Enantioselective synthesis of a key "A-ring" intermediate for the preparation of 1α-fluoro vitamin D3 analogues

Article abstract of DOI:10.1021/jo060516m

1α-Fluoro A-ring dienol 2, a useful building block for the preparation of fluorinated vitamin D₃ analogues, was synthesized in eight steps from 4-{[tert-butyldimethylsilyl]oxy}-cyclohexanone. The most distinctive synthetic development to emerge from this new synthesis is an unprecedented substrate-controlled diastereoselective fluorodesilylation of an advanced dienylsilane intermediate. This is the first enantioselective route to compound 2 relying on the use of an electrophilic fluorinating reagent.

Full text of DOI:10.1021/jo060516m

SCHEME 1. Structure of Ro 26-9228 and Known
Retrosynthesis from (S)-Carvone
Enantioselective Synthesis of a Key “A-Ring”
Intermediate for the Preparation of 1r-Fluoro
Vitamin D3 Analogues
Guy Giuffredi, Carla Bobbio, and Ve´ronique Gouverneur*
UniVersity of Oxford, Chemistry Research Laboratory,
12 Mansfield Road, Oxford OX1 3TA, U.K.
Veronique.gouVerneur@chemistry.oxford.ac.uk
ReceiVed March 9, 2006
featuring a functional group that will allow easy coupling with
the C-D ring system.12 In this context, the fluorinated dienol
2 emerged as a key intermediate for interactive chemical and
biological investigations.9 From a strictly chemical perspective,
this compound presents unusual synthetic challenges with the
construction of a fluorinated carbocycle featuring two adjacent
exocyclic double bonds and two stereogenic centers, one of them
being a fluorinated allylic carbon. Not surprisingly, compound
2 has stimulated the search of several inventive synthetic routes,
which are based on the use of (S)-carvone, an optically active
starting material provided by nature in abundance. Most of the
syntheses reported to date relied on the nucleophilic fluorinating
reagent DAST (dimethylaminosulfur trifluoride)6,9,11,12 or struc-
turally related sulfur trifluorides for the introduction of the
fluorine atom. The nucleophilic substitution on the precursor
dienol 3 proved to be particularly tricky, as it must be carried
out at low temperature and consistently gave a mixture of SN2
and SN2′ products that must be separated prior to further
functional manipulations. Alternative methods of fluorination
were also studied and include the nucleophilic displacement of
the corresponding mesylate with fluoride as well as substitutions
with perfluoro-1-butanesulfonyl fluoride/DBU or N,N-diisopro-
pyl-1-fluoro-2-methylpropenamine. None of these methods
proved fruitful (Scheme 1).9 A different route featured a
successful ring opening of an epoxide with Bu4NH2F3, but the
introduction of fluorine at an early stage of the synthesis caused
difficulties in the subsequent transformations.10
In this note, we present a new enantioselective synthesis of
2 that differs significantly from all the syntheses reported to
date. We decided to commit ourselves to the pursuit of a
conceptually novel strategy that did not use (S)-carvone as the
starting material (Scheme 2). We elected an electrophilic
fluorodesilylation reaction for the introduction of the fluorine
atom in order to avoid the inherent difficulties associated with
DAST chemistry. On the basis of relevant precedents from our
laboratory,13-15 it was anticipated that the allylic fluoride could
be constructed at a late stage of the synthesis from the
corresponding allylsilane upon treatment with an electrophilic
1R-Fluoro A-ring dienol 2, a useful building block for the
preparation of fluorinated vitamin D3 analogues, was syn-
thesized in eight steps from 4-{[tert-butyldimethylsilyl]oxy}-
cyclohexanone. The most distinctive synthetic development
to emerge from this new synthesis is an unprecedented
substrate-controlled diastereoselective fluorodesilylation of
an advanced dienylsilane intermediate. This is the first
enantioselective route to compound 2 relying on the use of
an electrophilic fluorinating reagent.
Fluorinated analogues of vitamin D have been used exten-
sively as molecular probes to determine the structure-function
relationship of vitamin D metabolites and their target mole-
cules.1-5 Early work on the synthesis and biological activity of
1R-fluoro-25-hydroxy vitamin D3 revealed that the addition of
this compound to human leukemia cells resulted in strong
phagocytic activity.6,7 Since then, Hoffmann-La Roche has
invested a great deal of effort on the synthesis, chemical
reactivity, and biological activity of numerous 1R-fluoro-25-
hydroxy vitamin D3 analogues, including compound 1, known
as Ro 26-9228 (Scheme 1).8-12 This molecule is of particular
interest as it was reported to restore bone mineral density without
inducing hypercalcemia in osteopenic rats.4 An essential com-
ponent of this research program was the availability of robust
synthetic routes to the 1R-fluorosubstituted A-ring fragment
* Corresponding author. Fax and Tel: + 44 (0) 1865 275644.
(1) Nagpal, S.; Na, S.; Rathnachalam, R. Endocr. ReV. 2005, 26, 662.
(2) Crescioli, C.; Ferruzzi, P.; Caporali, A.; Scaltriti, M.; Bettuzzi, S.;
Mancina, R.; Gelmini, S.; Serio, M.; Villari, D.; Vannelli, G. B.; Colli, E.;
Adorini, L.; Maggi, M. Eur. J. Endocrinol. 2004, 150, 591.
(3) Ismail, A.; Nguyen, C. V.; Ahene, A.; Fleet, J. C.; Uskokovic´, M.
R.; Peleg, S. Mol. Endocrinol. 2004, 18, 874.
(4) Peleg, S.; Ismail, A.; Uskokoviæ, M. R.; Avnur, Z. J. Cell. Biochem.
2003, 88, 267.
(5) Posner, G. H.; Kahraman, M. Eur. J. Org. Chem. 2003, 3889.
(6) Ohshima, E.; Takatsuto, S.; Ikekawa, N.; DeLuca, H. F. Chem.
Pharm. Bull. 1984, 32, 3518.
(8) Daniewski, A. R.; Garofalo, L. M.; Kabat, M. M. Synth. Commun.
2002, 32, 3031.
(9) Kabat, M. M.; Garofalo, L. M.; Daniewski, A. R.; Hutchings, S. D.;
Liu, W.; Okabe, M.; Radinov, R.; Zhou, Y. J. Org. Chem. 2001, 66, 6141.
(10) Barbier, P.; Mohr, P.; Muller, M.; Masciadri, R. J. Org. Chem. 1998,
63, 6984.
(11) Kiegiel, J.; Wovkulich, P. M.; Uskokovic´, M. R. Tetrahedron Lett.
1991, 32, 6057.
(7) Ohshima, E.; Sai, H.; Takatsuto, S.; Ikekawa, N.; Kobayashi, Y.;
Tanaka, Y.; DeLuca, H. F. Chem. Pharm. Bull. 1984, 32, 3525.
(12) Shiuey, S.-J.; Kulesha, I.; Baggiolini, E. G.; Uskokovic´, M. R. J.
Org. Chem. 1990, 55, 243.
10.1021/jo060516m CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/16/2006
J. Org. Chem. 2006, 71, 5361-5364
5361

SCHEME 2. Retrosynthetic Analysis of 2 Featuring the
Key Electrophilic Fluorodesilylation Step
SCHEME 4. Final Stages of the Synthesis of 2
source of fluorine. This retrosynthetic analysis revealed the
silylated diene 4, which could be formed upon C-C coupling
of the triflate derived from ketone 5 with trimethylsilylmeth-
ylmagnesium chloride. It remained to conceive an enantiose-
lective synthesis of the R,â-unsaturated ketone 5 from a readily
available starting material. We opted for a well-precedented
desymmetrization reaction of 4-{[tert-butyldimethylsilyl]oxy}-
cyclohexanone with a chiral base to form an intermediate silyl
enol ether,16-20 followed by a sequential aldolization-croton-
ization. For differential deprotection at the end of the synthesis,
the tert-butyldimethylsilyl- and the tert-butyldiphenylsilyl groups
were chosen to protect the secondary and the primary alcohol,
respectively.9,21
SCHEME 3. Enantioselective Synthesis of the
r,â-Unsaturated Ketone 5
Mukaiyama aldol reaction of 6 with {[tert-butyldiphenylsilyl]-
oxy}acetaldehyde23 employing a stoichiometric amount of
BF3‚Et2O afforded the aldol product 7 as a mixture of diaster-
eomers.24 The selectivity of this transformation was not critical,
as the two newly generated stereogenic centers are destroyed
during the course of the next steps through dehydration. This
elimination was best performed at room temperature by treat-
ment of the mixture of the corresponding mesylated aldol
products 8 with DBU in THF.25 This sequence of steps afforded
the desired ketone (S)-5 as the single geometrical E-isomer in
80% enantiomeric excess (ee).26
From intermediate 5, the completion of the synthesis required
four additional steps: the formation of the triflate, the C-C
coupling to generate the dienylsilane 4, the electrophilic
fluorodesilylation, and the final monodeprotection step (Scheme
4). Regioselective proton abstraction of (S)-5 was performed
with LDA at -40 °C in THF, and treatment of the resulting
enolate with N-phenyltrifluoromethanesulfonimide gave the
vinyl triflate (S)-9 in 60% yield. The preparation of the
dienylsilane (S)-4 was remarkably efficient upon treatment of
triflate (S)-9 with an excess of LiCl and trimethylsilylmethyl-
magnesium chloride in the presence of a catalytic amount of
Pd(PPh3)4.14,27 This reaction resulted in the formation of the
dienylsilane (S)-4 in 98% isolated yield. We were now in a
position to study the feasibility of the key fluorination process.
The introduction of the secondary fluorine atom, and thus the
second stereocenter, was performed by treating the dienylsilane
(S)-4 with 1.2 equiv of Selectfluor [1-chloromethyl-4-fluoro-
1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)]27 and 1.2
The overall synthesis of the chiral ketone 5 is illustrated in
Scheme 3. The requisite chiral trimethylsilyl enol ether (S)-6
was prepared as reported in the literature.17 Asymmetric
deprotonation of 4-{[tert-butyldimethylsilyl]oxy}cyclohexanone
using the lithium amide derived from (+)-bis(R-methylbenzyl)-
amine and silylation of the resulting lithium enolate afforded
the silyl enol ether (S)-6 in 69% yield. A subsequent classic
(13) Tredwell, M.; Tenza, K.; Pacheco, M. C.; Gouverneur, V. Org. Lett.
2005, 4891.
(14) Greedy, B.; Paris, J.-M.; Vidal, T.; Gouverneur, V. Angew. Chem.,
Int. Ed. 2003, 7, 3291.
(15) Thibaudeau, S.; Gouverneur, V. Org. Lett. 2003, 5, 4891.
(16) Rodeschini, V.; Van de Weghe, P.; Salomon, E.; Tarnus, C.;
Eustache, J. J. Org. Chem. 2005, 70, 2409.
(17) Poupon, J.-C.; Demont, E.; Prunet, J.; Fe´re´zou, J.-P. J. Org. Chem.
2003, 68, 4700.
(18) Aggarwal, V. K.; Olofsson, B. Angew. Chem., Int. Ed. 2005, 44,
5516.
(19) Parker, K. A.; Dermatakis, A. J. Org. Chem. 1997, 62, 6692.
(20) Majewski, M.; Irvine, N. M.; MacKinnon, J. Tetrahedron: Asym-
metry 1995, 6, 1837.
(21) Kabat, M. M.; Lange, M.; Wovkulich, P. M.; Uskokovic´, M. R.
Tetrahedron Lett. 1992, 33, 7701.
(22) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031.
(23) Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1996, 61, 8732.
(24) The diastereomeric ratio of the crude product could not be
determined. One diastereomer could be isolated and was assigned as
(S,S,R)-7 by NOESY analysis.
(25) Clive, D. L. J.; Huang, X. Tetrahedron 2001, 57, 3845.
(26) For determination of ee and NMR assignments, see the Experimental
Section and Supporting Information.
(27) Kamikawa, T.; Hayashi, T. J. Org. Chem. 1998, 63, 8922.
5362 J. Org. Chem., Vol. 71, No. 14, 2006

5.59 (t, J ) 5.6 Hz, 1H), 7.37-7.47 (m, 6H), 7.71-7.75 (m, 4H).
13C NMR (CDCl3, 101 MHz): δ -4.6, -4.6, -0.9, 18.1, 19.2,
22.1, 25.9, 26.8, 35.9, 36.1, 61.0, 68.1, 122.2, 124.8, 127.7, 127.7,
129.6, 129.6, 133.9, 134.9, 135.3, 135.6. IR (neat): 3072, 2955,
2857, 1642, 1472, 1375 cm-1. HRMS: calculated for C34H54NaO2-
Si3 m/z 601.3324, found m/z 601.3322. [R]23D ) -17.5 (c 1, CHCl3).
equiv of NaHCO3 in acetonitrile. The fluorodesilylation pro-
ceeded smoothly with full transposition of the double bond, as
expected for an SE2′ process.13-15,29 The reaction was completed
within 1.5 h at room temperature to afford the doubly protected
fluorinated dienes 10 with an overall yield of 74%. The crude
mixture revealed that two diastereomers were formed in a 3:1
ratio, and these were separated by preparative thin-layer
chromatography. The major isomer was fully characterized by
NMR studies26 and was unambiguously identified as the desired
anti product, (3R,5S)-10, resulting from a preferential axial attack
of Selectfluor on the endocyclic double bond (Scheme 4). The
completion of the synthesis required a final deprotection step
to release the primary alcohol. This deprotection took place in
the presence of an excess of KOH in methanol under reflux.
Under these conditions, the target compound (3R,5S)-2 was
remarkably stable and was isolated after purification in 91%
yield and with 80% enantiomeric excess. This ee was measured
unambiguously by chiral HPLC by comparison with HPLC data
of the structurally identical racemic compound (()-2, which
was prepared independently using the exact synthetic sequence
starting with the racemic silyl enol ether (()-6.26
tert-Butyl{[(2E)-2-((3S,5R)-5-{[tert-butyldimethylsilyl]oxy}-3-
fluoro-2-methylenecyclohexylidene)ethyl]oxy}diphenylsilane (10).
Sodium bicarbonate (82 mg, 1.0 mmol, 1.2 equiv) and Selectfluor
(0.35 g, 1.0 mmol, 1.2 equiv) were consecutively added to a solution
of allylsilane 4 (0.47 g, 0.80 mmol, 1.0 equiv) in acetonitrile (8.0
mL). The mixture was stirred for 1.5 h at room temperature, before
being quenched with water (8.0 mL). After extracting the aqueous
phase with diethyl ether (3 × 8.0 mL), the combined organic layers
were washed with brine (20 mL), dried over magnesium sulfate,
1
and filtered, and the solvents were removed in vacuo. H NMR
analysis of the crude mixture indicated the formation of two
diastereomers in a 3:1 ratio. Purification by preparative TLC (3 ×
hexane/diethyl ether, 45:1) afforded minor-10 (71.7 mg, 17%) and
major-10 (201 mg, 47%) as colorless oils. Rfminor ) 0.30, Rfmajor
)
0.23. The configuration of the major diastereomer was identified
by NOESY as (3S,5R)-10.
1
(3S,5R)-10. H NMR (CDCl3, 500 MHz): δ -0.02 (s, 3H),
In summary, we have developed a conceptually novel process
for the preparation of 1R-fluoro A-ring dienol 2, which is a
known key intermediate for the synthesis of numerous vitamin
D analogues bearing the same A-ring fragment.9,30 This first
enantioselective route comprises three crucial steps: an enan-
tioselective desymmetrization for the creation of the first
stereogenic center, a Pd-mediated C-C coupling for the
preparation of the dienylsilane, and a most synthetically useful
electrophilic fluorodesilylation for the substrate-controlled di-
astereoselective introduction of the fluorine atom. With the
preparation of compound 2, this recently developed fluorination
process bodes well for future applications of this reaction to
the total synthesis of other biologically active fluorinated targets.
-0.01 (s, 3H), 0.84 (s, 9H), 1.06 (s, 9H), 1.87 (dddd, J ) 31.0,
13.4, 8.6, 3.4 Hz, 1H), 1.97 (dd, J ) 13.9, 8.4 Hz, 1H), 2.10-2.17
(m, 1H), 2.36 (dd, J ) 13.9, 4.0 Hz, 1H), 4.05 (ddd, J ) 12.0, 7.9,
3.5 Hz, 1H), 4.24-4.33 (m, 2H), 5.02 (s, 1H), 5.15 (d, J ) 1.2 Hz,
1H), 5.15 (ddd, J ) 50.3, 6.0, 3.3 Hz, 1H), 5.84 (t, J ) 6.1 Hz,
1H), 7.36-7.45 (m, 6H), 7.68-7.72 (m, 4H). 13C NMR (CDCl3,
126 MHz): δ -4.9, -4.9, 18.0, 19.2, 25.7, 26.8, 37.2, 40.7 (d, J
) 20.6 Hz), 60.7, 66.0 (d, J ) 5.4 Hz), 91.7 (d, J ) 169.3 Hz),
112.3 (d, J ) 10.0 Hz), 127.6, 127.6, 127.8, 129.6, 133.7, 133.8,
135.1 (d, J ) 2.1 Hz), 135.6, 135.6, 146.7 (d, J ) 16.5 Hz). 19F
NMR (CDCl3, 375 MHz): δ -171.7 (ddd, J ) 50.2, 31.0, 9.9 Hz).
IR (neat): 3072, 2955, 2857, 1651, 1472, 1023 cm-1. HRMS:
calculated for C31H45FNaO2Si2 m/z 547.2834, found m/z 547.2836.
[R]23 ) -13.9 (c 1, CHCl3).
D
(3R,5R)-10. 1H NMR (CDCl3, 400 MHz): δ 0.01 (s, 3H), 0.04
(s, 3H), 0.87 (s, 9H), 1.07 (s, 9H), 1.70 (quint, J ) 11.2 Hz, 1H),
1.74-1.83 (m, 1H), 2.35-2.44 (m, 1H), 2.51 (dm, J ) 13.7 Hz,
1H), 3.56-3.65 (m, 1H), 4.24 (ddd, J ) 13.5, 5.5, 1.5 Hz, 1H),
4.32 (ddd, J ) 13.4, 7.0, 0.9 Hz, 1H), 4.88 (dddt, J ) 50.0, 11.3,
5.4, 2.1 Hz, 1H), 5.04 (brs, 1H), 5.07 (m, 1H), 5.82-5.87 (m, 1H),
7.38-7.48 (m, 6H), 7.68-7.73 (m, 4H). 13C NMR (CDCl3, 101
MHz): δ -4.8, -4.7, 18.0, 19.2, 25.8, 26.8, 37.7, 42.2 (d, J )
17.1 Hz), 60.8, 66.7 (d, J ) 13.5 Hz), 88.0 (d, J ) 182.9 Hz),
107.3 (d, J ) 10.2 Hz), 127.7, 127.7, 128.0 (d, J ) 2.7 Hz), 129.7,
129.7, 133.6, 133.7, 134.2 (d, J ) 5.0 Hz), 135.6, 135.6, 147.5 (d,
J ) 15.5 Hz). 19F NMR (CDCl3, 375 MHz): δ -180.1 (dm, J )
Experimental Section
tert-Butyl [((2E)-2-{(5S)-5-{[tert-butyldimethylsilyl]oxy}-2-
[(trimethylsilyl)methyl]cyclohex-2-en-1-ylidene}ethyl)oxy]di-
phenylsilane (4). Tetrakis(triphenyphosphine)palladium(0) (0.12 g,
0.10 mmol, 0.10 equiv) was added to a suspension of vinyl triflate
9 (0.65 g, 1.0 mmol, 1.0 equiv) and lithium chloride (0.22 g, 5.0
mmol, 5.0 equiv) in THF (4.0 mL). After 30 min, a solution of
trimethylsilylmethylmagnesium chloride, prepared from chlorotri-
methylsilylmethane (0.70 mL, 5.0 mmol, 5.0 equiv) and magnesium
(0.18 g, 7.5 mmol, 7.5 equiv) in THF (5.0 mL) was added dropwise
over 10 min. After being stirred for 2 h, the reaction mixture was
quenched with a saturated aqueous solution of sodium bicarbonate
(7.0 mL), and the phases were separated. The aqueous phase was
extracted with diethyl ether (3 × 5.0 mL) and the combined organic
layers were washed with water (15 mL) and brine (15 mL), dried
over magnesium sulfate, and filtered, and the solvents were removed
in vacuo. By column chromatography on silica gel (hexane/ethyl
acetate, 33:1) pure allylsilane 4 was obtained (0.58 g, 98%). Rf )
50.0). IR (neat): 3072, 2957, 2858, 1651, 1472, 1042 cm-1
.
HRMS: calculated for C31H45FNaO2Si2 m/z 547.2834, found m/z
547.2829. [R]23 ) -34.3 (c 1, CHCl3).
D
(2E)-2-((3S,5R)-5-{[tert-butyldimethylsilyl]oxy}-3-fluoro-2-
methylenecyclohexylidene)ethanol (2).22 Potassium hydroxide
(68 mg, 1.2 mmol, 7.5 equiv) and (3S,5R)-10 (86 mg, 0.16 mmol,
1.0 equiv) in methanol (8.0 mL) were stirred at 70 °C for 19 h. At
room temperature, an aqueous saturated solution of ammonium
chloride (3.0 mL) and diethyl ether (20 mL) was added, and the
phases were separated. The aqueous phase was washed with diethyl
ether (3 × 10 mL), and the combined organic layers were washed
with a saturated aqueous solution of ammonium chloride (30 mL)
and brine (30 mL). After drying over magnesium sulfate, filtration,
and removal of the solvents in vacuo, the crude mixture was purified
by column chromatography on silica gel (hexane/ethyl acetate, 3:1).
The pure alcohol 2 was obtained as colorless oil in 91% yield (43
mg) and 80% ee. The ee was determined by HPLC analysis
1
0.29. H NMR (CDCl3, 400 MHz): δ 0.02 (brs, 12H), 0.04 (s,
3H), 0.88 (s, 9H), 1.08 (s, 9H), 1.60 (d, J ) 14.0 Hz, 1H), 1.71 (d,
J ) 14.0 Hz, 1H), 2.00 (t, J ) 12.6 Hz, 1H), 2.12 (dd, J ) 16.9,
8.9 Hz, 1H), 2.33 (dt, J ) 17.0, 5.4 Hz, 1H), 2.49 (dd, J ) 14.3,
3.8 Hz, 1H), 3.75-3.84 (m, 1H), 4.33 (dd, J ) 13.3, 5.8 Hz, 1H),
4.41 (dd, J ) 13.3, 6.5 Hz, 1H), 5.35 (dd, J ) 5.5, 2.6 Hz, 1H),
(28) Nyffeler, P. T.; Duro´n, S. G.; Burkart, M. D.; Vincent, S. P.; Wong,
C.-H. Angew. Chem., Int. Ed. 2005, 44, 192.
(29) Tredwell, M.; Gouverneur, V. Org. Biomol. Chem. 2006, 4, 26.
(30) Zhu, G.-D.; Okamura, W. H. Chem. ReV. 1995, 95, 1877.
(CHIRACEL OD, hexane/ethanol 99:1, flow rate ) 0.7 mL/min-1
,
major
minor
1
tR
) 15.4, tR
) 17.1). Rf ) 0.32. H NMR (CDCl3, 400
J. Org. Chem, Vol. 71, No. 14, 2006 5363

MHz): δ 0.09 (s, 6H), 0.89 (s, 9H), 1.96 (dddd, J ) 27.7, 13.3,
8.0, 3.7 Hz, 1H), 2.08-2.18 (m, 1H), 2.24 (dd, J ) 13.9, 7.7, 1H),
2.54 (dd, J ) 13.9, 3.8 Hz, 1H), 4.14-4.21 (m, 1H), 4.21 (s, 1H),
4.23 (s, 1H), 5.06 (brs, 1H), 5.18 (ddd, J ) 50.2, 6.7, 3.7 Hz, 1H),
5.19 (s, 1H), 5.87 (t, J ) 6.8, 1H). 13C NMR (CDCl3, 101 MHz):
δ -4.8, -4.8, 18.0, 25.8, 37.0, 40.8 (d, J ) 20.2 Hz), 58.9, 66.2
(d, J ) 6.3 Hz), 91.4 (d, J ) 170.7 Hz), 112.0 (d, J ) 10.1 Hz),
126.9, 137.6 (d, J ) 2.4 Hz), 146.9 (d, J ) 16.3 Hz). 19F NMR
(CDCl3, 375 MHz): δ -173.8 (ddd, J ) 50.1, 27.7, 9.9 Hz). IR
(neat): 3356, 2955, 2858, 1651, 1023 cm-1. [R]23D ) -19.6 (c 1,
CHCl3).
C.B.), and the EPSRC (GR/S79268/01, to C.B.) for generous
financial support. We also thank Prof. Jacques Eustache (Ecole
Nationale Supe´rieure de Chimie de Mulhouse, France), Dr. Jean-
Christophe Poupon (Universite´ de Montreal, Canada), and Dr.
Joe¨lle Prunet (Ecole Polytechnique de Palaiseau, France) for
helpful advice on the preparation of the enantiopure silyl enol
ether 6.
Supporting Information Available: Detailed description of
experimental procedures and NMR spectra of compounds 2-10.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We sincerely thank the Royal Society
of Chemistry (2005/R1), the Swiss National Science Foundation
(Fellowship for Perspective Researchers FBEL2-106159, to
JO060516M
5364 J. Org. Chem., Vol. 71, No. 14, 2006