Synthetic studies on CP-225,917 and CP-263,114: Concise synthesis of the bicyclic core using an intramolecular Mukaiyama aldol reaction

Article abstract of DOI:10.1039/b202752f

A concise synthesis of the bicyclo[4.3.1]dec-1(9)-en-10-one core of the natural products CP-225,917 and CP-263,114 is reported, employing an intramolecular Mukaiyama aldol cyclisation as a key step.

Full text of DOI:10.1039/b202752f

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Synthetic studies on CP-225,917 and CP-263,114:
concise synthesis of the bicyclic core using an intramolecular
Mukaiyama aldol reaction†
1
Alan Armstrong,*‡a,b Trevor J. Critchley,a Marie-Edith Gourdel-Martin,a Richard D. Kelseyb
and Andrew A. Mortlockc
a School of Chemistry, University of Nottingham, Nottingham, UK NG7 2RD
b Department of Chemistry, Imperial College, London, UK SW7 2AY
c AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire,
UK SK10 4TG
Received (in Cambridge, UK) 19th March 2002, Accepted 10th April 2002
First published as an Advance Article on the web 1st May 2002
A concise synthesis of the bicyclo[4.3.1]dec-1(9)-en-10-one core of the natural products CP-225,917 and CP-263,114
is reported, employing an intramolecular Mukaiyama aldol cyclisation as a key step.
Introduction
The natural products CP-225,917 1 and CP-263,114 2 were
isolated by Pfizer workers in the mid-1990s from the ferment-
ation products of an unidentified fungus.1a,1b They were
identified as moderate inhibitors of squalene synthase and
ras-farnesyl protein transferase, enzymes of interest in the
cholesterol-lowering and anti-cancer areas respectively. A
major stimulus for the synthetic chemist to study these two
compounds is their highly novel structure. Common to both
is a highly functionalised bicyclo[4.3.1]dec-1(9)-en-10-one core
containing an anti-Bredt, bridgehead alkene. Further synthetic
challenges are presented by the fused maleic anhydride unit and
a quaternary stereocentre at C14 (natural product numbering)
which is part of a lactone acetal array. Compounds 1 and 2
display very similar structural features, the only difference
being the acetal linkage in 2 joining the sidechain C7-hydroxy
group to the bridgehead carbonyl. Interconversion of 1 and 2
has been shown to be feasible.1c The synthetic community has
Fig. 1
risen admirably to the challenges posed by the synthesis of
these compounds: as well as many inventive model studies,2,3
monumental total syntheses have been recorded by the
groups of Nicolaou,4 Danishefsky,5 Shair,6 and Fukuyama.7
Asymmetric total synthesis has allowed the absolute config-
uration of the natural products to be revised to that shown in
Fig. 1.4–7
When our own interest in these compounds began, no
synthetic studies of CP-225,917 had been reported. We hoped
to develop a route that would allow the rapid preparation of the
bicyclo[4.3.1]dec-1(9)-en-10-one core and a range of analogues.
Since we were concerned by the potential sensitivity of the
anhydride unit, we envisaged its introduction at a late stage
in the synthesis. Having simplified the polycyclic system by
removing the anhydride group (Scheme 1), the next problem
was how we were to construct the γ-lactone acetal moiety and
the C14 quaternary stereocentre. The natural product displays a
carboxylic acid at C14 cyclised onto a ketone at C26, and
Scheme 1
we hoped to utilise this feature in the construction of the C14
stereocentre, allowing differentiation of two diastereotopic
ester groups via the derived carboxylic acids. Having a gem-
diester at C14 was in turn a useful pointer to further facile bond
disconnections. It was envisaged that the anion-stabilising
properties of such a diester could be used to create the C13–
C14 bond via attack of a C14 anion onto a suitably activated
† Electronic supplementary information (ESI) available: crystal data for
13a. See http://www.rsc.org/suppdata/p1/b2/b202752f/
‡ Present address: Deptartment of Chemistry, Imperial College,
London, UK SW7 2AY
1344
J. Chem. Soc., Perkin Trans. 1, 2002, 1344–1350
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b202752f

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electrophilic centre at C13. A further bond disconnection
between C10 and C11 was suggested by the anion stabilising
properties of the C26 carbonyl group, i.e. an anion at C10
would attack a suitably activated C11. These latter two discon-
nections led to a simple cyclohexenone-malonate derivative 3
and a suitable bis-electrophile (Scheme 1).
Having devised a synthetic strategy, we began our investi-
gations by looking at a model synthesis of the core bicyclic
system lacking the side chains (i.e. R1 = R2 = H in Scheme 1).
Here we report in full the realisation of this goal,8 resulting in
the development of a highly concise synthesis of the key
bicyclo[4.3.1]dec-1(9)-en-10-one core.
the electrophile, and the cyclohexanone the nucleophile. Hence,
treatment of the lithium enolate of cyclohexanone with diethyl
oxomalonate generated the tertiary alcohol 6 in good yield
(Scheme 2). It was now hoped that we could effect elimination
of this alcohol to create the exocyclic olefin 4. Several con-
ditions were tried, without success: thionyl chloride,11 Burgess’
reagent12 and boron tribromide13 failed to react with the
tertiary alcohol. We were also unable to form a mesylate§ from
6. Reaction did occur with phosphorus tribromide, but the
major product was lactone 7 (Scheme 2), presumably derived
from elimination of the tertiary alcohol and subsequent
lactonisation of the enol form of the ketone. Exposure of
tertiary alcohols to Swern conditions ((COCl)2–DMSO) has
been reported to effect elimination,14 but treatment of 6 in this
way furnished only the corresponding methylthiomethyl ether.
Following these unsuccessful efforts to effect elimination of
alcohol 6, attempts to convert it to the corresponding acetate
leaving group yielded more interesting and encouraging results.
Treatment with acetic anhydride and triethylamine in the
presence of a catalytic amount of 4-dimethylaminopyridine
(DMAP) provided acetate 9 (19%) along with enol acetate
8 (20%) and—encouragingly—the desired enone 3 (8%),
presumed generated from 9 via base-mediated elimination
followed by alkene isomerisation.
Results and discussion
Our first challenge was the synthesis of the requisite bis-
nucleophile component, cyclohexenone 3. Since our actual
requirement was for an allylic anion that would act as a C14-
nucleophile, we initially reasoned that it would not matter if
we were to synthesise either endocyclic olefin 3, or exocyclic
isomer 4, since treatment of either with base should generate
the same allylic anion. In line with precedent for deconjugative
alkylation of α,β-unsaturated esters,9 we anticipated that
alkylation of such an anion would occur α to the diester,
leading to an endocyclic enone. Thus, our first explorations
were aimed at establishing a synthetic route to ketone 4, which
we anticipated being easier to prepare than 3. Attempted
synthesis of 4 by condensation of diethyl malonate and
cyclohexane-1,2-dione mediated by base (NaOMe, MeOH) or
Lewis acids was unsuccessful, perhaps unsurprisingly in view of
the likely predominance of the enol tautomer of the dione. In a
second approach, we hoped to use allylic oxidation to introduce
the ketone functionality in 4. Treatment of cyclohexanone with
dimethyl malonate under standard Knoevenagel conditions
afforded the known10 exocyclic olefin 5. However, attempted
allylic oxidation of 5 under various conditions (e.g. SeO2 or
CrO3) failed to effect the desired transformation, probably
because the alkene is highly electron deficient.
As a viable route for the synthesis of 3, this reaction was
clearly unsatisfactory, as it was low yielding and gave rise to
several unwanted by-products. Since 3 appeared to arise from
acetate 9, we attempted to find conditions for the clean form-
ation of the latter, and were pleased to find that the use of
catalytic trimethylsilyl trifluoromethanesulfonate in acetic
anhydride as recently reported by Procopiou and co-workers15
provided acetate 9 in a very rapid and clean reaction, with none
of the by-products observed under the base-mediated con-
ditions (Scheme 2). With a clean synthesis of acetate 9 in hand,
we next examined the elimination step. Reaction of 9 with NaH
in DMF afforded a moderate yield (43%) of a product which
was isomeric with the desired alkenes 3 and 4 but which did not
1
display the expected H and 13C NMR characteristics. Most
notably, it lacked the ketone carbon in the 13C NMR spectrum,
1
and the H NMR spectrum indicated the presence of only one
ethyl ester. This compound was tentatively assigned the
structure 10 which is believed to arise from elimination to give
the exocyclic alkene 4 followed by rearrangement to the more
stable pseudoester. There is precedent for this rearrangement
In view of these unsuccessful studies, we successfully reversed
the roles of the two components, making the malonate portion
§ The IUPAC name for mesylate is methanesulfonate.
Scheme 2 Reagents and conditions: (a) (i) LDA, THF, Ϫ78 ЊC, 1 h, (ii) diethyl oxomalonate, Ϫ78 to 0 ЊC, 12 h, 80%. (b) 1 eq. PBr3, PhH, reflux, 83%.
(c) 1.5 eq. Ac2O, 10 mol% DMAP, 10 eq. Et3N, 24 h, (9) 19%, (8) 20% and (3) 8%. (d) 1.5 eq. Ac2O, 2 mol% TMSOTf, 0 ЊC, 20 min, (9) 80%. (e) NaH,
DMF, 43%. (f ) 2 eq. DBU, toluene, 0 ЊC, 32%. (g) 2 eq. Dabco, toluene, reflux, 90 min, 75%.
J. Chem. Soc., Perkin Trans. 1, 2002, 1344–1350
1345

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in acyclic 4-oxo-2-alkan-2-ylidenemalonates.16 Fortunately,
however, amine bases did yield the desired elimination products.
Treatment of 9 with 2 eq. DBU in toluene at 0 ЊC led to form-
ation of endocyclic olefin 3, albeit in low yield (32%). We
attributed the low yield to base-induced polymerisation
side-reactions. This route gave us rapid access to our required
ketone 3 in just 3 steps, from cyclohexanone. However, it was
still rather inefficient at the elimination stage, and upon scaling
up to gram quantities of material, yields were found to drop
even further. In an effort to reduce polymerisation and other
side-reactions, we performed the reaction at lower temperatures
and higher dilutions. Adding the base at Ϫ20 ЊC caused com-
plete cessation of reaction, and no improvement in yield was
seen under higher dilution conditions. We then turned to alter-
native strong bases to effect the reaction. Neither LDA (2 eq.)
nor sodium tert-butoxide (2 eq.) caused any reaction to occur,
and treatment of 9 with two equivalents of triethylamine in
toluene at reflux gave only a 16% yield of 3. Eventually, 1,4-
diazabicyclo[2.2.2]octane (Dabco) in toluene at reflux was
found to effect the required conversion in high and reproducible
yields. It is assumed that the increase in yield relative to the
DBU conditions is due to the lower basicity of Dabco which
reduces polymerisation side-reactions that may be a problem
with the stronger base. It is possible, however, that Dabco
promotes alternative mechanistic pathways by acting as a
nucleophilic catalyst. While it is assumed that the formation of
3 from 9 proceeds via the exocyclic isomer 4, performing the
reaction in an NMR tube in d6-toluene at 100 ЊC, recording
spectra at 5 minute intervals, displayed no detectable inter-
mediates, suggesting that isomerisation of 4 is rapid.
Now that we had access to large quantities of ketone 3 via
a simple three-step route from cyclohexanone, we were in a
position to investigate its use as a bis-nucleophile. A range of
carbon–carbon bond-forming reactions were considered for
the cyclisation, and of these, the Mukaiyama directed aldol
reaction was thought to be a particularly good option.17 The
intramolecular Mukaiyama aldol reaction has frequently been
employed as a versatile tool for the synthesis of medium rings.18
Unlike the base-catalysed crossed-aldol reaction, it allows
control over which component is the nucleophile—the silyl enol
ether—and which is the electrophile: an aldehyde or acetal.
With this in mind, we proceeded to pursue a Mukaiyama aldol
cyclisation approach to the core bicycle of CP-225,917. In order
to introduce the acetal we required, ketone 3 was alkylated with
commercially available 3-bromopropionaldehyde dimethyl
acetal (Scheme 3), corresponding to the bis-electrophile unit
Formation of the silyloxydiene 12 was achieved by trapping
the kinetic lithium enolate of 11 with trimethylsilyl chloride. In
the key cyclisation reaction, treatment of 12 with titanium
tetrachloride in dichloromethane generated the model [4.3.1]-
bicycle 13 as a mixture of diastereomers, which could be
separated by flash chromatography to give 13a (12%) and 13b
(40%).
Assignment of the bicyclic structure shown to be ketone 13
was initially made by spectroscopic analysis. The upfield shift
observed for the vinylic proton at C16 (natural product number-
ing) in the 1H NMR spectrum (ca. 6.4 ppm in 13 compared to
6.95 ppm in 11) suggests that the enone is not able to adopt
planarity in the cyclised product and supports formation of
the anti-Bredt system. 1H-COSY, HMQC and HMBC data
confirmed the connectivity. Additionally, the carbonyl stretch-
ing frequencies in the IR spectrum of 13a (1708 cmϪ1) and 13b
(1715 cmϪ1) were similar to that reported (1710 cmϪ1) for
bicyclo[4.3.1]dec-1(9)-en-10-one itself.19 In our preliminary
communication of this work,8 we proposed a tentative assign-
ment of relative stereochemistry at the methoxy-bearing
C11-stereocentre based on NOE and molecular mechanics
studies. However, we subsequently obtained an X-ray crystal
structure20 of the minor isomer 13a which showed our initial
tentative assignment to be incorrect and allowed unambiguous
assignment of the stereochemistry as depicted in Scheme 3, as
well as structural confirmation.
Whilst the yield obtained in the initial small-scale
Mukaiyama aldol cyclisations of 12 was good, it proved
difficult to attain consistently high yields in repeat runs of the
experiment, particularly on larger scales. In the pursuit of
higher reproducibility, we examined alternative Lewis acids.
Boron trifluoride–diethyl ether gave a similar overall yield (20%
13a and 28% 13b), whilst none of the cyclised product could
be observed when trimethylsilyltrifluoromethanesulfonate or
TiCl(OiPr)3 was used. Use of scandium triflate ¶ in THF–
water21 afforded only the hydrolysed ketone 11, whilst the
same Lewis acid in dichloromethane at Ϫ78 ЊC gave only a 23%
yield of aldol products 13 (13a : 13b approx 1 : 4). The
best reproducibility on a larger scale was found using zinc()
chloride and 4 Å molecular sieves22 in dichloromethane at
room temperature, which gave a higher yield of aldol products
(40–62%) with a 40 : 60 diastereoisomeric ratio of 13a : 13b
along with 10–34% of starting ketone 11.
The C11-methoxy-substituent in 13 did not appear amenable
to further synthetic manipulation towards the required
anhydride unit. Indeed, preliminary attempts at its selective
cleavage using trimethylsilyl iodide18d resulted in the opening of
the bicyclic ring system by retro-aldol reaction. We were
attracted to the possibility of employing a dithioacetal in the
ring closure step, since the resulting thioether in the cyclisation
product could be converted to an alkene by oxidation and
sulfoxide syn-elimination, or transformed into a ketone by
a Pummerer-type process. The required dithioacetal 14 was
prepared by treatment of dimethoxyacetal 11 with (phenyl-
thio)trimethylsilane in the presence of TMSOTf (Scheme 4).
Scheme 3 Reagents and conditions: (a) (i) 1.05 eq. NaH, DMF, 0 ЊC,
1 h (ii) Bu4NI, 3-bromopropionaldehyde dimethylacetal, 60 ЊC, 21 h,
68%. (b) (i) LDA, THF, Ϫ78 ЊC, 10 min (ii) 1.8 eq. TMSCl, Ϫ78 ЊC, 4 h,
92%. (c) TiCl4, CH2Cl2, Ϫ78 ЊC to RT, 15 h, 13a: 12%, 13b: 40%.
Scheme 4 Reagents and conditions: (a) for 14: Me3SiSPh, TMSOTf,
CH2Cl2, 98%. For 15: Me3SiS(2,4,6-(CH3)3C6H2), TMSOTf, CH2Cl2,
64%. (b) TMSOTf, Et3N, CH2Cl2, 88%.
envisaged in our retrosynthesis (Scheme 1). The anion of 3 was
pre-formed by treatment with an equimolar amount of sodium
hydride in DMF and then alkylated with 3-bromopropion-
aldehyde dimethyl acetal in the presence of catalytic tetra-
butylammonium iodide, providing acetal 11 in 68% yield.
¶ The IUPAC name for triflate is trifluoromethanesulfonate.
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J. Chem. Soc., Perkin Trans. 1, 2002, 1344–1350

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Unfortunately, the derived silyl enol ether 16 did not undergo
cyclisation on exposure to a range of Lewis acids (Hg(OTf )2),
ZnCl2, TiCl4, or SnCl4). Heathcock and co-workers have
reported that the mesityl-dithioacetal counterparts are more
reactive in intermolecular reactions with silyl enol ethers.23
However, attempted cyclisation of 17 proved similarly unsuc-
cessful (using TMSOTf, ZnCl2, ZnBr2, TiCl4, SnCl4, Ag(OTf )2,
Hg(OTf )2, HgCl2, or Me2(MeS)SBF4). At this time, therefore,
it seems likely that the most fruitful approach for progressing
the total synthesis will involve the conventional acetal-mediated
cyclisation, using an acetal that leads to a more readily depro-
tected C11-ether (e.g. benzyl).
brine (100 ml), saturated aqueous sodium bicarbonate (50 ml)
and brine (100 ml), dried (MgSO4) and concentrated in vacuo.
Chomatography (5% EtOAc–petrol) gave the diester 5 (700 mg,
33%) as a yellow oil; δH (400 MHz, CDCl3) 3.75 (6H, s,
2 × OMe), 2.50 (4H, t, J 6.1, C(2)H2 and C(6)H2), 1.71–1.65
(4H, m, C(3)H2 and C(5)H2), 1.62–1.57 (2H, m, C(4)H2);
δC (100 MHz, CDCl3) 166.1, 162.3, 121.1, 52.0, 32.7, 28.1, 25.9.
Diethyl 2-hydroxy-2-(2-oxocyclohexyl)malonate 6
A solution of n-butyllithium (2.3 M, 4.35 ml, 10 mmol) was
added dropwise to an ice-cool solution of diisopropylamine
(1.4 ml, 10 mmol) in tetrahydrofuran (25 ml) under nitrogen.
The mixture was stirred at 0 ЊC for 30 min before being cooled
to Ϫ78 ЊC. Cyclohexanone (1.04 ml, 10 mmol) was added
dropwise and the solution stirred for 45 minutes. Diethyl
oxomalonate (1.52 ml, 10 mmol) was added and the mixture
stirred for 15 hours, before being quenched with saturated
aqueous ammonium chloride (30 ml), extracted with ethyl
acetate (6 × 10 ml), dried (MgSO4) and concentrated in vacuo.
Distillation of the crude residue gave the alcohol 6 (2.19 g, 80%)
as a yellow oil (Found: C, 57.14; H, 7.69; C13H20O6 requires C,
57.30; H, 7.43%); bp 149–151 ЊC (1.5 mmHg); νmax(film)/cmϪ1
3497, 1738 (br); δH (270 MHz, CDCl3) 4.26–4.12 (4H, m,
2 × CH2O), 3.87 (1H, br s, OH ), 3.45 (1H, dd, J 5, 12,
C(1Ј)HCO), 2.38–2.21 (2H, m, C(3Ј)H2CO), 2.05–1.55 (6H, m),
1.22 (6H, m, 2 × Me); δC (67.5 MHz, CDCl3) 208.9 (s), 169.8 (s),
169.0 (s), 78.9 (s), 62.5 (t), 62.5 (t), 55.3 (d), 41.8 (t), 27.5 (t),
26.8 (t), 24.5 (t), 14.0 (q), 13.8 (q); m/z (FAB) 295 (MNaϩ, 85%),
273 (100, MHϩ), 199 (40, Mϩ Ϫ CO2Et).
Conclusions
The work reported here is an important first step in the develop-
ment of a synthetic approach to the CP-compounds 1 and 2.
The bis-electrophile approach using the Mukaiyama aldol
reaction as the key cyclisation step has allowed a highly concise
synthesis of model bicycle 13 which incorporates several of the
key features of the natural product. It is noteworthy that the
anti-Bredt bicyclic system can be prepared using straight-
forward chemistry, and the diester 3 can be envisaged as a
versatile precursor to a variety of analogues. The model com-
pound 13 has a gem-diester group which could be converted to
the lactone acetal unit of the natural product, as well as having
the C26-bridgehead ketone in the correct oxidation state.
Further manipulations, as well as the asymmetric synthesis of
analogues of the key bis-nucleophile 3 bearing sidechain
functionality, are under exploration and will be reported in due
course.
Ethyl 2-oxo-2,4,5,6-tetrahydrobenzofuran-3-carboxylate 7
Phosphorus tribromide (44 µl, 0.48 mmol) was added dropwise
to a stirred solution of the alcohol 6 (64 mg, 0.24 mmol)
in benzene (0.5 ml). The solution was heated to reflux for
7 hours, then cooled and diluted with diethyl ether (15 ml) and
water (5 ml). The layers were separated, and the organic phase
washed with 5 M sodium bicarbonate (10 ml) and water
(10 ml), dried (MgSO4) and concentrated in vacuo to yield the
benzofuran 7 (41 mg, 83%) as an oil; νmax(film)/cmϪ1 1778, 1710,
1653, 1590; δH (400 MHz, CDCl ) 6.17 (1H, t, J 5, HC(7)᎐),
4.34 (2H, q, J 7.1, CH2O), 3.08 (2H, t, J 7, C(6)H2), 2.47 (2H,
dd, J 6, 11, C(4)H2), 1.94–1.64 (2H, m, C(5)H2), 1.36 (3H, t,
J 7.1, Me); m/z (EI) 208 (Mϩ, 100%), 163 (83, Mϩ Ϫ EtO),
135 (20, Mϩ Ϫ EtO2C) (Found Mϩ, 208.0737. C11H12O4 requires
M, 208.0736).
Experimental
1
Unless otherwise indicated, H and 13C spectra were recorded
in CDCl3 on Bruker DRX 500 MHz, AM 400 MHz or WM
250 MHz NMR spectrometers, using residual protic solvent
(CHCl3, δH = 7.26 ppm) or CDCl3 (δC = 77.0 ppm, t) as internal
reference. Coupling constants are measured in Hertz. The
multiplicities in 13C spectra were determined by DEPT experi-
ments. Infra-red spectra were run on a Perkin-Elmer 1605 FT-
IR machine from 4000–600 cmϪ1. Mass spectra were recorded
under conditions stated for that particular compound using
a VG-7070B, VG Micromass 70E, VG Biotech Quatro II,
VG ZAB-E, VG Autospec or Micromass LCT (Electrospray)
instrument. Microanalyses were performed at the University of
Nottingham. Column chromatography was performed on
Merck Kiesegel 60 (230–400 mesh). Diethyl ether and tetra-
hydrofuran solvents were distilled from sodium–benzophenone
ketyl, dichloromethane from calcium hydride and dimethyl-
formamide from anhydrous magnesium sulfate. Petrol refers
to petroleum ether of boiling range 40–60 ЊC which was
distilled prior to use. Analytical thin layer chromatography
was performed using pre-coated glass-backed plates (Merck
Kiesegel 60 F254) and visualised by ultra-violet light and/or
acidic ceric ammonium molybdate, or 2,4-dinitrophenyl-
hydrazine as appropriate.
᎐
3
Reaction of alcohol 6 with acetic anhydride–4-(dimethylamino)-
pyridine
4-(Dimethylamino)pyridine (5 mg, 37 µmol) was rapidly added
to a stirred solution of alcohol 6 (100 mg, 0.37 mmol) in
triethylamine (500 µl), followed by acetic anhydride (52 µl, 0.55
mmol). The solution was stirred for 24 hours, diluted with
methanol (5 ml), stirred for 10 minutes and then concentrated
in vacuo. The residue was dissolved in diethyl ether (10 ml),
washed successively with 2 M hydrochloric acid (5 ml),
saturated aqueous sodium bicarbonate (2 × 5 ml), dried
(MgSO4) and concentrated in vacuo. Chromatography (20%
EtOAc–petrol) gave acetate 9 (22 mg, 19%), alkene 3 (7 mg, 8%)
Dimethyl 2-cyclohexylidenemalonate 510a
A solution of titanium tetrachloride in dichloromethane (1 M,
20 ml, 20 mmol) was added dropwise over 1 h to dry tetrahydro-
furan (400 ml) and stirred under nitrogen at 0 ЊC. Subsequently,
cyclohexanone (1.04 ml, 10 mmol) and dimethyl malonate
(0.57 ml, 10 mmol) were added rapidly, followed by a solution
of pyridine (3.3 ml, 40 mmol) in tetrahydrofuran (10 ml), which
was added dropwise over 1 h. The mixture was allowed to warm
to room temperature, and was stirred for 135 hours. It was then
quenched with water (400 ml) and extracted with diethyl ether
(3 × 200 ml). The combined organic extracts were washed with
and diethyl 2-(2-acetoxycyclohex-2-enylidene)malonate,
8
(22 mg, 20%), as a colourless oil; 8 showed the following data:
νmax(film)/cmϪ1 1767, 1719, 1630, 1597; δH (250 MHz, CDCl3)
5.91 (1H, t, J 4.5, HC(3Ј)᎐), 4.27 (2H, q, J 7.1, CH O), 4.19
᎐
2
(2H, q, J 7.1, CH2O), 3.01–2.95 (2H, m, C(4Ј)H2), 2.40–2.33
(2H, m, C(6Ј)H2), 2.10 (3H, s, AcO), 1.80 (2H, q, J 6, C(5Ј)H2);
δC (67.5 MHz, CDCl3) 168.7, 166.4, 164.1, 145.5, 143.2, 129.6,
120.0, 61.3, 61.0, 27.7, 24.8, 21.5, 20.8, 14.0, 13.9; m/z (EI) 296
(Mϩ, 16 %), 253 (4, Mϩ Ϫ MeCO), 223 (7, Mϩ Ϫ CO2Et)
(Found Mϩ, 296.1250. C15H20O6 requires M, 296.1260).
J. Chem. Soc., Perkin Trans. 1, 2002, 1344–1350
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Diethyl 2-acetoxy-2-(2-oxocyclohexyl)malonate 9
hexane and suspended in dimethylformamide (5 ml). A solution
of diester 3 (743 mg, 2.9 mmol) in dimethylformamide (5 ml)
was added dropwise via cannula and the solution stirred
for 1 hour. Tetrabutylammonium iodide (35 mg, 0.09 mmol)
was added, followed by 3-bromopropionaldehyde dimethyl
acetal (460 µl, 3 mmol). The solution was warmed to 60 ЊC
overnight, cooled and diluted with ethyl acetate (100 ml),
washed with water (2 × 20 ml) and brine (20 ml), dried
(MgSO4) and concentrated in vacuo. Chromatography (20%
EtOAc–petrol) gave starting material 3 (200 mg, 27%) and
the acetal 11 (720 mg, 68%) as a colourless oil; νmax(film)/cmϪ1
Trimethylsilyl trifluoromethanesulfonate (2 µl, 5 mmol) was
added rapidly with stirring to an ice-cold solution of alcohol 6
(28 g, 0.1 mol) in acetic anhydride (20 ml) under nitrogen. The
solution was stirred vigorously for 20 minutes and then diluted
with dichloromethane (20 ml). After a further 15 minutes
the mixture was quenched with saturated aqueous sodium
bicarbonate (200 ml) and extracted with dichloromethane
(4 × 100 ml). The combined organic extracts were washed with
saturated aqueous sodium bicarbonate (100 ml) and brine
(50 ml), dried (MgSO4) and concentrated in vacuo. Azeotroping
with toluene (2 × 50 ml) and recrystallisation from pentane
gave the acetate 9 (25 g, 80%) as white crystals; mp 45–47 ЊC
(pentane) (Found C, 57.25; H, 7.05; C15H22O7 requires C, 57.32;
H, 7.05%); νmax(CHCl3)/cmϪ1 1747 br, 1719; δH (400 MHz,
CDCl3) 4.29–4.21 (4H, m, 2 × CH2O), 3.25 (1H, dd, J 12.8, 5.3,
C(1Ј)HCO), 2.42–2.33 (2H, m, C(3Ј)H2CO), 2.13 (3H, s, AcO),
2.12–1.95 (4H, m), 1.68–1.58 (2H, m), 1.28 (3H, t, J 7.1, Me),
1.27 (3H, t, J 7.0, Me); δC (100 MHz, CDCl3) 206.7 (s), 169.2
(s), 166.5 (s), 166.1 (s), 81.3 (s), 62.2 (t), 62.0 (t), 56.5 (d), 42.3
(t), 29.0 (t), 27.2 (t), 25.1 (t), 20.7 (t), 13.8 (q); m/z (EI) 314 (Mϩ,
2%), 272 (6, Mϩ Ϫ CH2CO), 254 (7, Mϩ Ϫ AcO).
1725, 1679; δH (400 MHz, CDCl ) 6.95 (1H, t, J 4, HC᎐),
᎐
3
4.33 (1H, t, J 6, HC(OMe)2), 4.20–4.14 (4H, m, 2 × CH2O),
3.28 (6H, s, 2 × MeO), 2.46–2.43 (4H, m), 2.15–2.10 (2H, m),
2.02–1.97 (2H, m), 1.64–1.58 (2H, m), 1.23 (6H, t, J 7.1,
2 × Me); δC (100 MHz, CDCl3) 197.2 (s), 170.1 (s),
147.0 (d), 137.2 (s), 104.4 (d), 61.5 (t), 59.6 (s), 52.6 (q), 38.6 (t),
29.1 (t), 28.5 (t), 26.2 (t), 22.3 (t), 13.9 (q); m/z (EI) 324
(Mϩ Ϫ MeOH, 5%), 251 (16, Mϩ Ϫ MeOH Ϫ CO2Et)
(Found Mϩ Ϫ MeO, 325.1630. C17H25O6 requires M Ϫ MeO,
325.1651).
Preparation of enol silane 12
Diethyl 2-(6-oxocyclohex-1-enyl)malonate 3
A solution of n-butyllithium (2.5 M, 800 µl, 2 mmol) was added
dropwise to a stirred, ice-cold solution of diisopropylamine
(280 µl, 2 mmol) in tetrahydrofuran (10 ml). The solution was
stirred for 30 minutes and then added via cannula to a stirred
solution of 11 (390 mg, 1.1 mmol) in tetrahydrofuran (15 ml) at
Ϫ78 ЊC. Trimethylsilyl chloride (255 ml, 2 mmol) was added
and stirring continued for 4 hours. The solution was diluted
with ethyl acetate (50 ml) and washed with 5% aqueous
ammonium hydroxide solution (2 × 10 ml), dried (MgSO4) and
concentrated in vacuo to give 12 (430 mg, 92%) as a yellow oil.
The crude silyloxydiene was used without further purification
and showed the following data: νmax(film)/cmϪ1 1730; δH (400
A solution of acetate 9 (1.0 g, 3.2 mmol) and 1,4-diaza-
bicyclo[2.2.2]octane (720 mg, 6.4 mmol) in dry toluene (10 ml)
was heated to reflux under nitrogen for 90 minutes. The solution
was diluted with diethyl ether (100 ml) and washed successively
with saturated aqueous ammonium chloride (100 ml) and brine
(100 ml), dried (MgSO4) and concentrated in vacuo. Chrom-
atography (20% EtOAc–petrol) gave the alkene 3 (612 mg, 75%)
as a colourless oil (Found: C, 61.63; H, 7.24; C13H18O5 requires
C, 61.41; H, 7.13%); νmax(film)/cmϪ1 1732, 1682, 1641 w; δH (250
MHz, CDCl ) 7.02 (1H, t, J 4.1, HC(2Ј)᎐), 4.69 (1H, d, J 1,
᎐
3
HC(2)(CO2Et)2), 4.20 (2H, q, J 7.1, CH2O), 4.18 (2H, q, J 7.1,
CH2O), 2.51–2.43 (4H, m, C(5Ј)H2, C(3Ј)H2), 2.08–2.00 (2H, m,
C(4Ј)H2), 1.25 (6H, t, J 7.1, 2 × Me); δC (100 MHz, CDCl3)
196.4 (s), 167.7 (s), 148.4 (d), 132.6 (s), 61.4 (t), 50.4 (d), 37.5 (t),
25.8 (t), 22.2 (t), 13.7 (q); m/z (FAB) 277 (MNaϩ, 54%), 255
(100, MHϩ), 209 (17, Mϩ Ϫ EtO).
MHz, CDCl ) 5.70 (1H, br s, HC᎐), 4.78 (1H, br s, HC᎐), 4.32
᎐
᎐
3
(1H, t, J 6, HC(OMe)2), 4.19–4.09 (4H, m, 2 × CH2O), 3.26
(6H, s, 2 × MeO), 2.11–2.01 (6H, m), 1.73–1.68 (2H, m), 1.22
(6H, t, J 7.1, 2 × Me), 0.15 (9H, s, Me3Si); δC (100 MHz, CDCl3)
170.6 (s), 147.9 (s), 133.3 (s), 126.6 (d), 104.6 (d), 100.5 (d), 61.0
(t), 60.6 (s), 52.2 (q), 29.2 (t), 28.2 (t), 23.1 (t), 21.3 (t), 13.9 (q),
Ϫ0.2 (q); m/z (EI) 428 (Mϩ, 13%), 413 (13, Mϩ Ϫ Me), 396 (7,
Mϩ Ϫ MeOH), 355 (37, Mϩ Ϫ TMS) (Found Mϩ, 428.2246.
C21H36O7Si requires M, 428.2230).
Ethyl 7a-ethoxy-2-oxo-2,4,5,6,7,7a-hexahydrobenzofuran-3-
carboxylate 10
Sodium hydride (60% in mineral oil, 26 mg, 0.64 mmol) was
washed with hexane and suspended in dimethylformamide
(1 ml). The suspension was cooled to 0 ЊC and a solution of
acetate 9 (100 mg, 0.32 mmol) in dimethylformamide (1 ml)
was added rapidly via cannula. The solution was stirred for
15 minutes and quenched with saturated aqeuous ammonium
chloride (10 ml) and extracted with diethyl ether (3 × 10 ml).
The combined organic extracts were washed with water (20 ml),
dried (MgSO4) and concentrated in vacuo. Chromatography
(15% EtOAc–petrol) gave the lactone 10 (35 mg, 43%) as a
colourless oil (Found: C, 61.11; H, 7.20; C13H18O5 requires C,
61.41; H, 7.13%); νmax(film)/cmϪ1 1789, 1716, 1672, 1444, 1295;
δH (400 MHz, CDCl3), 4.34 (2H, q, J 7.1, CH2O), 3.53–3.45
(2H, m, CH2O), 3.27–3.19 (1H, m), 2.54 (1H, dd, J 2, 13), 2.25
(1H, td, J 5.8, 13), 2.12–2.07 (1H, m), 1.78–1.67 (2H, m), 1.62–
1.39 (2H, m), 1.36 (3H, t, J 7.1), 1.19 (3H, t, J 7.0); δC (100
Diethyl 5-methoxy-10-oxobicyclo[4.3.1]dec-1(9)-ene-2,2-dicarb-
oxylate 13
A solution of titanium() chloride in dichloromethane (1 M,
240 µl, 0.24 mmol) was added dropwise to a stirred solution
of 12 (100 mg, 0.23 mmol) in dichloromethane (2 ml) under
nitrogen at Ϫ78 ЊC. The mixture was stirred at Ϫ78 ЊC for
2 hours and then allowed to warm to room temperature over
12 hours, quenched with saturated aqueous sodium bicarbon-
ate at 0 ЊC, and extracted with diethyl ether (3 × 10 ml). The
combined ether extracts were washed with water (10 ml), dried
(MgSO4), and concentrated in vacuo. Chromatography (20%
EtOAc–petroleum ether) yielded 13a (9 mg, 12%) and 13b
(30 mg, 40%) as oils. Data for 13a (less polar; Rf 0.28, 25%
EtOAc–petrol) (Found: C, 63.07; H, 7.45; C17H24O6 requires C,
62.95; H, 7.46%) νmax(film)/cmϪ1 1736, 1708, 1451, 1245, 1088;
MHz, CDCl ) 176.2 (s, C᎐O), 165.6 (s, C᎐O), 160.9 (s, C᎐C),
᎐
᎐
᎐
3
δH (400 MHz, CDCl ) 6.46 (1H, dd, J 4.3, 7.8, HC᎐), 4.31–4.20
᎐
3
118.6 (s, C3), 105.0 (s, C7a), 61.4 (t), 58.9 (t), 38.1 (t), 27.4 (t),
27.1 (t), 21.7 (t), 15.1 (q), 14.1 (q); m/z (EI) 254 (Mϩ, 4%), 209
(5, Mϩ Ϫ EtO), 181 (100, Mϩ Ϫ CO2Et), 163 (22) (Found Mϩ,
254.1164. C13H18O5 requires M, 254.1154).
(4H, m, 2 × CH2O), 3.29 (s, 2H, MeO), 3.28–3.15 (2H, m,
CHCO and CHOMe), 2.36–2.21 (2H, m, CH2), 2.09–1.94 (1H,
m), 1.87–1.56 (5H, m), 1.28 (6H, t, J 7.1, 2 × Me); δC (100 MHz,
CDCl3) 204.1, 169.3, 169.2, 137.6, 135.4, 82.2, 61.8, 61.8, 59.1,
56.6, 50.6, 30.7, 27.7, 22.3, 19.4, 14.0, 13.9; m/z (EI) 324 (Mϩ,
0.14 %), 279 (1, Mϩ Ϫ EtO), 251 (5, Mϩ Ϫ CO2Et) (Found Mϩ,
324.1554. C17H24O6 requires M, 324.1573). A sample of 13a
was further purified by Kugelrohr distillation; this sample
Diethyl 2-(3,3-dimethoxypropyl)-2-(6-oxocyclohex-1-enyl)-
malonate 11
Sodium hydride (60%, 120 mg, 3 mmol) was washed with
1348
J. Chem. Soc., Perkin Trans. 1, 2002, 1344–1350

View Article Online
crystallised on standing, allowing structure determination by
X-ray crystallography.†||
2.37 (2H, m), 2.13–1.96 (6H, m), 1.27–1.17 (6H, m, CH3), 0.20
(9-H, s, Si(CH3)3); δC (62.5 MHz, CDCl3) 170.3 (s), 147.6 (s),
134.5 (s), 133.0 (s), 132.3 (d), 128.6 (d), 127.3 (d), 126.7 (d),
100.4 (d), 61.0 (t), 60.7 (s), 59.3 (d), 31.9 (t), 29.5 (t), 23.0 (t),
21.2 (t), 13.9 (q), 1.0 (q); m/z (EI) 584 (Mϩ) (Found Mϩ,
584.2078. C31H40O5S2Si requires 584.2078).
Data for 13b (more polar Rf 0.22, 25% EtOAc–petrol):
νmax(film)/cmϪ1 1731, 1715, 1449, 1243, 1201; δH (500 MHz,
CDCl ) 6.34 (1H, dd, J 4.2 and 7.7, HC᎐), 4.28–4.19 (4H, m,
᎐
3
2 × CH2O), 3.30 (3H, s, CH3O), 3.15 (1H, m, CHOMe), 2.96
(1H, m—resolution enhanced to ddd, J 2.6, 5.2, 8.3, CHCO),
2.33–1.90 (6H, m, 3 × CH2), 1.85 (1H, m), 1.36–1.21 (7H, m);
δC (67.5 MHz, CDCl3) 202.8 (s), 169.6 (s), 169.2 (s), 138.2 (s),
133.4 (d), 81.0 (d), 61.8 (t), 57.3 (t), 56.3 (q), 51.8 (d), 27.4 (t),
24.9 (t), 24.5 (t), 21.7 (t), 14.0 (q); m/z (FAB) 347 (MNaϩ, 36%),
324 (18, MHϩ), 293 (10, Mϩ Ϫ OMe), 279 (15, Mϩ Ϫ EtO)
(Found MHϩ, 325.1640. C17H25O6 requires MH, 325.1651).
Diethyl 2-[3,3-bis(mesitylsulfanyl)propyl]-2-(6-oxocyclohex-1-
enyl)malonate 15
To a solution of (mesitylthio)trimethylsilane23 (1.31 g, 5.85
mmol) and acetal 11 (1.045 g, 2.93 mmol) in CH2Cl2 (20 ml) at
Ϫ78 ЊC under N2 was added dropwise TMSOTf (1.36 ml, 7.51
mmol). The reaction was stirred for 30 min before addition of a
concentrated aqueous solution of NaHCO3 and subsequent
warming of the reaction to room temperature. The organic
layer was then extracted with ether (3 × 30 ml), the combined
organic layers dried (MgSO4) and the solvent removed to pro-
duce a pale yellow oil. Purification was achieved by recrystal-
lisation (ether) to produce the thioacetal 15 (1.12 g, 64%) as
colourless rectangular prismatic crystals, mp 95–97 ЊC;
νmax(film)/cmϪ1 1731, 1681; δH (250 MHz, CDCl3) 6.92 (1H, t,
Cyclisation of 12 using ZnCl2. A suspension of silyl enol ether
12 (23.8 mmol) and activated 4 Å molecular sieves (3.5 g) in
dichloromethane (25 ml) was added via cannula to a suspension
of 4 Å molecular sieves (3.5 g) and a solution of ZnCl2 (1 M in
Et2O, 25 ml). The reaction mixture was stirred for 7 h at room
temperature, and then filtered on Celite. The filtrate was diluted
with dichloromethane and washed with saturated aqueous
NaHCO3. The combined organics were dried (MgSO4) and
concentrated in vacuo. Chromatography (20 to 50% EtOAc–
petrol) gave 13a (1.62 g, 21%) and 13b (2.38 g, 31%) as oils.
Ketone 11 (1.79 g, 16%) was also recovered.
J 4.3, HC᎐), 6.88–6.86 (4H, m, Ar–H), 4.11 (4H, q, J 7.1,
᎐
CH2O), 3.80 (1H, t, J 6.7, CH(SAr)2), 2.36 (12H, s, o-Ar–CH3),
2.41–2.26 (6H, m), 2.23 (6H, s, p-Ar–CH3), 1.98–1.85 (2H, m),
1.79–1.70 (2H, m), 1.18 (6H, t, J 7.0, CH3); δC (62.5 MHz,
CDCl3) 196.8 (s), 169.6 (s), 147.0 (d), 143.0 (s), 138.3 (s), 136.8
(s), 129.3 (s), 128.9 (d), 61.3 (t), 59.5 (s), 58.8 (d), 38.3 (t), 32.6
(t), 31.3 (t), 26.0 (t), 22.1 (t), 21.7 (q), 20.8 (q), 13.8 (q); m/z (CI)
614 (MNH4ϩ) (Found [MHϩ Ϫ ArSH] 445.2049. C25H33O5S
requires 445.2038).
Diethyl 2-[3,3-bis(phenylsulfanyl)propyl]-2-(6-oxocyclohex-1-
enyl)malonate 14
To a solution of (phenylthio)trimethylsilane24 (0.72 g, 3.23
mmol) and acetal 11 (576 mg, 1.61 mmol) in CH2Cl2 (10 ml) at
Ϫ78 ЊC under nitrogen was added dropwise TMSOTf (50 µl,
0.276 mmol). The reaction was then allowed to warm to room
temperature overnight. Solid NaHCO3 (ca. 5 g) was then added
and the mixture stirred for a further 2 hours before addition of
water (20 ml). The organic layer was then extracted with ether
(3 × 30 ml), the combined organic layers dried (MgSO4) and the
solvent removed to produce a pale yellow oil. Chromatography
(50% ether–petrol; Rf = 0.22) produced the thioacetal 14 (0.775
g, 98%) as a colourless oil; νmax(film)/cmϪ1 1729, 1679; δH (250
MHz, CDCl3) 7.46–7.41 (4H, m, Ar–H), 7.33–7.22 (6H, m,
Silyl enol ether 17
To a solution of thioacetal 14 (1.02 g, 1.66 mmol) in CH2Cl2
(100 ml) was added Et3N (1.4 ml, 10 mmol) followed by
TMSOTf (1.65 ml, 9.12 mmol). The reaction was then allowed
to stir at Ϫ78 ЊC for 20 h before addition of saturated aqueous
NaHCO3 solution and warming of the reaction to room tem-
perature. The aqueous layer was extracted with CH2Cl2 (3 × 100
ml) and the combined organic extracts washed with brine (70
ml), dried (MgSO4) and the solvent removed under reduced
pressure. Chromatography (50% ether–petrol ϩ 3% Et3N,
Rf = 0.63) provided the silyl enol ether 17 (0.97 g, 88%) as a
colourless oil, which was used crude in attempted cyclisations;
νmax(film)/cmϪ1 1742, 1731; δH (250 MHz, CDCl3) 6.87 (4H, br s,
Ar–H), 5.69–5.65 (1H, m, 2Љ-H), 4.72–4.69 (1H, m, 5Љ-H),
4.15–4.02 (4H, m, CH2O), 3.82 (1H, t, J 7.0, CH(SAr)2), 2.36
(12H, s, o-Ar–CH3), 2.35–2.26 (2H, m), 2.23 (6H, s, p-Ar–CH3),
2.09–2.04 (4H, m), 1.94–1.84 (2H, m), 1.17 (6H, t, J 7.2, CH3),
0.13 (9H, s, Si(CH3)3; δC (62.5 MHz, CDCl3) 170.4 (s), 147.7 (s),
143.1 (s), 138.2 (s), 133.1 (s), 129.5 (s), 128.9 (d), 126.5 (d),
100.3 (d), 61.0 (d), 60.6 (s), 59.4 (d), 32.8 (t), 32.0 (t), 23.1 (t),
21.8 (q), 21.2 (t), 20.9 (q) 13.8 (q), Ϫ0.2 (q); m/z (CI) 669
(MHϩ) (Found MHϩ Ϫ ArSH, 517.2408. C28H41O5SSi requires
517.2444).
Ar–H), 6.90 (1H, t, J 4.3, HC᎐), 4.35 (1H, t, J 6.6, CH(SPh) ),
᎐
2
4.14 (4H, q, J 7.1, CH2O), 2.45–2.33 (6H, m), 1.94–1.81 (4H,
m), 1.20 (6H, t, J 7.0, CH3); δC (62.5 MHz, CDCl3) 197.0 (s),
169.7 (s), 147.1 (d), 136.8 (s), 134.2 (s), 132.4 (d), 128.8 (d),
127.5 (d), 61.5 (t), 59.6 (s), 58.0 (d), 38.5 (t), 31.6 (t), 26.0 (t),
22.1 (t), 13.9 (q); m/z (CI) 513 (MHϩ) (Found MHϩ, 513.1763.
C28H33O5S2 requires 513.1769).
Silyl enol ether 16
To a solution of thioacetal 14 (301 mg, 0.611 mmol) and
triethylamine (1.28 ml, 9.16 mmol) in CH2Cl2 (5 ml) at Ϫ78ЊC
was added dropwise TMSOTf (1.58 ml, 8.73 mmol). The
reaction was then allowed to stir at Ϫ78ЊC for 1 h before being
allowed to warm to 0 ЊC and stirred for a further hour. After
this time an excess of solid NaHCO3 was added to the flask and
the solvent removed under reduced pressure. The remaining
residue was then stirred vigorously with n-pentane for 20 min
and the resulting slurry passed through a 5 cm Celite plug with
further washing with n-pentane. The solvent was then removed
under reduced pressure to produce the silyl enol ether 16
(302 mg, 88%) as a colourless oil, which was used crude in
attempted cyclisations; νmax(film)/cmϪ1 1729 (CO2Et); δH (250
MHz, CDCl3) 7.47–7.42 (4H, m, ArH), 7.32–7.20 (6H, m,
ArH), 5.74–5.68 (1H, m, 2Љ-H), 4.81–4.77 (1H, m, 5Љ-H), 4.39
(1H, t, J 6.7, CH(SPh)2), 4.25–4.09 (4H, m, 2 × CH2O), 2.44–
Acknowledgements
We thank the EPSRC (GR/M25438) and AstraZeneca (CASE
studentship to TJC) for their support of this work. We are
grateful to Pfizer, Merck Sharp and Dohme and Bristol-Myers
Squibb for their generous unrestricted support.
References and notes
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|| CCDC reference number(s) 182087. See http://www.rsc.org/
suppdata/p1/b2/b202752f/ for crystallographic files in .cif or other
electronic format.
J. Chem. Soc., Perkin Trans. 1, 2002, 1344–1350
1349

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