anti-Selective direct asymmetric Mannich reactions catalyzed by chiral pyrrolidine-based amino sulfonamides

Article abstract of DOI:10.1016/j.tet.2007.11.086

The novel pyrrolidine-based amino sulfonamides (R,R)-2, (S)-3, and (S)-4 were designed and synthesized as organocatalysts and successfully applied for the anti-selective direct asymmetric Mannich reaction.

Full text of DOI:10.1016/j.tet.2007.11.086

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1197e1203
www.elsevier.com/locate/tet
anti-Selective direct asymmetric Mannich reactions catalyzed by chiral
pyrrolidine-based amino sulfonamides
*
Taichi Kano, Yoshio Hato, Akihiro Yamamoto, Keiji Maruoka
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Received 14 September 2007; received in revised form 26 November 2007; accepted 26 November 2007
Abstract
The novel pyrrolidine-based amino sulfonamides (R,R)-2, (S)-3, and (S)-4 were designed and synthesized as organocatalysts and successfully
applied for the anti-selective direct asymmetric Mannich reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Mannich reaction; Organocatalyst; Asymmetric synthesis; Enamine catalysis
1. Introduction
of new pyrrolidine-based amino sulfonamides (R,R)-2, (S)-3,
and (S)-4, and their application to the anti-selective direct
asymmetric Mannich reaction.
Development of highly stereoselective asymmetric reac-
tions using organocatalysts has become a research area of
great importance, and a number of new organocatalysts have
been devised for this purpose.1 Accordingly, we already
designed several binaphthyl-based secondary amine catalysts
for aldol and other reactions involving enamine intermediates
in their transition state.2 Among them, chiral binaphthyl-based
amino sulfonamide (S)-1 showed excellent reactivity, dia-
stereo- and enantioselectivities in the anti-selective direct
asymmetric Mannich reaction between aldehydes and a-imino
esters.2b,3,4 However, sterically hindered aldehydes gave the
corresponding Mannich products in only moderate yields,
probably due to the low nucleophilicity of (S)-1.2b In this con-
text, we have designed and synthesized a new chiral amino
sulfonamide catalyst possessing a highly nucleophilic pyrroli-
dine core and two acidic triflamide groups from L-tartaric acid
as an inexpensive chiral starting material.3f We are also inter-
ested in the design of chiral pyrrolidine-type catalysts possess-
ing a triflamide or a more acidic nonafluorobutylsulfonamido
(nonaflamide, NfeNHe) group. We here report the synthesis
TfHN
NHTf
RHN
NHTf
N
H
N
H
N
H
(S)-1
(R,R)-2
(S)-3 (R = Tf)
(S)-4 (R = Nf)
2. Results and discussion
Our catalyst design is based on the proposal of transition-
state structures in the direct asymmetric Mannich reaction as
shown in Scheme 1. When L-proline is used as a catalyst,
the a-carboxyl group of L-proline controls the orientation of
the enamine moiety by the steric repulsion and the coordina-
tion pattern of the a-imino ester 5 by the acidebase interac-
tion, respectively. Consequently, the Si-face of the a-imino
ester approaches the Re-face of the enamine to furnish the
syn-product syn-6 (Scheme 1).5 On the other hand, the reaction
using (R,R)-2, (S)-3 or (S)-4 would be expected to give the
anti-product anti-6 as a result of the opposite facial orientation
of the a-imino ester 5.3c,3e In addition, the sterically less
* Corresponding author. Tel./fax: þ81 75 753 4041.
E-mail address: maruoka@kuchem.kyoto-u.ac.jp (K. Maruoka).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.086

1198
T. Kano et al. / Tetrahedron 64 (2008) 1197e1203
PMP
O
O
H
N
O
O
HN
O
N
N
PMP
H
L-proline
O
N
OH
OH
H
H
CO2Et
H
H
H
R'
CO2Et
R'
N
R'
PMP
H
R'
syn-6
O
N
H
CO2Et
RN
R''
RHN
R''
RHN
R''
H
R'
5
PMP
HN
H
PMP
N
N
CO2Et
N
(R,R)-2
or
(S)-3~4
R'
H
H
EtO2C
H
anti-6
R'
R'
R'
Scheme 1.
hindered (R,R)-2, and far less hindered (S)-3 and (S)-4 would
be capable of reacting with even bulky aldehydes and ketones,
which were found to be unsuitable substrates for the less
nucleophilic (S)-1.
asymmetric Mannich reaction without treatment with an ion
exchange resin.
H2N
RHN
The synthesis of the requisite chiral pyrrolidine (R,R)-2
began with the conversion of L-tartaric acid to the correspond-
ing imide (R,R)-7 by the direct condensation with benzylamine
(Scheme 2). Reduction of (R,R)-7 with LiAlH4 and subsequent
mesylation of both hydroxyl groups afforded amino dime-
sylate (S,S)-8 (95% yield in two steps), which was then con-
verted with NaN3 into diazide (R,R)-9 in 56% yield. The
resulting azide groups were reduced in the presence of Pd/C
under H2 atmosphere to give triamine (R,R)-10 in 99% yield.
Treatment of (R,R)-10 with Tf2O and i-Pr2NEt gave bis(trifl-
amide) (R,R)-11 in 76% yield. Finally, reductive cleavage of
the benzyl group provided the pyrrolidine-based amino sulfon-
amide (R,R)-2 in 93% yield, which was purified by an ion
exchange resin.
c
a or b
(S)-3 or (S)-4
N
Bn
(S)-12
N
Bn
(S)-13 (R = Tf)
(S)-14 (R = Nf)
Scheme 3. Reagents and conditions: (a) Tf2O, i-Pr2NEt, CH2Cl2, 0 ꢀC, 59%;
(b) Nf2O, i-Pr2NEt, CH2Cl2, ꢁ78 ꢀC to rt 89%; (c) H2, Pd/C, EtOH, rt, 99%
for (S)-3, 60% for (S)-4.
The new catalysts (R,R)-2, (S)-3, and (S)-4 thus obtained,
were utilized in the direct asymmetric Mannich reaction of
Table 1
anti-Selective Mannich reactions of aldehydesa
PMP
PMP
O
N
O
HN
10 mol% cat
THF
+
S
H
H
CO2Et
H
R
CO2Et
HO
OH
MsO
OMs
5
R'
R'
HO
OH
b, c
a
d
anti-6
O
O
N
Bn
N
Bn
HO2C
CO2H
Entry R0
Catalyst Conditions (ꢀC, h) % Yieldb (anti/syn)c % eed
L-tartaric acid
(R,R)-7
(S,S)-8
1
Me
(R,R)-2
(S)-3
ꢁ20, 9
ꢁ20, 9
ꢁ20, 9
ꢁ20, 2
ꢁ20, 3
ꢁ20, 3
ꢁ20, 1
ꢁ20, 4
ꢁ20, 4
ꢁ20, 24
ꢁ20, 46
ꢁ20, 30
64 (14:1)
50 (14:1)
65 (14:1)
82 (16:1)
75 (12:1)
76 (14:1)
93 (11:1)
88 (10:1)
88 (8:1)
98e
99e
99e
94
98
98
95
98
98
90
99
98
2
Me
Me
Et
N3 N3
H2N
NH2
f
TfHN
NHTf
3
(S)-4
(R,R)-2
(S)-3
e
g
4
(R,R)-2
N
Bn
(R,R)-9
N
N
5
Et
Bn
(R,R)-10
Bn
(R,R)-11
6
Et
(S)-4
7
i-Pr (R,R)-2
i-Pr (S)-3
i-Pr (S)-4
t-Bu (R,R)-2
t-Bu (S)-3
t-Bu (S)-4
8
Scheme 2. Reagents and conditions: (a) benzylamine, o-xylene, reflux, 99%;
(b) LiAlH4, THF, reflux; (c) MsCl, Et3N, CH2Cl2, rt, 95% in two steps; (d)
NaN3, DMF, 100 ꢀC, 56%; (e) H2, Pd/C, EtOH, rt, 99%; (f) Tf2O, i-Pr2NEt,
CH2Cl2, ꢁ78 ꢀC, 76%; (g) H2, Pd/C, AcOH, rt, 93%.
9
10
11
12
a
88 (18:1)
92 (20:1)
99 (>20:1)
The reaction of an aldehyde (3 equiv) and a-imino ester 5 was carried out
The chiral pyrrolidines (S)-3 and (S)-4 were prepared in a
two-step sequence from commercially available (S)-1-benz-
yl-3-aminopyrrolidine ((S)-12) as shown in Scheme 3. Treat-
ment of (S)-12 with the corresponding sulfonic anhydride
gave triflamide (S)-13 and nonaflamide (S)-14 in moderate
yields, respectively. Hydrogenative debenzylation of (S)-13
and (S)-14 proceeded smoothly in ethanol to provide the pyr-
rolidine-based amino sulfonamide (S)-3 and (S)-4, respec-
tively, which could be used as catalyst in the direct
in THF in the presence of a catalyst (10 mol %) at ꢁ20 ꢀC.
b
Isolated yield.
Determined by 1H NMR.
c
d
The enantiomeric excess of the anti-isomer anti-6 was determined by
HPLC analysis using chiral column (Chiralpak AS-H). The absolute configu-
ration was determined by comparison of the HPLC retention times of 6 with
the reported data.2b,3a
e
The enantiomeric excess and the absolute configuration of the anti-isomer
anti-6 were determined by HPLC analysis using chiral column (Chiralpak
AD-H) after reduction.2b

T. Kano et al. / Tetrahedron 64 (2008) 1197e1203
1199
NfN
H
NfN
aldehydes and results are summarized in Table 1. In each case,
the Mannich reaction between an aldehyde and a-imino ester 5
with 10 mol % of a catalyst proceeded in THF at ꢁ20 ꢀC to
give the corresponding anti-product anti-6 predominantly
with excellent enantioselectivity. The reaction of less hindered
propanal gave moderate yields of anti-6 (R0¼Me) due to the
competing self-aldol reaction (entries 1e3), while the use of
a sterically congested 3,3-dimethylbutanal resulted in the re-
tardation of the reaction rate, the corresponding anti-product
anti-6 (R0¼t-Bu) was obtained in good to excellent yield and
selectivity (entries 10e12). In general, the reaction with
non-C2-symmetric catalysts (S)-3 and (S)-4 showed higher
enantioselectivity than with the C2-symmetric catalyst (R,R)-2.
We next turned our attention to the reaction of ketones with
a-imino ester 5 (Table 2). With each catalyst, reactions of six-
membered cyclic ketones proceeded smoothly to give a satisfac-
tory result in terms of both reactivity and selectivity even at
lower catalyst loadings (entries 1e7). In the case of the less
reactive acyclic ketone 3-pentanone, moderate yields of the
desired anti-product anti-15 (R¼Et, R0¼Me) were obtained
with longer reaction time (entries 8e10). When the reaction
with (S)-4 was carried out in acetonitrile instead of THF, the
yield was improved without loss of stereoselectivity (entry
11). Although the use of 4-heptanone resulted in a significant
H
10 mol%
O
PMP
N
N
PMP
H
(S)-4
N
N
+
5
THF, rt
EtO2C
H
EtO2C
67%
anti/syn = 5.2:1
PMP
PMP
O
HN
O
HN
S
R
+
R
CO2Et
R CO2Et
(R,S)-15a (anti)
(R,R)-15a (syn)
98% ee
98% ee
Scheme 4.
decrease in yield and diastereoselectivity, the anti-isomer was
still dominant (entry 12). The reaction with the unsymmetrical
ketone 2-butanone gave the branched anti-isomer anti-15
(R¼R0¼Me) predominantly with good enantioselectivity
(entry 13). Again, non-C2-symmetric catalysts (S)-3 and (S)-4
exhibited higher levels of enantioselectivity than the C2-sym-
metric analogue (R,R)-2, as observed in the case of aldehydes.
In the reaction of 3-pentanone with a-imino ester 5 catalyzed
by (S)-4, both anti- and syn-product 15a were found to be ob-
tained with excellent enantioselectivity (Scheme 4). Based on
the observed stereochemistry in the reaction, transition state
models can be proposed as shown in Scheme 4.3c,3e In each
case the Re-face of the a-imino ester 5 approaches the enamine
intermediate as directed by the acidic proton of nonaflamide
group, and consequently, the CeC bond forming reaction takes
place on both the Re- and Si-faces of the enamine in highly enan-
tioselective fashion, giving (R,S)-15a (anti) and (R,R)-15a
(syn), respectively. When the diastereomixtures of 15a (anti/
syn¼7.8:1 and <1:20) were treated with 10 mol % of (S)-4 in
THF, respectively, no significant change in the diastereomeric
ratios was observed in both cases (Scheme 5). These results in-
dicated that the anti-selectivity in the present reaction originates
not from isomerization between anti-15a and syn-15a under the
reaction conditions but from the CeC bond forming step. In
addition, since the diastereomixture of 15a was quantitatively
recovered from the mixture of 15a, cyclohexanone, and
10 mol % of (S)-4 under the reaction conditions, the possibility
of the retro-Mannich reaction could be ruled out (Scheme 6).
Table 2
anti-Selective Mannich reactions of ketonesa
PMP
PMP
O
N
O
HN
10 mol% cat
THF
+
R
H
CO2Et
R
CO2Et
5
R'
R'
anti-15
Entry
Substrate
Catalyst
Conditions
(ꢀC, h)
% Yieldb
(anti/syn)c
% eed
O
1
(R,R)-2
rt, 1
rt, 4
rt, 35
rt, 2
rt, 2
rt, 2
rt, 6
99 (>20:1)
95 (>20:1)
98 (>20:1)
99 (>20:1)
98 (>20:1)
99 (16:1)
95
95
93
99
99
94
97
2e
3f
4
X
(S)-3
(S)-4
(S)-4
(S)-4
X = CH2
5
6
X¼O
7
X¼S
3-Pentanone
99 (>20:1)
8
(R,R)-2
(S)-3
rt, 70
rt, 90
rt, 43
rt, 24
rt, 168
rt, 12
56 (4.8:1)
55 (4.5:1)
67 (5.2:1)
82 (5.8:1)
22 (1.6:1)
70i (4.5:1)
92
98
9
10
11g
12
13
a
(S)-4
98
98
90, 99h
90
4-Heptanone
2-Butanone
(S)-4
(S)-4
PMP
PMP
O
HN
O HN
10 mol% (S)-4
THF, rt, 40 h
The reaction of a ketone (excess) and a-imino ester 5 was carried out in
CO2Et
CO2Et
THF in the presence of a catalyst (10 mol %) at room temperature.
b
Isolated yield.
Determined by 1H NMR.
15a
15a
c
(anti/syn = 7.8:1)
(anti/syn = 7.9:1)
d
The enantiomeric excess of the anti-isomer anti-15 was determined by
HPLC analysis using chiral column (Chiralpak AS and AS-H). The absolute
configuration was determined by comparison of the HPLC retention times
of anti-15 with the reported data.3e
PMP
PMP
O
HN
O
HN
10 mol% (S)-4
e
CO2Et
CO2Et
THF, rt, 40 h
Use of 2 mol % of (R,R)-2.
Use of 0.5 mol % of (R,R)-2.
Acetonitrile was used as a solvent.
f
15a
15a
(anti/syn = <1:20)
g
(anti/syn = <1:20)
h
The enantiomeric excess of the syn-isomer.
Containing 14% of regioisomer.
i
Scheme 5.

1200
T. Kano et al. / Tetrahedron 64 (2008) 1197e1203
procedure.6 The following compounds are all known:
PMP
PMP
10 mol%
O
O
HN
O
HN
(S)-4
(3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione ((R,R)-
7),7,8 (3S,4S)-1-benzyl-3,4-bis(methylsulfoxy)pyrrolidine ((S,S)-
8),9 (3R,4R)-3,4-diazido-1-benzylpyrrolidine ((R,R)-9),7 (3R,
4R)-3,4-diamino1-benzylpyrrolidine ((R,R)-10).7 (S)-1-Ben-
zyl-3-aminopyrrolidine ((S)-12) is commercially available
from Aldrich, TCI, and several other companies. Other simple
chemicals were purchased and used as such.
+
CO2Et
CO2Et
THF, rt
96 h
15a
15a
(anti/syn = 5.8:1)
(anti/syn = 5.8:1)
>99%
PMP
O
HN
CO2Et
0%
4.2. Synthesis and characterization of chiral amino
sulfonamide (R,R)-2
Scheme 6.
4.2.1. (3R,4R)-1-Benzyl-3,4-dihydroxypyrrolidine-2,5-dione
(R,R)-7
3. Conclusion
The title compound was synthesized according to the liter-
ature procedure.7
In summary, we have synthesized the pyrrolidine-based
amino sulfonamide (R,R)-2 from inexpensive and readily
available L-tartaric acid, and have shown the efficiency of
(R,R)-2 for the anti-selective direct asymmetric Mannich
reaction of even sterically hindered aldehydes and ketones.
Furthermore, the newly designed pyrrolidine-based amino sul-
fonamides (S)-3 and (S)-4 were also found to be effective for
the anti-selective direct asymmetric Mannich reaction.
4.2.2. (3S,4S)-1-Benzyl-3,4-bis(methylsulfoxy)pyrrolidine
(S,S)-8
To a solution of (3R,4R)-1-benzyl-3,4-dihydroxypyrroli-
dine-2,5-dione (R,R)-7 (1.11 g, 5 mmol) in THF (50 mL)
was added LiAlH4 (569 mg, 15 mmol) at 0 ꢀC. The reaction
mixture was stirred under reflux for 12 h. The reaction was
quenched by the sequential treatment with H2O (0.57 mL),
15%NaOH (0.57 mL), and H2O (1.7 mL). To the mixture
was then added ethyl acetate (100 mL) and stirred under reflux
for 4 h. The reaction mixture was filtered through a pad of
Celite and the filtrate was concentrated to give a crude
(3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine, which was used
for the next step without further purification.
To a stirred solution of (3S,4S)-1-benzyl-3,4-dihydroxypyr-
rolidine (1.47 g, 7.6 mmol) in CH2Cl2 (38 mL) was added tri-
ethylamine (2.54 mL, 18.2 mmol) and methanesulfonic chloride
(1.41 mL, 18.2 mmol) at 0 ꢀC. The reaction mixture was stirred
at room temperature for 6 h. The mixture was then quenched
with saturated NaHCO3 and extracted with CH2Cl2. The com-
bined organic layers were dried over Na2SO4 and concentrated.
The residue was purified by flash column chromatography on
silica gel (hexane/ethyl acetate¼2:1) to afford (S,S)-8 (2.65 g,
7.6 mmol, 95% yield over two steps).
4. Experimental
4.1. General information
Infrared (IR) spectra were recorded on a Shimadzu IRPres-
tige-21 spectrometer. 1H NMR spectra were measured on
a JEOL JNM-FX400 (400 MHz) spectrometer. Chemical shifts
were reported in parts per million from tetramethylsilane as an
internal standard. Data were reported as follows: chemical
shift, integration, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad, and app¼apparent), cou-
pling constants (Hz), and assignment. 13C NMR spectra
were recorded on a JEOL JNM-FX400 (100 MHz) spectro-
meter with complete proton decoupling. Chemical shifts were
reported in parts per million from the residual solvent as an
internal standard. High performance liquid chromatography
(HPLC) was performed on Shimadzu 10A instruments using
a Daicel CHIRALPAK AS-H and AD-H, 4.6 mmꢂ25 cm col-
umn. The high-resolution mass spectra (HRMS) were per-
formed on a Bruker microTOF. Optical rotations were
measured on a JASCO DIP-1000 digital polarimeter. For
thin layer chromatography (TLC) analysis throughout this
4.2.3. (3R,4R)-3,4-Diazido-1-benzylpyrrolidine (R,R)-9
To a stirred solution of (S,S)-8 (3.56 g, 10.2 mmol) in DMF
(51 mL) was added sodium azide (1.99 g, 30.6 mmol) at
100 ꢀC. The reaction mixture was stirred at 100 ꢀC overnight.
The mixture was then poured into H2O and extracted with
ethyl acetate. The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated. The residue
was purified by flash column chromatography on silica gel
(hexane/ethyl acetate¼40:1) to afford (R,R)-9 (1.39 mg,
5.7 mmol, 56% yield).
work, Merck precoated TLC plates (silica gel 60 GF254
,
0.25 mm) were used. The products were purified by flash col-
umn chromatography on silica gel 60 (Merck 1.09386.9025,
230e400 mesh). In experiments requiring dry solvents, tetra-
hydrofuran (THF) was purchased from Kanto Chemical Co.
Inc. as ‘dehydrated’. Acetonitrile was dried over anhydrous
˚
K2CO3 for 24 h, and dried over 3 A molecular sieves for
24 h, and then distilled. Aldehydes were distilled and stored
under argon atmosphere at ꢁ17 ꢀC. Ethyl (4-methoxyphenyl-
imino)acetate 5 was synthesized according to the literature
4.2.4. (3R,4R)-3,4-Diamino-1-benzylpyrrolidine (R,R)-10
The title compound was synthesized according to the litera-
ture procedure.7

T. Kano et al. / Tetrahedron 64 (2008) 1197e1203
1201
4.2.5. (3R,4R)-1-Benzyl-3,4-bis(trifluoromethylsulfonamido)-
pyrrolidine (R,R)-11
BnNCHHCH2), 2.57 (1H, dd, J¼10.2, 5.6 Hz, BnNCHHCH),
2.32e2.23 (1H, m, BnNCH2CHH), 1.82e1.74 (1H, m,
BnNCH2CHH) ppm; 13C NMR (100 MHz, CD3OD) d 137.8,
130.4, 129.6, 128.9, 121.8 (q, JCeF¼322 Hz), 61.6, 60.8,
54.8, 53.5, 33.4 ppm; IR (neat) 2361, 1647, 1274, 1192,
1176 cmꢁ1; HRMS (ESI-TOF) calcd for C12H16F3N2O2S:
309.0879 ([MþH]þ), found: 309.0877 ([MþH]þ).
To a stirred solution of triamine (R,R)-10 (191 mg,
1.0 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropylethyl-
amine (171 mL, 1.0 mmol) and trifluoromethanesulfonic anhy-
dride (337 mL, 2.0 mmol) at ꢁ78 ꢀC. The reaction mixture was
stirred at ꢁ78 ꢀC for 1 h. The reaction mixture was charged on
silica gel directly and purified by flash column chromatogra-
phy on silica gel (CH2Cl2/ethyl acetate¼2:1) to afford (R,R)-
11 (347 mg, 0.76 mmol, 76% yield): [a]3D0 ꢁ32.2 (c 1.0,
4.3.2. (S)-3-(Trifluoromethylsulfonamido)pyrrolidine (S)-3
A mixture of (S)-13 (273 mg, 0.88 mmol) and 10% palla-
dium on carbon (100 mg) in ethanol (15 mL) was stirred under
a hydrogen atmosphere for 20 h at room temperature. The
reaction mixture was then filtered through a pad of Celite
and the filtrate was concentrated to give (S)-3 (192 mg,
0.88 mmol, 99% yield): [a]3D0 ꢁ16.7 (c 1.0, MeOH); 1H
NMR (400 MHz, CD3OD) d 4.13e4.09 (1H, m, TfNHCH),
3.40e3.32 (1H, m, HNCHHCH2), 3.25 (1H, dd, J¼11.5,
5.9 Hz, HNCHHCH), 3.25e3.18 (1H, m, HNCHHCH2), 2.97
(1H, dd, J¼11.4, 4.8 Hz, HNCHHCH), 2.14e2.05 (1H, m,
HNCH2CHH), 1.89e1.81 (1H, m, HNCH2CHH) ppm; 13C
NMR (100 MHz, CD3OD) d 123.3 (q, JCeF¼326 Hz), 56.1,
54.1, 45.3, 34.7 ppm; IR (neat) 3227, 2970, 2361, 1744,
1
MeOH); H NMR (400 MHz, CD3OD) d 7.31e7.23 (5H, m,
ArH), 3.93e3.88 (2H, m, TfNHCH), 3.68 (1H, d, J¼
12.8 Hz, PhCHH), 3.56 (1H, d, J¼12.8 Hz, PhCHH), 2.95
(2H, dd, J¼9.7, 7.0 Hz, BnNCHH), 2.49 (2H, dd, J¼9.8,
5.9 Hz, BnNCHH) ppm; 13C NMR (100 MHz, CD3OD)
d 138.7, 129.9, 129.4, 128.5, 121.2 (q, JCeF 320 Hz),
61.0, 60.4, 59.7 ppm; IR (neat) 3040, 2922, 1472, 1377,
1196, 1099, 935 cmꢁ1
; HRMS (ESI-TOF) calcd for
C13H16F6N3O4S2: 456.0481 ([MþH]þ), found: 456.0482
([MþH]þ).
4.2.6. (3R,4R)-3,4-Bis(trifluoromethylsulfonamido)-
pyrrolidine (R,R)-2
1622, 1456, 1385, 1279, 1182, 1146, 1101, 941 cmꢁ1
;
A mixture of (R,R)-11 (295 mg, 0.65 mmol) and 10% palla-
dium on carbon (30 mg) in acetic acid (5 mL) was stirred under
a hydrogen atmosphere at room temperature overnight. The
reaction mixture was then filtered through a pad of Celite.
The filtrate was concentrated and the acquired residue was pu-
rified by using ion exchange resin (DowexÒ 50 W-X, supplied
by Dow chemical Co. Ltd.) (5% ammonium hydroxide as elu-
ent) to give (R,R)-2 (220 mg, 0.60 mmol, 93% yield): [a]D30
ꢁ36.5 (c 1.0, DMSO); 1H NMR (400 MHz, CD3OD) d 3.98e
3.95 (2H, m, TfNHCH), 3.51 (2H, dd, J¼12.1, 6.0 Hz,
HNCHH), 3.11 (2H, dd, J¼12.1, 5.3 Hz, HNCHH) ppm; 13C
NMR (100 MHz, CD3OD) d 122.1 (q, JCeF¼316 Hz), 61.4,
51.5 ppm; IR (neat) 3165, 2351, 1479, 1391, 1202, 1161,
921 cmꢁ1; HRMS (ESI-TOF) calcd for C6H10F6N3O4S2:
366.0011 ([MþH]þ), found: 366.0008 ([MþH]þ).
HRMS (ESI-TOF) calcd for C5H9F3N2NaO2S: 241.0229
([MþNa]þ), found: 241.0233 ([MþNa]þ).
4.4. Synthesis and characterization of chiral amino
sulfonamide (S)-4
4.4.1. (S)-1-Benzyl-3-(nonafluorobutylsulfonamido)-
pyrrolidine (S)-14
The title compound was prepared in a similar manner as
described above using nonafluorobutanesulfonic anhydride in-
stead of trifluoromethanesulfonic anhydride (89% yield): [a]D30
ꢁ8.6 (c 1.0, MeOH); 1H NMR (400 MHz, CD3OD)
d 7.37e7.31 (5H, m, ArH), 4.18e4.11 (1H, m, NfNHCH),
3.89 (1H, d, J¼12.8 Hz, PhCHH), 3.83 (1H, d, J¼12.6 Hz,
PhCHH), 3.07e3.02 (1H, m, BnNCHHCH), 2.95e2.89 (1H,
m, BnNCHHCH2), 2.81e2.79 (1H, m, BnNCHHCH2), 2.65
(1H, dd, J¼10.3, 5.4 Hz, BnNCHHCH), 2.32e2.23 (1H, m,
BnNCH2CHH), 1.85e1.77 (1H, m, BnNCH2CHH) ppm; 13C
NMR (100 MHz, DMSO-d6) d 136.4, 129.1, 128.3, 127.6,
4.3. Synthesis and characterization of chiral amino
sulfonamide (S)-3
2
1
2
4.3.1. (S)-1-Benzyl-3-(trifluoromethylsulfonamido)-
pyrrolidine (S)-13
116.9 (tq, JCeF¼33 Hz, JCeF¼288 Hz), 114.3 (tt, JCeF¼
1
35 Hz, JCeF¼294 Hz), 110.2 (m), 108.3 (m), 60.3, 58.5,
To a stirred solution of (S)-1-benzyl-3-aminopyrrolidine
((S)-12) (353 mg, 2.0 mmol) in CH2Cl2 (4 mL) was added
N,N-diisopropylethylamine (348 mL, 2.0 mmol) and trifluoro-
methanesulfonic anhydride (337 mL, 2.0 mmol) at 0 ꢀC. The
reaction mixture was stirred at 0 ꢀC for 2 h. The reaction mix-
ture was charged on silica gel directly and purified by flash
column chromatography on silica gel (CH2Cl2/ethyl
acetate¼6:1) to afford (S)-13 (363 mg, 1.2 mmol, 59% yield):
[a]3D1 ꢁ8.6 (c 1.0, MeOH); 1H NMR (400 MHz, CD3OD)
d 7.37e7.28 (5H, m, ArH), 4.12e4.05 (1H, m, TfNHCH),
3.81 (1H, d, J¼12.8 Hz, PhCHH), 3.75 (1H, d, J¼12.8 Hz,
PhCHH), 2.98 (1H, dd, J¼10.3, 7.1 Hz, BnNCHHCH),
2.86e2.80 (1H, m, BnNCHHCH2), 2.74e2.68 (1H, m,
53.7, 52.0, 32.3 ppm; IR (neat) 2980, 2311, 1350, 1277,
; HRMS (ESI-TOF) calcd for
1194, 1134, 1026 cmꢁ1
C15H16F9N2O2S: 459.0783 ([MþH]þ), found: 459.0787
([MþH]þ).
4.4.2. (S)-3-(Nonafluorobutylsulfonamido)pyrrolidine (S)-4
The title compound was prepared in a similar manner as
1
described above (60% yield): [a]2D9 ꢁ3.5 (c 1.0, DMSO); H
NMR (400 MHz, DMSO-d6) d 4.00e3.97 (1H, m, NfNHCH),
3.23e3.16 (1H, m, HNCHHCH2), 3.14e3.08 (1H, m,
HNCHHCH2), 3.04 (1H, dd, J¼10.9, 5.3 Hz, HNCHHCH),
2.79 (1H, dd, J¼10.6, 3.1 Hz, HNCHHCH), 1.94e1.85 (1H,
m, HNCH2CHH), 1.70e1.63 (1H, m, HNCH2CHH) ppm;

1202
T. Kano et al. / Tetrahedron 64 (2008) 1197e1203
2
13C NMR (100 MHz, DMSO-d6) d 117.3 (tq, JCeF¼34 Hz,
room temperature for the indicated time in Table 2, the reac-
tion mixture was then quenched with brine and extracted
with ethyl acetate. The combined organic layers were dried
over Na2SO4 and concentrated. The residue was purified by
preparative thin layer chromatography on silica gel (hexane/
ethyl acetate¼2:1) to afford the corresponding Mannich
adduct 15.
1JCeF¼288 Hz,), 115.5 (tt, JCeF¼35 Hz, JCeF¼292 Hz,),
110.7 (m), 108.7 (m), 54.7, 53.0, 43.4, 34.1 ppm; IR (neat)
3140, 2936, 2450, 1612, 1352, 1258, 1184, 1140, 1101,
1036 cmꢁ1; HRMS (ESI-TOF) calcd for C8H10F9N2O2S:
369.0314 ([MþH]þ), found: 369.0314 ([MþH]þ).
2
1
4.5. General procedure for the anti-selective direct
asymmetric Mannich reaction of aldehydes with a chiral
amino sulfonamide catalyst
4.6.1. Ethyl (2R,10S)-2-(p-methoxyphenylamino)-
2-(20-oxocyclohexyl)acetate
[a]2D9 ꢁ33.6 [c 1.0, CHCl3 (99% ee)]; spectral data were in
agreement with those previously reported.3e HPLC analysis:
Daicel Chiralpak AS, hexane/i-PrOH¼10:1, flow rate¼
1.0 mL/min, retention time: 11 min and 14 min (major).
To a stirred solution of a chiral amino sulfonamide
(0.015 mmol) in THF (1.5 mL) were added ethyl (4-methoxy-
phenylimino)acetate 5 (31 mg, 0.15 mmol) and aldehyde
(0.45 mmol) in this order at ꢁ20 ꢀC. After stirring at
ꢁ20 ꢀC for the indicated time in Table 1, the reaction mixture
was then quenched with brine and extracted with ethyl acetate.
The combined organic layers were dried over Na2SO4 and
concentrated. The residue was purified by preparative thin
layer chromatography on silica gel (hexane/ethyl acetate¼2:1)
to afford the corresponding Mannich adduct 6.
4.6.2. Ethyl (2R,30R)-2-(p-methoxyphenylamino)-
2-(40-oxotetrahydropyran-30-yl)acetate
Spectral data were in agreement with those previously
reported.3e HPLC analysis: Daicel Chiralpak AS-H, hexane/
i-PrOH¼4:1, flow rate¼1.0 mL/min, retention time: 15 min
and 19 min (major).
4.5.1. Ethyl (2R,3S)-3-formyl-2-(p-methoxyphenylamino)-
butanoate
Spectral data were in agreement with those previously
reported.3b,5a The enantiomeric excess was determined after
reduction in accordance with the literature procedure.2b
4.6.3. Ethyl (2R,30S)-2-(p-methoxyphenylamino)-2-
(40-oxotetrahydrothiopyran-30-yl)acetate
[a]2D6 ꢁ45.9 [c 1.0, CHCl3 (97% ee)]; spectral data were in
agreement with those previously reported.3e HPLC analysis:
Daicel Chiralpak AS-H, hexane/EtOH¼10:1, flow rate¼
1.0 mL/min, retention time: 14 min and 19 min (major).
4.5.2. Ethyl (2R,3S)-3-formyl-2-(p-methoxyphenylamino)-
pentanoate
Spectral data were in agreement with those previously
reported.3b HPLC analysis: Daicel Chiralpak AS-H, hexane/
i-PrOH¼99:1, flow rate¼1.0 mL/min, retention time: 29 min
and 35 min (major).
4.6.4. Ethyl (2R,3S)-2-(p-methoxyphenylamino)-3-methyl-4-
oxohexanoate
Spectral data were in agreement with those previously re-
ported.3e HPLC analysis: Daicel Chiralpak AS-H, hexane/
i-PrOH¼99:1, flow rate¼1.0 mL/min, retention time: 20 min
and 33 min (major).
4.5.3. Ethyl (2R,3S)-3-formyl-2-(p-methoxyphenylamino)-
4-methylpentanoate
Spectral data were in agreement with those previously
reported.3a HPLC analysis: Daicel Chiralpak AS-H, hexane/
i-PrOH¼99:1, flow rate¼1.0 mL/min, retention time: 23 min
and 43 min (major).
4.6.5. Ethyl (2R,3S)-3-ethyl-2-(p-methoxyphenylamino)-4-
oxoheptanoate
Spectral data were in agreement with those previously
reported.3e HPLC analysis: Daicel Chiralpak AD-H, hexane/
EtOH¼19:1, flow rate¼1.0 mL/min, retention time: 8 min
(anti, major), 12 min (anti, minor), 14 min (syn, major), and
17 min (syn, minor).
4.5.4. Ethyl (2R,3S)-3-formyl-2-(p-methoxyphenylamino)-
4,4-dimethylpentanoate
[a]3D1 44.7 [c 1.0, CHCl3 (98% ee)]; spectral data were in
agreement with those previously reported.3a HPLC analysis:
Daicel Chiralpak AS-H, hexane/EtOH¼100:1, flow
rate¼1.0 mL/min, retention time: 11 min and 23 min (major).
4.6.6. Ethyl (2R,3S)-2-(p-methoxyphenylamino)-3-methyl-4-
oxopentanoate
[a]2D6 27.6 [c 0.5, CHCl3 (99% ee)]; spectral data were in
agreement with those previously reported.3e HPLC analysis:
Daicel Chiralpak AS-H, hexane/i-PrOH¼100:1, flow rate¼
1.0 mL/min, retention time: 27 min and 54 min (major).
4.6. General procedure for the anti-selective direct
asymmetric Mannich reaction of ketones with a chiral
amino sulfonamide catalyst
Acknowledgements
To a stirred solution of a chiral amino sulfonamide
(0.015 mmol) in THF (1.2 mL) were added ethyl (4-methoxy-
phenylimino)acetate 5 (31 mg, 0.15 mmol) and ketone
(0.3 mL) in this order at room temperature. After stirring at
This work was partially supported by a Grant-in-Aid for
Scientific Research on Priority Areas ‘Advanced Molecular
Transformation of Carbon Resources’ from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.

T. Kano et al. / Tetrahedron 64 (2008) 1197e1203
1203
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Zhang, H.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2007, 129,
288; see also Ref. 2b.
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