Use of a highly effective intramolecular Pauson-Khand cyclisation for the formal total synthesis of (±)-α- and β-cedrene by preparation of cedrone

Article abstract of DOI:10.1016/j.tet.2006.05.044

The cedrene carbon skeleton was directly and efficiently assembled from a simple monocyclic precursor by the strategic use of a high yielding intramolecular Pauson-Khand cyclisation reaction. A small number of further synthetic manipulations provided a concise formal total synthesis of α- and β-cedrene. The cyclisation precursor was readily prepared, with a stereoselective ketone alkenylation selectively providing the olefin required for efficient access to the natural target.

Full text of DOI:10.1016/j.tet.2006.05.044

Tetrahedron 62 (2006) 11360–11370
Use of a highly effective intramolecular Pauson–Khand
cyclisation for the formal total synthesis of ( )-a- and
b-cedrene by preparation of cedrone
*
James J. Crawford, William J. Kerr, Mark McLaughlin, Angus J. Morrison,
Peter L. Pauson and Graeme J. Thurston
Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, Glasgow G1 1XL, Scotland, UK
Received 17 March 2006; revised 16 May 2006; accepted 18 May 2006
Available online 12 June 2006
Dedicated with warmth and the utmost respect to our fellow countryman, Professor David W. MacMillan, in recognition of his broad and outstanding
contributions to organic synthesis and on the occasion of being honoured with the first Tetrahedron Young Investigator Award
Abstract—The cedrene carbon skeleton was directly and efficiently assembled from a simple monocyclic precursor by the strategic use of
a high yielding intramolecular Pauson–Khand cyclisation reaction. A small number of further synthetic manipulations provided a concise
formal total synthesis of a- and b-cedrene. The cyclisation precursor was readily prepared, with a stereoselective ketone alkenylation selec-
tively providing the olefin required for efficient access to the natural target.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
effectiveness of our preparative pathway. Full details of
our revised synthetic approaches to this class of tricyclic
sesquiterpene natural product are now presented.
The tricyclic sesquiterpenes a-cedrene 1a and b-cedrene 1b
can be isolated from Juniperus cedrus and Juniperus thuri-
fera, alongside a variety of closely related oxygenated terpe-
noid analogues.1 Driven by the intriguing and preparatively
challenging [5.3.1.01,5] tricyclic structure, the cedrene fam-
ily of natural products has been the focus of considerable
synthetic endeavours2 over the years since initial character-
isation in 1953. As part of our continuing series of studies to
further develop the overall effectiveness and applicability
of the Pauson–Khandy annulation reaction,3 we sought to
utilise this cyclisation process as the central synthetic
transformation within routes towards a-cedrene 1a and, in
so doing, establish a direct and efficient pathway for the
synthesis of this structurally demanding tricyclic skeleton.
Following the preliminary communication of our initial
endeavours towards these goals,4 we have subsequently
made key improvements to the overall selectivity and
2. Results and discussion
2.1. Initial synthetic approaches to the Pauson–Khand
cyclisation precursor
Our synthetic approach is initiated with the introduction of
a,b-unsaturation into the commercially available cyclo-
hexanedione monoethylene acetal 2 (Scheme 1). Following
straightforward preparation of the enol ether 3, Saegusa
oxidation5 afforded the enone 4. More specifically, use of
stoichiometric quantities of palladium(II) acetate, provided
the enone 4 in 92% yield. On the other hand, the consider-
ably more economical catalytic modification6 of this useful
transformation was investigated and delivered 4 in a respect-
able 82% yield, whilst requiring the use of only 5 mol % of
palladium(II) acetate. With the desired enone in hand,
ytterbium(III) triflate trihydrate-catalysed7 1,4-addition of
the trimethylsilyl enol ether of ethyl isobutyrate directly
Keywords: Pauson–Khand reaction; Cedrene; Tricyclic sesquiterpene;
Stereoselective Wittig reaction; Cobalt.
* Corresponding author. Tel.: +44 141 548 2959; fax: +44 141 548 4246;
e-mail: w.kerr@strath.ac.uk
Hitherto one of us has preferred to use the initially designated name of
y
‘Khand’ reaction for this synthetic process; in light of what has now
become common usage and following comments from the referees, we
have subsequently employed the more widely accepted term ‘Pauson–
Khand’ throughout this paper.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.044

J. J. Crawford et al. / Tetrahedron 62 (2006) 11360–11370
11361
afforded the ester 5 in a yield of 81%. Use of the anhydrous
form of ytterbium(III) triflate led to the isolation of the tri-
methylsilyl enol ether of ketone 5, from the direct silylation
of the enolate resulting from conjugate addition, as a by-
product (cf. compound 13 vide infra). It should also be noted
that employment of the more commonly used titanium tetra-
chloride as a stoichiometric mediator of this type of Michael
addition resulted in unwanted removal of the ketone protec-
tion, even at ꢀ78 ꢁC.
desired tricyclic carbon a-cedrene skeleton could now be
investigated.
2.2. Pauson–Khand cyclisations to the tricyclic
cedrene skeleton
A series of techniques for promoting the key intramolecular
Pauson–Khand cyclisation of 10a/10b were probed. As
shown in Scheme 3, two different amine N-oxides were em-
ployed at room temperature,10 a soluble alkyl methyl sulfide
was used under more forcing conditions,11 and our more
recently developed solid-supported alkyl methyl sulfide
was also applied.3i To our delight, in every instance, the
Pauson–Khand cyclisation took place smoothly to provide
the enones 11a/11b in high yield. This clearly demon-
strates the novel applicability of this annulation process
to the direct construction of such complex tricyclic systems
from simple monocyclic substrates. The optimum Pauson–
Khand annulation yield of 95% was achieved using Sugi-
hara’s technique with the soluble n-butyl methyl sulfide
in 1,2-DCE at reflux.11 The alternative polymer-supported
sulfide provided a somewhat reduced yield of 80% for
the same cyclisation. Having stated this, it is worth noting
that the work-up procedure with this solid-phase reagent
was greatly facilitated by the ability of the resin-based
species to sequester the unwanted cobalt residues, enabling
removal of these by-products by simple filtration. It is im-
portant to point out that our key Pauson–Khand cyclisation
could also be achieved very effectively at room tempera-
ture. In this respect, the commercially available dihydrate
of trimethylamine N-oxide (TMANO$2H2O) and the mono-
hydrate of N-methylmorpholine N-oxide (NMO$H2O) af-
forded cyclopentenones 11a/11b in high yields of 91%
and 84%, respectively.
Scheme 1. Reagents and conditions: (i) TMSOTf, Et3N, DCM, ꢀ5 ꢁC,
15 min; (ii) 1.05 equiv Pd(OAc)2, CH3CN, rt, 24 h; (iii) 5 mol % Pd(OAc)2,
DPPE, 1.4 equiv diallyl carbonate, CH3CN, 81 ꢁC, 40 h; (iv) 10 mol %
Yb(OTf)3$3H2O, Me2CC(OEt)OTMS, DCM, rt, 24 h.
Ethylidenation of the ketone carbonyl of 5 was now consid-
ered as the next step in our synthetic sequence. Indeed,
this was viewed as a key transformation in a stereochemical
sense, with the (E)-isomer 6b being required to provide the
requisite orientation of the C-15 methyl group of a-cedrene
1a. Using the ethyltriphenylphosphonium bromide salt and
n-butyllithium with ketone 5 in a standard Wittig process
at 0 ꢁC, a 92% yield of olefins 6a/6b was obtained, as
a 2:1 mixture of geometric isomers (Scheme 2). Since the
products 6a and 6b were inseparable, they were employed
in combination to allow the planned synthetic route to be
established and with a view to identification of individual
isomers at a later stage. In this respect and as shown in
Scheme 2, total reduction of the ester functionality of 6a/6b
with lithium aluminium hydride delivered alcohols 7a/7b
in 99% yield. This was followed by oxidation to aldehydes
8a/8b in a yield of 97% using the Dess–Martin periodinane.8
For the conversion of aldehydes into alkynes, previous
studies in our laboratory had shown the Ohira–Bestmann
technique (with the reagent dimethyl acetyldiazomethyl-
phosphonate)9 to be practically accessible and effective.
In this instance, this mild protocol delivered alkynes 9a/9b
in 81% yield. In turn, these were routinely complexed
with octacarbonyldicobalt to furnish the stable cyclisation
precursors 10a/10b in almost quantitative yield. At this
stage and with the requisite complexes in hand, the pro-
posed Pauson–Khand annulation for the assembly of the
Scheme 3. Reagents and conditions: (i) 9 equiv TMANO$2H2O, acetone, rt,
16 h, 91%; (ii) 8 equiv NMO$H2O, DCM, rt, 16 h, 84%; (iii) 4.3 equiv
n-BuSMe, 1,2-DCE, 83 ꢁC, 30 min, 95%; (iv) 3.6 equiv polymer-supported
sulfide, 1,2-DCE, 83 ꢁC, 30 min, 80%.
Scheme 2. Reagents and conditions: (i) Ph3P+CH2CH3 Brꢀ, n-BuLi, THF, 0 ꢁC, 2 h; (ii) LiAlH4, Et2O, 0 ꢁC, 1 h; (iii) Dess–Martin periodinane, 10% CH3CN in
DCM, rt, 1 h; (iv) AcC(N2)P(O)(OMe)2, K2CO3, MeOH, rt, 5 d; (v) Co2(CO)8, petrol, rt, 2 h.

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J. J. Crawford et al. / Tetrahedron 62 (2006) 11360–11370
As shown in Scheme 3, the product cyclopentenones 11a/
11b were obtained as a mixture of stereoisomers in a ratio
of 2:1. This indicated that the relative stereochemistry pres-
ent in the initial olefins 6a/6b had been carried through to
cyclisation precursors 10a/10b and onto the Pauson–Khand
products without change. At this stage, the diastereomers
11a/11b were now separable by silica column chromato-
graphy and the individual cyclopentenones were indepen-
dently characterised by X-ray crystallographic analyses.12
Disappointingly, the major isomer 11a featured the (C-15)
methyl group, adjacent to the carbonyl, with the undesired
(a) stereochemistry, whilst the minor isomer 11b possessed
the required methyl group (b) orientation. Therefore, despite
the excellent levels of efficiency realised for the Pauson–
Khand cyclisation process, this stereochemical elucidation
and outcome identified a clearly limiting feature of our syn-
thetic route to this stage.
ytterbium(III) triflate as catalyst with enone 4, the desired
keto ester 12 was prepared in 67% yield, along with a 23%
yield of the silyl enol ether 13. This latter species was readily
converted to the ester 12 in 99% yield under mild conditions
with 2% aqueous oxalic acid, leaving the acetal protecting
group intact.
First of all, in order to obtain a direct comparison with the
ethyl ester 5, the methyl ester 12 was subjected to olefination
conditions, which were almost identical to those previously
employed as part of the initial synthetic route towards the
Pauson–Khand cyclisation precursor. More specifically,
use of the ethyltriphenylphosphonium bromide salt and
n-butyllithium with 12 at room temperature (Scheme 5,
Table 1, Entry 1) delivered the alkenes 14a and 14b in
similar yield and selectivity (89% and 1.6:1; 14a:14b) to that
obtained with the equivalent ethyl ester precursor 5 (with
1
olefin ratios being determined by H NMR spectroscopy;
see Section 4).
2.3. Probing the stereoselectivity of the key
Wittig olefination process
Having made the assignments of relative stereochemistry
within 11a and 11b, it was now apparent that the specific ratio
of olefin geometric isomers achieved through ethylidenation
of 5 (as shown in Scheme 2) was 2:1 (Z)-6a:(E)-6b. Accord-
ingly, endeavours to access enhanced proportions of the
requisite E-isomer (6b) and a generally more useful isomer
ratio, in relation to the synthesis of a-cedrene, were required.
In this regard and as part of preliminary investigations,
simply utilising a lower olefination reaction temperature
of ꢀ78 ꢁC, with n-butyllithium again being used as base,
did not affect the alkene stereoisomeric ratio obtained. Fur-
thermore, use of weaker bases (e.g., K2CO3, KOH, NaOEt)
in protic solvents (e.g., EtOH) at higher temperatures proved
ineffective.
Scheme 5. Wittig olefination of keto methyl ester 12; see Table 1.
Table 1. Wittig olefination of keto methyl ester 12
Entry
Ylide
Base
Yield (%)
Ratio 14a:14b
1
2
3
4
5
6
7
8
Ph3P+Et Brꢀ
Ph3P+Et Brꢀ
Ph3P+Et Brꢀ
Ph3P+Et Clꢀ
Ph3P+Et Iꢀ
Ph3P+Et Clꢀ
Et4P+ Brꢀ
n-BuLi
89
77
85
79
90
75
75
75
1.6:1
1:2.4
1:2.3
1:2.3
1:2.3
1:2.5
1:1.1
1:1.1
NaHMDS
KHMDS
KHMDS
KHMDS
NaHMDS
NaHMDS
KHMDS
At this stage it was clear that a more detailed exploration of
the Wittig olefination process was required. Having stated
this and prior to any investigation into the stereoselectivity
of olefin formation, it was recognised that use of the ethyl
Et4P+ Brꢀ
1
ester 5 did not readily allow use of H NMR techniques
for the determination of the product alkene ratios. Indeed,
to this stage in the programme, analysis of isomeric olefin
ratios had been performed by 13C NMR integration.
Whilst this had proved reliable, in the sense that the olefin
mixtures had been carried through the synthetic scheme
and the ratios confirmed as detailed above, a clearly more
readily utilisable 1H NMR spectroscopic method for alkene
composition determination was desired. To this end, the
equivalent methyl ester 12 was routinely prepared as shown
in Scheme 4; in this process, once again using hydrated
In a very general sense, the efficiency and stereoselectivity
of Wittig olefination reactions are known to be affected by
the type of ylide used, the base employed, the carbonyl com-
pound, the reaction solvent, and the base/ylide metal counter
ion.13 Whilst olefin stereoselectivity studies have focused on
the use of aldehyde substrates within the Wittig process, the
parameters and reaction components listed were considered
for investigation with the requisite starting cyclic ketone as
part of this programme. In this respect, with aldehydes, the
use of ‘salt-free’ conditions (traditionally defined as the ab-
sence of lithium salts) is known to enhance the Z-selectivity
of Wittig olefinations.13,14 In contrast, the presence of lith-
ium salts, as in the Wittig processes described to this stage,
is known to deplete this stereoselectivity. Based on this, we
moved to simply amend the counter ion associated with the
bases used. Remarkably, when NaHMDS and KHMDS were
employed with the same Wittig salt and keto ester 12, the se-
lectivity of our olefination process was completely reversed,
with the desired alkene 14b now being formed predomi-
nantly over 14a (Table 1, Entries 2 and 3) in ratios of 1:2.4
and 1:2.3, respectively. Considering the minimal local dif-
ferences on either side of the ketonic carbonyl group, these
Scheme 4. Reagents and conditions: (i) 10 mol % Yb(OTf)3$3H2O, Me2CC-
(OMe)OTMS, DCM, rt, 24 h; (ii) 2% aq oxalic acid, Et2O, rt, 12 h.

J. J. Crawford et al. / Tetrahedron 62 (2006) 11360–11370
11363
observed selectivities are even more notable. Amendment of
the halide counter ion associated with the Wittig salt moder-
ately affected yields (Table 1, Entries 4–6) but did deliver the
maximum 14a:14b ratio of 1:2.5 (Entry 6). Overall, these
were exceedingly pleasing outcomes from such a simple
change in reagents and, more importantly, overturned the
only significant inefficiency in the synthetic approach to
a-cedrene as previously described.4
optimal efficiency was provided by utilising LiOH in a re-
fluxing mixture of THF and H2O. This almost completely
transformed the unwanted stereoisomer 11a into the desired
cyclopentenone 11b and generated a separable 1:9 mixture
of undesired to desired stereoisomers in quantitative yield
(Scheme 7). Consequently, this provided further ampli-
fication of the efficiency of the overall synthetic pathway
described here. Moreover, separation of these isomers and
further epimerisation was facilitated allowing, in theory,
near complete transformation to the desired isomer over
several runs.
Finally in this area, Schlosser has shown how the replace-
ment of triarylphosphonium ylides with trialkylphos-
phonium species can, again, considerably affect the
stereoselectivity of such olefination processes.15 When the
tetraethylphosphonium bromide salt was utilised with both
NaHMDS and KHMDS, the ratios of alkenes produced
(1:1.1; 14a:14b; Table 1, Entries 7 and 8) provided no further
preparative advantages in this synthetic programme. Addi-
tionally, the application of a number of alternative solvents
(e.g., DME, glyme) and additives (e.g., 18-c-6) did nothing
to further enhance the proportion of 14b formed over that
described above.
Scheme 7. Reagents and conditions: (i) LiOH, THF/H2O (5:1), reflux, 3 d.
2.5. Formal total synthesis of a-cedrene 1a
and b-cedrene 1b
2.4. Selective access to the desired cyclopentenone
epimer 11b
From that described above, the desired olefin for use in the
a-cedrene synthesis could now be formed predominately
and in ratios of up to 1:2.5 (14a:14b). With this more
favourable and selective olefination procedure in place and
with a view to complete confirmation of our olefin stereo-
chemical assignments, an isomerically-enriched alkene
mixture (1:2.4; 14a:14b) was taken on in the synthetic
pathway, as described previously. In this respect, LiAlH4
reduction of 14a/14b proceeded in excellent yield to
deliver 7a/7b, with the same olefinic ratio of 1:2.4 being
observed (Scheme 6). From this point the remainder of
the synthetic pathway (as described in Scheme 2) pro-
ceeded without complication. Gratifyingly, on Pauson–
Khand cyclisation and stereoisomer separation, a 1:2.4
ratio of the undesired cyclopentone 11a to the required
epimer 11b was obtained.
In a number of instances a-cedrene 1a (and b-cedrene 1b)
have been readily accessed in two steps from cedrone
152a,e,h and, consequently, preparation of this latter com-
pound from the key Pauson–Khand cyclisation product
would complete our formal total synthesis of the natural ses-
quiterpenes. With an efficient and selective route to 11b now
having been established, this cyclopentenone was subjected
to palladium-catalysed hydrogenation to give 16 in 99%
yield (Scheme 8). This reduction process proved to be com-
pletely stereoselective, with the relative stereochemistry
present in this saturated tricyclic skeleton, again, being
confirmed by X-ray analysis.12 As shown, the newly intro-
duced bridgehead H-atom (at C-7) has the requisite stereo-
chemistry. In due course, lithium aluminium hydride
reduction of the carbonyl functionality of 16 was achieved
in an excellent 99% yield; at the 0 ꢁC reaction temperature
this protocol was totally selective and afforded only one
detectable alcohol isomer, tentatively assigned as compound
17. In turn, the secondary alcohol 17 was reduced following
the well-established Barton–McCombie method.16 In this
respect, the xanthate ester intermediate 18 was formed
very readily, and the required deoxygenated product 19
was obtained when 18 was treated with tributyltin hydride
in the presence of a catalytic amount of AIBN initiator, using
degassed benzene as solvent, and in a yield of 71% over the
two steps. Finally, the ketone protection was removed using
mild conditions, as discovered in our own laboratories,
which involved the use of sub-stoichiometric quantities of
carbon tetrabromide and triphenylphosphine in acetone.17
This delivered the desired cedrone target 15 in 99% yield,
to complete our concise formal total synthesis of a- and
b-cedrene, 1a and 1b.
Scheme 6. Reagents and conditions: (i) LiAlH4, Et2O, rt, 1 h.
As described to this stage, the desired cyclopentenone 11b
could now be accessed in excellent yield and in appreciable
excess. Despite this, since isomeric mixtures from olefins
14a/14b were carried through the synthesis, quantities of
the undesired cyclisation product 11a were also produced.
In order to further enhance the overall effectiveness of
our route towards the cedrene natural products, a simple
a-methyl epimerisation process was attempted. Following
a very short exploratory programme, it was found that

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J. J. Crawford et al. / Tetrahedron 62 (2006) 11360–11370
Scheme 8. Reagents and conditions: (i) 10% Pd/C, H2 (45 psi), toluene, rt, 3 h; (ii) LiAlH4, Et2O, 0 ꢁC, 2 h; (iii) n-BuLi, CS2, MeI, 0 ꢁC–rt, 110 min; (iv)
Bu3SnH, AIBN, degassed C6H6, 80 ꢁC, 48 h; (v) 8 mol % Ph3P/CBr4, acetone, rt, 1 h.
3. Conclusions
(1.86 g, 1.52 ml, 8.39 mmol) in dichloromethane (20 ml)
was added over a 10 min period to a stirred solution of
1,4-dioxaspiro[4.5]decan-8-one 2 (1.19 g, 7.63 mmol) and
triethylamine (2.30 g, 3.30 ml, 22.9 mmol) in dichloro-
methane (70 ml) at ꢀ5 ꢁC. The mixture was stirred for
15 min before the reaction was quenched by the addition
of saturated aqueous sodium hydrogen carbonate solution
(5 ml) and then water (35 ml). The organic phase was sepa-
rated, dried, and evaporated under reduced pressure to leave
a crude residue, which was extracted with light petroleum
(3ꢂ20 ml). The light petroleum extracts were combined
and filtered through a pad of silica using light petroleum
as the eluent. The filtrate was evaporated under reduced pres-
sure to give 8-((trimethylsilyl)oxy)-1,4-dioxaspiro[4.5]dec-
7-ene 3 (1.67 g, 96%) as a colourless oil. IR nmax (film)/
We have now shown that strategic use of an intramolecular
Pauson–Khand reaction, with a simple monocyclic precur-
sor, can allow the direct and highly efficient construction
of the challenging tricyclic [5.3.1.01,5] carbon skeleton of
a-cedrene 1a (and b-cedrene 1b). Furthermore, the overall
efficiency of this approach has been considerably enhanced
by the ability to reverse the originally observed selectivity of
the central Wittig olefination procedure on the requisite cy-
clic ketone intermediate. In the key Pauson–Khand annula-
tion process, the olefinic precursors react with retention of
stereochemistry to deliver the desired cyclopentenone epi-
mer, for synthesis of the targeted natural products, in excess.
To further amplify the efficiency of this overall synthetic
programme, the residual and undesired cyclopentenone
product was also shuttled through to the required isomer
by a simple base-mediated epimerisation process. In turn,
the desired cyclopentenone intermediate so obtained was
further elaborated to cedrone 15, thus constituting a formal
total synthesis of a- and b-cedrene. Finally, it is also worth
noting that compound 11a was subjected to a sequence of
reactions similar to those performed on 11b to deliver a
synthesis of epi-cedrone.
1
cmꢀ1 1664 (C]C); H NMR (400 MHz, CDCl3): d 0.19
(9H, s, (CH3)3Si), 1.81 (2H, t, J 6.6, C10-H), 2.20 (2H, m,
C9-H), 2.26 (2H, m, C6-H), 3.97 (4H, m, C2,3-H) and 4.73
(1H, m, C7-H); 13C NMR (100 MHz, CDCl3): d 0.5
((CH3)3Si), 28.7, 31.3, 34.1, 64.6 (C2,3), 100.8 (C7), 107.9
(C5) and 150.0 (C8); HRMS (EI) m/z Calcd for
C11H20O3Si (M+): 228.1182. Found: 228.1181.
4.1.2. 1,4-Dioxaspiro[4.5]dec-6-en-8-one 4. Palladium(II)
acetate (1.03 g, 4.60 mmol) was added to a solution of 8-
((trimethylsilyl)oxy)-1,4-dioxaspiro[4.5]dec-7-ene 3 (1.00 g,
4.39 mmol) in acetonitrile (70 ml) and themixturewas stirred
for 24 h at 25 ꢁC. The solvent was then evaporated under
reduced pressure and the black residue was filtered through
a pad of silica using dichloromethane as the eluent. The
filtrate was washed with saturated aqueous sodium hydrogen
carbonate solution (50 ml) to remove traces of acetic
acid. The organic phase was dried and evaporated under re-
duced pressure to give 1,4-dioxaspiro[4.5]dec-6-en-8-one 4
(0.62 g, 92%) as a pale yellow oil. Found: C, 62.31; H, 6.35.
C8H10O3 requires C, 62.30; H, 6.50%; IR nmax (film)/cmꢀ1
4. Experimental
4.1. General
Dry tetrahydrofuran (THF) and diethyl ether (Et2O) were
obtained by distilling commercial solvents from sodium
benzophenone ketyl and dichloromethane (CH2Cl2) was dis-
tilled from calcium hydride. Light petroleum refers to the
fraction of bp 30–40 ꢁC and was distilled prior to use. All
organometallic complexes were stored under nitrogen at,
or below, ꢀ20 ꢁC and all reactions were performed under
1
1683 (C]O); H NMR (400 MHz, CDCl3): d 2.20 (2H,
t, J 6.5, C10-H), 2.63 (2H, t, J 6.5, C9-H), 4.05 (4H, m,
a nitrogen atmosphere unless otherwise stated. H and 13C
1
NMR were run on a Bruker WM 250 and a Bruker WM
400 in CDCl3 solutions. Chemical shifts are reported in parts
per million downfield relative to tetramethylsilane (d 0.00);
coupling constants are reported in hertz. Infrared spectra
were obtained on a Mattson 1000 or Nicolet Impact 400D
FTIR spectrometer in CH2Cl2 solutions or as films. High
resolution mass spectrometry was performed on a JEOL
Instruments JMS-AX505HA mass spectrometer system or
a Finnigan MAT 900XLT high resolution double focussing
mass spectrometer. Mass spectral data are reported as m/z.
C
2,3-H), 6.00 (1H, d, J 10.2, C7-H) and 6.61 (1H, d,
J 10.2, C6-H); 13C NMR (100 MHz, CDCl3): d 33.0, 35.4,
65.2 (C2,3), 104.1 (C5), 130.6 (C7), 146.6 (C6) and 198.8
(C8); HRMS (EI) m/z Calcd for C8H11O3 (M++1):
155.0708. Found: 155.0710.
Compound 4 was also prepared by the following method: a
solution of palladium(II) acetate (36.0 mg, 0.16 mmol) and
1,2-bis-(diphenylphosphino)ethane (58.0 mg, 0.14 mmol)
in acetonitrile (50 ml) was heated to reflux before diallyl car-
bonate (0.64 g, 4.51 mmol) and 8-((trimethylsilyl)oxy)-1,4-
dioxaspiro[4.5]dec-7-ene 3 (0.74 g, 3.24 mmol) were added.
The mixture was heated under reflux for a further 40 h.
4.1.1. 8-((Trimethylsilyl)oxy)-1,4-dioxaspiro[4.5]dec-7-
ene 3. A solution of trimethylsilyl trifluoromethanesulfonate

J. J. Crawford et al. / Tetrahedron 62 (2006) 11360–11370
11365
The solvent was then evaporated under reduced pressure to
leave a crude residue, which was purified by filtration through
a pad of silica using 50% diethyl ether in light petroleum as
the eluent. The filtrate was then evaporated under reduced
pressure to give 1,4-dioxaspiro[4.5]dec-6-en-8-one 4 (0.41 g,
82%) as a pale yellow oil. Analytical data were as given above.
(OC]O); HRMS (EI) m/z Calcd for C16H26O4 (M+):
282.18311. Found: 282.18408.
4.1.5. (Z)/(E)-8-Ethylidene-6-(2-methylpropan-1-ol-2-
yl)-1,4-dioxaspiro[4.5]decane 7a/7b. Lithium aluminium
hydride (0.30 g, 7.81 mmol) was added to a stirred solution
of ethyl 2-((Z)/(E)-8-ethylidene-1,4-dioxaspiro[4.5]decan-
6-yl)-2-methylpropanoate 6a/6b (2.20 g, 7.80 mmol) in di-
ethyl ether (100 ml) at 0 ꢁC and the mixture was stirred for
a further 1 h. The reaction was quenched by the addition
of water (0.3 ml) then 10% aqueous sodium hydroxide solu-
tion (0.3 ml) and lastly another portion of water (0.9 ml).
This resulted in a white granular precipitate, which was
removed by filtration through a pad of kieselguhr that
was washed thoroughly with diethyl ether. The filtrate was
evaporated under reduced pressure to give 8-ethylidene-
6-(2-methylpropan-1-ol-2-yl)-1,4-dioxaspiro[4.5]decane 7
(1.86 g, 99%) as a colourless oil containing both (Z)- and
(E)-isomers in a ratio of 2:1. IR nmax (film)/cmꢀ1 3489
(O–H) and 1440 (C]C); 1H NMR (400 MHz, CDCl3):
d 0.83+0.87 (3H, 2ꢂs, 2ꢂCH3C), 1.01+1.05 (3H, 2ꢂs,
2ꢂCH3C), 1.31 (1H, dt, J 13.4 and 4.8), 1.57 (3H, m),
1.69 (1H, dd, J 13.4 and 4.8), 1.83–2.24 (4H, overlapping
m), 2.44+2.66 (1H, both m), 3.08 (1H, m), 3.38 (1H, m),
3.55 (1H, m), 3.88–4.22 (4H, overlapping m, OCH2CH2O)
and 5.16 (1H, m, ]CHCH3); 13C NMR (100 MHz,
CDCl3): d 12.8, 13.1, 22.0, 22.1, 24.6, 27.3, 27.5, 33.3,
35.3, 36.1, 36.4, 38.4, 38.6, 47.8, 48.4, 63.0 (OCH2CH2O),
63.4 (OCH2CH2O), 71.8 (CH2OH), 112.9 (OCO), 116.2
(]CHCH3), 116.5 (]CHCH3), 137.8 (C]CH) and 138.0
(C]CH); HRMS (EI) m/z Calcd for C14H24O3 (M+):
240.17254. Found: 240.17255.
4.1.3. Ethyl 2-(1,4-dioxaspiro[4.5]decan-8-on-6-yl)-2-
methylpropanoate 5. Ytterbium(III) trifluoromethanesulfo-
nate trihydrate (0.06 g, 0.09 mmol) was added to a stirred
solution of 1,4-dioxaspiro[4.5]dec-6-en-8-one 4 (0.14 g,
0.91 mmol) and 1-ethoxy-1-((trimethylsilyl)oxy)-2-methyl-
propene (0.23 g, 1.43 mmol) in dichloromethane (20 ml) at
25 ꢁC. The mixture was stirred for 24 h before it was filtered
through a pad of silica using diethyl ether as the eluent. The
filtrate was evaporated under reduced pressure to leave
a crude residue, which was purified by column chromato-
graphy on silica using a 10–50% diethyl ether in light
petroleum gradient as the eluent to give ethyl 2-(1,4-dioxa-
spiro[4.5]decan-8-on-6-yl)-2-methylpropanoate 5 (0.20 g,
81%) as a pale yellow oil. IR nmax (film)/cmꢀ1 1721
1
(C]O) and 1689 (C]O); H NMR (400 MHz, CDCl3):
d 1.10 (3H, s, CH3C), 1.13 (3H, s, CH3C), 1.24 (3H, t,
J 7.1, CH3CH2), 1.74 (1H, app dt, J 13.5 and 5.5),
1.99 (1H, m), 2.36 (1H, m), 2.48 (1H, m), 2.58 (2H, t,
J 13.5), 2.71 (1H, dd, J 13.5 and 3.9) and 3.91–4.14 (6H, over-
lapping m, CH3CH2, OCH2CH2O); 13C NMR (100 MHz,
CDCl3): d 14.3, 19.5, 27.1, 33.5, 38.3, 39.9, 42.6, 48.8,
60.4 (CH3CH2), 63.6 (OCH2), 64.8 (OCH2), 109.6 (OCO),
177.6 (OC]O) and 210.2 (C]O); HRMS (EI) m/z Calcd
for C14H22O5 (M+): 270.14672. Found: 270.14603.
4.1.4. Ethyl 2-((Z)/(E)-8-ethylidene-1,4-dioxaspiro[4.5]-
decan-6-yl)-2-methylpropanoate 6a/6b. A solution of
n-butyllithium in hexanes (2.5 M, 4.90 ml, 12.2 mmol) was
added over a 5 min period to a stirred solution of ethyltri-
phenylphosphonium bromide (4.40 g, 11.8 mmol) in tetra-
hydrofuran (170 ml) at 0 ꢁC. The resultant orange solution
was stirred for 5 min then a solution of ethyl 2-(1,4-di-
oxaspiro[4.5]decan-8-on-6-yl)-2-methylpropanoate 5 (2.60 g,
9.63 mmol) in tetrahydrofuran (30 ml) was added. The
mixture was stirred for a further 2 h before the solvent was
evaporated under reduced pressure and replaced by hexanes,
causing precipitation of triphenylphosphine oxide. This
precipitate was removed by filtration through a pad of silica
using 10% diethyl ether in light petroleum as the eluent. The
filtrate was evaporated under reduced pressure to leave a
residue, which was purified by filtration through a second
pad of silica using 10% diethyl ether in light petroleum as
the eluent to give ethyl 2-(8-ethylidene-1,4-dioxaspiro[4.5]-
decan-6-yl)-2-methylpropanoate 6 (2.50 g, 92%) as a pale
yellow oil containing both (Z)- and (E)-isomers in a ratio of
2:1. IR nmax (film)/cmꢀ1 1736 (C]O) and 1450 (C]C);
1H NMR (400 MHz, CDCl3): d 1.16–1.36 (12H, overlapping
m), 1.60 (2H, m), 1.79 (1H, m), 1.96 (1H, m), 2.08–2.28 (2H,
overlapping m), 2.51+2.65 (total of 1H, both m), 3.79–4.14
(6H, overlapping m, CH3CH2, OCH2CH2O) and 5.21 (1H,
m, ]CHCH3); 13C NMR (100 MHz, CDCl3): d 13.3, 13.5,
14.6, 20.3, 25.1, 25.8, 27.8, 27.9, 33.9, 34.8, 35.8, 36.9,
42.9, 43.1, 51.2, 51.8, 60.4 (CH3CH2), 60.5 (CH3CH2),
63.6 (OCH2CH2O), 64.6 (OCH2CH2O), 111.6 (OCO),
111.7 (OCO), 117.2 (]CHCH3), 117.6 (]CHCH3), 137.8
(C]CH), 137.9 (C]CH), 178.8 (OC]O) and 178.9
4.1.6. (Z)/(E)-8-Ethylidene-6-(2-methylpropanal-2-yl)-
1,4-dioxaspiro[4.5]decane 8a/8b. The Dess–Martin period-
inane (3.26 g, 7.69 mmol) was added to a stirred solution of
(Z)/(E)-8-ethylidene-6-(2-methylpropan-1-ol-2-yl)-1,4-di-
oxaspiro[4.5]decane (1.50 g, 6.25 mmol) in 10% aceto-
nitrile in dichloromethane (70 ml) at 25 ꢁC. The mixture was
stirred for 1 h before the reaction was quenched by the addi-
tion of aqueous sodium thiosulfate solution (8.5 g in 20 ml)
and saturated aqueous sodium hydrogen carbonate solution
(50 ml). This two phase mixture was stirred vigorously for
30 min before the organic phase was separated, dried, and
evaporated under reduced pressure to leave a crude residue,
which was purified by filtration through a pad of silica using
20% diethyl ether in light petroleum as the eluent. Evap-
oration of the solvent under reduced pressure gave 8-ethyl-
idene-6-(2-methylpropanal-2-yl)-1,4-dioxaspiro[4.5]decane
8 (1.44 g, 97%) as a pale yellow oil containing both (Z)- and
(E)-isomers in a ratio of 2:1. IR nmax (film)/cmꢀ1 2819 (alde-
1
hyde C–H), 2710 (aldehyde C–H) and 1727 (C]O); H
NMR (400 MHz, CDCl3): d 0.99+1.03 (6H, 2ꢂ(2ꢂs),
2ꢂ(2ꢂCH3C)), 1.31 (1H, m, (CH3)2CCH), 1.59 (3H, m,
(]CHCH3)), 1.81 (1H, m), 1.91 (1H, m), 2.08 (1H, m),
2.22 (2H, m), 2.54+2.67 (1H, 2ꢂm), 3.62 (1H, q, J 7.1,
OCH2CH2O), 3.86 (3H, m, OCH2CH2O), 5.24 (1H, m,
]CHCH3) and 9.31+9.32 (1H, 2ꢂs, O]CH); 13C NMR
(100 MHz, CDCl3): d 13.0, 13.2, 16.2, 23.4, 23.5, 24.6,
25.2, 33.4, 34.2, 35.4, 36.4, 46.9, 47.0, 50.5, 51.1, 63.1
(OCH2CH2O), 63.7 (OCH2CH2O), 111.0 (OCO), 111.1
(OCO), 117.2 (]CHCH3), 117.6 (]CHCH3), 136.9
(C]CH), 137.1 (C]CH), 202.4 (O]CH) and 202.6

11366
J. J. Crawford et al. / Tetrahedron 62 (2006) 11360–11370
(O]CH); HRMS (EI) m/z Calcd for C14H22O3 (M+):
238.15689. Found: 238.15734.
30.1, 30.2, 32.0, 32.2, 33.5, 34.6, 36.1, 37.0, 37.2, 42.1,
42.3, 52.2, 53.0, 63.3 (OCH2CH2O), 63.8 (OCH2CH2O),
75.5, 75.9, 113.2 (OCO), 113.4 (OCO), 116.8 (]CHCH3),
117.4 (]CHCH3), 137.4 (C]CH), 137.7 (C]CH) and
200.8 (CO); HRMS (EI) m/z Calcd for C20H22Co2O7
(M+ꢀCO): 492.00295. Found: 492.00162.
4.1.7. (Z)/(E)-8-Ethylidene-6-(3-methylbut-1-yn-3-yl)-
1,4-dioxaspiro[4.5]decane 9a/9b. Potassium carbonate
(1.30 g, 9.42 mmol) was added to a stirred solution of
(Z)/(E)-8-ethylidene-6-(2-methylpropanal-2-yl)-1,4-dioxas-
piro[4.5]decane 8a/8b (1.50 g, 6.30 mmol) and dimethyl
(1-diazo-2-oxopropyl)phosphonate (1.82 g, 9.48 mmol) in
methanol (40 ml) at 25 ꢁC. The mixture was stirred for 5 d
and further portions (5ꢂ0.5 equiv) of both potassium carbon-
ate (5ꢂ0.43 g) and dimethyl (1-diazo-2-oxopropyl)phospho-
nate (5ꢂ0.60 g) were added to the reaction mixture at regular
intervals over this time period. The solvent was evaporated
under reduced pressure and the residue was partitioned
between diethyl ether (50 ml) and water (50 ml). The organic
phase was separated and the aqueous phase was extracted
with another portion of diethyl ether (50 ml). The combined
organic phase was dried, filtered, and evaporated under re-
duced pressure to leave a crude residue, which was purified
by column chromatography on silica using 10% diethyl ether
in light petroleum as the eluent to give 8-ethylidene-6-(3-
methylbut-1-yn-3-yl)-1,4-dioxaspiro[4.5]decane 9 (1.19 g,
81%) as a pale yellow oil containing both (Z)- and (E)-iso-
mers in a ratio of 2:1. IR nmax (film)/cmꢀ1 2110 (C^C) and
4.1.9. Cyclopentenones 11a and 11b. A solution of hexa-
carbonyl((Z)/(E)-8-ethylidene-6-[m-[(1,2-h:1,2-h)-3-methyl-
but-1-yn-3-yl]]-1,4-dioxaspiro[4.5]decane)dicobalt-(Co–Co)
10a/10b (2:1) (188.0 mg, 0.36 mmol) and n-butyl methyl sul-
fide (0.16 g, 1.54 mmol) in 1,2-dichloroethane (5 ml) was
heated under reflux for 30 min. The black mixture was
then filtered through a pad of silica using diethyl ether as
the eluent. The filtrate was evaporated under reduced pres-
sure to leave a crude residue, which was purified by column
chromatography on silica using a 0–50% diethyl ether in
light petroleum gradient as the eluent to give cyclopente-
nones 11a and 11b (90.0 mg, 95% combined) as a 2:1 mix-
ture (by proton-NMR). Compounds 11a and 11b were
subsequently separated by column chromatography on silica
using a 0–30% diethyl ether in light petroleum gradient as
the eluent. This afforded 11a (59.0 mg) and 11b (31.0 mg)
as colourless crystalline solids.
1
1427 (C]C); H NMR (400 MHz, CDCl3): d 1.33–1.41
Analytical data for 11a are as follows: mp 90–91 ꢁC; IR nmax
(7H, 1ꢂm+4ꢂs, (CH3)2CCH), 1.59 (3H, m, (]CHCH3)),
1.71 (1H, m), 1.84 (1H, m), 1.90–2.28 (3H, overlapping
m), 2.45 (1H, m), 2.90 (1H, m), 3.95–4.06 (4H, overlapping
m, OCH2CH2O) and 5.21 (1H, m, ]CHCH3); 13C NMR
(100 MHz, CDCl3): d 13.0, 13.1, 24.7, 28.3, 28.4, 28.9,
30.2, 30.4, 33.4, 33.5, 34.1, 35.9, 36.9, 37.1, 51.4, 52.0,
63.5 (OCH2CH2O), 63.8 (OCH2CH2O), 63.9 (OCH2CH2O),
68.0 (^CH), 68.1 (^CH), 92.8 (C^), 93.0 (C^), 112.2
(OCO), 112.3 (OCO), 116.7 (]CHCH3), 117.0
(]CHCH3), 137.4 (C]CH) and 137.7 (C]CH); HRMS
(EI) m/z Calcd for C15H22O2 (M+): 234.16198. Found:
234.16165. Also isolated from this reaction was the starting
aldehyde 8a/8b (0.14 g).
(film)/cmꢀ1 3042 (vinyl C–H), 2978, 2927, 2876, 1702
(C]O) and 1625 (C]C); H NMR (400 MHz, CDCl3):
1
d 0.99 (3H, d, J 7.5, CHCH3), 1.17 (3H, s, (CH3)2C), 1.28
(1H, m), 1.47 (3H, s, (CH3)2C), 1.70–2.03 (6H, overlapping
m), 2.18 (1H, q, J 7.5, CHCH3), 3.82 (1H, m, OCH2CH2O),
3.91 (2H, m, OCH2CH2O), 3.98 (1H, m, OCH2CH2O) and
5.70 (1H, s, CH]C); 13C NMR (100 MHz, CDCl3): d 14.9
(CHCH3), 22.8 ((CH3)2C), 31.8, 32.7, 32.9 ((CH3)2C),
39.3, 42.5 ((CH3)2C), 52.7 (CHCH3), 55.8 (CCHCH2), 57.2
(CH2CCHCH3), 63.7 (OCH2CH2O), 65.0 (OCH2CH2O),
110.2 (OCO), 119.8 (CH]C), 201.3 (CH]C) and 213.8
(C]O); HRMS (EI) m/z Calcd for C16H22O3 (M+):
262.15689. Found: 262.15650. Single crystals of cyclopente-
none 11a were obtained from diethyl ether/light petroleum,
mounted in an inert oil, and transferred to the cold gas stream
of the diffractometer. Crystal data. C16H22O3, M¼262.16,
4.1.8. Hexacarbonyl((Z)/(E)-8-ethylidene-6-[m-[(1,2-h:1,2-
h)-3-methylbut-1-yn-3-yl]]-1,4-dioxaspiro[4.5]decane)-
dicobalt-(Co–Co) 10a/10b. A solution of (Z)/(E)-8-ethyl-
idene-6-(3-methylbut-1-yn-3-yl)-1,4-dioxaspiro[4.5]decane
9a/9b (1.18 g, 5.04 mmol) in light petroleum (10 ml) was
added to a stirred solution of octacarbonyldicobalt (1.78 g,
5.20 mmol) in light petroleum (40 ml) over a 5 min period
at 25 ꢁC. The mixture was stirred for 2 h before it was filtered
through a pad of silica using 10% diethyl ether in light petro-
leum as the eluent. The filtrate was evaporated under reduced
pressure to leave a crude residue, which was purified by
column chromatography on silica using a 0–10% diethyl
ether in light petroleum gradient as the eluent to give hexa-
carbonyl((Z)/(E)-8-ethylidene-6-[m-[(1,2-h:1,2-h)-3-methyl-
but-1-yn-3-yl]]-1,4-dioxaspiro[4.5]decane)dicobalt-(Co–Co)
10 (2.60 g, 99%) as a red oil containing both (Z)- and (E)-iso-
mers in a ratio of 2:1. IR nmax (film)/cmꢀ1 2089 (C]O), 2013
(C]O), 1465 (C]C) and 1442 (C]C); 1H NMR (400 MHz,
CDCl3): d 0.88–1.44 (7H, m), 1.57–1.76 (4H, m), 1.85–1.99
(1H, m), 2.01–2.23 (2H, m), 2.39–2.53 (1H, m), 2.97 (1H,
d, J 13.1), 4.02 (4H, m, OCH2CH2O), 5.20 (1H, m,
]CHCH3) and 6.17+6.22 (1H, 2ꢂs, ^CH); 13C NMR
(100 MHz, CDCl3): d 13.4, 13.7, 14.5, 22.8, 24.8, 28.3,
˚
monoclinic, a¼6.0402(13), b¼31.423(4), c¼7.7111(13) A,
3
ꢁ
˚
b¼107.469(15) , U¼1396.1(4) A , T¼295 K, space group
P21/n (no. 14), Z¼4, m(Mo Ka)¼0.085 mmꢀ1, 2977 reflec-
tions measured, 2721 unique (Rint¼0.0609), which were
used in all calculations. Final R1¼0.0481. The final wR(F2)
was 0.1418 (all data). See Ref. 12 for full crystal data.
Analytical data for 11b are as follows: mp 87–88 ꢁC; IR
nmax (film)/cmꢀ1 3039 (vinyl C–H), 2966, 2940, 2883,
1702 (C]O), 1625 (C]C), 1453, 1370, 1108 and 1095; 1H
NMR (400 MHz, CDCl3): d 1.07 (3H, d, J 7.2, CHCH3),
1.15 (1H, m), 1.19 (3H, s, (CH3)2C), 1.47 (3H, s, (CH3)2C),
1.71–1.86 (4H, overlapping m), 1.97 (1H, d, J 5.0, CCHCH2),
2.22 (1H, d, J 11.8), 2.27 (1H, q, J 7.2, CHCH3), 3.83 (1H, m,
OCH2CH2O), 3.91 (2H, m, OCH2CH2O), 4.00 (1H, m,
OCH2CH2O) and 5.80 (1H, s, CH]C); 13C NMR
(100 MHz, CDCl3): d 9.0 (CHCH3), 22.8 ((CH3)2C), 31.2,
33.0 ((CH3)2C), 33.9 (CCH2CH2), 38.0, 42.5 ((CH3)2C),
55.2 (CHCH3), 56.5 (CCHCH2), 56.7 (CH2CCHCH3), 63.7
(OCH2CH2O), 65.0 (OCH2CH2O), 110.2 (OCO), 121.1
(CH]C), 200.5 (CH]C) and 211.6 (C]O); HRMS (EI)

J. J. Crawford et al. / Tetrahedron 62 (2006) 11360–11370
11367
m/z Calcd for C16H22O3 (M+): 262.15689. Found:
262.15698. Single crystals of cyclopentenone 11b were
obtained from diethyl ether/light petroleum, mounted in an
inert oil, and transferred to the cold gas stream of the diffrac-
tometer. Crystal data. C16H22O3, M¼262.16, monoclinic,
trihydrate (20 mg, 0.03 mmol) was added to a stirred
solution of 1,4-dioxaspiro[4.5]dec-6-en-8-one 4 (50 mg,
0.32 mmol) and 1-methoxy-1-((trimethylsilyl)oxy)-2-meth-
ylpropene (87 mg, 0.50 mmol) in dichloromethane (5 ml) at
25 ꢁC. Stirring was continued for a further 24 h before filtra-
tion through a pad of silica using diethyl ether as the eluent
to give a crude residue. Separation was achieved using
column chromatography eluting with diethyl ether/light
petroleum (10–50% mixtures) yielding methyl 2-(1,4-dioxa-
spiro[4.5]decan-8-on-6-yl)-2-methylpropanoate 12 (55 mg,
67%) and methyl 2-(8-((trimethylsilyl)oxy)-1,4-dioxaspiro-
[4.5]dec-7-ene-6-yl)-2-methylpropanoate 13 (24 mg, 23%).
ꢁ
˚
a¼6.069(3), b¼16.253(5), c¼14.087(3) A, b¼93.40(3) ,
3
˚
U¼1387.1(7) A , T¼123 K, space group P21/n (no. 14),
Z¼4, m(Mo Ka)¼0.085 mmꢀ1, 3105 reflections measured,
2835 unique (Rint¼0.032), which were used in all calcula-
tions. Final R1¼0.067. The final wR(F2) was 0.084 (all
data). See Ref. 12 for full crystal data.
4.1.10. Alternative preparations of cyclopentenones 11a
and 11b.
Analytical data for 12 are as follows: Found: C, 61.06; H,
7.83. C13H20O5 requires C, 60.96; H, 7.87%; mp 60.6–
60.8 ꢁC; IR nmax (film)/cmꢀ1 1698 (C]O) and 1724
(C]O); 1H NMR (400 MHz, CDCl3): d 1.12 (3H, s,
CH3C), 1.15 (3H, s, CH3C), 1.71–1.79 (1H, m), 1.98–2.04
(1H, m), 2.37–2.41 (1H, m), 2.47–2.52 (1H, m), 2.53–2.71
(3H, overlapping m), 3.65 (3H, s, CH3O) and 3.92–4.05
(4H, m, OCH2CH2O); 13C NMR (100 MHz, CDCl3):
d 19.7 (CH3C), 27.3 (CH3C), 33.6 (CH2), 38.5 (CH2), 40.0
(CH2), 42.9 ((CH3)2C), 49.2 (CH), 52.0 (CH3O), 63.9
(OCH2CH2O), 65.0 (OCH2CH2O), 109.7 (OCO), 178.3
(OC]O) and 210.3 (C]O); HRMS (ES+) m/z Calcd for
C13H21O5 (M++1): 257.1389. Found: 257.1386.
4.1.10.1. Use of trimethylamine N-oxide. Trimethyl-
amine N-oxide dihydrate (0.18 g, 1.62 mmol) was added to
a stirred solution of hexacarbonyl((Z)/(E)-8-ethylidene-6-
[m-[(1,2-h:1,2-h)-3-methylbut-1-yn-3-yl]]-1,4-dioxaspiro-
[4.5]decane)dicobalt-(Co–Co) 10a/10b (2:1) (95.0 mg,
0.18 mmol) in acetone (3 ml) at 25 ꢁC. The mixture was
stirred for 16 h before it was filtered through a pad of silica
using diethyl ether as the eluent. The filtrate was evaporated
under reduced pressure to leave a crude residue, which was
purified by column chromatography on silica using a 0–50%
diethyl ether in light petroleum gradient as the eluent to give
cyclopentenones 11a and 11b (43.0 mg, 91% combined) as
a 2:1 mixture (by proton-NMR). Analytical data were as
given above.
Analytical data for 13 are as follows: Found: C, 58.85; H,
8.56. C16H28O5Si requires C, 58.56; H, 8.60%; IR nmax
(film)/cmꢀ1 1668 (C]C) and 1724 (C]O); 1H NMR
(400 MHz, CDCl3): d 1.19 (9H, s, (CH3)3Si), 1.14 (3H, s,
CH3C), 1.17 (3H, s, CH3C), 1.58–1.64 (1H, m), 1.89–1.97
(1H, m), 2.03–2.08 (1H, m), 2.27–2.37 (1H, m), 2.93–
2.94 (1H, m), 3.65 (3H, s, CH3O), 3.72–3.78 (2H, m,
OCH2CH2O), 3.89–3.96 (2H, m, OCH2CH2O) and 4.76–
4.78 (1H, m, C]CH); 13C NMR (100 MHz, CDCl3): d 0.6
((CH3)3Si), 20.0, 27.2, 28.4, 31.1, 44.3, 49.8, 51.8, 65.2,
101.8 (C]CH), 109.4 (OCO), 152.2 (C]CH) and 179.0
(OC]O); HRMS (ES+) m/z Calcd for C16H29O5Si
(M++1): 329.1784. Found: 329.1789.
4.1.10.2. Use of N-methylmorpholine N-oxide. N-Meth-
ylmorpholine N-oxide monohydrate (0.20 g, 1.48 mmol)
was added to a stirred solution of hexacarbonyl((Z)/(E)-8-
ethylidene-6-[m-[(1,2-h:1,2-h)-3-methylbut-1-yn-3-yl]]-
1,4-dioxaspiro[4.5]decane)dicobalt-(Co–Co) 10a/10b (2:1)
(99.0 mg, 0.19 mmol) in dichloromethane (3 ml) at 25 ꢁC.
The mixture was stirred for 16 h before it was filtered
through a pad of silica using diethyl ether as the eluent.
The filtrate was evaporated under reduced pressure to leave
a crude residue, which was purified by column chromato-
graphy on silica using a 0–50% diethyl ether in light petro-
leum gradient as the eluent to give cyclopentenones 11a and
11b (42.0 mg, 84% combined) as a 2:1 mixture (by proton-
NMR). Analytical data were as given above.
4.1.12. Methyl 2-(1,4-dioxaspiro[4.5]decan-8-on-6-yl)-
2-methylpropanoate 12 by hydrolysis of methyl 2-(8-
((trimethylsilyl)oxy)-1,4-dioxaspiro[4.5]dec-7-ene-6-yl)-
2-methylpropanoate 13. To a stirred solution of methyl
2-(8-((trimethylsilyl)oxy)-1,4-dioxaspiro[4.5]dec-7-ene-6-
yl)-2-methylpropanoate 13 (0.44 g, 1.35 mmol) in diethyl
ether (5 ml) aqueous oxalic acid (2% w/w, 5 ml) was added.
Stirring was continued for 12 h before saturated aqueous
sodium bicarbonate solution (5 ml) was added. Separa-
tion and evaporation under reduced pressure gave methyl
2-(1,4-dioxaspiro[4.5]decan-8-on-6-yl)-2-methylpropanoate
12 (0.34 g, 99%). Analytical data were as given above.
4.1.10.3. Use of polymer-supported sulfide.3i A mix-
ture of hexacarbonyl((Z)/(E)-8-ethylidene-6-[m-[(1,2-h:1,
2-h)-3-methylbut-1-yn-3-yl]]-1,4-dioxaspiro[4.5]decane)-
dicobalt-(Co–Co) 10a/10b (2:1) (54.0 mg, 0.10 mmol)
and polymer-supported sulfide (1 mmol gꢀ1, 0.36 g, 0.36
mmol) in 1,2-dichloroethane (3 ml) was heated under reflux
for 30 min. The mixture was then filtered through a pad
of silica using diethyl ether as the eluent. The filtrate was
evaporated under reduced pressure to leave a crude residue,
which was purified by column chromatography on silica
using a 0–50% diethyl ether in light petroleum gradient as
the eluent to give cyclopentenones 11a and 11b (21.0 mg,
80% combined) as a 2:1 mixture (by proton-NMR). Analyt-
ical data were as given above.
4.1.13. Methyl 2-((Z)/(E)-8-ethylidene-1,4-dioxaspiro-
[4.5]decan-6-yl)-2-methylpropanoate 14a/14b. To a stirred
suspension of ethyltriphenylphosphonium bromide (87 mg,
0.234 mmol) in THF (4 ml) at room temperature, a stan-
dardised solution of n-butyllithium (1.94 M, 0.13 ml,
0.252 mmol) in hexane was added dropwise. Stirring of the
resulting orange slurry was continued for 1 h before a solu-
tion of methyl 2-(1,4-dioxaspiro[4.5]decan-8-on-6-yl)-2-
methylpropanoate 12 (50 mg, 0.195 mmol) in THF (1 ml)
4.1.11. Methyl 2-(1,4-dioxaspiro[4.5]decan-8-on-6-yl)-2-
methylpropanoate 12 and methyl 2-(8-((trimethyl-
silyl)oxy)-1,4-dioxaspiro[4.5]dec-7-ene-6-yl)-2-methyl-
propanoate 13. Ytterbium(III) trifluromethanesulfonate

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J. J. Crawford et al. / Tetrahedron 62 (2006) 11360–11370
was added. Stirring was continued for a further 16 h before
evaporation of the solvent under reduced pressure. Diethyl
ether (10 ml) was added before the slurry was sonicated in
a cleaning bath for 2 min. Filtration through a pad of silica
using diethyl ether as the eluent gave a crude residue, which
was purified using column chromatography eluting with di-
ethyl ether/light petroleum (0–40% mixtures). This gave
methyl 2-(8-ethylidene-1,4-dioxaspiro[4.5]decan-6-yl)-2-
methylpropanoate 14 (46 mg, 89%) as a mixture containing
both (Z)- and (E)-isomers in a ratio of 1.6:1. This ratio was
4.1.14.5. Use of NaHMDS and ethyltriphenylphospho-
nium chloride. Using a similar procedure to that described
in Section 4.1.13, with ethyltriphenylphosphonium chloride
(76 mg, 0.234 mmol) and a standardised solution of sodium
hexamethyldisilazide (0.273 M, 0.86 ml, 0.234 mmol) in
THF, gave methyl 2-(8-ethylidene-1,4-dioxaspiro[4.5]-
decan-6-yl)-2-methylpropanoate 14 (39 mg, 75%) as a mix-
ture containing both (Z)- and (E)-isomers in a ratio of 1:2.5.
4.1.14.6. Use of NaHMDS and tetraethylphosphonium
bromide. Using a similar procedure to that described
in Section 4.1.13, with tetraethylphosphonium bromide
(53 mg, 0.234 mmol), a standardised solution of sodium
hexamethyldisilazide (0.273 M, 0.86 ml, 0.234 mmol) in
THF, and sonication for 5 min on reaction work-up, gave
methyl 2-(8-ethylidene-1,4-dioxaspiro[4.5]decan-6-yl)-2-
methylpropanoate 14 (39 mg, 75%) as a mixture containing
both (Z)- and (E)-isomers in a ratio of 1:1.1.
1
determined by the H NMR integration of the signals at
d 2.57–2.59 and 2.60–2.61 ppm; from correlation and full
assignment of both the 1H and 13C NMR spectra, these sig-
nals were identified as those relating to an allylic cyclohexyl
H positioned syn- to the olefinic methyl group within the (E)-
and (Z)-isomers, respectively. Found: C, 67.02; H, 9.06.
C15H24O4 requires C, 67.14; H, 9.01%; IR nmax (film)/
cmꢀ1 1443 (C]C) and 1730 (C]O); 1H NMR (400 MHz,
CDCl3): d 1.07–1.18 (m, 6H), 1.20–1.30 (m, 1H), 1.51 (t,
3H, J 6.5, CH3CH]C), 1.70–1.88 (m, 1H), 1.89–1.91 (m,
1H), 2.08–2.11 (m, 0.61H), 2.12–2.22 (m, 2.39H), 2.57–
2.59 (m, 0.39H), 2.60–2.61 (m, 0.61H), 3.75 (s, 3H,
CH3O), 3.76–3.91 (m, 4H, OCH2CH2O) and 5.12–5.20
(m, 1H, CH3CH]C); 13C NMR (100 MHz, CDCl3):
d 13.4, 20.1, 25.0, 25.7, 27.7, 32.2, 33.2, 33.8, 34.7, 35.6,
36.6, 36.7, 42.9, 51.3, 51.8, 63.5, 64.6, 111.5, 117.1, 137.5
and 179.2; HRMS (ES+) m/z Calcd for C15H25O4 (M++1):
269.1753. Found: 269.1752.
4.1.14.7. Use of KHMDS and tetraethylphosphonium
bromide. Using a similar procedure to that described
in Section 4.1.13, with tetraethylphosphonium bromide
(53 mg, 0.234 mmol), a standardised solution of potassium
hexamethyldisilazide (0.357 M, 0.67 ml, 0.239 mmol) in
THF, and sonication for 5 min on reaction work-up, gave
methyl 2-(8-ethylidene-1,4-dioxaspiro[4.5]decan-6-yl)-2-
methylpropanoate 14 (39 mg, 75%) as a mixture containing
both (Z)- and (E)-isomers in a ratio of 1:1.1.
4.1.14. Alternative preparations of alkenes 14a and 14b.
4.1.14.1. Use of NaHMDS and ethyltriphenylphospho-
nium bromide. Using a similar procedure to that described
in Section 4.1.13, with a standardised solution of sodium
hexamethyldisilazide (0.273 M, 0.86 ml, 0.234 mmol) in
THF, gavemethyl 2-(8-ethylidene-1,4-dioxaspiro[4.5]decan-
6-yl)-2-methylpropanoate 14 (40 mg, 77%) as a mixture con-
taining both (Z)- and (E)-isomers in a ratio of 1:2.4.
4.1.15. (Z)/(E)-8-Ethylidene-6-(2-methylpropan-1-ol-2-
yl)-1,4-dioxaspiro[4.5]decane 7a/7b from reduction of
methyl 2-((Z)/(E)-8-ethylidene-1,4-dioxaspiro[4.5]-
decan-6-yl)-2-methylpropanoate 14a/14b. To a stirred
solution of methyl 2-((Z)/(E)-8-ethylidene-1,4-dioxaspiro-
[4.5]decan-6-yl)-2-methylpropanoate 14a/14b (1:2.4) (35 mg,
0.137 mmol) in diethyl ether (5 ml) at room temperature,
lithium aluminium hydride (6 mg, 0.15 mmol) was added
as a powder. Stirring of the grey emulsion was continued
for 1 h at room temperature before water (0.1 ml) was added.
Stirring was continued for a further 5 min before addition
of aqueous sodium hydroxide solution (10% w/w, 0.1 ml).
Finally, water (0.3 ml) was added and the resulting granular
precipitate removed by filtration through Celite using diethyl
ether as the eluent. Water (30 ml) was added to the filtrate and
the organic phase was separated and dried over sodium
sulfate to give 8-ethylidene-6-(2-methylpropan-1-ol-2-yl)-
1,4-dioxaspiro[4.5]decane 7a/7b (32 mg, 97%) as a mixture
containing both (Z)- and (E)-isomers in a ratio of 1:2.4. This
ratio was determined by 1H NMR integration as shown
below. IR nmax (film)/cmꢀ1 3489 (O–H) and 1440 (C]C);
1H NMR (400 MHz, CDCl3): d 0.83 (2.13H, s, CH3), 0.87
(0.87H, s, CH3), 1.01 (2.13H, s, CH3), 1.05 (0.87H, s,
CH3), 1.27–1.35 (1H, m), 1.58–1.64 (3H, m), 1.70–1.78
(1H, m), 1.86–1.95 (2H, m), 2.08–2.09 (0.29H, m), 2.15–
2.24 (1.71H, overlapping m), 2.47–2.48 (0.29H, m), 2.71–
2.74 (0.71H, m), 3.08–3.14 (1H, m), 3.34–3.40 (1H, m),
3.53–3.59 (1H, m), 3.88–4.02 (4H, m) and 5.19–5.24
(1H, m, ]CHCH3); 13C NMR (100 MHz, CDCl3): d 12.8,
13.1, 22.0, 22.1, 24.6, 27.3, 27.5, 27.6, 33.3, 35.3,
36.1, 36.4, 38.4, 38.6, 47.8, 48.4, 63.0 (OCH2CH2O),
63.4 (OCH2CH2O), 71.8 (CH2OH), 112.9 (OCO), 116.2
(]CHCH3), 116.5 (]CHCH3), 137.8 (C]CH) and 138.0
(C]CH).
4.1.14.2. Use of KHMDS and ethyltriphenylphospho-
nium bromide. Using a similar procedure to that described
in Section 4.1.13, with a standardised solution of potassium
hexamethyldisilazide (0.357 M, 0.67 ml, 0.239 mmol) in
THF, gave methyl 2-(8-ethylidene-1,4-dioxaspiro[4.5]de-
can-6-yl)-2-methylpropanoate 14 (44 mg, 85%) as a mixture
containing both (Z)- and (E)-isomers in a ratio of 1:2.3.
4.1.14.3. Use of KHMDS and ethyltriphenylphospho-
nium chloride. Using a similar procedure to that described
in Section 4.1.13, with ethyltriphenylphosphonium chloride
(76 mg, 0.234 mmol) and a standardised solution of potas-
sium hexamethyldisilazide (0.357 M, 0.67 ml, 0.239 mmol)
in THF, gave methyl 2-(8-ethylidene-1,4-dioxaspiro[4.5]-
decan-6-yl)-2-methylpropanoate 14 (41 mg, 79%) as a mix-
ture containing both (Z)- and (E)-isomers in a ratio of 1:2.3.
4.1.14.4. Use of KHMDS and ethyltriphenylphospho-
nium iodide. Using a similar procedure to that described
in Section 4.1.13, with ethyltriphenylphosphonium iodide
(98 mg, 0.234 mmol) and a standardised solution of potas-
sium hexamethyldisilazide (0.357 M, 0.67 ml, 0.239 mmol)
in THF, gave methyl 2-(8-ethylidene-1,4-dioxaspiro[4.5]-
decan-6-yl)-2-methylpropanoate 14 (47 mg, 90%) as a mix-
ture containing both (Z)- and (E)-isomers in a ratio of 1:2.3.

J. J. Crawford et al. / Tetrahedron 62 (2006) 11360–11370
11369
4.1.16. Cyclopentenone 11b by epimerisation of cyclo-
pentenone 11a. Cyclopentenone 11a (25 mg, 0.095 mmol)
was treated with lithium hydroxide (11.5 mg, 0.48 mmol)
in THF (5 ml) and water (1 ml) at reflux for 3 d. This mixture
was then extracted with diethyl ether and the organic phase
washed with water before drying over sodium sulfate. This
gave a mixture of cyclopentenones 11a and 11b in a ratio
of 1:9 by H NMR integration of the signals at d 5.70 and
5.80 ppm. Separation of 11a and 11b was then achieved as
described in Section 4.1.9.
OCH2CH2O) and 3.95 (1H, m, OCH2CH2O); 13C NMR
(100 MHz, CDCl3): d 12.4 (CHCH3), 26.5 ((CH3)2C), 28.7
((CH3)2C), 30.6, 31.9, 35.6 (HOCHCH2CH), 40.7
((CH3)2C), 42.8, 50.2 (CH2CCHCH3), 50.4 (CHCH3), 52.6
(HOCHCH2CH), 57.9 (CCHCH2), 63.3 (OCH2CH2O),
64.7 (OCH2CH2O), 81.5 (HOCH) and 111.8 (OCO);
HRMS (EI) m/z Calcd for C16H26O3 (M+): 266.18819.
Found: 266.18727.
1
4.1.19. Xanthate ester 18. A solution of n-butyllithium
in hexanes (2.5 M, 0.30 ml, 0.75 mmol) was added over
a 5 min period to a stirred solution of cyclopentanol 17
(187.0 mg, 0.703 mmol) in tetrahydrofuran (5 ml) at 0 ꢁC.
The mixture was stirred for 5 min before carbon disulfide
(85.0 mg, 0.067 ml, 1.12 mmol) was added and the mixture
was allowed to warm to 25 ꢁC. The mixture was stirred for
80 min before the reaction was quenched by the addition
of methyl iodide (0.12 g, 0.052 ml, 0.84 mmol) and then
stirred for a further 30 min. The mixture was then partitioned
between diethyl ether (30 ml) and water (30 ml), the organic
phase separated, and the aqueous phase extracted with
another portion of diethyl ether (30 ml). The combined
organic phase was dried, filtered, and evaporated under re-
duced pressure to leave a crude residue, which was purified
by column chromatography on silica using a 0–30% diethyl
ether in light petroleum gradient as the eluent. This gave
xanthate ester 18 (235.0 mg, 94%) as a pale yellow oil,
which was characterised by infrared and NMR spectroscopy
and was then used immediately in the next synthetic step. IR
nmax (film)/cmꢀ1 2966, 1485, 1376, 1223 and 1057; 1H NMR
(400 MHz, CDCl3): d 0.94 (3H, d, J 7.2, CHCH3), 1.01 (3H,
s, (CH3)2C), 1.20 (3H, s, (CH3)2C), 1.47–1.57 (3H, m),
1.68–1.92 (6H, overlapping m), 2.06 (1H, m), 2.23 (1H,
m), 2.55 (3H, s, CH3S), 3.79–3.90 (3H, overlapping m,
OCH2CH2O), 3.97 (1H, m, OCH2CH2O) and 5.37 (1H, m,
CHOC]S); 13C NMR (100 MHz, CDCl3): d 12.9, 19.0,
26.6, 28.7, 31.9, 32.0, 32.8, 41.3, 42.5, 46.9, 50.0, 52.8,
58.0, 63.8 (OCH2CH2O), 65.2 (OCH2CH2O), 92.1
(CHOC]S), 111.5 (OCO) and 216.2 (OC]S).
4.1.17. Cyclopentanone 16. Palladium on charcoal (10%,
30 mg) was added to a solution of cyclopentenone 11b
(365.0 mg, 1.39 mmol) in toluene (20 ml). The mixture
was placed under 45 psi of hydrogen gas and agitated using
a Cook apparatus for 3 h. The mixture was then filtered
through a pad of silica using diethyl ether as the eluent.
The filtrate was evaporated under reduced pressure to give
cyclopentanone 16 (365.0 mg, 99%) as a colourless crystal-
line solid, mp 44–45 ꢁC; IR nmax (film)/cmꢀ1 2959, 2921,
1
2876, 1704 (C]O), 1459 and 1363; H NMR (400 MHz,
CDCl3): d 0.95 (3H, d, J 7.6, CHCH3), 0.96 (3H, s,
(CH3)2C), 1.22 (3H, s, (CH3)2C), 1.52 (2H, overlapping m),
1.62–1.69 (2H, overlapping m), 1.75 (1H, m), 1.83–1.94
(2H, m), 2.03 (1H, dt, J 8.6 and 1.2), 2.14 (1H, q, J 7.6,
CHCH3), 2.24 (1H, ddd, J 18.2, 6.9 and 1.5, O]CCH2CH),
2.34 (1H, dd, J 18.1 and 10.8, O]CCH2CH), 3.76–
3.89 (3H, overlapping m, OCH2CH2O) and 3.96 (1H, m,
OCH2CH2O); 13C NMR (100 MHz, CDCl3): d 11.8
(CHCH3), 26.7 ((CH3)2C), 29.2 ((CH3)2C), 30.5, 31.3, 38.3
(O]CCH2CH), 41.9 ((CH3)2C), 42.2 (CCH2CH), 49.4
(CH2CCHCH3), 49.5 (O]CCH2CH), 50.9 (CHCH3), 56.2
(CCHCH2), 63.4 (OCH2CH2O), 64.8 (OCH2CH2O), 111.0
(OCO) and 221.4 (C]O); HRMS (EI) m/z Calcd for
C16H24O3 (M+): 264.17254. Found: 264.17280. Single crys-
tals of ketone 16 were obtained from diethyl ether/light petro-
leum, mounted in an inert oil, and transferred to the cold
gas stream of the diffractometer. Crystal data. C16H24O3,
M¼264.17, monoclinic, a¼8.3280(3), b¼8.3930(3), c¼
3
ꢁ
˚
˚
10.2120(4) A, b¼106.696(2) , U¼683.70(4) A , T¼150 K,
space group P21/n (no. 14), Z¼2, m(Mo Ka)¼0.087 mmꢀ1
,
4.1.20. Acetal 19. A solution of xanthate ester 18 (45.0 mg,
0.126 mmol), tri-n-butyltin hydride (0.50 g, 1.71 mmol) and
AIBN (13.0 mg, 0.08 mmol) in deoxygenated benzene
(20 ml) was heated under reflux for 48 h. The solvent was
evaporated under reduced pressure to leave a crude residue,
which was purified by column chromatography on silica
using a 0–20% diethyl ether in light petroleum gradient as
the eluent to give acetal 19 (24.0 mg, 76%) as a colourless
oil. IR nmax (film)/cmꢀ1 2959, 2876, 1472, 1363 and 1102;
1H NMR (400 MHz, CDCl3): d 0.84 (3H, d, J 7.1,
CHCH3), 0.97 (3H, s, (CH3)2C), 1.17 (3H, s, (CH3)2C),
1.24–1.90 (13H, overlapping m), 3.78–3.90 (3H, overlap-
ping m, OCH2CH2O) and 3.97 (1H, m, OCH2CH2O); 13C
NMR (100 MHz, CDCl3): d 15.7 (CHCH3), 25.8, 26.9
((CH3)2C), 28.2 ((CH3)2C), 31.4, 31.6, 37.3 (CH2CHCH3),
41.6 ((CH3)2C), 41.7, 41.8 (CHCH3), 53.6 (CH2CCHCH3),
56.7 (CH2CH2CHC), 58.1 (CCHCH2), 63.4 (OCH2CH2O),
64.8 (OCH2CH2O) and 112.2 (OCO); HRMS (EI) m/z Calcd
for C16H26O2 (M+): 250.19328. Found: 250.19432.
5455 reflections measured, 3107 unique (Rint¼0.0273),
which were used in all calculations. Final R1¼0.0340. The
final wR(F2) was 0.0825 (all data). See Ref. 12 for full crystal
data.
4.1.18. Cyclopentanol 17. Lithium aluminium hydride
(37.0 mg, 0.97 mmol) was added to a stirred solution of
cyclopentanone 16 (260.0 mg, 0.985 mmol) in diethyl ether
(20 ml) at 0 ꢁC. The mixture was stirred for 2 h before it was
allowed to warm to 25 ꢁC and the reaction was quenched by
the addition of water (0.04 ml) then 10% aqueous sodium
hydroxide solution (0.04 ml) and, lastly, another portion of
water (0.12 ml). This resulted in a white granular precipitate,
which was removed by filtration through a pad of silica using
diethyl ether as the eluent. The filtrate was evaporated under
reduced pressure to give cyclopentanol 17 (259 mg, 99%) as
a colourless crystalline solid, mp 75–85 ꢁC; IR nmax (film)/
cmꢀ1 3317 (O–H), 2959, 2889, 1459, 1376, 1114 and
1
1051; H NMR (400 MHz, CDCl3): d 0.94 (3H, d, J 7.0,
CHCH3), 0.98 (3H, s, (CH3)2C), 1.18 (3H, s, (CH3)2C),
1.28–1.52 (4H, overlapping m), 1.63–1.93 (8H, overlapping
m), 3.57 (1H, m, CHOH), 3.75–3.87 (3H, overlapping m,
4.1.21. Cedrone 15.2a,e Triphenylphosphine (2.6 mg,
0.01 mmol) and carbon tetrabromide (3.3 mg, 0.01 mmol)
were added to a stirred solution of acetal 19 (32.0 mg,

11370
J. J. Crawford et al. / Tetrahedron 62 (2006) 11360–11370
0.13 mmol) in acetone (5 ml) at 25 ꢁC. The mixture was
stirred for 1 h before the solvent was evaporated under re-
duced pressure to leave a crude residue, which was purified
by column chromatography on silica using a 5–20% diethyl
ether in light petroleum gradient as the eluent to give
cedrone 15 (26.1 mg, 99%) as a colourless oil. IR nmax
(film)/cmꢀ1 2960, 2877, 1715 and 1460; 1H NMR
(400 MHz, CDCl3): d 0.89 (3H, d, J 7.1, CHCH3), 1.00
(3H, s, (CH3)2C), 1.01 (3H, s, (CH3)2C), 1.42 (1H, m),
1.51 (1H, m), 1.56–1.76 (4H, overlapping m), 1.80–2.00
(4H, overlapping m), 2.27–2.36 (2H, overlapping m,
O]CCHCH2+CH2CH2C]O) and 2.48 (1H, dd, J 18.3
and 7.8, CH2CH2C]O); 13C NMR (100 MHz, CDCl3):
d 15.7 (CHCH3), 25.7, 26.0 ((CH3)2C), 26.4 ((CH3)2C),
32.1, 36.8, 37.0, 41.5, 41.8, 43.0 ((CH3)2C), 54.6
(CH2CCHCH3), 57.1 (CH2CH2CHC), 67.3 (O]CCHCH2)
and 214.4 (C]O); HRMS (EI) m/z Calcd for C14H22O
(M+): 206.16707. Found: 206.16753.
Watson, S. P. J. Chem. Soc., Perkin Trans. 1 2000, 4366; (g)
Brown, D. S.; Campbell, E.; Kerr, W. J.; Lindsay, D. M.;
Morrison, A. J.; Pike, K. G.; Watson, S. P. Synlett 2000, 1573;
(h) Ford, J. G.; Kerr, W. J.; Kirk, G. G.; Lindsay, D. M.;
Middlemiss, D. Synlett 2000, 1415; (i) Kerr, W. J.; Lindsay,
D. M.; McLaughlin, M.; Pauson, P. L. Chem. Commun. 2000,
1467; (j) Carbery, D. R.; Kerr, W. J.; Lindsay, D. M.; Scott,
J. S.; Watson, S. P. Tetrahedron Lett. 2000, 41, 3235; (k) Kerr,
W. J.; Lindsay, D. M.; Rankin, E. M.; Scott, J. S.; Watson,
S. P. Tetrahedron Lett. 2000, 41, 3229; (l) Kerr, W. J.; Lindsay,
D. M.; Watson, S. P. Chem. Commun. 1999, 2551; (m) Kerr,
W. J.; McLaughlin, M.; Pauson, P. L.; Robertson, S. M. Chem.
Commun. 1999, 2171; (n) Clements, C. J.; Dumoulin, D.;
Hamilton, D. R.; Hudecek, M.; Kerr, W. J.; Kiefer, M.; Moran,
P. H.; Pauson, P. L. J. Chem. Res. 1998, (S) 636 (M) 2658;
(o) Donkervoort, J. G.; Gordon, A. R.; Johnstone, C.; Kerr,
W. J.; Lange, U. Tetrahedron 1996, 52, 7391; (p) Kerr, W. J.;
Kirk, G. G.; Middlemiss, D. Synlett 1995, 1085; (q) Gordon,
A. R.; Johnstone, C.; Kerr, W. J. Synlett 1995, 1083; (r) Hay,
A. M.; Kerr, W. J.; Kirk, G. G.; Middlemiss, D. Organometallics
1995, 14, 4986;(s)Johnstone, C.;Kerr, W. J.;Lange, U. J. Chem.
Soc., Chem. Commun. 1995, 457.
Acknowledgements
We are grateful to the Carnegie Trust for the Universities of
Scotland for the award of a postgraduate scholarship (MM)
and the EPSRC for further funding. We also wish to thank
AstraZeneca Pharmaceuticals for Strategic Research Fund-
ing (W.J.K.) and to M. Pervez of the same company for
the generous supply of some chemicals. We are also
indebted to A. R. Kennedy for X-ray crystallography and
to the EPSRC Mass Spectrometry Service, University of
Wales, Swansea, for analyses. Finally, we thank Messrs
William MacMillan and Glen Farclas for inspiration prior
to the production of this manuscript.
4. Kerr, W. J.; McLaughlin, M.; Morrison, A. J.; Pauson, P. L. Org.
Lett. 2001, 3, 2945.
5. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
6. (a) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24,
5635; (b) Minami, I.; Takahashi, K.; Shimizu, I.; Kimura, T.;
Tsuji, J. Tetrahedron 1986, 42, 2971.
7. Kobayashi, S.; Hachiya, I.; Takahori, T.; Araki, M.; Ishitani, H.
Tetrahedron Lett. 1992, 33, 6815.
8. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
9. (a) Ohira, S. Synth. Commun. 1989, 19, 561; (b) Muller, S.;
¨
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
10. (a) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron
Lett. 1990, 31, 5289; (b) Jeong, N.; Chung, Y. K.; Lee, B. Y.;
Lee, S. H.; Yoo, S.-E. Synlett 1991, 204; (c) Chung, Y. K.;
Lee, B. Y.; Jeong, N.; Hudecek, M.; Pauson, P. L. Organo-
metallics 1993, 12, 220; (d) Krafft, M. E.; Scott, I. L.; Romero,
R. H.; Feibelmann, S.; Van Pelt, C. E. J. Am. Chem. Soc. 1993,
115, 7199.
References and notes
1. (a) Barrero, A. F.; del Moral, J. Q.; Lara, A. Tetrahedron 2000,
56, 3717 and references therein; (b) Stork, G.; Breslow, R.
J. Am. Chem. Soc. 1953, 75, 3291; (c) Walter, P. Ann. Chem.
1841, 39, 247.
2. For example, see: (a) Stork, G.; Clark, F. H., Jr. J. Am. Chem.
Soc. 1955, 77, 1072; (b) Corey, E. J.; Girotra, N. N.; Mathew,
C. T. J. Am. Chem. Soc. 1969, 91, 1557; (c) Crandall, T. G.;
Lawton, R. G. J. Am. Chem. Soc. 1969, 91, 2127; (d) Kuehne,
M. E.; Damon, R. E. J. Org. Chem. 1977, 42, 1825; (e)
Breitholle, E. G.; Fallis, A. G. J. Org. Chem. 1978, 43, 1964;
(f) Wender, P. A.; Howbert, J. J. J. Am. Chem. Soc. 1981, 103,
688; (g) Rigby, J. H.; Kirova-Snover, M. Tetrahedron Lett.
1997, 38, 8153; (h) Lee, H.-Y.; Lee, S.; Kim, D.; Kim, B. K.;
Bahn, J. S.; Kim, S. Tetrahedron Lett. 1998, 39, 7713.
3. (a) Caldwell, J. J.; Cameron, I. D.; Christie, S. D. R.; Hay,
A. M.; Johnstone, C.; Kerr, W. J.; Murray, A. Synthesis 2005,
3293; (b) Brown, J. A.; Janecki, T.; Kerr, W. J. Synlett 2005,
2023; (c) Brown, J. A.; Irvine, S.; Kerr, W. J.; Pearson, C. M.
Org. Biomol. Chem. 2005, 3, 2396; (d) Kerr, W. J.;
McLaughlin, M.; Pauson, P. L. J. Organomet. Chem. 2001,
630, 118; (e) Kerr, W. J.; McLaughlin, M.; Pauson, P. L.;
Robertson, S. M. J. Organomet. Chem. 2001, 630, 104; (f)
Kennedy, A. R.; Kerr, W. J.; Lindsay, D. M.; Scott, J. S.;
11. Sugihara, T.; Yamada, M.; Yamaguchi, M.; Nishizawa, M.
Synlett 1999, 771.
12. Kennedy, A. R.; Kerr, W. J.; McLaughlin, M.; Pauson, P. L.
Acta Crystallogr. 2001, C57, 1316.
13. (a) Kelly, S. E. Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, p 729; (b)
Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
14. (a) Vedejs, E.; Meier, G. P.; Snoble, K. A. J. J. Am. Chem. Soc.
1981, 103, 2823; (b) Vedejs, E.; Marth, C. F.; Ruggeri, R. J. Am.
Chem. Soc. 1988, 110, 3940; (c) Vedejs, E.; Marth, C. F. J. Am.
Chem. Soc. 1988, 110, 3948; (d) Schlosser, M.; Schaub, B.; de
Oliveira-Neto, J.; Jeganathan, S. Chimia 1986, 40, 244.
15. Schlosser, M.; Schaub, B. J. Am. Chem. Soc. 1982, 104, 5821.
16. (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574; (b) Hartwig, W. Tetrahedron 1983, 39,
2609.
17. (a) Johnstone, C.; Kerr, W. J.; Scott, J. S. J. Chem. Soc., Chem.
Commun. 1996, 341; (b) Caldwell, J. J.; Kerr, W. J.; Scott, J. S.;
Shearer, G. C. Unpublished results.