Synthesis of the tetracyclic core skeleton of the lundurines by a gold-catalyzed cyclization

Article abstract of DOI:10.1016/j.tet.2009.08.067

The 1H-azocino[5,4-b]indole skeleton of the lundurines has been prepared by the 8-endo-dig cyclization of an alkynylindole using AuCl₃ or other gold complexes as catalysts.

Full text of DOI:10.1016/j.tet.2009.08.067

Tetrahedron 65 (2009) 9015–9020
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of the tetracyclic core skeleton of the lundurines by
a gold-catalyzed cyclization
*
Catalina Ferrer, Ana Escribano-Cuesta, Antonio M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ), Av. Pa¨ısos Catalans, 16, 43007 Tarragona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 June 2009
Received in revised form 14 August 2009
Accepted 27 August 2009
Available online 31 August 2009
The 1H-azocino[5,4-b]indole skeleton of the lundurines has been prepared by the 8-endo-dig cyclization
of an alkynylindole using AuCl3 or other gold complexes as catalysts.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
No synthesis of the lundurines has been reported, although the
group of Pearson had completed the synthesis of lapidilectine B
Plants of the genus Kopsia, growing in South and Southeast Asia,
are a rich source of novel alkaloids with intriguing carbon skeletons
that display a wide variety of biological activities.1,2 Prominent
examples are the lundurines A–D (1–4) (Fig. 1),3 which are char-
acterized by a cyclopropyl moiety embedded within a hexacyclic
ring system that includes an 1H-azocino[5,4-b]indole ring unit.
Lundurines B (2) and D (4) display significant cytotoxicity in vitro
toward B16 melanoma cells. Structurally related are the alkaloids
lapidilectine B (5) and isolapidilectine (6).4
(5).1 As a first step toward the synthesis of 1–4 we decided to study
the potential of the gold-catalyzed cyclization of indoles with
alkynes5–8 for the ready construction of the 1H-azocino[5,4-b]indole
skeleton of these alkaloids. Here we report the synthesis of the
tetracyclic ring compound 8 by the 8-endo-dig cyclization of 7 with
AuCl3 or other gold catalysts (Scheme 1).
O
N
O
N
O
AuCl3
N
N
N
H
N
H
MeO
MeO
7
8
N
N
CO2Me
Scheme 1. Gold(III)-catalyzed cyclization of alkynylindole 7 to give azocino[5,4-b]-
indole derivative 8.
CO2Me
1
2
N
N
2. Results and discussion
MeO
MeO
MeO
N
N
2.1. Synthesis of alkynylindole 7
CO2Me
CO2Me
3
4
For the synthesis of a suitable enantiomerically pure precursor
for the synthesis of the lundurines, we first tried to follow the
procedure described by Germanas and co-workers for the enan-
tioselective alkylation of proline.9,10 This procedure was based on
a method originally reported by Seebach,11 forms more stable
oxazolidinone 9 replacing pivalaldehyde by chloral in the conden-
sation with proline (Scheme 2). Alkylation of 9 using LDA and
commercially available ((2-bromoethoxy)methyl)benzene led only
to decomposition products. However, alkylation of the lithium
enolate of 9 with ((2-iodoethoxy)methyl)benzene gave the desired
derivative 10, albeit in only 33% yield, while 60% of the alkylating
MeO2C
N
O
N
O
N
N
MeO2C
CO2Me
6
MeO2C
5
Figure 1. Lundurines A–D (1–4), lapidilectine B (5), and isolapidilectine (6).
* Corresponding author.
E-mail address: aechavarren@iciq.es (A. M. Echavarren).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.067

9016
C. Ferrer et al. / Tetrahedron 65 (2009) 9015–9020
OBn
O
a related substrate. Thus, methyl 2-(1H-indol-3-yl)acetate (15a)
H
O
was protected as a Boc-carbamate using (Boc)2O to give known
16a,15 which was reduced with DIBAL to give aldehyde 17 (Scheme 4).
Reductive amination of aldehyde 17 with dimethyl (S)-glutamate in
the presence of sodium triacetoxyborohydride gave lactam 18 in
moderate yield. Alternatively, aldehyde 17 could also be prepared
from nitrile 16b.16
OBn
LDA, 3 h
COOH
O
I
Chloral
N
NH
N
CH3CN, 2.5 h
O
Cl3C
Cl3C
9 (40%)
10 (33%)
MeOH,
CH3COCl,
R
R
Cl3C
O
Δ
(Boc)2O,
DMAP, Et3N
DIBAL
O
OBn
N
N
CH2Cl2, rt
CH2Cl2, -78 °C
N
H
N
N
H
COOMe
11 (54%)
Scheme 2. Synthesis of alkylated proline derivative 11.
Boc
O
O
CCl3
15a: R = CO2Me
15b: R = CN
16a: R = CO2Me (87%)
12
16b: R = CN (96%)
MeOOC
O
H
N
O
NH2
HCl
COOMe
agent was recovered. Cleavage of the N,O-acetal function was per-
formed under the acidic conditions described by Germanas9 to give
11 in 54% yield. Interestingly, 10 was accompanied by small
amounts of dimeric compound 12, whose structure was confirmed
by X-ray crystallography (Fig. 2). A similar dimeric structure was
described by Johnson and co-workers in the alkylation of Seebach
oxazolidinone with dibromoethane.12
MeOOC
NaBH(OAc)3, Et3N,
CH2Cl2, 8 h, rt
N
Boc
17
N
Boc
18 (23-39%,
2 steps)
HO
N
O
NaBH4, CaCl2
DMP
CH2Cl2 rt, 10 min
THF/Et2O, 1-2 days
N
Boc
19
OHC
O
N
O
N
O
PO(OMe)2
N2
K2CO3, MeOH, 9 h
N
N
Boc
20
Boc
21
O
N
TFA
CH2Cl2, rt, 10 min
Figure 2. X-ray crystal structure of 12.
N
H
7 (14-23%,
Alkylation of proline derivative 11 with 3-(2-bromoethyl)-1H-
indole under the conditions developed by Rapoport afforded 14 in
23% yield (Scheme 3).13 Although it was described that NaHCO3 led
to a more efficient alkylation,13 in our case, using this base only
unchanged starting material was recovered. Using N-Boc protected
indole derivative14 for the alkylation was also unsuccessful. Simi-
larly ineffective was the alkylation of N-(trimethylsilyl)pyro-
glutamate with 3-(2-bromoethyl)-1H-indole.
4 steps)
Scheme 4. Synthesis of alkynylindole 7.
Ester 18 was reduced to alcohol 19 in 90% yield using NaBH4 and
CaCl2 (Scheme 4). Routinely this alcohol was submitted to the
17
subsequent transformation without purification. When lithium
aluminum hydride was used, competitive reduction of the lactam
was also observed, even at low temperature. Dess–Martin oxidation
of alcohol 19 gave aldehyde 20, which was used in the next step
without further purification. Aldehyde 20 reacted with the Best-
mann–Ohira reagent18 to give 21, from which alkynyl derivative 7
was obtained by Boc cleavage after brief exposure to trifluoroacetic
acid. This four-step procedure can be routinely carried out without
purification of any intermediate in 14–23% overall yield. Alterna-
tively, alkyne 21 could be prepared from aldehyde 20 by the Corey–
Fuchs procedure,19 although the overall yield was lower.
Since most of the steps in the synthetic route toward 14 were
low yielding, we sought alternative ways for the preparation of
OBn
OBn
COOMe
N
N
H
COOMe
11
NaH
+
DMF, 16 h, rt
Br
N
H
14 (23%)
2.2. Gold-catalyzed cyclization of alkynylindole 7
N
H
13
In our previous work, we have shown that protection of the
basic amine function as a sulfonamide was required for the success
Scheme 3. Alkylation of proline 11 with 3-(2-bromoethyl)-1H-indole 13.

C. Ferrer et al. / Tetrahedron 65 (2009) 9015–9020
9017
of the gold-catalyzed cyclization.5 Thus, not surprisingly, treatment
of N-benzyl-N-propargyltryptamine (22) with AuCl3 or Au(III)
complex 2320,21 (5 mol %) in CH2Cl2 solution failed to give cyclized
compound 24 or 25 (Scheme 5), presumably a result of the
coordination of the amine to Au(III). In situ protonation of the
amine 22 using trifluoroacetic acid prior to the addition of
the catalyst was not effective.
entry 4). Interestingly, cationic Au(I) complex 2823 favored the
8-exo-dig cyclization leading to 8 as the major product, whereas
related complex 2924 with a bulkier phosphine favored the forma-
tion of 27 (Table 1, compare entries 5 and 6). Similar selectivity was
observed using cationic catalysts 30 and 31,25 although lower re-
activity was observed using complex 30 with a more donating NHC
ligand. AuCl was also a catalyst for the formation of 8 (Table 1, entry 9).
A low conversion was achieved with cationic platinacycle 3226
(Table 1, entry 10). Low yields of 8 were obtained using Ag(I) salts
such as AgSbF6 or AgOTf27 whereas, GaCl3, InCl3, and Bro¨nsted acid
TfOH were not effective in this cyclization (Table 1, entries 11–15).
Bn
N
AuCl3
or
O
N
H
tBu
tBu
SbF6
SbF6
P
Au NCMe
N
N
Mes
O
24
Mes
N
23
Au
Bn
Au
NCAr
[Au(PPh3)(NCMe)]SbF6
and / or
N
Cl
Cl
Bn
N
28
29
30: Ar = 2,4,6-(MeO)3C6H2
N
H
CH2Cl2
-
tBu
SbF6
SbF6
O P Au NCPh
22
NCMe
NCMe
N
H
tBu
Pt
P
3
25
31
32
Scheme 5. Unsuccessful cyclization of N-benzyl-N-propargyltryptamine 22.
The fact that very similar results were obtained using AuCl3 and
AuCl (compare entries 1 and 9 in Table 1) suggests that Au(III)
might be reduced to Au(I) under the reaction conditions. However,
factors that control the exo versus endo selectivity in this cyclization
are not easy to rationalize since electronically similar Au(I) com-
plexes 28 and 29 give different results, whereas almost identical
regioselectivities were obtained using complexes 29–31 with very
different ligands.
On the other hand, cyclization of substrate 7 using 5 mol % AuCl3
as catalyst in CH2Cl2 at room temperature afforded the desired
indoloazocine 8 in 55% isolated yield (Table 1, entry 1). Traces of 26,
the product of Markovnikov gold-catalyzed hydrochlorination of
the alkyne were also isolated in this reaction.22 Vinyl chloride 26
was only observed in the presence of AuCl3. The cyclization was less
efficient with Au(III) complex 23 or HAuCl4 as catalysts (Table 1,
entries 2 and 3), whereas NaAuCl4 salt was not effective (Table 1,
Table 1
3. Conclusion
Gold-catalyzed cyclization of substrate 7a
O
N
The 1H-azocino[5,4-b]indole skeleton of the lundurines can be
readily obtained by using AuCl3 or other gold complexes as catalysts
by the 8-endo-dig cyclization of an alkynylindole substrate. Prog-
ress toward the synthesis of 1–4 using this type of gold-catalyzed
cyclization is in progress.
O
N
8
N
[M]
H
O
+
O
4. Experimental
N
H
Cl
N
N
7
4.1. General methods
N
H
N
H
All preparations and manipulations were carried out under an
oxygen-free nitrogen atmosphere using conventional Schlenk
techniques. NMR experiments were run in a Bruker Avance 400
Ultrashield spectrometer. HPLC chromatography was performed on
an Agilent Technologies Series 1100 chromatograph with UV de-
tector. Mass spectra were recorded on Waters LCT Premier (ESI) and
Waters GCT (EI, CI) spectrometers. Elemental analyses were per-
formed on a LECO CHNS 932 micro-analyzer at the Universidad
Complutense de Madrid. Melting points were determined using
a Bu¨chi melting point apparatus. Optical rotations were recorded
on a P-1030 polarimeter from Jasco at the sodium D line.
26
27
Entry
[M]
Conversion (%)
Products (ratio)
Yield (%)
1
2
3
4
5
6
7
8
AuCl3
23
HAuCl4
NaAuCl4
28
29
30
31
AuCl
32
AgSbF6
AgOTf
GaCl3
InCl3
TfOH
100
66
100
100
100
80
54
100
82
8þ26 (ca. 95:5)
55
34b
30b
d
8
8
dc
8þ27 (78:22)
d
8þ27 (27:73)
d
8þ27 (27:73)
d
8þ27 (13:87)
d
9
8
8
8
8
d
de
d
42b
d
10
11
12
13
14
15
13
4.1.1. (R)-Methyl
2-(2-(benzyloxy)ethyl)pyrrolidine-2-carboxylate
100
29
17
d
(11). An ice cold solution of LDA (0.86 mL diisopropylamine/
2.45 mL n-BuLi, 6.13 mmol) was added dropwise to a solution of 99
(1.00 g, 4.09 mmol) in THF (20 mL) at ꢀ78 ꢁC. After 30 min, ((2-
iodoethoxy)methyl)benzene (1.18 g, 4.5 mmol) was added and it
was stirred at this temperature for 3 h. Then, the reaction was
quenched with MeOH and it was allowed to warm up to room
temperature. The resulting mixture was portioned between chlo-
roform and water, the organic layer dried over MgSO4, and
dd
dd
dd
d
d
d
a
Reactions carried out with 5 mol % [M] in CH2Cl2 at room temperature for 24 h.
Determined by NMR using 1,3,5-trimethoxybenzene as standard.
Complex mixture.
b
c
d
e
Conversion <5%.
Traces of 8 were observed.

9018
C. Ferrer et al. / Tetrahedron 65 (2009) 9015–9020
evaporated under reduced pressure. The residue was purified by
1H), 7.52 (d, J¼7.7 Hz, 1H), 7.38 (t, J¼7.8 Hz, 1H), 7.29 (t, J¼7.2 Hz,
1H), 3.77 (d, J¼1.63 Hz, 2H), 1.67 (s, 9H); 13C NMR (100 MHz, CDCl3,
silica gel chromatography (10:1, hexane/EtOAc) to give 10 (510 mg,
33%) as an oil. Compound 10: 1H NMR (400 MHz, CDCl3)
d
7.36–7.27
DEPT) d 149.3 (C), 135.58 (C), 128.5 (C), 125.2 (CH), 124.3 (CH), 123.0
(m, 5H), 4.96 (s, 1H), 4.49 (s, 2H), 3.81–3.75 (m, 1H), 3.72–3.67 (m,
1H), 3.43–3.39 (m, 1H), 3.21 (dd, J¼8.6, 4.4 Hz, 2H), 2.30–2.16
(m, 3H), 2.11 (dt, J¼12.3, 6.2 Hz,1H),1.94–1.86 (m,1H),1.71–1.61 (m,
1H). (3R,30R,7aR)-3,30-Bis(trichloromethyl) tetrahydro-1H,10H-
7a,70a-bipyrrolo[1,2-c]oxazole-1,10(3H,30H,5H,50H)-dione (12) was
also formed as formed in variable amounts as a secondary product,
which could not be separated by chromatography, although a single
crystal could be obtained from an EtOAc solution, which allowed for
its structural characterization. The crystal structure of 12 has been
deposited at the Cambridge Crystallographic Data Centre (de-
position number CCDC 743970). Compound 12 (from a 1:5 mixture
(CH), 118.2 (CH), 117.1 (C), 115.6 (CH), 109.5 (C), 84.3 (C), 28.2 (CH3,
3C), 14.3 (CH2). HRMS-ESI m/z calcd for C15H16N2O2Na: 279.1109;
found: 279.111 [MþþNa].
4.1.4. tert-Butyl 3-(2-oxoethyl)-1H-indole-1-carboxylate (17).
4.1.4.1. Procedure A. To a solution of tert-butyl 3-(2-methoxy-2-
oxoethyl)-1H-indole-1-carboxylate (16a) (7.10 g, 24.54 mmol) in
CH2Cl2 (300 mL) at ꢀ78 ꢁC was added DIBAL (1 M solution in CH2Cl2,
49.1 mL, 49.10 mmol). The solution was allowed to stir for 1.5 h at
this temperature and then it was quenched with MeOH at ꢀ78 ꢁC
and warmed up to room temperature for 2 h. The mixture was di-
luted with EtOAc and washed with a Na/K tartrate saturated solu-
tion, the organic layer dried over MgSO4, and the solvent evaporated
under reduced pressure. The residue was purified by chromato-
graphy (10:1, hexane/EtOAc) to give 17 as a yellow oil (2.20 g, 37%).
with 10): 1H NMR (400 MHz, CDCl3)
d
4.86 (s, 2H), 2.40 (dd, J¼13.7,
10.6 Hz, 2H), 2.30–2.16 (m, 2H), 2.02–1.97 (m, 2H), 1.94–1.86 (m,
2H), 1.79 (dd, J¼13.3, 10.1 Hz, 2H), 1.71–1.61 (m, 2H).
To a solution of 10 (1.42 g, 3.75 mmol) in MeOH (16 mL) was
added a solution of acetyl chloride (0.60 mL, 8.36 mmol) in MeOH
(8 mL). The mixture was heated at reflux for 12 h. Then, the solvent
was evaporated and the residue was dissolved in CH2Cl2 and
washed with water. The aqueous phase was made basic and then it
was extracted again with CH2Cl2. The residue was purified by silica
gel chromatography eluting with EtOAc to give 11 as a colorless oil
4.1.4.2. ProcedureB. To a solution of tert-butyl 3-(cyanomethyl)-
1H-indole-1-carboxylate (16b) (1.96 g, 7.64 mmol) in CH2Cl2
(76 mL) at ꢀ78 ꢁC was added DIBAL (1 M solution in toluene,
11.46 mL, 11.46 mmol) during 30 min. The solution was allowed to
stir for 30 min at this temperature and then it was quenched with
EtOH (1.5 mL) at ꢀ78 ꢁC and warmed up to room temperature. The
reaction was treated with satd NH4Cl solution (30 mL) and 3 M
H2SO4 solution (100 mL). The aqueous phase was washed with
CH2Cl2, then the organic layer dried over MgSO4, and the solvent
evaporated under reduced pressure to afford aldehyde 17 as a yel-
low oil, which was used immediately without further purification.
(540 mg, 54%). 1H NMR (400 MHz, CDCl3)
d 7.34–7.26 (m, 5H), 4.42
(s, 2H), 3.60 (s, 3H), 3.53 (dd, J¼6.8, 5.3 Hz, 2H), 3.04–2.93 (m, 2H),
2.27 (dd, J¼13.9, 6.9 Hz, 1H), 2.17–2.10 (m, 1H), 1.84–1.63 (m, 5H);
13C NMR (100 MHz, CDCl3, DEPT)
d 177.6 (C), 138.3 (C), 128.3 (CH,
2C), 127.8 (CH, 2C), 127.5 (CH), 73.2 (CH2), 67.4 (C), 67.2 (CH2), 52.1
(CH3), 46.6 (CH2), 39.6 (CH2), 36.8 (CH2), 24.9 (CH2). Anal. Calcd for
C15H21NO3$1/2H2O: C, 66.15; H, 8.14; N, 5.14. Found: C, 66.59; H,
7.87; N, 5.74. HRMS-ESI m/z calcd for C15H22NO3: 264.1600; found:
264.1600 [MþþH].
1H NMR (400 MHz, CDCl3)
d
9.78 (t, J¼2.3 Hz, 1H), 8.16 (br d,
J¼8.6 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J¼7.8 Hz, 1H), 7.35 (td, J¼7.2,
1.2 Hz, 1H), 7.26 (td, J¼7.6, 1.0 Hz, 1H), 3.76 (dd, J¼2.1, 1.0 Hz, 2H),
1.67 (s, 9H); 13C NMR (100 MHz, CDCl3, DEPT)
d 198.5 (CH), 149.5
4.1.2. Methyl 1-(2-(1H-indol-3-yl)acetyl)-2-(2-(benzyloxy)ethyl)pyrro-
lidine-2-carboxylate (14). To a solution of NaH (60% in mineral oil,
8 mg, 0.79 mmol) in DMF (1 mL) was added 11 (50 mg, 0.79 mmol) at
0 ꢁC, the mixture was allowed to stir for 15 min. Then, 3-(2-bro-
moethyl)-1H-indole (13) (43 mg, 0.79 mmol) was added and the
reaction was stirred at room temperature for 16 h. The mixture was
diluted with EtOAc and washed with water. The organic layer was
dried with Na2SO4, filtered, and evaporated. The residue was purified
by chromatography (4:1, hexane/EtOAc) to give 14 as a colorless oil
(C), 135.5 (C), 130.1 (C), 124.8 (CH), 124.8 (CH), 122.8 (CH), 118.7
(CH), 115.4 (CH), 110.9 (C), 83.9 (C), 40.0 (CH2), 28.2 (CH3, 3C).
HRMS-ESI m/z calcd for C16H21NO4Na: 314.1368; found: 314.1369
[MþþMeOHþNa].
4.1.5. (S)-tert-Butyl 3-(2-(2-(methoxycarbonyl)-5-oxopyrrolidin-1-yl)-
ethyl)-1H-indole-1-carboxylate (18). To
(3.82 mmol) and -glutamic acid methyl ester hydrochloride
(889 mg, 4.20 mmol) in CH2Cl2 (39 mL), was added Et3N (0.798 mL,
5.73 mmol). After 15 min triacetoxyborohydride (1.21 g,
a solution of crude 17
L
(18 mg, 23%). 1H NMR (400 MHz, CDCl3)
d 7.89 (br s, 1H), 7.57 (d,
J¼7.7 Hz, 1H), 7.35–7.27 (m, 6H), 7.17 (t, J¼7.4 Hz, 1H), 7.10 (t, J¼7.6 Hz,
1H), 6.98 (d, J¼2.0 Hz, 1H), 4.39 (s, 2H), 3.59 (s, 3H), 3.50 (ddd, J¼9.4,
8.2, 6.3 Hz, 1H), 3.43 (ddd, J¼9.3, 7.9, 5.6 Hz, 1H), 3.32–3.27 (m, 1H),
3.03–2.97 (m, 1H), 2.93 (dd, J¼9.7, 4.2 Hz, 1H), 2.86–2.79 (m, 1H),
2.71–2.66 (m, 1H), 2.60–2.55 (m, 1H), 2.25 (ddd, J¼14.0, 7.7, 6.4 Hz,
1H), 2.19–2.14 (m, 1H), 1.94–1.77 (m, 4H); 13C NMR (100 MHz, CDCl3,
5.73 mmol) was added. The mixture was stirred at room temper-
ature for 12 h and after extractive workup (EtOAc/NaHCO3 satu-
rated solution) it was purified by chromatography (1:1–1:2,
hexane/EtOAc) to give 18 as a yellow oil (1.14 g, 39% over 2 steps):
[a
]
ꢀ6.61 (c 1.16, CHCl3). 1H NMR (400 MHz, CDCl3)
d 8.20 (br d,
D
J¼7.5 Hz, 1H), 7.54 (d, J¼7.7 Hz, 1H), 7.41 (s, 1H), 7.31 (td, J¼7.4,
1.2 Hz, 1H), 7.24 (td, J¼7.3, 1.0 Hz, 1H), 4.08 (dd, J¼9.0, 3.1 Hz, 1H),
4.00 (ddd, J¼13.9, 9.0, 5.6 Hz, 1H), 3.73 (s, 3H), 3.24 (ddd, J¼13.9,
8.6, 6.7 Hz, 1H), 3.00 (dddd, J¼14.5, 9.0, 6.6, 0.8 Hz, 1H), 2.87 (dddd,
J¼14.5, 8.7, 5.8, 0.9 Hz, 1H), 2.51 (ddd, J¼16.8, 9.3, 9.2 Hz, 1H), 2.36
(ddd, J¼16.7, 9.6, 3.8 Hz, 1H), 2.26–2.16 (m, 1H), 2.08–2.01 (m, 1H),
DEPT)
d 174.5 (C), 138.6 (C), 136.2 (C), 128.3 (CH, 2C), 127.6 (C), 127.6
(CH, 2C), 127.4 (CH), 121.9 (CH), 121.5 (CH), 119.2 (CH), 118.9 (CH), 111.0
(CH), 103.5 (C), 72.9 (CH2), 69.4 (C), 67.0 (CH2), 51.3 (CH2), 51.0 (CH3),
50.1 (CH2), 34.4 (CH2), 34.0 (CH2), 25.5 (CH2), 22.0 (CH2). HRMS-ESI m/z
calcd for C25H31N2O3: 407.2335; found: 407.2316 [MþþH].
1.66 (s, 9H); 13C NMR (100 MHz, CDCl3, DEPT)
d 175.3 (C), 172.5 (C),
4.1.3. tert-Butyl 3-(cyanomethyl)-1H-indole-1-carboxylate (16b). To
a mixture of 3-indoleacetonitrile (15b) (11.68 g, 74.80 mmol),
Boc2O (17.14 g, 79.00 mmol), and DMAP (457 mg, 3.74 mmol) in
CH2Cl2 (250 mL) was added Et3N (20.85 mL, 3.74 mmol). The
reaction was allowed to stir at room temperature for 2 h then it was
diluted with CH2Cl2. The organic phase was washed with 10% HCl
solution, brine and dried over Na2SO4, the solvent was removed
under reduced pressure. The residue was purified by chromatog-
raphy (10:1, hexane/EtOAc) to give 16b16 as a white solid (18.39 g,
149.7 (C), 135.5 (C), 130.3 (C), 124.5 (CH), 123.0 (CH), 122.5 (CH),
118.8 (CH), 117.5 (C), 115.3 (CH), 83.6 (C), 60.2 (CH), 52.5 (CH3), 42.1
(CH2), 29.5 (CH2), 28.2 (CH3, 3C), 23.1 (CH2, 2C). HRMS-ESI m/z calcd
for C21H26N2O5Na: 409.1739; found: 409.1741 [MþþNa].
4.1.6. (S)-tert-Butyl 3-(2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)-
ethyl)-1H-indole-1-carboxylate (19). To a solution of 18 (1.10 g,
2.83 mmol) and calcium chloride (649 mg, 5.67 mmol) in a mixture
of THF (38 mL) and Et2O (28 mL) was added sodium borohydride
(447 mg, 11.34 mmol) at 0 ꢁC. The reaction was allowed to warm up
96%). 1H NMR (400 MHz, CDCl3)
d
8.17 (br d, J¼8,1 Hz, 1H), 7.64 (s,

C. Ferrer et al. / Tetrahedron 65 (2009) 9015–9020
9019
to room temperature and it was left to stir for 1 day. Then the
equivalents of water necessary to react with the NaBH4 were added
and also MgSO4$7H2O, the mixture was stirred until the evolution
of gas ceased and then it was filtered through a path of Celite. After
4.1.8.2. Procedure B. To a stirring solution of 20 (765 mg,
2.15 mmol) and dimethyldiazo-2-oxopropylphosphonate (495 mg,
2.580 mmol) in MeOH (12 mL) was added potassium carbonate
(614 mg, 4.44 mmol). The resulting solution was allowed to stir for
12 h and then it was quenched with water (0.34 mL) and extracted
with CH2Cl2. The combined organic phases were washed with satd
NaHCO3 solution and brine. The organic layer was dried over
Na2SO4, filtered, and concentrated to afford the alkyne 21 as
a brown oil, which was used without further purification (25 mg,
evaporation of the solvent, 19 was obtained as a colorless oil: [
a]
D
13.40 (c 1.03, CHCl3). 1H NMR (400 MHz, CDCl3)
d
8.12 (br d,
J¼7.8 Hz, 1H), 7.58 (d, J¼7.5 Hz, 1H), 7.42 (s, 1H), 7.31 (td, J¼7.8,
1.1 Hz, 1H), 7.23 (td, J¼7.2, 0.9 Hz, 1H), 3.91 (ddd, J¼13.8, 9.2, 5.8 Hz,
1H), 3.77–3.73 (m, 1H), 3.62–3.55 (m, 2H), 3.36 (ddd, J¼13.8, 9.0,
6.2 Hz, 1H), 3.03 (ddd, J¼14.3, 9.1, 6.1 Hz, 1H), 2.90 (ddd, J¼14.3, 8.9,
5.9 Hz,1H), 2.45 (ddd, J¼17.0, 9.9, 7.3 Hz,1H), 2.33 (ddd, J¼17.0, 10.1,
5.3 Hz, 1H), 2.08–1.98 (m, 1H), 1.91–1.83 (m, 1H), 1.66 (s, 9H), 1.63
36%). 1H NMR (400 MHz, CDCl3)
d
8.13 (br d, J¼8.0 Hz, 1H), 7.59 (d,
J¼7.5 Hz, 1H), 7.44 (s, 1H), 7.31 (td, J¼7.6, 1.3 Hz, 1H), 7.24 (td, J¼7.2,
1.0 Hz, 1H), 4.25 (ddd, J¼7.4, 5.1, 2.2 Hz, 1H), 3.93 (ddd, J¼13.8, 9.3,
5.9 Hz, 1H), 3.46 (ddd, J¼13.6, 9.1, 6.2 Hz, 1H), 3.06–2.90 (m, 2H),
2.56–2.48 (m, 1H), 2.41 (d, J¼2.2 Hz, 1H), 2.40–2.24 (m, 2H), 2.12–
(br s, 1H); 13C NMR (100 MHz, CDCl3, DEPT)
d 176.0 (C), 149.7 (C),
135.5 (C), 130.4 (C), 124.5 (CH), 123.1 (CH), 122.5 (CH), 118.9 (CH),
117.7 (C), 115.3 (CH), 83.6 (C), 63.5 (CH2), 59.6 (CH), 41.3 (CH2), 30.4
(CH2), 28.2 (CH3, 3C), 23.3 (CH2), 21.3 (CH2). HRMS-ESI m/z calcd for
C20H26N2O4Na: 381.1790; found: 381.1773 [MþþNa].
2.04 (m, 1H), 1.66 (s, 9H); 13C NMR (100 MHz, CDCl3, DEPT)
d 174.2
(C), 149.7 (C), 135.5 (C), 130.4 (C), 124.5 (CH), 123.1 (CH), 122.5 (CH),
118.9 (CH), 117.5 (C), 115.3 (CH), 83.5 (C), 81.6 (CH), 73.5 (C), 49.5
(CH), 41.1 (CH2), 29.9 (CH2), 28.2 (CH3, 3C), 26.3 (CH2), 23.1 (CH2).
HRMS-ESI m/z calcd for C21H24N2O3Na: 375.1685; found: 375.1686
[MþþNa].
4.1.7. (S)-tert-Butyl 3-(2-(2-formyl-5-oxopyrrolidin-1-yl)ethyl)-1H-
indole-1-carboxylate (20). To a solution of 19 (0.77 g, 2.14 mmol) in
CH2Cl2 (24 mL) was added the Dess–Martin periodinane (1.00 g,
2.35 mmol). The reaction mixture was stirred at room temperature
for 20 min and then saturated aqueous Na2S2O3 was slowly added.
The aqueous layer was extracted with CH2Cl2, and the combined
organic phases were washed with saturated aqueous NaHCO3 and
brine. The organic layer was dried over Na2SO4, filtered, and con-
centrated in vacuum to afford aldehyde 20 as a yellow oil, which
was used immediately without further purification. 1H NMR
4.1.9. (S)-1-(2-(1H-Indol-3-yl)ethyl)-5-ethynylpyrrolidin-2-one
(7). A solution of 21 (626 mg, 1.78 mmol) in TFA/CH2Cl2 (18:5 mL)
was stirred at room temperature for 10 min. Then the solvent was
evaporated and the residue was diluted in EtOAc and washed with
NaHCO3, the aqueous phase was extracted with EtOAc several
times, and then the solvent was evaporated. Compound 7 was
obtained as a colorless oil (243 mg, 23% over four steps): [
ꢀ20.22 (c 0.93, CHCl3). IR thin film 3218.3 (s), 3053.3 (m), 2925.0
(s), 2853.8 (m), 2115.3 (w), 1654.3 (vs), 1455.9 (s) cmꢀ1 1H NMR
(400 MHz, CDCl3)
a]
D
(400 MHz, CDCl3)
d
9.50 (d, J¼2.3 Hz, 1H), 8.12 (br d, J¼7.8 Hz, 1H),
n
7.53 (d, J¼7.7 Hz,1H), 7.41 (s,1H), 7.31 (td, J¼7.8,1.1 Hz,1H), 7.24 (td,
J¼7.6, 1.0 Hz, 1H), 4.01–3.94 (m, 2H), 3.34 (ddd, J¼13.9, 8.5, 7.0 Hz,
1H), 3.01 (ddd, J¼14.4, 8.9, 6.8 Hz, 1H), 2.88 (dddd, J¼14.5, 8.5, 5.8,
0.8 Hz, 1H), 2.44–2.40 (m, 2H), 2.22–2.11 (m, 1H), 2.05–1.97 (m, 1H),
.
d
8.06 (br s, 1H), 7.65 (d, J¼7.8 Hz, 1H), 7.35 (d,
J¼7.8 Hz,1H), 7.19 (t, J¼7.6 Hz, 1H), 7.12 (t, J¼7.4 Hz,1H), 7.08 (s, 1H),
4.19 (ddd, J¼7.6, 5.1, 2.1 Hz, 1H), 4.05–3.98 (m, 1H), 3.48–3.41 (m,
1H), 3.12–2.99 (m, 2H), 2.51 (ddd, J¼16.6, 9.6, 6.6 Hz, 1H), 2.40 (d,
J¼2.2 Hz, 1H), 2.33 (ddd, J¼16.4, 9.2, 6.3 Hz, 1H), 2.27–2.17 (m, 1H),
1.66 (s, 9H); 13C NMR (100 MHz, CDCl3, DEPT)
d 198.6 (CH), 175.3
(C), 149.6 (C), 136.1 (C), 135.5 (C), 124.6 (CH), 123.2 (CH), 122.6 (CH),
118.8 (CH), 117.2 (C), 115.3 (CH), 83.7 (C), 66.1 (CH), 42.6 (CH2), 29.3
(CH2), 28.2 (CH3, 3C), 23.3 (CH2), 19.4 (CH2).
2.09–2.01 (m, 1H); 13C NMR (100 MHz, CDCl3, DEPT)
d 174.3 (C),
136.2 (C), 127.5 (C), 122.1 (CH), 121.8 (CH), 119.4 (CH), 118.7 (CH),
112.9 (C), 111.2 (CH), 81.6 (C), 73.4 (CH), 49.3 (CH), 41.4 (CH2), 30.0
(CH2), 26.2 (CH2), 23.1 (CH2). HRMS-ESI m/z calcd for C16H16N2ONa:
275.1160; found: 275.1168 [MþþNa].
4.1.8. (S)-tert-Butyl 3-(2-(2-ethynyl-5-oxopyrrolidin-1-yl)ethyl)-1H-
indole-1-carboxylate (21).
4.1.8.1. Procedure A. (i) (S)-tert-Butyl 3-(2-(2-(2,2-dibromo-
vinyl)-5-oxopyrrolidin-1-yl)ethyl)-1H-indole-1-carboxylate. Triphe-
nylphosphine (1.91 g, 7.29 mmol) was added at 0 ꢁC to a solution of
CBr4 (1.21 g, 3.65 mmol) in CH2Cl2 (30 mL). At the same tempera-
ture, aldehyde 20 (650 mg, 1.82 mmol) dissolved in CH2Cl2 (10 mL)
was dropped slowly into the reaction mixture and then it was stir-
red at room temperature for 10 min. After extractive workup
(CH2Cl2) and chromatography (2:1, hexane/EtOAc) the title com-
4.1.10. N-(2-(1H-Indol-3-yl)ethyl)-N-benzylprop-2-yn-1-amine
(22). To a solution of NaH (60% in mineral oil, 186 mg, 4.65 mmol)
in THF (10 mL) was added N-benzyl-2-(1H-indol-3-yl)ethanamine
(970 mg, 3.87 mmol) at 0 ꢁC. The mixture was allowed to stir for
15 min and propargyl bromide (0.41 mL, 4.65 mmol) was added.
The reaction was stirred at room temperature for 24 h. Then, the
mixture was washed with water and extracted with EtOAc. The
organic layer was dried over Na2SO4, filtered, and evaporated.
The residue was purified by chromatography (10:1, hexane/EtOAc)
to give 22 as a colorless oil (163 mg, 15%). 1H NMR (400 MHz, CDCl3)
pound was obtained as a light yellow oil (420 mg, 45%): [
a
]D 37.49 (c
1.15, CHCl3). 1H NMR (400 MHz, CDCl3)
d
8.12 (br d, J¼7.7 Hz, 1H),
7.57 (d, J¼7.6 Hz, 1H), 7.44 (s, 1H), 7.31 (td, J¼7.6, 1.3 Hz, 1H), 7.27–
7.23 (m,1H), 6.22 (d, J¼8.9 Hz,1H), 4.26 (ddd, J¼8.9, 8.0, 5.3 Hz,1H),
3.81 (ddd, J¼13.9, 8.9, 6.1 Hz, 1H), 3.23 (ddd, J¼13.8, 8.6, 6.2 Hz, 1H),
3.00 (dddd, J¼14.3, 8.9, 6.1, 0.8 Hz, 1H), 2.88 (dddd, J¼14.3, 8.7, 6.1,
0.8 Hz, 1H), 2.48–2.33 (m, 2H), 2.26–2.16 (m, 1H), 1.76–1.69 (m, 1H),
d
7.94 (br s, 1H), 7.59 (d, J¼7.8 Hz, 1H), 7.38–7.27 (m, 6H), 7.19 (td,
J¼7.6, 1.1 Hz, 1H), 7.10 (td, J¼7.3, 1.0 Hz, 1H), 7.05 (d, J¼2.3 Hz, 1H),
3.73 (s, 2H), 3.44 (d, J¼2.3 Hz, 2H), 3.02–2.98 (m, 2H), 2.95–2.90 (m,
2H), 2.26 (t, J¼2.3 Hz, 1H); 13C NMR (100 MHz, CDCl3, DEPT)
d 138.7
1.66 (s, 9H); 13C NMR (100 MHz, CDCl3, DEPT)
d
174.7 (C), 149.7 (C),
(C), 136.2 (C), 129.2 (CH, 2C), 128.4 (C), 128.3 (CH, 2C), 127.1 (CH),
121.9 (CH), 121.6 (CH), 119.2 (CH), 118.9 (CH), 114.4 (C), 111.1 (CH),
78.7 (C), 73.2 (CH), 58.0 (CH2), 53.9 (CH2), 41.5 (CH2), 23.7 (CH2).
Anal. Calcd for C20H20N2$1/3H2O: C, 81.60; H, 7.08; N, 9.52. Found:
C, 81.52; H, 7.68; N, 10.10. HRMS-ESI m/z calcd for C20H21N2:
289.1705; found: 289.1693 [MþþH].
137.6 (CH), 135.5 (C), 130.4 (C), 124.5 (CH), 123.3 (CH), 122.6 (CH),
118.9 (CH), 117.4 (C), 115.3 (CH), 93.0 (C), 83.6 (C), 60.7 (CH), 41.7
(CH2), 29.9 (CH2), 28.2 (CH3, 3C), 24.2 (CH2), 23.3 (CH2). HRMS-ESI
m/z calcd for C21H24N2O3NaBr2: 533.0051; found: 533.0070
[MþþNa]. (ii) To a solution of the dibromide (100 mg, 0.19 mmol) in
THF (5 mL) at ꢀ78 ꢁC was added n-BuLi (0.41 mmol). The reaction
was kept at this temperature for 1 h, then it was quenched with
MeOH and it was allowed to warm up to room temperature over-
night. After extractive workup (EtOAc), the residue was purified by
chromatography (2:1, hexane/EtOAc) to give 21 as a colorless oil.
4.1.11. Tetracyclic compound 8. To
a solution of 7 (45 mg,
0.18 mmol) in CH2Cl2 (2 mL) was added AuCl3 (3 mg, 0.008 mmol)
and the mixture was stirred at room temperature for 16 h. The
residue was purified by chromatography (1:2, hexane/EtOAc) to

9020
C. Ferrer et al. / Tetrahedron 65 (2009) 9015–9020
2. Lead references on alkaloids from Kopsia: (a) Subramaniam, G.; Kam, T.-S. Helv.
give compound 8 (25 mg, 55%): [a]
D 478.5 (c 0.46, CHCl3). 1H NMR
(400 MHz, CDCl3)
Chim. Acta 2008, 91, 930–937; (b) Subramaniam, G.; Choo, Y. M.; Hiraku, O.;
Komiyama, K.; Kam, T.-S. Tetrahedron 2008, 64, 1397–1408; (c) Subramaniam, G.;
Hiraku, O.; Hayashi, M.; Koyano, T.; Komiyama, K.; Kam, T.-S. J. Nat. Prod. 2008, 71,
53–57.
d
7.83 (br s, 1H), 7.50 (d, J¼7.9 Hz, 1H), 7.29 (d,
J¼8.1 Hz, 1H), 7.20 (t, J¼8.1 Hz, 1H), 7.12 (t, J¼7.5 Hz, 1H), 6.68 (d,
J¼10.9 Hz, 1H), 5.65 (dd, J¼10.7, 7.1 Hz, 1H), 4.52–4.47 (m, 1H), 3.90
(dt, J¼14.0, 4.6 Hz, 1H), 3.83–3.76 (m, 1H), 3.09 (dd, J¼5.9, 4.8 Hz,
2H), 2.50 (ddd, J¼16.3, 9.2, 6.6 Hz, 1H), 2.42–2.24 (m, 2H), 1.90–1.82
3. (a) Kam, T.-S.; Yoganathan, K.; Chuah, C.-H. Tetrahedron Lett. 1995, 36, 759–762;
(b) Kam, T.-S.; Lim, K.-H.; Yoganathan, K.; Hayashi, M.; Komiyama, K. Tetrahe-
dron 2004, 60, 10739–10745.
(m, 1H); 13C NMR (100 MHz, CDCl3, DEPT)
d 174.1 (C), 136.1 (C), 131.1
´
¨s,
4. (a) Awang, K.; Sevenet, T.; Paı M.; Hadi, A. H. A. J. Nat. Prod. 1993, 56, 1134–
1139; (b) Awang, K.; Se´venet, T.; Hadi, A. H. A.; David, B.; Pa¨ıs, M. Tetrahedron
Lett. 1992, 33, 2493–2496.
(CH), 129.7 (C), 128.6 (C), 124.6 (CH), 123.1 (CH), 119.8 (CH), 118.6
(CH), 113.6 (C), 110.6 (CH), 56.7 (CH), 37.8 (CH2), 30.4 (CH2), 29.7
(CH2), 26.3 (CH2). HRMS-ESI m/z calcd for C16H16N2ONa: 275.1160;
found: 275.1164 [MþþNa].
5. (a) Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 1105–1109;
(b) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.dEur. J. 2007,13,1358–1373.
6. Review on transition metal-catalyzed arylation of alkynes: Nevado, C.; Echa-
varren, A. M. Synthesis 2005, 167–182.
´
´ ˜
7. (a) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326–3350; (b)
Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351–3378; (c)
Michelet, V.; Toullec, P. Y.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268–
4315; (d) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180–3211; (e) Fu¨rstner, A.;
Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410–3449.
4.1.12. (S)-1-(2-(1H-Indol-3-yl)ethyl)-5-(1-chlorovinyl)pyrrolidin-2-
one (26). 1H NMR (400 MHz, CDCl3)
d 8.07 (br s, 1H), 7.61 (d,
J¼7.9 Hz, 1H), 7.39 (d, J¼8.1 Hz, 1H), 7.22 (td, J¼7.9, 0.8 Hz, 1H), 7.14
(td, J¼7.7, 0.7 Hz, 1H), 7.07 (d, J¼2.0 Hz, 1H), 5.33 (d, J¼1.5 Hz, 1H),
5.18 (d, J¼1.5 Hz, 1H), 4.07–3.96 (m, 2H), 3.18–2.95 (m, 3H), 2.55
(ddd, J¼17.3, 10.1, 7.6 Hz, 1H), 2.35 (ddd, J¼17.0, 10.1, 5.2 Hz, 1H),
8. Review on the synthesis of heterocycles by p-activation of alkynes: Kirsch, S. F.
Synthesis 2008, 3183–3204.
9. Wang, H.; Germanas, J. P. Synlett 1999, 33–36.
10. (a) Pettersen, D.; Ahlberg, P. Tetrahedron: Asymmetry 2005, 16, 2075–2080;
(b) Harris, P. W. R.; Brimble, M. A.; Muir, V. J.; Lai, M. Y. H.; Trotter, N. S.; Callis,
D. J. Tetrahedron 2005, 61, 10018–10035; (c) Bittermann, H.; Gmeiner, P. J. Org.
Chem. 2006, 71, 97–102; (d) Bittermann, H.; Bo¨ckler, F.; Einsiedel, J.; Gmeiner, P.
Chem.dEur. J. 2006, 12, 6315–6322; (e) Artman,G.D.;Grubbs,A.W.;Williams,R.M.
J. Am. Chem. Soc. 2007, 129, 6336–6342.
2.12–1.93 (m, 2H); 13C NMR (100 MHz, CDCl3, DEPT)
d 174.4 (C),
142.0 (C),136.4 (C),127.7 (C),122.3 (CH),122.0 (CH),119.6 (CH),118.9
(CH), 115.6 (CH2), 113.3 (C), 111.3 (CH), 64.2 (CH), 41.6 (CH2), 30.2
(CH2), 26.4 (CH2), 23.3 (CH2). LRMS m/z 287 [Mþ]. HRMS-ESI m/z
calcd for C16H17N2O35ClNa: 311.0927; found: 311.0919 [MþþNa].
11. Seebach, D.; Boes, M.; Naef, R.; Schweizer, B. J. Am. Chem. Soc. 1983, 105,
5390–5392.
12. Vartak, A. P.; Young, V. G.; Johnson, R. L. Org. Lett. 2005, 7, 35–38.
13. Johansen, J. E.; Christie, B. D.; Rapoport, H. J. Org. Chem. 1981, 46, 4914–4920.
14. Yang, J.; Song, H.; Xiao, X.; Wang, J.; Quin, Y. Org. Lett. 2006, 8, 2187–2190.
15. Davies, H. M. L.; Townsend, R. J. J. Org. Chem. 2001, 66, 6565–6603.
16. Horwell, D. C.; McKiernan, M. J.; Osborne, S. Tetrahedron Lett. 1998, 39,
8729–8732.
17. (a) Fujii, H.; Oshima, K.; Utimoto, K. Chem. Lett. 1991, 1847–1848; (b) Li, L.-C.;
Jiang, J.-X.; Ren, J.; Ren, Y.; Pittman, C. U.; Zhu, H. J. Eur. J. Org. Chem. 2006,
1981–1990.
18. (a) McElwee-White, L.; Dougherty, D. A. J. Am. Chem. Soc. 1984, 106, 3466–3474;
(b) Ohira, S. Synth. Commun.1989,19, 561–564; (c) Mu¨ller, S.; Liepold, B.; Roth, G. J.;
Bestmann, H.-J. Synlett 1996, 521–522; (d) Goundry, W. R. F.; Baldwin, J. E.; Lee, V.
Tetrahedron 2003, 59,1719–1729; (e) Roth, G. J.; Liepold, B.; Mu¨ller, S. G.; Bestmann,
H. J. Synthesis 2004, 59–62.
19. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769–3772.
20. Annibale, G.; Canovese, L. C.; Cattalini, L.; Marangoni, G.; Michelon, G.; Tobe, M. L.
J. Chem. Soc., Dalton Trans. 1984, 1641–1646.
4.1.13. Tetracyclic compound 27. Mixture of 8 and 27 was separated
by HPLC chromatography using a NH2 column (95:5, hexane/eth-
anol), flow¼1.5 mL/min,
l
¼254 nm. Retention times: 14.24 min,
compound 8; 16.35 min, compound 27. 1H NMR (400 MHz, CDCl3)
d
7.87 (br s, 1H), 7.49 (d, J¼8.0 Hz, 1H), 7.31 (d, J¼8.2 Hz, 1H), 7.22 (t,
J¼7.5 Hz, 1H), 7.11 (t, J¼7.6 Hz, 1H), 5.38 (s, 1H), 5.32 (s, 1H), 4.68 (d,
J¼7.7 Hz, 1H), 4.20–4.15 (m, 1H), 3.43–3.30 (m, 2H), 2.94–2.89 (m,
1H), 2.47–2.24 (m, 3H), 1.92–1.81 (m, 1H); 13C NMR (100 MHz,
CDCl3, DEPT)
d 174.3 (C), 160.9 (C), 142.2 (C), 135.8 (C), 128.8 (C),
123.3 (CH), 119.9 (CH), 119.1 (CH2), 113.2 (C), 112.8 (CH), 110.5 (CH),
65.1 (CH), 39.8 (CH2), 30.9 (CH2), 27.9 (CH2), 25.1 (CH2). HRMS-ESI
m/z calcd for C16H16N2ONa: 275.1160; found: 275.1156 [MþþNa].
The [a]D of pure compound 27 could not be obtained because of its
21. Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.; Kurpejovic, E. Angew. Chem., Int.
Ed. 2004, 43, 6545–6547.
partial isomerization to the endocyclic olefin.
22. Acetylene hydrochlorination with heterogeneous catalysts: (a) Nkosi, B.; Coville,
N. J.; Hutchings, G. J. J. Chem. Soc., Chem. Commun. 1988, 72–74; (b) Nkosi, B.;
Coville, N. J.; Hutchings, G. J.; Adams, M. D.; Friedl, J. A.; Wagner, F. E. J. Catal. 1991,
128, 366–377; (c) Conte, M.; Carley, A. F.; Hutchings, G. J. Catal. Lett. 2008, 124,
165–167.
Acknowledgements
We thank the MICINN (CTQ2007-60745/BQU and Consolider
Ingenio 2010, Grant CSD2006-0003, and FPU predoctoral fellow-
ship to A.E.-C.), the AGAUR (predoctoral fellowship to C.F.), and the
ICIQ Foundation for financial support.
23. Herrero-Go´mez, E.; Nieto-Oberhuber, C.; Lo´pez, S.; Benet-Buchholz, J.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2006, 45, 5455–5459.
24. Nieto-Oberhuber, C.; Lo´ pez, S.; Echavarren, A. M. J. Am. Chem. Soc. 2005, 127,
6178–6179.
´
´
´
25. Amijs, C. H. M.; Lopez-Carrillo, V.; Raducan, M.; Perez-Galan, P.; Ferrer, C.;
Echavarren, A. M. J. Org. Chem. 2008, 73, 7721–7730.
26. Ferrer, C.; Raducan, M.; Nevado, C.; Claverie, C. K.; Echavarren, A. M. Tetrahedron
2007, 63, 6306–6316.
References and notes
27. Silver catalyzed cyclization of enynes: Porcel, S.; Echavarren, A. M. Angew.
Chem., Int. Ed. 2007, 46, 2672–2676.
1. (a) Pearson, W. H.; Lee, I. Y.; Mi, Y.; Stoy, P. J. Org. Chem. 2004, 69, 9109–9122;
(b) Pearson, W. H.; Lee, I. Y.; Stoy, P. J. Am. Chem. Soc. 2001, 123, 6724–6725.