Control of six contiguous stereocenters in an asymmetric organocatalytic one-pot Michael/Michael/aldol addition sequence

Article abstract of DOI:10.1002/adsc.201200120

The asymmetric organocatalytic one-pot synthesis of polyfunctionalized cyclohexanes is described. Starting from β-keto esters, nitroalkenes and α,β-unstaturated aldehydes and employing a bifunctional norephedrine-based thiourea catalyst, six contiguous st

Full text of DOI:10.1002/adsc.201200120

FULL PAPERS
DOI: 10.1002/adsc.201200120
Control of Six Contiguous Stereocenters in an Asymmetric
Organocatalytic One-Pot Michael/Michael/Aldol Addition
Sequence
Dieter Enders,a,* Gregor Urbanietz,a Elisa Cassens-Sasse,a Sebastian Keeß,a
and Gerhard Raabea
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2127; e-mail: enders@rwth-aachen.de
Received: February 14, 2012; Revised: April 3, 2012; Published online: && &&, 0000
Dedicated to Professor Hans-Joachim Gais on the occasion of his 70th birthday
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200120.
Abstract: The asymmetric organocatalytic one-pot fords the highly substituted cyclohexanes in moder-
synthesis of polyfunctionalized cyclohexanes is de- ate to very good yields (22–70%), diastereomeric
scribed. Starting from b-keto esters, nitroalkenes and ratios of dr>95:5 and excellent enantioselectivities
a,b-unstaturated aldehydes and employing a bifunc- of 91–99% ee.
tional norephedrine-based thiourea catalyst, six con-
tiguous stereocenters including one quarternary
center are generated. The one-pot protocol follows Keywords: asymmetric synthesis; cyclohexanes; one-
a Michael/Michael/aldol addition sequence and af- pot reaction; organocatalysis; thioureas
Introduction
four different synthetically important aldehyde, alco-
hol, ester and nitro groups. As is depicted in
The rapid development of organocatalysis has opened Scheme 1 the retrosynthetic analysis leads to three
new, efficient and elegant routes for the asymmetric simple substrates, namely the b-keto esters B, the ni-
synthesis of chiral building blocks, natural products troalkenes C and the a,b-unsaturated aldehydes D.
and biologically active compounds in general.[1] When Mechanistically the new protocol consists of a first
it comes to the construction of complex organic mole- thiourea-catalyzed Michael addition of the b-keto
cules bearing multiple stereocenters, the subfield of esters to the nitroalkenes. The resulting intermediate
organocatalytic domino/cascade reactions seems to be g-nitro keto esters then serve as the donor in a regio-
ideal for this purpose and has been intensively investi- selective nitro-Michael addition to the a,b-unsaturat-
gated in recent years.[2] Besides the often used enam- ed aldehydes. Subsequent cyclization via an intramo-
ine/iminium activation modes via Lewis base catalysis, lecular aldol addition of the aldehyde to the methyl
hydrogen-bonding catalysis employing various enan- ketone function forms the desired cyclohexanecarbal-
tiopure thiourea catalysts is another elegant option.[3]
In this context, the application of organocatalytic
domino reactions in the asymmetric synthesis of poly-
substituted carbocycles, such as cyclohexanes, has at-
tracted a great deal of attention.[4]
Results and Discussion
Herein we report on the asymmetric organocatalytic
one-pot synthesis of polyfunctionalized cyclohexanes
Scheme 1. One-pot asymmetric synthesis of polysubstituted
cyclohexanes via an organocatalytic Michael/Michael/aldol
of type A bearing six contiguous stereocenters and addition sequence – retrosynthetic analysis.
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Table 1. Catalyst screening for the Michael addition of
methyl 3-oxobutanoate 1a to nitrostyrene 2a to yield 3a.
diamide-derived catalyst G gave only a low yield of
35% and no enantiomeric excess could be detected
(Table 1, entry 3). Readily accessible norpseudoephe-
drine (Table 1, entry 2) and norephedrine (Table 1,
entry 5) derived catalysts H and I, which were devel-
oped recently in our group,[6b] have been identified as
efficient bifunctional organocatalysts in asymmetric
Michael reactions of 1a and 2a. With these thiourea
organocatalysts the best enantioselectivities could be
achieved, with the additional option to synthesize
both enantiomers of 5 at will.
With a suitable catalyst in hand, we then tested if
the g-nitro keto ester 3a can act as an intermediate to
react with cinnamaldehyde (4a) in a regioselective
and stereoselective tandem manner to form the cyclo-
hexane 5a with six contiguous stereocenters (Table 2).
To find the best reaction conditions for the domino
Michael/aldol addition reaction sequence we screened
solvents, the temperature and the catalyst loading. As
the base we used 1 equivalent of pyrrolidine for the
iminium/enamine/activation of 4a to circumvent the
formation of mismatched pairs which could arise
when chiral amines are employed.
Entry[a]
Catalyst
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
E
F
G
H
I
0.5
16
24
72
24
91
96
35
69
65
89[d]
91[d]
0
Based on the excellent enantioselectivity obtained
with the norephedrine-based bifunctional thiourea
80[d]
97
Table 2. Screening of solvent, temperature and loading of
catalyst I in the one-pot tandem sequence of 1a, 2a and 4a
to form cyclohexane 5a.
[a]
The reactions were performed on a 0.4–1.0 mmol scale at
room temperature.
Yield of isolated product 3a as a ca. 1:1 mixture of epi-
mers.
Determined by HPLC analysis on a chiral stationary
phase.
The opposite enantiomer ent-3a was obtained.
[b]
[c]
[d]
dehydes in a tandem manner through a substrate-con-
trolled second cycle with pyrrolidine as the catalyst in
order to prevent mismatched pairs and to generate
four of the six stereogenic centers in the final opera-
tion. The challenge of designing such an efficient
strategy mainly depends on the nucleophilicity and se-
lectivity of the g-nitro keto ester intermediate to react
with the a,b-unsaturated aldehydes in a regioselective
and stereoselective manner.
To guarantee that the first Michael addition pro-
ceeds with high diastereo- and enantioselectivity, we
started our studies of the Michael/Michael/aldol reac-
tion sequence by screening the organocatalysts E–I
for the first Michael reaction of nitrostyrene (2a) with
1 equivalent of methyl 3-oxobutanoate (1a) (Table 1).
The intermediate g-nitro keto ester 3a was obtained
in moderate to excellent yields (35–96%) and good to
excellent enantioselectivities (80–97% ee). It turned
out that only thiourea-based catalysts (Table 1, E, F,
H, I) are suitable to perform the conjugate addition
of ß-keto esters and nitroalkenes.[5] The sulfuric acid
Entry[a] Solvent T [8C] I mol% Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
CH2Cl2 r.t.
10
10
10
10
10
10
20
10
5
37
36
31
–
95
96
98
–
98
96
96
96
97
98
–
CHCl3
THF
r.t.
r.t.
CH3CN r.t.
toluene
0
33[d]
49[d]
47[d]
70
toluene À26
toluene r.t.
toluene r.t.
toluene r.t.
toluene r.t.
toluene r.t.
9
10
11
33
30
15
1
0
[a]
[b]
[c]
[d]
The reactions were carried out on a 1.0 mmol scale for
48 h.
Yield of isolated product 5a after chromatography and
crystallization (dr>95:5).
Determined by HPLC analysis on a chiral stationary
phase.
One week reaction time.
2
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Control of Six Contiguous Stereocenters
used, the aprotic, non-polar solvent toluene was the
most suitable one, in which an excellent 70% yield of
5a was obtained with an enantiomeric excess of up to
98% after one recrystallization (Table 2, entry 8).
Temperature as well as catalyst loading had an impact
only on the yields but showed no influence on the dia-
stereo- and enantioselectivities which stayed constant-
ly excellent (>96% ee) (Table 2, entries 5–7, 9, 10). It
is interesting to note that the domino product 5a was
formed in a low yield of 15% using 1 equivalent of
pyrrolidine (Table 2, entry 11) and without the pres-
ence of the bifunctional thiourea catalyst I, of course
as a racemate.
Finally we investigated the scope of the new one-
pot sequential protocol. Different acyclic b-keto
esters (1a–c), nitroalkenes (2a–e) as well as a,b-unsa-
turated aldehydes (4a–d) were tested in the one-pot
procedure (Scheme 2; Table 3). These modifications
of the substrates were well tolerated and gave the re-
spective polyfunctionalized cyclohexanes 5a–j with
excellent diastereo- and enantioselectivities after
chromatography. All products 5 crystallized, except
for 5f which was isolated as yellow oil and gave the
lowest yield. One recrystallization allowed a further
enhancement of the enantiomeric excess to 96–99%.
Scheme 2. Organocatalytic asymmetric one-pot reaction to
form the highly functionalized cyclohexanes 5.
catalyst I for the first Michael-addition step to form When the steric demand of the b-keto esters 1 was in-
3a (Table 1, entry 5), the sequential one-pot proce- creased from R1 =methyl to ethyl and tert-butyl,
dure was carried out in toluene with 10 mol% of the a slight decrease of the enantioselectivity was ob-
chiral catalyst I. After 24 h at room temperature served (Table 3, 5a–c). The variation of R3 in the aro-
1 equivalent of pyrrolidine was added[7] together with matic a,b-unsaturated aldehydes 4 to electron-donat-
the a,b-unsaturated aldehyde 4a. To our delight, the ing (R3 =p-MeOC6H4) and electron-withdrawing
enantiomeric excess was conserved in the second groups (R3 =p-NO2C6H4) as well as to heterocycles
cycle consisting of a diastereoselective domino Mi- (R3 =2-furyl) led to moderate yields of 42–46% while
chael/aldol addition to yield the highly substituted cy- still keeping the excellent ee values (Table 3, 5h–j). It
clohexane 5a with excellent stereoselectivity (dr> is interesting to note that four of the six stereocenters
95:5, ee=96%, Table 2, entry 8). It turned out that of the cyclohexanes 5 are established in the second re-
several other solvents were quite suitable in terms of action cycle and each substituent occupies the ther-
enantioselectivity, but the obtained yields of 5a were modynamically preferred equatorial position, except
quite low (Table 2, entries 1–4). Among the solvents for the nitro and the hydroxy groups. The relative
Table 3. Scope of the asymmetric one-pot Michael/Michael/aldol addition to polyfunctionalized cyclohexanes 5a–g.
5[a]
R1
R2
R3
Yield [%][b]
ee [%][c]
a
b
c
d
e
f
g
h
i
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
70
40
68
63
66
22
53
42
44
46
96 (98)
92 (98)
91 (96)
99
94
96
t-Bu
Me
Me
Me
Me
Me
Me
Me
2-BrC6H4
3-ClC6H4
4-BrC6H4
3,4-OCH2OC6H3
Ph
92
4-MeOC6H4
2-NO2C6H4
2-furyl
95 (97)
94 (99)
93
Ph
Ph
j
[a]
All reactions were performed on a 0.3–1.0 mmol scale at room temperature with catalyst I with an overall reaction time
of 2 days.
Yield of isolated product 5a–g after chromatography (dr>95:5).
[b]
[c]
Determined by HPLC analysis on a chiral stationary phase, values in brackets after recrystallization.
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1
Spectrometer. H and 13C NMR spectra were measured at
ambient temperature with Varian Gemini 300, Varian Mer-
cury 300 or Varian Innova 600 spectrometers using TMS as
internal standard. Mass spectra were recorded on a Finnigan
SSQ7000 (EI 70 eV) spectrometer, high resolution mass
spectra on a Finnigan MAT 95 and high resolution ESI spec-
tra on a ThermoFisher Scientific LTQ-Orbitrap XL.
General Procedure for the Asymmetric Synthesis of
Cyclohexane Derivatives 5a–j
Figure 1. Determination of the relative and absolute config-
uration by NOE (5a) and X-ray crystal structure analysis
(5c).
In a glass vial equipped with a magnetic stirring bar the ni-
troalkene
2 (1.0 equiv., 0.3–1.0 mmol) and catalyst I
(10 mol%) were dissolved in toluene (1 mLmmolÀ1 nitroal-
kene) and stirred 10 min at room temperature followed by
configuration of the cyclohexanes 5 was determined
by NOE measurements on 5a and the absolute config-
uration is based on a X-ray single crystal structure
slow addition of the b-keto ester
1 (2.0 equiv., 0.6–
2.0 mmol). After stirring at room temperature for 1 day the
analysis of 5c (Figure 1)[8] as well as by comparison a,b-unsaturated aldehyde 4 (1.1 equiv., 0.33–1.1 mmol) and
with closely related literature data.[6]
pyrrolidine (1.0 equiv., 0.3–1.0 mmol) were added and
stirred for another day at room tempertaure. The crude
product was directly purified by successive flash column
chromatographies (first n-pentane/Et2O=6:1, then n-pen-
tane/ethyl acetate=3:1) to afford the polysubstituted cyclo-
Conclusions
hexanes 5a–j.
In summary, we have developed a flexible and simple
to perform asymmetric organocatalytic one-pot se-
quence for the assembly of highly substituted cyclo-
hexanecarbaldehydes 5 bearing hydroxy, ester and
3-Formyl-2-hydroxy-2-methyl-5-nitro-4,6-diphenylcyclo-
hexanecarboxylic acid methyl ester (5a): Synthesized ac-
cording to the general procedure using methyl 3-oxobuta-
noate (1a) (0.22 mL, 2.0 mmol), (E)-(2-nitrovinyl)benzene
nitro functional groups. Starting from simple b-keto (2a) (149 mg, 1.0 mmol) and cinnamaldehyde (4a) (0.14 mL,
1.1 mmol); yellow solid; yield: 278 mg (70%); [a]2D0: +4.8 (c
0.96, CHCl3); 98% ee; Rf =0.46 (n-pentane/ethyl acetate=
esters, nitroalkenes and a,b-unsaturated aldehydes
the products were formed in moderate to good yields
(22–70%) with perfect atom economy and high levels
2:1); mp 1658C. IR (film): n=3499, 2829, 1726, 1551, 1496,
1452, 1366, 1253, 1194, 1158, 751, 700 cmÀ1
;
1H NMR
of chemo-, regio- and stereoselectivities (dr>95:5,
91–98% ee). The one-pot procedure is initiated by
a bifunctional thiourea-amine-catalyzed asymmetric
Michael addition, followed by an amine catalyzed Mi-
chael/aldol addition sequence through iminium/enam-
(600 MHz, CDCl3): d=1.47 (s, 3H, CH3), 3.45 (s, 3H,
CO2CH3), 3.53 (dd, J=4, 13 Hz, 1H, CHCHO), 3.66 (s, 1H,
OH), 3.89 (d, J=13 Hz, 1H, CHCO2CH3), 4.03 (dd, J=5,
13 Hz, 1H, CHPh), 4.30 (dd, J=5, 13 Hz, 1H, CHPh), 5.05
(t, J=5 Hz, 1H, CHNO2), 7.15–7.29 (m, 10H, CHarom), 9.51
(d, J=5 Hz, 1H, CHO); 13C NMR (150 MHz, CDCl3): d=
À
ine activation modes. Three new C C bonds, six adja-
cent stereogenic centers including one quaternary ste- 27.3 (CH3), 41.7 (CHPh), 44.1 (CHPh), 49.8 (CHCO2CH3),
52.1 (CO2CH3), 54.7 (CHCHO), 72.1 (CCH3OH), 93.2
(CHNO2), 127.1–129.4 (CHarom), 135.2 (Carom), 135.5 (Carom),
174.5 (CO2CH3), 202.9 (CHO); MS (EI, 70 eV): m/z (%)=
397 [M+] (3), 368 (4), 351 (5), 336 (3), 321 (6), 305 (100),
273 (5), 245 (41), 229 (3), 205 (6), 167 (5), 133 (5), 131 (16),
115 (15), 103 (11), 101 (11), 91 (36), 77 (8), 59 (4); anal.
calcd. for C22H23NO6: C 66.49, H 5.83, N 3.52; found: C
66.30, H 5.65, N 3.43.
reocenter are formed by combining bifunctional weak
Brønsted acid/base and amine catalysis. Further work
is aimed to expand this concept to the asymmetric
synthesis of natural products and even more complex
molecular structures.
Experimental Section
3-Formyl-2-hydroxy-2-methyl-5-nitro-4,6-diphenylcyclo-
hexanecarboxylic acid ethyl ester (5b): Synthesized accord-
ing to the general procedure using ethyl 3-oxobutanoate
(1b) (0.26 mL, 2.0 mmol), (E)-(2-nitrovinyl)benzene (2a)
(149 mg, 1.0 mmol) and cinnamaldehyde (4a) (0.14 mL,
1.1 mmol); yellow solid; yield: 163 mg (40%); [a]2D0: +6.8 (c
1.10, CHCl3); 92% ee; Rf =0.47 (n-pentane/ethyl acetate=
2:1); mp 1208C. IR (film): n=3515, 2984, 1718, 1549, 1452,
Flash column chromatography: SIL G-25 UV254 (size 0.040–
0.063 mm) Machery&Nagel. TLC: silica gel 60 F254 plates,
Merck, Darmstadt. Visualization of the developed TLC
plates was performed with UV radiation (254 nm) or by
staining with a potassium permanganate solution. Elemental
analyses were carried out with a Vario EL element analyzer.
Melting points were determined with a Bꢁchi Melting Point
B-540 apparatus. Optical rotation values were taken on
a Perkin–Elmer P241 polarimeter. The ee-values were deter-
mined by analytical HPLC with a Hewlett–Packard 1100
Series instrument using chiral stationary phases. IR spectra
were recorded on a Perkin–Elmer FT-IR Spectrum 100
1370, 1257, 1182, 1158, 1027, 750, 699 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d=0.90 (t, J=7 Hz, 3H, CO2CH2CH3),
1.49 (s, 3H, CH3), 3.53 (dd, J=4, 14 Hz, 1H, CHCHO), 3.84
(d, J=13 Hz, 1H, CHCO2CH2CH3), 3.85 (s, 1H, OH), 3.94
(q, J=7 Hz, 2H, CO2CH2CH3), 4.02 (dd, J=4, 13 Hz, 1H,
CHPh), 4.31 (dd, J=5, 12 Hz, 1H, CHPh), 5.06 (t, J=4 Hz,
4
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Control of Six Contiguous Stereocenters
1H, CHNO2), 7.15–7.29 (m, 10H, CHarom), 9.52 (d, J=4 Hz,
1H, CHO); 13C NMR (75 MHz, CDCl3): d=13.6
(CO2CH2CH3), 27.2 (CH3), 41.7 (CHPh), 44.3 (CHPh), 49.7
(CHCO2CH2CH3), 54.7 (CHCHO), 61.3 (CO2CH2CH3), 72.0
(CCH3OH), 93.2 (CHNO2), 127.3–129.3 (CHarom), 135.3
(Carom), 135.5 (Carom), 174.1 (CO2Me), 202.9 (CHO); MS (EI,
70 eV): m/z (%)=412 [M+H]+ (2), 394 (2), 373 (4), 365
(5), 348 (3), 331 (7), 320 (26), 319 (100), 284 (16), 273 (5),
246 (9), 245 (43), 205 (5), 177 (4), 131 (12), 115 (10), 103 (8),
91 (15), 77 (5); anal. calcd. for C23H25NO6: C 67.14, H 6.12,
N 3.40; found: C 66.58, H 6.04, N 3.84.
(45), 91 (59), 77 (24), 59 (31); anal. calcd. for C22H22BrNO6 :
C 55.47, H 4.66, N 2.94; found: C 55.56, H 4.75, N 2.78.
6-meta-Chlorophenyl-3-formyl-2-hydroxy-2-methyl-5-
nitro-4-phenylcyclohexanecarboxylic acid methyl ester (5e):
Synthesized according to the general procedure using
methyl 3-oxobutanoate (1a) (0.22 mL, 2.0 mmol), (E)-1-
chloro-3-(2-nitrovinyl)benzene (2c) (184 mg, 1.0 mmol) and
cinnamaldehyde (4a) (0.13 mL, 1.1 mmol); colorless solid;
yield: 283 mg (66%); [a]D20: À28.1 (c 1.00, CHCl3); 94% ee;
Rf =0.27 (n-pentane/ethyl acetate=3:1); mp 1398C; IR
(film): n=3325, 2931, 1722, 1549, 1437, 1359, 1261, 1153,
1060, 897, 785, 815, 744, 697 cmÀ1 1H NMR (400 MHz,
;
3-Formyl-2-hydroxy-2-methyl-5-nitro-4,6-diphenylcyclo-
hexanecarboxylic acid tert-butyl ester (5c): Synthesized ac-
cording to the general procedure using tert-butyl 3-oxobuta-
noate (1c) (0.32 mL, 2.0 mmol), (E)-(2-nitrovinyl)benzene
(2a) (149 mg, 1.0 mmol) and cinnamaldehyde (4a) (0.14 mL,
1.1 mmol); colorless solid; yield: 300 mg (68%); [a]2D0: + 2.7
(c 1.01, CHCl3); 91% ee; Rf =0.68 (n-pentane/ethyl ace-
tate=2:1); mp 2078C. IR (film): n=3461, 2979, 1726, 1550,
CDCl3): d=1.49 (s, 3H, CH3), 3.47–3.57 (m, 4H, CO2CH3,
CHCO2CH3), 3.59 (s, 1H, OH), 3.87 (d, J=13 Hz, 1H,
CHCHO), 4.03 (dd, J=4, 13 Hz, 1H, CHPh), 4.30 (dd, J=4,
13 Hz, 1H, CHAr), 5.05 (t, J=4 Hz, 1H, CHNO2), 7.06–
7.13 (m, 1H, CHarom), 7.14–7.20 (m, 2H, CHarom), 7.22–7.36
(m, 6H, CHarom), 9.52 (d, J=5 Hz, 1H, CHO); 13C NMR
(100 MHz, CDCl3): d=27.2 (CH3), 41.6 (CHPh), 43.7
(CHAr), 49.6 (CHCO2CH3), 52.2 (CO2CH3), 54.5
(CHCHO), 72.0 (CCH3OH), 92.9 (CHNO2), 125.6 (Carom),
128.0 (CHarom), 128.4 (2CHarom), 128.6 (CHarom), 128.8
(CHarom), 129.3 (2CHarom), 130.3 (Carom), 134.8 (CHarom),
135.0 (Carom), 137.5 (Carom), 174.1 (CO2CH3), 202.6 (CHO);
MS (EI, 70 eV): m/z (%)=385 [M+ÀHNO3] (2), 341 (34),
339 (100), 281 (22), 279 (62), 165 (15), 125 (10), 115 (17),
105 (10), 91 (22), 77 (8), 59 (11); anal. calcd. for
C22H22ClNO6: C 61.18, H 5.13, N 3.24; found: C 61.00, H
5.18, N 2.99.
1454, 1368, 1349, 1250, 1148, 1071, 836, 747, 699 cmÀ1
1H NMR (300 MHz, CDCl3): d=1.10 [s, 9H, C
(CH3)3], 1.50
;
AHCTUNGTRENNUNG
(s, 3H, CH3), 3.50 (dd, J=3, 12 Hz, 1H, CHCHO), 3.69 (d,
J=13 Hz, 1H, CHCO2CH3), 3.95 (dd, J=4, 13 Hz, 1H,
CHPh), 4.15 (s, 1H, OH), 4.30 (dd, J=5, 13 Hz, 1H,
CHPh), 5.04 (t, J=4 Hz, 1H, CHNO2), 7.15–7.30 (m, 10H,
CHarom), 9.51 (d, J=5 Hz, 1H, CHO); 13C NMR (75 MHz,
CDCl3): d=27.1 (CH3), 27.4 [CO2C
44.6 (CHPh), 49.8 (CHCO2CH3), 54.8 (CHCHO), 72.1
(CCH3OH), 82.9 (CO2C(CH3)3), 93.1 (CHNO2), 127.4–129.3
ACHTUGNTRENUN(NG CH3)3], 41.6 (CHPh),
AHCTUNGTRENNUNG
6-para-Bromophenyl-3-formyl-2-hydroxy-2-methyl-5-
(CHarom), 135. (2Carom), 173.8 (CO2CH3), 203.1 (CHO); MS
(EI, 70 eV): m/z (%)=440 [(M+H]+ (3), 421 (7), 403 (6),
348 (3), 366 (8), 347 (11), 337 (4), 320 (5), 291 (72), 290 (74),
273 (6), 245 (34), 233 (7), 205 (7), 171 (5), 147 (5), 131 (10),
115 (12), 105 (12), 103 (10), 91 (25), 77 (5), 57 (100); anal.
calcd. for C25H29NO6: C 68.32, H 6.65, N 3.19; found: C
68.30, H 6.86, N 2.83.
nitro-4-phenylcyclohexanecarboxylic acid methyl ester (5f):
Synthesized according to the general procedure using
methyl 3-oxobutanoate (1a) (0.06 mL, 0.52 mmol), (E)-1-
bromo-4-(2-nitrovinyl)benzene (2d) (60 mg, 0.26 mmol) and
cinnamaldehyde (4a) (0.04 mL, 0.29 mmol); yellow soluid:
yield: 27 mg (22%); [a]20: +3.1 (c 1.11, CHCl3); 96% ee;
Rf =0.44 (n-pentane/ethyDl acetate=2:1). IR (film): n=3507,
2927, 1715, 1549, 1491, 1439, 1354, 1258, 1162, 1075, 1008,
6-ortho-Bromophenyl-3-formyl-2-hydroxy-2-methyl-5-
nitro-4-phenylcyclohexanecarboxylic acid methyl ester (5d):
Synthesized according to the general procedure using
methyl 3-oxobutanoate (1a) (0.22 mL, 2.0 mmol), (E)-1-
bromo-2-(2-nitrovinyl)benzene (2b) (228 mg, 1.0 mmol) and
cinnamaldehyde (4a) (0.13 mL, 1.1 mmol); colorless solid;
yield: 301 mg (63%); [a]D20: À41.1 (c 1.00, CHCl3); 99% ee;
Rf =0.29 (n-pentane/ethyl acetate=3:1); mp 2248C. IR
(film): n=3455, 2956, 1711, 1547, 1442, 1345, 1270, 1172,
909, 815, 731, 700 cmÀ1 1H NMR (300 MHz, CDCl3): d=
;
1.47 (s, 3H, CH3), 1.58 (s, 1H, OH), 3.51 (s, 3H, CO2CH3),
3.54 (dd, J=2, 12 Hz, 1H, CHCHO), 3.84 (d, J=13 Hz, 1H,
CHCO2Me), 4.00 (dd, J=4, 13 Hz, 1H, CHPh), 4.28 (dd,
J=5, 13 Hz, 1H, CHPh), 5.00 (t, J=4 Hz, 1H, CHNO2),
7.07–7.09 (m, 2H, CHarom), 7.13–7.17 (m, 2H, CHarom), 7.26–
7.30 (m, 3H, CHarom), 7.42–7.44 (m, 2H, CHarom), 9.50 (d, J=
4 Hz, 1H, CHO); 13C NMR (75 MHz, CDCl3): d=27.2
(CH3), 41.6 (CHPh), 43.6 (CHPh), 49.7 (CHCO2CH3), 52.2
(CO2CH3), 54.5 (CHCHO), 72.0 (CCH3OH), 92.9 (CHNO2),
122.7 (Carom), 127.3–13.2 (CHarom), 134.6 (Carom), 140.0
(Carom), 174.2 (CO2CH3), 202.6 (CHO); MS (EI, 70 eV): m/z
(%)=475 [M+H]+ (5), 460 (1), 429 (26), 399 (18), 385
(100), 383 (90), 369 (18), 353 (11), 337 (12), 325 (29), 319
(10), 295 (5), 271 (5), 258 (5), 244 (21), 229 (8), 204 (9), 192
(7), 171 (14), 145 (6), 131 (10), 128 (14), 115 (23), 105 (18),
91 (37), 77 (13), 65 (4), 59 (12); HR-MS (ESI): m/z=
498.0523, calcd. for C22H22NO6BrNa: 498.0528.
1099, 1070, 1025, 994, 935, 905, 863, 824, 797, 742, 703 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=1.50 (s, 3H, CH3), 3.54 (s,
3H, CO2CH3), 3.57 (s, 1H, OH), 3.57 (d, J=12 Hz, 1H,
CHCO2CH3), 3.91 (d, J=13 Hz, 1H, CHCHO), 4.36 (dd,
J=4, 13 Hz, 1H, CHPh), 4.69 (dd, J=4, 13 Hz, 1H, CHAr),
5.20 (t, J=4 Hz, 1H, CHNO2), 7.10–7.38 (m, 8H, CHarom),
7.61 (m, 1H, CHarom), 9.52 (d, J=4 Hz, 1H, CHO);
13C NMR (100 MHz, CDCl3): d=27.2 (CH3), 41.5 (CHPh),
42.5 (CHAr), 49.7 (CHCO2CH3), 52.2 (CO2CH3), 54.7
(CHCHO), 72.1 (CCH3OH), 90.7 (CHNO2), 125.2 (Carom),
127.8 (CHarom), 128.0 (2CHarom), 128.1 (CHarom), 128.6
(CHarom), 129.3 (2CHarom), 130.0 (Carom), 133.5 (CHarom),
135.0 (Carom), 134.3 (Carom), 173.9 (CO2CH3), 202.7 (CHO);
MS (EI, 70 eV): m/z (%)=431 [M+ÀHNO3] (6), 429
[M+ÀHNO3] (6), 385 (100), 383 (100), 325 (54), 323 (54),
244 (83), 229 (18), 204 (24), 171 (25), 145 (15), 128 (24),115
6-(Benzo[d]ACTHNUGTRNEUNG[1,3]dioxol-5-yl)-3-formyl-2-hydroxy-2-
methyl-5-nitro-4-phenylcyclohexanecarboxylic acid methyl
ester (5g): Synthesized according to the general procedure
using methyl 3-oxobutanoate (1a) (0.22 mL, 2.0 mmol), (E)-
5-(2-nitrovinyl)benzo[d]ACHTUNGTRNE[NUNG 1,3]dioxole (2e) (193 mg, 1.0 mmol)
and cinnamaldehyde (4a) (0.13 mL, 1.1 mmol); colorless
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Dieter Enders et al.
FULL PAPERS
solid; yield: 234 mg (53%); [a]2D0: À81.8 (c 1.00, CHCl3);
72% ee; Rf =0.24 (n-pentane/ethyl acetate=3:1); mp988C.
IR (film): n=3497, 2922, 1717, 1549, 1493, 1444, 1359, 1241,
4, 13 Hz, 1H, CHPh), 4.93 (dd, J=4, 12 Hz, 1H, CHPh),
5.45 (t, J=4 Hz, 1H, CHNO2), 7.17–7.19 (m, 1H, CHarom),
7.24–7.30(m, 5H, CHarom), 7.36–7.42(m, 1H, CHarom), 7.46–
7.49 (m, 1H, CHarom), 7.91–7.94 (m, 1H, CHarom), 9.51 (d, J=
4 Hz, 1H, CHO); 13C NMR (75 MHz, CDCl3): d=27.3
(CH3), 36.2 (CHPh), 42.3 (CHPh), 49.8 (CHCO2CH3), 52.2
(CO2CH3), 55.5 (CHCHO), 71.9 (CCH3OH), 91.8 (CHNO2),
125.6 (CHarom), 127.9–129.4 (CHarom), 130.4 (Carom), 133.9
(CHarom), 135.3 (Carom), 149.8 (Carom), 174.1 (CO2CH3), 201.7
(CHO); MS (EI, 70 eV): m/z (%)=443 [M+H]+ (4), 427
(12), 396 (13), 378 (8), 350 (44), 332 (66), 317 (14), 300 (33),
290 (23), 272 (100), 256 (70), 244 (25), 230 (23), 216 (19),
204 (23), 178 (11), 175 (41), 159 (21), 145 (37), 131 (61), 115
(51), 103 (38), 91 (50), 77 (31), 59 (30); anal. calcd. for
C22H22N2O8: C 59.73, H 5.01, N 6.33; found: C 59.44, H 5.35,
N 6.17.
1
1104, 1034, 928, 865, 805, 754, 700 cmÀ1; H NMR (400 MHz,
CDCl3): d=1.45 (s, 3H, CH3), 3.50 (dd, J=2, 13 Hz, 1H,
CHCO2CH3), 3.54 (s, 3H, CO2CH3), 3.59 (d, J=2 Hz, 1H,
OH), 3.79 (d, J=13 Hz, 1H, CHCHO), 3.94 (dd, J=4,
13 Hz, 1H, CHPh), 4.26 (dd, J=5, 13 Hz, 1H, CHAr), 5.00
(t, J=4 Hz, 1H, CHNO2), 5.91 (d, J=2 Hz, 1H, CH2), 5.92
(d, J=2 Hz, 1H, CH2), 6.61–6.76 (m, 3H, CHarom), 7.14 (dd,
J=2, 8 Hz, 1H, CHarom), 7.22–7.33 (m, 4H, CHarom), 9.49 (d,
J=5 Hz, 1H, CHO); 13C NMR (100 MHz, CDCl3): d=27.3
(CH3), 41.7 (CHPh), 43.8 (CHAr), 50.0 (CHCO2CH3), 52.2
(CO2CH3), 54.6 (CHCHO), 72.1 (CCH3OH), 93.4 (CHNO2),
101.3 (OCH2O), 108.1 (CHarom), 108.7 (CHarom), 121.3
(CHarom), 125.2 (Carom), 127.8 (CHarom), 128.1 (2CHarom),
128.6 (Carom), 129.2 (2CHarom), 129.3 (Carom), 135.2 (Carom),
174.5 (CO2CH3), 202.8 (CHO); MS (EI, 70 eV): m/z (%)=
441 [M+] (100), 317 (15), 291 (31), 260 (48), 229 (57), 215
(20), 197 (19), 175 (29), 152 (50), 135 (39), 115 (52), 91 (96),
77(33), 59 (17); anal. calcd. for C23H23NO8: C 62.85, H 5.25,
N 3.17; found: C 62.68, H 5.16, N 3.08.
3-Formyl-4-furyl-2-hydroxy-2-methyl-5-nitro-6-phenylcy-
clohexanecarboxylic acid methyl ester (5j): Synthesized ac-
cording to the general procedure using methyl 3-oxobuta-
noate (1a) (0.22 mL, 2.0 mmol), (E)-(2-nitrovinyl)benzene
(2b) (149 mg, 1.0 mmol) and (E)-3-(furan-2-yl)acrylaldehyde
(4d) (135 mg, 1.1 mmol); yellow solid; yield: 178 mg (46%);
[a]20: +18.6 (c 1.14, CHCl3); 93% ee; Rf =0.49 (n-pentane/
ethDyl acetate=2:1); mp 1478C. IR (film): n=3509, 2958,
1715, 1554, 1498, 1437, 1346, 1262, 1197, 1153, 1120, 1069,
3-Formyl-2-hydroxy-4-para-methoxyphenyl-2-methyl-5-
nitro-6-phenylcyclohexanecarboxylic acid methyl ester (5h):
Synthesized according to the general procedure using
methyl 3-oxobutanoate (1a) (0.22 mL, 2.0 mmol), (E)-(2-ni-
trovinyl)benzene (2a) (149 mg, 1.0 mmol) and (E)-3-(4-me-
thoxyphenyl)acrylaldehyde (4b) (180 mg, 1.1 mmol); color-
less solid; yield: 179 mg (42%); [a]2D0: +3.8 (c 0.48, CHCl3);
95% ee; Rf =0.49 (n-pentane/ethyl acetate=2:1); mp 2158C.
IR (film): n=3519, 2957, 1720, 1612, 1552, 1512, 1437, 1354,
1
1011, 940, 817, 742, 700 cmÀ1; H NMR (300 MHz, CDCl3):
d=1.46 (s, 3H, CH3), 3.30 (ddd, J=2, 4, 13 Hz, 1H,
CHCHO), 3.45 (s, 3H, CO2CH3), 3.66 (s, 1H, OH), 3.85 (d,
J=13 Hz, 1H, CHCO2CH3), 3.99 (dd, J=4, 13 Hz, 1H,
CHPh), 4.43 (dd, J=5, 13 Hz, 1H, CHPh), 5.26 (t, J=4 Hz,
1H, CHNO2), 6.07–6.09 (m, 1H, CHfuryl), 6.23–6.25 (m, 1H,
CHfuryl), 7.17–7.22 (m, 2H, CHarom), 7.26–7.31 (m, 3H,
CHarom, 1H, CHfuryl), 9.59 (d, J=4 Hz, 1H, CHO); 13C NMR
(75 MHz, CDCl3): d=26.5 (CH3), 35.9 (CHPh), 43.4
(CHPh), 49.6 (CHCO2CH3), 52.1 (CO2CH3), 54.2
(CHCHO), 71.8 (CCH3OH), 90.5 (CHNO2), 109.2 (CHfuryl),
110.6 (CHfuryl), 126.7–129.1 (CHarom), 135.4 (Carom), 143.0
(CHfuryl), 149.4 (Cfuryl), 174.3 (CO2CH3), 202.3 (CHO); MS
(EI, 70 eV): m/z (%)=387 [M+] (24), 356 (2), 341 (10), 323
(5), 295 (100), 280 (11), 263 (8), 235 (74), 225 25), 219 (25),
192 (14), 165 (22), 161 (30), 152 (12), 141 (17), 131 (25), 115
(30), 103 (19), 91 (55), 77 (24), 65 (15), 55 (23); anal. calcd.
for C20H21NO7: C 62.01, H 5.46, N 3.62; found: C 62.18, H
5.23, N 3.21.
1308, 1256, 1156, 1098, 1030, 937, 913, 815, 745 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=1.46 (s, 3H, CH3), 3.47 (s,
1H, OH), 3.47 (s, 3H, CO2CH3), 3.48 (dd, J=2, 13 Hz, 1H,
CHCHO), 3.74 (s, 3H, OCH3), 3.87 (d, J=13 Hz, 1H,
CHCO2CH3), 4.00 (dd, J=4, 13 Hz, 1H, CHPh), 4.25 (dd,
J=5, 12 Hz, 1H, CHPh), 5.01 (t, J=4 Hz, 1H, CHNO2),
6.79–6.83 (m, 2H, CHarom), 7.05–7.10 (m, 2H, CHarom), 7.17–
7.21 (m, 2H, CHarom), 7.25–7.31 (m, 3H, CHarom), 9.49 (d, J=
5 Hz, 1H, CHO); 13C NMR (75 MHz, CDCl3): d=27.3
(CH3), 40.9 (CHPh), 44.2 (CHPh), 49.8 (CHCO2CH3), 52.1
(CO2CH3), 54.9 (CHCHO), 55.2 (OCH3), 72.1 (CCH3OH),
93.4 (CHNO2), 114.7 (CHarom), 127.0 (Carom), 127.8–129.3
(CHarom), 135.3 (Carom), 159.5 (Carom), 174.6 (CO2CH3), 203.0
(CHO); MS (EI, 70 eV): m/z (%)=427 [M+] (100), 396 (3),
363 (4), 335 (67), 321 (5), 303 (6), 275 (25), 265 (12), 243 (4),
201 (12), 163 (10), 145 (8), 131 (13), 121 (22), 108 (15), 91
(21), 77(9), 59 (7); anal. calcd. for C23H25NO7: C 64.63, H
5.90, N 3.28; found: C 64.93, H 5.97, N 2.82.
Acknowledgements
This work was supported by the Fonds der Chemischen In-
dustrie. We thank BASF SE for the donation of chemicals
and Dr. I. Atodiresei (X-ray data) and Dr. J. Runsink (NOE
measurements) for their help.
3-Formyl-2-hydroxy-2-methyl-5-nitro-4-ortho-nitrophenyl-
6-phenylcyclohexanecarboxylic acid methyl ester (5i): Syn-
thesized according to the general procedure using methyl 3-
oxobutanoate (1a) (0.22 mL, 2.0 mmol), (E)-(2-nitrovinyl)-
benzene (2b) (149 mg, 1.0 mmol) and (E)-3-(2-nitrophenyl)
acrylaldehyde (4c) (195 mg, 1.1 mmol); red solid; yield:
193 mg (44%); [a]2D0: À51.4 (c 1.36, CHCl3); 94% ee; Rf =
0.42 (n-pentane/ethyl acetate=2:1); mp 2008C. IR (film):
n=3663, 3506, 3063, 2850, 1959, 1734, 1608, 1550, 1441,
References
[1] For selected general reviews on organocatalysis, see:
a) A. Berkessel, H. Grçger, Asymmetric Organocatalysis,
Wiley-VCH, Weinheim, 2005; b) P. I. Dalko, Enantiose-
lective Organocatalysis, Wiley-VCH, Weinheim, 2007;
c) special issue (Ed.: B. List): Chem. Rev. 2007, 107,
5413–5883; d) R. M. De Figuiredo, M. Christmann, Eur.
1379, 1073, 1032, 1006, 940, 857, 828, 791, 737, 704 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=1.51 (s, 3H, CH3), 3.46 (s,
3H, CO2CH3), 3.60 (dd, J=4, 12 Hz, 1H, CHCHO), 3.74 (s,
1H, OH), 3.98 (d, J=13 Hz, 1H, CHCO2CH3), 4.08 (dd, J=
6
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!

Control of Six Contiguous Stereocenters
J. Org. Chem. 2007, 63, 9267–9331; e) J. L. Vicario, D.
Badia, L. Carillo, Synthesis 2007, 2065–2092; f) S. B. Tso-
goeva, Eur. J. Org. Chem. 2007, 1701–1716; g) A. Don-
doni, A. Massi, Angew. Chem. 2008, 120, 4716–4739;
Angew. Chem. Int. Ed. 2008, 47, 4638–4660; h) D. W. C.
MacMillan, Nature 2008, 455, 304–308; i) C. F. Barbas
III, Angew. Chem. 2008, 120, 44–50; Angew. Chem. Int.
Ed. 2008, 47, 42–47; j) D. Enders, A. A. Narine, J. Org.
Chem. 2008, 73, 7857–7870; k) P. Melchiorre, M. Marigo,
A. Carlone, G. Bartoli, Angew. Chem. 2008, 120, 6232–
6265; Angew. Chem. Int. Ed. 2008, 47, 6138–6171; l) D.
Enders, C. Wang, J. X. Liebich, Chem. Eur. J. 2009, 15,
11058–11076; m) K. A. Jørgensen, S. Bertelsen, Chem.
Soc. Rev. 2009, 38, 2178–2189; n) M. Bella, T. Gasperi,
Synthesis 2009, 1583–1614; o) D. Roca-Lopez, D.
Sadaba, I. Delso, R. P. Herrera, T. Tejero, P. Merino, Tet-
rahedron: Asymmetry 2010, 21, 2561–2601; p) P. Merino,
E. Marquꢂz-Lopꢂz, T. Tejero, R. P. Herrera, Synthesis
2010, 1–26; q) T. Marcelli, H. Hiemstra Synthesis 2010,
1229–1279; r) M. Nielsen, D. Worgull, T. Zweifel, B.
Gschwend, S. Bertelsen, K. A. Jørgensen, Chem.
Commun. 2011, 47, 632–649; s) D. B. Ramachary, S. Jain,
Org. Biomol. Chem. 2011, 9, 1277–1300; t) A. Moyano,
R. Rios Chem. Rev. 2011, 111, 4703–4832.
Hꢁttl. G. Raabe, J. W. Bats, Adv. Synth. Catal. 2008, 350,
267–279; g) S. Cabrera, J. Alemꢃn, P. Bolze, S. Bertelsen,
K. A. Jørgensen, Angew Chem. 2008, 120, 127–131;
Angew. Chem. Int. Ed. 2008, 47, 121–125; h) B. Tan, P. J.
Chua, Y. li, G. Zhong, Org. Lett. 2008, 12, 2437–2440;
i) L.-Y. Wu, G. Bencivenni, M. Mancinelli, A. Mazzanti,
G. Bartoli, P. Melchiorre, Angew. Chem. 2009, 121,
7332–7335; Angew. Chem. Int. Ed. 2009, 48, 7196–7199;
j) W. J. Nodes, D. R. Nutt, A. M. Chippindale, A. J. A.
Cobb, J. Am. Chem. Soc. 2009, 131, 16016–16017; k) B.-
C. Hong, R.-H. Jan, C.-W. Tsai, R. Y. Nimje, J.-H. Liao,
G.-H. Lee, Org. Lett. 2009, 11, 5246–5249; l) J. L. Garciꢃ
Ruano, V. Marcos, J. A. Suanzes, L. Marzano, J.
Alemꢃn, Chem. Eur. J. 2009, 15, 6576–6580; m) D.
Enders, C. Wang, M. Mukanova, A. Greb, Chem.
Commun. 2010, 46, 2447–2449; n) D. Enders, R. Krꢁll,
W. Bettray, Synthesis 2010, 567–572; o) D. Enders, B.
Schmid, N. Erdmann, Synthesis 2010, 2271–2277; p) O.
Baslꢂ, W. Raimondi, M. del Mar Sanchez Duque, D.
Bonne, T. Constantieux, J. Rodriguez, Org. Lett. 2010,
12, 5246–5249; q) S. Anwar, H.-J. Chang, K. Chen, Org.
Lett. 2011, 13, 2200–2203; r) B.-C. Hong, A. A. Sadani,
R. Y. Roshan, N. S. Dange, G.-H. Lee, Synthesis 2011,
1887–1895; s) P. G. McGarraugh, J. H. Jones, S. E. Bren-
ner-Moyer, J. Org. Chem. 2011, 76, 6309–6319; t) P.
Chintala, S. K. Ghosh, E. Long, A. D. Headley, B. Ni,
Adv. Synth. Catal. 2011, 353, 2905–2909; u) Y. Jia, Z.
Mao, R. Wang, Tetrahedron: Asymmetry 2011, 22, 2018–
2023; v) D.-F. Yu, Y. Wang, P.-F. Xu, Adv. Synth. Catal.
2011, 353, 2960–2965; w) S. Varga, G. Jakab, L. Drahos,
T. Holczbauer, M. Czugler, T. Soꢄs, Org. Lett. 2011, 13,
5416–5419; x) C. T. Wong, Tetrahedron 2012, 68, 481–
487; y) B.-C. Hong, N. S. Dange, C.-F. Ding, J.-H. Liao,
Org. Lett. 2012, 14, 448–451; z) S. Rajkumar, K. Shank-
land, G. D. Brown, A. J. A. Cobb, Chem. Sci. 2012, 3,
584–588.
[2] For selected reviews on organocatalytic domino reac-
tions, see: a) D. Enders, C. Grondal, M. R. M. Hꢁttl,
Angew. Chem. 2007, 119, 1590–1601; Angew. Chem. Int.
Ed. 2007, 46, 1570–1581; b) X. Yu, W. Wang, Org.
Biomol. Chem. 2008, 6, 2037–2046; c) C. Grondal, M.
Jeanty, D. Enders, Nature Chemistry 2010, 2, 167–178;
d) A. Grossmann, D. Enders, Angew. Chem. 2012, 124,
320–332; Angew. Chem. Int. Ed. 2012, 51, 314–325; e) H.
Pellissier, Adv. Synth. Catal. 2012, 354, 237–294.
[3] For selected reviews in hydrogen-bonding catalysis, see:
a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289–296;
b) M. S. Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118,
1550–1573; Angew. Chem. Int. Ed. 2006, 45, 1520–1543;
c) S. J. Connon, Chem. Eur. J. 2006, 12, 5418–5427;
d) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107,
5713–5743; e) X. Yu, W. Wang, Chem. Asian. J. 2008, 3,
516–532; f) Z. Zhang, P. R. Schreiner, Chem. Soc. Rev.
2009, 38, 1187–1198; g) K. Etzenbach-Effers, A. Berkes-
sel Top. Curr. Chem. 2009, 291, 1–27; h) M. Kotke, P. R.
Schreiner, in: Hydrogen Bonding in Organic Synthesis,
(Ed.: P. M. Pihko), Wiley-VCH, Weinheim, 2009,
pp 141–352; i) Y. Takemoto, Chem. Pharm. Bull. 2010,
58, 593–601; j) R. R. Knowles, E. N. Jacobsen, Proc.
Natl. Acad. Sci. USA 2010, 107, 20678–20685; k) J.
Alemꢃn, A. Parra, H. Jiang, K. A. Jørgensen, Chem.
Eur. J. 2011, 17, 6890–6899.
[4] For selected examples of asymmetric organocatalytic
domino reactions in the synthesis of cyclohexane deriva-
tives, see: a) D. Enders, M. R. M. Hꢁttl, C. Grondal, G.
Raabe, Nature 2006, 441, 861–863; b) D. Enders,
M. R. M. Hꢁttl, J. Runsink, G. Raabe, B. Wendt, Angew.
Chem. 2007, 119, 471–473; Angew. Chem. Int. Ed. 2007,
46, 467–469; c) D. Enders, A. A. Narine, T. R. Benning-
haus, G. Raabe, Synlett 2007, 1667–1670; d) E. Reyes, H.
Jiang, A. Milelli, P. Elsner, R. G. Hazell, K. A. Jørgen-
sen, Angew. Chem. 2007, 119, 9362–9365; Angew. Chem.
Int. Ed. 2007, 46, 9202–9205; e) J. Zhou, B. List, J. Am.
Chem. Soc. 2007, 129, 7498–7499; f) D. Enders, M. R. M.
[5] For selected examples of organocatalytic asymmetric
Michael additions of 1,3-dicarbonyl compounds to nitro-
alkenes, see a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am.
Chem. Soc. 2003, 125, 12672–12673; b) M. Watanabe, A.
Ikagawa, H. Wang, K. Murata, T. Ikariya, J. Am. Chem.
Soc. 2004, 126, 11148–11149; c) S. H. McCooney, S. J.
Connon, Angew. Chem. 2005, 117, 6525–6528; Angew.
Chem. Int. Ed. 2005, 44, 6367–6370; d) J. P. Malerich, K.
Haghihara, V. H. Rawal, J. Am. Chem. Soc. 2008, 130,
14416–11441; e) P. Gao, C. Wang, Y. Wu, Z. Zhou, C.
Tang, Eur. J. Org. Chem. 2008, 4563–4566; f) Z.-H.
Zhang, X.-Q. Dong, D. Chen, C.-J. Wang, Eur. J. Org.
Chem. 2008, 8780–8783; g) Z. Yu, X. Liu, L. Zhou, L.
Lin, X. Feng, Angew. Chem. 2009, 121, 5297–5300;
Angew. Chem. Int. Ed. 2009, 48, 5195–5198; h) D.
Almas¸i, D. A. Alonso, E. Gꢄmez-Bengoa, C. Nꢃjera, J.
Org. Chem. 2009, 74, 6163–6168; i) X. Jiang, Y. Zhang,
X. Liu, G. Zhang, L. Lai, L. Wu, J. Zhang, R. Wang, J.
Org. Chem. 2009, 74, 5562–5567; j) Y. Oh, S. M. Kim,
D. Y. Kim, Tetrahedron Lett. 2009, 50, 4674–4676; k) X.-
W. Pu, F.-Z. Peng, H.-B. Zhang, Z.-H. Shao, Eur. J. Org.
Chem. 2009, 4622–4626; l) Y. Wang, R.-G. Han, Y.-L.
Zhao, S. Yang, P.-F. Xu, D. J. Dixon, Angew. Chem.
2009, 121, 10018–10022; Angew. Chem. Int. Ed. 2009, 48,
9834–9838; m) C. Min, X. Han, Z. Liao, X. Wu, H.-B.
Zhou, C. Dong, Adv. Synth. Catal. 2011, 353, 2715–2720;
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n) D. Enders, G. Urbanietz, R. Hahn, G. Raabe Synthe-
sis 2012, 44, 773–783.
[6] a) A. M. Flock, A. Krebs, C. Bolm, Synlett 2010, 1219–
1222; b) D. Enders, G. Urbanietz, G. Raabe, Synthesis
2011, 1905–1911.
[7] Product 5a was obtained in 59% yield, when a catalytic
amount (20 mol%) of pyrrolidine was used.
[8] CCDC 850476 (5c) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Control of Six Contiguous Stereocenters in an Asymmetric
Organocatalytic One-Pot Michael/Michael/Aldol Addition
Sequence
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Adv. Synth. Catal. 2012, 354, 1 – 9
Dieter Enders,* Gregor Urbanietz, Elisa Cassens-Sasse,
Sebastian Keeß, Gerhard Raabe
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!