Rh(I)/DpenPhos catalyzed asymmetric hydrogenation of enol esters and potassium (E)-3-cyano-5-methylhex-3-enoate

Article abstract of DOI:10.1016/j.tet.2012.05.096

Rh(I) complexes of a class of modular chiral monodentate phosphoramidites were highly efficient for the asymmetric hydrogenation of enol esters bearing α-aryl or α-alkyl groups, to afford the corresponding hydrogenation products in high enantioselectiviti

Full text of DOI:10.1016/j.tet.2012.05.096

Tetrahedron 68 (2012) 7581e7585
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rh(I)/DpenPhos catalyzed asymmetric hydrogenation of enol esters
and potassium (E)-3-cyano-5-methylhex-3-enoate
*
Yan Liu, Zheng Wang, Kuiling Ding
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Rh(I) complexes of a class of modular chiral monodentate phosphoramidites were highly efficient for the
Received 31 March 2012
Received in revised form 13 May 2012
Accepted 22 May 2012
asymmetric hydrogenation of enol esters bearing a-aryl or a-alkyl groups, to afford the corresponding
hydrogenation products in high enantioselectivities (87e95% ee) and reactivities (turnover number up to
10,000). These ligands were also shown to be effective in Rh(I)-catalyzed asymmetric hydrogenation of
the potassium salt of (E)-3-cyano-5-methylhex-3-enoate, to give the corresponding product (a precursor
to CI-1008) with up to 95% ee and complete conversion of substrate.
Available online 30 May 2012
Keywords:
Asymmetric catalysis
Enol ester
Ó 2012 Elsevier Ltd. All rights reserved.
Hydrogenation
Rhodium
Phosphoramidite
1. Introduction
ligand, herein we report the application of DpenPhos in Rh(I)-
catalyzed AH of enol esters and potassium (E)-3-cyano-5-
Since the pioneering work on Rh(I)-catalyzed asymmetric hy-
drogenation (AH) by Knowles in 1968,1 chemists have taken tre-
mendous efforts in generating new asymmetric catalytic
hydrogenation systems for synthetic organic chemistry.2 Today, AH
has become one of the most powerful methodologies for the con-
struction of chiral amino acids, chiral amines, chiral alcohols, and
many other important chiral compounds.3 Undoubtedly, chiral
phosphorus ligands, which are regarded as reaction speed accel-
erators and chirality inducers in the AH, play a central role.4
Bidentate phosphine ligands have been considered to be essential
for high reactivities and enantioselectivities for more than three
decades in the asymmetric hydrogenation of prochiral olefins.2e4
However, triggered by the pioneering works of Reetz, Ferringa, de
Vries, Pringle, and others in 2000,5 the development of mono-
dentate phosphorus ligands for asymmetric hydrogenation has
been a research topic of increasing interest due to their excellent
catalytic performances, simplicity of synthesis, and ease of struc-
tural variation.6 We have recently developed a new series of tun-
able chiral monodentate ligands, DpenPhos (Fig. 1), which has been
successfully applied in Rh-catalyzed asymmetric hydrogenation of
methylhex-3-enoate. High reactivities (turnover number up to
10,000) and enantioselectivities (up to 95% ee) were achieved for
acyclic enol esters bearing aromatic or aliphatic substituents. The
hydrogenation of potassium (E)-3-cyano-5-methylhex-3-enoate in
the presence of Rh(I)/DpenPhos afforded the corresponding prod-
uct with 95% ee, a key precursor for the synthesis of CI-1008
(pregabalin).
2. Results and discussions
2.1. Rh-catalyzed asymmetric hydrogenation of enol esters
Rh-catalyzed asymmetric hydrogenation of enol esters provides
a straightforward approach to chiral esters, which can be regarded
as an attractive alternative to the enantioselective reduction of the
corresponding prochiral ketones. Several efficient catalytic systems
have been reported for the AH of enol esters.8 However, in most
cases the acceptable enantioselectivities (ee >90%) were only
attained for the hydrogenation of aryl, vinyl or trifluoromethyl
substituted substrates. The AH of enol esters bearing alkyl group at
the olefinic function has been less explored despite the wide utility
of the hydrogenation products. The only example of high enantio-
selectivity for AH of this type of substrates was reported by Reetz
a
- or
toxy)acrylates,
phosphonates and
b
-(acylamino)acrylates,
-aryl substituted itaconates,
- or -acyloxy
-unsaturated phosphonates.7
a
-arylenamides, (Z)-methyl
a-(ace-
b
a
- or -enamido
b
a
b
a,b
As an ongoing effort to further explore the potential of this type of
and co-workers using
a
catalytic system based on Rh-
monophosphite complexes.9 Unfortunately, no results for the AH
of enol esters bearing an aromatic group at the vinyl position were
* Corresponding author. E-mail address: kding@mail.sioc.ac.cn (K. Ding).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.096

7582
Y. Liu et al. / Tetrahedron 68 (2012) 7581e7585
R1
N
R1
N
R2
R2
O
O
O
O
*
*
*
*
O
O
P
N
P N
R2
H
N
R1
N
R1
DpenPhos
DpenPhos
(S,S)-1d: R1 = Et, R2= n-Pr
(R,R)-1a: R1 = C6H5CH2, R2 = CH3
(S,S)-1e: R1 = Et, R2 = Bn
(R,R)-1b: R1 = 3,5-(CH3)2C6H3CH2, R2 = CH3
(R,R)-1c: R1 = 3,5-(t-C4H9)2C6H3CH2, R2 = CH3
(R,R)-1f: R1 = Bn, R2 = n-Pr
(R,R)-1g R1 = Bn, R2 = Bn
(S,S,R)-1h: R1 = Bn, R2 = (R)-1-phenylethyl
(S,S,S)-1i: R1= Bn, R2 = (S)-1-phenylethyl
(R,R)-1j: R1 = 3,5-diMeBn, R2 = n-Pr
(R,R,S)-1k: R1 = Et, R2 = (S)- -phenylethyl
(R,R,S)-1l: R1 = 3,5-diMeBn, R2 = (S)- -phenylethyl
Fig. 1. DpenPhos ligands 1ael employed in this study.
reported in this protocol. Accordingly, the development of chiral
catalysts for AH of both aromatic and aliphatic enol esters is still
highly desirable.
We began our study on AH of enol esters using 2a as the model
substrate and the Rh(I) complex generated in situ from [Rh(cod)BF4]
(1 mol %) and DpenPhos (2 mol %) as the catalyst, and the results are
summarized in Table 1. With dichloromethane as the solvent under
40 bar of H2, an initial survey of the monophosphoramidite ligands
(DpenPhos class and MonoPhos) indicated that 1h having a PeNeH
moiety, is an effective ligand for this reaction (entry 5). Complete
conversion of 2a to 3a with a good enantiomeric excess value (70%)
has been attained in this case (entry 5), whereas the use of Mono-
Phos or 1aec under the otherwise identical conditions only resulted
in no reactivity or modest enantioselectivities (Table 1, entries 1e4).
A dramatic solvent effect was observed in the AH of 2a using the Rh/
1h catalyst. While the reaction in 1,2-dichloroethane afforded the
product with an enhanced enantiomeric excess value (83%, entry 8),
no reaction occurred in toluene, methanol or isopropanol (entries 7,
10e11). Enlightened by the initial ligand screening results (entries
1e5), a series of DpenPhos ligands (1del) carrying the PeNeH
moiety and different R1 and R2 groups in their structures were
subsequently investigated in the Rh-catalyzed AH of 2a under
a lower pressure (5 bar) of H2. The identities of groups R1 and R2 on
the ligands were found to have a remarkable influence on the out-
come of AH of 2a, enantiomeric excess values of 3a ranging from
moderate to high were obtained under the tested conditions (entries
12e20). Intriguingly, for the AH of 2a catalyzed by Rh complex of 1h
and 1i, which are diastereomeric to each other in that they contain
a 1-phenylethylamine moiety with reversed chiralities, only a slight
difference in their chiral inductions was observed (entry 16 vs 17).
Though the Rh complexes of DpenPhos 1del can afford full con-
versions in the catalytic AH of 2a, those of 1h, 1i, and 1l are superior
in terms of chiral inductions to give 3a in good to high enantiomeric
excess values (entries 16, 17, and 20). Further screening of the dif-
ferent concentrations of substrate 2a revealed that a relatively dilute
substrate solution seems to favor the enantioselectivity (entries
21e24). Thus, ligand screening and condition optimizations in the
AH of 2a indicated that 1h and 1l could afford high enantioselectivity
with an opposite sense of chiral induction at room temperature
(entries 20 vs 24). Finally, lowering the reaction temperature from
room temperature to ꢀ20 ꢁC resulted in a slight enhancement of
enantiomeric excess values to 92% and 93%, respectively, for the Rh/
1h or Rh/1l catalyzed AH of 2a (entries 26 and 27).
Table 1
Asymmetric hydrogenation of 2a catalyzed by DpenPhos(1)/Rh
Entry
Ligand
Solvent
PH2 (bar)
[2a] (M)
Conva (%)
eeb (%)
1
2
3
4
5
6
7
8
MonoPhos
(R,R)-1a
(R,R)-1b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Toluene
DCE
CHCl3
i-PrOH
MeOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
40
40
40
40
40
40
40
40
40
40
40
5
5
5
5
5
5
5
5
5
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.045
0.045
0.36
0.09
0.06
0.045
0.045
0.045
0.045
>99
>99
Trace
Trace
>99
>99
N.R.
>99
>99
N.R.
N.R.
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
ꢀ29
ꢀ10
N.D.
N.D.
70
13
N.D.
83
(R,R)-1c
(S,S,R)-1h
(S,S,R)-1h
(S,S,R)-1h
(S,S,R)-1h
(S,S,R)-1h
(S,S,R)-1h
(S,S,R)-1h
(S,S)-1d
(S,S)-1e
(R,R)-1f
(R,R)-1g
(S,S,R)-1h
(S,S,S)-1i
(R,R)-1j
(R,R,S)-1k
(R,R,S)-1l
(S,S,R)-1h
(S,S,R)-1h
(S,S,R)-1h
(S,S,R)-1h
(S,S,R)-1h
(S,S,R)-1h
(R,R,S)-1l
9
70
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26c
27c
N.D.
N.D.
48
50
ꢀ37
ꢀ54
85
82
ꢀ46
ꢀ67
ꢀ91
83
88
88
90
88
92
ꢀ93
Having established the optimal conditions for the model re-
action, the AH of various enol esters was examined with Rh(I)/
DpenPhos complexes as the catalysts. The reactions were typically
performed in dichloroethane at ꢀ20 ꢁC for 10 h, and the results are
summarized in Table 2. Gratifyingly, high efficiency of Rh/1h and
Rh/1l was achieved for AH of enol acetates with different aromatic
groups on the a-vinyl positions, to afford the corresponding chiral
acetates in full conversions with excellent enantioselectivity (en-
tries 1e5). To demonstrate the efficiency of the catalyst Rh/1l, the
DCE
DCE
DCE
DCE
DCE
DCE
DCE
5
5
5
5
1
5
5
a
Determined by 1H NMR.
Determined by chiral GC.
Reaction was carried out under ꢀ20 ꢁC.
b
c

Y. Liu et al. / Tetrahedron 68 (2012) 7581e7585
7583
Table 2
Table 3
Asymmetric hydrogenation of 2 catalyzed by DpenPhos(1)/Rh(I)
Asymmetric hydrogenation of 5 catalyzed by Rh(I)/DpenPhos(1)
CN
CN
O
Rh(cod)2BF4/1(1 mol %), 5 h
O
R
*
CO2-K+
H2(40 bar), i-PrOH/CH2Cl2=1/1
H2 (5 bar), Rh(cod)2BF4/1 (1 mol %)
R'
O
CO2-K+
R'
O
DCE, [2] = 0.045 M, -20 °C, t = 10 h
*
6
R
5
2
3
Entry
Ligand
T (ꢁC)
Conva (%)
eeb (%)
1
2
3
4
(R,R)-1a
(R,R)-1g
45
45
45
45
35
20
20
20
59
ꢀ23
ꢀ47
69
77
89
Entry Sub.
R
R0
Me (R,R,S)-1l
Ligand
Conva (%) eeb (%) Config.c
>99
>99
>99
>99
>99
>99
>99
1
2
3
4
2a
2b
2c
2d
2e
2e
2f
C6H5
>99
93
91
88
92
95
91
90
87
88
87
R
S
(S,S,R)-1h
(S,S,S)-1i
(S,S,S)-1i
(S,S,S)-1i
(R,R,R)-1k
(R,R,R)-1l
2-Naphthyl Me (S,S,R)-1h >99
4-ClC6H4
3-ClC6H4
3-MeC6H4
3-MeC6H4
n-Bu
n-Pr
n-Pentyl
n-Hexyl
Me (R,R,S)-1l
Me (R,R,S)-1l
Me (R,R,S)-1l
Me (R,R,S)-1l
>99
>99
>99
>99
R
R
R
R
R
R
R
R
5
6c
7c
8c
90
5
ꢀ33
6d
7e
8e
9e
10e
ꢀ95
Ph
Ph
Ph
Ph
(S,S,R)-1h >99
(S,S,R)-1h >99
(S,S,R)-1h >99
(S,S,R)-1h >99
a
Determined by 1H NMR spectroscopy.
Determined by HPLC on Chiralcel column. Absolute configuration of 6 catalyzed
2g
2h
2i
b
by Rh/(R,R,R)-1l was determined to be R by comparison of [a]D value with those of
literature data.
a
Determined by 1H NMR.
Determined by HPLC on Chiralcel column or GC.
Absolute configurations were assigned by comparison of [a]D values with those
c
Reaction time: 24 h.
b
c
of literature data.
d
entry 1 vs 2e8). Similar behaviors have also been found in our
previous studies on the AH of -(acylamino) acrylates, (Z)-methyl
R-(acetoxy)acrylates, itaconate derivatives, )-enamido phos-
phonates, -(acylamino)-acrylates, and enol esters catalyzed by the
Substrate/[Rh]¼10,000:1, rt, 20 bar H2.
e
CHCl3 as solvent, and PH2¼40 bar.
a
a(b
b
hydrogenation of 2e was carried out in the presence of a reduced
catalyst loading (0.01 mol %) under a higher pressure of H2 (20 bar),
affording the corresponding ester 3e in complete conversion
without significant loss of enantioselectivity (entry 6 vs 5). To our
delight, AH of enolate esters with aliphatic substituents on the vinyl
positions, a class of particularly difficult substrates, also proceeded
smoothly to full conversion under 40 bar of H2 with Rh/1h as the
catalyst, to afford the corresponding benzoyl esters with high en-
antiomeric excess values (entries 7e10).
same type of Rh/DpenPhos complexes.7 The chiral induction varies
widely from modest to excellent depending on the N-substituents
(R1, R2) on the ligands (entries 2e4, 7e8). The reactions took
a prolonged time for full conversion when the temperature was
decreased from 45 to 20 ꢁC (entries 6e8). Among the ligands tested
for this Rh(I) catalyzed reaction, 1l turned out to be best in terms of
the enantioselectivity, giving the chiral product 6 (a precursor to CI-
1008) in complete conversion with 95% ee (entry 8).
3. Conclusions
2.2. Rh/DpenPhos catalyzed asymmetric hydrogenation of
(E)-3-cyano-5-methylhex-3-enoate for the synthesis of CI-
1008 precursor
In summary, chiral monodentate phosphoramidite ligands
DpenPhos have been successfully applied in the Rh(I)-catalyzed
asymmetric hydrogenation of enol esters with
a-aryl or a-alkyl
(S)-(þ)-3-Aminomethyl-5-methylhexanoic acid (4, pregabalin)
is a pharmaceutical used to treat psychotic disorders, seizure dis-
orders, and pain.10 A resolution process was employed in the classic
method to obtain the optical pure 4.11 Asymmetric catalytic hy-
drogenation of a suitable olefinic precursor, such as 5 represents
a concise way to chiral pregabalin via intermediate 6 (Fig. 2). Sev-
eral bidentate phosphines, such as DIPAMP,12 DuPhos,13 and
others14 have been identified as efficient ligands in the Rh(I)-
catalyzed AH of 5. However, to the best of our knowledge, there
was still no reported example of a successful use of monodentate
ligands in the Rh-catalyzed AH of 5.
groups, to afford the corresponding hydrogenation products in high
enantioselectivities (87e95% ee) and reactivities (turnover number
up to 10,000). These ligands were also demonstrated to be efficient
in the Rh(I)-catalyzed AH of the potassium salt of (E)-3-cyano-5-
methylhex-3-enoate, to give the corresponding product (a pre-
cursor to CI-1008) in complete conversion with up to 95% ee. Fur-
ther work on the extension of these ligands in transition metal
catalyzed asymmetric hydrogenation reactions are underway.
4. Experimental
4.1. General experimental
NMR spectra were recorded on a Varian Mercury 300 (1H
300 MHz; 13C 75 MHz) spectrometer in CDCl3. Chemical shifts were
expressed in parts per million with TMS as an internal standard
CN
CN
AH
NH2
CO2H
CO2K
CO2K
6
(d
¼0 ppm) for 1H NMR. Coupling constants, J, are listed in Hertz.
4
5
Optical rotations were measured on a PerkineElmer 341 automatic
polarimeter. HPLC analyses were carried out on a JASCO 1580 liquid
chromatograph with a JASCO CD-1595 detector and AS-1555
autosampler. GC analyses were measured on an Agilent 6890N
network system. Dichloromethane, chloroform, and tetrachloro-
methane were freshly distilled from calcium hydride, THF, diethyl
ether, and toluene from sodium benzophenone ketyl. All manipu-
lations involving air- and moisture-sensitive organometallic com-
pounds were carried out using standard Schlenk techniques under
Fig. 2. Asymmetric hydrogenation pathway to pregabalin (4).
We have examined the AH of 5 using the in situ generated Rh(I)
complex of DpenPhos as the catalyst. The reactions were carried out
in a CH2Cl2/i-PrOH (v/v¼1:1) solvent mixture, and the results were
shown in the Table 3. Remarkably, it was found that the presence of
the NeH moiety in the structure of DpenPhos is critically important
for achieving high activity and selectivity in the AH of 5 (Table 3,

7584
Y. Liu et al. / Tetrahedron 68 (2012) 7581e7585
an argon atmosphere. DpenPhos Ligands 1ael were synthesized by
atmosphere, and then sealed. After purging six times with hydrogen,
the final H2 pressure was adjusted to 20 bar. After stirring at room
temperature for 10 h, H2 was released and the solvent was removed
under the reduced pressure. The substrate conversion was assessed
by 1HNMR spectroscopic analysisof themixture, andthe residuewas
filtered through a short pad of Celite with ethyl acetate as the eluent.
The enantiomeric excess of the product was determined bychiral GC.
following our previously reported procedures.7aec
4.2. General procedure for catalytic asymmetric
hydrogenation of 2aee
[Rh(cod)2]BF4 (2.0 mg, 0.005 mmol), 1 (0.011 mmol) were dis-
solved in ClCH2CH2Cl (5 mL) under nitrogen and the solution was
stirred at room temperature for 10 min. The substrate (0.5 mmol) in
ClCH2CH2Cl (6 mL) was added to the above catalyst solution. The
mixture was then transferred to a stainless steel autoclave under
a nitrogen atmosphere, and then sealed. After purging six times
with hydrogen, the final H2 pressure was adjusted to 5 bar. After
stirring at ꢀ20 ꢁC for 10 h, H2 was released and the solvent was
removed under the reduced pressure. The substrate conversion was
assessed by 1H NMR spectroscopic analysis of the mixture, and the
residue was filtered through a short pad of Celite with ethyl acetate
as the eluent. The enantiomeric excess of the product was de-
termined by chiral HPLC or GC.
4.4. General procedure for catalytic asymmetric
hydrogenation of 2fei
[Rh(cod)2]BF4 (2.0 mg, 0.005 mmol) and (S,S,R)-1h 5.9 mg
(0.011 mmol) were dissolved in CHCl3 (5 mL) under nitrogen, and
the solution was stirred at room temperature for 10 min. A solution
of the substrate (0.5 mmol) in ClCH2CH2Cl (6 mL) was added to the
above catalyst solution. The resulting mixture was then transferred
to a stainless steel autoclave under nitrogen atmosphere, and then
sealed. After purging six times with hydrogen, the final H2 pressure
was adjusted to 40 bar. After stirring at ꢀ20 ꢁC for 10 h, H2 was
released and the solvent was removed under the reduced pressure.
The substrate conversion was assessed by 1H NMR spectroscopic
analysis of the mixture, and the residue was filtered through a short
pad of Celite with ethyl acetate as the eluent. The enantiomeric
excess of the product was determined by chiral HPLC.
4.2.1. (S)-(1-Phenyl)ethyl acetate (S)-3a. Conversion: >99%, 93% ee,
a 20
a 20
½ ꢂD ꢀ105.7 (c 2.2 in CHCl3), [lit.15 ½ ꢂD þ86.7 (c 1.00 in CHCl3) for
(R)]; 1H NMR (300 MHz, CDCl3)
d 7.29e7.40 (m, 5H), 5.88 (q,
J¼6.6 Hz, 1H), 2.07 (s, 3H), 1.54 (d, J¼6.6 Hz, 3H) ppm. The enan-
tiomeric excess was determined by GC on Chiralcel Supelco BATA-
DEX 120 column, 120 ꢁC, tR¼16.0 min (major), 17.0 min (minor).
4.4.1. (R)-Benzoic acid 1-methylpentyl ester,9 (R)-3f. Conversion:
>99%, 90% ee, ½a 2D0
ꢂ
þ92.8 (c 1.0 in CHCl3); 1H NMR (300 MHz,
4.2.2. (S)-1-(2-Naphthyl)ethyl acetate (S)-3b. Conversion: >99%,
CDCl3) d 8.04e8.07 (m, 2H), 7.52e7.58 (m, 1H), 7.41e7.46 (m, 2H),
88% ee, ½a 2D0
ꢂ
ꢀ108.6 (c 2.5 in CHCl3), [lit.16
½
a 2D0
ꢂ
þ109 (c 1.00 in
5.10e5.19 (m, 1H), 1.56e1.78 (m, 2H), 1.28e1.44 (m, 7H), 0.83e0.87
(m, 3H) ppm. The enantiomeric excess was determined by HPLC on
Chiralcel OB-H column, hexane/isopropanol¼100:0; flow
CHCl3) for (R)]; 1H NMR (300 MHz, CDCl3)
d 7.81e7.86 (m, 4H),
7.46e7.50 (m, 3H), 6.05 (q, J¼6.6 Hz, 1H), 2.11 (s, 3H), 1.62 (d,
J¼6.6 Hz, 3H) ppm. The enantiomeric excess was determined by
HPLC on Chiralcel AD column, hexane/isopropanol¼95:5; flow
rate¼0.2 mL/min; UV detection at ¼230 nm; tR¼32.1 min (minor),
l
34.2 min (major).
rate¼0.6 mL/min; UV detection at ¼230 nm; tR¼8.3 min (minor),
l
10.0 min (major), respectively.
4.4.2. (R)-Benzoic acid 1-methylbutyl ester, (R)-3g. Conversion:
>99%, 87% ee, ½a 2D0
ꢂ
þ180.0 (c 2.2 in CHCl3), [lit.18
½
a 2D0
ꢂ
ꢀ23 (c 1.00 in
4.2.3. (S)-1-(4-Chlorophenyl)ethyl
acetate
(S)-3c. Conversion:
a 2D0
þ88.25 (c 1.00
C2H5OH) for (R)]; 1H NMR (300 MHz, CDCl3)
d 8.03e8.06 (m, 2H),
>99%, 88% ee, ½a 2D0
ꢂ
ꢀ104.8 (c 2.0 in CHCl3), [lit.17
½
ꢂ
7.52e7.57 (m, 1H), 7.41e7.46 (m, 2H), 5.14e5.20 (m, 1H), 0.94e1.76
(m, 7H), 0.94 (t, J¼6.9 Hz, 3H) ppm. The enantiomeric excess was
determined by HPLC on Chiralcel OB-H column, hexane/iso-
propanol¼100:0; flow rate¼0.8 mL/min; UV detection at
in CHCl3) for (R)]; 1H NMR (300 MHz, CDCl3)
d 7.27e7.34 (m, 4H), 5.84
(q, J¼6.6 Hz, 1H), 2.09 (s, 3H), 1.51 (d, J¼6.6 Hz, 3H) ppm. The enan-
tiomeric excess was determined by GC on Chiralcel Supelco BATA-
DEX 120 column, 150 ꢁC, tR¼13.6 min (major), 14.0 min (minor).
l¼230 nm; tR¼8.1 min (minor), 9.4 min (major).
4.2.4. (S)-1-(3-Chlorophenyl)ethyl acetate8i (S)-3d. Conversion:
4.4.3. (R)-Benzoic acid 1-methylhexyl ester,19 (R)-3h. Conversion:
>99%, 92% ee, ½a 2D0
ꢂ
ꢀ65.0 (c 2.0 in CHCl3); 1H NMR (300 MHz,
>99%, 88% ee, ½a 2D0
ꢂ
þ87.3 (c 1.0 in CHCl3); 1H NMR (300 MHz,
CDCl3)
d
7.20e7.35 (m, 4H), 5.83 (q, J¼6.6 Hz, 1H), 2.10 (s, 3H), 1.52
CDCl3) d 8.03e8.06 (m, 2H), 7.53e7.58 (m, 1H), 7.41e7.46 (m, 2H),
(d, J¼6.6 Hz, 3H) ppm. The enantiomeric excess was determined by
GC on Chiralcel Supelco BATA-DEX 120 column, 150 ꢁC, tR¼15.0 min
(major), 15.6 min (minor).
5.13e5.19 (m, 1H), 1.55e1.76 (m, 1H), 1.26e1.43 (m, 10H), 0.88 (t,
J¼6.6 Hz, 3H) ppm. The enantiomeric excess was determined by
HPLC on Chiralcel OB-H column, hexane/isopropanol¼100:0; flow
rate¼0.2 mL/min; UV detection at ¼230 nm; tR¼38.0 min (minor),
l
4.2.5. (S)-1-(3-Methylphenyl)ethyl acetate8i (S)-3e. Conversion:
40.4 min (major).
>99%, 95% ee, ½a 2D0
ꢂ
ꢀ64.6 (c 2.2 in CHCl3); 1H NMR (300 MHz,
CDCl3)
d
7.22e7.27 (m, 1H), 7.10e7.16 (m, 3H), 5.85 (q, J¼6.9 Hz, 1H),
4.4.4. (R)-Benzoic acid 1-methylheptyl ester, (R)-3i. Conversion:
2.36 (s, 3H), 2.08 (s, 3H), 1.53 (d, J¼6.6 Hz, 3H) ppm. The enantio-
meric excess was determined by GC on Chiralcel Supelco BATA-DEX
120 column, 140 ꢁC, tR¼12.4 min (major), 12.8 min (minor).
>99%, 87% ee, ½a 2D0
ꢂ
ꢀ13.0 (c 1.0 in CHCl3), [lit.20
½
a 2D0
ꢂ
þ33.3 (c 1.00 in
CH2Cl2) for (R)]; 1H NMR (300 MHz, CDCl3)
d 8.03e8.06 (m, 2H),
7.52e7.58 (m, 1H), 7.41e7.46 (m, 2H), 5.12e5.19 (m, 1H), 1.55e1.76
(m, 1H), 1.25e1.42 (m, 12H), 0.87 (t, J¼6.6 Hz, 3H) ppm. The enan-
tiomeric excess was determined by HPLC on Chiralcel OB-H col-
umn, hexane/isopropanol¼100:0; flow rate¼0.2 mL/min; UV
4.3. Procedure for catalytic asymmetric hydrogenation of 2e
using 0.01 mol % catalyst
detection at
l¼230 nm; tR¼29.2 min (minor), 31.4 min (major).
[Rh(cod)2]BF4 (2.0 mg, 0.005 mmol) and (R,R,S)-1l 6.7 mg
(0.011 mmol) were dissolved in ClCH2CH2Cl (10 mL) under nitrogen
and the solution was stirred at room temperature for 10 min. A 1 mL
portion of the above solution was transferred to the solution of 2e
(880 mg, 5 mmol) in ClCH2CH2Cl (3 mL). The resulting mixture was
then transferred to a stainless steel autoclave under a nitrogen
4.5. General procedure for catalytic asymmetric
hydrogenation of 5
[Rh(cod)2]BF4 (2.0 mg, 0.005 mmol) and (R,R,R)-1l (6.7 mg,
0.011 mmol) were dissolved in CH2Cl2 (2 mL) under nitrogen and

Y. Liu et al. / Tetrahedron 68 (2012) 7581e7585
7585
H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal.
2003, 345, 103.
4. Phosporus Ligands in Asymmetric Catalysis: Synthesis and Applications; Borner, A.,
the solution was stirred at room temperature for 10 min. A solution
of 5 (0.5 mmol) in i-PrOH (2 mL) was added to the above catalyst
solution. The resulting mixture was then transferred to a stainless
steel autoclave under nitrogen atmosphere, and then sealed. After
purging six times with hydrogen, the final H2 pressure was adjusted
to 40 bar. After stirring at room temperature for 10 h, H2 was re-
leased. After removal of the solvent under the reduced pressure,
white solid was obtained and submitted to 1H NMR spectroscopic
analysis to assess the conversion of the substrate. Conversion:
€
Ed.; Wiley-VCH: Weinheim, 2008.
5. (a) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889; (b) van den
Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries,
J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539; (c) Claver, C.; Fernandez,
E.; Gillon, A.; Heslop, K.; Hyett, D. J.; Martorell, A.; Orpen, A. G.; Pringle, P. G.
Chem. Commun. 2000, 961.
6. (a) Bruneau, C.; Renaud, J.-L. In Phosporus Ligands in Asymmetric Catalysis:
€
Synthesis and Applications; Borner, A., Ed.; Wiley-VCH: Weinheim, 2008; pp pp.
36e69; (b) Guo, H. C.; Ding, K.; Dai, L.-X. Chin. Sci. Bull. 2004, 49, 2003; (c)
Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486; (d) Reetz, M. T.
Angew. Chem., Int. Ed. 2008, 47, 2256; (e) Minnaard, A. J.; Feringa, B. L.; Lefort, L.;
De Vries, J. G. Acc. Chem. Res. 2007, 40, 1267; Xie, J.-H.; Zhou, Q. L. Acc. Chem. Res.
2008, 41, 581.
>99%, ½a 2D0
ꢂ
þ18.9 (c 1.0 in MeOH), [lit.13
½
a 2D0
ꢂ
ꢀ20.6 (c 1.00 in
CH3OH) for (S)]; 1H NMR (300 MHz, D2O)
d
3.05e3.10 (m, 1H),
2.49e2.51 (m, 2H), 1.59e1.69 (m, 2H), 1.34e1.43 (m, 1H), 0.93e0.96
(m, 6H) ppm. The enantiomeric excess value was determined after
transformation into the corresponding methyl ester via the fol-
lowing procedure: the crude product was dissolved in the acetone
(3 mL). The solution was acidified to pH¼1 by 2 M HCl, followed by
treated with diazomethane in Et2O. The mixture was extracted with
ethyl acetate (3ꢃ3 mL), dried over Na2SO4, and concentrated in
vacuo. The enantiomeric excess of the product was determined by
7. (a) Liu, Y.; Ding, K. J. Am. Chem. Soc. 2005, 127, 10488; (b) Liu, Y.; Sandoval, C. A.;
Yamaguchi, Y.; Zhang, X.; Wang, Z.; Kato, K.; Ding, K. J. Am. Chem. Soc. 2006, 128,
14212; (c) Zhang, J. Z.; Li, Y.; Wang, Z.; Ding, K. Angew. Chem., Int. Ed. 2011, 50,
11743; (d) Zhang, J. Z.; Dong, K.; Wang, Z.; Ding, K. Org. Biomol. Chem. 2011, 11,
1598; (e) Liu, Y.; Wang, Z.; Ding, K. Acta Chim. Sin. 2012, 70, in press.
8. (a) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 646; (b) Stephan, M.; Terk, D.;
Mohar, B. Adv. Synth. Catal. 2009, 351, 2779; (c) Robert, T.; Abiri, Z.; Sandee, A.;
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Org. Lett. 2010, 12, 1296; (h) Zhang, X.; Huang, K.; Hou, G.; Cao, B.; Zhang, X.
Angew. Chem., Int. Ed. 2010, 49, 6421; (i) Burk, M. J. J. Am. Chem. Soc. 1991, 113,
8518; (j) Koenig, K. E.; Bachman, G. L.; Vineyard, B. D. J. Org. Chem. 1980, 45,
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chiral GC 95% ee. 1H NMR (300 MHz, CDCl3)
d 3.75 (s, 3H),
3.04e3.09 (m, 1H), 2.51e2.76 (m, 2H), 1.82e1.90 (m, 1H), 1.59e1.71
(m, 2H), 0.95e0.99 (m, 6H) ppm. The enantiomeric excess was
determined by GC on Chiralcel Supelco GAMA-DEX 225 column,
120 ꢁC, tR¼18.5 min (major), 19.2 min (minor).
Acknowledgements
9. Reetz, M. T.; Goossen, L. J.; Meiswinkel, A.; Paetzold, J.; Jensen, J. F. Org. Lett.
2003, 5, 3099.
Financial supports from National Natural Science Foundation of
China (Nos. 21172237, 21121062, 21032007), the Major Basic
Research Development Program of China (Grant No.
2010CB833300), the Science and Technology Commission of
Shanghai Municipality, and the Chinese Academy of Sciences are
gratefully acknowledged.
10. Burk, M. J.; Goel, O. P.; Hoekstra, M. S.; Mich, T. F.; Mulhern, T. A.; Ramsden, J. A.
PCT Int. Appl., 2001.
11. Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.; Grote, T. M.;
Huckabee, B. K.; Hendrickson, V. S.; Franklin, L. C.; Granger, E. J.; Karrick, G. L.
Org. Process Res. Dev. 1997, 1, 26.
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Am. Chem. Soc. 1977, 99, 5946.
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A.; Kissel, W. S.; Le, T. V.; Lennon, I. C.; Mulhern, T. A.; Ramsden, J. A.; Wade, R.
A. J. Org. Chem. 2003, 68, 5731.
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