Vinylogous anionic processes in the formation and interconversion of tetracyclic ring systems

Article abstract of DOI:10.1039/c0ob01152e

Tandem oxy-Cope and transannular vinylogous aldol reactions and/or vinylogous retro-aldol, conjugate addition, and transannular vinylogous aldol reactions transformed some tricyclic vinyl enones into fused tetracycles under basic conditions. Mesylates der

Full text of DOI:10.1039/c0ob01152e

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PAPER
Vinylogous anionic processes in the formation and interconversion of
tetracyclic ring systems†
Paul D. Thornton, T. Stanley Cameron and D. Jean Burnell*
Received 10th December 2010, Accepted 21st February 2011
DOI: 10.1039/c0ob01152e
Tandem oxy-Cope and transannular vinylogous aldol reactions and/or vinylogous retro-aldol,
conjugate addition, and transannular vinylogous aldol reactions transformed some tricyclic vinyl
enones into fused tetracycles under basic conditions. Mesylates derived from similar tetracyclic
products underwent efficient skeletal reorganization via transannular ring-opening but then different
modes of transannular ring-closure upon treatment with tert-butoxide.
instances in which the introduction of another, conjugating double
bond has enhanced anionic oxy-Cope reactivity.2
Introduction
In the course of the preparation of the ring-system of the
aquariolide diterpenes, a Pauson–Khand reaction of 1 was carried
out with high diastereoselectivity to give 2 when trimethylamine
N-oxide (TMANO) was used as the promoter.1 Efforts to initiate
anionic oxy-Cope rearrangement of 2 to 3 with a variety of
bases produced, instead, tetracycle 4 in high yield along with a
small amount of the fenestrane 5 (Scheme 1). A concerted, [3.3]
sigmatropic process would require propinquity of the termini of
the two alkenes of 2, but the trans relationship of these alkenes on
the five-membered ring renders this geometry difficult. Reduction
of the ketone of 2 stopped the reaction, but would very likely not
have inhibited the sigmatropic process, although there are a few
The mechanism for the formation of 4 was suggested to be via
a step-wise process of vinylogous retro-aldol reaction, followed
by conjugate addition of intermediate 6 to give 3 as a transient
species, deprotonation once again and a transannular vinylogous
aldol cyclization via conjugated enolate 7 (Scheme 2). Vinylogous
retro-aldol ring-opening and then vinylogous aldol reclosure, but
involving a six-membered ring, has been shown by Gribble3 to
be the mechanism by which some chiral Robinson annulation
products racemize. While the conjugate addition to form a nine-
membered ring is very unusual, a related process was reported
by Swaminathan,4 who had observed the formation of an eight-
membered product 10 when the hydroxyketone 8 was treated with
base. The transformation was suggested to occur via conjugate
addition to a vinylogous retro-aldol product 9 (Scheme 3) and
double-bond isomerization.
Scheme 2 Suggested pathway for the formation of 4 from 2.
Scheme 1 Pauson–Khand cyclization of 1 and treatment of 2 with base.
Department of Chemistry, Dalhousie University, Halifax, Nova Scotia,
Canada, B3H 4J3. E-mail: jean.burnell@dal.ca; Fax: +1 902-494-1310;
Tel: +1 902 494-1664
† Electronic supplementary information (ESI) available: NMR spectra,
ORTEPs and CIFs for 18, 37 and 41. CCDC reference numbers 804296
(18), 804297 (37) and 804298 (41). For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0ob01152e
Scheme 3 Ring expansion of 8 to 10.4
In the case of the formation of 4 from 2, the rigidity of the
diquinane moiety reduces the number of degrees of freedom in
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the nine-membered chain. The complexity of this ring-closing
process suggested that modification of the structure of 2 might
easily draw the reaction pathway in a different direction. If,
however, the reaction pathway were not significantly altered, then
other tetracyclic systems with architectures related to 4 might be
accessed in a similar way. We present here evidence that a change
in the ring-size still allows this complex cyclization to proceed, and
we show that the ring systems of the tetracyclic products can be
reorganized in different ways by tandem anionic processes.
cyclization in the context of these sterically demanding substrates.
Furthermore, the yield of 17 was good in spite of reports of
Pauson–Khand cyclizations in which the tether forms a six-
membered ring having widely different yields.9 The vinyl alcohol
17 was now ready for the cyclization. Compound 17 was consumed
within two hours in methanolic KOH at room temperature, and
treatment of the product with HF gave a tetracyclic product 18
amenable to X-ray crystallographic analysis.
The larger ring in 17, relative to 2, appeared to have no effect
on the cyclization. However, unlike in 2, the alkene moieties in
17 are syn with respect to the five-membered ring, and so 17
will have a geometry that would easily allow a [3.3] sigmatropic
pathway to a nine-membered-ring intermediate. The likelihood of
the cyclization to 18 involving a concerted, anionic oxy-Cope re-
arrangement, instead of, or in addition to, a step-wise, vinylogous
retro-aldol and conjugate recyclization, was demonstrated in the
following way. Reduction of the ketone of 17 and protection of
the resulting alcohol gave 19, for which intramolecular carbonyl
chemistry would be obviated. Nevertheless, treatment of 19 at 0 ◦C
with base gave the nine-membered-ring product 20 (Scheme 5).
Results and discussion
Replacing the butenyl chain of the Pauson–Khand substrate 1
with a pentenyl chain should give a product with a spiroannulated
hydrindenone ring-system. The Weinreb amide 115 derived from
5-hexenoic acid was treated with TMS-acetylide to give the ynone
12 (Scheme 4). Geminal acylation6 of 12 with the four-membered
acyloin 13 provided the 1,3-diketone 14 in good yield. Reduction
of only one ketone with triethylsilane/BF3·Et2O was carried out
with a dr of over 20 : 1, and the monoalcohol was protected as
the silyl ether 15. The stereochemistry of reduction was consistent
with the reduction of an analogue1 and this was corroborated by
the X-ray structure of the final tetracyclic product (18). Addition
of vinylmagnesium bromide in the presence of CeCl37 gave a single
diastereomer, and the TMS group was removed from the alkyne
by basic methanolysis to provide 16. Pauson–Khand cyclization
of 16 took place in good yield when TMANO was employed
as the promoter.8 The crude product appeared to be a mixture
of diastereomers with a dr of 5 : 1. Nevertheless, the yield of
the major diastereomer 17 was somewhat higher than that of
2, which suggested that the greater conformational mobility of
the developing six-membered ring may allow for a more facile
Scheme 5 Anionic oxy-Cope rearrangement of 19.
A sterner test for the formation of a tetracycle would be to use
a substrate for which a larger, ten-membered ring would need to
close in the Michael addition step while disfavoring the formation
of the ten-membered ring intermediate by a sigmatropic process.
This required a spiroannulated six-membered ring and a trans
relationship between the alkene moieties. Attempts to carry out a
geminal acylation directly on an alkynyl ketone using the acyloin
21 led mainly to decomposition, but an acceptable yield of 24 was
obtained by carrying out the geminal acylation in two steps from
the ketal10 22 (Scheme 6).
The initial step, a Mukaiyama aldol reaction of 21 with 22, gave
the diastereomeric cyclopentanones 23 in remarkably high yield.
Then, 23 was treated with Amberlyst-1511 in refluxing benzene
to produce 24. This diketone was very sensitive to ring-opening;
exposure of 24 to silica gel led rapidly to ring-opened material,
of which the allene 33 was a major component. Therefore, 24
was used immediately without purification. Monoreduction with
triethylsilane and acid was not compatible with 24. Monoreduc-
tion with NaBH4 took place in excellent yield but with no facial
selectivity. LiAl(Ot-Bu)3H provided the epimers 25 and 26 with
some modest diastereoselectivity. The alcohol function of the
major isomer 25 was protected as its TBS ether 27. Reactions of 27
with vinylmagnesium bromide, with and without CeCl3, showed
Scheme 4 Synthesis of 17 and its cyclization to 18.
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The original cyclization of 2 had yielded a small amount of
an intriguing fenestrane 5. It was proposed that 5 arose from an
alternate transannular cyclization pathway from 3.1 It was obvious
that cyclization as shown with 7 was favoured over any other
cyclization because 4 was the predominant product. However, if
the transannular cyclization represented by 7 could be rendered
less favorable, and if the tetracyclic products 4, 18, and 32 could
be returned to nine- or ten-membered tricyclics by cleavage of the
central bond, then reclosure across the medium-sized ring could be
diverted towards compounds resembling 5. To this end, mesylates
were obtained from 4, 18, and 32.
Mesylate 36 derived from 4 was in hand,1 and the idea was that
a Grob fragmentation would rupture the central bond forming a
nine-membered intermediate in the presence of base. When 36 was
added to tert-butoxide the unsaturated fenestrane 37 was produced
very efficiently (Scheme 7). The structure of 37 was established
by X-ray crystallography. Transannular cyclization of enolate 39,
likely derived from 38, would have produced 37. Enolate 39 can
attain the geometry required for the transannular 1,4-reaction with
little strain.
Scheme 6 Synthesis of 30 and its cyclization.
no stereoselectivity, but the reaction with vinyllithium yielded 28
with very good facial discrimination. This product was consistent
with axial attack on the lowest-energy conformer of 27. After
removal of the TMS from the alkyne, 29 underwent Pauson–
Khand cyclization using the same conditions as before to give
stereoisomer 30 along with some of the minor epimer 31. In the
presence of methanolic KOH, the vinyl alcohol 30 was transformed
slowly into tetracycle 32. After 28 h at room temperature the
yield of 32 was only 53%, and there was a significant amount
of decomposition. The poorer yield was consistent with the
removal of a [3.3] sigmatropic pathway for the opening the six-
membered ring as well as the added difficulty of closure of a
ten-membered ring via a Michael addition. In order to rule out
the Cope rearrangement, 30 and 31 were reduced and protected
to give 34 and 35,12 respectively. In contrast with 19, neither 34
nor 35 underwent Cope rearrangement under basic conditions.
Compounds 34 and 35, just like 2, have their alkene moieties trans
with respect to the ring that will undergo opening, and therefore
these compounds would require considerable energy to overcome
the strain required to attain a geometry in which a concerted Cope
process could occur.
Scheme 7 Proposed base-mediated elimination and skeletal reorganiza-
tion of mesylate 36.
The mesylate derived from tetracycle 32 gave intractable ma-
terial under the same basic conditions. Given the fate of the
mesylate from 32, mesylate 40, prepared from 18, was treated
with base for a shorter period of time (Scheme 8). Instead of
producing a fenestrane, 40 yielded the tetracycle 41 along with a
byproduct that appeared to be epimeric with 41 a to the carbonyl,
in a ratio of 3 : 1. Although the yield of 41 plus the byproduct
was only 51%, 40% of the starting mesylate 40 was recovered.
The byproduct was inseparable from 41 by flash chromatography,
but crystallization provided a few crystals of 41, from which the
structure was elucidated by X-ray crystallography. The skeleton of
41 is the core of the sesterterpene bolivianine.13
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spectra were recorded with an FT instrument using CsI plates. 1H
NMR spectra were acquired at 500 MHz and 13C NMR spectra at
125 MHz as CDCl3 solutions unless otherwise noted. 13C NMR
chemical shifts are often followed by the number of attached
hydrogens (DEPT) in parentheses.
N-Methoxy-N-methyl-5-hexenamide (11)
After the procedure of Snapper et al.,5 1,1-carbonyldiimidazole
(CDI) (0.850 g, 5.24 mmol) was added to a solution of 5-
hexenoic acid (0.500 g, 4.37 mmol) in CH2Cl2 (22 mL) at
0
◦C. The mixture was stirred at this temperature for 1 h.
N,O-Dimethylhydroxylamine hydrochloride was added, and the
mixture was stirred at rt for 4 h. The suspension was filtered
through a plug of cotton to remove the precipitate, and the cotton
plug was rinsed twice with CH2Cl2. The filtrate was washed with
1 M aqueous HCl and brine and was then dried over MgSO4.
Evaporation of the solvent gave 11 (0.538 g, 78%): IR (neat) 3077
Scheme 8 Base-mediated elimination and skeletal reorganization of
mesylate 40.
1
(w), 2937 (s), 1667 (s) cm-1; H NMR d 5.81 (1H, ddt, J = 17.0,
The relative stereochemistry of the alcohol and the mesylate
in 40 was not suited to the Grob fragmentation, unlike in 36
where these groups were antiperiplanar.14 Nevertheless, ejection
of the mesylate from the enolate 42, which would have arisen
from the vinylogous retro-aldol of 40, would have led to the nine-
membered diketone. (Indeed, a similar mechanism might have
operated in the conversion of 36 to 38.) In the basic medium this
diketone could have enolized and undergone a transannular 1,4-
reaction with little strain in the same way as was seen for 39,
but a fenestrane was not isolated. Instead, the product 41 must
have arisen via the 1,6-transannular reaction of enolate 43. It is
remarkable that the small difference in geometry and the minor
increase in flexibility imparted by the six-membered ring in 40,
relative to the five-membered ring in 39, must have been sufficient
to favor the formation of tetracycle 41 through a geometrically
more difficult transannular 1,6-reaction.
10.2, 6.6 Hz), 5.03 (1H, d, J = 17.0 Hz), 4.98 (1H, d, J = 10.2 Hz),
3.68 (3H, s), 3.18 (3H, s), 2.43 (2H, t, J = 7.6 Hz), 2.11 (2H, q, J =
7.6 Hz), 1.74 (2H, pentet, J = 7.6 Hz); 13C NMR d 174.8 (0), 138.4
(1), 115.3 (2), 61.4 (3), 33.6 (2), 32.5 (3), 31.4 (2), 29.7 (2); HRMS
(ESI TOF) m/z 180.1002, [C8H15NO2 +Na]+ requires 180.0995.
1-(Trimethylsilyl)oct-7-en-1-yn-3-one (12)
A 1.5 M solution of n-BuLi in hexane (9.8 mL, 15 mmol) was added
to a solution of ethynyltrimethylsilane (1.45 g, 14.8 mmol) in THF
(45 mL) at -78 ◦C. The solution was stirred at this temperature for
30 min. A solution of 11 (1.55 g, 9.86 mmol) in THF (15 mL) was
added dropwise over 5 min. The solution was stirred at -78 ◦C for
1 h after which time TLC analysis indicated that none of the amide
remained. The mixture was warmed to rt. Saturated aqueous
NH4Cl was added, and the solution became yellow. The mixture
was extracted thoroughly with Et2O. The combined organic layers
were washed with brine and dried over Na2SO4. Removal of the
solvent under vacuum left a residue that was purified by flash
chromatography (5% EtOAc/hexanes) to give 12 (1.73 g, 91%):
1H NMR d 5.77 (1H, ddt, J = 16.9, 10.3, 6.8 Hz), 5.03 (1H, dq,
J = 16.9, 1.6 Hz), 5.00 (1H, m), 2.57 (2H, t, J = 7.4 Hz), 2.09 (2H,
Conclusions
A number of tetracyclic systems have been accessed from spiro-
cyclic precursors resembling 1. Successful Pauson–Khand cycliza-
tions were followed by the transformation of the tricyclic products
into tetracyclic compounds under basic conditions. Two pathways
were available to the tetracycles, either an anionic oxy-Cope reac-
tion followed by a transannular conjugate addition or a vinylogous
retro-aldol, an extraordinary conjugate addition to form a nine- or
a ten-membered intermediate, and transannular vinylogous aldol
cyclization. Conversion of 4 and 18 to the mesylates 36 and 40
allowed the reopening of their central carbon–carbon bonds under
basic conditions and then reclosure of central bonds via different
modes of transannular aldol reaction to give different ring systems.
These findings offer potential for synthetic exploitation in the
construction and rearrangement of polycyclic systems.
qt, J = 6.8, 1.3 Hz), 1.76 (2H, pentet, J = 7.4 Hz), 0.24 (9H, s); 13
C
NMR d 187.9 (0), 137.7 (1), 115.6 (2), 102.2 (0), 97.8 (0), 44.6 (2),
33.0 (2), 23.1 (2), -0.6 (3C, 3); HRMS (ESI TOF) m/z 195.1203,
[C11H19OSi]+ requires 195.1200.
2-(Pent-4-enyl)-2-(2-(trimethylsilyl)ethynyl)cyclopentane-1,3-
dione (14)
BF3·OEt2 (1.65 mL, 13.1 mmol) was added to a solution of 12
◦
(1.70 g, 8.76 mmol) in CH2Cl2 (67 mL) at -78 C. The solution
became yellow and was stirred at this temperature for 15 min. Neat
◦
acyloin 1315 (2.42 g, 10.5 mmol) was added dropwise at -78 C,
and the mixture was stirred for 1 h. The mixture was warmed to
0 C and was treated sequentially with H2O (1.6 mL, 89 mmol)
Experimental
◦
Reactions were conducted under inert atmosphere (dry N2).
Dichloromethane was distilled from calcium hydride. Ethyl acetate
and hexanes were distilled. Flash chromatography employed silica
gel (40–63 mm particle size, 230–240 mesh). Melting points were
acquired using a Fisher–Johns apparatus and are uncorrected. IR
and BF3·OEt2 (11 mL, 88 mmol). The mixture was allowed to
warm to rt. After 30 min TLC revealed that rearrangement
was complete. The solution was poured into saturated aqueous
NaHCO3. The aqueous layer was extracted thoroughly with
CH2Cl2. The combined organic layers were washed with brine and
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dried over MgSO4. Removal of the solvent under reduced pressure
followed by flash chromatography (10% EtOAc/hexanes) gave 14
(1.78 g, 78%): mp 57–58 ◦C; IR (neat) 3078 (m), 2958 (s), 2173
(m), 1732 (s), 1641 (m) cm-1; 1H NMR d 5.74 (1H, ddt, J = 17.0,
10.3, 6.7 Hz), 5.00 (1H, br d, J = 17.0 Hz), 4.96 (1H, m), 2.99 (2H,
m), 2.74 (2H, m), 2.04 (2H, br q, J = 7.3 Hz), 1.80 (2H, m), 1.48
(2H, qt, J = 7.5, 4.6 Hz), 0.15 (9H, s); 13C NMR d 207.8 (2C, 0),
137.8 (1), 115.4 (2), 98.1 (0), 92.0 (0), 56.9 (0), 35.2 (2C, 2), 33.6 (2),
33.4 (2), 23.7 (2), -0.1 (3C, 3); HRMS (ESI TOF) m/z 285.1270,
[C15H22O2Si + Na]+ requires 285.1281.
4.50 mmol) in THF (10 mL) at -78 ◦C. The mixture was stirred at
this temperature for 2 h. A solution of 15 (0.850 g, 2.25 mmol) in
THF (5.0 mL) was added, and the mixture was stirred at -78 ◦C
for 1 h. After this time, TLC analysis indicated that no starting
material remained. The mixture was warmed to rt, and the
reaction was quenched with 5% aqueous citric acid. The mixture
was extracted thoroughly with Et2O. The combined organic
layers were washed with brine and dried over Na2SO4. The
solvent was evaporated, and the residue was purified using flash
chromatography (2% EtOAc/hexanes) to give (1R*,2S*,3R*)-3-
(tert-butyldimethylsilyl)oxy-2-((trimethylsilyl)ethynyl)-2-(pent-4-
enyl)-1-vinylcyclopentan-1-ol (15a) (0.816 g, 89%): IR (neat) 3504
(2R*,3S*)-3-(tert-Butyldimethylsilyl)oxy-2-(pent-4-enyl)-2-
((trimethylsilyl)ethynyl)cyclopentanone (15)
1
(br), 3077 (m), 2956 (s), 2161 (s), 1641 (s) cm-1; H NMR d 6.14
(1H, ddd, J = 17.3, 10.9, 1.6 Hz), 5.82 (1H, ddt, J = 17.1, 10.3,
6.8 Hz), 5.40 (1H, dd, J = 17.3, 2.1 Hz), 5.17 (1H, dd, J = 10.9,
2.1 Hz), 5.00 (1H, dd, J = 17.1, 1.7 Hz), 4.93 (1H, dd, J = 10.3,
1.2 Hz), 4.26 (1H, d, J = 4.8 Hz), 4.09 (1H, d, J = 1.3 Hz, OH),
2.40–2.28 (2H, m), 2.06 (2H, m), 1.92 (1H, m), 1.78 (1H, m), 1.70
(2H, m), 1.46–1.31 (2H, m), 0.90 (9H, s), 0.14 (9H, s), 0.13 (3H,
s), 0.11 (3H, s); 13C NMR d 140.5 (1), 139.1 (1), 114.5 (2), 114.2
(2), 108.4 (0), 90.3 (0), 85.3 (0), 80.9 (1), 56.1 (0), 38.8 (2), 34.6 (2),
32.4 (2), 27.3 (2), 26.0 (3C, 3), 25.2 (2), 18.0 (0), 0.2 (3C, 3), -4.2
(3), -5.0 (3); HRMS (ESI TOF) m/z 429.2607, [C23H42O2Si2 +
Na]+ requires 429.2616.
Triethylsilane (1.05 mL, 6.56 mmol) was added to a solution of 14
(1.50 g, 5.73 mmol) in CH2Cl2 (60 mL) at rt. BF3·OEt2 (0.82 mL,
6.54 mmol) was added, and the solution became bright yellow.
The mixture was stirred for 16 h after which time TLC analysis
indicated that some of the starting material still remained. Addi-
tional amounts of triethylsilane (0.20 mL, 1.3 mmol) and BF3·OEt2
(0.16 mL, 1.3 mmol) were added, and the solution was stirred for
4 h. The mixture was poured into saturated aqueous NaHCO3. The
mixture was extracted thoroughly with CH2Cl2. The combined
organic layers were washed with brine and dried over Na2SO4.
Evaporation of the solvent gave a residue that was purified using
flash chromatography (CH2Cl2) to provide (2R*,3S*)-3-hydroxy-
2-(pent-4-enyl)-2-(2-(trimethylsilyl)ethynyl)cyclopentanone (14a)
(1.21 g, 80%): IR (neat) 3463 (br m), 3077 (w), 2958 (s), 2161
(m), 1743 (s), 1641 (w) cm-1; 1H NMR d 5.83 (1H, ddt, J = 17.0,
10.2, 6.7 Hz), 5.04 (1H, br d, J = 17.0 Hz), 4.98 (1H, br d, J =
10.2 Hz), 4.41 (1H, narrow m), 2.51–2.39 (4H, m), 2.13 (2H, m),
1.97 (1H, m), 1.81–1.70 (2H, m), 1.58 (1H, m), 1.48 (1H, m), 0.14
(9H, s); 13C NMR d 212.7 (0), 138.7 (1), 115.1 (2), 102.9 (0), 91.1
(0), 76.1 (1), 55.5 (0), 34.0 (2), 33.4 (2), 28.4 (2), 28.3 (2), 24.4 (2),
0.1 (3C, 3); HRMS (ESI TOF) m/z 287.1442, [C15H24O2Si + Na]+
requires 287.1438.
Triethylamine (0.69 mL, 5.0 mmol) was added to a solution
of 14a (1.05 g, 3.98 mmol) in THF (40 mL) at 0 ◦C. TBSOTf
(1.04 mL, 4.54 mmol) was added, and the mixture was stirred
for 1 h. The reaction was quenched by the addition of saturated
aqueous NaHCO3, and the layers were separated. The aqueous
layer was extracted thoroughly with Et2O. The combined organic
layers were washed with brine and dried over Na2SO4. Removal of
the solvent under vacuum followed by flash chromatography (3%
EtOAc/hexanes) of the residue gave 15 (1.44 g, 95%): IR (neat)
3078 (m), 2955 (s), 2162 (s), 1756 (s), 1641 (m) cm-1; 1H NMR d
5.82 (1H, ddt, J = 17.1, 10.0, 6.9 Hz), 5.01 (1H, br d, J = 17.1 Hz),
4.94 (1H, br d, J = 10.0 Hz), 4.34 (1H, narrow m), 2.47–2.31 (3H,
m), 2.08 (2H, m), 1.89 (1H, m), 1.76–1.63 (2H, m), 1.58 (1H, m),
1.43 (1H, m), 0.86 (9H, s), 0.13 (9H, s), 0.10 (3H, s), 0.09 (3H, s);
13C NMR d 213.1 (0), 138.8 (1), 114.8 (2), 103.5 (0), 90.8 (0), 76.9
(1), 56.1 (0), 34.3 (2), 33.5 (2), 29.1 (2), 28.7 (2), 25.9 (3C, 3), 24.4
(2), 18.2 (0), 0.2 (3C, 3), -4.2 (3), -4.7 (3); HRMS (ESI TOF) m/z
401.2287, [C21H38O2Si2 + Na]+ requires 401.2303.
Anhydrous K2CO3 (0.380 g, 2.56 mmol) was added to a
◦
solution of 15a (0.800 g, 1.97 mmol) in MeOH (17 mL) at 0 C.
The mixture was allowed to warm to rt and stirred for 18 h.
The mixture was then diluted with water, and the MeOH was
removed under reduced pressure. The resulting suspension was
extracted thoroughly with Et2O. The combined organic layers
were washed with brine and then dried over Na2SO4. Removal
of the solvent under vacuum followed by flash chromatography
(2% EtOAc/hexanes) gave 16 (0.641 g, 97%): IR (neat) 3504 (br),
3308 (m), 3076 (m), 2932 (s), 2860 (m), 2106 (w), 1641 (m) cm-1;
1H NMR d 6.15 (1H, ddd, J = 17.2, 10.7, 1.8 Hz), 5.82 (1H, ddt,
J = 17.1, 10.3, 6.8 Hz), 5.41 (1H, dd, J = 17.2, 2.1 Hz), 5.18 (1H,
dd, J = 10.7, 2.1 Hz), 5.00 (1H, br d, J = 17.1 Hz), 4.93 (1H, d,
J = 10.3 Hz), 4.30 (1H, d, J = 4.9 Hz), 4.05 (1H, d, J = 1.8 Hz,
OH), 2.42–2.29 (2H, m), 2.22 (1H, s), 2.06 (2H, m), 1.95 (1H, m),
1.81 (1H, m), 1.73 (2H, m), 1.49–1.33 (2H, m), 0.91 (9H, s), 0.13
(3H, s), 0.11 (3H, s); 13C NMR d 140.2 (1), 138.9 (1), 114.6 (2),
114.5 (2), 85.8 (0), 85.1 (1), 80.8 (1), 73.7 (0), 55.1 (0), 38.7 (2), 34.6
(2), 32.2 (2), 27.4 (2), 25.9 (3C, 3), 25.1 (2), 18.0 (0), -4.2 (3), -5.0
(3); HRMS (ESI TOF) m/z 357.2197, [C20H34O2Si + Na]+ requires
357.2220.
(1R*,2R*,7a¢R*,5R*)-5-(tert-Butyldimethylsilyl)oxy-5¢,6¢,7¢,7a¢-
tetrahydro-2-hydroxy-2-vinylspiro[cyclopentane-1,4¢-inden]-
2¢(1¢H)-one (17)
Dicobalt octacarbonyl (0.350 g, 1.02 mmol) was added to a
solution of alcohol 16 (0.308 g, 0.922 mmol) in CH2Cl2 (4.0 mL).
The resulting red solution was stirred at rt for 18 h, after
which time TLC analysis indicated that none of the starting
material remained. The mixture was diluted with CH2Cl2 (60 mL)
and treated with a solution of anhydrous TMANO (0.575 g,
7.65 mmol) in CH2Cl2 (20 mL) at rt. The solution was stirred
for a further 16 h during which time a deep blue precipitate
formed. The mixture was filtered through a plug of silica gel
(1R*,2S*,3S*)-3-(tert-Butyldimethylsilyl)oxy-2-ethynyl-2-
(pent-4-enyl)-1-vinylcyclopentan-1-ol (16)
A 1.0 M solution of vinylmagnesium bromide in THF (4.5 mL,
4.5 mmol) was added to a suspension of anhydrous CeCl3 (1.11 g,
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(EtOAc eluent), and the solvent was removed under reduced
pressure. Flash chromatography (12% EtOAc/hexanes) of the
crude product gave 17 (0.232 g, 76%) and some material that
appeared to be epimeric at the bridgehead position (14%). For 17:
mp 114–116 ◦C; IR (neat) 3484 (br), 2951 (s), 2931 (s), 2858 (m),
(1R*,2R*,7a¢R*,5R*)-5-(tert-Butyldimethylsilyl)oxy-2-hydroxy-
2-vinyl-5¢,6¢,7¢,7a¢-tetrahydro-2¢-(methoxymethoxy)spiro[cyclo-
pentane-1,4¢-inden]-2¢-ol (19)
CeCl3·7H2O (128 mg, 0.344 mmol) was added to a solution of
17 (112 mg, 0.309 mmol) in MeOH (3.0 mL) at 0 ◦C. NaBH4
(12 mg, 0.32 mmol) was added, and the mixture was stirred
for 30 min. The reaction was quenched by the addition of
saturated aqueous NH4Cl, and the MeOH was then removed
under vacuum. The mixture was extracted thoroughly with Et2O.
The combined organic layers were washed with brine and dried
over Na2SO4. Evaporation of the solvent gave a solid residue that
was dissolved in CH2Cl2 (2.0 mL). N,N-Diisopropylethylamine
(0.60 mL, 0.35 mmol) and MOMCl (0.33 mL, 0.35 mmol) were
sequentially added at 0 ◦C. The mixture was allowed to warm
to rt and was stirred for 5 h. The reaction was quenched by the
addition of saturated aqueous NaHCO3, and the mixture was
extracted thoroughly with CH2Cl2. The combined organic layers
were washed with brine and then dried over Na2SO4. Removal
of the solvent under vacuum gave a residue that was purified
by flash chromatography (8% EtOAc/hexanes) to give the single
diastereomer 19 (90 mg, 72%): IR (neat) 3468 (br m), 3086 (w)
1
1714 (s), 1691 (s), 1597 (m) cm-1; H NMR d 6.07 (1H, dd, J =
17.6, 11.0 Hz), 6.00 (1H, d, J = 1.3 Hz), 5.48 (1H, dd, J = 17.6,
1.7 Hz), 5.26 (1H, dd, J = 11.0, 1.7 Hz), 4.45 (1H, s, OH), 4.39
(1H, d, J = 4.9 Hz), 2.81 (1H, m), 2.54 (1H, dd, J = 18.9, 6.6 Hz),
2.44 (1H, br d, J = 13.9 Hz), 2.37 (1H, ddd, J = 14.8, 12.0, 4.9 Hz),
2.25 (1H, ddd, J = 15.5, 9.9, 5.9 Hz), 2.13 (1H, m), 1.97 (1H, dd,
J = 18.9, 2.6 Hz), 1.94 (1H, m), 1.90–1.82 (2H, m), 1.53 (1H, qt,
J = 13.5, 3.5 Hz), 1.41 (1H, td, J = 13.9, 4.2 Hz), 1.15 (1H, qd,
J = 12.5, 3.7 Hz), 0.93 (9H, s), 0.16 (6H, s); 13C NMR d 208.6
(0), 181.6 (0), 138.2 (1), 131.0 (1), 117.1 (2), 84.5 (0), 79.1 (1), 60.8
(0), 41.7 (2), 41.5 (1), 37.1 (2), 34.3 (2), 31.7 (2), 25.9 (3C, 3), 25.6
(2), 22.7 (2), 18.1 (0), -4.1 (3), -4.9 (3); HRMS (ESI TOF) m/z
385.2162, [C21H34O3Si + Na]+ requires 385.2169.
(3aR*,7aR*,10S*,10aR*)-2,3,3a,4,6,7,7a,8,9,10-Decahydro-
7a,10-dihydroxycyclopenta[f ]acenaphthalen-5(1H)-one (18)
1
cm-1; H NMR d 6.23 (1H, dd, J = 17.2, 10.8 Hz), 5.51 (1H, s),
Compound 17 (120 mg, 0.33 mmol) was dissolved in MeOH
(3.0 mL) with KOH (25 mg, 0.45 mmol), and this was stirred for
2 h at rt at which time TLC indicated the complete disappearance
of 17. Saturated aqueous NH4Cl was added followed by water, and
the mixture was extracted thoroughly with Et2O. The combined
organic layers were washed with brine and then dried over Na2SO4.
Evaporation of the solvent gave a residue (94 mg) that was added to
HF·pyridine (0.4 mL) in CH2Cl2 (2.5 mL) at 0 ◦C. The mixture was
stirred for 1 h, after which time TLC analysis indicated that none
of the starting material remained. The mixture was poured into
cold saturated aqueous NaHCO3, which was extracted thoroughly
with a 1 : 1 CHCl3/CH2Cl2 solution. The combined organic layers
were washed with brine and then dried over Na2SO4. Removal of
the solvent in vacuo gave 18 (68 mg, 83%): mp 122–124 ◦C; IR
5.44 (1H, dd, J = 17.2, 2.0 Hz), 5.20 (1H, dd, J = 10.8, 1.8 Hz),
4.69 (1H, d, J = 6.8 Hz) 4.66 (1H, d, J = 6.8 Hz), 4.57 (1H, m),
4.42 (1H, s, OH), 4.22 (1H, d, J = 5.0 Hz), 3.37 (3H, s), 2.49–2.36
(3H, m), 2.25 (1H, br d, J = 13.8 Hz), 2.19 (1H, ddd, J = 15.6,
10.0, 6.0 Hz), 2.00 (1H, m), 1.92 (1H, m), 1.80–1.71 (2H, m), 1.40
(1H, qt, J = 13.4, 3.2 Hz), 1.33–1.27 (2H, m), 1.07 (1H, dt, J =
12.6, 3.2 Hz), 0.91 (9H, s), 0.13 (3H, s), 0.12 (3H, s); 13C NMR
d 147.9 (0), 139.3 (1), 128.0 (1), 115.6 (2), 96.3 (2), 84.9 (0), 83.2
(1), 79.1 (1), 58.8 (0), 55.5 (3), 43.6 (1), 38.3 (2), 38.2 (2), 35.1 (2),
31.6 (2), 25.9 (3C, 3), 25.2 (2), 23.2 (2), 18.1 (0), -4.1 (3), -4.9
(3); HRMS (ESI TOF) m/z 431.2595, [C23H40O4Si + Na]+requires
431.2588.
1
(neat) 3404 (br), 2929 (s), 2858 (m), 1686 (s), 1638 (s) cm-1; H
(1R*,2aS*,6R*,11aS*)-6-(tert-Butyldimethylsilyl)oxy-
2a,3,4,5,6,7,8,10,11,11a-decahydro-1-(methoxymethoxy)-1H-
cyclonona[cd]inden-9(2H)-one (20)
NMR d 4.43 (1H, narrow m), 2.70 (1H, narrow m), 2.58 (1H, m),
2.51 (1H, m, OH), 2.37 (2H, narrow m), 2.29 (1H, narrow m),
2.15–1.93 (4H, m), 1.86 (3H, narrow m), 1.80–1.62 (2H, m), 1.54
(1H, m), 1.24 (1H, m), 1.04 (1H, qd, J = 12.8, 4.2 Hz); 13C NMR
d 207.2 (0), 179.7 (0), 136.2 (0), 82.2 (0), 76.3 (1), 56.1 (0), 42.4 (2),
37.3 (2), 37.0 (1), 35.8 (2), 32.2 (2), 30.2 (2), 28.7 (2), 22.7 (2), 18.1
(2); HRMS (ESI TOF) m/z 271.1314, [C15H20O3 + Na]+ requires
271.1305.
18-Crown-6 (50 mg, 0.19 mmol) was added to a solution of
19 (69 mg, 0.17 mmol) in THF (1.5 mL) at 0 ◦C. KH (9 mg,
0.2 mmol) was added and the mixture was stirred for 20 min.
The reaction was quenched by the addition of saturated aqueous
NH4Cl, and the mixture was then extracted thoroughly with
CH2Cl2. The combined organic layers were washed with brine and
then dried over MgSO4. The solvent was removed under reduced
pressure, and the residue was purified by flash chromatography
(8% EtOAc/hexanes) to give 20 (54 mg, 78%): IR (neat) 1700 (s)
cm-1; 1H NMR d 4.72 (1H, d, J = 6.5 Hz), 4.68 (1H, d, J = 6.5 Hz),
4.40 (1H, dd, J = 11.5, 3.0 Hz), 4.03 (1H, ddd, J = 11.5, 8.6,
6.0 Hz), 3.39 (3H, s), 2.93 (1H, m), 2.68 (1H, td, J = 12.1, 5.3 Hz),
2.37–2.01 (9H, m), 1.90 (1H, m), 1.81–1.73 (3H, m), 1.42 (1H, m),
1.31 (1H, q, J = 11.5 Hz), 1.18 (1H, qd, J = 12.0, 3.0 Hz), 0.86
(9H, s), 0.02 (3H, s), -0.03 (3H, s); 13C NMR d 214.0 (0), 139.5
(0), 133.8 (0), 96.1 (2), 78.6 (1), 72.2 (1), 55.7 (3), 45.0 (2), 41.2 (1),
38.9 (1), 38.2 (2), 35.6 (2), 32.5 (2), 27.0 (2), 26.0 (3C, 3), 24.9 (2),
22.6 (2), 20.9 (2), 18.3 (0), -4.5 (3), -4.9 (3); HRMS (ESI TOF)
m/z 431.2591, [C23H40O4Si + Na]+ requires 431.2588.
X-Ray crystal structure determination for 18
Measurements were made on a Rigaku RAXIS RAPID imag-
ing plate area detector with graphite monochromated Mo-Ka
˚
radiation (l = 0.71070 A). The crystal was a colourless plate of
dimensions 0.23 ¥ 0.22 ¥ 0.06 mm, formula C15H20O3, M = 248.32,
˚
˚
˚
monoclinic, a = 11.2484(9) A, b = 8.5765(5) A, c = 12.9938(9) A,
◦
◦
◦
3
˚
a = 90.00 , b = 105.921(3) , g = 90.00 , V = 1205.45(15) A ,
P21/c (#14), Z = 4, F(000) = 536, T = 120.1 K, m(Mo-Ka)
0.094 mm-1, 2825 observed reflections (I > 3.00s(I)) and 183
variable parameters; R(Fo) = 0.0364, wR2(F2) = 0.0452, goodness
of fit = 1.014.
3452 | Org. Biomol. Chem., 2011, 9, 3447–3456
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3,3-Dimethoxy-1-(trimethylsilyl)hept-6-en-1-yne (22)
at -78 ◦C. When TLC analysis indicated that none of the starting
material remained (less than 10 min), the mixture was warmed
rapidly to 0 C, and saturated aqueous NH4Cl was added. After
Trimethyl orthoformate (20 mL) was added to a solution of 1-
(trimethylsilyl)hept-6-en-1-yn-3-one (4.65 g, 25.8 mmol) in MeOH
(20 mL) at rt. p-TsOH hydrate (0.05 g, 0.3 mmol) was added, and
the mixture was stirred for 20 h. The reaction was quenched by
the addition of saturated aqueous NaHCO3, and the bulk of the
organic solvent was removed under reduced pressure. The mixture
was then extracted thoroughly with CH2Cl2. The combined
organic layers were washed with brine and then dried over Na2SO4.
Evaporation of the solvent gave an oil that was purified by passage
through a plug of silica gel (5% EtOAc/hexanes) to give 22 (5.53 g,
95%): IR (neat) 3081 (w), 2961 (s), 2153 (w) cm-1; 1H NMR d 5.87
(1H, ddt, J = 10.2, 16.7, 5.5 Hz), 5.05 (1H, dq, J = 16.7, 1.7 Hz),
4.97 (1H, dq, J = 10.2, 1.7 Hz), 3.31 (6H, s), 2.24 (2H, m), 1.87
(2H, m), 0.20 (9H, s); 13C NMR d 138.2 (1), 114.7 (2), 101.4 (0),
99.2 (0), 90.8 (0), 50.2 (2C, 3), 36.5 (2), 28.8 (2), 0.0 (3C, 3); HRMS
(ESI TOF) m/z 249.1279, [C12H22O2Si + Na]+ requires 249.1281.
◦
addition of more water, the mixture was extracted thoroughly
with EtOAc/Et2O. The organic layers were combined and washed
with brine and then dried over Na2SO4. Removal of the solvent
under reduced pressure gave 1.92 g (87%) of a 2 : 1 mixture of
25 (major) and 26 (minor). Repeated flash chromatography (60%
CH2Cl2/hexanes) separated these epimers. For 25: mp 45–46 ◦C;
IR (neat) 3506 (br s), 3075 (m), 2956 (s), 2162 (m), 1708 (s), 1640
(m) cm-1; 1H NMR d 5.86 (1H, ddt, J = 10.2, 17.1, 6.7 Hz), 5.05
(1H, dq, J = 17.1, 1.8 Hz), 4.96 (1H, d, J = 10.2 Hz), 3.56 (1H, td,
J = 9.0, 4.6 Hz), 2.83 (1H, ddd, J = 13.3, 12.0, 6.0 Hz), 2.28 (1H,
dt, J = 13.3, 4.9 Hz), 2.22–2.14 (3H, m), 2.15 (1H, d, J = 9.0 Hz,
OH), 2.09–1.98 (3H, m), 1.88 (1H, m), 1.50 (1H, m), 0.20 (9H, s);
13C NMR d 206.2 (0), 138.7 (1), 114.8 (2), 103.4 (0), 94.1 (0), 76.2
(1), 59.9 (0), 37.9 (2), 32.0 (2), 30.7 (2), 29.9 (2), 20.9 (2), 0.2 (3C,
3); HRMS (ESI TOF) m/z 287.1438, [C15H24O2Si + Na]+ requires
287.1438.
2-(But-3-enyl)-2-((trimethylsilyl)ethynyl)cyclohexane-1,3-dione
(24)
For 26: IR (neat) 3441 (br s), 3076 (m), 2959 (s), 2161 (m),
1
1722 (s), 1641 (m) cm-1; H NMR d 5.89 (1H, ddt, J = 16.9,
10.2, 6.6 Hz), 5.08 (1H, dq, J = 16.9, 1.7 Hz), 4.98 (1H, d, J =
10.2 Hz), 4.20 (1H, br s, OH), 3.00 (1H, td, J = 12.8, 6.2 Hz),
2.44 (1H, m), 2.31–2.11 (3H, m), 2.05 (1H, m), 1.97 (1H, m),
1.87 (2H, m), 1.70–1.62 (2H, m), 0.17 (9H, s); 13C NMR d
207.5 (0), 138.8 (1), 114.9 (2), 105.2 (0), 92.3 (0), 76.5 (1), 55.9
(0), 38.4 (2), 30.3 (2), 29.2 (2), 28.9 (2), 21.6 (2), 0.2 (3C, 3);
HRMS (ESI TOF) m/z 287.1442, [C15H24O2Si + Na]+ requires
287.1438.
BF3·OEt2 (22.1 mL, 0.179 mol) was added to a solution of 22
(20.00 g, 0.0885 mol) and 2110b,15 (25.55 g, 0.105 mol) in CH2Cl2
(580 mL) at -78 ◦C. The solution became dark. The mixture was
stirred at this temperature for 3 h, and then it was warmed to rt. The
reaction was quenched with saturated aqueous NaHCO3. The so-
lution became pale yellow. The mixture was extracted thoroughly
with CH2Cl2. The combined organic layers were washed with brine
and then dried over Na2SO4. The solvent was removed under
reduced pressure, and the residue was eluted through a plug of
silica (10% EtOAc/hexanes) to give an inseparable diastereomeric
mixture 23 (31.19 g, 96%). A portion of this mixture (6.00 g,
16.4 mmol) was dissolved in benzene (340 mL) and Amberlyst-15
(3.00 g) was added. The vessel was fitted with a Dean–Stark appa-
ratus and reflux condenser, and the mixture was heated at reflux for
16 h. The mixture was cooled and filtered through sintered glass.
The filtrate was washed with saturated aqueous NaHCO3, and this
aqueous solution was back-extracted thoroughly with EtOAc. The
combined organic solutions were washed with brine and then dried
over Na2SO4. Evaporation of the solvent gave crude 24 (3.68 g,
85% mass recovery) as a yellow oil that largely decomposed upon
chromatography. (The crude product was used directly for the
preparation of 25 and 26.) Chromatography resulted in greatly
reduced yields (< 20%) but did provide 24 as a colourless solid:
mp: 32–35 ◦C; IR (neat) 2954 (s), 1711 (s) cm-1; 1H NMR d 5.86
(1H, ddt, J = 17.1, 10.2, 6.6 Hz), 5.05 (1H, ddd, J = 17.1, 3.5,
1.7 Hz), 4.96 (1H, ddd, J = 10.2, 3.5, 1.0 Hz), 3.27 (2H, dt, J =
15.0, 11.9 Hz), 2.52 (2H, dt, J = 15.0, 4.7 Hz), 2.21 (1H, m), 2.16
(2H, m), 1.97 (2H, m), 1.61 (1H, m), 0.17 (9H, s); 13C NMR d
201.7 (2C, 0), 138.5 (1), 114.7 (2), 101.3 (0), 94.1 (0), 67.2 (0), 37.6
(2C, 2), 29.4 (2), 28.8 (2), 18.0 (2), -0.2 (3C, 3); HRMS (EI) m/z
262.1399, [C15H22O2Si]+ requires 262.1389.
(2R*,3R*)-2-(But-3-enyl)-3-(tert-butyldimethylsilyl)oxy-2-
((trimethylsilyl)ethynyl)cyclohexanone (27)
Triethylamine (1.60 mL, 11.4 mmol) was added to a solution
of 25 (2.06 g, 7.78 mmol) in THF (75 mL) at 0 ◦C. TBSOTf
(1.9 mL, 8.4 mmol) was added and the solution was stirred for
1 h. The reaction was quenched by the addition of saturated
aqueous NaHCO3, and the mixture was extracted thoroughly with
CH2Cl2. The combined organic layers were washed with brine
and then dried over MgSO4. Evaporation of the solvent and flash
chromatography (5% EtOAc/hexanes) gave 27 (2.88 g, 98%): IR
1
(neat) 3078 (m), 2957 (s), 2160 (m), 1729 (s), 1641 (m) cm-1; H
NMR d 5.85 (1H, ddt, J = 17.0, 10.2, 6.3 Hz), 5.02 (1H, ddd, J =
17.0, 3.4, 1.8 Hz), 4.94 (1H, dd, J = 10.2, 1.8 Hz), 3.55 (1H, dd,
J = 9.8, 3.7 Hz), 2.91 (1H, dt, J = 12.4, 6.3 Hz), 2.24–2.08 (4H, m),
1.99–1.84 (2H, m), 1.80 (2H, m), 1.43 (1H, qt, J = 12.7, 4.1 Hz),
0.90 (9H, s), 0.16 (9H, s), 0.07 (3H, s), 0.06 (3H, s); 13C NMR d
206.9 (0), 139.2 (1), 114.3 (2), 105.1 (0), 91.7 (0), 77.2 (1), 59.9 (0),
37.9 (2), 32.1 (2), 31.2 (2), 29.6 (2), 25.9 (3C, 3), 20.9 (2), 18.3 (0),
0.2 (3C, 3), -3.7 (3), -4.5 (3); HRMS (ESI TOF) m/z 401.2304,
[C21H38O2Si2 + Na]+ requires 401.2303.
(2R*,3R*)-2-(But-3-enyl)-3-hydroxy-2-((trimethylsilyl)ethynyl)-
cyclohexanone (25) and (2R*,3S*)-2-(but-3-enyl)-3-hydroxy-2-
((trimethylsilyl)ethynyl)cyclohexanone (26)
(1R*,2R*,3R*)-2-(But-3-enyl)-3-(tert-butyldimethylsilyl)oxy-2-
((trimethylsilyl)ethynyl)-1-vinylcyclohexanol (28)
A 1.6 M solution of n-BuLi (2.4 mL, 3.8 mmol) was added to a
solution of tetravinyltin (217 mg, 0.956 mmol) in THF (1.8 mL)
at -78 ◦C. The mixture, which had become cloudy, was stirred at
A 1.0 M solution of LiAl(Ot-Bu)3H (9.0 mL, 9.0 mmol) was added
to a solution of diketone 24 (2.20 g, 8.40 mmol) in THF (100 mL)
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this temperature for 30 min and then allowed to warm to rt for
15 min during which time the mixture clarified. The mixture was
then cooled back to -78 ◦C, and ketone 27 (242 mg, 0.64 mmol)
in THF (4.2 mL) was added dropwise. TLC revealed that reaction
was complete in 10 min. The mixture was allowed to warm
to rt, and saturated aqueous NH4Cl was added. The mixture
was extracted thoroughly with Et2O. The combined organic
layers were washed with brine and then dried over Na2SO4. The
solvent was removed under reduced pressure, and the residue was
purified by flash chromatography (3% EtOAc/hexanes) to give 28
(221 mg, 85%) and a small amount of the epimer (1R*,2S*,3S*)-
2-(but-3-enyl)-3-(tert-butyldimethylsilyl)oxy-2-((trimethylsilyl)-
ethynyl)-1-vinylcyclohexanol (28a) (24 mg, 9%). For 28: IR (neat)
(1R*,2R*,3a¢R*,6R*)-6-(tert-Butyldimethylsilyloxy)-2-hydroxy-
2-vinyl-3a¢,4¢-dihydro-2¢H-spiro[cyclohexane-1,1¢-pentalen]-
5¢(3¢H)-one (30) and (1R*,2R*,3a¢S*,6R*)-6-(tert-butyl-dimethyl-
silyloxy)-2-hydroxy-2-vinyl-3a¢,4¢-dihydro-2¢H-spiro[cyclohexane-
1,1¢-pentalen]-5¢(3¢H)-one (31)
Dicobalt octacarbonyl (446 mg, 1.30 mmol) was added to a
solution of 29 (0.364 g, 1.09 mmol) in CH2Cl2 (8.0 mL) at rt. The
mixture was stirred for 20 h. At this time the TLC analysis showed
complete consumption of 29 and the formation of a new, less polar,
red compound. The mixture was diluted with CH2Cl2 (70 mL)
and anhydrous TMANO (740 mg, 9.90 mmol) in CH2Cl2 (10 mL)
was added. After 16 h a deep blue precipitate had formed. The
mixture was filtered through a plug of silica gel (EtOAc eluent).
Removal of the solvent under reduced pressure followed by flash
chromatography (5% EtOAc/hexanes) provided 30 (247 mg, 62%)
and 31 (48 mg, 12%). For 30: IR (neat) 3453 (br s), 1705 (s) cm-1;
1H NMR d 6.43 (1H, d, J = 2.3 Hz), 5.68 (1H, ddd, J = 17.2,
10.9, 0.9 Hz), 5.36 (1H, br s, OH), 5.25 (1H, dd, J = 17.2, 1.6 Hz),
5.05 (1H, dd, J = 10.9, 1.6 Hz), 3.83 (1H, t, J = 2.6 Hz), 2.91 (1H,
m), 2.55 (1H, dd, J = 17.9, 6.3 Hz), 2.16–1.96 (3H, m), 2.04 (1H,
dd, J = 17.9, 3.2 Hz), 1.81–1.52 (6H, m), 1.13 (1H, ddd, J = 20.0,
11.8, 8.0 Hz), 0.91 (9H, s), 0.05 (3H, s), -0.06 (3H, s); 13C NMR
d 211.1 (0), 189.2 (0), 140.3 (1), 129.8 (1), 115.4 (2), 76.0 (0), 75.9
(1), 53.9 (0), 45.2 (1), 41.4 (2), 35.9 (2), 34.6 (2), 30.5 (2), 28.0 (2),
25.8 (3C), 17.9 (0), 14.8 (2), -4.9 (3), -5.0 (3); HRMS (ESI TOF)
m/z 385.2160, [C21H34O3Si + Na]+ requires 385.2169.
1
3502 (br m), 3079 (w) cm-1; H NMR d 6.00 (1H, dd, J = 17.3,
10.8 Hz), 5.79 (1H, ddt, J = 17.0, 13.2, 6.6 Hz), 5.33 (1H, dd, J =
17.3, 1.7 Hz), 5.16 (1H, dd, J = 10.8, 1.7 Hz), 5.00 (1H, dq, J =
17.0, 1.7 Hz), 4.94 (1H, d, J = 10.1 Hz), 3.97 (1H, br s), 2.34 (1H,
m), 2.06 (1H, m), 1.96 (1H, m), 1.76–1.58 (4H, m), 1.55 (2H, m),
1.44 (1H, m), 0.94 (9H, s), 0.16 (3H, s), 0.15 (9H, s), 0.11 (3H,
s); 13C NMR d 140.6 (1), 139.0 (1), 114.9 (2), 114.4 (2), 108.1 (0),
89.0 (0), 75.6 (1), 73.8 (0), 49.6 (0), 34.1 (2), 32.7 (2), 29.7 (2), 28.2
(2), 25.9 (3C, 3), 18.1 (0), 15.6 (2), 0.22 (3C, 3), -4.5 (3), -4.9 (3);
HRMS (ESI TOF) m/z: 429.2630, [C23H42O2Si2 + Na]+ requires
429.2616.
1
For 28a: IR (neat) 3500 (m), 3078 (w) cm-1; H NMR d 6.42
(1H, dd, J = 17.4, 10.8 Hz), 5.78 (1H, ddt, J = 17.0, 10.3, 6.7 Hz),
5.23 (1H, dd, J = 17.4, 1.1 Hz), 5.11 (1H, dd, J = 10.8, 1.1 Hz),
4.96 (1H, dq, J = 17.0, 1.7 Hz), 4.88 (1H, d, J = 10.3 Hz), 3.83 (1H,
dd, J = 10.8, 3.9 Hz), 2.34 (1H, m), 2.21 (1H, m), 2.05 (1H, td, J =
13.4, 4.6 Hz), 1.85 (1H, m), 1.76–1.59 (4H, m), 1.55 (1H, m), 1.25
(1H, br d, J = 14.0 Hz), 0.89 (9H, s), 0.15 (9H, s), 0.07 (3H, s),
0.04 (3H, s); 13C NMR d 144.5 (1), 139.8 (1), 113.6 (2), 111.8 (2),
107.7 (0), 90.6 (0), 78.4 (0), 74.2 (1), 50.8 (0), 35.8 (2), 32.0 (2), 31.9
(2), 31.6 (2), 25.9 (3C, 3), 19.5 (2), 18.1 (0), 0.18 (3C, 3), -3.7 (3),
-4.5 (3); HRMS (ESI TOF) m/z 429.2592, [C23H42O2Si2 + Na]+
requires 429.2616.
1
For 31: IR (neat) 3443 (br w), 1704 (s) cm-1; H NMR d 6.22
(1H, d, J = 2.3 Hz), 5.83 (1H, dd, J = 17.1, 10.9 Hz), 5.28 (1H,
d, J = 17.1 Hz), 5.14 (1H, dd, J = 10.9, 1.5 Hz), 3.78 (1H, t, J =
3.5 Hz), 2.91 (1H, m), 2.55 (1H, dd, J = 17.5, 6.4 Hz), 2.10–1.99
(3H, m), 1.99 (1H, dd, J = 17.5, 3.8 Hz), 1.85–1.79 (3H, m), 1.74–
1.61 (2H, m), 1.56 (1H, m), 1.16 (1H, m), 0.95 (9H, s), 0.10 (3H,
s), 0.03 (3H, s); 13C NMR d 210.9 (0), 190.4 (0), 141.1 (1), 128.9
(1), 115.7 (2), 75.8 (1), 75.2 (0), 54.6 (0), 49.2 (1), 42.3 (2), 35.5 (2),
33.5 (2), 29.9 (2), 29.6 (2), 26.0 (3C, 3), 18.0 (0), 15.4 (2), -4.27 (3),
-4.29 (3); HRMS (ESI TOF) m/z 385.2173, [C21H34O3Si + Na]+
requires 385.2169.
(1R*,2R*,3R*)-2-(But-3-enyl)-3-(tert-butyldimethylsilyl)oxy-2-
ethynyl-1-vinylcyclohexanol (29)
(4aR*,8R*,8aR*,10aR*)-8-(tert-Butyldimethylsilyl)oxy-
3,4,4a,5,6,7,8,9,10,10a-decahydro-4a-hydroxy-1H-pentaleno[1,6-
ja]naphthalene-2(1H)-one (32)
K2CO3 (194 mg, 1.40 mmol) was added to a solution of 28 (477 mg,
1.17 mmol) in MeOH (10 mL) at 0 ◦C. The mixture was stirred at rt
for 14 h. Water was added, and MeOH was removed under reduced
pressure. The mixture was extracted thoroughly with Et2O. The
combined organic layers were washed with brine and dried over
Na2SO4. The solvent was evaporated, and the residue was purified
by flash chromatography (5% EtOAc/hexanes) to give 29 (364 mg,
93%): IR (neat) 3262 (s) cm-1; 1H NMR d 6.06 (1H, dd, J = 17.3,
10.9 Hz), 5.79 (1H, ddt, J = 17.0, 13.2, 6.6 Hz), 5.36 (1H, dd, J =
17.3, 1.7 Hz), 5.20 (1H, dd, J = 10.9, 1.7 Hz), 5.03 (1H, dq, J =
17.0, 1.6 Hz), 4.96 (1H, d, J = 10.1 Hz), 4.06 (1H, br s), 2.38 (1H,
m), 2.21 (1H, s), 2.12–1.96 (2H, m), 1.82–1.54 (6H, m), 1.49 (1H,
m), 0.96 (9H, s), 0.19 (3H, s), 0.14 (3H, s); 13C NMR d 140.7 (1),
138.5 (1), 115.0 (2), 114.8 (2), 85.6 (0), 75.7 (1), 73.7 (1), 72.8 (0),
48.3 (0), 33.7 (2), 32.2 (2), 29.4 (2), 27.8 (2), 25.8 (3C, 3), 18.0
(0), 15.2 (2), -4.7 (3), -4.8 (3); HRMS (ESI TOF) m/z 357.2231,
[C20H34O2Si + Na]+ requires 357.2220.
KOH (4 mg, 0.08 mmol) was added to a solution of 30 (19 mg,
0.052 mmol) in MeOH (1.0 mL) at rt. The mixture was stirred for
28 h. Saturated aqueous NH4Cl was added, and the mixture was
extracted thoroughly with Et2O. The combined organic layers were
washed with brine and then dried over Na2SO4. Evaporation of
the solvent under reduced pressure gave a residue that was purified
by flash chromatography to give 32 (10 mg, 53%): IR (neat) 3427
(br m), 1701 (s) cm-1; 1H NMR d 3.77 (1H, m), 3.02 (1H, m), 2.68
(1H, dd, J = 18.6, 6.0 Hz), 2.41–2.26 (3H, m), 2.23–2.14 (2H, m),
2.10 (1H, dd, J = 18.6, 1.6 Hz), 1.94 (1H, dd, J = 13.0, 8.8 Hz),
1.71–1.53 (5H, m), 1.37 (2H, m), 0.91 (1H, m), 0.88 (9H, s), 0.02
(3H, s), -0.08 (3H, s); 13C NMR d 209.5 (0), 188.8 (0), 133.4 (0),
75.1 (1), 72.9 (0), 54.0 (0), 43.1 (2), 42.1 (1), 36.1 (2), 32.0 (2), 31.9
(2), 29.7 (2), 27.1 (2), 25.9 (3C, 3), 20.1 (2), 18.0 (0), 17.1 (2), -4.3
(3), -4.6 (3); HRMS (ESI TOF) m/z 385.2150, [C21H34O3Si + Na]+
requires 385.2169.
3454 | Org. Biomol. Chem., 2011, 9, 3447–3456
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5-Oxo-6-vinylidenedec-9-enoic acid (33)
qt, J = 13.1, 4.8 Hz), 1.88 (1H, dd, J = 13.8, 8.3 Hz), 1.79 (1H,
dt, J = 11.7, 6.9 Hz), 1.74–1.55 (4H, m), 1.50–1.42 (2H, m), 1.36
(1H, dt, J = 12.2, 8.0 Hz), 1.10 (1H, ddd, J = 19.9, 11.7, 8.3 Hz),
0.91 (9H, s), 0.03 (3H, s), -0.04 (3H, s);13C NMR d 154.1 (0),
142.0 (1), 126.5 (1), 114.5 (2), 96.1 (2), 88.8 (1), 76.6 (0), 76.1
(1), 55.4 (3), 51.4 (0), 48.4 (1), 39.7 (2), 37.3 (2), 34.6 (2), 32.2
(2), 28.3 (2), 26.1 (3C, 3), 18.2 (0), 15.4 (2), -4.5 (3), -4.7 (3);
HRMS (ESI TOF) m/z 431.2549, [C23H40O4Si + Na]+ requires
431.2588.
Chromatography-grade SiO2 (200 mg) was added to a solution
of crude diketone 24 (50 mg, 0.19 mmol) in EtOAc (3.0 mL).
The slurry was stirred for 6 h, and was then filtered through
a plug of Celite (EtOAc eluent). Evaporation of the solvent
left a residue that was purified using flash chromatography (5%
MeOH/CH2Cl2) to give 33 (0.018 g, 51%): IR (neat) 3302 (very
br s), 2922 (s), 1710 (s) cm-1; 1H NMR d 5.80 (1H, ddt, J = 16.9,
10.2, 6.7 Hz), 5.22 (2H, t, J = 2.9 Hz), 5.02 (1H, dq, J = 16.9,
1.7 Hz), 4.96 (1H, d, J = 10.2 Hz), 2.75 (2H, t, J = 7.2 Hz), 2.40
(2H, t, J = 7.2 Hz), 2.28 (2H, m), 2.16 (2H, q, J = 7.1 Hz), 1.93
(2H, pentet, J = 7.2 Hz); 13C NMR d 216.4 (0), 200.2 (0), 177.0 (0),
137.9 (1), 115.3 (2), 108.0 (0), 80.4 (2), 38.0 (2), 32.8 (2), 31.9 (2),
25.7 (2), 19.8 (2); HRMS (ESI TOF) m/z 207.1019, [C12H16O3 +
Na]+ requires 207.1027.
(1R*,2R*,3a¢S*,5¢R*,6R*)-6-(tert-Butyldimethylsilyloxy)-5¢-
(methoxymethoxy)-2-vinyl-3¢,3a¢,4¢,5¢-tetrahydro-2¢H-
spiro[cyclohexane-1,1¢-pentalen]-2-ol (35)
Following the procedure for 34, 31 (40 mg, 0.11 mmol) gave 35
1
(30 mg, 67%). For 35: H NMR d 5.82 (1H, d, J = 0.5 Hz), 5.79
(1H, dd, J = 17.4, 10.9 Hz), 5.18 (1H, dd, J = 17.4, 1.6 Hz), 5.07
(1H, dd, J = 10.9, 1.7 Hz), 5.00 (1H, dd, J = 7.9, 6.6 Hz), 4.70
(1H, d, J = 5 Hz), 4.65 (1H, d, J = 5 Hz), 3.82 (1H, t, J = 3.0 Hz),
3.37 (3H, s), 2.61 (1H, m), 2.44 (1H, m), 2.05 (1H, m), 1.88 (1H,
m) 1.82–1.70 (4H, m) 1.66 (1H, dt, J = 15.0, 5.0 Hz), 1.57 (1H,
ddd, J = 15.0, 9.8, 5.0 Hz), 1.49 (1H, m), 1.25 (1H, m), 1.07 (1H,
m), 0.97 (9H, s), 0.14 (3H, s), 0.12 (3H, s); 13C NMR d 155.2
(0), 142.2 (2), 125.6 (1), 114.5 (2), 95.7 (2), 88.0 (1), 76.2 (1), 76.0
(0), 55.2 (3), 51.6 (1), 51.3 (0), 40.3 (2), 37.3 (2), 32.6 (2), 31.0
(2), 29.7 (2), 26.1 (3, 3C), 18.0 (0), 15.3 (2), -4.17 (3), -4.21 (3);
HRMS (ESI TOF) m/z 431.2598, [C23H40O4Si + Na]+ requires
431.2588.
(1R*,2R*,3a¢R*,5¢S*,6R*)-6-(tert-Butyldimethylsilyloxy)-5¢-
(methoxymethoxy)-2-vinyl-3¢,3a¢,4¢,5¢-tetrahydro-2¢H-
spiro[cyclohexane-1,1¢-pentalen]-2-ol (34)
NaBH4 (12 mg, 0.32 mmol) was added to a solution of 30
(53 mg, 0.15 mmol) and CeCl3·7H2O (82 mg, 0.22 mmol) in
MeOH (1.5 mL) at 0 ◦C. The mixture was stirred for 20 min,
and the reaction was then quenched by the addition of satu-
rated aqueous NH4Cl. The MeOH was removed under reduced
pressure, and the aqueous mixture was extracted thoroughly with
Et2O. The organic layers were combined and washed with brine
and then dried over Na2SO4. Evaporation of the solvent gave
(1R*,2R*,3a¢R*,5¢S*,6R*) - 6 - (tert - butyldimethylsilyloxy) - 2 -
vinyl-3¢,3a¢,4¢,5¢-tetrahydro-2¢H-spiro[cyclohexane-1,1¢-pentalene]-
2,5¢-diol (30a) (49 mg, 92%) that was used without further
(2aR*,6aS*,9aR*,9bR*)-2,2a,3,4,6,6a,9,9a-Octahydro-1H-
pentaleno[1,6-dc]indene-1,7(8H)-dione (37)
1
purification: IR (neat) 3406 (br s) cm-1; H NMR d 5.88 (1H,
KOt-Bu (7 mg, 0.06 mmol) was added to a solution of mesylate 361
(15.8 mg, 0.050 mmol) in t-BuOH (0.5 mL) at 0 ◦C. The mixture
was warmed to rt and stirred for 4 h. The reaction was quenched
with saturated aqueous NH4Cl, and the mixture was extracted
thoroughly with Et2O. The combined organic layers were washed
with brine and then dried over Na2SO4. Evaporation of the solvent
under reduced pressure yielded a residue that was purified by flash
column chromatography to give 37 (10 mg, 91%): mp 97–100 ◦C;
1H-NMR (C6D6) d 4.94 (1H, s), 2.70 (1H, t, J = 9.5 Hz), 2.58 (1H,
m), 2.49 (1H, m), 2.12 (3H, m), 1.80 (6H, m), 1.61 (1H, m), 1.54
(1H, m), 1.04 (1H, m); 13C NMR (C6D6) d 216.9 (0), 209.9 (0),
154.3 (0), 117.3 (1), 66.8 (0), 57.5 (1), 49.7 (1), 44.2 (2), 42.7 (1),
41.8 (2), 34.83 (2), 34.78 (2), 22.6 (2), 19.7 (2); HRMS (ESI TOF)
m/z 239.1040, [C14H16O2 + Na]+ requires 239.1043.
dd, J = 17.3, 10.9 Hz), 5.87 (1H, s), 5.36 (1H, br s, OH), 5.24 (1H,
dd, J = 17.3, 1.9 Hz), 5.08 (1H, dd, J = 10.9, 1.9 Hz), 5.02 (1H,
br t, J = 7.4 Hz), 3.62 (1H, t, J = 2.8 Hz), 2.67 (1H, m), 2.58 (1H,
dt, J = 12.3, 5.7 Hz), 2.07 (1H, qt, J = 13.1, 4.6 Hz), 1.90 (1H,
dd, J = 13.9, 8.1 Hz), 1.81 (1H, dt, J = 11.7, 7.3 Hz), 1.75–1.59
(5H, m), 1.51–1.46 (2H, m), 1.18 (1H, dt, J = 12.3, 7.5 Hz), 1.08
(1H, ddd, J = 19.9, 11.7, 8.3 Hz), 0.91 (9H, s), 0.03 (3H, s), -0.04
(3H, s); 13C NMR d 154.2 (0), 141.7 (1), 128.0 (1), 114.2 (2), 83.2
(1), 76.3 (0), 75.8 (1), 50.9 (0), 49.0 (1), 42.5 (2), 37.0 (2), 34.4
(2), 32.1 (2), 27.9 (2), 25.9 (3C, 3), 17.9 (0), 15.0 (2), -4.8 (3), -5.0
(3); HRMS (ESI TOF) m/z 387.2329, [C21H36O3Si + Na]+ requires
387.2326.
N,N-Diisopropylethylamine (40 mL, 0.24 mmol) was added to
a solution of 30a (30 mg, 0.082 mmol) in CH2Cl2 (0.7 mL) at
◦
0 C. MOMCl (12 mL, 0.15 mmol) was added, and the mixture
was allowed to warm to rt. After 6 h the reaction was quenched by
the addition of saturated aqueous NaHCO3, and the mixture was
extracted thoroughly with CH2Cl2. The combined organic layers
were washed with brine and dried over Na2SO4. Evaporation of the
solvent under reduced pressure, followed by flash chromatography
(10% EtOAc/hexanes) afforded 34 (27 mg, 81%): IR (neat) 3390
(br s), 1038 (s) cm-1; 1H NMR d 5.93 (1H, dd, J = 17.3, 11.0 Hz),
5.92 (1H, m), 5.30 (1H, br s, OH), 5.22 (1H, dd, J = 17.3, 1.8 Hz),
5.07 (1H, dd, J = 11.0, 1.8 Hz), 4.88 (1H, m), 4.71 (1H, d, J =
6.7 Hz), 4.69 (1H, d, J = 6.7 Hz), 3.61 (1H, t, J = 2.7 Hz), 3.38
(3H, s), 2.63 (1H, m), 2.50 (1H, dt, J = 12.3, 6.8 Hz), 2.07 (1H,
X-Ray crystal structure determination for 37
Measurements were made on a Rigaku AFC5R instrument with
graphite monochromated Mo-Ka radiation (l = 0.71069 A).
˚
The crystal was a colourless needle of dimensions 0.32 ¥
0.19 ¥ 0.11 mm, formula C14H16O2, M = 216.28, triclinic, a ◦=
˚
˚
˚
˚
8.5532(17) A, b◦= 18.428(5) A, c = 8.1080(17) A, a = 93.05(2) ,
◦
3
¯
b = 118.249(14) , g = 94.88(2) , V = 1115.3(5) A , P1(#2), Z = 4,
F(000) = 464, T = 296.1 K, m(Mo-Ka) 0.085 mm-1, 3193 observed
reflections (I > 3.00s(I)) and 291 variable parameters; R(Fo) =
0.0448, wR2(F2) = 0.0563, goodness of fit = 1.127.
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˚
(3aR*,7aR*,10S*,10aR*)-2,3,3a,4,6,7,7a,8,9,10-Decahydro-7a-
hydroxy-5-oxocyclopenta[f ]acenaphthalen-10-yl methanesulfonate
(40)
ation (l = 0.71070 A). The crystal was a colourless needle of
dimensions 0.25 ¥ 0.28 ¥ 0.33 mm, formula C15H18O2, M = 230.31,
˚
˚
˚
triclinic, a ◦= 8.3858(2) A, b = 8.9432(4) A, c = 16.6524(14) A, a =
◦
◦
3
˚
82.616(11) , b = 76.245(9) , g = 83.941(14) , V = 1199.33(12) A ,
Triethylamine (50 mL, 0.39 mmol) was added to a solution of 18
(65 mg, 0.26 mmol) in CH2Cl2 (2.5 mL). MsCl (23 mL, 0.30 mmol)
was added, and the mixture was allowed to warm to rt. After
5 h the reaction was quenched with saturated aqueous NaHCO3,
and the mixture was extracted thoroughly with CH2Cl2. The
combined organic layers were washed with brine and then dried
over Na2SO4. Evaporation of the solvent under reduced pressure
gave a residue that was purified using flash chromatography (75%
EtOAc/hexanes) to give 40 (0.068 g, 81%): IR (neat) 3443 (br),
2934 (s), 2859 (m), 1693 (s), 1644 (m) cm-1; 1H NMR d 5.32 (1H,
dd, J = 4.4, 1.9 Hz), 3.11 (3H, s), 2.77 (1H, m), 2.59 (1H, dd, J =
19.1, 6.4 Hz), 2.40 (1H, ddd, J = 17.9, 5.6, 2.1 Hz), 2.31–2.11 (4H,
m), 2.07–1.98 (3H, m), 1.94–1.63 (5H, m), 1.34 (1H, td, J = 13.0,
5.1 Hz), 1.05 (1H, qd, J = 13.0, 5.1 Hz); 13C NMR d 206.6 (0),
176.6 (0), 137.9 (0), 86.4 (1), 81.4 (0), 55.6 (0), 42.3 (2), 39.4 (1),
37.2 (3), 36.4 (2), 36.3 (2), 31.3 (2), 30.5 (2), 28.7 (2), 22.0 (2), 17.8
(2); HRMS (ESI TOF) m/z 349.1086, [C16H22O5S + Na]+ requires
349.1080.
-1
¯
P1(#2), Z = 4, F(000) = 496, T = 120.1 K, m(Mo-Ka) 0.0828 mm ,
4302 observed reflections (I > 3.00s(I)) and 343 variable param-
eters; R(Fo) = 0.0442, wR2(F2) = 0.0555, goodness of fit = 1.051.
Acknowledgements
We thank the Natural Sciences and Engineering Council of
Canada and the Killam Trusts for support of this research.
Notes and references
1 P. D. Thornton and D. J. Burnell, Org. Lett., 2006, 8, 3195.
2 (a) L. A. Paquette, D. T. DeRussy and R. D. Rogers, Tetrahedron, 1988,
44, 3139; (b) L. Gentric, I. Hanna and L. Ricard, Org. Lett., 2003, 5,
1139.
3 J. N. Payette, T. Honda, H. Yoshizawa, F. G. Favaloro Jr. and G. W.
Gribble, J. Org. Chem., 2006, 71, 416.
4 S. Swaminathan, J. P. John and S. Ramachandran, Tetrahedron Lett.,
1962, 729.
5 S. M. Ng, S. J. Bader and M. L. Snapper, J. Am. Chem. Soc., 2006, 128,
(3aR*,6aR*,9aR*,9bS*)-2,3,3a,4,6,6a,9,9a-Octahydro-1H-
cyclopenta[e]acenaphthalene-5,7(8H,9bH)-dione (41)
7315.
6 T. J. Jenkins and D. J. Burnell, J. Org. Chem., 1994, 59,
1485.
7 N. Takeda and T. Imamoto, Org. Synth., 1998, 76, 228. Proper
preparation of the CeCl3 is crucial to the success of cerium-mediated
Grignard reactions. In this regard, this contribution is invaluable: D.
A. Conlon, D. Kumke, C. Moeder, M. Hardiman, G. Hutson and L.
Sailor, Adv. Synth. Catal., 2004, 346, 1307.
8 (a) S. Shambayati, W. E. Crowe and S. L. Schreiber, Tetrahedron Lett.,
1990, 31, 5289; (b) N. Jeong, Y. K. Chung, B. Y. Lee, S. H. Lee and S.
Yoo, Synlett, 1991, 204; (c) T. Sugihara, M. Yamada, M. Yamaguchi
and M. Nishizawa, Synlett, 1999, 771.
9 Some good yields have been reported, e.g., (a) S. Hotha, S. K. Maurya
and M. K. Gurjar, Tetrahedron Lett., 2005, 46, 5329; (b) S. Sezer,
Y. G u¨mru¨kc¸u¨, E. S¸ahin and C. Tanyeli, Tetrahedron: Asymmetry,
2008, 19, 2705. However, modest yields have also appeared in which
similar ring systems are forming, e.g.; (c) S. Min and S. J. Danishefsky,
Angew. Chem., Int. Ed., 2007, 46, 2199; (d) K. Kaneda and T. Honda,
Tetrahedron, 2008, 64, 11589.
10 Geminal acylation with a ketal: (a) J. Shimada, K. Hashimoto, B. H.
Kim, E. Nakamura and I. Kuwajima, J. Am. Chem. Soc., 1984, 106,
1759; (b) Y.-J. Wu and D. J. Burnell, Tetrahedron Lett., 1989, 30, 1021;
(c) Y.-J. Wu, D. W. Strickland, T. J. Jenkins, P.-Y. Liu and D. J. Burnell,
Can. J. Chem., 1993, 71, 1311.
11 F. Gao and D. J. Burnell, J. Org. Chem., 2006, 71, 356.
12 NOE measurements with 35 were used to resolve issues of relative
stereochemistry in this series.
13 L. Acebey, M. Sauvin, S. Beck, C. Moulis, A. Gimenez and V. Jullian,
Org. Lett., 2007, 9, 4693.
14 E. L. Eliel, S. H. Wilen and L. N. Mander, in Stereochemistry of Organic
Compounds, Wiley, New York, 1994, pp 856–857.
15 J. J. Bloomfield and J. M. Nelke, Organic Syntheses, Wiley, New York,
1988, Collect. Vol. VI, pp 167–172.
KOt-Bu (13 mg, 0.12 mmol) was added to a solution of 40 (20 mg,
0.061 mmol) in t-BuOH (1 mL) at 0 ◦C. The mixture was allowed
to warm to rt after 1 h and was maintained at this temperature
for 1 h. The reaction was quenched by addition of saturated
aqueous NH4Cl, and the mixture was extracted thoroughly with
Et2O. The combined organic layers were washed with brine and
then dried over Na2SO4. Removal of the solvent under reduced
pressure gave a residue that was purified by flash chromatography
(15% EtOAc/hexanes) to yield 41 along with a compound that
appeared to be epimeric (7 mg, 51%) in a ratio of approximately
3 : 1, and 8 mg (40%) of 40 was recovered. Crystallization from
EtOAc/hexanes gave a small amount of homogeneous 41: mp
117–120 ◦C; IR (neat): 2929 (s), 1738 (s), 1696 (s) cm-1; 1H NMR
d 2.79–2.44 (5H, m), 2.52 (3H, m), 2.09–1.88 (6H, m), 1.79 (1H,
m), 1.61 (1H, m), 1.27 (1H, m), 1.05 (1H, m); 13C NMR d 216.8
(0), 207.0 (0), 181.2 (0), 135.1 (0), 48.0 (1), 42.52 (2), 42.48 (2),
40.1 (2), 39.6 (2), 38.5 (1), 36.5 (1), 28.4 (2), 25.2 (1), 22.7 (2), 20.5
(2); HRMS (ESI TOF) m/z 253.1205, [C15H18O2 + Na]+ requires
253.1199.
X-Ray crystal structure determination for 41
Measurements were made on a Rigaku RAXIS RAPID imaging
plate area detector with graphite monochromated Mo-Ka radi-
3456 | Org. Biomol. Chem., 2011, 9, 3447–3456
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