Asymmetric Conjugate Addition of α-Cyanoketones to Enones Using Diaminomethylenemalononitrile Organocatalyst

Article abstract of DOI:10.1021/acs.joc.7b02976

A diaminomethylenemalononitrile organocatalyst efficiently catalyzed the asymmetric conjugate addition of α-cyanoketones to vinyl ketones to give the corresponding 1,5-dicarbonyl compounds, which bear an all-carbon quaternary stereogenic center with high enantioselectivities. This report is the first example of the asymmetric conjugate addition of α-cyanoketones to vinyl ketones using an organocatalyst.

Full text of DOI:10.1021/acs.joc.7b02976

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Note
Asymmetric conjugate addition of #-cyanoketones to enones
using diaminomethylenemalononitrile organocatalyst
Kosuke Nakashima, Yuta Noda, Shin-ichi Hirashima, Yuji Koseki, and Tsuyoshi Miura
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02976 • Publication Date (Web): 15 Jan 2018
Downloaded from http://pubs.acs.org on January 15, 2018
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Asymmetric conjugate addition of α-cyanoketones to enones using
diaminomethylenemalononitrile organocatalyst
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Kosuke Nakashima, Yuta Noda, Shinꢀichi Hirashima, Yuji Koseki, Tsuyoshi Miura*
Tokyo University of Pharmacy and Life Sciences, 1432ꢀ1 Horinouchi, Hachioji, Tokyo 192ꢀ0392, Japan
ABSTRACT: A diaminomethylenemalononitrile organocatalyst efficiently catalyzed the asymmetric conjugate addition of αꢀ
cyanoketones to vinyl ketones to give the corresponding 1,5ꢀdicarbonyl compounds, which bear an allꢀcarbon quaternary stereogenꢀ
ic center, with high enantioselectivities. This report is the first example of the asymmetric conjugate addition of αꢀcyanoketones to
vinyl ketones using an organocatalyst.
Highly functionalized allꢀcarbon quaternary stereogenic cenꢀ
ters are ubiquitous as molecular skeletons in many natural
products and biologically active compounds. However, highly
reactive reagents and harsh conditions are required to conꢀ
struct them owing to steric hindrance.1 Therefore, the develꢀ
opment of efficient synthesis methodologies for the construcꢀ
tion of allꢀcarbon quaternary stereogenic centers under mild
reaction conditions is one of the most significant themes of
research in modern organic chemistry. Asymmetric conjugate
addition using a Michael donor bearing an active methine
group is an effective method for the construction of allꢀcarbon
quaternary stereogenic centers. In particular, the construction
of such centers using organocatalysts has been found to be
remarkably attractive with benefits such as environmentally
benign properties and mild reaction conditions.2 Among variꢀ
ous Michael donors with active methine groups, αꢀalkylated
αꢀcyanoketones are valuable because the corresponding conꢀ
jugate adducts, which bear a highly functionalized allꢀcarbon
quaternary stereogenic center, are versatile synthetic intermeꢀ
diates. However, catalytic asymmetric conjugate additions
using αꢀcyanoketones as Michael donors are scarce. In particꢀ
ular, asymmetric conjugate additions of αꢀcyanoketones using
organocatalysts are relatively rare.3 Chiral 1,5ꢀdicarbonylꢀ2ꢀ
cyano derivatives obtained by the asymmetric conjugate addiꢀ
tion of αꢀcyanoketones to aromatic vinyl ketones are valuable
building block because they can be easily transformed to enanꢀ
tioenriched spiroꢀpiperidine and bicycle[3.3.0]octane motif,
however, there has been only one pioneering example of the
asymmetric conjugate addition using a chiral yttrium catalyst
for access to chiral 1,5ꢀdicarbonylꢀ2ꢀcyano compounds, as
reported by Shibasaki et al. (Scheme 1)4 To the best of our
knowledge, there has been no report of the asymmetric conjuꢀ
gate addition of an αꢀcyanoketone to an aromatic vinyl ketone
using an organocatalyst under metalꢀfree conditions. Thereꢀ
fore, the development of the asymmetric conjugate addition of
αꢀcyanoketones to enones using an organocatalyst is highly
desirable from the viewpoint of green chemistry.
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On the other hand, thiourea and squaramide groups, which act
Page 2 of 7
Next, we examined the asymmetric conjugate addition using 7
in a representative range of solvents (Table 2). Toluene was
found to be the most suitable among the examined solvents,
and the enantioselectivity was increased to 89% ee (entries 1–
5). When the conjugate addition using 7 was carried out at
1
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4
5
6
7
8
as double hydrogenꢀbond donors, are excellent motifs for
asymmetric organocatalysis, and a number of significant
asymmetric reactions using chiral organocatalysts bearing
thiourea and squaramide groups have been reported by several
research groups.5,6 Recently, we developed organocatalysts
bearing a diaminomethylenemalononitrile (DMM) motif as a
double hydrogenꢀbond donor and reported their high catalytic
activities in various asymmetric reactions.7 In this context, to
further demonstrate the effectiveness of organocatalysts bearꢀ
ing a DMM unit, we attempted the construction of allꢀcarbon
quaternary stereogenic centers by the asymmetric conjugate
addition of αꢀcyanoketones to vinyl ketones using DMM orꢀ
ganocatalysts.
°
lower temperatures (−60 and −80 C), this resulted in decreasꢀ
es in enantioselectivity and yield (entries 6 and 7). To further
increase the stereoselectivity, we examined the concentration
of the reaction medium (entries 8–10). When the reaction was
performed in more dilute solvents, the enantioselectivity tendꢀ
ed to increase and reached a maximum at a solvent concentraꢀ
tion of 0.2 or 0.3 M (entries 9 and 10). The optimal conditions
for the reaction were determined to be as follows: organocataꢀ
lyst 7 at −50 °C in toluene (0.3 M).
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Firstly, quinine (1), thiourea derivative 2, and DMM catalysts
(3 and 4) bearing a chiral cinchona motif (Figure 1) were exꢀ
amined as catalysts for the conjugate addition of 2ꢀ
oxocyclopentaneꢀ1ꢀcarbonitrile (10a) to 1ꢀphenylpropꢀ2ꢀenꢀ1ꢀ
one (11a) as test reactants at room temperature in CH2Cl2 (Taꢀ
ble 1). Among the four examined catalysts, 4 was preferred for
this conjugate addition to afford the corresponding adduct
12aa, as it gave an enantiomeric excess (ee) of 54% (entries
1–4). Therefore, it was found that the DMM skeleton was a
preferable motif for the organocatalytic reaction between 10a
and 11a in comparison with the thiourea derivative 2. When
°
the reaction using 4 was carried out at −50 C, both the yield
and the enantioselectivity were increased (entry 5). The use of
the organocatalyst 5, which bears a simple benzylamine motif,
resulted in lower enantioselectivity (entry 6). The organocataꢀ
lyst 6, which bears an nꢀbutylamine group instead of a benzylꢀ
amine group, was a good catalyst for the conjugate addition
and provided higher stereoselectivity (entry 7). Organocataꢀ
lysts with alkyl groups of different lengths, namely, nꢀpropyl,
ethyl, and methyl groups, were examined, and it was found
that the organocatalyst 7, which bears an nꢀpropyl group, was
the most effective (entries 8–10).
NC
CN
N
N
N
S
F3C
F3C
HO
N
H
N
N
H
N
H
Table 2. Study of reaction conditionsa
H
N
N
N
O
catalyst 7
(10 mol%)
O
CF3
CF3
O
MeO
MeO
MeO
O
3
2
CN
1
Ph
+
Ph
CN
12aa
solvent (M), 24 h
temp. (°C)
11a
10a
NC
CN
NC
CN
NC
nBu
CN
% yieldb
% eec
N
N
N
entry
solvent (M)
N
H
N
H
N
H
N
H
N
N
H
CH2Cl2 (1.0)
THF (1.0)
1
2
-50
-50
-50
-50
-50
-60
-80
-50
-50
-50
86
46
59
43
86
85
55
94
88
86
83
59
67
28
89
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94
H
N
N
N
MeO
MeO
MeO
3
EtOAc (1.0)
hexane (1.0)
toluene (1.0)
toluene (1.0)
toluene (1.0)
toluene (0.5)
toluene (0.3)
toluene (0.2)
4
6
5
4
5
NC
CN
NC
CN
NC
Me
CN
N
N
N
6
nPr
Et
N
H
N
H
N
N
H
N
N
H
H
H
7
N
N
N
8
MeO
MeO
MeO
7
8
9
9
10
a
Figure 1. Structure of organocatalysts
10a
11a
7
(0.2 mmol), catalyst
(10 mol %), 24 h. b Isolated yield. c Determined by chiral HPLC
Reaction conditions:
(0.2 mmol),
analysis.
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Once the optimal conditions had been determined, we examꢀ
ined the scope and limitations of the asymmetric conjugate
addition of various αꢀcyanoketones 10 to various vinyl keꢀ
tones 11 (Table 3). Aromatic vinyl ketones 11b–11f, which
bear methyl and methoxy substituents as representative elecꢀ
tronꢀdonating groups on the benzene ring, reacted with the
cyclic αꢀcyanoketone 10a in the presence of the organocataꢀ
lyst 7 to afford the corresponding adducts 12aa–12af in high
yields with high enantioselectivities (entries 2–6). The conjuꢀ
gate addition of 10a to the vinyl ketones 11g and 11h, which
bear nitro and bromosubstituents, respectively, as representaꢀ
tive electronꢀwithdrawing groups, afforded the addition prodꢀ
ucts 12ag and 12ah, respectively, with excellent enantioselecꢀ
tivities (entries 7 and 8). The reaction of 1ꢀ(naphthalenꢀ2ꢀ
yl)propꢀ2ꢀenꢀ1ꢀone (11i) with 10a also proceeded well and
afforded the adduct 12ai with high enantioselectivity (entry 9).
The ketone 11j, as a representative aliphatic vinyl ketone, was
a poor substrate and gave a low yield (entry 10). 2ꢀ
Oxocyclohexaneꢀ1ꢀcarbonitrile (10b), as a representative cyꢀ
clic αꢀcyanoketone with a different ring size, reacted with 11a
and 11i to give the adducts 12ba and 12bi, respectively, with
excellent enantioselectivities (entries 11 and 12). In the previꢀ
ous report by Shibasaki et al., 2ꢀmethylꢀ3ꢀoxoꢀ3ꢀ
phenylpropanenitrile (10c), as a representative linear αꢀ
cyanoketone, was a poor substrate for asymmetric conjugate
addition using a rare earth catalyst and gave low yields and
low enantioselectivities.4 However, the reaction of 10c with
11a using the organocatalyst 7 afforded the corresponding
addition product 12ca in good yield with high enantioselectiviꢀ
ty (entry 13). The conjugate addition of 10a to 11k, which
bears a thiophene ring, provided the adduct 12ak in excellent
yield with excellent enantioselectivity (entry 14). (E)ꢀ1ꢀ
phenylbutꢀ2ꢀenꢀ1ꢀone (11l) was poor substrate to provide low
yield and low stereoselectivities (entry 15). The stereochemisꢀ
try of the products was determined by comparison with reportꢀ
ed chiralꢀphase HPLC retention times and optical rotations.
The products were selectively obtained with the opposite steꢀ
reochemistry (S configuration) in comparison with the stereoꢀ
chemistry (R configuration) reported by Shibasaki et al.4
5
6
7
8
Experimental Section
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
1
III Nanobay 400 MHz spectrometer (400 MHz for H NMR and 100
MHz for 13C NMR). The chemical shifts are expressed in ppm downꢀ
field from tetramethylsilane (δ = 0.00) as an internal standard. Mass
spectra were recorded by an electrospray ionizationꢀtime of flight
(ESIꢀTOF) mass spectrometer (Micromass LCT). Specific rotations
were measured on a Jasco Pꢀ1030. Melting points were obtained with
Yanaco MPꢀJ3 and are uncorrected. For thin layer chromatographic
(TLC) analyses, Merck precoated TLC plates (silica gel 60 F254) were
used. Flash column chromatography was performed on neutral silica
gel (Kanto Silica gel 60N, 40–50 ꢁm). Organocatalyst 2 was prepared
by reported method.9
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Preparation of organocatalysts 3–9
To a stirred solution of 2ꢀ(bis(methylthio)methylene)malononitrile10
(1.31 g, 7.7 mmol) in THF (29 mL) was added (S)ꢀ(6ꢀ
methoxyquinolinꢀ4ꢀyl)((1S,2S,4S,5R)ꢀ5ꢀvinylquinuclidinꢀ2ꢀ
yl)methanamine11 (2.48 g, 7.7 mmol). The mixture was stirred under
reflux for 21 h. TLC indicated the reaction was completed, the reacꢀ
tion mixture was cool to room temperature. The solvent was removed
under reduced pressure and the residue was purified by flash column
chromatography on silica gel with a mixture of CHCl3 and MeOH
affording the crude monoꢀamine products. To a stirred solution of the
crude monoꢀamine products (1.34 g, 3.0 mmol) in THF (11.4 mL)
was added the corresponding amine (6.0 mmol). The mixture was
stirred under reflux for 24 h. TLC indicated the reaction was completꢀ
ed, the reaction mixture was cool to room temperature. The solvent
was removed under reduced pressure and the residue was purified by
flash column chromatography on silica gel with a mixture of CHCl3
and MeOH affording the compound.
Organocatalyst 3
Yellow powder (817.5 mg, 43%); mp 105ꢀ108 °C; [α]27 = ꢀ95.3 °(c
D
1
1.0, CHCl3); H NMR (400 MHz, CDCl3): δ = 0.71 (t, J = 10.8 Hz,
1H), 0.88 (m, 1H), 1.24ꢀ1.35 (m, 2H), 1.46ꢀ1.52 (m, 2H), 1.65 (br s,
1H), 2.10ꢀ2.17 (m, 1H), 2.27 (br s, 1H), 2.81 (br d, J = 12.2 Hz, 2H),
2.93 (dd, J = 13.8, 9.9 Hz, 1H), 3.95 (s, 3H), 4.52 (br d, J = 12.7 Hz,
1H), 4.71 (br d, J = 14.4 Hz, 1H), 4.99ꢀ5.03 (m, 2H), 5.16 (br s, 1H),
5.64ꢀ5.72 (m, 1H), 7.18 (d, J = 2.6 Hz, 1H), 7.23 (br s, 1H), 7.42 (br
d, J = 8.3 Hz, 1H), 7.65 (s, 2H), 7.87 (s, 1H), 8.05 (br s, 1H), 8.66ꢀ
8.83 (br m, 1H); 13C NMR (100 MHz, CDCl3): δ =25.5, 26.9, 27.2,
35.4, 38.8, 40.2, 47.8, 53.4, 54.5, 55.6, 63.4, 100.5, 115.3, 117.7,
118.3, 122.2, 122.4, 122.9 (q, 1JCꢀF = 272.9 Hz ), 128.2, 132.5 (q, 2JCꢀF
= 33.6 Hz), 132.6, 138.8, 140.4, 141.8, 144.8, 145.4, 147.7, 158.6,
163.7; HRMS (ESIꢀTOF):Calcd for C33H31N6OF6 (M+H)+: 641.2464,
Found: 641.2471.
Although no experimental data that indicated the reaction
mechanism were obtained, we suggest that the two weakly
acidic protons of the DMM motif functioned as a hydrogenꢀ
bond donor to activate the carbonyl group of 11.8 The coordiꢀ
nation of the tertiary amine group in the quinine unit to the
enol generated from 10 resulted in highly efficient control of
the approach orientations of 10 and 11.
In conclusion, the DMM organocatalyst 7, which can be readiꢀ
ly prepared, efficiently promoted the asymmetric conjugate
addition of αꢀcyanoketones to aromatic vinyl ketones in toluꢀ
ene to afford the corresponding 1,5ꢀdicarbonyl compounds,
which bear an allꢀcarbon quaternary stereogenic center, in
high yields with excellent enantioselectivities. This report is
the first example of the asymmetric conjugate addition of αꢀ
cyanoketones to vinyl ketones using an organocatalyst. Further
applications of DMM catalysts to other types of asymmetric
reaction and the development of additional novel DMM orꢀ
ganocatalysts are currently being investigated in our laboratoꢀ
ry.
Organocatalyst 4
Orange powder (2.4 g, 85%); mp 125ꢀ127 °C; [α]29D = ꢀ168.8 °(c 1.0,
CHCl3); 1H NMR (400 MHz, CD3OD): δ = 0.93ꢀ0.98 (br m, 1H), 1.29
(s, 9H), 1.26ꢀ1.33 (m, 2H), 1.62 (br s, 3H), 2.31 (br s, 1H), 2.65 (br s,
1H), 2.79 (br d, J = 13.9, 1H), 3.08ꢀ3.23 (m, 3H), 3.96 (s, 3H), 4.32(d,
J = 14.4 Hz, 1H), 4.39 (d, J = 14.4 Hz, 1H), 4.93ꢀ5.01 (m, 2H), 5.70ꢀ
5.78 (m, 1H), 6.77 (br s, 2H), 7.19 (br d, J = 6.6 Hz, 2H), 7.29 (br s,
1H), 7.47 (dd, J = 9.2, 2.2 Hz, 1H), 7.58 (br s, 1H), 8.00 (d, J = 9.3
Hz, 1H), 8.56 (d, J = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
=25.6, 27.1, 27.4, 31.3, 34.6, 34.9, 39.1, 39.9, 48.6, 53.0, 54.9, 55.7,
63.1, 100.7, 115.0, 118.1, 118.6, 122.4, 125.9, 127.8, 132.5, 132.6,
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140.8, 142.4, 144.9, 147.7, 151.6, 158.4, 162.9; HRMS (ESIꢀ
13.3, 7.7 Hz, 1H), 1.33ꢀ1.40 (m, 1 H), 1.60ꢀ1.75 (m, 2H), 2.05 (s,
3H), 2.35 (br s, 1H), 2.82ꢀ2.89 (2H), 3.26ꢀ3.36 (m, 3H), 4.02 (s, 3H),
4.90 (d, J = 10.4 Hz, 1H), 5.00 (d, J = 17.1 Hz, 1H), 5.14 (br s, 1H),
5.55 (br s, 1H), 5.81(ddd, J = 17.4, 10.4, 7.2 Hz, 1H), 6.93 (br s, 1H),
7.14 (br s, 1H), 7.44 (dd, J = 9.2, 2.7 Hz, 1H), 7.64 (d, J = 4.5 Hz,
1H), 7.76 (br s, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.77 (d, J = 4.5 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ = 25.8, 27.2, 27.6, 31.2, 34.6,
39.2, 40.7, 53.8, 55.2, 56.0, 62.7, 101.2, 115.1, 118.3, 118.8, 122.3,
127.1, 132.4, 140.8, 142.7, 145.1, 147.7, 158.5, 164.5; HRMS (ESIꢀ
TOF):Calcd for C25H29N6O (M+H)+:429.2403, Found: 429.2399;
Anal. Calcd for C25H28N6O: C,70.07; H, 6.59; N,19.61. Found: C,
69.91; H, 6.60; N, 19.48.
TOF):Calcd for C35H41N6O (M+H)+: 561.3342, Found: 561.3316.
1
2
3
4
5
6
7
8
Organocatalyst 5
Yellow powder (158.8 mg, 63%); mp 100ꢀ103 °C; [α]29D = ꢀ184.8 °(c
1
1.0, CHCl3); H NMR (400 MHz, CD3OD): δ = 0.93ꢀ0.98 (m, 1H),
1.26ꢀ1.33 (m, 2H), 1.63 (br s, 3H), 2.32 (br s, 1H), 2.64ꢀ2.72 (m, 1H),
2.77ꢀ2.82 (m, 1H), 3.06ꢀ3.13 (br m, 1H), 3.06ꢀ3.24 (m, 2H), 3.98 (s,
3H), 4.35 (d, J =14.5 Hz, 1H), 4.46 (d, J =14.7 Hz, 1H), 4.93 (d, J =
10.4 Hz, 1H), 4.99 (d, J = 17.2 Hz, 1H), 5.75 (ddd, J = 17.2, 10.1, 7.3
Hz, 1H), 6.88 (br s, 2H), 7.17ꢀ7.24 (m, 3H), 7.29 (d, J =3.8 Hz, 1H),
7.47 (dd, J = 9.3, 2.6 Hz, 1H), 7.59 (br s, 1H), 7.99 (d, J = 9.2 Hz,
1H), 8.54 (d, J = 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 25.6,
27.1, 27.4, 34.9, 39.1, 40.0, 49.0, 53.2, 54.8, 55.7, 63.1, 100.7, 115.1,
118.1, 118.6, 122.3, 128.0, 128.4, 129.1, 132.5, 135.7, 140.7, 142.2,
145.1, 147.6, 158.5, 163.0; HRMS (ESIꢀTOF):Calcd for C31H33N6O
(M+H)+:505.2716, Found: 505.2725.
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Typical procedure for asymmetric conjugate addition and char-
acterization data of the products (12aa-12al).
To a solution of organocatalyst 7 (9.1 mg, 0.020 mmol), 1ꢀ
propenylpropꢀ2ꢀenꢀ1ꢀone (11a4, 26.4 mg, 0.20 mmol) in toluene (0.6
mL) were added 2ꢀoxocyclopentaneꢀ1ꢀcarbonitrile (10a4, 20.0 ꢁL,
0.20 mmol) at ꢀ50 °C for 24 h. The reaction mixture was directly
purified by flash column chromatography on silica gel with a 3:1
mixture of hexane and ethyl acetate to afford the pure 12aa (42.5 mg,
88%) as a white solid.
Oganocatalyst 6
White powder (215.2 mg, 91%); mp 93ꢀ94 °C; [α]29 = ꢀ191.7 °(c
D
1
1.0, CHCl3); H NMR (400 MHz, CDCl3): δ =0.73 (brs, 3H), 0.86ꢀ
1.12 (m, 6H), 1.39ꢀ1.44 (m, 1H), 1.63 (br s, 2H), 1.73 (br s, 1H), 2.35
(br s, 1H), 2.81ꢀ2.88 (br m, 2H), 3.04 (br s, 1H), 3.15ꢀ3.33 (m, 4H),
3.99 (s, 3H), 4.99 (d, J = 10.0 Hz, 1H), 5.01 (d, J = 17.0 Hz, 1H), 5.10
(br s, 1H), 5.66ꢀ5.74 (m, 1H), 6.40 (br s, 1H), 7.35 (br s, 2H), 7.47
(S)ꢀ2ꢀOxoꢀ1ꢀ(3ꢀoxoꢀ3ꢀphenylpropyl)cyclopentaneꢀ1ꢀcarbonitrile
(12aa)4. White solid, 42.5 mg, 88% yield (94% ee). 1H NMR (400
MHz, CDCl3): δ =2.07ꢀ2.18 (m, 4H), 2.32 (ddd, J = 5.6, 9.4, 14.6 Hz,
1H), 2.45ꢀ2.52 (m, 3H), 3.22 (ddd, J = 5.5, 9.5, 18.0 Hz, 1H), 3.41
(ddd, J = 5.6, 9.5, 18.0 Hz, 1H), 7.49 (dd, J = 7.8, 7.6 Hz, 2H), 7.57ꢀ
7.61 (m, 1H), 7.98 (dd, J = 1.3, 7.9 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ = 19.2, 28.0, 34.0, 35.2, 36.3, 47.9, 118.9, 128.1, 128.7,
133.5, 136.3, 198.0, 209.2; [α]29D = 9.0° (c 1.0, CHCl3); Enantiomeric
excess of the product was determined by chiral stationary phase
HPLC analysis using a CHIRALPAK IA column (hexane/iꢀPrOH =
90:10 at 1.0 mL/min); λ = 254 nm; t major = 16.2 min, t minor = 14.0
min.
(dd, J = 9.1, 1.7 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 8.81 (br s, 1H); 13
C
NMR (100 MHz, CDCl3): δ = 13.5, 19.6, 25.8, 27.2, 27.7, 31.6, 34.6,
39.3, 40.7, 44.6, 53.2, 55.3, 55.9, 63.0, 100.8, 115.2, 118.3, 119.2,
122.5, 127.2, 132.7, 140.9, 142.5, 145.1, 147.8, 158.7, 163.4; HRMS
(ESIꢀTOF):Calcd for C28H35N6O (M+H)+:471.2872, Found: 471.2872.
Oganocatalyst 7
Yellow powder (2.0 g, 99%); mp 234ꢀ236 °C; [α]29 = ꢀ200.5 °(c
D
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 0.62 (t, J =7.4 Hz, 3H),
0.87ꢀ0.91(m, 1H), 1.07ꢀ1.20 (m, 2H), 1.38ꢀ1.41 (m, 1H), 1.62 (br s,
2H), 1.72 (br s, 1H), 2.34 (br s, 1H), 2.80ꢀ2.87 (m, 2H), 3.09ꢀ3.14 (m,
3H), 3.21ꢀ3.27 (m, 2H), 3.99 (s, 3H), 4.98 (d, J = 13.0 Hz, 1H), 5.01
(d, J = 17.2 Hz, 1H), 5.26 (br s, 1H), 5.70 (br s, 1H), 6.80 (br s, 1H),
7.37 (d, J = 4.4 Hz, 1H), 7.39 (br s, 1H), 7.45 (dd, J = 9.2, 2.3 Hz,
1H), 8.08 (d, J = 9.2 Hz, 1H), 8.79 (br s, 1H); 13C NMR (100 MHz,
CDCl3): δ = 10.8, 22.8, 25.7, 27.2, 27.6, 34.4, 39.2, 40.6, 46.4, 53.2,
55.2, 55.9, 63.0, 100.7, 115.0, 118.4, 118.8, 122.4, 127.4, 132.5,
140.8, 142.6, 145.0, 147.7, 158.6, 163.3; HRMS (ESIꢀTOF):Calcd for
C27H33N6O (M+H)+:457.2716, Found: 457.2714. Anal. Calcd for
C27H32N6O: C,71.03; H, 7.06; N,18.41. Found: C, 70.92; H, 7.06; N,
18.14.
(S)ꢀ2ꢀOxoꢀ1ꢀ(3ꢀoxoꢀ3ꢀ(pꢀtolyl)propyl)cyclopentaneꢀ1ꢀcarbonitrile
(12ab) 4. White solid, 56.3 mg, 99% yield (88% ee). 1H NMR (400
MHz, CDCl3): δ =2.06ꢀ2.18 (m, 4H), 2.31 (ddd, J = 5.6, 9.4, 14.6 Hz,
1H), 2.42 (s, 3H), 2.44ꢀ2.53 (m, 3H), 3.19 (ddd, J = 5.5, 9.6, 18.0 Hz,
1H), 3.38 (ddd, J = 5.6, 9.6, 17.9 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H),
7.88 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 19.3, 21.8,
28.1, 33.9, 35.3, 36.4, 48.0, 119.0, 128.3, 129.5, 133.9, 144.5, 197.7,
209.3 [α]26D = 9.3° (c 1.0, CHCl3); Enantiomeric excess of the prodꢀ
uct was determined by chiral stationary phase HPLC analysis using a
ChiralCel ADꢀH column (hexane/iꢀPrOH = 90:10 at 1.0 mL/min); λ =
254 nm; t major = 16.7 min, t minor = 15.2 min.
(S)ꢀ2ꢀOxoꢀ1ꢀ(3ꢀoxoꢀ3ꢀ(mꢀtolyl)propyl)cyclopentaneꢀ1ꢀcarbonitrile
(12ac) 4. White solid, 45.3 mg, 89% yield (92% ee). 1H NMR (400
MHz, CDCl3): δ =2.04ꢀ2.17 (m, 4H), 2.32 (ddd, J = 5.6, 9.3, 14.6 Hz,
1H), 2.43 (s, 3H), 2.45ꢀ2.52 (m, 3H), 3.21 (ddd, J = 5.5, 9.5, 18.0 Hz,
1H), 3.40 (ddd, J = 5.5, 9.5, 18.0 Hz, 1H), 7.35ꢀ7.41 (m, 2H), 7.77ꢀ
7.78 (m, 2H); 13C NMR (100 MHz, CDCl3): δ = 19.2, 21.3, 28.0, 34.0,
35.2, 36.3, 47.9, 118.9, 125.3, 128.48, 128.53, 134.2, 136.3, 138.5,
198.1, 209.2; [α]26D = 8.2° (c 1.0, CHCl3); Enantiomeric excess of the
product was determined by chiral stationary phase HPLC analysis
using a ChiralCel ADꢀH column (hexane/iꢀPrOH = 90:10 at 1.0
mL/min); λ = 254 nm; t major = 15.3 min, t minor = 14.1 min.
Oganocatalyst 8
White powder (370.2 mg, 28%); mp 227ꢀ228 °C; [α]29D = ꢀ212.8 °(c
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ =0.82 (t, J =7.2 Hz, 3H),
0.87 (dd, J =13.5, 7.2 Hz, 1H), 1.38ꢀ1.44 (m, 1H), 1.61ꢀ1.65 (m, 2H),
1.74 (br s, 1H), 2.35 (br s, 1H), 2.81ꢀ2.88 (m, 2H), 3.05 (br s, 1H),
3.23ꢀ3.29 (m, 2H), 3.34ꢀ3.43 (m, 2H), 3.99 (s, 3H), 5.00 (d, J = 10.0
Hz, 1H), 5.02 (d, J = 17.2 Hz, 1H), 5.14 (br s, 1H), 5.66ꢀ5.75 (m, 1H),
6.69 (br s, 1H), 7.35 (br s, 2H), 7.47 (dd, J = 9.2, 2.2 Hz, 1H), 8.11 (d,
J = 9.2 Hz, 1H), 8.80 (br s, 1H) ; 13C NMR (100 MHz, CDCl3): δ =
14.5, 25.7, 27.1, 27.6, 34.4, 39.2, 39.6, 40.6, 53.2, 55.2, 55.9, 62.9,
100.8, 115.1, 118.3, 118.8, 122.4, 127.4, 132.5, 140.8, 142.6, 145.0,
147.7, 158.6, 163.2; HRMS (ESIꢀTOF):Calcd for C26H31N6O
(M+H)+:443.2559, Found: 443.2553; Anal. Calcd for C26H30N6O:
C,70.56; H, 6.83; N,18.99. Found: C,70.33; H, 6.87; N, 18.90.
(S)ꢀ1ꢀ(3ꢀ(3,4ꢀDimethylphenyl)ꢀ3ꢀoxopropyl)ꢀ2ꢀoxocyclopentaneꢀ1ꢀ
carbonitrile (12ad) 4. Colorless oil, 43.4 mg, 81% yield (91% ee). 1H
NMR (400 MHz, CDCl3): δ =2.06ꢀ2.17 (m, 4H), 2.27ꢀ2.35 (m, 1H),
2.33 (s, 6H), 2.43ꢀ2.51 (m, 3H), 3.18 (ddd, J = 5.5, 9.5, 17.9 Hz, 1H),
3.37 (ddd, J = 5.5, 9.5, 17.9 Hz, 1H), 7.23 (d, J = 7.8 Hz , 1H), 7.71
(dd, J = 1.7, 7.8 Hz, 1H), 7.74 (brs, 1H); 13C NMR (100 MHz,
CDCl3): δ = 19.2, 19.8, 20.0, 28.0, 33.8, 35.2, 36.3, 48.0, 119.0,
125.8, 129.2, 129.9, 134.3, 137.1, 143.1, 197.8, 209.2; [α]29D = 10.0°
(c 1.0, CHCl3); Enantiomeric excess of the product was determined by
Oganocatalyst 9
White powder (734.1 mg, 57%); mp: 223ꢀ226 °C; [α]29 = ꢀ156.1
D
1
°(c 1.0, CHCl3); H NMR (400 MHz, (CD3)2CO): δ =1.07 (dd, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 7
chiral stationary phase HPLC analysis using a CHIRALPAK IC colꢀ
umn (hexane/iꢀPrOH = 2:1 at 1.0 mL/min); λ = 254 nm; t major = 14.3
min, t minor = 15.8 min.
(S)ꢀ2ꢀOxoꢀ1ꢀ(3ꢀoxoꢀ4ꢀphenylbutyl)cyclopentaneꢀ1ꢀcarbonitrile (12aj)
4. White solid, 6.5 mg, 13% yield (65% ee). 1H NMR (400 MHz,
CDCl3): δ =1.87 (ddd, J = 5.8, 8.6, 14.5 Hz, 1H), 1.98ꢀ2.18 (m, 4H),
2.35ꢀ2.43 (m, 3H), 2.70 (ddd, J = 5.8, 8.7, 18.4 Hz, 1H), 2.90 (ddd, J
= 6.2, 8.6, 18.4 Hz, 1H), 3.74 (s, 2H), 7.20ꢀ7.36 (m, 5H); 13C NMR
(100 MHz, CDCl3): δ = 19.2, 27.6, 35.2, 36.3, 37.3, 47.8, 50.2, 118.8,
127.3, 128.9, 129.5, 133.7, 206.3, 209.2; [α]29D = ꢀ10.1° (c 0.25,
CHCl3); Enantiomeric excess of the product was determined by chiral
stationary phase HPLC analysis using a ChiralCel ADꢀH column
(hexane/iꢀPrOH = 90:10 at 0.8 mL/min); λ = 210 nm; t major = 22.9
min, t minor = 22.0min.
1
2
3
4
5
6
7
8
(S)ꢀ1ꢀ(3ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀoxopropyl)ꢀ2ꢀoxocyclopentaneꢀ1ꢀ
carbonitrile (12ae) 4. White solid, 47.8 mg, 88% yield (90% ee). 1H
NMR (400 MHz, CDCl3): δ =2.06ꢀ2.21 (m, 4H), 2.31 (ddd, J = 5.4,
9.4, 14.6 Hz, 1H), 2.42ꢀ2.52 (m, 3H), 3.17 (ddd, J = 5.6, 9.6, 17.7 Hz,
1H), 3.35 (ddd, J = 5.6, 9.6, 17.7 Hz, 1H), 3.38 (s, 3H), 6.95 (d, J =
8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
= 19.2, 28.0, 33.5, 35.2, 36.3, 47.9, 55.8, 113.8, 118.9, 129.4, 130.4,
163.8, 196.4, 209.1; [α]26D = 11.2° (c 1.0, CHCl3); Enantiomeric exꢀ
cess of the product was determined by chiral stationary phase HPLC
analysis using a ChiralCel ADꢀH column (hexane/iꢀPrOH = 90:10 at
1.0 mL/min); λ = 254 nm; t major = 35.6 min, t minor = 31.8 min.
9
(S)ꢀ2ꢀOxoꢀ1ꢀ(3ꢀoxoꢀ3ꢀphenylpropyl)cyclohexaneꢀ1ꢀcarbonitrile
(12ba). Colorless oil, 38.0 mg, 74% yield (94% ee). 1H NMR (400
MHz, CDCl3): δ =1.78ꢀ1.97 (m, 3H), 2.02ꢀ2.15 (m, 3H), 2.36ꢀ2.47
(m, 2H), 2.45ꢀ2.56 (m, 1H), 2.84 (ddd, J = 5.6, 11.3, 13.6 Hz, 1H),
3.16 (ddd, J = 5.1, 10.7, 17.6 Hz, 1H), 3.30 (ddd, J = 5.3, 10.9, 17.5
Hz, 1H),7.46ꢀ7.52 (m, 2H), 7.56ꢀ7.60 (m, 1H), 7.98 (d, J = 7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ = 22.0, 27.8, 28.1, 34.4, 39.1,
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
(S)ꢀ1ꢀ(3ꢀ(3ꢀMethoxyphenyl)ꢀ3ꢀoxopropyl)ꢀ2ꢀoxocyclopentaneꢀ1ꢀ
carbonitrile (12af)4. White solid, 54.1 mg, 99% yield (91% ee). 1H
NMR (400 MHz, CDCl3): δ =2.05ꢀ2.18 (m, 4H), 2.32 (ddd, J = 5.5,
9.3, 14.6 Hz, 1H), 2.45ꢀ2.52 (m, 3H), 3.20 (ddd, J = 5.5, 9.5, 18.0 Hz,
1H), 3.39 (ddd, J = 5.6, 9.5, 18.0 Hz, 1H), 3.87 (s, 3H), 7.12ꢀ7.15 (m,
1H), 7.39 (dd, J = 7.9, 7.9 Hz, 1H), 7.48ꢀ7.49 (m, 1H), 7.57 (d, J =
7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 19.2, 28.0, 34.1, 35.2,
36.3, 47.9, 55.5, 112.3, 118.9, 120.0, 120.7, 129.7, 137.7, 159.9,
197.8, 209.1; [α]27D = ꢀ2.0° (c 1.0, CH2Cl2); Enantiomeric excess of
the product was determined by chiral stationary phase HPLC analysis
using a ChiralCel ADꢀH column (hexane/iꢀPrOH = 90:10 at 0.8
mL/min); λ = 254 nm; t major = 29.7 min, t minor = 28.5 min.
39.3, 51.1, 119.6, 128.1, 128.7, 133.4, 136.4, 198.1, 203.2; [α]29
=
D
85.0° (c 1.0, CHCl3); HRMS (ESIꢀTOF): Calcd for C16H17NO2Na
(M+Na)+: 278.1157, Found: 278.1164; Enantiomeric excess of the
product was determined by chiral stationary phase HPLC analysis
using a CHIRALPAK IC column (hexane/iꢀPrOH = 90:10 at 0.8
mL/min); λ = 254 nm; t major = 33.8 min, t minor = 36.2 min.
(S)ꢀ1ꢀ(3ꢀ(naphthalenꢀ2ꢀyl)ꢀ3ꢀoxopropyl)ꢀ2ꢀoxocyclohexaneꢀ1ꢀ
carbonitrile (12bi) 4. Colorless oil, 46.0 mg, 60% yield (92% ee). 1H
NMR (400 MHz, CDCl3): δ =1.79ꢀ1.98 (m, 3H), 2.05ꢀ2.16 (m, 3H),
2.39ꢀ2.44 (m, 1H), 2.46ꢀ2.59 (m, 2H), 2.87 (ddd, J = 5.6, 11.2, 13.5
Hz, 1H), 3.30 (ddd, J = 5.1, 10.7, 17.4 Hz, 1H), 3.43 (ddd, J = 5.2,
10.9, 17.5 Hz, 1H), 7.55ꢀ7.64 (m, 2H), 7.87ꢀ7.92 (m, 2H), 7.99 (d, J =
8.0 Hz, 1H), 8.04 (dd, J = 1.5, 8.6 Hz, 1H), 8.51(brs, 1H); 13C NMR
(100 MHz, CDCl3): δ = 22.0, 27.8, 28.3, 34.4, 39.2, 39.2, 51.2, 119.7,
123.7, 126.9, 127.8, 128.5, 128.6, 129.6, 129.9, 132.5, 133.7, 135.7,
198.0, 203.3; [α]27D = 54.6° (c 1.0, CHCl3); Enantiomeric excess of
the product was determined by chiral stationary phase HPLC analysis
using a CHIRALPAK IC column (hexane/iꢀPrOH = 90:10 at 0.8
mL/min); λ = 254 nm; t major = 44.1 min, t minor = 48.3 min.
(S)ꢀ1ꢀ(3ꢀ(4ꢀNitrophenyl)ꢀ3ꢀoxopropyl)ꢀ2ꢀoxocyclopentaneꢀ1ꢀ
carbonitrile (12ag). White solid, 56.5 mg, 99% yield (90% ee). mp
144ꢀ146 °C;1H NMR (400 MHz, CDCl3): δ =2.10ꢀ2.21 (m, 4H), 2.35
(ddd, J = 5.6, 9.2, 14.6 Hz, 1H), 2.46ꢀ2.55 (m, 3H), 3.27 (ddd, J = 5.5,
9.3, 18.5 Hz, 1H), 3.50 (ddd, J = 5.7, 9.2, 18.5 Hz, 1H), 8.15 (d, J =
8.8 Hz, 2H), 8.34 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
= 19.3, 27.8, 34.6, 35.5, 36.4, 47.6, 118.7, 124.0, 129.2, 140.6, 150.6,
196.5, 209.2; [α]28D = 28.1° (c 1.0, CHCl3); HRMS (ESIꢀTOF): Calcd
for C15H14N2O4Na (M+Na)+: 309.0851, Found: 309.0859; Enantioꢀ
meric excess of the product was determined by chiral stationary phase
HPLC analysis using a CHIRALPAK IA column (hexane/iꢀPrOH =
80:20 at 0.8 mL/min); λ = 254 nm; t major = 35.3 min, t minor = 32.7
min.
2ꢀbenzoylꢀ2ꢀmethylꢀ5ꢀoxoꢀ5ꢀphenylpentanenitrile (12ca) 4. White
solid, 36.1 mg, 62% yield (72% ee). mp 83ꢀ84 °C; 1H NMR (400
MHz, CDCl3): δ =1.80 (s, 3H), 2.32 (ddd, J = 5.0, 10.8, 14.2 Hz, 1H),
2.71 (ddd, J = 5.2, 10.7, 14.2 Hz, 1H), 3.16 (ddd, J = 5.1, 10.6, 17.5
Hz, 1H), 3.25 (ddd, J = 5.2, 10.8, 17.5 Hz, 1H),7.45ꢀ7.67 (m, 6H),
7.95ꢀ7.97 (m, 2H), 8.18ꢀ8.21 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
= 24.5, 32.3, 34.3, 45.4,121.6, 128.1, 128.7, 128.8, 129.4, 133.4,
133.9, 134.0, 136.4, 193.7, 197.8; [α]29D = ꢀ16.8° (c 0.5, CHCl3);
HRMS (ESIꢀTOF): Calcd for C19H18NO2 (M+Na)+: 292.1338, Found:
292.1327; Enantiomeric excess of the product was determined by
chiral stationary phase HPLC analysis using a ChiralCel OJꢀH column
(hexane/iꢀPrOH = 90:10 at 1.0 mL/min); λ = 254 nm; t major = 31.6
min, t minor = 27.4 min.
(S)ꢀ1ꢀ(3ꢀ(3ꢀBromophenyl)ꢀ3ꢀoxopropyl)ꢀ2ꢀoxocyclopentaneꢀ1ꢀ
carbonitrile (12ah) 4. White solid, 51.3 mg, 80% yield (90% ee). 1H
NMR (400 MHz, CDCl3): δ =2.07ꢀ2.19 (m, 4H), 2.32 (ddd, J = 5.5,
9.3, 14.6 Hz, 1H), 2.46ꢀ2.52 (m, 3H), 3.19 (ddd, J = 5.5, 9.4, 18.3 Hz,
1H), 3.40 (ddd, J = 5.7, 9.4, 18.3 Hz, 1H), 7.37 (dd, J = 7.9, 7.9 Hz,
1H), 7.71ꢀ7.73 (m, 1H), 7.89ꢀ7.92 (m, 1H), 8.10ꢀ8.10 (m, 1H); 13
NMR (100 MHz, CDCl3): δ = 19.2, 27.8, 34.1, 35.3, 36.3, 47.7,
C
118.8, 123.1, 126.6, 130.3, 131.1, 136.4, 138.0, 196.6, 209.1; [α]28
=
D
10.2° (c 1.0, CHCl3); Enantiomeric excess of the product was deterꢀ
mined by chiral stationary phase HPLC analysis using a ChiralCel
ODꢀH column (hexane/iꢀPrOH = 90:10 at 1.0 mL/min); λ = 254 nm; t
major = 28.1 min, t minor = 22.6 min.
(S)ꢀ2ꢀoxoꢀ1ꢀ(3ꢀoxoꢀ3ꢀ(thiophenꢀ2ꢀyl)propyl)cyclopentaneꢀ1ꢀ
1
carbonitrile (12ak) 4. White solid, 46.8 mg, 95% yield (92% ee). H
NMR (400 MHz, CDCl3): δ =2.07ꢀ2.17 (m, 4H), 2.31 (ddd, J = 5.6,
9.3, 14.6 Hz, 1H), 2.44ꢀ2.53 (m, 3H), 3.17 (ddd, J = 5.8, 9.5, 17.4 Hz,
1H), 3.34 (ddd, J = 5.7, 9.5, 17.4 Hz, 1H), 7.16 (dd, J = 3.8, 4.9 Hz,
(S)ꢀ1ꢀ(3ꢀ(Naphthalenꢀ2ꢀyl)ꢀ3ꢀoxopropyl)ꢀ2ꢀoxocyclopentaneꢀ1ꢀ
carbonitrile (12ai) 4. White solid, 52.6 mg, 90% yield (89% ee). 1H
NMR (400 MHz, CDCl3): δ =2.12ꢀ2.21 (m, 4H), 2.38 (ddd, J = 5.4,
9.4, 14.6 Hz, 1H), 2.48ꢀ2.57 (m, 3H), 3.37 (ddd, J = 5.5, 9.6, 18.0 Hz,
1H), 3.56 (ddd, J = 5.6, 9.6, 17.9 Hz, 1H), 7.56ꢀ7.64 (m, 2H), 7.88ꢀ
7.92 (m, 2H), 8.00ꢀ8.04 (m, 2H), 8.52 (brs, 1H); 13C NMR (100 MHz,
CDCl3): δ = 19.3, 28.1, 34.0, 35.3, 36.3, 47.9, 119.0, 123.6, 126.9,
127.8, 128.6, 128.7, 129.7, 129.9, 132.5, 133.6, 135.8, 197.9, 209.2;
[α]27D =24.5° (c 1.0, CHCl3); Enantiomeric excess of the product was
determined by chiral stationary phase HPLC analysis using a
CHIRALPAK IC column (hexane/iꢀPrOH = 2:1 at 1.0 mL/min); λ =
254 nm; t major = 15.3 min, t minor = 17.5 min.
1H), 7.67 (dd, J = 1.1, 4.9 Hz, 1H), 7.80 (dd, J = 1.0,3.8 Hz, 1H); 13
C
NMR (100 MHz, CDCl3): δ = 19.2, 28.0, 34.6, 35.2, 36.3, 47.9,
118.8, 128.3, 132.4, 134.1, 143.4, 190.8, 209.0; [α]27 = 8.9° (c 1.0,
D
CHCl3); Enantiomeric excess of the product was determined by chiral
stationary phase HPLC analysis using a ChiralCel ADꢀH column
(hexane/iꢀPrOH = 90:10 at 1.0 mL/min); λ = 254 nm; t
= 24.4
major
min, t minor = 22.4 min.
2ꢀOxoꢀ1ꢀ(4ꢀoxoꢀ4ꢀphenylbutanꢀ2ꢀyl)cyclopentaneꢀ1ꢀcarbonitrile
(12al). White solid, 12.5 mg, 24% yield, diastereomeric ratio (56:44)
(7% ee, 60% ee). Major isomer; 1H NMR (400 MHz, CDCl3): δ =1.16
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The Journal of Organic Chemistry
(d, J = 6.7 Hz, 3H), 2.04ꢀ2.21 (m, 2H), 2.24ꢀ2.31 (m, 1H), 2.39ꢀ2.47
(3)
(a) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006,
(m, 3H), 2.72ꢀ2.80 (m, 1H), 2.95 (dd, J = 7.9, 17.8 Hz, 1H), 3.68 (dd,
J = 4.2, 17.8 Hz, 1H), 7.46ꢀ7.49 (m, 2H), 7.56ꢀ7.60 (m, 1H), 7.97 (d,
J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 16.9, 19.0, 31.7,
33.5, 36.9, 41.1, 52.8, 118.3, 128.1, 128.7, 133.4, 136.7, 198.1, 209.5;
[α]26D = ꢀ1.2° (c 0.2, CHCl3); mp 83ꢀ85 °C; HRMS (ESIꢀTOF):Calcd
for C16H17NO2Na (M+Na)+: 278.1157, Found: 278.1152. Minor isoꢀ
128, 3928. (b) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am.
Chem. Soc. 2007, 129, 768. (c) Luo, J.; Xu, L. W.; Hay, R. A. S.; Lu,
Y. Org. Lett. 2009, 11, 437. (d) Li, H.; Song, J.; Deng, L. Tetrahedron
2009, 65, 3139. (e) Chen, P.; Bao, X.; Zhang, L.ꢀF.; Ding, M.; Han,
X.ꢀJ.; Li, J.; Zhang, G.ꢀB.; Tu, Y.ꢀQ.; Fan, C.ꢀA. Angew. Chem. Int.
Ed. 2011, 50, 8161. (f) Lee, H. J.; Woo, S. B.; Kim, D. Y. Tetrahe-
dron Lett. 2012, 53, 3374. (g) Wei, M.ꢀX.; Wang, C.ꢀT.; Du, J.ꢀY.;
Qu, H.; Yin, P.ꢀR.; Bao, X.; Ma, X.ꢀY.; Zhao, X.ꢀH.; Zhang, G.ꢀB.;
Fun, C.ꢀA. Chem. Asian J. 2013, 8, 1966. (h) Chen, P.; Bao, X.;
Zhang, L.ꢀF.; Liu, G.ꢀJ.; Jiang, Y.ꢀJ. Eur. J. Org. Chem. 2016, 704.
1
2
3
4
5
6
7
8
1
mer; H NMR (400 MHz, CDCl3): δ =1.17 (d, J = 6.7 Hz, 3H), 2.08ꢀ
2.20 (m, 3H), 2.36ꢀ2.45 (m, 2H), 2.50ꢀ2.58 (m, 1H), 2.80 (dt, J =
6.60, 13.1 Hz, 1H), 3.09 (d, J = 6.4 Hz, 2H), 7.48ꢀ7.51 (m, 2H), 7.58ꢀ
7.62 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 16.2, 19.0, 32.1,
32.9, 37.1, 41.7, 53.2, 118.4, 128.2, 128.8, 133.6, 136.6, 197.7, 208.7;
9
(4)
Kawato, Y.; Takahashi, N.; Kumagai, N.; Shibasaki, M.
[α]27 = ꢀ21.2° (c 0.2, CHCl3); mp 87ꢀ89 °C; HRMS (ESIꢀ
Org. Lett. 2010, 12, 1484.
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
D
TOF):Calcd for C16H17NO2Na (M+Na)+: 278.1157, Found: 278.1155.
Enantiomeric excess of the product was determined by chiral stationꢀ
ary phase HPLC analysis using a ChiralCel OJꢀH column (hexane/iꢀ
(5)
Thiourea, see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J.
Am. Chem. Soc. 2003, 125, 12672; For reviews, see: (b) Miyabe, H.;
Takemoto, Y. Bull. Chem. Soc. Jpn. 2008, 81, 785; (c) Fang, X.;
Wang, C.ꢀJ. Chem. Commun. 2015, 51, 1185; (d) Held, F. E.;
Tsogoeva, S. B. Catal. Sci. Technol. 2016, 6, 645 and references cited
therein.
PrOH = 90:10 at 1.0 mL/min); λ = 220 nm; Major isomer; t
=
=
major
30.7 min, t
76.0 min.
= 62.6 min, Minor isomer; t
= 58.0 min, t
minor
major
minor
(6)
Squaramide, see: (a) Malerich, J. P.; Hagihara, K.; Rawal,
V. H. J. Am. Chem. Soc. 2008, 130, 14416; For review, see: (b) Aleꢀ
mán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. Eur. J. 2011, 17,
6890; (c) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Ender, D.
Adv. Synth. Catal. 2015, 357, 253; (d) Abdul, R.; Cihangir, T. Curr.
Org. Chem. 2016, 20, 2996.
ASSOCIATED CONTENT
Supporting Information
(7) (a) Kanada, Y.; Yuasa, H.; Nakashima, K.; Murahashi, M.; Tada,
N.; Itoh, A.; Koseki, Y.; Miura, T. Tetrahedron Lett. 2013, 54, 4896;
(b) Hirashima, S.; Sakai, T.; Nakashima, K.; Watanabe, N.; Koseki,
Y.; Mukai, K.; Kanada, Y.; Tada, N.; Itoh, A.; Miura, T. Tetrahedron
Lett. 2014, 55, 4334; (c) Nakashima, K.; Hirashima, S.; Kawada, M.;
Koseki, Y.; Tada, N.; Itoh, A.; Miura, T. Tetrahedron Lett. 2014, 55,
2703; (d) Nakashima, K.; Hirashima, S.; Akutsu, H.; Koseki, Y.;
Tada, N.; Itoh, A.; Miura, T. Tetrahedron Lett. 2015, 56, 558; (e)
Hirashima, S.; Nakashima, K.; Fujino, Y.; Arai, R.; Sakai, T.; Kawaꢀ
da, M.; Koseki, Y.; Murahashi, M.; Tada, N.; Itoh, A.; Miura, T. Tet-
rahedron Lett. 2014, 55, 4619; (f) Hirashima, S.; Arai, R.;
Nakashima, K.; Kawai, N.; Kondo, J.; Koseki, Y.; Miura, T. Adv.
Synth. Catal. 2015, 357, 3863; (g) Sakai, T.; Hirashima, S.;
Nakashima, K.; Maeda, C.; Yoshida, A.; Koseki, Y.; Miura, T. Chem.
Pharm. Bull. 2016, 64, 1781.
(8) We inferred that organocatalyst 7 exhibited higher asymmetric
catalytic activity compared with thiourea organocatalyst because
DMM motif bears appropriate acidity for the asymmetric conjugate
addition of αꢀcyanoketones to aromatic vinyl ketones. The pKa value
of model DMM compound was published on the following manuꢀ
script: Akutsu, H.; Nakashima, K.; Yanai, H.; Kontani, A.; Hirashima,
S.; Yamamoto, T.; Takahashi, R.; Yoshida A.; Koseki, Y.; Hakamata,
H.; Matsumoto, T.; Miura T. Synlett 2017, 28, 1363.
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
* Eꢀmail: tmiura@toyaku.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI Grant Number
16K08178. The authors would like to thank Enago
(www.enago.jp) for the English language review.
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