Organocatalytic double Michael reaction of 7-oxohept-2-enoates and nitrostyrene - Formal synthesis of (-)-α- and (-)-β-lycorane

Article abstract of DOI:10.1002/ejoc.200701122

Organocatalytic conjugate addition of 7-oxohept-2-enoate to nitrostyrene provided an ω-nitro-α,β-unsaturated ester. Subsequent intramolecular cyclization afforded the highly functionalized cyclohexane carboester with four stereogenic centers with high dia

Full text of DOI:10.1002/ejoc.200701122

FULL PAPER
DOI: 10.1002/ejoc.200701122
Organocatalytic Double Michael Reaction of 7-Oxohept-2-enoates and
Nitrostyrene – Formal Synthesis of (–)-α- and (–)-β-Lycorane
Bor-Cherng Hong,*[a] Roshan Y. Nimje,[a] Ming-Fun Wu,[a] and Amit A. Sadani[a]
Dedicated to Professor Elias J. Corey on the occasion of his 80th birthday
Keywords: Asymmetric synthesis / Organocatalysis / Michael additions / Domino reactions / Tandem reactions
Organocatalytic conjugate addition of 7-oxohept-2-enoate to
nitrostyrene provided an ω-nitro-α,β-unsaturated ester. Sub-
sequent intramolecular cyclization afforded the highly func-
tionalized cyclohexane carboester with four stereogenic cen-
ters with high diastereoselectivity and high enantio-
selectivity (Ͼ99% ee). Some adducts were transformed into
the intermediates of the synthesis of (–)-α- and (–)-β-lycorane.
Application of the reactions to the corresponding dialdehyde
provided bicyclo[2.2.2]octanes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Results and Discussion
The asymmetric organocatalytic domino reaction[1] has
emerged as a powerful paradigm in accelerating the devel-
opment of new methods for the synthesis of diverse chiral
molecules.[2] With the benefits of ease of operation, ready
availability, and low toxicity, these organocatalytic reactions
are attractive methods in modern synthetic chemistry and
have received remarkable attention during the past dec-
ade.[3] Among the organocatalytic reactions explored, ex-
tensive effort has been devoted to the Michael addition[4]
of aldehydes to nitrostyrene.[5,6] Despite a large number of
publications dealing with organocatalytic Michael reac-
tions, however, only a few examples have focused on the
domino (or tandem) reaction as a stratagem. A tour de
force was demonstrated by Enders et al.: a triple cascade
organocatalytic reaction for the synthesis of tetrasubsti-
tuted cyclohexenecarbaldehydes. In a Michael–Michael–
aldol sequence they generated four stereogenic centers with
high diastereo- and enantioselectivity (Ͼ99% ee).[7] In con-
junction with our continuing efforts in exploring new or-
ganocatalytic annulations,[8] we investigated the domino
double Michael reaction. Herein we report the development
of a new domino organocatalytic nitro-Michael and conju-
gate addition for the diastereo- and enantioselective synthe-
sis of highly functionalized cyclohexane derivatives with
four stereocenters in a one-pot procedure.
Initially, -proline (0.2 equiv.) was added to a solution of
ethyl (E)-7-oxohept-2-enoate (1) and nitrostyrene in
CH3CN (3 mL, 0.25 ) and the solution was stirred at
25 °C for 24 h until completion of reaction. The nitro-
Michael product 2 was obtained in 53% yield with a dia-
stereomeric ratio of 13:1. In a separate reaction, addition
of Et3N to the reaction mixture not only facilitated the re-
action (completed in 0.5 h), but also improved the yield
(75%). Recently, pyrrolidine derivatives, for example, di-
arylprolinol TMS ether, have emerged as promising general
enamine organocatalysts.[9,10] A series of organocatalysts,
additives, and various conditions were screened, and se-
lected results are summarized in Table 1. The enantio-
selectivity of 2 was determined from the corresponding
alcohol 3, prepared in situ from 2 by reduction with
NaBH4.[11] The reduction of 2 in CH2Cl2 at –20 °C pro-
vided 3 in 25% ee and 71% yield after the two-step reaction
(Table 1, entry 1). Nitro-Michael reaction of 1 and nitrosty-
rene catalyzed by II/HOAc or II/C6H5CO2H with either
CH2Cl2 or toluene as solvent, followed by reduction at
–20 °C afforded 3 in Ͼ99% ee (Table 1, entries 2–4). The
reaction in toluene was somewhat slower and gave a lower
yield than in CH2Cl2. On the other hand, the reaction with
catalyst III in iPrOH gave only moderate enantioselectivity
(41% ee, Table 1, entry 5). Interestingly, the products from
the reduction of 2 with NaBH4 were solvent- and tempera-
ture-dependent. The reaction of 2 with NaBH4 in EtOH at
a low temperature (–20 °C) led to the reduction of not only
the aldehyde group, but also afforded the Michael cycliza-
tion adducts 4 and 5 in a ratio of 2:3 with 23 and 24% ee,
respectively (Table 1, entry 6).[12] Apparently, the alkalinity
[a] Department of Chemistry, National Chung Cheng University,
Chia-Yi 621, Taiwan, R.O.C
Fax: +886-5-2721040
E-mail: chebch@ccu.edu.tw
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 1449–1457
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B.-C. Hong, R. Y. Nimje, M.-F. Wu, A. A. Sadani
FULL PAPER
Table 1. Screening of the catalyst, solvent, and reaction conditions for the catalytic nitro-Michael addition reaction of 7-oxohept-2-enoate
and nitrostyrene.
[e]
Entry Cat.[a] Additive[b]
Solvent
T [°C], t [h]
dr[c] (syn/anti) Solvent[d] T [°C], t [h][d] Yield [%]
Product(s) [ratio][c] ee [%][f]
1
2
3
4
5
6
7
8
9
10
I
II
II
II
III
I
I
II
I
Et3N
CH3CN
CH2Cl2
toluene
CH2Cl2
iPrOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
28, 0.5
0, 18
0, 30
0, 18
0, 36
28, 0.5
0, 1.5
0, 8
13:1
21:1
11:1
12:1
8:1
13:1
13:1
9:1
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
EtOH
EtOH
CH3CN
EtOH
–20, 18
–20, 24
–20, 24
–20, 24
–20, 24
–20, 12
–20, 12
–20, 12
28, 0.5
28, 0.5
71
82
75
80
72
71
78
75
68
65
3
3
3
3
3
25
Ͼ99
Ͼ99
Ͼ99
41
23/24
31/31
Ͼ99/Ͼ99
24/22
Ͼ99/Ͼ99
HOAc
HOAc
C6H5CO2H
–
Et3N
Et3N
HOAc
Et3N
HOAc
4, 5 [2:3]
4, 5 [2:3]
4, 5 [1:1]
4, 6 [1:1][g]
4, 6 [1:1][g]
28, 0.5
0, 8
13:1
10:1
II
EtOH
1
[a] 0.2 equivalents of catalysts were used. [b] 0.2 equivalents of additives were used. [c] Determined by H NMR prior to work up. [d]
Conditions for the reaction with NaBH4. [e] Isolated yields. [f] Enantiomeric excesses (ee values) were determined by HPLC with a chiral
column (Chiracel OD). [g] Compound 5 was obtained in less than 5% yield.
of NaBH4 caused the deprotonation of the methylene pro- more stable C3–C4 anti product.[16,17] More interestingly,
ton adjacent to the nitro group of 2 and triggered the under the same reaction conditions, reaction of the anti and
Michael reaction. The enantioselectivity was increased syn mixture of 10, prepared from (Z)-1 and nitrostyrene,
slightly to 31% ee when the first-step nitro-Michael reac- gave 8 as the only observed product in 92% yield. The dif-
tion proceeded at 0 °C, and attained a maximum (Ͼ99% ferent stereoselectivities observed in the cyclization of the
ee) in the 1st-step reaction with II/HOAc (Table 1, entries 7 E/Z isomers 2 and 10 can be rationalized through the
and 8). On the other hand, performing the 2nd-step re- mechanism shown in Scheme 2.[18] A 6-exo cyclization of 2
duction process at 28 °C afforded a 1:1 ratio of 4 and 6 (not (or 10) proceeds through the chair transition state E-eq with
5) in 24 and 22% ee, respectively (Table 1, entry 9). The an equatorial side-chain (alkene) to give 8, or through the
enantioselectivity was improved and reached Ͼ99% ee by chair transition state E-ax with an axial side-chain (alkene)
replacing -Pro with II/HOAc (Table 1, entry 10).[13]
to give 9. Such transition states have been shown to be close
For decades, the Michael reaction has been one of the in energy, and similar effects of alkene geometry (E and Z)
most important methodologies for ring construction.[14,15] on the formation of ring stereochemistry have been ob-
Many fascinating examples of tandem Michael reactions served in 6-exo radical cyclization reactions.[19]
have been achieved in which the first intermolecular
Alternatively, the (Z)-alkene ester substituent on 10 raises
Michael reaction was followed by an intramolecular variant the transition state of Z-ax as a result of A strain leading to
leading to ring-formation. Accordingly, we attempted the the predominant formation of 8 via the Z-eq transition state.
intramolecular Michael cyclization of 2. Reaction of a syn Based on these results, a series of nitrostyrene derivatives were
and anti mixture of 2 (3:1) with CsF and nBu4NBr in THF treated with the (Z)-7-oxohept-2-enoate. The two-step reac-
gave a 90% yield of 8 and 9 in a ratio of 1:2 (Scheme 1). tions were carried out in one pot by reaction with catalyst II
Unexpectedly, the formyl and phenyl groups at C-3 and C- (0.25 equiv.) and HOAc in CH2Cl2 at 0 °C for 1–4 h followed
4 are orientated anti in both 8 and 9. As there are eight by the addition of a THF solution of CsF and TBAF at 0 °C
possible diastereomeric isomers, and twice as many if both and stirring for 1–2 h (Table 2).
enantiomers are considered, it is interesting that even mod-
Significantly, all of the examples gave excellent enantio-
est enantioselectivity was observed. Subjecting pure syn-2 selectivity, diastereoselectivity (Ͼ30:1), and high yields (75–
to the same reaction conditions gave similar selectivity. Ap- 92%, Table 2, entries 1–7). Noteworthy, for the reaction
parently, under basic conditions, isomerization of the for- with ortho-substituted nitrostyrene, for example, 1-chloro-
myl group occurred in the original 2 (syn/anti) and/or the 2-(2-nitrovinyl)benzene, the C3–C4 cis isomer 17 was ob-
formed C3–C4 syn adduct leading to the formation of the tained when the second step of the reaction was maintained
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Organocatalytic Double Michael Reaction
Scheme 1. Intramolecular Michael cyclization of 2 and 10.
Scheme 2. Proposed mechanism for the cyclization reaction of 2 and 10.
Table 2. One-pot reactions of the domino Michael reactions.
Entry
Product
t [h] (step 1, step 2)
Yield [%][a]
ee [%][b]
1
2
3
8: R = Et, R1 = Ph
1, 1
1, 1
2, 1
92
80
75
Ͼ99[c]
87 (97)[d]
Ͼ99
11: R = Et, R1 = p-OMe-C6H4
12: R = Et, R1 = p-Br-C6H4
4
13: R = tBu, R1 =
3, 1
79
98
5
6
7
14: R = Et, R1 = p-Me-C6H4
15: R = Et, R1 = p-F-C6H4
16: R = Et, R1 = o-Cl-C6H4
2, 2
2, 1
2, 3
81
78
76
94
Ͼ99[e]
99[e,f]
[a] Isolated yield. [b] Unless otherwise noted, the enantiomeric excesses (ee values) were determined from the corresponding alcohol
(prepared in situ with NaBH4) by HPLC with a chiral column (Chiracel OD). [c] Also confirmed from the Mosher derivatives by 1H
NMR analysis. [d] The first-step reaction proceeded at –20 °C for 6 h. [e] The enantiomeric excesses (ee values) were determined from
the aldehyde by using a Chiralpak-IA column. [f] Compound 17 was obtained exclusively in 85% yield and Ͼ99% ee when the second-
step reaction was maintained at 0 °C for 3 h. Compound 16 was obtained exclusively in 76% yield and 99% ee when the second-step
reaction was maintained at 28 °C for 3 h.
at 0 °C. In contrast, the C3–C4 trans isomer 16 was isolated to the congestion at C-4 around the aldehyde group, caused
when the second step of the reaction was carried out at by the ortho effect of the aromatic ring.
28 °C for 3 h. The slow isomerization of the cis product
Amaryllidaceae alkaloids, for example, α-, β-, and γ-lyco-
towards the trans product in this system was probably due ranes, have attracted considerable synthetic efforts[20] due to
Eur. J. Org. Chem. 2008, 1449–1457
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B.-C. Hong, R. Y. Nimje, M.-F. Wu, A. A. Sadani
FULL PAPER
Scheme 3. Application of double Michael adducts in the synthesis of (–)-α- and (–)-β-lycorane.
the unique structural features of the tetracyclic galanthan two bicyclic compounds may be the result of a subsequent
skeleton and its biological activities.[21] We envisioned that intramolecular aldol reaction of the formylcyclohexanecar-
the double Michael adducts would be versatile intermedi- baldehyde (Scheme 4).
ates in the synthesis of amaryllidaceae alkaloids. The tert-
butyl ester 13 was therefore transformed into 19,[22] an in-
termediate used in the synthesis of (Ϯ)-β-lycorane,
(Scheme 3). Chlorite oxidation of aldehyde 13 to acid 18
Conclusions
We have developed a highly diastereoselective and enan-
tioselective domino organocatalytic Michael addition reac-
tion which provides expedited access to highly function-
alized and enatiomerically enriched cyclohexane derivatives
(Ͼ99% ee). Adducts 13, 20, and 23 were used in the formal
synthesis of (–)-β- and (–)-α-lycorane, and the generality of
this methodology was further demonstrated by the domino
reaction of the dialdehyde 26 providing bicyclo[2.2.2]oc-
tanes. The simple experimental procedures, high enantio-
selectivity, and great synthetic versatility of the products
render this new methodology highly appealing for asym-
metric synthesis. The full scope of this methodology is cur-
rently under investigation.
(NaClO2, tBuOH, 2-methyl-2-butene, NaH2PO4, 25 °C;
82%) followed by transformation into the acyl chloride and
esterification with 2-mercaptopyridine N-oxide afforded the
corresponding Barton ester, which was decarboxylated
(nBu3SnH, toluene, reflux) without purification to provide
19 in 70% yield. Similarly, 22[23] and 25,[22] intermediates in
the synthesis of β- and α-lycorane, respectively, were pre-
pared from 20 and 23 by the same reaction sequence. Com-
parison of the optical rotation data obtained from (–)-22
with literature values revealed the absolute stereochemistry
of 20 as that depicted in Scheme 3.
Encouraged by the success of these results, the reaction
of α,β-unsaturated dialdehyde 26 was examined. Interest-
ingly, the reaction of 26 with -proline and Et3N in CH3CN
at ambient temperature for 3 h afforded two bicyclo[2.2.2]-
octanes 27 and 28 in a 3.7:1 ratio in 41% yield.[24] These
Experimental Section
General Methods: All solvents were reagent grade. -Proline (99+%)
was purchased from Bachem. Other chemicals were purchased
from Aldrich or Acros Chemical Co. Reactions were normally car-
ried out under argon in flame-dried glassware. Merck silica gel 60
(particle size 0.04–0.063 mm) was employed for flash chromatog-
1
raphy. Melting points are uncorrected. H NMR and COSY spec-
tra were obtained in CDCl3 at 400 (Bruker DPX-400) or 500 MHz
(Varian-Unity INOVA-500) unless otherwise noted. 13C NMR
spectra and HMBC, HMQC, and DEPT experiments were per-
formed at 100 or 125 MHz. The ee values were measured by GC–
MS (Shimadzu QP 5000, chiral capillary column, γ-cyclodextrin
trifluoroacetyl, Astec Type G-TA, size 30 mϫ0.25 mm, flow rate
24 mL/min, temperature range: 60–120 °C, gradient 3 °C/min) or
by HPLC on a chiral column. The HPLC apparatus was equipped
with ultraviolet and refractive index detectors. Samples were ana-
lyzed on a chiral column (Chiracel OD-H or Chiralpak-IA, 0.46 cm
(i.d.)ϫ25 cm, particle size 5 µ) by elution with EtOAc/hexane or
Scheme 4. Domino Michael reaction of dialdehyde 26.
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Organocatalytic Double Michael Reaction
iPrOH/hexane. The flow rate of the indicated eluent was main-
tained at 1 mL/min and the retention times were recorded accord-
ingly.
tion of reaction (monitored by TLC). The solution was then diluted
with EtOAc (25ϫ2 mL), washed with brine (10 mL), dried with
Na2SO4, and concentrated in vacuo to give the crude product. The
residue was purified by flash column chromatography with 20%
EtOAc/hexane (4: Rf = 0.35; 5: Rf = 0.35; 40% EtOAc/hexane) to
give a mixture of 4 and 5 which was separated by HPLC (4: Rt =
21.1 min; 5: Rt = 19.0 min; 10% iPrOH/hexane, flow rate 1 mL/
min, 210 nm) to give 4 (16 mg, 28% yield) and 5 (25 mg, 43% yield)
as colorless oils. Spectroscopic data for 4: [α]2D5 = –19.2 (c = 2.5,
General Procedure for the Preparation of 2: A solution of catalyst
II (41 mg, 0.13 mmol) and acetic acid (8 mg, 0.13 mmol) in CH2Cl2
(1 mL) was added dropwise to a solution of (E)-1 (102 mg,
0.6 mmol)[25] and trans-nitrostyrene (75 mg, 0.5 mmol) in CH2Cl2
(2 mL). The solution was stirred for 1 h, diluted with EtOAc
(10 mL), washed with brine (2 mL), dried with Na2SO4, and con-
centrated in vacuo to give the crude product. The residue was puri-
fied by flash column chromatography with 10% EtOAc/hexane (Rf
= 0.28 in 20% EtOAc/hexane) to give a 3:1 diastereomeric mixture
of 2 as a colorless oil (149 mg, 93%). Selected spectroscopic data
CHCl ). IR (neat): ν = 3442, 2920, 1728, 1549, 1371, 1176, 1032,
˜
3
702 cm–1. 1H NMR (C6D6, 500 MHz): δ = 7.08–6.97 (5 H), 5.26
(dd, J = 12.0, 11.0 Hz, 1 H), 3.94–3.86 (m, 2 H), 3.40 (dd, J = 12.0,
4.5 Hz, 1 H), 3.12–3.05 (m, 1 H), 2.94 (d, J = 10.5 Hz, 1 H), 2.42–
2.38 (m, 2 H), 2.29 (dd, J = 16.5, 8.0 Hz, 1 H), 1.77 (d, J = 13.5 Hz,
1 H), 1.70–1.50 (m, 3 H), 1.40–1.25 (m, 1 H), 0.93 (t, J = 7.0 Hz,
3 H) ppm. 13C NMR (C6D6, 125 MHz): δ = 170.8 (C), 138.9 (C),
128.7 (CH), 128.3 (CH), 128.1 (CH), 127.9 (CH), 127.4 (CH), 89.3
(CH), 61.0 (CH2), 60.4 (CH2), 50.1 (CH), 42.1 (CH), 39.6 (CH),
37.1 (CH2), 27.6 (CH2), 25.9 (CH2), 14.1 (CH3) ppm. MS: m/z (%)
= 321 (1) [M]+, 274 (4), 256 (27), 244 (32), 169 (92), 91 (100).
HRMS: calcd. for C17H23NO5 [M]+ 321.1576; found 321.1582.
for 2: [α]2D5 = +23.2 (c = 0.6, CHCl ). IR (neat): ν = 2825, 1739,
˜
3
1678, 1577, 1372, 1233, 1178, 1038, 790, 755 cm–1. 1H NMR
(CDCl3, 500 MHz): δ = 9.71 (s, 1 H), 7.38–7.05 (m, 5 H), 6.75–
6.62 (m, 1 H), 5.68 (d, J = 15.5 Hz, 1 H), 4.70–4.58 (m, 2 H), 4.14
(q, J = 7.0 Hz, 2 H), 3.80–3.72 (m, 1 H), 2.18–2.08 (m, 1 H), 2.04–
1.95 (m, 1 H), 1.65–1.45 (m, 3 H), 1.25 (t, J = 7.0 Hz, 3 H) ppm.
13C NMR (CDCl3, 125 MHz): δ = 202.2 (CH), 166.1 (C), 146.3
(CH), 136.2 (C), 129.3 (2 CH), 128.4 (CH), 127.9 (2 CH), 122.5
(CH), 78.1 (CH2), 60.3 (CH2), 53.1 (CH), 43.0 (CH), 28.8 (CH2),
25.6 (CH2), 14.1 (CH3) ppm. MS: m/z (%) = 319 (0.2) [M]+, 272
(6), 225 (10), 117 (40), 104 (84), 91 (100). HRMS: calcd. for
C17H21NO5 [M]+ 319.1420; found 319.1411.
Spectroscopic Data for 5: [α]2D5 = –37.2 (c = 1.5, CHCl3). IR (neat):
1
ν = 3445, 2923, 2853, 1730, 1550, 1033, 757, 702 cm–1. H NMR
˜
(CDCl3, 500 MHz): δ = 7.35–7.20 (m, 5 H), 5.23 (dd, J = 6.5,
5.0 Hz, 1 H), 4.11 (q, J = 7.0 Hz, 2 H), 3.65 (dd, J = 7.5, 6.5 Hz,
1 H), 3.45–3.32 (m, 2 H), 3.02–2.96 (m, 1 H), 2.55–2.40 (m, 2 H),
2.39–2.32 (m, 1 H), 2.00–1.90 (m, 1 H), 1.88–1.72 (m, 3 H), 1.75
(s, 1 H), 1.22 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 171.5 (C), 138.8 (C), 128.9 (2 CH), 128.1 (CH),
127.4 (2 CH), 88.0 (CH), 63.2 (CH2), 60.8 (CH2), 44.3 (CH), 40.0
(CH), 34.4 (CH2), 33.7 (CH), 25.2 (CH2), 23.0 (CH2), 14.1
(CH3) ppm. MS: m/z (%) = 321 (1) [M]+, 256 (26), 244 (32), 169
(80), 91 (100). HRMS: calcd. for C17H23NO5 [M]+ 321.1576;
321.1577.
General Procedure for the Preparation of 3 (Table 1, Entry 1): -
Proline (4 mg, 0.036 mmol) and Et3N (3.6 mg, 0.036 mmol) were
added to a solution of (E)-1 (30 mg, 0.18 mmol) and trans-nitrosty-
rene (29 mg, 0.2 mmol) in CH3CN (2 mL). The solution was stirred
for 0.5 h, diluted with EtOAc (25ϫ2 mL), washed with brine
(10 mL), dried with Na2SO4, and concentrated in vacuo to give the
crude product. NaBH4 (20 mg, 0.52 mmol) was added to a solution
of the residue in CH2Cl2 (2 mL) at –20 °C. The solution was stirred
at the same temperature for 18 h, diluted with EtOAc (25ϫ2 mL),
washed with brine (10 mL), dried with Na2SO4, and concentrated
in vacuo to give the crude product. The residue was purified by
flash column chromatography with 20% EtOAc/hexane (Rf = 0.35
in 40% EtOAc/hexane) to give 3 as a colorless oil (41 mg, 71%
yield). Spectroscopic data for 3: [α]2D5 = –20.1 (c = 7.8, CHCl3). IR
General Procedure for the Preparation of 4 and 6 (Table 1, Entry 9):
-Proline (4 mg, 0.036 mmol) and Et3N (3.6 mg, 0.036 mmol) were
added to a solution of (E)-1 (30 mg, 0.18 mmol) and trans-nitrosty-
rene (29 mg, 0.2 mmol) in CH3CN (2 mL). The solution was stirred
for 0.5 h, diluted with EtOAc (25ϫ2 mL), washed with brine
(10 mL), dried with Na2SO4, and concentrated in vacuo to give the
crude product. NaBH4 (20 mg, 0.52 mmol) was added to a solution
of the residue in EtOH (2 mL) at 30 °C. The solution was stirred
at the same temperature for 0.5 h until completion of reaction
(monitored by TLC). The solution was diluted with EtOAc
(25ϫ2 mL), washed with brine (10 mL), dried with Na2SO4, and
concentrated in vacuo to give the crude product. The residue was
purified by flash column chromatography with 20% EtOAc/hexane
(4: Rf = 0.35; 6: Rf = 0.28; 40% EtOAc/hexane) to give 4 (21 mg,
36% yield) and 6 (18 mg, 32% yield) as colorless oils. Selected spec-
(neat): ν = 3460, 2927, 1712, 1551, 1378, 1278, 1200, 1041,
˜
703 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.36–7.30 (m, 2 H),
7.28–7.22 (m, 1 H), 7.20–7.16 (m, 2 H), 6.82–6.74 (m, 1 H), 5.72
(d, J = 15.5 Hz, 1 H), 4.86 (dd, J = 13.0, 5.5 Hz, 1 H), 4.77 (dd, J
= 12.5, 10.0 Hz, 1 H), 4.15 (q, J = 7.0 Hz, 2 H), 3.78–3.72 (m, 1
H), 3.70–3.62 (m, 1 H), 3.60–3.52 (m, 1 H), 2.30–2.18 (m, 1 H),
2.12–2.02 (m, 1 H), 1.84–1.82 (m, 1 H), 1.50–1.34 (m, 2 H), 1.26
(t, J = 7.0 Hz, 3 H), 1.25–1.20 (m, 1 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 166.4 (C), 147.8 (CH), 138.2 (C), 128.9 (2 CH),
128.1 (2 CH), 127.7 (CH), 122.0 (CH), 78.5 (CH2), 62.0 (CH2),
60.3 (CH2), 45.9 (CH), 43.0 (CH), 29.7 (CH2), 27.1 (CH2), 14.2
(CH3) ppm. MS: m/z (%) = 321 (1) [M]+, 275 (4), 256 (12), 169
(40), 129 (44), 104 (64), 91 (100). HRMS: calcd. for C17H23NO5
[M]+ 321.1577; found 321.1572.
troscopic data for 6: [α]2D5 = –25.5 (c = 2.1, CHCl ). IR (neat): ν =
˜
3
3442, 2925, 1728, 1547, 1371, 1178, 1032, 704 cm–1. 1H NMR
(CDCl3, 500 MHz): δ = 7.28 (br. s, 5 H), 4.70 (dd, J = 12.0, 6.0 Hz,
1 H), 4.13 (q, J = 7.0 Hz, 2 H), 3.90 (dd, J = 6.0, 6.0 Hz, 1 H),
3.30 (dd, J = 10.5, 6.0 Hz, 1 H), 3.20 (dd, J = 10.5, 8.5 Hz, 1 H),
3.05–2.95 (m, 1 H), 2.45 (d, J = 15.5 Hz, 1 H), 2.30–2.10 (m, 3 H),
1.70–1.60 (m, 2 H), 1.50–1.30 (m, 2 H), 1.24 (t, J = 7.0 Hz, 3
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 171.3 (C), 135.2 (C),
130.4 (2 CH), 128.6 (2 CH), 128.1 (CH), 91.7 (CH), 64.8 (CH2),
60.7 (CH2), 47.4 (CH), 43.1 (CH), 37.9 (CH2), 31.8 (CH), 29.3
(CH2), 22.8 (CH2), 14.2 (CH3) ppm. MS: m/z (%) = 321 (1) [M]+,
274 (4), 256 (24), 244 (33), 169 (93). HRMS: calcd. for C17H23NO5
[M]+ 321.1576; found 321.1582.
Representative Procedure for the Preparation of 4 and 5 (Table 1,
Entry 6): -Proline (4 mg, 0.036 mmol) and Et3N (3.6 mg,
0.036 mmol) were added to a solution of (E)-1 (30 mg, 0.18 mmol)
and trans-nitrostyrene (29 mg, 0.2 mmol) in CH3CN (2 mL). The
solution was stirred for 0.5 h, diluted with EtOAc (25ϫ2 mL),
washed with brine (10 mL), dried with Na2SO4, and concentrated
in vacuo to give the crude product. NaBH4 (20 mg, 0.52 mmol) was
added to a solution of the residue in EtOH (2 mL) at –20 °C. The
solution was stirred at the same temperature for 12 h until comple-
Eur. J. Org. Chem. 2008, 1449–1457
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1453

B.-C. Hong, R. Y. Nimje, M.-F. Wu, A. A. Sadani
FULL PAPER
Typical Procedure for the Preparation of 8 from 10: Tetrabutylam-
monium bromide (52.5 mg, 0.16 mmol) and cesium fluoride
(12.4 mg, 0.08 mmol) were added to a solution of 10 (26 mg,
0.08 mmol) in THF (2 mL). The resulting mixture was stirred for
1 h. The solution was diluted with EtOAc (25 mL), washed with
brine, dried with Na2SO4, and concentrated in vacuo to give the
crude product. The residue was purified by flash column
chromatography with 10% EtOAc/hexane to give 8 as a colorless
oil (24 mg, 92%). Selected spectroscopic data for 8: [α]2D5 = –35.4
40 mg, 0.125 mmol) and acetic acid (7.5 mg, 0.125 mmol) in
CH2Cl2 (1 mL). The resulting mixture was stirred for 1 h. The solu-
tion was diluted with EtOAc (25 mL), washed with brine, dried
with Na2SO4, concentrate in vacuo to give the crude product. The
residue was purified by flash column chromatography with 10%
EtOAc/hexane (Rf = 0.38 for 10 in 20% EtOAc/hexane) to give 10
as a colorless oil (153 mg, 95% yield). Selected spectroscopic data
for 10: [α]2D5 = +20.4 (c = 3, CHCl3). 1H NMR (CDCl3, 500 MHz):
δ = 9.75 (s, 1 H), 7.38–7.22 (m, 3 H), 7.18–7.10 (m, 2 H), 6.00–5.90
(m, 1 H), 5.73 (d, J = 11.5 Hz, 1 H), 4.78–4.60 (m, 2 H), 4.12 (q,
(c = 2.3, CHCl ). IR (neat): ν = 2925, 2856, 1726, 1550, 1371, 1176,
˜
3
700 cm–1. H NMR (CDCl3, 500 MHz): δ = 9.36 (d, J = 2.5 Hz, 1 J = 7.0 Hz, 2 H), 3.82–3.76 (m, 1 H), 2.78–2.70 (m, 1 H), 2.68–
1
H), 7.32–7.22 (m, 3 H), 7.20–7.16 (m, 2 H), 4.68 (dd, J = 11.0, 2.50 (m, 2 H), 1.70–1.60 (m, 1 H), 1.55–1.45 (m, 1 H), 1.23 (t, J =
11.0 Hz, 1 H), 4.13 (q, J = 7.0 Hz, 2 H), 3.41 (dd, J = 11.5, 12.0 Hz,
7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 202.9 (CH),
1 H), 2.80–2.72 (m, 1 H), 2.60–2.50 (m, 1 H), 2.39 (dd, J = 16.0, 165.9 (C), 147.2 (CH), 136.5 (C), 129.1 (2 CH), 128.2 (CH), 128.0
3.0 Hz, 1 H), 2.30–2.22 (m, 1 H), 2.20–2.16 (m, 1 H), 2.06–2.02 (m, (2 CH), 121.3 (CH), 78.1 (CH2), 60.0 (CH2), 53.2 (CH), 43.1 (CH),
1 H), 1.70–1.40 (m, 2 H), 1.24 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR 26.6 (CH2), 25.8 (CH2), 14.2 (CH3) ppm. MS: m/z (%) = 319 (4)
(CDCl3, 125 MHz): δ = 200.9 (CH), 170.7 (C), 136.4 (C), 129.2 (2
CH), 128.4 (CH), 127.9 (2 CH), 94.6 (CH), 60.9 (CH2), 53.5 (CH),
48.4 (CH), 38.2 (CH), 36.7 (CH2), 28.7 (CH2), 25.4 (CH2), 14.1
(CH3) ppm. MS: m/z (%) = 320 (10) [M + 1]+, 272 (42), 242 (26),
198 (100), 167 (78), 155 (77). HRMS: calcd. for C17H21NO5 [M]+
319.1420; found 319.1417.
[M]+, 272 (8), 225 (16), 199 (20), 169 (30), 129 (36), 104 (96), 91
(100), 55 (16). HRMS: calcd. for C17H21NO5 [M]+: 319.1420; found
319.1412.
Ester 11: 163 mg, 80% yield. Rf = 0.29 for 11 in 30% EtOAc/hex-
ane. Selected spectroscopic data for 11: [α]2D5 = –19.6 (c = 2.5,
CHCl ). IR (neat): ν = 2931, 1728, 1550, 1514, 1252, 1180, 1032,
˜
3
833 cm–1. H NMR (CDCl3, 500 MHz): δ = 9.35 (s, 1 H), 7.10 (d,
1
Typical Procedure for the Preparation of 8 and 9 from 2: Tetrabu-
tylammonium bromide (141 mg, 0.44 mmol) and cesium fluoride
(34 mg, 0.22 mmol) were added to a solution of 2 (70 mg,
0.22 mmol) in THF (4 mL). The resulting mixture was stirred for
1 h. The solution was diluted with EtOAc (25 mL), washed with
brine, dried with Na2SO4, and concentrated in vacuo to give the
crude product. The residue was purified by flash column
chromatography with 10% EtOAc/hexane to give 8 and 9 (8: Rf =
0.50; 9: Rf = 0.48, 30% EtOAc/hexane) in a ratio of 1:2 as colorless
oils in a combined yield of 90% (63 mg). Selected spectroscopic
J = 8.0 Hz, 2 H), 6.81 (d, J = 8.0 Hz, 2 H), 4.61 (dd, J = 11.0,
11.0 Hz, 1 H), 4.12 (q, J = 7.0 Hz, 2 H), 3.74 (s, 3 H), 3.35 (dd, J
= 11.5, 11.5 Hz, 1 H), 2.75–2.68 (m, 1 H), 2.58–2.48 (m, 1 H), 2.37
(d, J = 16.0 Hz, 1 H), 2.30–2.20 (m, 1 H), 2.20–2.12 (m, 1 H), 2.05–
1.95 (m, 1 H), 1.60–1.40 (m, 2 H), 1.24 (t, J = 7.0 Hz, 3 H) ppm.
13C NMR (CDCl3, 125 MHz): δ = 201.1 (CH), 170.7 (C), 159.4
(C), 128.9 (2 CH), 128.2 (C), 114.6 (2 CH), 94.8 (CH), 60.8 (CH2),
55.2 (CH3), 53.6 (CH), 47.6 (CH), 38.2 (CH), 36.7 (CH2), 28.7
(CH2), 25.4 (CH2), 14.1 (CH3) ppm. MS: m/z (%) = 349 (55) [M]+,
302 (71), 274 (40), 228 (70), 121 (100). HRMS: calcd. for
C18H23NO6 [M]+: 349.1525; found 349.1526.
data for 9: [α]2D5 = –12.2 (c = 4, CHCl ). IR (neat): ν = 2925, 2854,
˜
3
1726, 1549, 1456, 1373, 1181, 701 cm–1. 1H NMR (CDCl3,
500 MHz): δ = 9.38 (d, J = 1.5 Hz, 1 H), 7.31–7.20 (m, 5 H), 4.98
(dd, J = 12.0, 5.0 Hz, 1 H), 4.12 (q, J = 7.0 Hz, 2 H), 3.51 (dd, J
= 12.0, 12.0 Hz, 1 H), 3.20–3.10 (m, 1 H), 2.75–2.62 (m, 1 H), 2.57
(d, J = 6.0 Hz, 2 H), 2.10–2.00 (m, 1 H), 1.90–1.80 (m, 2 H), 1.70–
1.55 (m, 1 H), 1.23 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 200.8 (CH), 171.0 (C), 137.0 (C), 129.1 (2 CH),
128.2 (CH), 128.1 (2 CH), 91.6 (CH), 61.0 (CH2), 54.3 (CH), 41.9
(CH), 34.0 (CH), 31.9 (CH2), 27.9 (CH2), 20.2 (CH2), 14.1
(CH3) ppm. MS: m/z (%) = 319 (1) [M]+, 272 (30), 198 (57), 155
(74), 91 (100). HRMS: calcd. for C17H21NO5 [M]+ 319.1420; found
319.1415.
Ester 12: 87 mg, 75% yield. Rf = 0.26 for 12 in 30% EtOAc/hexane.
Selected spectroscopic data for 12: [α]2D5 = –27.4 (c = 2.8, CHCl3).
IR (neat): ν = 2925, 2856, 1728, 1550, 1373, 1011, 818 cm–1. 1H
˜
NMR (CDCl3, 500 MHz): δ = 9.36 (s, 1 H), 7.42 (d, J = 8.0 Hz, 2
H), 7.07 (d, J = 8.0 Hz, 2 H), 4.64 (dd, J = 11.5, 11.5 Hz, 1 H),
4.13 (q, J = 7.0 Hz, 2 H), 3.40 (dd, J = 11.5, 11.5 Hz, 1 H), 2.80–
2.70 (m, 1 H), 2.58–2.44 (m, 1 H), 2.38 (dd, J = 17.0, 2.5 Hz, 1 H),
2.30–2.20 (m, 1 H), 2.19–2.12 (m, 1 H), 2.10–2.02 (m, 1 H), 1.62–
1.42 (m, 2 H), 1.25 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 200.4 (CH), 170.8 (C), 135.8 (C), 132.6 (2 CH),
129.8 (2 CH), 122.7 (C), 94.5 (CH), 61.1 (CH2), 53.7 (CH), 47.8
(CH), 38.4 (CH), 36.8 (CH2), 28.9 (CH2), 25.6 (CH2), 14.4
(CH3) ppm. MS: m/z (%) = 399 (8) [M+ + 2], 397 (8) [M]+, 352
(19), 322 (20), 278 (60), 276 (55), 179 (49), 171 (81), 169 (100).
HRMS: calcd. for C17H20BrNO5 [M]+: 397.0525; found 397.0522.
Typical Procedure for the Preparation of 8 from (Z)-1 (Two Reac-
tions in One Pot): A solution of II (40 mg, 0.125 mmol) and acetic
acid (7.5 mg, 0.125 mmol) in CH2Cl2 (1 mL) was added dropwise
to a solution of (Z)-1 (102.2 mg, 0.6 mmol)[26] and trans-nitrosty-
rene (75 mg, 0.5 mmol) in CH2Cl2 (2 mL). The resulting mixture
was stirred for 2 h at 0 °C. The solution was diluted with THF
(10 mL) and then tetrabutylammonium bromide (141 mg,
0.44 mmol) and cesium fluoride (34 mg, 0.22 mmol) were added.
The resulting mixture was stirred for 1 h at 0–10 °C. The solution
was diluted with EtOAc (30 mL), washed with brine, dried with
Na2SO4, and concentrated in vacuo to give the crude product. The
residue was purified by flash column chromatography with 10%
EtOAc/hexane (Rf = 0.50 for 8 in 30% EtOAc/hexane) to give 8 as
a colorless oil (147 mg, 92% yield).
Ester 13: 160 mg, 79% yield. Rf = 0.40 for 13 in 30% EtOAc/hex-
ane. Selected spectroscopic data for 13: [α]2D5 = –18.4 (c = 4,
CHCl ). IR (neat): ν = 2925, 1724, 1550, 1248, 1155, 1039 cm–1.
˜
3
1H NMR (CDCl3, 500 MHz): δ = 9.38 (s, 1 H), 6.71–6.60 (m, 3
H), 5.91 (d, J = 2.0 Hz, 2 H), 4.58 (dd, J = 13.0, 13.0 Hz, 1 H),
3.32 (dd, J = 13.0, 13.0 Hz, 1 H), 2.70–2.60 (m, 1 H), 2.50–2.40
(m, 1 H), 2.30 (d, J = 13.5 Hz, 1 H), 2.20–2.10 (m, 1 H), 2.00 (d,
J = 10.5 Hz, 1 H), 1.60–1.20 (m, 3 H), 1.42 (s, 9 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 200.9 (CH), 169.9 (C), 148.3 (C), 147.6
(C), 130.0 (C), 121.5 (CH), 108.8 (CH), 107.8 (CH), 101.3 (CH2),
94.8 (CH), 81.4 (C), 53.6 (CH), 48.1 (CH), 38.4 (CH), 37.8 (CH2),
28.6 (CH2), 28.0 (three CH3), 25.4 (CH2) ppm. MS: m/z (%) = 391
(54) [M]+, 318 (16), 288 (100), 199 (43), 135 (75). HRMS: calcd.
for C20H25NO7 [M]+: 391.1631; found 391.1628.
Ester 10: To a solution of (Z)-1 (102.2 mg, 0.6 mmol)[27] and trans-
nitrostyrene (75 mg, 0.5 mmol) in CH2Cl2 (2 mL) was added drop-
wise a solution of (S)-diphenylpyrrolinol trimethylsilyl ether (II,
1454
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1449–1457

Organocatalytic Double Michael Reaction
Ester 14: 83 mg, 81% yield. Rf = 0.38 for 14 in 30% EtOAc/hexane.
Selected spectroscopic data for 14: [α]2D5 = –17.6 (c = 6.5, CHCl3).
NMR ([D6]acetone, 500 MHz): δ = 6.86 (s, 1 H), 6.73 (s, 2 H), 5.96
(s, 2 H), 4.85 (dd, J = 11.5, 11.5 Hz, 1 H), 3.33 (dd, J = 11.5,
11.5 Hz, 1 H), 3.00–2.70 (m, 4 H), 2.58–2.42 (m, 1 H), 2.30–2.10
(m, 2 H), 1.80–1.68 (m, 1 H), 1.62–1.50 (m, 1 H), 1.44 (s, 9 H) ppm.
13C NMR ([D6]acetone, 125 MHz): δ = 173.4 (C), 169.8 (C), 147.7
IR (neat): ν = 2927, 2861, 1728, 1550, 1373, 1176, 1028, 814 cm–1.
˜
1H NMR (CDCl3, 500 MHz): δ = 9.36 (s, 1 H), 7.15–7.05 (m, 4
H), 4.66 (dd, J = 11.5, 11.0 Hz, 1 H), 4.14 (q, J = 7.0 Hz, 2 H),
3.38 (dd, J = 11.5, 11.5 Hz, 1 H), 2.80–2.70 (m, 1 H), 2.60–2.50 (C), 147.2 (C), 132.0 (C), 122.0 (CH), 108.2 (CH), 108.0 (CH),
(m, 1 H), 2.39 (dd, J = 16.5, 3.5 Hz, 1 H), 2.30–2.20 (m, 1 H), 2.30 101.3 (CH2), 94.5 (CH), 80.4 (C), 49.8 (CH), 48.1 (CH), 38.7 (CH),
(s, 3 H), 2.20–2.15 (m, 1 H), 2.05–2.00 (m, 1 H), 1.65–1.40 (m, 2 38.1 (CH2), 29.4 (CH2), 29.3 (CH2), 27.3 (three CH3) ppm. MS:
H), 1.25 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz):
m/z (%) = 407 (11) [M]+, 334 (19), 304 (55), 258 (100), 135 (24).
δ = 201.4 (CH), 170.9 (C), 138.4 (C), 133.5 (C), 130.1 (2 CH), 127.9 HRMS: calcd. for C20H25NO8 [M]+: 407.1580; found 407.1580.
(2 CH), 95.0 (CH), 61.0 (CH2), 53.7 (CH), 48.3 (CH), 38.5 (CH),
Ester 19: 23 mg, 70% yield. Rf = 0.68 for 19 in 30% EtOAc/hexane.
36.9 (CH2), 28.9 (CH2), 25.6 (CH2), 21.3 (CH3), 14.4 (CH3) ppm.
Selected spectroscopic data for 19: [α]2D5 = –47.3 (c = 2, CHCl3). IR
MS: m/z (%) = 333 (11) [M]+, 286 (43), 258 (28), 212 (100), 181
1
(neat): ν = 2925, 1728, 1550, 1248, 1036 cm–1. H NMR (CDCl ,
˜
3
(69), 169 (63). HRMS: calcd. for C18H23NO5 [M]+: 333.1576; found
500 MHz): δ = 6.71 (d, J = 8.0 Hz, 1 H), 6.67 (s, 1 H), 6.62 (d, J
333.1574.
= 8.0 Hz, 1 H), 5.92 (d, J = 1.5 Hz, 2 H), 4.49 (dd, J = 11.0,
Ester 15: 78 mg, 78% yield. Rf = 0.25 for 15 in 30% EtOAc/hexane.
Selected spectroscopic data for 15: [α]2D5 = –25.5 (c = 2, CHCl3). IR
11.0 Hz, 1 H), 3.60–3.10 (m, 1 H), 2.52–2.40 (m, 1 H), 2.29 (dd, J
= 16.0, 3.5 Hz, 1 H), 2.14 (dd, J = 16.0, 8.5 Hz, 1 H), 2.08–1.90
(m, 2 H), 1.84–1.80 (m, 1 H), 1.44 (s, 9 H), 1.60–1.20 (m, 3 H) ppm.
13C NMR (CDCl3, 125 MHz): δ = 170.2 (C), 147.9 (C), 146.9 (C),
134.0 (C), 120.6 (CH), 108.5 (CH), 107.4 (CH), 101.0 (CH2), 95.4
(CH), 81.1 (C), 48.4 (CH), 38.9 (CH), 38.3 (CH2), 33.0 (CH2), 30.1
(CH2), 28.1 (three CH3), 24.9 (CH2).[22] MS: m/z (%) = 363 (33)
(neat): ν = 2925, 2856, 1728, 1550, 1512, 1227, 1165, 839, 773 cm–1.
˜
1H NMR (CDCl3, 500 MHz): δ = 9.36 (d, J = 2.0 Hz, 1 H), 7.24–
7.15 (m, 2 H), 7.00–6.95 (m, 2 H), 4.64 (dd, J = 11.5, 11.5 Hz, 1
H), 4.15–4.10 (m, 2 H), 3.42 (dd, J = 11.5, 11.5 Hz, 1 H), 2.76–
2.71 (m, 1 H), 2.60–2.42 (m, 1 H), 2.40–2.36 (m, 1 H), 2.30–2.20
(m, 1 H), 2.19–2.10 (m, 1 H), 2.08–2.00 (m, 1 H); 1.60–1.42 (m, 2 [M]+, 290 (10), 259 (100), 201 (37), 135 (45), 57 (36). HRMS: calcd.
H), 1.24 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 200.4 (CH), 170.6 (C), 162.4 (J = 246.3 Hz, C), 132.3 (J =
3.9 Hz, C), 129.5 (J = 7.8 Hz, two CH), 116.2 (J = 22.0 Hz, two
CH), 94.6 (CH), 60.9 (CH2), 53.6 (CH), 47.5 (CH), 38.2 (CH), 36.5
(CH2), 28.6 (CH2), 25.4 (CH2), 14.1 (CH3) ppm. MS: m/z (%) =
337 (3) [M]+, 290 (12), 262 (19), 216 (81), 173 (58), 109 (100).
HRMS: calcd. for C17H20FNO5 [M]+: 337.1326; found 337.1324.
for C19H25NO6 [M]+: 363.1682; found 363.1684.
Ester 20: 90 mg, 90% yield. Rf = 0.20 for 20 in 30% EtOAc/hexane.
Selected spectroscopic data for 20: [α]2D5 = –36.0 (c = 3, CHCl3). IR
1
(neat): ν = 2951, 1730, 1550, 1248, 1038 cm–1. H NMR (CDCl ,
˜
3
500 MHz): δ = 9.37 (d, J = 2.0 Hz, 1 H), 6.70 (d, J = 8.0 Hz, 1 H),
6.66 (d, J = 1.0 Hz, 1 H), 6.62 (d, J = 8.0 Hz, 1 H), 5.91 (d, J =
2.0 Hz, 2 H), 4.60 (dd, J = 11.0, 11.0 Hz, 1 H), 3.66 (s, 3 H), 3.32
(dd, J = 11.5, 11.5 Hz, 1 H), 2.72–2.62 (m, 1 H), 2.58–2.42 (m, 1
H), 2.38 (dd, J = 16.5, 3.5 Hz, 1 H), 2.25 (dd, J = 16.5, 8.5 Hz, 1
H), 2.16–2.10 (m, 1 H), 2.02–1.96 (m, 1 H), 1.60–1.40 (m, 2
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 200.8 (CH), 171.1 (C),
Ester 16: 73 mg, 76% yield. Rf = 0.34 for 16 in 30% EtOAc/hexane.
Selected spectroscopic data for 16: [α]2D5 = –23.6 (c = 4, CHCl3). IR
1
(neat): ν = 2925, 2852, 1730, 1550, 1371, 1178, 1034, 758 cm–1. H
˜
NMR ([D6]acetone, 500 MHz): δ = 9.41 (s, 1 H), 7.71 (d, J =
7.5 Hz, 1 H), 7.42–7.20 (m, 3 H), 5.07 (dd, J = 11.0, 11.0 Hz, 1 H), 148.3 (C), 147.6 (C), 129.9 (C), 121.5 (CH), 108.8 (CH), 107.8
4.22 (dd, J = 12.0, 15.0 Hz, 1 H), 4.11 (q, J = 7.0 Hz, 2 H), 2.95–
2.80 (m, 4 H), 2.62–2.52 (m, 1 H), 2.40–2.00 (m, 1 H), 1.85–1.72
(m, 1 H), 1.70–1.60 (m, 1 H), 1.23 (t, J = 7.0 Hz, 3 H) ppm. 13C
(CH), 101.3 (CH2), 94.7 (CH), 53.5 (CH), 51.9 (CH3), 48.1 (CH),
38.2 (CH), 36.4 (CH2), 28.6 (CH2), 25.4 (CH2) ppm. MS: m/z (%)
= 349 (5) [M]+, 247 (10), 231 (17), 117 (100). HRMS: calcd. for
NMR ([D6]acetone, 125 MHz): δ = 201.4 (CH), 171.3 (C), 136.6 C17H19NO7 [M]+: 349.1162; found 349.1160.
(C), 135.2 (C), 130.7 (CH), 130.2 (CH), 129.6 (CH), 128.8 (CH),
Ester 21: 71 mg, 85% yield. Rf = 0.33 for 21 in 80% EtOAc/hexane.
94.5 (CH), 61.2 (CH2), 55.7 (CH), 44.3 (CH), 39.4 (CH), 37.7
(CH2), 29.1 (CH2), 26.0 (CH2), 14.5 (CH3) ppm. MS: m/z (%) =
353 (12) [M]+, 308 (10), 261 (21), 233 (22), 215 (65), 191 (53), 189
(50), 125 (100). HRMS: calcd. for C17H20ClNO5 [M]+: 353.1030;
found 353.1029.
Selected spectroscopic data for 21: [α]2D5 = –17.7 (c = 1, MeOH).
1
IR (neat): ν = 2925, 1734, 1550, 1248, 1038 cm–1. H NMR ([D ]-
˜
6
acetone, 500 MHz): δ = 6.86 (s, 1 H), 6.73 (s, 2 H), 5.95 (d, J =
2.0 Hz, 2 H), 4.87 (dd, J = 11.0, 11.0 Hz, 1 H), 3.64 (s, 3 H), 3.33
(dd, J = 11.5, 11.5 Hz, 1 H), 2.86–2.80 (m, 1 H), 2.60–2.50 (m, 1
H), 2.38–2.30 (m, 2 H), 2.18–2.02 (m, 2 H), 1.82–1.70 (m, 1 H),
1.62–1.52 (m, 1 H) ppm. 13C NMR ([D6]acetone, 125 MHz): δ =
172.4 (C), 171.8 (C), 148.6 (C), 148.0 (C), 132.8 (C), 122.8 (CH),
109.1 (CH), 108.8 (CH), 102.1 (CH2), 95.3 (CH), 51.9 (CH3), 50.6
Ester 17: 82 mg, 85% yield. Rf = 0.55 for 17 in 30% EtOAc/hexane.
Selected spectroscopic data for 17: [α]2D5 = –16.5 (c = 4.0, CHCl3).
IR (neat): ν = 2933, 2867, 1731, 1571, 1550, 1181, 1034, 755 cm–1.
˜
1H NMR (CDCl3, 500 MHz): δ = 9.46 (s, 1 H), 7.46 (d, J = 8.0 Hz,
1 H), 7.34 (d, J = 7.5 Hz, 1 H), 7.21–7.10 (m, 2 H), 5.53 (dd, J = (CH), 49.0 (CH), 39.4 (CH), 37.4 (CH2), 30.1 (CH2), 29.5
11.0, 11.0 Hz, 1 H), 4.12 (q, J = 7.0 Hz, 2 H), 4.07 (dd, J = 12.0,
4.0 Hz, 1 H), 3.37 (s, 1 H), 2.60–2.49 (m, 1 H), 2.43 (dd, J = 16.5,
(CH2) ppm. MS: m/z (%) = 365 (58) [M]+, 301 (13), 272 (100),
258 (50), 199 (30), 135 (53). HRMS: calcd. for C17H19NO8 [M]+:
3.5 Hz, 1 H), 2.31 (d, J = 16.5, 9.0 Hz, 1 H), 2.17 (d, J = 14.5 Hz, 365.1111; found 365.1112.
1 H), 2.00–1.85 (m, 2 H), 1.39–1.30 (m, 1 H), 1.24 (t, J = 7.0 Hz,
Ester 22: 27 mg, 80% yield. Rf = 0.50 for 22 in 30% EtOAc/hexane.
3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 201.5 (C), 170.7 (C),
134.0 (two C), 130.1 (CH), 128.9 (CH), 128.8 (CH), 126.9 (CH),
88.2 (CH), 60.8 (CH2), 49.4 (CH), 44.0 (CH), 39.1 (CH), 37.1
(CH2), 26.1 (CH2), 23.9 (CH2), 14.1 (CH3) ppm. HRMS: calcd. for
C17H20ClNO5 [M]+: 353.1030; found 353.1032.
Selected spectroscopic data for 22: [α]2D5 = –57.5 (c = 6, CHCl3);[20e]
IR (neat): ν = 2925, 2858, 1738, 1549, 1248, 1038, 933, 812 cm–1.
˜
1H NMR (CDCl3, 500 MHz): δ = 6.69 (d, J = 7.5 Hz, 1 H), 6.65
(d, J = 1.0 Hz, 1 H), 6.60 (dd, J = 8.0, 1.5 Hz, 1 H), 5.90 (d, J =
1.5 Hz, 2 H), 4.48 (dd, J = 11.0, 11.0 Hz, 1 H), 3.66 (s, 3 H), 3.10–
3.00 (m, 1 H), 2.52–2.42 (m, 1 H), 2.36 (dd, J = 16.0, 3.5 Hz, 1 H),
2.23 (dd, J = 16.0, 8.5 Hz, 1 H), 2.04–1.92 (m, 2 H), 1.90–1.80 (m,
1 H), 1.60–1.48 (m, 2 H), 1.38–1.20 (m, 1 H) ppm. 13C NMR
Ester 18: 85 mg, 82% yield. Rf = 0.58 for 18 in 80% EtOAc/hexane.
Selected spectroscopic data for 18: [α]2D5 = –24.4 (c = 0.15, CHCl3).
IR (neat): ν = 2966, 2925, 1722, 1676, 1549, 1255, 802 cm–1. 1H
˜
Eur. J. Org. Chem. 2008, 1449–1457
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1455

B.-C. Hong, R. Y. Nimje, M.-F. Wu, A. A. Sadani
FULL PAPER
(CDCl3, 125 MHz): δ = 171.4 (C), 147.9 (C), 146.9 (C), 133.9 (C),
120.6 (CH), 108.5 (CH), 107.3 (CH), 101.1 (CH2), 95.3 (CH), 51.7
(CH), 47.5 (CH), 38.3 (CH), 32.1 (CH), 23.0 (CH2), 17.4
(CH2) ppm. MS (m/z, relative intensity): 257 [M+, 3], 210 (56), 182
(CH3), 48.4 (CH), 38.7 (CH), 36.9 (CH2), 32.9 (CH2), 30.1 (CH2), (100), 91 (51), 79 (50), 77 (40); HRMS: calcd. for C15H15NO3
24.8 (CH2) ppm. HRMS: calcd. for C16H19NO6 [M]+: 321.1212;
found 321.1213.
[M]+: 257.1052; found 257.1048.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and full characterizations of
products.
Ester 23: 40 mg, 40% yield (along with 35 mg and 35% yield of
ester 13). Rf = 0.38 for 23 in 30% EtOAc/hexane. Selected spectro-
scopic data for 23: [α]2D5 = –33.1 (c = 2.5, CHCl ). IR (neat): ν =
˜
3
2923, 1724, 1610, 1550, 1489, 1369, 1255, 1155, 1039, 804,
756 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 9.41 (s, 1 H), 6.72–
6.64 (m, 3 H), 5.91 (s, 1 H), 4.87 (dd, J = 12.0, 5.0 Hz, 1 H), 3.42
(dd, J = 11.5, 11.5 Hz, 1 H), 3.10–3.05 (m, 1 H), 2.70–2.56 (m, 1
H), 2.50–2.40 (m, 2 H), 2.08–2.00 (m, 1 H), 1.87–1.75 (m, 2 H),
1.62–1.50 (m, 2 H), 1.42 (s, 9 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 200.9 (CH), 170.1 (C), 148.1 (C), 147.3 (C), 130.6
(C), 121.5 (CH), 108.7 (CH), 108.3 (CH), 101.3 (CH2), 91.8 (CH),
81.4 (C), 54.5 (CH), 41.7 (CH), 34.0 (CH), 33.1 (CH2), 28.1 (CH2),
28.0 (three CH3), 20.4 (CH2) ppm. MS: m/z (%) = 391 (36) [M]+,
344 (16), 288 (92), 200 (36), 135 (48), 57 (100). HRMS: calcd. for
C20H25NO7 [M]+: 391.1631; found 391.1637.
Acknowledgments
We acknowledge the National Science Council, ROC for financial
support of this study. Assistance from the National Center for
High-Performance Computing (NCHC) is gratefully acknowl-
edged.
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Ester 25: 19 mg, 65% yield. Rf = 0.64 for 25 in 30% EtOAc/hexane.
Selected spectroscopic data for 25: [α]2D5 = –44 (c = 4, CHCl3). IR
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(neat): ν = 2927, 2858, 1726, 1549, 1489, 1369, 1248, 1153,
˜
1
1039 cm–1. H NMR (CDCl3, 500 MHz): δ = 6.70–6.62 (m, 3 H),
5.89 (s, 2 H), 4.82 (dd, J = 12.0, 4.5 Hz, 1 H), 3.16 (ddd, J = 12.0,
12.0, 4.0 Hz, 1 H), 3.05–3.02 (m, 1 H), 2.46 (d, J = 7 Hz, 2 H),
1.96–1.85 (m, 2 H), 1.70–1.40 (m, 4 H), 1.41 (s, 9 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 170.6 (C), 147.8 (C), 146.7 (C), 134.8
(C), 120.3 (CH), 108.5 (CH), 107.5 (CH), 101.0 (CH2), 92.1 (CH),
81.1 (C), 41.7 (CH), 34.6 (CH), 33.9 (CH2), 33.5 (CH2), 29.3 (CH2),
28.0 (three CH3), 19.9 (CH2) ppm. MS: m/z (%) = 363 (38) [M]+,
290 (12), 259 (100), 201 (52), 135 (72), 71 (28), 57 (96). HRMS:
calcd. for C19H25NO6 [M]+: 363.1682; found 363.1674.
Representative Procedure for the Preparation of 27 and 28: To a
solution of (E)-26 (30 mg, 0.24 mmol) and trans-nitrostyrene
(43 mg, 0.29 mmol) in CH3CN (2 mL) was added -Proline (5 mg,
0.048 mmol) and Et3N (5 mg, 0.048 mmol). The solution was
stirred for 3 h, diluted with EtOAc (25ϫ2 mL), washed with brine
(10 mL), dried with Na2SO4, and concentrated in vacuo to give the
crude product. The residue was purified by flash column
chromatography with 10% EtOAc/hexane (27: Rf = 0.30. 28: Rf =
0.25 in 20% EtOAc/hexane) to give 27 (20 mg, 32% yield) and 28
(6 mg, 10% yield) as colorless oils. Selected spectroscopic data for
27: [α]2D5 = –53.6 (c = 4, CHCl ). IR (neat): ν = 2920, 1682, 1545,
˜
3
1365, 1165, 750, 700 cm–1. H NMR (CDCl3, 500 MHz): δ = 9.60
1
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(s, 1 H), 7.45 (d, J = 6.5 Hz, 1 H), 7.29–7.20 (m, 3 H), 7.04 (d, J
= 7.5 Hz, 2 H), 4.46–4.43 (m, 1 H), 4.07 (s, 1 H), 3.92 (d, J =
5.5 Hz, 1 H), 3.18–3.15 (m, 1 H), 2.10–2.00 (m, 1 H), 1.90–1.80 (m,
1 H), 1.52–1.42 (m, 1 H), 1.30–1.20 (m, 1 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 187.8 (CH), 154.5 (CH), 144.1 (C), 142.3
(C), 129.0 (2 CH), 127.4 (CH), 127.0 (2 CH), 91.4 (CH), 47.2 (CH),
38.3 (CH), 32.5 (CH), 25.7 (CH2), 18.0 (CH2) ppm. MS: m/z (%)
= 257 (39) [M]+, 210 (45), 182 (78), 108 (100), 91 (75), 79 (85).
HRMS: calcd. for C15H15NO3 [M]+: 257.1052; found 257.1048. Se-
lected spectroscopic data for 28: [α]2D5 = –20 (c = 2.1, CHCl3). IR
(neat): ν = 2922, 1682, 1547, 1371, 1173, 702 cm–1. 1H NMR
˜
(CDCl3, 500 MHz): δ = 9.57 (s, 1 H), 7.55 (d, J = 6.5 Hz, 1 H),
7.40–7.20 (m, 5 H), 5.03 (dd, J = 5.5, 2.0 Hz, 1 H), 4.01 (s, 1 H),
3.49 (dd, J = 3.0, 2.5 Hz, 1 H), 3.00 (dd, J = 3.0, 2.5 Hz, 1 H),
1.90–1.72 (m, 2 H), 1.50–1.40 (m, 1 H), 1.20–1.10 (m, 1 H) ppm.
13C NMR (CDCl3, 125 MHz): δ = 188.5 (CH), 153.2 (CH), 143.1
(C), 138.1 (C), 129.1 (2 CH), 127.63 (CH), 127.59 (2 CH), 87.5
1456
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1449–1457

Organocatalytic Double Michael Reaction
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CCDC-655610 contains the supplementary crystallographic
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[17]
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[19]
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Some of the phenyl and formyl substituents in the transition
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cases, even with a UV photo-diarray detector. The inability to
detect the compound may be due to the rapid formation of the
equilibrium of several isomers.
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change of the solvent (e.g., to CH2Cl2) lowered the syn/anti
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sequence of addition/vacuum concentration procedures with
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[21e]
[23]
[24]
For compound (+)-22, see ref.
.
The other possible dialdehyde isomers (less than 35% yield)
were unstable and gave complicated mixtures during the isola-
tion process. The same reaction at –30 °C followed by re-
duction with NaBH4 provided a 70% yield of the two diol
products, which were identical to the product from the re-
duction of 4 and 5 with LiAlH4.
For the preparation, see: E. L. Richards, P. J. Murphy, F. Di-
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[27]
For the preparation, see: F. C. Bargiggia, W. V. Murray, Tetra-
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Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405–4408. The
straightforward preparation of pure (Z)-1 (methyl ester) was
achieved by reaction with methyl bis(2,2,2-trifluoroethyl)phos-
phonoacetate, see: S. E. Denmark, C. B. W. Senanayake, G.-D.
Ho, Tetrahedron 1990, 46, 4857–4876.
Received: November 28, 2007
Published Online: January 22, 2008
Eur. J. Org. Chem. 2008, 1449–1457
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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