A new pathway to chiral tetracyclic indolidines via Pauson-Khand reaction

Article abstract of DOI:10.1016/S0040-4039(01)00645-1

Reaction of enynes 1 and 3 with Co₂(CO)₈ in the presence of DMSO, NMO or TMANO as promoters produced tricyclic indolidine derivatives 5 and 7 stereoselectively in moderate to excellent yield. The stereochemistry at the C-7 position of the indolidines 5 and 7 was confirmed by their conversion into the bridged azacycles 10 and 13.

Full text of DOI:10.1016/S0040-4039(01)00645-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4013–4016
A new pathway to chiral tetracyclic indolidines via
Pauson–Khand reaction
Shinji Tanimori,* Kouji Fukubayashi and Mitsunori Kirihata
Department of Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, Osaka Prefecture University,
1-1 Gakuen-cho, Sakai, Osaka 599-8531, Japan
Received 5 March 2001; revised 11 April 2001; accepted 13 April 2001
Abstract—Reaction of enynes 1 and 3 with Co2(CO)8 in the presence of DMSO, NMO or TMANO as promoters produced
tricyclic indolidine derivatives 5 and 7 stereoselectively in moderate to excellent yield. The stereochemistry at the C-7 position of
the indolidines 5 and 7 was confirmed by their conversion into the bridged azacycles 10 and 13. © 2001 Elsevier Science Ltd. All
rights reserved.
The Pauson–Khand reaction has come to be considered
as a valuable and convergent method for synthesizing
cyclopentenone derivatives.1 Especially, an intramolecu-
lar series of the Pauson–Khand reaction such as that of
enyne in which three or four atoms separate the double
and triple bonds give bicyclic enones, and the method-
ology has been widely applied to the synthesis of
cyclopentane-based polycyclic natural products.2
Despite the rich literature on the chemistry of con-
structing fused terpenoids and derivatives such as
triquinanes based on the Pauson–Khand methodology,2
to the best of our knowledge, there are few reports
dealing with the synthesis of other types of natural
products. We now report a new pathway to chiral tri-
Br
SOCl2
ref. 3
NaHCO3, LiI
N
MeOH
NH2Cl
NH
HO2C
NH
MeCN, 60°C
reflux
99%
CO2H
L-proline
MeO2C
MeO2C
96%
1
1. SOCl2, MeOH, reflux
O
2.
NaHCO3
THF
R2
Cl
O
Ph
LDA
Br
1. TMSCl, NaI
O
O
O
MeCN, rt
R1
N
N
O
Ph
N
Ph
R1
R1
2.
CO2Me
THF, -78 to 0°C
Br
MeO2C
MeO2C
R2
R2
NaHCO3, LiI
MeCN, 60°C
2 R1=R2=H, 81%
R1=R2=H, 80%
3 R1=Me, R2=H, 78%
4 R1=R2=Me, 64%
R1=Me, R2=H, 77%
R1=R2=Me, 46%
Scheme 1.
Keywords: Pauson–Khand reaction; diazabicyclo[2.2.2]octane; asperparaline.
* Corresponding author. Fax: +81-722-54-9918; e-mail: tanimori@biochem.osakafu-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00645-1

4014
S. Tanimori et al. / Tetrahedron Letters 42 (2001) 4013–4016
Table 1. The Pauson–Khand reaction of 1
(OC)6Co2
N
N
N
O
MeO2C
MeO2C
MeO2C
5
6
1
Entry
Co2(CO)8
(equiv.)
Solvent
Conditions for formation of 6
Promoter
(equiv.)
Conditions for formation of 5
Yield (%)a
1
2
3
4
0.1
1.1
1.2
1.05
DME
PhH
CH2Cl2
THF
CO, rt, 10 min
Ar, rt, 2 h
CO, rt, 2 h
Ar, rt, 2 h
CO
CO, 60°C, 42 h
O2, 50°C, 3 days
CO, rt, 22 h
6
46
72
94
DMSO (0.1)
NMO (6)
DMSO (6)
Ar, 50°C, 26 h
a Isolated yield.
Table 2. The Pauson–Khand reaction of 3
(OC)6Co2
N
Co2(CO)8 (1 eq)
N
N
O
Ar, rt, 2 h
MeO2C
MeO2C
MeO2C
4:1
8
7
3
Entry
Solvent
Promoter (equiv.)
Conditions for formation of 7
Yield (%)a
1
2
3
4
THF
THF
CH2Cl2
CH2Cl2
DMSO (6)
DMSO (12)
TMANO (9)
NMO (9)
Ar, 50°C, 35 h
Ar, 50°C, 3 days
Ar, rt, 15 h
34
48
53
61
Ar, rt, 22 h
a Isolated yield.
Co2(CO)8, promoters
N
N
O
MeO2C
MeO2C
9
4
Scheme 2.
and tetracyclic indolidine derivatives starting from
proline via Pauson–Khand cycloaddition reaction of
enynes 1 and 3.
L
-
conditions as in 1 gave enone 7 in only 34% yield as a
4:1 mixtures of diastereomers resulting from the addi-
The starting enynes 1–4 were synthesized from L-pro-
Co
Co
line by the standard procedure3 as chiral and racemic
forms as shown in Scheme 1.
N
N
Co
Co
O
O
O
O
The [2+2+1] cycloaddition of enyne 1 using a stoichio-
metric amount of Co2(CO)8 gave tricyclic indolidinone
5 as a single diastereomer in a moderate to excellent
yield depending on the reaction conditions (Table 1).4 It
was found that the use of an excess amount (6 equiv.)
of DMSO5 as promoter6 in an argon atmosphere is
essential for the efficiency of the cycloaddition step
(entry 4).
i
ii
N
N
O
O
7
MeO2C
H
MeO2C
H
5
7-epi-5
The same reaction of enyne 3 possessing E-olefin was
less effective than 1 (Table 2). Indeed, almost the same
Figure 1.

S. Tanimori et al. / Tetrahedron Letters 42 (2001) 4013–4016
4015
Me
N
1. 40% MeNH2 aq.
NHMe
cat. MeNH3Cl, rt
N
N
N
O
O
7
O
95%
2. SiO2, MeOH-H2O
MeO2C
H
MeO2C
H
H
O
5
rt to 45°C
11
10
NHMe
No cyclization
product
N
N
O
O
MeO2C
H
MeO2C
H
12
7-epi-5
Scheme 3.
tional methyl group (entry 1).7 Accordingly, the yield
was increased to 61% by using NMO8 as a promoter in
CH2Cl2 at room temperature for 22 h (entry 4).
transition state model (i and ii, Fig. 1). Clearly, transoid
conformer i is more stable than cisoid one ii to produce
(7R)-isomer 5. Furthermore, the speculation was con-
firmed chemically as follows (Scheme 3). Thus, enone 5
was treated with 40% methylamine and a catalytic
amount of methylamine hydrochloride followed by sil-
ica-gel in aqueous methanol at 45°C to afford bridged
tetracyclic lactam 10 in 95% yield.9 This result suggests
that the arrangement of the carbomethoxy group of 5
and the C-7 hydrogen should be cis because the attack
of methylamine to the b-position of the enone would
occur smoothly only from the convex face of molecular
iii to produce intermediate 11 (Fig. 2). Then,
intramolecular amide bond formation would afford
lactam 10. On the other hand, the same pathway could
not occur in the case of stereoisomer 7-epi-5, because
the potential intermediate 12 has an anti relationship of
the methoxycarbonyl and N-methyl amino group (vi).
Reaction of enyne 4 possessing trisubstituted olefin
gave no [2+2+1] cycloaddition product in spite of using
a large excess of promoters, heating and prolonging the
reaction times and the starting material was recovered
or a complex mixture was obtained (Scheme 2). It is
assumed that due to the steric hindrance of the geminal
dimethyl group, the approach of the cobalt complexed
alkyne part to alkene is difficult or due to the instability
of the transition state or intermediate, the reaction
resulted in decomposition of the intermediate.
The stereochemical outcome of the newly produced
asymmetric center (C-7) of enone 5 was estimated as
follows. At first, it was postulated by considering a
In the same way, the conversion of enone 7 and 9 to
lactam 13 and 1410 was achieved in 39 and 17% yield,
respectively (Scheme 4). The enone 9 was prepared
from 7 by treating with LDA and MeI at −78°C in 58%
yield. The inefficiency of these cyclizations was proba-
bly due to the steric hindrance of the additional methyl
substituents at the C-6 position.
N
O
10
11
O
O
iii
MeNH2
N
O
In summary, we have demonstrated a new pathway to
12
O
chiral indolidine derivatives starting from
L-proline
O
using the Pauson–Khand reaction followed by facile
formation of a bridged lactam. These results described
above would serve for the synthesis of an indolidine
alkaloid such as asperparaline11 and derivatives12 (Fig.
vi
Figure 2.
Me
N
2
1. MeNH2
2. SiO2
N
O
N
6
O
R2
MeO2C
H
R1
R2
H
R1
O
7 (racemic): R1=H, R2=Me
9 (racemic): R1=R2=Me
LDA, MeI, THF/HMPA, -78°C
13 (racemic): R1=H, R2=Me; 39%
14 (racemic): R1=R2=Me; 17%
Scheme 4.

4016
S. Tanimori et al. / Tetrahedron Letters 42 (2001) 4013–4016
Me
N
O
Me
N
Me
N
O
NH
N
HN
N
N
N
O
O
O
H
H
O
H
O
O
O
Asperparaline C
Brevinamide A
Paraherquamide B
Figure 3.
3) possessing a common diazabicyclo[2.2.2]octane core
and exhibiting potent paralytic, insecticidal, antifeedant
and anthelmintic activity in the search for effective drugs.
5. Chung, Y. K.; Lee, B. Y.; Jeong, N.; Hudecek, M.; Pauson,
P. L. Organometallics 1993, 12, 220–223.
6. Recent report on promoters: Sugihara, T.; Yamada, M.;
Ban, H.; Yamaguchi, M.; Kaneko, C. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2801–2804 and references cited therein.
7. The diastereometic ratio of 7 was determined by integra-
tion ratio of 1H NMR signal of diastereomeric methyl
group: l (CDCl3): 1.18 (d, J=6.7 Hz, main) and 1.09 (d,
J=7.6 Hz, minor).
Acknowledgements
We thank Professor H. Hayashi of Graduate School of
Agriculture and Life Sciences at Osaka Prefecture Uni-
versity for his kind cooperation with this project and
useful advice. This work was supported by the Ministry
of Education, Science, Sports and Culture of Japan.
8. Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron
Lett. 1990, 31, 5289–5292.
9. Typical experimental procedure for lactam formation (syn-
thesis of 10): Enone 5 (0.1 g, 0.43 mmol) was dissolved in
40% aqueous methylamine and methylamine hydrochlo-
ride (5.8 mg, 85 mmol) was added. After stirring for 16 h
at room temperature, NaHCO3 (14 mg, 0.17 mmol) and
water (2 ml) was added and the mixture was stirred for 10
min at room temperature. After concentration, the residue
was dissolved in MeOH (5 ml) and water (1 ml) and SiO2
(1 g) was added. The mixture was stirred for 3 h at room
temperature and then 45°C for 4 h. After cooling, the
mixture was filtered and the filtrate was washed with
methanol, and the solvent was concentrated in vacuo. The
residue was purified by silica-gel column chromatography
(eluting with EtOAc:acetone=1:1) to give lactam 10 (201
mg, 94%) as a brown oil. Rf=0.43 (acetone); [h]2D0−149.6°
(c 1.1, CHCl3); IR (KBr, disk) wmax cm−1: 3440 (br), 2923,
1750 (ketone CꢀO), 1666 (lactam CꢀO), 1651, 1390, 1097;
1H NMR l (CDCl3): 1.35–1.46 (1H, m, H-C6), 1.65–1.73
(1H, m, H-C6), 1.82–1.95 (2H, m), 2.16–2.36 (5H, m),
2.48–2.68 (4H, m), 2.98 (3H, s, CH3-N13), 3.06–3.13 (1H,
m, H-C10), 3.18–3.22 (1H, d, J=11.6 Hz, H-C12); 13C
NMR l (CDCl3): 22.2, 26.9, 27.8, 34.3, 40.9, 42.6, 45.5,
53.7, 53.8, 62.8, 66.0 (C7), 172.8 (C14), 211.4 (C3); EI MS
m/z (%): 234 (M+, 5), 206 (3), 175 (100), 149 (51), 137 (21),
108 (12), 96 (20).
10. The direct conversion of enone 10 to 14 was unsuccessful.
Methylation of 10 with MeI in the presence of several bases
(LDA, NaHMDS, NaH, t-BuOK, NaOMe) occurred
predominantly at C-2 position to give undesired regioiso-
mer.
11. (a) Hayashi, H.; Nishimoto, Y.; Nozaki, H. Tetrahedron
Lett. 1997, 38, 5655–5658; (b) Banks, R. M.; Blanchflower,
S. E.; Everett, J. R.; Manger, B. R.; Reading, C. J. Antibiot.
1997, 50, 840–846; (c) Synthetic approach for asperpara-
line, see: Tanimori, S.; Fukubayashi, K.; Kirihata, M.
Biosci. Biotechnol. Biochem. 2000, 64, 1758–1760; Gonza-
lez, F.; Sanz-Cervera, J. F.; Williams, R. M. Tetrahedron
Lett. 1999, 40, 4519–4522.
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4. Typical experimental procedure for Pauson–Khand reac-
tion (synthesis of enyne 5): To a stirred solution of
Co2(CO)8 (0.31 g, 0.91 mmol) in dry THF (9 ml) under Ar
at room temperature was added dropwise a solution of
enyne 1 (0.19 g, 0.91 mmol) in THF (1 ml). After 2 h of
stirring at room temperature, DMSO (0.39 ml, 5.46 mmol)
was added in one portion. The reaction mixture was stirred
for 26 h at 50°C. After cooling, the mixture was filtered
through Celite, which was thoroughly washed with ace-
tone. The solvent was eliminated under reduced pressure,
and the crude product was purified by silica-gel column
chromatography (eluting with hexane: EtOAc=1:1) to give
enone 5 (201 mg, 94%) as a pale yellow crystal. Rf=0.25
(EtOAc); [h]1D8+56.2° (c 1.0, CHCl3); IR (NaCl, film) wmax
cm−1: 2954, 1713 (CꢀO), 1630 (CꢀC), 1445, 1198, 1152; 1H
NMR l (CDCl3): 1.37 (1H, t, J=12.5 Hz, H-C8), 1.73–2.19
(5H, m), 2.57–2.66 (2H, m, H2-C6), 2.70–2.77 (1H, m,
H-C7), 2.87–2.96 (1H, m, H-C12), 3.09–3.17 (1H, m,
H-C12), 3.79–3.94 (5H, m), 5.98 (1H, s, H-C4); 13C NMR
l (CDCl3): 21.0, 36.5, 38.1, 38.7, 42.0, 47.8, 49.9, 52.1, 67.3
(C9), 128.4 (C4), 174.5 (C6 O2Me), 176.4 (C3), 207.7 (C5);
FAB MS m/z (%): 236 ([M+H]+, 69), 176 ([M−CO2Me]+,
100); HRMS (EI) m/z (M+): calcd. For C13H17O3N,
235.1209. Found: 235.1220.
12. Synthetic approach for other related alkaloids, see:
Williams, R. M.; Cao, J.; Tsujishima, H. Angew. Chem.,
Int. Ed. 2000, 39, 2540–2544.