Organocatalyst-mediated enantioselective intramolecular Michael addition of aldehydes to vinyl sulfones

Article abstract of DOI:10.1016/j.tetasy.2010.03.043

Chiral amines with a hydrogen bond donor promote the intramolecular conjugate addition of aldehydes to vinyl sulfones. Chiral cyclic sulfone-aldehydes are obtained in good yields with an ee of up to 82%.

Full text of DOI:10.1016/j.tetasy.2010.03.043

Tetrahedron: Asymmetry 21 (2010) 1666–1673
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalyst-mediated enantioselective intramolecular Michael addition
of aldehydes to vinyl sulfones
*
Chloée Bournaud, Estelle Marchal, Adrien Quintard, Sarah Sulzer-Mossé, Alexandre Alexakis
University of Geneva, Department of Organic Chemistry, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral amines with a hydrogen bond donor promote the intramolecular conjugate addition of aldehydes
to vinyl sulfones. Chiral cyclic sulfone-aldehydes are obtained in good yields with an ee of up to 82%.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 17 March 2010
Accepted 31 March 2010
Available online 11 May 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
1. Introduction
Palomo et al. also reported the organocatalytic addition of alde-
hydes and ketones to vinyl sulfones.13 In all of these examples,
During the last decade, asymmetric organocatalysis has gained
considerable attention1 and remarkable progress has been made
since the pioneering reports of the proline intermolecular aldol
reaction2 and iminium ion catalysis concept.3 For stereoselective
C–C bond formation, Michael addition via enamine activation rep-
resents a very powerful method.4 Moreover, different withdrawing
groups on the Michael acceptors have been well described in amin-
ocatalysis including ester,5 carbonyl6 and nitro groups.7 More re-
cently, much effort has been made to apply organocatalytic
asymmetric conjugate addition to more challenging Michael
acceptors such as vinyl phosphonates8 and vinyl sulfones.9 The
intermolecular Michael reaction has been well studied while intra-
molecular versions have received less attention. To the best of our
knowledge, the catalytic amine-mediated intramolecular Michael
addition has only been reported with enals or enones.10 Expanding
the scope of Michael acceptors in the intramolecular reaction still
remains a challenge. Herein we wish to report the first organocat-
alyst-mediated enantioselective intramolecular Michael addition
of aldehydes to vinyl sulfone.
the intermolecular addition of carbonyl compounds is performed
on a bis-activated substrate, these two activating groups are
needed to ensure good reactivities. Our goal was to carry out an
intramolecular version of this reaction on vinyl mono-sulfones. In-
deed, we hoped that the intramolecular reaction would favour the
cyclisation avoiding the use of two activating groups.
To investigate this intramolecular Michael reaction, we syn-
thesised different substrates 5 bearing an aldehyde functionality
and a vinyl mono-sulfone moiety (Schemes 1 and 2). Compounds
5a–e were obtained starting from commercially available lactones
1a and 1b which were first reduced by DIBAL-H (Scheme 1). Then,
the resulting aldehydes were protected with 1,3-propanedithiol to
afford compounds 2a and 2b. Oxidation of alcohols to aldehydes 3a
and 3b was achieved using the complex SO3–pyridine in the pres-
ence of DMSO and triethylamine. To obtain the vinyl sulfone deriv-
atives, we decided to perform a Horner–Wadsworth–Emmons
olefination of these aldehydes with various sulfonyl phosphonates.
To this end, we prepared phosphonates 11b–d by a nucleophilic
substitution reaction of the commercially available diethyl
iodomethylphosphonate 9 with aromatic thiols 8b–d (Scheme 3).
Then, thioethers 10a–d were oxidised to the corresponding sulf-
ones 11 with oxone. With these phosphonates in hand, we per-
formed the olefination in THF using NaH as a base, and sulfones
4a–e were isolated in good yields. Finally, the removal of the dithi-
ane moiety gave rise to the desired vinyl mono-sulfone aldehydes
5a–e in good yields (Scheme 1).
2. Results and discussion
Vinyl sulfones are very useful intermediates in organic11 and
medicinal chemistry.12 This functional group can be used, for
example, in cycloaddition reactions or Michael additions. In the
last decade, our group has developed various methodologies for
the Michael addition of aldehydes to vinyl sulfones catalysed by or-
ganic molecules such as N-iPr-2,20-bipyrrolidine (i-PBP),9a aminal
pyrrolidine9c and diphenylprolinol silyl ether.9b Recently, Lu and
Substrates 5f and 5g could be prepared without protection of
the aldehyde functional group, but in modest yields in a two-step
procedure (Scheme 2). Reduction of the starting lactones with DI-
BAL-H gave the corresponding aldehydes that were directly re-
acted with phosphonate 11a in the Horner–Wadsworth–Emmons
olefination. The resulting olefins 6 and 7 were then oxidised with
* Corresponding author. Tel.: +41 22 379 65 22; fax: +41 22 379 32 15.
E-mail address: alexandre.alexakis@unige.ch (A. Alexakis).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.043

C. Bournaud et al. / Tetrahedron: Asymmetry 21 (2010) 1666–1673
1667
a) DIBAL-H, CH2Cl2/THF,
-78 °C to rt
O
n
SO3/pyridine
S
S
O
OH
O
b) 1,3-propanedithiol,
BF3-Et2O, 0 °C to rt
DMSO, Et3N,
CH2Cl2, rt, 4 h
n
n
S
S
2a, n = 1, 64 %
2b, n = 3, 46 %
3a, n = 1, 56 %
3b, n = 3, 72 %
1a, n = 1
1b, n = 3
O
S
MeI, CaCO3
Phosphonate 11
SO2Ar
SO2Ar
n
NaH, THF,
0 °C to RT, 2.5 h
n
S
MeCN/H2O
45 °C, 2 h
5a, n = 1, Ar = -m(CF3)2-Ph, 68 %
5b, n = 3, Ar =-m(CF3)2-Ph, 81 %
5c, n = 3, Ar = -Ph, 90 %
4a, n = 1, Ar = -m(CF3)2-Ph, 68 %
4b, n = 3, Ar =-m(CF3)2-Ph, 93 %
4c, n = 3, Ar = -Ph, 86 %
5d, n = 3, Ar = -2-pyridinyl, 83 %
5e, n = 3, Ar = -pNO2-Ph, 78 %
4d, n = 3, Ar = -2-pyridinyl, 97 %
4e, n = 3, Ar = -pNO2-Ph, 82 %
Scheme 1.
a) DIBAL-H, CH2Cl2,
-78 °C to rt
O
SO3/pyridine
O
SO2Ph
n
O
SO2Ph
HO
n
b) Phosphonate 11a,
NaH, THF,
DMSO, Et3N,
CH2Cl2, rt, 4 h
n
1a, n = 1
1c, n = 2
5f, n = 1, 64 %
5g,n = 2, 46 %
6, n = 1, -40 °C, 51 %
7, n = 2, 0 °C, 60 %
Scheme 2.
Conditions A:
1)(CH2O)n, toluene, HCl, 50°C, 1 h
2) P(OEt)3, 130 °C, 16 h
or
Conditions B:
NaH, CH3CN, rt, 24 h
O
EtO
9
P
OEt
Ar
O
O
Oxone
MeOH/H2O,
EtO
I
EtO
P
S
P
SO2
ArSH
Ar
EtO
EtO
rt, 24 h
8a, Ar = -Ph
10a, Ar = -Ph, 67 %
Condition A
Condition B
11a, Ar = -Ph, 90 %
8b, Ar = -2-pyridinyl
8c, Ar = -m(CF3)2-Ph
8d, Ar = -pNO2-Ph
10b, Ar = -2-pyridinyl, 85 %
10c, Ar = -m(CF3)2-Ph, 90 %
10d, Ar = -pNO2-Ph, 82 %
11b, Ar = -2-pyridinyl, 80 %
11c, Ar = -m(CF3)2-Ph, 87 %
11d, Ar = -pNO2-Ph, 81 %
Scheme 3.
SO3–pyridine complex to furnish aldehydes 5f and 5g with 64% and
46% yield, respectively.
Next, we focused on chiral diamines. With our catalyst i-PBP 16,
adduct 12c was obtained in a good yield but with a very low enan-
tiomeric excess (Table 1, entry 1). Reaction performed with the
1-pyrrolidinylmethylpyrrolidine 17 afforded the cyclic sulfone-
aldehyde 12c in moderate yield and a good trans-diastereoselec-
tivity, but a modest enantioselectivity (entry 2).
The activity of a series of catalysts was then studied using
mono-phenylsulfone aldehydes
5 having various alkyl chain
lengths (Scheme 4). The results are summarised in Table 1.
We first evaluated the intramolecular Michael reaction of 5c
using a catalytic amount of
L
-proline 13. Unfortunately, no cyclisa-
Quite recently, it was found by Chen et al.9e that amine–thio-
tion product 12c was observed. We then treated compound 5c
with the prolinol silyl ether 14, which is an effective catalyst for
the intermolecular version of this transformation,9b but no reaction
occurred. Next we investigated MacMillan’s imidazolidinone 15.
Although it proved to be very efficient to promote the asymmetric
intramolecular Michael reaction of aldehydes to enones or enals,10b
no desired product was formed in our reaction.
ureas can promote the Michael addition of a-substituted cyanoac-
etate to vinyl sulfones. The authors proposed that the sulfone
group was activated by a double-hydrogen-bonding interaction be-
tween the NH of the thiourea and the sulfone. This report led us to
examine catalysts bearing a hydrogen bond donor functionality.
For this purpose, we performed the intramolecular Michael addi-
tion reaction catalysed by thioureas 18 and 19. After a prolonged

1668
C. Bournaud et al. / Tetrahedron: Asymmetry 21 (2010) 1666–1673
SO2Ph
O
cat* (20 mol %)
O
SO2Ph
n
solvent, rt
n
5c, n = 3
5f, n = 1
5g, n = 2
12c, n = 3
12f, n = 1
12g, n = 2
Ph
Ph
OTMS
O
S
CF3
CF3
N
CO2H
N
H
N
H
N
HN
N
H
N
N
H
N
H
N
HN
Bn
H2
Cl
13
14
15
16
17
18
HO
O
N
MeO
HO
O
O
N
O
S
N
H
N
N
H
N
N
H
N
H
N
Bn
N
N
Ph
H
H
O
NH2
Ph
23
19
20
21
22
Scheme 4.
reaction time, compound 12c was obtained in moderate yield and
selectivity (entries 3 and 4). Then, we turned our attention to other
bifunctional catalysts trans-4-hydroxyprolylamides 20 and 21
(bearing a H-bond donor and a secondary amine) which were de-
scribed as very efficient catalysts in the asymmetric addition of
an aldehyde to a nitroalkene.14 As described, we carried out the
intramolecular reaction in i-PrOH with catalyst 20. After a week
at room temperature the expected product was isolated in modest
yield, good diastereoselectivity and encouraging enantioselectivity
(entry 5). Screening various solvents with this organocatalyst 20
proved that dichloromethane gave the highest activity and enanti-
oselectivity (entries 5–7). When the reaction was conducted with
another trans-4-hydroxyprolylamide 21, a modest yield was ob-
served but the sulfone aldehyde 12c was obtained with a promis-
ing 71% ee (entry 8). Finally we tested this reaction with substrates
5f and 5g; cyclobutane and cyclopropane adducts were not formed
(entries 9 and 10).
on the phenylsulfone, was treated with catalyst 20 under the
same conditions as previously described. As expected, the cyclic
sulfone-aldehyde 12b was isolated in a good yield in only 6 h
(vs 4 days), with comparable selectivity (Table 2, entry 1). The
shorter reaction time led us to run the experiment at lower
temperatures to increase the stereoselectivity (entries 5–7). The
best result was achieved at ꢀ15 °C and the adduct 12b was
isolated in good yield and enantioselectivity (82% ee, entry 7).
The efficiency of this withdrawing group lead us to perform the
cyclisation of the adduct 5a but the enhanced reactivity of the vi-
nyl-sulfone is not efficient enough to promote the formation of a
cyclopropane ring (entry 8).
As mentioned above, Chen et al. proposed that sulfones could be
activated by a thiourea via a hydrogen-bonding interaction. We
Table 2
Intramolecular conjugate addition to activated vinyl sulfone
We have reported the first intramolecular Michael addition of
an aldehyde to a vinyl mono-phenylsulfone but the major prob-
lem of this transformation is a very long reaction time. To over-
come this problem, we hoped that substitution on the sulfone
by an electron-withdrawing group would accelerate the
reaction.13d For this purpose, compound 5b, bearing CF3 groups
F3C
CF3
CF3
cat* (20 mol %)
SO2
n
O
SO2
CF3
CH2Cl2
n
O
Table 1
5a, n = 1
5b, n = 3
12a, n = 1
12b, n = 3
Screening of catalysts in the intramolecular Michael addition
Ent.
Substrate
Cat.
Solvent
Time
days
Yield
(%)
dr anti/
syn
ee (%)
Ent.
Substrate
Cat.
Temp.
Time
Yield (%)
dr anti/syn
ee (%)
1
2
3
4
5
6
7
8
5b
5b
5b
5b
5b
5b
5b
5a
20
21
23
22
20
21
21
20
rt
rt
rt
6 h
80
91/9
65
67
40
0
72
77
82
—
1
2
3
4
5
6
7
8
9
5c
5c
5c
5c
5c
5c
5c
5c
5f
16
17
18
19
20
20
20
21
20
20
CHCl3
1
2
7
7
7
16
4
4
7
7
70
52
54
70
50
62
52
24
nra
nra
90/10
92/8
89/11
91/9
90/10
89/11
90/10
93/7
—
5
42
58
41
52
62
65
71
—
b
24 h
30 d
9 d
5 d
4 d
4 d
7 d
80
—
—
—
i-PrOH
Benzene
CH2Cl2/H2O
i-PrOH
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
43a
57a
65
b
b
rt
0 °C
0 °C
ꢀ15 °C
rt
85/15
95/5
86/14
—
64
75
nrc
Conversion determined by 1H NMR.
Not determined.
No reaction.
a
b
c
10
5g
—
—
a
No reaction.

C. Bournaud et al. / Tetrahedron: Asymmetry 21 (2010) 1666–1673
1669
Table 3
column. Gradient programs are described as follows: initial meth-
anol concentration (%)—initial time (min)—percent gradient of
methanol (%/min)—final methanol concentration (%)—retention
times RT are given in minutes.
Scope of the intramolecular Michael addition
O
SO2Ar
SO2Ar
O
21 (20 mol %)
Sulfones 11a,16 11b17 and 11c18 were prepared according to the
reported procedures.
CH2Cl2, rt
4.1.1. Diethylphosphorylmethyl 4-(nitro)phenyl sulfone 11d
To a room temperature solution of NaH (192 mg, 60% in mineral
oil, 4.8 mmol) in CH3CN under argon atmosphere, 4-nitrobenze-
nethiol (775 mg, 4 mmol) was added dropwise. After 20 min, the
iodomethylphophonate (1.22 g, 4.4 mmol) was added and the mix-
ture was stirred at room temperature for a day. After quenching
the reaction with water (30 mL), the mixture was extracted with
ethyl acetate (2 ꢁ 30 mL). The combined organic layers were dried
over Na2SO4 and evaporated to afford the corresponding sulfane
10d which was used directly in the next step.
5b, Ar =-m(CF3)2-Ph
5c, Ar = -Ph
5d, Ar = -2-pyridinyl
5e, Ar = -pNO2-Ph
12b, Ar =-m(CF3)2-Ph
12c, Ar = -Ph
12d, Ar = -2-pyridinyl
12e, Ar = -pNO2-Ph
Entry
Substrate
Time
Yield (%)
dr anti/syn
ee (%)
1
2
3
4
5ba
5c
4 d
4 d
2 d
2.5 h
75
24
50
76
86/14
93/7
93/7
82
71
67
72
5d
5eb
83/17
To a stirred solution of sulfane 10d (950 mg, 2.82 mmol) in a 1/1
mixture MeOH/H2O (40 mL) was slowly added oxone (17.4 g,
28.2 mmol) and the corresponding mixture was stirred at room
temperature for a day. Then, MeOH was evaporated, the residue
was dissolved in CH2Cl2 (100 mL) and filtered through Celite. To
the resulting solution water (20 mL) was added and the mixture
was extracted with CH2Cl2 (2 ꢁ 50 mL). The organic phase was
washed with a saturated solution of NaCl (3 ꢁ 100 mL) and dried
over Na2SO4. Purification by flash column chromatography on
silica gel gave sulfone (730 g, 81%). 1H NMR (300 MHz, CDCl3):
d = 8.42 (d, J = 9.0 Hz, 2H), 8.23 (d, J = 9.0 Hz, 1H), 4.19 (m, 4H),
3.81 (d, J = 16.7 Hz, 2H), 1.33 (t, J = 7.1 Hz, 6H). 13C NMR
(75 MHz, CDCl3): d = 151.1, 145.1, 130.2, 124.2, 63.7 (d,
J = 6.4 Hz), 53.9 (d, J = 139.0 Hz), 16.3 (d, J = 6.4 Hz). 31P NMR
(121 MHz, CDCl3): d = 10.5. MS (ESI): m/z = 338 [M+H]+. HRMS
(ESI): calcd C11H17NO7PS [M+H]+ 338.0457, found 338.0459.
a
Reaction carried out at ꢀ15 °C.
Reaction with 30 mol % of 21.
b
hypothesise that catalyst 20 or 21 could also activate adduct 5 by a
hydrogen-bonding interaction between the hydroxyl group and
the sulfone moiety. To evaluate this hypothesis, we performed
the reaction with catalyst 22, without a hydroxyl group, and cata-
lyst 23, with a methoxy substituent. In these cases, the reactions
were very slow (Table 2, entries 3 and 4), and even after 9 or
30 days, the reaction was not completed and the cyclised product
was obtained as a racemic mixture with catalyst 22. These results
indicate that the reaction is accelerated with catalysts bearing
hydrogen bond donors, thus confirming that sulfones might be
activated by a hydrogen bond interaction.
The generality of the present intramolecular Michael addition to
various substituted sulfone was examined, and the results are
summarised in Table 3.
Whatever might be the substituents on the sulfone, the diaste-
roselectivity and enantioselectivity are in the same range (83/17–
93/7 dr and 67–82% ee). Moreover, the reaction is faster with nitro-
phenyl sulfone than with pyridyl sulfone.
4.1.2. 3-(1,3-Dithian-2-yl)propan-1-ol (2a)
DIBAL-H (28 mL, 27.8 mmol) was added to a solution of c-buty-
rolactone (1.8 mL, 23.2 mmol) in Et2O (25 mL) at ꢀ78 °C. After 3 h
MeOH (3 mL) was added to the solution followed by brine (2 mL).
The solution was allowed to warm to room temperature, diluted
with Et2O and a gel appeared. The gel was filtered on a pad of Celite
with Et2O. Solvents were removed under reduced pressure. The
crude product was diluted with Et2O (100 mL) and dried over
MgSO4, filtered and concentrated under reduced pressure to give
the lactol which was directly used in the next step.
To a solution of lactol (840 mg, 9.54 mmol) in MeNO2 (80 mL),
1,3-propanedithiol (1.9 mL, 19 mmol) was added followed by
BF3ꢂEt2O (3.6 mL, 28.6 mmol) at 0 °C. The reaction was stirred for
1 h at this temperature and then water and Et2O were added.
The organic phase was separated and washed with brine and then
dried over Na2SO4. The solvents were removed by vaccuo. Purifica-
tion by flash column chromatography on silica gel (EtOAc/pentane
4:6) gave dithiane 2b as a colourless oil (1.26 g, 64% yield over two
steps). 1H NMR (400 MHz, CDCl3): d = 4.07 (t, J = 6.5 Hz, 1H), 3.65–
3.68 (m, 2H), 2.80–2.91 (m, 4H), 2.08–2.14 (m, 1H), 1.76–1.88 (m,
5H), 1.40 (s, 1H, OH). 13C NMR (100 MHz, CDCl3): d = 62.0, 47.3,
31.9, 30.4, 29.7, 25.9. HRMS (ESI): calcd C7H14OS2 [M]+ 178.0486,
found 178.0484. Spectroscopic data are in agreement with the
literature.15
3. Conclusion
In conclusion, we have disclosed the first organocatalytic intra-
molecular Michael addition of aldehydes bearing various vinyl
sulfones in good yield and with good enantioselectivity and diaste-
reoselectivity. In the intermolecular version, no reaction occured
with mono vinyl phenylsulfone whereas in the intramolecular ver-
sion, full conversion was observed. This reaction was promoted by
readily available trans-4-hydroxyprolylamide 21, and the catalytic
reaction might involve an activation of the sulfone by a hydrogen-
bonding interaction.
4. Experimental part
4.1. General methods
Solvents were dried by filtration over alumina previously acti-
vated at 350 °C during 12 h under nitrogen before use. Evolution
of the reaction was followed with TLC (visualisation by UV KMnO4
or PMA staining). Flash chromatography was performed using sil-
4.1.3. 5-(1,3-Dithian-2-yl)pentan-1-ol 2b
To a solution of e-caprolactone (2.8 g, 24.25 mmol, 1 equiv) in
ica gel 32–63 lm, 60 Å. NMR spectra were recorded in CDCl3 on
dry CH2Cl2/THF (1:1) (150 mL) was added dropwise Dibal-H
(25 mL, 1 M in hexane, 25 mmol, 1.03 equiv) at ꢀ78 °C and stir-
red for 15 min. The reaction mixture was then allowed to warm
to room temperature, the reaction was quenched with Et2O
(100 mL) and H2O (30 mL) and the reaction mixture was stirred
Bruker AMX-300, -400 or -500 spectrometers. Chemical shift (d)
is given in ppm relative to residual deuterated solvent. Coupling
constants are reported in hertz. Enantiomeric excesses were deter-
mined by chiral-SFC measurement on a Berger SFC with the stated

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C. Bournaud et al. / Tetrahedron: Asymmetry 21 (2010) 1666–1673
until it became a translucent white gel. The solution was further
diluted with Et2O (100 mL), and Celite was added and then stir-
red until the solution became clear. The resulting mixture was
filtered and concentrated under reduced pressure. The crude
product was diluted with Et2O (100 mL) and dried over MgSO4,
filtered and concentrated under reduced pressure to give lactol
which was diluted in dry CH2Cl2 (100 mL) and used directly for
the next step.
To a solution of lactol (2.81 mmol, 24.25 mmol, 1 equiv) in
CH2Cl2 (100 mL) was successively added 1,3-propanedithiol
(2.86 g, 26.4 mmol, 1.1 equiv) and BF3ꢂEt2O (4.5 mL, 36 mmol,
1.5 equiv) dropwise at 0 °C. After 1.5 h, the reaction was quenched
with satd aq NaHCO3 (200 mL). The biphasic mixture was stirred
for 30 min. at room temperature and then extracted with CH2Cl2
(4 ꢁ 80 mL). The combined organic layers were dried over Na2SO4,
filtered and concentrated under reduced pressure. Purification by
flash column chromatography on silica gel (EtOAc/c-Hex, 1:4) gave
dithiane 2b (2.32 g, 46% yield over two steps). 1H NMR (400 MHz,
CDCl3): d = 4.05 (t, J = 7.1 Hz, 1H), 3.64 (t, J = 6.6 Hz, 2H), 2.91–2.78
(m, 4H), 2.15–2.01 (m, 1H), 1.92–1.73 (m, 3H), 1.64–1.50 (m, 4H),
1.38–1.34 (m, 2H). 13C NMR (100 MHz, CDCl3): d = 62.9, 60.6, 47.8,
35.6, 32.6, 30.7, 26.6, 26.2, 25.6. MS (EI): 206.
Na2SO4, filtered and evaporated. Purification by flash column chro-
matography on silica gel (c-Hex/EtOAc, 8:2) afforded the alkene.
4.3.1. 2-[4-(3,5-Bis(trifluoromethyl)phenylsulfonyl)but-3-enyl]-
[1,3]-dithiane 4a
The Wittig Horner reaction was performed according to the
general procedure with phosphonate 11c and aldehyde 3a
(1.23 mmol) to afford alkene 4a (350 mg, 68%) as a colourless oil.
1H NMR (400 MHz, CDCl3): d = 8.33 (s, 2H), 8.11 (s, 1H), 7.13 (dt,
J = 6.8 Hz, 1H), 6.39 (d, J = 15.1 Hz, 1H), 3.99 (t, J = 6.9 Hz, 1H),
2.81–2.84 (m, 4H), 2.54 (q, J = 7.3 Hz, 2H), 2.08–2.15 (m, 1H),
1.93–199 (m, 2H), 1.81–1.99 (m, 1H), 13C NMR (100 MHz, CDCl3):
d = 149, 143.7, 133.2 (q, J2C—F = 35 Hz,), 129.9, 128.2, 127.1, 122.5
(q, J1C—F = 274 Hz), 46.4, 33.1, 30.2, 28.8, 25.8, HRMS (ESI): calcd
C
16H17F6O5S3 [M+H]+ 451.0330, found 451.0289.
4.3.2. 2-[6-(3,5-Bis-trifluoromethyl-phenylsulfonyl)hex-5-enyl]-
[1,3]dithiane 4b
The Wittig Horner reaction was performed according to the
general procedure with phosphonate 11c and aldehyde 3b
(1.23 mmol) to afford alkene 4b (550 mg, 93%). 1H NMR
(300 MHz, CDCl3): d = 8.33 (s, 2H), 8.11 (s, 1H), 7.14 (dt, J = 6.8
and 15.1 Hz, 1H), 6.36 (d, J = 15.1 Hz, 1H), 4.02 (t, J = 6.8 Hz, 1H),
2.85 (m, 4H), 2.33 (m, 2H), 2.12 (m, 1H), 1,74–1.87 (m, 3H), 1.54
(m, 4H). 13C NMR (75 MHz, CDCl3): d = 150.2, 143.7, 133.2 (q,
J2C—F = 34 Hz, 2C), 129.2, 128.1, 126.9, 122.4 (q, J1C—F = 273 Hz, 2C),
47.2, 35.0, 31.4, 30.5, 27.0, 25.9 ppm. 19F NMR (282 MHz, CDCl3):
d = 62.8. MS (ESI) m/z: 479 [M+H]+ HRMS (ESI): calcd C18H21O2F6S3
[M+H]+ 479.0602, found 479.0616.
4.2. General procedure for the oxidation of the alcohol
To a solution of alcohol 2 (1 equiv, 11 mmol) in dry CH2Cl2
(22 mL) were successively added DMSO (10 equiv), freshly distilled
triethylamine (10 equiv) and SO3/pyridine (5 equiv) at room tem-
perature. The resulting mixture was stirred 4 h at room tempera-
ture and then diluted with Et2O (150 mL), and water was added
(150 mL). The combined organic layers were washed with brine,
dried over Na2SO4, filtered and concentrated under reduced pres-
sure. Purification by flash column chromatography on silica gel
(c-Hex/EtOAc, 2:1) afforded aldehyde 3.
4.3.3. 2-[6-(Phenylsulfonyl)hex-5-enyl]-[1,3]dithiane 4c
The Wittig Horner reaction was performed according to the
general procedure with phosphonate 11a and aldehyde 3b
(5.13 mmol) to afford alkene 4c (1.5 g, 86%). 1H NMR (400 MHz,
CDCl3): d = 7.94–7.91 (m, 2H), 7.68–7.31 (m, 3H), 7.07–7.04 (m,
1H), 6.39–6.34 (d, 1H, J = 20.1 Hz), 4.08–4.03 (m, 1H), 2.95–2.86
(m, 4H), 2.31–2.09 (m, 3H), 1.91–1.81 (m, 3H), 1.75–1.47 (m,
4H). 13C NMR (100 MHz, CDCl3): d =146.7, 139.9, 133.3, 130.6,
129.30, 127.6, 47.3, 35.0, 31.3, 30.5, 27.2, 26.0, 26.0. MS (EI):
4.2.1. 3-(1,3-Dithian-2-yl)ethanal 3a
The oxidation reaction was performed according to the general
procedure with alcohol 2a (7.07 mmol) to afford aldehyde 3a
(700 mg, 56%) as a colourless oil. 1H NMR (400 MHz, CDCl3):
d = 9.79 (s, 1H), 4.03 (t, J = 7.1 Hz, 1H), 2.85–2.82 (m, 4H), 2.70
(dt, J = 7.1 and 1.0 Hz, 2H), 2.14–2.07 (m, 3H), 1.87–1.84 (m, 1H).
13C NMR (100 MHz, CDCl3): d = 200.8, 60.3, 46.1, 40.7, 29.8, 27.6,
25.7. HRMS (ESI): calcd C7H13OS2 [M+H]+ 177.0418, found
177.0402.
342. HRMS (ESI): calcd
343.0867.
C
16H22O2S3 [M+H]+ 343.0854, found
4.3.4. 2-[6-(Pyridine-2-sulfonyl)hex-5-enyl]-[1,3]dithiane 4d
The Wittig Horner reaction was performed according to the
general procedure with phosphonate 11b and aldehyde 3b
(522 mg, 2.56 mmol) to afford alkene 4d (853 mg, 97%). 1H NMR
(300 MHz, CDCl3): d = 8.74 (d, J = 4.6 Hz, 1H), 8.09 (d, J = 7.8 Hz,
1H), 7.94 (td, J = 1.7 and 7.8 Hz, 1H), 7.52 (m, 2H), 7.11 (dt, J = 6.7
and 15.2 Hz, 1H), 6.55 (d, J = 15.1 Hz, 1H), 4.02 (t, J = 6.9 Hz, 1H),
2.84 (m, 4H), 2.31 (m, 2H), 2.04–2.17 (m, 1H), 1,73–1.90 (m, 3H),
1.53 (m, 4H). 13C NMR (75 MHz, CDCl3): d = 158.5, 150.3, 149.7,
138.2, 127.9, 127.0, 121.9, 47.3, 35.1, 31.6, 30.5, 27.1, 26.0. MS
(ESI): 344 [M+H]+. HRMS (ESI): calcd C15H22NO2S3 [M+H]+
344.0807, found 344.0803.
4.2.2. 5-(1,3-Dithian-2-yl)butanal 3b
The oxidation reaction was performed according to the general
procedure with alcohol 2b (11.3 mmol) to afford aldehyde 3b
(1.65 g, 72%). 1H NMR (400 MHz, CDCl3): d = 9.76 (s, 1H), 4.06–
4.02 (m, 1H), 2.91–2.79 (m, 4H), 2.47–2.43 (m, 2H), 2.15–2.08
(m, 1H), 1.90–1.80 (m, 3H), 1.74–1.52 (m, 4H). 13C NMR
(100 MHz, CDCl3): d = 202.5, 47.5, 43.8, 35.4, 30.7, 26.3, 26.2,
21.8. MS (EI): 204. HRMS (ESI): calcd C9H17OS2 [M+H]+ 205.0715,
found 205.0717.
4.3. General procedure for the Horner–Wadsworth–Emmons
reaction
4.3.5. 2-((E)-6-(4-Nitrophenylsulfonyl)hex-5-enyl)-1,3-dithiane
4e
The Wittig Horner reaction was performed according to the
general procedure with phosphonate 11d and aldehyde 3b
(1 mmol) to afford alkene 4e (320 mg, 82%).1H NMR (300 MHz,
CDCl3): d = 8.38 (d, J = 8.9 Hz, 2H), 8.07 (d, J = 8.9 Hz, 2H), 7.08
(dt, J = 6.9 and 15.1 Hz, 1H), 6.33 (d, J = 15.1 Hz, 1H), 4.00 (t,
J = 6.7 Hz, 1H), 2.82 (m, 4H), 2.29 (m, 2H), 2.04–2.17 (m, 1H),
1,73–1.88 (m, 3H), 1.51 (m, 4H). 13C NMR (75 MHz, CDCl3):
d = 150.5, 149.7, 146.5, 129.6, 129.0, 128.7, 124.5, 47.3, 35.0, 31.4,
To a solution of phosphonate 11 (1.4 equiv) in THF (30 mL) was
added NaH (1.4 equiv) at 0 °C. After stirring for 0.5 h, this solution
was added to aldehyde 3 (1 equiv) dissolved in THF (20 mL). Then,
the ice bath was removed and the solution was stirred at room
temperature until completion of the reaction. Then saturated
NH4Cl solution and Et2O were added. The aqueous phase was ex-
tracted with Et2O (3 ꢁ 50 mL). The organic phase was dried over

C. Bournaud et al. / Tetrahedron: Asymmetry 21 (2010) 1666–1673
1671
30.5, 27.0, 25.9. MS (ESI): 388 [M+H]+. HRMS (EI): calcd
16H21NO4S3 [M]+ 387.0630, found 387.0633.
8.36 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 8.6 Hz, 2H), 7.07 (dt, J = 6.7
and 15.1 Hz, 1H), 6.37 (d, J = 15.1 Hz, 1H), 2.46 (t, J = 6.8 Hz, 2H),
2.30 (q, J = 7.0 Hz, 2H), 1.47–1.67 (m, 2H), 1.60–1.67 (m, 2H). 13C
NMR (75 MHz, CDCl3): d = 201.8, 150.5, 149.2, 146.4, 129.6,
129.0, 124.5, 43.4, 31.4, 26.9, 21.3.
C
4.4. General procedure for the deprotection of the dithiane
A stirred mixture of dithiane 4 (1 equiv), MeI (10.3 equiv) and
CaCO3 (5.2 equiv) in MeCN/H2O (9:1) was heated to 45 °C for 3 h,
cooled to room temperature and concentrated under reduced pres-
sure. The residue was diluted in AcOEt and water. The organic
phase was separated and the aqueous phase was extracted with
AcOEt. Then, the organic phase was dried over Na2SO4, filtered
and concentrated under reduced pressure. Purification by flash col-
umn chromatography on silica gel (c-Hex/EtOAc, 8:2) afforded
aldehyde 5.
4.4.6. (E)-4-(Phenylsulfonyl)but-3-en-1-ol 6
DIBAL-H (28 mL, 27.8 mmol) was added to a solution of c-buty-
rolactone (1.8 mL, 23.2 mmol) in Et2O (25 mL) at ꢀ78 °C. After 3 h
MeOH (3 mL) was added to the solution followed by brine (2 mL).
The solution was allowed to warm to room temperature, diluted
with Et2O and a gel appeared. The gel was filtered on a pad of Celite
with Et2O. Solvents were removed under reduced pressure. The
crude product was diluted with Et2O (100 mL) and dried over
MgSO4, filtered and concentrated under reduced pressure to give
the lactol which was directly used in the next step.
4.4.1. (E)-5-(3,5-Bis-(trifluoromethyl) phenylsulfonyl)pent-4-
enal 5a
NaH (115 mg, 4.8 mmol) was washed with hexane (5 mL) and
dissolved in THF (20 mL).Then phosphonate 11a (1.4 g, 4.8 mmol)
dissolved in THF (20 mL) was added to NaH at 0 °C. The solution
was stirred for 30 min at room temperature and then added to
the lactol (380 mg, 4.35 mmol) dissolved in THF (20 mL) at
ꢀ40 °C. After 2 h 30 min at this temperature the reaction was
quenched with a solution of NH4Cl satd and extracted with Et2O,
washed with water and brine and then dried (Na2SO4). Purification
by flash column chromatography on silica gel (Et2O 100%) gave
Deprotection of the dithiane 4a (350 mg, 0.77 mmol, 1 equiv)
was performed according to the general procedure to give alde-
hyde (190 mg, 68%) as a white solid. 1H NMR (400 MHz, CDCl3):
d = 9.78 (s, 1H), 8.30 (s, 2H), 8.10 (s, 1H), 7.12 (dt, J = 15.0 and
6.6 Hz, 1H), 6.39 (dt, J = 15.0 and 1.4 Hz, 1H), 2.72 (t, J = 6.9 Hz,
2H), 2.61 (q, J = 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3): 148.5,
143.6, 133.4 (q, J2C—F = 35 Hz, 2C), 130.2, 128.3, 127.3, 122.6 (q,
J1C—F = 274 Hz, 2C), 41.3, 24.1.
alcohol
6 (500 mg, 51% yield) as a
colourless oil. 1H NMR
4.4.2. (E)-7-(3,5-Bis-trifluoromethylphenylsulfonyl)hept-6-enal
5b
(400 MHz, CDCl3): d = 7.92–7.94 (m, 1H), 7.52–7.69 (m, 3H), 7.07
(dt, J = 15.1, 6.8 Hz, 1H), 6.39–6.44 (m, 1H), 3.71 (t, J = 6.2 Hz,
2H), 2.39–2.45 (m, 2H), 1.78 (q, J = 6.8 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d = 146.8, 140.9, 133.6, 131.1, 129.6, 127.9,
61.9, 30.7, 28.2. HRMS (ESI): calcd [M+H]+ C17H14OS2 178.0486,
found 178.0484.
Deprotection of the dithiane 4b (380 mg, 0.795 mmol, 1 equiv)
was performed according to the general procedure to give the alde-
hyde (250 mg, 81%). 1H NMR (300 MHz, CDCl3): d = 9.77 (s, 1H),
8.33 (s, 2H), 8.12 (s, 1H), 7.15 (dt, J = 6.7 and 15.1 Hz, 1H), 6.37
(d, J = 15.1 Hz, 1H), 2.47 (t, J = 12.8 Hz, 2H), 2.35 (q, J = 6.6 Hz,
2H), 1.49–1.66 (m, 4H). 13C NMR (75 MHz, CDCl3): d = 201.6,
149.8, 143.7, 133.2 (q, J2C—F = 35 Hz, 2C), 129.4, 128.0, 127.0, 122.4
(q, J1C—F = 274 Hz, 2C), 43.4, 31.5, 26.9, 21.3. MS (ESI) m/z: 389
[M+H]+. HRMS (ESI): calcd C15H15O3F6S2 [M+H]+ 389.0646, found
389.0651.
4.4.7. (E)-5-(Phenylsulfonyl)pent-4-en-1-ol 7
To a solution of d-valerolactone (0.93 mL, 9.99 mmol) in CH2Cl2
(30 mL) at ꢀ78 °C was slowly added DIBAL-H (12 mL, 12.00 mmol).
After 1 h 30 min stirring at this temperature the reaction was
quenched with MeOH (3 mL) and brine (3 mL). The cold bath was
removed, the solution was diluted with EtOAc and then a gel ap-
peared which was filtered and washed with EtOAc. The solvents
were removed under reduced pressure .The crude product was di-
luted with EtOAc (100 mL) and dried over MgSO4, filtered and con-
centrated under reduced pressure to give the lactol which was
used directly in the next step.
NaH (142 mg, 5.92 mmol) was added to phosphonate 11a
(1.73 mg, 5.92 mmol) dissolved in THF (20 mL) at 0 °C. The solution
was stirred for 30 min at this temperature. Then the solution was
added to the lactol (550 mg, 5.39 mmol) dissolved in THF (15 mL)
at 0 °C. The ice bath was removed and the solution was stirred
for 3 h. The reaction was quenched with NH4Cl sat (15 mL) and
the reaction mixture was extracted with Et2O (3 ꢁ 20 mL). The
combined organic layers were washed with brine and then dried
(Na2SO4). Purification by flash column chromatography on silica
gel (Et2O 100%) gave alcohol 7 (765 mg, 60% yield) as a colourless
oil. 1H NMR (400 MHz, CDCl3): d = 7.85–7.87 (m, 1 H), 7.64–7.67
(m, 1H), 7.50–7.60 (m, 1H), 7.04 (dt, J = 14.9 and 6.7 Hz, 1H), 6.32
(dt, J = 14.9 and 1.6 Hz, 1H), 3.61–3.64 (m, 2H), 2.26–2.28 (m,
2H), 1.54–1.57 (m, 4H). 13C NMR (100 MHz, CDCl3): d = 146.9,
140.6, 133.4, 130.5, 129.3, 127.5, 62.2, 31.9, 31.2, 24.0. HRMS
(ESI): calcd C12H17O3S [M+H]+ 241.0892, found 241.0892.
4.4.3. (E)-7-(Phenylsulfonyl)hept-6-enal 5c
Deprotection of the dithiane 4c (610 mg, 1.62 mmol, 1 equiv)
was performed according to the general procedure to afford the
aldehyde (400 mg, 90%). 1H NMR (300 MHz, CDCl3): d = 9.78 (s,
1H), 7.90 (d, J = 8.1 Hz, 2H), 7.57–7.60 (m, 3H), 7.00 (m, 1H), 6.37
(d, J = 15.1 Hz, 1H), 2.48 (t, J = 7.0 Hz, 2H), 2.30 (q, J = 7.0 Hz, 2H),
1.67–1.53 (m, 4H). 13C NMR (75 MHz, CDCl3): d = 201.8, 146.2,
140.6, 133.3, 130.9, 129.3, 127.8, 43.4, 31.2, 27.1, 21.4. MS (EI):
252. HRMS (ESI): calcd
253.0884.
C
13H16O3S [M+H]+ 253.0892, found
4.4.4. (E)-7-(Pyridine-2-sulfonyl)hept-6-enal 5d
Deprotection of the dithiane 4d(150 mg, 0.437 mmol, 1 equiv)
was performed according to the general procedure to give the alde-
hyde (92 mg, 83%). 1H NMR (300 MHz, CDCl3): d = 9.75 (s, 1H), 8.73
(d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 7.94 (dt, J = 1.7 and
7.8 Hz, 1H), 7.52 (dd, J = 4.7 and 7.6 Hz, 1H), 7.10 (dt, J = 6.7 and
15.2 Hz, 1H), 6.56 (d, J = 15.1 Hz, 1H), 2.46 (t, J = 6.9 Hz, 2H), 2.35
(q, J = 7.3 Hz, 2H), 1.51–1.71 (m, 4H). 13C NMR (75 MHz, CDCl3):
d = 201.9, 158.4, 150.3, 149.3, 138.2, 128.1, 127.1, 121.8, 43.5,
31.5, 27.0, 21.4. HRMS (ESI): calcd C12H16O3NS [M+H]+ 254.085,
found 254.0842.
4.4.8. (E)-4-(Phenylsulfonyl)but-3-enal 5f
4.4.5. (E)-7-(4-Nitro-phenylsulfonyl)hept-6-enal 5e
The oxidation reaction was performed according to the general
Deprotection of the dithiane 4e (225 mg, 0.58 mmol, 1 equiv)
was performed according to the general procedure to give the alde-
hyde (134 mg, 78%). 1H NMR (300 MHz, CDCl3): d = 9.73 (s, 1H),
procedure with alcohol 6 (0.9 mmol.) to afford aldehyde 5f
(137 mg, 64%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3):
d = 7.91–7.94 (m, 2H), 7.58–7.70 (m, 3H), 7.03 (dt, J = 15.2 and

1672
C. Bournaud et al. / Tetrahedron: Asymmetry 21 (2010) 1666–1673
6.7 Hz, 1H), 6.42 (dt, J = 15.2 and 1.5 Hz, 1H), 2.66–2.70 (m, 2H),
2.55–2.59 (m, 2H). 13C NMR (100 MHz, CDCl3): d = 199.6, 144.5,
140.4, 133.6, 131.7, 129.4, 127.7, 41.5, 23.8. HRMS (ESI): calcd
d = 9.65 (s, 1H), 8.75 (d, J = 4.1 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H),
7.98 (d, J = 7.8 Hz, 1H), 7.56 (m, 1H), 3.51 (m, 2H), 2.73 (m, 2H),
2.09 (m, 1H), 1.88 (m, 2H), 1.72 (m, 1H), 1.42–1.61 (m, 2H) ppm.
13C NMR (75 MHz, CDCl3): d = 202.1, 157.4, 150.3, 138.3, 127.5,
122.2, 56.8, 56.0, 34.0, 33.1, 26.4, 24.7 ppm. MS (ESI): 254
[M+H]+. HRMS (ESI): calcd C12H16O3NS [M+H]+254.085, found
254.0839.
C
11H13O3S [M+H]+ 225.0579, found 225.0570.
4.4.9. (E)-5-(Phenylsulfonyl)pent-4-enal 5g
The oxidation reaction was performed according to the general
procedure with alcohol 7 (0.9 mmol.) to afford aldehyde 5g
(340 mg, 46%) as a colourless oil. 1H NMR (400 MHz, CDCl3):
d = 9.75 (s, 1H), 7.92–7.95 (m, 2H), 7.66–7.71 (m, 1H), 7.58–7.63
(m, 2H), 7.00 (dt, J = 6.7and 15.0 Hz, 1H), 6.40 (dt, J = 1.5 and
15.0 Hz, 1H), 2.54 (dt, J = 1.1 and 7.3 Hz, 2H), 2.31–2.37 (m, 2H),
1.85 (q, J = 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3): d = 201.2,
145.6, 140.5, 133.5, 131.4, 129.4, 127.7, 42.9, 30.6, 20.0. HRMS
(ESI): calcd C12H15O3S [M+H]+ 239.0736, found 239.0739.
4.5.4. 2-(4-Nitro-phenylsulfonylmethyl)-cyclopentane
carbaldehyde 12e
Intramolecular conjugate addition was performed according to
the general procedure with sulfone 5e (26.2 mg, 0.088 mmol) in
dichloromethane with catalyst 21(5.2 mg, 0.03 mmol) at room
temperature during 2.5 h to afford compound 12e (20 mg, 76%).
The enantiomeric excess was determined by SFC (chiralcel OB col-
umn, 2 mL/min, 200 bar, MeOH 10%-2-1-25%, 30 °C), RT: 9.41,
4.5. General procedure for the intramolecular conjugate
addition
12.41. ½a 2D5
ꢃ
¼ ꢀ0:7 (c 0.74, 72% ee, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 9.68 (s, 1H), 8.44 (d, J = 8.6 Hz, 2H), 8.13 (d, J = 8.6 Hz,
2H), 3.14–3.33 (m, 2H), 2.63–2.76 (m, 2H), 2.14 (m, 1H), 1.61–
1.93 (m, 3H), 1.40–1.61 (m, 2H). 13C NMR (75 MHz, CDCl3):
d = 201.8, 151.0, 144.9, 129.7, 124.6, 60.4, 56.8, 33.7, 33.1, 26.6,
24.6. HRMS (ESI): calcd C13H15O5NSNa [M+Na]+ 320.0568, found
320.0577.
To a solution of vinyl sulfone 5 (0.1 mmol) in solvent (2.5 mL)
was added a catalyst (20 mol %) at rt. The evolution of the reaction
was controlled by TLC until completion of the reaction. The organic
solvent was removed under reduced pressure and the crude mix-
ture was purified by flash column chromatography on silica gel
(c-Hex/EtOAc, 8:2) to give cyclopentane 12.
References
4.5.1. 2-Phenylsulfonylmethyl-cyclopentane carbaldehyde 12c
Intramolecular conjugate addition was performed according to
the general procedure with sulfone 5c (25 mg, 0.1 mmol) in dichlo-
romethane with catalyst 20 (6.8 mg, 0.02 mmol) at room tempera-
ture for four days to afford compound 12c (13 mg, 52%). The
enantiomeric excess was determined by SFC (chiralcel OB column,
2 mL/min, 200 bar, MeOH 10%-2-1-25%, 30 °C), RT: 4.26, 7.56.
1. For recent reviews on organocatalysis see: (a) Jarvo, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481; (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2004, 43, 5138; (c) List, B.; Seayad, J. Org. Biomol. Chem. 2005, 3, 719; (d) Gaunt,
M. J.; Johson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today 2007, 12, 8; (e)
Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638; See also special
issues on asymmetric organocatalysis: (f) Acc. Chem. Res. 2004, 37, issue 8; (g)
Adv. Synth. Catal. 2004, 346, issue 9–10; (h) Chimia 2007, issue 5; (i) Chem. Rev.
2007, issue 12; (j) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178.
2. List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395.
3. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
4243.
4. For selected reviews on organocatalytic Michael addition see: (a) Tsogoeva, S.
B. Eur. J. Org. Chem. 2007, 1701; (b) Almasi, D.; Alonso, D. A.; Nájera, C.
Tetrahedron: Asymmetry 2007, 18, 299; (c) Sulzer-Mossé, S.; Alexakis, A. Chem.
Commun. 2007, 3123.
5. (a) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J.
Am. Chem. Soc. 2006, 128, 4966; (b) Betancort, J. M.; Sakthivel, K.;
Thayumanavan, R.; Barbas, C. F., III Tetrahedron Lett. 2001, 42, 4441; (c)
Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III
Synthesis 2004, 1509; (d) Cao, C.-L.; Sun, X.-L.; Zhou, J.-L.; Tang, Y. J. Org. Chem.
2007, 72, 4073; (e) Wang, J.; Yu, F.; Zhang, X.; Ma, D. Org. Lett. 2008, 10,
2561.
½
a 2D0
ꢃ
¼ ꢀ5:5 (c 0.3, 65% ee, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 9.65 (d, 1H, J = 1.7 Hz), 7.92–7.90 (m, 2H), 7.66–7.51 (m, 3H),
3.25–3.10 (m, 2H), 2.74–2.63 (m, 2H), 2.12–2.05 (m, 1H), 1.92–
1.86 (m, 2H), 1.78–1.70 (m, 1H), 1.69–1.52 (m, 1H), 1.48–1.38
(m, 1H). 13C NMR (100 MHz, CDCl3): d = 202.3, 139.6, 134.1,
129.6, 128.2, 60.7, 57.1, 34.4, 33.2, 26.6, 24.9. HRMS (ESI): calcd
C
13H16O3S [M+H]+ 253.0892, found 253.0883.
4.5.2. 2-(3,5-Bis-Trifluoromethyl-phenylsulfonylmethyl)-
cyclopentane carbaldehyde 12b
Intramolecular conjugate addition was performed according to
the general procedure with sulfone 5b (39 mg, 0.1 mmol) in dichlo-
romethane with catalyst 21 (4 mg, 0.02 mmol) at ꢀ15 °C for four
days to afford compound 12b (30 mg, 75%). The enantiomeric ex-
cess was determined by SFC (chiralcel OD column, 2 mL/min,
6. (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44,
4212; (b) Wang, J.; Li, H.; Zhu, L.; Wang, W. Adv. Synth. Catal. 2006, 348, 425; (c)
Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151; (d) Chi, Y.; Gellman,
S. H. Org. Lett. 2005, 7, 4253; (e) Peelen, T. J.; Chi, Y.; Gellman, S. H. J. Am. Chem.
Soc. 2005, 127, 11598; (f) Alonso, D. A.; Kitagaki, S.; Utsumi, N.; Barbas, C. F., III
Angew. Chem., Int. Ed. 2008, 120, 4588.
200 bar, MeOH 1%-10-1-15%, 30 °C), RT: 2.75, 3.08. ½a D20
¼ þ0:5 (c
ꢃ
7. (a) List, B.; Pojarliev, P.; Martina, H. J. Org. Lett. 2001, 16, 2423; (b) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
1.54, 82% ee, CHCl3). 1H NMR (300 MHz, CDCl3): d = 9.70 (s, 1H),
8.39 (s, 2H), 8.18 (s, 1H), 3.22 (m, 2H), 2.75 (m, 2H), 2.13 (m,
1H), 1.98 (m, 1H), 1.91 (m, 1H), 1.76 (m, 1H), 1.43–1.66 (m, 2H)
ppm. 13C NMR (75 MHz, CDCl3): d = 201.6, 142.2, 133.0 (q,
J = 35 Hz), 128.7, 127.5, 122.0 (q, J = 274 Hz), 60.5, 56.7, 33.5,
33.1, 26.6, 24.6 ppm. MS (ESI): 389 [M+H]+. HRMS (ESI): calcd
8. (a) Enders, D.; Wahl, H.; Papadopoulos, K. Tetrahedron 1997, 53, 1291; (b) Ruiz,
M.; Vicente, O.; Shapiro, G.; Shapiro, G.; Weber, H.-P. Tetrahedron Lett. 1994, 35,
4551; (c) Schick, A.; Kolter, T.; Giannis, A.; Sandhoff, K. Tetrahedron 1995, 51,
11207; (d) Fernandez, M. C.; Quintela, J. M.; Ruiz, M.; Vicente, O. Tetrahedron:
Asymmetry 2002, 13, 233; (e) Fernandez, M. C.; Diaz, A.; Guillin, J. J.; Blanco, O.;
Vicente, M. J. Org. Chem. 2006, 71, 6958; (f) Sulzer-Mossé, S.; Tissot, M.;
Alexakis, A. Org. Lett. 2007, 9, 3749; (g) Capuzzi, M.; Perdicchia, D.; Jørgensen, K.
A. Chem. Eur. J. 2008, 14, 128.
C
15H15O3F6S2 [M+H]+ 389.0646, found 389.0657.
9. (a) Mossé, S.; Alexakis, A. Org. Lett. 2005, 7, 4361; (b) Sulzer-Mossé, S.; Alexakis,
A.; Mareda, J.; Bollot, G.; Bernardinelli, G.; Filinchuk, Y. Chem. Eur. J. 2009, 15,
3204; (c) Quintard, A.; Bournaud, C.; Alexakis, A. Chem. Eur. J. 2008, 14, 7504;
(d) Li, H.; Song, S.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948; (e) Liu, T.-
Y.; Long, J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org. Biomol.
Chem. 2006, 4, 2097; (f) Zhu, Q.; Lu, Y. Org. Lett. 2009, 11, 1721; (g) Zhang, S.;
Zhang, Y.; Ji, Y.; Wang, W. Chem. Commun. 2009, 4886; (h) Quintard, A.;
Alexakis, A. Chem. Eur. J. 2009, 15, 11109–11113; (i) Quintard, A.; Belot, S.;
Marchal, E.; Alexakis, A. Eur. J. Org. Chem. 2010, 927.
10. (a) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am.
Chem. Soc. 2005, 127, 1608; (b) Fonseca, M. T. H.; List, B. Angew. Chem., Int. Ed.
2004, 43, 3958; (c) Kikuchi, M.; Inagaki, T.; Nishiyame, H. Synlett 2007, 1075;
(d) Nodes, W. J.; Nutt, D. R.; Chippindale, A. M.; Cobb, A. J. A. J. Am. Chem. Soc.
4.5.3. 2-(Pyridine-2-sulfonylmethyl)cyclopentane carbaldehyde
12d
Intramolecular conjugate addition was performed according to
the general procedure with sulfone 5d (25 mg, 0.1 mmol) in dichlo-
romethane with catalyst 21 (4 mg, 0.02 mmol) at room tempera-
ture for 2 days to afford compound 12d (12 mg, 50%). The
enantiomeric excess was determined by SFC (chiralcel OB column,
2 mL/min, 200 bar, MeOH 2%-10-1-15%, 30 °C), RT: 10.01, 10.57.
½
a 2D5
ꢃ
¼ ꢀ10:3 (c 0.57, 67% ee, CHCl3). 1H NMR (300 MHz, CDCl3):

C. Bournaud et al. / Tetrahedron: Asymmetry 21 (2010) 1666–1673
1673
2009, 131, 16016; (e) Marqués-López, E.; Herrera, R. P.; Marks, T.; Jacobs, W. C.;
Könning, D.; de Figueiredo, RE M.; Christmann, M. Org. Lett. 2009, 11, 4116.
11. Simpkins, N. S. Tetrahedron 1990, 46, 6951.
12. Meadows, D. C.; Gerva-Hague, J. Med. Res. Rev. 2006, 6, 793.
13. (a) Zhu, Q.; Cheng, L.; Lu, Y. Chem. Commun. 2008, 6315; (b) Zhu, Q.; Lu, Y. Org.
Lett. 2008, 10, 4803; (c) Landa, A.; Maestro, M.; Masdeu, C.; Puente, A.; Vera, S.;
Oiarbide, M.; Palomo, C. Chem. Eur. J. 2009, 15, 1562; (d) Li, H.; Song, J.; Deng, L.
Tetrahedron 2009, 65, 3139.
14. Palomo, C.; Vera, S.; Mieglo, A.; Gomez-Bengoa, E. Angew. Chem., Int. Ed. 2006,
45, 5984.
15. Gibson, M.; Goodman, J. M.; Farrugia, L. J.; Hartley, R. C. Tetrahedron Lett. 2003,
44, 2841.
16. Enders, D.; von Berg, S.; Jandeleit, B. Org. Synth. 2002, 78, 169.
17. Mauléon, P.; Carretero, J.-C. Org. Lett. 2004, 6, 3195.
18. Alonso, D. A.; Babrowski, A.; Fuensanta, M.; Najera, C.; Varea, M. Arkivoc 2007,
243.