Synthesis of chiral lactams: Via asymmetric hydrogenation of α,β-unsaturated nitriles

Article abstract of DOI:10.1039/c6ob00310a

A highly efficient Rh-catalyzed enantioselective hydrogenation of α,β-unsaturated nitriles containing ester/amide groups has been developed. Under mild conditions, with a complex of rhodium and (S,S)-f-spiroPhos as the catalyst, a variety of α,β-unsaturated nitriles bearing an ester or amide group were successfully hydrogenated to the corresponding chiral nitriles with excellent enantioselectivities (up to 99.7% ee) and high turnover numbers (TON = 10000). Furthermore, this catalyst system was also successfully applied to the synthesis of important chiral pharmacophore fragments, lactams, Paroxetine and amino acids.

Full text of DOI:10.1039/c6ob00310a

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DOI: 10.1039/C6OB00310A
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Synthesis of Chiral Lactams via Asymmetric Hydrogenation of α,β-
Unsaturated Nitriles†
Received 00th January 20xx,
Accepted 00th January 20xx
Duanyang Kong, Meina Li, Guofu Zi, and Guohua Hou*
A highly efficient Rh-catalyzed enantioselective hydrogenation of α,β-unsaturated nitriles containing ester/amide groups
has been developed. Under mild conditions, with a complex of rhodium and (S,S)-f-spiroPhos as the catalyst, a variety of
α,β-unsaturated nitriles bearing an ester or amide group were successfully hydrogenated to the corresponding chiral
nitriles with excellent enantioselectivities (up to 99.7% ee) and high turnover numbers (TON=10,000). Furthermore, this
catalyst system was also successfully applied to the synthesis of important chiral pharmacophore fragments, lactams,
Paroxetine and amino acids.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Although a number of prochiral compounds have been
successfully hydrogenated with high enantioselectivity and
Introduction
activity,7 the direct hydrogenation of
α,β-unsaturated nitriles
Chiral lactams are extremely important building blocks present
in a broad range of biologically active molecules such as
natural products and pharmaceuticals.1 Typical examples
include a number of widely employed medicinal antibiotics
bearing chiral lactams.2,3 Accordingly, various chiral lactams
and structurally related derivatives have also attracted
considerable attention from chemists because of biological
properties of this kind of compounds, including anti-HIV agents,
anti-tumour compounds, enzyme inhibitors, and anti-
thrombotic agents.1b,4 For example, enantiomerically pure δ-
lactams, as key intermediates, are readily converted into
pharmacologically important molecules, such as 3, 4-
disubstituted piperidines represented by Paroxetine and
Femoxetine (Figure 1).5 Moreover, lactams can be easily
hydrolyzed to the corresponding amino acids and their
derivatives.6 Accordingly, it is not surprising that considerable
efforts have been directed towards a rapid access to optically
active lactams.
containing ester/amide groups to produce chiral nitriles is
rarely reported. The resulting hydrogenation products can be
readily converted into the corresponding lactams and amino
acids.6b,8 Recently using a chiral ferrocenyl diphosphine ligand
f-spiroPhos bearing privileged spirobiindane skeleton,9 we
reported the asymmetric hydrogenation of γ-cyano acrylate
esters and ketones, and similar excellent enantioselectivity
and activity was revealed as in the asymmetric hydrogenation
of other various substrates.10 As an extension of this part of
work, We herein wish to report the highly efficient and
enantioselective hydrogenation of
α,β-unsaturated nitriles
containing ester/amide groups, which provides an efficient
route to optically active lactams and amino acids (Scheme
1).5a,11
Figure 1. Structures of biologically active compounds.
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Scheme 1. Rh-Catalyzed asymmetric hydrogenation of α,β-unsaturated nitriles
containing ester/amide groups.
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DOI: 10.1039/C6OB00310A
Results and discussion
Initially, (E)-methyl 4-cyano-3-phenylbut-3-enoate 1a was
chosen as a model substrate and hydrogenated under 80 atm
o
of H2 in CH2Cl2 at 40 C using the complex of (S,S)-f-spiroPhos
and [Rh(COD)Cl]2. To our delight, a full conversion with
excellent enantioselectivity was achieved in 8 hours (Table 1,
entry 1). Some other phosphine ligands including Binap,
DuanPhos, JosiPhos, f-Binaphane and MonoPhos (Table 1)
were also screened, but low conversions and poor
enantioselectivities were observed (entries 2–6) except for
JosiPhos-1 and f-Binaphane providing a moderate conversion
Under the optimized reaction conditions, a variety of
α,β-
and ee value. The introduction of the rigid spirobiindane
skeleton presumably resulted in higher activity and
enantioselectivity of the ligand, (S,S)-f-spiroPhos. The solvent
effect was subsequently investigated and showed that most of
non-polar solvents such as toluene, THF and DME were
suitable for this transformation albeit with slightly lower
unsaturated nitriles containing an ester group 1b 1j, which
–
were prepared as a single isomer from β-ketoesters, were then
evaluated for the hydrogenation and results are illustrated in
Table 2. All substrates bearing different substituents in the
phenyl ring were successfully hydrogenated providing the
corresponding products
2 with excellent enantioselectivities,
enantioselectivities (entries 710). However, polar solvent,
94% – 99.4% ee, regardless of the position or electronic
property of substituents. For example, the substrates 1d and
1e with an electron-withdrawing para-chloro or bromo group
and the substrate 1b bearing an electron-donating para-
methyl group gave similar enantioselectivities, 99% and 98%
ee respectively (entries 4-5). The substrate 1c with a fluoro
group at the para-position of phenyl ring provided 2c with the
highest enantioselectivity, 99.4% ee (entry 3). The similar
effect was also observed for the meta-substituted substrates
(entries 6-8). The substrate 1j with a 2-naphthyl group also
afforded 2j in full conversion with 99% ee (entry 10).
MeOH, provided decreased conversion and enantioselectivity
(entry 11). Even under lower hydrogen pressure, 30 atm, the
hydrogenation could smoothly complete in 4 hours and the
enantioselectivity was maintained (entries 12).
Table 1. Rh-Catalyzed asymmetric hydrogenation of (E)-methyl 4-cyano-3-phenylbut-3-
enoate 1a, optimizing reaction conditions.a
Table 2. Rh-Catalyzed asymmetric hydrogenation of α,β-unsaturated nitriles containing
ester/amide groups 1.a
entry
ligand
solvent
conv.
(%)b
>99
6
13
78
ee. (%)c
1
2
3
4
5
6
7
8
9
(S,S)-f-spiroPhos
(S)-Binap
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
dioxane
DME
MeOH
CH2Cl2
98
12
18
34
80
ND
93
94
95
95
76
98
(S,R)-DuanPhos
(R)-JosiPhos-1
(S,S)-f-Binaphane
(S)-MonoPhos
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
60
<5
entry
R
product
2a
conv. (%)b)
>99(97)
>99(97)
>99(98)
>99(98)
>99(98)
>99(96)
>99(97)
>99(98)
>99(96)
>99(98)
ee (%)c)
98(S)
98(+)
99.4(S)
99(+)
99(+)
96(+)
96(+)
96(+)
94(+)
99(+)
>99
>99
>99
>99
89
1
2
3
4
5
6
7
8
9
C6H5 (1a)
4-CH3C6H4 (1b)
4-FC6H4 (1c)
4-ClC6H4 (1d)
4-BrC6H4 (1e)
3-CH3OC6H4 (1f)
3-FC6H4 (1g)
3-ClC6H4 (1h)
2-ClC6H4 (1i)
2-naphthyl (1j)
2b
2c
2d
2e
2f
2g
2h
2i
2j
10
11
12d
>99
a
Unless otherwise mentioned, all reactions were carried out with
a
h.
[Rh(COD)Cl]2/diphosphine/substrate ratio of 0.5
:
1.1
:
100, 40 oC,
8
b Determined by 1H NMR. c Determined by HPLC analysis using a chiral stationary
phase. d 30 atm H2, 4 h.
10
a
Unless otherwise mentioned, all reactions were carried out with
a
[Rh(COD)Cl]2/(S,S)-f-spiroPhos/substrate ratio of 0.5 : 1.1 : 100, CH2Cl2, 30 atm H2,
b
40 oC, 4 h. Determined by 1H NMR spectroscopy or GC analysis; data in
c
parentheses are isolated yields. Determined by HPLC analysis using a chiral
stationary phase or chiral GC analysis.
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Furthermore, the Rh-(S,S)-f-spiroPhos catalyst was also applied
to the asymmetric hydrogenation of ,β-unsaturated nitriles
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DOI: 10.1039/C6OB00310A
α
containing an amide group and exhibited comparable high
efficiency and enantioselectivity. Under the optimized reaction
conditions, substrates 3a and 3b were smoothly hydrogenated
to the corresponding products 4a and 4b in full conversions
and excellent enantioselectivities, 99.7% and 98% ee
respectively (Scheme 2). However, a dramatically decreased ee
value was observed when the alkyl substituted substrate 3c
was evaluated. Encouraged by the results of the
hydrogenation of substrates
unsaturated nitriles bearing
1
a
and
3, some other α,β-
long chain ester group,
substrates 5a-c
corresponding hydrogenated products 6a-c with high yields
and excellent enantioselectivitis.
, were also evaluated to provide the
Scheme 3. Asymmetric hydrogenation of 1d under lower catalyst loading and synthesis
of chiral amino ester 7.
Finally, this catalyst system can also be successfully applied to
the synthesis of important chiral pharmacophore fragments, δ-
and ε-lactams and amino acids (Scheme 4).6b The
hydrogenation products were further reduced to amines
followed by subsequent cyclization.6a δ- and ε-lactams were
then obtained. By this route, the key intermediate, δ-lactam 8,
for the synthesis of the selective serotonin reuptake inhibitors
Paroxetine and Femoxetine11e,12 was accessed in high yield
without any loss of enantioselectivity. Treatment of 8b with
BnBr followed by a nucleophilic substitution in the presence of
LDA, gave the desired product 10 with > 99:1 dr and 96%
ee,5a,13 which could be easily transformed to Paroxetine and
Femoxetine according to literature procedures.5
Scheme 2. Rh-Catalyzed asymmetric hydrogenation of α,β-unsaturated nitriles
containing ester/amide groups.
To further evaluate the performance and application potency
of this catalyst system, a gram scale hydrogenation with much
lower catalyst loading was carried out. The result revealed that
the high activity and excellent enantioselectivity could be
maintained under even lower catalyst loading. With the Rh-
(S,S)-f-spiroPhos catalyst, the substrate 1d was hydrogenated
on gram scale at a catalyst loading of 0.01 mol% under 100
atm of initial H2 pressure, the desired product 2d was obtained
in full conversion without any erosion of enantioselectivity.
The results indicated that this catalyst is exceptionally highly
efficient for the asymmetric hydrogenation of these substrates
and can achieve very high turnover numbers (TON)
approaching 10,000 (Scheme 3). The product 2d could be
readily converted to the amino acid derivative
and almost unchanged ee value.
7 in good yield
Scheme 4. Synthesis of δ-lactams and Paroxetine.
Experimental
General Information
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All the air or moisture sensitive reactions and manipulations MHz) δ: 7.49-7.46 (m, 2H), 7.26-7.19 (m, 2H), 5.71 (s, 1H), 3.81
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were performed by using standard Schlenk techniques and in a (s, 2H), 3.62 (s, 3H). 13C NMR (CDCl3, 100DMOIH: 1z0).1δ0:319/6C86.O8,B0105341.05A,
nitrogen-filled glovebox. DME, THF, dioxane and toluene were 135.7, 132.3, 127.6, 125.1, 116.4, 99.7, 52.6, 38.9. APCI-HRMS
distilled from sodium benzophenone ketyl. CH2Cl2 was distilled Calcd. for C12H11NO2Br [M+H+]: 279.9973, found 279.9975.
from calcium hydride. Anhydrous MeOH was distilled from (E)-methyl 4-cyano-3-(3-methoxyphenyl)but-3-enoate (1f):
1
1
magnesium. H NMR and 13C NMR spectra were recorded on yellow liquid; Yield: 59%; H NMR (CDCl3, 400 MHz) δ: 7.26-
Bruker AV (400 MHz) spectrometers. CDC13 was the solvent 7.22 (m, 1H), 6.95-6.88 (m, 3H), 5.71 (s, 1H), 3.81 (s, 2H), 3.75
used for the NMR analysis, with TMS as the internal standard. (s, 3H), 3.61 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ: 169.1, 159.9,
Chemical shifts were reported upfield to TMS (0.00 ppm) for 155.4, 138.1, 130.1, 118.5, 116.8, 115.8, 112.0, 99.4, 55.3, 52.5,
1H NMR. Data is represented as follows: chemical shift, 39.0. APCI-HRMS Calcd. for C13H14NO3 [M+H+]: 232.0974,
integration, multiplicity (s = singlet, d = doublet, dd = double of found 232.0971.
doublets, t = triplet, q = quartet, m = multiplet) and coupling (E)-methyl 4-cyano-3-(3-fluorophenyl)but-3-enoate (1g):
1
constants (J) in Hertz (Hz). Optical rotation was determined yellow liquid; Yield: 62%; H NMR (CDCl3, 400 MHz) δ: 7.16-
using a Perkin Elmer 241 MC polarimeter. GC analysis was 7.14 (m, 1H), 7.09-7.03 (m, 3H), 5.73 (s, 1H), 3.81 (s, 2H), 3.62
conducted on an Agilent 7890A series instrument. HPLC (s, 3H). 13C NMR (CDCl3, 100 MHz) δ: 168.8, 162.9 (d, J = 247.0
analysis was conducted on Agilent 1260 series instrument. Hz), 154.3 (d, J = 3.0 Hz), 138.9 (d, J = 8.0 Hz), 130.7 (d, J = 9.0
HRMS were recorded on a Waters LCT Premier XE mass Hz), 121.9 (d, J = 4.0 Hz), 117.5 (d, J = 21.0 Hz), 116.3, 113.3 (d,
spectrometer with APCI or ESI.
J = 22.0 Hz), 100.4, 52.6, 39.0. 19F NMR (CDCl3, 376 MHz) δ: -
General procedure for the preparation of compounds 1a-j 111.4. APCI-HRMS Calcd. for C12H11NO2F [M+H+]: 220.0774,
and 3a-b:8b The appropriate β-keto esters and amides (0.02 found 220.0777.
mol) and 2-(triphenylphosphoranylidene)-acetonitrile (0.024 (E)-methyl 3-(3-chlorophenyl)-4-cyanobut-3-enoate (1h):
1
mol) were dissolved in toluene (30 ml) in a round bottle flask yellow liquid; Yield: 75%; H NMR (CDCl3, 400 MHz) δ: 7.35-
equipped with a reflux condenser. The solution was stirred at 7.23 (m, 4H), 5.71 (s, 1H), 3.80 (s, 2H), 3.62 (s, 3H). 13C NMR
reflux temperature until no starting material was detected by (CDCl3, 100 MHz) δ: 168.7, 154.3, 138.7, 135.1, 130.5, 130.3,
TLC. After the solvent was removed in vacuo, the residue was 126.3, 124.3, 116.3, 100.6, 52.6, 39.0. APCI-HRMS Calcd. for
purified by silica gel column chromatography using petroleum C12H11NO2Cl [M+H+]: 236.0478, found 236.0472.
ether/AcOEt as an eluent to afford the compounds 1a-j and (E)-methyl 3-(2-chlorophenyl)-4-cyanobut-3-enoate (1i):
1
3a-b
.
yellow liquid; Yield: 52%; H NMR (CDCl3, 400 MHz) δ: 7.36-
(E)-methyl 4-cyano-3-phenylbut-3-enoate (1a): yellow liquid; 7.26 (m, 4H), 5.57 (s, 1H), 3.92 (s, 2H), 3.66 (s, 3H). 13C NMR
Yield: 80%; 1H NMR (CDCl3, 400 MHz) δ: 7.36-7.34 (m, 5H), (CDCl3, 100 MHz) δ: 168.5, 156.0, 137.2, 131.4, 130.5, 130.1,
5.72 (s, 1H), 3.83 (s, 2H), 3.61 (s, 3H). 13C NMR (CDCl3, 100 MHz) 130.0, 127.1, 115.6, 104.4, 52.3, 40.1. APCI-HRMS Calcd. for
δ: 169.1, 155.6, 136.7, 130.6, 129.0, 126.1, 116.8, 99.2, 52.6, C12H11NO2Cl [M+H+]: 236.0478, found 236.0472.
39.0. APCI-HRMS Calcd. for C12H12NO2 [M+H+]: 202.0868, (E)-methyl 4-cyano-3-(naphthalen-2-yl)but-3-enoate (1j):
o
found 202.0864.
colorless crystal; MP: 58-60 C; Yield: 68%; 1H NMR (CDCl3, 400
(E)-methyl 4-cyano-3-(p-tolyl)but-3-enoate (1b): yellow solid; MHz) δ: 7.92-7.83 (m, 4H), 7.57-7.26 (m, 3H), 5.93 (s, 1H), 4.03
o
MP: 68-70 C; Yield: 67%; 1H NMR (CDCl3, 400 MHz) δ: 7.27 (d, (s, 2H), 3.69 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ: 169.2, 155.3,
J = 8.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 5.70 (s, 1H), 3.82 (s, 2H), 134.1, 133.9, 132.9, 129.0, 128.8, 127.7, 127.6, 127.0, 126.4,
3.61 (s, 3H), 2.30 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ: 169.2, 122.9, 116.9, 99.4, 52.6, 39.1. APCI-HRMS Calcd. for C16H14NO2
155.3, 141.1, 133.8, 129.8, 126.0, 117.1, 98.0, 52.5, 38.9, 21.3. [M+H+]: 252.1025, found 252.1019.
APCI-HRMS Calcd. for C13H14NO2 [M+H+]: 216.1025, found (E)-4-cyano-N-phenyl-3-(p-tolyl)but-3-enamide (3a): white
o
216.1023.
solid; MP: 164-166 C; Yield: 78%; 1H NMR (CDCl3, 400 MHz) δ:
(E)-methyl 4-cyano-3-(4-fluorophenyl)but-3-enoate (1c): 7.50-7.43 (m, 5H), 7.30-7.08 (m, 5H), 5.83 (s, 1H), 3.94 (s, 2H),
o
colorless crystal; MP: 60-62 C; Yield: 70%; 1H NMR (CDCl3, 400 2.37 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ: 166.2, 156.9, 141.4,
MHz) δ: 7.39-7.36 (m, 2H), 7.05-7.01 (m, 2H), 5.68 (s, 1H), 3.82 137.5, 133.7, 129.8, 128.9, 126.3, 124.7, 120.3, 117.7, 97.5,
(s, 2H), 3.62 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ: 169.0, 164.0 41.9, 21.3. TOF-HRMS Calcd. for C18H17N2O [M+H+]: 277.1335,
(d, J = 250.0 Hz), 154.4, 132.9 (d, J = 4.0 Hz), 128.3 (J = d, 2.0 found 277.1334.
Hz), 116.7, 116.1 (d, J = 22.0 Hz), 99.1 (d, J = 1.0 Hz), 52.6, 39.0. (E)-4-cyano-3-(4-fluorophenyl)-N-phenylbut-3-enamide (3b):
o
19F NMR (CDCl3, 376 MHz) δ: -109.4. APCI-HRMS Calcd. for white solid; MP: 162-164 C; Yield: 85%; 1H NMR (CDCl3, 400
C12H11NO2F [M+H+]: 220.0774, found 220.0777.
MHz) δ: 7.50-7.44 (m, 3H), 7.31 (d, J = 7.9 Hz, 2H), 7.17-7.12 (m,
(E)-methyl 3-(4-chlorophenyl)-4-cyanobut-3-enoate (1d): 2H), 6.99-6.94 (m, 3H), 5.64 (s, 1H), 3.78 (s, 2H). 13C NMR
o
colorless crystal; MP:76-78 C; Yield: 85%; 1H NMR (CDCl3, 400 (CDCl3, 100 MHz) δ: 165.5, 165.4, 163.0, 156.2, 137.2, 132.9,
MHz) δ: 7.38 (s, 4H), 5.77 (s, 1H), 3.89 (s, 2H), 3.69 (s, 3H). 13C 129.0, 128.7, 128.6, 124.9, 120.2, 117.4, 116.3, 116.1, 98.3,
NMR (CDCl3, 100 MHz) δ: 168.9, 154.3, 136.7, 135.2, 129.3, 42.5. 19F NMR (CDCl3, 376 MHz) δ: -108.9. TOF-HRMS Calcd. for
127.5, 116.5, 99.7, 52.6, 38.9. APCI-HRMS Calcd. for C17H14N2OF [M+H+]: 281.1084, found 281.1083.
C12H11NO2Cl [M+H+]: 236.0478, found 236.0472.
(Z)-4-cyano-3-methyl-N-phenylbut-3-enamide (3c): white
(E)-methyl 3-(4-bromophenyl)-4-cyanobut-3-enoate (1e): solid; MP: 110-112 C; Yield: 78%; 1H NMR (CDCl3, 400 MHz) δ:
o
1
colorless crystal; MP: 92-94 oC; Yield: 80%; H NMR (CDCl3, 400 7.51-7.49 (m, 3H), 7.35-7.30 (m, 2H), 7.15-7.11 (m, 1H), 5.35 (s,
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1H), 3.48 (s, 2H), 2.13 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ: methyl 4-cyano-3-(p-tolyl)butanoate (2b): colorless liquid;
View Article Online
25
DOI: 10.1039/C6OB00310A
166.5, 159.6, 138.1, 129.6, 125.3, 120.8, 117.4, 99.3, 44.9, 24.4. Yield: 97%; 98% ee; [α]D = +19.4 (c = 0.5, CHCl3); GC condition:
TOF-HRMS Calcd. for C12H13N2O [M+H+]: 201.1022, found Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25
201.1023.
µm), N2 1.0 mL/min, programmed 100 oC – 0.6 oC/min – 200 oC
1
General procedure for the preparation of compound 5: NaH – 100 min; tR = 108.4 min (major), tR = 109.0 min (minor). H
(0.03 mol) and THF (50 mL) were placed in an oven-dried two- NMR (CDCl3, 400 MHz) δ: 7.26-7.13 (m, 4H), 3.65 (s, 3H), 3.51-
neck round bottom flask under nitrogen. The reaction mixture 3.44 (m, 1H), 2.87-2.71 (m, 4H), 2.33 (s, 3H). 13C NMR (CDCl3,
was cooled and diethyl cyanomethylphosphonate (0.024 mol) 100 MHz) δ: 171.5, 137.5, 137.4, 129.7, 126.8, 118.0, 51.9,
was added dropwise at 0 C. The solution was stirred at room 38.9, 37.7, 24.4, 21.0. APCI-HRMS Calcd. for C13H16NO2 [M+H+]:
o
temperature until gas evolution had ceased. And then, the 218.1181, found 218.1175.
corresponding keto esters (0.02 mol) were added dropwise. (S)-methyl
4-cyano-3-(4-fluorophenyl)butanoate
(2c):
25
The solution was stirred at room temperature until no starting colorless liquid; Yield: 98%; 99.4% ee; [α]D = +20.2 (c = 0.5,
material was detected by TLC. The reaction mixture was CH3CN); GC condition: Supelco gamma DexTM 225 column (30
quenched with water and extracted with ethyl acetate. The m × 0.25 mm × 0.25 µm), N2 1.0 mL/min, programmed 100 oC –
o
o
combined organic layers were washed with brine, dried over 1 C/min – 200 C – 100 min; tR = 71.7 min (major), tR = 72.8
1
Na2SO4. After the solvent was removed in vacuo, the residue min (minor). H NMR (CDCl3, 400 MHz) δ: 7.19-7.15 (m, 2H),
was purified by silica gel column chromatography using 6.99-6.95 (m, 2H), 3.57 (s, 3H), 3.46-3.42 (m, 1H), 2.80-2.64 (m,
petroleum ether/AcOEt as an eluent.
4H). 13C NMR (CDCl3, 100 MHz) δ: 170.2, 161.2 (d, J = 245.0 Hz),
(E)-methyl 5-cyano-4-phenylpent-4-enoate (5a): colorless 135.1 (d, J = 4.0 Hz), 127.7 (d, J = 8.0 Hz), 116.7, 115.0 (d, J =
liquid; Yield: 87%; 1H NMR (CDCl3, 400 MHz) δ: 7.43-7.26 (m, 22.0 Hz), 51.0, 37.9, 36.4, 23.4. 19F NMR (CDCl3, 376 MHz) δ: -
5H), 5.54 (s, 1H), 3.64 (s, 3H), 3.20 (t, J = 8.0 Hz, 2H), 2.45 (t, J = 114.3.15
8.0 Hz, 2H). 13C NMR (CDCl3, 100 MHz) δ: 172.2, 162.8, 136.7, methyl 3-(4-chlorophenyl)-4-cyanobutanoate (2d): yellow
25
130.4, 129.1, 126.4, 116.9, 97.0, 51.9, 32.5, 29.1.
liquid; Yield: 98%; 99% ee; [α]D = +26.6 (c = 0.5, CHCl3); GC
(E)-methyl 6-cyano-5-phenylhex-5-enoate (5b): Yield: 81%; 1H condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm
NMR (CDCl3, 400 MHz) δ: 7.43 (s, 5H), 5.56 (s, 1H), 3.68 (s, 3H), × 0.25 µm), N2 1.0 mL/min, programmed 100 C – 1 C/min –
o
o
o
2.95 (t, J = 8.0 Hz, 2H), 2.38 (t, J = 8.0 Hz, 2H), 1.85-1.78 (m, 2H). 200 C – 100 min; tR = 90.8 min (major), tR = 91.9 min (minor).
13C NMR (CDCl3, 100 MHz) δ: 173.2, 163.8, 137.0, 130.3, 129.0, 1H NMR (CDCl3, 400 MHz) δ: 7.33-7.31 (m, 2H), 7.22-7.18 (m,
126.3, 117.2, 96.3, 51.7, 33.1, 32.9, 23.5. TOF-HRMS Calcd. for 2H), 3.64 (s, 3H), 3.51-3.46 (m, 1H), 2.86-2.71 (m, 4H). 13C NMR
C14H16NO2 [M+H+]: 230.1175, found 230.1177.
(CDCl3, 100 MHz) δ: 171.2, 138.8, 133.8, 129.2, 128.4, 117.6,
(E)-methyl 7-cyano-6-phenylhept-6-enoate (5c): Yield: 89%; 1H 52.0, 38.6, 37.5, 24.3. APCI-HRMS Calcd. for C12H13NO2Cl
NMR (CDCl3, 400 MHz) δ: 7.42-7.26 (m, 5H), 5.51 (s, 1H), 3.62 [M+H+]: 238.0635, found 238.0629.
(s, 3H), 2.89 (t, J = 8.0 Hz, 2H), 2.30 (t, J = 8.0 Hz, 2H), 1.72-1.64 methyl 3-(4-bromophenyl)-4-cyanobutanoate (2e): colorless
25
(m, 2H), 1.54-1.46 (m, 2H). 13C NMR (CDCl3, 100 MHz) δ: 173.7, liquid; Yield: 98%; 99% ee; [α]D = +24.0 (c = 0.5, CHCl3); GC
164.5, 137.3, 130.2, 129.0, 126.3, 117.3, 96.0, 51,5, 33.6, 33.4, condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm
27.8, 24.3. TOF-HRMS Calcd. for C15H18NO2 [M+H+]: 244.1332, × 0.25 µm), N2 1.0 mL/min, programmed 100 C – 1 C/min –
o
o
found 244.1330.
200 oC – 100 min; tR = 100.0 min (major), tR = 100.9 min
General procedure for asymmetric hydrogenation of (minor). 1H NMR (CDCl3, 400 MHz) δ: 7.50-7.46 (m, 2H), 7.14 (d,
compounds 1, 3 and 5: A stock solution was made by mixing J = 8.4 Hz, 2H), 3.64 (s, 3H), 3.52-3.45 (m, 1H), 2.86-2.71 (m,
[Rh(COD)Cl]2 with (S,S)-f- spiroPhos in a 1:1.1 molar ratio of 4H). 13C NMR (CDCl3, 100 MHz) δ: 171.1, 139.3, 132.2, 128.6,
Rh/(S,S)-f-spiroPhos in CH2Cl2 at room temperature for 20 min 121.8, 117.6, 52.0, 38.6, 37.6, 24.2. APCI-HRMS Calcd. for
in a nitrogen-filled glovebox. An aliquot of the catalyst solution C12H13NO2Br [M+H+]: 282.0130, found 282.0124.
(1.0 mL, 0.001 mmol) was transferred by syringe into the vials methyl 4-cyano-3-(3-methoxyphenyl)butanoate (2f): colorless
charged with different substrates (0.1 mmol for each) in liquid; Yield: 96%; 96% ee; [α]D25 = +18.4 (c = 0.5, CHCl3); HPLC
anhydrous CH2Cl2 (2.0 mL). The vials were then placed into a condition: Lux 5u Cellulose-3 (250 × 4.60mm), ipa : hex = 20:80,
steel autoclave. The inert atmosphere was replaced by H2 and 1.0 mL/min, 225 nm; tR = 19.1 min (major), tR = 24.1 min
o
1
the reaction mixture was stirred under H2 (30 atm) at 40 C. (minor). H NMR (CDCl3, 400 MHz) δ: 7.19 (t, J = 8.0 Hz, 1H),
The hydrogen gas was released slowly and carefully. The 6.77-6.72 (m, 3H), 3.73 (s, 3H), 3.58 (s, 3H), 3.44-3.37 (m, 1H),
solution was concentrated and passed through a short column 2.79-2.65 (m, 4H). 13C NMR (CDCl3, 100 MHz) δ: 170.4, 159.0,
of silica gel to remove the metal complex. The ee values of all 141.0, 129.1, 118.1, 116.9, 112.1, 112.0, 54.2, 50.9, 37.8, 37.1,
products were determined by GC or HPLC analysis on a chiral 23.2. APCI-HRMS Calcd. for C13H16NO3 [M+H+]: 234.1130,
stationary phase.
found 234.1123.
(S)-methyl 4-cyano-3-phenylbutanoate (2a): colorless liquid; methyl 4-cyano-3-(3-fluorophenyl)butanoate (2g): colorless
25
25
Yield: 97%; 98% ee; [α]D = +22.6 (c = 0.5, CHCl3); HPLC liquid; Yield: 97%; 96% ee; [α]D = +20.6 (c = 0.5, CHCl3); GC
condition: Lux 5u Cellulose-3 (250 × 4.60mm), ipa : hex = 40:60, condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm
o
o
1.0 mL/min, 220 nm; tR = 13.8 min (major), tR = 24.2 min × 0.25 µm), N2 1.0 mL/min, programmed 100 C – 1 C/min –
(minor).1H NMR (CDCl3, 400 MHz) δ: 7.30-7.18 (m, 5H), 3.58 (s, 200 C – 100 min; tR = 71.5 min (major), tR = 72.7 min (minor).
o
3H), 3.48-3.41 (m, 1H), 2.82-2.67 (m, 4H).14
1H NMR (CDCl3, 400 MHz) δ: 7.32-7.26 (m, 1H), 7.06-6.95 (m,
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3H), 3.66 (s, 3H), 3.55-3.48 (m, 1H), 2.87-2.73 (m, 4H). 13C NMR 1.0 mL/min, 254 nm; tR = 5.7 min (major), tR = 7.1VmiewinAr(timcleinOonlirn)e.
1
DOI: 10.1039/C6OB00310A
H NMR (CDCl3, 400 MHz) δ: 7.87 (s, 1H), 7.51 (d, J = 8.0 Hz,
(CDCl3, 100 MHz) δ: 171.1, 163.0 (d, J = 246.0 Hz), 142.8 (d, J =
7.0 Hz), 130.6 (d, J = 8.0 Hz), 122.7 (d, J = 3.0 Hz), 117.5, 114.9 2H), 7.30 (t, J = 8.0 Hz, 2H), 7.12 (t, J = 8.0 Hz, 1H), 2.53-2.38 (m,
(d, J = 21.0 Hz), 114.1 (d, J = 22.0 Hz), 52.0, 38.6, 37.8 (d, J = 1.0 5H), 1.16 (d, J = 8.0 Hz, 3H). 13C NMR (CDCl3, 100 MHz) δ: 169.7,
Hz), 24.2. 19F NMR (CDCl3, 376 MHz) δ: -112.7. APCI-HRMS 138.2, 129.6, 125.1, 120.6, 119.0, 43.0, 28.0, 24.5, 19.9. TOF-
Calcd. for C12H13NO2F [M+H+]: 222.0930, found 222.0928.
HRMS Calcd. for C12H15N2O [M+H+]: 203.1178, found 203.1180.
methyl 3-(3-chlorophenyl)-4-cyanobutanoate (2h): yellow methyl 5-cyano-4-phenylpentanoate (6a): colorless liquid;
25
liquid; Yield: 98%; 96% ee; [α]D = +25.6 (c = 0.5, CHCl3); GC Yield: 98%; 98% ee; HPLC condition: Lux 5u Cellulose-1 (250 ×
condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm 4.60mm), ipa : hex = 10:90, 1.0 mL/min, 225 nm; tR = 16.4 min
o
o
× 0.25 µm), N2 1.0 mL/min, programmed 100 C – 1 C/min – (major), tR = 18.2 min (minor). 1H NMR (CDCl3, 400 MHz) δ:
o
200 C – 100 min; tR = 88.1 min (major), tR = 89.0 min (minor). 7.35-7.18 (m, 5H), 3.56 (s, 3H), 3.02-2.95 (m, 1H), 2.61 (d, J =
1H NMR (CDCl3, 400 MHz) δ: 7.21-7.08 (m, 4H), 3.59 (s, 3H), 7.2 Hz, 2H), 2.20-2.05 (m, 4H). 13C NMR (CDCl3, 100 MHz) δ:
3.46-3.39 (m, 1H), 2.80-2.66 (m, 4H). 13C NMR (CDCl3, 100 MHz) 173.1, 140.4, 129.1, 127.8, 127.3, 118.3, 51.7, 41.5, 31.6, 29.9,
δ: 170.1, 141.4, 133.8, 129.3, 127.1, 126.2, 124.3, 116.5, 51.0, 25.1. TOF-HRMS Calcd. for C13H16NO2 [M+H+]: 218.1175, found
37.5, 36.8, 23.1. APCI-HRMS Calcd. for C12H13NO2Cl [M+H+]: 218.1178.
238.0635, found 238.0629.
methyl 6-cyano-5-phenylhexanoate (6b): colorless liquid;
methyl 3-(2-chlorophenyl)-4-cyanobutanoate (2i): yellow Yield: 97%; 98% ee; HPLC condition: Lux 5u Cellulose-1 (250 ×
25
liquid; Yield: 96%; 94% ee; [α]D = +26.8 (c = 0.5, CHCl3); GC 4.60mm), ipa : hex = 20:80, 1.0 mL/min, 225 nm; tR = 21.3 min
1
condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm (minor), tR = 22.6 min (major). H NMR (CDCl3, 400 MHz) δ:
o
o
× 0.25 µm), N2 1.0 mL/min, programmed 100 C – 1 C/min – 7.35-7.19 (m, 5H), 3.63 (s, 3H), 2.93-2.91 (m, 1H), 2.61-2.58 (m,
o
200 C – 100 min; tR = 79.7 min (major), tR = 80.0 min (minor). 2H), 2.29-2.26 (m, 2H), 2.84-1.75 (m, 2H), 1.76-1.50 (m, 2H).
1H NMR (CDCl3, 400 MHz) δ: 7.32-7.14 (m, 4H), 4.02-3.95 (m, 13C NMR (CDCl3, 100 MHz) δ: 173.5, 141.2, 128.9, 127.6, 127.2,
1H), 3.60 (s, 3H), 2.88-2.70 (m, 4H). 13C NMR (CDCl3, 100 MHz) 118.5, 51.6, 42.0, 34.2, 33.6, 25.1, 22.6. TOF-HRMS Calcd. for
δ: 171.2, 137.4, 133.6, 130.2, 129.0, 127.6, 127.5, 117.5, 52.0, C14H18NO2 [M+H+]: 232.1332, found 232.1330.
37.0, 33.9, 22.5. APCI-HRMS Calcd. for C12H13NO2Cl [M+H+]: methyl 7-cyano-6-phenylheptanoate (6c): colorless liquid;
238.0635, found 238.0629.
Yield: 97%; 98% ee; HPLC condition: Lux 5u Cellulose-1 (250 ×
methyl 4-cyano-3-(naphthalen-2-yl)butanoate (2j): white solid; 4.60mm), ipa : hex = 10:90, 1.0 mL/min, 225 nm; tR = 26.4 min
1
MP: 68-70 oC; Yield: 98%; 99% ee; [α]D25 = +24.4 (c = 0.5, CHCl3); (minor), tR = 28.3 min (major). H NMR (CDCl3, 400 MHz) δ:
HPLC condition: Lux 5u Cellulose-3 (250 × 4.60mm), ipa : hex = 7.35-7.18 (m, 5H), 3.62 (s, 3H), 2.94-2.88 (m, 1H), 2.58 (d, J =
30:70, 1.0 mL/min, 254 nm; tR = 18.5 min (major), tR = 23.3 min 7.2 Hz, 2H), 2.26-2.22 (m, 2H), 1.87-1.70 (m, 2H), 1.66-1.55 (m,
1
(minor). H NMR (CDCl3, 400 MHz) δ: 7.83-7.73 (m, 4H), 7.53- 2H), 1.27-1.16 (m, 2H). 13C NMR (CDCl3, 100 MHz) δ: 173.9,
7.36 (m, 3H), 3.73-3.65 (m, 4H), 2.99-2.86 (m, 2H), 2.83 (d, J = 141.5, 128.9, 127.5, 127.2, 118.6, 51.5, 42.0, 34.5, 33.7, 26.7,
6.7 Hz, 2H). 13C NMR (CDCl3, 100 MHz) δ: 171.4, 137.8, 133.4, 25.2, 24.6. TOF-HRMS Calcd. for C15H20NO2 [M+H+]: 246.1488,
132.9, 129.0, 127.9, 127.7, 126.5, 126.2, 126.0, 124.8, 117.9, found 246.1486.
52.0, 38.9, 38.2, 24.3. APCI-HRMS Calcd. for C16H16NO2 [M+H+]: Procedure for the synthesis of compound 7:8b To a stirring
254.1181, found 254.1180.
solution of the hydrogenation product 2d (0.2 mmol) in MeOH
4-cyano-N-phenyl-3-(p-tolyl)butanamide (4a): white solid; (3.0 mL) Boc2O (0.4 mmol) and NiCl2•6H2O (0.4 mmol) were
Yield: 97%; 99.7% ee; HPLC condition: Lux 5u Cellulose-3 (250 × first added, then NaBH4 (1.6 mmol) was added portionwise at
4.60mm), ipa : hex = 10:90, 1.0 mL/min, 254 nm; tR = 23.1 min 0 oC over 1 hour. The mixture was stirred at room temperature
1
(major), tR = 33.7 min (minor). H NMR (CDCl3, 400 MHz) δ: until no starting material was detected by TLC and carefully
7.70 (br, 1H), 7.42-7.08 (m, 9H), 3.59 (t, J = 6.7 Hz, 1H), 2.85- quenched with H2O. The aqueous layer was extracted with
2.74 (m, 4H), 2.32 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ: 168.6, ethyl acetate, dried over MgSO4. After the solvent was
137.6, 137.5, 129.8, 129.0, 126.9, 124.6, 120.1, 118.4, 41.8, removed in vacuo, the residue was purified by silica gel column
37.7, 24.3, 21.1.
4-cyano-3-(4-fluorophenyl)-N-phenylbutanamide
chromatography using petroleum ether/AcOEt as an eluent.
(4b): colorless liquid; Yield: 84%; 98% ee; [α]D = -5.2 (c = 0.5,
25
colorless liquid; Yield: 97%; 98% ee; HPLC condition: Lux 5u CHCl3); HPLC condition: Lux 5u Cellulose-2 (250 × 4.60mm), ipa :
Cellulose-3 (250 × 4.60mm), ipa : hex = 20:80, 1.0 mL/min, 254 hex = 5:95, 1.0 mL/min, 230 nm; tR = 14.6 min (major), tR =
1
nm; tR = 13.5 min (major), tR = 16.1 min (minor). 1H NMR (CDCl3, 16.3 min (minor). H NMR (CDCl3, 400 MHz) δ: 7.19-7.11 (m,
400 MHz) δ: 7.68 (br, 1H), 7.42-7.22 (m, 6H), 7.12-6.99 (m, 3H), 2H), 7.10-7.02 (m, 2H), 4.42 (s, 1H), 3.49 (s, 3H), 3.07-3.03 (m,
3.66-3.59 (m, 1H), 2.85-2.70 (m, 4H). 13C NMR (CDCl3, 100 MHz) 1H), 2.87 (s, 2H), 2.58-2.44 (m, 2H), 1.82-1.64 (m, 2H), 1.33 (s,
δ: 168.1, 163.2, 160.8, 137.2, 136.2, 136.1, 128.8, 128.6, 128.5, 9H). 13C NMR (CDCl3, 100 MHz) δ: 172.2, 155.8, 141.5, 132.5,
124.6, 119.9, 117.9, 115.9, 115.7, 41.4, 37.1, 24.2. 19F NMR 128.8, 128.7, 127.3, 126.8, 51.6, 41.2, 39.1, 36.1, 28.4. ESI-
(CDCl3, 376 MHz) δ: -114.2. TOF-HRMS Calcd. for C17H16N2OF HRMS Calcd. for C17H24NO4ClNa [M+Na+]: 364.1292, found
[M+H+]: 283.1241, found 283.1242.
364.1286.
4-cyano-3-methyl-N-phenylbutanamide (4c): colorless liquid; Procedure for the synthesis of compound 8-10:16 To a stirring
25
Yield: 98%; 80% ee; [α]D = -15.2 (c = 0.5, CHCl3); HPLC solution of the hydrogenation product 2(0.2 mmol) in MeOH
condition: Lux 5u Cellulose-1 (250 × 4.60mm), ipa : hex = 30:70, (3.0 mL) NiCl2•6H2O (0.4 mmol) was first added, then NaBH4
6 | J. Name., 2012, 00, 1-3
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(1.6 mmol) was added portionwise at 0 oC over 1 h. The (2.0 M, 0.53 mL, 1.05 mmol). After 1 hour, dimethyl carbonate
View Article Online
DOI: 10.1039/C6OB00310A
mixture was stirred at room temperature for 2 h and carefully (0.158 g, 1.75 mmol) was added dropwise. The resultant
quenched with H2O. The aqueous layer was extracted with solution was stirred at −78 oC for 4 hours and quenched at this
ethyl acetate, dried over MgSO4. After the solvent was temperature with aqueous ammonium chloride. The aqueous
removed in vacuo, the residue was purified by silica gel column layer was extracted with ethyl acetate, dried over MgSO4 and
chromatography using petroleum ether/ AcOEt as an eluent.
concentrated. Purification by column chromatography gave
(S)-4-phenylpiperidin-2-one (8a): white solid; Yield: 85%; MP: white solid. Yield: 80%; MP: 96-98 oC; 96% ee; [α]D25 = +3.2 (c =
137-139 oC; 98% ee; [α]D25 = -20.2 (c = 0.5, CHCl3); GC condition: 0.5, CHCl3); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm),
Supelco beta DexTM 225 column (30 m × 0.25 mm × 0.25 µm), ipa : hex = 10:90, 1.0 mL/min, 254 nm; tR = 21.9 min (minor), tR
o
o
o
N2 1.0 mL/min, programmed 100 C – 1 C/min – 200 C – 100 = 27.8 min (major). 1H NMR (CDCl3, 400 MHz) δ: 7.34-7.25 (m,
min; tR = 93.0 min (major), tR = 93.4 min (minor). 1H NMR 5H), 7.16-7.12 (m, 2H), 7.01-6.97 (m, 2H), 4.80 (d, J = 14.5 Hz,
(CDCl3, 400 MHz) δ: 7.29-7.14 (m, 5H), 6.24 (s, 1H), 3.35-3.32 1H), 4.78 (d, J = 14.5 Hz, 1H), 3.64 (s, 3H), 3.59 (d, J = 11.0 Hz,
(m, 2H), 3.04-3.02 (m, 1H), 2.65-2.59 (m, 1H), 2.46-2.39 (m, 1H), 3.47-3.36 (m, 2H), 3.31-3.29 (m, 1H), 2.04-1.98 (m, 2H).
1H), 2.04-2.00 (m, 1H), 1.91-1.85 (m, 1H).7a
13C NMR (CDCl3, 100 MHz) δ: 171.0, 166.2, 161.0, 137.1, 129.3,
(S)-4-(4-fluorophenyl)piperidin-2-one (8b): white solid; Yield: 129.2, 128.8, 128.7, 128.5, 128.2, 128.0, 116.4, 115.9, 57.2,
o
25
87%; MP: 156-158 C; 99.4% ee; [α]D = -22.2 (c = 0.5, CHCl3); 52.9, 50.9, 46.7, 42.3, 29.2. 19F NMR (CDCl3, 376 MHz) δ: -
GC condition: Supelco beta DexTM 225 column (30 m × 0.25 115.1.19
mm × 0.25 µm), N2 1.0 mL/min, programmed 100 oC – 1
oC/min – 200 C – 50 min; tR = 97.9 min (major), tR = 98.9 min
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1
Conclusions
(minor). H NMR (CDCl3, 400 MHz) δ: 7.19-7.15 (m, 2H), 7.04-
7.00 (m, 2H), 6.17 (s, 1H), 3.42-3.38 (m, 2H), 3.10-3.08 (m, 1H),
2.70-2.64 (m, 1H), 2.48-2.40 (m, 1H), 2.08-2.05 (m, 1H), 1.95-
1.67 (m, 1H). 19F NMR (CDCl3, 376 MHz) δ: -116.9.17
In conclusion, we have developed a highly efficient and
enantioselective hydrogenation of ,β-unsaturated nitriles
α
bearing an ester or amide group to produce chiral nitriles with
excellent enantioselectivities (up to 99.7% ee) and high
turnover numbers (TON up to 10,000). Moreover, this method
is also successfully employed to the synthesis of the chiral
lactams including pharmaceuticals, Paroxetine and Femoxetine
in high yields with excellent enantioselectivities.
5-phenylazepan-2-one (8c): Same protocol as for 5a. The
mixture was stirred at reflux temperature until no starting
material was detected by TLC and carefully quenched with H2O.
colorless liquid; Yield: 87%; 98% ee; HPLC condition: Lux 5u
Cellulose-1 (250 × 4.60mm), ipa : hex = 20:80, 1.0 mL/min, 225
nm; tR = 13.8 min (major), tR = 15.2 min (minor). 1H NMR (CDCl3,
400 MHz) δ: 7.32-7.16 (m, 5H), 6.52 (s, 1H), 3.43-3.27 (m, 2H),
2.58 (t, J = 12.0 Hz, 1H), 2.66-2.53 (m, 2H), 2.02-1.99 (m, 2H),
1.84-1.68 (m, 2H). 13C NMR (CDCl3, 100 MHz) δ: 178.0, 145.9,
128.2, 126.2, 126.1, 48.4, 41.7, 36.9, 35.4, 30.1. TOF-HRMS
Calcd. for C12H16NO [M+H+]: 190.1226, found 190.1227.
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (grant nos. 21272026,
21172022 and 21472013), the Fundamental Research Funds
for the Central Universities, Specialized Research Fund for the
Doctoral Program of Higher Education of China, Program for
Changjiang Scholars and Innovative Research Team in
University, and Beijing Municipal Commission of Education.
(S)-1-benzyl-4-(4-fluorophenyl)piperidin-2-one (9b): To
a
solution of 8b (0.200 g, 1.04 mmol) in THF (4.0 mL) under an N2
atmosphere at room temperature was added NaH (0.124 g,
3.12 mmol), followed by benzylbromide (0.62 mL, 5.2 mmol).
The mixture was stirred until no starting material was detected
by TLC and carefully quenched with H2O. The aqueous layer
was extracted with ether, dried over MgSO4 and concentrated.
Purification by column chromatography gave white solid. Yield:
87%; MP: 64-66 oC; 99% ee; [α]D25 = -15.2 (c = 0.5, CHCl3); HPLC
condition: Lux 5u Cellulose-3 (250 × 4.60mm), ipa : hex = 10:90,
1.0 mL/min, 230 nm; tR = 10.0 min (minor), tR = 10.3 min
(major). 1H NMR (CDCl3, 400 MHz) δ: 7.33-7.26 (m, 5H), 7.16-
7.12 (m, 2H), 7.02-6.98 (m, 2H), 4.73 (d, J = 14.5 Hz, 1H), 4.54
(d, J = 14.5 Hz, 1H), 3.30-3.25 (m, 2H), 3.09-3.08 (m, 1H), 2.82-
2.76 (m, 1H), 2.57-2.50 (m, 1H), 2.04-2.03 (m, 1H), 1.94-1.84
(m, 1H). 13C NMR (CDCl3, 100 MHz) δ: 169.5, 163.4, 160.9,
139.7, 139.6, 137.6, 129.2, 128.7, 128.5, 128.0, 116.7, 116.0,
50.6, 46.8, 40.2, 38.5, 30.9. 19F NMR (CDCl3, 376 MHz) δ: -
116.1.18
Notes and references
1
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