Catalytic asymmetric assembly of octahydroindolones: Divergent synthesis of lycorine-type amaryllidaceae alkaloids (+)-α-lycorane and (+)-lycorine

Article abstract of DOI:10.1002/chem.201400178

We report the first catalytic asymmetric approach to octahydroindolones and a divergent enantioselective synthesis of perhydroindole alkaloids, as exemplified by lycorine-type Amaryllidaceae alkaloids (+)-α-lycorane and (+)-lycorine, from a common intermediate by using a highly concise route. The assembly of octahydroindolones employs a catalytic enantioselective 1,4-conjugate addition of nitro dienynes, followed by a TsOH-catalyzed cascade synthesis of highly functionalized enones, and a diastereoselective intramolecular Michael addition. Octahydroindolone motifs are constructed diastereo- and enantioselectively through a catalytic enantioselective 1,4-conjugate addition of nitro dienynes, followed by a TsOH-catalyzed cascade reaction. This methodology has been applied in the divergent enantioselective synthesis of perhydroindole alkaloids, as exemplified by lycorine-type Amaryllidaceae alkaloids (+)-α-lycorane and (+)-lycorine (see scheme; Ts=p-toluenesulfonyl), from a common intermediate by using a highly concise synthetic route.

Full text of DOI:10.1002/chem.201400178

DOI: 10.1002/chem.201400178
Full Paper
&
Alkaloid Synthesis
Catalytic Asymmetric Assembly of Octahydroindolones:
Divergent Synthesis of Lycorine-type Amaryllidaceae Alkaloids
(+)-a-Lycorane and (+)-Lycorine
Zhongwen Sun, Mingtao Zhou, Xiang Li, Xueling Meng, Fangzhi Peng,* Hongbin Zhang,
and Zhihui Shao*[a]
Abstract: We report the first catalytic asymmetric approach
to octahydroindolones and a divergent enantioselective syn-
thesis of perhydroindole alkaloids, as exemplified by lycor-
ine-type Amaryllidaceae alkaloids (+)-a-lycorane and (+)-ly-
corine, from a common intermediate by using a highly con-
cise route. The assembly of octahydroindolones employs
a catalytic enantioselective 1,4-conjugate addition of nitro
dienynes, followed by a TsOH-catalyzed cascade synthesis of
highly functionalized enones, and a diastereoselective intra-
molecular Michael addition.
Introduction
Facile access to versatile building blocks or structural motifs,
and divergent syntheses of structurally and stereochemically
complex natural products, are among the most highly sought
after tasks in synthetic chemistry. As part of ongoing studies
on polycyclic alkaloid syntheses,[1] we noted a lack of methods
for the assembly of octahydroindolones I, motifs common in
natural-product chemistry[2] (Figure 1a). Motivated by the
notion that facile stereocontrolled access to octahydroindo-
lones I should provide a distinct strategic point from which to
direct efforts towards divergent syntheses of perhydroindole
alkaloids, a structurally diverse group of natural products in-
cluding some of the Stemonaceae and Amaryllidaceae alkaloids,
we commenced studies on this topic. We envisioned that octa-
hydroindolones I could be produced from rationally designed
functionalized nitrocyclohexanes II, featuring a strategically
positioned carbonyl group and an ester functionality (Fig-
ure 1b). Nitrocyclohexanes are valuable building blocks for the
synthesis of natural products and biologically active com-
pounds. Therefore, numerous methods have been developed
for the synthesis of functionalized nitrocyclohexanes.[3]
However, these reported protocols are not applicable to the
synthesis of II. To address the synthetic challenges posed by I
and II, an enabling approach was devised. We envisioned that
Figure 1. a) Octahydroindolones I and representative natural products. b)
Working hypothesis for the construction of I.
II could be constructed through a diastereoselective intramo-
lecular Michael addition from functionalized enones III, bearing
a nitro group and an ester functionality (Figure 1b).
[a] Z. Sun,+ M. Zhou,+ X. Li,+ X. Meng, F. Peng, Prof. H. Zhang, Prof. Z. Shao
Key Laboratory of Medicinal Chemistry for Natural Resource
Ministry of Education, School of Chemical Science and Technology
Yunnan University, Kunming, Yunnan 650091 (P.R. China)
Fax: (+86)871-65035538
E-mail: pengfangzhi@ynu.edu.cn
zhihui_shao@hotmail.com
[+] These authors contributed equally to this work.
Despite the potential attractions of this method, an ap-
proach towards highly functionalized enones III has not yet
been reported. Inspired by the lack of methods towards these
highly functionalized enones, we very recently introduced con-
jugated nitro dienynes as a new class of Michael acceptors and
developed a catalytic cascade reaction of 1,3-enynes, leading
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400178.
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daceae species of plants,[5] and have been high-profile targets
for chemical synthesis[6] and medicinal chemistry studies[7]
owing to their intriguing molecular architectures and wide
range of biological activities.[8] Structurally, the lycorine-type
Amaryllidaceae alkaloids are characterized by a tetracyclic
pyrrolo[d,e]phenanthridine (galanthan) framework. Stereo-
chemically, most lycorine-type alkaloids have a trans B/C-ring
junction. Our strategy is outlined in Scheme 2. The synthesis
was designed with the intention of applying the methodology
recently developed in our laboratory[4] to diastereo- and enan-
tioselectively construct the octahydroindolone structural motif
and developing a general route to lycorine-type Amaryllidaceae
alkaloids. Chemically, the diverse substituents at C1 and C2 in
the target alkaloids could be derived by manipulation of the
“masked” carbonyl group in the common intermediate 1,
which could be accessed from the masked octahydroindolone
2. Strategically, the logical disconnection of the C5ÀN bond of
2 would deliver key cyclohexanone intermediate 3, which
could be generated by a diastereoselective intramolecular Mi-
chael addition of enone 4. A TsOH-catalyzed cascade of 5 and
the 1,4-regioselective catalytic asymmetric conjugate addition[9]
of conjugated nitro dienyne 6 with di-tert-butyl malonate
could be considered for the formation of chiral enone 4.
Although we anticipated that the proposed intramolecular
Michael addition of enones (Scheme 2) could occur in the pres-
ence of a suitable base, the crucial relative stereochemical out-
come remained to be explored. Thus, we initially decided to in-
vestigate the stereochemistry by using a model reaction. The
results are summarized in Table 1.
Scheme 1. Recently developed catalytic cascade synthesis of highly function-
alized enones.
to the required enantioenriched functionalized enones in good
yields with high enantioselectivity (Scheme 1).[4]
Herein, we report the first catalytic asymmetric approach to
octahydroindolones and the divergent enantioselective synthe-
sis of perhydroindole alkaloids, as exemplified by lycorine-type
Amaryllidaceae alkaloids (+)-a-lycorane and (+)-lycorine from
a common intermediate.
Results and Discussion
The lycorine-type Amaryllidaceae alkaloids (Scheme 2) were se-
lected as targets for probing the synthetic design outlined in
Figure 1. Lycorine-type alkaloids are isolated from the Amarylli-
In the presence of TMG (1,1,3,3-tetramethylguanidine),
enone 7 underwent a diastereoselective intramolecular Michael
addition to give cyclohexanone 8 as the major diastereoisomer
(entry 1). The relative configuration of 8 was assigned on the
Table 1. Study of the model reaction.[a]
Entry
Base
Solvent
Yield [%][b]
d.r.[c]
1
2
3
TMG
DBU
KOH
CH2Cl2
CH2Cl2
EtOH
65
56
44
7:1
5:1
4:1
[a] The reaction was performed in the presence of base (1.0 equiv) at
room temperature. [b] Isolated yield. [c] Determined by 1H NMR analysis.
Scheme 2. Structural motif-guided retrosynthetic analysis of the lycorine-
type alkaloids.
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Figure 2. Transition-state analysis of intramolecular Michael addition of 7.
basis of X-ray crystal structural analysis.[10] The stereoselective
formation of 8 might be rationalized by considering a chair-
like transition state TS-I, shown in Figure 2.
After solving the stereochemical issue, we focused our atten-
tion on the stereocontrolled synthesis of octahydroindolones
and lycorine-type Amaryllidaceae alkaloids. Two representative
lycorine-type alkaloids, a-lycorane[11,12,3f,g] and (+)-lycorine,[13,14]
were selected as synthetic targets.
Scheme 4. Catalytic asymmetric synthesis of functionalized cyclohexanone 3.
clohexanone 3[15] as a single diastereoisomer in 60% yield after
column chromatography.
Our efforts began with the synthesis of conjugated nitro di-
enyne 6 (Scheme 3). Vinyl bromide 9 underwent Sonogashira
With a catalytic asymmetric approach to the desired cyclo-
hexanones in hand, the synthesis of octahydroindolones was
initiated (Scheme 5). Treatment of 3 with ethane-1,2-dithiol in
Scheme 3. Synthesis of conjugated nitro dienyne 6.
coupling with propargylic alcohol, leading to the correspond-
ing alcohol, 10. Oxidation of the hydroxyl group of 10 with IBX
(2-iodoxybenzoic acid) afforded enynal 11. Compound 11 un-
derwent a Henry reaction with CH3NO2, followed by treatment
with TFAA (trifluoroacetic anhydride) in the presence of Et3N,
to produce the desired conjugated nitro dienyne 6 with com-
plete stereoselectivity.
Scheme 5. Stereocontrolled construction of the “masked” octahydroindo-
lones.
The catalytic enantioselective synthesis of functionalized cy-
clohexanone 3 is outlined in Scheme 4. In the presence of
chiral diamine–NiBr2 complex, the 1,4-conjugate addition of
nitro dienyne 6 with di-tert-butyl malonate proceeded smooth-
ly to provide enantioenriched 1,3-enyne 5 in 91% yield with
93% enantiomeric excess (ee). It is worth noting that 1,6- or
1,8-addition was not observed. Then, treatment of 1,3-enyne 5
with a catalytic amount of TsOH (20 mol%) directly led to com-
pound 12 with complete regioselectivity. Compound 12 was
then esterified to provide the desired enone 4 in good yield
without loss of enantiomeric purity. Compound 4 underwent
a stereoselective intramolecular Michael addition with a diaste-
reomeric ratio (d.r.) of 6:1, providing the enantioenriched cy-
the presence of BF3·OEt2 afforded thioketal 13. Reduction of
the nitro group of 13 with zinc powder in 10% aq HCl/ethanol,
followed by treatment with sodium methoxide, gave bicyclic
lactam 14. Finally, reduction of 14 with LiAlH4 resulted in the
formation of the masked octahydroindolone 2, which was fur-
ther converted into the corresponding carbamate 15.
With the key octahydroindolone in hand, the divergent syn-
thesis of a-lycorane and lycorine was undertaken. The enantio-
selective synthesis of (+)-a-lycorane is shown in Scheme 6.
Compound 15 was subjected to a Bischler–Napieralski reaction
and afforded the desired compound 1. Then, 1 was converted
into 16, which was reduced with LiAlH4 to afford (+)-a-lycor-
ane. All of the spectroscopic data for synthetic (+)-a-lycorane
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the total synthesis or formal synthesis of racemic lycorine,[13]
only two asymmetric syntheses have been reported to date.[14]
These syntheses employed a stoichiometric amount of chiral
controls. Thus, our synthesis represents the first catalytic enan-
tioselective approach to lycorine.
Conclusion
We have developed the first catalytic asymmetric approach to
octahydroindolones, structural motifs common in natural-prod-
uct chemistry. The method holds great potential for enantiose-
lective syntheses of perhydroindole alkaloids. In this context,
we used this protocol to develop a general route to lycorine-
type Amaryllidaceae alkaloids, exemplified by (+)-a-lycorane
(1.9% overall yield from 9) and (+)-lycorine (1.1% overall yield
from 9), from a common intermediate on the basis of a highly
concise route. The synthesis of octahydroindolones features
the catalytic enantioselective 1,4-conjugate addition of nitro di-
enynes and the TsOH-catalyzed cascade synthesis of highly
functionalized enones that we have recently developed.[4] Fur-
ther application of this methodology to the enantioselective
syntheses of other perhydroindole alkaloids are currently
under way in our research group.
Scheme 6. Enantioselective total synthesis of (+)-a-lycorane.
were in accordance with the data reported previously.[11j] There
are three elegant asymmetric total syntheses or formal synthe-
ses of (À)-a-lycorane to date,[12,3f,g] however, their applications
to the synthesis of the more complex alkaloid, lycorine, re-
mained unknown. In contrast, the strategically positioned car-
bonyl group featured in 3 provided a good handle to install
the hydroxyl groups at the C1 and C2 positions and introduce
the olefin functionality in lycorine.
The enantioselective synthesis of (+)-lycorine is shown in
Scheme 7. Treatment of common intermediate 1 with HgCl2
Experimental Section
General methods
1H NMR and 13C NMR spectra were recorded at 300 MHz and
400 MHz. Chemical shifts (d) are expressed in ppm, and J values
are given in Hz. The enantiomeric excess was determined by chiral
HPLC with n-hexane and isopropanol as eluents. High resolution
mass spectrometry (HRMS) was recorded on a VG Auto Spec-3000
spectrometer. Optical rotations were measured on a JASCO DIP-
370 polarimeter. All chemicals and solvents were used as received
without further purification unless otherwise stated. Flash column
chromatography was performed on silica gel (230–400 mesh).
Ethyl 2-(2-nitro-5-oxo-3-phenylcyclohexyl)acetate (8)
TMG (86 mg, 0.75 mmol) was added to a solution of compound 7
(229 mg, 0.75 mmol) in dry dichloromethane (10 mL). The reaction
mixture was stirred at room temperature until the reaction was
complete (monitored by TLC). The mixture was quenched with 1 n
HCl and extracted with AcOEt. The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure, and the
crude product was purified by silica gel chromatography (ethyl
acetate/petroleum ether=1:3) to afford
8 (149 mg, 65%) as
1
a white solid. H NMR (300 MHz, CDCl3): d=7.30 (m, 3H), 7.22 (m,
2H), 5.20 (t, J=5.1 Hz, 1H), 4.09 (q, J=6.9 Hz, 2H), 3.93 (q, J=
6.6 Hz, 1H), 3.03 (m, 1H), 2.89 (m, 1H), 2.80–2.51 (m, 4H), 2.33 (m,
1H), 1.20 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
206.41, 170.33, 139.01, 129.33, 128.13, 127.18, 89.34, 61.13, 43.14,
42.82, 42.15, 34.97, 32.93, 14.06 ppm; HRMS: m/z calcd for
C16H19NO5: 305.1263 [M]+; found: 305.1263 [M]+.
Scheme 7. Enantioselective formal synthesis of (+)-lycorine.
gave ketone 17. Selective reduction of 17 with NaBH4/CeCl3 af-
forded alcohol 18 in high yield with 3:1 d.r. Subsequently, 18
was mesylated, followed by treatment with DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene) to produce compound 20 with
complete regioselectivity, and intercepting an advanced inter-
mediate in the racemic synthesis of lycorine by Torssell and co-
workers,[13b] thus completing the formal synthesis of (+)-lycor-
ine. Although many elegant methods have been developed for
1-Methoxy-4-((1E,5E)-6-nitrohexa-1,5-dien-3-ynyl)benzene
(10)
[Pd(PPh3)4] (46 mg, 0.04 mmol, 0.004 equiv), CuI (25 mg, 0.13 mmol,
0.013 equiv), and propargylic alcohol (560 mg, 10 mmol) were
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added to a solution of vinyl bromide 9 (2.26 g, 10 mmol) in dry di-
ethylamine (25 mL) and the resulting mixture was stirred for 36 h
at room temperature. The solvent was removed under reduced
pressure, and the crude product was purified by flash silica gel
chromatography (ethyl acetate/petroleum ether=1:3) to give 10
crude was purified by flash silica gel chromatography (ethyl ace-
tate/petroleum ether=1:6) to give 5 (84 mg, 91%) as a yellow
1
solid. [a]2D0 = +47.8 (c=1.0 in CHCl3); H NMR (300 MHz, CDCl3): d=
6.81 (m, 1H), 6.73 (m, 3H), 5.98 (s, 2H), 5.85 (dd, J=16.2 Hz, J=
1.8 Hz, 1H), 4.80–4.65 (m, 2H), 4.01–3.98 (m, 1H), 3.52 (d, J=
7.8 Hz, 1H), 1.49 ppm (s, 18H); 13C NMR (75 MHz, CDCl3): d=166.1,
165.8, 148.3, 148.2, 142.0, 130.5, 121.7, 108.4, 105.2, 105.1, 101.3,
85.4, 84.6, 83.0, 82.9, 76.5, 55.0, 30.9, 27.9, 27.8 ppm; HRMS: m/z
calcd for C24H29NO8: 459.1893 [M]+; found: 459.1896 [M]+; HPLC
(Chiralpak AD-H, isopropanol/n-hexane=15:85, flow rate
0.8 mLminÀ1, l=254 nm): tmajor =28.726 min, tminor =35.973 min.
1
(1.62 g, 80%) as a light-yellow solid. H NMR (300 MHz, CDCl3): d=
6.72 (m, 4H), 5.95 (m, 3H), 4.43 (m, 2H), 2.33 ppm (m, 1H);
13C NMR (75 MHz, CDCl3): d=148.2, 148.1, 141.5, 130.6, 121.8,
108.4, 105.5, 105.2, 101.3, 89.1, 85.0, 51.6 ppm; HRMS: m/z calcd
for C12H10O3: 202.0623 [M]+; found: 202.0630 [M]+.
(E)-5-(Benzo[d][1,3]dioxol-5-yl)pent-4-en-2-ynal (11)
(R,E)-7-(Benzo[d][1,3]dioxol-5-yl)-3-(nitromethyl)-5-oxohept-
6-enoic acid (12)
IBX (1.68 g, 6 mmol, 1.2 equiv) was added to a solution of 10
(1.01 g, 5 mmol) in THF/DMSO (14 mL, VTHF/VDMSO =6:1) and the re-
sulting mixture was stirred for 8 h at room temperature. The or-
ganic layer was washed with saturated aqueous Na2S2O3 solution
and brine. The organic phase was dried over anhydrous Na2SO4, fil-
tered and concentrated under reduced pressure, and the crude
was purified by flash silica gel chromatography (ethyl acetate/pe-
troleum ether=1:6) to give 11 ( 0.79 g, 79%) as a yellow solid.
1H NMR (300 MHz, CDCl3): d=9.33 (s, 1H), 7.18 (d, J=16.2 Hz, 1H),
6.91 (m, 2H), 6.79 (d, J=14.1 Hz, 1H), 6.06 (dd, J=16.2 Hz, J=
1.2 Hz, 1H), 6.01 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): d=176.6,
149.8, 148.9, 148.5, 129.5, 123.7, 108.6, 105.5, 102.5, 101.7, 95.9,
90.6 ppm; HRMS: m/z calcd for C12H8O3 200.0475 [M]+; found:
200.0473 [M]+.
TsOH (38 mg, 0.2 equiv) was added to a solution of compound 5
(459 mg, 1 mmol) in toluene (20 mL). The reaction mixture was
stirred for 6 h under reflux. After removal of solvent, the crude
product was purified by silica gel chromatography (ethyl acetate/
petroleum ether=1:1) to afford compound 12 (263 mg, 82%) as
1
a yellow liquid. [a]2D0 = +10.8 (c=1.0 in CHCl3); H NMR (300 MHz,
CDCl3), d=7.40 (d, J=15.9 Hz, 1H), 6.95 (m, 2H), 6.73 (m, 1H), 6.46
(d, J=15.9 Hz, 1H), 5.94 (s, 2H), 4.55 (d, J=6.0 Hz, 2H), 3.07 (m,
1H), 2.81 (d, J=6.0 Hz, 2H), 2.56 ppm (d, J=6.3 Hz, 2H); 13C NMR
(75 MHz, CDCl3), d=197.2, 176.4, 150.3, 148.5, 143.8, 128.4, 125.4,
123.6, 108.7, 106.6, 101.7, 77.6, 41.1, 35.1, 29.7 ppm; HRMS: m/z
calcd for C15H15NO7: 321.0849 [M]+; found: 321.0857 [M]+.
5-((1E,5E)-6-Nitrohexa-1,5-dien-3-ynyl)benzo[d][1,3]dioxole
(R,E)-Ethyl 7-(benzo[d][1,3]dioxol-5-yl)-3-(nitromethyl)-5-oxo-
(6)
hept-6-enoate (4)
A slurry of LiAlH4 (3.8 mg, 0.1 mmol, 0.1 equiv) in dry THF (4 mL)
was stirred for 30 min at 08C, and then nitromethane (305 mg,
5 mmol, 5 equiv) was added. After 30 min, 11 (200 mg, 1 mmol)
was added in one portion. The mixture was stirred until the reac-
tion was complete (monitored by TLC). Then 1 n HCl was added
and the reaction mixture was extracted with dichloromethane. The
organic layer was dried over Na2SO4 and concentrated under re-
duced pressure to give the nitro alcohol product, which was used
without purification for the next step. Trifluoroacetic anhydride
(198 mg, 0.945 mmol, 1.05 equiv) and triethylamine (190 mg,
1.89 mmol, 2.1 equiv) were added to a solution of the nitro alcohol
(0.9 mmol, 1 equiv) in dry dichloromethane (3 mL) at 08C. The reac-
tion mixture was stirred at 08C until the reaction was complete
(monitored by TLC). Then, the organic layer was washed with satu-
rated aqueous NH4Cl solution and brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure, and the crude was purified by flash silica gel chromatography
(ethyl acetate/petroleum ether=1:10) to give 6 (122 mg, 50%) as
Thionylchloride (95 mg, 0.8 mmol) was added to a solution of com-
pound 12 (257 mg, 0.8 mmol) in absolute ethanol (10 mL). The re-
action mixture was stirred for 3 h under reflux. The solvent was re-
moved under reduced pressure, and the mixture was diluted with
AcOEt. The organic layer was washed with saturated aqueous
NaHCO3 solution and brine. The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure, and the
crude product was purified by silica gel chromatography (ethyl
acetate/petroleum ether=1:4) to afford compound 4 (229 mg,
82%) as a yellow liquid. [a]2D0 = +20.7 (c=1.0 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.48 (d, J=15.9 Hz, 1H), 7.05 (d, J=6.3 Hz,
2H), 6.83 (d, J=8.4 Hz, 1H), 6.54 (d, J=16.2 Hz, 1H), 6.04 (s, 2H),
4.60 (d, J=6.0 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.16 (m, 1H), 2.89
(d, J=6.3 Hz, 2H), 2.57 (d, J=6.3 Hz, 2H), 1.26 ppm (t, J=7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=196.9, 171.2, 150.2, 148.5, 143.4,
128.6, 125.2, 123.8, 108.6, 106.6, 101.7, 77.8, 60.9, 41.2, 35.4, 30.1,
14.1 ppm; HRMS: m/z calcd for C17H19NO7: 349.1162 [M]+; found:
349.1163 [M]+; HPLC (Chiralpak AD-H, isopropanol/hexane=25:75,
1
flow rate 1.0 mLminÀ1
27.483 min.
, l=254 nm): tminor =25.471 min. tmajor =
a yellow solid. H NMR (300 MHz, CDCl3): d=7.25 (m, 2H), 7.04 (d,
J=16.2 Hz, 1H), 6.92 (m, 1H), 6.89 (m, 1H), 6.79 (d, J=8.1 Hz, 1H),
6.13 (dd, J=16.2 Hz, J=2.1 Hz, 1H), 6.01 ppm (s, 2H); 13C NMR
(75 MHz, CDCl3): d=149.4, 148.5, 145.9, 144.8, 129.9, 123.2, 121.3,
108.6, 105.8, 105.4, 104.3, 101.6, 84.2 ppm; HRMS: m/z calcd for
C13H9NO4: 243.0532 [M]+; found: 243.0523 [M]+.
Ethyl 2-((1R,2S,3R)-3-(benzo[d][1,3]dioxol-5-yl)-2-nitro-5-oxo-
cyclohexyl)acetate (3)
1,1,3,3-Tetramethylguanidine (86 mg, 0.75 mmol) was added to
a solution of compound 4 (262 mg, 0.75 mmol) in dry dichlorome-
thane (10 mL). The reaction mixture was stirred at room tempera-
ture until the reaction was complete (monitored by TLC). The mix-
ture was quenched with 1 n HCl and extracted with AcOEt. The or-
ganic layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure, and the crude product was purified by silica gel
chromatography (ethyl acetate/petroleum ether=1:3) to afford 3
(147 mg, 60%) as a yellow solid. [a]2D0 = +25.8 (c=1.0 in CHCl3);
(S,E)-Di-tert-butyl 2-(6-(benzo[d][1,3]dioxol-5-yl)-1-nitrohex-
5-en-3-yn-2-yl)malonate (5)
Di-tert-butyl malonate (65 mg, 0.3 mmol, 1.5 equiv) and nitro dien-
yne 6 (0.2 mmol) were added to a solution of catalyst NiBr2/2l
(5 mol%) in m-xylene (0.5 mL). The reaction mixture was stirred at
room temperature until the reaction was complete (monitored by
TLC). The solvent was removed under reduced pressure and the
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1H NMR (300 MHz, CDCl3): d=6.67 (m, 1H), 6.59 (m, 2H), 5.89 (s,
2H), 5.06 (m, 1H), 4.02 (q, J=7.2 Hz, 2H), 3.73 (m, 1H), 2.93 (m,
1H), 2.76 (m, 1H), 2.66–2.49 (m, 3H), 2.28 (m, 1H), 2.24 (m, 1H),
1.14 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=206.3,
170.4, 148.4, 147.4, 132.7, 120.6, 108.8, 107.5, 101.4, 89.6, 61.1, 43.2,
42.9, 42.1, 34.9, 32.9, 14.1 ppm; HRMS: m/z calcd for C17H19NO7:
349.1162 [M]+; found: 349.1169 [M]+; HPLC (Chiralcel OD-H, isopro-
tion mixture was extracted with CH2Cl2. The organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure, and the crude product 2 was used for
next step without further purification. Methyl chloroformate
(51 mg, 0.468 mmol) was added to a solution of crude product 2
and triethylamine (59 mg, 0.585 mmol) in CH2Cl2 (5 mL) at 08C, and
the resulting solution was stirred at room temperature for 6 h. The
mixture was diluted with CH2Cl2. The organic layer was washed
with saturated aqueous NaHCO3 solution and brine. The organic
layer was dried over Na2SO4, filtered, and concentrated under re-
duced pressure, and the residue was purified by flash silica gel
chromatography (ethyl acetate/petroleum ether=1:3) to give 15
(84 mg, 53% (over two steps)) as a white powder. [a]2D0 = +16.5
panol/n-hexane=25:75, flow rate 0.8 mLminÀ1, l=220 nm): tmajor
30.586 min, tminor =34.880 min.
=
Ethyl 2-((7S,8S,9R)-9-(benzo[d][1,3]dioxol-5-yl)-8-nitro-1,4-
dithiaspiro[4.5]decan-7-yl)acetate (13)
1
Boron trifluoride etherate (170 mg, 0.12 mmol) was added to a solu-
tion of compound 3 (380 mg, 1.09 mmol) and 1,2-dithioethane
(102 mg, 1.09 mmol) in dry dichloromethane (6 mL). The resulting
solution was stirred at room temperature for 30 min. The mixture
was diluted with ether and saturated aqueous NaHCO3 solution,
and then the organic layer was washed with brine and dried over
Na2SO4, filtered, and concentrated under reduced pressure. The res-
idue was purified by flash silica gel chromatography (ethyl acetate/
petroleum ether=1:4) to give 13 (356 mg, 77%) as a white
powder. [a]2D0 = +2.6 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=6.68 (m, 3H), 5.94 (s, 2H), 4.90 (dd, J=17.4 Hz, J=5.1 Hz, 1H),
4.12 (m, 2H), 3.40 (m, 1H), 3.25 (m, 5H), 2.90 (m, 1H), 2.66 (m, 1H),
2.38 (m, 3H), 2.17 (m, 1H), 1.25 ppm (t, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=171.2, 148.0, 147.0, 133.1, 120.4, 108.6, 107.7,
101.1, 90.8, 64.2, 60.9, 50.1, 42.9, 41.8, 40.5, 37.8, 34.9, 33.6,
14.2 ppm; HRMS: m/z calcd for C19H23NO6S2: 425.0967 [M]+; found:
425.0953 [M]+.
(c=1.0 in CHCl3); H NMR (400 MHz, CDCl3): d=6.62 (m, 2H), 6.51
(m, 1H), 5.82 (s, 2H), 3.64 (m, 2H), 3.20 (m, 4H), 3.11 (m, 4H), 2.66
(m, 1H), 2.43 (m, 1H), 2.20 (m, 3H), 2.14 (m, 2H), 0.76 ppm (t, J=
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=155.5, 147.4, 146.0,
136.6, 121.5, 108.2, 107.9, 100.7, 65.7, 62.1, 60.6, 48.1, 44.9, 44.4,
40.7, 40.3, 39.7, 36.9, 26.7, 14.1 ppm; HRMS: m/z calcd for
C20H25NO4S2: 407.1225 [M]+; found: 407.1234 [M]+.
(3aS,3a1S,12bR)-1,3,3a,4,5,12b-Hexahydrospiro[[1,3]dioxolo-
[4,5-j]pyrrolo[3,2,1-de]phenanthridine-2,2’-[1,3]dithiolan]-
7(3a1H)-one (1)
A mixture of 15 (35 mg, 0.086 mmol) and POCl3 (1 mL) was heated
at 908C for 16 h, and the mixture was slowly poured into cold
water and basified (pH 11) with 8% NaOH. The mixture was ex-
tracted with CH2Cl2 and washed with brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure, and the residue was purified by flash silica gel chromatogra-
phy (ethyl acetate/petroleum ether=2:1) to give 1 (26 mg, 85%)
(3a’S,7’R,7a’S)-7’-(Benzo[d][1,3]dioxol-5-yl)hexahydrospiro-
[[1,3]dithiolane-2,5’-indol]-2’(1’H)-one (14)
as
a
white powder. [a]D20 = +39.0 (c=1.0 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.39 (s, 1H), 6.54 (s, 1H), 5.92 (s, 2H), 4.07 (m,
1H), 3.48 (m, 1H), 3.30 (m, 4H), 3.16 (m, 1H), 2.97 (m, 1H), 2.67 (m,
1H), 2.61 (m, 1H), 2.34 (m, 1H), 2.20 (m, 1H), 2.03 (m, 1H),
1.92 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=162.9, 150.4, 146.5,
136.7, 125.2, 108.6, 103.6, 101.5, 65.2, 59.6, 45.7, 41.9, 41.8, 40.2,
38.9, 37.6, 37.3, 30.7 ppm; HRMS: m/z calcd for C18H19NO3S2:
361.0806 [M]+; found: 361.0806 [M]+.
Zinc power (161 mg, 2.47 mmol, 3.5 equiv) and 10% HCl (2 mL)
were added to a solution of compound 13 (300 mg, 0.706 mmol)
in EtOH (10 mL), and the resulting solution was stirred at room
temperature for 24 h. After filtration, the filtrate was evaporated
under vacuum. Then 2m NaOH was added and extracted with
CH2Cl2. The organic phase was dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure, and the crude
product was used for the next step without further purification.
CH3ONa (3.52 mmol, 190 mg) was added to a solution of the crude
product in CH3OH (5 mL), and the reaction mixture was stirred at
room temperature for 24 h. After removal of solvent, the mixture
was diluted with EtOAc and H2O. The organic layer was washed
with brine and dried over Na2SO4. The organic layer was filtered
and concentrated under reduced pressure, and the residue was pu-
rified by flash silica gel chromatography (ethyl acetate/petroleum
ether=2:1) to give 14 (172 mg, 70%) as a white powder. [a]2D0 = +
(3aR,3a1S,12bR)-3,3a,3a1,4,5,12b-Hexahydro-1H-
[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridin-7(2H)-one
(16)
Raney Ni (200 mg) was added to a solution of 15 (30 mg,
0.083 mmol) in EtOH (4 mL) and the resulting solution was stirred
under a hydrogen atmosphere at 608C for 60 h. After completion
of the reaction, the mixture was filtered and concentrated under
reduced pressure, and the residue was purified by flash silica gel
chromatography (ethyl acetate/petroleum ether=2:1) to give 16
(19 mg, 85%) as a white powder. [a]2D0 = +150.0 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.45 (s, 1H), 6.66 (s, 1H), 5.98 (s, 2H),
4.11 (dd, J=11.7 Hz, J=7.5 Hz, 1H), 3.45 (dd, J=12.6 Hz, J=9.0 Hz,
1H), 3.21 (m, 1H), 2.64 (m, 1H), 2.45 (m, 1H), 2.12 (m, 1H), 1.97 (m,
1H), 1.82 (m, 1H), 1.79–1.62 (m, 4H), 1.34 ppm (m, 1H); 13C NMR
(75 MHz, CDCl3): d=162.7, 149.9, 145.9, 137.9, 124.9, 108.1, 103.4,
101.0, 60.5, 45.2, 36.9, 36.7, 30.4, 25.1, 22.8, 20.4 ppm; HRMS: m/z
calcd for C16H17NO3: 271.1208 [M]+; found: 271.1211 [M]+.
1
51.3 (c=1.0 in CHCl3); H NMR (300 MHz, CDCl3): d=6.57 (m, 3H),
5.88 (s, 2H), 5.53 (brs, 1H), 3.31 (m, 1H), 3.17 (m, 4H), 2.68 (m, 3H),
2.34 (m, 2H), 2.08 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=
177.0, 148.2, 146.8, 135.3, 120.9, 108.6, 107.6, 101.1, 65.4, 59.1, 47.1,
46.9, 40.9, 40.3, 37.6, 35.5, 34.2 ppm; HRMS: m/z calcd for
C17H19NO3S2: 349.0806 [M]+; found: 349.0799 [M]+.
(3a’S,7’R,7a’S)-Ethyl 7’-(benzo[d][1,3]dioxol-5-
yl)hexahydrospiro[[1,3]dithiolane-2,5’-indole]-1’(6’H)-carbox-
ylate (15)
(+)-a-Lycorane
LiAlH4 (74 mg, 1.95 mmol, 5 equiv) was added to a solution of 14
(136 mg, 0.39 mmol) in dry THF (5 mL) and the resulting solution
was stirred under reflux for 12 h. 1m NaOH was added. The reac-
LiAlH4 (11 mg, 0.275 mmol, 5 equiv) was added to a solution of 16
(15 mg, 0.055 mmol) in dry THF (5 mL) and the resulting solution
Chem. Eur. J. 2014, 20, 6112 – 6119
www.chemeurj.org
6117
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
was stirred under reflux for 12 h. 1m NaOH was added and extract-
ed with CH2Cl2. The organic layer was washed with brine and dried
over Na2SO4. The organic layer was filtered, and concentrated
under reduced pressure, and the residue was purified by flash
silica gel chromatography (ethyl acetate/triethylamine=50:1) to
give (+)-a-lycorane (11 mg, 80%) as a white solid. [a]2D0 = +34.2
The organic layer was washed brine and dried over Na2SO4. The
mixture was filtered and concentrated under reduced pressure to
give the product 19, which was used without purification for the
next step. 1,8-diazabicyclo [5.4.0]undec-7-ene (41 mg, 0.278 mmol)
and DMF (20 mg, 0.278 mmol) were added to a solution of com-
pound 19 (18 mg) in dry toluene (2 mL) and the reaction mixture
was stirred for 5 h under reflux. The mixture was poured into H2O
and extracted with CH2Cl2. The organic layer was dried over anhy-
drous Na2SO4. The mixture was filtered and concentrated under re-
duced pressure, and the residue was purified by flash silica gel
chromatography (ethyl acetate/petroleum ether=2:1) to give 20
(7 mg, 50% (over two steps)) as a white solid. [a]2D0 = +136.1 (c=
1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.47 (s, 1H), 6.67 (m,
1H), 5.99 (s, 2H), 5.85 (m, 2H), 4.16 (m, 1H), 3.62 (m, 1H), 3.26 (m,
1H), 2.88 (m, 1H), 2.67 (m, 1H), 2.50 (m, 1H), 2.14 (m, 1H), 2.00 (m,
1H), 1.63 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=162.8, 150.4,
146.5, 137.0, 127.9, 126.4, 125.1, 108.5, 103.9, 101.5, 59.6, 45.4, 39.2,
35.8, 31.4, 25.5 ppm; HRMS: m/z calcd for C16H15NO3: 269.1052
[M]+; found: 269.1053 [M]+.
1
(c=1.0 in CHCl3); H NMR (400 MHz, CDCl3), d=6.69 (s, 1H), 6.64 (s,
1H), 5.91 (s, 2H), 4.27 (d, J=14.8 Hz, 1H), 3.74 (d, J=14.8 Hz, 1H),
3.40 (m, 1H), 2.91 (m, 1H), 2.70 (m, 1H), 2.49 (brs, 1H), 2.38 (m,
1H), 2.25 (m, 1H), 1.88 (m, 2H), 1.68 (m, 3H), 1.58 (m, 1H),
1.22 ppm (m, 1H); 13C NMR (100 MHz, CDCl3), d=147.1, 145.9,
134.5, 126.7, 107.4, 104.5, 101.0, 65.1, 54.7, 54.2, 36.8, 34.0, 27.7,
25.7, 25.3, 20.7 ppm; HRMS: m/z calcd for C16H19NO2: 257.1416
[M]+; found: 257.1419 [M]+.
(3aS,3a1S,12bR)-3,3a,4,5-Tetrahydro-1H-[1,3]dioxolo[4,5-
j]pyrrolo[3,2,1-de]phenanthridine-2,7(3a1H,12bH)-dione (17)
HgCl2 (136 mg, 0.5 mmol, 5 equiv) was added to a solution of
1 (36 mg, 0.1 mmol) in 4 mL (CH3CN/H2O=7:1) and the reaction
mixture was stirred at 408C for 24 h. The mixture was extracted
with AcOEt. The organic layer was washed with brine and dried
over Na2SO4. The organic layer was filtered and concentrated
under reduced pressure, and the residue was purified by flash
silica gel chromatography (ethyl acetate/petroleum ether=10:1) to
give 17 (23 mg, 80%) as a white powder. [a]2D0 = +121.0 (c=1.0 in
Acknowledgements
We gratefully acknowledge financial support from the NSFC
(21162034, 21372193, 21362040), the Program for Changjiang
Scholars and Innovative Research Team in University
(IRT13095), the Doctoral Fund of Ministry of Education of
China (20135301110002), and the Government of Yunnan Prov-
ince (2012FB114, 2013 A026). We thank Prof. Baomin Wang at
Dalian University of Technology for providing the chiral guani-
dine catalysts.
1
CHCl3); H NMR (300 MHz, CDCl3): d=7.45 (s, 1H), 6.52 (s, 1H), 5.95
(s, 2H), 4.17 (m, 1H), 3.58 (m, 1H), 3.17 (m, 2H), 2.84 (dd, J=
15.6 Hz, J=5.1 Hz, 1H), 2.63 (m, 2H), 2.28 (m, 2H), 2.12 (m, 1H),
1.70 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=209.3, 161.9, 150.8,
147.1, 134.7, 124.6, 108.8, 104.0, 101.7, 59.7, 44.9, 43.9, 38.8, 35.5,
34.9, 33.7 ppm; HRMS: m/z calcd for C16H15NO4: 285.1001 [M]+;
found: 285.0994 [M]+.
Keywords: cascade reactions · conjugate additions · divergent
total synthesis · enantioselective catalysis · octahydroindolones
(3aS,3a1S,12bR)-2-Hydroxy-3,3a,3a1,4,5,12b-hexahydro-1H-
[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridin-7(2H)-one
(18)
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NaBH4 (5.6 mg, 0.147 mmol) was added to a solution of 17 (21 mg,
.
0.0737 mmol) and CeCl3 7H2O (27 mg, 0.0737 mmol) in MeOH
(1.0 mL) at 08C and the resulting solution was stirred at 08C for
10 min. The mixture was quenched with water and extracted with
AcOEt. The organic layer was washed with brine and dried over
Na2SO4. The organic layer was filtered, and concentrated under re-
duced pressure, and the residue was purified by flash silica gel
chromatography (ethyl acetate/methanol=10:1) to give 18
(20 mg, 95%) as a white powder. [a]2D0 = +78.9 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.36 (s, 1H), 6.54 (s, 0.29H), 6.47 (s,
0.70H), 5.92 (s, 2H), 4.04 (m, 2H), 3.40 (m, 0.29H), 3.34 (m, 0.74H),
3.18 (m, 1H), 2.92 (m, 0.73H), 2.59 (m, 0.58H), 2.33 (m, 1.29H), 1.91
(m, 3H), 1.66 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=162.9,
150.4, 146.4, 137.6, 125.0, 108.5, 108.4, 103.8, 103.6, 101.5, 66.6,
66.3, 60.2, 45.8, 45.6, 36.5, 35.5, 35.3, 34.3, 34.1, 33.7, 33.2, 32.2,
32.1, 31.1 ppm; HRMS: m/z calcd for C16H17NO4: 287.1158 [M]+;
found: 287.1151 [M]+.
(3aS,3a1S,12bR)-3a1,4,5,12b-Tetrahydro-1H-[1,3]dioxolo[4,5-
j]pyrrolo[3,2,1-de]phenanthridin-7(3aH)-one (20)
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sulting solution was stirred at 08C for 3 h. The mixture was diluted
with dichloromethane and saturated aqueous NaHCO3 solution.
Chem. Eur. J. 2014, 20, 6112 – 6119
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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[15] An optical purity of 99% ee could be achieved after one recrystalliza-
tion.
Received: January 16, 2014
Published online on April 3, 2014
Chem. Eur. J. 2014, 20, 6112 – 6119
www.chemeurj.org
6119
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