Preparation of optically pure cross-conjugated cyclopentadienones

Article abstract of DOI:10.1016/j.tet.2004.01.047

The synthesis of optically pure cross-conjugated cyclopentadienones is readily achieved in two steps via a one-pot alkylcuprate addition/aldol condensation/dehydration sequence using racemic or enantioenriched endo-3a,4,7,7a-tetrahydro-1H-4,7-methano-inden-1-ones followed by microwave-mediated Lewis acid-catalysed retro Diels-Alder reaction. An alternative route involving a modified Baylis-Hillman protocol followed by conjugate addition with alkylcuprates and a retro Diels-Alder reaction was also investigated.

Full text of DOI:10.1016/j.tet.2004.01.047

Tetrahedron 60 (2004) 2539–2550
Preparation of optically pure cross-conjugated
cyclopentadienones
a
a
b
Jonathan P. Eddolls,a Mazhar Iqbal, Stanley M. Roberts and M. Gabriella Santoro
,
*
aCharterhouse Therapeutics Laboratories, Department of Chemistry, Robert Robinson Building, University of Liverpool,
Liverpool L69 7ZD, UK
bDepartment of Biology, University of Rome, Tor Vergata, Via della Ricerca Scientifica, 100-133 Rome, Italy
Received 22 October 2003; revised 22 December 2003; accepted 15 January 2004
Abstract—The synthesis of optically pure cross-conjugated cyclopentadienones is readily achieved in two steps via a one-pot alkylcuprate
addition/aldol condensation/dehydration sequence using racemic or enantioenriched endo-3a,4,7,7a-tetrahydro-1H-4,7-methano-inden-1-
ones followed by microwave-mediated Lewis acid-catalysed retro Diels–Alder reaction. An alternative route involving a modified Baylis–
Hillman protocol followed by conjugate addition with alkylcuprates and a retro Diels–Alder reaction was also investigated.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Although the enolate trapping route has enjoyed con-
siderable popularity in the synthesis of structures of type
C, Noyori’s pathway has not been employed to the same
extent, probably due to the greater number of steps
involved, as well as the potential hazards from handling
toxic selenide reagents and intermediates. Interestingly,
Noyori’s procedure had notable mechanistic similarities
with the Baylis–Hillman reaction and, in particular, with
a recently reported variant involving mild cooperative
catalysis (from tributylphosphine as a Lewis base with
phenol as a Brønsted acid) to give a-methylene-b-
hydroxy enones F via enolate G and adduct H
(Scheme 2).9
Recent reports of the potent biological properties exhibited
by many prostanoid compounds containing a cross-con-
jugated cyclopentadienone unit has heightened our interest
in the synthesis of this important structural motif.1
The clavulone series of marine natural products 1,2 the
unsaturated prostaglandin (PG) D12,14-15-deoxy-PG-J2 2,3
the related C-18 chromomoric acid 34 and the potential
anticancer agent TEI-9826 45 all contain the 5-alkylidene-
cyclopent-2-enone unit (Fig. 1). In addition, similar
compounds have recently been implicated in the develop-
ment and progression of atherosclerosis.6
We surmised that a novel synthetic sequence that comprised
a mechanistically similar and higher yielding Baylis–
Hillman reaction as its key step, circumventing the
disadvantages of Noyori’s method, might offer a more
efficient approach to cross-conjugated cyclopentadienones.
In general there exists a number of approaches to cross-
conjugated dienone-containing ring structures D from
enones A that involve the formation of a b-hydroxy
alkylated species C, their further derivatisation and
subsequent b-elimination (Scheme 1).
In many of these cases, the b-hydroxy alkylated moiety of C
can be obtained by either trapping the enolate B (resulting
from conjugate addition) with a suitable aldehyde6b,7 or
through conjugate addition to an a-alkoxy alkylated enone
F (derived from seleno enolate E) using alkylcuprates, as
reported by Noyori.8
2. Results and discussion
We chose to conduct the modified Baylis–Hillman reaction
on racemic endo-3a,4,7,7a-tetrahydro-1H-4,7-methano-
inden-1-one 510 to give b-hydroxy alkylated enones which
we wished to derivatise (e.g. by acetoxylation) and finally
perform an alkylcuprate conjugate addition to give an
exocyclic alkene, after spontaneous b-elimination. Lewis
acid-catalysed retro Diels–Alder would then release the
corresponding cross-conjugated cyclopentadienone
(Scheme 3).
Keywords: Microwave-promoted reactions; retro-Diels–Alder reaction; 4-
Alkyl 5-alkyli-denecyclopent-2-enones; Baylis–Hillman reaction.
*
Corresponding author. Tel.: þ44-151-794-3501; fax: þ44-151-794-2304;
e-mail address: smrsm@liv.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.047

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J. P. Eddolls et al. / Tetrahedron 60 (2004) 2539–2550
Figure 1. Alkylidenecyclopentenones of biological interest.
The Baylis–Hillman adducts 6–10 were easily prepared,
usually in high yield (87–93%) after stirring a mixture of
racemic enone, phenol, tributylphosphine and aldehyde in
THF at room temperature for 24 h. The corresponding
acetates 11–15 were prepared in the standard manner (47–
97% yield).
Clearly continuing with this strategy with its unpredictable
overall yields and, more significantly, the often-observed
poor regioselectivity, was not appealing. Our attention
turned to a one-pot alkylcuprate addition/aldol condensation/
dehydration procedure which had literature precedent4d and,
we felt, could be applied with more confidence to racemic and
enantioenriched endo-3a,4,7,7a-tetrahydro-4,7-methano-
inden-1-one 5 in order to access a range of target compounds.
Indeed cross-conjugated cyclopentenedione precursors have
been obtained from 5 previously.11 However the required
intermediate was obtained only after isolation of the aldol and
subsequent acid-catalysed rearrangement, generating a mix-
ture of Z- and E-geometrical isomers (Scheme 4). More
recently cross-conjugated cyclopentadienones have been
accessed from enone 29 using a one-pot conjugate addition/
Peterson olefination sequence followed by a retro Diels–
Alder reaction.12
The key conjugate addition/elimination tandem reaction
worked well for the isopropyl compound 11, furnishing the
alkylated products 16 and 17 as the only isolable
compounds in 57 and 59% yield, respectively. However,
the procedure was not as satisfactory for other substrates.
For example, when the compound 12 was used as starting
material in a reaction with dimethylcuprate, the desired
compound 18 was formed (34%) in admixture with the
bis-alkylated product 25 (28%). Reaction of 12 with
butylcyanocuprate was even more complex furnishing the
bis-alkylated product 26 (7%) as well as the required
product 19 which was not separated from the isomer 27
(42% yield; ratio 19:27 9:1 by NMR spectroscopy).
Similarly addition of methylcyanocuprate to the acetoxy-
enone 13 was not regioselective, the desired product 20 (61%)
being contaminated with the (separable) isomer 28 (19%).
Both enantioenriched (þ)-5 and (2)-5 were available in
high yield and on a multi-gram scale.13 The enantiomers
underwent facile chemo- and diastereoselective 1,4-con-
jugate addition with an alkylcuprate; aldehyde quench of the
intermediate enolate and spontaneous dehydration upon
Scheme 1. Approaches towards b-hydroxy alkylated species.

J. P. Eddolls et al. / Tetrahedron 60 (2004) 2539–2550
2541
Scheme 2. An approach comprising the modified Baylis–Hillman reaction.
Scheme 3. Baylis–Hillman adducts and cross-conjugated cyclopentadienones derived from (^)-endo enone 5.
In a few cases the one-pot strategy provided some
unexpected by-products. In addition to the desired exo-
cyclic enones (þ)-22 and (þ)-24 (entries 5 and 10
respectively), more polar compounds were also isolated
(15% yield in each case). After NMR spectroscopic and
high resolution mass spectrometric analysis the compounds
were assigned the structures of the tri-aryl species (þ)-30
and (þ)-31.
work-up furnished the desired products (Table 1).
Generally, the one-pot three component coupling
proceeded smoothly giving good or very good yields of
exo-cyclic enones. Entries 1–4 and 10, demonstrated
that the reaction exhibited exclusively E-selectivity,
whilst the remainder (entries 5–8) provided the same
isomer in very high purity (.95%). It is possible that
the small contamination by the Z-isomer may have been
due to photolytic and or thermally induced isomerisation.
Differentiation between E- and Z-isomers of
Previously, it has been reported that Lewis acid-catalysed
retro Diels–Alder reactions involving exo-cyclic enones
similar to 16, 21–24 were achievable only with reaction
times of between 1 and 24 h duration.12 It was found that a
1
compounds 32–36 was possible using H NMR spectro-
scopic techniques and was in accordance with literature
precedent.4d
Scheme 4. Synthesis of cross-conjugated cyclopentadienone precursors.

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J. P. Eddolls et al. / Tetrahedron 60 (2004) 2539–2550
Table 1. Synthesis of some exo-cyclic enones by one-pot conjugate
addition/aldol condensation/dehydration
3. Conclusions
We have combined a one-pot three-component coupling
procedure on racemic and enantioenriched substrate 5 with a
facile microwave-mediated retro Diels–Alder reaction to
give optically pure cross-conjugated cyclopentadienones in
two steps. Significantly the initial alkylcuprate conjugate
addition reaction proceeds with high diastereoselectivity
and the condensation with very high E-selectivity; the
overall yield for the whole process is 50% or greater in the
vast majority of the cases studied.
Entry
Substrate
Cuprate
reagent
Aldehyde
Product (yield, %)a
(E/Z ratio)b
1
2
3
4
5
6
7
8
9
10
(þ)-5
(2)-5
(þ)-5
(2)-5
(þ)-5
(2)-5
(þ)-5
(2)-5
(^)-5
(þ)-5
Me2CuLi
Me2CuLi
Oct2CuLi
Oct2CuLi
Me2CuLi
Me2CuLi
Oct2CuLi
Oct2CuLi
Me2CuLi
Me2CuLi
Me2CHCHO
Me2CHCHO
Me2CHCHO
Me2CHCHO
PhCHO
PhCHO
PhCHO
PhCHO
p-F.C6H4CHO
p-F.C6H4CHO
(þ)-16 (76) (100:0)
(2)-16 (60) (100:0)
(þ)-21 (61) (100:0)
(2)-21 (54) (100:0)
(þ)-22 (64) (97:3)
(2)-22 (75) (92:8)
(þ)-23 (57) (92:8)
(2)-23 (83) (99:2)
(^)-24 (83) (99:1)
(þ)-24 (55) (100:0)
4. Experimental
4.1. General
a
Yield following purification by flash column chromatography.
Ratio determined by 1H NMR spectroscopy of the crude reaction mixture.
b
Starting materials were purchased from commercial sources
and were used without further purification. 1HNMR
(400 MHz) and 13C NMR (100 MHz) spectra were recorded
using a Bruker AMX400 spectrometer. 13C NMR assign-
ments were made using DEPT experiments. Infra red
spectroscopy was performed on a Perkin–Elmer Paragon
1000 FT1R machine. Optical rotation measurements were
recorded using an Optical Activity, Polar 2001 polarimeter
considerable enhancement of the reaction rate was possible,
for the exo-cyclic enones 16, 21–24, when the [4þ2]-
cycloreversion step was carried out in a microwave reactor
(SmithCreator, ,20 W).
at 589 nm and are quoted in units of 1021 deg cm2 g21
.
Flash column chromatography was performed using silica
˚
gel-ICN 32-63, 60 A.
4.2. Baylis–Hillman reaction representative procedure
4.2.1. (6)-2-(1-Hydroxy-octyl)-3a,4,7,7a-tetrahydro-4,7-
methanoinden-1-one 7. Phenol (0.2 equiv.) and n-tributyl-
phosphine (0.4 equiv.) was added to a stirring solution of
enone 5 (1.0 g, 6.91 mmol) and n-octylaldehyde (1.5 equiv.)
in anhydrous THF (6.2 cm3) at room temperature under
nitrogen stream. After 5–8 days at this temperature, flash
silica (4.5 g) was added and the solvent removed in vacuo to
afford crude product, pre-absorbed on silica. Purification
using flash column chromatography (SiO2), eluting with n-
hexane/2-butanone, (9:1) afforded the allylic alcohol 7
(1.63 g, 86%) as a transparent pale yellow oil; Rf 0.24 (SiO2,
n-hexane/diethyl ether, 2:1); dH (400 MHz, CDCl3) 7.10
(1H, d, J¼2.6 Hz, H3), 5.91 (1H, dd, J¼5.6, 2.9 Hz, H5/6),
5.79 (1H, m, H6/5), 4.20 (1H, s, 2CH(OH) n-hep), 3.27 (2H,
m), 2.91 (2H, m), 1.75 (1H, m), 1.75 (1H, d, J¼8.5 Hz,
4-CHH-7), 1.62 (1H, d, J¼8.5 Hz, 4-CHH-7), 1.26 (1H,
s, 1CH(OH)(CH2)6Me), 0.87 (3H, t, J¼6.7 Hz,
1CH(OH)(CH2)6Me); dC (100 MHz, CDCl3) 210.9 (s, C1),
158.1 (d, C3), 150.9 (s, C2), 133.0 (d, C5/6), 132.7 (C6/5),
68.7 (2CH(OH) n-hep), 53.1 (t, 4-CH2-7), 52.0 (d), 45.89,
45.5, 44.5, 36.6 (t, 2CH(OH)(CH2)6Me), 32.1, 29.7, 29.6,
25.8, 23.0, 14.4 (q, 2CH(OH)(CH2)6Me); m/z (CI/NH3) 275
(MHþ, 100%), 257 ([MH2H2O]þ, 97), 144 (29); (HRMS:
found MHþ, 275.2011. C18H27Oþ2 requires 275.2018).
Thus microwave-mediated reactions of exo-cyclic enones
16, 21–24 were performed in DCM in sealed glass vials at
60 8C with MeAlCl2 as Lewis acid catalyst and an excess of
maleic anhydride as a cyclopentadiene trap.13 In most cases,
the reaction was stopped after 25 min. Continued irradiation
eroded the yields of products 32–36 which were generally
very respectable (Table 2). In contrast to earlier reports,12
little significant change in the E/Z isomer ratios was
observed.
Table 2. Synthesis of some optically active cross-conjugated cyclopenta-
dienones 32–36
Entry
Substrate
Product (yield %)a (E/Z ratio)b
1
2
3
4
5
6
7
8
9
10
(þ)-16
(2)-16
(þ)-21
(2)-21
(þ)-22
(2)-22
(þ)-23
(2)-23
(^)-24
(þ)-24
(þ)-32 (63)* (98:2)
(2)-32 (83)* (97:3)
(þ)-33 (84)* (100:0)
(2)-33 (65)* (94:6)
(2)-34 (74) (97:3)
(þ)-34 (69) (97:3)
(þ)-35 (82)* (99:1)
(2)-35 (62)* (98:2)
(^)-36 (83) (96:4)
(2)-36 (91) (100:0)
4.2.2. (6)-2-(1-Hydroxy-2-methylpropyl)-3a,4,7,7a-
tetrahydro-4,7-methanoinden-1-one 6. (1.32 g, 87%), a
transparent pale yellow oil; Rf 0.25 (SiO2, n-hexane/2-
butanone, 4:1); dH (400 MHz, CDCl3) 7.07 (1H, d,
J¼2.5 Hz, H3), 5.94 (1H, dd, J¼5.5, 2.8 Hz, H5/6), 5.80
(1H, dd, J¼5.5, 3.0 Hz, H6/5), 3.99 (1H, d, J¼5.8 Hz,
2CH(OH) i-prop), 3.34 (1H, m), 3.22 (1H, m), 2.97 (1H, m),
a
Yield following purification by flash column chromatography and taking
into account recovered starting material (10–20%) where indicated (*).
b
1
Estimated by H NMR spectroscopy.

J. P. Eddolls et al. / Tetrahedron 60 (2004) 2539–2550
2543
2.88 (1H, t, J¼4.8 Hz), 1.87–1.75 (1H, m), 1.64–1.57 (1H,
m), 0.89 (3H, d, J¼6.8 Hz, 2CH(OH)CHMeMe), 0.83 (3H,
d, J¼6.8 Hz, 2CH(OH)CHMeMe); dC (100 MHz, CDCl3)
211.1 (s, C1), 159.5 (d, C3), 149.3 (s, C2), 133.2 (d, C5/6),
133.0 (C6/5), 74.9 (2CH(OH) i-prop), 53.2 (t, 4-CH2–7),
52.0 (d), 46.1, 45.5, 44.6, 33.6, 19.3 (q, 2CH(OH)CH-
MeMe), 17.9 (2CH(OH)CHMeMe); m/z (CI/NH3) 219
(MHþ, 100%), 201 ([MH2H2O]þ, 75), 137 (42.3);
(HRMS: found MHþ, 219.1393. C14H19Oþ2 requires
219.1385).
1.59 (1H, m, 4-CHH-7); dC (100 MHz, CDCl3) 213.9 (s,
C1), 163.4 (d, C3), 155.9 (s), 143.4, 137.5 (d, C5/6), 136.9
(C6/5), 134.4 (2d, 2CH(OH)CH2Ph), 132.8, 130.9 (d,
2CH(OH)CH2Ph), 72.7 (2CH(OH)CH2Ph), 57.3 (t, 4-CH2-
7), 56.5 (d), 56.5, 50.1, 49.7, 48.7, 47.2 (t, 1CH(OH)CH2Ph);
m/z (CI/NH3) 387 (100%), 369 (58.1), 351 (18.0), 266
([MHþNH3-H2O]þ, 7.3), 249 ([MH2H2O]þ, 26.9), 194
(17.4), 91 (26.4); (HRMS: found MHþ, 267.1391.
C18H19Oþ2 requires 267.1385).
4.3. Acetylation of Baylis–Hillman products
representative procedure
4.2.3. (6)-2-(Cyclopropyl-hydroxy-methyl)-3a,4,7,7a-
tetrahydro-4,7-methanoinden-1-one 8. (3.44 g, 93%), a
transparent yellow oil; Rf 0.17 (SiO2, n-hexane/2-butanone,
4:1); dH (400 MHz, CDCl3) 7.20 (1H, d, J¼2.6 Hz, H3),
5.92 (1H, dd, J¼5.3, 2.7 Hz, H6), 5.80 (1H, dd, J¼5.3,
3.0 Hz, H5), 3.67 (1H, d, J¼8.1 Hz, 2CH(OH) cycloprop),
3.33 (1H, m, H3a), 3.22 (1H, m, H7), 3.12 (1H, br. s,
2CH(OH) cycloprop), 2.97 (1H, m, H4), 2.89 (1H, t,
J¼5.12 Hz, H7a), 1.75 (1H, dd, J¼8.4, 1.4 Hz, 4-CHH-7),
1.62 (1H, d, J¼8.4 Hz, 4-CHH-7), 1.07–0.94 (1H, m,
2CH(OH) cycloprop), 0.57–0.42 (2H, m, 2CH(OH) cyclo-
prop), 0.38–0.33 (1H, m, 2CH(OH) cycloprop), 0.27–0.21
(1H, m, 2CH(OH) cycloprop); dC (100 MHz, CDCl3) 210.9
(s, C1), 158.4 (d, C3), 150.3 (s, C2), 132.9 (d, C6), 132.7
(C5), 72.2 (2CH(OH) cycloprop), 51.9 (C7a), 45.9 (C3a),
45.5 (C7), 44.4 (C4), 17.0 (2CH(OH) cycloprop), 3.5 (t,
2CH(OH) cycloprop), 2.5 (2CH(OH) cycloprop); m/z (CI/
NH3) 234 ([MHþNH3]þ, 3.7%), 216 ([MHþNH3-H2O]þ,
74.4), 199 (100); (HRMS: found MHþNHþ3 , 234.1498.
C14H20NOþ2 requires 234.1494).
4.3.1. (6)-Acetic acid 1-(1-oxo-3a,4,7,7a-tetrahydro-1H-
4,7-methano-inden-2-yl)-octyl ester 12. Acetic anhydride
(11 equiv.) was added to a solution of allylic alcohol 7
(0.25 g, 0.91 mmol) in freshly distilled pyridine (1.6 cm3)
and stirred at room temperature for 17 h under nitrogen
atmosphere. Water (8 cm3) and ethyl acetate (8 cm3) were
added, the aqueous layer separated and extracted further
with ethyl acetate (3£8 cm3). The combined organic layers
were washed with 10% NaHCO3 solution (8 cm3), water
(8 cm3), dried (MgSO4) and solvent removed in vacuo to
afford crude acetate. Purification using flash column
chromatography (SiO2), eluting with n-hexane/2-butanone
(9:1) gave allylic acetate 12 (0.21 g, 72%) as a transparent
amber oil; Rf 0.46 (SiO2, n-hexane/2-butanone, 4:1); dH
(400 MHz, CDCl3) 7.11 (1H, d, J¼2.5 Hz, H3), 5.91 (1H, m,
H5/6), 5.71 (1H, m, H6/5), 5.34 (1H, m, 2CH(OAc) n-hep),
3.31–3.28 (1H, m), 3.21 (1H, m), 2.94 (1H, m), 2.84 (1H,
m), 2.03 (3H, s, 2CH(OCOMe) n-hep), 1.74–1.58 (4H, m,
2CH(OAc)(CH2)6Me), 1.24 (10H, m, 2CH(OAc)(CH2)6-
Me), 0.86 (3H, m, 2CH(OAc)(CH2)6Me); dC (100 MHz,
CDCl3) 207.5 (s, C1), 169.9 (2CH(OCOMe) n-hep), 158.8
(d, C3), 148.0 (s, C2), 132.7 (d, C5/6), 132.3 (C6/5), 69.7
(2CH(OAc) n-hep), 52.5 (t, 4-CH2-7), 53.0 (d), 45.5, 45.2,
44.2, 33.0 (t, 2CH(OAc)(CH2)6Me), 31.8, 29.2, 29.1, 25.2,
4.2.4. (6)-2-(1-Hydroxy-phenyl-methyl)-3a,4,7,7a-tetra-
hydro-4,7-methanoinden-1-one 9. (0.73 g, 89%), an off-
white crystalline solid; Rf 0.28 (SiO2, n-hexane/diethyl
ether, 1:1); nmax (film)/cm21 3355 (OH), 1664.9 (CO); dH
(400 MHz, CDCl3) 7.34–7.31 (5H, m, 2CH(OH)Ph), 6.94
(1H, d, J¼1.9 Hz, H3), 5.90 (1H, dd, J¼5.6, 2.9 Hz, H5/6),
5.76 (1H, dd, J¼5.6, 3.0 Hz, H6/5), 5.42 (1H, s,
2CH(OH)Ph), 3.45 (1H, s, 2CH(OH)Ph), 3.29 (1H, m,
H3a), 3.22 (1H, m, H4/7), 2.93 (1H, m, H7/4), 2.89 (1H, t,
J¼5.1 Hz, H7a), 1.74 (1H, dt, J¼8.5, 1.7 Hz, 4-CHH-7),
1.60 (1H, d, J¼8.5 Hz, 4-CHH-7); dC (100 MHz, CDCl3)
210.7 (s, C1), 159.7 (d, C3), 150.7 (s, C2), 141.9
(2CH(OH)Ph), 133.0 (d, C6), 132.9 (C5), 128.8 (2d,
2CH(OH)Ph), 128.1 (d, 2CH(OH)Ph), 126.8 (2d,
2CH(OH)Ph), 70.6 (d, 2CH(OH)Ph), 53.1 (t, 4-CH2-7),
52.0 (d, C3a), 45.9 (C7a), 45.6 (C4), 44.5 (C7); m/z (CI/NH3)
504 (7.0%), 487 (8.8), 270 ([MHþNH3]þ, 7.9), 252 (44.8),
235 (100), 207 (35.7), 169 (13.8); (HRMS: found
MHþNHþ3 , 270.1498. C17H20NOþ2 requires 270.1501).
22.6,
21.1
(q,
2CH(OCOMe)
n-hep),
14.1
(2CH(OAc)(CH2)6Me); m/z (CI/NH3) 334 ([MHþNH3]þ,
30.7%), 317 (MHþ, 93.4), 274 (3.3), 257 (100), 144 (21.9);
(HRMS: found MHþ, 317.2116. C20H29Oþ3 requires
317.2117).
4.3.2. (6)-Acetic acid 2-methyl-1-(1-oxo-3a,4,7,7a-tetra-
hydro-1H-4,7-methano-inden-2-yl)-propyl ester 11.
(0.25 g, 83%), a transparent pale yellow oil; Rf 0.49
(SiO2, n-hexane/2-butanone, 4:1); nmax (film)/cm21 3061,
2966, 2934, 2873, 1738, 1703, 1627; dH (400 MHz, CDCl3)
7.11 (1H, d, J¼2.5 Hz, H3), 5.91 (1H, m, H5/6), 5.70 (1H, m,
H6/5), 5.15 (1H, d, J¼6.3 Hz, 2CH(OAc) i-prop), 3.31 (1H,
m), 3.22 (1H, m), 2.94 (1H, m), 2.85 (1H, m), 2.12 (1H, m,
2CH(OAc)CHMe2), 2.03 (3H, s, 2CH(OAc) i-prop), 1.75
(1H, m, 4-CHH-7), 1.60 (1H, m, 4-CHH-7), 0.84 (3H, s,
2CH(OH)CHMeMe), 0.83 (3H, 2CH(OH)CHMeMe); dC
(100 MHz, CDCl3) 207.5 (s, C1), 170.0 (2CH(OCOMe)
i-prop), 160.0 (d, C3), 147.1 (s, C2), 132.9 (d, C5/6), 132.4
(C6/5), 74.1 (2CH(OAc) i-prop), 52.5 (t, 4-CH2-7), 51.6 (d),
45.6, 45.2, 44.2, 30.3 (2CH(OAc)CHMe2), 21.0 (q,
2CH(OCOMe) i-prop), 18.7 (2CH(OH)CHMeMe), 17.5
(2CH(OH)CHMeMe); m/z (CI/NH3) 278 ([MHþNH3]þ,
16.1%), 261 (MHþ, 71.4), 201 (100); (HRMS: found MHþ,
261.1485. C16H21Oþ3 requires 261.1491); Found: C, 73.7; H,
7.8%, C16H20O3 requires C, 73.8; H, 7.7%.
4.2.5. (6)-2-(1-Hydroxy-2-phenyl-ethyl)-3a,4,7,7a-tetra-
hydro-4,7-methano inden-1-one 10. (0.51 g, 56%), a
yellow crystalline solid; Rf 0.24 (SiO2, n-hexane/diethyl
ether, 1:1); dH (250 MHz, CDCl3) 7.27–7.16 (6H, m,
2CH(OH)CH2Ph, H3), 5.83 (1H, dd, J¼5.5, 3.1 Hz, H5/6),
5.66 (1H, dd, J¼5.5, 3.1 Hz, H6/5), 4.44 (1H, m,
2CH(OH)CH2Ph), 4.30 (1H, br. s, 2CH(OH)CH2Ph), 3.22
(1H, m, H3a), 3.15 (1H, m, H4/7), 2.96 (1H, dd, J¼13.7,
4.1 Hz, 2CH(OH)CHHPh), 2.90 (1H, m, H7/4), 2.83 (1H, t,
J¼5.1 Hz, H7a), 2.68 (1H, dd, J¼13.7, 8.2 Hz,
2CH(OH)CHHPh), 1.69 (1H, d, J¼8.6 Hz, 4-CHH-7),

2544
J. P. Eddolls et al. / Tetrahedron 60 (2004) 2539–2550
4.3.3. (6)-Acetic acid cyclopropyl-(1-oxo-3a,4,7,7a-tet-
rahydro-1H-4,7-methano-inden-2-yl)-methyl ester 13.
(4.56 g, 97%), a transparent pale brown oil; Rf 0.35 (SiO2,
n-hexane/Et2O, 1:1); dH (400 MHz, CDCl3) 7.19 (1H, d,
J¼2.6 Hz, H3), 5.90 (1H, dd, J¼5.6, 2.9 Hz, H5/6), 5.72 (1H,
dd, J¼5.6, 3.0 Hz, H6/5), 4.78 (1H, d, J¼8.9 Hz, 2CH(OAc)
cycloprop), 3.31 (1H, m), 3.22 (1H, m), 2.96 (1H, m), 2.86
(1H, t, J¼5.0 Hz), 2.03 (3H, s, 2CH(OCOMe) cycloprop),
1.74 (1H, dt, J¼8.4, 1.7 Hz, 4-CHH-7), 1.60 (1H, d,
J¼8.4 Hz, 4-CHH-7), 1.24–1.16 (1H, m, 2CH(OAc)
cycloprop), 0.55–0.44 (2H, m, 2CH(OAc) cycloprop),
0.39–0.28 (2H, m, 2CH(OAc) cycloprop); dC (100 MHz,
CDCl3) 207.7 (s, C1), 170.3 (2CH(OCOMe) cycloprop),
159.4 (C2), 148.0 (d, C3), 133.0 (C5/6), 132.6 (C6/5), 73.1 (t,
2CH(OAc) cycloprop), 52.8 (4-CH2-7), 51.7 (d), 45.9, 45.6,
44.9, 21.5 (2CH(OAc) cycloprop), 14.6 (q, 2CH(OCOMe)
cycloprop), 4.3 (t, 2CH(OAc) cycloprop), 2.9 (2CH(OAc)
cycloprop); m/z (CI/NH3) 276 ([MHþNH3]þ, 11.0%), 259
(MHþ, 13.3), 216 (100), 199 (94.5), 164 (16.4), 147 (20.3),
135 (9.6); (HRMS: found MHþ, 259.1329. C16H18Oþ3
requires 259.1334).
249 (100); (HRMS: found MHþ, 309.1491. C20H21Oþ3
requires 309.1491) as well as its elimination product (0.23 g,
48%) as white crystalline solid; Rf 0.54 (SiO2, n-hexane/
diethyl ether, 1:1); nmax (film)/cm21 3061, 3028, 2978, 2940,
2869, 1748, 1697, 910, 734; dH (400 MHz, CDCl3) 7.45–7.30
(2H, m, 2CHCHPh), 7.29–7.16 (5H, m, H3, 2CHCHPh), 6.65
(1H, d, J¼16.4 Hz, 2CHCHPh), 5.94 (1H, dd, J¼5.6, 3.0 Hz,
H5/6), 5.80 (1H, dd, J¼5.6, 2.8 Hz, H6/5), 3.33 (1H, m, H3a/7a),
3.26 (1H, m, H4/7), 2.98 (1H, m, H7/4), 2.94 (1H, t, J¼5.1 Hz,
H7a/3a), 1.76 (1H, dt, J¼8.4, 1.7 Hz, 4-CHH-7), 1.62 (1H, d,
J¼8.4 Hz, 4-CHH-7); dC (100 MHz, CDCl3) 208.7 (CO, C1),
158.8 (CH, C3), 144.0 (R4C, C2), 137.6 (2CHCHPh), 133.1
(CH), 133.0, 128.9, 128.3, 127.0, 118.7 (2CHCHPh), 53.1
(R2CH2, 4-CH2-7), 52.4(R3CH), 45.9(2R3CH), 45.1; m/z (CI/
NH3)266([MHþNH3]þ, 22.9%), 249([MH]þ, 100);(HRMS:
found MHþ, 249.1275. C18H17Oþ requires 249.1279).
4.4. Alkylcuprate addition and acetate elimination
representative procedure
4.4.1. (6)-2-(E)-Octylidene-3-methyl-2,3,3a,4,7,7a-hexa-
hydro-4,7-methanoinden-1-one 18 and (6)-2-(1-methyl-
octyl)-3-methyl-2,3,3a,4,7,7a-hexahydro-4,7-methanoin-
den-1-one 25. 1.4 M Methyllithium in diethyl ether
(3.3 equiv.) was added to a suspension of anhydrous copper
(I) iodide (1.7 equiv.) in diethyl ether (1.6 cm3) at 278 8C
under nitrogen atmosphere. The reaction mixture was
allowed to warm to 240 8C and stirred for 30 min. The
alkylcuprate reagent was added dropwise to a stirring
solution of acetate 12 (53 mg, 0.17 mmol) in anhydrous
diethyl ether (0.17 cm3) at 278 8C and the reaction allowed
to warm to room temperature. After 12.5 h at room
temperature, saturated aqueous NH4Cl solution (0.75 cm3)
was added and the reaction mixture extracted with diethyl
ether (3£0.75 cm3). The combined organic layers were
dried (MgSO4) and the solvent removed in vacuo to afford
crude product. Preparative thin layer chromatography
(SiO2) eluting with n-hexane/2-butanone (5:1) gave the
methylated adduct 18 (15.8 mg, 34%) as a pale yellow
transparent oil; Rf 0.56 (SiO2, n-hexane/2-butanone, 4:1);
dH (400 MHz, CDCl3) 6.94 (1H, d, J¼2.7 Hz, 2CHn-hep),
5.87 (1H, dd, J¼5.5, 2.7 Hz, H5/6), 5.73 (1H, dd, J¼5.5,
2.9 Hz, H6/5), 3.25–3.22 (1H, m), 3.20 (1H, m), 2.92 (1H,
m), 2.89 (1H, t, J¼5.1 Hz), 2.38 (1H, m, H3), 1.74–1.71
(1H, dt, J¼8.3, 1.8 Hz, 4-CHH-7), 1.61–1.59 (1H, m,
4-CHH-7), 1.41–1.09 (12H, m, 2CH(CH2)6Me), 0.98 (3H,
d, J¼6.9 Hz, 3Me), 0.87 (3H, t, J¼6.8 Hz, 2CH(CH2)3Me);
dC (100 MHz, CDCl3) 209.6 (s, C1), 155.9 (d, 2CH n-hep),
154.7 (s, C2), 132.5 (d, C5/6), 132.4 (C6/5), 52.6 (t, 4-CH2-7),
51.1 (d), 49.0, 45.2, 44.2, 35.9 (t, 2CH(CH2)6Me), 31.9,
31.8, 29.6, 29.3, 27.1, 22.1, 19.6 (q, 3Me), 14.1
(2CH(CH2)6Me); m/z (CI/NH3) 303 (0.5%), 290
([MHþNH3]þ, 0.9), 273 (MHþ, 100), 173 (26.4);
(HRMS: found MHþ, 273.2224. C19H19Oþ requires
273.2218) and the bis-alkylated adduct 25 (13.9 mg, 28%)
as a pale yellow transparent oil; Rf 0.66 (SiO2, n-hexane/2-
butanone, 4:1); dH (400 MHz, CDCl3) 6.14 (1H, dd, J¼5.6,
3.0 Hz, H5/6), 6.04 (1H, dd, J¼5.6, 3.0 Hz, H6/5), 3.13 (1H,
m), 3.03 (1H, m), 2.97–2.92 (1H, m), 2.48–2.43 (1H, m),
1.95 (1H, dt, J¼11.8, 2.8 Hz), 1.67–1.55 (3H, m), 1.40 (1H,
d, J¼8.1 Hz), 1.29–1.20 (12H, m, 2CHMe(CH2)6Me), 1.17
(3H, d, J¼6.6 Hz, 2CHMen-hep), 0.87 (3H, t, J¼6.6 Hz,
2CHMe(CH2)3Me), 0.83 (3H, d, J¼6.8 Hz, 3Me); dC
4.3.4. (6)-Acetic acid (1-oxo-3a,4,7,7a-tetrahydro-1H-
4,7-methano-inden-2-yl)-phenyl-methyl ester 14. (0.74 g,
93%), an off-white crystalline solid; Rf 0.34 (SiO2,
n-hexane/diethyl ether, 1:1); dH (400 MHz, CDCl3) 7.33–
7.22 (5H, m, 2CH(OCOMe)Ph), 7.19 (1H, m, H3), 6.38 (1H,
dd, J¼5.2, 2.9 Hz, H5/6), 5.91 (1H, dd, J¼5.2, 2.5 Hz, H6/5),
3.30–3.27 (1H, m, H3a/7a), 3.18 (1H, m, H4/7), 2.95 (1H, m,
H7/4), 2.80 (1H, t, J¼4.9 Hz, H7a/3a), 2.05 (3H, s,
2CH(OCOMe)Ph), 1.71 (1H, d, J¼8.4 Hz, 4-CHH-7), 1.56
(1H, d, J¼8.4 Hz, 4-CHH-7); dC (100 MHz, CDCl3) 207.0
(s, C1), 169.8 (2CH(OCOMe)Ph), 159.1 (d, C3), 148.4 (s, C2),
138.6 (2CH(OCOMe)Ph), 133.0 (d, C5/6), 132.7 (C6/5), 128.8
(2d, 2CH(OCOMe)Ph), 128.5, 127.4 (d, 2CH(OCOMe)Ph),
70.7 (2CH(OCOMe)Ph), 52.9 (t, 4-CH2-7), 51.8 (d, C3a/7a),
46.0 (C4/7), 45.6 (C7/4), 44.6 (C7a/3a), 21.4 (q, 2CH(OCO-
Me)Ph); m/z (ESþ) 413 (5.0%), 408 (5.0), 333 ([MþK]þ,
5.6), 317 ([MþNa]þ, 100), 301 (29.4), 251 (36.9); (HRMS:
found MþNaþ, 317.1160. C19H18O323Na requires
317.1154); Found: C, 77.5; H, 6.2%, C19H18O3 requires
C, 77.5; H, 6.2%.
4.3.5. (6)-Acetic acid-1-(1-oxo-3a,4,7,7a-tetrahydro-1H-
4,7-methano-inden-2-yl)-2-phenyl-ethyl ester 15. (0.27 g,
47%), a transparent pale yellow oil; Rf 0.22 (SiO2, n-hexane/
diethyl ether, 2:1); nmax (film)/cm21 3469, 3062, 3029,
2979, 2936, 2869, 1742, 1698; dH (400 MHz, CDCl3) 7.27–
7.12 (5H, m, 2CH(OAc)CH2Ph), 7.01 (1H, d, J¼2.4 Hz,
H3), 5.86 (1H, dd, J¼5.6, 2.8 Hz, H5/6), 5.61 (1H, m,
2CH(OAc)CH2Ph), 5.54 (1H, dd, J¼5.6, 2.9 Hz, H6/5),
3.24–3.20 (2H, m), 3.10 (1H, dd, J¼14.0, 5.5 Hz,
2CH(OAc)CHHPh), 2.92 (1H, m, 2CH(OAc)CHHPh), 2.88
(1H, m), 2.84 (1H, t, J¼5.1 Hz), 1.98 (3H, s,
2CH(OCOMe)CH2Ph), 1.70 (1H, dt, J¼8.4, 1.6 Hz, 4-CHH-
7), 1.56 (1H, d, J¼8.4 Hz, 4-CHH-7); dC (100 MHz, CDCl3)
207.8 (s, C1), 170.0 (2CH(OCOMe)Ph), 160.1 (d, C3), 147.2
(s, C2), 137.3 (2CH(OCOMe)CH2Ph), 133.0 (d, C5/6), 132.6
(C6/5), 129.9 (2d, 2CH(OCOMe)CH2Ph), 128.5, 126.9 (d,
2CH(OCOMe)Ph), 70.5 (2CH(OCOMe)CH2Ph), 52.8 (t, 4-
CH2-7), 52.0 (d, C3a/7a), 45.9 (C4/7), 45.5 (C7/4), 44.4 (C7a/3a),
39.3 (t, 2CH(OAc)CH2Ph), 21.3 (q, 2CH(OCOMe)CH2Ph);
m/z (CI/NH3) 326 ([MHþNH3]þ, 15.1%), 309 ([MH]þ, 48.8),

J. P. Eddolls et al. / Tetrahedron 60 (2004) 2539–2550
2545
(100 MHz, CDCl3) 218.3 (s, C1), 137.1 (d, C5/6), 135.7 (C6/5),
65.1 (d), 55.1, 52.3 (t, 4-CH2-7), 48.0 (d), 45.5, 44.7, 35.7,
34.5, 31.9 (t, 2CH(CH2)6Me), 31.6, 29.8, 29.4, 28.0, 22.7,
21.8 (q), 16.8, 14.1; m/z (CI/NH3) 306 ([MHþNH3]þ,
20.7%), 289 (MHþ, 6.3), 240 (37.6), 223 (100), 96 (20), 60
(15.5); (HRMS: found MHþNHþ3 , 306.2799. C20H36NOþ
requires 306.2797).
3-butylated adduct 19 and its exo-butylated regioisomer 27
(0.21 g, 42%) as a transparent pale yellow oil; Rf 0.43 (SiO2,
n-hexane/diethyl ether, 4:1); nmax (film)/cm21 2958, 2927,
2857, 1712, 1639; dH (400 MHz, CDCl3) 6.31 (1H, m,
2CHn-hep), 5.98 (2H, m, H5, H6), 3.26 (1H, m), 3.04 (1H,
m), 2.99 (1H, m), 2.55 (1H, m), 2.43 (1H, m), 2.08 (2H, m),
1.51 (1H, m, 4-CHH-7), 1.43 (1H, d, J¼8.1 Hz, 4-CHH-7),
1.39–1.25 (15H, m, 2CH(CH2)6Me, 3(CH2)3Me), 0.95–
0.89 (6H, m, 2CH(CH2)6Me, 3(CH2)3Me); dC (100 MHz,
CDCl3) 209.8 (s, C1), 143.9 (C2), 137.6 (d, 2CH n-hep),
136.2 (C5/6), 133.9 (C6/5), 54.2, 51.9 (t, 4-CH2-7), 47.9 (d),
47.8, 44.6, 40.8, 36.8 (t), 32.2, 29.8, 29.7, 29.5, 29.4, 29.0,
23.3, 23.0, 14.5 (q, 2CH(CH)6Me), 14.5 (3(CH2)3Me); m/z
(CI/NH3) 315 (MHþ, 19.4%), 249 (100); (HRMS: found
MHþ, 315.2681. C22H35Oþ requires 315.2688) as well as
the bis-alkylated adduct 26 (38.3 mg, 7%) as a transparent
pale yellow oil; Rf 0.59 (SiO2, n-hexane/diethyl ether, 4:1);
nmax (film)/cm21 2924, 2854, 1733, 1466, 1229, 731; dH
(400 MHz, CDCl3) 6.13 (1H, dd, J¼5.5, 2.9 Hz, H5/6), 6.04
(1H, dd, J¼5.5, 2.9 Hz, H6/5), 3.13 (1H, m), 2.99 (1H, m),
2.97–2.92 (1H, m), 2.54–2.49 (1H, m), 2.15 (1H, dt,
J¼11.8, 2.4 Hz), 1.67–1.61 (1H, m), 1.59–1.50 (3H, m),
1.45–1.09 (24H, m), 0.95 (3H, t, J¼6.8 Hz), 0.89 (6H, m);
dC (75.5 MHz, CDCl3) 218.9 (s, C1), 137.3 (d, C5/6), 135.8
(C6/5), 61.0, 55.1, 52.59 (t, 4-CH2-7), 47.4 (d), 46.2, 44.5,
40.5, 36.9, 36.65 (t), 32.2, 31.8, 31.5, 30.5, 29.9, 29.8, 29.2,
28.1, 22.8, 22.7, 14.0 (q), 13.9, 13.89; m/z (CI/NH3) 390
(MHþNHþ3 , 18.2%), 373 (MHþ, 14.2), 324 (21.0), 138
(26.2); (HRMS: found MHþ, 373.3462. C26H45Oþ requires
373.3470).
4.4.2. (6)-2-(2-(E)-Methylpropylidene)-3-methyl-
2,3,3a,4,7,7a-hexahydro-4,7-methano-inden-1-one
16.
(50.7 mg, 57%), a pale yellow transparent oil; Rf 0.50
(SiO2, n-hexane/2-butanone, 4:1); dH (400 MHz, CDCl3)
6.06 (1H, dd, J¼10.5, 2.1 Hz, 2CHi-prop), 5.95 (2H, m, H5,
H6), 3.23 (1H, m), 3.06 (1H, m), 3.00 (1H, m), 2.52 (1H, m),
1.47 (1H, dt, J¼8.3, 1.7 Hz, 4-CHH-7), 1.37 (1H, d,
J¼8.3 Hz, 4-CHH-7), 1.11 (3H, d, J¼7.3 Hz, 3Me), 1.00
(3H, d, J¼7.3 Hz, 2CHCHMeMe), 0.95 (3H, d, J¼6.6 Hz,
2CHCHMeMe); dC (100 MHz, CDCl3) 209.7 (s, C1), 143.2
(C2), 142.8 (d), 136.1, 133.0, 53.3 (d),51.4 (t, 4-CH2-7),
47.4 (d), 47.1, 46.9, 35.0, 28.5, 23.4 (q, 3Me), 22.1
(2CHCHMeMe), 21.9 (2CHCHMeMe); m/z (CI/NH3) 234
([MHþNH3]þ, 3.1%), 217 (MHþ, 16.8), 168 (23.7), 151
(100); (HRMS: found MHþ, 217.1595. C15H21Oþ requires
217.1592).
4.4.3. (6)-2-(2-(E)-Methylpropylidene)-3-butyl-
2,3,3a,4,7,7a-hexahydro-4,7-methano-inden-1-one
17.
(28.2 mg, 59%) as a transparent pale yellow oil; Rf 0.54
(SiO2, n-hexane/2-butanone, 4:1); dH (400 MHz, CDCl3)
6.07 (1H, dd, J¼10.7, 2.1 Hz, 2CHi-prop), 5.95 (2H, m, H5,
H6), 3.23 (1H, m), 3.00 (1H, m), 2.96 (1H, m), 2.51 (1H, m),
2.43–2.34 (2H, m), 1.41–1.31 (8H, m, 4-CH2-7 and
3(CH2)3Me), 1.00 (3H, d, J¼6.6 Hz, 2CH(OH)CHMeMe),
0.95 (3H, d, J¼6.5 Hz, 2CH(OH)CHMeMe), 0.90 (3H, t,
J¼6.6 Hz, 3(CH2)3Me); dC (100 MHz, CDCl3) 210.4 (s,
C1), 143.3 (d, 2CH i-prop), 142.5 (s, C2), 136.3 (d, C5/6),
133.8 (C6/5), 54.2, 51.9 (t, 4-CH2-7), 47.9 (d), 44.6, 40.8,
37.4 (t), 29.4, 29.0 (d), 23.3 (t), 22.3 (2q, 2CHMe2), 14.5 (q,
3(CH2)3Me); m/z (CI/NH3) 278 (3.6%), 259 (MHþ, 11.3),
210 (25.2), 193 (100); (HRMS: found MHþ, 259.2060.
C18H27Oþ requires 259.2062).
4.5.2. (6)-2-(E)-Cyclopropylmethylene-3-methyl-
2,3,3a,4,7,7a-hexahydro-4,7-methano-inden-1-one 20
and 2-(1-cyclopropyl-ethyl)-3a,4,7,7a-tetrahydro-4,7-
methano-inden-1-one 28. Methylated enone 20 (0.25 g,
61%), a pale yellow transparent oil; Rf 0.36 (SiO2, n-hexane/
Et2O, 2:1); dH (400 MHz, CDCl3) 6.02 (1H, dd, J¼5.7,
3.0 Hz, H6), 5.96 (1H, dd, J¼5.7, 2.9 Hz, H5), 5.71 (1H, dd,
J¼11.0, 2.2 Hz, 2CH cycloprop), 3.23 (1H, m, H4), 3.08
(1H, m, H7), 3.01 (1H, m, H3a), 2.61 (1H, m, H3), 2.43 (1H,
m, H7a), 1.48 (1H, dt, J¼8.3, 1.8 Hz, 4-CHH-7), 1.44–1.36
(2H, m, 4-CHH-7, 2CH cycloprop), 1.20 (3H, d, J¼7.3 Hz,
3Me), 0.99–0.90 (2H, m, 2CH cycloprop), 0.63–0.58 (2H,
m, 2CH cycloprop); dC (100 MHz, CDCl3) 208.1 (s, C1),
143.6 (C2), 142.3 (d, 2CH cycloprop), 136.0 (C5), 133.5
(C6), 53.8 (d, C3a), 51.4 (t, 4-CH2-7), 47.2 (d, C4), 46.9 (C7),
46.9 (C7a), 35.2 (C3), 22.3 (q, 3Me), 12.3 (d, 2CH
cycloprop), 9.5 (t, 2CH cycloprop), 8.8 (2CH cycloprop);
m/z (CI/NH3) 429 (2.4%), 363 (4.7), 232 ([MHþNH3]þ,
1.3), 215 (MHþ, 34.6), 149 (100); (HRMS: found MHþ,
215.1441. C15H19Oþ3 requires 215.1436); and its regio-
isomer 28 (77.3 mg, 19%) as a pale yellow transparent oil;
Rf 0.49 (SiO2, n-hexane/diethyl ether, 2:1); nmax (film)/
cm21 3062, 2962, 2931, 2870, 1698, 1621; dH (400 MHz,
CDCl3) 7.04 (1H, d, J¼2.6 Hz, H3), 5.84 (1H, dd, J¼5.5,
2.9 Hz, H5/6), 5.72 (1H, dd, J¼5.5, 2.9 Hz, H6/5), 3.23 (1H,
m), 3.18 (1H, m), 2.90 (1H, m), 2.79 (1H, t, J¼5.1 Hz), 1.71
(1H, d, J¼8.4 Hz, 4-CHH-7), 1.58 (1H, d, J¼8.4 Hz,
4-CHH-7), 1.05 (3H, d, J¼7.0 Hz, 2CHCHMe cycloprop),
0.66 (1H, m, 2CHCHMe cycloprop), 0.39 (1H, m), 0.20
(1H, m), 0.03-(-0.02) (2H, m); m/z (CI/NH3) 232
([MHþNH3]þ, 0.6%), 215 (MHþ, 100); (HRMS: found
MHþ, 215.1441. C15H19Oþ requires 215.1436).
4.5. Alkyl cyanocuprate addition and elimination
representative procedure
4.5.1. (6)-2-(E)-Octylidene-3-butyl-2,3,3a,4,7,7a-hexa-
hydro-4,7-methano-inden-1-one 19 and (6)-2-(1-butyl-
octyl)-3-butyl-2,3,3a,4,7,7a-hexahydro-4,7-methano-
inden-1-one 26. 2.5 M n-Butyllithium in diethyl ether
(1.2 equiv.) was added to a suspension of anhydrous copper
(I) cyanide (1.2 equiv.) in diethyl ether (3.1 cm3) at 278 8C
under nitrogen atmosphere. The reaction mixture was
allowed to warm to 240 8C and stirred for 40 min. The
alkyl cyanocuprate reagent was added dropwise to a stirring
solution of acetate 12 (0.5 g, 1.58 mmol) in anhydrous
diethyl ether (1.6 cm3) at 278 8C. After 45 min at this
temperature, saturated aqueous NH4Cl solution (2.5 cm3)
was added and the reaction mixture extracted with diethyl
ether (3£4 cm3). The combined organic layers were dried
(MgSO4) and the solvent removed in vacuo to afford a
yellow opalescent oil. Purification by flash column chro-
matography (SiO2), eluting with n-hexane/diethyl ether
(9:1 and 4:1), gave an inseparable mixture (9:1) of the

2546
J. P. Eddolls et al. / Tetrahedron 60 (2004) 2539–2550
4.6. Alkyl cuprate addition/aldol condensation/
dehydration representative procedure
4.6.3. (1)-2-(E)-Isobutylidene-3(S)-octyl-2,3,3a,4,7,7a-
hexahydro-4,7-methano-inden-1-one (1)-21. (0.26 g,
61%) as a very pale yellow transparent oil; Rf 0.38 (SiO2,
n-hexane/ethyl acetate, 9:1); [a]2D1 2.39 (c 8.49 CHCl3); dH
(400 MHz, CDCl3) 6.07 (1H, dd, J¼10.7, 2.1 Hz, 2CHi-
prop), 5.97 (1H, d, J¼5.6, 3.0 Hz, H5/6), 5.93 (1H, dd,
J¼5.6, 2.9 Hz, H6/5), 3.32 (1H, m, H4/7), 3.01 (1H, br. s, H7/
4), 2.96 (1H, dd, J¼8.7, 4.8 Hz, H3a/7a), 2.51 (1H, ddd,
J¼8.7, 4.1, 1.4 Hz, H7a/3a), 2.43–2.36 (2H, m, H3,
2CHCHMe2), 1.47 (1H, d, J¼8.2 Hz, 4-CHH-7), 1.40
(1H, d, J¼8.2 Hz, 4-CHH-7), 1.37–1.27 (14H, m,
3(CH2)7Me), 1.00 (3H, d, J¼6.6 Hz, 2CHCHMeMe), 0.96
(3H, d, J¼6.6 Hz, 2CHCHMeMe), 0.88 (3H, t, J¼6.7 Hz,
3(CH2)7Me); dC (100 MHz, CD2Cl2) 210.5 (s, C1), 143.3 (d,
2CH i-prop), 142.5 (s, C2), 136.3 (d, C6), 133.8 (C5), 54.2
(C7a), 51.9 (t, 4-CH2-7), 47.9 (2d, C4, C7), 44.6 (C3a), 40.8
(C3), 37.7 (t, 3(CH2)7Me), 32.3, 30.2, 29.6, 29.7, 29.0 (d,
2CHCHMe2), 27.2 (t, 3(CH2)7Me), 23.0, 22.3 (2q,
2CHCHMe2), 14.5 (q, 3(CH2)7Me); m/z (CI/NH3) 332
([MHþNH3]þ, 0.5%), 315 (MHþ, 4.0), 287 (0.3), 266 (4.1),
249 ([MHþNH3–C5H6]þ, 100), 150 (4.0), 66 (C5H6, 3.7);
(HRMS: found MHþ, 315.2689. C22H35Oþ requires
315.2688).
4.6.1.
(1)-2-(E)-Isobutylidene)-3(S)-methyl-
2,3,3a,4,7,7a-hexahydro-4,7-methanoinden-1-one (1)-
16. 1.6 M Methyl lithium in diethyl ether (2.4 equiv.) was
added to a stirring suspension of copper (I) iodide
(1.2 equiv.) in anhydrous diethyl ether (6 cm3) at 278 8C
under nitrogen stream. After 3.0 h stirring at this tempera-
ture, a solution of (þ)-enone (þ)-5 (0.2 g, 0.37 mmol) in
diethyl ether (3 cm3) was added dropwise over 5 min at
278 8C and stirred for 1.5 h. Whereupon, a solution of
freshly distilled isobutyraldehyde (3.0 equiv.) was added,
the reaction mixture stirred at 278 8C for 2 h and then
allowed to warm to 0 8C overnight. The reaction was
quenched with saturated aqueous NH4Cl (9 cm3), aqueous
ammonia (2–3 drops) added and the reaction mixture
extracted with diethyl ether (3£15 cm3). The combined
organic layers were washed with saturated aqueous NaCl
(3£7 cm3), dried (MgSO4) and the solvent removed in
vacuo to afford crude enone as a dark green transparent oil.
Purification using flash column chromatography (SiO2),
eluting with n-hexane/acetone, (38:1) afforded the (þ)-16
(0.23 g, 76%) as a transparent pale yellow oil; Rf 0.50 (SiO2,
n-hexane/acetone, 4:1); [a]2D4 2.89 (c 2.27 CHCl3); dH
(400 MHz, CD2Cl2) 5.91 (1H, d, J¼2.1 Hz, 2CHi-prop),
5.88 (1H, m, H6), 5.81 (1H, dd, J¼5.7, 2.9 Hz, H5), 3.08
(1H, m, H4), 2.97 (1H, br. s, H7), 2.87 (1H, dd, J¼8.8,
4.8 Hz, H3a), 2.47–2.41 (1H, m, H3), 2.39–2.29 (2H, m,
H7a, 2CHCHMe2), 1.36 (1H, dt, J¼8.1, 1.8 Hz, 4-CHH-7),
1.29 (1H, d, J¼8.1, 1.4 Hz, 4-CHH-7), 1.02 (3H, d,
J¼7.2 Hz, 3Me), 0.91 (3H, d, J¼6.7 Hz, 2CHCHMeMe),
0.87 (3H, d, J¼6.5 Hz, 2CHCHMeMe); dC (100 MHz,
CD2Cl2) 209.5 (s, C1), 144.2 (C2), 142.9 (d, 2CH i-prop),
136.6 (C5), 134.2 (C6), 54.2 (C3a), 52.0 (t, 4-CH2-7), 48.1 (d,
C4), 47.9 (C7), 47.6 (2CHCHMe2), 35.7 (C3), 29.1 (C7a),
23.9 (q, 3Me), 22.6 (2CHCHMeMe), 22.4 (2CHCHMeMe);
m/z (CI/NH3) 234 ([MHþNH3]þ, 2.6%), 217 (MHþ, 8.9),
168 ([MHþNH3–C5H6]þ, 15.3), 151 ([MH2C5H6]þ,
100.0), 66 (C5H6, 5.8); (HRMS: found MHþ, 217.1592.
C15H21Oþ requires 217.1597).
4.6.4. (2)-2-(E)-Isobutylidene)-3(R)-octyl-2,3,3a,4,7,7a-
hexahydro-4,7-methanoinden-1-one (2)-21. (0.23 g,
54%), a very pale yellow transparent oil; Rf 0.38 (SiO2,
n-hexane/ethyl acetate, 9:1); [a]2D7 22.27 (c 8.34 CHCl3);
dH (400 MHz, CDCl3) 6.06 (1H, dd, J¼10.6, 2.0 Hz, 2CHi-
prop), 5.96 (1H, d, J¼5.6, 3.0 Hz, H5/6), 5.93 (1H, dd,
J¼5.6, 2.8 Hz, H6/5), 3.22 (1H, m, H4/7), 3.00 (1H, m, H7/4),
2.95 (1H, dd, J¼8.7, 4.8 Hz, H3a/7a), 2.50 (1H, ddd, J¼8.7,
4.1, 1.8 Hz, H7a/3a), 2.43–2.34 (2H, m, H3, 2CHCHMe2),
1.48 (1H, dt, J¼8.3, 1.6 Hz, 4-CHH-7), 1.39 (1H, m,
4-CHH-7), 1.43–1.21 (14H, m, 3(CH2)7Me), 1.00 (3H, d,
J¼6.5 Hz, 2CHCHMeMe), 0.96 (3H, d, J¼6.7 Hz,
2CHCHMeMe), 0.88 (3H, t, J¼6.7 Hz, 3(CH2)7Me); dC
(100 MHz, CDCl3) 210.3 (s, C1), 143.3 (d, 2CH i-prop),
142.5 (s, C2), 136.3 (d, C6), 133.7 (C5), 54.2 (C7a), 51.8 (t,
4-CH2-7), 47.9 (d, C4), 47.8 (C7), 44.7 (C3a), 40.8 (C3), 37.7
(t, 3(CH2)7Me), 32.3, 30.2, 29.9, 26.6, 29.0 (d,
2CHCHMe2), 27.1 (t, 3(CH2)7Me), 23.0, 22.30 (q,
2CHCHMeMe), 22.98 (2CHCHMeMe), 14.3 (q,
3(CH2)7Me); m/z (CI/NH3) 315 (MHþ, 3.9%), 266
([MHþNH3–C5H6]þ, 4.8), 249 ([MH2C5H6]þ, 100), 163
(7.4), 150 (10), 135 (7.4), 121 (3.5), 107 (5.7), 91 (7.1), 66
(C5H6, 15.8); (HRMS: found MHþ, 315.2692. C22H35Oþ
requires 315.2688).
4.6.2. (2)-2-(E)-Isobutylidene)-3(R)-methyl-
2,3,3a,4,7,7a-hexahydro-4,7-methanoinden-1-one (2)-16.
(0.14 g, 60%), a transparent pale brown oil; Rf 0.55
(SiO2, n-hexane/acetone, 4:1); [a]2D2¼23.13 (c 6.90
CHCl3); dH (400 MHz, CD2Cl2) 6.03 (1H, d, J¼2.1 Hz,
2CHi-prop), 6.00 (1H, m, H6), 5.93 (1H, dd, J¼5.6,
2.8 Hz, H5), 3.20 (1H, m, H4), 3.08 (1H, m, H7), 2.98
(1H, dd, J¼8.6, 4.8 Hz, H3a), 2.55 (1H, m, H3), 2.51–
2.40 (2H, m, H7a, 2CHCHMe2), 1.47 (1H, dt, J¼8.2,
1.6 Hz, 4-CHH-7), 1.40 (1H, d, J¼8.2 Hz, 4-CHH-7),
1.14 (3H, d, J¼7.3 Hz, 3Me), 1.03 (3H, d, J¼6.7 Hz,
2CHCHMeMe), 0.95 (3H, d, J¼6.7 Hz, 2CHCHMeMe);
dC (100 MHz, CD2Cl2) 209.5 (s, C1), 144.2 (C2), 142.8
(d, 2CH i-prop), 136.6 (C5), 134.2 (C6), 54.2 (C3a), 52.0
(t, 4-CH2-7), 48.1 (d, C4), 47.9 (C7), 47.6 (2CHCHMe2),
35.7 (C3), 29.1 (C7a), 23.9 (q, 3Me), 22.6
(2CHCHMeMe), 22.4 (2CHCHMeMe); m/z (CI/NH3)
234 ([MHþNH3]þ, 1.0%), 217 (MHþ, 5.4), 168
([MHþNH3–C5H6]þ, 6.7), 151 ([MH2C5H6]þ, 100), 91
(6.7), 66 (C5H6, 13.7); (HRMS: found MHþ, 217.1602.
C15H21Oþ requires 217.1592).
4.6.5. (1)-2-(E)-Benzylidene-3(S)-methyl-2,3,3a,4,7,7a-
hexahydro-4,7-methanoinden-1-one (1)-(22) and (1)-
7a(S)-(1,3-bisphenyl-3-oxo-propyl)-2-(E)-benzylidene-
3(S)-methyl-2,3,3a,4,7,7a-hexahydro-4,7-methano-
inden-1-one (1)-30. Methylated enone (þ)-22 (0.22 g,
64%), a pale yellow crystalline solid; Rf 0.43 (SiO2,
n-hexane:diethyl ether, 2:1); dH (400 MHz, CDCl3) 7.50
(2H, d, J¼7.3 Hz, 2CHPh), 7.38–7.29 (3H, m, 2CHPh),
7.07 (1H, d, J¼1.9 Hz, 2CHPh), 5.98 (2H, m, H5, H6), 3.30
(1H, m, H4), 3.11 (1H, m, H7), 3.08–3.02 (2H, m, H3, H3a),
2.56 (1H, ddd, J¼8.7, 4.1, 1.3 Hz, H7a), 1.50 (1H, m,
4-CHH-7), 1.42 (1H, d, J¼8.2 Hz, 4-CHH-7), 1.18 (3H, d,
J¼7.1 Hz, 3Me); dC (100 MHz, CDCl3) 210.3 (s, C1), 144.8
(2CHPh), 136.7 (d, C5/6), 135.4 (s, C2), 133.8 (d, C6/5),

J. P. Eddolls et al. / Tetrahedron 60 (2004) 2539–2550
2547
132.7 (2CHPh), 130.8 (2CHPh), 129.5 (2CHPh), 129.1
(2CHPh), 52.9 (C3a), 51.8 (t, 4-CH2-7), 48.0 (d, C4), 47.5
(C7/7a), 47.5 (C7a/7), 36.64 (C3), 21.2 (q, 3Me); m/z (CI/NH3)
502 (3.0%), 435 (4.2), 268 ([MHþNH3]þ, 2.4), 251 (MHþ,
36.1), 222 (5.6), 202 ([MHþNH3–C5H6]þ, 6.1),
185([MH2C5H6]þ, 100), 156 (7.9), 141 (4.3), 115 (3.2),
91 (4.1), 66 (C5H6, 4.3); (HRMS: found MHþ, 251.1434.
C18H19Oþ requires 251.1436), and the 7a(S)-alkylated by-
product, (þ)-30 (108 mg, 15%) as a transparent pale yellow
oil; Rf 0.18 (SiO2, n-hexane/acetone, 9:1); dH (400 MHz,
CDCl3) 7.84 (2H, d, J¼7.2 Hz, 2CHPh), 7.51 (2H, m, 10/
300Ph), 7.43–7.48 (3H, m, 10/30Ph), 7.30–7.39 (4H, m, 10/
3 Ph), 7.25 (2H, m, 10/30Ph), 7.16 (2H, m, 2CHPh, 10/30Ph),
6.07 (1H, dd, J¼5.6, 2.7 Hz, H6), 5.97 (1H, dd, J¼5.6,
133.9 (d, C5), 132.8 (2CHPh), 130.8 (2d, 2CHPh), 129.50
(d, 2CHPh), 129.0 (2d, 2CHPh), 53.4 (C7a), 51.9 (t, 4-CH2-7),
48.1 (d, C7), 48.0 (C4), 45.0 (C3a), 42.3 (C3), 34.8 (t,
3(CH2)7Me), 32.2, 30.0, 29.9, 29.6, 27.6, 23.0, 14.5 (q,
3(CH2)7Me); m/z (CI/NH3) 349 (MHþ, 9.7%), 320 (1.3),
283 ([MH2C5H6]þ, 48.9), 169 (4.1), 141 (10.4), 128 (3.3),
115 (9.8), 91 (11.1), 66 (C5H6, 100), 55 (5.5); (HRMS:
found MHþ, 349.25394. C25H33Oþ requires 349.25314).
4.6.8. (2)-2-(E)-Benzylidene-3(R)-octyl-2,3,3a,4,7,7a-
hexahydro-4,7-methano-inden-1-one (2)-23. (0.40 g,
83%) as a transparent pale yellow oil; Rf 0.31 (SiO2,
n-hexane/ethyl acetate, 9:1); [a]2D4 20.87 (c 12.09 CHCl3);
dH (400 MHz, CDCl3) 7.48 (2H, dd, J¼8.6, 1.5 Hz,
2CHPh), 7.39–7.32 (3H, m, 2CHPh), 7.09 (1H, d,
J¼2.2 Hz, 2CHPh), 5.99 (2H, m, H5, H6), 3.30 (1H, m,
H7), 3.07–3.06 (1H, m, H4), 3.03 (1H, dd, J¼8.7, 4.8 Hz,
H7a), 2.90 (1H, d, J¼8.1 Hz, H3), 2.67 (1H, ddd, J¼8.1, 4.0,
1.3 Hz, H3a), 1.62–1.18 (12H, m, 3(CH2)7Me), 1.52 (1H, m,
4-CHH-7), 1.47 (1H, m, 4-CHH-7), 0.88 (3H, t, J¼6.7 Hz,
3(CH2)7Me); dC (100 MHz, CDCl3) 210.5 (s, C1), 143.9
(C2), 136.6 (d, C6), 135.6 (s, 2CHPh), 133.9 (d, C5), 132.8
(2CHPh), 130.8 (2d, 2CHPh), 129.50 (d, 2CHPh), 129.0
(2d, 2CHPh), 53.4 (C7a), 51.9 (t, 4-CH2-7), 48.1 (d, C7),
48.0 (C4), 45.1 (C3a), 42.3 (C3), 34.8 (t, 3(CH2)7Me), 32.2,
30.0, 29.9, 29.6, 27.6, 23.0, 14.5 (q, 3(CH2)7Me); m/z (CI/
NH3) 349 (MHþ, 11.4%), 320 (2.9), 300 (9.3), 284
([MH2C5H6]þ, 70.9), 169 (16.9), 155 (10.8), 141 (22.9),
115 (12.8), 91 (12.6), 66 (C5H6, 16.3); (HRMS: found MHþ,
349.25362. C25H33Oþ requires 349.25314).
0
3.0 Hz, H5), 3.91 (1H, dd, J¼10.3, 3.2 Hz, H1 ), 3.79 (1H,
dd, J¼100.5, 4.9 Hz, 10CHHCOPh), 3.54 (1H, dd, J¼16.7,
3.3 Hz, 1 CHHCOPh), 3.03 (1H, br. s, H4), 3.00 (1H, m,
H3), 2.91 (1H, br. s, H7), 2.44 (1H, dd, J¼3.8, 1.0 Hz, H3a),
1.61 (1H, d, J¼8.6 Hz, 4-CHH-7), 1.36 (1H, d, J¼8.6 Hz,
4-CHH-7), 1.16 (3H, d, J¼7.2 Hz, 3Me); dC (100 MHz,
0
CDCl3) 211.0 (s, C1), 198.8 (C3 ), 145.1 (2CHPh), 141.8
(30COPh), 138.6 (d, C5), 137.7 (s, 10Ph), 135.9 (d, C6), 135.4
(s, C2), 133.7 (d, 2CHPh), 133.2 (10/30Ph), 131.0 (2d,
2CHPh), 130.4 (d, 10/30Ph), 129.7 (2CHPh), 129.1 0 (2d,
2CHPh), 128.9 (10/30Ph), 128.5, 128.4, 127.1 (d, 10/3 Ph),
64.9 (s, C7a), 54.6 (d, C3a), 51.2 (C7), 4.3 (t, 4-CH2-7), 48.5
0
0
(d, C4), 47.4 (C1 ), 41.4 (t, C2 ), 36.4 (d, C3), 20.6 (q, 3Me);
m/z (ESþ) 939 ([2MþNa]þ, 57.8%), 518 (10.2), 481
([MþNa]þ, 100), 415 (9.6); (HRMS: found MþNaþ,
481.216. C33H30O2Naþ requires 481.2144).
4.6.6. (2)-2-(E)-Benzylidene-3(R)-methyl-2,3,3a,4,7,7a-
hexahydro-4,7-methanoinden-1-one (2)-22. (0.13 g,
75%) as a transparent pale yellow oil; Rf 0.51 (SiO2,
n-hexane/Et2O, 2:1); dH (400 MHz, CDCl3) 7.51 (2H, d,
J¼7.2 Hz, 2CHPh), 7.40–7.30 (3H, m, 2CHPh), 7.08 (1H,
d, J¼2.1 Hz, 2CHPh), 5.99 (2H, m, H5, H6), 3.30 (1H, m,
H4), 3.13 (1H, m, H7), 3.08 (1H, dd, J¼8.6, 4.8 Hz, H3a),
3.06 (1H, m, H3), 2.57 (1H, ddd, J¼8.6, 4.0, 1.3 Hz, H7a),
1.51 (1H, dt, J¼8.2, 1.6 Hz, 4-CHH-7), 1.43 (1H, d,
J¼8.2 Hz, 4-CHH-7), 1.18 (3H, d, J¼7.3 Hz, 3Me); dC
(100 MHz, CDCl3) 210.6 (s, C1), 144.7 (2CHPh), 136.7 (d,
C5/6), 135.4 (s, C2), 133.8 (d, C6/5), 132.7 (2CHPh), 130.9
(2CHPh), 129.6 (2CHPh), 129.1 (2CHPh), 52.9 (C3a), 51.8
(t, 4-CH2-7), 48.0 (d, C4), 47.5 (C7/7a), 47.5 (C7a/7), 36.7
(C3), 21.2 (q, 3Me); m/z (EI) 250 (Mþ, 53.2%), 222 (8.6),
185 (88.5), 183 (100), 165 (16.3), 156 (33.6), 147 (37.9),
129 (25.5), 128 (32.3), 115 (57.5), 91 ([M2PhCH2]þ, 47.2),
66 (92.8); (HRMS: found Mþ, 250.1360. C18H19Oþ
requires 250.1358).
4.6.9. (6)-2-(4-(E)-Fluorobenzylidene)-3(R/S)-methyl-
2,3,3a,4,7,7a-hexahydro-4,7-methanoinden-1-one (6)-24.
(0.15 g, 83%), a pale yellow crystalline solid; Rf 0.47 (SiO2,
n-hexane/Et2O, 2:1); dH (400 MHz, CD2Cl2) 7.42 (2H, m,
2CHPh·p-F), 6.99 (2H, m, 2CHPh·p-F), 6.89 (1H, d,
J¼2.1 Hz, 2CHPh·p-F), 5.89 (1H, dd, J¼5.6, 2.8 Hz, H6),
5.85 (1H, dd, J¼5.6, 2.7 Hz, H5), 3.15 (1H, m, H4), 3.02
(1H, m, H7), 2.94 (1H, m, H3a), 2.90 (1H, dd, J¼14.3,
7.1 Hz, H3), 2.47 (1H, ddd, J¼8.6, 4.0, 1.4 Hz, H7a), 1.39
(1H, m, 4-CHH-7), 1.34 (1H, m, 4-CHH-7), 1.07 (3H, d,
J¼7.1 Hz, 3Me); dC (100 MHz, CD2Cl2) 209.9 (s, C1),
163.7 (sd, JC,F¼249.0 Hz, 2CHPh·p-F), 145.1 (sd,
JC,F¼2.3 Hz, C2), 136.9 (d, C5), 134.2 (C6), 133.1 (dd,
JC,F¼8.3 Hz, 2CHPh·p-F), 132.2 (sd, JC,F¼3.2 Hz,
2CHPh·p-F), 131.2 (d, 2CHPh·p-F), 116.4 (dd,
JC,F¼21.7 Hz, 2CHPh·p-F), 53.2 (C3a), 52.6 (t, 4-CH2-7),
48.4 (d, C4), 48.0 (C7), 47.9 (C7a), 36.8 (C3), 21.2 (q, 3Me);
m/z (CI/NH4) 286 ([MHþNH4]þ, 1.5%), 269 (MHþ, 31.2),
240 (3.9), 220 (7.7), 203 ([MH2C5H6]þ, 100); (HRMS:
found MHþ, 269.1333. C18H18OFþ requires 269.1342).
4.6.7. (1)-2-(E)-Benzylidene-3(S)-octyl-2,3,3a,4,7,7a-
hexahydro-4,7-methano-inden-1-one (1)-23. (0.27 g,
57%) as a transparent yellow oil; Rf 0.36 (SiO2, n-hexane/
ethyl acetate, 9:1); [a]2D2 1.13 (c 8.33 CHCl3); dH (400 MHz,
CDCl3) 7.48 (2H, dd, J¼7.3, 1.4 Hz, 2CHPh), 7.39–7.30
(3H, m, 2CHPh), 7.09 (1H, d, J¼2.1 Hz, 2CHPh), 5.98 (2H,
m, H5, H6), 3.30 (1H, m, H7), 3.07 (1H, m, H4), 3.03 (1H,
dd, J¼8.6, 4.8 Hz, H7a), 2.89 (1H, d, J¼8.1 Hz, H3), 2.67
(1H, ddd, J¼8.1, 4.0, 1.3 Hz, H3a), 1.52 (1H, m, 4-CHH-7),
1.47 (1H, m, 4-CHH-7), 1.50–1.24 (12H, m, 3(CH2)7Me),
0.87 (3H, t, J¼6.8 Hz, 3(CH2)7Me); dC (100 MHz, CDCl3)
210.6 (s, C1), 143.9 (C2), 136.6 (d, C6), 135.6 (s, 2CHPh),
4.6.10. (1)-2-(4-(E)-Fluorobenzylidene)-3(S)-methyl-
2,3,3a,4,7,7a-hexahydro-4,7-methanoinden-1-one (1)-24
and (1)-7a(S)-[1,3-bis-(4-fluoro-phenyl)-3-oxo-propyl]-2-
(4-(E)-fluorobenzylidene)-3(S)-methyl-2,3,3a,4,7,7a-hexa-
hydro-4,7-methano-inden-1-one (1)-31. Methylated enone
(þ)-24 (0.20 g, 55%) as a transparent pale yellow oil; Rf 0.29
(SiO2, n-hexane/acetone, 9:1); [a]2D0 0.89 (c 8.50, CHCl3); dH
(400 MHz, CDCl3) 7.49 (2H, m, 2CHPh·p-F), 7.06 (2H, m,
2CHPh·p-F), 7.03 (1H, d, J¼2.0 Hz, 2CHPh·p-F), 5.99 (2H,
m, H6, H5), 3.30 (1H, m, H4), 3.12 (1H, m, H7), 3.07 (1H,
dd, J¼8.6, 4.8 Hz, H3a), 3.00 (1H, m, H3), 2.57 (1H, ddd,

2548
J. P. Eddolls et al. / Tetrahedron 60 (2004) 2539–2550
J¼8.7, 4.1, 1.4 Hz, H7a), 1.51 (1H, m, 4-CHH-7), 1.43 (1H,
m, 4-CHH-7), 1.17 (3H, d, J¼7.3 Hz, 3Me); dC (100 MHz,
CDCl3) 210.1 (s, C1), 163.3 (sd, JC,F¼250.0 Hz, 2CHPh·p-
F), 144.3 (JC,F¼2.9 Hz, C2), 136.7 (d, C5), 133.7 (C6), 132.7
(dd, JC,F¼8.1 Hz, 2CHPh·p-F), 131.6 (sd, JC,F¼3.6 Hz,
2CHPh·p-F), 131.4 (d, 2CHPh·p-F), 116.3 (dd,
JC,F¼21.2 Hz, 2CHPh·p-F), 52.9 (d, C3a), 51.8 (t, 4-CH2-
7), 48.0 (d, C4), 47.5 (C7, C7a), 36.5 (C3), 21.0 (q, 3Me); m/z
(CI/NH4) 286 ([MHþNH4]þ, 1.5%), 269 (MHþ, 34.7), 240
(6.5), 220 (6.1), 203 ([MH2C5H6]þ, 100), 174 (10.5), 66
(7.5); (HRMS: found MHþ, 269.1343. C18H18OFþ requires
269.1342), and the 7a(S)-alkylated by-product (þ)-31
(108 mg, 15%) as a transparent pale yellow oil; Rf 0.18
(SiO2, n-hexane/acetone, 9:1); [a]1D8 0.44 (c 6.65, CHCl3);
dH (400 MHz, CDCl3) 7.85 (2H, m, 30Ph·p-F), 7.51 (2H, m,
Ph·p-F), 7.43 (2H, m, Ph·p-F), 7.14 (1H, d, J¼2.2 Hz,
2CHPh·p-F), 7.11–7.02 (4H, m, Ph·p-F), 6.95 (2H, m, Ph·p-
F), 6.08 (1H, dd, J¼5.6, 2.9 Hz, H5/6), 5.97 (1H, dd, J¼5.6,
(3H, d, J¼6.7 Hz, 5CHCHMeMe), 0.98 (3H, d, J¼6.6 Hz,
5CHCHMeMe); dC (100 MHz, CD2Cl2) 197.4 (s, C1), 164.2
(d, C3), 142.0 (5CH i-prop), 137.7 (s, C5), 134.5 (d, C2),
39.0 (d, C4), 29.3 (5CHCHMe2), 22.6 (q, 5CHCHMeMe),
22.6 (5CHCHMeMe), 19.4 (4Me); m/z (CI/NH3) 233
(5.2%), 220 (12.3), 205 (19.9), 168 ([MHþNH3]þ, 7.0),
151 (MHþ, 100); (HRMS: found MHþ, 151.1120.
C10H15Oþ requires 151.1123).
4.7.2. (2)-5-(E)-Isobutylidene-4(R)-methyl-cyclopent-2-
enone (2)-32. (69.7 mg, 73%), a transparent yellow oil; Rf
0.32 (SiO2, n-hexane/diethyl ether, 2:1); [a]2D2 210.52 (c
4.44 CHCl3); dH (250 MHz, CD2Cl2) 7.40 (1H, ddd, J¼5.8,
2.4, 1.1 Hz, H3), 6.25 (1H, dt, J¼10.6, 1.0 Hz 5CHi-prop),
6.19 (1H, dd, J¼5.8, 1.7 Hz, H2), 3.47 (1H, m, H4), 2.65
(1H, m, 5CHCHMe2), 1.23 (3H, d, J¼7.2 Hz, 4Me), 1.05
(3H, d, J¼6.5 Hz, 5CHCHMeMe), 1.03 (3H, d, J¼6.5 Hz,
5CHCHMeMe); dC (100 MHz, CD2Cl2) 197.4 (s, C1), 164.2
(d, C3), 142.0 (5CH i-prop), 136.7 (s, C5), 134.5 (d, C2),
39.0 (C4), 28.7 (5CHCHMe2), 22.7 (q, 5CHCHMeMe), 22.6
(5CHCHMeMe), 19.4 (4Me); m/z (CI/NH3) 168
([MHþNH3]þ, 7.4%), 151 (MHþ, 100); (HRMS: found
MHþ, 151.1123. C10H15Oþ requires 151.1123).
0
3.0 Hz, H6/5), 3.85 (1H, dd, J¼10.6, 3.3 Hz, H1 ), 3.66 (1H,
m, 10CHHCOPh·p-F), 3.42 (1H, dd, J¼16.7, 3.3 Hz,
10CHHCOPh.p-F), 3.08 (1H, br. s, H4), 2.96 (1H, dd,
J¼14.3, 7.3 Hz, H3), 2.84 (1H, br. s, H7), 2.41 (1H, dd,
J¼4.0, 1.3 Hz, H3a), 1.63 (1H, m, 4-CHH-7), 1.39 (1H, m,
4-CHH-7), 1.17 (3H, d, J¼7.3 Hz, 3Me); dC (100 MHz,
0
CDCl3) 210.4 (s, C1), 196.7 (C3 ), 165.7 (sd, JC,F¼253.4 Hz,
4.7.3. (1)-5-(E)-Isobutylidene-4(S)-octyl-cyclopent-2-
enone (1)-33. (94.2 mg, 74%) a transparent pale yellow
oil; Rf 0.28 (SiO2, n-hexane/ethyl acetate, 9:1); [a]2D2 1.70 (c
4.65 CHCl3); dH (400 MHz, CD2Cl2) 7.46 (1H, dd, J¼6.0,
2.5 Hz, H3), 6.19 (1H, m, H2), 6.17 (1H, dd, J¼1.4 Hz, 5CH i-
prop), 3.42 (1H, m, H4), 2.58 (1H, m, 5CHCHMe2), 1.75 (1H,
m, 4CHH(CH2)6Me), 1.45 (1H, m, 4CHH(CH2)6Me), 1.26–
1.12 (12H, m, 4CH2(CH2)6Me), 0.98 (6H, m, 5CHCHMe2),
0.79 (3H, t, J¼6.5 Hz, 4(CH2)7Me); dC (100 MHz, CD2Cl2)
197.8 (s, C1), 162.8 (d, C3), 141.9 (5CH i-prop), 136.4 (s, C5),
135.3 (d, C2), 44.0 (C4), 33.7 (t, 4CH2(CH2)6Me), 32.6
(4CH2(CH2)6Me), 30.6, 30.2, 29.3 (d, 5CHCHMe2), 26.6 (t,
4CH2(CH2)6Me), 23.4, 22.7 (q, 5CHCHMeMe), 22.5
(5CHCHMeMe), 14.7 (4(CH2)7Me); m/z (CI/NH3) 266
([MHþNH3]þ, 2.0%), 249 (MHþ, 100), 163 (4.0), 150 (5.8),
135 (3.7), 121 (2.3), 107 (3.7), 91 (2.2); (HRMS: found MHþ,
249.2222. C17H29Oþ requires 249.2218).
Ph·p-F),
163.3
(JC,F¼250.4 Hz,
Ph·p-F),
161.8
(JC,F¼244.4 Hz, Ph·p-F), 144.2 (JC,F¼2.3 Hz, Ph·p-F),
138.0 (d, C5/6), 137.7 (sd, JC,F¼12.7 Hz, Ph·p-F), 135.7
(d, C6/5), 133.6 (sd, JC,F¼9.6 Hz, Ph·p-F), 132.6 (dd,
JC,F¼8.8 Hz, Ph·p-F), 132.4 (d, 2CHPh·p-F), 131.4 (dd,
JC,F¼7.2 Hz, Ph·p-F), 131.1 (sd, JC,F¼12.7 Hz, Ph·p-F),
130.6 (dd, JC,F¼8.8 Hz, Ph·p-F), 115.9 (JC,F¼21.6 Hz,
Ph·p-F), 115.6, 115.0 (JC,F¼20.8 Hz, Ph·p-F), 64.5 (s,
C7a), 54.7 (d, C3a), 50.9 (C7), 48.8 (t, 4-CH2-7), 47.6 (d, C4),
0
0
46.7 (C1 ), 41.1 (t, C2 ), 35.9 (d, C3), 20.2 (q, 3Me); dF
(376 MHz, CDCl3) 2105.7 (Ph·p-F), 2110.4, 2116.5; m/z
(ESþ) 1047 ([2MþNa]þ, 3.7%), 551 (4.4), 535 ([MþNa]þ,
100), 469 ([M2C5H6]þ, 87.0), 449 (3.1), 413 (4.4), 331
(3.4); (HRMS: found MþNaþ, 535.1843. C33H27O2F3Naþ
requires 535.1861).
4.7. Microwave assisted retro Diels–Alder reaction:
representative procedure
4.7.4. (2)-5-(E)-Isobutylidene-4(R)-octyl-cyclopent-2-
enone (2)-33. (95 mg, 60%) a transparent pale yellow oil;
Rf 0.28 (SiO2, n-hexane/ethyl acetate, 9:1); [a]2D4 21.76 (c
4.35 CHCl3); dH (400 MHz, CD2Cl2) 7.56 (1H, ddd, J¼6.0,
2.7, 1.0 Hz, H3), 7.47 (0.06H, dd, J¼6.0, 2.6 Hz, Z-isomer
H3), 6.31–6.27 (2H, m, H2, 5CHi-prop), 6.23 (0.06H, m,
Z-isomer H2), 5.83 (0.06H, d, J¼9.8 Hz, Z-isomer 5CHi-
prop), 3.93 (0.06H, m, Z-isomer H4), 3.53 (1H, m, H4), 3.28
(0.06H, m, Z-isomer 5CHCHMe2), 2.69 (1H, m,
5CHCHMe2), 1.86 (1H, m, 4CHH(CH2)6Me), 1.55 (1H,
m, 4CHH(CH2)6Me), 1.29 (12H, m, 4CH2(CH2)6Me), 1.10
(3H, d, J¼6.7 Hz, 5CHCHMeMe), 1.08 (3H, d, J¼6.8 Hz,
5CHCHMeMe), 1.03 (0.18 Hz, d, J¼2.1 Hz, Z-isomer
5CHCHMeMe), 1.02 (0.18 Hz, d, J¼2.1 Hz, Z-isomer
5CHCHMeMe), 0.90 (3H, t, J¼6.8 Hz, 4(CH2)7Me); dC
(100 MHz, CD2Cl2) 197.65 (s, C1), 162.7 (d, C3), 161.3
(Z-isomer C3), 147.1 (Z-isomer 5CH i-prop), 141.9 (5CH
i-prop), 136.7 (Z-isomer C2), 136.4 (s, C5), 135.3 (d, C2), 46.2
(Z-isomer C4), 44.0 (C4), 34.3 (t, Z-isomer 4CH2(CH2)6Me),
33.7 (4CH2(CH2)6Me), 32.6 (4CH2(CH2)6Me), 30.5, 30.5
(Z-isomer 4CH2(CH2)6Me), 30.2 (4CH2(CH2)6Me), 30.0,
4.7.1. (1)-5-(E)-Isobutylidene-4(S)-methyl-cyclopent-2-
enone (1)-32. To a stirring solution of (þ)-16 (0.22 g,
1.02 mmol) and maleic anhydride (5.0 equiv.) in anhydrous
DCM (5.1 cm3) was added 1.0 M methyl aluminiumdichlor-
ide in hexanes (0.5 equiv.) at room temperature under a
nitrogen stream. The mixture was heated at 60 8C for 30 min
in a microwave (Smith-Creator), and cooled to room
temperature under a nitrogen stream. Flash silica (0.94 g)
was added and the solvent removed in vacuo to afford pre-
absorbed crude product. Purification by flash column
chromatography (SiO2), eluting with n-hexane/diethyl
ether (5:1), gave recovered enone (þ)-16 (32 mg, 14%) as
a pale yellow transparent oil and an inseparable mixture
(98:2) of E- and Z-isomers of dienone (þ)-32 (81.8 mg,
54%) as a transparent yellow oil; Rf 0.31 (SiO2, n-hexane/
diethyl ether, 2:1); dH (400 MHz, CD2Cl2) 7.37 (1H, dd,
J¼5.9, 2.6 Hz, H3), 6.19 (1H, d, J¼10.7 Hz 5CHi-prop),
6.13 (1H, dd, J¼5.9, 1.7 Hz, H2), 3.40 (1H, m, H4), 2.59
(1H, m, 5CHCHMe2), 1.18 (3H, d, J¼7.2 Hz, 4Me), 1.00

J. P. Eddolls et al. / Tetrahedron 60 (2004) 2539–2550
2549
29.2 (d, 5CHCHMe2), 26.6 (t, 4CH2(CH2)6Me), 26.3 (d,
Z-isomer 5CHCHMe2), 23.4 (t, 4(CH2)7Me), 23.0 (q,
Z-isomer 5CHCHMeMe), 22.9 (Z-isomer 5CHCHMeMe),
22.7 (q, 5CHCHMeMe), 22.4 (5CHCHMeMe), 14.6
(4(CH2)7Me); m/z (CI/NH3) 266 ([MHþNH3]þ, 3.8%), 249
(MHþ, 100), 163 (4.3), 149 (6.1), 135 (4.6), 121 (3.0), 107
(4.8), 91 (3.0); (HRMS: found MHþ, 249.2219. C17H29Oþ
requires 249.2218).
196.0 (s, C1), 160.1 (d, C3), 138.0 (s, C5), 137.2 (d, C2),
136.5 (5CHPh), 134.8 (s, 5CHPh), 131.2 (2d, 5CHPh),
129.8 (d, 5CHPh), 128.4 (2d, 5CHPh), 47.7 (d, C4), 34.4 (t,
4(CH2)7Me), 32.2, 30.2, 29.8, 29.6, 26.6, 23.0, 14.4 (q,
4(CH2)7Me); m/z (CI/NH3) 300 ([MHþNH3]þ, 1.4%), 283
(MHþ, 100), 225 (6.7), 211 (9.5), 199 (6.7), 183 (20.6), 169
(32.5), 156 (35.0), 141 (60.8), 128 (24.6), 115 (36.5), 91
(26.2), 55 (11.2); (HRMS: found MHþ, 283.2065.
C20H27Oþ requires 283.2062).
4.7.5. (2)-5-(E)-Benzylidene-4(S)-methyl-cyclopent-2-
enone (2)-34. (54.5 mg, 74%) as a transparent pale yellow
oil; Rf 0.34 (SiO2, n-hexane/ethyl acetate, 3:1); [a]2D1 20.61
(c 5.34 CHCl3); dH (400 MHz, CD2Cl2) 7.53 (1H, ddd,
J¼5.9, 2.7, 1.0 Hz, H3), 7.48 (2H, d, J¼7.2 Hz 5CHPh),
7.34–7.25 (3H, m, 5CHPh), 7.21 (1H, m, 5CHPh), 6.27
(1H, dd, J¼5.9, 1.9 Hz, H2), 3.86 (1H, m, H4), 1.10 (3H, d,
J¼7.2 Hz, 4Me); dC (100 MHz, CD2Cl2) 197.7 (s, C1),
164.9 (d, C3), 139.4 (s, 5CHPh), 135.6 (C5), 134.1 (d, C2),
131.8 (5CHPh), 131.4 (2d, 5CHPh), 129.9 (d, 5CHPh),
129.5 (2d, 5CHPh), 39.6 (d, C4), 16.9 (q, 4Me); m/z (CI/
NH3) 185 (MHþ, 100%), 202 ([MHþNH3]þ, 2.4); (HRMS:
found MHþ, 185.0969. C13H13Oþ requires 185.0967).
4.7.8. (2)-5-(E)-Benzylidene-4(R)-octyl-cyclopent-2-
enone (2)-35. (0.15 g, 54%) as a transparent pale yellow
oil; Rf 0.23 (SiO2, n-hexane/ethyl acetate, 9:1); [a]2D2 20.48
(c 4.67 CHCl3); dH (400 MHz, CDCl3) 7.69 (1H, ddd,
J¼6.0, 2.7, 0.8 Hz, H3), 7.52 (2H, dd, J¼7.2, 1.4 Hz,
5CHPh), 7.43–7.34 (4H, m, 5CHPh, 5CHPh), 6.45 (1H, dd,
J¼6.0, 1.9 Hz, H2), 3.92 (1H, m, H4), 1.87–1.79 (1H, m,
4CHH(CH2)6Me), 1.43–1.33 (1H, m, 4CHH(CH2)6Me),
1.31–1.08 (12H, m, 4CH2(CH2)6Me), 0.86 (3H, t, J¼6.8 Hz,
4(CH2)7Me); dC (100 MHz, CDCl3) 197.9 (s, C1), 162.8 (d,
C3), 137.6 (s, 5CHPh), 135.2 (C5), 134.8 (d, C2), 132.0
(5CHPh), 130.8 (2d, 5CHPh), 129.6 (d, 5CHPh), 129.1 (2d,
5CHPh), 44.7 (d, C4), 32.2 (t, 4(CH2)7Me), 30.6, 29.8, 29.6,
29.5, 26.4, 23.0, 14.4 (q, 4(CH2)7Me); m/z (CI/NH3) 300
([MHþNH3]þ, 5.7%), 283 (MHþ, 100), 186 (3.0), 169 (4.5),
156 (3.5), 141 (6.7), 128 (2.9), 115 (4.5), 91 (4.3); (HRMS:
found MHþ, 283.2070. C20H27Oþ requires 283.2062).
4.7.6. (1)-5-(E)-Benzylidene-4(R)-methyl-cyclopent-2-
enone (1)-34. (62.0 mg, 69%) as a transparent pale yellow
oil; Rf 0.33 (SiO2, n-hexane/ethyl acetate, 3:1); [a]1D8 0.88 (c
5.02 CHCl3); dH (400 MHz, CD2Cl2) 7.53 (1H, ddd, J¼5.9,
2.6, 0.8 Hz, H3), 7.47 (2H, d, J¼7.3 Hz, 5CHPh), 7.34 (2H,
t, J¼7.0 Hz, 5CHPh), 7.29 (1H, d, J¼7.1 Hz, 5CHPh), 7.35
(1H, br. s, 5CHPh), 6.27 (1H, dd, J¼5.9, 1.9 Hz, H2), 3.85
(1H, m, H4), 1.10 (3H, d, J¼7.2 Hz, 4Me); dC (100 MHz,
CD2Cl2) 197.7 (s, C1), 164.9 (d, C3), 139.4 (s, 5CHPh),
135.6 (C5), 134.1 (d, C2), 131.8 (5CHPh), 131.4 (2d,
5CHPh), 130.0 (d, 5CHPh), 129.5 (2d, 5CHPh), 39.6 (d,
C4), 16.9 (q, 4Me); m/z (CI/NH3) 202 ([MHþNH3]þ, 3.0%),
185 (MHþ, 100); (HRMS: found MHþ, 185.0967.
C13H13Oþ requires 185.0967).
4.7.9. (6)-5-(4-(E)-Fluorobenzylidene)-4(R/S)-methyl-
cyclopent-2-enone (6)-36. (96.9 mg, 86%) as a transparent
pale yellow oil; Rf 0.35 (SiO2, n-hexane/ethyl acetate, 3:1);
dH (400 MHz, CD2Cl2) 7.52 (1H, ddd, J¼5.9, 2.5, 0.8 Hz,
H3), 7.47 (2H, m, 5CHPh·p-F), 7.21 (1H, m, 5CHPh·p-F),
7.04 (2H, m, 5CHPh·p-F), 6.27 (1H, dd, J¼5.9, 1.9 Hz, H2),
3.81 (1H, m, H4), 1.10 (3H, d, J¼7.2 Hz, 4Me); dC (100 MHz,
CD2Cl2) 197.5 (s, C1), 164.6 (d, C3), 163.8 (sd,
JC,F¼250.0 Hz, 5CHPh·p-F), 139.1 (JC,F¼1.6 Hz, C5), 134.1
(d, C2), 133.23 (dd, JC,F¼8.4 Hz, 5CHPh·p-F), 131.9 (sd,
JC,F¼3.2 Hz, 5CHPh·p-F), 130.5 (d, 5CHPh·p-F), 116.5 (dd,
JC,F¼21.6 Hz, 5CHPh·p-F), 39.5 (C4), 16.9 (q, 4Me); m/z (CI/
NH3) 220 ([MHþNH3]þ, 3.7%), 203 (MHþ, 100); (HRMS:
found MHþ, 203.0873. C13H12OFþ requires 203.0872).
4.7.7. (1)-5-(E)-Benzylidene-4(S)-octyl-cyclopent-2-
enone (1)-35. (91 mg, 56%) as a transparent pale yellow
oil; E-isomer; Rf 0.26 (SiO2, n-hexane/ethyl acetate, 9:1);
[a]2D2 0.61 (c 6.07 CHCl3); dH (400 MHz, CD2Cl2) 7.63 (1H,
ddd, J¼6.0, 2.7, 1.0 Hz, H3), 7.47–7.44 (2H, m, 5CHPh),
7.36–7.25 (4H, m, 5CHPh, 5CHPh), 6.31 (1H, dd, J¼6.0,
1.9 Hz, H2), 3.84 (1H, m, H4), 1.79–1.70 (1H, m,
4CHH(CH2)6Me), 1.33–1.25 (1H, m, 4CHH(CH2)6Me),
1.23–1.05 (12H, m, 4CH2(CH2)6Me), 0.77 (3H, t,
J¼7.0 Hz, 4(CH2)7Me); dC (100 MHz, CD2Cl2) 197.7 (s,
C1), 163.2 (d, C3), 138.3 (s, 5CHPh), 135.8 (C5), 134.9 (d,
C2), 131.7 (5CHPh), 131.2 (2d, 5CHPh), 129.9 (d, 5CHPh),
129.4 (2d, 5CHPh), 44.7 (d, C4), 32.6 (t, 4(CH2)7Me), 31.0,
30.3, 30.1, 29.9, 26.8, 23.4, 14.6 (q, 4(CH2)7Me); m/z (CI/
NH3) 300 ([MHþNH3]þ, 11.5%), 283 (MHþ, 100), 195
(6.2), 186 (8.3), 169 (4.7), 156 (5.9), 141 (8.6), 128 (5.0),
115 (5.8), 91 (6.9); (HRMS: found MHþ, 283.2070.
C20H27Oþ requires 283.2062); Z-isomer; Rf 0.36 (SiO2, n-
hexane/ethyl acetate, 9:1); dH (400 MHz, CDCl3) 7.98 (2H,
dd, J¼8.3, 1.6 Hz, 5CHPh), 7.48 (1H, dd, J¼6.0, 2.6 Hz,
H3), 7.44–7.32 (3H, m, 5CHPh), 6.76 (1H, br. s, 5CHPh),
6.34 (1H, dd, J¼6.0, 1.8 Hz, H2), 3.47 (1H, m, H4), 1.89–
1.81 (1H, m, 4CHH(CH2)6Me), 1.66–1.56 (1H, m,
4CHH(CH2)6Me), 1.43–1.23 (12H, m, 4CH2(CH2)6Me),
0.88 (3H, t, J¼6.5 Hz, 4(CH2)7Me); dC (100 MHz, CDCl3)
4.7.10. (2)-5-(4-(E)-Fluorobenzylidene)-4(S)-methyl-
cyclopent-2-enone (2)-36. (0.14 g, 91%) as a transparent
yellow oil; Rf 0.31 (SiO2, n-hexane/ethyl acetate, 3:1); [a]D22
20.87 (c 7.50, CHCl3); dH (400 MHz, CD2Cl2) 7.51 (1H, m,
H3), 7.45 (2H, m, 5CHPh·p-F), 7.21 (1H, br. s, 5CHPh·p-F),
7.03 (2H, m, 5CHPh·p-F), 6.26 (1H, dd, J¼5.9, 1.8 Hz, H2),
3.80 (1H, m, H4), 1.08 (3H, d, J¼7.2 Hz, 4Me); dC
(100 MHz, CD2Cl2) 197.5 (s, C1), 164.6 (d, C3), 163.8
(sd, JC,F¼250.0 Hz, 5CHPh·p-F), 139.1 (JC,F¼2.4 Hz, C5),
134.1 (d, C2), 133.2 (dd, JC,F¼8.8 Hz, 5CHPh·p-F), 131.9
(sd, JC,F¼3.2 Hz, 5CHPh·p-F), 130.5 (d, 5CHPh·p-F), 116.5
(dd, JC,F¼3.2 Hz, 5CHPh·p-F), 39.4 (d, C4), 16.9 (q, 4Me);
m/z (CI/NH3) 220 ([MHþNH3]þ, 3.7%), 203 (MHþ, 100),
174 (9.4), 159 (6.6), 133 (4.9); (HRMS: found MHþ,
203.0877. C13H12OFþ requires 203.0872).
Acknowledgements
The DTI is thanked for funding via a SMART award (J. P. E.)

2550
J. P. Eddolls et al. / Tetrahedron 60 (2004) 2539–2550
R.; Sasaki, H.; Kikuchi, Y.; Kita, T.; Yamori, T.; Sawada, J.;
Kojima, M.; Hazato, A.; Kurozumi, S.; Fukushima, M. Anti-
Cancer Drugs 2001, 12, 221. (b) Weaving, R.; Roulland, E.;
Monneret, C.; Florent, J. C. Tetrahedron Lett. 2003, 44, 2579.
6. (a) Morrow, J. D.; Awad, J. A.; Boss, H. J.; Blair, A.; Roberts,
L. J. Proc. Natl. Acad. Sci. 1992, 89, 10271–10725. (b) Jung,
M. E.; Kers, A.; Subbanagounder, G.; Berliner, J. A. J. Chem.
Soc., Chem. Commun. 2003, 196–197.
and the Ministry of Science and Technology and NIBGE,
´ ˆ
Pakistan for a PhD scholarship award (M. I.). Drs. Jerome
Dauvergne, Paul Evans and Alan Happe are thanked for
helpful advice and discussions.
References and notes
7. (a) Suzuki, M.; Kawagishi, T.; Yanagisawa, A.; Susuki, T.;
Okamura, N.; Noyori, R. Bull. Chem. Soc. Jpn 1988, 61,
1299–1312. (b) Wiel, J.-P.; Roussac, F. J. Chem. Soc., Chem.
Commun. 1976, 446–447.
1. (a) Straus, D. S.; Glass, C. K. Med. Res. Rev. 2001, 21, 185. (b)
Roberts, S. M.; Santoro, M. G.; Sickle, E. S. J. Chem. Soc.,
Perkin Trans. 1 2002, 1735.
2. (a) Kikuchi, H.; Tsukitani, Y.; Iguchi, K.; Yamada, Y.
Tetrahedron Lett. 1983, 24, 1549. (b) Nagaoka, H.; Iguchi,
K.; Miyakoshi, T.; Yamada, N.; Yamada, Y. Tetrahedron Lett.
1986, 27, 223.
8. Suzuki, M.; Kawagishi, T.; Noyori, R. Tetrahedron Lett. 1981,
22, 1809.
9. Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41,
2165–2169.
3. Fitzpatrick, F. A.; Wynalda, M. A. J. Biol. Chem. 1983, 258,
11713.
10. Klunder, A. J. H.; Zhu, J.; Zwanenburg, B. Chem. Rev. 1999,
99, 1163–1190.
4. (a) Bohlmann, F.; Borthakur, N.; King, R. M.; Robinson, H.
Phytochemistry 1982, 21, 125. (b) Bohlmann, F.; Singh, P.;
Jakupovic, J.; King, R. M.; Robinson, H. Phytochemistry
1982, 21, 371. (c) Kru¨ger, G.; Harde, C.; Bohlmann, F.
Tetrahedron Lett. 1985, 26, 6027. (d) Liu, Z. Y.; Dong, H.;
Chu, X. J. Tetrahedron 1994, 50, 12337. (e) Liu, Z. Y.; Chu,
X.-J. Tetrahedron Lett. 1993, 34, 3885.
11. Wiel, J.-P.; Roussac, F. J. Chem. Soc., Chem. Commun. 1976,
446–447.
12. (a) Iqbal, M.; Evans, P. Tetrahedron Lett. 2003, 44,
5741–5745. (b) Iqbal, M.; Li, Y.; Evans, P. Tetrahedron
2004, 60, 2531–2538.
13. Takano, S.; Inomata, K.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1989, 271.
5. (a) Fukushima, S.; Takeuchi, Y.; Kishimoto, S.; Yamashita,
S.; Uetsuki, K.; Shirakawa, S.; Suzuki, M.; Furuta, K.; Noyori,