Asymmetric addition of diethylzinc to benzaldehyde catalyzed by novel chiral C2-symmetric tetrakis(sulfonamide)-titanium(IV) complexes

Article abstract of DOI:10.1016/j.tetasy.2010.11.023

A series of chiral C₂-symmetric tetrakis(sulfonamides) 3a-f, 4a-f were prepared and employed as ligands for titanium(IV) complexes in the asymmetric addition of diethylzinc to benzaldehyde. The chiral secondary alcohols were obtained in high yi

Full text of DOI:10.1016/j.tetasy.2010.11.023

Tetrahedron: Asymmetry 21 (2010) 2944–2948
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric addition of diethylzinc to benzaldehyde catalyzed by novel chiral
C2-symmetric tetrakis(sulfonamide)–titanium(IV) complexes
Antonio Venegas a, Lucrecia Rivas b, Gabriela Huelgas b, Cecilia Anaya de Parrodi b, , Domingo Madrigal a,
⇑
Gerardo Aguirre a, Miguel Parra-Hake a, Daniel Chávez a, Ratnasamy Somanathan a,
⇑
a Centro de Graduados e Investigación, Instituto Tecnológico de Tijuana, Apartado Postal 1166, Tijuana, B. C. 22000, Mexico
b Departamento de Ciencias Químico-Biológicas, Universidad de las Américas-Puebla, Ex Hacienda Santa Catarina Mártir s/n Cholula, Puebla 72810, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral C2-symmetric tetrakis(sulfonamides) 3a–f, 4a–f were prepared and employed as ligands
for titanium(IV) complexes in the asymmetric addition of diethylzinc to benzaldehyde. The chiral second-
ary alcohols were obtained in high yields and in moderate enantioselectivities.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 October 2010
Accepted 22 November 2010
Available online 13 January 2011
HO
O
H
1. Introduction
ZnEt2
H
Ti(OiPr)4
The catalytic asymmetric addition of organozinc to various
aldehydes is an important method for the preparation of optically
active secondary alcohols, and this has attracted a great deal of
interest since the first report in 1984 by Oguni, who used (S)-leu-
cinol, a b-amino alcohol as the base catalyst.1,2 Subsequent work
by Noyori et al. with DAIB amino alcohol contributed a great deal
to the understanding of the mechanism of the catalyzed diethylzinc
addition to the aldehydes to obtain amino alcohols.3 It is well estab-
lished that enantioselectivity can be accomplished either by Lewis
base or by Lewis acid catalysis. Consequently, there are now a series
of chiral functionalities that have been successfully used, either as a
base catalyst or as ligands for transition metal complexes. These in-
O2S NH HN SO2
Ar
Ar
Scheme 1. A chiral bis(sulfonamide) with Ti(OiPr)4 as the catalyst of the
asymmetric addition of organozinc to benzaldehyde.
2. Results and discussion
clude the well known b,
c
, d-amino alcohols,4 b-imino alcohols,5
We recently reported on the use of C2-symmetric bis(sulfon-
amide) ligands 1 and 2, which with Ru(II) and Rh(III) catalyzed the
asymmetric transfer hydrogenation of aromatic ketones to second-
ary alcohols in excellent yields and enantioselectivities.18 Inspired
by these results, we further explored the possibility of transforming
bis(sulfonamides) 1 and 2 into tetrakis(sulfonamides) ligands 3 and
4, using various sulfonyl chlorides, as shown in Scheme 2. Our inten-
tion with ligand 3 was to surround the Lewis acid titanium metal
center with four chiral nitrogen atoms in a cisoid conformation,
hoping that the additional chirality would enhance the enantiose-
lectivity in the diethylzinc addition to benzaldehyde.
The tetrakis(sulfonamides) 3a–f and 4a–f coordinated to Ti(IV)
were tested as catalysts in the alkylation of benzaldehyde. The re-
sults are summarized in Table 1.
The results from the catalytic use of tetrakis(sulfonamide)–
Ti(IV) complexes show the same trend that was previously ob-
served by Walsh et al. with the bis(sulfonamide) ligands,2c but
with moderate enantioselectivities (57–81%). Ligands 3a–f and
4a–f gave good yields (82–98%). These results also show that
electron withdrawing and donating groups on the sulfonamide
piperazines,6 oxazaborolidines,7 aminothiolates,8 aminothiols,9
aminoesters,10 diols,11 disulfonamides,2c,12 diphosphoramides,13
amino acid derivatives,14 ferrocene-based amino alcohols,15 and
oxazolines.16
The use of a chiral bis(sulfonamide) with titanium(IV) iso-prop-
oxide [Ti(OiPr)4] as a catalyst to add diethylzinc to benzaldehyde
was first reported by Ohno et al. (Scheme 1).12a,b
The synthesis of a variety of C2-symmetric bis(sulfonamides)
and the extensive mechanistic studies reported by Walsh et al.
have greatly contributed to our understanding of the mechanism
of this reaction.2c,17 Nonetheless, the identification of new catalytic
systems for this transformation remains an important challenge. In
this context, to the best of our knowledge no C2-symmetric tetra-
kis(sulfonamide)–Ti(IV) complexes have been employed as a cata-
lyst in the asymmetric addition of organozinc to benzaldehyde.
⇑
Corresponding authors.
E-mail address: somanatha@sundown.sdsu.edu (R. Somanathan).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.023

A. Venegas et al. / Tetrahedron: Asymmetry 21 (2010) 2944–2948
2945
O2S
NH
SO2
HN
O2S
NH
SO2
HN
NH2
H2N
NH2
H2N
1
2
O2S
SO2
NH
HN
O2S
SO2
NH
HN
NH
HN
SO2
O2S
NH
HN
SO2
O2S
R
R
3
4
R
R
R: a = H, b = p-CH3, c = p-CF3, d = p-NO2, e = 2,4,6-trimethyl, f = 2,4,6-triisopropyl
Scheme 2. Bis(sulfonamides) 1 and 2 and tetrakis(sulfonamides) 3a–f and 4a–f.
Table 1
Diethylzinc addition of benzaldehyde with Ti(OiPr)4 complexesa
O
1) L ( 5 mol %), PhMe, 25 °C, 20 h
H
Ph
OH
Et2Zn
1.6 eq
Ph
H
+
Ti(OiPr)4
+
2) H2O
1 eq
2.4 eq
Ligand
R
3
4
Yieldb (%)
eec (%)
Yieldb (%)
eec (%)
a = H
b = p-CH3
c = p-CF3
d = p-NO2
e = 2,4,6-trimethyl
f = 2,4,6-triisopropyl
98
98
97
97
82
95
78
81
57
64
70
68
90
97
98
98
96
90
68
64
68
65
71
68
a
b
c
Absolute configuration of the alcohols is (S), assigned by comparing the specific rotation with literature values.8 Reaction conditions: 20 °C. S/C = 20.
Yields were measured after column chromatography on silica gel (Et3N/SiO2 = 2.5% v/v, hexanes/EtOAc 15:1 as eluent).
The enantiomeric excesses were determined by HPLC with a Chiracel OD column.21
benzene ring have a modest effect on the enantioselectivity. The
use of complexes formed with ligands 3c,d (p-CF3 and p-NO2
substitution, respectively) resulted in lower enantioselectivity
compared with either 3a or 3b (H and p-CH3 substitution, respec-
tively), while steric bulk appears to play a major role with ligands
3e (2,4,6-trimethyl substitution) and 3f (2,4,6-triisopropyl substi-
tution), which is again in agreement with Walsh et al.’s observa-
tions that 2,6-substitution on the sulfonamide ring leads to lower
enantioselectivity.2c
Based on our earlier studies on the conformation of ligand 1,
these results indicate that the ligand prefers a transoid conformation
by ꢀ3 kcal/mol over the cisoid conformer.19 Further experimental
data showed that increasing the titanium(IV) isopropoxide from 1
to 2 equiv increases the enantioselectivity by 10%, suggesting the
two coordinating sites act independently and are more likely in a
transoid conformation. This is further supported by the similar re-
sults obtained with ligands 3 and 4.
Results with tetrakis(sulfonamide)–Ti(IV) complexes 4a–f
showed lower enantioselectivities than with 3a–f, probably due
to the fact that the two bis(sulfonamides) were farther apart from
each other, and thus did not result in enough steric interaction
when the Ti(IV) is complexed to the ligand. Better yields and
enantioselectivities were achieved when 2.4 equiv of metal was
used, suggesting the formation of binuclear complexes.
Finally, the lower activities of the tetrakis(sulfonamides) 3a–f
and 4a–f compared to the bis(sulfonamides) may be attributed to
the partial solubility of the former when using toluene as the reac-
tion solvent.
3. Conclusion
In conclusion, a series of novel chiral C2-symmetric tetrakis
(sulfonamide) ligands 3a–f and 4a–f, have been prepared from
bis(sulfonamide) ligands 1 and 2 and employed as ligands for tita-

2946
A. Venegas et al. / Tetrahedron: Asymmetry 21 (2010) 2944–2948
nium(IV) complexes in the asymmetric addition of diethylzinc to
benzaldehyde. High yields (82–98%) and moderate enantioselec-
tivities (64–81%) have been obtained for the chiral secondary
alcohol.
4.3.2. N1,N3-Bis[(1R,2R)-2-(4-methylphenylsulfonamido]cyclo-
hexyl)benzene-1,3-disulfonamide 3b
White solid 0.5 g (86% yield). Mp 144–145 °C. ½a D25
¼ ꢂ10 (c 1.0,
ꢁ
CH2Cl2). IR (KBr): 3280, 2937, 2862, 1598, 1451, 1329, 1158 cmꢂ1
.
1H NMR (CDCl3, 600 MHz) d 8.46 (t, J = 1.5 Hz, 1H), 8.15 (dd, J = 7.9,
1.8 Hz, 2H), 7.78 (t, J = 7.9 Hz, 1H), 7.66 (d, J = 7.9 Hz, 4H), 7.29 (d,
J = 7.9 Hz, 4H), 5.49 (d, J = 8.8 Hz, 2NH), 5.41 (d, J = 8.5 Hz, 2NH),
2.98 (m, 2H), 2.76 (m, 2H), 2.41 (s, 6H), 2.24 (m, 2H), 1.59 (m,
2H), 1.47 (m, 4H), 1.30 (m, 2H), 1.02 (m, 6H). 13C NMR (CDCl3,
150 MHz) d 143.9, 141.6, 137.3, 131.4, 130.5, 130.0, 126.9, 125.3,
57.8, 56.1, 34.5, 32.3, 24.5, 24.0, 21.6. Anal. Calcd for C32H42N4O8S4:
C, 52.01; H, 5.73. Found: C, 52.05; H, 5.76.
4. Experimental
4.1. Instrument and measurements
Melting points were determined on a Fisher–Johns melting-
point apparatus and are uncorrected. Infrared (IR) spectra were ta-
ken on a Perkin–Elmer FT-IR 1600 spectrometer. 1H and 13C NMR
spectra were recorded either on a Varian Nova 600 or 500 MHz
spectrometer. Rotation was measured with a Perkin–Elmer 343
Polarimeter. Elemental analyses were conducted by NuMega San
Diego.
4.3.3. N1,N3-Bis[(1R,2R)-2-(4-trifluoromethylphenylsulfonami-
do]cyclohexyl)benzene-1,3-disulfonamide 3c
White solid 0.5 g (86% yield). Mp 237–238 °C. ½a D25
¼ þ15 (c 0.2,
ꢁ
CH2Cl2). IR (KBr): 3257, 2942, 2865, 1475, 1440, 1324, 1167 cmꢂ1
.
1H NMR (CDCl3 + DMSO-d6 600 MHz) d 8.39 (t, J = 1.7 Hz, 1H), 8.06
(dd, J = 8.0, 2.0 Hz, 2H), 8.05 (d, J = 8.3 Hz, 4H), 7.78 (d, J = 8.5 Hz,
4H), 7.70 (dd, J = 7.8, 7.8 Hz, 1H), 7.10 (d, J = 6.8 Hz, 2NH), 7.02
(d, J = 6.3 Hz, 2NH), 3.00–2.70 (m, 4H), 1.75 (m, 2H), 1.60 (m,
2H), 1.51 (m, 4H), 1.20 (m, 4H), 1.06 (m, 4H). 13C NMR
(CDCl3 + DMSO-d6, 150 MHz) d 144.8, 142.4, 133.5 (JCF = 32.5 Hz),
130.4, 130.2, 127.6 (br), 126.0 (br), 125.5, 123.4 (JCF = 271.4 Hz),
56.8, 56.4, 32.6, 32.4, 23.9, 23.8. Calcd for C32H36F2N4O8S4: C,
45.38; H, 4.28. Found: C, 45.33; H, 4.25.
4.2. General procedure for synthesis of monosulfonamides
Monosulfonamides were obtained as reported in the literature
from the corresponding commercially available benzenesulfonyl
chloride with chiral (1R,2R)-1,2-cyclohexanediamine and were
characterized by comparison of the spectroscopic data with litera-
ture values.20
4.2.1. N-[(1R,2R)-2-Aminocyclohexyl]-2,4,6-triisopropylbenzen-
sulfonamide f
4.3.4. N1,N3-Bis[(1R,2R)-2-(4-nitrophenylsulfonamido]cyclo-
Grey solid 1.9 g (87% yield). ½a D25
ꢁ
¼ ꢂ26 (c 0.5, CHCl3). IR (KBr):
.
1H NMR (CDCl3, 600 MHz) d
hexyl)benzene-1,3-disulfonamide 3d
3347, 3286, 1602, 1448, 1150 cmꢂ1
Yellow solid 0.5 g (80% yield). Mp 150–152 °C. ½a D25
¼ þ36 (c 0.
ꢁ
7.10 (s, 2H), 4.20 (sept, J = 6.8 Hz, 2H), 3.56 (dt, J = 11.0, 3.5 Hz,
1H), 3.54 (dt, J = 11.0, 3.8 Hz, 1H), 2.87 (m, sept, J = 6.8 Hz, 1H),
2.54 (d, J = 5.5 Hz, 1H), 1.65 (m, 2H), 1.49 (m, 1H), 1.35 (m, 2H)
1.23 (d, J = 6.8 Hz, 6H), 1.20 (d, 6.8 Hz, 12H), 1.06 (m, 4H). 13C
NMR (CDCl3, 150 MHz) d 152.4, 149.8, 135.3, 123.9, 55.5, 53.5,
34.1, 31.8, 30.4, 29.5, 24.9, 24.5, 23.7, 23.6.
32, CH2Cl2). IR (KBr): 3286, 3105, 2938, 2862, 1605, 1503, 1450,
1350, 1162 cmꢂ1 1H NMR (CDCl3 + DMSO-d6, 600 MHz) d 8.38 (d,
.
J = 8.8 Hz, 4H), 8.05 (d, J = 8.8 Hz, 4H), 8.16 (s, 1H), 7.97 (dd,
J = 7.9, 1.2 Hz, 2H), 7.92 (d, J = 7.6 Hz, 2NH), 7.75 (t, J = 7.6 Hz,
1H), 7.71 (d, J = 7.9 Hz, 2NH), 2.87 (m, 4H), 2.32 (m, 2H), 1.43 (m,
2H), 1.33 (m, 2H), 1.23 (m, 2H), 1.03 (m, 8H). 13C NMR (CDCl3
+
DMSO-d6, 125 MHz) d 149.7, 147.0, 142.5, 130.3, 130.1, 128.4,
125.4, 124.2, 57.0, 56.3, 32.9, 32.2, 24.0, 23.9. Calcd for
4.3. General procedure for synthesis of ligands 3a–f
C
30H36N6O12S4: C, 44.99; H, 4.53. Found: C, 45.02; H, 4.58.
To a stirred solution of the corresponding monosulfonamide
(1.6 mmol) in CH2Cl2 (32 mL) was added triethylamine (0.8 mL,
15.2 mmol). The mixture was cooled to 0 °C and a solution of ben-
zene-1,3-disulfonyl chloride (0.8 mmol) in dichloromethane
(30 mL) was added over 30 min. After the addition was complete,
the mixture was allowed to warm to room temperature and stirred
for 12 h. The resulting reaction mixture was washed with aqueous
4.3.5. N1,N3-Bis[(1R,2R)-2-(2,4,6-trimethylphenylsulfonamido]
cyclohexyl)benzene-1,3-disulfonamide 3e
White solid 0.5 g (76% yield). Mp 138–140 °C. ½a D25
¼ ꢂ30 (c
ꢁ
0.12, CH2Cl2). IR (KBr): 3381, 2937, 2859, 1629, 1597, 1312,
1154 cmꢂ1 1H NMR (CDCl3, 600 MHz) d 8.49 (t, J = 2.0 Hz, 1H),
.
8.19 (dd, J = 8.0, 2.0 Hz, 2H), 7.97 (t, J = 8.0 Hz, 1H), 6.95 (s, 4H),
5.89 (d, J = 5.6 Hz, 2NH), 5.20 (d, J = 8.5 Hz, 2NH), 2.99 (m, 2H),
2.65 (m, 2H), 2.54 (m, 2H), 2.24 (m, 2H), 2.17 (s, 6H), 2.15 (s,
12H), 1.59 (m, 2H), 1.49 (m, 2H), 1.44 (m, 4H), 1.38 (m, 2H), 1.26
(m, 2H). 13C NMR (CDCl3, 150 MHz) d 142.5, 141.5, 138.7, 134.0,
132.1, 131.2, 130.7, 126.2, 57.6, 55.1, 34.5, 31.9, 24.6, 23.9, 22.9,
20.9. Calcd for C36H50N4O8S4: C, 54.38; H, 6.34. Found: C, 54.34;
H, 6.32.
HCl (2 mol Lꢂ1
,
3 ꢃ 50 mL),
a saturated solution of NaHCO3
(1 ꢃ 30 mL) and water (2 ꢃ 30 mL). The dichloromethane layer
was dried over anhydrous MgSO4, filtered, and the solvent was re-
moved under reduced pressure to obtain the tetrakis(sulfonamide)
ligands 3a–f.
4.3.1. N1,N3-Bis[(1R,2R)-2-(phenylsulfonamido]cyclohexyl)ben-
zene-1,3-disulfonamide 3a
White solid 0.5 g (82% yield). Mp 129–131 °C. ½a D25
¼ ꢂ16 (c
ꢁ
4.3.6. N1,N3-Bis[(1R,2R)-2-(2,4,6-triisopropylphenylsulfonami-
1.28, CH2Cl2). IR (KBr): 3282, 2938, 2861, 1448, 1328,
1157 cmꢂ1.1H NMR (CDCl3, 600 MHz) d 8.47 (t, J = 1.8 Hz, 1H),
8.16 (dd, J = 7.6, 1.8 Hz, 2H), 7.80 (m, 5H), 7.57 (tt, J = 8.0,
1.8 Hz, 2H), 7.49 (t, J = 8.0 Hz, 4H), 5.57 (d, J = 5.3 Hz, 2NH),
5.50 (d, J = 8.3 Hz, 2NH), 3.00 (m, 2H), 2.80 (m, 2H), 2.20 (m,
2H), 1.58 (m, 2H), 1.46 (m, 4H), 1.29 (m, 2H), 1.12 (m, 4H),
1.08 (m, 2H). 13C NMR (CDCl3, 150 MHz) d 141.6, 140.3, 133.0,
131.8, 130.6, 129.3, 126.9, 125.3, 57.7, 56.3, 34.3, 32.3, 24.5. Anal.
Calcd for C30H38N4O8S4: C, 50.68; H, 5.39. Found: C, 50.66; H,
5.36.
do]cyclohexyl)benzene-1,3-disulfonamide 3f
Pale white solid 0.6 g (75% yield). Mp 131–133 °C. ½a D25
¼ ꢂ30 (c
ꢁ
0.12, CH2Cl2). IR (KBr): 3286, 2958, 2868, 1600, 1462, 1331,
1154 cmꢂ1 1H NMR (CDCl3, 600 MHz) d 8.52 (t, J = 1.8 Hz, 1H),
.
8.21 (dd, J = 7.9 Hz, 1.8 Hz, 2H), 7.80 (t, J = 7.9 Hz, 1H), 7.10 (s,
4H), 5.98 (d, J = 5.3 Hz, 2NH), 4.80 (d, J = 7.3 Hz, 2NH), 3.96 (sept,
J = 6.8 Hz, 4H), 2.98 (m, 4H), 2.88 (sept, J = 7.0 Hz, 2H), 2.20 (m,
2H), 1.61 (m, 2H), 1.52 (m, 4H), 1.41 (m, 8H), 1.24 (d, J = 7.0 Hz,
12H), 1.22 (d, J = 6.8 Hz, 12H) 1.18 (d, J = 6.8 Hz, 12H). 13C NMR
(CDCl3, 150 MHz) d 153.0, 149.9, 141.7, 133.3, 131.2, 130.7,

A. Venegas et al. / Tetrahedron: Asymmetry 21 (2010) 2944–2948
2947
125.9, 124.0, 57.4, 55.9, 34.3, 34.1, 32.4, 29.7, 25.0, 24.7, 24.6, 24.0,
23.6, 23.5. Calcd for C48H74N4O8S4: C, 59.84; H, 7.64. Found: C,
59.84; H, 7.74.
J = 7.3 Hz, 2NH), 2.84 (m, 2H), 2.76 (m, 2H), 2.58 (s, 12H), 2.29 (s,
6H), 1.65 (m, 2H), 1.57 (m, 4H), 1.22 (m, 8H). 13C NMR (CDCl3,
150 MHz) d 143.5, 142.5, 139.9, 138.9, 134.1, 132.1, 128.1, 128.0,
57.2, 56.0, 33.8, 32.6, 24.4, 24.1. 23.1, 21.0. Calcd for C42H54N4O8S4:
C, 57.91; H, 6.25. Found: C, 57.91; H, 6.24.
4.4. General procedure for the synthesis of ligands 4a–f
0
4.4.6. N4,N4 -Bis[(1R,2R)-2-(2,4,6-triisopropylphenylsulfonami-
Ligands 4a–f were obtained as described for ligands 3a–f, but
using the corresponding monosulfonamide (1.6 mmol) and biphe-
nyl-4,40-disulfonyl chloride (0.8 mmol).
do)cyclohexyl] biphenyl-4,40-disulfonamide 4f
White solid 0.6 g (74% yield). Mp 138–139 °C. ½a D25
ꢁ
¼ þ20 (c
1H
0.32, CH2Cl2). IR (KBr): 3285, 1599, 1460, 1328, 1161 cmꢂ1
.
0
4.4.1. N4,N4 -Bis[(1R,2R)-2-(phenylsulfonamido)cyclohexyl]
NMR (CDCl3, 600 MHz)
d 8.05 (d, J = 8.5 Hz, 4H), 7.79 (d,
biphenyl-4,40-disulfonamide 4a
J = 8.5 Hz, 4H), 7.15 (s, 4H), 5.79 (d, J = 6.2 Hz, 2NH), 4.67 (d,
J = 7.0 Hz, 2NH), 4.06 (sept, J = 7.0 Hz, 4H), 3.28 (m, 2H), 3.08 (m,
2H), 2.90, (sept, J = 7.0 Hz, 2H), 2.05 (m, 2H), 1.62 (m, 2H), 1.59
(m, 2H), 1.52 (m, 2H), 1.45 (m, 2H), 1.25 (d, J = 7.0 Hz, 12H), 1.24
(d, J = 7.0 Hz, 24H), 1.19–1.10 (m, 6H). 13C NMR (CDCl3, 150 MHz)
d 153.0, 150.0, 143.5, 140.3, 133.3, 128.1, 128.0, 123.9, 57.2, 56.0,
34.1, 33.8, 33.1, 29.8, 25.0, 24.8, 24.5, 24.2, 23.5. Calcd for
White solid 0.6 g (75% yield). Mp 141–142 °C. ½a D25
¼ þ15 (c 0.6,
ꢁ
CH2Cl2). IR (KBr): 3279, 2937, 2860, 1595, 1448, 1327, 1159 cmꢂ1
.
1H NMR (CDCl3, 600 MHz) d 7.98 (d, J = 8.3 Hz, 4H), 7.86 (dd, J = 7.0,
3.2 Hz, 4H), 7.74 (d, J = 8.3 Hz, 4H), 7.57 (td, J = 7.3, 1.2 Hz, 2H), 7.51
(t, J = 7.9 Hz, 4H), 5.37 (d, J = 5.9 Hz, 2NH), 5.07 (d, J = 6.8 Hz, 2NH),
2.81 (m, 4H), 1.99 (m, 2H), 1.66 (m, 2H), 1.54 (m, 4H), 1.41 (m, 8H).
13C NMR (CDCl3, 150 MHz) d 143.6, 140.2, 139.8, 132.9, 129.3,
128.2, 128.0, 127.1, 57.1, 56.6, 33.6, 32.9, 24.4, 24.1. Calcd for
C
54H78N4O8S4: C, 62.39; H, 7.56. Found: C, 62.34; H, 7.52.
C
36H42N4O8S4: C, 54.94; H, 5.38. Found: C, 54.98; H, 5.43.
4.5. General procedure for the asymmetric diethylzinc addition
to benzaldehyde
0
4.4.2. N4,N4 -Bis[(1R,2R)-2-(4-methylphenylsulfonamido)
cyclohexyl]biphenyl-4,40-disulfonamide 4b
Ligands 3a–f and 4a–f (5 mol %) were weighed into the reaction
vessel and diethylzinc (1.0 M in hexane, 1.6 equiv, 1.5 mL) and tita-
nium(IV) isopropoxide (2.4 equiv, 0.76 mL) were then added at rt.
After 10 min, benzaldehyde (1.0 equiv, 0.94 mmol) was added.
The homogeneous reaction mixture was stirred at rt. After 20 h
the reaction was quenched with water (5 mL), extracted with
EtOAc (2 ꢃ 40 mL) and the combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuo. The res-
idue was purified by flash chromatography on deactivated silica
gel (Et3N/SiO2 = 2.5% v/v, hexanes/EtOAc 95:5) to afford 1-phe-
nyl-1-propanol.
White solid 0.5 g (79% yield). Mp 139–140 °C. ½a D25
¼ ꢂ19 (c 1.0,
ꢁ
CH2Cl2). IR (KBr): 3278, 2936, 2860, 1596, 1450, 1328, 1159,
1109 cmꢂ1 1H NMR (CDCl3, 600 MHz) d 7.99 (d, J = 8.2 Hz, 4H),
.
7.75 (d, J = 8.3 Hz, 4H), 7.73 (d, J = 8.2 Hz, 4H), 7.28 (d, J = 8.3 Hz,
4H), 5.53 (d, J = 5.6 Hz, 2NH), 5.08 (d, J = 6.8 Hz, 2NH), 2.81 (m,
4H), 2.40 (s, 6H), 2.03 (m, 2H), 1.63 (m, 2H), 1.53 (m, 4H), 1.50
(m, 8H). 13C NMR (CDCl3, 150 MHz) d 143.7, 143.5, 139.8, 137.3,
129.8, 128.1, 128.0, 127.1, 57.2, 56.4, 33.6, 32.8, 24.4, 24.1, 21.6.
Calcd for C38H46N4O8S4: C, 56.00; H, 5.69. Found: C, 56.04; H, 5.72.
0
4.4.3. N4,N4 -Bis[(1R,2R)-2-(4-trifluoromethylphenylsulfonami-
do)cyclohexyl]biphenyl-4,40-disulfonamide 4c
4.6. Conditions for the determination of enantiomeric excess
White solid 0.5 g (79% yield). Mp 253–254 °C. ½a D25
¼ þ25 (c 0.3,
ꢁ
CH2Cl2). IR (KBr): 3282, 2938, 2863, 1595, 1440, 1405, 1325, 1162,
Chiral HPLC: Chiracel OD column, 254 nm UV detector, 95:5
hexanes/IPA, flow rate 0.5 mL/min, retention time (R) 15 min,
retention time (S): 18 min.21
1163 cmꢂ1 1H NMR (CDCl3 + DMSO-d6, 600 MHz)
. d 8.07 (d,
J = 8.3 Hz, 4H), 7.98 (d, J = 8.3 Hz, 4H), 7.79 (d, J = 8.3 Hz, 4H),
7.77 (d, J = 8.3 Hz, 4H), 7.13 (d, J = 5.4 Hz, 2NH), 7.09 (d,
J = 6.4 Hz, 2NH), 2.87 (m, 4H), 1.78 (m, 2H), 1.68 (m, 2H), 1.33
(m, 4H), 1.21 (m, 4H), 1.08 (m, 4H). 13C NMR (CDCl3 + DMSO-d6,
150 MHz) d 144.3, 142.2, 140.3, 132.7 (JCF = 32.5 Hz), 126.9 (br),
125.2 (br), 122.7 (JCF = 271.0 Hz), 56.0, 55.5, 31.8, 31.4, 23.2, 23.1.
Calcd for C38H40F6N4O8S4: C, 49.45; H, 4.37. Found: C, 49.40; H,
4.35.
Acknowledgments
Support for this work from Dirección General de Educación
Superior Tecnológica (DGEST) Grant 2572.09P is gratefully
acknowledged. C.A.P. also acknowledges Consejo Nacional de Cien-
cia y Tecnología (CONACyT Grant No. 55802), L.R.C. for postdoc-
toral scholarship and A.V. for a graduate scholarship.
0
4.4.4. N4,N4 -Bis[(1R,2R)-2-(4-nitrophenylsulfonamido)cyclo-
hexyl]biphenyl-4,40-disulfonamide 4d
References
Yellow solid 0.6 g (80% yield). Mp 164–167 °C. ½a D25
¼ þ15 (c
ꢁ
0.5, MeOH). IR (KBr): 3287, 2937, 2862, 1596, 1530, 1349, 1161,
1. Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823–2824.
1092 cmꢂ1 1H NMR (CDCl3, 600 MHz) d 8.34 (d, J = 8.6 Hz, 4H),
.
2. (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856; (b) Pu, L.; Yu, H. B. Chem.
Rev. 2001, 101, 757–824; (c) Walsh, P. J. Acc. Chem. Res. 2003, 36, 739–749.
3. (a) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 9800–
9809; (b) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989,
111, 4028–4036; (c) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49–69.
4. (a) Prasad, K. R. K.; Joshi, N. N. J. Org. Chem. 1997, 62, 3770–3771; (b) Anaya de
Parrodi, C.; Juaristi, E.; Quintero-Cortes, P.; Amador, P. Tetrahedron: Asymmetry
1996, 7, 1915–1918; (c) Kitamura, S.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem.
Soc. 1986, 109, 6071–6072; (d) Wu, Y.; Yun, H.; Wu, Y.; Ding, K.; Zhu, Y.
Tetrahedron: Asymmetry 2000, 11, 3543–3552; (e) Dai, W.-M.; Zhu, H.-J.; Hao,
X.-J. Tetrahedron: Asymmetry 2000, 11, 2315–2337; (f) García Martínez, A.; Teso
Vilar, E.; García Fraile, A.; De la Moya Cerero, S.; Martínez-Ruiz, P.; Chicharo
Villas, P. Tetrahedron: Asymmetry 2002, 13, 1–4; (g) Rasmussen, T.; Norrby, P.-O.
J. Am. Chem. Soc. 2001, 123, 2464–2465; (h) Nugent, W. A. Chem. Commun. 1999,
1369–1370; (i) Cicchi, S.; Crea, S.; Goti, A.; Brandi, A. Tetrahedron: Asymmetry
1997, 8, 293–301; (j) Panev, S.; Linden, A.; Dimitrov, V. Tetrahedron: Asymmetry
2001, 12, 1313–1321; (k) Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron:
8.12 (d, J = 8.6 Hz, 4H), 7.95 (d, J = 8.4 Hz, 4H), 7.75 (d, J = 8.4 Hz,
4H), 7.18 (d, J = 6.1 Hz, 2NH), 7.05 (d, J = 7.0 Hz, 2NH), 2.88 (m,
4H), 1.88 (m, 2H), 1.72–1.45 (m, 6H), 1.30–1.04 (m, 8H). 13C NMR
(CDCl3, 150 MHz) d 149.0, 146.5, 142.3, 140.5, 127.8, 127.1, 126.
9, 123.5, 56.4, 55.5, 32.3, 31.4, 23.4, 23.2. Calcd for C36H40N6O12S4:
C, 49.30; H, 4.60. Found: C, 49.34; H, 4.64.
40
4.4.5. N4,N -Bis[(1R,2R)-2-(2,4,6-trimethylphenylsulfonamido)
cyclohexyl]biphenyl-4,40-disulfonamide 4e
White solid 0.5 g (75% yield). Mp 140–143 °C. ½a D25
¼ ꢂ5 (c 4.8,
ꢁ
CH2Cl2). IR (KBr): 3286, 2937, 2860, 1602, 1452, 1328, 1158 cmꢂ1
.
1H NMR (CDCl3, 600 MHz) d 8.01 (d, J = 8.8 Hz, 4H), 7.75 (d,
J = 8.8 Hz, 4H), 6.95 (s, 4H), 5.56 (d, J = 5.6 Hz, 2NH), 4.71 (d,

2948
A. Venegas et al. / Tetrahedron: Asymmetry 21 (2010) 2944–2948
Asymmetry 1997, 8, 1869–1876; (l) Genov, M.; Dimitrov, V.; Ivanova, V.
Tetrahedron: Asymmetry 1997, 8, 3703–3706; (m) Xu, Q.; Zhu, G.; Pan, X.; Chan,
A. S. C. Chirality 2002, 14, 716–723.
13. (a) Min, S.; Sui, W. S. Tetrahedron: Asymmetry 1999, 10, 3319–3325; (b) Min, S.;
Sui, W. S. Tetrahedron: Asymmetry 2000, 11, 835–841.
14. Dangel, B. D.; Polt, R. Org. Lett. 2000, 2, 3003–3006.
5. (a) Dahmen, S.; Bräse, S. Org. Lett. 2001, 3, 4119–4122; (b) Bolm, C.; Schlingloff,
G.; Harms, K. Chem. Ber. 1992, 125, 1191–1203; (c) Ding, K.; Ishii, A.; Mikami, K.
Angew. Chem., Int. Ed. 1999, 38, 497–501.
15. (a) Patti, A.; Nicolosi, G.; Howell, J. A. S.; Humphries, K. Tetrahedron: Asymmetry
1998, 9, 4381–4394; (b) Fukuzawa, S.-I.; Tsuchiya, D.; Sasamoto, K.; Hirano, K.;
Ohtaguchi, M. Eur. J. Org. Chem. 2000, 2877–2883.
6. (a) Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1991, 2717–2720; (b) Shono,
T.; Kise, N.; Shirakawa, E.; Matsumoto, H.; Okazaki, E. J. Org. Chem. 1991, 56,
3063–3067; (c) Soai, K.; Niwa, S.; Yamada, Y.; Inoue, H. Tetrahedron Lett. 1987,
28, 4841–4842.
7. Joshi, N. N.; Srebnik, M.; Brown, H. C. Tetrahedron Lett. 1989, 30, 5551–
5554.
8. Rijnberg, E.; Jastrzebski, J. T. B. H.; Janssen, M. D.; Boersma, J.; van Koten, G.
Tetrahedron Lett. 1994, 35, 6521–6524.
9. (a) Hof, R. P.; Poelert, M. A.; Peper, N. C. M. W.; Kellog, R. M. Tetrahedron:
Asymmetry 1994, 5, 31–34; (b) Kang, J.; Lee, J. W.; Kim, J. I. J. Chem. Soc., Chem.
Commun. 1994, 2009–2010.
16. (a) Li, X.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Tetrahedron: Asymmetry
2003, 14, 3819–3821; (b) Braga, A. L.; Rubim, R. M.; Schrekker, H. S.;
Wessjohann, L. A.; de Bolster, M. W. G.; Zeni, G.; Sehnem, J. A. Tetrahedron:
Asymmetry 2003, 14, 3291–3295; (c) Schinnerl, M.; Seitz, M.; Kaiser, A.; Reiser,
O. Org. Lett. 2002, 4, 471–472; (d) Västilä, P.; Pastor, I. M.; Adolfsson, H. J. Org.
Chem. 2005, 70, 2921–2929; (e) Wu, X.-W.; Hou, X.-L.; Dai, L.-X.; Tao, J.; Cao, B.-
X.; Sun, J. Tetrahedron: Asymmetry 2001, 12, 529–532.
17. Pritchett, S.; Woodmansee, D. H.; Gantzel, P.; Walsh, P. J. J. Am. Chem. Soc. 1998,
120, 6423–6424.
18. Cortez, N. A.; Aguirre, G.; Parra-Hake, M.; Somanathan, R. Tetrahedron Lett.
2009, 50, 2228–2231.
10. Jin, M.-J.; Ahn, S.-J.; Lee, K.-S. Tetrahedron Lett. 1996, 37, 8767–8770.
11. (a) Paquette, L. A.; Zhou, R. J. Org. Chem. 1999, 64, 7929–7934; (b) Yang, X.-W.;
Sheng, J.-H.; Da, C.-S.; Wang, H.-S.; Su, W.; Wang, R.; Chan, A. S. C. J. Org. Chem.
2000, 65, 295–296; (c) Oguni, N.; Omi, T.; Yamamoto, Y.; Nakamura, Y. Chem.
Lett. 1983, 841–842; (d) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl.
1991, 30, 99–101.
12. (a) Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989, 30, 1657–1660;
(b) Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi, S.; Ohno, M.
Tetrahedron Lett. 1989, 30, 7095–7098; (c) Zhang, X.; Guo, C. Tetrahedron Lett.
1995, 36, 4947–4950; (d) Guo, C.; Qiu, J.; Zhang, X.; Verdugo, D.; Larter, M. L.;
Christie, R.; Kenny, P.; Walsh, P. J. Tetrahedron 1997, 53, 4145–4158.
19. Cortez, N. A.; Rodríguez-Apodaca, R.; Aguirre, G.; Parra-Hake, M.; Cole, T.;
Somanathan, R. Tetrahedron Lett. 2006, 47, 8515–8518.
20. (a) Balsells, J.; Mejorado, L.; Phillips, M.; Ortega, F.; Aguirre, G.; Somanathan, R.;
Walsh, P. J. Tetrahedron: Asymmetry 1998, 9, 4135–4142; (b) Z. Flores-López, C.;
Z. Flores-López, L.; Aguirre, G.; Hellberg, L. H.; Parra-Hake, M.; Somanathan, R. J.
Mol. Catal. A: Chem. 2009, 50, 73–79; (c) Jiang, L.; Wu, T.-F.; Chen, Y.-C.; Zhu, J.;
Deng, J.-G. Org. Bimol. Chem. 2006, 4, 3319–3324.
21. Sosa-Rivadeneyra, M.; Muñoz-Muñiz, O.; de Parrodi, C. A.; Quintero, L.; Juaristi,
E. J. Org. Chem. 2003, 68, 2369–2375.