Synthesis of new C2-symmetrical bissulfonamide ligands and application in the enantioselective addition of alkynylzinc to aldehydes and ketones

Article abstract of DOI:10.1002/adsc.200505162

Novel C₂-symmetrical bissulfonamide ligands were easily prepared in three simple steps and applied in the enantioselective addition of alkynylzinc reagents to aldehydes. Compound 7a was found to be an outstanding ligand for this reaction. When

Full text of DOI:10.1002/adsc.200505162

FULL PAPERS
DOI: 10.1002/adsc.200505162
Synthesis of New C2-Symmetrical Bissulfonamide Ligands and
Application in the Enantioselective Addition of Alkynylzinc to
Aldehydes and Ketones
Ming Ni,a Rui Wang,a, b,* Zhi-jian Han,a Bin Mao,a Chao-shan Da,a Lei Liu,a
Chao Chena
a
Department of Biochemistry &Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000,
Peopleꢀs Republic of China
b
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences, Lanzhou 730000, Peopleꢀs Republic of China
Fax: (þ86)-931-891-2561, e-mail: wangrui@lzu.edu.cn
Received: April 19, 2005; Accepted: July 23, 2005
Abstract: Novel C2-symmetrical bissulfonamide li- to aromatic aldehydes in terms of ligand loading
gands were easily prepared in three simple steps and enantioselectivity. Moreover, ligand 7a in combi-
and applied in the enantioselective addition of alky- nation with Ti(O-i-Pr)4 was found to be effective in
nylzinc reagents to aldehydes. Compound 7a was promoting the addition reaction of an alkynylzinc re-
found to be an outstanding ligand for this reaction. agent to unactivated simple ketones under very mild
When the catalyst loading, 4 mol % of 7a, was used, conditions. The corresponding chiral tertiary propar-
high enantioselectivity with an ee value up to 97% gylic alcohols were obtained with enantiomeric ex-
was achieved under very mild conditions. When the cesses of up to 81%.
amount of ligand 7a was lowered to 2 mol %, excel-
lent levels of enantiocontrol up to 95% ee were still
achieved. So far the most economic catalyst system Keywords: aldehydes; alkynylation; asymmetric catal-
was developed for the addition of terminal alkynes ysis; homogeneous catalysis; ketones
Introduction
to aldehydes catalyzed by a b-sulfonamide alcohol 3 in
combination with Ti(O-i-Pr)4.[11a]
The enantioselective alkynylzinc addition to carbonyl
compounds[1,2] is very useful for the synthesis of chiral
propargyl alcohols, which are important and versatile
building blocks for many biologically active compounds
and natural products,[3] and has gained considerable sig-
nificance in recent years. Among the catalytic methods
developed for the asymmetric alkyne addition to alde-
hydes, the following three are currently considered the
most practical. Carreira and co-workers discovered a
catalyst based on the chiral amino alcohol N-methyl-
Although these advances have been achieved, the al-
ephedrine (1) for the alkynylzinc addition to alde- kynylation of aldehydes has not yet reached the level
hydes.[4] High enantioselectivity and high product yields of practicability that is required for a synthetically useful
were achieved for the reaction of alkynylzincs with a va- catalytic reaction. High loadings of ligands (usually
riety of aliphatic aldehydes, and the method could even 20 mol %) had to be employed in many examples cited
be run solvent-free with catalytic amounts of ligand and above for achieving excellent stereoselectivity. And
metal. Pu et al.[5] and Chan et al.[6] have found that binol even in some cases, the gram amount of the employed li-
(2) in combination with Ti(O-i-Pr)4 can catalyze the al- gand exceeded the amount of substrate. So the develop-
kynylzinc addition to aromatic aldehydes or aliphatic al- ment of highly enantioselective processes with low chi-
dehydes with high enantioselectivity. We have described ral catalyst loading and readily available chiral ligands
the highly enantioselective addition of phenylacetylene is still a challenging problem.
Adv. Synth. Catal. 2005, 347, 1659 – 1665
ꢁ 2005 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim
1659

Ming Ni et al.
FULL PAPERS
Recent investigations in the field of metal catalysis
have focused on the use of dinuclear metal complexes.[7]
In these complexes, there are distinct synergistic effects
occurring at the proximal metal centers (one metal cen-
ter acts usually behaves as a Lewis acid to activate the
carbonyl derivative, while the other metal center acts
as an activating metal for the nucleophile[8]). As a result,
the complexes display unique catalytic properties. On
the other hand, it is almost universally observed that
auxiliaries with C2-symmetry elements perform in their
capacity as stereochemical directors to provide higher
levels of absolute stereochemical control as compared
to those totally lacking in symmetry. The presence of a
C2-symmetry axis within a chiral ligand dramatically re-
duces the number of possible competing diastereomeric
transition states.[9] Thus, Yus and co-workers reported Scheme 1. Preparation of 7a and 7b from benzene-1,3-disul-
fonyl chloride and natural l-phenylalanine. Reagents and
conditions: a) SOCl2, MeOH, À308C; b) Et3N, DCM, ben-
zene-1,3-disulfonyl chloride, room temperature, 5% HCl; b)
RMgBr, THF, room temperature.
the use of C2-symmetrical bissulfonamide ligands in
the addition of Et2Zn to ketones, discovering the en-
hanced reactivity of these ligands.[10] Based on the above
facts (the high enantioselectivities were obtained in the
addition of phenylacetylene to aldehydes catalyzed by a
C1-symmetrical mononucleating b-sulfonamide alcohol in the addition of phenylacetylene to aldehydes and ke-
3 in combination with titanium tetraisopropoxide and tones, expecting that this kind of ligand with a C2-sym-
the synergistic effects in dinuclear metal complexes) metry axis can afford good results. Herein, we describe
and our previous works,[11] we decided to prepare novel the preparation and use as chiral ligands of different bis-
C2-symmetrical bissulfonamide ligands and apply them sulfonamide derivatives with C2-symmetry.
Table 1. Asymmetric addition of phenylacetylene to benzaldehyde using 7a and 7b as ligands.[a]
[b]
Entry Ligand Ligand [mol %] Ligand/Ti(O-i-Pr)4
Et2Zn [mol %] Solvent Temperature ee[c] [%]/Config.[d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
10
10
10
10
10
10
10
10
10
10
15
5
4
3
2
1.5
1
4
4
1/4
1/5
1/6
1/7
1/8
1/6
1/6
1/6
1/6
1/6
1/6
1/6
1/6
1/6
1/6
1/6
1/6
1/6
1/6
200
200
200
200
200
200
200
200
300
400
300
300
300
300
300
300
300
300
300
toluene rt
toluene rt
toluene rt
toluene rt
toluene rt
80/R
87/R
90/R
82/R
79/R
83/R
86/R
6/R
93/R
90/R
90/R
94/R
95/R
93/R
92/R
90/R
50/R
93/R
30/R
Et2O
CH2Cl2 rt
THF rt
rt
toluene rt
toluene rt
toluene rt
toluene rt
toluene rt
toluene rt
toluene rt
toluene rt
toluene rt
toluene 08C
toluene rt
[a]
[b]
[c]
[d]
Phenylacetylene/Et2Zn¼1: 1.
Ti(O-i-Pr)4 Was freshly distilled.
The enantiomeric excess was determined by HPLC analysis of the corresponding products on a Chiracel OJ-H column.
The absolute configuration was based on determination of the specific rotation and in comparison with the literature, see
ref.[12]
1660
asc.wiley-vch.de
ꢁ 2005 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim
Adv. Synth. Catal. 2005, 347, 1659 – 1665

Synthesis of New C2-Symmetrical Bissulfonamide Ligands
FULL PAPERS
Table 3. Asymmetric addition of phenylacetylene to alde-
hydes using 2 mol % of ligand 7a.[a-d]
Results and Discussion
Entry
Aldehyde
Yield [%]
ee [%][e]
Preparation of Chiral Bissulfonamide Ligands
1
2
3
4
5
6
benzaldehyde
4-chlorobenzaldehyde
4-tolualdehyde
3-tolualdehyde
4-bromobenzaldehyde
4-fluorohenzaldehyde
84
82
83
81
82
78
92
90
95
87
90
86
Three simple steps were required to prepare 7a and 7b
from commercially available benzene-1,3-disulfonyl
chloride and natural l-phenylalanine (Scheme 1). Com-
pound 6 was prepared from benzene-1,3-disulfonyl
chloride by reaction with (S)-phenylalanine methyl es-
ter 5 in the presence of triethylamine at 08C. Then the
successive reaction of the Grignard reagents with 6
gave ligands 7a and 7b.
[a]
In all of the entries, the Et2Zn/phenylacetylene/aldehyde/
Ti(O-i-Pr)4/7a ratio was 3: 3: 1: 0.12: 0.02.
All reactions were performed under argon and at room
temperature.
Ti(O-i-Pr)4 was freshly distilled before use.
The reactions were carried out for 37 h.
The enantiomeric excess was determined by HPLC analy-
sis of the corresponding products on a Chiracel OJ-H col-
umn.
[b]
[c]
[d]
[e]
Asymmetric Addition of Alkynylzinc to Aldehydes
Once ligands 7a and 7b were prepared, they were ap-
plied in the enantioselective addition of alkynylzinc to
benzaldehyde in the presence of Ti(O-i-Pr)4 (Table 1).
We varied the amount of Ti(O-i-Pr)4 and found that The sequence of enantioselectivities in solvents was tol-
the best ee values are obtained when the 7a/Ti(O-i- uene>CH2Cl2 >Et2O>THF (Table 1, entries 3, 6, 7
Pr)4 ratio is 1:6 (Table 1, entries 1–5). We found that and 8). The reaction was also affected by the amount
the reaction was strongly influenced by the solvent. of Et2Zn. When we increased the amount of Et2Zn,
the ees increased from 90% to 93% (Table 1, entries 3,
9 and 10). When the amount of the ligand was increased
Table 2. Asymmetric addition of phenylacetylene to alde-
hydes using 4 mol % of ligand 7a.[a-d]
from 10% to 15%, the ees decreased from 93% to 90%
(Table 1, entries 9, 11). To our astonishment, the ees in-
creased when we decreased the amount of ligand (Ta-
ble 1, entries 11–17). With 4 mol % of 7a, the reaction
gave the best ee (95%). We were pleased to find that
working at a catalyst loading of 1.5 mol % still afforded
excellent levels of enantiocontrol (90% ee). No signifi-
cant changes in ee values were observed when the tem-
perature of the reaction was deceased from room tem-
perature to 08C (Table 1, entry 18). Ligand 7b was tested
in this reaction and resulted in a low enantioselectivity
(Table 1, entry 19).
Under the above optimized reaction conditions, li-
gand 7a was employed to promote the enantioselective
addition of phenylacetylene to a number of aldehydes.
In most cases, enantioselectivities x90% could be ob-
tained using 4 mol % ligand for aromatic aldehydes (Ta-
ble 2, entries 1–12). Moreover, 4-tolualdehyde gave the
best ee (97% ee). Only 2-anisaldehyde, 4-anisaldehyde,
3-bromobenzaldehyde and 1-naphthaldehyde gave low-
Entry
Aldehyde
Yield
[%]
ee[e]
[%]/Config.[g]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
benzaldehyde
3-tolualdehyde
4-tolualdehyde
2-anisaldehyde
3-anisaldehyde
4-anisaldehyde
4-fluorohenzaldehyde
3-bromobenzaldehyde
4-bromobenzaldehyde
4-chlorobenzaldehyde
2-naphthaldehyde
1-naphthaldehyde
cinnamic aldehyde
isobutyl aldehyde
92
86
90
85
89
87
86
83
86
89
68
65
63
89
95/R
94
97
84[f]
91
81
90
84
93
91
91
83
71[f]
57[f]
[a]
In all of the entries, the Et2Zn/phenylacetylene/aldehyde/
Ti(O-i-Pr)4/7a ratio was 3: 3: 1: 0.24: 0.04.
[b]
All reactions were performed under argon and at room er ee values (Table 2, entries 4, 6, 8 and 12). When ali-
temperature.
phatic aldehydes were used as substrates, moderate to
good enantioselectivity was achieved. For example, cin-
namic aldehyde and isobutyl aldehyde gave respectively
71 and 57% ee (Table 2, entries 13 and 14). This also sup-
ports the literature evidence that the Zn(OTf)2/Et3N
protocol seems to be superior for aliphatic substrates.[2p]
In order to exemplify the effectiveness of the present
catalytic system even at lower catalyst loadings, a series
of substrates was submitted to the enantioselective addi-
tion of phenylacetylene using a 2 mol % loading (Ta-
[c]
[d]
[e]
Ti(O-i-Pr)4 was freshly distilled before use.
The reactions were carried out for 32 h.
The enantiomeric excess was determined by HPLC analy-
sis of the corresponding products on a Chiracel OJ-H col-
umn.
The enantiomeric excess was determined by HPLC analysis
of the corresponding products on a Chiracel OD-H column.
The absolute configuration was based on determination of
the specific rotation and in comparison with the literature,
see ref.[12]
[f]
[g]
Adv. Synth. Catal. 2005, 347, 1659 – 1665
ꢁ 2005 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim
asc.wiley-vch.de
1661

Ming Ni et al.
FULL PAPERS
Table 4. Asymmetric addition of phenylacetylene to acetophenone with 7a and 7b as ligands.[a]
[b]
Entry
Ligand
Ligand [mol%]
Solvent
Ligand\Ti(O-i-Pr)4
Et2Zn
ee[c] [%]
1
2
3
4
5
6
7
8
9
7a
7b
7a
7a
7a
7a
7a
7a
7a
7a
10
10
10
10
10
10
15
15
20
25
Toluene
Toluene
Et2O
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1: 2
1: 2
1: 2
1: 2
1: 4
1: 6
1: 2
1: 2
1: 2
1: 2
200
200
200
200
200
200
200
300
300
300
61
25
10
3
50
35
65
67
69
71
10
[a]
Phenylacetylene/Et2Zn¼1: 1.
Ti(O-i-Pr)4 was freshly distilled.
The enantiomeric excess was determined by HPLC analysis of the corresponding products on a Chiracel OD-H column.
[b]
[c]
Table 5. Asymmetric addition of phenylacetylene to aromat-
ic ketones promoted by ligand 7a.[a-d]
ble 3). Although the ee values exhibited slight drops,
high to excellent enantioselectivities were still obtained
(up to 95% ee).
Entry
Ketone
Yield [%]
ee [%][e]
1
2
3
4
5
6
7
8
9
Acetophenone
64
62
46
74
51
36
60
42
58
70
71
62
67
77
70
81
74
68
74
55
2’-Fluoroacetophenone
4’-Fluoroacetophenone
3’-Bromoacetophenone
4’-Chloroacetophenone
1’-Naphthacetophenone
3’-Methylacetophenone
4’-Methylacetophenone
3’-Methoxyacetophenone
Benzalacetone
Asymmetric Addition of Alkynylzincs to Ketones
Ligands 7a and 7b were initially tested in the asymmetric
addition of phenylacetylene to acetophenone (Table 4).
We found that ligand 7a afforded a higher ee value than
ligand 7b (Table 4, entries 1 and 2). Also, the solvents
strongly influenced the results of the reaction. Highest
enantioselectivities were obtained in toluene while low-
er enantioselectivities were afforded respectively in
ether (Table 4, entry 3), CH2Cl2 (Table 4, entry 4). Li-
gand 7a and Ti(O-i-Pr)4 were mixed in different propor-
tions and tested. When the 7a/Ti(O-i-Pr)4 ratio is 1:2,
the reaction gave the highest ee value (Table 4, entries
1, 5 and 6). When we increased the amount of ligand
7a from 10 mol % to 15 mol %, the ee increased (Ta-
ble 4, entries 1, 7). When we increased the amount of
Et2Zn from 200 to 300 mol %, the enantioselectivity in-
creased slightly (Table 4, entry 8). When the amount of
the ligand was increased from 15 mol % to 25 mol %, the
10
[a]
In all of the entries, the Et2Zn/phenylacetylene/ketone/
Ti(O-i-Pr)4/7a ratio was 3: 3: 1: 0.5: 0.25.
All reactions were performed under argon and at room
temperature.
Ti(O-i-Pr)4 was freshly distilled before use.
The reactions were carried out for 120 h.
The enantiomeric excess was determined by HPLC analy-
sis of the corresponding products on a Chiracel OD-H col-
umn.
[b]
[c]
[d]
[e]
ees increased from 67% to 71% (Table 4, entries 8, 9 and Conclusion
10).
Under the above optimized reaction conditions, li- We have readily synthesized new C2-symmetrical bissul-
gand 7a was employed to induce the enantioselective ad- fonamide ligands in three simple steps and applied them
dition ofphenylacetylenetoa number ofketones. The ee in the enantioselective addition of alkynylzincs to alde-
values were up to 81% while yields up to 74% were ob- hydes under very mild conditions. Ligand 7a exhibits ex-
tained (Table 5).
cellent catalytic activity in this reaction with a low cata-
lyst loading(4 mol %). Lowering the amount of ligand 7a
to 2 mol % still provided excellent levels of enantiocon-
trol (up to 95% ee). As a result, the developed protocol
reflects the most economic catalyst system so far for the
1662
asc.wiley-vch.de
ꢁ 2005 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim
Adv. Synth. Catal. 2005, 347, 1659 – 1665

Synthesis of New C2-Symmetrical Bissulfonamide Ligands
FULL PAPERS
77.315, 125.700, 127.410, 128.670, 129.293, 130.010, 130.726,
134.689, 141.283, 170.974; IR (KBr): n¼3455, 3428, 3326,
3248, 3093, 3029, 3003, 2953, 2861, 2761, 1813, 1721, 1603,
1584, 1495, 1450, 1431, 1339, 1311, 1274, 1253, 1207, 1178,
1156, 1099, 1079, 1041, 1010, 936, 910, 837, 802, 773, 747, 702,
683, 615, 605, 580, 559, 534, 502, 421 cmÀ1; FAB-MS: m/z¼
561.4 [calcd. for (MþH)þ: 561].
addition of a terminal alkyne to aromatic aldehydes in
terms of ligand loading and enantioselectivity. Also,
we have successfully demonstrated that ligand 7a in
combination with Ti(O-i-Pr)4 is an effective chiral cata-
lyst for the asymmetric addition of alkynylzinc to unac-
tivated simple ketones under very mild conditions.
Experimental Section
General Procedure for Preparation of 7 via the
Reaction of 6 with Grignard Reagents
A solution of 6 (1.53 g, 2.72 mmol) in 8 mL THF was added
dropwise under an argon atmosphere at 08C to a solution of
RMgBr (32.6 mmol) in 15 mL THF, which was freshly pre-
pared in the usual way. The reaction mixture was then stirred
at room temperature over 38 h. When the reaction was com-
plete (checked by TLC), a cold saturated aqueous NH4Cl sol-
ution was dropped into the mixture under vigorous stirring.
The mixture was extracted three times, then the combined or-
ganic layer was washed with brine, dried over Na2SO4 and con-
centrated under vacuum. The crude residue was purified by
column chromatography with ethyl acetate and petroleum
ether as mobile phase.
General Remarks
All reactions were carried out under an argon atmosphere and
solvents dried according to established procedures. Reactions
were monitored by thin layer chromatography (TLC). Column
chromatographic purifications were carried out using silica gel.
All aldehydes, ketones and amino acids were purchased from
Acros or Fluka. Diethylzinc was prepared from EtI with Zn
and then diluted with toluene to 1.0 M. Melting points are un-
corrected and were recorded on an X-4 melting point appara-
tus. 1H NMR spectra were measured on a Mercury Plus-300 BB
(in CDCl3 with TMS as an internal standard). IR spectra were
obtained on a Nicolet NEXUS 670 FT-IR. Optical rotations
were recorded on a Perkin-Elmer 341 polarimeter. Mass spec-
tra were recorded on VG-FAB mass spectrometer. The ee val-
ue determination was carried out using chiral HPLC with a
Chiralcel OJ-H column on a Waters apparatus with a 996
UV-detector.
Bissulfonamide (7a): White solid; yield: 1.11 g (66%); mp
1
72–738C; [a]1D8: À124 (c 1.14, CHCl3); H NMR (300 MHz,
CDCl3, TMS): d¼0.98–1.04 (m, 12H, CH3), 1.51–1.85 (m,
3
2
8H, CH2Me), 2.41–2.49 (dd, JH,H ¼10.8 Hz, JH,H ¼14.1 Hz,
3
2H, PhHAHB), 2.65 (s, 2H, OH), 2.84–2.90 (dd, JH,H
¼
2
2.7 Hz, JH,H ¼14.1 Hz, 2H, PhHAHB), 3.61–3.67 (m, 2H,
CHN), 6.00–6.03 (d, 3JH,H¼8.7 Hz, 2H, NH), 6.82–7.65 (m,
14H, 3ꢀPh-H); 13C NMR (75 MHz, CDCl3 ): d¼7.460,
7.765, 27.638, 28.035, 36.475, 62.484, 76.161, 76.573, 77.000,
77.427, 124.759, 126.637, 128.499, 128.835, 129.201, 129.506,
137.382; IR (KBr): n¼3524, 3284, 3064, 3027, 2970, 2941,
2883, 2251, 1721, 1602, 1495, 1458, 1427, 1324, 1260, 1201,
Preparation of (S)-Phenylalanine Methyl Ester (5)
(S)-Phenyalanine methyl ester was easily prepared according
to literature procedures from natural l-phenylalanine.[11i]
1
[a]2D3: þ25.0 (c 4.04, C2H5OH); H NMR (200 MHz, CDCl3,
1147, 1081, 1053, 965, 909, 837, 794, 734, 699, 679, 589 cmÀ1
;
TMS): d¼1.44 (s, 2H, NH2), 2.74–2.85 (dd, 1H, PhCH),
FAB-MS: m/z¼623 [calcd. for (MþLi)þ: 623], 639 [calcd.
¼
2.99–3.08 (dd, J 13.4 Hz, 1H, PhCH), 3.65–3.71 (m, J¼
for (MþNa)þ]: 639.
5.2 Hz, J¼8.0 Hz, 4H, CHN, CH3), 7.11–7.30 (m, 5H, Ph-H);
IR (KBr): n¼3380, 3314, 3061, 3028, 2950, 2852, 1738, 1602,
1495, 1438, 1276, 1198, 1174, 112, 1076, 1010, 839, 747,
701 cmÀ1; ESI-MS: m/z¼180 (MþH)þ.
Bissulfonamide (7b):White solid; yield: 1.27 g (58%); mp
1
119–1208C; [a]1D8: þ79 (c 1.04, CHCl3); H NMR (300 MHz,
3
CDCl3, TMS): d¼2.50 (s, 2H, OH), 2.74–2.81 (dd, JH,H
¼
¼
7.05 Hz, 2JH,H ¼14.1 Hz, 2H, PhHAHB), 3.12–3.17 (dd, 3JH,H
2
2.55 Hz, JH,H ¼14.1 Hz, 2H, PhHAHB), 4.64–4.70 (m, 2H,
3
CHN), 5.09–5.12 (d, JH,H ¼8.1 Hz, 2H, NH), 6.80–7.82 (m,
34H; 7ꢀPh-H); 13C NMR (75 MHz, CDCl3): d¼37.880,
62.103, 76.573, 77.000, 77.427, 80.877, 124.851, 125.187,
125.874, 127.003, 127.125, 127.492, 128.163, 128.575, 128.728,
128.942, 129.629, 136.970, 141.442, 143.534; IR (KBr): 3525,
3303, 3060, 3027, 2974, 2930, 2866, 1954, 1889, 1809, 1709,
1600, 1494, 1449, 1418, 1375, 1332, 1257, 1171, 1148, 1083,
1058, 1035, 1000, 974, 909, 828, 795, 770, 744, 701, 679, 577,
553, 509 cmÀ1; FAB-MS: m/z¼815 [calcd. for (MþLi)þ:
815], 831 [calcd. for (MþNa)þ: 831].
Preparation of Bissulfonamide (6)
To a solution of (S)-phenylalanine methyl ester (2.58 g,
14.4 mmol) and triethylamine (3.9 mL, 28 mmol) in CH2Cl2
(10 mL) at 08C was slowly introduced a solution of benzene-
1,3-disulfonyl chloride (1.93 g, 7 mmol) in CH2Cl2 (10 mL).
The temperature was allowed to rise to room temperature
and the reaction mixture stirred overnight. Then the mixture
was extracted with HCl (5%) and the organic layer was dried
over anhydrous Na2SO4. The solvents were removed under re-
duced pressure, the product recrystallized as a white solid;
yield: 3.18 g (81.1%); mp 133.5–134.58C; [a]1D8: À20 (c 1.16,
CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d¼2.98–3.03
Typical Procedure for Catalytic Asymmetric Addition
of Phenylacetylene to Aldehydes
3
2
(dd, JH,H ¼6.4 Hz, JH,H ¼14.2 Hz, 2H, PhHAHB), 3.04–3.09
(dd, 3JH,H ¼5.6 Hz, 2JH,H ¼14.2 Hz, 2H, PhHAHB), 3.52 (s, 6H,
3
CH3), 4.22–4.27 (m, 2H, CHN), 5.24–5.26 (d, JH,H ¼9.2 Hz,
Under an argon atmosphere, in a 10-mL round-bottom flask,
6.2 mg (0.01 mmol) of ligand 7a was dissolved in 2 mL of dry
toluene and 17.8 mL (0.06 mmol) of Ti(O-i-Pr)4 were added
2H, NH), 7.04–8.14 (m, 14H; 3ꢀPh-H); 13C NMR
(100 MHz, CDCl3): d¼39.226, 52.579, 56.880, 76.685, 77.000,
Adv. Synth. Catal. 2005, 347, 1659 – 1665
ꢁ 2005 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim
asc.wiley-vch.de
1663

Ming Ni et al.
FULL PAPERS
at room temperature followed by a solution of diethylzinc
(0.75 mL; 0.75 mmol, 1.0 M in dry toluene). After the mixture
was stirred for 12 h, 82.4 mL (0.75 mmol) of phenylacetylene
were added into the flask and the reaction continued for 1 h
at the same temperature. The flask was put into an ice-water
bath and the mixture was cooled to 08C, and 25 mL
(0.25 mmol) of benzaldehyde were introduced. The reaction
temperature returned to room temperature naturally. The re-
action mixture was stirred to completion (checked by TLC).
After the reaction was complete, it was cooled to 08C and
quenched with cold aqueous HCl (5%). The mixture was ex-
tracted with diethyl ether. The organic layer was washed with
brine, dried over Na2SO4, and concentrated under vacuum.
The resulting oil was purified by flash column chromatography
to give the product. The ee values were measured by HPLC us-
ing a chiral column.
dron: Asymmetry 1994, 5, 1901; b) Z. Li, V. Upadhyay,
A. E. DeCamp, L. DiMichele, P. J. Reider, Synthesis
1999, 1453; c) D. Boyall, F. Lopez, H. Sasaki, D. E.
Frantz, E. M. Carreira, Org. Lett. 2000, 2, 4233;
d) D. E. Frantz, R. Fässler, C. S. Tomooka, E. M. Car-
reira, Acc. Chem. Res. 2000, 33, 373; e) G. Lu, X. S. Li,
Z. Y. Zhou, W. L. Chan, A. S. C. Chan, Tetrahedron:
Asymmetry 2001, 12, 2147; f) L. Pu, H. B. Yu, Chem.
Rev. 2001, 101, 757; g) M. H. Xu, L. Pu, Org. Lett.
2002, 4, 4555; h) J. W. Bode, E. M. Carreira, J. Am.
Chem. Soc. 2001, 123, 3611; i) D. Boyall, D. E. Frantz,
E. M. Carreira, Org. Lett. 2002, 4, 2605; j) R. M. Kamble,
V. K. Singh, Tetrahedron Lett. 2003, 44, 5347; k) G. Lu,
X. S. Li, G. Chen, W. L. Chan, A. S. C. Chan, Tetrahe-
dron: Asymmetry 2003, 14, 449; l) D. Moore, W. S.
Huang, M. H. Xu, L. Pu, Tetrahedron Lett. 2002, 43,
8831; m) A. L. Braga, H. R. Appelt, C. C. Silveira,
L. A. Wessjohann, P. H. Schneider, Tetrahedron 2002,
58, 10413; n) M. Li, X. Z. Zhu, K. Yuan, B. X. Cao,
X. L. Hou, Tetrahedron: Asymmetry 2004, 15, 219;
o) Q. Z. Liu, N. S. Xie, Z. B. Luo, X. Cui, L. F. Cun,
L. Z. Gong, A. Q. Mi, Y. Z. Jiang, J. Org. Chem. 2003,
68, 7921; p) L. Pu, Tetrahedron 2003, 59, 9873; q) S. Deg-
General Procedures for the Addition of
Phenylacetylene to Ketones
Under argon, the ligand 7a (23.1 mg, 0.0375 mmol) and Ti(O-i-
Pr)4 (22.2 mL, 0.075 mmol) were mixed in dry tolue-
ne(0.50 mL) at room temperature. A solution of Et2Zn (1.0
M in toluene, 0.45 mL) was then added. After the mixture
was stirred at room temperature for 24 h, phenylacetylene
(49.4 mL, 0.45 mmol) was added and the stirring continued
for 1 h. The solution was cooled to 08C and treated with ketone
(0.15 mmol). The resulting mixture was allowed to warm to
room temperature and stirred to completion (checked by
TLC). After the reaction was complete, it was cooled to 08C
and quenched with cold aqueous HCl (5%). The mixture was
extracted with diethyl ether. The organic layer was washed
with brine, dried over Na2SO4, and concentrated under vac-
uum. The resulting oil was purified by flash column chromatog-
raphy to give the product. The ee values were measured by
HPLC using a chiral column.
´
ni, C. Wilen, R. Leino, Tetrahedron: Asymmetry 2004, 15,
231; r) S. Dahmen, Org. Lett. 2004, 6, 2113; s) Z. B. Li, L.
Pu, Org. Lett. 2004, 6, 1065.
[3] a) B. M. Trost, M. J. Krische, J. Am. Chem. Soc. 1999,
121, 6131; b) W. R. Roush, R. J. Sciotti, J. Am. Chem.
Soc. 1994, 116, 6457; c) E. J. Corey, K. A. Cimprich, J.
Am. Chem. Soc. 1994, 116, 3151.
[4] a) N. K. Anand, E. M. Carreira, J. Am. Chem. Soc. 2001,
123, 9687; b) D. E. Frantz, R. Fässler, E. M. Carreira, J.
Am. Chem. Soc. 2000, 122, 1806.
[5] a) D. Moore, L. Pu, Org. Lett. 2002, 4, 1855; b) G. Gao,
D. Moore, R. G. Xie, L. Pu, Org. Lett. 2002, 4, 4143;
[6] a) X. S. Li, G. Lu, W. H. Kwok, A. S. C. Chan, J. Am.
Chem. Soc. 2002, 124, 12636; b) G. Lu, X. S. Li, W. L.
Chan, A. S. C. Chan, Chem. Commun. 2002, 172.
[7] a) R. G. Konsler, J. Karl, E. N. Jacobsen, J. Am. Chem.
Soc. 1998, 120, 10780; b) Y. N. Belokon, B. Green, N. S.
Ikonnikov, M. North, V. I. Tararov, Tetrahedron Lett.
1999, 40, 8147; c) Q. Xu, H. Wang, X. Pan, A. S. C.
Chan, T. K. Yang, Tetrahedron Lett. 2001, 42, 6171;
d) C. W. Chang, C. T. Yang, C. D. Hwang, B. J. Uang,
Chem. Commun. 2002, 54; e) A. Picot, F. P. Gabbaꢂ, Tet-
rahedron Lett. 2002, 43, 11; f) N. Yoshikawa, N. Kumagai,
S. Matsunaga, G. Moll, T. Ohshima, T. Suzuki, M. Shiba-
saki, J. Am. Chem. Soc. 2001, 123, 2466.
Acknowledgements
We are grateful to grants from the National Natural Science
Foundation of China (Nos.20372028, 20472026), the Ministry
of Science and Technology of China, the Ministry of Education
of China, and the Chinese Academy of Sciences for financial
support.
References and Notes
[8] S. Woodward, Tetrahedron 2002, 58, 1017.
[1] Selected references on the enantioselective alkyne addi-
tion to ketones: a) L. Tan, C. Y. Chen, R. D. Tillyer,
E. J. J. Grabowski, P. J. Reider, Angew. Chem. Int. Ed.
1999, 38, 711; b) G. Lu, X. L. Li, X. Jia, W. L. Chan,
A. S. C. Chan, Angew. Chem. Int. Ed. 2003, 42, 5057;
c) P. G. Cozzi, Angew. Chem. Int. Ed. 2003, 42, 2895;
d) B. Saito, T. Katsuki, Synlett 2004, 1557; e) B. Jiang,
Z. L. Chen, X. X. Tang, Org. Lett. 2002, 4, 3451; f) P. G.
Cozzi, S. Alesi. Chem. Commun. 2004, 2448;
[9] J. K. Whitesell, Chem. Rev. 1989, 89, 1581.
´
[10] a) D. J. Ramon, M. Yus, Angew. Chem. Int. Ed. 2004, 43,
´
284; b) M. Yus, D. J. Ramon, O. Prieto, Tetrahedron:
´
Asymmetry 2003, 14, 1103; c) M. Yus, D. J. Ramon, O.
Prieto, Tetrahedron: Asymmetry 2002, 13, 2291.
[11] Selected recent examples of our group: a) Z. Q. Xu, R.
Wang, J. K. Xu, C. S. Da, W. J. Yan, C. Chen, Angew.
Chem. Int. Ed. 2003, 42, 5747; b) L. Liu, Y. F. Kang, R.
Wang, C. Chen, M. Ni, M. Z. Gong, Tetrahedron: Asym-
metry 2004, 15, 3757; c) L. Liu, R. Wang, Y. F. Kang, C.
[2] Selected references on the enantioselective alkyne addi-
tion to aldehydes: a) M. Ishizaki, O. Hoshino, Tetrahe-
1664
asc.wiley-vch.de
ꢁ 2005 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim
Adv. Synth. Catal. 2005, 347, 1659 – 1665

Synthesis of New C2-Symmetrical Bissulfonamide Ligands
FULL PAPERS
Chen, Z. Q. Xu, Y. F. Zhou, M. Ni, H. Q. Cai, M. Z.
Gong, J. Org. Chem. 2005, 70, 1084; d) Y. F. Kang, L.
Liu, R. Wang, Y. F. Zhou, W. J. Yan, Adv. Syth. Catal.
2005, 347, 243. e) Y. F. Zhou, R. Wang, Z. Q. Xu, W. J.
Yan, L. Liu, Y. F. Kang, Z. J. Han, Org. Lett. 2004, 6,
4147; f) Z. Q. Xu, C. Chen, J. K. Xu, M. B. Miao, W. J.
Yan, R. Wang, Org. Lett. 2004, 6, 1193; g) Y. F. Zhou,
R. Wang, Z. Q. Xu, W. J. Yan, L. Liu, Y. F. Gao, C. S.
Da, Tetrahedron: Asymmetry 2004, 15, 589; h) Y. F.
Kang, L. Liu, R. Wang, W. J. Yan, Y. F. Zhou, Tetrahe-
dron: Asymmetry 2004, 15, 3155; i) C. C. Da, Z. J. Han,
M. Ni, F. Yang, D. X. Liu, Y. F. Zhou, R. Wang, Tetrahe-
dron: Asymmetry 2003, 14, 659; j) D. X. Liu, L. C. Zhang,
Q. Wang, C. S. Da, Z. Q. Xin, R. Wang, M. C. K. Choi,
A. S. C. Chan, Org. Lett. 2001, 3, 2733; k) X. W. Yang,
J. H. Sheng, C. S. Da, H. S. Wang, R. Wang, A. S. C.
Chan, J. Org. Chem. 2000, 62, 295.
[12] P. V. Ramachandran, A. V. Teodorovic, M. V. Rangaish-
envi, H. C. Brown, J. Org. Chem. 1992, 57, 2379.
Adv. Synth. Catal. 2005, 347, 1659 – 1665
ꢁ 2005 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim
asc.wiley-vch.de
1665