Preparation of proximal β-hydroxy silyl enol ethers from α,β-epoxyketones using silyllithium reagents

Article abstract of DOI:10.1016/j.tetlet.2009.04.085

A new method for the stereoselective preparation of proximal β-hydroxy silyl enol ethers from α,β-epoxyketones using silyllithium reagents has been developed. The reaction is believed to proceed via Brook rearrangement assisted by opening of the adjacent

Full text of DOI:10.1016/j.tetlet.2009.04.085

Tetrahedron Letters 50 (2009) 4012–4014
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Preparation of proximal b-hydroxy silyl enol ethers from a,b-epoxyketones
using silyllithium reagents
*
Heather K. Baker, Aaron M. Hartel
Department of Chemistry, Winthrop University, Rock Hill, SC 29733, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for the stereoselective preparation of proximal b-hydroxy silyl enol ethers from
epoxyketones using silyllithium reagents has been developed. The reaction is believed to proceed via
Brook rearrangement assisted by opening of the adjacent epoxide. A number of ,b-epoxyketones were
reacted with methyldiphenylsilyllithium to form the corresponding proximal b-hydroxy silyl enol ethers
in good to excellent yield and excellent stereoselectivity.
a,b-
Received 26 February 2009
Revised 21 April 2009
Accepted 22 April 2009
Available online 3 May 2009
a
Ó 2009 Elsevier Ltd. All rights reserved.
O-
Recently, we reported a selective
a
-reduction of
a
,b-epoxyke-
O
OSiR3
R3Si
R1
R3SiLi
Brook
Rearrangement
O
O
O
-
tones 1 using silyllithium reagents to form b-hydroxyketones (ald-
ols) 3.1 The proposed mechanism (Scheme 1) involves initial
nucleophilic attack of the silyllithium reagent on the carbonyl to
R1
R2
R2
R1
R2
1
form an
comitant
a
p
-silylalkoxide, triggering a Brook rearrangement. Con-
bond formation and opening of the epoxide ring result
OSiR3 O-
O-
O-
O
OH
H2O, H+
R3SiLi
in the formation of a silyl enol ether. Desilylation of the silyl enol
ether by the silyllithium reagent then forms an aldolate dianion,
providing the b-hydroxyketone upon acidic aqueous work-up.
We were intrigued by the possibility of isolating the initially
formed b-hydroxy silyl enol ethers 2, which would have great po-
tential as multifunctional synthetic intermediates. b-hydroxy silyl
enol ethers have already been shown to be valuable substrates
R1
R2
R1
R2
R1
R2
2
3
Scheme 1.
O
R3SiO
Ph
OH
O
OH
O
R3SiLi (1.5 equiv)
Solvent, Temperature
+
for the stereoselective preparation of
a
,b-dihydroxycarbonyls2
Ph
Ph
4
5
6
and could find further application in the synthesis of ‘asymmetri-
cal’ or proximal double aldols, for which there are few synthetic
routes.3
Scheme 2.
Existing methods for the preparation of proximal b-hydroxy si-
lyl enol ethers are sparse and of limited utility due to narrow sub-
strate scope, poor stereoselectivity, or the need for complex
substrate functionalization.2,4 The preparation of b-hydroxy silyl
enol ethers from a,b-epoxyketones is attractive, given the accessi-
bility of the substrates.
Reactions performed in THF produced substantial amounts of the
undesired aldol 6. The use of the less polar solvents toluene and
ether suppressed Si–O bond cleavage and provided significantly
improved yields of 5. Lower temperatures also generally enhanced
the yield of the silyl enol ether 5.6 The reaction of 4 with methyl-
diphenylsilyllithium in toluene at À78 °C provided the highest
yield of desired 5. The use of methyldiphenylsilyllithium provided
another critical advantage, as unlike dimethylphenylsilyl enol
ethers, methyldiphenylsilyl enol ethers are known to be stable to
silica gel chromatography.7
Isolation of proximal b-hydroxy silyl enol ethers from
a,b-
epoxyketones would require the suppression of the observed
cleavage of the Si–O bond by the silyllithium reagent. A series of
reactions using
a,b-epoxyketone 4 was performed to determine
the effect of temperature, solvent, and silyllithium reagent on the
relative amounts of silyl enol ether 5 and aldol 6 formed (Scheme
2). The results are summarized in Table 1.
The scope of the method was demonstrated by reacting a num-
As expected from our previous studies with acyloins,5 the reac-
tion solvent had a significant influence on product distribution.
ber of
a,b-epoxyketones with methyldiphenylsilyllithium in tolu-
ene at À78 °C. Under these conditions, we found that a larger
excess of silyllithium reagent could be used to ensure complete
reaction of the
undesired aldol. The results are summarized in Table 2. Good to
a,b-epoxyketones without formation of the
* Corresponding author. Tel.: +1 803 323 4942; fax: +1 803 323 2246.
E-mail address: hartela@winthrop.edu (A.M. Hartel).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.085

H. K. Baker, A. M. Hartel / Tetrahedron Letters 50 (2009) 4012–4014
4013
Table 1
were found to decompose under these conditions, giving predom-
inantly the enone. It is likely that in the absence of an anion stabi-
lizing aryl substituent, the use of an apolar solvent significantly
suppresses the rate of the Brook rearrangement, allowing a com-
peting carbon–carbon migration of the silyl group to dominate.9
Subsequent Peterson elimination would then result in the enone.
In conclusion, a new method for the stereoselective preparation
Reaction of 4 with silyllithium reagents (1.5 equiv)
Entry
Silyllithium
Solvent
Temperature (°C)
5a (%)
6a (%)
1
2
3
4
5
6
7
8
Me2PhSiLi
Me2PhSiLi
Me2PhSiLi
Me2PhSiLi
MePh2SiLi
MePh2SiLi
MePh2SiLi
MePh2SiLi
THF
Ether
Toluene
Toluene
THF
Ether
Toluene
Toluene
À40
À40
À40
À78
À40
À40
À40
À78
35
54
53
54
2
51
45
72
13
2
0
2
47
13
5
of proximal b-hydroxy silyl enol ethers from
a,b-epoxyketones
using silyllithium reagents has been developed. The method was
effective for aryl ketones lacking an
a
-substituent, but was ineffec-
2
tive for alkyl ketones.
Effects of silyl group, solvent, and temperature.
a
Yields determined by 1H NMR using hexamethylbenzene as an internal
Typical
procedure:
2,3-Epoxy-1-phenyl-1-propanone (4)
(0.150 g, 1.0 mmol) was dissolved in 10 mL of dry toluene and
was cooled to À78 °C under argon. A 1.0 M solution of methyldi-
phenylsilyllithium in THF (2.0 mL, 2.0 equiv) was added dropwise
via syringe with stirring. After 15 min, the reaction was quenched
at À78 °C with 10 mL of saturated NH4Cl and warmed to room
temperature. The mixture was extracted with CH2Cl2 (3 Â 15 mL)
and the combined organic layers were dried over Na2SO4. The dried
solution was concentrated in vacuo and the residue was purified by
standard.
excellent yields were obtained with all aromatic ketones except
the -substituted ketone (entry 5), which gave exclusively 2-
a
methyl-3-(methyldiphenylsilyl)-1-phenyl-1-propanone. In all
cases, the reaction greatly favored the E stereoisomer,8 and in sev-
eral cases was the exclusive isomer observed. Aliphatic ketones
Table 2
Reaction of
a,b-epoxyketones with methyldiphenylsilyllithium (1.7–2.0 equiv) in toluene at À78 °C
Entry
Substrate
Product
Yield (%)
81
E/Za
O
O
Ph2MeSiO
Ph
OH
OH
OH
1
2
3
4
5
6
7
100/0
Ph
O
O
Ph2MeSiO
Ph
71
66
91
0b
100/0
80/20
100/0
—
Ph
Pr
Pr
O
O
Ph2MeSiO
Ph
Ph
Ph
Ph
O
O
Ph2MeSiO
Ph
OH
OH
Ph
O
O
Ph2MeSiO
Ph
Ph
O
Ph2MeSiO
OH
O
74
66
83
96/4
96/4
100/0
O
Ph2MeSiO
OH
O
F
F
O
Ph2MeSiO
OH
O
8
CH3O
CH3O
a
Determined by 1H NMR.
2-Methyl-3-(methyldiphenylsilyl)-1-phenyl-1-propanone was isolated in 55% yield.
b

4014
H. K. Baker, A. M. Hartel / Tetrahedron Letters 50 (2009) 4012–4014
flash chromatography (dry silica gel, 20% ethyl acetate/petroleum
ether) to give 0.283 g of E-3-methyldiphenylsiloxy-3-phenyl-2-
propen-1-ol (5) as a colorless oil.
References and notes
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6753.
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5. Robertson, B. D.; Hartel, A. M. Tetrahedron Lett. 2008, 49, 2088–2090.
6. Epoxyketone 4 was insoluble in ether at À78 °C.
Acknowledgments
This work was supported by the Department of Chemistry and
the Research Council, Winthrop University. We also thank Michael
Walla, University of South Carolina, for measurement of mass
spectra.
7. Denmark, S. E.; Hammer, R. P.; Weber, E. J.; Habermas, K. L. J. Org. Chem. 1987,
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Supplementary data
9. For examples of this effect, see: (a) Brook, A. G.; Limburg, W. W.; MacRae, D. M.;
Fieldhouse, S. A. J. Am. Chem. Soc. 1967, 89, 704–706; (b) Nakajima, T.; Segi, M.;
Sugimoto, F.; Hioki, R.; Yokota, S.; Miyashita, K. Tetrahedron 1993, 49, 8343–
8358.
Supplementary data (spectroscopic data for the b-hydroxy silyl
enol ethers) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.04.085.