First total synthesis of (-)- and (+)-6-O-desmethylantofine

Article abstract of DOI:10.1039/c0ob00287a

The first total synthesis of (-)-6-O-desmethylantofine (A) and its unnatural enantiomer (+)-6-O-desmethylantofine (B) is described. The synthetic route is efficient and practical with easily available glutamic acid dimethyl ester hydrochloride as the chir

Full text of DOI:10.1039/c0ob00287a

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First total synthesis of (-)- and (+)-6-O-desmethylantofine†
Meng Wu, Ling Li, Bo Su, Zhihui Liu and Qingmin Wang*
Received 18th June 2010, Accepted 12th August 2010
DOI: 10.1039/c0ob00287a
The first total synthesis of (-)-6-O-desmethylantofine (A) and its unnatural enantiomer
(+)-6-O-desmethylantofine (B) is described. The synthetic route is efficient and practical with easily
available glutamic acid dimethyl ester hydrochloride as the chiral material under mild conditions.
0.003% of the extraction of the plant mentioned above),6 which
Introduction
restricts our research on the antiviral agent. Thus, an efficient
and general approach to prepare 6-O-desmethylantofine would be
very desirable. Due to the hydroxyl group at C6, the synthesis of
6-O-desmethylantofine is difficult. Only a few syntheses of ( )-
6-O-desmethylantofine have been reported.4b,7 However, optically
pure (-)-6-O-desmethylantofine (A) or its unnatural enantiomer
(+)-6-O-desmethylantofine (B) has not been reported. Herein, we
report the first total synthesis of (-)-6-O-desmethylantofine (A)
and its enantiomer B.
In 1965, Haznagy isolated a compound from C. vincetoxicum
and named it C-1.1 In 1969, Wiegrebe also isolated C-1 from
C. vincetoxicum and confirmed its configuration as (-)-6-O-
desmethylantofine (A)2 (Fig. 1).
(-)-Antofine (C) (Fig. 1) is known for its extremely potent
inhibition of cancer cell growth. Antofine has IC50 values in the
low nanomolar range, comparable to that of clinically employed
cytotoxic drugs.3 As an analogue of (-)-antofine (C), (-)-6-O-
desmethylantofine (A) has attracted more and more attention in
recent years. There were many reports about in vitro cytotoxic
activity of (-)-6-O-desmethylantofine (A) against the KB cancer
cell lines,3a,4 with IC50 values lower than that of (-)-antofine (C).
Cytotoxicity significantly increased for A relative to C, indicating
that the hydroxy group at C6 is of importance.
We have previously reported that (-)-antofine (C), isolated
from Cynanchum komarovii, possessed excellent antiviral activity
against tobacco mosaic virus (TMV).5 (-)-6-O-Desmethylantofine
(A) was also isolated from the same plant for the first time and was
found to exhibit better anti-TMV activity than (-)-antofine (C).6
Up to now, (-)-6-O-desmethylantofine (A) can only be obtained
by isolation. However, its natural abundance is very low (about
Results and discussion
Our synthetic route is shown in Scheme 1. Perkin condensation
of 3,4-dimethoxybenzaldehyde (1) and 4-hydroxyphenylacetic
acid (2) could easily afford (E)-2-(4-acetoxyphenyl)-3-(3,4-
dimethoxyphenyl)acrylic acid (3), which was converted to its cor-
responding ester 4 with methanol in the presence of concentrated
sulfuric acid. Remarkably, acetyl deprotection and esterification
of 3 was accomplished in one pot to afford 4.
To the best of our knowledge, intramolecular oxidative cou-
pling using oxidative coupling reagents such as thallium(III)
trifluoroacetate (TTFA),8 lead(IV) tetraacetate (Pb(OAc)4),9 vana-
dium oxytrifluoride (VOF3),10 iron(III) chloride (FeCl3)11 and
manganese(IV) dioxides (MnO2)12 is the most convenient way
to construct phenanthrene ring system. To test the coupling
of ester 4, we tried many oxidative coupling reagents such as
VOF3, FeCl3 and MnO2. The reaction using FeCl3 gave the
best yield (58%), whereas no oxidative coupling product 5 was
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, People’s
Republic of China. E-mail: wang98h@263.net; Fax: +86-22-23499842
† Electronic supplementary information (ESI) available: 1H, 13C NMR and
HRMS spectra for the compounds 1–7, 8a–11a, A. (To avoid repetition,
the NMR and HRMS spectra for 8b–11b, B are not given.) See DOI:
10.1039/c0ob00287a
Fig. 1 Chemical structures of compounds A, B and C.
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Scheme 1 Synthesis of (-)-6-O-desmethylantofine (A) and (+)-6-O-desmethylantofine (B). Reagents and conditions: (a) Ac2O/Et3N; (b) CH3OH/concd.
H2SO4; (c) FeCl3/CH2Cl2; (d) BnBr/K2CO3/CH3COCH3; (e) LiAlH4/THF; (f) PBr3/CH2Cl2; (g) Ra or Rb/K2CO3/DMF; (h) AcOH/MeOH; (i)
KOH/MeOH/dioxane; (j) (COCl)2/CH2Cl2, SnCl4/CH2Cl2 (k) NaBH4/EtOH, Et3SiH/CF3COOH/CH2Cl2 (l) LiAlH4/THF.
found when using VOF3 or MnO2. The coupling of ester 4 is
much more complicated than that of polymethoxy substituted 2,3-
diphenylacrylate.11b,12 Then we protected the hydroxyl using a series
of protecting groups such as acetyl, benzyl and methoxymethyl
before coupling, but only to make the coupling reaction more
complex.
to give 11a. At last, 11a was reduced with lithium aluminium hy-
dride to afford (-)-6-O-desmethylantofine (A). The overall yield is
9.68%. By the same procedure, we got (+)-6-O-desmethylantofine
(B) using L-glutamic acid dimethyl ester hydrochloride in an
overall yield of 9.32%. The enantiomeric excesses of A and B
were determined. The ee values were 90% and 91% respectively.
Ester 5 was converted to its corresponding alcohol using lithium
aluminium hydride, but the solubility of the corresponding alcohol
was so poor that it was difficult to be purified, so it was impossible
to be used in the following route. To improve the solubility in the
following route, it is necessary to protect the hydroxy group. We
introduced a benzyl group to compound 5 using benzyl bromide
to afford 6.
Ester 6 was easily converted to corresponding alcohol 7
by lithium aluminium hydride. 7 was treated with phosphorus
tribromide and then reacted with D-glutamic acid dimethyl ester
hydrochloride followed by cyclization in warm methanol and
acetic acid to afford lactam ester 8a successfully. The yield of
the combined three steps from 7 to 8a is high (60%). Ester 8a
was easily converted to the corresponding acid 9a with potassium
hydroxide.
Conclusion
Optically pure (-)-6-O-desmethylantofine (A) and its enantiomer
(+)-6-O-desmethylantofine (B) were first synthesized efficiently
from cheap materials under mild conditions and their ee values
is up to 90%. Intramolecular Friedel–Crafts acylation and depro-
tection of benzyl group of compounds 9a and 9b was successfully
achieved in one pot using SnCl4. The chemistry described here
provided a practical synthetic method of optically pure phenan-
throindolizidine alkaloids for biochemical and pharmaceutical
studies.
Experimental
The benzyl derivative was stable in strong base (KOH) and
strong acid (HCl) from 8a to 9a. But interestingly, using SnCl4
as Lewis acid, deprotection of benzyl group and intramolecular
Friedel–Crafts acylation occurred in one pot to afford 10a from
9a.
The melting points were determined with an X-4 binocular
microscope melting-point apparatus (Beijing Tech Instruments
Co., Beijing, China) and were uncorrected. 1H NMR spectra were
obtained by using Bruker AV 400 spectrometer. Chemical shifts (d)
were given in parts per million (ppm) and were measured downfield
from internal tetramethylsilane. 13C NMR spectra were recorded
by using Bruker AV 400 (100 MHz) and CDCl3 or DMSO-d6 as a
10a was treated with sodium borohydride and then immediately
converted to methylene using triethylsilane and trifluoroacetic acid
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solvent. Chemical shifts (d) are reported in parts per million using
the solvent peak. High-resolution mass spectra were obtained with
an FT-ICR MS spectrometer (Ionspec, 7.0 T). The enantiomeric
excesses of A and B 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. All
anhydrous solvents were dried and purified by standard techniques
just before use.
H, Ar–H), 4.04 (s, 3 H, OMe), 3.93 (s, 3 H, OMe), 3.92 (s, 3 H,
OMe); 13C NMR (100 MHz, CDCl3) d 168.3, 154.1, 150.9, 149.7,
131.9, 129.6, 128.6, 126.5, 125.5, 123.7, 123.2, 116.6, 109.1, 106.4,
103.1, 55.9, 52.1. HRMS (ESI): calcd. for C18H16O5 [M + Na]+
335.0890; found 335.0889
6-Benzyloxy-2,3-dimethoxyphenanthrene-9-carboxylic
acid
methyl ester (6). To a solution of 5 (15.24 g, 48.85 mmol)
in acetone (300 mL) was added benzyl bromide (10.02 g,
58.62 mmol), and potassium carbonate (10.11 g, 73.28 mmol).
The reaction mixture was stirred for 10 h at reflux, then filtered.
The filtrate was concentrated. The residue was purified by column
chromatography (petroleum ether/EtOAc/CH2Cl2, 60 : 10 : 1,
v/v/v) to give 17.28 g (88%) of 6 as a white solid. mp 156–157 ◦C;
1H NMR (400 MHz, CDCl3): d 8.94 (d, J = 9.2 Hz, 1 H, Ar–H),
8.31 (s, 1H, Ar–H), 7.97 (d, J = 2.8 Hz, 1 H, Ar–H), 7.78 (s, 1 H,
Ar–H), 7.54 (d, J = 7.2 Hz, 2 H, Ar–H), 740–7.44 (m, 2 H, Ar–H),
7.34–7.37 (m, 2 H, Ar–H), 7.26 (s, 1 H, Ar–H), 5.30 (s, 2 H,
benzyl-CH2), 4.10 (s, 3 H, OMe), 4.03 (s, 3 H, OMe), 4.01 (s, 3 H,
OMe); 13C NMR (100 MHz, CDCl3) d 168.1, 157.2, 150.9, 149.6,
136.9, 131.6, 129.6, 128.7, 128.4, 128.1, 127.6, 126.7, 125.5, 123.7,
123.3, 116.2, 109.2, 106.0, 103.1, 70.4, 56.0, 55.9, 52.1. HRMS
(ESI): calcd. for C25H22O5 [M + Na]+ 425.1359; found 425.1352
(E)-2-(4-Acetoxyphenyl)-3-(3,4-dimethoxyphenyl)acrylic acid
(3).
A mixture of 4-hydroxyphenylacetic acid 2 (66.8 g,
0.44 mol), 3,4-dimethoxybenzaldehyde 1 (83.0 g, 0.44 mol),
acetic anhydride (200 mL), and triethylamine (66.7 g, 0.66 mol)
was heated at reflux for 9 h. The solution was cooled to room
temperature, water (250 mL) was added, and the mixture was
heated at reflux for 1 h. After being cooled to room temperature,
the mixture was stirred in cold water for another 1 h. The
precipitate was filtrated, washed with anhydrous ethanol to give
(E)-2-(4-Acetoxyphenyl)-3-(3,4-dimethoxyphenyl)acrylic acid 3
117.4 g (78%). mp 244–247 ◦C; 1H NMR (400 MHz, DMSO-d6):
d 12.59 (br, 1 H, COOH), 7.72 (s, 1 H, C CH), 7.23 (d, J =
7.6 Hz, 2 H, Ar–H), 7.17 (d, J = 7.6 Hz, 2 H, Ar–H), 6.87 (m, 2
H, Ar–H), 6.41 (s, 1 H, Ar–H), 3.72 (s, 3 H, OMe), 3.30 (s, 3 H,
OMe), 2.22 (s, 3 H, COCH3); 13C NMR (100 MHz, DMSO) d
169.2, 168.3, 149.8, 149.7, 147.8, 139.5, 134.3, 130.7, 129.6, 126.6,
125.2, 122.1, 111.9, 111.1, 55.3, 54.5, 20.8. HRMS (ESI): calcd.
for C19H18O6 [M - H]+ 341.1031; found 341.1031.
(6-Benzyloxy-2,3-dimethoxyphenanthren-9-yl)methanol
(7).
To a mixture of lithium aluminium hydride (2.84 g, 74.78 mmol)
in tetrahydrofuran (150 mL) at 0 ◦C was added dropwise a
solution of 6 (10.02 g, 24.93 mmol) in tetrahydrofuran (150 mL).
The solution was stirred at room temperature for 20 min, then
heated at reflux for another 1.5 h. Then the solution was brought
back to 0 ◦C, dichloromethane (200 mL) was added, followed by
2 N hydrochloric acid (70 mL). The solution was separated, the
water phase was extracted with dichloromethane, the combined
organic phase was dried over sodium sulfate and filtered. The
solvent was removed by evaporation to give 9.12 g (97.9%) of 7 as
(E)-3-(3,4-Dimethoxyphenyl)-2-(4-hydroxyphenyl)acrylic acid
methyl ester (4). Compound 3 (40.4 g, 118.1 mmol) was added
to dry methanol (600 mL). Concentrated sulfuric acid (24.1 g)
was added, and the solution was stirred at reflux for 10 h. Most of
the methanol was removed by rotary evaporation, and the residue
was redissolved in dichloromethane and washed with saturated
sodium hydrogen carbonate. The organic phase was dried over
sodium sulfate,◦filtered, and evaporated to give 36.0 g (97%) of
1
4. mp 127–128 C; H NMR (400 MHz, CDCl3): d 7.76 (s, 1 H,
◦
1
a white solid. mp 184–186 C; H NMR (400 MHz, CDCl3): d
8.10 (d, J = 8.8 Hz, 1 H, Ar–H), 7.98 (d, J = 2.8 Hz, 1 H, Ar–H),
7.78 (s, 1 H, Ar–H), 7.53–7.55 (m, 3 H, Ar–H), 7.40–7.44 (m, 2
H, Ar–H), 7.30–7.37 (m, 2 H, Ar–H), 7.19 (s, 1 H, Ar–H), 5.29 (s,
2 H, benzyl-CH2), 5.13 (d, J = 6.0 Hz, 2 H, CH2), 4.08 (s, 3 H,
OMe), 4.023 (s, 3 H, OMe), 1.75 (t, J = 6.0 Hz, 1 H, OH); 13C
NMR (100 MHz, DMSO-d6) d 156.6, 149.3, 148.7, 137.2, 133.8,
131.0, 128.4, 127.9, 127.8, 126.7, 125.8, 123.8, 123.4, 121.8, 115.7,
108.5, 106.0, 104.0, 69.5, 61.6, 55.8, 55.4. HRMS (ESI): calcd. for
C24H22O4 [M + Na]+ 397.1410; found 397.1402
C
CH), 7.10 (d, J = 8.4 Hz, 2 H, Ar–H), 6.83–6.85 (m, 3 H,
Ar–H), 6.73 (d, J = 8.4 Hz, 1 H, Ar–H), 6.48 (d, J = 1.6 Hz, 1
H, Ar–H), 3.84 (s, 3 H, OMe), 3.79 (s, 3 H, OMe), 3.46 (s, 3 H,
OMe); 13C NMR (100 MHz, CDCl3) d 169.2, 155.6, 149.9, 148.0,
140.6, 131.2, 129.5, 128.0, 127.5, 125.5, 115.9, 112.4, 110.4, 55.7,
55.1, 52.4. HRMS (ESI): calcd. for C18H18O5 [M + Na]+ 337.1046;
found 337.1041
6-Hydroxy-2,3-dimethoxyphenanthrene-9-carboxylic
acid
methyl ester (5). To a solution of 4 (10.10 g, 32.17 mmol)
in dichloromethane (250 mL) was added anhydrous Iron(III)
chloride (13.07 g, 80.41 mmol). The reaction solution was stirred
at room temperature for 4.5 h, and then quenched with methanol
(50 mL). Then H2O (200 mL) was added, and the mixture was
stirred for an additional 0.5 h. The water phase was extracted
with dichloromethane, the combined organic phase was dried
over sodium sulfate and filtered. The solvent was removed by
rotary evaporation, and the crude product was purified by column
chromatography (petroleum ether/EtOAc, 3 : 1, ◦v/v) to give
(R)-1-((6-Benzyloxy-2,3-dimethoxyphenanthren-9-yl)methyl)-5-
oxo-pyrrolidine-2-carboxylic acid methyl ester (8a). Compound
7 (9.30 g, 24.87 mmol) was dissolved in dry dichloromethane
(500 mL) and cooled to 0 ◦C. A solution of phosphorus tribromide
(3.5 mL, 37 mmol) in dichloromethane (20 mL) was added
dropwise. The solution was then stirred at room temperature
overnight, then poured over ice water, the water phase was ex-
tracted with dichloromethane (40 mL ¥ 2). The combined organic
phase was dried over sodium sulfate, filtered and evaporated
to give a white solid. The solid was then dissolved in N,N-
dimethylformamide (300 mL). D-Glutamic acid dimethyl ester
hydrochloride (7.89 g, 37.31 mmol) was added and allowed to
1
5.82 g (58%) of 5 as a white solid. mp 188–190 C; H NMR
(400 MHz, DMSO-d6): d 9.91 (s, 1 H, Ar–OH), 8.66 (d, J =
9.2 Hz, 1 H, Ar–H), 8.26 (s, 1 H, Ar–H), 8.03 (s, 1 H, Ar–H),
7.94 (s, 1 H, Ar–H), 7.59 (s, 1 H, Ar–H), 7.18 (d, J = 8.8 Hz, 1
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stir for 20 min. Potassium carbonate (5.15 g, 37.31 mmol) was
added, and the mixture was allowed to stir at room temperature
for 12 h. The solution was then distilled under reduced pressure
to remove N,N-dimethylformamide. To the residue was added
dichloromethane and water. The water phase was extracted with
dichloromethane. The combined organic phase was dried over
sodium sulfate, filtered and rotary evaporated. The crude product
was dissolved in methanol (200 mL) and acetic acid glacial
(120 mL) and stirred for 8 h at 45–50 ◦C. The solution was
rotary evaporated, and the crude product was purified by column
chromatography (petroleum ether/EtOAc, 2 : 1 then 1 : 1◦, v/v) to
give 7.49 g (60%) of 8a as a white solid. mp 182–183 C; [a]D20
rotary evaporated, and the crude product was purified by column
chromatography (CH2Cl2–EtOAc, 3 : 1, v/v◦) to give 0.62 g (55%)
of 10a as a light-yellow solid. mp 260–261 C; [a]2D0 -94.4 (c 0.5,
DMF); 1H NMR (400 MHz, DMSO-d6): d 10.41(s, 1 H, Ar–OH),
8.99 (s, 1 H, Ar–H), 8.14 (d, J = 8.8 Hz, 1 H, Ar–H), 8.02 (d, J =
2.0 Hz, 1 H, Ar–H), 7.95 (s, 1 H, Ar–H), 7.23 (dd, J = 2.0, 8.8 Hz,
1 H, Ar–H), 5.55 (d, J = 18.4 Hz, 1 H, 9-H), 4.78 (d, J = 18.0 Hz,
1 H, 9-H), 4.54–4.57 (m, 1 H,13a-H), 4.02 (s, 3 H, OMe), 3.91 (s, 3
H, OMe), 2.30–2.44 (m, 4 H, 12-H, 13-H); 13C NMR (100 MHz,
DMSO-d6) d 196.1, 172.8, 159.2, 149.6, 148.4, 139.6, 133.9, 127.3,
123.7, 123.3, 120.3, 119.8, 117.5, 107.4, 106.7, 103.5, 60.5, 55.3,
55.1, 39.9, 29.4, 20.4. HRMS (ESI): calcd. for C22H19NO5 [M +
Na]+ 400.1155; found 400.1152
1
-56.0 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3): d 8.03 (d,
J = 8.8 Hz, 1 H, Ar–H), 7.97 (d, J = 2.4 Hz, 1 H, Ar–H), 7.78 (s,
1 H, Ar–H), 7.52–7.54 (m, 2 H, Ar–H), 7.40–7.44 (m, 2 H,Ar–H),
7.34–7.37 (m, 2 H, Ar–H), 7.31 (dd, J = 2.4, 8.8 Hz, 1H, Ar–H),
7.16 (s, 1 H, Ar–H), 5.50 (d, J = 14.4 Hz, 1 H, N–CH2), 5.28 (s,
2 H, benzyl-CH2), 4.40 (d, J = 14.4 Hz, 1 H, N–CH2), 4.09 (s,
3 H, OMe), 4.03 (s, 3 H, OMe), 3.84 (dd, J = 2.8, 9.2 Hz, 1 H,
N–CH), 3.58 (s, 3 H, OMe), 2.55–2.64 (m, 1 H, N–CH–CH2),
2.04–2.48 (m, 1 H, NCO–CH2), 2.08–2.18 (m, 1 H, N–CH–CH2),
1.95–2.02 (m, 1 H, NCO–CH2) 13C NMR (100 MHz, CDCl3) d
174.6, 172.3, 157.4, 149.6, 149.4, 137.0, 131.7, 128.7, 128.1, 127.7,
127.6, 126.6, 126.2, 126.2, 124.6, 124.4, 115.8, 108.2, 106.4, 103.3,
70.4, 58.6, 56.0, 55.9, 52.2, 44.4, 29.8, 22.8. HRMS (ESI): calcd.
for C30H29NO6 [M + Na]+ 522.1887; found 522.1883
(R)-6-Hydroxy-2,3-dimethoxyphenanthro[9,10-b]-11-quinolizi-
dinone(11a). A mixture of 10a (0.41 g, 1.09 mmol), sodium
borohydride (0.12 g, 3.26 mmol) and ethanol (50 mL) was stirred
for 40 min at room temperature. The mixture was cooled to 0 ◦C,
and then 2 mol L-1 hydrochloric acid (10 mL) was added slowly.
Dichloromethane (100 mL) and water (50 mL) was added to the
solution, then the water phase was extracted with dichloromethane
(30 mL). The combined organic phase was dried over sodium
sulfate, filtered, and rotary evaporated, and the product was
dissolved in dry dichloromethane (50 mL), and then triethylsilane
(0.63 g, 5.44 mmol) and trifluoroacetic acid (1.24 g, 20.88 mmol)
was added. The mixture was stirred for 3.5 h at 33–36 ◦C. The
solution was cooled to room temperature, and dichloromethane
(50 mL) and water (50 mL) was added. The water phase was
extracted with dichloromethane (20 mL ¥ 3). The combined
organic phase was rotary evaporated, and the crude product was
purified by column chromatography (petroleum ether/EtOAc,
1 : 3, v/v and then CH2Cl2–EtOAc, 1 : 8, ◦v/v) to give 0.34 g (85%)
of 11a as a light-yellow solid. mp 221 C dec; [a]2D0 -85.6 (c 1,
DMF); 1H NMR (400 MHz, CDCl3): d 7.76 (s, 1 H, Ar–H), 7.74
(s, 1 H, Ar–H), 7.55 (d, J = 8.8 Hz, 1 H, Ar–H), 7.10 (d, J =
8.4 Hz, 1 H, Ar–H), 7.04 (s, 1 H, Ar–H), 6.94 (s, 1 H, OH), 5.30
(d, J = 17.2 Hz, 1 H, 9-H), 4.47 (d, J = 17.2 Hz, 1 H, 9-H),
4.06 (s, 3 H, OMe), 4.01 (s, 3 H,OMe), 3.93–3.94 (m, 1H, 13a-H),
3.30–3.34 (m, 1H, 14-H), 2.53–2.78 (m, 4H, 14-H, 12-H, 13-H),
2.00–2.09 (m, 1H, 13-H); 13C NMR (100 MHz, DMSO-d6) d 173.1,
155.6, 149.0, 148.2, 130.0, 125.7, 124.0, 123.4, 123.2, 122.8, 121.6,
116.5, 106.5, 104.1, 103.9, 55.4, 55.3, 52.3, 40.1, 32.1, 29.4, 24.4.
HRMS (ESI): calcd. for C22H21NO4 [M + H]+ 364.1543; found
364.1540
(R)-1-((6-Benzyloxy-2,3-dimethoxyphenanthren-9-yl)methyl)-5-
oxo-pyrrolidine-2-carboxylic acid (9a). Compound 8a (2.18 g,
4.37 mmol) was stirred in a solution of dioxane (50 mL), methanol
(40 mL) and 2 mol L-1 aqueous potassium hydroxide (30 mL)
for 2 h. The mixture was rotary evaporated to remove dioxane
and methanol, and the resulting mixture was cooled to 0 ◦C and
acidified with 2 mol L-1 hydrochloric acid until pH = 1–2, then
washed with water and dried to give 2.08 g (98%) of 9a as a
◦
white solid. mp 276–278 C; [a]2D0 -67.6 (c 0.5, DMF); 1H NMR
(400 MHz, DMSO-d6): d 8.21 (d, J = 2.4 Hz, 1 H, Ar–H), 8.02 (s,
1 H, Ar–H), 7.96 (d, J = 9.2 Hz, 1 H, Ar–H), 7.57–7.59 (m, 2 H,
Ar–H), 7.40–7.45 (m, 4 H, Ar–H), 7.33–7.37 (m, 1 H, Ar–H), 7.30
(dd, J = 2.4, 9.2 Hz, 1H, Ar–H), 5.38 (d, J = 14.8 Hz, 1 H, N–CH2),
5.37 (s, 2 H, benzyl-CH2), 4.23 (d, J = 15.2 Hz, 1 H, N–CH2), 4.02
(s, 3 H, OMe), 3.91 (s, 3 H,OMe), 3.75 (dd, J = 2.8, 9.2 Hz, 1 H,
N–CH), 2.33–2.43 (m, 2 H, N–CH–CH2, NCO–CH2), 2.13–2.23
(m, 1 H, NCO–CH2), 1.90–1.96 (m, 1 H, N–CH–CH2); 13C NMR
(100 MHz, DMSO-d6) d 174.1, 173.1, 156.9, 149.4, 149.2, 137.1,
131.3, 128.4, 128.0, 127.9, 127.5, 126.3, 125.5, 124.8, 123.9, 123.7,
116.0, 108.5, 106.2, 104.0, 69.5, 58.0, 55.8, 55.4, 43.3, 29.2, 22.4.
HRMS (ESI): calcd. for C29H27NO6 [M - H]+ 484.1766; found
484.1765
(-)-6-O-desmethylantofine (A). A mixture of 11a (0.18 g,
0.50 mmol), lithium aluminium hydride (0.04 g, 1.00 mmol) and
tetrahydrofuran (25 mL) was heated at reflux under nitrogen for
0.5 h. The solution was cooled to 0 ◦C, at which point EtOAc
(10 mL) was added dropwise, followed by water (20 ml). Then
dichloromethane (100 mL) and methanol (50 mL) was added, then
the water phase was extracted with dichloromethane (20 mL ¥ 3).
The combined organic phase was dried over sodium sulfate, filtered
and evaporated, then the product was placed under vacuum in the
dark for ◦2 h to give 0.16◦g (94%) of A as a white solid. mp:
217–218 C (lit.2 226–228 C); [a]2D0 -51.2 (c 0.25, MeOH) (lit.4
[a]2D0 -54.5 (c 0.88, MeOH)); 90% ee [flow rate 1.0 mL min-1,
n-hexane/2-propanol 85 : 15 and 0.1% triethylamine, 254 nm, tR
(major) = 22.75 min, tR (minor) = 25.14 min]. 1H NMR (400 MHz,
(R)-6-Hydroxy-2,3-dimethoxyphenanthro[9,10-b]-11,14-indo-
lizidinedione(10a). To a solution of 9a (1.44 g, 2.97 mmol) in
dry dichloromethane (100 mL) was added oxalyl chloride (0.49 g,
3.86 mmol) and N,N-dimethylformamide (0.1 ml). The mixture
was stirred for 4.5 h at room temperature. Tin(IV) chloride
(0.69 mL, 5.94 mmol) was added slowly under nitrogen at 0 ◦C, and
◦
then the mixture was stirred overnight at 35 C under nitrogen.
The solution was cooled to room temperature, and 2 mol L-1
hydrochloric acid (70 mL) was added. The organic phase was
144 | Org. Biomol. Chem., 2011, 9, 141–145
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DMSO-d6): d 9.69 (s,1 H, OH), 7.95 (s, 1 H, Ar–H), 7.92 (s, 1
H, Ar–H), 7.73 (d, J = 8.8 Hz, 1 H, Ar–H), 7.31 (s, 1 H, Ar–H),
7.09 (d, J = 9.2 Hz, 1 H, Ar–H), 4.55 (d, J = 15.2 Hz, 1 H, 9-H),
3.99 (s, 3 H, OMe), 3.94 (s, 3 H, OMe), 3.53 (d, J = 14.8 Hz, 1 H,
9-H), 3.30–3.35 (m, 2 H, 13a-H, 11-H), 2.72–2.78 (m, 1 H, 11-H),
2.32–2.38 (m, 2 H, 14-H), 2.12–2.18 (m, 1 H, 13-H), 1.82–1.90
(m, 2 H, 12-H), 1.59–1.69 (m, 1 H, 13-H); 13C NMR (100 MHz,
DMSO-d6) d 155.3, 149.0, 148.0, 129.9, 126.3, 126.1, 124.4, 124.0,
122.6, 122.2, 116.2, 106.4, 104.0, 103.9, 59.8, 55.4, 55.3, 54.4, 53.2,
32.9, 30.8, 21.1. HRMS (ESI): calcd. for C22H23NO3 [M + H]+
350.1751; found 350.1753
Acknowledgements
We are grateful to the National Key Project for Basic Research
(2010CB126100) and the National Natural Science Foundation
of China (20872072, 30890143) for generous financial support for
our programs
Notes and references
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(S)-1-((6-Benzyloxy-2,3-dimethoxyphenanthren-9-yl)methyl)-5-
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L-Glutamic acid dimethyl ester hydrochloride as a material, a
procedure analogous to the preparation of 8a was used, 7 (8.52 g,
22.78 mmol) give 8b (6.70 g, 59%) as a white solid: mp 182–
183 ◦C; [a]D20 52.4 (c 1, CH2Cl2); other data are the same as those
for 8.
(S)-1-((6-Benzyloxy-2,3-dimethoxyphenanthren-9-yl)methyl)-5-
oxo-pyrrolidine-2-carboxylic acid (9b). A procedure analogous
to the preparation of 9a was used, 8b (3.06 g, 6.12 mmol) gave 9b
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◦
(2.91 g, 98%) as a white solid: mp 277–279 C; [a]2D0 40.8 (c 0.5,
DMF); other data are the same as those for 9.
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(S)-6-Hydroxy-2,3-dimethoxyphenanthro[9,10-b]-11,14-indoli-
zidinedione(10b). A procedure analogous to the preparation of
10a was used, 9b (2.00 g, 4.12 mmol) gave 10b (0.80 g, 52%) as a
◦
light-yellow solid. mp 253–255 C; [a]2D0 63.4 (c 1, DMF); other
data are the same as those for 10a.
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(S)-6-Hydroxy-2,3-dimethoxyphenanthro[9,10-b]-11-quinolizi-
dinone(11b). A procedure analogous to the preparation of 11a
was used, 10b (0.52 g,◦1.38 mmol) gave 11b (0.44 g, 88%) as a light-
yellow solid. mp 230 C dec; [a]2D0 56.2 (c 1,DMF); other data are
the same as those for 11a.
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(+)-6-O-desmethylantofine (B). A procedure analogous to the
preparation of A was used, 11a (0.20 g, 0.55 ◦mmol) gave 12a
(0.18 g, 95%) as a white solid. mp: 219–220 C; [a]2D0 66.4 (c
0.25, Methanol); 91% ee [flow rate 1.0 mL min-1, n-hexane/2-
propanol 85 : 15 and 0.1% triethylamine, 254 nm, tR (major) =
25.02 min, tR (minor) = 22.80 min]. other data are the same as those
for B.
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The Royal Society of Chemistry 2011
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