Asymmetric Total Synthesis of Tylophorine through a Formal [2+2] Cycloaddition Followed by Migrative Ring Opening of a Cyclobutane

Article abstract of DOI:10.1055/s-0034-1380430

The asymmetric total synthesis of phenanthroindolizidine alkaloid (-)-tylophorine was achieved by asymmetric transfer hydrogenation of a cyclic imine. The cyclic imine with a pendant phenanthrene core was synthesized by a TfOH-promoted domino ring-contraction/ring-opening sequence of a cyclobutanol bearing an azide group, which was constructed by a formal [2+2] cycloaddition of a 2′-vinyl-1,1′-biaryl-2-yl ketone enolate. Catalytic asymmetric hydrogenation of the cyclic imine intermediate allowed the late-stage construction of the asymmetric center.

Full text of DOI:10.1055/s-0034-1380430

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2015, 47, 2819–2825
2819
special topic
Synthesis
Y. Yamaoka et al.
Special Topic
Asymmetric Total Synthesis of Tylophorine through a Formal
2+2] Cycloaddition Followed by Migrative Ring Opening of a
[
Cyclobutane
Yousuke Yamaoka*
Marie Taniguchi
Ken-ichi Yamada
Kiyosei Takasu*
OMe
OMe
MeO
MeO
formal
2+2]
cycloaddition
asymmetric
transfer
hydrogenation
H
N
[
OTBS
3
O
ring-contraction/
ring-opening
Pictet–Spengler
reaction
Graduate School of Pharmaceutical Sciences, Kyoto University,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
yyamaoka@pharm.kyoto-u.ac.jp
OMe
MeO
kay-t@pharm.kyoto-u.ac.jp
OMe
OMe
(R)-(–)-tylophorine (1)
Received: 28.04.2015
Accepted after revision: 12.05.2015
Published online: 01.07.2015
OMe
A
OMe
MeO
MeO
OMe
DOI: 10.1055/s-0034-1380430; Art ID: ss-2015-c0267-st
H
H
N
Abstract The asymmetric total synthesis of phenanthroindolizidine al-
kaloid (–)-tylophorine was achieved by asymmetric transfer hydrogena-
tion of a cyclic imine. The cyclic imine with a pendant phenanthrene
core was synthesized by a TfOH-promoted domino ring-contrac-
tion/ring-opening sequence of a cyclobutanol bearing an azide group,
which was constructed by a formal [2+2] cycloaddition of a 2′-vinyl-
B
D
E
N
n
C
R
OMe
OMe
1
,1′-biaryl-2-yl ketone enolate. Catalytic asymmetric hydrogenation of
R = OMe, n = 1: (R)-(–)-tylophorine (1) (S)-(+)-tylophorine (ent-1)
R = H, n = 1: (R)-(–)-antofine (2)
R = H, n = 2: (R)-(–)-cryptopleurine (3)
the cyclic imine intermediate allowed the late-stage construction of the
asymmetric center.
Figure 1 Structures of representative phenanthroindolizidine and
phenanthroquinolizidine alkaloids
Key words heterocycles, natural products, cycloaddition, asymmetric
synthesis, anticancer agents
Phenanthroindolizidine and phenanthroquinolizidine
alkaloids including tylophorine (1), antofine (2), and cryp-
topleurine (3), have received increasing attention over re-
phenanthroindolizidines have been synthesized by using
9
10
chiral building blocks and chiral auxiliaries. The catalytic
enantioselective synthesis of these alkaloids has also been
reported.11
cent years because of their attractive biological activities
1
(
Figure 1). Tylophorine (1), a phenanthroindolizidine alka-
Recently, we reported a new method of preparing poly-
2
12a
loid, was first isolated from Tylophora indica and has been
cyclic aromatic hydrocarbons (PAHs, 8). Deprotonation of
shown to have a wide range of biological activities such as
2′-vinylbiaryl-2-yl ketones 4 induced a formal [2+2] cyc-
loaddition of enolates 5 to produce ring-fused cyclobuta-
nols 6. Subsequent treatment with acid promoted a domino
ring-contraction/ring-opening sequence of 6 via cationic
3
4
anti-inflammatory and antiviral activities. It has also
been shown to be a potent inhibitor of eukaryotic protein
5
biosynthesis and RNA transcription, as well as an inhibitor
6
of several cyclins that regulate the cell cycle.
intermediate 7 in the presence of a nucleophile to give 8
Naturally occurring tylophorine is found as an almost
(Scheme 1).1
2b–d
Herein, we report a distinct enantioselec-
racemic mixture, with a slight excess of the R-enantiomer
tive total synthesis of (R)-(–)-tylophorine by using our ex-
isting methodology for phenanthrene synthesis, followed
by catalytic late-stage hydrogenation of a cyclic imine.
Our synthetic plan is shown in Scheme 2. (R)-(–)-Tylo-
phorine (1) can be synthesized from (R)-9 by using a well-
established Pictet–Spengler method.13 The asymmetric cen-
ter of (R)-9 would be generated by ruthenium-catalyzed
asymmetric transfer hydrogenation14 of cyclic imine 10. We
7
(
(
1). Interestingly, the minor enantiomer, (S)-tylophorine
ent-1), has been found to be even more potent in the
8
growth inhibition of some specific cancer cells. This clearly
demonstrates the importance of facile and selective access
to both enantiomers of the alkaloids to enable investigation
of their biological activities. To date, optically active
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2819–2825

2
820
Synthesis
Y. Yamaoka et al.
Special Topic
R
O
OH
R
R
R
KHMDS
THF
TfOH
Nu-H
R
Nu
O
H
Nu
H
4
5
6
7
8
Scheme 1 Our synthetic methodology for the synthesis of PAHs
planned to synthesize cyclic imine 10 through a base-pro-
moted formal [2+2] cycloaddition of biaryl 12, followed by
an acid-promoted domino ring-contraction/ring-opening
sequence. Biaryl 12 could be prepared from readily avail-
able fragments 13, 14, and 15.
converted into ketone 16 by a Grignard reaction followed by
tetra-n-propylammonium perruthenate (TPAP) mediated
oxidation of the resulting alcohol. The Suzuki–Miyaura
cross-coupling reaction between ketone 16 and boronic
acid 15 provided biaryl 17 in 86% yield.
Our synthesis began with preparation of biaryl 17, the
precursor to the key formal [2+2] cycloaddition (Scheme 3).
Commercially available 6-bromoveratraldehyde (13) was
OMe
OMe
1
2
) 14
CH2Cl2, 98%
MeO
MeO
) TPAP (3 mol%)
NMO, MS4A
OTBS
CHO
3
Br
CH2Cl2, 95%
Br
O
OMe
MeO
13
16
OMe
H
N
H
Pictet–Spengler
reaction
MeO
15, K2CO3
HN
OTBS
Pd(PPh3)4 (5 mol%)
3
(R)-9
toluene–EtOH, 90 °C
O
MeO
86%
OMe
R)-(–)-tylophorine (1)
OMe
(
OMe
OMe
MeO
17
asymmetric
transfer
hydrogenation
ring-contraction/
ring-opening
Scheme 3 Preparation of biaryl 17
N
We then attempted the key formal [2+2] cycloaddition
of 17 (Scheme 4). After brief experimentation, we found the
optimal conditions to form the desired cyclobutanol as a
single diastereomer in excellent yield was to treat biaryl 17
with potassium hexamethyldisilazide (KHMDS) in 1,2-di-
methoxyethane (DME) at reflux. The cycloaddition reaction
was followed by tetrabutylammonium fluoride (TBAF) me-
diated cleavage of the TBS group in situ, providing cyclobu-
tanediol 18 in 94% yield. A two-step chemoselective azida-
tion of cyclobutanediol 18 delivered the cyclobutanol 11,
bearing an azide group.
1
0
MeO
OMe
OMe
MeO
OMe
MeO
formal
2+2]
OH
[
X
cycloaddition
3
N3
O
H
MeO
OMe
OMe
OMe
With cyclobutanol 11 in hand, we turned to our atten-
tion to the domino ring-contraction/ring-opening sequence
to construct the E-ring of tylophorine. While it is known
that an azide group reacts with carbocations under highly
acidic conditions,15 it has also been reported that some
azide groups decompose to form aldehydes on reaction
with TfOH.16 Fortunately, simple TfOH treatment of 11
formed the cyclic imine ring system concomitantly with the
phenanthrene skeleton in approximately 50% yield. To our
1
1
12
OMe
B(OH)2
MeO
OTBS
+
IMg
+
3
CHO
OMe
Br
OMe
13
14
15
Scheme 2 Retrosynthetic analysis of tylophorine (1)
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2819–2825

2
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Synthesis
Y. Yamaoka et al.
Special Topic
gave the desired product 9 with high enantioselectivity
OMe
MeO
OMe
(84% ee). Subsequent Pictet–Spengler reaction provided
MeO
(
R)-(–)-tylophorine (1).
OH
H
KHMDS
DME, reflux
OTBS
3
Table 1 Exploration of Asymmetric Transfer Hydrogenation Condi-
O
then TBAF
R
tionsa
94%
OMe
MeO
OMe
MeO
OMe
OMe
17
1) TsCl, DMAP
Et3N, CH2Cl2
R = OH (18)
R = N3 (11)
H
1) Ru cat. (10 mol%)
HCO2H, Et3N
TfOH
2
) NaN3, DMF
1
1
10
91% (2 steps)
MeCN
2) HCHO (aq)
concd HCl
N
EtOH, reflux
OMe
MeO
MeO
OMe
(R)-(–)-1
TfOH
MeCN
NaBH3CN
AcOH
O
R
then Et3N
N
MeOH
7% (from 11)
O
N
4
S
Ts
Ru
H2N
Ru
N
Cl
Cl
MeO
H2N
Ph
Ph
OMe
Ph
Ph
(S,S)-20
10
R = 4-MeC6H4: (S,S)-19
R = Me: (S,S)-21
OMe
OMe
MeO
MeO
MeO
R = 1-naphthyl: (S,S)-22
R = 4-O2NC6H4: (S,S)-23
H
H
N
HCHO (aq)
concd HCl
Entry Ru cat.
Solvent
Temp (°C)
Yield (%)b
ee (%)c
HN
EtOH, reflux
quant.
1d
2
(S,S)-19
DMF
r.t.
28
42
35
27
25
30
37
60
72
65
45
73
76
84
MeO
(S,S)-19
(S,S)-20
(S,S)-21
(S,S)-22
DMF
–40 to 0
–10
OMe
OMe
3
DMF
rac-9
rac-1
4
DMF
–10
Scheme 4 Synthesis of racemic tylophorine (1)
5
e
DMF
–10
6
(S,S)-23e
(S,S)-23e
DMF
–10
7f
DMSO/CH
Cl
2
–20 to 0
2
knowledge, this is the first report of a cyclopropane ring be-
ing cleaved by nucleophilic attack of an organic azide. The
TfOH-mediated construction of cyclic imine 10 was fol-
a
Unless otherwise noted, the reaction was carried out with freshly pre-
pared crude imine 10 (1 equiv), Ru cat. (10 mol%), and a formic acid/tri-
ethylamine mixture in solvent (0.1 M) at the indicated temperature for 2
days.
Isolated yield (from 11) after chromatography on silica gel.
Chiral HPLC analysis using a Daicel Chiralpak AD-H column.
lowed by neutralization with Et N, then reduction of the
3
b
imine in situ gave amine rac-9 in 47% yield from 11. The
amine rac-9 was converted into (±)-tylophorine (1) with a
Pictet–Spengler reaction according the reported proce-
c
d
Reaction time: 18 hours.
e
The catalyst was prepared in situ.
f
Reaction time: 3 days.
13
dure.
Finally, asymmetric reduction by using Noyori–Ikariya
14
asymmetric transfer hydrogenation of cyclic imine 10 was
investigated (Table 1). Asymmetric transfer hydrogenation
of cyclic N-alkyl imines with chiral ruthenium catalysts can
give racemic products.17 Fortunately, the reduction of cyclic
imine 10 with (S,S)-19 as catalyst in N,N-dimethylforma-
mide (DMF) gave the product 9 with good enantioselectivi-
ty (60% ee). After several experiments, the use of readily ac-
In summary, we have achieved the asymmetric total
synthesis of (R)-(–)-tylophorine (1) in 23% overall yield and
84% ee over nine operations. The key features of our synthe-
sis are: (i) a formal [2+2] cycloaddition to provide a ring-
fused cyclobutanol, (ii) an acid-promoted domino ring-con-
traction/ring-opening sequence of a cyclobutanol to form a
cyclic imine ring concomitantly with a phenanthrene skele-
ton, and (iii) a catalytic late-stage installation of an asym-
metric center by the asymmetric transfer hydrogenation of
a cyclic imine. The syntheses of several other phenan-
18
cessible ruthenium complex (S,S)-23 in a mixed solvent of
dimethyl sulfoxide (DMSO) and CH Cl at low temperature
2
2
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2
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Synthesis
Y. Yamaoka et al.
Special Topic
throindolizidine and phenanthroquinolizidine alkaloids,
and their unnatural derivatives, are in progress and will be
reported in due course.
through a Celite pad (CHCl3 eluent) and the solvent was removed in
vacuo. The residue was purified by silica gel chromatography (hex-
ane–EtOAc, 5:1) to afford 16.
Yield: 10.1 g (95%); colorless oil; R = 0.48 (hexane–EtOAc, 3:1, UV).
f
IR (neat): 2932, 2855, 1694, 1258, 1096, 837 cm–1
.
All solvents and materials were obtained from commercial suppliers
and used without further purification unless otherwise noted. Col-
umn chromatography was performed on Fuji Silysia BW-200 silica gel.
Reactions and chromatography fractions were analyzed with pre-
coated silica gel plates (Merck Silica Gel 60 F254) and visualized by
UV irradiation at 254 nm and/or with the indicated stains. IR spectra
1
H NMR (500 MHz, CDCl ): δ = 0.04 (s, 6 H), 0.88 (s, 9 H), 1.54–1.63
3
(m, 2 H), 1.73–1.81 (m, 2 H), 3.00 (t, J = 7.3 Hz, 2 H), 3.64 (t, J = 6.4 Hz,
2 H), 3.89 (s, 3 H), 3.91 (s, 3 H), 7.01 (s, 1 H), 7.04 (s, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 5.4, 18.3, 21.0, 25.9, 32.2, 42.1, 56.1,
3
5
6.2, 62.8, 110.8, 112.0, 116.3, 133.2, 148.1, 151.2, 202.7.
1
13
MS (FAB): m/z = 431/433 [M + H]+.
were measured with Shimadzu IRAffinity-1. H and C NMR spectra
1
13
were recorded with JEOL ECS-400 ( H, 400 MHz; C, 100 MHz) or
Anal. Calcd for C19H31BrO Si: C, 52.89; H, 7.24. Found: C, 52.71; H,
7.15.
4
1
13
JEOL ECA-500 ( H, 500 MHz; C, 125 MHz) spectrometers. Chemical
shifts are presented in ppm relative to tetramethylsilane ( H, δ =
.00 ppm) or solvents as follows: CDCl ( C, δ = 77.0 ppm); acetone-
d ( H, δ = 2.04 ppm; C, δ = 30.0 ppm). Abbreviations are as follows:
1
13
0
3
(4,5-Dimethoxy-2-vinylphenyl)boronic Acid (15)
To a stirred solution of 1-bromo-4,5-dimethoxy-2-vinylbenzene19
1
13
6
s, singlet; d, doublet; dd, doublet of doublets; t, triplet; td, triplet of
doublets; q, quartet; m, multiplet; br, broad. Low-resolution mass
spectra were recorded with JEOL JMS-700 (FAB) or JEOL JMS-HX211A
(8.18 g, 33.6 mmol) in anhydrous THF (170 mL) under an argon atmo-
sphere, a solution of n-BuLi (1.6 M in hexane, 25.0 mL, 40.0 mmol)
was added carefully at –78 °C. The reaction mixture was stirred at the
same temperature for 20 min, then trimethyl borate (11.5 mL, 103
mmol) was added. The resulting mixture was stirred for a further 20
min and then warmed to r.t. The reaction mixture was acidified with
(FAB) spectrometers with 3-nitrobenzylalcohol (NBA) as matrix, or
with a Shimadzu GCMS-QP2010 SE (EI) mass spectrometer. High-res-
olution mass spectra were recorded with a Shimadzu LCMS-IT-TOF
(ESI) mass spectrometer using MeOH as mobile phase. Optical rota-
1
0% aq HCl, the organic layer was separated, and the aqueous layer
tions were recorded with a JASCO P-1030 polarimeter. Chiral HPLC
analyses were performed with a Shimadzu Prominence HPLC system.
was extracted with Et O (3 × 100 mL). The combined organic layers
were washed with H O (2 × 100 mL), brine (50 mL), dried over Na SO ,
2
2
2
4
filtered, and concentrated in vacuo. The residue was purified by tritu-
ration with EtOAc–hexane to afford 15.
1
-(2-Bromo-4,5-dimethoxyphenyl)-5-[(tert-butyldimethylsi-
lyl)oxy]pentan-1-one (16)
Yield: 4.78 g (68%); pale-yellow powder; mp 130–138 °C.
To a stirred solution of 2-bromo-4,5-dimethoxybenzaldehyde (6.13 g,
IR (neat): 3402, 3194, 1400, 1331, 1204, 795 cm–1
1H NMR (500 MHz, acetone-d
–D O): δ = 3.79 (s, 3 H), 3.84 (s, 3 H),
.
2
5.0 mmol) in anhydrous CH Cl2 (175 mL) under an argon atmo-
2
sphere, a freshly prepared 1.0 M Et O solution of {4-[(tert-butyldi-
6
2
2
methylsilyl)oxy]butyl}magnesium iodide (75 mL, 75.0 mmol) was
added at r.t. over 10 min. After stirring for 1 h, the reaction was
5.05 (dd, J = 1.4, 10.9 Hz, 1 H), 5.58 (dd, J = 1.3, 17.6 Hz, 1 H), 7.18 (s,
1 H), 7.19 (s, 1 H), 7.40 (dd, J = 11.0, 17.6 Hz, 1 H).
quenched with sat. aq NH Cl (50 mL), and the organic layer was sepa-
13
4
C NMR (100 MHz, acetone-d ): δ = 55.8, 55.9, 108.7, 112.1, 117.9,
6
rated. The aqueous layer was extracted with CHCl3 (2 × 100 mL) and
the combined organic layers were washed with brine (20 mL), dried
over Na SO , filtered, and concentrated in vacuo. The residue was
136.8, 138.8, 149.3, 151.4.
MS (FAB): m/z = 570 [boroxine, M]+.
2
4
+
HRMS (ESI): m/z [dimethyl ester + H] calcd for C12H BO : 237.1298;
found: 237.1291.
purified by silica gel chromatography (hexane–EtOAc, 3:1 → 2:1) to
afford 1-(2-bromo-4,5-dimethoxyphenyl)-5-[(tert-butyldimethylsi-
lyl)oxy]pentan-1-ol.
18
4
5
-[(tert-Butyldimethylsilyl)oxy]-1-(4,4′,5,5′-tetramethoxy-2′-vi-
Yield: 10.6 g (98%); pale-yellow oil; R = 0.28 (hexane–EtOAc, 3:1, UV).
f
nyl-[1,1′-biphenyl]-2-yl)pentan-1-one (17)
IR (neat): 3426, 2931, 2855, 1501, 1254, 1096, 833 cm–1
.
To a stirred mixture of 16 (6.34 g, 14.7 mmol), 15 (4.58 g, 22.0 mmol),
and K CO (6.10 g, 44.1 mmol) in anhydrous toluene–EtOH (4:1 v/v,
1
H NMR (500 MHz, CDCl ): δ = 0.04 (s, 6 H), 0.88 (s, 9 H), 1.39–1.47
3
2
3
(m, 1 H), 1.50–1.64 (m, 3 H), 1.67–1.78 (m, 2 H), 2.04 (d, J = 2.9 Hz,
150 mL) under an argon atmosphere, Pd(PPh ) (849 mg, 0.74 mmol)
3 4
1
6
H), 3.63 (t, J = 5.4 Hz, 1 H), 3.86 (s, 3 H), 3.89 (s, 3 H), 5.02 (m, 1 H),
.96 (s, 1 H), 7.07 (s, 1 H).
was added. After heating at 90 °C for 3 h, the resulting mixture was
cooled to r.t. and H O was added. The organic layer was separated, and
the aqueous layer was extracted with EtOAc (2 × 100 mL). The com-
bined organic layers were washed with brine (20 mL), dried over Na2-
2
13
C NMR (100 MHz, CDCl ): δ = 5.3, 18.3, 22.1, 25.9, 32.4, 37.6, 56.0,
3
56.1, 63.1, 72.7, 109.7, 111.6, 115.1, 136.0, 148.6, 148.7.
MS (FAB): m/z = 432/434 [M]+.
SO , filtered, and concentrated in vacuo. The residue was purified by
silica gel chromatography (hexane–EtOAc, 3:1 → 2:1) to afford 17.
4
Anal. Calcd for C19H33BrO Si: C, 52.65; H, 7.67. Found: C, 52.44; H,
4
Yield: 6.49 g (86%); pale-yellow solid; mp 61–63 °C; Rf = 0.46
7.66.
(hexane–EtOAc, 2:1, UV).
To a stirred mixture of 1-(2-bromo-4,5-dimethoxyphenyl)-5-[(tert-
butyldimethylsilyl)oxy]pentan-1-ol (10.6 g, 24.4 mmol), NMO (4.3 g,
IR (neat): 2932, 2855, 1670, 1504, 1254 cm–1
.
1
3
6.6 mmol) and 4Å MS powder (4.8 g) in anhydrous CH Cl2 (50 mL)
H NMR (500 MHz, CDCl ): δ = 0.01 (s, 6 H), 0.85 (s, 9 H), 1.24–1.29
2
3
under argon atmosphere, TPAP (284 mg, 0.808 mmol) was added at
r.t. After stirring for 15 min, the resulting mixture was filtered
(m, 2 H), 1.37–1.50 (m, 2 H), 2.12–2.23 (m, 2 H), 3.44 (t, J = 6.4 Hz,
2 H), 3.85 (s, 3 H), 3.90 (s, 3 H), 3.96 (s, 3 H), 3.98 (s, 3 H), 5.10 (d, J =
11.2 Hz, 1 H), 5.57 (d, J = 17.5 Hz, 1 H), 6.49 (dd, J = 11.0, 17.3 Hz, 1 H),
6
.64 (s, 1 H), 6.69 (s, 1 H), 7.14 (s, 1 H), 7.21 (s, 1 H)
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2
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Synthesis
Y. Yamaoka et al.
Special Topic
13
1
C NMR (125 MHz, CDCl ): δ = 5.4, 18.3, 21.0, 25.9, 32.2, 41.5, 55.9,
H NMR (500 MHz, CDCl ): δ = 1.60 (ddd, J = 11.1, 8.5, 8.5 Hz, 1 H),
3
3
5
1
5.99, 56.01, 56.1, 62.7, 107.5, 111.0, 112.8, 113.4, 113.9, 128.7, 132.4,
32.9, 133.3, 134.4, 148.0, 148.6, 148.9, 150.4, 204.7
1.70–1.79 (m, 3 H), 1.91 (ddd, J = 11.0, 9.9, 3.2 Hz, 1 H), 2.07 (br s,
1 H), 2.08–2.17 (m, 1 H), 2.53–2.57 (m, 1 H), 3.34–3.42 (m, 2 H), 3.64
(t, J = 9.3 Hz, 1 H), 3.90 (s, 3 H), 3.94 (s, 3 H), 3.97 (s, 3 H), 4.00 (s, 3 H),
MS (FAB): m/z = 515 [M + H]+.
6
.65 (s, 1 H), 7.00 (s, 1 H), 7.23 (s, 1 H), 7.27 (s, 1 H).
Anal. Calcd for C29H42O Si: C, 67.67; H, 8.22. Found: C, 67.66; H, 8.30.
6
13
C NMR (125 MHz, CDCl ): δ = 27.0, 27.4, 28.2, 45.0, 47.7, 51.6, 55.9,
3
5
6.0, 56.1, 56.4, 71.4, 105.1, 106.7, 110.1, 111.3, 123.6, 125.2, 128.6,
(
1
2S*,2aS*,10bR*)-2-(3-Hydroxypropyl)-4,5,8,9-tetramethoxy-
,10b-dihydrocyclobuta[l]phenanthren-2a(2H)-ol (18)
To a stirred solution of 17 (257 mg, 0.500 mmol) in anhydrous DME
4.4 mL) heated to reflux under an argon atmosphere, a solution of
131.7, 148.1, 148.7, 149.1, 149.2.
+
MS (FAB): m/z = 380 [M – HN O] .
2
(
Anal. Calcd for C23
H N O : C, 64.93; H, 6.40; N, 9.88. Found: C, 65.01;
27 3 5
KHMDS (1.0 M in THF, 0.60 mL, 0.60 mmol) was added. After stirring
for 30 min, the resulting mixture was cooled to r.t., then a solution of
TBAF (1.0 M in THF, 2.50 mL, 2.50 mmol) was added. After stirring for
H, 6.45; N, 9.85.
(±)-2-[(2,3,6,7-Tetramethoxyphenanthren-9-yl)methyl]pyrroli-
1
h, the reaction was quenched with sat. aq NH Cl, then the mixture
dine (rac-9)
4
was extracted with EtOAc (3 × 10 mL). The combined organic layers
To a stirred solution of 11 (22.3 mg, 0.0524 mmol) in anhydrous
MeCN (0.3 mL) under an argon atmosphere, TfOH (0.1 M in MeCN,
0.70 mL, 0.070 mmol) was added at r.t. After stirring for 5 min, the
were washed with H O (2 × 5 mL), followed by brine (5 mL), dried
2
over Na SO , filtered, and concentrated in vacuo. The residue was
2
4
purified by silica gel chromatography (hexane–EtOAc, 1:2 → 0:1) to
afford 18.
reaction was quenched with Et N (14 μL, 0.100 mmol) and the mix-
3
ture was stirred for 10 min. To the resulting mixture, MeOH (0.50
Yield: 188 mg (94%); white solid; mp 175–177 °C; R = 0.22 (EtOAc,
mL), AcOH (0.01 mL, 0.175 mmol), and NaBH CN (31.4 mg, 0.500
f
3
UV).
mmol) were added. After stirring for 24 h, the resulting mixture was
acidified to pH 1 with 10% aq HCl. The acidic aqueous layer was
IR (neat): 3480, 3364, 2936, 1508, 1246, 752 cm–1
.
washed with Et O (2 × 5 mL). The resulting aqueous layer was basified
2
1
H NMR (500 MHz, CDCl ): δ = 1.57–1.63 (m, 2 H), 1.70–1.79 (m, 3 H),
3
to pH 11 with NaOH pellets and then extracted with CHCl3 (3 × 10
1
1
3
.90 (ddd, J = 11.0, 9.9, 2.6 Hz, 1 H), 2.09 (br s, 1 H), 2.12–2.19 (m,
H), 2.54–2.58 (m, 1 H), 3.65 (t, J = 9.5 Hz, 1 H), 3.74–3.81 (m, 2 H),
.90 (s, 3 H), 3.94 (s, 3 H), 3.98 (s, 3 H), 4.01 (s, 3 H), 6.66 (s, 1 H), 7.03
mL). The combined CHCl3 layers were washed with H O (2 × 10 mL),
2
followed by brine (10 mL), dried over Na SO , filtered, and concentrat-
2
4
ed in vacuo. The residue was purified by silica gel chromatography
MeOH–NH (28% aq), 30:1] to afford rac-9.
(s, 1 H), 7.24 (s, 1 H), 7.27 (s, 1 H).
[
3
13
C NMR (125 MHz, CDCl ): δ = 26.5, 28.3, 30.8, 45.0, 48.2, 55.8, 55.9,
3
Yield: 9.4 mg (47%); pale-yellow solid; mp >150 °C; R = 0.34 [MeOH–
f
5
1
6.1, 56.3, 62.9, 71.3, 105.1, 106.7, 110.3, 111.3, 123.7, 125.2, 128.7,
31.8, 148.0, 148.6, 149.0, 149.1.
NH (28% aq), 30:1, UV].
3
IR (neat): 3368, 2955, 2936, 1620, 1508, 1474, 1427, 1254, 1200,
MS (FAB): m/z = 383 [M – OH].
HRMS (ESI): m/z [M + K]+ calcd for C23H28KO : 439.1523; found:
–1
1150, 1042, 910, 841, 772, 729 cm
.
6
1
H NMR (500 MHz, CDCl ): δ = 1.50–1.58 (m, 1 H), 1.71–1.80 (m, 1 H),
3
439.1529.
1
1
6
.83–1.94 (m, 3 H), 2.86 (ddd, J = 9.6, 7.7, 7.6 Hz, 1 H), 3.10 (ddd, J =
0.2, 7.6, 5.2 Hz, 1 H), 3.19 (d, J = 6.6 Hz, 2 H), 3.53 (ddd, J = 13.7, 6.8,
.8 Hz, 1 H), 4.03 (s, 3 H), 4.05 (s, 3 H), 4.11 (s, 3 H), 4.12 (s, 3 H), 7.18
(2S*,2aS*,10bR*)-2-(3-Azidopropyl)-4,5,8,9-tetramethoxy-1,10b-
dihydrocyclobuta[l]phenanthren-2a(2H)-ol (11)
(s, 1 H), 7.44 (s, 1 H), 7.47 (s, 1 H), 7.77 (s, 1 H), 7.78 (s, 1 H).
To a stirred solution of 18 (422 mg, 1.05 mmol), DMAP (130 mg, 1.06
13
C NMR (100 MHz, CDCl ): δ = 24.7, 31.6, 39.6, 46.0, 55.8, 55.97,
3
mmol), and Et N (0.73 mL, 5.24 mmol) in anhydrous CH Cl (10 mL)
3
2
2
56.03, 58.7, 102.7, 103.3, 104.8, 108.0, 123.6, 124.6, 124.9, 125.4,
26.2, 131.4, 148.5, 148.79, 148.84.
MS (FAB): m/z = 382 [M + H]+.
under an argon atmosphere, tosyl chloride (231 mg, 1.21 mmol) was
added at r.t. After stirring for 8 h, additional tosyl chloride (171 mg,
1
0.90 mmol) was added to the resulting mixture. After stirring for
1
.5 h, the reaction was quenched with sat. aq NH Cl and the organic
4
(±)-Tylophorine (rac-1)
layer was separated. The aqueous layer was extracted with CHCl3
(
2 × 10 mL). The combined organic layers were washed with H O
This reaction was performed by a modification of the reported meth-
2
13
(2 × 10 mL), sat. aq NaHCO (2 × 10 mL) and brine (10 mL), dried over
od. To a stirred solution of rac-9 (39.1 mg, 0.103 mmol) in EtOH (2
mL), 37% aq HCHO (2 mL, 26.9 mmol) and conc. HCl (17 μL, 0.204
mmol) were successively added at r.t. After heating to reflux in the
dark for 26 h, the resulting mixture was cooled to r.t., basified to
3
Na SO , filtered, and concentrated in vacuo. To a stirred solution of
the crude material in anhydrous DMF (5.3 mL) under an argon atmo-
sphere, NaN (683 mg, 10.5 mmol) was added at r.t. After stirring for
2
4
3
1
2 h, the reaction was quenched with H O (5 mL), then the mixture
pH 11 with 15% NaOH and then extracted with CHCl (3 × 10 mL). The
2
3
was extracted with Et O (5 × 10 mL). The combined organic layers
combined organic layers were washed with H O (2 × 10 mL), followed
2
2
were washed with H O (2 × 10 mL), followed by brine (10 mL), dried
by brine (10 mL), dried over Na SO , filtered, and concentrated in vac-
2
2
4
over Na SO , filtered, and concentrated in vacuo. The residue was pu-
uo. The residue was purified by silica gel chromatography (CHCl3–
2
4
rified by silica gel chromatography (hexane–EtOAc, 1.5:1 → 1:1.5) to
afford 11.
MeOH, 20:1) to afford rac-1.
Yield: 40.7 mg (quant.); pale-yellow solid; mp >270 °C; Rf = 0.33
Yield: 408 mg (91%); white solid; mp 100–102 °C; R = 0.48 (hexane–
(CHCl –MeOH, 10:1, UV).
f
3
EtOAc, 2:1, UV).
IR (neat): 3487, 2936, 2095, 1508, 1246, 752 cm–1
IR (neat): 2936, 1620, 1516, 1474, 1427, 1250, 1196, 1150, 1038,
–1
.
1015, 910, 841, 756 cm
.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2819–2825

2
824
Synthesis
Y. Yamaoka et al.
Special Topic
1
H NMR (500 MHz, CDCl ): δ = 1.73–1.81 (m, 1 H), 1.88–1.96 (m, 1 H),
.00–2.09 (m, 1 H), 2.21–2.27 (m, 1 H), 2.43–2.51 (m, 2 H), 2.90 (dd,
Spectroscopic properties were consistent with those reported in the
literature.
3
10e
2
J = 10.7, 15.6 Hz, 1 H), 3.36 (dd, J = 2.7, 15.6 Hz, 1 H), 3.46–3.49 (m,
1
4
H), 3.65 (d, J = 14.6 Hz, 1 H), 4.05 (s, 3 H), 4.06 (s, 3 H), 4.11 (s, 6 H),
.62 (d, J = 14.6 Hz, 1 H), 7.15 (s, 1 H), 7.30 (s, 1 H), 7.81 (s, 1 H), 7.82
Acknowledgment
(s, 1 H).
1
3
This work was supported by a Sasakawa Scientific Research Grant
from The Japan Science Society (M.T.), the Kurata Memorial Hitachi
Science and Technology Foundation, a Grant-in-Aid for Young Scien-
tists (B), and ‘Platform for Drug Design, Discovery and Development’
from the Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan.
C NMR (100 MHz, CDCl ): δ = 21.6, 31.3, 33.8, 54.0, 55.1, 55.8, 55.9,
3
5
1
6.0, 60.2, 103.1, 103.3, 103.4, 103.9, 123.4, 123.6, 124.3, 125.8, 126.0,
26.3, 148.4, 148.5, 148.7.
MS (FAB): m/z = 394 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C24H28NO : 394.2018; found:
4
3
94.2029.
Spectroscopic properties were consistent with those reported in the
literature.
Supporting Information
Supporting information for this article is available online at
Asymmetric Synthesis of (R)-(–)-Tylophorine
http://dx.doi.org/10.1055/s-0034-1380430.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
To a stirred solution of 11 (132 mg, 0.310 mmol) in anhydrous MeCN
(1.8 mL) under an argon atmosphere, TfOH (0.1 M in MeCN, 4.4 mL,
0
.440 mmol) was added at r.t. After stirring for 10 min, the reaction
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(
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(
(
Pictet–Spengler Reaction
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3
20
10e
Yield: 14.7 mg (95%); white solid; [α]
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Special Topic
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2819–2825