Diastereo- and enantioselective synthesis of hexasubstituted cyclohexanes via a metal-organocatalytic quadruple cascade sequence

Article abstract of DOI:10.1055/s-0033-1341103

A quadruple cascade reaction, comprising iminium, enamine-copper, iminium, and enamine catalysis, was investigated. This reaction afforded highly optically active hexasubstituted cyclohexanes from α,β-unsaturated aldehydes, nitromethane, and 2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO). To enhance the stereoselectivity of the organocatalytic cyclization, TEMPO was incorporated into the cyclohexane skeleton using copper catalysts. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1341103

SPECIAL TOPIC
▌1329
sDpeicaialsttopeicreo- and Enantioselective Synthesis of Hexasubstituted Cyclohexanes
via a Metal–Organocatalytic Quadruple Cascade Sequence
Quadruple Cascade Metal–Organocatalysis
Hwa-Jung Lee,a Pranab Kumar Shyam,a Woojin Yoon,a Hoseop Yun,a Hye-Young Jang*a,b
a
Division of Energy Systems Research, Ajou University, Suwon 443-749, Korea
Fax +82(31)2191615; E-mail: hyjang2@ajou.ac.kr
b
Korea Carbon Capture & Sequestration R&D Center, Deajeon 305-343, Korea
Received: 05.01.2014; Accepted after revision: 13.03.2014
organocatalyzed synthesis of chiral cyclohexanes using
Abstract: A quadruple cascade reaction, comprising iminium, en-
metal catalysts and chiral amines to afford diverse cyclo-
amine–copper, iminium, and enamine catalysis, was investigated.
hexanes.
This reaction afforded highly optically active hexasubstituted cy-
clohexanes from α,β-unsaturated aldehydes, nitromethane, and
2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO). To enhance the
stereoselectivity of the organocatalytic cyclization, TEMPO was in-
copper complexes by considering the advantages of the
corporated into the cyclohexane skeleton using copper catalysts.
We have previously reported cascade organocatalytic re-
actions using chiral secondary amines with ruthenium and
metal catalytic activity in the chiral amine-catalyzed reac-
Key words: asymmetric catalysis, domino reaction, radicals, cop-
tions.7 Among these, tandem reactions using α,β-unsatu-
per, cyclization
rated
aldehydes,
nitromethane,
and
2,2,6,6-
tetramethylpiperidin-1-yloxy (TEMPO) afforded diverse
α-oxyaminated and β-alkylated nitroaldehydes with good
enantioselectivity. With the same combination of starting
materials, we could optimize the reaction conditions to af-
ford highly stereoselective hexasubstituted nitrocyclohex-
anecarbaldehydes. A similar Michael addition of
nitromethane to α,β-unsaturated aldehydes to afford tetra-
substituted cyclohexenes has been reported by Enders, in
which the reaction of two molecules of an α,β-unsaturated
aldehyde reacted with nitromethane to afford a trisubsti-
tuted cyclohexene with modest diastereoselectivity and
good enantioselectivity.6i In this study, the highly diaste-
reo- and enantioselective formation of hexasubstituted ni-
Organocatalyzed domino reactions have been extensively
studied for the synthesis of highly substituted organic
compounds with control of the stereochemistry in a one-
pot operation. This offers practical advantages, including
that protecting groups for the reactants and the isolation of
products from each step are not required under environ-
mentally benign conditions.1,2 In addition to the opera-
tional convenience, multistep protocols may provide
enhanced stereoselectivity of the products because the
chiral center generated at each step controls the stereo-
chemistry of the bonds formed in the subsequent steps, re-
sulting in higher stereoselectivity in the final product.
Therefore, diverse organocatalyzed domino reactions us-
ing one type of organocatalyst or a mixture of different
types of organocatalysts have been reported. Furthermore,
the scope of organocatalytic reactions has expanded to
radical reactions and nonconventional reactions using
transition-metal complexes in organocatalysis to afford
complex organic compounds in good yields and with high
selectivities.1a,c,3–5
trocyclohexanecarbaldehydes
by
iminium–copper
complex involved enamine–iminium–enamine catalysis
is reported, in which two molecules of an α,β-unsaturated
aldehyde, nitromethane, and TEMPO react to afford hex-
asubstituted cyclohexanes. The addition of TEMPO cata-
lyzed
by
copper
complexes
increased
the
diastereoselectivity, and prevented the dehydration of the
final enamine-catalyzed aldol reaction.
The optimization results are shown in Table 1. Cinnamal-
dehyde (1a, 1 equiv), nitromethane (1 equiv), and TEMPO
(1 equiv) were added to a solution of (S)-2-[diphenyl(tri-
methylsiloxy)methyl]pyrrolidine (20 mol%), copper(I)
chloride (10 mol%), and lithium acetate (30 mol%) in tol-
uene at ambient temperature, to afford hexasubstituted 3-
nitrocyclohexanecarbaldehyde 2a in 15% yield as a single
diastereomer (entry 1). When the temperature increased to
40 °C, 2a was isolated in 40% yield and 99% ee (entry 2).
In our previous studies on enamine and iminium catalysis,
acid and base additives affected the yield and selectivity
of the reaction. Therefore, 30 mol% sodium acetate and
carboxylic acids (benzoic acid and pivalic acid) and 50
mol% lithium acetate were screened; however, they re-
sulted in lower yields (entries 3–6). Other copper com-
plexes [CuCl2, CuBr, and Cu(OTf)2] did not improve the
yield dramatically (entries 7–9). Different solvents, ace-
Among the complex organic frameworks prepared by chi-
ral amine-catalyzed domino reactions, the enantioselec-
tive synthesis of cyclohexane building blocks attracted
our attention owing to their synthetic and biological im-
portance.6 In the pioneering work by Enders, Jørgensen,
and Hayashi, diverse cyclohexane derivatives were pre-
pared by iminium and enamine catalysis using chiral
amine catalysts. Tri-, tetra-, penta- and hexasubstituted
cyclohexanes were prepared with excellent stereoselectiv-
ity using various protocols involving organocatalysts and
different types of substrates. We planned to introduce var-
ious functional groups with stereochemical control in the
SYNTHESIS 2014, 46, 1329–1333
Advanced online publication: 27.03.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1341103; Art ID: SS-2014-C0009-OP
© Georg Thieme Verlag Stuttgart · New York

1330
H.-J. Lee et al.
SPECIAL TOPIC
Ph
OSiMe3
termined based on the X-ray crystallographic analyses
and previously reported data (Figure 2).6i
N
H
Ph
A
Ph
Ph
F3C
CO2H
CO2Me
Cl
CF3
N
N
H
N
H
H
C
D
E
OSiMe3
Me
N
Me
H
O
O
N
CF3
N
N
t-Bu
N
H
F3C
N
H
Bn
N
H
Bn
HCl
B
F
G
H
Figure 1 Organocatalysts utilized (Table 1)
Figure 2 X-ray crystal structure of 2a8
tone, 1,2-dimethoxyethane, acetonitrile, tetrahydrofuran,
and chloroform were used to afford 2a in 18% to 34%
yields (entries 10–14). In addition to catalyst A, proline
and proline-derived chiral amine catalysts B, C, D, E, and
F and imidazolidinones G and H were employed (Figure
1); however, they did not induce the desired cyclization.
The absolute and relative stereochemistry of 2a were de-
With the optimized reaction conditions in hand, the cycli-
zation reactions of various α,β-unsaturated aldehydes
with nitromethane and TEMPO were carried out, to afford
the corresponding hexasubstituted nitrocyclohexanecarb-
aldehydes (Table 2). The reactions of 4-methyl- and 4-
methoxy-substituted cinnamaldehydes 1b and 1c afforded
2b and 2c in 45% and 43% yields, respectively (entries 1
Table 1 Optimization of Tandem Michael–Oxyamination–Michael–Aldol Reaction of 1a
OH
R
CHO
Ph
metal complex (10 mol%)
O
organocatalyst A (20 mol%)
O
N
R =
H
Ph
Ph
MeNO2 (1 equiv), additives
TEMPO (1 equiv), 20 h
solvent (0.4 M)
NO2
2a
1a
Entry
Metal complex
Additives (mol%)
Solvent
Temp (°C)
Yield (%)
1
2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl2
CuBr2
Cu(OTf)2
CuCl
CuCl
CuCl
CuCl
CuCl
LiOAc (30)
LiOAc (30)
NaOAc (30)
LiOAc (50)
PhCO2H(30)
pivalic acid (30)
LiOAc (30)
LiOAc (30)
LiOAc (30)
LiOAc (30)
LiOAc (30)
LiOAc (30)
LiOAc (30)
LiOAc (30)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DME
r.t.
40
40
40
40
40
40
40
40
40
40
40
40
40
15
40a
12
29
33
22
17
33
31
18
30
34
28
24
3
4
5
6
7
8
9
10
11
12
13
14
MeCN
THF
CHCl3
a >95% de, 99% ee.
Synthesis 2014, 46, 1329–1333
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Quadruple Cascade Metal–Organocatalysis
1331
and 2). The reaction of naphthalene-substituted aldehyde
1d afforded 2d in 41% yield (entry 3). The reaction of 4-
chloro-substituted cinnamaldehyde 1e afforded 2e in a
slightly lower yield (entry 4, 36% yield). The reactions of
heteroaromatic-substituted aldehydes 1f and 1g afforded
the corresponding cyclohexane derivative 2f and 2g in
similar yields to those of the other aromatic-substituted
compounds (entries 5 and 6).
N
O
R
N
Cu(II)
Cu(I)
H
MeNO2
TEMPO
O2
O2N
Ph
II
R
R
N
R
N
A reaction mechanism is proposed in Scheme 1. The cat-
alytic cycle begins with the reaction of 1a with the pro-
line-derived chiral amine catalyst to afford iminium I,
which then reacts with nitromethane to afford enamine in-
termediate II. In the presence of a copper complex and
TEMPO, II undergoes oxyamination to afford iminium
intermediate III, followed by the hydrolysis to afford 2a.
This reaction mechanism was proposed in our previous
publication.7c To form the cyclohexane framework, 2a
acts as a nucleophile and attacks in the second catalytic
cycle to afford enamine intermediate IV, which then un-
dergoes the intramolecular aldol reaction to afford 2a.
H
H
O2N
Ph
Ph
I
III
O
N
R =
H2O
O
O
R
N
R
H
Ph
H
H
1a
O2N
Ph
2a′
OH
OHC
Ph
R
R
N
In conclusion, the combination of a chiral amine catalyst
and copper complex was used to afford optically active
hexasubstituted cyclohexanes from easily accessible start-
ing materials in a one-pot operation. The cyclohexane
core was prepared by the tandem iminium–enamine–
iminium–enamine catalysis, and TEMPO was inserted to
the cyclohexane core using copper catalysts, resulting in
the high diastereo- and enantioselectivity of the desired
cyclization product. The stereochemistry of the cyclohex-
ane product was established by X-ray crystallographic
analysis.
Ph
H
NO2
2a
Ph
I
H2O
O
R
N
R
OHC
H
R
H
O2N
Ph
Ph
Ph
2a′
NO2
IV
Scheme 1 Catalytic cycle for the tandem Michael–oxyamination–
Michael–aldol reaction of 1a
Anhydrous solvents were transferred using an oven-dried syringe.
Toluene was distilled from CaH2. H NMR spectra were recorded
1
using a Varian Mercury Plus (400 MHz) spectrometer referenced to
TMS. 13C NMR spectra were recorded using a Varian Mercury Plus
(100 MHz) spectrometer referenced to CDCl3 [δ = 77.00 (t)]. Com-
mercially available chemicals were used as received without further
purification.
Table 2 Synthesis of Diverse Hexasubstituted Nitrocyclohexanecarbaldehydes
CuCl (10 mol%)
OH
O
organocatalyst A (20 mol%)
R2
R1
CHO
R1
O
R2
=
N
H
R1
MeNO2 (1 equiv), LiOAc (30 mol%)
TEMPO (1 equiv)
toluene (0.4 M)
40 °C, 20 h
NO2
1
2
Entry
Reactant
R1
Product
Yield (%)
de (%)
ee (%)
1
2
3
4
5
6
1b
1c
1d
1e
1f
4-MeC6H4
4-MeOC6H4
2-naphthyl
4-ClC6H4
2-thienyl
2-furyl
2b
2c
2d
2e
2f
45
43
41
36
41
38
>95
>95
>95
>95
>95
>95
98
98
98
99
99
99
1g
2g
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1329–1333

1332
H.-J. Lee et al.
SPECIAL TOPIC
2-Hydroxy-5-nitro-4,6-diphenyl-3-(2,2,6,6-tetramethylpiperi-
din-1-yloxy)cyclohexanecarbaldehyde (2a); Typical Procedure
A mixture of cinnamaldehyde (66 mg, 0.5 mmol), MeNO2 (31 mg,
0.5 mmol), LiOAc (10 mg, 0.15 mmol), TEMPO (78 mg, 0.5
mmol), CuCl (2.5 mg, 0.05 mmol), and catalyst A (33 mg, 0.10
mmol) in toluene (0.8 M, 0.625 mL) was added to a vial and O2 gas
was purged through it for 10 min. Then, the mixture was stirred at
40 °C for 18 h. The solvent was removed under reduced pressure to
afford a crude product that was chromatographed (silica gel, hex-
ane–CH2Cl2–Et2O, 8:1:1), to afford 2a as a yellow solid; yield: 47.7
mg (0.0993 mmol, 40%); mp 178 °C; Rf = 0.27 (EtOAc–hexane,
1:4); HPLC (Chiralcel OJ-H, hexane–i-PrOH, 90:10, 0.5 mL/min):
tR = 21.8 (minor), 27.4 min (major).
(m, 1 H), 5.03 (t, J = 10 Hz, 1 H), 5.42 (dd, J = 6.4, 5.6 Hz, 1 H),
7.20–7.23 (m, 2 H), 7.43–7.49 (m, 4 H), 7.58–7.60 (m, 2 H), 7.75–
7.87 (m, 8 H), 9.80 (d, J = 2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 17.0, 20.1, 20.5, 31.3, 34.7, 40.0,
40.3, 41.3, 49.8, 58.8, 60.7, 62.3, 71.2, 81.2, 90.0, 125.5, 126.2,
126.2, 126.3, 127.4, 127.5, 127.6, 127.7, 127.9, 128.0, 128.7, 130.5,
130.9, 132.7, 132.8, 133.0, 133.1, 134.3, 201.3.
HRMS (FAB): m/z [M + H]+ calcd for C36H41N2O5: 581.3015;
found: 581.3018.
2,4-Bis(4-chlorophenyl)-6-hydroxy-3-nitro-5-(2,2,6,6-tetra-
methylpiperidin-1-yloxy)cyclohexanecarbaldehyde (2e)
Yellow solid; yield: 49 mg (0.0892 mmol, 36%); mp 113 °C; HPLC
(Chiralcel OJ-H, hexane–EtOH, 90:10, 0.5 mL/min): tR = 25.8 (mi-
nor), 18.1 min (major).
IR (KBr): 1455, 1725, 2933, 3427 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.59–1.51 (m, 18 H), 3.07–3.13
(m, 1 H), 4.14 (t, J = 5.6 Hz, 1 H), 4.29 (t, J = 12.4 Hz, 1 H), 4.47
(dd, J = 10, 6 Hz, 1 H), 4.85 (t, J = 10 Hz, 1 H), 5.19 (dd, J = 12.4,
6 Hz, 1 H), 7.15–7.38 (m, 10 H), 9.74 (d, J = 2.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 17.2, 20.3, 20.6, 31.4, 34.8, 40.1,
40.5, 41.3, 49.7, 58.9, 60.9, 62.4, 71.1, 81.1, 89.8, 128.1, 128.2,
128.3, 128.4, 128.9, 130.8, 133.5, 137.1, 201.3.
IR (KBr): 1421, 1712, 3004, 3523 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.62–1.57 (m, 18 H), 3.08 (m, 1
H), 4.11 (t, J = 5.6 Hz, 1 H), 4.21 (t, J = 12.4 Hz, 1 H), 4.45–4.49
(m, 1 H), 4.74 (t, J = 10 Hz, 1 H), 5.13 (dd, J = 5.6, 6 Hz, 1 H),
7.16–7.34 (m, 8 H), 9.75 (d, J = 1.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 16.9, 20.2, 20.3, 30.3, 31.3, 34.6,
39.8, 40.1, 40.2, 48.7, 58.3, 60.7, 62.2, 71.0, 80.6, 89.3, 128.4,
128.9, 129.4, 131.6, 131.8, 133.8, 134.2, 135.2, 201.0.
HRMS (FAB): m/z [M + H]+ calcd for C28H37N2O5: 481.2702;
found: 481.2705.
HRMS (FAB): m/z [M + H]+ calcd for C28H35N2O5Cl2: 549.1923;
found: 549.1922.
2-Hydroxy-5-nitro-3-(2,2,6,6-tetramethylpiperidin-1-yloxy)-
4,6-di-4-tolylcyclohexanecarbaldehyde (2b)
Yellow solid; yield: 57 mg (0.1120 mmol, 45%); mp 117 °C; HPLC
(Chiralcel OD-H, hexane–EtOH, 94:6, 0.5 mL/min): tR = 28.1 (mi-
nor), 18.8 min (major).
IR (KBr): 1422, 1710, 3006, 3445 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.60–1.57 (m, 18 H), 2.26 (s, 3 H),
2.31 (s, 3 H), 3.01–3.08 (m, 1 H), 4.08 (t, J = 5.6 Hz, 1 H), 4.21 (t,
J = 12.4 Hz, 1 H), 4.35–4.47 (m, 1 H), 4.84 (t, J = 9.6 Hz, 1 H), 5.16
(dd, J = 6, 6.4 Hz, 1 H), 7.06–7.24 (m, 8 H), 9.72 (d, J = 2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 16.7, 20.0, 20.1, 20.8, 31.1, 34.3,
39.6, 40.0, 40.3, 48.9, 58.5, 60.3, 61.8, 70.5, 80.7, 89.6, 127.6,
128.5, 129.1, 129.9, 130.2, 133.5, 137.2, 200.9.
2-Hydroxy-5-nitro-3-(2,2,6,6-tetramethylpiperidin-1-yloxy)-
4,6-di(thiophen-2-yl)cyclohexanecarbaldehyde (2f)
Yellow solid; yield: 51 mg (0.1027 mmol, 41%); mp 172 °C; HPLC
(Chiralcel AS-H, hexane–EtOH, 80:20, 0.5 mL/min): tR = 31.2 (mi-
nor), 19.4 min (major).
IR (KBr): 3362, 2932, 1731, 1435 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.74–1.58 (m, 18 H), 3.03 (m, 1
H), 4.37–4.41 (m, 1 H), 4.45 (t, J = 5.2 Hz, 1 H), 4.57 (t, J = 12.4
Hz, 1 H), 4.81 (t, J = 10 Hz, 1 H), 5.05 (dd, J = 5.2, 5.2 Hz, 1 H),
6.86–6.88 (m, 1 H), 6.96–6.99 (m, 2 H), 7.11–7.18 (m, 2 H), 7.29–
7.30 (m, 1 H), 9.78 (d, J = 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 16.9, 20.2, 20.3, 31.3, 34.6, 36.2,
39.9, 40.2, 44.8, 59.3, 60.7, 62.2, 71.0, 79.7, 90.1, 124.8, 126.0,
126.5, 126.9, 127.1, 129.9, 133.1, 139.2, 200.0.
HRMS (FAB): m/z [M + H]+ calcd for C30H41N2O5: 509.3015;
found: 509.3018.
2-Hydroxy-4,6-bis(4-methoxyphenyl)-5-nitro-3-(2,2,6,6-tetra-
methylpiperidin-1-yloxy)cyclohexanecarbaldehyde (2c)
Yellow solid; yield: 58 mg (0.1073 mmol, 43%); mp 110 °C; HPLC
(Chiralcel OJ-H, hexane–EtOH, 80:20, 0.5 mL/min): tR = 35.2 (mi-
nor), 45.5 min (major).
HRMS (FAB): m/z [M + H]+ calcd for C24H33N2O5S2: 493.1831;
found: 493.1830.
2,4-Di(furan-2-yl)-6-hydroxy-3-nitro-5-(2,2,6,6-tetramethylpi-
peridin-1-yloxy)cyclohexanecarbaldehyde (2g)
Yellow solid; yield: 44 mg (0.0957 mmol, 38%); mp 176 °C; HPLC
(Chiralcel AS-H, hexane–EtOH, 80:20, 0.5 mL/min): tR = 24.1 (mi-
nor), 13.6 min (major).
IR (KBr): 1464, 1725, 2936, 3444 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.60–1.57 (m, 18 H), 2.26 (s, 3 H),
2.31 (s, 3 H), 3.01–3.08 (m, 1 H), 4.08 (t, J = 5.6 Hz, 1 H), 4.21 (t,
J = 12.4 Hz, 1 H), 4.35–4.47 (m, 1 H), 4.84 (t, J = 9.6 Hz, 1 H), 5.16
(dd, J = 6, 6.4 Hz, 1 H), 7.06–7.24 (m, 8 H), 9.72 (d, J = 2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.3, 17.1, 20.3, 20.5, 22.8, 30.5,
31.4, 34.3, 31.8, 34.7, 40.0, 40.3, 40.4, 49.0, 55.3, 59.0, 60.8, 62.3,
70.9, 81.0, 90.1, 113.7, 114.3, 125.4, 128.8, 129.2, 131.8, 159.0,
159.2, 201.5.
IR (KBr): 1455, 1731, 2932, 3439 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.79–1.60 (m, 18 H), 2.98–3.05
(m, 1 H), 4.08 (t, J = 5.2 Hz, 1 H), 4.33 (m, 1 H), 4.43 (t, J = 12 Hz,
1 H), 4.93 (t, J = 10 Hz, 1 H), 5.11 (dd, J = 5.2, 5.2 Hz, 1 H), 6.16–
6.34 (m, 3 H), 7.02 (s, 1 H), 7.27 (d, J = 1.6 Hz, 1 H), 7.49 (d,
J = 1.6 Hz, 1 H), 9.77 (d, J = 3.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 17.1, 20.3, 20.5, 31.4, 34.6, 35.1,
39.9, 40.1, 40.4, 42.3, 56.0, 60.7, 62.3, 70.0, 79.9, 86.9, 109.1,
110.6 (2), 112.5, 142.2, 143.2, 147.1, 149.4, 200.0.
HRMS (FAB): m/z [M + H]+ calcd for C30H41N2O7: 541.2914;
found: 541.2917.
2-Hydroxy-4,6-di(naphthalen-2-yl)-5-nitro-3-(2,2,6,6-tetra-
methylpiperidin-1-yloxy)cyclohexanecarbaldehyde (2d)
Yellow solid; yield: 59 mg (0.1016 mmol, 41%); mp 140 °C; HPLC
(Chiralcel OD-H, hexane–EtOH, 92:8, 0.5 mL/min): tR = 54.8 (mi-
nor), 39.3 min (major).
HRMS (FAB): m/z [M + H]+ calcd for C24H33N2O7: 461.2288;
found: 461.2291.
Acknowledgment
IR (KBr): 3442, 3056, 1724, 1466 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.43–1.58 (m, 18 H), 3.30 (m, 1
H), 4.36 (t, J = 5.6 Hz, 1 H), 4.57 (t, J = 12.4 Hz, 1 H), 4.61–4.65
This study was supported by the Korea Research Foundation (Grant
Nos. 2009-0094046 and 2013008819) and the Korea CCS R&D
Synthesis 2014, 46, 1329–1333
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Quadruple Cascade Metal–Organocatalysis
1333
Center (KCRC) grant funded by the Korea government (Ministry of
Science, ICT & Future Planning) (Grant No. 2012-0008935).
Matovic, R.; Saicic, R. N. Tetrahedron 2009, 65, 10485.
(g) Ikeda, M.; Miyake, Y.; Nishibayshi, Y. Angew. Chem.
Int. Ed. 2010, 49, 7289. (h) Zweifel, T.; Hollmann, D.;
Prüger, B.; Nielsen, M.; Jørgensen, K. A. Tetrahedron:
Asymmetry 2010, 21, 1624.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. The co-
pies of 1H NMR, 13C NMR, and HPLC spectra of cyclohexane pro-
(5) For selected articles regarding sequential
metal/organocatalysis, see refs. 3a–e,g.
ducts are included.SunogIopirftminSratnuIfpoori
m
pgnirtat
(6) For selected recent articles of organocatalyzed domino
reactions for chiral cyclohexane derivatives, see: (a) Enders,
D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Nature (London)
2006, 441, 861. (b) Marigo, M.; Bertelsen, S.; Landa, A.;
Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 5475.
(c) Carlone, A.; Marigo, M.; North, C.; Landa, A.;
Jørgensen, K. A. Chem. Commun. 2006, 4928. (d) Enders,
D.; Hüttl, M. R. M.; Runsink, J.; Raabe, G.; Wendt, B.
Angew. Chem. Int. Ed. 2007, 46, 467. (e) Carlone, A.;
Cabrera, S.; Marigo, M.; Jørgensen, K. A. Angew. Chem. Int.
Ed. 2007, 46, 1101. (f) Hayashi, Y.; Okano, T.; Aratake, S.;
Hazelard, D. Angew. Chem. Int. Ed. 2007, 46, 4922.
(g) Reyes, E.; Jiang, H.; Milelli, A.; Elsner, P.; Hazell, R. G.;
Jørgensen, K. A. Angew. Chem. Int. Ed. 2007, 46, 9202.
(h) Ramachary, D. B.; Reddy, Y. V.; Prakash, B. V. Org.
Biomol. Chem. 2008, 6, 719. (i) Enders, D.; Jeanty, M.; Bats,
J. W. Synlett 2009, 3175. (j) Wang, Y.; Han, R.-G.; Zhao,
Y.-L.; Yang, S.; Xu, P.-F.; Dixon, D. J. Angew. Chem. Int.
Ed. 2009, 48, 9834. (k) Hong, B.-C.; Nimje, R. Y.; Lin, C.-
W.; Liao, J.-H. Org. Lett. 2011, 13, 1278. (l) Ishikawa, H.;
Sawano, S.; Yasui, Y.; Shibata, Y.; Hayashi, Y. Angew.
Chem. Int. Ed. 2011, 50, 3774. (m) Mao, Z.; Jia, Y.; Xu, Z.;
Wang, R. Adv. Synth. Catal. 2012, 354, 1401. (n) Ma, C.;
Jia, Z.-J.; Liu, J.-X.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C.
Angew. Chem. Int. Ed. 2013, 52, 948. (o) Zeng, X.; Ni, Q.;
Raabe, G.; Enders, D. Angew. Chem. Int. Ed. 2013, 52, 2977.
(7) (a) Yoon, H.-S.; Ho, X.-H.; Jang, J.; Lee, H.-J.; Kim, S.-J.;
Jang, H.-Y. Org. Lett. 2012, 14, 3272. (b) Ho, X.-H.; Oh, H.-
J.; Jang, H.-Y. Eur. J. Org. Chem. 2012, 5655. (c) Kim, J.-
H.; Park, E.-J.; Lee, H.-J.; Ho, X.-H.; Yoon, H.-S.; Kim, P.;
Yun, H.; Jang, H.-Y. Eur. J. Org. Chem. 2013, 4337.
(8) CCDC-977839 contains the crystallographic data for 2a;
C28H36N2O5, Mr = 480.59, orthorhombic, space group
P212121, a = 8.7335(4) Å, b = 15.6355(5) Å, c = 19.6968(6)
Å, V = 2689.67(16) Å3, Z = 4, T = 290(1) K,
References and Notes
(1) For review articles of multi-catalytic reactions using
transition-metal catalysts, biocatalysts, and organocatalysts:
(a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745.
(b) Zhou, J. Chem. Asian J. 2010, 5, 422. (c) Zhong, C.; Shi,
X. Eur. J. Org. Chem. 2010, 2999.
(2) For reviews on organocatalytic domino reactions, see ref. 1b
and: (a) List, B. Chem. Commun. 2006, 819. (b) Enders, D.;
Grondal, C.; Hüttl, M. R. M. Angew. Chem. Int. Ed. 2007,
46, 1570. (c) Tsogoeva, S. B. Eur. J. Org. Chem. 2007,
1701. (d) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6,
2037. (e) Dondoni, A.; Massi, A. Angew. Chem. Int. Ed.
2008, 47, 4638. (f) Westermann, B.; Ayaz, M.; van Berkel,
S. S. Angew. Chem. Int. Ed. 2010, 49, 846. (g) Pellissier, H.
Adv. Synth. Catal. 2012, 354, 237. (h) Wende, R. C.;
Schreiner, P. R. Green Chem. 2012, 14, 1821.
(3) For selected recent reviews and articles of tandem
organocatalytic reactions using transition-metal complexes,
see refs. 1a,c and: (a) Poe, S. L.; Kobašlija, M.; McQuade,
D. T. J. Am. Chem. Soc. 2006, 128, 15586. (b) Poe, S. L.;
Kobašlija, M.; McQuade, D. T. J. Am. Chem. Soc. 2007, 129,
9216. (c) Simmons, B.; Walji, A. M.; MacMillan, D. W. C.
Angew. Chem. Int. Ed. 2009, 48, 4349. (d) Chercheja, S.;
Nadakudity, S. K.; Eilbracht, P. Adv. Synth. Catal. 2010,
352, 637. (e) Quintard, A.; Alexakis, A. Adv. Synth. Catal.
2010, 352, 1856. (f) Lin, S.; Zhao, G.-L.; Deiana, L.; Sun, J.;
Zhang, Q.; Leijonmarck, H.; Córdova, A. Chem. Eur. J.
2010, 16, 13930. (g) Quintard, A.; Alexakis, A.; Mazet, C.
Angew. Chem. Int. Ed. 2011, 50, 2354. (h) Rueping, M.;
Sundén, H.; Hubener, L.; Sugiono, E. Chem. Commun.
2012, 48, 2201. (i) Du, Z.; Shao, Z. Chem. Soc. Rev. 2013,
42, 1337.
(4) For selected recent articles of transition-metal-catalyzed
activation of allyl and alkyne groups for the reaction with
enamines, see: (a) Ibrahem, I.; Córdova, A. Angew. Chem.
Int. Ed. 2006, 45, 1952. (b) Bihelovic, F.; Matovic, R.;
Vulovic, B.; Saicic, R. N. Org. Lett. 2007, 9, 5063. (c) Ding,
Q.; Wu, J. Org. Lett. 2007, 9, 4959. (d) Binder, J. T.; Crone,
B.; Haug, T. T.; Menz, H.; Kirsch, S. F. Org. Lett. 2008, 10,
1025. (e) Yang, T.; Ferrali, A.; Campbell, L.; Dixon, D. J.
Chem. Commun. 2008, 2923. (f) Vulovic, B.; Bihelovic, F.;
μ(MoKα) = 0.081 mm–1. Of 26365 reflections collected in
the θ range 3.0°–27.50° using ω scans on a Rigaku R-axis
Rapid S diffractometer, 6162 were unique reflections
(Rint = 0.0255, completeness = 99.7%). The structure was
solved and refined against F2 using SHELX97, 460
variables, wR2 = 0.0899, R1 = 0.0309 [Fo2 > 2σ(Fo2)],
GOF = 1.107, and max/min residual electron density
0.129/–0.169 e Å–3. Bond lengths and angles are included in
the Supporting Information.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1329–1333