Highly enantioselective addition of 1-fluoro-1-nitro(phenylsulfonyl)methane to α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/ejoc.201000851

An organocatalytic, highly enantioselective addition of 1fluoro-1-nitro(phenylsulfonyl)methane to α,β-unsaturated aldehydes is reported. The reaction is simply catalyzed by secondary amines and furnishes the corresponding fluorinated derivatives in good y

Full text of DOI:10.1002/ejoc.201000851

FULL PAPER
DOI: 10.1002/ejoc.201000851
Highly Enantioselective Addition of 1-Fluoro-1-nitro(phenylsulfonyl)methane to
α,β-Unsaturated Aldehydes
Martin Kamlar,[a] Natalia Bravo,[b] Andrea-Nekane R. Alba,[b] Simona Hybelbauerová,[c]
[d]
[a]
[b]
[b,e]
ˇ
Ivana Císarová, Jan Veselý,* Albert Moyano,* and Ramon Rios*
Keywords: Fluorine / Organocatalysis / Aldehydes / Enantioselectivity / Diastereoselectivity / Michael addition
An organocatalytic, highly enantioselective addition of 1-
fluoro-1-nitro(phenylsulfonyl)methane to α,β-unsaturated al-
dehydes is reported. The reaction is simply catalyzed by sec-
ondary amines and furnishes the corresponding fluorinated
derivatives in good yields, with moderate diastereoselectivi-
ties and excellent enantioselectivities. The absolute configu-
ration of the major diastereomers was unambiguously ascer-
tained by X-ray diffraction analysis.
philic fluorination of commercially available (phenylsulfon-
yl)nitromethane, to α,β-unsaturated aldehydes as an easy
and versatile entry to interesting products for medicinal
chemistry such as building blocks for drug synthesis or of
fluoride-labeled natural products. It is worth noting that
during the experimental implementation of this concept,
Córdova and co-workers[6] described a single example of
the catalytic asymmetric addition of FNSM to cinnamal-
dehyde. We report herein our results on the chiral pyrrol-
idine-catalyzed addition of this reagent to a range of aro-
matic and aliphatic enals, as well as on the unambiguous
determination of the stereochemical course of this process.
Introduction
The chemistry of fluorinated compounds and materials
is a very active field, fostered by the unique physical, chemi-
cal, and biological properties often resulting from the pres-
ence of fluorine atoms in organic molecules.[1,2] In the case
of biologically active molecules, the need for the stereocon-
trolled introduction of fluorine or of fluorinated moieties is
particularly important, and research in this area continues
unabated.[3]
In 2009 one of our research groups,[4] concurrently with
those of Wang[5] and Córdova,[6] reported a practical and
highly enantioselective formal addition of the fluoromethyl
anion to α,β-unsaturated aldehydes on the basis of an asym-
metric organocatalytic Michael addition of fluorobis(phen-
ylsulfonyl)methane.[7] Very recently, we have also disclosed
the first enantioselective addition of 2-fluoromalonates to
α,β-unsaturated aldehydes.[8,9] In this context, we turned
our attention to the addition of 1-fluoro-1-nitro(phenyl-
sulfonyl)methane (FNSM), readily prepared by electro-
Results and Discussion
In our initial screening we tested the addition of FNSM
(1) to cinnamyl aldehyde (2a) in the presence of several chi-
ral secondary amines (Table 1). To our delight, we found
that the reaction was efficiently catalyzed by the well-known
TMS-protected diphenylprolinol I (Jørgensen–Hayashi cat-
alyst)[10] by using toluene as the solvent at –20 °C. Initially
formed Michael adduct 3a (1H NMR monitoring of the
reaction mixture) was not isolated, and in situ reduction
with NaBH4 afforded alcohol 4a in 46% yield (after chro-
matographic purification). The diastereomeric ratio of in-
[a] Department of Organic and Nuclear Chemistry, Faculty of
Science Charles University in Prague,
Hlavova 2030, 12840 Prague, Czech Republic
Fax: +420-221951326
E-mail: jxvesely@natur.cuni.cz
[b] Department of Organic Chemistry, Universitat de Barcelona,
c/Martí i Franqués 1-11, 08028 Barcelona, Spain
Fax: +34-933397878
1
termediate aldehyde 3a, determined by H NMR spectro-
scopic analysis of the crude reaction mixture, was 2:1. The
enantiomeric ratios of the major and minor diastereomers
of 4a, determined by chiral HPLC, were 95:5 and 96:4,
respectively (Table 1, Entry 1). When the reaction was cata-
lyzed by MacMillan’s first generation imidazolidinone II,[11]
only trace amounts of the final product were detected
(Table 1, Entry 2). The reaction was also very poorly cata-
lyzed by prolinol III (Table 1, Entry 3). When proline (IV)
was used as the catalyst, the final reduced Michael adducts
were obtained in good yields, but with low enantioselectivi-
E-mail: amoyano@ub.edu
rios.ramon@icrea.cat
Website: www.runam.xtreemhost.com
[c] Department of Teaching and Didactics of Chemistry, Faculty
of Science Charles University in Prague,
Hlavova 2030, 12840 Prague, Czech Republic
[d] Department of Inorganic Chemistry, Faculty of Science Charles
University in Prague,
Hlavova 2030, 12840 Prague, Czech Republic
[e] ICREA, Passeig Lluis Companys 23,
08010 Barcelona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000851.
View this journal online at
wileyonlinelibrary.com
5464
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5464–5470

Highly Enantioselective Addition to α,β-Unsaturated Aldehydes
ties (Table 1, Entry 4). Finally, when diamine V was used, Table 2. Solvent and temperature screening for the reaction be-
tween 1 and 2a.[a]
product 4a was obtained in moderate yields and in almost
racemic form (Table 1, Entry 5).
Table 1. Catalyst screening for the reaction between 1 and 2a.[a]
Entry
Solvent
T
[°C]
dr (3a)[b]
er (4a)[c]
Yield[d]
[%]
1
2
3
4
5
6
7
CH2Cl2
CHCl3
Et2O
toluene
toluene
toluene
EtOH
–20
–20
–20
–20
0
r.t.
0
1:1
3:2
2:3
2:1
2:1
2:1
1:1
84:16/85:15
92:8/84:16
91:9/95:5
51
43
16
46
51
53
53
Entry
Catalyst
dr (3a)[b]
er (4a)[c]
Yield [%][d]
96:4/95:5
1
2
3
4
5
I
II
III
IV
V
2:1
n.d.
n.d.
3:1
96:4/95:5
n.d.
n.d.
60:40/50:50
51:49/51:49
46
traces
traces
57
88:12/79:21
75:25/55:45
87:13/80:20
3:1
64
[a] In a small vial, 1 (0.25 mmol, 1 equiv.) was treated with 2a
(0.5 mmol, 2 equiv.) for 24 h in the solvent and at the temperature
specified in the presence of I (0.05 mmol, 0.2 equiv.) at –20 °C;
then, the reaction mixture was subjected to “in situ” reduction to
afford 4a. [b] Determined by 1H NMR spectroscopic analysis of
the crude reaction mixture. [c] Determined by chiral HPLC analysis
of compound 4a. [d] Isolated yield of 4a after column chromatog-
raphy.
[a] In a small vial, 1 (0.25 mmol, 1 equiv.) was treated with 2a
(0.5 mmol, 2 equiv.) in toluene (1 mL) in the presence of catalyst
I–V (0.05 mmol, 0.2 equiv.) for 24 h at –20 °C; then, the reaction
mixture was subjected to “in situ” reduction to afford 4a. [b] Deter-
mined by 1H NMR spectroscopic analysis of the crude reaction
mixture. [c] Determined by chiral HPLC analysis of compound 4a.
[d] Isolated yield of 4a after column chromatography.
We decided next to test the same reaction in other sol-
vents (Table 2). The addition performed well in several rela-
tively nonpolar solvents such as dichloromethane, chloro-
form, ethanol, or diethyl ether, but with lower diastereo-
and enantioselectivities (Table 2, Entries 1–3 and 7). When
the reaction was run in toluene at temperatures higher than
–20 °C, the diastereomer ratio was not affected, but the
enantioselectivities decreased dramatically (Table 2, En-
tries 5 and 6).
the major diastereomer of 4e. The diastereomers of final
alcohols 4a–i could be separated by careful chromato-
graphic purification.
Table 3. Scope of the organocatalytic FSNM additions.[a]
With these optimized conditions in hand, we decided to
study the scope of the reaction with different α,β-unsatu-
rated aldehydes 2a–i (Table 3). The addition can be per-
formed both with both aromatic and aliphatic α,β-unsatu-
rated aldehydes and tolerates different functional groups
such as halogens, nitro, or nitriles. As before, initial Michael
adducts 3a–i were not isolated but were reduced in situ to
afford corresponding alcohols 4a–i, which were more stable
and easier to purify. The diastereoselectivity of the reaction
is somewhat dependent of the nature of the substituent in
the aromatic ring. For example, when electron-withdrawing
groups were placed in the para position, the diastereoselec-
tivity decreased (Table 3, Entries 2 and 3). On the opposite
hand, when halogen or electron-donating groups were
placed in the aromatic rings, the diastereoselectivity in-
creased up to 2.5:1 (Table 3, Entry 5). It is noteworthy that
the yields are higher with aliphatic aldehydes, and surpris-
ingly the diastereoselectivity decreased when the steric bulk
of the aliphatic group increased. For example, crotonalde-
hyde (2g) afforded Michael adduct 3g in 4:1dr (Table 3, En-
Entry
R
Product dr (3a)[b]
er (4a)[c]
Yield [%][d]
1
2
3
4
5
6
7
8
9
Ph
p-NO2C6H4
p-CNC6H4
naphthyl
p-ClC6H4
p-BrC6H4
Me
4a
4b
4c
4d
4e
4f
2:1
1:1
3:2
3:1
5:2
2:1
4:1
3.3:1
3:1
96:4/95:5
96:4/95:5
87:13/n.d.
91:9/81:19
99:1/98:2
95:5/93:7
96:4/n.d.
96:4/95:5
96:4/95:5
46
80
36
20
45
42
77
70
73
4g
4h
4i
Et
Pr
[a] In a small vial, 1 (0.25 mmol, 1 equiv.) and 2a–i (0.5 mmol,
2 equiv.) were added in toluene (1 mL) in the presence of I
(0.05 mmol, 0.2 equiv.) at –20 °C; then, the reaction was subjected
to “in situ” reduction to afford 4. [b] Determined by 1H NMR
spectroscopic analysis of the crude reaction mixture. [c] Deter-
mined by chiral HPLC analysis of compound 4a–i. [d] Isolated
yield of 4a–i after column chromatography.
To ascertain the absolute configuration of the adducts,
try 7), whereas 2-pentenaldehyde (2h) afforded compound we performed an anomalous X-ray diffraction analysis of
3h in 3:1dr (Table 3, Entry 8). In all of the examples, the compound 5f, obtained from the major diastereomer of 4f
enantioselectivities were good to excellent, up to 99:1er for after pivaloylation (Scheme 1).
Eur. J. Org. Chem. 2010, 5464–5470
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5465

J. Veselý, A. Moyano, R. Rios et al.
FULL PAPER
Scheme 1. Synthesis of compound 5f.
As shown in Figure 1, both stereogenic centers (C3 and
C4) have an (S) absolute configuration. We assume that all
of adducts (both diastereomers) have the same absolute
configuration at C3 [(S) for cinnamaldehyde derivatives 4a–
f and (R) for 4g–i] and that at least for the aromatic enal
adducts, the major diastereomer has a (4S) configuration.
Scheme 2. Proposed mechanism for the chiral pyrrolidine-catalyzed
addition of 1-fluoro-1-nitro(phenylsulfonyl)methane to enals.
to the anti disposition of the phenyl and nitro groups. This
small difference should explain the diastereoselection ob-
served in the reaction.
Figure 1. Molecular structure (anomalous X-ray diffraction analy-
sis) of 5f.[12] The displacement ellipsoids are drawn at the 30%
probability level. Only the most populated positions of atoms in
the disordered tert-butyl moiety are shown for clarity.
As expected, the stereochemical course of the Michael
addition at C3 is coherent with the hypothesis that the
mechanism and transition states (TSs) are similar to those
described for other organocatalytic Michael additions cata-
lyzed by diphenylprolinol derivatives reported in the litera-
ture.[4,13] Thus, efficient shielding of the Si face of chiral
iminium intermediate 6 by the bulky aryl groups of chiral
pyrrolidine I leads to the stereoselective Re facial nucleo-
philic conjugate addition by the FNSM anion, as shown in
Scheme 2.
Figure 2. Transition states suggested for the FNMS addition to un-
saturated aldehydes.
Previous reports on the addition of FNSM to different
electrophiles can also account for the diastereoselectivity of
the reaction.[3k] As previously reported, the stereoselectivity
at C4 (α-fluoro carbon) does not originate from the stereo-
Conclusions
In summary, we have reported the asymmetric organoca-
selective deprotonation of FNMS by the secondary amine. talytic Michael addition of 1-fluoro-1-nitro(phenylsulf-
The stereoselectivity is actually derived from the interaction onyl)methane (FNSM) to aromatic or aliphatic α,β-unsatu-
between the FNSM anion and the iminium ion. Figure 2 rated aldehydes. The reaction is efficiently catalyzed by
shows clearly that TSs A and D minimize the steric interac- commercially available chiral pyrrolidine derivatives and
tion between the bulky phenylsulfonyl moiety and the un- gives the corresponding adducts in moderate to good yields,
saturated iminium ion. Moreover, TS D, leading to the (4S) with moderate to good diastereoselectivities and with excel-
diastereomer, should be slightly more stable than TS A due lent enantioselectivities (up to 99:1er). Mechanistic studies
5466
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5464–5470

Highly Enantioselective Addition to α,β-Unsaturated Aldehydes
289.7 Hz), 43.73 (br. s), 41.59 (d, J = 16.5 Hz) ppm. 19F NMR
(375 MHz, CDCl3, 25 °C): δ = –67.39 (d, J = 31.6 Hz) ppm.
and synthetic applications of this new methodology, as well
as the discovery of new reactions based on this concept, are
currently ongoing in our laboratories.
1
3aЈ (Minor Diastereomer): H NMR (600 MHz, CDCl3, 25 °C): δ
= 9.49 (t, J = 1.3 Hz, 1 H, CHO), 7.90–7.22 (m, 10 H, Ar), 4.88
(ddd, J = 26.2 Hz, J = 10.8 Hz, J = 2.9 Hz, 1 H, CH), 3.18 (ddd,
J = 17.9 Hz, J = 10.7 Hz, J = 1.5 Hz, 1 H, CH2), 2.90 (dd, J =
18.0 Hz, J = 2.9 Hz, 1 H, CH2) ppm. 13C NMR (150 MHz, CDCl3,
25 °C): δ = 195.8 (d, J = 3.2 Hz), 136–129 (m, 12 C), 124.6 (d, J =
287.8 Hz), 44.0 (d, J = 2.2 Hz), 42.4 (d, J = 17.6 Hz) ppm. 19F
NMR (375 MHz, CDCl3, 25 °C): δ = –60.02 (d, J = 25.4 Hz) ppm.
Experimental Section
General Methods: Chemicals and solvents were either purchased
(puriss p.A.) from commercial suppliers or purified by standard
techniques. For thin-layer chromatography (TLC), silica gel plates
Merck 60 F254 were used, and compounds were visualized by irra-
diation with UV light and/or by treatment with a solution of phos-
phomolybdic acid (25 g), Ce(SO4)2·H2O (10 g), concd. H2SO4
(60 mL), and H2O (940 mL) followed by heating or by treatment
with a solution of p-anisaldehyde (23 mL), concd. H2SO4 (35 mL),
acetic acid (10 mL), and ethanol (900 mL) followed by heating.
Flash chromatography was performed by using silica gel Merck 60
(particle size 0.040–0.063 mm). 1H, 19F and 13C NMR spectra were
recorded with Varian AS 400 or Bruker 300 instruments. Chemical
shifts are given in ppm relative to tetramethylsilane (TMS), and
coupling constants J are given in Hz. The spectra were recorded in
CDCl3 as solvent at room temperature. TMS served as internal
standard (δ = 0 ppm) for 1H NMR, CDCl3 was used as internal
standard (δ = 77.0 ppm) for 13C NMR, and TFA was used as exter-
nal standard for 19F NMR. High-resolution mass spectra were re-
corded with a Bruker MicrOTOF spectrometer. Chiral HPLC was
carried out by using an LCP 5020 Ignos liquid chromatography
pump with LCD 5000 spectrophotometric detector.
4a: Yield: 40 mg (46%), mixture of diastereomers, pale-yellow oil.
IR (KBr): ν = 3584.27, 3346.14, 3053.05, 2958.15, 3884.88,
˜
1577.21, 1493.81, 1447.48, 1346.58, 1314.67, 1158.17, 1081.98,
788.32, 753.47, 715.31, 683.79, 603.73 cm–1. [α]D = +24.8 (c = 1.5,
CHCl3). HRMS (ESI): calcd. for C16H16O5NFS [M – H]– 352.0655;
found 352.0663.
4a (Major Diastereomer): 1H NMR (600 MHz, CDCl3, 25 °C): δ =
7.92–7.21 (m, 10 H, Ar), 4.55 (ddd, J = 12.3 Hz, J = 13.1 Hz, J =
13.4 Hz, 1 H, CH), 3.64 (ddd, J = 10.7 Hz, J = 6.1 Hz, J = 3.5 Hz,
1 H, CH2OH), 3.27 (ddd, J = 10.1 Hz, J = 10.1 Hz, J = 4.7 Hz, 1
H, CH2OH), 2.83 (dddd, J = 13.9 Hz, J = 7.5 Hz, J = 6.1 Hz, J =
3.1 Hz, 1 H, CH2), 2.13 (dddd, J = 14 Hz, J = 12.1 Hz, J = 3.7 Hz,
J = 3.7 Hz, 1 H, CH2) ppm. 13C NMR (150 MHz, CDCl3, 25 °C):
δ = 136–128 (m, 12 C), 126.4 (d, J = 290.6 Hz), 58.4 (s), 44.9 (d, J
= 16.4 Hz), 32.1 (s) ppm. 19F NMR (375 MHz, CDCl3, 25 °C): δ
= –63.5 (d, J = 31.06 Hz) ppm. Enantiomeric excess was deter-
mined by HPLC with an IC chiral column (n-heptane/iPrOH =
92:8,
(minor) min.
λ
=
230 nm, 1 mL/min): tR = 72.83 (major), 50.22
General Procedure for the Formation of 3-Substituted-4-fluoro-4-ni-
tro-4-(phenylsulfonyl)butanal Derivatives 3a–i: To a sample vial
equipped with a magnetic stirring bar was added toluene (1 mL),
catalyst I (16 mg, 20 mol-%, 0.05 mmol), α,β-unsaturated aldehyde
2a–i (0.5 mmol, 2 equiv.), and [fluoro(nitro)methylsulfonyl]benzene
(1; 55 mg, 0.25 mmol, 1 equiv.) at –20 °C. The reaction mixture was
stirred at –20 °C for 24 h and purified by column chromatography
(hexane/EtOAc, 5:1) to afford aldehydes 3a–i.
1
4aЈ (Minor Diastereomer): H NMR (600 MHz, CDCl3, 25 °C): δ
= 7.92–7.21 (m, 10 H, Ar), 4.51 (td, J = 12.5 Hz, J = 3.1 Hz, 1 H,
CH), 3.5 (ddd, J = 10.8 Hz, J = 6.0 Hz, J = 3.6 Hz, 1 H, CH2OH),
3.15 (ddd, J = 10.8 Hz, J = 9.8 Hz, J = 3.6 Hz, 1 H, CH2OH), 1.99
(dddd, J = 13.7 Hz, J = 12.0 Hz, J = 4.6 Hz, J = 3.7 Hz, 1 H,
CH2), 1.77 (dddd, J = 12.9 Hz, J = 9.4 Hz, J = 6.1 Hz, J = 3.1 Hz,
1 H, CH2) ppm. 13C NMR (150 MHz, CDCl3, 25 °C): δ = 136–128
(m, 12 C), 125.9 (d, J = 290.7 Hz), 59.2 (s), 44.7 (d, J = 16.8 Hz),
32.8 (s) ppm. 19F NMR (375 MHz, CDCl3, 25 °C): δ = –67.9 (d, J
= 31.6 Hz) ppm. Enantiomeric excess was determined by HPLC
with an IC chiral column (n-heptane/iPrOH = 92:8, λ = 230 nm,
1 mL/min): tR = 27.44 (major), 24.75 (minor) min.
4b: Yield: 80 mg (80%), mixture of diastereomers, colorless oil. 1H
NMR (400 MHz, CDCl3, TMSint, diastereomer 1): δ = 8.17 (d, J
= 8.8 Hz, 2 H, Ar), 7.69 (t, J = 6.8 Hz, 1 H, Ar), 7.61 (d, J =
8.2 Hz, 2 H, Ar), 7.56 (d, J = 8.2 Hz, 2 H, Ar), 7.45 (t, J = 7.6 Hz,
2 H, Ar), 4.78 (ddd, J = 3.0 Hz, J = 11.6 Hz, J = 30.5 Hz, 1 H,
CH), 3.63–3.58 (m, 1 H, CH2OH), 315–3.10 (m, 1 H, CH2OH),
2.08–2.00 (m, 1 H, CH2), 1.88–1.80 (m, 1 H, CH2) ppm. 1H NMR
(400 MHz, CDCl3, TMSint, diastereomer 2): δ = 8.17 (d, J =
9.3 Hz, 2 H, Ar), 7.93 (d, J = 7.1 Hz, 2 H, Ar), 7.79 (t, J = 7.2 Hz,
1 H, Ar), 7.61 (d, J = 8.2 Hz, 2 H, Ar), 7.46 (t, J = 8.2 Hz, 2 H,
Ar), 5.02–4.91 (m, 1 H, CH), 3.77–3.72 (m, 1 H, CH2OH), 323–
3.17 (m, 1 H, CH2OH), 1.97–1.89 (m, 2 H, CH2) ppm. 13C NMR
(100 MHz, CDCl3, diastereomer 1): δ = 131.9, 130.8, 128.1, 125.3,
125.2, 64.3, 59.8, 33.2, 30.8, 30.8 ppm. 13C NMR (100 MHz,
CDCl3, diastereomer 2): δ = 128.3, 127.3, 125.9, 123.0, 122.8, 62.1,
56.8, 29.9, 28.7, 28.4 ppm. 19F NMR (375 MHz, CDCl3, dia-
stereomer 1): δ = –127.95 (d, J = 30.5 Hz) ppm, 19F NMR
(375 MHz, CDCl3, diastereomer 2): δ = –130.63 (d, J = 29.8 Hz)
General Procedure for Formation of 3-Aryl-4-fluoro-4-nitro-4-(phen-
ylsulfonyl)butanol (4a–i): To a sample vial equipped with a mag-
netic stirring bar was added toluene (1 mL), catalyst I (16 mg,
20 mol-%, 0.05 mmol), α,β-unsaturated aldehyde 2a–i (0.5 mmol,
2 equiv.), and [fluoro(nitro)methylsulfonyl]benzene (1; 55 mg,
0.25 mmol, 1 equiv.) at –20 °C. The reaction mixture was stirred at
–20 °C for 24 h, poured into cold (–20 °C) MeOH (4 mL). Next,
the reaction mixture was treated with NaBH4 (1.5 mmol, 3 equiv.)
and after 15 min at 0 °C was poured over a solution EtOAc
(40 mL)/HCl (1 , 4 mL) at 0 °C. The reaction mixture was
warmed to room temperature, and the organic layer was separated,
dried with anhydrous magnesium(II) sulfate, and filtered. The sol-
vent were removed in vacuo, and the crude mixture was purified by
column chromatography (silica gel; hexane/EtOAc, 4:1) to afford
alcohols 4a–i.
3a: Mixture of diastereomers 3a/3aЈ (dr = 2:1), pale-yellow oil. IR
(KBr): ν = 3065, 3035, 2960, 2923, 2846, 2736, 1970, 1906, 1725,
˜
1576, 1449, 1353, 1185, 1158, 1082, 977, 754, 716, 699, 684, 599,
561, 540, 446.74 cm–1. HRMS (ESI): calcd. for C16H14O5NFSNa
[M + Na]+ 374.0474; found 374.0468.
3a (Major Diastereomer): 1H NMR (600 MHz, CDCl3, 25 °C): δ =
9.60 (br. s, 1 H, CHO), 7.90–7.22 (m, 10 H, Ar), 4.94 (ddd, J =
31.6 Hz, J = 10.9 Hz, J = 2.9 Hz, 1 H, CH), 3.73 (dd, J = 18.4 Hz,
J = 3.0 Hz, 1 H, CH2), 3.26 (ddd, J = 18.4 Hz, J = 10.9 Hz, J = ppm. HRMS (ESI): calcd. for C16H16FN2O7S [M + H]+ 399.0657;
1.6 Hz, 1 H, CH2) ppm. 13C NMR (150 MHz, CDCl3, 25 °C): δ = found 399.0660. HPLC (Chiralpak® IC, n-hexane/iPrOH = 90:10,
196.36 (d, J = 3.3 Hz), 136.64–129.00 (m, 12 C), 124.85 (d, J = λ = 254 nm, 1 mL/min): tR1 = 36.919 and 50.895 min, tR2 = 28.024
Eur. J. Org. Chem. 2010, 5464–5470
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5467

J. Veselý, A. Moyano, R. Rios et al.
FULL PAPER
and 31.838 min. [α]2D5 (diastereomer 1) = –6.0 (c = 0.74, CHCl3,
18.6 Hz, J = 2.9 Hz, 1 H, CH2), 3.26 (ddd, J = 18.6 Hz, J =
11.0 Hz, J = 1.3 Hz, 1 H, CH2) ppm. 13C NMR (150 MHz, CDCl3,
25 °C): δ = 195.9 (s), 136–129 (m, 12 C), 124.3 (d, J = 289.9 Hz),
43.7 (s), 40.9 (d, J = 16.8 Hz) ppm. 19F NMR (375 MHz, CDCl3,
25 °C): δ = –67.5 (d, J = 31.4 Hz) ppm.
28%ee), [α]2D5 (diastereomer 2) = +8.1 (c = 0.84, CHCl3, 92%ee).
1
4c: Yield: 34 mg (36%), mixture of diastereomers, colorless oil. H
NMR (400 MHz, CDCl3, TMSint): δ = 7.92 (d, J = 7.2 Hz, 2 H,
Ar), 7.78 (t, J = 7.5 Hz, 1 H, Ar), 7.63–7.59 (m, 4 H, Ar), 7.39 (d,
J = 7.2 Hz, 2 H, Ar), 4.72 (ddd, J = 3.0 Hz, J = 11.8 Hz, J =
31.7 Hz, 1 H, CH), 3.75–3.70 (m, 1 H, CH2OH), 3.20 (td, J =
3.6 Hz, J = 10.4 Hz, 1 H, CH2OH), 2.95–2.87 (m, 1 H, CH2), 2.15–
2.07 (m, 1 H, CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.1,
133.6, 132.4, 131.6, 130.5, 59.0, 45.8, 45.6, 33.5, 32.1, 30.9 ppm.
19FNMR (375 MHz, CDCl3): δ = –127.25 (J = 31.7 Hz) ppm.
HRMS (ESI): calcd. for [C17H19FN3O5S]+ [M + NH4]+ 396.1026;
found 396.1022. HPLC (Chiralpak® IB, n-hexane/iPrOH = 90:10,
λ = 254 nm, 1 mL/min): tR = 30.582, 32.699 min. [α]2D5 = +12.9 (c
= 1.00, CHCl3, 74%ee).
3eЈ (Minor Diastereomer): 1H NMR (600 MHz, CDCl3, 25 °C): δ
= 9.54 (t, J = 1.3 Hz, 1 H, CHO), 7.93 –7.21 (m, 9 H, Ar), 4.92
(ddd, J = 26.5 Hz, J = 10.9 Hz, J = 2.8 Hz, 1 H, CH), 3.19 (ddd,
J = 18.2 Hz, J = 10.9 Hz, J = 1.47 Hz, 1 H, CH2), 2.92 (dd, J =
18.2 Hz, J = 2.8 Hz, 1 H, CH2) ppm. 13C NMR (150 MHz, CDCl3,
25 °C): δ = 195.0 (s), 136–129 (m, 12 C), 124.5 (d, J = 287.6 Hz),
43.9 (s), 41.7 (d, J = 17.3 Hz) ppm. 19F NMR (375 MHz, CDCl3,
25 °C): δ = –60.6 (d, J = 25.98 Hz) ppm.
4e: Yield: 44 mg (45%), mixture of diastereomers, pale-yellow oil.
IR (KBr): ν = 3586, 3315, 3095, 3065, 2956, 2925, 2854, 1714, 1579,
˜
3d: Mixture of diastereomers, pale-yellow oil. IR (KBr): ν = 3061,
˜
1492, 1446, 1415, 1349, 1158, 1092, 1016, 843, 756, 722, 685, 577,
542 cm–1. [α]2D5 = +79.5 (c = 1.075, CHCl3). HRMS (ESI): calcd.
for C16H15O5NClFS [M + Na]+ 410.0241; found 410.0236.
2923, 2841, 2733, 1726, 1577, 1448, 1352, 1274, 1158, 1081, 998,
816, 753, 716, 684, 618, 584, 541, 477 cm–1. HRMS (ESI): calcd.
for C20H16O5NFS [M + Na]+ 424.0631; found 424.0624.
1
4e (Major diastereomer): H NMR (600 MHz, CDCl3, 25 °C): δ =
1
3d (Main Diastereomer): H NMR (600 MHz, CDCl3, 25 °C): δ =
7.91–7.12 (m, 9 H, Ar), 4.59 (ddd, J = 16.4 Hz, J = 12.1 Hz, J =
3.0 Hz, 1 H, CH), 3.66 (ddd, J = 10.6 Hz, J = 6.5 Hz, J = 4.1 Hz,
1 H, CH2OH), 3.24 (td, J = 10.3 Hz, J = 4.3 Hz, 1 H, CH2OH),
2.86 (m, 1 H, CH2), 2.07 (m, 1 H, CH2) ppm. 13C NMR (150 MHz,
CDCl3, 25 °C): δ = 136–129 (m, 12 C), 125.5 (d, J = 290.9 Hz), 58.9
(s), 44.1 (s), 32.0 (s) ppm. 19F NMR (375 MHz, CDCl3, 25 °C): δ
= –68.1 (d, J = 31.3 Hz) ppm. Enantiomeric excess was determined
by HPLC with an IC chiral column (n-heptane/iPrOH = 92:8, λ =
230 nm, 1 mL/min): tR = 41.96 (major), 32.85 (minor) min.
9.63 (br. s, 1 H, CHO), 7.95–7.10 (m, 12 H, Ar), 5.13 (ddd, J =
31.6 Hz, J = 10.9 Hz, J = 2.9 Hz, 1 H, CH), 3.81 (ddd, J = 18.4 Hz,
J = 10.9 Hz, J = 1.4 Hz, 1 H, CH2), 3.38 (dd, J = 18.4 Hz, J =
2.9 Hz, 1 H, CH2) ppm. 13C NMR (150 MHz, CDCl3, 25 °C): δ =
196.3 (s), 136–123 (m, 16 C), 43.9 (s), 41.7 (d, J = 16.8 Hz) ppm.
19F NMR (375 MHz, CDCl3, 25 °C): δ = –67.0 (d, J = 31.5 Hz)
ppm.
1
3dЈ (Minor Diastereomer): H NMR (600 MHz, CDCl3, 25 °C): δ
4eЈ (Minor Diastereomer): 1H NMR (600 MHz, CDCl3, 25 °C): δ
= 7.91–7.12 (m, 9 H, Ar), 4.53 (ddd, J = 16.1 Hz, J = 11.9 Hz, J
= 3.0 Hz, 1 H, CH), 3.53 (ddd, J = 9.9 Hz, J = 5.6 Hz, J = 3.3 Hz,
1 H, CH2OH), 3.12 (td, J = 10.3 Hz, J = 4.3 Hz, 1 H, CH2OH),
1.92 (m, 1 H, CH2), 1.75 (m, 1 H, CH2) ppm. 13C NMR (150 MHz,
CDCl3, 25 °C): δ = 136–129 (m, 12 C), 126.1 (d, J = 290.4 Hz), 58.1
(s), 44.4 (s), 32.5 (s) ppm. 19F NMR (375 MHz, CDCl3, 25 °C): δ
= –64.2 (d, J = 31.1 Hz) ppm. Enantiomeric excess was determined
by HPLC with an IC chiral column (n-heptane/iPrOH = 92:8, λ =
230 nm, 1 mL/min): tR = 136.50 (major), 89.37 (minor) min.
= 9.51 (br. s, 1 H, CHO), 7.92–7.10 (m, 12 H, Ar), 5.05 (ddd, J =
26.8 Hz, J = 10.9 Hz, J = 2.9 Hz, 1 H, CH), 3.28 (ddd, J = 18.0 Hz,
J = 10.8 Hz, J = 1.4 Hz, 1 H, CH2), 2.94 (dd, J = 18.1 Hz, J =
2.9 Hz, 1 H, CH2) ppm. 13C NMR (150 MHz, CDCl3, 25 °C): δ =
195.7 (s), 136–123 (m, 18 C), 44.1 (s), 42.6 (d, J = 17.0 Hz) ppm.
19F NMR (375 MHz, CDCl3, 25 °C): δ = –60.0 (d, J = 27.0 Hz)
ppm.
4d: Yield: 20 mg, 20%, mixture of diastereomers, pale-yellow oil.
IR (KBr): ν = 3296, 3059, 2957, 2925, 2854, 1716, 1578, 1448, 1350,
˜
1158, 1081, 817, 757, 683, 590, 514, 478 cm–1. [α]2D5 = +6.5 (c =
0.31, CDCl3). HRMS (ESI): calcd. for C20H18O5NFS [M + Na]+
426.0787; found 426.0782.
3f: Mixture of diastereomers, pale-yellow. IR (KBr): ν = 3094,
˜
3067, 2918, 2843, 2734, 1726, 1579, 1488, 1447, 1410, 1354, 1157,
1082, 1012, 755, 719, 683, 613, 564, 541 cm–1. HRMS (EI): calcd.
for C16H13NO5FSBr [M]+ 428.9682; found 428.9690.
1
4d (Major Diastereomer): H NMR (600 MHz, CDCl3, 25 °C): δ =
7.95–7.33 (m, 16 H, Ar), 4.74 (ddd, J = 31.9 Hz, J = 12.0 Hz, J =
3.0 Hz, 1 H, CH), 3.65 (m, 1 H, CH2OH), 3.27 (td, J = 10.4 Hz, J
= 4.5 Hz, 1 H, CH2OH), 2.91 (m, 1 H, CH2), 2.25 (m, 1 H, CH2)
ppm. 13C NMR (150 MHz, CDCl3, 25 °C): δ = 130.42 (d, J =
26.5 Hz), 136–123 (m, 16 C), 59.2 (s), 44.8 (s), 32.1 (s) ppm. 19F
NMR (375 MHz, CDCl3, 25 °C): δ = –67.6 (d, J = 31.9 Hz) ppm.
Enantiomeric excess was determined by HPLC with an IC chiral
1
3f (Major Diastereomer): H NMR (600 MHz, CDCl3, 25 °C): δ =
9.61 (t, J = 1.3 Hz, 1 H, CHO), 7.88–7.11 (m, 9 H, Ar), 4.93 (ddd,
J = 31.4 Hz, J = 10.9 Hz, J = 2.8 Hz, 1 H, CH), 3.75 (dd, J =
18.5 Hz, J = 2.8 Hz, 1 H, CH2), 3.22 (ddd, J = 18.6 Hz, J =
10.9 Hz, J = 1.3 Hz, 1 H, CH2) ppm. 13C NMR (150 MHz, CDCl3,
25 °C): δ = 195.9 (s), 136–129 (m, 12 C), 124.5 (d, J = 290.1 Hz),
43.7 (s), 41.0 (d, J = 16.7 Hz) ppm. 19F NMR (375 MHz, CDCl3,
25 °C): δ = –67.4 (d, J = 31.5 Hz) ppm.
column (n-heptane/iPrOH = 92:8, λ = 230 nm, 1 mL/min): tR
=
62.87 (major), 54.11 (minor) min.
4dЈ (Minor Diastereomer): Enantiomeric excess was determined by
HPLC with an IC chiral column (n-heptane/iPrOH = 92:8, λ =
230 nm, 1 mL/min): tR = 223.70 (major), 134.20 (minor) min.
3fЈ (Minor Diastereomer): 1H NMR (600 MHz, CDCl3, 25 °C): δ =
9.50 (t, J = 1.3 Hz, 1 H, CHO), 7.88–7.11 (m, 9 H, Ar), 4.86 (ddd,
J = 24.1 Hz, J = 10.9 Hz, J = 2.6 Hz, 1 H, CH), 3.14 (ddd, J =
18.2 Hz, J = 10.8 Hz, J = 1.3 Hz, 1 H, CH2), 2.87 (dd, J = 18.3 Hz,
J = 2.8 Hz, CH2) ppm. 13C NMR (150 MHz, CDCl3, 25 °C): δ =
195.3 (s), 136–129 (m, 12 C), 124.4 (d, J = 287.2 Hz), 43.9 (s), 41.6
(d, J = 17.2 Hz) ppm. 19F NMR (600 MHz, CDCl3, 25 °C): δ =
–60.7 (d, J = 26.8 Hz) ppm.
3e: Mixture of diastereomers, pale-yellow oil. IR (KBr): ν = 3095,
˜
3066, 2959, 2922, 2844, 2735, 1726, 1579, 1497, 1448, 1413, 1355,
1158, 1094, 1013, 757, 719, 684, 626, 572, 542 cm–1. HRMS (ESI):
calcd. for C16H13O5NClFS [M + Na]+ 408.0085; found 408.0080.
1
3e (Major Diastereomer): H NMR (600 MHz, CDCl3, 25 °C): δ =
9.65 (t, J = 1.1 Hz, 1 H, CHO), 7.93 –7.21 (m, 9 H, Ar), 4.99 (ddd, 4f: Yield: 45 mg (42%), mixture of diastereomers, pale-yellow oil.
J = 31.4 Hz, J = 10.9 Hz, J = 2.8 Hz, 1 H, CH), 3.80 (dd, J = IR (KBr): ν = 3588, 3313, 3093, 3064, 2955, 2926, 2888, 2855, 1713,
˜
5468
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5464–5470

Highly Enantioselective Addition to α,β-Unsaturated Aldehydes
1577, 1488, 1447, 1410, 1349, 1158, 1081, 1012, 840, 756, 719, 685,
623, 572, 541 cm–1. [α]2D5 = +10.5 (c = 0.43, CHCl3). HRMS (ESI):
calcd. for C16H14O5NBrFS [M]– 429.9760; found 429.9767.
1 H, CH2OH), 2.41–2.32 (m, 1 H, CH2), 2.06–1.87 (m, 1 H, CH2),
1.51–1.37 (m, 4 H, CH2), 0.86 (t, J = 7.0 Hz, 3 H, CH3) ppm. 13C
NMR (100 MHz, CDCl3, major diastereomer): δ = 136.9, 131.6,
130.4, 60.5, 39.1, 32.0, 31.1, 30.6, 20.5, 15.0 ppm. 13C NMR
(100 MHz, CDCl3, minor diastereomer): δ = 136.0, 130.7, 129.5,
59.7, 37.8, 31.4, 30.9, 29.7, 19.6, 13.9 ppm. 19F NMR (375 MHz,
CDCl3, major diastereomer): δ = –125.09 (d, J = 27.4 Hz) ppm.
19F NMR (375 MHz, CDCl3, minor diastereomer): δ = –126.37 (d,
J = 30.0 Hz) ppm. HRMS (ESI): calcd. for C13H18FNNaO5S [M +
Na]+ 342.0783; found 342.0782. HPLC (Chiralpak® IC, n-hexane/
iPrOH = 95:5, λ = 254 nm, 1 mL/min): tmajor = 25.527 and
27.924 min, tminor = 17.470 and 21.643 min. [α]2D5 (major) = –5.8 (c
= 0.98, CHCl3, 87%ee), [α]2D5 (minor) = +6.7 (c = 0.41, CHCl3,
92%ee).
1
4f (Major Diastereomer): H NMR (600 MHz, CDCl3, 25 °C): δ =
7.90 (br. d, J = 7.6 Hz, 2 H, Ar), 7.74 (m, 1 H, Ar), 7.57 (m, 2 H,
Ar), 7.40 (br. d, J = 8.5 Hz, 2 H, Ar), 7.10 (br. d, J = 8.2 Hz, 2 H,
Ar), 4.56 (ddd, J = 31.6 Hz, J = 12.0 Hz, J = 3.0 Hz, 1 H, CH),
3.67 (ddd, J = 10.7 Hz, J = 5.9 Hz, J = 3.4 Hz, 1 H, CH2OH), 3.23
(td, J = 10.4 Hz, J = 4.4 Hz, 1 H, CH2OH), 2.83 (m, 1 H, CH2OH),
2.07 (m, 1 H, CH2) ppm. 13C NMR (150 MHz, CDCl3, 25 °C): δ
= 136.2 (s), 132.2 (s, 2 C), 132.1 (s), 132.0 (s), 130.8 (s, 2 C), 130.6
(s, 2 C), 129.5 (s, 2 C), 125.5 (d, J = 289.1 Hz), 123.2 (s), 58.9 (s),
44.1 (d, J = 17.1 Hz), 32.0 (s) ppm. 19F NMR (375 MHz, CDCl3,
25 °C): δ = –68.1 (d, J = 31.7 Hz) ppm. Enantiomeric excess was
determined by HPLC with an IC chiral column (n-heptane/iPrOH
= 92:8, λ = 230 nm, 1 mL/min): tR = 41.96 (major), 32.85
(minor) min.
5f: Yield: 75 mg (42%), white solid, m.p. 132.3 °C. IR (KBr): ν
˜
= 3097.42, 3064.58, 2974.28, 2932.32, 2905.86, 2871.20, 1729.09,
1584.53, 1478.48, 1348.18, 1284.27, 1159.35, 1076.08, 773.95,
568.66 cm–1. [α]2D5 = 69.2 (c = 0.46, CDCl3). HRMS (ESI): calcd.
for C21H23BrFNO6S [M + Na]+ 538.0331; found 538.0306. 1H
NMR (600 MHz, CDCl3, 25 °C): δ = 7.66 (br. t, J = 7.4 Hz, 1 H,
Ar), 7.47 (br. d, J = 7.7 Hz, 2 H, Ar), 7.41 (br. t, J = 7.8 Hz, 2 H,
Ar), 7.39 (br. d, J = 8.1 Hz, 2 H, Ar), 7.11 (br. d, J = 8.0 Hz, 2 H,
Ar), 4.41 (ddd, J = 30.8 Hz, J = 12.1 Hz, J = 2.4 Hz, 1 H, CH),
4.01 (m, 1 H, CH2OH), 3.50 (td, J = 10.9 Hz, J = 4.1 Hz, 1 H,
CH2OH), 2.03 (m, 1 H, CH2), 1.87 (m, 1 H, CH2), 1.21 (s, 9 H,
CH3) ppm. 13C NMR (150 MHz, CDCl3, 25 °C): δ = 135.5 (s, 2
C), 132.1 (s), 132.1 (s, 2 C), 131.8 (s, 2 C), 130.5 (s), 130.3 (s, 2 C),
129.1 (s, 2 C), 178.0 (s), 125.6 (d, J = 290.4 Hz), 123.5 (s), 59.6 (s),
44.8 (s), 38.9 (s), 29.3 (s), 27.1 (s, 3 C) ppm. 19F NMR (375 MHz,
CDCl3, 25 °C): δ = –65.4 (d, J = 31.2 Hz) ppm.
4fЈ (Minor Diastereomer): Enantiomeric excess was determined by
HPLC with an IC chiral column (n-heptane/iPrOH = 92:8, λ =
230 nm, 1 mL/min): tR = 136.50 (major), 89.37 (minor) min.
4g: Yield: 56 mg (77%), colorless oil. 1H NMR (400 MHz, CDCl3,
TMSint): δ = 7.91 (d, J = 7.9 Hz, 2 H, Ar), 7.77 (t, J = 7.3 Hz, 1
H, Ar), 7.60 (t, J = 7.9 Hz, 2 H, Ar), 4.07–4.0 (m, 1 H, CH), 3.81–
3.63 (m, 1 H, CH2OH), 3.45–3.27 (m, 1 H, CH2OH), 1.74–1.50 (m,
2 H, CH2), 1.40 (d, J = 6.1 Hz, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 137.0, 131.6, 130.4, 60.0, 35.0, 34.8. 33.7,
30.6, 13.8 ppm. 19FNMR (375 MHz, CDCl3): δ = –130.3 (d, J =
27.2 Hz) ppm. HRMS (ESI): calcd. for C11H14FNNaO5S [M +
Na]+ 314.0467; found 314.0469. HPLC: (Chiralpak® IC, n-hexane/
iPrOH = 90:10, λ = 254 nm, 1 mL/min): tR = 31.017, 36.460 min.
[α]2D5 = +3.2 (c = 1.13, CHCl3, 92%ee).
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra and HPLC traces.
4h: Yield: 53 mg (70%), mixture of diastereomers, colorless oil. 1H
NMR (400 MHz, CDCl3, TMSint, major diastereomer): δ = 7.90
(d, J = 7.9 Hz, 2 H, Ar), 7.77 (t, J = 7.3 Hz, 1 H, Ar), 7.60 (t, J =
7.9 Hz, 2 H, Ar), 3.74–3.61 (m, 2 H, CH, CH2OH), 3.26–3.14 (m,
1 H, CH2OH), 2.01–1.99 (m, 1 H, CH2), 1.87–1.67 (m, 3 H, CH2),
1.06 (td, J = 1.3, J = 7.5 Hz 3 H, CH3) ppm. 1H NMR (400 MHz,
CDCl3, TMSint, minor diastereomer): δ = 7.90 (d, J = 7.6 Hz, 2 H,
Ar), 7.77 (t, J = 7.7 Hz, 1 H, Ar), 7.60 (t, J = 7.6 Hz, 2 H, Ar),
3.93–3.75 (m, 2 H, CH, CH2OH), 3.29–3.16 (m, 1 H, CH2OH),
2.43–2.33 (m, 1 H, CH2), 2.05–1.95 (m, 1 H, CH2), 1.45–1.38 (m,
2 H, CH2), 0.96 (td, J = 1.0, J = 7.6 Hz 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3, major diastereomer): δ = 136.9, 131.6, 130.4,
60.5, 40.2, 40.0, 31.2, 30.6, 21.9, 11.5 ppm. 13C NMR (100 MHz,
CDCl3, minor diastereomer): δ = 136.0, 130.7, 129.5, 59.7, 38.9,
31.4, 30.9, 30.2, 21.7, 10.6 ppm. 19F NMR (375 MHz, CDCl3,
major diastereomer): δ = –124.87 (d, J = 30.5 Hz) ppm. 19F NMR
(375 MHz, CDCl3, minor diastereomer): δ = –126.35 (d, J =
29.8 Hz) ppm. HRMS (ESI): calcd. for C12H15FN3O4S [M + H]+
288.0703; found 288.0700. HPLC (Chiralpak® IC, n-hexane/iPrOH
= 95:5, λ = 254 nm, 1 mL/min): tmajor = 28.588 and 34.130 min,
tminor = 26.088 and 30.874 min. [α]2D5 (major) = –6.8 (c = 1.00,
CHCl3, 89%ee), [α]2D5 (minor) = +1.8 (c = 0.67, CHCl3, 90%ee).
Acknowledgments
We thank the Spanish Ministry of Science and Innovation
(MICINN) (Project AYA2009-13920-C02-02), the Ministry of Edu-
cation of the Czech Republic (Grant No. MSM0021620857), and
the Grant Agency of the Czech Republic (Grant No. 203/09/P193)
for financial support. A.-N.R.A. is also grateful to the MICINN
for a predoctoral fellowship.
[1] a) T. Hiyama (Ed.), Organofluorine Compounds: Chemistry and
Applications, Springer, New York, 2000; b) K. Uneyama, Or-
ganofluorine Chemistry, Blackwell, Oxford, 2006; c) P. Kirsch,
Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Appli-
cations, Wiley-VCH, Weinheim, 2008; d) J.-P. Begué, D. Bon-
net-Delpon, Bioorganic and Medicinal Chemistry of Fluorine,
Wiley-VCH, Weinheim, 2008; e) I. Ojima, Fluorine in Medicinal
Chemistry and Chemical Biology, Blackwell, Oxford, 2009.
[2] For two excellent recent reviews on the synthesis of fluorine-
containing compounds, see: a) G. K. S. Prakash, J. Hu, Acc.
Chem. Res. 2007, 40, 921–930; b) V. A. Brunet, D. O’Hagan,
Angew. Chem. Int. Ed. 2008, 47, 1179–1182.
[3] For some recent references, see: a) M. Marigo, D. Fielenbach,
A. Braunton, A. Kjaesgaard, K. A. Jørgensen, Angew. Chem.
Int. Ed. 2005, 44, 3703–3706; b) D. D. Steiner, N. Mase, C. F.
Barbas III, Angew. Chem. Int. Ed. 2005, 44, 3706–3710; c) T. D.
Beeson, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127,
8826–8828; d) C. Ni, L. Zhang, J. Hu, J. Org. Chem. 2008, 73,
5699–5713; e) G. K. S. Prakash, X. Zhao, S. Chacko, F. Wang,
H. Vaghoo, G. A. Olah, Beilstein J. Org. Chem. 2008, 4, 17; f)
G. K. S. Prakash, S. Chacko, S. Alconcel, T. Stewart, T. Ma-
thew, G. A. Olah, Angew. Chem. Int. Ed. 2007, 46, 4933–4936;
1
4i: Yield: 58 mg (73%), mixture of diastereomers, colorless oil. H
NMR (400 MHz, CDCl3, TMSint, major diastereomer): δ = 7.90
(d, J = 8.0 Hz, 2 H, Ar), 7.77 (t, J = 7.6 Hz, 1 H, Ar), 7.60 (t, J =
7.9 Hz, 2 H, Ar), 3.74–3.60 (m, 2 H, CH, CH2OH), 3.27–3.15 (m,
1 H, CH2OH), 1.99–1.80 (m, 2 H, CH2), 1.73–1.62 (m, 2 H, CH2),
1
1.51–1.39 (m, 2 H, CH2), 0.96 (t, J = 7.2 Hz, 3 H, CH3) ppm. H
NMR (400 MHz, CDCl3, TMSint, minor diastereomer): δ = 7.90
(d, J = 8.4 Hz, 2 H, Ar), 7.77 (t, J = 7.8 Hz, 1 H, Ar), 7.60 (t, J =
7.8 Hz, 2 H, Ar), 3.93–3.74 (m, 2 H, CH, CH2OH), 3.32–3.18 (m,
Eur. J. Org. Chem. 2010, 5464–5470
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5469

J. Veselý, A. Moyano, R. Rios et al.
FULL PAPER
g) T. Fukuzumi, N. Shibata, M. Sugiura, H. Yasui, S. Naka-
mura, T. Toru, Angew. Chem. Int. Ed. 2006, 45, 4973–4977; h)
S. Mizuta, N. Shibata, Y. Goto, T. Furukawa, S. Nakamura, T.
Toru, J. Am. Chem. Soc. 2007, 129, 6394–6395; i) T. Furukawa,
N. Shibata, S. Mizuta, S. Nakamura, T. Toru, M. Shiro, Angew.
Chem. Int. Ed. 2008, 47, 8051–8054; j) J. Liu, L. Zhang, J. Hu,
Zhu, Y. Lu, Chem. Commun. 2010, 46, 2235–2237; g) A.
Quintard, S. Belot, E. Marchal, A. Alexakis, Eur. J. Org. Chem.
2010, 927–936; h) S. Zhang, J. Li, W. Wang, Tetrahedron Lett.
2010, 51, 1766–1769.
[8] X. Companyó, M. Hejnová, M. Kamlar, J. Vesely, A. Moyano,
R. Rios, Tetrahedron Lett. 2009, 50, 5021–5024.
Org. Lett. 2008, 10, 5377–5380; k) G. K. S. Prakash, F. Wang, [9] For previous reports on asymmetric conjugate additions of
T. Stewart, T. Mathew, G. A. Olah, Proc. Natl. Acad. Sci. USA
2009, 108, 4090–4094; l) D. A. Nagib, M. E. Scott, D. W. C.
MacMillan, J. Am. Chem. Soc. 2009, 131, 10875–10877; m) P.
Li, Z. Chai, S.-L. Zhao, Y.-Q. Yang, H.-F. Wang, C.-W. Zheng,
Y.-P. Cai, G. Zhao, S.-Z. Zhu, Chem. Commun. 2009, 7369–
7371; n) H.-F. Cui, Y.-Q. Yang, Z. Chai, P. Li, C.-W. Zheng,
S.-Z. Zhu, G. Zhao, J. Org. Chem. 2010, 75, 117–122; o) T.
Furukawa, Y. Goto, J. Kawazoe, E. Tokunaga, S. Nakamura,
Y. Yang, H. Du, A. Kakehi, M. Shiro, N. Shibata, Angew.
Chem. Int. Ed. 2010, 49, 1642–1647; p) A. E. Allen, D. W. C.
MacMillan, J. Am. Chem. Soc. 2010, 132, 4986–4987.
[4] A.-N. Alba, X. Companyó, A. Moyano, R. Rios, Chem. Eur.
J. 2009, 15, 7035–7038.
fluoromalonates or fluoro-β-keto esters, see: a) P. J. Nichols,
J. A. DeMattei, B. R. Barnett, N. A. LeFur, T. Chuang, A. D.
Piscopio, K. Koch, Org. Lett. 2006, 8, 1495–1498; b) D. Y.
Kim, S. M. Kim, K. O. Koh, J. Y. Mang, K. Lee, Bull. Korean
Chem. Soc. 2003, 24, 1425–1426; c) X. Han, J. Luo, Y. Lu,
Chem. Commun. 2009, 2044–2046; d) H. Li, S. Zhang, C. Yu,
X. Song, W. Wang, Chem. Commun. 2009, 2136–2138; e) H.
Li, L. Zu, H. Xie, W. Wang, Synthesis 2009, 1525–1530.
[10] a) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen,
Angew. Chem. Int. Ed. 2005, 44, 794–797; b) Y. Hayashi, H.
Gotoh, T. Hayashi, M. Shoji, Angew. Chem. Int. Ed. 2005, 44,
4212–4215.
[11] K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am.
Chem. Soc. 2000, 122, 4243–4244.
[12] CCDC-772949 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[5] S. Zhang, Y. Zhang, Y. Ji, H. Li, W. Wang, Chem. Commun.
2009, 4886–4888.
[6] F. Ullah, G.-L. Zhao, L. Deiana, M. Zhu, P. Dziedzic, I. Ib-
rahem, P. Hammar, J. Sun, A. Córdova, Chem. Eur. J. 2009,
15, 10013–10017.
[7] For reviews on asymmetric organocatalysis with sulfones, see:
a) M. Nielsen, C. B. Jacobsen, N. Holub, M. W. Paixao, K. A.
Jørgensen, Angew. Chem. Int. Ed. 2010, 49, 2668–2679; b) A.-
N. R. Alba, X. Companyó, R. Rios, Chem. Soc. Rev. 2010, 39,
2018–2033; for recent references, see: c) A.-N. Alba, X. Com-
panyó, A. Moyano, R. Rios, Chem. Eur. J. 2009, 15, 11095–
11099; d) A. Quintard, A. Alexakis, Chem. Eur. J. 2009, 15,
11109–11114; e) A.-N. R. Alba, X. Companyó, G. Valero, A.
Moyano, R. Rios, Chem. Eur. J. 2010, 16, 5354–5362; f) Q.
[13] a) For a review on iminium catalysis, see: A. Erkkilä, I. Ma-
jander, P. M. Pihko, Chem. Rev. 2007, 107, 5416–5470; see also:
b) G. Valero, J. Schimer, I. Císarˇová, J. Vesely, A. Moyano, R.
Rios, Tetrahedron Lett. 2009, 50, 1943–1946; c) A.-N. Alba, N.
Bravo, A. Moyano, R. Rios, Tetrahedron Lett. 2009, 50, 3067–
3069; d) N. Bravo, I. Mon, X. Companyó, A.-N. Alba, A. Moy-
ano, R. Rios, Tetrahedron Lett. 2009, 50, 6624–6626.
Received: June 14, 2010
Published Online: August 16, 2010
5470
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5464–5470