Efficient and chirally specific synthesis of phenanthro-indolizidine alkaloids by parham-type cycloacylation

Article abstract of DOI:10.1002/ejoc.200900920

A concise, efficient and modular route involving Parhamtype cycloacylation as the key step has been used to synthesize six enantiopure phenanthro- indolizidine alkaloids 1a-c. The preparation of enantiomerically pure tylophora alkaloids and their seco analogues on a large-scale is now feasible. The alcohol intermediates 8a-c, which are difficult to prepare by other synthetic methodologies, have been synthesized by a metallation-cyclization-reduction sequence in excellent yields.

Full text of DOI:10.1002/ejoc.200900920

FULL PAPER
DOI: 10.1002/ejoc.200900920
Efficient and Chirally Specific Synthesis of Phenanthro-Indolizidine Alkaloids
by Parham-Type Cycloacylation
Ziwen Wang,[a] Zheng Li,[a] Kailiang Wang,[a] and Qingmin Wang*[a]
Keywords: Alkaloids / Synthetic methods / Metalation / Cyclization / Reduction / Cycloacylation
A concise, efficient and modular route involving Parham-
type cycloacylation as the key step has been used to synthe-
size six enantiopure phenanthro-indolizidine alkaloids 1a–c.
The preparation of enantiomerically pure tylophora alkaloids
and their seco analogues on a large-scale is now feasible.
The alcohol intermediates 8a–c, which are difficult to prepare
by other synthetic methodologies, have been synthesized by
a metallation–cyclization–reduction sequence in excellent
yields.
cleus. In the last three decades, the most commonly re-
ported synthetic methodology for the construction of this
structure was the acid-catalysed cyclization of an amino
acid.[8] However, in each case, racemic products and low
yields resulted due to the harsh conditions employed for
ring closure.
On the other hand, the intramolecular cyclization reac-
tions that employ aryllithiums generated by lithium–halo-
gen exchange, known as Parham cyclization reactions, have
become a valuable protocol for the regiospecific construc-
tion of carbocyclic and heterocyclic systems.[9] Inspired by
the methodology of Lete and co-workers,[9g,9i] this aromatic
metallation–cyclization procedure has been successfully
used to prepare the indolizidine nucleus of phenanthro-
indolizidine alkaloids. In these cases, the unstable ketone
intermediates (analogues of 6) were directly reduced to the
corresponding alcohols 8a–c to avoid decomposition. In
this paper, we report full details of this synthetic approach
to enantiopure phenanthro-indolizidine alkaloids 1a–c in
high overall yields.
Introduction
Since the first isolation of (–)-tylophorine [1a-(R), see
Scheme 2] in 1935,[1] many phenanthro-indolizidine alka-
loids have been found to exhibit interesting pharmacologi-
cal properties,[2] especially antitumour activity.[3] We have
previously reported that (–)-antofine, isolated from Cynan-
chum komarovii, possesses excellent antiviral activity against
the tobacco mosaic virus (TMV).[4] To extend our research
on phenanthro-indolizidine alkaloids as antiviral agents, we
developed an efficient approach to the preparation of race-
mic alkaloids on a large-scale.[5] Now to further explore the
effect of α-C chirality on antiviral activity, a series of
enantiopure phenanthro-indolizidine alkaloids need to be
tested.
So far, many of the enantiopure alkaloids have been syn-
thesized selectively using the chiron approach starting with
either proline, glutamic acid or pyroglutamate, as well as
the chiral auxiliary approach manifested in diastereoselec-
tive Grignard additions and double Michael additions,
respectively.[6] However, these reported approaches are not
suitable for large-scale preparation due to low yields, harsh
conditions or the many steps required.
Results and Discussion
The construction of the phenanthrene and indolizidine
nuclei always plays a key role in the synthesis of phenan-
thro-indolizidine alkaloids. In our previous work, FeCl3
was used as the oxidative coupling reagent to construct the
phenanthrene nucleus efficiently.[5,7] We then directed our
attention towards the construction of the indolizidine nu-
To test the feasibility of this new approach the synthetic
plan depicted in Scheme 1 was initially designed. Ester 2a
was treated with lithium aluminium hydride to give alcohol
3a in 96% yield.
It has been reported that polymethoxylated benzyl
alcohols can be converted into the corresponding dibro-
mides in excellent yields in one step.[10] By using this pro-
cedure, 3a was successfully converted into dibromide 4a in
92% yield, thus improving the results previously reported
by Ishibashi and co-workers.[11] N,N-Diethyl-1H-pyrrole-2-
carboxamide was alkylated with the dibromide 4a to pro-
duce the amide 5 in 95% yield. When 5 was treated with
[a] State Key Laboratory of Element-Organic Chemistry, Research
Institute of Element-Organic Chemistry, Nankai University,
Tianjin, P.R. China
Fax: +86-22-23499842
E-mail: wang98h@263.net
wangqm@nankai.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900920.
292
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 292–299

Synthesis of Phenanthro-indolizidine Alkaloids
Scheme 1. Synthesis of the new structural seco analogue 6.
nBuLi (2.2 equiv.) and TMEDA (2.3 equiv.) at –78 °C for (2.2 equiv.) and TMEDA (2.3 equiv.) and then sodium
4 h, lithium–bromine exchange and the subsequent cycliza- borohydride (5 equiv.) to give 8a-(13aS,14S) stereoselec-
tion efficiently afforded the ketone 6 in 90% yield. However, tively in 94% yield. The absolute configuration of 8a-
if the reaction mixture was allowed to reach room tempera- (13aS,14S) was determined by comparison with authentic
ture before quenching, the yield of ketone 6 was reduced to samples (DCB-3501 and DCB-3503) prepared according to
82%. Similar results were also reported by Lete and a reported procedure.[6c] The alcohol 8a-(13aS,14S) was re-
co-workers.[9g,9i]
duced using triethylsilane and trifluoroacetic acid to give
The synthetic route to enantiopure phenanthro-indolizi- (+)-tylophorine [1a-(S)] in 94% yield and 97% ee. When
dine alkaloids 1a–c is illustrated in Scheme 2. Amide 7a-(S) using (R)-N,N-diethylpyrrolidine-2-carboxamide instead of
was prepared by alkylation of (S)-N,N-diethylpyrrolidine-2- (S)-N,N-diethylpyrrolidine-2-carboxamide, (–)-tylophorine
carboxamide with dibromide 4a under the above condi- [1a-(R)] was obtained by the same procedure in 73% overall
tions. Amide 7a-(S) was subsequently treated with nBuLi yield and 93% ee.
Scheme 2. Synthesis of a series of phenanthro-indolizidine alkaloids 1a–c.
Eur. J. Org. Chem. 2010, 292–299
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293

Z. Wang, Z. Li, K. Wang, Q. Wang
FULL PAPER
High-resolution mass spectra were obtained with an FT-ICR MS
spectrometer (Ionspec, 7.0 T). The enantiomeric excesses of 1a–c
were determined by HPLC with a Chiralcel AD-H column using
Agilent 1100 instrument. Optical rotations were recorded with a
Perkin–Elmer 341 MC polarimeter. Chromatographic separations
were carried out under pressure on silica gel using flash column
techniques. All anhydrous solvents were dried and purified by stan-
dard techniques just before use. The corresponding esters 2a–c[7]
and α-amino acid derivatives (S)-N,N-diethylpyrrolidine-2-carbox-
amide, (R)-N,N-diethylpyrrolidine-2-carboxamide[12] and N,N-di-
Although a similar approach seemed directly applicable
to the preparation of 1b,c, differences were immediately
noted. When 3b was treated with bromine in chloroform at
0 °C, dibromide 4b was obtained accompanied by a small
percentage of tribromide 4d. The two compounds could be
separated by silica gel chromatography with chloroform/
hexane (5:1) as eluent, and the mass ratio of 4b and 4d was
about 19:1. The 1H NMR spectrum of 4d indicated that the
additional bromine was located at the 5-position. As the
bromides appeared to be sensitive to silica gel, 4b and 4d ethyl-1H-pyrrole-2-carboxamide[13] were prepared by the reported
1
procedures, and the H NMR spectra of these compounds are in
accord with the literature.
were directly converted into amides 7b-(S) and 7d-(S) in a
combined yield of 95%. Because the bromine at the 5-posi-
tion of 7d-(S) could be reduced under metallation–cycliza-
tion–reduction conditions, 7d-(S) could afford same prod-
uct 8b-(13aS,14S) as 7b-(S), but a little excess of nBuLi
(3.2 equiv.), TMEDA (3.3 equiv.) and sodium borohydride
(5 equiv.) was required. Without separation, 7b-(S) and 7d-
(S) were directly converted into 8b-(13aS,14S) in 95% yield.
Alcohol 8b-(13aS,14S) was reduced using triethylsilane and
trifluoroacetic acid to give (+)-deoxytylophorinine [1b-(S)]
in 96% yield and 95% ee. By using the same procedure,
(–)-deoxytylophorinine [1b-(R)], (+)-antofine [1c-(S)] and
(–)-antofine [1c-(R)] were obtained in overall yields of 71,
75 and 71% and enantiomeric excess of 97, 99 and 98%,
respectively.
2,3,6,7-Tetramethoxy-9-(hydroxymethyl)phenanthrene (3a): A sus-
pension of ester 2a (15 g, 42 mmol) in dry tetrahydrofuran
(200 mL) was added in small portions to a suspension of lithium
aluminium hydride (4.8 g, 0.13 mol) in dry tetrahydrofuran
(150 mL) at ice-bath temperature. After the reaction mixture had
been stirred at room temperature under dry nitrogen for 3 h, the
mixture was cooled and water (7 mL) was carefully added dropwise,
followed by 20% HCl (10 mL) and water (25 mL). The precipitated
inorganic salts were removed by filtration through Celite and
washed with chloroform (100 mL). The organic layer was dried
with anhydrous magnesium sulfate and the solvent was evaporated.
The crude product was recrystallized from ethyl acetate to afford
3a (13.27 g, 96%) as a white solid; m.p. 183–184 °C (ref.[8c] m.p.
183–184 °C). 1H NMR (400 MHz, CDCl3): δ = 7.60 (s, 1 H, Ar-H),
7.53 (s, 1 H, Ar-H), 7.35 (s, 2 H, Ar-H), 6.95 (s, 1 H, Ar-H), 4.94
(s, 2 H, ArCH2), 4.04 (s, 3 H, OMe), 4.02 (s, 3 H, OMe), 3.96
(s, 3 H, OMe), 3.88 (s, 3 H, OMe), 2.37 (s, 1 H, OH) ppm.
13C NMR (100 MHz, CDCl3): δ = 148.8, 148.6, 148.4, 148.3, 131.9,
125.6, 124.7, 124.3, 124.1, 123.3, 108.1, 104.5, 102.9, 102.4, 64.1,
55.8, 55.8, 55.7, 55.6 ppm.
Conclusions
A short, simple and efficient route to enantiopure phen-
anthro-indolizidine alkaloids has been accomplished with
Parham-type cycloacylation as the key step. This new pro-
10-(Hydroxymethyl)-2,3,6-trimethoxyphenanthrene (3b):
A pro-
cedure has distinct advantages over previous ones: It is sim- cedure analogous to the preparation of alcohol 3a was used. Ester
2b (15 g, 46 mmol) gave 3b (13.3 g, 97%) as a white solid; m.p. 161–
162 °C (ref.[14] m.p. 155–156 °C). 1H NMR (400 MHz, CDCl3):
δ = 7.85 (s, 1 H, Ar-H), 7.79 (s, 1 H, Ar-H), 7.74 (d, J = 8.7 Hz, 1
H, Ar-H), 7.56 (s, 1 H, Ar-H), 7.50 (s, 1 H, Ar-H), 7.17 (d, J =
8.7 Hz, 1 H, Ar-H), 5.06 (s, 2 H, ArCH2), 4.09 (s, 3 H, OMe), 4.04
(s, 3 H, OMe), 4.00 (s, 3 H, OMe), 1.78 (s, 1 H, OH) ppm.
13C NMR (100 MHz, CDCl3): δ = 158.4, 149.4, 148.8, 131.4, 131.2,
130.2, 125.8, 125.5, 124.8, 124.6, 115.4, 104.8, 103.9, 103.7, 64.7,
56.0, 55.9, 55.5 ppm.
ple and practical, allowing a series of phenanthro-indolizid-
ine alkaloids to be prepared on a large scale, it involves few
steps and high overall yields (Ͼ70%) and ee values (up to
99%) were obtained. The versatility and flexibility of the
method was demonstrated by the preparation of six repre-
sentative phenanthro-indolizidine alkaloids. As a result of
the robust nature of this approach, a systematic exploration
of the pharmacological profile of this promising class of
bioactive natural products may be possible.
2,3,6-Trimethoxy-9-(hydroxymethyl)phenanthrene (3c): A procedure
analogous to the preparation of alcohol 3a was used. The ester 2c
(15 g, 46 mmol) gave 3c (13 g, 95%) as a white solid; m.p. 183–
184 °C (ref.[6c] m.p. 187 °C). 1H NMR (400 MHz, CDCl3): δ = 8.05
(d, J = 9.0 Hz, 1 H, Ar-H), 7.83 (s, 1 H, Ar-H), 7.77 (s, 1 H, Ar-H),
7.45 (s, 1 H, Ar-H), 7.21 (d, J = 9.0 Hz, 1 H, Ar-H), 7.09 (s, 1 H,
Ar-H), 5.07 (s, 2 H, ArCH2), 4.06 (s, 3 H, OMe), 4.00 (s, 3 H,
OMe), 3.96 (s, 3 H, OMe), 2.02 (s, 1 H, OH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 158.0, 149.4, 149.1, 132.8, 131.7, 127.0,
126.1, 124.3, 124.1, 123.1, 115.1, 108.3, 104.6, 103.3, 64.2, 56.0,
55.8, 55.5 ppm.
Experimental Section
General: The melting points were determined with an X-4 binocu-
lar microscope melting-point apparatus (Beijing Tech Instruments
Co., Beijing, China) and are uncorrected. 1H NMR spectra were
obtained by using Bruker AC-P 300, Bruker AC-P 400 and Varian
Mercury Plus 400 spectrometers. Chemical shifts (δ) are given in
parts per million and were measured downfield from internal tet-
ramethylsilane. 13C NMR spectra were recorded by using Bruker
AC-P 300 (75 MHz), Bruker AC-P 400 (100 MHz) and Varian
Mercury Plus 400 spectrometers (100 MHz) and CDCl3 as solvent.
Chemical shifts (δ) are reported in parts per million using the sol-
vent peak (δ =77.0 ppm) as reference. IR spectra were recorded
with a MAGNA-560 FTIR (Nicolet Company) spectrometer. Mass
spectra were obtained with VG ZAB-HS and LCQ Advantage spec-
trometers using the EI or FAB and ESI methods, respectively.
9-Bromo-10-(bromomethyl)-2,3,6,7-tetramethoxyphenanthrene (4a):
A solution of bromine (5.12 g, 32 mmol) in chloroform (50 mL)
was added to a solution of alcohol 3a (10 g, 30.5 mmol) in chloro-
form (250 mL) at 0 °C. The mixture was stirred at room tempera-
ture for 10 h and cooled to 0 °C for 1 h. Then the mixture was
filtered to afford 4a (13.18 g, 92%) as a grey solid; m.p. 245–246 °C
1
(dec.). H NMR (400 MHz, CDCl3): δ = 7.77 (s, 1 H, Ar-H), 7.73
294
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Synthesis of Phenanthro-indolizidine Alkaloids
(s, 1 H, Ar-H), 7.69 (s, 1 H, Ar-H), 7.44 (s, 1 H, Ar-H), 5.25 (s, 2 H, 1093, 1050, 850, 806, 765, 750 cm–1. HRMS (ESI): calcd. for
ArCH2), 4.12 (s, 6 H, OMe), 4.10 (s, 3 H, OMe), 4.08 (s, 3 H, C18H15Br3NaO3 [M + Na]+ 538.8464; found 538.8466.
OMe) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.1, 149.4, 149.1,
(S)-1-[(9-Bromo-2,3,6,7-tetramethoxyphenanthren-10-yl)methyl]-
N,N-diethylpyrrolidine-2-carboxamide [7a-(S)]: A solution of bro-
128.3, 125.6, 124.7, 124.4, 124.1, 123.1, 109.3, 105.0, 103.0, 102.5,
56.1, 56.0, 56.0, 33.4 ppm. IR (KBr): ν = 3018, 2832, 1617, 1507,
˜
mide 4a (5 g, 10.6 mmol), (S)-N,N-diethylpyrrolidine-2-carboxam-
ide (1.99 g, 11.7 mmol) and potassium carbonate (6.46 g,
46.8 mmol) in N,N-dimethylformamide (150 mL) was heated at re-
flux for 8 h. After cooling, the reaction mixture was filtered and
concentrated in vacuo and the residue was purified by flash column
chromatography on silica gel to give amide 7a-(S) (5.7 g, 97%) as
a light-yellow solid; m.p. 150–151 °C. [α]2D0 = –75 (c = 2.0, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 8.52 (s, 1 H, Ar-H), 7.86 (s, 1
H, Ar-H), 7.78 (s, 1 H, Ar-H), 7.73 (s, 1 H, Ar-H), 4.54 (d, J =
12.2 Hz, 1 H, ArCH2), 4.37 (d, J = 12.3 Hz, 1 H, ArCH2), 4.21 (s,
3 H, OMe), 4.12 (s, 3 H, OMe), 4.11 (s, 3 H, OMe), 4.08 (s, 3 H,
OMe), 3.33–3.50 (m, 5 H, N-CH2, 2-H), 2.88–2.94 (m, 1 H, 5-H),
2.65–2.71 (m, 1 H, 5-H), 2.08–2.16 (m, 1 H, 3-H), 1.71–1.91 (m,
3 H, 3-H, 4-H), 1.10–1.09 (m, 6 H, NCH2-CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.3, 149.5, 149.4, 149.3, 149.1, 131.0,
127.1, 125.4, 125.0, 123.9, 122.5, 109.9, 108.5, 102.9, 102.4, 64.0,
56.9, 56.1, 56.0, 56.0, 51.7, 41.4, 40.3, 29.8, 22.9, 14.8, 13.2 ppm.
1410, 1253, 1196, 1150, 1058, 1040, 833, 759, 743, 657, 547 cm–1.
MS (EI, 70 eV): m/z (%) = 470 (20) [M]+, 391 (100), 347 (8), 326
(8), 268 (7), 169 (13), 150 (9), 80 (8), 43 (7). HRMS (ESI): calcd.
for C19H18BrO4 [M – Br]+ 389.0383; found 389.0377.
9-Bromo-10-(bromomethyl)-2,3,6-trimethoxyphenanthrene (4b) and
5,9-Dibromo-10-(bromomethyl)-2,3,6-trimethoxyphenanthrene (4d):
A solution of bromine (5.9 g, 36.9 mmol) in chloroform (50 mL)
was added to a solution of alcohol 3b (10 g, 33.6 mmol) in chloro-
form (250 mL) at 0 °C and the mixture was stirred at room tem-
perature for 10 h. The solvent was evaporated in vacuo and the
residue was purified by column chromatography over silica gel elut-
ing with chloroform to give a 19:1 (mass ratio) mixture of dibro-
mide 4b and tribromide 4d (13.2 g, 89% combined yield). The mix-
ture was purified by chromatography again with chloroform/hexane
(5:1) to give 4b and a little of 4d for spectral and mass analysis. 4b:
1
m.p. 207–209 °C (dec.). H NMR (400 MHz, CDCl3): δ = 8.36 (d,
IR (KBr): ν = 2966, 2934, 1649, 1619, 1510, 1469, 1420, 1251, 1198,
˜
J = 9.2 Hz, 1 H, 8-H), 7.82 (s, 1 H, Ar-H), 7.78 (d, J = 2.4 Hz, 1
H, Ar-H), 7.45 (s, 1 H, 5-H), 7.24 (dd, J = 9.2, 2.4 Hz 1 H, 7-H),
5.23 (s, 2 H, ArCH2), 4.10 (s, 3 H, OMe), 4.10 (s, 3 H, OMe), 4.02
(s, 3 H, OMe) ppm. 13C NMR (100 MHz,CDCl3): δ = 159.2, 149.9,
149.3, 132.3, 131.3, 127.9, 125.6, 124.4, 124.1, 124.1, 116.1, 105.3,
1147, 1070, 846, 752 cm–1. HRMS (ESI): calcd. for C28H36BrN2O5
[M + H]+ 559.1802; found 559.1810.
(R)-1-[(9-Bromo-2,3,6,7-tetramethoxyphenanthren-10-yl)methyl]-
N,N-diethylpyrrolidine-2-carboxamide [7a-(R)]: A procedure analo-
gous to the preparation of 7a-(S) was used. Bromide 4a (5 g,
10.6 mmol) and (R)-N,N-diethylpyrrolidine-2-carboxamide (1.99 g,
11.7 mmol) gave 7a-(R) (5.6 g, 94%) as a light-yellow solid; m.p.
142–143 °C. [α]2D0 = +67.5 (c = 2.0, CHCl3); other data are the same
as those of 7a-(S).
104.2, 103.8, 56.1, 56.0, 55.6, 33.3 ppm. IR (KBr): ν = 2925, 1615,
˜
1527, 1506, 1457, 1434, 1261, 1205, 1118, 1060, 1036, 842 cm–1.
HRMS (ESI): calcd. for C18H16Br2O3Na [M + Na]+ 460.9358;
1
found 460.9360. 4d: m.p. 224–226 °C (dec.). H NMR (400 MHz,
CDCl3): δ = 9.30 (s, 1 H, Ar-H), 8.49 (d, J = 9.1 Hz, 1 H, Ar-H),
7.50 (s, 1 H, Ar-H), 7.29 (d, J = 9.2 Hz, 1 H, Ar-H), 5.20 (s, 2 H,
ArCH2), 4.11 (s, 3 H, OMe), 4.10 (s, 3 H, OMe), 4.07 (s, 3 H,
OMe) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.4, 149.5, 147.1,
131.2, 130.7, 130.4, 129.3, 126.9, 126.2, 124.0, 123.5, 111.7, 110.1,
(S)-1-[(9-Bromo-2,3,6-trimethoxyphenanthren-10-yl)methyl]-N,N-di-
ethylpyrrolidine-2-carboxamide [7b-(S)] and (S)-1-[(4,10-Dibromo-
3,6,7-trimethoxyphenanthren-9-yl)methyl]-N,N-diethylpyrrolidine-2-
carboxamide [7d-(S)]: A procedure analogous to the preparation of
7a-(S) was used. A mixture (19:1, mass ratio) of bromides 4b and
4d (5 g, 11.3 mmol) and (S)-N,N-diethylpyrrolidine-2-carboxamide
(2.12 g, 12.5 mmol) gave a mixture of 7b-(S) and 7d-(S) (5.7 g, 95%
combined yield). 7b-(S): m.p. 69–70 °C. [α]2D0 = –74 (c = 2.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.51 (s, 1 H, Ar-H),
104.8, 57.1, 56.3, 56.0, 33.0 ppm. IR (KBr): ν = 3437, 2954, 2922,
˜
2850, 2380, 2310, 1598, 1531, 1502, 1469, 1378, 1279, 1266, 1206,
1150, 1127, 1068, 1055, 765, 750 cm–1. HRMS (ESI): calcd. for
C18H15Br3NaO3 [M + Na]+ 538.8464; found 538.8480.
10-Bromo-9-(bromomethyl)-2,3,6-trimethoxyphenanthrene (4c) and
5,10-Dibromo-9-(bromomethyl)-2,3,6-trimethoxyphenanthrene (4e): 8.36 (d, J = 9.2 Hz, 1 H, Ar-H), 7.78 (s, 1 H, Ar-H), 7.76 (s, 1 H,
A procedure analogous to the preparation of 4b and 4d was used.
The alcohol 3c (10 g, 33.6 mmol) gave a 15:1 (mass ratio) mixture
of dibromide 4c and tribromide 4e (13.4 g, 90% combined yield).
Ar-H), 7.18 (d, J = 9.0 Hz, 1 H, Ar-H), 4.48 (d, J = 12.1 Hz, 1 H,
ArCH2), 4.33 (d, J = 12.2 Hz, 1 H, ArCH2), 4.22 (s, 3 H, OMe),
4.08 (s, 3 H, OMe), 3.98 (s, 3 H, OMe), 3.30–3.47 (m, 5 H, N-CH2,
2-H), 2.89–2.92 (m, 1 H, 5-H), 2.61–2.72 (m, 1 H, 5-H), 2.06–2.14
(m, 1 H, 3-H), 1.69–1.88 (m, 3 H, 3-H, 4-H), 1.09–1.16 (m, 6 H,
NCH2-CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.2, 158.4,
149.8, 149.0, 132.0, 131.1, 131.2, 128.0, 124.5, 123.6, 123.1, 115.4,
108.5, 103.9, 102.6, 64.0, 56.9, 56.0, 55.9, 55.5, 51.7, 41.3, 40.3,
1
4c: m.p. 180–182 °C (dec.). H NMR (400 MHz, CDCl3): δ = 8.03
(d, J = 9.2 Hz, 1 H, 8-H), 7.74 (d, J = 2.4 Hz, 1 H, 5-H), 7.72
(s, 1 H, Ar-H), 7.71 (s, 1 H, Ar-H), 7.26 (dd, J = 9.2, 2.32 Hz, 1
H, 7-H), 5.19 (s, 2 H, ArCH2), 4.08 (s, 3 H, OMe), 4.06 (s, 3 H,
OMe), 4.00 (s, 3 H, OMe) ppm. 13C NMR (100 MHz, CDCl3):
δ = 158.3, 150.0, 150.0, 130.8, 129.4, 126.4, 125.8, 125.4, 123.8,
122.8, 115.8, 109.4, 104.8, 103.1, 56.1, 56.0, 55.5, 32.8 ppm. IR
29.7, 22.8, 14.8, 13.2 ppm. IR (KBr): ν = 3445, 3080, 2968, 2934,
˜
2871, 2851, 2380, 2310, 1648, 1615, 1526, 1504, 1468, 1414, 1379,
(KBr): ν = 3007, 2958, 2931, 2849, 2833, 1616, 1511, 1469, 1420, 1260, 1236, 1206, 1168, 1121, 1070, 1035, 895, 751 cm–1. HRMS
˜
1261, 1235, 1205, 1165, 1061, 846, 754 cm–1. HRMS (ESI): calcd.
(ESI): calcd. for C27H34BrN2O4 [M + H]+ 529.1696; found
529.1695. 7d-(S): m.p. 190–192 °C. [α]2D0 = –82.5 (c = 2.0, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 9.18 (s, 1 H, Ar-H), 8.55 (s, 1
H, Ar-H), 8.49 (d, J = 9.2 Hz, 1 H, Ar-H), 7.24 (d, J = 9.2 Hz, 1
H, Ar-H), 4.52 (d, J = 12.4 Hz, 1 H, ArCH2), 4.36 (d, J = 12.4 Hz,
1 H, ArCH2), 4.22 (s, 3 H, OMe), 4.08 (s, 3 H, OMe), 4.05 (s, 3 H,
for C18H16Br2O3Na [M + Na]+ 460.9358; found 460.9366. 4e: m.p.
1
241–243 °C (dec.). H NMR (400 MHz, CDCl3): δ = 9.30 (s, 1 H,
Ar-H), 8.14 (d, J = 9.2 Hz, 1 H, Ar-H), 7.85 (s, 1 H, Ar-H), 7.34
(d, J = 9.2 Hz, 1 H, Ar-H), 5.24 (s, 2 H, ArCH2), 4.10 (s, 3 H,
OMe), 4.10 (s, 3 H, OMe), 4.08 (s, 3 H, OMe) ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.7, 149.8, 147.9, 130.0, 128.9, 127.3, OMe), 3.26–3.47 (m, 5 H, N-CH2, 2-H), 2.90–2.94 (m, 1 H, 5-H),
126.0, 125.5, 125.3, 124.2, 111.8, 109.7, 109.0, 107.4, 57.1, 56.4,
2.60–2.66 (m, 1 H, 5-H), 2.07–2.15 (m, 1 H, 3-H), 1.70–1.87 (m,
3 H, 3-H, 4-H), 1.08–1.15 (m, 6 H, NCH2-CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.1, 155.6, 149.5, 146.7, 131.7, 131.1,
56.0, 33.1 ppm. IR (KBr): ν = 3446, 2993, 2957, 2929, 2849, 2380,
˜
2310, 1599, 1524, 1510, 1462, 1423, 1379, 1285, 1262, 1206, 1138,
Eur. J. Org. Chem. 2010, 292–299
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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295

Z. Wang, Z. Li, K. Wang, Q. Wang
FULL PAPER
130.2, 129.3, 126.4, 123.5, 122.3, 111.2, 109.0, 107.7, 106.4, 63.8,
57.0, 56.9, 56.1, 56.0, 51.7, 41.3, 40.3, 29.8, 22.8, 14.8, 13.2 ppm.
combined yield). 7c-(R): m.p. 174–176 °C. [α]2D0 = +64 (c = 2.0,
CHCl3); other data are the same as those for 7c-(S). 7e-(R): m.p.
174–176 °C. [α]2D0 = +56.5 (c = 2.0, CHCl3); other data are the same
as those for 7e-(S).
IR (KBr): ν = 3077, 2970, 2935, 2871, 2845, 1648, 1615, 1594, 1525,
˜
1499, 1464, 1429, 1382, 1282, 1263, 1210, 1121, 1093, 1061, 862,
791, 753 cm–1. HRMS (ESI): calcd. for C27H33Br2N2O4 [M + H]+
607.0802; found 607.0811.
1-[(9-Bromo-2,3,6,7-tetramethoxyphenanthren-10-yl)methyl]-N,N-di-
ethyl-1H-pyrrole-2-carboxamide (5): A procedure analogous to the
preparation of 7a-(S) was used. The bromide 4a (5 g, 10.6 mmol)
and N,N-diethyl-1H-pyrrole-2-carboxamide (1.94 g, 11.7 mmol)
gave 5 (5.6 g, 95%) as a light-yellow solid; m.p. 192–194 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.89 (s, 1 H, Ar-H), 7.86 (s, 1 H,
Ar-H), 7.80 (s, 1 H, Ar-H), 7.75 (s, 1 H, Ar-H), 6.43 (s, 1 H, 5-H), 6.39
(s, 1 H, 3-H), 6.14 (s, 2 H, ArCH2), 5.94 (s, 1 H, 4-H), 4.15 (s, 3 H,
OMe), 4.14 (s, 3 H, OMe), 4.10 (s, 3 H, OMe), 3.92 (s, 3 H, OMe),
3.62–3.64 (m, 4 H, N-CH2), 1.29 (t, 6 H, NCH2-CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 164.2, 150.1, 149.7, 149.5, 149.4,
128.4, 126.1, 125.8, 125.6, 124.7, 124.3, 124.2, 123.4, 111.4, 109.7,
106.9, 106.7, 102.8, 102.8, 56.6, 56.2, 56.1, 56.0, 50.0, 41.6, 41.5,
(R)-1-[(9-Bromo-2,3,6-trimethoxyphenanthren-10-yl)methyl]-N,N-di-
ethylpyrrolidine-2-carboxamide [7b-(R)] and (R)-1-[(4,10-Dibromo-
3,6,7-trimethoxyphenanthren-9-yl)methyl]-N,N-diethylpyrrolidine-2-
carboxamide [7d-(R)]: A procedure analogous to the preparation of
7a-(S) was used. A mixture (19:1, mass ratio) of bromides 4b and
4d (5 g, 11.3 mmol) and (R)-N,N-diethylpyrrolidine-2-carboxamide
(2.12 g, 12.5 mmol) gave a mixture of 7b-(R) and 7d-(R) (5.6 g, 93%
combined yield). 7b-(R): m.p. 67–69 °C. [α]2D0 = +76 (c = 2.0,
CHCl3); other data are the same as those for 7b-(S). 7d-(R): m.p.
187–189 °C. [α]2D0 = +80 (c = 2.0, CHCl3); other data are the same
as those for 7d-(S).
13.8, 13.6 ppm. IR (KBr): ν = 3105, 3000, 2967, 2934, 2835, 1615,
˜
1530, 1512, 1470, 1422, 1253, 1212, 1151, 1070, 752 cm–1. HRMS
(ESI): calcd. for C28H32BrN2O5 [M + H]+ 555.1489; found
555.1490.
(S)-1-[(10-Bromo-2,3,6-trimethoxyphenanthren-9-yl)methyl]-N,N-di-
ethylpyrrolidine-2-carboxamide [7c-(S)] and (S)-1-[(5,10-Dibromo-
2,3,6-trimethoxyphenanthren-9-yl)methyl]-N,N-diethylpyrrolidine-2-
carboxamide [7e-(S)]: A procedure analogous to the preparation of
7a-(S) was used. A mixture (15:1, mass ratio) of bromides 4c and
4e (5 g, 11.3 mmol) and (S)-N,N-diethylpyrrolidine-2-carboxamide
(2.12 g, 12.5 mmol) gave a mixture of 7c-(S) and 7e-(S) (5.7 g, 95%
combined yield). 7c-(S): m.p. 74–76 °C. [α]2D0 = –60 (c = 2.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.93 (d, J = 9.2 Hz,
1 H, Ar-H), 7.85 (s, 2 H, Ar-H), 7.80 (d, J = 2.1 Hz, 1 H, Ar-H),
7.34 (dd, J = 9.2, 2.21 Hz, 1 H, Ar-H), 4.57 (d, J = 12.2 Hz, 1 H,
ArCH2), 4.32 (d, J = 12.3 Hz, 1 H, ArCH2), 4.10 (s, 3 H, OMe),
4.07 (s, 3 H, OMe), 4.00 (s, 3 H, OMe), 3.26–3.54 (m, 5 H, N-CH2,
2-H), 2.92–2.96 (m, 1 H, 5-H), 2.63–2.70 (m, 1 H, 5-H), 2.09–2.18
(m, 1 H, 3-H), 1.71–1.93 (m, 3 H, 3-H, 4-H), 1.10–1.17 (m, 6 H,
NCH2-CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.5, 158.1,
149.7, 149.2, 131.7,130.5, 129.5, 126.2, 126.0, 125.2, 122.0, 115.3,
109.8, 104.2, 103.2, 64.3, 56.1, 55.9, 55.8, 55.5, 51.9, 41.3, 40.3,
Ketone 6: A solution of nBuLi in hexane (2.64 mL, 3.92 mmol) was
added to a solution of amide 5 (1 g, 1.8 mmol) and TMEDA
(0.48 g, 4.14 mmol) in dry tetrahydrofuran (80 mL) at –78 °C and
the resulting mixture was stirred at this temperature for 4 h under
nitrogen and then quenched by the addition of saturated ammo-
nium chloride (30 mL) at –78 °C. The product was extracted with
methylene dichloride (3ϫ30 mL). The combined organic extracts
were dried with anhydrous magnesium sulfate and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel to give 6 (0.65 g, 90%) as a yellow solid; m.p. 253–
255 °C (dec.). 1H NMR (400 MHz, CDCl3): δ = 9.54 (s, 1 H,
Ar-H), 7.56 (s, 2 H, Ar-H), 7.13 (s, 1 H, Ar-H), 7.09 (s, 1 H, 11-
H), 6.88 (s, 1 H, 13-H), 6.48 (s, 1 H, 12-H), 5.41 (s, 2 H, 9-H),
4.08 (s, 9 H, OMe), 4.02 (s, 3 H, OMe) ppm. 13C NMR (100 MHz,
CDCl3): δ = 177.4, 151.3, 148.9, 148.9, 148.7, 129.7, 126.8, 125.0,
124.4, 123.0, 121.1, 120.5, 111.3, 111.1, 107.9, 104.7, 103.7, 103.5,
29.5, 22.9, 14.7, 13.1 ppm. IR (KBr): ν = 3445, 3084, 2961, 2931,
˜
2871, 2853, 1729, 1643, 1617, 1510, 1466, 1435, 1366, 1302, 1261,
1233, 1204, 1164, 1129, 1069, 848, 830, 751 cm–1. HRMS (ESI):
calcd. for C27H34BrN2O4 [M + H]+ 529.1696; found 529.1701. 7e-
(S): m.p. 174–176 °C. [α]2D0 = –62.5 (c = 2.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 9.32 (s, 1 H, Ar-H), 9.22 (d, J = 9.3 Hz,
1 H, Ar-H), 7.90 (s, 1 H, Ar-H), 7.43 (d, J = 9.3 Hz, 1 H, Ar-H),
4.52 (d, J = 12.2 Hz, 1 H, ArCH2), 4.31 (d, J = 12.2 Hz, 1 H,
ArCH2), 4.10 (s, 3 H, OMe), 4.09 (s, 3 H, OMe), 4.05 (s, 3 H,
OMe), 3.28–3.57 (m, 5 H, N-CH2, 2-H), 2.85–2.89 (m, 1 H, 5-H),
2.59–2.66 (m, 1 H, 5-H), 2.10–2.19 (m, 1 H, 3-H), 1.69–1.91
(m, 3 H, 3-H, 4-H), 1.10–1.20 (m, 6 H, NCH2-CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 172.3, 155.5, 149.3, 147.1, 131.0,
129.5, 128.9, 128.3, 127.3, 125.0, 123.2, 112.1, 109.7, 109.3, 105.9,
64.4, 56.9, 56.3, 55.9, 51.8, 41.3, 40.4, 29.7, 22.9, 14.7, 13.0 ppm.
103.4, 55.9, 55.6, 55.6, 55.1, 45.5 ppm. IR (KBr): ν = 2992, 2956,
˜
2925, 2851, 1622, 1527, 1513, 1473, 1423, 1403, 1338, 1260, 1197,
1149, 1097, 1043, 831, 764, 750 cm–1. HRMS (ESI): calcd. for
C24H21NNaO5 [M + Na]+ 426.1312; found 426.1306.
(13aS,14S)-14-Hydroxytylophorine (DCB-3503) and (13aS,14R)-14-
Hydroxytylophorine (DCB-3501): Following the reported synthetic
sequences,[6c] DCB-3503 and DCB-3501 were prepared. DCB-3503:
m.p. 271–272 °C (dec.) (ref.[6c] m.p. 270 °C). [α]2D0 = +81.0 (c = 2.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.92 (s, 1 H, Ar-H),
7.61 (s, 1 H, Ar-H), 7.38 (s, 1 H, Ar-H), 5.98 (s, 1 H, Ar-H), 4.83
(s, 1 H, 14-H), 4.15 (s, 3 H, OMe), 4.11 (s, 3 H, OMe), 4.10 (s, 3 H,
OMe), 3.77 (s, 3 H, OMe), 3.28–3.35 (m, 1 H, 13a-H), 3.19 (d, J =
14.8 Hz, 1 H, 9-H), 2.89 (d, J = 14.8 Hz, 1 H, 9-H), 2.39–2.46 (m,
1 H, 11-H), 2.24–2.29 (m, 1 H, 11-H), 2.13–2.21 (m, 1 H, 13-H),
2.03–2.09 (m, 1 H, 13-H), 1.84–1.93 (m, 2 H, 12-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 148.7, 148.6, 148.4, 147.8, 127.7, 126.5,
125.9, 123.9, 123.8, 122.6, 105.5, 102.8, 102.7, 102.3, 65.5, 64.7,
56.1, 55.9, 55.6, 55.6, 53.2, 23.9, 21.6 ppm. DCB-3501: m.p. 243–
IR (KBr): ν = 3446, 2963, 2933, 2870, 2854, 1643, 1598, 1509, 1463,
˜
1426, 1385, 1283, 1261, 1213, 1142, 1107, 1051, 860, 751 cm–1
.
HRMS (ESI): calcd. for C27H33Br2N2O4 [M + H]+ 607.0802; found
607.0800.
(R)-1-[(10-Bromo-2,3,6-trimethoxyphenanthren-9-yl)methyl]-N,N-di- 245 °C (dec.) (ref.[6c] m.p. 245 °C). [α]2D0 = +74.9 (c = 2.0, CHCl3).
ethylpyrrolidine-2-carboxamide [7c-(R)] and (R)-1-[(5,10-Dibromo-
2,3,6-trimethoxyphenanthren-9-yl)methyl]-N,N-diethylpyrrolidine-2-
carboxamide [7e-(R)]: A procedure analogous to the preparation of
7a-(S) was used. A mixture (15:1, mass ratio) of bromides 4c and
4e (5 g, 11.3 mmol) and (R)-N,N-diethylpyrrolidine-2-carboxamide
(2.12 g, 12.5 mmol) gave a mixture of 7c-(R) and 7e-(R) (5.6 g, 94%
1H NMR (400 MHz, CDCl3): δ = 7.52 (s, 1 H, Ar-H), 7.50 (s, 1
H, Ar-H), 7.47 (s, 1 H, Ar-H), 6.58 (s, 1 H, Ar-H), 4.41 (d, J =
7.5 Hz, 1 H, 14-H), 4.08 (s, 3 H, OMe), 4.05 (s, 3 H, OMe), 3.93
(d, J = 11.5 Hz, 1 H, 9-H), 3.91 (s, 3 H, OMe), 3.77 (s, 3 H, OMe),
2.96–3.01 (m, 1 H, 13a-H), 2.87 (d, J = 13.8 Hz, 1 H, 9-H), 1.95–
2.00 (m, 1 H, 11-H), 1.85–1.90 (m, 1 H, 11-H), 1.73–1.79 (m, 1 H,
296
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 292–299

Synthesis of Phenanthro-indolizidine Alkaloids
13-H), 1.55–1.62 (m, 1 H, 13-H), 1.43–1.50 (m, 1 H, 12-H), 1.23–
1.33 (m, 1 H, 12-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.8,
148.6, 148.3, 148.1, 129.1, 127.4, 124.8, 124.3, 124.1, 123.3, 107.2,
103.4, 103.2, 102.9, 72.9, 68.7, 55.9, 55.9, 55.8, 54.8, 53.8, 29.7,
21.5 ppm.
light-yellow solid; m.p. 229–231 °C (dec.). [α]2D0 = –156.5 (c = 2.0,
CHCl3); other data are the same as those for 8b-(13aS,14S).
(13aS,14S)-14-Hydroxyantofine [8c-(13aS,14S)]: A procedure anal-
ogous to the preparation of 8b-(13aS,14S) was used. A mixture of
7c-(S) and 7e-(S) (2 g, 3.8 mmol) gave 8c-(13aS,14S) (1.35 g, 95%)
as a light-yellow solid; m.p. 229–231 °C (dec.). [α]2D0 = +209.5
(13aS,14S)-14-Hydroxytylophorine [8a-(13aS,14S)]: A solution of
nBuLi in hexane (13.1 mL, 19.7 mmol) was added to a solution of
amide 7a-(S) (5 g, 8.9 mmol) and TMEDA (2.4 g, 20.6 mmol) in
dry tetrahydrofuran (200 mL) at –78 °C and the resulting mixture
was stirred at this temperature for 4 h under nitrogen. Then meth-
anol (50 mL) and sodium borohydride (1.7 g, 44.7 mmol) were
added to the mixture. After stirring at –40 °C for 1 h at room tem-
perature for 8 h, the reaction mixture were quenched with water
(100 mL) and the products were extracted with methylene dichlo-
ride (3ϫ80 mL). The combined organic extracts were dried with
anhydrous magnesium sulfate and concentrated in vacuo. The resi-
due was purified by flash column chromatography on silica gel to
give 8a-(13aS,14S) (3.4 g, 94%) as a light-yellow solid; m.p. 267–
269 °C (dec.) (ref.[6c] m.p. 270 °C). [α]2D0 = +148.5 (c = 2.0, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.94 (s, 1 H, Ar-H), 7.62 (s, 1
H, Ar-H), 7.39 (s, 1 H, Ar-H), 6.00 (s, 1 H, Ar-H), 4.84 (s, 1 H,
14-H), 4.15 (s, 3 H, OMe), 4.12 (s, 3 H, OMe), 4.10 (s, 3 H, OMe),
3.77 (s, 3 H, OMe), 3.28–3.35 (m, 1 H, 13a-H), 3.19 (d, J = 13.9 Hz,
1 H, 9-H), 2.90 (d, J = 14.8 Hz, 1 H, 9-H), 2.39–2.46 (m, 1 H, 11-
H), 2.24–2.29 (m, 1 H, 11-H), 2.13–2.21 (m, 1 H, 13-H), 2.03–2.09
(m, 1 H, 13-H), 1.84–1.93 (m, 2 H, 12-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 148.5, 148.3, 148.2, 147.5, 127.6, 126.7,
126.0, 123.6, 122.5, 105.4, 102.5, 102.4, 101.9, 65.4, 64.7, 56.1, 55.9,
1
(c = 2.0, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.86 (s, 1 H,
Ar-H), 7.76 (s, 1 H, Ar-H), 7.59 (s, 1 H, Ar-H), 6.67 (d, J = 8.4 Hz,
1 H, Ar-H), 6.59 (d, J = 9.0 Hz, 1 H, Ar-H), 5.73 (br., 1 H, OH),
4.75 (s, 1 H, 14-H), 4.15 (s, 3 H, OMe), 4.08 (s, 3 H, OMe), 4.00
(s, 3 H, OMe), 2.96–3.02 (m, 1 H, 13a-H), 2.96 (d, J = 15.8 Hz,
1 H, 9-H), 2.81 (d, J = 15.1 Hz, 1 H, 9-H), 2.32–2.40 (m, 1 H,
11-H), 2.10–2.14 (m, 1 H, 11-H), 1.93–2.02 (m, 2 H, 13-H), 1.77–
1.84 (m, 2 H, 12-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.6,
149.4, 148.3, 130.4, 127.7, 127.4, 127.0, 124.0, 123.7, 122.9, 114.5,
105.4, 103.9, 103.5, 65.4, 64.8, 56.1, 56.0, 55.4, 55.2, 53.3, 24.0,
21.5 ppm. IR (KBr): ν = 3177, 3105, 2956, 2936, 2877, 2830, 2379,
˜
2310, 1618, 1512, 1469, 1416, 1305, 1257, 1234, 1203, 1142, 1112,
1036, 751 cm–1. HRMS (ESI): calcd. for C23H26NO4 [M + H]+
380.1856; found 380.1861.
(13aR,14R)-14-Hydroxyantofine [8c-(13aR,14R)]:
A procedure
analogous to the preparation of 8b-(13aS,14S) was used. A mixture
of 7c-(R) and 7e-(R) (2 g, 3.8 mmol) gave 8c-(13aR,14R) (1.32 g,
93% combined yield) as a light-yellow solid; m.p. 243–245 °C
(dec.). [α]2D0 = –231 (c = 2.0, CHCl3); other data are the same as
those for 8c-(13aS,14S).
(+)-Tylophorine [1a-(S)]: Triethylsilane (0.64 g, 5.5 mmol) was
added to a solution of 8a-(13aS,14S) (1 g, 2.44 mmol) in trifluoro-
acetic acid (30 mL) and the resulting mixture was stirred at room
temperature for 10 h in the dark. The solvent was evaporated in
vacuo and the residue was made basic with a 10% aqueous solution
of sodium carbonate. The product was extracted with methylene
dichloride (3ϫ50 mL). The combined organic extracts were dried
with anhydrous magnesium sulfate and concentrated in vacuo to
give 1a-(S) (0.9 g, 94%) as a light-yellow solid; m.p. 282–284 °C
55.7, 55.6, 53.1, 23.9, 21.6 ppm. IR (KBr): ν = 3445, 3167, 3103,
˜
2956, 2830, 2379, 2310, 1620, 1512, 1472, 1424, 1249, 1211, 1197,
1149, 1115, 1047, 1020, 855, 836, 750 cm–1. HRMS (ESI): calcd.
for C24H28NO5 [M + H]+ 410.1962; found 410.1970.
(13aR,14R)-14-Hydroxytylophorine [8a-(13aR,14R)]: A procedure
analogous to the preparation of 8a-(13aS,14S) was used. The amide
7a-(R) (5 g, 8.9 mmol) gave 8a-(13aR,14R) (3.36 g, 92%) as a light-
yellow solid; m.p. 240–241 °C (dec.). [α]2D0 = –136 (c = 2.0, CHCl3);
other data are the same as those for 8a-(13aS,14S).
(dec.). [α]2D0 = +102 (c = 1.0, CHCl3) {ref.[6d] m.p. 284–286 °C, [α]
21
= +73 (c = 0.7, CHCl3)}; 97% ee [flow rate 1.0 mL/min n-hex-
D
ane/2-propanol 75:25 and 0.1% triethylamine, 41 bar, 254 nm, tR
(major) = 10.38 min, tR (minor) = 13.32 min]. 1H NMR (400 MHz,
CDCl3): δ = 7.83 (s, 2 H, Ar-H), 7.32 (s, 1 H, Ar-H), 7.16 (s, 1 H,
Ar-H), 4.63 (d, J = 14.8 Hz, 1 H, 9-H), 4.12 (s, 6 H, OMe), 4.06
(s, 6 H, OMe), 3.69 (d, J = 14.9 Hz, 1 H, OMe), 3.46–3.50 (m, 1
H, 13a-H), 3.34–3.40 (m, 1 H, 14-H), 2.87–2.96 (m, 1 H, 14-H),
2.43–2.50 (m, 2 H, 11-H), 2.21–2.29 (m, 1 H, 13-H), 2.02–2.07 (m,
1 H, 13-H), 1.93–1.95 (m, 1 H, 12-H), 1.72–1.82 (m, 1 H, 12-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.7, 148.5, 148.4,
126.3, 126.0, 125.9, 124.4, 123.6, 123.4, 104.0, 103.5, 103.4, 103.2,
(13aS,14S)-Tylophorinine [8b-(13aS,14S)]: A procedure analogous
to the preparation of 8a-(13aS,14S) was used. A mixture of 7b-(S)
and 7d-(S) (2 g, 3.8 mmol), TMEDA (1.45 g, 12.5 mmol) and
nBuLi in hexane (8.1 mL, 12.1 mmol) gave 8b-(13aS,14S) (1.35 g,
95%) as a light-yellow solid; m.p. 227–229 °C (dec.). [α]2D0 = +153
(c = 2.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.41 (d, J =
9.1 Hz, 1 H, Ar-H), 7.64 (s, 1 H, Ar-H), 7.42 (s, 1 H, Ar-H), 7.22
(d, J = 9.0 Hz, 1 H, Ar-H), 6.09 (br., 1 H, OH), 5.81 (s, 1 H, Ar-
H), 4.74 (s, 1 H, 14-H), 4.09 (s, 3 H, OMe), 4.03 (s, 3 H, OMe),
3.71 (s, 3 H, OMe), 3.15–3.22 (m, 1 H, 13a-H), 2.93 (d, J = 14.8 Hz,
1 H, 9-H), 2.69 (d, J = 14.7 Hz, 1 H, 9-H), 2.34–2.40 (m, 1 H, 11-
H), 2.06–2.11 (m, 1 H, 11-H), 1.94–2.06 (m, 2 H, 13-H), 1.74–1.83
(m, 2 H, 12-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.3,
148.3, 148.2, 130.4, 128.4, 126.9, 126.0, 125.4, 123.8, 123.4, 114.7,
103.9, 102.6, 102.5, 65.3, 64.3, 55.7, 55.6, 55.4, 55.3, 53.0, 23.7,
60.2, 56.0, 55.9, 55.9, 55.2, 54.0, 33.8, 31.3, 21.6 ppm. IR (KBr): ν
˜
= 3014, 2954, 2932, 2917, 2873, 2831, 2790, 2379, 2310, 1688, 1619,
1532, 1514, 1471, 1441, 1426, 1248, 1211, 1197, 1150, 1047, 1017,
841, 751 cm–1. HRMS (ESI): calcd. for C24H28NO4 [M + H]+
394.2013; found 394.2009.
(–)-Tylophorine [1a-(R)]: A procedure analogous to the preparation
of 1a-(S) was used. 8a-(13aR,14R) (1 g, 2.44 mmol) gave 1a-(R)
(0.91 g, 95%) as a light-yellow solid; m.p. 277–279 °C (dec.). [α]2D0
= –103 (c = 1.0, CHCl3); 93% ee [flow rate 1.0 mL/min n-hexane/
2-propanol 75:25 and 0.1% triethylamine, 46 bar, 254 nm, tR
(minor) = 11.31 min, tR (major) = 14.98 min]; other data are the
same as those for 1a-(S).
21.7 ppm. IR (KBr): ν = 3181, 3104, 2957, 2877, 2830, 2379, 2354,
˜
2319, 2277, 2050, 1725, 1618, 1529, 1512, 1470, 1417, 1372, 1303,
1259, 1232, 1204, 1165, 1111, 1042, 1007, 974, 838, 751 cm–1.
HRMS (ESI): calcd. for C23H26NO4 [M + H]+ 380.1856; found
380.1861.
(13aR,14R)-Tylophorinine [8b-(13aR,14R)]: A procedure analogous
to the preparation of 8b-(13aS,14S) was used. A mixture of 7b-(R)
and 7d-(R) (2 g, 3.8 mmol) gave 8b-(13aR,14R) (1.3 g, 91%) as a
(+)-Deoxytylophorinine [1b-(S)]: A procedure analogous to the
preparation of 1a-(S) was used. 8b-(13aS,14S) (1 g, 2.64 mmol)
gave 1b-(S) (0.92 g, 96%) as a light-yellow solid; m.p. 220–221 °C
Eur. J. Org. Chem. 2010, 292–299
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
297

Z. Wang, Z. Li, K. Wang, Q. Wang
FULL PAPER
(dec.). [α]2D0 = +90 (c = 2.0, CHCl3) [ref.[15] m.p. 202 °C, [α]2D5
=
Acknowledgments
+3.6 (c = 0.86, CHCl3)]; 95% ee [flow rate 1.0 mL/min n-hexane/
2-propanol 75:25 and 0.1% triethylamine, 48 bar, 254 nm, tR
(major) = 17.46 min, tR (minor) = 24.82 min]. 1H NMR (400 MHz,
CDCl3): δ = 7.94 (d, J = 9.1 Hz, 1 H, Ar-H), 7.91 (s, 1 H, Ar-H),
7.89 (d, J = 2.4 Hz, 1 H, Ar-H), 7.21 (dd, J = 2.4, 9.02 Hz, 1 H,
Ar-H), 7.15 (s, 1 H, Ar-H), 4.60 (d, J = 14.7 Hz, 1 H, 9-H), 4.10
This work was financially supported by the National Key Project
for Basic Research (2010CB126100) and the National Natural Sci-
ence Foundation of China (20872072).
(s, 3 H, OMe), 4.06 (s, 3 H, OMe), 4.01 (s, 3 H, OMe), 3.65 (d, J [1] A. N. Ratnagiriswaran, K. Venkatachalam, Indian J. Med. Res.
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= 14.5 Hz, 1 H, 9-H), 3.39–3.49 (m, 2 H, 13a-H, 14-H), 2.91–2.97
(m, 1 H, 14-H), 2.44–2.50 (m, 2 H, 11-H), 2.19–2.27 (m, 1 H, 13-
H), 1.99–2.06 (m, 1 H, 13-H), 1.87–1.96 (m, 1 H, 12-H), 1.73–1.81
(m, 1 H, 12-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.6,
149.4, 148.3, 130.4, 127.0, 125.6, 125.6, 125.2, 125.2, 123.3, 114.8,
104.6, 103.9, 103.1, 60.2, 56.0, 55.9, 55.5, 55.2, 53.9, 33.6, 31.2,
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˜
1616, 1530, 1512, 1470, 1442, 1416, 1258, 1235, 1204, 1165, 1151,
1128, 1032, 1005, 918, 842, 822, 753 cm–1. HRMS (ESI): calcd. for
C23H26NO3 [M + H]+ 364.1907; found 364.1914.
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(–)-Deoxytylophorinine [1b-(R)]: A procedure analogous to the
preparation of 1a-(S) was used. 8b-(13aR,14R) (1 g, 2.44 mmol)
gave 1b-(R) (0.93 g, 97%) as a light-yellow solid; m.p. 217–219 °C
(dec.). [α]2D0 = –101 (c = 2.0, CHCl3); 97% ee [flow rate 1.0 mL/min
n-hexane/2-propanol 75:25 and 0.1% triethylamine, 41 bar, 254 nm,
tR (minor) = 16.52 min, tR (major) = 23.18 min]; other data are the
same as those for 1b-(S).
(+)-Antofine [1c-(S)]: A procedure analogous to the preparation of
1a-(S) was used. 8c-(13aS,14S) (1 g, 2.64 mmol) gave 1c-(S) (0.93 g,
97%) as a light-yellow solid; m.p. 209–211 °C (dec.). [α]2D0 = +85 (c
= 2.0, CHCl3); 99% ee [flow rate 1.0 mL/min n-hexane/2-propanol
75:25 and 0.1% triethylamine, 48 bar, 254 nm, tR (major) =
1
15.10 min, tR (minor) = 17.80 min]. H NMR (400 MHz, CDCl3):
δ = 7.89 (s, 1 H, Ar-H), 7.88 (s, 1 H, Ar-H), 7.79 (d, J = 9.0 Hz, 1
H, Ar-H), 7.28 (s, 1 H, Ar-H), 7.19 (dd, J = 2.2, 9.00 Hz, 1 H, Ar-
H), 4.68 (d, J = 14.9 Hz, 1 H, 9-H), 4.10 (s, 3 H, OMe), 4.05 (s, 3
H, OMe), 4.01 (s, 3 H, OMe), 3.68 (d, J = 14.9 Hz, 1 H, 9-H),
3.44–3.50 (m, 1 H, 13a-H), 3.29–3.34 (m, 1 H, 14-H), 2.85–2.96
(m, 1 H, 14-H), 2.42–2.50 (m, 2 H, 11-H), 2.19–2.26 (m, 1 H, 13-
H), 2.00–2.06 (m, 1 H, 13-H), 1.89–1.94 (m, 1 H, 12-H), 1.75–1.79
(m, 1 H, 12-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.5,
149.4, 148.3, 130.1, 127.0, 126.5, 125.5, 124.2, 124.1, 123.5, 114.9,
104.6, 103.9, 103.8, 60.2, 56.0, 55.9, 55.5, 55.0, 54.4, 53.7, 48.8,
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33.6, 31.2, 21.6 ppm. IR (KBr): ν = 3019, 2961, 2930, 2914, 2877,
˜
2830, 2793, 1616, 1604, 1529, 1512, 1469, 1440, 1400, 1276, 1258,
1234, 1205, 1169, 1127, 1034, 843, 813, 751 cm–1. HRMS (ESI):
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(–)-Antofine [1c-(R)]: A procedure analogous to the preparation of
1a-(S) was used. 8c-(13aR,14R) (1 g, 2.64 mmol) gave 1c-(R)
(0.91 g, 95%) as a light-yellow solid; m.p. 210–212 °C (dec.). [α]2D0
= –124 (c = 2.0, CHCl3) {ref.[16] m.p. 212–214 °C, [α]1D9 = –125.2 (c
= 1.27, CHCl3)}; 98% ee [flow rate 1.0 mL/min n-hexane/2-propa-
nol 75:25 and 0.1% triethylamine, 43 bar, 254 nm, tR (minor) =
14.55 min, tR (major) = 19.99 min]; other data are the same as
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Supporting Information (see also the footnote on the first page of
this article): Spectroscopic data for 3a–c, 4a–e, 7a-(S), 7b-(S), 7c-
(S), 7d-(S), 7e-(S), 5, 6, 8a-(13aS,14S), 8b-(13aS,14S), 8c-
(13aS,14S), DCB-3503, DCB-3501, 1a-(S), 1b-(S) and 1c-(S). [To
avoid repetition, the NMR, IR and HRMS spectra for 7a-(R), 7b-
(R), 7c-(R), 7d-(R), 7e-(R), 8a-(13aR,14R), 8b-(13aR,14R), 8c-
(13aR,14R), 1a-(R), 1b-(R) and 1c-(R) are not given.]
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Received: August 14, 2009
Published Online: November 25, 2009
Eur. J. Org. Chem. 2010, 292–299
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