Total synthesis 2-epi-α-cedren-3-one via a cobalt-catalysed Pauson-Khand reaction

Article abstract of DOI:10.1016/j.tet.2018.06.032

Herein we target the total synthesis of 2-epi-α-cedren-3-one, a natural compound isolated from the essential oil of Juniperus thurifera. Overall, our synthetic sequence presents an optimised and robust series of chemical transformations, with prominent features including a low temperature and highly (Z)-selective Wittig olefination reaction, which is vital for the establishment of the relative stereochemistry within the final natural product, and a microwave-assisted, catalytic, intramolecular Pauson-Khand cyclisation reaction, which is used to construct the intriguing tricyclic core of the target molecule. Our optimum cyclisation protocol utilises only 20 mol% of transition metal, and delivers the complex tricyclic structure in just 10 min. Further manipulations of the annulation product culminate in the first total synthesis of the described natural target.

Full text of DOI:10.1016/j.tet.2018.06.032

Accepted Manuscript
Total synthesis 2-epi-α-cedren-3-one via a cobalt-catalysed Pauson-Khand reaction
William J. Kerr, Mark McLaughlin, Laura C. Paterson, Colin M. Pearson
PII:
S0040-4020(18)30721-X
10.1016/j.tet.2018.06.032
TET 29628
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 March 2018
Revised Date: 11 June 2018
Accepted Date: 13 June 2018
Please cite this article as: Kerr WJ, McLaughlin M, Paterson LC, Pearson CM, Total synthesis 2-epi-
α-cedren-3-one via a cobalt-catalysed Pauson-Khand reaction, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.06.032.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Leave this area blank for abstract info.
Total synthesis 2-epi-α-cedren-3-one via a
cobalt-catalysed Pauson-Khand reaction
William J. Kerr, Mark McLaughlin, Laura C. Paterson,
Colin M. Pearson
Department of Pure and Applied Chemistry
WestCHEM
University of Strathclyde
295 Cathedral Street
Glasgow
G1 1XL
Scotland, UK

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Total synthesis 2-epi-α-cedren-3-one via a cobalt-catalysed Pauson-Khand reaction
William J. Kerr , Mark McLaughlin, Laura C. Paterson, Colin M. Pearson
Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, Scotland, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we target the total synthesis of 2-epi-α-cedren-3-one, a natural compound isolated from the
essential oil of Juniperus thurifera. Overall, our synthetic sequence presents an optimised and
robust series of chemical transformations, with prominent features including a low temperature and
highly (Z)-selective Wittig olefination reaction, which is vital for the establishment of the relative
stereochemistry within the final natural product, and a microwave-assisted, catalytic, intramolecular
Pauson-Khand cyclisation reaction, which is used to construct the intriguing tricyclic core of the
target molecule. Our optimum cyclisation protocol utilises only 20 mol% of transition metal, and
delivers the complex tricyclic structure in just 10 minutes. Further manipulations of the annulation
product culminate in the first total synthesis of the described natural target.
Available online
Keywords:
Natural product;
Organic synthesis;
Catalysis;
Pauson-Khand;
Cobalt
2009 Elsevier Ltd. All rights reserved
.
———
Corresponding Author. E-mail: w.kerr@strath.ac.uk (William J. Kerr)

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
The synthetic chemistry community continually strives to
develop methods to create complex, yet adaptable, molecular
frameworks in a direct and effective manner. In this regard, the
discovery and growth of metal-mediated transformations has
vastly increased the spectrum of molecular architectures that are
accessible via organic synthesis, often delivering simplification
of synthetic routes with enhanced levels of efficiency.
A valuable, metal-mediated, method for generating molecular
complexity in a single step is the Pauson-Khand reaction (PKR).1
Traditionally, this annulation technique has been mediated by
cobalt, with the PKR bringing an alkene, alkyne (normally
present as its hexacarbonyl dicobalt complex) and a carbon
monoxide moiety together to construct a cyclopentenone ring
system. Since its discovery, this organocobalt cyclisation process
has been developed into an effective method, that has found
increasing use as the key transformation in the synthesis of
natural products and other cyclic compounds possessing an array
of skeletal frameworks. Indeed, recent examples include Baran’s
Scheme 1. Synthesis of ketoester 4.
α,β-unsaturated ketone 3 (via the trimethylsilyl enol ether) using
a palladium-mediated Saegusa oxidation protocol.9 This reaction
could also be carried out using sub-stoichiometric quantities10 of
palladium(II) acetate to deliver the desired unsaturated ketone in
a very good yield. Following this, ketoester 4 was furnished
directly via a conjugate addition reaction of the silyl ketene acetal
of methyl isobutyrate, catalysed by ytterbium(III) triflate
trihydrate.11
development
of
an
N-oxide/ethylene
glycol-assisted
intermolecular PKR towards the synthesis of axinellamines,2 and
Sabitha’s use of oxindole enynes to deliver interesting fused
spiro-oxindole scaffolds.3 In 2018, Xu elegantly utilised an
intramolecular PKR in the construction of the rare, and highly
congested, sesterterpenoid, astellatol.4 Having stated all of this, in
the main, many current examples make use of an intramolecular
protocol to obtain bicyclic motifs, with the preparation of more
elaborate, and more strained, structures remaining much less
common. Furthermore, carrying out the PKR using sub-
stoichiometric quantities of metal remains somewhat under-
developed, with the scope, again, remaining limited and the
majority of examples requiring an external source of toxic carbon
monoxide gas under forcing reaction conditions.1,5
The next step in our synthetic sequence involved the
installation of the requisite alkene moiety. Experience from the
syntheses α- and β-cedrene revealed that the stereochemical
outcome of this olefination reaction has a direct impact upon the
later stages in the synthetic programme. In this regard, and in
contrast to our previous syntheses of the related natural
sesquiterpenes,8 a (Z)-selective olefination reaction was required
in order to establish the relative stereochemistry at C2 in the final
target and, more specifically, to align the methyl group (C12) syn
to the methylene bridge (C11) in 2-epi-α-cedren-3-one, 1a. Whilst
the previous studies within our laboratories had allowed the
preparation of desired (Z)-isomer, 5a, the selectivity achieved
had been, at best, moderate. As part of this programme of work,
our preliminary efforts towards obtaining an enhanced isomeric
ratio involved a standard Wittig protocol at room temperature
(Scheme 2), which, pleasingly, delivered olefins 5a and 5b in an
excellent 92% yield. In terms of selectivity, a modest 2:1 ratio in
favour of the desired (Z) olefinic product was achieved (with
As part of our ongoing endeavours to further develop the
proficiency and applicability of this annulation process,6 we
sought to establish a direct and efficient pathway for the
synthesis of the structurally demanding natural target 2-epi-α-
cedren-3-one7 (1a, Fig. 1) using the PKR as our central
transformation. Isolated in 2000 from the essential oil of
Juniperus thurifera, 1a is part of a sesquiterpene family of
continuing interest to our research laboratory. More specifically,
in our previously reported syntheses of related natural species, α-
and β-cedrene (1b and 1c, respectively)8 we have shown that the
intriguing tricyclic core skeleton of such targets can be accessed
expediently using a cobalt-mediated PKR strategy. As part of the
programme of work described herein, we sought to develop a
novel, catalytic, PKR, which would result in the construction of
the core carbon skeleton of 1a using sub-stoichiometric quantities
of cobalt metal.
1
olefin ratios being determined by H NMR spectroscopy (see
Section 4), based on that described in our previous work8). With
this initial and encouraging result in hand, the temperature of the
reaction was lowered to -78°C in an attempt to improve the
selectivity. This delivered a more appreciable 4:1 ratio of Z:E
isomers, again in a very high yield. With this notable increase in
selectivity, the reaction temperature was further reduced and,
more specifically, with the mixture cooled to -196°C and allowed
to warm slowly to room temperature. Despite the reaction solvent
being completely frozen at the initial reaction temperature, with
the reaction perceived to be occurring during the slow melting
process, a very good selectivity of 7.2:1 Z:E was achieved, in
near quantitative yield. Accordingly, it was envisaged that
cooling to -196°C and warming slowly to -78°C would boost the
selectivity even further. Using this modified method, further
improvement in the selectivity was achieved. Furthermore, we
Fig. 1. 2-epi-α-Cedren-3-one and related sesquiterpenes.
2. Results and Discussion
Our synthetic sequence began with the preparation of
ketoester
4
(Scheme
1).
Commercially
available
cyclohexanedione monoethylene acetal 2 was transformed to
Scheme 2. Probing the stereoselectivity of the key olefination reaction.

3
Table 1. Optimisation studies for the key catalytic PKR.
were delighted to realise our optimised conditions upon cooling
ACCEPTED MANUSCRIPT
to -196°C and warming to -90°C, with this process delivering a
9.2:1 (Z):(E) alkene product ratio.
With the ethylidene functionality in place and based on
previously published precedent from our laboratories,8a attention
was focused upon the preparation of the central Pauson-Khand
annulation precursor, 7 (Scheme 3). At this stage, compounds 5a
and 5b existed as an inseparable mixture, therefore, both
geometrical isomers were used in combination in the following
synthetic steps, with a view to separating the individual isomers
at a later stage. In this vein, aldehydes 6a/b were prepared via a
two-step reduction/oxidation sequence in an overall yield of
90%. Following this, 6a/b were treated with the Ohira-Bestmann
reagent12 (dimethyl acetyldiazomethylphosphonate) to install the
alkyne moiety, delivering the key PKR precursors 7a/b in an
80% yield.
Entry Co2(CO)8
Conditionsa
Yield
20%b
48%
69%
65%
1
2
3
10 mol%
10 mol%
20 mol%
TMTU, 1 atm. CO, PhH, 80°C, 6 h
Bu3PS, 1 atm. CO, PhH, 80°C, 18 h
CyNH2, PhMe, MWI, 100°C, 10 min
nBuSMe, 1,2-DCE, MWI, 100°C, 10
min
4
5
20 mol%
20 mol%
nBuSMe, PhMe, MWI, 100°C, 10 min
85%
a MWI: microwave irradiation; b Conversion.
result, we further optimised the annulation method by utilising
nBuSMe as an additive (Entries 4 and 5). In toluene, the desired
enone products were delivered in an 85% yield; this protocol
required only 10 minutes under MWI and used 20 mol% of
dicobalt octacarbonyl with no requirement for additional CO gas
(Entry 5). It is important to note that, in line with that described
previously,8 the ratio of stereoisomers generated via the Wittig
olefination reaction corresponds directly to the ratio of
cyclopentenone epimers 8a/b obtained in every PKR described.
In addition to this, from a practical perspective, purification was
now trivial and it was possible to separate cyclopentenones 8a
(arising from the predominant Z-alkene, 7a) and 8b.
Scheme 3. Preparation of enyne 7.
At this stage, with enynes 7a/b in hand, the efficiency of the
Pauson-Khand annulation, for the assembly of the core tricyclic
skeleton, could now be investigated. Initially, sulfide-promoted
conditions were examined for use within this cyclisation process.
In particular, nbutyl methyl sulfide, as first described by Sugihara
and Yamaguchi,13 was used as a promoter within this attempted
annulation (Scheme 4). Pleasingly, the desired cyclopentenone
products 8a/b were delivered in an excellent 83% yield following
heating for 40 minutes.
With the development of
a new microwave-promoted
technique for performing Pauson-Khand reactions with a sub-
stoichiometric quantity of transition metal and no required
external source of CO achieved, attention turned to the
completion of the synthesis of the natural target. To this end, an
efficient and completely facially selective, hydrogenation
reaction was realised using palladium catalysis (Scheme 5). The
resulting cyclopentanone 9 was treated with sodium borohydride,
followed directly with sub-stoichiometric quantities of protic acid
in acetone to furnish 10 in a good 82% overall yield, along with
10% of the diastereomeric alcohol. Following silyl protection,
compound 11 was prepared in an appreciable 79% yield via
treatment with freshly prepared methyllithium in refluxing ether.
With the tertiary alcohol in hand, elimination was carried out,
which provided compounds 12a and 12b in a combined yield of
60%. After partial separation, compound 12b was taken through
a deprotection and oxidation sequence to yield the final desired
natural product in an overall 95% yield in these closing two
steps.
Scheme 4. Construction of the tricyclic core via the Pauson-Khand
reaction.
Of course, the described Pauson-Khand annulation procedure
involved a stoichiometric amount of transition metal. As alluded
to previously, our aim was to establish a robust and efficient
catalytic protocol within which the core tricyclic skeleton of the
natural target could be constructed. Accordingly, a variety of
methods employing sub-stoichiometric quantities of Co2(CO)8
were probed (Table 1). These included the use of
tetramethylthiourea (TMTU),14 employment of tributyl phosphine
sulfide,15 and also the application of microwave technology in the
presence of both amine and sulfide additives. In the case of
TMTU (Entry 1) and Bu3PS (Entry 2), not only did the protocols
demand use of gaseous carbon monoxide, the desired
cyclopentenone products were delivered in poor conversions.
However, upon carrying out the PKR in a sealed vessel under
microwave irradiation, a protocol based on seminal outputs by
Groth et al.,5c we obtained the desired products in 69% yield and
after only 10 minutes reaction time (Entry 3). Based on this
The structure of 2-epi-α-cedren-3-one was confirmed by
comparison to the literature isolation data,7 with matching infra-
red, proton, and carbon NMR spectra being obtained. Further
confirmation was also achieved via high resolution mass
spectrometry. In order to completely authenticate the
stereochemistry of the epimerisable C2 stereocentre, NOE
experiments were employed. Pleasingly, the key NOE interaction
between the C12 methyl group and the C11 methylene bridge was
clearly visible (Fig. 2), thereby corroborating the formation of
exclusively the desired α-methyl epimer.
3. Conclusions
In summary, the first total synthesis of 2-epi-α-cedren-3-one
has been completed in 17 steps. Amongst the salient features of
this preparative approach is a highly efficient, low temperature,

4
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 5. Towards the final natural target, 2-epi-α-cedrene-3-one, 1a.
Z-selective olefination protocol, which ultimately established the
desired relative stereochemistry of the final natural target. In
addition to this, the intriguing tricyclic core of this product was
constructed in one step, from a relatively simple monocyclic
precursor, utilising a cobalt-catalysed Pauson-Khand annulation
process. Moreover, the optimum cyclisation protocol utilised 20
mol% of Co2(CO)8 (which also acted as the CO source), and
delivered the desired tricyclic structure in just 10 minutes under
microwave irradiation. The cyclopentenone so obtained was
further elaborated to 2-epi-α-cedren-3-one, thus, delivering the
first total synthesis of this natural target molecule.
Purifications were carried out according to standard laboratory
methods, as detailed below.16
Dry tetrahydrofuran (THF) and diethyl ether (Et2O) were
obtained by refluxing commercial solvents over sodium wire,
with sodium benzophenone ketyl as an indicator, and then
distilled under a nitrogen atmosphere. Dry dichloromethane
(DCM) was obtained by refluxing over calcium hydride and then
distilled under a nitrogen atmosphere. Petrol refers to the fraction
of b.p. 30-40°C and was distilled prior to use. 1,2-DCE, MeOH,
and cyclohexylamine were distilled from CaH2 immediately prior
to use. Acetone was dried by refluxing over flame-dried
potassium carbonate and then distilled prior to use.
n
Triethylamine, thionyl chloride, and BuSMe were all distilled
n
prior to use. BuLi, obtained as a solution in hexanes, was
standardised using salicyldehyde phenylhydrazone.17 EtPh3PBr
was dried at 50°C under high vacuum for 2 d prior to use.
Molecular sieves were powdered and activated by heating in an
oven (120°C) before use. NMO.H2O was dried at 100°C under
vacuum for 3 h before use.
Fig. 2. Confirmation of the stereochemistry of 1a.
4.3. Intermediates
Compound 3 was prepared as delineated in our previous
syntheses of α- and β-cedrene.8
4. Experimental
4.1. General
Methyl 2-(1,4-dioxaspiro[4,5]decan-8-on-6-yl)-2-
methylpropanoate (4)8
Chromatographic separations were performed either on
Prolabo silica gel (230-400 mesh) or on prepacked Bond Elute®
silica columns. Thin layer chromatography was carried out using
Merck silica plates coated with fluorescent indicator F254 and
analysed using a Mineralight UVGL-25 lamp, or developed using
To a stirring solution of 1,4-dioxaspiro[4,5]dec-6-en-8-one 3
(4.77 g, 31 mmol) in DCM (200 mL, bench grade) was added 1-
methoxy-1-[(trimethylsilyl)oxy]-2-methylpropene18 (5.67 g, 32.5
mmol) and ytterbium(III) triflate trihydrate (1.92 g, 3.1 mmol).
After stirring for 18 h at room temperature, the reaction mixture
was filtered through a pad of silica (eluent: diethyl ether) and the
solvent was removed in vacuo. The residue was dissolved in
diethyl ether (120 mL) and oxalic acid (2%, 120 mL) was added.
Following vigorous stirring for 24 h, the organics were separated,
washed with water (100 mL), dried over sodium sulfate, filtered,
and the solvent removed in vacuo. The residue was purified
directly via column chromatography (eluent: 30% diethyl
ether/petrol) to yield the desired compound 4 (5.96 g, 75%) as a
colourless oil, which solidified on standing; melting point: 60-
62°C; IR (liq. film): 3343, 2974, 1728, 1690 cm-1; 1H NMR
(CDCl3): δ 4.05-3.92 (m, 4H, OCH2CH2O), 3.65 (s, 3H, OCH3),
2.71-2.53 (m, 4H, ring), 2.52-2.47 (m, 1H, ring), 2.04-1.98 (m,
1H, ring), 1.79-1.71 (m, 1H, ring) 1.15 (s, 3H, CH3), 1.12 (s, 3H,
CH3).
potassium permanganate or vanillin dips. H and 13C NMR were
1
recorded on a Bruker DMX 400 spectrometer at 400 MHz and
100 MHz, respectively. Chemical shifts are reported in parts per
million (ppm) and are referenced to the appropriate solvent peak.
3
Coupling constants refer to JH-H interactions, unless otherwise
stated, and are reported in Hz. Elemental analysis was obtained
using a Carlo Erba 1106 CHN analyser. Melting points were
obtained on a Büchi 545 using open capillaries and are
uncorrected. High resolution mass spectra were recorded on a
Finnigan MAT 90XLT instrument at the EPSRC Mass
Spectrometry facility at Swansea University, Wales. Reactions
performed in the microwave were performed using a CEM
Discovery apparatus.
4.2. Reagents
All reagents were obtained from commercial suppliers and
were used without additional purification unless otherwise stated.

5
Methyl (E)/(Z)-2-(8-ethylidene-1,4-dioxaspiro[4.5]decan-6-yl)-2-
purified via column chromatography (eluent: 10% diethyl
ACCEPTED MANUSCRIPT
methylpropanoate (5a/b)8
ether/petrol) to yield 7a/b as a colourless liquid (1.86 g, 80%),
and starting aldehydes 6a/b (0.28 g, 12%); IR (liq. film): 2972,
2305, 1440 cm-1; 1H NMR (CDCl3): δ 5.30-5.20 (m, 1H,
C=CHCH3), 4.05-3.95 (m, 4H, OCH2CH2O), 2.95-2.90 (m, 1H),
2.50-2.39 (m, 1H), 2.20-2.04 (m, 3H), 1.87-1.84 (m, 1H), 1.77-
1.70 (m, 1H), 1.63-1.56 (m, 3H), 1.41-1.33 (m, 7H).
Scheme 2, reaction e:
To a flame dried flask, under a nitrogen atmosphere, was added
ethyl triphenylphosphonium bromide (0.297 g, 0.80 mmol) and
THF (15 mL). To the resulting slurry was added freshly
n
standardised BuLi (0.36 mL, 2.25 M in hexanes, 0.80 mmol)
Cyclopentenones (8a/b)8
dropwise. The resulting orange solution was then stirred for a
further 1 h before cooling to -196°C in a liquid N2 bath
(completely immersed). Once the solution had completely frozen,
To a stirring solution of (E)/(Z)-8-ethylidene-6-[3-methylbut-
1-yn-3-yl]-1,4-dioxaspiro[4.5]decane 7a/b (1.05 g, 4.47 mmol) in
petrol (90 mL) was added octacarbonyldicobalt (1.61 g, 4.69
mmol) in one portion. After stirring for 2 h, the solvent was
removed in vacuo and the brown residue was filtered through a
short pad of silica gel. The intermediate cobalt complex was then
dissolved in 1,2-DCE (60 mL) and nBuSMe (2.25 mL, 18.5
mmol) was added. The resulting solution was heated to reflux
(83°C) for 40 minutes before cooling to room temperature and
removing the solvent in vacuo. The residue was purified via
column chromatography (eluent: 20% diethyl ether/petrol) to
yield the desired cyclopentenone epimer 8a (0.85 g) and the
undesired cyclopentenone epimer 8b (0.12 g) in a combined 83%
yield.
methyl
2-(1,4-dioxaspiro[4,5]decan-8-on-6-yl)-2-
methylpropanoate, 4 (0.128 g, 0.50 mmol) was carefully added as
a solution in THF (3 mL) down the wall of the flask to freeze the
solution. The reaction was then warmed slowly to -90°C and left
for 18 h before the solvent was removed in vacuo. NOTE: as the
mixture began to melt, the liquid N2 bath was replaced with a
liquid N2/pentane bath. The crude residue was purified via
column chromatography (eluent: 20% diethyl ether/petrol) to
yield the desired compounds 5a/b (0.127 g, 95%) as a clear
liquid. The Z/E ratio was determined to be 9.2:1 by the
1
integration of the H NMR signals at δ 2.70-2.65 and δ 2.60-
2.55.8
(E)/(Z)-2-(8-Ethylidene-1,4-dioxaspiro[4.5]decan-6-yl)-2-
Data for epimer 8a: melting point: 90-92°C; lit. value:8 90-91°C;
1
methylpropanal, (6a/b)8
IR (liq. film): 3042, 2978, 1702, 1625 cm-1; H NMR (CDCl3):
δ 5.71 (s, 1H, C=CH), 4.01-3.80 (m, 4H, OCH2CH2O), 2.19 (q, J
= 7.5 Hz, 1H, OCCHCH3), 2.04-1.87 (m, 4H), 1.82-1.71 (m, 2H),
1.48 (s, 3H, CH3), 1.33-1.27 (m, 1H), 1.20 (s, 3H, CH3), 1.00 (d,
J = 7.5 Hz, 3H, CHCH3).
To a stirred solution of methyl (E)/(Z)-2-(8-ethylidene-1,4-
dioxaspiro[4.5]decan-6-yl)-2-methylpropanoate 5a/b (2.66 g,
9.88 mmol) in diethyl ether (100 mL) was added lithium
aluminium hydride (0.41 g, 10.9 mmol) portionwise. After
stirring for 1 h, water (0.4 mL) was added, followed by 15%
NaOH (0.4 mL), followed by water (1.2 mL). After stirring for a
further 30 minutes the granular precipitate was removed by
filtration through a pad of celite (eluent: diethyl ether). The
filtrate was evaporated in vacuo, delivering the intermediate
alcohol. The product was immediately dissolved in DCM (120
mL) and pyridinium chlorochromate (6.37 g, 29.6 mmol) added.
After stirring for 18 h, the solid chromium residues were
removed by filtration through celite and washed thoroughly with
DCM. The crude products were then adsorbed onto silica and
purified via column chromatography (eluent: 30% diethyl
ether/petrol) to yield the desired compounds 6a/b (2.11 g, 90%);
Data for epimer 8b: melting point: 87-89°C; lit. value:8 87-88°C;
1
IR (liq. film): 3035, 2979, 1702, 1625 cm-1; H NMR (CDCl3):
δ 5.81 (s, 1H, C=CH), 4.02-3.82 (m, 4H, OCH2CH2O), 2.27 (q, J
= 7.2 Hz, 1H, OCCHCH3), 1.97 (d, J = 5.0 Hz, 1H, CH), 1.86-
1.71 (m, 4H), 1.48 (s, 3H, CH3), 1.32-1.28 (m, 1H), 1.20 (s, 3H,
CH3), 1.18-1.15 (m, 1H), 1.07 (d, J = 7.2 Hz, 3H, CHCH3).
Table 1, entry 1:
To a stirring solution of (E)/(Z)-8-ethylidene-6-[3-methylbut-
1-yn-3-yl]-1,4-dioxaspiro[4.5]decane 7a/b (0.060 g, 0.256 mmol)
and tetramethylthiourea (0.020 g, 0.154 mmol) in benzene (7.5
mL) was added octacarbonyldicobalt (0.009 g, 0.026 mmol) in
one portion. The reaction was then purged with CO (balloon) and
heated to reflux (80°C) for 6 h. After cooling to room
temperature, the solvent was removed in vacuo and purification
of the residue was attempted via column chromatography (eluent:
20% diethyl ether/petrol). The product was found to be
1
IR (liq. film): 2819, 2710, 1725 cm-1; H NMR (CDCl3): δ 9.34
(s, 1H, CHO), 5.27-5.22 (m, 1H, C=CHCH3), 3.95-3.81 (m, 3H,
OCH2CH2O), 3.62 (m, 1H, OCH2), 2.71-2.52 (m, 1H, ring), 2.30-
2.22 (m, 2H, ring), 2.11-2.07 (m, 1H, ring), 2.03-1.91 (m, 1H,
ring), 1.85-1.80 (m, 1H, ring), 1.63-1.59 (m, 3H, CH3), 1.35-1.25
(m, 1H, ring), 1.02-0.98 (s, 6H, 2xCH3).
1
contaminated with TMTU by H NMR; the conversion of the
desired cyclopentenones 8a/b was calculated to be 20%.
(E)/(Z)-8-Ethylidene-6-[3-methylbut-1-yn-3-yl]-1,4-
dioxaspiro[4.5]decane, (7a/b)8
Table 1, entry 2:
To
a
stirring solution of (E)/(Z)-2-(8-ethylidene-1,4-
To a stirring solution of (E)/(Z)-8-ethylidene-6-[3-methylbut-
1-yn-3-yl]-1,4-dioxaspiro[4.5]decane 7a/b (0.060 g, 0.256 mmol)
and tributylphosphine sulfide (0.036 g, 0.154 mmol) in benzene
(3.6 mL) was added octacarbonyldicobalt (0.009 g, 0.026 mmol)
in one portion. The reaction was then purged with CO (balloon)
and heated to reflux (80°C) for 18 h. After cooling to room
temperature, the solvent was removed in vacuo and the residue
purified via column chromatography (eluent: 50% diethyl
ether/petrol) to yield the desired products 8a/b (0.032 g, 48%).
dioxaspiro[4.5]decan-6-yl)-2-methylpropanal, 6a/b (2.35 g, 9.93
mmol) in anhydrous methanol (60 mL) was added dimethyl 1-
diazo-2-oxypropylphosphonate (2.92 g, 14.9 mmol) and
potassium carbonate (2.09 g, 14.9 mmol). The reaction mixture
was stirred for 24 h before the addition of more dimethyl 1-
diazo-2-oxypropylphosphonate (0.70 g, 4.21 mmol) and
potassium carbonate (0.59 g, 4.21 mmol). The reaction was
stirred for a further 4 d with further dimethyl 1-diazo-2-
oxypropylphosphonate (0.70 g, 4.21 mmol) and potassium
carbonate (0.59 g, 4.21 mmol) being added every 24 h. The
solvent was then removed in vacuo and the residue taken up in
diethyl ether (100 mL) and washed with water (100 mL). The
organics were then dried over sodium sulfate, filtered, and the
solvent removed in vacuo to yield a gummy residue, which was
General Procedure for Microwave-assisted PKRs
To a 10 mL CEM microwave vessel, equipped with a stirrer
bar, was added (E)/(Z)-8-ethylidene-6-[3-methylbut-1-yn-3-yl]-
1,4-dioxaspiro[4.5]decane 7a/b, solvent, additive, and

6
Tetrahedron
ACCEPTED MANUSCRIPT
octacarbonyldicobalt. The tube was sealed immediately and was
1.68 (m, 1H), 1.57-1.51 (m, 1H), 1.38-1.33 (m, 2H), 1.12 (s, 3H,
placed in the microwave. The reaction was then carried out at the
allotted temperature for the specified time. Following this, the
crude mixture was purified directly via column chromatography
(eluent: 50% diethyl ether/petrol) to yield cyclopentenones 8a/b.
CH3), 1.02 (s, 3H, CH3), 1.01 (d, J = 7.2 Hz, 3H, CHCH3); 13C
NMR (CDCl3): δ 214.3, 79.0, 66.4, 56.3, 46.5, 43.9, 37.4, 36.9,
36.2, 34.2, 27.5, 27.1, 9.8; HRMS m/z (ES): C14H26NO2
(M++NH4) requires 240.1958, found: 240.1959; elemental
analysis: C14H22O2 requires C, 75.63%; H, 9.97%, found: C,
75.72%; H, 10.13%.
The following experiments were carried out according to the
above General Procedure. The data are presented as follows: (a)
quantity of 7a/b, (b) volume of solvent, (c) quantity of additive,
(d) quantity of Co2(CO)8, (e) temperature, (f) time, and (g)
reaction yield.
Data for the diastereomeric alcohol; appearance: white solid;
melting point: 174-176°C; IR (CH2Cl2): 3605, 1690 cm-1; 1H
NMR (CDCl3): δ 4.26-4.23 (m, 1H, CHOH), 3.80-3.74 (m, 1H),
2.52-2.46 (m, 1H), 2.36 (q, J = 10.0 Hz, 1H, CHCH3), 2.25 (d, J
= 4.2 Hz, 1H), 2.10-2.00 (m, 2H), 1.96-1.88 (m, 1H), 1.85-1.80
(m, 1H), 1.72 (br s, 1H), 1.63-1.57 (m, 1H), 1.40 (d, J = 12.5 Hz,
Table 1, entry 3:
(a) 0.060 g, 0.256 mmol, (b) toluene, 3 mL, (c) CyNH2, 0.035
mL, 0.307 mmol, (d) 0.018 g, 0.0512 mmol, (e) 100°C, (f) 10
minutes, and (g) 0.046 g, 69%.
1H), 1.12 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.02-0.99 (m, 3H); 13
C
NMR (CDCl3): δ 213.5, 79.0, 66.7, 53.6, 52.1, 48.7, 44.0, 36.9,
35.7, 34.0, 26.4, 25.1, 11.8; HRMS m/z (ES): C14H23O2 (M++H)
requires 223.1689, found: 223.1689; elemental analysis:
C14H22O2 requires C, 75.63%; H, 9.97%, found: C, 75.58%; H,
9.78%.
Table 1, entry 4:
n
(a) 0.060 g, 0.256 mmol, (b) 1,2-DCE, 3 mL, (c) BuSMe, 0.038
mL, 0.307 mmol, (d) 0.018 g, 0.0512 mmol, (e) 100°C, (f) 10
minutes, and (g) 0.043 g, 65%.
2-((tert-Butyldimethylsilyl)oxy)-3,8,8-trimethylhexahydro-1H-
3a,7-methanoazulen-6(7H)-one.
Table 1, entry 5:
n
To a stirring solution of alcohol 10 (0.044 g, 0.196 mmol),
DMAP (2 crystals), and triethylamine (0.055 mL, 0.392 mmol) in
DCM (10 mL) was added tert-butyldimethlsilyl triflate (0.09 mL,
0.392 mmol). After stirring at room temperature for 18 h, 2 N
HCl (10 mL) was added and the organics separated, washed with
2 N NaOH (10 mL), dried over sodium sulfate, and the solvent
removed in vacuo. The crude residue was then purified via
column chromatography (eluent: 0-10% diethyl ether in petrol) to
yield the title compound (0.066 g, 100%); melting point: 70-
72°C; IR (CH2Cl2): 2958, 1693 cm-1; 1H NMR (CDCl3): δ 4.11 (t,
J = 4.8 Hz, 1H, H), 2.51 (dt, 2J = 12.3 Hz, J = 3.8 Hz, 1H), 2.46-
(a) 0.060 g, 0.256 mmol, (b) toluene, 3 mL, (c) BuSMe, 0.038
mL, 0.307 mmol, (d) 0.018 g, 0.0512 mmol, (e) 100°C, (f) 10
minutes, and (g) 0.057 g, 85%.
Cyclopentanone (9)
To a stirred solution of cyclopentenone 8a (0.75 g, 2.86
mmol) in toluene (50 mL) was added 10% palladium on charcoal
(0.03 g) and the reaction purged twice with hydrogen and then
placed under an atmosphere of hydrogen (balloon). The reaction
was then stirred at room temperature for 1 h, before filtration
through a pad of silica (eluent: diethyl ether). The volatiles were
then removed in vacuo to yield the desired ketone 9 (0.75 g,
99%) as a white solid; Melting point: 95-96°C; IR (CH2Cl2):
2966, 1740 cm-1; 1H NMR (CDCl3): δ 3.99-3.79 (m, 4H,
2
2.22 (m, 3H), 2.02 (dd, J = 11.0 Hz, J = 3.7 Hz, 1H), 1.89-1.69
(m, 3H), 1.60-1.56 (m, 1H), 1.47-1.44 (m, 1H), 1.24 (d, J = 12.3
Hz, 1H), 1.04 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.88 (d, J = 7.0
Hz, 3H, CHCH3), 0.84 (s, 9H, SitBu), 0.00 (s, 6H, SiCH3); 13C
NMR (CDCl3): δ 214.5, 79.4, 66.5, 56.6, 56.4, 47.1, 44.0, 37.5,
36.8, 35.9, 34.8, 27.9, 27.1, 26.4, 18.7, 10.5, -4.7; HRMS m/z
(ES): C20H40NO2Si (M++NH4) requires 354.2823, found:
354.2819; elemental analysis: C20H36O2Si requires C, 71.37%; H,
10.78%, found: C, 71.52%; H, 10.72%.
2
4
OCH2CH2O), 2.43 (ddd, J = 19.1 Hz, J = 11.9 Hz, J = 1.8 Hz,
1H), 2.25-2.14 (m, 2H), 2.11-1.91 (m, 3H), 1.77 (dd, J = 13.7
2
Hz, J = 6.0 Hz, 1H), 1.63-1.60 (m, 2H), 1.55-1.40 (m, 2H), 1.26
(s, 3H, CH3), 0.96 (d, J = 7.1 Hz, 3H, CHCH3), 0.92 (s, 3H,
CH3); 13C NMR (CDCl3): δ 219.8, 110.9, 64.9, 63.5, 55.3, 52.6,
52.1, 48.5, 42.3, 38.0, 35.8, 35.0, 31.1, 29.4, 27.0, 9.0; HRMS
m/z (EI): C16H24O3 (M+) requires 264.1725, found: 264.1737.
Tertiary alcohol, (11)
Alcohol (10)
To a flame dried flask, under an atmosphere of nitrogen, was
charged diethyl ether (5 mL) and freshly prepared19 MeLi (2.1
mL, 1.0 M in diethyl ether, 2.1 mmol). To this solution was
To a stirring solution of cyclopentanone 9 (0.74 g 2.79 mmol)
in methanol (35 mL) was added sodium borohydride (0.127 g,
3.34 mmol) in one portion. After stirring for 2 h, a saturated
aqueous solution of ammonium chloride (35 mL) was added and
the product was extracted with diethyl ether (2 x 50 mL), dried
over sodium sulfate, filtered, and the solvent removed in vacuo.
The crude residue was then dissolved in acetone (30 mL) and
para-toluenesulfonic acid (0.048 g, 0.279 mmol) was added. The
reaction was then stirred for 4 h at room temperature, before the
addition of a saturated, aqueous solution of sodium bicarbonate
(30 mL), and extraction with diethyl ether. The organics were
then dried over sodium sulfate and the solvent removed in vacuo.
The crude residue was then purified by column chromatography
(eluent: 25% diethyl ether/petrol) to yield the desired compound
10 (0.508 g, 82%), along with the diastereomeric alcohol (0.063
g, 10%); appearance: white solid; melting point: 174-176°C; IR
added
a
solution of 2-((tert-butyldimethylsilyl)oxy)-3,8,8-
trimethylhexahydro-1H-3a,7-methanoazulen-6(7H)-one (0.10 g,
0.30 mmol) in diethyl ether (5 mL) via syringe pump over 3 h.
After stirring at reflux for a further 15 h, TLC analysis indicated
that starting material remained, and, thus, a further quantity of
MeLi (2.1 mL, 1.0 M in diethyl ether, 2.1 mmol) was added.
After stirring for a further 30 h, a saturated, aqueous solution of
ammonium chloride (5 mL) was added and the organics were
extracted with diethyl ether (20 mL), dried over sodium sulfate,
and the solvent removed in vacuo. The crude residue was then
purified via column chromatography (eluent: 1:9 diethyl
ether/petrol) to yield the desired product (0.083 g, 79%) as a
white solid, along with returned starting material (0.017 g, 17%);
melting point: 115-117°C; IR (CH2Cl2): 3637, 2929, 1463 cm-1;
1H NMR (CDCl3): δ 4.16-4.12 (m, 1H, SiOCH), 2.31-2.26 (m,
1H), 1.96-1.90 (m, 2H), 1.82-1.72 (m, 5H), 1.65-1.60 (m, 3H),
1.30 (s, 3H, CH3), 1.22 (s, 3H, CH3), 1.03 (s, 3H, CH3), 0.87
(overlapping s & d, 12H, SitBu and CHCH3), 0.00 (s, 6H,
(CH2Cl2): 3609, 1694 cm-1; H NMR (CDCl3): δ 4.25-4.23 (m,
1H, CHOH), 2.57-2.52 (m, 1H), 2.47 (d, J = 8.1 Hz, 1H), 2.39 (q,
J = 9.8 Hz, 1H, CHCH3), 2.33-2.31 (m, 1H), 2.10 (dd, J = 10.9
Hz, J = 4.3 Hz, 1H), 1.95-1.87 (m, 2H), 1.85-1.80 (m, 1H), 1.75-
1
2

7
SiCH3); 13C NMR (CDCl3): δ 79.3, 75.3, 60.5, 56.5, 55.3, 47.3,
44.5, 37.0, 36.4, 36.2, 34.7, 30.7, 30.5, 28.4, 26.4, 18.7, 10.6, -
4.2; HRMS m/z (ES): C21H40O2Si (M+) requires 352.2790, found:
352.2792; elemental analysis: C21H40O2Si requires C, 71.53%; H,
11.43%, found: C, 71.62%; H, 11.66%.
(d, J = 7.0 Hz, 3H, CHCH3), 0.91 (s, 3H, CH3); 13C (60 MHz,
ACCEPTED MANUSCRIPT
CDCl3), δ 219.7, 140.4, 118.8, 52.5, 52.4, 51.7, 51.4, 48.7, 41.7,
38.0, 34.4, 27.8, 27.1, 24.7, 8.3; HRMS m/z (EI): C15H22O (M+)
requires 218.1665, found: 218.1665.
Acknowledgments
Alkenes (12a/b)
We are grateful to the Carnegie Trust for the Universities of
Scotland (M.M.) and the C. K. Marr Trust (C.M.P.) for
postgraduate scholarships. We are also thankful to the EPSRC
Mass Spectrometry Service, Swansea University, Wales, for
analyses.
To a stirring solution of tertiary alcohol 11 (0.075 g, 0.212
mmol) in pyridine (5 mL) was added thionyl chloride (0.308 mL,
98%, 4.25 mmol) dropwise. After 1 h, diethyl ether (25 mL) and
2 N HCl (25 mL) were added, and the organics extracted with
diethyl ether (50 mL). The organics were then washed with a
further volume of 2 N HCl (2 x 25 mL) and the aqueous layers
back-extracted with fresh diethyl ether (25 mL). The combined
organics were dried over sodium sulfate and the solvent removed
in vacuo. The resulting residue was purified via column
chromatography (eluent: petrol) to yield the desired product as a
mixture with the β-isomer (12a) of the double bond (0.041 g,
60%). The ratio of 12a:12b was 20:80. Repurification of the
mixture by column chromatography (eluent: petrol) allowed
partial separation of 12a and 12b.
References and notes
1. For selected reviews, see: (a) The Pauson-Khand Reaction, Scope,
Variations and Applications; Torres, R. R., Ed.; John Wiley &
Sons, Ltd.: Chichester, 2012;
(b) Lee H-W, Kwong F-Y. Eur J Org Chem. 2010:789-811;
(c) Shibata T. Adv Synth Catal. 2006;348:2328-2336;
(d) Laschat S, Becheanu A, Bell T, Baro A. Synlett 2005:2547-
2570.
2. Rodriguez RA, Barrios Steed D, Kawamata Y, Su S, Smith PA,
Steed TC, Romesberg FE, Baran PS. J. Am. Chem. Soc.
2014;136:15403-15413.
3. Reddy Kandimalla S, Sabitha G. Adv. Synth. Catal.
2017;359:3444-3453.
4. Zhao N, Yin S, Xie S, Yan H, Ren P, Chen G, Chen F, Xu, J.
Angew. Chem. Int. Ed. 2018;57:3386-3390.
5. For selected milder examples, see: (a) Wang Y, Xu L, Yu R, Chen
J, Yang Z. Chem. Commun. 2012;48:8183-8185;
(b) Blanco-Urgoiti J, Abdi D, Domínguez G, Pérez-Castells J.
Tetrahedron 2008;64:67-74;
(c) Fischer S, Groth U, Jung M, Schneider A. Synlett 2002:2023-
2026;
(d) Krafft ME, Boñaga LVR. Synlett 2000:959-962.
6. (a) Kerr WJ, Morrison AJ, Paterson LC. Tetrahedron 2015;71:
5356-5361;
Data for 12b: appearance: colourless oil; IR (liq. film): 2957,
1471 cm-1; 1H NMR (CDCl3): δ 5.16 (br s, 1H, C=CH), 4.09-4.07
2
(m, 1H, SiOCH), 2.31-2.25 (m, 1H), 2.17 (dd, J = 10.7 Hz, J =
3.6 Hz, 1H), 1.73-1.69 (m, 3H), 1.63-1.61 (m, 3H, C=CCH3),
1.59-1.52 (m, 2H), 1.46-1.43 (m, 1H), 1.08 (d, 2J = 10.8 Hz, 1H),
0.99-0.98 (2 overlapping singlets, 6H, CH3), 0.87-0.84
(overlapping s & d, 12H, SitBu and CHCH3), 0.00 (s, 6H,
SiCH3); 13C NMR (CDCl3): δ 141.6, 119.4, 79.4, 59.2, 55.6, 54.8,
48.8, 47.1, 43.2, 35.6, 34.5, 28.5, 27.6, 26.5, 25.2, 18.8, 10.4, -
4.7; HRMS m/z (ES): C21H39OSi (M++H) requires 335.2765,
found: 335.2760.
3,6,8,8-Tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-
methanozulen-2-ol.
(b) Kędzia JL, Kerr WJ, McPherson AR. Synlett 2010:649-653;
(c) Caldwell JJ, Cameron ID, Christie SDR, Hay AM, Johnstone
C, Kerr WJ, Murray A. Synthesis 2005:3293-3296.
(d) Brown JA, Janecki T, Kerr WJ. Synlett 2005:2023-2026;
(e) Brown JA, Irvine S, Kerr WJ, Pearson CM. Org Biomol Chem.
2005;3:2396-2398;
(f) Kerr WJ, McLaughlin M, Pauson PL. Organomet Chem.
2001;630:118-124;
(g) Kerr WJ, McLaughlin M, Pauson PL, Robertson SM. J
Organomet Chem. 2001;630:104-117;
(h) Kennedy AR, Kerr WJ, Lindsay DM, Scott JS, Watson SP. J
Chem Soc, Perkin Trans 1 2000:4366-4372;
(i) Brown DS, Campbell E, Kerr WJ, Lindsay DM, Morrison AJ,
Pike KG, Watson SP. Synlett 2000:1573-1576;
(j) Ford JG, Kerr WJ, Kirk GG, Lindsay DM, Middlemiss D.
Synlett 2000:1415-1418;
(k) Kerr WJ, Lindsay DM, McLaughlin M, Pauson PL. Chem
Commun. 2000:1467-1468;
(l) Carbery DR, Kerr WJ, Lindsay DM, Scott JS, Watson SP.
Tetrahedron Lett. 2000;41:3235-3239;
(m) Kerr WJ, Lindsay DM, Rankin EM, Scott JS, Watson SP.
Tetrahedron Lett. 2000;41:3229-3233;
(n) Kerr WJ, Lindsay DM, Watson SP. Chem Commun.
1999:2551-2552;
(o) Kerr WJ, McLaughlin M, Pauson PL, Robertson SM. Chem
Commun. 1999:2171-2172;
(p) Clements CJ, Dumoulin D, Hamilton DR, Hudecek M, Kerr
WJ, Kiefer M, Moran PH, Pauson PL. J Chem Res. 1998:(S) 636-
637; (M):2658-2677;
(q) Donkervoort JG, Gordon AR, Johnstone C, Kerr WJ, Lange U.
Tetrahedron 1996;52:7391-7420;
(r) Kerr WJ, Kirk GG, Middlemiss D. Synlett 1995:1085-1086;
(s) Gordon AR, Johnstone C, Kerr WJ. Synlett 1995:1083-1084;
(t) Hay AM, Kerr WJ, Kirk GG, Middlemiss D. Organometallics
1995;14:4986-4988;
To a stirring solution of alkene 12b (0.136 g, 0.408 mmol) in
THF (5 mL) was added TBAF (1.22 mL, 1 M in THF, 1.22
mmol) in one portion. After stirring for 3 days at room
temperature, the solvent was removed in vacuo, and the residue
purified directly via column chromatography (eluent: 0-20%
diethyl ether in petrol) to yield the desired compound (0.09 g,
100%) as a colourless oil; IR (CH2Cl2): 3300, 2957, 1471 cm-1;
1H NMR (250 MHz, CDCl3): δ 5.20 (s, 1H, C=CH), 4.21-4.17
(m, 1H, CHOH), 2.17 (dd, J = 10.8 Hz, J = 4.0 Hz, 1H), 1.86-
1.77 (m, 3H), 1.68-1.67 (m, 4H), 1.64-1.55 (m, 3H), 1.19 (d, J =
10.8 Hz, 1H), 1.05 (s, 6H, CH3), 0.97 (d, J = 7.2 Hz, 3H); 13C
NMR: δ 141.5, 119.8, 79.8, 59.2, 55.2, 54.7, 48.6, 47.0, 43.0,
37.6, 34.5, 28.4, 27.5, 25.2, 10.2; HRMS m/z (EI): C15H24O (M+)
requires 220.1822, found: 220.1823.
2-epi-α-Cedren-3-one (1a)7
To a stirred solution of 3,6,8,8-tetramethyl-2,3,4,7,8,8a-
hexahydro-1H-3a,7-methanozulen-2-ol (0.0165 g, 0.074 mmol)
and activated 4Å molecular sieves (~ 0.05 g) in DCM (4 mL) was
added NMO.H2O (0.015 g, 0.112 mmol). After stirring for 30
minutes, TPAP (0.0026 g, 0.007 mmol) was added and the
reaction stirred room temperature for 30 minutes. The reaction
mixture was then filtered through a short pad of silica using
DCM as the eluent to yield the desired compound 1a (0.0155 g,
95%) as a colourless oil; IR (CH2Cl2): 2961, 1737, 1471, 1455
1
cm-1; H NMR (250 MHz, CDCl3): δ 5.30 (s, 1H, C=CH), 2.54-
2.40 (m, 2H), 2.17-2.07 (m, 2H), 1.98 (dd, J = 12.4 Hz, J = 4.0
Hz, 1H), 1.86 (d, J = 17.1 Hz, 1H), 1.77 (d, J = 4.0 Hz, 1H), 1.70
(apparent q, 4J = 1.7 Hz, 3H, C=CCH3), 1.46 (dd, 2J = 11.5 Hz, J
= 3.5 Hz, 1H), 1.32 (d, 2J = 11.2 Hz, 1H), 1.12 (s, 3H, CH3), 0.97
(u) Johnstone C, Kerr WJ, Lange U. J Chem Soc, Chem Commun.
1995:457-458.

8
Tetrahedron
7. Barrero AF, del Moral JQ, Lara A. Tetrahedron 2000;56:3717-
(b) Ohira S. Synth Commun. 1989;19:561-564.
ACCEPTED MANUSCRIPT
3723 and references therein.
13. Sugihara T, Yamada M, Yamaguchi M, Nishizawa M. Synlett
8. (a) Crawford JJ, Kerr WJ, McLaughlin M, Morrison AJ, Pauson
PL, Thurston GJ. Tetrahedron 2006;62:11360-11370;
(b) Kerr WJ, McLaughlin M, Morrison AJ, Pauson PL. Org Lett.
2001;3:2945-2948.
9. Ito Y, Hirao T, Saegusa T. J Org Chem. 1978;43:1011-1013.
10. (a) Minami I, Takahashi K, Shimizu I, Kimura T, Tsuji J.
Tetrahedron 1986;42:2971-2977;
(b) Tsuji J, Minami I, Shimizu I. Tetrahedron Lett. 1983;24:5635-
5638.
11. Kobayashi S, Hachiya I, Takahori T, Araki M, Ishitani H.
Tetrahedron Lett. 1992;33:6815-6818.
1999:771-773.
14. Tang Y, Deng L, Zhang Y, Dong G, Chen J, Yang Z. Org Lett.
2005;7:593-595.
15. Hayashi M, Hashimoto Y, Yamamoto Y, Usuki J, Saigo K. Angew
Chem Int Ed. 2000;39:631-633.
16. Perrin, D. D.; Amarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon Press: Oxford, 3rd Edition, 1988.
17. Love BE, Jones EG. J Org Chem. 1999;64:3755-3756.
18. Revis A, Hilty TK. J Org Chem. 1990;55:2972-2973; this
compound is commercially available from Sigma-Aldrich, CAS:
31469-15-5.
12. (a) Müller S, Liepold B, Roth GJ, Bestmann HJ. Synlett 1996:
521-522;
19. Wakefield B. J. Organolithium Methods; Academic: London,
1988.