Total synthesis of lycorine-type alkaloids by cyclopropyl ring-opening rearrangement

Article abstract of DOI:10.1039/c4ob00126e

A practical method for the synthesis of lycorine-type alkaloids with cis-B/C ring structure has been developed. Based on the reactions of aminocyclization, palladium-mediated arylation and especially cyclopropyl ring-opening rearrangement, the synthesis o

Full text of DOI:10.1039/c4ob00126e

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Total synthesis of lycorine-type alkaloids by
cyclopropyl ring-opening rearrangement†
Cite this: Org. Biomol. Chem., 2014,
12, 3191
Dandan Liu,a,b Long Ai,a Fan Li,b Annan Zhao,a Jingbo Chen,a Hongbin Zhanga and
Jianping Liu*a
Received 17th January 2014,
Accepted 11th March 2014
A practical method for the synthesis of lycorine-type alkaloids with cis-B/C ring structure has been deve-
loped. Based on the reactions of aminocyclization, palladium-mediated arylation and especially cyclopro-
pyl ring-opening rearrangement, the synthesis of anhydrocaranine, ( )-γ-lycorane and putative
( )-amarbellisine was accomplished.
DOI: 10.1039/c4ob00126e
www.rsc.org/obc
With their rich biological properties including antifungal, anti- and some interesting bio-activities, was reported by Evidente’s
bacterial and antineoplastic activities,1 like tetracyclic pyrrolo- group.5 We would like to present a new method for the syn-
[d,e]phenanthridine frameworks (galanthan ring system), thesis of these scaffolds with a cyclopropyl ring-opening
lycorine-type alkaloids have attracted the interest of chemists rearrangement to compose the cis-B/C ring junction structures
and pharmacologists for decades.2 This paper deals with the in galanthan as a key step to prepare the above compounds.
synthesis of anhydrocaranine, γ-lycorane and amarbellisine.
The initial retrosynthetic approach to anhydrocaranine and
Anhydrocaranine (1) (Fig. 1) was explored by Wildman and γ-lycorane is briefly outlined in Scheme 1, and the former was
Heimer in 19673 but no NMR data have been reported until obtained from alcohol 4. Ketone 5, the precursor of compound
now; γ-lycorane (2) with cis-B/C, C/D rings is one of the mole- 4, would be obtained from compounds 7 and 8 via compound
cular targets in the field with the highest interest;4 and the 6 (Scheme 1).
synthesis of amarbellisine (3), also with both cis-B/C, C/D rings
Our synthesis began with secondary amine 6 (Scheme 2),
which was prepared from 2-(4-methoxycyclohexa-1,4-dienyl)-
ethylamine (7) and 6-bromopiperonal (8). The aminocycliza-
tion reaction6 of compound 6 did not form ketone 5 directly
but cyclopropyl ketone 9 was obtained. Compound 6 could
only be converted to ketone 5 via a series of reactions accord-
ing to previous research.7 Unfortunately, compound 10 could
not be prepared from ketone 5 by palladium-mediated aryla-
tion,8 but compound 11 was afforded. It seems that the aroma-
Fig. 1 The structures of anhydrocaranine (1), γ-lycorane (2) and amar-
bellisine (3).
aKey Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University),
Ministry of Education, School of Chemical Science and Technology, Yunnan
University, Kunming, Yunnan 650091, P. R. China. E-mail: jpliu@ynu.edu.cn;
Fax: +86-871-65035538
bSchool of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for
Natural Products, Kunming Medical University, 1168 Western Chunrong Road,
Yuhua Street, Chenggong New City, Kunming, Yunnan 650500, P. R. China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00126e
Scheme 1 Retrosynthetic analysis of anhydrocaranine (1) and γ-lycor-
ane (2).
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proceeded smoothly from cycloketone 9 to 12 in a yield of 82%
(Scheme 3). This result suggested that the cyclopropyl ring pro-
tected the C ring from aromatization and provided a potential
double bond. The full C ring configuration of compound 12
was confirmed by 1H, 13C NMR and X-ray crystallography
(Fig. 2).9 With ketone 12 in hand, we explored a way to open
the three-membered ring. When treated with 40% hydro-
bromic acid in acetic acid at room temperature, ketone 12 was
converted to compound 13, which was not our desired
product. To avoid this, ketone 12 was reduced to cyclopropyl
alcohol 14, and the latter was converted to corresponding
cyclopropyl bromide 15 in the presence of phosphorus tribro-
mide. Secondary bromide 15 could further undergo a cyclopro-
pyl ring opening rearrangement reaction to form homo-allylic
bromide 16 with the full lycorine-type skeleton. It was interest-
ing to observe that the final ratio of compound 15 to 16 was
constant at about 1 to 4, when either 15 or 16 was treated with
aqueous hydrogen bromide. The structure and stereochemistry
of compound 16 were confirmed by its NMR data and further
by its X-ray crystallography (Fig. 2).9
Scheme 2 Synthesis of the intermediate 9. Reagents and conditions:
(a) (1) EtOH, 60 °C, 3 h; (2) NaBH4, EtOH, 0 °C, 99%; (3) 2 M HCl aq., rt,
99%; (b) (1) Br2, AcOH, rt; (2) K2CO3, MeOH, reflux, 82%; (c) NaBH4,
EtOH, 0 °C, 96%; (d) TBDMSCl, imidazole, DMF, rt, 94%; (e) (1) Br2, DCM,
−78 °C; (2) K2CO3, MeOH, reflux, 80%; (f) TBAF, THF, rt, 85%; (g) DMSO,
oxalyl chloride, DCM, −78 °C, 1 h, then triethylamine, 91%; (h) Pd2(dba)3,
BINAP, tBuONa, toluene, 100 °C, 85%.
Cyclopropyl ring opening to form homo-allylic bromide was
first reported by Julia over 50 years ago and was followed by
considerable development and synthetic applications
(Scheme 4, 1),10 while the reverse reaction from homo-allylic
bromide to a cyclopropyl ring was reported before our research
started mainly in anhydrous media such as silver nitrate–
alumina, and also received some attention (Scheme 4, 2).11
But, to the best of our knowledge, no equilibrium conversion
between a cyclopropyl ring and a homo-allylic halide has been
tization of the C ring was initiated by the C3–C3a double-bond
in ketone 5.
In view of this disappointing result, we decided to use
three-membered ring compound 9 for further palladium-
mediated arylation. The palladium catalytic coupling reaction
Scheme 3 Construction of lycorine-type skeleton and rearrangement
between 15 and 16. Reagents and conditions: (a) Pd2(dba)3, BINAP, tBuONa,
toluene, 100 °C, 82%; (b) 40% HBr–AcOH, rt, 97%; (c) NaBH4, EtOH, 0 °C,
95%; (d) PBr3, DCM, 0 °C, 95%; (e) 47% HBr aq., rt. 15 : 16 ≈ 1 : 4.
Scheme 4 The initial cyclopropyl ring opening (1) and corresponding
formation (2) reactions.
Fig. 2 Crystal structures of compounds 12 and 16.
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Scheme 5 Proposed equilibrium between 15 and 16 via a nonclassical carbocation intermediate.
reported to date. We presumed that the multi-ring fused struc- from silyl ether 21 by selective hydroxyl protect/deprotect
ture of compound 15 would enable the rearrangement of this sequence followed by Swern oxidation. Dimethyl ketal 24 was
nonclassical carbocation as an equilibrium reaction formed from ketone 23 by treatment with trimethyl orthofor-
(Scheme 5).
mate and p-toluenesulfonic acid,15 and the 1-acetyl was also
Utilizing this rearrangement, cyclopropyl compound 15 was removed at the same time. α,β-Unsaturated ketone 26 was
converted to homo-allylic bromide 16 in 77% yield. With the afforded by careful removal of one methanol molecule from
key intermediate 16 in hand, we could modify the functional dimethoxyl ketone 25, which was formed from 1-hydroxyl com-
groups to form different target products. Anhydrocaranine (1) pound 24 by Swern oxidation. Compound (3) and its epi-
was formed and no conjugated diene 17 observed, when isomer 27 were formed in a ratio of about 3 to 1 when either
t
bromide 16 was treated with bases such as NaOH or BuONa. NaBH4–CeCl3 or Red-Al were employed to treat ketone 26,16
( )-γ-Lycorane (2) was conveniently obtained as the only and finally, the target molecule (3) was obtained as the only
product from anhydrocaranine (1) by hydrogenation isomer when DIBAL-H was used as the reagent (Scheme 7).
(Scheme 6).
The structure and configuration of compound 3 were con-
The structure of anhydrocaranine (1) was confirmed by its firmed by its NMR data and further by its X-ray crystallography
1H NMR, 13C NMR data and COSY, HMQC, HMBC data. The (Fig. 3).
NMR data of ( )-γ-lycorane (2) were identical to the data
The NMR data of our synthesized compound (3) were com-
pared with the reported vales for natural amarbellisine from
reported before.12
At this stage, we hoped to use the cyclopropyl ring-opening Evidente’s group5a and the results are summarized below
rearrangement to synthesize a more complex lycorine-type (Tables 1 and 2).
compound such as amarbellisine (3). Alkene 18 was obtained
Given the obvious differences in the resonance values for
by reduction of bromide 16 with lithium aluminium hydride. the two compounds appearing at C3a, C3, C1 and C11c from
The desired product 19 was obtained when compound 18 was 13C NMR spectra, and H11c, H3, H3a, H1, H5 and H7 from 1H
treated with Cl3CCN–H2O2 according to von Holleben’s NMR spectra, this suggests that the B/C or C/D ring configur-
report,13 but trifluoroacetic acid (TFA) was employed to protect ations for the two compounds might be different. These ring
the nitrogen in the molecule from oxidation. Diol 20 was easily configurations cause the protons at the C5 and C7 positions in
obtained by acid hydrolysis14 of epoxide 19 and further investi- the two compounds to be surrounded by different environ-
gation showed that it could be afforded from olefin 18 directly ments. The X-ray crystallography data showed that the C ring
by treatment with a TFA–Cl3CCN–H2O2 system for a longer of the synthesized product adopts a half chair-like confor-
reaction time. The 2-hydroxyl moiety in diol 20 was selectively mation (Fig. 3), and the six carbons on the ring remain nearly
protected by TBS group, while compound 23 was afforded on one plane except for C11b, so the NMR values for axial–
equatorial or axial–axial couplings in the system would not be
the typical ones observed for chair-like conformation systems.
On a side note, the Rf value of compound 3 on a silica gel
TLC plate was greater than 0.85 (while the Rf of the HCl salt of
compound 3 was smaller than 0.10), but that of the natural
compound was 0.48 under the reported conditions.5a
Based on the comparison, we suggest that the structure of
natural amarbellisine should be reconfirmed, and our syn-
thesized compound (3) can only be named as putative rac-
amarbellisine. Part of the synthesis work for putative amarbel-
lisine as well as structure discussion were published previously
as a letter.9
Scheme 6 Synthesis of anhydrocaranine (1) and ( )-γ-lycorane (2). (a)
tBuONa, EtOH, 60 °C, 81%; (b) Pd/C, H2, AcOH, rt, 85%.
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Scheme 7 Synthesis of putative ( )-amarbellisine (3). Reagents and conditions: (a) LiAlH4, THF, 0 °C, 80%; (b) TFA, Cl3CCN, H2O2, rt, 24 h, 54%; (c)
TFA, Cl3CCN, H2O2, rt, 48 h, 55%; (d) 10% H2SO4 aq., rt, 98%; (e) TBSCl, imidazole, DMF, 99%; (f) (1) Ac2O, Et3N, (2) 2 M HCl aq., 98% for 2 steps; (g)
DMSO, oxalyl chloride, DCM, −78 °C, 1 h, then triethylamine, 75%; (h) CH(OMe)3, TsOH, MeOH, 98%; (i) as step g above, 72%; ( j) AcOH, toluene,
80 °C, 98%; (k) DIBAL-H, toluene −78 °C, 96%.
Table 1 Comparison of the 13C NMR spectral data
C
Synthetic product δa
Natural product δa
Δδ
−8.6b
1
2
3
3a
4
71.2 d
157.2 s
96.9 d
35.3 d
33.5 t
79.8 d
154.3 s
112.9 d
58.6 d
32.7 t
2.9
−16
−23.3
0.8
5
7
7a
8
9
10
11
11a
11b
11c
12
OMe
54.6 t
56.2 t
55.4 t
60.9 t
−0.8
−4.7
−3.6
−1.0
0.6
−0.1
1.5
128.9 s
106.3 d
146.6 s
146.6 s
108.3 d
128.2
42.8 d
62.0 d
100.9 t
54.4 q
132.5 s
107.3 d
146.0 s
146.7 s
106.8 d
124.6 s
45.6 d
69.1 d
100.7 t
57.6 q
Fig. 3 Half chair-like C ring conformation of the synthesized com-
pound 3 as seen from the crystal structure.
3.6
−2.8
−7.1
0.2
−3.2
In summary, we developed a new practical method which
includes a cyclopropyl ring-opening rearrangement for the syn-
thesis of lycorine-type alkaloids. By this method, we success-
fully accomplished the synthesis of anhydrocaranine (1),
( )-γ-lycorane (2) and putative ( )-amarbellisine (3). The struc-
ture of anhydrocaranine (1) was confirmed by its one and two
a Multiplicities determined by DEPT spectrum. b Obvious differences
were highlighted.
with the literature, the structure and relative stereochemistry
dimensional NMR data, and the data were reported for the of putative amarbellisine 3 were confirmed by its NMR data
and X-ray crystallography, and were found to be a different
first time to the best of our knowledge. While the structure of
isomer of natural amarbellisine.
( )-γ-lycorane (2) was confirmed by comparing its NMR data
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Table 2 Comparison of the 1H NMR spectral data
(1H, s), 6.83 (1H, s), 5.92 (2H, s), 5.47 (1H, s), 3.72 (2H, s), 2.81
(2H, brs), 2.67 (2H, t, J = 6.6 Hz), 2.45–2.41 (2H, m), 2.35–2.31
(2H, m) , 2.25 (2H, t, J = 6.6 Hz), 1.53 (1H, s). 13C NMR (CDCl3,
75 MHz) δ: 210.43, 147.38, 147.37, 136.38, 132.36, 119.66,
114.03, 112.71, 110.17, 101.69, 53.56, 46.37, 39.57, 38.54,
37.36, 28.35. HRMS (EI, m/z): calcd for C16H18NO3Br (M+):
351.0470, found: 351.0464.
C
Synthetic product δH
Natural product δH
Δδ
0.50
−0.91
−0.34
0.16
0.15
0.17
−0.89
−0.25
−0.50
0.11
1
3
3a
4
3.98
4.65
3.07
2.30
1.71
3.24
2.16
4.08
3.29
6.56
6.72
2.99
2.68
5.93
5.90
3.57
3.48
5.56
3.41
2.14
1.56
3.07
3.02
4.33
3.79
6.45
6.54
3.28
4.08
5.88
5.86
3.43
5
7
Compound 9
8
To a solution of compound 6 (176 mg, 0.5 mmol) in acetic
acid (4 mL) at room temperature was added bromine (80 mg,
0.5 mmol). The reaction mixture was stirred for 5 min, and
then quenched with saturated aqueous sodium bisulfate and
neutralized with saturated aqueous sodium bicarbonate. The
reaction mixture was extracted with ethyl acetate, washed with
brine, the organic solvent was dried (sodium sulfate), evapor-
ated, and a colorless oil was obtained. To a solution of color-
less oil (258 mg, 0.6 mmol) in methanol (5 mL) was added
potassium carbonate (166 mg, 1.2 mmol). After being stirred
at 60 °C for 12 h, the solvents were filtered and evaporated.
The residue was purified by flash chromatography (elution
with petroleum ether–ethyl acetate: 4/1) to give compound 9
11
11b
11c
12
0.18
−0.29
−1.40
0.05
0.04
0.14
OMe
Experiment
Proton nuclear magnetic resonance (1H-NMR) spectra were
recorded on a Bruker Avance 300 or 400 spectrometer at 300 or
400 MHz. Carbon-13 nuclear magnetic resonance (13C-NMR)
spectra were recorded on a Bruker Avance 300 or 400 spectro-
meter at 75 or 100 MHz. Chemical shifts are reported as δ
values in parts per million (ppm) relative to tetramethylsilane
(TMS) for all recorded NMR spectra. High resolution mass
spectra were taken on an AB QSTAR Pulsar mass spectrometer
and Autospec Premier P776, by ESI or EI, as indicated in each
individual instance. Melting points were determined on a
capillary melting point apparatus and are uncorrected. Com-
mercial starting materials and reagents were obtained from
Acros, Aldrich, Fluka and were used without further purifi-
cation, unless otherwise indicated. All reactions were con-
ducted in dried glassware under a positive pressure of dry
nitrogen. Silica gel (Qingdao, 200–300 mesh) was used for
column chromatography.
1
(209 mg, >99%) as a white powder. H NMR (CDCl3, 300 MHz)
δ: 6.95 (1H, s), 6.91 (1H, s), 5.94 (2H, s), 3.78 (1H, d, J = 13.8
Hz), 3.41 (1H, d, J = 13.8 Hz), 3.18 (1H, td, J = 9.0, 3.0 Hz), 2.97
(1H, d, J = 2.4 Hz), 2.43 (1H, dd, J = 8.6, 9.3 Hz), 2.20–2.16 (2H,
m) , 2.14–2.09 (1H, m), 1.98–1.87 (1H, m), 1.66 (1H, dd, J = 9.0,
3.6 Hz), 1.46–1.41 (1H, m), 1.21–1.18 (1H, m). 13C NMR
(CDCl3, 75 MHz) δ: 212.86, 147.39, 147.37, 130.85, 114.26,
112.52, 110.41, 101.66, 65.53, 57.53, 53.48, 40.46, 39.92, 35.00,
27.55, 16.72. HRMS (ESI, m/z): calcd for C16H17NO3Br
([M + H]+): 350.0391, found: 350.0394. m.p.: 118–119 °C.
Compound 12
A mixture of tris(dibenzylideneacetone)dipalladium (18 mg,
0.02 mmol), ( )-2,2′-bis (diphenylphosphino)-1,1′-binaphtha-
lene (25 mg, 0.04 mmol) and sodium tertiary butoxide (38 mg,
Compound 6
A solution of bromopiperonal 8 (4.6 g, 20 mmol) and 2-(4- 0.4 mmol) in dry toluene (10 mL) was stirred at room tempera-
methoxycyclohexa-1,4-dienyl) ethylamine 7 (3.1 g, 20 mmol) in ture for 1 h. Then a solution of 9 (70 mg, 0.2 mmol) in dry
dry methanol (100 mL) was refluxed for 2.5 h. The solution toluene (5 mL) was added. The reaction mixture was placed
was cooled to room temperature, then sodium borohydride under nitrogen atmosphere. After being stirred at 95 °C for
(760 mg, 20 mmol) was added and the reaction mixture was 24 h, the reaction mixture was filtered and evaporated. The
stirred at room temperature for 30 min. The solvent was residue was purified by flash chromatography (elution with
removed in vacuo. The residue was diluted with ethyl acetate, petroleum ether–ethyl acetate: 3/1) to give 12 (44 mg, 82%) as
1
washed with brine, and dried over sodium sulfate, then the a white solid. H NMR (CDCl3, 300 MHz) δ: 6.78 (1H, s), 6.55
solvent was evaporated. To a solution of the above residue (1H, s), 5.90 (1H, d, J = 1.4 Hz), 5.87 (1H, d, J = 1.4 Hz), 3.79
(183 mg, 0.5 mmol) in acetone (4 mL) was added aqueous (1H, d, J = 13.8 Hz), 3.44–3.38 (2H, m), 3.04 (1H, d, J = 4.2 Hz),
hydrochloric acid (2 M, 1 mL) at room temperature. After being 2.87 (1H, d, J = 4.5 Hz), 2.70 (1H, ddd, J = 9.0, 9.0, 9.0 Hz), 2.30
stirred at room temperature for 10 min, the reaction mixture (1H, ddd, J = 12.3, 9.9, 2.0 Hz), 2.05–1.95 (1H, m), 1.59–1.55
was quenched with saturated aqueous potassium carbonate and (2H, m), 1.52–1.48 (1H, m). 13C NMR (CDCl3, 75 MHz) δ:
extracted with ethyl acetate. The combined organic layers were 209.66, 146.25, 146.19, 129.02, 122.43, 110.95, 106.60, 100.90,
washed with brine, the organic solvent was dried (sodium 64.38, 52.55, 52.47, 47.33, 38.64, 33.09, 27.91, 16.58. HRMS
sulfate), filtered, and evaporated. Compound 6 (174 mg, 99%) (ESI, m/z): calcd for C16H16NO3 ([M + H]+): 270.1130, found:
was obtained as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ: 6.94 270.1135. m.p.: 175–176 °C.
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Compound 13
48.70, 39.73, 32.86, 28.50, 12.74. HRMS (EI, m/z): calcd for
C16H15NO2Br ([M − H]+): 332.0286, found: 332.0288.
To a solution of compound 12 (50 mg, 0.19 mmol) in acetic
acid (4 mL) at room temperature was added 40% HBr–AcOH
(0.3 mL). The reaction mixture was stirred for 2 min, then neu-
tralized with saturated aqueous sodium bicarbonate, and
extracted with ethyl acetate and washed with brine. The
organic layer was dried (sodium sulfate) and evaporated. The
residue was purified by flash chromatography (elution with
petroleum ether–ethyl acetate: 4/1) to give compound 13
Compound 16
To a solution of 15 (120 mg, 0.36 mmol) in methanol (20 mL)
was added 47% hydrobromic acid aqueous solution (2 mL,
0.44 mL). After being stirred at room temperature for 144 h,
the reaction mixture was quenched with saturated aqueous
potassium carbonate, extracted with ethyl acetate, washed with
brine, dried (sodium sulfate), and evaporated. The residue was
purified by flash chromatography (elution with petroleum
ether–ethyl acetate: 5/1), to give 16 (92 mg, 77%) as a yellow
1
(63 mg, 97%) as a white powder. H NMR (CDCl3, 300 MHz) δ:
6.82 (1H, s), 6.54 (1H, s), 5.92 (1H, d, J = 1.2 Hz), 5.90 (1H, d, J
= 1.2 Hz), 3.82 (1H, d, J = 14.4 Hz), 3.61 (1H, s), 3.50–3.43 (2H,
m), 3.26–3.20 (1H, m), 2.87 (1H, d, J = 3.9 Hz), 2.78 (1H, d, J =
18.9 Hz), 2.63 (1H, dd, J = 8.7, 17.4 Hz), 2.46 (1H, d, J = 19.2
Hz), 2.11–2.04 (2H, m). 13C NMR (CDCl3, 75 MHz) δ: 212.81,
146.52, 146.32, 127.48, 122.58, 110.47, 106.41, 100.96, 69.53,
52.73, 52.45, 49.33, 47.51, 41.26, 38.12. HRMS (ESI, m/z): calcd
for C16H17NO3Br ([M + H]+): 350.0391, found: 350.0397. m.p.:
113–115 °C.
1
solid and recovered 15 (21 mg, 18%) as a light yellow oil. H
NMR (CDCl3, 300 MHz) δ: 6.80 (1H, s), 6.50 (1H, s), 5.92 (2H,
s), 5.78 (1H, d, J = 10.1 Hz), 5.63–5.58 (1H, m), 3.98 (1H, d, J =
14.1 Hz), 3.64 (1H, brs), 3.39 (1H, d, J = 14.0 Hz), 3.40–3.33
(1H, m), 2.95 (1H, d, J = 4.6 Hz), 2.74–2.71 (2H, m), 2.60–2.53
(1H, m), 2.44–2.36 (2H, m). 13C NMR (CDCl3, 75 MHz) δ:
146.89, 146.25, 129.11 × 2, 127.23, 121.53, 108.79, 106.49,
101.03, 68.25, 60.88, 55.93, 51.53, 41.38, 37.85, 36.44. HRMS:
(ESI, m/z) calcd for C16H17NO2 ([M + H]+): 334.0442, found:
334.0447. m.p.: 187–190 °C.
Compound 14
To a solution of 12 (200 mg, 0.74 mmol) in methanol (20 mL)
was added sodium borohydride (56.3 mg, 1.5 mmol). After
being stirred at room temperature for 1 h, the reaction mixture
was extracted with ethyl acetate, washed with brine, dried
Treating compound 16 as starting material under the above
reaction conditions, a similar ratio of compound 15 to 16 was
observed.
(sodium sulfate), and evaporated. The residue was purified by Anhydrocaranine (1)
flash chromatography (elution with ethyl acetate) to give 14
To a solution of 16 (50 mg, 0.15 mmol) in EtOH (10 mL) was
1
(191 mg, 95%) as a yellow solid. H NMR (CDCl3, 300 MHz) δ:
added NaOH (12 mg, 0.3 mmol). After being stirred at 60 °C
for 12 h, the reaction mixture was cooled to room temperature
and extracted with AcOEt, washed with brine, dried (sodium
sulfate), and evaporated. The residue was purified by flash
chromatography (elution with petroleum ether–AcOEt: 3/1) to
give anhydrocaranine (1) (31 mg, 81%) as a yellow solid. The
NMR data of compound 1 are listed below (Table 3).
6.66 (1H, s), 6.55 (1H, s), 5.90 (1H, d, J = 1.3 Hz), 5.89 (1H, d, J
= 1.3 Hz), 4.16 (1H, d, J = 5.5 Hz), 3.83 (1H, d, J = 13.9 Hz), 3.37
(1H, ddd, J = 8.8, 8.7, 2.0 Hz), 3.27 (1H, d, J = 13.9 Hz), 2.66
(1H, t, J = 4.6 Hz), 2.51 (1H, ddd, J = 9.9, 9.0, 9.0 Hz), 2.44 (1H,
d, J = 4.1 Hz), 2.28–2.21 (1H, m), 2.03–1.95 (1H, m), 1.27–1.23
(1H, m), 1.03–0.98 (1H, m), 0.68–0.64 (1H, m). 13C NMR
(CDCl3, 75 MHz) δ: 146.47, 146.12, 130.02, 125.44, 109.39,
106.72, 100.85, 76.74, 69.19, 53.79, 53.10, 45.43, 34.07, 32.43, γ-Lycorane (2)
28.10, 10.19. HRMS (EI, m/z): calcd for C16H17NO3 (M+):
271.1208, found: 271.1203. m.p.: 114–116 °C.
To a solution of anhydrocaranine (1) (50 mg, 0.2 mmol) in
acetic acid (10 mL) was added 10% Pd/C (15 mg). The reaction
mixture was placed under an atmosphere of hydrogen and
stirred for 6 h at room temperature. The reaction mixture was
Compound 15
To a solution of 14 (100 mg, 0.37 mmol) in dichloromethane then filtered and concentrated in vacuo. The mixture was
(20 mL) was added phosphorus tribromide (0.04 mL, quenched with saturated aqueous potassium carbonate,
0.44 mmol). After being stirred at 0 °C for 1 h, the reaction extracted with ethyl acetate, washed with brine, dried (sodium
mixture was quenched with saturated aqueous potassium car- sulfate), and the organic solvent evaporated. The residue was
bonate, extracted with ethyl acetate, washed with brine, dried purified by flash chromatography (elution with petroleum
(sodium sulfate), and evaporated. The residue was purified by ether–ethyl acetate: 3/1), to give γ-lycorane (2) (43 mg, 85%) as
flash chromatography (elution with petroleum ether–ethyl a colorless oil. NMR data of our synthesized compound 2 as
1
acetate: 5/1) to give 15 (116 mg, 95%) as a yellow oil. H NMR well as reported data12a are shown in Tables 4 and 5.
(CDCl3, 300 MHz) δ: 7.17 (1H, s), 6.55 (1H, s), 5.91 (2H, s), 4.57
(1H, dd, J = 7.5, 5.0 Hz), 3.81 (1H, d, J = 13.9 Hz), 3.38 (1H, dd,
Compound 18
J = 8.8, 2.2 Hz), 3.32 (1H, d, J = 14.1 Hz), 3.04 (1H, t, J = 5.3 To a solution of 16 (50 mg, 0.15 mmol) in dry tetrahydrofuran
Hz), 2.58–2.52 (2H, m), 2.15 (1H, t, J = 9.0 Hz), 1.92–1.87 (1H, (10 mL) was added lithium aluminium hydride (7 mg,
m), 1.54–1.51 (1H, m), 1.17 (1H, t, J = 6.2 Hz), 1.03 (1H, t, J = 0.18 mmol). The reaction mixture was placed under a nitrogen
4.4 Hz). 13C NMR (CDCl3, 75 MHz) δ: 146.50, 146.40, 128.96, atmosphere and stirred for 12 h at 0 °C. The reaction mixture
127.21, 108.97, 106.90, 101.03, 69.54, 62.44, 53.57, 53.08, was quenched with saturated aqueous ammonium chloride,
3196 | Org. Biomol. Chem., 2014, 12, 3191–3200
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Table 3 13C NMR and 1H NMR data of anhydrocaranine (1)
H
1H NMR δ
C
13C NMR δ
HMBC
2.89
6.11, 3.33, 2.97, 2.45
5.91
1
6.11 (1H, d, J = 2.8 Hz)
2.89 (2H, brs)
5.58 (1H, s)
1
2
3
3a
4
115.4 d
28.7 t
115.1 d
132.0 s
27.4 t
2 + 2′
3
3a
5′ + 4
7.11, 3.55
2.57 (2H, overlap)
4′
5
7 + 7′
2.45 (1H, t, J = 9.1 Hz)
3.33 (1H, m)
4.01 (1H, d, J = 14.0 Hz) 3.55
(1H, d, J = 14.0 Hz)
5
7
52.6 t
56.1 t
3.55, 2.57, 2.45
6.54, 3.33, 2.97, 2.57
7a
8
9
10
11
11a
11b
11c
12
7a
8
9 (or 10)
10 (or 9)
11
11a
11b
11c
126.2 s
107.0 d
146.9 s
147.0 s
102.8 d
128.8 s
137.7 s
61.3 d
7.11, 6.54, 4.01,
6.11, 4.01, 3.55, 3.33
7.11, 6.54, 5.91
6.54 (1H, s)
7.11 (1H, s)
6.54
7.11, 4.01, 3.55, 3.33, 2.89
2.97, 2.89, 2.57
6.11, 4.01, 3.55, 3.33
6.11, 5.58
2.97 (1H, d, J = 8.1 Hz)
5.91 (2H, s)
12
101.1 t
1/1) to give 18 (30 mg, 80%) as a colorless oil. 1H NMR (CDCl3,
300 MHz) δ: 6.75 (1H, s), 6.50 (1H, s), 5.90 (2H, s), 5.72 (2H, s),
4.98 (1H, d, J = 14.1 Hz), 3.42–3.28 (3H, m), 2.57 (1H, t, J = 5.1
Hz), 2.37–2.31 (2H, m), 2.29–2.12 (1H, m), 2.09–1.90 (2H, m),
1.61–1.57 (1H, m). 13C NMR (CDCl3, 75 MHz) δ: 146.41, 145.75,
130.76, 129.92, 128.11, 124.82, 108.60, 106.43, 100.72, 61.87,
56.09, 52.31, 38.04, 33.90, 30.59, 27.82. HRMS (EI, m/z): calcd
for C16H17NO2 (M+): 255.1259, found: 255.1259.
Table 4 Comparison of the 13C NMR spectra data of γ-lycorane (2)
C
Synthetic product δ
Reported data δ
Δδ
1
2
29.3 t
25.2 t
29.3 t
25.2 t
0
0
0
0
0
0
0
3
3a
4
30.4 t
37.4 d
31.7 t
30.4 t
37.4 d
31.7 t
5
7
53.7 t
57.1 t
53.7 t
57.1 t
7a
8
9
10
11
11a
11b
11c
12
127.3 s
106.3 d
145.7 s
146.1 s
108.3 d
133.2 s
39.5 d
62.9 d
100.7 t
127.3 s
106.3 d
145.6 s
146.0 s
108.3 d
133.2 s
39.5 d
62.9 d
100.7 t
0
0
0.1
0.1
0
0
0
0
0
Compound 19
A mixture of trichloroacetonitrile (0.1 mL) and 30% hydrogen
peroxide (0.1 mL) in dichloromethane (5 mL) was stirred at
room temperature for 1 h. Then a solution of 18 (100 mg,
0.4 mmol) in a mixture of dichloromethane (3 mL) and tri-
fluoroacetic acid (1 mL) was added. After being stirred at room
temperature for 24 h, the reaction mixture was quenched with
26% aqueous ammonia, extracted with ethyl acetate, washed
with brine, dried (sodium sulfate), and evaporated. The
residue was purified by flash chromatography (elution with
petroleum ether–ethyl acetate: 1/1) to give 19 (57 mg, 54%) as
Table 5 Comparison of the 1H NMR spectra data of γ-lycorane (2)
C
Synthetic product δH
Natural product δH
Δδ
1
a colorless oil. H NMR (CDCl3, 300 MHz) δ: 6.85 (1H, s), 6.52
1–4
1.22–1.60 (4H, m)
1.62–1.93 (3H, m)
1.98–2.07 (1H, m)
2.12–2.24 (2H, m)
1.23–1.54 (4H, m)
1.59–1.81 (3H, m)
1.95–2.07 (1H, m)
2.09–2.24 (2H, m)
0.02
0.08
0.02
0.02
(1H, s), 5.92 (1H, d, J = 1.2 Hz), 5.91 (1H, d, J = 1.2 Hz), 3.93
(1H, d, J = 14.4 Hz), 3.37–3.23 (4H, m), 3.13 (1H, dd, J = 3.9, 1.2
Hz), 2.36–2.28 (2H, m), 2.25–2.18 (1H, m), 2.08 (1H, ddd, J =
15.0, 6.6, 2.1 Hz), 1.98–1.86 (1H, m) 1.77 (1H, ddd, J = 15.0,
10.2, 1.5 Hz), 1.56–1.50 (1H, m). 13C NMR (CDCl3, 75 MHz) δ:
146.70, 146.26, 129.13, 127.53, 108.94, 106.39, 100.92, 58.92,
55.83, 55.54, 54.29, 51.06, 37.36, 31.29, 28.64, 26.57. HRMS
(EI, m/z): calcd for C16H17NO3 (M+): 271.1208, found: 271.1214.
3a +
5
11c
11b
7
2.39 (1H, t, J = 4.8 Hz)
2.71–2.78 (1H, m)
3.21 (1H, d, J = 14.4 Hz)
3.38 (1H, ddd, J = 9.3, 9.2, 3.38 (1H, ddd, J = 9.3, 9.2, 0.00
3.8 Hz)
4.01 (1H, d, J = 14.4 Hz)
5.87 (1H, d, J = 1.4 Hz)
5.89 (1H, d, J = 1.4 Hz)
6.49 (1H, s)
2.37 (1H, t, J = 4.8 Hz)
2.70–2.78 (1H, m)
3.21 (1H, d, J = 14.4 Hz)
0.02
0.01
0.00
5′
3.8 Hz)
7′
12
4.02 (1H, d, J = 14.4 Hz)
5.88 (1H, d, J = 1.4 Hz)
5.89 (1H, d, J = 1.4 Hz)
6.49 (1H, s)
−0.01
−0.01
0.00
Compound 20
8
0.00
11
6.61 (1H, s)
6.61 (1H, s)
0.00
To a solution of 19 (50 mg, 0.18 mmol) in methanol (4 mL)
was added 10% sulfuric acid (1 mL) at room temperature. After
being stirred for 24 h, the reaction mixture was quenched with
saturated aqueous potassium carbonate and extracted with
ethyl acetate. The combined organic layers were washed with
brine, the organic solvent was dried (sodium sulfate), filtered,
extracted with ethyl acetate, washed with brine, dried (sodium
sulfate), and evaporated. The residue was purified by flash
chromatography (elution with petroleum ether–ethyl acetate:
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and evaporated. Compound 20 (51 mg, 98%) was obtained as Compound 23
yellow solid. 1H NMR (CDCl3, 300 MHz) δ: 6.91 (1H, s), 6.49
To a solution of oxalyl chloride (0.24 mL, 2.8 mmol) in dry
dichloromethane (3 mL) under a nitrogen atmosphere was
added dropwise dimethyl sulfoxide (0.35 mL, 4.9 mmol) in dry
dichloromethane (3 mL) at −78 °C for 40 min. Then a solution
of 22 (230 mg, 0.7 mmol) in dry dichloromethane (10 mL) was
added dropwise. After being stirred at −78 °C for 1 h, triethyl-
amine (1 mL, 7 mmol) was added slowly and the solution was
kept at the same temperature for another 10 min. The reaction
mixture was then warmed to room temperature, quenched
with saturated aqueous sodium bicarbonate and extracted with
ethyl acetate. The combined organic layers were washed with
brine, the organic solvent was dried (sodium sulfate), filtered,
and evaporated. The residue was purified by flash chromato-
graphy (elution with petroleum ether–ethyl acetate: 4/1) to give
(1H, s), 5.87 (2H, s), 3.97 (1H, d, J = 14.4 Hz), 3.45–3.42 (2H,
m), 3.32–3.24 (2H, m), 2.63–2.61 (1H, m), 2.46 (1H, t, J = 4.2
Hz), 2.33–2.25 (1H, m), 2.23–2.12 (1H, m), 2.03–1.91 (1H, m),
1.88–1.83 (1H, m), 1.54–1.48 (1H, m). 13C NMR (CDCl3,
75 MHz) δ: 146.24, 145.42, 128.76, 127.90, 111.00, 106.07,
100.70, 76.68, 73.35, 64.00, 56.77, 53.07, 44.42, 36.51, 36.03,
28.52. HRMS (EI, m/z): calcd for C16H19NO4 (M+): 289.1314,
found: 289.1311. m.p.: 101–104 °C.
Compound 21
A mixture of imidazole (48 mg, 0.70 mmol), t-butyl dimethyl
chlorosilane (63 mg, 0.42 mmol) and 20 (100 mg, 0.35 mmol)
in dry N,N-dimethylformamide (10 mL) was stirred at 60 °C for
24 h. Then the reaction mixture was quenched with saturated
aqueous potassium carbonate and extracted with ethyl acetate.
The combined organic layers were washed with brine, the
organic solvent was dried (sodium sulfate), filtered, and evap-
orated. Compound 21 (138 mg, 99%) was obtained as yellow
oil. 1H NMR (CDCl3, 300 MHz) δ: 6.99 (1H, s), 6.50 (1H, s), 5.90
(1H, d, J = 1.2 Hz), 5.87 (1H, d, J = 1.2 Hz), 4.06 (1H, d, J = 14.4
Hz), 3.55–3.51 (2H, m), 3.38–3.25 (2H, m), 2.73 (1H, dd, J = 9.0,
3.9 Hz), 2.61 (1H, s), 2.47 (1H, t, J = 4.3 Hz), 2.35–2.29 (1H, m),
2.26–2.15 (1H, m), 2.06–1.94 (1H, m), 1.81–1.75 (1H, m),
1.74–1.61 (1H, m) , 1.60–1.47 (1H, m) , 0.87 (9H, s) , 0.11–0.10
(6H, m). 13C NMR (CDCl3, 75 MHz) δ: 146.34, 145.46, 128.78,
127.93, 111.05, 105.94, 100.70, 76.62, 75.47, 63.47, 56.79,
53.06, 43.65, 37.51, 36.27, 28.57, 25.74, 17.96, −3.96, −4.72.
HRMS (EI, m/z): calcd for C22H33NO4Si (M+): 403.2179, found:
403.2170.
1
23 (174 mg, 76%) as a yellow solid. H NMR (CDCl3, 300 MHz)
δ: 6.68 (1H, s), 6.53 (1H, s), 5.90 (2H, s), 5.39 (1H, d, J = 11.1
Hz), 4.15 (1H, d, J = 14.7 Hz), 3.48–3.40 (2H, m), 3.17 (1H, dd,
J = 11.1, 3.3 Hz), 2.75–2.68 (2H, m), 2.64–2.59 (1H, m), 2.48–2.35
(2H, m), 2.14–2.11 (4H, m), 1.69–1.60 (1H, m). 13C NMR
(CDCl3, 75 MHz) δ: 204.61, 169.94, 146.97, 145.76, 128.19,
126.85, 109.84, 106.37, 100.93, 78.51, 62.59, 56.24, 52.52,
45.07, 43.30, 39.55, 29.58, 20.76. HRMS (EI, m/z): calcd for
C18H19NO5 (M+): 329.1263, found: 329.1269. m.p.: 199–202 °C.
Compound 24
A mixture of 23 (300 mg, 0.9 mmol), trimethyl orthoformate
(1.2 mL, 7.8 mmol) and p-toluenesulfonic acid (300 mg,
1.74 mmol) in methanol (20 mL) was refluxed for 30 h under
nitrogen atmosphere. Then the reaction mixture was quenched
with saturated aqueous sodium bicarbonate and extracted with
ethyl acetate. The combined organic layers were washed with
brine, the organic solvent was dried (sodium sulfate), filtered,
and evaporated. The residue was purified by flash chromato-
graphy (elution with ethyl acetate) to give 24 (298 mg, 98%) as
Compound 22
To the solution 21 (740 mg, 1.8 mmol) in dry triethylamine
(15 mL) was added acetic anhydride (0.35 mL, 3.6 mmol) and
4-dimethylaminopyridine (9 mg, 0.07 mmol). The reaction
mixture was placed under nitrogen atmosphere. After being
stirred at 60 °C for 24 h, the reaction mixture was neutralized
by aqueous potassium carbonate, extracted with ethyl acetate
and evaporated. The crude product was suspended in 20 mL of
methanol at 0 °C. Hydrochloric acid (2 M, 2 mL) was added
slowly and the mixture was stirred at room temperature. After
being stirred at room temperature for 4 h, the reaction mixture
was quenched with saturated aqueous sodium bicarbonate
and extracted with ethyl acetate. The combined organic layers
were washed with brine, the organic solvent was dried (sodium
sulfate), filtered, and evaporated. Compound 22 (595 mg, 98%)
1
a colorless oil. H NMR (CDCl3, 300 MHz) δ: 6.94 (1H, s), 6.50
(1H, s), 5.89 (1H, s), 5.87 (1H, s), 4.05 (1H, d, J = 14.7 Hz), 3.78
(1H, d, J = 10.2 Hz), 3.43 (3H, s), 3.35–3.25 (5H, m), 2.90 (1H,
dd, J = 10.2, 3.6 Hz), 2.47 (1H, t, J = 4.2 Hz), 2.36–2.28 (2H, m),
2.24–2.16 (1H, m) , 2.05–1.92 (2H, m) , 1.59–1.43 (2H, m). 13C
NMR (CDCl3, 75 MHz) δ: 146.4, 145.4, 128.6, 128.2, 111.3,
105.9, 100.7, 99.8, 75.9, 63.2, 56.7, 53.2, 49.9, 49.8, 43.4, 35.0,
34.8, 28.3. HRMS (EI, m/z): calcd for C18H23NO5 (M+):
333.1576, found: 333.1584.
Compound 25
was obtained as yellow solid. 1H NMR (CDCl3, 300 MHz) The procedure was similar to the one employed to prepare
δ: 6.64 (1H, s), 6.49 (1H, s), 5.87 (2H, s), 4.97 (1H, t, J = 9.6 Hz), compound 23 above. The residue was purified by flash chrom-
4.06 (1H, d, J = 14.7 Hz), 3.67–3.59 (1H, m), 3.38–3.26 (2H, m), atography (elution with petroleum ether–sodium sulfate: 2/1)
2.84 (1H, dd, J = 10.2, 3.9 Hz), 2.54 (1H, t, J = 4.2 Hz), 2.35–2.19 to give 25 (275 mg, 72%) as a colorless oil. 1H NMR (CDCl3,
(3H, m), 2.09 (3H, s), 2.03–1.94 (2H, m), 1.73–1.65 (1H, m), 300 MHz) δ: 6.52 (1H, s), 6.45 (1H, s), 5.92 (2H, s), 4.07 (1H, d,
1.61–1.50 (1H, m). 13C NMR (CDCl3, 75 MHz) δ: 171.9, 146.6, J = 4.8 Hz), 4.02 (1H, d, J = 14.7 Hz), 3.42–3.25 (8H, m), 2.92
145.6, 128.4, 127.4, 109.5, 106.4, 100.8, 79.4, 72.5, 63.2, 56.4, (1H, t, J = 4.2 Hz), 2.70–2.64 (1H, m), 2.34–2.27 (2H, m),
52.7, 42.7, 37.6, 36.1, 28.5, 21.3. HRMS (EI, m/z): calcd for 2.11–2.02 (1H, m) , 1.86–1.78 (1H, m) , 1.57–1.50 (1H, m). 13C
C18H21NO5 (M+): 331.1420, found: 331.1410. m.p.: 169–170 °C.
NMR (CDCl3, 75 MHz) δ: 204.50, 146.86, 145.96, 128.71,
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123.56, 110.54, 106.15, 100.91, 99.93, 66.45, 55.85, 52.80, ether–ethyl acetate: 1/1) to give 3 (29 mg, 72%) as a white
50.60, 49.89, 49.15, 37.64, 34.34, 27.81. HRMS (EI, m/z): calcd solid, and 27 (9 mg, 22%) as a white powder with the following
1
for C18H21NO5 (M+): 331.1420, found: 331.1418.
data: H NMR (CDCl3, 300 MHz) δ: 6.99 (1H, s), 6.53 (1H, s),
5.91 (1H, d, J = 1.5 Hz), 5.89 (1H, d, J = 1.5 Hz), 4.61 (1H, d, J =
3.9 Hz), 4.13–4.08 (2H, m), 3.55 (3H, s) , 3.31–3.22 (2H, m),
Compound 26
A solution of 25 (120 mg, 0.36 mmol) and glacial acetic acid 3.01–2.97 (1H, m), 2.79 (1H, dd, J = 8.7, 3.6 Hz), 2.50 (1H, dd,
(0.01 mL, 0.18 mmol) in 5 mL of dry toluene was stirred at J = 7.2, 3.9 Hz), 2.28–2.20 (1H, m), 2.18–2.05 (1H, m), 1.62–1.53
80 °C for 3 h, then the reaction mixture was cooled to room (1H, m) . 13C NMR (CDCl3, 75 MHz) δ: 151.9, 146.5, 145.6,
temperature and quenched with saturated aqueous sodium 129.9, 127.6, 110.7, 106.2, 100.8, 98.6, 69.6, 61.9, 56.8, 54.6,
bicarbonate, extracted with ethyl acetate. The combined 54.5, 44.6, 35.1, 32.2. HRMS (EI, m/z): calcd for C17H19NO4
organic layers were washed with brine, the organic solvent was (M+): 301.1314, found: 301.1309. m.p.: 122–125 °C.
dried (sodium sulfate), filtered, and evaporated. The residue
was purified by flash chromatography (elution with petroleum
ether–ethyl acetate: 4/1) to give 26 (106 mg, 98%) as a yellow
solid. H NMR (CDCl3, 300 MHz) δ: 6.73 (1H, s), 6.50 (1H, s),
Acknowledgements
1
5.93 (2H, s), 5.52 (1H, d, J = 3.3 Hz), 4.02 (1H, d, J = 14.7 Hz), This work was supported by grants (no. 20562012, 21162033)
3.65 (1H, d, J = 3.9 Hz), 3.58 (3H, s), 3.38–3.25 (3H, m), 2.90 from the National Natural Science Foundation of China and
(1H, t, J = 5.1 Hz), 2.40–2.24 (2H, m), 1.82–1.77 (1H, m). 13C the Open Research Foundation of Yunnan Key Laboratory of
NMR (CDCl3, 75 MHz) δ: 191.26, 148.28, 147.97, 145.83, Pharmacology for Natural Products (no. 2013G003).
127.86, 123.52, 117.22, 112.01, 105.93, 100.92, 62.02, 55.99,
54.96, 54.20, 49.62, 35.33, 31.58. HRMS (EI, m/z): calcd for
C17H17NO4 (M+): 299.1158, found: 299.1157. m.p.: 147–149 °C.
References
Putative amarbellisine (3)
1 (a) S. F. Martin, in The Alkaloids, ed. A. Brossi, Academic
Compound 26 (32 mg, 0.1 mmol) was suspended in dry
toluene (5 mL) and cooled to −78 °C under nitrogen atmos-
phere. Diisobutylaluminum hydride (1.1 M in cyclohexane,
0.12 mL, 0.13 mmol) was added slowly by syringe and the
mixture was stirred at −78 °C for 30 min. The mixture was
quenched with 5 mL saturated ammonium chloride solution
and extracted with additional portions ethyl acetate. The com-
bined organic layers were washed with brine, the organic
solvent was dried (sodium sulfate), filtered, and evaporated.
The residue was purified by flash chromatography (elution
with petroleum ether–ethyl acetate: 1/1) to give 3 (31 mg, 96%)
as a white solid. 1H NMR (CDCl3, 400 MHz) δ: 6.72 (1H, s),
6.56 (1H, s), 5.93 (1H, d, J = 1.6 Hz), 5.90 (1H, d, J = 1.6 Hz),
4.65 (1H, d, J = 4.8 Hz), 4.08 (1H, d, J = 14.4 Hz), 3.98 (1H, d,
J = 1.6 Hz) , 3.57 (3H, s), 3.29 (1H, d, J = 14.8 Hz), 3.24 (1H, d,
J = 8.4 Hz), 3.10–3.04 (1H, m), 2.99 (1H, t, J = 6.8 Hz) , 2.68
(1H, dd, J = 8.4, 1.6 Hz) , 2.34–2.26 (1H, m) , 2.19–2.12 (1H, m),
1.74–1.67 (1H, m). 13C NMR (CDCl3, 100 MHz) δ: 157.2, 146.6,
128.9, 128.2, 108.3, 106.3, 100.9, 96.9, 71.2, 62.0, 56.2, 54.6,
54.4, 42.8, 35.3, 33.5. HRMS (EI, m/z): calcd for C17H19NO4
(M+): 301.1314, found: 301.1325. m.p.: 185–187 °C.
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K. S. Saini and S. Razdan, Phytochemistry, 1985, 24, 2141;
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2 (a) A. Padaw and H. Zhang, J. Org. Chem., 2007, 72, 2570;
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