Investigation of the synthesis of angular tricyclic compounds by intramolecular Pauson-Khand reaction of exo- and endo-cyclic enynes

Article abstract of DOI:10.1016/S0040-4020(01)00151-X

Intramolecular Pauson-Khand reaction of various alkynyl exo-alkylidene-cyclohexanes and -pentane gives angular type 6-5-5 and 5-5-5 tricyclic compounds in good to high yield. The present reaction also offers convenient construction of two contiguous quaternary centers, which could not be synthesized from alkynyl endo-cycloolefins. Scope and limitation of the present reaction of various exo- and endo-cyclic enynes are also described.

Full text of DOI:10.1016/S0040-4020(01)00151-X

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2729±2738
Investigation of the synthesis of angular tricyclic compounds
by intramolecular Pauson±Khand reaction of exo- and
endo-cyclic enynes
Miyuki Ishizaki,p Kazuhiko Iwahara, Yuka Niimi, Hiroshi Satoh and Osamu Hoshinop
Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12, Ichigaya Funagawara-machi, Shinjuku-ku, Tokyo 162-0826, Japan
Received 11 January 2001; accepted 5 February 2001
AbstractÐIntramolecular Pauson±Khand reaction of various alkynyl exo-alkylidene-cyclohexanes and -pentane gives angular type 6±5±5
and 5±5±5 tricyclic compounds in good to high yield. The present reaction also offers convenient construction of two contiguous quaternary
centers, which could not be synthesized from alkynyl endo-cycloole®ns. Scope and limitation of the present reaction of various exo- and
endo-cyclic enynes are also described. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
reaction of various exo- and endo-cyclic enynes to form
angular type 6±5±5 and 5±5±5 tricyclic compounds
(Scheme 1).9
Since the ®rst report1 of intermolecular Pauson±Khand
reaction in 1971, it is well known to be a useful reaction
for formation of cyclopentenones from an alkyne±cobalt
complex with alkenes by [21211] cycloaddition.2 In
1981, Schore and co-workers3 reported the ®rst intra-
molecular version of the Pauson±Khand reaction and the
reaction has been widely applicable protocol for synthesis
of natural products.4 However, for the intramolecular reac-
tion of cyclic ole®ns, there are many reports on the reaction
of endo-cyclic cyclopentenes5 having alkynyl group on
ole®nic moiety to give angular tricyclic compounds,
which constitute the 5±5±5 ring system, so called tri-
quinanes. The similar reaction of exo-cyclic enynes is an
alternative useful approach to obtain angular tricyclic
compounds. However, only a few reports6 on exo-cyclic
enynes containing three or four membered ring systems
have appeared, despite of the possibility that the latter
approach should be superior to the former one; highly
hindered tetra-substituted cyclic enynes are required for
synthesis of angular tricyclic compounds having continuous
quaternary carbon centers7 by the reaction of endo-cyclic
enynes.8 Concurrently, Malacria and co-workers have
reported6d synthesis of angular triquinane by intramolecular
Pauson±Khand reaction of exo-cyclic enyne, although the
yield was quite moderate (20%). Therefore, the difference of
reactivity on intramolecular Pauson±Khand reaction of exo-
and endo-cyclic ole®ns attracted us to investigate its scope
and limitation. Here, we wish to report our results on the
O
R
Pauson-Khand
reaction
m
R
m
n
X
n
X
m
m
Pauson-Khand
reaction
O
R = H, Me, CO2Et
X = CH2, O, NCO2Bn, NTs
m= 1, 2, n = 1, 2
Scheme 1.
2. Results and discussion
At ®rst, we examined intramolecular Pauson±Khand
reactions of various exo-cyclic enynes (1±11), which would
lead to 6±5±5 and 5±5±5 angular tricyclic compounds.
Synthesis of various exo-cyclic enynes (1±11) was as
follows (Scheme 2). Namely, conversion of alcohol (23)10
to iodide (24), treatment of which with acetylene±ethylene-
diamine complex gave an enyne (1) in 64% overall yield.
Enynes (2, 4, 6, 8±10) were synthesized in 25±90% yield by
Wittig ole®nation of the corresponding ketones (25,11 29,12
33,13 34,13 3514). Treatment of 2 with BuLi followed by
exposure with MeI afforded 7 in 91% yield. Enynes (3, 5)
Keywords: Pauson±Khand reaction; exocyclic enyne; endocyclic enyne;
angular tricyclic compound.
p
Corresponding authors. Tel.: 181-3-3260-6725; fax: 181-3-3258-3045;
e-mail: ishizaki@ps.kagu.sut.ac.jp; hoshino@ps.kagu.sut.ac.jp
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00151-X

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M. Ishizaki et al. / Tetrahedron 57 (2001) 2729±2738
R'
R
R
R
Me
Me
R'
23 : R = OH
24 : R = I
1 : R = C CH
25 : R = O, R' = H
26 : R = O, R' = CO2Me
27 : R = CH2, R' = CO2Me
28 : R = CH2, R' = CHO
3 : R = CH2, R' = C CH
a
b
c
f
g
h
2 : R = CH2, R' = H
7 : R = CH2, R' = Me
6 : R = CHMe, R' = H
e
d
R'
R
R
R
OCH2C CH
CO2Et
R'
Me
O
O
t
33: R = O, R' = H
8: R = CH2, R' = H
34: R = O, R' = Me
9: R = CH2, R' = Me
30 : R = O, R' = CO2 Bu
c
c
c
t
29 : R = O
31 : R = CH2, R' = CO2 Bu
32 : R = CH2, R' = CHO
5 : R = CH2, R' = C CH
g
h
c
4 : R = CH2
R
Ts
N
R
Me
35 : R = O
36 : R = CO2H
f
i
j
10 : R = CH2
37 : R = NHCO2Bn
11 : R = N(CH2C CH)CO2Bn
Scheme 2. (a) PPh3, I2, Py, CH2Cl2; (b) HCuCLi(en), DMSO±Et2O; (c) MeBr´PPh3, t-BuOK, THF; (d) BuLi, MeI, THF; (e) EtBr´PPh3, t-BuOK, THF; (f)
CH2Br2, Zn, TiCl4, CH2Cl2; (g) DIBAH, THF; (h) MeCOC(vN2)P(vO)(OEt)2, K2CO3, MeOH; (i) DPPA, Et3N, BnOH, PhMe; (j) NaH, 3-bromopropyne,
THF.
were obtained from 2615 and 3016 by Wittig ole®nation,
reduction with DIBAH and reaction with diethyl 1-diazo-
2-oxopropylphosphonate.17 A nitrogen atom containing
enyne (11) was synthesized from 3618 by Curtius rearrange-
ment and propargylation.
would produce (1R,8S)-13, stereoselectively. On the basis
of the reaction mechanism, stereochemistry of other angular
tricyclic products was estimated. Kundensen and Shore
have reported5a,b that intramolecular Pauson±Khand reac-
tion of endo-cyclic tetra-substituted ole®n could not give
the desired product bearing two continuous quaternary
carbon centers, which was attributed to steric hindrance of
tetra-substituted ole®ns. Therefore, the present reaction
offers practical method for construction of such product.8
Similarly, 1-(3-butynyl)-1-methyl-2-methylenecyclopentane
(3) furnished triquinane (14) in 89% yield by Method B
(run 7). Functionalized enynes (4, 5) gave the corresponding
tricyclic compounds (15, 16) in 50±86% yield (runs 8±10).
The reaction of tri-substituted ole®n (6) afforded 17 as a sole
stereochemical product in low yield with amine N-oxide
(Methods A and B), however, in 49% yield under re¯uxing
in benzene (Method C) and in 53% yield in toluene (Method
D) (runs 11±14).20 Stereochemistry of 17 was determined
by NOE experiment between two Me groups attached to C2
(d 0.90) and C8 (d 1.28). Similarly, the reaction of substi-
tuted alkyne (7) gave tricyclic compound (18) in 32% yield
by Method C, and in 63% yield by Method D (runs 17 and
18). This remarkable temperature effect suggested that the
transition state in the reaction of hindered enynes (6, 7)
would require high activation energy. Synthesis of various
angular aza- and oxa-tricyclic compounds (19±22) from
enynes (8±11) was also successful in good yield (runs
19±29).
With exo-cyclic enynes (1±11) in hand, intramolecular
reaction of an alkyne±cobalt complex bearing exo-cyclic
ole®ns (1±11) was performed by the following methods
although there are many methods19 for the reaction as a
convenient treatment; treatment with NMO (N-methyl-
morpholine N-oxide)19a in CH2Cl2 at rt (Method A); re¯ux-
ing in benzene with TMANO (trimethylamine N-oxide)19b
(Method B); re¯uxing in benzene (Method C); re¯uxing in
toluene (Method D). The results are shown in Table 1.
At ®rst, we investigated the reaction of 1-(3-butynyl)-2-
methylenecyclohexane (1). The reaction by Methods A±C
smoothly proceeded stereoselectively to give the desired
angular tricyclic compound (12), which constitutes the
6±5±5 ring system, in 66±81% yield (runs 1±3). To the
best of our knowledge, this is the ®rst synthesis of angular
type 6±5±5 ring system by intramolecular Pauson±Khand
reaction. The reaction of 1-(3-butynyl)-1-methyl-2-
methylenecyclohexane (2) afforded 13, which has two
continuous quaternary carbon centers, in 57±85% yield
(runs 4±6). Stereochemistry of 13 was con®rmed by NOE
experiment between Me group (d 0.77) and C2±H (d 2.10).
Plausible reaction mechanisms on the formation of 13 from
2 are depicted in Scheme 3. The reaction of 2 with Co2(CO)8
gives a cobalt-complex, the preferable conformation of
which would be 2a by the 1,3-allylic strain. Then, 2a
We next carried out the reaction of homologues (40, 44) of
exo-cyclic enynes (2, 3), in order to examine the possibility
of formation of 6±6±5 and 5±6±5 tricyclic systems by the

M. Ishizaki et al. / Tetrahedron 57 (2001) 2729±2738
2731
Table 1. Intramolecular Pauson±Khand reaction of various exocyclic ole®ns bearing alkynyl group
Product(%)b
Methoda
Product(%)b Run
Methoda
Time(h)
Time(h)
Substrate
Run
Substrate
O
Me
Me
Me
1
8
Me
O
H
H
1
2
3
(±)-1
71
(±)-12
A
B
C
2
3
1
(±)-18
27
13
8
6
A
B
C
D
15
(±)-7
66
16
36
32
63
81
17
18
O
6
Me
O
O
H
Me
(1R,8S)-13
4
5
6
(S)-2
57
85
74
3
2
2
A
B
C
O
H
(±)-19
65
67
71
3
2
3
19
20
21
(±)-8
A
B
C
O
Me
O
Me
O
7
8
(R)-3
89
(1S,8R)-14
B
B
2
Me
O
Me
Me
O
Me
O
(±)-20
73
43
68
2
2
3
(±)-9
A
B
C
22
23
24
O
O
O
(1S,8S)-15 86
(S)-4
(S)-5
4
O
O
NTs
H
CO2Et
N
Ts
H
CO2Et
88
48
77
1
2
2
(±)-21
3
3
A
C
(1S,8R)-16 50
25
26
27
(±)-10
9
10
A
B
C
73
Me
O
Me
O
Me
2
8
NCO2Bn
Me
Me
N
CO2Bn
Me
A
B
C
D
(±)-17 22
(±)-6
(E/Z = 18/82)
2
3
2
2
11
12
13
14
25
49
53
80
80
2
2
(±)-22
28
29
(±)-11
A
C
a
See text.
b Isolated yield.
intramolecular Pauson±Khand reaction (Scheme 4). Thus,
1-methyl-2-methylene-1-(4-pentynyl)cyclo-hexane (40)
Pd-mediated coupling with trimethylsilylacetylene and
desilylation.23 Gratifyingly, the reaction of 48 by Method
D gave a new desired angular tetracyclic compound (49),
although in low yield (11.3%). These results indicated that
conformational change of the substrate would be an impor-
tant factor to occur in the Pauson±Khand reaction of exo-
cyclic enynes.
and -pentane (44) were prepared from alcohol (38)21 and
ester (27) in several steps. However, the reaction of 40
and 44 by both Methods A and C did not afford the desired
tricyclic compounds (41, 45) at all, although formation of
alkyne±cobalt complex was detected on TLC. These results
mean that a conformation in transition state would play an
important role. For con®rming the assumption, we also
synthesized enyne (48) having a rigid conformation due to
an aromatic ring by Wittig ole®nation of 4622 followed by
Finally, we examined to synthesize 6±5±5 and 6±5±6
tricyclic compounds by intramolecular Pauson±Khand
reaction of endo-cyclic enynes (52, 55) (Scheme 5). Thus,

2732
M. Ishizaki et al. / Tetrahedron 57 (2001) 2729±2738
CO
Co
Co(CO)3
Me
Me
Co2(CO)8
Me
Co(CO)3
Co
(CO)3
CO
(S)-2
2a
NOE
Me
Co(CO)2
(CO)2
Co(CO)3
O
H O
Co(CO)3
H
Co
2
Me
Me
(1R, 8S)-13
Scheme 3.
O
CH2I
CH2OH
a
CH2C CH
Pauson-
b
a
Me
Me
Me
41 : n = 2
45 : n = 1
n
Khand
reaction
39
40
38
Me
Pauson-
Khand
reaction
Me
Me
Me
Me
c
b
CH2C CH
CO2Me
CH2OH
CH2I
44
27
42
43
O
I
I
O
Pauson
Khand
e
d
CO2Et
CO2Et
CO2Et
CO2Et
49
47
46
48
Scheme 4. (a) PPh3, I2, Py, CH2Cl2; (b) HCuCLi(en), DMSO±Et2O; (c) LiAIH4, THF; (d) MeBr´PPh3, t-BuOK, THF; (e) TMSCuCH, PdCl2(PPh3)2, CuI,
Et3N, CH2Cl2, TBAF, THF.
a
b
OH
I
52
50
51
c
n
R
•
+
TMS
O
54 : R = TMS
55 : R = H
56 : n = 1
57 : n = 2
53
d
Scheme 5. (a) PPh3, I2, Py, CH2Cl2; (b) HCuCLi(en), DMSO±Et2O; (c) TMSCuCCH3, BuLi, THF; (d) NaOH, MeOH, H2O.
enyne (52) was prepared from 50 in the usual manner as
described above. Propargylation24 of iodide (51) with
trimethylsilypropynyllithium afforded propadiene (53) and
enyne (54) in 15 and 85% yield, respectively. Desilylation23
of 54 gave 55 in 94% yield. The reaction of both enynes
(52, 55) by Methods A and C did not produce the desired
tricyclic compounds (56, 57) at all. At this stage, the
reason why desired compounds could not be formed was
uncertain.
3. Conclusions
In summary, we have investigated intramolecular Pauson±
Khand reaction of exo- and endo-cyclic enynes. Feature of
the present reaction is as follows: (1) 6±5±5 and 5±5±5
type angular tricyclic skeletons including continuous
quaternary centers were constructed by the reaction of
exo-cyclic enynes (1±11) in good to high yield; (2) cycliza-
tion of homologues (40, 44) of enynes (2, 3) did not afford

M. Ishizaki et al. / Tetrahedron 57 (2001) 2729±2738
2733
the desired tricyclic compound, except for the reaction of
enyne (48) containing an aromatic ring; (3) under conditions
similar to those noted for exo-cyclic enynes, the reaction of
endo-cyclic enynes (52, 55) did not give 6±5±5 and 5±6±5
type angular tricyclic compounds at all. Thus, intramolecu-
lar Pauson±Khand reaction of exo-cyclic enynes offers a
convenient preparation of angular type 6±5±5 and 6±6±5
tricyclic compounds, which could not be synthesized from
endo-cyclic enynes. Furthermore, it is noteworthy that the
present reaction is effective for construction of contiguous
quaternary centers, which is dif®cult in the reaction of endo-
cyclic ole®ns.8
pentane (43). From 42 (0.581 g, 3.78 mmol), 43 (0.916 g,
29
92.0%) was obtained as a colorless oil; [a]D ˆ142.08 (c
1.06, CHCl3); 1H NMR d 4.85, 4.69 (each 1H, s), 3.16 (2H,
t, Jˆ6.9 Hz), 2.33±2.41 (2H, m), 1.73±1.87 (2H, m), 1.39±
1.67 (6H, m), 1.03 (3H, s); IR 1740, 1690, 1680 cm21; MS
m/z 264 (M1); high-resolution mass m/z calcd for C10H17I
(M1) 264.0375, found: 264.0380.
4.2.4. 1-(3-Iodopropyl)cyclohexene (51). From 50
(0.420 g, 3.0 mmol), 51 (0.600 g, 80.0%) was obtained as
a colorless oil; H NMR d 5.45 (1H, brs), 3.16 (2H, t,
1
Jˆ6.8 Hz), 1.86±2.05 (8H, m), 1.49±1.66 (4H, m); IR
2924, 1437 cm21; EI MS m/z 250 (M1); high-resolution
mass m/z calcd for C9H15I (M1) 250.0219, found: 250.0222.
4. Experimental
4.1. General
4.3. General procedure for conversion of iodides (24, 39,
43, 51) to acetylenes (1, 40, 44, 52)
All melting and boiling points were measured on a BuÈchi or
a Yanagimoto (hot plate) melting point apparatus and by
bulb-to-bulb distillation apparatus, and are uncorrected. IR
spectra were obtained with a Hitachi 260-10 spectro-
photometer or JASCO FT/IR-400. 1H and 13C NMR spectra
were taken with a JEOL EX-270 (270 MHz for 1H NMR and
67.5 MHz for 13C NMR) spectrometer in CDCl3 solution
with tetramethylsilane as an internal standard. Mass spectra
were measured on a Hitachi M-80 or a JEOL JMS D-300
spectrometer. Column chromatography was performed over
silica gel (Wako gel C-200 or Merck Kiegelsel 60). Prepara-
tive TLCs were run on Merck 5744, or Merck 5715 plates.
Organic extracts were dried over MgSO4, unless otherwise
indicated.
To a stirred suspension of lithium acetylide ethylenediamine
complex (1.4 equiv.) in DMSO (1 mL per 1 mmol of iodide)
and Et2O (1 mL per 1 mmol of iodide) at 58C under argon
was added a solution of iodide (1 equiv.) in Et2O (0.25 mL
per 1 mmol of iodide). After being stirred for 0.5 h, the
reaction was quenched with water. The mixture was
extracted with Et2O. The organic layer was washed with
brine and dried. Usual work-up followed by column chro-
matography (pentane) afforded the corresponding acetylene.
4.3.1. (^)-1-(3-Butynyl)-2-methylenecyclohexane (1).
From 24 (5.05 g, 20 mmol), 1 (2.40 g, 80.3%) was obtained
as a colorless oil; bp 1408C/60 mmHg; H NMR d 4.68,
1
4.59 (each 1H, s), 1.93 (1H, t, Jˆ2.6 Hz), 1.27±2.23
(13H, m); IR 3311, 2931, 2856, 2118, 1645, 1446 cm21
;
MS m/z 148 (M1); high-resolution mass m/z calcd for
4.2. General procedure for conversion of alcohols (23,
38, 42, 50) to iodides (24, 39, 43, 51)
C11H16 (M1) 148.1252, found: 148.1244.
4.3.2.
(S)-1-Methyl-2-methylene-1-(4-pentynyl)cyclo-
To a stirred solution of alcohol (1 equiv.), PPh3 (1.2 equiv.),
and pyridine (1.9 equiv.) in CH2Cl2 (8 mL per 1 mmol of
alcohol) at 08C was added I2 (1.2 equiv.) in one portion.
After being stirred for 0.5 h, the mixture was washed with
1 M aqueous HCl, 10% aqueous Na2S2O3, saturated aqueous
NaHCO3, and brine, in order. The organic layer was dried
and evaporated in vacuo to give a residue, which was puri-
®ed by column chromatography (hexane) to furnish the
corresponding iodide.
hexane (40). From 39 (1.974 g, 7.1 mmol), 40 (1.097 g,
87.8%) was obtained as a colorless oil; bp 1608C/
27
1
15 mmHg; [a]D ˆ280.08 (c 1.07, CHCl3); H NMR d
4.70, 4.59 (each 1H, s), 2.11±2.19 (4H, m), 1.94 (1H, t,
Jˆ2.6 Hz), 1.22±1.85 (10H, m), 1.01 (3H, s); IR 3311,
2933, 2856, 1637, 1450 cm21; MS m/z 176 (M1); high-
resolution mass m/z calcd for C13H20 (M1) 176.1565,
found: 176.1575.
4.3.3. (R)-1-Methyl-2-methylene-1-(4-pentynyl)cyclopen-
tane (44). From 43 (0.863 g, 3.3 mmol), 44 (0.451 g,
85.3%) was obtained as a colorless oil; bp 1408C/
4.2.1. (^)-1-(2-Iodoethyl)-2-methylenecyclohexane (24).
From 23 (3.50 g, 25 mmol), 24 (5.05 g, 80.0%) was
obtained as a colorless oil; H NMR d 4.70, 4.61 (each
1
29
1
16 mmHg; [a]D ˆ148.48 (c 1.06, CHCl3); H NMR d
4.85, 4.69 (each 1H, s), 2.34±2.40 (2H, m), 2.16 (2H, dt,
Jˆ2.6, 6.6 Hz), 1.94 (1H, t, Jˆ2.6 Hz), 1.39±1.68 (8H, m),
1.03 (3H, s); IR 3310, 2951, 2118, 1650 cm21; MS m/z 161
(M121); high-resolution mass m/z calcd for C12H17
(M121) 161.1296, found: 161.1313.
1H, s), 3.14±3.26 (2H, m), 1.24±2.27 (11H, m); IR 2928,
2854, 1643 cm21; MS m/z 250 (M1); high-resolution mass
m/z calcd for C9H15I (M1) 250.0219, found: 250.0230.
4.2.2. (S)-1-(3-Iodopropyl)-1-methyl-2-methylenecyclo-
hexane (39). From 38 (1.352 g, 8.05 mmol), 39 (2.004 g,
32
89.6%) was obtained as a colorless oil; [a]D ˆ257.58 (c
1.15, CHCl3); 1H NMR d 4.71, 4.58 (each 1H, s), 3.17 (2H,
t, Jˆ6.6 Hz, H), 2.10±2.19 (2H, m), 1.41±1.81 (7H, m),
1.20±1.40 (3H, m), 1.02 (3H, s); IR 2925, 2854,
1637 cm21; MS m/z 278 (M1); high-resolution mass m/z
calcd for C11H19I (M1) 278.0531, found: 278.0527.
4.3.4. 1-(4-Pentynyl)cyclohexene (52). From 51 (0.500 g,
2.0 mmol), 52 (0.224 g, 75.8%) was obtained as a colorless
oil; bp 1408C/60 mmHg; 1H NMR d 5.42 (1H, s), 2.16 (2H,
dt, Jˆ2.6, 7.1 Hz), 1.91±2.05 (6H, m), 1.94 (1H, t,
Jˆ2.6 Hz), 1.52±1.68 (6H, m); IR 3311, 2931, 2119,
1439 cm21; EI MS m/z 148 (M1); high-resolution mass
m/z calcd for C11H16 (M1) 148.1255, found: 148.1252.
4.2.3. (R)-1-(3-Iodopropyl)-1-methyl-2-methylenecyclo-

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M. Ishizaki et al. / Tetrahedron 57 (2001) 2729±2738
4.4. General procedure for Wittig reaction of ketones
(25, 29, 30, 33, 34, 46)
resolution mass m/z calcd for C10H14O (M1) 150.1044,
found: 150.1043.
4.4.5. (^)-1-Methyl-2-methylene-1-propargyloxycyclo-
hexane (9). PPh3´MeBr (7.86 g, 22.0 mmol), t-BuOK
(2.40 g, 21.4 mmol) in THF (100 mL), and 34 (1.660 g,
10 mmol) in THF (12 mL) were used (reaction time: 1 h).
A suspension of PPh3´MeBr and t-BuOK in THF was stirred
for 10 min at rt. To this mixture was added a solution of
ketone (1 equiv.) in THF over a period of 3 min. After being
stirred, the reaction was quenched with water. The
mixture was extracted with Et2O. The extracts were washed
with brine and dried. Usual work-up followed by column
chromatography or bulb-to-bulb distillation gave the
corresponding exo-ole®n.
Column
chromatography
(hexane
then
hexane/
AcOEtˆ10:1) gave 9 (1.05 g, 64.0%) as a colorless oil;
1
bp 1508C/15 mmHg; H NMR d 4.95, 4.85 (each 1H, s),
3.95, 3.86 (each 1H, dd, Jˆ2.3, 15.2 Hz), 2.37 (1H, t,
Jˆ2.3 Hz), 2.10±2.28 (2H, m), 1.71±1.95 (3H, m), 1.22±
1.57 (3H, m), 1.31 (3H, s); IR 2940, 1643 cm21; MS m/z 164
(M1); high-resolution mass m/z calcd for C11H16O (M1)
164.1201, found: 164.1191.
4.4.1. (S)-1-(3-Butynyl)-1-methyl-2-methylenecyclohexane
(2). PPh3´MeBr (4.30 g, 12.0 mmol), t-BuOK (1.35 g,
12.0 mmol) in THF (40 mL), and 25 (0.984 g, 6.0 mmol)
in THF (10 mL) were used (reaction time: 1 h). Column
chromatography (hexane) gave 2 (0.877 g, 90.2%) as a
4.4.6. (^)-1-Ethoxycarbonyl-1-(2-iodobenzyl)-2-methyl-
enecyclohexane (47). PPh3´MeBr (1.68 g, 4.6 mmol),
t-BuOK (0.505 g, 4.5 mmol) in THF (40 mL), and 46
(1.16 g, 3.0 mmol) were used (reaction time: 3 h). Column
chromatography (hexane/AcOEtˆ30:1) gave 47 (0.985 g,
24
1
colorless oil; [a]D ˆ1116.18 (c 1.07, CHCl3); H NMR
d 4.74, 4.59 (each 1H, s), 1.93 (1H, t, Jˆ2.4 Hz), 1.91±
2.14 (5H, m), 1.22±1.76 (7H, m), 1.01 (3H, s); 13C NMR
d 153.8, 107.6, 85.5, 67.7, 40.4, 39.2, 36.4, 33.1, 28.4, 25.2,
1
21.9, 13.5; IR 3311, 2931, 2856, 2119, 1637, 1450 cm21
;
85.5%) as colorless crystals; mp 85±868C; NMR d 7.83
MS m/z 162 (M1); high-resolution mass m/z calcd for
(1H, dd, Jˆ1.3, 7.9 Hz), 7.20 (1H, dd, Jˆ1.3, 7.9 Hz), 7.06
(1H, dd, Jˆ1.6, 7.9 Hz), 6.87 (1H, dt, Jˆ1.6, 7.9 Hz), 5.00,
4.97 (each 1H, s), 4.15 (2H, q, Jˆ7.1 Hz), 3.42, 3.22 (each
1H, d, Jˆ14.2 Hz), 2.34±2.41 (1H, m), 2.00±2.12 (2H, m),
1.28±1.77 (5H, m), 1.20 (3H, t, Jˆ7.1 Hz); MS m/z 384
(M1); high-resolution mass m/z calcd for C17H21IO2 (M1)
384.0497, found: 384.5013.
C12H18 (M1) 162.1407, found: 162.1405.
4.4.2. (S)-6-(3-Butynyl)-6-methyl-7-methylene-1,4-diox-
aspiro[4.5]decane (4). PPh3´MeBr (0.380 g, 1.06 mmol),
t-BuOK (0.119 g, 1.06 mmol) in THF (3 mL), and 29
(0.118 g, 0.53 mmol) in THF (2 mL) were used (reaction
time:
24 h).
Column
chromatography
(hexane/
4.4.7. (^)-1-(3-Butynyl)-2-ethylidene-1-methylcyclohex-
ane (6). A suspension of PPh3´EtBr (2.251 g, 6.06 mmol)
and t-BuOK (0.676 g, 6.00 mmol) in THF (25 mL) was
stirred for 5 min at rt. To this mixture was added a solution
of 25 (0.492 g, 3.0 mmol) in THF (7 mL) over a period of
2 min. After being stirred for 24 h, similar work-up as
described above gave a residue, which was puri®ed by
column chromatography (hexane) to afford 6 (0.321 g,
AcOEtˆ20:1) gave 4 (0.048 g, 41.1%) as colorless crystals;
24
1
mp 80±828C; [a]D ˆ257.88 (c 1.32, CHCl3); H NMR d
4.91 (1H, d, Jˆ1 Hz), 4.72 (1H, d, Jˆ1.3 Hz), 3.88±4.00
(4H, m), 2.14±2.20 (2H, m), 1.43±2.01 (9H, m), 1.02 (3H,
s); 13C NMR d 150.6, 112.9, 110.7, 85.2, 67.9, 65.2, 65.1,
49.1, 33.6, 31.7, 30.2, 23.4, 15.5, 13.4; MS m/z 220 (M1);
high-resolution mass m/z calcd for C14H20O2 (M1)
220.1463, found: 220.1470.
1
60.9%) as a colorless oil; bp 1708C/25 mmHg; H NMR d
5.30 (0.82H, q, Jˆ7.3 Hz, ole®nic H), 5.16 (0.18H, q,
Jˆ6.7 Hz, ole®nic H), 1.71 (2.46H, dd, Jˆ1.8, 7.3 Hz,
CHMe), 1.59 (0.54H, dd, Jˆ1.3, 6.7 Hz, CHMe), 1.95±
2.56 (5H, m), 1.92 (1H, t, Jˆ2.5 Hz), 1.25±1.68 (7H, m),
4.4.3. (R)-2-(1-tert-Butoxycarbonyl)ethyl-1-ethoxycarbo-
nyl-2-methylenecyclohexane (31). PPh3´MeBr (10.75 g,
30.1 mmol) and t-BuOK (3.36 g, 30.0 mmol) in THF
(250 mL), and 30 (5.96 g, 20 mmol) were used (reaction
time: 1 h). Column chromatography (hexane/AcOEtˆ5:1)
gave 31 (5.41 g, 91.4%) as a colorless oil; bp 1708C/
30 mmHg; [a]D ˆ143.78 (c 1.04, CHCl3); H NMR d
4.90, 4.77 (each 1H, s), 4.17 (2H, q, Jˆ7.1 Hz), 1.87±
2.35 (8H, m), 1.53±1.72 (3H, m), 1.44 (9H, s), 1.36±1.44
(1H, m), 1.26 (3H, t, Jˆ7.1 Hz); IR 2980, 2935, 2860,
1728, 1643, 1448 cm21; MS m/z 296 (M1); high-resolution
mass m/z calcd for C17H28O4 (M1) 296.1988, found:
296.1978.
1.23 (3H, s); IR 3311, 2926, 2864, 2119, 1466, 1450 cm21
;
MS m/z 176 (M1); high-resolution mass m/z calcd for
C13H20 (M1) 176.1564, found: 176.1577.
29
1
4.4.8.
(^)-1-Methyl-2-methylene-1-(3-pentynyl)cyclo-
hexane (7). To a stirred suspension of 2 (0.324 g,
2.0 mmol) in THF (8 mL) was added at 08C BuLi
(1.8 mL, 2.9 mmol, 1.6 M in hexane). After being stirred
for 10 min, MeI (160 mL, 2.6 mmol) was added. The
mixture was stirred for 0.5 h. The reaction was quenched
with water and extracted with hexane. Usual work-up
afforded 7 (0.321 g, 91.2%) as a colorless oil; bp 1608C/
4.4.4. (^)-2-Methylene-1-propargyloxycyclohexane (8).
PPh3´MeBr (3.929 g, 11.0 mmol), t-BuOK (1.209 g,
10.7 mmol) in THF (50 mL), and 33 (0.761 g, 5.0 mmol)
in THF (4 mL) were used (reaction time: 1 h); 8 (0.595 g,
79.2%) was obtained as a colorless oil; bp 1408C/14 mmHg;
1H NMR d 4.87, 4.86 (each 1H, s), 4.17, 4.00 (each 1H, dd,
Jˆ2.3, 15.6 Hz), 3.98 (1H, t, Jˆ3.3 Hz), 2.39 (1H, t,
Jˆ2.3 Hz), 2.25 (1H, ddd, Jˆ4.3, 9.6, 13.3 Hz), 2.06 (1H,
dt, Jˆ5, 13.3 Hz), 1.58±1.85 (4H, m), 1.39±1.55 (2H, m);
IR 2935, 2858, 2118, 1650 cm21; MS m/z 150 (M1); high-
1
40 mmHg; H NMR d 4.71, 4.57 (each 1H, s), 1.84±2.15
(5H, m), 1.76 (3H, t, Jˆ2.3 Hz), 1.22±1.73 (7H, m), 0.99
(3H, s); IR 2928, 1637, 1448 cm21; MS m/z 176 (M1); high-
resolution mass m/z calcd for C13H20 (M1) 176.1564, found:
176.1563.
4.4.9. (R)-1-(2-Methoxycarbonyl)ethyl-1-methyl-2-methyl-
enecyclopentane (27). To a stirred mixture of Zn (3.704 g,

M. Ishizaki et al. / Tetrahedron 57 (2001) 2729±2738
2735
56.7 mmol) and CH2Br2 (3.422 g, 19.1 mmol) in THF
(100 mL) at rt under argon was added TiCl4 (13.8 mL,
13.8 mmol, 1 M in CH2Cl2). After being stirred for
15 min, the mixture was cooled to 08C and a solution of
26 (90% ee, 2.35 g, 12.8 mmol) in CH2Cl2 (10 mL) was
added. After being stirred for 1.5 h, the reaction was
diluted with hexane (50 mL). Then, a solution of Na2CO3
(24 g) in H2O (15 mL) was added to the mixture. The
precipitate was ®ltered through Celite 545 short pad.
Usual work-up followed by column chromatography
(hexane/AcOEtˆ20:1) gave 27 (1.23 g, 52.7%) as a color-
(0.145 g, 0.65 mmol) and K2CO3 in MeOH (10 mL) was
added at rt diethyl 1-diazo-2-oxopropylphosphonate
(0.166 g, 0.75 mmol) in one portion. After being stirred
for 2.5 h, the reaction was diluted with Et2O. The mixture
was washed with saturated aqueous NaHCO3 and brine,
successively. Usual work-up afforded 5 (0.080 g, 56.3%)
26
as a colorless oil; bp 1708C/20 mmHg; [a]D ˆ158.88 (c
1.01, CHCl3); 1H NMR d 4.91, 4.74 (each 1H, s), 4.17 (2H,
q, Jˆ7.1 Hz), 1.96 (1H, t, Jˆ2.5 Hz), 1.83±2.31 (6H, m),
1.30±1.74 (6H, m), 1.26 (3H, t, Jˆ7.1 Hz); IR 3292, 2937,
2858, 2119, 1727, 1643, 1448 cm21; MS m/z 220 (M1);
high-resolution mass m/z calcd for C14H20O2 (M1)
220.1463, found: 220.1463.
26
less oil; bp 160±1708C/50 mmHg; [a]D ˆ138.28 (c 1.06,
1
CHCl3); H NMR d 4.88, 4.70 (each 1H, s), 3.66 (3H, s),
2.25±2.43 (4H, m), 1.44±1.76 (6H, m), 1.03 (3H, s); IR
2954, 2871, 1743, 1650, 1452, 1434 cm21; MS m/z 182
(M1); high-resolution mass m/z calcd for C11H18O2 (M1)
182.1307, found: 182.1300.
4.4.14.
(^)-2-Methylene-1-(propargylamino)-N-tosyl-
cyclohexane (10). To a stirred mixture of Zn (0.882 g,
13.5 mmol) and CH2Br2 (0.791 g, 4.55 mmol) in THF
(25 mL) at rt under argon was added TiCl4 (3.3 mL,
3.3 mmol, 1 M in CH2Cl2). After being stirred for 15 min,
35 (0.9150 g, 3.0 mmol) was added in one portion and the
mixture was stirred for 5 h. The mixture was diluted with
Et2O and washed with 1 M HCl, and brine, successively.
Work-up as noted above (hexane/AcOEtˆ3:1) afforded 10
4.4.10.
cyclopentane (28). To
(R)-1-(2-Formyl)ethyl-1-methyl-2-methylene-
solution of 27 (0.592 g,
a
3.0 mmol) in toluene (15 mL) was added at 2788C under
argon DIBAH (3 mL, 3 mmol, 1 M in toluene). After being
stirred for 2 h, the reaction was quenched with 3 M HCl.
The mixture was extracted with CHCl3. The extracts were
washed with brine and dried. Usual work-up as noted above
(hexane/AcOEtˆ10:1) afforded 27 (0.106 g, 19.4%) and 28
1
(0.230 g, 25.3%) as crystals; mp 111±1128C; H NMR d
7.82, 7.27 (each 2H, d, Jˆ8.6 Hz), 4.78, 4.63 (each 1H, s),
4.38, 3.87 (each 1H, dd, Jˆ2.3, 18.5 Hz), 4.28±4.38
(1H, m), 2.42 (3H, s), 2.11 (1H, t, Jˆ2.3 Hz), 1.98±2.08
(1H, m), 1.16±1.90 (7H, m); IR 3307, 2941, 2862, 1650,
1599, 1448 cm21; MS m/z 303 (M1); high-resolution
mass m/z calcd for C17H21NO2S (M1) 303.1293, found:
303.1290.
1
(0.310 g, 68.0%) as a colorless oil; H NMR d 9.77 (1H, t,
Jˆ1.9 Hz), 4.89 (1H, t, Jˆ2 Hz), 4.70 (1H, t, Jˆ2.3 Hz),
2.34±2.45 (4H, m), 1.48±1.74 (6H, m), 1.04 (3H, s); IR
2956, 1726, 1650 cm21; MS m/z 152 (M1); high-resolution
mass m/z calcd for C10H16O (M1) 152.1201, found:
152.1200.
4.4.15. (^)-1-Benzyloxycarbonylamino-1-methyl-2-methyl-
enecyclohexane (37). A solution of 36 (1.00 g, 6.5 mmol),
DPPA (1.86 g, 6.8 mmol), Et3N (0.712 g, 7.0 mmol), and
benzyl alcohol (0.90 g, 8.3 mmol) in toluene (40 mL) was
re¯uxed for 6 h. After the solvent was removed in vacuo, the
residue was puri®ed by column chromatography (hexane/
AcOEtˆ5:1) to afford 37 (0.656 g, 39.0%) as a colorless oil;
1H NMR d 7.35 (5H, s), 5.08, 5.03 (each 1H, d, Jˆ12.9 Hz),
4.87, 4.85 (each 1H, s), 4.76 (1H, brs), 2.04±2.39 (3H, m),
1.49 (3H, s), 1.34±1.72 (5H, m); IR 3350, 2935, 2858, 1724,
1498 cm21; MS m/z 259 (M1); high-resolution mass m/z
calcd for C16H21NO2 (M1) 259.1571, found: 259.1552.
4.4.11. (R)-1-Methyl-2-methylene-1-propargylclopentane
(3). To a stirred suspension of 28 (0.674 g, 3.81 mmol)
and K2CO3 (1.055 g, 7.64 mmol) in MeOH (50 mL) was
added at rt diethyl 1-diazo-2-oxopropylphosphonate
(0.861 g, 4.57 mmol) in one portion. After being stirred
for 3 h, the reaction was diluted with Et2O. The mixture
was washed with saturated aqueous NaHCO3 and brine,
successively. Usual work-up afforded 3 (0.291 g, 51.7%)
1
as a colorless oil; bp 1358C/60 mmHg; H NMR d 4.88,
4.69 (each 1H, s), 1.92 (1H, t, Jˆ2.6 Hz), 2.32±2.42 (2H,
m), 2.10±2.22 (2H, m), 1.20±1.44 (6H, m), 1.01 (3H, s); MS
m/z 148 (M1); high-resolution mass m/z calcd for C11H16
(M1) 148.1252, found: 148.1248.
4.4.16. (^)-1-(N-Benzyloxycarbonylpropargylamino)-1-
methyl-2-methylenecyclohexane (11). To a mixture of
NaH (0.060 g, 1.5 mmol) in DMF (3 mL) at 08C under
argon was added a solution of 37 (0.259 g, 1.0 mmol) in
DMF (2 mL). After being stirred for 1 h, propargyl bromide
(0.104 g, 1.2 mmol) was added and the mixture was stirred
for 3 h at rt. Then, the reaction was quenched with water.
The mixture was extracted with Et2O. The extracts were
washed with brine and dried (K2CO3). Work-up as noted
above (hexane/AcOEtˆ20:1) afforded 11 (0.160 g, 54.0%)
as a colorless oil; 1H NMR d 7.30±7.43 (5H, m, Ph), 5.19,
5.14 (each 1H, d, Jˆ13.2 Hz), 4.93, 4.91 (each 1H, s), 4.15,
3.38 (each 1H, dd, Jˆ2.3, 17.8 Hz), 3.04±3.10 (1H, m),
2.17 (1H, t, Jˆ2.3 Hz), 2.08±2.28 (2H, m), 1.71±1.79
(1H, m), 1.50 (3H, s), 1.15±1.57 (4H, m); IR 3302, 2935,
2858, 1709, 1444 cm21; MS m/z 297 (M1); high-resolution
mass m/z calcd for C19H23NO2 (M1) 297.1728, found:
297.1730.
4.4.12. (R)-1-Ethoxycarbonyl-1-(2-formyl)ethyl-2-methyl-
enecyclohexane (32). To a solution of 31 (0.592 g,
2.0 mmol) in THF (15 mL) was added at 2788C under
argon DIBAH (3 mL, 3 mmol, 1 M in toluene). After
being stirred for 2 h, the reaction was quenched with 3 M
HCl. The mixture was extracted with CHCl3. Work-up as
noted above (hexane/AcOEtˆ10:1) afforded 32 (0.145 g,
32.4%) and 31 (0.347 g, 58.7%) as a colorless oil; 1H
NMR d 9.78 (1H, t, Jˆ1.2 Hz), 5.91, 4.73 (each 1H, s),
4.16 (2H, q, Jˆ7 Hz), 1.90±2.65 (8H, m), 1.40±1.79 (4H,
m), 1.26 (3H, t, Jˆ7 Hz); IR 2930, 1748, 1643 cm21; MS
m/z 224 (M1); high-resolution mass m/z calcd for C13H20O3
(M1) 224.1409, found: 224.1413.
4.4.13. (R)-1-(3-Butynyl)-1-ethoxycarbonyl-2-methyl-
enecyclohexane (5). To a stirred suspension of 32

2736
M. Ishizaki et al. / Tetrahedron 57 (2001) 2729±2738
4.4.17. (R)-1-(3-Hydroxypropyl)-1-methyl-2-methylene-
cyclopentane (42). To a stirred solution of 27 (0.876 g,
4.81 mmol) in THF (15 mL) at 08C was added LiAlH4
(0.183 g, 4.82 mmol) in small portions. After being stirred
for 1 h, the reaction was quenched with saturated aqueous
Na2SO4. The precipitate was ®ltered off and the ®ltrate was
dried and evaporated under reduced pressure to give 42
(0.706 g, 95.2%) as a colorless oil; bp 180±1908C/
30 mmHg; [a]D ˆ142.18 (c 1.06, CHCl3); H NMR d
4.85, 4.69 (each 1H, s), 3.62 (2H, t, Jˆ6.4 Hz), 2.34±2.42
(2H, m), 1.26±1.64 (8H, m), 1.03 (3H, s); IR 3334, 2952,
2870, 1650, 1456, 1432 cm21; MS m/z 154 (M1); high-
resolution mass m/z calcd for C10H18O (M1) 154.1358,
found: 154.1355.
1.83±2.01 (6H, m), 1.44±1.64 (8H, m), 0.13 (9H, s); EI MS
m/z 234 (M1); high-resolution mass m/z calcd for C15H26Si
(M1) 234.1804, found: 234.1800.
4.4.20. 1-(4-Pentynyl)cyclohexene (55). A mixture of 54
(0.199 g, 0.85 mmol) and 3 M NaOH (5 mL) in MeOH
(5 mL) was stirred for 14 h at rt. The mixture was extracted
with Et2O. The organic extracts were washed with brine and
dried. Usual work-up afforded 55 (0.130 g, 94.4%) as a
29
1
1
colorless oil; bp 1708C/60 mmHg; H NMR d 5.30 (1H,
brs, ole®nic H), 2.14±2.23 (2H, m), 1.93 (1H, t,
Jˆ2.6 Hz), 1.85±2.00 (6H, m), 1.45±1.64 (8H, m); IR
3296, 2940, 2172 cm21; EI MS m/z 162 (M1); high-resolu-
tion mass m/z calcd for C12H18 (M1) 162.1409, found:
162.1411.
4.4.18. (^)-1-Ethoxycarbonyl-1-(2-ethynylbenzyl)-2-methyl-
enecyclohexane (48). A mixture of 47 (0.768 g, 2.0 mmol),
trimethylsilylacetylene (0.34 mL, 2.4 mmol), Et3N (10 mL),
CuI (0.004 g, 0.02 mmol), and PdCl2(PPh3)2 (0.028 g,
0.04 mmol) in CH2Cl2 (1 mL) was stirred for 1 h at rt.
The mixture was washed with saturated aqueous NaHCO3,
brine, successively, and dried. Work-up as noted above
(AcOEt/hexaneˆ1:30) afforded 1-ethoxycarbonyl-1-(2-
trimthylsilylethynylbenzyl)-2-methylenecyclohexane (0.705
4.5. General procedures for Pauson±Khand reaction of
exocyclic enynes
A mixture of enyne (1 equiv.) and Co2(CO)8 (1.1 equiv.) in
CH2Cl2, benzene or toluene was stirred for 1 h at rt. Method
A: NMO (3 equiv.) was added to the mixture in three times
at intervals of 15 min. The solvent was removed under
reduced pressure to give a residue, which was diluted with
Et2O. The precipitate was removed by suction ®ltration
through Celite 545 short pad. Method B: TMANO
(3 equiv.) was added to the mixture and the mixture was
re¯uxed for 2±4 h. Methods C and D: The mixture was
re¯uxed for appropriate time. Puri®cation of the products
obtained by Methods A±D was carried out on preparative
TLC.
1
g, 99.5%) as colorless crystals; H NMR d 7.39 (1H, dd,
Jˆ1.7, 7.3 Hz), 7.12±7.30 (2H, m), 6.97 (1H, dd, Jˆ1.7,
7.3 Hz), 4.97, 4.95 (each 1H, s), 4.96 (2H, q, Jˆ7.1 Hz),
3.40, 3.27 (each 1H, d, Jˆ13.2 Hz), 2.30±2.40 (1H, m),
1.91±2.00 (2H, m), 1.28±1.76 (5H, m), 1.17 (3H, t,
Jˆ7.1 Hz), 0.20 (9H, s). A solution of the 2-(trimethylsilyl-
ethynyl)benzyl product (0.531 g, 1.5 mmol) and TBAF
(0.45 mL, 0.45 mmol) in THF (3 mL) was stirred for 1 h
at rt. After the solvent was removed in vacuo, the residue
was puri®ed by column chromatography (hexane/
AcOEtˆ30:1) to afford 48 (0.413 g, 97.5%) as colorless
4.5.1. (1Rp,8Sp)-Tricyclo[6.4.0.01,5]dodec-4-en-3-one (12).
Oil; 1H NMR d 5.75 (1H, dd, Jˆ1, 2.3 Hz), 2.52±2.82 (2H,
m), 2.37, 2.11 (each 1H, d, Jˆ17.5 Hz), 2.08±2.20 (1H, m),
1.09±1.95 (10H, m); 13C NMR d 210.7, 195.6, 123.6, 52.9,
48.7, 41.9, 31.8, 26.8, 24.9, 24.5, 23.4, 19.6; IR 2926, 2858,
1709, 1626, 1456, 1410 cm21; MS m/z 176 (M1); high-
resolution mass m/z calcd for C12H16O (M1) 176.1200,
found: 176.1205.
1
crystals; mp 93±958C; H NMR d 7.47 (1H, dd, Jˆ1.7,
7.3 Hz), 7.16±7.23 (2H, m), 7.04 (1H, dd, Jˆ1.7, 7.3 Hz),
5.00, 4.97 (each 1H, s), 4.13 (2H, q, Jˆ7.1 Hz), 3.40, 3.30
(each 1H, d, Jˆ13.5 Hz), 3.21 (1H, s), 2.34±2.41 (1H, m),
1.97±2.13 (2H, m), 1.32±1.76 (5H, m), 1.19 (3H, t,
Jˆ7.1 Hz); IR 3248, 2935, 2863, 1716, 1600 cm21; MS
m/z 282 (M1); high-resolution mass m/z calcd for
C19H22O2 (M1) 282.1620, found: 282.1639.
4.5.2. (1R,8S)-8-Methyltricyclo[6.4.0.01,5]dodec-4-en-3-
24
1
one (13). Oil; [a]D ˆ2146.58 (c 1.0, CHCl3); H NMR d
5.77 (1H, t, Jˆ1.7 Hz), 2.54±2.81 (2H, m), 2.43 (1H, dt,
Jˆ7.6, 12.2 Hz), 2.29, 2.10 (each 1H, d, Jˆ17.8 Hz), 1.22±
1.80 (9H, m), 0.77 (3H, s); 13C NMR d 212.5, 196.5, 124.5,
57.6, 44.8, 41.0, 36.0, 35.6, 34.2, 26.1, 24.9, 24.5, 22.7; IR
2929, 2864, 1705, 1624, 1448, 1412 cm21; MS m/z 190
(M1); high-resolution mass m/z calcd for C13H18O (M1)
190.1357, found: 190.1358.
4.4.19. 1-[3-(1-Trimethylsilylpropadienyl)propyl]- and
1-(5-pentynyl-6-trimethylsilyl)-cyclohexane (53 and 54).
To a stirred solution of 1-trimethylsilylpropyne (225 mL,
1.5 mmol) in THF (4 mL) at 08C under argon was added
BuLi (0.90 mL, 1.39 mmol, 1.54 M in hexane). After being
stirred for 30 min, a solution of 51 (0.250 g, 1.0 mmol) in
THF (3 mL) was added and stirring was continued for addi-
tional 1 h. The reaction was quenched with water. The
mixture was extracted with Et2O. The organic extracts
were washed with water, brine, successively, and dried.
Work-up as noted above (pentane) to afford 53 (0.035 g,
15.0%) and 54 (0.199 g, 85.0%).
4.5.3. (1S,8R)-8-Methyltricyclo[6.3.0.01,5]undodec-4-en-
27
1
3-one (14). Oil; [a]D ˆ163.98 (c 1.0, CHCl3); H NMR
d 5.73 (1H, dd, Jˆ1, 2 Hz), 2.53±2.70 (2H, m), 2.48, 2.13
(each 1H, d, Jˆ17.7 Hz), 1.61±2.06 (8H, m), 0.96 (3H, s);
13C NMR d 211.4, 193.1, 122.9, 63.0, 49.4, 46.9, 42.0, 41.0,
40.6, 26.5, 24.5, 24.1; MS m/z 176 (M1); high-resolution
mass m/z calcd for C12H16O (M1) 176.1201, found:
176.1205.
1
53: Oil; H NMR d 5.38 (1H, brs, ole®nic H), 4.31 (2H, t,
Jˆ3.1 Hz), 1.87±2.00 (8H, m), 1.49±1.65 (6H, m), 0.08
(9H, s); EI MS m/z 234 (M1); high-resolution mass m/z
calcd for C15H26Si (M1) 234.1804, found: 234.1803.
4.5.4. (1S,8S)-9,9-Ethylenedioxy-8-methyltricyclo[6.4.0.01,5]-
24
dodec-4-en-3-one (15). Oil; [a]D ˆ2121.78 (c 1.03,
1
1
54: Oil; H NMR d 5.38 (1H, brs), 2.20 (2H, t, Jˆ6.8 Hz),
CHCl3); H NMR d 5.77 (1H, dd, Jˆ1.3, 2 Hz, ole®nic

M. Ishizaki et al. / Tetrahedron 57 (2001) 2729±2738
2737
H), 3.91±3.99 (4H, m, OCH2CH2O), 2.70±2.83 (1H, m),
2.40±2.67 (2H, m), 2.47, 2.15 (each 1H, d, Jˆ18.2 Hz),
1.60±1.82 (6H, m), 1.12±1.17 (1H, m), 0.78 (3H, s, Me);
13C NMR d 211.9, 193.7, 124.5, 111.6, 65.6, 59.2, 48.5,
45.3, 34.9, 34.5, 30.8, 24.0, 22.2, 16.0; IR 2933, 2870,
1705, 1628 cm21; MS m/z 248 (M1); high-resolution mass
m/z calcd for C15H20O3 (M1) 248.1410, found: 248.1411.
207.0, 180.8, 144.0, 132.6, 129.9, 127.4, 123.8, 63.7, 52.4,
49.0, 46.0, 32.7, 25.7, 23.1, 21.5, 18.9 cm21; MS m/z 331
(M1); high-resolution mass m/z calcd for C18H21NO3S (M1)
331.1240, found: 331.1231.
4.5.11.
(1Sp,8Rp)-7-Aza-8-benzyloxycarbonyltricyclo-
[6.4.0.01,5]dec-4-en-3-one (22). Oil; H NMR d 7.36 (5H,
s), 5.90 (1H, s), 5.16, 5.10 (each 1H, d, Jˆ12.9 Hz), 4.62,
4.28 (each 1H, Jˆ18.2 Hz), 3.15, 2.77 (each 1H, d,
Jˆ13 Hz), 2.18±2.32 (2H, m), 1.18±1.88 (6H, m),
1.07(3H, s); 13C NMR d 208.7, 182.9, 154.0, 136.6,
128.5, 128.0, 127.7, 123.1, 66.4, 64.1, 55.8, 46.1, 43.3,
35.7, 32.3, 23.5, 21.6, 21.2; IR 2933, 2860, 1713, 1655,
1448 cm21; MS m/z 325 (M1); high-resolution mass m/z
calcd for C20H23NO3 (M1) 325.1676, found: 325.1686.
1
4.5.5. (1S,8R)-8-Ethoxycarbonyltricyclo[6.4.0.01,5]dodec-
26
1
4-en-3-one (16). Oil; [a]D ˆ291.28 (c 1.04, CHCl3); H
NMR d 5.74 (1H, t, Jˆ1.3 Hz), 4.04 (2H, q, Jˆ7.1 Hz),
2.75±2.94 (2H, m), 2.38 (1H, dt, Jˆ9.2, 13.8 Hz), 2.24
(2H, s), 2.17 (1H, ddd, Jˆ4, 7.7, 13.8 Hz), 2.03 (1H, dt,
Jˆ4.3, 14 Hz), 1.73±1.80 (3H, m), 1.26±1.62 (4H, m),
1.17 (3H, t, Jˆ7.1 Hz); 13C NMR d 210.0, 194.4, 175.4,
123.1, 60.6, 55.9, 53.0, 45.6, 36.0, 30.8, 27.1, 25.5, 22.9,
20.9, 14.0; IR 3022, 2935, 1712, 1697, 1628, 1470, 1448,
1417 cm21; MS m/z 248 (M1); high-resolution mass m/z
calcd for C15H20O3 (M1) 248.1410, found: 248.1407.
4.5.12.
(1Sp,9Sp)-Benzo[e]-9-ethoxycarbonyltricyclo-
[7.4.0.01,5]tridec-4-en-3-one (49). Oil; 1H NMR d 7.64
(1H, d, Jˆ7.9 Hz), 7.20±7.40 (3H, m), 6.31 (1H, s), 3.93
(2H, q, Jˆ7.1 Hz), 3.55, 2.92 (each 1H, d, Jˆ18.2 Hz), 2.66,
2.53 (each 1H, d, Jˆ18.4 Hz), 1.40±1.95 (6H, m), 1.18±
1.31 (2H, m), 0.97 (3H, t, Jˆ7.1 Hz); 13C NMR d 207.2,
179.1, 174.9, 136.4, 131.1, 129.0, 128.8, 127.0, 126.4,
122.6, 60.7, 48.0, 46.8, 45.0, 34.7, 32.8, 29.7, 22.2, 20.3,
13.8; IR 2935, 2864, 1716, 1647, 1446 cm21; MS m/z 310
(M1); high-resolution mass m/z calcd for C20H22O3 (M1)
310.1567, found: 310.1556.
4.5.6. (1Rp,2Rp,8Sp)-2,8-Dimethyltricyclo[6.4.0.01,5]dodec-
4-en-3-one (17). Oil; H NMR d 5.82 (1H, s), 2.45±2.77
1
(3H, m), 2.36 (1H, q, Jˆ7.9 Hz), 1.48±1.75 (7H, m), 1.22±
1.34 (1H, m), 1.28 (3H, d, Jˆ7.9 Hz), 1.04±1.12 (1H, m),
0.90 (3H, s); 13C NMR d 213.8, 194.1, 123.0, 58.9, 53.2,
46.2, 38.4, 36.8, 33.5, 27.0, 23.9, 23.5, 22.0, 15.0; IR 2927,
2868, 1701, 1632, 1458 cm21; MS m/z 204 (M1); high-
resolution mass m/z calcd for C14H20O (M1) 204.1513,
found: 204.1506.
Acknowledgements
4.5.7. (1Rp,8Sp)-4,8-Dimethyltricyclo[6.4.0.01,5]dodec-4-
en-3-one (18). Mp 87±898C; H NMR d 2.38±2.68 (3H,
m), 2.26, 2.10 (each 1H, d, Jˆ17.8 Hz), 1.06±1.78 (12H,
m), 0.71 (3H, s); 13C NMR d 211.2, 187.7, 130.8, 54.0, 43.3,
40.2, 35.2, 33.6, 25.3, 23.8, 22.9, 22.7, 8.2; IR 2915, 2852,
1700, 1662 cm21; MS m/z 204 (M1); high-resolution mass
m/z calcd for C14H20O (M1) 204.1513, found: 204.1518.
1
The authors are grateful to Mrs F. Hasegawa of this faculty
for her mass spectral measurement.
References
1. Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.
J. Chem. Soc., Chem. Commun. 1971, 36.
4.5.8. (1Sp,8Rp)-7-Oxatricyclo[6.4.0.01,5]dodec-4-en-3-one
1
(19). Oil; H NMR d 5.90 (1H, dd, Jˆ1.1, 1.7 Hz), 4.80
2. For reviews: (a) Brummond, K. M.; Kent, J. L. Tetrahedron
2000, 56, 3263. (b) Fletcher, A. J.; Christie, S. D. R. J. Chem.
Soc., Perkin Trans. 1 2000, 1657. (c) Chung, Y. K. Coord.
Chem. Rev. 1999, 188, 297.
(1H, dd, Jˆ1.7, 16.3 Hz), 4.56 (1H, dd, Jˆ1.1, 16.3 Hz),
3.63 (1H, s), 2.37, 2.13 (each 1H, d, Jˆ17.3 Hz), 2.07±2.17
(1H, m), 1.50±1.79 (5H, m), 1.19±1.32 (2H, m); 13C NMR
d 208.9, 189.1, 122.7, 79.9, 64.8, 51.6, 45.5, 32.2, 26.1,
22.9, 19.3; IR 2933, 2856, 1716, 1643, 1446 cm21; MS m/
z 178 (M1); high-resolution mass m/z calcd for C11H14O2
(M1) 178.0994, found: 178.0990.
3. Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46, 5436.
4. (a) Price, M. E.; Schore, N. E. Tetrahedron Lett. 1989, 30,
5865. (b) Price, M. E.; Schore, N. E. J. Org. Chem. 1989, 54,
È
5662. (c) Castro, J.; Sorensen, H.; Riera, A.; Morin, C.;
Moyano, A.; Pericas, M. A.; Greene, A. E. J. Am. Chem.
Á
4.5.9. (1Sp,8Rp)-8-Methyl-7-oxatricyclo[6.4.0.01,5]dodec-
4-en-3-one (20). Mp 57±598C; H NMR d 5.88 (1H, t,
Soc. 1990, 112, 9388. (d) Bernardes, V.; Kann, N.; Riera,
Á
A.; Moyano, A.; Pericas, M. A.; Greene, A. E. J. Org.
1
Jˆ1.7 Hz), 4.75, 4.53 (each 1H, dd, Jˆ1.7, 16.8 Hz),
2.29, 2.19 (each 1H, d, Jˆ17.5 Hz), 2.04 (1H, dt, Jˆ3,
14.2 Hz), 1.15±1.77 (7H, m), 1.01 (3H, s); 13C NMR d
210.0, 190.1, 122.0, 80.6, 63.1, 54.9, 44.7, 35.5, 33.6,
23.3, 22.7, 21.4; IR 2934, 2852, 1702 cm21; MS m/z 192
(M1); high-resolution mass m/z calcd for C12H16O2 (M1)
192.1149, found: 192.1147.
Chem. 1995, 60, 6670. (e) Smit, W. A.; Buhanjuk, S. M.;
Simonyan, S. O.; Shashkov, A. S.; Struchkov, Y. T.;
Yanovsky, A. I.; Caple, R.; Gybin, A. S.; Anderson, L. G.;
Whiteford, J. A. Tetrahedron Lett. 1991, 32, 2105.
(f) Cassayre, J.; Zard, S. Z. J. Am. Chem. Soc. 1999, 121,
6072. (g) Krafft, M. E.; Wright, C. Tetrahedron Lett. 1992,
33, 151. (h) Van der Waals, A.; Keese, R. J. Chem. Soc.,
Chem. Commun. 1992, 570. (i) Takano, S.; Inomata, K.;
Ogasawara, K. Chem. Lett. 1992, 443. (j) Takano, S.; Inomata,
K.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1992, 169.
(k) Yoo, S.-E.; Lee, S. H.; Jeong, N.; Cho, I. Tetrahedron Lett.
1993, 34, 3435. (l) Yoo, S.-E.; Lee, S. H. J. Org. Chem. 1994,
59, 6968. (m) Jeong, N.; Lee, B. Y.; Lee, S. M.; Chung, Y. K.;
4.5.10. (1Sp,8Rp)-7-Aza-8-tosyltricyclo[6.4.0.01,5]dec-4-
en-3-one (21). Mp 92±938C; H NMR d 7.67, 7.34 (each
1
2H, d, Jˆ8.3 Hz), 5.76 (1H, s), 4.53, 4.09 (each 1H, d,
Jˆ17.2 Hz), 2.73±2.77 (2H, m), 2.44 (3H, s), 2.23, 2.02
(each 1H, d, Jˆ17.3 Hz), 1.18±1.83 (7H, m); 13C NMR d

2738
M. Ishizaki et al. / Tetrahedron 57 (2001) 2729±2738
intermolecular Pauson±Khand reaction of tetra-substituted
Lee, S.-G. Tetrahedron Lett. 1993, 34, 4023. (n). Johnstone,
C.; Kerr, W. J.; Lange, U. J. Chem. Soc., Chem. Commun.
1995, 457. (o). Van Ornum, S. G.; Cook, J. M. Tetrahedron
Lett. 1996, 37, 7185. (p). Van Ornum, S. G.; Bruendl, M. M.;
Cook, J. M. Tetrahedron Lett. 1998, 39, 6649. (q). Thommen,
M.; Keese, R. Synlett 1997, 231. (r). Jamison, T. F.;
Shambayati, S.; Crowe, W. E.; Screiber, S. L. J. Am. Chem.
Soc. 1994, 116, 5505. (s). Brummond, K. M.; Lu, J. J. Am.
Chem. Soc. 1999, 121, 5087.
ole®n. Thus, the reaction of an ethyne±cobalt complex with
tetra-substituted ole®n, which was in situ generated by isomer-
ization of trisubstituted ole®n, gave angular tricyclic
compound in less than 1% yield (6.5% yield when 20 equiv.
of ole®n was used). Billington, D. C.; Kerr, W. J.; Pauson,
P. L.; Farnocchi, C. F.; J. Organomet. Chem., 1998, 356, 213.
Intramolecular Pauson±Khand reaction of tetra-substituted
ole®n does not give desired tricyclic product.5a,b
9. For a preliminary account of this work: Ishizaki, M.; Iwahara,
K.; Kyoumura, K.; Hoshino, O. Synlett 1999, 587.
10. Ikeda, T.; Yue, S.; Hutchinson, C. R. J. Org. Chem. 1985, 50,
5193.
5. (a) Kundsen, M. J.; Schore, N. E. J. Org. Chem. 1984, 49,
5025. (b) Schore, N. E.; Kundsen, M. J. J. Org. Chem. 1987,
52, 569. (c) Schore, N. E.; Rowley, E. G. J. Am. Chem. Soc.
1988, 110, 5224. (d) Rowley, E. G.; Schore, N. E. J. Org.
Chem. 1992, 57, 6853. (e) Gybin, A. S.; Smit, W. A.; Caple,
R.; Veretenov, A. L.; Shashkov, A. S.; Vorontsova, L. G.;
Kurella, M. G.; Chertkov, V. S.; Carapetyan, A. A.; Kosnikov,
A. Y.; Alexanyan, M. S.; Lindeman, S. V.; Panov, V. N.;
Maleev, A. V.; Struchkov, Y. T.; Sharpe, S. M. J. Am.
Chem. Soc. 1992, 114, 5555. (f) Tormo, J.; Moyano, A.; Peri-
11. Grattan, T. J.; Whitehurst, J. S. J. Chem. Soc., Perkin Trans. 1
1990, 11.
12. Jung, M. E.; Hat®eld, G. L. Tetrahedron Lett. 1983, 24, 3175.
13. Begley, M. J.; Ladlow, M.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1 1988, 1095.
14. Nishida, A.; Takahashi, H.; Takeda, H.; Takada, N.;
Yonemitsu, O. J. Am. Chem. Soc. 1990, 112, 902.
15. Pfau, M.; Revial, G.; Guingant, A.; d'Angelo,, J. J. Am. Chem.
Soc. 1985, 107, 273.
Á
cas, M. A.; Riera, A. J. Org. Chem. 1997, 62, 4851. (g)
Paquette, L. A.; Borrelly, S. J. Org. Chem. 1995, 60, 6912.
(h) Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber,
S. L. J. Am. Chem. Soc. 1997, 119, 4353. (i) Montana, A.-M.;
16. Guingant, A.; Hammami, H. Tetrahedron: Asymmetry 1991,
2, 411.
Á
Moyano, A.; Pericas, M. A.; Serratosa, F. Tetrahedron 1985,
17. MuÈller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett
1996, 521.
18. Karpf, M. Helv. Chim. Acta 1984, 67, 73.
41, 5995. (j) Van Ornum, S. G.; Cook, J. M. Tetrahedron Lett.
1997, 38, 3657. (k) Marco-Contelles, J. J. Org. Chem. 1996,
61, 7666. (l) Almansa, C.; Moyano, A.; Serratosa, F.
Tetrahedron 1988, 44, 2657. (m) Castro, J.; Moyano, A.;
19. (a) NMO: Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
Tetrahedron Lett. 1990, 31, 5289. (b) TMANO: Jeong, N.;
Chung, Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett
1991, 204. (c) BuSMe: Sugihara, T.; Yamada, M.; Yamaguchi,
M.; Nishizawa, M. Synlett 1999, 771. (d) primary amines:
Sugihara, T.; Yamada, M.; Ban, H.; Yamaguchi, M.; Kaneko,
C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2801.
Á
Pericas, M. A.; Riera, A. J. Org. Chem. 1998, 63, 3346.
6. Intramolecular reaction: (a) Stolle, A.; Becker, H.; SalauÈn, J.;
È
de Meijere, A. Tetrahedron Lett. 1994, 35, 3517. (b) Brase, S.;
È
Schomenauer, S.; McGaf®n, G.; Stolle, A.; de Meijere, A.
Chem. Eur. J. 1996, 2, 545. (c) Corlay, H.; Fouquet, E.;
Magnier, E.; Motherwell, W. B. J. Chem. Soc., Chem.
Commun. 1999, 183. (d) Renaud, J.-L.; Aubert, C.; Malacria,
M. Tetrahedron 1999, 55, 5113. Intermolecular reaction:
(e) Smit, W. A.; Kireev, S. L.; Nefedov, O. M.; Tarasov,
V. A. Tetrahedron Lett. 1989, 30, 4021. (f) Corlay, H.;
James, I. W.; Fouquet, E.; Schmidt, J.; Motherwell, W. B.
Synlett 1996, 990.
20. It is known that Pauson±Khand reaction of tri-substituted
ole®ns furnishes tricyclic products in low yield. Montana,
Á
A. M.; Moyano, A.; Pericas, M. A.; Serratosa, F. An. Quim.
Ser. C 1988, 84, 82.
21. Lee, E.; Lee, Y. R.; Moon, B.; Kwon, O.; Shim, M. S.; Yun,
J. S. J. Org. Chem. 1994, 59, 1444.
22. Mori, M.; Kaneta, N.; Isono, N.; Shibasaki, M. Tetrahedron
Lett. 1991, 32, 6139.
7. Reviews for construction of quaternary centers: (a) Martin,
S. F. Tetrahedron 1980, 36, 419. (b) Fuji, K. Chem. Rev.
1993, 93, 2037.
23. The reaction of the trimethylsilylacetylene did not afford the
corresponding tetracyclic compound.
24. Corey, E. J.; Kirst, H. A. Tetrahedron Lett. 1968, 5041.
8. To our knowledge, only one example has been reported on