Concise construction of the tetracyclic core of lycorine-type alkaloids and the formal synthesis of α-lycorane based on asymmetric bifunctional thiourea-catalyzed cascade reaction

Article abstract of DOI:10.1039/c2ob26422f

A concise and stereoselective construction of the tetracyclic core of lycorine-type alkaloids and the formal synthesis of α-lycorane has been achieved. The feature of the current method is the employment of a bifunctional thiourea-catalyzed cascade reaction as a powerful tool to construct the skeleton of the natural product, which is a challenging yet very rarely explored strategy. As a result, the tetracyclic core is efficiently synthesized in just three simple operations involving two consecutive cascade reactions. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob26422f

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PAPER
Concise construction of the tetracyclic core of lycorine-type alkaloids and the
formal synthesis of α-lycorane based on asymmetric bifunctional
thiourea-catalyzed cascade reaction†
Yao Wang, Yong-Chun Luo, Hong-Bo Zhang and Peng-Fei Xu*
Received 20th July 2012, Accepted 28th August 2012
DOI: 10.1039/c2ob26422f
A concise and stereoselective construction of the tetracyclic core of lycorine-type alkaloids and the formal
synthesis of α-lycorane has been achieved. The feature of the current method is the employment of a
bifunctional thiourea-catalyzed cascade reaction as a powerful tool to construct the skeleton of the natural
product, which is a challenging yet very rarely explored strategy. As a result, the tetracyclic core is
efficiently synthesized in just three simple operations involving two consecutive cascade reactions.
Introduction
Organocatalytic cascade reactions have emerged as a powerful
tool for the rapid construction of complex molecules with mul-
tiple stereocenters in a biomimetic way.1 These efficient trans-
formations allow multiple bond-forming events to occur in a
single vessel and as a consequence significantly increase
resource efficiency for the overall process. Remarkably, despite
great advances in the development of organocatalytic cascade
reactions,1 the application of these transformations remains a big
challenge and only a few of them have been successfully applied
in the total synthesis of natural products.2 More specially, these
applicable cascade reactions are predominantly secondary-
Fig. 1 Lycorine-type alkaloids.
amine-catalyzed transformations and the bifunctional thiourea-
catalyzed cascade reactions are very rarely applied in natural
product synthesis.2a To this end, it is highly desirable to
implement this strategy into the synthesis of bioactive natural
The Amaryllidaceae alkaloids are a large family of natural
products existing as potential drug candidates4 which display
biological properties including analgesic,5a antiviral,5b and anti-
products to complement the current chemical synthesis. Thus,
neoplastic activities,5c–e as well as insect antifeedant activities.5f,g
with our ongoing interest in the study of bifunctional thiourea-
catalyzed cascade reactions3 and extending our strategy for the
The lycorine-type alkaloids, which are characterized by the pres-
construction of synthetically useful cyclohexanes,3a we describe
ence of the ABCD tetracyclic core structure, represent an impor-
tant subclass of this family (Fig. 1). Owing to the intriguing
polycyclic structures and the special bioactive properties, lycor-
herein an efficient strategy for the construction of lycorine-type
alkaloids which is facilitated by a bifunctional thiourea-catalyzed
cascade reaction in a sequence of reactions free of protection and
ane alkaloids have attracted numerous synthetic interest and
deprotection steps.
studies.6
Results and discussion
State Key Laboratory of Applied Organic Chemistry, College of
Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, P.R. China. E-mail: xupf@lzu.edu.cn;
Retrosynthetic analysis
Fax: (+86) 931 8915557; Tel: +86 931 8912281
Our retrosynthetic analysis is depicted in Scheme 1. We envi-
saged that ring C is the crucial structure to construct these alka-
loids. An organocatalytic enantioselective double Michael
cascade reaction was designed for the modular synthesis of ring
1
†Electronic supplementary information (ESI) available: H, 13C, HPLC
spectra and cif file of compound 3a. CCDC 724268. For ESI and crys-
tallographic data in CIF or other electronic format see DOI:
10.1039/c2ob26422f
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Scheme 3 Construction of the tetracyclic core of lycorine-type
alkaloids.
Scheme 1 Retrosynthetic analysis.
Scheme 2 Michael addition with difficult substrates.
C. Followed by a reduction/cyclization cascade and Pictet–Spen-
gler cyclization, the desired tetracyclic core structure of 5 would
be efficiently constructed in this consecutive cascades and cycli-
zation process. We anticipated that the key unit of 5 could be
transformed to lycoranes and other related Amaryllidaceae alka-
loids. Although the Michael addition between malonate and
nitroolefins has been well established,7 the challenge of this strat-
egy is obvious: the alkyl substituted malonate 1 with very low
reactivity meets strong electron-donating nitroolefin 2 to con-
struct an all-carbon quaternary carbon center. However, we
reasoned that an appropriate Michael addition reaction of second
step would significantly promote the whole cascade process that
is essential to the success of our strategy (Scheme 2).
Fig. 2 X-ray crystal structure of 3a.
enantiomeric excess was determined by HPLC analysis of pure
product 3 and the diastereoisomer ratio was determined by H
1
NMR analysis of the crude reaction mixture. As shown in Fig. 2,
the stereochemistry was established by X-ray crystallographic
determination of 3a (99% ee) which was efficiently synthesized
by using the similar method with excellent result (95% yield,
99% ee, 13 : 1 dr).† Reduction of 3 with nickel boride followed
by cyclization cascade successfully afforded the product 4 in
70% yield. The tetracyclic structure 5 of lycorine-type alkaloids
was obtained in 95% yield by treatment of 4 with paraformalde-
hyde and trifluoroacetic acid. As a result, the key skeleton 5 was
efficiently synthesized with a total yield of 63% in only three
simple operations involving two consecutive cascade reactions.
The construction of the tetracyclic core
An extensive survey of reaction conditions and organocatalysts
was carried out to establish the optimal reaction condition. To
our delight, we found that this difficult cascade reaction indeed
can work and the desired product 3 could be obtained with
excellent yield (95%) and stereoselectivity (90% ee, 12 : 1 dr)
using 20 mol % QT as the catalyst in toluene (Scheme 3). The
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W. L. F.; Perrin, D. D. Butterworth Heinemann: 1997). Analyti-
cal thin-layer chromatography (TLC) was performed on silica
gel plates with F-254 indicator and compounds were visualized
by irradiation with UV light and/or by treatment with a solution
of phosphomolybdic acid in ethanol followed by heating. Flash
column chromatography was carried out using silica gel
1
(300–400 mesh) at increased pressure. H NMR and 13C NMR
(400 MHz 1H, 100 MHz 13C) spectra were recorded in CDCl3 as
solvents at room temperature. 1H and 13C chemical shifts are
reported in ppm relative to either the residual solvent peak (13C)
or TMS (1H) as an internal standard. Data for 1H NMR are
reported as follows: chemical shift (δ ppm), multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet, dd = doublet),
coupling constant (Hz), and integration. Data for 13C NMR are
reported in terms of chemical shift. IR spectra are reported in
wavenumbers (cm−1). HRMS were measured with mass spec-
trometer (ESI). Enantiomeric excess values were determined by
HPLC analysis. Optical rotation was measured on a polarimeter
with [α]D values reported in degrees with the concentration (c)
in g per 100 mL.
Scheme 4 Application in the formal synthesis of α-lycorane.
Application in the formal synthesis of α-lycorane
(2R,3R,4S)-Diethyl 2-(benzo[d][1,3]dioxol-5-yl)-4-(2-methoxy-
2-oxoethyl)-3-nitrocyclohexane-1,1-dicarboxylate
(3). To
a
mixture of 1 (0.5 mmol, 136.1 mg) and 2 (0.2 mmol, 38.6 mg)
in toluene (0.4 mL) was added catalyst QT (20 mol %,
0.04 mmol, 23.76 mg). The reaction mixture was then stirred at
room temperature for 15 days and a clear solution appeared. The
double Michael addition reaction was complete as judged by
TLC analysis. Then the reaction mixture was concentrated and
the residue was purified by column chromatography (eluent:
petroleum ether–ethyl acetate = 6 : 1) to afford 3 (88.4 mg, 95%
Then we applied this strategy to the formal synthesis of α-lycor-
ane (Scheme 4). Compound 5 was subjected to deethoxycarbo-
nylation, and the product 6 was obtained in 81% yield.
Reduction of 6 to 7 with lithium borohydride followed by oxi-
dation of 7 with Dess–Martin periodinane smoothly produced
the target compound 8. Then decarbonylation in the presence of
Rh(PPh3)3Cl in dry benzonitrile afforded the desired product 9
in 82% yield. The optical purities for the compounds 4–9 are not
determined. Reduction of 9 by LiAlH4 with well established
reaction condition as reported in the literature gave the desired
final product α-lycorane.
1
yield) as a colorless oil. H NMR (400 MHz, CDCl3) δ 6.96 (d,
J = 1.2 Hz, 1H), 6.75 (dd, J = 8.0, 1.2 Hz, 1H), 6.65 (d, J =
8.0 Hz, 1H), 5.90 (d, J = 3.0 Hz, 2H), 5.79 (dd, J = 12.0,
5.2 Hz, 1H), 4.15–4.03 (m, 3H), 3.98–3.88 (m, 1H), 3.67 (s,
3H), 3.65 (d, J = 12.0 Hz, 1H), 3.18–3.10 (m, 1H), 2.65 (dd, J =
16.4, 8.8 Hz, 1H), 2.53 (dd, J = 16.4, 5.2 Hz, 1H), 2.29–2.15
(m, 2H), 1.92–1.84 (m, 2H), 1.14 (t, J = 6.8 Hz, 3H), 1.05 (t,
J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.7, 170.1,
169.7, 147.3, 147.0, 129.5, 123.0, 109.8, 107.7, 101.0, 87.2,
61.6, 61.3, 60.3, 51.9, 46.0, 33.8, 32.1, 28.1, 25.0, 13.8, 13.7;
IR (KBr): 2983, 1727, 1552, 1492, 1445, 1371, 1260, 1037,
934, 864, 815, 756, 638 cm−1; HRMS (ESI+) exact mass calcu-
lated for [M + NH4]+ (C22H31NO10) requires m/z 483.1973,
found m/z 483.1981; [α]D20 = −16 (c 1.0, CHCl3, 90% ee); HPLC
(AD-H), n-hexane–i-PrOH = 90 : 10, 1.0 mL min−1, λ =
206 nm, tmajor = 16.31 min, tminor = 15.02 min, 90% ee.
Conclusions
In conclusion, the tetracyclic core of lycorine-type alkaloids has
been efficiently constructed in only three simple operations
involving a bifunctional thiourea-catalyzed cascade reaction as
the key step. The strategy described here was successfully
applied to the formal synthesis of α-lycorane which demonstrates
the synthetic potential of this method. Thus, this work is a nice
complement to this research field. It is reasonable for us to
suggest that further transformation should permit the efficient
total synthesis of other members of the lycorine-type alkaloids.
Further applications of this method are currently under active
investigation, the results of which will be disclosed in due
course.
(2S,3R,4S)-Dimethyl 4-((ethoxycarbonyl)methyl)-2-(2-bromo-
phenyl)-3-nitro-cyclohexane-1,1-dicarboxylate (3a). The title
compound was prepared according to the similar procedure, as
described above in 95% yield. 1H NMR (400 MHz, CDCl3)
δ 7.83–7.81 (m, 1H), 7.52–7.50 (m, 1H), 7.26–7.21 (m, 1H),
7.08–7.04 (m, 1H), 6.09 (dd, J = 5.2, 11.6 Hz, 1H), 4.32 (d, J =
11.6 Hz, 1H), 4.17–4.11 (m, 2H), 3.65 (s, 3H), 3.54 (s, 3H),
3.18–3.16 (m, 1H), 2.68 (dd, J = 9.6, 16.4 Hz, 1H), 2.52–2.45
(m, 2H), 2.13–2.08 (m, 1H), 1.94–1.90 (m, 1H), 1.84–1.81 (m,
1H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 171.1, 170.0, 169.2, 135.9, 132.7, 129.2, 129.1, 127.8, 127.6,
Experimental section
General information
Chemicals and solvents were either purchased from commercial
suppliers or purified by standard procedures as specified in
Purification of Laboratory Chemicals, 4th Ed. (Armarego,
This journal is © The Royal Society of Chemistry 2012
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87.4, 60.9, 59.3, 53.0, 52.6, 43.7, 33.9, 32.1, 27.9, 24.4, 14.1;
IR (KBr): 2954, 1732, 1551, 1436, 1372, 1266, 1182, 1026,
755, 721 cm−1; [α]D20 = −61 (c 1.0, CHCl3, 99% ee); the enantio-
meric excess was determined by HPLC with an AD-H column
(n-hexane–i-PrOH = 90 : 10, flow rate 1.0 mL min−1, λ =
210 nm), major enantiomer tR = 11.21 min, minor enantiomer
tR = 15.73 min; HRMS (ESI): [M + NH4] calcd for
[C20H24BrNO8 + NH4]+: 503.1024, found: 503.1016.
exact mass calculated for [M + H]+ (C22H26NO7) requires m/z
416.1704, found m/z 416.1712.
(3aS,3a1R,12bS)-Ethyl-5-oxo-2,3,3a,3a1,4,5,7,12b-octahydro-
1H-[1,3]dioxolo[4,5-j]-pyrrolo[3,2,1-de]phenanthridine-1-carboxy-
late (6). To a solution of 5 (0.2 mmol, 83.0 mg) in EtOH–H2O
(8.0 mL, 1 : 1, v/v) was added LiOH (25 mmol, 600 mg). The
reaction mixture was then stirred at 40 °C for 48 h. After cooled,
the solvent was removed and the residue was adjusted to neutral
with 6N HCl. Then the mixture was extracted with ethyl acetate
and the organic layer was dried over anhydrous Na2SO4, filtered,
and concentrated. The residue was dissolved in DMSO–H2O
(7.2 mL, 8 : 1, v/v) and NaCl (10 mmol, 585 mg) was added to
this mixture. The reaction mixture was then heated at 140 °C for
24 h. After cooled, the reaction mixture was extracted with ethyl
acetate (20 mL × 3) and the organic layer was dried over anhy-
drous Na2SO4, filtered, and concentrated. The residue was
purified by flash column chromatography (eluent: petroleum
ether–ethyl acetate = 1 : 1) to afford 6 (55.6 mg, 81%) as a color-
(3aS,7R,7aR)-Diethyl-7-(benzo[d][1,3]dioxol-5-yl)-2-oxohexahy-
dro-1H-indole-6,6-(2H)-dicarboxylate
(4). Compound
3
(0.2 mmol, 93.3 mg) was dissolved in dry methol (5.0 mL) and
cooled to 0 °C. Then NiCl2·6H2O (0.2 mmol, 47.6 mg) was
added to the reaction mixture and the reaction mixture was
stirred for 30 min. Then NaBH4 (2.4 mmol, 90.7 mg) was added
in portions and the reaction mixture was allowed to stir at room
temperature. After 12 h, the reaction mixture was quenched with
saturated NH4Cl and the solvent was evaporated. The residue
was extracted with ethyl acetate and the organic layer was dried
over anhydrous Na2SO4, filtered, and concentrated. The residue
was purified by flash column chromatography (eluent: petroleum
ether–ethyl acetate = 1 : 1 then ethyl acetate) to afford 4
1
less oil. H NMR (400 MHz, CDCl3) δ 6.64 (s, 1H), 6.58 (s,
1H), 5.92 (s, 2H), 4.97 (d, J = 16.8 Hz, 1H), 4.20 (d, J =
17.2 Hz, 1H), 4.14–4.06 (m, 3H), 3.34 (dd, J = 10.0, 5.2 Hz,
1H), 2.75–2.67 (m, 2H), 2.54 (dd, J = 16.8, 8.8 Hz, 1H), 2.25
(dd, J = 16.8, 11.2 Hz, 1H), 2.02–1.92 (m, 2H), 1.73–1.67 (m,
2H), 1.21 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 174.4, 173.5, 146.4, 129.5, 125.6, 106.7, 104.8, 101.0, 60.5,
55.4, 42.9, 42.7, 39.4, 38.9, 35.1, 30.0, 25.1, 23.0, 14.2; IR
(KBr): 2929, 1727, 1684, 1485, 1419, 1247, 1178, 1036, 935,
853, 785 cm−1; [α]D25 = −41 (c 1.0, CHCl3); HRMS (ESI+) exact
mass calculated for [M + H]+ (C19H22NO5) requires m/z
344.1492, found m/z 344.1487.
1
(56.4 mg, 70% yield) as a colorless oil. H NMR (400 MHz,
CDCl3) δ 7.07 (s, 1H), 6.73–6.67 (m, 2H), 5.93 (s, 2H), 5.43 (s,
1H), 4.43 (dd, J = 10.4, 7.2 Hz, 1H), 4.12 (q, J = 6.0 Hz, 2H),
4.02–3.91 (m, 1H), 3.89–3.82 (m, 1H), 2.82 (d, J = 10.4 Hz,
2H), 2.39 (dd, J = 16.8, 11.2 Hz, 1H), 2.28 (dd, J = 16.8,
8.8 Hz, 1H), 2.26–2.22 (m, 2H), 1.79–1.67 (m, 2H), 1.20 (t, J =
6.8 Hz, 3H), 0.95 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 176.8, 170.7, 170.0, 147.6, 147.0, 131.0, 123.8, 110.0,
107.9, 101.0, 61.3, 61.1, 60.0, 55.3, 52.1, 33.7, 33.6, 29.2, 22.7,
13.9, 13.7; IR (KBr): 2979, 1720, 1491, 1445, 1367, 1261,
1185, 1036, 931, 815, 641 cm−1; [α]D25 = +74 (c 1.0, CHCl3);
HRMS (ESI+) exact mass calculated for [M + H]+ (C21H26NO7)
requires m/z 404.1704, found m/z 404.1709.
(3aS,3a1R,12bS)-1-(Hydroxymethyl)-2,3,3a,4,7,12b-hexahydro-
1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridin-5(3a1H)-one
(7). To a solution of 6 (0.1 mmol, 34.3 mg) in dry THF
(2.0 mL) was added LiBH4 (2 mmol, 43.6 mg). The reaction
mixture was then stirred at 50 °C for 48 h. After cooled, the reac-
tion mixture was quenched with saturated NH4Cl at 0 °C and
extracted with ethyl acetate, the organic layer was then dried
over anhydrous Na2SO4, filtered, and concentrated. The residue
was purified by flash column chromatography (eluent: petroleum
ether–ethyl acetate = 1 : 2) to afford 7 (21.1 mg, 70%) as a color-
(3aS,3a1R,12bR)-Diethyl 5-oxo-3,3a,4,5,7,12b-hexahydro-1H-
[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridine-1,1(2H,3a1H)-
dicarboxylate (5). To a solution of 4 (0.2 mmol, 80.6 mg) in
CH2Cl2 (5.0 mL) was added (CH2O)m (1.0 mmol, 30.0 mg) and
CF3COOH (1.2 mmol, 89.1 μL). The reaction mixture was then
stirred at room temperature for 12 h. The mixture was quenched
by saturated NaHCO3 and then diluted with CH2Cl2 (30 mL),
followed by washing with H2O and brine. The organic extract
was dried over anhydrous Na2SO4 and concentrated. The residue
was purified by flash column chromatography (eluent: petroleum
ether–ethyl acetate = 1 : 1) to afford 5 (79.2 mg, 95%) as a color-
1
less oil. H NMR (400 MHz, CDCl3) δ 6.78 (s, 1H), 6.58 (s,
1H), 5.93 (d, J = 4.0 Hz, 2H), 4.94 (d, J = 16.8 Hz, 1H), 4.14
(d, J = 16.8 Hz, 1H), 3.77–3.61 (m, 3H), 3.42 (dd, J = 11.6,
7.6 Hz, 1H), 2.56–2.76 (m, 3H), 2.50 (dd, J = 16.8, 9.2 Hz, 1H),
2.27 (dd, J = 16.8, 11.2 Hz, 1H), 1.96–2.04 (m, 2H), 1.83–1.77
(m, 1H), 1.76–1.72 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 174.3, 146.6, 146.4, 128.9, 126.1, 106.7, 105.5, 101.1, 59.5,
55.8, 42.8, 39.7, 35.1, 34.8, 30.4, 23.4, 21.5; IR (KBr): 3374,
1
less oil. H NMR (400 MHz, CDCl3) δ 6.68 (s, 1H), 6.54 (s,
2924, 1663, 1484, 1449, 1243, 1037, 934, 859 cm−1; [α]D25
=
1H), 5.89 (dd, J = 6.0, 1.2 Hz, 2H), 4.97 (d, J = 16.8 Hz, 1H),
4.39–4.26 (m, 2H), 4.21–4.14 (m, 3H), 3.78 (dd, J = 10.8,
7.6 Hz, 1H), 3.25 (d, J = 10.8 Hz, 1H), 2.76–2.66 (m, 1H), 2.54
(dd, J = 16.8, 8.8 Hz, 1H), 2.37–2.22 (m, 3H), 1.95–1.87 (m,
1H), 1.70–1.63 (m, 1H), 1.32 (t, J = 6.8 Hz, 3H), 1.18 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.0, 172.3,
169.6, 146.2, 145.9, 128.5, 125.7, 107.3, 106.2, 100.9, 62.3,
61.4, 56.4, 56.1, 43.0, 42.5, 35.1, 31.8, 30.5, 23.2, 14.0, 13.9;
IR (KBr): 2979, 1724, 1692, 1448, 1369, 1242, 1210, 1037,
936, 862, 650 cm−1; [α]D25 = +46 (c 1.0, CHCl3); HRMS (ESI+)
−68 (c 1.0, CHCl3); HRMS (ESI+) exact mass calculated for
[M + H]+ (C17H20NO4) requires m/z 302.1387, found m/z
302.1377.
(3aS,3a1R,12bS)-5-Oxo-2,3,3a,3a1,4,5,7,12b-octahydro-1H-[1,3]-
dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridine-1-carbaldehyde (8).
To a solution of 7 (0.1 mmol, 30.2 mg) in CH2Cl2 (3.0 mL) was
added DMP (1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-
(1H)-one) (0.2 mmol, 84.8 mg). The reaction mixture was then
8214 | Org. Biomol. Chem., 2012, 10, 8211–8215
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stirred at room temperature for 2 h. After the reaction was com-
plete as judged by TLC analysis, the mixture was filtered and
concentrated. The residue was purified by flash column chrom-
atography (eluent: petroleum ether–ethyl acetate = 1 : 2) to afford
8 (27.2 mg, 91%) as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 9.81 (s, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 5.93 (d, J =
0.8 Hz, 2H), 4.98 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 17.2 Hz,
1H), 3.76 (dd, J = 11.2, 7.6 Hz, 1H), 3.39–3.37 (m, 1H), 2.85
(dd, J = 11.2, 4.8 Hz, 1H), 2.73–2.64 (m, 1H), 2.55 (dd, J =
16.8, 9.2 Hz, 1H), 2.25 (dd, J = 16.8, 10.8 Hz, 1H), 2.19–2.11
(m, 1H), 1.95–1.84 (m, 2H), 1.79–1.70 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 202.3, 174.2, 146.7, 146.6, 128.0, 125.7,
106.8, 105.2, 101.1, 55.9, 45.3, 42.9, 38.5, 35.0, 30.1, 23.0,
21.5; IR (KBr): 2927, 1682, 1485, 1422, 1371, 1244, 1036, 932,
860 cm−1; [α]2D5 = −60 (c 1.0, CHCl3); HRMS (ESI+) exact
mass calculated for [M + H]+ (C17H18NO4) requires m/z
300.1230, found m/z 300.1225.
Notes and references
1 For selected reviews, see: (a) A. M. Walji and D. W. C. MacMillan,
Synlett, 2007, 1477; (b) D. Enders, C. Grondal and M. R. M. Hüttl,
Angew. Chem., Int. Ed., 2007, 46, 1570; (c) A. Dondoni and A. Massi,
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Nature, 2008, 455, 304; (e) M. Nielsen, D. Worgull, T. Zweifel,
B. Gschwend, S. Bertelsen and K. A. Jørgensen, Chem. Commun.,
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2 For selected reviews, see: (a) C. Grondal, M. Jeanty and D. Enders, Nat.
Chem., 2010, 2, 167; (b) E. Marqués-López, R. P. Herrerabc and
M. Christmann, Nat. Prod. Rep., 2010, 27, 1138.
3 (a) Y. Wang, R.-G. Han, Y.-L. Zhao, S. Yang, P.-F. Xu and D. J. Dixon,
Angew. Chem., Int. Ed., 2009, 48, 9834; (b) Y. Wang, D.-F. Yu, Y.-Z. Liu,
H. Wei, Y.-C. Luo, D. J. Dixon and P.-F. Xu, Chem.–Eur. J., 2010, 16,
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(d) J.-B. Ling, Y. Su, H.-L. Zhu, G.-Y. Wang and P.-F. Xu, Org. Lett.,
2012, 14, 1090.
4 For reviews on Amaryllidaceae alkaloids, see: (a) S. F. Martin, in The
Alkaloids, ed. A. Brossi, Academic Press, New York, 1987, vol. 30,
pp. 251–376; (b) O. Hoshino, in The Alkaloids, ed. G. A. Cordell, Aca-
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5 (a) M. Tanker, G. Citoglu, B. Gumusel and B. Sener, Int. J. Pharmacogn.,
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K. Sato and S. Kobayashi, Chem. Pharm. Bull., 1983, 31, 2146;
(g) R. P. Singh and N. C. Pant, Experientia, 1980, 36, 552.
6 For selected examples on the total syntheses of optically active lycoranes,
see: (a) H. Yoshizaki, H. Satoh, Y. Sato, S. Nukui, M. Shibasaki and
M. Mori, J. Org. Chem., 1995, 60, 2016; (b) J. Cossy, L. Tresnard and
D. G. Pard, Eur. J. Org. Chem., 1999, 1925; (c) M. G. Banwell,
J. E. Harvey and D. C. Hockless, J. Org. Chem., 2000, 65, 4241;
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Org. Lett., 2006, 8, 1395; (f) H. Fujioka, K. Murai, Y. Ohba, H. Hirose
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(3aS,3a1R,12bS)-2,3,3a,4,7,12b-Hexahydro-1H-[1,3]dioxolo-
[4,5-j]pyrrolo[3,2,1-de]phenanthridin-5(3a1H)-one (9). To a solu-
tion of 8 (0.1 mmol, 29.9 mg) in dry benzonitrile (2.0 mL) was
added Rh(PPh3)3Cl (0.15 mmol, 138.8 mg) under argon atmos-
phere. The reaction mixture was then heated to reflux for 24 h.
The solvent was evaporated under reduced pressure, and the
reside was purified by a flash silica gel column (eluent: pet-
roleum ether–ethyl acetate = 1 : 1) to afford 9 (22.2 mg, 82%) as
1
a white solid. H NMR (400 MHz, CDCl3) δ 6.70 (s, 1H), 6.60
(s, 1H), 5.93 (d, J = 2.4 Hz, 2H), 4.98 (d, J = 17.2 Hz, 1H), 4.20
(d, J = 17.2 Hz, 1H), 3.22 (dd, J = 10.4, 7.6 Hz, 1H), 2.66–2.61
(m, 1H), 2.51 (dd, J = 16.8, 8.8 Hz, 1H), 2.42 (dt, J = 11.4,
3.4 Hz, 1H), 2.29–2.21 (m, 2H), 1.81–1.75 (m, 3H), 1.61–1.60
(m, 1H); 1.26–1.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
175.2, 146.4, 146.2, 132.1, 125.4, 106.6, 104.9, 101.0, 59.7,
43.3, 38.1, 35.1, 30.7, 25.6, 24.2, 21.0; IR (KBr): 3386, 3192,
1647, 1576, 1404, 1243, 1119, 1035, 931, 852, 772, 696,
634 cm−1; [α]2D5 = −20 (c 1.0, CHCl3); HRMS (ESI+) exact
mass calculated for [M + H]+ (C16H18NO3) requires m/z
272.1281, found m/z 272.1284.
the total syntheses of racemic lycoranes, see:
(g) A. Padwa,
M. A. Brodney and S. M. Lynch, J. Org. Chem., 2001, 66, 1716;
(h) O. Tamura, H. Matsukida, A. Toyao, Y. Takeda and H. Ishibashi,
J. Org. Chem., 2002, 67, 5537; (i) L. D. Miranda and S. Z. Zard, Org.
Lett., 2002, 4, 1135; ( j) T. Yasuhara, K. Nishimura, M. Yamashita,
N. Fukuyama, K.-i. Yamada, O. Muraoka and K. Tomioka, Org. Lett.,
2003, 5, 1123; (k) S. Gao, Y. Q. Tu, Z. Song, A. Wang, X. Fan and
Y. Jiang, J. Org. Chem., 2005, 70, 6523; (l) R. J. Huntley and R. L. Funk,
Tetrahedron Lett., 2011, 52, 6671. See also ref. 4.
7 For selected examples of organocatalytic enantioselective addition of
malonates on nitroolefins, see: (a) H. Li, Y. Wang, L. Tang and L. Deng,
J. Am. Chem. Soc., 2004, 126, 9906; (b) J. Ye, D. J. Dixon and
P. S. Hynes, Chem. Commun., 2005, 4481; (c) T. Okino, Y. Hoashi,
T. Furukawa, X. Xu and Y. Takemoto, J. Am. Chem. Soc., 2005, 127, 119;
(d) J. M. Andrés, R. Manzano and R. Pedrosa, Chem.–Eur. J., 2008, 14,
5116.
Acknowledgements
We thank Syngenta Ltd. for financial support. We are grateful for
the NSFC (21032005, 20972058, 21172097), the National Basic
Research Program of China (No. 2010CB833203) and the “111”
program from MOE of P. R. China.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8211–8215 | 8215