Synthesis of the AB-DE ring system present in the alstoscholarine alkaloids

Article abstract of DOI:10.1055/s-0031-1289745

A practical protocol is presented for the construction of the AB-DE rings present in (19,20)-(E)- and (19,20)-(Z)-alstoscholarine alkaloids from the commercially available glutamic acid 5-methyl ester, employing only a six-step synthetic sequence. The main features include the synthesis of the alkynylindolizinone core and the use of Sonogashira cross-coupling and base-mediated cyclization to afford a 2-substituted indole without the use of protecting groups. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289745

PAPER
1051
Synthesis of the AB-DE Ring System Present in the Alstoscholarine Alkaloids
S
ynthesis of the
u
A
B-DE Rin
i
gs of th
s
e
A
lstoscholarin
A
e
A
lkaloids . Polindara-García, Luis D. Miranda*
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior S.N., Ciudad Universitaria, Coyoacán, México,
D.F. 04510, México
Fax +52(55)56162217; E-mail: lmiranda@unam.mx
Received 3 January 2012; revised 31 January 2012
COOMe
COOMe
Abstract: A practical protocol is presented for the construction of
the AB-DE rings present in (19,20)-(E)- and (19,20)-(Z)-alstoschol-
arine alkaloids from the commercially available glutamic acid 5-
methyl ester, employing only a six-step synthetic sequence. The
main features include the synthesis of the alkynylindolizinone core
and the use of Sonogashira cross-coupling and base-mediated cy-
clization to afford a 2-substituted indole without the use of protect-
ing groups.
16
A
15
19
20
B
C
D
N
N
H
H
3
N
N
E
22
O
O
H
H
1
2
Key words: alkaloids, indoles, pyrroles, cross-coupling, heterocy-
cles
Figure 1 (19,20)-(E)-Alstoscholarine (1) and (19,20)-(Z)-alsto-
scholarine (2)
In this context, we envisioned that the dihydroindolizi-
none 3, which includes a 2-indolyl substituent at C-5, a
motif present in 1 and 2, might be assembled starting from
the commercially available glutamic acid 5-methyl ester
(7), using the synthesis of indolizinones reported by Jefford
and co-workers,10 followed by transformation of the
alkyne 5 into the corresponding 2-substituted indole 3
(Scheme 1). This practical synthetic sequence might al-
low the construction of the AB-DE ring system present in
1 and 2. The implementation of this approach is reported
herein.
The monoterpene indole alkaloids form a group of com-
pounds of great structural diversity,1 which have demon-
strated important pharmacological activities.2 One of the
main sources of this type of alkaloid is the Alstonia (Apo-
cynaceae) sp. genus, which is distributed mainly in Asia
and Africa, with about 60 species reported.3 The extensive
study of the constituents of this genus has led to the isola-
tion of more than 400 compounds, many of them monot-
erpene indole alkaloids. Usually, these alkaloids have 18
or 19 carbon atoms at the core, and various biological
properties have been assigned to them, including antican-
cer and antibacterial activities, among others.1a In 2007,
Luo and co-workers isolated (19,20)-(E)- and (19,20)-(Z)-
alstoscholarine (1 and 2), novel alkaloids from the aerial
part of Alstonia scholaris, a Chinese plant used in tradi-
tional medicine against dysentery and malaria (Figure 1).4
These novel pentacyclic structures include a pyrrole- and
indole-fused system with three stereogenic centers and
two additional carbons atoms with respect to other mono-
terpene indole alkaloids (Figure 1). Recently, Zhu and co-
workers reported the first total synthesis of both diaste-
reomers using a protecting-group-free strategy, featuring
a Pictet–Spengler cyclization for the construction of the
pentacyclic core.5 Interestingly, in the structure of als-
toscholarines 1 and 2, a single carbon atom joins the pyr-
role and indole nuclei, with the pyrrole being part of an
8-oxo-5,6,7,8-tetrahydroindolizine ring system. The
indolizine and indolizinone ring systems are the main
core of a large alkaloid family widely distributed in
nature,6 and several members of this family of com-
pounds display biological activities7 against cancer8 and
against Alzheimer’s disease and Parkinson’s disease.9
Bestmann–Ohira
indole synthesis
5
homologation
5
I
O
+
N
N
H
N
NH2
O
4
3
Friedel–Crafts
acylation
5
O
O
O
O
H
OMe
HO
OMe
N
NH2
glutamic acid 5-methyl ester
6
7
Scheme 1 Retrosynthetic analysis of the AB-DE rings present in al-
stoscholarines
We started with synthesis of the pyrrole nucleus by react-
ing the commercially available glutamic acid 5-methyl
ester (7) with 2,5-dimethoxytetrahydrofuran. Previously
reported conditions10a [such as neat AcOH, H2O–AcOH–
DCE (1:2:3), or H2O–DCE (1:1) systems] proved to be in-
effective as only trace amounts of the desired pyrrole were
SYNTHESIS 2012, 44, 1051–1056
x
x.
x
x.
2
0
1
2
Advanced online publication: 15.03.2012
DOI: 10.1055/s-0031-1289745; Art ID: M00612SS
© Georg Thieme Verlag Stuttgart · New York

1052
L. A. Polindara-García, L. D. Miranda
PAPER
observed; however, the use of 2,5-dimethoxytetrahydro-
furan and a catalytic amount of acetic acid, in a 1:1 mix-
ture of water–1,2-dichloroethane (DCE) at reflux for one
hour, afforded the pyrrole 8. Then, we focused our efforts
on the reduction of the carboxylic acid to the correspond-
ing aldehyde without affecting the ester functionality. To
this end, we elected to prepare the thioester 9, and then to
reduce it to the a-amino aldehyde as in the protocol re-
ported by Fukuyama and co-workers.11 Thus, treatment of
the carboxylic acid 8 with ethyl chloroformate, triethyl-
amine and ethanethiol in dichloromethane at 0 °C for 3.5
hours afforded the thioester 9. The aldehyde 6 was ob-
tained in good yield upon treatment of the thioester 9 with
one-pot
I
NH2
1) Pd(PPh3)2Cl2 (3 mol%)
CuI (7 mol%)
Et2NH (1.5 equiv)
DMF, MW, 70 °C, 10 min
N
N
O
H
2) NaOH (10 equiv)
reflux, 1.5 h
or MW,140 °C, 30 min
N
O
5
64%
3
Scheme 3 Synthesis of the AB-DE rings of alstoscholarines
triethylsilane and 10% Pd/C in tetrahydrofuran. Despite In an ancillary study, we successfully undertook a related
our efforts to avoid racemization of the chiral center, 6 synthetic approach for the synthesis of 2-substituted in-
was always obtained as a racemic mixture. In a straight- dole 3, as depicted in Scheme 4. Treatment of the terminal
forward manner, alkyne 10 was obtained in good yield alkyne 10 and o-iodoaniline under Sonogashira cross-
using the Bestmann–Ohira reagent12 (dimethyl 1-diazo-2- coupling conditions14 afforded the o-alkynylaniline 11 in
oxopropylphosphonate). The anticipated cyclization of 10 excellent yield. Subsequent intramolecular Friedel–Crafts
into the alkynylindolizinone 5 was efficiently accom- acylation10 and N-trifluoromethylamidation15 using tri-
plished using boron tribromide in dichloromethane, under fluoroacetic anhydride furnished the o-alkynyltrifluoro-
reaction conditions described previously by Jefford and acetanilide 13 in good yield. Previously reported
co-workers10 (Scheme 2).
cyclization conditions (such as t-BuOK, NMP, r.t., 5 h,16
or InBr3, toluene, reflux, 3 h17) proved to be inefficient to
give the desired indole 3. In contrast, under the Castro in-
dole synthesis conditions,18 which use inexpensive cop-
per(I) iodide and triethylamine in ethylene glycol–N,N-
dimethylformamide at reflux for 22 hours, the indole 3
was afforded in good yield (Scheme 4). Additionally, the
structure of compound 3 was proved by X-ray
crystallography19 (Figure 2).
O
O
O
O
i
ii
HO
OMe
HO
EtS
OMe
OMe
95%
75%
N
NH2
7
8
O
O
O
O
iii
iv
H
OMe
83%
80%
N
N
O
O
ii
i
6
9
OMe
OMe
NH2
57%
97%
O
N
N
OMe
v
10
11
N
N
O
71%
10
5
iii
iv
62%
3
80%
Scheme 2 Synthesis of alkyne 5. Reagents and conditions: i) 2,5-di-
methoxytetrahydrofuran (1.1 equiv), AcOH (cat.) (0.1 equiv), H2O–
DCE (1:1), reflux, 1 h, 95%; ii) ClCOOEt (1.2 equiv), Et3N (2 equiv),
EtSH (2.2 equiv), CH2Cl2, 0 °C, 3.5 h, 75%; iii) Et3SiH (1.5 equiv),
10% Pd/C (0.05 equiv), THF, 3.5 h, 83%; iv) dimethyl 1-diazo-2-oxo-
propylphosphonate (1.3 equiv), K2CO3 (2.0 equiv), MeOH, r.t., 8 h,
80%; v) BBr3 (2 equiv), CH2Cl2, r.t., 0.5 h, 71%.
H2N
NH
CF3
O
N
N
O
O
12
13
Scheme 4 Synthesis of the 2-substituted indole 3. Reagents and
conditions: i) o-iodoaniline, Pd(PPh3)2Cl2 (3 mol%), CuI (7 mol%),
Et2NH (1.5 equiv), DMF, MW, 70 °C, 1 h, 97%; ii) BBr3 (2 equiv),
CH2Cl2, r.t., 1 h, 57%; iii) TFAA (2 equiv), THF, 0 °C, 24 h, 80%; iv)
CuI (1 equiv), Et3N (2 equiv), ethylene glycol–DMF (1:5.3), reflux,
22 h, 62%.
The corresponding 2-substituted indole 3 was prepared
using a one-pot two-step process: initial Sonogashira
cross-coupling between alkyne 5 and o-iodoaniline (4),
and subsequent intramolecular base-mediated cyclization
of the o-alkynylaniline intermediate.13 Interestingly, this
last step could be carried out under reflux or microwave
conditions (Scheme 3). Other conditions14 [such as reac-
tion with Pd(PPh3)2Cl2, CuI and Et3N in DMF for 24 h at
r.t. or under reflux] were not successful in providing the
desired indole.
In a preliminary study, we examined the introduction of
the diethyl malonate group into the indole at C-3 using di-
ethyl diazomalonate20 under reaction conditions described
in the literature.21 Surprisingly, the reaction of 3 did not
afford the expected C-3-substituted indole, but instead
Synthesis 2012, 44, 1051–1056
© Thieme Stuttgart · New York

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Synthesis of the AB-DE Rings of the Alstoscholarine Alkaloids
1053
i
N
N
N
+
H
H
H
49%
N
N
N
EtOOC
EtOOC
O
O
O
3
14
EtOOC
COOEt
15
Scheme 5 Efforts toward alkylation at the indole 3-position. Reagents and conditions: i) diethyl diazomalonate (1.5 equiv), Rh2(OAc)4 (3
mol%), CH2Cl2, reflux, 15 h, 49% (1:1 mixture).
available, and were acquired from Sigma-Aldrich and used without
further purification. DMF and CH2Cl2 were dried over CaH2, THF
over Na, and MeOH over Mg, then vacuum-distilled and stored
over molecular sieves. Dimethyl 1-diazo-2-oxopropylphos-
phonate12 and diethyl diazomalonate20 were obtained according to
the methods described in the literature.
5-Methoxy-5-oxo-2-(1H-pyrrol-1-yl)pentanoic Acid (8)
A soln of glutamic acid 5-methyl ester (7; 0.5 g, 3.1 mmol), 2,5-
dimethoxytetrahydrofuran (0.45 g, 3.4 mmol) and AcOH (0.31
mmol) in a H2O–DCE mixture (1:1, 10 mL) was refluxed for 1 h.
The reaction mixture was diluted with H2O (5 mL) and extracted
with CH2Cl2 (3 × 15 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The crude mix-
ture was separated by silica gel column chromatography (EtOAc) to
give 8 (0.623 g, 95%) as a brown oil.
Figure 2 X-ray crystal structure of compound 3
Rf = 0.2 (hexane–EtOAc, 1:1).
IR (CHCl3): 3007, 2954, 1734, 1236 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.20–2.60 (m, 4 H), 3.65 (s, 3 H),
produced the two isomers 14 and 15 in a 1:1 mixture that
resulted from alkylation of the pyrrole (Scheme 5). In 4.75 (m, 1 H), 6.17 (dd, J = 2.2, 2.2 Hz, 2 H), 6.69 (dd, J = 2.2, 2.2
principle, the pyrrole nucleus bearing an acyl substituent
would be less reactive than the indole system. The regio-
selectivity observed may be attributed to steric factors in
the vicinity of the C-3 position of the indole nucleus.21a
Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 27.6, 29.6, 51.8, 60.5, 109.0,
129.1, 172.9, 175.5.
MS (EI, 70 eV): m/z (%) = 211 (66) [M]+, 180 (51), 106 (100).
HRMS–FAB: m/z [M]+ calcd for C10H13NO4: 211.0845; found:
211.0851.
In summary, we have developed a practical protocol for
the construction of the AB-DE rings present in the als-
toscholarine alkaloids from the commercially available
glutamic acid 5-methyl ester (7), employing a six-step
synthetic sequence. The main features include the synthe-
sis of the alkynylindolizinone core 5 and the use of
Sonogashira cross-coupling/base-mediated cyclization to
afford the 2-substituted indole 3 without the use of pro-
tecting groups.
Methyl 5-(Ethylthio)-5-oxo-4-(1H-pyrrol-1-yl)pentanoate (9)
A soln of 8 (0.60 g, 2.8 mmol) in anhyd CH2Cl2 (5 mL) was cooled
to 0 °C, and then ethyl chloroformate (0.37 g, 3.4 mmol) and Et3N
(0.28 g, 2.8 mmol) were added dropwise, under an argon atmo-
sphere, and the mixture was stirred for 30 min. Then, EtSH (0.38 g,
6.22 mmol) and Et3N (0.28 g, 2.8 mmol) were added and the mix-
ture was stirred at 0 °C for 3.5 h. The resulting solution was diluted
with CH2Cl2 (5 mL) and washed consecutively with 1 M HCl (1 × 6
mL), H2O (1 × 6 mL), 1 M NaOH (1 × 6 mL), H2O (1 × 6 mL) and
brine (1 × 6 mL). The organic layer was dried (Na2SO4) and con-
centrated under reduced pressure. The crude material was separated
by silica gel column chromatography (hexane–EtOAc, 9:1) to af-
ford 9 (0.544 g, 75%) as a yellow oil.
1H and 13C NMR spectra were recorded on Varian Gemini FT 200A
(200 MHz), Varian Unity (300 MHz), Bruker Avance (300 MHz),
Bruker Avance III (400 MHz) and Varian Unity Inova (500 MHz)
spectrometers; TMS was used as the internal reference. Low-reso-
lution mass spectra were recorded on a Jeol JMS AX-505 HA in-
strument (EI, 70 eV) and HRMS on a Jeol SX-102A instrument. IR
spectra were measured on a Bruker Tensor 27 spectrophotometer.
X-ray crystal structure analysis was undertaken on a Bruker Smart
Apex diffractometer (CCD detector). The microwave-assisted reac-
tions were performed using a CEM Discover Synthesis™ Unit
(CEM Corp., Matthews, NC) with a monomodal open-vessel sys-
tem. Reaction progress was monitored by TLC on precoated Merck
silica gel Kieselgel 60 F254 plates; the spots were visualized under
UV light (254 nm). Flash chromatography was conducted on silica
gel (230–400 mesh). Melting points were determined on a Fisher–
Johns instrument. General starting materials are commercially
Rf = 0.6 (hexane–EtOAc, 8:2).
IR (CHCl3): 3562, 2953, 1734, 1680, 1277, 1171 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.31 (t, J = 7.2 Hz, 3 H), 2.15–
2.37 (m, 3 H), 2.45–2.62 (m, 1 H), 2.85 (q, J = 7.2 Hz, 2 H), 3.66 (s,
3 H), 4.71–4.79 (m, 1 H), 6.24 (dd, J = 2.2, 2.2 Hz, 2 H), 6.70 (dd,
J = 2.2, 2.2 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 14.2, 23.5, 27.1, 29.6, 51.8, 67.4,
109.3, 120.5, 172.7, 199.0.
MS (EI, 70 eV): m/z (%) = 255 (15) [M]+, 166 (80), 106 (100).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1051–1056

1054
L. A. Polindara-García, L. D. Miranda
PAPER
HRMS–FAB: m/z [M]+ calcd for C12H17NO3S: 255.0929; found:
255.0926.
13C NMR (50 MHz, CDCl3): d = 30.1, 34.4, 46.6, 74.2, 79.7, 110.8,
114.9, 125.5, 129.9, 186.1.
MS (FAB+): m/z (%) = 159 (7) [M]+, 136 (30), 91 (24), 73 (100).
HRMS–FAB: m/z [M + H]+ calcd for C10H10NO: 160.0762; found:
Methyl 5-Oxo-4-(1H-pyrrol-1-yl)pentanoate (6)
To a soln of thioester 9 (0.055 g, 0.22 mmol) and Pd/C (10% wt. dry
basis) (0.011 g, 5 mol%) in freshly distilled THF (0.21 mL), Et3SiH
(0.069 mL, 0.31 mmol) was added dropwise, under an argon atmo-
sphere, using a syringe pump (1 h total time of addition). The result-
ing solution was stirred at r.t. for 3.5 h and then filtered over a
Celite® pad and concentrated under reduced pressure. The crude
mixture was purified by silica gel column chromatography (hex-
ane–EtOAc, 8:2) to afford 6 (0.035 g, 83%) as a brown oil.
160.0757.
5-(1H-Indol-2-yl)-6,7-dihydroindolizin-8(5H)-one (3)
To a deoxygenated soln of Et2NH (0.02 mL, 0.19 mmol) in anhyd
DMF (0.4 mL), 2-iodoaniline (0.029 g, 0.13 mmol), Pd(PPh3)2Cl2
(0.0027 g, 3 mol%), CuI (0.0017 g, 7 mol%) and alkyne 5 (0.031 g,
0.20 mmol) were added. The resulting solution was heated to 70 °C
under microwave irradiation for 10 min. Then, freshly powdered
NaOH (0.052 g, 1.3 mmol) and additional DMF (0.26 mL) were
added and the mixture was then refluxed under conventional heat-
ing (1.5 h) or under microwave irradiation (140 °C, 30 min). The
mixture was diluted with H2O (5 mL) and extracted with CH2Cl2
(3 × 5 mL). The combined organic layers were washed with H2O
(15 mL) and dried (Na2SO4), and the solvent was removed under re-
duced pressure. The product was purified by silica gel column chro-
matography (hexane–EtOAc, 7:3) to afford 3 (0.021 g, 64%) as a
yellow solid.
Rf = 0.2 (hexane–EtOAc, 8:2).
IR (CHCl3): 2953, 1732, 1439, 1231, 1173 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.00–2.60 (m, 4 H), 3.66 (s, 3 H),
4.63 (m, 1 H), 6.27 (dd, J = 2.2, 2.2 Hz, 2 H), 6.66 (dd, J = 2.2, 2.2
Hz, 2 H), 9.67 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 25.0, 29.2, 51.8, 66.4, 110.0,
119.9, 172.8, 197.6.
MS (EI, 70 eV): m/z (%) = 195 (45) [M]+, 166 (50), 106 (100).
HRMS–FAB: m/z [M + H]+ calcd for C10H14NO3: 196.0974; found:
Mp 215–218 °C; Rf = 0.2 (hexane–EtOAc, 6:4).
IR (KBr): 3277, 1643, 1530, 1463, 1297, 1073 cm–1.
196.0976.
1H NMR (500 MHz, DMSO-d6): d = 2.56–2.70 (m, 4 H), 5.56 (dd,
J = 5.0, 3.2 Hz, 1 H), 6.31 (dd, J = 2.6, 1.6 Hz, 1 H), 6.46 (s, 1 H),
6.76 (s, 1 H), 7.10–7.24 (m, 2 H), 7.13 (s, 1 H), 7.33 (d, J = 4.8 Hz,
1 H), 7.59 (d, J = 4.8 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 30.7, 34.6, 53.7, 102.5, 111.0,
111.1, 114.8, 120.5, 120.7, 122.8, 124.2, 126.0, 127.9, 135.5, 186.7.
MS (EI, 70 eV): m/z (%) = 250 (100) [M]+, 193 (40), 156 (64), 94
(33).
HRMS–FAB: m/z [M]+ calcd for C16H14N2O: 250.1106; found:
250.1104.
Methyl 4-(1H-Pyrrol-1-yl)hex-5-ynoate (10)
To a soln of aldehyde 6 (0.800 g, 4.10 mmol) and K2CO3 (1.134 g,
8.20 mmol) in anhyd MeOH (6 mL), a soln of dimethyl 1-diazo-2-
oxopropylphosphonate (1.023 g, 5.33 mmol) in MeOH (1 mL) was
added under an argon atmosphere. The reaction mixture was stirred
at r.t. over an 8 h period. Then, the resulting solution was diluted
with CH2Cl2 (5 mL) and washed with 10% aq NaHCO3 (1 × 5 mL)
and H2O (1 × 5 mL). The organic layer was dried (Na2SO4) and con-
centrated under reduced pressure. The crude mixture was separated
by silica gel column chromatography (hexane–EtOAc, 8:2) to give
10 (0.628 g, 80%) as a yellow oil.
Rf = 0.5 (hexane–EtOAc, 8:2).
IR (CHCl3): 3307, 3004, 1733, 1439, 1272, 1170 cm–1.
Methyl 6-(2-Aminophenyl)-4-(1H-pyrrol-1-yl)hex-5-ynoate
(11)
To a deaerated soln of Et2NH (0.35 mL, 3.45 mmol) in anhyd DMF
(6.3 mL), 2-iodoaniline (0.504 g, 2.30 mmol), Pd(PPh3)2Cl2 (0.048
g, 3 mol%), CuI (0.030 g, 7 mol%) and alkyne 10 (0.659 g, 3.45
mmol) were added. The resulting solution was heated to 70 °C un-
der microwave irradiation for 60 min. The mixture was diluted with
H2O (10 mL) and extracted with CH2Cl2 (3 × 16 mL). The com-
bined organic layers were washed with H2O (1 × 16 mL) and dried
(Na2SO4). The crude mixture was separated by silica gel column
chromatography (hexane–EtOAc, 9:1) to afford 11 (0.637 g, 97%)
as a pale brown oil.
1H NMR (200 MHz, CDCl3): d = 2.20–2.40 (m, 4 H), 2.51 (d,
J = 2.4 Hz, 1 H), 3.67 (s, 3 H), 4.94 (m, 1 H), 6.17 (dd, J = 2.2, 2.2
Hz, 2 H), 6.80 (dd, J = 2.2, 2.2 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 29.7, 32.9, 49.9, 51.7, 74.1, 80.7,
108.7, 119.2, 172.9.
MS (EI, 70 eV): m/z (%) = 191 (35) [M]+, 101 (100).
HRMS–FAB: m/z [M]+ calcd for C11H13NO2: 191.0946; found:
191.0952.
Rf = 0.3 (hexane–EtOAc, 8:2).
5-Ethynyl-6,7-dihydroindolizin-8(5H)-one (5)
IR (CHCl3): 3496, 3006, 2954, 2224, 1732, 1615, 1490, 1290 cm–1.
To a soln of alkyne 10 (0.149 g, 0.78 mmol) in CH2Cl2 (1 mL), 1 M
BBr3 in CH2Cl2 (1.56 mL, 1.56 mmol) was added dropwise. The re-
action mixture was stirred under an argon atmosphere at r.t. for 30
min. The reaction crude was diluted with H2O (4 mL) and neutral-
ized with 10% aq NaHCO3. The resulting mixture was extracted
with CH2Cl2 (3 × 5 mL) and the combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The product
was purified by silica gel column chromatography (hexane–EtOAc,
6:4) to afford 5 (0.088 g, 71%) as a pale brown solid.
1H NMR (200 MHz, CDCl3): d = 2.20–2.62 (m, 4 H), 3.67 (s, 3 H),
5.01 (t, J = 6.4 Hz, 1 H), 6.18 (dd, J = 4.0, 2.0 Hz, 2 H), 6.66–6.74
(m, 2 H), 6.75 (t, J = 2.0 Hz, 1 H), 6.87 (t, J = 2.2 Hz, 1 H), 7.14 (t,
J = 7.2 Hz, 1 H), 7.28 (d, J = 6.6 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 29.9, 33.4, 50.9, 51.8, 82.7, 91.2,
106.6, 108.6, 109.0, 114.3, 117.8, 119.2, 130.1, 132.4, 148.0, 172.9.
MS (EI, 70 eV): m/z (%) = 282 (91) [M]+, 216 (62), 184 (94), 156
Mp 74–75 °C; Rf = 0.5 (hexane–EtOAc, 8:2).
(100), 91 (57).
IR (CHCl3): 3306, 1659, 1534, 1463, 1202 cm–1.
HRMS–FAB: m/z [M]+ calcd for C17H18N2O2: 282.1368; found:
282.1361.
1H NMR (200 MHz, CDCl3): d = 2.32–2.67 (m, 3 H), 2.55 (d,
J = 2.4 Hz, 1 H), 2.76–2.91 (m, 1 H), 5.02 (m, 1 H), 6.31 (d, J = 4.0
Hz, 1 H), 7.06 (d, J = 4.0 Hz, 1 H), 7.13 (d, J = 4.0 Hz, 1 H).
Synthesis 2012, 44, 1051–1056
© Thieme Stuttgart · New York

PAPER
Synthesis of the AB-DE Rings of the Alstoscholarine Alkaloids
1055
5-[(2-Aminophenyl)ethynyl]-6,7-dihydroindolizin-8(5H)-one
(12)
ture was purified by silica gel column chromatography (hexane–
EtOAc, 7:3) to afford 3 (0.162 g, 62%) as a yellow solid.
To a soln of o-alkynylaniline 11 (1.723 g, 6.17 mmol) in CH2Cl2 (17
mL), 1 M BBr3 in CH2Cl2 (12.3 mL, 12.3 mmol) was added drop-
wise. The reaction mixture was stirred under an argon atmosphere
at r.t. for 1 h. The crude material was diluted with H2O (10 mL) and
neutralized with 10% aq NaHCO3. The resulting mixture was ex-
tracted with CH2Cl2 (3 × 25 mL) and the combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure. The
crude mixture was separated by silica gel column chromatography
(hexane–EtOAc, 6:4) to give 12 (0.879 g, 57%) as a yellow oil.
Diethyl [5-(1H-Indol-2-yl)-8-oxo-5,6,7,8-tetrahydroindolizin-3-
yl]malonate (14) and Diethyl [5-(1H-Indol-2-yl)-8-oxo-5,6,7,8-
tetrahydroindolizin-2-yl]malonate (15)
To a refluxed soln of indole 3 (0.073 g, 0.29 mmol) and Rh2(OAc)4
(0.004 g, 3 mol%) in anhyd CH2Cl2 (2.5 mL), a soln of diethyl dia-
zomalonate (0.08 g, 0.43 mmol) in CH2Cl2 (1 mL) was slowly add-
ed. The reaction mixture was stirred under an argon atmosphere for
15 h until complete consumption of the starting material. The solu-
tion was filtered over a Celite® pad and concentrated under reduced
pressure. The crude mixture was purified by silica gel column chro-
matography (hexane–EtOAc, 8:2) to afford a 1:1 mixture of com-
pounds 14 and 15 as a brown oil (0.058 g, 49%). These compounds
were separated by preparative TLC.
Rf = 0.25 (hexane–EtOAc, 6:4).
IR (CHCl3): 3352, 2222, 1656, 1620, 1459, 1307, 749 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.45–2.95 (m, 4 H), 5.28 (dd,
J = 5.2, 2.8 Hz, 1 H), 6.32 (dd, J = 2.6, 1.6 Hz, 1 H), 6.69 (s, 1 H),
6.71 (s, 1 H), 7.06–7.29 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 30.7, 34.8, 47.7, 82.9, 90.2, 110.8,
114.5, 115.0, 118.1, 121.4, 125.5, 130.1, 130.4, 132.5, 148.0, 186.1.
MS (EI, 70 eV): m/z (%) = 250 (100) [M]+, 195 (28), 130 (26), 94
(79).
Compound 14
Brown oil; Rf = 0.3 (hexane–EtOAc, 8:2).
IR (CHCl3): 3545, 3447, 3292, 2930, 1735, 1659, 1539, 1305, 1185
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.09 (t, J = 7.2 Hz, 3 H), 1.15 (t,
J = 7.2 Hz, 3 H), 2.53–2.62 (m, 4 H), 3.85–4.10 (m, 4 H), 4.67 (s, 1
H), 5.86 (br s, 1 H), 6.09 (s, 1 H), 6.52 (d, J = 4.4 Hz, 1 H), 7.08 (t,
J = 8.0 Hz, 1 H), 7.14 (t, J = 8.0 Hz, 1 H), 7.18 (d, J = 4.4 Hz, 1 H),
7.29 (d, J = 8.2 Hz, 1 H), 7.49 (d, J = 8.2 Hz, 1 H), 7.96 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.7, 13.7, 29.9, 32.0, 50.4, 50.9,
62.3, 62.5, 101.6, 111.0, 112.9, 114.8, 120.3, 120.3, 122.4, 128.1,
129.2, 131.7, 135.4, 136.1, 166.2, 166.3, 186.8.
MS (EI, 70 eV): m/z (%) = 408 (100) [M]+, 362 (25), 261 (54), 252
(98).
HRMS–FAB: m/z [M]+ calcd for C23H24N2O5: 408.1685; found:
408.1675.
HRMS–FAB: m/z [M]+ calcd for C16H14N2O: 250.1106; found:
250.1111.
2,2,2-Trifluoro-N-{2-[(8-oxo-5,6,7,8-tetrahydroindolizin-5-
yl)ethynyl]phenyl}acetamide (13)
A soln of o-alkynylaniline 12 (0.879 g, 3.51 mmol) in anhyd THF
(7.5 mL) was cooled to 0 °C and TFAA (0.97 mL, 7.02 mmol) was
added dropwise, over 0.5 h. After a stirring period of 24 h at 0 °C,
the reaction mixture was diluted with sat. aq NaHCO3 (10 mL) and
extracted with EtOAc (3 × 10 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure. The
crude mixture was purified by silica gel column chromatography
(hexane–EtOAc, 9:1) to afford 13 as the main product (0.969 g,
80%) as an orange oil.
Compound 15
Brown oil; Rf = 0.3 (hexane–EtOAc, 8:2).
Rf = 0.2 (hexane–EtOAc, 6:4).
IR (CHCl3): 3389, 1742, 1660, 1536, 1460, 1401, 1289, 1152 cm–1.
IR (CHCl3): 3502, 3458, 2931, 1730, 1660, 1484, 1399, 1303, 1156
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.11–1.20 (m, 6 H), 2.50–2.61 (m,
4 H), 3.85–4.10 (m, 4 H), 4.46 (s, 1 H), 5.40 (m, 1 H), 6.43 (s, 1 H),
6.78 (d, J = 4.0 Hz, 1 H), 7.08–7.30 (m, 4 H), 7.57 (d, J = 8.0 Hz, 1
H), 8.72 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.9, 14.0, 30.3, 34.8, 50.8, 53.8,
61.8, 61.8, 102.6, 111.3, 114.7, 117.3, 120.2, 120.6, 122.6, 125.6,
127.7, 130.6, 135.1, 136.5, 168.0, 168.0, 188.8.
MS (EI, 70 eV): m/z (%) = 408 (100) [M]+, 362 (25), 261 (54), 252
(98).
HRMS–FAB: m/z [M]+ calcd for C23H24N2O5: 408.1685; found:
408.1678.
1H NMR (300 MHz, CDCl3): d = 2.48–2.91 (m, 4 H), 5.33 (m, 1 H),
6.35 (dd, J = 4.2, 2.7 Hz, 1 H), 7.05–7.24 (m, 3 H), 7.39–7.49 (m, 2
H), 8.27 (d, J = 8.4 Hz, 1 H), 8.51 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 30.1, 34.2, 47.1, 79.9, 93.5, 111.3,
112.0, 115.2, 120.2, 125.2, 125.7, 130.0, 130.7, 132.3, 136.3, 154.1,
154.6, 185.7.
MS (EI, 70 eV): m/z (%) = 346 (100) [M]+, 277 (86), 134 (16), 94
(68).
HRMS–FAB: m/z [M]+ calcd for C18H13F3N2O2: 346.3032; found:
346.3121.
2-Substituted Indole 3 from o-Alkynyltrifluoroacetanilide 13
(Scheme 4)
A deaerated soln of acetanilide 13 (0.360 g, 1.04 mmol), CuI (0.198
g, 1.04 mmol) and Et3N (0.289 mL, 2.08 mmol) in ethylene glycol–
DMF (1:5.3, 34 mL) was refluxed under an argon atmosphere for 22
h until complete consumption of the starting material. Then, the re-
action mixture was diluted with H2O (35 mL) and extracted with
EtOAc (3 × 35 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The crude mix-
Acknowledgment
Financial support from the DGAPA, UNAM is gratefully acknow-
ledged. We also thank R. Patiño, A. Peña, E. Huerta, E. García-
Rios, L. Velasco and J. Pérez for technical support, and A. Toscano
for the X-ray crystallography. L.A.P.G. is a CONACYT (223857)
graduate scholarship holder.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1051–1056

1056
L. A. Polindara-García, L. D. Miranda
PAPER
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