1156
A. Alexakis, C. Benhaim / Tetrahedron: Asymmetry 12 (2001) 1151–1157
alent to g/0.1 dm3). Specific rotations denoted as [h]TD,
imply units of deg. dm2 g−1 (T=temp (°C)).
3.4. Preparation of 2-(1-phenyl-propyl)-malonic acid
diethyl ester
Conjugate addition of diethylzinc onto benzylidene
malonate S3 using the general procedure followed by
purification by flash chromatography (98/2 pen-
tane:ether, Rf=0.3) afforded the title compound as a
colourless oil.
3.1. General procedure for catalytic conjugate addition
To a solution of copper triflate (3.6 mg, 0.01 mmol) in
dry toluene (2 mL) at room temperature under argon
was added 2 equiv. of ligand (0.02 mmol). The solu-
tion was stirred at 25°C for 30 min and then cooled to
−15°C. A solution of Et2Zn (1N in hexane 2.4 mL) or
Et3Al (2.4 mL, 1N in hexane) was added dropwise at
a rate such that the temperature did not rise above
0°C. After stirring for 5 min, the malonate (2 mmol)
was added dropwise over 1 min. The reaction mixture
was stirred at 0°C for 3 h before being quenched by
HCl (2N). The product was extracted with Et2O (10
mL), dried (MgSO4) and the solvent was removed in
vacuo. The e.e. of the product was determined by
Chiral GC.
The separation on Chiral GC was measured on the
monoester. lH (400 MHz, CDCl3) 0.75 (t, JHH=7.3
Hz, 3H, CH3), 0.97 (t, JHH=7.0 Hz, 3H, CH3) 1.35
(t, JHH=7.0 Hz, 3H, CH3), 1.85–1.56 (2m, 2H, CH2),
3.34 (dt, JHH=3.5 Hz, JHH=10.9 Hz, 1H, CHbenz),
3.70 (d, JHH=11 Hz, 1H, CH), 3.91 (q, JHH=6.5 Hz,
2H, CH2O), 4.28 (q, JHH=6.5 Hz, 2H, CH2O), 7.30–
7.22 (2m, 5H, Ph); lC (100 MHz, CDCl3) 11.6 (CH3),
13.6 (CH3), 14.0 (CH3), 27.0 (CH2), 47.2 (CH), 58.6
(CH), 61.0 (CH2O), 61.4 (CH2O), 126.7, 128.2, 128.3,
140.6, 167.8 (CO), 168.5 (CO).
3.2. 2-sec-Butyl-malonic acid diethyl ester
3.5. Preparation of 3-phenyl-pentanoic acid ethyl ester
Conjugate addition of diethylzinc onto ethylidene mal-
onate S1 using the general procedure, followed by
flash chromatography purification of the crude
product (49/1 pentane:ether, Rf=0.4), afforded the
title compound as a colourless oil.
The monoester was obtained by using Krapcho’s
method:12 the corresponding malonic acid diethyl ester
(2 mmol) was added to a solution of DMSO (2 mL),
water (8 mmol) and LiCl (2.5 mmol). The mixture was
warmed to 160°C for 15 h. The product was extracted
with Et2O and the ethereal extract washed with water.
The organic layers were combined and dried (MgSO4).
The product was obtained in quantitative yield as a
colourless oil (64% e.e. (R): [h]2D5 −13.7 (c=1.4 in
CHCl3)). E.e. was measured on a ChirasildexGTA, 25
m, 50 cm3 s−1, T: 70°C, 1°C/min, 95°C, 35 min. Rt
(R)-(−)-enantiomer=52.48 min, rt (S)-(+)-enan-
tiomer=53.37 min; lH (400 MHz, CDCl3) 0.84 (t,
Enantiomer separation: ChirasildexGTA, 25 m, 50 cm3
s−1, T: 75°C, 80 min, 1°C/min, 110°C. Rt (R)-(−)-
enantiomer=70.0 min, rt (S)-(+)-enantiomer=72.00
min. Purification by flash chromatography on silica gel
(98/2 pentane:ether, Rf=0.3) to afford a colourless oil
(64% e.e. (R): [h]D25=−3.5 (c=2.0 in CHCl3)); lH (400
MHz; CDCl3) 0.85 (t, J=7.6 Hz, 3H), 0.91 (d, J=6.7
Hz, 3H), 1.2 (t, J=12.5 Hz, 6H), 1.25–1.4 (2m, 2H),
2.15 (m, 1H), 3.2 (d, J=8.6 Hz, 1H), 4.14 (q, J=7.3
Hz, 4H); lC (50 MHz; CDCl3) 11.1, 13.9, 14.0, 16.3,
27.0, 34.8, 57.4, 60.9, 60.9, 168.7, 168.9.
J
HH=7.3 Hz, 3H, CH3), 1.20 (t, JHH=7.0 Hz, 3H,
CH3), 1.76–1.62 (2m, 2H, CH2), 2.68 (dq, JHH=8 Hz,
HH=14.8 Hz, 2H), 3.04 (m, 1H, CH), 4.09 (q, JHH
J
=
7.2 Hz, 2H, CH2O), 7.25 (2m, 5H, Ph); lC (100 MHz,
CDCl3) 11.8 (CH3), 14.0 (CH3), 29.0 (CH2), 41.4
(CH2), 43.8 (CH), 60.1 (CH2O), 126.3, 127.4, 128.2,
143.8, 172.4 (CO).
3.3. 2-(1-Ethyl-pentyl)-malonic acid diethyl ester
Conjugate addition of diethylzinc onto pentylidene
malonate18 S2 using the general procedure, followed
by flash chromatography purification of the crude
product (98/2 pentane:ether, Rf=0.4), afforded the
title compound as a colourless oil.
3.6. Preparation of 3-phenyl-pentanoic acid19
In a 5 mL flask equipped with a condenser was placed
3-phenyl-pentanoic acid ethyl ester (1 mmol). Potas-
sium hydroxide (0.1 g) and ethanol (0.5 mL) were then
added. The reaction mixture was heated under reflux
overnight. The mixture was cooled to room tempera-
ture and the ethanol was evaporated under reduced
pressure. The residue was diluted with water (3 mL)
and extracted with ethyl acetate (5 mL). The layers
were separated and the aqueous phase was acidified to
pH 2 (HCl) and extracted with ethyl acetate (2×10
mL). The organic extracts were dried over MgSO4 and
evaporated under reduced pressure. The product was
isolated after chromatography on silica gel (95/5 pen-
tane:ether, Rf=0.3) to afford a white solid in quantita-
tive yield. E.e.=64% (R)-enantiomer; [h]2D5=−33
(c=5.2 in C6H6; lit.:13 [h]2D5 −51.7 100% e.e. (R)-enan-
Enantiomer separation: ChirasildexGTA, 25 m, 50 cm3
s−1, T: 80°C, 50 min, 1°C/min, 140°C. Rt (R)-(+)-
enantiomer=87.65 min, rt (S)-(−)-enantiomer=88.27
min. Purification by flash chromatography (98/2 pen-
tane: ether, Rf=0.3) to obtain a colourless oil (73%
e.e. (S): [h]2D5=−1.5 (c=1.6 in CHCl3)); lH (400 MHz,
CDCl3) 0.87 (t, 6H, CH3), 1.50–1.25 (m, CH2), 1.27 (t,
6H, CH3CH2O), 2.07 (m, CH), 3.41 (d, CH), 4.18 (q,
4H, CH2O); lC (100 MHz, CDCl3) 2×10.6 (CH3), 13.8
(CH3CH2O), 13.9 (CH3CH2O), 22.7, 23.4, 28.6, 29.9
(4×CH2), 39.3 (CH), 55.1 (CH2), 2×60.9 (CH2O), 2×
169 (CO).
.