Direct catalytic asymmetric aldol reaction of thioamides: A concise asymmetric synthesis of (R)-fluoxetine

Article abstract of DOI:10.1016/j.tetasy.2010.04.034

A direct catalytic asymmetric aldol reaction of aromatic aldehydes and thioamides is described. A soft Lewis acid/hard Bronsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH₃CN)₄]PF ₆/Li(OC₆H₄-p-OMe) promoted the title reaction efficiently, triggered by in situ generation of the active thioamide enolate through a soft-soft interaction of Cu(I) and the thioamide. The aldol product was transformed into (R)-fluoxetine, an antidepressant agent.

Full text of DOI:10.1016/j.tetasy.2010.04.034

Tetrahedron: Asymmetry 21 (2010) 1688–1694
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Direct catalytic asymmetric aldol reaction of thioamides: a concise
asymmetric synthesis of (R)-fluoxetine
a,b,
Mitsutaka Iwata a,b, Ryo Yazaki a,b, Naoya Kumagai a,b, , Masakatsu Shibasaki
*
*
a Microbial Chemistry Research Foundation, Microbial Chemistry Research Center, 3-14-23 Kamioosaki, Shinagawa-ku, Tokyo 141-0021, Japan
b Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct catalytic asymmetric aldol reaction of aromatic aldehydes and thioamides is described. A soft
Lewis acid/hard Brønsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH3CN)4]PF6/
Li(OC6H4-p-OMe) promoted the title reaction efficiently, triggered by in situ generation of the active thi-
oamide enolate through a soft–soft interaction of Cu(I) and the thioamide. The aldol product was trans-
formed into (R)-fluoxetine, an antidepressant agent.
Received 22 March 2010
Accepted 19 April 2010
Available online 2 June 2010
Dedicated to Professor Henri B. Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
direct catalytic asymmetric aldol reaction of aliphatic aldehydes
1 and thioamides 2, affording b-hydroxy thioamides 3 in high
The aldol reaction is one of the most fundamental and ubiqui-
tous carbon–carbon bond-forming reactions in both bioorganic
transformations and organic synthesis.1 Due to the synthetic utility
of enantioenriched b-hydroxy carbonyl entities produced by enan-
tioselective aldol reactions, the catalytic asymmetric aldol reaction
is a subject of intense research.2 Although a number of methodol-
ogies using preactivated enolates have been developed for the cat-
alytic asymmetric aldol reaction, the direct catalytic asymmetric
aldol reaction, in which an active enolate is generated in a catalytic
manner via proton-transfer and coupled with subsequent asym-
metric addition to aldehydes, is attracting increasing attention as
a more atom-economical3 and environmentally benign synthetic
methodology.4–6 The key issue of the direct aldol reaction is effi-
cient catalytic generation of active enolates in situ, thus the aldol
donors implemented in the direct aldol reaction have been largely
enantioselectivity,11,12 whereas aromatic aldehydes were not
applicable due to retro-reaction and subsequent dehydration to
give unsaturated thioamides. Herein, we report the direct catalytic
asymmetric aldol reaction of thioamides with aromatic aldehydes.
The utility of the reaction is highlighted by a concise enantioselec-
tive synthesis of (R)-fluoxetine, a widely used antidepressant
agent.
2. Results and discussion
Previous studies have reported that soft Lewis acid/hard
Brønsted base cooperative catalysts comprising (R,R)-Ph-BPE/
[Cu(CH3CN)4]PF6/LiOAr are effective for chemoselective activation
of thioamides as a soft Lewis basic pronucleophile through a
soft–soft interaction.11 As for the direct aldol reaction of thioam-
ides, DMF as a Lewis basic solvent is essential for efficient catalytic
turnover.11a,13 A model reaction of benzaldehyde 1a and N,N-dial-
lylthioacetamide 2a under the standard aldol reaction conditions
for aliphatic aldehydes with 10 mol % catalyst resulted in moderate
limited to ketones and aldehydes in which the acidity of the a-pro-
ton is high enough for deprotonative activation. For further elabo-
ration of synthetically versatile aldol products, the direct aldol
reaction with aldol donors in the carboxylic acid oxidation state
provides b-hydroxy carboxylates, which offer broader functional
group manipulation.7–9
In this context, we focused on thioamide functionality as a suit-
able aldol donor that can be activated through a soft Lewis acid/
hard Brønsted base cooperative catalysis.10 In addition, thioamide
functionality in the aldol product serves as a useful handle for
subsequent functional group transformations. A catalytic system
comprising (R,R)-Ph-BPE/[Cu(CH3CN)4]PF6/LiOAr promoted the
enantioselectivity and the time-dependent formation of a,b-unsat-
urated thioamide 4aa (Table 1, entries 1–3). When the isolated al-
dol product 3aa was again subjected to the reaction conditions, a
mixture of 1a, 2a, 4aa, as well as 3aa was produced (Scheme 1a),
whereas the aldol product derived from aliphatic aldehyde 30 re-
mained unchanged in the same procedure (Scheme 1b), indicating
that the aldol product derived from the aromatic aldehyde was
more prone to retro-aldol reaction and b-elimination. A THF/DMF
mixed solvent system attenuated the Brønsted basicity of
Li(OC6H4-p-OMe) and prevented the b-elimination at ꢀ70 °C (en-
tries 4–8). When the reaction was conducted in THF/DMF = 9/1 sol-
vent, catalytic turnover was arrested likely due to product
* Corresponding authors.
E-mail addresses: nkumagai@mol.f.u-tokyo.ac.jp (N. Kumagai), mshibasa@mol.f.
u-tokyo.ac.jp (M. Shibasaki).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.034

M. Iwata et al. / Tetrahedron: Asymmetry 21 (2010) 1688–1694
1689
Table 1
Direct catalytic asymmetric aldol reaction of benzaldehyde 1a and N,N-diallylthioacetamide 2aa
[Cu(CH3CN)4]PF6
(R,R)-Ph-BPE
Li(OC6H4-p-OMe)
S
OH
S
S
O
x mol %
+
+
R = allyl
Ph
Ph
Ph
NR2
NR2
NR2
H
1a
2a
y equiv.
3aa
4aa
Entry
x
y
Solvent
Temp (°C)
Time (h)
Yieldb (%)
ee (%)
(3aa)
3aa
4aa
1
2
3
4
5
6c
7
8
10
10
10
5
5
5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
DMF
DMF
DMF
THF/DMF 9/1
THF/DMF 1/3
THF/DMF 1/3
THF/DMF 1/7
THF/DMF 1/7
ꢀ60
ꢀ60
ꢀ60
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
8
24
40
20
20
20
20
20
72
73
42
23
80
84
74
94
9
19
30
68
72
66
70
78
59
83
79
NDd
NDd
7
5
5
NDd
1.7
Ph
P
Ph
P
Ph
Ph
(R,R)-Ph-BPE
a
b
c
1a: 0.2 mmol.
Determined by 1H NMR analysis with 1,2-dimethoxyethane as an internal standard.
Li salt of 2,2,5,7,8-pentamethylchromanol was used as a Brønsted base instead of Li(OC6H4-p-OMe).
Not detected.
d
(a) Aldol product derived from aromatic aldehyde.
OH
S
S
[Cu(CH3CN)4]PF6
(R,R)-Ph-BPE
Li(OC6H4-p-OMe)
Ph
Ph
+
N
N
10 mol %
3aa
41%, 69% ee
4aa
38%
3aa
(53% ee)
DMF, —60 ºC, 40 h
S
O
+
N
Ph
H
1a
6.5%
2a
5.1%
(b) Aldol product derived from aliphatic aldehyde.
[Cu(CH3CN)4]PF6
(R,R)-Ph-BPE
Li(OC6H4-p-OMe)
OH
S
OH
S
10 mol %
N
N
DMF, —60 ºC, 40 h
3'
(88% ee)
3'
(88% ee)
Scheme 1. Re-subjection of aldol products to aldol reaction conditions in DMF at ꢀ60 °C.

1690
M. Iwata et al. / Tetrahedron: Asymmetry 21 (2010) 1688–1694
Table 2
Direct catalytic asymmetric aldol reaction of aromatic aldehydes 1 and thioamides 2aa
[Cu(CH3CN)4]PF6
(R,R)-Ph-BPE
Li(OC6H4-p-OMe)
OH
O
S
S
5 mol %
+
THF/DMF= 1/7
—70 ºC
Ar
Ar
H
N(allyl)2
N(allyl)2
1
2a
3
Entry
1c
Aldehyde
Ar
Product
Time (h)
Yieldb (%)
94 (1.7)
ee (%)
79
1a
1b
3aa
20
2c
3
3ba
3ca
20
40
96 (3.0)
89 (3.6)
79
67
1c
4
5
1d
1e
3da
3ea
20
40
88 (2.1)
85 (3.4)
79
82
MeO
F
6
1f
3fa
40
96 (3.0)
74
7
8
1g
1h
3ga
3ha
40
40
80 (2.2)
71
91
Cl
S
74 (NDd)
a
b
c
1: 0.3 mmol, 2a: 0.45 mmol.
Isolated yield. Yield of dehydrated product is provided in parentheses (determined by 1H NMR of the crude mixture).
1: 0.4 mmol, 2a: 0.6 mmol.
Not detected.
d
inhibition, affording 3aa in only 23% yield. Increasing the DMF
content allowed the reaction to proceed smoothly without the for-
mation of 4aa. The formation of 4aa was sensitive to the Brønsted
basicity of the catalyst, as shown in the reaction using Li salt of
2,2,5,7,8-pentamethylchromanol as a stronger Brønsted base (en-
try 6). In terms of chemical yield and enantioselectivity, the reac-
tion conditions with THF/DMF = 1/7 and 1.5 equiv of 2a were
optimum (entry 8).14,15
Having developed suitable conditions for the catalytic asym-
metric aldol reaction of aromatic aldehydes and the thioamides,
we next examined the substrate scope of the present catalytic sys-
tem. Aromatic aldehydes 1b–d bearing non-polar substituents pro-
duced the corresponding aldol products in comparable yield and
enantioselectivity (entries 1–4), whereas an ortho methyl group
may negatively affect stereoselection, leading to a marginal loss
of enantioselectivity, probably due to the increased steric factors
close to the carbonyl group (entry 3). The effect of heteroatom sub-
stituents was negligible, affording the aldol product 3ea–ga in
comparable yield and enantioselectivity (entries 5–7). The reaction
with heteroaromatic aldehyde 1h proceeded with the highest
enantioselectivity (91% ee) albeit with a moderate yield (entry 8)
(Table 2).
Fluoxetine (Prozac™, Eli Lilly Co Ltd) is a selective serotonin
reuptake inhibitor (SSRI) and widely used for the treatment of
depression and anxiety. Although fluoxetine is clinically used as
a racemate, accumulating evidence16 that the (R)- and (S)-enantio-
mers of fluoxetine have different pharmacokinetics and bioactivi-
ties have led to the catalytic asymmetric synthesis of fluoxetine,
largely through catalytic asymmetric hydrogenation,17 epoxida-
tion,18 or dihydroxylation.19 Facile manipulation of the thioamide
functionality of the aldol product 3aa enabled a concise asymmet-
ric synthesis of (R)-fluoxetine, in which the stereogenic center was
generated concomitantly with C–C bond formation (Scheme 2).20
Desulfurization of the aldol product 3aa (78% ee sample) was per-
formed by the activation of thioamide with MeI and subsequent
hydride reduction with NaBH4,21 affording the corresponding
diallylamine 5 in 94% yield. Installation of the requisite 4-trifluoro-
methylphenyl group under basic conditions gave aryl ether 6.17–19
A palladium-catalyzed deallylation protocol and the following car-
bamate formation afforded 7 in 71% yield in two steps.22 Reduction

M. Iwata et al. / Tetrahedron: Asymmetry 21 (2010) 1688–1694
1691
S
OH
OH
1. MeI, rt
N
N
2. NaBH4,
MeOH, 0 ºC to rt
3aa
(78% ee)
5
y. 94%
4-chloro-
benzotrifluoride
NaH
DMA, 95 ºC
y. 73%
1. Pd(PPh3)4 6 mol %
N,N-dimethylbarbituric
acid
CF3
O
CF3
CH2Cl2, rt
O
O
2. methyl chloroformate
K2CO3, CH2Cl2/H2O
N
H
O
N
7
6
rt
y. 71%
(2 steps)
(77% ee)
1. LiAlH4
y. 90%
(2 steps)
THF, reflux
2. HCl/MeOH
CF3
O
N
H
•HCl
(R)-fluoxetine•HCl
Scheme 2. Asymmetric synthesis of (R)-fluoxetine.
of 7 with LiAlH4 and subsequent treatment with HCl/MeOH deliv-
ered (R)-fluoxetineꢁHCl.17–19
d 7.26 ppm). For 13C NMR, chemical shifts were reported in the
scale relative to NMR solvent (CDCl3: 77.0 ppm) as an internal ref-
erence. For 19F NMR, chemical shifts were reported in the scale rel-
ative to CF3COOH as an external reference. NMR data are reported
as follows: chemical shifts, multiplicity (s: singlet, d: doublet, dd:
doublet of doublets, t: triplet, m: multiplet, br: broad signal),
coupling constant (Hz), and integration. Optical rotation was
measured using a 1 mL cell with a 0.5 dm path length on a JASCO
polarimeter P-1010. ESI mass spectra were measured on Waters-
ZQ4000. High-resolution mass spectra (ESI (+)) were measured
on JEOL AccuTOF JMS-T100LC. HPLC analysis was conducted on a
JASCO HPLC system equipped with Daicel chiral stationary phase
columns.
3. Conclusion
A direct catalytic asymmetric aldol reaction of aromatic alde-
hydes and thioamides with a soft Lewis acid/hard Brønsted base
cooperative catalyst was developed. Exquisite control of the reac-
tion conditions effectively prevented a retro-reaction as well as
dehydration, affording the desired aldol products with moderate
to good enantioselectivity. Facile manipulation of the N,N-dially-
lthioamide functionality allowed for a concise asymmetric synthe-
sis of (R)-fluoxetine. Further efforts will be devoted to the
development of a diasteroselective version of the direct catalytic
asymmetric aldol reaction of thioamides.
4.2. Direct catalytic asymmetric aldol reaction of aromatic
aldehyde and thioamide
4. Experimental
4.1. General
4.2.1. Representative procedure for the preparation of (R)-N,N-
diallyl-3-hydroxy-3-phenylpropanethioamide 3aa
To a flame-dried 20 mL test tube equipped with a magnetic stir-
ring bar and a three-way glass stopcock were added (R,R)-Ph-BPE/
Catalytic asymmetric aldol reactions were performed in a
flame-dried 20 mL test tube with a Teflon-coated magnetic stirring
bar unless otherwise noted. The test tubes were fitted with a three-
way glass stopcock and the reactions were run under Ar atmo-
sphere. All work-up and purification procedures were carried out
with reagent-grade solvents under ambient atmosphere.
Infrared (IR) spectra were recorded on a JASCO FT/IR 410 Fourier
transform infrared spectrophotometer. NMR was recorded on JEOL
LA-500, JEOL ECX-500 spectrometers. Chemical shifts for proton
are reported in parts per million downfield from tetramethylsilane
and are referenced to residual protium in the NMR solvent (CDCl3:
[Cu(CH3CN)4]PF6 solution (0.1 M/THF, 200
(0.5 mL), dry DMF (3.5 mL), N,N-diallylthioacetamide 2a (95.4
0.60 mmol), and benzaldehyde 1a (40.6 L, 0.4 mmol) under Ar
lL, 0.02 mmol), dry THF
l
L,
l
at room temperature. The test tube was immersed into the elec-
tronically controlled cooling bath at ꢀ70 °C with 2-propanol as
medium. To the solution was added Li(OC6H4-p-OMe) (0.2 M/
THF, 100
ring, AcOH in THF (0.1 M, 300
l
L, 0.02 mmol) and stirred at ꢀ70 °C. After 20 h of stir-
l
L), satd NH4Cl aq, and bipyridine
(9.4 mg, 0.06 mmol) were added to the reaction mixture (essential
to make sure of the dissociation of the aldol product from the Cu

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M. Iwata et al. / Tetrahedron: Asymmetry 21 (2010) 1688–1694
complex) and the aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with H2O and brine,
then dried over Na2SO4. The filtrate was concentrated under re-
duced pressure and the resulting residue was submitted to 1H
NMR analysis to determine the yield of the dehydrated product.
The residue was purified by silica gel column chromatography
(SiO2, eluent: n-hexane/CH2Cl2 = 1/1–1/10) to give 3aa as a pale
yellow oil (98.7 mg, 0.378 mmol, 94% yield). Enantiomeric excess
117.9, 72.1, 55.7, 52.8, 50.2, 21.1; ½a D23
¼ þ95:0 (c 1.2, CHCl3, 79%
ꢂ
ee sample); ESI-MS m/z 298 [M+Na]+; HRMS (ESI-TOF) Anal. Calcd
for C16H21NNaOS m/z 298.1242 [M+Na]+. Found: 298.1240; HPLC:
Daicel CHIRALCEL OZ-H (/ 0.46 cm ꢃ 25 cm), 2-propanol/n-hex-
ane = 1/9, flow rate 1.0 mL/min, detection 254 nm, tR = 16.1 min
(minor), 18.2 min (major).
4.2.5. (R)-N,N-Diallyl-3-hydroxy-3-(3-methoxyphenyl)propan-
was determined by HPLC analysis. Pale yellow oil; IR (neat)
m
ethioamide 3ae
3390, 1642, 1495, 1411 cmꢀ1 1H NMR (CDCl3) d 7.42–7.39 (m,
;
Colorless oil; IR (neat) m
3380, 2932, 1602, 1586, 1411 cmꢀ1; 1H
2H), 7.38–7.34 (m, 2H), 7.31–7.26 (m, 1H), 5.89 (dddd, J = 17.4,
10.4, 5.8, 5.8 Hz, 1H), 5.72 (dddd, J = 17.1, 10.4, 4.6, 4.6 Hz, 1H),
5.28–5.23 (m, 1H), 5.29–5.24 (m, 2H), 5.23–5.17 (m, 1H), 5.15–
5.10 (m, 1H), 4.74 (dd, J = 15.0, 5.8 Hz, 1H), 4.64 (d, J = 3.1 Hz,
1H), 4.56 (dd, J = 15.0, 6.1 Hz, 1H), 4.18–4.12 (m, 1H), 4.06–4.00
(m, 1H), 2.97–2.94 (m, 2H); 13C NMR (CDCl3) d 201.8, 143.0,
130.4, 130.4, 128.5, 127.6, 125.9, 118.4, 117.9, 72.3, 55.7, 52.8,
NMR (CDCl3) d 7.28–7.24 (m, 1H), 7.00–6.95 (m, 2H), 6.82 (dd,
J = 8.3, 2.8 Hz, 1H), 5.89 (dddd, J = 16.8, 10.1, 6.1, 6.1 Hz, 1H), 5.72
(dddd, J = 17.1, 10.4, 4.6, 4.6 Hz, 1H), 5.29–5.10 (m, 5H), 4.74 (dd,
J = 14.7, 5.8 Hz, 1H), 4.66 (d, J = 2.5 Hz, 1H), 4.55 (dd, J = 14.6,
6.1 Hz, 1H), 4.18–4.13 (m, 1H), 4.05–4.00 (m, 1H), 3.81 (s, 3H),
2.97–2.94 (m, 2H); 13C NMR (CDCl3) d 201.8, 159.7, 144.7, 130.4,
130.4, 129.5, 118.8, 118.1, 117.9, 113.1, 111.3, 72.2, 55.7, 55.2,
50.1; ½a 2D3
ꢂ
¼ þ105:0 (c 1.2, CHCl3, 79% ee sample); ESI-MS m/z
52.8, 50.0; ½a 2D3
¼ þ88:1 (c 0.9, CHCl3, 82% ee sample); ESI-MS m/
ꢂ
284 [M+Na]+; HRMS (ESI-TOF) Anal. Calcd for C15H19NNaOS m/z
284.1085 [M+Na]+. Found: 284.1076; HPLC: Daicel CHIRALCEL
OZ-H (/ 0.46 cm ꢃ 25 cm), 2-propanol/n-hexane = 1/9, flow rate
1.0 mL/min, detection 254 nm, tR = 12.4 min (minor), 14.6 min
(major).
z 314 [M+Na]+; HRMS (ESI-TOF) Anal. Calcd for C16H21NNaO2S m/
z 314.1191 [M+Na]+. Found: 314.1189; HPLC: Daicel CHIRALCEL
OZ-H (/ 0.46 cm ꢃ 25 cm), 2-propanol/n-hexane = 1/9, flow rate
1.0 mL/min, detection 254 nm, tR = 14.3 min (minor), 18.7 min
(major).
4.2.2. (R)-N,N-Diallyl-3-hydroxy-3-(naphthalen-2-yl)propanethio-
4.2.6. (R)-N,N-Diallyl-3-(4-fluorophenyl)-3-hydroxypropanethi-
amide 3ab
oamide 3af
Colorless oil; IR (neat)
m
3388, 1640, 1497, 1411 cmꢀ1
;
1H NMR
Colorless oil; IR (neat) m ;
3389, 1604, 1509, 1411 cmꢀ1 1H NMR
(CDCl3) d 7.90 (br s, 1H), 7.85–7.82 (m, 3H), 7.52–7.45 (m, 3H), 5.89
(dddd, J = 17.1, 10.4, 5.8, 5.8 Hz, 1H), 5.72 (dddd, J = 17.1, 10.4, 4.6,
4.6 Hz, 1H), 5.50–5.46 (m, 1H), 5.30–5.10 (m, 4H), 4.75 (d,
J = 2.8 Hz, 1H), 4.74 (dd, J = 14.6, 5.8 Hz, 1H), 4.57 (dd, J = 14.6,
6.1 Hz, 1H), 4.18–4.12 (m, 1H), 4.06–4.00 (m, 1H), 3.05–3.02 (m,
2H); 13C NMR (CDCl3) d 201.8, 140.4, 133.3, 132.9, 130.4, 130.3,
128.2, 128.0, 127.7, 126.2, 125.9, 124.6, 124.0, 118.9, 117.9, 72.4,
(CDCl3) d 7.38 (m, 2H), 7.05–7.00 (m, 2H), 5.88 (dddd, J = 17.1, 10.4,
5.8, 5.8 Hz, 1H), 5.72 (dddd, J = 17.1, 10.4, 4.9, 4.9 Hz, 1H), 5.30–
5.10 (m, 5H), 4.72 (d, J = 3.1 Hz, 1H), 4.71 (dd, J = 14.4, 6.1 Hz,
1H), 4.55 (dd, J = 15.0, 6.2 Hz, 1H), 4.17–4.12 (m, 1H), 4.06–4.00
(m, 1H), 2.92–2.90 (m, 2H); 13C NMR (CDCl3) d 201.6, 162.1
(J1C—F ¼ 245:0Hz), 138.7 (JC4—F ¼ 3:1Hz), 130.3, 130.3, 127.5
(J3C—F ¼ 8:3Hz), 118.9, 117.9, 115.2 (JC2—F ¼ 21:7Hz), 71.6, 55.7,
55.7, 52.8, 50.1; ½a D23
ꢂ
¼ þ92:4 (c 1.1, CHCl3, 79% ee sample); ESI-
52.8, 50.0; 19F NMR d ꢀ81.9; ½a 2D3
¼ þ92:1 (c 1.0, CHCl3, 74% ee
ꢂ
MS m/z 334 [M+Na]+; HRMS (ESI-TOF) Anal. Calcd for
C
sample); ESI-MS m/z 302 [M+Na]+; HRMS (ESI-TOF) Anal. Calcd
for C15H18NNaOSF m/z 302.0991 [M+Na]+. Found: 302.0989; HPLC:
Daicel CHIRALCEL OZ-H (/ 0.46 cm ꢃ 25 cm), 2-propanol/n-hex-
ane = 1/9, flow rate 1.0 mL/min, detection 254 nm, tR = 10.8 min
(minor), 12.9 min (major).
19H21NNaOS m/z 334.1242 [M+Na]+. Found: 334.1233; HPLC: Dai-
cel CHIRALCEL OZ-H (/ 0.46 cm ꢃ 25 cm), 2-propanol/n-hex-
ane = 1/9, flow rate 1.0 mL/min, detection 254 nm, tR = 16.7 min
(minor), 21.5 min (major).
4.2.3. (R)-N,N-Diallyl-3-hydroxy-3-o-tolylpropanethioamide 3ac
4.2.7. (R)-N,N-Diallyl-3-(4-chlorophenyl)-3-hydroxypropanethio-
Colorless oil; IR (neat)
m
3405, 2924, 1641, 1490, 1411 cmꢀ1; 1H
amide 3ag
NMR (CDCl3) d 7.56 (dd, J = 7.6, 1.5 Hz, 1H), 7.23 (dd, J = 7.4, 1.5 Hz,
1H), 7.19 (ddd, J = 7.6, 7.4, 1.6 Hz, 1H), 7.15–7.13 (m, 1H), 5.90
(dddd, J = 16.7, 10.1, 6.1, 6.1 Hz, 1H), 5.72 (dddd, J = 17.1, 10.1,
4.6, 4.6 Hz, 1H), 5.56–5.53 (m, 1H), 5.30–5.24 (m, 2H), 5.24–5.20
(m, 1H), 5.15–5.10 (m, 1H), 4.85 (dd, J = 15.0, 5.2 Hz, 1H), 4.49 (d,
J = 2.7 Hz, 1H), 4.46 (dd, J = 14.6, 6.2 Hz, 1H), 4.23–4.17 (m, 1H),
4.06–3.99 (m, 1H), 2.89–2.87 (m, 2H), 2.33 (s, 3H); 13C NMR
(CDCl3) d 202.2, 141.1, 134.0, 130.5, 130.4, 130.4, 127.3, 126.3,
Colorless oil; IR (neat) m
3386, 1642, 1492, 1411 cmꢀ1; 1H NMR
(CDCl3) d 7.34–7.31 (m, 4H), 5.88 (dddd, J = 17.1, 10.1, 6.1, 6.1 Hz,
1H), 5.72 (dddd, J = 17.1, 10.4, 4.6, 4.6 Hz, 1H), 5.30–5.10 (m, 5H),
4.73 (d, J = 2.8 Hz, 1H), 4.72 (dd, J = 14.7, 6.1 Hz, 1H), 4.57 (dd,
J = 9.9, 6.1 Hz, 1H), 4.17–4.12 (m, 1H), 4.06–4.02 (m, 1H), 2.92–
2.88 (m, 2H); 13C NMR (CDCl3) d 201.5, 141.5, 133.2, 130.3,
130.2, 128.6, 127.3, 119.0, 118.0, 71.5, 55.8, 52.8, 49.2;
½
a 2D3
ꢂ
¼ þ87:2 (c 1.0, CHCl3, 71% ee sample); ESI-MS m/z 318
125.8, 118.9, 117.7, 69.1, 55.8, 52.7, 48.6, 19.1; ½a D23
ꢂ
¼ þ92:3 (c
[M+Na]+; HRMS (ESI-TOF) Anal. Calcd for C15H18NNaOSCl m/z
318.0695 [M+Na]+. Found: 318.0682; HPLC: Daicel CHIRALCEL
OZ-H (/ 0.46 cm ꢃ 25 cm), 2-propanol/n-hexane = 1/9, flow rate
1.0 mL/min, detection 254 nm, tR = 11.2 min (minor), 13.3 min
(major).
0.9, CHCl3, 67% ee sample); ESI-MS m/z 298 [M+Na]+; HRMS (ESI-
TOF) Anal. Calcd for C16H21NNaOS m/z 298.1242 [M+Na]+. Found:
298.1240; HPLC: Daicel CHIRALCEL OZ-H (/ 0.46 cm ꢃ 25 cm), 2-
propanol/n-hexane = 1/9, flow rate 1.0 mL/min, detection 254 nm,
tR = 7.0 min (minor), 10.3 min (major).
4.2.8. (R)-N,N-Diallyl-3-hydroxy-3-(thiophen-2-yl)propanethi-
4.2.4. (R)-N,N-Diallyl-3-hydroxy-3-p-tolylpropanethioamide 3ad
oamide 3ah
Colorless oil; IR (neat)
m
3389, 2921, 1642, 1495, 1411 cmꢀ1; 1H
Colorless oil; IR (neat) m
3387, 1642, 1495, 1411 cmꢀ1; 1H NMR
NMR (CDCl3) d 7.29 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 7.6 Hz, 2H), 5.89
(dddd, J = 17.1, 10.0, 5.8, 5.8 Hz, 1H), 5.71 (dddd, J = 17.4, 10.4, 4.6,
4.6 Hz, 1H), 5.29–5.10 (m, 5H), 4.73 (dd, J = 14.9, 5.8 Hz, 1H), 4.56
(dd, J = 14.9, 6.1 Hz, 1H), 4.55 (d, J = 2.8 Hz, 1H), 4.20–4.14 (m,
1H), 4.06–4.01 (m, 1H), 2.95–2.94 (m, 2H), 2.34 (s, 3H); 13C NMR
(CDCl3) d 202.0, 140.1, 137.3, 130.5, 130.4, 129.2, 125.8, 118.8,
(CDCl3) d 7.24 (dd, J = 4.8, 1.3 Hz, 1H), 7.00–6.96 (m, 2H), 5.88
(dddd, J = 17.1, 10.1, 6.1, 6.1 Hz, 1H), 5.75 (dddd, J = 17.4, 10.7,
4.6, 4.6 Hz, 1H), 5.61–5.57 (m, 1H), 5.31–5.13 (m, 4H), 4.77 (d,
J = 3.1 Hz, 1H), 4.72 (dd, J = 14.7, 5.8 Hz, 1H), 4.58 (dd, J = 14.7,
5.8 Hz, 1H), 4.23–4.17 (m, 1H), 4.12–4.06 (m, 1H), 3.06–3.02 (m,
2H); 13C NMR (CDCl3) d 201.2, 146.6, 130.4, 130.3, 126.6, 124.5,

M. Iwata et al. / Tetrahedron: Asymmetry 21 (2010) 1688–1694
1693
123.3, 118.9, 118.1, 68.6, 55.7, 52.9, 49.9; ½a D23
ꢂ
¼ þ110:0 (c 1.1,
bituric acid (1.16 g, 7.46 mmol) and the resulting solution was stir-
red at 35 °C for 4 h. After cooling to room temperature, the mixture
was diluted with CHCl3. The solution was washed with satd
Na2CO3 aq three times to remove barbituric acid, then dried over
Na2SO4. Volatiles were removed under reduced pressure and the
resulting residue was dissolved in CH2Cl2 (2.5 mL). To the solution
CHCl3, 91% ee sample); ESI-MS m/z 290 [M+Na]+; HRMS (ESI-
TOF) Anal. Calcd for C13H17NNaOS2 m/z 290.0649 [M+Na]+. Found:
290.0646; HPLC: Daicel CHIRALCEL OZ-H (/ 0.46 cm ꢃ 25 cm), 2-
propanol/n-hexane = 1/9, flow rate 1.0 mL/min, detection 254 nm,
tR = 14.3 min (minor), 18.7 min (major).
were added methyl chloroformate (124 lL, 1.61 mmol) and K2CO3
4.3. Preparation of (R)-fluoxetine
(857 mg, 6.2 mmol) in H2O (2.5 mL) and the resulting biphasic
solution was stirred at room temperature. After stirring for
90 min, the mixture was extracted with CH2Cl2 and the combined
organic extracts were dried over Na2SO4. Volatiles were removed
under reduced pressure and the resulting residue was purified by
silica gel column chromatography (SiO2, eluent: n-hexane/ethyl
4.3.1. Preparationof(R)-3-(diallylamino)-1-phenylpropan-1-ol5
The aldol product 3aa (2.11 g, 8.07 mmol, 78% ee) was placed in
a 300 mL pear-shaped flask and stirred with MeI (8.1 mL) at room
temperature for 18 h. Then MeI was removed under reduced pres-
sure to give a residue, which was dissolved in MeOH (80 mL) and
the resulting solution was cooled to 0 °C. To the solution was added
NaBH4 (611 mg, 16.1 mmol) and the resulting solution was stirred
at 0 °C for 30 min and at room temperature for 3 h. The reaction
was quenched with H2O, and MeOH was removed under reduced
pressure. The aqueous solution was extracted with CHCl3 and the
combined organic extracts were dried over Na2SO4. Volatiles were
removedunder reduced pressureand the resulting residue was puri-
fied by silica gel column chromatography (SiO2, eluent: CHCl3/
MeOH = 1/0–20/1) to give 5 as a colorless oil (1.75 g, 7.55 mmol,
acetate = 30/1–5/1) to give
0.875 mmol, 71% yield (two steps)). Enantiomeric excess was
determined by HPLC analysis (77% ee). IR (neat) 3334, 3065,
2952, 1714, 1328 cmꢀ1 1H NMR (CDCl3) d 7.43 (d, J = 8.9 Hz, 2H),
7 as a pale yellow oil (309 mg,
m
;
7.36–7.26 (m, 5H), 6.89 (d, J = 8.9 Hz, 2H), 5.24 (dd, J = 8.6,
4.3 Hz, 1H), 4.93 (br s, 1H), 3.65 (s, 3H), 3.41–3.36 (m, 2H), 2.22–
2.08 (m, 2H); 13C NMR (CDCl3) d 160.2, 157.0, 140.3, 128.9,
128.0, 126.8 (JC–F = 3.6 Hz), 125.6, 124.3 (JC–F = 274.6 Hz), 122.9
(JC–F = 33.4 Hz), 115.7, 78.5, 52.0, 38.6, 38.0; 19F NMR d ꢀ28.5;
½
a 2D7
ꢂ
¼ þ5:8 (c 0.9, CHCl3); ESI-MS m/z 376 [M+Na]+; HRMS (ESI-
94% yield). IR (neat)
m
3245, 3077, 2926, 2818, 1643, 1451,
TOF) Anal. Calcd for C18H18F3NNaO3 m/z 376.1136 [M+Na]+. Found:
376.1132. Daicel CHIRALCEL OZ-H (/ 0.46 cm ꢃ 25 cm), 2-propa-
nol/n-hexane = 1/9, flow rate 1.0 mL/min, detection 254 nm,
tR = 7.1 min (major), 8.3 min (minor).
920 cmꢀ1 1H NMR (CDCl3) d 7.39–7.22 (m, 5H), 6.60 (br s, 1H),
;
5.93–5.85 (m, 2H), 5.23–5.19 (m, 4H), 4.90 (dd, J = 9.2, 2.8 Hz, 1H),
3.33 (dd, J = 14.0, 5.7 Hz, 2H), 2.99 (dd, J = 14.0, 7.7 Hz, 2H), 2.87
(ddd, J = 13.1, 10.6, 3.4 Hz, 1H), 2.61 (ddd, J = 13.1, 4.9, 3.4 Hz, 1H),
1.91–1.76 (m, 2H); 13C NMR (CDCl3) d 145.0, 134.4, 128.2, 126.9,
4.3.4. Preparation of (R)-fluoxetine from 7
125.6, 118.6, 75.6, 56.6, 52.3, 34.6; ½a D24
ꢂ
¼ þ31:6 (c 1.2, CHCl3);
To a stirred solution of 7 (265 mg, 0.75 mmol) in THF (10 mL)
was added LiAlH4 (57 mg, 1.5 mmol) at 0 °C. After refluxing the
resulting suspension for 1 h, the mixture was cooled to 0 °C, then
MeOH, H2O, Celite, and ethyl acetate were added and the resulting
suspension was stirred at room temperature for 30 min. The sus-
pension was filtered through a pad of Celite and rinsed with ethyl
acetate and the filtrate was concentrated to give a free amine,
which was treated with 2 M HCl/MeOH (1.5 mL) at room tempera-
ture for 5 min. Then MeOH was removed under reduced pressure
and the resulting residue was triturated with AcOEt/n-hexane to
give (R)-fluoxetineꢁHCl as a colorless solid (234 mg, 0.677 mmol,
ESI-MS m/z 232 [M+H]+; HRMS (ESI-TOF) Anal. Calcd for
C
15H21NNaO m/z 254.1521 [M+Na]+. Found: 254.1511.
4.3.2. Preparation of (R)-N-allyl-N-(3-phenyl-3-(4-
(trifluoromethyl)phenoxy)propyl)prop-2-en-1-amine 6
Into a 20 mL flame-dried test tube were placed 5 (50 mg,
0.216 mmol) and DMA (1.0 mL) and the resulting solution was
cooled to 0 °C. Then NaH (13 mg, 0.324 mmol) was added to the
solution and the mixture was stirred at 55 °C for 45 min. The solu-
tion was cooled to room temperature and 4-chlorobenzotrifluoride
(87
l
L, 0.648 mmol) was added, then the resulting solution was
90% (two steps), ½a D24
¼ ꢀ11:9 (c 0.9, CHCl3), specific rotation of
ꢂ
stirred at 95 °C for 90 min. After cooling to room temperature,
additional NaH (13 mg, 0.324 mmol) and 4-chlorobenzotrifluoride
enantiopure (R)-fluoxetine reported in the literature:
½
a 2D4
ꢂ
¼
ꢀ13:8 (c 1, CHCl3)16b). Other spectroscopic data were in full agree-
(87
l
L, 0.648 mmol) were added and the mixture was stirred at
ment with the literature.
95 °C for 90 min. The reaction was quenched with H2O at 0 °C,
and the resulting mixture was extracted with AcOEt and the com-
bined organic extracts were washed with H2O and brine, then dried
over Na2SO4. Volatiles were removed under reduced pressure and
the resulting residue was purified by preparative thin layer chro-
matography (SiO2, eluent: n-hexane/ethyl acetate = 2/1) to give 6
4.4. Determination of absolute configuration
4.4.1. Preparation of (R)-3-(tert-butyldimethylsilyloxy)-3-
phenylpropanal (TBS protection of 3aa, followed by reduction
of the thioamide to an aldehyde)
as a pale yellow oil (59 mg, 0.157 mmol, 73% yield). IR (neat)
m
To a stirred solution of 3aa (127 mg, 0.486 mmol) in CH2Cl2
3076, 2925, 2808, 1615, 1329 cmꢀ1 1H NMR (CDCl3) d 7.42 (d,
;
(5 mL) were added 2,6-lutidine (113
lL, 0.972 mmol) and TBSOTf
J = 8.6 Hz, 2H), 7.33–7.25 (m, 5H), 6.89 (d, J = 8.6 Hz, 2H), 5.83–
5.74 (m, 2H), 5.28 (dd, J = 8.6, 4.6 Hz, 1H), 5.16–5.06 (m, 4H),
3.14–3.03 (m, 4H), 2.67 (ddd, J = 13.1, 7.4, 7.4 Hz, 1H), 2.55 (ddd,
J = 13.1, 7.7, 5.2 Hz, 1H), 2.17–2.10 (m, 1H), 1.99–1.92 (m, 1H);
13C NMR (CDCl3) d 160.7, 141.3, 135.5, 128.7, 127.7, 126.7 (JC–
(168 L, 0.729 mmol) at 0 °C. The resulting solution was stirred
l
at room temperature for 8 h. The reaction was quenched with satd
NH4Cl aq, and the biphasic mixture was extracted with CH2Cl2. The
combined organic layers were washed with brine and dried over
Na2SO4. Volatiles were removed under reduced pressure and the
resulting residue was purified by silica gel column chromatogra-
phy (SiO2, eluent: n-hexane/AcOEt = 1/0–20/1) to give the TBS
ether as a pale yellow oil (180 mg, 0.479 mmol, 99% yield). A
flame-dried 20 mL pear-shaped flask was charged with Cp2Zr(H)Cl
(82.4 mg, 0.319 mmol) in a dry box under Ar atmosphere. Toluene
(1.5 mL) and the TBS ether (60.0 mg, 0.16 mmol) in toluene (3 mL)
were added to the flask at room temperature. After stirring for
90 min, the mixture was cooled to ꢀ78 °C and silica gel (82 mg)
was added to the cooled reaction mixture. After stirring for
F = 4.1 Hz), 125.8, 124.6 (JC–F = 307 Hz), 122.6 (JC–F = 31.9 Hz),
117.5, 115.7, 78.3, 56.9, 49.1, 36.3; 19F NMR d ꢀ28.4; [
a]
+5.0
27
D
(c 1.4, CHCl3); ESI-MS m/z 376 [M+H]+; HRMS (ESI-TOF) Anal. Calcd
for C22H25F3NO m/z 376.1888 [M+H]+. Found: 376.1883.
4.3.3. Preparation of (R)-methyl 3-phenyl-3-(4-(trifluoromethyl)-
phenoxy)propylcarbamate 7
To a stirred solution of 6 (467 mg, 1.24 mmol) in CH2Cl2 (12 mL)
were added Pd(PPh3)4 (87 mg, 0.075 mmol) and N,N-dimethylbar-

1694
M. Iwata et al. / Tetrahedron: Asymmetry 21 (2010) 1688–1694
Kuwano, R.; Miyazaki, H.; Ito, Y. Chem. Commun. 1998, 71; glycine Schiff base:
(c) Yoshikawa, N.; Shibasaki, M. Tetrahedron 2002, 58, 8289; (d) Ooi, T.;
30 min at the same temperature, the resulting suspension was stir-
red at room temperature for 2 h. The suspension was filtered
through a short pad of silica gel and rinsed with CH2Cl2, and the fil-
trate was concentrated under reduced pressure. The resulting res-
idue was purified by silica gel column chromatography (SiO2,
eluent: n-hexane/ether = 20/1–10/1) to give the title compound
as a colorless oil (17.0 mg, 0.0642 mmol, 40% yield). The absolute
configuration of the aldehyde was determined to be (R)
Kameda, M.; Taniguchi, M.; Maruoka, K. J. Am. Chem. Soc. 2004, 126, 9685;
a-
diazoacetate: (e) Yao, W.; Wang, J. Org. Lett. 2003, 5, 1527; (f) Hasegawa, K.;
Arai, S.; Nishida, A. Tetrahedron 2006, 62, 1390; (g) Trost, B. M.; Malhotra, S.;
Fried, B. A. J. Am. Chem. Soc. 2009, 131, 1674; a-isothiocyanato imide or ester:
(h) Willis, M. C.; Cutting, G. A.; Piccio, V. J.-D.; Durbin, M. J.; John, M. P. Angew.
Chem., Int. Ed. 2005, 44, 1543; (i) Li, L.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc.
2008, 130, 12248; (j) Yoshino, T.; Morimoto, H.; Lu, G.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 17082; malonic acid half thioester:
(k) Fortner, K. C.; Shair, M. D. J. Am. Chem. Soc. 2007, 129, 1032.
{½a 2D9
ꢂ
¼ þ58:3 (c 0.72, CHCl3)} by comparing the reported specific
8. For direct catalytic asymmetric aldol (-type) reactions using aldol donors in the
rotation {[a]
D = +64.3 (c 1, CHCl3)} in the literature,23 indicating
carboxylic acid oxidation state without electron-withdrawing
a-substituents:
alkylnitriles (up to 77% ee): (a) Suto, Y.; Tsuji, R.; Kanai, M.; Shibasaki, M. Org.
Lett. 2005, 7, 3757; activated amides (up to 33% ee): (b) Saito, S.; Kobayashi, S. J.
Am. Chem. Soc. 2006, 128, 8704; b,c-unsaturated ester: (c) Yamaguchi, A.;
that the absolute configuration of 3aa was (R). The absolute config-
uration of other aldol products was deduced to be (R) by analogy.
The tendency of the specific rotation and HPLC analysis are consis-
tent for all the aldol products.
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 10842.
9. Direct catalytic asymmetric aldol reaction of thiazolidinethiones where the use
of a stoichiometric amount of silylating reagent was essential: Evans, D. A.;
Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706.
10. Asymmetric aldol reaction of thioamides using stoichiometric chiral sources,
see: (a) Cinquini, M.; Manfredi, A.; Molinari, H.; Restelli, A. Tetrahedron 1985,
41, 4929; (b) Iwasawa, N.; Yura, T.; Mukaiyama, T. Tetrahedron 1989, 45,
1197.
11. (a) Iwata, M.; Yazaki, R.; Suzuki, Y.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2009, 131, 18244; for direct catalytic asymmetric Mannich-type reactions with
similar catalytic system, see: (b) Suzuki, Y.; Yazaki, R.; Kumagai, N.; Shibasaki,
M. Angew. Chem., Int. Ed. 2009, 48, 5026.
Acknowledgments
Financial support was provided from Grant-in-Aid for Scientific
Research (S) from JSPS and the Sumitomo Foundation.
References
12. Related catalytic system for direct catalytic asymmetric addition of allyl
cyanide to ketoimines and ketones, see: (a) Yazaki, R.; Nitabaru, T.; Kumagai,
N.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 14477; (b) Yazaki, R.; Kumagai, N.;
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13. The Lewis basic solvent DMF facilitated the liberation of aldol product from the
Cu catalyst to enhance the catalytic turnover.
14. The pKa of 2,2,5,7,8-pentamethylchromanol was calculated as 12.3 (H2O). See
ref 11a for details. The absolute configuration of 3aa was determined to be (R)
after converting the corresponding TBS-protected aldehyde. See Section 4.4 for
details.
15. N,N-Dimethylthioacetamide 2b exhibited lower reactivity to afford the desired
aldol product in 18% yield and comparable enantioselectivity (78% ee).
16. (a) Robertson, D. W.; Jones, N. D.; Swartzendruber, J. K.; Yang, K. S.; Wong, D. T.
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Biomol. Chem. 2005, 3, 2513.
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20. For an example of the catalytic asymmetric synthesis of fluoxetine via catalytic
asymmetric C–C bond-forming reaction, see: Miles, W. H.; Fialcowitz, E. J.;
Halstead, E. S. Tetrahedron 2001, 57, 9925.
1. (a) Trost, B. M.; Fleming, I.; Heathcock, C.-H. In Comprehensive Organic
Synthesis; Pergamon: Oxford, 1991; Vol. 2; (b)Modern Aldol Reaction;
Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004.
2. For recent reviews on asymmetric aldol reaction, see: (a) Nelson, S. G.
Tetrahedron: Asymmetry 1998, 9, 357; (b) Gröger, H.; Vogl, E. M.; Shibasaki,
M. Chem. Eur. J. 1998, 4, 1137; (c) Mahrwald, R. Chem. Rev. 1999, 99, 1095; (d)
Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352; (e)
Palomo, C.; Oiarbide, M.; García, J. M. Chem. Soc. Rev. 2004, 33, 65; (f) Geary, L.
M.; Hultin, P. G. Tetrahedron: Asymmetry 2009, 20, 131.
3. Trost, B. M. Science 1991, 254, 1471.
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B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595; (b) Shibasaki, M.; Yoshikawa, N.
Chem. Rev. 2002, 102, 2187; (c) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37,
570; (d) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580; (e)
Guillena, G.; Nájera, C.; Ramón, D. J. Tetrahedron: Asymmetry 2007, 18, 2249; (f)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
Also see Ref. 1b, chap 6.
5. Pioneering examples of direct catalytic asymmetric aldol reaction promoted by
metal-based catalysts, see: (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.;
Shibasaki, M. Angew. Chem., Int. Ed. 1997, 36, 1871; (b) Yoshikawa, N.; Yamada,
Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168; (c)
Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003; (d) Mahrwald, R.; Ziemer,
B. Tetrahedron Lett. 2002, 43, 4459.
6. Pioneering examples of direct catalytic asymmetric aldol reaction promoted by
organocatalysts, see: (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc.
2000, 122, 2395; (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem.
Soc. 2001, 123, 5260; (c) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001,
1245.
7. Direct catalytic asymmetric aldol reaction using aldol donors in the carboxylic
21. Sundberg, R. J.; Walters, C. P.; Bloom, J. D. J. Org. Chem. 1981, 46, 3730.
22. Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993, 58, 6109.
23. Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1897.
oxidation state bearing electron-withdrawing
readily enolized under mild basic conditions: -isocyano or
(a) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405; (b)
a
-substituents, which are
a
a-cyanoacetate: