Iron(III) chloride-based mild synthesis of phenanthrene and its application to total synthesis of phenanthroindolizidine alkaloids

Article abstract of DOI:10.1016/j.tet.2008.06.003

Iron(III) chloride has been used to prepare polymethoxy-substituted phenanthrene-9-carboxylic acid via intramolecular oxidative coupling at room temperature in excellent yields. Mild reaction conditions and the use of environmentally friendly FeCl₃

Full text of DOI:10.1016/j.tet.2008.06.003

Tetrahedron 64 (2008) 7504–7510
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iron(III) chloride-based mild synthesis of phenanthrene and its application
to total synthesis of phenanthroindolizidine alkaloids
*
Kai-Liang Wang, Mao-Yun Lu¨, Qing-Min Wang , Run-Qiu Huang
State Key Laboratory of Elemento-Organic Chemistry, Tianjin Key Laboratory of Pesticide Science, Research Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Iron(III) chloride has been used to prepare polymethoxy-substituted phenanthrene-9-carboxylic acid via
intramolecular oxidative coupling at room temperature in excellent yields. Mild reaction conditions and
the use of environmentally friendly FeCl3 provide a novel practical route for the synthesis of the im-
portant phenanthrene ring. The further application of this protocol as the key step to total synthesis of
tylophorine, deoxytylophorinine, and antofine was achieved starting from readily available pyrrole in
48%, 44%, and 46% overall yields, respectively. This new and efficient strategy enjoys a number of ad-
vantages. The experimental procedure is simple under mild conditions, atom economy is very high
without any protecting-group, starting materials are cheap or easily prepared. Hence this short and
practical method is applicable to large-scale production.
Received 20 March 2008
Received in revised form 28 May 2008
Accepted 3 June 2008
Available online 6 June 2008
Keywords:
Iron (III) chloride
Oxidative coupling
Phenanthrene ring system
Total synthesis
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
first synthesis of phenanthrene core in 1896 via an arenediazonium
salt to effect intramolecular coupling,6 and the Pschorr reaction has
Phenanthroindolizidine alkaloids isolated mainly from Cyn-
anchum, Pergularia, Tylophora, and some genera of the Asclepiada-
ceae family exhibit interesting biological activities and
pharmacological properties,1 among which antitumor activity is
most notable.2 We have found that (ꢀ)-antofine (3) (Fig. 1) from
Cynanchum komarovii possesses excellent antiviral activity against
the tobacoo mosaic virus (TMV).3 As a consequence of their ex-
ceptional bioactivity and unusual pentacyclic architecture, together
with very low natural abundance, many synthetic studies have
been made on phenanthroindolizidine alkaloids and their deriva-
tives.1b,4 As part of our ongoing program aimed at screening plants
for biologically active natural products as alternatives to conven-
tional synthetic agrochemicals, we have recently focused on the
synthesis of phenanthroindolizidine alkaloids and developed three
different synthetic approaches to (þ)-tylophorine (1), (þ)-deoxy-
tylophorinine (2), and 2,3,6,7-tetramethoxyphenanthro[9,10,30,40]-
indolizidine (4) (Fig. 1).5 But these reported approaches were not
suitable for large-scale preparation due to low yield, harsh condi-
tions or long steps.
been widely used and become a classical method to synthesize
phenanthrene ring system.7 But the long linear sequence and low
overall yields restrict the practical application of this method.
Subsequently, a number of alternative methods have been de-
veloped to synthesize the phenanthrene ring system.1b,1c,4 Spe-
cially, intramolecular oxidative coupling to yield phenanthrene ring
system using oxidative coupling reagents such as thallium(III) tri-
flouroacetate (TTFA),8 lead(IV) tetraacetate (Pb(OAc)4),9 phenyl-
iodine(III) bis(trifluoroacetate) (PIFA) and phenyliodine(III)
diacetate (PIDA).10 Among them vanadium oxytrifluoride
(VOF3)4g,11 has attracted more and more attention. However, ex-
tensive application of these reagents has been limited by high
toxicity, severe conditions, and low yields. We have recently
reported the use of vanadium oxytrichloride (VOCl3) for the syn-
thesis of polymethoxy-substituted phenanthrene derivatives by
oxidative coupling of substituted methyl (E)-a
-phenyl cinnamate.12
Despite that we decrease the loading of the oxidant and increase
the yield, broad scope of synthesis has been limited by severe
conditions and side reactions. In addition, there was an example of
using iron(III) complex and some iron(III) solvates for oxidative
aryl–aryl coupling reactions,13 but the preparation of the complex
was usually troubled and the yield was moderate. Therefore, an
improved method for the synthesis of the phenanthrene ring sys-
tem needs to be explored.
The synthesis of polymethoxy-substituted phenanthrene unit is
the key step in the preparation of these alkaloids.1b,1c,4 Therefore,
development of an effective protocol to access polymethoxy-
substituted phenanthrenes is noteworthy. Pschorr proposed the
Iron(III) chloride is extensively used in organic synthesis in re-
cent years since it is an inexpensive, environmentally friendly, and
strong oxidizing agent for several useful reactions such as
* Corresponding author. Tel./fax: þ86 (0)22 23499842.
E-mail address: wangqm@nankai.edu.cn (Q.-M. Wang).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.003

K.-L. Wang et al. / Tetrahedron 64 (2008) 7504–7510
7505
R1
OMe
OMe
MeO
MeO
MeO
R1 = R2 = OMe, tylophorine (1)
(4)
R1 = H, R2 = OMe, deoxytylophorinine (2)
N
N
R1 = OMe, R2 = H, antofine (3)
MeO
R2
Figure 1. Structures of alkaloids (1), (2), (3), and their analogue (4).
polymerizations and oxidations.14,15 For example, binaphthols and
polycyclic arenes have been synthesized through FeCl3-mediated
oxidative couplings.16 We found that construction of phenan-
threne-9-carboxylate from 2,3-diphenylacrylate was achieved by
intramolecular oxidative coupling using iron(III) chloride in excel-
lent yield.17
in the presence of FeCl3 at room temperature in 87% yield. In
contrast to the Pschorr synthesis of phenanthrene, the reaction
makes full use of the minor (Z)-isomer 7a, which was a byproduct
in the Pschorr reaction. This facile and efficient synthesis of the
oxidative coupling product 8a has been applicable to large-scale
production.
Herein, we wish to report a facile synthesis of polymethoxy-
substituted phenanthrene-9-carboxylic acid by using FeCl3 at room
temperature with excellent yield and its further application to the
total synthesis of the representative phenanthroindolizidine alka-
loids, tylophorine, deoxytylophorinine, and antofine.
With a large amount of carboxylic acid 8a in hand, we use in-
termolecular Friedel–Crafts acylation of the corresponding acyl-
chloride (prepared by chlorination of acid 8a with oxalyl chloride)
and pyrrole catalyzed by tin tetrachloride (SnCl4) to construct
pyrrolidine ring system 9a under mild conditions in 79% yield. As
expected, pyrrole is an electron-rich aromatic heterocycle, which
has stronger electrophilic substitution reaction ability than furan,
thiophene, and free benzene ring. This synthesis is very straight
forward but unspectacular during the total synthesis of phenan-
throindolizidine alkaloids.
2-Acylpyrrole 9a was transformed to the corresponding
2-alkylpyrrole 11a by using sodium borohydride in boiling 2-
propanol19 with 94% yield. Subsequent catalytic hydrogenation20 of
11a in acetic acid gave a quantitative yield of pyrrolidine 10a. Fi-
nally, the Pictet–Spengler cyclomethylenation of 10a afforded the
racemic tylophorine 1 in 95% yield.4h Thus, the shortest synthetic
route to a large-scale preparation of tylophorine 1 was achieved
starting from readily available pyrrole under mild conditions free of
any protecting-group in 48% overall yield. We have used the route
and synthesized 200 g of tylophorine for testing against TMV.
Having demonstrated the feasibility of the above synthetic
pathway to tylophorine 1, we then turned our attention to the
preparation of deoxytylophorinine 2 and antofine 3 (Scheme 3).
Deoxytylophorinine 2 and antofine 3 have been synthesized on
a large scale in 44% and 46% overall yields, respectively, in six steps
such as Perkin condensation of the appropriate benzeneacetic acids
5b,c and the corresponding aromatic aldehydes 6b,c, intramolecular
oxidative coupling of acids 7b,c in the presence of FeCl3, chlorination
of acids 8b,c, and subsequent intermolecular Friedel–Crafts re-
actions with pyrrole in one pot, deketonization of 2-acylpyrroles
9b,c, catalytic hydrogenation of 2-alkylpyrroles 11b,c, and Pictet–
Spengler cyclomethylenation of pyrrolidines 10b,c.
2. Results and discussion
The E- and Z-2,3-diphenylacrylic acid 7 are easily available from
Perkin condensation of the appropriate benzeneacetic acid 5 with
the corresponding aromatic aldehyde 6 as shown in Scheme 1 (R1,
R2¼OMe, H).11a,12,18 We found that such condensations invariably
yield a mixture of E-isomer as the main product and Z-isomer as the
minor product. For example, Perkin condensation of 3,4-dime-
thoxyphenylacetic acid with 3,4-dimethoxybenzadehyde provided
(E)-methyl 2,3-bis(3,4-dimethoxyphenyl)acrylic acid E-7a, at the
same time, (Z)-methyl 2,3-bis(3,4-dimethoxyphenyl)acrylic acid Z-
7a as a minor product. Compounds E-7a and Z-7a can be obtained,
respectively, by precipitation at different pH.11a,18
Construction of phenanthrene-9-carboxylic acid 8 from the
mixture of E- and Z-2,3-diphenylacrylic acid 7 was achieved by an
intramolecular oxidative coupling reaction using iron(III) chloride
at room temperature in excellent yield for the first time. Hence, by
using this facile and efficient protocol as the key step, we explored
a practical synthetic route for the large-scale preparation of the
phenanthroindolizidine alkaloids tylophorine 1 (R1¼R2¼OMe),
deoxytylophorinine 2 (R1¼H, R2¼OMe), and antofine 3 (R1¼OMe,
R2¼H) from pyrrole as shown in Scheme 2.
Tylophorine 1 was chosen as our initial target since its simplicity
would allow us to test the feasibility of the approach (Scheme 3).
The key intermediate for our synthesis was the known carboxylic
acid 8a, which was obtained from the commercially available
homoveratric acid 5a and veratraldehyde 6a. Perkin con-
densation11a,18 of acid 5a with aldehyde 6a gave mainly (E)-isomer
7a and (Z)-isomer 7a as a separable mixture (82%, 10:1 E/Z) by re-
crystallization from methanol. Interestingly, not only (E)-isomer 7a
but also (Z)-isomer 7a gave the same oxidative coupling product 8a
3. Conclusion
In summary, iron(III) chloride has been applied to prepare
polymethoxy-substituted phenanthrene-9-carboxylic acid via
R1
R1
CO2H
MeO
MeO
MeO
CHO
CO2H
CO2H
FeCl3 (s) (3.5equiv)
Ac2O, Et3N
reflux, 24h
81~83%
+
CH2Cl2, r.t, N2
82~87%
R1
R2
OMe
OMe
MeO
5
6
R2
R2
7
8
Scheme 1. Synthesis of the compounds 7 and 8.

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K.-L. Wang et al. / Tetrahedron 64 (2008) 7504–7510
R1
R1
MeO
MeO
O
Pictet-Spengler
annulation
N
H
1, 2, 3
HN
HN
Friedel-Crafts
reaction
MeO
MeO
R2
R2
10
9
R1
R1
R1
MeO
Perkin condensation
MeO
MeO
MeO
5
O
O
O
Oxidative coupling
OH
OH
OH
+
CHO
MeO
MeO
6
R2
R2
R2
8
7
Scheme 2. Retrosynthetic analysis of phenanthroindolizidine alkaloids 1, 2, and 3.
intramolecular oxidative coupling at room temperature in excellent
yield. This reaction utilizes environmentally friendly oxidant FeCl3
and can be carried out in one step under simple and mild condi-
tions. And it is suitable for large-scale synthesis of phenanthrene
derivatives. By using this facile and efficient protocol as the key
step, we have developed the shortest, practical, green, and modular
route to naturally occurring phenanthroindolizidine alkaloids. The
versatility and flexibility of the method have been demonstrated by
the large-scale preparations of three representative phenan-
throindolizidine alkaloids, tylophorine, deoxytylophorinine, and
antofine in 48%, 44% and 46% overall yields, respectively. This new
and efficient strategy enjoys a number of advantages of which the
experimental procedure is simple under mild conditions, atom
economy is very high without any protecting-group, starting ma-
terials are cheap or easily prepared. Hence this shortest and prac-
tical method is applicable to large-scale production.
4. Experimental
4.1. General
The melting points were determined on an X-4 binocular mi-
croscope melting point apparatus (Beijing Tech Instruments Co.,
Beijing, China) and were uncorrected. 1H NMR spectra were
R1
R1
CHO
MeO
MeO
R1
MeO
MeO
O
O
MeO
O
Ac2O, Et3N
reflux, 20h
FeCl3, CH2Cl2
r. t
MeO
OH
OH
+
R2
6a-c
OH
5a-c
a
R1 = R2 = OMe
R1 = H, R2 = OMe
R1 = OMe, R2 = H
87%
a
b
c
a
b
c
82% (E/Z, 10:1)
81% (E/Z, 4:1)
83% (E/Z, 3:1)
b
82%
R2
R2
8a-c
c
84%
7a-c
R1
R1
MeO
MeO
MeO
O
1. (COCl)2, DMF(cat)
reflux 3 h
NaBH4, i-PrOH
reflux, 15 h
H2 (90 - 100 atm)
10% Pd - C, AcOH
2. Pyrrole, SnCl4, CH2Cl2
0 °C to r. t
HN
HN
a
94%
a
a
79%
95%
MeO
b
93%
b
c
77%
75%
b
c
96%
97%
R2
9a-c
R2
11a-c
c
96%
R1
R1
MeO
MeO
MeO
MeO
HCHO, HCl, EtOH
reflux, 15 h
1 tylophorine R1 = R2 = OMe
2 deoxytylophorinine R1 = H, R2 = OMe
3 antofine
1 = OMe, R2 = H
HN
N
R
a
95%
b
97%
R2
R2
c
95%
10a-c
Scheme 3. Synthesis of tylophorine (1), deoxytylophorinine (2), and antofine (3).

K.-L. Wang et al. / Tetrahedron 64 (2008) 7504–7510
7507
obtained using a Bruker AC-P 300 and a Varian Mercury Plus
400 MHz spectrometer. Chemical shift values ( ) are given in parts
per million and were downfield from internal tetramethylsilane. 13
NMR spectra were recorded using a Bruker AC-P 300 (75 MHz) and
a Varian Mercury Plus 400 spectrometer (100 MHz) using CDCl3 or
washed with methanol (3ꢁ30 mL) again to give acid 8a (20.8 g,
d
87%) as a light yellow solid. Mp 285–287 ꢂC (lit.24 mp 280–282 ꢂC);
C
1H NMR (300 MHz, DMSO)
d
8.58 (s, 1H), 8.43 (s, 1H), 8.03 (s, 1H),
7.99 (s,1H), 7.54 (s,1H), 4.08 (s, 3H), 4.07 (s, 3H), 3.94 (s, 3H), 3.93 (s,
3H); 13C NMR (75 MHz, DMSO)
169.0, 151.0, 148.8, 148.7, 129.6,
d
DMSO-d6 as a solvent. Chemical shift values (
d
) are reported in parts
126.4, 124.9, 124.1, 123.4, 122.8, 109.5, 106.8, 103.9, 103.4, 55.9, 55.8,
55.5, 55.2.
per million from the solvent peak (77.0 ppm). IR spectra were
recorded with an EQUINOX FTIR (Bruker Company) spectrometer.
Mass spectra were obtained on a VG ZAB-HS instrument spec-
trometer using the EI method and LCQ Advantage instrument
spectrometer using the ESI method. HRMS was obtained on FT-ICR
MS (Ionspec, 7.0T). All anhydrous solvents were dried and purified
by standard techniques just before use. FeCl3 is commercially
available from J&K Chemical Ltd. and it was used without further
purification.
4.6. Preparation of 2,3,6-trimethoxyphenanthrene-9-
carboxylic acid (8b)
To a solution of the mixture of E/Z isomer 7b (15.7 g, 0.05 mol) in
CH2Cl2 (500 mL) was added anhydrous FeCl3 (28.4 g, 0.17 mol). The
reaction solution was stirred at room temperature for 8 h, the
mixture was concentrated, and the residue was washed with ethyl
ether (200 mL), filtered, washed with ethyl ether (3ꢁ30 mL) again
to give acid 8b (12.8 g, 82%) as a light yellow solid. Mp 221–223 ꢂC
4.2. Preparation of 2,3-bis(3,4-dimethoxyphenyl)acrylic
acid (7a)
(lit.25 mp 220–221 ꢂC); 1H NMR (300 MHz, DMSO)
d 8.87 (dd,
4JHH¼1.2 Hz, 3JHH¼9.3 Hz, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 7.10 (s, 1H),
A mixture of homoveratric acid 5a (98.0 g, 0.5 mol), vera-
traldehyde 6a (90.0 g, 0.54 mol), acetic anhydride (200 mL), and
triethylamine (100 mL) was heated at reflux for 20 h with the ex-
clusion of moisture. The solution was allowed to cool to room
temperature, water (400 mL) was added, and the mixture was
stirred for 1 h. The mixture was then poured into aqueous potas-
sium carbonate (350.0 g in 800 mL water) and refluxed until nearly
all the gummy material was dissolved. The solution obtained was
cooled, extracted with ether (3ꢁ120 mL), and carefully acidified
with concentrated hydrochloric acid (pH 4w5) to produce a white
precipitate. The solid was collected and washed with methanol
(400 mL) to give 2,3-bis(3,4-dimethoxyphenyl)acrylic acid 7a
(141.0 g, 82%) as a mixture of E/Z isomer (10:1). The solid was col-
lected and recrystallized from methanol to give E-2,3-bis(3,4-
dimethoxyphenyl)acrylic acid 7a as a white solid (118.7 g, 69%). Mp
214–216 ꢂC (lit.21 mp 216–217 ꢂC); 1H NMR (400 MHz, DMSO)
4
3
7.60 (s, 1H), 7.30 (dd, JHH¼1.8 Hz, JHH¼9.3 Hz, 1H), 4.07 (s, 3H),
4.01 (s, 3H), 3.93 (s, 3H); 13C NMR (75 MHz, DMSO)
d 168.9, 157.8,
150.9, 149.6, 131.4, 128.9, 127.9, 126.0, 125.2, 124.0, 122.7, 116.1,
109.6, 104.5, 103.9, 56.0, 55.6, 55.4.
4.7. Preparation of 2,3,6-trimethoxyphenanthrene-10-
carboxylic acid (8c)
By following the same procedure as for 8b gave 8c as a light
yellow solid (84%). Mp 210–212 ꢂC (lit.26 mp 215 ꢂC); 1H NMR
(300 MHz, DMSO)
d 13.0 (br, 1H), 8.58 (s, 1H), 8.45 (s, 1H), 8.14 (s,
4
3
1H), 8.10 (d, JHH¼2.1 Hz, 1H), 8.03 (d, JHH¼9.0 Hz, 1H), 7.28 (dd,
3
4JHH¼2.1 Hz, JHH¼8.7 Hz, 1H), 4.06 (s, 3H), 4.04 (s, 3H), 3.92
(s, 3H).
d
12.50 (br, 1H), 7.68 (s, 1H), 6.54–6.98 (m, 6H), 3.74 (s, 3H), 3.69 (s,
3H), 3.66 (s, 3H), 3.45 (s, 3H).
4.8. Preparation of (2,3,6,7-tetramethoxyphenanthren-9-
yl)(1H-pyrrol-2-yl)methanone (9a)
4.3. Preparation of 2-(4-methoxyphenyl)-3-(3,4-dimethoxy-
phenyl)acrylic acid (7b)
To acid 8a (6.84 g, 0.02 mol) was added dropwise freshly dis-
tilled oxalyl chloride (50 mL, 0.58 mol) and dimethylformamide
(two drops) at 0 ꢂC. The reaction mixture was then stirred at room
temperature for 1 h and refluxed for 3 h. The excess of oxalyl
chloride was removed under reduced pressure, the residue was
dissolved in dry CH2Cl2 (150 mL) at 0 ꢂC, and a solution of anhy-
drous SnCl4 (2.8 mL, 0.024 mol) in CH2Cl2 (30 mL) was added
slowly under N2. The mixture was stirred at 0 ꢂC for 0.5 h, and
a solution of freshly distilled pyrrole (1.87 g, 0.028 mol) in CH2Cl2
(50 mL) was slowly added to the mixture and warmed to room
temperature for 10 h, and quenched with 5% dilute hydrochloric
acid (100 mL). The mixture was filtered on Celite and washed with
CH2Cl2 (3ꢁ30 mL), the organic phase was washed successively with
10% aqueous Na2CO3 (30 mL), water, and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (CH2Cl2/EtOAc, 10:1 v/v) to
obtain acylpyrrole 9a (6.17 g, 79%) as a light yellow solid. Mp 258–
By following the same procedure as for 7a gave 7b as a mixture
of E/Z isomer (4:1) in 81% yield. The solid was recrystallized from
methanol to give E-2-(4-methoxyphenyl)-3-(3,4-dimethoxy-
phenyl)acrylic acid 7b as a white solid in 67% yield. Mp 208–210 ꢂC
(lit.22 mp 213–214 ꢂC); 1H NMR (400 MHz, DMSO)
d 12.55 (br, 1H),
7.69 (s, 1H), 6.54–7.12 (m, 7H), 3.78 (s, 3H), 3.72 (s, 3H), 3.37 (s, 3H).
4.4. Preparation of 2-(3,4-dimethoxyphenyl)-3-(4-methoxy-
phenyl)acrylic acid (7c)
By following the same procedure as for 7a gave 7c as a mixture
of E/Z isomer (3:1) in 83% yield. The mixture was recrystallized
from methanol to give E-2-(3,4-dimethoxyphenyl)-3-(4-methoxy-
phenyl)acrylic acid 7c as a white solid in 66% yield. Mp 210–212 ꢂC
(lit.23 mp 207–208 ꢂC); 1H NMR (400 MHz, DMSO)
d 12.48 (br, 1H),
7.71 (s, 1H), 6.70–7.09 (m, 7H), 3.80 (s, 3H), 3.72 (s, 3H), 3.68 (s, 3H).
260 ꢂC; 1H NMR (300 MHz, CDCl3)
d 9.83 (br, 1H), 7.97 (s, 1H), 7.81–
7.84 (m, 3H), 7.25 (s, 1H), 7.20–7.21 (m, 1H), 6.83–6.84 (m, 1H),
6.34–6.36 (m, 1H), 4.16 (s, 3H), 4.14 (s, 3H), 4.03 (s, 3H), 3.98 (s, 3H);
4.5. Preparation of 2,3,6,7-tetramethoxyphenanthrene-9-
carboxylic acid (8a)
13C NMR (100 MHz, CDCl3)
d 186.7, 150.9, 149.6, 149.3, 133.1, 131.9,
127.7, 126.2,125.7,125.4,124.8,123.9,120.1,111.2, 109.3,106.7, 103.0,
102.9, 56.3, 56.2, 56.1, 56.0; IR (KBr, cmꢀ1) 3313, 3296, 3093, 2294,
1619, 1508, 1468, 1427, 1375, 1319, 1254, 1157, 1105, 781, 750, 608,
531; MS (EI) m/z 391 (Mþ, 42), 360 (2), 196 (5), 94 (10), 44 (18), 28
(100); HRMS (ESI) m/z calcd for C23H22NO5 [MþH]þ 392.1493,
found 392.1493.
To a solution of the mixture of E/Z isomer 7a (24.1 g, 0.07 mol) in
CH2Cl2 (600 mL) was added anhydrous FeCl3 (39.8 g, 0.25 mol). The
reaction solution was stirred at room temperature for 8 h, and then
quenched with methanol (150 mL). The mixture was concentrated
and the residue was washed with methanol (200 mL), filtered,

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K.-L. Wang et al. / Tetrahedron 64 (2008) 7504–7510
4.9. Preparation of (2,3,6-trimethoxyphenanthren-9-yl)(1H-
4.13. Preparation of 2-((2,3,6-trimethoxyphenanthren-10-
pyrrol-2-yl)methanone (9b)
yl)methyl)-1H-pyrrole (11c)
By following the same procedure as for 9a gave 9b as a white
By following the same procedure as for 11a gave 11c as a white
solid (77%). Mp 244–246 ꢂC; 1H NMR (300 MHz, DMSO)
d
12.25 (br,
solid (96%). Mp 184–185 ꢂC; 1H NMR (300 MHz, CDCl3)
d 7.85 (s,
1H), 8.08–8.19 (m, 3H), 7.94 (s, 1H), 7.60 (s, 1H), 7.25–7.30 (m, 2H),
1H), 7.80 (d, 4JHH¼2.4 Hz, 1H), 7.72 (d, 3JHH¼8.7 Hz, 1H), 7.45 (s, 1H),
6.68 (d, 4JHH¼1.2 Hz, 1H), 6.27 (d, 4JHH¼1.8 Hz, 1H), 4.10 (s, 3H), 4.03
7.38 (s, 1H), 7.18 (dd, JHH¼2.4 Hz, JHH¼8.7 Hz, 1H), 6.57–6.59 (m,
4
3
(s, 3H), 3.94 (s, 3H); 13C NMR (75 MHz, DMSO)
d
185.3, 158.0, 150.3,
1H), 6.14–6.17 (m, 2H), 4.38 (s, 2H), 4.07 (s, 3H), 4.00 (s, 3H), 3.88 (s,
149.7, 132.9, 132.4, 131.3, 127.5, 126.7, 125.4, 125.3, 124.9, 122.6,
119.7,115.9,110.2,109.5,104.6,104.0, 56.0, 55.5; IR (KBr, cmꢀ1) 3361,
3332, 3107, 2926, 2831, 1612, 1510, 1452, 1416, 1373, 1315, 1285,
1256, 1196, 1162, 1104, 1075, 1024, 981, 835, 763, 683; MS (ESI) m/z
761 [2MþK]þ; HRMS (ESI) m/z calcd for C22H19NO4Na [MþNa]þ
384.1206, found 384.1212.
3H); 13C NMR (75 MHz, DMSO)
d 157.7, 149.0, 148.6, 131.4, 130.1,
129.8, 129.5, 126.2, 125.5, 124.4, 116.5, 115.7, 107.3, 105.9, 105.5,
104.7, 104.1, 55.9, 55.5, 55.4, 31.7; IR (KBr, cmꢀ1) 3396, 2998, 2824,
1605, 1503, 1452, 1423, 1235, 1208, 1148, 1119, 1017, 865, 785, 712,
523; MS (ESI) m/z 346 [MꢀH]ꢀ; HRMS (ESI) m/z calcd for
C
22H22NO3 [MþH]þ 348.1594, found 348.1593.
4.10. Preparation of (2,3,6-trimethoxyphenanthren-10-
yl)(1H-pyrrol-2-yl)methanone (9c)
4.14. Preparation of 2-((2,3,6,7-tetramethoxyphenanthren-9-
yl)methyl)pyrrolidine (10a)
By following the same procedure as for 9a gave 9c as a light
The mixture of 11a (4.9 g, 0.013 mol), acetic acid (350 mL), and
10% Pd–C (1.5 g) was shaken under hydrogen at a pressure of 90–
100 atm for 12 h. The mixture was filtered, and the filtrate was
evaporated to dryness in vacuo. The residue was dissolved in H2SO4
(2 N, 200 mL) at 0 ꢂC and washed with ether (60 mL). The acid layer
was cooled and made alkaline with aqueous NaOH to pHw12, and
then extracted with chloroform (2ꢁ150 mL), dried over Na2SO4,
filtered, and concentrated in vacuo to give amine 10a (4.70 g, 95%)
as a white solid. Mp 155–157 ꢂC (lit.28 mp 152 ꢂC); 1H NMR
yellow solid (75%). Mp 182–184 ꢂC; 1H NMR (300 MHz, CDCl3)
d
10.00 (br, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.82–7.87 (m, 3H), 7.18–
7.24 (m, 2H), 6.81–6.84 (m, 1H), 6.32–6.35 (m, 1H), 4.12 (s, 3H), 4.04
(s, 3H), 3.98 (s, 3H); 13C NMR (75 MHz, DMSO)
185.3, 159.4, 149.4,
d
149.2,132.4,131.8,131.4,131.2,127.0,126.7,124.6, 124.2,123.8,119.6,
116.3,110.2, 106.3,104.5,104.2, 55.9, 55.6, 55.2; IR (KBr, cmꢀ1) 3296,
3223, 3107, 2908, 2940, 2831, 1605, 1510, 1460, 1416, 1380, 1315,
1264, 1097, 1024, 886, 865, 748, 596; MS (ESI) m/z 362 [MþH]þ, 745
[2MþNa]þ; HRMS (ESI) m/z calcd for C22H20NO4 [MþH]þ 362.1387,
found 362.1389.
(300 MHz, CDCl3) d 7.83 (s, 1H), 7.76 (s, 1H), 7.47 (s, 1H), 7.43 (s, 1H),
7.18 (s, 1H), 4.12 (s, 3H), 4.11 (s, 3H), 4.05 (s, 3H), 4.02 (s, 3H), 3.45–
3.55 (m, 1H), 3.05–3.22 (m, 3H), 2.82–2.90 (m, 1H), 1.70–1.95 (m,
4.11. Preparation of 2-((2,3,6,7-tetramethoxyphenanthren-9-
yl)methyl)-1H-pyrrole (11a)
3H), 1.47–1.60 (m, 1H); 13C NMR (75 MHz, DMSO)
d
149.1, 149.0,
148.75, 148.7, 128.7, 125.6, 124.8, 124.7, 124.4, 123.7, 108.2, 104.8,
104.6, 103.8, 59.0, 56.0, 55.4, 44.1, 34.8, 29.6, 22.7; IR (KBr, cmꢀ1
)
A mixture of 9a (5.87 g, 0.015 mol), sodium borohydride (3.42 g,
0.09 mol), and 2-propanol (500 mL) was refluxed under nitrogen
for 15 h. The solution was concentrated under reduced pressure,
diluted with methylene chloride (200 mL) and water (50 mL),
acidified with 10% hydrochloric acid (pHw6). The organic phase
was washed with water (2ꢁ50 mL), brine (2ꢁ50 mL), dried over
MgSO4, and filtered. The filtrate was concentrated under reduced
pressure, and the residue was purified by flash column chroma-
tography on silica gel to obtain 11a (5.32 g, 94%) as a white solid. Mp
3400, 2955, 2831, 1612, 1510, 1467, 1416, 1358, 1242, 1198, 1140,
1031, 981, 843, 763, 523; MS (ESI) m/z 382 [MþH]þ, 745 [2MþH]þ;
HRMS (ESI) m/z calcd for C23H28NO4 [MþH]þ 382.2013, found
382.2009.
4.15. Preparation of 2-((2,3,6-trimethoxyphenanthren-9-
yl)methyl)pyrrolidine (10b)
By following the same procedure as for 10a gave 10b as a white
220–222 ꢂC (lit.20a mp 212 ꢂC); 1H NMR (300 MHz, CDCl3)
d
8.02 (br,
solid (96%). Mp 143–145 ꢂC (lit.27 mp 140 ꢂC); 1H NMR (300 MHz,
1H), 7.70 (s, 1H), 7.66 (s, 1H), 7.35 (s, 1H), 7.34 (s, 1H), 7.09 (s, 1H),
6.62–6.63 (m, 1H), 6.16–6.18 (m, 2H), 4.36 (s, 2H), 4.05 (s, 6H), 3.96
CDCl3)
d
8.02 (d, 3JHH¼9.0 Hz, 1H), 7.87 (d, 4JHH¼2.4 Hz, 1H), 7.81 (s,
1H), 7.39 (s, 1H), 7.18–7.22 (m, 1H), 7.15 (s, 1H), 4.07 (s, 3H), 4.00 (s,
3H), 3.99 (s, 3H), 3.40–3.50 (m, 1H), 3.14–3.17 (m, 2H), 3.02–3.09
(s, 3H), 3.88 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
149.0, 148.9, 148.6,
130.9, 130.1, 126.2, 125.5, 125.0, 124.8, 124.0, 116.9, 108.4, 108.1,
106.3, 105.1, 103.2, 102.8, 56.0, 55.9, 55.8, 55.7, 32.7; IR (KBr, cmꢀ1
(m, 1H), 2.75–2.84 (m, 1H), 1.65–1.90 (m, 4H), 1.45–1.55 (m, 1H); 13
C
)
NMR (75 MHz, CDCl3) d 157.8, 149.5, 148.7, 132.6, 131.6, 127.5, 126.2,
3376, 3267, 3006, 2904, 2831, 1612, 1510, 1460, 1431, 1249, 1191,
1140, 1031, 981, 828, 763, 712, 647, 581, 509; MS (EI) m/z 377 (Mþ,
100), 346 (6), 311 (8), 189 (10), 80 (7); HRMS (ESI) m/z calcd for
125.2, 124.1, 123.6, 114.8, 108.0, 104.6, 103.4, 59.1, 56.1, 55.8, 55.5,
46.2, 40.0, 31.7, 24.8; IR (KBr, cmꢀ1) 3296, 2955, 2926, 2853, 1721,
1605, 1510, 1460, 1431, 1293, 1249, 1206, 1155, 1119, 1082, 981, 821,
770, 690, 567, 523; MS (ESI) m/z 352 [MþH]þ; HRMS (ESI) m/z calcd
for C22H26NO3 [MþH]þ 352.1907, found 352.1912.
C
23H24NO4 [MþH]þ 378.1700, found 378.1702.
4.12. Preparation of 2-((2,3,6-trimethoxyphenanthren-9-
yl)methyl)-1H-pyrrole (11b)
4.16. Preparation of 2-((2,3,6-trimethoxyphenanthren-10-
yl)methyl)pyrrolidine (10c)
By following the same procedure as for 11a gave 11b as a white
solid (93%). Mp 218–220 ꢂC (lit.27 mp 203 ꢂC); 1H NMR (300 MHz,
By following the same procedure as for 10a gave 10c as a white
DMSO)
1H), 5.94–5.95 (m, 1H), 5.76–5.80 (m, 1H), 4.32 (s, 2H), 4.02 (s, 3H),
3.99 (s, 3H), 3.90 (s, 3H); 13C NMR (75 MHz, DMSO)
157.6, 149.4,
d
10.66 (s, 1H), 8.07–8.12 (m, 3H), 7.20–7.37 (m, 3H), 6.65 (s,
solid (97%). Mp 147–149 ꢂC (lit.4h mp 144–145 ꢂC); 1H NMR
(300 MHz, CDCl3)
d
7.69–7.74 (m, 2H), 7.60 (d, 4JHH¼1.5 Hz, 1H), 7.42
d
(s, 1H), 7.28 (s, 1H), 7.12 (dd, 4JHH¼2.1 Hz, 3JHH¼8.7 Hz, 1H), 4.06 (s,
3H), 4.01 (s, 3H), 3.90 (s, 3H), 3.72–3.78 (m, 1H), 3.46–3.51 (m, 1H),
3.21–3.33 (m, 2H), 1.86–2.10 (m, 5H); 13C NMR (75 MHz, CDCl3)
148.7,132.5,131.3,129.8,127.1,126.2,124.6,123.5,123.2,116.4,115.2,
108.2, 107.3, 105.9, 104.7, 104.3, 55.9, 55.4, 31.3; IR (KBr, cmꢀ1) 3376,
2933, 2831, 1612, 1503, 1460, 1431, 1285, 1249, 1184, 1148, 1119, 1017,
981, 879, 828, 785, 712, 589, 531; MS (ESI) m/z 346 [MꢀH]ꢀ; HRMS
(ESI) m/z calcd for C22H22NO3 [MþH]þ 348.1594, found 348.1595.
d
158.1, 149.8, 148.9, 130.7, 129.9, 127.5, 126.0, 125.6, 125.4, 124.6,
115.4, 104.4, 103.9, 103.7, 59.8, 56.7, 55.9, 55.4, 44.6, 35.7, 30.4, 23.2;
IR (KBr, cmꢀ1) 3412, 2962, 2752, 1605, 1518, 1460, 1380, 1271, 1206,

K.-L. Wang et al. / Tetrahedron 64 (2008) 7504–7510
7509
1148, 1111, 1066, 1024, 865, 828, 785, 573, 531; MS (ESI) m/z 352
Supplementary data
[MþH]þ; HRMS (ESI) m/z calcd for C22H26NO3 [MþH]þ 352.1907,
found 352.1910.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.06.003.
4.17. Preparation of ( )-tylophorine (1)
References and notes
To a solution of 10a (4.95 g, 0.013 mol) in EtOH (150 mL) were
added 37% formaldehyde (75 mL) and concentrated HCl (7.5 mL).
The reaction mixture was refluxed for 15 h in the dark. The reaction
mixture was concentrated to near dryness under reduced pressure.
The residue was dissolved in CH2Cl2 (300 mL) and washed with 1 N
NaOH (100 mL), water (50 mL), and brine (50 mL), dried over
MgSO4, filtered, and concentrated in vacuo to afford tylophorine (1)
(4.85 g, 95%) as a white solid. Mp 275–282 ꢂC dec (lit.29 mp 287 ꢂC
1. (a) Gellert, E. J. J. Nat. Prod. 1982, 45, 50–73; (b) Li, Z. G.; Jin, Z.; Huang, R. Q.
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542; (d) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603–626.
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dec); 1H NMR (300 MHz, CDCl3)
d 7.83 (s, 2H), 7.31 (s, 1H), 7.16 (s,
2
1H), 4.62 (d, JHH¼14.7 Hz, 1H), 4.11 (s, 6H), 4.05 (s, 6H), 3.66 (d,
2JHH¼14.7 Hz, 1H), 3.44–3.50 (m, 1H), 3.32–3.39 (m, 1H), 2.86–2.95
(m,1H), 2.41–2.50 (m, 2H), 2.17–2.30 (m,1H), 1.76–2.05 (m, 3H); 13
C
NMR (75 MHz, CDCl3) d 148.8, 148.6, 148.5, 126.4, 126.1, 125.9,124.4,
123.7, 123.5, 104.1, 103.6, 103.5, 103.3, 60.2, 56.1, 55.9, 55.8, 55.2,
54.1, 33.9, 31.3, 21.6; IR (KBr, cmꢀ1) 3400, 2966, 2919, 2788, 1612,
1510,1460,1423,1249,1191, 1140,1039,1010, 835, 763, 689, 516; MS
(ESI) m/z 394 [MþH]þ; HRMS (ESI) m/z calcd for C24H28NO4
[MþH]þ 394.2013, found 394.2015.
4.18. Preparation of ( )-deoxytylophorinine (2)
By following the same procedure as for tylophorine 1 gave 2 as
a light yellow solid (97%). Mp 250 ꢂC dec (lit.27 mp 252–254 ꢂC); 1H
5. (a) Jin, Z.; Li, S. P.; Wang, Q. M.; Huang, R. Q. Chin. Chem. Lett. 2004, 15, 1164–
1166; (b) Li, H.; Hu, T. S.; Wang, K. L.; Liu, Y. X.; Fan, Z. J.; Huang, R. Q.; Wang,
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R. Q. J. Org. Chem. 2007, 72, 8416–8421; (d) Cui, M. B.; Wang, K. L.; Wang, Q. M.;
Huang, R. Q. Lett. Org. Chem. 2008, 5, 98–102.
NMR (400 MHz, CDCl3)
d 7.87–7.94 (m, 3H), 7.19–7.22 (m, 1H), 7.13
(s, 1H), 4.58 (d, 2JHH¼14.8 Hz, 1H), 4.09 (s, 3H), 4.05 (s, 3H), 4.00 (s,
2
3H), 3.61 (d, JHH¼14.8 Hz, 1H), 3.37–3.48 (m, 2H), 2.88–2.94 (m,
6. Pschorr, R. Chem. Ber. 1896, 29, 496–501.
1H), 2.40–2.46 (m, 2H), 2.17–2.25 (m, 1H), 1.67–2.05 (m, 3H); 13C
7. (a) Bradsher, C. K.; Berger, H. J. Am. Chem. Soc. 1957, 79, 3287–3288; (b) Go-
vindachari, T. R.; Pai, B. R.; Prabhakar, S.; Savitri, T. S. Tetrahedron 1965, 21,
2573–2578; (c) Floyd, A. J.; Dyke, S. F.; Ward, S. E. Chem. Rev. 1976, 76, 509–562;
(d) Duclos, R. I.; Tung, J. S.; Rapoport, H. J. Org. Chem. 1984, 49, 5243–5246; (e)
Karady, S.; Abramson, N. L.; Dolling, U.-H.; Douglas, A. W.; McManemin, G. J.;
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Zhang, R. Chem. Commun. 2001, 2656–2657; (g) Chandler, S. A.; Hanson, P.;
Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc., Perkin Trans. 2 2001, 214–
228.
8. (a) Taylor, E. C.; Andrade, J. G.; Rall, G. J. H.; Mckillop, A. J. Am. Chem. Soc. 1980,
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Chem. Soc. 1980, 102, 6504–6512; (c) Bringmann, G.; Walter, R.; Weirich, R.
Angew. Chem., Int. Ed. Engl. 1990, 29, 977–991.
NMR (75 MHz, CDCl3) d 157.6, 149.4, 148.3, 130.4, 127.0, 125.6, 125.5,
125.3, 125.1, 123.4, 114.8, 104.6, 104.1, 103.2, 60.1, 56.0, 55.9, 55.5,
55.1, 53.9, 33.6, 31.3, 21.6; IR (KBr, cmꢀ1) 3419, 2940, 2868, 2766,
1605, 1503, 1467, 1409, 1249, 1206, 1149, 1031, 821, 777, 589, 509;
MS (ESI) m/z 364 [MþH]þ; HRMS (ESI) m/z calcd for C23H26NO3
[MþH]þ 364.1907, found 364.1903.
4.19. Preparation of ( )-antofine (3)
9. Feldman, K. S.; Ensel, S. M. J. Am. Chem. Soc. 1994, 116, 3357–3366.
10. (a) Kita, Y.; Gyoten, M.; Ohtsubo, M.; Tohma, H.; Takada, T. Chem. Commun.
1996, 1481–1482; (b) Takada, T.; Arisawa, M.; Gyoten, M.; Hamada, R.; Tohrma,
H.; Kita, Y. J. Org. Chem. 1998, 63, 7698–7706; (c) Olivera, R.; Sanmartin, R.;
Pascual, S.; Herrero, M.; Dominguez, E. Tetrahedron Lett. 1999, 40, 3479–3480;
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2001, 57, 345–352; (e) Hamamoto, H.; Shiozaki, Y.; Nambu, H.; Hata, K.; Tohma,
H.; Kita, Y. Chem.dEur. J. 2004, 10, 4977–4982; (f) Dohi, T.; Maruyama, A.;
Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem., Int. Ed. 2005, 44,
6193–6196; (g) Dohi, T.; Maruyama, A.; Minamitsuji, Y.; Takenage, N.; Kita, Y.
Chem. Commun. 2007, 1224–1226.
By following the same procedure as for tylophorine 1 gave 3 as
a light yellow solid (97%). Mp 210 ꢂC dec (lit.4c mp 212–214 ꢂC); 1H
NMR (400 MHz, CDCl3)
d
7.91 (s, 1H), 7.90 (d, 4JHH¼2.0 Hz, 1H), 7.82
(d, 3JHH¼8.8 Hz, 1H), 7.31 (s, 1H), 7.20 (dd, 4JHH¼2.4 Hz, 3JHH¼9.2 Hz,
1H), 4.69 (d, 2JHH¼14.8 Hz, 1H), 4.11 (s, 3H), 4.06 (s, 3H), 4.02 (s, 3H),
2
3.69 (d, JHH¼14.8 Hz, 1H), 3.44–3.49 (m, 1H), 3.32–3.37 (m, 1H),
2.86–2.93 (m, 1H), 2.42–2.50 (m, 2H), 2.20–2.27 (m, 1H), 1.86–2.05
(m, 2H), 1.74–1.80 (m, 1H); 13C NMR
d 157.5, 149.4, 148.4, 130.2,
11. (a) Halton, B.; Maidment, A. I.; Officer, D. L.; Warner, J. M. Aust. J. Chem. 1984, 37,
2119–2128; (b) Evans, D. A.; Dinsmore, C. J.; Evrard, D. A.; DcVries, K. M. J. Am.
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457–476.
127.1, 126.7, 125.6, 124.2, 124.1, 123.5, 114.8, 104.7, 104.1, 104.0, 60.2,
56.0, 55.9, 55.5, 55.1, 53.9, 33.7, 31.3, 21.6; IR (KBr, cmꢀ1) 3419,
2955, 2911, 2617, 2788, 1612, 1510, 1467, 1416, 1255, 1213, 1169,
1133, 1039, 995, 828, 770, 596, 516; MS (ESI) m/z 364 [MþH]þ;
HRMS (ESI) m/z calcd for C23H26NO3 [MþH]þ 364.1907, found
364.1902.
16. (a) Jempty, T. C.; Miller, L. L.; Mazur, Y. J. Org. Chem. 1980, 45, 749–751; (b)
Jempty, T. C.; Gogins, K. A. Z.; Mazur, Y.; Miller, L. L. J. Org. Chem. 1981, 46, 4545–
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845–846; (f) Boden, N.; Bushby, R. J.; Cammidge, A. N.; Headdock, G. Synthesis
1995, 31–32; (g) Sartori, G.; Maggi, R.; Bigi, F.; Arienti, A.; Mori, G. J. Chem. Res.,
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Acknowledgements
We thank the National Key Project for Basic Research
(2003CB114404) and the National Natural Science Foundation of
China (20472039) and the Key Project of Chinese Ministry of Edu-
cation (106046).

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