Desymmetrisation of 4,4-disubstituted cyclohexanones by enzyme-catalysed resolution of their enol acetates

Article abstract of DOI:10.1039/b005466f

Enol acetates 3 10 derived from prochiral 4,4-disubstituted cyclohexanones can be resolved with Pseudomonas fiuorescens lipase to give enantiomerically pure (>99% ee) enol esters by transesterification with n-BuOH. The product ketones are prochiral and can easily be recycled giving an overall desymmetrisation of the ketone. Highest selectivity was obtained for substrates containing a 4-cyano and 4-aryl or a 4-benzyloxy substituent. The methodology was compared to asymmetric deprotonation-enolate trapping using the chiral base (S,S)-bis(α-methylbenzyl)amide which gave low (54-64%) ee's for this class of ketones.

Full text of DOI:10.1039/b005466f

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Desymmetrisation of 4,4-disubstituted cyclohexanones by
enzyme-catalysed resolution of their enol acetates
Graham Allan,a Andrew J. Carnell,*a Maria Luisa Escudero Hernandeza and Alan Pettmanb
1
a Department of Chemistry, Robert Robinson Laboratories, University of Liverpool, Liverpool,
UK L69 7ZD
b Department of Process Research and Development, Pfizer Ltd, Sandwich, Kent,
UK CT13 9NJ
Received (in Cambridge, UK) 7th July 2000, Accepted 24th August 2000
First published as an Advance Article on the web 3rd October 2000
Enol acetates 3–10 derived from prochiral 4,4-disubstituted cyclohexanones can be resolved with Pseudomonas
fluorescens lipase to give enantiomerically pure (>99% ee) enol esters by transesterification with n-BuOH. The
product ketones are prochiral and can easily be recycled giving an overall desymmetrisation of the ketone.
Highest selectivity was obtained for substrates containing a 4-cyano and 4-aryl or a 4-benzyloxy substituent.
The methodology was compared to asymmetric deprotonation–enolate trapping using the chiral base
(S,S)-bis(α-methylbenzyl)amide which gave low (54–64%) ee’s for this class of ketones.
than 50% yields of enantiopure enol ester after several cycles,
Introduction
constituting a desymmetrisation of the prochiral ketone.
We now report the use of related enol acetate substrates
derived from prochiral 4,4-disubstituted cyclohexanones to
probe the structural requirements for enantioselectivity with
this enzyme.
The desymmetrisation of prochiral ketones has become an
important method in asymmetric synthesis. The use of chiral
lithium amides for the deprotonation of 4-substituted cyclo-
hexanones and prochiral bicyclic ketones has been developed
by Koga1 and Simpkins2 respectively.3 High enantioselectivity
has been achieved using a number of specialised chiral amines.
However, in order to achieve high selectivity, the reactions
are run at low temperatures (Ϫ78 ЊC or Ϫ100 ЊC) and require
anhydrous conditions. The chiral silyl enol ethers which result
from enolate trapping can provide a handle for maintaining the
newly introduced asymmetry by oxidative cleavage or electro-
philic addition. Baeyer–Villiger reactions using monooxygenase
enzymes4 and asymmetric copper and platinum catalysts5,6
have also recently attracted attention but suffer from low
substrate concentrations and moderate enantioselectivities
respectively. Despite recent progress, methods to achieve this
type of transformation which are amenable to scale-up using
commercially available catalysts which can operate at ambient
temperature are needed.
Results and discussion
In the preliminary work6 we varied the chain length of the ester
group of the substrate, the reaction solvent and the alcohol for
transesterification. The nature of the ester group turned out not
to affect the enantioselectivity of PFL so in all subsequent
substrates we have employed the enol acetate. Tetrahydrofuran,
toluene, diisopropyl ether and acetonitrile were tested as
solvents and all gave approximately the same enantioselectivity
with 1–2 equivalents of n-BuOH for the transesterification.
Tetrahydrofuran was the solvent of choice since the reaction
time (18 h) allowed us to closely monitor the progress of the
reaction and stop it at an appropriate degree of conversion to
recover a maximum yield of optically pure enol ester. It was
found that the reaction needed to be run to 67% conversion to
leave unreacted optically pure (100% ee) (S)-enol acetate 2. In
order to test the scope of this biotransformation for the prod-
uction of chiral enol esters derived from 4,4-disubstituted
prochiral cyclohexanones, we synthesized racemic enol acetates
3–10 as new substrates (Fig. 1). These were chosen with some
synthetic targets in mind and to test the importance of the
aromatic and cyano groups for selectivity. The enol acetate
3 was chosen since synthetic elaboration to a series of Pfizer
NK-2 antagonists was envisaged and substrates 4 and 5 would
further test the effect of substitution on or in the phenyl ring.
Substrate 6 would test the requirement for the cyano group.
Substrate 7 was chosen with the view to converting the chiral
enol acetate to a chiral dione equivalent 11 by Tsuji7 oxidative
rearrangement to the enone followed by cis dihydroxylation of
the alkene (Scheme 2). Cyanohydrins can be considered to be
protected ketones and in compound 11 there exist two dis-
tinguishable ketones. The possibility of bi-directional synthesis
is available by first reacting the free ketone and then unmasking
the protected ketone or conversely protecting the free ketone,
then unmasking and reacting the protected ketone. The bicyclic
structure which results from the acetonide formation should
We recently reported the use of a lipase enzyme for the
effective desymmetrisation of prochiral ketone 4-cyano-4-
phenylcyclohexanone 1 (Scheme 1).6 The racemic enol acetate 2
Scheme 1 Reagents and conditions: i, Pseudomonas fluorescens lipase,
THF, n-BuOH; ii, isopropenyl acetate, p-TsOH.
derived from ketone 1 was resolved using Amano Pseudomonas
fluorescens lipase (PFL) to give unreacted enantiomerically
pure (100% ee) (S)-enol acetate 2 and recovered ketone 1, the
product of the lipase transesterification. Unlike most enzyme
kinetic resolutions this reaction has the advantage that the
prochiral ketone can be chemically recycled leading to greater
3382
J. Chem. Soc., Perkin Trans. 1, 2000, 3382–3388
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b005466f

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Fig. 1 New substrates for resolution by PFL-catalysed transesterifi-
cation.
Scheme 3 Reagents and conditions: i, TMSCN, ZnCl2, Et2O, rt, 18 h
(81%); ii, TBAF, THF, rt, 2 h (82%); iii, benzyl trichloroacetimidate,
TMS-triflate, Et2O, rt, 17 h (60%); iv, HCl, THF, reflux, 6 h (52%); v,
LiHMDS, Ac2O, THF, 0 ЊC, 1.5 h (81%).
Scheme 2 Potential application of enol acetate 7 to make the chiral
diketone equivalent 11 for bi-directional synthesis.
confer diastereocontrol upon subsequent nucleophilic addition
to the ketone. Substrate 8 contains the acetylene group as an
isosteric replacement for the cyano group to probe the need for
the polar nitrogen in substrate 7. Substrate 9 replaces the cyano
with a polar ester group and substrate 10 replaces the aromatic
group with the ester group.
The cyclohexanone precursors to enol esters 3–5 and 9 and
10 were readily made using a procedure similar to that pre-
viously described by Dei8 involving Michael addition of the
appropriate arylacetonitrile or activated ester to methyl acrylate
followed by Dieckmann cyclisation, hydrolysis and decarboxyl-
ation. 4-Methyl-4-phenylcyclohexanone, the precursor to enol
acetate 6, was made by reduction of 4-methyl-4-phenylcyclohex-
2-en-1-one which was prepared according to the literature.9 The
enol acetates were prepared using either acetic anhydride with a
catalytic amount of toluene-p-sulfonic acid or LiHMDS–acetic
anhydride.
The enol acetate 7 was synthesised starting from the com-
mercially available cyclohexane-1,4-dione monoethylene acetal
12 (Scheme 3). The TMS-cyanohydrin 13 was prepared in good
yield from ketone 12 using trimethylsilyl cyanide in the presence
of zinc chloride. The removal of both the TMS and acetal
protecting groups simultaneously with strong acid gave the
hydroxyketone. However all attempts to benzylate this met with
failure and so it was decided to sequentially remove the two
protecting groups, removing the acetal after benzylation of the
secondary alcohol 14. Treatment of TMS-cyanohydrin 13 with
tetra-n-butylammonium fluoride and HCl (to minimise elim-
ination of HCN; giving 12) gave alcohol 14 in good yield.
Subsequent benzylation with benzyl trichloroacetimidate and
TMS-triflate gave the benzylated acetal 15. Removal of the
acetal protecting group was achieved by stirring in refluxing
HCl to afford the ketone target 16. The corresponding enol
acetate 7 was formed in good yield using lithium hexamethyl-
disilazide–acetic anhydride.
Scheme 4 Reagents and conditions: i, TMS-acetylene, n-BuLi, THF,
Ϫ10 ЊC, 5 h (49%); ii, benzyl trichloroacetimidate, TMS-triflate, Et2O,
rt, 5 h (60%); iii, HCl, THF, reflux, 2 h (42%); iv, LiHMDS, Ac2O, THF,
0 ЊC, 1.5 h (88%); v, TBAF, THF, rt, 2 h (74%).
of the silylated compound 17 with benzyl trichloroacetimidate
followed by removal of the acetal gave the required cyclo-
hexanone 19. The low yield (42%) in the second step was
possibly caused by removal of the TMS group although the
corresponding deprotected compound was not isolated. The
enol acetate 20 was formed using LiHMDS and Ac2O in good
yield from ketone 19. The final step involved deprotection of
the TMS-acetylene moiety by stirring with TBAF in THF to
give the target enol acetate 8 in 74% yield.
The synthetic route to the enol acetate 8 was analogous to
the route used for the synthesis of enol acetate 7 (Scheme 4).
Reaction of the anion of TMS-acetylene with cyclohexane-1,4-
dione monoethylene acetal 12 in THF gave the required alcohol
17 in moderate yield. A small amount (9%) of the desilylated
acetylene was also isolated from this reaction, although the
reason for this desilylation reaction is unknown. Benzylation
Results of biotransformations
Having screened around 25 lipases with substrate 2 in the early
stages of this work we decided to use the commercially supplied
J. Chem. Soc., Perkin Trans. 1, 2000, 3382–3388
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Table 1 Biotransformation of substrates 2–10 with Pseudomonas fluorescens lipasea
Substrate
R1
R2
Solvent
Conversion to ketone (%)
Ee of enol acetate (%)
>99
E
2
3
Ph
CN
CN
CN
CN
CN
CN
CH3
CN
C2H
CO2CH3
CO2CH3
THF
THF
Toluene
THF
THF
Toluene
Hexane
THF
THF
THF
64
70
52
71
84
71
75
73
82
62
30
24
15
3,4-Cl2Ph
3,4-Cl2Ph
3,4-(MeO)2Ph
2-Pyridyl
2-Pyridyl
Ph
OBn
OBn
Ph
CN
>99
61
95
93
94
17
91
12
7
3
6.5
7.4
2.2
7
1.3
5.6
1.2
1.2
—
4
5
5
6
7
8
9
10
THF
0
a Reactions were carried out in organic solvent, 1.2 eq. n-BuOH, 100 mg of enol acetate (10 mg mlϪ1) and PFL (30 mg) at room temperature.
Ee’s determined by chiral HPLC, Chiralcel OJ and Chiralpak AD.
freeze-dried Amano PFL for all further studies with the new
substrates. Under optimised conditions the enol acetate 2 was
resolved to give enantiomerically pure enol ester (S)-2 (>99%
ee) after 67% conversion giving an enantiomeric ratio (E-value)
of 24. The 3,4-dichlorophenyl substrate 3 was resolved with
slightly reduced but satisfactory selectivity giving the enol
ester (S)-3 in >99% ee after 70% conversion to ketone (E = 15)
(Table 1). The reaction in toluene was less selective (E = 6.5).
The absolute configurations of enol acetates (S)-2 and (S)-3
were determined by X-ray crystal analysis of camphanic ester
derivatives.6,10 Substrates 4 and 5 were both resolved with
similar enantioselectivity in THF and toluene respectively
(E = 7.4 and 7). Evidently the active site of PFL can accom-
modate changes in the nature of the substitution on the phenyl
ring of the substrate without affecting the selectivity signifi-
cantly. The change in solvent requirement for optimum selec-
tivity with substrate 5 may reflect small conformational changes
in the enzyme in these solvents. We have previously shown
that enol acetates derived from 4-methyl- and 4-phenylcyclo-
hexanone did not undergo biotransformation in tetrahydro-
furan but in hexane they were poorly resolved and reaction
times were considerably longer.6
4-phenyl substrate were poorly resolved. Compound 10, con-
taining the cyano and ester groups in the 4-position was also a
poor substrate suggesting the requirement for both 4-cyano and
4-aryl substituents.
The use of chiral lithium amides for the desymmetrisation of
prochiral ketones is well developed for a number of substrate
types. A range of chiral lithium amides have been developed
which can, under appropriate conditions, give high enantio-
meric selectivity for the silyl enol ether products. As a com-
parison we have examined a limited number of asymmetric
deprotonation reactions with the prochiral ketone precursors to
the current class of substrates using the lithium amide derived
from the commercially available (S,S )-(Ϫ)-bis(α-methylbenzyl)-
amine hydrochloride (Scheme 5). Honda11 reported the asym-
Substrate 6 containing both 4-phenyl and 4-methyl groups
was transformed in hexane with very low selectivity (E = 1.3),
supporting the finding with the earlier monosubstituted
substrates that the cyano group is important for selectivity.
This substrate was not transformed in THF. Incubation of
the benzyl-protected cyanohydrin enol acetate 7, in which the
aromatic group is more remote from the chiral center, gave
comparable (E = 5.6) but slightly diminished selectivity when
compared to substrates 2 and 3–5. However, these reactions
have been run under unoptimised conditions and there is scope
for improving the selectivity for this potentially useful substrate
7 by screening other enzymes or using immobilised PFL. In
substrate 8 the 4-cyano group is replaced by the linear 4-
acetylene group which would place similar steric demands on
the enzyme active site but would lack the polarity which might
be required for binding. Indeed the considerably lower selec-
tivity (E = 1.2) with this substrate compared to substrate 7
confirms this. Earlier results showed that the rate of biotrans-
formation of substrate 2 in acetonitrile was very slow (9 days
for 62% conversion compared with 2.75–18 h in other solvents
for 60–70% conversion).6 This could result from a change in
overall conformation of the enzyme or the stripping of essential
water from the enzyme by the acetonitrile.
Scheme 5 Asymmetric deprotonation of ketones 21–23 using chiral
lithium (S,S)-bis(α-methylbenzyl)amide.
metric deprotonation of 4-phenyl-4-methylcyclohexanone 21
at Ϫ100 ЊC to give the (S)-silyl enol ether 24 in 71% ee and 81%
yield. We have carried out this reaction on the 4-cyano-4-phenyl
ketone 22 under the same conditions and obtained a slightly
lower 64% ee and 64% yield of the enol ether 25. We also
carried out asymmetric deprotonations on ketones 22 and 23
with this base at Ϫ78 ЊC with an external acetic anhydride
quench and obtained lower selectivity giving the corresponding
(R)-enol acetates 2 and 3 with 54% and 57% ee respectively.
Evidently enantioselectivities for these 4,4-disubstituted
cyclohexanones are moderate and not preparatively useful for
Substrate 9, in which the cyano is replaced with the polar
ester group, and 10 in which the aromatic is replaced with the
ester group both gave very poor (E = 1.2) or no selectivity, with
substrate 10 reacting very slowly. These results confirm the
requirement for a cyano group at the 4-position for reasonable
enantioselectivity with this enzyme. The absolute requirement
for an aromatic group at the 4-position is less clear since
substrates 6 and 9 and the previously studied monosubstituted
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J. Chem. Soc., Perkin Trans. 1, 2000, 3382–3388

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chiral synthesis using the commercially available base. As enol
esters can be regarded as enolate equivalents in the same way as
silyl enol ethers, our enzymatic resolution method provides the
best approach to obtaining these materials from this class of
ketones. We have recently scaled up the resolution of enol ester
3 (10 g) and shown application of (S)-3 in the synthesis of an
important class of tachykinin NK-2 antagonists.10 Although
the resolutions are not optimal, the product ketone is not chiral
and can be recycled, hence there is no loss of the ‘unwanted’
enantiomer normally associated with resolutions. Pseudo-
monas fluorescens lipase is commercially available in large (kg)
quantities and the reactions are run at room temperature.
For the enzyme reactions the results show the importance of
steric and electronic effects, both playing a crucial role in the
enantioselective binding and turnover of this class of substrates
with PFL. Obviously it will be important to screen more
enzymes for subtrates not well resolved by PFL which has been
used in this study. This can be readily done with the wide range
of commercially available enzymes for a substrate of specific
synthetic interest. We are currently showing synthetic appli-
cation of some of these enol acetates as outlined above in
addition to developing a one pot deracemisation strategy.
N, 5.81%) (HRMS: found Mϩ, 241.10996. C15H15NO2 requires
241.11026); νmax(Nujol)/cmϪ1 2235 (CN) and 1745 (CO); δH(300
MHz; CDCl3) 2.12 (3 H, s, AcCH3), 2.26–3.23 (6 H, m, H-3,
H-5 and H-6), 5.49 (1 H, dd, J 3.9, J 4.4, H-2) and 7.22–7.50
(5 H, m, Ar-H); δC(75 MHz, CDCl3) 20.9 (AcCH3), 24.9, 32.8,
35.6 (C-3, C-5 and C-6), 40.5 (C-4), 110.8 (C-2), 122.2 (CN),
125.7, 128.2 and 129.1 (Ar-H), 139.1 (quaternary Ar), 148.0
(C-1) and 169.2 (CO); m/z (CI) 259 (100%, [M ϩ NH4]ϩ);
m/z (EI) 241 (5%, Mϩ), 199 (53), 70 (100), 55 (23), 43 (80).
4-Cyano-4-phenyl-1-(trimethylsilyloxy)cyclohexene 25
To a stirred solution of (S,S)-(Ϫ)-bis(α-methylbenzyl)amine
hydrochloride (0.20 g, 0.76 mmol) in dry THF (50 cm3) at
Ϫ20 ЊC under argon was added n-BuLi (1.0 cm3, 1.67 mmol).
The mixture was strirred for 30 min and then cooled to Ϫ100 ЊC
whereupon TMSCl (0.06 g, 0.55 mmol) followed by ketone
1 (0.10 g, 0.55 mmol) in THF (5.0 cm3) was added. The mixture
was stirred for a further 1 h and then quenched by the addition
of ammonium chloride solution (50 cm3). Ether (50 cm3) was
added and the organic layer was washed with water (50 cm3),
dried (MgSO4) and concentrated under reduced pressure to
yield the crude product as a yellow oil, which was purified by
flash column chromatography on silica (eluent 9:1 petrol–ethyl
acetate) to give the title compound as a clear oil (0.087 g,
64%) with a 64% ee (Found: C, 70.86; H, 7.78; N, 5.11. C16H21-
NOSi requires C, 70.80; H, 7.80; N, 5.16%); νmax(neat)/cmϪ1
2238 (CN) and 1747 (CO); δH(300 MHz; CDCl3) 0.27 (9 H,
s, TMS-CH3), 2.12 (3 H, s, CH3), 2.16–2.24 (3 H, m, CH2),
2.59–2.63 (3 H, m, CH2), 4.91 (1 H, dd, J 3.0, J 4.2, H-3) and
7.22–7.56 (5 H, m, Ar-H); δC(75 MHz, CDCl3) 0.2 (TMSCH3),
27.9, 33.0 and 36.1 (C-3, C-5 and C-6), 40.8 (C-4), 100.7 (C-2),
122.6 (CN), 125.7, 127.9 and 128.9 (Ar-H), 140.0 (quaternary
Ar) and 150.4 (C-1); m/z (CI) 272 (35%, [M ϩ H]ϩ) and 90 (100,
[C3H10OSi]ϩ). HPLC Chiralpak AD, tR 9.7 min, 11.2 min, eluent
9:1 hexane–isopropyl alcohol, flow rate 1 cm3 minϪ1, λ 220 nm.
Experimental
General
Elemental microanalyses were performed in the departmental
microanalytical laboratory. NMR spectra were recorded on a
Gemini-300 (1H, 300 MHz; 13C, 75 MHz) spectrometer. Chem-
ical shifts are described in parts per million downfield shift
from SiMe4 and are reported consecutively as position (δH or
δC), relative integral, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, dd = doublet of doublets, sep = septet,
m = multiplet, and br = broad), coupling constant (J/Hz) and
assignment (numbering according to the IUPAC nomenclature
for the compound). 1H NMR spectra were referenced internally
on CHCl3 (δ 7.27), 13C NMR spectra were referenced on CDCl3
(δ 77.5). IR spectra were recorded on a Perkin-Elmer 1710 FT-
IR spectrometer. The samples were prepared as Nujol mulls
between sodium chloride discs. The frequencies (ν) as absorp-
tion maxima are given in wavenumbers (cmϪ1) relative to a
polystyrene standard. Mass spectra and accurate mass meas-
urements were recorded on a VG 70-070E, or a TRIO 1000.
Major fragments were given as percentages of the base peak
intensity (100%). Melting points were taken on a Gallenkamp
melting point apparatus and are uncorrected. Flash chrom-
atography was performed using Sorbsil C 60 (40–60 µm mesh)
silica gel. Analytical thin layer chromatography (TLC) was
carried out on 0.25 mm pre-coated silica gel plates (Macherey-
Nagel SIL g/UV254) and compounds were visualised using UV
fluorescence or permanganate. The solvents used were either
distilled or of analytical reagent quality and light petrol ether
refers to that portion boiling between 40 and 60 ЊC. THF was
dried over sodium–benzophenone and distilled under nitrogen.
Treatment of 4-cyano-4-phenylcyclohexanone with lithium
(S,S)-bis(ꢀ-methylbenzyl)amide–acetic anhydride
4-Cyano-4-phenylcyclohexanone (50 mg, 0.25 mmol) was dis-
solved in THF (3.0 cm3) and added to a solution of (S,S)-bis(α-
methylbenzyl)amine hydrochloride (65 mg, 0.25 mmol) in THF
(6.0 cm3) and n-BuLi (1.6 M, 0.31 cm3, 0.50 mmol) at Ϫ78 ЊC.
The mixture was stirred for 10 min at Ϫ78 ЊC and Ac2O (0.035
cm3, 0.37 mmol) was added. The reaction was left to warm
to room temperature over 1 h and quenched with a saturated
solution of NH4Cl before extraction with Et2O and drying over
MgSO4 to yield the enol acetate (R)-2 (30 mg) in 49% yield.
HPLC showed an enantiomeric excess of 54%. HPLC Chiralcel
OJ, tR (S)-2 33 min, (R)-2 39 min, eluent: isopropyl alcohol–
hexane (10:90), 1 cm3 minϪ1, λ 220 nm.
4-Cyano-4-(3Ј,4Ј-dichlorophenyl)cyclohex-1-enyl acetate 3
To a stirred solution of 4-cyano-4-(3Ј,4Ј-dichlorophenyl)cyclo-
hexanone (20 g, 75 mmol) in dry THF (400 ml) at Ϫ78 ЊC under
argon was added LiHMDS (97 cm3 1 M solution in THF, 97
mmol). The mixture was stirred for 15 min whereupon acetic
anhydride (10.6 cm3) was added and the mixture allowed to
warm to rt for 1 h. The reaction was quenched by the addition
of ammonium chloride solution (100 cm3) and ether was
added (200 cm3). The organic layer was washed with saturated
ammonium chloride solution (3 × 300 cm3) and brine (3 ×
300 cm3), dried (MgSO4) and concentrated under reduced
pressure to yield the crude product as a yellow oil, which was
purified by flash column chromatography on silica (eluent
2:1 hexane–diethyl ether) to give the title compound 6 as a
white solid (20.00 g, 86%); mp 153–154 ЊC (Found: C, 57.81;
H, 4.18; N, 4.48. C15H13Cl2NO2 requires C, 58.08; H, 4.22; N,
4.52%) (HRMS: found Mϩ 309.03227. C15H13Cl2NO2 requires
4-Cyano-4-phenylcyclohex-1-enyl acetate 2
To a stirred solution of 4-cyano-4-phenylcyclohexanone (0.50
g, 2.51 mmol) in dry THF (80 cm3) at 0 ЊC under an argon
atmosphere was added potassium tert-butoxide (6.0 cm3, 3.00
mmol). The mixture was stirred at 0 ЊC for 30 min whereupon
isopropenyl acetate (2.0 cm3, excess) was added and the mixture
stirred for a further 1 hour. The reaction was then quenched by
the addition of ammonium chloride solution (50 cm3) and ether
(50 cm3) was added. The organic layer was washed with water
(50 cm3), dried (MgSO4) and concentrated under reduced pres-
sure to yield the crude product as a yellow solid, which was
recrystallised from ether–hexane to give the title compound 2 as
a white crystalline solid (0.57 g, 94%); mp 104–105 ЊC (Found:
C, 74.54; H, 6.27; N, 5.78. C15H15NO2 requires C, 74.67; H, 6.26;
J. Chem. Soc., Perkin Trans. 1, 2000, 3382–3388
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309.03235); νmax(neat)/cmϪ1 2233 (CN) and 1755 (CO); δH(300
MHz, CDCl3) 2.23 (3 H, s, AcCH3), 2.23–2.67 (6 H, m, 2 × H-3,
2 × H-5 and 2 × H-6), 5.46 (1 H, s, H-2), 7.22–7.56 (3 H, Ar);
δC(75 MHz, CDCl3) 20.9 (AcCH3), 24.6, 32.7, 35.4 (C-3, C-5,
and C-6), 40.0 (C-4), 110.5 (C-2), 121.5 (CN), 125.3, 128.1 and
131.1 (C-2Ј, C-5Ј, C-6Ј), 132.8, 133.5 and 139.6 (C-1Ј, C-3Ј and
cyclohexanone (0.50 g, 2.69 mmol) to yield the crude product
as a yellow oil, which was purified by flash column chroma-
tography on silica (eluent 10:1 petrol–ethyl acetate) to give the
title compound 6 as a clear oil (HRMS: found [M ϩ NH4]ϩ,
248.16598. C15H22NO2 requires 248.16563); νmax(neat)/cmϪ1
3032 (CH) and 1742 (CO); δH(300 MHz; CDCl3) 1.32 (3 H, s,
CH3), 1.92–1.98 (2 H, m, 2 × H-5), 2.05 (3 H, s, Ac-CH3), 2.13–
2.24 (2 H, m, 2 × H-3), 2.51–2.54 (2 H, m, 2 × H-6), 5.43 (1 H,
dd, J 6.6, J 5.1, H-2) and 7.15–7.38 (5 H, m, Ar-H); δC(75 MHz;
CDCl3) 21.0 (AcCH3), 24.8, 34.9, 36.1 (C-3, C-5 and C-6), 27.9
(CH3), 36.2 (C-4), 112.8 (C-2), 125.7, 125.9 and 128.3 (Ar-H),
146.2 (quat. Ar), 148.6 (C-1) and 169.5 (CO); m/z (CI) 248
(100%, [M ϩ NH4]ϩ) and 230 (50, [M ϩ H]ϩ). HPLC Chiralcel
OJ, tR 7.8 min, 9.7 min, eluent 4:1 hexane–isopropyl alcohol,
flow rate 1 cm3 minϪ1, λ 220 nm.
C-4Ј), 148.1 (C-1), 169.3 (C᎐O); m/z (EI) 309 (3%, Mϩ), 267
᎐
(11), 70 (69), 43 (100). HPLC Chiralpak AD, tR (R)-3 15.5 min,
(S)-3 20.9 min, eluent 100% EtOH, flow rate 0.5 cm3 minϪ1
λ 220 nm.
,
Treatment of 4-cyano-4-(3Ј,4Ј-dichlorophenyl)cyclohexanone
with lithium (S,S)-bis(ꢀ-methylbenzyl)amide
The ketone (50 mg, 0.19 mmol) was treated with the chiral base
lithium (S,S)-bis(α-methylbenzyl)amide as described above to
yield the enol acetate (R)-3 (30 mg) in 54% yield. HPLC showed
an enantiomeric excess of 57%.
4-Benzyloxy-4-cyanocyclohex-1-enyl acetate 7
The enol acetate 7 was synthesised in an identical manner to
that used for the synthesis of compound 3 using the ketone 16
(0.23 g, 1.01 mmol) to yield the crude product as a yellow oil,
which was purified by flash column chromatography on silica
(eluent 5:1 petrol–ethyl acetate) to give the title compound 7 as
a yellow oil (0.22 g, 81%); mp 58.5–60.0 ЊC (HRMS: found
[M ϩ NH4]ϩ, 289.15537. C16H21N2O3 requires 289.15522);
νmax(neat)/cmϪ1 2230 (CN) and 1748 (CO); δH(300 MHz; CDCl3)
2.19 (3 H, s, AcCH3), 2.21–2.64 (6 H, m, C-3, C-5 and 2 × H-6),
4.66 (2 H, s, BnCH2), 5.26 (1 H, m, 2 × H-2) and 7.24–7.39
(5 H, m, Ar-H); δC(75 MHz; CDCl3) 23.9 (Ac-CH3), 33.8, 34.9
and 36.6 (C-3, C-5 and C-6), 67.1 (BnCH2), 72.5 (C-4), 110.0
(C-2), 126.1, 126.7 and 128.1 (Ar-H), 141.1 (quat. Ar), 149.2
(C-1) and 171.1 (CO); m/z (CI) 289 (100%, [M ϩ NH4]ϩ), 108
(10, [C7H8O]ϩ) and 91 (20, [C7H7]ϩ). HPLC Chiralcel OJ,
tR 43.1 min, 44.9 min, eluent 9:1 hexane–isopropyl alcohol,
flow rate 1 cm3 minϪ1, λ 220 nm.
4-Cyano-4-(3Ј,4Ј-dimethoxyphenyl)cyclohex-1-enyl acetate 4
4-Cyano-4-(3Ј,4Ј-dimethoxyphenyl)cyclohexanone (260 mg,
1.00 mmol) was dissolved in isopropenyl acetate (2.0 cm3, 18.10
mmol) in the presence of a catalytic amount of toluene-p-
sulfonic acid. The mixture was heated under reflux for 18 h. The
excess isopropenyl acetate was removed in vacuo. The product
was dissolved in dimethyl ether (20.0 cm3) and washed with
saturated aqueous sodium hydrogen carbonate (3 × 5.0 cm3).
The product was recrystallised from ethyl acetate to give a
white solid 4 (240 mg, 80%); Rf (ethyl acetate–hexane, 1:1)
0.36; mp 99–100 ЊC (from ethyl acetate) (Found: C, 67.8; H,
6.38; N, 4.62. C17H19NO4 requires C, 67.76, H, 6.36; N, 4.65%)
(HRMS: found Mϩ, 301.1314. C17H19NO4 requires 301.1317);
νmax(CDCl3)/cmϪ1 2255 (CN) and 1755 (CO); δH(200 MHz;
CDCl3 2.25–2.70 (6 H, m, H-3, H-5 and H-6), 3.86 and 3.89
(each 3 H, s, 2 × -OCH3), 5.46 (1 H, s, H-2), 6.82–7.03 (3 H, m,
Ar-H); δC(75 MHz; CDCl3) 20.9 (AcCH3), 24.9, 33.0 and 35.8
(C-3, C-5 and C-6), 40.0 (C-4), 56.1 and 56.0 (2 × Ar-OCH3),
109.3 (C-2), 110.9, 111.4 and 117.9 (C-2Ј, C-5Ј and C-6Ј), 122.1
(CN), 132.2 and 149.1 (C-3Ј and C-4Ј), 169.1 (CO); m/z (EI)
301 (Mϩ, 9%), 190 (10), 189 (100). HPLC Chiralpak AD, tR
13.5 min and 14.9 min, eluent 100% EtOH, flow rate 0.5 cm3
minϪ1, λ 220 nm.
4-Benzyloxy-4-trimethylsilylethynylcyclohex-1-enyl acetate 20
The enol acetate 20 was synthesised in an identical manner to
that described for enol acetate 7, using ketone 19 (0.08 g, 0.27
mmol) to give the title compound after chromatography as a
clear oil (0.08 g, 88%) (HRMS: found [M ϩ NH4]ϩ, 360.20058.
C20H30NO3Si requires 360.19950); νmax(neat)/cmϪ1 1748 (CO);
δH(300 MHz; CDCl3) 0.02 (3 H, s, TMSCH3), 1.98 (3 H, s,
AcCH3), 2.19–2.40 (3 H, m, H-3, H-5 and 2 × H-6), 4.46 (2 H, s,
BnCH2), 5.06 (1 H, dd, J 5.5, J 4.1, H-2) and 7.05–7.21 (5 H, m,
Ar-H); δC(75 MHz; CDCl3) 0.0 (TMSCH3), 21.0 (AcCH3), 24.5,
33.1 and 35.9 (C-3, C-5 and C-6), 66.3 (BnCH2), 71.5 (C-4),
90.3 (C-1Ј), 106.3 (C-2Ј), 110.1 (C-2), 127.5, 127.9 and 128.4
(Ar-H), 139.1 (quat. Ar), 147.9 (C-1) and 169.3 (CO); m/z (CI)
360 (100%, [M ϩ NH4]ϩ), 235 (80, [M ϩ H Ϫ BnOH]ϩ), 193
(65, [M ϩ H Ϫ CH2CO Ϫ BnOH]ϩ) and 91 (50, [C7H7]ϩ).
4-Cyano-4-(2Ј-pyridyl)cyclohex-1-enyl acetate 5
Enol acetate 5 was synthesised in an identical manner to that
described for compound 4, using 4-cyano-4-(2Ј-pyridyl)cyclo-
hexanone (250 mg, 1.25 mmol). The crude residue was purified
by column chromatography (eluent 1:1 ethyl ether–hexane)
to yield the product enol acetate 5 as a white solid (193 mg,
64%); Rf (ethyl acetate–hexane, 1:1) 0.46; mp 92–93 ЊC (from
ethyl acetate) (Found C, 69.31; H, 5.82; N, 11.55. C14H14-
O2N2 requires C, 69.41; H, 5.82; N, 11.56%) (HRMS: found
Mϩ, 242.1052. C14H14O2N2 requires 242.1055); νmax(neat)/cmϪ1
2238.0 (CN) and 1755 (CO); δH(200 MHz; CDCl3) 2.13 (3 H, s,
AcCH3), 2.27–3.07 (6 H, m, H-3, H-5 and H-6), 5.49 (1 H, br,
H-2), 7.24 (1 H, m, Ar-H), 7.60–7.76 (2 H, m, Ar-H), 8.58 (1 H,
d, J 4.7, H-3Ј); δC(75 MHz; CDCl3) 20.9 (AcCH3), 24.7, 31.9
and 39.9 (C-3, C-5 and C-6), 42.8 (C-4), 110.7 (C-2), 120.7,
123.0 and 137.2 (C-4Ј, C-5Ј and C-6Ј), 147.2 (C-1), 149.7 (C-3Ј),
157.9 (C-1Ј), 169.1 (CO); m/z (EI) 242 (Mϩ, 4.46%), 200
(Mϩ Ϫ C2H2O, 20.05), 199 (Mϩ Ϫ C2H3O, 100), 183 (11.74),
181 (14.70), 172 (18.41), 171 (26.37), 144 (17.03), 142 (15.25),
131 (60.44), 118 (10.99), 104 (16.41), 79 (20.05), 43 (52.47).
HPLC Chiralpak AD, tR 11.5 min and 12.5 min, eluent 100%
EtOH, flow rate 0.5 cm3 minϪ1, λ 250 nm.
4-Ethynyl-4-benzyloxycyclohex-1-enyl acetate 8
To a stirred solution of enol acetate 20 (0.09 g, 0.26 mmol) in
dry THF (10 cm3) was added TBAF (0.52 cm3, 0.52 mmol) and
the mixture was stirred at rt for 1 h, whereupon ether (40 cm3)
was added and the reaction quenched by the addition of water
(50 cm3). The organic layer was dried (MgSO4) and concen-
trated under reduced pressure to yield the crude product as a
yellow oil. The crude mixture was purified by flash column
chromatography on silica (eluent 4:1 petrol–ethyl acetate) to
give the title compound 8 as a yellow oil (0.05 g, 74%) (Found:
C, 75.81; H, 7.00. C17H18O3 requires C, 75.53; H, 6.71%);
νmax(neat)/cmϪ1 1747 (CO); δH(300 MHz; CDCl3) 2.01 (3 H, s,
AcCH3), 2.18–2.25 (3 H, m, ring-CH2), 2.41–2.47 (3 H, m, ring-
CH2), 2.55 (1H, s, H-2Ј), 4.50 (2 H, s, BnCH2), 5.12 (1 H, dd,
J 5.7, J 4.2, H-2) and 7.15–7.31 (5 H, m, Ar-H); δC(75 MHz;
CDCl3) 24.5, 33.5 and 35.3 (C-3, C-5 and C-6), 27.8 (AcCH3),
65.9 (BnCH2), 71.2 (C-4), 73.3 (C-2Ј), 90.3 (C-1Ј), 112.2 (C-2),
127.2, 127.8 and 128.8 (Ar-H), 140.0 (quat. Ar), 146.9 (C-1)
4-Methyl-4-phenylcyclohex-1-enyl acetate 6
The enol acetate 6 was synthesised in an identical manner
to that described for compound 4, using 4-methyl-4-phenyl-
3386
J. Chem. Soc., Perkin Trans. 1, 2000, 3382–3388

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and 168.8 (CO); m/z (CI) 288 (100%, [M ϩ NH4]ϩ), 162 (30,
[M ϩ H Ϫ BnOH]ϩ), and 91 (80, [C7H7]ϩ). HPLC Chiralcel OJ,
tR 8.7 min, 9.8 min, eluent 95:5 hexane–isopropyl alcohol, flow
rate 0.8 cm3 minϪ1, λ 220 nm.
C, 59.21; H, 7.28; N, 7.58. C9H13NO3 requires C, 59.00; H, 7.15;
N, 7.65%); νmax(Nujol)/cmϪ1 3267 (OH) and 2248 (CN); δH(300
MHz; CDCl3) 1.65–1.74 (4 H, m, 2 × H-7 and H-9), 1.98–2.10
(4 H, m, 2 × H-6 and H-10), 2.46 (1 H, t, J 7.27, OH) and 3.89
(4 H, s, acetal-CH2); δC(75 MHz; CDCl3) 30.5 (C-7 and C-9),
35.2 (C-6 and C-10), 64.5 (C-2 and C-3), 67.8 (C-8), 107.0
(C-5) and 121.7 (CN); m/z (CI) 201 (1%, [M ϩ NH4]ϩ), 183
(1, [M ϩ H]ϩ), 157 (50, [M ϩ H Ϫ HCN]) and 99 (100).
4-Methoxycarbonyl-4-phenylcyclohex-1-enyl acetate 9
Enol acetate 9 was synthesised in an identical manner to that
described for enol acetate 7, using the corresponding ketone
(0.12 g, 0.52 mmol) to give the title compound after chrom-
atography (eluent 6:1 petrol–ethyl acetate) as a yellow oil (0.09
g, 64%) (HRMS: found [M ϩ H]ϩ, 241.12899. C16H19O4
requires 275.12828); νmax(neat)/cmϪ1 1741 and 1750 and 1740
(CO); δH(300 MHz; CDCl3) 2.11 (3 H, s, AcCH3), 2.20–2.76
(6 H, m, 2 × H-3, 2 × H-5 and 2 × H-6), 3.56 (3 H, s, CO2CH3),
5.10–5.22 (1 H, m, H-2) and 7.17–7.30 (5 H, m, Ar-H); δC(75
MHz; CDCl3) 24.6 (AcCH3), 31.3, 32.6 and 35.4 (C-3, C-5 and
C-6), 49.7 (C-4), 52.9 (CO2CH3), 116.8 (C-2), 125.8, 127.9 and
128.4 (Ar-H), 142.0 (quat. ArC), 144.3 (C-1), 165.1 (CO2CH3)
and 168.1 (AcCO); m/z (CI) 241 (100, [M ϩ NH]ϩ). HPLC
Chiralcel OJ, tR 17.3 min, 19.2 min, eluent 9:1 hexane–
isopropyl alcohol, flow rate 1 cm3 minϪ1, λ 220 nm.
8-Benzyloxy-1,4-dioxaspiro[4.5]decane-8-carbonitrile 15
To a stirred solution of acetal 14 (0.20 g, 1.10 mmol) in dry DCM
(50.0 cm3) at 0 ЊC under argon was added benzyl trichloro-
acetimidate (0.33 cm3, 1.77 mmol) followed by trimethylsilyl
triflate (0.04 cm3, 0.20 mmol). The mixture was allowed to
warm to rt and stirred for 17 h, whereupon the reaction was
quenched by the addition of water (60 cm3). The organic layer
was dried (MgSO4) and concentrated under reduced pressure to
yield the crude product as a yellow solid, which was purified by
flash column chromatography on silica (eluent 7:1 petrol–ethyl
acetate) to give the title compound 15 as a clear oil (0.18 g, 60%)
(HRMS: found [M ϩ NH4]ϩ, 291.17104. C16H23N2O3 requires
291.17087); νmax(neat)/cmϪ1 2225 (CN); δH(300 MHz; CDCl3)
1.75–1.82 (4 H, m, 2 H-7 and H-9), 2.07–2.14 (4 H, m, 2 × H-6
and H-10), 3.96 (4 H, s, acetal-CH2), 4.67 (2 H, s, BnCH2) and
7.26–7.36 (5 H, m, Ar-H); δC(75 MHz; CDCl3) 30.3 (C-7 and
C-9), 32.6 (C-6 and C-10), 64.5 (C-2 and C-3), 67.9 (BnCH2),
73.5 (C-8), 107.0 (C-5), 119.9 (CN), 127.9, 128.1 and 128.6
(Ar-H) and 137.2 (quat. Ar); m/z (CI) 291 (100%, [M ϩ NH4]ϩ),
247 (10, [M ϩ H Ϫ HCN]ϩ), 167 (10, [M ϩ H Ϫ OBn]ϩ), 108
(5, [C7H8O]ϩ) and 91 (5, [C7H7]ϩ).
4-Cyano-4-methoxycarbonylcyclohex-1-enyl acetate 10
The enol acetate 10 was synthesised in an identical manner
to that described for enol acetate 7, using the corresponding
ketone (0.09 g, 0.50 mmol) to give the title compound after
chromatography as a clear oil (0.085 g, 77%) (HRMS: found
[M ϩ NH4]ϩ, 241.11890. C11H17N2O4 requires 241.11877);
νmax(neat)/cmϪ1 2247 (CN), 1741 and 1748 (CO); δH(300 MHz;
CDCl3) 2.01 (3 H, s, AcCH3), 2.30–3.01 (6 H, m, 2 × H-3,
2 × H-5 and 2 × H-6), 3.86 (3 H, s, CO2CH3) and 5.02–5.13
(1 H, m, H-2); δC(75 MHz; CDCl3) 24.6 (AcCH3), 30.3, 31.6
and 36.4 (C-3, C-5 and C-6), 45.7 (C-4), 52.7 (CO2CH3), 115.8
(C-2), 118.3 (CN), 147.3 (C-1), 169.1 (CO2CH3) and 170.1
(AcCO); m/z (CI) 241 (100, [M ϩ NH]ϩ). HPLC Chiralcel OJ,
tR 22.2 min, 24.7 min, eluent 4:1 hexane–isopropyl alcohol,
flow rate 1 cm3 minϪ1, λ 220 nm.
4-Benzyloxy-4-cyanocyclohexanone 16
To a stirred solution of acetal 15 (0.25 g, 0.92 mmol) in THF
(50 cm3) at rt was added 2 M HCl (30 cm3) and the mixture was
stirred for 6 h. The mixture was diluted with ether (90 cm3)
and sodium hydrogen carbonate solution (150 cm3) was added
slowly. The organic layer was washed with water (50 cm3), dried
(MgSO4) and concentrated under reduced pressure to yield the
crude product as a yellow oil, which was purified by flash col-
umn chromatography on silica (eluent 3:1 petrol–ethyl acetate)
to give the title compound 16 as a clear oil (0.11 g, 52%)
(HRMS: found [M ϩ NH4]ϩ, 247.14501. C14H19N2O2 requires
247.14462); νmax(neat)/cmϪ1 2238 (CN) and 1710 (CO); δH(300
MHz; CDCl3) 2.17–2.25 (4 H, m, 2 × H-2), 2.56–2.60 (4 H, m,
2 × H-3), 4.48 (2 H, s, BnCH2) and 7.22–7.41 (5 H, m, Ar-H);
δC(75 MHz; CDCl3) 33.7 (C-3 and C-5), 35.6 (C-2 and C-6),
67.6 (BnCH2), 71.5 (C-4), 121.9 (CN), 126.9, 128.3 and 129.2
(Ar-H), 141.6 (quat. Ar) and 201.6 (CO); m/z (CI) 247 (100%,
[M ϩ NH4]ϩ), 229 (5, [M ϩ H]ϩ), 203 (10, [M ϩ H Ϫ HCN]ϩ),
108 (55, [C7H8O]ϩ) and 91 (95, [C7H7]ϩ).
8-Trimethylsilyloxy-1,4-dioxaspiro[4.5]decane-8-carbonitrile 13
To a stirred solution of cyclohexanedione monoethylene
acetal (5.00 g, 32.05 mmol) in dry ether (200 cm3) under argon
at rt was added ZnCl2 (0.05 g, 0.36 mmol) and TMSCN (4.8
cm3, 36.0 mmol). The mixture was stirred at rt for 18 h, where-
upon the solvent was removed under reduced pressure to yield
the crude product as a yellow oil, which was purified by flash
column chromatography on silica (eluent DCM) to give the title
compound 13 as a clear oil (6.60 g, 81%) (Found: C, 56.68;
H, 8.30; N, 5.72. C12H21NO3Si requires C, 56.44; H, 8.29; N,
5.48%) (HRMS: found [M ϩ H]ϩ, 256.13725. C12H22NO3Si
requires 256.13690); νmax(neat)/cmϪ1 2246 (CN); δH(300 MHz;
CDCl3) 0.25 (9 H, s, TMSCH3), 1.77–1.86 (4 H, m, H-7 and
H-9), 2.00–2.11 (4 H, m, H-6 and H-10) and 3.94 (4 H, s, acetal-
CH2); δC(75 MHz; CDCl3) 0.2 (TMSCH3), 29.6 (C-7 and C-9),
35.5 (C-6 and C-10), 63.2 (C-2 and C-3), 67.6 (C-8), 105.8 (C-5)
and 120.7 (CN); m/z (CI) 273 (20%, [M ϩ NH4]ϩ), 256 (100,
[M ϩ H]ϩ) and 229 (50, [M ϩ H Ϫ HCN]ϩ).
8-Trimethylsilylethynyl-1,4-dioxaspiro[4.5]decan-8-ol 17
To a stirred solution of trimethylsilylacetylene (1.00 g, 10.18
mmol) in dry THF (50.0 cm3) at Ϫ10 ЊC under argon was added
LiHMDS (11.0 cm3, 11.0 mmol). The mixture was stirred for 30
min at Ϫ10 ЊC whereupon it was added via cannula to a solu-
tion of cyclohexane-1,4-dione monoethylene acetal 12 (1.60
g, 10.20 mmol) in THF (100 cm3) at Ϫ10 ЊC under argon. The
mixture was stirred for 3 h at Ϫ10 ЊC whereupon the reaction
was quenched by the addition of ammonium chloride solution
(160 cm3) and ether added (200 cm3). The organic layer was
washed with water (150 cm3), dried (MgSO4) and concentrated
under reduced pressure to yield the crude product as a yellow
oil. The crude mixture was purified by flash column chrom-
atography on silica (eluent 4:1 petrol–ethyl acetate) to give two
major components. The high running component, identified as
alcohol 17, was isolated as a clear oil (1.27 g, 49%) (HRMS:
found [M]ϩ, 254.13399. C13H22O3Si requires 254.13378);
8-Hydroxy-1,4-dioxaspiro[4.5]decane-8-carbonitrile 14
To a stirred solution of acetal 13 (2.00 g, 7.84 mmol) in dry
THF (100 cm3) at rt was added dilute HCl (0.5 cm3) and TBAF
(8.0 cm3, 8.00 mmol). The mixture was stirred at rt for 2 h
whereupon ether (100 cm3) was added followed by sodium
hydrogen carbonate solution (30 cm3). The organic layer was
washed with water (50.0 cm3), dried (MgSO4) and concentrated
under reduced pressure to yield the crude product as a brown
oil, which was purified by flash column chromatography on
silica (eluent 3:1 petrol–ethyl acetate) to give the title com-
pound 14 as a white solid (1.17 g, 82%) mp 56–58 ЊC (Found:
J. Chem. Soc., Perkin Trans. 1, 2000, 3382–3388
3387

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νmax(neat)/cmϪ1 3210 (OH); δH(300 MHz; CDCl3) 0.15 (9 H, s,
TMSCH3), 1.66–1.72 (4 H, m, 2 × H-7 and H-9), 1.75–1.82
(5 H, m, OH and 2 × H-6 and H-10) and 3.79 (4 H, s, acetal-
CH2); δC(75 MHz; CDCl3) 0.5 (TMSCH3), 31.5 (C-7 and
C-9), 37.2 (C-6 and C-10), 64.4 (acetal-CH2), 67.7 (C-8), 88.5
(C-1Ј), 108.1 (C-2Ј) and 108.9 (C-5); m/z (EI) 254 (2%, [M]ϩ),
239 (40, [M Ϫ CH3]ϩ), 226 (45, [M Ϫ C2H4]ϩ) and 181 (100,
[M Ϫ TMS]ϩ).
The lower running component, identified as the desilylated
analogue of alcohol 17, was isolated as a clear oil (0.21 g, 9%)
(HRMS: found [M ϩ H]ϩ, 183.10237. C10H15O3 requires
183.10212); νmax(neat)/cmϪ1 3227 (OH); δH(300 MHz; CDCl3)
1.79–1.83 (4 H, m, 2 × H-7 and H-9), 1.90–1.95 (4 H, m, 2 × H-6
and H-10), 2.50 (1 H, s, H-10), 2.96 (1 H, br s, OH) and 3.94
(4 H, s, acetal-CH2); δC(75 MHz; CDCl3) 31.2 (C-7 and C-9),
36.9 (C-6 and C-10), 64.2 (acetal-CH2), 66.9 (C-8), 72.0 (C-1Ј),
87.2 (C-2Ј) and 108.0 (C-5); m/z (CI) 183 (25%, [M ϩ H]ϩ) and
165 (100, [M ϩ H Ϫ H2O]ϩ).
and 128.5 (Ar-H), 139.1 (quat. Ar) and 181.0 (CO); m/z (EI)
300 (2%, [M]ϩ), 227 (5, [M Ϫ TMS]ϩ) and 91 (100, [C7H7]ϩ).
Typical biotransformation protocol
To a solution of enol acetate 2 (0.10 g, 0.41 mmol) in dry THF
(10 cm3) at 30 ЊC was added n-BuOH (0.046 cm3, 0.50 mmol)
and lipase from Pseudomonas fluorescens (30 mg). The solution
was stirred for 6 h, until 65% conversion to ketone was observed
by GC, whereupon the mixture was filtered through a Celite
pad and the enzyme washed with dimethyl ether. The filtrate
was concentrated under reduced pressure to give the crude
product as a yellow solid which was purified by flash column
chromatography on silica (eluent 5:1 petrol–ethyl acetate) to
give the enantiomerically pure enol acetate 2 as a white crystal-
line solid (29 mg, 29%); mp 100–101 ЊC; [α]D = ϩ8.52 (c = 1.76,
CHCl3).
Scale-up biotransformation procedure
The enol acetate 3 (10 g, 32.4 mmol), lipase from Pseudomonas
fluorescens (8 g) and n-BuOH (5.21 ml, 64.7 mmol) were stirred
in THF at room temperature for 9.5 h whereupon HPLC
(Chiralpak AD) indicated 100% ee for the enol acetate. tR (R)-3
15.5 min, (S)-3 20.9 min, eluent 100% EtOH, 0.5 cm3 minϪ1. The
solution was filtered through a glass sinter funnel, the residual
enzyme washed with tetrahydrofuran and the solvent removed
by evaporation under reduced pressure. The crude residue
was purified by flash column chromatography (eluent 1:2
diethyl ether–petroleum ether) to give the ketone (7 g) and
the (S)-enol acetate 3 (2.8 g, 28%) as a white solid; mp 148–
150 ЊC; [α]D = ϩ11.5 (c = 1.74, CHCl3). Other analytical data
as reported above.
8-Benzyloxy-8-trimethylsilylethynyl-1,4-dioxaspiro[4.5]decane
18
To a stirred solution of alcohol 17 (0.48 g, 1.87 mmol) in dry
ether (50.0 cm3) at 0 ЊC under argon was added benzyl
trichloroacetimidate (0.63 cm3, 2.52 mmol) followed by
trimethylsilyl triflate (0.08 cm3, 0.40 mmol). The mixture was
stirred at 0 ЊC and then allowed to warm to rt and stirred
for a further 5 h, whereupon the reaction was quenched by the
addition of water (30.0 cm3). The organic layer was dried
(MgSO4) and concentrated under reduced pressure to yield the
crude product as a yellow solid, which was purified by flash
column chromatography on silica (eluent 10:1 petrol–ethyl
acetate) to give the title compound 18 as a clear oil (0.39 g,
60%) (HRMS: found [M]ϩ, 344.18104. C20H28O3Si requires
344.18073); δH(300 MHz; CDCl3) 0.10 (3 H, s, TMSCH3), 1.58–
1.61 (4 H, m, 2 × H-7 and H-9), 1.82–1.85 (4 H, m, 2 × H-6 and
H-10), 3.78 (4 H, s, acetal-CH2), 4.40 (2 H, s, BnCH2) and 7.06–
7.20 (5 H, m, Ar-H); δC(75 MHz; CDCl3) 0.1 (TMSCH3), 31.1
(C-7 and C-9), 36.4 (C-6 and C-10), 64.5 (acetal-CH2), 66.1
(BnCH2), 68.2 (C-8), 88.7 (C-1Ј), 107.6 (C-2Ј), 108.3 (C-5),
127.4, 128.4 and 128.5 (Ar-H) and 138.1 (quat. Ar); m/z (EI)
344 (5%, [M]ϩ), 329 (10, [M Ϫ CH3]ϩ), 271 (15, [M Ϫ TMS]ϩ)
and 91 (100, [C7H7]ϩ).
Acknowledgements
We are grateful to the University of Liverpool and Pfizer Ltd
for a studentship to M. L. E. H., to the BBSRC for a PDRA
(G. A.) and to Amano Enzyme Europe Ltd for kind donation
of Pseudomonas fluorescens lipase.
References
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4-Benzyloxy-4-trimethylsilylethynylcyclohexanone 19
To a stirred solution of acetal 18 (0.11 g, 0.32 mmol) in THF
(20.0 cm3) was added 0.1 M HCl (5 cm3). The solution was
heated under reflux for 2 h, whereupon 0.1 M NaOH was added
followed by ether (50 cm3). The organic layer was washed with
water (50 cm3), dried (MgSO4) and concentrated under reduced
pressure to yield the crude product as a yellow oil. The crude
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19 as a yellow oil (0.04 g, 42%) (Found: C, 72.34; H, 7.48.
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300.15374. C18H24O2Si requires 300.15457); νmax(neat)/cmϪ1
1712 (CO); δH(300 MHz; CDCl3) 0.02 (3 H, s, TMSCH3), 1.95–
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3388
J. Chem. Soc., Perkin Trans. 1, 2000, 3382–3388