A practical synthesis of optically active δ-nitro-α-ketoesters and 4-cyclohexyl-proline catalyzed by chiral squamides

Article abstract of DOI:10.1016/j.tetasy.2015.10.009

Inexpensive and readily available squamides derived from 9-amino-9-deoxyepiquinine or 9-amino-9-deoxyepiquinidine were found to be superior catalysts for the asymmetric conjugate additions of t-butyl nitroacetate to β,γ-unsaturated-α-ketoesters. After the subsequent decarboxylation with silica gel, a variety of δ-nitro-α-ketoesters were obtained in good yields and with excellent enantioselectivities. The products were further transformed into ethyl 4-aryl-prolinate via a cascade nitro reduction and amination. A new synthesis of (2S,4S)-4-cyclohexyl-proline was also developed. A practical synthesis of optically active δ-nitro-α-ketoesters and 4-aryl-proline derivatives is described.

Full text of DOI:10.1016/j.tetasy.2015.10.009

Tetrahedron: Asymmetry 26 (2015) 1416–1422
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A practical synthesis of optically active d-nitro-
a-ketoesters
and 4-cyclohexyl-proline catalyzed by chiral squamides
Ri-long Liu a, Yun-yun Yan b, Ting Zhang a, Xue-jing Zhang a, Ming Yan a,
⇑
a Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China
b Shaanxi Key Laboratory of Phytochemistry, College of Chemistry, Baoji University of Arts & Sciences, Baoji, 721013 Shaanxi, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Inexpensive and readily available squamides derived from 9-amino-9-deoxyepiquinine or 9-amino-9-
Received 14 September 2015
Accepted 12 October 2015
Available online 29 October 2015
deoxyepiquinidine were found to be superior catalysts for the asymmetric conjugate additions of t-butyl
nitroacetate to b,
c
-unsaturated-
a-ketoesters. After the subsequent decarboxylation with silica gel, a
variety of d-nitro-
a
-ketoesters were obtained in good yields and with excellent enantioselectivities.
The products were further transformed into ethyl 4-aryl-prolinate via a cascade nitro reduction and
amination. A new synthesis of (2S,4S)-4-cyclohexyl-proline was also developed. A practical synthesis
of optically active d-nitro-
a
-ketoesters and 4-aryl-proline derivatives is described.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
available squamides derived from 9-amino-9-deoxyepiquinine
and 9-amino-9-deoxyepiquinidine are superior catalysts.8 Excel-
lent yields and enantioselectivities were obtained for the conjugate
additions of t-butyl nitroacetate to b,c-unsaturated-a-ketoesters.
Furthermore, a new synthesis for the valuable chiral intermediate
Nitroacetates are useful nucleophilic reagents in organic synthe-
sis,1 since they readily generate stabilized carbanions due to the
conjugate effect of the nitro and the ester group. The nitro and
the ester group also provide good potential for further functional
group transformations. In recent years, organocatalytic asymmetric
conjugate additions have evolved as a powerful tool for the
synthesis of chiral compounds.2 Organocatalytic asymmetric
conjugate additions of nitroacetates to enones,3a–e maleimides,3f
and nitroolefins3g,h have already been developed. The resulting
adducts were transformed into various chiral derivatives via
decarboxylation, denitration, and catalytic hydrogenation. In
2012, we reported the first asymmetric conjugate addition of
trans-4-cyclohexyl-proline is developed.
2. Results and discussion
We prepared chiral squamides 1a–1g derived from 9-amino-9-
deoxyepiquinine based on the reported procedures.9 The reaction
of t-butyl nitroacetate with b,c-unsaturated-a-ketoester 2a was
examined using 1a–1g as the catalysts. The results are summarized
in Table 1. The primary adduct 3a was obtained as a nearly 1:1
mixture of two diastereoisomers in all runs. d-Nitro-a-ketoester
nitroacetates to b,c-unsaturated-a
-ketoesters.4 A chiral pyrro-
lidine-based thiourea–tertiary amine was identified as the best cat-
alyst. Later Zhou et al. found that chiral squamides derived from
1,2-diphenylethylenediamine are also efficient catalysts.5 Wong
et al. developed a chiral copper catalyst for this transformation.6
Although good yields and enantioselectivities could be achieved
with our thiourea–tertiary amine and Zhou’s squamide organocat-
alysts, the synthesis of these organocatalysts requires expensive
starting material 3,5-bistrifluoromethyl-phenyl isothiocyanate or
3,5-bis(trifluoromethyl)aniline.7 In addition, the catalyst loadings
are generally high (typically 5–20 mol %). These drawbacks hamper
the application of this reaction for the synthesis of chiral drugs and
intermediates. Herein, we report that inexpensive and readily
(R)-4a was prepared via the reflux of 3a with chromatograph silica
gel (200–300 mesh) in p-xylene. This decarboxylation method is
more convenient and productive than the previous procedure with
trifluoroacetic acid (TFA).10 Catalysts 1a–1e with phenyl and vari-
ous 3,5-disubstituted phenyl groups gave the product 4a in similar
yields and enantioselectivities (Table 1, entries 1–5). Catalyst 1c
with a 3,5-bistrifluoromethylphenyl group did not show any
advantage over other catalysts. The results indicate that the 9-
amino-9-deoxyepiquinine moiety exerts the dominant effect on
the enantioselectivity. Replacing the phenyl group of squamide
1a with benzyl or trifluoroethyl groups led to slightly lower enan-
tioselectivities (Table 1, entries 6 and 7). Squamide 1h derived
from 9-amino-9-deoxyepiquinidine was also prepared and gave
(S)-4a in a good yield and enantioselectivity (Table 1, entry 8).
⇑
Corresponding author. Tel./fax: +86 20 39943049.
E-mail address: yanming@mail.sysu.edu.cn (M. Yan).
http://dx.doi.org/10.1016/j.tetasy.2015.10.009
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

R.-l. Liu et al. / Tetrahedron: Asymmetry 26 (2015) 1416–1422
1417
Table 1
Screening of organocatalysts 1a–1ha
O
Ot-Bu
O
O2N
O
O2N
O
O
OEt
catalyst (5 mol%)
CH2Cl2, rt, 12 h
silica gel
OEt
Ot-Bu
OEt
+
O
p-xylene,reflux,1.5h
NO2
O
O
4a
3a
2a
Entry
Catalyst
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
79
72
77
72
73
83
77
72
94
94
94
94
93
92
87
87d
1g
1h
a
b
c
The reactions were carried out with 2a (0.20 mmol), t-butyl nitroacetate (0.22 mmol), and catalyst (0.01 mmol) in CH2Cl2 (2.0 mL) at room temperature for 12 h.
Isolated yields of 4a.
The ee values of 4a were determined by chiral HPLC with a Chiralpak-IC column. The absolute configurations of 4a were assigned as R by comparing the sequence of
chromatography peaks with our previous study.4
d
(S)-4a was obtained in this case.
Table 2
Optimization of the reaction conditionsa
O2N
O
O
O
(1) 1a (x mol%)
OEt
OEt
Ot-Bu
solvent
+
NO2
(2) silica gel, p-xylene
reflux,1.5h
O
O
2a
4a
Entry
Solvent
x
T (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Dichloromethane
Dichloroethane
Toluene
Acetonitrile
THF
Dioxane
EtOAc
t-BuOMe
p-Xylene
Toluene
5
5
5
5
5
5
5
5
5
5
5
2
10
rt
rt
rt
rt
rt
rt
rt
rt
rt
12
12
12
12
12
12
12
12
12
24
48
12
12
78
79
83
83
81
82
83
82
78
81
86
78
82
94
94
96
82
92
79
92
94
93
96
95
95
96
9
10
11
12
13
0
Toluene
Toluene
Toluene
ꢀ20
rt
rt
a
b
c
The reactions were carried out with 2a (0.20 mmol), t-butyl nitroacetate (0.22 mmol), and 1a in solvent (2.0 mL).
Isolated yields of 4a.
The ee values of 4a were determined by chiral HPLC with a Chiralpak-IC column.
Using 1a as the catalyst, we examined the effect of reaction
enantioselectivity was achieved when the reaction was carried
out at 0 °C and ꢀ20 °C (Table 2, entries 10 and 11). The use of
2 mol % 1a led to a lower yield, but the enantioselectivity remained
good (Table 2, entry 12). Increasing the catalyst loading (10 mol %)
did not give a better yield or enantioselectivity (Table 2, entry 13)
(Scheme 1).
solvent, temperature, and catalyst loading. The results are
summarized in Table 2. Good yields and enantioselectivities were
generally obtained in a variety of solvents (Table 2, entries 1–9).
Toluene was identified as the best solvent in terms of yield
and enantioselectivity (Table 2, entry 3). No improvement in the
1a
: R = C6H5
1b: R = 3,5-Me2-C6H3
1c
N
N
HN
R
H
N
: R = 3,5-(CF3)2-C6H3
1d: R = 3,5-Cl2-C6H3
1e
HN
H
N
H
H
: R = 3,5-F2-C6H3
1f: R = Benzyl
1g
MeO
MeO
O
O
O
: R = CF3CH2
O
1h
N
N
Scheme 1. Squamide organocatalysts 1a–1h.

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R.-l. Liu et al. / Tetrahedron: Asymmetry 26 (2015) 1416–1422
Table 3
Reaction of substrates 2a-2ka
O2N
O
O
1a
(1)
(5 mol%)
O
OEt
toluene, rt, 12 h
OEt
Ot-Bu
R'
+
R'
(2) silica gel
p-xylene, reflux,1.5h
O
NO2
O
4a 4k
-
2a-2k
Entry
Substrate
R0
C6H5
4-Me-C6H4
4-MeO-C6H4
4-Br-C6H4
4-F-C6H4
4-Cl-C6H4
4-CF3-C6H4
3-Me-C6H4
2-Me-C6H4
2-Thiophenyl
t-Bu
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
4a
4b
4c
4d
4e
4f
4g
4h
4i
83
81
76
77
88
85
88
68
49
78
59
96
94
94
96
94
93
95
95
91
95
86
9
10
11
2j
2k
4j
4k
a
The reactions were carried out with 2a–2k (0.20 mmol), t-butyl nitroacetate (0.22 mmol), and 1a (0.01 mmol) in toluene (2.0 mL) at room temperature for 12 h.
Isolated yields.
The ee values of 4a–4k were determined by chiral HPLC with a Chiralpak-IC column or AS-H column.
b
c
The reactions of a variety of b,
studied and the results are summarized in Table 3. Substitution
with electron-donating group (4-methyl, 4-MeO) at the -phenyl
gave slightly lower yields (Table 3, entries 2 and 3). Substitution
with electron-withdrawing groups (4-F, 4-Cl, 4-CF3) had a benefi-
cial effect on the yield (Table 3, entries 5–7). Excellent enantiose-
lectivities were generally achieved in these cases. The 3-methyl
and 2-methyl substituted substrates 2h–2i afforded significantly
lower yields (Table 3, entries 8 and 9). The increased steric
c
-unsaturated-
a
-ketoesters were
new synthetic route for (2S,4S)-4-cyclohexyl-proline based on the
present organocatalytic transformation. The asymmetric conjugate
addition of t-butyl nitroacetate to 2a was achieved with 1h as the
catalyst. After the decarboxylation, (S)-4a was obtained in 77%
yield and with 91% ee (Scheme 2).
The cascade nitro reduction and amination of (S)-4a were
achieved via catalytic hydrogenation over Pd/C (Scheme 3). Ethyl
4-phenyl-proline 5 was obtained in excellent yield as a mixture
of cis/trans-isomers (3:1). The reduction with Zn/AcOH was also
successful. Ethyl 4-phenyl-proline 5 was obtained as an equivalent
mixture of cis/trans-isomers.
Furthermore, we developed another more diastereoselective
route for the preparation of trans-5 (Scheme 4). The asymmetric
transfer hydrogenation of (S)-4a was achieved with Noyori’s
Ts-DPEN-Ru catalyst.12 Alcohol 6 was obtained in 91% yield and
with a favorable diastereoselectivity. Alcohol 6 was transformed
into its tosylate 7. The reduction of the nitro group and subsequent
intramolecular amination were completed in one pot via catalytic
hydrogen over Pd/C. Compound trans-5 was prepared in good
c
hindrance possibly accounts for the decrease in the yield. The
thiophenyl- -ketoester 2j is a suitable substrate, and provided
good yields and excellent enantioselectivities (Table 3, entry 10).
The -t-butyl- -ketoester 2k is also applicable, but a lower yield
c-
a
c
a
and enantioselectivity were observed (Table 3, entry 11).
Optically active 4-substituted prolines are valuable intermedi-
ates for a number of synthetic drugs. (2S,4S)-4-Cyclohexyl-proline
is an important intermediate for the synthesis of antihypertension
drug Fosinopril. The reported synthetic methods require chiral
starting materials and tedious synthetic steps.11 We explored a
O2N
O
O
1h
)
O
(1)
(5 mol%
OEt
toluene,rt,12 h
OEt
Ot-Bu
+
(2) silica gel, p-xylene
reflux,1.5h
O
NO2
O
2a
(S)-4a
77% yield, 91% ee
Scheme 2. Preparation of (S)-4a catalyzed by 1h.
O2N
O
O
O
[H]
OEt
OEt
OEt
+
NH
NH
O
5
5
cis-
trans-
(S)-4a
(a) Pd/C, EtOH, 75oC, 4 h
(b) Zn/AcOH, rt, 3 h
95% yield, cis-5/trans-5 = 3:1
5
5
90% yield, cis- /trans- = 1:1
Scheme 3. Cascade nitro reduction and amination of (S)-4a.

R.-l. Liu et al. / Tetrahedron: Asymmetry 26 (2015) 1416–1422
1419
O2N
O2N
OH
O2N
O
OTs
Ru-(R,R)-Ts-DPEN
OEt
OEt
TsCl, DABCO
54%
OEt
DMF, HCOOH/Et3N
O
O
91%
O
6
(S)-4a
7
cis/trans = 10: 1
O
O
Pd/C, H2, EtOH
98%
1. PtO2, H2, EtOH, HCl
OH
OEt
NH
NH
2. MeOH/H2O, LiOH, reflux
76%
8
5
trans-
Scheme 4. Synthesis of (2S,4S)-4-cyclohexyl-proline 8.
yield. After the platinum-catalyzed hydrogenation of the phenyl
group and the hydrolysis of the ester group, (2S,4S)-4-cyclohexyl-
proline 8 was obtained in good yield.
toluene (2.0 mL) was stirred at rt for 12 h. After the evaporation
of the solvent under vacuum, the residue was purified by flash
chromatography over silica gel (petroleum ether/ethyl acet-
ate = 10:1) to give adducts 3a–3k.
A mixture of 3a–3k and silica gel (0.20 g, 200–300 mesh) in
p-xylene (5 mL) was refluxed for 1.5 h. The mixture was filtered
and the filtrate was evaporated under vacuum. The residue was
purified by flash chromatography over silica gel (petroleum
ether/ethyl acetate = 10:1) to afford 4a–4k.
3. Conclusion
In conclusion, we found that chiral squamides derived from
9-amino-9-deoxyepiquinine and 9-amino-9-deoxyepiquinidine
are superior catalysts for the asymmetric conjugate additions of
t-butyl nitroacetate to b,c-unsaturated-a-ketoesters. The catalysts
4.3. Spectroscopic data of products 4a–4k
are inexpensive and readily available. They possess better practi-
cability in comparison with previously used organocatalysts in
this transformation. The decarboxylation of the primary adducts
4.3.1. (R)-Ethyl 5-nitro-2-oxo-4-phenylpentanoate 4a
Colorless oil (83% yield); 1H NMR (400 MHz, CDCl3) d 7.37–7.21
(m, 5H), 4.69 (dd, J = 12.6, 7.3 Hz, 1H), 4.62 (dd, J = 12.6, 7.5 Hz,
1H), 4.28 (q, J = 7.1 Hz, 2H), 4.07 (m, 1H), 3.41 (dd, J = 18.7,
7.3 Hz, 1H), 3.29 (dd, J = 18.7, 6.7 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 191.3, 160.3, 138.1, 129.2, 128.2,
127.5, 79.2, 62.8, 42.2, 38.7, 13.9; HRMS (ESI) calcd for
was achieved via refluxing over silica gel. A variety of d-nitro-a-
ketoesters were obtained in good yields and with excellent
enantioselectivities. The products could be transformed into
4-aryl-prolinate via the cascade nitro reduction and amination.
A new synthesis for optically active trans-4-cyclohexyl-proline
has also been developed. The results provide a practical synthesis
C
14H17NO5 (MꢀH)ꢀ: 264.0877, found: 264.0871; the enantiomeric
for optically active d-nitro-a-ketoesters and 4-aryl-proline
derivatives.
excess was determined by HPLC with a Chiralpak IC column (hex-
ane/2-PrOH = 60:40, k = 254 nm, 1.0 mL/min), tminor = 8.6 min,
tmajor = 9.9 min, 96% ee.
4. Experimental
4.1. General
4.3.2. (R)-Ethyl 5-nitro-2-oxo-4-p-tolylpentanoate 4b
Colorless oil (81% yield); 1H NMR (400 MHz, CDCl3) d 7.21–7.07
(m, 4H), 4.69 (dd, J = 12.5, 7.3 Hz, 1H), 4.62 (dd, J = 12.5, 7.5 Hz,
1H), 4.30 (q, J = 7.1 Hz, 2H), 4.10–4.01 (m, 1H), 3.41 (dd, J = 18.6,
7.4 Hz, 1H), 3.29 (dd, J = 18.6, 6.7 Hz, 1H), 3.29 (dd, J = 18.6,
6.7 Hz, 1H), 2.33 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 191.4, 160.3, 137.9, 135.0, 129.8, 127.3, 79.3,
62.8, 42.2, 38.3, 21.0, 13.9; HRMS (ESI) calcd for C14H17NO5
(M+Na)+: 302.1004, found: 302.0992; The enantiomeric
excess was determined by HPLC with a Chiralpak AS-H column
(hexane/EtOH = 80:20, k = 265 nm, 0.8 mL/min), tminor = 9.2 min,
tmajor = 9.8 min, 94% ee.
1H and 13C NMR spectra were recorded on a Bruker Advance
400 MHz spectrometer as solutions in CDCl3 or CD3OD. Chemical
shifts in 1H NMR spectra are reported in parts per million (ppm,
d) downfield from the internal standard Me4Si (TMS, d = 0 ppm).
Chemical shifts in 13C NMR spectra are reported relative to the cen-
tral line of the chloroform signal (d = 77.0 ppm). Flash column
chromatography was carried out over silica gel (230–400 mesh),
purchased from Qingdao Haiyang Chemical Co. Ltd. Melting points
were recorded on an electrothermal digital melting point appara-
tus and are uncorrected. TLC analysis was performed on precoated
silica gel GF254 slides, and visualized by UV irradiation. Unless
otherwise stated, all reagents were obtained from commercial
sources and used as received. The solvents were used as commer-
cial anhydrous grade without further purification. Enantiomeric
excesses were determined by HPLC using a Daicel Chiralpak IC or
AS-H column (4.6 mm ꢁ 25 cm) and eluting with hexane/2-PrOH
or hexane/EtOH solution.
4.3.3. (R)-Ethyl 4-(4-methoxyphenyl)-5-nitro-2-oxopentanoate
4c
Colorless oil (76% yield); 1H NMR (400 MHz, CDCl3) d 7.15 (d,
J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.65 (dd, J = 12.5, 7.2 Hz,
1H), 4.58 (dd, J = 12.5, 7.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.02
(m, J = 7.3 Hz, 1H), 3.78 (s, 3H), 3.38 (dd, J = 18.5, 7.5 Hz, 1H),
3.25 (dd, J = 18.6, 6.7 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 191.4, 160.3, 159.3, 129.9, 128.6, 114.5, 79.4,
62.8, 55.3, 42.3, 38.0, 13.9; HRMS (ESI) calcd for C14H17NO6
(M+Na)+: 318.0954, found: 318.0939; The enantiomeric
excess was determined by HPLC with a Chiralpak IC column
(hexane/EtOH = 80:20, k = 220 nm, 0.8 mL/min), tminor = 12.7 min,
tmajor = 13.3 min, 94% ee.
4.2. General procedure for the conjugate addition of t-butyl
nitroacetate to b,c-unsaturated a-keto esters and subsequent
decarboxylation
A mixture of t-butyl nitroacetate (0.22 mmol), b,c-unsaturated
a-ketoester 2a–2k (0.20 mmol), and catalyst 1a (0.01 mmol) in

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R.-l. Liu et al. / Tetrahedron: Asymmetry 26 (2015) 1416–1422
4.3.4. (R)-Ethyl 4-(4-bromophenyl)-5-nitro-2-oxopentanoate 4d
Colorless oil (77% yield); 1H NMR (400 MHz, CDCl3) d 7.46 (d,
J = 8.5 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 4.67 (dd, J = 12.7, 7.0 Hz,
1H), 4.60 (dd, J = 12.7, 7.8 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.08–
3.98 (m, 1H), 3.38 (dd, J = 18.8, 7.5 Hz, 1H), 3.27 (dd, J = 18.9,
6.6 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
191.0, 160.2, 137.1, 132.3, 129.2, 122.2, 78.8, 63.0, 42.0, 38.1,
13.9; HRMS (ESI) calcd for C13H14BrNO5 (M+Na)+: 365.9953, found:
365.9943; The enantiomeric excess was determined by HPLC with a
Chiralpak AS-H column (hexane/EtOH = 80:20, k = 208 nm, 0.8 mL/
min), tminor = 11.8 min, tmajor = 13.2 min, 96% ee.
4.3.9. (R)-Ethyl 5-nitro-2-oxo-4-o-tolylpentanoate 4i
Colorless oil (49% yield); 1H NMR (400 MHz, CDCl3) d 7.24–7.08
(m, 4H), 4.64 (dd, J = 12.7, 7.9 Hz, 1H), 4.58 (dd, J = 12.7, 6.9 Hz, 1H),
4.43–4.32 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.44 (dd, J = 18.6, 7.6 Hz,
1H), 3.25 (dd, J = 18.6, 6.4 Hz, 1H), 2.46 (s, 3H), 1.33 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) d: 191.4, 160.2, 136.6, 136.3,
131.3, 127.8, 126.7, 125.5, 78.8, 62.8, 42.3, 33.8, 19.5, 13.9; HRMS
(ESI) calcd for C14H17NO5 (M+Na)+: 302.1004, found: 302.0996;
The enantiomeric excess was determined by HPLC with a Chiralpak
AS-H column (hexane/EtOH = 80:20, k = 254 nm, 0.8 mL/min),
tminor = 14.8 min, tmajor = 16.1 min, 91% ee.
4.3.10. (S)-Ethyl 5-nitro-2-oxo-4-(thiophen-2-yl)pentanoate 4j
Brown oil (78% yield); 1H NMR (400 MHz, CDCl3) d 7.23 (m, 1H),
6.95 (m, 2H), 4.72 (dd, J = 12.8, 7.0 Hz, 1H), 4.66 (dd, J = 12.8,
7.2 Hz, 1H), 4.40 (m, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.46 (dd,
J = 18.8, 7.1 Hz, 1H), 3.35 (dd, J = 18.8, 6.6 Hz, 1H), 1.36 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d: 190.9, 160.1, 140.6,
127.2, 125.9, 125.1, 79.4, 63.0, 43.0, 34.1, 13.9; HRMS (ESI) calcd
for C11H13NO5S (M+Na)+: 294.0412, found: 294.0412; The enan-
tiomeric excess was determined by HPLC with a Chiralpak AS-H
4.3.5. (R)-Ethyl 4-(4-fluorophenyl)-5-nitro-2-oxopentanoate 4e
Colorless oil (88% yield); 1H NMR (400 MHz, CDCl3) d 7.24–7.20
(m, 2H), 7.05–6.99 (m, 2H), 4.68 (dd, J = 12.7, 7.0 Hz, 1H), 4.60 (dd,
J = 12.6, 7.8 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.11–4.02 (m, 1H),
3.39 (dd, J = 18.8, 7.5 Hz, 1H), 3.27 (dd, J = 18.8, 6.6 Hz, 1H), 1.34
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d: 191.1, 162.3 (d,
J = 245.7 Hz), 160.2, 133.8(d, J = 3.3 Hz), 129.2(d, J = 8.2 Hz), 116.1
(d, J = 21.5 Hz), 79.1, 62.9, 42.2, 38.0, 13.9; HRMS (ESI) calcd for
C
13H14FNO5 (MꢀH)ꢀ: 282.0783, found: 282.0787; The enantiomeric
column
(hexane/EtOH = 80:20,
k = 254 nm,
0.8 mL/min),
excess was determined by HPLC with a Chiralpak AS-H column
(hexane/EtOH = 80:20, k = 220 nm, 0.8 mL/min), tminor = 11.4 min,
tmajor = 12.3 min, 94% ee.
tminor = 12.4 min, tmajor = 13.3 min, 95% ee.
4.3.11. (R)-Ethyl 5,5-dimethyl-4-(nitromethyl)-2-oxohexanoate
4k
4.3.6. (R)-Ethyl 4-(4-chlorophenyl)-5-nitro-2-oxopentanoate 4f
Colorless oil (85% yield); 1H NMR (400 MHz, CDCl3) d 7.31 (d,
J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 4.68 (dd, J = 12.7, 7.0 Hz,
1H), 4.60 (dd, J = 12.7, 7.8 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.10–
4.00 (m, 1H), 3.39 (dd, J = 18.9, 7.5 Hz, 1H), 3.27 (dd, J = 18.9,
6.6 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d:
191.0, 160.2, 136.5, 134.1, 129.4, 128.9, 78.9, 63.0, 42.0, 38.0,
13.9; HRMS (ESI) calcd for C13H14ClNO5 (M+Na)+: 322.0458, found:
322.0443; The enantiomeric excess was determined by HPLC with a
Chiralpak AS-H column (hexane/EtOH = 80:20, k = 220 nm, 0.8 mL/
min), tminor = 11.3 min, tmajor = 12.5 min, 93% ee.
Colorless oil (49% yield), an inseparable mixture of ketone and
enol tautomers (3:1). Ketone tautomer, 1H NMR (400 MHz, CDCl3)
d 4.56 (dd, J = 12.8, 4.3 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.31–4.27
(m, 1H), 3.14 (dd, J = 18.6, 4.6 Hz, 1H), 2.92 (m, 1H), 2.81–2.74
(m, 1H), 1.38 (t, J = 7.1 Hz, 3H), 0.96 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 192.5, 160.6, 76.9, 62.8, 41.8, 38.4, 33.2, 27.3, 14.0. Enol
tautomer, 1H NMR (400 MHz, CDCl3) d 5.82 (d, J = 1.1 Hz, 1H),
5.55 (dd, J = 10.5, 1.0 Hz, 1H), 4.61 (dd, J = 11.6, 4.0 Hz, 1H), 4.34
(q, J = 7.1 Hz, 2H), 4.31–4.27 (m, 1H), 3.39 (td, J = 10.7, 4.0 Hz,
1H), 1.38 (t, J = 7.1 Hz, 3H), 0.99 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 164.6, 142.6, 109.0, 77.3, 62.6, 44.9, 34.0, 27.5, 14.0. HRMS (ESI)
calcd for C11H19NO5 (M+Na)+: 268.1161, found: 268.1148; The
enantiomeric excess was determined by HPLC with a Chiralpak
AS-H column (hexane/EtOH = 99:1, k = 230 nm, 0.8 mL/min),
tminor = 19.6 min, tmajor = 33.5 min, 86% ee.
4.3.7. (R)-Ethyl 5-nitro-2-oxo-4-(4-(trifluoromethyl)phenyl)
pentanoate 4g
Colorless oil (88% yield); 1H NMR (400 MHz, CDCl3) d 7.62 (d,
J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 4.74 (dd, J = 12.9, 6.9 Hz,
1H), 4.67 (dd, J = 12.9, 7.9 Hz, 1H), 4.31 (q, J = 7.1, 2H), 4.21–
4.11 (m, 1H), 3.44 (dd, J = 19.0, 7.4 Hz, 1H), 3.34 (dd, J = 19.0,
6.6 Hz, 1H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
190.9, 160.1, 142.2, 130.4 (q, J = 30.4 Hz), 128.1, 126.2
(d, J = 3.5 Hz), 126.1 (d, J = 3.5 Hz), 123.8 (d, J = 272.2 Hz),
78.6, 63.0, 41.9, 38.3, 13.9; HRMS (ESI) calcd for C14H14F3NO5
(M+Na)+: 365.0722, found: 356.0716; The enantiomeric excess
4.4. Preparation of (S)-4a
A mixture of t-butyl nitroacetate (7.08 g, 44 mmol), b,
c-unsatu-
rated -ketoester 2a (8.16 g, 40 mmol), and catalyst 1h (988 mg,
a
2 mmol) in toluene (400 mL) was stirred at rt for 12 h. After evap-
oration of the solvent under vacuum, the residue was purified by
flash chromatography over silica gel (petroleum ether/ethyl acet-
ate = 10:1) to give adduct 3a.
A mixture of 3a and silica gel (36 g, 200–300 mesh) in p-xylene
(300 mL) was refluxed for 1.5 h. The mixture was then filtered and
the filtrate was evaporated under vacuum. The residue was puri-
fied by flash chromatography over silica gel (petroleum ether/ethyl
acetate = 10:1) to afford (S)-4a as a colorless oil (8.16 g, 77% yield);
the enantiomeric excess was determined by HPLC with a Chiralpak
IC column (hexane/2-PrOH = 60:40, k = 254 nm, 1.0 mL/min),
tmajor = 8.6 min, tminor = 9.9 min, 91% ee.
was determined by HPLC with
a Chiralpak AS-H column
(hexane/EtOH = 80:20, k = 220 nm, 0.8 mL/min), tminor = 8.1 min,
tmajor = 8.8 min, 95% ee.
4.3.8. (R)-Ethyl 5-nitro-2-oxo-4-m-tolylpentanoate 4h
Colorless oil (68% yield); 1H NMR (400 MHz, CDCl3) d 7.21 (t,
J = 7.5 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H),
7.03 (s, 1H), 4.67 (dd, J = 12.6, 7.4 Hz, 1H), 4.61 (dd, J = 12.6,
7.4 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.03 (m, 1H), 3.40 (dd,
J = 18.6, 7.3 Hz, 1H), 3.27 (dd, J = 18.6, 6.7 Hz, 1H), 2.33 (s, 3H),
1.33 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 191.4, 160.3,
138.9, 138.0, 129.0, 128.9, 128.3, 124.3, 79.2, 62.8, 42.2, 38.6,
4.5. Cascade nitro reduction and amination of (S)-4a
21.4, 13.9; HRMS (ESI) calcd for
C
14H17NO5 (M+Na)+: 302.
(a) A mixture of (S)-4a (265 mg, 1.0 mmol), and 10% Pd/C
(65 mg) in EtOH (10 mL) was shaken under a hydrogen atmosphere
(40 bar) at 75 °C for 4 h. The mixture was then cooled to room tem-
perature and filtered through a pad of Celite. The Celite was
washed with ethyl acetate (15 mL ꢁ 2). The combined filtrate
1004, found: 302.0992; The enantiomeric excess was determined
by HPLC with a Chiralpak AS-H column (hexane/EtOH = 80:20,
k = 230 nm,
0.8 mL/min),
tminor = 9.9 min,
tmajor = 10.5 min,
95% ee.

R.-l. Liu et al. / Tetrahedron: Asymmetry 26 (2015) 1416–1422
1421
was concentrated under vacuum. Ethyl 4-phenyl-prolinate 5 was
obtained as a colorless oil (95% yield). A ratio of cis/trans = 3:1
was determined by 1H NMR. cis-5: 1H NMR (400 MHz, CDCl3) d
7.38–7.15 (m, 5H), 4.21 (q, J = 7.1 Hz, 2H), 3.96 (t, J = 8.1 Hz, 1H),
3.40–3.29 (m, 2H), 3.10–3.01 (m, 1H), 2.69–2.57 (m, 1H),
2.21–1.90 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H); trans-5: 1H NMR
(400 MHz, CDCl3) d 7.34–7.17 (m, 5H), 4.21 (q, J = 7.1 Hz, 2H),
3.98 (dd, J = 9.1, 4.0 Hz, 1H), 3.51 (dd, J = 10.7, 7.4 Hz, 1H),
3.26–3.15 (m, 1H), 2.90 (dd, J = 10.6, 9.0 Hz, 1H), 2.41–2.32 (m,
1H), 2.30–2.21 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H).
(b) To a solution of (S)-4a (265 mg, 1.0 mmol) in acetic acid
(15 mL) was added zinc dust (2.60 g, 40 mmol) by portion. The
mixture was stirred at rt for 3 h. The mixture was then filtered
through a pad of Celite. The Celite was washed with ethyl acetate
(15 mL ꢁ 2). The combined filtrate was concentrated under vac-
uum. The residue was neutralized by the addition of saturated
aqueous NaHCO3. The solution was extracted with ethyl acetate
(20 mL ꢁ 3). The combined organic layer was dried over anhydrous
Na2SO4. After the evaporation of the solvent, ethyl 4-phenyl-proli-
nate 5 was obtained as a colorless oil (90% yield). A ratio of cis/
trans = 1:1 was determined by 1H NMR.
C
20H23NO7S (M+Na)+: 444.1093, found: 444.1093; mp 98.5–
100.8 °C; [
20 = +24.0 (c 0.7, CH2Cl2).
a]
D
4.8. (2S,4S)-Ethyl 4-phenylpyrrolidine-2-carboxylate trans-5
A mixture of 7 (452 mg, 1.07 mmol), 10% Pd/C (200 mg), and
EtOH (8 mL) was shaken under a hydrogen atmosphere (40 bar)
at 40 °C for 6 h. The mixture was cooled to rt and filtered through
a
pad of Celite. The Celite was washed with ethyl acetate
(15 mL ꢁ 2). The combined filtrate was concentrated under
vacuum. The residue was purified by column chromatography over
silica gel to afford trans-5 (230 mg, 98%). 1H NMR (400 MHz, CDCl3)
d 7.33–7.28 (m, 2H), 7.26–7.19 (m, 3H), 4.22 (q, J = 7.1 Hz, 2H), 3.99
(dd, J = 9.2, 4.0 Hz, 1H), 3.53 (dd, J = 10.7, 7.4 Hz, 1H), 3.28–3.15 (m,
1H), 2.92 (dd, J = 10.7, 9.0 Hz, 1H), 2.51 (s, 1H), 2.43–2.34 (m, 1H),
2.27 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
175.3, 142.3, 128.6, 127.2, 126.5, 61.2, 60.1, 54.8, 44.5, 38.4, 14.3.
4.9. (2S,4S)-4-Cyclohexyl-pyrrolidine-2-carboxylic acid 8
A mixture of trans-5 (132 mg, 0.60 mmol), PtO2 (30 mg), EtOH
(5 mL), and six drops of concentrated HCl, was shaken under a
hydrogen atmosphere (10 bar) at 75 °C for 24 h. The mixture was
cooled to room temperature and filtered through a pad of Celite.
The Celite was washed with ethyl acetate (5 mL ꢁ 3). The combined
filtrate was concentrated under vacuum. The residue was dissolved
in MeOH/H2O (v/v = 4:1, 16 mL). LiOHꢂH2O (150 mg) was added,
and the mixture was refluxed for 30 min. The solution was cooled
to room temperature and concentrated under vacuum. The residue
was acidified by HCl (1 M) to pH 6.3, and extracted with n-butyl
alcohol (5 mL ꢁ 3). The combined organic layer was evaporated
under vacuum. The residue was recrystallized from water to give
8 as a white solid (90 mg, 76% yield). 1H NMR (400 MHz, CD3OD)
d 4.01 (dd, J = 9.2, 2.8 Hz, 1H), 3.55 (dd, J = 11.4, 7.0 Hz, 1H), 2.83
(t, J = 10.9 Hz, 1H), 2.38–2.29 (m, 1H), 2.02–1.82 (m, 2H), 1.81–
1.61 (m, 5H), 1.35–1.11 (m, 5H), 1.09–0.93 (m, 2H); 13C NMR
(100 MHz, D2O) d: 175.0, 61.0, 49.4, 42.7, 40.1, 33.0, 31.2, 30.9,
4.6. Ethyl 2-hydroxy-5-nitro-4-phenylpentanoate 6
A mixture of [RuCl2(p-cymene)]2 (30 mg, 0.05 mmol) and (R,R)-
Ts-DPEN (22 mg, 0.06 mmol) was heated in DMF (5 mL) at 80 °C for
20 min. The solution was cooled to rt. A solution of HCOOH/Et3N
(5:2, 380 lL/555 lL) and (S)-4a (531 mg, 2 mmol) were subse-
quently added. The reaction mixture was stirred at room tempera-
ture for 24 h. Water (10 mL) was added and the solution was
extracted with diethyl ether (10 mL ꢁ 2). The combined organic
layer was dried over anhydrous Na2SO4. After the solvent was
evaporated under vacuum, the residue was purified by flash chro-
matography over silica gel to afford 6 as a colorless oil (486 mg,
91% yield). A ratio of cis/trans = 10:1 was determined by 1H NMR.
cis-Diastereoisomer, 1H NMR (400 MHz, CDCl3) d 7.30–7.12 (m,
5H), 4.59 (dd, J = 12.4, 7.3 Hz, 1H), 4.51 (dd, J = 12.4, 8.3 Hz, 1H),
4.08 (q, J = 7.1 Hz, 2H), 3.80–3.75 (m, 1H), 3.75–3.71 (m, 1H),
3.00 (d, J = 4.1 Hz, 1H), 2.09 (ddd, J = 13.5, 10.7, 2.6 Hz, 1H), 1.81
(ddd, J = 13.8, 10.9, 4.6 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 174.6, 138.2, 129.1, 127.9, 127.8, 80.5, 68.0,
62.0, 40.9, 37.6, 14.1; HRMS (ESI) calcd for C13H17NO5 (M+Na)+:
290.1004, found: 290.0997. trans-Diastereoisomer, 1H NMR
(400 MHz, CDCl3) d 7.30–7.12 (m, 5H), 4.59 (dd, J = 12.4, 7.3 Hz,
1H), 4.51 (dd, J = 12.4, 8.3 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 4.00–
3.91 (m, 1H), 3.89–3.82 (m, 1H), 3.15 (s, 1H), 2.09 (ddd, J = 13.5,
10.7, 2.6 Hz, 1H), 1.81 (ddd, J = 13.8, 10.9, 4.6 Hz, 1H), 1.13–1.09
(t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) d174.2, 138.7,
128.9, 127.9, 127.8, 80.0, 68.0, 62.0, 40.0, 37.1, 14.0.
25.8, 25.5; mp 253.0–255.0 °C; [
a]
20 = ꢀ31.8 (c 0.2, AcOH).11d
D
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 21202208, 21172270, 21472248), Guangdong Engineering
Research Center of Chiral Drugs for the financial support of this
study.
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