Synthesis of C2-symmetrical bis(1,2-hydroxy sulfonamide) ligands and application in the enantioselective addition of dialkylzinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(02)00378-6

The preparation of several C₂-symmetric disulfonamides derived from 1,2-amino alcohols and disulfonyl derivatives, as well as their use in the titanium tetraisopropoxide-promoted enantioselective additions of dialkylzinc to aldehydes are described. The enantiomeric ratio is up to 96:4, the best results being obtained for aromatic aldehydes with electron-donating groups in the para-position. There are some differences in the enantioselectivity depending on the relative positioning of the amino alcohol moieties in the chiral ligand, the 1,3-disulfonyl derivative being the best system. In the case of para-substituted benzaldehyde derivatives, a negative relationship between the electron-withdrawing character of the para-substituted group and the enantioselectivity of the addition was seen, whereas the more electronic-donating character the substituent has, the higher the observed enantioselectivity.

Full text of DOI:10.1016/S0957-4166(02)00378-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1573–1579
Synthesis of C -symmetrical bis(1,2-hydroxy sulfonamide) ligands
2
and application in the enantioselective addition of dialkylzinc to
aldehydes
Miguel Yus,* Diego J. Ram o´ n and Oscar Prieto
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Received 10 July 2002; accepted 12 July 2002
Abstract—The preparation of several C -symmetric disulfonamides derived from 1,2-amino alcohols and disulfonyl derivatives, as
2
well as their use in the titanium tetraisopropoxide-promoted enantioselective additions of dialkylzinc to aldehydes are described.
The enantiomeric ratio is up to 96:4, the best results being obtained for aromatic aldehydes with electron-donating groups in the
para-position. There are some differences in the enantioselectivity depending on the relative positioning of the amino alcohol
moieties in the chiral ligand, the 1,3-disulfonyl derivative being the best system. In the case of para-substituted benzaldehyde
derivatives, a negative relationship between the electron-withdrawing character of the para-substituted group and the enantioselec-
tivity of the addition was seen, whereas the more electronic-donating character the substituent has, the higher the observed
enantioselectivity. © 2002 Elsevier Science Ltd. All rights reserved.
2
1
. Introduction
of achieving this goal. Among these approaches,
the enantioselective addition of dialkylzinc reagents
3
–6
One of the major challenges in organic synthesis is the
asymmetric preparation of compounds by means of
to aldehydes is the most widely used methodology.
An interesting modification involves the use of tita-
nium tetralkoxides as Lewis acids, which usually
allows the same enantioselectivity irrespective of the
nature of both the aldehyde or the organozinc reagent
used.
1
7
forming carbonꢀcarbon bonds. Among the different
strategies, the enantioselective 1,2-addition of
organometallic reagents to carbonyl compounds is
probably the most straightforward and useful manner
O
Ph
O
Ph
Ph
Ph
Ph
Ph
MeO
O
O2S NH OH
O2S NH OH
O2S NH OH
2
O S NH OH
X
Y
MeO
R
X
3: Y = X = H, R = Me
: Y = OH, X = Cl, R = H
1
2
4
5
O2S NH HN SO2
OH HO
O2S NH HN SO2
Ph
Ph
OH
SO2NH
HO
Ph OH Ph
Cl Cl
Cl
Cl
Cl
Cl
Ar
Cl
Cl
6
7
8
*
0
Corresponding author. Tel.: +34-965.903548; fax: +34-965.903549; URL: www.ua.es/dept.quimorg; e-mail: yus@ua.es
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00378-6

1
574
M. Yus et al. / Tetrahedron: Asymmetry 13 (2002) 1573–1579
After the pioneering work of Reetz’s group using b-
alkoxides using C -symmetrical mononucleating
hydroxy sulfonamides] we examined the synthesis of
1
8
hydroxy sulfonamide 1, a new class of ligands for the
aforementioned reaction is emerging. Concerning the
enantioselectivity, this new type of ligand has proved to
different C -symmetrical b-hydroxy sulfonamides and
2
their use as ligands in the enantioselective alkylation of
aldehydes. We think that these kind of ligands may be
useful in the aforementioned addition process. Further-
6
be equal or superior to other types of ligands having
the advantage that a huge number of different building
blocks may be used because of its modular synthesis9.
Thus, other b-hydroxy sulfonamides, such as ligands 2,
more, the presence of a C -symmetry axis within a
2
chiral ligand dramatically reduces the number of possi-
2
9
1
0
11
12
ble competing diastereomeric transition states and the
distance between both metal centers may be modulated
very easily by choosing the appropriate starting disul-
fonyl derivative, these two factors may be crucial when
we try to understand the possible role of the two metal
atoms in the chiral ligand. Herein, we describe the
preparation and use as chiral ligands of different
3
and 4, as well as tridentate ligand 5, have been
introduced for the enantioselective alkylation of alde-
hydes. In addition, g-hydroxy sulfonamide 6
the corresponding d-derivatives 7 and 8 have proved
to be excellent ligands in the aforementioned reaction.
It must be pointed out that system 8 is the only chiral
ligand able to induce the catalytic enantioselective addi-
13,14
and
15
16
bis(hydroxysulfonamide) derivatives with C -symmetry.
1
7,18
2
tion of dialkylzinc reagents to ketones.
On the other hand, recent investigations in the field of
2
. Results and discussion
Lewis acid catalysis have focused on the use of di-
19–25
nuclear metal complexes.
These complexes show
2
.1. Preparation of chiral disulfonamide ligands
unique catalytic properties as a result of distinct syner-
gistic effects occurring at the proximal metal centers.
One metal center acts usually behaves as a Lewis acid,
activating the carbonyl derivative, while the other metal
Disulfonamide ligands 9 and 10 were prepared from the
corresponding commercially available benzenedisul-
fonyl chloride by reaction with the corresponding chiral
amino alcohol (2 equiv) in the presence of triethylamine
at 0°C. After, subsequent quenching with HCl (2 M)
for removing all amine derivatives followed by treat-
ment with NaOH for removing the sulfonic acid deriva-
tives, the expected pure ligands (>95% from 300 MHz
26
center acts as an activating metal for the nucleophile,
although the possibility of forming a double coordina-
tion complex of the carbonyl compound with both
22,27,28
Lewis acidic metal centers can not be ruled out.
1
With these two facts in mind [(a) the possible synergis-
tic effect in dinuclear metal complexes and the high
enantioselectivities observed in the addition of dialkyl-
zinc reagents to aldehydes in the presence of titanium
H NMR; Table 1, entries 1–7).
The naphthalene ligand derivative 11 was prepared
from commercially available 1,5-naphthalenedisulfonic
Table 1.
Entry
Arenedisulfonyl chloride
C -ligand
2
No.
R1
R2
Yield (%)a,b
1
2
3
4
5
6
7
8
Benzene-1,2-disulfonyl chloride
Benzene-1,3-disulfonyl chloride
Benzene-1,3-disulfonyl chloride
Benzene-1,3-disulfonyl chloride
Benzene-1,3-disulfonyl chloride
Benzene-1,3-disulfonyl chloride
Benzene-1,3-disulfonyl chloride
Naphthalene-1,5-disulfonyl chloride
9
Me
Me
Ph
H
Ph
H
H
Ph
79
65
80
73
75
10a
10b
10c
10d
10e
10f
11
Me
Ph
c
1,2-C H (CH )
85
6
4
2 2
c
Ph
Me
Ph
Ph
83
d
45
a
Yield of isolated product.
Samples for HRMS were obtained by flash chromatography.
Sample for HRMS was obtained by recrystallisation from hot CH Cl .
Overall yield from the corresponding 1,5-naphthalenedisulfonic acid tetrahydrate.
b
c
2
2
d

M. Yus et al. / Tetrahedron: Asymmetry 13 (2002) 1573–1579
1575
acid tetrahydrate by reaction with a large excess of
in a synergistic way. In the 1,5-naphthelene derivative
11 the two metal centers are too far away from each
other to work together. Conversely, in the case of the
1,2-benzene derivative 9 there is not enough space for
the two metal centers, which may either force a confor-
mation in which both centers act independently or the
chiral ligand bears only one metal atom.
30
SOCl2 in refluxing benzene catalysed by DMF to
afford the expected 1,5-naphthalenedisulfonyl chloride
which, without further purification, was reacted with
(
−)-norephedrine as in the previous cases to afford the
pure ligand in reasonable overall yield (Table 1, entry
8).
3
1–34
2
.2. Asymmetric addition of dialkylzinc to aldehydes
Having established that the 1,3-arene derivatives
were the appropriate amino alcohol-linking system, the
influence of temperature was studied.
35,36
Once ligands 9–11 were prepared, the next aim was to
find the best one among them for the enantioselective
addition of diethylzinc to benzaldehyde in the presence
of titanium tetraisopropoxide to give 1-phenyl-1-
propanol 12. Firstly, the influence of the sulfonyl moi-
ety was studied using (−)-norephedrine as the amino
alcohol in all cases (Table 2, entries 1, 6 and 11). The
reaction using the ligand bearing the amino alcohol
moieties either very close to each other (such in the case
of the 1,2-benzene derivative 9; Table 2, entry 1) or
remote from each other (as in the case of 1,5-naphtha-
lene derivative 11; Table 2, entry 11) gave in both cases
a modest chemical yield and enantiomeric ratio, after 1
day reaction time. However, in the case of the 1,3-ben-
zene derivative 10d (Table 2, entry 5), under the previ-
ously mentioned conditions, the chemical yield was
excellent, the enantiomeric ratio being good, in a
shorter reaction time. This result indicates that the
length is adequate to incorporate two metal atoms only
in the 1,3-system, allowing both metal centers to work
It was found
that the best enantiomeric ratios were obtained at 0°C
with these 1,3-arene derivatives (Table 2, entries 5–7).
The influence of different substitution of the amino
alcohol was also studied. The addition of diethylzinc to
benzaldehyde using the aminopropanol derivative 10a
(Table 2, entry 2) afforded the expected alcohol 12 as a
near-racemic mixture. However, when the reaction was
performed with the corresponding phenylglycinol
derivative 10b (Table 2, entry 3), which presents a
higher steric hindrance, the enantiomeric ratio
increased to 74:26. The same result was found using the
corresponding 2-amino-1-phenylethanol derivative 10c
(Table 2, entry 4), which allows us to conclude that
both possible stereogenic centers of the amino alcohol
play a similar role in the enantiodiscrimination step.
After studying amino alcohol derivatives 10a–c with
only one stereogenic center as chiral ligands, we exam-
ined amino alcohol derivatives with two stereogenic
Table 2.
Entry
Ligand
T (°C)
t (h)
Alcohol 12
e.r. R:S
Yield (%)a
b
e.e.
1
2
3
4
5
6
7
8
9
9
0
0
0
0
24
8
8
8
16
8
8
8
8
96
24
56c
\95
\95
\95
\95
\95
\95
\95
\95
75:25
52:48
74:26
74:26
89:11
92:8
84:16
66:34
95:5
50
4
10a
10b
10c
10d
10d
10d
10e
10f
10f
11
48
48
78
84
68
32
90
30
50
−20
0
25
0
0
0
0d
1
78
e
65:35
75:25
1
1
f
0
30
a
b
c
d
e
f
Isolated yield after bulb-to-bulb distillation.
Determined by GLC analysis using a i-CD column.
Starting aldehyde was recovered in 40% yield.
The reaction was performed in the absence of Ti(OPr ) .
Starting aldehyde and benzylic alcohol were detected in 10% yield each.
Starting aldehyde was recovered in 65% yield.
i
4

1
576
M. Yus et al. / Tetrahedron: Asymmetry 13 (2002) 1573–1579
centers (Table 2, entries 6, 8 and 9). The presence of a
methyl and a phenyl group in the starting amino alco-
hol [(−)-norephedrine derivative 10d; Table 2, entry 6]
led to an increase in the enantiomeric ratio to 92:8.
When the same reaction was performed with the
bicyclic ligand 10e, derived from cis-1-amino-2-indanol,
the enantiomeric ratio in the secondary alcohol 15 fell
dramatically to 66:34 (Table 2, entry 8). However, when
the 1,2-diphenyl derivative 10f was used as chiral lig-
and, the observed enantiomeric ratio was the highest of
all of the ligands examined here (Table 2, entry 9).
Finally, it must be pointed out that the enantioselective
addition of diethylzinc to benzaldehyde performed
using chiral ligand 10f in absence of titanium alcohox-
and the enantiomeric ratio of the secondary alcohol
derivatives obtained. It is believed that the rate-deter-
mining step in this reaction is the transfer of the alkyl
group from the metal to the carbonyl moiety, indepen-
44
45
dently of the positive or negative sign of the afore-
mentioned relationship. There are other possibilities,
46
such as unchanging enantioselectivity irrespective of
the para-substituted group, which has been interpreted
considering that the rate-determining step of the reac-
tion is the removal of the alkoxide-product from the
catalytic species: Finally, it is also possible to find a
negative relationship between the basicity of the para-
functional group (instead of their electronic properties)
16
and the enantioselectivity of the reaction, which could
indicate that the rate-determining step of the reaction is
the complexation between the acidic catalytic species
and the carbonyl compound. In our case, we found that
electron-donating groups (methoxy; Table 3, entry 2),
neutral (hydrogen; Table 2, entry 9) or lightly electron-
withdrawing groups (chlorine; Table 3, entry 3) have a
slight influence on the enantioselectivity, while, strong
electron-withdrawing groups such as trifluoromethyl or
cyano substituents gave much lower enantiomeric ratios
(Table 3, entries 4 and 5). It must be pointed out that
the trend followed by para-substituted benzaldehydes
(with the exception of benzaldehyde) is that the more
electronic donating character of group the higher the
enantioselectivity of the addition reaction.
37,38
ide, (as has been reported for related hydroxy
as
3
9–42
well as different functionalised
sulfonamides),
induced poor enantioselectivity (Table 2, entry 10).
Once the optimal ligand 10f was found, different alde-
hydes were tested as substrates in the enantioselective
addition of dialkylzinc under the same conditions
described in Table 2, entry 9 (Table 3). The first remark
is that the enantioselectivity of the reaction using
dimethylzinc instead of diethylzinc as source of nucleo-
phile is slightly lower (compare Table 2, entry 9 with
Table 3, entry 1).
The influence of different para-substituted benzalde-
hyde derivatives on the enantioselectivity of the reac-
tion was also studied in order to establish whether there
The enantiomeric excess found in the case of using
aliphatic aldehydes was lower than for aromatic ones
43
is any relationship between the Hammet constants
Table 3.
Ph
Ph
O2S NH OH
i
OH
Ti(OPr)4 / PhMe
ºC
1
2
R CHO + R 2Zn +
R1
R2
3-22
0
1
O2S NH OH
Ph
Ph
(10%)
1
Alcohola
e.r.b R:S
Entry
R CHO
No.
R2
e.e.
1
2
3
4
5
6
7
8
9
PhCHO
13
14
15
16
17
18
19
20
21
22
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
89:11
96:4
78
92
88
78
74
60
54
48
74
72
4-CH OC H CHO
3
6
4
4-ClC H CHO
94:6
6
4
c
4-CF C H CHO
89:11
87:13
80:20
77:23
74:26
87:13
86:14
3
6
4
4-NCC H CHO
6
4
d
n-C H13CHO
6
d
c-C H11CHO
6
e
c,d
c,d,f
c,d,f
PhCH CH CHO
2
2
(E)-PhCHꢁCHCHO
PhCꢂCCHO
1
0
a
b
c
d
e
f
>
95% isolated yield after bulb-to-bulb distillation.
Determined by GLC analysis using a b-CD column.
Determined by GLC analysis using a g-CD column.
Determined as trifluoroacetate derivative.
>
95% isolated yield after 48 h.
Determined after transformation into compound 20 by standard hydrogenolysis using Pd/C.

M. Yus et al. / Tetrahedron: Asymmetry 13 (2002) 1573–1579
1577
(
Table 3, entries 6–8), the reaction time being longer for
3306, 3280 (OH, NH), 3091, 1610 (CꢁCH), 1329 (SO ),
2
−
1
the first ones. The reaction with aldehydes conjugated
with alkenes or alkynes gave enantioselectivities similar
to slightly electron-deficient aromatic aldehydes (Table
1120 cm (CO); lH (CDCl ) 0.74 (6H, d, J=6.7,
3
2×CH ), 2.88 (2H, s, 2×OH), 3.55–3.65 (2H, m, 2×
3
CHN), 4.75–4.80 (2H, m, CHO), 6.38 (2H, d, J=7.9,
2×NH), 7.20–7.30 (10H, m, 2×Ph), 7.70–7.75, 8.20–8.25
(2 and 2H, respectively, 2m, C H S ; l (CDCl ) 13.9
3
, entries 9 and 10). Finally, it must be pointed out that
17,18
the addition of diethylzinc to acetophenone
under
6
4
2
C
3
the same reaction conditions failed after 8 days, the
unchanged starting ketone being recovered.
(2C), 55.8 (2C), 75.6 (2C), 126.0 (4C), 127.5 (2C), 128.2
(4C), 131.35 (2C), 133.1 (2C), 138.15 (2C), 140.0 (2C);
+
m/z (DIP) 504 (M , <1%), 398 (11), 397 (30), 381 (19),
3
80 (21), 379 (53), 338 (68), 337 (41), 336 (43), 318 (11),
3. Conclusion
272 (20), 247 (37), 246 (40), 220 (22), 205 (15), 189 (10),
83 (13), 169 (12), 168 (29), 166 (14), 150 (10), 141 (18),
1
In conclusion, we have described new chiral C -symme-
135 (17), 134 (59), 133 (35), 132 (49), 131 (18), 130 (20),
118 (47), 117 (30), 115 (11), 109 (13), 108 (43), 107 (22),
106 (41), 105 (20), 104 (11), 97 (19), 96 (11), 93 (19), 92
(70), 91 (53), 90 (12), 79 (88), 78 (67), 77 (100), 76 (31),
74 (11), 65 (20), 64 (12), 57 (16), 51 (13). HRMS calcd
for C H N O S : 504.1388. Found: 504.1394.
2
try disulfonamide ligands, which can be easily prepared
from chiral amino alcohols and disulfonyl derivatives
and have been successfully tested in the enantioselective
addition of dialkylzinc reagents to aldehydes in the
presence of titanium isopropoxide. The enantioselectiv-
ity is higher for aromatic aldehydes than either
aliphatic or a,b-unsaturated ones. In the case of para-
substituted benzaldehyde derivatives, the method seems
to show a very slight negative relationship between the
electron-withdrawing character of the para-substituted
group and the observed enantioselectivity of the addi-
tion reaction, whereas the more electronic-donating
character the substituent has, the higher the observed
enantioselectivity.
24
28
2
6 2
4.3. N,N%-Di[(1S)-2-hydroxy-1-methylethyl]-1,3-ben-
zenedisulfonamide 10a
White solid, R 0.34 (ethyl acetate); mp 76–78°C (ethyl
f
acetate/hexane); [h] =−5.1 (c 3.4, EtOH); w (melted)
D
3513, 3256 (OH, NH), 3052, 1631 (CꢁCH), 1356 (SO ),
2
−
1
1153 cm (CO); lH (CD OD) 0.93 (6H, d, J=6.1,
3
2×CH ), 3.26 (4H, d, J=7.3, 2×CH O), 3.30–3.40 (2H,
3
2
m, 2×CHN), 7.70, 8.03, 8.29 (1, 2 and 1H, respectively,
t, d and s, respectively, J=7.3, C H S ); l (CD OD)
6
4
2
C
3
4
. Experimental
18.0 (2C), 52.6 (2C), 66.75 (2C), 126.0, 131.3 (2C),
+
1
31.4 (2C), 144.5; m/z (DIP) 352 (M , <1%), 335 (26),
324 (15), 323 (90), 322 (64), 321 (29), 305 (21), 304 (26),
03 (36), 289 (18), 265 (30), 264 (37), 263 (13), 262 (10),
4.1. General
3
36
Full general statements were described elsewhere. All
reactions using dialkylzinc reagents were carried out
under argon atmosphere using standard techniques.
260 (11), 248 (18), 247 (18), 246 (100), 232 (15), 222
(18), 221 (18), 220 (43), 215 (32), 214 (49), 196 (19), 185
(27), 184 (66), 183 (36), 182 (87), 157 (20), 156 (85), 145
(
45), 141 (43), 140 (50), 124 (35), 123 (13), 119 (73), 118
(49), 117 (33), 109 (10), 108 (20), 107 (61), 96 (11), 92
17), 91 (41), 89 (16), 77 (75), 76 (27), 75 (65), 74 (12),
4.2. Preparation of ligands
(
To a solution of the corresponding amino alcohol (26.5
65 (15), 59 (19), 58 (34). HRMS calcd for
mmol) and triethylamine (53 mmol, 7.5 mL) in CH Cl2
C H N O S ·H O: 334.0657. Found: 334.0673.
2
12 20
2
6
2
2
(
25 mL) at 0°C was slowly added (ca. 10 min) a
solution of corresponding arenedisulfonyl chloride (10
mmol) in CH Cl (15 mL). The temperature was
allowed to rise to 25°C overnight. The mixture was
extracted with HCl (2×50 mL, 2 M) and the resulting
organic layer was extracted again with NaOH (2×25
mL, 2 M) and the organic layer was dried over Na SO .
4.3.1.
N,N%-Di[(1S)-2-hydroxy-1-phenylethyl]-1,3-ben-
zenedisulfonamide 10b. White solid, R 0.28 (hexane/
2
2
f
ethyl
acetate:
3/7);
mp
142–144°C
(ethyl
acetate/hexane); [h] =+56.4 (c 3.7, EtOH); w (melted)
D
3513 (OH), 3283, 3280 (NH), 3060, 1647 (CꢁCH), 1318
−
1
(SO ), 1159 cm (CO); lH (CD OD) 3.69 (4H, d,
2
4
2
3
The solvents were removed under reduced pressure (15
torr), obtaining the pure title compounds 9–11 in yields
indicated in Table 1. Naphthalene-1,5-disulfonyl chlo-
ride was prepared by reaction of commercially available
J=6.1, 2×CH O), 4.47 (2H, t, J=6.1, 2×CHN), 7.16
2
(10H, s, 2×Ph), 7.29, 7.73, 8.14 (1, 2 and 1H, respec-
tively, t, d and s, respectively, J=7.3, C H S ); l
C
6
4
2
(CD OD) 61.1 (2C), 66.4 (2C), 126.3, 128.0 (4C), 128.4
3
1
9
,5-naphthalenedisulfonic acid tetrahydrate (25 mmol,
g) with SOCl2 (250 mmol, 18.5 mL) in refluxing
(2C), 129.2 (4C), 130.35 (2C), 131.0 (2C), 139.3 (2C),
+
143.2; m/z (DIP) 476 (M , <1%), 446 (11), 445 (65), 379
benzene (175 mL) catalysed by DMF (0.5 mL), accord-
(15), 367 (43), 327 (18), 326 (70), 325 (18), 287 (13), 246
(14), 245 (42), 220 (11), 208 (11), 207 (22), 181 (25), 180
(16), 165 (15), 157 (23), 156 (46), 154 (10), 153 (25), 149
(50), 148 (65), 134 (14), 133 (56), 132 (29), 131 (40), 130
30
ing to the literature method and was used without
further purification. Spectroscopic, physical and analyt-
ical data follow.
(
63), 121 (35), 120 (13), 119 (35), 118 (10), 117 (23), 116
4
.2.1.
N,N%-Di[(1S,2R)-2-hydroxy-1-methyl-2-phenyl-
(64), 115 (15), 107 (14), 106 (57), 105 823), 104 (42), 93
(13), 92 (23), 91 (48), 89 (10), 79 (53), 78 (25), 77 (46),
76 (30), 75 (17), 65 (15), 64 (78), 51 (13). HRMS calcd
for C H N O S : 476.1075. Found: 476.1075.
ethyl]-1,2-benzenedisulfonamide 9. White solid, R 0.69
f
(
hexane/ethyl acetate: 1/1); mp 111–113°C (ethyl ace-
tate/hexane); [h] =−63.3 (c 3.0, EtOH); w (melted)
D
22 24
2
6 2

1
578
M. Yus et al. / Tetrahedron: Asymmetry 13 (2002) 1573–1579
4
.3.2. N,N%-Di[(2R)-2-hydroxy-2-phenylethyl]-1,3-ben-
(11), 64 (69), 63 (10). HRMS calcd for C H N O S :
24 24 2 6 2
500.1075. Found: 500.1089.
zenedisulfonamide 10c. White solid, R 0.33 (hexane/
f
ethyl
acetate:
2/3);
mp
116–118°C
(ethyl
acetate/hexane); [h] =−54.7 (c 2.8, EtOH); w (melted)
4.3.5. N,N%-Di[(1S,2R)-2-hydroxy-1,2-diphenylethyl]-1,3-
D
3
507, 3291 (OH, NH), 3070, 1632 (CꢁCH), 1330 (SO ),
benzenedisulfonamide 10f. White solid, R 0.55 (hexane/
2
f
−
1
1
152 cm (CO); l (CDCl ) 2.95–3.00, 3.15–3.20 (2
ethyl acetate: 2/3); mp 88–90°C (CH Cl ); [h] =−60.6
H
3
2
2
D
and 2H, respectively, 2m, 2×CH N), 3.80 (2H, s, 2×
OH), 4.60–4.65 (2H, m, 2×CHO), 6.22 (2H, s, 2×NH),
(c 2.9, EtOH); w (melted) 3510, 3284 (OH, NH), 3060,
2
−1
1606 (CꢁCH), 1328 (SO ), 1152 cm (CO); l (DMSO-
6
2
H
7
.05–7.15 (10H, s, 2×Ph), 7.53, 7.94, 8.50 (1, 2 and 1H,
d ) 2.55 (2H, s, 2×OH), 4.25–4.30 (2H, m, 2×CHN),
respectively, t, d and s, respectively, J=7.3, C H S ); l
4.55-4.65 (2H, m, 2×CHO), 5.41 (2H, d, J=4.8, 2×
NH), 6.95-7.00, 7.10-7.15 (10 and 10H, respectively,
2m, 4×Ph), 7.23, 7.71, 8.35 (1, 1 and 2H, respectively, t,
s and d, respectively, J=9.6, C H S ); l (DMSO-d6)
6
4
2
C
(
CDCl ) 50.1 (2C), 72.4 (2C), 125.5, 125.75 (4C), 128.05
3
(
2C), 128.45 (4C), 130.0 (2C), 130.9 (2C), 140.3 (2C),
+
41.35; m/z (DIP) 476 (M , <1%), 352 (14), 351 (48),
41 (17), 325 (20), 324 (27), 323 (24), 306 (17), 277 (56),
61 (54), 260 (17), 259 (60), 196 (28), 194 (35), 169 (19),
67 (16), 166 (13), 165 (11), 141 (35), 140 (16), 120 (40),
19 (19), 118 (34), 117 (10), 108 (52), 106 (11), 105 (19),
04 (33), 91 (50), 79 (51), 78 (35), 77 (55), 76 (41), 64
6
4
2
C
63.5 (2C), 75.36 (2C), 124.25, 126.7 (2C), 126.8 (4C),
127.15 (2C), 127.2 (4C), 127.6 (4C), 128.2 (4C), 128.8
(2C), 129.15 (2C), 138.5 (2C), 141.75, 142.6 (2C); m/z
+
(DIP) 628 (M , <1%), 504 (17), 503 (50), 458 (10), 325
(40), 245 (15), 167 (14), 141 (20), 105 (35), 79 (45), 77
(38), 76 (28), 64 (100). HRMS calcd for
C H N O S ·H O: 610.1596. Found: 610.1592.
22 24 2 6 2 2
440.0864. Found: 440.0859.
34
32
2
6
2
2
4
.3.3. N,N%-Di[(1S,2R)-2-hydroxy-1-methyl-2-phenyl-
4.3.6.
N,N%-Di[(1S,2R)-2-hydroxy-1-methyl-2-phenyl]-
ethyl]-1,3-benzenedisulfonamide 10d. White solid, Rf
1,5-naphthalenedisulfonamide 11. White solid, R 0.44
f
0.58 (ethyl acetate); mp 82–84°C (ethyl acetate/hexane);
(hexane/ethyl acetate: 2/3); mp 208–210°C (ethyl ace-
h] =−8.9 (c 2.05, EtOH); w (melted) 3515 (OH), 3279,
tate/hexane); [h] =−23.5 (c 2.35, DMF); w (melted)
D
D
−
1
211 (NH), 3022, 1605 (CꢁCH), 1328 (SO ), 1129 cm
3382, 3298 (OH, NH), 3060, 1647 (CꢁCH), 1316 (SO ),
2
2
−
1
CO); lH (CDCl ) 0.78 (6H, d, J=6.7, 2×CH ), 3.33
1129 cm (CO); lH (CD OD) 0.81 (6H, d, J=6.1,
3
3
3
2H, s, 2×OH), 3.60–3.65 (2H, m, 2×CHN), 4.75–4.80
2H, m, 2×CHO), 5.81 (2H, s, 2×NH), 7.15–7.25 (10H,
2×CH ), 3.20–3.25 (2H, m, CHO), 3.25–3.35 (2H, m,
3
CHN), 4.39 (2H, d, J=6.1, 2×NH), 6.80–7.05 (10H, m,
2×Ph), 7.55, 8.15, 8.71 (2, 2 and 2H, respectively, dd, d
and d respectively, J=7.3, 8.5, C H S ); l (CD OD)
6
4
2
C
3
10
6
2
C
3
(
(
(
2C), 55.25 (2C), 75.65 (2C), 125.45, 125.55 (4C), 127.65
2C), 128.27 (4C), 130.05 (2C), 130.49 (2C), 139.85
2C), 142.55; m/z (DIP) 504 (M , <1%), 382 (29), 381
22), 380 (76), 379 (12), 355 (34), 339 (16), 338 (33), 337
16.5 (2C), 57.75 (2C), 77.6 (2C), 126.9 (2C), 127.1 (4C),
128.25 (2C), 128.6 (2C) 128.7 (4C), 130.45 (2C), 131.6
(2C), 138.5 (2C), 143.15 (2C); m/z (DIP) 554 (M ,
+
+
8
<1%), 429 (47), 341 (11), 323 (72), 259 (48), 233 (12),
195 (48), 163 (12), 127 (16), 126 (51), 119 (15), 118 (22),
108 (12), 107 (100), 106 (86), 105 (56), 104 (28), 77 (61).
HRMS calcd for C H N O S : 554.1545. Found:
(
(
25), 334 (40), 292 (17), 291 (74), 289 (44), 275 (30), 274
100), 273 (76), 263 (24), 248 (28), 246 (24), 210 (37),
09 (61), 208 (21), 205 (27), 193 (13), 185 (22), 184 (56),
83 (45), 182 (86), 168 (14), 167 (58), 166 (11), 165 (30),
56 (13), 155 (18), 154 (10), 153 (14), 152 (11), 142 (13),
41 (68), 140 (57), 135 (11), 134 (73), 133 (66), 124 (21),
23 (16), 120 (11), 119 (70), 118 (57), 117 (86), 108 (70),
07 (33), 106 (27), 105 (39), 104 (13), 92 (19), 91 (85), 80
28
30
2
6 2
554.1588.
4.4. Enantioselective addition of dialkylzinc to alde-
hydes in the presence of ligands 9–11 and titanium
tetraisopropoxide. General procedure
HRMS calcd for C H N S O : 504.1388. Found:
To a solution of the corresponding ligand 9–11 (0.5
mmol) in toluene (5 mL) under nitrogen atmosphere
was added a solution of the appropriate dialkylzinc
reagent (9 mmol, 4.5 mL, ca. 2 M) at 0°C. After 10
min, titanium tetraisopropoxide (6.5 mmol, 2 mL) was
added to the above solution and after 10 additional
min, the corresponding aldehyde (5 mmol) was succes-
sively added. The resulting mixture was stirred at the
same temperature for 5 h. Then methanol (ca. 1 mL)
2
4
28
2
2
6
504.1398.
4
.3.4.
N,N%-Di[(1R,2S)-1-hydroxy-2,3-dihydro-1H-2-
indenyl]-1,3-benzenedisulfonamide 10. White solid, Rf
0.34 (hexane/ethyl acetate: 3/7); mp 150–152°C
(
3
CH Cl ); [h] =+9.8 (c 2.85, DMSO); w (melted) 3469,
2
2
D
267 (OH, NH), 3060, 1444 (CꢁCH), 1330 (SO ), 1150
2
−
1
cm (CO); lH (CD OD) 2.64, 2.83 (2 and 2H, respec-
3
tively, d and dd, respectively, J=15.8, 4.2, 2×CH2),
and saturated NH Cl solution (ca. 20 mL) were succes-
4
4
.05–4.10 (2H, m, 2×CHO), 4.60–4.65 (2H, m, 2×
sively added, the mixture was filtered through Celite,
extracted with ethyl acetate (3×50 mL) and the organic
layer was dried over Na SO . The solvents were
CHN), 6.75–6.80, 6.95–7.00, 7.05–7.15 (2, 2 and 4H,
respectively, 3m, 2×C H C ), 7.78, 8.14, 8.39 (1, 2 and
6
4
2
2
4
1
H, respectively, t, d and s, respectively, J=7.3,
removed under reduced pressure (15 torr) and the
residue was distilled bulb-to-bulb to yield the expected
alcohols. Yields and enantiomeric ratios (e.r.) are
C H S ), 8.02 (2H, s, 2×NH); l (CD OD) 55.2 (2C),
6
4
2
C
3
7
1
1
0.65 (2C), 81.8 (2C), 133.55 (2C), 134.15, 134.55 (2C),
35.8 (2C), 137.1 (2C), 139.8 (2C), 140.05, 149.9 (2C),
50.4 (2C), 152.6 (2C); m/z (DIP) 500 (M , <1%), 379
1
6
included in Tables 2 and 3. Compounds 12–15, 17, as
+
36
well as 18–22, were already described by us and were
(
100), 273 (15), 148 (97), 132 (18), 130 (10), 105 (13), 91
characterised by comparison of their physical and spec-

M. Yus et al. / Tetrahedron: Asymmetry 13 (2002) 1573–1579
1579
troscopic data with those reported in the literature.
Spectroscopic and physical data, as well as literature
references follow.
16. Ram o´ n, D. J.; Yus, M. Tetrahedron: Asymmetry 1997, 8,
2479–2496.
17. Ram o´ n, D. J.; Yus, M. Tetrahedron Lett. 1998, 39,
1239–1242.
4
7,48
4.4.1.
1-(4-Trifluomethylphenyl)propan-1-ol
16.
R
18. Ram o´ n, D. J.; Yus, M. Tetrahedron 1998, 54, 5651–5666.
19. Konsler, R. G.; Karl, J.; Jacobsen, E. N. J. Am. Chem.
Soc. 1998, 120, 10780–10781.
Colourless oil, bp 140–145°C (0.1 torr), t 6.06; t (R)
R
54.17, tR (S) 55.40 [Conditions: Tcolumn=90°C (5 min)
and 180°C (0.1°C/min)]; R 0.54 (hexane/ethyl acetate:
20. Belokon’, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.;
Tararov, V. I. Tetrahedron Lett. 1999, 40, 8147–8150.
21. Xu, Q.; Wang, H.; Pan, X.; Chan, A. S. C.; Yang, T.-k.
Tetrahedron Lett. 2001, 42, 6171–6173.
f
7
/3); [h] =+19.45 [c 3.2, MeOH; e.r. (R/S) 89.0:11.0];
D
w (film) 3361 (OH), 3027, 1618 (CHꢁC), 1327 (CF),
−
1
1
125 cm (CO); l (CDCl ) 0.93 (3H, t, J=7.3, CH ),
H 3 3
1
.65–1.80 (2H, m, CH ), 1.84 (1H, s, OH), 4.67 (1H, t,
22. Ooi, T.; Saito, A.; Maruoka, K. Chem. Lett. 2001, 1108–
1109.
23. Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.;
Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 2466–2467.
2
J=6.4, CHO), 7.45, 7.60 (2 and 2H, respectively, 2d,
J=8.1, C H ); l (CDCl ) 9.35, 31.5, 74.5, 127.95 (q,
6
4
C
3
1
3
2
JCF=890.8), 120.15 (q, JCF=271.1), 124.8 (2C, q,
JCF=10.9), 125.75 (2C), 148.05; m/z 204 (M , 3%), 175
+
(
100), 145 (10), 127 (78).
24. Picot, A.; Gabba ¨ı , F. P. Tetrahedron Lett. 2002, 43,
11–13.
25. Chang, C.-W.; Yang, C.-T.; Hwang, C.-D.; Uang, B.-J.
Acknowledgements
Chem. Commun. 2002, 54–55.
2
2
6. Woodward, S. Tetrahedron 2002, 58, 1017–1050.
7. Hanawa, H.; Kii, S.; Maruoka, K. Adv. Synth. Catal.
2001, 343, 57–60.
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1939.
This work was financially supported by the DGICYT
Project PB97-0133) and DGI (Project BQU2001-0538)
from the Spanish Ministerio de Educaci o´ n, Cultura y
(
Deporte.
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