Organocatalytic domino double Michael reaction of ethyl (E)-7-oxohept-2-enoate and ,-unsaturated aldehydes: Efficient asymmetric synthesis of cyclohexanes with four contiguous stereocenters

Article abstract of DOI:10.1055/s-0030-1260469

Organocatalytic domino double Michael reactions of ethyl (E)-7-oxohept-2-enoate and ,-unsaturated aldehydes provided ethyl 2-(2,4-diformyl-3-phenylcyclohexyl)acetate with excellent diastereoselectivities (>20:1 dr) and enantioselectivities (>99% ee). The adducts were further transformed to octahydro-3H-2-benzopyran-3-ones, octahydroisoquinolin-3(2H)- ones, and decahydro-5H-oxazolo[2,3-a]isoquinolin-5-ones. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260469

PAPER
1887
Organocatalytic Domino Double Michael Reaction of Ethyl (E)-7-Oxohept-
2-enoate and a,b-Unsaturated Aldehydes: Efficient Asymmetric Synthesis of
Cyclohexanes with Four Contiguous Stereocenters
O
rganocatalytic
D
o
ominoDou
r
ble Mich
-
ael Reac
C
tion herng Hong,*a Amit A. Sadani,a Roshan Y. Nimje,a Nitin S. Dange,a Gene-Hsiang Leeb
a
Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi, 621, Taiwan, R.O.C.
Fax +886(5)2721040; E-mail: chebch@ccu.edu.tw
Instrumentation Center, National Taiwan University, Taipei, 106, Taiwan, R.O.C.
b
Received 14 March 2011
Initially, we chose ethyl (E)-7-oxohept-2-enoate (1) and
cinnamaldehyde (2a) to test the feasibility of the proposed
double Michael reaction (Table 1). No reaction occurred
with L-proline (I) in acetonitrile, even after six days. We
Abstract: Organocatalytic domino double Michael reactions of
ethyl (E)-7-oxohept-2-enoate and a,b-unsaturated aldehydes pro-
vided ethyl 2-(2,4-diformyl-3-phenylcyclohexyl)acetate with ex-
cellent diastereoselectivities (>20:1 dr) and enantioselectivities
(>99% ee). The adducts were further transformed to octahydro- were encouraged by the 22% yield of the expected dou-
3H-2-benzopyran-3-ones, octahydroisoquinolin-3(2H)-ones, and
ble-Michael adduct 3a when we conducted the reaction in
decahydro-5H-oxazolo[2,3-a]isoquinolin-5-ones.
the presence of triethylamine and L-proline for 16 hours
Key words: Michael addition, aldehydes, organocatalysis, aldol re-
action, quinolines
(entries 1 and 2). As a further improvement, the same re-
action with the Jørgensen–Hayashi catalyst II–AcOH in
acetonitrile for 14 hours provided 3a in 78% yield with
99% ee (entry 3). Reactions in other solvents (e.g.,
The Michael reaction1 has long served as one of the most CH2Cl2, EtOH, toluene, CHCl3), however, afforded lower
powerful protocols in organic synthesis, and accordingly, yields of 3a (entries 4–7). The reactions with other cata-
the reaction has broad application in many sophisticated lysts, e.g., III–X, provided no product or gave lower
natural products syntheses. Supported by recent advances yields of 3a (entries 8–15). Replacement of acetic acid
in organocatalysis, the synthetic methodologies involving with other additives (PhCO2H, PNBA, DABCO, HFIP)
Michael reactions have expanded the realm of their tradi- and the II-catalyzed reaction in acetonitrile afforded low-
tional applications, resulting in success in diverse utiliza- er yields or only trace amounts of the product (entries 16–
tions.2 Among them, several strategies are noteworthy, 19). Apparently, the original combination of components
including cascade reactions,3 multicomponent reactions,4 of II–AcOH in acetonitrile was the best condition (entry
and the construction of polycontiguous stereocenters in a 3).
stereoselective manner.5 Despite recent successes in
Having established the optimal reaction conditions
domino6 organocatalytic double Michael reactions,7,8 an
(Table 1, entry 3), we next examined the scope and limi-
efficient and highly enantioselective procedure for con-
structing cyclohexanes with appropriated functionalities,
tations of the above system with various a,b-unsaturated
aldehydes. The reaction appears quite general with respect
e.g., dialdehydes, remains a compelling area of investiga-
to the substrates tested, providing the desired adducts with
tion. Particularly, polysubstituted cyclohexanes are prev-
excellent enantiomeric excess values and diastereomeric
alent in natural products and their derivatives have long
ratios (>20:1) in good yields (Table 2). The reaction with
an a,b-unsaturated aldehyde with an electron-withdraw-
ing substituent gave a somewhat lower yield (entry 3).
served as important intermediates in organic synthesis.9
As an extension of our efforts to develop organocatalytic
annulations,10 we report herein a strategy that involves the
The structure as well as the absolute configuration of
organocatalytic domino double Michael reaction which
the products were assigned based on the X-ray analysis
furnishes tetrasubstituted cyclohexanedicarbaldehydes
of (–)-3e (Figure 1). Thus, the origin of the stereoselectiv-
ity in this double-Michael reaction by catalyst II was sim-
ilar to that observed in other examples of organocatalytic
having four contiguous stereocenters with excellent dia-
stereoselectivities and enantioselectivities. We also report
the preliminary applications of this new reaction sequence
in the subsequent transformations of the reaction products
into octahydro-3H-2-benzopyran-3-ones, octahydroiso-
quinolin-3(2H)-ones, and decahydro-5H-oxazolo[2,3-
a]isoquinolin-5-ones.
conjugate addition of aldehydes to a,b-unsaturated alde-
hydes (Figure 1).11
To demonstrate the potential synthetic applications of the
obtained optically active cyclohexane derivatives, 3a was
transformed into several cyclic compounds, including oc-
tahydro-3H-2-benzopyran-3-ones, octahydroisoquinolin-
3(2H)-ones, and decahydro-5H-oxazolo[2,3-a]isoquino-
lin-5-ones (Figure 2). For example, 3a was converted into
octahydro-3H-2-benzopyran-3-one 5 via the reduction of
3a [NaBH4 (0.7 equiv), EtOH, 0 °C, 6 h; 63% yield],
SYNTHESIS 2011, No. 12, pp 1887–1895
x
x.
x
x
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0
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Advanced online publication: 16.05.2011
DOI: 10.1055/s-0030-1260469; Art ID: C28011SS
© Georg Thieme Verlag Stuttgart · New York

1888
B.-C. Hong et al.
PAPER
Table 1 Screening of the Catalyst, Solvent, and Reaction Condi-
Table 2 Scope of the Double Michael Reactiona
tions for the Domino Reactiona
OHC
II–AcOH
O
O
O
OHC
(20 mol%)
CO2Et
O
catalyst
H
CO2Et
R
+
MeCN, r.t.
H
CO2Et
H
CO2Et
+
additive
solvent, r.t.
CHO
H
Ph
R
1
2
3
Ph
CHO
2a
1
3a
Entry
Product
Time
(h)
Yieldb
(%)
eec,d
3
R
(%)
>99
>99
>99
>99
>99e
>99
>99
>99
>99f
>99f
>99f
NHSO2Ar
CO2H
N
N
N
H
N
H
1
2
3a
3b
3c
3d
3e
3f
Ph
14
16
33
46
16
40
12
14
26
32
37
78
87
61
65
79
72
75
70
73
68
69
H
H
O
NHSO2CF3
V Ar = Ph
VI Ar = 2-(CO2Me)-C6H4
I
III
IV
4-BrC6H4
4-O2NC6H4
3
Me
O
N
N
Ar
Ar
OTMS
N
N
4
4-MeOC6H4
3-naphthyl
2-O2NC6H4
4-ClC6H4
N
N
H
N
N
N
H
H
N
N
H
Ph
5
II Ar = Ph
VII
VIII
X
IX Ar = 3,5-(CF3)2C6H3
6
Entry Catalyst–additiveb Solvent
Time (h)
150
16
Yieldc (%)
n.r.
22
7
3g
3h
3i
8
4-FC6H4
1
2
I
MeCN
MeCN
MeCN
CH2Cl2
EtOH
9
4-MeC6H4
2-MeC6H4
CH(OMe)2
I–Et3N
10
11
3j
3
II–AcOH
II–AcOH
II–AcOH
II–AcOH
II–AcOH
III–AcOH
IV–AcOH
V–AcOH
VI–AcOH
VII–TFA
VIII–piperidine
IX–AcOH
X–AcOH
II–PhCO2H
II–PNBA
II–DABCO
II–HFIP
14
78d
60
3k
4
16
a Reaction conditions: 1 (0.2 M), 2 (1.2 equiv), MeCN, 20 °C.
b Isolated yield, dr >20:1.
5
40
58
c Determined on the corresponding a,b-unsaturated ester (prepared
with Ph3P=CO2Et, CHCl3, reflux).
6
toluene
CHCl3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
18
44
d Unless otherwise noted, determined by chiral column (Chiralcel
OD-H).
7
24
40
e Determined by chiral column (Chiralpak IB).
f Determined by chiral column (Chiralpak IA).
8
12
50
9
75
33
10
11
12
13
14
15
16
17
18
19
120
120
120
14
n.r.
n.r.
n.r.
37
120
120
26
n.r.
n.r.
52
35
58
120
120
n.r.
8
a Reaction conditions: 1 (0.2 M), 2a (1.2 equiv), r.t.
b PNBA = 4-nitrobenzoic acid; DABCO = 1,4-diazabicyclo[2.2.2]oc-
tane; HFIP = hexafluoropropan-2-ol.
Figure 1 Stereo plots of the X-ray crystal structures of (–)-3e: C,
gray; O, red, and the ORTEP diagram
c Isolated yields of the adducts 3a; n.r. = no reaction.
d 99% ee, determined by chiral column (Chiralcel OD-H).
the hemiacetal obtained was oxidized by the Fétizon re-
along with a trace amount of the corresponding hemiace- agent (Ag2CO3, celite, toluene, reflux, 4 h; 86% yield).
tal. In contrast, the hemiacetal was obtained in 65% yield Reduction of 3a with diisobutylaluminum hydride (4
when an excess of sodium borohydride (2 equiv) was ap- equiv, CH2Cl2, 0 °C, 4 h) afforded the triol 4 in 62% yield.
plied under the same reaction conditions. Alternatively, Hexahydro-2H-oxazolo[3,2-a]pyridines have been re-
Synthesis 2011, No. 12, 1887–1895 © Thieme Stuttgart · New York

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Organocatalytic Domino Double Michael Reaction
1889
ported to exhibit a wide spectrum of biological activities, borohydride reduction of the Schiff base, prepared in situ
and have been shown to be versatile intermediates in in- from 3a and the corresponding amine (BnNH2, MgSO4,
dole alkaloid syntheses.12 Accordingly, synthetic ap- benzene, reflux, 4 h; NaBH4, MeOH, r.t. to 50 °C, 3 h).
proaches toward the oxazolidinones have continued to be Moreover, 1 and a mixture of cinnamaldehyde 2a and 1-
of interest.13 We therefore explored the possibility of [(E)-2-nitrovinyl]benzene underwent double-Michael–
transforming 3a using our novel synthetic system. Reac- aldol condensation to afford the highly functionalized cy-
tion of 3a with 2.5 equivalents of racemic serine methyl clohexenecarbaldehyde 9 in 61% yield (Figure 2).16
ester hydrochloride (DL-Ser-OMe·HCl) and magnesium
sulfate in toluene at 80 °C for eight hours afforded
A plausible mechanism to account for the formation of 3a
and 9 is proposed as shown in Scheme 2. Initial formation
of the enamine 1a, followed by the nucleophilic attack on
the iminium-activated cinnamaldehyde from the Re face
under the control of the catalyst (TS A) gives intermediate
B, which cyclizes by Michael reaction to afford 3a. Alter-
natively, enamine 1a may be attached to 1-[(E)-2-nitrovi-
nyl]benzene via the transition state (TS C), giving
decahydro-2H-oxazolo[2,3-a]isoquinoline 8 in 68% yield
as the only observable stereoisomer.14,15 The proposed
mechanism is depicted in Scheme 1, and the resulting ste-
reoselectivity demonstrated an example of kinetic asym-
metric transformation. In addition, octahydroisoquinolin-
3(2H)-one 7 was obtained in 83% yield via the sodium
OHC
Ph
OHC
Ph
OHC
Ph
CO2Et
O
CO2Et
DL-Ser-OMe•HCl
NH2
OEt
N
N
CHO
O
HO
CO2Me
3a
CO2Me
R
HO
CO2Me
H
H
D-Ser-OMe
OHC
H
H
H
S
CO2Me
Ph
HO
N
O
NH2
O
L-Ser-OMe
8
CO2Me
H
Scheme 1 Proposed mechanism for the stereoselective synthesis of isoquinoline 8
EtO2C
CHO
Ph
HOH2C
Ph
CO2Et
9
NO2
CHO
3a
EtO2C
NO2
Ph
N
O
N
H
N
O
OHC
Ph
N
CO2Et
= CPh2OTMS
H
B
N
CO2Et
NO2
1a
O
H
N
H
CO2Et
D
Ph
CHO
H
NO2
CO2Et
N
N
NO2
Ph
Ph
H
H
Ph
EtO2C
TS A
TS C
EtO2C
Scheme 2 Proposed mechanisms for the organocatalytic double Michael and double Michael–aldol reactions
Synthesis 2011, No. 12, 1887–1895 © Thieme Stuttgart · New York

1890
B.-C. Hong et al.
PAPER
a yellow oil; HPLC: (Chiralcel OD-H, 250 × 4.6 mm, n-hexane–
i-PrOH, 98:2, 1.0 mL/min): tR = 16.96 (>99% ee), 18.65 min.
[a]D26 –48 (c 2, CHCl3).
BnHN
HO
HO
Ph
R
4-BrC6H4
OH
N
O
O
O
OH
Bn
IR (neat): 2927, 2857, 2723, 1725, 1452, 1375, 1260, 1214, 1166,
1090, 939, 852, 760 cm–1.
5 R = Ph
6 R = 4-BrC6H4
7
4
1H NMR (500 MHz, CDCl3): d = 9.39 (d, J = 2.6 Hz, 1 H), 9.35 (d,
J = 4.2 Hz, 1 H), 7.30–7.22 (m, 2 H), 7.20–7.12 (m, 3 H), 4.09 (q,
J = 7.1 Hz, 2 H), 3.09 (dd, J = 11.5, 11.5 Hz, 1 H), 2.70–2.61 (m, 1
H), 2.53–2.48 (m, 1 H), 2.36 (dd, J = 15.4, 4.2 Hz, 1 H), 2.27–2.20
(m, 1 H), 2.17 (dd, J = 15.4, 8.0 Hz, 1 H), 2.12–2.05 (m, 1 H), 2.02–
1.98 (m, 1 H), 1.57–1.48 (m, 1 H), 1.38–1.30 (m, 1 H), 1.22 (t,
J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 203.2 (CH), 202.7 (CH), 171.8
(C), 139.1 (C), 129.2 (2 CH), 127.9 (2 CH), 127.7 (CH), 60.6 (CH2),
59.9 (CH), 54.5 (CH), 45.4 (CH), 38.6 (CH2), 33.8 (CH), 30.1
(CH2), 25.8 (CH2), 14.1 (CH3).
H
OHC
H
CHO
EtO2C
H
Ph
H
H
O
Ph
Ph
O
N
NO2
8
9
CO2Me
H
Figure 2 Derivatives of the double-Michael adducts
intermediate D, followed by the nitro-Michael and the
subsequent aldol condensation to give 9.
MS: m/z (%) = 302 (M+, 2), 274 (2), 256 (39), 227 (7), 197 (18), 182
(30), 168 (75), 129 (39), 115 (37), 91 (100).
In conclusion, we have realized an asymmetric domino
double Michael reaction for the facile synthesis of cyclo-
hexanedicarbaldehydes, and their subsequent transforma-
HRMS: m/z [M]+ calcd for C18H22O4: 302.1518; found: 302.1521.
Ethyl [(1S,2S,3S,4R)-3-(4-Bromophenyl)-2,4-diformylcyclohex-
tions to octahydro-3H-2-benzopyran-3-ones, octahydro- yl]acetate (3b)
Yellow oil; Rf = 0.39 (30% EtOAc–hexane); HPLC: (Chiralcel OD-
H, 250 × 4.6 mm, n-hexane–i-PrOH, 98:2, 1.0 mL/min): tR = 26.35
(>99% ee), 32.80 min.
[a]D26 –13.9 (c 3.2, CHCl3).
isoquinolin-3(2H)-ones, and decahydro-5H-oxazolo[2,3-
a]isoquinolin-5-ones. It is worth noting that this reaction
cascade provides four contiguous stereogenic centers in
the domino reaction adducts with excellent diastereo-
selectivities (>20:1) and enantioselectivities (>99% ee).
The structure was confirmed by X-ray crystal structure
analysis of the appropriate adduct.17 Further work is under
way to explore its synthetic applications.
IR (neat): 2926, 2857, 2722, 1725, 1484, 1376, 1260, 1213, 1166,
1079, 1018, 821, 711, 672, 530, 472 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.39 (d, J = 2.5 Hz, 1 H), 9.35 (d,
J = 4.3 Hz, 1 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.04 (d, J = 8.5 Hz, 2 H),
4.09 (q, J = 7.1 Hz, 2 H), 3.09 (dd, J = 11.5, 11.5 Hz, 1 H), 2.67–
2.59 (m, 1 H), 2.48–2.43 (m, 1 H), 2.35 (dd, J = 15.3, 3.9 Hz, 1 H),
2.27–2.13 (m, 2 H), 2.11–1.97 (m, 2 H), 1.53–1.44 (m, 1 H), 1.38–
1.28 (m, 1 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 202.9 (CH), 202.1 (CH), 171.7
(C), 138.4 (C), 132.2 (2 CH), 129.6 (2 CH), 121.5 (C), 60.6 (CH2),
59.7 (CH), 54.4 (CH), 44.4 (CH), 38.5 (CH2), 33.9 (CH), 30.0
(CH2), 25.7 (CH2), 14.1 (CH3).
MS: m/z (%) = 382 (M+ + 2, 5), 380 (M+, 5), 336 (26), 334 (26), 290
(10), 277 (16), 248 (34), 209 (11), 181 (20), 169 (46), 167 (78), 141
(23), 128 (48), 116 (48), 88 (100).
HRMS: m/z [M]+ calcd for C18H21BrO4: 380.0623; found:
380.0625.
All solvents were reagent grade. L-proline (+99%) was purchased
from Bachem. Other chemicals were purchased from Aldrich or
Acros Chemical Co. Reactions were normally carried out under an
argon atmosphere in glassware. Merck silica gel 60 (particle size
0.04–0.063 mm) was employed for flash chromatography. Melting
1
points are uncorrected. H NMR spectra were obtained in CDCl3
unless otherwise noted at 400 MHz (Bruker DPX-400) or 500 MHz
(Varian-Unity INOVA-500). 13C NMR spectra were obtained at
100 MHz or 125 MHz. Enantiomeric excess values were measured
by HPLC on a chiral column (Chiralpak IA, Chiralpak IB, Chiral-
pak IC, or Chiralcel OD-H, 0.46 cm ID × 25 cm, particle size 5 m)
by elution with i-PrOH–hexane. The flow rate of the indicated elu-
tion solvent is maintained at 1 mL/min, and the retention time of a
compound is recorded accordingly. HPLC was equipped with the
UV and refractive index detectors. The melting point was recorded
on a melting point apparatus (MPA100– Automated melting point
system, Stanford Research Systems, Inc.) and is uncorrected. The
optical rotation values were recorded with a Jasco-P-2000 digital
polarimeter.
Ethyl [(1S,2S,3S,4R)-2,4-Diformyl-3-(4-nitrophenyl)cyclohex-
yl]acetate (3c)
Pale-yellow oil; Rf = 0.56 (50% EtOAc–hexane); HPLC: (Chiralcel
OD-H, 250 × 4.6 mm, n-hexane–i-PrOH, 96:4, 1.0 mL/min):
tR = 40.57 (>99% ee), 49.76 min.
[a]D26 +1.9 (c 2.8, CHCl3).
Ethyl [(1S,2S,3S,4R)-2,4-Diformyl-3-phenylcyclohexyl]acetate
(3a); Typical Procedure
IR (neat): 2929, 1722, 1604, 1515, 1459, 1353, 1180, 1093, 1025,
848, 696 cm–1.
To a solution of ethyl (E)-7-oxohep-2-enoate (1, 100 mg, 0.59
mmol) and cinnamaldehyde (2a, 93 mg, 0.7 mmol) in MeCN (2
mL) was added dropwise a solution of catalyst II (38 mg, 0.12
mmol) and AcOH (7 mg, 0.12 mmol) in MeCN (1 mL). The result-
ing solution was stirred at r.t. for 14 h, and diluted with EtOAc (30
mL). The solution was washed with brine (10 mL), dried (Na2SO4),
and concentrated in vacuo to give the crude product. The residue
was purified by flash column chromatography [10% EtOAc–hex-
ane; Rf = 0.41 (30% EtOAc–hexane)] to give 3a (138 mg, 78%) as
1H NMR (500 MHz, CDCl3): d = 9.41 (d, J = 2.1 Hz, 1 H), 9.38 (d,
J = 4.2 Hz, 1 H), 8.12 (d, J = 8.8 Hz, 2 H), 7.36 (d, J = 8.8 Hz, 2 H),
4.10 (q, J = 7.1 Hz, 2 H), 3.29 (dd, J = 11.5, 11.5 Hz, 1 H), 2.76–
2.71 (m, 1 H), 2.56–2.51 (m, 1 H), 2.40–2.34 (m, 1 H), 2.29–2.19
(m, 2 H), 2.18–2.07 (m, 2 H), 1.53–1.34 (m, 2 H), 1.22 (t, J = 7.1
Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 202.3 (CH), 201.0 (CH), 171.5
(C), 147.4 (C), 147.1 (C), 129.1 (2 CH), 124.2 (2 CH), 60.7 (CH2),
Synthesis 2011, No. 12, 1887–1895 © Thieme Stuttgart · New York

PAPER
Organocatalytic Domino Double Michael Reaction
1891
59.5 (CH), 54.4 (CH), 44.3 (CH), 38.3 (CH2), 34.0 (CH), 30.1
(CH2), 25.7 (CH2), 14.1 (CH3).
MS: m/z (%) = 348 (M+ + 1, 3), 319 (34), 302 (33), 273 (6), 256
(12), 227 (17), 214 (22), 196 (11), 137 (12), 128 (27), 115 (35), 88
(100).
1H NMR (500 MHz, CDCl3): d = 9.48 (d, J = 4.7 Hz, 1 H), 9.38 (d,
J = 1.9 Hz, 1 H), 7.71 (dd, J = 8.1, 1.0 Hz, 1 H), 7.56–7.52 (m, 1 H),
7.40 (d, J = 7.8 Hz, 1 H), 7.35–7.30 (m, 1 H), 4.10 (q, J = 7.1 Hz, 2
H), 3.92 (dd, J = 11.5, 11.5 Hz, 1 H), 2.68–2.61 (m, 1 H), 2.52–2.46
(m, 1 H), 2.38 (dd, J = 15.6, 4.2 Hz, 1 H), 2.34–2.26 (m, 1 H), 2.21
(dd, J = 15.6, 7.8 Hz, 1 H), 2.15–2.10 (m, 2 H), 1.55–1.34 (m, 2 H),
1.23 (t, J = 7.1 Hz, 3 H).
HRMS: m/z [M]+ calcd for C18H21NO6: 347.1369; found: 347.1366.
13C NMR (125 MHz, CDCl3): d = 202.3 (CH), 201.0 (CH), 171.5
(C), 150.5 (C), 134.3 (C), 133.1 (CH), 128.7 (CH), 128.2 (CH),
124.5 (CH), 60.7 (CH2), 60.3 (CH), 55.2 (CH), 38.5 (CH2), 37.5
(CH), 33.8 (CH), 30.1 (CH2), 25.7 (CH2), 14.1 (CH3).
Ethyl [(1S,2S,3S,4R)-2,4-Diformyl-3-(4-methoxyphenyl)cyclo-
hexyl]acetate (3d)
Yellow oil; Rf = 0.49 (40% EtOAc–hexane); HPLC: (Chiralcel OD-
H, 250 × 4.6 mm, n-hexane–i-PrOH, 96:4, 1.0 mL/min): tR = 32.75
(>99% ee), 35.58 min.
MS: m/z (%) = 348 (M+ + 1, 17), 302 (36), 272 (39), 256 (74), 238
(48), 228 (33), 196 (53), 182 (62), 180 (63), 168 (100).
HRMS: m/z [M]+ calcd for C18H21NO6: 347.1369; found: 347.1368.
[a]D26 –34.7 (c 3.6, CHCl3).
IR (neat): 2929, 1724, 1600, 1500, 1458, 1377, 1255, 1176, 1028,
825, 561 cm–1.
Ethyl [(1S,2S,3S,4R)-3-(4-Chlorophenyl)-2,4-diformylcyclohex-
yl]acetate (3g)
Yellow oil; Rf = 0.41 (30% EtOAc–hexane); HPLC (Chiralcel OD-
H, 250 × 4.6 mm, n-hexane–i-PrOH, 98:2, 1.0 mL/min): tR = 24.12
min (>99% ee), 29.25 min.
1H NMR (500 MHz, CDCl3): d = 9.38 (d, J = 2.7 Hz, 1 H), 9.33 (d,
J = 4.3 Hz, 1 H), 7.07 (d, J = 8.7 Hz, 2 H), 6.78 (d, J = 8.7 Hz, 2 H),
4.08 (q, J = 7.1 Hz, 2 H), 3.72 (s, 3 H), 3.05 (dd, J = 11.5, 11.5 Hz,
1 H), 2.63–2.54 (m, 1 H), 2.46–2.40 (m, 1 H), 2.38–2.32 (m, 1 H),
2.27–2.12 (m, 2 H), 2.08–2.03 (m, 1 H), 1.99–1.93 (m, 1 H), 1.56–
1.45 (m, 1 H), 1.35–1.24 (m, 1 H), 1.21 (t, J = 7.1 Hz, 3 H).
[a]D26 –18.3 (c 4, CHCl3).
IR (neat): 2929, 1724, 1477, 1390, 1182, 1093, 1024, 819, 696, 541,
433 cm–1.
13C NMR (125 MHz, CDCl3): d = 203.4 (CH), 203.0 (CH), 171.8
(C), 158.8 (C), 131.0 (C), 128.9 (2 CH), 114.5 (2 CH), 60.5 (CH2),
60.1 (CH), 55.1 (CH3), 54.6 (CH), 44.5 (CH), 38.5 (CH2), 33.8
(CH), 30.0 (CH2), 25.8 (CH2), 14.1 (CH3).
MS: m/z (%) = 332 (M+, 28), 314 (8), 287 (11), 258 (6), 227 (33),
197 (22), 187 (14), 159 (23), 147 (24), 121 (100).
1H NMR (500 MHz, CDCl3): d = 9.39 (d, J = 2.5 Hz, 1 H), 9.35 (d,
J = 4.2 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 2 H), 7.10 (d, J = 8.4 Hz, 2 H),
4.09 (q, J = 7.1 Hz, 2 H), 3.10 (dd, J = 11.5, 11.5 Hz, 1 H), 2.67–
2.57 (m, 1 H), 2.49–2.43 (m, 1 H), 2.35 (dd, J = 15.3, 3.9 Hz, 1 H),
2.28–2.14 (m, 2 H), 2.12–1.99 (m, 2 H), 1.53–1.45 (m, 1 H), 1.40–
1.27 (m, 1 H), 1.22 (t, J = 7.1 Hz, 3 H).
HRMS: m/z [M]+ calcd for C19H24O5: 332.1624; found: 332.1621.
13C NMR (125 MHz, CDCl3): d = 202.9 (CH), 202.1 (CH), 171.7
(C), 137.8 (C), 133.4 (C), 129.3 (4 CH), 60.6 (CH2), 59.8 (CH), 54.5
(CH), 44.4 (CH), 38.5 (CH2), 33.9 (CH), 30.1 (CH2), 25.8 (CH2),
14.1 (CH3).
Ethyl [(1S,2S,3S,4R)-2,4-Diformyl-3-(2-naphthyl)cyclohex-
yl]acetate (3e)
Yellow solid; mp 150–152 °C; Rf = 0.36 (30% EtOAc–hexane;
HPLC (Chiralpak IB, 250 × 4.6 mm, n-hexane–i-PrOH, 98:2, 1.0
mL/min): tR = 37.16 (>99%), 44.46 min.
MS: m/z (%) = 336 (M+, 5), 290 (36), 255 (24), 231 (20), 216 (25),
202 (48), 191 (29), 167 (49), 125 (91), 115 (43), 88 (100).
HRMS: m/z [M]+ calcd for C18H21O4Cl: 336.1128; found: 336.1129.
[a]D26 –22.1 (c 1.6, CHCl3).
IR (neat): 2929, 1720, 1454, 1373, 1263, 1153, 1028, 808, 744, 465,
424 cm–1.
Ethyl [(1S,2S,3S,4R)-3-(4-Fluorophenyl)-2,4-diformylcyclohex-
yl]acetate (3h)
Yellow oil; Rf = 0.39 (30% EtOAc–hexane); HPLC (Chiralcel OD-
H, 250 × 4.6 mm, n-hexane–i-PrOH, 98:2, 1.0 mL/min): tR = 23.13
(>99% ee), 27.55 min.
1H NMR (500 MHz, CDCl3): d = 9.41 (d, J = 2.5 Hz, 1 H), 9.39 (d,
J = 4.2 Hz, 1 H), 7.81–7.72 (m, 3 H), 7.62 (s, 1 H),7.46–7.41 (m, 2
H), 7.32 (d, J = 8.5 Hz, 1 H), 4.11 (q, J = 7.1 Hz, 2 H), 3.27 (dd,
J = 11.5, 11.5 Hz, 1 H), 2.82–2.76 (m, 1 H), 2.68–2.61 (m, 1 H),
2.40 (dd, J = 15.6, 4.3 Hz, 1 H), 2.34–2.25 (m, 1 H), 2.20 (dd,
J = 15.5, 7.9 Hz, 1 H), 2.14–2.10 (m, 1 H), 2.06–2.03 (m, 1 H),
1.62–1.54 (m, 1 H), 1.43–1.35 (m, 1 H), 1.23 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 203.2 (CH), 202.7 (CH), 171.9
(C), 136.6 (C), 133.4 (C), 132.8 (C), 129.2 (CH), 127.73 (CH),
127.68 (CH), 127.2 (CH), 126.5 (CH), 126.1 (CH), 125.3 (CH),
60.6 (CH2), 59.8 (CH), 54.4 (CH), 45.6 (CH), 38.6 (CH2), 33.9
(CH), 30.1 (CH2), 25.8 (CH2), 14.2 (CH3).
[a]D26 –21.0 (c 2.8, CHCl3).
IR (neat): 2929, 1724, 1500, 1373, 1234, 1174, 1024, 833, 553, 433
cm–1.
1H NMR (500 MHz, CDCl3): d = 9.39 (d, J = 2.6 Hz, 1 H), 9.35 (d,
J = 4.3 Hz, 1 H), 7.14 (dd, J = 8.6, 5.3 Hz, 2 H), 6.96 (dd, J = 8.6,
5.3 Hz, 2 H), 4.09 (q, J = 7.1 Hz, 2 H), 3.12 (dd, J = 11.5, 11.5 Hz,
1 H), 2.66–2.58 (m, 1 H), 2.48–2.43 (m, 1 H), 2.35 (dd, J = 15.3, 4.0
Hz, 1 H), 2.28–2.14 (m, 2 H), 2.10–1.96 (m, 2 H), 1.55–1.46 (m, 1
H), 1.37–1.28 (m, 1 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 203.0 (CH), 202.3 (CH), 171.7
(C), 161.9 (d, J = 245.3 Hz, C), 135.0 (d, J = 2.9 Hz, C), 129.5 (d,
J = 7.6 Hz, 2 CH), 116.1 (d, J = 22.0 Hz, 2 CH), 60.6 (CH2), 60.0
(CH), 54.7 (CH), 44.4 (CH), 38.5 (CH2), 33.9 (CH), 30.1 (CH2),
25.8 (CH2), 14.1 (CH3).
MS: m/z (%) = 352 (M+, 18), 332 (13), 305 (10), 277 (7), 255 (62),
222 (51), 182 (44), 179 (35), 165 (49), 141 (100).
HRMS: m/z [M]+ calcd for C22H24O4: 352.1675; found: 352.1672.
Ethyl [(1S,2S,3S,4R)-2,4-Diformyl-3-(2-nitrophenyl)cyclohex-
yl]acetate (3f)
Pale-yellow oil; Rf = 0.51 (50% EtOAc–hexane); HPLC (Chiralpak
IA, 250 × 4.6 mm, n-hexane–EtOAc, 90:10, 1.0 mL/min):
tR = 58.55 (>99% ee), 77.95 min.
MS: m/z (%) = 320 (M+, 2), 274 (32), 255 (10), 215 (17), 200 (29),
186 (52), 175 (22), 147 (33), 135 (26), 109 (100).
[a]D26 +93.5 (c 4, CHCl3).
HRMS: m/z [M]+ calcd for C18H21O4F: 320.1424; found: 320.1426.
IR (neat): 2933, 1724, 1525, 1359, 1186, 1024, 856, 767, 561, 443
cm–1.
Synthesis 2011, No. 12, 1887–1895 © Thieme Stuttgart · New York

1892
B.-C. Hong et al.
PAPER
Ethyl [(1S,2S,3S,4R)-2,4-Diformyl-3-(4-methylphenyl)cyclo-
hexyl]acetate (3i)
Yellow oil; Rf = 0.46 (30% EtOAc–hexane); HPLC (Chiralcel OD-
H, 250 × 4.6 mm, n-hexane–i-PrOH, 99:1, 1.0 mL/min): tR = 51.60
(>99% ee), 57.16 min.
MS: m/z (%) = 301 (M+ + 1, 1), 299 (1), 253 (5), 237 (15), 223 (6),
207 (6), 179 (5), 166 (5), 149 (6), 135 (6), 105 (12), 91 (11), 79 (14),
75 (100).
HRMS: m/z [M]+ calcd for C15H24O6: 300.1573; found: 300.1573.
[a]D26 –37.5 (c 1.4, CHCl3).
IR (neat): 2931, 1724, 1454, 1384, 1280, 1174, 1025, 811, 528 cm–1.
2-[(1S,2S,3S,4R)-3-(4-Bromophenyl)-2,4-bis(hydroxymeth-
yl)cyclohexyl]ethanol (4)
To a solution of 3b (38 mg, 0.1 mmol) in CH2Cl2 (3 mL) was added
a solution of 1.2 M DIBAL-H in toluene (0.4 mL, 0.48 mmol) at 0
°C. The solution was stirred at 0 °C for 4 h until completion of the
reaction. The reaction was quenched by the addition of H2O (0.5
mL), and the solution was diluted with EtOAc (10 mL). The result-
ing solution was washed with brine (2 mL), dried (MgSO4), and
concentrated in vacuo to give the crude product. The residue was
purified by flash column chromatography [80% EtOAc–hexane,
Rf = 0.29 (100% EtOAc)] to give 4 (21 mg, 62%) as a white solid;
mp 133–135 °C.
1H NMR (500 MHz, CDCl3): d = 9.38 (d, J = 2.7 Hz, 1 H), 9.34 (d,
J = 4.3 Hz, 1 H), 7.07 (d, J = 8.2 Hz, 2 H), 7.04 (d, J = 8.2 Hz, 2 H),
4.09 (q, J = 7.1 Hz, 2 H), 3.05 (dd, J = 11.5, 11.5 Hz, 1 H), 2.66–
2.58 (m, 1 H), 2.49–2.44 (m, 1 H), 2.39–2.33 (m, 1 H), 2.25 (s, 3 H),
2.24–2.13 (m, 1 H), 2.09–1.96 (m, 2 H), 1.56–1.47 (m, 1 H), 1.36–
1.25 (m, 2 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 203.4 (CH), 203.0 (CH), 171.8
(C), 137.4 (C), 136.0 (C), 129.9 (2 CH), 127.7 (2 CH), 60.6 (CH2),
60.0 (CH), 54.5 (CH), 45.0 (CH), 38.6 (CH2), 33.8 (CH), 30.1
(CH2), 25.8 (CH2), 21.0 (CH3), 14.2 (CH3).
[a]D26 –4.1 (c 1.4, acetone).
IR (neat): 3351, 2922, 1479, 1018, 813, 544 cm–1.
MS: m/z (%) = 317 (M+ + 1, 12), 298 (19), 270 (39), 241 (9), 211
(42), 196 (23), 183 (55), 182 (61), 143 (35), 129 (40), 105 (100).
HRMS: m/z [M]+ calcd for C19H24O4: 316.1675; found: 316.1674.
1H NMR (500 MHz, acetone-d6): d = 7.44 (d, J = 8.3 Hz, 2 H), 7.19
(d, J = 8.3 Hz, 2 H), 3.68–3.55 (m, 2 H), 3.31–3.17 (m, 2 H), 3.04–
2.93 (m, 1 H), 2.85 (s, 3 H), 2.65 (dd, J = 11.5, 11.5 Hz, 1 H), 2.06–
1.89 (m, 3 H), 1.99–1.89 (m, 1 H), 1.76–1.62 (m, 1 H), 1.41–1.22
(m, 5 H).
13C NMR (125 MHz, acetone-d6): d = 145.3 (C), 131.9 (4 CH),
119.7 (C), 65.7 (CH2), 60.8 (CH2), 59.6 (CH2), 50.6 (CH), 47.1
(CH), 46.4 (CH), 37.2 (CH2), 35.2 (CH), 32.6 (CH2), 30.1 (CH2).
Ethyl [(1S,2S,3S,4R)-2,4-Diformyl-3-(2-methylphenyl)cyclo-
hexyl]acetate (3j)
Yellow oil; Rf = 0.49 (30% EtOAc–hexane); HPLC (Chiralpak IA,
250 × 4.6 mm, n-hexane–EtOAc, 90:10, 1.0 mL/min): tR = 15.47
min (>99% ee), 17.37 min.
[a]D26 –24.2 (c 2, CHCl3).
MS: m/z (%) = 342 (M+, 5), 324 (18), 294 (12), 277 (17), 249 (33),
196 (23), 171 (94), 169 (100), 141 (35), 129 (68), 116 (88), 91 (43),
77 (26), 55 (23).
IR (neat): 2931, 1724, 1461, 1376, 1274, 1174, 1093, 1027, 746,
572, 424 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.34 (d, J = 1.9 Hz, 1 H), 9.33 (d,
J = 3.8 Hz, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 7.21–7.14 (m, 1 H), 7.07
(d, J = 4.1 Hz, 2 H), 4.09 (q, J = 7.1 Hz, 2 H), 3.30 (dd, J = 11.5,
11.5 Hz, 1 H), 2.78–2.68 (m, 1 H), 2.62–2.57 (m, 1 H), 2.36 (dd,
J = 15.3, 4.3 Hz, 1 H), 2.28 (s, 3 H), 2.17 (dd, J = 15.4, 7.9 Hz, 1 H),
2.09–2.00 (m, 2 H), 1.56–1.47 (m, 1 H), 1.38–1.29 (m, 2 H), 1.22 (t,
J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 203.3 (CH), 202.6 (CH), 171.8
(C), 137.8 (C), 135.6 (C), 130.8 (CH), 127.2 (CH), 126.9 (CH),
126.5 (CH), 60.64 (CH2), 60.55 (CH), 55.4 (CH), 39.9 (CH), 38.6
(CH2), 34.2 (CH), 30.2 (CH2), 25.8 (CH2), 20.1 (CH3), 14.1 (CH3).
HRMS: m/z [M]+ calcd for C16H23BrO3: 342.0831; found:
342.0828.
(4aS,7R,8S,8aS)-7-(Hydroxymethyl)-8-phenyloctahydro-3H-2-
benzopyran-3-one (5); Typical Procedures
Method A: To a solution of 3a (30 mg, 0.1 mmol) in EtOH (3 mL)
was added NaBH4 (3 mg, 0.07 mmol) at 0 °C, and the solution was
stirred for 6 h, followed by the addition of H2O (0.5 mL). The solu-
tion was diluted with EtOAc (10 mL), washed with brine (2 mL),
dried (MgSO4), and concentrated in vacuo to give the crude product.
The residue was purified by flash column chromatography [40%
EtOAc–hexane, Rf = 0.46 (80% EtOAc–hexane)] to give lactone 5
(16 mg, 63%) as a white solid; mp 164–166 °C.
MS: m/z (%) = 316 (M+, 2), 298 (3), 270 (12), 255 (11), 252 (9), 211
(13), 196 (15), 183 (30), 182 (51), 143 (21), 129 (28), 111 (24), 105
(77), 85 (40), 71 (62), 57 (100).
[a]D26 –15.2 (c 1.8, CHCl3).
HRMS: m/z [M]+ calcd for C19H24O4: 316.1675; found: 316.1677.
A trace amount of hemiacetal product (10%) was also obtained
along with the lactone 5.
Ethyl [(1S,2S,3S,4R)-3-(Dimethoxymethyl)-2,4-diformylcyclo-
hexyl]acetate (3k)
Yellow oil; Rf = 0.32 (40% EtOAc–hexane); HPLC (Chiralpak IA,
250 × 4.6 mm, n-hexane–EtOAc, 90:10, 1.0 mL/min): tR = 21.93
(>99% ee), 25.63 min.
Method B: To a solution of the hemiacetal obtained above (26 mg,
0.1 mmol) and Celite (40 mg) in toluene (3 mL) was added Ag2CO3
(41 mg, 0.15 mmol). The solution was heated to reflux for 4 h until
completion of the reaction. The mixture was filtered, and the result-
ing solution was concentrated in vacuo to give the crude product.
The residue was purified by flash column chromatography [40%
EtOAc–hexane, Rf = 0.46 (80% EtOAc–hexane)] to give lactone 5
(22 mg, 86%) as a white solid; mp 164–166 °C.
26
[a]D –10.9 (c 2.6, CHCl3).
IR (neat): 2929, 1722, 1454, 1376, 1187, 1062, 811 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.41 (d, J = 4.2 Hz, 1 H), 9.39 (d,
J = 4.3 Hz, 1 H), 4.08 (q, J = 7.1 Hz, 2 H), 4.01 (d, J = 6.1 Hz, 1 H),
3.30 (s, 3 H), 3.28 (s, 3 H), 2.48–2.42 (m, 1 H), 2.39–2.33 (m, 1 H),
2.22–2.14 (m, 2 H), 2.08–1.95 (m, 3 H), 1.78–1.72 (m, 1 H), 1.40–
1.32 (m, 2 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 201.6 (CH), 201.5 (CH), 171.9
(C), 108.3 (CH), 60.5 (CH2), 56.3 (CH3), 56.2 (CH3), 54.5 (CH),
49.8 (CH), 42.5 (CH), 38.4 (CH2), 32.7 (CH), 29.6 (CH2), 25.2
(CH2), 14.1 (CH3).
[a]D26 –15.2 (c 1.8, CHCl3).
IR (neat): 3437, 2919, 1726, 1449, 1253, 1217, 1050, 800, 755, 702,
563 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.32–7.29 (m, 2 H), 7.23–7.21 (m,
1 H), 7.13 (br s, 2 H), 3.83–3.76 (m, 2 H), 3.34 (dd, J = 10.8, 3.0 Hz,
1 H), 3.20–3.17 (m, 1 H), 2.73 (dd, J = 18.1, 5.2 Hz, 1 H), 2.20–2.13
(m, 2 H), 2.06–1.98 (m, 1 H), 1.97–1.89 (m, 1 H), 1.86–1.79 (m, 2
Synthesis 2011, No. 12, 1887–1895 © Thieme Stuttgart · New York

PAPER
Organocatalytic Domino Double Michael Reaction
1893
H), 1.76–1.65 (m, 1 H), 1.5 (br s, 1 H), 1.48–1.39 (m, 1 H), 1.27–
1.19 (m, 1 H).
HRMS: m/z [M]+ calcd for C30H34N2O: 438.2671; found: 438.2673.
Methyl (3R,6aS,9R,10R,10aS,10bS)-9-Formyl-5-oxo-10-phenyl-
decahydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-3-carboxylate
(8)
13C NMR (125 MHz, CDCl3): d = 170 (C), 140.9 (C), 129.1 (2 CH),
127.3 (3 CH), 73.7 (CH2), 65.1 (CH2), 48.0 (CH), 45 (CH), 43.1
(CH), 37.1 (CH2), 36.6 (CH), 32 (CH2), 28.5 (CH2).
To a solution of 3a (20 mg, 0.06 mmol) and racemic serine methyl
ester hydrochloride (DL-Ser-OMe·HCl, 26 mg, 0.16 mmol) in tolu-
ene was added Et3N (23 mg, 0.23 mmol) and MgSO4. The solution
was stirred at 80 °C for 8 h until the completion of reaction (TLC
and NMR). The mixture was diluted with EtOAc (5 mL), and the re-
sulting solution was washed with 1 M aq HCl solution, dried
(Na2SO4), and concentrated in vacuo to give the crude product. The
residue was purified by flash column chromatography [Rf = 0.3,
(80% EtOAc–hexane)] to afford isoquinoline 8 (16 mg, 68%) as a
yellow oil.
MS: m/z (%) = 261 (M+ + 1, 7), 260 (M+, 30), 255 (12), 242 (5), 189
(12), 155 (13), 149 (16), 129 (26), 117 (30), 105 (19), 91 (59), 71
(65), 57 (100), 55 (59).
HRMS: m/z [M]+ calcd for C16H20O3: 260.1412; found: 260.1409.
(4aS,7R,8S,8aS)-8-(4-Bromophenyl)-7-(hydroxymethyl)octahy-
dro-3H-2-benzopyran-3-one (6)
White solid (23 mg, 67%); mp 139–141 °C; Rf = 0.50 (80% EtOAc–
hexane).
[a]D26 –17.1 (c 3, CHCl3).
[a]D26 –21.7 (c 2.6, CHCl3).
IR (neat): 2928, 2861, 1729, 1655, 1459, 1367, 1202, 1104, 960,
874, 757, 701, 589, 556 cm–1.
IR (neat): 3441, 2918, 1726, 1482, 1407, 1217, 1057, 811, 754, 534
cm–1.
1H NMR (500 MHz, CDCl3): d = 9.31 (d, J = 2.3 Hz, 1 H), 7.22 (d,
J = 7.6 Hz, 2 H), 7.18–7.12 (m, 3 H), 4.52 (d, J = 8.5 Hz, 1 H), 4.26
(d, J = 6.2 Hz, 1 H), 3.77 (dd, J = 9.8, 1.3 Hz, 1 H), 3.69 (d, J = 5.3
Hz, 1 H), 3.66 (s, 3 H), 2.75–2.69 (m, 1 H), 2.58 (dd, J = 18.1, 5.6
Hz, 1 H), 2.21 (dd, J = 18.2, 11.8 Hz, 1 H), 2.05–1.94 (m, 3 H),
1.79–1.73 (m, 1 H), 1.52–1.43 (m, 1 H), 1.39–1.30 (m, 1 H), 1.24–
1.18 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 203.5 (CH), 169.9 (C), 167.4 (C),
140.9 (C), 128.5 (2 CH), 128.4 (CH), 128.2 (CH), 126.9 (CH), 92.8
(CH), 68.9 (CH2), 56.0 (CH), 55.7 (CH), 52.5 (CH3), 47.9 (CH),
46.7 (CH), 38.1 (CH2), 34.2 (CH), 30.7 (CH2), 25.7 (CH2).
1H NMR (500 MHz, CDCl3): d = 7.44 (d, J = 7.9 Hz, 2 H), 7.02 (d,
J = 5.1 Hz, 2 H), 3.85–3.72 (m, 2 H), 3.32 (dd, J = 10.7, 2.9 Hz, 1
H), 3.16 (dd, J = 10.7, 5.6 Hz, 1 H), 2.72 (dd, J = 18.1, 5.2 Hz, 1 H),
2.22–2.16 (m, 2 H), 2.04–1.96 (m, 1 H), 1.96–1.87 (m, 1 H), 1.84–
1.64 (m, 3 H), 1.54 (br s, 1 H), 1.49–1.41 (m, 1 H), 1.29–1.17 (m, 1
H).
13C NMR (125 MHz, CDCl3): d = 169.9 (C), 140.1 (C), 132.2 (4
CH), 121 (C), 73.5 (CH2), 64.7 (CH2), 47.2 (CH), 45 (CH), 43 (CH),
37.1 (CH2), 36.5 (CH), 31.9 (CH2), 28.4 (CH2).
MS: m/z (%) = 340 (M+ + 2, 99), 338 (M+, 100), 278 (10), 262 (22),
221 (9), 195 (14), 182 (22), 169 (63), 149 (38), 129 (53), 116 (69),
91 (29), 77 (29), 59 (52), 57 (71).
HRMS: m/z [M]+ calcd for C16H19BrO3: 338.0518; found:
338.0519.
MS: m/z (%) = 357 (M+, 8), 341 (9), 285 (100), 226 (6), 130 (20),
115 (7), 91 (9), 71 (7), 57 (13).
HRMS: m/z [M]+ calcd for C20H23NO5: 357.1576; found: 357.1575.
Ethyl (2E,1S,4R,5R,6S)-5-(3-Formyl-5-nitro-4,6-diphenylcyclo-
hex-2-enyl)pent-2-enoate (9)
(4aS,7R,8S,8aS)-2-Benzyl-7-[(benzylamino)methyl]-8-phenyl-
octahydroisoquinolin-3(2H)-one (7)
To a solution of ethyl (E)-7-oxohept-2-enoate (1, 34 mg, 0.2 mmol)
and b-nitrostyrene (36 mg, 0.24 mmol) in MeCN (1 mL) was added
a solution of catalyst II (13 mg, 0.04 mmol) and AcOH (2.4 mg,
0.04 mmol) in MeCN (1 mL). The solution was stirred at r.t. for 0.5
h, followed by the addition of cinnamaldehyde (40 mg, 0.3 mmol),
and the resulting solution was stirred for 24 h until completion of re-
action. The solution was concentrated in vacuo to give the crude
product. The residue was purified by flash column chromatography
[20% EtOAc–hexane, Rf = 0.50 (30% EtOAc–hexane)] to give 9
(53 mg, 61%) as a yellow oil.
A solution of 3a (50 mg, 0.17 mmol), BnNH2 (40 mg, 0.36 mmol),
and MgSO4 (100 mg) in benzene (5 mL) was heated to reflux for 4
h until the completion of the reaction (1H NMR). The mixture was
filtered, and concentrated in vacuo to give a residue. To a solution
of the crude imine product in MeOH was added NaBH4 (13 mg,
0.36 mmol). The solution was stirred at r.t. for 2 h, followed by
heating to 50 °C for an additional 1 h. After cooling to r.t., the reac-
tion was quenched by the addition of H2O (1 mL), followed by the
extraction with EtOAc (30 mL). The organic layer was washed with
brine (10 mL), dried (MgSO4), and concentrated in vacuo to give
the crude product. The residue was purified by flash column chro-
matography [Rf = 0.47 (10% MeOH–EtOAc)] to afford lactam 7
(60 mg, 83%) as a yellow oil.
[a]D26 +3.2 (c 3.2 CHCl3).
IR (neat): 2930, 2722, 1694, 1652, 1547, 1492, 1267, 1037, 758,
700, 507 cm–1.
[a]D26 +7.1 (c 2.8, CHCl3).
1H NMR (500 MHz, CDCl3): d = 9.59 (s, 1 H), 7.39–7.34 (m, 2 H),
7.28–7.25 (m, 2 H), 7.28–7.25 (m, 3 H), 7.17 (d, J = 7.2 Hz, 2 H),
6.96 (dd, J = 6.7, 2.8 Hz, 1 H), 6.87–6.82 (m, 1 H), 5.80 (d, J = 15.7
Hz, 1 H), 4.85 (br s, 1 H), 4.45 (br s, 1 H), 4.16 (q, J = 7.1 Hz, 2 H),
3.42–3.35 (m, 1 H), 2.99 (dd, J = 10.5, 3.4 Hz, 1 H), 2.44–2.35 (m,
1 H), 2.33–2.27 (m, 1 H), 1.83–1.76 (m, 1 H), 1.64–1.55 (m, 2 H),
1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 191.7 (CH), 166.2 (C), 153.0
(CH), 146.9 (CH), 138.5 (C), 137.8 (C), 136.8 (C), 129.3 (4 CH),
128.3 (CH), 128.1 (CH), 127.9 (2 CH), 127.7 (2 CH), 122.5 (CH),
92.3 (CH), 60.3 (CH2), 43.3 (CH), 43.0 (CH), 36.5 (CH), 30.8
(CH2), 28.9 (CH2), 14.2 (CH3).
IR (neat): 2919, 2856, 1642, 1492, 1449, 1264, 1126, 746, 701, 485
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.35–7.28 (m, 2 H), 7.24–7.15 (m,
9 H), 7.11–7.08 (m, 2 H), 7.07–7.03 (m, 2 H), 4.68 (d, J = 14.7 Hz,
1 H), 4.09 (d, J = 14.7 Hz, 1 H), 3.52 (d, J = 13.2 Hz, 1 H), 3.44 (d,
J = 13.2 Hz, 1 H), 2.73 (dd, J = 10, 10 Hz, 1 H), 2.60 (dd, J = 5.0,
1.6 Hz, 1 H), 2.59–2.56 (m, 1 H), 2.30 (dd, J = 12.0, 3.8 Hz, 1 H),
2.18–2.08 (m, 2 H), 2.02 (dd, J = 13.1, 8.4 Hz, 2 H), 1.90–1.88 (m,
1 H), 1.81–1.54 (m, 4 H), 1.23–1.13 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 169.3 (C), 141.8 (C), 140.1 (C),
136.9 (C), 128.5 (2 CH), 128.4 (2 CH), 128.2 (2 CH), 127.9 (3 CH),
127.7 (2 CH), 127.1 (2 CH), 126.7 (2 CH), 54.0 (CH2), 53.1 (CH2),
52.3 (CH2), 51.7 (CH), 50.0 (CH2), 43.5 (CH), 42.8 (CH), 39.2
(CH2), 37.0 (CH), 32.1 (CH2), 30.0 (CH2).
MS: m/z (%) = 433 (M+, 1), 386 (27), 313 (18), 295 (18), 273 (30),
243 (35), 193 (13), 167 (42), 115 (35), 91 (100), 81 (17), 77 (15), 57
(3).
Synthesis 2011, No. 12, 1887–1895 © Thieme Stuttgart · New York

1894
B.-C. Hong et al.
PAPER
Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12, 4588.
HRMS: m/z [M]+ calcd for C26H27NO5: 433.1889; found: 433.1886.
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Zhong, G. Angew. Chem. Int. Ed. 2009, 48, 6089.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We acknowledge the financial support for this study from the Na-
tional Science Council, Taiwan, ROC. Thanks to the National Cen-
ter for High-Performance Computing (NCHC) for their assistance
in literature searching, and the instrument center of National Cheng
Kung University for HRMS analysis.
(k) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem. Int.
Ed. 2009, 48, 1304. (l) Simmons, B.; Walji, A. M.;
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Synthesis 2011, No. 12, 1887–1895 © Thieme Stuttgart · New York

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(17) CCDC-815738 contains the supplementary crystallographic
data for (–)-3e, radiation type: CuKa. CCDC-815739
contains the supplementary crystallographic data for (–)-3e,
radiation type: MoKa. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Synthesis 2011, No. 12, 1887–1895 © Thieme Stuttgart · New York