11a-ma
SCHEME 6. Generation of a Small Library via
A3-Couplinga
a Reagents and conditions: (a) AcOH, THF, H2O (3:1:1), rt, 18 h.
a Reagents and conditions: (a) alkyne (3.0 equiv), amine (1.5 equiv),
CuBr (5 mol %), neat, MW, 15 min, 100 W.
TABLE 5. Deprotection of the Hydroxyl Group in 11a-m to
Generate 12a-m
SCHEME 7. Acylation of the Propargylamines 11a-la
entry compda
R1
R2
R3
R4
R5 yield (%)b
1
2
3
4
5
6
7
8
12a
3,4-OMe
H
Ph
n-Bu
4-OMe Ph Ph
4-F-Ph
2-Me-Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
75
78
90
89
87
84
82
84
72
87
83
86
89
12b 3,4-OMe
12c 3,4-OMe
12d 3,4-OMe
12e
12f
12g
12h 3,4-OMe
12i
12j
H
H
H
H
H
H
H
H
H
Ph
Ph
3,4-OMe
3,4-OMe
3,4-OMe
3,4-diCl-Ph Ph
2-pyridine Ph
3-Br-Ph
Ph
9
3,4-OMe
3,4-OMe
3-CF3-Ph TMSfHc Me
a Reagents and conditions: (a) (R5CO)2O (2.5 equiv), MeCN, MW, 150
°C, 30 min, 300 W.
10
11
12
13
4-F-Ph
Ph
4-F-Ph
Ph
Me
Me
Me
CF3
12k 3,4,5-OMe H
12l
12m 3,4-OMe
3,4,5-OMe OMe 3-CF3 Ph Ph
Ph Ph
H
(Table 3, entry 10). For further increasing diversity the aldehydes
4b,c were used (Scheme 6) rendering the desired products 10k
and 10l in 81% and 85% yield, respectively (Table 3, entries
11 and 12).
a All reactions were carried out on a 1.0 mmol scale in 4 mL of
AcOH/THF/H2O (3:1:1) at rt for 18 h. b Yields are isolated yields. c 3.0
equiv of TBAF was used to deprotect the hydroxyl group and the
acetylene moiety simultaneously.
Next the newly generated propargylamines 10a-l were
protected, in view of decreasing the nucleophilicity of the
nitrogen. However, attempts at Boc-protection of propargy-
lamine 10a resulted in no reaction as all starting material was
recovered, presumably owing to the steric bulk of the substrate
and reagent. Acylation of 10a (Scheme 7) with classical
conditions as acetic anhydride in the presence of triethylamine,
pyridine, or diisopropylethylamine as the base at 0 °C resulted
in low yields of the target amide 11a. Switching to acetyl
chloride did not solve the problem. However, microwave-
assisted acylation with acetic anhydride (2.5 equiv) in aceto-
nitrile at a ceiling temperature of 150 °C for 30 min at 300 W
maximum irradiation power furnished the desired acetamide 11a
in 75% yield (Table 4, entry 1).
78% (Table 4, entries 1-12) next to an array of unidentified
side compounds.
As acylation could be used to generate diversity in the target
aza-analogues, propargylamine 10a was reacted with trifluoro-
acetic anhydride in DCM for 2 h at rt with pyridine as base
yielding the corresponding trifluoroacetamide 11m in an excel-
lent yield of 96% (Table 4, entry 13).
The TBS protective group was easily removed upon stirring
with AcOH/THF/H2O (3:1:1) for 18 h at rt, yielding the cor-
responding alcohols 12a-h and 12j-m in 75-90% yield
(Scheme 8, Table 5).
Analogously, all other generated propargylamines 10b-l
yielded the acetamides 11b-l in yields ranging from 70% to
In the case of the TMS-substituted propargylamine 12i, 3
equiv of tetrabutylammonium fluoride (TBAF) was used to
J. Org. Chem. Vol. 73, No. 19, 2008 7513

Mont et al.
SCHEME 9. Cyclization of the Intermediates 12a-m to the
Target Triazolodibenzo[1,5-a]azocines 13a-ma
FIGURE 2. Numbering and the key 1H and 13C NMR displacements.
43% to 52%. In the case of compound 12g, which was generated
with 2-aminopyridine during A3-coupling, no cyclized com-
pound 13g could be isolated (Table 6, entry 7). Probably, the
pyridine nitrogen causes problems during bromination.
Stereochemical Discussion: Surprisingly, in comparison with
our previous observations,10c the cyclization of the intermediate
azides was found to result in the formation of only one of the
two possible diastereoisomers of compounds 13a-m. Therefore,
a detailed NMR analysis of compound 13d was performed. Both
protons C-13 (Figure 2) are showing up as only two doublets
at δ 4.59 and 5.59 ppm clearly indicating the presence of only
one diastereomer.10c This high diastereoselectivity during ring
closure could probably be explained by the severe steric bulk
around the biaryl axis, caused by the densely substituted nitrogen
at C-4.
1H, 13C, DEPT, 2D HMBC, HMQC, and NOESY were used
to confirm the structure and to assign unambiguously the various
1H and 13C nuclei (see Figure 2). On the basis of 1HNMR, three
well-separated singlets (δ 6.96, 6.98, 7.02 ppm) were observed.
Two of the three are directly correlated via HMQC with the
aromatic carbons, δ 6.96 ppm with δ 111.3 ppm and δ 7.02
ppm with δ 113.5 ppm. The third singlet at δ 6.98 ppm
corresponds with the methine carbon at δ 58.1 ppm and is an
aliphatic proton. Hence, from the above results, it was seen that
the proton signals at δ 6.96 and 7.02 ppm belong to the aromatic
protons on the ring C-9 and C-12 while the proton signal at δ
) 6.98 ppm belongs to C-4 (Figure 2).
a Reagents and conditions: (a) CBr4 (3.0 equiv), PPh3 (3.0 equiv), 0 °C
to rt, 6 h; (b) NaN3 (3.0 equiv), DMF, MW, 80 °C, 20 min, 25 W; (c)
DMF, MW, 120 °C, 15 min, 50 W.
TABLE 6. Yields of the Cyclized Final Products 13a-m
entry compda
R1
R2
R3
R4
Ph
Ph
4-OMe-Ph Ph
R5 yield (%)b
1
2
3
4
5
6
7
8
13a
13b
13c
13d
13e
13f
13g
13h
13i
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
3,4-OMe
H
Ph
n-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Me
59
47
50
49
48
43
0
52
51
52
49
47
50
H
H
H
H
H
H
H
H
H
4-F-Ph
2-Me-Ph
Ph
Ph
3,4-diCl-Ph Ph
2-pyridine Ph
3-Br-Ph
3-CF3-Ph
4-F-Ph
Ph
Ph
H
9
10
11
12
13
13j
13k
13l
4-F-Ph Me
3,4,5-OMe H
3,4,5-OMe OMe 3-CF3-Ph
Ph
Ph
Ph
Ph
Me
Me
CF3
13m 3,4-OMe
H
a All reactions were carried out on a 0.1 mmol scale. b Yields are
calculated over three steps.
Then NOESY correlation confirms the proposed structure and
the assignment of the various protons. The aliphatic proton (δ
6.98 ppm) correlates with the aromatic doublet (δ 7.64 ppm)
and with the ortho proton (δ 7.54 ppm) of the phenyl ring. The
1H singlet at δ 6.96 ppm correlates with the aromatic doublet
deprotect the hydroxyl group and the acetylene moiety simul-
taneously (Table 5, entry 9).
Thus, having all required key intermediates 12a-m at hand,
we focused our attention on one-pot three-step cyclization for
the generation of the target aza-analogues 13a-m (Scheme 9).
Our optimized procedure10c was attempted applying alcohol 12a.
Appel bromination of alcohol 12a with CBr4 and PPh3 at rt
proceeded smoothly, affording the corresponding benzyl bro-
mide (TLC- and MS-monitoring), which was not isolated. The
nucleophilic displacement of the bromo group with azide fun-
ctionality, using NaN3 in DMF at 80 °C under microwave
irradiation, resulted in the formation of the corresponding azide
(TLC- and MS-monitoring). Finally, the intramolecular Huisgen
1,3-dipolar cycloaddition reaction was performed upon micro-
wave irradiation at a ceiling temperature of 120 °C in DMF
furnishing the target molecule 13a in an overall yield of 59%
(Table 6, entry 1). The three steps were performed consecutively,
without isolation of the intermediates. Interestingly, the 1H NMR
spectrum of 13a indicated the presence of only one diastere-
oisomer after final cyclization. Analogously, the other alcohols
12b-m were subjected to this optimized pseudo one-pot three-
step protocol (Table 6), furnishing the target aza-analogous
13b-m as single diastereoisomers in overall yields ranging from
1
(δ 7.29 ppm) and the H singlet at δ 7.02 ppm correlates with
the aliphatic methylene protons (δ 4.59 and 5.59 ppm). Finally
the most interesting NOESY correlation allows the determination
of the obtained diastereomer. It is the correlation between the
-CH3 protons (δ 1.32 ppm) of the acetamide and the aromatic
proton at (δ 6.96 ppm) revealing a spatial proximity between
these two nuclei. Moreover the rather high field chemical shift
of the acetamide at δ 1.32 ppm suggests an influence of the
magnetic anisotropy of the ring R1.
To investigate the possibility of the formation of the R and
S diastereomers of 13d, both were modeled using MOE with
the MMFF94 force field (chemical computing group) in the R
and S conformation (Figure 4). We could clearly see a difference
in total energy between the R (184.8 kcal/mol) and the S (164.4
kcal/mol) conformation. This difference can be explained by
the higher ring strain of the eight-membered ring in the R
diastereomer. Furthermore, these models show that the
distance between the protons of the acetamide group and the
7514 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of (-)-Steganacin Aza-Analogues
Conclusion
To conclude, we have developed a novel microwave-assisted
synthetic protocol for the formation of hitherto unknown aza-
analogues of (-)-Steganacin. We prepared a small library of
diversely functionalized target molecules, starting from cheap
and readily available benzyl alcohols, and proved the versatility
of this methodology. The key steps of this novel protocol highly
benefit from focused microwave irradiation, as the reactions
proving to be faster and cleaner. Microwave-assisted A3-
coupling was performed as a handy tool to impart additional
diversity to the strategy. Furthermore, the formation of the rigid,
medium-sized, and fused ring systems of the title molecules
greatly benefited from focused microwave irradiation and the
title molecules were generated in high overall yields and purity.
Exclusive diastereoselectivity was observed during the cycliza-
tion process, furnishing only the 13-(S)-isomer of the target
molecules. These compounds are under current investigation
to identify their antileukemic and tubulin polymerization inhibi-
tory activities.
FIGURE 3. Structure of isomer 13-(S) and NOE correlations.
Experimental Section
General Procedure for the Synthesis of Propargylamines
10a-l via A3-Coupling. CuBr (7 mg, 5 mol%), alkyne (3.0 mmol,
3.0 equiv), aldehydes 4a, 4b, and 4c (1.0 mmol, 1.0 equiv), and
amine (1.5 mmol, 1.5 equiv) were placed in a 10 mL reaction vial
containing a stirring bar. The vial was kept under argon for 30 s
and then sealed tightly with a Teflon septum and placed into the
microwave cavity. It was irradiated at a ceiling temperature of 90
°C, using 100 W maximum power, for 20 min. Then the reaction
mixture was rapidly cooled with gas jet cooling to ambient
temperature. The crude product was purified by column chroma-
tography [silica gel, heptane/EtOAc (9:1) with 1% TEA] affording
the propargylamine 10a-l as a light yellow oil.
Synthesis of {1-[2′-(tert-Butyldimethylsilanyloxymethyl)-4′,5′-
dimethoxybiphenyl-2-yl]-3-phenylprop-2-ynyl}phenylamine (10a).
Compound 10a was synthesized as described in the general
procedure with 4a as the aldehyde (387 mg, 1 mmol), aniline (140
mg, 1.5 mmol), and phenylacetylene (306 mg, 3.0 mmol) at a ceiling
temperature of 90 °C. Column chromatography [silica gel, heptane/
EtOAc (9:1) with 1% TEA] afforded propargylamine 10a (502 mg,
89%) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.93 (q,
1H, J ) 7.3 Hz), 7.53-7.07 (m, 12H), 6.84 (d, 1H, J ) 16.6 Hz),
6.73 (q, 1H, J ) 7.3 Hz), 6.56 (d, 1H, J ) 7.6 Hz), 6.47 (d, 1H,
J ) 7.6 Hz), 5.30 (d, 1H, J ) 5.6 Hz), 4.50 (d,1H, J ) 13.2 Hz),
4.44 (d, 1H, J ) 13.2 Hz), 3.97, 3.95 (s, 3H), 3.81, 3.48 (s, 3H),
0.91 (s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 148.8,
147.7, 146.8, 146.4, 139.5, 139.4, 139.0, 132.1, 132.0, 131.8, 131.2,
130.2, 130.1, 129.5, 129.3, 128.7, 128.6, 128.2, 128.0, 123.3, 123.2,
118.9, 118.8, 114.3, 113.2, 110.9, 90.1, 89.8, 85.1, 84.6, 63.2, 56.4,
56.2, 55.9, 48.6, 48.0, 26.4, 18.8, -4.9; MS (EI): 563 (M+), 413
(100); HRMS (EI) m/z calcd for C36H41O3NSi [M+] 563.2855, found
563.2852.
General Procedure for the Acetylation of Propargylamines
11a-m. To a solution of compounds 10a-l (1.0 mmol) in
acetonitrile (2.5 mL) was added acetic anhydride (255 mg, 2.5
mmol) in a 10 mL reaction glass vial containing a stirring bar. The
vial was kept under argon for 30 s and then sealed tightly with a
Teflon septum and placed into the microwave cavity. It was
irradiated at a ceiling temperature of 150 °C, using 300 W maximum
power, for 30 min. Then the reaction mixture was rapidly cooled
with gas jet cooling to ambient temperature. The crude mixture
was washed with a saturated solution of NaHCO3 (50 mL) and
extracted with EtOAc (50 mL). The organic layer was separated
and the aqueous layer was further extracted with EtOAc (3 × 15
mL). The combined organic fractions were dried over anhydrous
FIGURE 4. MOE models for the molecule 13d.
proton at C-9 is 5.12 Å for the R diastereomer and 4.0 Å for
the S isomer being in accordance with the observed NOE
correlation indicating that only the S diastereomer is formed.
In Figure 4 the upper part shows the conformation of the
13d molecule in the S and R conformation, while the lower
part shows the molecules colored by force (blue to red). We
can clearly see that the strain in the R conformation is higher
(more red) compared to the S conformation. Hence we could
conclude that the increased steric bulk at the C-4 position is
responsible for the high torsional energy observed for the
minor 13-(R) isomer and hence this results in the exclusive
formation of diastereomer 13-(S) (Figure 3).
Finally, X-ray crystallographic analysis20 fully confirmed the
structure of compound 13d.
(20) See the Supporting Information for the X-ray structure. CCDC-687382
contains the supplementary crystallographic data for structure 13d. These data
can be obtained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.com.ac.uk/data_request/cif.
J. Org. Chem. Vol. 73, No. 19, 2008 7515

Mont et al.
MgSO4 and then evaporated under reduced pressure to afford crude
acetylated product as a pale yellow oil. Column chromatography
[silica gel heptane/EtOAc (9:1) with 1% TEA] afforded pure
compound 11a-m as a yellow oil.
mmol) in THF (2 mL). The reaction mixture was allowed to warm
to room temperature, and the stirring was continued for an additional
6 h. The colorless precipitate (Ph3PdO) was then filtered off and
the solvent was removed under reduced pressure to furnish the crude
bromide. This was dissolved in dry DMF (1 mL) and the solution
was placed in a 10 mL reaction vial containing a small magnetic
stirring bar. NaN3 (20 mg, 0.30 mmol) was added and the vial was
sealed tightly with a Teflon crimp top. It was irradiated at a ceiling
temperature of 80 °C, using 25 W as maximum power, for 20 min.
Then the reaction mixture was rapidly cooled with gas jet cooling
to ambient temperature. After this irradiation period, the solution
of crude azide was additionally irradiated at a ceiling temperature
of 120 °C, using 50 W as maximum power, for 15 min. Then the
reaction mixture was rapidly cooled with gas jet cooling to ambient
temperature. Water (30 mL) was added and the product was
extracted with diethyl ether (3 × 30 mL). The combined organic
layers were dried over anhydrous MgSO4 and the solvent was
removed under reduced pressure to furnish the crude product as a
yellowish oil. Column chromatography [silica gel heptane/EtOAc
(2:1)] afforded the products 13a-m.
Synthesis of N-{1-[2′-(tert-Butyldimethylsilanyloxymethyl)-4′,5′-
dimethoxybiphenyl-2-yl]-3-phenylprop-2-ynyl}-N-phenylaceta-
mide (11a). Compound 11a was synthesized from 10a (564 mg,
1.0 mmol) as described in the general procedure. Column chro-
matography [silica gel heptane/EtOAc (9:1) with 1% TEA] afforded
1
acetylated product 11a (454 mg, 75%) as a yellow oil. H NMR
(300 MHz, CDCl3) δ 7.35-6.8 (m, 16H), 6.72, 6.69 (s, 1H), 4.51
(d, J ) 13.2 Hz), 4.35 (d, 1H, J ) 13.2 Hz), 3.96, 3.84 (s, 3H),
3.94, 3.84 (s, 3H), 1.67, 1.65 (s, 3H), 0.91, 0.88 (s, 9H), 0.07 (s,
3H), 0.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.6, 168.5,
148.9, 148.7, 147.5, 143.0, 140.0, 139.9, 139.5, 135.7, 131.7, 131.5,
130.8, 130.7, 130.4, 130.3, 129.9, 129.8, 128.8, 128.2, 128.0, 127.0,
123.9, 113.2, 113.1, 112.4, 110.7, 110.6, 87.7, 87.5, 86.9, 86.0,
62.8, 62.3, 56.1, 55.8, 48.8, 48.0, 25.9, 22.8, 22.5, 18.3, -5.4; MS
(EI) 605 (M+), 338 (100); HRMS (EI) m/z calcd for C38H43O4NSi
[M+] 605.2962, found 605.2959.
Synthesis of N-(10,11-Dimethoxy-3-phenyl-4,13-dihydrodibenzo-
[d,f][1,2,3]triazolo[1,5-a]azocin-4-yl)-N-phenylacetamide (13a). Com-
pound 13a was synthesized from 12a (49 mg, 0.10 mmol) as
described in the general procedure. Column chromatography [silica
gel heptane/EtOAc (2:1)] afforded product 13a (30 mg, 59%, over
General Procedure for the Deprotection of the TBDMS Group
To Afford the Corresponding Alcohols 12a-m. To the TBS-
protected alcohols 11a-m was added a mixture of AcOH:THF:
H2O (3:1:1) (25 mL). The solution was stirred at room temperature
for 18 h. The reaction mixture was diluted with water (50 mL),
washed with a saturated solution of NaHCO3 (50 mL), and extracted
with EtOAc. The organic layer was separated and the aqueous layer
was further extracted with EtOAc (3 × 15 mL). The combined
organic layers were dried over anhydrous MgSO4 and the solvent
was removed under reduced pressure to yield the crude product as
a yellow oil. Column chromatography [silica gel heptane/EtOAc
(2:1)] afforded analytically pure products 12a-m.
Synthesis of N-[1-(2′-Hydroxymethyl-4′,5′-dimethoxybiphenyl-
2-yl)-3-phenylprop-2-ynyl]-N-phenylacetamide (12a). Compound
12a was synthesized from 11a (606 mg, 1.0 mmol) as described in
the general procedure. Column chromatography [silica gel heptane/
EtOAc (2:1)] afforded product 12a (369 mg, 75%) as a pale yellow
oil. 1H NMR (300 MHz, CDCl3) δ 7.43 (br s, 4H,), 7.34-7.08 (m,
7H), 6.95 (br s, 3H), 6.77 (d, 2H, J ) 13.0 Hz), 6.58 (s, 1H), 4.61
(dd, 2H, J ) 11.7, 4.5 Hz), 4.41 (d, 1H, J ) 11.7 Hz), 3.98, 3.97,
3.84, 3.79 (s, 6H), 1.73, 1.61 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 170.8, 148.2, 148.4, 147.8, 140.8, 140.3, 140.0, 139.7, 138.8,
136.0, 132.8, 132.0, 131.7, 131.6, 131.3, 131.1, 130.5, 129.4, 129.2,
129.1, 128.8, 128.6, 128.0, 127.7, 127.6, 124.1, 123.9, 123.1, 122.9,
113.7, 113.3, 112.7, 112.0, 89.5, 87.8, 87.2, 87.1, 62.7, 56.5, 56.4,
56.3, 51.0, 45.3, 23.9; MS (EI) 491 (M+), 225 (100); HRMS (EI)
m/z calcd for C32H29O4N [M+] 491.2097, found 491.2103.
General Procedure for the Synthesis of Triazolo[1,5-a]azo-
cines (13a-m). To a solution of alcohols 12a-m (0.10 mmol) and
CBr4 (99 mg, 0.30 mmol) in freshly distilled THF (10 mL) at 0 °C
was slowly added under stirring a solution of Ph3P (79 mg, 0.30
1
the 3 steps) as a pale yellow oil. H NMR (300 MHz, CDCl3) δ
7.64 (d, 1H, J ) 7.6 Hz), 7.51-7.47 (m, 7H), 7.27 (dd, 2H, J )
7.6, 1.5 Hz), 7.03-7.00 (m, 1H), 7.00 (d, 2H, J ) 10.8 Hz,), 6.94
(s, 1H), 6.84 (br s, 2H), 6.11 (br s, 1H), 5.59 (d, 1H, J ) 14.7 Hz),
4.60 (d, 1H, J ) 14.7 Hz), 3.97 (s, 3H), 3.93 (s, 3H), 1.31 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 171.8, 150.3 149.3, 148.3, 140.2,
138.5, 137.6, 137.2, 136.3, 131.6, 131.2, 130.9, 128.9, 128.8, 128.6,
128.3, 127.9, 123.4, 113.6, 111.4, 58.2, 56.5, 56.3, 53.4, 23.8; MS
(EI) 516 (M+), 225 (100); HRMS (EI) m/z calcd for C32H28O3N4
[M+] 516.2161, found 516.2154.
Acknowledgment. The authors wish to thank the FWO (Fund
for Scientific ResearchsFlanders (Belgium)) and the Research
Fund of the University of Leuven for financial support to the
laboratory. P.A. and T.B. are grateful to the University of
Leuven for obtaining a postdoctoral fellowship and V.P.M. for
obtaining a (pre)doctoral scholarship. The authors thank Ir. B.
Demarsin for HRMS measurements and D. Henot for prepara-
tive HPLC.
Supporting Information Available: Detailed experimental
description, spectral data (NMR, HRMS), and copies of spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801290J
7516 J. Org. Chem. Vol. 73, No. 19, 2008