Chiral phosphine-prolineamide as an organocatalyst in direct asymmetric aldol reactions

Article abstract of DOI:10.1016/j.tetasy.2011.11.021

Chiral phosphine-prolineamide 1a was employed as an organocatalyst in direct asymmetric aldol reactions of various aromatic aldehydes with ketones. Cyclohexanone led to the aldol products in up to 98% ee and with good diastereoselectivity using 10 mol % o

Full text of DOI:10.1016/j.tetasy.2011.11.021

Tetrahedron: Asymmetry 22 (2011) 2024–2028
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Chiral phosphine-prolineamide as an organocatalyst in direct asymmetric
aldol reactions
⇑
Takashi Mino , Ayaka Omura, Yukari Uda, Kazuya Wakui, Yuri Haga, Masami Sakamoto, Tsutomu Fujita
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral phosphine-prolineamide 1a was employed as an organocatalyst in direct asymmetric aldol reac-
tions of various aromatic aldehydes with ketones. Cyclohexanone led to the aldol products in up to
98% ee and with good diastereoselectivity using 10 mol % of TFA and 30 mol % of prolineamide 1a in
DMF at 0 °C.
Received 2 November 2011
Accepted 29 November 2011
Available online 11 January 2012
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The aldol reaction is considered to be one of the most important
C–C bond formations in organic synthesis. After the discovery of the
2.1. Preparation of organocatalyst 1
direct intermolecular asymmetric aldol reaction using
L
-proline as
Organocatalyst 1a was easily prepared from N-Boc-proline
(Scheme 1). The N-Boc-phosphineamide 2 was obtained by the reac-
tion of ethyl chloroformate in the presence of N-methylmorpholine
in THF, followed by amidation with 2-(diphenylphosphino)ani-
line.14 This phosphineamide 2 was converted into the desired
organocatalyst 1a using TFA in good yield. The phosphine-oxide-
type organocatalyst 1b was prepared by the oxidation of 1a using
H2O2 in CHCl3.
an organocatalyst by List and Barbas in 2000,1 proline-derived
organocatalysts were developed for aldol reactions and many other
reactions.2 Many prolineamide-type organocatalysts from chiral
amines, such as phenylethylamine,3 aminoalcohols,3b,4 BINAM,5
and NOBIN,6 and also aniline-type compounds without chirality,
such as aminophenol,7 and 8-aminoquinoline,8 have been reported
in recent years. On the other hand, phosphine atom containing
pyrrolidine-type organocatalysts such as chiral phosphonates,9
phosamides,10 phosphinyl oxides,11 and MOP-type12 phosphine-
prolineamides have also been reported. In continuation of our stud-
ies on the chiral P,N-type ligand design13 for transition metal
catalysts, we designed chiral phosphine-prolineamide-type com-
pound 1a as a chiral building block from 2-(diphenylphosphino)ani-
line. Herein we report chiral compound 1a as an organocatalyst for
the direct asymmetric aldol reactions of aromatic aldehydes with
ketones.
2.2. Direct asymmetric aldol reactions of ketones using 1
We investigated the ability of chiral phosphine-prolineamide 1a
as an organocatalyst for the direct asymmetric aldol reaction of
aromatic aldehydes with ketones. p-Nitrobenzaldehyde 3a and
cyclohexanone 4a were chosen as model substrates with 30 mol %
of catalyst for 48 h under an argon atmosphere at 0 °C (Table 1).
Using phosphine-prolineamide 1a as an organocatalyst under neat
conditions, we observed that the aldol reaction gave the corre-
sponding product 5aa in an 80% yield and with good enantioselec-
tivity (96% ee) and diastereoselectivity (anti/syn = 92:8) (entry 1).
When the reaction was carried out by adding 10 mol % of TFA as a
Brønsted acid15 in DMF as a solvent, the yield improved to 93% also
with high enantioselectivity (97% ee) and diastereoselectivity (anti/
syn = 98:2) (entry 2).16 When the reaction was carried out using
20 mol % of the catalyst, the enantioselectivity and diastereoselec-
tivity were slightly decreased (95% ee; anti/syn = 97:3) (entry 3).
We tested phosphine-oxide-type organocatalyst 1b and found that
the reaction rate became slower with moderate diastereoselectivity
(entry 4). Using organocatalyst 1c3,15a,17 without the 2-diphenyl-
phosphino group led to a moderate yield (59%) with good diastere-
oselectivity (entry 5). Under the optimized reaction conditions, we
R
H
N
N
H
O
1a: R = PPh2
1b: R = P(O)Ph2
1c: R = H
⇑
Corresponding author. Tel.: +81 43 290 3385; fax: +81 43 290 3401.
E-mail address: tmino@faculty.chiba-u.jp (T. Mino).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.021

T. Mino et al. / Tetrahedron: Asymmetry 22 (2011) 2024–2028
2025
p-bromobenzaldehyde 3e, methyl 4-formylbenzoate 3f, and p-tri-
fluoromethylbenzaldehyde 3g led to low-to-moderate yields with
moderate enantioselectivities (entries 9–11). Using 2,4-dinitro-
benzaldehyde 3h gave the product 5ha in high yield and with good
enantioselectivity (entry 12). Conversely, the reaction with a het-
eroaryl containing aldehyde, such as 4-pyridinecarboxaldehyde 3i
gave product 5ia in moderate yield with good enantioselectivity
(entry 13). We also tested the reaction of p-nitrobenzaldehyde 3a
with various ketones (entries 14–16). Using tetrahydro-4H-pyran-
4-one 4b led to good yield (85%) and diastereoselectivity with mod-
erate enantioselectivity (entry 14). The reaction of cyclopentanone
4c gave the corresponding product 5ac with a moderate enantiose-
lectivity in moderate yield (entry 7). When acetone 4d was used,
the reaction gave product 5ad in a 48% yield with moderate enanti-
oselectivity (entry 16).
ClCOOEt (1.1 eq.)
N-methylmorpholine (1.1
eq.)
OH
N
THF, -15 °C, 3 h
Boc
O
NH2
PPh2
H
N
PPh2
(1.0 eq.)
N
Boc
THF, rt, 17 h
O
2
81%
The mechanism of this reaction using organocatalyst 1a is be-
lieved to be similar to that of the previously reported prolineamide
via an enamine intermediate.6a,8,15a Organocatalyst 1a showed a
much better ability at controlling the enantioselectivity and diaste-
reoselectivity of the direct aldol reaction than N-phenylprolinea-
mide 1c. At this stage, we propose that not only does the hydrogen
bonding between the aryl aldehyde and the amide NH group play
an important role in the selectivity but also the steric hindrance of
TFA (2.0 eq.)
H2O2
CHCl3, rt, 3 h
1b
1a
CHCl3, 50 °C, 3 h
97%
98%
Scheme 1. Preparation of chiral phosphine-prolineamides 1.
the 2-diphenylphosphino group or p–p
interactions6b between the
aryl aldehyde and the aromatic ring at 2-diphenylphosphino group
plays an important role.
investigated the aldol reactions of various aromatic aldehydes with
cyclohexanone 4a using 30 mol % of phosphine-prolineamide 1a
and 10 mol % of TFA in DMF at 0 °C (entries 6–13). The reaction with
m-nitrobenzaldehyde 3b gave the corresponding product 5ba in
moderate enantioselectivity (88% ee) and with high diastereoselec-
tivity (anti/syn = 98:2) (entry 6). The reaction with o-nitrobenzalde-
hyde 3c gave the corresponding product 5ca with high
enantioselectivity (98% ee) and diastereoselectivity (anti/
syn = 98:2) in moderate yield (entry 7). When p-cyanobenzalde-
hyde 3d was used, the reaction gave product 5da in moderate yield
with good enantioselectivity (entry 8). However, the reactions with
3. Conclusion
In conclusion, we found that a chiral phosphine-prolineamide
with a 2-(diphenylphosphino)aniline backbone can be employed
as an organocatalyst in the direct asymmetric aldol reactions of
various aromatic aldehydes with ketones giving up to 98% ee with
good diastereoselectivity using 10 mol % of TFA and 30 mol % of
catalyst 1a in DMF at 0 °C. Further studies focusing on the
Table 1
Direct asymmetric aldol reaction of ketones using 1a
OH
O
O
O
1 (30 mol%)
TFA (10 mol%)
DMF (0.67 M)
0 °C, 48 h
+
Ar
Ar
H
R
R
R
R
4
3
5
(27 eq.)
Entry
Catalyst
Ar
R
Yieldb (%)
drc (anti/syn)
eed (%)
1e
2
1a
1a
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
p-NO2C6H4 3a
p-NO2C6H4 3a
p-NO2C6H4 3a
p-NO2C6H4 3a
p-NO2C6H4 3a
m-NO2C6H4 3b
o-NO2C6H4 3c
p-CNC6H4 3d
p-BrC6H4 3e
p-(COOMe)C6H4 3f
p-CF3C6H4 3g
2,4-NO2C6H3 3h
4-pyridyl 3i
–(CH2)3– 4a
–(CH2)3– 4a
–(CH2)3– 4a
–(CH2)3– 4a
–(CH2)3– 4a
–(CH2)3– 4a
–(CH2)3– 4a
–(CH2)3– 4a
–(CH2)3– 4a
–(CH2)3– 4a
–(CH2)3– 4a
–(CH2)3– 4a
–(CH2)3– 4a
–CH2OCH2– 4b
–(CH2)2– 4c
H 4d
80 5aa
93 5aa
86 5aa
57 5aa
59 5aa
71 5ba
64 5ca
77 5da
37 5ea
67 5fa
57 5ga
100 5ha
58 5ia
92:8
98:2
97:3
81:19
92:8
98:2
98:2
95:5
84:16
88:12
90:10
98:2
96:4
91:9
34:66
—
96
97
95
94
97
88
98
92
60
73
78
90
93
83
84
62
3f
4
5
6
7
8
9
10
11
12
13
14
15
16
p-NO2C6H4 3a
p-NO2C6H4 3a
p-NO2C6H4 3a
85 5ab
54 5ac
48 5ad
a
b
c
d
e
f
The reactions were carried out on a 0.25 mmol scale of 3 in DMF (0.375 mL) at 0 °C with 27 equiv of 4 in the presence of 1 (30 mol %) and TFA (10 mol %).
Isolated yields (anti/syn).
Determined by 1H NMR of the crude mixture.
Determined for the anti-isomer by HPLC analysis using a chiral column.
This reaction was carried out without using TFA and DMF.
This reaction was carried out using 20 mol % of 1.

2026
T. Mino et al. / Tetrahedron: Asymmetry 22 (2011) 2024–2028
generality of other substrates and the application of 1a and 1b in
other reactions are currently in progress in our laboratory and will
be reported in due course.
1H), 11.4 (s, 1H); 13C NMR (CDCl3) d 25.6, 30.9, 47.1, 61.1, 120.0
(d, JCP = 101.8 Hz), 122.6 (d, JCP = 7.4 Hz), 122.9 (d, JCP = 13.1 Hz),
128.5 (d, JCP = 12.4 Hz), 128.6 (d, JCP = 12.4 Hz), 131.0, 131.7 (d,
JCP = 104.9 Hz), 131.8 (d, JCP = 9.5 Hz), 132.1 (d, JCP = 9.5 Hz),
132.1, 132.2 (d, JCP = 2.9 Hz), 132.7 (d, JCP = 10.5 Hz), 133.2 (d,
JCP = 2.9 Hz), 142.9 (d, JCP = 3.8 Hz), 174.9; 31P NMR (121 MHz,
CDCl3) d 34.5; HRMS (FAB-MS) m/z calcd for C23H23N2O2P + H
391.1575, found 391.1576.
4. Experimental
4.1. Preparation of 2
To a solution of N-Boc-proline (0.65 g, 3.0 mmol) in THF
(4.0 mL), were added ClCOOEt (0.32 mL, 3.3 mmol) and N-methyl-
morpholine (0.36 mL, 3.3 mmol). After 3 h at ꢀ15 °C, 2-(diphenyl-
phosphino)aniline13 (0.83 g, 3.0 mmol) in THF (6.0 mL) was added
and the stirring was continued for 17 h at room temperature. The
reaction mixture was filtered and evaporated under reduced pres-
sure. The residue was purified by silica gel chromatography (hex-
ane/EtOAc = 8:1): 1.16 g, 2.44 mmol, 81% as a white solid; mp
4.4. General procedure for the direct asymmetric aldol reaction
of ketones using 1
To a mixture of aryl aldehyde 3 (0.25 mmol), and chiral phos-
phineamide 1 (0.075 mmol) in DMF (0.275 mL) were added TFA
(0.025 mmol) in DMF (0.25 M, 0.1 mL) and ketone 4 (6.75 mmol)
at 0 °C under an argon atmosphere. After 48 h, the reaction mixture
was quenched with satd NH4Cl (aq) and diluted with EtOAc. The
organic layer was washed with water and brine, and dried over
MgSO4. The filtrate was concentrated with a rotary evaporator
and the residue was purified by column chromatography.
109–110 °C; ½a 2D5
ꢁ
¼ ꢀ103:9 (c 0.30, CHCl3); 1H NMR (CDCl3) d
1.25–2.04 (m, 13H), 3.24 and 3.36 (br s and br s, 2H, rotamer),
4.21 and 4.39 (br s and br s, 1H, rotamer), 6.80 (s, 1H), 7.04, (t,
J = 7.2 Hz, 1H), 7.22–7.42 (m, 11H), 8.22 (dd, J = 4.7 and 7.9 Hz,
1H), 8.61 (s, 1H, major rotamer), 8.99 (s, 1H, minor rotamer), 13C
NMR (CDCl3, major rotamer) d 23.6, 28.4, 31.0, 46.9, 62.2, 80.6,
121.5 (JCP = 10.0 Hz), 124.9, 126.6 (JCP = 10.5 Hz), 128.7, 128.8,
128.9, 129.2, 130.1, 133.4, 133.5 (JCP = 10.6 Hz), 133.9
(JCP = 19.6 Hz), 140.4, 154.4, 171.1; 31P NMR (CDCl3) d ꢀ20.5;
HRMS (ESI-MS) m/z calcd for C28H31N2O3P + Na 497.1965, found
497.1953.
4.4.1. Compound 5aa6a (Table 1, entry 2)
93% yield [mixture of anti- and syn-products (anti/syn = 98:2)];
97% ee; ½a 2D0
ꢁ
¼ þ10:0 (c 0.50, CHCl3); 1H NMR (CDCl3) d 1.25–1.86
(m, 5H), 2.08–2.18 (m, 1H), 2.31–2.64 (m, 3H), 4.09 (d, J = 3.1 Hz,
1H), 4.90 (dd, J = 2.9 and 8.4 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 8.22
(d, J = 8.7 Hz, 2H); 13C NMR (CDCl3) d 24.6, 27.6, 30.7, 42.7, 57.2,
74.0, 123.6, 127.8, 147.5, 148.3, 214.7; HRMS(ESI-MS) m/z calcd
for C13H15O4N + Na 272.0893, found 272.0891; HPLC (Daicel CHIR-
ALPAKÒ AD-H, 0.46 / ꢂ 25 cm, UV 254 nm) tR (major) = 33.3 min,
tR (minor) = 25.9 min (hexane/2-propanol = 80:20, 0.5 mL/min).
4.2. Preparation of 1a
To a solution of N-Boc-phosphineamide 2 (0.47 g, 1.0 mmol) in
CHCl3 (5.0 mL) was added TFA (1.49 mL, 20.0 mmol). The reaction
mixture was stirred for 3 h at 50 °C. Next, the reaction mixture
was evaporated under reduced pressure, the residue was diluted
with CHCl3, and quenched with sat. NaHCO3 aq. The organic layer
was washed with water, dried over MgSO4, and concentrated un-
der reduced pressure. The residue was purified by silica gel chro-
matography (CHCl3/MeOH = 60:1): 0.37 g, 0.98 mmol, 98% as a
4.4.2. Compound 5ba18 (Table 1, entry 6)
71% yield [mixture of anti- and syn-products (anti/syn = 98:2)];
88% ee; ½a 2D0
ꢁ
¼ þ26:9 (c 0.50, CHCl3); 1H NMR (CDCl3) d 1.32–1.86
(m, 5H), 2.09–2.18 (m, 1H), 2.32–2.43 (m, 1H), 2.47–2.55 (m, 1H),
2.58–2.67 (m, 1H), 4.14 (d, J = 3.0 Hz, 1H), 4.90 (dd, J = 2.9, 8.5 Hz,
1H), 7.53 (t, J = 7.9 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 8.15–8.22 (m,
2H), 13C NMR (CDCl3) d 24.6, 27.6, 30.7, 42.6, 57.1, 74.0, 122.0,
122.9, 129.3, 133.2, 143.2, 148.2, 214.9; HRMS (ESI-MS) m/z calcd
for C13H15O4N+Na 272.0893, found 272.0892; HPLC (Daicel CHIR-
white solid; mp 94–95 °C; ½a D25
ꢁ
¼ ꢀ39:3 (c 0.30, CHCl3); 1H NMR
(CDCl3) d 1.27–1.41 (m, 1H), 1.46–1.59 (m, 1H), 1.71–1.81 (m,
1H), 1.92–2.09 (m, 2H), 2.66 (dt, J = 6.4 and 9.3 Hz, 1H), 2.88 (dt,
J = 7.0 and 9.9 Hz, 1H), 3.72 (dd, J = 4.7 and 9.3 Hz, 1H), 6.75
(ddd, J = 1.4, 2.8, and 6.3 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H), 7.25–
7.40 (m, 11H), 8.28 (ddd, J = 0.9, 4.4, and 5.4 Hz, 1H), 10.43 (d,
J = 4.6 Hz, 1H); 13C NMR (CDCl3) d 25.8, 30.7, 47.1, 61.1, 121.1 (d,
JCP = 2.2 Hz), 124.3 (d, JCP = 1.2 Hz), 126.6 (d, JCP = 11.4 Hz), 128.6
(d, JCP = 2.7 Hz), 128.7 (d, JCP = 3.0 Hz), 129.1, 129.2, 129.9, 133.1
(d, JCP = 1.2 Hz), 133.7 (d, JCP = 19.6 Hz), 134.1 (d, JCP = 19.8 Hz),
134.7 (d, JCP = 7.9 Hz), 134.8 (d, JCP = 7.9 Hz), 140.6 (d,
JCP = 18.1 Hz), 173.6 (d, JCP = 2.0 Hz), 31P NMR (CDCl3) d ꢀ17.2;
HRMS (ESI-MS) m/z calcd for C23H23ON2P+H 375.1621, found
375.1616.
ALPAKÒ AD-H, 0. 46
tR (minor) = 47.5 min (hexane/2-propanol = 92:8, 0.8 mL/min).
u
ꢂ25 cm, UV 220 nm) tR (major) = 37.1 min,
4.4.3. Compound 5ca6a (Table 1, entry 7)
64% yield [mixture of anti- and syn-products (anti/syn = 98:2)];
98% ee; ½a 2D0
ꢁ
¼ þ10:0 (c 0.50, CHCl3); 1H NMR (CDCl3) d 1.52–1.88
(m, 5H), 2.05–2.18 (m, 1H), 2.28–2.50 (m, 2H) 2.72–2.80 (m, 1H)
4.20 (s, 1H), 5.45 (d, J = 7.0 Hz, 1H), 7.41–7.46 (m, 1H), 7.64 (td,
J = 1.2, 7.6 Hz, 1H), 7.77 (dd, J = 1.4 and 7.9 Hz, 1H), 7.85 (dd,
J = 1.2 and 8.2 Hz, 1H); 13C NMR (CDCl3) d 25.0, 27.7, 31.1, 42.8,
57.3, 69.8, 124.1, 128.4, 129.0, 133.1, 136.6, 214.9; HRMS(ESI-
MS) m/z calcd for C13H15O4N + Na 272.0893, found 272.0892; HPLC
(Daicel CHIRALPAKÒ AD-H, 0.46 / ꢂ 25 cm, UV 220 nm) tR (ma-
jor) = 29.4 min, tR (minor) = 31.5 min (hexane/2-propanol = 92:8,
0.8 mL/min).
4.3. Preparation of 1b
To a solution of phosphineamide 1a (0.11 g, 0.3 mmol) in CHCl3
(2.0 mL) was added hydrogen peroxide (30%) (2.0 mL) at room
temperature. The reaction mixture was stirred for 3 h at room tem-
perature. The reaction mixture was diluted with CHCl3 and 2 M
NaOH aq. The organic layer was washed with water, dried over
MgSO4, and concentrated under reduced pressure: 0.11 g,
4.4.4. Compound 5da6a (Table 1, entry 8)
77% yield [mixture of anti- and syn-products (anti/syn = 95:5)];
92% ee; ½a 2D0
ꢁ
¼ þ24:4 (c 0.50, CHCl3); 1H NMR (CDCl3) d 1.25–1.43
(m, 1H), 1.48–1.85 (m, 4H), 2.08–2.14 (m, 1H), 2.31–2.41 (m, 1H)
2.47–2.62 (m, 2H), 4.06 (d, J = 3.0 Hz, 1H), 4.84 (dd, J = 2.5 and
8.4 Hz, 1H), 7.43–7.46 (m, 2H), 7.63–7.66 (m, 2H); 13C NMR (CDCl3)
d 24.7, 27.6, 30.7, 42.6, 57.1, 74.2, 111.7, 118.7, 127.7, 132.2, 146.3,
214.8; HRMS(ESI-MS) m/z calcd for C14H15O2N + Na 252.0995,
0.29 mmol, 97%; as a white solid; mp 129–131 °C; ½a D25
¼ þ36:8
ꢁ
(c 0.30, CHCl3); 1H NMR (CDCl3) d 1.26–1.38 (m, 1H), 1.46–1.66
(m, 2H), 1.95–2.07 (m, 2H), 2.87–2.98 (m, 2H), 3.70 (dd, J = 4.6
and 9.0 Hz, 1H), 6.92 (ddd, J = 1.5, 7.6, and 14.0 Hz, 1H), 6.99–
7.05 (m, 1H), 7.43–7.67 (m, 11H), 8.46 (dd, J = 4.4 and 8.3 Hz,
found 252.0995; HPLC (Daicel CHIRALPAKÒ AD-H, 0.46
/

T. Mino et al. / Tetrahedron: Asymmetry 22 (2011) 2024–2028
2027
ꢂ 25 cm, UV 254 nm) tR (major) = 33.9 min, tR (minor) = 26.8 min
J = 8.7 Hz, 2H), 8.24 (dt, J = 2.0 and 6.8 Hz, 2H); 13C NMR (CDCl3)
d 42.8, 57.6, 68.3, 69.8, 71.3, 123.7, 123.8, 126.3, 127.4, 147.3,
147.7, 209.3; HRMS (Negative ESI-MS) m/z calcd for C12H13NO5-H
250.0721, found 250.0723; HPLC (Daicel CHIRALPAKÒ AD-H, 0.46
/ ꢂ 25 cm, UV 254 nm) tR (major) = 76.1 min, tR (minor) = 66.7 min
(hexane/2-propanol = 90:10, 0.8 mL/min).
(hexane/2-propanol = 90:10, 1.0 mL/min).
4.4.5. Compound 5ea19 (Table 1, entry 9)
37% yield [mixture of anti- and syn-products (anti/syn = 84:16)];
60% ee; ½a 2D0
ꢁ
¼ þ6:1 (c 0.50, CHCl3); 1H NMR (CDCl3) d 1.21–1.37
(m, 1H), 1.46–1.83 (m, 4H), 2.06–2.15 (m, 1H), 2.30–2.60 (m,
3H), 3.99 (s, 1H), 4.75 (d, J = 8.7 Hz, 1H), 7.18–7.22 (m, 2H), 7.45–
7.50 (m, 2H); 13C NMR (CDCl3) d 24.7, 27.7, 30.7, 42.7, 57.3, 74.2,
121.7, 128.7, 131.5, 140.0, 215.3; HRMS(ESI-MS) m/z calcd for
4.4.11. Compound 5ac6a (Table 1, entry 15)
54% yield [mixture of anti- and syn-products (anti/syn = 34:66)];
84% ee; ½a 2D0
ꢁ
¼ ꢀ29:9 (c 0.50, CHCl3); 1H NMR (CDCl3) d 1.47–1.84
C
13H15O2Br + Na 305.0148, found 305.0146; HPLC (Daicel CHIR-
(m, 3H), 1.95–2.02 (m, 1H), 2.10–2.53 (m, 3H), 4.77 (s, 1H), 4.85 (d,
J = 9.2 Hz, 1H), 7.51–7.56 (m, 2H), 8.20–8.24 (m, 2H); 13C NMR
(CDCl3) d 20.3, 26.8, 38.6, 55.1, 74.4, 123.7, 127.3, 147.6, 148.6,
222.2; HRMS(ESI-MS) m/z calcd for C12H13O4N + Na 258.0737,
ALPAKÒ AD-H, 0.46 / ꢂ 25 cm, UV 254 nm) tR (major) = 19.6 min,
tR (minor) = 16.8 min (hexane/2-propanol = 90:10, 1.0 mL/min).
4.4.6. Compound 5fa19 (Table 1, entry 10)
found 258.0735; HPLC (Daicel CHIRALPAKÒ AD-H, 0.46
/
67% yield [mixture of anti- and syn-products (anti/syn = 88:12)];
ꢂ 25 cm, UV 254 nm) tR (major) = 108.2 min, tR (minor) = 102.1 -
73% ee; ½a 2D0
ꢁ
¼ þ12:5 (c 0.50, CHCl3); 1H NMR (CDCl3) d 1.25–1.38
min (hexane/2-propanol = 95:5, 0.5 mL/min).
(m, 1H), 1.47–1.82 (m, 4H), 2.06–2.14 (m, 1H), 2.31–2.65 (m, 3H)
3.92 (s, 3H), 4.03 (s, 1H), 4.85 (d, J = 8.6 Hz, 1H), 7.40 (d,
J = 8.1 Hz, 2H), 8.02 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3) d 24.7,
27.7, 30.7, 42.7, 52.1, 57.3, 74.4, 127.0, 129.65, 129.68, 146.0,
4.4.12. Compound 5ad6a (Table 1, entry 16)
48% yield; 62% ee; ½a D20
ꢁ
¼ þ27:4 (c 0.50, CHCl3); 1H NMR (CDCl3)
d 2.22 (s, 3H), 2.85 (d, J = 8.1 Hz, 1H), 2.86 (d, J = 4.1 Hz, 1H), 3.61 (s,
1H), 5.26 (dd, J = 4.6, 7.5 Hz, 1H), 7.52–7.55 (m, 2H), 8.19–8.23 (m,
2H); 13C NMR (CDCl3) d 30.7, 51.5, 68.9, 123.8, 126.4, 147.3, 149.9,
208.5; HRMS(ESI-MS) m/z calcd for C10H11O4N+Na 232.0580, found
232.0584; HPLC (Daicel CHIRALPAKÒ AS-H, 0.46 / ꢂ 25 cm, UV
254 nm) tR (major) = 32.1 min, tR (minor) = 39.1 min (hexane/2-
propanol = 70:30, 0.5 mL/min).
166.8, 215.1; HRMS(ESI-MS) m/z calcd for
C15H18O4 + Na
285.1097, found 285.1092; HPLC (Daicel CHIRALPAKÒ AS-H, 0.46
/ ꢂ 25 cm, UV 254 nm) tR (major) = 28.4 min, tR (minor) = 44.9 min
(hexane/2-propanol = 80:20, 0.8 mL/min).
4.4.7. Compound 5ga6a (Table 1, entry 11)
57% yield [mixture of anti- and syn-products (anti/syn = 90:10)];
78% ee; ½a 2D0
ꢁ
¼ þ16:3 (c 0.50, CHCl3); 1H NMR (CDCl3) d 1.26–1.41
References
(m, 1H), 1.48–1.84 (m, 4H), 2.07–2.16 (m, 1H), 2.31–2.64 (m, 3H),
4.05 (s, 1H), 4.85 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.61 (d,
J = 8.1 Hz, 2H); 13C NMR (CDCl3) d 24.7, 27.7, 30.7, 42.7, 57.2, 74.3,
121.3 (q, JCF = 271.8 Hz), 125.3 (q, JCF = 3.85 Hz), 127.4, 130.1 (q,
JCF = 32.4 Hz), 145.0, 215.1; HRMS(ESI-MS) m/z calcd for
1. (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395–2396;
(b) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386–7387.
2. For reviews, see the following: (a) Geary, L. M.; Hultin, P. G. Tetrahedron:
Asymmetry 2009, 20, 131–173; (b) Guillena, G.; Nájera, C.; Ramón, D. J.
Tetrahedron: Asymmetry 2007, 18, 2249–2293; (c) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569; (d) List, B. Chem.
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2186–2188; (f) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37,
580–591; (g) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570–579; (h) List,
B. Acc. Chem. Res. 2004, 37, 548–557.
C
14H15O2F3+Na 295.0916, found 295.0914; HPLC (Daicel CHIR-
ALPAKÒ AD-H, 0.46 / ꢂ 25 cm, UV 220 nm) tR (major) = 16.3 min,
tR (minor) = 12.8 min (hexane/2-propanol = 90:10, 1.0 mL/min).
4.4.8. Compound 5ha20 (Table 1, entry 12)
3. (a) Chimni, S. S.; Mahajan, D. Tetrahedron: Asymmetry 2006, 17, 2108–2119; (b)
Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5755–5760.
100% yield [mixture of anti- and syn-products (anti/syn = 98:2)];
90% ee; ½a 2D0
ꢁ
¼ þ11:5 (c 0.50, CHCl3); 1H NMR (CDCl3) d 1.55–1.93
4. (a) Vishnumaya, M. R.; Singh, V. K. J. Org. Chem. 2009, 74, 4289–4297; (b) Tang,
Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am.
Chem. Soc. 2005, 127, 9285–9289; (c) Tang, Z.; Jiang, F.; Yu, L. T.; Cui, X.; Gong,
L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262–5263.
5. (a) Guillena, G.; Nájera, C.; Viózquez, S. F.; Yus, M. ARKIVOC 2011, 166–178; (b)
Bañón-Caballero, A.; Guillena, G.; Nájera, C. Green Chem. 2010, 12, 1599–1606;
(c) Guillena, G.; Nájera, C.; Viózquez, S. F. Synlett 2008, 3031–3035; (d)
Guillena, G.; Hita, M.; Del, C.; Nájera, C.; Viózquez, S. F. Tetrahedron: Asymmetry
2007, 18, 2300–2304.
6. (a) Russo, A.; Botta, G.; Lattanzi, A. Tetrahedron 2007, 63, 11886–11892; (b)
Wang, C.; Jiang, Y.; Zhang, X.-X.; Huang, Y.; Li, B.-G.; Zhang, G.-L. Tetrahedron
Lett. 2007, 48, 4281–4285; (c) Russo, A.; Botta, G.; Lattanzi, A. Synlett 2007,
795–799.
7. (a) Zhang, S.-P.; Fu, X.-K.; Fu, S.-D. Tetrahedron Lett. 2009, 50, 1173–1176; (b)
Sathapornvajana, S.; Vilaivan, T. Tetrahedron 2007, 63, 10253–10259.
8. Reddy, B. V. S.; Bhavani, K.; Raju, A.; Yadav, J. S. Tetrahedron: Asymmetry 2011,
22, 881–886.
9. Dinér, P.; Amedjkouh, M. Org. Biomol. Chem. 2006, 4, 2091–2096.
10. Yu, G.; Ge, Z.-M.; Cheng, T.-M.; Li, R.-T. Chin. J. Chem. 2008, 26, 911–915.
11. (a) Tan, B.; Zeng, X.; Lu, Y.; Chua, P. J.; Zhong, G. Org. Lett. 2009, 11, 1927–1930;
(b) Liu, X.-W.; Le, T.-N.; Lu, Y.; Ma, J.; Li, X. Org. Biomol. Chem. 2008, 6, 3997–
4003.
12. Ma, G.-N.; Cao, S.-H.; Shi, M. Tetrahedron: Asymmetry 2009, 20, 1086–1092.
13. For recent reports see: (a) Mino, T.; Yamada, H.; Komatsu, S.; Kasai, M.;
Sakamoto, M.; Fujita, T. Eur. J. Org. Chem. 2011, 4540–4542; (b) Mino, T.;
Komatsu, S.; Wakui, K.; Yamada, H.; Saotome, H.; Sakamoto, M.; Fujita, T.
Tetrahedron: Asymmetry 2010, 21, 711–718; (c) Mino, T.; Tanaka, Y.; Hattori, Y.;
Yabusaki, T.; Saotome, H.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2006, 71, 7346–
7353; (d) Mino, T.; Sato, Y.; Saito, A.; Tanaka, Y.; Saotome, H.; Sakamoto, M.;
Fujita, T. J. Org. Chem. 2005, 70, 7979; (e) Mino, T.; Saito, A.; Tanaka, Y.;
Hasegawa, S.; Sato, Y.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2005, 70,
1937.
(m, 5H), 2.05–2.18 (m, 1H), 2.28–2.50 (m, 2H) 2.71–2.89 (m, 1H),
4.32 (d, J = 5.8 Hz, 1H), 5.52 (t, J = 5.9 Hz, 1H), 8.08 (d, J = 8.7 Hz,
1H), 8.48 (dd, J = 2.3 and 8.7 Hz, 1H), 8.75 (d, J = 2.3 Hz, 1H); 13C
NMR (CDCl3) d 24.9, 27.7, 31.4, 42.8, 56.9, 70.1, 119.8, 127.1,
131.0, 143.8, 147.0, 148.1, 214.5; HRMS(ESI-MS) m/z calcd for
C
13H14O6N2+Na 317.0744, found 317.0741; HPLC (Daicel CHIR-
ALPAKÒ AD-H, 0.46 / ꢂ 25 cm, UV 254 nm) tR (major) = 37.3 min,
tR (minor) = 33.2 min (hexane/2-propanol = 85:15, 0.7 mL/min).
4.4.9. Compound 5ia18 (Table 1, entry 13)
58% yield [mixture of anti- and syn-products (anti/syn = 96:4)];
93% ee; ½a 2D0
ꢁ
¼ þ13:9 (c 0.50, CHCl3); 1H NMR (CDCl3) d 1.25–1.87
(m, 5H), 2.06–2.18 (m, 1H), 2.30–2.63 (m, 3H), 4.03 (br s, 1H), 4.78
(d, J = 8.2 Hz, 1H), 7.25–7.26 (m, 2H), 8.59 (d, J = 4.9 Hz, 2H); 13C
NMR (CDCl3) d 24.7, 27.7, 30.8, 42.7, 56.8, 73.7, 122.0, 149.8,
149.9, 214.8; HRMS(ESI-MS) m/z calcd for
C12H15O2N + Na
228.0995, found 228.0993; HPLC (Daicel CHIRALPAKÒ AD-H, 0.46
/ ꢂ 25 cm, UV 220 nm) tR (major) = 44.3 min, tR (minor) = 39.6 min
(hexane/2-propanol = 98:2, 0.8 mL/min).
4.4.10. Compound 5ab6a (Table 1, entry 14)
85% yield [mixture of anti- and syn-products (anti/syn = 91:9)];
83% ee; ½a 2D0
ꢁ
¼ ꢀ6:9 (c 0.50, CHCl3); 1H NMR (CDCl3) d 2.51–2.57
(m, 1H), 2.64–2.70 (m, 1H), 2.88–2.92 (m, 1H), 3.46 (dd, J = 10.0
14. Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5, 2315–2318.
and 11.3 Hz, 1H), 3.70–4.22 (m, 3H), 4.97–5.00 (m, 1H), 7.52 (d,

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Zimnicka, M.; Lipinski, R. J. Org. Chem. 2007, 72, 964–970.
18. Kanemitsu, T.; Umehara, A.; Miyazaki, M.; Nagata, K.; Itoh, T. Eur. J. Org. Chem.
2011, 993–997.
16. When the reaction was carried out under an air atmosphere, we observed that
the aldol reaction proceeded to give corresponding product 5aa in 95% yield
with 98% ee (anti/syn = 97:3).
17. Fuentes de Arriba, Á. L.; Simón, L.; Raposo, C.; Alcázar, V.; Sanz, F.; Muñiz, F. M.;
Morán, J. R. Org. Biomol. Chem. 2010, 8, 2979–2985.
19. Martínez-Castañeda, Á.; Poladura, B.; Rodríguez-Solla, H.; Concellón, C.; del
Amo, V. Org. Lett. 2011, 13, 3032–3035.
20. Yang, H.; Mahapatra, S.; Cheong, P. H.-Y.; Carter, R. G. J. Org. Chem. 2010, 75,
7279–7290.