Squaramide-Sulfonamide Organocatalyst for Asymmetric Direct Vinylogous Aldol Reactions

Article abstract of DOI:10.1021/acs.joc.7b00287

Asymmetric direct vinylogous aldol reactions of furan-2(5H)-one with aldehydes in the presence of a catalytic amount of novel squaramide-sulfonamide organocatalyst resulted in the corresponding addition products with high to excellent enantioselectivities. This is the first successful report illustrating an example of highly stereoselective reactions using a squaramide-sulfonamide organocatalyst.

Full text of DOI:10.1021/acs.joc.7b00287

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Article
Squaramide–sulfonamide organocatalyst for
asymmetric direct vinylogous aldol reactions
Takaaki Sakai, Shin-ichi Hirashima, Yoshifumi Yamashita, Ryoga Arai,
Kosuke Nakashima, Akihiro Yoshida, Yuji Koseki, and Tsuyoshi Miura
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00287 • Publication Date (Web): 10 Apr 2017
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The Journal of Organic Chemistry
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Squaramide–sulfonamide organocatalyst for asymmetric direct vi-
nylogous aldol reactions
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Takaaki Sakai, Shin-ichi Hirashima*, Yoshifumi Yamashita, Ryoga Arai, Kosuke Nakashima,
Akihiro Yoshida, Yuji Koseki, Tsuyoshi Miura*
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
* E-mail: tmiura@toyaku.ac.jp; * E-mail: hirashim@toyaku.ac.jp
ABSTRACT: Asymmetric direct vinylogous aldol reactions of furan-2(5H)-one with aldehydes in the presence of a catalytic
amount of novel squaramide–sulfonamide organocatalyst resulted in the corresponding addition products with high to excellent
enantioselectivities. This is the first successful report illustrating an example of highly stereoselective reactions using a squara-
mide–sulfonamide organocatalyst.
INTRODUCTION
required low temperatures and its yield and enantioselectivity
were not satisfactory (Scheme 1, eq 4).5d Therefore, the devel-
opment of highly efficient asymmetric direct vinylogous aldol
reactions still remains one of the most challenging research
themes in modern organic chemistry.
The γ-substituted butenolides are remarkably valuable synthet-
ic intermediates considering that several natural products con-
taining butenolide motif exhibit significant biological activi-
ties.1 The chirality of γ-substituted butenolides plays a crucial
role in the biological activities of these natural products. To
synthesize chiral γ-substituted butenolides, the vinylogous
Mukaiyama aldol reactions of activated 2-siloxyfuran with
aldehydes are one of the most powerful synthetic methodolo-
Organocatalysts involving thiourea motifs as double hydro-
gen-bond donors are excellent catalysts for various asymmet-
ric reactions to access valuable enantiomerically enriched
molecules.6 In addition, squaramide organocatalysts have been
reported as good double hydrogen-bond donors; their excellent
catalytic activities have been demonstrated.7 Furthermore,
since Wang et al. reported asymmetric conjugate additions of
1,3-diketones to nitroalkenes using the sulfonamide–thiourea
organocatalyst, organocatalysts with motif involving multiple
hydrogen-bond donors have attracted considerable attention.8
On the other hand, we have reported that β-
aminosulfonamides 1 and 2 as a single hydrogen-bond donor
are good catalysts for asymmetric direct aldol reactions of
ketones with aromatic aldehydes (Figure 1).9 In addition, β-
aminosulfonamide organocatalysts were applied to the asym-
metric conjugate additions of branched aldehydes to vinyl-
sulfones10 and malonates to enones.11 Among the examined β-
aminosulfonamides, organocatalysts with a perfluorobutane
sulfonamide group exhibited more effective catalytic activi-
ty.9e, 10, 11 In this context, organocatalysts bearing both squara-
mide and sulfonamide motifs are expected to have excellent
gies, which has been reported by several research groups.2, 3
A
more convenient synthesis of chiral γ-substituted butenolides
is the direct vinylogous aldol reactions between simple furan-
2(5H)-one derivatives and aldehydes using organocatalysts;
however, they have rarely been reported.4, 5 Although the di-
rect vinylogous aldol reactions are highly valuable from the
viewpoint of atom economy, the reactions of furan-2(5H)-one
with aldehydes reported previously were not highly efficient
methodologies.5 Feng et al., in their pioneering work, reported
the direct vinylogous aldol reactions using thiourea organocat-
alyst, which did not result in satisfactory enantioselectivity
(Scheme 1, eq 1).5a Pansare et al. reported methods of using
squaramide organocatalysts; these methods provided excellent
enantioselectivity but required long reaction time and had
moderate yields (Scheme 1, eq 2 and 3).5b, c The direct vinylo-
gous aldol reactions using quaternary ammonium organocata-
lyst were reported by Levacher et al.; however, the method
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catalytic activity as multiple hydrogen-bond donors. However, strated that the chiral sulfonamide unit of 3 is essential for
high stereoselectivity because the use of organocatalyst 1013
without the chiral sulfonamide unit significantly decreased
stereoselectivity (entry 9). The use of organocatalyst 11 bear-
ing thiourea motif instead of squaramide also provided lower
enantioselectivity (entry 10). The absolute configuration of
14a was determined by comparison with reported chiral-phase
HPLC retention times.
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to the best of our knowledge, only one report has been pub-
lished on asymmetric reactions using squaramide–sulfonamide
organocatalysts by Du et al.12 Unfortunately, the three squara-
mide–sulfonamide organocatalysts in the aforementioned
study are poor catalysts for the Friedel–Crafts alkylation of
indoles with iminochromenes, providing low stereoselectivi-
ties. To date, there is no successful example for asymmetric
reactions using organocatalysts bearing both squaramide and
sulfonamide motifs. Herein, we describe highly efficient direct
asymmetric vinylogous aldol reactions using organocatalyst
with both squaramide and perfluorobutanesulfonamide groups
as multiple hydrogen-bond donors.
With this optimized catalyst, various reaction solvents for
vinylogous aldol reactions of 12a with 13 using catalyst 3
were studied (Table 2). Among the examined reaction solvents,
relatively satisfactory results were obtained when Et2O or 1,4-
dioxane was used (entry 9 and 10). Finally, Et2O was judged
to be the most suitable reaction solvent considering both yield
and stereoselectivity. Further, optimization of reaction condi-
tions was studied (Table 3). When the amount of 13 (3, 4, and
5 equiv) under diluted conditions (0.2 M) was increased, the
use of 5 equiv of 13 afforded the aldol product in high yield
with excellent stereoselectivity (entry 5).
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RESULTS AND DISCUSSION
We examined various sulfonamide
2 and squaramide–
sulfonamide organocatalysts (3–9) for model vinylogous aldol
reactions of furan-2(5H)-one (13) with 4-chlorobenzaldehyde
(12a), as summarized in Table 1. The β-aminosulfonamide
organocatalyst 2 proved to be a poor catalyst for the direct
vinylogous aldol reaction (entry 1). Among the examined
squaramide–sulfonamide organocatalysts 3–9, organocatalyst
3 was the most preferable catalyst considering both diastere-
oselectivity and enantioselectivity (entries 2–8). We demon-
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Under the optimized reaction conditions, the scope and limita-
tion of asymmetric direct vinylogous aldol reactions of 13
with various aldehydes 12b–j were analyzed (Table 4). Aro-
matic aldehydes bearing electron-withdrawing groups, such as
bromo and trifluoromethyl, at the para position reacted with
furan-2(5H)-one (13) in the presence of organocatalyst 3 to
afford the corresponding anti-products 14b–c in high yields
with high enantioselectivities (entries 2–3). The reactions of 2-
chlorobenzaldehyde (12d) with 13 resulted in the anti-adducts
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used. Flash column chromatography was performed on neutral silica
gel (Kanto Silica gel 60N, 40–50 µm).
14d in high yields with high stereoselectivities (entry 4). The
reaction between aldehyde 12e with the methyl group as a
moderate electron-donating group and 13 proceeded, resulting
in the corresponding product 14e in high yield with excellent
enantioselectivity (entry 5). Although 4-methoxybenzaldehyde
(12f) bearing a strong electron-donating group is a poor sub-
strate and provided moderate yield, high enantioselectivity
was obtained (entry 6). Organocatalyst 3 promoted the reac-
tions of aromatic aldehydes without substituent groups, includ-
ing 12g, 12h, and 12i, to provide adducts 14g–i in high yields
with a high degree of enantioselectivity (entries 7–9). Cyclo-
hexanecarbaldehyde (12j), an aliphatic aldehyde, reacted with
13, affording the corresponding product 14j in moderate yield
with excellent enantioselectivity (entry 10). The stereochemis-
try of the products was determined by comparison with report-
ed chiral-phase HPLC retention times. Although the transition
state for direct vinylogous aldol reactions is unclear, we infer
that three acidic protons of squaramide and sulfonamide form
multiple hydrogen bonds with aldehydes and the furan-2-ol
derived from furan-2(5H)-one and the tertiary amine activates
the furan-2-ol to afford high stereoselectivities (Figure 2).
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Preparation of organocatalyst 3
To a solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (499 mg,
3.51 mmol) in dry MeOH (35 mL) was added 29e (1.52 g, 3.51 mmol)
at room temperature. After stirring for 20 h at room temperature, the
reaction mixture was evaporated. The residue was purified by flash
column chromatography on silica gel with a 80:1 mixture of CHCl3
and MeOH to give the crude product (1.96 g) as a pale yellow solid.
To a solution of the crude product (1.63 g, 3.00 mmol) in dry MeOH
(12 mL) was added (S)-((1S,2S,4S,5R)-5-ethylquinuclidin-2-yl)(6-
methoxyquinolin-4-yl)methanamine14a (976 mg, 3.00 mmol) at room
temperature. After stirring for 31 h at room temperature, the reaction
mixture was evaporated. MeOH was added to the residue, and the
precipitate was collected over grass filter to give the pure 3 (1.58 g,
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63%) as a white powder. Mp 156-158 °C; [α]25 = -40.3 ° (c 1.00,
D
CHCl3); 1H NMR (400 MHz, CD3OD, 50 ºC): δ = 0.92 (t, J = 7.3 Hz,
3H), 0.92 (br s, 1H, overlapping signal), 1.48 (s, 2H), 1.82 (br s, 5H),
2.74-3.03 (br m, 4H), 3.26-3.33 (br m, 2H, overlapping signals), 3.39-
3.76 (br m, 2H), 3.95 (s, 3H), 3.98-4.24 (br m, 2H), 6.29 (br s, 1H),
7.01 (br s, 5H), 7.47 (dd, J = 9.2, 2.5 Hz, 1H), 7.55 (d, J = 2.9 Hz,
1H), 7.75 (br s, 1H), 8.01 (d, J = 9.1 Hz, 1H), 8.76 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ = 11.3, 24.3, 24.7, 25.2, 26.8, 35.0, 39.0, 42.9,
50.9, 51.4, 56.1, 60.2, 60.6, 100.0, 108.3-119.4 (complex signals of –
CF2 and –CF3), 118.4, 123.2, 126.2, 127.4, 128.2, 129.3, 132.1, 137.9,
141.4, 145.0, 148.0, 159.2, 166.9, 169.4, 182.1, 183.5; HRMS (ESI-
TOF): calcd for C37H39F9N5O5S [M+H]+: 836.2523, Found: 836.2527;
Anal. Calcd for C37H38F9N5O5S: C, 53.17; H, 4.58; N, 8.38. Found: C,
52.97; H, 4.76; N, 8.17.
Organocatalyst 4
To a solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (426 mg,
3.00 mmol) in dry MeOH (30 mL) was added 29e (1.30 g, 3.00 mmol)
at room temperature. After stirring for 24 h at room temperature, the
reaction mixture was evaporated. The residue was purified by flash
column chromatography on silica gel with a 80:1 mixture of CHCl3
and MeOH to give the crude product (1.62 g) as a pale yellow solid.
To a solution of the crude product (542 mg, 1.00 mmol) in dry
CH2Cl2 (3 mL) was added (R)-((1S,2R,4S,5R)-5-ethylquinuclidin-2-
yl)(6-methoxyquinolin-4-yl)methanamine14b (326 mg, 1.00 mmol) at
room temperature. After stirring for 24 h at room temperature, the
reaction mixture was evaporated. MeOH was added to the residue,
and the precipitate was collected over grass filter to give the pure 4
CONCLUSION
In brief, the novel organocatalyst 3 bearing the squaramide–
sulfonamide motif as a multiple hydrogen-bond donor effi-
ciently catalyzed the direct vinylogous aldol reactions of vari-
ous aldehydes with furan-2(5H)-one to yield the correspond-
ing anti-aldol products with high to excellent enantioselectivi-
ties. We first demonstrated that the squaramide–sulfonamide
skeleton is an excellent motif for organocatalysis. Further ap-
plication of squaramide–sulfonamide organocatalysts in the
synthesis of bioactive compounds is currently under progress
in our laboratory.
(418 mg, 50%) as a white solid; mp 162-163 °C; [α]25 = +11.5 ° (c
D
1
1.00, CHCl3); H NMR (400 MHz, CD3OD, 50 ºC): δ = 0.94 (t, J =
7.3 Hz, 3H), 1.10-1.19 (m, 1H), 1.36-1.58 (m, 3H), 1.76-1.89 (m,
4H), 2.53-2.59 (m, 1H), 2.88-2.90 (m, 1H), 3.27-3.35 (br m, 5H),
3.45-3.49 (m, 1H), 3.90 (br s, 1H), 3.95 (s, 3H), 4.29 (br s, 1H), 6.29
(br s, 1H), 6.78-7.00 (m, 5H), 7.50 (dd, J = 9.2, 2.5 Hz, 1H), 7.60-
7.67 (m, 1H), 7.72 (s, 1H), 8.03 (d, J = 9.3 Hz, 1H), 8.76 (d, J = 4.7
Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 11.2, 22.9, 23.6, 24.7,
25.1, 35.1, 40.0, 49.1, 49.5, 49.7, 51.4, 55.9, 61.5, 62.9, 100.0, 108.8-
119.0 (complex signals of –CF2 and –CF3), 119.6, 121.9, 123.1,
125.9, 127.3, 127.7, 129.1, 132.0, 137.1, 141.3, 144.7, 147.9, 158.9,
169.9, 170.1, 180.7, 187.2; HRMS (ESI-TOF): calcd for
C37H39F9N5O5S [M+H]+: 836.2523, Found: 836.2538.
EXPERIMENTAL SECTION
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
1
Organocatalyst 5
III Nanobay 400 MHz spectrometer (400 MHz for H NMR and 100
MHz for 13C NMR). The chemical shifts are expressed in ppm down-
field from tetramethylsilane (δ = 0.00) as an internal standard. Mass
spectra were recorded by an electrospray ionization-time of flight
(ESI-TOF) mass spectrometer (Micromass LCT). Specific rotations
were measured on a Jasco P-1030. Melting points were obtained with
Yanaco MP-J3 and are uncorrected. For thin layer chromatographic
(TLC) analyses, Merck precoated TLC plates (silica gel 60 F254) were
To a solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (284 mg,
2.00 mmol) in dry MeOH (20 mL) was added (S)-N-(2-Amino-3-
methylbutyl)-perfluorobutanesulfonamide10b (769 mg, 2.00 mmol) at
room temperature. After stirring for 24 h at room temperature, the
reaction mixture was evaporated. The residue was purified by flash
column chromatography on silica gel with a 80:1 mixture of CHCl3
and MeOH to give the crude product (852 mg) as a pale yellow solid.
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To a solution of the crude product (420 mg, 0.85 mmol) in dry MeOH
To a solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (499 mg,
3.51 mmol) in dry MeOH (35 mL) was added 29e (1.52 g, 3.51 mmol)
at room temperature. After stirring for 20 h at room temperature, the
reaction mixture was evaporated. The residue was purified by flash
column chromatography on silica gel with a 80:1 mixture of CHCl3
and MeOH to give the crude product (1.96 g) as a pale yellow solid.
To a solution of the crude product (542 mg, 1.00 mmol) in dry MeOH
(10 mL) was added (1R,2R)-N1,N1-dimethylcyclohexane-1,2-
diamine15 (284 mg, 2.00 mmol) at room temperature. After stirring for
24 h at room temperature, the reaction mixture was evaporated.
MeOH was added to the residue, and the precipitate was collected
(5 mL) was added (S)-((1S,2S,4S,5R)-5-ethylquinuclidin-2-yl)(6-
methoxyquinolin-4-yl)methanamine14a (300 mg, 0.92 mmol) at room
temperature. After stirring for 144 h at room temperature, the reaction
mixture was evaporated. The residue was purified by flash column
chromatography on silica gel with CHCl3 and MeOH (gradually 1:0-
10:1) to give the pure 5 (317 mg, 47%) as a white solid; mp 164-165
°C; [α]27D = -78.8 ° (c 1.00, CHCl3); 1H NMR (400 MHz, CD3OD, 50
ºC): δ = 0.89-0.97 (m, 10H), 1.28-1.33 (m, 1H), 1.46 (br s, 2H), 1.60-
1.83 (br m, 5H), 2.65-3.18 (m, 3H), 3.35-3.64 (m, 4H), 4.00 (s, 3H),
4.00 (br s, 1H, overlapping signal), 6.21 (br m, 1H), 7.44 (dd, J = 9.3,
2.5 Hz, 1H), 7.57 (s, 1H), 7.84 (s, 1H), 7.97 (d, J = 9.1 Hz, 1H), 8.73
(d, J = 3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 11.3, 18.3,
19.0, 24.3, 24.6, 25.3, 26.7, 29.7, 31.0, 35.6, 41.2, 42.5, 48.9, 51.6,
56.1, 60.0, 64.5, 100.1, 108.3-116.1 (complex signals of –CF2 and –
CF3), 118.7, 123.2, 127.5, 132.0, 141.8, 145.0, 148.0, 159.2, 166.8,
170.1, 182.2, 183.5; HRMS (ESI-TOF): calcd for C33H39F9N5O5S
[M+H]+:788.2523, Found: 788.2528.
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over grass filter to give the pure 8 (174 mg, 27%) as a white solid; mp
1
253-255 °C (decomp.); [α]25 = -69.3 ° (c 0.20, DMSO); H NMR
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D
(400 MHz, DMSO): δ = 1.23-1.32 (br m, 5H), 1.65-1.98 (m, 5H),
2.43 (br s, 5H), 2.76-2.95 (m, 3H), 3.85 (br s, 2H), 4.13-4.24 (m, 1H),
7.17-7.28 (m, 6H), 7.55 (br s, 2H); 13C NMR (100 MHz, DMSO): δ =
21.9, 24.0, 24.1, 34.4, 48.4, 53.1, 56.4, 66.6, 105.8-121.3 (complex
signals of –CF2 and –CF3), 126.3, 128.2, 129.4, 138.2, 167.4, 182.1;
HRMS (ESI-TOF): calcd for C25H30F9N4O4S [M+H]+: 653.1839,
Found: 653.1853.
Organocatalyst 6
Organocatalyst 9
To a solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (284 mg,
2.00 mmol) in dry MeOH (20 mL) was added (S)-N-(2-Amino-3-
methylbutyl)-perfluorobutanesulfonamide10b (769 mg, 2.00 mmol) at
room temperature. After stirring for 24 h at room temperature, the
reaction mixture was evaporated. The residue was purified by flash
column chromatography on silica gel with a 80:1 mixture of CHCl3
and MeOH to give the crude product (852 mg) as a pale yellow solid.
To a solution of the crude product (420 mg, 0.85 mmol) in dry MeOH
(5 mL) was added (R)-((1S,2R,4S,5R)-5-ethylquinuclidin-2-yl)(6-
methoxyquinolin-4-yl)methanamine14b (300 mg, 0.92 mmol) at room
temperature. After stirring for 144 h at room temperature, the reaction
mixture was evaporated. The residue was purified by flash column
chromatography on silica gel with CHCl3 and MeOH (gradually 1:0-
10:1) to give the pure 6 (415 mg, 47%) as a white solid; mp 224-225
°C (decomp.); [α]25D = +189.5 ° (c 1.00, CHCl3); 1H NMR (400 MHz,
CD3OD, 50 ºC): δ = 0.84-0.96 (m, 9H), 1.15-1.20 (m, 1H), 1.29-1.59
(m, 3H), 1.72-1.83 (m, 5H), 3.14-3.29 (m, 4H), 3.35-3.43 (m, 2H),
3.74-3.92 (br m, 2H), 4.00 (s, 3H), 6.36 (d, J = 10.8 Hz, 1H), 7.46
(dd, J = 9.2, 2.5 Hz, 1H), 7.06 (d, J = 3.7 Hz, 1H), 7.84 (s, 1H), 7.99
(d, J = 9.1 Hz, 1H), 8.74 (d, J = 4.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ = 11.4, 17.7, 19.0, 23.1, 23.9, 25.0, 25.2, 31.9, 35.4, 47.5,
49.0, 49.5, 51.9, 55.9, 61.4, 65.6, 100.5, 108.0-119.1 (complex signals
of –CF2 and –CF3), 119.3, 123.1, 127.5, 132.0, 142.8, 144.8, 147.9,
158.7, 169.8, 170.5, 181.6, 187.2; HRMS (ESI-TOF): calcd for
C33H39F9N5O5S [M+H]+: 788.2523, Found: 788.2518.
To a solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (284 mg,
2.00 mmol) in dry MeOH (35 mL) was added N-((1S,2S)-2-amino-
1,2-diphenylethyl)-3,5-bis(trifluoromethyl)benzenesulfonamide16
(977 mg, 2.00 mmol) at room temperature. After stirring for 23 h at
room temperature, the reaction mixture was evaporated. The residue
was purified by flash column chromatography on silica gel with a
80:1 mixture of CHCl3 and EtOAc to give the crude product (850 mg)
as a pale yellow solid. To a solution of the crude product (359 mg,
0.60 mmol) in dry MeOH (4 mL) was added (S)-((1S,2S,4S,5R)-5-
ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methanamine14a (195
mg, 0.60 mmol) at room temperature. After stirring for 24 h at room
temperature, the reaction mixture was evaporated. The residue was
purified by flash column chromatography on silica gel with CHCl3
and MeOH (gradually 1:0-20:1) to give the pure 9 (299 mg, 56%) as a
white solid; mp 290-291 °C (decomp.); [α]25 = 115.3 ° (c 0.25,
D
1
DMSO); H NMR (400 MHz, DMSO): δ = 0.59 (s, 1H), 0.81 (t, J =
7.0 Hz, 3H), 1.36-1.55 (m, 7H), 2.33-2.57 (m, 2H), 3.10-3.15 (m,
1H), 3.95 (s, 3H), 4.67-4.71 (m, 1H), 5.31-5.36 (m, 1H), 5.95 (br s,
1H), 6.68-6.79 (m, 5H), 7.08-7.19 (m, 5H), 7.47 (d, J = 9.5 Hz, 1H),
7.65 (d, J = 4.0 Hz, 1H), 7.81 (s, 3H), 7.93-8.18 (m, 4H), 8.83 (s, 1H),
8.98 (s, 1H); 13C NMR (100 MHz, DMSO): δ = 12.0, 25.1, 26.2, 26.9,
28.1, 52.9, 55.8, 57.2, 58.7, 61.3, 62.0, 101.6, 119.3, 121.9, 121.9,
1
122.4 (q, JC–F = 273 Hz), 125.6, 126.8, 127.3, 127.4, 127.6, 127.6,
2
127.7, 128.5, 130.6 (q, JC–F = 33.8 Hz), 131.6, 135.9, 139.1, 143.6,
Organocatalyst 7
144.4, 147.8, 157.8, 166.7, 166.9, 181.7, 182.6; HRMS (ESI-TOF):
calcd for C46H44F6N5O5S [M+H]+: 892.2962 Found: 892.2964.
To a solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (499 mg,
3.51 mmol) in dry MeOH (35 mL) was added 29e (1.52 g, 3.51 mmol)
at room temperature. After stirring for 20 h at room temperature, the
reaction mixture was evaporated. The residue was purified by flash
column chromatography on silica gel with a 80:1 mixture of CHCl3
and MeOH to give the crude product (1.96 g) as a pale yellow solid.
To a solution of the crude product (542 mg, 1.00 mmol) in dry MeOH
(10 mL) was added (1S,2S)-N1,N1-dimethylcyclohexane-1,2-
diamine15 (284 mg, 2.00 mmol) at room temperature. After stirring for
40 h at room temperature, the reaction mixture was evaporated. The
residue was purified by flash column chromatography on silica gel
with CHCl3 and MeOH (gradually 1:0-14:1) to give the pure 7 (579
mg, 90%) as a white solid; mp 257-260 °C (decomp.); [α]21D = -49.3 °
Organocatalyst 11
To
a
solution of 29e (720 mg, 1.67 mmol) and N,N’-
dicyclohexylcarbodiimide (344 mg, 1.67 mmol) in dry THF (5 mL)
was added carbon disulfide (664 µL, 11.0 mmol) at 0 °C. After stir-
ring for 24 h at room temperature, the reaction mixture was evapo-
rated. The residue was purified by flash column chromatography on
silica gel with a 10:1 mixture of Hexane and EtOAc to give the crude
product (1.03 g) as a pale yellow solid. To a solution of the crude
product (1.03 g, 1.67 mmol) in dry THF (6 mL) was added (S)-
((1S,2S,4S,5R)-5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-
yl)methanamine14a (976 mg, 3.00 mmol) at room temperature. After
stirring for 94 h at room temperature, the reaction mixture was evapo-
rated. The residue was purified by flash column chromatography on
silica gel with CHCl3 and EtOAc (gradually 1:0-50:1) to give the pure
1
(c 0.25, DMSO); H NMR (400 MHz, CD3OD, 50 ºC): δ = 1.29-1.46
(m, 4H), 1.75-2.12 (m, 4H), 2.49 (br s, 7H), 2.83-2.89 (m, 1H), 2.97-
3.02 (m, 1H), 3.34-3.49 (m, 2H), 4.04-4.23 (br m, 2H), 7.18-7.30 (m,
5H); 13C NMR (100 MHz, DMSO): δ = 22.2, 24.0, 34.5, 48.3, 53.2,
56.2, 66.5, 105.5-118.5 (complex signals of –CF2 and –CF3), 126.3,
128.2, 138.1, 167.5, 182.2; HRMS (ESI-TOF): calcd for
C25H30F9N4O4S [M+H]+: 653.1839, Found: 653.1852.
11 (1.14 g, 85%) as a white solid; mp 116-118 °C; [α]27 = -78.7 ° (c
D
1.00, CHCl3); 1H NMR (400 MHz, CD3OD, 50 ºC): δ = 0.91 (t, J =
7.3 Hz, 3H), 1.03-1.08 (m, 1H), 1.46-1.47 (br m, 2H), 1.85-1.92 (br
m, 5H), 2.73 (br s, 2H), 3.13-3.19 (m, 3H), 3.35-3.55 (br m, 3H), 3,96
(s, 3H), 3.96 (br s, 1H, overlapping signal), 6.46 (br s, 1H), 6.97 (br s,
Organocatalyst 8
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Page 6 of 8
5H), 7.45 (dd, J = 9.2, 2.5 Hz, 1H), 7.49 (d, J = 4.9 Hz, 1H), 7.97 (d,
J = 9.3 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 8.68 (d, J = 4.7 Hz, 1H); 13
(R)-5-((S)-(2-chlorophenyl)(hydroxy)methyl)furan-2(5H)-one (14d).
According to the general procedure, 2-chlorobenzaldehyde 12d
17a
C
1
2
3
4
5
6
7
8
NMR (100 MHz, CDCl3): δ = 11.3, 24.0, 24.4, 24.8, 26.0, 29.7, 34.8,
39.0, 43.2, 52.6, 55.1, 55.8, 59.5, 60.2, 102.2, 107.9-119.2 (complex
signals of –CF2 and –CF3), 120.0, 122.8, 126.8, 127.9, 128.5, 128.8,
131.6, 136.0, 141.6, 144.9, 147.8, 158.6, 181.8; HRMS (ESI-TOF):
calcd for C34H39F9N5O3S2 [M+H]+: 800.2345, Found: 800.2356.
(22.5 µL, 0.2 mmol) afforded product 14d (43.2 mg, 96%) as a white
solid, (anti/syn = 88:12) (91% ee); [α]24 = +188.0° (c 1.0, CHCl3);
D
1H NMR (400 MHz, CDCl3): δ = 2.82 (d, J = 3.7 Hz, 1H), 5.40-5.41
(m, 1H), 5.60 (dd, J = 3.7 Hz, 3.6 Hz, 1H), 6.19 (dd, J = 5.8 Hz, 2.0
Hz, 1H), 7.25 (dd, J = 5.8 Hz, 1.4 Hz, 1H) 7.29-7.41 (m, 3H), 7.56
(dd, J = 7.6 Hz, 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 69.5,
84.8, 123.6, 127.5, 128.0, 129.7, 132.0, 135.6, 152.4, 173.4; Enantio-
meric excess of the product was determined by chiral stationary phase
HPLC analysis using a ChiralPak AD-H column (hexane/i-PrOH =
95:5 at 0.8 mL/min); λ = 254 nm; t major = 19.4 min, t minor = 28.1 min;
HRMS (ESI): Calcd for C11H9ClO3Na [M+Na]+: 247.0132, Found:
247.0138.
General procedure for asymmetric direct vinylogous aldol reac-
tion and characterization date of the vinylogous aldol reaction
products (14a-j).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Furan-2(5H)-one 13 (70 µL, 1.0 mmol) was added to a solution of
aldehyde 12 (0.2 mmol) and organocatalyst (0.02 mmol, 10 mol%) in
dry Et2O (1.0 mL) at 25 ºC. After stiring for indicated time, the reac-
tion mixture was purified by silica gel choromatography with CHCl3
and EtOAc (gradually 1:0-50:3) to afforded the title compound 14.
3a, 5a, 5b
(R)-5-((S)-hydroxy(p-tolyl)methyl)furan-2(5H)-one (14e).
According to the general procedure, p-tolualdehyde 12e (23.6 µL, 0.2
mmol) afforded product 14e (33.2 mg, 81%) as a white solid, (an-
1
(R)-5-((S)-(4-chlorophenyl)(hydroxy)methyl)furan-2(5H)-one (14a).
3a, 5a, 5b According to the general procedure, 4-chlorobenzaldehyde 12a
(28.1 mg, 0.2 mmol) afforded product 14a (41.6 mg, 93%) as a white
ti/syn = 88:12) (91% ee); H NMR (400 MHz, CDCl3): δ = 2.37 (s,
3H, syn, anti), 2.54 (br d, J = 2.9 Hz, 1H, anti), 2.80 (s, 1H, syn), 4.66
(d, J = 7.0 Hz, 1H, syn), 5.04-5.05 (br, 1H, anti), 5.13-5.17 (m, 1 H,
syn, anti), 6.12 (dd, J = 5.8 Hz, 2.0 Hz, 1H, syn), 6.17 (dd, J = 5.8 Hz,
2.0 Hz, 1H, anti), 7.16 (dd, J = 5.8 Hz, 1.5 Hz, 1H, syn), 7.19-7.29
(m, 4H, syn, anti), 7.36 (dd, J = 5.8 Hz, 1.5 Hz, 1H, anti); 13C NMR
(100 MHz, CDCl3) anti diastereomer: δ = 21.3, 73.1, 86.8, 123.2,
126.1, 126.8, 129.5, 135.4, 138.5, 153.1, 173.2, syn diastereomer: δ =
75.6, 87.2, 123.0, 126.8, 134.9, 138.9, 153.4; Enantiomeric excess of
the product was determined by chiral stationary phase HPLC analysis
using a ChiralPak AD-H column (hexane/i-PrOH = 95:5 at 1.0
1
solid, (anti/syn = 92:8) (93% ee); H NMR (400 MHz, CDCl3): δ =
2.46 (d, J = 4.0 Hz, 1H, anti), 2.72 (d, J = 3.2 Hz, 1H, syn), 4.74 (dd,
J = 6.8 Hz, 3.2 Hz, 1H, syn), 5.06 (dd, J = 4.3 Hz, 4.0 Hz, 1H, anti),
5.14-5.16 (m, 1H, syn, anti), 6.15 (dd, J = 5.8 Hz, 2.0 Hz, 1H, syn),
6.20 (dd, J = 5.8 Hz, 1.9 Hz, 1H, syn), 7.20 (dd, J = 5.8 Hz, 1.4 Hz,
1H, syn), 7.32-7.41 (m, 5H);13C NMR (100 MHz, CDCl3) anti dia-
stereomer: δ = 72.5, 86.5, 123.4, 127.6, 128.2, 129.0, 134.4, 136.9,
152.9, 173.2, syn diastereomer: δ = 74.6, 86.6, 123.3, 128.2, 134.8,
136.4; Enantiomeric excess of the product was determined by chiral
stationary phase HPLC analysis using a ChiralPak AD-H column
(hexane/i-PrOH = 95:5 at 0.8 mL/min); λ = 254 nm; t major = 40.2 min,
mL/min); λ = 254 nm; t
= 23.9 min, t
= 26.6 min; HRMS
major
minor
(ESI): Calcd for C12H12O3Na [M+Na]+: 227.0679, Found: 227.0683.
t
= 46.2 min; HRMS (ESI): Calcd for C11H9ClO3Na [M+Na]+:
minor
(R)-5-((S)-hydroxy(4-methoxyphenyl)methyl)furan-2(5H)-one (14f).
5a, 5b
247.0132, Found: 247.0123.
According to the general procedure, 4-methoxybenzaldehyde 12f
(24.2 µL, 0.2 mmol) afforded product 14f (20.9 mg, 47%) as a white
1
(R)-5-((S)-(4-bromophenyl)(hydroxy)methyl)furan-2(5H)-one
solid, (anti/syn = 88:12) (92% ee); H NMR (400 MHz, CDCl3): δ =
3a, 5a, 5b
(14b).
According to the general procedure, 4-
2.69 (br d, J = 3.2 Hz, 1H, anti), 2.92 (br s, 1H, syn), 3.82 (s, 3H, syn,
anti), 5.65 (d, J = 7.0 Hz, 1H, syn), 5.00 (br dd, J = 3.2 Hz, 2.8 Hz,
1H, anti), 5.13-5.16 (m, 1H, syn, anti), 6.11 (dd, J = 5.8 Hz, 2.0 Hz,
1H , syn), 6.16 (dd, J = 5.8 Hz, 2.0 Hz, 1H, anti), 6.90-6.94 (m, 2H,
syn, anti), 7.16 (dd, J = 5.8 Hz, 1.6 Hz, 1H, syn), 7.28-7.33 (m, 2H,
syn, anti), 7.38 (dd, J = 5.8 Hz, 1.5 Hz, 1H, anti); 13C NMR (100
MHz, CDCl3) anti diastereomer: δ = 55.4, 73.0, 86.8, 114.2, 123.2,
127.5, 130.5, 153.2, 159.8, 173.2, syn diastereomer: δ =75.3, 87.2,
123.0, 128.1, 130.0, 153.4, 160.1, 172.8; Enantiomeric excess of the
product was determined by chiral stationary phase HPLC analysis
using a ChiralPak AD-H column (hexane/i-PrOH = 90:10 at 1.0
bromobenzaldehyde 12b (37.0 mg, 0.2 mmol) afforded product 14b
(46.8 mg, 87%) as a white solid, (anti/syn = 93:7) (94% ee); 1H NMR
(400 MHz, CDCl3): δ = 3.15 (br d, J = 3.0 Hz, 1H, anti), 3.24 (br s,
1H, syn), 4.74 (d, J = 6.6 Hz, 1H, syn), 5.05 (br dd, J = 3.4 Hz, 3.0
Hz, 1H, anti), 5.13-5.15 (m, 1H, syn, anti), 6.11-6.13 (m, 1H, syn),
6.17 (dd, J = 5.8 Hz, 1.9 Hz, 1H, anti), 7.20-7.22 (m, 1H, syn), 7.24-
7.29 (m, 2H, syn, anti), 7.32 (dd, J = 1.5 Hz, 5.8 Hz, 1H, anti) 7.50-
7.55 (m, 2H, syn, anti); 13C NMR (100 MHz, CDCl3) anti diastere-
omer: δ = 72.5, 86.5, 122.5, 123.5, 127.9, 132.0, 152.8, 173.2, syn
diastereomer: δ = 74.7, 86.6, 123.0, 123.3, 128.5, 136.9, 153.1, 172.7;
Enantiomeric excess of the product was determined by chiral station-
ary phase HPLC analysis using a ChiralPak AD-H column (hexane/i-
mL/min); λ = 254 nm; t
= 17.5. min, t
= 20.5 min; HRMS
minor
major
(ESI): Calcd for C12H12O4Na [M+Na]+: 243.0628, Found: 243.0629.
PrOH = 95:5 at 0.8 mL/min); λ = 254 nm; t
= 40.2 min, t
=
minor
major
46.2 min; HRMS (ESI): Calcd for C11H9BrO3Na [M+Na]+: 290.9627,
Found: 290.9630.
3a, 5a, 5b
(R)-5-((S)-hydroxy(phenyl)methyl)furan-2(5H)-one (14g).
According to the general procedure, benzaldehyde 12g (20.3 µL, 0.2
mmol) afforded product 14g (34.9 mg, 92%) as a white solid, (an-
ti/syn = 87:13) (93% ee); 1H NMR (400 MHz, CDCl3): δ = 2.52 (d, J
= 3.6 Hz, 1H, anti), 2.79 (d, J = 2.4 Hz, 1H, syn), 4.70-4.72 (m, 1H,
syn), 5.10. (dd, J = 3.6 Hz, 4.0 Hz, 1H, anti), 5.16-5.20 (m, 1H, syn,
anti), 6.13 (dd, J = 5.8 Hz, 2.0 Hz, 1H, syn), 6.18 (dd, J = 5.7 Hz, 2.0
Hz, 1H, anti), 7.17 (dd, J = 5.8 Hz, 1.6 Hz, 1H, syn), 7.34-7.44 (m,
6H); 13C NMR (100 MHz, CDCl3) anti diastereomer: δ = 73.1, 86.8,
123.3, 126.1, 128.6, 128.9, 138.4, 153.0, 173.3, syn diastereomer: δ =
75.7, 87.1, 123.0, 126.8, 129.1, 137.9, 153.4, 172.8; Enantiomeric
excess of the product was determined by chiral stationary phase
HPLC analysis using a ChiralPak AS-H column (hexane/i-PrOH =
(R)-5-((S)-hydroxy(4-(trifluoromethyl)phenyl)methyl)furan-2(5H)-
5b
one (14c).3a,
According to the general procedure, 4-
(trifluoromethyl)benzaldehyde 12c (26.8 µL, 0.2 mmol) afforded
product 14c (50.1 mg, 97%) as a white solid, (anti/syn = 91:9) (91%
1
ee); H NMR (400 MHz, CDCl3): δ = 2.76 (d, J = 3.7 Hz, 1 H, anti),
2.91-2.95 (m, 1H, syn), 4.84-4.88 (m, 1H, syn), 5.15-5.20 (m, 2 H),
6.15 (dd, J = 5.8 Hz, 2.0 Hz, 1H, syn), 6.21 (dd, J = 5.8 Hz, 1.8 Hz,
1H, anti), 7.22-7.24 (m, 1H, syn), 7.31 (dd, J = 5.8 Hz, 1.4 Hz, 1H,
anti) 7.51-7.56 (m, 2H, syn, anti), 7.65-7.69 (m, 2H, syn, anti); 13C
NMR (100 MHz, CDCl3) anti diastereomer: δ = 72.6, 86.4, 123.6,
1
3
124.0 (q, JC-F = 272 Hz), 125.8 (q, JC-F = 3.7 Hz), 126.6, 130.8 (q,
2JC-F = 32.3 Hz), 142.5, 152.6, 173.2, syn diastereomer: δ = 74.6, 86.5,
123.4, 128.1, 152.9, ; Enantiomeric excess of the product was deter-
mined by chiral stationary phase HPLC analysis using a ChiralPak
AS-H column (hexane/i-PrOH = 90:10 at 1.0 mL/min); λ = 254 nm; t
90:10 at 1.0 mL/min); λ = 254 nm; t
= 31.2 min, t
= 75.0.
minor
major
min; HRMS (ESI): Calcd for C11H10O3Na [M+Na]+: 213.0522,
Found: 213.0531.
(R)-5-((S)-hydroxy(naphthalen-2-yl)methyl)furan-2(5H)-one (14h).
3a, 5a, 5b According to the general procedure, 2-nafthaldehyde 12h (31.2
mg, 0.2 mmol) afforded product 14h (34.9 mg, 73%) as a white solid,
= 18.6 min, t
= 29.3 min; HRMS (ESI): Calcd for
minor
major
C12H9F3O3Na [M+Na]+: 281.0396, Found: 281.0404.
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The Journal of Organic Chemistry
1
(anti/syn = 82:18) (89% ee); H NMR (400 MHz, CDCl3): δ = 2.71
(d, J = 3.4 Hz, 1H, anti), 2.95 (d, J = 3.0 Hz, 1H, syn), 4.87 (dd, J =
7.0 Hz, 3.0 Hz, 1H, syn), 5.24-5.29 (m, 2 H), 6.12 (dd, J = 5.8 Hz, 2.0
Hz, 1H, syn), 6.19 (dd, J = 5.8 Hz, 1.5 Hz, 1H, anti), 7.18 (dd, J = 5.8
Hz, 1.5 Hz, 1H, syn), 7.34 (dd, J = 5.8 Hz, 1.3 Hz, 1H, anti), 7.46-
7.54 (m, 3H, syn, anti), 7.85-7.90 (m, 4H, syn, anti); 13C NMR (100
MHz, CDCl3) anti diastereomer: δ = 73.3, 86.6, 123.4, 123.6, 125.4,
126.6, 126.7, 127.9, 128.2, 128.8, 133.3, 133.4, 135.7, 152.8, 173.0,
syn diastereomer: δ = 76.0, 87.1, 123.2, 124.2, 125.4, 128.2, 128.9,
135.2, 153.2; Enantiomeric excess of the product was determined by
chiral stationary phase HPLC analysis using a ChiralPak AD-H col-
The authors would like to thank Enago (www.enago.jp) for the
English language review.
1
2
3
4
5
6
7
8
REFERENCES
(1) For selected examples, see: (a) Negishi, E.; Kotora, M.
Tetrahedron 1997, 53, 6707–6738. (b) Fukushima, T.; Tanaka, M.;
Gohbara, M.; Fujimori, T. Phytochemistry 1998, 48, 625–630. (c)
Murakami, T.; Morikawa, Y.; Hashimoto, M.; Okuno, T.; Harada, Y.
Org. Lett. 2004, 6, 157–160. (d) Li, Y.; Zhang, D.-M.; Li, J.-B.; Yu,
S.-S.; Li, Y.; Luo, Y.- M. J. Nat. Prod. 2006, 69, 616–620.
(2) For reviews on asymmetric vinylogous aldol reactions, see: (a)
Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem.
Rev. 2011, 111, 3076–3154. (b) Pansare, S. V.; Paul, E. K. Chem.
Eur. J. 2011, 17, 8770–8779. (c) Bisai, V. Synthesis 2012, 44, 1453–
1463. (d) Miao, Z.; Chen, F. Synthesis 2012, 44, 2506–2514.
(3) For selected recent examples, see: (a) Singh, R. P.; Foxman, B.
M.; Deng, L. J. Am. Chem. Soc. 2010, 132, 9558–9560. (b) Curti, C.;
Ranieri, B.; Battistini, L.; Rassu, G.; Zambrano, V.; Pelosi, G.;
Casiraghi, G.; Zanardi, F. Adv. Synth. Catal. 2010, 352, 2011–2022.
(c) Curti, C.; Brindani, N.; Battistini, L.; Sartori, A.; Pelosi, G.; Mena,
P.; Brighenti, F.; Zanardi, F.; Rio, D. D. Adv. Synth. Catal. 2015, 357,
4082–4092.
9
umn (hexane/i-PrOH = 90:10 at 1.0 mL/min); λ = 254 nm; t
=
major
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15.8. min, t
= 20.5 min; HRMS (ESI): Calcd for C15H12O3Na
minor
[M+Na]+: 263.0679, Found: 263.0662.
(R)-5-((S)-hydroxy(naphthalen-1-yl)methyl)furan-2(5H)-one
(14i).17b According to the general procedure, 1-nafthaldehyde 12i (
µL, 0.2 mmol) afforded product 14i (27.2 µL, 91%) as a white solid,
1
(anti/syn = 88:12) (91% ee); H NMR (400 MHz, CDCl3): δ = 2.71
(br d, J = 3.5 Hz, 1H, anti), 3.00-3.01 (m, 1H, syn), 5.37-5.40 (m, 1H,
syn), 5.43-5.44 (m, 1H, anti), 5.99 (br dd, J = 3.5 Hz, 3.2 Hz, 1 H,
anti), 6.14 (ddd, J = 5.8 Hz, 2.0Hz, 0.9 Hz 1H, syn), 6.20 (ddd, J =
5.8 Hz, 2.0Hz, 0.4 Hz 1H, anti), 6.95 (dd, J = 5.8 Hz, 1.5 Hz, 1H,
syn), 7.26 (dd, J = 5.8 Hz, 1.3 Hz, 1H, anti), 7.52-7.62 (m, 3H, syn,
anti), 7.73-7.78 (m, 1H, syn, anti), 7.87-7.94 (m, 2H, syn, anti), 7.97-
8.03 (m, 1H, syn, anti); 13C NMR (100 MHz, CDCl3) anti diastere-
omer: δ = 69.6, 85.7, 122.2, 123.3, 124.1, 125.7, 126.1, 127.0, 129.1,
129.3, 130.0, 133.7, 133.8, 153.0, 173.3, syn diastereomer: δ = 87.7,
122.8, 122.9, 125.3, 125.6, 126.1, 126.8, 129.3, 129.6, 130.5, 133.9,
153.6; Enantiomeric excess of the product was determined by chiral
stationary phase HPLC analysis using a ChiralPak AD-H column
(4) (a) Ube, H.; Shimada, N.; Terada, M. Angew. Chem. Int. Ed.
2010, 49, 1858–1861. (b) Mirabdolbaghi, R.; Hassan, M.; Dudding,
T. Tetrahedron: Asymmetry 2015, 26, 560–566.
(5) (a) Yang, Y.; Zheng, K.; Zhao, J.; Shi, J.; Lin, L.; Liu, X.;
Feng, X. J. Org. Chem. 2010 , 75, 5382–5384. (b) Pansare, S. V.;
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Commun. 2008, 1431-1433. For review, see: (b) Fang, X.; Wang, C.-J.
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M.; Tada, N.; Imai, N.; Itoh, A. Org. Lett. 2010, 12, 1620-1623. (c)
Miura, T.; Ina, M.; Imai, K.; Nakashima, K.; Masuda, A.; Imai, N.;
Tada, N.; Itoh, A. Synlett 2011, 410-414. (d) Miura, T.; Ina, M.; Imai,
K.; Nakashima, K.; Yasaku, Y.; Koyata, N.; Murakami, Y.; Imai, N.;
Tada, N.; Itoh, A. Tetrahedron: Asymmetry 2011, 22, 1028-1034. (e)
Miura, T.; Imai, K.; Kasuga, H.; Ina, M.; Tada, N.; Imai, N.; Itoh, A.
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2209-2213.
(hexane/i-PrOH = 90:10 at 1.0 mL/min); λ = 254 nm; t
= 13.7.
major
min, t minor = 15.6 min; HRMS (ESI): Calcd for C15H12O3Na [M+Na]+:
263.0679, Found: 263.0681.
(R)-5-((S)-cyclohexyl(hydroxy)methyl)furan-2(5H)-one (14j).3a, 5a, 5b
According to the general procedure, cyclohexanecalbaldehyde 12j
(24.2 µL, 0.2 mmol) afforded product 14j (19.5 mg, 50%) as a white
1
solid, (anti/syn = 89:11) (94% ee); H NMR (400 MHz, CDCl3): δ =
1.06-1.36 (m, 5 H, syn, anti), 1.58-1.83 (m, 6H), 2.19 (br, 1H, anti),
3.45-3.49 (m, 1 H, syn), 3.61 (dd, J = 5.9 Hz, 5.7 Hz, 1H, anti), 5.11
(ddd, J = 5.7 Hz, 1.8 Hz, 1.6 Hz, 1H, anti), 5.18-5.20 (m, 1 H, syn),
6.16-6.17 (m, 1 H, syn), 6.19 (dd, J = 5.8 Hz, 1.8 Hz, 1H, anti), 7.45-
7.48 (m, 1 H, syn), 7.60 (dd, J = 5.8 Hz, 1.6 Hz, 1H, anti); 13C NMR
(100 MHz, CDCl3) anti diastereomer: δ = 25.8, 26.1, 26.3, 27.9, 29.4,
40.7, 75.7, 83.9, 122.8, 154.5, 173.3, syn diastereomer: δ = 25.9, 26.1,
26.2, 28.6, 29.6, 41.4, 75.8, 84.2, 122.5, 154.8; Enantiomeric excess
of the product was determined by chiral stationary phase HPLC anal-
ysis using a ChiralPak AS-H column (hexane/i-PrOH = 80:20 at 1.0
mL/min); λ = 220 nm; t
= 7.6 min, t
= 13.0 min; HRMS
minor
major
(ESI): Calcd for C11H16O3Na [M+Na]+: 219.0992, Found: 219.0990.
ASSOCIATED CONTENT
(10) (a) Miura, T.; Yuasa, H.; Murahashi, M.; Ina, M.; Nakashima,
K.; Tada, N.; Itoh, A. Synlett 2012, 23, 2385-2388. (b) Nakashima,
K.; Murahashi, M.; Yuasa, H.; Ina, M.; Tada, N.; Itoh, A.; Hirashima,
S.; Koseki, Y.; Miura, T. Molecules 2013, 18, 14529-14542.
(11) (a) Kamito, Y.; Masuda, A.; Yuasa, H.; Tada, N.; Itoh, A.;
Koseki, Y.; Miura, T. Chem. Lett. 2013, 42, 1151-1153. (b) Kamito,
Y.; Masuda, A.; Yuasa, H.; Tada, N.; Itoh, A.; Nakashima, K.;
Hirashima, S.; Koseki, Y.; Miura, T. Tetrahedron: Asymmetry 2014,
25, 974-979.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Spectra data, and copies of all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
(12) Gao, Y.; Du, D.-M. Tetrahedron: Asymmetry 2013, 24, 1312-
1317.
* E-mail: tmiura@toyaku.ac.jp
* E-mail: hirashim@toyaku.ac.jp
(13) Bae, H. Y.; Some, S.; Lee, J. H.; Kim, J.-Y.; Song, M. J.; Lee,
S.; Zhang, Y. J.; Song, C. E. Adv. Synth. Catal. 2011, 353, 3196-3202.
(14) (a) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett.
2005, 7, 1967-1969. (b) Oliva, C. G.; Silva, A. M. S.; Resende, D. I.
ACKNOWLEDGMENT
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