Synthesis and utilization of trifluoromethylated amino alcohol ligands for the enantioselective Reformatsky reaction and addition of diethylzinc to N-(diphenylphosphinoyl)imine

Article abstract of DOI:10.1016/j.tet.2008.05.043

A series of trifluoromethylated amino alcohol ligands, which had been designed and conveniently prepared, were successfully applied in the enantioselective Reformatsky reaction and addition of diethylzinc to N-(diphenylphosphinoyl)imine, respectively. The influence of the substituents on C-3 position and the amino moiety on the enantioselectivity has been carefully investigated. In the best cases, ligand 1b exhibited good selectivity for the enantioselective Reformatsky reaction in 86% ee and ligand 12d provided excellent enantioselectivity in the addition of diethylzinc to N-(diphenylphosphinoyl)imine with 95% ee.

Full text of DOI:10.1016/j.tet.2008.05.043

Tetrahedron 64 (2008) 7353–7361
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and utilization of trifluoromethylated amino alcohol ligands for the
enantioselective Reformatsky reaction and addition of diethylzinc to
N-(diphenylphosphinoyl)imine
,b,
Xiu-Hua Xu a, Xiao-Long Qiu a, Feng-Ling Qing a
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 354 Fenglin Lu, Shanghai 200032, China
b College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2008
Received in revised form 9 May 2008
Accepted 9 May 2008
Available online 14 May 2008
A series of trifluoromethylated amino alcohol ligands, which had been designed and conveniently pre-
pared, were successfully applied in the enantioselective Reformatsky reaction and addition of diethylzinc
to N-(diphenylphosphinoyl)imine, respectively. The influence of the substituents on C-3 position and the
amino moiety on the enantioselectivity has been carefully investigated. In the best cases, ligand 1b
exhibited good selectivity for the enantioselective Reformatsky reaction in 86% ee and ligand 12d pro-
vided excellent enantioselectivity in the addition of diethylzinc to N-(diphenylphosphinoyl)imine with
95% ee.
Keywords:
Trifluoromethylation
Amino alcohol ligands
Asymmetric reaction
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
CF3
OH
R
CF3
OH
*
* *
3 2
R1
N
R1
N
Organozinc reagents are useful synthetic intermediates as a
result of their convenient synthesis and high tolerance toward
functional groups.1 Nucleophilic addition of organozinc reagents to
aldehydes and imines are very important reactions in organic
synthesis. The design of economical and efficient chiral ligands for
highly enantioselective transformations has been one of the major
projects in asymmetric synthesis.2 Recently, the study of tri-
fluoromethylated ligands has attracted more and more attention3
due to the fact that both the strong electron-withdrawing property4
and steric bulkiness5 of the trifluoromethyl group may play an es-
sential role for rate enhancement and stereocontrol. For example,
Nelson group successfully developed the enantioselective cross
aldol reaction with the CF3-containing Al(III) triamine complex as
catalyst.3d The CF3-containing molybdenum alkylidene complexes
were also utilized in asymmetric ring-closing metathesis.3b What
mostly interests us is that, in 2002, Katagiri and Uneyama found
that a type of trifluoromethylated amino alcohols ligands (Fig. 1)
promoted the unexpectedly higher aggregation of the diethylzinc
species, the extent of which correlated well to the asymmetric in-
duction in the reaction with benzaldehyde.3h In addition, these
trifluoromethylated amino alcohols were used as the chiral ligands
R2
R2
Katagiri and Uneyama's ligands
novel ligands
Figure 1. The trifluoromethylated amino alcohol ligands.
for enantioselective Reformatsky reaction with up to 90% ee.3i
These results prompted us to design and synthesize novel tri-
fluoromethylated amino alcohol ligands for enantioselective
nucleophilic addition reactions of organozinc reagents to aldehydes
and imines.
Katagiri and Uneyama’s trifluoromethylated amino alcohols
ligands were some optically pure N-monosubstituted or N,N-di-
substituted 1,1,1-trifluoromethyl-3-amino-propan-2-ols (Fig. 1).3i
We proposed that an additional stereocenter at C-3 position would
improve the enantioselectivities of nucleophilic addition reactions
of organozinc reagents to aldehydes and imines. Thus, we designed
a series of novel trifluoromethylated amino alcohol ligands, which
possessed an additional substitution group at C-3 position. Most
importantly, these novel trifluoromethylated amino alcohol ligands
would be conveniently accessed from readily available amino
acids. Herein, we would like to describe the synthesis of new
trifluoromethylated amino alcohol ligands, and further
evaluate these ligands as promoters for the enantioselective
Reformatsky reactions and addition of diethylzinc to N-
(diphenylphosphinoyl)imine.
* Corresponding author. Tel.: þ86 21 54925187; fax: þ86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.043

7354
X.-H. Xu et al. / Tetrahedron 64 (2008) 7353–7361
2. Results and discussion
Starting from the natural amino acid
2b was conveniently synthesized (Scheme 2). Thus, treatment of
compound with SOCl2/MeOH delivered the corresponding
L-isoleucine 5, the ligand
2.1. Synthesis and evaluation of novel trifluoromethylated
amino alcohol ligands for the enantioselective Reformatsky
reaction
5
methyl ester hydrochloride, which was subsequently hydrogenated
in the presence of aqueous formaldehyde to give the ester 6. Re-
duction of the ester 6 with LiAlH4 followed by Swern oxidation
furnished the corresponding aldehyde, which was subjected to
Ruppert–Prakash reagent (TMSCF3) in the presence of TBAF10 to
afford the mixture of trifluoromethylated amino alcohols 2b and
2b0. During the four steps from the ester 6 to the compounds 2b
and 2b0, all the intermediates were subjected to the next step
without further isolation after work-up. The ratio of the dia-
stereoisomers 2b and 2b0 was 5.5:1 according to 19F NMR and they
could be readily separated on silica gel chromatography. The
stereochemistry of the isomers 2b (2S,3S) and 2b0 (2R,3S) was
assigned on the basis of their 1H NMR characteristics. The signal
(3.83 ppm) of the methine proton at C-2 in the isomer 2b0 appeared
upfield relative to that of the compound 2b (3.97 ppm), and the
vicinal coupling constant (5.7 Hz) between protons at C-2 and C-3
for the isomer 2b0 is larger than that of the compound 2b (4.8 Hz).
These data are coincident with those described for the reported
1,2-amino alcohols.8,11
The Reformatsky reaction is one of the most synthetically useful
methods for the preparation of
b
-hydroxyesters.6 Attainment of
high stereoselectivity of the reaction would be a key issue for fur-
ther extension of its applicability. Until now, a wide range of chiral
ligands has been applied to this reaction,3i,7 but high enantiose-
lectivities were hard to be achieved. Figure 2 outlined the designed
trifluoromethylated amino alcohol ligands 1a–f, 2a, b, and 3a, b.
These ligands could be grouped into three types. Ligands 1a–f
featured that a methyl group occupied the C-3 position and the
amino group was alkylated by the different straight-chain or cyclic
groups (or the amino group was naked). For the ligands 2a, b, an
iso-propyl group or sec-butyl group possessed the C-3 position and
the amino groups were alkylated with two methyl groups. In the
ligands 3a, b, the rigidity of ligands was improved by connecting
C-3 position and amino group into the pyrrolidine ring. All of these
ligands could be easily prepared starting from some reported
intermediates in a straightforward fashion.
Me
Me
1. SOCl2, MeOH
2. H2, Pd/C, HCHO, EtOH
Et
O
Et
O
R1
R2
CF3
OH
R
CF3
OH
77% (two steps)
Me2N
OMe
H2N
OH
R1
N
N
Me
OH
Me
N
Me
5
6
R2
Me
Me
1a: R1 = R2 = Me;
1b: R1 = R2 = Et;
3a: R1 = CF3, R2 = H;
3b: R1 = H, R2 = CF3;
1. LiAlH4, THF;
2. (COCl)2, DMSO, CH2Cl2;
2a: R = i-Pr;
Et
CF3
OH
Et
CF3
OH
2b: R = s-Bu
+
1c: R1 = R2 = Bn;
1d: R1 = R2 = H;
3. TMSCF3, TBAF(cat.),
THF;
4. TBAF, THF
Me2N
Me2N
1e: R1 = R2 = -(CH2)4-;
1f: R1 = R2 = -(CH2)5-;
2b´ (7%)
.
2b (37%)
Scheme 2.
Figure 2. Novel trifluoromethylated amino alcohol ligands.
Synthesis of the
L
-prolinal ligands 3a and 3b commenced with
the methyl ester 7,12 itself available from the
L-proline (Scheme 3).
Reduction of the compound 7 with LiAlH4 followed by Swern oxi-
dation gave the aldehyde, which was further subjected to TMSCF3/
TBAF to afford the diastereoisomers 8 and 80 in 60% total yield. The
isomers 8 and 80 could be easily separated on silica gel chroma-
tography. The dr and stereochemistry of compounds 8 and 80 were
determined on the basis of 19F NMR and 1H NMR spectral data,
respectively. Removal of the benzyl group in the isomer 8 via hy-
drogenation with Pd(OH)2/C as catalyst yielded the amino alcohol
9 in 86% yield, which was further methylated to provide the
The ligand 1c was prepared according to the reported literature
(Scheme 1).8 Hydrogenolysis of the compound 1c with Pd(OH)2/C
as catalyst produced the debenzylated primary amine alcohol 1d in
78% yield. The N,N-dimethylated derivative 1a was accessed from
the compound 1d by refluxing with HCO2H/HCHO.9 Exposure of the
compound 1d to different alkyl halides with K2CO3/CH3CN as base
system afforded the cyclic tertiary amines 1e, 1f and acyclic tertiary
amine 1b. In addition, treatment of trifluoromethylated primary
amine 48 with HCO2H/HCHO under refluxing condition could
conveniently provide another trifluoromethylated amino alcohol
ligand 2a.
1. LiAlH4, THF;
2. (COCl)2, DMSO,
CF3
OH
CF3
OH
O
CH2Cl2;
+
3. TMSCF3, TBAF(cat.),
THF;
4. TBAF, THF.
N
Bn
N
Bn
N
OMe
HCO2H, HCHO,
H2O, 68%.
H2, Pd(OH)2/C,
Bn
CF3
OH
CF3
OH
CF3
OH
MeOH, 78%
.
8 (27%)
8´ (33%)
7
H2, Pd(OH)2/C,
MeOH, 86%.
Bn2N
H2N
N
1a
H2, Pd(OH)2/C,
MeOH, 80%.
1c
1d
C2H5I, K2CO3,
CH3CN, 84%.
Br(CH2)4Br or
Br(CH2)5Br
CF3
CF3
OH
CF3
OH
CF3
N
H
N
H
OH
R12N
K2CO3, CH3CN.
Et2N
OH
9
9´
1e: R1 = -(CH2)4-(78%);
1b
HCO2H, HCHO,
H2O, 67%.
HCO2H, HCHO,
H2O, 59%.
1f: R1 = -(CH2)5- (85%).
HCO2H, HCHO,
H2O, 71%.
CF3
OH
CF3
OH
CF3
OH
CF3
OH
N
N
H2N
Me2N
2a
4
3a
3b
Scheme 1.
Scheme 3.

X.-H. Xu et al. / Tetrahedron 64 (2008) 7353–7361
7355
Table 1
2.2. Synthesis and evaluation of the trifluoromethylated
amino alcohol ligands for the highly enantioselective addition
of diethylzinc to N-(diphenylphosphinoyl)imine
Reformatsky reaction promoted by various trifluoromethylated amino alcohol
ligands
O
OH
*
O
O
ligand
THF
+
BrZn
Chiral amines are widely used in the synthesis of natural
products and physiologically active substances, in chiral separation,
and in asymmetric synthesis as chiral auxiliaries.14,15 An attractive
and direct access to the chiral amines was the enantioselective
addition of organometallic reagents to imines.16 Among the or-
ganometallic reagents, dialkylzinc reagents are very useful since
organozinc reagents bearing several functional groups could be
easily available,17 and their usage would lead to a lot of poly-
functionalized compounds. Since Soai and co-workers reported
that an ephedrine derivative was used as a chiral ligand in the
addition of diethylzinc to N-(diphenylphosphinoyl)imines,18a
enantioselective alkylations of N-diphenylphosphinoyl arylimines
with dialkylzinc reagents catalyzed by amino alcohols,18 hydroxy-
oxazolines,19 and copper,20 zirconium21 or nickel22 complexes have
been described. Of all the reported chiral amino alcohol ligands, the
conformationally restricted and structurally rigid artificial amino
alcohols generally exhibit higher enantioselectivities than those
simple and flexible analogues. Although a lot of chiral amino al-
cohols possessing different substitution on amino group and car-
bon chain were synthesized and evaluated, no concerned
description was given to the influence of fluorine substitution on
enantioselectivity. As the trifluoromethylated amino alcohol ligand
11 had been proved successful in the enantioselective alkylation of
PhCHO with Et2Zn in our aforementioned description,3h it was
reasonable to use our trifluoromethylated amino alcohol ligand 1f
as the promoter in the enantioselective addition of Et2Zn to imines
(Fig. 3). What is more, the presence of an aromatic ring in the
nitrogen substituent of the amino alcohol ligands seems to be
important to the enantioselectivity. So two types of simple tri-
fluoromethylated amino alcohols featuring a N-benzyl group and
different groups occupying the C-3 position were designed as
ligands to promote the enantioselective addition of Et2Zn to imines
(Fig. 3). The first type of ligands 12a–e has flexible structure, while
the second type of ligands 8 and 80 is conformationally restricted
with the prolinol skeleton.
OEt
Ph
OEt
Ph
H
10
Entry
Ligand
Temp (ꢀC)
Yielda (%)
ee % (config.)b,c
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1c
1d
1e
1f
2a
2b
3a
3b
0
20
40
40
40
40
40
40
40
40
40
40
<5
32
87
89
85
76
88
90
92
82
94
90
n.d.d
n.d.d
83 (R)
86 (R)
39 (R)
49 (R)
82 (R)
76 (R)
58 (R)
49 (R)
82 (R)
74 (S)
9
10
11
12
a
Yield of isolated product after flash chromatography.
Determined by HPLC analysis on a chiral column (ChiralCel OD).
The absolute stereochemistry was assigned by comparison with the reported
b
c
optical rotation.13
d
n.d.¼not determined.
trifluoromethylated pyrrolidine ligand 3a in 67% yield. The isomer
ligand 3b was prepared from the alcohol 80 in 47% total yield over
two steps using the same procedures.
With all the desired trifluoromethylated amino alcohols 1a–f,
2a, b, and 3a, b in hand, the Reformatsky reaction between PhCHO
and BrZnCH2CO2Et was used to evaluate these ligands. The results
are summarized in Table 1. First of all, the temperature was a key for
the Reformatsky reaction. Using the ligand 1a as catalyst, little re-
actant was consumed when the reaction was carried out at 0 ꢀC
(entry 1), while this reaction can generate the desired alcohol 10 in
32% yield at 20 ꢀC (entry 2). The yield could be further improved to
87% when the reaction was performed at 40 ꢀC and the product 10
was provided in 83% ee (entry 3). Compared to the N,N-dimethyl
1,1,1-trifluoromethyl-3-amino-propan-2-ol ligand used in Katagiri
and Uneyama group (80% yield, 81% ee),3i our ligand N,N-dimethyl
1,1,1-trifluoromethyl-3-amino-butan-2-ol 1a gave almost the same
result (87% yield, 83% ee) except that the reaction temperature was
lower (reflux THF vs 40 ꢀC). The ligand 1b with substitution of ethyl
group for methyl group in 1a afforded the better enantioselectivity
(86% ee) and yield (89%) (entry 4). This enantioselectivity was as
high as the best record, which has been attained. However, the
enantioselectivity decreased significantly when the methyl or ethyl
groups in ligand 1a or 1b were replaced with the benzyl groups in
ligand 1c (entry 5), which demonstrated that substitution of large
steric hindrance at amino group was disadvantageous for the
enantioselectivity. The ligand 1d with no protecting group on
amino group only provide the product in 49% ee although the yield
did not change significantly (76%) (entry 6). Interestingly, the
enantioselectivities were obtained in 82 and 76% ee, respectively, if
the ligands 1e and 1f were utilized (entries 7 and 8). The re-
placement of methyl at C-3 position with large steric iso-propyl or
sec-butyl would resulted in the significant decrease in enantiose-
lectivities (entries 9 and 10), which unambiguously indicated that
the substitution group at C-3 position played an important role on
the enantioselectivity (entries 9 and 10 vs entry 3) and the large
steric group at C-3 position was unbeneficial. To our delight, usage
of the ligands 3a, b, which featured that C-3 position and amino
group were jointed into the pyrrolidine ring, also delivered the
product 10 in 82 and 74% ee, respectively (entries 11 and 12). The
opposite configurations of the product 10 were induced by the li-
gands 3a and 3b, which showed that the chirality resulted from the
configurations of the carbon bonded to the hydroxyl group.
R1
R2
R
N
CF3
OH
R
CF3
N
Bn
Bn NH OH
OH
11: R = H;
1f: R = Me.
12a: R = Me;
12b: R = i-Pr;
12c: R = s-Bu;
12d: R = t-Bu;
12e: R = Ph.
8: R1 = CF3, R2 = H;
8´: R1 = H, R2 = CF3;
Figure 3. Trifluoromethylated amino alcohol ligands for the addition of diethylzinc to
imines.
The synthesis of the ligands 12a, 12b, and 12e was accomplished
in high yield from the aforementioned intermediates 1d, 4, and 138
via treatment with BnBr/K2CO3 in CH3CN, respectively (Scheme 4).
Ligands 12c and 12d were prepared beginning from the readily
available L-isoleucine 5 and L-tert-leucine 14, respectively. Thus,
treatment of the compound 5 with BnBr/K2CO3/NaOH produced the
benzyl ester 15 in 68% yield. Reduction of the compound 15 with
LiAlH4, followed by Swern oxidation and trifluoromethylation
provided the diastereoisomers 17 and 170 in a ratio of 6.3:1. The two
isomers 17 and 170 were easily separated on silica gel chromatog-
raphy and the stereochemistry was also determined on the basis of
1H NMR. Hydrogenolysis of the major isomer 17 with Pd(OH)2/C as
catalyst gave the primary amine intermediate, which was then
subjected to treatment with BnBr/K2CO3 to afford the ligand 12c in

7356
X.-H. Xu et al. / Tetrahedron 64 (2008) 7353–7361
58% total yield. By the same producers, the ligand 12d was prepared
for the titled reaction (entries 6–9). Ligands 12b, 12c, 12d, and 12e
catalyzed the reaction in excellent enantioselectivities of 94, 94, 95,
and 90% ee, respectively. These results indicated that the enantio-
selectivity was not very sensitive to the steric hindrance of the
substituent group at the C-3 position.
from
L
-tert-leucine 14 through the intermediate benzyl ester 16.23
BnBr, K2CO3,
CH3CN.
R
CF3
OH
CF3
OH
R
BnHN
H2N
3. Conclusion
12a: R = Me (76%);
12b: R = i-Pr (74%)
12e: R = Ph (78%)
1d: R = Me;
4: R = i-Pr;
13: R = Ph.
A set of trifluoromethylated amino alcohol ligands have been
conveniently prepared from commercially available amino acids,
and were successfully applied in the enantioselective Reformatsky
reaction and enantioselective addition of diethylzinc to N-(diphe-
nylphosphinoyl)imine, respectively. Usage of the ligand 1b afforded
the good enantioselectivity for Reformatsky reaction with up to 86%
ee. Ligands 12b, 12c, and 12d gave excellent enantioselectivity for
the addition of diethylzinc to N-(diphenylphosphinoyl)imine in 94,
94, and 95% ee, respectively. These successful examples using
trifluoromethylated amino alcohol ligands to promote the title
reactions illustrated that a large family of chiral compounds
containing a trifluoromethylated amino alcohol moiety had the
potential to be developed as useful ligands. Further studies to use
these trifluoromethylated amino alcohol ligands and develop novel
trifluoromethylated ligands in other asymmetric catalytic reactions
are currently in progress in our laboratory.
BnBr, K2CO3/NaOH,
EtOH/H2O;
O
R
O
R
H2N
OH
Bn2N
OBn
5: R = s-Bu;
15: R = s-Bu (68%);
14: R = t-Bu.
16: R = t-Bu.
1. LiAlH4;
R
CF3
OH
R
CF3
OH
2. (COCl)2, DMSO;
+
3. TMSCF3,
TBAF(cat.);
Bn2N
Bn2N
17: R = s-Bu (49%); 17´: R = s-Bu (8%);
4. TBAF.
18: R = t-Bu (53%). 18´: R = t-Bu (6%).
1. H2, Pd(OH)2/C, MeOH;
2. BnBr, K2CO3, CH3CN.
R
CF3
OH
BnHN
12c: R = s-Bu (58%);
12d: R = t-Bu (52%).
Scheme 4.
4. Experimental
Then, the trifluoromethylated amino alcohol ligands, 1f, 8, 80,
and 12a–e were evaluated for the addition of diethylzinc to N,N-
diphenylphosphinoyl benzalimine 19. The results are summarized
in Table 2. The piperidinyl derivative 1f showed a decrease of the
enantioselectivity compared to ligand 12a (entries 1 and 2), from
which it could be concluded that the aryl substituent in ligands 12a
had an obvious effect on the enantioselectivity of this reaction. The
possibility of using a substoichiometric amount of the ligand was
then investigated. The enantioselectivity dropped down from 92 to
87% ee when the amount of ligand 12a was reduced from 1.0 to
0.5 equiv (entries 2 and 3). The rigid ligand 8 exhibited lower
enantioselectivity than the flexible ligand 12a (entries 3 and 4). The
difference of chirality of the carbon bonded to the hydroxyl group
between compounds 8 and 80 also resulted in different configura-
tions of the product 20 (compare entries 4 and 5). With the dif-
ferent substituent groups at the C-3 position, all the other ligands
12b–e were efficient and high enantioselectivities were obtained
4.1. General information
All reagents were used as received from commercial sources,
unless specified otherwise, or prepared as described in the litera-
ture. Reactions requiring anhydrous conditions were performed in
vacuum heat-dried glassware under nitrogen atmosphere. Reaction
mixtures were stirred magnetically. 1H NMR and 13C NMR spectra
were recorded on a Bruker AM300 spectrometer. 19F NMR spectra
was recorded on a Bruker AM300 spectrometer (FCCl3 as outside
standard and low field is positive). Chemical shifts (d) are reported
in parts per million and coupling constants (J) are in hertz. The
following abbreviations were used to explain the multiplicities:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet. All the
melting points and optical rotations are uncorrected. The enan-
tiomeric excesses were determined by HPLC analysis on Chiralpak
OD column.
4.2. Synthesis of chiral ligands for the enantioselective
Reformatsky reactions
Table 2
Addition of diethylzinc to N-(diphenylphosphinoyl)imine promoted by trifluoro-
methylated amino alcohol ligands
4.2.1. (2S,3S)-3-(Dimethylamino)-1,1,1-trifluoro-2-butanol (1a)
A
mixture of (2S,3S)-3-amino-1,1,1-trifluoro-2-butanol 1d
O
P
O
P
Ph
Ph
Ph
Ph
(572 mg, 4.00 mmol), formic acid (2.00 mL), and 37% aqueous
formaldehyde (2.00 mL) was heated at reflux overnight. The re-
action was then cooled to room temperature rendered alkaline with
20% aqueous NaOH until Dragendorff test was negative, then
extracted with ethyl ether. The combined organic phase was
washed with brine, dried over NaSO4, and concentrated in vacuo.
The residue was purified by silica gel flash column chromatography
N
HN
ligand
+
Zn
Et2
*
toluene
Ph
H
Ph
20
19
Entry
Ligand
Ligand (equiv)
Yielda
ee %b (config.c)
1
2
3
4
5
6
7
8
9
1f
1.0
1.0
0.5
0.5
0.5
1.0
1.0
1.0
1.0
92
89
90
79
87
90
91
92
95
87 (R)
92 (R)
87 (R)
70 (R)
65 (S)
94 (R)
94 (R)
95 (R)
90 (R)
12a
12a
8
(CH2Cl2/MeOH¼15:1) to give compound 1a (465 mg, 68%) as
28
a white solid: mp 178–180 ꢀC; [
a
]
D
þ25.7 (c 1.08, MeOH); 1H NMR
80
(300 MHz, MeOH-d4)
d
4.35 (dq, J¼7.8, 1.8 Hz, 1H), 3.26 (dq, J¼6.9,
12b
12c
12d
12e
1.8 Hz, 1H), 2.56 (s, 6H), 1.25 (d, J¼7.8 Hz, 3H); 13C NMR (75.5 MHz,
MeOH-d4)
d
126.7 (q, JC–F¼282.7 Hz), 70.1 (q, JC–F¼29.1 Hz), 59.3,
41.2, 8.6; 19F NMR (282 MHz, MeOH-d4)
d
ꢁ79.8 (d, J¼8.5 Hz, 3F);
MS (ESI) m/z 172.1 (MþH)þ; IR (thin film) 3175, 2963, 2702, 1465,
1279, 1161, 1059, 904 cmꢁ1. Anal. Calcd for C6H12F3NO: C, 42.10; H,
7.07; N, 8.18. Found: C, 41.67; H, 6.82; N, 7.93.
a
Yield of isolated product after flash chromatography.
Determined by HPLC analysis on a chiral column (ChiralCel OD).
Configuration was determined as described in Ref. 18d.
b
c

X.-H. Xu et al. / Tetrahedron 64 (2008) 7353–7361
7357
4.2.2. (2S,3S)-3-(Diethylamino)-1,1,1-trifluoro-2-butanol (1b)
1085, 944, 703 cmꢁ1
200.1265. Found: 200.1257.
;
HRMS calcd for C8H17F3NO (MþH)þ:
Ethyl iodide (0.53 mL, 6.60 mmol), potassium carbonate
(1037 mg, 7.50 mmol), and 1d (429 mg, 3.00 mmol) were added to
acetonitrile (20 mL) and heated at reflux for 24 h. The reaction was
then cooled to room temperature, filtered, and concentrated in
vacuo. The residue was purified by silica gel flash column chro-
4.2.6. N,N-Dimethyl-
L-isoleucine methyl ester (6)
A suspension of -isoleucine (3.933 g, 30.00 mmol) in methanol
L
(60 mL) was cooled to 0 ꢀC. Thionyl chloride (2.40 mL, 33.00 mmol)
was added dropwise and then the cooling bath was removed. The
clear mixture was left at room temperature for 1 day. The solvent
was then removed by rotary evaporation and the crude product
(4.998 g, 92%) was crystallized from isopropanol/hexane. A mixture
of the above methyl ester hydrochloride (4.998 g, 27.60 mmol), 37%
aqueous formaldehyde (16.47 mL, 220.80 mmol), and 10% Pd/C
(2400 mg) was stirred in ethanol (450 mL) under hydrogen at room
temperature overnight. The filtrate was evaporated, dissolved in
chloroform, washed with 2 M NaOH, dried over NaSO4, and con-
centrated in vacuo. The residue was purified by silica gel flash col-
matography (CH2Cl2/MeOH¼25:1) to give compound 1b (502 mg,
27
84%) as a clear oil: [
a]
þ50.7 (c 1.02, CHCl3); 1H NMR (300 MHz,
D
CDCl3)
d
3.87 (dq, J¼8.1, 5.1 Hz, 1H), 3.48 (s, 1H), 3.12 (m, 1H), 2.55
(m, 4H), 1.15 (dd, J¼7.2, 1.5 Hz, 3H), 1.04 (t, J¼7.2 Hz, 6H); 13C NMR
(75.5 MHz, CDCl3)
d
125.2 (q, JC–F¼284.8 Hz), 70.2 (q, JC–F¼29.1 Hz),
54.8, 43.9, 13.3, 9.7; 19F NMR (282 MHz, CDCl3)
d
ꢁ74.2 (d, J¼8.5 Hz,
3F); MS (ESI) m/z 200.2 (MþH)þ; IR (thin film) 3421, 2977, 2826,
1458, 1388, 1274, 1166, 885 cmꢁ1; HRMS calcd for C8H17F3NO
(MþH)þ: 200.1266. Found: 200.1257.
4.2.3. (2S,3S)-3-(1-Pyrrolidinyl)-1,1,1-trifluoro-2-butanol (1e)
1,4-Dibromobutane (0.39 mL, 3.30 mmol), potassium carbonate
(1037 mg, 7.50 mmol), and 1d (429 mg, 3.00 mmol) were added to
acetonitrile (20 mL) and heated at reflux for 24 h. The reaction was
then cooled to room temperature, filtered, and concentrated in
vacuo. The residue was purified by silica gel flash column chro-
umn chromatography (petroleum ether/ethyl acetate¼3:2) to give
27
compound 6 (4.014 g, 77% for two steps) as a clear oil: [
a]
ꢁ28.0 (c
D
1.01, CHCl3); 1H NMR (300 MHz, CDCl3)
J¼9.6 Hz,1H), 2.29 (s, 6H),1.82 (m,1H),1.66 (m,1H),1.14 (m,1H), 0.91
d 3.70 (s, 3H), 2.87 (d,
(m, 6H); 13C NMR (75.5 MHz, CDCl3)
d 171.9, 72.4, 50.2, 41.4, 33.1,
25.0,15.4,10.3; MS (ESI) m/z 174.2 (MþH)þ; IR (thin film) 2967, 2789,
1733, 1457, 1258, 1150, 996, 775 cmꢁ1. Anal. Calcd for C9H19NO2: C,
62.39; H, 11.05; N, 8.08. Found: C, 62.27; H, 10.85; N, 7.95.
matography (CH2Cl2/MeOH¼20:1) to give compound 1e (461 mg,
24
78%) as a white solid: mp 55–57 ꢀC; [
a]
þ33.7 (c 0.66, CHCl3); 1H
D
NMR (300 MHz, CDCl3)
d
4.79 (s, 1H), 4.13 (dq, J¼8.1, 2.4 Hz, 1H),
2.67 (m, 5H), 1.83 (m, 4H), 1.21 (d, J¼6.6 Hz, 3H); 13C NMR
4.2.7. (2S,3S)-3-(Dimethylamino)-1,1,1-trifluoro-4-methyl-2-
hexanol (2b) and (2R,3S)-3-(dimethylamino)-1,1,1-trifluoro-4-
methyl-2-hexanol (2b0)
(75.5 MHz, CDCl3)
d
125.0 (q, JC–F¼283.3 Hz), 69.9 (q, JC–F¼28.2 Hz),
59.9, 52.1, 22.9, 12.5; 19F NMR (282 MHz, CDCl3)
d
ꢁ75.5 (d,
J¼7.9 Hz, 3F); MS (ESI) m/z 198.1 (MþH)þ; IR (thin film) 2973, 2831,
1771, 1462, 1278, 1131, 1027, 900 cmꢁ1. Anal. Calcd for C8H14F3NO: C,
48.73; H, 7.16; N, 7.10. Found: C, 48.74; H, 7.11; N, 6.86.
To a suspension of lithium aluminum hydride (1.020 g,
27.50 mmol) in dry THF (32 mL) was added compound 6 (2.162 g,
12.50 mmol) in dry THF (10 mL) at 0 ꢀC, and the mixture was
warmed to room temperature. After 3 h of being stirred, the mixture
was cooled to 0 ꢀC, excess hydride was quenched with EtOAc, and
then a 10% NaOH aqueous solution was slowly added. Finally, the
mixture was filtered and washed with EtOAc. The filtrates were
concentrated in vacuo to give the crude reduction product (1.598 g,
88%). The crude product was subjected to the next step without
purification. To a stirred solution of oxalyl chloride (1.32 mL,
15.13 mmol) in dry CH2Cl2 (32 mL) cooled to ꢁ78 ꢀC under nitrogen
was added dropwise of DMSO (2.24 mL, 31.47 mmol). After 15 min,
a solution of the above reduction product (1.598 g, 11.01 mmol) in
dry CH2Cl2 (32 mL) was added and the mixture was stirred for
30 min at ꢁ78 ꢀC before addition of triethylamine (4.48 mL,
32.14 mmol). Then, the reaction was allowed to reach the room
temperature under stirring for 45 min and the mixture quenched
with water. The aqueous phase was extracted with CH2C12, and the
combined organic layers were washed with saturated aqueous
NaHCO3 and brine. The organic phase was dried (MgSO4) and then
concentrated to give the crude oxidation product (1.411 g, 79% for
two steps). The crude product was subjected to the next step
without purification. To a solution of TMSCF3 (2.19 mL, 14.79 mmol)
in dry THF (30 mL) were added a solution of the above oxidation
product (1.411 g, 9.86 mmol) in dry THF (20 mL) and TBAF (0.50 mL,
1.0 M in THF, 0.50 mmol) cooled to 0 ꢀC under nitrogen. The mixture
was stirred at that temperature until the reaction was complete.
Subsequently, TBAF (2.00 mL, 1.0 M in THF, 2.00 mmol) was added,
the reaction mixture was stirred at room temperature for 1 h, and
quenched by addition of aqueous saturated NH4Cl solution. The THF
was removed and the aqueous phase was extracted with diethyl
ether. The combined organic phase was washed with brine, dried
over NaSO4, and concentrated in vacuo. The residue was purified by
silica gel flash column chromatography (petroleum ether/ethyl
4.2.4. (2S,3S)-3-(1-Piperidinyl)-1,1,1-trifluoro-2-butanol (1f)
1,5-Dibromopentane (0.45 mL, 3.30 mmol), potassium carbon-
ate (1037 mg, 7.50 mmol), and 1d (429 mg, 3.00 mmol) were added
to acetonitrile (20 mL) and heated at reflux for 24 h. The reaction
was then cooled to room temperature, filtered, and concentrated in
vacuo. The residue was purified by silica gel flash column chro-
matography (CH2Cl2/MeOH¼25:1) to give compound 1f (538 mg,
27
85%) as a white solid: mp 87–89 ꢀC; [
a
]
þ21.8 (c 1.12, CHCl3); 1H
D
NMR (300 MHz, CDCl3)
d
3.99 (dq, J¼8.1, 1.5 Hz, 1H), 3.79 (s, 1H),
2.90 (dq, J¼6.9, 4.5 Hz, 1H), 2.61 (m, 2H), 2.47 (m, 2H), 1.59 (m, 4H),
1.44 (m, 2H), 1.15 (dd, J¼7.5, 1.5 Hz, 3H); 13C NMR (75.5 MHz, CDCl3)
d
125.2 (q, JC–F¼282.5 Hz), 69.6 (q, JC–F¼28.9 Hz), 59.4, 50.9, 26.2,
24.3, 9.4; 19F NMR (282 MHz, CDCl3)
d
ꢁ75.1 (d, J¼7.9 Hz, 3F); MS
(ESI) m/z 212.4 (MþH)þ; IR (thin film) 2940, 2820, 1444, 1260, 1159,
1039, 883, 754 cmꢁ1. Anal. Calcd for C9H16F3NO: C, 51.18; H, 7.64; N,
6.63. Found: C, 50.84; H, 7.52; N, 6.49.
4.2.5. (2S,3S)-3-(Dimethylamino)-1,1,1-trifluoro-4-methyl-2-
pentanol (2a)
A mixture of compound 4 (684 mg, 4.00 mmol), formic acid
(2 mL), and 37% aqueous formaldehyde (2 mL) was heated at reflux
overnight. The reaction was then cooled to room temperature
rendered alkaline with 20% aqueous NaOH until Dragendorff test
was negative, then extracted with ethyl ether. The combined
organic phase was washed with brine, dried over NaSO4, and
concentrated in vacuo. The residue was purified by silica gel flash
column chromatography (petroleum ether/ethyl acetate¼10:1) to
28
give compound 2a (565 mg, 71%) as a clear oil: [
a
]
þ9.1 (c 0.98,
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
4.14 (s, 1H), 3.95 (dq, J¼7.8,
1.5 Hz, 1H), 2.49 (s, 6H), 2.44 (d, J¼4.5 Hz, 1H), 2.18 (m, 1H), 1.05 (d,
J¼6.3 Hz, 3H), 0.98 (d, J¼6.3 Hz, 3H); 13C NMR (75.5 MHz, CDCl3)
acetate¼20:1) to give compounds 2b (984 mg, 37% for four steps)
26
d
125.4 (q, JC–F¼284.8 Hz), 72.2, 67.9 (q, JC–F¼29.1 Hz), 42.9, 27.6,
and 2b0 (180 mg, 7% for four steps) as clear oils. Compound 2b: [
a]
D
22.7, 20.8; 19F NMR (282 MHz, CDCl3)
d
ꢁ72.6 (d, J¼9.0 Hz, 3F); MS
þ8.2 (c 1.05, CHCl3); 1H NMR (300 MHz, CDCl3)
d 4.04 (s, 1H), 3.97
(dq, J¼7.2, 4.8 Hz, 1H), 2.57 (dd, J¼10.8, 4.8 Hz, 1H), 2.46 (s, 6H), 1.93
(ESI) m/z 200.3 (MþH)þ; IR (thin film) 3423, 2962, 2784,1463,1295,

7358
X.-H. Xu et al. / Tetrahedron 64 (2008) 7353–7361
(m,1H), 1.62 (m,1H), 1.12 (m, 1H), 0.93 (m, 6H); 13C NMR (75.5 MHz,
CDCl3)
125.4 (q, JC–F¼283.7 Hz), 69.7, 68.0 (q, JC–F¼29.1 Hz), 42.8,
organic phase was washed with brine, dried over NaSO4, and
concentrated in vacuo. The residue was purified by silica gel flash
d
33.3, 27.9,16.3,10.6; 19F NMR (282 MHz, CDCl3)
d
ꢁ72.8 (d, J¼7.1 Hz,
column chromatography (CH2Cl2/MeOH¼10:1) to give compound
23
3F); MS (ESI) m/z 214.2 (MþH)þ; IR (thin film) 3438, 2969, 2783,
3a (246 mg, 67%) as a clear oil: [
a
]
ꢁ19.6 (c 1.10, CHCl3); 1H NMR
D
1460, 1271, 1128, 1083, 703 cmꢁ1. Anal. Calcd for C9H18F3NO: C,
(300 MHz, CDCl3)
d
4.38 (s, 1H), 4.01 (dq, J¼7.8, 2.1 Hz, 1H), 3.12 (m,
50.69; H, 8.51; N, 6.57. Found: C, 51.06; H, 8.81; N, 6.20. Compound
1H), 2.56 (m, 1H), 2.39 (s, 3H), 2.29 (m, 1H), 2.10 (m, 1H), 1.75 (m,
26
2b0: [
a
]
þ10.6 (c 0.50, CHCl3); 1H NMR (300 MHz, CDCl3)
d
5.43 (s,
3H); 13C NMR (75.5 MHz, CDCl3)
d
125.0 (q, JC–F¼282.5 Hz), 68.0 (q,
D
1H), 3.83 (dq, J¼7.2, 5.7 Hz, 1H), 2.61 (dd, J¼5.7, 4.5 Hz, 1H), 2.41 (s,
JC–F¼29.6 Hz), 65.2, 56.7, 40.8, 23.7, 23.6; 19F NMR (282 MHz, CDCl3)
6H), 1.78 (m, 1H), 1.44 (m, 1H), 1.23 (m, 1H), 0.94 (m, 6H); 13C NMR
d
ꢁ76.0 (d, J¼7.6 Hz, 3F); MS (ESI) m/z 184.1 (MþH)þ; IR (thin film)
(75.5 MHz, CDCl3)
d
125.5 (q, JC–F¼281.8 Hz), 66.2 (q, JC–F¼30.4 Hz),
3102, 2955, 1459, 1276, 1137, 1035, 835, 684 cmꢁ1; HRMS calcd for
64.9, 42.5, 33.8, 28.1,15.8,12.0; 19F NMR (282 MHz, CDCl3)
d
ꢁ77.0 (d,
C7H10F3N (MꢁH2O)þ: 165.0765. Found: 165.0769.
J¼7.1 Hz, 3F); MS (ESI) m/z 214.3 (MþH)þ; IR (thin film) 3428, 2969,
2802, 1465, 1273, 1165, 1133, 692 cmꢁ1; HRMS calcd for C9H19F3NO
(MþH)þ: 214.1411. Found: 214.1413.
4.2.11. (R)-2-[(S)-2-Pyrrolidinyl]-1,1,1-trifluoro-2-ethanol (90)
Pd(OH)2/C (20%, 600 mg) was added in one portion to a solution
of the appropriate compound 80 (1.036 g, 4.00 mmol) in methanol
(32 mL). The mixture was stirred under hydrogen and the reaction
was monitored by TLC. After completion of the reaction, the catalyst
was removed by filtration, washed with methanol, and then con-
centrated in vacuo. The residue was purified by silica gel flash
4.2.8. (S)-2-[(S)-1-Benzyl-2-pyrrolidinyl]-1,1,1-trifluoro-2-ethanol
(8) and (R)-2-[(S)-1-benzyl-2-pyrrolidinyl]-1,1,1-trifluoro-2-
ethanol (80)
By use of the same procedures as that described for 2b and 2b0,
compound 7 (9.820 g, 44.81 mmol) was converted to compound 8
column chromatography (CH2Cl2/MeOH¼8:1) to give compound 90
24
(3.126 g, 27% for four steps) and compound 80 (3.785 g, 33% for four
(541 mg, 80%) as a white solid: mp 86–88 ꢀC; [
a]
ꢁ5.7 (c 1.04,
D
27
steps) as clear oils. Compound 8: [
NMR (300 MHz, CDCl3)
a
]
ꢁ67.3 (c 0.51, CHCl3); 1H
MeOH); 1H NMR (300 MHz, MeOH-d4)
3.26 (m, 1H), 2.97 (m, 1H), 2.85 (m, 1H), 1.94 (m, 1H), 1.82 (m, 2H),
d
3.82 (dq, J¼7.5, 5.1 Hz, 1H),
D
d
7.29 (m, 5H), 4.11 (dq, J¼7.8, 2.4 Hz, 1H),
3.96 (d, J¼12.9 Hz, 1H), 3.49 (s, 1H), 3.42 (d, J¼12.9 Hz, 1H), 3.00 (m,
1H), 2.91 (dt, J¼7.2, 2.1 Hz, 1H), 2.34 (dd, J¼13.8, 9.3 Hz, 1H), 2.10
1.66 (m, 1H); 13C NMR (75.5 MHz, MeOH-d4)
d 126.7 (q,
JC–F¼282.3 Hz), 72.2 (q, JC–F¼30.6 Hz), 58.3, 47.1, 29.6, 26.1; 19F NMR
(m, 1H), 1.79 (m, 3H); 13C NMR (75.5 MHz, CDCl3)
d
137.9, 128.8,
(282 MHz, MeOH-d4)
d
ꢁ78.9 (d, J¼8.7 Hz, 3F); MS (ESI) m/z 170.0
128.4, 127.4, 124.9 (q, JC–F¼281.2 Hz), 68.2 (q, JC–F¼29.7 Hz), 62.6,
(MþH)þ; IR (thin film) 3273, 2891, 2530, 1368, 1256, 1163, 1083,
849 cmꢁ1. Anal. Calcd for C13H16F3NO: C, 42.61; H, 5.96; N, 8.28.
Found: C, 42.46; H, 5.94; N, 8.20.
58.1, 53.6, 23.9, 23.3; 19F NMR (282 MHz, CDCl3)
d
ꢁ75.4 (d,
J¼6.8 Hz, 3F); MS (ESI) m/z 260.2 (MþH)þ; IR (thin film) 2970, 2808,
1741, 1456, 1274, 1138, 836, 701 cmꢁ1. Anal. Calcd for C13H16F3NO: C,
60.22; H, 6.22; N, 5.40. Found: C, 60.22; H, 6.35; N, 5.23. Compound
4.2.12. (R)-2-[(S)-1-Benzyl-2-pyrrolidinyl]-1,1,1-trifluoro-2-
ethanol (3b)
27
80: [
a
]
ꢁ10.8 (c 0.91, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.32 (m,
D
5H), 5.23 (s, 1H), 4.04 (d, J¼13.2 Hz, 1H), 3.60 (dq, J¼7.8, 2.7 Hz, 1H),
3.59 (d, J¼12.6 Hz, 1H), 3.29 (dt, J¼13.5, 3.0 Hz, 1H), 2.93 (m, 1H),
2.52 (m, 1H), 2.15 (m, 1H), 1.77 (m, 3H); 13C NMR (75.5 MHz, CDCl3)
A mixture of compound 90 (338 mg, 2.00 mmol), formic acid
(2.00 mL), and 37% aqueous formaldehyde (2.00 mL) was heated at
reflux overnight. The reaction was then cooled to room temperature
rendered alkaline with 20% aqueous NaOH until Dragendorff test
was negative, then extracted with ethyl ether. The combined organic
phasewas washed with brine, dried over NaSO4, and concentratedin
vacuo. The residue was purified by silica gel flash column chroma-
d
138.5, 128.6, 128.4, 127.3, 125.2 (q, JC–F¼285.5 Hz), 72.0 (q, JC–F¼
29.1 Hz), 61.3 (q, JC–F¼2.9 Hz), 60.4, 54.1, 32.5, 24.5; 19F NMR
(282 MHz, CDCl3)
d
ꢁ78.2 (d, J¼6.5 Hz, 3F); MS (ESI) m/z 260.1
(MþH)þ; IR (thin film) 2970, 2822, 1455, 1280, 1164, 1139, 875,
704 cmꢁ1. Anal. Calcd for C13H16F3NO: C, 60.22; H, 6.22; N, 5.40.
Found: C, 60.33; H, 6.20; N, 5.24.
tography (CH2Cl2/MeOH¼10:1) to give compound 3b (217 mg, 59%)
23
as a white solid: mp 44–46 ꢀC; [
a
]
D
þ16.4 (c 1.09, CHCl3); 1H NMR
(300 MHz, CDCl3)
d
4.70 (s, 1H), 3.53 (dq, J¼7.5, 3.0 Hz, 1H), 3.16 (m,
4.2.9. (S)-2-[(S)-2-Pyrrolidinyl]-1,1,1-trifluoro-2-ethanol (9)
1H), 2.92 (m, 1H), 2.51 (m, 4H), 2.14 (m, 1H), 1.75 (m, 3H); 13C NMR
(75.5 MHz, CDCl3)
125.1 (q, JC–F¼282.4 Hz), 72.1 (q, JC–F¼30.5 Hz),
Pd(OH)2/C (20%, 600 mg) was added in one portion to a solution
of the appropriate compound 8 (1.036 g, 4.00 mmol) in methanol
(32 mL). The mixture was stirred under hydrogen and the reaction
was monitored by TLC. After completion of the reaction, the catalyst
was removed by filtration, washed with methanol, and then con-
centrated in vacuo. The residue was purified by silica gel flash
d
62.6, 57.3, 43.0, 32.4, 24.8; 19F NMR (282 MHz, CDCl3)
d
ꢁ78.0 (d,
J¼7.6 Hz, 3F); MS (ESI) m/z 184.1 (MþH)þ; IR (thin film) 2855, 1466,
1274, 1165, 1118, 1033, 846, 697 cmꢁ1; HRMS calcd for C7H10F3N
(MꢁH2O)þ: 165.0765. Found: 165.0764.
column chromatography (CH2Cl2/MeOH¼8:1) to give compound 9
4.3. General procedure for asymmetric Reformatsky reactions
25
(578 mg, 86%) as a white solid: mp 106–108 ꢀC; [
a
]
ꢁ22.2 (c 0.93,
D
MeOH); 1H NMR (300 MHz, MeOH-d4)
d
4.03 (dq, J¼7.5, 4.5 Hz, 1H),
4.3.1. Preparation of Reformatsky reagent
3.28 (m, 1H), 3.05 (m, 1H), 2.86 (m, 1H), 1.84 (m, 4H); 13C NMR
A flame dried three-necked flask fitted with a reflux condenser
and septum was charged with zinc dust (1.260 g, 19.27 mmol),
TMSCl (0.30 mL, 2.40 mmol), and THF (7.70 mL), then heated to
reflux with stirring under nitrogen for 15 min. The flask was then
removed from the heat and ethyl bromoacetate (1.97 mL,
17.70 mmol) in dry THF (7.70 mL) was added via syringe at such
a rate as to maintain gentle reflux. Stirring was resumed for 5 min
then stopped and the suspension allowed to settle leaving a green
solution of the Reformatsky reagent.
(75.5 MHz, MeOH-d4)
d
126.6 (q, JC–F¼282.0 Hz), 71.6 (q,
JC–F¼31.0 Hz), 59.1, 47.3, 26.9, 26.1; 19F NMR (282 MHz, MeOH-d4)
d
ꢁ78.5 (d, J¼7.9 Hz, 3F); MS (ESI) m/z 170.1 (MþH)þ; IR (thin film)
3311, 2878, 2567, 1357, 1256, 1169, 1082, 847 cmꢁ1; HRMS calcd for
C6H9F3NO (MꢁH)þ: 168.0636. Found: 168.0644.
4.2.10. (S)-2-[(S)-1-Methyl-2-pyrrolidinyl]-1,1,1-trifluoro-2-
ethanol (3a)
A mixture of compound 9 (338 mg, 2.00 mmol), formic acid
(2.00 mL), and 37% aqueous formaldehyde (2.00 mL) was heated at
reflux overnight. The reaction was then cooled to room tempera-
ture rendered alkaline with 20% aqueous NaOH until Dragendorff
test was negative, then extracted with ethyl ether. The combined
4.3.2. Reformatsky reaction, representative procedure
The ligand (0.48 mmol) was dissolved in THF (1.00 mL) and
stirred under nitrogen at 40 ꢀC. A solution of the Reformatsky re-
agent (1.44 mL, 1.44 mmol) was added by syringe and stirred for

X.-H. Xu et al. / Tetrahedron 64 (2008) 7353–7361
7359
10 min. Benzaldehyde (424 mg, 0.40 mmol) in dry THF (2.40 mL)
was then added in one portion and the reaction was stirred for 24 h.
The reaction was quenched by the addition of saturated, aqueous
NH4Cl (2 mL) and extracted three times with ethyl acetate; the
combined organic layers were then washed with saturated sodium
bicarbonate solution and brine, dried over NaSO4, then concen-
trated in vacuo. The residue was purified by silica gel flash column
chromatography (petroleum ether/ethyl acetate¼10:1) to give
ethyl (S)-3-hydroxy-3-phenylpropanoate 10 as a colorless oil. The
ee was determined HPLC analysis (Chiralpak OD column, hexane/
propan-2-ol¼90:10; flow rate 0.7 mL minꢁ1; rt, UV detection at
214 nm).
1455, 1268, 1162, 927, 699 cmꢁ1. Anal. Calcd for C16H16F3NO: C,
65.08; H, 5.46; N, 4.74. Found: C, 65.10; H, 5.51; N, 4.82.
4.4.4. N,N-Dibenzyl-
L
-isoleucine benzyl ester (15)
-isoleucine 5 (3.933 g, 30.00 mmol)
To a refluxing suspension of
L
was added a solution of K2CO3 (6.996 g, 50.40 mmol) and NaOH
(2.016 g, 50.40 mmol) in H2O/MeOH (36 mL, 1:1) followed by BnBr
(10.68 mL, 90.00 mmol). Stirring under reflux was continued for 1 h.
The cooled mixture was extracted with Et2O. The combined Et2O
extracts were washed with brine, dried over NaSO4, and concen-
trated in vacuo. The residue was purified by silica gel flash column
chromatography (petroleum ether/ethyl acetate¼50:1) to give
27
compound 15 (8.184 g, 68%) as a clear oil: [
a
]
ꢁ93.1 (c 1.10, CHCl3);
D
4.4. Synthesis of chiral ligands for the enantioselective
addition of diethylzinc to N-(diphenylphosphinoyl)imine
1H NMR (300 MHz, CDCl3)
d
7.33 (m, 15H), 5.30 (d, J¼12.0 Hz, 1H),
5.17 (d, J¼12.0 Hz, 1H), 3.97 (d, J¼13.8 Hz, 2H), 3.28 (d, J¼13.8 Hz,
2H), 3.02 (d, J¼10.8 Hz, 1H), 1.96 (m, 2H), 1.08 (m, 1H), 0.74 (m, 6H);
4.4.1. (2S,3S)-3-Benzylamino-1,1,1-trifluoro-2-butanol (12a)
13C NMR (75.5 MHz, CDCl3)
d 171.7, 139.4, 136.1, 128.8, 128.6, 128.4,
Benzyl bromide (0.24 mL, 2.00 mmol), potassium carbonate
(305 mg, 2.20 mmol), and 1d (286 mg, 2.00 mmol) were added to
acetonitrile (6 mL) and stirred overnight. The reaction was then
filtered and concentrated in vacuo. The residue was purified by
silica gel flash column chromatography (petroleum ether/ethyl
128.2,128.1,126.8, 66.3, 65.6, 54.6, 33.0, 24.6,15.4,10.0; MS (ESI) m/z
402.2 (MþH)þ, 424.2 (MþNa)þ; IR (thin film) 3065, 2965,1729,1455,
1139, 968, 746, 697 cmꢁ1; HRMS calcd for C27H32NO2 (MþH)þ:
402.2419. Found: 402.2428.
acetate¼3:1) to give compound 12a (354 mg, 76%) as a white solid:
4.4.5. (2S,3S)-3-(Dibenzylamino)-1,1,1-trifluoro-4-methyl-2-
hexanol (17) and (2R,3S)-3-(dibenzylamino)-1,1,1-trifluoro-4-
methyl-2-hexanol (170)
23
mp 67–69 ꢀC; [
a
]
þ42.0 (c 1.12, CHCl3); 1H NMR (300 MHz, CDCl3)
D
d
7.33 (m, 5H), 3.91 (dq, J¼8.1, 4.5 Hz, 1H), 3.90 (d, J¼12.9 Hz, 1H),
3.73 (d, J¼13.2 Hz, 1H), 3.04 (m, 1H), 2.79 (s, 2H), 1.23 (dq, J¼6.9,
By use of the same procedures as that described for 2b and 2b0,
compound 15 (5.080 g, 12.66 mmol) was converted to compounds
1.5 Hz, 3H); 13C NMR (75.5 MHz, CDCl3)
d
139.0, 128.6, 128.1, 127.4,
125.1 (q, JC–F¼282.1 Hz), 69.9 (q, JC–F¼29.1 Hz), 52.4, 51.3, 14.5 (q,
17 (2.264 g, 49% for four steps) and 170 (360 mg, 8% for four steps) as
26
JC–F¼2.9 Hz); 19F NMR (282 MHz, CDCl3)
d
ꢁ75.1 (d, J¼7.6 Hz, 3F);
clear oils. Compound 17: [
a]
þ12.5 (c 0.97, CHCl3); 1H NMR
D
MS (ESI) m/z 234.1 (MþH)þ; IR (thin film) 3288, 2947, 1463, 1274,
1157, 1035, 897, 700 cmꢁ1. Anal. Calcd for C11H14F3NO: C, 56.65; H,
6.05; N, 6.01. Found: C, 56.52; H, 5.75; N, 5.90.
(300 MHz, CDCl3) d 7.31 (m, 10H), 4.11 (s, 1H), 3.74 (m, 4H), 3.02 (s,
1H), 2.85 (m, 1H), 2.08 (m, 1H), 1.95 (m, 1H), 1.28 (m, 1H), 0.96 (m,
6H); 13C NMR (75.5 MHz, CDCl3)
139.1, 129.2,128.4,127.3,125.5 (q,
JC–F¼284.0 Hz), 67.9 (q, JC–F¼29.3 Hz), 62.6, 55.2, 33.5, 27.8, 16.2,
d
4.4.2. (2S,3S)-3-Benzylamino-1,1,1-trifluoro-4-methyl-2-
pentanol (12b)
11.3; 19F NMR (282 MHz, CDCl3)
d
ꢁ72.9 (d, J¼8.2 Hz, 3F); MS (ESI)
m/z 366.3 (MþH)þ, 388.1 (MþNa)þ; IR (thin film) 3449, 2968, 1455,
Benzyl bromide (0.24 mL, 2.00 mmol), potassium carbonate
(305 mg, 2.20 mmol), and 4 (342 mg, 2.00 mmol) were added to
acetonitrile (6 mL) and stirred overnight. The reaction was then
filtered and concentrated in vacuo. The residue was purified by
silica gel flash column chromatography (petroleum ether/ethyl
1274, 1157, 1070, 865, 699 cmꢁ1; HRMS calcd for C21H27F3NO
26
(MþH)þ: 366.2039. Found: 366.2043. Compound 170: [
a
]
þ33.4 (c
D
1.98, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.31 (m, 10H), 5.56 (s, 1H),
4.09 (m, 1H), 3.91 (d, J¼11.4 Hz, 2H), 3.53 (d, J¼13.2 Hz, 2H), 2.94 (d,
J¼8.4 Hz, 1H), 1.99 (m, 1H), 1.38 (m, 2H), 1.10 (d, J¼6.6 Hz, 3H), 0.95
acetate¼10:1) to give compound 12b (386 mg, 74%) as a clear oil:
(t, J¼7.2 Hz, 3H); 13C NMR (75.5 MHz, CDCl3)
d 137.8, 129.2, 128.6,
23
[
a]
þ23.3 (c 1.14, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.33 (m, 5H),
127.6, 125.3 (q, JC–F¼282.5 Hz), 66.0 (q, JC–F¼30.5 Hz), 60.2, 54.2,
D
4.25 (s, 1H), 4.00 (m, 2H), 3.76 (d, J¼12.9 Hz, 1H), 2.66 (t, J¼6.0 Hz,
33.2, 28.8, 16.3, 12.5; 19F NMR (282 MHz, CDCl3)
d
ꢁ75.6 (d,
1H), 2.04 (m, 1H), 1.49 (s, 1H), 1.11 (d, J¼6.9 Hz, 3H), 1.01 (d,
J¼7.3 Hz, 3F); MS (ESI) m/z 366.3 (MþH)þ, 388.1 (MþNa)þ; IR (thin
film) 3066, 2968, 1455, 1274, 1164, 1073, 873, 699 cmꢁ1; HRMS
calcd for C21H27F3NO (MþH)þ: 366.2039. Found: 366.2036.
J¼6.6 Hz, 3H); 13C NMR (75.5 MHz, CDCl3)
d 139.0, 128.6, 128.1,
127.4, 125.6 (q, JC–F¼284.1 Hz), 69.0 (q, JC–F¼28.2 Hz), 63.9, 54.1,
29.7, 20.7, 18.9; 19F NMR (282 MHz, CDCl3)
d
ꢁ75.1 (d, J¼7.9 Hz, 3F);
MS (ESI) m/z 262.1 (MþH)þ, 284.1 (MþNa)þ; IR (thin film) 3386,
4.4.6. (2S,3S)-3-Benzylamino-1,1,1-trifluoro-4-methyl-2-
hexanol (12c)
2966, 1455, 1276, 1163, 1103, 861, 700 cmꢁ1; HRMS calcd for
C
13H19F3NO (MþH)þ: 262.1414. Found: 262.1413.
Pd(OH)2/C (20%, 650 mg) was added in one portion to a solution
of the appropriate compound 17 (1.360 g, 3.72 mmol) in methanol
(30 mL). The mixture was stirred under hydrogen and the reaction
was monitored by TLC. After completion of the reaction, the catalyst
was removed by filtration, washed with methanol, and then con-
centrated in vacuo to give the crude reduction product (602 mg,
87%). The crude product was subjected to the next step without
purification. Benzyl bromide (0.39 mL, 3.25 mmol), potassium car-
bonate (541 mg, 3.90 mmol), and the above product (602 mg,
3.25 mmol) were added to acetonitrile (6 mL) and stirred over-
night. The reaction was then filtered and concentrated in vacuo. The
residue was purified by silica gel flash column chromatography
4.4.3. (2S,3S)-3-Benzylamino-1,1,1-trifluoro-3-phenyl-2-
propanol (12e)
Benzyl bromide (0.24 mL, 2.00 mmol), potassium carbonate
(305 mg, 2.20 mmol), and 13 (410 mg, 2.00 mmol) were added to
acetonitrile (6 mL) and stirred overnight. The reaction was then
filtered and concentrated in vacuo. The residue was purified by
silica gel flash column chromatography (petroleum ether/ethyl
acetate¼6:1) to give compound 12e (460 mg, 78%) as a white solid:
mp 63–65 ꢀC; [
d
a
]
D
þ73.6 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3)
26
7.33 (m, 10H), 4.23 (dq, J¼6.9, 4.8 Hz, 1H), 4.06 (d, J¼5.1 Hz, 1H),
3.82 (d, J¼12.8 Hz, 1H), 3.59 (d, J¼12.8 Hz, 1H), 3.05 (s, 2H); 13C
(petroleum ether/ethyl acetate¼10:1) to give compound 12c
26
NMR (75.5 MHz, CDCl3)
d
138.9, 136.8, 128.6, 128.5, 128.3, 128.2,
(590 mg, 58% for two steps) as a clear oil: [
a
]
þ19.0 (c 0.83,
D
128.0, 127.4, 124.7 (q, JC–F¼283.5 Hz), 72.2 (q, JC–F¼28.9 Hz), 61.4,
CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.33 (m, 5H), 4.28 (s, 1H), 4.00
51.0; 19F NMR (282 MHz, CDCl3)
d
ꢁ73.5 (d, J¼7.6 Hz, 3F); MS (ESI)
(m, 2H), 3.74 (d, J¼13.2 Hz, 1H), 2.74 (t, J¼5.7 Hz, 1H), 1.81 (m, 2H),
m/z 296.1 (MþH)þ, 318.1 (MþNa)þ; IR (thin film) 3322, 3071, 2717,
1.47 (s, 1H), 1.24 (m, 1H), 0.96 (m, 6H); 13C NMR (75.5 MHz, CDCl3)

7360
X.-H. Xu et al. / Tetrahedron 64 (2008) 7353–7361
d
139.7, 128.6, 128.1, 127.4, 125.6 (q, JC–F¼284.3 Hz), 68.9 (q,
References and notes
JC–F¼28.5 Hz), 63.7, 54.1, 36.3, 25.3, 16.4, 11.6; 19F NMR (282 MHz,
ꢁ73.0 (d, J¼7.1 Hz, 3F); MS (ESI) m/z 276.1 (MþH)þ; IR (thin
1. (a) Knochel, P. Sci. Synth. 2004, 3, 5; (b) Nakamura, E. Organometallics in Syn-
thesis: A Manual; Schlosser, M., Ed.; Wiley: New York, NY, 2002; p 579; (c)
Fu¨ rstner, A. Organozinc Reagents; Knochel, P., Jones, P., Eds.; Oxford University
Press: New York, NY, 1999; p 287; (d) Erdik, E. Organozinc Reagents in Organic
Synthesis; CRC: Boca Raton, FL, 1996; (e) Knochel, P. Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Shreiber, S. L., Eds.; Pergamon: Oxford, 1991;
Vol. 1, Chapter 1.7.
2. (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.
, Eds.; Springer: Berlin, 1999; (b) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, NY, 1994; (c) Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; VCH: New York, NY, 1993; (d) Principle and Application of Asymmetric
Synthesis; Lin, G.-Q., Li, Y.-M., Chan, A. S. C., Eds.; Wiley-Interscience, John Wiley
and Sons: New York, NY, 2001.
3. (a) Corey, E. J.; Sarshar, S.; Bordner, J. J. Am. Chem. Soc. 1992, 114, 7938; (b)
Fujimura, O.; Grubbs, R. H. J. Org. Chem. 1998, 63, 824; (c) Murakata, M.; Jono, T.;
Hoshino, O. Tetrahedron: Asymmetry 1998, 9, 2087; (d) Nelson, S. G.; Peelen, T.
J.; Wan, Z. J. Am. Chem. Soc. 1999, 121, 9742; (e) Nelson, S. G.; Spencer, K. L.
Angew. Chem., Int. Ed. 2000, 39, 1323; (f) Li, G.; Wei, H.-X.; Phelps, B. S.; Purkiss,
D. W.; Kim, S. H. Org. Lett. 2001, 3, 823; (g) Suri, J. T.; Vu, T.; Hernandez, A.;
Congdon, J.; Singaram, B. Tetrahedron Lett. 2002, 43, 3649; (h) Katagiri, T.;
Fujiwara, Y.; Takahashi, S.; Ozaki, N.; Uneyama, K. Chem. Commun. 2002, 986; (i)
Fujiwara, Y.; Katagiri, T.; Uneyama, K. Tetrahedron Lett. 2003, 44, 6161; (j) Fache,
F. New J. Chem. 2004, 28, 1277; (k) Katagiri, T.; Iguchi, N.; Kawate, T.; Takahashi,
S.; Uneyama, K. Tetrahedron: Asymmetry 2006, 17, 1157.
CDCl3)
d
film) 3362, 2967, 1456, 1269, 1163, 1103, 851, 701 cmꢁ1; HRMS calcd
for C14H21F3NO (MþH)þ: 276.1570. Found: 276.1579.
4.4.7. (2S,3S)-3-(Dibenzylamino)-1,1,1-trifluoro-4,4-dimethyl-2-
pentanol (18) and (2R,3S)-3-(dibenzylamino)-1,1,1-trifluoro-4,4-
dimethyl-2-pentanol (180)
By use of the same procedures as that described for 2b and 2b0,
compound 16 (5.468 g, 13.63 mmol) was converted to compounds
18 (2.628 g, 53% for four steps) and 180 (286 mg, 6% for four steps) as
26
clear oils. Compound 18: [
a]
ꢁ13.5 (c 1.04, CHCl3); 1H NMR
D
(300 MHz, CDCl3) d 7.31 (m, 10H), 4.53 (m, 1H), 3.77 (m, 4H), 2.75 (s,
1H), 2.34 (d, J¼6.3 Hz, 1H), 0.96 (s, 9H); 13C NMR (75.5 MHz, CDCl3)
d
139.3, 129.3, 128.2, 127.2, 125.5 (q, JC–F¼283.3 Hz), 70.5 (q, JC–F¼
30.9 Hz), 63.0, 56.9, 36.6, 29.2; 19F NMR (282 MHz, CDCl3)
d
ꢁ74.3 (d,
J¼9.3 Hz, 3F); MS (ESI) m/z 366.2 (MþH)þ, 388.1 (MþNa)þ; IR (thin
film) 3554, 2962,1455,1283,1141,1028, 852, 699 cmꢁ1; HRMS calcd
for C21H27F3NO (MþH)þ: 366.2039. Found: 366.2044. Compound
27
180: [
a]
ꢁ12.8 (c 0.80, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.28 (m,
4. McDaniel, D. H.; Brown, H. C. J. Org. Chem. 1958, 23, 420.
5. Charton, M. J. Am. Chem. Soc. 1969, 91, 615.
D
10H), 4.56 (s, 1H), 4.42 (m, 1H), 3.95 (m, 4H), 3.04 (d, J¼3.0 Hz, 1H),
6. (a) Reformatsky, S. Chem. Ber. 1887, 20, 1210; (b) Fu¨rstner, A. Synthesis 1989,
571; (c) Organozinc Reagent; Knochel, P., Philips, J., Eds.; Oxford University
Press: New York, NY, 1999; (d) Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004,
60, 9325; (e) Cozzi, P. G. Angew. Chem., Int. Ed. 2007, 46, 2568.
7. (a) Soai, K.; Kawase, Y. Tetrahedron: Asymmetry 1991, 2, 781; (b) Pini, D.;
Mastantuono, A.; Salvadori, P. Tetrahedron: Asymmetry 1994, 5, 1875; (c) Mas-
tatuono, A.; Pini, D.; Rolfini, C.; Salvadori, P. Chirality 1995, 7, 499; (d) Mi, A.;
Wang, Z.; Chen, Z.; Jiang, Y.; Chan, A. S. C.; Yang, T.-K. Tetrahedron: Asymmetry
1995, 6, 2641; (e) Andre´s, J. M.; Martin, Y.; Pedrosa, R.; Pe´rez-Encabo, A.
1.12 (s, 9H); 13C NMR (75.5 MHz, CDCl3)
125.7 (q, JC–F¼283.7 Hz), 68.7 (q, JC–F¼29.8 Hz), 63.2, 56.6, 37.8, 29.3;
d 138.8, 129.3, 128.4, 127.3,
19F NMR (282 MHz, CDCl3)
d
ꢁ75.0 (d, J¼9.9 Hz, 3F); MS (ESI) m/z
366.2 (MþH)þ, 388.2(MþNa)þ;IR (thin film)3444, 2960,1455,1282,
1163, 1029, 863, 699 cmꢁ1; HRMS calcd for C21H27F3NO (MþH)þ:
366.2039. Found: 366.2038.
´
´
Tetrahedron 1997, 53, 3787; (f) Andres, J. M.; Pedrosa, R.; Perez-Encabo, A.
Tetrahedron 2000, 56, 1217; (g) Ojida, A.; Yamano, T.; Taya, N.; Tasaka, A. Org.
Lett. 2002, 4, 3051; (h) Emmerson, D. P. G.; Hems, W. P.; Davis, B. G. Tetrahedron:
Asymmetry 2005, 16, 213; (i) Shin, E.-K.; Kim, H. J.; Kim, Y.; Kim, Y.; Park, Y. S.
Tetrahedron Lett. 2006, 47, 1933; (j) Kloetzing, R. J.; Thaler, T.; Knochel, P. Org.
Lett. 2006, 8, 1125.
4.4.8. (2S,3S)-3-Benzylamino-1,1,1-trifluoro-4,4-dimethyl-2-
pentanol (12d)
By use of the same procedures as that described for 12c, com-
pound 18 (1.480 g, 4.05 mmol) was converted to compound 12d
27
8. Andre´s, J. M.; Pedrosa, R.; Pe´rez-Encabo, A. Eur. J. Org. Chem. 2004, 1558.
9. Jiang, Y. Z.; Mi, A. Q.; Wang, Z. Y.; Li, S. J. Youji Huaxue 1994, 14, 68.
10. (a) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25, 2195; (b)
Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
11. (a) van der Zeijden, A. A. H. Tetrahedron: Asymmetry 1995, 6, 913; (b) Ishimaru,
K.; Tsuru, K.; Yabuta, K.; Wada, M.; Yamamoto, Y.; Akiba, K. Tetrahedron 1996, 52,
(580 mg, 52% for two steps) as a clear oil: [
1H NMR (300 MHz, CDCl3)
3.92 (m, 1H), 3.74 (d, J¼13.2 Hz, 1H), 3.65 (s, 1H), 2.66 (d, J¼5.1 Hz,
1H), 1.32 (s, 1H), 1.01 (s, 9H); 13C NMR (75.5 MHz, CDCl3)
140.3,
128.6, 128.1, 127.3, 125.6 (q, JC–F¼283.3 Hz), 70.4 (q, JC–F¼28.5 Hz),
a
]
þ24.5 (c 1.11, CHCl3);
D
d
7.25 (m, 5H), 4.01 (d, J¼13.2 Hz, 1H),
d
´
´
13137; (c) Andres, J. M.; de Elena, N.; Pedrosa, R.; Perez-Encabo, A. Tetrahedron
1999, 55, 14137; (d) Andre´s, J. M.; Pedrosa, R.; Pe´rez, A.; Pe´rez-Encabo, A.
Tetrahedron 2001, 57, 8521; (e) Andre´s, J. M.; Pedrosa, R.; Pe´rez-Encabo, A.;
Ramı´rez, M. Tetrahedron 2006, 62, 7783.
68.9, 55.6, 35.6, 27.6; 19F NMR (282 MHz, CDCl3)
d
ꢁ71.6 (d,
J¼6.8 Hz, 3F); MS (ESI) m/z 276.1 (MþH)þ, 298.1 (MþNa)+; IR (thin
film) 3429, 2962, 1455, 1262, 1164, 1074, 846, 700 cmꢁ1; HRMS
calcd for C14H21F3NO (MþH)þ: 276.1570. Found: 276.1567.
12. Hedenstro¨m, E.; Andersson, F.; Hjalmarsson, M. J. Chem. Soc., Perkin Trans. 1
2000, 1513.
13. Cohen, S. C.; Khedouri, E. J. Am. Chem. Soc. 1961, 83, 4228.
14. (a) Moser, H.; Rihs, G.; Sauter, H. Z. Z. Naturforsch., B. 1982, 37, 451; (b) Bloch, R.
Chem. Rev. 1998, 98, 1407; (c) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry
1997, 8, 1895; (d) Johansson, A. Contemp. Org. Synth. 1995, 2, 393.
15. (a) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolution;
Wiley: New York, NY, 1981; (b) Whitesell, J. K. Chem. Rev. 1989, 89, 1581.
16. For review, see: Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
17. (a) Rozema, M. J.; Sidduri, A.; Knochel, P. J. Org. Chem. 1992, 57, 1956; (b)
Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117; (c) Vettel, S.; Vaupel, A.;
Knochel, P. Tetrahedron Lett. 1995, 36, 1023; (d) Vettel, S.; Vaupel, A.; Knochel, P.
J. Org. Chem. 1996, 61, 7473; (e) Langer, F.; Schwink, L.; Devasagayaraj, A.;
Chavant, P.-Y.; Knochel, P. J. Org. Chem. 1996, 61, 8229; (f) Micouin, L.; Knochel, P.
Synlett 1997, 327.
18. (a) Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem. Soc., Chem. Commun. 1992, 1097;
(b) Suzuki, T.; Narisada, N.; Shibata, T.; Soai, K. Tetrahedron: Asymmetry 1996, 7,
2519; (c) Andersson, P. G.; Guijarro, D.; Tanner, D. Synlett 1996, 727; (d) An-
dersson, P. G.; Guijarro, D.; Tanner, D. J. Org. Chem. 1997, 62, 7364; (e) Guijarro,
D.; Pinho, P.; Andersson, P. G. J. Org. Chem. 1998, 63, 2530; (f) Jimeno, C.; Vidal-
4.5. General procedure for the enantioselective addition of
diethylzinc to N-(diphenylphosphinoyl)imine
Phosphinoylimine 19 (46 mg, 0.15 mmol) and the ligand
(0.15 mmol) were dissolved in dry toluene (0.9 mL) under nitrogen,
and the mixture was stirred for 10 min at room temperature. To the
mixture was added Et2Zn in hexane (0.45 mL, 0.45 mmol) at room
temperature. After the mixture was stirred for 24 h, the reaction
was quenched with saturated aqueous ammonium chloride and the
aqueous layer was extracted with CH2Cl2. The combined organic
phase was washed with brine, dried over NaSO4, and concentrated
in vacuo. The residue was purified by silica gel flash column
chromatography (petroleum ether/ethyl acetate¼2:3) to give N-(1-
phenylpropyl)-P,P-diphenylphosphinoylamide 20 as a white solid.
The ee was determined HPLC analysis (Chiralpak OD column,
hexane/propan-2-ol¼90:10; flow rate 0.8 mL minꢁ1; rt, UV de-
tection at 214 nm).
`
Ferran, A.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron Lett. 1999, 40, 777;
(g) Brandt, P.; Hedberg, C.; Lawonn, K.; Pinho, P.; Andersson, P. G. Chem.dEur. J.
1999, 5, 1692; (h) Jimeno, C.; Reddy, K. S.; Sola`, L.; Moyano, A.; Perica`s, M. A.;
Riera, A. Org. Lett. 2000, 2, 3157; (i) Pinho, P.; Andersson, P. G. Tetrahedron 2001,
57, 1615; (j) Zhang, X.-M.; Gong, L.-Z.; Mi, A.-Q.; Cui, X.; Jiang, Y.-Z.; Choi, M. C.
K.; Chan, A. S. C. Tetrahedron Lett. 2001, 42, 6369; (k) Zhang, H.-L.; Zhang, X.-M.;
Gong, L.-Z.; Mi, A.-Q.; Cui, X.; Jiang, Y.-Z.; Choi, M. C. K.; Chan, A. S. C. Org. Lett.
2002, 4, 1399; (l) Beresford, K. J. M. Tetrahedron Lett. 2002, 43, 7175; (m) Zhang,
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Acknowledgements
We thank the National Natural Science Foundation of China,
Ministry of Education of China and Shanghai Municipal Scientific
Committee for funding this work.

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