Highly enantioselective addition of in situ prepared arylzinc to aldehydes catalyzed by a series of atropisomeric binaphthyl-derived amino alcohols

Article abstract of DOI:10.1002/chem.200501048

The direct addition of in situ prepared arylzinc to aldehydes with chiral binaphthyl-derived amino alcohols as catalysts can afford optically active diarylmethanols in high yields and with excellent enantioselectivities (up to 99% ee, ee = enantiomeric excess). By using a single catalyst, both enantiomers of many pharmaceutically interesting diarylmethanols can be obtained by the proper combination of various arylzinc reagents with different aldehydes; this catalytic system also works well for the phenylation of aliphatic aldehydes to give up to 96 % ee.

Full text of DOI:10.1002/chem.200501048

FULL PAPER
DOI: 10.1002/chem.200501048
Highly Enantioselective Addition of In Situ Prepared Arylzinc to Aldehydes
Catalyzed by a Series of Atropisomeric Binaphthyl-Derived Amino Alcohols
[
a, b]
[a]
[a]
[a]
[a]
Gui Lu,
Fuk Yee Kwong, Ji-Wu Ruan, Yue-Ming Li, and Albert S. C. Chan*
Abstract: The direct addition of in situ prepared arylzinc to aldehydes with chiral
binaphthyl-derived amino alcohols as catalysts can afford optically active diaryl-
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methanols in high yields and with excellent enantioselectivities (up to 99% ee,
Keywords:
amino alcohols
·
ee=enantiomeric excess). By using a single catalyst, both enantiomers of many
pharmaceutically interesting diarylmethanols can be obtained by the proper com-
bination of various arylzinc reagents with different aldehydes; this catalytic system
also works well for the phenylation of aliphatic aldehydes to give up to 96% ee.
arylation · arylzinc · binaphthyl ·
enantioselectivity
Introduction
reported: (1) the asymmetric reduction of prochiral diaryl
ketones and (2) the enantioselective aryl transfer to aromat-
ic aldehydes. The successful examples of the former, such as
Chiral diarylmethanols are important precursors to many bi-
[9–11]
ologically active compounds, such as (R)-neobenodine, (R)-
Coreyꢀs CBS reduction
alyzed ketone hydrogenation (BINAP=2,2’-diphenylphos-
and Noyoriꢀs Ru-(S)-BINAP-cat-
[1–8]
orphenadrine, and (S)-cetirizine.
Two scientifically impor-
[12,13]
tant protocols for their enantioselective syntheses have been
phino-1,1’-binaphthyl),
butes, such as ortho-substitution of one of the aryl groups or
required certain substrate attri-
AHCTREUNG
the presence of electronically differentiated aryl groups.
Thus, precursors not possessing these structural features had
to be synthesized through indirect protocols. For example, in
the asymmetric synthesis of (R)-neobenodine, compound 2
was synthesized by the asymmetric hydrogenation of inter-
mediate ketone 1, in which the ortho-bromo group acted as
an enantiodirective functional substituent and subsequently
[12]
had to be removed (Scheme 1).
[
a] Dr. G. Lu, Dr. F. Y. Kwong, Dr. J.-W. Ruan, Dr. Y.-M. Li,
Prof. Dr. A. S. C. Chan
Scheme 1.
Open Laboratory of Chirotechnology of the Institute of Molecular
Technology for Drug Discovery and Synthesis State Key Laboratory
of Chinese Medicine and Molecular Pharmacology (Shenzhen);
and Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University
Hung Hom, Kowloon, Hong Kong (China)
Fax : (+852)2364-9932
E-mail: bcachan@polyu.edu.hk
The chiral induction in the asymmetric addition of aryl
groups to aromatic aldehydes seems easy to realize because
of the significant difference between the hydrogen atom and
the aryl group of the aldehydes, yet successful examples of
this reaction are mostly limited to the addition of diphenyl-
[
b] Dr. G. Lu
[14–27]
zinc to aldehydes.
and aldehydes can provide an array of optically active di-
arylmethanols and is of high interest. However, the prepara-
Altering the structure of diarylzinc
Current address: Institut für Organische Chemie
Friedrich-Alexander Universität Erlangen-Nürnberg
Erlangen (Germany)
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ACHTREUNG
Chem. Eur. J. 2006, 12, 4115 – 4120
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4115

tion of diarylzinc reagents (usually from transmetalation
with lithium or Grignard reagents) is tedious and difficult as
salt-free reagents are required for achieving high enantiose-
lectivity. Furthermore, many functionalized diarylzincs
remain inaccessible due to the high reactivity of the organo-
lithium or -magnesium intermediates.
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for fine-tuning, seems to be a good candidate for this reac-
tion.
First we examined the chiral amino alcohols 5–9 on their
catalytic performance in the asymmetric phenylation addi-
tion of 4-chlorobenzaldehyde, for which the arylzinc re-
agents were prepared in situ by the transmetalation of phe-
nylboronic acid with diethylzinc (Scheme 2). All catalysts
gave good yields with ee values ranging from 52 to 96%.
[28–30]
Recently, the metal exchange between organoboron
[31–34]
or organoboronic derivatives
proposed as an alternative for the synthesis of salt-free or-
gan zinc reagents. A notable example of an asymmetric aryl
and diethylzinc has been
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o
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The best result was obtained with (1R ,2S,3R)-5, giving a
transfer reaction to aldehydes that involved an arylzinc spe-
cies prepared in situ by an aryl boronic acid/diethylzinc ex-
chiral alcohol with 96% ee, while ligand (1R,2S)-8 bearing a
smaller backbone gave significantly lower ee (80% ee). The
match of the configurations between the binaphthyl back-
bone and the phenyl substituent alpha to the amino moiety
was quite important for obtain-
[31]
change
has been described by Bolm and coworkers. By
using chiral ferrocenyl oxazoline 3 as a ligand, the catalytic
ing high enantioselectivity in the
product. In contrast, the un-
matched
configuration
(
1R ,2R,3S)-6 was detrimental to
a
the enantioselectivity (69% ee).
Amino alcohol ligands contain-
ing phenyl substituents at the a-
position were found to be more
effective than those containing a
methyl substituent. In most
cases, the configuration of the al-
cohol product could be correlat-
ed with the chirality of the
amino alcohol moiety of the
ligand.
reaction was easy to perform and a broad range of products
were prepared in high yields and with high enantioselectivi-
[31]
ties.
We also found that easily accessible chiral tertiary
aminonaphthol 4 could serve as an efficient ligand for this
[35]
asymmetric phenyl transfer reaction.
We have reported the application of binaphthyl-derived
amino alcohol ligands 5–9 in the asymmetric alkyl- and alky-
Scheme 2.
[36]
nylzinc additions with high stereoselectivities. The salient
features of these chiral amino alcohol ligands include their
ease of preparation and the flexibility of modifications on
both the binaphthyl moiety and the amino alcohol back-
bone. Their unique rigidity and fine-tuning capability are ex-
pected to play a crucial role in catalytic asymmetric reac-
tions. Herein, we report the application of these ligands to
the asymmetric addition of different arylzinc reagents (pre-
pared in situ) to various aldehydes with high stereoselectivi-
ty and broad substrate tolerance.
Further investigations into the optimization of the reac-
tion conditions, such as solvent, reaction temperature, and
catalyst loading for the asymmetric phenylation of 4-chloro-
benzaldehyde with (1R ,2S,3R)-5 as catalyst are listed in
a
Table 1. When the reactions were carried out in mixed
Table 1. Optimization of the phenylation of 4-chlorobenzaldehyde in the
[
a]
a
presence of (1R ,2S,3R)-5.
[
b]
Entry
T [8C]
Catalyst [mol%]
Yield [%]
ee [%]
Results and Discussion
1
2
3
4
À20
0
0
10
10
5
93
96
74
83
97(R)
96(R)
87(R)
95(R)
The enantioselective arylation of aromatic aldehydes was
achieved by differentiation between the aryl group and the
hydrogen atom of the aldehydes. A suitable chiral ligand
with hindered geometry may specifically favor one enantio-
pathway in the transition states and lead to highly enantio-
selective outcomes. The sterically congested chiral binaph-
25
10
[
a] Aldehyde/phenylboronic acid/diethylzinc=0.5:1.2:3.6 (molar ratio),
toluene as solvent, 12 h. [b] The ee values were determined by HPLC
analysis with a 25 cm”4.6 mm Chiralcel OB-H column (Daicel Chemical
Industries). Absolute configuration was determined by comparison of the
order of peak elution from HPLC analysis with literature values.
4116
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Chem. Eur. J. 2006, 12, 4115 – 4120

Addition of Arylzinc to Aldehydes
FULL PAPER
hexane-toluene (1:1) solvent, the enantioselectivity was
about 5% lower than in toluene solvent. A slight increase in
the ee was observed when the reaction temperature was low-
ered from 25 to À208C (Table 1, entries 1, 2, and 4). A de-
crease of catalyst loading caused a significant drop in the ee
of the product (Table 1, entries 2 and 3).
metric phenylation reaction (Table 2, entries 11 and 12). The
in situ prepared phenylzinc reagent also worked well for the
phenyl addition to other aldehydes, particularly aliphatic al-
dehydes, furaldehyde, and a,b-unsaturated trans-cinnamyl
aldehydes, giving products with good to excellent eeꢀs in
most cases.
The preliminary optimized reaction conditions were then
applied to the phenyl transfer reaction for a variety of aro-
matic aldehydes (Table 2). The reaction generally proceeded
with excellent enantioselectivities (up to 99% ee). Under
the newly developed protocol, the scope of substrates was
not limited to para-substituted aromatic aldehydes, the
meta- or even ortho-substituted substrates also afforded the
corresponding products with good yields and excellent eeꢀs
Another significant advantage of this protocol was that
various substituted arylzinc reagents could be easily transfer-
red to aldehydes by using different arylboronic acids as aryl
sources. We further explored the asymmetric arylzinc addi-
tion and the results indicated that various substituted aryl
groups worked satisfactorily to afford the corresponding di-
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This reaction was rather sensitive to the electronic effect of
arylboronic acids. The presence of an electron-donating
group in the arylboronic acids greatly facilitated the addi-
tion process to give high eeꢀs (up to 99%; Table 3, entries 1,
2, 5, and 6), suggesting a mechanism that involves a nucleo-
philic attack by the aryl group onto the carbonyl carbon.
Steric hindrance around the boron atom retarded the rate of
reaction and lowered both product yield and enantioselec-
tivity (Table 3, entries 8–10). The use of alkylboronic acid
afforded the product in 67% yield and with 45% ee, while
(
Table 2, entries 2–4, 6 and 10).
Next we examined the reactivity of phenyl addition to
para-tolualdehyde and ortho-tolualdehyde. The products of
these reactions were highly-valued intermediates for antihis-
taminic neobenodine and orphenadrine. In this study, we
found that not only the yields of the addition products, but
also the enantioselectivities were uniformly high (>97% ee)
(
Table 2, entries 9 and 10). Aromatic aldehydes possessing
steric hindrance, such as 1-naphthaldehyde and 2-naphthal-
dehyde, also proved to be suitable substrates for the asym-
[
a]
Table 2. Asymmetric phenyl transfer to various aldehydes.
[
b]
[b]
Entry
1
RCHO
Product
T [8C] Yield [%] ee [%]
Entry
9
RCHO
Product
T [8C] Yield [%] ee [%]
0
0
96
95
96
96
96(R)
94(R)
90(R)
93(R)
À20
0
92
95
94
91
97(R)
98(R)
93(R)
95(R)
2
3
4
10
11
12
À20
0
À20
0
5
À20
95
99(R)
13
À20
91
92(R)
6
7
8
0
À20
À20
95
93
96
97(R)
98(R)
96(R)
14
15
16
À20
0
96
96
88
79(R)
91(R)
96(R)
0
[
a] Aldehyde/5/phenylboronic acid/diethylzinc=0.5:0.05:1.2:3.6 (molar ratio), toluene as solvent, 608C, 12 h. [b] The eeꢀs were determined by HPLC
spectroscopic analyses. Absolute configurations were determined by comparison of the order of peak elution from HPLC analyses with literature values.
Chem. Eur. J. 2006, 12, 4115 – 4120
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4117

A. S. C. Chan et al.
[
a]
Table 3. Asymmetric aryl transfer to benzaldehyde.
[
b]
[b]
Entry
1
ArB(OH)
2
Product
T [8C] Yield [%] ee [%]
Entry
8
ArB(OH)
2
Product
T [8C] Yield [%] ee [%]
À20
À20
96
91
97(S)
0
0
92
89
74(S)
2
98(S)
9
rac
3
4
0
À20
95
91
87(S)
73(S)
1
1
0
1
0
0
0
85
90
67
rac
16(S)
45(R)
5
6
0
À20
95
92
93(S)
99(S)
7
À20
90
71(S)
12
1
3
0
91
61(S)
[
a] Benzaldehyde/5/arylboronic acid/diethylzinc=0.5:0.05:1.2:3.6 (molar ratio), toluene as solvent, 12 h. [b] The eeꢀs were determined by HPLC spectro-
scopic analyses. Absolute configurations were determined by comparison of the order of peak elution from HPLC analyses with literature values.
ferrocenylboronic acid produced the product in a 91% yield
and with 61% ee (Table 3, entries 12–13).
This methodology was quite flexible for the asymmetric
syntheses of diarylmethanols. By using the same chiral
binaphthyl-derived amino alcohol (e.g., (1R ,2S,3R)-5) as a
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a
catalyst, both enantiomers of the corresponding alcohols
could be obtained in good yields and with high eeꢀs. Hence,
with the aid of a proper combination of arylboronic acids
and aromatic aldehydes, a diverse array of oppositely config-
ured chiral diarylmethanols can be obtained.
Scheme 3.
In the structural evaluation of the ligand backbone of the
chiral ferrocenyl oxazoline ligand 3, binaphthyl-derived N,O
poration of the azepine moiety in ligand 5 to provide a
better stereooutcome. Notably, apart from the 7-membered
azepine scaffold, we also introduced atropo-chirality into
this ligand to provide a better match for stereocommunica-
tion to the orientation of the substrate on approach. The
unique features of this ligand design are the chiral-wall
(from binaphthyl-skeleton) moiety and the rigid ligand scaf-
fold. These rational concepts will potentially provide us with
a valuable direction for future ligand design in related asym-
metric catalysis.
ligand (1R ,2S,3R)-5 offers additional parameters (bi-
a
naphthyl-moiety) for fine-tuning the ligand structure, which
will have high potential and versatility in dealing with a
board scope of reactants. In our experiments, ligand 5 did
provide us comparable and sometimes even higher enantio-
selectivities for the arylation of both aromatic and aliphatic
aldehydes when compared with ligand 3.
The rational design of the ligand scaffold 5 was based on
the rigidity level of the ligand architecture (Scheme 3). We
speculated that the low rigidity of the amino-alcohol 9 (op-
posite configuration) afforded low enantioselectivity in the
product (Schemes 2 and 3). In contrast, the relatively rigid
structure of 8 produced better enantioselectivity. This rigid
configuration presumably provided a better enantio-locking
of the substrate. Thus, it prompted us to propose the incor-
Conclusion
We have applied a series of structurally rigid chiral bi-
naphthyl-derived amino alcohol ligands to the asymmetric
4118
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4115 – 4120

Addition of Arylzinc to Aldehydes
FULL PAPER
[
26] 1
addition of arylzinc (prepared in situ) to various aldehydes.
(R)-(2-Methoxyphenyl)phenylmethanol:
3
H NMR (500 MHz, CDCl ):
d=7.47–7.26 (m, 7H; ArH), 7.03–7.00 (m, 1H; ArH), 6.94–6.92 (m, 1H;
The N,O ligand (1R ,2S,3R)-5 produced excellent enantiose-
a
ArH), 6.12 (s, 1H; CH), 3.81 (s, 3H; CH
3
), 3.32 ppm (s, 1H; OH); HPLC
lectivities (up to 99% ee) in the asymmetric arylation of
both aromatic and aliphatic aldehydes. A diverse array of
optically active diarylmethanols, which are of high interest
in biological and pharmaceutical sciences, can be obtained
in one step by altering the structures of nucleophiles and the
aldehydes. Because of the simplicity of the ligand synthesis
and the ease of ligand modification, these chiral amino alco-
hols may constitute a new set of versatile catalysts for the
enantioselective arylation of various carbonyl compounds.
À1
(
Daicel Chiralcel OD-H; hexane/iPrOH 97:3; 0.8 mLmin ; l=254 nm):
t
R
(S)=38.9 min, t
R
(R)=43.9 min.
[26]
1
(
R)-(4-Biphenyl)phenylmethanol:
3
H NMR (500 MHz, CDCl ): d)=
7.59–7.57 (m, 4H; ArH), 7.47–7.42 (m, 6H; ArH), 7.38–7.33 (m, 3H;
ArH), 7.31–7.26 (m, 1H; ArH), 5.91 (d, J=3.0 Hz, 1H; CH), 2.26 ppm
d, J=3.5 Hz, 1H; OH); HPLC (Daicel Chiralcel OB-H; hexane/iPrOH
(
9
À1
5:5; 1.0 mLmin ; l=254 nm): t
R
(R)=42.2 min, t
R
(S)=66.3 min.
[26] 1
(
R)-(3-Methoxyphenyl)phenylmethanol:
H NMR (500 MHz, CDCl ):
3
d=7.41–7.27 (m, 6H; ArH), 6.98–6.96 (m, 2H; ArH), 6.85–6.82 (m, 1H;
ArH), 5.78 (d, J=15.5 Hz, 1H; CH), 3.79 (s, 3H; CH ), 2.67 (d, J=
3
3
0
.5 Hz, 1H; OH); HPLC (Daicel Chiralcel OD-H; hexane/iPrOH 95:5;
À1
.8 mLmin ; l=254 nm): t
R
(S)=30.9 min, t
R
(R)=47.0 min.
[26] 1
(
R)-(4-Methoxyphenyl)phenylmethanol:
3
H NMR (500 MHz, CDCl ):
d=7.39–7.26 (m, 7H; ArH), 6.89–6.87 (m, 2H; ArH), 5.78 (s, 1H; CH),
Experimental Section
3
.79 (s, 3H; CH
3
), 2.54 ppm (s, 1H; OH); HPLC (Daicel Chiralcel AD;
À1
hexane/iPrOH 97:3; 0.5 mLmin ; l=254 nm): t
R
(R)=64.6 min, t
R
(S)=
All experiments were carried out under a nitrogen atmosphere. Unless
otherwise stated, commercial reagents were used as received without fur-
ther purification. The reactions were carried out in solvents distilled from
standard drying agents. Toluene and THF were freshly distilled from
70.0 min; HPLC (Daicel Chiralcel OJ; hexane/iPrOH 90:10;
À1
1.0 mLmin ; l=254 nm): t (R)=30.7 min, t (S)=34.1 min.
R
R
[31]
1
(
R)-(4-Bromophenyl)phenylmethanol:
3
H NMR (500 MHz, CDCl ):
d=7.47–7.44 (m, 2H; ArH), 7.37–7.29 (m, 5H; ArH), 7.21–7.19 (m, 2H;
[
37]
sodium and sodium benzophenone ketyl under nitrogen, respectively.
ArH), 5.67 (d, J=3.0 Hz, 1H; CH), 3.16 (d, J=3.0 Hz, 1H; OH); HPLC
Aldehydes were freshly distilled under reduced pressure before use.
À1
(
Daicel Chiralcel OB-H; hexane/iPrOH 90:10; 0.5 mLmin ; l=254 nm):
1
H NMR spectra were recorded on a Varian (500 MHz) spectrometer.
t
R
(R)=26.3 min, t
R
(S)=35.2 min.
Spectra were referenced internally to the residual proton resonance in
[
26] 1
(
R)-(4-Tolyl)phenylmethanol:
H NMR (500 MHz, CDCl
.34 (m, 4H; ArH), 7.29–7.26 (m, 3H; ArH), 7.18–7.16 (m, 2H; ArH),
.81 (d, J=3.5 Hz, 1H; CH), 2.36 (s, 3H; CH ), 2.32 ppm (d, J=3.0 Hz,
3
): d=7.40–
CDCl
3
(d)=7.26 ppm) or with tetramethylsilane (TMS, d=0.00 ppm) as
7
5
1
0
the internal standard. Chemical shifts (d) were reported as parts per mil-
1
3
3
lion (ppm) in d scale downfield from TMS. C NMR spectra were re-
corded on a Varian 500 spectrometer and referenced to CDCl (d=
7.0 ppm). TLC was performed on Merck precoated silica gel 60 F254
H; OH); HPLC (Daicel Chiralcel OD-H; hexane/iPrOH 98:2;
3
À1
.9 mLmin ; l=254 nm): t
R
(S)=28.5 min, t
R
(R)=33.7 min.
7
[
26] 1
(
R)-(2-Tolyl)phenylmethanol:
H NMR (500 MHz, CDCl ): d=7.55 (d,
3
plates. Silica gel (Merck or MN, 230–400 mesh) was used for flash-
TM
J=7.0 Hz, 1H; ArH), 7.38–7.24 (m, 7H; ArH), 7.19 (m, 1H; ArH), 6.00
column chromatography. HPLC analyses were conducted on a Waters
6
ꢂ
(d, J=3.5 Hz, 1H; CH), 2.35 (d, J=3.5 Hz, 1H; OH), 2.27 ppm (s, 3H;
00 instrument by using Chiralcel columns (0.46 cm diameter”25 cm
À1
CH
l=254 nm): t
(R)-(2-Naphthyl)phenylmethanol:
3
); HPLC (Daicel Chiralcel OB-H; hexane/iPrOH 96:4; 0.8 mLmin
;
length). The absolute configurations of the products were determined
based on the comparison of HPLC traces and/or the direction of optical
rotation with known compounds.
R
(R)=24.9 min, t (S)=32.4 min.
R
[
26]
1
H NMR (500 MHz, CDCl
3
): d=
7
1
.90 (m, 1H; ArH), 7.87–7.84 (m, 2H; ArH), 7.82–7.80 (d, J=9.0 Hz,
H; ArH), 7.54–7.49 (m, 2H; ArH), 7.45–7.43 (m, 3H; ArH), 7.39–7.35
General procedure for the catalytic addition of arylzinc to benzaldehyde:
A
(
3
solution of phenylboronic acid (1.2 mmol, 146.3 mg) in toluene
1.5 mL) was mixed with diethylzinc solution (1.1m in toluene,
.6 mmol, 3.27 mL) in a sealed vessel under a nitrogen atmosphere. After
(
m, 2H; ArH), 7.33–7.30 (m, 1H; ArH), 5.96 (s, 1H; CH), 2.73 ppm (d,
a
J=3.5 Hz, 1H; OH); HPLC (Daicel Chiralcel OD-H; hexane/iPrOH
9
À1
5:5; 1.0 mLmin ; l=254 nm): t
R
(S)=28.2 min, t
R
(R)=34.8 min.
the reaction mixture had been stirred for 12 h at 608C, the vessel was
cooled to 08C and a solution of chiral amino alcohol 5 (0.05 mmol) in tol-
uene was added with continued stirring for 15 min. 4-Chlorobenzalde-
hyde (0.50 mmol, 70.3 mg) was subsequently added and the mixture was
allowed to stir at 08C overnight. The reaction was then quenched with
aqueous HCl solution (5%, ~6 mL), extracted with EtOAc (3”5 mL),
[
31]
1
(R)-(1-Naphthyl)phenylmethanol:
H NMR (500 MHz, CDCl ): d=
3
8.07 (d, J=8.5 Hz, 1H; ArH), 7.96 (d, J=7.0 Hz, 1H; ArH), 7.90 (d, J=
8.5 Hz, 1H; ArH), 7.66 (d, J=7.0 Hz, 1H; ArH), 7.57–7.48 (m, 3H;
ArH), 7.45–7.34 (m, 5H; ArH), 6.43 (s, 1H; CH), 3.47 (d, J=4.5 Hz, 1H;
OH); HPLC: Daicel Chiralcel OD-H; hexane:iPrOH=90:10;
À1
and dried with Na
2
SO
4
. The crude product diarylmethanol was purified
1.0 mLmin ; l=254 nm; t
R
(S)=13.2 min, t
R
(R)=28.3 min.
H NMR (500 MHz, CDCl
.43 (m, 2H; 1 ArH, 1=CH O), 7.40–7.37 (m, 3H; ArH), 7.35–7.32 (m,
by flash- column chromatography (silica gel, 10% EtOAc/hexane) to
give the product in 96% yield and with 96% ee. T heee was determined
by HPLC analysis with a 25 cm”4.6 mm Chiralcel OB-H column (Daicel
[16] 1
(
R)-(2-Furyl)phenylmethanol:
3
): d=7.45–
7
1
1
À
H; ArH), 6.33 (m, 1H; =CH ), 6.12 (d, J=3.0 Hz, 1H; =CH ), 5.81 (s,
À
À
Chemical Industries) (eluent: 10% 2-propanol in hexane; flow rate:
H; CH(OH)), 2.69 ppm (s, 1H; OH); HPLC (Daicel Chiralcel OD-H;
À1
0
.5 mLmin ; UV lamp=270 nm): t
R
(R)=27.4 min, t
R
(S)=42.5 min.
H NMR (500 MHz, CDCl
d=7.37–7.26 (m, 9H; ArH), 5.72 (s, 1H; CH), 2.90 ppm (d, J=3.5 Hz,
À1
hexane/iPrOH 97:3; 1.0 mLmin ; l=254 nm): t
25.1 min.
R
(S)=21.2 min, t
R
(R)=
[
26]
1
(
R)-(4-Chlorophenyl)phenylmethanol:
3
):
[26]
1
(
S)-(E)-1,3-Diphenyl-2-propenol:
H NMR (500 MHz, CDCl
3
): d=
1
0
H; OH); HPLC (Daicel Chiralcel OB-H; hexane/iPrOH 90:10;
7
.47–7.45 (m, 2H; ArH), 7.42–7.38 (m, 4H; ArH), 7.35–7.31 (m, 3H;
À1
.5 mLmin ; l=270 nm): t
R
(R)=27.4 min, t
R
(S)=42.5 min.
ArH), 7.29–7.26 (m, 1H; ArH), 6.72–6.69 (d, J=15.5 Hz, 1H; CH=
CHCH(OH)(Ph)), 6.43–6.38 (m, 1H; PhCH=CH), 5.39 (d, J=6.5 Hz,
[
21]
1
(
R)-(3-Chlorophenyl)phenylmethanol:
H NMR (500 MHz, CDCl ):
3
d=7.40 (m, 1H; ArH), 7.37–7.33 (m, 4H; ArH), 7.32–7.29 (m, 1H;
ArH), 7.26–7.23 (m, 3H; ArH), 5.74 (d, J=3.0 Hz, 1H; CH), 2.69 ppm
1H; CH), 2.41 ppm (s, 1H; OH); HPLC (Daicel Chiralcel OD-H;
À1
hexane/iPrOH 80:20; 0.8 mLmin ; l=254 nm): t
R
(S)=10.6 min, t
R
(R)=
(
9
d, J=3.0 Hz, 1H; OH); HPLC (Daicel Chiralcel OB-H; hexane/iPrOH
12.9 min.
À1
5:5; 1.0 mLmin ; l=254 nm): t
R
(R)=28.5 min, t
R
(S)=44.5 min.
[26] 1
(
S)-Cyclohexylphenylmethanol:
7.33 (m, 2H; ArH), 7.31–7.27 (m, 3H; ArH), 4.37–4.36 (m, 1H; CHOH),
1.97–2.05 (m, 2H; 1CH, 1OH), 1.78–1.75 (m, 1H; CH ), 1.70–1.59 (m,
3H; CH ), 1.40–1.37 (m, 1H; CH ), 1.25–0.92 ppm (m, 5H; CH ); HPLC
(Daicel Chiralcel AD; hexane/iPrOH 97:3; 0.5 mLmin ; l=254 nm):
(S)=22.0 min, t (R)=24.1 min.
H NMR (500 MHz, CDCl ): d=7.36–
3
[
26]
1
(
R)-(2-Chlorophenyl)phenylmethanol:
H NMR (500 MHz, CDCl ):
3
d=7.63 (m, 1H; ArH), 7.41–7.28 (m, 7H; ArH), 7.25–7.22 (m, 1H;
ArH), 6.21 (d, J=3.5 Hz, 1H; CH), 2.72 ppm (d, J=4.0 Hz, 1H; OH);
HPLC (Daicel Chiralcel OD-H; hexane/iPrOH 95:5; 1.0 mLmin ; l=
2
2
2
2
À1
À1
2
54 nm): t
R
(R)=12.9 min, t
R
(S)=16.7 min.
t
R
R
Chem. Eur. J. 2006, 12, 4115 – 4120
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4119

A. S. C. Chan et al.
[
26] 1
(
S)-2,2-Dimethyl-1-phenylpropanol:
H NMR (500 MHz, CDCl
3
): d=
[11] E. J. Corey, Pure Appl. Chem. 1990, 62, 1209–1216.
7
0
9
.34–7.25 (m, 5H; ArH), 4.39 (d, J=3.0 Hz, 1H; CH), 1.93 (s, 1H; OH);
[12] T. Ohkuma, M. Koizumi, H. Ikehira, T. Yokozawa, R. Noyori, Org.
Lett. 2000, 2, 659–662.
[13] R. Noyori, T. Ohkuma, Pure Appl. Chem. 1999, 71, 1493–1501.
[14] L. Pu, H. B. Yu, Chem. Rev. 2001, 101, 757–824.
.93 ppm (s, 9H; CH
8:2; 0.9 mLmin ; l=254 nm): t
3
); HPLC (Daicel Chiralcel OD-H; hexane/iPrOH
(S)=11.7 min, t (R)=13.4 min.
3
H NMR (500 MHz, CDCl ):
À1
R
R
[
31]
1
(
S)-(2-Bromophenyl)phenylmethanol:
[
15] C. Bolm, J. P. Hildebrand, K. MuÇiz, N. Hermanns, Angew. Chem.
001, 113, 3282–3407; Angew. Chem. Int. Ed. 2001, 40, 3284–3308.
[16] C. Bolm, N. Hermanns, J. P. Hildebrand, K. MuÇiz, Angew. Chem.
000, 112, 3607–3609; Angew. Chem. Int. Ed. 2000, 39, 3465–3467.
[17] P. I. Dosa, J. C. Ruble, G. C. Fu, J. Org. Chem. 1997, 62, 444–445.
d=7.60–7.54 (m, 2H; ArH), 7.42–7.29 (m, 6H; ArH), 7.17–7.14 (m, 1H;
ArH), 6.19 (d, J=4.0 Hz, 1H; CH), 2.52 ppm (d, J=3.5 Hz, 1H; OH);
HPLC (Daicel Chiralcel OD-H; hexane/iPrOH 90:10; 1.0 mLmin ; l=
2
À1
2
2
54 nm): t
R
(R)=8.8 min, t
R
1
(S)=11.9 min.
[
38]
(
R)-1-Phenylpentanol:
3
H NMR (500 MHz, CDCl ): d=7.28–7.23 (m,
[
[
18] W.-S. Huang, Q.-S. Hu, L. Pu, J. Org. Chem. 1999, 64, 7940–7956.
19] W.-S. Huang, L. Pu, Tetrahedron Lett. 2000, 41, 145–149.
4
1
H; ArH), 7.21–7.17 (m, 1H; ArH), 4.49 (t, J=6.5 Hz, 1H; CH), 2.01 (s,
H; OH), 1.78–1.62 (m, 3H; CH
2
), 0.83 ppm (m, 4H; 3CH
3
, 1CH
2
);
À1
[20] C. Bolm, N. Hermanns, A. Claßen, K. MuÇiz, Bioorg. Med. Chem.
Lett. 2002, 12, 1795–1798.
HPLC (Daicel Chiralcel OD-H; hexane/iPrOH 99:1; 1.0 mLmin ; l=
2
54 nm): t
R R
(R)=24.3 min, t (S)=31.5 min.
[
[
21] D.-H. Ko, K. H. Kim, D.-C. Ha, Org. Lett. 2002, 4, 3759–3762.
22] C. Bolm, M. Kesselgruber, A. Grenz, N. Hermanns, J. P. Hildebrand,
New J. Chem. 2001, 25, 13–15.
[
31]
1
(
S)-(Ferrocenyl)phenylmethanol:
H NMR (500 MHz, CDCl
3
): d=
7
.31–7.30 (m, 2H; ArH), 7.24 (t, J=7.5 Hz, 2H; ArH), 7.18–7.15 (m, 1H;
ArH), 5.38 (s, 1H; CH), 4.14 (s, 5H; CH=CH), 4.14–4.00 (m, 4H; CH=
CH), 2.45 ppm (s, 1H; OH); C NMR (125 MHz, CDCl
[
[
23] C. Bolm, N. Hermanns, M. Kesselgruber, J. P. Hildebrand, J. Orga-
nomet. Chem. 2001, 624, 157–161.
24] G. Zhao, X.-G. Li, X.-R. Wang, Tetrahedron: Asymmetry 2001, 12,
1
3
3
): d=143.3,
1
6
1
28.3, 127.5, 126.3, 94.3, 73.8, 72.4, 72.1, 68.8, 68.6, 68.2, 68.2, 67.5,
6.1 ppm; HPLC (Daicel Chiralcel OD-H; hexane/iPrOH 93:7;
3
99–403.
À1
.0 mLmin ; l=254 nm): t
R
(R)=14.8 min, t
R
(S)=24.3 min.
[
[
25] C. Bolm, K. MuÇiz, Chem. Commun. 1999, 1295–1296.
26] M. Fontes, X. Verdaguer, L. Solꢃ, M. A. Pericꢃs, A. Riera, J. Org.
Chem. 2004, 69, 2532–2543.
[
27] C. Bolm, M. Kesselgruber, N. Hermanns, J. P. Hildebrand, G. Raabe,
Angew. Chem. 2001, 113, 1536–1538; Angew. Chem. Int. Ed. 2001,
Acknowledgements
4
0, 1488–1490.
We thank the Hong Kong Research Grants Council (Project No. PolyU
001/03P), the University Grants Committee Areas of Excellence
Scheme in Hong Kong (Project AoE P/10-01), and the Hong Kong Poly-
technic University ASD Fund for financial support.
[
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Received: August 26, 2005
Revised: December 19, 2005
Published online: March 23, 2006
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5
4120
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4115 – 4120