Synthesis of chiral sulfinamido-sulfonamides and their evaluation as ligands for the enantioselective ethylation of aldehydes

Article abstract of DOI:10.1016/j.tet.2009.02.033

A family of chiral sulfinamido-sulfonamide ligands have been synthesized from sulfinimines and has been evaluated as ligands for the enantioselective addition of diethylzinc to aldehydes with Ti(OⁱPr)₄. The structure of these diamino compounds has been systematically modified to optimize the results.

Full text of DOI:10.1016/j.tet.2009.02.033

Tetrahedron 65 (2009) 3757–3766
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of chiral sulfinamido-sulfonamides and their evaluation as ligands
for the enantioselective ethylation of aldehydes
*
´
˜
Alma Viso , Roberto Fernandez de la Pradilla, Mercedes Urena
´
Instituto de Qu´ımica Organica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A family of chiral sulfinamido-sulfonamide ligands have been synthesized from sulfinimines and has
been evaluated as ligands for the enantioselective addition of diethylzinc to aldehydes with Ti(OiPr)4. The
structure of these diamino compounds has been systematically modified to optimize the results.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 13 November 2008
Received in revised form 3 February 2009
Accepted 14 February 2009
Available online 24 February 2009
Keywords:
Sulfinamido-sulfonamide ligands
Aldehyde
Diethylzinc
Ti(OiPr)4
1. Introduction
bifunctional catalysts, where a simultaneous Lewis acid/base sys-
tem activates both nucleophilic and electrophilic reaction coun-
Nowadays, processes based on asymmetric metal catalysis in-
volving chiral sulfur-containing ligands are common within the
plethora of methods available to produce chiral molecules. How-
ever, the amount of successful reactions developed for these types
of ligands is still significantly smaller than for other ligands based
on P, N or O complexation.1
Within this context, sulfoxides and sulfoximines have been
applied, with excellent to moderate success, to catalytic enantio-
selective reductions and carbon–carbon bond forming reactions
such as cycloadditions, aldol reactions, allylic substitutions, and
alkylation of carbonyl compounds.2 In contrast, sulfinimines and
sulfinamides, compounds of established versatility in asymmetric
synthesis based on chiral auxiliaries,3 have been less exploited in
enantioselective catalysis and only recently, some examples have
been described of their use as ligands in asymmetric transfer
hydrogenation,4a cycloadditions,4b allylic alkylations,4c additions
to C]O/C]N,4d,e Pauson–Khand reaction4f or even in
organocatalysis.4g,h
terparts.6 In this context, the addition of diethylzinc to aldehydes,
developed by Ohno and Kobayashi7 that relies on using a catalytic
amount of a bis-sulfonamide and a stoichiometric amount of
Ti(OiPr)4 offers a good opportunity for testing ligands containing
various heteroatoms available for metal coordination. Herein we
wish to report our recent investigations on the synthesis and
evaluation of a novel class of enantiopure N-sulfinyl diamino
compounds I (Fig. 1) as chiral ligands in the enantioselective al-
kylation of aldehydes.
In the last years, we have been involved in the synthesis of
enantiopure vicinal diamino compounds from chiral sulfinimines.8
This methodology provides a broad number of sulfinamides (I) and
also would allow us to change easily groups R–R4 in order to op-
timize their steric and electronic environments and thus forming
efficient metal complexes that could yield high enantioselectivities
for the alkylation. This report reveals some key structural features
required for the success of this new family of ligands. As it will be
explained in detail below, a combination of factors such as the
The asymmetric addition of organozinc reagents to aldehydes is
a well-known reaction for the testing and optimization of new li-
gands and numerous experimental and theoretical studies have
been developed on this process.5 In the field of enantioselective
catalysis, there is a growing interest on the design and evaluation of
(O)n
O
S
S
R
NH
N
R
NR3R4
R2
R1
R1
I
* Corresponding author. Tel.: þ34 91 561 88 06x335; fax: þ34 91 564 48 53.
E-mail address: iqov379@iqog.csic.es (A. Viso).
Figure 1. General skeleton of the sulfinamide ligands I.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.033

3758
A. Viso et al. / Tetrahedron 65 (2009) 3757–3766
presence of two nitrogens with different coordinating capabilities
and the relative configuration of the stereocenters in the ligands
among others have shown an important influence in the enantio-
control of the process.
2.2. Enantioselective addition of Et2Zn to aldehydes
Preliminary studies on the enantioselective alkylation of aldehydes
were focused on the ethylation of benzaldehyde. To our disappoint-
ment, standard conditions using 2.0 equiv of Et2Zn and 0.05 equiv of
chiral ligands 2–5 only yielded variable small amounts of racemic 1-
phenylpropanol (5–48%) and high proportions of benzaldehyde, ben-
zoic acid, probably generated during work-up, and benzylic alcohol.9,2i
On the contrary, when the reactions of diethylzinc and benzal-
dehyde were conducted in CH2Cl2 with Ti(OiPr)4 (Scheme 2) and
using sulfinamides 2–5, excellent conversions to 1-phenylpropanol
were obtained but the low enantiomeric excesses (<10%) con-
firmed that an effective asymmetric catalyst was not formed in
these reactions.
2. Results and discussion
2.1. Synthesis of ligands
Most ligands employed in this study are described here for
first time (see Experimental section) and have been synthe-
sized through methodologies previously reported by us. The
general synthetic approach is depicted in Scheme 1. The step-
wise [3þ2] cycloaddition between enantiopure sulfinimines (1)
and N-benzylidene glycine-derived enolate stands as a very
efficient and direct route to enantiopure imidazolidines 2,8b our
main intermediate in this synthetic approach. Initially, we
chose p-tolyl sulfinimine 1a (R1¼iPr) as starting material, since
excellent diastereoselectivity is accomplished in the cyclization
step; however sulfinimines 1b with a naphthyl group (R1) as
well as 1c and 1d incorporating mesityl and 2-methoxy-1-
naphthyl groups in the sulfinyl moiety (R) were also considered
for this study. N-Sulfinyl imidazolidine 2a was smoothly re-
duced preserving the imidazolidine ring by treatment with
NaBH4/LiI to afford hydroxymethyl imidazolidine 3a. Alterna-
tively, simultaneous reduction of the ester and reductive
opening of the aminal took place with LiAlH4 thus rendering N-
sulfinyl diaminoalcohol 4a8b in good yield that could be further
protected to render silyl ether 4b.8a
N-Sulfinyl diaminoesters 5 were prepared from 2 by using
H3PO4 in THF8c and reaction of the primary amine in 5 with dif-
ferent reagents provided a new assembly of compounds in one
synthetic step. Thus, treatment of 5 with 1,1-diphenylmethan
imine or 1,4-dibromobutane rendered 6a and 6b, respectively, in
good yields.8c On the other hand, a wide variety of sulfonamides
7a–m were synthesized by reaction with different commercially
available sulfonyl chlorides. Further transformations of sulfina-
mido-sulfonamides 7 such as oxidation of the sulfinyl group and
reduction of the ester led us to bis-sulfonamides 8a,b and
hydroxymethyl sulfonamide 9. Moreover, the hydroxyl group of 9
was protected to silyl ether 10. As shown, a wide collection of
compounds were obtained with the aim of testing them as chiral
ligands.
1.5 equiv Et2Zn
O
OH
i
1.2 equiv Ti(OPr)4
H
Ph
0.05 equiv 2-10
Ph
CH2Cl2
Scheme 2. Diethylzinc addition onto benzaldehyde.
At this point we planned to examine the influence of different
groups on the nitrogen atom at C-2 and we submitted to the reaction
conditions N-benzyhydryl, pyrrolidine and sulfonamido derivatives
6a, 6b, and 7a. From these experiments we observed that sulfon-
amide 7a provided a slightly better conversion (71%) and ee (20%)
than diamino esters 6a and 6b (ee<5%) and therefore, we focused on
optimizing this result (Table 1). Based on earlier studies in this
matter,10 we evaluated the effect of changing the order of addition of
the reagents on the enantioselectivity. Certainly, we noticed a sig-
nificant enhancement of the enantiocontrol to a 40% ee when
diethylzinc was firstly added over 7a and then the titanium alkoxide
(Table 1, entry 2). In fact, we examined the 1H NMR spectrum of an
equimolecular mixture of sulfonamido ligand 7a with Ti(OiPr)4 in
CDCl3 and no significant variations occurred for proton signals of 7a.
Consequently, it looks likely that 7a would react initially with
diethylzinc through deprotonation of the sulfonamide moiety and
then would be transferred to titanium in a subsequent step.11
Encouraged by these results, we screened a battery of sulfon-
amides 7b–m under the optimized conditions. The outcome is
summarized in Table 1 (entries 3–16). As shown, neither the use of
methyl sulfonamide or variation of p-substituents on the aromatic
ring had a significant impact on the enantioselectivity (entries 3, 5,
i
1a, R = p-Tol, R1 = Pr
O
O
Ph
1b, R = p-Tol, R1 = 1-Naphth
S
S
p-Tol
N
N
R
1c, R = Mes, R1 = Pr
i
NH
R1
1d, R = 2-(OMe)-1-Naphth, R1 = Pr
i
i
b)
85%
a)
49-93%
Pr
OH
O
O
Ph
3a
O
O
S
S
p-Tol
R
NH
S
N
NR3R4
CO2Me
R
NH
NH
S
p-Tol
NH2
f)
NH
c)
R1
e)
60-88%
NHBn
OP
R1
R1
CO2Me
i
92%
i
6a, R1 = Pr,
Pr
CO2Me
62-99%
5
2a,b,c, dr > 99:1
2d, dr = 78:22
R3 = R4 = CPh2, 99%
4a, P = H
6b, R1 = p-FC6H4,
d)
g)
R3 = R4 = -(CH2)4-, 65%
4b, P = TBS, 77%
O
O
S
O
S
S
R
p-Tol
p-Tol
RO2SHN
NH
NH
NH
h)
NHSO2P
CO2Me
NHSO2P
CO2Me
b)
d)
NHSO21-Naphth
OTBS
NHSO21-Naphth
OH
79-99%
70%
i
R1
8a,b
87%
R1
i
Pr
Pr
10
7a-m
9
Scheme 1. Synthesis of chiral ligands from sulfinimines. Reagents and conditions: (a) methyl (E)-N-benzylideneglycinate, LDA, BF3$OEt2, THF, ꢀ78 ꢁC. (b) NaBH4, LiI, THF, 0 ꢁC to rt.
(c) LiAlH4, Et2O, 0 ꢁC to rt. (d) TBSCl, ImH, DMAP, CH2Cl2, 0 ꢁC to rt. (e) H3PO4, THF/H2O, rt. (f) Ph2C]NH or 1,4-dibromobutane, NaHCO3. (g) PSO2Cl, Et3N or iPr2EtN, CH2Cl2, 0 ꢁC to rt.
(h) m-CPBA, CH2Cl2, 0 ꢁC to rt.

A. Viso et al. / Tetrahedron 65 (2009) 3757–3766
3759
Table 1
Enantioselective addition of Et2Zn onto benzaldehyde using Ti(OiPr)4 and ligands 7–10, according to Scheme 2
Entry
Liganda
Conversionb (%)
(S:R)c
ee (%)
1
2
3
4
5
6
7
8
7a, R¼p-Tol, R1¼iPr, P¼p-Tol
71
100
76
100
50
60:40d
70:30
72:28
80:20
72:28
47:53
72:28
73:27
55:45
84:16
87:13e
59:41
60:40
65:35
87:13
75:25
20
40
44
60
44
6
44
46
10
68
74
18
20
30
74
50
7a, R¼p-Tol, R1¼iPr, P¼p-Tol
7b, R¼p-Tol, R1¼iPr, P¼Me
7c, R¼p-Tol, R1¼iPr, P¼2,4,6-(iPr)3-C6H2
7d, R¼p-Tol, R1¼iPr, P¼p-NO2-C6H4
7e, R¼p-Tol, R1¼iPr, P¼2,4-NO2-C6H4
7f, R¼p-Tol, R1¼iPr, P¼p-Br-C6H4
7g, R¼p-Tol, R0¼iPr, P¼p-MeO-C6H4
7h, R¼p-Tol, R1¼iPr, P¼3,5-Cl2-2-OH-C6H4
7i, R¼p-Tol, R1¼iPr, P¼1-Naphth
7i, R¼p-Tol, R1¼iPr, P¼1-Naphth
7j, R¼p-Tol, R1¼iPr, P¼D-Camphor
7j0, R¼p-Tol, R1¼iPr, P¼L-Camphor
7k, R¼p-Tol, R1¼1-Naphth, P¼1-Naphth
7l, R¼Mes, R1¼iPr, P¼1-Naphth
O
64
76
S
R
100
70
100
100
66
100
91
100
100
NH
NHSO2P
2
9
R1
3
10
11
12
13
14
15
16
CO2Me
7m, R¼2-(OMe)-1-Naphth, R1¼iPr, P¼1-Naphth
O
S
R
7m0, R¼2-(OMe)-1-Naphth, R1¼iPr, P¼1-Naphth
100
42:58
16
NH
17
NHSO2P
R1
CO2Me
TsHN
Pr
NHSO2P
18
19
8a, P¼p-Tol
100
82
50:50
52:48
0
4
i
8b, P¼1-Naphth
CO2Me
20
21
9, P¼H
91
80
50:50
53:47
0
6
O
10, P¼TBS
S
p-Tol
NH
NHSO21-Naphth
OP
i
Pr
a
To a solution of 7–10 in CH2Cl2 was added: (1) Et2Zn; (2) Ti(OiPr)4; (3) PhCHO.
b
c
Conversions were determined by 1H NMR of the crude.
Enantiomeric ratio determined by chiral HPLC (Chiralcel OD).
d
e
Sequence of addition of the reactants over 7a in CH2Cl2: (1) Ti(OiPr)4; (2) Et2Zn; (3) PhCHO.
When the amount of Ti(OiPr)4 was reduced to 0.8 equiv, the selectivity slightly improved to 87:13 (S:R).14
7, and 8). In contrast, the introduction of several electron-with-
drawing groups on aromatic sulfonamides caused drastic
To clarify the role of the chiral sulfinamide in the enantiocontrol
of the reaction, we tested (Ss)-7m0 thus comparing both di-
astereomeric ligands isomers (2S,3R,Ss)-7m and (2R,3S,Ss)-7m0
(Scheme 3). These compounds were prepared from the two
a
decrease in the enantiocontrol (entry 6). The presence of an
o-phenol12 group or a chiral camphor13 moiety at the sulfonamides,
successfully employed in other examples of enantioselective sul-
fonamido ligands had a negative effect in the present study (entries
9, 12, and 13). The best enantioselectivities were achieved for 2,4,6-
triisopropylbenzene and 1-naphthyl sulfonamides (entries 4, 10,
and 11) being (S)-1-phenylpropanol the major enantiomer. Likely
both sulfonamides contain in their structure an optimal combina-
tion of electron-donating effects and conformational rigidity re-
quired for an effective chiral metal catalyst.14
With the aim of improving the enantioselectivity of these sulfina-
mide-sulfonamido ligands, we carried out further modifications of their
structure. Therefore we tested the effect of the nature of R1, however
changing from iPr to naphthyl group (7k) had a negative impact on the
ee (entry 14). In addition, the ester moiety was replaced for either
ahydroxymethylorasilyloxymethylgroupinthesearchofanadditional
point of coordination to the metal15 (9 and 10) but racemic 1-phenyl-
propanol was recovered in both experiments (Table 1, entries 20 and 21).
Interestingly, the experimental evidences showed a crucial co-
operation between sulfinyl and sulfonyl functionalities to reach
enantiocontrol in the alkylation process since suppressing the
sulfur chiral atom by oxidation to the sulfonamide led to bis-sul-
fonamides 8a and 8b that provided racemic 1-phenylpropanol
when tested under the same conditions (entries 18 and 19). Sub-
sequently, we tried to vary the nature of the sulfinyl group (R) with
mixed results. While (S)-mesityl sulfoxide slightly improved the
enantioselectivity, (S)-2-methoxy-1-naphthyl sulfoxide had the
opposite effect16 (entries 15 and 16).
O
S
O
S
Ph
Ph
2-(OMe)-1-Naphth
2-(OMe)-1-Naphth
N
N
NH
CO2Me
NH
CO2Me
+
i
i
Pr
Pr
2 steps
2d, (78)
2d', (22)
O
S
O
2-(OMe)-1-Naphth
NH
S
2-(OMe)-1-Naphth
NHSO21-Naphth
CO2Me
NH
NHSO21-Naphth
i
Pr
i
Pr
CO2Me
(Ss)-7m', (22)
(Ss)-7m, (78)
Scheme 3. Synthesis of (2S,3R,Ss)-7m and (2R,3S,Ss)-7m0.
Table 2
Enantioselective addition of Et2Zn to RCHO using ligand 7ia
Entry
R
Conversionb (%)
(S:R)
ee (%)
1
2
3
4-ClC6H4
3,4-(MeO)2C6H3
1-Naphth
100
26
85
77:23c
63:37c
75:25d
54
26
50
a
1.5 equiv Et2Zn, 1.2 equiv Ti(OiPr)4, 0.05 equiv 7i, CH2Cl2, rt, 24 h.
Determined by 1H NMR.
b
c
Determined by 1H NMR of (þ)-MPA esters.
Determined by HPLC (Chiralcel OD).
d

3760
A. Viso et al. / Tetrahedron 65 (2009) 3757–3766
4. Experimental
O
O
4.1. General
O
O
S
S
MeO2C
Reagents and solvents were handled by using standard syringe
MeO2C
N
N
N
N
RO
techniques. All reactions were carried out under an argon atmo-
sphere. Crude products were purified by flash chromatography on
Merck 230–400 mesh silica gel with distilled solvents. Analytical
TLC was carried out on Merck (Kieselgel 60 F254) silica gel plates.
Throughout this section, the volume of solvents is reported in mL/
mmol of starting material. Infrared spectra (IR) were obtained on
a Perkin–Elmer 681 and on a Perkin–Elmer Spectrum one. 1H and
13C NMR spectra were recorded at 200 MHz, 300 MHz, 400 MHz or
500 MHz using CDCl3 as solvent and with the residual solvent
signal as internal reference (CDCl3, 7.24 and 77.0 ppm) unless
otherwise noted. Melting points were determined on a Reichert
Kofler microscope and are uncorrected. Optical rotations were
measured at 20 ꢁC using a sodium lamp and in CHCl3 solution. HPLC
Ti
O
Ti
Ti
S
S
O
O
RO
OR
RO
O
OR
O
Et
H
O
Et
H
SI
R SI
Et
R
A
B
Figure 2. Proposed stereochemical outcome for ligand 7i.
diastereofacial isomers 2d and 2d0 obtained in the initial [3þ2]
cyclization step, after selective aminal removal, sulfonylation, and
separation.17 By changing the relative configuration of the carbon
skeleton relative to the chiral sulfinamide (2R,3S,Ss)-7m0 the
enantioselectivity of the ethylation of benzaldehyde dramatically
dropped to a 16% ee isolating (R)-1-phenylpropanol as the major
isomer (Table 1, compare entries 16 and 17). This result reveals that
the sulfinamide exerts a high influence but it is not the only ster-
eogenic center that controls the stereochemical pathway of the
reaction existing a reinforcing/non-reinforcing combination of
configurations of the stereocenters in the ligands.
Finally, other aldehydes have been tested in the alkylation using
ligand 7i, however the enantioselectivities were always lower than
when benzaldehyde was used. The results are gathered in Table 2.
In order to rationalize the stereochemical outcome of the al-
kylation, and based on prior studies in this area,18 we propose the
formation of a bimetallic catalytic species where ligand (7i) co-
ordinates to the titanium atom arranging its substituents in an anti
disposition and placing the sulfonamide and the sulfinamide in
opposite faces of the complex, which in turn would provide a ster-
eoelectronic discrimination at the metal that should be responsible
of the different behavior of ligands 7a,i (sulfinamido-sulfonamide)
and 8a,b (bis-sulfonamide). In this scenario, it seems plausible that
coordination of the sulfonamide through one of the oxygen atoms
i
was carried out on Daicel Chiralcel-OD chiral column (5% PrOH/
hex, 1 mL/min, 250 nm). Low resolution mass spectra were recor-
ded by direct injection using the electronic impact technique with
an ionization energy of 70 eV or using the atmospheric pressure
chemical ionization (APCI) or electrospray (ES) chemical ionization
techniques in its positive or negative modes. High resolution mass
spectra were recorded in an Accurate Mass Q-TOF, LC/MS, Agilent
technologies 6520. Elemental analyses were carried out at Instituto
de Quı´mica Orga´nica General, CSIC.
4.2. Synthesis of chiral ligands
Compounds 2ab, 4ab, 5ab, and 6b were prepared following
procedures previously reported.8a–c Sulfinimines 1c and 1d were
prepared from the corresponding (S)-sulfinamide following
a reported procedure.21 New compounds are described below.
4.2.1. (þ)-(S)-2,4,6-Trimethyl-N-[(1E)-2-methylpropyliden]-
benzenesulfinamide, 1c
From (þ)-(S)-2,4,6-trimethylbenzenesulfinamide22 (430 mg,
2.4 mmol), isobutyraldehyde (0.21 mL, 2.4 mmol), and Ti(OEt)4
(2.5 mL, 11.7 mmol), following the reported procedure21 (4 h) and
after purification by column chromatography (30% CH2Cl2/hex to
to titanium would block the
b-face of the complex, leaving the
-face accessible for coordination of the aldehyde. The lack of
a
enantioselectivity of the bis-sulfonamido ligands 8a and 8b (S:R,
50:50) along with the change in the magnitude and sense of the
enantioselectivity encountered for 7m0 (S:R, 42:58) reveals the
crucial role of the chiral sulfinamide moiety in the catalytic process.
Consequently, the addition of the ethyl group onto the si face of
benzaldehyde, delivered either from a second titanium atom18b,7b A
or directly from ZnEt2 B,15,19 would be guided by coordination with
the sulfinamide group. Additionally, a hydrogen bond between the
sulfinamide and the aldehyde would contribute to organize the
approach of the reagents (Fig. 2).20
CH2Cl2), sulfinimine 1c was obtained as a colorless oil (585 mg, 92%).
20
Data for 1c: Rf 0.34 (20% EtOAc/hex). [
a]
þ328.8 (c 1.01). 1H NMR
D
(300 MHz)
d
1.14 (d, 3H, J¼3.7 Hz, Me iPr), 1.16 (d, 3H, J¼3.7 Hz, Me
iPr), 2.26 (s, 3H, Me Ar), 2.43 (s, 6H, Me Arꢂ2), 2.73 (m, 1H, CH iPr),
6.82 (s, 2H, Ar–H), 8.16 (d, 1H, J¼5.1 Hz, CH]N). 13C NMR (75 MHz)
d
18.7 (2C), 18.8, 18.9, 20.9, 34.7, 130.7 (2C), 135.1, 138.2 (2C), 141.5,
172.0 (C]N). IR (film): 2966, 2926, 2871, 1616, 1600, 1569, 1463,
1380, 1291, 1089, 1050, 851, 711, 677, 620 cmꢀ1. HRMS (ESI) m/z for
C13H19NNaOS [MþNa]þ calcd: 260.1085, found: 260.1079.
3. Conclusions
4.2.2. (þ)-(S)-N-[(1E)-2-Methylpropyliden]-2-methoxy-1-
naphthylsulfinamide, 1d
A large amount of research has been devoted to the un-
derstanding of the role of sulfonamides as chiral ligands, however
the use of enantiopure sulfinamides in enantioselective catalysis is
still under examination. The synthesis and evaluation of a number
of sulfinamido-sulfonamide compounds as ligands for the enan-
tioselective alkylation of aldehydes with Et2Zn and Ti(OiPr)4 have
been carried out in our laboratory. The systematic study of the
structural requirements to create enantioselective metal species
has entailed testing a broad collection of chiral diamino derivatives
as ligands easily available from chiral sulfinamides through the
methodology developed in our group. Further investigations to-
ward the applications of these compounds in new asymmetric
processes are now underway in our laboratory.
From (ꢀ)-(S)-2-methoxy-1-naphthylsulfinamide21a (480 mg,
2.17 mmol), isobutyraldehyde (0.2 mL, 2.17 mmol), and Ti(OEt)4
(2.3 mL, 10.85 mmol), following the reported procedure21 (6 h) and
after purification by column chromatography (60% CH2Cl2/hex to
CH2Cl2), sulfinimine 1d was obtained as a yellow solid (520 mg,
20
87%). Data for 1d: Rf 0.27 (5% EtOAc/CH2Cl2). Mp: 118–120 ꢁC. [
a]
D
þ259.4 (c 0.72). 1H NMR (300 MHz)
d
1.13 (d, 3H, J¼6.8 Hz, Me iPr),
1.17 (d, 3H, J¼7.1 Hz, Me iPr), 2.76 (m, 1H, CH iPr), 3.98 (s, 3H, OMe),
7.26 (d, 1H, J¼9.0 Hz, Ar–H), 7.36 (m, 1H, Ar–H), 7.48 (m, 1H, Ar–H),
7.78 (d, 1H, J¼8.1 Hz, Ar–H), 7.94 (d,1H, J¼9.3 Hz, Ar–H), 8.38 (d, 1H,
J¼5.4 Hz, CH]N), 8.48 (d, 1H, J¼8.5 Hz, Ar–H). 13C NMR (75 MHz)
d
18.9, 19.1, 34.8, 56.7, 113.1, 121.8, 122.1, 124.3, 127.8, 128.7, 129.2,
131.3,134.6,157.1,172.3. IR (KBr): 2967, 2931, 2865, 2841,1619,1592,

A. Viso et al. / Tetrahedron 65 (2009) 3757–3766
3761
1562, 1506, 1467, 1428, 1336, 1272, 1251, 1149, 1134, 1065, 1024, 982,
4.2.6. (þ)-Methyl [(2R,3R,Ss)-2-amino-3-(mesitylsulfinylamino)-
4-methyl]pentanoate, 5c
From 2c (264 mg, 0.64 mmol) and aqueous H3PO4 (0.5 M,
5.1 mL, 2.55 mmol), following the reported procedure8c (18 h) and
after chromatographic purification (CH2Cl2 to 10% EtOH/CH2Cl2), 5c
896, 811, 747 cmꢀ1. HRMS (ESI) m/z for C30H34N2NaO4S2 [2MþNa]þ
calcd: 573.1858, found: 573.1854. Anal. Calcd for C15H17NO2S: C,
65.43; H, 6.22; N, 5.09; S, 11.64. Found: C, 65.06; H, 5.98; N, 5.12; S,
11.48.
was obtained as a colorless oil (125 mg, 60%). Data for 5c: Rf 0.34
20
4.2.3. (þ)-Methyl [(2S,4S,5R,Ss)-5-isopropyl-1-(mesitylsulfinyl)-2-
phenylimidazolidin-4-yl]carboxylate, 2c
(5% EtOH/CH2Cl2). [
a
]
þ136.9 (c 1.69). 1H NMR (300 MHz)
d 1.00
D
i
i
(d, 3H, J¼6.8 Hz, Me Pr), 1.08 (d, 3H, J¼6.8 Hz, Me Pr), 1.60 (s, 2H,
i
From LDA [iPr2NH (0.57 mL, 4.07 mmol) and n-BuLi (0.15 mL,
3.45 mmol)], methyl (E)-N-benzylideneglycinate (556 mg, 3.14 mmol),
1c (372 mg, 1.57 mmol), and 4.25 equiv of BF3$OEt2 (0.85 mL), in
THF following the reported procedure8b (15 min), was obtained
2c after column chromatography (CH2Cl2 to 40% Et2O/CH2Cl2) as
NH2), 1.87 (m, 1H, CH Pr), 2.24 (s, 3H, Me Ar), 2.53 (s, 6H, Me Ar),
3.50 (dd, 1H, J¼7.6, 2.7 Hz, H-3), 3.62 (d, 1H, J¼2.7 Hz, H-2), 3.72 (s,
3H, OMe), 4.47 (d, 1H, J¼7.6 Hz, NH), 6.81 (s, 2H, Ar–H). 13C NMR
(75 MHz)
d 19.3, 19.5, 19.8, 20.7, 30.6, 51.9, 51.9, 55.4, 63.3, 130.6
(2C), 135.9 (2C), 138.7, 140.2, 174.9 (C]O). IR (film): 3233, 2958,
2926, 1739, 1602, 1436, 1225, 1071, 851, 755 cmꢀ1. HRMS (ESI) m/z
for C16H27N2O3S [MþH]þ calcd: 327.1742, found: 327.1737.
a yellow oil (380 mg, 58%). Data for 2c: Rf 0.36 (20% Et2O/
20
CH2Cl2). [
a]
þ94.6 (c 1.6). 1H NMR (300 MHz)
d 0.28 (d, 3H,
D
i
i
J¼6.8 Hz, Me Pr), 0.79 (d, 3H, J¼6.8 Hz, Me Pr), 1.15 (m, 1H, CH
iPr), 2.22 (br s, 10H, Me Arꢂ3þNH), 3.82 (s, 4H, H-4þOMe), 3.93
(dd, 1H, J¼8.8, 2.7 Hz, H-5), 5.77 (s, 1H, H-2), 6.74 (s, 2H, Ar–H),
7.24–7.38 (m, 3H, Ar–H), 7.51–7.54 (m, 2H, Ar–H). 13C NMR
4.2.7. Methyl [(2S,3R,Ss)-2-amino-4-methyl-3-(2-methoxy-1-
naphthylsulfinylamino)]pentanoate, 5d and methyl [(2R,3S,Ss)-
2-amino-4-methyl-3-(2-methoxy-1-naphthylsulfinylamino)]-
pentanoate, 5d0
(75 MHz)
d 19.1, 19.2, 19.3, 20.9 (2C), 32.9, 52.5, 63.5, 67.1, 80.4,
127.3 (4C), 128.2 (5C), 134.5, 140.5, 140.7, 172.7 (C]O). IR (film):
From a 78:22 mixture of 2d:2d0 (13 mg, 0.03 mmol) and aque-
ous H3PO4 (0.5 M, 0.21 mL, 0.11 mmol), following the reported
procedure8c (6 h), a 78:22 mixture of 5d:5d0 was obtained as
a colorless oil (9 mg, 70%) that was used without further purifica-
tion. Data for 5d from the mixture: Rf 0.26 (5% EtOH/CH2Cl2). 1H
3335, 2956, 1739, 1602, 1455, 1435, 1206, 1092, 901, 700 cmꢀ1
.
HRMS (ESI) m/z for C23H31N2O3S [MþH]þ calcd: 415.2055,
found: 415.2068.
4.2.4. Methyl [(2S,4S,5R,Ss)-5-isopropyl-1-(2-methoxy-1-
naphthylsulfinyl)-2-phenylimidazolidin-4-yl]carboxylate,
NMR (300 MHz)
d
1.07 (d, 3H, J¼6.6 Hz, Me iPr), 1.20 (d, 3H,
J¼6.6 Hz, Me iPr),1.94 (m,1H, CH iPr), 3.48 (s, 3H, OMe), 3.54 (m,1H,
H-3), 3.62 (d, 1H, J¼2.9 Hz, H-2), 4.08 (s, 3H, OMe), 5.89 (d, 1H,
J¼7.1 Hz, NH), 7.30 (dd, 1H, J¼9.0, 2.0 Hz, Ar–H), 7.37 (dd, 1H, J¼8.1,
1.0 Hz, Ar–H), 7.53 (dt, 1H, J¼7.1, 1.5 Hz, Ar–H), 7.79 (d, 1H, J¼8.3 Hz,
Ar–H), 7.90 (d, 1H, J¼9.3 Hz, Ar–H), 8.53 (d, 1H, J¼8.8 Hz, Ar–H).
2d and methyl [(2R,4R,5S,Ss)-5-isopropyl-1-(2-methoxy-1-
naphthylsulfinyl)-2-phenylimidazolidin-4-yl]carboxylate, 2d0
From LDA [iPr2NH (0.034 mL, 0.31 mmol) in THF and n-BuLi
(0.13 mL, 0.21 mmol)], methyl (E)-N-benzylideneglycinate (33 mg,
0.19 mmol), 1d (26 mg, 0.09 mmol), and 3.25 equiv of BF3$OEt2
(0.039 mL, 0.31 mmol), following the reported procedure8b (1 h),
a 78:22 inseparable mixture of 2d:2d0 was obtained after column
chromatography (60% Et2O/hex to Et2O) as a yellow oil (20 mg,
Partial data for 5d0 from the mixture: 1H NMR (300 MHz)
d 0.99 (d,
i
i
3H, J¼6.6 Hz, Me Pr), 0.98 (d, 3H, J¼6.8 Hz, Me Pr), 6.21 (d, 1H,
J¼8.5 Hz, NHSO), 8.61 (d, 1H, J¼8.5 Hz, Ar–H).
49%). Data for 2d from the mixture: 1H NMR (300 MHz)
d
0.25 (d,
4.2.8. (þ)-Methyl [(2S,3R,Ss)-N-(diphenylmethylene)-4-methyl-
3-(p-tolylsulfinylamino)]pentanoate, 6a
i
i
3H, J¼6.8 Hz, Me Pr), 0.65 (d, 3H, J¼6.8 Hz, Me Pr), 1.04 (m, 1H,
i
CH Pr), 3.76 (d, 1H, J¼3.4 Hz, H-4), 3.85 (s, 3H, OMe), 3.89 (s, 3H,
To a solution of 5a8c (86 mg, 0.288 mmol) in CH2Cl2 (10 mL/
mmol), 1.15 equiv of Ph2C]NH was added (0.06 mL, 0.331 mmol).
The mixture was stirred at room temperature until the disappear-
ance of 5a monitored by TLC (22 h). The solvent was removed under
reduced pressure and the crude was purified by column chroma-
OMe), 4.14 (dd, 1H, J¼8.8, 3.4 Hz, H-5), 5.92 (s, 1H, H-2), 7.19–7.49
(m, 7H, Ar–H), 7.61–7.93 (m, 4H, Ar–H). 13C NMR (100 MHz)
d 19.1,
19.3, 33.0, 52.5, 56.4, 64.0, 68.5, 80.7, 112.3, 122.8, 124.2, 126.1,
127.0 (2C), 127.5, 127.7, 127.8, 128.0 (2C), 128.4, 128.5, 134.2, 140.9,
156.3, 172.7 (C]O). HRMS (ESI) m/z for C25H29N2O4S [MþH]þ
calcd: 453.1848, found: 453.1873. Partial data for 2d0 from the
tography (20–50% Et2O/hex) to render 6a as a white solid (133 mg,
20
99%). Data for 6a: Rf 0.41 (Et2O). Mp: 47 ꢁC. [
a]
þ2.2 (c 1.55). 1H
D
mixture: 1H NMR (300 MHz)
OMe), 6.20 (s, 1H, H-2).
d
3.89 (s, 3H, OMe), 3.90 (s, 3H,
NMR (300 MHz)
d
0.75 (d, 3H, J¼6.8 Hz, Me iPr), 0.88 (d, 3H,
J¼6.8 Hz, Me iPr),1.65 (m,1H, CH iPr), 2.38 (s, 3H, Me p-Tol), 3.72 (m,
1H, H-3), 3.74 (s, 3H, OMe), 4.23 (d, 1H, J¼2.2 Hz, H-2), 5.16 (d, 1H,
4.2.5. (þ)-[(2S,4S,5R,Ss)-5-Isopropyl-2-phenyl-1-(p-tolylsulfinyl)-
imidazolidin-4-yl]methanol, 3a
From 2a (108 mg, 0.279 mmol), LiI (112 mg, 0.838 mmol), and
NaBH4 (32 mg, 0.838 mmol), following the reported procedure8b
(3 h) and after chromatographic purification (40–80% EtOAc/hex),
3a was obtained as a white solid (85 mg, 85%). Compound 3a was
J¼9.7 Hz, NHSO), 7.10 (m, 2H, Ar–H), 7.28 (m, 4H, Ar–H), 7.40 (m,
4H, Ar–H), 7.60 (m, 4H, Ar–H). 13C NMR (75 MHz)
d
19.3 (Me Pr),
i
i
i
19.7 (Me Pr), 21.3 (Me p-Tol), 31.7 (CH Pr), 52.3, 63.9, 67.2, 125.9
(2C), 127.2 (2C), 128.1 (2C), 128.6 (2C), 128.9 (2C), 129.4 (2C), 130.0,
130.7, 136.3, 139.0, 141.0, 143.3, 171.8 (C]O, C]N). IR (KBr): 3304,
2956, 1742, 1624, 1443, 1197, 1089, 1067, 695 cmꢀ1. HRMS (ESI) m/z
for C27H31N2O3S [MþH]þ calcd: 463.2055, found: 463.2073. Anal.
Calcd for C27H30N2O3S: C, 70.10; H, 6.54; N, 6.06; S, 6.93. Found: C,
69.89; H, 6.62; N, 5.87; S, 7.21.
further crystallized in Et2O/hex (1:1). Data for 3a: Rf 0.26 (5%
20
MeOH/CH2Cl2). Mp: 105–106 ꢁC. [
a
]
þ56.6 (c 2.62). 1H NMR
D
i
(300 MHz)-selective decouplings
d
0.36 (d, 3H, J¼6.0 Hz, Me Pr),
0.67 (d, 3H, J¼6.5 Hz, Me iPr), 0.74 (m, 1H, CH iPr), 2.39 (s, 3H, Me p-
Tol), 2.88 (br s, 1H), 3.28 (dd, 1H, J¼4.7, 2.8 Hz, H-4), 3.49 (dd, 1H,
J¼5.9, 2.9 Hz, H-5), 3.64 (dd, 1H, J¼11.4, 4.8 Hz, CH2OH), 3.75 (dd,
1H, J¼11.4, 7.3 Hz, CH2OH), 5.72 (s, 1H, H-2), 7.25–7.62 (m, 9H, Ar–
4.2.9. General procedure for the synthesis of sulfonamides
To a solution of 1.0 equiv of amine 5 in anhydrous CH2Cl2 (3 mL/
mmol) was added 1.0–1.5 equiv of PSO2Cl and 2.0–2.5 equiv of Et3N
or iPr2EtN. The mixture was stirred from 0 ꢁC to room temperature
and was monitored by TLC until completion. Then, it was hydro-
lyzed with a 50% aqueous solution of K2CO3 (15 mL/mmol) and
extracted with CH2Cl2 (3ꢂ10 mL/mmol). The combined organic
phases were washed with a saturated solution of NaCl (10 mL/
mmol), dried over anhydrous Na2SO4, filtered, and the solvent was
H). 13C NMR (75 MHz)
d
17.4 (Me iPr), 19.7 (Me iPr), 21.4 (Me p-Tol),
i
31.6 (CH Pr), 59.8 (C–O), 61.8 (C–N), 63.0 (C–N), 80.8 (C-2), 125.2
(2C), 127.1 (2C), 128.6, 128.6 (2C), 129.5 (2C), 139.7, 140.3, 141.8. IR
(KBr): 3401, 2960, 2927, 2869, 1641, 1490, 1450, 1385, 1201, 1085,
1046, 1013, 916, 812, 745, 699 cmꢀ1
. HRMS (ESI) m/z for
C20H27N2O2S [MþH]þ calcd: 359.1793, found: 359.1803.

3762
A. Viso et al. / Tetrahedron 65 (2009) 3757–3766
evaporated under reduced pressure. The crude was purified by
chromatography on silica gel using the appropriate mixture of el-
uents. Note: careful attention should be paid to the presence of
water in the reaction since traces of sulfonic acid can led to epi-
merization of the sulfinamide moiety in 7. Azeotropic co-evapora-
tion with anhydrous cyclohexane of substrate and pure PSO2Cl
prior to use prevent this process.
NMR (75 MHz)-HSQC
23.5 (CH iPr Ar), 23.6 (CH iPr Ar), 24.7 (2Me iPr), 24.9 (2Me iPr), 29.8
d
18.3 (Me iPr), 19.6 (Me iPr), 21.4 (Me p-Tol),
i
i
i
(CH Pr), 30.0 (2Me Pr), 34.2 (CH Pr Ar), 52.3 (OMe), 56.5 (C–N),
61.0 (C–N), 123.6 (2C), 125.7 (2C), 129.5 (2C), 132.9, 140.9, 141.8,
150.2 (2C), 152.8, 171.1 (C]O). IR (film): 3275, 2956, 2927, 2869,
1747, 1598, 1461, 1429, 1327, 1255, 1197, 1161, 1147, 1085, 1056, 879,
811 cmꢀ1
565.2770, found: 565.2788.
.
HRMS (ESI) m/z for C29H45N2O5S2 [MþH]þ calcd:
4.2.10. (þ)-Methyl [(2S,3R,Ss)-4-methyl-3-(p-tolylsulfinylamino)-
2-(p-tolylsulfonylamino)]pentanoate, 7a
From 5a (31 mg, 0.10 mmol), Et3N (0.029 mL, 0.21 mmol,
2.0 equiv), and p-TolSO2Cl (20 mg, 0.10 mmol), following the gen-
eral procedure (6 h) and after chromatographic purification (20–
4.2.13. (þ)-Methyl (2S,3R,Ss)-[4-methyl-2-(p-nitrophenyl-
sulfonylamino)-3-(p-tolylsulfinylamino)]pentanoate, 7d
From 5a (25 mg, 0.08 mmol), Et3N (0.023 mL, 0.17 mmol,
2.0 equiv), and p-NO2C6H4SO2Cl (19 mg, 0.08 mmol, 1.0 equiv),
following the general procedure (1.5 h) and after chromatographic
purification (20–30% EtOAc/hex), 7d was obtained as a white solid
30% EtOAc/hex), 7a was obtained as a white solid (44 mg, 93%). Data
20
for 7a: Rf 0.12 (10% EtOAc/CH2Cl2). Mp: 62 ꢁC. [
a
]
þ6.3 (c 0.87). 1H
D
NMR (CDCl3, 300 MHz)
d
0.85 (d, 3H, J¼6.6 Hz, Me iPr), 0.94 (d, 3H,
(40 mg, 98%). Data for 7d: Rf 0.28 (50% EtOAc/hex). Mp: 75–76 ꢁC.
20
J¼6.6 Hz, Me iPr), 1.81 (m, 1H, CH iPr), 2.38 (s, 3H, Me p-Tol), 2.41 (s,
3H, Me p-Tol), 3.35 (td, 1H, J¼8.3, 3.4 Hz, H-3), 3.49 (s, 3H, OMe),
4.06 (d, 1H, J¼9.3 Hz, NHSO), 4.09 (dd, 1H, J¼9.9, 3.4 Hz, H-2), 5.85
(d, 1H, J¼9.3 Hz, NHTs), 7.24–7.30 (m, 4H, Ar–H), 7.51 (d, 2H,
J¼8.0 Hz, Ar–H), 7.73 (d, 2H, J¼8.3 Hz, Ar–H). 1H NMR (C6D6,
[a
]
þ74.9 (c 0.39). 1H NMR (300 MHz)
d
0.82 (d, 3H, J¼6.6 Hz, Me
D
iPr), 0.95 (d, 3H, J¼6.8 Hz, Me iPr), 1.83 (m, 1H, CH iPr), 2.38 (s, 3H,
Me p-Tol), 3.35 (tdd, 1H, J¼8.8, 3.9, 1.5 Hz, H-3), 3.48 (s, 3H, OMe),
4.16 (dd, 1H, J¼9.0, 3.9 Hz, H-2), 4.28 (br s, 1H, NHSO), 6.65 (br s, 1H,
NHSO2), 7.27 (d, 2H, J¼8.0 Hz, Ar–H), 7.48 (d, 2H, J¼8.3 Hz, Ar–H),
8.06 (d, 2H, J¼8.0 Hz, Ar–H), 8.32 (d, 2H, J¼8.3 Hz, Ar–H). 13C NMR
300 MHz)
d
0.69 (d, 3H, J¼6.7 Hz, Me iPr), 0.80 (d, 3H, J¼6.7 Hz, Me
iPr), 1.71 (m, 1H, CH iPr), 1.84 (s, 3H, p-Tol), 1.92 (s, 3H, p-Tol), 3.10 (s,
3H, OMe), 3.40 (td, 1H, J¼7.3, 4.2 Hz, H-3), 4.07 (d, 1H, J¼9.0 Hz,
NH–SO), 4.31 (dd, 1H, J¼8.1, 4.1 Hz, H-2), 6.61 (d, 1H, J¼8.8 Hz, NH–
Ts), 6.75 (d, 2H, J¼8.1 Hz, Ar–H), 6.84 (d, 2H, J¼8.3 Hz, Ar–H), 7.60
(d, 2H, J¼8.3 Hz, Ar–H), 7.86 (d, 2H, J¼8.1 Hz, Ar–H). 13C NMR
(75 MHz)-HSQC d 18.5 (Me Pr), 19.8 (Me Pr), 21.4 (Me p-Tol), 29.5
i
i
i
(CH Pr), 52.7 (OMe), 57.5 (C-2), 61.1 (C-3), 124.1 (2C), 125.7 (2C),
128.5 (2C), 129.6 (2C), 139.8, 142.0, 145.9, 150.0, 170.4 (C]O). IR
(KBr): 3435, 2956, 2920, 1748, 1606, 1531, 1432, 1350, 1309, 1168,
1091, 1053, 854, 735 cmꢀ1. HRMS (ESI) m/z for C20H26N3O7S2
[MþH]þ calcd: 484.1212, found: 484.1223.
(CDCl3, 75 MHz)
d
18.8 (Me iPr), 19.8 (Me iPr), 21.4 (Me p-Tol), 21.5
i
(Me p-Tol), 29.8 (CH Pr), 52.6 (OMe), 57.4 (C–N), 61.8 (C–N), 125.7
(2C), 127.3 (2C), 129.6 (4C), 136.8, 140.7, 141.8, 143.7, 170.9 (C]O). IR
(KBr): 3275, 2959, 2920, 1747, 1598, 1435, 1338, 1163, 1092, 1035,
814, 775, 667 cmꢀ1. HRMS (ESI) m/z for C21H29N2O5S2 [MþH]þ
calcd: 453.1518, found: 453.1528.
4.2.14. (þ)-Methyl [(2S,3R,Ss)-2-(2,4-dinitrophenylsulfonylamino)-
4-methyl-3-(p-tolylsulfinylamino)]pentanoate, 7e
From 5a (23 mg, 0.08 mmol), Et3N (0.021 mL, 0.16 mmol), and
2,4-(NO2)2C6H3SO2Cl (21 mg, 0.08 mmol), following the general
procedure (32 h) and after chromatographic purification (5–15%
4.2.11. (ꢀ)-Methyl [(2S,3R,Ss)-4-methyl-2-(methylsulfonylamino)-
3-(p-tolylsulfinylamino)]pentanoate, 7b
EtOAc/hex), 7e was obtained as a yellow oil (26 mg, 64%). Data for
20
7e: Rf 0.26 (50% EtOAc/hex). [
d
a
]
ꢀ65.8 (c 0.83). 1H NMR (300 MHz)
D
From 5a (38 mg, 0.13 mmol), iPr2EtN (0.043 mL, 0.25 mmol), and
MeSO2Cl (0.01 mL, 0.13 mmol), following the general procedure
(4 h) and after chromatographic purification (10–30% EtOAc/
1.04 (ap t, 6H, J¼7.7, 6.8 Hz, Me iPr),1.91 (m,1H, CH iPr), 2.39 (s, 3H,
Me p-Tol), 3.51 (s, 3H, OMe), 3.58 (td, 1H, J¼6.7, 2.2 Hz, H-3), 4.14 (d,
1H, J¼6.9 Hz, H-2), 4.46 (d, 1H, J¼7.5 Hz, NHSO), 6.88 (d, 1H,
J¼9.4 Hz, NHSO2), 7.28 (d, 2H, J¼8.4 Hz, Ar–H), 7.49 (d, 2H, J¼8.2 Hz,
Ar–H), 8.28 (d, 1H, J¼8.6 Hz, Ar–H), 8.51 (ddd, 1H, J¼8.6, 2.2, 0.4 Hz,
CH2Cl2), 7b was obtained as a colorless oil (35 mg, 73%). Data for 7b:
20
Rf 0.21 (30% EtOAc/CH2Cl2). [
d
a
]
ꢀ8.7 (c 0.77). 1H NMR (300 MHz)
D
i
i
0.90 (d, 3H, J¼6.7 Hz, Me Pr), 0.97 (d, 3H, J¼6.7 Hz, Me Pr), 1.83
Ar–H), 8.77 (d, 1H, J¼2.3 Hz, Ar–H). 13C NMR (75 MHz)
d 19.1 (Me
(m, 1H, CH iPr), 2.39 (s, 3H, Me p-Tol), 2.99 (s, 3H, Me–Ms), 3.42 (td,
1H, J¼8.3, 2.7 Hz, H-3), 3.77 (s, 3H, OMe), 4.27 (dd, 1H, J¼9.8, 2.9 Hz,
H-2), 4.42 (d, 1H, J¼8.3 Hz, NHSO), 5.94 (d, 1H, J¼9.7 Hz, NHMs),
7.27 (d, 2H, J¼8.1 Hz, Ar–H), 7.49 (d, 2H, J¼8.3 Hz, Ar–H). 13C NMR
iPr), 19.6 (Me iPr), 21.4 (Me p-Tol), 30.1 (CH iPr), 52.9 (OMe), 58.8 (C–
N), 61.6 (C–N), 121.0, 125.5 (2C), 127.1, 129.7 (2C), 132.0, 140.2, 140.5,
142.1, 147.9, 149.7, 170.6 (C]O). IR (film): 3304, 3101, 2956, 2920,
1743, 1602, 1551, 1539, 1432, 1350, 1172, 1049, 811, 746 cmꢀ1. HRMS
(ESI) m/z for C20H25N4O9S2 [MþH]þ calcd: 529.1063, found:
529.1082.
(75 MHz) d
19.0 (Me iPr), 19.6 (Me iPr), 21.4 (Me p-Tol), 30.0 (CH iPr),
41.6 (Me–Ms), 52.9 (OMe), 57.8 (C–N), 61.4 (C–N), 125.8 (2C), 129.5
(2C), 140.4, 141.7, 171.7 (C]O). IR (film): 3271, 2959, 2927, 2876,
1746, 1436,1327, 1216, 1142, 1087, 1055, 813, 754 cmꢀ1. MS (ES): 775
[2MþNa]þ (100%), 399 [MþNa]þ, 377 [Mþ1]þ.
4.2.15. (þ)-Methyl [(2S,3R,Ss)-2-(p-bromophenylsulfonylamino)-
4-methyl-3-(p-tolylsulfinylamino)]pentanoate, 7f
From 5a (28 mg, 0.09 mmol), Et3N (0.026 mL, 0.19 mmol), and
p-BrC6H4SO2Cl (24 mg, 0.09 mmol), following the general pro-
cedure (5 h) and after chromatographic purification (20–50%
4.2.12. (þ)-Methyl [(2S,3R,Ss)-4-methyl-3-(p-tolylsulfinylamino)-
2-(2,3,6-triisopropylphenylsulfonylamino)]pentanoate, 7c
From 5a (30 mg, 0.10 mmol), Et3N (0.028 mL, 0.20 mmol), and
2,4,6-(iPr)3C6H2SO2Cl (31 mg, 0.10 mmol), following the general
procedure (26 h) and after chromatographic purification (5–20%
EtOAc/hex), 7f was obtained as a white solid (40 mg, 82%). Data
þ28.7 (c 0.54). 1H
20
for 7f: Rf 0.34 (50% EtOAc/hex). Mp: 65 ꢁC. [
a
]
D
NMR (300 MHz)
d
0.83 (d, 3H, J¼6.6 Hz, Me iPr), 0.94 (d, 3H,
i
i
EtOAc/hex), 7c was obtained as a colorless oil (56 mg, 99%). Data for
J¼6.8 Hz, Me Pr), 1.81 (m, 1H, CH Pr), 2.38 (s, 3H, Me p-Tol), 3.34
(td, 1H, J¼8.3, 3.7 Hz, H-3), 3.50 (s, 3H, OMe), 4.10 (dd, 1H, J¼9.0,
3.7 Hz, H-2), 4.24 (d, 1H, J¼8.3 Hz, NHSO), 6.24 (d, 1H, J¼9.0 Hz,
NHSO2), 7.25 (d, 2H, J¼8.1 Hz, Ar–H), 7.49 (d, 2H, J¼8.1 Hz, Ar–H),
7.62 (d, 2H, J¼8.5 Hz, Ar–H), 7.72 (d, 2H, J¼8.7 Hz, Ar–H). 13C NMR
20
7c: Rf 0.23 (50% Et2O/hex). [
d
a
]
þ53.4 (c 0.98). 1H NMR (300 MHz)
D
0.76 (d, 3H, J¼6.6 Hz, Me iPr), 0.95 (d, 3H, J¼6.8 Hz, Me iPr),1.23 (d,
6H, J¼6.8 Hz, Me iPr Ar),1.24 (d, 6H, J¼6.8 Hz, Me iPr Ar),1.30 (d, 6H,
J¼6.8 Hz, Me iPr Ar), 1.76 (m, 1H, CH iPr), 2.38 (s, 3H, Me p-Tol), 2.87
(m, 1H, CH Ar), 3.38 (ddd, 1H, J¼8.3, 7.1, 4.4 Hz, H-3), 3.44 (s, 3H,
OMe), 4.11 (m, 2H, 2CH Ar), 4.23 (dd, 1H, J¼9.3, 4.4 Hz, H-2), 4.27 (d,
1H, J¼8.0 Hz, NHSO), 6.15 (d, 1H, J¼9.5 Hz, NHSO2), 7.14 (s, 2H, Ar–
H), 7.26 (d, 2H, J¼8.0 Hz, Ar–H), 7.54 (d, 2H, J¼8.0 Hz, Ar–H). 13C
i
i
(75 MHz)
d 18.6 (Me Pr), 19.8 (Me Pr), 21.3 (Me p-Tol), 29.6 (CH
iPr), 52.6 (OMe), 57.4 (C–N), 61.5 (C–N), 125.7 (2C), 127.7, 128.8
(2C), 129.5 (2C), 132.1 (2C), 139.0, 140.4, 141.8, 170.6 (C]O). IR
(KBr): 3435, 3297, 2956, 1748, 1575, 1468, 1432, 1389, 1342, 1166,

A. Viso et al. / Tetrahedron 65 (2009) 3757–3766
3763
1091, 1067, 1010, 813, 739, 610 cmꢀ1
.
HRMS (ESI) m/z for
4.2.19. (þ)-Methyl {[(2S,3R,Ss)-2-[(1S,4R)-7,7-dimethyl-2-
oxabicyclo[2.2.1]heptan-1-yl-methylsulfonylamino]-4-methyl-3-
(p-tolylsulfinylamino)}pentanoate, 7j
C40H50Br2N4NaO10S4 [2MþNa]þ calcd: 1057.0654, found:
1057.0678.
From 5a (28 mg, 0.09 mmol), Et3N (0.026 mL, 0.19 mmol), and
(1S)-(þ)-camphor-10-sulfonyl chloride (29 mg, 0.11 mmol), fol-
lowing the general procedure (4 d) and after chromatographic pu-
4.2.16. (þ)-Methyl [(2S,3R,Ss)-4-methyl-2-(p-methoxyphenyl-
sulfonylamino)-3-(p-tolylsulfinylamino)]pentanoate, 7g
From 5a (20 mg, 0.07 mmol), Et3N (0.019 mL, 0.14 mmol), and p-
MeOC6H4SO2Cl (14 mg, 0.07 mmol), following the general pro-
cedure (21 h) and after chromatographic purification (20–40%
rification (CH2Cl2 to 40% EtOAc/CH2Cl2), 7j was obtained as a yellow
20
oil (27 mg, 62%). Data for 7j: Rf 0.14 (40% EtOAc/hex). [
a
]
þ24.4 (c
D
0.81). 1H NMR (400 MHz)
d
0.99 (s, 3H, Me camphor), 1.00 (d, 3H,
EtOAc/hex), 7g was obtained as a yellow oil (22 mg, 70%). Data for
J¼6.6 Hz, Me iPr),1.01 (s, 3H, Me camphor),1.03 (d, 3H, J¼6.6 Hz, Me
iPr),1.44 (m,1H, camphor) 1.84 (m,1H, CH iPr),1.95 (d,1H, J¼18.4 Hz,
H-30 camphor), 2.05 (m, 3H, camphor), 2.14 (t, 1H, J¼4.3 Hz, H-40
camphor), 2.39 (s, 3H, Me p-Tol), 2.47 (ddd,1H, J¼18.7, 4.7, 2.5 Hz, H-
30 camphor), 3.00 (d, 1H, J¼15.2 Hz, CH2S), 3.59 (ddd, 1H, J¼8.9, 7.4,
2.3 Hz, H-3), 3.70 (d, 1H, J¼14.8 Hz, CH2S), 3.75 (s, 3H, CO2Me), 4.06
(d,1H, J¼7.4 Hz, NHSO), 4.45 (dd,1H, J¼9.8, 2.3 Hz, H-2), 6.99 (d,1H,
J¼10.1 Hz, NHSO2), 7.25 (d, 2H, J¼7.8 Hz, Ar–H), 7.60 (d, 2H,
20
7g: Rf 0.16 (50% EtOAc/hex). [
d
a]
þ30.8 (c 0.94). 1H NMR (300 MHz)
D
i
i
0.84 (d, 3H, J¼6.6 Hz, Me Pr), 0.93 (d, 3H, J¼6.6 Hz, Me Pr), 1.80
(m, 1H, CH iPr), 2.37 (s, 3H, Me p-Tol), 3.34 (td, 1H, J¼8.1, 3.4 Hz, H-
3), 3.51 (s, 3H, OMe), 3.84 (s, 3H, OMe), 4.08 (m, 2H, H-2, NHSO),
5.85 (d, 1H, J¼9.3 Hz, NHSO2), 6.94 (d, 2H, J¼8.8 Hz, Ar–H), 7.25 (d,
2H, J¼8.3 Hz, Ar–H), 7.50 (d, 2H, J¼8.1 Hz, Ar–H), 7.77 (d, 2H,
J¼8.5 Hz, Ar–H). 13C NMR (75 MHz)-DEPT
d
18.7 (Me iPr), 19.8 (Me
i
iPr), 21.4 (Me p-Tol), 29.8 (CH Pr), 52.7 (C–O), 55.6 (C–O), 57.4 (C–
N), 61.8 (C–N), 114.1 (2C), 125.7 (2C), 129.5 (2C), 129.6 (2C), 131.3,
140.8, 141.8, 163.0, 171.0 (C]O). IR (film): 3268, 3166, 2962, 2927,
1747, 1597, 1498, 1441, 1338, 1260, 1158, 1094, 1030, 893, 835, 813,
756, 670 cmꢀ1. MS (ES): 959 [2MþNa]þ, 491 [MþNa]þ (100%), 469
[Mþ1]þ.
J¼8.6 Hz, Ar–H). 13C NMR (75 MHz)
d 19.4, 19.5, 19.6, 20.1, 21.4, 27.1,
27.8, 30.1, 42.9, 43.1, 48.9, 52.6, 52.8, 58.9, 59.7, 62.5,126.0 (2C),129.4
(2C), 141.5 (2C), 172.0 (C]O), 184.0 (C]O). IR (film): 3279, 2961,
1742, 1452, 1435, 1393, 1373, 1334, 1257, 1216, 1141, 1090, 1055, 935,
812, 755, 663 cmꢀ1. HRMS (ESI) m/z for C24H37N2O6S2 [MþH]þ
calcd: 513.2093, found: 513.2108.
4.2.17. (þ)-Methyl [(2S,3R,Ss)-2-(3,5-dichloro-2-hydroxy-
phenylsulfonylamino)-4-methyl-3-(p-tolylsulfinyl-
amino)]pentanoate, 7h
4.2.20. (þ)-Methyl {[(2S,3R,Ss)-2-[(1R,4S)-7,7-dimethyl-2-
oxabicyclo[2.2.1]heptan-1-yl-methylsulfonylamino]-4-methyl-3-
(p-tolylsulfinylamino)}pentanoate, 7j0
From 5a (40 mg, 0.13 mmol), Et3N (0.037 mL, 0.27 mmol), and
3,5-Cl2-2-(OH)C6H2SO2Cl (36 mg, 0.13 mmol), following the gen-
eral procedure (26 h) and after chromatographic purification (5–
From 5a (18 mg, 0.06 mmol), Et3N (0.02 mL, 0.14 mmol), and
(1R)-(þ)-camphor-10-sulfonyl chloride (18 mg, 0.07 mmol), fol-
lowing the general procedure (2 h) and after chromatographic
30% EtOAc/CH2Cl2), 7h was obtained as a colorless oil (68 mg,
purification (20–40% EtOAc/hex), 7j0 was obtained as a colorless oil
20
20
97%). Data for 7h: Rf 0.20 (80% EtOAc/hex). [
a
]
þ77.9 (c 0.57). 1H
(30 mg, 97%). Data for 7j0: Rf 0.27 (50% EtOAc/hex). [
a]
þ36.3 (c
D
D
NMR (300 MHz)
d
0.81 (d, 3H, J¼6.6 Hz, Me iPr), 0.95 (d, 3H,
1.45). 1H NMR (CDCl3, 500 MHz)-COSY
d
0.74 (d, 3H, J¼6.6 Hz, Me
i
i
J¼6.8 Hz, Me Pr), 1.83 (m, 1H, CH Pr), 2.38 (s, 3H, Me p-Tol), 3.36
(ap tdd, 1H, J¼8.1, 3.9 Hz, H-3), 3.54 (s, 3H, OMe), 4.14 (m, 1H, H-
2), 4.32 (d, 1H, J¼8.3 Hz, NHSO), 6.86 (d, 1H, J¼7.6 Hz, NHSO2),
7.27 (d, 2H, J¼8.1 Hz, Ar–H), 7.49 (d, 2H, J¼8.1 Hz, Ar–H), 7.52 (d,
1H, J¼2.4 Hz, Ar–H), 7.60 (d, 1H, J¼2.4 Hz, Ar–H). 13C NMR
iPr), 0.85 (s, 3H, Me camphor), 0.98 (d, 3H, J¼6.8 Hz, Me iPr), 1.05 (s,
3H, Me camphor), 1.44 (ddd, 1H, J¼12.9, 9.3, 3.7 Hz, camphor) 1.74
(m, 1H, CH iPr), 1.88 (ddd, 1H, J¼14.1, 9.3, 4.9 Hz, camphor), 1.93 (d,
1H, J¼18.6 Hz, H-30 camphor), 2.03 (m, 1H, camphor), 2.10 (t, 1H,
J¼4.4 Hz, camphor), 2.34 (dd, 1H, J¼4.4, 3.4 Hz, H-40 camphor), 2.39
(s, 3H, Me p-Tol), 2.44 (ddd, 1H, J¼14.7, 11.7, 3.9 Hz, camphor), 2.96
(d, 1H, J¼14.9 Hz, CH2S), 3.38 (ddd, 1H, J¼8.8, 6.8, 4.6 Hz, H-3), 3.50
(d, 1H, J¼14.9 Hz, CH2S), 3.77 (s, 3H, OMe), 4.34 (dd, 1H, J¼8.1,
4.6 Hz, H-2), 4.50 (d, 1H, J¼8.6 Hz, NHSO), 6.40 (d, 1H, J¼8.3 Hz,
NHSO2), 7.28 (d, 2H, J¼8.1 Hz, Ar–H), 7.53 (d, 2H, J¼8.1 Hz, Ar–H).
i
i
(75 MHz)
d 18.4 (Me Pr), 19.7 (Me Pr), 21.4 (Me p-Tol), 29.6 (CH
iPr), 52.8 (OMe), 57.4 (C–N), 60.8 (C–N), 124.0, 124.6, 125.8 (2C),
126.8, 126.9, 129.5 (2C), 134.2, 139.5, 141.9, 149.5, 170.4 (C]O). IR
(film): 3304, 3079, 2964, 1748, 1468, 1436, 1338, 1212, 1164, 1085,
811, 755 cmꢀ1. HRMS (ESI) m/z for C20H25Cl2N2O6S2 [MþH]þ calcd:
523.0531, found: 523.0518.
13C NMR (CDCl3, 100 MHz)-HSQC
d 18.0, 19.7, 19.8, 19.9, 21.4 (p-Tol),
24.9 (camphor), 27.0 (camphor), 29.8 (CH iPr), 42.6 (camphor), 42.8
(camphor), 48.5 (camphor), 50.3 (CH2S), 52.8 (OMe), 57.6 (C-2),
58.6 (camphor), 60.6 (C-3), 125.9 (2C), 129.5 (2C), 140.2, 141.8, 171.9
(C]O), 216.3 (C]O). IR (film): 3291, 2959, 1744, 1451, 1436, 1334,
1141, 1052, 813 cmꢀ1. HRMS (ESI) m/z for C24H37N2O6S2 [MþH]þ
calcd: 513.2093, found: 513.2113.
4.2.18. (þ)-Methyl [(2S,3R,Ss)-4-methyl-2-(1-naphthylsulfonyl-
amino)-3-(p-tolylsulfinylamino)]pentanoate, 7i
From 5a (34 mg, 0.11 mmol), Et3N (0.032 mL, 0.23 mmol), and 1-
naphthalene sulfonyl chloride (27 mg, 0.11 mmol), following the
general procedure (7.5 h) and after chromatographic purification
(20–30% EtOAc/hex), 7i was obtained as a white solid (48 mg, 86%).
20
Data for 7i: Rf 0.27 (50% EtOAc/hex). Mp: 67 ꢁC. [
a
]
D
þ91.9 (c 0.48).
4.2.21. (þ)-Methyl [(2S,3R,Ss)-3-naphthyl-2-(1-naphthyl-
sulfonylamino)-3-(p-tolylsulfinylamino)]propanoate, 7k
From 5b (64 mg, 0.17 mmol), Et3N (0.063 mL, 0.45 mmol), and
1-naphthalene sulfonyl chloride (57 mg, 0.25 mmol), following the
general procedure (24 h) and after chromatographic purification
i
1H NMR (300 MHz)
d
0.62 (d, 3H, J¼6.9 Hz, Me Pr), 0.82 (d, 3H,
J¼6.9 Hz, Me iPr), 1.63 (m, 1H, CH iPr), 2.36 (s, 3H, Me p-Tol), 3.15 (s,
3H, OMe), 3.27 (td, 1H, J¼8.5, 4.1 Hz, H-3), 4.04 (dd, 1H, J¼9.3,
4.0 Hz, H-2), 4.17 (d, 1H, J¼8.4 Hz, NHSO), 6.51 (d, 1H, J¼9.2 Hz,
NHSO2), 7.23 (d, 2H, J¼7.3 Hz, Ar–H), 7.47 (d, 2H, J¼8.1 Hz, Ar–H),
7.50–7.74 (m, 3H, Ar–H), 7.93 (d, 1H, J¼8.1 Hz, Ar–H), 8.05 (d, 1H,
J¼8.3 Hz, Ar–H), 8.23 (d, 1H, J¼7.5 Hz, Ar–H), 8.72 (d, 1H, J¼8.7 Hz,
(5–20% EtOAc/CH2Cl2), 7k was obtained as a white solid (65 mg,
20
68%). Data for 7k: Rf 0.28 (20% EtOAc/CH2Cl2). Mp: 98–100 ꢁC. [
a]
D
þ123.4 (c 0.73). 1H NMR (500 MHz)
d 2.17 (s, 3H, Me p-Tol), 3.14 (s,
Ar–H). 13C NMR (75 MHz)
d
18.3 (Me iPr), 19.6 (Me iPr), 21.3 (Me p-
3H, OMe), 4.36 (t, 1H, J¼6.6 Hz), 5.37 (t, 1H, J¼6.6 Hz), 5.47 (d, 1H,
J¼7.6 Hz, NHSO), 6.88 (d, 1H, J¼7.6 Hz, NHSO2), 6.91 (d, 3H,
J¼8.3 Hz, Ar–H), 7.06 (d, 1H, J¼6.4 Hz, Ar–H), 7.24 (m, 2H, Ar–H),
7.29 (d, 2H, J¼8.3 Hz, Ar–H), 7.33 (t, 1H, J¼7.0 Hz, Ar–H), 7.41 (d, 1H,
J¼8.1 Hz, Ar–H), 7.45 (d, 1H, J¼8.6 Hz, Ar–H), 7.56 (td, 1H, J¼6.9,
1.0 Hz, Ar–H), 7.64 (m, 2H, Ar–H), 7.86 (d, 1H, J¼8.1 Hz, Ar–H), 7.91
(m, 2H, Ar–H), 8.66 (d, 1H, J¼8.6 Hz, Ar–H). 13C NMR (75 MHz)
Tol), 29.6 (CH iPr), 52.2 (OMe), 57.3 (C–N), 60.9 (C–N), 124.0, 124.8,
125.7 (2C), 126.9, 128.4, 128.9, 129.5 (2C), 129.6, 134.1, 134.4 (2C),
134.8, 140.4, 141.8, 170.6 (C]O). IR (KBr): 3282, 2956, 2920, 2869,
1744, 1432, 1331, 1262, 1201, 1134, 1085, 1046, 767, 755 cmꢀ1. HRMS
(ESI) m/z for C24H29N2O5S2 [MþH]þ calcd: 489.1518, found:
489.1532.

3764
A. Viso et al. / Tetrahedron 65 (2009) 3757–3766
d
21.1, 52.4, 60.4, 60.8, 122.1, 123.8, 124.6, 124.9, 125.2, 125.6, 125.8
(C]O). IR (film): 3435, 2955, 2925, 1745, 1621, 1506, 1464, 1331,
1198, 1165, 1038, 772, 589 cmꢀ1. HRMS (ESI) m/z for C28H31N2O6S2
[MþH]þ calcd: 555.1624, found: 555.1641.
(2C), 126.1, 126.7, 127.9, 128.2, 128.3, 128.7, 128.7, 129.1 (2C), 129.4,
129.5, 133.1, 133.2, 133.9, 134.0, 134.3, 139.3, 141.2, 169.5 (C]O). IR
(KBr): 3435, 3059, 2947, 2355, 1749, 1624, 1506, 1434, 1335, 1162,
1086, 771 cmꢀ1. HRMS (ESI) m/z for C31H29N2O5S2 [MþH]þ calcd:
573.1518, found: 573.1531. Anal. Calcd for C31H28N2O5S2: C, 65.01;
H, 4.93; N, 4.89; S, 11.20. Found: C, 65.30; H, 5.20; N, 5.18; S, 10.97.
4.2.24. General procedure for oxidation of sulfinamides to
sulfonamides with m-CPBA
m-CPBA (1.3 equiv, 70%) was added at 0 ꢁC to a solution of the
sulfinamide in CH2Cl2 (15 mL/mmol). The reaction mixture was
allowed to warm up slowly to room temperature and was moni-
tored by TLC. Then, it was quenched with 1 M aqueous solution of
Na2S2O4 (3 mL/mmol), a saturated solution of NaHCO3 (3 mL/
mmol), and H2O (3 mL/mmol), and was diluted with CH2Cl2 (8 mL/
mmol). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3ꢂ10 mL/mmol). The organic layer was
washed with a saturated solution of NaCl (10 mL/mmol), dried over
Na2SO4, filtered, and concentrated under reduced pressure to give
a crude product that was purified by column chromatography.
4.2.22. (þ)-Methyl [(2S,3R,Ss)-3-(mesitylsulfinylamino)-4-methyl-
2-(1-naphthylsulfonylamino)]pentanoate, 7l
From 5c (107 mg, 0.33 mmol), Et3N (0.11 mL, 0.82 mmol), and 1-
naphthalene sulfonyl chloride (112 mg, 0.49 mmol), following the
standard procedure (20 h) and after chromatographic purification
(10–40% EtOAc/hex), 7l was obtained as a white solid (147 mg, 87%).
20
Data for 7l: Rf 0.14 (30% EtOAc/hex). Mp: 95 ꢁC. [
a]
þ115.9 (c 0.66).
D
1H NMR (300 MHz)
d
0.76 (d, 3H, J¼6.6 Hz, Me Pr), 0.96 (d, 3H,
i
i
i
J¼6.6 Hz, Me Pr), 1.88 (m, 1H, CH Pr), 2.25 (s, 3H, Me Ar), 2.46 (s,
6H, Me Ar), 3.09 (s, 3H, OMe), 3.37 (ddd, 1H, J¼8.1, 6.3, 3.7 Hz, H-3),
4.12 (dd, 1H, J¼9.3, 3.7 Hz, H-2), 4.36 (d, 1H, J¼6.3 Hz, NHSO), 6.82
(m, 3H, NHSO2þ2Ar–H), 7.49 (m, 1H, Ar–H), 7.59 (m, 1H, Ar–H), 7.67
(m,1H, Ar–H), 7.92 (d,1H, J¼8.1 Hz, Ar–H), 8.03 (d,1H, J¼8.3 Hz, Ar–
H), 8.21 (dd, 1H, J¼7.3, 1.2 Hz, Ar–H), 8.68 (d, 1H, J¼7.8 Hz, Ar–H).
4.2.25. (þ)-Methyl [(2S,3R)-4-methyl-2,3-bis(p-tolylsulfonyl-
amino)]pentanoate, 8a
From 7a (10 mg, 0.022 mmol) and m-CPBA (6.5 mg, 0.026 mmol),
following the general procedure (1.5 h) and after chromatographic
13C NMR (75 MHz)
d
19.0, 19.4 (2C), 20.8, 28.7 (2C), 51.9, 57.0, 63.2,
purification (10–20% EtOAc/hex), 8a was obtained as a white solid
20
123.9, 124.7, 126.7, 128.1, 128.2, 128.7, 129.1, 130.8 (2C), 133.9, 134.1,
135.0, 136.5 (2C), 136.8, 140.8, 170.6 (C]O). IR (KBr): 3449, 2955,
2926, 1742, 1600, 1436, 1335, 1200, 1164, 1134, 1065, 1044, 982, 804,
772, 593 cmꢀ1. MS (ES): 1055 [2MþNa]þ, 539 [MþNa]þ (100%), 517
[Mþ1]þ. Anal. Calcd for C26H32N2O5S2: C, 60.44; H, 6.24; N, 5.42; S,
12.41. Found: C, 60.33; H, 6.18; N, 5.31; S, 12.24.
(10 mg, 99%). Data for 8a: Rf 0.15 (30% EtOAc/hex). Mp: 152 ꢁC. [
a]
D
þ54.8 (c 0.73). 1H NMR (300 MHz)
d
0.57 (d, 3H, J¼6.8 Hz, Me iPr),
0.88 (d, 3H, J¼6.8 Hz, Me iPr), 1.83 (m, 1H, CH iPr), 2.38 (s, 3H, Me p-
Tol), 2.39 (s, 3H, Me p-Tol), 3.36 (td, 1H, J¼9.0, 2.3 Hz, H-3), 3.44 (s,
3H, OMe), 4.02 (dd, 1H, J¼9.3, 2.4 Hz, H-2), 4.66 (d, 1H, J¼9.5 Hz,
NHSO2), 5.50 (d, 1H, J¼8.8 Hz, NHSO2), 7.24 (d, 2H, J¼8.3 Hz, Ar–H),
7.26 (d, 2H, J¼8.5 Hz, Ar–H), 7.66 (d, 2H, J¼8.3 Hz, Ar–H), 7.67 (d, 2H,
4.2.23. (þ)-Methyl [(2S,3R,Ss)-4-methyl-3-(2-methoxynaphthyl-
sulfinylamino)-2-(1-naphthylsulfonylamino)]pentanoate, 7m
and (ꢀ)-methyl [(2R,3S,Ss)-4-methyl-3-(2-methoxynaphthyl-
sulfinylamino)-2-(1-naphthylsulfonylamino)]pentanoate, 7m0
From a 78:28 mixture of 5d:5d0 (67 mg, 0.18 mmol), Et3N
(0.051 mL, 0.37 mmol), and 1-naphthalene sulfonyl chloride
(46 mg, 0.20 mmol), following the general procedure (24 h) and
after chromatographic purification (CH2Cl2 to 20% EtOAc/CH2Cl2),
J¼8.0 Hz, Ar–H).13C NMR (75 MHz)
d
18.6 (Me iPr),19.9 (Me iPr), 21.5
(Me p-Tol), 29.7 (CH iPr), 29.8 (Me p-Tol), 52.8 (OMe), 56.9 (C–N), 61.7
(C–N),127.2 (2C),127.3 (2C),129.6 (2C),129.7 (2C),136.2,137.6,143.5,
143.8, 170.0 (C]O). IR (KBr): 3436, 2956, 2920, 1739, 1628, 1436,
1335, 1262, 1163, 1093, 1017, 802, 667, 551 cmꢀ1. HRMS (ESI) m/z for
C42H56N4NaO12S4 [2MþNa] calcd: 959.2675, found: 959.2665.
4.2.26. (þ)-Methyl [(2S,3R)-4-methyl-2-(1-naphthyl-
7m (75 mg, 73%) and 7m0 (23 mg, 22%) were obtained as yellow
sulfonylamino)-3-(p-tolylsulfonylamino)]pentanoate, 8b
20
oils. Data for 7m: Rf 0.11 (10% EtOAc/CH2Cl2). [
a]
þ112.0 (c 1.29).
From 7i (27 mg, 0.055 mmol) and m-CPBA (16 mg, 0.066 mmol),
following the general procedure (45 min) and after chromato-
graphic purification (CH2Cl2 to 10% EtOAc/CH2Cl2), 8b was obtained
D
1H NMR (300 MHz)-COSY
d
0.90 (d, 3H, J¼6.7 Hz, Me Pr), 1.05 (d,
i
i
i
3H, J¼6.7 Hz, Me Pr), 1.98 (m, 1H, CH Pr), 3.04 (s, 3H, OMe), 3.45
(ddd, 1H, J¼8.7, 5.6, 2.7 Hz, H-3), 4.00 (s, 3H, OMe), 4.20 (dd, 1H,
J¼10.0, 2.8 Hz, H-2), 5.65 (d, 1H, J¼5.6 Hz, NHSO), 6.38 (d, 1H,
J¼10.0 Hz, NHSO2), 7.27 (d, 1H, J¼9.3 Hz, Ar–H), 7.33–7.48 (m, 3H,
Ar–H), 7.51–7.60 (m, 2H, Ar–H), 7.77 (d, 1H, J¼7.6 Hz, Ar–H), 7.85–
7.92 (m, 2H, Ar–H), 8.01 (d, 1H, J¼8.3 Hz, Ar–H), 8.18 (d, 1H, J¼7.3,
1.2 Hz, Ar–H), 8.42 (d, 1H, J¼8.5 Hz, Ar–H), 8.60–8.63 (m, 1H, Ar–H).
as a white solid (22 mg, 79%). Data for 8b: Rf 0.27 (10% EtOAc/
20
CH2Cl2). Mp: 198 ꢁC. [
a
]
þ149.1 (c 0.44). 1H NMR (500 MHz)
d 0.45
D
(d, 3H, J¼6.8 Hz, Me iPr), 0.72 (d, 3H, J¼6.8 Hz, Me iPr), 1.67 (m, 1H,
CH iPr), 2.37 (s, 3H, Me p-Tol), 3.13 (s, 3H, OMe), 3.28 (td, 1H, J¼8.8,
2.4 Hz, H-3), 4.04 (br s, 1H, H-2), 4.92 (d, 1H, J¼9.3 Hz, NHSO2), 5.96
(br s, 1H, NHSO2), 7.22 (d, 2H, J¼8.3 Hz, Ar–H), 7.50 (t, 1H, J¼7.8 Hz,
Ar–H), 7.58 (t, 1H, J¼7.3 Hz, Ar–H), 7.67 (m, 3H, Ar–H), 7.91 (d, 1H,
J¼7.8 Hz, Ar–H), 8.04 (d, 1H, J¼8.3 Hz, Ar–H), 8.21 (d, 1H, J¼7.3 Hz,
Ar–H), 8.68 (d, 1H, J¼8.8 Hz, Ar–H). 13C NMR (125 MHz)-HSQC
13C NMR (75 MHz)-HSQC
d 19.5 (2C), 28.6, 51.9, 57.0, 57.5, 64.5,
113.6, 122.0, 124.0, 124.4, 124.6 (2C), 126.7, 127.9, 128.2, 128.3, 128.6,
128.7, 129.0, 129.2, 130.2, 133.5, 133.9, 134.2, 135.0, 155.1, 170.5
(C]O). IR (film): 3326, 2950, 1741, 1622, 1594, 1508, 1433, 1335,
1273, 1252, 1202, 1164, 1135, 1062, 806, 754 cmꢀ1. HRMS (ESI) m/z
i
i
i
d
18.4 (Me Pr), 19.8 (Me Pr), 21.5 (Me p-Tol), 29.6 (CH Pr), 52.4
(OMe), 57.3, 61.5, 124.1, 124.6, 127.0, 127.2 (2C), 128.3, 128.6, 128.9,
129.6 (2C), 129.7, 134.1, 134.2, 134.6, 137.4, 143.5, 169.8 (C]O). IR
(KBr): 3432, 3266, 2955, 2925, 1719, 1622, 1595, 1506, 1439, 1337,
1321, 1301, 1160, 1067, 952, 806, 773, 665, 591, 574, 545 cmꢀ1. HRMS
(ESI) m/z for C48H56N4NaO12S4 [2MþNa] calcd: 1031.2675, found:
1031.2657. Anal. Calcd for C24H28N2O6S2: C, 57.12; H, 5.59; N, 5.55;
S, 12.71. Found: C, 57.31; H, 5.71; N, 5.35; S, 12.48.
for C28H31N2O6S2 [MþH]þ calcd: 555.1624, found: 555.1656. Data
20
for 7m0: Rf 0.28 (70% EtOAc/hex). [
a]
ꢀ12.9 (c 0.82). 1H NMR
D
(300 MHz)
d
0.82 (d, 3H, J¼6.7 Hz, Me iPr), 0.95 (d, 3H, J¼6.7 Hz, Me
iPr),1.79 (m,1H, CH iPr), 2.84 (s, 3H, OMe), 3.59 (ddd,1H, J¼10.2, 6.0,
4.8 Hz, H-3), 4.15 (dd, 1H, J¼8.6, 4.8 Hz, H-2), 4.25 (s, 3H, OMe), 6.13
(d, 1H, J¼10.2 Hz, NHSO), 6.67 (d, 1H, J¼8.6 Hz, NHSO2), 7.37–7.42
(m, 2H, Ar–H), 7.50–7.60 (m, 3H, Ar–H), 7.69 (m, 1H, Ar–H), 7.81 (d,
1H, J¼8.1 Hz, Ar–H), 7.92 (d, 1H, J¼8.1 Hz, Ar–H), 7.97 (d, 1H,
J¼9.0 Hz, Ar–H), 8.05 (d, 1H, J¼8.2 Hz, Ar–H), 8.25 (dd, 1H, J¼7.3,
1.1 Hz, Ar–H), 8.46 (d, 1H, J¼8.4 Hz, Ar–H), 8.70 (d, 1H, J¼8.8 Hz, Ar–
4.2.27. (þ)-N-[(1S,2R,Ss)-1-(Hydroxymethyl)-3-methyl-2-(p-
tolylsulfinylamino)butyl]-1-naphthylsulfonamide, 9
A round-bottomed flask was charged with anhydrous THF
(2 mL/mmol), LiI (29 mg, 0.215 mmol, 3.0 equiv), and NaBH4 (8 mg,
0.215 mmol, 3.0 equiv). The resulting suspension was cooled to 0 ꢁC
and a solution of 7i (35 mg, 0.072 mmol, 1.0 equiv) in anhydrous
H). 13C NMR (75 MHz)
d 17.4, 19.9, 30.9, 51.8, 57.1, 57.6, 63.9, 113.7,
122.1, 124.0, 124.6, 124.8, 125.3, 126.8, 128.2, 128.4, 128.5, 128.5,
128.7, 128.8, 129.5, 130.6, 133.7, 134.0, 134.3, 135.0, 155.7, 170.4

A. Viso et al. / Tetrahedron 65 (2009) 3757–3766
3765
THF (6 mL/mmol) was added dropwise and the reaction mixture
was stirred at 0 ꢁC (30 min) and then at room temperature moni-
tored by TLC. When the reaction reached completion (2 d) the
mixture was quenched with a 5% NaHCO3 solution (2 mL/mmol)
and diluted with CH2Cl2 (5 mL/mmol). The crude was filtered
through Celite and the residue was washed with CH2Cl2 (3ꢂ8 mL/
mmol). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3ꢂ8 mL/mmol). The combined organic ex-
tracts were washed with a saturated NaCl solution (4 mL/mmol),
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to give a crude product, which was purified by
column chromatography on silica gel (10–40% EtOAc/hex). Com-
mixture was stirred at room temperature for 10 min. Then,
1.2 equiv of Ti(OiPr)4 were added and, after 30 min, 1.0 equiv of
aldehyde. After 24 h, the reaction was quenched at 0 ꢁC with 1 M
aqueous solution of HCl (10 mL/mmol). The layers were separated
and the aqueous phase was extracted with Et2O (3ꢂ10 mL/mmol);
the combined organic phase was washed with saturated solution of
NaCl (10 mL/mmol) and was dried over anhydrous Na2SO4. The
solvent was evaporated and the crude mixture was purified by
chromatography on silica gel using CH2Cl2 as eluent. Enantiomeric
ratios were determined by chiral HPLC. Conditions: Daicel Chiralcel
OD, 95:5 hex/iPrOH, 0.5 mL/min flow rate,
l
¼254 nm. For 1-phenyl-
1-propanol: tR (R): 7.61 min; tR (S): 8.32 min. For 1-(1-naphthyl)-1-
propanol: tR (major): 13.22 min; tR (minor): 21.87 min.
pound 9 was obtained as a white solid (26 mg, 70%). Data for 9: Rf
20
0.22 (50% EtOAc/hex). Mp: 59 ꢁC. [
a]
þ99.3 (c 0.74). 1H NMR
D
(500 MHz)
d
0.27 (d, 3H, J¼6.7 Hz, Me iPr), 0.40 (d, 3H, J¼6.7 Hz, Me
4.4. General procedure for the synthesis of
methoxyphenylacetic esters
iPr), 1.43 (m, 1H, H-3), 2.35 (s, 3H, Me p-Tol), 2.67 (t, 1H, J¼6.4 Hz,
OH), 2.79 (ddd, 1H, J¼9.9, 5.1 Hz, H-2), 3.13 (ddd, 1H, J¼8.6, 5.1 Hz,
H-1), 3.31 (m, 2H, CH2), 4.27 (d, 1H, J¼9.9 Hz, NHSO), 7.16 (d, 1H,
J¼8.6 Hz, NHSO2), 7.23 (d, 2H, J¼8.0 Hz, Ar–H), 7.45 (d, 2H, J¼8.3 Hz,
Ar–H), 7.52 (t, 1H, J¼7.9 Hz, Ar–H), 7.62 (td, 1H, J¼7.0, 1.0 Hz, Ar–H),
7.74 (ddd, 1H, J¼8.5, 7.0, 1.3 Hz, Ar–H), 7.94 (d, 1H, J¼8.0 Hz, Ar–H),
To a cold solution (0 ꢁC) of 1.0 equiv of alcohol in CH2Cl2 (10 mL/
mmol) were added 1.05 equiv of (þ)-MPA, 1.0 equiv of DCC, and
0.05 equiv of DMAP. The mixture was allowed to reach room tem-
perature and stirred until completion, monitored by TLC. The sol-
vent was evaporated and the crude was filtered through a plug of
silica gel.
8.06 (d, 1H, J¼8.3 Hz, Ar–H), 8.29 (dd, 1H, J¼7.4, 1.0 Hz, Ar–H), 8.83
(d, 1H, J¼8.6 Hz, Ar–H). 13C NMR (125 MHz)-HSQC
d
16.6 (Me Pr),
i
i
i
19.9 (Me Pr), 21.4 (Me p-Tol), 29.7 (CH Pr), 55.6 (C-1), 56.6 (C-2),
63.9 (CH2), 124.2, 124.6, 126.1 (2C), 127.1, 127.9, 128.7, 129.2, 129.4
(2C), 130.0, 134.2, 134.5, 134.8, 138.8, 142.0. IR (KBr): 3435, 2925,
2852, 1740, 1628, 1594, 1508, 1461, 1330, 1200, 1162, 1134, 1085,
4.4.1. (S)-[1-(RS)-(4-Chlorophenyl)propyl]methoxy(phenyl)acetate
(Table 2, entry 1)
1H NMR (300 MHz)
d
0.62 (t, 3H, J¼7.3 Hz, Me), 0.82 (t, 3H,
1040, 985, 806, 772, 677, 592 cmꢀ1
. HRMS (ESI) m/z for
J¼7.3 Hz, Me0), 1.68–1.86 (m, 4H, CH2/CH2 ), 3.36 (s, 3H, OMe), 3.38
(s, 3H, OMe0), 4.75 (s, 1H, CHOMe), 4.78 (s, 1H, CHOMe0), 5.63 (t, 2H,
J¼6.8 Hz, CH–OCO/CH0–OCO), 6.89–7.44 (m, 18H, Ar–H/Ar–H0).
0
C23H29N2O4S2 [MþH]þ calcd: 461.1569, found: 461.1568. Anal. Calcd
for C23H28N2O4S2: C, 59.97; H, 6.13; N, 6.08; S, 13.92. Found: C,
60.10; H, 5.96; N, 6.31; S, 13.81.
4.4.2. (S)-[1-(RS)-(3,4-Dimethoxyphenyl)propyl]methoxy(phenyl)-
acetate (Table 2, entry 2)
4.2.28. (þ)-N-{(1S,2R,Ss)-1-[(tert-Butyldimethylsilyloxymethyl)-3-
methyl-2-(p-tolylsulfinylamino)butyl]}-1-naphthylsulfonamide, 10
To a solution of 9 (8 mg, 0.016 mmol, 1.0 equiv) in CH2Cl2
(5 mL/mmol), TBSCl (6 mg, 0.032 mmol, 2.0 equiv), imidazole
(3 mg, 0.032 mmol, 2.0 equiv), and 0.05 equiv of DMAP were
added. The reaction was stirred at room temperature until the
disappearance of 9 by TLC. It was quenched with H2O (10 mL/
mmol) and the layers were separated. It was extracted with
CH2Cl2 (2ꢂ10 mL) and the combined organic phases were washed
with saturated solution of NaCl, dried over anhydrous Na2SO4, and
the solvent was evaporated. Purification by column chromato-
1H NMR (300 MHz)
d
0.64 (t, 3H, J¼7.3 Hz, Me), 0.84 (t, 3H,
J¼7.5 Hz, Me0), 1.04–1.36 (m, 2H, CH2), 1.63–1.93 (m, 2H, CH2 ), 3.36
(s, 6H, OMe/OMe0), 3.80 (s, 6H, OMe/OMe0), 3.84 (s, 6H, OMe/OMe0),
4.76 (d, 2H, J¼6.8 Hz, CHOMe/CHOMe0), 5.62 (t, 2H, J¼6.0 Hz, CH–
OCO/CH0–OCO), 6.74–6.86 (m, 6H, Ar–H/Ar–H0), 7.26–7.43 (m, 10H,
Ar–H/Ar–H0).
0
Acknowledgements
This research was supported by DGI MEC (CTQ2006-04522/
BQU) and CM (S-SAL-0249-2006). We also thank CM for the addi-
tional support to M.U.
graphy (10–30% EtOAc/hex) yielded 10 as a colorless oil (8 mg,
20
87%). Data for 10: Rf 0.29 (30% EtOAc/hex). [
NMR (300 MHz)
0.30 (d, 3H, J¼6.8 Hz, Me Pr), 0.57 (d, 3H, J¼6.7 Hz, Me Pr), 0.67
a
]
þ61.5 (c 0.39). 1H
D
d
ꢀ0.24 (s, 3H, Me TBS), ꢀ0.22 (s, 3H, Me TBS),
i
i
t
(s, 9H, Bu TBS), 1.57 (m, 1H, H-3), 2.36 (s, 3H, Me p-Tol), 3.04 (dt,
References and notes
1H, J¼8.5, 5.4 Hz, H-2), 3.21 (m, 1H, H-1), 3.34 (m, 2H, CH2), 4.08
(d, 1H, J¼8.8 Hz, NHSO), 6.95 (d, 1H, J¼9.0 Hz, NHSO2), 7.23 (d, 2H,
J¼7.8 Hz, Ar–H), 7.49 (m, 3H, Ar–H), 7.60 (ddd, 1H, J¼8.0, 6.8,
1.1 Hz, Ar–H), 7.73 (ddd, 1H, J¼8.5, 6.8, 1.4 Hz, Ar–H), 7.93 (d, 1H,
J¼8.0 Hz, Ar–H), 8.05 (d, 1H, J¼8.3 Hz, Ar–H), 8.29 (dd, 1H, J¼7.3,
1.2 Hz, Ar–H), 8.81 (dd, 1H, J¼8.8, 0.7 Hz, Ar–H). 13C NMR
1. (a) Mellah, M.; Voituriez, A.; Schulz, E. Chem. Rev. 2007, 107, 5133–5209; (b)
Ferna´ndez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651–3705; (c) Pellissier, H. Tet-
rahedron 2007, 63, 1297–1330.
´
2. (a) Langner, M.; Remy, P.; Bolm, C. Chem.dEur. J. 2005, 11, 6254–6265; (b)
Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 482–487; (c) Bolm, C.; Verrucci, M.;
Simic, O.; Hackenberger, C. P. R. Adv. Synth. Catal. 2005, 347, 1696–1700; (d)
Mariz, R.; Luan, X.; Gatti, M.; Linden, A.; Dorta, R. J. Am. Chem. Soc. 2008, 130,
2172–2173; (e) Hiroi, K.; Watanabe, K.; Abe, I.; Koseki, M. Tetrahedron Lett. 2001,
42, 7617–7619; (f) Hiroi, K.; Izawa, I.; Takizawa, T.; Kawai, K. Tetrahedron 2004,
60, 2155–2162; (g) Priego, J.; Garcı´a Manchen˜o, O.; Cabrera, S.; Carretero, J. C.
J. Org. Chem. 2002, 67, 1346–1353; (h) Grach, G.; Reboul, V.; Metzner, P. Tetra-
hedron: Asymmetry 2008, 19, 1744–1750; (i) Carren˜o, M. C.; Garcı´a Ruano, J. L.;
Maestro, M. C.; Martı´n Cabrejas, L. M. Tetrahedron: Asymmetry 1993, 4, 727–734.
3. Some leading references: (a) Davis, F. A. J. Org. Chem. 2006, 71, 8993–9003; (b)
Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc. Chem. Res. 2008, 41, 831–
840; (c) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984–995.
4. (a) Zani, L.; Eriksson, L.; Adolfsson, H. Eur. J. Org. Chem. 2008, 4655–4664; (b)
Owens, T. D.; Souers, A. J.; Ellman, J. A. J. Org. Chem. 2003, 68, 3–10; (c) Schenkel,
L. B.; Ellman, J. A. Org. Lett. 2003, 5, 545–548; (d) Huang, Z.; Lai, H.; Qin, Y. J. Org.
Chem. 2007, 72, 1373–1378; (e) Tan, K. L.; Jacobsen, E. N. Angew. Chem., Int. Ed.
(75 MHz)
d
ꢀ5.8, 1.0, 16.6, 17.9, 20.0, 21.4, 25.6 (3C), 29.0, 54.5,
58.3, 63.9, 124.1, 125.1, 126.1 (2C), 127.0, 128.0, 128.5, 128.9, 129.3
(3C), 134.1, 134.2, 135.9, 139.9, 141.6. IR (film): 3287, 3056, 2955,
2927, 2854, 1506, 1463, 1387, 1328, 1258, 1213, 1162, 1106, 1044,
1015, 935, 837, 805, 771, 675 cmꢀ1. MS (ES): 1171 [2MþNa]þ
(100%), 597 [MþNa]þ, 575 [Mþ1]þ.
4.3. General procedure for the addition of diethylzinc
to aldehydes
To a solution of 0.05 equiv of chiral ligand in CH2Cl2 (50 mL/
mmol ligand) was added 1.5 equiv of Et2Zn 1.0 M in hexane and the
`
´
2007, 46, 1315–1317; (f) Sola, J.; Reves, M.; Riera, A.; Verdager, X. Angew. Chem.,
Int. Ed. 2007, 46, 5020–5023; (g) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am.

3766
A. Viso et al. / Tetrahedron 65 (2009) 3757–3766
Chem. Soc. 2007, 129, 15110–15111; (h) Pei, D.; Zhang, Y.; Wei, S.; Wang, M.; Sun,
J. Adv. Synth. Catal. 2008, 350, 619–623.
11. We have also examined the 1H NMR (C6D6) spectrum of an equimolecular
mixture of Et2Zn/7a finding splitting of signals (Ar–H, NHSO2, H-2) and modi-
fication of the coupling pattern for (H-2: 4.31 ppm, from dd to br s; NHSO: 4.
07 ppm, from m to d). However, an unambiguous disappearance of NHSO2
could not be observed.
12. Qiu, J.; Guo, C.; Zhang, X. J. Org. Chem. 1997, 62, 2665–2668.
13. Rajaram, S.; Sigman, M. S. Org. Lett. 2005, 7, 5473–5475.
14. An increase of the amount of ligand to 0.1 equiv did not improve the ee.
Changing CH2Cl2 to Et2O or toluene affected negatively catalytic process: er
(Et2O): 81:19, er (toluene): 80:20.
5. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, NY,
1994; Chapter 5; (b) Pu, L.; Yu, H. Chem. Rev. 2001, 101, 757–824; Recent ref-
erences: (c) de las Casas Engel, T.; Lora Maroto, B.; Garcı´a Martı´nez, A.; de la
Moya Cerero, S. Tetrahedron: Asymmetry 2008, 19, 2003–2006; (d) Martins, J. E.
D.; Wills, M. Tetrahedron: Asymmetry 2008, 19, 1250–1255.
6. (a) Paull, D. H.; Abraham, C. J.; Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc.
Chem. Res. 2008, 41, 655–663; (b) Ma, J.-A.; Cahard, D. Angew. Chem., Int. Ed.
2004, 43, 4566–4583.
7. (a) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S. Tetrahe-
dron 1992, 48, 5691–5700; For a recent review of the relevance of titanium in
asymmetric reactions: (b) Ramo´n, D. J.; Yus, M. Chem. Rev. 2006, 106, 2126–
2208; For recent references: (c) Satyanarayana, T.; Ferber, B.; Kagan, H. B. Org.
Lett. 2007, 9, 251–253; (d) Bisai, A.; Singh, P. K.; Singh, V. K. Tetrahedron 2007,
63, 598–601.
15. Mao, J.; Wan, B.; Zhang, Z.; Wang, R.; Wu, F.; Lu, S. J. Mol. Catal. A: Chem. 2004,
225, 33–37.
16. In some examples, the 2-methoxy-1-naphthyl sulfinyl group has turned su-
perior in asymmetric catalysis: see Ref. 2f.
17. We took advantage of the unexpectedly low dr for this example.
18. (a) Pritchett, S.; Woodmansee, D.; Gantzel, P.; Walsh, P. J. J. Am. Chem. Soc. 1998,
120, 6423–6424; (b) Wu, K.-H.; Gau, H.-M. Organometallics 2004, 23, 580–588;
(c) Walsh, P. J. Acc. Chem. Res. 2003, 36, 739–749; (d) Pescitelli, G.; Di Bari, L.;
Salvadori, P. Organometallics 2004, 23, 4223–4229.
8. (a) Viso, A.; Ferna´ndez de la Pradilla, R.; Garcı´a, A.; Flores, A.; Tortosa, M.; Lo´pez-
Rodrı´guez, M. L. J. Org. Chem. 2006, 71, 1442–1448; (b) Viso, A.; Ferna´ndez de la
´
Pradilla, R.; Garcıa, A.; Guerrero-Strachan, C.; Alonso, M.; Tortosa, M.; Flores, A.;
Martı´nez-Ripoll, M.; Fonseca, I.; Andre´, I.; Rodrı´guez, A. Chem.dEur. J. 2003, 9,
19. Di Mauro, E. F.; Kozlowski, M. C. Org. Lett. 2002, 4, 3781–3784.
20. (a) Corey, E. J.; Lee, T. W. Chem. Commun. 2001, 1321–1329; (b) Forrat, V. J.;
Prieto, O.; Ramo´n, D. J.; Yus, M. Chem.dEur. J. 2006, 12, 4431–4445.
21. (a) Davis, F. A.; Mohanty, P. K. J. Org. Chem. 2002, 67, 1290–1296; (b) Davis, F. A.;
Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.; Zhang, H. J. Org. Chem. 1999,
64, 1403–1406; (c) Davis, F. A.; Song, M.; Augustine, A. J. Org. Chem. 2006, 71,
2779–2786.
´
´
´
2867–2876; (c) Viso, A.; Fernandez de la Pradilla, R.; Lopez-Rodrıguez, M. L.;
Garcı´a, A.; Flores, A.; Alonso, M. J. Org. Chem. 2004, 69, 1542–1547; (d) Viso, A.;
Ferna´ndez de la Pradilla, R.; Uren˜a, M.; Colomer, I. Org. Lett. 2008, 10, 4775–4778.
9. Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49–69.
10. (a) Pritchett, S.; Woodmansee, H.; Davis, T. J.; Walsh, P. J. Tetrahedron Lett. 1998,
39, 5941–5942; (b) Denmark, S. E.; O’Connor, S. P.; Wilson, S. R. Angew. Chem.,
Int. Ed. 1998, 37, 1149–1151.
22. Ramachandar, T.; Wu, Y.; Zhang, J.; Davis, F. A. Org. Synth. 2006, 83, 131–140.