Synthesis of 13a-methylphenanthroindolizidines using radical cascade cyclization: synthetic studies toward (±)-hypoestestatin 1

Article abstract of DOI:10.1016/j.tet.2007.08.030

A radical cascade involving 6-endo cyclization of aryl radicals generated from N-acryloyl-N-(1-methylethenyl)-9-bromophenanthren-10-ylmethylamines, followed by 5-endo-trig cyclization of the resulting α-amidoyl radicals afforded phenanthroindolizidines be

Full text of DOI:10.1016/j.tet.2007.08.030

Tetrahedron 63 (2007) 11101–11107
Synthesis of 13a-methylphenanthroindolizidines using
radical cascade cyclization: synthetic studies toward
( )-hypoestestatin 1
*
Kosuke Takeuchi, Atsuko Ishita, Jun-ichi Matsuo and Hiroyuki Ishibashi
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi,
Kanazawa 920-1192, Japan
Received 3 July 2007; revised 9 August 2007; accepted 9 August 2007
Available online 14 August 2007
Abstract—A radical cascade involving 6-endo cyclization of aryl radicals generated from N-acryloyl-N-(1-methylethenyl)-9-bromo-
phenanthren-10-ylmethylamines, followed by 5-endo-trig cyclization of the resulting a-amidoyl radicals afforded phenanthroindolizidines
bearing a methyl substituent at the angular C13a position. 2,3,6-Trimethoxy derivative was synthesized by using this method, but its spectral
data were not in accord with those of literature values reported for hypoestestatin 1. Further synthetic study toward hypoestestatin 1 is dem-
onstrated.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of a methyl substituent onto the alkenic bond of enamide
(such as 6) also gives the radical cascade product. In this
paper, we describe the results in this area together with an
application of this method to the synthesis of a phenanthro-
indolizidine skeleton bearing a methyl substituent at the
angular position.
Radical cascade cyclization is recognized as a powerful tool
for the construction of polycyclic compounds, including nat-
ural products.1 We recently reported that Bu3SnH-mediated
radical cyclization of N-methacryloyl bromoenamine 1a
gave the tricyclic compound 4a together with tetrahydro-
isoquinoline 5a (Scheme 1).2 Formation of 4a from 1a can
be explained in terms of a radical cascade that involves 6-
endo cyclization of aryl radical 2a and successive 5-endo
cyclization of the resulting a-amidoyl radical 3a. Compound
5a might be a so-called reduction product derived from 3a.
We also reported that N-acryloyl enamine 1b gave no corre-
sponding radical cascade product 4b but afforded only com-
pound 5b. These results indicated that the methyl substituent
at the a-position of a,b-unsaturated amide acted as an effec-
tive radical-stabilizing group for the cyclization of a-ami-
doyl radical 3a. We have now found that the introduction
2. Results and discussion
2.1. Attempt to synthesize hypoestestatin 1
The compound 6 having a methyl substituent on the alkenic
bond of enamide was treated with Bu3SnH in the presence of
azobis(cyclohexanecarbonitrile) (ACN) in boiling toluene to
give the radical cascade product 8 in 22% yield (Scheme 2).
As mentioned above, the compound 1b having no methyl
substituent on the alkenic bond of enamide gave no radical
Br
Bu3SnH
ACN
+
N
N
N
N
N
toluene
reflux
R
R
R
R
R
O
O
O
3a,b
O
O
5a: R = Me (25%)
5b: R = H (11%)
1a: R = Me
2a,b
4a: R = Me (26%)
1b: R = H
4b: R = H (0%)
Scheme 1.
Keywords: Enamide; Hypoestestatin 1; ortho-Lithiation; Phenanthroindolizidine; Radical cascade.
* Corresponding author. Tel.: +81 76 234 4474; fax: +81 76 234 4476; e-mail: isibasi@p.kanazawa-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.030

11102
Br
K. Takeuchi et al. / Tetrahedron 63 (2007) 11101–11107
Me
bromo alcohol 15, which was converted to the secondary
Bu3SnH
ACN
toluene
reflux
Me
O
Me
O
amine 17 by treatment with Ph3P and CBr4 and successive
condensation of the resulting allyl bromide with amine
16.8 Treatment of 17 with acryloyl chloride gave a,b-unsat-
urated amide 18, whose oxidation with MCPBA and thermal
elimination of the resulting sulfoxide in the presence of
sodium hydrogen carbonate in boiling xylene gave 11.
N
N
N
O
8 (22%)
6
7
Scheme 2.
cascade product 4b by the cyclization of 3b.2 The successful
formation of 8 from 6 was probably because the presence of
a methyl substituent on the radical center of a-amidoyl rad-
ical 7 retarded the intermolecular reduction with Bu3SnH
more effectively than the radical 3b.
The radical cyclization of 11 with Bu3SnH in the presence of
ACN gave lactam 10 in 39% yield (Scheme 5). Lactam 10
was reduced with LiAlH4 to give the target molecule 9.
Bu3SnH
We then applied this method to the synthesis of phenan-
throindolizidines3 bearing a methyl substituent at angular
position. Hypoestestatin 1 (9) is one such compound that
was isolated from the extract of the East African shrub
Hypoe€stes verticillaris by Pettit’s group4 and was found to
markedly inhibit the growth of the murine P-388 cell line.
There has been no report in the literature on the synthesis
of hypoestestatin 1. Our retrosynthetic analysis of hypo-
estestatin 1 involved 6-endo/5-endo radical cascade cycli-
zation of enamide 11 followed by reduction of the
resulting lactam 10 (Scheme 3).
ACN
LiAlH4
11
10
9
(39%)
(96%)
Scheme 5.
1H and 13C NMR spectra of 9, however, were not in accord
with those of hypoestestatin 1 reported by Pettit et al. In the
1H NMR spectrum of compound 9 in CD3OD, the signal due
to the angular methyl group appeared as a singlet at d 1.07,
whereas the corresponding signal reported for hypoestesta-
tin 1 was shifted to a lower field at d 1.30. Its lower field shift
was presumed to be a result of the formation of the quater-
nary ammonium salt. Hence, we turned our attention to the
1H NMR spectra of carbonate salt derived from compound
9. In the event, the signal due to the methyl protons of car-
bonate salt of 9 was shifted to a lower field at d 1.27, but
the other signals were not in accord with those reported
for hypoestestatin 1. Therefore, it was thought that com-
pound 9 was not hypoestestatin 1.
A radical precursor 11 was prepared as shown in Scheme 4.
The Perkin reaction5 of potassium p-methoxyphenylacetate
and 2-bromo-4,5-dimethoxybenzaldehyde gave carboxylic
acid 12, whose esterification gave the corresponding methyl
ester 13. Radical cyclization of 136 followed by reduction of
the ester group with LiAlH4 gave known phenanthrenyl
methanol 14.7 Treatment of 14 with NBS in CH2Cl2 afforded
OMe
OMe
OMe
MeO
MeO
MeO
MeO
Me
N
Me
N
Br
Me
O
N
O
MeO
MeO
( )-hypoestestatin 1 [( )-9]
10
11
Scheme 3.
OMe
OMe
OMe
1) Bu3SnH
ACN
MeO
MeO
MeO
MeO
MeO
COOK
MeO
toluene
reflux
Br
NBS
CH2Cl2
r.t.
(CH3CO)2O
Br
OH
OH
2) LiAlH
OR
4
MeO
MeO
Br
CHO
O
MeO
OMe
15 (61%)
14 (71%, 2 steps)
CH3I
12 (R = H)
DBU
CH3CN
13 (R = Me) (68%, 2 steps)
O
OMe
OMe
MeO
MeO
MeO
MeO
Cl
SPh
SPh
Br
Br
1) PPh3, CBr4
CH3CN
Br
1) MCPBA
Et3N
CH2Cl2
CH2Cl2
NH
N
N
O
2) NaHCO3
xylene
reflux
Me
2)
SPh
O
H2N
MeO
MeO
16
17 (84%, 2 steps)
18 (quant.)
11 (75%, 2 steps)
Scheme 4.

K. Takeuchi et al. / Tetrahedron 63 (2007) 11101–11107
11103
2.2. Attempt to synthesize another possible structure
of hypoestestatin 1
of the tert-butyl group of 24 with trifluoroacetic acid af-
forded secondary amide 25. Subsequent hydrolysis of 25,
however, did not proceed under several conventional condi-
tions, probably because of steric hindrance of a neighboring
bromine. Therefore, we explored another functional group
transformation of 25, that is, hydride was used for the nucle-
ophile instead of sterically more demanding hydroxide ion.
It was found that a combination of DIBAL and Schwartz
reagent13 reduced secondary amide 25 to the corresponding
imine 26, and aqueous treatment of 26 gave aldehyde 27 in
a moderate yield (Scheme 7).
We speculated the correct structure of hypoestestatin 1 to be
32 in which three methoxy groups occupied 3, 6, and 7
positions on the phenanthroindolizidine ring. Our attention
was then turned to the synthesis of 32 by radical cascade
cyclization of compound 30 (Scheme 8). The synthesis of
compound 30 was begun by Perkin reaction of 2-bromo-
4,5-dimethoxyphenylacetic acid9 and p-anisaldehyde fol-
lowed by esterification to give 19 (Scheme 6). A subsequent
radical cyclization of 19 in toluene gave the known phenan-
threne ester 2010 in 43% yield. The low yield of 20 might be
ascribed to the formation of dehydro congener of 20 as a
result that toluene acted as a hydrogen source. So, we then
turned our attention to the use of chlorobenzene as a solvent
for the radical cyclization of 19 to afford 20 in 53% yield.
MeO
1) sec-BuLi
TMEDA
THF
1) 10% NaOH.
2) SOCl2, DMF
Me
N
20
2) CBr4
3) N-t-Butyl-
methylamine
Et3N
t-Bu
O
MeO
OMe
23 (90% from 20)
MeO
MeO
CHO
1) (CH3CO)2O
Et3N
MeO
MeO
MeO
Br
Br
O
Br
O
2) CH3I, DBU
CH3CN
H
N
TFA
Me
N
MeO
MeO
Br
COOMe
Me
t-Bu
COOH
MeO
OMe
19 (43%, 2 steps)
MeO
OMe
OMe
25 (80% from 23)
24
MeO
MeO
MeO
MeO
MeO
Bu3SnH
ACN
PhCl
9
LiAlH4
COOMe
1) DIBAL
2) Cp2Zr(H)Cl
Br
Br
+
H3O
OH
N
CHO
Me
MeO
MeO
MeO
OMe
OMe
OMe
20 (53%)
OMe
26
21 (99%)
27 (43% from 25)
MeO
Scheme 7.
Br
The method for the synthesis of the target compound 32 from
aldehyde 27 is shown in Scheme 8. Reductive amination of
aldehyde 27 with primary amine 16 afforded the secondary
amine 28, which was converted to the radical precursor 30
via compound 29 by a similar sequence of reactions of 17
giving 11 (see Scheme 4). The radical cascade of 30 involv-
ing 6-endo/5-endo cyclizations proceeded successfully to
give lactam 31. The subsequent reduction of 31 with LiAlH4
gave the target compound 32. However, unfortunately, the
1H NMR spectral data of 32 were again not in accord with
OH
MeO
OMe
22
Scheme 6.
Reduction of 20 with LiAlH4 gave alcohol 21. However,
treatment of 21 with NBS or Br2 under various conditions
afforded no brominated compound 22. A substitution pattern
of the methoxy groups on the phenanthrene ring probably
caused a reduction of relative electron density at the C-9
position of 21 as compared to compound 14.
1
those of hypoestestatin 1 reported by Pettit et al. In the H
NMR spectrum, the signal due to the angular methyl group
of 32 appeared as a singlet at d 1.07 in CD3OD, whereas
the corresponding signal of carbonate salt of 32 was shifted
to a lower field at d 1.22 ppm. However, the other signals of
carbonate salt of 32 were not in accord with those reported
for hypoestestatin 1.
We therefore tried to introduce a bromine atom at the desired
position through an ortho-lithiation of amide.11 N-tert-
Butylmethyl amide 23 was chosen as a substrate for the
ortho-lithiation reaction, since the tert-butylmethyl amide
group has higher direction ability for ortho-lithiation and
is known to be hydrolyzed more easily than other tertiary
amides such as diethylamide.12 Lithiation of compound 23
with sec-BuLi in the presence of tetramethylethylene-
diamine (TMEDA) at ꢀ94 ꢁC to ꢀ78 ꢁC followed by bromi-
nation with CBr4 gave the desired bromide 24. Deprotection
3. Conclusion
We accomplished the synthesis of 2,3,6-trimethoxy phenan-
throindolizidine 9 and 3,6,7-trimethoxy isomer 32 by
6-endo/5-endo radical cascade cyclization of the corre-
sponding bromo enamide 11 and 30, respectively. Although

11104
K. Takeuchi et al. / Tetrahedron 63 (2007) 11101–11107
Me
16
MeO
MeO
acryloyl
chloride
Et3N
SPh
SPh
SPh
O
Br
Me
H2N
Br
Me
1) mCPBA
NaBH3CN
CH2Cl2
27
NH
N
THF / AcOH
2) NaHCO3
xylene
reflux
CH2Cl2
MeO
MeO
OMe
28
OMe
29 (quant., 2 steps)
MeO
MeO
MeO
MeO
MeO
Me
Me
N
Br
Bu3SnH
ACN
Me
LiAlH4
N
N
THF
reflux
toluene
reflux
O
O
MeO
OMe
OMe
OMe
30 (78%, 2 steps)
32 (quant.)
31 (36%)
Scheme 8.
1H NMR spectral data of the resulting 9 and 32 were not in
accord with those of reported hypoestestatin 1, the present
study revealed that a phenanthroindolizidine skeleton bear-
ing a methyl substituent at the angular C13a position can
be easily constructed by this method.
extracted with AcOEt. The organic layer was washed with
brine, dried (MgSO4), and concentrated under a reduced
pressure. The residue was purified by column chromato-
graphy on silica gel (hexane/AcOEt, 10:1/6:1) to afford
6 (490 mg, 62%, two steps) as a colorless oil. IR (CHCl3)
1
n 1645, 1615 cmꢀ1; H NMR (270 MHz, CDCl3) d 1.90
(3H, s), 4.77 (1H, s), 4.89 (2H, s), 5.03 (1H, d, J¼1.3 Hz),
5.69 (1H, dd, J¼10.1, 2.1 Hz), 6.45 (1H, dd, J¼16.8,
2.3 Hz), 6.65 (1H, dd, J¼16.8, 9.9 Hz), 7.10 (1H, td,
J¼7.7, 1.9 Hz), 7.22–7.35 (2H, m), 7.52 (1H, dd, J¼7.9,
1.0 Hz); 13C NMR (68 MHz, CDCl3) d 21.2, 48.7, 115.6,
123.2, 127.3, 127.8, 128.0, 128.5, 129.4, 132.4, 136.2,
143.2, 165.0. Anal. Calcd for C12H12BrNO: C, 55.73; H,
5.04; N, 5.00. Found: C, 55.61; H, 5.04; N, 5.02.
4. Experimental
4.1. General
Melting points are uncorrected. Infrared (IR) spectra were
recorded on a Shimadzu FTIR-8100 spectrophotometer for
1
solutions in CHCl3. H NMR and 13C NMR spectra were
measured on a JEOL JNM-EX 270 or a JEOL JNM-GSX
500 spectrometer for solutions in CDCl3. d values quoted
are relative to tetramethylsilane. High-resolution mass spec-
tra (HRMS) were obtained with a JEOL JMS-SX-102A mass
spectrometer. Column chromatography was performed on
silica gel 60 N (Kanto Kagaku Co., Ltd., spherical, neutral,
63–210 mm) under pressure. Thin layer chromatography was
carried out on silica gel Wakogel B-5F.
4.1.2. ( )-1,2,3,5,10,10a-Hexahydro-10a-methylpyr-
rolo[1,2-b]isoquinolin-3-one (8). To a boiling solution of
6 (264.0 mg, 0.94 mmol) in toluene (30 mL) was added
dropwise a solution of Bu3SnH (0.38 mL, 1.41 mmol)
and ACN (46.7 mg, 0.19 mmol) in toluene (30 mL) over
2.5 h by employing a syringe-pump technique and the
mixture was further heated for 10 min. After removal of
solvent, the residue was purified by column chromato-
graphy on silica gel containing 10% KF (hexane/AcOEt,
3:1/2:1/1:1/2:3) to afford 8 (41.1 mg, 22%) as a col-
4.1.1. ( )-N-Acryloyl-N-(1-methylethenyl)-2-bromobenz-
ylamine (6). To a solution of N-acryloyl-N-[1-methyl-
1
2-(phenylsulfanyl)ethyl]-2-bromobenzylamine
(1.09 g,
orless oil. IR (CHCl3) n 1670 cmꢀ1; H NMR (270 MHz,
2.80 mmol), prepared in a manner similar to that described
for 18 (see Supplementary data), in CH2Cl2 (25 mL) was
added dropwise a solution of MCPBA (80%) (604 mg,
2.80 mmol) in CH2Cl2 (25 mL) at 0 ꢁC. After stirring at the
same temperature for 30 min, an aqueous 10% Na2S2O3 so-
lution was added to the reaction mixture and the mixture was
extracted with CHCl3. The organic layer was washed with
a saturated aqueous NaHCO3 solution and brine, dried
(MgSO4), and concentrated under a reduced pressure. The
residue was purified by column chromatography on silica
gel (hexane/AcOEt, 3:1) to afford N-acryloyl-N-[1-methyl-
2-(phenylsulfinyl)ethyl]-2-bromobenzylamine as a colorless
oil.
CDCl3) d 1.23 (3H, s), 1.95–2.15 (2H, m), 2.35–2.65 (2H,
m), 2.76 (1H, d, J¼15.6 Hz), 2.92 (1H, d, J¼15.6 Hz),
4.16 (1H, d, J¼17.6 Hz), 5.02 (1H, d, J¼17.6 Hz),
7.06–7.36 (5H, m); 13C NMR (68 MHz, CDCl3) d 23.8,
29.7, 33.1, 40.1, 41.5, 58.0, 126.4, 126.5, 126.6, 129.6,
131.0, 133.7, 173.4; HRMS calcd for C13H15NO:
201.1154, found: 201.1154.
4.1.3. 10-Bromo-9-hydroxymethyl-2,3,6-trimethoxyphe-
nanthrene (15). To
a solution of 14 (119.0 mg,
0.399 mmol) in CH2Cl2 (5 mL) was added NBS (78.1 mg,
0.439 mmol) at room temperature in the dark and the mix-
ture was stirred at the same temperature for 3 h. An aqueous
10% Na2S2O3 solution was added to the reaction mixture
and the mixture was extracted with CH2Cl2. The organic
layer was washed with a saturated aqueous NaHCO3 solu-
tion and brine, dried (MgSO4), and concentrated under a
reduced pressure. The residue was purified by column
The above sulfoxide (882 mg, 2.17 mmol) was heated in
boiling xylene (40 mL) in the presence of NaHCO3
(365 mg) for 12 h. A saturated aqueous NH4Cl solution
was added to the reaction mixture and the mixture was

K. Takeuchi et al. / Tetrahedron 63 (2007) 11101–11107
11105
chromatography on silica gel (CHCl3) to afford 15 (92.0 mg,
61%) as a colorless crystal. Mp 176–177 ꢁC (hexane/
The above sulfoxide was heated in boiling xylene (30 mL) in
the presence of NaHCO3 (218 mg, 2.59 mmol) for 12 h. To
the reaction mixture was added a saturated aqueous NH4Cl
solution and the mixture was extracted with AcOEt. The or-
ganic layer was washed with brine, dried (MgSO4), and con-
centrated under a reduced pressure. The residue was purified
by column chromatography on silica gel (hexane/AcOEt,
2:1) to afford 11 (459 mg, 75%, two steps) as a colorless
crystal. Mp 203 ꢁC (hexane/AcOEt); IR (CHCl3) n 1615,
1
AcOEt); IR (CHCl3) n 3020 cmꢀ1; H NMR (500 MHz,
CDCl3) d 1.96 (1H, t, J¼6.5 Hz), 4.02 (3H, s), 4.07
(3H, s), 4.11 (3H, s), 5.41 (2H, d, J¼6.5 Hz), 7.26 (1H, dd,
J¼9.0, 2.5 Hz), 7.80 (1H, s), 7.83 (1H, s), 7.84 (1H, d,
J¼2.5 Hz); 13C NMR (125 MHz, CDCl3) d 55.5, 55.8,
56.0, 63.5, 103.1, 104.6, 109.3, 115.7, 121.9, 125.0,
125.2, 125.6, 127.1, 130.8, 132.1, 149.5, 149.7, 158.1.
Anal. Calcd for C19H17BrO4: C, 57.31; H, 4.54. Found: C,
57.23; H, 4.57.
1
1645 cmꢀ1; H NMR (500 MHz, CDCl3) d 1.76 (3H, s),
4.00 (3H, s), 4.10 (3H, s), 4.12 (3H, s), 4.30 (1H, s), 4.80
(1H, s), 5.68–5.72 (3H, m), 6.51–6.58 (2H, m), 7.24 (1H,
dd, J¼9.0, 2.5 Hz), 7.86 (1H, d, J¼2.5 Hz), 7.86 (1H, s),
7.88 (1H, s), 8.18 (1H, d, J¼9.5 Hz); 13C NMR (68 MHz,
CDCl3) d 22.6, 47.2, 55.8, 56.3, 56.4, 103.6, 105.0, 110.1,
116.1, 117.9, 124.7, 125.5, 126.1, 128.0, 128.5, 128.6,
129.7, 130.8, 142.2, 150.0, 150.2, 158.5, 164.7. Anal. Calcd
for C24H24BrNO4: C, 61.28; H, 5.14; N, 2.98. Found: C,
61.08; H, 5.33; N, 2.90.
4.1.4. ( )-10-Bromo-2,3,6-trimethoxy-N-[1-methyl-2-
(phenylsulfanyl)ethyl]phenanthren-9-ylmethylamine
(17). To a solution of 15 (151.2 mg, 0.401 mmol) in CH3CN
(40 mL) were added PPh3 (485.6 mg, 1.84 mmol) and CBr4
(597.0 mg, 1.80 mmol) at room temperature and the mixture
was stirred at the same temperature for 2 h. After removal of
solvent, the residue was purified by column chromatography
on silica gel (CHCl3) to afford 10-bromo-9-bromomethyl-
2,3,6-trimethoxyphenanthrene quantitatively. 1H NMR
(270 MHz, CDCl3) d 4.02 (3H, s), 4.08 (3H, s), (3H, s),
5.24 (2H, s), 7.29 (1H, dd, J¼8.2, 2.3 Hz), 7.79 (1H, s), 7.80
(1H, s), 7.83 (1H, d, J¼2.6 Hz), 8.08 (1H, d, J¼8.2 Hz). Due
to its lability, it was used in the next step immediately.
4.1.6. ( )-9,11,12,13,13a,14-Hexahydro-2,3,6-trime-
thoxy-13a-methyldibenzo[f,h]pyrrolo[1,2-b]isoquinolin-
11-one (10). To a boiling solution of 11 (80 mg, 0.17 mmol)
in toluene (15 mL) was added dropwise a solution of
Bu3SnH (0.07 mL, 0.26 mmol) and ACN (8 mg,
0.03 mmol) in toluene (15 mL) over 2 h by employing a sy-
ringe-pump technique. After removal of solvent, AcOEt
(20 mL) and an aqueous 8% KF solution (20 mL) were
added to the residue and the mixture was vigorously stirred
at room temperature overnight. The precipitate was filtered
off and the filtrate was extracted with AcOEt. The organic
layer was washed with brine, dried (MgSO4), and concen-
trated under a reduced pressure. The residue was purified
by column chromatography on silica gel (hexane/AcOEt,
1:1/1:3/AcOEt) to afford 10 (26 mg, 39%) as a colorless
crystal. Mp 222–223 ꢁC (dec) (hexane/AcOEt); IR (CHCl3)
To a mixture of 1-methyl-2-(phenylsulfanyl)ethylamine (16)
(149.6 mg, 0.89 mmol), Na2CO3 (37.2 mg, 0.35 mmol), NaI
(37.2 mg, 0.25 mmol), and Et4NI (12.4 mg, 0.05 mmol) in
THF (10 mL)/1,4-dioxane (5 mL) was added dropwise a so-
lution of the above bromide (0.401 mmol) in THF (5 mL) at
room temperature over 1.5 h and the mixture was stirred at
the same temperature for 27 h. The reaction mixture was di-
luted with H2O and the mixture was extracted with AcOEt.
The organic layer was dried (MgSO4) and concentrated un-
der a reduced pressure. The residue was purified by column
chromatography on silica gel (CHCl3/MeOH, 50:1) to afford
1
n 1675 cmꢀ1; H NMR (500 MHz, CDCl3) d 1.35 (3H, s),
1
17 (178.2 mg, 84%) as a yellow oil. H NMR (270 MHz,
2.20–2.30 (2H, m), 2.52–2.69 (2H, m), 3.06 (1H, d,
J¼16.5 Hz), 3.24 (1H, d, J¼16.0 Hz), 4.03 (3H, s), 4.07
(3H, s), 4.11 (3H, s), 4.49 (1H, d, J¼16.5 Hz), 5.47
(1H, dd, J¼17.5, 2.5 Hz), 7.25–7.28 (2H, m), 7.91 (1H, d,
J¼6.5 Hz), 7.92 (1H, s), 7.94 (1H, s); 13C NMR (68 MHz,
CDCl3) d 24.3, 29.9, 33.4, 38.2, 38.6, 55.5, 55.9, 56.1,
57.5, 103.8, 104.1, 105.0, 115.1, 123.0, 123.3, 123.4,
124.0, 124.4, 126.7, 130.3, 148.7, 149.6, 157.9, 173.3;
HRMS calcd for C24H27NO4: 391.1784, found: 391.1782.
Anal. Calcd for C24H27NO4: C, 73.64; H, 6.44; N, 3.58.
Found: C, 73.36; H, 6.44; N, 3.56.
CDCl3) d 1.33 (3H, d, J¼5.6 Hz), 1.87 (1H, br s), 2.98–
3.13 (3H, m), 4.02 (3H, s), 4.09 (3H, s), 4.12 (3H, s), 4.40
(1H, d, J¼12.2 Hz), 4.51 (1H, d, J¼12.2 Hz), 7.13–7.33
(6H, m), 7.82 (1H, s), 7.84 (1H, s), 7.85 (1H, s), 8.14 (1H,
d, J¼8.9 Hz); 13C NMR (68 MHz, CDCl3) d 20.9, 41.7,
49.8, 52.5, 55.9, 56.4, 56.5, 103.6, 105.0, 110.0, 116.2,
122.4, 125.3, 125.8, 126.5, 127.5, 129.2, 130.2, 131.3,
132.8, 136.5, 149.8, 150.3, 158.5. Anal. Calcd for
C27H28BrNO3S: C, 61.59; H, 5.36; N, 2.66. Found: C,
61.54; H, 5.49; N, 2.64.
4.1.5. N-Acryloyl-10-bromo-N-(1-methylethenyl)-2,3,6-
trimethoxyphenanthren-9-ylmethylamine (11). To a solu-
tion of 18 (753 mg, 1.30 mmol) in CH2Cl2 (30 mL) was
added dropwise a solution of MCPBA (80%) (280 mg,
1.30 mmol) in CH2Cl2 (30 mL) at 0 ꢁC and the mixture
was stirred at the same temperature for 10 min. An aqueous
10% Na2S2O3 solution was added to the reaction mixture
and the mixture was extracted with CHCl3. The organic layer
was washed with a saturated aqueous NaHCO3 solution and
brine, dried (MgSO4), and concentrated under a reduced
pressure to give N-acryloyl-N-[1-methyl-2-(phenylsulfinyl)-
ethyl]-10-bromo-2,3,6-trimethoxyphenanthren-9-ylmethyl-
amine. The residue was used in the next step without further
purification.
4.1.7. ( )-9,11,12,13,13a,14-Hexahydro-2,3,6-trime-
thoxy-13a-methyldibenzo[f,h]pyrrolo[1,2-b]isoquinoline
(9). To a suspension of LiAlH4 (6 mg, 0.13 mmol) in THF
(5 mL) was added a solution of 10 (26 mg, 0.07 mmol) in
THF (5 mL) at room temperature and the mixture was heated
at reflux for 2 h. H2O (0.1 mL) was added to the reaction
mixture and the precipitate was filtered off through a Celite
pad. The filtrate was concentrated in a reduced pressure and
the residue was purified by column chromatography on silica
gel (CHCl3/MeOH, 15:1) to afford 9 (24 mg, 96%) as a yel-
1
low crystal. Mp was not determined due to its lability. H
NMR (500 MHz, CDCl3) d 1.05 (3H, s), 1.90–2.00 (4H,
m), 2.88–2.94 (1H, m), 3.00 (2H, s), 3.08–3.14 (1H, m),
4.01 (3H, s), 4.07 (3H, s), 4.10 (3H, s), 4.11 (1H, d,

11106
K. Takeuchi et al. / Tetrahedron 63 (2007) 11101–11107
J¼16.5 Hz), 4.45 (1H, d, J¼16.5 Hz), 7.21 (1H, dd, J¼9.2,
2.4 Hz), 7.33 (1H, s), 7.85 (1H, d, J¼9.2 Hz), 7.91 (1H, d,
J¼2.4 Hz), 7.93 (1H, s); 13C NMR (68 MHz, CDCl3)
d 17.8, 20.1, 35.7, 39.3, 47.0, 50.8, 55.5, 55.9, 56.0, 58.9,
103.9, 104.0, 104.8, 114.9, 123.7, 124.1, 124.2, 124.4,
124.6, 127.3, 130.0, 148.4, 149.4, 157.5; HRMS calcd for
C24H27NO3: 377.1991, found: 377.1990.
toluene (8 mL) was added dropwise a solution of Bu3SnH
(0.04 mL, 0.15 mmol) and ACN (4.6 mg, 0.02 mmol) in tol-
uene (8 mL) over 2 h by employing a syringe-pump tech-
nique and the mixture was further heated for 1 h. After
removal of solvent, the residue was purified by column chro-
matography on silica gel containing 10% KF (hexane/
AcOEt, 1:1/1:3/AcOEt) to give 31 (11.6 mg, 36%) as
a pale yellow crystal. Mp 198.0–202.5 ꢁC (dec) (Hexane/
1
4.1.8. 9-Bromo-2,3,6-trimethoxy-N-methylphenan-
threne-10-carboxamide (25). To
AcOEt); IR (CHCl3) n 1675 cmꢀ1; H NMR (500 MHz,
a
solution of 23
CDCl3) d 1.25 (3H, s, Me), 2.16 (2H, t, J¼8.0 Hz), 2.52–
2.67 (2H, m), 2.86 (1H, d, J¼15.6 Hz), 3.23 (1H, d,
J¼15.6 Hz), 4.01 (3H, s), 4.02 (3H, s), 4.11 (3H, s), 4.34
(1H, d, J¼17.1 Hz), 5.24 (1H, d, J¼17.1 Hz), 7.18 (1H,
dd, J¼9.2, 2.4 Hz), 7.80 (1H, d, J¼9.2 Hz), 7.88 (2H, like
s); 13C NMR (68 MHz, CDCl3) d 24.0, 29.8, 33.2, 37.9,
38.6, 55.4, 55.9, 55.9, 57.3, 102.7, 103.8, 104.6, 114.9,
121.1, 123.2, 124.6, 124.6, 124.7, 124.9, 130.6, 148.4,
149.5, 157.7, 173.3; HRMS calcd for C24H27NO4:
391.1784, found: 391.1776.
(738 mg, 1.94 mmol) and TMEDA (0.35 mL, 2.32 mmol)
in THF (20 mL) was added sec-BuLi (1.00 M in cyclohex-
ane/hexane, 2.37 mL, 2.37 mmol) at ꢀ94 ꢁC and the mix-
ture was slowly warmed to ꢀ78 ꢁC. After the mixture was
stirred for 1 h, a solution of CBr4 (3.27 g, 9.86 mmol) in
THF (5 mL) was added and the mixture was slowly warmed
to room temperature. H2O was added to the reaction mixture
and the mixture was extracted with AcOEt. The organic
layer was washed with brine, dried (Na2SO4), and concen-
trated under a reduced pressure. The crude product was
purified by column chromatography on silica gel (hexane/
AcOEt, 3:1/1:1) to afford 9-bromo-N-tert-butyl-2,3,6-
trimethoxy-N-methylphenanthrene-10-carboxamide (24)
along with a little amount of 23.
4.1.11. 9,11,12,13,13a,14-Hexahydro-3,6,7-trimethoxy-
13a-methyldibenzo[f,h]pyrrolo[1,2-b]isoquinoline (32).
To a solution of 31 (12.2 mg, 0.03 mmol) in THF (2 mL)
was added LiAlH4 (10.5 mg, 0.28 mmol) at 0 ꢁC and the
mixture was heated at reflux for 30 min. H2O was added to
the reaction mixture at 0 ꢁC and the precipitates were filtered
off through a Celite pad. The filtrate was concentrated under
a reduced pressure and the residue was purified by column
chromatography on silica gel (MeOH/AcOEt, 1:4) to afford
32 (13.4 mg, quant.) as a pale yellow solid. Mp was not de-
The mixture containing 24 was heated at reflux in TFA
(5 mL) for 42 h. After evaporation of TFA, the residue was
purified by column chromatography on silica gel (hexane/
AcOEt, 1:1/1:3/AcOEt) to afford 25 (515 mg, ca.
80%) along with a little amount of inseparable by-product.
HRMS calcd for C19H18O4N81Br: 405.0399, found:
405.0411. This mixture was used in the next step without
further purification:
1
termined due to its lability. H NMR (270 MHz, CDCl3)
d 1.02 (3H, s), 1.80–2.05 (4H, m), 2.85–3.20 (4H, m), 4.02
(3H, s), 4.06 (3H, s), 4.06–4.10 (1H, m), 4.11 (3H, s), 4.38
(1H, d, J¼16.2 Hz), 7.20 (1H, s), 7.19–7.25 (2H, m), 7.91
(1H, d, J¼2.5 Hz), 7.93 (1H, s), 7.96 (1H, d, J¼9.1 Hz);
13C NMR (68 MHz, CDCl3) d 17.3, 20.2, 36.1, 39.4, 47.4,
50.9, 55.5, 55.9, 56.0, 57.6, 103.1, 103.9, 104.7, 114.7,
123.2, 123.6, 125.0, 125.7, 125.8, 126.1, 130.5, 148.2,
149.4, 157.5; HRMS calcd for C24H27NO3: 377.1991,
found: 377.1987.
4.1.9. 9-Bromo-2,3,6-trimethoxyphenanthrene-10-car-
baldehyde (27). To a suspension of 25 containing a little
amount of unidentified product (206 mg, 0.51 mmol) (purity
of 25¼ca. 80%) in THF (18 mL) was added DIBAL (0.94 M
in hexane, 0.66 mL, 0.62 mmol) at ꢀ20 ꢁC and the mixture
was slowly warmed to room temperature. Cp2Zr(H)Cl
(191 mg, 0.74 mmol) was added at ꢀ20 ꢁC and the mixture
was stirred at room temperature for 4 h. The mixture was fil-
tered off through short column on silica gel (AcOEt) and the
filtrate was concentrated under a reduced pressure. The res-
idue was purified by column chromatography on silica gel
(hexane/AcOEt, 3:1/2:1/1:1/1:3). The first eluate
gave 27 (101 mg, 43%, three steps) as a yellow crystal.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Mp 185.5–186.0 ꢁC (hexane/AcOEt); IR (CHCl3)
n
1680 cmꢀ1; H NMR (00 MHz, CDCl3) d 4.06 (H, s), 4.07
(3H, s), 4.10 (3H, s), 7.28 (1H, dd, J¼9.3, 2.4 Hz), 7.78
(1H, s), 7.78 (1H, d, J¼2.4 Hz), 8.56 (1H, d, J¼9.3 Hz),
8.72 (1H, s), 10.9 (1H, s); 13C NMR (125 MHz, CDCl3)
d 55.5, 55.7, 55.8, 102.6, 103.7, 105.3, 116.3, 123.3,
123.7, 124.3, 124.6, 130.8, 133.0, 134.0, 149.0, 150.4,
160.9, 196.0. Anal. Calcd for C18H15BrO4: C, 57.62; H,
4.03. Found: C, 57.25; H, 3.99.
1
Supplementary data
Experimental procedure for the preparation of 12–14,
18–21, 23, and 28–30. Supplementary data associated with
this article can be found in the online version, at doi:10.1016/
j.tet.2007.08.030.
References and notes
The second eluate gave the recovered 25 (68 mg) (purity of
25¼ca. 80%).
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13a-methyldibenzo[f,h]pyrrolo[1,2-b]isoquinolin-11-one
(31). To a boiling solution of 30 (39.1 mg, 0.083 mmol) in

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