Asymmetric Michael addition reaction organocatalyzed by stereoisomeric pyrrolidine sulfinamides under neat conditions. A brief study of self-disproportionation of enantiomers

Article abstract of DOI:10.1016/j.tet.2017.05.016

This paper describes the synthesis of all four possible stereoisomers of the pyrrolidine sulfinamides derived from (S)-proline or (R)-proline and either enantiomer of t-butylsulfinamide. These bifunctional derivatives were examined as organocatalysts in t

Full text of DOI:10.1016/j.tet.2017.05.016

Accepted Manuscript
Asymmetric Michael addition reaction organocatalyzed by stereoisomeric pyrrolidine
sulfinamides under neat conditions. A brief study of self-disproportionation of
enantiomers
Gloria Reyes-Rangel, Jorge Vargas-Caporali, Eusebio Juaristi
PII:
S0040-4020(17)30482-9
10.1016/j.tet.2017.05.016
TET 28682
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 March 2017
Revised Date: 1 May 2017
Accepted Date: 3 May 2017
Please cite this article as: Reyes-Rangel G, Vargas-Caporali J, Juaristi E, Asymmetric Michael addition
reaction organocatalyzed by stereoisomeric pyrrolidine sulfinamides under neat conditions. A brief study
of self-disproportionation of enantiomers, Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.016.
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ACCEPTED MANUSCRIPT
Asymmetric Michael addition
organocatalyzed by
stereoisomeric pyrrolidine
sulfinamides under neat
conditions. A brief study on
self-disproportionation of
enantiomers
Gloria Reyes-Rangel, Jorge Vargas-Caporali and Eusebio Juaristi*
Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, 07360 Ciudad
de México, México.
O
O
N
H
N
H
N
N
S
S
R
R
O2N
+
H
H
O
O
O
(1R,2S)-5
10%mol
(1S,2R)-5
10%mol
NO2
NO2
(R)-mandelic acid
neat
(R)-mandelic acid
neat
R
(1R,2S)-7
(1S,2R)-7
rt, 24 h
rt, 24 h

ACCEPTED MANUSCRIPT
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Asymmetric Michael addition reaction
organocatalyzed by stereoisomeric
pyrrolidine sulfinamides under neat
conditions. A brief study of self-
disproportionation of enantiomers
Leave this area blank for abstract info.
Gloria Reyes-Rangel, Jorge Vargas-Caporali and Eusebio Juaristi*
Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, 07360, Ciudad de México.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Asymmetric Michael addition reaction organocatalyzed by stereoisomeric pyrrolidine
sulfinamides under neat conditions. A brief study of self-disproportionation of
enantiomers
Gloria Reyes-Rangela, Jorge Vargas-Caporalia, and Eusebio Juaristia, b, *
a Departamento de Química, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, Avenida IPN No. 2508, 07360 Ciudad de México,
México
b El Colegio Nacional, Luis González Obregón No. 23, Centro Histórico, 06020 Ciudad de México, México
We dedicate this manuscript to Prof. Marian Mikołajczyk, a distinguished researcher in organosulfur chemistry, on the occasion of his 80th birthday.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
This paper describes the synthesis of all four possible stereoisomers of the pyrrolidine
sulfinamides derived from (S)-proline or (R)-proline and either enantiomer of t-
butylsulfinamide. These bifunctional derivatives were examined as organocatalysts in the
asymmetric Michael addition reaction, finding that the pyrrolidine stereocenter, rather than the
stereogenic sulfur, is responsible for the observed stereocontrol in the asymmetric reaction. This
result is in accordance with previous reports in the literature (aldol reactions: W. Wan, J. Hao,
and coworkers, RSC Adv. 2014, 4, 26563-26568; J. A. Ellman, et al., Tetrahedron 2011, 67,
4412-4416). Consequently, no evidence for double stereoinduction is found. The desired
Michael adducts were obtained with good yields, high diastereoselectivities, and moderate to
good enantioselectivities. Some tests designed to examine the potential manifestation of self-
disproportionation of enantiomers (SDE) were carried out by means of chromatographic
purification and subsequent evaluation of the enantiopurity of the corresponding Michael
adducts.
Available online
Keywords:
Organocatalysis
Pyrrolidine sulfinamides
Bifunctional organocatalysts
Asymmetric Michael addition
Self-disproportionation of enantiomers
2017 Elsevier Ltd. All rights reserved
.
1. Introduction
derivatives of N-aminoacyl sulfinamides as organocatalysts in the
enantioselective aldol reaction between acetone and p-
nitrobenzaldehyde, corroborating that the best combination of
stereoisomeric fragments resulted from the combination of (S)-
proline and (S)-2-methylpropane-2-sulfinamide (Scheme 1).
Ellman, et al. concluded that “the inductive effect of the electron-
withdrawing sulfinyl group acidifies the N-H bond, which serves
to modulate hydrogen bonding interactions and at the same time,
the close proximity between the stereogenic sulfur and the active
site of the catalyst, contributes to the high level of stereocontrol
in this reaction”.6
N-t-Butylsulfinamide has proved to be an efficient scaffold in
asymmetric synthesis, either as chiral auxiliary or chiral reagent.
In particular, the N-t-butylsulfinamide moiety is extremely useful
in the preparation of chiral imines, that activate the electrophilic
C=N function in addition reactions, simultaneously rendering
diastereotopic faces of the double bond.1 Lately, various
organocatalytic applications of N-t-butyl sulfinamide derivatives
have been reported.2 For instance, Sun and coworkers, developed
a series of chiral ligands containing the sulfinamide fragment
that, by using HSiCl3 as reducing agent, were evaluated as
organocatalysts in the enantioselective reduction of aromatic N-
alkyl ketimines and β-enamino esters via hydrogen transfer.3
O
O
N
H
N
S
H
In this context, asymmetric organocatalysis via chiral enamine
intermediates derived from pyrrolidine bifunctional compounds4
has proven to be one of the most effective methods to carry out
enantioselective α-functionalizations of aldehydes and ketones.5
In this regard, the ability of the N-sulfinyl functionality both as a
chiral directing group and Brønsted acid moiety suitable for
hydrogen-bonding has been amply studied by Ellman and
coworkers.6 These researchers evaluated various diastereomeric
(S,S)-A
10 mol%
O
OH O
H
acetone (30 % equiv)
water (5 equiv)
DMSO-d6, rt, 1.5 h
O2N
O2N
91% conv, 96% ee
Scheme 1. Asymmetric aldol reaction catalyzed by N-sulfinyl prolinamide
(S,S)-A.
__________
Corresponding author. Tel.: +52-55-5747-3722; fax: +52-55-5747-3897; e-mail: juaristi@relaq.mx (E. Juaristi)

2
Tetrahedron
ACCEPTED MANUSCRIPT
More recently, Wan, Hao, and coworkers7 reported the
the four possible stereoisomers prepared from the coupling of
asymmetric aldol reaction between cyclohexanone and diverse
aryl-substituted aldehydes organocatalyzed by stereoisomers of A
(Scheme 2). These researchers found that the most effective
organocatalysts for these reactions are the unlike enantiomeric
pair (S,R)-A and (R,S)-A, which affords the corresponding
enantiomeric aldol adducts, (2S,1’R) and (2R,1’S), respectively,
with high stereoselectivity.
(S)-proline or (R)-proline with (S)- or (R)-t-butylsulfinamide.
Furthermore, these diastereomeric proline sulfinamides were
evaluated as organocatalysts in the asymmetric Michael addition
reaction.
2. Results and discussion
2.1. Synthesis of stereoisomeric pyrrolidine-2-ylmethyl-N-t-
butyl-sulfinamides, 5
Based on a previous report by Sun and coworkers,8 the
derivatives of interest were prepared from N-Fmoc protected (S)-
or (R)-proline 1, by reduction of the carboxyl moiety employing
NaBH4 combined with Et2O:BF3, to give the Fmoc prolinols (S)-
2 or (R)-2 (Scheme 3). Reoxidation of the carbinol functionality
under Swern conditions using oxalyl chloride, generated the
corresponding prolinals, which in turn were condensed with the
appropriate enantiomer of t-butylsulfinamide to afford the
expected imines (1S,2R)-3, (1S,2S)-3, (1R,2S)-3, or (1R,2R)-3.
This reaction was achieved by means of Lewis acid catalysis with
anhydrous CuSO4. Each of the resulting stereoisomeric
sulfinimides was reduced with NaBH4, and final N-deprotection
of the pyrrolidine derivatives 4 was accomplished by using
Et2NH as the required base to provide (1S,2R)-5, (1S,2S)-5,
(1R,2S)-5, or (1R,2R)-5 (Scheme 3).
Scheme 2. Aldol reaction of cyclohexanone with substituted benzaldehyde
under solvent-free conditions.
The Michael addition reaction constitutes a prototypical
application of proline-derived organocatalysts,5e-g but as far as we
are aware there are no examples reported in the literature
describing applications of proline sulfinamides as organocatalysts
in asymmetric Michael reactions. Here, we report the synthesis of
1
iv
v
O
S
O
O
2
N
N
Fmoc
N
N
H
HN
N
S
S
ii, iii
Fmoc
H
(1S,2R)-3
(1S,2R)-4
(1S,2R)-5
i
CO2H
N
N
OH
Fmoc
Fmoc
ii, iii
(S)-1
(S)-2
iv
v
O
O
O
S
N
N
N
HN
N
H
N
S
S
Fmoc
H
Fmoc
(1S,2S)-3
(1S,2S)-4
(1S,2S)-5
iv
v
O
O
O
S
N
N
H
N
HN
N
H
N
S
S
ii, iii
Fmoc
Fmoc
(1R,2S)-3
(1R,2S)-4
(1R,2S)-5
i
CO2H
N
N
OH
Fmoc
Fmoc
ii, iii
(R)-1
(R)-2
iv
v
O
S
O
S
O
S
N
N
N
H
N
HN
N
H
Fmoc
Fmoc
(1R,2R)-3
(1R,2R)-4
(1R,2R)-5
aReagents and conditions: (i) NaBH4, Et2O:BF3, anhydrous THF, 0 °C, 18 h. (ii) CH2Cl2, (CO)Cl2, dry DMSO, Et3N. (iii) CuSO4 anhydrous, dry CH2Cl2, (S)- or (R)-t-butylsulfinamide,
25 °C, 24 h. (iv) NaBH4, MeOH, THF. (v) Et2NH, THF, 25 °C, 5 h.
Scheme 3. Synthesis of the four stereoisomers of pyrrolidine t-butylsulfinamide, 5.
BnBr
Et3N
O
O
N
H
N
N
N
S
S
THF
0 °C to rt
18 h
H
H
Ph
70%
(1S,2S)-5
(1S,2S)-6
Scheme 4. N-Benzylation of pyrrolidine-sulfinamide (1S,2S)-5.
Fig. 1. X-ray crystallographic structure of the resulting N-benzyl pyrrolidine-
sulfinamide (1S,2S)-6 (thermal ellipsoids at 30 % probability).

3
Derivative (1S,2S)-6 obtained by N-benzylation of (1S,2S)-5
(Scheme 4) afforded a suitable crystal for analysis by means of
X-ray diffraction, corroborating the expected absolute
configuration for both stereogenic centers (Flack x parameter –
0.0336 with su 0.1470) (Fig. 1). In the crystallographic structure
it can be appreciated that both pyrrolidine substituents are
oriented trans to each other. Additionally, the N-H bond is
oriented far away to the pyrrolidine fragment (N1-C2-C6-N7
torsion angle = 173.1°), which indicates that no intramolecular
hydrogen bond is formed between both fragments. The
stereogenic sulfur in the anticipated pyramidal molecular
geometry is defined by the following angles: N7-S8-O9 =
111.73°, N7-S8-C10 = 98.15°, O9-S8-C10 = 105.52°.
Additionally, under neat conditions the reaction time
ACCEPTED MANUSCRIPT
diminished from three days to 24 h (compare entries 4 and 5 with
entries 6-8 in Table 1). On the other hand, at 2 °C (entry 12 in
Table 1), the reaction yield and the diastereomeric ratio of the
Michael product remained high while the enantiomeric ratio
decreased slightly. When lowering the amount of catalyst from
20 mol-% to 10 mol-%, no significant change in yield and
enantioselectivity was observed (compare entries 6 and 7 in
Table 1). Nevertheless, with 5 mol-% of catalyst the yield
decreased dramatically (compare entry 8 in Table 1), and actually
no product was observed when 2 mol-% of catalyst was used
(entry 9 in Table 1). Product formation was also inhibited in the
absence of the acidic additive or at temperatures below –15 °C
(entries 10 and 11 in Table 1).
With isomeric pyrrolidine sulfinamides (1S,2R)-5, (1S,2S)-5,
(1R,2S)-5, and (1R,2R)-5 at hand, we proceeded to their
evaluation as organocatalysts in the Michael addition reaction
between cyclohexanone and various β-nitrostyrenes.
In order to confirm whether double stereoinduction is
operative in the system, the results achieved with organocatalyst
(1S,2R)-5 (Table 1) were compared with those obtained with
diastereomeric (1S,2S)-5, with opposite configuration at sulfur. In
the event, the stereoselectivities were similar, and thus it is
concluded that there is no significant contribution on
stereocontrol from the stereogenic sulfur moiety.
2.2 Evaluation of stereoisomeric pyrrolidine t-
butylsulfinamides, 5, as organocatalysts.
We first evaluated derivative (1S,2R)-5 as organocatalyst,
screening several variables in order to optimize the reaction
conditions (Table 1). While (1S,2R)-5 (20 mol-%) in the presence
of PhCO2H as additive in combination with common solvents
such as toluene, IPA and DMSO (entries 1-3 in Table 1) did not
afford the Michael adduct 7a; water and brine as reaction media
afforded the expected product with good diastereo- and high
enantioselectivity, although in moderate yields (entries 4-5 in
Table 1). Importantly, the reaction proceeded efficiently under
solvent-free conditions, observing that not only the yield
increased significantly to 80%, but also good diastereo- and
enantioselectivities were maintained (entry 6 in Table 1). That an
organocatalytic reaction can be carried out in the absence of
solvent, that is under more sustainable conditions, is a rather
attractive feature of the present system.9
Comparison of entries 7 and 10 in Table 1 gives evidence of
the prominent role of benzoic acid as activating additive in the
reaction. At this point it was decided to examine alternative
Brønsted acids as additives; no drastic differences were observed
(Table 2), so it is apparent that the acid catalysis is of the general
type and independent of the particular structural features of the
proton source, as long as the pKa is constrained within an
appropriate range (pKa = 4-5).10 Furthermore, the use of either
enantiomer of mandelic acid as Brønsted acid additive afforded
the same configuration of the product (compare entries 5 and 6 in
Table 2), which argues against the possible existence of a double
stereoinducing effect by the chiral acid additive.11
Table 2. Evaluation of diverse Brønsted acids additives.
Table 1. Asymmetric Michael reaction organocatalyzed by pyrrolidine t-
butylsulfinamide (1S,2R)-5.a
O
N
H
N
S
O2N
H
O
O
(1S,2R)-5
1
O
N
NO2
2
N
10 mol-%
O2N
S
H
+
O
O
H
neat
rt, 24 h
1
NO2
(1S,2R)-5
(1S,2R)-7a
2
+
rt
(1S,2R)-7a
Additive
10 mol-%
p-nitrobenzoic acid
p-chlorobenzoic acid
p-methoxybenzoic acid 63
benzoic acid
(S)-mandelic acid
(R)-mandelic acid
Yielda
drb
erc
Entry
(%) syn:anti (1S,2R):(1R,2S)
83
93
erf
(1S,2R)-5 PhCO2H
Yieldd
dre
1
2
3
4
5
6
89:11
93:7
92:8
93:7
93:7
95:5
74:26
84:16
79:21
85:15
79:21
84:16
Entry
Solvent
mol-%
mol-%
(%) syn:anti (1S,2R):(1R,2S)
1
2
3
20
20
20
20
20
20
10
5
20
20
20
20
20
20
10
5
Toluene
IPA
DMSO
H2O
Brine
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
—
—
—
56
54
80
76
20
—
—
—
89
87
—
—
—
94:6
94:6
90:10
93:7
93:7
—
—
—
94:6
93:7
—
—
—
86:14
89:11
89:11
85:15
85:15
—
—
—
85:15
89:11
76
83
83
4**
5**
6*
Isolated yield. b Determined by 1H NMR of crude product. c HPLC analysis
a
with chiral columns for the syn isomer.
7*
8*
Each stereoisomer of pyrrolidine sulfinamide 5 was evaluated
in combination with either enantiomer of mandelic acid, and
therefore each chiral organocatalyst generated
9*
2
2
10*
11b,*
12c,*
13g
10
10
10
10
—
10
10
10
a pair of
diastereomeric salts. The yields and diastereomeric ratios of the
Michael products obtained with these diastereomeric salts were
good in all cases, reaching up to 80% ee (Table 3). Importantly,
enantioenriched Michael adducts (1S,2R)-7a and (1R,2S)-7a were
obtained with (S)-pyrrolidine [(1S,2R)-5 and (1S,2S)-5] or (R)-
pyrrolidine [(1R,2S)-5 and (1R,2R)-5] derivatives, respectively,
regardless the configuration of the t-butylsulfinamide moiety or
the mandelate counterion.12
a
Unless otherwise specified, reaction conditions were as follows:
cyclohexanone (0.2 mL), β-nitrostyrene (0.5 mmol), stirring during 24 h* or
72 h**, and using the indicated solvent. b Reaction at –15 °C. c Reaction at 2
d
°C. Isolated yield [gravity-driven chromatography, employing silica-gel
(14g, 230-400 mesh) packed in glass columns (ø 1.8-2 cm, stationary phase
e
1
@ 45 cm length)] and Hexane:EtOAc (8:2) as eluent. Determined by H
f
NMR of crude products. HPLC analysis with chiral columns for the syn
isomer. (g) Reaction conducted with catalyst (1S,2S)-5.

4
Tetrahedron
Table 3. Asymmetric Michael reaction organocatalyzed by pyrrolidine t-
entry 6 in Table 4). Stereoselectivities induced by the salt formed
ACCEPTED MANUSCRIPT
butylsulfinamides 5 in combination with mandelic acid.a
between (1S,2R)-5 and (R)-mandelic acid remained practically
constant for all aryl-nitrostyrenes with electron-withdrawing
substituents, with ee values around 70%. As already noticed
above, electron-donating substituents in these electrophiles
provoked a marked decrease in enantioinduction.
O2N
O
O
O
(1R,2S)-5 or (1R,2R)-5
(1S,2R)- or (1S,2S)-5
NO2
NO2
10 mol-%
10 mol-%
+
mandelic acid
10 mol-%
neat
mandelic acid
10 mol-%
neat
(1R,2S)-7a
(1S,2R)-7a
rt, 24 h
rt, 24 h
2.3 Evaluation of self-disproportionation of enantiomers
via achiral chromatography.
Mandelic
acid
10 mol-%
Major
Stereoisomer
Yieldb
(%)
drc
erd
Entry Organocatalyst
The self-disproportionation of enantiomers (SDE) refers to
any manipulation process under achiral conditions in which a
non-racemic (scalemic) chiral compound leads to fractions
containing variable proportions –either enriched and depleted, in
comparison to the enantiomeric composition of the starting
sample– of the enantiomers.13 Specifically, SDE has been
observed after fractional crystallization,14 sublimation,15
distillation16 and achiral chromatography.17
syn:anti (1S,2R):(1R,2S)
1
2
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(1S,2R)-7a
(1S,2R)-7a
(1S,2R)-7a
(1S,2R)-7a
(1R,2S)-7a
(1R,2S)-7a
(1R,2S)-7a
(1R,2S)-7a
83
83
71
89
74
77
75
75
93:7
93:7
94:6
92:8
92:8
90:10
84:16
83:17
85:15
79:21
85:15
86:14
11:89
12:88
16:84
10:90
(1S,2R)-5
3
4
(1S,2S)-5
5
6
(1R,2S)-5
7
8
(1R,2R)-5
a Reactions were performed with cyclohexanone (0.2 mL), β-nitrostyrene (0.5
Diverse factors influence the magnitude in which chiral
compounds may exhibit SDE when being purified by means of
gravity-driven column chromatography, such as the polarity of
the solvent employed as eluent, the nature of stationary phase
(e.g. alumina, silica gel), as well as particle and pore size.13
Chiral compounds, such as β-amino acid esters,18 acylated
amines,19 thioamides and sulfoxides20 have exhibited SDE.
mmol), 10 mol-% of organocatalyst stirring at rt during 24 h. b Isolated yield.
c
1
d
Determined by H NMR of crude product. HPLC analysis with chiral
columns for the syn isomer.
Table 4. Asymmetric Michael reaction with substituted β-nitrostyrene under
solvent free conditions.a
With the aim of examining whether the Michael adducts
obtained in the present work might exhibit SDE, we considered
two of the products described above: one obtained in high ee
[(1R,2S)-7h] and the other obtained with the lowest ee [(1S,2R)-
7e]. For this study, we focused on gravity driven column
chromatography since it is the most common method to purify
this class of compounds. In particular, the nature of the mobile
phase was the variable to evaluate, considering a mixture of
hexane-ethyl acetate 8:2, and pure methylene chloride as eluents.
O
O
N
H
N
H
N
N
S
S
H
H
O
Ar
O
O
Ar
O2N
(1R,2S)-5
10 mol-%
(1S,2R)-5
10 mol-%
NO2
NO2
+
(R)-mandelic acid
10 mol-%
neat
(R)-mandelic acid
10 mol-%
neat
Ar
(1R,2S)-7
(1S,2R)-7
rt, 24 h
rt, 24 h
Yieldb
drc
erd
ee
Entry
Ar
Product
(%) syn:anti (S,R):(R,S)
(%)
1
2
3
4
5
6
7
8
9
(1S,2R)-7a
(1R,2S)-7a
(1S,2R)-7b
(1R,2S)-7b
(1S,2R)-7c
(1R,2S)-7c
(1S,2R)-7d
(1R,2S)-7d
(1S,2R)-7e
(1R,2S)-7e
(1S,2R)-7f
(1R,2S)-7f
(1S,2R)-7g
(1R,2S)-7g
(1S,2R)-7h
(1R,2S)-7h
97
74
83
88
93
82
95
91
61
64
84
62
89
65
86
84
96:4
92:8
94:6
95:5
96:4
96:4
95:5
94:6
87:13
87:13
96:4
91:9
91:9
91:9
90:10
91:9
85:15
11:89
85:15
12:88
83:17
10:90
84:16
9:91
70:30
22:78
73:27
11:89
76:24
10:90
84:16
9:91
70
78
70
76
66
80
68
82
40
56
46
78
52
80
70
82
C6H5
Table 5. Effect of a low-polarity eluent [Hexane:EtOAc (8:2)] on the SDE of
Michael adduct (1R,2S)-7h obtained from the reaction catalyzed by (1R,2S)-
5.a
o-Cl-C6H4-
o-MeO-C6H4-
o-Br-C6H4-
p-MeO-C6H4-
p-Me-C6H4-
p-Cl-C6H4-
p-F-C6H4-
F
O
N
N
S
H
O2N
H
O
O
(R)
(1R,2S)-5
10 mol-%
NO2
(S)
10
11
12
13
14
15
16
+
(R)-mandelic acid
neat
F
rt, 24 h
(1R,2S)-7h
Mass/fraction
(mg) c
er d
(S,R):(R,S)
ee
(%)
Fraction b
Weight %
1
2
3
4
5
6
7
8
9
4.0
8.3
7.0
13.3
11.0
7.3
6.5
5.1
3.3
2.8
5.66
11.74
9.90
18.81
15.56
10.32
9.19
7.21
4.67
3.96
2.97
7:93
7:93
8:92
8:92
9:91
9:91
9:91
9:91
10:90
10:90
10:90
86
86
84
84
82
82
82
82
80
80
80
a Reactions were performed with cyclohexanone (0.2 mL, 0.19 g, 1.93 mmol),
β-nitrostyrene (0.5 mmol), 10 mol-% of organocatalyst and 10 mol-% of
mandelic acid, stirring at rt during 24 h. b Isolated yield by means of gravity-
driven chromatography, employing silica-gel (14 g, 230-400 mesh) packed in
glass columns (ø 2 cm, stationary phase @ 45 cm length) and Hexane:EtOAc
(8:2) as eluent. Determined by 1H NMR of crude product. HPLC analysis
c
d
with chiral columns for the syn isomer.
10
11
2.1
To study the scope of the reaction, we chose enantiomeric
organocatalysts (1S,2R)-5 and (1R,2S)-5, both in combination
with (R)-mandelic acid (Table 4). Notably, enhanced
stereoinduction was observed when electron-withdrawing
substituents are present in the aryl fragment of the nitrostyrene,
achieving for example 82% ee for products o-Br (7d, entry 8 in
Table 4) and p-F (7h, entry 16 in Table 4). By contrast, electron-
donating substituents led to diminished stereoselectivity (entries
5, 9, 10 and 11 in Table 4). An exception was o-methoxy, which
gave rise to the corresponding product (1R,2S)-7c in 80% ee (7c,
a
The reaction was carried out under the previously described conditions [Cf.
Table 4 (a)]. b Product eluted in fractions of 10 mL each. c Isolated weight per
corresponding fraction by means of gravity-driven chromatography,
employing silica-gel (14 g, 230-400 mesh) packed in a glass column (ø 2 cm,
d
stationary phase @ 45 cm length). HPLC conditions: Chiralpak AS-H
column, 210 nm, n-Hexane/iPrOH 95:5, U = 0.5 mL/min [tR(minor syn) =
55.4 min, tR(major syn) = 81.2 min].

5
Table 7. Effect of a low-polarity eluent [Hexane:EtOAc (8:2)] on the SDE
SDE for (1R,2S)-7h [Hexane:EtOAAcC(8C:2E)] PTED MANUSCRIPT
100
80
of Michael adduct (1S,2R)-7e obtained from reaction catalyzed by (1S,2R)-5.a
ee (%)/fraction
[Hex:EtOAc
(8:2)]
OCH3
O
S
N
H
N
O2N
H
O
O
60
% ee (global)*
(S)
(1S,2R)-5
10 mol-%
NO2
(R)
+
(R)-mandelic acid
neat
40
OCH3
rt, 24 h
0
1
2
3
4
5
6
7
8
9 10 11 12
(1S,2R)-7e
fraction
Mass/fraction
(mg) c
er d
(S,R):(R,S)
ee
(%)
Fraction b
Weight %
Fig. 2. Graphical representation of chromatographic behavior for Michael
reaction test to obtain adduct (1R,2S)-7h after purification using a non-polar
eluent [Hexane:EtOAc (8:2)] showing the % ee of the corresponding eluted
fraction (Cf. Table 5). The global value 82% ee corresponds to the originally
determined value (see entry 16, Table 4).
1
2
3
4
5
6
7
8
9
5.2
7.5
5.08
7.32
70:30
63:37
66:34
70:30
75:25
77:23
77:23
81:19
93:7
40
26
32
40
50
54
54
62
86
14.4
12.4
12.7
15.4
13.9
12.5
8.4
14.06
12.11
12.40
15.04
13.57
12.20
8.20
It can be appreciated that Michael product (1R,2S)-7h,
obtained with 82% of global ee, exhibited a rather small
difference of enantiomeric excess (ꢀee) of 4% between fractions
when employing a low-polarity mobile phase (see Table 5 and
Fig. 2). Furthermore, in the case of polar methylene chloride as
eluent, the SDE (ꢀee = 2%) is almost negligible (Cf. Table 6 and
Fig. 3). It is worth mentioning that this behavior is in line with
the anticipated performance for samples of high enantiopurity.13
a
The reaction was carried out under the previously described conditions [Cf.
Table 4, (a)]. b Product eluted in fractions of 10 mL each c Isolated weight per
corresponding fraction by means of gravity-driven chromatography,
employing silica-gel (14 g, 230-400 mesh) packed in a glass column (ø 2 cm,
d
stationary phase @ 45 cm length). HPLC conditions: Chiralpak AD-H
column, λ = 210 nm, n-Hexane/iPrOH 90:10, U = 0.5 mL/min [tR(minor syn)
= 22.9 min, tR(major syn) = 28.9 min].
Table 6. Effect of a polar eluent [100% CH2Cl2] on the SDE of Michael
adduct (1R,2S)-7h obtained from reaction catalyzed by (1R,2S)-5.a
F
SDE for (1S,2R)-7e [Hexane:EtOAc (8:2)]
100
O
S
N
H
N
90
O2N
H
O
O
ee (%)/fraction
[Hex:EtOAc (8:2)]
80
70
(R)
(1R,2S)-5
NO2
(S)
10 mol-%
+
(R)-mandelic acid
neat
F
60
50
rt, 24 h
(1R,2S)-7h
er d
(S,R):(R,S)
ee
(%)
40
Mass/fraction
(mg) c
Fraction b
Weight %
% ee (global)*
30
20
10
1
2
3
4
5
6
16.8
21.9
13.1
10.6
7.4
22.76
29.71
17.77
14.38
10.04
5.29
92:8
91:9
91:9
91:9
91:9
91:9
84
82
82
82
82
82
0
1
2
3
4
5
6
7
8
9 10
Fraction
3.9
a
Fig. 4. Graphical representation of chromatographic behavior for Michael
reaction test to obtain adduct (1S,2R)-7e after purification using non-polar
[Hexane:EtOAc (8:2)] as eluent, showing the % ee of the corresponding
eluted fraction (Cf. Table 7). The global % ee of 40% corresponds to the
originally determines value (see entry 9, Table 4).
The reaction was carried out under the previously described conditions [Cf.
b
c
Table 4, (a)]. Product eluted in fractions of 10 mL each. Isolated weight
per corresponding fraction by means of gravity-driven chromatography,
employing silica-gel (14 g, 230-400 mesh) packed in a glass column (ø 2 cm,
d
stationary phase @ 45 cm length). HPLC conditions: Chiralpak AS-H
column, 210 nm, n-Hexane/iPrOH 95:5, U = 0.5 mL/min [tR(minor syn) =
55.4 min, tR(major syn) = 81.2 min].
By contrast, compound (1S,2R)-7h, that had been obtained
with 40% of global ee, exhibited 60% of ꢀee which is
significantly high (see Table 7 and Fig. 4). Also remarkable is the
fact that methylene chloride leads to almost complete depletion
of the major enantiomer by self-disproportionation of
enantiomers for this Michael adduct (Cf. Table 8 and Fig. 5).
SDE for (1R,2S)-7h (100% DCM)
100
ee (%)/fraction
[100% DCM]
Given that polar methylene chloride diminishes the SDE
effect, we deemed this solvent as a more suitable mobile phase in
order to unambiguously determine the enantioselectivity induced
by our organocatalysts, (1R,2S)-5 and (1S,2R)-5. Therefore, we
repeated the tests described in Table 4 (to obtain syn Michael
adducts 7a-h). To our surprise, the great majority of (1S,2R)-7
products exhibited higher enantiopurity (compare for example
entry 13 in Table 4 with entry 13 in Table 9), whereas
stereoisomers (1R,2S)-7 exhibited essentially unchanged
enantiomeric excesses. This contrasting behavior might be
explained in terms of the possible formation of homochiral
dimers and/or conglomerates in the case of (1S,2R)-7.21 Though
90
80
% ee (global)*
70
0
1
2
3
4
5
6
7
fraction
Fig. 3. Graphical representation of chromatographic behavior for Michael
reaction test to obtain adduct (1R,2S)-7h after purification using polar 100%
CH2Cl2, showing the % ee of the corresponding eluted fraction (Cf. Table 6).
The global value 82% ee corresponds to the originally determined value (see
entry 16, Table 4).

6
Tetrahedron
Table 9. Asymmetric Michael reaction with substituted β-nitrostyrene under
additional studies would be necessary to confirm this point, a
ACCEPTED MANUSCRIPT
solvent free reaction conditions.a Isolation of products, followed by
quantification of ee values was carried out with methylene chloride solvent.
more detailed approach is beyond the scope of the present work.
Table 8. Effect of a more polar eluent [100% CH2Cl2] on the SDE of Michael
adduct (1S,2R)-7e obtained from reaction catalyzed by (1S,2R)-5.a
O
O
N
H
N
H
N
N
S
S
H
H
O
Ar
O
O
Ar
O2N
OCH3
(1R,2S)-5
10 mol-%
(1S,2R)-5
10 mol-%
NO2
NO2
+
O
S
N
H
(R)-mandelic acid
neat
(R)-mandelic acid
neat
Ar
N
(1R,2S)-7
(1S,2R)-7
O2N
H
rt, 24 h
rt, 24 h
O
O
(S)
(1S,2R)-5
10 mol-%
NO2
(R)
+
Yieldb
drc
erd
ee
(%)
(R)-mandelic acid
neat
Entry
Ar
Product
OCH3
(%) syn:anti (S,R):(R,S)
rt, 24 h
(1S,2R)-7e
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
(1S,2R)-7a
(1R,2S)-7a
(1S,2R)-7b
(1R,2S)-7b
(1S,2R)-7c
(1R,2S)-7c
(1S,2R)-7d
(1R,2S)-7d
(1S,2R)-7e
(1R,2S)-7e
(1S,2R)-7f
(1R,2S)-7f
(1S,2R)-7g
(1R,2S)-7g
(1S,2R)-7h
(1R,2S)-7h
86
76
99
90
65
70
99
92
75
65
80
68
81
70
81
80
97:3
94:6
97:3
94:6
97:3
94:6
97:3
94:6
89:11
83:17
92:8
92:8
97:3
97:3
97:3
91:8
86:14
13:87
93:7
12:88
92:8
9:91
94:6
9:91
80:20
27:73
91:9
13:87
95:5
11:89
93:7
9:91
72
74
86
76
84
82
88
82
60
46
82
74
90
78
86
82
C6H6
Mass/fraction
(mg) c
40.2
er d
(S,R):(R,S)
71:29
72:28
75:25
73:27
77:23
ee
(%)
Fraction b
Weight %
o-Cl-C6H5-
o-MeO-C6H5-
o-Br-C6H5-
p-MeO-C6H5-
p-Me-C6H5-
p-Cl-C6H5-
p-F-C6H5-
1
2
3
4
5
41.53
36.98
13.84
5.68
42
44
50
46
54
35.8
13.4
5.5
1.9
1.96
a
The reaction was carried out under the previously described conditions [Cf.
b
c
Table 4, (a)]. Product eluted in fractions of 10 mL each. Isolated weight
per corresponding fraction by means of gravity-driven chromatography,
employing silica-gel (14 g, 230-400 mesh) packed in a glass column (ø 2 cm,
d
stationary phase @ 45 cm length). HPLC conditions: Chiralpak AD-H
column, λ = 210 nm, n-Hexane/iPrOH 90:10, U = 0.5 mL/min [tR(minor syn)
= 22.9 min, tR(major syn) = 28.9 min].
a Reactions were performed with cyclohexanone (0.2 mL), β-nitrostyrene (0.5
mmol), 10 mol-% of organocatalyst and 10 mol-% of mandelic acid, stirring
at rt. b Isolated yield by means of gravity-driven chromatography, employing
silica-gel (230-400 mesh) packed in glass columns (1.8 cm ø, stationary
c
1
SDE for (1S,2R)-7e (100% DCM)
phase @ 23 cm length) and CH2Cl2 as eluent. Determined by H NMR of
crude product. d HPLC analysis with chiral columns for the syn isomer.
80
70
ee (%)/fraction
[100% DCM]
3. Conclusions
60
We report synthetic routes for the preparation of all possible
stereoisomers of pyrrolidine sulfinamides obtained from proline
and t-butylsulfinamide. The four stereoisomers were tested in the
asymmetric Michael reaction between cyclohexanone and β-
nitrostyrene, in the presence of either enantiomer of mandelic
acid as additive. No significant match/mismatch double
stereoinduction was observed. It was found that the best catalytic
system corresponds to the (R)-pyrrolidine-(S)-t-butylsulfinamide
(1R,2S)-5 combination, in the presence of (R)-mandelic acid.
This catalytic system was evaluated in the Michael addition
reaction of cyclohexanone with a series of aryl-substituted β-
nitrostyrenes, obtaining the anticipated products in good yields
and high diastereoselectivities, as well as good enantioselectivity.
50
40
% ee (global)*
30
20
0
1
2
3
4
5
6
fraction
Fig. 5. Graphical representation of chromatography for Michael reaction test
to obtain adduct (1S,2R)-7e after purification using 100% CH2Cl2 showing
the % ee of the corresponding eluted fraction (Cf. Table 8). The global value
40% ee corresponds to the originally determined value (see entry 9, Table 4).
A preliminary study on potential self-disproportionation of
enantiomers (SDE) of the Michael adducts is reported. It was
found that non-polar mixtures of hexane-ethyl acetate as eluent
do give rise to this effect, especially when the enantiopurity of
the sample is moderate. By contrast, polar methylene chloride
seems to inhibit the disproportionation of enantiomers.
Most outstanding is the fact that the enantiopurity of the
isolated product from organocatalyzed asymmetric reactions
might be modulated by simply changing the polarity of the
mobile phase during chromatographic purification. On the other
hand, SDE represents a potentially ubiquitous phenomenon that
must be considered before unambiguous evaluation of the
stereoinduction by a given chiral catalyst or reagent.

7
4. Experimental section
4.1. General information
4.2.1
(S)-(9H-Fluoren-9-yl)methyl
2-
(S)-Fmoc-prolinol.
(S)-2. The general procedure was followed to obtain 6.3 g (95 %
ACCEPTED MANUSCRIPT
(hydroxymethyl)pyrrolidine-1-carboxylate.
yield) of (S)-2, mp 86-88 °C.
25 = −29.4 (c 1.0, CHCl3). IR
(cm-1): νmax 3421, 3330, 2947, 2879, 1730, 1672, 1434, 1359,
[ ]
α
The material employed to carry out reactions in anhydrous
conditions was dried at 120 °C, and conserved under inert
atmosphere. Tetrahydrofuran (THF) employed anhydrous was
dried by means of distillation with metallic Na under inert
atmosphere. CH2Cl2 was dried by stirring with P2O5 and distilling
under inert atmosphere. The reactions were monitored by TLC,
D
1
1130, 1100, 758. H NMR (CDCl3, 300 MHz) δ (ppm): 7.77 (d,
2H, J = 7.5 Hz), 7.60 (d, 2H, J = 7.2 Hz), 7.34 (m, 4H), 4.44 (s,
2H), 4.25 (t, 1H, J = 6.6 Hz), 3.99 (s, 1H), 3.10-3.80 (m, 5H),
1.50-2.10 (m, 4H). 13C NMR (CDCl3, 75.5 MHz) δ (ppm): 24.05,
28.28, 47.3, 60.69, 67.50, 120.0, 125.0, 127.10, 127.76, 141.37,
143.9. HR-ESI-TOF Calcd. for C20H22NO3 [M + H]+: 324.1594;
found: 324.1593.
employing precoated aluminum sheets (silica gel Merck 60 F254
)
plates and visualizing by UV lamp (254 nm), staining with iodine
chamber, ninhydrin or ammonium ceric sulfate. Purification was
mainly carried out by flash CC, utilizing silica gel Merck (230-
400 mesh) and bidistilled technical grade solvent. Optical
rotations were determined in a Perkin-Elmer Model 241
polarimeter, using a 0.1 dm length cell; and for measurement, it
was employed sodium D line (589 nm), at the temperature of
sample compartment of the apparatus (20-25 °C). Specific
rotations were reported with the sample concentration in g/100
mL, together with the solvent employed. Uncorrected melting
4.2.2 (R)-(9H-Fluoren-9-yl)methyl 2-(hydroxymethyl)pyrrolidine-
1-carboxylate. (R)-Fmoc-prolinol. (R)-2. The general procedure
was followed with 2.73 g (8.1 mmol) (R)-Fmoc proline (50 mL
THF), 0.49 g (12.9 mmol) of NaBH4 , 2.3 g (16.2 mmol, 2 mL)
of boron trifluoride diethyl etherate to obtain 2.39 g (93 % yield)
= +26.3 (c 1, CHCl3). IR (cm-1):
25
D
of (R)-2, mp 86-87 °C.
[ ]
α
νmax 3421, 3328, 2948, 2879, 1703, 1671, 1434, 1359, 1130,
1100, 758,738. NMR data were identical to those recorded for
enantiomer (S)-2. HR-ESI-TOF Calcd. for C20H22NO3 [M + H] +:
324.1594; found: 324.1595.
points were determined in
apparatus.
a Melt-Temp Electrothermal
1H, 13C and two dimensions NMR spectra were obtained in
the spectrometers JEOL GSX-270 (270 MHz), Bruker Advance
300 (300 MHz), JEOL Eclipse 400 (400 MHz) and JEOL ECA-
500 (500 MHz). Tetramethylsilane (TMS) was usually employed
as internal reference and the chemical shifts (δ) were reported in
parts per million (ppm). Coupling constants (J) are reported in
4.3 General Procedure for the preparation 3
Part 1. Swern oxidation.24 A solution of 0.3 mL (0.32 g, 4.1
mmol) of anhydrous dimethyl sulfoxide in anhyd. CH2Cl2 (15
mL) was placed in a round-bottom flask with magnetic stirrer and
under inert atmosphere (N2). The mixture was cooled at –78 °C,
0.32 mL (0.48 g, 3.7 mmol) of oxalyl chloride was added drop-
wise and the reaction mixture was stirred during thirty additional
minutes at –78 °C. (S)- or (R)-Fmoc prolinol (0.56 g, 1.7 mmol)
of 2 dissolved in anhydrous CH2Cl2 (10 mL) was added dropwise
1
hertz (Hz). Multiplicity of the signals in H NMR are indicated
according to the following abbreviations: (s) single, (d) double,
(t) triple, (q) quartet, (m) multiple and (br) broad; reporting in the
last two cases, the interval where these appears.
Infrared spectra were performed in a Varian model 640
(ATR) spectrometer or in a Perkin-Elmer FTIR spectrum-GX
apparatus. High resolution mass spectra were obtained in one
HPLC 1100 equipment coupled to MSDTOF Agilent Series HR-
MSTOF model 1069 A.
X-ray crystallographic analysis was carried out in an Enraf-
Nonius Kappa CCD diffractometer. Programs SHELX-97,22 and
WinGX,23 were used for solving and refining, while graphics
were obtained with the Diamond 2.1 software. The collected
structures (atomic coordinates) were deposited in the database of
°
and the resulting mixture was stirred for 60 minutes at –78 C.
Triethylamine (1.44 mL, 1.04 g, 10.28 mmol) was added drop-
wise and the resulting reaction mixture was stirred during 60
minutes at –78 °C and 30 minutes at 0 °C. The organic layer was
washed with brine (3 x 25 mL), dried over anhydrous Na2SO4,
filtered and concentrated in vacuo to obtain the crude product as
an oil. The crude was used immediately in the next step without
further purification.
the
Cambridge
Crystallographic
Data
Centre
(http://www.ccdc.cam.ac.uk/).
Part 2. Formation of the sulfinimide: In a round bottom flask (50
mL) provided with magnetic stirrer and inert atmosphere was
placed 208 mg (1.7 mmol) of (S)- or (R)-2-methylpropane-2-
sulfinamide dissolved in 3 mL of anhydrous dichloromethane. To
this solution was added 605 mg (3.8 mmol) of anhydrous CuSO4,
followed by the aldehyde previously prepared (part 1) dissolved
in 2 mL of dichloromethane. The mixture was stirred at room
temperature during 48 hours. TLC CH2Cl2:EtOAc 95:5. The
reaction mixture was filtered through a celite pad, and the filter
cake was washed with dichloromethane. The filtrate was
evaporated in vacuo and the residue was purified by flash
chromatography using CH2Cl2:EtOAc 95:5 as eluent. The
product (hard gum) was precipitated with cold hexane to obtain a
powdery product that was stored at –15 °C.
4.2 General procedure for the preparation of prolinols 2
(S)- or (R)-Fmoc proline (4.58 g, 13.6 mmol) in anhydrous
THF (125 mL) was placed in a round-bottomed flask with
magnetic stirrer and under inert atmosphere (N2). The resulting
solution was cooled to 0 °C, before the slow addition of NaBH4
(0.82 g, 21.7 mmol). The reaction mixture was stirred during 60
minutes at 0 °C, and then 3.4 mL (3.85 g, 27.1 mmol) of boron
trifluoride diethyl etherate were added dropwise, and stirring was
continued for 18 hours at 0 °C. The reaction progress was
monitored by TLC (CH2Cl2/EtOAc 70:30). Thirty milliliters of
water were added at 0 °C and the resulting mixture was stirred
for 30 minutes. THF was evaporated in vacuo, the remaining
aqueous layer was extracted with EtOAc (3 x 100 mL) and the
combined organic fractions were washed with brine, dried over
anhydrous Na2SO4 and filtered. The solvent was evaporated
under reduced pressure and the crude product was purified by
4.3.1
(S)-(9H-Fluoren-9-yl)methyl
2-{(E)-[((R)-tert-
butylsulfinyl)imino]methyl}pyrrolidine-1-carboxylate. (1S,2R)-3.
The general procedure describe above was followed with (S)-2
and (R)-2-methylpropane-2-sulfinamide, to obtain 617 mg (84%
yield) of (1S,2R)-3, mp 126-127 °C.
2D5 = –206.4 (c = 1.0,
[α ]
flash
chromatography,
using
gradient
CH2Cl2:EtOAc
CHCl3). IR (cm -1) νmax 2958, 2889, 2160, 1702, 1451, 1408,
(95:5)→(85:15) as eluent. The product (hard gum) was
precipitated with cold hexane to obtain a white powder, which
was stored at –15 °C.
1
1332, 1113, 1268, 1080, 760. H NMR (CDCl3, 400 MHz) δ
(ppm): 7.9 (t, 1H, J = 3.2 Hz), 7.76 (t, 2H, J = 7.7 Hz), 7.66-7.50

8
Tetrahedron
ACCEPTED MANUSCRIPT
(m, 2H), 7.48-7.36-7.28 (m, 2H), 4.80-4.70 (m, 0.5H), 4.70-
141.41, 141.28, 127.80, 127.25, 127.16, 125.21, 125.15, 120.0,
4.60 (m, 0.5H), 4.50-4.38 (m, 1H), 4.36-4.12 (m, 2H), 3.69-3.43
(m, 2H), 2.38-1.77(m, 4H), 1.17 (s, 9H). 13C NMR (CDCl3, 100
MHz) δ (ppm): 168.64, 167.69, 154.84, 154.74, 144.15, 144.03,
143.80, 141.40, 141.29, 127.81, 127.22, 127.16, 125.27, 125.17,
120.07, 67.74, 67.47, 61.18, 60.79, 57.33, 57.11, 47.34, 47.15,
46.53, 30.72, 39.07, 23.99, 23.34, 22.44. HR-ESI-TOF Calcd. for
C24H28N2O3S [M + H] +: 425.1893; found: 425.1898.
67.60, 67.47, 60.95, 60.62, 57.35, 57.02, 47.35, 47.02, 46.71,
30.32, 29.56, 24.44, 23.21, 22.59, 22.50. HR-ESI-TOF Calcd. for
C24H28N2O3S [M + H] +: 425.1893; found: 425.1895.
4.4. General Procedure for the preparation of 4
In a round bottom flask (50 mL) provided with magnetic stirrer,
and inert atmosphere, were placed 497 mg (1.17 mmol) of 3 in 15
mL of anhydrous THF. The resulting solution was stirred at 0 °C,
then 44.28 mg (1.17 mmol) of NaBH4 was added and 3 mL of
methanol were introduced dropwise with stirring at 0 °C during
60 min. TLC ethyl acetate-hexane 80:20. The reaction was
quenched with acetone (2 mL), and then 20 mL of saturated
aqueous ammonia chloride were added. The organic solvents
were evaporated under vacuum at rt, the remaining aqueous
phase was extracted with ethyl acetate (3 x 25 mL) and the
combined organic fractions were dried over anhydrous Na2SO4
filtered, and evaporated under reduced pressure. The residue was
purified by flash chromatography using ethyl acetate-hexane
80:20 and pure ethyl acetate. The product (hard gum) was
precipitated with cold hexane to obtain a powder, which was
stored at –15 °C.
4.3.2
(S)-(9H-Fluoren-9-yl)methyl
2-{(E)-[((S)-tert-
butylsulfinyl)imino]methyl}pyrrolidine-1-carboxylate. (1S,2S)-3.
The general procedure was followed with 2 g (6.2 mmol) of
prolinol (S)-2, 1.06 mL (1.16 g, 14.8 mmol) DMSO, 1.17 mL
(1.73 g, 13.6 mmol) of oxalyl chloride, 5.18 mL (3.73 g, 36.9
mmol) of triethylamine, 0.75
methylpropane-2-sulfinamide, and 2.17 g (13.6 mmol) of anhyd.
g (6.18 mmol) of (S)-2-
CuSO4 to obtain 2.26 g (86% yield) of (1S,2S)-3, mp 99-100 °C.
25 = +42.5 (c = 1.0, CHCl3). IR (cm -1) νmax 2966, 2879, 2162,
[ ]
α
D
1697, 1450, 1401, 1352, 1326, 1106, 1088, 760. 1H NMR
(CDCl3, 400 MHz) δ (ppm): 7.94 (t, J = 5.2 Hz, 1H), 7.76 (t, J =
7.2 Hz, 2H), 7.64-7.50 (m, 2H), 7.45-7.36 (m, 2H), 7.35-7.26 (m,
2H), 4.78-4.60 (m, 1H), 4.52-4.38 (m, 1H), 4.38-4.12 (m, 2H),
3.64-3.44 (m, 2H), 2.26-1.80 (m, 4H), 1.22 (s, 5H), 1.14 (s, 4H).
13C NMR (CDCl3, 100 MHz) δ (ppm): 168.58, 168.41, 154.93,
154.79, 144.11, 144.03, 143.95, 141.41, 141.29, 127.80, 127.25,
123.16, 125.21, 125.15, 120.07, 67.59, 67.46, 60.95, 60.62,
57.35, 57.02, 47.34, 47.02, 46.72, 30.33, 29.56, 24.45, 23.2,
22.60, 22.50. HR-ESI-TOF Calcd. for C24H28N2O3 S [M + H] +:
425.1893; found: 425.1893.
4.4.1
(S)-(9H-Fluoren-9-yl)methyl
2-{[(R)-1,1-
dimethylethylsulfinamido]methyl}pyrrolidine-1-carboxylate.
(1S,2R)-4. The general procedure was followed with (1S,2R)-3 to
25
D
obtain 429 mg (86% yield) of (1S,2R)-4, mp 102-103 °C.
=
[α ]
4.3.3
(R)-(9H-Fluoren-9-yl)methyl
2-{(E)-[((S)-tert-
–63.9 (c = 1.0, CHCl3). IR (cm-1) νmax 3199, 2949, 2161, 1696,
1410, 1332, 1114, 1045, 771, 738. 1H NMR (CDCl3, 400 MHz) δ
(ppm): 7.76 (t, J = 7.7 Hz, 2H), 7.60 (d, J = 7.4 Hz, 2H), 7.40 (d,
J = 7.2 Hz, 2H); 7.36-7.26 (m, 2H), 4.62-4.50 (m, 0.6H), 4.48-
4.30 (m, 1.4H), 4.30-4.14 (m, 2H), 4.10-3.93 (br, 0.7H), 3.74-
3.55 (broad, 0.3H), 3.55-2.80 (m, 4H), 2.10-1.60 (m, 4H), 1.18
(s, 9H). 13C NMR (CDCl3, 100 MHz) δ (ppm): 155.92, 155.0,
144.12, 141.42, 127.80, 127.23, 127.14, 125.16, 124.90, 124.80,
120.09, 67.35, 66.74, 58.65, 57.73, 56.01, 49.43, 47.52, 47.38,
47.31, 46.97, 29.12, 23.96, 22.80, 22.71. HR-ESI-TOF Calcd. for
C24H30N2O3S [M + H]+: 427.2050; found: 427.2052.
butylsulfinyl)imino]methyl}pyrrolidine-1-carboxylate. (1R,2S)-3.
The general procedure describe above was followed with 2.93 g
(9.06 mmol) of prolinol (R)-2, 1.54 mL (1.7g, 21.7 mmol) of
DMSO, 1.71 mL (2.53g, 19.9 mmol) of oxalyl chloride, 7.6 mL
(5.46 g, 54 mmol) of triethylamine, 1.01g (8. mmol) of (S)-2-
methylpropane-2-sulfinamide, and 2.92g (18.3 mmol) of anhyd.
CuSO4 to obtain 3.43g (89% yield) of (1R,2S)-3, mp 128-130 °C.
= +214.0 (c = 1.0, CHCl3). IR (cm-1) νmax 2958, 2889,
25
D
[ ]
α
2159, 1702, 1408, 1451, 1408, 1333, 1114, 1080, 760. 1H NMR
(CDCl3, 400 MHz) δ (ppm): 7.94 (t, J = 5.0 Hz, 1H), 7.76 (t, J =
7.2 Hz, 2H), 7.66-7.50 (m, 2H), 7.44-7.35 (m, 2H), 7.35-7.26 (m,
2H), 4.79-4.61 (m, 1H), 4.55-4.39 (m, 1H), 4.39-4.14 (m, 2H),
3.60-3.45 (m, 2H), 2.30-1.70 (m, 4H), 1.22 (s, 4.75H), 1.13 (s,
4.25H). 13C NMR (CDCl3, 100 MHz) δ (ppm): 168.60, 168.41,
154.93, 154.79, 144.11, 144.03, 141.40, 141.28, 127.80, 127.25,
127.15, 125.20, 125.14, 120.06, 67.59, 67.46, 60.95, 60.61,
57.34, 57.02, 47.35, 47.02, 46.71, 30.32, 29.56, 24.45, 23.21,
22.59, 22.50. HR-ESI-TOF Calcd. for C24H28N2O3 S [M + H] +:
425.1893; found: 425.1889.
4.4.2
(S)-(9H-Fluoren-9-yl)methyl
2-{[(S)-1,1-
dimethylethylsulfinamido]methyl}pyrrolidine-1-carboxylate.
(1S,2S)-4. The general procedure was followed with 1.57 g (3.71
mmol) of (1S,2S)-3, 140 mg (3.71 mmol) of NaBH4, 25.0 mL of
THF, 5 mL of MeOH, 5 mL of acetone and 20 mL of saturated
aqueous ammonium chloride, to obtain 1.45 g (92% yield) of
(1S,2S)-4, mp 131-132 °C.
2D5 = –18.2 (c = 1.01, MeOH). IR
[α ]
(cm-1) νmax 3262, 2952, 2160, 1664, 1416, 1332, 1109, 1063, 764,
736. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.6 (d, J = 7 Hz, 2H),
7.65-7.53 (m, 2H); 7.45-7.27 (m, 4H), 4.72-4.55 (br, 0.6H), 4.55-
4.45 (m, 0.6H), 4.45-4.28 (m, 1.4H), 4.23 (t, J = 6.8 Hz, 0.5H),
4.8-3.94 (br, 0.6H), 3.60-3.22 (m, 3H), 3.20-3.02 (m, 0.6H), 3.0-
4.3.4
(R)-(9H-Fluoren-9-yl)methyl
2-{(E)-[((R)-tert-
butylsulfinyl)imino]methyl}pyrrolidine-1-carboxylate. (1R,2R)-3.
The general procedure was followed with 1.91 g (5.9 mmol) of
prolinol (R)-2, 1.0 mL (1.1 g, 14.2 mmol) of DMSO, 1.11 mL
(1.65 g, 13 mmol) of oxalyl chloride, 4.95 mL (3.6 g, 35.2 mmol)
of triethylamine, 0.72 g (5.9 mmol) (R)-2-methylpropane-2-
sulfinamide, and 2.1g (13 mmol) of anhyd. CuSO4 to obtain 2.1 g
2.58 (m, 0.5H), 2.14-1.66 (m, 5H), 1.21 (s, 6H), 1,18 (s, 3H). 13
C
NMR (CDCl3, 100 MHz) δ (ppm): 156.11, 154.86, 144.17,
144.05, 127.93, 127.80, 127.48, 127.15, 125.22, 125.14, 124.74,
120.07, 67.45, 66.32, 58.69, 57.93, 55.93, 49.63, 48.07, 47.56,
47.37, 47.01, 29.00. HR-ESI-TOF Calcd. for C24H30N2O3 S [M +
H]+: 427.2050; found: 427.2050.
(85% yield) of (1R,2R)-3, mp 126-128 °C.
2D5 = –42.0 (c = 1.0,
[α ]
CHCl3). IR (cm-1) νmax 2957, 2889, 2160, 1701, 1450, 1332,
1113, 1080, 760. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.94 (t, J
= 5.4 Hz, 1H), 7.76 (t, J = 7.2 Hz, 2H), 7.65-7.50 (m, 2H), 7.45-
7.36, (m, 2H), 7.36-7.28 (m, 2H), 4.80-4.58 (m, 1H), 4.58-4.40
(m, 1H), 4.40-4.10 (m, 2H), 3.66-3.46 (m, 2H), 2.28-1.80 (m,
4H), 1.22 (s, 5H), 1.14(s, 4H). 13C NMR (CDCl3, 100 MHz) δ
(ppm): 168.58, 168.42, 154.93, 154.80, 144.11, 144.03, 143.94,
4.4.3
(R)-(9H-Fluoren-9-yl)methyl
2-{[(S)-1,1-
dimethylethylsulfinamido]methyl}pyrrolidine-1-carboxylate.
(1R,2S)-4. The general procedure was followed with 1.79 g (4.22
mmol) of (1R,2S)-3, 160 mg (4.22 mmol) of NaBH4, THF 25.0
mL, MeOH 5 mL, 5 mL of acetone and 20 mL of saturated

9
aqueous ammonium chloride, obtaining 1.48 g (82% yield) of
Et2NH, and 20 mL of THF, to obtain 402 mg (70% yield) of
ACCEPTED MANUSCRIPT
(1R,2S)-4, mp 128-130 °C.
25 = +61.9 (c = 1.0, CHCl3). IR
(1S,2S)-5 as an oil.
25 = +89.8 (c = 1.0, CHCl3). IR (cm-1) νmax
α
D
[α
]
[ ]
D
(cm-1) νmax 3190, 2949, 2163, 1696, 1411, 1333, 1114, 1043, 739.
1H NMR (CDCl3, 400 MHz) δ (ppm): 7.77 (d, J = 7.7 Hz, 2H),
7.64-7.53 (m, 2H); 7.40 (t, J = 7.4 Hz, 2H), 7.36-7.28 (m, 2H),
4.62-4.32 (m, 2H), 4.28-3.96 (m, 2H), 3.78-3.38 (m, 2H), 3.38-
2.86 (m, 2H), 2.10-1.70 (m, 5H), 1.2 (s, 1H), 1.18 (s, 8H). 13C
NMR (CDCl3, 100 MHz) δ (ppm): 155.94, 155.06, 144.12,
141.42, 127.80, 127.24, 127.13, 125.16, 124.91, 124.80, 120.09,
67.35, 66.74, 58.65, 57.72, 56.03, 49.45, 47.52, 47.37, 46.97,
29.13, 23.96, 23.06, 22.80, 22.22. HR-ESI-TOF Calcd. for
C24H30N2O3S [M+H]+: 427.2050; found: 427.2044.
3438, 3193, 2955, 2867, 1456, 1407, 1363, 1048, 731. H NMR
(CDCl3, 400 MHz) δ (ppm): 4.30-4.21 (br, 1H), 4.11 (s, 1H),
3.44-3.32 (m, 1H), 3.22-3.06 (m, 2H), 3.04-2.09 (m, 2H), 1.97-
1.65 (m, 3H), 1.51-1.38 (m, 1H), 1.19 (s, 8H), 1.66 (s, 1H). 13C
NMR (CDCl3, 100 MHz) δ (ppm): 59.22, 55.97, 49.72, 46.04,
29.03, 25.31, 22.83. HR-ESI-TOF Calcd. for C9H20N2OS [M +
H]+: 205.1369; found: 205.1370.
1
4.5.3
(S)-2-Methyl-N-[(R)-pyrrolidin-2-ylmethyl]propane-2-
sulfinamide. (1R,2S)-5. The general procedure described above
was followed with 1.48 g (3.5 mmol) of (1R,2S)-4, 3.6 mL (2.6 g,
35 mmol) of Et2NH, and 20 mL of THF to obtain 481 mg (68%
4.4.4
(R)-(9H-Fluoren-9-yl)methyl
2-{[(R)-1,1-
dimethylethylsulfinamido]methyl}pyrrolidine-1-carboxylate.
(1R,2R)-4. The general procedure was followed with 0.77 g (1.81
mmol) of (1R,2R)-3, 68.6 mg (1.81 mmol) of NaBH4, 20 mL of
THF, 4 mL of MeOH, 4 mL of acetone and 20 mL of saturated
aqueous ammonium chloride, to obtain 634 mg (82% yield) of
yield) of (1R,2S)-5 as an oil.
25 = +38.5 (c = 1.0, CHCl3). IR
[ ]
α
D
(cm-1) νmax 3420, 3210, 2954, 2867, 1457, 1399, 1363, 1046, 731.
1H NMR (CDCl3, 400 MHz) δ (ppm): 4.33-4.14 (br, 1H), 3.77-
3.50 (br, 1H), 3.47-3.35 (m, 1H), 3.32-3.15 (m, 1H), 3.03-2.85
(m, 3H), 1.90-1.64 (m, 3H), 1.45-1.32 (m, 1H), 1.19 (s, 7.5H),
1.17 (s, 1.5H). 13C NMR (CDCl3, 100 MHz) δ (ppm): 58.94,
56.01, 50.39, 46.24, 28.84, 25.70, 22.79. HR-ESI-TOF Calcd. for
C9H20N2OS [M + H]+: 205.1369; found: 205.1371.
(1R,2R)-4, mp 128- 130 °C.
2D5 = +17.4 (c = 1.0, MeOH). IR
[α ]
(cm-1) νmax 3263, 2953, 2159, 1684, 1416, 1332, 1110, 1063, 736.
1H NMR (CDCl3, 400 MHz) δ (ppm): 7.87-7.70 (m, 2H), 7.66-
7.52 (m, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.37-7.30 (m, 2H), 4.70-
4.56 (br, 0.6 H), 4.55-4.28 (m, 2H), 4.23 (t, J = 7 Hz, 1H), 4.08-
3.94 (br, 0.6H), 3.57-3.21 (m, 3H), 3.13-3.10 (m, 0.6H), 3.10-
2.90 (m, 0.3H), 2.88-2.78 (m, 0.3H), 2.72-2.56 (m, 0.3H), 2.10-
1.65 (m, 4.7H), 1.21 (s, 6H), 1.18 (s, 3H). 13C NMR (CDCl3, 100
MHz) δ (ppm): 156.12, 154.85, 144.16, 144.04, 141.58, 141.42,
127.80, 127.49, 127.15, 125.22, 125.14, 124.75, 120.07, 67.45,
66.31, 58.69, 57.92, 55.94, 49.65, 48.06, 47.55, 47.36, 47.01,
29.60, 29.05, 24.00, 22.86, 22.76. HR-ESI-TOF Calcd. for
C24H30N2O3S [M+H]+: 427.2050; found: 427.2050.
4.5.4
(R)-2-Methyl-N-[(R)-pyrrolidin-2-ylmethyl]propane-2-
sulfinamide. (1R,2R)-5. The general procedure was followed with
0.634 g (1.48 mmol) of (1R,2R)-4, 1.5 mL (1.09g, 14.8 mmol) of
Et2NH, and 10 mL of THF to obtain 212 mg (70% yield) of
(1R,2R)-5 as an oil.
25 = +87.7 (c = 1.0, CHCl3). IR (cm-1) νmax
[ ]
α
D
1
3426, 3204, 2954, 2868, 1458, 1406, 1363, 1045, 795. H NMR
(CDCl3, 400 MHz) δ (ppm): 4.13-3.98 (br, 1H), 3.72-3.48 (br,
1H), 3.36-3.20 (m, 1H), 3.17-3.02 (m, 2H), 2.98-2.86 (m, 2H),
1.97-1.63 (m, 3H), 1.47-1.33 (m, 1H), 1.19 (s, 9H). 13C NMR
(CDCl3, 100 MHz) δ (ppm): 59.04, 55.83, 50.02, 46.17, 29.21,
25.53, 22.80. HR-ESI-TOF Calcd. for C9H20N2OS [M + H]+:
205.1369; found: 205.1373.
4.5 General procedure for the preparation of organocatalysts
5
4.6 Procedure for the N-benzylation of (1S,2S)-5 to obtain its
crystalline derivative (1S,2S)-6
1.8 g (4.2 mmol) of 4 dissolved in 20 mL of anhydrous THF
were placed in a round bottom flask (100 mL) provided with
magnetic stirrer and inert atmosphere. The solution was stirred at
rt before the addition of 4.4 mL (3.1g, 42.2 mmol) of Et2NH, and
stirring was continued during 2 h. The reaction was monitored by
TLC with ethyl acetate as eluent. If the starting material was not
consumed after 2 h, additional 10 equiv. of Et2NH was added;
however, the reaction time should not exceed 5 h because of
product decomposition. The mixture was concentrated under
vacuum and the residue was purified by flash chromatography
using pure methylene chloride, then methylene chloride-methanol
95:5, 100% methanol and finally methanol-NH4OHaq 95:5.
In a round bottom flask (25 mL) provided with magnetic stirrer,
and argon atmosphere, were placed 163 mg (0.8 mmol) of
(1S,2S)-5 and the content was dissolved with 10 mL of
anhydrous THF. The solution was cooled at 0 °C and 0.123 mL
(88.8 mg, 1.1 equiv.) of triethylamine were added, later stirring
during 10 min and subsequently adding 0.094 mL (135 mg, 1
equiv.) of benzyl bromide. The reaction mixture was left at room
temperature during 18 h, and after this lapse, 20 mL of saturated
solution of ammonium chloride were added to quench the
reaction. The resulting biphasic mixture was extracted twice with
15 mL of EtOAc, the combined organic phases were dried with
Na2SO4, filtrated and concentrated under reduced pressure. The
crude was purified by column chromatography using a gradient
starting from 100% ethyl acetate to EtOAc:MeOH (90:10). The
expected product was recrystallized from ethyl acetate-heptane,
so it was obtained 164 mg of (1S,2S)-6, corresponding to 70%
4.5.1
(R)-2-Methyl-N-[(S)-pyrrolidin-2-ylmethyl]propane-2-
sulfinamide. (1S,2R)-5. The general procedure was followed with
(1S,2R)-4 to obtain 450 mg (52% yield) of (1S,2R)-5 as an oil.
25 = –37.8 (c = 1.0, CHCl3). IR (cm-1) νmax 3422, 3214, 2954,
[ ]
α
D
1
2D5 = –20.2 (c = 1.0, MeOH). IR
2868, 1457, 1405, 1364, 1044, 795. H NMR (CDCl3, 400 MHz)
δ (ppm): 4.14-4.2 (br, 1H), 3.45-3.34 (m, 1H), 3.29,-3.16 (m,
1H), 3.12-3.10 (br, 1H), 2.99-2.85 (m, 3H), 1.98-1.63 (m, 3H),
1.44-1.31 (m, 1H), 1.19 (s, 9H). 13C NMR (CDCl3, 100 MHz) δ
(ppm): 58.87, 55.98, 50.62, 46.39, 28.90, 25.79, 22.80. HR-ESI-
TOF Calcd. for C9H20N2OS [M + H]+: 205.1369; found:
205.1369.
isolated yield, mp 71-73 °C.
[α ]
(cm-1) νmax 3204, 2921, 2866, 2774, 1453, 1362, 1052, 919, 823,
1
738, 697, 597. H NMR (CDCl3, 400 MHz) δ (ppm): 7.23-7.34
(m, 5H), 3.98 (d, J = 13.2 Hz, 1H), 3.88-3.80 (m, 1H), 3.39 (d, J
= 13.2 Hz, 1H), 3.26-3.10 (m, 2H), 3.00-2.93 (m, 1H), 2.81-2.74
(m, 1H), 2.32-2.24 (m, 1H), 2.02-1.90 (m, 1H), 1.82-1.68 (m,
3
3H), 1.27 (s, 1H), 1.21 (s, 9H). C NMR (CDCl3, 100 MHz) δ
(ppm): 128.62, 128.34, 126.99, 63.74, 59.12, 55.85, 54.33, 47.75,
28.54, 22.98, 22.78. HR-ESI-TOF Calcd. For C16H27N2OS [M +
H]+: 295.1839; found: 295.1842. Crystal data for (1S,2S)-6:
4.5.2
(S)-2-Methyl-N-[(S)-pyrrolidin-2-ylmethyl]propane-2-
sulfinamide. (1S,2S)-5. The general procedure was followed with
1.2 g (2.8 mmol) of (1S,2S)-4, 2.90 mL (2.05g, 28 mmol) of

10
Tetrahedron
ACCEPTED MANUSCRIPT
C16H26N2OS, orthorhombic, space group P212121, Z = 4, a =
2.89 (br, 1H), 2.54-2.26 (m, 2H), 2.18-2.00 (m, 1H), 1.94-1.50
5.6850(0) Å, b = 14.7770(0) Å, c = 20.7670(0) Å, α = β = γ =
(m, 4H), 1.48-1.30 (m, 1H). 13C NMR (CDCl3, 100 MHz) δ
(ppm): 210.0, 137.32, 133.79, 129.23, 129.05, 77.46, 52.48,
42.95, 33.14, 28.64, 25.41. HPLC: [Chiralpak AD-H column,
210 nm, n-Hexane/iPrOH 98:2, U = 0.5 mL/min]: tR(major syn) =
37.9 min, tR(minor syn) = 63.3 min. Optical rotation, melting
point and spectroscopic data are consistent with those reported in
the literature.25
90°, V = 1744.58(0) Å3, crystal size: 0.35 x 0.2 x 0.08 mm3, R1 =
0.0498 (wR2
=
0.1517). CCDC 000000 contains de
supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge
Crystallographic Data Centre.
4.7 General procedure for the Michael addition reaction.
4.7.5
(R)-2-[(S)-1-(4-Methoxyphenyl)-2-nitroethyl]
The organocatalyst (10.2 mg, 10 mol-%) was mixed with 0.2 mL
(0.197 g, 2 mmol) of cyclohexanone. The mixture was stirred for
15 min, before the addition of trans-β-nitrostyrene (0.5 mmol)
and the additive (acid, 10 mol %). Stirring was continued for 24 h
and the crude product was purified by flash chromatography
using hexane-EtOAc (8:2) or CH2Cl2.
cyclohexanone. (1R,2S)-7e. mp 152-154 °C.
1.0, CHCl3). IR (cm-1) νmax 2931, 1699, 1551, 1514, 1390, 1292,
1255, 1181, 1130, 1026, 830, 728, 649. H NMR (CDCl3, 400
2D5 = +17.0 (c =
[α ]
1
MHz) δ (ppm): 7.12-7.07 (m, 2H), 6.88-6.82 (m, 2H), 4.91 (dd J
= 12.4, 4.5 Hz, 1H), 4.57 (dd, J = 12.3, 10 Hz, 1H), 3.77 (s, 3H),
3.71 (ddd, J = 9.9, 10.1, 4.5 Hz, 1H), 2.68-2.58 (m, 1H), 2.52-
2.32 (m, 2H), 2.14, 1.98 (m, 1H), 1.82-1.48 (m, 4H), 1.30-1.12
(m, 1H). 13C NMR (CDCl3, 100 MHz) δ (ppm): 210.0, 160.0,
129.61, 129.27, 114.38, 80.0, 55.32, 53.90, 52.76, 43.30, 42.84,
33.26, 28.64, 25.11. HPLC: [Chiralpak AD-H column, 210 nm,
n-Hexane/iPrOH 90:10, U = 0.5 mL/min]: tR(major syn) = 22.3
min, tR(minor syn) = 27.9 min. Optical rotation, melting point
and spectroscopic data are congruent with the previously reported
values.4c
4.7.1 (R)-2-[(S)-2-Nitro-1-phenylethyl]cyclohexanone. (1R,2S)-
7a. mp 128-130 °C.
25 = +19.1 (c = 1.0, CHCl3). IR (cm-1) νmax
[ ]
α
D
2955, 1704, 1548, 1477, 1434, 1378, 1293, 1129, 1037, 887, 753,
1
688. H NMR (CDCl3, 400 MHz) δ (ppm): 7.34-7.24 (m, 3H),
7.2-7.4 (m, 2H), 3.76 (ddd, J = 10.2, 10.0, 4.5 Hz, 1H), 2.68
(ddd, J = 10.9. 11.2, 5.2 Hz, 1H), 2.52-2.34 (m, 2H), 2.15-2.01
(m, 1H), 1.82-1.15 (m, 4H), 1.30-1.15 (m, 1H). 13C NMR
(CDCl3, 100 MHz) δ (ppm): 212.11, 137.84, 128.45, 128.27,
127.87, 79.0, 52.61, 44.03, 42.87, 33.34, 28.65, 25.14. HPLC:
[Chiralpak AD-H column, 210 nm, n-Hexane/iPrOH 90:10, U =
0.5 mL/min]: tR(major syn) = 17.1 min, tR(minor syn) = 20.5 min.
Optical rotation, melting point and spectroscopic data are
consistent with those reported in the literature.25
4.7.6 (R)-2-[(S)-2-Nitro-1-(p-tolyl)ethyl]cyclohexanone. (1R,2S)-
7f. mp 122-124 °C.
25 = +21.8 (c = 1.0, CHCl3). IR (cm-1) νmax
[ ]
α
D
2932, 1698, 1550, 1516, 1384, 1313, 1130, 1015, 884, 818, 636.
1H NMR (CDCl3, 400 MHz) δ (ppm): 7.16-6.98 (m, 4H), 4.92
(dd, J = 12.4, 4.5 Hz, 1H), 4.6 (dd, J = 12.3, 10 Hz, 1H) 3.72
(ddd, J = 9.9, 9.9, 4.5 Hz, 1H), 2.72-2.58 (m, 1H), 2.51-2.34 (m,
2H), 2.3 (s, 3H), 2.12-1.98 (m, 1H), 1.82-1.44 (m, 4H), 1.32-1.10
(m, 1H). 13C NMR (CDCl3, 100 MHz) δ (ppm): 210.0, 137.53,
134.68, 129.72, 128.31, 79.13, 52.65, 43.67, 42.85, 33.31, 28.66,
25.11, 21.17. HPLC: [Chiralpak AD-H column, 210 nm, n-
Hexane/iPrOH = 90:10, U = 0.5 mL/min]: tR(major syn) = 15.0
min, tR(minor syn) = 18.9 min. Optical rotation, melting point
and spectroscopic data are consistent with those values reported
in the literature.25
4.7.2 (R)-2-[(S)-1-(2-Chlorophenyl)-2-nitroethyl]cyclohexanone.
(1R,2S)-7b. mp 64-66 °C.
25 = +45.3 (c = 1.0, CHCl3). IR (cm-
[α ]
D
1) νmax 2941, 1704, 1548, 1477, 1434, 1378, 1293, 1129, 1037,
1
883, 753, 688. H NMR (CDCl3, 400 MHz) δ (ppm): 7.41-7.35
(m, 1H), 7.28-7.18 (m, 3H), 4.90 (m, 3H), 4.90 (m, 2H), 4.36-
4.23 (m, 1H), 3.01-2.82 (m, 1H), 2.51-2.31 (m, 2H), 2.13,-2.2
(m, 1H), 1.86-1.53 (m, 4H), 1.42-1.26 (m, 1H). 13C NMR
(CDCl3, 100 MHz) δ (ppm): 211.80, 135.51, 134.63, 130.46,
129.56, 128.00, 127.49, 77.30, 51.80, 42.93, 41.07, 33.15, 28.64,
24.37. HPLC: [Chiralpak AD-H column, 210 nm, n-
Hexane/iPrOH = 95:5, U = 0.5 mL/min]: tR(major syn) = 22.5
min, tR(minor syn) = 36.0 min. Optical rotation, melting point
and spectroscopic data are in accordance with those values
reported in the literature.25
4.7.7 (R)-2-[(S)-1-(4-Chlorophenyl)-2-nitroethyl]cyclohexanone.
(1R,2S)-7g. mp 101-103 °C.
(cm-1) νmax 2947, 1697, 1552, 1491, 1385, 1311, 1198, 1130,
1099, 1013, 833, 825, 785, 666. H NMR (CDCl3, 400 MHz) δ
25 = +20.4 (c = 1.0, CHCl3). IR
[ ]
α
D
1
(ppm): 7.32-7.25 (m, 2H), 7.14-7.08 (m, 2H), 4.94 (dd, J = 12.5,
10 Hz, 1H), 4.59 (dd, J = 12.5, 10 Hz, 1H), 3.75 (ddd, J = 10,
9.8, 4.5 Hz, 1H), 2.69-2.58 (m, 1H), 2.50-2.32, (m, 2H), 2.14-2.0
(m, 1H), 1.84-1.48 (m, 4H), 1.28-1.16 (m, 1H). 13C NMR
(CDCl3, 100 MHz) δ (ppm): 211.0, 136.38, 133.71, 129.66,
129.24, 78.67, 52.48, 43.46, 42.86, 33.28, 28.55, 25.17. HPLC:
[Chiralpak AD-H column, 210 nm, n-Hexane/iPrOH 90:10, U =
0.5 mL/min]: tR (major syn) = 20.5 min, tR(minor syn) = 30.1
min. Optical rotation, melting point and spectroscopic data are in
accord with those reported in the literature.25
4.7.3
(R)-2-[(S)-1-(2-Methoxyphenyl)-2-nitroethyl]cyclo-
2D5 = +32.1 (c = 1.0,
hexanone. (1R,2S)-7c. mp 118-120 °C.
[α ]
CHCl3). IR (cm-1) νmax 2939, 1702, 1544, 1493, 1432, 1379,
1297, 1244, 1123, 1023, 755, 641. 1H NMR (CDCl3, 400 MHz) δ
(ppm): 7.31-7.14 (m, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.87 (t, J =
8.1, 2H), 4.88-4.76 (m, 2H), 3.95 (ddd, J = 10.0, 9.0, 5.0 Hz,
1H), 3.88 (s, 3H), 2.97 (ddd, J = 11.5, 11.0, 5.0 Hz, 1H), 2.54-
2.22 (m, 2H), 2.12-1.98 (m, 1H), 1.86-1.38 (m, 4H), 1.28-1.08
(m, 1H). 13C NMR (CDCl3, 100 MHz) δ (ppm): 210.0, 157.72,
131.16, 129.06, 125.45, 121.0, 111.12, 77.60, 55.49, 50.70,
42.85, 41.45, 33.43, 28.68, 25.29. HPLC: [Chiralpak AS-H
column, 210 nm, n-Hexane/iPrOH 90:10, U = 0.5 mL/min]:
tR(major syn) = 24.3 min, tR(minor syn) = 24.6 min. Optical
rotation, melting point and spectroscopic data are congruent with
values reported in the literature.26
4.7.8 (R)-2-[(S)-1-(4-Fluorophenyl)-2-nitroethyl]cyclohexanone.
(1R,2S)-7h. mp 68-70 °C.
25 = +19.6 (c = 1.0, CHCl3). IR (cm-
[ ]
α
D
1) νmax 2934, 1702, 1551, 1511, 1381, 1310, 1225, 1160, 1130,
1109, 1013, 832, 730, 648. 1H NMR (CDCl3, 400 MHz) δ (ppm):
7.18-7.12 (m, 2H), 7.4-6.96 (m, 2H), 4.94 (dd, J = 12.4. 4.5 Hz,
1H), 4.58 (dd, J = 12.6, 10.2 Hz, 1H), 3.76 (ddd, J = 10, 10, 4.5
Hz, 1H), 2.68-2.58 (m, 1H), 2.52-2.43 (m, 1H), 2.44-2.32 (m,
4.7.4 (R)-2-[(S)-1-(2-Bromophenyl)-2-nitroethyl]cyclohexanone.
(1R,2S)-7d. mp 68-70 °C.
1) νmax 2937, 1699, 1547, 1471, 1434, 1378, 1132, 1059, 1024,
885, 771, 753, 662. H NMR (CDCl3, 400 MHz) δ (ppm): 7.57
(m, 1H), 7.33-7.02 (m, 3H), 5.02-4.72 (m, 2H), 4.30 (br, 1H),
25 = +40.8 (c = 1.0, CHCl3). IR (cm-
1H), 2.14-2.0 (m, 1H), 1.83-1.50 (m, 4H), 1.28-1.14 (m, 1H). 13
C
[ ]
α
D
NMR (CDCl3, 100 MHz) δ (ppm): 211.0, 162.23 (d, J = 245.5
Hz), 129.86 (d, J = 8.4 Hz), 116.0 (d, J = 21.4 Hz), 78.94, 52.61,
43.34, 42.85, 33.27, 28.57, 25.15. HPLC: [Chiralpak AS-H
1

11
column, 210 nm, n-Hexane/iPrOH 95:5, U = 0.5 mL/min]:
tR(major syn) = 52.8 min, tR(minor syn) = 81.3 min. Optical
rotation, melting point and spectroscopic data are consistent with
those reported in the literature.25
77.47, 55.32, 52.76, 43.30, 42.69, 33.26, 28.64, 25.11. HPLC:
ACCEPTED MANUSCRIPT
[Chiralpak AD-H column, 210 nm, n-Hexane/iPrOH 90:10, U =
0.5 mL/min]: tR(minor syn) = 22.9 min, tR(major syn) = 28.9 min.
4.7.14
(S)-2-[(R)-2-Nitro-1-(p-tolyl)ethyl]cyclohexanone.
4.7.9 (S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanone. (1S,2R)-
[ ]
α
(1S,2R)-7f. mp 114-116 °C.
25 = –16.1 (c = 1.0, CHCl3). IR
D
7a. mp 126-128 °C.
25 = –16.7 (c = 1.0, CHCl3). IR (cm-1) νmax
(cm-1) νmax 2940, 1698, 1551, 1445, 1385, 1312, 1198, 1129,
[ ]
α
D
1
2955, 1697, 1548, 1449, 1384, 1313, 1129, 1013, 791, 746, 695,
1065, 817, 773, 636, 586. H NMR (CDCl3, 400 MHz) δ (ppm):
1
641, 559. H NMR (CDCl3, 400 MHz) δ (ppm): 7.35-7.23 (m,
7.12 (d, J = 7.7 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 4.92 (dd, J =
12.4, 4.5 Hz, 1H), 3.72 (ddd, J = 10, 10, 4.5 Hz, 1H), 2.52-2.43
(m, 1H), 2.43-2.33 (m, 1H), 2.31 (s, 3H), 2.13-2.02 (m, 1H),
1.82-1.5 (m, 4H), 1.32-1.13 (m, 1H). 13C NMR (CDCl3, 100
MHz) δ (ppm): 210.0, 137.54, 134.69, 129.71, 128.32, 79.13,
52.66, 43.68, 42.85, 33.30, 28.65, 25.11, 21.17. HPLC:
[Chiralpak AD-H column, 210 nm, n-Hexane/iPrOH 90:10, U =
0.5 mL/min]: tR(minor syn) = 15.2 min, tR(major syn) = 19.23
min.
3H), 7.20-7.14 (m, 2H), 4.94 (dd, J = 12.6, 4.9 Hz, 1H), 4.57 (dd,
J = 12.5, 10 Hz, 1H), 3.76 (ddd, J = 10, 10, 4.5 Hz, 1H), 2.51-
2.44 (m, 1H), 2.44-2.36 (m, 1H), 2.14-2.01 (m, 1H), 1.81-1.48
(m, 4H), 1.31-1.12 (m, 1H). 13C NMR (CDCl3, 100 MHz) δ
(ppm): 210.0, 137.8, 129.0, 128.27, 79.0, 52.61, 44.04, 42.86,
33.33, 28.65, 25.14. HPLC: [Chiralpak AD-H column, 210 nm,
n-Hexane/iPrOH 90:10, U = 0.5 mL/min]: tR(minor syn) = 18.3
min, tR(major syn) = 22.7 min.
4.7.10
(S)-2-[(R)-1-(2-Chlorophenyl)-2-
2D5 = –
4.7.15
(S)-2-[(R)-1-(4-Chlorophenyl)-2-
nitroethyl]cyclohexanone. (1S,2R)-7g. mp 96-98 °C.
2D5 = –
nitroethyl]cyclohexanone. (1S,2R)-7b. mp 65-67 °C.
36.3 (c = 1.0, CHCl3). IR (cm-1) νmax 2941, 1699, 1544, 1432,
1378, 1294, 1188, 1129, 1059, 1038, 753, 688. H NMR (CDCl3,
[α
]
[α ]
13.1 (c = 1.0, CHCl3). IR (cm-1) νmax 2941, 1698, 1552, 1492,
1
1
1384, 1310, 1196, 1130, 1099, 1014, 823, 785, 644. H NMR
400 MHz) δ (ppm): 7.41-7.34 (m, 1H), 7.28-7.13 (m, 3H), 4.89
(d, J = 6.7 Hz, 2H), 4.33-4.18 (br, 1H), 3.0-2.73 (br, 1H), 2.52-
2.22 (m, 2H), 2.13-1.97 (m, 1H), 1.82-1.48 (m, 4H), 1.42-1.18
(m, 1H). 13C NMR (CDCl3, 100 MHz) δ (ppm): 210.0, 135.5,
134.6, 130.45, 129.51, 129.0, 127.48, 76.82, 51.75, 42.93, 41.05,
33.15, 28.63, 25.37. HPLC: [Chiralpak AD-H column, 210 nm,
n-Hexane/iPrOH 90:10, U = 0.5 mL/min]: tR(minor syn) = 22.4
min, tR(major syn) = 35.1 min.
(CDCl3, 400 MHz) δ (ppm): 7.32-7.26 (m, 2H), 7.15-7.08 (m,
2H), 4.94 (dd, J = 12.5, 4.5 Hz, 1H), 4.59 (dd, J = 12.5, 10 Hz,
1H), 3.76 (ddd, J = 9.9, 9.9, 4.5 Hz, 1H), 2.75-2.60 (m, 1H),
2.52-2.44 (m, 1H), 2.44-2.30 (m, 1H), 2.15-2.02 (m, 1H), 1.84-
1.5 (m, 4H), 1.28-1.14 (m, 1H). 13C NMR (CDCl3, 100 MHz) δ
(ppm): 211.7, 136.38, 133.7, 129.6, 129.25, 78.7, 52.49, 43.46,
42.86, 33.28, 28.5, 25.10. HPLC: [Chiralpak AD-H column, 210
nm, n-Hexane/iPrOH 90:10, U = 0.5 mL/min]: tR(minor syn) =
20.9 min, tR(major syn) = 31.2 min.
4.7.11
(S)-2-[(R)-1-(2-Methoxyphenyl)-2-nitroethyl]cyclo-
2D5 = –26.8 (c = 1.0,
4.7.16
(S)-2-[(R)-1-(4-Fluorophenyl)-2-
hexanone. (1S,2R)-7c. mp 116-118 °C.
[α ]
nitroethyl]cyclohexanone. (1S,2R)-7h. mp 62-64 °C.
2D5 = –
CHCl3). IR (cm-1) νmax 2938, 1701, 1542, 1494, 1432, 1378,
1245, 1123, 1023, 755, 641. 1H NMR (CDCl3, 400 MHz) δ
(ppm): 7.30-7.22 (m, 1H), 7.12-7.06 (m, 1H), 6.92-6.84 (m, 2H),
4.90-4.78 (m, 2H), 4.06-3.90 (m, 1H), 3.82 (s, 3H), 3.04-2.98 (m,
1H), 2.52-2.34 (m, 2H), 2.14-2.0 (m, 1H), 1.82-1.50 (m, 4H),
1.28-1.18 (m, 1H). 13C NMR (CDCl3, 100 MHz) δ (ppm): 210.0,
157.71, 131.17, 129.06, 125.44, 121.01, 111.11, 77.59, 55.50,
50.69, 42.85, 41.44, 33.42, 28.68, 25.30. HPLC: [Chiralpak AS-
H column, 210 nm, n-Hexane/iPrOH 90:5, U = 0.5 mL/min]:
tR(minor syn) = 25.7 min, tR(major syn) = 29.7 min.
[α ]
14.2 (c = 1.0, CHCl3). IR (cm-1) νmax 2928, 1699, 1549, 1511,
1
1383, 1237, 1160, 1129, 1014, 832, 730, 558. H NMR (CDCl3,
400 MHz) δ (ppm): 7.20-7.12 (m, 2H), 7.06-6.93 (m, 2H), 4.93
(dd, J = 12.5, 4.5 Hz, 1H), 4.59 (dd, J = 12.5, 10 Hz, 1H), 3.76
(ddd, J = 9.9, 9.9, 4.5 Hz, 1H), 2.72-2.58 (m, 1H), 2.52-2.43 (m,
1H), 2.42-2.32, (m, 1H), 2.14-2.02 (m, 1H), 1.84-1.50 (m, 1H),
1.30-1.16, (m, 1H). 13C NMR (CDCl3, 100 MHz) δ (ppm): 210.0,
162.2 (d, J = 245.5 Hz), 133.56, 129.86 (d, J = 8.4 Hz), 116.0 (J
= 21.4 Hz), 80.0, 52.63, 43.35, 42.86, 33.27, 28.58, 25.16.
HPLC: [Chiralpak AS-H column, 210 nm, n-Hexane/iPrOH 95:5,
U = 0.5 mL/min]: tR(minor syn) = 55.4 min, tR(major syn) = 81.2
min.
4.7.12
(S)-2-[(R)-1-(2-Bromophenyl)-2-
2D5 = –
[α ]
nitroethyl]cyclohexanone. (1S,2R)-7d. mp 72-74 °C.
36.6 (c = 1.0, CHCl3). IR (cm-1) νmax 2939, 1701, 1547, 1471,
1
1434, 1378, 1132, 1024, 885, 753, 719, 661. H NMR (CDCl3,
Acknowledgements
400 MHz) δ (ppm): 7.57 (d, J = 8 Hz, 1H), 7.35-7.25 (m, 1H),
7.25-7.18 (m, 1H), 7.17-7.09 (m, 1H), 5.0-4.84 (m, 2H), 4.4-4.27
(br, 1H), 3.02-2.80 (br, 1H), 2.58-2.32 (m, 2H), 2.18-2.04 (m,
1H), 1.96-1.52 (m, 4H), 1.48-1.30 (m, 1H). 13C NMR (CDCl3,
100 MHz) δ (ppm): 210.00, 137.32, 133.94, 133.80, 128.12,
77.46, 52.31, 42.96, 33.14, 28.65, 25.41. HPLC: [Chiralpak AD-
H column, 210 nm, n-Hexane/iPrOH 98:2, U = 0.5 mL/min]:
tR(minor syn) = 39.0 min, tR(major syn) = 65.3 min.
We are grateful with (Consejo Nacional de Ciencia y Tecnología
(CONACYT), Mexico for financial support via grant 220945.
We are also indebted to Víctor González Díaz (CINVESTAV-
IPN) for his assistance in the recording of NMR spectra, and to
Marco Antonio Leyva (CINVESTAV-IPN) for his assistance in
the operation of the X-ray diffractometer and in the refinement of
the crystallographic structure.
4.7.13
(S)-2-[(R)-1-(4-Methoxyphenyl)-2-nitroethyl]cyclo-
Supplementary Material
hexanone. (1S,2R)-7e. mp 130-132 °C.
2D5 = –15.5 (c = 1.0,
[α ]
CHCl3). IR (cm-1) νmax 2951, 1699, 1551, 1514, 1390, 1292,
Supplementary data associated with this article can be found in
the online version.
1
1254, 1181, 1130, 1026, 830, 728, 560. H NMR (CDCl3, 400
MHz) δ (ppm): 7.12-7.04 (m, 2H), 6.88-6.78 (m, 2H), 4.91, (dd,
J = 12.3, 4.6 Hz, 1H), 4.57 (dd, J = 12.3, 10 Hz, 1H), 3.71 (ddd, J
= 9.9, 9.9, 4.5 Hz, 1H), 2.52-2.30 (m, 2H), 2.12-1.98 (m, 1H),
1.81-1.48 (m, 4H), 1.31-1.14 (m, 1H). 13C NMR (CDCl3, 100
MHz) δ (ppm): 210.0, 159.09, 129.6, 129.26, 114.38, 114.18,
References and notes
1. Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600-3740.

12
Tetrahedron
ACCEPTED MANUSCRIPT
2. See, for example: Dinér, P.; Sadhukhan, A.; Blomkvist B.
Chirality 2013, 25, 365-368. (d) Nakamura, T.; Tateishi, K.;
ChemCatChem 2014, 6, 3063-3066.
Tsukagoshi, S.; Hasimoto, S.; Watanabe, S.; Soloshonok, V. A.
Aceña, J. L.; Kitagawa, O. Tetrahedron 2012, 68, 4013-4017.
18. Wzorek, A.; Sato, A.; Drabowicz, J.; Soloshonok, V. A.; Klika, K.
D. Amino Acids 2016, 48, 605–613.
3. (a) Wu, X.; Li, Y.; Wang, C.; Zhou, L.; Lu, X.; Sun J. Chem. Eur.
J. 2011, 17, 2846-2848. (b) Wang, C.; Wu, X.; Zhou, L; Sun J.
Chem. Eur. J. 2008, 14, 8789-8792.
4. (a) Holland, M. C.; Gilmour, R. Angew. Chem., Int. Ed. 2015, 54,
3862-3871. (b) Panday, S. K. Tetrahedron: Asymmetry 2011, 22,
1817-1847. (c) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang,
W. Chem. Eur. J. 2006, 12, 4321-4332. (d) Cao, C.-L.; Ye, M.-C.;
Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901-2904. (e) Cobb, A.
J. A.; Shaw, D. M.; Longbottom, D. A.; Gold J. B.; Ley S. V. Org.
Biomol. Chem. 2005, 3, 84-96. (f) Vega-Peñaloza, A.; Sánchez-
Antonio, O.; Avila-Ortiz, C. G.; Escudero-Casao, M.; Juaristi. E.
Asian J. Org. Chem. 2014, 3, 487-496.
19. (a) Wzorek, A.; Sato, A.; Drabowicz, J.; Soloshonok, V. A.; Klika,
K. Helv. Chim. Acta 2015, 98, 1147–1159. (b) Wzorek, A.; Sato,
A.; Drabowicz, J.; Soloshonok, V. A. Isr. J. Chem. 2016, 56, 977–
989.
20. Drabowicz, J.; Jasiak, A.; Wzorek, A.; Sato, A.; Soloshonok, V.
A. Arkivoc 2017, ii, 557-578.
21. Soloshonok, V. A.; Roussel, C.; Kitagawa, O. ; Soroshinsky, A. E.
Chem. Soc. Rev. 2012, 41, 4180-4188.
22. (a) SHELX-97, Sheldrick, G. M. Programs for Crystal Structure
Analysis; University of Göttingen: Germany, 1997. (b) Sheldrick,
G. M. Acta Crystallographica 2008, A64, 112-122.
5. Aldol reaction: (a) Wang, W.; Li, H.; Wang, J. Tetrahedron Lett.
2005, 46, 5077-5079. (b) Trost, B. M.; Brindle, C. S. Chem. Soc.
Rev. 2010, 39, 1600-1632. Mannich reaction: (c) Wang, W.;
Wang, J.; Li, H. Tetrahedron Lett. 2004, 45, 7243-7246. (d) α-
Aminoxylation: Wang, W.; Wang, J.; Liao, H. L. Tetrahedron
Lett. 2004, 45, 7235-7238. Michael reaction: (e) Aitken, L. S.;
Arezki, N. R.; Dell’Isola, A.; Cobb, A. J. A. Synthesis 2013, 45,
2627-2648. (f) Wang, W.; Wang, J.; Li, H. Angew. Chem. Int. Ed.
2005, 44, 1369-1371. (g) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo,
H.; Wang W. Chem. Eur. J. 2006, 12, 4321-4332.
23. (a) WinGX and ORTEP for Windows: an update, Farrugia, L. J. J.
Appl. Cryst. 2012, 45, 849-854. (b) WinGX suite for small
molecule single-crystal crystallography, Farrugia, L. J. J. Appl.
Cryst. 1999, 32, 837-838.
24. Sabidó, E.; Tarragó, T.; Giralt, E. Bioorg. Med. Chem. Lett. 2009,
19, 3752-3755.
25. Zeng, Z.; Luo, P.; Jiang, Y.; Liu, Y.; Tang, G.; Xu, P.; Zhao, Y.;
Blackburn, G. M. Org. Biomol. Chem. 2011, 9, 6973-6978.
26. Lu, A.; Gao, P.; Wu, Y.; Wang, Y.; Zhou, Z.; Tang, C. Org.
Biomol. Chem. 2009, 7, 3141-3147.
6. Robak, M. T.; Herbage, M. A.; Ellman, J. A. Tetrahedron 2011,
67, 4412-4416.
7. Wan, W.; Gao, W.; Ma, G.; Ma, L.; Wang, F.; Wang, J.; Jiang, H.;
Zhu, S.; Hao, J. RSC Advances 2014, 4, 26563-26568.
8. Wang, M.; Wang, C.; Lu, X.-X., Sun, J. Hecheng Huaxue, 2011,
19, 7-10. The accessible experimental information in this paper is
very limited.
9. Hernández J. G., Juaristi E. Chem. Commun., 2012, 48, 5396-
5409.
10. Patora-Komisarska, K.; Benohoud, M.; Ishikawa, H.; Seebach, D.;
Hayashi, Y. Helv. Chim. Acta 2011, 94, 719-745.
11. Compare: Ávila-Ortiz, C. G.; López-Ortiz, M.; Vega-Peñaloza,
A.; Regla, I.; Juaristi, E. Asymmetric Catal. 2015, 2, 37-44.
12. Neither matching effect nor double stereoinduction was observed.
For salient papers on double stereoinduction in asymmetric
catalysis, see: (a) Binder, C. M.; Bautista, A.; Zaidlewicz, M.;
Krzemiński, M. P.; Oliver, A.; Singaram, B. J. Org. Chem. 2009,
74, 2337-2343. (b) Hirose, T.; Sugawara, K.; Kodama, K. J. Org.
Chem. 2011, 76, 5413-5428.
13. Suziki, Y.; Han, J.; Kitagawa, O.; Aceña, J. L.; Klika, K. D.;
Soloshonok, V. A. RSC Adv. 2015, 5, 2988-2993.
14. Faigl, F.; Fogassy, E.; Nógrádi, M.; Pálovics, E.; Schindler, J.
Org. Biomol. Chem. 2010, 8, 947-959.
15. (a) Pracejus, G. Liebigs Ann. Chem. 1959, 622, 10-22. (b) Han, J.;
Nelson, D. J.; Sorochinsky, A. E.; Soloshonok, V. A. Curr. Org.
Synth. 2011, 8, 310-317. (c) Soloshonok, V. A.; Ueki, H.;
Yasumoto, M.; Mekala, S.; Hirschi, J. S.; Singleton, D. A. J. Am.
Chem. Soc. 2007, 129, 12112-12113. (d) Ueki, H.; Yasumoto, M.;
Soloshonok, V. A. Tetrahedron: Asymmetry 2010, 21, 1396-1400.
(e) Tarasevych, A. V.; Sorochinsky, A. E.; Kukhar, V. P.; Chollet,
A.; Daniellou, R.; Guillemin, J.-C. J. Org. Chem. 2013, 78,
10530-10533. (f) Bellec, A.; Guillemin, J.-C. Chem. Commun.
2010, 46, 1482-1484.
16. (a) Koppenhoefer, B.; Trettin, U. Fresenius’ Z. Anal. Chem. 1989,
333, 750. (b) Katagiri, T.; Yoda, C.; Furuhashi, K.; Ueki, K.;
Kubota, T. Chem. Lett. 1996, 25, 115-116. (c) Katagiri, T.;
Takahashi, S.; Tsuboi, A.; Suzaki, M.; Uneyama, K. J. Fluorine
Chem. 2010, 131, 517-520.
17. (a) Cundy, K. C.; Crooks, P. A. J. Chromatogr. 1983, 281, 17-33.
(b) Aceña, J. L.; Soroshinsky, A. E.; Katagiri, T.; Soloshonok, V.
A. Chem. Commun. 2013, 49, 373-375. (c) Soroshinsky, A. E.;
Katagiri, T.; Ono, T.; Wzorek, A.; Aceña, J. L.; Soloshonok, V. A.