Stereocontrol in a one-pot procedure for anionic oxy-Cope rearrangement followed by intramolecular aldol reaction

Article abstract of DOI:10.1039/b010138i

Racemic β-hydroxycyclohexanones with up to three chiral centres have been synthesized in a stereocontrolled way using the novel anionic oxy-Cope (AOC) rearrangement of acyclic enol ethers. The first examples of compounds containing an aldehyde and an enol ether in a 1,5 relationship are reported. Stereocontrol in the cyclisation of these compounds by a 6-(enolendo)-exo-trig intramolecular aldol reaction has been studied: there is high stereoselectivity for an axial hydroxy group in the product β-hydroxycyclohexanones. AM1 calculations show that there is a stabilising electrostatic attraction between the oxygen atom of the axial C-3 hydroxy group and the electron-poor carbon at C-1 in the intermediate oxonium ions. ≥87% of AOC rearrangement occurs via a chair-like transition state giving rise to the 5,6-anti stereochemistry of the β-hydroxycyclohexanones. Trapping the enolate product of AOC rearrangement with oxygen gives fragmentation via a 1,2-dioxetane.

Full text of DOI:10.1039/b010138i

View Article Online / Journal Homepage / Table of Contents for this issue
Stereocontrol in a one-pot procedure for anionic oxy-Cope
rearrangement followed by intramolecular aldol reaction
Alistair P. Rutherford,a Cameron S. Gibb,a Richard C. Hartley*a and Jonathan M. Goodmanb
1
a Department of Chemistry, University of Glasgow, Glasgow, UK G12 8QQ
b Department of Chemistry, Lensfield Road, Cambridge, UK CB2 1EW
Received (in Cambridge, UK) 19th December 2000, Accepted 23rd March 2001
First published as an Advance Article on the web 18th April 2001
Racemic β-hydroxycyclohexanones with up to three chiral centres have been synthesized in a stereocontrolled way
using the novel anionic oxy-Cope (AOC) rearrangement of acyclic enol ethers. The first examples of compounds
containing an aldehyde and an enol ether in a 1,5 relationship are reported. Stereocontrol in the cyclisation of these
compounds by a 6-(enolendo)-exo-trig intramolecular aldol reaction has been studied: there is high stereoselectivity
for an axial hydroxy group in the product β-hydroxycyclohexanones. AM1 calculations show that there is a stabilising
electrostatic attraction between the oxygen atom of the axial C-3 hydroxy group and the electron-poor carbon at C-1
in the intermediate oxonium ions. ≥87% of AOC rearrangement occurs via a chair-like transition state giving rise to
the 5,6-anti stereochemistry of the β-hydroxycyclohexanones. Trapping the enolate product of AOC rearrangement
with oxygen gives fragmentation via a 1,2-dioxetane.
titanium() alkylidenes in a way that tolerates β-hydrogen
atoms. Furthermore, their reagents convert esters into enol
Introduction
We have been developing a general method for the stereo-
ethers with good Z-selectivity. Thus, the alkylidenation step
controlled synthesis of polyfunctionalised ring systems using
may introduce further stereochemical information.
four key reactions: the aldol reaction, Takai alkylidenation, a
The third key step is AOC rearrangement of enol ether 3 to
give enolate 5. This moves the stereochemical information into
positions that are less accessible by ‘direct’ synthesis, and it may
novel anionic oxy-Cope (AOC) rearrangement of acyclic enol
ethers and a new intramolecular aldol reaction (Scheme 1).1
also increase the stereochemical complexity of the system. The
AOC rearrangement of rigid cyclic substrates is well known to
give high levels of stereocontrol and is widely used.9 Our
method employs the rarer AOC rearrangement of acyclic sub-
strates.10 Prior to our work, only five examples of AOC
rearrangement of enol ethers had been reported;11–13 all were
cyclic and only two had our 1,3-relationship between the enol
ether and the oxyanion.12,13 Enolate 5 is quenched with water to
give the novel aldehyde–enol ether 6. Compounds containing
an aldehyde and an enol ether in a 1,5 relationship were
unknown prior to our work.
The fourth key step is acid-induced carbocyclisation14 of
aldehyde 6 to give a β-hydroxycyclohexanone 7 producing up to
two new chiral centres. 6-(enolendo)-exo-trig cyclisation of enol
ethers onto aldehydes is new. However, since our communi-
cation1 similar reactions of enol ethers with ketones have been
reported.15 Similar 6-(enolendo)-exo-trig intramolecular aldol
reactions16 are some of the most important synthetic (e.g. the
Robinson annulation) and biological transformations (e.g.
aromatic ring formation in polyketide synthesis). However,
there had been no systematic study of the stereochemical
aspects of this highly favoured process prior to the work that
we report here. There were reports where the orientation of
the 3-hydroxy group had been determined by face selectivity
on a carbocycle present in the reactant,17 but reported
stereoselectivities in the formation of monocyclic β-hydroxy-
cyclohexanones varied from only axial,15,18,19 to mostly
equatorial.19,20
Scheme 1
The starting α,β-unsaturated aldehyde 1 has one piece of
stereochemical information, the E double bond geometry. The
aldol reaction then introduces up to two chiral centres in a
controlled way. The aldol reaction is chosen as the first step
because it is reliable and has efficient diastereoselective and
enantioselective versions.2
The second key step is the conversion of ester 2 into enol
ether 3 using a titanium() alkylidene reagent 4. Titanium
alkylidene reagents 4 developed by Tebbe3 and by Grubbs4
are limited to methylenation (R4 = H), while those developed
by Petasis5 can only be generated if R4 does not allow
β-elimination (i.e. R4 = H, aryl, SiMe3). However, Takai6,7 and,
more recently, Takeda8 have reported methods of generating
We here give full details of our first studies1 on the route
outlined in Scheme 1. We wished to determine whether acyclic
enol ethers 3 would undergo AOC rearrangement; whether the
acid-induced cyclisation would be selective for an axial or for
an equatorial 3-hydroxy in β-hydroxycyclohexanone 7; whether
there would be good control of the 5,6-relative stereochemistry
DOI: 10.1039/b010138i
J. Chem. Soc., Perkin Trans. 1, 2001, 1051–1061
This journal is © The Royal Society of Chemistry 2001
1051

View Article Online
of cyclohexanones 7, which is set up in the AOC rearrange-
ment; and whether the bifunctional aldehydes 6 could be
isolated. By choosing racemic substrates 3 (R2 = H) that had
only one chiral centre, we avoided the complex issue of the
orientation of the oxyanion during AOC rearrangement.
in the cyclisation step. isopropyl enol ether 12b reacted with
potassium hydride and 18-crown-6 (18-c-6) in DME to give
alkoxide 14 which underwent AOC rearrangement to enolate 15
(Scheme 3). This was quenched with aqueous hydrochloric acid
Results and discussion
We synthesised a range of substrates 12 and 13 for the AOC
rearrangement by the route shown in Scheme 2. Reaction of
Scheme 3
to generate the desired aldehyde 16 which cyclised under these
acid conditions to give a 95 : 5 ratio of 3,5-anti- and 3,5-syn-β-
hydroxycyclohexanones28 17 and 18 (no dehydration). The
crude mixture was not amenable to chromatography so pure
β-hydroxycyclohexanone 17 was obtained in 43% yield by
crystallisation. Dehydration of the crude mixture of products
from rearrangement of alcohol 12b gave 5-phenylcyclohex-2-
enone29 19 in 61% yield.
The above rearrangement–cyclisation and the rearrange-
ments of enol ethers 13 that follow gave crude product mixtures
with 80–100% mass balance after work-up. The 1H NMR
spectra showed that the desired β-hydroxycyclohexanones were
essentially the only products and the characteristic olefinic
signals (δ 5–6 ppm) for the starting 1,5-dienes were absent. In
each case, the ratio of isomers was determined by integration
of the CHOH signal in the H NMR spectrum of the crude
mixture. Structural assignment is described below.
A much longer reaction time was required for the rearrange-
ment of aliphatic alcohol 12c. Acid-induced cyclisation then
gave a 51% isolated yield of a 90 : 10 mixture of 3,5-anti- and
3,5-syn-β-hydroxycyclohexanones 20 and 21 (Scheme 4).
1
Scheme 2 Reagents and conditions: i, TBDMSCl or TESCl, EtNPri2,
DMF; ii, TMSCl, EtNPri2, THF or CH2Cl2; iii, TiCl4, TMEDA, Zn,
CH2Br2, THF; iv, TiCl4, TMEDA, Zn, CH3CHBr2, THF; v, TBAF,
THF.
cinnamaldehyde with the appropriate lithium enolates gave
aldols 8a and 8b in close to quantitative yield. The aliphatic
aldol 8c was made from (E)-hex-2-enal in 89% yield. The
aldols 8d and 8e were made in 82% and 43% yield respectively
by Mukaiyama reaction21 between 1-phenoxy-1-trimethyl-
silyloxyethylene22 and the appropriate aldehyde. The use of
Mukaiyama conditions is necessary as β-lactones are formed
in aldol reactions using phenyl esters.23 Indeed, Schick and
co-workers24 have used related indium-mediated Reformatsky
reaction as a method for the synthesis of β-lactones.
Scheme 4
Alkylidenation of β-hydroxyesters 8 using a modification7,25
of Takai’s procedure6 failed, so the aldols 8 were protected as
silyl ethers 9. Methylenation then gave enol ethers 10, while
ethylenation gave mixtures of Z and E enol ethers 11 with the Z
isomers predominating (81–85% Z). Much higher Z-selectivity
has been observed in the ethylenation of esters having a branch
alpha to the carbonyl group.6,26 It is noteworthy that even
the trimethylsilyl group is stable to Takai alkylidenation. The
trimethylsilyl ethers were carried through all steps with no
purification after work-up.
We concluded from the above cyclisations that there is a
strong preference for the formation of an axial hydroxy group
in the product β-hydroxycyclohexanones. An explanation for
this selectivity is given below.
We next examined control of the 5,6-relative stereochemistry†
of β-hydroxycyclohexanones 7 (R2 = H) by the AOC rearrange-
ment (Scheme 1).
The 5,6-anti-β-hydroxycyclohexanones 22 and 24 were the
major products when Z enol ethers Z-13a and Z-13b were
rearranged and cyclised (Scheme 5, Table 1). We presume that
the 5,6-anti isomers arise from AOC rearrangement via chair-
like conformation 26; if this is so, then 87–89% of the reaction
proceeds via this conformation. Similarly, we believe that
the 5,6-syn-β-hydroxycyclohexanones 23 and 25 arise from
rearrangement via boat-like conformation 27. The orientation
Removal of the silyl protecting groups gave alcohols 12 and
13 in 18–52% overall yield from the corresponding aldols. The
E and Z isomers of enol ethers 13a and 13b were separated
in order to study their rearrangement products. The double
bond geometries were assigned from the chemical shifts of
RC(OR3)᎐CHCH in the 13C NMR spectra as described by
᎐
3
Strobel et al.27 Z-enol ethers have δC = 109.5 and 110.6 ppm
respectively, while δC = 93.7 and 94.8 ppm for E-enol ethers.
Initially, we attempted to rearrange and cyclise alcohols 12b
and 12c so that we could determine the diastereoselectivity
† For ease of comparison with the 3,5-disubstituted cyclohexanones,
the substituents of the trisubstituted cyclohexanones are considered to
be at positions 3, 5 and 6. The latter compounds would be named as
2,3,5-trisubstituted cyclohexanones according to IUPAC nomenclature.
1052
J. Chem. Soc., Perkin Trans. 1, 2001, 1051–1061

View Article Online
Scheme 6
22. This was evident from loss of couplings to CHOH and
CHPh, and a reduction in the size of the signal for the C-4
1
methylene in the H NMR spectrum of the product 22. The
doublet due to the methyl group showed no trace of collapse to
a singlet and the C-2 protons were unaffected. The lack of
deuterium incorporation at C-2 confirms that cyclisation is
faster than protonation of the enol ether, a result that
mirrors kinetic studies of base-catalysed intramolecular aldol
reactions.30
E Enol ethers E-B13a and E-13b gave the 5,6-syn isomer 23
as the major product of rearrangement, presumably as a result
of rearrangement via chair-like conformation 31 (Scheme 5).
However, substantial amounts of 5,6-anti isomer 22 were also
formed, indicating that the boat-like conformation 30 com-
1
petes. The CHOH signal of the all syn isomer 25 in the H
NMR spectrum overlaps sufficiently with that of its C-6 epimer
24 to prevent the ratio of 24 : 25 from being determined accur-
ately. We estimate that the ratio of 24 : 25 is 3 : 5 since the
5,6-anti isomers 22 and 24 should be produced in the same ratio
by rearrangement of either E or Z enol ethers 13.
In all the above cyclisations, there is a strong preference for
the formation of an axial hydroxy group (i.e. 3,5-anti stereo-
chemistry) in the product β-hydroxycyclohexanones. The alde-
hydes 16 and 32 produced by aqueous quench of the AOC
rearrangement of isopropyl enol ethers 12b and 13b might
become protonated to give oxonium ions 33 (Scheme 7), which
Scheme 5 a R = Et, b R = Pri.
Table 1 Products from AOC rearrangement of alcohols 13
Ratio of products (%)b
Reactant
22
23
24
25
28 : 29
a
a
Z-13a
Z-13b
E-13a
E-13b
74
78
24
24
12
11
66
67
13
10
1
1
1
1
9
8
a Not detected and expected to be <1%. b Ratio of products as
determined by 1H NMR spectroscopy of the crude mixture after
work-up.
Scheme 7
would undergo intramolecular aldol reactions to give the
3,5-anti oxonium ions 34, and 3,5-syn oxonium ions 35.
Hydrolysis of 3,5-anti oxonium ions 34 would then give the
favoured β-hydroxycyclohexanones 17, 22 and 23, while
hydrolysis of 3,5-syn oxonium ions 35 would give β-hydroxy-
cyclohexanones 18, 24 and 25. MM2 calculations as imple-
mented in MacroModel version 5.531,32 show that there is a
modest thermodynamic preference for 3,5-anti-β-hydroxy-
cyclohexanones 17, 22 and 23 with an axial hydroxy group over
the corresponding 3,5-syn β-hydroxycyclohexanones 18, 24
and 25 with an equatorial hydroxy group (Table 2, entries 1–3).
The preference is lower than that observed experimentally and
AM1 calculations33 carried out using MOPAC version 734
indicate that the 3,5-syn-β-hydroxycyclohexanones 18, 24 and
25 are lower in energy (Table 2, entries 4–6). However, AM1
of the oxyanion is unknown, but recent evidence suggests that it
is axial.26 The major isomer 22 was isolated by crystallisation in
31% yield from the rearrangement–cyclisation of enol ether
Z-13b. Unfortunately, dehydration of alcohol 22 proceeded
with epimerisation to give an 87 : 13 mixture of cyclohexenones
28 and 29 (Scheme 6). Under the same conditions, the crude
mixture from rearrangement–cyclisation of enol ether Z-13b
gave the same 87 : 13 ratio of cyclohexenones 28 and 29 in 57%
yield (Scheme 6).
We confirmed that the 5,6 stereochemistry reflects whether
the transition state of AOC rearrangement is chair-like or boat-
like and is not the result of epimerisation. When enol ether
Z-13a was rearranged and quenched with 1 M DCl in D2O the
label was incorporated only at C-4 of β-hydroxycyclohexanone
J. Chem. Soc., Perkin Trans. 1, 2001, 1051–1061
1053

View Article Online
Table 2 MM2 and AM1 calculations
3,5-anti (axial OH)
3,5-syn (equatorial OH)
Method of
calculation
Ratio at 0 ЊC
3,5-anti : syn
Compound
kJ molϪ1
Compound
kJ molϪ1
MM2
MM2
MM2
AM1
AM1
AM1
AM1
AM1
AM1
17
21.16
26.35
39.55
18
22.84
28.17
41.19
68 : 32
69 : 31
67 : 33
20 : 80
21 : 79
7 : 93
98 : 2
99 : 1
99 : 1
22
24
23
25
17
Ϫ325.4
18
Ϫ328.6
Ϫ340.6
Ϫ336.0
343.4
331.5
334.5
22
Ϫ337.6
Ϫ330.1
334.2
320.4
324.4
24
23
25
34a
34b
34c
35a
35b
35c
calculations strongly favour oxonium ions 34 with an axial
hydroxy group over the corresponding oxonium ions 35 with an
equatorial hydroxy group. The Mulliken population analysis
suggests that there is a positive charge on C-1 and a partial
negative charge on the oxygen atom of the hydroxy group, so
there should be an electrostatic interaction between these two
centres. When the hydroxy group is equatorial the distance
between C-1 and the oxygen atom of the hydroxy group is
about 3.7 Å, while this distance is only approximately 2.5 Å for
an axial hydroxy group. Thus, the electrostatic interaction in
3,5-anti oxonium ions 34 would be stronger than that in 3,5-syn
oxonium ions 35 and probably accounts for the greater stability
of the 3,5-anti configuration. Stabilisation of the intermediate
3,5-anti oxonium ions 34 could lead to the observed preference
for β-hydroxycyclohexanones 17, 22 and 23. It seems likely that
the rate of hydrolysis of oxonium ions 34 and 35 would be
similar. The calculated thermodynamic preference for 3,5-anti
oxonium ions 34 could, therefore, lead to the observed prefer-
ence for β-hydroxycyclohexanones 17, 22 and 23, provided the
ratio of 34 : 35 is thermodynamically controlled. If, however,
this ratio is kinetically controlled (i.e. ions 34 and 35 do not
equilibrate), it is likely that there will still be a preference for β-
hydroxycyclohexanones 17, 22 and 23, because the interactions
which lead to the thermodynamic preference for the 3,5-anti
stereochemistry should be partially present in the transition
state for its formation; thus, there will be a kinetic preference for
the 3,5-anti oxonium ions 34 and the cyclohexanones 17, 22 and
23 derived from them.
enolate 38 resulting from AOC rearrangement of alcohol
12e with oxygen12,36 would give aldehyde 39, which would
cyclise upon acid quench to give compound 40 (Scheme 9).
Scheme 9
Unfortunately, aldehyde 39 fragments (presumably via 1,2-
dioxetane 41) to give ketone 42, which could be isolated in
71% yield when a neutral quench was used. Autooxidation of
enolisable carbonyl groups in protic solvents is well known,37
but regiocontrol can be problematic and multiple fragmen-
tations can occur. Since our oxygenation–fragmentation occurs
at low temperature (perhaps limiting multiple fragmentation)
and the position of the enolate is determined by the AOC
rearrangement, the reaction could be synthetically useful.
Recently, a similar fragmentation of a peroxide derived from a
potassium enolate has been exploited in gibberellin synthesis.38
The bifunctional intermediates 6 (Scheme 1) are interesting
in that they contain both a nucleophilic enol ether and an
electrophilic aldehyde group. Alkyl enol ethers proved too
nucleophilic to allow the isolation of such intermediates, but
alcohols 12d and 12e underwent AOC rearrangement followed
by alkaline quench to give phenyl enol ethers–aldehydes 36 and
37 that could be isolated (Scheme 8). Recently, the relative rates
Stereochemical assignment
The spectroscopic data for the 3,5-anti-β-hydroxycyclo-
hexanone 17 correspond to that reported by Fleming and
co-workers28 and the 3,5-syn diastereomer 18 was identified in
1
the H NMR spectrum of the crude mixture by comparison
Scheme 8
1
with their data for the 3,5-syn compound 18. The H NMR
of enolate protonation and intramolecular reaction between an
enolate and an aldehyde have been studied.30 Compounds 36
and 37 may prove useful for similar studies of acid-induced
aldol reactions.
Finally, we wished to test whether our method could be used
to make cyclic peroxides that would be potential antibiotics.
The 1,2,4-trioxane component of artemisinin is known to be
responsible for its antimalarial activity, and other cyclic per-
oxides have antifungal activity.35 We hoped that quenching the
signal for CHOH of 3,5-anti-β-hydroxycyclohexanone 20 is a
narrow multiplet of approximately 16 Hz, showing no large
axial–axial couplings.
The 3,5-anti,5,6-anti-β-hydroxycyclohexanone 22 was
isolated and its stereochemistry determined by 1H NMR
spectroscopy (see Fig. 1 and Table 3). The rows in Table 3 show
the unadjusted coupling constants measured from the signal at
the chemical shift shown. The signal for CHOH is a 2.9 Hz
quintet, confirming that it is equatorial and the hydroxy group
1054
J. Chem. Soc., Perkin Trans. 1, 2001, 1051–1061

View Article Online
Table 3 Selected 1H NMR data for cyclohexanone 22
δ
Assignment
H2
H2Ј
H3
H4
H4Ј
H5
H6
Me
2.77
2.62
4.59
2.13–2.19
2.13–2.19
3.13
2.64
0.84
H2
H2Ј
H3
H4
H4Ј
H5
H6
Me
14.1
3.0
—
—
2.9
—
—
—
—
—
—
—
—
—
11.8
—
—
—
—
—
—
6.6
a
14.1
2.9
—
—
—
—
—
2.9
—
—
—
—
2.9
—
a
a
a
a
a
a
—
—
—
9.1
—
—
7.5
—
—
11.9
—
—
6.5
a Coupling constant could not be determined; — indicates no coupling.
Table 4 Selected 1H NMR data for cyclohexanone 43
δ
Assignment
H2
H2Ј
H3
H4
H4Ј
H5
H6
Me
2.74
2.38
4.40
2.29
1.96
3.71
2.70
0.88
H2
H2Ј
H3
H4
H4Ј
H5
H6
Me
14.5
3.7
4.9
—
—
—
—
—
10.9
3.5
—
—
—
—
—
4.3
—
—
—
—
—
14.6
—
—
a
a
a
a
—
—
—
—
—
—
—
—
—
—
2.5
4.5
—
—
—
13.5
13.7
11.0
—
4.3
—
—
—
a
a
—
—
7.2
a Coupling constant could not be determined; — indicates no coupling.
Table 5 Selected 1H NMR data for cyclohexanone 44
δ
Assignment
H2
H2Ј
H3
H4
H4Ј
H5
H6
Me
2.58
2.76
3.95
2.04
2.20
2.38
2.52
0.78
H2
H2Ј
H3
H4
H4Ј
H5
H6
Me
12.2
4.8
12.2
4.9
—
—
10.9
—
—
—
—
—
—
—
—
—
12.3
—
—
—
—
—
13.0
10.9
—
—
—
—
—
2.2
4.8
12.9
—
10.7
12.9
a
a
a
a
—
—
—
—
—
—
12.3
—
—
3.3
—
—
—
a
a
—
6.4
a Coupling constant could not be determined; — indicates no coupling.
Fig. 3
Fig. 1
signal for H-6 was partly obscured and when the methyl group
was irradiated, one line of the doublet was coincident with a
neighbouring signal, so J5,6 is determined from the signal for
H-5. Averaging two or more similar couplings leads to minor
discrepancies in the coupling constants measured from different
signals.
The signal for CHOTBDMS of silyl ether 43 is a narrow
multiplet and J2,3, J2Ј,3, J4,3 and J4Ј,3 are all less than 5 Hz. Thus,
the silyloxy group is axial. J5,6 is 4.3 Hz, allowing us to assign
the 5,6-syn stereochemistry. The signal for CHOTBDMS of
silyl ether 44 shows large axial–axial couplings to H2 and H4,
confirming that the silyloxy group is equatorial. J5,6 is large,
confirming the 5,6-anti stereochemistry.
Unfortunately, treatment of the silyl derivatives with TBAF
generated a mixture of isomers, presumably by a fluoride
induced retro-aldol process. However, the assignment of the
stereochemistry of the silyl ethers allows us to identify the
corresponding alcohols in the crude mixture produced by
rearrangement–cyclisation because the 1H NMR signal
for CHOTBDMS in each silyl derivative was the same shape
Fig. 2
is axial. The signals for H5 and H6 show a large axial–axial
coupling to each other, confirming the 5,6-anti stereochemistry.
Isomers 23 and 24 could not be isolated by chromatography
or crystallisation, but silylation of the product mixture from
rearrangement of Z-enol ether 13 followed by exhaustive chro-
matography gave samples of the silylated derivatives 43 and 44.
1
The stereochemistry of each isomer was assigned using H
NMR spectroscopy (see Fig. 2 and Table 4, Fig. 3 and Table 5).
In each case, the connectivity was established by irradiating
the signals for CHOTBDMS (leading to simplification of the
signals for H2, H2Ј, H4 and H4Ј) and the methyl group (leading
to the signal for H6 collapsing to a doublet). In each case, the
J. Chem. Soc., Perkin Trans. 1, 2001, 1051–1061
1055

View Article Online
and almost the same chemical shift as the CHOH of the
corresponding alcohol.
mmol) and diisopropylamine (9.9 g, 12.8 cm3, 97.9 mmol)],
and (E)-cinnamaldehyde (12.3 cm3, 97.5 mmol) gave aldol 8b
(23.63 g, 103%) as a pale yellow oil, sufficiently pure for the silyl
protection reaction; Rf (alumina, 1 : 1 ether–hexane) 0.21;
νmax(thin film)/cmϪ1 3449 br s (OH), 2981 m, 2935 w, 1726 s
Conclusion
We have synthesised racemic β-hydroxycyclohexanones with up
to three chiral centres in a stereocontrolled way using the novel
AOC rearrangement of acyclic enol ethers. We have isolated the
first examples of compounds containing an aldehyde and an
enol ether in a 1,5 relationship. We have studied stereocontrol in
the novel 6-(enolendo)-exo-trig intramolecular aldol reaction
between enol ethers and aldehydes and shown that the reaction
favours the formation of an axial hydroxy group. We have
shown that the 5,6-relative stereochemistry of β-hydroxycyclo-
hexanones is controlled by the AOC rearrangement and у87%
of AOC rearrangement occurs via a chair-like transition state.
Finally, we have observed an oxidative fragmentation of an
enolate prepared by AOC rearrangement.
(C᎐O), 1495 m, 1374 w, 1107 m, 966 m, 818 m and 751 s; δ (400
MHz, CDCl3) 7.37–7.21 (5H, m, Ph), 6.64 (1H, d, J 16.0,
᎐
H
PhCH᎐), 6.21 (1H, dd, J 16.0 and 6.0, PhCH᎐CH), 5.06 (1H,
᎐
᎐
sep, J 6.4, OCHMe2), 4.74–4.68 (1H, br m, CHOH), 3.26 (1H,
d, J 4.2, OH), 2.63 [1H, dd, J 16.0 and 4.8, CH(OH)CHAHB],
2.58 [1H, dd, J 16.0 and 7.4, CH(OH)CHAHB] and 1.24 (6H, d,
J 6.4, OCHMe2); δC(100 MHz, CDCl3) 171.7 (C), 136.5 (C),
130.6 (CH), 130.1 (CH), 128.6 (CH), 127.8 (CH), 126.5 (CH),
68.9 (CH), 67.9 (CH), 41.9 (CH2) and 21.8 (CH3); m/z (EI)
ϩ
ϩ
ؒ
234.1 (M , 25%), 174.1 (40), 133.1 (100) (Found: M ,
234.1256, C14H18O3 requires M, 234.1256).
Isopropyl (E)-3-hydroxyoct-4-enoate 8c
In the same way, isopropyl acetate (7.2 cm3, 61 mmol), LDA [ex
38.2 cm3 of a 1.6 mol dmϪ3 solution of butyllithium in hexane
and 8.0 cm3, 61.1 mmol of diisopropylamine] and (E)-hexenal
(7.1 cm3, 61 mmol) gave the aldol 8c as a pale yellow oil (12.68 g,
103%) sufficiently pure for the silyl protection reaction. A pure
sample was obtained by column chromatography on silica using
1 : 1 ether–hexane as eluent to give a colourless oil (89%), Rf
(silica, 1 : 1 ether–hexane) 0.42; νmax (thin film) 3448 s br (OH),
Experimental
All reactions were carried out under an atmosphere of nitrogen,
using oven-dried glassware. All solutions were added via syringe
unless otherwise stated. THF, ether and DME were freshly dis-
tilled from sodium–benzophenone. Dichloromethane, hexane
and all amines were distilled from CaH2 prior to use. DMF was
distilled from BaO or from calcium hydride and was stored over
4 Å MS. Petroleum ether refers to the fraction boiling at 40–
60 ЊC. Cinnamaldehyde was distilled. 18-Crown-6 was dried
by azeotrope with toluene. Reagents were obtained from com-
mercial suppliers and used without further purification unless
otherwise stated. Purification by column chromatography was
carried out using Fisher MatrexTM silica gel, mesh size 35–70
µm, Fluka basic alumina Brockmann grade III or Aldrich
neutral alumina Brockmann grade III mesh size ~150 as the
stationary phase. Melting points are uncorrected. IR spectra
were recorded using a Nicolet Impact 410 FTIR spectrometer.
NMR spectra were recorded using Bruker AM-200SY, AM-360
and DPX-400 spectrometers. Chemical shifts are given in
ppm relative to tetramethylsilane using residual CHCl3 as an
internal standard (7.26 ppm). J Values are given in Hz. The
multiplicities of 13C nuclei were determined using the DEPT
pulse sequence. Mass spectra were recorded on a JEOL JMS700
spectrometer. Combustion analysis was carried out using a
Carlo-Erba 1106 elemental analyser.
2961 s, 2932 s, 1732 s (C᎐O), 1468 m, 1108 m and 966 m; δ (400
᎐
H
MHz, CDCl ) 5.68 (1H, dt, J 15.2 and 6.8, CH CH᎐), 5.45 (1H,
᎐
3
2
dd, J 15.2 and 6.8, CH CH᎐CH), 5.02 (1H, sep, J 6.4, CHMe ),
᎐
2
2
4.45 (1H, m, CHOH), 2.51–2.45 [2H, m, CH(OH)CH2], 1.97
(2H, dt, J 7.4 and 6.8, CH CH᎐), 1.36 (2H, sex, J 7.2, CH CH ),
᎐
2
3
2
1.22 (6H, d, J 6.4, CHMe2) and 0.86 (3H, t, J 7.2, CH3CH2);
δC(100 MHz, CDCl3) 172.3 (C), 132.8 (CH), 131.1 (CH), 69.4
(CH), 68.5 (CH), 42.3 (CH2), 34.6 (CH2), 22.6 (CH2), 22.2
(CH3) and 14.0 (CH3); m/z (CI) 218.2 [(M ϩ NH4)ϩ, 45%],
200.0 (ϪH2O, 52), 183.1 (100) [Found (EI): Mϩ, 200.1413.
C11H20O3 requires M, 200.1412].
Phenyl (E)-3-hydroxy-5-phenylpent-4-enoate 8d
BF3ؒOEt2 (11.2 cm3, 0.09 mol) was added to a stirred solution
of (E)-cinnamaldehyde (11.5 cm3, 0.09 mol) in dry CH2Cl2 (200
cm3) over 0.5 h at Ϫ78 ЊC under nitrogen. After stirring for
30 min at Ϫ78 ЊC, 1-phenoxy-1-trimethylsiloxyethylene22 (19 g,
0.09 mol, approx. 70% pure) was added, over 30 min and stir-
ring was continued at Ϫ78 ЊC for 30 min. The temperature was
allowed to rise to Ϫ30 ЊC over 30 min and stirring was con-
tinued for a further 3 h. The mixture was then poured into pH 7
phosphate buffer (200 cm3) and warmed to room temperature.
The organic phase was separated and the aqueous phase was
extracted with CH2Cl2 (2 × 100 cm3), the organic washings were
combined, dried (MgSO4) and concentrated to give ester 8d as
needles (8.25 g, 43%‡). Rf (DCM) 0.13; mp 99–101 ЊC; νmax
Ethyl (E)-3-hydroxy-5-phenylpent-4-enoate 8a39
Ethyl acetate (11.1 cm3, 113.6 mmol) in dry THF (230 cm3) was
added to a stirred solution of LDA [made from butyllithium
(1.0 mol dmϪ3 solution in THF, 113.5 cm3, 113.5 mmol)
and diisopropylamine (14.9 cm3, 113.5 mmol)]. After 40 min
(E)-cinnamaldehyde (14.3 cm3, 113.4 mmol) was added.
Stirring continued for 20 min, then the mixture was poured into
aqueous hydrochloric acid (200 cm3, 1 mol dmϪ3). The layers
were separated and the aqueous phase extracted with ether
(2 × 200 cm3). The combined organic extracts were washed with
aqueous hydrochloric acid (100 cm3) and saturated aqueous
sodium bicarbonate solution (100 cm3). The organic phase was
dried (MgSO4) and the solvent removed under reduced pressure
to give the aldol 8a as a yellow oil (23.43 g, 106.4 mmol, 94%),
sufficiently pure for the silyl protection reaction; δH(200 MHz,
CDCl3) 7.40–7.19 (5H, m, Ph), 6.65 (1H, dd, J 16.0 and 1.2,
(KBr) 3447 (OH), 1737 (C᎐O), 1489 (C᎐C), 1195, 1145, 743 and
᎐
᎐
690 cmϪ1; δH(200 MHz; CDCl3) 7.35–6.99 (10H, m, 2 × Ph),
6.65 (1H, d, J 15.9, ᎐CHPh), 6.23 (1H, dd, J 15.9 and 6.2,
᎐
᎐CHCHOH), 4.77 (1H, m, CHOH), 2.84 (2H, d, J 6.7, CH )
᎐
2
and 2.76 (1H, br s, OH); δC(100 MHz) 170.6 (C), 150.3 (C),
136.2 (C), 131.1 (CH), 129.6 (CH), 129.5 (2 × CH), 128.6
(2 × CH), 127.9 (CH), 126.5 (2 × CH), 126.0 (CH), 121.4
ϩ
ؒ
(2 × CH), 68.9 (CH) and 41.7 (CH2); m/z 268 (5, M ), 175 (49,
ϩ
Mϩ Ϫ PhO ), 157 (16.4, M Ϫ PhO and H2O), 133 (96), 115
(29) and 94 (100, PhOH) (Found: C 75.91, H 5.91%. C17H16O3
requires C 76.12, H 5.97%).
ؒ
ؒ
ؒ
ؒ
PhCH᎐), 6.21 (1H, dd, J 16.0 and 6.0, PhCH᎐CH), 4.89–4.64
᎐
᎐
(1H, br m, CHOH), 4.18 (2H, q, J 6.0, OCH2CH3), 2.62–2.59
[2H, m, CH(OH)CH2] and 1.26 (3H, d, J 6.0, OCH2CH3).
Phenyl 3-hydroxy-4-methyleneoctanoate 8e
Isopropyl (E)-3-hydroxy-5-phenylpent-4-enoate 8b40
Aldol 8e (17.73 g, 82%) was prepared from 2-butylacrolein
In the same way, isopropyl acetate (11.5 cm3, 98.2 mmol), LDA
[ex butyllithium (1.6 mol dmϪ3 solution in THF, 61.2 cm3, 97.9
‡ Based on the aldehyde.
1056
J. Chem. Soc., Perkin Trans. 1, 2001, 1051–1061

View Article Online
(11.5 g, 87 mmol) using the method described for 8d as an oil.
Rf (DCM) 0.10; νmax(thin film) 3458 (OH), 2956, 2931, 1760
254.4 mmol) to give an orange–brown suspension. The mixture
was stirred at 0 ЊC for 20 min, then zinc powder (18.7 g, 286.2
mmol, preactivated by sequential washing with 5% aqueous
hydrochloric acid, water, acetone and ether) mixed with a small
amount of lead() chloride (~20 mg) was added. An exotherm
occurred and the mixture turned a grey–blue colour. The ice
bath was removed and the suspension stirred for 40 min, over
which time a dark green colour developed. The mixture was
then re-cooled in an ice bath and a solution of the ester 9c (9.98
g, 31.8 mmol) and dibromomethane (4.9 cm3, 70.0 mmol) in
THF (5 cm3) was added dropwise. After addition was complete
the ice bath was removed and the reaction mixture stirred for
17 h (the suspension turned dark brown–black after ~20 min at
rt). The reaction mixture was then re-cooled with an ice bath,
and saturated potassium carbonate (40 cm3) solution was added
via syringe. The resulting thick black slurry was stirred for a
further 15 min, then poured into ether (200 cm3). The reaction
vessel was washed repeatedly with ether and the combined
washings were then passed through a short column of basic
alumina to filter off the solid formed during the quench. After
washing the filtrate with additional ether, the combined wash-
ings were dried and concentrated under reduced pressure. The
residue was treated with hexane, and the insoluble white pre-
cipitate formed on concentration was filtered off by passing the
hexane solution through a short column of basic alumina. The
precipitate was washed with additional hexane and the com-
bined washings concentrated under reduced pressure to give a
pale yellow oil (8.46 g, 85%) containing the enol ether 10c and
a small amount of TMEDA. This was used without further
purification in the deprotection reaction. A pure sample was
obtained as a colourless oil by chromatography on basic
alumina using hexane as eluent, Rf (alumina, hexane) 0.63;
νmax(thin film)/cmϪ1 2956 s, 2876 s, 1655 m, 1459 m, 1370 m,
1005 m and 741 m; δH(400 MHz, CDCl3) 5.53 (1H, dt, J 15.2
(C᎐O), 1650 (C᎐C), 1594 (aromatic ring) and 1493 (aromatic
᎐
᎐
ring) cmϪ1; δH(200 MHz; CDCl3) 7.42–7.04 (5H, m, Ph), 5.17
(1H, s, ᎐CHH), 4.96 (1H, s, ᎐CHH), 4.62 (1H, dd, J 7.6 and 5,
᎐
᎐
CHOH), 2.93–2.74 (2H, m, CH2C(O)), 2.30–1.97 (2H, m,
᎐CCH ), 1.93 (1H, d, J 1.6, OH), 1.67–1.15 (4H, m, MeCH -
᎐
2
2
CH2) and 0.93 (3H, t, J 7.0, Me); m/z (CI) 249 (100, M ϩ Hϩ),
231 (45, M ϩ Hϩ Ϫ H2O) and 94 (61, PhOH) [Found:
(M ϩ H)ϩ, 249.1489. C15H21O3 requires M ϩ H, 249.1488].
Isopropyl (E)-3-(tert-butyldimethylsilyloxy)-5-phenylpent-4-
enoate 9b
Ester 8b (8.90 g, 38.0 mmol) was dissolved in dry DMF (80 cm3)
and diisopropylethylamine (20.0 cm3, 114.9 mmol), then
TBDMSCl (11.55 g, 76.6 mmol) were added. After 17 h the
mixture was poured into saturated aqueous sodium bicarbon-
ate solution (100 cm3) and extracted with ether (2 × 100 cm3).
The combined ethereal extracts were washed with aqueous
hydrochloric acid solution (2 × 100 cm3, 1.1 mol dmϪ3) then
brine (100 cm3) and dried over magnesium sulfate. The solvent
was removed under reduced pressure to give, after chromato-
graphy on silica gel using 10 : 1 hexane–ether as eluent, the silyl
ether 9b as a pale yellow oil (12.95 g, 37.2 mmol, 98%); Rf
(alumina, 1 : 1 ether–hexane) 0.76; νmax(thin film)/cmϪ1 2930 s,
2886 s, 1736 s (C᎐O), 1495 m, 1472 m, 1374 m, 1257 w, 965 m,
᎐
840 m, 777 m, 746 m and 693 m; δH(400 MHz, CDCl3) 7.38–
7.24 (5H, m, Ph), 6.58 (1H, d, J 16.0, PhCH᎐), 6.21 (1H, dd,
᎐
J 16.0 and 6.8, PhCH᎐CH), 5.02 (1H, sep, J 6.4, CHMe ), 4.78
᎐
2
(1H, dd, J 12.8 and 6.8, CHOSi), 2.61 [1H, dd, J 14.4 and 7.6,
CH(OSi)CHAHB], 2.50 [1H, dd, J 14.4 and 5.2, CH(OSi)-
CHAHB], 1.26 (3H, d, J 6.4, CHMeAMeB), 1.23 (3H, d, J 6.4,
CHMeAMeB), 0.75 (9H, s, SiCMe3), Ϫ0.08 (3H, s, SiMeAMeB)
and Ϫ0.10 (3H, s, SiMeAMeB); δC(100 MHz, CDCl3) 170.5 (C),
136.6 (C), 131.7 (CH), 129.8 (CH), 128.5 (CH), 127.6 (CH),
126.4 (CH), 70.7 (CH), 67.8 (CH), 44.2 (CH2), 25.8 (CH3),
21.87 (CH3), 21.82 (CH3), 18.1 (C), Ϫ4.2 (CH3) and Ϫ5.0 (CH3);
m/z (CI, NH3) 366 [(M ϩ NH3)ϩ], 234 (100) [Found: (M ϩ
NH3)ϩ 366.2459, C20H36O3Si requires M ϩ NH3 366.2464].
and 6.4, CH CH᎐), 5.40 (1H, ddt, J 15.2, 6.8 and 1.2,
᎐
2
CH CH᎐CH), 4.28 (1H, q, J 6.8, CHOSi), 4.17 (1H, sep, J 6.0,
᎐
2
CHMe ), 3.88 (1H, d, J 1.6, ᎐CHAHB), 3.81 (1H, d, J 1.6,
᎐
2
᎐CHAHB), 2.29 [1H, dd, J 13.6 and 6.8, CH(OSi)CHAHB], 2.12
᎐
[1H, dd, J 13.6 and 6.4, CH(OSi)CHAHB], 2.03–1.89 (2H, m,
CH CH᎐), 1.37 (2H, sex, J 7.2, CH CH ), 1.22 (3H, d, J 6.0,
᎐
2
3
2
CHMeAMeB), 1.19 (3H, d, J 6.0, CHMeAMeB), 0.94 (9H, t,
J 8.0, SiCH2CH3), 0.88 (3H, t, J 7.2, CH3CH2) and 0.58 (6H, q,
J 8.0, SiCH2CH3); δC(100 MHz, CDCl3) 158.5 (C), 133.4 (CH),
130.6 (CH), 83.6 (CH2), 71.8 (CH), 68.5 (CH), 45.7 (CH2), 34.6
(CH2), 22.8 (CH2), 22.2 (CH3), 21.7 (CH3), 14.1 (CH3), 7.2
Isopropyl (E)-3-triethylsilyloxyoct-4-enoate 9c
In the same way, ester 8c (11.0 g, 54.9 mmol), diisopropylethyl-
amine (28.7 cm3, 165.0 mmol) and triethylsilyl chloride (TESCl)
(18.4 cm3, 110.0 mmol) in dry DMF (110 cm3) gave silyl ether
9c as a pale yellow oil (23.27 g) which was used in the Takai
reaction without further purification. A pure sample was
obtained by column chromatography on silica gel using 10 : 1
hexane–ether as eluent to give a colourless oil (88%); νmax(thin
ϩ
ؒ
(CH3) and 5.3 (CH2); m/z (EI) 312.2 (M , 11%), 213 (100)
(Found: Mϩ, 312.2487. C18H39O2Si requires M, 312.2485).
(1E,5Z)-3-(tert-Butyldimethylsilyloxy)-5-isopropoxy-1-phenyl-
hepta-1,5-diene 11b
film)/cmϪ1 2956 s, 2877 s, 1735 s (C᎐O), 1466 w, 1374 m, 968 m
᎐
and 744 m; δH(400 MHz, CDCl3) 5.57 (1H, dt, J 15.3 and 6.8,
In the same way as above for 10c, a solution of the ester 9b
(4.00 g, 11.5 mmol) and 1,1-dibromoethane (2.3 cm3, 25 mmol)
in THF (3 cm3) was added to the suspension formed from
titanium tetrachloride (5.0 cm3, 8.7 mmol), TMEDA (13.9 cm3,
91.8 mmol), activated zinc powder (6.75 g, 103 mmol) and
lead() chloride (~10 mg) in THF (15 cm3). The reaction was
stirred for 4 h, then worked-up as above to give a pale yellow oil
(3.37 g). Chromatography on basic alumina using hexane as
eluent gave a 15 : 85 E–Z mixture of enol ethers 11b as an oil
(2.45 g, 59%). The NMR data given are for the major Z isomer;
Rf (alumina, hexane) 0.71; νmax(thin film)/cmϪ1 2956 m, 2929 m,
2857 m, 1679 w, 1494 m, 1369 m, 1254 m, 1196 m, 1115 m and
838 m; δH(360 MHz, CDCl3) 7.38–7.22 (5H, m, Ph), 6.53 (1H,
CH CH᎐), 5.39 (1H, ddt, J 15.3 ,7.2 and 1.2, CH CH᎐CH),
᎐
᎐
2
2
4.94 (1H, sep, J 6.4, CHMe2), 4.49 (1H, br dt, J 7.2 and 6.4,
CHOSi), 2.46 [1H, dd, J 14.4 and 7.6, CH(OSi)CHAHB], 2.33
[1H, dd, J 14.4 and 6.0, CH(OSi)CHAHB], 1.93 (2H, br q, J 7.2,
CH CH᎐), 1.34 (2H, sex, J 7.2, CH CH ), 1.18 (3H, d, J 6.4,
᎐
2
3
2
CHMeAMeB), 1.17 (3H, d, J 6.4, CHMeAMeB), 0.89 (9H, t,
J 8.0, SiCH2CH3), 0.84 (3H, t, J 7.2, CH3CH2) and 0.54 (6H, q,
J 8.0, SiCH2CH3); δC(100 MHz, CDCl3) 171.0 (C), 132.6 (CH),
131.7 (CH), 71.1 (CH), 67.9 (CH), 44.7 (CH2), 34.5 (CH2), 22.6
(CH2), 22.2 (CH3), 22.1 (CH3), 14.0 (CH3), 7.1 (CH3) and 5.2
(CH2); m/z (CI) 315.3 [(M ϩ H)ϩ, 7%], 285.2 (20), 183.2 (100)
[Found: (M ϩ H)ϩ, 315.2352, C17H34O3Si requires M ϩ H,
315.2355].
d, J 15.9, PhCH᎐), 6.26 (1H, dd, J 15.9 and 5.8, PhCH᎐CH),
᎐
᎐
4.73 (1H, q, J 6.7, ᎐CHMe), 4.42 (1H, br q, J 6.6, CHOSi), 4.10
᎐
(5E)-2-Isopropoxy-4-triethylsilyloxynona-1,5-diene 10c
(1H, sep, J 6.1, CHMe2), 2.36 [1H, br dd, J 14.2 and 6.7,
Titanium tetrachloride (13.9 cm3, 127.2 mmol) was added
slowly to THF (100 cm3) under nitrogen at 0 ЊC. To the result-
ing bright yellow suspension was added TMEDA (38.4 cm3,
CH(OSi)CHAHB], 2.28 [1H, dd, J 14.6 and 6.6, CH(OSi)-
CHAHB], 1.57 (3H, d, J 6.7, ᎐CHMe), 1.21 (3H, d, J 6.1,
᎐
CHMeAMeB), 1.20 (3H, d, J 6.1, CHMeAMeB), 0.92 (9H, s,
J. Chem. Soc., Perkin Trans. 1, 2001, 1051–1061
1057

View Article Online
SiCMe3), 0.08 (3H, s, SiMeAMeB) and 0.07 (3H, s, SiMeAMeB);
δC(90 MHz, CDCl3) 149.3 (C), 137.2 (C), 132.9 (CH), 128.43
(CH), 127.1 (CH), 126.31 (CH), 126.26 (CH), 109.5 (CH), 71.1
(CH), 68.8 (CH), 41.8 (CH2), 25.8 (CH3), 22.5 (CH3), 22.3
(CH3), 18.2 (C), 10.6 (CH3), Ϫ4.6 (CH3) and Ϫ5.0 (CH3); m/z
(CH2), 37.4 (CH2), 22.7 (CH2), 22.0 (CH3), 21.9 (CH3) and 14.1
(CH3); m/z (CI) 199.2 [(M ϩ H)ϩ, 95%], 101.1 (100) [Found
(EI): Mϩ, 198.1617. C12H22O2 requires M, 198.1620].
(1E)-5-Phenoxy-1-phenylhexa-1,5-dien-3-ol 12d
ϩ
ϩ
ؒ
(EIϩ) 360.2 (M , 2%), 247.2 (100) (Found: M , 360.2487.
C22H36O2Si requires M, 360.2485).
Diisopropylethylamine (8.04 cm3, 46 mmol) then chloro-
trimethylsilane (5.84 cm3, 46 mmol) were added to a solution of
ester 8d (8.25 g, 30.7 mmol) in dry CH2Cl2 (150 cm3) with stir-
ring at 0 ЊC under nitrogen. Stirring was continued for 13 h at
room temperature. Hexane was added to the mixture which was
then filtered and concentrated to give the silyl ether 9d. Takai
methylenation followed by deprotection in the same way as
described for enol ether 12a gave alcohol 12d (1.80 g, 25%) as a
pale yellow oil. Rf (DCM) 0.63; νmax(thin film)/cmϪ1 3384 (OH),
(1E)-5-Isopropoxy-1-phenylhexa-1,5-dien-3-ol 12b
In the same way as for 10c, a solution of the ester 9b (13.0 g,
37.3 mmol) and dibromomethane (5.8 cm3, 82.1 mmol) in THF
(5 cm3) was added to the mixture formed from titanium tetra-
chloride (16.4 cm3, 149.2 mmol), TMEDA (45.0 cm3, 298.4
mmol), zinc powder (21.9 g, 335.7 mmol) and lead() chloride
(~20 mg) in THF (150 cm3). Stirring was continued for 17 h,
whereupon the reaction mixture was worked up as described to
give the crude enol ether 10b as a pale yellow oil (9.35 g, 27.0
mmol). Tetrabutylammonium fluoride (67.5 cm3 of a 1.0 mol
dmϪ3 solution in THF) and 4 Å molecular sieves (12.2 g) were
added. After stirring for 2.5 h, the reaction mixture was poured
through filter paper into saturated sodium bicarbonate solution
(50 cm3). The layers were separated and the aqueous phase
extracted with ether (2 × 50 cm3). The combined organic
extracts were dried over magnesium sulfate and the solvent
removed under reduced pressure to give a dark brown oil. The
alcohol 12b was obtained as a pale yellow oil (3.52 g, 41% over
two steps) after column chromatography on alumina, using
1 : 1 ether–hexane as eluent; Rf (alumina, 1 : 1 ether–hexane)
0.46; νmax(thin film)/cmϪ1 3415 br s (OH), 2976 s, 2922 sm,
1640 (C᎐C), 1592 (aromatic ring), 1491 (aromatic ring) and
᎐
1218; δH(200 MHz; CDCl3) 7.43–7.02 (10H, m, 2 × Ph), 6.70
(1H, d, J 15.8, ᎐CHPh), 6.31 (1H, dd, J 15.8 and 6.1,
᎐
᎐CHCHOH), 4.78–4.63 (1H, m, CHOH), 4.25 (1H, d, J 1.8,
᎐
᎐CHH), 4.02 (1H, d, J 1.8, ᎐CHH), 2.66 (1H, dd, J 12.9 and
᎐
᎐
4.6, CHAHB), 2.58 (1H, dd, J 12.9 and 7.9, CHAHB) and 2.31
(1H, br s, OH); δC(50 MHz) 159.8 (C), 154.8 (C), 136.6 (C),
131.1 (CH), 130.5 (CH), 129.6 (2 × CH), 128.5 (2 × CH), 127.6
(CH), 126.5 (2 × CH), 124.4 (CH), 121.1 (2 × CH), 91.0 (CH2),
ϩ
ؒ
70.4 (CH) and 42.4 (CH2); m/z (EI) 266 (3, M ), 248 (6,
ϩ
Mϩ Ϫ H2O), 173 (10), 155 (8) and 133 (100) (Found: M ,
ؒ
266.1306. C18H18O2 requires M, 266.1305).
5-Methylene-2-phenoxynon-1-en-4-ol 12e
Enol ether 12e was prepared using the method described for
preparation of 12d: alcohol 8e (17.0 g, 68.5 mmol) gave silyl
ether 9e (18.5 g) as a red oil. A portion of the ester 9e (13.1 g,
41.2 mmol) then gave enol ether 12e (2.20 g, 18% over 3 steps)
as a pale yellow oil. Rf (DCM) 0.71; νmax(thin film)/cmϪ1 3450
1653 s (enol ether C᎐C), 1619 m, 1495 m, 1291 m, 1001 m, 965
m, 801 m, 749 s and 693 m; δH(400 MHz, CDCl3) 7.39 (2H, d,
J 7.2, o-Ph), 7.32 (2H, t, J 7.2, m-Ph), 7.24 (1H, t, J 7.2, p-Ph),
᎐
6.65 (1H, d, J 16.0, PhCH᎐), 6.26 (1H, dd, J 16.0 and 6.4,
᎐
PhCH᎐CH), 4.54–4.51 (1H, m, CHOH), 4.29 (1H, sep, J 6.0,
᎐
CHMe ), 4.05 (1H, d, J 2.0, ᎐CHAHB), 3.99 (1H, d, J 2.0,
(OH), 2954, 2929, 1645 (C᎐C), 1593 (aromatic ring) and 1493
᎐
᎐
2
᎐CHAHB), 2.87 (1H, d, J 3.6, OH), 2.45 [1H, dd, J 14.0 and 4.4,
(aromatic ring); δH(360 MHz; CDCl3) 7.35–7.03 (5H, m, Ph),
᎐
CH(OH)CHAHB], 2.36 [1H, dd, J 14.0 and 8.0, CH(OH)-
CHAHB], 1.28 (3H, d, J 6.0, CHMeAMeB) and 1.27 (3H, d,
J 6.0, CHMeAMeB); δC(100 MHz, CDCl3) 157.7 (C), 136.8 (C),
131.3 (CH), 129.6 (CH), 128.6 (CH), 127.3 (CH), 126.3 (CH),
84.1 (CH2), 70.6 (CH), 68.7 (CH), 43.5 (CH2), 21.44 (CH3) and
21.37 (CH3); m/z (CI) 233.2 [(M ϩ H)ϩ, 15%)], 215.2 (40), 173.1
(100) [Found: (M ϩ H)ϩ, 233.1541. C15H21O2 requires M ϩ H,
233.1542].
5.15 (1H, s, (HO)HCC᎐CHH), 4.91 (1H, s, (HO)HCC᎐CHH),
᎐
᎐
4.45 (1H, dd, J 8.6 and 3.6, CHOH), 4.21 (1H, d, J 1.4, PhOC᎐
᎐
CHH), 3.98 (1H, d, J 1.4, PhOC᎐CHH), 2.61 (1H, dd, J 14.3
᎐
and 3.6, CHAHBCHOH), 2.44 (1H, dd, J 14.3 and 8.6, CHAHB),
2.37 (1H, br s, OH), 2.18–1.98 (2H, m, ᎐CCH ), 1.52–1.26 (4H,
᎐
2
m, MeCH2CH2) and 0.91 (3H, t, J 7.2, Me); δC(100 MHz) 160.5
(C), 154.8 (C), 150.9 (C), 129.6 (2 × CH), 124.4 (CH), 121.1
(2 × CH), 109.4 (CH2), 90.5 (CH2), 72.5 (CH), 41.1 (CH2), 31.4
(CH2), 30.1 (CH2), 22.6 (CH2) and 14.0 (CH3); m/z (CI) 247 (43,
M ϩ Hϩ), 229 (100, M ϩ Hϩ Ϫ H2O), 169 (29), 153 (34) and
135 (65) [Found: (M ϩ H)ϩ, 247.1700. C16H23O2 requires
247.1702].
(5E)-2-Isopropoxynona-1,5-dien-4-ol 12c
Tetrabutylammonium fluoride (52 cm3 of a 1.0 mol dmϪ3 solu-
tion in THF) and 4 Å MS (10 g) were added to the crude enol
ether 10c (8.02 g, 25.6 mmol). The orange solution was stirred
for 2.5 h, then poured through filter paper into saturated
sodium bicarbonate solution (50 cm3), washing the sieves with
ether. The layers were separated and the aqueous phase extracted
with ether (2 × 50 cm3). The combined organic extracts
were dried over magnesium sulfate and the solvent removed
under reduced pressure to give a dark brown oil. The alcohol
12c was obtained as a pale yellow oil (1.91 g, 38%) after column
chromatography on alumina, using 1 : 1 ether–hexane as eluent,
Rf (alumina, 1 : 1 ether–hexane) 0.61; νmax(thin film)/cmϪ1 3399
br s (OH), 2960 s, 2929 s, 1654 m, 1294 m, 1121 m and 799 m;
δH(400 MHz, CDCl3) 5.67 (1H, dtd, J 15.2, 6.8 and 0.8,
CH CH᎐), 5.44 (1H, ddt, J 15.2, 6.8 and 1.2, CH CH᎐CH),
(1E,5ZE)-5-Ethoxy-1-phenylhepta-1,5-dien-3-ol 13a
Aldol 8a (23.43 g, 106.4 mmol) was dissolved in THF (100 cm3),
chlorotrimethylsilane (16.0 cm3, 125.4 mmol) and diisopropyl-
ethylamine (19.8 cm3, 125.4 mmol) were added and the reaction
was stirred at rt for 17 h. The bulk of the amine hydrochloride
salt formed during the reaction was filtered off and the precipi-
tate washed with hexane. The combined washings were concen-
trated under reduced pressure, and the process repeated to
remove the remaining salt. The silyl ether 9a was obtained as a
yellow oil (22.54 g, 77.0 mmol, 72%). In the same way as for
enol ether 11b, a solution of the crude ester 9a (7.54 g, 25.8
mmol) and 1,1-dibromoethane (5.7 cm3, 63 mmol) in THF
(5 cm3) was added to the suspension formed from titanium
tetrachloride (12.5 cm3, 114 mmol), TMEDA (34.4 cm3, 228
mmol), activated zinc powder (16.8 g, 257 mmol) and lead()
chloride (~10 mg) in THF (50 cm3). The reaction was stirred for
4 h, then worked-up as above to give the enol ether 11a as a
yellow oil (5.25 g, 17.2 mmol, 67%). The oil was dissolved in a
solution of TBAF in THF (18.0 cm3, 1.0 mol dmϪ3) and the
mixture stirred for 1 h. Work-up as above gave a yellow oil
᎐
᎐
2
2
4.25 (1H, sep, J 6.0, CHMe2), 4.25–4.20 (1H, m, CHOH), 3.96
(1H, d, J 1.6, ᎐CHAHB), 3.92 (1H, d, J 1.6, ᎐CHAHB), 2.49 (1H,
᎐
᎐
d, J 3.2, OH), 2.29 [1H, dd, J 14.0 and 3.8, CH(OH)CHAHB],
2.20 [1H, dd, J 14.0 and 8.4, CH(OH)CHAHB], 1.99 (2H, br q,
J 7.2, CH CH᎐), 1.38 (2H, sex, J 7.2, CH CH ), 1.23 (3H, d,
᎐
2
3
2
J 6.0, CHMeAMeB), 1.22 (3H, d, J 6.0, CHMeAMeB) and 0.88
(3H, t, J 7.2, CH3CH2); δC(100 MHz, CDCl3) 158.6 (C), 132.2
(CH), 131.9 (CH), 84.3 (CH2), 71.3 (CH), 69.2 (CH), 44.2
1058
J. Chem. Soc., Perkin Trans. 1, 2001, 1051–1061

View Article Online
which was chromatographed on basic alumina using 1 : 1
hexane–ether as eluent to give the alcohols 13a as a pale yellow
oil (2.06 g, 8.87 mmol, 25% over 3 steps). Repeated chromato-
graphy was required to obtain a sample of each isomer free
from the other.
CDCl3) 7.38 (2H, d, J 7.2, o-Ph), 7.26 (2H, t, J 7.2, m-Ph), 7.23
(1H, t, J 7.2, p-Ph), 6.63 (1H, d, J 15.9, PhCH᎐), 6.24 (1H, dd,
᎐
J 15.9 and 6.1, PhCH᎐CH), 4.58 (1H, q, J 6.8, ᎐CHMe), 4.53–
᎐
᎐
4.48 (1H, m, CHOH), 4.25 (1H, sep, J 6.0, CHMe2), 2.88 (1H,
d, J 3.7, OH), 2.48 [1H, dd, J 14.3 and 4.6, CH(OH)CHAHB],
2.43 [1H, dd, J 14.4 and 7.4, CH(OH)CHAHB], 1.62 (3H, d,
J 6.8, ᎐CHMe), 1.23 (3H, d, J 6.0, CHMeAMeB) and 1.22 (3H,
(1E,5Z)-5-Ethoxy-1-phenylhepta-1,5-dien-3-ol, Z-13a. Rf
(alumina, 1 : 1 hexane–ether) 0.57; νmax(thin film)/cmϪ1 3409 br
᎐
d, J 6.0, CHMeAMeB); δC(90 MHz, CDCl3) 151.1 (C), 137.0 (C),
131.7 (CH), 129.6 (CH), 128.4 (CH), 127.4 (CH), 126.4 (CH),
94.8 (CH), 71.3 (CH), 67.7 (CH), 37.5 (CH), 21.9 (CH3), 21.8
(CH3) and 11.9 (CH3).
m (OH), 2977 m, 2915 m, 2863 m, 1670 m (enol ether C᎐C),
᎐
1494 m, 1448 m, 1193 m, 966 m, 743 m and 694 m; δH(400 MHz,
CDCl3) 7.38 (2H, d, J 7.2, o-Ph), 7.31 (2H, t, J 7.2, m-Ph), 7.23
(1H, t, J 7.2, p-Ph), 6.65 (1H, d, J 16.0, PhCH᎐), 6.26 (1H, dd,
᎐
(3SR,5SR)-3-Hydroxy-5-phenylcyclohexanone28 17
J 16.0 and 4.4, PhCH᎐CH), 4.81 (1H, q, J 6.4, ᎐CHMe), 4.48–
᎐
᎐
4.43 (1H, m, CHOH), 3.87–3.75 (2H, m, OCH2CH3), 2.56 (1H,
d, J 2.8, OH), 2.46 [1H, dd, J 14.4 and 4.0, CH(OH)CHAHB],
2.30 [1H, dd, J 14.4 and 8.4, CH(OH)CHAHB], 1.64 (3H, d,
Alcohol 12b (500 mg, 2.15 mmol) and 18-crown-6 (1.14 g, 4.30
mmol) in DME (4 cm3) were added with stirring to a suspension
of potassium hydride (617 mg of 35% suspension in mineral oil,
5.38 mmol) in DME (6 cm3). After stirring for 4 h, the mixture
was poured into cold aqueous hydrochloric acid (25 cm3, 1 mol
dmϪ3). The mixture was stirred for 15 min at 0 ЊC, then allowed
to warm to room temperature over 15 min. After an additional
15 min at rt, ether (50 cm3) was added and the layers separated.
The aqueous phase was extracted with ether (10 cm3) and the
combined organic extracts were washed with hydrochloric acid
(10 cm3), water (10 cm3) and brine (10 cm3). Solvent removal
under reduced pressure yielded a yellow solid (402 mg, 80%
w/w). Purification by trituration with ether gave the cyclo-
hexanone28 17 as an amorphous solid (215 mg, 43%); δH(360
MHz, CDCl3) 7.35–7.19 (5H, m, Ph), 4.60 [1H, qn, J 3.0,
CH(OH)], 3.57 [1H, tt, J 12.2 and 4.1, CH(Ph)], 2.69–2.51 [4H,
m, CH2C(O)CH2], 2.35–2.19 (1H, br s, OH), 2.21 [1H, m with
large doublet splitting, J 14.0, CH(Ph)CHeqHax] and 2.06 [1H,
distorted ddd, J 14.1, 12.2 and 2.4, CH(Ph)CHeqHax].
J 6.8, ᎐CHMe) and 1.29 (3H, t, J 7.0, OCH CH ); δ (100 MHz,
᎐
2
3
C
CDCl3) 151.4 (C), 136.8 (C), 131.4 (CH), 129.8 (CH), 128.5
(CH), 127.5 (CH), 126.4 (CH), 109.5 (CH), 70.5 (CH), 68.5
(CH2), 40.5 (CH2), 15.4 (CH3) and 10.5 (CH3); m/z (EI) 232.2
ϩ
ϩ
ؒ
(M , 5%), 133.1 (100) (Found: M , 232.1463. C15H20O2
requires M, 232.1463).
(1E,5E)-5-Ethoxy-1-phenylhepta-1,5-dien-3-ol, E-13a. Rf
(alumina, 1 : 1 hexane–ether) 0.60; νmax(thin film)/cmϪ1 3458
br s (OH), 2861 w, 1668 m (enol ether C᎐C), 1495 w, 1226 w,
᎐
1103 w, 963 w and 748 w; δH(360 MHz, CDCl3) 7.37 (2H, d,
J 7.2, o-Ph), 7.31 (2H, t, J 7.2, m-Ph), 7.23 (1H, t, J 7.2, p-Ph),
6.63 (1H, d, J 15.9, PhCH᎐), 6.26 (1H, dd, J 15.9 and 6.1,
᎐
PhCH᎐CH), 4.58 (1H, q, J 6.8, ᎐CHMe), 4.55–4.48 (1H, partly
᎐
᎐
obscured m, CHOH), 3.74–3.66 (2H, m, OCH2CH3), 2.75 (1H,
br d, J 3.0, OH), 2.48 [2H, m, CH(OH)CHAHB], 1.62 (3H, d,
J 6.8, ᎐CHMe) and 1.29 (3H, t, J 7.0, OCH CH ); δ (90 MHz,
᎐
2
3
C
New data: δC(100 MHz, CDCl3) 209.7 (C), 143.7 (C), 128.7
(CH), 126.7 (2 × CH), 68.3 (CH), 48.7 (2 × CH2), 39.2 (CH2)
and 38.2 (CH).
CDCl3) 153.0 (C), 137.0 (C), 131.7 (CH), 129.6 (CH), 128.5
(CH), 127.4 (CH), 126.4 (CH), 93.7 (CH), 71.2 (CH), 62.0
(CH), 37.5 (CH2), 14.7 (CH3) and 11.8 (CH3); m/z (EI) 232
ϩ
ϩ
ؒ
(M , 7%), 133 (100) (Found: M , 232.1464. C15H20O2 requires
5-Phenylcyclohex-2-enone29 19
M 232.1463).
Crude alcohols 17 and 18 (211 mg, 1.11 mmol) were dissolved
in DCM (10 cm3) and treated with methanesulfonyl chloride
(0.1 cm3, 1.2 mmol) and triethylamine (0.62 cm3, 4.4 mmol).
Work-up as for compound 28 gave the cyclohexenone 19 as a
yellow oil29 (117 mg, 61%). A pure sample was obtained as a
solid in 34% yield after further chromatography using DCM as
eluent; δH(400 MHz, CDCl3) 7.40–7.24 (5H, m, Ph), 7.06 [1H,
(1E,5EZ)-5-Isopropoxy-1-phenylhepta-1,5-dien-3-ol, 13b
In the same way as above for 12c, silyl ether 11b (2.40 g, 6.66
mmol) was dissolved in a solution of TBAF in THF (18.1 cm3,
1.1 mol dmϪ3). 4 Å MS were added and the mixture stirred for
2 h. Work-up as above gave a yellow oil which was chromato-
graphed on basic alumina using 1 : 1 hexane–ether as eluent to
give the alcohols as a pale yellow oil (1.45 g, 5.9 mmol, 88%).
Repeated chromatography was required to obtain a sample of
each isomer free from the other.
ddd, J 10.0, 6.0 and 2.8, CH᎐CHC(O)], 6.13 [1H, d br d, J 10.0
᎐
and 2.8, CH᎐CHC(O)], 3.36 (1H, ddt, J 12.4, 10.4 and 5.2,
᎐
CHPh), 2.72–2.61 [3H, m, C(O)CH and ᎐CHCH H ] and
᎐
2
eq ax
2.54 (1H, ddt, J 18.8, 10.8 and 2.4, ᎐CHCH H ).
᎐
eq ax
(1E,5Z)-5-Isopropoxy-1-phenylhepta-1,5-dien-3-ol, Z-13b. Rf
(alumina, 2 : 1 petroleum ether–ether) 0.61; νmax(thin film)/cmϪ1
3425 br m (OH), 2974 m, 1678 m, 1494 m, 1449 m, 1196 m,
1113 m, 965 m, 747 m and 693 m; δH(360 MHz, CDCl3) 7.39
(2H, d, J 7.2, o-Ph), 7.31 (2H, t, J 7.2, m-Ph), 7.24 (1H, t, J 7.2,
(3SR,5RS)-3-Hydroxy-5-(n-propyl)cyclohexanone 20
Potassium hydride (173 mg of a 35% suspension in mineral oil,
1.50 mmol) was washed with hexane (3 × 4 cm3) to remove oil
and then suspended in dry THF (1.5 cm3) under nitrogen. To
the suspension was added a solution of alcohol 12c (100 mg,
0.50 mmol) and 18-crown-6 (269 mg, 1.00 mmol) in THF
(1 cm3) with stirring at rt. The resulting dark brown mixture was
stirred for 5 days, whereupon it was poured into cold (ice bath)
aqueous hydrochloric acid (5 cm3, 1 mol dmϪ3) with vigorous
stirring. The mixture was stirred at 0 ЊC for 10 min, then the ice
bath was removed and stirring continued for an additional 15
min. Ether (10 cm3) was then added and the layers separated.
The aqueous phase was extracted with ether (2 × 10 cm3) and
the combined organic extracts were dried over magnesium
sulfate. Solvent removal under reduced pressure yielded the
alcohols 20 and 21 (54 mg, 69%) as a brown oil. This was
washed quickly through a short column of neutral alumina
with ether to give a pure sample of a 90 : 10 anti–syn mixture of
isomers as a yellow oil (40 mg, 51%); data for the major isomer
p-Ph), 6.63 (1H, d, J 15.9, PhCH᎐), 6.26 (1H, dd, J 15.9 and
᎐
6.1, PhCH᎐CH), 4.87 (1H, q, J 6.7, ᎐CHMe), 4.49–4.41 (1H,
᎐
᎐
m, CHOH), 4.17 (1H, sep, J 6.1, CHMe2), 2.57 (1H, br d, J 2.5,
OH), 2.45 [1H, dd, J 14.4 and 4.1, CH(OH)CHAHB], 2.29 [1H,
dd, J 14.4 and 8.5, CH(OH)CHAHB], 1.63 (3H, d, J 6.7,
᎐CHMe), 1.25 (3H, d, J 6.1, CHMeAMeB) and 1.22 (3H, d,
᎐
J 6.1, CHMeAMeB); δC(90 MHz, CDCl3) 149.7 (C), 136.8 (C),
131.4 (CH), 129.7 (CH), 128.4 (CH), 127.4 (CH), 126.4 (CH),
110.6 (CH), 70.5 (CH), 69.8 (CH), 40.6 (CH2), 22.4 (CH3), 22.2
(CH3) and 10.7 (CH3); m/z (CI) 247.2 [(M ϩ H)ϩ, 9%], 229.2
(90), 187.2 (100) [Found: (M ϩ H)ϩ, 247.1697. C16H23O2
requires M ϩ H, 247.1698].
(1E,5E)-5-Isopropoxy-1-phenylhepta-1,5-dien-3-ol, E-13b. Rf
(alumina, 2 : 1 petroleum ether–ether) 0.69; δH(400 MHz,
J. Chem. Soc., Perkin Trans. 1, 2001, 1051–1061
1059

View Article Online
20: νmax(thin film)/cmϪ1 3423 brs (OH), 2958 s, 2928 s, 1708 s
(CH), 128.7 (CH), 127.4 (CH), 126.9 (CH), 48.6 (CH), 46.8
ϩ
ؒ
(C᎐O), 1413 m, 1292 m, 1236 m, 1095 m, 1062 m, 1037 m and
(CH), 34.9 (CH2) and 12.5 (CH3); m/z (EI) 186.1 (M , 40%),
118.1 (100) (Found: Mϩ, 186.1044, C13H14O requires M,
186.1045).
᎐
970 m; δH(360 MHz, CDCl3) 4.50–4.44 (1H, m, CHOH), 2.54
[1H, dd, J 14.2 and 3.7, CH(OH)CHaxHeqC(O)], 2.50–2.40 [2H,
m, CH(OH)CHaxHeqC(O)CHaxHeq], 2.30–2.21 (1H, m, CHPr),
2.03–1.96 [2H, m, CH(Pr)CHaxHeqC(O) and CH(OH)-
CHaxHeqCH(Pr)], 1.89 (1H, br s, OH), 1.56 [1H, ddd, J 13.9,
11.4 and 2.5, CH(OH)CHeqHaxCH(Pr)], 1.40–1.25 (4H, m,
MeCH2CH2) and 0.91–0.88 (3H, m, Me); δC(90 MHz, CDCl3)
210.4 (C), 68.4 (CH), 49.1 (CH2), 47.7 (CH2), 38.5 (CH2), 38.0
(CH2), 32.4 (CH), 19.7 (CH2) and 14.0 (CH3); m/z (EI) 156
5-Phenoxy-3-phenylhex-5-enal 36
A solution of 12d (0.10 g, 0.38 mmol) and 18-crown-6 (0.20 g,
0.74 mmol) in dry THF (1 cm3) was added to a flask containing
potassium hydride (0.11 g of a 35% dispersion in mineral oil
prewashed with dry hexane 4 × 2 cm3), in dry THF (5 cm3)
under nitrogen. The resulting mixture was stirred for 2 h at
room temperature then poured into aqueous saturated sodium
bicarbonate (50 cm3). The product was extracted into ether
(2 × 50 cm3) and dried (MgSO4). Purification by chromato-
graphy on alumina, eluting with hexane–ether (20 : 1), gave
aldehyde 36 as an oil (41 mg, 41%). Rf (hexane–ether, 5 : 1)
0.40; νmax(thin film)/cmϪ1 2924, 1724 (C᎐O), 1634 (C᎐C), 1592
ϩ
ϩ
ؒ
(M , 45%), 113 (52), 96 (90), 69 (100) (Found: M , 156.1150.
C9H16O2 requires M, 156.1150).
(3SR,5SR,6RS)-3-Hydroxy-6-methyl-5-phenylcyclohexanone 22
Potassium hydride (1.16 g of 35% suspension in mineral oil,
10.15 mmol) was washed with hexane (3 × 2 cm3) to remove oil
and then suspended in dry 1,2-dimethoxyethane (DME) (15
cm3) under nitrogen. To the suspension was added a solution of
alcohol 13b (85% Z, 1 g, 4.06 mmol) and 18-crown-6 (2.15 g,
8.12 mmol), in DME (5 cm3) with stirring at rt. The resulting
dark brown mixture was stirred for 3 h, whereupon it was
poured into cold (ice bath) aqueous hydrochloric acid (50 cm3,
1 mol dmϪ3) with vigorous stirring. The mixture was stirred for
15 min at 0 ЊC, then allowed to warm to room temperature over
15 min. After an additional 15 min at rt, ether (50 cm3) was
added and the layers separated. The aqueous phase was
extracted with ether (10 cm3) and the combined organic extracts
were washed with hydrochloric acid (10 cm3), water (10 cm3)
and brine (10 cm3). Solvent removal under reduced pressure
yielded a brown solid (757 mg, 91% w/w). Purification was
achieved by trituration with cold ether to give cyclohexanone 22
as a white solid (150 mg, 31%); mp 156–157 ЊC (Found: C 76.4;
H 7.9, C13H16O2 requires C 76.4; H 7.9%); νmax(KBr)/cmϪ1 3369
᎐
᎐
(aromatic ring), 1491 (aromatic ring) and 1218; δH(200 MHz;
CDCl3) 9.63 (1H, t, J 2.0, CHO), 7.30–6.83 (10H, m, 2 × Ph),
3.97 (1H, d, J 1.8, ᎐CHH), 3.78 (1H, d, J 1.8, ᎐CHH), 3.64 (1H,
᎐
᎐
broad qn, J 7.6, CHPh), 2.82 (1H, ddd, J 16.7, 6.2 and 1.9,
CHAHBCHO), 2.73 (1H, ddd, J 16.7, 8.4 and 2.1, CHAHBCHO)
and 2.54 [2H, d, J 7.7, ᎐C(OPh)CH CHPh]; δ (50 MHz) 201.8
᎐
2
C
(CH), 160.4 (C), 154.8 (C), 142.9 (C), 129.5 (2 × CH), 128.6
(2 × CH), 127.5 (2 × CH), 126.6 (CH), 124.4 (CH), 121.0
(2 × CH), 90.3 (CH2), 49.3 (CH2), 41.3 (CH2) and 37.7 (CH);
m/z (CI) 267 (100, M ϩ Hϩ), 249 (22) and 173 (M ϩ Hϩ Ϫ
HOPh) [Found: (M ϩ H)ϩ, 267.1386. C18H19O2 requires M,
267.1385].
5-Formyl-2-phenoxynon-1-ene 37
Aldehyde 37 was prepared (0.10 g, 59%) as an oil from hexa-
dienol 12e (0.17 g, 0.69 mmol) using the method described
for synthesis of 36. Rf (hexane–ether 5 : 1) 0.43; νmax(thin film)/
br (OH), 1713 vs (C᎐O), 1492 m, 1452 m, 1230 m, 1015 m, 753
᎐
cmϪ1 2930, 1725 (C᎐O), 1593 (aromatic ring), 1491 (aromatic
᎐
m and 700 s; δH(360 MHz, CDCl3) 7.36–7.22 (5H, m, Ph), 4.59
[1H, qn, J 2.9, CH(OH)], 3.13 [1H, ddd, J 11.8, 9.1 and 7.5,
CH(Ph)], 2.77 [1H, dd, J 14.1 and 3.0, C(O)CHeqHax], 2.64 [1H,
partly obscured dq, J 11.9 (by irradiation of Me) and 6.6,
CHMe], 2.62 [1H, d with poorly resolved smaller couplings,
J 14.1, C(O)CHeqHax], 2.19–2.13 (2H, m, CH(Ph)CH2), 1.94
(1H, br s, OH), 0.84 (3H, d, J 6.5, Me); δC(90 MHz, CDCl3)
210.92 (C), 143.15 (C), 128.70 (CH), 127.43 (CH), 126.75 (CH),
68.92 (CH), 50.63 (CH), 49.05 (CH2), 46.50 (CH), 40.58 (CH2)
ring), 1220 and 693; δH(360 MHz; CDCl3) 9.63 (1H, d, J 2.5,
CHO), 7.35–7.00 (5H, m, Ph), 4.15 (1H, s, ᎐CHH), 3.94 (1H, s,
᎐
᎐CHH), 2.40–2.36 (1H, m, CHCHO), 2.32–2.27 (2H, m,
᎐
᎐CCH ), 2.00–1.94 (2H, m, ᎐CCH CH ), 1.79–1.64 (2H, m,
᎐
᎐
2
2
2
PrCH2), 1.53–1.46 (2H, m, EtCH2), 1.34–1.26 (2H, m, MeCH2)
and 0.90 (3H, t, J 7.2, Me); δC(50 MHz) 205.0 (CH), 162.3 (C),
155.1 (C), 129.5 (2 × CH), 124.0 (CH), 120.9 (2 × CH), 89.0
(CH2), 51.0 (CH), 31.5 (CH2), 29.0 (CH2), 28.5 (CH2), 26.0
ϩ
ؒ
ϩ
ϩ
ؒ
ؒ
(CH2), 22.7 (CH2) and 13.8 (CH3); m/z (EI) 246 (5, M ), 229
(14), 183 (23), 149 (32), 94 (45) and 43 (100) (Found: Mϩ,
246.2019. C16H22O2 requires M, 246.2026).
and 11.99 (CH3); m/z (EI) 204 (M , 62%), 186 (M Ϫ H2O,
29), 91 (100), 77 (Ph, 49) (Found: Mϩ, 204.1151. C13H16O2
requires M, 204.1150).
(5SR,6SR)-6-Methyl-5-phenylcyclohex-2-enone 28
2-Phenoxynon-1-en-5-one 42
The crude alcohols 22–24 (241 mg, 1.18 mmol) were dissolved
in DCM (10 cm3) under nitrogen and cooled in an ice bath.
Methanesulfonyl chloride (0.1 cm3, 1.18 mmol) was added in
one portion, then triethylamine (0.7 cm3, 4.72 mmol) was added
dropwise. The resulting solution was stirred for 15 min then
poured into water (10 cm3) and the layers separated. The
organic phase was washed with hydrochloric acid (10 cm3, 1.1
mol dmϪ3) then brine (10 cm3) and dried over magnesium
sulfate. Concentration under reduced pressure followed by col-
umn chromatography on silica using DCM as eluent gave the
cyclohexenones as a pale yellow oil (125 mg, 57%), containing a
13 : 87 mixture of syn and anti isomers 29 and 28; data for anti
isomer 28: Rf (silica, DCM) 0.79; νmax(thin film)/cmϪ1 3029 w,
A solution of alcohol 12e (0.10 g, 0.41 mmol) and 18-crown-6
(0.21 g, 0.82 mmol) in dry THF (1 cm3) was added to a flask
containing potassium hydride (0.14 g of a 35% dispersion in
mineral oil prewashed with dry hexane 4 × 2 cm3) in dry THF
(5 cm3). The resulting mixture was stirred for 1.5 h at room
temperature, then cooled to Ϫ78 ЊC and dry oxygen gas was
bubbled through the solution over 30 min. pH 7 phosphate
buffer (15 cm3) was then added dropwise to the mixture and the
solution was then allowed to warm to room temperature. The
organic phase was separated and the aqueous phase was
extracted with ether (2 × 25 cm3). The ethereal extracts were
combined, dried (MgSO4) and concentrated. Chromatography
on alumina, eluting with hexane–ether (10 : 1), gave ketone 42
as an oil (71 mg, 71%). Rf [alumina, hexane–ether (10 : 1)] 0.27;
νmax(thin film)/cmϪ1 2958, 2930, 2871, 1715 (C᎐O), 1657 (C᎐C),
2970 w, 2929 w, 2877 w, 1676 vs (C᎐O), 1494 m, 1454 m, 1388
᎐
m, 1232 m, 769 m, 748 m and 702 s; δH(400 MHz, CDCl3)
7.30–7.10 (5H, m, Ph), 6.97 [1H, ddd, J 10.0, 4.8 and 2.8,
᎐
᎐
1638, 1592 (aromatic ring), 1490 (aromatic ring) and 1220;
CH᎐CHC(O)], 6.12 [1H, br d, J 10.0, CH᎐CHC(O)], 2.97 (1H,
δH(360 MHz; CDCl3) 7.35–7.00 (5H, m, Ph), 4.17 (1H, d, J 1.8,
᎐
᎐
ddd, J 12.8, 9.6 and 6.0, CHPh), 2.69 (1H, dq, J 12.8 and 6.8,
CHMe), 2.65–2.55 (2H, m, CH2) and 0.94 (3H, d, J 6.8, Me);
δC(100 MHz, CDCl3) 201.3 (C), 148.2 (CH), 142.8 (C), 129.3
᎐CHH), 3.93 (1H, d, J 1.8, ᎐CHH), 2.73 (2H, t, J 7.2,
᎐ ᎐
᎐CCH CH or ᎐CCH ), 2.56 (2H, t, J 7.2, ᎐CCH CH or
᎐
᎐
᎐
2
2
2
2
2
᎐CCH ), 2.45 (2H, t, J 7.5, PrCH ), 1.65–1.53 (2H, m, EtCH ),
᎐
2
2
2
1060
J. Chem. Soc., Perkin Trans. 1, 2001, 1051–1061

View Article Online
3 F. N. Tebbe, G. W. Parshall and G. S. Reddy, J. Am. Chem. Soc.,
1978, 100, 3611.
1.37–1.26 (2H, m, MeCH2) and 0.90 (3H, t, J 7.7, Me); δC(50
MHz) 210.1 (C), 162.0 (C), 155.1 (C), 129.5 (2 × CH), 124.0
(CH), 120.7 (2 × CH), 89.0 (CH2), 42.6 (CH2), 40.1 (CH2), 29.6
(CH2), 28.2 (CH2), 22.3 (CH2) and 13.8 (CH3); m/z (EI) 232
(M , 9%) and 147 (100) [Found (CI): (M ϩ H) , 233.1544.
C15H21O2 requires (M ϩ Hϩ) 233.1541].
4 T. R. Howard, J. B. Lee and R. H. Grubbs, J. Am. Chem. Soc., 1980,
102, 6876; K. A. Brown-Wensley, S. L. Buchwald, L. Cannizzo,
L. Clawson, S. Ho, D. Meinhardt, J. R. Stille, D. Straus and
R. H. Grubbs, Pure Appl. Chem., 1983, 55, 1733.
5 N. A. Petasis and S.-P. Lu, Tetrahedron Lett., 1995, 36, 2393 and refs.
1–3 therein.
ϩ
ϩ
ؒ
6 T. Okazoe, K. Takai, K. Oshima and K. Utimoto, J. Org. Chem.,
1987, 52, 4410.
7 K. Takai, Y. Kataoka, J. Miyai, T. Okazoe, K. Oshima and
K. Utimoto, Org. Synth., 1996, 73, 73.
(3RS,5SR,6SR)- and (3RS,5SR,6RS)-3-tert-Butyldimethyl-
silyloxy-6-methyl-5-phenylcyclohexanone, 43 and 44
A mixture of alcohols 22–24 (776 mg, 3.7 mmol) was dissolved
in dry DMF (10 cm3) under nitrogen. Diisopropylethylamine
(1.2 cm3, 6.7 mmol) then tert-butyldimethylsilyl chloride (468
mg, 3.1 mmol) were added at 0 ЊC. The reaction mixture was
allowed to warm to room temperature and then left to stir over
three days (~60 h). The mixture was then poured into saturated
aqueous sodium bicarbonate solution (20 cm3). The aqueous
phase was separated and extracted with ether (2 × 10 cm3). The
combined organic extracts were washed with aqueous hydro-
chloric acid (2 × 10 cm3, 1 mol dmϪ3 solution) then brine
(10 cm3) and dried (MgSO4). Concentration under reduced
pressure gave a mixture of the unprotected alcohol 22, its
TBDMS ether, and silyl ethers 43 and 44. Separation of the two
diastereoisomers was achieved by column chromatography
followed by preparative TLC.
8 Y. Horikawa, M. Watanabe, T. Fujiwara and T. Takeda, J. Am.
Chem. Soc., 1997, 119, 1127.
9 For a review see: L. A. Paquette, Tetrahedron, 1997, 53, 13971.
10 N. Greeves and W.-M. Lee, Tetrahedron Lett., 1997, 35, 6445
and refs. 10 and 11 therein; E. Lee, Y. R. Lee, B. Moon, O. Kwon,
M. S. Shim and J. S. Yun, J. Org. Chem., 1994, 59, 1444; S.-Y. Wei,
K. Tamooka and T. Nakai, Tetrahedron, 1993, 49, 1025; L. A.
Paquette and G. D. Maynard, J. Am. Chem. Soc., 1992, 114,
5018.
11 L. A. Paquette, D. T. DeRussy and R. D. Rogers, Tetrahedron, 1988,
44, 3139; L. A. Paquette, J. Reagan, S. L. Schreiber and C. A.
Teleha, J. Am. Chem. Soc., 1989, 111, 2331; R. E. Maleczka, Jr. and
L. A. Paquette, J. Org. Chem., 1991, 56, 6538.
12 L. A. Paquette, D. T. DeRussy, N. A. Pegg, R. T. Taylor and
T. M. Zydowsky, J. Org. Chem., 1989, 54, 4576.
13 L. A. Paquette, T. M. Morwick, J. T. Negri and R. D. Rogers,
Tetrahedron, 1996, 52, 3075.
14 For a review of carbocyclisations see: R. C. Hartley and S. T.
Caldwell, J. Chem. Soc., Perkin Trans. 1, 2000, 477.
15 H. Ohtake, X.-L. Li, M. Shiro and S. Ikegami, Tetrahedron, 2000,
56, 7109.
16 J. E. Baldwin and M. J. Lusch, Tetrahedron, 1982, 38, 2939.
17 Examples include: J. R. Bull and J. H. S. Borry, J. Chem. Soc., Perkin
Trans. 1, 1994, 913; I. Shiina, H. Iwadare, M. Saitoh, N. Ohkawa,
T. Nishimura and T. Mukaiyama, Chem. Lett., 1995, 781;
T. Mukaiyama, I. Shiina, K. Kimura, Y. Akiyama and H. Iwadare,
Chem. Lett., 1995, 229; Y. Tsuda, Y. Sakai, T. Sano and J. Toda,
Chem. Pharm. Bull., 1991, 39, 1402.
18 K. Tadano, S. Kanazawa, K. Takao and S. Ogawa, Tetrahedron,
1992, 48, 4283.
19 H. Fukase and S. Horii, J. Org. Chem., 1992, 57, 3642.
20 M.-H. Filippini, R. Faure and J. Rodriguez, J. Org. Chem., 1995, 60,
6872.
21 T. Mukaiyama, Org. React. (N. Y.), 1982, 28, 238.
22 N. Sloughi and G. Rousseau, Synth. Commun., 1987, 17, 1.
23 C. Wedler, A. Kunath and H. Schick, J. Org. Chem., 1995, 60, 758.
24 H. Schick, R. Ludwig, K. Kleiner and A. Kunath, Tetrahedron,
1995, 51, 2939.
25 M. Mortimore and P. Kocienski, Tetrahedron Lett., 1988, 29, 3357.
26 A. P. Rutherford and R. C. Hartley, Tetrahedron Lett., 2000, 41,
737.
27 M. P. Strobel, C. G. Andrieu, D. Paquer, M. Vazeux and C. C.
Pham, Nouv. J. Chim., 1980, 4, 101.
28 A route to these β-hydroxycyclohexanones is known: I. Fleming,
R. Henning, D. C. Parker, H. E. Plaut and P. E. J. Sanderson,
J. Chem. Soc., Perkin Trans. 1, 1995, 317.
(3RS,5SR,6SR)-3-tert-Butyldimethylsilyloxy-6-methyl-5-
phenylcyclohexanone 43. Spectral data for 43: νmax(thin film)/
cmϪ1 2954, 2929, 2856, 1714 (C᎐O); δ (360 MHz, CDCl )
᎐
H
3
7.37–7.13 (5H, m, Ph), 4.40 [1H, m, ΣJ ~16, CH(OTBDMS)],
3.71 [1H, dt, J 11.0 and 4.3, CH(Ph)], 2.74 [1H, dd, J 14.5 and
3.7, C(O)CHaxHeq], 2.70 [1H, dq partly obscured, CHMe],
2.38 [1H, dd, J 14.6 and 4.9, C(O)CHeqHax], 2.29 [1H, ddd,
J 13.5, 10.9 and 2.5, CH(Ph)CHaxHeq], 1.96 [1H, ddd, J 13.7,
4.5 and 3.5, CH(Ph)CHaxHeq], 0.88 (3H, d, J 7.2, CHMe), 0.84
(9H, s, SitBu), 0.03 (3H, s, SiMeAMeB), Ϫ0.01 (3H, s, SiMeA-
t
MeB); m/z (EI) 261 (Mϩ Ϫ Bu , 20%), 157 (100) [Found (CI):
(M ϩ NH3)ϩ 336.2345. C19H34NO2Si requires M ϩ NH3,
336.2359].
ؒ
ؒ
(3RS,5SR,6RS)-3-tert-Butyldimethylsilyloxy-6-methyl-5-
phenylcyclohexanone 44. Spectral data for 44: νmax(thin film)/
cmϪ1 2956 m, 2856 m, 1715 vs (C᎐O), 1376 m, 1254 m, 1095 s,
᎐
777 m and 700 m; δH(360 MHz, CDCl3) 7.40–7.15 (5H, m, Ph),
3.95 [1H, tt, J 10.9 and 4.8, CH(OTBDMS)], 2.76 [1H, ddd,
J 13.0, 4.9 and 2.2, C(O)CHeqHax], 2.58 [1H, t, J 12.2, C(O)-
CHaxHeq], 2.52 [1H, dq partly obscured, CHMe], 2.38 [1H, td,
J 12.3 and 3.3, CH(Ph)], 2.20 [1H, doublet with poorly-resolved
smaller couplings, J approx. 13.0, CH(Ph)CHaxHeq], 2.04 [1H,
td, J 12.9 and 10.7, CH(Ph)CHaxHeq], 0.87 (9H, s, SitBu), 0.78
29 M. J. Aurell, P. Gavina and R. Mestres, Tetrahedron, 1994, 50, 2571.
30 J. P. Richard and R. W. Nagorski, J. Am. Chem. Soc., 1999, 121,
4763.
31 N. L. Allinger, J. Am. Chem. Soc., 1977, 99, 8127.
32 F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp,
M. Lipton, C. Caufield, G. Chang, T. Hendrickson and W. C. Still,
J. Comput. Chem., 1990, 11, 440.
(3H, d, J 6.4, CHMe), 0.06 (3H, s, SiMeAMeB), 0.05 (3H, s,
t
SiMeAMeB); m/z (EI) 261 (Mϩ Ϫ Bu , 7%), 157 (38), 31 (100)
[Found (CI): (M ϩ H)ϩ, 319.2090. C19H31O2Si requires M ϩ H,
319.2093].
ؒ
ؒ
33 M. J. S. Dewar, E. G. Zoebisch, E. F. Healy and J. J. P. Stewart,
J. Am. Chem. Soc., 1985, 107, 3902.
Acknowledgements
34 J. J. P. Stewart, J. Comput. Aided Mol. Des., 1990, 4, 1.
35 K. J. McCullough, Contemp. Org. Synth., 1995, 3, 225.
36 L. A. Paquette and R. C. Thompson, J. Org. Chem., 1993, 58, 4952.
37 J. Zabicky, The Chemistry of the Carbonyl Group, Wiley, New York,
1970, Vol. 2, pp. 81–87.
38 L. N. Mander and D. J. Owen, Tetrahedron, 1997, 53, 2137.
39 S. Matsubara, N. Tsuboniwa, Y. Morizawa, K. Oshima and
H. Nozaki, Bull. Chem. Soc. Jpn., 1984, 3242.
University of Glasgow for a scholarship for A. P. R., Loudon
bequest for supporting C. S. G.
References
1 A. P. Rutherford, C. S. Gibb and R. C. Hartley, Tetrahedron Lett.,
1998, 39, 685.
2 For a review see: A. S. Franklin and I. Paterson, Contemp. Org.
Synth., 1994, 317.
40 K. Inomata, T. Kawahara and T. Mukaiyama, Chem. Lett., 1974,
245.
J. Chem. Soc., Perkin Trans. 1, 2001, 1051–1061
1061