Mixed La-Li heterobimetallic complexes for tertiary nitroaldol resolution

Article abstract of DOI:10.1016/j.tet.2009.02.031

Full details of the kinetic resolution of tertiary nitroaldols derived from simple ketones are described. Mixed BINOL/biphenol La-Li heterobimetallic complexes gave the best selectivity in retro-nitroaldol reactions of racemic tertiary nitroaldols. Using

Full text of DOI:10.1016/j.tet.2009.02.031

Tetrahedron 65 (2009) 5030–5036
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Tetrahedron
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Mixed La–Li heterobimetallic complexes for tertiary nitroaldol resolution
Keiichi Hara, Shin-ya Tosaki, Vijay Gnanadesikan, Hiroyuki Morimoto, Shinji Harada, Mari Sugita,
*
*
Noriyuki Yamagiwa, Shigeki Matsunaga , Masakatsu Shibasaki
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, 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:
Received 9 January 2009
Received in revised form 16 February 2009
Accepted 16 February 2009
Available online 24 February 2009
Full details of the kinetic resolution of tertiary nitroaldols derived from simple ketones are described.
Mixed BINOL/biphenol La–Li heterobimetallic complexes gave the best selectivity in retro-nitroaldol
reactions of racemic tertiary nitroaldols. Using a 2:1 mixture of La–Li3-(binaphthoxide 1a)3 complex
(LLB) and La–Li3-(biphenoxide 1e)3 complex, chiral tertiary nitroaldols were obtained in 80–97% ee and
30–47% recovery yield. Transformations of products were also investigated.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Bifunctional catalysis
Kinetic resolution
Nitroaldol
Tertiary alcohol
1. Introduction
the full details of a kinetic resolution approach using BINOL 1a-H2/
biphenol 1e-H2 mixed La–Li heterobimetallic complexes (Fig. 1).9
Catalytic asymmetric nitroaldol (Henry) reactions1 are syn-
thetically useful carbon–carbon bond-forming reactions. Since our
first report of the catalytic asymmetric nitroaldol reaction of alde-
hydes,2 various chiral catalysts effective for the reaction of nitro-
methane with aldehydes have been developed.3 Diastereo- and
enantioselective nitroaldol reactions using nitroethane and other
nitroalkanes as donors have also been intensively studied by us4
and other groups.5 In contrast, there is only a limited number of
nitroaldol reactions of ketones that lead to synthetically versatile
chiral tertiary nitroaldols. Enantioselective nitroaldol reactions of
X
X = H: (R)-BINOL 1a-H2
X = TMS
: 1b-H2 MeO
MeO
OH
OH
OH
OH
X = Ph
:1c-H2
X = Br: 1d-H2
X
X
(R)-1e-H2
X
a
-keto esters have been achieved using chiral Cu6a–e and Mg
Me
complexes,6f and cinchona alkaloids.6g,h A highly enantioselective
nitroaldol reaction of trifluoromethyl ketone has also been realized
using a chiral rare earth metal catalyst.7 There are no reports,
however, on the asymmetric synthesis of tertiary nitroaldols de-
rived from simple non-activated ketones. Even for a racemic ver-
sion, only a few methodologies with limited substrate scope are
available.8 The difficulty is due to the attenuated reactivity of ke-
tones and the strong tendency toward a retro-nitroaldol reaction
under basic conditions. Therefore, the synthesis of tertiary nitro-
aldols with chirality control is in high demand. Herein, we describe
O
Me
O
X
X
M
Li
O
RE
O
O
O
Me
O
O
O
O
O
O
O
M
Li
La
O
O
O
Me
M
Li
O
X
Me
(R)-REMB
O
Me
X
RE = La, M = Li, X = H
(R)-La-L i3-(1e)3
LaLi3tris(binaphthoxide 1a) (LLB)
* Corresponding authors. Tel.: þ81 3 5841 4835; fax: þ81 3 5684 5206 (S.M.);
tel.: þ81 3 5841 4830; fax: þ81 3 5684 5206 (M.S.).
Figure 1. Structures of (R)-BINOL 1a-H2, BINOL derivatives 1b–1d-H2, biphenyldiol
(R)-1e-H2, and La–Li3-(ligand)3 heterobimetallic complexes (R)-REMB (RE¼rare earth),
(R)-LLB, and (R)-La–Li3-(1e)3.
E-mail addresses: smatsuna@mol.f.u-tokyo.ac.jp (S. Matsunaga), mshibasa@
mol.f.u-tokyo.ac.jp (M. Shibasaki).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.031

K. Hara et al. / Tetrahedron 65 (2009) 5030–5036
5031
Table 2
2. Initial trials of a catalytic asymmetric nitroaldol reaction
Optimization studies of kinetic resolution using various (R)-REMB complexes
of simple ketones
Me
Me
HO
HO
(R)-RE-M -(ligand)
3
3
NO
NO
2
2
Initially, we investigated the catalytic asymmetric nitroaldol
reaction of ketone
(REMB, 5 mol %)
THF, –20 °C
2 with nitromethane. Catalyst screening
( )-3a
(R)-3a
2a, CH NO
revealed that (R)-LLB (Fig. 1),10 which is suitable for the nitroaldol
reaction of aldehydes, had high enantioselectivity with ketones.
(R)-LLB promoted the reaction of ketone 2a with 10 equiv of ni-
tromethane at ꢀ40 ꢁC to afford (S)-3a in 95% ee, albeit in poor yield
(2%), after very long reaction time (Table 1, entry 1, 120 h). Excess
nitromethane was essential to obtain product 3a. The yield of the
nitroaldol adducts depended on the substituents of the methyl
ketones,11 and nitroaldol adduct 3c was obtained in 18% yield and
90% ee at ꢀ40 ꢁC (entry 3). Further trials to improve the yield,
however, failed. When the reaction of 2c was performed at ꢀ20 ꢁC,
3c was obtained in 15–20% yield (entries 4–6). The enantiomeric
excess of 3c gradually decreased at ꢀ20 ꢁC over time, but the
conversion yield did not change much. The results shown in entries
4–6 suggested that the nitroaldol reaction of simple ketone 2 is
thermodynamically unfavorable, and that the retro-nitroaldol re-
action catalyzed by (R)-LLB gradually decreased the enantiomeric
excess.11 Good conversion is difficult to achieve in the absence of
stoichiometric amounts of trapping reagents, such as a silylating
reagent to make the reaction irreversible or stoichiometric
amounts of chelating metals to stabilize the product.
+
3
2
Entry
RE
M
Ligand
Time (h)
Yielda (%)
eeb (%)
s
1
2
3
4
5
6
7
8
La
Pr
Li
Li
Li
Li
Li
Na
K
Li
Li
Li
Li
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
24
24
24
42
42
36
36
24
24
24
48
48
57
83
67
46
68
57
42
35
45
58
86
39
3
5
1
3
2
56
83
75
14
23.8
4.5
1.4
1.3
1.0
1.2
1.1
Sm
Gd
Dy
La
La
La
La
La
La
4.0
6.3
9.1
1.7
9
10
11
a
Determined by 1H NMR analysis using mesitylene as an internal standard.
Determined by chiral HPLC analysis.
b
Alkali metals Na and K also resulted in poor selectivity (entries 6–
7). The combination of La and Li produced the best results (entry
1). Several chiral ligands such as BINOL derivatives 1b–1d and
biphenol 1e15 were also investigated, but the results were not
promising (entries 8–11).
For the REMB complexes, three same BINOL units and three
same alkali metals were utilized to construct a symmetric chiral
environment. REMB complexes have a D3-symmetric structure
under strictly anhydrous conditions and a C3-symmetric crystal
structure in the presence of H2O.16 We hypothesized that symmetry
in the REMB complexes is not always required to induce high
enantioselectivity in asymmetric reactions. To increase the di-
versity of the chiral environment in REMB complexes, mixed-ligand
and/or mixed-alkali metal complexes would be potentially more
suitable for some asymmetric reactions. Inspired by recent reports
of a mixed-ligand chiral catalyst screening strategy,17,18 we exam-
ined the mixture of two chiral ligands (Table 3). Because the ligands
of REMB complexes are known to readily exchange in situ,19 we
performed the reactions by mixing two different (R)-La–Li3-(li-
gand)3 complexes. Although mixtures of BINOL 1a with BINOL
derivatives 1b–1d did not afford positive results (entries 2–4)
compared with the result with LLB alone (entry 1), a mixture of
BINOL 1a with biphenol 1e gave a promising result (entry 5, 90% ee
of 3a with 50% conversion, s¼58.4). The best selectivity was
3. Kinetic resolution of tertiary nitroaldols via a retro-
nitroaldol reaction
On the basis of the results shown in Table 1, we planned to use
(R)-LLB for the kinetic resolution of racemic tertiary nitroaldols
via a retro-nitroaldol reaction.12,13 The high enantioselectivity
achieved in the nitroaldol reaction shown in Table 1, entries 1–3,
led us to hypothesize that (R)-LLB would preferentially convert
the matched enantiomer (S)-3a into 2a and nitromethane, and
the mismatched enantiomer (R)-3a would remain unchanged and
be recovered in an enantiomerically enriched form. Kinetic reso-
lution of (ꢂ)-3a using 5 mol % of (R)-LLB proceeded at ꢀ40 ꢁC. As
expected, 3a was recovered in 76% yield and 30% ee [(R)-3a major,
selectivity factor: s¼52.3]14 after 24 h, together with ketone 2a
and nitromethane. To enhance the reaction rate, the reaction was
performed at ꢀ20 ꢁC, giving good enantioselectivity (86% ee) in
48% recovery yield of (R)-3a (Table 2, entry 1, 24 h, s¼23.8). To
further improve selectivity, we investigated several REMB com-
plexes (Fig. 1, RE¼rare earth, M¼alkali metal, B¼biaryldiol). Rare
earth metal screening and alkali metal screening results are
summarized in entries 2–7. Rare earth metals with a smaller ionic
radius, such as Pr, Sm, Gd, and Dy, had poor selectivity (entries 2–5).
Table 3
Optimization studies of kinetic resolution using mixtures of (R)-LLB and (R)-REMB-
type La–Li3-(ligand 1)3 complexes
Table 1
(R)-LLB (x mol %)
Me
HO
Initial trials on catalytic asymmetric nitroaldol reaction of simple ketones
Me
HO
(R)-La-Li -(ligand 1)
3
3
NO
NO
2
2
(R)-LLB (5 mol %)
(y mol %)
O
HO Me
MeNO (10 equiv)
2
NO
THF, –20 °C
(R)-3a
+ 2a, CH NO
(
)-3a
2
R
R
Me
2a-c
THF
3
2
(S)-3a-c
Entry LLB
(x mol %)
La–Li3-(ligand)3 (y mol %) Time Recov. yielda eeb
s
Entry
1
Ketone: R
Temp (ꢁC)
Time (h)
120
Yield (%)
2
ee (%)
95
(h)
(%)
(%)
Cyclohexyl 2a
ꢀ40
1
2
3
4
5
6
7
5
None (0)
24
24
24
24
23
24
48
48
49
39
44
50
51
58
86
57
93
74
90
52
14
23.8
5.9
12.7
8.1
58.4
5.5
3.33
3.33
3.33
3.33
1.67
0
Ligand 1b (1.67)
ligand 1c (1.67)
Ligand 1d (1.67)
Ligand 1e (1.67)
Ligand 1e (3.33)
Ligand 1e (5)
2
ꢀ40
120
5
90
2b
3
4
5
6
PhCH2CH2– 2c
PhCH2CH2– 2c
PhCH2CH2– 2c
PhCH2CH2– 2c
ꢀ40
ꢀ20
ꢀ20
ꢀ20
96
24
48
72
18
15
20
20
90
66
55
43
1.7
a
Determined by 1H NMR analysis using mesitylene as an internal standard.
Determined by chiral HPLC analysis.
b

5032
K. Hara et al. / Tetrahedron 65 (2009) 5030–5036
Table 4
a
Kinetic resolution of tert-nitroaldols 3a–3g promoted by a 2:1 mixture of (R)-LLB and (R)-La–Li3-(1e)3
(R)-LLB (x mol %)
2
2
HO
1
R
(R)-La-Li -(1e)
3
3
O
HO
1
R
(y mol %)
NO
2
NO
2
+ CH NO
3
2
+
1
R
2
R
R
R
THF, –20 °C
3
2
(
)-3
Entry
3
R1
R2
LLB (x mol %)
3.33
La–Li3-(1e)3
(y mol %)
Time (h)
23
Conv.b (%)
Yield of 3c (%)
ee d (%)
90
s
1
2
3a
3b
Cyclohexyl
Me
Me
1.67
50
58
47
40
58.4
19.3
3.33
1.67
15
95
3
4
3c
PhCH2CH2
Me
Me
6.67
3.33
3.33
1.67
19
15
60
58
40
40
80
97
7.7
3d
23.1
5
3d
Me
1.67
0.83
48
57
40
90
15.7
6
3e
3f
Me
Me
3.33
3.33
1.67
1.67
24
26
58
69
41
30
85
88
11.0
6.1
7e
Ph
8
3g
Et
3.33
1.67
13
65
33
88
7.6
a
Reaction was performed in THF (0.4 M) at ꢀ20 ꢁC using a 2:1 mixture of (R)-LLB and (R)-La–Li3-(1e)3 unless otherwise noted.
Determined by 1H NMR analysis using mesitylene as an internal standard.
Isolated yields after column chromatography. The theoretical maximum is 100ꢀconv. (%).
Determined by chiral HPLC analysis.
b
c
d
e
Reaction was run at ꢀ40 ꢁC.
obtained when using a 2:1 mixture of (R)-LLB and (R)-La–Li3-(1e)3
(Fig. 1). Neither LLB/La-Li3-(1e)3 at a 1:2 ratio nor La–Li3-(1e)3 alone
produced satisfactory selectivity (entries 6 and 7).
A postulated catalytic cycle of the reaction is shown in Figure 3.
We assume that the reaction would proceed in the reverse fashion
of the LLB-catalyzed nitroaldol reaction of aldehydes. The mixed-
ligand (R)-La–Li3-(1a)2/(1e) complex selectively reacts with (S)-3
over (R)-3. Because both La and Li metals were essential for good
selectivity (Table 2), we believe that both La and Li in the La–Li3-
(1a)2/(1e) complex might interact with tert-nitroaldol 3 in the
The substrate scopes and limitations of the present kinetic
resolution are summarized in Table 4. Retro-nitroaldol re-
actions of methylketone-derived substrates 3a–3e with ali-
phatic substituents proceeded smoothly to afford chiral 3a–3e
with good enantioselectivity (entries 1–6). For each substrate,
the reaction time was optimized to achieve both a good re-
covery yield of 3 and good to high enantiomeric excess (97–80%
ee, 47–40% isolated yield). With 3d, catalyst loading was suc-
cessfully reduced to 2.5 mol % (LLB: 1.67 mol %, La–Li3-(1e)3:
0.83 mol %), still affording good selectivity (entry 5, 90% ee and
40% yield). In the case of acetophenone-derived substrate 3f
and ethylketone-derived substrate 3g, higher conversion (entry
7: 69% conv., 30% recovery yield of 3f; entry 8: 65% conv., 33%
recovery yield of 3g) was required to achieve good enantiose-
lectivity (3f: 88% ee, 3g: 88% ee).
In the present reaction, a 2:1 mixture of (R)-LLB and (R)-La–Li3-
(1e)3 gave the best results. To gain insight into the structure of the
active species in the reaction, we analyzed the mixture of LLB/La-
Li3-(1e)3¼2:1 by ESI-MS (Fig. 2). Peaks corresponding to [La–Li3-
(1a)2/(1e)þLi]þ and [La–Li3-(1a)/(1e)2þLi]þ complexes were
observed as major peaks in addition to minor peaks of LLB and
La–Li3-(1e)3. In the retro-nitroaldol reaction of 3a, the selectivity
factor was 58.4 with LLB/La-Li3-(1e)3¼2:1 mixture (Table 3, entry
5), while the selectivity factor was 5.5 with LLB/La-Li3-(1e)3¼1:2
mixture (Table 3, entry 6). Furthermore, a 2:1 mixture of LLB/La-Li3-
(1e)3 gave better results than LLB alone (s¼23.8, Table 3, entry 1).
On the basis of these experimental results and ESI-MS observations,
we speculate that a ligand exchange between LLB and La–Li3-(1e)3
occurred to generate a mixed-ligand La–Li3-(1a)2/(1e) complex in
equilibrium, which would be the most enantioselective and re-
active catalyst. We assume that distorted, less symmetric, chiral
environment of the mixed-ligand La–Li3-(1a)2/(1e) complex was
suitable for the present kinetic resolution.
Me
O
Me
O
Li
Li
O
La
O
O
La
O
O
O
O
O
O
O
Li
Li
O
Li
O
Li
+ Li
+ Li
La-Li3-(1a)/(1e)2
O
O
Me
Me
O
Me
O
Me
La-Li3-(1a)2/(1e)
939.7
979.7
[La-Li3-(1e)3 + Li]+
[La-Li3-(1e)3 + H]+
893.6
899.7
[LLB + Li ]+
1019.8
900
1000
m/z
Figure 2. ESI-MS chart of a 2:1 mixture of LLB/La-Li3-(1e)3 [m/z: 840–1060].

K. Hara et al. / Tetrahedron 65 (2009) 5030–5036
5033
R2
5. Conclusion
HO
1
R1
R2
NO2
Li
O
R
In summary, we achieved a kinetic resolution of tertiary nitro-
aldols (ꢂ)-3 derived from simple ketones. A 2:1 mixture of La–Li3-
(binaphthoxide 1a)3 complex (LLB) and La–Li3-(biphenoxide 1e)3
complex had the best selectivity, giving tertiary nitroaldols in 97–
80% ee with 47–30% recovery yield. ESI-MS analysis supported the
idea that a mixed-ligand La–Li3-(1a)2/(1e) complex was generated
in equilibrium as the most enantioselective active species in the
present system. It is interesting to note that the chiral environment
of the mixed-ligand heterobimetallic complex with less symmetry
was more suitable for the present kinetic resolution. Further ap-
plication of the present mixed heterobimetallic catalyst system to
other asymmetric reactions is ongoing.
(S)-3
O
O
more reactive
O H
O
La
O
deprotonation
Li
cat•tert-alkoxide
N+
O
O
Li
Li
O
–
*
O
O
O
Li
O
O
La
O
Li
*
O
C-C cleavage
R1
R2
2
*
(R)-La-Li3-(1a)2/(1e)
*
Li
O
O
Li
O
protonation
O
O
O
O
H
+
N
CH2
La
O
Li
*
–
CH3NO2
6. Experimental section
6.1. General
*
cat•nitronate
Figure 3. Postulated catalytic cycle of the retro-nitroaldol reaction.
Infrared (IR) spectra were recorded on a JASCO FT/IR 410 Fourier
transform infrared spectrophotometer. NMR spectra were recorded on
JEOL JNM-LA500 and JNM-ECX500 spectrometers, operating at
500 MHz for 1H NMR and 125.65 MHz for 13C NMR. For 1H NMR,
chemical shifts in CDCl3 were reported downfield from TMS (¼0) or in
the scale relative to CHCl3 (7.24 ppm); chemical shifts in CD3OD were
reported in the scale relative to CH3OH (3.31 ppm). For 13C NMR,
chemical shifts were reported in the scale relative to CHCl3 (77.0 ppm for
13C NMR) or to CH3OH (49.0 ppm for 13C NMR) as an internal reference.
Optical rotations were measured on a JASCO P-1010 polarimeter. ESI
mass spectra were measured on Waters-ZQ4000. FAB mass spectra
were measured on a JEOL JMS-MS700V in positive ion mode. Column
chromatography was performed with silica gel Merck 60 (230–400
mesh ASTM). The enantiomeric excess (ee) was determined by HPLC
analysis. HPLC was performed on JASCO HPLC systems consisting of the
following: pump, PU-2080; detector, UV-2075, measured at 230 nm or
254 nm; column, DAICEL CHIRALPAK AD-H, DAICEL CHIRALCEL OD-H;
mobile phase, hexane/2-propanol. Reactions were carried out in dry
solvents under an argon atmosphere, unless otherwise stated. Tetra-
hydrofuran (THF) was distilled from sodium benzophenone ketyl. La(O-
i-Pr)3 was purchased from Kojundo Chemical Laboratory Co., LTD.,
(sales@kojundo.co.jp). La(O-i-Pr)3 is also available from Aldrich (Cat. No.
665193).
enantio-discrimination step. La–Li3-(1a)2/(1e) would function as
a Brønsted base to deprotonate the hydroxyl group of (S)-3 to
afford a cat$tert-alkoxide complex. The tert-nitroaldol 3 is ther-
modynamically unfavorable; thus, carbon–carbon bond-cleavage
via the retro-nitroaldol reaction proceeds to give a cat$nitronate
complex and ketone 2. Protonation of the nitronate regenerates
the (R)-La–Li3-(1a)2/(1e) complex. After appropriate reaction time,
less reactive (R)-3 can be recovered in an enantiomerically
enriched form.
4. Transformation of tert-nitroaldol
To demonstrate the synthetic utility of tertiary nitroaldols as
chiral building blocks, several transformations were investigated
(Scheme 1). Hydrogenation of 3a with Pd/C under H2 atmosphere
(1 atm), followed by acetylation, gave N-Ac amine 4a in 86% yield.
Protection of the hydroxyl group in 3c was performed with Et3SiH
and 20 mol % of B(C6F5)3 at room temperature to avoid retro-
nitroaldol reaction,20 giving silylated adduct 5c in 90% yield. The
reaction of 5c with phenyl acetylene proceeded in the presence of
PhNCO and catalytic amount of Et3N to afford isoxazole 6c in 84%
yield.21 Compound 5c was also successfully converted into
droxy carboxylic acid 7c in 99%.22
a-hy-
6.2. General procedure for catalyst preparation
To a stirred solution of (R)-BINOL 1a-H2 (859 mg, 3.00 mmol) in
THF (8 mL) at 0 ꢁC was added slowly a solution of La(O-i-Pr)3 (5 mL,
1.00 mmol, 0.20 M in THF). The solution was allowed to stir for
30 min at room temperature, and then solvent and i-PrOH was
removed slowly under reduced pressure and dried for 1 h under
vacuum. The residue was cooled at 0 ꢁC and THF (8 mL) was added.
To the solution was added slowly n-BuLi (1.88 mL, 3.00 mmol,
1.60 M in hexane). After stirring for 1 h at room temperature, the
solvent was removed slowly under reduced pressure and dried for
3 h under vacuum. The residue was cooled at 0 ꢁC and THF
(7.52 mL) was added. The mixture was stirred at room temperature
for 1 h to afford (R)-LLB solution (0.133 M in THF). (R)-La–Li3-
(biphenoxide 1e)3 was prepared in a similar procedure using (R)-
biphenol 1e-H2. (R)-La–Li3-(1e)3was stocked as 0.067 M solution in
THF.
HO Me
HO Me
H
N
NO2
Ac
a
b
c
3a
4a
HO Me
Et3SiO Me
NO2
NO2
Ph
Ph
3c
5c
5c
Et3SiO Me
N
Ph
O
6c
Ph
HO Me
d
5c
Ph
CO2H
6.3. General procedure for kinetic resolution of racemic
tertiary nitroaldols
7c
Scheme 1. Transformations of tert-nitroaldols: reagents and conditions: (a) cat. Pd/C,
H2 (1 atm), MeOH, rt; Ac2O, Et3N, CH2Cl2, 86% (two steps) (b) cat. B(C6F5)3, Et3SiH,
CH2Cl2, rt, 90%; (c) Ph-acetylene, PhNCO, cat. Et3N, benzene, reflux, 84%; (d) NaNO2,
AcOH, DMSO, rt to 40 ꢁC, 99%.
To a test tube were added THF (0.2 mL), (R)-LLB (0.050 mL,
0.0067 mmol, 0.133 M in THF), and (R)-La–Li3-(1e)3 (0.0500 mL,

5034
K. Hara et al. / Tetrahedron 65 (2009) 5030–5036
0.0033 mmol, 0.067 M in THF), and the mixture solution was stirred
for 45 min at room temperature. The solution was cooled at ꢀ20 ꢁC,
and then (ꢂ)-3a (0.200 mL, 0.200 mmol, 1 M solution in THF) was
added. After stirring for 23 h at ꢀ20 ꢁC, the reaction was quenched
by citric acid (0.5 mL, 0.25 M solution in THF). The resulting mixture
was diluted with Et2O and poured onto water. The aqueous layer
was extracted with Et2O (ꢃ3) and the combined organic layers
were washed with brine, and then dried over Na2SO4. After re-
moving solvent under reduced pressure, the residue was purified
by flash column chromatography (neutral SiO2, hexane/
acetone¼20/1) to give (R)-3a (47% recovery) as pale yellow oil.
6.3.6. (R)-1-Nitro-2-phenyl-2-propanol (3f)
22
(ꢂ)-3f is a known compound.23 Colorless oil; [
a
]
þ6.7 (c 3.6,
D
CHCl3); HPLC (DAICEL CHIRALCEL OD-H, 2-propanol/hexane 1/6,
flow 1.0 mL/min, detection at 230 nm) tR 13.0 min (major) and
15.3 min (minor). The absolute configuration of 3f was determined
after conversion into a known acetamide by following the reaction
conditions in Scheme 1, conditions (a).
6.3.7. (R)-2-Ethyl-4-methyl-1-nitro-2-pentanol (3g)
Colorless oil; IR (neat)
(CDCl3)
n ;
3550, 2958, 1555, 1381 cmꢀ1 1H NMR
4.44 (d, J¼12.0 Hz,1H), 4.41 (d, J¼12.0 Hz,1H), 2.73 (s,1H),
d
1.82–1.74 (m, 1H), 1.67–1.56 (m, 2H), 1.47 (dd, J¼15.0, 5.5 Hz, 1H),
6.3.1. (R)-2-Cyclohexyl-1-nitro-2-propanol (3a)
1.38 (dd, J¼15.0, 6.8 Hz, 1H), 0.97–0.90 (m, 9H); 13C NMR (CDCl3)
Pale yellow oil; IR (neat)
(CDCl3)
4.52 (d, J¼12.0 Hz,1H), 4.41 (d, J¼12.0 Hz,1H), 2.81 (s,1H),
1.87–1.79 (m, 4H), 1.70 (m, 1H), 1.44 (m, 1H), 1.25–0.97 (m, 5H), 1.23
n
3543, 2926, 2855,1384 cmꢀ1; 1H NMR
d 82.9, 74.4, 44.7, 30.2, 24.6, 24.3, 23.6, 8.1; ESI-MS m/z 198
d
[MþNa]þ; HRMS [FAB(þ)] calcd for C8H17CsNOþ3 [MþCs]þ:
22
308.0263; found 308.0262; [
a
]
þ1.0 (c 2.05, CHCl3); HPLC (DAICEL
D
(s, 3H); 13C NMR (CDCl3)
d
83.3, 73.8, 46.4, 27.7, 26.7, 26.4, 26.2, 21.5;
CHIRALPAK AD-H, 2-propanol/hexane 1/20, flow 1.0 mL/min, de-
ESI-MS m/z 210 [MþNa]þ; HRMS [FAB(þ)] calcd for C9H17CsNOþ3
tection at 230 nm) tR 9.5 min (minor) and 13.6 min (major).
22
[MþCs]þ: 320.0257; found 320.0265; [
a
]
ꢀ2.7 (c 2.4, CHCl3);
D
HPLC (DAICEL CHIRALPAK AD-H, 2-propanol/hexane 1/9, flow
1.0 mL/min, detection at 230 nm) tR 8.3 min (minor) and 11.5 min
(major). The absolute configuration of 3a was determined after
conversion into known acetamide 4a.
6.4. Transformation of tert-nitroaldols
6.4.1. (R)-N-(2-Cyclohexyl-2-hydroxy-propyl)-acetamide (4a)
A suspension of 3a (21.4 mg, 0.114 mmol) and 10% Pd/C (6.1 mg)
in MeOH (1 mL) was stirred under H2 (1 atm) at room temperature
for 12 h. Then, the reaction mixture was filtrated through Celite pad
and washed with Et2O. The filtrates were evaporated under re-
duced pressure to give a crude amine. To a solution of the crude
amine and Et3N (0.017 mL, 0.122 mmol) in CH2Cl2 was added acetic
anhydride (0.013 mL, 0.138 mmol) at 0 ꢁC and the reaction mixture
was stirred at room temperature for 2 h. The reaction was
quenched satd aq NH4Cl. The mixture was extracted with Et2O (ꢃ3),
and combined organic layers were washed with brine and dried
over Na2SO4. After concentration under reduced pressure, the res-
idue was purified by silica gel column chromatography (CH2Cl2/
MeOH¼90:10) to give 4a (19.5 mg, 86%) as a colorless solid. Ana-
lytical data matched well with reported data in the literature.24
6.3.2. (R)-3-Cyclohexyl-2-methyl-1-nitro-2-propanol (3b)
Pale yellow oil; IR (neat)
NMR (CDCl3)
4.45 (d, J¼12.0 Hz, 1H), 4.39 (d, J¼12.0 Hz, 1H), 2.80
(s, 1H), 1.84–1.44 (m, 8H), 1.32 (s, 3H), 1.30–0.95 (m, 5H); 13C NMR
n
3541, 2923, 2851, 1550, 1382 cmꢀ1; 1H
d
(CDCl3)
d 84.9, 72.2, 46.8, 35.1, 34.9, 33.3, 26.3, 26.2, 26.1, 24.8; ESI-
MS m/z 224 [MþNa]þ; HRMS [FAB(þ)] calcd for C10H19CsNOþ3
20
[MþCs]þ: 334.0414; found 334.0410; [
a]
ꢀ1.9 (c 1.3, CHCl3); HPLC
D
(DAICEL CHIRALPAK AD-H, 2-propanol/hexane 1/9, flow 1.0 mL/
min, detection at 230 nm) tR 8.3 min (minor) and 12.7 min (major).
6.3.3. (R)-2-Methyl-1-nitro-4-phenyl-2-butanol (3c)
Colorless oil; IR (neat)
NMR (CDCl3)
7.31–7.18 (m, 5H), 4.50 (d, J¼12.0 Hz, 1H), 4.45 (d,
J¼12.0 Hz,1H), 2.92 (s,1H), 2.77–2.74 (m, 2H),1.90–1.86 (m, 2H),1.39
n ;
3269, 2922, 2849, 1548, 1384 cmꢀ1 1H
d
Colorless solid; 1H NMR (CDCl3)
d
5.85 (br s, 1H), 3.31 (dd, J¼14,
6.4 Hz, 1H), 3.21 (dd, J¼14.0, 5.2 Hz, 1H), 2.00 (s, 3H), 1.83–1.64 (m,
(s, 3H); 13C NMR (CDCl3)
d
141.0, 128.6, 128.3, 126.2, 84.1, 71.5, 41.5,
5H), 1.41–1.33 (m, 1H), 1.25–0.95 (m, 5H); 13C NMR (CDCl3)
d
170.3,
26
29.8, 24.4; ESI-MS m/z 232 [MþNa]þ; HRMS [FAB(þ)] calcd for
74.7, 47.6, 46.5, 27.8, 26.7, 26.6, 26.6, 26.4, 23.2, 21.4; [
1.2, CHCl3).
a]
D
þ2.4 (c
C11H15CsNOþ3 [MþCs]þ: 342.0101; found 342.0094; [
a]
ꢀ3.7 (c 2.40,
20
D
CHCl3); HPLC (DAICEL CHIRALCEL OD-H, 2-propanol/hexane 1/4, flow
1.0 mL/min, detection at 254 nm) tR 12.0 min (major) and 15.3 min
(minor). For the absolute configuration of 3c, see section 6.4.4.
6.4.2. (R)-Triethyl-(1-methyl-1-nitromethyl-3-phenyl-propoxy)-
silane (5c)
To a stirred solution of 3c (51.7 mg, 0.247 mmol), and Et3SiH
(0.047 mL, 0.296 mmol) in CH2Cl2 (0.5 mL) was added B(C6F5)3
(12.6 mg, 0.0247 mmol) at room temperature. After being stirred
for 1.5 h at the same temperature, B(C6F5)3 (12.6 mg) was added
again. After 2.5 h, the reaction was quenched with H2O. The mix-
ture was extracted with Et2O (ꢃ3). The combined organic layers
were washed with brine and dried over Na2SO4. After concentra-
tion under reduced pressure, the residue was purified by neutral
silica gel column chromatography (neutral SiO2, hexane/
6.3.4. (R)-2,4-Dimethyl-1-nitro-2-pentanol (3d)
Pale yellow oil; IR (neat)
NMR (CDCl3)
4.45 (d, J¼12.0 Hz, 1H), 4.39 (d, J¼12.0 Hz, 1H), 2.81
n
3541, 2958, 2872, 1551, 1382 cmꢀ1; 1H
d
(s, 1H), 1.88–1.81 (m, 1H), 1.52–1.43 (m, 2H), 1.32 (s, 3H), 1.00 (d,
J¼6.4 Hz, 3H), 0.98 (d, J¼6.7 Hz, 3H); 13C NMR (CDCl3)
d 84.9, 72.1,
47.9, 24.7, 24.6, 24.3, 24.0; ESI-MS m/z 184 [MþNa]þ; HRMS
[FAB(þ)] calcd for C7H15CsNOþ3 [MþCs]þ: 294.0101; found
22
294.0097; [
a]
ꢀ2.3 (c 1.4, CHCl3); HPLC (DAICEL CHIRALPAK AD-
D
H, 2-propanol/hexane 1/20, flow 1.0 mL/min, detection at 230 nm)
Et2O¼95:5) to give 5c (71.9 mg, 90%) as a colorless oil. IR (neat)
n
tR 10.7 min (minor) and 12.4 min (major).
2956, 1552, 1145, 745 cmꢀ1 1H NMR (CDCl3)
;
d
7.30–7.18 (m, 5H),
4.40 (d, J¼10.0 Hz, 1H), 4.11 (d, J¼10.0 Hz, 1H), 2.77–2.64 (m, 2H),
6.3.5. (R)-3-Ethyl-2-methyl-1-nitro-2-pentanol (3e)
1.98–1.87 (m, 2H), 1.46 (s, 3H), 0.96 (t, J¼8.0 Hz, 9H), 0.63 (q,
Pale yellow oil; IR (neat)
n
3544, 2967, 2878,1553,1382 cmꢀ1; 1H
J¼8.0 Hz, 6H); 13C NMR (CDCl3)
d 141.4, 128.5, 128.3, 126.0, 83.9,
NMR (CDCl3)
d
4.54 (d, J¼12.0 Hz, 1H), 4.43 (d, J¼12.0 Hz, 1H), 2.84
74.2, 43.1, 30.4, 26.2, 7.0, 6.6; ESI-MS m/z 346 [MþNa]þ; HRMS
(s, 1H), 1.67 (m, 1H), 1.54 (m, 1H), 1.27–1.20 (m, 3H), 1.24 (s, 3H), 1.00
[FAB(þ)] calcd for C17H29CsNO3Siþ [MþCs]þ: 456.0971; found
29
(t, J¼7.1 Hz, 3H), 0.97 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3)
d
83.5, 75.0,
456.0964; [
a]
ꢀ6.5 (c 2.4, CHCl3).
D
50.1, 23.2, 22.2, 21.8, 13.9, 13.4; ESI-MS m/z 198 [MþNa]þ; HRMS
[FAB(þ)] calcd for C8H17CsNOþ3 [MþCs]þ: 308.0263; found
6.4.3. (R)-3-(1-Methyl-3-phenyl-1-triethylsilanyloxy-propyl)-5-
phenyl-isoxazole (6c)
22
308.0261; [
a]
þ1.4 (c 1.4, CHCl3); HPLC (DAICEL CHIRALPAK AD-H,
D
2-propanol/hexane 1/20, flow 1.0 mL/min, detection at 230 nm) tR
To a solution of 5c (6.51 mg, 20.1
with one drop of Et3N was added phenyl acetylene (4.4
m
mol) in dry benzene (0.5 mL)
L,
8.9 min (minor) and 10.7 min (major).
m

K. Hara et al. / Tetrahedron 65 (2009) 5030–5036
5035
2006, 45, 5978; (h) Xiong, Y.; Wang, F.; Huang, X.; Wen, Y.; Feng, X. Chem.dEur.
J. 2007, 13, 829; (i) Bandini, M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.;
Ventrici, C. Chem. Commun. 2007, 616; (j) Ma, K.; You, J. Chem.dEur. J. 2007, 13,
40.2 mmol) and phenyl isocyanate (10.9 mL, 0.10 mmol) successively
at room temperature. After stirring for 30 min, the mixture was
refluxed for 40 h. Water was added to the mixture at rt, then one
drop of 1 M HCl was added. The product was extracted with Et2O
(ꢃ3), and combined organic layer was washed with brine, and then
dried over Na2SO4. After filtration, Et2O was evaporated under re-
duced pressure and the residue was purified by silica gel column
chromatography (hexane/ethyl acetate¼12:1) to give 6c (6.87 mg,
¨
1863; (k) Bulut, A.; Aslan, A.; Dogan, O J. Org. Chem. 2008, 73, 7373; (l) Liu, S.;
Wolf, C. Org. Lett. 2008, 10, 1831; (m) Kowalczyk, R.; Kwiatkowski, P.; Skar-
zewski, J.; Jurczak, J. J. Org. Chem. 2009, 74, 753 and references therein.
4. syn-Selective reaction: (a) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh,
N.; Shibasaki, M. J. Org. Chem. 1995, 60, 7388; anti-selective reaction; (b) Ni-
tabaru, T.; Kumagai, N.; Shibasaki, M. Tetrahedron Lett. 2008, 49, 272; (c) Handa,
S.; Nagawa, K.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed.
2008, 47, 3230.
5. (a) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054; (b) Risgaard,
T.; Gothelf, K. V.; Jørgensen, K. A. Org. Biomol. Chem. 2003, 1, 153; (c) Sohtome,
Y.; Hashimoto, Y.; Nagasawa, K. Eur. J. Org. Chem. 2006, 2894; (d) Purkarthofer,
T.; Gruber, K.; Gruber-Khadjawi, M.; Waich, K.; Skranc, W.; Mink, D.; Griengl, H.
Angew. Chem., Int. Ed. 2006, 45, 3454; (e) Sohtome, Y.; Takemura, N.; Takada, K.;
Takagi, R.; Iguchi, T.; Nagasawa, K. Chem. Asian J. 2007, 2, 1150; (f) Arai, T.;
Watanabe, M.; Yanagisawa, A. Org. Lett. 2007, 9, 3595; (g) Uraguchi, D.; Sakaki,
S.; Ooi, T. J. Am. Chem. Soc. 2007, 129, 12392; (h) Gruber-Khadjawi, M.; Pur-
karthofer, T.; Skranc, W.; Griengl, H. Adv. Synth. Catal. 2007, 349, 1445; (i) Blay,
84% yield) as a colorless oil. IR (neat)
(CDCl3)
n ;
2954, 1450 cmꢀ1 1H NMR
7.81–7.79 (m, 2H), 7.49–7.43 (m, 3H), 7.26 (dd, J¼7.6,
d
7.7 Hz, 2H), 7.17–7.14 (m, 3H), 6.57 (s, 1H), 2.71 (ddd, J¼4.9, 12.5,
13.5 Hz, 1H), 2.61 (ddd, J¼5.2, 12.5, 12.5 Hz, 1H), 2.20 (ddd, J¼5.2,
12.5, 13.5 Hz, 1H), 2.09 (ddd, J¼4.9, 12.5, 12.5 Hz, 1H), 1.77 (s, 3H),
1.00–0.97 (m, 9H), 0.67–0.62 (m, 6H); 13C NMR (CDCl3)
d 171.1,
169.3, 142.2, 130.0, 128.9, 128.3, 127.7, 125.8, 125.7, 98.4, 73.7, 46.7,
30.5, 27.5, 7.1, 6.6; ESI-MS m/z 193 [MþNa]þ; HRMS [FAB(þ)] calcd
´
G.; Domingo, L. R.; Hernandez-Olmos, V.; Pedro, J. R. Chem.dEur. J. 2008, 14,
26
for C25H33CsNO2Siþ [MþCs]þ: 540.1329; found 540.1334; [
(c 3.2, CHCl3).
a
]
þ1.1
4725.
D
6. (a) Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem. Commun. 2001, 2222; (b)
Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
4875; (c) Lu, S. F.; Du, D. M.; Zhang, S. W.; Xu, J. Tetrahedron: Asymmetry 2004,
15, 3433; (d) Du, D.-M.; Lu, S.-F.; Fang, T.; Xu, J. J. Org. Chem. 2005, 70, 3712; (e)
Qin, B.; Xiao, X.; Liu, X.; Huang, J.; Wen, Y.; Feng, X. J. Org. Chem. 2007, 72, 9323;
(f) Choudary, B. M.; Ranganath, K. V. S.; Pal, U.; Kantam, M. L.; Sreedhar, B. J. Am.
Chem. Soc. 2005, 127, 13167; (g) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006,
6.4.4. (R)-2-Hydroxy-2-methyl-4-phenyl-butyric acid (7c)
To a stirred solution of 5c (28.4 mg, 87.8
mmol) in dimethyl
sulfoxide (0.44 mL) and acetic acid (75.4 L, 1.32 mmol) was added
m
128, 732; (h) For a-keto phosphonates, see: Mandal, T.; Samanta, S.; Zhao, C.-G.
Org. Lett. 2007, 9, 943.
sodium nitrite (60.6 mg, 0.878 mmol) at room temperature. The
resulting mixture was stirred at room temperature for 12 h and
then at 40 ꢁC for 8 h. The solution was cooled down to room tem-
perature and quenched with 1 M HCl. The mixture was extracted
with Et2O (ꢃ3). The combined organic layers were washed with
2 M NaOH (3). Then, the combined water layers were acidified with
4 M HCl. The acidic water layer was again extracted with diethyl
ether (ꢃ3), and combined organic layers were dried over Na2SO4.
After filtration of Na2SO4, solvent was evaporated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (CH2Cl2/MeOH¼6:1) to give 7c (16.8 mg, 99% yield) as
a colorless solid. 7c is known compound.25 The absolute configu-
ration of 7c was determined after conversion into a known ethyl
7. (a) For early works, see Tur, F.; Saa´, J. M. Org. Lett. 2007, 9, 5079 also; (b) Misumi,
Y.; Bulman, R. A.; Matsumoto, K. Heterocycles 2002, 56, 599.
8. (a) Seebach, D.; Lehr, F. Angew. Chem., Int. Ed. Engl. 1976, 15, 505; (b) Eyer, M.;
Seebach, D. J. Am. Chem. Soc. 1985, 107, 3601; (c) Kisanga, P. B.; Verkade, J. G.
J. Org. Chem. 1999, 64, 4298; (d) Gan, C.; Chen, X.; Lai, G.; Wang, Z. Synlett 2006,
387.
9. A portion of this work was previously reported as a preliminary communica-
tion: Tosaki, S.-y.; Hara, K.; Gnanadesikan, V.; Morimoto, H.; Harada, S.; Sugita,
M.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128,
11776.
10. (a) For selected recent examples using rare earth-alkali metal heterobimetallic
catalysts, see: Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2002, 41, 3636; (b) Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 16178; (c) Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shibasaki,
M. J. Am. Chem. Soc. 2005, 127, 13419; (d) Yamagiwa, N.; Tian, J.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 3413; (e) Sone, T.; Yamaguchi, A.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 10078; See also: (f)
Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2007, 129, 9588; (g) Lu, G.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2008, 47, 6847.
11. In the nitroaldol reaction in Table 1, excess nitromethane was required to
suppress undesired retro-nitroaldol reaction and to obtain kinetically con-
trolled product. We speculate that excess nitromethane was also important due
to a low equilibrium constant. Generally, equilibrium constants for aldol(-type)
reactions of ketone-electrophiles are much lower than those of aldehydes.
Different yields in entries 1–3 in Table 1 can be ascribed to the difference in
equilibrium constant depending on the substituents. For example, an equilib-
rium constant for aldol reaction of benzaldehyde and acetone is 11.7 Mꢀ1, while
that of acetophenone and acetone is 1.89ꢃ10ꢀ3 Mꢀ1. (a) Guthrie, J. P. J. Am.
Chem. Soc. 1991, 113, 7249; (b) Guthrie, J. P.; Wang, X.-P. Can. J. Chem. 1992, 70,
1055 and references therein.
12. For a kinetic resolution of tertiary aldols via retro-aldol reaction with a catalytic
antibody, see: (a) List, B.; Shabat, D.; Zhong, G.; Turner, J. M.; Li, A.; Bui, T.;
Anderson, J.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 1999, 121, 7283 and
references therein; For a retro-nitroaldol reaction with a catalytic antibody, see:
(b) Flanagan, M. E.; Jacobsen, J. R.; Sweet, E.; Schultz, P. G. J. Am. Chem. Soc. 1996,
118, 6078.
13. A general review for non-enzymatic kinetic resolution: (a) Vedejs, E.; Jure, M.
Angew. Chem., Int. Ed. 2005, 44, 3974; For examples of nonenzymatic kinetic
resolution of tert-alcohols, see: (b) Angione, M. C.; Miller, S. J. Tetrahedron 2006,
62, 5254 and references therein.
ester. 1H NMR (CD3OD)
d 7.21–7.18 (m, 2H), 7.13–7.09 (m, 3H), 2.82
(ddd, J¼3.4, 13.2, 13.2 Hz, 1H), 2.53 (ddd, J¼4.1, 12.6, 13.2 Hz, 1H),
2.10 (ddd, J¼3.4, 12.6, 13.2 Hz, 1H), 1.85 (ddd, J¼4.1, 13.2, 13.2 Hz,
1H), 1.45 (s, 3H); 13C NMR (CD3OD)
d 179.4, 143.3, 129.4, 129.3,
31
126.8, 75.4, 43.7, 31.3, 26.5; [
a
]
þ16.9 (c 0.13, MeOH).
D
Acknowledgements
This work was partially supported by Grant-in-Aid for Specially
Promoted Research, Grant-in-Aid for Scientific Research (S), Grant-
in-Aid for Scientific Research on Priority Areas (No. 20037010,
Chemistry of Concerto Catalysis) (for S.M.) from JSPS and MEXT.
H.M. and S.H. thank JSPS fellowships.
References and notes
1. For recent reviews of the catalytic asymmetric nitroaldol reaction, see: (a)
Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561; (b) Boruwa, J.;
Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron: Asymmetry 2006, 17, 3315; (c)
Palomo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442.
2. (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114,
4418; For reviews, see: (b) For selected recent works from our group, see Shi-
basaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed.1997, 36, 1236; (c) Sohtome, Y.;
Kato, Y.; Handa, S.; Aoyama, N.; Nagawa, K.; Matsunaga, S.; Shibasaki, M. Org. Lett.
2008, 10, 2231; (d) Mihara, H.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. Chem.
Asian J. 2008, 3, 359.
14. For discussion on validity of calculated s values, see s values in this manuscript
were calculated based on conversion and ee of recovered 3 assuming first-
order kinetic dependence on 3. Kinetic studies are required to determine
accurate s values Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal.
2001, 343, 5.
15. Biphenyldiol 1e: (a) Meyers, A. I.; Nelson, T. D.; Moorlag, H.; Rawson, D. J.;
Meier, A. Tetrahedron 2004, 60, 4459; For the utility of biphenyldiols in other
asymmetric reactions, see: (b) Harada, T.; Tuyet, T. M. T.; Oku, A. Org. Lett. 2000,
2, 1319; (c) Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2007, 129, 13410; (d) Kakei, H.; Tsuji, R.; Ohshima, T.; Morimoto, H.;
Matsunaga, S.; Shibasaki, M. Chem. Asian J. 2007, 2, 257; (e) Yamaguchi, A.;
Aoyama, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2007, 9, 3387; (f) Hara, K.;
Park, S.-y.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Chem. Asian J. 2008, 3,
1500.
3. For selected examples using nitromethane and aldehydes by other groups, see:
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