butylcyclohexanone 1a under control of a chiral diether 5
giving the corresponding olefin 4a (Y ) 2-Naph, R1 ) t-Bu,
R2 ) H) in 90% ee.6b Extension of the procedure to a
phosphonate 2b possessing an ester portion, however, was
unsatisfactory, giving 4b (Y ) CO2Et, R1 ) t-Bu, R2 ) H)
in 0% ee. On the basis of our previous finding that a reaction
of a lithium ester enolate with an imine or aldehyde is
controllable by 5,11 we chose an R-trimethylsilanyl ester 2c
as a silico equivalent to a phosphonate 2b. A chelate of a
lithium enolate of 2c with 5 undergoes a face differentiating
equatorial12 attack to 1a, giving 3 that instantly eliminates
lithium trimethylsilanoxide in syn fashion to result in the
formation of an axially chiral olefin 4c (Y ) CO2R, R1 )
t-Bu, R2 ) H).
Successive treatment of 2c13 with LDA in the presence of
1.3 equiv of 514 in toluene at -20 °C for 1 h to generate a
lithium enolate-5 chelate, and then with 1a at -78 °C for 1
h directly gave an olefin S-(+)-4c (Y ) 2,4-dimethyl-3-
pentyloxycarbonyl, R1 ) t-Bu, R2 ) H) in 83% yield. The
enantioselectivity was determined to be 27% ee by chiral
stationary phase HPLC (DAICEL Chiralcel OD-H, propan-
2-ol/hexane 1/1000). The absolute configuration of (+)-4c
was determined to be S by reduction with DIBALH in
toluene to the corresponding (+)-allylic alcohol of the
established absolute configuration.15
temperature for 6 h to make sure the chelate formation before
treatment with 1a, 4c was obtained in as high as 84% ee
and 18% chemical yield. Since the Claisen-type condensation
of the lithium enolate seemed one of the factors responsible
for the low chemical yield and also for the improved
enantioselectivity, the effect of the side products of the
Claisen reaction, lithiated keto ester and lithium 2,4-dimethyl-
3-pentoxide, on enantioselectivity were examined. The
presence of 1 equiv of lithiated keto ester (2,4-dimethyl-3-
pentyl acetoacetate) was a moderate improving factor to
afford (-)-4c in 61% ee in the reaction of 2c with 1a using
7 at -78 °C. The presence of 1 equiv of lithium 2,4-
dimethyl-3-pentoxide improved the enantioselectivity up to
65% from 52%. Other lithium alkoxides derived from
ethanol, phenol, pentan-3-ol, and (-)- and (+)-menthol
exhibited negative or marginal effects on enantioselectivity,
giving (-)-4c in 44%, 29%, 54%, 50%, and 51% ee,
respectively.
Since Claisen-type condensation consumes the lithium
enolate of 2c, the increased ratio of chiral ligand 7 to the
enolate seemed an improving factor of the enantioselectivity.
In the presence of 12 equiv of 7 the reaction of 3 equiv of
2c with 1a at -78 °C afforded (-)-4c in 73% ee and 98%
yield. The ligand 7 was recovered in quantitative yield and
was recyclable. The reaction above at -100 °C for 0.5 h
gave (-)-4c in 85% ee and 95% yield. On the contrary, the
reaction using 1.5 equiv of the enolate and 6 equiv of 7 at
-100 °C gave (-)-4c in 52% ee and 92% yield. The
diminished enantioselectivity was probably due to the
negative influence of lithium silanoxide, which is the side
product in every Peterson reaction.
We then examined several factors to improve the enan-
tioselectivity of the reaction. The size of the ester component
of 2c affected enantioselectivity, giving 19% and 23% ee
with use of ethyl and tert-butyl esters, respectively. Another
chiral ligand, sparteine 6, was not satisfactory in the reaction
of 2c with 1a to give S-(+)-4c in 14% ee. Fortunately a
tridentate amino diether 716 gave R-(-)-4c in 52% ee of
moderate selectivity.17 Another silyl group TBDMS, instead
of TMS, at the R-position of the ester 2c using 7 gave the
olefin (-)-4c in 46% ee and 81% yield.
Therefore it was also a logical extension to examine the
effect of lithium trimethylsilanoxide. Actually, the addition
of the equimolar silanoxide to the enolate exhibited a
negative effect to decrease the enantioselectivity down to
54% in the reaction of 3 equiv of 2c with 1a under 12 equiv
of 7 at -100 °C. The use of 3 equiv of the lithium enolate-
chiral ligand complex was effective in surmounting the
negative influence of lithium silanoxide, because at least 2
equiv of the reagent complex are free from complexation
with lithium silanoxide.
When the mixture of the lithium enolate of 2c and chiral
ligand 7 was allowed to warm to 0 °C and stand at the same
(10) (a) Tomioka, K. Synthesis 1990, 541-549. (b) Nishimura, K.; Ono,
M.; Nagaoka, Y.; Tomioka, K. J. Am. Chem. Soc. 1997, 119, 12974-12975.
(c) Fujihara, H.; Nagai K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122,
12055-12056. (d) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa, Y.; Taga,
T.; Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932-8939.
(11) (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J.
Am. Chem. Soc. 1997, 119, 2060-2061. (b) Nomura, Y.; Iguchi, M.; Doi,
H.; Tomioka, K. Chem. Pharm. Bull. 2002, 50, 1131-1134.
(12) (a) Ashby, E. C.; Laemmle, J. T. Chem. ReV. 1975, 75, 521-546.
(b) Gillies, M. B.; Tønder, J. E.; Tanner, D.; Norrby P.-O. J. Org. Chem.
2002, 67, 7378-7388.
(13) The R-trimethylsilanylacetate 2c was prepared in 74% yield upon
treatment of 2,4-dimethyl-3-pentyl acetate with lithium cyclohexylisopro-
pylamide and silylation with trimethylchlorosilane. Rathke, M. W.; Sullivan,
D. F. Synth. Commun. 1973, 3, 67-72.
(14) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111,
8266-8268. Shindo, M.; Koga, K.; Tomioka, K. J. Org. Chem. 1998, 63,
9351-9357.
(15) Duraisamy, M.; Walborsky, H. M. J. Am. Chem. Soc. 1983, 105,
3252-3264.
The enantioselective Peterson reactions of the lithium
enolate of 2c with 4-phenyl-, 4-methyl-, and 3,5-disubsti-
tuted18 cyclohexanones 1b-d were examined under the
established conditions and gave the corresponding chiral
olefins 4d-f in enantioselectivity of 76, 70, and 80%,19
respectively (Table 1).20
(18) Majewski, M.; Gleave, D. M. J. Org. Chem. 1992, 57, 3599-3605.
(19) The enantiomeric excess of 4f was determined by a chiral stationary
phase HPLC (DAICEL Chiralcel OD-H, propan-2-ol/hexane 1/100) of the
corresponding allylic alcohol, which was prepared by reducing 4f with
DIBALH.
(20) A typical procedure (Table 1): A solution of 2c (1.5 mmol) in
toluene (2.5 mL) was added to a solution of LDA (1.6 mmol) in toluene
(2.5 mL) at -78 °C. After the mixture was stirred at -78 °C for 0.5 h a
solution of 7 (6.0 mmol) in toluene (1.5 mL) was added dropwise over 10
min. The mixture was stirred for 1 h at -20 °C, and allowed to cool to
-100 °C. A solution of 1a (0.5 mmol) in toluene (1.5 mL) was added
dropwise over a period of 5 min, and the whole was stirred for 0.5 h at the
same temperature and was then quenched with saturated ammonium chloride
and extracted with ethyl acetate. The organic layers were washed with brine
(16) (a) Tomioka, K.; Okuda, M.; Nishimura, K.; Manabe, S.; Kanai,
M.; Nagaoka, Y.; Koga, K. Tetrahedron Lett. 1998, 39, 2141-2144. (b)
Kambara, T.; Tomioka. K. J. Org. Chem. 1999, 64, 9282-9285. (c)
Tomioka, K.; Fujieda, H.; Hayashi, S.; Hussein, M. A.; Kambara, T.;
Nomura, Y.; Kanai, M.; Koga, K. Chem. Commun. 1999, 715-716.
(17) The use of lithium N-trityl-tert-butylamide (Busch-Petersen, J.;
Corey, E. J. Tetrahedron Lett. 2000, 41, 2515-2518) instead of LDA gave
4c in the same level of 50% ee.
4330
Org. Lett., Vol. 4, No. 24, 2002