Organocatalytic Michael addition of aldehydes to trisubstituted nitroolefins

Article abstract of DOI:10.1016/j.tet.2012.05.088

The combination of O-TMS protected diphenyl-prolinol and benzoic acid was found to be effective to catalyze the Michael addition of aldehydes to 3-substituted 3-nitroacrylates. The reaction provided syn,anti-Michael adducts with good diastereoselectivity

Full text of DOI:10.1016/j.tet.2012.05.088

Tetrahedron 68 (2012) 7675e7679
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalytic Michael addition of aldehydes to trisubstituted nitroolefins
,
b,
Leilei Wang a, Xiaojing Zhang a , Dawei Ma
*
*
a Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang 110016, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The combination of O-TMS protected diphenyl-prolinol and benzoic acid was found to be effective to
catalyze the Michael addition of aldehydes to 3-substituted 3-nitroacrylates. The reaction provided
Received 27 February 2012
Received in revised form 15 May 2012
Accepted 22 May 2012
syn,anti-Michael adducts with good diastereoselectivity and excellent enantioselectivity. Some
b-aryl and
a
-methyl substituted nitroolefins also worked under these conditions, although prolonging reaction time
Available online 29 May 2012
was required. These adducts could be used for assembling 2,3,4-trisubstituted pyrrolidines through
simple hydrogenation.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Organocatalysis
Michael addition
Nitroolefins
1. Introduction
2. Results and discussion
Michael addition of aldehydes to nitroolefins is one of the most
attractive reactions for testing organocatalysts, mainly because this
reaction can proceed smoothly under catalysis by a variety of
amines, particularly modified proline analogues.1,2 Although great
progress has been achieved in this special area, limited attention
has been given to exploring the reaction scope by using function-
alized nitroolefins as the Michael acceptors.2j,3 In terms of less re-
active trisubstituted nitroolefins, only 1-nitrocyclohexene,4 1-
nitrocyclopentene,5 and Cbz-protected 1-aminomethyl nitro-
olefins3f have been reported to be suitable substrates for this re-
2.1. Michael addition of aldehydes to 3-substituted
3-nitroacrylates
The required Michael acceptors, (E)-ethyl-3-nitrobut-2-enoate
1a and (E)-ethyl-3-nitropent-2-enoate 1b were prepared from
ethyl glyoxylate according to Stewart’s7 and Stephens’8 procedures.
Reaction of 1a with pentan-1-al as a model, we explored the suit-
able conditions for this Michael addition. As indicated in Table 1, it
was found that under the catalysis of 10 mol % O-TMS protected
diphenyl-prolinol 3 and 10 mol % benzoic acid, the reaction pro-
ceeded in water at room temperature to afford the desired Michael
adduct 2a, together with other diastereomers. The ratio for these
isomers was about 81:2:5:13 as measured by 1H NMR spectroscopy,
and ee value of 2a was greater than 99% (entry 1). Changing solvent
from water to chloroform gave a better yield and improved dia-
stereoselectivity (entry 2), while the best result was observed by
using methylene chloride as the reaction solvent (entry 3). When
less polar solvents were used, the reaction turned to be rather
sluggish and unsatisfactory yields and stereochemistry were
obtained (entries 4 and 5). Interestingly, Michael addition did not
occur in three other commonly used solvents, methanol, acetoni-
trile, and THF (entries 6e8). In this case pentan-1-al might undergo
some side reactions under these conditions, because the nitroolefin
1a was recovered. These results demonstrated that solvents have
great influence to the present reaction, which has been seen in
many organocatalytic Michael additions.1,2
ꢀ
action. Quiet recently, Wennemers and Duschmale reported that
Michael addition of b-aryl and a-methyl substituted nitroolefins
with aldehydes could take place under the catalysis of some
peptides.6
Obviously, the poor reactivity of trisubstituted nitroolefins is
caused by their steric hindrance and electronic nature. We envi-
sioned that introduction of an additional electron-withdrawing
group might enhance their reactivity, and we therefore tried to
use 3-substituted 3-nitroacrylates as the Michael acceptors. We
were pleased to find that Michael addition of these olefins with
aldehydes under the catalysis of O-TMS protected diphenyl-prolinol
occurred to afford the corresponding Michael adducts. Further at-
tempts revealed that some b-aryl and a-methyl substituted nitro-
olefins also worked under these conditions. Herein we wish to
report our results.
With the optimized conditions in hand, we explored the re-
action scope by varying aldehydes and nitroolefins. As summarized
* Corresponding authors. E-mail addresses: madw@sioc.ac.cn, madw@mail.sio-
c.ac.cn (D. Ma).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.088

7676
L. Wang et al. / Tetrahedron 68 (2012) 7675e7679
Table 1
Table 2
Effect of the solvents on the Michael addition of pentan-1-al to (E)-ethyl-3-nitrobut-
Michael addition of aldehydes to 3-substituted 3-nitroacrylatesa
2-enoatea
Entry
1
Product
Yieldb (%)
drc
eed (%)
Entry
Solvent
Time (h)
Yieldb (%)
drc
eed (%)
80
90:1:4:5
>99
1
2
3
4
5
6
7
8
H2O
12
24
12
36
48
48
48
48
66
86
86
80
73
de
de
de
81:2:5:13
w90:7:3
w93:4:4
88:1:5:6
89:1:6:4
d
>99
>99
>99
>99
>99
d
CHCl3
CH2Cl2
Hexane
Toluene
MeOH
MeCN
THF
2
3
4
5
6
37
82
82
65
75
48:9:17:26
93:2:5
97
>99
>99
>99
>99
d
d
d
d
a
Reaction conditions: (E)-ethyl-3-nitrobut-2-enoate (0.2 mmol), pentan-1-al
(0.4 mmol), 3 (0.02 mmol), benzoic acid (0.02 mmol), solvent (0.4 ml), rt.
b
Isolated yield for a mixture of diastereoisomers.
c
Determined by 1H NMR spectroscopy of the crude product.
d
Determined by chiral-phase HPLC of isolated product (for major isomer).
No desired adducts were determined and 1a was recovered.
e
93:6:1
in Table 2, greater than 90% diastereoselectivity was also observed
when butyraldehyde, 3-methylbutanal, and 2-phenylacetaldehyde
were utilized (entries 1, 3, and 4). However, when propionalde-
hyde was used, the reaction gave the corresponding adduct in only
37% yield with poor diastereoselectivity (entry 2), indicating that
the size of the aldehydes plays an important role during the re-
action course. To our delight, two functionalized aldehydes worked
well, affording adducts 2f and 2g in good yields. Their additional
functional groups would allow further manipulation for assembling
more complicated molecules. The reaction of (E)-ethyl-3-nitropent-
2-enoate 1b with two aldehydes also proceeded smoothly (entries
84:7:9
90:7:3
7 and 8), illustrating that tuning the
a-position of the nitro-
products is possible. Noteworthy is that recrystallization of the
adduct 2i could afford a single crystal, which allowed us to de-
termine its stereochemistry via X-ray analysis. As shown in Fig. 1, X-
ray analysis of 2i clearly indicated that the major isomer has
a syn,anti-structure. This result implied that after Michael addition,
protonation could stereoselectively occur to control the stereo-
chemistry of the nitro group.
7
79
83
92:7:1
>99
8
97:3
98
2.2. Michael addition of aldehydes to b-aryl and a-methyl
substituted nitroolefins
a
Reaction conditions: 1 (0.2 mmol), aldehyde (0.4 mmol), 3 (0.02 mmol), benzoic
acid (0.02 mmol), methylene chloride (0.4 ml), rt, 12e24 h.
b
Isolated yield for a mixture of diastereoisomers.
Further attempts revealed that some
b-aryl and a-methyl
c
Determined by 1H NMR spectroscopy of the crude product.
d
substituted nitroolefins were compatible with the standard re-
action conditions, providing the Michael adducts with good yields
(Table 3). Their reactivity was found to be highly dependent on the
electronic nature of the aromatic ring, as shown by reaction of
nitro-embodied substrate being much faster that that of methoxy
substituted nitroolefin (compare entries 2 and 3).
Determined by chiral-phase HPLC of isolated product (major isomer).
which is consistent with that observed for 2i via X-ray analysis
(Scheme 1).
3. Conclusions
2.3. Conversion of Michael adducts to polysubstituted
pyrrolidines
In conclusion, we have demonstrated that two classes of tri-
substituted nitroolefins, 3-substituted 3-nitroacrylates, and
b-aryl
and -methyl substituted nitroolefins, are suitable substrates for
a
These Michael adducts are obviously ideal precursors for
synthesizing polysubstituted pyrrolidines. To illustrate this possi-
bility, we carried out hydrogenation of 2a under the catalysis of
Pd(OH)2/C. It was found that the reaction took place in methanol,
furnishing pyrrolidine 6 in 75% yield, upon treatment with TsCl/
TEA. Its stereochemistry was established via NOSEY studies,
organocatalytic Michael addition. Their reaction with aldehydes
could afford syn,anti-products with good diastereoselectivity and
excellent enantioselectivity. These products could be easily con-
verted into polysubstituted pyrrolidines. Our result further illus-
trated the potential usage of this organocatalytic reaction in organic
synthesis.

L. Wang et al. / Tetrahedron 68 (2012) 7675e7679
7677
layer chromatography (TLC) and silica gel Silicycle (60 A,
40e63 m, purchased from a Canada Co. Int.) was used for flash
m
column chromatography. Enantiomeric excesses were determined
by HPLC using an IC-H column (wavelength¼254 or 214 nm) with
hexane/i-PrOH as the eluent.
4.2. General procedure for the Michael addition of aldehydes
to trisubstituted nitroolefins
Aldehyde (0.4 mmol) was added to a suspension of catalyst 3
(0.02 mmol), (E)-ethyl-3-nitrobut-2-enoate (0.2 mmol), and ben-
zoic acid (0.02 mmol) in methylene chloride (0.4 ml) at 0 ꢀC. After
0.5 h at 0 ꢀC, the reaction mixture was allowed to warm to room
temperature and then stirred until the starting material was con-
sumed as monitored by TLC. The solvent was removed at reduced
pressure and the resulting crude product was purified by flash
column chromatography (silica gel, petroleum ether/ethyl acetate)
to afford the Michael adduct.
4.2.1. Ethyl (2R,3R)-3-formyl-2-((R)-1-nitroethyl)hexanoate (2a).
27
Colorless oil, 42 mg (86%), [
a
]
D
þ40.5 (c 0.95, CHCl3); IR (neat):
2983, 2854, 1727, 1556, 1462, 1396, 1386, 1204, 1019, 966, 871 cmꢁ1
;
Fig. 1. X-ray structure of 2i.
1H NMR (400 MHz, CDCl3)
d
9.75 (s, 1H, CHO), 4.99e4.91 (m, 1H,
CHNO2), 4.18e4.13 (m, 2H, OCH2CH3), 3.57e3.53 (m, 1H, CHCO2),
2.61e2.56 (m, 1H, CHCHO), 1.69e1.64 (m, 1H, CHaHbCH2), 1.61
(d, J¼6.4 Hz, 3H, CHCH3), 1.50e1.41 (m, 1H, CHaHbCH2), 1.38e1.26
(m, 2H, CH2CH3), 1.23 (t, J¼7.2 Hz, 3H, OCH2CH3), 0.92 (t, J¼7.2 Hz,
Table 3
Michael addition of aldehydes to
b
-aryl and a
-methyl substituted nitroolefinsa
3H, CH2CH3); 13C NMR (100 MHz, CDCl3)
d 201.1, 169.7, 81.2, 61.8,
49.4, 48.2, 27.9, 20.8, 17.8, 14.1, 14.0; HRMS (ESI) m/z calcd for
C11H19NNaO5 (MþNa)þ 268.1161, found: 268.1162. HPLC: IC col-
umn, hexane/i-PrOH¼95:5, flow rate 0.7 ml/min, 214 nm,
tR¼21.27 min (major), tR¼40.37 min (minor); ee¼99%.
Entry
Ar (product)
Time (h)
Yieldb (%)
drc
eed (%)
1
2
3
4
Ph (5a)
48
10
48
24
74
90
60
88
94:4:2
92:1:2:5
91:5:4
96:1:3
98
>99
>99
95
4.2.2. Ethyl (2R,3R)-3-formyl-2-((R)-1-nitroethyl)pentanoate (2b).
4-NO2C6H4 (5b)
4-MeOC6H4 (5c)
2-Naphthyl (5d)
28
Colorless oil, 37 mg (80%), [
(400 MHz, CDCl3)
a
]
þ47.28 (c 1.00, CHCl3); 1H NMR
D
d
9.76 (s, 1H, CHO), 4.99e4.92 (m, 1H, CHNO2),
a
4.19e4.13 (m, 2H, eOCH2CH3), 3.55e3.51 (m, 1H, CHCO2e),
2.60e2.55 (m, 1H, CHCHO), 1.74e1.66 (m, 1H, CHaHbCH2), 1.61
(d, J¼7.2 Hz, 3H, CHCH3), 1.53e1.47 (m, 1H, CHaHbCH2), 1.23
(t, J¼6.8 Hz, 3H, OCH2CH3), 0.98 (t, J¼7.2 Hz, 3H, CH2CH3); 13C NMR
Reaction conditions:
4
(0.2 mmol), pentan-1-al (0.4 mmol),
3
(0.02 mmol),
benzoic acid (0.02 mmol), methylene chloride (0.4 ml), rt.
b
Isolated yield for a mixture of diastereoisomers.
c
Determined by 1H NMR spectroscopy of the crude product.
d
Determined by chiral-phase HPLC of isolated product (major isomer).
(100 MHz, CDCl3)
d 201.1, 169.7, 81.2, 61.9, 51.1, 48.1, 19.1, 17.8, 14.1,
11.9; HRMS (ESI) m/z calcd for C10H17NNaO5 (MþNa)þ 254.1005,
found: 254.1000. HPLC: IC column, hexane/i-PrOH¼95:5, flow rate
0.7 ml/min, 214 nm, tR¼16.72 min (major), tR¼26.52 min (minor);
ee¼99%.
4.2.3. Ethyl (2R,3R)-3-methyl-2-((R)-1-nitroethyl)-4-oxobutanoate
29
(2c). Colorless oil, 16 mg (37%), [
a
]
þ32.74 (c 0.50, CHCl3); 1H
D
Scheme 1.
NMR (400 MHz, CDCl3)
d
9.77 (s, 1H, CHO), 4.98e4.94 (m, 1H,
CHNO2), 4.18e4.13 (m, 2H, OCH2CH3), 3.72e3.68 (m, 1H, CHCO2),
2.64e2.61 (m, 1H, CHCHO), 1.64 (d, J¼6.8 Hz, 3H, CHCH3), 1.22
(t, J¼6.8 Hz, 3H, OCH2CH3), 1.09 (d, J¼6.8 Hz, 3H, CHCH3); 13C NMR
4. Experimental
4.1. General remarks
(100 MHz, CDCl3) d 200.3, 169.6, 81.2, 62.0, 48.3, 44.7, 17.8, 14.0, 9.4;
HRMS (ESI) m/z calcd for C9H15NNaO5 (MþNa)þ 240.0848, found:
240.0843. HPLC: IC column, hexane/i-PrOH¼95:5, flow rate 0.7 ml/
min, 214 nm, tR¼15.32 min (major), tR¼20.32 min (minor);
ee¼97%.
All solvents were purified and dried prior to use. Optical rota-
tions were measured on a PerkineElmer 241MC polarimeter in the
solvent indicated. 1H NMR and 13C NMR spectra were recorded on
a Bruker Avance 400 MHz, and assigned in parts per million (
NMR chemical shifts were given on the scale (ppm) and were
d
). 1H
d
4.2.4. Ethyl (2R,3R)-3-formyl-4-methyl-2-((R)-1-nitroethyl)pentanoate
referenced to internal TMS. Reference peaks for chloroform in 13C
NMR spectra were set at 77.0 ppm. For DMSO-d6, the reference
peaks in 1H NMR and 13C NMR spectra were set at 2.50 and
40.0 ppm, respectively. Low-resolution mass spectra were recorded
on a GILENT5973 instrument (EI) and an LCMS-2010EV instrument
(ESI). High-resolution mass spectra were recorded on an IonSpec
4.7 Tesla FTMS instrument. Silica gel plate GF254 was used for thin
(2d). Colorless oil, 40 mg (82%), [
a
]
þ102.29 (c 0.50, CHCl3); IR
28
D
(neat): 2970, 2939, 1736, 1555, 1446, 1365, 1227, 1216, 1021,
865 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
9.90 (d, J¼1.2 Hz, 1H, CHO),
4.92e4.85 (m, 1H, CHNO2), 4.21e4.16 (q, J¼7.6 Hz, 2H, OCH2CH3),
3.33e3.30 (m, 1H, CHCO2), 3.05e3.01 (m, 1H, CHCHO), 1.98e1.90 (m,
1H, CH(CH3)2), 1.55 (d, J¼6.4 Hz, 3H, CHCH3), 1.26 (t, J¼7.2 Hz, 3H,
OCH2CH3), 1.19 (d, J¼7.2 Hz, 3H, CHMeaMeb), 0.93 (d, J¼6.8 Hz, 3H,

7678
L. Wang et al. / Tetrahedron 68 (2012) 7675e7679
CHMeaMeb); 13C NMR (100 MHz, CDCl3)
d
202.9, 169.8, 80.5, 61.7,
(400 MHz, CDCl3)
d
9.76 (s, 1H, CHO), 7.32 (t, J¼6.8 Hz, 2H, CH]C),
55.0, 48.1, 29.0, 21.7, 18.0, 17.3, 14.1; HRMS (ESI) m/z calcd for
C11H19NNaO5 (MþNa)þ 268.1161, found: 268.1157. HPLC: IC column,
hexane/i-PrOH¼95:5, flow rate 0.7 ml/min, 214 nm, tR¼11.57 min
(major), tR¼16.77 min (minor); ee¼99%.
7.26 (m, 1H, CH]C), 7.16 (d, J¼7.2 Hz, 2H, CH]C), 4.69e4.64 (m, 1H,
CHNO2), 4.22e4.16 (m, 2H, OCH2CH3), 3.68e3.65 (m, 1H, CHCO2),
3.13 (dd, J¼8.0, 14.4 Hz, 1H, CHaHbPh), 2.96e2.91 (m, 1H, CHCHO),
2.65 (dd, J¼6.0, 14.4 Hz, 1H, CHaHbPh), 1.85e1.77 (m, 2H, CH2CH3),
1.27 (t, J¼6.8 Hz, 3H, OCH2CH3), 0.86 (t, J¼7.6 Hz, 3H, CH2CH3); 13
C
4.2.5. Ethyl (2R,3R)-3-benzyl-2-((R)-1-nitroethyl)-4-oxobutanoate
NMR (100 MHz, CDCl3) d 200.4, 169.6, 137.7, 129.1 (2C), 129.0 (2C),
30
(2e). Colorless oil, 48 mg (82%), [
a
]
ꢁ4.13 (c 1.00, CHCl3); 1H
127.3, 86.8, 62.1, 51.4, 47.1, 32.2, 24.6, 14.1, 9.5; HRMS (ESI) m/z calcd
for C16H21NNaO5 (MþNa)þ 330.1318, found: 330.1323. HPLC: IC
column, hexane/i-PrOH¼95:5, flow rate 0.7 ml/min, 214 nm,
tR¼20.72 min (major), tR¼24.07 min (minor); ee¼98%.
D
NMR (400 MHz, CDCl3)
d
9.75 (s, 1H, CHO), 7.31 (t, J¼7.2 Hz, 2H,
CH]C), 7.26 (d, J¼7.2 Hz, 1H, CH]C), 7.16 (d, J¼7.2 Hz, 2H, CH]C),
4.86e4.79 (m, 1H, CHNO2), 4.22e4.15 (m, 2H, OCH2CH3), 3.65e3.62
(m, 1H, CHCO2), 3.13 (dd, J¼8.0, 14.4 Hz, 1H, CHaHbPh), 2.98e2.94
(m, 1H, CHCHO), 2.64 (dd, J¼6.0, 14.4 Hz, 1H, CHaHbPh), 1.48 (d,
J¼6.8 Hz, 3H, CHCH3), 1.25 (t, J¼7.2 Hz, 3H, OCH2CH3); 13C NMR
4. 2.10. (2R,3S,4R)-4-Nitro-3-phenyl-2-propylpentanal
(5a). Colorless oil, 37 mg (74%), [
28
a
]
þ62.03 (c 0.95, CHCl3); IR
D
(100 MHz, CDCl3)
d
200.4, 169.6, 137.7, 129.1, 129.0 (2C), 127.3 (2C),
(neat): 3086, 3065, 2958, 2932, 2872, 1722, 1545, 1454, 1389, 1361,
80.9, 62.1, 51.5, 48.6, 32.1, 17.8, 14.1; HRMS (ESI) m/z calcd for
C15H19NNaO5 (MþNa)þ 316.1161, found: 316.1165. HPLC: IC column,
hexane/i-PrOH¼95:5, flow rate 0.7 ml/min, 214 nm, tR¼19.17 min
(major), tR¼33.77 min (minor); ee¼99%.
852, 736, 703 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
9.83 (d, J¼1.6 Hz,
1H, CHO), 7.32e7.30 (m, 3H, CH]C), 7.06e7.04 (m, 2H, CH]C),
5.06e4.99 (m, 1H, CHNO2), 3.43e3.11 (m, 1H, CHPh), 3.16e3.11 (m,
1H, CHCHO), 1.42 (d, J¼6.8 Hz, 3H, CHCH3), 1.40e1.35 (m, 2H,
CH2CH3), 1.31e1.23 (m, 1H, CHaHbCH2), 1.20e1.10 (m, 1H,
CHaHbCH2), 0.77 (t, J¼7.2 Hz, 3H, CH2CH3); 13C NMR (100 MHz,
4.2.6. Ethyl (2R,3R)-6-chloro-3-formyl-2-((R)-1-nitroethyl)hexanoate
29
(2f). Colorless oil, 36 mg (65%), [
a
]
þ15.95 (c 1.05, CHCl3); IR
CDCl3) d 204.2, 135.2, 129.0 (2C), 128.9 (2C), 128.3, 83.8, 51.9, 49.2,
D
(neat): 2962, 2928, 2853, 1732, 1555, 1447, 1392, 1360, 1197, 1019,
30.0, 19.6, 17.6, 14.2; HRMS (ESI) m/z calcd for C14H19NNaO3
(MþNa)þ 272.1263, found: 272.1265. HPLC: IC column, hexane/i-
PrOH¼95:5, flow rate 0.7 ml/min, 214 nm, tR¼13.44 min (major),
tR¼15.71 min (minor); ee¼98%.
868 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
9.77 (s, 1H, CHO), 5.01e4.94
(m, 1H, CHNO2), 4.21e4.11 (m, 2H, OCH2CH3), 3.62e3.58 (m, 1H,
CHCO2), 3.53 (t, J¼6.4 Hz, 2H, CH2Cl), 2.65e2.61 (m, 1H, CHCHO),
2.01e1.92 (m, 1H, CHaHbCH2), 1.79e1.71 (m, 2H, CH2CH2), 1.65 (d,
J¼7.2 Hz, 3H, CHCH3), 1.63e1.56 (m, 1H, CHaHbCH2), 1.23 (t, J¼7.6 Hz,
4.2.11. (2R,3S,4R)-4-Nitro-3-(4-nitrophenyl)-2-propylpentanal
(5b). Colorless oil, 53 mg (90%), [
29
3H, OCH2CH3); 13C NMR (100 MHz, CDCl3)
d
200.2, 169.5, 81.1, 62.1,
a]
þ62.03 (c 0.95, CHCl3); IR
D
49.0, 48.0, 44.4, 33.1, 22.7, 17.9, 14.0; HRMS (ESI) m/z calcd for
C11H18ClNNaO5 (MþNa)þ 302.0772, found: 302.0769. HPLC: IC col-
umn, hexane/i-PrOH¼95:5, flow rate 0.7 ml/min, 214 nm,
tR¼12.37 min (major), tR¼19.67 min (minor); ee¼99%.
(neat): 3230, 3086, 2969, 2873, 1736, 1723, 1551, 1522, 1455, 1363,
1349, 1228, 1216, 854 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
9.86 (d,
J¼1.2 Hz, 1H, CHO), 8.20 (d, J¼8.4 Hz, 2H, CH]C), 7.26 (d, J¼8.8 Hz,
2H, CH]C), 5.11e5.05 (m, 1H, CHNO2), 3.58e3.54 (m, 1H,
CHC6H4NO2), 3.22e3.16 (m, 1H, CHCHO), 1.43 (d, J¼6.8 Hz, 3H,
CHCH3), 1.39e1.33 (m, 2H, CH2CH3), 1.31e1.25 (m, 1H, CHaHbCH2),
1.22e1.15 (m, 1H, CHaHbCH2), 0.78 (t, J¼7.2 Hz, 3H, CH2CH3); 13C
4.2.7. Ethyl (2R,3R)-3-formyl-2-((R)-1-nitroethyl)dodec-11-enoate
28
(2g). Colorless oil, 49 mg (75%), [
a
]
þ29.17 (c 1.35, CHCl3); IR
D
(neat): 3075, 2998, 2927, 2855, 1736, 1720, 1556, 1442, 1364, 1217,
NMR (100 MHz, CDCl3) d 203.0, 147.9, 142.8, 130.2 (2C), 124.0 (2C),
908 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
9.74 (s, 1H, CHO), 5.83e5.76
83.4, 51.4, 48.6, 30.0, 19.4, 17.6, 14.1; HRMS (ESI) m/z calcd for
C14H19N2O5 (MþH)þ 295.1294, found: 295.1293. HPLC: IC column,
hexane/i-PrOH¼95:5, flow rate 0.7 ml/min, 214 nm, tR¼43.12 min
(major), tR¼46.52 min (minor); ee¼99%.
(m, 1H, CH2]CH), 5.00e4.91 (m, 3H, CHNO2, CH2]CH), 4.18e4.13
(m, 2H, OCH2CH3), 3.55e3.52 (m, 1H, CHCO2), 2.59e2.57 (m, 1H,
CHCHO), 2.05e2.00 (m, 2H, CH2CH]CH2), 1.61 (d, J¼6.8 Hz, 3H,
CHCH3), 1.39e1.36 (m, 4H, CH2CH2), 1.27e1.21 (m, 11H, (CH2)4,
OCH2CH3); 13C NMR (100 MHz, CDCl3)
d
201.2, 169.8, 139.1, 114.4,
4.2.12. (2R,3S,4R)-3-(4-Methoxyphenyl)-4-nitro-2-propylpentanal
(5c). Colorless oil, 33 mg (60%), [
29
81.2, 62.0, 49.7, 48.3, 33.8, 29.7, 29.3, 29.1, 28.9, 27.6, 26.0, 17.9, 14.1;
HRMS (ESI) m/z calcd for C17H29NNaO5 (MþNa)þ 350.1944, found:
350.1951. HPLC: IC column, hexane/i-PrOH¼95:5, flow rate 0.7 ml/
min, 214 nm, tR¼17.35 min (major), tR¼31.78 min (minor); ee¼99%.
a
]
þ71.36 (c 0.55, CHCl3); IR
D
(neat): 3001, 2969, 2956, 2929, 1723, 1549, 1514, 1456, 1364, 1253,
1228, 1217, 1033, 833 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
9.81 (d,
J¼2.0 Hz, 1H, CHO), 6.96 (d, J¼8.4 Hz, 2H, CH]C), 6.83 (d, J¼8.8 Hz,
2H, CH]C), 5.01e4.95 (m, 1H, CHNO2), 3.78 (s, 3H, OCH3),
3.37e3.33 (m, 1H, CHC6H4OMe), 3.11e3.05 (m, 1H, CHCHO), 1.40 (d,
J¼6.8 Hz, 3H, CHCH3), 1.38e1.32 (m, 2H, CH2CH3), 1.30e1.23 (m, 1H,
CHaHbCH2), 1.18e1.11 (m, 1H, CHaHbCH2), 0.77 (t, J¼7.2 Hz, 3H,
4.2.8. Ethyl (2R,3R)-3-formyl-2-((R)-1-nitropropyl)hexanoate (2h).
28
Colorless oil, 41 mg (79%), [
a
]
þ45.70 (c 1.05, CHCl3); IR (neat):
D
2964, 2938, 2867, 1739, 1556, 1463, 1375, 1192, 1028, 811 cmꢁ1; 1H
NMR (400 MHz, CDCl3) 9.75 (s, 1H, CHO), 4.84e4.79 (m, 1H,
d
CH2CH3); 13C NMR (100 MHz, CDCl3)
d 204.4, 159.5, 130.0 (2C),
CHNO2), 4.18e4.13 (m, 2H, OCH2CH3), 3.58e3.55 (m, 1H, CHCO2),
2.58e2.54 (m, 1H, CHCHO), 1.99e1.88 (m, 2H, CH2CH3), 1.71e1.61
(m, 1H, CHaHbCH2), 1.51e1.42 (m, 1H, CHaHbCH2), 1.38e1.31 (m, 2H,
CH2CH3), 1.23 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.00 (t, J¼8.0 Hz, 3H,
CH2CH3), 0.92 (t, J¼7.2 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3)
127.0, 114.2 (2C), 84.0, 55.3, 52.0, 48.5, 30.0, 19.6, 17.6, 14.2; HRMS
(ESI) m/z calcd for C15H21NNaO4 (MþNa)þ 302.1369, found:
302.1373. HPLC: IC column, hexane/i-PrOH¼95:5, flow rate 0.7 ml/
min, 214 nm, tR¼25.57 min (major), tR¼30.82 min (minor);
ee¼99%.
d
201.2, 169.7, 87.0, 61.9, 49.4, 46.8, 28.1, 24.6, 20.8, 14.2, 14.1, 9.6;
HRMS (ESI) m/z calcd for C12H21NNaO5 (MþNa)þ 282.1318, found:
282.1313. HPLC: IC column, hexane/i-PrOH¼95:5, flow rate 0.7 ml/
min, 214 nm, tR¼17.45 min (major), tR¼23.41 min (minor); ee¼99%.
4.2.13. (2R,3S,4R)-3-(Naphthalen-2-yl)-4-nitro-2-propylpentanal
28
(5d). Colorless oil, 53 mg (88%), [
a]
þ76.53 (c 1.00, CHCl3); IR
D
(neat): 3060, 2957, 2940, 2870, 1723, 1541, 1463, 1389, 1352, 1127,
995, 867, 851, 826, 813, 748 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
9.89
4.2.9. Ethyl (2R,3R)-3-nitro-2-((R)-1-oxo-3-phenylpropan-2-yl)pen-
(d, J¼1.6 Hz, 1H, CHO), 7.84e7.79 (m, 3H, CH]C), 7.54e7.48 (m, 3H,
CH]C), 7.15 (d, J¼9.2 Hz, 1H, CH]C), 5.14e5.08 (m, 1H, CHNO2),
3.60e3.56 (m, 1H, CHnaphthyl), 3.28e3.23 (m, 1H, CHCHO), 1.46 (d,
J¼6.8 Hz, 3H, CHCH3), 1.43e1.38 (m, 2H, CH2CH3), 1.33e1.25 (m, 1H,
tanoate (2i). Colorless oil, 51 mg (83%), [
a
]
D
28 þ1.57 (c 1.05, CHCl3);
IR (neat): 3085, 3064, 3027, 2982, 2943, 2885, 1735, 1553, 1455,
1378, 1246, 1200, 1012, 893, 859, 804, 744, 704 cmꢁ1 1H NMR
;

L. Wang et al. / Tetrahedron 68 (2012) 7675e7679
7679
CHaHbCH2), 1.22e1.13 (m, 1H, CHaHbCH2), 0.74 (t, J¼7.2 Hz, 3H,
CH2CH3); 13C NMR (100 MHz, CDCl3)
204.3, 133.3, 133.2, 132.7,
Acknowledgements
d
128.7, 128.7, 128.0, 127.8, 126.6, 126.5, 126.1, 83.8, 51.93, 49.3, 30.3,
19.6, 17.7, 14.2; HRMS (ESI) m/z calcd for C18H21NNaO3 (MþNa)þ
322.1419, found: 322.1424. HPLC: IC column, hexane/i-PrOH¼95:5,
flow rate 0.7 ml/min, 214 nm, tR¼20.57 min (major), tR¼25.32 min
(minor); ee¼95%.
The authors are grateful to the Chinese Academy of Sciences and
the National Natural Science Foundation of China (grants 20621062
and 20872156) for their financial support.
References and notes
1. For reviews, see: (a) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638;
(b) Vicario, J. L.; Badía, D.; Carrillo, L. Synthesis 2007, 2065; (c) Palomo, C.; Mielgo,
4.3. Ethyl (2R,3R,4R)-2-methyl-4-propyl-1-tosylpyrrolidine-3-
carboxylate (6)
A. Angew. Chem., Int. Ed. 2006, 45, 7876.
ꢀ
ꢀ
ꢀ
2. For selected examples, see: (a) Rahaman, H.; Madarasz, A; Papai, I.; Pihko, P. M.
Angew. Chem., Int. Ed. 2011, 50, 6123; (b) Belot, S.; Quintard, A.; Krause, N.;
Alexakis, A. Adv. Synth. Catal. 2010, 352, 667; (c) Ting, Y.-F.; Chang, C.; Reddy, R. J.;
Magar, D. R.; Chen, K. Chem.dEur. J. 2010, 16, 7030; (d) Enders, D.; Wang, C.;
Greb, A. Adv. Synth. Catal. 2010, 352, 987; (e) Zheng, Z.; Perkins, B. L.; Ni, B. J. Am.
Chem. Soc. 2010, 132, 50; (f) Lombardo, M.; Chiarucci, M.; Quintavalla, A.;
Trombini, C. Adv. Synth. Catal. 2009, 351, 2801; (g) Alza, E.; Pericas, M. Adv. Synth.
Catal. 2009, 351, 3051; (h) Uehara, H.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2009,
48, 9848; (i) Wiesner, M.; Revell, J. D.; Wennemers, H. Angew. Chem., Int. Ed.
To a solution of 2a (145 mg, 0.6 mmol) in MeOH (18 ml) was
added 10% Pd(OH)2/C (30 mg). The resultant mixture was stirred
under hydrogen at 5 atm for 24 h. After the catalyst was filtered off,
the filtrate was concentrated and the residue was dissolved in
CH2Cl2 (15 ml). To this solution were added TsCl (126 mg,
0.66 mmol) and TEA (0.13 ml, 0.9 mmol) at 0 ꢀC. The mixture was
stirred at room temperature overnight and quenched by adding
1 M HCl. The mixture was extracted with CH2Cl2, washed with
brine, and dried over Na2SO4. Concentration and flash chroma-
2008, 47, 1871; (j) Zhu, Sˇ .; Yu, S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 545; (k)
ꢀ
García-García, P.; Ladepeche, A.; Halder, R.; List, B. Angew. Chem., Int. Ed. 2008, 47,
4719; (l) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed.
2006, 45, 3093; (m) Palomo, C.; Vera, S.; Mielgo, A.; Gomez-Bengoa, E. Angew.
Chem., Int. Ed. 2006, 45, 5984; (n) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 4966; (o) Wang, W.; Wang,
J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369; (p) Hayashi, Y.; Gotoh, H.; Hayashi,
T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212; (q) Betancort, J. M.; Barbas, C. F.
, III. Org. Lett. 2001, 3, 3737.
tography (1:50 to 1:20 EtOAc/hexanes as elute) afforded 6 (155 mg,
29
73%) as a colorless oil. [
(400 MHz, CDCl3)
a]
þ2.99 (c 0.95, CHCl3); 1H NMR
D
d
7.72 (d, J¼8.0 Hz, 2H, CH]C), 7.33 (d, J¼8.0 Hz,
3. (a) Andrey, O.; Vidonne, A.; Alexakis, A. Tetrahedron Lett. 2003, 44, 7901; (b)
Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo, L. Org. Lett. 2006, 8, 6135; (c)
Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304; (d)
Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem., Int. Ed. 2010, 49, 4656; (e)
Reddy, R. J.; Chen, K. Org. Lett. 2011, 13, 1458; (f) Wang, Y.; Zhu, S.; Ma, D. Org.
Lett. 2011, 13, 1602.
2H, CH]C), 4.16e4.10 (m, 2H, OCH2CH3), 4.08e4.03 (m, 1H,
CHCH3), 3.68e3.64 (m, 1H, eNCHaHbe), 2.71e2.66 (m, 1H,
eNCHaHb), 2.63e2.56 (m, 1H, CHCOOEt), 2.44 (s, 3H, eC6H4CH3),
2.32e2.27 (m, 1H, CHCH2), 1.46e1.38 (m, 1H, CHaHbCH2CH3),
1.26e1.22 (m, 2H, CH2CH3), 1.26 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.19 (d,
J¼6.4 Hz, 3H, CHCH3), 1.02e1.92 (m, 1H, CHaHbCH2CH3), 0.86 (t,
4. Guo, L.; Chi, Y.; Almeida, A. M.; Guzei, I. A.; Parker, B. K.; Gellman, S. H. J. Am.
Chem. Soc. 2009, 131, 16018.
J¼7.2 Hz, 3H, CHaHbCH2CH3); 13C NMR (100 MHz, CDCl3)
d 170.5,
5. Stevenson, B.; Lewis, W.; Dowden, J. Synlett 2010, 672.
ꢀ
6. Duschmale, J.; Wennemers, H. Chem.dEur. J. 2012, 18, 1111.
143.7, 134.7, 129.9 (2C), 127.6 (2C), 60.9, 57.1, 53.5, 52.8, 38.6, 34.6,
21.7, 21.2, 19.2, 14.3, 14.2; HRMS (ESI) m/z calcd for C18H27NNaO4S
(MþNa)þ 376.1559, found: 376.1554.
7. Swiderska, M. A.; Stewart, J. D. Org. Lett. 2006, 8, 6131.
8. Fryszkowska, A.; Fisher, K.; Gardiner, J. M.; Stephens, G. M. J. Org. Chem. 2008, 73,
4295.