An efficient construction of bridged chiral tetracyclic indolidines, a core structure of asperparaline, via stereocontrolled catalytic Pauson-Khand reaction

Article abstract of DOI:10.1016/j.tet.2004.12.057

A reaction of chiral enyne 22 derived from l-proline with a catalytic amount of cobalt (0) octacarbonyl in the presence of N-methylmorphorine N-oxide gave tricyclic enone 24 in 54% yield (73% based on consumed starting material). Treatment of enone 11 with aqueous methylamine followed by silica gel afforded bridged tetracyclic indolidine 1, a common structural motif of natural metabolites, an asperparaline series of compounds and also a potential intermediate for the synthesis of a paralytic alkaloid, asperparaline C (4), in 70% yield.

Full text of DOI:10.1016/j.tet.2004.12.057

Tetrahedron 61 (2005) 2481–2492
An efficient construction of bridged chiral tetracyclic indolidines,
a core structure of asperparaline, via stereocontrolled catalytic
Pauson–Khand reaction
*
Shinji Tanimori, Tatsuya Sunami, Kouji Fukubayashi and Mitsunori Kirihata
Department of Applied Biochemistry, Graduate School of Agriculture and Life Sciences, Osaka Prefecture University, 1-1 Gakuen-cho,
Sakai, Osaka 599-8531, Japan
Received 26 November 2004; revised 22 December 2004; accepted 24 December 2004
Available online 27 January 2005
Abstract—A reaction of chiral enyne 22 derived from L-proline with a catalytic amount of cobalt (0) octacarbonyl in the presence of
N-methylmorphorine N-oxide gave tricyclic enone 24 in 54% yield (73% based on consumed starting material). Treatment of enone 11 with
aqueous methylamine followed by silica gel afforded bridged tetracyclic indolidine 1, a common structural motif of natural metabolites, an
asperparaline series of compounds and also a potential intermediate for the synthesis of a paralytic alkaloid, asperparaline C (4), in 70%
yield.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
are numerous other structurally related natural methabolites
including brevinamides 6,7 paraherquamides 7,8 macro-
fortine 8,9 and sclerotamide 9,10 which have a variety of
biological activities such as anthelmintic,6 antinematodal,8
and antiinsectant10 activities.
In our previous report,1 we briefly communicated the
racemic synthesis of tetracyclic indolidine 1, which
constitutes the C3 and C10–C25 portions of a paralytic
alkaloid, asperparaline C (4) (Fig. 1),2 via Pauson–Khand
cycloaddition reaction3 mediated by a stoichiometric
amount of cobalt (0) octacarbonyl. In this paper, we wish
to describe full details of the work which includes additional
new work such as a catalytic version of the key Pauson–
Khand reaction,4 chiral synthesis of 1 starting from
L-proline using Seebach’s protocol5 and also improvement
of the yield of each step to result in a concise, enantio- and
stereo-controlled synthesis of 1.
Asperparalines and related compounds have a common
unique diazabicyclo[2.2.2]octane skeleton formed from
biosynthetic intramolecular [4C2] cycloaddition.11 Asper-
paralines and asperdillimides have also 3-spiro-succinimide
which is rare in naturally occurring products.12 Previously,
we reported the model studies for constructing spiro-
succinimide from 2,2-dimethylcyclopentanone as shown
in Scheme 1.13
Our retro-synthetic plan for asperparaline C (4) is shown in
Figure 2. Following the results of our previous model
studies for the construction of spirosuccinimide from
cyclopentanone (Scheme 1),13 tetracyclic ketone 1 could
be a precursor for introducing the spirosuccinimide. The
energy minimized 3D-structure of a,b-unsaturated dinitrile
10,14 which would be derived from ketone 1 by
Knoevenagel condensation based on the model study,13
indicated that a Michael-type nucleophilic attack such as the
cyanide anion to the b-position of an unsaturated system
would occur from the convex face to produce the
corresponding trinitrile possessing the correct stereo-
chemistry at C-3 (asperparaline numbering) in accord with
asperparaline. The ketone 1 could be transformed from
enone 11 by stereoselective 1,4-addition of methylamine
The indolidine alkaloids, asperparalines A to C (2 to 4),
were discovered by Hayashi and co-workers from ‘okara’
(the insoluble residue of whole soybeans) that has been
fermented with Aspergillus japonicus JV-23.2 Asper-
paralines showed interesting paralytic activity within 1 h
against silkworms at a dose of 10 mg of diet which lasted for
7 to 10 h upon oral administration. On the other hand,
Everett and co-workers also isolated the same compound as
asperparaline A (2) named aspergillimide (VM55598) along
with SB202327 (5) possessing anthelmintic activity.6 There
Keywords: Asperparaline; Pauson–Khand reaction; Indolidine alkaloid;
Paralytic activity; Spiro-succinimide.
* Corresponding author. Tel.: C81 72 254 9469; fax: C81 72 254 9918;
e-mail: tanimori@biochem.osakafu-u.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.057

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S. Tanimori et al. / Tetrahedron 61 (2005) 2481–2492
Figure 1. Asperparaline and related methabolites.
Scheme 1. Model studies for the synthesis of 3-spiro-succinimide.13
followed by intramolecular amide formation with an ester.
The 3D structure of enone 11 suggested that the amine
would attack from the same face with the ester group at
C-13 (asperparaline numbering) to produce the desired
stereochemistry at C-11. The precursor of 11 would be
enyne 12 by the transformation using Pauson–Khand
[2C2C1] cycloaddition reaction. The reaction would
proceed via the stable conformer 13 other than 14 to
produce 11, as a major product. Enyne 12 could be prepared
starting from L-proline as a chiral form by the use of
Seebach’s protocol5 for synthesizing chiral a-substituted
proline.
12 under various conditions (Table 1) gave no desired
product 11. Probably, the approach of the cobalt complex
formed on alkyne to alkene would be prevented due to the
steric bulk of the terminal geminal dimethy group. To
confirm this speculation, two enynes, allyl proline 21 and
crotyl proline 22, were synthesized along the same reaction
sequences. Indeed, as shown in Table 2, allyl proline 21
yielded tricyclic enone 23 in high yield by the use of a
stoichiometric amount of cobalt (0) octacarbonyl in THF in
the presence of DMSO as promoter15 as a single stereo-
isomer. At this point, the stereochemistry of the newly
produced C-20 position (asperparaline numbering) of enone
23 was tentatively estimated by molecular calculation as
follows. A plausible mechanism of the Pauson–Khand
reaction is shown in Scheme 3.3 The stereo-discrimination
step should be the stage from complex 25 to metallacycle
26. Although the best way to predict the stereochemical
outcome would be to calculate the transition state energy of
every possible conformer of 25, it is necessary to use an
accurate molecular calculation program. We conducted the
calculation with 26 instead of transition state 25 based upon
the hypothesis that the steric energy of 26 would reflect that
2. Results and discussion
We initially intended to establish the synthetic route by the
use of readily available racemic material. The racemic
enyne 12 was prepared from N-Cbz-proline by the standard
method involving the sequential alkylation of ester enolate,
deprotection, followed by N-alkylation via 15 and 18
(Scheme 2). Disappointingly, the Pauson–Khand reaction of

S. Tanimori et al. / Tetrahedron 61 (2005) 2481–2492
2483
Figure 2. Retro-synthetic approach to asperparaline C.
Scheme 2. Synthesis of racemic enone 11, 23 and 24.
Table 1. Reaction condition from enyne 12 to enone 11
Entry
Co2(CO)8
(equiv)
Solvent
Conditions for
the formation of
cobalt–alkyne
complex
Promoter
Conditions for
Yield (%)
the reaction of
cobalt–alkyne
complex with alkene
1
2
3
4
5
1.05
1.05
1.0
1.05
1.0
THF
Ar, rt, 2 h
Ar, rt, 2 h
Ar, rt, 2 h
Ar, rt, 2 h
Ar, rt, 2 h
DMSO (6 equiv)
NMO (9 equiv)
NMO (6 equiv)
TMANO$2H2O (6 equiv) Ar, rt, 12 h
TMANO (6 equiv) Ar, rt, 24 h
Ar, 50 8C, 72 h
Ar, rt, 96 h
Ar, rt, 15 h
0
0
0
0
0
CH2Cl2
THF
THF
THF

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S. Tanimori et al. / Tetrahedron 61 (2005) 2481–2492
Table 2. Reaction conditions for the synthesis of enone 23
Entry
Co2(CO)8
(equiv)
Solvent
Conditions for
the formation of
cobalt–alkyne
complex
Promoter
Conditions for
Isolated
yield (%)
the reaction of
cobalt–alkyne
complex with alkene
1
2
3
4
1.2
1.1
1.05
0.1
CH2Cl2
PhH
THF
CO, rt, 2 h
Ar, rt, 2 h
Ar, rt, 2 h
NMO (6 equiv)
DMSO (0.1 equiv)
DMSO (6 equiv)
CO
CO, rt, 22 h
72
46
94
6
O2, 50 8C, 72 h
Ar, 50 8C, 26 h
CO, 60 8C, 42 h
DME
CO, rt, 10 min
of 25. The possible conformer of transition state 25 would
be 25a to 25h (Scheme 4) and the corresponding metalla-
cycle 26a to 26d should afford enone (7aR*,9R*)-23; on the
other hand, 26e to 26h from 25e to 25h should provide
diastereomer (7aS*,9R*)-23. Table 3 shows the calculated
steric energy of 26a to 26h, the difference in energy between
26b to 26h and the most stable conformer 26a, the
equilibrium constants based on Boltzmann equation, the
calculated distribution of 26a to 26h, and the ratio of
formation on (7aR*,9R*)-23 and (7aS*,9R*)-23 based on
the MM2 calculation composed in Chem3D program.14 The
carbonyl group on cobalt was replaced to hydrogen to
simplify the calculation. These results well reflected the
experimental results.
treatment to hydrolyze imine 29 would produce the desired
lactam 27. Especially, silica gel in aqueous methanol was
extremely effective (Table 4, entry 5). The relative
stereochemistry of 27 and also the precursor enone 23
became undoubtedly apparent by this transformation,
because another Michael adduct 30 from stereoisomer 7a-
epi-23 could not cyclyze to lactam as shown in Scheme 5. It
was assumed that the attack of methylamine to enone 23
would occur from the convex face of the molecule,
predominantly. Consequently, the chirality of the quater-
nary carbon of enyne 21 was effectively transformed into
C-1 and C-5 of the product 27 via the Pauson–Khand
reaction followed by Michael-type addition.
Unfortunately, introduction of a geminal dimethyl group on
enone 23 at C7 position was ineffective to yield the desired
11 in only 3% yield along with mono methylated 24 (14%)
and recovered 23 (28%) by treatment of 23 with LDA and
MeI in the presence of HMPA at K78 8C (Scheme 6). We
next examined the cycloaddition of enyne 22 possessing a
crotyl side chain. Although the efficiency rather declined in
comparison to 21, the enone 24 was obtained in 62% yield in
a ratio of 4:1 based on the stereochemistry of the secondary
methyl group at C7 (Table 5). Introduction of a lacked
The formation of bridged lactam was studied using enone 23
(Table 4). Thus, enone 23 was treated with methyl amine in
the presence of additives followed by acidic treatment to
produce lactam 27 in excellent yield as a single dia-
stereomer. The reaction pathway was assumed as follows
shown in Scheme 5. The first Michael-type addition of
methylamine to enone 23 would give intermediate 28
stereoselectively (not isolated), then spontaneous intra-
molecular lactam formation afforded imine 29. Acidic
Scheme 3. Plausible mechanism of Pauson–Khand reaction.

S. Tanimori et al. / Tetrahedron 61 (2005) 2481–2492
2485
Scheme 4. Reaction pathway from transition state 25 to enone 23 via metallacycle 26.
Table 3. Calculated product distribution based on steric energy of metallacycle 26
26a
26b
26c
26d
Steric energy (kcal/mol)
Difference of steric energy
to 26a (kcal/mol)
Equilibrium constant
Calculated distribution
Total distribution of
(7aR*,9R*)-23 (%)
299.55
0
301.62
2.07
300.97
1.42
302.66
3.11
1
85.8
3.97!10K2
3.41
1.09!10-1
9.35
7.90!10K3
6.78!10-1
99
26e
26f
26g
26h
Steric energy (kcal/mol)
Difference of steric energy
to 26a (kcal/mol)
Equilibrium constant
Calculated distribution
Total distribution of
(7aS*,9R*)-23 (%)
302.58
3.03
304.63
5.08
307.35
7.80
305.54
5.99
8.87!10K3
7.61!10K1
3.67!10-4
3.15!10-2
5.28!10K6
4.53!10K4
8.92!10-5
7.65!10-3
1

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S. Tanimori et al. / Tetrahedron 61 (2005) 2481–2492
Table 4. Reaction conditions for the synthesis of lactam 27 from enone 23
Entry
1
Conditions
Isolated yield (%)
52
(1) 40% MeNH2 aq (20 equiv), Na2CO3 (0.2 equiv), rt, 24 h
(2) Concd HCl, rt, 24 h/40 8C, 3 h
(1) 40% MeNH2 aq (20 equiv), Na2CO3 (0.05 equiv), rt, 15 h
(2) Concd HCl, 45 8C, 24 h
2
3
4
5
57
60
69
95
(1) 40% MeNH2 aq (20 equiv), NaHCO3 (0.1 equiv), rt, 13 h
(2) Concd HCl, rt, 7 h
(1) 40% MeNH2 aq (20 equiv), MeNH3Cl (0.2 equiv), rt, 21 h
(2) Concd HCl, 45 8C, 13 h
(1) 40% MeNH2 aq (20 equiv), MeNH3Cl (0.2 equiv), rt, 16 h
(2) SiO2, MeOH–H2O, rt–45 8C, 7 h
Scheme 5. Reaction pathway from enone 23 to lactam 27.
Scheme 6. Introduction of methyl group at C7 of enone 23.

S. Tanimori et al. / Tetrahedron 61 (2005) 2481–2492
Table 5. Reaction conditions for the synthesis of enone 24 from enyne 22
2487
Entry
Co2(CO)8
(equiv)
Solvent
Conditions for
the formation of
cobalt–alkyne
complex
Promoter
Conditions for
Isolated
yield (%)
the reaction of
cobalt–alkyne complex
with alkene
1
2
3
4
5
1.0
1.0
1.0
1.0
1.0
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
Ar, rt, 2 h
Ar, rt, 2 h
Ar, rt, 2 h
Ar, rt, 2 h
Ar, rt, 2 h
DMSO (6 equiv)
DMSO (12 equiv)
TMANO (9 equiv)
NMO (9 equiv)
NMO (9 equiv)
Ar, 50 8C, 35 h
Ar, 50 8C, 72 h
Ar, rt, 21 h
Ar, rt, 15 h
Ar, rt, 24 h/O2, 1 h
34
48
53
53
62
Table 6. Reaction conditions for the synthesis of lactam 1 from enone 11
Entry
1
Conditions
Isolated yield (%)
(1) 40% MeNH2 aq (20 equiv), MeNH3Cl (0.2 equiv), rt, 16 h
(2) Concd HCl, 45 8C, 18 h/rt, 41 h
28
39
39
70
2
3
4
(1) 40% MeNH2 aq (20 equiv), MeNH3Cl (0.5 equiv), rt, 96 h
(2) SiO2, MeOH, H2O, reflux, 4 h
(1) 40% MeNH2 aq (20 equiv), MeNH3Cl (0.5 equiv), rt, 48 h
(2) SiO2, MeOH, H2O, rt, 18 h/reflux, 1 h
(1) 40% MeNH2 aq (40 equiv), rt, 48 h/reflux, 4 h
(2) SiO2, MeOH, H2O, rt, 18 h
methyl group on 24 was successfully accomplished to give
enone 11 in 77% yield by treatment with LDA and MeI
(Scheme 6). The lactam formation of 11 needed stronger
conditions (Table 6) to produce racemic lactam 1 in 70%
yield again as a single diastereomer.
compound 315 via 32 and 33 by the stereoselective
crotylation, hydrolysis, followed by esterification
(Scheme 7), by the same reaction sequence as the racemic
series.
The catalytic Pauson–Khand reaction4 was successively
introduced as shown in Table 7. The reaction was
undertaken under a carbon monoxide atmosphere using a
catalytic amount of Co2(CO)8 and NMO as promoter
to yield 24 in moderate yield. The efficiency was
almost the same as that of the stoichiometric series (see
Table 5).
As the synthetic route to 1 was established as racemic form,
we next examined the chiral synthesis of 1 and also a
catalytic approach for the key Pauson–Khand reaction.
The optically active indolidine 1 was synthesized starting
from chiral crotyl proline 34, prepared from bicyclic
Scheme 7. Synthesis of chiral indolidine (K)-1.

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S. Tanimori et al. / Tetrahedron 61 (2005) 2481–2492
Table 7. Catalytic Pauson–Khand reaction of enyne 22 to enone 24
Entry
Co2(CO)8 (equiv)
Solvent
Conditions
Promoter (equiv)
Isolated yield (%)
1
2
3
0.05
0.05
0.05
CH2Cl2
Benzene
Toluene
CO, 22 h, rt
CO, 22 h, 70 8C
CO, 22 h, 120 8C
NMO (0.05)
NMO (0.05)
NMO (0.05)
23 (76)a
54 (26)a
49 (33)a
a Values in parentheses represent recovery yields of compound 22.
Scheme 8. Knoevenagel reaction of lactams.
The next stage was set for the construction of 3-spiro-
succinimide relying on our earlier study (Scheme 1).13
Unfortunately, the Knoevenagel reaction of ketone 1 with
malononitrile under the same reaction condition as the
model studies and also stronger conditions such as heating
and using a Lewis acid catalyst16 gave no desired product.17
The results would be attributed to the additional steric bulk
by the bridged lactam on the convex face from which the
nucleophile would approach and also the neighboring
geminal dimethyl group and hydrogens, one of which
would occupy pseudo axial position, respectively, to
carbonyl group. Energy minimized conformation of 1
suggested that the N-methyl group would shield the convex
face of the molecule and the pseudo axial methyl group and
hydrogen would also prevent the nucleophilic attack
(Scheme 8). To confirm this point, the Knoevenagel reaction
of 27 and 36, derived from enone 24 in 73% yield by the
same procedure as the synthesis of 1 and 27, was examined.
Although unsaturated dinitrile 35 was obtained in 63%
yield, 36 gave no condensed product.
stereochemical outcome in the key metal-mediated cycload-
dition step (from 21 to 23) and this assumption was
confirmed later by the chemical transformation (from 23 to
27). Further study directed toward the total synthesis of
asperparaline C (4) from tetracycle 1 by another approach is
currently under investigation.
In addition, biological tests for most of the synthetic
compounds described in this paper were conducted. As a
result, all compounds have not revealed remarkable
paralysis against silkworms at a dose of 0.1 mg of diet
and also agrochemical profiles on the usual random
screening program such as antifungal, insecticidal, and
herbicidal activity at 100 ppm. The results suggested that
the whole molecular architecture of asperparaline should be
essential for exhibiting biological activities.
4. Experimental
4.1. General
3. Conclusion
Infrared (IR) spectra were recorded on a Perkin–Elmer
FT-IR 1760X spectrometer. NMR spectra were recorded on
a JEOL JNM-GX 270 spectrometer, operating at 270 MHz
for 1H NMR and 67.5 MHz for 13C NMR. Chemical shifts in
CDCl3 are reported on the d scale relative to CHCl3
(7.26 ppm for 1H NMR and 77.00 ppm for 13C NMR) as an
internal reference. The following abbreviations are used to
multiplicities: ‘s’ (singlet), ‘d’ (doublet), ‘t’ (triplet), ‘m’
(multiplet), ‘br’ (broad). Optical rotations were measured on
a JASCO DIP-360 polarimeter. Mass spectra were measured
on a JEOL JNM-AX 500 mass spectrometer. Column
chromatography was carried out with silica gel Merck 60
(230–400 mesh ASTM). Reactions were carried out in dry
solvents under an argon atmosphere. Tetrahydrofuran
(THF) was distilled from sodium benzophenone ketyl.
In summary, a concise and stereocontrolled approach for the
construction of tetracyclic indolidine 1, a common struc-
tural motif for the biologically active alkaloid asperparaline
series of natural products and a potential intermediate for
asperparaline C (4), has been demonstrated in 8 steps in
12% overall yield starting from L-proline as a chiral process.
This protocol constitutes the following three key features:
(i) an efficient synthesis of chiral enyne 22 using Seebach’s
protocol from L-proline; (ii) a stereocontrolled catalytic
Pauson–Khand cycloaddition reaction (from 22 to 24); (iii)
a novel facile formation of bridged lactam (from 11 to 1).
The molecular modeling calculation using a popular
program (Chem3D) satisfactorily predicted the

S. Tanimori et al. / Tetrahedron 61 (2005) 2481–2492
2489
Dichloromethane (CH2Cl2) was distilled from calcium
hydride. Other reagents were purified by usual methods.
7.27–7.37 (5H, m, Ph). 13C NMR d (CDCl3): 18.0, 28.5,
35.3, 43.0, 50.7, 66.1, 69.0, 117.3, 127.3, 127.6, 128.1,
128.5, 128.6, 140.6, 140.9, 159.3, 174.1.
4.1.1.
2-(3-Methyl-but-2-enyl)-pyrrolidine-1,2-di-
carboxylic acid 1-benzyl ester 2-methyl ester (15),
2-allyl-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester
2-methyl ester (16), and 2-but-2-enyl-pyrrolidine-1,2-
dicarboxylic acid 1-benzyl ester 2-methyl ester (17). 15%
n-BuLi in hexane (18.8 mL, 30.4 mmol) was added slowly
to a solution of diisopropylamine (3.08 g, 4.27 mL,
30.4 mmol) in anhydrous THF (100 mL) at K78 8C under
nitrogen atmosphere and stirred for 30 min at 0 8C. After
cooling to K78 8C, N-Cbz-proline methyl ester (5.0 g,
19.0 mmol) in anhydrous THF (25 mL) was added over
20 min. After stirring for 1 h, HMPA (6.81 g, 6.61 mL,
38.0 mmol) was added dropwise over 5 min and stirred for
10 min. Crotyl bromide (3.13 mL, 30.4 mmol) in anhydrous
THF (25 mL) was added over 1 h and warmed to 0 8C over
30 min and stirred for 1 h at 0 8C. 1 N HCl solution (50 mL)
was added to the reaction mixture and the organic layer was
separated. The water layer was extracted with ethyl acetate
(50 mL) and the combined organic layer was washed with
satd aq NaHCO3 (30 mL) and brine (30 mL) and dried over
MgSO4. Concentration in vacuo gave a crude product,
which was purified by silica gel column chromatography
(eluting with EtOAc–hexaneZ1:9) to give crotyl proline
methyl ester 17 (4.88 g, 81%) as a pale yellow oil. RfZ0.67
(EtOAc–hexaneZ1:2, I2). IR (NaCl, film) nmax cmK1: 2954,
2881, 1742 (ester C]O), 1704 (carbamate C]O), 1408,
1357, 1169, 1120, 1025, 699. 1H NMR d (CDCl3): 1.64 (3H,
d, JZ6.4 Hz, CH]CH–CH3), 1.77–2.15 (4H, m), 2.48–
3.07 (2H, m, CH2–CH]CH), 3.47 (2H, s, O–CH2–Ph), 3.70
(3H, s, O–CH3), 5.11 (1H, dd, JZ12.2, 47.3 Hz), 5.14 (1H,
br s), 5.23–5.38 (1H, m), 5.38–5.58 (1H, m), 7.32–7.37 (5H,
m, Ph). 13C NMR d (CDCl3): 18.2, 18.7, 23.3, 36.6, 48.3,
52.1, 67.0, 68.2, 125.0, 127.5, 127.5, 127.7, 127.8, 128.0,
130.3, 136.9, 154.0, 174.6. FAB MS m/z (%):318 (MHC,
19), 274 ([MKCO2]C, 9), 182 ([MKCbz]C, 16). HRMS
(FAB) m/z (MHC): calcd for C18H24NO4, 318.1705; found,
318.1694.
4.1.2. 2-(3-Methyl-but-2-enyl)-1-prop-2-ynyl-pyrroli-
dine-2-carboxylic acid methyl ester (12), 2-allyl-1-prop-
2-ynyl-pyrrolidine-2-carboxylic acid methyl ester (21),
and 2-but-2-enyl-1-prop-2-ynyl-pyrrolidine-2-car-
boxylic acid methyl ester (22). Under nitrogen atmosphere,
sodium iodide (7.36 g, 49.1 mmol) was added to a solution
of N-Cbz-crotyl proline 17 (2.0 g, 6.3 mmol) in anhydrous
MeCN (20 mL) and cooled to 0 8C. TMSCl (3.20 mL,
25.2 mmol) was added to the mixture and the mixture was
stirred for 6 h at room temperature. After cooling to 0 8C,
1 N HCl (20 mL) was added to the mixture. After stirring for
30 min, the phases were separaterd and the water layer was
washed with hexane (20 mL!2). The water layer was
converted to pH 9–10 by adding 50% K2CO3 and extracted
with methylene chloride (20 mL!3). The organic phase
was washed with brine, dried over MgSO4, and concentrated
in vacuo to give free amine 20.
A mixture of the above amine 20, propargyl bromide
(0.71 mL, 9.4 mmol), sodium bicarbonate (1.59 g,
18.9 mmol), LiI (84.3 mg, 0.63 mmol) in MeCN (20 mL)
was heated at 60 8C with stirring for 14 h. After cooling,
water (20 mL) was added to the mixture and the two layers
were separated. The water layer was extracted with ether
(20 mL!2) and the combined organic phase was washed
with brine, dried (MgSO4) and evaporated. The residue was
purified by silica gel column chromatography (EtOAc–
hexaneZ1:19) to give enyne 22 (1.12 g, 80%) as a colorless
oil. RfZ0.72 (EtOAc–hexaneZ1:2, I2). IR (NaCl, film)
nmax cmK1: 3300 (C^C–H), 2950, 2856, 1728 (C]O),
1435, 1195, 970, 651. 1H NMR d (CDCl3): 1.65 (3H, d, JZ
7.1 Hz, CH]CH–CH3), 1.72–1.90 (3H, m), 2.16–2.26 (3H,
m), 2.60 (1H, dd, JZ7.0, 13.7 Hz, H–CH–CH]CH–CH3),
2.72–2.84 (1H, m), 3.16–3.22 (1H, m), 3.34 (1H, dd, JZ2.4,
16.8 Hz, H–CH–C^CH), 3.61 (1H, dd, JZ2.4, 16.8 Hz,
H–CH–C^CH), 3.68 (3H, s, O–CH3), 5.30–5.41 (1H, m,
CH]CH–CH3), 5.46–5.59 (1H, m, CH]CH–CH3). 13C
NMR d (CDCl3): 18.2, 21.4, 33.9, 37.7, 38.2, 51.2, 51.3,
69.7, 71.3 (C^CH), 80.9 (C^CH), 125.8 (CH]CH–CH3),
128.7 (CH]CH–CH3), 173.7. FAB MS m/z (%): 222
(MHC, 13), 190 ([MKOMe]C, 56), 162 ([MKCO2Me]C,
100). HRMS (FAB) m/z (MHC): calcd for C13H20NO2,
222.1494; found, 222.1499.
Compound 15. Pale yellow oil. RfZ0.61 (EtOAc–hexaneZ
1:2, I2). IR (NaCl, film) nmax cmK1:2955, 2880, 1742 (ester
C]O), 1705 (carbamate C]O), 1409, 1355, 1127, 1028,
1
699. H NMR d (CDCl3): 1.58 (3H, s), 1.70 (3H, s), 1.74–
2.08 (4H, m), 2.58–3.05 (2H, m, CH2–CH]C(CH3)2), 3.46
(2H, s, O–CH2–Ph), 3.71 (3H, s, O–CH3), 4.97–5.24 (3H,
m), 7.26–7.36 (5H, m, Ph). 13C NMR d (CDCl3) cisCtrans
rotamers: 18.1, 18.1, 22.8, 23.3, 26.1, 26.2, 31.9, 33.2, 35.7,
37.1, 48.4, 49.2, 52.1, 52.4, 66.6, 67.0, 68.0, 68.8, 118.3,
118.5, 127.5, 127.7, 127.8, 128.0, 128.3, 128.3, 135.1,
135.3, 136.3, 136.9, 154.0, 154.2, 174.7, 174.8. FAB MS
m/z (%): 332 (MHC, 15), 288 ([MKCO2]C, 10), 196
([MKCbz]C, 8). HRMS (FAB) m/z (MHC): calcd for
C19H26NO4, 332.1862; found, 332.1850.
Compound 12. RfZ0.79 (EtOAc–hexaneZ1:2, I2). IR
(NaCl, film) nmax cmK1: 3298 (C^C–H), 2951, 1727
(C]O), 1435, 1195, 1175, 647. H NMR d (CDCl3): 1.63
1
(3H, s), 1.70 (3H, s), 1.58–1.86 (3H, m), 2.19–2.24 (3H, m),
2.65 (1H, dd, JZ7.6, 14.3 Hz, H–CH–CH]C(CH3)2),
2.74–2.83 (1H, m, H–C5), 3.17–3.24 (1H, m, H–C5),
3.34 (1H, dd, JZ2.4, 16.8 Hz, H–CH–C^CH), 3.67 (3H, s,
O–CH3), 3.60–3.68 (1H, m), 5.02–5.08 (1H, m,
CH]C(CH3)2). 13C NMR d (CDCl3):18.1, 21.4, 26.1,
33.6, 34.0, 37.8, 51.2, 51.3, 70.0 (C2), 71.3 (C^CH), 81.0
(C^CH), 119.0 (CH]C(CH3)2), 134.2 (CH]C(CH3)2),
173.7 (C]O). FAB MS m/z (%): 236 (MHC, 31), 176
([MKCO2Me]C, 38), 166 ([MKCH2CH]C(CH3)2]C,
100). HRMS (FAB) m/z (MHC): calcd for C14H22NO2,
236.1651; found, 236.1628.
Compound 16.18 Pale yellow oil. RfZ0.59 (EtOAc–
hexaneZ1:2, I2).IR (NaCl, film) nmax cmK1: 2954, 2880,
1742 (ester C]O), 1704 (carbamate C]O), 1408, 1357,
1170, 1119, 1026, 699. 1H NMR d (CDCl3): 1.82–2.16 (4H,
m), 2.56–2.72 (1H, m, H–CH–CH]CH2), 2.88–3.17 (1H,
m, H–CH–CH]CH2), 3.47 (2H, s, O–CH2–Ph), 3.71 (3H, s,
O–CH3), 5.00–5.23 (4H, m), 5.62–5.80 (1H, m, CH]CH2),

2490
S. Tanimori et al. / Tetrahedron 61 (2005) 2481–2492
Compound 21. RfZ0.72 (EtOAc–hexaneZ1:2, I2). IR
(NaCl, film) nmax cmK1: 3299, 2952, 2837, 1727 (C]O),
1641 (C]C), 1433, 1197, 1171, 989, 918, 649. 1H NMR d
(CDCl3): 1.81–1.88 (3H, m), 2.18–2.23 (2H, m), 2.32 (1H,
dd, JZ7.1, 14.3 Hz, H–CH–CH]CH2), 2.65 (1H, dd, JZ
7.3, 14.6 Hz, H–CH–CH]CH2), 2.77–2.85 (1H, m), 3.17–
3.23 (1H, m), 3.35 (1H, dd, JZ7.6, 15.6 Hz, H–CH–
C^CH), 3.61 (1H, dd, JZ7.4, 15.4 Hz, H–CH–C^CH),
3.68 (3H, s, O–CH3), 5.06–5.13 (2H, m, CH]CH2), 5.69–
5.85 (1H, m, CH]CH2). 13C NMR d (CDCl3): 21.4, 33.9,
37.6, 39.3, 51.2, 51.3, 69.2, 71.3 (C^CH), 80.8 (C^CH),
118.0 (CH]CH2), 133.5 (CH]CH2), 173.6.
2.16 (1H, dt, JZ12.2, 7.1 Hz, H–C1), 2.27–2.36 (1H, m,
H–C7a), 2.67 (1H, dd, JZ5.6, 12.9 Hz, H–C8), 2.93 (1H,
dd, JZ8.5, 15.3 Hz, H–C3), 3.12 (1H, dd, JZ8.5, 15.3 Hz,
H–C3), 3.68–3.92 (2H, m, H2–C4), 3.79 (3H, s, O–CH3),
5.95 (1H, br s, H–C5); 13C NMR d (CDCl3): 14.2, 21.0,
36.5, 37.8, 46.4, 47.8, 47.9, 50.0, 52.1, 67.3 (C8a), 127.2
(C5), 174.0 (C4a), 174.5 (CO2Me), 209.9 (C6). EI-MS m/z
(%): 249 (MC, 39), 190 ([MKCO2Me]C, 32), 154 (100),
136 (83). HRMS (EI) m/z (MC): calcd for C14H19NO3,
249.1365; found, 249.1382.
4.1.4. 7,7-Dimethyl-6-oxo-2,3,6,7,7a,8-hexahydro-1H,
4H-3a-aza-s-indacene-8a-carboxylic acid methyl ester
(11). 15% n-BuLi in hexane (2.61 mL, 4.21 mmol) was
added slowly to a solution of diisopropylamine (0.43 g,
0.59 mL, 4.21 mmol) in anhydrous THF (15 mL) at K78 8C
under nitrogen atmosphere and stirred for 30 min at 0 8C.
After cooling to K78 8C, enone 24 (350 mg, 1.40 mmol) in
anhydrous THF (1.5 mL) was added to the above solution
over 5 min. After stirring for 5 min, HMPA (0.50 g,
0.49 mL, 2.81 mmol) was added dropwise and stirred for
10 min. MeI (0.80 g, 0.35 mL, 5.61 mmol) was added and
stirred for 1 h at K78 8C. Saturated aqueous NaCl (15 mL)
was added and the organic layer was separated. The water
layer was extracted with ethyl acetate (30 mL) and the
combined organic layer was washed with brine (30 mL) and
dried over MgSO4. Concentration in vacuo gave a residue,
which was purified by silica gel column chromatography
(hexane–EtOAcZ3:2) to give enone 11 (285 mg, 77%) as a
pale yellow oil. RfZ0.30 (EtOAc, I2). [a]2D2 C18.18 (c 0.65,
CHCl3); IR (NaCl, film) nmax cmK1: 2965, 2869, 1729 (ester
C]O), 1708 (ketone C]O), 1633 (C]C), 1449, 1191,
1152. 1H NMR d (CDCl3): 0.92 (3H, s, CH3–C6), 1.03 (3H,
s, CH3–C6), 1.26–1.38 (1H, m, H–C8), 1.71–1.88 (3H, m),
2.04–2.13 (1H, m), 2.27–2.39 (2H, m), 2.92 (1H, dd, JZ7.6,
15.6 Hz, H–C12), 3.12 (1H, dd, JZ7.5, 15.4 Hz, H–C12),
3.72 (3H, s, O–CH3), 3.79–3.87 (2H, m, H2–C2), 5.83 (1H,
br s, H–C4). 13C NMR d (CDCl3): 20.4, 21.0, 25.2, 33.8,
36.7, 46.3, 48.0, 49.7, 50.0, 52.1, 67.2, (C8a), 125.3 (C5),
174.0 (C4a), 174.5 (CO2Me), 209.9 (C6). EI-MS m/z (%):
263 (MC, 100), 204 ([MKCO2Me]C, 82), 154 (62), 136
(43). HRMS (EI) m/z (MC): calcd for C15H21NO3,
263.1521; found, 263.1544.
4.1.3. 6-Oxo-2,3,6,7,7a,8-hexahydro-1H,4H-3a-aza-s-
indacene-8a-carboxylic acid methyl ester (23) and
7-methyl-6-oxo-2,3,6,7,7a,8-hexahydro-1H,4H-3a-aza-s-
indacene-8a-carboxylic acid methyl ester (24).
4.1.3.1. Synthesis of 23 by a stoichiometric Pauson–
Khand reaction (Table 2, entry 3). 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 21 (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 8C. After cooling, the mixture was filtered
through Celite, which was thoroughly washed with acetone.
The solvent was eliminated under reduced pressure, and the
crude product was purified by silica gel column chroma-
tography (eluting with hexane: EtOAcZ1:1) to give enone
23 (201 mg, 94%) as a pale yellow crystal. RfZ0.25
(EtOAc). Mp 80.2–81.1 8C. [a]1D8 C34.18 (c 1.9, CHCl3). IR
(NaCl, film) nmax cmK1:2954, 1713 (C]O), 1630 (C]C),
1
1445, 1198, 1152. H NMR d (CDCl3): 1.37 (1H, t, JZ
12.5 Hz, H–C8), 1.73–2.19 (5H, m), 2.57–2.66 (2H, m, H2–
C7), 2.70–2.77 (1H, m, H–C7a), 2.91 (1H, dd, JZ7.3,
16.5 Hz, H–C3), 3.09–3.17 (1H, m, H–C3), 3.79 (3H, s,
O–CH3), 3.79–3.94 (2H, m, H2–C4), 5.98 (1H, br s, H–C5).
13C NMR d (CDCl3): 21.0, 36.5, 38.1, 38.7, 42.0, 47.8, 49.9,
52.1, 67.3 (C8a), 128.4 (C5), 174.5 (C4a), 176.4 (CO2Me),
207.7 (C6). FAB MS m/z (%): 236 (MHC, 69), 176
([MKCO2Me]C, 100). HRMS (EI) m/z (MC): calcd for
C13H17O3N, 235.1209; found, 235.1220.
4.1.3.2. Synthesis of 24 by a catalytic Pauson–Khand
reaction (Table 7, entry 2). To a stirred solution of
Co2(CO)8 (37 mg, 0.11 mmol) in dry benzene (50 mL)
under CO atmosphere at room temperature was added
dropwise a solution of enyne 22 (500 mg, 2.26 mmol) in
benzene (5 mL). After 2 h of stirring at room temperature,
NMO (50% in water, 0.028 mL, 0.11 mmol) was added in
one portion. The reaction mixture was stirred for 22 h at
70 8C. After cooling, the mixture was filtered through
Celite, which was thoroughly washed with acetone. The
solvent was eliminated under reduced pressure, and the
crude product was purified by silica gel column chroma-
tography (eluting with hexane–EtOAcZ1:1) to give enone
24 (304 mg, 54%) as a brown oil and recovered enyne 22
(130 mg, 26%). RfZ0.30 (EtOAc, I2). [a]2D2 C44.98(c 1.0,
CHCl3). IR (NaCl, film) nmax cmK1: 2957, 2878, 1728 (ester
C]O), 1708 (ketone C]O), 1632 (C]C), 1449, 1176. 1H
NMR d (CDCl3): 1.07 (3H, d, JZ7.3 Hz, CH3–C7), 1.36
(1H, t, JZ12.9 Hz, H-8), 1.73–1.85 (1H, m, H–C1), 1.85–
1.95 (2H, m, H2–C2), 1.99 (1H, dq, JZ2.9, 7.3 Hz, H–C7),
4.1.5.
11,13-Diaza-4,4,13-trimethyltetracyclo-
[5.5.2.01,5.07,11]tetradecane-3,14-dione (1), 11,13-diaza-
13-methyltetracyclo[5.5.2.01,5.07,11]tetradecane-3,14-
dione (27), and 11,13-diaza-4,13-dimethyltetracyclo-
[5.5.2.01,5.07,11]tetradecane-3,4-dione (36). A solution of
enone 11 (0.2 g, 0.76 mmol) in 40% aqueous methylamine
(2.62 mL, 30.4 mmol) was stirred for 48 h at room
temperature. Water (10 mL) was added to the mixture and
the solution was heated at reflux for 4 h. After cooling, the
mixture was concentrated in vacuo, the residue was
dissolved in MeOH (6 mL) and water (1.2 mL), and SiO2
(0.8 g) was added. The mixture was stirred for 18 h at
room temperature. After cooling, the mixture was filterd
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–acetoneZ1:1) to give lactam 1 (140 mg, 70%)
as a brown oil. RfZ0.7 (acetone, I2). [a]2D2 K43.68(c 0.96,
CHCl3). IR (NaCl, film) nmax cmK1: 2991, 2887, 1766

S. Tanimori et al. / Tetrahedron 61 (2005) 2481–2492
2491
(ketone C]O), 1660, (lactam C]O), 1650, 1388, 1095. 1H
NMR d (CDCl3): 0.97 (3H, s, CH3–C4), 1.07 (3H, s, CH3–
C4), 1.38–1.49 (1H, m, H–C6), 1.65–1.74 (1H, m, H–C6),
1.83–1.99 (2H, m), 2.15–2.44 (4H, m), 2.47 (1H, dd, JZ1.5,
2.0 Hz), 2.53–2.67 (2H, m), 2.99 (3H, s, CH3–N13), 3.05–
3.13 (1H, m, H–C10), 3.24 (1H, d, JZ11.3 Hz, H–C12). 13C
NMR d (CDCl3): 17.7, 20.9, 22.2, 23.1, 27.9, 29.8, 36.5,
43.9, 46.2, 52.2, 54.0, 56.0, 61.2, 173.0 (C14), 217.6 (C3).
EI-MS m/z (%): 262 (MC, 1), 247 (1), 234 (1), 219 (8), 203
(80), 190 (6), 176 (7), 165 (8), 138 (17), 133 (33), 120 (13),
96 (27), 83 (12), 68 (15), 55 (25), 41 (100). HRMS (EI) m/z
(MC): calcd for C15H22N2O2, 262.1681; found, 262.1679.
JZ7.4 Hz, CH2–CH]CH), 2.74–2.99 (2H, m), 4.24 (1H,
s), 5.46–5.58 (2H, m). 13C NMR d (CDCl3): 17.3, 21.1, 21.2,
21.3, 28.8, 34.3, 36.8, 49.5, 107.1, 124.8, 133.1, 174.5
(C]O). FAB MS m/z (%): 238 (MHC, 4), 180 ([MKt-
Bu]C,100), 135 (89). HRMS (FAB) m/z (MHC): calcd for
C14H24NO2, 238.1807; found, 238.1834.
4.1.7. 2-But-2-enyl-pyrrolidine-2-carboxylic acid (33). A
mixture of crotyl oxazolidone 32 (3.0 g, 13.4 mmol) and
silica gel (SiO2, 3.0 g) in MeOH/H2O (6:1, 30 mL) was
stirred for 48 h at room temperature. After filtration, the
residue was washed with MeOH and the filtrate was
concentrated in vacuo. The residue was dissolved in
CHCl3/MeOH (20:1, 30 mL) and again filtered. The residue
was washed with CHCl3/MeOH (20:1) and the filtrate was
concentrated in vacuo. The residue was washed with ether
and dried over P2O5 under reduced pressure to give
carboxylic acid 33 (2.0 g, 88%) as a colorless crystal.
RfZ0.23 (MeOH–CHCl3Z1:4, ninhydrin).Mp 280–285 8C.
Compound 27. RfZ0.43 (acetone). [a]2D0 K149.68 (c 1.1,
CHCl3). IR (KBr, disk) nmax cmK1:3440 (br), 2923, 1750
(ketone C]O), 1666 (lactam C]O), 1651, 1390, 1097. 1H
NMR d (CDCl3): 1.35–1.46 (1H, m, H–C6), 1.69 (1H, dd,
JZ5.5, 12.5 Hz, 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, JZ11.6 Hz, H–C12).
13C NMR d (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 (MC, 5), 206 (3), 175 (100), 149 (51), 137
(21), 108 (12), 96 (20). HRMS (EI) m/z (MC): calcd for
C13H18N2O2, 234.1368; found, 234.1349.
[a]2D0 K70.48(c 1.0, CH3OH). IR (KBr, disk) nmax cmK1
:
3085, 1628 (C]O), 1390, 933. 1H NMR d (D2O): 1.64 (3H,
d, JZ6.4 Hz, CH]CH–CH3), 1.73–1.90 (4H, m), 2.24 (1H,
dd, JZ7.1, 14.6 Hz, H–CH–CH]CH), 2.69 (1H, dd, JZ
7.3, 14.6 Hz, H–CH–CH]CH), 2.88–3.03 (2H, m), 5.46–
5.58 (2H, m). 13C NMR d (D2O): 17.3, 22.6, 31.3, 37.8,
42.5, 77.1, 123.8, 133.2, 179.5 (CO2H). FAB MS m/z
(%):170 (MHC, 100), 124 ([MKCO2H]C, 100). HRMS
(FAB) m/z (MHC): calcd for C9H16NO2, 170.1181; found,
170.1100.
Compound 36. RfZ0.49 (acetone, I2). Mp 116–118.2 8C. IR
(KBr, disk) nmax cmK1: 2980, 2875, 2798, 1746 (ketone
C]O), 1662 (lactam C]O), 1651, 1390, 1324, 1098. H
1
NMR d (CDCl3): 1.15 (3H, d, JZ7.0 Hz, CH3–C4), 1.36–
1.48 (1H, m, H–C6), 1.64–1.73 (1H, m, H–C6), 1.84–1.96
(3H, m), 2.18–2.39 (4H, m), 2.51–2.64 (3H, m), 2.98 (3H, s,
CH3–N13), 3.05–3.13 (1H, m, H–C10), 3.24 (1H, d, JZ
11.3 Hz, H–C12). 13C NMR d (CDCl3): 12.8, 22.1, 26.6,
27.6, 33.4, 44.1, 47.9, 48.3, 53.7, 54.7, 60.9, 65.8, 172.6
(C14), 213.4 (C3). EI-MS m/z (%): 249 (MHC, 56), 189
(37), 154 (100), 136 (89). HRMS (EI) m/z (MC): calcd for
C14H20N2O2, 248.1525; found, 248.1521.
4.1.8. (R)-2-(K)-Crotylproline methyl ester hydro-
chloride (34). Thionyl chloride (4.31 mL, 59.1 mmol) was
added dropwise to a solution of a-crotyl proline 33 (2.00 g,
11.82 mmol) in anhydrous MeOH (50 mL) at 0 8C and the
mixture was stirred for 48 h at room temperature. After
refluxing for 1 h, the mixture was concentrated in vacuo.
The residue was crystallized in MeOH/EtOAc followed by
drying over P2O5 under reduced pressure to give methyl
ester 34 (2.34 g, 90%) as a colorless crystal. RfZ0.74
(MeOH–CHCl3Z1:4, ninhydrin). Mp 166.5–170.0 8C.
4.1.6. 7a-But-2-enyl-3-tert-butyl-tetrahydro-pyrrolo-
[1,2-c]oxazol-1-one (32). 15% n-BuLi in hexane
(28.71 mL, 46.4 mmol) was added slowly to a solution of
diisopropylamine (6.52 mL, 46.4 mmol) in anhydrous THF
(100 mL) at K78 8C under nitrogen atmosphere and stirred
for 30 min at 0 8C. After cooling to K78 8C, oxazolidone 31
(5.00 g, 27.3 mmol) in anhydrous THF (25 mL) was added
over 20 min. After stirring for 1 h, HMPA (9.49 mL,
54.6 mmol) was added dropwise over 5 min and stirred
for 10 min. Crotyl bromide (4.77 mL, 46.4 mmol) in
anhydrous THF (25 mL) was added over 1 h and stirred
for 1 h at K78 8C. The mixture was warmed to K30 8C over
1 h and saturated aqueous NaHCO3 (50 mL) was added. The
organic layer was separated. The water layer was extracted
with ethyl acetate (50 mL) and the combined organic layer
was washed with satd aq NaHCO3 (50 mL) and brine
(50 mL) and dried over MgSO4. Concentration in vacuo
gave a residue, which was purified by distillation under
reduced pressure to give crotyl Oxazolidinone 32
(3.78 g, 64%) as a pale yellow oil. RfZ0.60 (EtOAc–
C6H6Z1:200). Bp3: 85–90 8C. [a]2D2 C13.58(c 1.0, CHCl3).
IR (NaCl, film) nmax cmK1: 2963, 2871, 1780 (C]O), 1633,
[a]2D2 K48.78(c 1.0, CH3OH). IR (KBr, disk) nmax cmK1
:
2880, 2711, 2490, 1759 (C]O), 1644 (C]C), 1588, 1341,
1
1220, 1154, 946. H NMR d (CD3OD): 1.73 (3H, d, JZ
6.4 Hz, CH]CH–CH3), 1.88–2.50 (4H, m), 2.71 (1H, dd,
JZ7.1, 14.6 Hz, H–CH–CH]CH), 2.93 (1H, dd, JZ7.1,
14.6 Hz, H–CH–CH]CH), 3.40–3.48 (2H, m), 3.89, (3H, s,
O–CH3), 5.55–5.78 (2H, m). 13C NMR d (CD3OD): 17.6,
20.8, 31.3, 37.8, 42.2, 50.7, 67.7, 123.1, 133.0, 174.5.
4.1.9. 11,13-Diaza-3-(dicyanomethylene)-13-methyl-
tetracyclo-[5.5.2.01,5.07,11]tetradecan-14-one (35). The
lactam 27 (90.3 mg, 0.385 mmol) and malononitrile
(51 mg, 0.77 mmol) were added to benzene (10 mL)
containing piperidine (7.99 mg, 0.039 mmol) and benzoic
acid (18.8 mg, 0.154 mmol), and the mixture was heated to
reflux with azeotropic removal of water by Dean–Stark trap
for 28 h. After cooling, the mixture was diluted with diethyl
ether (20 mL), and successively washed with water
(10 mL), a 10% NaHCO3 solution (10 mL) and brine
(10 mL). The organic phase was dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash
chromatography over silica gel (eluting with EtOAc) to give
unsaturated dinitrile 35 (68.5 mg, 63%) as an pale yellow
1
1191. H NMR d (CDCl3): 0.92 (9H, s), 1.64 (3H, d, JZ
7.1 Hz, CH]CH–CH3), 1.73–1.90 (4H, m), 2.35 (2H, d,

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S. Tanimori et al. / Tetrahedron 61 (2005) 2481–2492
5. Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am.
Chem. Soc. 1983, 5390–5398.
crystal. RfZ0.70 (acetone, I2). Mp 151.6–153.0 8C. IR
(KBr, disk) nmax cmK1:3437 (br), 2946, 2806, 2234 (C^N),
1661 (amide C]O), 1620 (C]C), 1386, 1320, 1103. H
1
6. Banks, R. M.; Blanchflower, S. E.; Everett, J. R.; Manger,
B. R.; Reading, C. J. Antibiot. 1997, 50, 840–846.
NMR d (CDCl3): 1.34–1.46 (1H, m, H–C6), 1.68 (1H, dd,
JZ6.3, 13.2 Hz, H–C6), 1.80-1.92 (2H, m), 2.13–2.39 (5H,
m), 2.48–2.72 (4H, m), 2.96 (3H, s, CH3–N13), 3.01–3.15
(1H, m, H–C10), 3.21 (1H, dd, JZ7.8, 20.0 Hz, H–C12).
13C NMR d (CDCl3): 22.3, 27.0, 27.7, 33.2, 37.9, 40.3, 43.0,
53.6, 53.7, 64.7, 66.0, 84.9 (C(CN)2), 110.5 (CN), 110.9
(CN), 172.5 (C14), 184.4 (C3). FAB MS m/z (%): 283
(MHC, 100), 223 (53). HRMS (FAB) m/z (MHC): calcd for
C16H19N4O, 283.1559; found, 283.1548.
7. Paterson, R. R. M.; Hawksworth, D. L. Trans. Br. Mycol. Soc.
1985, 85, 95–100 and references cited therein.
8. Blanchflower, S. E.; Banks, R. M.; Everett, J. R.; Reading, C.
J. Antibiot. 1993, 46, 1355–1363 and references cited therein.
9. (a) Polonsky, J.; Merrien, M. A.; Prangee, T.; Pascard, C.;
Moreau, S. J. Chem. Soc., Chem. Commun. 1980, 601–602. (b)
Prange, T.; Bullion, M.-A.; Vuilhorgne, M.; Pascard, C.;
Polosky, J. Tetrahedron Lett. 1980, 22, 1977–1980.
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11. Williams, R. M. Chem. Pharm. Bull. 2002, 50, 711–740 and
references cited therein.
Acknowledgements
12. Biosynthetic studies of the spirosuccinimide ring system, see:
Gray, C. R.; Sanz-Cervera, J. F.; Silks, L. A.; Williams, R. M.
J. Am. Chem. Soc. 2003, 125, 14692–14693.
We thank Professor H. Hayashi of Graduate School of
Agriculture and Life Sciences at Osaka Prefecture
University for his kind cooperation with this project and
helpful advice.
13. Tanimori, S.; Fukubayashi, K.; Kirihata, M. Biosci.
Biotechnol. Biochem. 2000, 64, 1758–1760. Earlier studies
on spirosuccinimide ring system, see: Gonzalez, F.; Sanz--
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4519–4522.
References and notes
14. All calculations were carried out using the MM2 in CS
Chem3D version 5.0, Cambridge Soft Corporation.
15. Effect of promoters on Pauson–Khand reaction, see: Chung,
Y. K.; Lee, B. Y.; Jeong, N.; Hudecek, M.; Pauson, P. L.
Organomettalics 1993, 12, 220–223.
1. Tanimori, S.; Fukubayashi, K.; Kirihata, M. Tetrahedron Lett.
2001, 42, 4013–4016.
2. Hayashi, H.; Nishimoto, Y.; Nozaki, H. Tetrahedron Lett.
1997, 38, 5655–5658. Hayashi, H.; Nishimoto, Y.; Akiyama,
K.; Nozaki, H. Biosci. Biotech. Biochem. 2000, 64, 111–115.
3. A review for Pauson–Khand reaction, see: Shore, N. E. Org.
React. 1991, 40, 1–90. Shore, N. E. In Trost, B. M., Fleming,
I., Pattanden, G., Eds.; Comprehensive Organic Synthesis;
Pergamon: Oxford, 1991; Vol. 5, pp 1037–1064. Ching, Y. K.
Coord. Chem. Rev. 1999, 188, 297–341. Brummond, K. M.;
Kent, J. L. Tetrahedron 2000, 56, 3263–3283.
16. For Lewis acid-catalyzed Knoevenagel reaction, see: Mori, K.;
Hara, T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am. Chem.
Soc. 2003, 125, 11460–11461.
17. Only a small amount of decomposed ring-opening and/or
retro-Michael products was obtained.
18. (a) Dumas, J.-P.; Germanas, J. P. Tetrahedron Lett. 1994, 35,
1493–1496. (b) Kim, K.; Dumas, J.-P.; Germanas, J. P. J. Org.
Chem. 1996, 61, 3138–3144. (c) Pfeifer, M. E.; Linden, A.;
Robinson, J. A. Helv. Chim. Acta 1997, 80, 1513–1527.
4. Recent review for catalytic Pauson–Khand reaction, see:
Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int. Ed. 2003, 42,
1800–1810.