Synthesis of C3-symmetric tris(β-hydroxy amide) ligands and their Ti(IV) complex-catalyzed enantioselective alkynylation of aldehydes

Article abstract of DOI:10.1021/ol050047v

(Chemical Equation Presented) A series of new chiral C₃- symmetric tris(β-hydroxy amide) ligands have been synthesized via the reaction of 1,3,5-benzenetricarboxylic chloride and optically pure amino alcohols (up to 96% yield). The asymmetric catalytic alkynylation of aldehydes with these new C₃-symmetric chiral tris(β-hydroxy amide) ligands and Ti (OⁱPr)₄ was investigated. Ligand 4c synthesized from (1R,2S)-(-)-2-amino-1,2-diphenylethanol is effective for the enantioselective alkynylation of various aldehydes, and high enantioselectivity was obtained with aromatic aldehydes and α,β-unsaturated aldehyde (up to 92% ee).

Full text of DOI:10.1021/ol050047v

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2081-2084
Synthesis of C3-Symmetric
Tris( -hydroxy amide) Ligands and
â
Their Ti(IV) Complex-Catalyzed
Enantioselective Alkynylation of
Aldehydes
Tao Fang, Da-Ming Du,* Shao-Feng Lu, and Jiaxi Xu*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, College of Chemistry and Molecular Engineering, Peking UniVersity,
Beijing 100871, P. R. China
dudm@pku.edu.cn
Received January 10, 2005
ABSTRACT
A series of new chiral C3-symmetric tris(
and optically pure amino alcohols (up to 96% yield). The asymmetric catalytic alkynylation of aldehydes with these new C3-symmetric chiral
tris( )-2-amino-1,2-diphenylethanol is effective
-hydroxy amide) ligands and Ti (OiPr)4 was investigated. Ligand 4c synthesized from (1R,2S)-(
â-hydroxy amide) ligands have been synthesized via the reaction of 1,3,5-benzenetricarboxylic chloride
â
−
for the enantioselective alkynylation of various aldehydes, and high enantioselectivity was obtained with aromatic aldehydes and
aldehyde (up to 92% ee).
r,â-unsaturated
C3 symmetry is intriguing in chemistry, and many
C3-symmetric compounds and their applications in chiral
molecular recognition and asymmetric catalysis have ap-
peared in the literature.1 For example, the rhodium(I) com-
plexes of enantiomerically pure tripodal phosphanes with C3
symmetry have been reported in the hydrogenation of di-
methyl itachonate giving high ee (95%).2 The C3-symmetric
diborate catalyzed the Diels-Alder reaction of cyclopenta-
diene and methacrolein in a highly enantioselective manner.3
C3-symmetric tris(2-hydroxypropyl)-amine Zr(IV) complex
has been employed in the asymmetric ring-opening of meso-
epoxides with high selectivity.4 Katsuki and co-workers have
developed tridentate tris(oxazoline) ligands as chiral auxil-
iaries in the asymmetric allylic oxidation of cycloalkenes,
and moderate to excellent enantioselectivities (up to 93%
ee) were obtained.5 Chan and co-workers have also reported
that the C3-symmetric oxazolinyl ligands catalyzed the
addition of diethylzinc to aromatic aldehydes to give second-
ary alcohols with high enantiomeric excesses (up to 90%).6
(4) Nugent, W. A.; RajanBabu, T. V.; Burk, M. J. Science 1993, 259,
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10.1021/ol050047v CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/26/2005

Development of new types of C3-symmetric ligands for
asymmetric reaction is an intriguing research area.7
BINOL 2-Ti(IV) complex can catalyze alkynylzinc addition
to both aromatic and aliphatic aldehydes with high ee values
and good yields. Recently, Wang and co-workers reported
that sulfoamido alcohol 3 and other amino alcohols can
catalyze alkynylzinc addition to aromatic aldehydes with very
good efficiency.12
Although many significant results have been achieved in
this area, much effort to develop new types of efficient chiral
catalysts for this important asymmetric reaction is still in
great need to probe the relation between the ligand struc-
ture and catalytic activity. To the best of our knowledge, no
C3-symmetric chiral ligand or catalyst has been success-
fully employed to the reaction of alkynylzinc addition to
aldehydes. Herein, we report a new approach in which
C3-symmetric chiral tris(â-hydroxy amide) ligands combined
with Ti(OiPr)4 are used to catalyze the enantioselective
alkynylation of aldehydes.
During our studies, a series of C3-symmetric ligands were
easily prepared from commercially available amino alcohols
in excellent yields. 1,3,5-Benzenetricarboxylic acid, SOCl2,
and several drops of DMF were refluxed to afford the 1,3,5-
benzenetricarboxylic chloride. Without further purification,
the trichloride reacted with chiral amino alcohols in the
presence of excess triethylamine in CH2Cl2 at room tem-
perature to afford tris(â-hydroxy amide)s 4a-d in 88-96%
yields (Figure 1).
The catalytic asymmetric alkynylation of carbonyl com-
pounds has attracted intense attention in recent years, and
many significant chiral ligands in this area have been
disclosed.8-15 This process provides a very convenient route
to afford chiral propargylic alcohols that have been applied
widely in chemistry.16 Among the catalytic methods devel-
oped for the asymmetric alkyne addition to aldehydes, several
methods are currently considered to be practical. For
example, Carreira and co-workers9 developed a highly
enantioselective catalyst based on N-methylephedrine 1 for
the alkynylation of aliphatic aldehydes. Chan and co-
workers10b and Pu’s group,11 respectively, reported that
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6863. (e) Huang, W.; Song, Y. M.; Bai, C. M.; Cao, G. Y.; Zheng, Z.
Tetrahedron Lett. 2004, 45, 4763-4767.
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Carreira, E. M. Acc. Chem. Res. 2000, 33, 373-381. (b) Pu, L.; Yu, H.-B.
Chem. ReV. 2001, 101, 757-824. (c) Pu, L. Tetrahedron 2003, 59, 9873-
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Org. Lett. 2000, 2, 4233-4236. (b) Frantz, D. E.; Fa¨ssler, R.; Carreira, E.
M. J. Am. Chem. Soc. 2000, 122, 1806-1807. (c) Bode, J. W.; Carreira, E.
M. J. Am. Chem. Soc. 2001, 123, 3611-3612. (d) Anand, N. K.; Carreira,
E. M. J. Am. Chem. Soc. 2001, 123, 9687-9688. (e) Boyall, D.; Frantz, D.
E.; Carreira, E. M. Org. Lett. 2002, 4, 2605-2606.
(10) (a) Lu, G.; Li, X.; Zhou, Z.; Chan, W. L.; Chan, A. S. C.
Tetrahedron: Asymmetry 2001, 12, 2147-2152. (b) Li, X.; Lu, G.; Kwok,
W. H.; Chan, A. S. C. J. Am. Chem. Soc. 2002, 124, 12636-12637. (c)
Lu, G.; Li, X.; Chen, G.; Chan, W. L.; Chan, A. S. C. Tetrahedron:
Asymmetry 2003, 14, 449-452.
(11) (a) Xu, M.-H.; Pu, L. Org. Lett. 2002, 4, 4555-4557. (b) Moore,
D.; Huang, W.-S.; Xu, M.-H.; Pu, L. Tetrahedron Lett. 2002, 43, 8831-
8834. (c) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855-1857. (d) Gao, G.;
Moore, D.; Xie, R. G.; Pu, L. Org. Lett. 2002, 4, 4143-4146. (e) Li, Z.-
B.; Pu, L. Org. Lett. 2004, 6, 1065-1068.
(12) (a) Xu, Z.; Wang, R.; Xu, J.; Da, C.-s.; Yan, W.-j.; Chen, C. Angew.
Chem., Int. Ed. 2003, 42, 5747-5749. (b) Zhou, Y.-f.; Wang, R.; Xu, Z.-
q.; Yan, W.-j.; Liu, L.; Gao, Y.-f.; Da, C.-s. Tetrahedron: Asymmetry 2004,
15, 589-591. (c) Kang, Y.-F.; Liu, L.; Wang, R.; Yan, W.-J.; Zhou, Y.-F.
Tetrahedron: Asymmetry 2004, 15, 3155-3159. (d) Xu, Z.; Chen, C.; Xu,
J.; Miao, M.; Yan, W.; Wang, R. Org. Lett. 2004, 6, 1193-1195.
(13) (a) Braga, A. L.; Appelt, H. R.; Silveira, C. C.; Wessjohann, L. A.;
Schneider, P. H. Tetrahedron 2002, 58, 10413-10416. (b) Liu, Q.-Z.; Xie,
N.-S.; Luo, Z.-B.; Cui, X.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-
Z. J. Org. Chem. 2003, 68, 7921-7924. (c) Marshall, J. A.; Bourbeau, M.
P. Org. Lett. 2003, 5, 3197-3199. (d) Li, M.; Zhu, X.-Z.; Yuan, K.; Cao,
B.-X.; Hou, X.-L. Tetrahedron: Asymmetry 2004, 15, 219-222.
(14) Recent examples for enantioselective alkynylation of ketones: (a)
Tan, L.; Chen, C. Y.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Angew.
Chem., Int. Ed. 1999, 38, 711-713. (b) Lu, G.; Li, X.; Jia, X.; Chan, W.
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Figure 1. New C3-symmetric ligands.
First, the C3-symmetric ligands were examined in the
asymmetric addition of phenylacetylene to benzaldehyde in
the presence of Et2Zn and Ti(OiPr)4. The zinc phenylacetylide
was obtained using the method developed by Pu and co-
workers,11c producing a white precipitate. The titanium
complex was prepared by mixing the ligand with Ti(OiPr)4.
The ligand itself was not very soluble in the reaction solvent,
while a clear solution was formed after Ti(OiPr)4 was added.
(15) Enantioselective alkynylation of R-keto ester: Jiang, B.; Chen, Z.;
Tang, X. X. Org. Lett. 2002, 4, 3451-3453.
2082
Org. Lett., Vol. 7, No. 11, 2005

The addition reactions were carried out at room temperature
for 6 h, and the results are summarized in Table 1. Ligands
Table 2. Asymmetric Addition of Phenylacetylene to
Benzaldehyde under Different Conditionsa
Table 1. Enantioselective Addition of Phenylacetylene to
Benzaldehydea
ligand
T
t
yield ee
entry ligand (mol %) yield (%)b ee (%)c configurationd
entry
solvent
L*/Ti(OiPr)4 (°C) (h) (%)b (%)c,d
1
2
3
4
5
6
7
8
9
toluene 4 mL
1:7
1:7
1:7
1:7
1:8
1:7
1:6
1:5
1:3
1:1
1:6
1:6
1:7
1:7
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
6
6
6
6
6
6
6
6
6
6
76
80
84
82
80
84
85
84
78
72
0
10
29
7
49
86
78
64
33
13
77
78
55
37
1
2
3
4
5
6
4a
4b
4c
4d
4c
4c
20
20
20
20
10
5
88
76
84
80
80
74
19
6
78
11
60
33
R
R
S
R
S
S
CH2Cl2 4 mL
hexane 4 mL
hexane 1 mL, toluene 4 mL
hexane 1 mL, CH2Cl2 4 mL
hexane 1 mL, CH2Cl2 4 mL
hexane 1 mL, CH2Cl2 4 mL
hexane 1 mL, CH2Cl2 4 mL
hexane 1 mL, CH2Cl2 4 mL
a Mole ratio of PhCHO:phenylacetylene:Et2Zn:Ti(OiPr)4 ) 1:4:4:1.2,
hexane/CH2Cl2 ) 1:4, rt. b Isolated yield by column chromatography. c Ee
was determined by HPLC analysis using Daicel Chiralcel OD col-
umn. d Absolute configurations were assigned by comparison with the
literature.17
10 hexane 1 mL, CH2Cl2 4 mL
11 hexane 1 mL, CH2Cl2 4 mL
12 hexane 1 mL, CH2Cl2 4 mL
13 hexane 2 mL, CH2Cl2 8 mL
14 hexane 3 mL, CH2Cl2 12 mL
12 83
-15 24 80
rt
rt
8
8
78
70
a Reaction was performed with mole ratio of PhCHO:phenylacetylene:
Et2Zn ) 1:4:4. b Isolated yield by column chromatography. c Ees were
determined by HPLC analysis on a Chiracel OD column. d Absolute
configurations were assigned as S by comparison with the literature.17
4a, 4b, and 4d gave low enantioselectivity (less than 20%
ee), and the corresponding propargyl alcohol has R config-
uration (Table 1, entries 1, 2, and 4). A promising result
was obtained with ligand 4c, and the corresponding optically
active propargyl alcohol was obtained in 85% yield and 78%
ee with S configuration (Table 1, entry 3). Interestingly, the
starting amino alcohols of ligands 4c and 4d are enantio-
meric, but the results obtained in the enantioselective
reactions carried out with the ligands 4c and 4d are quite
different. A cooperative effect of the ligand and Lewis acid
probably plays a decisive role. It was observed that a decrease
in the catalyst loading from 20 to 10 or 5 mol % resulted in
only a small loss of yield but a dramatic decrease in the
enantioselectivity (Table 1, entries 3, 5, and 6).
was applied, the corresponding product was obtained in 60%
yield and 3% ee, and 86% yield and 25% ee was obtained
using Wang’s method.12a
Under the optimal reaction conditions, ligand 4c was
applied to the reaction of phenylacetylene with a variety of
aromatic and aliphatic aldehydes. As the results summarized
in Table 3 show, highly enantioselective additions of
phenylacetylene to substituted benzaldehydes containing
Table 3. Catalytic Asymmetric Alkynylation of Aldehydesa
To improve the enantioselectivity, the reaction conditions,
including solvent, temperature, and amount of Ti(OiPr)4, were
optimized with 4c. The results were summarized in Table
2. We found that this reaction was strongly influenced by
solvents and the amount of Ti(OiPr)4. When the reaction was
carried out in toluene, no enantioselectivity was afforded
(Table 2, entry 1). In dichloromethane, hexane, and hexane/
toluene (v/v 1:4), low ee values (no more than 30%) were
observed (Table 2, entries 2-4). The best solvent was
hexane/dichloromethane (v/v 1:4). Gradually decreasing the
amount of Ti(OiPr)4 from 1:6 to 1:1 dramatically decreased
the enantioselectivity (Table 2, entries 7-10). Fine-tuning
the ratio of 4c/Ti(OiPr)4 from 1:6 to 1:7 produced the best
result. The corresponding optically active propargyl alcohol
was obtained in 84% yield and 86% ee (Table 2, entry 6).
When the ratio of 4c/Ti(OiPr)4 exceeded 1:7, the enantiose-
lectivity also decreased dramatically (Table 2, entry 5). When
the temperature of this reaction was decreased from room
temperature to 0 or -15 °C, no significant change in
enantioselectivity occurred but a long reaction time was
needed (Table 2, entries 11 and 12). The concentration of
the reaction is also important, as the enantiomeric excess
decreased in diluted conditions (Table 2, entries 13 and 14).
Other conditions were also tested. When Chan’s method10a
entry
R
Ar
yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
C6H5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
84
86
84
81
78
83
79
83
72
81
81
64
79
77
87
92
82
92
90
87
87
84
90
91
72
47
82
85
2-CH3OC6H4
4-CH3OC6H4
2-CH3C6H4
4-CH3C6H4
2-FC6H4
2-ClC6H4
4-ClC6H4
1-naphthyl
PhCHdCH
PhCH2CH2
(CH3)2CH
C6H5
4-CH3C6H4
4-BuC6H4
C6H5
a Reaction conditions: mole ratio of aldehyde:phenylacetylene:Et2Zn:
Ti(OiPr)4 ) 1:4:4:1.4, hexane/CH2Cl2 ) 1:4 as a solvent. b Isolated yield
by column chromatography. c Ees were determined by HPLC analysis on
Chiracel OD column (hexane/2-propanol 90:10, 1.0 mL/min). d Absolute
configurations were assigned as S according to the literature.17
Org. Lett., Vol. 7, No. 11, 2005
2083

electron-withdrawing or electron-donating groups have been
achieved by using the 4c-Ti(OiPr)4 catalyst (Table 3, entries
1-9). R,â-Unsaturated trans-cinnamaldehyde also afforded
high enantioselectivity (Table 3, entry 10). Aliphatic alde-
hydes such as 3-phenylpropionaldehyde and iso-butyralde-
hyde also gave moderate to good enantioselectivity (Table
3, entries 11 and 12). Other aryl-substituted alkynes also
worked in this reaction; 4-methyl or 4-butylphenyl acetylene
also gave high ees in the enantioselective addition to
benzaldehyde. However, alkyl-substituted acetylenes such as
(trimethylsilyl)acetylene and (triisopropylsilyl)acetylene did
not work in our conditions.
ligands, C2- and C1-symmetric ligands 5 and 6 were
synthesized. When 20 mol % ligand 5-Ti(IV) complex was
used to catalyze the addition of phenylacetylene to benzal-
dehyde, the corresponding alcohol was obtained in 51% ee
and 86% yield. The 20 mol % ligand 6-Ti(IV) complex
furnished 62% ee and 82% yield. When 30 mol % ligand 5
was used, the enantioselectivity was enhanced only slightly
(60% ee and 85% yield). Use 60 mol % ligand 6 gave the
corresponding alcohol in 40% ee and 88% yield. This result
demonstrates the efficiency of C3-symmetric ligands.
In summary, a series of new C3-symmetric tris(â-hydroxy
amide) ligands have been conveniently synthesized from
commercially available chiral amino alcohols in two steps
with excellent yields. In combination with Ti(OiPr)4, they
have been successfully applied in the asymmetric addition
of aryl alkynes to various types of aldehydes. 4c-Ti(OiPr)4
complex is a highly enantioselective catalyst for the alky-
nylzinc addition to aromatic and R,â-unsaturated aldehydes.
This simple catalyst system is practical for the asymmetric
synthesis of chiral propargylic alcohols containing aromatic
rings. The development of a library of C3-symmetric ligands
and new reactions is ongoing in our group.
To verify the structure of the titanium complex, we carried
1
out H NMR measurement. However, from the NMR data,
we cannot confirm the formation of C3 titanium complexes.
To confirm the catalytic activity of tris(â-hydroxy amide)
Acknowledgment. This project was supported by Na-
tional Natural Science Foundation of China (Grants 20372001
and 20172001) and Peking University.
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Supporting Information Available: Experimental pro-
1
cedure for synthesis of 4-6, copies of H and 13C NMR
spectra of 4a-d, and the general procedure for asymmetric
addition. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P. J.
Synthesis 1999, 1453-1458.
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