Alternative mild route to the synthesis of 4-methylenecyclohex-2-enone, a key moiety of the anticancer compounds ottelione A and B

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Alternative Mild Route to the Synthesis
of 4-Methylenecyclohex-2-enone, a Key
Moiety of the Anticancer Compounds
Ottelione A and B
Elena Lestini a , Keith Robertson a , Cormac D. Murphy a & Francesca
Paradisi a
a University College Dublin , Dublin , Ireland
Accepted author version posted online: 07 Dec 2011.Published
online: 27 Feb 2012.
To cite this article: Elena Lestini , Keith Robertson , Cormac D. Murphy & Francesca Paradisi
(2012) Alternative Mild Route to the Synthesis of 4-Methylenecyclohex-2-enone, a Key Moiety
of the Anticancer Compounds Ottelione A and B, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:12, 1864-1876, DOI:
10.1080/00397911.2011.607936
To link to this article: http://dx.doi.org/10.1080/00397911.2011.607936
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Synthetic Communications1, 42: 1864–1876, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.607936
ALTERNATIVE MILD ROUTE TO THE SYNTHESIS OF
4-METHYLENECYCLOHEX-2-ENONE, A KEY MOIETY
OF THE ANTICANCER COMPOUNDS OTTELIONE A
AND B
Elena Lestini, Keith Robertson, Cormac D. Murphy, and
Francesca Paradisi
University College Dublin, Dublin, Ireland
GRAPHICAL ABSTRACT
Abstract
INTRODUCTION
In recent years, the discovery of the powerful anticancer and antitubercular
properties of otteliones A and B, originally extracted from the freshwater plant
Ottelia alismoides, have aroused great interest in the total synthesis of otteliones
and their analogs.[1–4] Alternative mild synthetic strategies to the preparation of
the key dienone, 4-methylenecyclohex-2-enone 6, become an important task, because
otteliones embed this rare electrophilic dienone in their bicyclic hydrindane skeleton
(Fig. 1).
The cytotoxicity of this class of compounds is strongly related to the presence
of the dienone functionality. Indeed, the aromatic analogs of ottelione, in which the
embedded dienone functionality is not present, display significantly lower biological
activity than that of the otteliones.[3b,3c] Although biological activity has not been
assessed so far for the 4-methylenecyclohex-2-enone 6, it has been reported that
ottelione A inhibits tubulin polymerization.[3c]
Received July 12, 2011.
Address correspondence to Francesca Paradisi, University College Dublin, Dublin 4, Ireland.
E-mail: francesca.paradisi@ucd.ie
1864

SYNTHESIS OF 4-METHYLENECYCLOHEX-2-ENONE
1865
Figure 1. Representative 4-methylenecyclohex-2-enone embedded structure in ottelione A and B. (Figure
is provided in color online.)
It is proposed that the disruption of the microtubule dynamics results from the
specific binding of the 4-methylenecyclohex-2-enone functionality embedded in
otteliones to the sulfhydryl groups of the cysteine residues in tubulin.[3b] The mech-
anism is believed to be similar to that of the cytotoxic molecule T138067 and of the
alkaloids colchicine, vincristine, and vinbrastine.[5] The antitumor activity of the
otteliones has stimulated interest in the synthesis of dienones such as 6.
Thus far, however, few synthetic procedures are available in the literature.[6]
The first approach reported relies on the Birch reduction of 4-methoxybenzyl alcohol
followed by deoxygenation of the reduced products, affording 6 in yields of around
40%.[6a] The most recent approach employs a Diels–Alder adduct from the Diels–
Alder reaction between Danishefsky’s diene and methyl acrylate followed by acidic
hydrolysis of the b-methoxy silyl enol ether adducts to ketones in p-toluene sulfonic
acid. The compounds are converted to the final product by a stepwise procedure that
employs ketalization with ethylene glycol, reduction of the ester adduct with diiso-
butylaluminium hydride (DIBALH), and final ketal deprotection with pyridinium
p-toluenesulfonate in acetone. Following such a procedure, dienone 6 was obtained
in 65–75% overall yield.[6b] 4-Methylenecyclohex-2-enone analogs may also be
obtained via cross coupling of Baylis–Hillman acetates and aliphatic 1,3-diketones
in ethanol and in the presence of K2CO3 with yields up to 70%.[6c] A bicyclic core
intermediate for the synthesis of (þ)-ottelione A was also synthesized using an enan-
tioselective Diels–Alder strategy that in principle allows the preparation of a variety
of chiral 4-methylenecyclohex-2-enone derivatives.[6d]
Extended structures of 4-methylenecyclohex-2-enone were also obtained by
flash-vacuum pyrolysis of ketone spiro[5.6]dodeca-l,4,9-trien-3-one. However, in
the latter case the synthesis of 4-methylenecyclohex-2-enone analogs is carried out
under quite harsh conditions, which can promote unwanted tautomerization.[6e]
Not only is 4-methylenecyclohex-2-enone 6 a target product for potential bio-
logical activity when used on its own or when embedded in otteliones, but it is also a
valuable starting material in the synthesis of several natural antifungal and antibiotic
products such as chlorotetaine, bacilysin, and anticapsin.[7]
In this article, we describe an alternative synthesis of 6 using methanesulfonate
4a and sodium iodide in acetone. Methanesulfonate adduct 4a was obtained from
Diels–Alder cycloaddition between the commercially available Danishefky’s diene
trans-4-methoxy-3-buten-2-one (1a) and acrolein under mild conditions.[8]

1866
E. LESTINI ET AL.
DISCUSSION
The Diels–Alder reaction in principle allows access to a range of methanesul-
fonate adducts that we envisage could be converted through this synthetic procedure
to their 4-methylenecyclohex-2-enone analogs, which may exhibit biological activity
similar to that of the otteliones.
Our approach to the synthesis of 4-methylenecyclohex-2-enone 6 employs
milder conditions than those previously reported in literature and allows 6 to be
obtained in yields up to 70% from commercially available materials (Scheme 1).[6]
The tert-butyldimethylsilyl analog of Danishefsky’s diene 1a chosen as this
compound is highly reactive to cycloaddition reactions but is more stable to hydroly-
sis than the classic Danishefsky diene, owing to the presence of the more robust tert-
butyldimethylsilyl protecting group. However, the tert-butyl silyl group can still be
easily cleaved by a variety of selective conditions.[8f,9] Because the stereoselectivity
of the cycloaddition was not relevant to the synthesis of 4-methylenecyclohex-2-
enone 6, the reaction of cycloaddition was carried out in the absence of conventional
Lewis acids such as ZnCl2 or AlCl3 to minimise decomposition of 1a.
Cycloaddition was performed under solvent-free conditions and irradiated by
microwave (150 W) at 50 ꢀC for 30 min (Scheme 1). Acrolein was used in excess to
trans-3-(tert-butyldimethylsiloxy)-1-methoxy-1,3-butadiene 1a, acting both as
reagent and solvent. Under such conditions, no decomposition of diene 1a was
observed and aldehyde 2a was obtained in almost quantitative yield. Side products
due to the polymerization of acrolein were detected, but they were easily separated
Scheme 1. Stepwise synthesis of mesylate intermediates 4a and 4b from Danishefsky diene 1a and 1b,
respectively.

SYNTHESIS OF 4-METHYLENECYCLOHEX-2-ENONE
1867
from aldehyde 2a by filtration, as they precipitate in diethyl ether. It is noteworthy to
mention that the amount of acrolein seems critical to the cycloaddition reaction.
Indeed, when acrolein was used in equimolar ratio to diene 1a, considerable amounts
of undesired products due to cycloaddition between trans-4-methoxy-3-buten-2-one,
arising from deprotection of 1a, and acrolein or 1,3-diene 1a were detected. Thus,
lower amounts of acrolein seem to favor the formation of side products over
cross-cycloaddition of acrolein to 1,3-diene 1a. It is likely that the polymerization
process of acrolein, taking place under microwave irradiation, leads to depletion
of free dienophile available for the reaction of cycloaddition with 1,3-diene 1a, thus
lowering the yield of 2a to 50%.
Cycloaddition of acrolein and 1,3-diene 1a showed moderate stereoselectivity;
the ratio of syn and anti diasteroisomers was evaluated to be 69:31 by NMR spec-
troscopy. Aldehyde 2a was reduced with NaBH4 in methanol to yield the corre-
sponding alcohol 3a as a racemic mixture of syn and anti diastereoisomers in
almost quantitative yield.[10] However, the yield varied depending on the amount
of sodium borohydride used. The best yield was obtained when sodium borohydride
was used in slight molar excess to aldehyde 2a.
Alcohol 3a was easily converted to mesylate 4a in the presence of triethylamine
and mesyl chloride (Scheme 1). Dry conditions were employed to avoid acid-catalyzed
deprotection of tert-butyldimethylsilyl group and elimination of methanol from alco-
hol 3a. The formation of methanesulfonic acid was avoided by employing activated
molecular sieves in situ. Under such conditions, mesylate 4a was obtained in practi-
cally quantitative yield and was used directly in the next step of the reaction.
The use of strong bases such as sodium methoxide or 1,8-diazabicyclo[5.4.0.]-
undec-7-ene (DBU) was unnecessary to promote formation of the methylene func-
tionality (as in the synthesis of glucose derivatives bearing the methylene
moiety).[11] When NaI was employed, formation of the methylene group along with
desilanization of the silyl enol ether functionality and elimination of the b-methoxy
silil enol ether in 4a occurred, leading to the formation of the target product 6. To
investigate the possible role of sodium iodide in the formation of 6, mesylate 4a
was refluxed in acetone in the absence of sodium iodide (Scheme 2). The reaction
led to practically quantitative formation of ketone 7 (due to desilanization of the silyl
enol ether and elimination of b-methoxy silyl enol ether), but to only traces of ketone
6. This result strongly suggests that the reaction leading to the formation of ketone 6
and employing Finkelstein conditions[12] still needs a better leaving group and pro-
ceeds through formation of a halide intermediate such as 5. The iodide intermediate
5 was isolated in traces when the reaction between 4a and sodium iodide was carried
out at 20 ꢀC. However, it was found that such an intermediate readily undergoes
elimination of hydrogen iodide under our experimental conditions. Subsequent elim-
ination of hydrogen iodide from this intermediate might range from a concerted
mechanism to a stepwise sequence, involving cationic intermediates and leading to
the formation of the methylene functional group in 6.
The latter findings underline the importance of sodium iodide in the formation
of ketone 6 from mesylate 4a. Indeed, simply refluxing 6 in acetone leads only to the
formation of ketone 7 (Scheme 2).
However, the embedded b-methoxy silyl enol ether moiety in 4a also appears to
play an important role in the formation of ketone 6. To investigate the role of this

1868
E. LESTINI ET AL.
Scheme 2. Synthesis of 4-methylenecyclohex-2-enone 6, mesylate 7, and iodide 5 from mesylate 4a under
different experimental conditions.
group, a model mesylate 4b, bearing a b-phenyl silyl enol ether group, neither heat
nor acid labile was prepared following the same synthetic strategy employed for
mesylate 4a (Scheme 2) and reacted with sodium iodide under similar experimental
conditions (Scheme 3).
It is noteworthy to compare the results obtained from the exchange reaction
between sodium iodide and mesylate 4a in acetone with those of model mesylate
4b. When 4b was exchanged with sodium iodide in acetone, intermediate 8 was
isolated in 35% yield but no products bearing the methylene functional group in
the c-position to the carbonyl group were detected (Scheme 3) as in the case of mesy-
late 4a (Scheme 2).
This result, along with the finding that ketone 6 was also formed in significant
yield (50%) when 4a was reacted with sodium iodide in acetone at 20 ꢀC over 3 days
(Scheme 2), indicates that the formation of a highly conjugated ketone such as 6
Scheme 3. Reaction of exchange between model mesylate 4b and sodium iodide.

SYNTHESIS OF 4-METHYLENECYCLOHEX-2-ENONE
1869
might be regarded as the overall driving force for the process of dehydroiodination
of intermediate 5 (Scheme 2).
In summary, an alternative four-step procedure for the synthesis of
4-methylenecyclohex-2-enone 6 was developed employing relatively mild conditions
of reaction, leading to formation of ketone 6 in relatively good yields. The results
underline the importance of both sodium iodide and of the embedded b-methoxy
silyl enol ether functionality in 4a in the formation of the target product
4-methylenecyclohex-2-enone 6.
Finally, we believe that this procedure could effectively be employed in the
synthesis of biologically active ottelione-type molecules. Further studies on the opti-
mization of experimental conditions of the last step of synthetic scheme and on the
application of this reaction to the synthesis of ottelione-type compounds are cur-
rently in progress.
EXPERIMENTAL
Synthesis of (E)-tert-Butyldimethyl(4-phenylbut-1,3-dien-2-
yloxy)silane (1b)
(E)-4-Phenylbut-3-en-2-one (6 mmol, 0.61 mL) was added to a solution of dry
triethyl amine (15 mmol, 2.1 mL) in dry diethyl ether (20 mL) in the presence of acti-
vated molecular sieves under a nitrogen atmosphere. The stirred mixture was cooled
to 0 ꢀC and tert-butyldimethylsilyl triflate (TBDMSTf, 6.3 mmol, 1.45 ml) was added
dropwise. Once addition of TBDMSTf was complete, the mixture was allowed to
warm to room temperature and stirred overnight. The reaction was worked up by
filtration to remove the molecular sieves and washed successively with saturated
sodium bicarbonate solution (20 mL), deionized water (20 mL), and brine (20 mL).
The organic phase was collected and dried over magnesium sulfate and filtered,
and the solvent was removed under reduced pressure to afford a pale yellow oil in
87% yield. The product was used without further purification.
1H NMR (500 MHz, CDCl3 d=ppm 7.41 (d, J ¼ 7.3 Hz, 2H, ArH), 7.32 (t,
J ¼ 7.5 Hz, 2H, ArH), 7.23 (t, J ¼ 7.4 Hz, 1H, ArH), 6.86 (d, J ¼ 15.7 Hz, 1H,
=
=
=
Ar-CH CH), 6.58 (d, J ¼ 15.7 Hz, 1H, Ar-CH CH), 4.45 (s, 1H, C CHH), 4.42
(s, 1H, C CHH), 1.03 [bs, 9H, SiC(CH3)3], 0.23 [bs, 6H, Si(CH3]2]. 13C NMR
=
(126 MHz, CDCl3) d=ppm: 155.3 (CO), 136.9, 129.3, 128.6, 127.6, 126.8, 126.6,
=
96.7 (C CHH), 25.9 [SiC(CH3]3), 18.4 [SiC(CH3]3), ꢁ4.6 [Si(CH3]2). HR-MS:
m=z calcd for C16H25OSi (M þ H)þ: 261.1675; found: 261.1675.
Synthesis of 4-(tert-Butyldimethylsilyloxy)-2-methoxycyclohex-3-
enecarbaldehyde (2a)
A mixture of diene 1a (0.32 g, 1.5 mmol) and acrolein (0.17 mL, 0.25 mmol) was
irradiated for 30 min at 50 ꢀC by microwave (150 W). The reaction was worked up by
addition of diethyl ether to precipitate the insoluble acrolein polymers, filtration, and
removal of the solvent under reduced pressure. No further purification was neces-
sary. Product 2a was obtained as a colorless oil in 89% yield as a mixture of the
syn and anti diastereomers. The 1H NMR spectrum of aldehyde 2a reveals the

1870
E. LESTINI ET AL.
presence of two distinct diastereomers. More specifically, the integrals of the well-
=
resolved pair of diastereotopic protons corresponding to the O CH protons at
9.78 ppm and 9.74 ppm display a 69:31 ratio.
Major diastereomer. 1H NMR (500 MHz, CDCl3) d=ppm: 9.78 (s, 1H,
=
=
O CH), 5.18 (d, J ¼ 5.1 Hz, 1H, OC CH), 4.26 (t, J ¼ 4.4 Hz, 1H, CHOCH3),
=
3.31 (s, 3H, OCH3,), 2.41 (dt, J ¼ 10.4, 3.4 Hz, 1H, O CHCH), 2.14–1.87 (m, 4H,
overlap with minor diastereomer), 0.91 [9H, bs, SiC(CH3]3), 0.17 (bs, 3H,
CH3SiCH3), 0.16 (bs, 3H, CH3SiCH3). 13C NMR (126 MHz, CDCl3) d=ppm:
=
=
=
203.2 (O CH), 156.3 (OC CH), 102.0 (OC CH), 73.3 (CHOCH3), 55.8 (OCH3),
=
50.5 (O CHCH), 28.9 (SiOCCH2CH2), 25.6 [SiC(CH3)3], 19.4 (SiOCCH2CH2),
18.0 [SiC(CH3)3], ꢁ4.4 (CH3SiCH3), ꢁ4.5 (CH3SiCH3).
Main resonances of minor diastereomer. 1H NMR (500 MHz, CDCl3)
=
=
d=ppm: 9.74 (d, J ¼ 0.9 Hz, 1H, O CH), 5.05 (dt, J ¼ 3.8, 1.2 Hz, 1H, OC CH),
=
4.24–4.20 (m, 1H, CHOCH3), 3.35 (s, 3H, OCH3), 2.59–2.54 (m, 1H, O CHCH),
2.14–1.87 (m, 4H, overlap with major diastereomer), 0.91 [s, 9H, SiC(CH3)3], 0.15
(s, 3H, CH3SiCH3), 0.14 (s, 3H, CH3SiCH3). 13C NMR (126 MHz, CDCl3) d=
=
=
=
ppm: 202.7 (O CH), 152.6 (OC CH), 102.5 (OCCH C), 74.2 (CHOCH3), 55.6
=
(OCH3), 50.5 (O CHCH), 28.0 (SiOCCH2CH2), 25.6 [SiC(CH3)3], 19.5
(SiOCCH2CH2), 18.1 [SiC(CH3)3], ꢁ4.4 (CH3SiCH3), ꢁ4.5 (CH3SiCH3). HR-MS:
m=z C14H26O3Si (M)þ: 270.1651; found: 270.1650.
Synthesis of 4-(tert-Butyldimethylsilyloxy)-2-phenylcyclohex-3-
enecarbaldehyde (2b)
A mixture of diene 1b (5 mmol, 1.3 g) and acrolein (0.84 mL, 12.5 mmol) was
irradiated for 45 min at 50 ꢀC by microwave (150 W). The reaction was worked up
by addition of diethyl ether to precipitate the insoluble acrolein polymers and fil-
tered, and the solvent was removed under reduced pressure. No further purification
was necessary. Product 2b was obtained as a colorless oil in 87% yield as a mixture of
the syn and anti diastereomers in 60:40 ratio. However, it was possible to isolate, for
characterization purposes, the major diastereomer but, this was never achieved for
the minor diastereomer, which remained partially contaminated by the other one.
Main resonances of major diastereomer. 1H NMR (500 MHz, CDCl3) (d=
=
ppm): 9.63 (d, J ¼ 1.2 Hz, 1H, O CH), 7.28–7.22 (m, 2H, ArH), 7.20–7.14 (m, 3H,
=
ArH), 4.86–4.81 (m, 1H, OC CH), 3.83–3.77 (t, J ¼ 4.8 Hz, 1H, MeOCH),
2.45–2.38 (m, 1H), 2.19–2.07 (m, 2H), 1.90–1.86 (m, 1H), 1.83–1.77 (m, 1H), 0.88
[bs, 9H, SiC]CH3)3,), 0.11 (s, 3H, CH3SiCH3), 0.09 (s, 3H, CH3SiCH3). 13CNMR
=
=
(126 MHz, CDCl3) d=ppm: 204.4 (O CH), 152.4 (OC CH), 141.0 (Ar), 129.0
=
(Ar), 128.3 (Ar), 126.7 (Ar), 105.7 (OCCH C), 50.5, 41.4, 27.9 (SiOCCH2CH2),
25.6 [SiC(CH3)3, overlap with minor], 19.5 (SiOCCH2CH2), 18.0 [SiC(CH3)3],
ꢁ4.3 (CH3SiCH3), ꢁ4.4 (CH3SiCH3).
Main resonances from minor diastereomer. 1H NMR (500 MHz, CDCl3)
=
d=ppm: 9.46 (d, J ¼ 1.8 Hz, 1H, O CH), 7.30–7.16 (5H, ArH, overlap with minor
=
diastereomer), 5.02 (dt, 4.5, 1.3 Hz, 1H, OC CH), 4.03 (t, J ¼ 5.0 Hz, 1H, MeOCH),
2.70–2.64 (m, 1H), 2.26–2.10 (m, 2H, overlap with major diastereomer), 2.01–1.80

SYNTHESIS OF 4-METHYLENECYCLOHEX-2-ENONE
1871
(m, 2H, overlap with major diastereomer), 0.93 [bs, 9H, SiC(CH3)3], 0.16 (s, 3H,
CH3SiCH3), 0.16 (s, 3H, CH3SiCH3). 13C NMR (126 MHz, CDCl3) d=ppm: 203.6
=
(O CH), 151.6 (OC CH), 144.3 (Ar), 128.5 (Ar), 128.1 (Ar), 126.7 (Ar), 106.7
=
=
(OC CH), 53.7, 41.2, 27.9 (SiOCCH2CH2), 25.6 [SiC(CH3)3], 21.0 (SiOCCH2CH2),
18.0 [SiC(CH3)3], ꢁ4.4 (CH3SiCH3), ꢁ4.4 (CH3SiCH3). HR-MS: m=z calcd
C19H28O2SiNa (M þ Na)þ: 339.1756; found 339.1770.
Synthesis of (4-(tert-Butyldimethylsilyloxy)-2-methoxycyclohex-3-
enyl)methanol (3a)
Aldehyde 2a (2.8 mmol, 0.76 g) was dissolved in ethanol (30 mL) and cooled to
0 ꢀC. Sodium borohydride (1.5 mmol, 57 mg) was added portionwise, and the reac-
tion mixture was allowed to warm to room temperature and stirred overnight.
The reaction was quenched by the addition of ammonium chloride (ꢂ100 mg) and
stirred for an additional 5 min. The solvent was removed under reduced pressure,
and the residue was dissolved in dichloromethane and washed successively with satu-
rated sodium bicarbonate solution (20 mL), deionised water (20 mL), and brine
(20 mL). The organic layer was dried over magnesium sulfate and filtered, and the
solvent was removed under reduced pressure. The viscous, orange oil was then pur-
ified on alumina using 5% ethyl acetate in cyclohexane running to pure ethyl acetate.
The product 3a as mixture of diastereoisomes (69:31 1H NMR ratio) was obtained as
a colorless oil in 84% yield.
1
=
H NMR (500 MHz, CDCl3) d=ppm: 5.14 (d, J ¼ 5.1, 1H, OC CH), 3.95 (t,
J ¼ 4.4 Hz, 1H, MeOCH), 3.82–3.77 (m, 1H, HOCHH), 3.74–3.68 (m, 1H,
HOCHH), 3.34 (s, 3H, OCH3), 2.66 (m, 1H), 2.12–2.08 (m, 1H), 1.95–1.85 (m,
1H), 1.78–1.70 (m, 1H), 1.60–1.55 (m, 1H, overlap with water), 0.93 [bs, 9H,
SiC(CH3)3], 0.17 (bs, 3H, CH3SiCH3), 0.16 (bs, 3H, CH3SiCH3). 13C NMR
=
(126 MHz, CDCl3) d=ppm: 156.2 (OCCH), 102.4 (OC CH), 76.9 (CHOCH3), 65.4
(CH2OH), 55.6 (CHOCH3), 39.8 (CHCH2OH), 29.9 (SiOCCH2CH2), 25.6
[SiC(CH3)3], 20.8 (SiOCCH2CH2), 18.0 [SiC(CH3]3), ꢁ4.4 (CH3SiCH3), ꢁ4.4
(CH3SiCH3).
Main resonances of minor diastereomer. 1H NMR (500 MHz, CDCl3)
=
d=ppm: 4.97 (t, J ¼ 2.0 Hz, 1H, OCCH C), 3.93–3.89 (m, 1H, CH3OCH),
3.71–3.54 (m, 2H), 3.33 (s, 3H, OCH3), 2.57–2.51 (m, 1H), 2.20–2.08 (m 1H),
2.01–1.96 (m, 1H), 1.87–1.79 (m, 1H), 1.46–1.36 (m, 1H), 0.92 [bs, 9H, SiC(CH3)3],
13
=
016 (bs, 6H, CH3SiCH3). C NMR (126 MHz, CDCl3) d=ppm: 155.2 (OC CH),
=
103.1 (OC CH), 80.0 (CHOCH3), 66.8 (CH2OH), 54.5 (CHOCH3), 40.3
(CHCH2OH), 29.0 (SiOCCH2CH2), 25.6 [SiC(CH3)3], 22.9 (SiOCCH2CH2), 18.0
[SiC(CH3]3), ꢁ4.3 (CH3SiCH3), ꢁ4.5 (CH3SiCH3). HR-MS: m=z calcd. for
C19H30O2Si (M þ H)þ: 295.1705; found: 295.1707.
Synthesis of (4-(tert-Butyldimethylsilyloxy)-2-phenylcyclohex-3-
enyl)methanol (3b)
Aldehyde 2b (2.9 mmol, 0.92 g) was dissolved in ethanol (30 mL) and cooled to
0 ꢀC. Sodium borohydride (1.5 mmol, 57 mg) was added portionwise to the stirred

1872
E. LESTINI ET AL.
solution, and the reaction mixture was allowed to warm to room temperature and
stirred overnight. The reaction was quenched by the addition of ammonium chloride
(ꢂ100 mg) and stirred for an additional 5 min. The solvent was removed under
reduced pressure, and the residue was dissolved in dichloromethane and washed suc-
cessively with saturated sodium bicarbonate solution (20 mL), deionized water
(20 mL), and brine (20 mL). The organic layer was dried over magnesium sulfate
and filtered, and the solvent was removed under reduced pressure. The viscous,
orange oil was then purified on silica using 10% ethyl acetate in cyclohexane running
to pure ethyl acetate. Product 3b was recovered as a colorless oil in 82% yield. The
=
well-resolved pair of diastereotopic protons corresponding to the OC CH protons
at 4.98 ppm and 4.81–4.79 ppm display a 60:40 ratio.
Main resonances of minor diastereomer. 1H NMR (500 MHz, CDCl3) d=
ppm: 7.32–7.26 (ArH, m, 3H, overlap with major diastereomer), 7.24–7.19 (m, 2H,
=
ArH, overlap with major diastereomer), 4.81–4.79 (m, 1H, OC CH), 3.62–3.56
(m, 1H), 3.45–3.38 (m, 1H), 3.32–3.17 (m, 1H, overrun with major diastereomer),
2.33–2.06 (m, 3H, overlap with major diastereomer), 1.99–1.96 (m, 1H), 1.71–1.57
(m, 1H, overlap with major diastereomer), 0.93 [s, 9H, SiC(CH3)3], 0.16 (s, 3H,
CH3SiCH3), 0.14 (s, 3H, CH3SiCH3). 13C NMR (126 MHz, CDCl3) d=ppm: 151.2
=
=
(OC CH), 145.8, 128.3, 128.2, 126.3, 108.0 (OCCH C), 65.1, 44.1, 43.9, 29.2
(SiOCCH2CH2), 25.7 [SiC(CH3)3], 25.0 (SiOCCH2CH2), 18.0 [SiC(CH3)3], ꢁ4.3
(CH3SiCH3), ꢁ4.4 (CH3SiCH3). HR-MS: m=z calcd for C14H28O3Si (M þ Na)þ:
319.2088; found 319.2078.
Synthesis of (4-(tert-Butyldimethylsilyloxy)-2-methoxycyclohex-3-
enyl)methyl Methanesulfonate (4a)
Alcohol 3a (1.6mmol, 0.44g) was dissolved in dry dichloromethane (10 mL)
under a nitrogen atmosphere, utilizing activated molecular sieves, and cooled to
0 ꢀC. Dry triethyl amine (2 mmol, 0.28mL) was added to the solution, and mesyl
chloride (1.8 mmol, 0.14mL) was added dropwise. The reaction mixture was stirred
for 5 min and then allowed to warm to room temperature and stirred for a further
72h. The mixture was filtered to remove molecular sieves, washed with deionized
water (15 mL) and brine (15 mL), dried over magnesium sulfate, filtered, and the sol-
vent was removed under reduced pressure to give a pale yellow oil in 88% yield. The
product was used immediately without further purification due to decomposition. An
attempt to purify the product for analysis using alumina and 5% ethyl acetate in cyclo-
hexane running to pure ethyl acetate as an eluant was partially successful. Purification
gave the major diastereomer with some minor contamination.
Major diastereomer. 1H NMR (500 MHz, CDCl3) d=ppm: 5.07 (d,
=
J ¼ 5.3 Hz, 1H, OC CH), 4.27 (dd, J ¼ 9.6, 7.6 Hz, 1H, SOCHH), 4.07 (dd,
J ¼ 9.6, 7.2 Hz, 1H, SOCHH), 3.76 (t, J ¼ 4.5 Hz, 1H, CH3OCH), 3.23 (s, 3H,
OCH), 2.93 (bs, 3H SCH3), 2.06–1.92 (m, 3H), 1.72–1.53 (m, 2H), 0.85 [bs, 9H,
SiC(CH3)3], 0.10 (bs, 3H, CH3SiCH3), 0.09 (bs, 3H, CH3SiCH3). 13C NMR
=
=
(126 MHz, CDCl3) d=ppm: 155.7 (OCCH C), 102.1 (OCCH C), 72.5, 71.3, 55.5
(OCH3), 38.1, 36.8, 29.2 (SiOCCH2CH2), 25.5 [SiC(CH3)3], 20.1 (SiOCCH2CH2),

SYNTHESIS OF 4-METHYLENECYCLOHEX-2-ENONE
1873
17.9 [SiC(CH3)3], ꢁ4.5 (CH3SiCH3), ꢁ4.6 (CH3SiCH3). HR-MS: m=z calcd. for
C15H30O5SSiNa (M þ Na)þ: 373,1481; found 373.1498.
Synthesis of (4-(tert-Butyldimethylsilyloxy)-2-phenylcyclohex-3-
enyl)methyl Methanesulfonate (4b)
Alcohol 3b (1.2 mmol, 0.38 g) was dissolved in dry dichloromethane (10 mL)
under a nitrogen atmosphere, utilizing activated molecular sieves, and cooled to
0 ꢀC. Dry triethyl amine (2 mmol, 0.28 mL) was added to the solution, and mesyl
chloride (1.3 mmol, 0.1 mL) was added dropwise. The reaction mixture was stirred
for 5 min, allowed to warm to room temperature, and stirred for a further 72 h.
The mixture was filtered to remove molecular sieves, washed with deionized water
(15 mL) and brine (15 mL), dried over magnesium sulfate, filtered, and the solvent
was removed under reduced pressure. The product was obtained as a pale yellow
oil in 85% yield. The product was used immediately without further purification
to avoid decomposition. The well-resolved pair of diastereotopic protons corre-
=
sponding to the OC CH protons at 4.96 ppm and 4.81–4.78 ppm display a 60:40
ratio.
Major diastereomer. 1H NMR (500 MHz, CDCl3) d=ppm: 7.34–7.28 (m,
2H, ArH, overlap with minor diastereomer), 7.26–7.19 (m, 3H, ArH, overlap with
=
minor diastereomer), 4.96 (d, J ¼ 5.0 Hz, 1H, OCCH C), 3.78–3.73 (m, 2H,
SOCH2), 3.71 (t, J ¼ 5.3 Hz, 1H, SOCH2CH), 2.92 (s, 3H, SCH3), 2.36–2.18 (m,
4H), 1.70–1.63 (m, 1H, overlap with minor diastereomer), 0.94 [s, 9H, SiC(CH3)3),
=
0.17 (bs, 3H], 0.17 (bs, 3H). 13CNMR (126 MHz, CDCl3) d=ppm: 151.7 (OCCH C),
=
140.8 (Ar), 129.4 (Ar), 128.2 (Ar), 126.9 (Ar), 106.0 (OCCH C), 71.7 (SOCH2), 41.6,
37.5, 37.2, 28.6 (SiOCCH2CH2), 25.7 [SiC(CH3)3], 20.8 (SiOCCH2CH2), 18.0
[SiC(CH3)3], ꢁ4.3 (CH3SiCH3), ꢁ4.4 (CH3SiCH3).
Minor diastereomer. 1H NMR (500 MHz, CDCl3) d=ppm: 7.34–7.28 (ArH,
m, 2H, overlap with minor diastereomer), 7.26–7.19 (ArH, m, 3H, overlap with
=
minor diastereomer), 4.81–4.78 (OCCH C, m, 1H), 4.13–4.08 (SOCHH, m, 1H),
4.06–4.00 (SOCHH, m, 1H), 3.34–3.27 (SOCH2CH, m, 1H), 2.89 (SCH3, s, 3H),
2.16–2.09 (m, 1H), 2.02–1.95 (m, 1H), 1.94–1.87 (m, 1H), 1.70–1.63 (m, 1H, overlap
with major diastereomer), 0.93 [SiC(CH3)3, s, 9H], 0.16 (bs, 3H, CH3SiCH3), 0.14
13
=
(bs, 3H, CH3SiCH3). C NMR (126 MHz, CDCl3) d=ppm: 151.1 (OCCH C),
=
144.5 (Ar), 128.6 (Ar), 128.1 (Ar), 126.7 (Ar), 107.1 (OCCH C), 71.6 (SOCH2),
43.3, 41.3, 37.1, 28.8 (SiOCCH2CH2), 25.6 (SiC(CH3)3), 24.7 (SiOCCH2CH2),
18.0 (SiC(CH3)3), ꢁ4.3 (CH3SiCH3), ꢁ4.4 (CH3SiCH3). HR-MS: m=z calcd. for
C20H33O4SSi (M þ H)þ: 397.1869; found: 397.1880.
Synthesis of 4-Methylenecyclohex-2-enone (6) and
(4-Oxocyclohex-2-enyl)methylmethanesulfonate (7)
Methanesulfonate 4a (1.07 mmol, 0.37 g) was added to a solution of sodium
iodide (2 mmol, 0.13 g) in acetone (15 ml). The reaction was refluxed under stirring
for 12 h. The solvent was removed under reduced pressure, and the residue was dis-
solved in ethyl acetate (20 ml). The resulting solution was washed with water (15 mL)

1874
E. LESTINI ET AL.
and brine (15 mL). The organic phase was collected, dried with magnesium sulfate,
filtered, and the solvent was removed under reduced pressure. The products 6 and 7
were purified on silica gel using 30% ethyl acetate in cyclohexane as an eluant. Pro-
duct 6 was obtained as a colorless oil in 70% yield; 7 was obtained as an off-white,
waxy solid as a minor side product.
Compound 6. 1H NMR (500 MHz, CDCl3) d=ppm 7.09 (d, J ¼ 9.9 Hz, 1H,
=
=
=
=
=
O CCH CH), 5.96 (d, J ¼ 9.9 Hz, 1H, O CCH CH), 5.34 (s, 1H, C CHH),
13
=
=
5.29 (s, 1H, C CHH), 2.76 (t, J ¼ 7.2 Hz, 2H, O CCH2), 2.53 (t, 7.3 Hz, 2H,
=
O CCH2CH2).
=
C NMR (126 MHz, CDCl3) d=ppm: 199.0 (C O), 147.3
=
=
=
=
=
=
(O CCH CH), 140.6 (CH2 C), 128.1 (O CCH CH), 119.3 (CH2 C), 37.1
þ
=
(O CCH2), 29.2 (O CCH2CH2). HR-MS: m=z calcd. for C7H8O (M) ; 108.0575,
=
found: 108.0573.
Compound 7. 1H NMR (500 MHz, CDCl3) d=ppm: 6.87–6.83 (m, 1H,
=
=
=
=
O CCH CH), 6.11 (1H, dd, J ¼ 10.2 Hz, 2.3 Hz, O CCH CH), 4.28–4.13 (2H,
=
m, CH2OS), 3.05 (3H, s, SCH3), 2.93–2.86 (1H, m, O CCHH), 2.47–2.37 (1H, m,
=
=
O CCHH), 2.47–2.37 (1H, m, SOCH2CH), 2.23–2.15 (1H, m, O CCH2CHH),
=
1.92–1.85 (1H, m, O CCH2CHH). 13C NMR (500 MHz, CDCl3) d=ppm: 198.2
=
=
=
=
=
(C O), 147.8 (O CCH CH), 131.3 (O CCH CH), 70.4 (CH2OS), 37.6, 36.þ2,
=
36.2, 25.3 (O CCH2CH2). HR-MS: m=z calcd. for C8H12OSNa (M þ Na) :
227.0354; found: 227.0348.
Synthesis of (4-Oxocyclohex-2-enyl)methylmethanesulfonate (7)
Methanesulfonate 4a (1.5 mmol, 0.53 g) was dissolved in acetone (20 mL) and
refluxed for 8 h. The reaction was worked up and purified as described for 6 and
7. Product 7 was obtained as an off-white waxy solid in 76% yield.
4-(Iodomethyl)-3-phenylcyclohexanone (8)
The synthetic procedure employed for 6 and 7 was utilized to produce 8, using
methanesulfonate 4b as a starting material. The product was purified on silica gel,
eluant 10% ethyl acetate in cyclohexane. Compound 8 was recovered as a white solid
in 35% yield. No optimization was attempted. A mixture of diastereomers was
obtained in 70:30 ratio. The major diastereomer was obtained as a pure sample
for analysis; it was not possible to obtain the minor diastereomer as a pure sample
and the NMR of a mixture is given.
Major. 1H NMR (500 MHz, CDCl3) d=ppm: 7.35–7.26 (m, 3H, ArH), 7.14 (d,
J ¼ 7.0 Hz, 2H, ArH), 3.63 (q, J ¼ 5.8 Hz, 1H, HC-Ar), 3.07–2.94 (m, 2H, CH2I),
13
=
2.75–2.63 (m, 2H, O CCH2CH-Ar), 2.57–2.42 (m, 3H), 2.10–1.93 (m, 2H,
=
=
O CCH2CH2). C NMR (126 MHz, CDCl3) d=ppm: 210.6 (C O), 140.0 (Ar),
=
128.6 (Ar), 128.2 (Ar), 127.2 (Ar), 44.7, 44.2, 42.7, 38.6 (O CCH2CH2), 27.7
=
(O CCH2CH2), 8.1 (CH2I).
Minor. 1H NMR (500 MHz, CDCl3) d=ppm: 7.37–7.26 (m, 3H, ArH, overlap
with major diastereomer), 7.26–7.23 (m, 1H, ArH, overlap with major diasteromer),
7.15–7.13 (m, 1H, ArH), 3.20–3.15 (m, 1H, HC-Ar), 2.86–2.78 (m, 2H, CH2I),

SYNTHESIS OF 4-METHYLENECYCLOHEX-2-ENONE
1875
2.76–2.42 (m, 4H, overlap with major diastereomer), 2.32–2.24 (m, 1H), 1.93–1.83
(m, 1H), 1.81–1.69 (m, 1H). 13C NMR (126 MHz, CDCl3) d=ppm: 209.4, 141.8,
129.1, 127.3, 127.2, 49.0, 48.2, 41.9, 40.5, 32.4, 26.9, 12.9 HR-MS: m=z calcd. for
C13H15IO (M)þ: 314.0168; found: 314.0172.
ACKNOWLEDGMENTS
This work was supported by HEA PRTLI cycles 3 and 4. The authors thank
Michael Carroll for his contribution to the project.
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