Catalytic enantioselective conjugate additions with α,β-unsaturated sulfones

Article abstract of DOI:10.1016/j.tet.2008.11.054

We describe the development of a highly efficient catalytic asymmetric conjugate addition to α,β-unsaturated sulfones. Utilizing practical bifunctional organic catalysts and involving air- and moisture-tolerant conditions, conjugate additions of a wide range of Michael donors to α,β-unsaturated sulfones proceeded in excellent enantioselectivity/diastereoselectivity and high yield. This efficient and operationally simple new catalytic asymmetric reaction should provide a versatile approach for the asymmetric synthesis of chiral sulfones bearing all-carbon quaternary stereocenters.

Full text of DOI:10.1016/j.tet.2008.11.054

Tetrahedron 65 (2009) 3139–3148
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic enantioselective conjugate additions with a,b-unsaturated sulfones
*
Hongming Li, Jun Song, Li Deng
Department of Chemistry, Brandeis University, Waltham, MA 02454-9110, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 October 2008
Received in revised form 16 November 2008
Accepted 19 November 2008
Available online 25 November 2008
We describe the development of a highly efficient catalytic asymmetric conjugate addition to
saturated sulfones. Utilizing practical bifunctional organic catalysts and involving air- and moisture-
tolerant conditions, conjugate additions of a wide range of Michael donors to -unsaturated sulfones
proceeded in excellent enantioselectivity/diastereoselectivity and high yield. This efficient and opera-
tionally simple new catalytic asymmetric reaction should provide a versatile approach for the asym-
metric synthesis of chiral sulfones bearing all-carbon quaternary stereocenters.
Ó 2008 Elsevier Ltd. All rights reserved.
a,b-un-
a,b
Keywords:
Organocatalyst
Hydrogen bonding
Cinchona alkaloids
Chiral sulfones
Conjugate addition
1. Introduction
additions to nitroalkenes 1. In this model the C60–OH cinchona al-
kaloids 5, adopting the gauche-open conformation, simultaneously
Sulfones are versatile intermediates in organic synthesis.1
Enantioselective C–C bond forming reactions generating chiral
sulfones are of significant interest to asymmetric synthesis.2 In
particular asymmetric conjugate additions with trisubstituted
activated and oriented the Michael donors 3 (generated by tauto-
merization of ketones 2) and the nitroalkenes 1 via a network of
hydrogen bonding interactions.5b We reasoned that if the re-
placement of the nitro with the sulfone functionality in the Michael
donor did not disrupt or alter the pattern of hydrogen bonding
network between the catalyst and the reacting substrates, 60-OH
cinchona alkaloid 5 might be able to catalyze conjugate additions of
carbon nucleophiles to
a,b-unsaturated sulfones 4 (Scheme 1)
provide a straightforward strategy to form optically active building
blocks bearing the sulfone functionality and a quaternary stereo-
center.3,4 In this full article, we document in detail our efforts on the
development of such reactions catalyzed by practically accessible,
cinchona alkaloid-based organic catalysts.3
enolizable Michael donors 2 to
a,b-unsaturated sulfones with high
diastereoselectivity and enantioselectivity. Thus, we initiated an
investigation of these conjugate additions to
a,b-unsaturated
In 2004 we demonstrated that 60-OH cinchona alkaloid de-
rivatives such as 5, bearing a hydrogen bond acceptor in quinucli-
dine and a hydrogen bond donor in 60-OH, could catalyze the
conjugate additions of a broad range of enolizable carbon Michael
donors 2 to nitroalkenes 1 with remarkably high enantioselectivity
and diastereoselectivity (Scheme 1).5,6 These studies provided the
first examples of cinchona alkaloids with rotational freedom
around C8–C9 and C40–C9 bonds serving as highly efficient acid-
base bifunctional catalysts for asymmetric reactions. Mechanistic
and conformational studies unambiguously established that 5
adopted a gauche-open active conformer (Scheme 1) in the tran-
sition state.5b With this key information in hand, we are able to
construct a transition state model (6, Scheme 1) that is consistent
with the stereochemistry outcome of the 5-catalyzed conjugate
sulfones with cinchona alkaloids 5.
2. Results and discussion
2.1. Catalyst discovery and reaction optimizations
Our experiments began with a screening of a variety of cinchona
alkaloid derivatives for their ability to promote enantioselective
addition of
a-phenyl a-cyanoacetate 10A to the commercially
available phenyl vinyl sulfone (4a). As summarized in Table 1, the
conjugate addition proceeded smoothly in toluene at room tem-
perature in the presence of various natural and modified cinchona
alkaloids. The enantioselectivity of the reaction was, however,
found to be critically dependent on the structure of the cinchona
alkaloid derivatives. Reactions with natural cinchona alkaloids such
as quinidine and quinine generated the 1,4-adduct 11A as a nearly
racemic mixture (entries 1 and 2). The enantioselectivity was in
general improved with cinchona alkaloids bearing a C9-substituent
* Corresponding author. Tel.: þ1 781 736 2529; fax þ1 781 736 2516.
E-mail address: deng@brandeis.edu (L. Deng).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.054

3140
H. Li et al. / Tetrahedron 65 (2009) 3139–3148
O
H
NO2
O
SO2R"'
R"
X
R"
X
R
1
4
R
R'
2
R'
3
R"
R
R"
N
O
N
O
R'O
N
R'O
N
OH
N
H
O
H
H
H
OR
H
H
N
O
H
O
H
H
O
O
H
X
X
H
N+
R
S
Q-5
O-
R"
R"
R"'
R'
R'
O
7
6
R"
H
O
R"
H
SO2R"'
NO2
R
R
9
R'
high ee? high dr?
a,b
-unsaturated sulfones (4) with 60-OH cinchona alkaloids 5.
X
X
R'
up to >99% ee, up to >50/1 dr
Scheme 1. Rationale for the development of a catalytic asymmetric conjugate addition to
8
(entries 3–7, 9–12). Importantly, in line with our hypothesis, the 60-
OH cinchona alkaloids 5 were found to be much more effective than
those bearing C60–OMe. The pronounced effect of the C9-sub-
stituent on the enantioselectivity of the C60–OH cinchona alkaloids
5 is also noteworthy. While modest enantioselectivity was afforded
by either the C60–OH cinchona alkaloid bearing a C9–OH (entry 8)
or a rigid C60–OH cinchona alkaloid derivative (entry 7), signifi-
cantly higher enantioselectivity could be attained with C60–OH
Table 1
Cinchona alkaloid-catalyzed addition of
a
-phenyl
a
-cyanoacetate 10A to vinyl phenyl sulfone (4a)a
OH
OMe
N
OMe
OH
6'
6'
6'
6'
OH
OR
OH
OR
9
N
9
9
N
9
N
N
H
H
N
N
H
H
N
Q-5
Quinine (Q)
QD-5
Quinidine (QD)
5a: R = H
5b: R = Bn
5c: R =
(PHN)
Ph
OH
6'
DHQD
DQHD
O
DHQD
DHQD
DQHD
DHQD
O
9
N
N
N
N
N
Ph
DHQD
O
N
(DHQD)2AQN
DHQD-PHN
(DHQD)2PHAL
(DHQD)2PYR
β-ICD
EtO2C
CN
EtO2C CN
toluene ( 0.5M)
rt, 17h
SO2Ph
4a
+
Ph
SO2Ph
*
11A
Ph
10A
Entry
Catalyst
Conversionb/%
eec/%
1
2
3
4
5
6
7
8
Q
QD
DHQD-PHN
(DHQD)2PYR
(DHQR)2PHAL
(DHQR)2AQN
>98
>98
79
>98
80
>98
98
90
0
3
24
33
9
4
b-ICD
42
45
63
74
74
84
QD-5a
QD-5b
QD-5c
Q-5b
9
>98
91
65
10
11
12
Q-5c
>98
a
Reactions were run with 10A (0.3 mmol), 4a (0.1 mmol), and the catalyst (0.02 mmol) in toluene (0.2 mL) at rt for 17 h.
b
c
Determined by 1H NMR analysis.
Determined by HPLC analysis.

H. Li et al. / Tetrahedron 65 (2009) 3139–3148
3141
Table 2
Table 4
Solvent effect on the addition of
fone (4a) with Q-5ca
a
-phenyl
a
-cyanoacetate 10A to vinyl phenyl sul-
Enantioselective conjugate addition of
a
-alkyl
a
-cyanoacetates 10 to vinyl sulfone
with 5ca,b,c
EtO2C
R
Conversionb/%
eec/%
EtO2C CN
Entry
Time/h
Solvent
CN
Q-5c (QD-5c)
SO2R'
+
1
2
3
4
5
6
17
17
17
17
17
72
TBME
9
17
17
22
46
95
58
79
74
81
95
95
R
*
SO2R'
CHCl3
CH2Cl2
DCE
Toluene
Toluene
CF3
11J R' = Ph
12
CF3
4a: R' = Ph
4b: R' =
10J: R=Allyl
10K: R=Methyl
R' =
CF3
a
Reactions were run with 10A (0.3 mmol), 4a (0.1 mmol), and Q-5c (0.02 mmol)
in toluene (0.2 mL) at ꢀ25 ꢁC.
CF3
b
Determined by 1H NMR analysis.
Determined by HPLC analysis.
Entry 10
4
T/ꢁC Time/h Product Conversion/% Yieldd/% eee/%
c
1
2
3
4
10J
10J
10J
4a 23
4b 23
17
17
96
11J
12J
12J
17
88
100
100 (100)
N.D.
N.D.
76
87
86
94f
cinchona alkaloids bearing either an aryl or alkyl ether at C9
(entries 9 and 10). Thus, the tunable group at C9 provided a crucial
handle for the optimization of the catalytic enantioselectivity of 5.
Our screening studies identified 5c as the best catalyst (entries 10
and 12).
Next, we examined the reaction in various solvents. The reaction
was found to proceed at the fastest rate and in the highest enan-
tioselectivity in toluene. It is noteworthy that such a non-polar
solvent is known to favor the formation and stabilization of
hydrogen bonding complexes between solvates. An excellent
enantioselectivity could be achieved with Q-5c in toluene at ꢀ25 ꢁC
(entries 5 and 6, Table 2).
4b
0
0
10K 4b
96 (96) 12K
85 (83)
92 (88)
a
Unless noted, reactions were run with 10 (0.5–0.6 mmol) and 4 (0.2 mmol) with
5c (0.04 mmol).
b
The catalyst was recovered in greater than 95% yield after the reaction.
c
The results in parentheses were obtained with QD-5c to give the opposite
enantiomer.
d
Isolated yield.
Determined by HPLC analysis.
The absolute configuration of adduct (þ)-12J was determined to be ‘S’ by X-ray
e
f
structure analysis, see Section 4.5 for details.
vinyl sulfones. While addition of
phenyl vinyl sulfone 4a with Q-5c proceeded to completion at room
temperature after 17 h (entry 12, Table 1), the addition of -allyl-
cyanoacetate 10J to 4a proceeded to only 17% conversion during the
same period (entry 1, Table 4). Importantly, both reactions pro-
ceeded in comparable enantioselectivity (87% ee vs 84% ee).
We reasoned that the cinchona alkaloid-catalyzed conjugate
a-phenyl a-cyanoacetate 10A to
a
a-
2.2. Conjugate additions of
vinyl sulfones
a-substituted a-cyanoacetate to
After establishing the optimal reaction conditions we began to
investigate the substrate scope of the 5c-catalyzed conjugate ad-
addition with
a-alkyl a-cyanoacetate might be accelerated con-
dition to vinyl sulfone (4a). The
a-cyanoacetates 10 bearing a range
siderably by enhancing the electrophilicity of the vinyl sulfone,
which could be implemented via the introduction of electron-
of -aryl and -heteroaryl groups of varying electronic and steric
a
a
properties underwent efficient enantioselective additions to phenyl
vinyl sulfone (4a), providing the corresponding 1,4-adducts 11
bearing the all-carbon quaternary stereocenter in excellent enan-
tioselectivity and good to excellent yield (Table 3).
Table 5
Enantioselective conjugate addition of
a
-cyanoketones 13 and
b
-ketoesters 14 to
Having established a general scope with respect to
-cyanoacetates, we attempted to extend the scope to
a
-aryl
vinyl sulfone 4a catalyzed by 5ca,b
a
a
a
a-alkyl
O
X
O
-cyanoacetates. We found that, compared to their aryl congeners,
-alkyl -cyanoacetates were significantly less active as Michael
X
Q-5c (QD-5c)
SO2Ar
a
+
R
SO2Ar
R
(20 mol%)
donor for the cinchona alkaloid-catalyzed conjugate addition to
R'
R'
15: X = CN
4a: Ar = Ph
13: X = CN
16: X = CO2R"
14: X = CO2R"
Table 3
Additions of
O
O
O
a
-aryl
CN
a
-cyanoacetates 10 to vinyl phenyl sulfone (4a) with 5ca,b,c
O
O
O
CN
EtO2C CN
CO2tBu
CN
EtO2C
CO2tBu
O
Q-5c (QD-5c)
SO2Ph
4a
+
Ph
13D
R
SO2Ph
*
n
R
10
11
14C
14A
14B
13:A n=1 B n=2
C n=3
Entry
R
T/ꢁC
Time/h
Product
Yieldd/%
eee/%
1
2
3
4
5
6
7
8
9
10A
Ph–
ꢀ25
0
0
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
72 (72)
48
70
11A
11B
11C
11D
11E
11F
11G
11H
11I
89 (80)
96
92
95 (91)
93
93
Entry
Michael Donor
Time/h
Product
Yieldc/%
eed/%
10B
10C
10D
10E
10F
10G
10H
10I
4-Me–Ph–
4-MeO–Ph–
4-F–Ph–
4-Cl–Ph–
4-Br–Ph–
3-Cl–Ph–
2-Naphthyl–
2-Thienyl
1
2
3
4
5
6
7
13A
13B
13C
13D
14A
14B
14C
24
24
24
24
48
48
24
15A
15B
15C
15D
16A
16B
16C
96 (90)
96 (98)
91 (91)
0
93 (96)
96 (100)
0
95 (97)
95 (95)
96e (97)
N.D.
96 (96)
96 (97)
N.D.
72
90
94
69 (72)
69 (72)
60
60 (60)
48 (48)
95 (94)
95 (95)
96
96 (95)
95 (91)
94 (89)
94 (88)
93
97 (90)
93 (88)
a
a
Unless noted, reactions were run with 10 (0.5–0.6 mmol), 4a (0.2 mmol), and 5c
(0.04 mmol).
Unless noted, reactions were run with 13 or 14 (0.40 mmol), 4a (0.20 mmol) in
toluene (0.40 mL) with Q-5c (20 mol %).
b
b
The catalyst was recovered in greater than 95% yield after the reaction.
The results in parentheses were obtained with QD-5c.
Isolated yield.
Determined by HPLC analysis.
The absolute configuration of (ꢀ)-15C was determined to be ‘S’ by X-ray struc-
c
c
The results in parentheses were obtained with QD-5c to give the opposite
enantiomer.
d
d
e
Isolated yield.
Determined by HPLC analysis.
e
ture analysis, see Section 4.5 for details.

3142
H. Li et al. / Tetrahedron 65 (2009) 3139–3148
Table 6
Additions of
b
-ketoester 14D to b
-substituted vinyl triflone 17 with Q-5ca
O
*
O
COOMe
SO2R'
R
QD-5c (20 mol%)
R
COOMe
+
SO2R'
toluene (1.0 M), rt, 24h
*
17a: R=Me, R'=Ph
17a': R=Ph, R'=Ph
17b: R=n-C5H11, R'=CF3
14D
18
Entry
Acceptor
Solvent
Conversion
drb
ee of major
isomerc/%
ee of minor
isomerc/%
1
2
3
4
5
6
7
8
17a
17b
17b
17b
17b
17b
17b
17b
Toluene
Toluene
THF
Et2O
EtOAc
ClCH2Cl2Cl
CHCl3
CH2Cl2
0
100
100
100
100
100
100
100
ND
ND
96
81
92
87
94
96
95
ND
56
6
12
6
23
26
20
5.5:1
3.7:1
4.3:1
4.6:1
7.0:1
5.7:1
8.0:1
a
Unless noted, reactions were run with 14D (0.025 mmol), 17 (0.0275 mmol) in a solvent (0.10 mL) with QD-5c (10 mol %).
b
c
Determined by 1H NMR analysis.
Determined by HPLC analysis.
withdrawing substituents on the aromatic ring of the phenyl vinyl
conjugate additions of an a-alkyl a-cyanoacetate by tuning the
sulfone 4. Based on our proposed transition state model outlined in
Scheme 1, steric variations of the phenyl group of 4 should not
disrupt how catalyst 5c interacts with the reacting substrates. With
this consideration in mind, we investigated the conjugate addition
of 10J to 3,5-bis(triflouromethyl)phenyl vinyl sulfone (4b)7with
Q-5c at room temperature. We were pleased to find that the
reaction was indeed significantly accelerated, proceeding to 88%
conversion after 17 h. Importantly, the corresponding 1,4-adduct 12
was obtained in 86% ee (entry 2, Table 4). Thus, the ability of 60-OH
cinchona alkaloid catalysts to tolerate the structural change of the
vinyl sulfone 4 allowed us to significantly improve the rate of the
electronic property of the vinyl sulfone acceptor. Importantly, the
high enantioselectivity could be readily extended to the conjugate
addition of a-methyl a-cyanoacetate 10K to 4b (entry 4, Table 4).
2.3. Conjugate additions of
a-substituted a-cyanoketones and
b-ketoesters to vinyl sulfones
We also investigated the 5c-catalyzed additions of cyclic
-cyanoketones (13A–C) and cyclic -ketoesters (14A and B) to
a
b
vinyl sulfone 4a. Asillustrated inTable 5, reactions with these Michael
donors proceeded in high yield and excellent enantioselectivity.
Table 7
Diastereoselective and enantioselective conjugate additions to
b
-alkyl vinyl triflones 17 catalyzed by 5ca
X
Y
Q-5c (QD-5c)
R
Michael
SO2CF3
+
*
R'
*
SO2CF3
(10 mol%)
Donors
R
17
18: X=CN, Y=CO2Et
19: X=COR, Y=CN
20: X=COR, Y=CO2Me
17
Michael Donors
n-C5H11
SO2CF3
F
Br
COOEt
COOEt
COOEt
CN
17b
CN
O
CN
O
SO2CF3
10A
10D
10F
O
17c
O
O
Ph
CN
SO2CF3
OMe
OEt
17d
14E
14D
13E
Entry
Donor
17
T/ꢁC
Time/h
Product
dr
eeb/%
yieldc/%
1
2
3
4
5
6
7
10A
10D
10F
13E
14D
14D
14E
17b
17b
17b
17b
17b
17c
17d
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ20
ꢀ20
ꢀ20
96
96
96
24
96
72
48
18Ab
18Db
18Fb
19Eb
20Db
20Dc
20Ed
5.6:1 (4.6:1)
26:1 (12:1)
49:1 (26:1)
>49:1 (>49:1)
32:1 (9:1)
93 (87)
92 (84)
81 (86)
99 (94)
98 (97)
98 (95)
95 (89)
87d (76)d
94d (91)d
92d (92)d
95d (94)
90d (93)d
100 (95)
91d (80)d
24:1 (8:1)
>49:1 (>49:1)
a
Unless noted, reactions were run with 10 or 13 or 14 (0.10 or 0.20 mmol), 17 (0.10 mmol), and Q-5c (0.02 mmol) in methylene chloride (0.20 mL), and the results in
parentheses were obtained with QD-5c to give the opposite enantiomer.
b
Determined by HPLC analysis.
c
Isolated yield.
d
Yield of pure major diastereomer.

H. Li et al. / Tetrahedron 65 (2009) 3139–3148
3143
However, with either acyclic
ketoester (14C), no conjugate addition product was obtained.
Only starting materials were recovered.
a
-cyanoketone (13D) or acyclic
b
-
exact mass spectra on a VG 7070 high resolution mass spectrom-
eter. Infrared spectra were recorded on a Perkin Elmer FT-IR
Spectrometer. Specific rotations were measured on a Jasco Digital
Polarimeter. Liquid chromatography was performed using forced
flow (flash chromatography) of the indicated solvent system on EM
Science silica gel 60 (SiO2, 230–400 mesh). Analytical gas–liquid
chromatography (GLC) was performed on a Hewlett-Packard 6890
Series instrument equipped with a split mode capillary injection
system, a flame ionization detector, using a HP-5 GC column or a GC
column with chiral stationary phase [Gamma cyclodextrin
Trifluoroacetyl (30 mꢂ0.25 mm) or HP Chiral (20% Permethylated
B-Cyclodextrin, 30 mꢂ0.25 mm)]. All the GC analyses of chiral cy-
anohydrin carbonates were carried out with both a crude reaction
sample and a sample purified by silica gel chromatography. High
performance liquid chromatography (HPLC) analyses were per-
formed on a Hewlett-Packard 1100 Series instrument equipped
with an isostatic pump, using a Daicel Chiralpak AS (250ꢂ4.6 mm),
AD (250ꢂ4.6 mm) or Hypersil SI (200ꢂ4.6 mm) Column. UV de-
tection was monitored at 254 nm or 220 nm.
2.4. Conjugate additions to
sulfones
b-substituted a,b-unsaturated
Adjacent quaternary and tertiary stereocenters are common
structural motifs in natural products. Highly diastereoselective and
enantioselective conjugate additions of prochiral trisubstituted
carbon nucleophiles to prochiral b-substituted Michael acceptors
with a chiral catalyst could provide a one-step and stereoselective
construction of such complex motifs from simple precursors. Thus,
we began to investigate the conjugate additions of various nucleo-
philes to
We first examined the Q-5c-catalyzed conjugate additions of
-ketoester 14D to -methyl vinyl sulfone 17a and -phenyl vinyl
b-substituted a,b-unsaturated sulfones with Q-5c.
b
b
b
sulfone 17a0 in toluene at room temperature. Unfortunately, no
addition product was found, and only starting materials were re-
covered. Trifluoromethanesulfonyl group (CF3SO2–) is one of the
strongest neutral electron-withdrawing groups known. If SO2Ph in
17 was replaced by SO2CF3, the resulting vinyl sulfones should be
much more active toward conjugate additions. Following this
thought, we began to investigate the QD-5c-catalyzed conjugate
4.2. Typical procedure for enantioselective addition of
a-aryl (10A–I) or alkyl
a-cyanoacetates (10J–K) to vinyl
sulfone 4a or 4b with 5c
addition of
b-ketoester 14D to
b
-substituted vinyl triflone 17b.8 We
At ꢀ25 ꢁC or 0 ꢁC, to a solution of
a-cyanoacetate 10 (for 10A–C,
were pleased to find that, in contrast to reactions with 17a, the
reaction proceeded smoothly to completion after 12 h at room
temperature in toluene to afford the desired 1,4-adduct in excellent
ee and promising dr (entry 2, Table 6). Further optimization
revealed that CH2Cl2, ClCH2CH2Cl, and CHCl3 were better solvents,
and the conjugate addition proceeded in the highest enantiose-
lectivity and diastereoselectivity in CH2Cl2 (entry 8, Table 6).
Encouraged by these results, a variety of trisubstituted carbon
Michael donors were subjected to the 5c-catalyzed conjugate ad-
using 0.6 mmol; for 10D–I, using 0.5 mmol, for 10J–K, using
0.2 mmol) in toluene (0.4 mL) was added either Q-5c or QD-5c
(20 mol %) and vinyl phenyl sulfone 4a or 4b (0.2 mmol) as speci-
fied in Tables 3 and 4. The resulting mixture was kept at the in-
dicated temperature until sulfone is completely consumed. The
reaction mixture was directly subjected to silica gel flash chroma-
tography using the eluent specified below to afford the 1,4-adduct
in the yields and enantiomeric excess summarized above. Finally,
the column was washed with MeOH and the catalyst was recovered
in greater than 95% yield. The recovered catalyst was shown to be
identical to that before the reaction by NMR analysis.
ditions to various
diastereoselectivity and enantioselectivity were obtained with
various -aryl -cyanoacetates 10, -cyanoketones 13, and cyclic
-ketoesters 14 (Table 7).
b
-substituted vinyl triflones 17b–d.8 Excellent
a
a
a
b
4.2.1. Compound (þ)-11A (Table 3, entry 1)
This product was obtainedas a colorless oil in 89% yield afterflash
chromatography (elution gradient: ethyl acetate/hexane¼1:8 to
6:1) and 95% ee as determined by HPLC analysis [Daicel chiralcel OD,
3. Conclusions
In summary, we have developed a highly efficient catalytic
asymmetric conjugate addition to -unsaturated sulfones. This
reaction utilizes readily accessible and recyclable chiral organic
catalysts and involves an air- and moisture-tolerant simple experi-
mental protocol that avoids low temperature and low volumetric
productivity. The general scopes with respect to both the donors
hexanes/IPA¼90:10, 1.0 mL/min, ¼220 nm, tR (major)¼16.48 min,
l
a
,
b
tR (minor)¼14.93 min] from a reaction catalyzed by Q-5c (20 mol %)
25
at ꢀ25 ꢁC for 72 h. [
a
]
þ31.6 (c 1.0, CHCl3); 1H NMR (400 MHz,
D
CDCl3)
d
7.89 (d, J¼8.0 Hz, 2H), 7.69 (t, J¼7.2 Hz,1H), 7.59 (t, J¼8.0 Hz,
2H), 7.45–7.39 (m, 5H), 4.28–4.15 (m, 2H), 3.27 (dt, J¼4.4, 12.8 Hz,
1H), 3.04 (dt, J¼4.4,12.8 Hz,1H), 2.75–2.59 (m, 2H),1.21 (t, J¼7.2 Hz,
and
a
,b
-unsaturated sulfones attained by the bifunctional cinchona
3H); 13C NMR (100 MHz, CDCl3)
d 166.2, 138.3, 134.1, 132.6, 129.54,
alkaloid catalysts are particularly noteworthy. A wide range of
129.48, 128.0, 125.8, 117.0, 63.7, 52.3, 52.1, 30.8, 13.7; HRMS (CI) m/z
a
a
-substituted
-cyanoketone, and
b
-carbonyl Michael donors, such as
-ketoesters, could be employed in the re-
-unsaturated
sulfones. Specifically, vinyl sulfones bearing either no or a -sub-
a
-cyanoacetate,
calcd for (C19H19NO4SþHþ): 358.1113, found: 358.1108; IR (CHCl3)
n
b
3064, 2984, 2939, 1745, 1448, 1321, 1237, 1087 cmꢀ1
.
action. The reaction also tolerates variations in the a,b
b
4.2.2. Compound (ꢀ)-11A
stituent could be applied in this reaction. Consequently, the
reaction provides a highly versatile catalytic entry for the asym-
metric synthesis of chiral sulfones containing all-carbon quaternary
stereocenters.
This product was obtained as a colorless oil in 80% yield and 91%
ee from a reaction catalyzed by QD-5c (20 mol %) at ꢀ25 ꢁC for 72 h.
4.2.3. Compound (þ)-11B (Table 3, entry 2)
This product was obtained as a colorless oil in 96% yield after
flash chromatography (ethyl acetate/hexane¼1:7) and 93% ee as
determined by HPLC analysis [Daicel Chiralpak AD, hexanes/
4. Experimental
4.1. General
IPA¼85:15, 1.0 mL/min,
l
¼220 nm, tR (major)¼13.33 min, tR
(minor)¼22.06 min] from a reaction catalyzed by Q-4c (20 mol %)
25
1H and 13C NMR spectra were recorded on a Varian instrument
(400 MHz and 100 MHz, respectively) and internally referenced to
SiMe4 signal. Low resolution mass spectra for all the new com-
pounds were recorded on a Hewlett-Packard 5989A GC/MS, and
at 0 ꢁC for 48 h. [
CDCl3)
a
]
D
þ31.4 (c 1.02, CHCl3); 1H NMR (400 MHz,
d
7.89 (d, J¼8.0 Hz, 2H), 7.69 (t, J¼7.2 Hz, 1H), 7.58 (t,
J¼8.0 Hz, 2H), 7.30 (d, J¼8.4 Hz, 2H), 7.20 (d, J¼8.4 Hz, 2H), 4.27–
4.11 (m, 2H), 3.25 (dt, J¼5.6, 12.8 Hz, 1H), 3.03 (dt, J¼4.4, 12.8 Hz,

3144
H. Li et al. / Tetrahedron 65 (2009) 3139–3148
25
1H), 2.72–2.58 (m, 2H), 2.35 (s, 3H), 1.21 (t, J¼7.2 Hz, 3H); 13C NMR
at ꢀ25 ꢁC for 66 h. [
a
]
þ28.8 (c 1.10, CHCl3); 1H NMR (400 MHz,
D
(100 MHz, CDCl3)
d
166.3, 139.5, 138.3, 134.0, 130.1, 129.5, 129.4,
CDCl3)
d
7.89 (d, J¼8.0 Hz, 2H), 7.70 (t, J¼8.0 Hz, 1H), 7.60 (t,
127.9, 125.6, 117.2, 63.6, 52.06, 51.98, 30.7, 20.9, 13.6; HRMS (CI) m/z
J¼8.0 Hz, 2H), 7.54 (d, J¼8.8 Hz, 2H), 7.32 (d, J¼8.8 Hz, 2H), 4.29–
4.16 (m, 2H), 3.25 (dt, J¼4.4, 13.2 Hz, 1H), 3.01 (dt, J¼4.0, 13.2 Hz,
1H), 2.71 (dt, J¼4.4, 13.2 Hz, 1H), 2.60 (dt, J¼4.0, 13.2 Hz, 1H), 1.23 (t,
calcd for (C20H21NO4SþHþ): 372.1270, found: 372.1276; IR (CHCl3)
n
2983, 1744, 1447, 1321, 1235, 1148, 1087 cmꢀ1
.
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 165.8, 138.2, 134.2,
4.2.4. Compound (þ)-11C (Table 3, entry 3)
132.7, 131.6, 129.5, 128.0, 127.5, 123.9, 116.6, 64.0, 52.01, 51.96, 30.7,
This product was obtained as a colorless oil in 92% yield after
flash chromatography (ethyl acetate/hexane¼1:6) and 93% ee as
determined by HPLC analysis [Daicel Chiralpak AD, hexanes/
13.7; HRMS (CI) m/z calcd for (C19H18BrNO4SþHþ): 436.0218,
found: 436.0208; IR (CHCl3)
n 2983, 1745, 1489, 1447, 1322, 1236,
1148 cmꢀ1
.
IPA¼85:15, 0.9 mL/min,
l
¼220 nm, tR (major)¼28.93 min, tR
(minor)¼33.20 min] from a reaction catalyzed by Q-5c (20 mol %)
4.2.9. Compound (ꢀ)-11F
25
at 0 ꢁC for 70 h. [
CDCl3)
a]
þ31.0 (c 1.10, CHCl3); 1H NMR (400 MHz,
This product was obtained as a colorless oil in 95% yield and 88%
D
d
7.89 (d, J¼7.2 Hz, 2H), 7.69 (t, J¼7.2 Hz, 1H), 7.58 (t, 7.2 Hz,
ee from a reaction catalyzed by QD-5c (20 mol %) at ꢀ25 ꢁC for 72 h.
2H), 7.34 (td, J¼2.4, 9.2 Hz, 2H), 6.90 (td, J¼2.4, 9.2 Hz, 2H), 4.27–
4.14 (m, 2H), 3.81 (s, 3H), 3.25 (dt, J¼5.2, 12.0 Hz, 1H), 3.04 (dt,
J¼4.0, 12.0 Hz, 1H), 2.72–2.57 (m, 2H), 1.21 (t, J¼6.8 Hz, 3H); 13C
4.2.10. Compound (þ)-11G (Table 3, entry 7)
This product was obtainedas a colorless oil in 96% yield afterflash
chromatography (ethyl acetate/hexane¼1:7) and 93% ee as de-
termined by HPLC analysis [Daicel chiralpak AD, hexane/IPA¼85:15,
NMR (100 MHz, CDCl3)
d 166.4, 160.2, 138.3, 134.1, 129.4, 128.0,
127.1, 124.2, 117.2, 114.8, 63.6, 55.3, 52.1, 51.6, 30.7, 13.7; HRMS (CI)
m/z calcd for (C20H21NO5SþHþ): 388.1219, found: 388.1210; IR
1.0 mL/min,
l
¼220 nm, tR (major)¼15.00 min, tR (minor)-
(CHCl3)
n
2982, 1743, 1512, 1307, 1257, 1236, 1147 cmꢀ1
.
¼12.58 min] from a reaction catalyzed by Q-5c (20 mol %) at ꢀ25 ꢁC
25
for 60 h. [
a
]
þ29.5 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
D
4.2.5. Compound (þ)-11D (Table 3, entry 4)
d
7.91–7.88 (m, 2H), 7.73–7.68 (m, 1H), 7.60 (t, J¼7.2 Hz, 2H), 7.42–
This product was obtained as a colorless oil in 90% yield after
flash chromatography (ethyl acetate/hexane¼1:5) and 94% ee as
determined by HPLC analysis [Daicel chiralcel OD, hexane/
7.33 (m, 4H), 4.31–4.17 (m, 2H), 3.27 (dt, J¼4.4,13.6 Hz,1H), 3.04 (dt,
J¼3.6, 12.8 Hz, 1H), 2.73 (dt, J¼4.8, 12.8 Hz, 1H), 2.58 (dt, J¼4.4,
12.8 Hz, 1H), 1.23 (t, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
IPA¼90:10, 1.0 mL/min,
l¼220 nm, tR (major)¼21.42 min, tR
d 165.7, 138.2, 135.6, 134.5, 134.2, 130.8, 129.8, 129.5, 128.0, 126.1,
(minor)¼17.98 min] from a reaction catalyzed by Q-5c (20 mol %) at
124.0, 116.5, 64.1, 52.0, 30.9, 13.7; HRMS (CI) m/z calcd for
25
ꢀ25 ꢁC for 72 h. [
a
]
þ27.2 (c 1.13, CHCl3); 1H NMR (400 MHz,
(C19H18ClNO4SþHþ): 392.0723, found: 392.0721; IR (CHCl3)
n 2984,
D
CDCl3)
d
7.90–7.88 (m, 2H), 7.70 (tt, J¼1.2, 7.6 Hz, 1H), 7.59 (t,
1746, 1478, 1447, 1309, 1322, 1237, 1148 cmꢀ1
.
J¼7.2 Hz, 2H), 7.45–7.41 (m, 2H), 7.11 (tt, J¼1.6, 8.0 Hz, 2H), 4.29–
4.16 (m, 2H), 3.26 (dt, J¼4.8, 13.6 Hz, 1H), 3.03 (dt, J¼3.6, 12.8 Hz,
1H), 2.72 (dt, J¼4.4, 14.0 Hz, 1H), 2.61 (dt, J¼4.4, 14.0 Hz, 1H), 1.22 (t,
4.2.11. Compound (þ)-11H (Table 3, entry 8)
This product was obtained as a colorless oil in 96% yield after
flash chromatography (elution gradient: ethyl acetate/hexane¼1:6)
and 98% ee as determined by HPLC analysis [Daicel chiralcel OD,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.0, 163.0 (d,
1JC,F¼249.0 Hz), 138.3, 134.1, 129.5, 128.4 (d, JC,F¼3.0 Hz), 128.0,
127.8 (d, 3JC,F¼8.3 Hz), 116.9, 116.6 (d, 2JC,F¼22.1 Hz), 63.9, 52.0, 51.7,
30.8, 13.6; HRMS (CI) m/z calcd for (C19H18FNO4SþHþ): 376.1019,
4
hexane/IPA¼90:10, 1.0 mL/min, ¼220 nm, tR (major)¼23.90 min,
l
tR (minor)¼27.21 min] from a reaction catalyzed by Q-5c (20 mol %)
25
found: 376.1015; IR (CHCl3)
1447, 1307, 1237, 1087 cmꢀ1
n
3070, 2985, 2940, 1745, 1604, 1510,
at ꢀ25 ꢁC for 60 h. [
a]
þ46.7 (c 1.00, CHCl3); 1H NMR (400 MHz,
D
.
CDCl3)
d
7.97 (d, J¼1.6 Hz, 1H), 7.88–7.84 (m, 5H), 7.68–7.64 (m, 1H),
7.57 (m, 4H), 7.44 (dd, J¼2.4, 8.4 Hz, 1H), 4.29–4.15 (m, 2H), 3.32 (dt,
J¼4.8, 13.6 Hz, 1H), 3.04 (dt, J¼4.4, 12.4 Hz, 1H), 2.87–2.71 (m, 2H),
4.2.6. Compound (þ)-11E (Table 3, entry 5)
This product was obtained as a colorless oil in 95% yield after
flash chromatograph (ethyl acetate/hexane¼1:6) and 94% ee as
determined by HPLC analysis [Daicel chiralcel OD, hexane/
1.20 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.2, 138.3,
134.0, 133.1, 132.9, 129.7, 129.6, 129.4, 128.2, 127.9, 127.6, 127.4,
127.2, 125.9, 122.0, 117.1, 63.8, 52.5, 52.1, 30.6, 13.6; HRMS (CI) m/z
calcd for (C23H21NO4SþHþ): 408.1270, found: 408.1266; IR (CHCl3)
IPA¼85:15, 1.0 mL/min,
l¼220 nm, tR (major)¼16.75 min, tR
(minor)¼13.57 min] from a reaction catalyzed by Q-5c (20 mol %) at
n .
3061, 2983, 1744, 1321, 1234, 1151, 1087 cmꢀ1
25
ꢀ25 ꢁC for 69 h. [
a
]
þ31.9 (c 1.10, CHCl3); 1H NMR (400 MHz,
D
CDCl3)
d
7.85 (d, J¼8.8 Hz, 2H), 7.65 (t, J¼7.2 Hz, 1H), 7.55 (t,
4.2.12. Compound (ꢀ)-11H
J¼6.4 Hz, 2H), 7.34 (s, 4H), 4.22–4.14 (m, 2H), 3.23 (dt, J¼4.4,
12.8 Hz, 1H), 2.99 (dt, J¼4.4, 12.8 Hz, 1H), 2.69 (dt, J¼4.4, 12.8 Hz,
1H), 2.56 (dt, J¼4.4, 12.8 Hz, 1H), 1.17 (t, J¼7.2 Hz, 3H); 13C NMR
This product was obtained as a colorless oil in 95% yield and
90% ee from a reaction catalyzed by QD-5c (20 mol %) at ꢀ25 ꢁC for
60 h.
(100 MHz, CDCl3)
d 165.8, 138.2, 135.6, 134.1, 131.1, 129.6, 129.4,
127.9,127.2,116.6, 63.9, 51.9, 51.8, 30.6,13.6; HRMS (CI) m/z calcd for
4.2.13. Compound (þ)-11I (Table 3, entry 9)
(C19H18ClNO4SþHþ): 392.0723, found: 392.0728; IR (CHCl3)
n
3066,
This product was obtained as a brown oil in 95% yield after flash
chromatography (ethyl acetate/hexane¼1:6) and 93% ee as de-
termined by HPLC analysis [Daicel chiralcel OD, hexane/IPA¼90:10,
2984, 1745, 1493, 1447, 1322, 1236, 1148 cmꢀ1
.
4.2.7. Compound (ꢀ)-11E
1.0 mL/min,
l
¼220 nm, tR (major)¼20.54 min, tR (minor)¼18.50
This product was obtained as a colorless oil in 94% yield and 89%
min] from a reaction catalyzed by Q-5c (20 mol %) at ꢀ25 ꢁC for 48 h.
25
ee from a reaction catalyzed by QD-5c (20 mol %) at ꢀ25 ꢁC for 72 h.
[
a
]
þ20.2 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.91–7.88 (m,
D
2H), 7.72–7.68 (m, 1H), 7.59 (t, J¼8.0 Hz, 2H), 7.36 (dd, J¼1.2, 4.8 Hz,
2H), 7.20 (dd, J¼1.2, 4.0 Hz, 1H), 6.99 (dd, J¼3.6, 4.8 Hz, 1H), 4.29–
4.23 (m, 2H), 3.27 (dt, J¼4.8,12.8 Hz,1H), 3.14 (dt, J¼4.4,12.4 Hz,1H),
2.78–2.61 (m, 2H), 1.27 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
4.2.8. Compound (þ)-11F (Table 3, entry 6)
This product was obtained as a colorless oil in 95% yield after
flash chromatography (ethyl acetate/hexane¼1:6) and 94% ee as
determined by HPLC analysis [Daicel chiralpak AD, hexane/
d
165.5,138.2,134.9,134.1,129.4,127.9,127.5,127.4,127.1,116.3, 64.0,
IPA¼85:15, 1.0 mL/min,
l
¼220 nm, tR (major)¼22.51 min, tR
52.0, 49.3, 32.1, 13.6; HRMS (CI) m/z calcd for (C17H17NO4S2þHþ):
(minor)¼26.82 min] from a reaction catalyzed by Q-5c (20 mol %)
364.0677, found: 364.0669.

H. Li et al. / Tetrahedron 65 (2009) 3139–3148
3145
4.2.14. Compound (ꢀ)-11I
1H), 7.90–7.96 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
19.2, 26.6, 35.0,
This product was obtained as a brown oil in 91% yield and 88% ee
from a reaction catalyzed by QD-5c (20 mol %) at ꢀ25 ꢁC for 48 h.
36.3, 46.7, 51.9, 117.5, 128.0, 129.5, 134.2, 138.4, 207.9; HRMS
[MþH]þ calcd for: C14H16O3SN: 278.0851, found: 278.0854.
4.2.15. Compound (þ)-12J (Table 4, entry 3)
4.3.2. Compound (þ)-15A
This product was obtained as a white solid in 76% yield after flash
chromatography (ethyl acetate/hexane¼1:10) and in 93% ee as de-
termined by HPLC analysis [Daicel Chiralcel OD, hexane/IPA¼90:10,
This product was obtained as a white solid in 90% isolated yield
and in 95% ee from a reaction of 13A (43.6 mg, 0.40 mmol) and vinyl
sulfone 4a (33.6 mg, 0.20 mmol) in toluene (400
QD-5c (0.04 mmol) at room temperature for 24 h.
mL) catalyzed by
1.0 mL/min,
l
¼220 nm, tR (major)¼9.78 min, tR (minor)¼13.73 min]
25
from the reaction catalyzed by Q-5c (20 mol %) at 0 ꢁC for 96 h. [
a]
D
þ1.6 (c 1.5, CHCl3); mp 96–98 ꢁC; 1H NMR (400 MHz, CDCl3)
d
8.36 (s,
4.3.3. Compound (ꢀ)-15B (Table 5, entry 2)
2H), 8.18 (s,1H), 5.66–5.78 (m, 2H), 5.20–5.30 (m,1H), 4.18–4.32 (m,
2H), 3.36 (dt, J¼12.8, 4.4 Hz, 1H), 3.32 (dt, J¼12.8, 4.4 Hz, 1H), 2.68
(dd, J¼13.6, 6.8 Hz,1H), 2.65 (dd, J¼13.6, 6.8 Hz,1H), 2.40 (dt, J¼12.4,
4.4 Hz, 1H), 2.24 (dt, J¼12.4, 4.4 Hz, 1H), 1.29 (t, J¼6.8, 3H); 13C NMR
This product was obtained as a white solid in 96% yield after
flash chromatography and in 95% ee as determined by HPLC [de-
termined by HPLC, Daiso Chiralcel OJ, hexanes/IPA¼70:30, 1.0 mL/
min,
l
¼220 nm, tR (major)¼42.83 min, tR (minor)¼36.97 min] from
(100 MHz, CDCl3)
d
166.8, 141.4, 133.5 (q, J¼34 Hz), 129.2, 128.5,
a reaction of 13B (49.2 mg, 0.40 mmol) and vinyl sulfone 4a
(33.6 mg, 0.20 mmol) in toluene (400 L) catalyzed by Q-5c
(0.04 mmol) at room temperature for 24 h. [
CHCl3); mp 68–70 ꢁC; 1H NMR (400 MHz, CDCl3)
127.9, 122.3 (q, J¼273.0 Hz), 122.2, 117.2, 63.6, 52.3, 47.4, 41.3, 28.0,
m
25
13.9; IR (CHCl3)
n
3088, 2987, 1739, 1360, 1279, 1185, 1147 cmꢀ1
;
a]
ꢀ97.1 (c 1.1,
D
HRMS (CI) m/z calcd for (C18H17F6NO4SþHþ): 458.0861, found
d
1.64–1.76 (m,
458.0862.
2H), 1.86–1.96 (m, 1H), 1.98–2.10 (m, 2H), 2.10–2.18 (m, 1H), 2.28–
2.36 (m, 2H), 2.46 (dt, J¼3.6, 14.0 Hz, 1H), 2.79 (dt, J¼6.4, 20.0 Hz,
1H), 3.22 (dt, J¼4.4, 13.2 Hz, 1H), 3.39 (dt, J¼4.4, 13.2 Hz, 1H), 7.61 (t,
J¼7.6 Hz, 2H), 7.71 (m, 1H), 7.90–7.96 (m, 2H); 13C NMR (100 MHz,
The absolute configuration of adduct (þ)-12J was determined to
be ‘S’ by X-ray structure analysis, see Section 4.5 for details.
4.2.16. Compound (ꢀ)-12K (Table 4, entry 4)
CDCl3) d 22.1, 26.8, 27.7, 39.0, 39.1, 49.9, 52.0, 118.3, 128.0, 129.4,
This product was obtained as a white solid in 85% yield after
flash chromatography (ethyl ether/hexane¼1:5) and in 92% ee as
determined by HPLC analysis [Daicel Chiralcel OD, hexane/
134.0, 138.5, 201.9; HRMS [MþH]þ calcd for: C15H18O3SN: 292.1007,
found: 292.1008.
IPA¼90:10, 1.0 mL/min,
l
¼220 nm, tR (major)¼10.88 min, tR
4.3.4. Compound (þ)-15B
(minor)¼17.64 min] from the reaction catalyzed by Q-5c (20 mol %)
This product was obtained as a white solid in 98% isolated yield
and in 95% ee from a reaction of 13B (49.2 mg, 0.40 mmol) and vinyl
25
at 0 ꢁC for 96 h. [
(400 MHz, CDCl3)
a
d
]
ꢀ1.0 (c 2.0, CHCl3); mp 64–66 ꢁC; 1H NMR
D
8.40 (s, 2H), 8.21 (s, 1H), 4.28 (dq, J¼1.6, 7.2 Hz,
sulfone 4a (33.6 mg, 0.20 mmol) in toluene (400 mL) catalyzed by
QD-5C (0.04 mmol) at room temperature for 24 h.
2H), 3.38 (dt, J¼13.6, 4.4 Hz, 1H), 3.31 (dt, J¼12.8, 4.4 Hz, 1H), 2.45
(dt, J¼12.8, 4.4 Hz, 1H), 2.27 (dt, J¼12.8, 4.4 Hz, 1H), 1.67 (s, 3H), 1.32
(t, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 167.6, 141.4, 133.5 (q,
4.3.5. Compound (ꢀ)-15C (Table 5, entry 3)
J¼30 Hz), 128.5, 128.0, 127.9, 122.1 (q, J¼272.4 Hz), 118.2, 63.1, 52.4,
This product was obtained as a white solid in 91% yield after
flash chromatography and in 96% ee as determined by HPLC [de-
termined by HPLC, Daiso Chiralcel OJ, hexanes/IPA¼70:30, 1.0 mL/
42.4, 29.8, 23.7, 13.9; IR (CHCl3)
n 3088, 2990, 1745, 1281, 1186,
1147 cmꢀ1; HRMS (CI) m/z calcd for (C16H15F6NO4SþHþ): 432.0708,
found 432.0712.
min,
l
¼220 nm, tR (major)¼16.27 min, tR (minor)¼22.27 min] from
a reaction of 13C (54.8 mg, 0.40 mmol) and vinyl sulfone 4a
(33.6 mg, 0.20 mmol) in toluene (400 L) catalyzed by Q-5c
(0.04 mmol) at room temperature for 24 h. [
CHCl3); mp 153–156 ꢁC; 1H NMR (400 MHz, CDCl3)
4.2.17. Compound (þ)-12K
m
25
This product was obtained as a white solid in 83% yield and 88%
ee from a reaction catalyzed by QD-5c (20 mol %) at 0 ꢁC for 96 h.
a
]
ꢀ16.2 (c 1.0,
D
d
1.24–1.36 (m,
1H), 1.58–1.70 (m, 2H), 1.72–1.82 (m, 1H), 1.88–1.98 (m, 3H), 2.10–
2.22 (m, 2H), 2.32 (dq, J¼4.4, 8.0 Hz, 1H), 2.61 (dq, J¼4.8, 10.8 Hz,
1H), 2.72 (dt, J¼5.2, 13.6 Hz, 1H), 3.16 (dt, J¼4.4, 13.6 Hz, 1H), 3.27
(dt, J¼4.4, 13.6 Hz, 1H), 7.61 (t, J¼7.6 Hz, 2H), 7.67–7.72 (m, 1H),
4.3. Typical procedure for enantioselective additions of
a
-cyanoketones (13A–C) or
b-ketoesters (14A and B) to vinyl
sulfone 4a with 5c
7.90–7.94 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 24.1, 25.8, 28.2,
To a mixture of 4a (0.20 mmol) and 5c (20 mol %) in toluene
(0.40 mL) was added 13 (0.20 mmol) or 14 (0.40 mmol) in one
portion. The resulting reaction mixture was kept at either room
temperature or 0 ꢁC from 24 h to 96 h. The reaction mixture was
purified by silica gel chromatography directly using the eluent
specified below.
28.9, 36.2, 40.6, 52.0, 53.2, 118.7, 127.9, 129.5, 134.1, 138.4, 204.0;
HRMS [MþH]þ calcd for: C16H20O3SN: 306.1163, found: 306.1161.
The absolute configuration of (ꢀ)-15C was determined to be ‘S’
by X-ray structure analysis, see Section 4.5 for details.
4.3.6. Compound (þ)-15C
This product was obtained as a white solid in 91% isolated yield
and in 97% ee from a reaction of 13C (54.8 mg, 0.40 mmol) and vinyl
4.3.1. Compound (ꢀ)-15A (Table 5, entry 1)
This product was obtained as a white solid in 96% yield after
flash chromatography (silica gel, ethyl acetate/hexanes¼1:10) and
in 95% ee as determined by HPLC [determined by HPLC, Daiso
sulfone (33.6 mg, 0.20 mmol) in toluene (400 mL) catalyzed by QD-
2c (20 mol %) at room temperature for 24 h.
Chiralpak AD, hexanes/IPA¼80:20, 1.0 mL/min,
l
¼220 nm, tR
4.3.7. Compound (ꢀ)-16A (Table 5, entry 5)
(major)¼32.66 min, tR (minor)¼27.03 min] from a reaction of 13A
This product was obtained as a white solid in 93% yield after flash
chromatography (silica gel, ethyl ether/hexanes¼1:2) and in 96% ee
as determined by HPLC [determined by HPLC, Daiso Chiralpak AD,
(43.6 mg, 0.40 mmol) and vinyl sulfone 4a (33.6 mg, 0.20 mmol) in
toluene (400
ature for 24 h. [
(400 MHz, CDCl3)
2.36–2.46 (m, 1H), 2.46–2.58 (m, 2H), 3.265 (dt, J¼4.4, 12.4 Hz, 1H),
3.47 (dt, J¼4.4, 12.4 Hz, 1H), 7.61 (t, J¼7.6 Hz, 2H), 7.71 (d, J¼7.6 Hz,
mL) catalyzed by Q-5c (0.04 mmol) at room temper-
25
a]
ꢀ12.8 (c 1.0, CHCl3); mp 113–115 ꢁC; 1H NMR
1.98–2.18 (m, 4H), 2.25 (dt, J¼4.4, 12.4 Hz, 1H),
hexanes/IPA¼90:10, 1.0 mL/min,
tR (minor)¼19.24 min] from a reaction of 14a (73.6 mg, 0.40 mmol)
and vinyl sulfone 4a (33.6 mg, 0.20 mmol) in toluene (400 L) cat-
l¼220 nm, tR (major)¼15.64 min,
D
d
m
25
alyzed by Q-5c (0.04 mmol) at room temperature for 72 h. [
a]
ꢀ7.3
D

3146
H. Li et al. / Tetrahedron 65 (2009) 3139–3148
(c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
d
0.84 (t, J¼6.8 Hz, 3H),
(m, 1H), 3.40–3.48 (m, 2H), 4.18–4.42 (m, 2H), 7.38–7.44 (m, 3H);
7.50–7.58 (m, 2H); 13C NMR (100 MHz, CDCl3)
13.9,14.0, 22.2, 26.1,
1.04–1.54 (m, 8H), 1.56–1.78 (m, 1H), 2.84–2.96 (m, 1H), 3.20 (d,
J¼17.6 Hz, 1H), 3.40 (dd, J¼6.8, 6.8 Hz, 1H), 3.70 (s, 3H), 3.87 (d,
J¼17.6 Hz,1H), 4.12 (dd, J¼6.8, 6.8 Hz,1H), 7.43 (t, J¼7.2 Hz,1H), 7.53
(d, J¼8.0 Hz,1H), 7.67 (dt, J¼1.2, 8.0 Hz,1H), 7.8 (d, J¼8.0 Hz,1H); 13C
d
31.1, 31.6, 39.5, 51.8, 59.3, 64.3,116.9,119.5 (q, J¼325 Hz),126.7,129.7,
130.0, 132.2, 166.5; 19F NMR (376 MHz, CF3COOH¼ꢀ78.5 ppm)
ꢀ81.9; IR (neat)
n 2959, 1746, 1510, 1374, 1228, 1122; HRMS (ESI)
NMR (100 MHz, CDCl3)
d
19.5, 26.5, 27.7, 34.4, 33.7, 52.0, 58.6, 82.6,
[MþH]þ calcd for: C19H24F4O4S: 438.1362, found: 438.1358.
128.0, 129.3, 133.7, 138.7, 169.6, 214.2; IR (neat)
n 2977, 1746, 1719,
1147; HRMS [MþNa]þ calcd for: C18H24O5SNa: 375.1242, found:
4.4.2. Compound (ꢀ)-18Ab
375.1233.
This product was obtained as an colorless oil in 76% yield (single
diastereomer) and 87% ee from the corresponding QD-5c-catalyzed
reaction of 17b (23.0 mg, 0.10 mmol) and 10A (37.8 mg, 0.20 mmol)
4.3.8. Compound (þ)-16A
This product was obtained as a white solid in 96% isolated yield
and in 96% ee from a reaction of 14A (73.6 mg, 0.40 mmol) and vinyl
in methylene chloride (200
m
L) at ꢀ50 ꢁC for 96 h. The dr (4.6:1) of
the reaction was determined by 1H NMR analysis of the crude
product.
sulfone 4a (33.6 mg, 0.20 mmol) in toluene (400
QD-5c (0.04 mmol) at room temperature for 72 h.
mL) catalyzed by
4.4.3. Compound (þ)-18Db (Table 7, entry 2)
4.3.9. Compound (ꢀ)-16B (Table 5, entry 6)
This product was obtained from a Q-5c (4.8 mg, 0.01 mmol,
10 mol %) catalyzed reaction of 17b (23.0 mg, 0.10 mmol) and 10D
This product was obtained as a white solid in 100% yield after
flash chromatography (silica gel, ethyl ether/hexanes¼2:3) and
in 97% ee as determined by HPLC [determined by HPLC, Daiso
(41.0 mg, 0.20 mmol) in methylene chloride (200
m
L) at ꢀ50 ꢁC for
96 h. The dr (26:1) was determined by an analysis of the
Chiralpak AD, hexanes/IPA¼90:10, 1.0 mL/min,
l¼220 nm, tR
crude product via integration of one set of 19F NMR (376 MHz,
(major)¼28.57 min, tR (minor)¼24.85 min] from a reaction of 14B
CF3COOH¼ꢀ78.5 ppm) signals (s,
d
(major)¼ꢀ81.78 ppm,
(93.0 mg, 0.40 mmol) and vinyl sulfone 4a (33.6 mg, 0.20 mmol) in
d
(minor)¼ꢀ82.11 ppm)]. The crude product was purified by flash
toluene (400
ature for 36 h. [
(400 MHz, CDCl3)
m
L) catalyzed by Q-5c (0.04 mmol) at room temper-
chromatography (silica gel, hexanes/ethyl ether¼30:1) to give ad-
duct 18Db as a colorless oil (41 mg, 94% yield, single diastereomer)
and in 92% ee [determined by HPLC, Daiso Chiralpak AD, hexanes/
25
a]
ꢀ8.5 (c 2.00, CHCl3); mp 114–116 ꢁ; 1H NMR
D
d
0.84 (t, J¼6.8 Hz, 3H), 1.04–1.54 (m, 8H), 1.56–
1.78 (m, 1H), 2.84–2.96 (m, 1H), 3.20 (d, J¼17.6 Hz, 1H), 3.40 (dd,
J¼6.8, 6.8 Hz, 1H), 3.70 (s, 3H), 3.87 (d, J¼17.6 Hz, 1H), 4.12 (dd,
J¼6.8, 6.8 Hz, 1H), 7.43 (t, J¼7.2 Hz, 1H), 7.53 (d, J¼8.0 Hz, 1H), 7.67
(dt, J¼1.2, 8.0 Hz, 1H), 7.8 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz,
IPA¼98:2, 1.0 mL/min, ¼220 nm, tR (major)¼5.94 min, tR (minor)¼
l
25
8.01 min]. [
d
a
]
þ11.0 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
D
0.79 (t, J¼6.8 Hz, 3H),1.00–1.20 (m, 5H),1.26 (t, J¼7.0 Hz, 3H),1.28–
1.38 (m,1H),1.42–1.52 (m, 2H), 3.20–3.30 (m,1H), 3.40–3.48 (m, 2H),
CDCl3)
d
26.6, 27.7, 37.86, 52.2, 59.1, 82.6, 124.9, 126.4, 128.1, 129.3,
4.20–4.36 (m, 2H), 7.16 (t, J¼8.4 Hz, 2H), 7.50–7.60 (m, 2H); 13C NMR
133.8, 134.7, 135.6, 138.7, 140.0, 152.3, 169.3, 201.7; IR (neat)
n
2978,
(100 MHz, CDCl3) d 13.9, 14.0, 22.2, 26.1, 31.0, 31.5, 39.5, 51.6, 58.7,
1733,1707, 1149; HRMS [MþNa]þ calcd for: C22H24O5SNa: 423.1242,
64.5, 116.7, 116.8 (d, J¼22 Hz), 119.52 (q, J¼325 Hz), 128.00 (d,
found: 423.1245.
J¼3.0 Hz),128.79 (d, J¼8.0 Hz),163.50 (d, J¼118 Hz),166.45; IR (neat)
n
2959, 1746, 1510, 1374, 1228, 1122; 19F NMR (376 MHz,
4.3.10. Compound (þ)-16B
CF3COOH¼ꢀ78.5 ppm) ꢀ81.7, ꢀ113.8; HRMS (ESI) [MþH]þ calcd for:
This product was obtained as a white solid in 96% isolated yield
and in 96% ee from a reaction of 14B (93.0 mg, 0.40 mmol) and vinyl
C19H24F4O4S: 438.1362, found: 438.1358.
sulfone 4a (33.6 mg, 0.20 mmol) in toluene (400
QD-5c (0.04 mmol) at room temperature for 36 h.
m
L) catalyzed by
4.4.4. Compound (ꢀ)-18Db
This product was obtained as an colorless oil in 91% yield (single
diastereomer) and 84% ee from the corresponding QD-5c-catalyzed
reaction of 17b (23.0 mg, 0.10 mmol) and 10D (41.0 mg, 0.20 mmol)
4.4. Typical procedure for enantioselective additions of
-cyanocyanoacetates 10, -cyanoketones 13 and -ketoesters
-substituted vinyl triflones 17 with 5c
a
a
b
in methylene chloride (200
m
L) at ꢀ50 ꢁC for 96 h. The dr (12:1) of
14 to
b
the reaction was determined by 1H NMR analysis of the crude
product.
To
a mixture of 17 (0.10 mmol) and 5c (0.01 mmol) in
dichloromethane (0.2 mL) was added 10 or 13 or 14 in one portion.
The resulting reaction mixture was kept at ꢀ20 or ꢀ50 ꢁC from 24 h
to 96 h. The reaction mixture was purified by silica gel chroma-
tography directly using the eluent specified below.
4.4.5. Compound (þ)-18Fb (Table 7, entry 3)
This product was obtained from a Q-5c (4.8 mg, 0.010 mmol,
10 mol %) catalyzed reaction of 17b (23.0 mg, 0.10 mmol) and 10F
(53.2 mg, 0.20 mmol, 2.0 equiv) in methylene chloride (200 mL)
at ꢀ50 ꢁC for 96 h. The dr (49:1) was determined by an analysis
4.4.1. Compound (þ)-18Ab (Table 7, entry 1)
of the crude product via integration of one set of 19F NMR
This product was obtained from a Q-5c (4.8 mg, 0.01 mmol,
10 mol %) catalyzed reaction of 17b (23.0 mg, 0.10 mmol) and 10A
(376 MHz, CF3COOH¼ꢀ78.5 ppm) signals (s, (major)¼ꢀ81.69 ppm,
d
d
(minor)¼ꢀ81.95 ppm)]. The crude product was purified by flash
(37.8 mg, 0.20 mmol) in methylene chloride (200
m
L) at ꢀ50 ꢁC for
chromatography (silica gel, hexanes/ethyl ether¼30:1) to give ad-
duct 18Fb as a colorless oil (46 mg, 92% yield, single diastereomer)
and in 81% ee [determined by HPLC, Daiso Chiralpak AD, hexanes/
96 h. The dr (5.6:1) was determined by an analysis of the crude
product via integrations of one set of 19F NMR (376 MHz,
CF3COOH¼ꢀ78.5 ppm) signals (s,
d
(major)¼ꢀ81.86 ppm,
IPA¼98:2, 1.0 mL/min, ¼220 nm, tR (major)¼5.92 min, tR (minor)¼
l
25
d
(minor)¼ꢀ82.06 ppm)]. The crude product was purified by flash
9.91 min]. [
a
]
þ4.6 (c 2.00, CHCl3); 1H NMR (400 MHz, CDCl3)
D
chromatography (silica gel, hexanes/ethyl ether¼20:1) to give the
major diastereomer of the 1,4-adduct as a colorless oil (36 mg, 85%
yield, single diastereomer) and in 93% ee [determined by HPLC,
d
0.79 (t, J¼6.8 Hz, 3H),1.04–1.20 (m, 5H),1.26 (t, J¼7.0 Hz, 3H),1.30–
1.38 (m,1H),1.41–1.52 (m, 2H), 3.20–3.30 (m,1H), 3.40–3.50 (m, 2H),
4.20–4.36 (m, 2H), 7.46 (d, J¼9.2 Hz, 2H), 7.60 (d, J¼8.4 Hz, 2H); 13C
Daiso Chiralpak AD, hexanes/IPA¼98:2, 1.0 mL/min,
l¼220 nm, tR
NMR (100 MHz, CDCl3) d 13.6, 13.7, 22.0, 25.8, 30.8, 31.3, 39.1, 51.3,
25
(major)¼5.70 min, tR (minor)¼6.75 min]. [
1H NMR (400 MHz, CDCl3)
0.75 (t, J¼7.2 Hz, 3H), 0.94–1.14 (m, 5H),
1.23 (t, J¼6.4 Hz, 3H),1.22–1.34 (m,1H),1.42–1.52 (m, 2H), 3.20–3.30
a
]
þ12.0 (c 1.00, CHCl3);
58.8, 64.4, 116.2, 119.3 (q, J¼327 Hz), 124.2, 128.2, 131.0, 132.7, 166.0;
D
d
19F NMR (376 MHz, CF3COOH¼ꢀ78.5 ppm) ꢀ81.7; IR (neat)
n 2932,
1746, 1373, 1225, 1122.

H. Li et al. / Tetrahedron 65 (2009) 3139–3148
3147
4.4.6. Compound (ꢀ)-18Fb
(200
m
L) at ꢀ50 ꢁC for 96 h. The dr (9:1) of the reaction was de-
This product was obtained as an colorless oil in 92% yield (single
diastereomer) and 86% ee from the corresponding QD-5c-catalyzed
reaction of 17b (23.0 mg, 0.10 mmol) and 10F (53.2 mg, 0.20 mmol)
termined by 1H NMR analysis of the crude product.
4.4.11. Compound 20Dc (Table 7, entry 6)
This product was obtained from a Q-5c (4.8 mg, 0.010 mmol,
10 mol %) catalyzed reaction of 14D (38.0 mg, 0.20 mmol) and 17c
inmethylene chloride (200
m
L)at ꢀ50 ꢁC for96 h. Thedr (26:1) of the
reaction was determined by 1H NMR analysis of the crude product.
(21.6 mg, 0.10 mmol) in methylene chloride (200
m
L) at ꢀ20 ꢁC for
4.4.7. Compound (þ)-19Eb (Table 7, entry 4)
72 h. The crude product was purified by flash chromatography (silica
gel, hexanes/methylene chloride¼1:1) to give the adduct 20Dc as
a colorless oil and a diastereomeric mixture (41 mg, 100% yield,
dr¼24:1). The ee of the major diastereomer is determined to be 99%.
Both dr and ee were determined by HPLC [Daiso Chiralcel
This product was obtained from a Q-5c (4.8 mg, 0.010 mmol,
10 mol %) catalyzed reaction of 13E (15.7 mg, 0.10 mmol) and
17b (25.3 mg, 0.11 mmol) in methylene chloride (400
m
L) at ꢀ50 ꢁC
for 96 h. The dr (>49:1) was determined by an analysis of
the crude product via integration of one set of 19F NMR (376 MHz,
ADþChiralcel AD, hexanes/IPA¼98:2, 1.0 mL/min,
l
¼220 nm, tR
þ153.0 (c 1.00,
CHCl3); 1H NMR (400 MHz, CDCl3, major diastereomer was reported)
25
CF3COOH¼ꢀ78.5 ppm) signals (s,
d
(major)¼ꢀ81.50 ppm,
d
(minor)¼
(major)¼21.10 min, tR (minor)¼27.65 min]. [
a]
D
ꢀ81.24 ppm)]. The crude product was purified by flash chroma-
tography (silica gel, hexanes/ethyl acetate¼3:1) to give adduct
19Eb as a colorless oil (39 mg, 95% yield, single diastereomer)
and in 99% ee [determined by HPLC, Daiso Chiralcel OJ, hexanes/
d
0.90 (d, J¼6.4 Hz, 3H), 0.91 (d, J¼6.4 Hz, 3H), 1.02–1.12 (m, 1H), 1.60–
1.76 (m, 2H), 2.92–3.06 (m, 1H), 3.18 (d, J¼17.2 Hz, 1H), 3.36 (dd, J¼6.8,
14.4 Hz,1H), 3.71(s, 3H), 3.88(d, J¼17.2 Hz,1H), 4.12 (dd, J¼6.8,14.4 Hz,
1H), 7.44 (t, J¼7.2 Hz, 1H), 7.53 (d, J¼7.20 Hz,1H), 7.68 (t, J¼6.8 Hz,1H),
IPA¼90:10, 1.0 mL/min,
l
¼220 nm, tR (major)¼19.15 min, tR
25
(minor)¼24.02 min].
(400 MHz, CDCl3)
[a
]
þ75.0 (c 1.00, CHCl3); 1H NMR
7.80 (d, J¼8.0 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 21.1, 23.7, 25.1, 34.9,
D
d
0.89 (t, J¼6.8 Hz, 3H), 1.20–1.42 (m, 5H), 1.50–
35.7, 41.3, 50.2, 53.2, 63.6,119.4 (q, J¼327 Hz),125.2,126.3,128.2,134.7,
1.64 (m, 1H), 1.68–1.88 (m, 2H), 2.52–2.62 (m, 1H), 3.37 (dd, J¼6.8,
6.8 Hz, 1H), 3.47 (d, J¼17.2 Hz, 1H), 3.73 (d, J¼7.2 Hz, 1H), 4.33 (dd,
J¼3.6, 6.8 Hz, 1H), 7.52 (dd, J¼8.0, 8.0 Hz, 2H), 7.75 (dd, J¼8.0,
8.0 Hz, 1H), 7.87 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz,
134.0, 152.7, 169.7, 200.1; 19F NMR (376 MHz, CF3COOH¼ꢀ78.5 ppm)
ꢀ82.0; IR (neat)
n 2960, 1742, 1715, 1367, 1200, 1121; HRMS (ESI)
[MþH]þ calcd for: C18H22F3O5S: 407.1140, found: 407.1150.
The QD-5c (4.8 mg, 0.010 mmol, 10 mol %) catalyzed reaction of
14E (38.0 mg, 0.20 mmol) and 17c (21.6 mg, 0.10 mmol) in methy-
CDCl3¼77.0 ppm)
d 14.1, 22.5, 26.4, 31.7, 32.6, 37.7, 38.0, 49.2, 50.7,
63.9, 118.2, 119.5 (q, J¼325 Hz), 126.27, 126.66, 129.42, 133.44,
lene chloride (200
m
L) was carried out at ꢀ20 ꢁC for 72 h to furnish
137.27, 150.09, 196.55; 19F NMR (376 MHz, CF3COOH¼ꢀ78.5 ppm)
the crude product (dr¼8:1). The crude product was purified by
flash chromatography to give the adduct 20Dc as a colorless oil and
a diastereomeric mixture (40 mg, 98% yield, dr¼8:1). The ee of the
major diastereomer is determined to be 95%.
ꢀ81.5. IR (neat)
n
2934, 1725, 1370, 1206, 1121; HRMS (ESI) [MþH]þ
calcd for: C18H21NF3O5S: 388.1194, found: 388.1188.
4.4.8. Compound (ꢀ)-19Eb
This product was obtained as an colorless oil in 94% yield (single
diastereomer) and 94% ee from the corresponding QD-5c-catalyzed
reaction of 17b (25.3 mg, 0.11 mmol) and 13E (15.7 mg, 0.10 mmol) in
4.4.12. Compound (ꢀ)-20Ed (Table 7, entry 7)
This product was obtained from a Q-5c (4.8 mg, 0.010 mmol,
10 mol %) catalyzed reaction of 14E (28.4 mg, 0.20 mmol) and 17d
methylene chloride (200
m
L) at ꢀ50 ꢁC for 96 h. The dr (>49:1) of the
(26.4 mg, 0.10 mmol) in methylene chloride (100
m
L) at ꢀ20 ꢁC for
reaction was determined by 1H NMR analysis of the crude product.
96 h. The crude product (single diastereomer by 1H NMR analysis)
[determined by integration of one set of 19F NMR (376 MHz,
4.4.9. Compound (þ)-20Db (Table 7, entry 5)
CF¼ꢀ78.5 ppm) signals (s,
d
(major)¼ꢀ81.57 ppm)]. The crude
This product was obtained from a Q-5c (4.8 mg, 0.010 mmol,
10 mol %) catalyzed reaction of 14D (19.0 mg, 0.10 mmol) and 17b
product was purified by flash chromatography (silica gel, hexanes/
methylene chloride¼2:1) to give adduct 20Ed as a colorless oil
(37 mg, 91% yield, single diastereomer) and in 95% ee [determined
(23 mg, 0.10 mmol)inmethylenechloride(200
m
L)atꢀ20 ꢁCfor96 h.
The dr (32:1) was determined by an analysis of the crude product via
by HPLC, Daiso Chiralcel OJ, hexanes/IPA¼90:10, 1.0 mL/min,
25
integration of one set of 19F NMR (376 MHz, CF3COOH¼ꢀ78.5 ppm)
l
¼220 nm, tR (major)¼17.45 min, tR (minor)¼14.30 min]. [
a]
ꢀ57.4
D
signals (s,
d
(major)¼ꢀ81.87 ppm,
d
(minor)¼ꢀ81.79 ppm)]. The
(c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
d 1.70–2.00 (m, 5H), 2.30–
crude product was purified by flash chromatography (silica gel,
hexanes/ethyl ether¼5:1) to give adduct 20Db as a colorless oil
(38 mg, 90% yield, single diastereomer) and in 98% ee [determined by
HPLC, Daiso Chiralcel ODþRegis (R,R)-whelk 1 O, hexanes/IPA¼99:1,
2.42 (m, 2H), 2.52–2.70 (m, 3H), 2.80–2.92 (m, 1H), 3.32 (dd, J¼6.4,
14.4 Hz, 1H), 3.71 (s, 3H), 4.25 (dd, J¼4.0, 14.4 Hz, 1H), 7.12–7.32 (m,
5H); 13C NMR (100 MHz, CDCl3¼77.0 ppm)
d 19.3, 32.6, 34.0, 34.8,
35.4, 38.4, 50.6, 53.1, 63.2, 119.7 (q, J¼325 Hz), 126.5, 128.7, 128.8,
1.0 mL/min,
l
¼220 nm, tR (major)¼20.15 min, tR (minor)¼29.10 min].
140.9, 170.0, 213.1; IR (neat) n 1751, 1725, 1364, 1200, 1120; HRMS
25
[a]
þ116.4 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
d
0.84 (t,
(ESI) [MþH]þ calcd for: C18H22F3O5S: 407.1140, found: 407.1145.
D
J¼6.8 Hz, 3H),1.06–1.54 (m, 7H),1.56–1.70 (m,1H), 2.82–2.96 (m,1H),
3.20(d, J¼17.6 Hz,1H), 3.40(dd,J¼6.8, 6.8 Hz,1H), 3.70(s, 3H), 3.87(d,
J¼17.6 Hz,1H), 4.12 (dd, J¼3.2,14.4 Hz,1H), 7.43 (t, J¼7.2 Hz,1H), 7.53
(d, J¼8.0 Hz, 1H), 7.67 (dt, J¼1.2, 8.0 Hz, 1H), 7.8 (d, J¼8.0 Hz, 1H); 13C
4.4.13. Compound (þ)-20Ed
The QD-5c (4.8 mg, 0.010 mmol, 10 mol %) catalyzed reaction of
14E (38.0 mg, 0.20 mmol) and 17c (21.6 mg, 0.10 mmol) in methy-
NMR (100 MHz, CDCl3¼77.0 ppm)
d
14.1, 22.5, 27.4, 31.7, 32.3, 35.8,
lene chloride (200
m
L) was carried out at ꢀ20 ꢁC for 72 h to furnish
37,3, 50.4, 53.4, 63.9, 119.6 (q, J¼325 Hz), 125.4, 126.6, 128.4, 135.0,
the crude product as a single diastereomer (by 1H NMR analysis).
The crude product was purified by flash chromatography to give the
adduct 20Ed as a colorless oil and a single diastereomer (33 mg,
80% yield) in 89% ee.
136.2,152.9,170.0, 200.4; 19F NMR (376 MHz, CF3COOH¼ꢀ78.5 ppm)
ꢀ81.8; IR (neat)
n 2957, 1742, 1717, 1367, 1200, 1122; HRMS (ESI)
[MþH]þ calcd for: C19H24F3O5S: 421.1297, found: 421.1289.
4.4.10. Compound (ꢀ)-20Db
4.5. X-ray analysis for the determination of the absolute
configurations of (D)-12J and (L)-15C
This product was obtained as an colorless oil in 93% yield
(contains minor diastereomer, dr¼90:10) and 97% ee from the
corresponding QD-5c-catalyzed reaction of 17b (23.0 mg,
0.10 mmol) and 10F (53.2 mg, 0.20 mmol) in methylene chloride
X-ray analysis was performed by Richard J. Staples at the De-
partment of Chemistry and Chemical Biology, Harvard University.

3148
H. Li et al. / Tetrahedron 65 (2009) 3139–3148
Alexakis, A. Org. Lett. 2007, 9, 3749; (h) Zhu, Q.; Lu, Y. Org. Lett. 2008, 10, 4803;
For examples involving chiral metallic catalysts, see: (i) Llamas, T.; Arrayas, R. G.;
Carretero, J. C. Angew. Chem., Int. Ed. 2007, 46, 3329; (j) Desrosiers, J.-N.; Charette,
Crystallographic data (excluding structure factors) for the struc-
tures in this paper have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication nos. CCDC
709230 [(þ)-12J] and CCDC 709231 [(ꢀ)-15C]. The absolute con-
figurations of compounds (þ)-12J and (ꢀ)-15C were established
using the anomalous scattering technique; Flack parameters were
ꢀ0.06(10) and ꢀ0.06(6), respectively. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: þ44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
´
A. B. Angew. Chem., Int. Ed. 2007, 46, 5955; (k) Mauleon, P.; Alonso, I.; Rivero,
M. R.; Carretero, J. C. J. Org. Chem. 2007, 72, 9924; (l) Desrosiers, J.-N.; Bechara,
W. S.; Charette, A. B. Org. Lett. 2008, 10, 2315; (m) Bos, P. H.; Minnaard, A. J.;
Feringa, B. L. Org. Lett. 2008, 10, 4219.
3. For a preliminary communication of our studies of 5c-catalyzed conjugate ad-
ditions to vinylsulfones, see: (a) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc.
2005, 127, 8948.
4. For select reviews of catalytic enantioselective construction of all carbon qua-
ternary chiral centers, see: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5363; (b) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42,
1688; (c) Christoffers, J. Chem.dEur. J. 2003, 9, 4862; (d) Christoffers, J.; Mann, A.
Angew. Chem., Int. Ed. 2001, 40, 4591; (e) Corey, E. J.; Guzman-Perez, A. Angew.
Chem., Int. Ed. 1998, 37, 388.
Acknowledgements
5. (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906; (b) Li, H.;
Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem.,
Int. Ed. 2005, 44, 105; For other select examples of 5c-catalyzed other asym-
metric reactions, see: (c) Wu, F.; Hong, R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem.,
Int. Ed. 2006, 45, 4301; (d) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128,
3928; (e) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732; (f) Li, H.;
Wang, Y.-Q.; Deng, L. Org. Lett. 2006, 8, 4063; (g) Wang, Y.; Li, H.; Wang, Y.-Q.;
Liu, Y.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2007, 129, 6364.
6. For a minireview of asymmetric catalysis with C60–OH cinchona alkaloids (cu-
preines and cupreidines), see: Marcelli, T.; van Maarseveen, J.; Hiemstra, H.
Angew. Chem., Int. Ed. 2006, 45, 7496; For a review of asymmetric catalysis by
hydrogen-bond donors, see: Doyle, A.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
7. For the synthesis of 4b, see: Alonso, D. A.; Na´jera, C.; Varea, M. Synthesis 2003,
277.
We gratefully acknowledge the financial support of NIH (GM-
61951) and Daiso Inc.
References and notes
1. Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon: Oxford, 1993.
2. For selective examples of asymmetric conjugate additions to
a,b-unsaturated
sulfones catalyzed by organic catalysts, see: (a) Pinheiro, S.; Guingant, A.; Des-
mae¨le, D.; d’Angelo, J. Tetrahedron: Asymmetry 1992, 3, 1003; (b) d’Angelo, J.;
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´
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