Tandem cyclisations involving α-ketenyl alkyl radicals. New syntheses of the natural triquinanes pentalenene and modhephene

Article abstract of DOI:10.1039/b413817c

New synthetic approaches to the angular and propellane sesquiterpene triquinanes (±)-pentalenene 2 and (±)-modhephene 3, respectively, are described. The syntheses are based on tandem cyclisations involving α-ketene alkyl radical intermediates produced fr

Full text of DOI:10.1039/b413817c

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A R T I C L E
Tandem cyclisations involving a-ketenyl alkyl radicals. New
syntheses of the natural triquinanes pentalenene and modhephene
Beno ˆı t De Boeck, Nicole M. Harrington-Frost and Gerald Pattenden*
School of Chemistry, The University of Nottingham, Nottingham, NG7 2RD, UK
Received 7th September 2004, Accepted 27th October 2004
First published as an Advance Article on the web 16th December 2004
New synthetic approaches to the angular and propellane sesquiterpene triquinanes (± )-pentalenene 2 and
(
± )-modhephene 3, respectively, are described. The syntheses are based on tandem cyclisations involving a-ketene
alkyl radical intermediates produced from a,b-unsaturated acyl radical species, as highlighted in Schemes 2 and 4.
Introduction
The linear, angular and propellane triquinanes capnellene 1, pen-
talenene 2 and modhephene 3 respectively, and their various oxy-
1
genated congeners are biologically important sesquiterpenoids,
whose interesting structures have captured the attention of
synthetic chemists for almost two decades. Prominent among
Scheme 1
2
the synthetic approaches that have been developed towards
these triquinanes are those based on tandem radical-mediated
Results and discussion
5
Based on our earlier studies leading to diquinanes (Scheme 1),
3
4
cyclisation processes , arene–alkene photocycloadditions and
any of the cyclopentene containing a,b-unsaturated acyl radical
species 6–9 would be predicted to undergo tandem cyclisations
via their ketene alkyl counterparts, leading to tricyclic intermedi-
ates, viz. 10 and 11, suitable for elaboration to (± )-pentalenene
5
electrophilic transannulation reactions. In the immediately pre-
ceding papers we highlighted the propensity for a,b-unsaturated
acyl radical intermediates 4 to react with alkene electrophores
via their corresponding a-ketenyl alkyl radical counterparts
2
(Scheme 2). After a brief inspection of the alternatives we
5
, leading to useful syntheses of ring systems, including
decided to study the tandem cyclisation from the cyclopentene-
substituted a,b-unsaturated acyl radical 9.
The feasibility of this approach was swiftly demonstrated by
elaborating the known carboxylic acid 12a to the model selenyl
ester 12b and then treating the ester with Bu SnH–AIBN in hot
benzene. To our satisfaction work up and chromatography gave
the anticipated tricyclic ketone 13 in 26% yield; the aldehyde 12c,
resulting from in situ reduction of the selenyl ester 12b under the
reaction conditions, was also isolated.
6
diquinanes (Scheme 1). In this paper we now describe the
scope for 2,7-diene acyl radicals and their ketene alkyl radical
counterparts in tandem radical transannulation and cyclisation
8
reactions leading to concise syntheses of (± )-pentalenene 2 and
3
7
(
± )-modhephene 3.
The trimethyl-substituted analogue of 12b, i.e. the a,b-
unsaturated phenyl selenyl ester 19, was then prepared starting
from the cyclopentylidene acetic acid ester 14, as outlined in
9
Scheme 3. Thus, based on precedent, deprotonation of 14
1
0
using lithium 2,2,6,6-tetramethylpiperidinamide and DMPU
◦
at −90 C, followed by trapping of the resulting enolate anion
with the TBDMS ether of 3-iodo-1-propanol, first gave the b,c-
unsaturated ester 15 in 49% overall yield. Reduction of the ester
1
5, using DIBAL, next gave the alcohol 16a, which, in three
straightforward steps, was then converted into the alcohol 17. A
Scheme 2
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
3
4 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 – 3 4 7

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◦
◦
Scheme 3 Reagents: i, LiTMP, DMPU, I(CH
iv, LiEt BH, THF, 97%; v, AcOH, H O, THF, 93%; vi, (COCl)
8%; viii, NPSP, Bu
2
)
3
OTBS, THF, −90 C, 49%; ii, DIBAL, toluene, −78 C, 98%; iii, TsCl, DMAP, Et
3
N, CH
2
Cl
2
, 88%;
O,
P=CHCO
O, THF, H
3
2
◦
2
, DMSO, CH Cl , Et N, then Ph Me, 80%; vii, LiOH·H
2
2
3
3
2
2
2
n
9
3
P, CH
2
Cl
2
, −30 C, 57%.
in 19 were also isolated by chromatography. The relative
stereochemistry of the major diastereoisomer of the triquinane,
1
i.e. 22, followed conclusively from comparison of its H NMR
1
3
and C NMR spectroscopic data with those described in the
12
literature by Burnell et al. for the same compound prepared by
an independent route.
The stage was now set to complete a synthesis of (± )-
pentalenene from the tricyclic ketone 22 based on three straight-
forward functional group manipulations. Thus, deprotonation
of 22, using LDA, followed by treatment with methyl iodide first
gave the a-methyl derivative 23 as a mixture of epimers in modest
◦
yield. Reduction of 23 using NaBH
4
in MeOH at 0 C next
led to alcohol 24, seemingly as a single diastereoisomer, which
then underwent dehydration in the presence of p-toluenesulfonic
acid, leading to pentalenene 2. The synthetic (± )-pentalenene
displayed spectroscopic data which were identical to those
reported in the literature, and superimposable on those obtained
from an earlier synthesis developed in our laboratory.
We next examined a synthesis of the 3,3,3-propellane ring
system, i.e. 27, in the natural sesquiterpene modhephene
1
1
one-pot Swern–Wittig procedure then elaborated 17 to the E-
a,b-unsaturated ester 18a in 80% yield. Finally, saponification of
the ester 18a and treatment of the resulting carboxylic acid with
13
N-(phenylseleno)phthalimide (NPSP) in the presence of Bu
led to the key phenyl selenyl ester 19.
When a solution of the selenyl ester 19 in benzene was treated
with Bu SnH–AIBN it underwent tandem radical cyclisation
via the a-ketene alkyl species 20 and the cyclopentyl radical
1, leading to the tricyclic ketone 22 as a 5 : 1 mixture of b-
and a-methyl epimers in a combined yield of approximately
3
P
3
based on a tandem transannulation–cyclisation sequence
3
from the unsaturated radical species 25 and 26 containing
a cyclooctane ring. Thus, a Peterson olefination between 5-
2
14
methylenecyclooctanone and ethyl trimethylsilylacetate in the
◦
presence of LDA at −78 C first gave the a,b-unsaturated
5
1
0% (Scheme 4). Varying amounts (>25%) of the aldehyde
8c resulting from reduction of the selenyl ester functionality
ester 28a, which was then saponified to the corresponding
carboxylic acid 28b. To our surprise, treatment of 28b with N-
(
phenylselenyl)phthalimide and PPh
3
failed to produce any of
the corresponding selenyl ester 28c. We therefore prepared 29,
15
the 2-(o-iodophenyl)ethyl thioester of 28b. Crich and Yao have
shown such thioesters to be equally useful precursors to acyl
radical intermediates. When a solution of the thioester 29 was
treated with Bu
3
SnH–AIBN in refluxing benzene it did indeed
undergo the anticipated tandem transannulation–cyclisation
1
,5
sequence and produced the known tricyclo[3.3.3.0 ]undecan-
16
3
-one 27 in 53% yield. Although we could have elaborated
the undecan-3-one 27 to the corresponding gem-dimethyl-
substituted derivative 34 en route to modhephene 3, in-
stead we next synthesized the gem-dimethyl-substituted car-
bethoxymethylene cyclooctane 33c and examined its separate
radical chemistry. Thus, an intermolecular McMurry coupling
17
18
reaction between the cyclooctanone 30 and acetone first led to
the alkene 31, which was then converted into the corresponding
cyclooctanone 32, in two straightforward steps (Scheme 5). A
Peterson olefination between 32 and ethyl trimethylsilylacetate,
Scheme 4 Reagents: i, LDA, MeI, 37%; ii, NaBH
p-TsOH, benzene, D, 70%.
4
, MeOH, 53%; iii,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 – 3 4 7
3 4 1

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Scheme 5 Reagents: i, Li, TiCl
3
, AlCl
3
, Me
2
CO, 38%; ii, DMSO, (COCl)
2
, 69%; iii, Me
3
SiCH
2
CO
, Et
2
Et, LDA, THF, 65%; iv, NaOH·H
2
O, 55%; v,
NH, 38%; viii, CuSO , toluene, 36%.
IC CH CH SH, DCC, DMAP, 84%; vi, Bu
6
H
4
2
2
3
SnH, AIBN, 60%; vii, NaH, MeOCHO, then TsN
3
2
4
followed by saponification of the resulting a,b-unsaturated ester
3a and treatment of the carboxylic acid product 33b with 2-
o-iodophenyl)ethane thiol, next gave the thioester 33c. When
this thioester was treated with Bu SnH–AIBN in hot benzene
added and the resulting bright yellow mixture was stirred at
◦
3
(
−30 C for a further 15 min. Ether (25 ml) was added and
the solution was then washed with water (2 × 10 ml), followed
by brine, and dried. The solvents were evaporated to leave an
oily residue. Repeated chromatography on silica using graduated
0–1% petroleum ether–diethyl ether as eluent gave the selenyl
ester and its corresponding exocyclic double bond regioisomer
(endo : exo, 10 : 1; 430 mg, 41%) as a yellow oil. No satisfactory
3
for 5 h, work up and chromatography produced the tricyclic
ketone 34 in a satisfying 60% yield. Finally, the tricyclic ketone
1
,5 2,8
3
3
4 was converted into the tricyclo[3.3.3.0 .0 ]undecan-3-one
6 via the corresponding a-diazo derivative 35, which has been
−
1
converted previously into modhephene via 37 in three steps by
microanalytical data could be obtained. mmax(film)/cm 1697,
1
18
Cook and his colleagues. Our concise synthesis of the tricyclic
ketone 34 based on tandem transannulation–cyclisation from
an a-ketenyl alkyl radical intermediate of type 26 derived from
a substituted analogue of 25, thereby constitutes a new and
unusual formal synthesis of (± )-modhephene, and complements
the earlier described synthesis of (± )-pentalenene using similar
interesting radical cascade chemistry.
1625, 1579; H NMR (360 MHz, CDCl
CH CH
CH=CH), 1.82–1.92 (2H, m, CH
2.08–2.36 (8H, m), 5.32–5.40 (1H, m, CH
(1H, dt, J 15.4, 1.5 Hz, CH
CH=CH), 6.95 (1H, dt, J 15.4,
6.9 Hz, CH
3
) d 1.58–1.71 (2H, m,
CH ),
CH=CCH
C=CHCH
), 6.19
2
2
2
2
2
2
2
2
CH=CH), 7.34–7.44 (3H, m, 3 × ArH), 7.50–7.58
2
13
(2H, m, 2 × ArH); C NMR d 23.4 (t), 25.8 (t), 30.5 (t), 32.0
(t), 32.4 (t), 34.9 (t), 124.1 (d), 126.1 (s), 128.8 (d), 129.3 (2 × d),
1
30.3 (d), 135.9 (2 × d), 143.7 (s), 146.8 (d), 190.9 (s); m/z (EI)
+
found 163.1121 (M − SePh), C17
H20OSe requires 163.1123.
Experimental
For general experimental details see the first paper in this series.6a
Octahydrocyclopenta[c]pentalen-4-one 13
Se-Phenyl 6-cyclopent-1-enylhex-2E-eneselenoate 12b
A solution of tributyltin hydride (0.24 ml, 0.89 mmol) and AIBN
(12 mg, 0.073 mmol) in dry, degassed benzene (5 ml) was added
dropwise over 4.25 h via syringe pump to a stirred, refluxing
solution of the selenyl ester 12b and its exocyclic double bond
regioisomer (endo : exo, 10 : 1; 236 mg, 0.74 mmol) and AIBN
(13 mg, 0.079 mmol) in dry, degassed benzene (235 ml) under
an argon atmosphere. The mixture was heated under reflux for
Tri-n-butylphosphine (1.20 ml, 4.82 mmol) was added dropwise
over 5 min to a stirred solution of (E)-6-cyclopent-1-enylhex-
8
2
-enoic acid 12a and its exocyclic double bond regioisomer
(
endo : exo, 10 : 1; 586 mg, 3.25 mmol) in dry CH
2
Cl (13 ml) at
2
◦
−
30 C under a nitrogen atmosphere. The mixture was stirred
◦
at −30 C for 10 min, then NPSP (1.44 g, 4.77 mmol) was
3
4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 – 3 4 7

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a further 45 min, then allowed to cool to room temperature,
and the solvent was evaporated. The residue was purified by
chromatography on silica using petroleum ether–diethyl ether as
eluent to give: (i), the tricyclic ketone (32 mg, 26%) as a colourless
washed with 2 N HCl, then with saturated aqueous NH Cl and
brine, and dried. The residue was purified by chromatography
4
on silica using petroleum ether as eluent to give the cyclopentene
−
1
ester (4 g, 49%) as a colourless oil; mmax(film)/cm 1740, 1646;
−
1
1
1
oil; mmax(film)/cm 1725; H NMR (360 MHz, CDCl
.49 (2H, m), 1.60–2.05 (10H, m), 2.13 (1H, ddd, J 18.0, 5.9
and 1.8 Hz, CHHCO), 2.17–2.38 (2H, m), 2.55 (1H, dd J 18.0
3
) d 1.36–
H NMR (360 MHz, CDCl
(9H, s, SiC(CH
), 1.06 (6H, s, 2 × CH
CH CH OTBS), 1.60–1.71 (1H, m, CHHCHCO
1.85 (1H, m, CHHCHCO Me), 2.09 (2H, br. s, CH
br. s, CH ), 3.14 (1H, br. t, J 7.6 Hz, CHCO
m, CH OTBS), 3.68 (3H, s, CO CH
3
) d 0.04 (6H, s, Si(CH
3
) ), 0.90
2
1
3
)
3
3
), 1.45–1.52 (2H, m,
2
2
2
2
Me), 1.75–
), 2.13 (2H,
1
3
and 8.8 Hz, CHHCO); C NMR d 25.8 (t), 26.8 (t), 30.9 (t),
2
3
2
4.5 (t), 40.8 (t), 42.0 (t), 44.8 (d), 46.5 (d), 58.6 (s), 59.5 (d),
2
2
Me), 3.56–3.66, (2H,
23.8 (s); and (ii), the corresponding aldehyde 12c (25 mg, 21%)
2
2
3
), 5.42 (1H, br. s, =CH);
−
1
1
13
as an oil; mmax(film)/cm 1693, 1637; H NMR (360 MHz,
CDCl ) d 1.62–1.72 (2H, m, CH CH
2H, m, CH CH ), 2.07–2.39 (8H, m), 5.31–5.38
CH=CCH
1H, m, CH ), 6.13 (1H, ddt, J 15.6, 7.9, 1.5 Hz,
C=CHCH
CH=CH), 6.86 (1H, dt, J 15.6, 6.8 Hz, CH CH=CH), 9.51
1H, d, J 7.9 Hz, CHO); C NMR d 23.4 (t), 25.8 (t), 30.5
C NMR d −5.3 (q), 18.3 (s), 25.9 (q), 26.6 (t), 29.6 (q), 29.7
CH=CH), 1.81–1.91
(q), 30.6 (t), 38.4 (s), 47.3 (t), 47.6 (d), 47.8 (t), 51.6 (q), 62.8 (t),
3
2
2
+
(
(
2
2
2
126.0 (d), 139.7 (s), 174.3 (s); m/z (ES) found 363.2343 (M +
2
2
Na), C19
H
36
O Si requires 363.2331.
3
CH
2
2
1
3
(
(
(
5
1
-(t-Butyldimethylsilanyloxy)-2-(4,4-dimethyl-1-cyclopent-
-enyl)pentan-1-ol 16a
t), 32.4 (2 × t), 34.9 (t), 124.1 (d), 133.1 (d), 143.6 (s), 158.7
+
d), 194.1 (s); m/z (EI) found 164.1207 (M ), C11
H
16O requires
DIBAl-H (1.5 M in toluene; 36 ml, 54 mmol) was added over
164.1201.
1
0 min to a stirred solution of the ester 15 (4 g) in toluene (90 ml)
◦
at −78 C under a nitrogen atmosphere and the mixture was
◦
Methyl 5-(t-Butyldimethylsilanyloxy)-2-(4,4-dimethylcyclopent-
stirred for 20 min and then quenched at −78 C with a saturated
1-enyl)pentanoate 15
solution of Rochelle’s salt. The mixture was allowed to warm
to room temperature and then it was extracted with ether. The
combined ether extracts were washed with water and brine, then
dried. The solvents were evaporated and the residue was purified
by chromatography on silica using petroleum ether–diethyl ether
(1 : 9) as eluent to give thealcohol (3.62 g, 98%) as a colourless oil;
(found, C, 16.2%; H, 11.7%; C H O Si requires C, 16.2%; H,
A solution of t-butyldimethylsilyl chloride (24.5 g, 163 mmol)
in dry CH Cl (40 ml) was added slowly over 10 min to a stirred
mixture of triethylamine (19.0 ml, 136 mmol), DMAP (1.88 g,
2
2
1
5.4 mmol) and 3-bromopropan-1-ol (10.5 ml, 116 mmol) in
◦
dry CH
2
Cl
2
(100 ml) at 0 C under a nitrogen atmosphere.
◦
1
8
36
2
The resulting heterogeneous mixture was stirred at 0 C for
−
1
1
1
1.6%); mmax(film)/cm 3358 (br); H NMR (360 MHz, CDCl
d 0.05 (6H, s, Si(CH ), 0.90 (9H, s, SiC(CH ), 1.08 (6H, s,
× CH ), 1.30–1.58 (4H, m, (CH CH OTBS), 1.98–2.10 (2H,
m, Me CCH ), 2.13–2.17 (2H, m, Me CCH ), 2.33–2.41 (1H,
m, CHCH OH), 3.46 (1H, dd, J 10.4, 8.2, CHHOH), 3.52 (1H,
dd, J 10.4, 5.3, CHHOH), 3.55–3.65 (2H, m, CH OTBS), 5.41
3
)
2
0 min, then water was added, followed by ether and 2 N HCl.
The organic phase was separated and washed successively with
N HCl, saturated, aqueous NH Cl and brine, then dried. The
3
)
2
)
3 3
2
3
2
)
2
2
2
4
2
2
2
2
solvents were evaporated and the residue was quickly passed
through a silica column (eluent: 2% diethyl ether–petroleum
ether) to give t-butyl-(3-bromopropoxy)dimethylsilane (32 g) as
2
2
1
3
−
1
1
(1H, br. s, =CH); C NMR d −5.3 (q), 18.3 (s), 25.6 (t), 26.0
an oil; mmax(film)/cm 1472, 1256, 1103; H NMR (360 MHz,
CDCl ) d 0.07 (6H, s, Si(CH ), 0.90 (9H, s, SiC(CH ), 2.04
2H, tt, J 6.5, 5.7, CH CH Br), 3.52 (2H, t, J 6.5, CH Br),
OTBS); C NMR d −5.4 (Si(CH ),
), 25.9 (SiC(CH ), 30.7 (CH ), 35.5 (CH ), 60.4
(
(
C
q), 29.9 (2 × q), 30.5 (t), 38.2 (s), 44.1 (d), 46.6 (t), 47.3 (t), 63.1
3
3
)
2
)
3 3
+
t), 64.2 (t), 126.4 (d), 142.9 (s); m/z (EI) found 255.1776 (M −
(
3
1
(
2
2
2
1
3
4
H
9
), C18
H
36
2
O Si requires 255.1780.
.74 (2H, t, J 5.7, CH
8.3 (SiCMe
OTBS).
The bromide was taken up in acetone (520 ml) and heated
2
3
)
2
3
3
)
3
2
2
5
-(t-Butyldimethylsilanyloxy)-2-(4,4-dimethylcyclopent
CH
2
-1-enyl)pentyl toluene-4-sulfonate 16b
under reflux with sodium iodide (71.9 g, 480 mmol) for 7 h.
The acetone was evaporated, then water and ether were added
and the organic layer was washed with brine and dried. The
solvents were evaporated to leave the corresponding iodide
A solution of the alcohol 16a in dry CH
with p-toluenesulfonyl chloride (770 mg, 4.04 mmol), DMAP
48 mg, 0.39 mmol) and triethylamine (0.76 ml, 5.45 mmol) at
room temperature under a nitrogen atmosphere for 22 h. Water
was added and the mixture was stirred for 10 min, and then
extracted with ether. The extracts were washed with 2 N HCl,
then brine, and dried. The solvents were evaporated and the
2
Cl (25 ml) was stirred
2
(
(
32.6 g, 94%) as an oil, which was dried in vacuo and used
−
1
without purification in the next reaction. mmax(film)/cm 1471,
1
0
(
1
256, 1101; H NMR (360 MHz, CDCl
.91 (9H, s, SiC(CH , 2.00 (2H, tt, J 6.7, 5.7, CH
I), 3.68 (2H, t, J 5.7, CH
), 3.7 (CH I), 18.3 (SiCMe
), 62.1 (CH OTBS).
n-Butyllithium (2.5 M in hexanes; 19.5 ml, 48.8 mmol)
3
) d 0.07 (6H, s, Si(CH
CH I), 3.29
OTBS); C NMR d
), 25.9 (SiC(CH ),
3
)
2
),
3
)
3
2
2
residue was passed through a silica column (eluent: CH
2
Cl
2
)
1
3
2H, t, J 6.7, CH
2
2
3
to give the tosylate (1.47 g, 88%) as a colourless solid; (found,
−
5.3 (Si(CH
3
)
2
2
)
3 3
C, 64.2%; H, 9.1%; C25
H
42
O
4
SiS requires C, 64.3%; H, 9.1%);
) d 0.03
), 1.02 (6H, s, 2 × CH ),
OTBS), 1.87 (1H, dq, J 15.6,
CCHH), 1.94 (1H, dq, J 15.6, 1.8 Hz, Me CCHH),
.04–2.09 (2H, m, Me CCH ), 2.45 (3H, s, ArCH ), 2.45–2.53
OTs), 3.49–3.60 (2H, m, CH OTBS), 3.89–3.97
3
6.1 (CH
2
2
−1
1
mmax(Nujol)/cm 1596; H NMR (360 MHz, CDCl
3
(
6H, s, Si(CH
3
)
2
, 0.88 (9H, s, SiC(CH)
.26–1.48 (4H, m, (CH CH
.9 Hz, Me
3
3
was added over 10 min to a stirred solution of 2,2,6,6-
tetramethylpiperidine (8.6 ml, 50.7 mmol) in dry THF (65 ml)
1
1
2
2
)
2
2
2
2
◦
◦
at 0 C under a nitrogen atmosphere. The mixture was stirred
2
2
3
◦
at 0 C for 30 min, then between −60 and −90 C for 25 min.
(
(
2
(
(
(
1H, m, CHCH
2H, m, CH
2
2
◦
DMPU (35 ml) was added at −90 C, and the resulting homoge-
OTs), 5.27 (1H, br. s, =CH), 7.34 (2H, d, J 8.2 Hz,
2
neous mixture was stirred for 30 min, while the temperature of
13
× ArH), 7.78 (2H, d, J 8.2 Hz, 2 × ArH); C NMR d −5.3
◦
the cooling bath was maintained between −85 and −100 C. A
q), 18.3 (s), 21.6 (q), 25.6 (t), 25.9 (q), 29.7 (2 × q), 29.9 (t), 38.2
9
solution of methyl (3,3-dimethylcyclopentylidene)acetate 14
s), 40.3 (d), 47.0 (t), 47.2 (t), 62.8 (t), 72.1 (t), 126.1 (d), 127.9
(
3.97 g, 23.6 mmol) in dry THF (25 ml) was added dropwise
2 × d), 129.7 (2 × d), 133.1 (s), 140.7 (s), 144.6 (s); m/z (FAB)
via cannula at the same temperature as the reaction mixture
+
found 467.2650 (M + H), C25
H
42
4
O SiS requires 467.2651.
◦
◦
(
4
−100 C). The resulting mixture was stirred at −100 C for
0 min, before it was added rapidly via cannula to a solution
t-Butyl[4-(4,4-dimethylcyclopent-1-enyl)pentyloxy]dimethyl-
silane 16c
of t-butyl(3-iodopropoxy)dimethylsilane (32.6 g, 109 mmol) in
◦
dry THF (70 ml) at −100 C. After 5 min, the reaction was
quenched with water. 2 N HCl was added, and the mixture
was extracted with ether. The combined ether extracts were
Super-Hydride (1.0 M in THF; 8.8 ml, 8.8 mmol) was added
slowly over 5 min to a stirred solution of the tosylate 16b (1.87 g,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 – 3 4 7
3 4 3

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◦
4
.01 mmol) in THF (15 ml) at 0 C under a nitrogen atmosphere.
m, Me
CHCH
(1H, dt, J 15.6, 1.6 Hz, =CHCO
Me); C NMR d 19.3 (q), 29.8 (q), 29.9
2
CCH
2
, =CHCH
2
CH
2
), 2.25 (1H, app. sx, J 6.9 Hz,
3
The mixture was stirred at room temperature for 2.75 h before
it was again cooled in ice, and 2 M NaOH (15 ml) and then
hydrogen peroxide (5 ml) were carefully added. The resulting
mixture was heated under reflux for 1.25 h, then allowed to
cool, and extracted with ether. The combined ether extracts
were washed with 2 N HCl, then brine, and dried. The solvents
were evaporated under reduced pressure to leave a residue
which was purified by chromatography on silica using petroleum
ether–diethyl ether (2 : 98) as eluent to give the cyclopentene
3
), 3.73 (3H, s, CO
2
CH
), 5.21 (1H, br. s, =CH), 5.81
2
Me), 6.97 (1H, dt, J 15.6,
1
3
7.0 Hz, CH=CHCO
2
(q), 30.1 (t), 33.2 (t), 34.8 (d), 38.2 (s), 47.0 (t), 47.3 (t), 51.4 (q),
120.7 (d), 122.0 (d), 146.9 (s), 149.9 (d), 167.2 (s); m/z (EI) found
+
236.1776 (M ), C15
H
24
2
O requires 236.1776.
6
-(4,4-Dimethylcyclopent-1-enyl)hept-2E-enoic acid 18b
A solution of the methyl ester 18a (852 mg, 3.60 mmol) in THF–
water (3 : 1; 24 ml) was heated under reflux in the presence
of lithium hydroxide (331 mg, 7.89 mmol) for 21 h. 2 N HCl
was added to acidify the mixture, which was then extracted
with ether, and the combined extracts were washed with brine
and dried. The solvents were evaporated to leave the carboxylic
acid (782 mg, 98%) as a pale yellow oil; (found, C, 75.7%; H,
(
C
1.15 g, 97%) as a colourless oil; (found, C, 73.3%; H, 12.4%;
−
1
18
H
36OSi requires C, 72.9%; H, 12.2%); mmax(film)/cm 1647;
) d 0.05 (6H, s, Si(CH ), 0.90 (9H, s,
), 0.99 (3H, d, J 6.9 Hz, CHCH
), 1.07 (6H, s, 2 ×
), 1.21–1.51 (4H, m, (CH CH OTBS), 1.99 (1H, dq, J 15.6,
.8 Hz, Me CCHH), 2.06 (1H, dq, J 15.6, 1.8 Hz, Me CCHH),
.07–2.12 (2H, m, Me CCH ), 2.16–2.25 (1H, m, CHMe), 3.59
OTBS), 5.19 (1H, br. s, =CH); C NMR
1
H NMR (360 MHz, CDCl
3
)
3 2
SiC(CH
CH
1
2
3
)
3
3
3
2
)
2
2
2
2
2
2
−
1
1
3
10.1%; C14
3
H
22
O requires C, 75.6%, H, 10.0%); mmax(film)/cm
2
(
2H, t, J 6.5 Hz, CH
2
1
400–2400 (br), 1697, 1650; H NMR (360 MHz, CDCl
.01 (3H, d, J 6.9 Hz, CHCH ), 1.07 (3H, s, CH ), 1.08 (3H, s,
), 1.39–1.60 (2H, m, =CHCH
CH ), 1.98 (1H, dq, J 15.5,
.7 Hz, Me CCHH), 2.06 (1H, dq, J 15.5, 1.8 Hz, Me CCHH),
.09–2.13 (2H, m, Me CCH CH
), 2.14–2.31 (3H, m, =CHCH
3
) d
d −5.3 (q), 18.4 (s), 19.4 (q), 26.0 (q), 29.8 (q), 29.9 (q), 30.7
1
3
3
(
(
t), 31.2 (t), 35.1 (d), 38.1 (s), 47.1 (t), 47.3 (t), 63.5 (t), 121.2
+
CH
3
2
2
d, 147.9 (s); m/z (EI) found 239.1823 (M − C
4
9
H ), C18H36OSi
1
2
2
2
requires 239.1831.
2
2
2
2
,
CHMe), 5.23 (1H, br. s, =CH), 5.82 (1H, dt, J 15.6, 1.5 Hz,
4
-(4,4-Dimethylcyclopent-1-enyl)pentan-1-ol 17
1
3
=
CHCO H), 7.09 (1H, dt, J 15.6, 7.0 Hz, CH=CHCO H);
C
2
2
A solution of the silyl ether 16c (1.15 g, 3.88 mmol) in acetic
acid–water–THF (1 : 1 : 2; 32 ml) was stirred at 45 C for
4 h. The mixture was cooled in ice and neutralised with
saturated aqueous NaHCO , then extracted with ether. The
NMR d 19.3 (q), 29.8 (q), 29.9 (q), 30.2 (t), 33.0 (t), 34.9 (d),
◦
3
(
8.2 (s), 46.9 (t), 47.2 (t), 120.5 (d), 122.1 (d), 146.8 (s), 152.6
d), 172.6 (s); m/z (EI) found 222.1626 (M ), C14
+
1
H
22
2
O requires
3
222.1620.
extracts were washed with brine, dried and concentrated under
reduced pressure to leave an oil. Purification by chromatography
on silica using petroleum ether–diethyl ether as eluent gave the
alcohol (657 mg, 93%) as a colourless oil; (found, C, 78.8%; H,
Se-Phenyl 6-(4,4-Dimethylcyclopent-1-enyl)hept-2E-
eneselenoate 19
−
1
Tri-n-butylphosphine (940 ll, 3.77 mmol) was added dropwise
over 3 min to a stirred solution of the acid 18b (540 mg,
1
3
6
1
Me
2
2.1%; C12
330 (br), 1646; H NMR (360 MHz, CDCl
.9 Hz, CHCH ), 1.06 (3H, s, CH ), 1.07 (3H, s, CH
.57 (4H, m, (CH CH OH), 1.99 (1H, dq, J 15.6, 1.6 Hz,
CCHH), 2.06 (1H, dq, J 15.6, 1.7 Hz, Me CCHH), 2.09–
.11 (2H, m, Me CCH ), 2.18–2.88 (1H, m, CHMe), 3.63 (2H,
t, J 6.5 Hz, CH
OH), 5.20 (1H, br. s, =CH); C NMR d 19.4
q), 29.8 (q), 29.9 (q), 30.6 (t), 31.1 (t), 35.1 (d), 38.1 (s), 47.1 (t),
H22O requires C, 79.1%; H, 12.2%); mmax(film)/cm
1
3
) d 1.00 (3H, d, J
), 1.23–
◦
2
.43 mmol) in dry CH
2
Cl
2
(20 ml) at −30 C under a nitrogen
3
3
3
◦
atmosphere and the mixture was stirred at −30 C for 15 min.
2
)
2
2
NPSP (1.11 g, 3.67 mmol) was added and the resulting mixture
2
2
◦
was stirred at −30 C for a further 10 min, then diluted with
2
2
1
3
ether. The ether extracts were washed with water and brine,
dried and evaporated in vacuo. The residue was purified by
chromatography on silica using petroleum ether–diethyl ether as
eluent to give the phenyl selenyl ester (500 mg, 57%) as a yellow
2
(
4
7.2 (t), 63.2 (t), 121.4 (d) 147.6 (s); m/z (EI) found 182.1673
+
(
M ), C12
H
22O requires 182.1671.
−
1
1
oil; mmax(film)/cm 1698, 1626, 1580; H NMR (360 MHz,
CDCl ) d 1.02 (3H, d, J 6.9 Hz, CHCH ), 1.08 (3H, s, CH ),
.09 (3H, s, CH CH ), 1.99
), 1.40–1.63 (2H, m, =CHCH
1H, dqd, J 15.5, 1.9, 0.5 Hz, Me CCHH), 2.06 (1H, dqd, J
5.5, 1.9, 0.5 Hz, Me CCHH), 2.10–2.32 (5H, m, Me CCH
CH
Methyl 6-(4,4-dimethylcyclopent-1-enyl)hept-2E-enoate 18a
3
3
3
1
(
1
3
2
2
Dimethyl sulfoxide (0.81 ml, 11.4 mmol) was added dropwise
2
over 10 min to a stirred solution of oxalyl chloride (0.5 ml,
2
2
2
,
◦
5
.73 mmol) in dry CH
2
Cl
2
(18 ml) at −60 C under a nitrogen
CH=CH, CHCH ), 5.21–5.25 (1H, m, =CH), 6.16 (1H,
2
3
◦
atmosphere. The mixture was stirred at −60 C for 40 min
dt, J 15.4, 1.5 Hz, =CHCOSePh), 6.94 (1H, dt, J 15.4, 6.9 Hz,
CH=CHCOSePh), 7.37–7.42 (3H, m, 3 × ArH), 7.52–7.56 (2H,
and then a solution of the alcohol 17 (863 mg, 4.73 mmol)
◦
in CH
2
Cl
2
(8 ml) was added. The mixture was stirred at −60 C,
13
m, 2 × ArH); C NMR d 19.3 (q), 29.8 (q), 29.9 (q), 30.3 (t),
for a further 15 min, then triethylamine (3.3 ml, 23.7 mmol)
3
1
(
3.0 (t), 34.9 (d), 38.2 (s), 46.9 (t), 47.3 (t), 122.2 (d), 126.2 (s),
was added and the resulting opaque, viscous mixture was
28.8 (d), 129.3 (2 × d), 130.0 (d), 135.9 (2 × d), 146.7 (s), 147.2
◦
warmed to 0 C. Further CH
2
Cl
2
(4 ml) was added, and the
+
d), 190.9 (s); m/z (ES) found 363.1204 (M + H), C20
H26OSe
◦
mixture was stirred at 0 C for 1.75 h. A solution of methyl
requires 363.1227.
(
triphenylphosphoranylidene)acetate (3.17 g, 9.48 mmol) in
CH Cl (18 ml) was added, and the mixture was then warmed
2
2
2
,2,8-Trimethyloctahydrocyclopenta[c]pentalen-4-one 22
and stirred at room temperature for 17 h. Water was added and
the mixture was extracted twice with ether. The combined ether
extracts were washed with 2 N HCl and brine, dried and
concentrated under reduced pressure. The residue was purified
by chromatography on silica using petroleum ether–diethyl
ether (2 : 98) as eluent to give the E-a,b-unsaturated ester
A solution of tributyltin hydride (180 ll, 0.67 mmol) and AIBN
(12.5 mg, 0.08 mmol) in dry, degassed benzene (5 ml) was added
over 7.5 h via syringe pump to a stirred, refluxing solution of the
phenyl selenyl ester 19 (163 mg, 0.45 mmol) and AIBN (6.8 mg,
0.04 mmol) in dry, degassed benzene (190 ml), under an argon
atmosphere. The mixture was heated under reflux for a further
1 h, then allowed to cool to room temperature. The solvent was
removed under reduced pressure, and the residue was purified by
chromatography on silica using petroleum ether–diethyl ether as
eluent to give a 5 : 1 mixture of the diastereomeric triquinanes
(31 mg, 33%) along with the aldehyde 18c (25 mg, 27%). 22:
(
890 mg, 80%) (the corresponding Z-isomer was also isolated
in 7% yield) as a colourless liquid; (found, C, 76.3%; H, 10.4%;
−
1
C
1
15
H
24
1
O
2
requires C, 76.2%; H, 10.2%); mmax(film)/cm 1728,
657; H NMR (360 MHz, CDCl ) d 1.00 (3H, d, J 6.9 Hz,
CHCH ), 1.06 (3H, s, CH ), 1.07 (3H, s, CH ), 1.37–1.58 (2H,
m, =CHCH
CH ), 1.98 (1H, dq, J 15.5, 1.7 Hz, Me CCHH),
.05 (1H, dq, J 15.5, 1.7 Hz, Me CCHH), 2.08–2.19 (4H,
3
3
3
3
2
2
2
−
1
1
2
2
mmax(film)/cm 1737; H NMR (500 MHz, CDCl ) d 0.97 (3H,
3
3
4 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 – 3 4 7

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d, J 6.9 Hz, CHCH
.30–1.38 (3H, m, 3 × CHH), 1.63 (1H, dd, J 12.9, 7.0 Hz,
CHHCHCO), 1.72 (1H, dd, J 12.9, 9.5 Hz, CHHCHCO),
3
), 0.99 (3H, s, CH
3
), 1.01 (3H, s, CH
3
),
28.4 (t), 30.7 (q), 30.9 (q), 33.8 (t), 40.2 (t), 41.2 (s), 42.5 (d), 48.4
(d), 48.7 (t), 57.2 (d), 58.1 (d), 65.7 (s), 78.2 (d).
1
1
2
CH
.79–1.86 (2H, m, 2 × CHH), 1.86–1.95 (1H, m, CHMe),
(
± )-Pentalenene 2
.07–2.14 (2H, m, CHH, CHHCO), 2.40–2.47 (2H, m, CHCO,
1
3
2
CHCH ), 2.78 (1H, dd, J 18.6, 9.2 Hz, CHHCO); C NMR
2
A solution of the alcohol 24 (3 mg, 0.014 mmol) and p-
toluenesulfonic acid (1 mg, 5 lmol) in dry benzene (0.5 ml) was
stirred and heated under reflux under a nitrogen atmosphere for
d 15.5 (q), 29.2 (q), 29.5 (q), 31.3 (t), 34.4 (t), 41.2 (s), 42.9 (d),
4.6 (t), 45.8 (d), 46.8 (t), 47.9 (t), 59.4 (d), 62.7 (s), 222.9 (s);
4
+
+
+
m/z (EI ) found 206.1678 (M ), C14
H
22O requires M , 206.1671.
22O requires C, 81.5%;
6
h, and then poured into saturated, aqueous NaHCO , and
3
18c: (found, C, 81.4%; H, 10.9%; C14
H
1
extracted with ether. The combined ether extracts were washed
with brine, dried and concentrated under reduced pressure.
The residue was purified by chromatography on silica using
−
1
H, 10.8%); mmax(film)/cm 1695, 1638; H NMR (360 MHz,
CDCl ) d 1.02 (3H, d, J 6.9 Hz, CHCH ), 1.067 (3H, s, CH ),
.074 (3H, s, CH CH ), 1.98 (1H,
), 1.42–1.64 (2H, m, =CHCH
dq, J 15.6, 1.9 Hz, Me CCHH), 2.06 (1H, dq, J 15.6, 1.9 Hz,
Me CCHH), 2.09–2.12 (2H, m, Me CCH ), 2.23–2.33 (3H, m,
CHCH CH , CHMe), 5.23 (1H, br. s, =CH), 6.12 (1H, ddt,
3
3
3
1
3
2
2
petroleum ether–diethyl ether as eluent to give (± )-pentalenene
2
1
(
(
2 mg, 70%) as a colourless oil; H NMR (500 MHz) d 0.91
2
2
2
3H, d, J 7.0 Hz, CHCH
.18 (1H, dd, J 12.5, 5.1 Hz), 1.25–1.34 (3H, m), 1.36 (1H, d,
), 1.74
3
), 0.99 (2 × 3H, 2 × s, 2 × CH
3
),
=
2
2
1
J 15.6, 7.9, 1.5 Hz, =CHCHO), 6.86 (1H, dt, J 15.6, 6.8 Hz,
CH=CHCHO), 9.50 (1H, d, J 7.9 Hz, CHO); C NMR d 19.3
q), 29.7 (q), 29.9 (q), 30.6 (t), 33.0 (t), 34.9 (d), 38.2 (s), 46.9 (t),
J 13.0 Hz), 1.58–1.65 (1H, m), 1.62 (3H, br. s, =CCH
3
1
3
(
1H, d, J 13.0 Hz), 1.74–1.87 (2H, m), 2.55 (1H, d, J 9.2 Hz),
(
13
2
1
1
.64–2.70 (1H, m), 5.16 (1H, br. s); C NMR (125 MHz) d 15.5,
7.0, 27.6, 29.1, 29.9, 33.5, 40.5, 44.6, 46.8, 48.9, 59.4, 62.1, 64.7,
29.5, 140.6.
4
7.2 (t), 122.3 (d), 132.9 (d), 146.6 (s), 159.1 (d), 194.1 (s); m/z
+
(
EI) found 206.1663 (M ), C14
H
22O requires 206.1671.
2
,2,5,8-Tetramethyloctahydrocyclopenta[c]pentalen-4-one 23
Ethyl (5-methylenecyclooctylmethylene)acetate 28a
A solution of a mixture of the diastereoisomeric ketones 22
51 mg, 0.25 mmol) in THF (1 ml) was added via cannula to
A solution of LDA in THF (2.3 ml 2 M, 4.5 mmol) was added
over 5 min to a stirred solution of ethyl trimethylsilylacetate
(728 mg, 4.5 mmol) in THF (50 ml), and the mixture was stirred
(
a stirred solution of freshly prepared LDA (1.0 M; 0.32 ml,
0
◦
.32 mmol) in THF (1 ml) at −78 C. The stirred mixture was
◦
14
◦
at −78 C for 0.25 h. 5-Methylenecyclooctanone (316 mg,
allowed to warm to −20 C over 1.25 h, then methyl iodide
2
.27 mmol) was added dropwise over 15 min, and the pale
(
0.05 ml, 0.80 mmol) was added, and the resulting mixture was
◦
◦
yellow solution was stirred at −78 C for a further 1 h and
stirred at 0 C for 1.5 h. The mixture was quenched with NH
4
Cl
then allowed to warm to room temperature over 2 h. Water
and then ether and water were added. The separated organic
extracts were washed with brine and dried. Evaporation of the
solvents left a residue which was purified by chromatography on
silica using petroleum ether–diethyl ether (1 : 99) as eluent to
give the methylated ketone (20 mg, 37%), along with unreacted
(
(
20 ml) was added and the mixture was extracted with ether
4 × 50 ml). The combined organic extracts were dried and then
evaporated under reduced pressure. The residue was purified by
chromatorgraphy on silica using petroleum ether–diethyl either
(9 : 1) as eluent to give the ethyl ester (0.26 g, 54%) as a yellow
−
1
starting material (8 mg, 16%) as a colourless oil; mmax(film)/cm
1
oil; (found: C, 75.3%, H, 10.1%; C13
H O
20
1
2
requires C, 75.0%,
H, 9.7%); mmax(film)/cm 1712, 1636; H NMR (360 MHz,
CDCl ) d 1.24 (3H, t, J 7.1 Hz, CO CH CH ), 1.80–2.00 (4H, m,
CH CH CH ), 2.07–2.22 (4H, m, CH ), 2.30 (2H, app.
C=CH
dd, J ∼5.6 Hz, CH
C=CHCO
CH Et), 4.10 (2H, q, J 7.1 Hz, CO
C=CHCO
2H, s, C=CH
1
0
736; H NMR (360 MHz, CDCl
.98 (3H, d, J 6.6 Hz, CH CHCH ), 1.00 (3H, s, CH
CHCO), 1.19 (1H, d, J 13.2 Hz,
CCHHCquat.), 1.30–1.39 (1H, m, CH CHCHH), 1.41–1.50
CHCH CHH), 1.61 (1H, dd, J 12.9, 9.8 Hz,
CHHCHCO), 1.69 (1H, d, J 13.2 Hz, Me
1H, ddd, J 12.9, 4.8, 1.0 Hz, CHHCHCO), 1.80–2.17 (5H, m),
3
) d 0.85 (3H, s, CH
3
),
−
1
2
3
3
), 1.09
3
2
2
3
(
3H, d, J 6.8 Hz, CH
3
2
2
2
2
2
Me
2
3
2
2
Et), 2.72 (2H, app. dd, J ∼6.1 Hz,
(
1H, m, CH
3
2
2
2
2
3
CH
2
CH ), 4.71
3
2
CCHHCquat.), 1.75
1
(
2
), 5.60 (1H, s, C=CHCO
2
Et); C NMR d 14.3
(
1
3
(q), 25.3 (t), 29.0 (t), 30.6 (t), 34.1 (t), 36.2 (t), 38.9 (t), 59.2
2
.52 (1H, ddd, J 9.8, 4.8, 1.7 Hz, CH
2
CHCO); C NMR d 13.5
(
2
t), 113.1 (t), 116.5 (d), 149.4 (s), 166.1 (2 × s); m/z (EI) found
(
q), 14.5 (q), 28.8 (q), 29.8 (q), 29.9 (t), 35.0 (t), 40.8 (s), 43.1 (d),
+
08.1470 (M ), C13
H
20
O requires 208.1463.
2
4
3.5 (t), 46.7 (t), 53.2 (d), 55.3 (d), 58.0 (d), 59.5 (s), 222.7 (s).
2,2,5,8-Tetramethyldecahydrocyclopenta[c]pentalen-4-ol 24
(5-Methylenecyclooctylmethylene)acetic acid 28b
A solution of the ketone 23 (17 mg, 0.077 mmol) in methanol
A solution of the ester 28a (180 mg, 0.86 mmol) in aqueous
sodium hydroxide (20 ml, 1 M) was heated under reflux for 10 h,
then cooled and extracted with ether. The separated aqueous
layer was acidified with dilute HCl (to pH 3) and then extracted
with ether (3 × 100 ml). The combined ether extracts were
dried and then evaporated under reduced pressure to leave a 7 :
3 mixture of (5-methylenecyclooctylmethylene)acetic acid and
its positional isomer, (5-methylenecycloocten-1-yl)acetic acid
(
1 ml) was stirred with sodium borohydride (9 mg, 0.24 mmol)
◦
at 0 C for 1.25 h. Water was added, and most of the methanol
was then evaporated. The residue was extracted with ether,
and the extracts were then washed with brine and dried. The
solvents were evaporated, and the residue was redissolved in
◦
methanol (1 ml) and cooled to 0 C. More sodium borohydride
(
9 mg, 0.24 mmol) was added, and the mixture was stirred at
−
1
this temperature for 1.75 h. The reaction was quenched by the
addition of water, and most of the methanol was then removed
under reduced pressure. The residue was again extracted with
ether, and the combined extracts were washed with brine,
then dried, and concentrated. The residue was purified by
chromatography on silica using petroleum ether–diethyl ether
(0.15 g, 96%), as a colourless solid; mmax(film)/cm 3484, 1714;
1
H NMR (360 MHz, CDCl
2.27 (1.25H, app. dd, J ∼5.7 Hz, CHHC=CCO
(1.25H, app. dd, J ∼5.8 Hz, CHHC=CCO
H), 2.95 (0.5H, s,
CO major isomer), 4.70 (0.5H, s,
C=CH
CH
3
) d 1.45–2.17 (6H, m, CH
2
CH
2
CH
2
),
2
H), 2.66
2
CH
2
2
H), 4.66 (1.5H, s, C=CH
2
minor isomer), 5.56 (1H, br. s, C=CHCO
H and
2
2
1
2
13
(
1 : 99) as eluent to give the alcohol (9 mg, 53%) as a colourless
2
CH=C), 11.60 (1H, br. s, CO
2
H); C NMR major isomer: d
−
1
1
oil; mmax(film)/cm 3490 (br); H NMR (360 MHz, CDCl
3
) d
), 1.04 (3H, d, J
), 1.17–1.39 (3H, m), 1.44–1.55
25.08 (t), 28.95 (t), 30.67 (t), 34.00 (t), 36.17 (t), 39.12 (t), 113.42
(t), 116.05 (d), 149.02 (s), 169.77 (s), 171.78 (s); minor isomer:
26.7 (t), 27.8 (t), 28.4 (t), 32.7 (t), 39.7 (t), 42.5 (2 × t), 112.7 (t),
0
7
.88 (3H, d, J 7.0 Hz, CH
3
), 1.02 (3H, s, CH
3
.0 Hz, CH ), 1.09 (3H, s, CH
3
3
(
(
2H, m), 1.65–1.88 (6H, m), 2.25–2.33 (1H, m, CHCHOH), 3.95
1H, app. t, J 5.2 Hz, CHOH); C NMR d 14.2 (q), 17.3 (q),
129.4 (d), 133.4 (s), 150.7 (s), 178.9 (s); m/z (EI) found 180.1148
1
3
+
(M ), C11
H
16
O requires 180.1150.
2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 – 3 4 7
3 4 5

View Article Online
◦
The thioester 29
10 min at −78 C, and the pale yellow solution was stirred at
◦
−
78 C for 1 h and then at room temperature for 4 h. Water
A mixture of the acid 28b and its positional isomer (84 mg,
was added and the mixure was extracted with ether. The dried
ether extracts were evaporated under reduced pressure to leave
a residue which was purified by chromatography on silica using
petroleum ether–diethyl ether (95 : 5) as eluent to give the alkene
0
.46 mmol), was treated with 2-(o-iodophenyl)ethanethiol
15
(
3
147.3 mg, 0.55 mmol), as described previously, and gave a 7 :
mixture of the corresponding conjugated and non-conjugated
−
1
thioesters (109 mg, 55%) as a colourless oil; mmax(film)/cm 1669,
−
1
1
(
46 mg, 65%) as a colourless oil; mmax(film)/cm 1712, 1632; H
NMR (360 MHz, CDCl ) d 1.28 (3H, t, J 7.1 Hz, CO CH CH ),
.53 (3H, s, =CCH ), 1.57 (3H, s, =CCH
), 1.84–1.93 (2H, m,
CH CH CH ), 1.94–2.00 (2H, m, CH CH CH ), 2.19 (4H, br.
t, J∼6.1 Hz, CH )2), 2.24 (2H, ddd, J 6.1, 6.2, 1.0 Hz,
C=C(CH
CH Et), 2.73 (2H, dd, J 6.1, 6.2 Hz, CH
C=CCO
.13 (2H, q, J 7.1 Hz, CO CH CH
), 5.59 (1H, s, C=CHCO
1
1
1
2
2
608, H NMR (360 MHz, CDCl
.88–2.00 (2H, m, CH ), 2.07 (2H, dd, J 6.2, 6.2 Hz, CH
.28 (4.5H, m, CH ), 2.32 (1H, dd, J 6.0, 6.2 Hz, CH
C=CCO),
.74 (1H, dd, J 6.2, 6.0 Hz, CH
C=CCO), 3.00 (1H, t, J 8.6 Hz,
Ar), 3.02 (1H, t, J 8.6 Hz, SCH CH Ar), 3.1–3.2 (2H,
), 3.24 (1H, s, CH CO, minor isomer), 4.77 (1.5H, s,
3
) d 1.55–1.62 (1H, m, CH
2
),
3
2
2
3
2
2
), 2.15–
1
3
3
2
2
2
2
2
2
2
2
2
2
3
SCH
m, ArCH
C=CH
2
CH
2
2
2
2
C=CCO
Et),
Et);
2
2
2
2
2
4
2
2
3
2
, major isomer), 4.81 and 4.82 (0.25H, s, C=CHH and
CH=CCH
CO),
.96 (0.5H, s, =CHCO), 6.91–6.98 (1H, m, arom. CH), 7.27–
.35 (2H, m, arom. CH), 7.84 (1H, d, J 7.7 Hz, arom. CH);
2
1
3
C NMR d 14.3 (q), 20.31 (s), 20.8 (q), 24.9 (t), 26.5 (t), 30.7
C=CHH, minor isomer), 5.66 (0.5H, m, CH
2
2
(
(
t), 31.0 (t), 32.0 (t), 39.0 (t), 76.5 (t), 113.7 (d), 127.1 (s), 130.8
s), 166.3 (s), 167.0 (s); m/z (EI) found 236.1767 (M ), C15
requires 236.1776.
5
7
+
H
24
O
2
1
3
C
NMR (both isomers) d 25.2 (t), 26.9 (t), 27.9 (t), 28.5 (t), 28.7
t), 28.9 (t), 29.0 (t), 31.6 (t), 32.8 (t), 34.1 (t), 36.3 (t), 38.6 (t),
9.7 (t), 40.5 (t), 40.7 (t), 52.1 (t), 100.7, 100.8 (arom. CI), 112.8
t), 113.4 (t), 123.7 (d), 128.3 (d), 128.4 (d), 129.9 (d), 130.0 (d),
(
3
(
[5-(Isopropylidene)cyclooctylmethylene]acetic acid 33b
Ethyl (5-(isopropylidene)cyclooctylmethylene)acetate 33a was
saponified with NaOH as described earlier in the synthesis of
8b to give a 4 : 1 mixture of 5-(isopropylidene)cyclooctylmethy-
lene)acetic acid and its positional isomer 5-(isopropylidene)-
cycloocten-1-ylacetic acid (22 mg, 55%) as a colourless solid;
max(film)/cm 3188, 1692, 1626; H NMR (360 MHz, CDCl
d 1.45, 1.48 (2.4H each, s, CH , major isomer), 1.56, 1.57 (0.6H
each, s, CH , minor isomer), 1.68–1.91 (4H, m, CH ), 2.02–
C=CHCO
2.20 (6H, m, CH and CH H, major isomer), 2.64
C=CHCO
(1.6H, dd, J 6.1, 6.2 Hz, CH H, major isomer), 2.94
H, minor isomer), 5.53 (0.8H, s, =CHCO
(0.4H, s, CH CO H,
major isomer), 5.57 (0.2H, m, =CHCH
, minor isomer);
NMR d 20.3 (q), 20.6 (q), 24.9 (t), 26.6 (t), 28.7 (t), 30.8 (t), 31.0
t), 32.0 (t), 34.6 (t), 39.2 (t), 42.6 (t), 113.0 (d), 126.5 (s), 127.7
1
30.3 (d), 133.8 (s), 139.5 (d), 139.5 (d), 142.6, (s), 149.2, 151.0
+
(
s), 163.7 (s), 187.7 (s), 197.9 (s); m/z (EI) found 426.0512 (M ),
2
19
C H23OSI requires 426.0514.
1
,5
Tricyclo[3.3.3.0 ]undecane-3-one 27
−
1
1
m
3
)
A 7 : 3 mixture of the thioester 29 and its positional isomer
3
(
0
70 mg, 0.16 mmol) was heated with tributyltin hydride (62 mg,
.21 mmol) and AIBN (2.7 mg, 0.01 mmol) in argon-degassed
benzene (60 ml) under reflux for 1.5 h, as described previously,
3
2
2
2
2
2
2
16
and gave the tricycloundecane-3-one (14.2 mg, 53%), whose
spectroscopic data were identical to those described in the
literature.
2
2
2
1
3
2
C
(
5
-(Isopropylidene)cyclooctanol 31
(s), 129.78 (s), 130.7 (d), 131.9 (s), 133.1 (s), 171.0 (s), 171.8
+
(
s), 178.5 (s); m/z (EI) found 208.1464 (M ), C13
H
20
2
O requires
THF (1.5 l) was degassed with argon and then added slowly
via cannula to TiCl
lithium metal (8.1 g, 1.2 mmol) were added portionwise and
the mixture was stirred at room temperature for 12 h under
an argon atmosphere. A solution of 5-(tert-butyldimethyl-
208.1463.
1
7
3
·AlCl
3
(100 g, 390 mmol). Slices of
The thioester 33c
15
Following the general procedure, a 4 : 1 mixture of the acid 33b
and its positional isomer was converted into a mixture of the cor-
responding conjugated and non-conjugated thioesters (41 mg,
14
silanyloxy)cyclooctanone 30 (6.7 g, 26 mmol) in acetone (23 ml,
12 mmol) was added dropwise via syringe pump over 5 h
3
at room temperature, and the mixture was stirred at room
temperature for 14 h and then under reflux for 10 h. Water
−
1
8
2
1
4%), which was obtained as a colourless oil; mmax(film)/cm
1
923, 1667, 1605; H NMR (360 MHz, CDCl
.56 (6H, s, 2 × CH ), 1.79–1.92 (4H, m, CH
), 2.63 (1.4H, dd, J 5.9, 6.3 Hz, CH
major isomer), 2.86–2.98 (2H, m, ArCH CH S), 2.99–3.07 (2H,
m, ArCH CH S), 3.12 (0.6H, s, CH COS, minor isomer), 5.58
0.3H, m, CH COS, minor isomer), 5.86 (0.7H, br. s,
CH=CCH
CHCOS, major isomer), 6.80–6.86 (1H, m, arom. CH), 7.18–
3
) d 1.44, 1.50,
), 2.02–2.14
C=CHCOS,
(
50 ml) was added slowly (exothermic) to the cooled mixture
3
2
which was then extracted with ether, dried and evaporated in
vacuo. The residue was purified by chromatography on silica
using petroleum ether–diethyl ether (1 : 1) as eluent to give the
(
6H, m, CH
2
2
2
2
−
1
2
2
2
cyclooctanol (1.7 g, 38%); as a colourless oil; mmax(film)/cm
(
2
2
1
3342; H NMR (360 MHz, CDCl
1.60–1.90 (8H, m, CHOHCH CH
2.40 (4H, m, CH
3
) d 1.45 (1H, br. s, CHOH),
), 1.75 (6H, s, CH ), 2.10–
=
2
2
3
1
3
7
.23 (3H, m, arom. CH), 7.73 (1H, d, J 8.2 Hz, arom. CH);
C
1
3
C=), 3.91 (1H, br. s, CHOH); C NMR d 20.3
2
NMR d 20.0 (q), 20.4 (q), 20.5 (q), 20.8 (q), 24.8 (t), 25.0 (t),
6.5 (t), 26.8 (t), 28.6 (t), 29.0 (t), 31.0 (t), 31.1 (t), 31.7 (t), 32.0
(
q), 22.9 (t), 31.7, 35.8 (t), 71.4 (d), 126.2 (s), 131.9 (s); m/z (EI)
2
+
found 149.1328 (M − H
3
O), C11H17 requires 149.1330.
(
(
t), 34.7 (t), 38.8 (t), 40.5 (t), 40.8 (t), 52.1 (t), 100.4 (s), 121.1
d), 126.5 (s), 128.0 (d), 128.3 (d), 128.4 (d), 128.5 (d), 128.6 (d),
Ethyl [5-(isopropylidene)cyclooctylmethylene]acetate 33a
1
30.0 (d), 130.6 (d), 131.9 (s), 132.3 (s), 133.6 (s), 139.5 (d), 139.4
The cyclooctanol 31 was oxidized using DMSO–(COCl) as
2
(d), 142.9 (s), 143.8 (s), 165.0 (s), 187.4 (s), 197.8 (s).
described previously for the synthesis of 18a to give 5-
isopropylidene)cyclooctanone 32 (69%) as a colourless oil,
(
1
,5
2
,2-Dimethyltricyclo[3.3.3.0 ]undecane-3-one 34
−
1
1
which crystallised slowly; mmax(film)/cm 1698; H NMR
360 MHz, CDCl ) d 1.64 (6H, s, CH ), 1.95–2.10 (4H, m,
CH CH CH ), 2.26 (4H, app. t, J 6.2 Hz, CH
C=), 2.35 (4H,
m, CH
C=O); C NMR d 20.5 (q), 24.8 (t), 31.8 (t), 41.6 (t),
28.9 (s), 130.8 (s), 215.4 (s).
Ethyl trimethylsilylacetate (110 ll, 0.6 mmol) was added
(
3
3
The thioester 33c was treated with Bu SnH–AIBN, according to
3
1
,5
2
2
2
2
the general procedure and gave the tricyclo[3.3.3.0 ]undecane-
3-one (60%) as colourless crystals which melted just above room
1
3
2
−
1
1
1
temperature; mmax(film)/cm 1735; H NMR (360 MHz, CDCl )
3
d 1.0 (6H, s, CH
3
), 1.33–1.54 (4H, m, CH
m, CH ), 1.66–1.85 (4H, m, CH
NMR d 22.8 (q), 26.1 (t), 36.5 (t), 43.3 (t), 50.3 (t), 51.1 (s), 53.6
(s), 63.2 (s), 223.4 (s); m/z (EI) found 192.1514 (M ), C13
2
), 1.56–1.66 (4H,
1
3
dropwise over 5 min to a stirred solution of LDA (2 M; 300 ll,
2
2
), 2.37 (2H, s, CH
2
C=O);
C
◦
0
.6 mmol) in THF (10 ml) at −78 C and the mixture was then
◦
+
stirred at −78 C for 30 min. A solution of the cyclooctanone
H O
20
3
2 (50 mg, 0.3 mmol) in THF (2 ml) was added dropwise over
requires 192.1514.
3
4 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 – 3 4 7

View Article Online
1
,5 2,8
4
,4-Dimethyltetracyclo[3.3.3.0 .0 ]undecane-3-one 35
Tetrahedron Lett., 1991, 32, 5753–5756; G. L. Lange and C. Gottardo,
J. Org. Chem., 1995, 60, 2183–2187.
18
Following the procedures described by Cook et al., the
tricyclo[3.3.3.0 ]undecane-3-one 34 (215.9 mg) was first con-
verted into 2,2-dimethyltricyclo[3.3.3.0 ]4-diazaundecane-3-
6
7
(a) C. J. Hayes, N. M. A. Herbert, N. M. Harrington-Frost and
G. Pattenden, Org. Biomol. Chem., 2004, DOI: 10.1039/b413815p;
(b) B. De Boeck, N. M. A. Herbert, N. M. Harrington-Frost and G.
Pattenden, Org. Biomol. Chem., 2004, DOI: 10.1039/b413816n.
For earlier syntheses of pentalenene, see: G. D. Annis and L. A.
Paquette, J. Am. Chem. Soc., 1982, 104, 4504–4506; L. A. Paquette
and G. D. Annis, J. Am. Chem. Soc., 1983, 105, 7358–7363; E.
Piers and V. Karunaratne, J. Chem. Soc., Chem. Commun., 1984,
105, 959–960; E. Piers and V. Karunaratne, Can. J. Chem., 1989,
105, 160–164; D. H. Hua, J. Am. Chem. Soc., 1986, 108, 3835–
1
,5
1
,5
1
one (78 mg, 32%); H NMR (360 MHz, CDCl
3
) d 1.08
), 1.66–1.93
); C NMR d 24.1 (q), 26.5 (t), 36.1 (t), 39.6
t), 42.4 (s), 51.1 (s), 59.2 (s), 64.8 (s), 205.0 (s), and then
(
(
(
6H, s, CH
10H, m, CH
3
), 1.42 (2H, dd, J 12.5, 6.3 Hz, CH
2
1
3
2
1
,5 2,8
into the tetracyclo[3.3.3.0 .0 ]-undecane-3-one (25 mg, 36%);
−
1
1
m
max(film)/cm 1712; H NMR d 0.84 (3H, s, CH
CH ), 1.25–1.4 (1H, m, cyclopropyl CH), 1.5–1.6 (1H, m,
cyclopropyl CH), 1.75–1.98 (6H, m, CH ), 2.01–2.16 (4H, m,
); C NMR d 17.7 (q), 25.9 (q), 27.3 (t), 28.6 (t), 28.7 (t),
0.4 (t), 35.6 (d), 39.5 (d), 41.6 (t), 52.5 (s), 54.7 (s), 63.1 (s),
20.8 (s).
3
), 1.01 (3H, s,
3
837; T. Imanishi, F. Ninbari, M. Yamashita and C. Iwata, Chem.
3
Pharm. Bull., 1986, 34, 2268–2271; T. Imanishi, M. Yamashita, F.
Ninbari, T. Tanaka and C. Iwata, Chem. Pharm. Bull., 1988, 36,
1
2
1
3
CH
3
2
2
371–1378; T. Imanishi, M. Yamashita, Y. Hirokawa, T. Tanaka and
C. Iwata, Chem. Pharm. Bull., 1990, 38, 1124–1128; T. Hudlicky,
M. G. Natchus and G. Sinai-Zingde, J. Org. Chem., 1987, 52, 4641–
4
644; T. Hudlicky, G. Sinai-Zingde, M. G. Natchus, B. C. Ranu and P.
Papadopolous, Tetrahedron, 1987, 43, 5685–5721; Y. Shizuri, S. Maki,
M. Ohkubo and S. Yamamura, Tetrahedron Lett., 1990, 31, 7167–
7168; M. Franck-Neumann, M. Miesch and L. Gross, Tetrahedron
Lett., 1992, 33, 3879–3882; M. Miesch, L. Miesch-Gross and M.
Franck-Neumann, Tetrahedron, 1997, 53, 2111–2118; M. Hatanaka,
F. Uena and I. Ueda, Tetrahedron Lett., 1996, 37, 89–90; M. T.
Crimmins and J. A. DeLoach, J. Am. Chem. Soc., 1986, 108, 800–
804; Y-J. Wu and D. J. Burnell, J. Chem. Soc., Chem. Commun., 1991,
108, 764–765; Y.-J. Wu, Y.-Y. Zhu and D. J. Burnell, J. Org. Chem.,
1994, 59, 104–110; see ref. 4. For syntheses of modhephene, see:; M.
Karpf and A. S. Dreiding, Tetrahedron Lett., 1980, 21, 4569–4570;
A. B. Smith III and P. J. Jerris, J. Am. Chem. Soc., 1981, 103, 194–
195; L. A. Paquette and H. Schostarez, J. Am. Chem. Soc., 1981, 103,
722–724; W. Oppolzer and F. Marazza, Helv. Chim. Acta, 1981, 64,
1575–1578; W. Oppolzer and K. Baettig, Helv. Chim. Acta, 1981, 64,
2489–2491; J. Wrobel, K. Takahashi, V. Honkan, G. Lannoye, J. M.
Cook and S. H. Bertz, J. Org. Chem., 1983, 48, 139–141; E. A. Mash,
S. K. Math and C. J. Flann, Tetrahedron Lett., 1988, 29, 2147–2150;
and also under ref. 3 in this paper.
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4
5
See: P. A. Wender, L. Sigget and J. M. Nuss, in Comprehensive Organic
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1
984, 25, 3021–3024; G. Pattenden and S. J. Teague, Tetrahedron,
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 – 3 4 7
3 4 7