Total synthesis of the tylophora alkaloids rusplinone, 13aα- secoantofine, and antofine using a multicatalytic oxidative aminochlorocarbonylation/Friedel-Crafts reaction

Article abstract of DOI:10.1016/j.tet.2010.03.021

A rapid synthetic approach to the tylophora alkaloids antofine and 13aα-secoantofine is presented that makes use of a multicatalytic oxidative aminochlorocarbonylation/Friedel-Crafts reaction as the key step. This reaction, along with a one-pot, three-ste

Full text of DOI:10.1016/j.tet.2010.03.021

Tetrahedron 66 (2010) 4882–4887
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of the tylophora alkaloids rusplinone, 13aa-secoantofine,
and antofine using a multicatalytic oxidative aminochlorocarbonylation/
Friedel–Crafts reaction
*
Lisa M. Ambrosini, Tim A. Cernak, Tristan H. Lambert
Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid synthetic approach to the tylophora alkaloids antofine and 13aa-secoantofine is presented that
Received 15 January 2010
Received in revised form 4 March 2010
Accepted 5 March 2010
makes use of a multicatalytic oxidative aminochlorocarbonylation/Friedel–Crafts reaction as the key step.
This reaction, along with a one-pot, three-step telescoped process offers a three or four-pot sequence to
access the title compounds in high overall yield.
Available online 11 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Oxidative carbonylation
Multicatalysis
Tylophora alkaloids
Antofine
Palladium
1. Introduction
terminated by the reaction of a penultimate acyl palladium in-
termediate with an equivalent of alcohol (often as solvent) or with
A primary goal of synthetic organic chemistry is to discover new
approaches to rapidly achieve molecular complexity in a highly
efficient manner. Traditional iterative synthetic approaches often
lack economy of time, effort, and materials and tend to produce
large amounts of waste. Of the many varied efforts to address these
issues, the concept of multicatalytic reaction development offers an
especially promising venue for process optimization and chemical
discovery.1 As such, multicatalysis, the execution of multiple
distinct catalytic reactions in a single flask, has been garnering
significant attention from the synthetic community. Our own
multicatalytic program is focused on the development of new
chemical technologies designed for integration into multicatalytic
processes and the invention of multicatalytic strategies for the
preparation of structurally complex molecular motifs.2
As part of this program we have been exploring new intra-
molecular oxidative carbonylation methods conceptually related to
those developed by Semmelhack3 and Hegedus.4 Such reactions
allow for the preparation of carbonyl-bearing complex heterocycles
from simple alkenyl alcohols and amines and thus offer intriguing
possibilities for incorporation into synthetically productive
multicatalytic processes. Normally, oxidative carbonylations are
a pendant hydroxyl or amino moiety to produce esters, lactones, or
lactams, respectively (Scheme 1). Though the high utility of these
transformations has been demonstrated, ester and amide func-
tionalities lack broad utility as participants in catalytic reactions
cat.
O
PdCl2, CuCl2
OR
X
X = O, NR
XH
CO, ROH
carbonylation
oxidative
Scheme 1. Oxidative carbonylation (Semmelhack, Hegedus).
and thus are not ideal for the development of multicatalytic pro-
cesses. Accordingly, we have aimed to develop novel oxidative
carbonylation reactions that produce alternative carbonyl func-
tionalities capable of undergoing further catalytic transformations.
In this regard, we recently reported the development a Pd(II)-
catalyzed aminochlorocarbonylation reaction of alkenyl amines to
produce reactive acid chloride intermediates.2a This method could
be used to produce acid chlorides 2 or alternative acyl derivatives
such as Weinreb amides by introduction of a suitable nucleophile
(Scheme 2). More importantly, we found that this oxidative
chlorocarbonylation method could be combined in tandem with
* Corresponding author. E-mail address: TL2240@columbia.edu (T.H. Lambert).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.021

L.M. Ambrosini et al. / Tetrahedron 66 (2010) 4882–4887
4883
In(OTf)3-catalyzed Friedel–Crafts reactions with electron rich are-
southeastern Asia (Fig. 1).5 The tylophora alkaloids have long been
of synthetic and medicinal interest due to the panoply of biological
activities they possess, which include antibacterial, anticancer,
nes to produce complex
a
-aryl ketones (Scheme 3).
O
Filter
93% yield
94% yield
OMe
OMe
OMe
Cl
N
OMe
Aminochloro-
carbonylation
Ts
OMe
OMe
OMe
2
H
N
NH
Ts
H
N
H
N
O
NHMe(OMe)
1
NMe(OMe)
N
Ts
3
OMe
OMe
OMe
11 (–)-tylophorine
Scheme 2. Formation of acid chloride and Weinreb’s amide.
9 (–)-13aα-secoantofine
10 (–)-antofine
Figure 1. Structures of some tylophora alkaloids.
antifungal, antiviral, and anti-inflammatory properties.6,7 Specifi-
cally, we surmised that a total synthesis of the tylophora alkaloid
antofine would be an especially apt venue to apply our multi-
catalytic technology. Antofine is of particular interest because it has
been shown to be very effective against multidrug-resistant cancer
cell lines with IC50 values in the low nanomolar range.8
O
O
1
2
R
R
aminochloro-
carbonylation
R
N
Friedel-
Crafts
NH
Ts
R
Cl
N
Ts
Ts
Scheme 3. Aminochlorocarbonylation/Friedel–Crafts.
Due to their wide range of biological activity, there have been
a number of total syntheses of tylophora alkaloids reported.9 Re-
cent approaches have included such key steps as Pt(II)-catalyzed
cycloisomerization,9a [5þ5]-cycloaddition,9b intramolecular al-
kene carboamination,9c and 1,3-dipolar cycloaddition,9d among
others. Despite achievements made toward this class of molecules,
it can be said that the reported strategies leave room for im-
provement in terms of the number of synthetic steps, overall yield,
or potential for diverse analogue preparation. We recognized that
our aminochlorocarbonylation/Friedel–Crafts reaction might allow
for the rapid and easily diversifiable construction of a substantial
portion of the phenanthroindolizidine skeleton common to the
tylophora alkaloids. We thus set as our goal the realization of a total
synthetic strategy toward this intriguing class of molecules.
A variety of alkenyl amine and aryl coupling partners proved to
be compatible with this process. For example, when amine 4 was
added slowly to a solution of anisole, catalytic Pd(PhCN)2Cl2, cat-
alytic In(OTf)3, and CuCl2 under a CO atmosphere, the amino ketone
5A was produced in high yield as essentially a single diastereomer
(Scheme 4). A number of other electron-rich aromatic nucleophiles
were productive in this transformation including both benzene
derivatives and heterocycles (Scheme 4). Variations in the alkenyl
substrate were also tolerated (Scheme 5).
10 mol%
10 mol%
Pd(PhCN)2Cl2 In(OTf)3
O
1
2
+
ArH
iPr
iPr
Ar
aminochloro-
carbonylation
Friedel-
Crafts
NH
Ts
N
Ts
2. Results and discussion
2.1. Synthesis of antofine
CuCl2, CO, 4Å MS
4
5
ArH: A 92% yield, >97:3 dr
B 66% yield, >97:3 dr
C 91% yield, >97:3 dr
D 72% yield, >97:3 dr
OMe
Br
OMe
S
Ph
N
MeO
SO2Ph
D
The key step in our synthetic strategy was the multicatalytic
aminochlorocarbonylation/Friedel–Crafts acylation of a protected
A
B
C
4-pentenyl amine to provide
a b-pyrrolidinyl ketone in-
Scheme 4. Scope of nucleophiles for aminochlorocarbonylation/Friedel–Crafts.
termediate. Importantly, we discovered that the easily removable
nosyl (Ns) group could be employed successfully for this chem-
istry instead of the tosyl group we had previously reported. Thus
subjecting the readily available nosyl protected alkenyl amine 12
and veratrole to our standard aminochlorocarbonylation condi-
10 mol%
10 mol%
Pd(PhCN)2Cl2 In(OTf)3
OMe
OMe
1
2
H
tions, we were gratified to find that the b-pyrrolidinyl ketone 13
+
could be isolated in high yield (Scheme 6). Moreover, we
have successfully scaled this reaction to produce 1.6 g of the
product 13.
aminochloro-
carbonylation
Friedel-
Crafts
H
NTs
O
OMe
NHTs
CuCl2, CO, 4Å MS
OMe
8
6
7
85% yield
>97:3 dr
Scheme 5. Aminochlorocarbonylation/Friedel–Crafts of an internal olefin.
PdII
1
InIII
2
O
OMe
OMe
aminochloro- Friedel-
carbonylation Crafts
N
NH
Ns
Given the high synthetic productivity of this process, we became
interested in applying this tandem aminochlorocarbonylation/
Friedel–Crafts reaction to the preparation of biologically active
natural products. We were particularly drawn to the tylophora
alkaloids, a group of approximately 60 alkaloids isolated from
plants of the Ascelpiadaceae and Morceae family native to India and
Ns
CuCl2, ArH
CO
13
12
88% yield
Scheme 6. Aminochlorocarbonylation/Friedel–Crafts key step.

4884
L.M. Ambrosini et al. / Tetrahedron 66 (2010) 4882–4887
Removal of the nosyl protecting group from 13 proved to be
product was transformed to this pyridone adduct. Rigorous exclu-
sion of oxygen from the reaction did not fully attenuate the for-
mation of this product. Nevertheless, the dramatically greater
efficiency of the telescopic process versus the iterative one led us to
consider this minor side product an acceptable loss of material.
straightforward by treatment with thiophenol under basic condi-
tions. This deprotection furnished the small alkaloid natural
product rusplinone (14) in 75% yield. This material was acylated
with p-methoxyphenylacetyl chloride to provide amide 15, which
was subjected to aldol condensation by warming in basic ethanol.
Finally, reduction with sodium bis-(2-methoxyethoxy)aluminum
Given the efficiency with which 13aa-secoantofine had been
accessed, we decided to utilize our strategy to synthesize the
related and biologically more interesting antofine, in which the two
aryl substituents are joined to form a phenanthryl ring system. To
accomplish this goal, we required a means to oxidatively couple the
hydride (Red-Al) furnished 13a
(Scheme 7). Thus the total synthesis of 13a
achieved in a five-flask process with a 19% overall yield.
a
-secoantofine in 60% yield
a-secoantofine was
aryl groups of 13aa-secoantofine or its precursor. Fortunately,
oxidative aryl coupling of diaryl indolizidine natural products
has been achieved using a number of different conditions, including
I2/light,10 Tl(TFA)3,9k VOF3/TFA,9j,m and VOCl3.11 After some exper-
imentation, we found the VOCl3 oxidation of 16 to be most effective,
when care was taken to rigorously exclude oxygen. The crude
reaction mixture produced by this coupling was subjected to
deoxygenative reduction conditions using LiAlH4 to furnish anto-
fine in 75% yield over two steps (Scheme 9). Overall, the synthesis
of antofine was achieved in four reaction pots in 48% yield.
O
O
OMe
OMe
PhSH, Cs2CO3
OMe
OMe
N
H
N
MeCN
Ns
75% yield
rusplinone
13
14
OMe
X
N
O
O
OMe
Ar
Cl
N
KOH
NEt3, CH2Cl2
59% yield
EtOH
82% yield
OMe
O
OMe
15
OMe
OMe
OMe
OMe
O
16 X = O
17 X = H2
60% yield 13a -secoantofine
OMe
N
N
1. VOCl3, CH2Cl2
Red-Al
2. LiAlH4, THF
75% yield (2 steps)
α
10
antofine
OMe
16
Scheme 7. Synthesis of rusplinone and 13aa-secoantofine.
OMe
OMe
• four-pot total synthesis of antofine
• 48% overall yield
Although the efficiency of this synthesis was acceptable, we
wondered if the conversion of adduct 13 into indolizidine 16 could
be executed as a single telescopic reaction, given that each in-
dividual step occurred under basic conditions. Indeed, a one-pot
procedure was realized by the sequential addition of thiophenol,
p-methoxyphenylacetyl chloride, and ethanolic potassium hy-
droxide to a solution of 13 and excess cesium carbonate in aceto-
nitrile (Scheme 8). In addition to doubling the yield (72% vs 36% for
the stepwise procedure), the telescopic procedure was consider-
ably more simple and rapid to execute, requiring just 5 h of total
Scheme 9. Synthesis of antofine.
3. Conclusions
Multicatalytic processes promise to provide novel and highly
efficient approaches to prepare molecules of value. We have dem-
onstrated the ability of one such multicatalytic process to facilitate
the rapid and efficient production of several tylophora alkaloids,
including 13aa-secoantofine and antofine, which were prepared in
three and four-pot sequences, respectively. We believe the effi-
ciency, convergency, and potential for structural variation our
approach offers compares quite favorably with other reported
syntheses of these molecules. Indeed, modification of the alkenyl
O
OMe
OMe
O
O
Cl
Cs2CO3
nosylate
PhSH,
KOH,
EtOH
aldol
N
8
OMe
OMe
Ar
N
amide
Ns
amine, electron-rich aryl, and
a-arylacetyl chloride components
8a
removal formation
one-pot
13
16
should provide ready access to a diverse library of novel tylophora
analogues. Efforts in this regard are currently underway.
72% yield
OMe
OMe
4. Experimental section
4.1. General information
N
• three-pot total synthesis of seco-antofine
• 38% overall yield
Red-Al
60% yield
OMe
13a -secoantofine
α
OMe
All reactions were performed in base-washed, oven-dried
glassware under an atmosphere of argon or carbon monoxide
unless otherwise noted. Indium(III) triflate, bis-benzoni
triledichloropalladium and copper(II) chloride (99.999%) were
purchased from Aldrich then opened and stored in an inert atmo-
sphere glovebox. Molecular sieves (4 Å) were finely ground then
activated (300 ꢀC, 10 mmHg) for several hours. 1,2-Dichloroethane
was freshly distilled from calcium hydride just prior to use. All
other reagents were used as received from commercial vendors.
1H and 13C NMR were recorded in CDCl3 on Brucker DRX-300
and DRX-400 as noted, and are internally referenced to the re-
sidual solvent peak. Data from 1H NMR are reported as follows:
Scheme 8. Synthesis of 13a
a-secoantofine.
reaction time with only one required chromatographic purification.
Thus the combination of our multicatalytic synthesis of ketone 13
and the telescopic conversion of 13 to 16 has allowed us to realize
a three-pot synthesis of 13aa-secoantofine in 38% overall yield.
It should be noted that during the one-pot conversion of 13 to
16, an additional 8% yield of a pyridone product resulting from
oxidation of the 8–8a bond was also isolated. When the final step of
the telescopic reaction was carried out for extended periods or at
temperatures above 60 ꢀC, a significant amount of the desired
chemical shift (
d
ppm), multiplicity (s¼singlet, br s¼broad singlet,

L.M. Ambrosini et al. / Tetrahedron 66 (2010) 4882–4887
4885
d¼doublet, t¼triplet, q¼quartet, m¼multiplet), integration, cou-
pling constant (Hz) and assignment. Data for 13C NMR are reported
in terms of chemical shift. IR spectra were recorded on a Nicolet
Avatar 370 DTGS (Thermo) using NaCl salt plates and reported in
terms of frequency of absorption (cmꢁ1). High-resolution mass
spectra were obtained from the Columbia University Mass Spec-
troscopy Facility on JOEL JMS-HX110 HF mass spectrometer using
the FABþ ionization mode.
added dropwise and the mixture stirred at 40 ꢀC for 15 h. The
reaction mixture was cooled to room temperature, quenched by
addition of water (25 mL), poured into ether (25 mL) and hexanes
(25 mL), and separated. The organic layer was washed further with
water (2ꢂ20 mL), then brine (20 mL), then dried over anhydrous
sodium sulfate, filtered, and concentrated. The residue was purified
by flash column chromatography on silica gel (20%/30% ethyl
acetate/hexanes) to give the title compound 12 (541 mg, 60% yield)
and N,N-dipent-5-enyl-20-(nitrobenzene)sulfonamide (120 mg,
11%).13
4.2. General procedure for the aminochlorocarbonylation/
Friedel–Crafts reaction
4.2.3. 1-(3,4-Dimethoxyphenyl)-2-(1-(2-nitrophenylsulfonyl)pyrroli-
din-2-yl)ethanone (13). Following general procedure but excluding
In(OTf)3 and aromatic nucleophile, a solution of N-nosylpenten-
amine 12 (480 mg, 1.78 mmol, 1 equiv) in DCE (6.6 mL) was added
via syringe pump at a rate of 0.50 mL/hour to a stirring suspension
of PdCl2(PhCN)2 (68 mg, 10 mol %), CuCl2 (716 mg, 3.0 equiv) and
finely ground activated 4 Å molecular sieves (1.78 g) in DCE
(2.2 mL) under an atmosphere of carbon monoxide and at 23 ꢀC.
After 16 h, conversion to the acid chloride intermediate was com-
plete as judged by ESIMS analysis of an aliquot diluted in methanol
(observed methyl ester: [MHþ] 329 m/z). Working quickly, the flask
was opened to air and In(OTf)3 (100 mg, 0.18 mmol, 10 mol %) was
added in one portion followed by anhydrous veratrole (2.23 mL,
17.8 mmol, 10 equiv). The flask was fitted with a reflux condenser
and heated at 70 ꢀC for 42 h, then cooled to room temperature and
worked up in the usual manner. Purification by flash column
chromatography on silica gel (20%/50% ethyl acetate/hexanes)
gave the title compound 13 (680 mg, 88% yield) as a colorless oil
that solidified to a waxy solid on standing. 1H NMR (300 MHz,
A dry screwcap vial fitted with a Teflon septum and magnetic
stirbar was moved into the glovebox and charged with In(OTf)3
(10 mol %), PdCl2(PhCN)2 (10 mol %), CuCl2 (3.0 equiv), and 4 Å
molecular sieves (1000 mg/mmol substrate). The sealed vial was
removed from the glovebox and filled with carbon monoxide from
a balloon by evacuating and back-filling three times. 1,2-Di-
chloroethane (1.65 mL/mmol substrate) was added to make a sus-
pension, followed by the addition of the aromatic nucleophile. The
substrate was then dissolved in 1,2-dichloroethane to make
a 0.30 M solutiondextra solution was prepared to account for the
dead volume of the syringe. This solution was then added to the
catalyst mixture via syringe pump at a rate of 0.075 equiv/hour
unless otherwise noted. After complete addition of the substrate,
the reaction was monitored by mass spectrometry or thin layer
chromatography. Once complete, the reaction was quenched by the
addition of ethyl acetate (2 mL for 0.12 mmol substrate), saturated
aqueous ammonium chloride (1 mL), and water (1 mL) and stirred
vigorously for several minutes. The mixture was then filtered
through a short plug of Celite into ethyl acetate (5 mL) and washed
further with saturated ammonium chloride (3 mL). The organic
layer was dried on anhydrous sodium sulfate, filtered, and con-
centrated in vacuo. Purification by flash column chromatography
on silica gel, eluting with a gradient of 5–30% EtOAc/hexanes unless
otherwise noted, afforded the title compound.
CDCl3)
d 8.04–8.00 (m, 1H, Ar–H), 7.79–7.53 (m, 5H, Ar–H), 6.92
(d, 2H, J¼8.4, Ar–H), 4.55–4.44 (m,1H, NCH), 3.95 (s, 6H, OCH3), 3.74
(dd,1H, J¼16.2, 3.1, CH2C(O)), 3.56–3.37 (m, 2H, NCH2), 3.04 (dd, 1H,
J¼16.2, 10.5, CH2C(O)), 2.11–1.92 (m, 2H, CH2), 1.87–1.71 (m, 2H,
CH2); 13C NMR (100 MHz, CDCl3)
d 196.5, 153.5, 148.9, 148.5, 133.6,
131.4, 131.3, 130.6, 129.6, 123.9, 123.0, 110.1, 110.1, 57.3, 56.0, 55.9,
48.9, 44.6, 31.7, 23.8, 14.1; IR: 3079, 2940, 1670, 1587, 1545, 1372,
1263, 1164, 1022, 730 cmꢁ1. HRMS (FABþ) exact mass calcd for
C20H23N2O7S (MH)þ requires m/z 435.1220, found m/z 431.1230.
4.2.1. N-Methoxy-N-methyl-2-(1-tosylpyrrolidin-2-yl)ethanamide
(3). Following general procedure but excluding In(OTf)3 and aro-
matic nucleophile, a solution of N-tosylpentenamine 112 (29.0 mg,
1.78 mmol, 1 equiv) in DCE (400
m
L) was added via syringe pump at
4.2.4. 1-(3,4-Dimethoxyphenyl)-2-(pyrrolidin-2-yl)ethanone
a rate of 0.03 mL/hour to a stirring suspension of PdCl2(PhCN)2
(68.3 mg, 10 mol %), CuCl2 (718 mg, 3.0 equiv) and finely ground
(14). Thiophenol (34
mL, 0.331 mmol, 1.2 equiv) was added drop-
wise to stirring suspension of the nosylate 13 (120 mg,
a
activated 4 Å molecular sieves (1.78 g) in DCE (200
m
L) under an
0.276 mmol, 1 equiv) and cesium carbonate (135 mg, 0.414 mmol,
1.5 equiv) in acetonitrile (1.4 mL) under argon at 23 ꢀC. After 5 h,
the reaction was complete as judged by TLC (50% ethyl acetate/
hexanes) and was diluted with ethyl acetate (1 mL). Solids were
removed by filtration through a short plug of Celite and the filter
cake washed with ethyl acetate (3ꢂ2 mL) then concentrated in
vacuo. The residue was loaded onto a short plug of silica gel,
washed with ethyl acetate (25 mL) to collect a fraction of mostly
20-nitrodiphenylsulfide (80.1 mg) followed by elution with
dichloromethane/methanol/triethylamine (80:18:2, 25 mL) to give
rusplinone 14 (51.5 mg, 75% yield) as a clear oil.14
atmosphere of carbon monoxide and at 23 ꢀC. After 15 h, the re-
action mixture was cooled to 0 ꢀC and solid N,O-dimethylhydrox-
ylammonium chloride (58.7 mg, 0.605 mmol, 5 equiv) then 15%
sodium hydroxide (600 mL) were added. The ice bath was removed
and the heterogeneous mixture stirred at room temperature for
two hours. Workup in the usual manner gave a residue that was
purified by flash column chromatography on silica gel (20%/60%
ethyl acetate/hexanes) to give the title compound 3 (37.2 mg, 94%
yield). 1H NMR (400 MHz, CDCl3)
d
7.72 (d, 2H, J¼8.1, Ar–H), 7.30
(d, 2H, J¼8.0, Ar–H), 4.01–3.96 (m, 1H, NCH), 3.72 (s, 3H, NOCH3),
3.49–3.44 (m, 1H, NCH2), 3.22–3.18 (m, 1H, NCH2), 3.16 (s, 3H, CH3),
3.09–3.03 (m, 1H, CH2C(O)), 2.66–2.58 (m, 1H, CH2C(O)), 2.41 (s, 3H,
CH3), 1.84–1.67 (m, 3H, CH2), 1.54–1.48 (m, 1H, CH2); 13C NMR
4.2.5. 1-(3,4-Dimethoxyphenyl)-2-(1-(2-(4-methoxyphenyl)ethan-
oyl)pyrrolidin-2-yl)ethanone (15). To a solution of rusplinone 14
(100 MHz, CDCl3)
d
172.0, 143.4, 133.8, 129.7, 127.6, 61.3, 56.6, 49.2,
(48.0 mg, 0.192 mmol, 1.0 equiv) and triethylamine (80
0.576 mmol, 3.0 equiv) in dichloromethane (1 mL) was added
solution of p-methoxyphenylacetyl chloride (70.0 mg,
0.384 mmol, 2.0 equiv) in dichloromethane (1.0 mL) at 0 ꢀC. The
reaction was then warmed to room temperature and stirred for
12 h. The mixture was poured into ethyl acetate (10 mL) and
washed with saturated ammonium chloride (2ꢂ3 mL) then brine
(2 mL) then dried on sodium sulfate, filtered, and concentrated in
vacuo. The residue was purified on silica gel (0%/10% acetone/
mL,
39.4, 31.8, 23.7, 21.5; IR: 2927, 1659, 1598, 1343, 1159, 1093, 817,
665 cmꢁ1. HRMS (FABþ) exact mass calcd for C15H23N2O4S (MH)þ
requires m/z 327.1373, found m/z 327.1394.
a
4.2.2. 2-Nitro-N-(pent-4-enyl)aniline (12). 2-Nitrobenzenesulfona
mide (746 mg, 3.69 mmol, 1.1 equiv) and potassium carbonate
(926 mg, 6.70 mmol, 2.0 equiv) were taken up in DMF (8.5 mL)
under argon. 5-Bromopentene (500 mg, 3.35 mmol, 1 equiv) was

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L.M. Ambrosini et al. / Tetrahedron 66 (2010) 4882–4887
dichloromethane) to give amide 15 (44.9 mg, 59% yield). 1H NMR
(400 MHz, CDCl3)
mixture heated at reflux for 2 h. The reaction mixture was cooled,
volatiles removed in vacuo and excess hydride was quenched by
careful addition of water (10 mL) then 15% NaOH (3 mL) then brine
(20 mL). The aqueous mixture was extracted with chloroform
(5ꢂ30 mL) and the combined organic fractions dried on sodium
sulfate, filtered, and concentrated in vacuo. The residue was puri-
d
7.86 (d, 1H, J¼8.4, Ar–H), 7.61 (s, 1H, Ar–H), 7.17
(d, 2H, J¼8.4, Ar–H), 6.89–6.83 (m, 3H, Ar–H), 4.53–4.49 (m, 1H,
NCH), 3.92 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.85 (dd, 2H, J¼13.8,
2.6, CH2C(O)), 3.58 (s, 3H, OCH3), 3.54–3.38 (m, 2H, NCH2), 2.55
(dd, 1H, J¼13.7, 10.6, CH2C(O)), 2.01–1.73 (m, 3H, CH2); 13C NMR
(100 MHz, CDCl3)
d
197.5, 170.0, 158.4, 153.2, 148.8, 129.9, 129.7,
fied on silica gel (3% acetone/dichloromethane) to give 13aa-
126.6, 123.7, 114.0, 110.2, 110.1, 55.9, 55.3, 55.1, 47.2, 42.7, 42.0, 41.5,
29.1, 23.8. HRMS (FABþ) exact mass calcd for C23H28NO5 (MH)þ
requires m/z 398.1962, found m/z 398.1945.
secoantofine 9 (109 mg, 60% yield).15
4.2.8. Antofine (10). To a solution of indolizidine 16 (20.0 mg,
0.053 mmol, 1.0 equiv) in degassed DCE (2 mL) at 0 ꢀC was added
4.2.6. 7-(3,4-Dimethoxyphenyl)-6-(4-methoxyphenyl)-2,3,8,8a-tet-
rahydroindolizin-5(1H)-one (16). A stock solution of 7.5% (w/w)
potassium hydroxide in ethanol was prepared before initiating the
reaction. The acid chloride was prepared by dropwise addition of
VOCl3 (15.0 mL, 0.158 mmol, 3.0 equiv). The solution was allowed to
warm to room temperature and stir overnight. The reaction mix-
ture was quenched with saturated ammonium chloride (1 mL).
Then wash with 1 M ammonium hydroxide (3ꢂ1 mL) and brine
(1 mL). Dry on sodium sulfate and filter through silica plug using
10% acetone/dichloromethane. The crude reaction mixture con-
tains both desired coupled product and side product corresponding
to the desired product containing an additional Cl atom [MHþ] 413
m/z. This mixture of products was then added as a THF solution
(2 mL) to a suspension of LiAlH4 (20.1 mg, 0.53 mmol, 10 equiv) in
THF (3 mL) at 0 ꢀC. The reaction mixture was then heated to reflux
for 2 h. After cooling to 0 ꢀC, three drops of 1 M NaOH was added
(until bubbling subsided). This crude mixture was filtered through
Celite followed by a silica plug to provide antofine 10 (14.5 mg,
75% yield over two steps).9b
thionyl chloride (440
p-methoxyphenylacetic acid (500 mg, 3.01 mmol, 1 equiv) and
DMF (10
L) in dichloromethane (5 mL) at 0 ꢀC. After 5 min, the
mL, 6.02 mmol, 2.0 equiv) to a solution of
m
solution was warmed to 23 ꢀC and stirred at this temperature for
4 h. Volatiles were removed by concentration in vacuo. Traces of
hydrochloric acid were removed by dissolution in dichloromethane
and concentration in vacuo. The acid chloride was carried forward
without purification.
The starting nosylate 3 (260 mg, 0.598 mmol, 1 equiv), azeo-
tropically dried by three cycles of concentrating in vacuo from
anhydrous benzene, and cesium carbonate (390 mg, 1.196 mmol,
2.0 equiv) were taken up in acetonitrile (2 mL). Thiophenol (64 mL,
0.628 mmol, 1 equiv) in acetonitrile (1 mL) was then added drop-
wise and the mixture stirred at 23 ꢀC for 3 h. The yellow suspension
was cooled to 0 ꢀC and a solution of p-methoxyphenylacetyl chlo-
ride (166 mg, 0.897 mmol, 1.5 equiv) in acetonitrile (0.5 mL) was
added dropwise. After 3 min, the reaction mixture was warmed to
23 ꢀC and stirred for one hour. The solution of 7.5% (w/w) potassium
hydroxide in ethanol (1.25 mL, 2.99 mmol, 5.0 equiv) was added
causing the solution to turn black. The flask was quickly fitted with
a reflux condenser and the reaction mixture heated at 60 ꢀC for 1 h.
Extended reaction time or elevated temperatures should be avoi-
ded at this step to minimize oxidation of the desired product. The
reaction mixture was cooled to room temperature and quenched
with a saturated aqueous solution of sodium thiosulfate (3 mL),
a saturated aqueous solution of ammonium chloride (3 mL), and
ethyl acetate (10 mL). The biphasic mixture was stirred at 23 ꢀC for
30 min, then poured into ethyl acetate (30 mL): if necessary,
dichloromethane (w5 mL) was added to the organic layer to form
a clear solution. The layers were separated and the organic layer
washed further with a saturated aqueous solution of ammonium
chloride (15 mL), then dried on sodium sulfate, filtered, and con-
centrated in vacuo. The residue was purified by flash column
chromatography on silica gel (5%/20% acetone/dichloromethane)
to give the title compound 16 (165 mg, 72% yield) and the 2-pyr-
idone resulting from oxidation of the product (18 mg, 8% yield). 1H
Acknowledgements
L.M.A. thanks Novartis for a graduate fellowship. T.A.C. thanks
FQRNT for a post-doctoral fellowship.
References and notes
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NMR (300 MHz, CDCl3)
d
7.04 (d, 2H, J¼8.7, Ar–H), 6.74–6.71 (m, 4H,
Ar–H), 6.43 (d, 1H, J¼1.2, Ar–H), 6.89–6.83 (m, 3H, Ar–H), 3.98–3.87
(m, 1H, NCH2), 3.87 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.69–3.53
(m, 2H, NCH2, and NCH), 3.48 (s, 3H, OCH3), 2.85 (dd,1H, J¼22.2, 4.8,
CH2CH), 2.70 (dd, 1H, J¼16.2, 13.8, CH2CH), 2.32–2.25 (m, 1H, CH2),
2.12–2.04 (m, 1H, CH2), 1.97–1.63 (m, 2H, CH2); 13C NMR (100 MHz,
CDCl3)
d 164.2, 158.4, 149.3, 147.9, 144.0, 132.6, 132.1, 131.8, 128.8,
120.8, 113.2, 112.7, 110.3, 55.7, 55.5, 55.4, 55.1, 44.7, 37.2, 22.8, 23.1.
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L.M. Ambrosini et al. / Tetrahedron 66 (2010) 4882–4887
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