ASYMMETRIC ADDITIONS OF DIETHYLZINC TO ALDEHYDES BY CHIRAL LIGANDS DERIVED FROM CINCHONA ALKALOIDS
563
(
(
m, 0.6H), 7.79-7.93 (m, 2.4H), 7.96-8.00(m, 0.4H), 8.23(d, 0.3H), 8.62
2.27-2.69 (br, 1H), 3.80 (S, 3H), 4.50 (s, 1H), 6.83-7.28 (m, 4H); 13C
1
3
48
d, 0.7H); C NMR (100MHz, CDCl
3
) (mixture of rotamers ) : d 25.4,
NMR (100 MHz, CDCl ) d 10.1, 31.6, 55.1, 75.4, 113.6, 127.1, 136.8, 158.8.
3
2
1
1
6.7, 27.4, 39.1, 40.4, 49.7, 55.5, 57.1, 61.6, 100.7, 103.4, 114.8, 120.4, 120.9,
21.4, 123.5, 126.9, 127.2, 128.3, 130.3, 130.8, 131.1, 131.3, 131.7, 131.9,
40.6, 144.0, 145.5, 146.7, 147.1, 157.4. HRMS m/z: calcd. for C32H N O P
34 3 2
R)-1-(2’-methoxyphenyl)-1-propanol (B5, entry 5 in Table 3):49
(
. Col-
orless oil (81.4mg, 98% yield); 96% ee value was determined by Chiral GC
(M + 1), 524.2449; found, 524.2461.
ꢂ
Chirasil Dex CB [150 C, t
R
= 6.6 min (minor, S), t
R
= 7.4 min (major, R)].
32:4
26:0
½
aꢀ
+22.8 (c 1.50, CHCl
ee (R)]; H NMR (400 MHz, CDCl
3
) [Lit. 49 ½aꢀ
+23.7 (c 1.40, CHCl ) for 95%
3
(Diphenylphosphoryl)[(S)-[(2S,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]
D
D
1
3
) d 0.98 (t, 3H), 1.79-1.89 (m, 2H),
octan-2-yl] (quinolin -4-yl)methyl]amine (L7). L7 was synthesized
from cinchonidine following the same procedure described for L4 on the
same scale and was obtained as a white solid with the yield of 1085.1 mg
2
.82 (d, 1H), 3.86 (S, 3H), 4.79-4.86 (m, 1H), 6.87-7.36 (m, 4H);
1
3
C NMR (100 MHz, CDCl
28.0, 132.4, 156.4.
3
) d 10.3, 30.1, 55.1, 71.9, 110.4, 120.5, 126.9,
23:1
D
1
1
ꢂ
(
44%). mp 190–191 C; ½aꢀ
2 2
-4.4 (c 1.00, CH Cl ) ; H NMR (400 MHz,
3
CDCl ) (mixture of rotamers) : d 0.73-0.90 (m, 1H), 1.19-1.30 (m,
2
3
H), 1.53-1.64 (m, 2H), 2.24 (s, 1H), 2.63-2.80 (m, 2H), 2.92-2.99 (m, 1H),
.14-3.28 (m, 1H), 3.35-3.51 (M, 1H), 4.54(t, 0.4H), 4.78-4.98 (m, 2H), 5.19
(R)-1-(2-methylphenyl)-1-propanol (B6, entry 6 in Table 3):50. Col-
orless oil (74.3 mg, 99% yield); 99% ee value was determined by Chiral
ꢂ
(
(
t, 1.2H), 5.30(s, 0.4H), 5.49-5.76 (m, 1H), 6.62-6.73 (m, 2H), 6.80-6.87
m,1H), 6.95(t, 0.3H), 7.15-7.24 (m, 0.7H), 7.27-7.32 (m, 1H), 7.35-7.44 (m,
GC Chirasil Dex CB [150 C, t = 5.2 min (major, R), t = 5.5 min (minor,
R
R
32:0
26:0
S)]. ½aꢀ
+63.9 (c 1.30, CHCl
0% ee (R)]; H NMR (400 MHz, CDCl
3
) [Lit. 50 ½aꢀ
3
+40.5 (c 0.45, CHCl ) for
3
) d 1.01 (t, J = 7.4 Hz, 3H), 1.73-
D
D
1
3
2
H), 7.51-7.57 (m, 1H), 7.58-7.62 (m, 1H), 7.66(t, 0.4H), 7.78-7.92 (m,
7
.6H), 8.00 (d, 1H), 8.37(d, 0.3H), 8.74 (d, 0.7H) ; 13C NMR (100MHz,
1
.83 (m, 2H), 2.19 (br, 1H), 2.37 (s, 3H), 4.87 (t, 1H), 7.13-7.52 (m, 4H);
1
3
CDCl
3
) (mixture of rotamers) : d 25.4, 27.4, 27.6, 39.5, 40.3, 55.7, 55.9,
2.2, 114.4, 120.3, 122.7, 123.2, 125.4, 126.2, 126.9, 127.4, 128.4, 128.7,
29.6, 130.4, 130.7, 131.4, 131.7, 131.9, 133.3, 141.2, 144.0, 147.7, 148.8,
49.1, 149.5. HRMS m/z: calcd. for C31H N OP (M + 1), 494.2352; found,
32 3
94.2356.
3
C NMR (100 MHz, CDCl ) d 10.3, 19.0, 30.8, 71.9, 125.1, 126.1, 127.0,
6
1
1
4
130.2, 134.5, 142.7.
(
R)-1-(naphthalen-2-yl)-1-propanol (B7, entry 7 in Table 3):50
. Col-
orless oil (90.3 mg, 97% yield); 95% ee value was determined by Chiral GC
Chirasil Dex CB [170 C, t
ꢂ
R
= 13.2 min (major, R), t
R
= 13.7 min (minor, S)].
Experimental Procedure for Enantioselective Addition of
Diethylzinc to Aldehyde
32:5
25:0
½
aꢀ
+58.2 (c 1.50, CHCl
3
) [Lit. 50 ½aꢀ
+28.6 (c 0.77, CHCl ) for 81%
3
D
D
1
3
ee (R)]; H NMR (400 MHz, CDCl ) d 0.95 (t, 3H), 1.78-1.97 (m, 2H), 2.61
To a solution of L4 (26.2mg, 0.05 mmol) in toluene (0.5 mL), diethylzinc
13
(
(
1
br, 1H), 4.71 (t, 1H), 7.43-7.55 (m, 3H), 7.73-7.90 (m, 4H); C NMR
100 MHz, CDCl ) d 10.0, 31.6, 75.9, 124.1, 124.6, 125.6, 126.0, 127.6,
27.8, 128.1, 132.8, 133.1, 141.8.
ꢂ
(0.5 mL of 1.5 M solution in toluene, 0.75 mmol) was slowly added at –30 C
3
under nitrogen atmosphere and stirred for 30 min. Then benzaldehyde
53.9 mg, 0.5 mmol) was added dropwise. The reaction temperature was
allowed to warm to room temperature. After being stirred at room tempera-
ture for 6 h, the solution was quenched with saturated aqueous NH Cl solu-
tion. Extraction with EtOAc gave combined organic layers that were washed
with brine, dried over Na SO , and concentrated in vacuo to give a residue
that was subjected to silica gel column chromatography (EtOAc/hexane=
/10), which afforded (R)-1-phenylpropan-1-ol.
(
(R)-1-(1-naphthyl)-1-propanol (B8, entry 8 in Table 3):49
. Color-
less oil (89.3 mg, 96% yield); 96% ee value was determined by Chiral GC
4
ꢂ
2
4
Chirasil Dex CB [170 C, t
R
= 13.0 min (minor, S), t
R
= 13.9 min (major,
32:5
26:0
R)]. ½aꢀ
+58.2 (c 1.50, CHCl
3
) [Lit. 49 ½aꢀ
+60.3 (c 1.11, CHCl ) for
3
) d 1.03 (t, 3H), 1.84-2.08
3
D
D
1
1
9
7% ee (R)]; H NMR (400 MHz, CDCl
m, 2H), 2.95 (br, 1H), 5.32 (t, 1H), 7.44-8.15 (m, 7H); C NMR
100 MHz, CDCl ) d 10.3, 30.9, 72.1, 122.8, 123.1, 125.3, 125.2, 125.7,
27.6, 128.7, 130.3, 133.6, 140.1.
13
(
(
(
(
R)-1-phenylpropan-1-ol (B1, entry 1 in Table 3):49
67.4 mg, 99% yield); 95% ee value was determined by Chiral GC Chirasil
. Colorless oil
3
1
ꢂ
20:9
Dex CB [130 C, t
R
= 7.4 min (major, R), t
R
= 7.8 min (minor, S)]. ½aꢀD
26:0
+
20.3 (c 1.00, CHCl
3
) [Lit. 49 ½aꢀ
3
+40.3 (c 1.21, CHCl ) for 95%
): d 0.93 (t, 3H), 1.70-1.88 (m, 2H),
D
1
ee (R)]; H NMR (400 MHz, CDCl
3
TABLE 1. Asymmetric additions of Et
2
Zn to PhCHO catalyzed
a
13
1
.92-1.98 (br, 1H), 4.60 (t, 1H), 7.26-7.39 (m, 5H); C NMR (100 MHz,
by L4-L7
3
CDCl ): d 10.2, 31.9, 75.9, 126.1, 127.4, 128.3, 144.8.
(
R)-1-(4-trifluoromethylphenyl)-1-propanol (B2, entry
2
in
5
0
Table 3): . Colorless oil (102.0 mg, >99% yield); 95% ee value was
determined by Chiral GC Chirasil Dex CB [150 C, t
R), t
+
ꢂ
R
= 4.7 min (major,
3
D
2:0
25:0
D
R
= 5.1 min (minor, S)]. ½aꢀ
+46.7 (c 1.80, CHCl
3
) [Lit. 50 ½aꢀ
1
40.3 (c 1.30, CHCl
3
) for 72% ee (R)]; H NMR (400 MHz, CDCl
3
) d 0.91
b
c
d
(
1
1
t, J = 7.4 Hz, 3H), 1.69-1.83 (m, 2H), 2.31 (br, 1H), 4.64 (t, J = 6.2 Hz,
Entry
Ligand
Yield
ee
Config.
H), 7.39-7.64 (m, 4H); 13C NMR (100 MHz, CDCl
22.8, 125.2, 125.5, 126.2, 129.4, 129.7, 148.5.
3
) d 9.8, 32.0, 75.2,
1
2
3
4
5
6
7
8
L4e
Qd
L5e
Cn
L6e
Qn
L7e
Cd
97
90
77
90
94
92
72
89
94
48
77
46
90
68
72
58
R
S
R
S
S
R
S
R
(
R)-1-(4-chlorophenyl)-1-propanol (B3, entry 3 in Table 3):49
. Color-
less oil (84.2 mg, 99% yield); 94% ee value was determined by Chiral GC
ꢂ
Chirasil Dex CB [150 C, t
R
= 8.7 min (major, R), t
R
= 9.4 min (minor, S)].
3
2:4
26:0
½
aꢀ
+37.8 (c 1.50, CHCl
3
) [Lit. 49 ½aꢀ
+30.6 (c 2.08, CHCl ) for 96% ee
3
D
D
1
(
3
R)]; H NMR (400MHz, CDCl ) d 0.87 (t, J = 7.5 Hz, 3H), 1.62-1.82 (m,
1
3
2
H), 2.32-2.39 (br, 1H), 4.53 (t, J = 6.8 Hz, 1H), 7.19-7.33 (m, 4H); C NMR
(
100 MHz, CDCl
3
) d 9.9, 31.8, 75.2, 127.3, 128.4, 133.0, 142.9.
aAll reactions were conducted with PhCHO (0.5 mmol) and Et
Zn (1.5 M in
2
4
9
toluene, 1.0 mL; 1.5 mmol) in the presence of 10 mol% of chiral ligand.
(
R)-1-(4-methoxyphenyl)-1-propanol (B4, entry 4 in Table 3): . Color-
b
Isolated yield based on PhCHO.
less oil (70.6 mg, 85% yield); 88% ee value was determined by Chiral GC
c
Determined by chiral GC analysis.
ꢂ
Chirasil Dex CB [150 C, t
R
= 8.7 min (major, R), t
R
= 9.0 min (minor, S)].
d
The configuration was determined by comparing the sign of specific rotation
3
2:0
26:0
½aꢀ
+34.5 (c 2.00, CHCl
3
) [Lit. 49 ½aꢀ
+38.9 (c 1.23, CHCl
3
) for 96%
value with the literature value.
D
D
1
e
ee (R)]; H NMR (400 MHz, CDCl
3
) d 0.89 (t, 3H), 1.62-1.90 (m, 2H),
Ref. 29.
Chirality DOI 10.1002/chir