Asymmetric domino nitro-michael/horner-wadsworth-emmons reaction for disubstituted cyclohexenecarboxylate annulation: Efficient synthesis of dipeptidyl peptidase IV inhibitor ABT-341 and influenza neuraminidase inhibitor

Article abstract of DOI:10.1002/adsc.201200093

An asymmetric domino nitro-Michael/Horner-Wadsworth-Emmons (HWE) reaction involving α,β-unsaturated aldehydes and nitro phosphonates has been developed, which gave 4,5-disubstituted cyclohexenecarboxylates with high stereoselectivities (dr up to >20:1, ee

Full text of DOI:10.1002/adsc.201200093

FULL PAPERS
DOI: 10.1002/adsc.201200093
Asymmetric Domino Nitro-Michael/Horner–Wadsworth–Emmons
Reaction for Disubstituted Cyclohexenecarboxylate Annulation:
Efficient Synthesis of Dipeptidyl Peptidase IV Inhibitor ABT-341
and Influenza Neuraminidase Inhibitor
Jiang Weng,a Jun-Ming Li,a Feng-Quan Li,a Zhi-Sheng Xie,a and Gui Lua,b,*
a
Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Peopleꢀs
Republic of China
Fax : (+86)-20-3994-3048; e-mail: lugui@mail.sysu.edu.cn
Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, Peopleꢀs Republic of China
b
Received: February 4, 2012; Revised: April 18, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200093.
Abstract: An asymmetric domino nitro-Michael/ pharmaceutically useful compounds (such as the di-
Horner–Wadsworth–Emmons (HWE) reaction in- peptidyl peptidase IV inhibitor ABT-341 and an in-
volving a,b-unsaturated aldehydes and nitro phos- fluenza neuraminidase inhibitor) has also been ac-
phonates has been developed, which gave 4,5-disub- complished.
stituted cyclohexenecarboxylates with high stereose-
lectivities (dr up to >20:1, ee 83–92%) in good
yields (44–76%). Furthermore, using this methodolo- Keywords: asymmetric synthesis; domino reactions;
gy as a key step, a short and practical synthesis of Michael addition; organocatalysis
Introduction
the development of conceptually different and target-
oriented synthetic alternatives is still in the nascent
In the past decade organocatalytic domino reactions stage.
have attracted increasing attention and become a pow-
ABT-341 is a highly potent, selective and orally ef-
erful tool for the efficient and stereoselective con- ficacious third-generation DPP-4 inhibitor developed
struction of complex molecules.[1,2] These reactions by Abbott laboratories in 2006.[5] In Abbottꢀs synthe-
allow the formation of multiple new bonds and ste- sis, the chiral ABT-341 was obtained after 11 steps
reocenters in a single operation under mild condi-
tions, thereby minimizing the time- and cost-consum-
ing purification steps and reducing the generation of
wastes. They also offer the opportunity to access com-
plex organic molecules which are difficult to assemble
by traditional chemical synthesis.
Highly functional cyclohexene groups are privi-
leged structural motifs of many natural products and
pharmaceutical molecules, such as the neuraminidase
(NA) inhibitors tamiflu (oseltamivir phosphate)[3] and
tamiphosphor,[4] the dipeptidyl peptidase IV (DPP-4)
inhibitor ABT-341[5] (Figure 1). Consequently, asym-
metric reactions involved in the synthesis of cyclohex-
ene scaffolds have attracted considerable interest
from the organic synthesis community.[6] Following
the pioneering work of Enders and co-workers in
2006,[7] different types of organocatalytic domino an-
Figure 1. Representative chiral drugs containing a highly
nulation reactions have been explored.[8] However, functional cyclohexene scaffold.
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with very low yield. Moreover, chiral high-perfor- needed to be considered. (i) The addition of nitroal-
mance liquid chromatography (HPLC) separation of kane to a,b-unsaturated aldehyde is the initial step of
the key intermediate aminocyclohexenecarboxylate the cascade reaction, but the diastereoselectivity was
(1, Figure 1) was needed for obtaining the optically moderate (usually 1:1) in most cases when long-chain
pure inhibitor. Furthermore, substituted cyclohexene- nitroalkanes were used as substrates.[14] (ii) The HWE
carboxylate 1 could also serve as the precursor for reaction, as an important olefin-formation reaction,
oseltamivir and tamiphosphor. Therefore develop- has been reported to a lesser extent in organocatalytic
ment of an efficient and general enantioselective syn- domino annulation reactions compared with the
thetic approach for obtaining the building block 1 is Wittig reaction,[15] ring-closing metathesis reaction,[6b]
highly desirable.
aldol reaction,[7,8h,i,16] and other reactions, mainly be-
As a part of our ongoing research on organocataly- cause of the need to use large amount of bases.
sis[9] and drug synthesis,[10] we set out to develop a gen- Hence, the basicity and quantity of the base used
eral organocatalytic approach for the asymmetric syn- should be compatible with the initial Michael reac-
thesis of 4,5-disubstituted cyclohexenecarboxylate (1), tion. (iii) The sequence of the domino reaction should
and then apply the method for the synthesis of ABT- be a Michael reaction, followed by the HWE reaction.
341 and oseltamivir analogues.[11] In the meantime, If the HWE reaction takes place first, then the enan-
Hayashi and co-workers have recently developed tioselectivity will be decreased because the aldehyde
a one-pot, high-yielding synthesis of ABT-341, in will be consumed and the chiral iminium intermediate
which the asymmetric domino Michael/Michael/ cannot be formed.
Horner–Wadsworth–Emmons (HWE) reaction of
acetaldehyde, nitroalkene and vinyl phosphonate was
used as the key step (Scheme 1).[12] Differently, herein Results and Discussion
we envisioned that the key intermediate 2 in Haya-
shiꢀs route towards ABT-341 could also be assembled Screening of Organocatalysts and Optimization of
from an a,b-unsaturated aldehyde (3) and a nitro Reaction Conditions for the Domino Reaction
phosphonate (4) through a secondary amine-catalyzed
domino nitro-Michael/HWE reaction.
Based on these considerations, the domino reaction
The racemic version of this reaction has been car- between cinnamaldehyde (3a) and nitro phosphonate
ried out by Kraus using stoichiometric 1,8- (4a) was selected as a model reaction. We first studied
diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU), although gen- the domino reaction catalyzed by diphenyl prolinol
erally low to moderate yields (seven examples, 26– silyl ether I (20 mol%) in the presence of Et3N and
74% yields) have been obtained.[13] However, for our LiCl in chloroform at ambient temperature. To our
newly designed asymmetric reaction, some challenges delight, the reaction proceeded smoothly to furnish
the desired product 2a with modest stereoselectivity
(72% ee, 2:1 dr); however, the yield was low (Table 1,
entry 1). Then several organic and inorganic bases
were screened (Table 1, entries 2–7), a higher yield
was obtained when 1,4-diazabicycloACTHNUGRTENUNG[2.2.2]octane
(DABCO) was used, and the diastereo- and enantio-
selectivity were also improved (entry 4). Considering
the positive role of lithium salt additives in HWE re-
actions, other lithium salts (LiClO4 and LiBr) were
also examined, higher yield and diastereoselectivity
were obtained when the additive was LiClO4
(entry 8). Next, a range of solvents was explored, and
the highest ee value was achieved in CH2Cl2
(entry 10).[17] Subsequently, other secondary amine or-
ganocatalysts II–VII were screened to improve the
enantioselectivity (entries 11–16) and catalyst III was
found to be the most promising candidate for this
transformation (entry 12).
Scheme 1. Domino Michael/Michael/HWE and Michael/
HWE annulation for the synthesis of the ABT-341 inter-
mediate 2.
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Asymmetric Domino Nitro-Michael/Horner–Wadsworth–Emmons Reaction
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Solvent
Base
Lithium salt
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et3N
DIPEA
DBU
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiClO4
LiBr
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
35
54
70
54
68
52
36
68
46
70
48
75
53
36
30
50
2:1
2:1
3:1
6:1
3:1
1.5:1
2:1
20:1
5:1
>20:1
10:1
>20:1
>20:1
>20:1
5:1
72
41
27
86
78
70
85
86
70
88
90
92
89
24
38
70
DABCO
NaOAc
Cs2CO3
K2CO3
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
9
I
I
10
11
12
13
14
15
16
II
III
IV
V
VI
VII
6:1
[a]
Reactions were performed with cinnamaldehyde 3a (0.3 mmol), nitro phosphonate 4a (0.36 mmol), base (0.3 mmol) and
lithium salt (0.3 mmol) with a secondary amine (0.06 mmol) as catalyst in solvent (1.5 mL) at room temperature for 60 h.
Isolated yield.
Determined by H NMR spectroscopy of the crude products.
Determined by chiral HPLC analysis.
[b]
[c]
[d]
1
Domino Nitro-Michael/HWE Reactions of Various
a,b-Unsaturated Aldehydes and Nitro Phosphonate
and diastereoselectivities were slightly lower, and
a longer reaction time was needed (entries 12 and 13).
With the optimized reaction conditions in hand, vari-
ous a,b-unsaturated aldehydes were examined and Absolute Structure Determination and Proposed
the results are summarized in Table 2. In most cases, Mechanism
the annulation products were obtained in good yields
with high dr and ee values. For aryl-substituted unsa- To determine the absolute configuration of the prod-
turated aldehydes, the steric hindrance of the aryl ucts, a single crystal of compound 2b was obtained for
group showed some influence on the diastereoselec- X-ray crystallographic analysis (Figure 2).[18] The
tivities (entries 2, 3, 5–7), while the electronic proper- newly formed chiral centers of 2b were confirmed as
ties of the aryl groups have limited effects, both elec- (4S,5R). On the basis of this observation, a plausible
tron-deficient (Cl, F) and electron-rich (OMe, Me) catalytic cycle for the asymmetric domino nitro-Mi-
aryl substituents exhibited similar efficiency on the chael/HWE reaction is proposed in Scheme 2. The re-
process (entries 2, 4, 7, 8). Good results were also ob- action starts with the iminium activation of the a,b-
tained for 2,4,5-trifluorophenyl-substituted (precursor unsaturated aldehyde 3 by the secondary amine, fol-
of ABT-341) and 2-furyl-substituted a,b-unsaturated lowed by the nitro-Michael addition of the nitro com-
aldehyde (entries 10 and 11). Moreover, the reaction pound 4 to the iminium ion to give the intermediate
could be successfully extended to a,b-unsaturated al- A. After enamine/iminium transformation, the inter-
dehydes with alkyl substituents; however, the yields mediate B then hydrolyzes to release C and regener-
ates the secondary amine catalyst. The following cas-
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Table 2. Substrate scope of the asymmetric domino nitro-Michael/HWE reaction.[a]
Entry
R group
Product
Time [h]
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
60
72
72
72
60
60
60
60
48
48
72
96
72
75
68
62
66
66
65
61
63
76
65
54
44
51
>20:1
>20:1
10:1
>20:1
6:1
92
92
89
89
89
87
88
90
86
83
88
83
89
p-MeO-C6H4
o-MeO-C6H4
p-Me-C6H4
o-Cl-C6H4
m-Cl-C6H4
p-Cl-C6H4
p-F-C6H4
o-NO2-C6H4
2,4,5-F3-C6H2
2-furyl
10:1
>20:1
>20:1
>20:1
10:1
10:1
2:1
9
10
11
12
13
2j
2k
2l
n-Pr
(CH3O)2CH
2m
3:1
[a]
Reactions were performed with a,b-unsaturated aldehyde 3 (0.3 mmol), nitro phosphonate 4a (0.36 mmol), DABCO
(0.3 mmol) and LiClO4 (0.3 mmol), III (0.06 mmol) as catalyst in CH2Cl2 (1.5 mL) at room temperature.
Isolated yield.
Determined by H NMR spectroscopy of the crude products.
Determined by chiral HPLC analysis.
[b]
[c]
[d]
1
cade reaction involves intramolecular HWE cycliza- Application in the Synthesis of DPP-4 Inhibitor
tion of C to yield the disubstituted cyclohexenecar- ABT-341
boxylate 5. Then the cis isomer 5 is converted to the
trans isomer for the latter is thermodynamically more As shown in Figure 1 and Scheme 1, the disubstituted
stable under basic conditions.
cyclohexenecarboxylate (1) can be the key precursor
for oseltamivir, tamiphosphor and ABT-341. The use-
fulness of our methodology in organic synthesis was
further illustrated by the short synthesis of ABT-341
as outlined in Scheme 3. The asymmetric domino
nitro-Michael/HWE reaction of the a,b-unsaturated
aldehyde 3n with nitro phosphonate 4b in the pres-
ence of 20 mol% catalyst (R)-III provided the cycliza-
tion product 2n (65% isolated yield, 10:1 dr, 90% ee).
Then we adopted Hayashiꢀs strategy[12] to convert 2n
to ABT-341 in a one-pot operation: deprotection of
the tert-butyl ester group with CF3CO2H, amidation
with the amine 6 in the presence of the coupling re-
agent TBTU, and reduction of the nitro moiety of 7
with Zn and AcOH. ABT-341 was obtained in 55%
overall yield from a,b-unsaturated aldehyde 3n.
Application in the Synthesis of Influenza
Neuraminidase Inhibitor
Furthermore, using this methodology as a key step,
a short method for the synthesis of NA inhibitors has
also been established. The selection of our NA inhibi-
tor scaffold was based on the structures of oseltamivir
Figure 2. X-ray crystal structure of the compound 2b.
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Asymmetric Domino Nitro-Michael/Horner–Wadsworth–Emmons Reaction
Scheme 2. Proposed mechanism for the domino nitro-Michael/HWE reaction.
Scheme 3. Synthesis of DPP-4 inhibitor ABT-341.
and peramivir.[19] As illustrated in Scheme 4, we have 12. Our synthesis started with the construction of
developed an efficient method for the diversity-ori- a disubstituted cyclohexenecarboxylate 9 from g-
ented synthesis of a new type of NA inhibitor such as amino-a,b-unsaturated aldehyde 8 and nitro phospho-
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Scheme 4. Synthesis of the neuraminidase inhibitor 12.
nate 4a. Substrate 8 can be easily prepared from l- DPP-4 inhibitor ABT-341, influenza neuraminidase
leucinol. Initially the catalytic reaction of 8 and 4a inhibitors and other therapeutically useful compounds
was performed under the optimized reaction condi- can be achieved. Further investigations into the appli-
tion using (R)-III, but low yield and stereoselectivity cation of this methodology are currently ongoing, the
(12% 9b and 11% 9a) were obtained even after 96 h. results of which will be presented in due course.
Then a stoichiometric organic base was adopted to ac-
celerate the reaction. The treatment of 8 and 4a with
stoichiometric DBU in CH2Cl2 at ambient tempera- Experimental Section
ture yielded the cyclization products 9a–c in 52%
yield. The absolute configurations of the diastereoiso- General Remarks
mers 9a and 9b were determined by X-ray crystallo-
graphic analysis. Then after deprotection and acetyla-
All the commercial reagents were used as such without fur-
ther purification. All solvents were used as commercial an-
tion of the diastereoisomer 9b, 10 was obtained in
73% overall yield. The following reduction of 10 gave
the amine 11 in 52% isolated yield. After hydrolysis
of the ester 11, the desired inhibitor 12 was obtained
with IC50 =1.9 mm for NA inhibition. Using this
domino nitro-Michael/HWE reaction as a key step,
diversity-oriented synthesis of new types of NA inhib-
itors is currently being developed in our laboratory,
together with their biological testing as anti-influenza
agents.[20]
hydrous grade without further purification. The flash
column chromatography was carried out over silica gel
1
(230–400 mesh). H and 13C NMR spectra were recorded on
1
a 400 MHz spectrometer. Chemical shifts in H NMR spec-
tra were reported in parts per million (ppm, d) downfield
from the internal standard Me4Si (TMS, d=0 ppm). Chemi-
cal shifts in 13C NMR spectra were reported relative to the
central line of the chloroform signal (d=77.0 ppm). Peaks
were labeled as singlet (s), doublet (d), triplet (t), quartet
(q), and multiplet (m). High-resolution mass spectra were
obtained with an LC-MS-IT-TOF mass spectrometer. Enan-
tiomeric excesses of compounds were determined by HPLC
using a Daicel Chiralpak IC, AD-H or AS-H column.
Conclusions
In summary, motivated by the lack of an efficient
method for the preparation of the DPP-4 inhibitor
ABT-341 and its analogues, we have developed an ef-
ficient asymmetric domino nitro-Michael/HWE reac-
tion involving a,b-unsaturated aldehydes and nitro
phosphonates. This mild and simple experiment pro-
tocol yields disubstituted cyclohexenecarboxylates
with high diastereo- and enantioselectivity. Using this
General Procedure for the Asymmetric Domino
Michael/HWE Reactions
To a solution of a,b-unsaturated aldehyde 3a (40.0 mg,
0.3 mmol), LiClO4 (31.5 mg, 0.3 mmol), DABCO (33.6 mg,
0.3 mmol) and catalyst III (22.9 mg, 0.06 mmol) in CH2Cl2
(1.5 mL) was added nitro phosphonate 4a (0.36 mmol,
106.9 mg), and the resulting solution was stirred for 60 h at
ambient temperature. The reaction mixture was directly pu-
methodology as a key step, the short synthesis of rified by silica gel chromatography eluted with EtOAc/pe-
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Asymmetric Domino Nitro-Michael/Horner–Wadsworth–Emmons Reaction
troleum ether, and fractions were collected and concentrat-
136.7, 133.9, 130.4, 128.9, 127.6, 127.2, 127.1, 84.2, 61.0, 39.3,
ed under vacuum to provide the pure desired product 2a.
ACHTUNGTRENNUNG(4S,5R)-Ethyl 5-nitro-4-phenylcyclohex-1-enecarboxylate
31.4, 29.4, 14.2; HR-MS (ESI): m/z=332.0655, calcd. for
+
C15H16ClNNaO4 [M+Na]+: 332.0660; [a]2D5: À19.1 (c 0.5,
(2a): yield: 75%; yellow oil; 1H NMR (400 MHz, CDCl3):
d=7.34–7.20 (m, 5H), 7.06 (m, 1H), 4.94 (td, J=5.4,
13.0 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.44 (td, J=5.9,
10.4 Hz, 1H), 3.16–3.09 (m, 1H), 3.00–2.92 (m, 1H), 2.78–
2.70 (m, 1H), 2.57–2.48 (m, 1H), 1.31 (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=166.5, 139.0, 137.4, 129.0,
127.9, 127.3, 127.1, 86.7, 61.0, 43.2, 32.9, 29.7, 14.2; HR-MS
CHCl3). The enantiomeric excess was determined by HPLC
(Chiralpak IC column, hexane/i-PrOH=95/5, 1.0 mLminÀ1,
254 nm): tmajor =27.8 min, tminor =25.9 min.
AHCTUNGTREG(NNUN 4S,5R)-Ethyl 5-nitro-4-(3-chlorophenyl)cyclohex-1-ene-
carboxylate (2f): yield: 65%; white solid; mp 92–938C;
1H NMR (400 MHz, CDCl3): d=7.27–7.25 (m, 2H), 7.21 (m,
1H), 7.12–7.09 (m, 1H), 7.04 (m, 1H), 4.91 (td, J=5.4,
10.4 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.42 (td, J=5.6,
10.4 Hz, 1H), 3.18–3.12 (m, 1H), 2.99–2.91 (m, 1H), 2.77–
2.69 (m, 1H), 2.54–2.46 (m, 1H), 1.31 (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=165.4, 141.1, 137.0, 134.8,
130.3, 128.2, 127.6, 127.2, 125.5, 86.4, 61.0, 43.0, 32.8, 29.8,
+
(ESI): m/z=298.1036, calcd. for C15H17NNaO4 [M+Na]+:
298.1050; [a]25: À34.7 (c 0.5, CHCl3); The enantiomeric
excess was dDetermined by HPLC (Chiralpak IC column,
hexane/i-PrOH=95/5, 1.0 mLminÀ1,
29.9 min, tminor =28.3 min.
230 nm):
tmajor =
A
5-nitro-4-(4-methoxyphenyl)cyclohex-1-
14.2;
HR-MS
(ESI):
m/z=332.0672,
calcd.
for
+
C15H16ClNNaO4 [M+Na]+: 332.0660; [a]2D5: À41.8 (c 0.5,
CHCl3). The enantiomeric excess was determined by HPLC
(Chiralpak IC column, hexane/i-PrOH=90/10, 1.0 mLminÀ1,
230 nm): tmajor =25.2 min, tminor =16.7 min.
enecarboxylate (2b): yield: 68%; white solid; mp 149–
1
1528C; H NMR (400 MHz, CDCl3): d=7.14–7.11 (m, 2H),
7.05 (m, 1H), 6.86–6.83 (m, 2H), 4.90–4.84 (td, J=5.2,
10.1 Hz, 1H), 4.23 (q, J=7.2 Hz, 2H), 3.77 (s, 3H), 3.38 (td,
J=6.4, 10.8 Hz, 1H), 3.18–3.08 (m, 1H), 2.99–2.95 (m, 1H),
2.73–2.66 (m, 1H), 2.54–2.49 (m, 1H), 1.31 (t, J=7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=165.6, 159.2, 137.6,
130.9, 128.3, 127.0, 114.4, 87.1, 60.9, 55.2, 42.6, 33.0, 29.8,
AHCTUNGTREG(NNUN 4S,5R)-Ethyl 5-nitro-4-(4-chlorophenyl)cyclohex-1-ene-
carboxylate (2g): yield: 61%; white solid; mp 92–948C;
1H NMR (400 MHz, CDCl3): d=7.31–7.28 (m, 2H), 7.16–
7.14 (m, 2H), 7.05–7.03 (m, 1H), 4.89 (td, J=5.6, 10.4 Hz,
1H), 4.24 (q, J=7.2 Hz, 2H), 3.41 (td, J=6.0, 10.4 Hz, 1H),
3.17–3.10 (m, 1H), 2.98–2.90 (m, 1H), 2.76–2.68 (m, 1H),
2.53–2.43 (m, 1H), 1.31 (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=165.4, 137.5, 137.1, 133.8, 129.2,
128.7, 127.2, 86.6, 61.0, 42.8, 32.9, 29.8, 14.2; HR-MS (ESI):
14.2;
HR-MS
(ESI):
m/z=328.1155,
calcd.
for
+
C16H19NNaO5 [M+Na]+: 328.1155; [a]2D5: À60.0 (c 0.5,
CHCl3); The enantiomeric excess was determined by HPLC
(Chiralpak
0.8 mLminÀ1, 230 nm): tmajor =22.5 min, tminor =18.9 min;
(4S,5R)-Ethyl 5-nitro-4-(2-methoxyphenyl)cyclohex-1-
AS-H
column,
hexane/i-PrOH=95/5,
ACHTUNGTRENNUNG
+
m/z=332.0658, calcd. for C15H16ClNNaO4 [M+Na]+:
enecarboxylate (2c): yield: 62%; white solid; mp 77–788C;
1H NMR (400 MHz, CDCl3): d=7.26–7.21 (m, 1H), 7.11–
7.06 (m, 2H), 6.91–6.87 (m, 2H), 5.28 (td, J=6.4, 9.2 Hz,
1H), 4.23 (q, J=7.2 Hz, 2H), 3.84 (s, 3H), 3.75–3.68 (m,
1H), 3.07–2.89 (m, 2H), 2.69–2.67 (m, 2H), 1.33 (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=165.8, 157.3,
138.1, 129.0, 128.9, 126.8, 121.0, 111.3, 84.3, 60.8, 55.4, 39.6,
30.7, 29.5, 14.2; HR-MS (ESI): m/z=328.1145, calcd. for
332.0660; [a]2D5: À48.2 (c 0.5, CHCl3). The enantiomeric
excess was determined by HPLC (Chiralpak IC column,
hexane/i-PrOH=95/5, 1.0 mLminÀ1,
33.9 min, tminor =30.3 min.
230 nm):
tmajor =
AHCTUNGTREG(NNUN 4S,5R)-Ethyl 5-nitro-4-(4-fluorophenyl)cyclohex-1-ene-
carboxylate (2h): yield: 63%; white solid; mp 79–818C;
1H NMR (400 MHz, CDCl3): d=7.21–7.17 (m, 2H), 7.05–
6.99 (m, 3H), 4.92–4.86 (td, J=5.6, 10.6 Hz, 1H), 4.24 (q,
J=7.2 Hz, 2H), 3.42 (td, J=6.4, 10.4 Hz, 1H), 3.17–3.15 (m,
1H), 2.99–2.91 (m, 1H), 2.76–2.69 (m, 1H), 2.53–2.45 (m,
1H), 1.31 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=165.5, 162.2, 137.2, 134.7, 128.9, 127.1, 116.0, 115.8, 86.9,
61.0, 42.6, 33.0, 29.8, 14.2; HR-MS (ESI): m/z=316.0953,
+
C16H19NNaO5 [M+Na]+: 328.1155; [a]2D5: À28.6 (c 0.5,
CHCl3); The enantiomeric excess was determined by HPLC
(Chiralpak IC column, hexane/i-PrOH=95/5, 1.0 mLminÀ1,
230 nm): tmajor =26.2 min, tminor =22.1 min.
ACHTUNGTRENNUNG(4S,5R)-Ethyl 5-nitro-4-(4-methylphenyl)cyclohex-1-ene-
carboxylate (2d): yield: 66%; white solid; mp 125–1278C;
1H NMR (400 MHz, CDCl3): d=7.26–7.05 (m, 5H), 4.90 (td,
J=5.6, 10.4 Hz, 1H), 4.23 (q, J=7.2 Hz, 2H), 3.39 (td, J=
6.0, 10.4 Hz, 1H), 3.14–3.08 (m, 1H), 2.99–2.90 (m, 1H),
2.75–2.68 (m, 1H), 2.56–2.45 (m, 1H), 2.31 (s, 3H), 1.31 (t,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=165.6,
137.6, 137.5, 136.0, 129.7, 127.1, 127.0, 86.9, 60.9, 42.9, 33.0,
29.8, 21.0, 14.2; HR-MS (ESI): m/z=312.1204, calcd. for
+
calcd. for C15H16FNNaO4 [M+Na]+: 316.0956; [a]D25: À36.4
(c 0.5, CHCl3); The enantiomeric excess was determined by
HPLC (Chiralpak IC column, hexane/i-PrOH=95/5,
1.0 mLminÀ1, 230 nm): tmajor =31.1 min, tminor =28.4 min.
AHCTUNGERTG(NNUN 4S,5R)-Ethyl 5-nitro-4-(2-nitrophenyl)cyclohex-1-enecar-
boxylate (2i): yield: 76%; yellow oil; 1H NMR (400 MHz,
CDCl3): d=7.85 (m, 1H), 7.63–7.58 (m, 1H), 7.45–7.41 (m,
2H), 7.07 (m, 1H), 5.09 (td, J=5.2, 10.4 Hz, 1H), 4.25 (q,
J=7.2 Hz, 2H), 4.09 (td, J=4.8, 10.8 Hz, 1H), 3.24 (dd, J=
5.2, 17.6 Hz, 1H), 3.11–3.03 (m, 1H), 2.92–2.86 (m, 1H),
2.49–2.42 (m, 1H), 1.32 (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=165.3, 150.4, 137.1, 134.0, 133.4,
128.6, 127.3, 127.1, 125.1, 85.2, 61.1, 37.9, 32.9, 30.3, 14.2;
+
C16H19NNaO4 [M+Na]+: 312.1206; [a]2D5: À54.9 (c 0.72,
CHCl3). The enantiomeric excess was determined by HPLC
(Chiralpak IC column, hexane/i-PrOH=95/5, 1.0 mLminÀ1,
230 nm): tmajor =28.1 min, tminor =26.2 min.
ACHTUNGTRENNUNG(4S,5R)-Ethyl-5-nitro-4-(2-chlorophenyl)cyclohex-1-ene-
carboxylate (2e): yield: 66%; colorless oil; 1H NMR
(400 MHz, CDCl3): d=7.38 (m, 1H), 7.26–7.19 (m, 3H),
7.07 (m, 1H), 5.13 (td, J=5.6, 9.6 Hz, 1H), 4.24 (q, J=
7.2 Hz, 2H), 4.09 (td, J=6.0, 9.6 Hz, 1H), 3.12–2.96 (m,
2H), 2.86–2.78 (m, 1H), 2.47–2.40 (m, 1H), 1.32 (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=165.5, 137.2,
+
HR-MS (ESI): m/z=343.0910, calcd. for C15H16N2NaO6
[M+Na]+: 343.0901; [a]D25: +92.5 (c 0.5, CHCl3). The enan-
tiomeric excess was determined by HPLC (Chiralpak AD-H
column, hexane/i-PrOH=87/13, 0.8 mLminÀ1, 254 nm):
t
major =14.4 min, tminor =16.4 min.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
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Jiang Weng et al.
FULL PAPERS
A
(Chiralpak IC column, hexane/i-PrOH=99/1, 1.0 mLminÀ1,
210 nm): tmajor =20.4 min, tminor =26.1 min.
enecarboxylate (2j): yield: 65%; yellow oil; 1H NMR
(400 MHz, CDCl3): d=7.05–6.91 (m, 3H), 5.02 (td, J=6.0,
10.4 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.63 (td, J=6.0,
10.4 Hz, 1H), 3.19–3.13 (m, 1H), 2.98–2.89 (m, 1H), 2.76–
2.69 (m, 1H), 2.61–2.51 (m, 1H) 1.31 (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=165.3, 136.5, 127.2, 122.3,
122.1, 117.6, 117.0, 106.5, 106.2, 84.5, 61.1, 38.1, 31.2, 29.7,
tert-Butyl 2-(Diethoxyphosphoryl)-4-nitrobutanoate
(4b)
Product 4b was synthesized from tert-butyl 2-(diethoxyphos-
phoryl)acrylate[11] according to the literature;[12] yield: 65%;
yellow oil; 1H NMR (400 MHz, CDCl3): d=4.57–4.43 (m,
2H), 4.16–4.10 (m, 1H), 2.96 (td, J=7.3, 19.3 Hz, 1H), 2.51
(td, J=7.2, 16.6 Hz, 1H), 1.45 (s, 9H), 1.33 (t, J=7.1 Hz,
3H), 1.31 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=166.7 (d, J=5.6 Hz), 82.7, 73.1 (d, J=12.8 Hz), 62.9 (t,
J=6.3 Hz), 43.5, 42.2, 27.7, 24.5, 16.2, 16.1; HR-MS (ESI):
m/z=348.1180, calcd. for C12H24NNaO7P+ [M+Na]+:
348.1183.
14.2;
C15H14F3NNaO4 [M+Na]+: 352.0767; [a]2D5: À93.0 (c 0.5,
CHCl3). The enantiomeric excess was determined by HPLC
(Chiralpak IC column, hexane/i-PrOH=95/5, 1.0 mLminÀ1,
254 nm): tmajor =18.9 min, tminor =15.3 min.
ACHTUNGTRENNUNG(4S,5R)-Ethyl 5-nitro-4-(furan-2-yl)cyclohex-1-enecarbox-
ylate (2k): yield: 54%; yellow oil; 1H NMR (400 MHz,
CDCl3): d=7.34 (d, J=1.3 Hz, 1H), 7.03 (m, 1H), 6.28 (dd,
J=1.9, 3.0 Hz, 1H), 6.15 (d, J=3.2 Hz, 1H), 4.93 (m, 1H),
4.22 (q, J=7.2 Hz, 2H), 3.65 (td, J=9.2, 12.4 Hz, 1H), 3.00–
AHCTUNGTREG(NNNU 4R,5S)-Ethyl 4-{(S)-1-[(tert-Butoxycarbonyl)amino]-
2.97 (m, 2H), 2.73–2.68 (m, 2H), 1.30 (t, J=7.2 Hz, 3H); 3-methylbutyl}-5-nitrocyclohex-1-enecarboxylate (9b)
13C NMR (100 MHz, CDCl3): d=165.5, 151.9, 142.4, 136.5,
To a solution of a,b-unsaturated aldehyde 8 (121 mg,
0.5 mmol) and nitro phosphonate 4a (149 mg, 0.5 mmol) in
126.7, 110.4, 107.3, 84.6, 60.9, 36.4, 29.1, 28.6, 14.2; HR-MS
+
(ESI): m/z=288.0832, calcd. for C13H15NNaO5 [M+Na]+:
CH2Cl2 (2 mL) was added DBU (152 mg, 1 mmol) at 08C,
288.0842; [a]25: À40.7 (c 1.0, CHCl3). The enantiomeric
excess was dDetermined by HPLC (Chiralpak IC column,
and the resulting solution was stirred for 24 h at ambient
temperature. The reaction mixture was directly purified by
hexane/i-PrOH=95/5, 1.0 mLminÀ1,
25.3 min, tminor =23.8 min.
230 nm):
tmajor =
silica gel chromatography eluted with EtOAc/petroleum
ether, and fractions were collected and concentrated under
vacuum to provide pure products 9a, 9b and other diastereo-
isomers 9c. Data for 9b: [a]2D5: +15.8 (c 1.0, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=6.96 (s, 1H), 4.75–4.54 (m,
1H), 4.27 (d, J=8.3 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.97–
3.77 (m, 1H), 3.21–2.98 (m, 1H), 2.75 (d, J=15.4 Hz, 1H),
2.58–2.24 (m, 2H), 2.16 (s, 1H), 1.70–1.47 (m, 2H), 1.43 (s,
10H), 1.29 (t, J=7.1 Hz, 3H), 0.98–0.87 (m, 6H); 13C NMR
(100 MHz, CDCl3): d=165.4, 155.5, 137.0, 126.9, 83.1, 79.7,
60.8, 48.2, 41.5, 39.6, 29.8, 28.2, 25.0, 24.8, 23.0, 21.9, 14.2;
ACHTUNGTRENNUNG(4R,5R)-Ethyl 5-nitro-4-propylcyclohex-1-enecarboxylate
(2l): yield: 44%; yellow oil; 1H NMR (400 MHz, CDCl3):
d=6.95 (s, 1H), 4.50 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 2.91
(m, 2H), 2.59–2.51 (m, 1H), 2.32–2.27 (m, 1H), 2.07–1.99
(m, 1H), 1.47–1.24 (m, 4H), 1.30 (t, J=7.2 Hz, 3H), 0.91 (t,
J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=165.8,
137.2, 126.6, 86.6, 60.8, 35.7, 33.9, 29.3, 28.5, 19.2, 14.2, 13.9;
+
HR-MS (ESI): m/z=264.1202, calcd. for C12H19NNaO4
[M+Na]+: 264.1206; [a]D25: À48.4 (c 1.0, CHCl3). The enan-
tiomeric excess was determined by HPLC (Chiralpak IC
column, hexane/i-PrOH=95/5, 1.0 mLminÀ1, 210 nm):
+
HR-MS (ESI): m/z=407.2156, calcd. for C19H32N2NaO6
[M+Na]+: 407.2153.
t
major =20.2 min, tminor =15.2 min.
(4R,5R)-Ethyl 5-nitro-4-(dimethoxymethyl)cyclohex-1-
A
4-{(S)-1-[(tert-butoxycarbonyl)amino]-3-
ACHTUNGTRENNUNG
methylbutyl}-5-nitrocyclohex-1-enecarboxylate (9a): [a]2D5:
enecarboxylate (2m): yield: 51%; yellow oil; 1H NMR
(400 MHz, CDCl3): d=6.97 (s, 1H), 4.94 (dt, J=2.9, 5.6 Hz,
1H), 4.43–4.30 (m, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.37 (s,
3H), 3.31 (s, 3H), 3.06 (d, J=18.8 Hz, 1H), 2.72–2.55 (m,
1H), 2.49–2.20 (m, 3H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=165.0, 136.6, 125.2, 103.4, 78.6, 59.8,
54.8, 52.5, 37.8, 27.0, 23.5, 13.2; HR-MS (ESI): m/z=
296.1102, calcd. for C12H19NO6Na+ [M+Na]+: 296.1105;
[a]2D5: À37.4 (c 0.5, CH2Cl2). The enantiomeric excess was de-
termined by HPLC (Chiralcel OD-H column, hexane/-
1
À24.8 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3): d=6.94
(s, 1H), 4.76 (dd, J=6.5, 13.7 Hz, 1H), 4.63 (d, J=9.4 Hz,
1H), 4.21 (q, J=7.1 Hz, 2H), 3.74–3.47 (m, 1H), 3.02–2.91
(m, 2H), 2.51–2.21 (m, 3H), 1.73–1.49 (m, 2H), 1.43 (s,
10H), 1.30 (t, J=7.1 Hz, 4H), 0.89 (dd, J=6.5, 16.5 Hz,
6H); 13C NMR (100 MHz, CDCl3): d=165.5, 155.7, 136.4,
126.6, 82.9, 79.5, 60.7, 49.8, 41.7, 40.8, 28.2, 27.8, 26.7, 24.9,
23.4, 21.3, 14.1; HR-MS (ESI): m/z=407.2153, calcd. for
C19H32N2NaO6 [M+Na]+: 407.2153.
iPrOH=90/10, 0.8 mLminÀ1, 210 nm); tmajor =8.8 min, tminor
=
AHCTUNGTREG(NNNU 4R,5S)-Ethyl 4-[(S)-1-Acetamido-3-methylbutyl]-5-
nitrocyclohex-1-enecarboxylate (10)
8.4 min.
ACHTUNGTRENNUNG(4R,5S)-tert-Butyl 5-nitro-4-(2,4,5-trifluorophenyl)cyclo-
hex-1-enecarboxylate[11] (2n): yield: 65%; yellow solid;
1H NMR (400 MHz, CDCl3): d=7.05–6.90 (m, 3H), 5.02
(ddd, J=5.6, 10.8, 10.8 Hz, 1H), 3.60 (ddd, J=6.0, 10.8,
10.8 Hz, 1H), 3.13 (dd, J=5.2, 17.2 Hz, 1H), 2.94–2.83 (m,
1H), 2.70 (ddd, J=5.2, 5.2, 19.6 Hz, 1H), 2.59–2.47 (m, 1H),
1.51 (s, 9H); 13C NMR (100 MHz, CDCl3): d=164.5, 157.2,
148.2, 146.2, 135.5, 128.5, 122.4, 117.2, 106.5, 84.5, 81.4, 38.2,
31.3, 30.0, 28.0; HR-MS (ESI): m/z=380.1085, calcd. for
To a solution of 9b (140 mg, 0.36 mmol) in CH2Cl2 (2 mL)
was added CF3COOH (0.3 mL, 0.4 mmol) at 08C and the re-
sulting solution was stirred for 3 h at ambient temperature.
The reaction was quenched by saturated NaHCO3 solution
(5 mL), then extracted with CH2Cl2 (3ꢂ5 mL). The com-
bined organic layer was dried over anhydrous Na2SO4. After
removal of the solvent under vacuum, DIPEA (93 mg,
0.72 mmol) and AcCl (37 mg, 0.47 mmol) were successively
added to the free amine in dry DCM (2 mL) and stirred for
3 h at room temperature. The resulting mixture was careful-
+
C17H18F3NNaO4 [M+Na]+: 380.1080; [a]2D5: +40.6 (c 0.5,
CHCl3). The enantiomeric excess was determined by HPLC
8
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Asymmetric Domino Nitro-Michael/Horner–Wadsworth–Emmons Reaction
ly quenched by saturated NH4Cl solution (5 mL) and ex-
Acknowledgements
tracted with CH2Cl2 (3ꢂ10 mL). Then the combined organic
layer was dried over Na2SO4 and concentrated under
vacuum. Flash chromatography (SiO2, 2:1 hexane: EtOAc
as eluent) afforded compound 10 as a light yellow white
solid; yield: 86 mg (73%); [a]2D5: +16.3 (c 0.38, CH2Cl2).
1H NMR (400 MHz, CDCl3): d=6.95 (s, 1H), 5.28 (d, J=
8.6 Hz, 1H), 4.63 (td, J=5.6, 9.8 Hz, 1H), 4.21 (q, J=
7.1 Hz, 2H), 4.15–4.10 (m, 1H), 3.06–3.01 (m, 1H), 2.81–
2.75 (m, 1H), 2.66–2.39 (m, 2H), 2.22–2.05 (m, 1H), 1.95 (s,
3H), 1.70–1.37 (m, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.39–1.12
(m, 3H), 0.93 (dd, J=6.5, 18.6 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=170.1, 165.4, 136.8, 126.8, 83.0, 60.9,
47.6, 40.3, 39.6, 29.7, 25.6, 25.1, 23.2, 23.1, 21.8, 14.2; HR-MS
This work was financially supported by The European Com-
mission through the project FP7–201431(CATAFLU.OR)
and the introduction of innovative R&D program of Guang-
dong Province (No. 2009010058). We also thank Dr. Jia-Mei
Chen (Sun Yat-sen University) for X-ray crystal structure
analysis.
References
+
(ESI): m/z=349.1724, calcd. for C16H26N2NaO5 [M+Na]+:
[1] For recent reviews on organocatalysis, see: a) G. Lelais,
D. W. C. MacMillan, Aldrichimica Acta 2006, 39, 79–87;
b) P. I. Dalko, Enantioselective Organocatalysis, Wiley-
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349.1734.
ACHTUNGTRENNUNG(4S,5S)-Ethyl 4-[(S)-1-Acetamido-3-methylbutyl]-5-
aminocyclohex-1-enecarboxylate (11)
To a solution of 10 (43 mg, 0.13 mmol) in EtOH (3 mL) was
added activated Zn powder (425 mg, 6.5 mmol) and trime-
thylsilyl chloride (1.14 mL, 37.2 mmol) slowly at room tem-
perature under an N2 atmosphere. The resulting mixture was
stirred for 2 h. After filtration, the mixtute was neutralized
with ammonia (2 mL) and extracted with CH2Cl2 (3ꢂ5 mL).
Then the combined organic layer was dried over Na2SO4
and concentrated under vacuum. Flash chromatography
(SiO2, 30:1 CH2Cl2: methanol as eluent) afforded compound
11 as a light yellow oil; yield: 20 mg (52%); [a]2D5: +15.0 (c
1
1.07, CH2Cl2). H NMR (400 MHz, CDCl3): d=6.89 (s, 1H),
[2] For reviews on organocatalytic domino reactions, see:
a) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010,
2, 167–178; b) A. Alba, X. Companyo, M. Viciano, R.
Rios, Curr. Org. Chem. 2009, 13, 1432–1474; c) D.
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2007, 119, 1590–1601; Angew. Chem. Int. Ed. 2007, 46,
1570–1581; d) B. Westermann, M. Ayaz, S. S. van Ber-
kel, Angew. Chem. 2010, 122, 858–861; Angew. Chem.
Int. Ed. 2010, 49, 846–849; e) X. Yu, W. Wang, Org.
Biomol. Chem. 2008, 6, 2037–2046.
[3] M. von Itzstein, W.-Y. Wu, G. B. Kok, M. S. Pegg, J. C.
Dyason, B. Jin, T. V. Phan, M. L. Smythe, H. F. White,
S. W. Oliver, P. M. Colman, J. N. Varghese, D. M. Ryan,
J. M. Woods, R. C. Bethell, V. J. Hotham, J. M. Camer-
on, C. R. Penn, Nature 1993, 363, 418–423.
[4] a) J.-J. Shie, J.-M. Fang, S.-Y. Wang, K.-C. Tsai, Y.-S. E.
Cheng, A.-S. Yang, S.-C. Hsiao, C.-Y. Su, C.-H. Wong,
J. Am. Chem. Soc. 2007, 129, 11892–11893; b) J.-J. Shie,
J.-M. Fang, C.-H. Wong, Angew. Chem. 2008, 120,
5872–5875; Angew. Chem. Int. Ed. 2008, 47, 5788–5791.
[5] Z. Pei, X. Li, T. W. von Geldern, D. J. Madar, K. Lon-
genecker, H. Yong, T. H. Lubben, K. D. Stewart, B. A.
Zinker, B. J. Backes, A. S. Judd, M. Mulhern, S. J. Bal-
laron, M. A. Stashko, A. K. Mika, D. W. A. Beno, G. A.
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5.77 (d, J=9.4 Hz, 1H), 4.37–4.31 (m, 1H), 4.18 (dd, J=7.1,
14.2 Hz, 2H), 2.82–2.67 (m, 1H), 2.53–2.27 (m, 2H), 2.00 (s,
3H), 1.98–1.94 (m, 2H), 1.71–1.32 (m, 3H), 1.30–1.26 (m,
3H), 0.97–0.86 (m, 6H); 13C NMR (100 MHz, CDCl3): d=
170.7, 166.9, 137.1, 129.4, 60.4, 46.1, 42.0, 38.7, 29.7, 28.6,
25.5, 25.2, 23.3, 23.0, 22.1, 14.2; HR-MS (ESI): m/z=
+
297.2164, calcd. for C16H28N2O3 [M+H]+: 297.2173.
ACHTUNGTRENNUNG(4S,5S)-4-[(S)-1-Acetamido-3-methylbutyl]-5-amino-
cyclohex-1-enecarboxylic Acid (12)
To a solution of 11 (20 mg, 0.068 mmol) in THF (1 mL) was
added aqueous NaOH solution (1N, 1 mL) and the mixture
was stirred at room temperature for 3 h. Then the solvent
was removed under vacuum, and the pH value was adjusted
to 3–4 by addition of Amberlite IR-120. After filtration and
concentration, the crude product was purified by flash chro-
matography (C18 column, pure water as eluent) to give com-
pound 12 as a light yellow oil; yield: 9.3 mg (51%); [a]2D5:
1
+28.3 (c 0.5, H2O). H NMR (400 MHz, D2O): d=6.84 (s,
1H), 4.01 (d, J=9.2 Hz, 1H), 3.12 (td, J=5.2, 10.5 Hz, 1H),
2.77–2.58 (m, 1H), 2.43 (d, J=19.0 Hz, 1H), 2.31–2.17 (m,
1H), 2.10–1.83 (m, 5H), 1.62–1.47 (m, 2H), 1.21 (dd, J=5.5,
9.8 Hz, 1H), 0.81 (dd, J=6.3, 17.6 Hz, 6H); 13C NMR
(100 MHz, D2O): d=175.5, 171.4, 138.4, 127.3, 48.4, 46.3,
40.6, 39.9, 28.9, 24.6, 24.3, 22.2, 21.4, 20.9; HR-MS (ESI):
+
m/z=291.1681, calcd. for C14H24N2NaO3
[M+Na]+:
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toluene: 55% yield, 3:1 dr, 30% ee; THF: 68% yield,
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Asymmetric Domino Nitro-Michael/Horner–Wadsworth–
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11
Cyclohexenecarboxylate Annulation: Efficient Synthesis of
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Adv. Synth. Catal. 2012, 354, 1 – 11
Jiang Weng, Jun-Ming Li, Feng-Quan Li, Zhi-Sheng Xie,
Gui Lu*
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