A trans-chelating bisphosphine possessing only planar chirality and its application to catalytic asymmetric reactions

Article abstract of DOI:10.1016/j.tetasy.2004.04.033

A new chiral bisphosphine, (S,S)-2,2″-bis[(diethylphosphino)methyl]- 1,1″-biferrocene [(S,S)-EtTRAP-H], was synthesized in seven steps in 45% overall yield from ferrocenyloxazoline derived from (S)-valinol. The new chiral phosphine has only planar chirality, and is able to form a trans-chelate metal complex. (S,S)-EtTRAP-H is an effective ligand in rhodium-catalyzed asymmetric hydrosilylation of ketones (up to 94% ee). In particular, the hydrosilylation of 2-octanone yielded (S)-2-octanol with 77% ee.

Full text of DOI:10.1016/j.tetasy.2004.04.033

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2263–2271
A trans-chelating bisphosphine possessing only planar chirality and
its application to catalytic asymmetric reactions
Ryoichi Kuwano,a,* Takashi Uemura,b,ꢀ Makoto Saitohb and Yoshihiko Itob,*
aDepartment of Chemistry, Graduate School of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
bDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Sakyo-ku,
Kyoto 606-8501, Japan
Received 12 March 2004; accepted 8 April 2004
Available online 4June 2004
Abstract—A new chiral bisphosphine, (S,S)-2,200-bis[(diethylphosphino)methyl]-1,100-biferrocene [(S,S)-EtTRAP-H], was synthe-
sized in seven steps in 45% overall yield from ferrocenyloxazoline derived from (S)-valinol. The new chiral phosphine has only
planar chirality, and is able to form a trans-chelate metal complex. (S,S)-EtTRAP-H is an effective ligand in rhodium-catalyzed
asymmetric hydrosilylation of ketones (up to 94% ee). In particular, the hydrosilylation of 2-octanone yielded (S)-2-octanol with
77% ee.
Ó 2004Elsevier Ltd. All rights reserved.
1. Introduction
chirality in the latter reaction. Chiral ligands, which only
possess planar chirality, are relatively rare.10
Asymmetric catalysis is an important subject in syn-
thetic organic chemistry.1 The design of new chiral
catalysts is essential for exploring new classes of cata-
lytic asymmetric reactions as well as for achieving high
enantioselectivities.2 Typical chiral catalysts are transi-
tion metal complexes modified with optically active
organic molecules, which have Lewis basic functional
groups, for example, alkoxide, oxazoline, and phos-
phine.3 So far, numerous chiral phosphine ligands have
been developed and employed for catalytic asymmetric
syntheses.2 Various types of chirality have been utilized
for design of chiral phosphines. Most of the chiral
phosphines possess a stereogenic center. Many axially
chiral ligands, for example, BINAP,4 have been re-
ported.5 Planar chirality has frequently appeared in
ferrocene-based chiral ligands along with central chi-
rality.6 Hayashi’s ferrocenyl phosphines are typical,7
with the role of each chiral element being investigated in
asymmetric Grignard cross-coupling8 and aldol reac-
tions of isocyanoacetate.9 The stereogenic center scar-
cely affects the enantioselectivity in the former reaction,
while the enantioselectivity is controlled by the central
We have designed and synthesized a new family of fer-
rocene-based chiral bisphosphines, TRAP 1 (Fig. 1).11
Characteristically, TRAP forms a nine-membered che-
late complex with a transition metal and is able to
coordinate to a metal atom in trans-chelation. The
ligands display high enantioselectivities for various cat-
alytic asymmetric reactions, Michael12 and aldol addi-
tions13 of 2-cyanopropionates, allylation,14 hydro-
silylation of ketones,15 hydrogenations of olefins16–18 and
indoles,19 and cycloisomerization of 1,6-enynes.20 (R,R)-
(S,S)-TRAP ligands possess two stereogenic centers
with an (R)-configuration at each a-position of phos-
phino groups as well as two chiral planes with (S)-con-
figurations on the biferrocene backbone, due to the
Me
H
R PR2
PEt2
S
S
Fe
R2P
Fe
Fe
Et2P
(S,S)-EtTRAP-H (2)
Fe
S
S
H
R Me
(R,R)-(S,S)-TRAP (1)
* Corresponding authors. Tel.: +81-92-642-2572; fax: +81-92-642-26-
07; e-mail: rkuwascc@mbox.nc.kyushu-u.ac.jp
1a: R = Et (EtTRAP)
1b: R = Bu (BuTRAP)
ꢀ
Present address: Department of Synthetic Chemistry and Biological
Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan.
Figure 1. Structures of TRAP and TRAP-H.
0957-4166/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.033

2264
R. Kuwano et al. / Tetrahedron: Asymmetry 15 (2004) 2263–2271
unsymmetrical disubstitution on the cyclopentadienes.
We synthesized a new optically active phosphine, (S,S)-
cenecarboxylic acid (S)-5 possessing only planar chiral-
ity. We next attempted to convert (S)-5 into primary
alcohol (S)-6, but an undesired deiodination side-prod-
uct was yielded mainly by the use of LiAlH4 and the
BH3ÆTHF, which are typical reducing agents for car-
boxylic acids to primary alcohols. Treatment with
NaBH4 after transformation of (S)-5 into acyl chloride
gave the desired primary alcohol (S)-6 with no forma-
tion of the deiodinated product. Esterification of (S)-6
with acetic anhydride gave acetate (S)-7 quantitatively.
Nucleophilic substitution of the acetoxy group with di-
ethylphosphine was conducted in acetic acid.24 The
resulting tertiary phosphine was converted into the
corresponding phosphine oxide (S)-8 by H2O2 in ace-
tone, because the unprotected phosphine was expected
to inhibit the following Ullmann coupling as well as to
be readily oxidized by air. The homocoupling of (S)-8
was performed with activated copper powder without
the use of solvent, producing C2-symmetric biferrocene
(S,S)-9. Finally, the reduction of phosphine oxide 9 with
HSiCl3–Et3N gave (S,S)-EtTRAP-H 2. The new chiral
phosphine (S,S)-2 was obtained from (S)-3 via seven
steps in 45% overall yield.
2,200-bis[(diethylphosphino)methyl]-1,100-biferrocene
2
[(S,S)-EtTRAP-H], in order to clarify the role of the
central chirality of 1. The TRAP-H ligand only has
planar chirality for lack of methyl groups on the
a-positions of diethylphosphino groups. Herein we de-
scribe the synthesis of 2 and its application to catalytic
asymmetric hydrogenation of enamides and hydrosilyl-
ation of ketones. EtTRAP-H exhibited higher enantio-
selectivity for the asymmetric hydrosilylation than Et- or
BuTRAP.21 To the best of our knowledge, EtTRAP-H
provides the highest stereoselectivity recorded to date
for catalytic asymmetric reduction of linear 2-alkanone,
which is one of the more challenging substrates for
enantioselective reduction with asymmetric catalysis.
2. Results and discussion
2.1. Synthesis of (S,S)-EtTRAP-H
The new chiral phosphine (S,S)-EtTRAP-H was pre-
pared from optically active ferrocenyloxazoline (S)-3
derived from (S)-valinol (Scheme 1).22 Diastereoselective
ortho-lithiation of (S)-3 was carried out with sec-butyl-
lithium in the presence of N,N,N0,N0-tetramethyl-1,2-
ethylenediamine (TMEDA) according to Sammakia’s
procedure.23 Reaction of the resulting lithioferrocene
with 1,2-diiodoethane gave iodoferrocene 4 with (S)-
planar chirality. Stereoselectivity of the ortho-lithiation
EtTRAP-H as well as other TRAP ligands can be han-
dled in the air and can be stored for over a year under
argon in a freezer. The new peralkylphosphine 2, how-
ever, is less stable to air oxidation when compared with
1a. We previously reported that the 13C resonances for a
and b-carbons of the phosphorus atom of 1a split into
more than two lines because of virtual through-space
31P–31P coupling.11c The through-space coupling sug-
gests the proximity of the two phosphorus atoms of 1a.
In contrast to 1a, five simple doublet peaks were ob-
served as the resonances of the 13-carbons a and b to the
phosphorus atoms of 2 (Fig. 2). This observation indi-
cates the remarkable difference between the most
favorable conformations of 1a and 2: two phosphorus
atoms in 2 cannot be located close each other.
1
was determined to be 98% de by H NMR analysis of
the crude product. After treatment of 4 with methyl
trifluoromethanesulfonate, the resulting oxazolinium
salt was hydrolyzed with aqueous KOH to give ferro-
O
N
O
N
1. sec-BuLi, TMEDA
Fe
Fe
i-Pr
i-Pr
I
2. ICH2CH2I
91%
(S)-3
(S)-(S)-4 (98% de)
OH
CO2H
1. MeOTf
1. (COCl)2
Fe
Fe
I
I
2. NaBH4
85%
2. KOH aq.
93%
(S)-5
(S)-6
O
OAc
PEt2
Figure 2. 13C{1H} NMR spectrum (75 MHz, CDCl3) of 2 (alkyl
region).
Ac2O, Et3N
DMAP
1. HPEt2
Fe
O
Fe
I
I
2. H2O2
90%
100%
Cu
(S)-7
(S)-8
2.2. Rhodium complex of EtTRAP-H
PEt2
PEt2
Fe
HSiCl3, Et3N
To confirm whether EtTRAP-H 2 is able to form a
trans-chelate complex or not, we conducted the reaction
of the bisphosphine with 0.5 equivalent of [RhCl(CO)2]2
in CD2Cl2, and monitored the reaction by 31P NMR
measurement. The reaction went to completion imme-
diately, forming a single rhodium complex, RhCl(CO) 2,
whose 31P NMR spectrum exhibited a pair of double
Fe
Et2P
Fe
Fe
Et2P
(S,S)-2
72%
97%
O
(S,S)-9
Scheme 1. Synthesis of EtTRAP-H 2.

R. Kuwano et al. / Tetrahedron: Asymmetry 15 (2004) 2263–2271
2265
doublet peaks at d 20.8 and 26.5 ppm with JP–P ¼ 340 Hz
[Rh(cod)2]BF4 (1.0 mol%)
TRAP (1.1 mol%)
(Fig. 3). The large P–P spin coupling constant is char-
acteristic of trans-bis(phosphine)-metal complexes. This
observation indicates that ligand 2, as well as other
TRAP ligands, is able to coordinate to a transition
metal atom in trans-chelation.
Me
Me
CO2Me
CO2Me
Me
Me
H2 (1.0 kg/cm2)
NHAc
12
NHAc
13
i-PrOH, 0 ˚C, 24 h
(R,R)-(S,S)-EtTRAP 1a
(R,R)-(S,S)-BuTRAP 1b
(S,S)-EtTRAP-H 2
83% ee (S) (ref 16a)
88% ee (S) (ref 16a)
54% ee (S)
ð2Þ
Piperazine-2-carboxamide is a constituent of Merck
HIV protease inhibitor Crixivan.27 Some TRAP ligands
showed high enantioselectivities for the hydrogenations
of 1,4,5,6-tetrahydropyrazine-2-carboxamides to afford
the optically active piperazine.17;28 (R,R)-(S,S)-i-Bu-
TRAP– and MeTRAP–rhodium catalyst gave pipera-
zine-2-carboxamide with 97% ee (S) and 85% ee (R),
respectively. The asymmetric hydrogenation of 14 using
EtTRAP was less enantioselective than that with i-Bu-
or MeTRAP, giving 35% ee of (S)-15. Hydrogenation of
14 with EtTRAP-H–rhodium catalyst was conducted
under the conditions indicated in Eq. 3. In contrast to
the reactions of acyclic a-(acetamido)acrylates, 10 and
12, EtTRAP-H showed higher enantioselectivity than
1a. However, ligand 2 was less effective than i-Bu- and
MeTRAP.
Figure 3. 31P{1H} NMR spectrum (121.5 MHz, CD2Cl2, 85% H3PO4)
of trans-[RhCl(CO){(S,S)-EtTRAP-H}].
2.3. Catalytic asymmetric hydrogenations of enamides
using EtTRAP-H
First, we evaluated the new chiral ligand, EtTRAP-H,
for the rhodium-catalyzed asymmetric hydrogenation of
methyl 2-(N-acetylamino)acrylate 10 (Eq. 1). The
hydrogenation of 10 using 2 was conducted in 1,2-
dichloroethane at 60 °C and under 0.5 kg/cm2 of partial
hydrogen pressure for 24h. The EtTRAP-H-
[Rh(cod)2]BF4 complex catalyzed the hydrogenation of
10, giving product 11 in high yield (97%). However, the
enantiomeric excess of 11 was significantly low (45% ee)
when compared with the enantioselectivity of the
hydrogenation using 1a (96% ee).16a
PhO
[Rh(nbd)2]PF6 (1.0 mol%)
O
PhO
O
N
N
N
N
TRAP (1.1 mol%)
NH(t-Bu)
H2 (1.0 kg/cm2)
NH(t-Bu)
Cl(CH2)2Cl, 50 ˚C, 24 h
Boc
O
Boc
14
O
15
(R,R)-(S,S)-EtTRAP 1a
(S,S)-EtTRAP-H 2
35% ee (S) (ref 17)
57% ee (S)
ð3Þ
[Rh(cod)2]BF4 (1.0 mol%)
CO2Me
Me
CO2Me
TRAP (1.1 mol%)
A divergent effect of the stereogenic centers of TRAP
ligand was observed in the asymmetric hydrogenation of
each substrate. In every case, the sense of asymmetric
induction by EtTRAP-H ligand was the same as that by
EtTRAP. Employment of EtTRAP-H never caused the
formation of a racemic product, while the reaction
proceeded with moderate to high enantioselectivity with
the EtTRAP ligand. These findings suggest that stereo-
determining step in the asymmetric hydrogenations
using 1 was controlled predominantly by the planar
chirality. The central chirality of 1 may play an impor-
tant role in tuning of the chiral reaction field on asym-
metric catalyst.
H2 (0.5 kg/cm2)
Cl(CH2)2Cl, 60 ˚C, 24 h
NHAc
10
NHAc
11
(R,R)-(S,S)-EtTRAP (1a)
(S,S)-EtTRAP-H (2)
96% ee (R) (ref 16a)
45% ee (R)
ð1Þ
Enantioselective hydrogenation of b,b-disubstituted a-
(acetamido)acrylates offers an efficient and straightfor-
ward synthetic approach to optically active b-branched
a-amino acids. However, steric congestion of the tetra-
substituted olefins has made hydrogenation difficult.25
Only a few successful examples have been reported for
this asymmetric reaction so far.26 Et- and BuTRAP are
effective in the asymmetric hydrogenation of various
b,b-disubstituted a-(acetamido)acrylates.16 Hydrogena-
tion of 12 with EtTRAP-H–rhodium catalyst was con-
ducted in 2-propanol at 0 °C and under 1.0 kg/cm2 of H2
pressure for 24h (Eq. 2). Catalytic hydrogenation gave
the desired product 13 in 87% isolated yield, although
the ee value was moderate.
2.4. Catalytic asymmetric hydrosilylation of ketones using
EtTRAP-H
We reported previously that rhodium complexes bear-
ing Et- and BuTRAP are useful chiral catalysts in
the enantioselective reduction of ketones with di-
phenylsilane 16a (hydrosilylation).15;29 We evaluated

2266
R. Kuwano et al. / Tetrahedron: Asymmetry 15 (2004) 2263–2271
[Rh(cod)2]BF4 (1.0 mol%)
TRAP (1.1 mol%)
(S,S)-EtTRAP-H 2 for the asymmetric hydrosilylation
of ketones (Eq. 4). The hydrosilylation of acetophenone
using 2 was conducted in THF at À40 °C (Table 1, entry
3). The reaction was completed within 4h and produced
(S)-1-phenylethanol with 94% ee in 89% isolated yield.
Using 2 enhanced both the reaction rate and enantio-
selectivity (entries 1, 2 vs 3). A significant improvement
in reaction rate as well as enantioselectivity was
obtained by use of 2 in the reaction of propiophenone
(entry 5), which was hard to reduce with high ee by
BuTRAP–rhodium catalyzed hydrosilylation (entry 4).
These findings suggest that the methyl groups at the
stereogenic centers of ligand 1 hinder the approach of
propiophenone to BuTRAP–rhodium catalyst sterically.
Bis(3-fluorophenyl)silane 16b was preferable to 16a for
the asymmetric reduction of the aryl alkyl ketones
(entries 5–9). Terminal chloro and olefin groups on the
ketonic substrates were tolerable to the present hydro-
silylation conditions.
K2CO3
MeOH
O
OH
R2
+ Ar2SiH2
R1
R2
R1
THF
16
16a: Ar = Ph
16b: Ar = m-F-C6H4
ð4Þ
The asymmetric hydrosilylation using 2 was applicable
to the enantioselective reductions of dialkyl ketones,
which are more challenging substrates than aryl alkyl
ketones. In particular, the asymmetric reduction of lin-
ear 2-alkanones is regarded as difficult for providing the
corresponding 2-alkanols with high enantiomeric ex-
cesses. EtTRAP-H was superior to TRAP ligands in the
asymmetric hydrosilylation of dialkyl ketones (entries
10–17). Cyclohexyl methyl ketone was hydrosilylated
Table 1. Asymmetric hydrosilylation of ketones using (S,S)-EtTRAP-H 2a
Entry
Ketone
Temperature (°C)
Time (h)
Yield (%)b
Eec
1d
2e
3
À40
À40
À40
24
11
4
90
89
89
85 (Ref. 15b)
92 (Ref. 15b)
94
O
Me
O
4e
5
6f
À10
À30
À40
48
73
80
99
62 (Ref. 15b)
88
Me
2496
24
O
O
O
O
7f
8f
9f
À40
À40
À40
24
24
24
93
99
90
89
88
89
Me
Cl
10d;g
11
À40
À40
24
4
76
90
81 (Ref. 15b)
89
Me
O
12e;g
13
À40
À40
30
48
93
94
70 (Ref. 15b)
81
Ph
Ph
Me
O
14e;g
15
À40
À40
20
24
93
99
60 (Ref. 15b)
76
Me
O
16d;g
17
À30
À50
2488
48
65 (Ref. 15b)
n-C6H13
Me
82
77
a Reactions were conducted in THF with 16a as a reducing agent unless otherwise noted. The ratio of ketone/16a/[Rh(cod)2]BF4/2 was 100:150:1:1.1.
b Isolated yield.
c Determined by chiral HPLC or GLC.
d Ligand 1a was used.
e Ligand 1b was used.
f Compound 16b was used as a reducing agent.
g The reactions were conducted in DME.

R. Kuwano et al. / Tetrahedron: Asymmetry 15 (2004) 2263–2271
2267
with 89% ee (entry 11). It is noteworthy that the hy-
drosilylation of 2-octanone afforded (S)-2-octanol with
77% ee by the use of EtTRAP-H (entry 17). To the best
of our knowledge, the ee value is the highest yet attained
in the catalytic asymmetric reduction of linear 2-alka-
nones.30–32 Employment of 16b, which was effective in
the hydrosilylation of aryl alkyl ketones, failed to im-
prove the enantioselectivity (74% ee). Primary alkyl
methyl ketones, which have a phenyl group at the b and
c-positions, were also reduced with good enantioselec-
tivities by hydrosilylation using the EtTRAP-H ligand
(entries 13, 15).33
the literature procedures. Copper powder (300 mesh)
was purchased from Lancaster.
4.1.1. (S)-1-Iodo-2-[(S)-4,5-dihydro-4-isopropyl-2-oxaz-
olyl]ferrocene 4. A solution of sec-butyl lithium in
cyclohexane (1.16 M, 22 mL, 26 mmol) was added
dropwise to a mixture of [(S)-4,5-dihydro-4-isopropyl-2-
oxazolyl]ferrocene 3 (5.94g, 20 mmol) and N,N,N0,N0-
tetramethylethylenediamine (3.92 mL, 26 mmol) in hex-
ane (400 mL) at À78 °C for 20 min. The mixture was
stirred at À78 °C for 2 h, and then allowed to warm to
0 °C. A solution of 1,2-diiodoethane (7.89 g, 28 mmol) in
THF (28 mL) was added dropwise to the reaction mix-
ture at À78 °C for 20 min. The resulting mixture was
allowed to warm to room temperature. After saturated
Na2S2O3 aq was carefully added, the mixture was ex-
tracted with Et2O. The organic layer was washed with
brine, dried over Na2SO4 and evaporated. The residue
was purified by flash column chromatography on silica
gel (hexanes/EtOAc), giving 7.64g (91%) of ( S)-(S)-4:
3. Conclusion
A trans-chelating optically active diphosphine, (S,S)-
EtTRAP-H 2, was synthesized via seven steps in 45%
overall yield from enantiomerically pure ferrocenylox-
azoline derived from (S)-valinol and ferrocenecarboxylic
acid. The new phosphine only had planar chirality and
was proven able to form a trans-chelate complex. The
new chiral phosphine 2 was evaluated for the asym-
metric hydrogenation of enamides and hydrosilylation
of ketones. In the former reactions, the use of 2 was less
effective than those of TRAPs 1, which possess stereo-
genic centers. On the other hand, ligand 2 was superior
to 1 in the hydrosilylation of ketones. It is noteworthy
that the highest ee value (77% ee) in the asymmetric
reduction of linear 2-alkanone was recorded by the Et-
TRAP-H–rhodium catalyst. In all cases, the lack of a
central chirality did not cause a drastic change in
enantioselectivity. These observations suggest that the
stereodetermining step in the asymmetric reaction using
TRAP was dominantly controlled by the planar chiral-
ity. However, the central chirality of 1 may play an
important role in tuning of the chiral reaction field on
asymmetric catalyst.
20
D
1
Orange oil; ½aŠ ¼ À131:0 (c 0.46, CHCl3); H NMR
(300 MHz, CDCl3, TMS) d 0.99 (d, J ¼ 6:6 Hz, 3H),
1.06 (d, J ¼ 6:6 Hz, 3H), 1.87 (octet, J ¼ 6:6 Hz, 1H),
4.00–4.15 (m, 2H), 4.21 (s, 5H), 4.30 (dd, J ¼ 7:8,
9.8 Hz, 1H), 4.36 (t, J ¼ 2:7 Hz, 1H), 4.62 (dd, J ¼ 1:6,
2.7 Hz, 1H), 4.73 (dd, J ¼ 1:6, 2.7 Hz, 1H); 13C{1H}
NMR (75 MHz, CDCl3) d 18.1, 18.6, 32.5, 38.8, 69.3,
69.5, 70.9, 72.6, 78.4, 163.8; Anal. Calcd for
C16H18NOFeI: C, 45.42; H, 4.29; N, 3.31. Found: C,
45.21; H, 4.19; N, 3.04.
4.1.2. (S)-2-Iodoferrocenecarboxylic acid 5.35 Methyl
trifluoromethanesulfonate (5.97 g, 36 mmol) was added
to a solution of (S,S)-4 (7.64g, 18 mmol) in CH 2Cl2
(36 mL) at 0 °C. After 1 h, the mixture was concentrated
under reduced pressure. The residue was dissolved in
EtOH (36 mL) and 10% KOH aq (36 mL), and refluxed
for 24h. The resulting mixture was diluted with water
(100 mL) and washed with Et2O (100 mL). The aqueous
layer was filtered through a Celite pad, acidified to pH 1
with concd HCl, and extracted twice with EtOAc. The
organic layer was washed with brine, dried over Na2SO4
and evaporated. The residue was suspended in hexane
and 6.01 g (93%) of (S)-5 separated from the suspension
4. Experimental
4.1. General
Melting points were measured with a Yamato-MP
apparatus and are uncorrected. Optical rotations were
measured with a Perkin–Elmer 243 polarimeter. 1H, 31P,
and 13C NMR spectra were measured with a Varian
Gemini-2000 spectrometer (7.0 T magnet) at room
temperature. Flash column chromatographies and pre-
parative thin-layer chromatographies were performed
with silica gel 60 (230–400 mesh, Merck) and silica gel 60
PF254 (Merck), respectively.
by filtration: Orange powder; mp 172–173 °C (decomp.);
20
½aŠ ¼ À64:5 (c 2.17, CHCl3); 1H NMR (300 MHz,
D
CDCl3, TMS) d 4.29 (s, 5H), 4.52 (t, J ¼ 2:7 Hz, 1H),
4.77 (dd, J ¼ 1:7, 2.7 Hz, 1H), 4.95 (dd, J ¼ 1:7, 2.7 Hz,
1H); 13C{1H} NMR (75 MHz, CDCl3) d 39.5, 69.6, 71.0,
72.9, 73.1, 80.5, 176.2.
4.1.3. (S)-(2-Iodoferrocenyl)methanol 6.36 Oxalyl chlo-
ride (3.14g, 25 mmol) and N,N-dimethylformamide
(9.6 lL, 0.12 mmol) were added to a solution of (S)-5
(4.42 g, 12.4 mmol) in CH2Cl2 (25 mL). The mixture was
stirred at room temperature until the evolution of CO
and CO2 ceased (1 h), after which it was concentrated
under reduced pressure. The residue was dissolved in
THF (25 mL) and then sodium borohydride (1.03 g,
28 mmol) added to the solution at 0 °C. After 1 h, the
All reactions were conducted under a N2 atmosphere
except for the conversion of 4 into 5 and the oxidation
of phosphine in the conversion of 7 into 8. Solvents were
distilled from the indicated drying agents: hexane (Na/
benzophenone); benzene (Na/benzophenone); THF (Na/
benzophenone); CH2Cl2 (P2O5); 1,2-dichloroethane
(CaH2); 2-propanol (CaH2), Et2O (Na/benzophenone).
Diethylphosphine34 and 322 were prepared according to

2268
R. Kuwano et al. / Tetrahedron: Asymmetry 15 (2004) 2263–2271
mixture was allowed to warm to room temperature and
stirred for 11 h. The reaction was carefully quenched
with saturated NH4Cl aq at 0 °C. The mixture was fil-
tered through a Celite pad and extracted twice with
Et2O. The organic layer was washed with brine, dried
over Na2SO4 and evaporated. The residue was purified
by flash column chromatography on silica gel (hexanes/
74.3, 81.4; 31P{1H} NMR (121 MHz, CDCl3, 85%
H3PO4) d 48.2.
4.1.6. (S,S)-2,200-Bis[(diethylphosphinyl)methyl]-1,100-bi-
ferrocene 9. Copper powder (15 g)37 was shaken with
iodine (1.5 g) in acetone until the brown color of iodine
disappeared, and then successively washed with acetone,
acetone/concd HCl ¼ 1/1, and then acetone. The acti-
vated copper powder was dried in vacuo.38 The freshly
activated copper powder (13.1 g, 206 mg-atom) was
added to a solution of (S)-8 (1.77 g, 4.1 mmol) in CH2Cl2
(10 mL). Immediately, the mixture evaporated in vacuo.
The mixture was heated at 80 °C for 24h under an argon
atmosphere. The mixture was dissolved in EtOAc, fil-
tered through a Celite pad and evaporated. The residue
was purified by flash column chromatography on silica
gel (EtOAc/diethylamine), giving an orange solid. The
orange solid was recrystallized from CH2Cl2/EtOAc/
1
EtOAc), giving 3.59 g (85%) of (S)-6: Yellow solid; H
NMR (300 MHz, CDCl3, TMS) d 1.62 (t, J ¼ 6:0 Hz,
1H), 4.17 (s, 5H), 4.24 (t, J ¼ 2:6 Hz, 1H), 4.33 (dd,
J ¼ 1:4, 2.6 Hz, 1H), 4.38 (dd, J ¼ 6:0, 12.5 Hz, 1H),
4.47 (dd, J ¼ 1:4, 2.6 Hz, 1H), 4.50 (dd, J ¼ 6:0, 12.5
Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) d 43.7, 61.3,
67.7, 69.0, 71.3, 75.1, 88.2. The enantiomeric excess of 6
was determined to be 99.1% ee by HPLC analysis with a
chiral stationary phase column, CHIRALCEL OJ
(4.6 mm
0.5 mL/min flow, at 35 °C, UV 254nm detection, ( R)
t1 ¼ 37:7 min, (S) t2 ¼ 43:4min.
/ Â 250 mm):
hexane/2-propanol ¼ 96:4,
hexane, giving 895 mg (72%) of (S,S)-9: Orange solid;
20
D
½aŠ ¼ À773:7 (c 0.49, CHCl3); mp 160–165 °C (de-
1
comp.); H NMR (300 MHz, CDCl3, TMS) d 1.00 (dt,
4.1.4. (S)-(2-Iodoferrocenyl)methyl acetate 7. Acetic
anhydride (612 mg, 6.0 mmol), triethylamine (658 mg,
6.5 mmol), and 4-(dimethylamino)pyridine (6.1 mg,
50 lmol) were added to a solution of (S)-6 (1.71 g,
5.0 mmol) in THF (10 mL) at 0 °C. The mixture was
stirred at room temperature for 1 h and then saturated
NaHCO3 aq added. The resulting mixture was extracted
twice with EtOAc. The combined organic layer was
washed with brine, was dried Na2SO4 and evaporated to
give 1.92 g (100%) of (S)-7: Orange oil; 1H NMR
(300 MHz, CDCl3, TMS) d 2.06 (s, 3H), 4.17 (s, 5H),
4.27 (t, J ¼ 2:6 Hz, 1H), 4.36 (dd, J ¼ 1:4, 2.6 Hz, 1H),
4.49 (dd, J ¼ 1:4, 2.6 Hz, 1H), 4.87 (d, J ¼ 12:0 Hz,
1H), 5.04(d, J ¼ 12:0 Hz, 1H); 13C{1H} NMR (75 MHz,
CDCl3) d 20.8, 44.5, 62.9, 69.0, 69.6, 71.5, 75.5, 82.7,
170.9.
J ¼ 16:5, 7.8 Hz, 3H), 1.03 (dt, J ¼ 16:5, 7.7 Hz, 3H),
1.32–1.65 (m, 4H), 2.68 (dd, J ¼ 11:4, 15.6 Hz, 1H), 2.87
(dd, J ¼ 14:7, 15.6 Hz, 1H), 4.30 (s, 5H), 4.32 (t, J ¼ 2:5
Hz, 1H), 4.47 (d, J ¼ 2:5 Hz, 2H); 13C{1H} NMR
(75 MHz, CDCl3) d 5.6 (d, J ¼ 6 Hz), 5.7, 19.9 (d,
J ¼ 65 Hz), 20.4(d, J ¼ 66 Hz), 27.5 (d, J ¼ 62 Hz),
67.2, 69.1, 70.3, 79.9, 84.6 (d, J ¼ 5 Hz); 31P{1H} NMR
(121 MHz, CDCl3, 85% H3PO4) d 49.1.
4.1.7. (S,S)-2,200-Bis[(diethylphosphino)methyl]-1,100-bifer-
rocene 2 [(S,S)-EtTRAP-H]. Trichlorosilane (400 mg,
3.0 mmol) was added at 0 °C to a mixture of (S,S)-9
(303 mg, 0.50 mmol) and triethylamine (410 mg,
4.0 mmol) in benzene (2.5 mL) in a glass tube. The tube
was cooled to À78 °C and sealed in vacuo. The mixture
was heated at 100 °C for 10 h. After being cooled to
À78 °C, the tube was opened. The excess trichlorosilane
was carefully decomposed with 15% NaOH aq. The
resulting mixture was filtered through a Celite pad and
extracted twice with benzene. The combined organic
layer was washed with brine, dried over Na2SO4, and
evaporated. The residue was purified by a short column
chromatography on activated alumina (benzene/
4.1.5.
(S)-Diethyl[(2-iodoferrocenyl)methyl]phosphine
oxide 8. Diethylphosphine (849 mg, 9.4 mmol) was
added to a solution of (S)-7 (1.81 g, 4.7 mmol) in acetic
acid (50 mL) degassed by two freeze-thaw cycles. The
mixture was stirred at 80 °C for 30 min. After the solvent
and excess diethylphosphine were removed in vacuo, the
residue was dissolved in acetone (20 mL) and then 30%
H2O2 aq (2.0 mL) carefully added to the mixture at 0 °C.
After 5 min, excess H2O2 was carefully decomposed with
saturated Na2S2O3 aq. The mixture was diluted with
water and was extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4 and evapo-
rated. The residue was purified by flash column chro-
Et2O ¼ 10/1), giving 278 mg (97%) of (S,S)-2: Orange
24
D
oil; ½aŠ ¼ À750:2 (c 0.50, CHCl3); 1H NMR (300 MHz,
CDCl3, TMS) d 0.81–1.14(m, 12H), 1.14–1.33 (m, 8H),
2.28 (dd, J ¼ 2:3, 14.9 Hz, 1H), 2.37 (d, J ¼ 14:9 Hz,
1H), 4.19 (s, 2H), 4.27 (s, 5H), 4.4 (s, 1H); 13C{1H}
NMR (75 MHz, CDCl3) d 9.3 (d, J ¼ 13 Hz), 9.7 (d,
J ¼ 14Hz), 19.0 (d, J ¼ 13 Hz), 19.1 (d, J ¼ 12 Hz),
25.2 (d, J ¼ 15 Hz), 66.0, 68.5 (d, J ¼ 7 Hz), 69.7, 70.5,
84.6, 86.8 (d, J ¼ 12 Hz); 31P{1H} NMR (121 MHz,
CDCl3, 85% H3 PO4) d À17:7.
matography on silica gel (hexane/EtOAc), giving 1.82 g
20
D
(90%) of (S)-8: Orange oil; ½aŠ ¼ þ13:0 (c 0.61,
1
CHCl3); H NMR (300 MHz, CDCl3, TMS) d 1.03 (dt,
J ¼ 16:5, 7.7 Hz, 3H), 1.16 (dt, J ¼ 16:5, 7.8 Hz, 3H),
1.44–1.58 (m, 2H), 1.63–1.77 (m, 2H), 2.90 (dd, J ¼ 9:0,
15.2 Hz, 1H), 3.02 (dd, J ¼ 15:2, 17.1 Hz, 1H), 4.09 (s,
5H), 4.23 (t, J ¼ 2:6 Hz, 1H), 4.36–4.41 (m, 1H), 4.43–
4.48 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3) d 5.3 (d,
J ¼ 6 Hz), 5.8 (d, J ¼ 6 Hz), 19.2 (d, J ¼ 67 Hz), 20.8 (d,
J ¼ 65 Hz), 30.2 (d, J ¼ 59 Hz), 45.9, 67.6, 69.4, 72.0,
4.1.8. 31P NMR study for the reaction of EtTRAP-H with
[RhCl(CO)2]2. [RhCl(CO)2]2 (1.94mg, 5.0 lmol) was
added to a solution of 2 (5.75 mg, 10 lmol) in CD2Cl2
(0.7 mL) at room temperature. After 10 min, the result-
ing solution was transferred to an NMR tube equipped

R. Kuwano et al. / Tetrahedron: Asymmetry 15 (2004) 2263–2271
2269
with a septum rubber. 31P{1H} NMR (121 MHz,
mined to be 57% ee (S) by HPLC analysis with a chiral
stationary phase column, SUMICHIRAL OA-2000
CDCl3, 85% H3PO4) d 20.8 (dd, JPÀRh ¼ 119 Hz,
JP–P ¼ 340 Hz), 26.5 (dd, JP–Rh ¼ 120 Hz, JPÀP
¼
(4.6 mm
/ Â 250 mm):
hexane/2-propanol/metha-
340 Hz).
nol ¼ 90/10/0.5, 1.0 mL/min flow, at 35 °C, UV 254nm
detection, (S) t1 ¼ 23:3 min, (R) t2 ¼ 26:0 min.
4.1.9. Catalytic asymmetric hydrogenation of 10. A
solution of [Rh(cod)2]BF4 (2.0 mg, 5.0 lmol) and (S,S)-2
(3.2 mg, 5.6 lmol) in 1,2-dichloroethane (0.5 mL) was
stirred at room temperature for 10 min and then 10
(71.6 mg, 0.50 mmol) added. Immediately, the flask was
cooled to À78 °C, repeatedly evacuated and filled with
H2–N2 1:1 mixture. The reaction mixture was stirred at
60 °C for 24h. After the solvent had evaporated, the
residue was passed through a short column chroma-
tography on silica gel (hexane/EtOAc ¼ 1:3), giving
70.7 mg (97%) of 11: 1H NMR (200 MHz, CDCl3, TMS)
d 1.41 (d, J ¼ 7:1 Hz, 3H), 2.02 (s, 3H), 3.76 (s, 3H), 4.59
(quintet, J ¼ 7:3 Hz, 1H), 6.08 (br d, 1H). The enan-
tiomeric excess of 11 was determined to be 45% ee (R) by
HPLC analysis with a chiral stationary phase column,
SUMICHIRAL OA-3000 (4.0 mm / Â 250 mm): hex-
ane/1,2-dichloroethane/ethanol ¼ 100:20:1, 1.0 mL/min
flow, at 35 °C, UV 230 nm detection, (R) t1 ¼ 20:0 min,
(S) t2 ¼ 25:1 min.
4.1.12. Bis(3-fluorophenyl)silane 16b. 3-Fluorophenyl-
magnesium bromide was prepared from 3-bromoflu-
orobenzene (9.63 g, 55 mmol) and magnesium turnings
(55 mg-atom) in THF. The Grignard reagent was added
dropwise to a solution of tetrachlorosilane (4.24 g,
25 mmol) in THF (25 mL) at 40 °C for 1 h. After being
stirred for 2 h, the resulting mixture was added dropwise
to a suspension of lithium aluminum hydride (1.42 g,
37 mmol) in Et2O (20 mL) at room temperature for 1 h.
After 16 h, the mixture was carefully added to saturated
NH4Cl aq (100 mL) at 0 °C, filtered through a Celite pad
and extracted with Et2O. The organic layer was dried
over CaSO4 and was evaporated. The residue was
purified by vacuum distillation (0.3 mmHg), giving
1
3.26 g (59%) of 16b: Colorless oil; H NMR (200 MHz,
CDCl3, TMS) d 4.91 (s, 2H), 7.04–7.45 (m, 8H).
4.1.13. General procedure for catalytic asymmetric
hydrosilylation of ketones. A solution of [Rh(cod)2]BF4
(2.0 mg, 5.0 lmol) and 2 (3.2 mg, 5.6 lmol) in THF
(0.5 mL) was stirred at room temperature for 10 min.
Ketone (0.50 mmol) and 16 (0.75 mmol) were added to
the mixture at the temperature indicated in Table 1.
After 24or 48 h, a solution of K 2CO3 (0.5 mg) in MeOH
(0.5 mL) was added to the resulting mixture. The mix-
ture was stirred at room temperature for 4h and evap-
orated. The residue was purified by preparative thin-
layer chromatography or by medium-pressure liquid
chromatography after passing through a short column
chromatography on silica gel (hexane/EtOAc).
4.1.10. Catalytic asymmetric hydrogenation of 12. A
solution of [Rh(cod)2]BF4 (2.0 mg, 5.0 lmol) and (S,S)-2
(3.2 mg, 5.6 lmol) in 2-propanol (0.5 mL) was stirred at
room temperature for 10 min and 12 (85.6 mg,
0.50 mmol) then added. Immediately, the flask was
cooled to À78 °C, repeatedly evacuated and filled with
H2. The reaction mixture was stirred at 0 °C for 24h.
After the solvent had evaporated, the residue was passed
through a short column chromatography on silica gel
1
(hexane/EtOAc ¼ 1:3), giving 75.5 mg (87%) of 13: H
NMR (200 MHz, CDCl3, TMS) d 0.91 (d, J ¼ 6:6 Hz,
3H), 0.94(d, J ¼ 6:6 Hz, 3H), 2,05 (s, 3H), 2.15 (double
septet, J ¼ 5:0, 6.6 Hz, 1H), 3.75 (s, 3H), 4.57 (dd,
J ¼ 5:0, 8.9 Hz, 1H), 5.96 (br d, 1H). The enantiomeric
excess of 13 was determined to be 54% ee (S) by HPLC
analysis with a chiral stationary phase column, SU-
MICHIRAL OA-3000 (4.0 mm / Â 250 mm): hexane/
1,2-dichloroethane/ethanol ¼ 100:20:1, 1.0 mL/min flow,
at 35 °C, UV 230 nm detection, (R) t1 ¼ 11:2 min, (S)
t2 ¼ 15:9 min.
4.1.13.1. 1-Phenylethanol (Table 1, entry 3). 1H NMR
(200 MHz, CDCl3, TMS) d 1.48 (d, J ¼ 6:4Hz, 3H),
1.98 (br s, 1H), 4.87 (q, J ¼ 6:4Hz, 1H), 7.19–7.41 (m,
5H). The enantiomeric excess of the product was
determined by GLC analysis with a chiral stationary
phase column, Chiraldex G-TA (0.25 mm / Â 30 m): at
95 °C, (S) t1 ¼ 9:8 min, (R) t2 ¼ 10:6 min.
4.1.13.2. 1-Phenylpropanol (Table 1, entries 5 and 6).
1H NMR (200 MHz, CDCl3, TMS) d 0.91 (t, J ¼ 7:4Hz,
3H), 1.61–1.91 (m, 2H), 1.95 (br s, 1H), 4.58 (t,
J ¼ 6:6 Hz, 1H), 7.20–7.42 (m, 5H). The enantiomeric
excess of the product was determined by HPLC analysis
with a chiral stationary phase column, CHIRALCEL
OB-H (4.6 mm / Â 250 mm): hexane/2-propanol ¼ 9:1,
0.5 mL/min flow, at 35 °C, UV 254nm detection, ( S)
t1 ¼ 11:8 min, (R) t2 ¼ 13:5 min.
4.1.11. Catalytic asymmetric hydrogenation of 14. A
solution of [Rh(nbd)2]PF6 (1.1 mg, 2.5 lmol) and (S,S)-2
(1.6 mg, 2.8 lmol) in 1,2-dichloroethane (1.0 mL) was
stirred at room temperature for 20 min and 14
(100.4mg, 0.25 mmol) then added. Immediately, the
flask was cooled to À78 °C, repeatedly evacuated and
filled with H2. The reaction mixture was stirred at 50 °C
for 24h. After the solvent had evaporated, the residue
was passed through a short column chromatography on
silica gel (hexane/EtOAc ¼ 1:3), giving 93.2 mg (92%) of
1
15: H NMR (300 MHz, CDCl3, TMS) d 1.35 (s, 9H),
4.1.13.3. 1-Phenylbutanol (Table 1, entry 7). 1H NMR
(200 MHz, CDCl3, TMS) d 0.93 (t, J ¼ 7:2 Hz, 3H),
1.20–1.92 (m, 5H), 4.69 (dd, J ¼ 5:9, 7.4Hz, 1H), 7.22–
7.48 (m, 5H). The enantiomeric excess of the product
1.51 (s, 9H), 3.02–3.43 (br m, 3H), 3.84–4.10 (br m, 2H),
4.32–4.82 (br m, 2H), 5.93 (br s, 1H), 7.04–7.24 (m, 3H),
7.35 (t, 2H). The enantiomeric excess of 15 was deter-

2270
R. Kuwano et al. / Tetrahedron: Asymmetry 15 (2004) 2263–2271
was determined by HPLC analysis with a chiral sta-
tionary phase column, CHIRALCEL OB-H (4.6 mm
/ Â 250 mm): hexane/2-propanol ¼ 96:4, 0.5 mL/min
flow, at 35 °C, UV 254nm detection, ( S) t1 ¼ 14:4min,
(R) t2 ¼ 16:6 min.
nol ¼ 96:4, 0.5 mL/min flow, at 35 °C, UV 254nm
detection, (S) t1 ¼ 23:2 min, (R) t2 ¼ 25:9 min.
4.1.13.9. 2-Octanol (Table 1, entry 17). 1H NMR
(200 MHz, CDCl3, TMS) d 0.80–0.98 (m, 3H), 1.19 (d,
J ¼ 6:1 Hz, 3H), 1.14–1.53 (m, 11H), 3.80 (sextet,
J ¼ 6:1 Hz, 1H). The enantiomeric excess of the product
was determined by HPLC analysis of its N-(3,5-dini-
trophenyl)carbamate derivative with a chiral stationary
phase column, SUMICHIRAL OA-4500 (4.6 mm /Â
250 mm): hexane/1,2-dichloroethane/ethanol ¼ 50:15:1,
1.0 mL/min flow, at 35 °C, UV 254nm detection, ( S)
t1 ¼ 35:4min, ( R) t2 ¼ 40:4min.
4.1.13.4. 4-Chloro-1-phenylbutanol (Table 1, entry 8).
1H NMR (200 MHz, CDCl3, TMS) d 1.57 (br s, 1H),
1.70–2.09 (m, 4H), 3.48–3.67 (m, 2H), 4.67–4.78 (m,
1H), 7.22–7.45 (m, 5H). The enantiomeric excess of the
product was determined by HPLC analysis with a chiral
stationary phase column, CHIRALCEL OD-H (4.6 mm
/ Â 250 mm): hexane/2-propanol ¼ 96:4, 0.5 mL/min
flow, at 35 °C, UV 254nm detection, ( S) t1 ¼ 31:9 min,
(R) t2 ¼ 34:2 min.
Acknowledgements
4.1.13.5. 1-Phenyl-4-pentenol (Table 1, entry 9). 1H
NMR (200 MHz, CDCl3, TMS) d 1.65–2.27 (m, 5H),
4.71 (dd, J ¼ 5:7, 7.4Hz, 1H), 4.95–5.12 (m, 2H), 5.85
(ddt, J ¼ 10:3, 17.1, 6.6, 1H), 7.22–7.47 (m, 5H). The
enantiomeric excess of the product was determined by
HPLC analysis with a chiral stationary phase column,
CHIRALCEL OB-H (4.6 mm / Â 250 mm): hexane/2-
propanol ¼ 96:4, 0.5 mL/min flow, at 35 °C, UV 254nm
detection, (S) t1 ¼ 17:1 min, (R) t2 ¼ 20:4min.
This work was partly supported by a Grant-in-Aid for
Scientific Research on Priority Areas, No. 706: Dynamic
Control of Stereochemistry, from the Ministry of Edu-
cation, Science, Sports, and Culture.
References and notes
1. (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vols. 1–3; (b) Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; 2nd ed.; Wiley-VCH: New York, 2000.
2. Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–3070.
3. Brunner, H.; Zettlmeier, W. In Handbook of Enantio-
selective Catalysis with Transition Metal Compounds;
VCH: Weinheim, 1993; Vol. II.
4. Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito,
T.; Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102,
7932–7934.
5. McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809–
3844.
6. Reviews: (a) Hayashi, T. In Ferrocenes; Togni, A.,
Hayashi, T., Eds.; VCH: Weinheim, 1995, pp 105–142;
(b) Colacot, T. J. Chem. Rev. 2003, 103, 3101–3118; (c)
Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L.
Acc. Chem. Res. 2003, 36, 659.
7. (a) Hayashi, T.; Yamamoto, K.; Kumada, M. Tetrahedron
Lett. 1974, 15, 4405–4408; (b) Hayashi, T.; Mise, T.;
Fukushima, M.; Kagotani, M.; Nagashima, N.; Hamada,
Y.; Matsumoto, A.; Kawakami, S.; Konishi, M.; Yama-
moto, K.; Kumada, M. Bull. Chem. Soc. Jpn. 1980, 53,
1138–1151; (c) Hayashi, T.; Kumada, M. Acc. Chem. Res.
1982, 15, 395–401.
8. (a) Hayashi, T.; Tajika, M.; Tamao, K.; Kumada, M. J.
Am. Chem. Soc. 1976, 98, 3718–3719; (b) Hayashi, T.;
Konishi, M.; Fukushima, M.; Mise, T.; Kagotani, M.;
Tajika, M.; Kumada, M. . J. Am. Chem. Soc. 1982, 104,
180–186.
1
4.1.13.6. 1-Cyclohexylethanol (Table 1, entry 11). H
NMR (200 MHz, CDCl3, TMS) d 0.81–1.37 (m, 6H),
1.15 (d, J ¼ 6:3 Hz, 3H), 1.53–1.92 (m, 6H), 3.54
(quintet, J ¼ 6:3 Hz, 1H). The enantiomeric excess of
the product was determined by HPLC analysis of its N-
(3,5-dinitrophenyl)carbamate derivative with a chiral
stationary phase column, SUMICHIRAL OA-4500
(4.0 mm / Â 250 mm): hexane/1,2-dichloroethane/etha-
nol ¼ 50:15:1, 1.0 mL/min flow, at 35 °C, UV 254nm
detection, (S) t1 ¼ 25:1 min, (R) t2 ¼ 28:1 min. The N-
(3,5-dinitrophenyl)carbamate derivative was prepared as
follows. A mixture of the alcohol (ca 1 mg), 3,5-dini-
trophenylisocyanate (ca 5 mg), and pyridine (50 lL) in
toluene (0.5 mL) was vigorously stirred at 75 °C for
30 min and then concentrated in vacuo. The residue was
purified by a preparative thin-layer chromatography
(hexane/EtOAc).
1
4.1.13.7. 4-Phenyl-2-butanol (Table 1, entry 13). H
NMR (200 MHz, CDCl3, TMS) d 1.22 (d, J ¼ 6:2 Hz,
3H), 1.57 (br s, 1H), 1.65–1.88 (m, 2H), 2.57–2.85 (m,
2H), 3.81 (sextet, J ¼ 6:2 Hz, 1H), 7.10-7.41 (m, 5H).
The enantiomeric excess of the product was determined
by HPLC analysis with a chiral stationary phase col-
umn, CHIRALCEL OD-H (4.6 mm / Â 250 mm): hex-
ane/2-propanol ¼ 9:1, 0.5 mL/min flow, at 35 °C, UV
254nm detection, ( R) t1 ¼ 13:8 min, (S) t2 ¼ 17:2 min.
9. Pastor, S. D.; Togni, A. J. Am. Chem. Soc. 1989, 111,
2333–2334.
10. Examples (a) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou,
N. N.; Volante, R. P.; Reider, P. J. J. Am. Chem. Soc.
1997, 119, 6207; (b) Tao, B.; Fu, G. C. Angew. Chem., Int.
Ed. 2002, 41, 3892.
11. (a) Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron:
Asymmetry 1991, 2, 593–596; (b) Sawamura, M.; Hama-
shima, H.; Sugawara, M.; Kuwano, R.; Ito, Y. Organo-
metallics 1995, 14, 4549–4558;
1
4.1.13.8. 5-Phenyl-2-pentanol (Table 1, entry 15). H
NMR (200 MHz, CDCl3, TMS) d 1.17 (d, J ¼ 6:2 Hz,
3H), 1.33–1.88 (m, 5H), 2.63 (t, J ¼ 7:5 Hz, 2H), 3.80
(sextet, J ¼ 6:2 Hz, 1H), 7.10–7.41 (m, 5H). The enan-
tiomeric excess of the product was determined by HPLC
analysis with a chiral stationary phase column, CHI-
RALCEL OJ (4.6 mm / Â 250 mm): hexane/2-propa-

R. Kuwano et al. / Tetrahedron: Asymmetry 15 (2004) 2263–2271
2271
(c) Kuwano, R.; Sawamura, M.; Okuda, S.; Asai, T.; Ito,
Y.; Redon, M.; Krief, A. Bull. Chem. Soc. Jpn. 1997, 70,
2807–2822.
27. Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.;
McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.;
Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.;
Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M.
K.; Lin, J.; Chen, I.; Vastag, K.; Ostovic, D.; Anderson, P.
S.; Emini, E. A.; Huff, J. R. Proc. Natl. Acad. Sci. U.S.A.
1994, 91, 4096.
28. (a) Rossen, K.; Weissman, S. A.; Sager, J.; Reamer, R. A.;
Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett.
1995, 36, 6419–6422; (b) Rossen, K.; Pye, P. J.; DiMichele,
L. M.; Volante, R. P.; Reider, P. J. Tetrhedron Lett. 1998,
39, 6823–6826.
29. Representative examples of catalytic asymmetric hydrosi-
lylation of ketones: (a) Brunner, H.; Becker, R.; Riepl, G.
Organometallics 1984, 3, 1354–1359; (b) Nishiyama, H.;
Kondo, M.; Nakamura, T.; Itoh, K. Organometallics
1991, 10, 500; (c) Nishibayashi, Y.; Segawa, K.; Ohe, K.;
Uemura, S. Organometallics 1995, 14, 5486–5487; (d)
Nishibayashi, Y.; Segawa, K.; Singh, J. D.; Fukuzawa, S.;
Ohe, K.; Uemura, S. Organometallics 1996, 15, 370–379,
and Refs. 10.
12. (a) Sawamura, M.; Hamashima, H.; Ito, Y. J. Am. Chem.
Soc. 1992, 114, 8295–8296; (b) Sawamura, M.; Hama-
shima, H.; Ito, Y. Tetrahedron 1994, 50, 4439.
13. (a) Kuwano, R.; Miyazaki, H.; Ito, Y. Chem. Commun.
1998, 71–72; (b) Kuwano, R.; Miyazaki, H.; Ito, Y.
J. Orgganomet. Chem. 2000, 603, 18.
14. Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc.
1996, 118, 3309–3310.
15. (a) Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 111; (b) Kuwano, R.; Sawamura,
M.; Shirai, J.; Takahashi, M.; Ito, Y. Bull. Chem. Soc. Jpn.
2000, 73, 485–496.
16. (a) Sawamura, M.; Kuwano, R.; Ito, Y. J. Am. Chem. Soc.
1995, 117, 9602–9603; (b) Kuwano, R.; Okuda, S.; Ito, Y.
Tetrahedron Lett. 1998, 39, 1017–1020; (c) Kuwano, R.;
Okuda, S.; Ito, Y. Tetrahedron: Asymmetry 1998, 9, 2773–
2775; (d) Kuwano, R.; Sawamura, M.; Ito, Y. Bull. Chem.
Soc. Jpn. 2000, 73, 2571–2578.
17. Kuwano, R.; Ito, Y. J. Org. Chem. 1999, 64, 1232.
18. Kuwano, R.; Karube, D.; Ito, Y. Tetrahedron Lett. 1999,
40, 9045–9049.
19. Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y.
J. Am. Chem. Soc. 2000, 122, 7614.
20. Goeke, A.; Sawamura, M.; Kuwano, R.; Ito, Y. Angew.
Chem., Int. Ed. Engl. 1996, 35, 662–663.
21. Preliminary communication: Kuwano, R.; Uemura, T.;
Saitoh, M.; Ito, Y. Tetrahedron Lett. 1999, 40, 1327.
22. Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org.
Chem. 1995, 60, 10.
23. Sammakia, T.; Latham, H. A. J. Org. Chem. 1995, 60,
6002.
24. Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Land-
ert, H.; Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062.
25. Hayashi, T.; Kawamura, N.; Ito, Y. J. Am. Chem. Soc.
1987, 109, 7876.
26. (a) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am.
Chem. Soc. 1995, 117, 9375; (b) Imamoto, T.; Watanabe,
J.; Wada, Y.; Masuda, H.; Yamada, H.; Tsuruta, H.;
Matsukawa, S.; Yamaguchi, K. J. Am. Chem. Soc. 1998,
120, 1635–1636; (c) Yamanoi, Y.; Imamoto, T. J. Org.
Chem. 1999, 64, 2988–2989; (d) Marinetti, A.; Jus, S.;
Genet, J.-P. Tetrahedron Lett. 1999, 40, 8365; (e) Ohashi,
A.; Kikuchi, S.-i.; Yasutake, M.; Imamoto, T. Eur. J. Org.
Chem. 2002, 2535–2546; (f) Liu, D.; Li, W.; Zhang, X.
Org. Lett. 2002, 4, 4471–4474; (g) Evans, D. A.; Michael,
F. E.; Tedrow, J. S.; Campos, K. R. J. Am. Chem. Soc.
2003, 125, 3534.
30. So far, the highest ee value (75% ee) in catalytic
asymmetric reduction of linear 2-alkanone has been
recorded in asymmetric hydrogenation with PennPhos-
Rh catalyst, see: Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.;
Zhang, X. Angew. Chem., Int. Ed. 1998, 37, 1100–1103.
31. During preparation of this manuscript, the highest ee
value (79% ee) was attained by Gade and Bellemin–
Laponnaz in asymmetric hydrosilylation of 2-ocatanone:
Gade, L. H.; Cesar, V.; Bellemin-Laponnaz, S. Angew.
Chem., Int. Ed. 2004, 43, 1014.
32. Excellent enantioselectivity (>99% ee) has been observed
in asymmetric reduction of 2-pentanone using a biocata-
lyst, see: Matsuda, T.; Nakajima, Y.; Harada, T.;
Nakamura, K. Tetrahedron: Asymmetry 2002, 13, 971.
33. With several chiral catalyst, catalytic asymmetric hydro-
silylation of 4-phenyl-2-butanone have proceeded with 80–
82% ees, see: Nishiyama, H.; Yamaguchi, S.; Kondo, M.;
Itoh, K. J. Org. Chem. 1992, 57, 4306–4309, and Refs. 10.
34. Issleib, K.; Tzschach, A. Chem. Ber. 1959, 92, 704.
35. Bolm, C.; Muniz-Fernandez, K.; Seger, A.; Raabe, G.;
€
Gunter, K. J. Org. Chem. 1998, 63, 7860.
36. Patti, A.; Lambusta, D.; Piatteli, M.; Nicolosi, G. Tetra-
hedron: Asymmetry 1998, 9, 3073.
37. For the Ullmann coupling, the copper powder (300 mesh)
purchased from Lancaster should be used. In our exper-
iments, the reaction with copper powder purchased from
other companies gave 9 in very low yield (<20%).
38. Fuson, R. C.; Cleveland, E. A. Org. Synth. Colloid 1955,
III, 339–340.