Perfluoroalkanesulfonamide organocatalysts for asymmetric conjugate additions of branched aldehydes to vinyl sulfones

Article abstract of DOI:10.3390/molecules181214529

Asymmetric conjugate additions of branched aldehydes to vinyl sulfones promoted by sulfonamide organocatalyst 6 or 7 have been developed, allowing facile synthesis of the corresponding adducts with all-carbon quaternary stereocenters in excellent yields w

Full text of DOI:10.3390/molecules181214529

Molecules 2013, 18, 14529-14542; doi:10.3390/molecules181214529
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Perfluoroalkanesulfonamide Organocatalysts for Asymmetric
Conjugate Additions of Branched Aldehydes to Vinyl Sulfones
Kosuke Nakashima 1, Miho Murahashi 2, Hiroki Yuasa 2, Mariko Ina 2, Norihiro Tada 2,
Akichika Itoh 2, Shin-ichi Hirashima 1, Yuji Koseki 1 and Tsuyoshi Miura 1,*
1
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji,
Tokyo 192-0392, Japan
2
Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
* Author to whom correspondence should be addressed; E-Mail: tmiura@toyaku.ac.jp;
Tel./Fax: +81-42-676-4479.
Received: 30 October 2013; in revised form: 20 November 2013 / Accepted: 21 November 2013 /
Published: 25 November 2013
Abstract: Asymmetric conjugate additions of branched aldehydes to vinyl sulfones
promoted by sulfonamide organocatalyst 6 or 7 have been developed, allowing facile
synthesis of the corresponding adducts with all-carbon quaternary stereocenters in
excellent yields with up to 95% ee.
Keywords: organocatalyst; sulfonamide; vinyl sulfone; conjugate addition; quaternary
stereocenters; fluorous
1. Introduction
All-carbon quaternary stereocenters are one of the most important motifs in many natural products
and bioactive compounds; however, relatively harsh reaction conditions are required to construct these
stereocenters due to their steric hindrance. In addition, combinations of electrophile and nucleophile
are limited, and the stereoselective construction of all-carbon quaternary stereocenters is not generally
straightforward. Therefore, development of efficient synthetic methods to stereoselectively construct
all-carbon quaternary stereocenters under mild reaction conditions is highly desirable in organic
synthesis [1–13]. Among various methodologies to construct these centers, organocatalysis is one of
the most effective processes that can be performed under mild conditions. The synthetic methods for
compounds with quaternary stereogenic centers using organocatalysts have received considerable

Molecules 2013, 18
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attention, particularly in the field of green chemistry [14,15]. Michael additions of various carbonyl
compounds to 1,1-bis(benzenesulfonyl)ethylene (11) using organocatalysts are efficient synthetic
methods, and several research groups have reported findings in this area [16–33]; however, successful
conjugate additions of α-branched aldehydes and 11 for the construction of such all-carbon quaternary
stereocenters have been rarely reported [34–38]. Alexakis and coworkers reported that L-proline
derivatives catalyze the reaction of 11 with α-branched aldehyde 12a to give the corresponding adduct
13a with up to 73% ee [34,35]. Lu and coworkers reported that the sulfonamide organocatalyst derived
from L-threonine promotes the conjugate addition of 12a to 11 in the unusual reaction solvent
p-fluorotoluene to afford the corresponding adduct 13a in high yield with high enantioselectivity (up to
83% ee) [36]. Furthermore, Maruoka and coworkers reported efficient conjugate additions of
α-heterosubstituted aldehydes with 11 using a sulfonamide organocatalyst with a dihydroanthracene
framework (up to 95% ee) [37]. Recently, we also reported that a diaminomethylenemalononitrile
organocatalyst catalyzes similar conjugate additions to afford 13a with high enantioselectivity (up to
89% ee) [38].
On the other hand, fluorous compounds with a perfluoroalkyl group can be easily separated from
nonfluorous compounds by fluorous organic solvent extraction or fluorous solid phase extraction
(FSPE) using fluorous silica gel [39]. Several research groups have reported asymmetric reactions in
which fluorous organocatalysts are recyclable [40]. We have also reported a direct aldol reaction in
water using fluorous sulfonamide organocatalyst 3 and related catalysts [41–43], Michael addition
reactions using a fluorous thiourea organocatalyst [44], and an oxidation reaction using fluorous
IBX [45]. In addition, we have reported a method for the synthesis of both enantiomeric aldol products
in water using sulfonamide organocatalysts 1 [46] and 2 [47,48], prepared from L-phenylalanine.
Very recently, we reported in a preliminary communication that perfluoroalkanesulfonamides 5 and 6
catalyze the conjugate additions of branched aldehydes to vinyl sulfone 11 to give the corresponding
adducts with excellent stereoselectivities [49]; however, development of a protocol for recovery and
reuse of 5 and 6 is yet to be reported. Herein, we describe the full details of the conjugate additions of
branched aldehydes to vinyl sulfone using 6 and novel fluorous sulfonamide 7 (Figure 1).
Figure 1. Structure of organocatalysts.
2. Results and Discussion
We initially examined the sulfonamide organocatalysts 1–7 for the conjugate addition of 12a to 11
as a test reactant (Table 1). Sulfonamide organocatalysts 1–4 derived from L-phenylalanine were
superior to catalyst 5 derived from L-valine for the direct aldol reactions in water [37,46,48]; however,
5 bearing the valine skeleton resulted more suitable for the conjugate addition with vinyl sulfone 11
(entries 1–5). Furthermore, to develop a more powerful organocatalyst, we synthesized 6, which

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enhanced the acidity of the sulfonamide group by the introduction of the perfluorobutyl group.
Treatment of compound 8 [50] with perfluorobutanesulfonyl fluoride in presence of triethylamine in
dichloromethane provided the intermediate 9 in 79% yield. The Boc protective group was removed by
treatment of hydrogen chloride in ethyl acetate to give the desired perfluorobutanesulfonamide 6 in
90% yield (Scheme 1). Organocatalyst 6 was more effective for conjugate additions with vinyl sulfone
11, resulting in the highest enantioselectivity (91% ee) and excellent yield (entry 6). Furthermore, to
develop an organocatalyst that can be recovered and reused, 7 was synthesized by a similar procedure
(Scheme 2). The stereoselectivity was slightly reduced in the reaction using 7 (entry 7).
Table 1. Selection of organocatalyst.
Entry Catalyst Time (h) Yield a (%) ee b (%)
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
1.5
2
2
2
95
99
88
97
95
−2
80
86
79
88
91
89
2
2
100
99
a isolated yield; b determined by HPLC analysis.
Scheme 1. Preparation of organocatalyst 6.
C4F9SO2F, Et3N
HCl, EtOAc
H2N NHSO2C4F9
BocHN NH
BocHN NHSO2C4F9
2 CH2Cl2, rt, 46 h
79%
rt, 2.5 h
90%
6
9
8
Scheme 2. Preparation of organocatalyst 7.
We investigated the optimal reaction conditions for the enantioselective conjugate additions using
6, various solvents, and additives (Table 2). Conjugate additions were performed with vinyl sulfone 11
and 2-methylphenylethanal (12a) as test reactants in the presence of a catalytic amount of 6 and
trifluoroacetic acid (TFA) at room temperature. A slight reduction in enantioselectivity and much
longer reaction time were observed without TFA (entries 1 and 2). Aprotic solvents such as
dichloromethane, diethyl ether, ethyl acetate, acetonitrile, chloroform, 1,2-dichloroethane, and p, m, and
o-xylene were accepted well in this conjugate addition with good enantioselectivity (entries 3 and 5–12).
A protic polar solvent such as methanol is a poor solvent for this reaction and provided low yield and
enantioselectivity (entry 4). Among the solvents probed, the best results (95% yield and 93% ee) were

Molecules 2013, 18
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achieved when the reaction was performed in m-xylene (entry 11). We also examined the effects
associated with the presence of other protic acids, including benzoic acid, p-nitrobenzoic acid, and
trifluoromethanesulfonic acid; however, TFA was found to be the most suitable additive (entries 13–15).
Additions of 0.2 or 0.05 equiv of TFA resulted in a slight reduction in stereoselectivity (entries 16 and
17). The highest enantioselectivity (95% ee) was obtained when the reaction was performed at 0 °C or
−10 °C, although longer reaction time (21 h or 72 h) was required (entries 18 and 19). Enantioselectivity
was slightly reduced when the catalyst loading was lowered to 0.05 equiv (entry 20). Considering the
reaction time, the optimal conditions were determined to be 0.1 equiv of 6 and 0.1 equiv of TFA in
m-xylene at room temperature (entry 11).
Table 2. Optimization of reaction conditions using organocatalyst 6.
Entry
1
Solvent
toluene
toluene
CH2Cl2
MeOH
Et2O
EtOAc
MeCN
CHCl3
Temp
Additive (equiv)
none
Time (h) Yield a (%) ee b (%)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
24
2
75
100
97
33
87
98
87
99
98
94
95
97
46
85
24
97
98
99
94
99
96
86
91
91
32
82
86
77
91
92
92
93
89
80
82
83
91
91
95
95
90
89
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20 c
21 d
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
2.5
24
5
2.5
4
2
2
2
2
ClCH2CH2Cl
p-xylene
m-xylene
o-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
TFA (0.1)
TFA (0.1)
TFA (0.1)
2
PhCO2H (0.1)
4-NO2C6H4CO2H (0.1)
TfOH (0.1)
TFA (0.2)
5.5
24
24
2
TFA (0.05)
TFA (0.1)
TFA (0.1)
TFA (0.05)
TFA (0.01)
2
0 °C
−10 °C
rt
21
72
3
rt
20
a Isolated yield; b Determined by HPLC analysis; c Catalyst (0.05 equiv) was used; d Catalyst (0.01 equiv) was used.
In order to identify the scope and limitations of aldehyde substrates, we investigated substituent effects
of the branched aromatic aldehydes on the conjugate additions (Table 3). A range of electron-withdrawing
substituents such as bromo and fluoro moieties, and electron-donating substituents such as methyl and
methoxy groups on the aromatic ring of branched aldehydes 12b–g provided the corresponding
adducts in excellent yields with good enantioselectivities (83%–92% ee) (entries 2–7). The additions
of branched aldehydes possessing a naphthalene motif, 12h and 12i, to vinyl sulfone 11 proceeded
smoothly in the presence of a catalytic amount of 6 to afford the corresponding adducts 13h and 13i in

Molecules 2013, 18
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excellent yields with 92% ee, respectively (entries 8 and 9). Interestingly, 2-methoxy-2-phenylacetaldehyde
(12j) was also applicable and gave the corresponding adduct 13j in high yield, albeit with reduced
enantioselectivity (entry 10). In addition, 6 promoted the reaction of N-Boc α-aminophenylacetaldehyde
(12k) with 11 to yield the corresponding adduct 13k in 68% yield with 60% ee (entry 11).
Table 3. Conjugate additions using organocatalyst 6.
Entry
Aldehyde
Product
Time (h) Yield a (%) ee b (%)
1
2
95
93
2
3
4
5
6
3
97
89
2
2
95
99
99
98
91
92
92
83
CHO
Me
12d
4
10
7
8
9
4
3
4
99
99
97
91
92
92
10
11
77
6
88
68
68
60
a Isolated yield; b Determined by HPLC analysis.

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Based on the optimal conditions for conjugate additions using 6, the reaction conditions were
optimized for the enantioselective conjugate additions using 7 (Table 4). 1,2-Dichloroethane was the
most suitable solvent among those examined in the presence of 0.1 equiv of TFA at room temperature.
The reaction in 1,2-dichloroethane provided high yield and enantioselectivity (entry 8). It should be
noted that 7 can promote the conjugate additions in brine because the perfluoroalkyl chain of 7
functions as the hydrophobic reaction field in water as described in our previous report [42,43].
Table 4. Optimization of reaction conditions using organocatalyst 7.
Entry
Solvent
toluene
toluene
CH2Cl2
hexane
Additive (Equiv) Time (h) Yield a (%) ee b (%)
1
2
3
4
5
6
7
8
9
none
24
2
85
99
90
91
85
68
100
87
84
83
89
91
86
89
78
91
92
91
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
2
2
Et2O
2
brine
24
2
CHCl3
ClCH2CH2Cl
m-xylene
2
2
a Isolated yield; b Determined by HPLC analysis.
The generality and substrate scope were probed for the optimal conditions (Table 5). The tendency
of reactivities using 7 was quite similar to that using 6; however, aldehydes 12e, 12i, and 12j were
poor substrates and gave low to moderate yields (entries 5, 9, and 10). Interestingly, the stereoselectivity
with 12g was improved up to 94% ee (entry 7). In addition, the yield in the reaction with 12k was
improved up to 100% yield (entry 11).
The recyclability of 7 was evaluated. After use of 7 in the conjugate addition of 12a to 11 under the
optimal conditions, it was readily recovered by the FSPE technique using fluorous silica gel.
Furthermore, the recovered catalyst 7 can be reused without further purification, and its catalytic
activity was retained for the first reuse. Unfortunately, the catalytic activity of the recovered catalyst 7
decreased significantly for the second reuse.
We infer that the conjugate additions of aldehydes 12 to vinyl sulfone 11 using 6 or 7 proceed via a
plausible transition state (Scheme 3) based on the stereochemistry of addition products 13a–i. The
primary amino group of 6 or 7 condenses with aldehydes 12 to generate the corresponding imine
intermediate. The imine intermediate is subsequently isomerized to the E-enamine intermediate
because of the resonance stabilizing effect of the aromatic ring. Then, the acidic proton of the
sulfonamide group, which coordinates intramolecularly to nitrogen in the enamine transition state,
successfully interacts with the oxygen of vinyl sulfone to control the approach direction of vinyl
sulfone to the Re face of the enamine intermediate. This ultimately affords the corresponding addition

Molecules 2013, 18
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products with high stereoselectivities. We believe that the acidity of 6 and 7 is enhanced by the
powerful electron-withdrawing effect of the perfluoroalkyl chains, enabling strong coordination to
vinyl sulfone and stabilizing the rigid transition states during conjugate additions. Moreover, the
addition of TFA to the conjugate additions might accelerate the formation of the imine and enamine
intermediates as well as reinforce the rigid transition state of the conjugate additions.
Table 5. Conjugate additions using organocatalyst 7.
Entry
Aldehyde
Product
Time (h) Yield a (%) ee b (%)
1
2
4
87
90
92
90
CHO
2
3
4
5
Br
12b
6
2
3
100
92
92
82
80
13
6
5
100
83
7
8
4
3
81
76
94
92
9
24
45
89
10
11
24
6
64
68
64
100
a Isolated yield; b Determined by HPLC analysis.

Molecules 2013, 18
Scheme 3. Plausible mechanism and transition state model of reaction.
14536
3. Experimental
3.1. General
13
1H-NMR and C-NMR spectra were measured with a JEOL AL 400 spectrometer (400 MHz for
13
1
1H-NMR and 100 MHz for C-NMR), or JEOL ECA-500 spectrometer (500 MHz for H-NMR and
13
125 MHz for C-NMR). The chemical shifts are expressed in ppm downfield from tetramethylsilane
(δ = 0.00) as an internal standard. For thin layer chromatographic (TLC) analyses, Merck precoated TLC
plates (silica gel 60 F254, Art 5715) were used. The products were isolated by flash column chromatography
on silica gel (Kanto Chemical, Tokyo, Japan, silica gel 60N, spherical, neutral, 40–50 µm).
3.2. Preparation of Organocatalyst 6
(S)-tert-Butyl 3-methyl-1-(perfluorobutanesulfonamido)butan-2-ylcarbamate (9). To a solution of
(S)-tert-butyl 1-amino-3-methylbutan-2-ylcarbamate (8, 300 mg, 1.48 mmol) [50] in dry CH2Cl2
(5 mL) was added triethylamine (0.46 mL, 3.06 mmol) at room temperature under an argon
atmosphere. After stirring for 5 min, perfluorobutanesulfonyl fluoride (0.87 mL, 4.45 mmol) was
added to the reaction mixture at 0 °C. After stirring for 1 h at 0 °C, the reaction mixture was
additionally stirred for 45 h at room temperature. The reaction mixture was added to water and
extracted three times with EtOAc. The EtOAc layers were combined, washed with brine, dried over
anhydrous MgSO4, and evaporated. The residue was purified by flash column chromatography on
silica gel with a 7:1 mixture of hexane and EtOAc to give the pure 9 (566 mg, 79%) as a colorless
powder. Mp = 74–75 °C; [α]2D4 = −5.4° (c = 0.62 in MeOH); 1H-NMR (400 MHz, CD3OD): δ = 0.81 (d,
J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 1.35 (s, 9H), 1.65–1.71 (m, 1H), 3.08 (dd, J = 8.1, 13.5 Hz,
13
1H), 3.28 (dd, J = 4.5, 13.5 Hz, 1H), 3.31–3.37 (m, 1H); C-NMR (125 MHz, CD3OD): δ = 18.2,
19.9, 28.8, 31.0, 47.1, 57.6, 80.2, 110.2–121.0 (complex signals of –CF2 and –CF3), 158.5; HRMS
(ESI-TOF): calcd for C14H21F9N2O4SNa (M+Na)+: 507.0976, Found: 507.0991.
(S)-N-(2-Amino-3-methylbutyl)-perfluorobutanesulfonamide (6). To a solution of 9 (300 mg, 0.619 mmol)
in EtOAc (2.5 mL) was added a 4 M solution of hydrochloric acid in EtOAc (2.5 mL) at 0 °C.
After stirring for 2.5 h at room temperature, the reaction mixture was evaporated. The residue was
added to saturated aqueous NaHCO3 and extracted three times with EtOAc. The EtOAc layers were

Molecules 2013, 18
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combined, washed with brine, dried over anhydrous MgSO4, and evaporated. The residue was purified
by flash column chromatography on silica gel with a 20:1 mixture of CHCl3 and MeOH to give the
pure 6 (214 mg, 90%) as a colorless powder. Mp = 134–136 °C; [α]2D0 = +7.9° (c = 1.01 in MeOH);
1H-NMR (500 MHz, CD3OD): δ = 1.01 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 1.90–1.97
(m, 1H), 2.82–2.86 (m, 1H), 3.14 (dd, J = 8.6, 13.1 Hz, 1H), 3.41 (dd, J = 3.5, 13.1 Hz, 1H); 13C-NMR
(125 MHz, CD3OD): δ = 18.9, 19.0, 30.1, 47.4, 60.7, 110.2–120.4 (complex signals of –CF2 and
–CF3); Anal. Calcd for C9H13F9N2O2S: C, 28.13; H, 3.41; N, 7.29. Found: C, 28.07; H, 3.39; N, 7.26.
3.3. Preparation of Organocatalyst 7
(S)-tert-Butyl 3-methyl-1-(perfluorooctanesulfonamido)butan-2-ylcarbamate (10). To a solution of
(S)-tert-butyl 1-amino-3-methylbutan-2-ylcarbamate (8) [50] (385 mg, 1.90 mmol) in dry CH2Cl2 (20 mL)
was added triethylamine (0.80 mL, 5.71 mmol) at room temperature under an argon atmosphere. After
stirring for 5 min, perfluorooctanesulfonyl fluoride (1.57 mL, 5.71 mmol) was added to the reaction
mixture at 0 °C. After stirring for 2 h at 0 °C, the reaction mixture was additionally stirred for 90 h at
room temperature. The reaction mixture was added to water and extracted three times with EtOAc.
The EtOAc layers were combined, washed with brine, dried over anhydrous MgSO4, and evaporated.
The residue was purified by flash column chromatography on silica gel with a 6:1 mixture of hexane
and EtOAc to give the pure 10 (602 mg, 46%) as a pale yellow oil. [α]2D4 = −4.2° (c = 1.28 in MeOH);
1H-NMR (500 MHz, CDCl3): δ = 0.95 (d, J = 7.4 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.44 (s, 9H),
1.80–1.85 (m, 1H), 3.25 (m, 1H), 3.46 (brd, J = 12.6 Hz, 1H), 3.55 (m, 1H), 4.67 (brd, J = 8.0 Hz, 1H),
7.13 (brs, 1H); 13C-NMR (125 MHz, CDCl3): δ = 18.0, 19.2, 28.2, 30.1, 48.4, 55.7, 80.8, 108.0–113.0
(complex signals of –CF2 and –CF3), 157.6; HRMS (ESI-TOF): calcd for C18H21F17N2O4SNa
(M+Na)+: 707.0848, Found: 707.0873.
(S)-N-(2-Amino-3-methylbutyl)-perfluorooctanesulfonamide (7). To a solution of 10 (570 mg, 0.833 mmol)
in EtOAc (3.5 mL) was added a 4M solution of hydrochloric acid in EtOAc (3.5 mL) at 0 °C.
After stirring for 2 h at room temperature, the reaction mixture was evaporated. The residue was added
to saturated aqueous NaHCO3 and extracted three times with EtOAc. The EtOAc layers were
combined, washed with brine, dried over anhydrous MgSO4, and evaporated. The residue was purified
by flash column chromatography on silica gel with a 20:1 mixture of CHCl3 and MeOH to give the
pure 7 (444 mg, 91%) as a colorless powder. Mp = 144–145 °C; [α]2D4 = + 6.9° (c = 1.01 in MeOH);
1H-NMR (500 MHz, CD3OD): δ = 1.01 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 1.90–1.97 (m,
13
1H), 2.82–2.86 (m, 1H), 3.15 (dd, J = 8.5, 13.1 Hz, 1H), 3.41 (dd, J = 4.0, 13.1 Hz, 1H); C-NMR
(125 MHz, CD3OD): δ = 18.9, 19.0, 30.1, 47.5, 60.7, 109.7–121.5 (complex signals of –CF2 and
–CF3); Anal. Calcd for C13H13F17N2O2S: C, 26.72; H, 2.24; N, 4.79. Found: C, 26.75; H, 2.41; N, 4.86.
3.4. Typical Procedure for Michael Addition (Table 3)
A typical procedure of the Michael additions using 6 is as follows: To a solution of 11 (30.8 mg,
0.100 mmol) and organocatalyst 6 (3.8 mg, 0.010 mmol) in m-xylene (1.0 mL) was added
2-phenylpropanal (26.8 µL, 0.200 mmol) and trifluororacetic acid (0.7 µL, 0.010 mmol) at room
temperature. After stirring at room temperature for 2 h, the reaction mixture was directly purified by

Molecules 2013, 18
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flash column chromatography on silica gel with a 3:1 mixture of hexane and EtOAc to afford the pure
13a (42.0 mg, 95%) as a colorless powder. All the Michael addition products 13 in the paper are
known compounds that exhibited spectroscopic data identical to those reported in the literature [36,37].
(R)-2-Methyl-2-phenyl-4,4-bis(phenylsulfonyl)butanal (13a). [α]1D8 = −25.6° (c = 1.00, CHCl3); 95% ee;
enantiomeric excess was determined by HPLC with Chiralpak AS-H column (hexane/2-propanol = 70:30),
flow rate = 1.0 mL/min; λ = 220 nm; tmajor = 21.7 min, tminor = 25.9 min.
(R)-2-(4-Bromophenyl)-2-methyl-4,4-bis(phenylsulfonyl)butanal (13b). [α] 2D2 = −15.2° (c = 1.00,
CHCl3); 89% ee; enantiomeric excess was determined by HPLC with Chiralpak AS-H column
(hexane/2-propanol = 70:30), flow rate = 1.0 mL/min; λ = 220 nm; tmajor = 27.1 min, tminor = 38.5 min.
(R)-2-(4-Fluorophenyl)-2-methyl-4,4-bis(phenylsulfonyl)butanal (13c). [α] 1D8 = +23.5° (c = 1.00,
CHCl3); 91% ee; enantiomeric excess was determined by HPLC with Chiralpak AS-H column
(hexane/2-propanol = 70:30), flow rate = 1.0 mL/min; λ = 220 nm; tmajor = 25.5 min, tminor = 32.1 min.
(R)-2-Methyl-4,4-bis(phenylsulfonyl)-2-p-tolylbutanal (13d). [α]1D8 = +25.4° (c = 1.00, CHCl3); 92% ee;
enantiomeric excess was determined by HPLC with Chiralpak AS-H column (hexane/2-propanol = 70:30),
flow rate = 1.0 mL/min; λ = 220 nm; tmajor = 21.3 min, tminor = 29.7 min.
(R)-2-(3-Methoxyphenyl)-2-methyl-4,4-bis(phenylsulfonyl)butanal (13e). [α]1D9 = +10.6° (c = 1.00,
CHCl3); 92% ee; enantiomeric excess was determined by HPLC with Chiralcel AD-H column
(hexane/2-propanol = 80:20), flow rate = 1.0 mL/min; λ = 220 nm; tmajor = 27.4 min, tminor = 38.6 min.
(R)-2-(2-Methoxyphenyl)-2-methyl-4,4-bis(phenylsulfonyl)butanal (13f). [α]1D8 = −70.8° (c = 1.00,
CHCl3); 83% ee; enantiomeric excess was determined by HPLC with Chiralcel AD-H column
(hexane/2-propanol = 80:20), flow rate = 1.0 mL/min; λ = 220 nm; tmajor = 18.8 min, tminor = 25.9 min.
(R)-2-(3-Bromophenyl)-2-methyl-4,4-bis(phenylsulfonyl)butanal (13g). [α] 1D8 = −71.7° (c = 1.00,
CHCl3); 91% ee; enantiomeric excess was determined by HPLC with Chiralpak AS-H column
(hexane/2-propanol = 80:20), flow rate = 1.0 mL/min; λ = 220 nm; tmajor = 41.3 min, tminor = 47.1 min.
(R)-2-Methyl-2-(naphthalen-2-yl)-4,4-bis(phenylsulfonyl)butanal (13h). [α] 1D8 = +13.0° (c = 1.00,
CHCl3); 92% ee; enantiomeric excess was determined by HPLC with Chiralpak AS-H column
(hexane/2-propanol = 70:30), flow rate = 1.0 mL/min; λ = 220 nm; tmajor = 32.9 min, tminor = 39.1 min.
(R)-2-Methyl-2-(naphthalen-1-yl)-4,4-bis(phenylsulfonyl)butanal (13i). [α] 2D2 = −31.8° (c = 1.00,
CHCl3); 92% ee; enantiomeric excess was determined by HPLC with Chiralcel AD-H column
(hexane/2-propanol = 70:30), flow rate = 1.0 mL/min; λ = 220 nm; tmajor = 16.7 min, tminor = 22.4 min.
(R)-2-Methoxy-2-phenyl-4,4-bis(phenylsulfonyl)butanal (13j). 68% ee; enantiomeric excess was
determined by HPLC with Chiralcel AD-H column (hexane/2-propanol = 5:1), flow rate = 1.0 mL/min;
λ = 220 nm; tmajor = 37.1 min, tminor = 44.5 min.

Molecules 2013, 18
14539
(R)-tert-Butyl 1-oxo-2-phenyl-4,4-bis(phenylsulfonyl)butan-2-ylcarbamate (13k). [α] 2D5 = +10.0°
(c = 1.00, CHCl3) 64% ee; enantiomeric excess was determined by HPLC with Chiralcel OD-H column
(hexane/2-propanol = 90:10), flow rate = 0.5 mL/min; λ = 220 nm; tmajor = 19.9 min, tminor = 22.2 min.
4. Conclusions
Novel organocatalysts 6 and 7 can easily be prepared from L-valine, an inexpensive and commercially
available natural amino acid. Organocatalysts 6 and 7, which are simple β-aminosulfonamides with
only one stereogenic center, efficiently catalyze the conjugate additions of various branched aldehydes
to vinyl sulfone 11 with a short reaction time at room temperature to give the corresponding addition
products possessing all-carbon quaternary stereocenters with high enantioselectivities. The excellent
performance is probably due to the carbon skeleton of L-valine and the electron-withdrawing effect of
the perfluoroalkyl groups on 6 and 7. Moreover, fluorous organocatalyst 7 bearing a perfluorooctyl
group was readily recovered by simple solid phase extraction using fluorous silica gel and was immediately
reusable without further purification for the first cycle. Further application of these organocatalysts in
the synthesis of bioactive compounds is currently being investigated in our laboratory.
Acknowledgments
This work was supported in part by Grants-in-Aid for Scientific Research (C) (No. 22590007) from
the Japan Society for the Promotion of Science.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Fuji, K. Asymmetric creation of quaternary carbon centers. Chem. Rev. 1993, 93, 2037–2066.
2. Corey, E.J.; Guzman-Perez, A. The catalytic enantioselective construction of molecules with
quaternary carbon stereocenters. Angew. Chem. Int. Ed. 1998, 37, 388–401.
3. Christoffers, J.; Mann, A. Enantioselective construction of quaternary stereocenters.
Angew. Chem. Int. Ed. 2001, 40, 4591–4597.
4. Christoffers, J.; Baro, A. Construction of quaternary stereocenters: New perspectives through
enantioselective Michael reactions. Angew. Chem. Int. Ed. 2003, 42, 1688–1690.
5. Douglas, C.J.; Overman, L.E. Catalytic asymmetric synthesis of all-carbon quaternary
stereocenters. Proc. Natl. Acad. Sci. USA 2004, 101, 5363–5367.
6. Christoffers, J.; Baro, A. Stereoselective construction of quaternary stereocenters. Adv. Synth. Catal.
2005, 347, 1473–1482.
7. Trost, B.M.; Jiang, C. Catalytic enantioselective construction of all-carbon quaternary stereocenters.
Synthesis 2006, 2006, 369–396.
8. Cozzi, P.G.; Hilgraf, R.; Zimmermann, N. Enantioselective catalytic formation of quaternary
stereogenic centers. Eur. J. Org. Chem. 2007, 2007, 5969–5994.

Molecules 2013, 18
14540
9. Marek, I.; Sklute, G. Creation of quaternary stereocenters in carbonyl allylation reactions.
Chem. Commun. 2007, 2007, 1683–1691.
10. Riant, O.; Hannedouche, J. Asymmetric catalysis for the construction of quaternary carbon
centres: nucleophilic addition on ketones and ketimines. Org. Biomol. Chem. 2007, 5, 873–888.
11. Hawner, C.; Alexakis, A. Metal-catalyzed asymmetric conjugate addition reaction: Formation of
quaternary stereocenters. Chem. Commun. (Camb) 2010, 46, 7295–7306.
12. Shimizu, M. Construction of asymmetric quaternary carbon centers with high enantioselectivity.
Angew. Chem. Int. Ed. 2011, 50, 5998–6000.
13. Das, J.P.; Marek, I. Enantioselective synthesis of all-carbon quaternary stereogenic centers in
acyclic systems. Chem. Commun. (Camb) 2011, 47, 4593–4623.
14. Bella, M.; Gasperi, T. Organocatalytic formation of quaternary stereocenters. Synthesis 2009,
2009, 1583–1614.
15. Figueiredo, R.M.; Christmann, M. Organocatalytic synthesis of drugs and bioactive natural
products. Eur. J. Org. Chem. 2007, 2007, 2575–2600.
16. Mossé, S.; Alexakis, A. First organocatalyzed asymmetric Michael addition of aldehydes to Vinyl
sulfones. Org. Lett. 2005, 7, 4361–4364.
17. Liu, T.-Y.; Long, J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Enantioselective
construction of quaternary carbon centre catalysed by bifunctional organocatalyst. Org. Biomol.
Chem. 2006, 4, 2097–2099.
18. Zhu, Q.; Lu, Y. Organocatalytic michael addition of aldehydes to vinyl sulfones: Enantioselective
α-alkylations of aldehydes and their derivatives. Org. Lett. 2008, 10, 4803–4806.
19. Zhu, Q.; Cheng, L.; Lu, Y. Asymmetric organocatalytic Michael addition of ketones to vinyl
sulfone. Chem. Commun. 2008, 2008, 6315–6317.
20. Quintard, A.; Bournaud, C.; Alexakis, A. Diversity-oriented synthesis towards conceptually new
highly modular aminal–pyrrolidine organocatalysts. Chem. Eur. J. 2008, 14, 7504–7507.
21. Zhu, Q.; Lu, Y. Enantioselective conjugate addition of nitroalkanes to vinyl sulfone: An
organocatalytic access to chiral amines. Org. Lett. 2009, 11, 1721–1724.
22. Landa, A.; Maestro, M.; Masdeu, C.; Puente, A.; Vera, S.; Oiarbide, M.; Palomo, C. Highly
enantioselective conjugate additions of aldehydes to vinyl sulfones. Chem. Eur. J. 2009, 15,
1562–1565.
23. Quintard, A.; Alexakis, A. Organocatalytic addition on 1,2-bis(sulfone)vinylenes leading to an
unprecedented rearrangement. Chem. Eur. J. 2009, 15, 11109–11113.
24. Xiao, J.; Liu, Y.-L.; Loh, T.-P. The organocatalytic enantioselective Michael addition of
aldehydes to vinyl sulfones in water. Synlett 2010, 2010, 2029–2032.
25. Quintard, A.; Alexakis, A. Asymmetric addition of α-hetero-disubstituted aldehydes to vinyl
sulfones; formation of highly functionalized tetrasubstituted carbon centres. Chem. Commun. (Camb)
2010, 46, 4085–4087.
26. Alba, A.-N.R.; Conpanyó, X.; Valero, G.; Moyano, A.; Rios, R. Enantioselective organocatalytic
addition of oxazolones to 1,1-bis(phenylsulfonyl)ethylene: A convenient asymmetric synthesis of
quaternary α-amino acids. Chem. Eur. J. 2010, 16, 5354–5361.

Molecules 2013, 18
14541
27. Chua, P.J.; Tan, B.; Yang, L.; Zeng, X.; Zhu, D.; Zhong, G. Highly stereoselective synthesis of
indanes with four stereogenic centers via sequential Michael reaction and [3+2] cycloaddition.
Chem. Commun. 2010, 46, 7611–7613.
28. Zhu, Q.; Lu, Y. Stereocontrolled creation of all-carbon quaternary stereocenters by
organocatalytic conjugate addition of oxindoles to vinyl sulfone. Angew. Chem. Int. Ed. 2010, 49,
7753–7756.
29. Quintard, A.; Alexakis, A. 1,2-Sulfone rearrangement in organocatalytic reactions. Org. Biomol.
Chem. 2011, 9, 1407–1418.
30. Quintard, A.; Alexakis, A. Highly enantioselective organocascade intermolecular iminium/enamine
Michael addition on enals. Chem. Commun. (Camb) 2011, 47, 7212–7214.
31. Xiao, J.; Lu, Y.-P.; Liu, Y.-L.; Wong, P.-S.; Loh, T.-P. A New class of structurally rigid tricyclic
chiral secondary amine organocatalyst: Highly enantioselective organocatalytic michael addition
of aldehydes to vinyl sulfones. Org. Lett. 2011, 13, 876–879.
32. Kang, J.Y.; Carter, R.G. Primary Amine, Thiourea-based dual catalysis motif for synthesis of
stereogenic, all-carbon quaternary center-containing cycloalkanones. Org. Lett. 2012, 14,
3178–3181.
33. Dou, X.; Lu, Y. Enantioselective Conjugate addition of 3-fluorooxindoles to vinyl sulfone: An
organocatalytic access to chiral 3-fluoro-3-substituted oxindoles. Org. Biomol. Chem. 2013, 11,
5217–5221.
34. Mossé, S.; Alexakis, A.; Mareda, J.; Bollot, G.; Bernardinelli, G.; Filinchuk, Y. Enantioselective
organocatalytic conjugate addition of aldehydes to vinyl sulfones and vinyl phosphonates as
challenging michael acceptors. Chem. Eur. J. 2009, 15, 3204–3220.
35. Quintard, A.; Belot, S.; Marchal, E.; Alexakis, A. Aminal–pyrrolidine organocatalysts—highly
efficient and modular catalysts for α-functionalization of carbonyl compounds. Eur. J. Org. Chem.
2010, 2010, 927–936.
36. Zhu, Q.; Lu, Y. Chiral primary amine mediated conjugate addition of branched aldehydes to vinyl
sulfone: Asymmetric generation of quaternary carbon centers. Chem. Commun. (Camb) 2010, 46,
2235–2237.
37. Moteki, S.A.; Xu, S.; Arimitsu, S.; Maruoka, K. Design of structurally rigid trans-diamine-based
tf-amide organocatalysts with a dihydroanthracene framework for asymmetric conjugate additions
of heterosubstituted aldehydes to vinyl sulfones. J. Am. Chem. Soc. 2010, 132, 17074–17076.
38. Kanada, Y.; Yuasa, H.; Nakashima, K.; Murahashi, M.; Tada, N.; Itoh, A.; Koseki, Y.; Miura, T.
Asymmetric conjugate addition of aldehydes to vinyl sulfone using a diaminomethylenemalononitrile
organocatalyst. Tetrahedron Lett. 2013, 54, 4896–4899.
39. Gladysz, J.A., Horváth, I.T., Curran, D.P., Eds.; The Handbook of Fluorous Chemistry;
Wiley-VCH: Weinheim, Germany, 2004.
40. Zhang, W.; Cai, C. New chemical and biological applications of fluorous technologies.
Chem. Commun. 2008, 2008, 5686–5694.
41. Miura, T.; Imai, K.; Ina, M.; Tada, N.; Imai, N.; Itoh, A. Direct asymmetric aldol reaction with
recyclable fluorous organocatalyst. Org. Lett. 2010, 12, 1620–1623.

Molecules 2013, 18
14542
42. Miura, T.; Imai, K.; Kasuga, H.; Ina, M.; Tada, N.; Imai, N.; Itoh, A. Direct asymmetric aldol
reactions in brine with recyclable fluorous β-aminosulfonamide organocatalysts. Tetrahedron
2011, 67, 6340–6346.
43. Miura, T.; Imai, K.; Kasuga, H.; Ina, M.; Tada, N.; Imai, N.; Itoh, A. Highly efficient asymmetric
aldol reaction in brine using fluorous sulfonamide organocatalyst. Org. Biomol. Chem. 2012, 10,
2209–2213.
44. Miura, T.; Nishida, S.; Masuda, A.; Tada, N.; Itoh, A. Asymmetric Michael additions of
aldehydes to maleimides using a recyclable fluorous thiourea organocatalyst. Tetrahedron Lett.
2011, 52, 4158–4160.
45. Miura, T.; Nakashima, K.; Tada, N.; Itoh, A. An Effective and catalytic oxidation using recyclable
fluorous IBX. Chem. Commun. 2011, 47, 1875–1877.
46. Miura, T.; Ina, M.; Imai, K.; Nakashima, K.; Masuda, A.; Imai, N.; Tada, N.; Itoh, A.
β-Aminosulfonamide-catalyzed direct asymmetric Aldol reaction in brine. Synlett 2011, 2011,
410–414.
47. Miura, T.; Yasaku, Y.; Koyata, N.; Murakami, Y.; Imai, N. Direct asymmetric aldol reactions in
brine using novel sulfonamide catalyst. Tetrahedron Lett. 2009, 50, 2632–2635.
48. Miura, T.; Ina, M.; Imai, K.; Nakashima, K.; Yasaku, Y.; Koyata, N.; Murakami, Y.; Imai, N.;
Tada, N.; Itoh, A. Direct asymmetric aldol reactions in water with a β-aminosulfonamide
organocatalyst. Tetrahedron Asymmetry 2011, 22, 1028–1034.
49. Miura, T.; Yuasa, H.; Murahashi, M.; Ina, M.; Nakashima, K.; Tada, N.; Itoh, A. Highly efficient
asymmetric conjugate additions of aldehydes with vinyl sulfones using sulfonamide
organocatalyst. Synlett 2012, 2012, 2385–2388.
50. Imai, N.; Nokami, J.; Nomura, T.; Ninomiya, Y.; Shinobe, A.; Matsushiro, S. Convenient
preparation of various chiral disulfonamides from α-amino acid and alkylation of cinnamaldehyde
in the presence of the chiral disulfonamides. Bull. Okayama Univ. Sci. 2002, 47–52.
Sample Availability: Samples of the compounds are not available from the authors.
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