Tri- and tetrasubstituted α-fluorocyclohexanones with enantiomeric excesses in the range of 97-100%

Article abstract of DOI:10.1016/S0957-4166(01)00118-5

The α-fluorinated trisubstituted ketones (2S,5R)-(-)-7-Ia, (2R,5R)-(+)-7-IIe, (2S,5R)-(-)-8-Ia and (2R,5R)-(+)-8-IIe were synthesised from (+)-dihydrocarvone (99% (R)-configuration at C-5) and fully characterised. α-Fluorinated tetrasubstituted ketones (-)-9-Ia, (+)-9-Ia, (+)-9-IIa and (+)-10-Ia having e.e.s of ≥97% were synthesised as racemates from 3-methyl cyclo-hexenone then resolved into the pure enantiomers using chiral HPLC and fully characterised.

Full text of DOI:10.1016/S0957-4166(01)00118-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 883–891
Tri- and tetrasubstituted a-fluorocyclohexanones with
enantiomeric excesses in the range of 97–100%
Arlette Solladie´-Cavallo,a,* Lo¨ıc Jierry,a Lae¨titia Boue´rata and Philippe Taillassonb
aLaboratoire de Ste´re´ochimie Organome´tallique associe´ au CNRS, ECPM/Universite´ L. Pasteur, 25 rue Becquerel,
67087 Strasbourg, France
bSylachim-Finorga, Route de Givors, 38670 Chasse sur Rhone, France
Received 19 February 2001; accepted 8 March 2001
Abstract—The a-fluorinated trisubstituted ketones (2S,5R)-(−)-7-Ia, (2R,5R)-(+)-7-IIe, (2S,5R)-(−)-8-Ia and (2R,5R)-(+)-8-IIe
were synthesised from (+)-dihydrocarvone (99% (R)-configuration at C-5) and fully characterised. a-Fluorinated tetrasubstituted
ketones (−)-9-Ia, (+)-9-Ia, (+)-9-IIa and (+)-10-Ia having e.e.s of ]97% were synthesised as racemates from 3-methyl cyclo-
hexenone then resolved into the pure enantiomers using chiral HPLC and fully characterised. © 2001 Published by Elsevier
Science Ltd.
lectivity,9 and led to the synthesis and full characterisa-
tion of ketones 7 and 8. Ketones 9 and 10 have been
1. Introduction
Since the first use by Curci et al.1 in 1989 of trifl-
uoromethyl acetone as a dioxirane precursor for the
epoxidation of olefins, the observed activating effect of
fluorine substitution has been extended to the asymmet-
ric epoxidation of olefins and chiral ketones 1–6 have
been reported.2–7
envisaged to desymmetrise the axial face and thereby
check whether or not axial approaches to the corre-
sponding dioxiranes made significant contributions dur-
ing epoxidations.7,10
Herein, we present the synthesis of both diastereomers
of ketones 7 and 8 from commercially available (+)-
dihydrocarvone (79% (2R,5R) and 21% (2S,5R)).
Because carbon C-(5) in this natural product is 99%
(R)-configured, the desired ketones 7-Ia, 7-IIe, 8-Ia and
8-IIe will similarly have e.e.s of ]98%.
Ketones 9-Ia, 9-IIa, 10-Ia and 10-IIe, synthesised from
3-methyl cyclohexenone, were obtained in racemic
form. The most promising ketones having axial fluorine
and either axial methyl as in 9-Ia and 10-Ia or axial
phenyl as in 9-IIa, were subsequently resolved using
chiral chromatography.
2. Results and discussion
2.1. Synthesis
The observation that a fluorine atom at C-(2)7,8 and
replacement of the proton of the iso-propyl group
located at C-(5) by a halogen increased the enantiose-
As shown in Scheme 1, the 2-fluoro-2-methyl-5-(R)-
(chloro-isopropyl) cyclohexanone 7 was obtained (72%
isolated) as a 43:57 mixture of 7-Ia (43%) and 7-IIe
(57%) in three steps, from (+)-dihydrocarvone 11.
Hydrochlorination was performed following the litera-
ture procedure.11 The thermodynamic silylenolate 13
* Corresponding author. Fax: 33
ascava@ecpm.u-strasbg.fr
3
90 24 27 06; e-mail:
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00118-5

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(2R,5R)-8-IIe were obtained over the three steps, in
27% and 24% overall yield, respectively, with enan-
tiomeric purities of ]98%, identical to that of the
starting (+)-dihydrocarvone.
As shown in Scheme 2, racemic 2-fluoro-2-methyl-5-
methyl-5-phenylcyclohexanone 9 was also obtained
(61% isolated yield) as a 46/54 mixture of 9-Ia (46%)
and 9-IIa (54%) in four steps from 3-methylcyclo-
hexenone 16. Conjugate addition of phenyl Grignard
reagent was performed in the presence of CuBr/Me2S15
affording 18 in 84% isolated yield. The thermodynamic
silylenolate 20 was subsequently obtained in 90%
yield.16 Fluorination was performed with Selectfluor
analogously to the synthesis of 7 and 15. After chro-
matographic separation ( )-9-Ia (2S,5R/2R,5S) and
( )-9-IIa (2S,5S/2R,5R) were obtained in overall yields
of 28 and 33%, respectively.
( )-2-Fluoro-2-methyl-5-methyl-5-benzylcyclohexanone
10 was obtained (38% isolated) as a mixture of 10-Ia
(72%) and 10-IIe (28%) in four steps from 3-methyl-
cyclohexenone 16.
was obtained in quantitative yield after modification of
the literature work-up12 and the fluorination was per-
formed with Selectfluor according to the literature pro-
cedure.13 After chromatographic separation (2S,5R)-7-
Ia and (2R,5R)-7-IIe were obtained in 31 and 41%
overall yields, respectively, with enantiomeric excesses
of ]98%, identical to that of the starting dihydrocar-
vone.
Conjugate addition of the commercial benzyl Grignard
reagent in the presence of CuBr/Me2S15 gave, as
expected, a lower isolated yield of 53%. The thermody-
namic silylenolate 21 was obtained in quantitative yield
after modification of the literature work-up12 and
fluorination was also effected with Selectfluor. After
chromatographic separation ( )-10-Ia (2S,5S/2R,5R)
and ( )-10-IIe (2R,5S/2S,5R) were obtained with an
overall yield of 27 and 11%, respectively.
The 2-fluoro-2-methyl-5-(R)-(fluoro-iso-propyl) cyclo-
hexanone 8 was also obtained from 11 in three steps
(Scheme 1). The thermodynamic silylenolate 14 was
obtained in quantitative yield after modification of the
literature work-up12 and the fluorination, performed
with Selectfluor according to the literature procedure,13
provided a near 1:1 mixture of 15-I (51%) and 15-II
(49%) which were separated by chromatography. Fluo-
rination of the double bond was carried out on 15-I
and/or 15-II, with pyridinium hydrofluoride 70% HF
following a literature method.14 (2S,5R)-8-Ia and
2.2. Structural determination of ketones 7, 8, 9 and 10
by NMR
For all ketones full assignment of the 1H signals was
done using 2D C/H correlations, COSY and analysis of
the multiplicity.
Scheme 1.

A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 883–891
885
Scheme 2.
The well recognisable H-(6a) signals (two large cou-
fluorine atom at C-(2) is axial, it was concluded (see
Fig. 1) that in ketones 7-Ia and 8-Ia the fluorine atom
2
3
pling constants of about 11–12 Hz, a J and a J180
)
can be easily assigned in the 1H NMR spectra of
ketones 7-Ia, 7-IIe, 8-Ia and 8-IIe (Fig. 1). From our
previous results,17 which showed that the H-(6a) signal
is deshielded compared to H-(6e) signal when the
is axial (which is also supported by the JHF coupling
4
constant value of about 5 Hz as already observed17)
and that in ketones 7-IIe and 8-IIe fluorine is equato-
rial. This assignment was confirmed by NOESY experi-
Figure 1. 1H NMR 400 MHz (C6D6/TMS): AB part (CH2 at C6) of the ABX system for ketones 7-Ia, 7-IIe, 8-Ia and 8-IIe.

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A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 883–891
4
consistent with the 5 Hz value found for JHF for the
H-(6a) signal, leading to the conclusion that the
fluorine atom was axial. Thus, both 9-Ia and 9-IIa have
an axial fluorine (see Fig. 2).
ments on isomers 7-IIe and 8-IIe which exhibited, in
both cases, correlation spots between the H-(6a) multi-
plet and the doublet of the, thus axial, methyl at C-(2).
In ketones 9 and 10 the two protons at C-(6) give an
AB system having long range couplings with the
fluorine atom and assignment to H-(6a) or H-(6e) is less
obvious. A NOESY experiment on isomer 9-Ia showed
that the singlet for the C-(5) methyl group was corre-
lated with one proton at C-(6), one proton at C-(4) and
one proton at C-(3). It can thus be concluded that the
C-(5) methyl group is axial (otherwise it would have
been correlated with the two protons at C-(6) and the
two protons at C-(4) but not with any C-(3) protons),
as a consequence, the H-(6), H-(4) and H-(3) signals
were assigned to H-(6e), H-(4e) and H-(3a). Moreover,
the doublet for the C-(2) methyl group had no correla-
tion spot with H-(6a) indicating its equatorial position
and the axial position of fluorine, in accord with the
4JHF value of 5.5 Hz found for H-(6a).17 Although in
1-methyl-1-phenylcyclohexane axial phenyl orientation
is preferred by 0.32 kcal/mol,18 it appears that the
conformer having axial fluorine at C-(2) and axial
methyl at C-(5) is the most populated for diastereomer
9Ia in C6D6, probably due to the absence of syn–axial
interactions between the methyl and the carbonyl
groups and possible C-F/CꢀO hyperconjugative interac-
tions (s*.p/s.p*) favouring axial fluorine.19
The inversion of the H-(6a) and H-(6e) chemical shifts,
with H-(6a) more shielded than H-(6e) in 9-IIa, instead
of what is generally observed when the fluorine is axial,
is due to the fact that in 9-IIa H-(6e) is in the deshield-
ing cone of the phenyl ring.
A NOESY experiment on isomer 10-Ia showed that the
methyl singlet at C-(5) was correlated with one proton
at C-(6), one proton at C-(4) and one proton at C-(3).
It can thus be concluded that the C-(5) methyl is axial,
as a consequence, the H-(6), H-(4) and H-(3) signals
were assigned to H-(6e), H-(4e) and H-(3a). Moreover,
the doublet of the C-(2) methyl group had no correla-
tion spot with H-(6a) indicating its equatorial position
and the axial position of the fluorine, in accord with the
4
6 Hz value of the JHF found for H6a.
A NOESY experiment on isomer 10-IIe showed that
the methyl group at C-(5) correlated with one proton at
C-(6), one proton at C-(4) and one proton at C-(3). It
can thus be concluded that the methyl group at C-(5) is
axial. As a consequence, the H-(6), H-(4) and H-(3)
signals were assigned to H-(6e), H-(4e) and H-(3a).
Moreover, the doublet for the methyl group at C-(2)
was correlated with H-(6a) indicating its axial position
and the equatorial position of the fluorine, in accord
A differential-NOE experiment on isomer 9-Iia, irradi-
ating the C-(5) methyl group showed that this methyl
group, being correlated to the two protons at C-(6) and
the two protons at C-(4), was equatorial. Assignment of
H-(6a) was done by irradiation of H-(4a) and was
4
with the 5.5 Hz value of the JHF found for H-(6e).
It thus appeared that in the most populated conformers
in C6D6 the benzylic group is equatorial in isomers
Figure 2. 1H NMR 400 MHz (C6D6/TMS): AB system (at C-(6) methylene) for ketones 9-Ia and 9-IIa.

A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 883–891
887
4
Figure 3. NOE (from NOESY, 400 MHz, C6D6) and JHF
.
10-Ia and 10-IIe while the fluorine is axial in 10-Ia and
equatorial in 10-IIe (Fig. 3). Although from known
conformational energies (calculated for monosubstited
cyclohexane) one would expect axial benzyl,18 it is
known that deviations from additivity occur for disub-
stitution which could reverse the equilibrium and it thus
appears that the 1-methyl-1-benzyl analogue behaves
differently to the monobenzyl analogue.
4. Experimental
1H and 13C NMR spectra were recorded on a Bruker
AC 200 (200 MHz) or a Bruker Avance (400 MHz)
spectrometer with CDCl3 or C6D6 as solvent. Chemical
shifts (l) are given in ppm downfield from TMS.
Optical rotations were determined with a Perkin–Elmer
341 polarimeter. TLC was performed on Merck’s glass
plates with silica gel 60 F254. Silica gel Si 60 (40–60 mm)
from Merck was used for the chromatographic purifica-
tions. (+)-Dihydrocarvone was purchased from Fluka.
Grignard reagents in THF solution were purchased
from Aldrich.
2.3. Resolution of 9-Ia, 9-IIa and 10-Ia
Preparative resolution of ( )-9-Ia (0.500 g) was per-
formed on a (200×5, 20 mm) Chiralpak AD column
through 20 injections of 0.025 g using heptane/ethanol
(98.5/1.5) as mobile phase (5 mL/min). Detection, 210–
550 nm. Two samples were obtained: (9-Ia)-1, rt=4.7
min; 0.150 g, e.e.=99.1%; [h]D=−55 (c=1.02, CHCl3)
and (9-Ia)-2, rt=5.8 min; 0.150 g, e.e.=100%; [h]D=+
56 (c=1.03, CHCl3).
4.1. 3,6-Dimethylcyclohexenone 17
Compound 17 was prepared by methylation of 3-
methylcyclohexen-1-one following a known literature
procedure.20 Isolated as a colourless oil; Rf=0.48 (hex-
1
ane/ether, 1:1); H NMR (CDCl3, 400 MHz): l 1.14 (d,
3J=6.5 Hz, 3H, CH3), 1.72 (m, 1H), 1.94 (s, 3H, CH3),
Preparative resolution of ( )-9-IIa (0.600 g) was per-
formed on a (250×5, 20 mm) Chiralcel OD column
through 25 injections of 0.024 g using MeOH/H2O
(90/10) as mobile phase (100 mL/min). Detection, 210
nm. Two samples were obtained: (9-IIa)-1, rt=6.9 min;
0.270 g, e.e.=91.8%; [h]D=−13.5 (c=1.1, CHCl3) and
(9-IIa)-2, rt=8.4 min; 0.180 g, e.e. =97%; [h]D=+16
(c=1.05, CHCl3).
2
3
2.06 (qt, J=12 Hz, J=3J=3J=4 Hz, 1H, H5e), 2.32
(m, 3H, H4a, H4e and H6), 5.85 (s, 1H). 13C NMR
(CDCl3, 100 MHz): l 15.5, 24.6, 31.0, 31.1, 40.8, 126.6,
161.9, 202.5. IR (CHCl3): wCꢀO, wC=C=1660 (broad,
strong) cm−1.
4.2. General procedure for Grignard addition
Preparative resolution of ( )-10-Ia (0.900 g) was per-
formed on a (250×20, 5 mm) Chirose C1 column
through three injections of 0.250, 0.300 and 0.350 g
using heptane/CHCl3 (90/10) as mobile phase (10 mL/
min). Detection, 254 nm. Two samples were obtained:
(10-Ia)-1, rt=11.4 min; 0.290 g, e.e.=100%; [h]D=+4
(c=1, CHCl3) and (10-Ia)-2, rt=12.5 min; 0.096 g,
e.e.=91%; [h]D=−3.5 (c=1, CHCl3). Three other sam-
ples having lower e.e. have been obtained (0.350 g).
To a stirred suspension of CuBr:S(Me)2 (0.12 equiv.) in
anhydrous THF (0.75 mL for 75 mg) under argon, was
added at −20°C a solution of 3,6-dimethylcyclohexen-1-
one (1 equiv.) in THF (0.6 mL for 400 mg). A 2 M
solution of the desired Grignard in THF (1.4 equiv.)
was then added dropwise. After stirring at −20°C for 3
h, the reaction mixture was poured into a cold solution
of hydrochloric acid 2N and ice (4 mL) and extracted
with ether (4×6 mL). The combined organic phases
were dried over Na2SO4 and concentrated. The crude
product was purified by column chromatography.
3. Conclusion
In conclusion, a-fluorinated ketones trisubstituted,
(2S,5R)-(−)-7-Ia, (2R,5R)-(+)-7-IIe, (2S,5R)-(−)-8-Ia
and (2R,5R)-(+)-8-IIe, as well as tetrasubstituted, (−)-9-
Ia, (+)-9-Ia, (+)-9-IIa and (+)-10-Ia, having e.e. of
]97% were obtained and fully characterised.
4.3. 2,5-Dimethyl-5-phenylcyclohexanone 18
Eluent: pentane/Et2O (100/0–85/15), colourless oil,
1
84%, two diastereomers, I/II=86/14. H NMR (CDCl3,
3
400 MHz): I (major), l 0.96 (d, J=6.5 Hz, 3H, CH3),

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A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 883–891
2
1.14 (qd, J=3Jaa=3Jaa=13 Hz,3Jae=3 Hz, s,1H, H3a),
(CH3), 32.7 (CH2), 48.1 (CH), 74.1 (Cq), 111.9 (Cq),
142.3 (Cq).
2
3
1.38 (s, 3H, CH3), 1.87 (ddt, J=13 Hz, Jee=6 Hz,
3Jea=3Jea=3.5 Hz, 1H, H3e), 1.97 (td, 2J=3Jaa=13 Hz,
3Jae=3.5 Hz, 1H, H4a), 2.35 (m, 2H), 2.42 (dd, J=
4.7. (5R)-(+)-(5-Iso-propenyl-2-methyl-cyclohexenyloxy)-
trimethylsilane, 14
2
4
2
14.5 Hz, J=1 Hz, 1H, H6e), 3.06 (dd, J=14.5 Hz,
4J=3 Hz, 1H, H6a), 7.20 (m, 1H, Harom.), 7.35 (m,
4H, Harom.). II (minor): overlapped with I but l 1.12
Colourless liquid, [h]2D0=+72 (c=1.0, CHCl3); 1H NMR
(CDCl3, 400 MHz): l 0.18 (s, 9H, 3MeSi), 1.39 (qd,
3
(d, J=6.5 Hz, 3H, CH3), 1.26 (s, 3H, CH3), 2.10 (m,
3H), 2.60 (A from ABX, JAB=13 Hz, JAX=2.5 Hz,
2
3
3
2J=3Jaa=3Jaa=12 Hz, Jae=5.5 Hz, 1H, H4a), 1.57 (s,
2
1H, H6a), 2.75 (B from ABX, JAB=13 Hz, 1H, H6e).
3H, Me), 1.74–1.75 (s, 3H, Me and m, 1H), 2.02 (m,
4H), 2.23 (m, 1H), 4.72 (bs, 2H); 13C NMR (CDCl3,
100 MHz): l 1.1 (3CH3Si), 16.5, 21.2, 28.3 (CH2), 30.5
(CH2), 36.0 (CH2), 42.8, 109.1 (CH2), 111.7 (Cq), 142.7
(Cq), 149.8 (CO). IR (CHCl3): wC-H=3050, 2900, wC=
C=1690 cm−1.
13C NMR (CDCl3, 100 MHz), I: l 14.8 (CH3), 31.2
(CH2), 33.6 (CH3), 39.1 (CH2), 44.5 (CH), 45.0 (Cq),
52.7 (CH2), 126.6 (CHarom.), 128.6 (CHarom.), 146.7
(Cq), 212.9 (CO). II: l 15.0 (CH3), 26.2 (CH3), 31.8
(CH2), 37.5 (CH2), 43.4 (Cq), 44.8 (CH), 53.5 (CH2),
125.3 (CHarom.), 126.6 (CHarom.), 149.6 (Cq), 213.2
(CO).
4.8. ( )-(2,5-Dimethyl-5-phenyl-cyclohexenyloxy)-
trimethylsilane 20
4.4. 2,5-Dimethyl-5-benzylcyclohexanone 19
1
Colourless oil, H NMR (CDCl3, 400 MHz): l 0.23 (s,
Eluent: pentane/Et2O (9/1), colourless oil, 53%, two
diastereomers, I/II=66/34. 1H NMR (CDCl3, 400
9H, 3CH3Si), 1.30 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.75
(m, 1H), 1.87 (m, 2H), 2.30 (m, 1H), 2.15 (A from AB,
3
2
MHz), I (major): l 0.95 (s, 3H, CH3), 1.11 (d, J=6.5
2JAB=16.5 Hz, 1H, H6), 2.49 (B from AB, JAB=16.5
Hz, 3H, CH3), 1.70 (m, 3H), 2.08 (m, 1H), 2.15 (A from
Hz, 1H, H6), 7.20 (m, 1H, Harom.), 7.35 (m, 4H,
2
2
ABX, JAB=13 Hz, 1H), 2.33 (B from ABX, JAB=13
Harom.); 13C NMR (CDCl3, 100 MHz):
l 1.2
4
Hz, JHF=2 Hz, 1H), 2.42 (m, 1H), 2.47 (A from AB,
(3CH3Si), 16.4 (CH3), 28.1 (CH3), 28.1 (CH2-4), 35.2
(CH2-3), 38.5 (Cq), 43.1 (CH2-6), 111.2 (Cq), 125.9
(CHarom.), 126.1 (CHarom.), 128.5 (CHarom.), 142.0
(Cq), 149.8 (Cq).
2JAB=13.5 Hz, 1H), 2.55 (B from AB, JAB=13.5 Hz,
2
1H), 7.16 (m, 2H, Harom.), 7.30 (m, 3H, Harom.). II
(minor), signals overlapped with I but: l 0.88 (s, 3H,
CH3), 1.01 (d, 3J=6.5 Hz, 3H, CH3), 1.56 (m, 2H,
2
CH2), 2.01 (m, 1H), 2.63 (AB, JAB=12 Hz, 2H). 13C
4.9. ( )-(5-Benzyl-2,5-dimethyl-cyclohexenyloxy)-
trimethylsilane 21
NMR (CDCl3, 100 MHz), I: l 15.1 (CH3), 28.3 (CH3),
31.6 (CH2), 36.4 (CH2), 41.1 (Cq), 44.3 (CH2), 44.8
(CH), 52.8 (CH2), 126.5 (CH arom.), 128.3 (CH arom.),
131.1 (CH arom.) 138.3 (Cq), 213.9 (CO). II: l 14.7
(CH3), 23.7 (CH3), 31.7 (CH2), 36.3 (CH2), 40.9 (Cq),
44.8 (CH), 51.1 (CH2), 53.2 (CH2), 126.7 (CH arom.),
128.3 (CH arom.), 131.1 (CH arom.) 137.9 (Cq arom),
213.6 (CO). IR (CHCl3), I and II: wCꢀO=1705 cm−1.
1
Colourless oil, H NMR (CDCl3, 400 MHz): l 0.19 (s,
9H, 3CH3Si), 0.89 (s, 3H, CH32), 1.38 (m, 2H), 1.59 (s,
3H, CH3), 1.70 (A from AB, JAB=15 Hz, 1H), 2.03
(bm, 2H overlapped with B of AB, 1H), 2.58 (s, 2H),
7.17 (m, 2H, Harom.), 7.23 (m, 1H, Harom.), 7.30 (m,
2H, Harom.); 13C NMR (CDCl3, 100 MHz): l 1.2
(3CH3), 16.4 (CH3), 24.5 (CH3), 27.9 (CH2), 33.8 (CH3),
35.2 (Cq), 42.8 (CH2), 48.7 (CH2), 110.5 (Cq), 126.3
(CHarom.), 128.1 (CHarom.), 131.1 (CHarom.), 139.2
(Cq), 142.0 (Cq).
4.5. General procedure for the preparation of silylenol
ethers
To a solution of the desired ketone (1 equiv.) in dry
pentane (7 mL for 9 mmol) was added, under argon,
NEt3 (2 equiv.), TMSCl (2 equiv.) followed by a solu-
tion of anhydrous NaI (2 equiv.) in dry CH3CN (20
mL).12 After stirring for 3–4 h at room temperature,
stirring was stopped and the upper organic layer (pen-
tane) transferred into a dry flask. The remaining mix-
ture was extracted with dry pentane until no trace of
silylenol ether was detected by TLC.12 The pentane
phases were gathered and evaporated to afford a
colourless oil, pure by NMR analysis.
4.10. General procedure for fluorination reactions with
Selectfluor
To a solution of the desired silylenol ether (1 equiv.) in
dry DMF (25 mL for 7 mmol) was added dropwise,
under argon, a solution of Selectfluor (1.4 equiv.) in
DMF (40 mL). The mixture was stirred at 0°C for 2 h.
Then water (50 mL) and ether (50 mL) was poured into
the reaction mixture, the phases were separated and the
aqueous phase extracted with ether (3×100 mL). The
organic phases were dried over MgSO4. After filtration
and evaporation, the residue (containing DMF) was
directly purified by column chromatography with an
appropriate pentane/ether gradient.
4.6. (5R)-(+)-[5-(1-Chloro-1-methyl-ethyl)-2-methylcyclo-
hexenyloxy]-trimethylsilane 13
Colourless liquid, [h]2D0=+61.5 (c=1.1, CHCl3); 1H
NMR (CDCl3, 200 MHz): l 0.20 (s, 9H, MeSi), 1.32
(m, 1H), 1.55 (s, 6H, 2 Me), 1.58 (s, 3H, Me), 1.98 (m,
6H); 13C NMR (CDCl3, 100 MHz): l 1.1 (3CH3Si),
16.4 (CH3), 25.2 (CH2), 30.5 (CH2), 30.55 (CH3), 30.9
4.11. ( )-2-Fluoro-2,5-dimethyl-5-phenylcyclohexanone 9
A colourless oil, 92%, two racemic diastereomers, 9-Ia/
9-IIa=46/54. After separation: 9-Ia (minor): Anal.

A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 883–891
889
calcd for C14H17FO: C, 76.33; H, 7.78. Found: C,
75.96; H, 7.26. Rf=0.17 (pentane/ether, 95/5); 1H
NMR (C6D6, 400 MHz): l 0.93 (s, 3H, Me), 1.30 (d,
3JHF=22 Hz, 3H, Me), 1.37 (m, 1H, H4e), 1.41 (dddd,
49.8 (CH2Ph), 95.6 (d, 1JCF=173 Hz, Cq-2), 126.4
(CHarom.), 128.2 (CHarom.), 130.9 (CHarom.), 137.5
(Cq), 205.9 (d, 2JCF=23.5 Hz, CO). IR (CHCl3):
wCꢀO=1735 cm−1. Resolution by preparative HPLC on
Chirose C1 5 mm (250×20); 90% heptane+10% CHCl3;
10 mL/min: rt of 10-Ia-(+)=11.4 min; 100% e.e.,
[h]2D0=+4 (c=1, CHCl3) and rt of 10-Ia-(−) =12.5
min, 91% e.e., [h]2D0=−3.2 (c=1, CHCl3).
3
3
3
2J=15 Hz, JHF=31 Hz, Jaa=11.5 Hz, Jae=4.5 Hz,
2
3
3
1H, H3a), 1.76 (ddt, J=15 Hz, JHF2=12.5 Hz, Jea=
3Jae=4.5 Hz, 1H, H3e), 2.08 (ddd, J=15 Hz, Jaa=
3
3
2
11.5 Hz, Jae=4.5 Hz, 1H, H4a), 2.25 (dd, J=13 Hz,
4JHF=1.5 Hz, 1H, H6e), 3.09 (dd, J=13 Hz, JHF
=
2
4
5.5 Hz, 1H, H6a), 7–7.2 (m, 5H, Harom.); 13C NMR
Compound 10-IIe (minor): colourless oil. Anal. calcd
2
(C6D6, 100 MHz): l 20.8 (d, JCF=24 Hz, CH3), 26.4
(CH3), 33.9 (d, JCF=4 Hz, CH2-4), 35.3 (d, JCF=23
Hz, CH2-3), 43.0 (Cq), 49.8 (CH2-6), 95.4 (d, JCF
for C15H19FO: C, 76.89; H, 8.17. Found: C, 77.13; H,
3
2
1
8.28. Rf=0.25 (benzene); H NMR (C6D6, 400 MHz):
1
=
3
l 0.61 (s, 3H, Me), 1.10 (m, 1H, H4a), 1.24 (d, JHF
=
175 Hz, Cq-2), 125.4 (CHarom.), 126.6 (CHarom.),
24 Hz, 3H, Me), 1.48 (m, 1H, H4e), 1.55 (m, 1H,
H3e), 1.80 (m, 1H, H3a), 2.09 (A from ABX over-
lapped with A from AB, 2H, H6a and H), 2.24 (B
from AB, 2JAB=13 Hz, 1H), 2.34 (B from ABX,
2JAB=13 Hz, 4JHF=5.5 Hz, 1H, H6e), 6.95 (m, 2H,
Harom.), 7.10 (m, 3H, Harom.). 13C NMR (C6D6, 100
2
128.8 (CHarom.), 148.2 (Cq), 205.6 (d, JCF=23 Hz,
CO). IR (CHCl3): wCꢀO=1730 cm−1. Resolution by
preparative HPLC: Chiralpak AD 20 mm (25×200);
98.5% heptane+1.5% EtOH; 30°C; 5.0 mL/min: rt of
9-Ia-(−)=4.7 min; 99.1% e.e., [h]2D0=−55 (c=1.02,
CHCl3) and rt of 9-Ia-(+)=5.8 min; 100% e.e., [h]2D0=
+56 (c=1.03, CHCl3).
2
MHz): l 21.1 (d, JCF=24 Hz, CH3), 26.3 (CH3), 32.8
3
2
(d, JCF=5 Hz, CH2-4), 35.1 (d, JCF=23 Hz, CH2-3),
40.4 (Cq-5), 45.5 (CH2Ph), 46.2 (CH2-6), 95.6 (d,
1JCF=177 Hz, Cq-2), 126.7 (CHarom.), 131.0
(CHarom.), 131.2 (CHarom.), 137.8 (Cq), 206.0 (d,
2JCF=21 Hz, CO). IR (CHCl3): wCꢀO=1735 cm−1.
Compound 9-IIa (major): colourless oil. Anal. calcd
for C14H17FO: C, 76.33; H, 7.78. Found: C, 76.46; H,
1
7.37. Rf=0.31 (pentane/ether, 95/5); H NMR (C6D6,
3
400 MHz): l 0.97 (s, 3H, Me), 1.14 (d, JHF=22 Hz,
3H, Me), 1.23 (m, 1H, H3a), 1.70 (m, 1H, H4e), 1.71
(m, 1H, H3e), 1.89 (m, 1H, H4a), 2.65 (A from ABX,
2JAB=14 Hz, 4JHF=5 Hz, 1H, H6a), 2.77 (B from
4.13. 2-Fluoro-5-iso-propenyl-2-methylcyclohexanone 15
2
4
A colourless liquid; 67%, two diastereomers, 15I/
15II=51/49. After separation, 15I-(−)-(2S,5R): Anal.
calcd for C10H15FO: C, 70.49; H, 8.81. Found: C, 69.
85; H, 8.74. [h]2D0=−3 (c=1.0, CHCl3); 1H NMR
ABX, JAB=14 Hz, JHF=2 Hz, 1H, H6e), 7.00 (m,
1H, Harom.), 7.1–7.2 (m, 1H, Harom.); 13C NMR
2
(C6D6, 100 MHz): l 20.5 (d, JCF=24 Hz, CH32), 32.3
(CH3), 33.9 (d, 3JCF=3 Hz, CH2-4), 35.2 (d, JCF
=
2
3
22.5 Hz, CH2-3), 43.8 (Cq), 49.1 (CH2-6), 95.0 (d,
1JCF=173 Hz, Cq-2), 126.2 (CHarom.), 126.6
(CHarom.), 128.0 (CHarom.), 146.0 (Cq), 204.4 (d,
2JCF=22 Hz, CO). IR (CHCl3): wCꢀO=1730 cm−1.
(C6D6, 400 MHz): l 1.03 (dddd, J=15 Hz, JHF=39
3
3
Hz, Jaa=13.5 Hz, Jae=4.5 Hz, 1H, H3a), 1.23 (bd,
2J=13.5 Hz, 1H, H4e), 1.31 (d, 3JHF=22 Hz, 3H,
Me), 1.42 (s, 3H, Me), 1.72 (qd, J=3Jaa=3Jaa=13.5
2
3
3
Hz, Jae=4 Hz, 1H, H4a), 1.82 (ddt, Jaa=13.5 Hz,
3Jaa=13 Hz, Jae=3Jae=3.5 Hz, 1H, H5), 1.93 (bt,
3
Resolution by preparative HPLC: Chiralcel OD 20 mm
(250×5); 90% MeOH+10% H2O; 0°C; 100 mL/min
Detection, 210 nm: rt of 9-IIa-(−)=6.9 min; 91.8%
e.e., [h]2D0=−13.5 (c=1.1, CHCl3) and rt of 9-IIa-(+)=
8.4 min; 97% e.e., [h]2D0=+16 (c=1.05, CHCl3).
2J=3JHF=15 Hz, 1H, H3e), 2.29 (d, J=13 Hz, 1H,
2
H6e), 2.72 (td, 2J=3Jaa=13 Hz, 4JHF=6 Hz, 1H,
H6a), 4.59 (bs, 1H), 4.63 (bs, 1H). 13C NMR (C6D6,
2
100 MHz): l 20.2 (CH3), 20.4 (d, JCF=24 Hz, CH3),
3
2
26.1 (d, JCF=2 Hz, CH2-4), 38.3 (d, JCF=22.5 Hz,
CH2-3), 43.5 (d, 3JCF=2.5 Hz, CH2-6), 46.9 (CH-5),
4.12. ( )-2-Fluoro-2,5-dimethyl-5-benzylcyclohexanone,
10
1
95.6 (d, JCF=172 Hz, Cq-2), 110.5 (CH2), 147.1 (Cq),
205.6 (d, 2JCF=24.5 Hz, CO). IR (CHCl3): wCꢀO
1700, wCꢀC=1610 cm−1.
=
A colourless oil; 83%, two racemic diastereomers, 10-
Ia/10-IIe=72/28. After separation, 10-Ia (major):
Anal. calcd for C15H19FO: C, 76.89; H, 8.17. Found:
C, 77.11; H, 7.72. Rf=0.41 (benzene); 1H NMR
Compound 15II-(+)-(2R,5R): [h]2D0=+103 (c=1.0,
1
CHCl3); H NMR (C6D6, 400 MHz): l 1.11–1.15 (m,
2
1H, H4 overlapped with d, 3JHF=22 Hz, 3H, Me),
(C6D6, 400 MHz): l 0.56 (s, 3H, Me), 0.93 (bd, J=
12.5 Hz, 1H, H4e), 1.27 (d, 3JHF=22 Hz, 3H, Me),
1.37 (s, 3H, Me), 1.48 (m, 1H, H4), 1.64 (m, 2H, H3),
2
3
3
1.32 (dddd, 2J=12 Hz, 3JHF=35 Hz, Jaa=14 Hz,
1.86 (m, 1H, H5), 2.08 (dd, J=13.5 Hz, Jaa=10 Hz,
1H, H6a), 2.41 (dtd, J=13.5 Hz, Jea=4JHF=4.5 Hz,
2
3
3Jae=5 Hz, 1H, H3a), 1.75 (m, 2H, H3e and H4a),
1.90 (A from ABX, JAB=12.5 Hz, 4JHF=1 Hz, 1H,
H6e), 2.24 (AB system, JAB4=13 Hz, 2H, H9), 2.67 (B
from ABX, JAB=12.5 Hz, JHF=6 Hz, 1H, H6a), 6.86
(m, 2H, H aromatic), 7.11 (m, 3H, H aromatic); 13C
NMR (C6D6, 100 MHz): l 20.6 (d, 2JCF=24 Hz,
4J=2 Hz, 1H, H6e), 4.55 (bs, 1H), 4.65 (bs, 1H). 13C
2
NMR (C6D6, 100 MHz): l 20.9 (CH3), 21.9 (d, JCF
=
3
25.5 Hz, CH3), 26.8 (d, JCF=8.5 Hz, CH2-4), 37.2 (d,
2JCF=22 Hz, CH2-3), 43.6 (CH2-6), 44.7 (CH-5), 96.0
(d, 1JCF=182.5 Hz, Cq-2), 110.9 (CH2), 146.5 (Cq),
2
3
204.8 (d, JCF=18 Hz, CO). IR (CHCl3): wCꢀO=1735,
CH3), 22.7 (CH3), 32.1 (d, JCF=3 Hz, CH2-4), 35.1
(d, 2JCF=23 Hz, CH2-3), 40.3 (Cq-5), 49.7 (CH2-6),
wCꢀC=1650 cm−1.

890
A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 883–891
Compound 8-IIe-(+)-(2R,5R) (from 15II): white solid,
mp=65°C. Anal. calcd for C10H16F2O: C, 63.49; H,
8.45. Found: C, 63.04; H, 8.08. [h]2D0=+134 (c=0.3,
CHCl3); 1H NMR (C6D6, 400 MHz): l 0.88 (d,
3JHF=21.5 Hz, 3H, CH3), 0.89 (d, 3JHF=21.5 Hz,
3H, CH3), 1.03 (qm, 3JHF=3Jaa=3Jaa=15 Hz, 1H,
4.14. 5-(1-Chloro-1-methyl-ethyl)-2-fluoro-2-methyl-
cyclohexanone, 7
A colourless liquid; 80%, two diastereomers, 7-Ia/7-
IIe=43/57. Anal. calcd for C10H16ClFO: C, 58.91; H,
7.74. Found: C, 57.79; H, 7.51. After separation, 7-
3
1
Ia-(2S,5R)-(−): [h]2D0= −3 (c=1.0, CHCl3); H NMR
H5), 1.12 (d, JHF=21.5 Hz, 3H, Me), 1.36 (m, 2H,
H4a and H4e), 1.59 (qd, 2J=3JHF=3Jaa=13.5 Hz,
3Jae=4 Hz, 1H, H3a), 1.69 (m, 1H, H3e), 1.92 (t,
2J=3Jaa=14 Hz, 1H, H6a), 2.36 (dtd, 2J=14 Hz, 3Jae=
4JHF=4 Hz, 4JHF=2.5 Hz, 1H, H6e); 13C NMR
2
3
(C6D6, 400 MHz): l 0.93 (dddd, J=15 Hz, JHF=40
3
3
Hz, Jaa=13.5 Hz, Jae=4 Hz, 1H, H3a), 1.14 (s, 3H,
CH3), 1.15 (s, 3H, CH3), 1.32 (d, 3JHF=22 Hz, 3H,
Me), 1.38 and 1.43 (m, 2H, H4e and H5), 1.71 (qd,
2
(C6D6, 100 MHz): l 22.1 (d, JCF=26 Hz, CH3), 23.5
2J=3Jaa=3Jaa=13.5 Hz, Jae=4 Hz, 1H, H4a), 1.81
3
(d, 3JCF=4.5 Hz, 3JCF=10 Hz, CH2-4), 24.5 (d,
2
2
(m, 1H, H3e), 2.45 (bd, J=13 Hz, H6e), 2.67 (td, J=
2
2JCF=25 Hz, CH3), 24.6 (d, JCF=25 Hz, CH3), 37.4
3Jaa=13 Hz, 4JHF=6 Hz, 1H, H6a); 13C NMR
2
3
(d, JCF=21.5 Hz, CH2-3), 40.1 (d, JCF=5 Hz, CH2
2
(C6D6, 100 MHz): l 20.1 (d, JCF=24 Hz, CH3), 22.3
(d, JCF=2 Hz, CH2-4), 30.0 (CH3), 30.3 (CH3), 37.4
(d, JCF=23 Hz, CH2-3), 40.3 (d, JCF=2.5 Hz, CH2-
6), 51.3 (CH-5), 72.1 (Cq), 95.0 (d, 1JCF=172 Hz,
Cq-2), 205.3 (d, 2JCF=25 Hz, CO). IR (CHCl3):
wCꢀO=1715 cm−1.
2
1
-6), 47.1 (d, JCF=22.5 Hz, CH-5), 95.2 (d, JCF2=170
3
1
Hz, Cq), 95.9 (d, JCF=185 Hz, Cq), 204.6 (d, JCF
=
2
3
16.5 Hz, CO). IR (CHCl3): wCꢀO=1730 cm−1.
Acknowledgements
Compound 7-IIe-(+)-(2R,5R): white solid, mp=49°C;
[h]2D0=+73 (c=1.0, CHCl3); 1H NMR (C6D6, 400
MHz): l 1.06 (s, 3H, CH3), 1.10 (s, 3H, CH3), 1.14
(d, 3JHF=21.5 Hz, 3H, Me), 1.21 (m, 2H, H5 and
H4a), 1.40 (m, 1H, H4e), 1.58 (qd, 2J=3JHF=3Jaa=
Dr. A. Wick, President of Sylachim-Finorga, is grate-
fully acknowledged for financial support. This work
was also supported by the MENRT-France with
grants to L. Boue´rat and L. Jierry. M. M. Schmitt
(ECPM) is acknowledged for the 2D NMR studies.
3
13 Hz, Jae=4 Hz, 1H, H3a), 1.66 (dq, 2J=13 Hz,
3
2
3Jea=3Jea= Jee=3 Hz, 1H, H3e), 2.10 (dd, JHH=14
3
2
Hz, Jaa=12.5 Hz, 1H, H6a), 2.39 (qd, JHH=14 Hz,
4JHF=3Jea=4JH6eH4=3 Hz, 1H, H6e); 13C NMR
2
(C6D6, 100 MHz): l 22.1 (d, JCF=26 Hz, CH3), 24.3
(d, JCF=10 Hz, CH2-4), 30.6 (CH3), 30.8 (CH3), 36.9
(d, JCF=22 Hz, CH2-3), 41.5 (d, JCF=1.5 Hz, CH2
-6), 49.6 (CH-5), 72.2 (Cq), 95.8 (d, JCF=186.5 Hz,
3
References
2
3
1
1. Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J. Am.
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2. Curci, R.; D’Alccolti, L.; Fiorentino, M.; Rosa, A. Tetra-
Cq-2), 204.7 (d, 2JCF=16 Hz, CO). IR (CHCl3):
wCꢀO=1715 cm−1.
hedron Lett. 1995, 36, 5831.
3. Brown, D. S.; Marples, B. A.; Smitt, P.; Walton, L.
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11. cf. Supplementary material of Ref. 9.
12. No addition of water. CH3CN was extracted with pen-
tane and the extraction monitored by TLC. Moreover
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4.15. 5-(1-Fluoro-1-methyl-ethyl)-2-fluoro-2-methylcyclo-
hexanone 8
Hydrofluorination was completed following a litera-
ture procedure.14
Compound 8-Ia-(−)-(2S,5R)- (from 15I): colourless
liquid; [h]2D0=−10 (c=1.0, CHCl3); 1H NMR (C6D6,
3
400 MHz): l 0.93 (d, JHF=21.5 Hz, 3H, CH3), 0.94
3
2
(d, JHF=21.5 Hz, 3H, CH3), 0.95 (dddd, J=15 Hz,
3JHF=40 Hz, Jaa=13 Hz, Jae=4.5 Hz, 1H, H3a),
1.26 (m, 1H, H4e) overlapped with 1.30 (d, JHF=22
3
3
3
Hz, 3H, Me), 1.50 (bq, 1H, H5) overlapped with 1.56
3
(qd, 2J=3Jaa=3Jaa=13 Hz, Jea=3.5 Hz, 1H, H4a),
3
1.81 (ddt, 2J=15 Hz, 3J=10 Hz, Jea=3Jee=3.5 Hz,
1H, H3e), 2.37 (bd, 2J=13 Hz, 1H, H6e), 2.54 (td,
2J=3Jaa=13 Hz, 4JHF=6 Hz, 1H, H6a); 13C NMR
(C6D6, 100 MHz): l 20.2 (d, 2JCF=23.5 Hz, CH3),
3
3
21.5 (dd, JCF=5.5 Hz, JCF=2 Hz, CH2-4), 24.1 (d,
2JCF=25 Hz, CH3), 24.2 (d, JCF=25 Hz, CH3), 37.9
2
(d, 2JCF=23 Hz, CH2-3), 39.5 (dd, 3JCF=5.5 Hz,
3JCF=2 Hz, CH2-6), 48.8 (d, 2JCF=23 Hz, CH-5),
95.4 (d, 1JCF=171 Hz, Cq-2 and Cq), 205.3 (d,
2JCF=25 Hz, CO). IR (CHCl3): wCꢀO=1730 cm−1.
14. Mass, D. D.; Blagg, M.; Wiemer, D. F. J. Org. Chem.
1984, 49, 853.
15. House, H. O.; Respess, W. L.; Whitesides, G. M. J. Org.
Chem. 1966, 31, 3128.

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16. This lower yield was obtained using the usual work-up
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1959; (b) Stereochemistry of Organic Compounds; Eliel
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19. (a) Londet, M.; Metras, F.; Petrissans, J.; Pfister-Guil-
louzo, G. J. Mol. Struct. 1975, 29, 263; (b) Schmidt, H.;
Schweig, A.; Mathey, F.; Mu¨ller, G. Tetrahedron 1975, 31,
1287.
17. Solladie´-Cavallo, A.; Boue´rat, L. Tetrahedron: Asymmetry
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20. Marino, J. P.; Jaen, J. C. J. Am. Chem. Soc. 1982, 104, 3165.
.