Highly enantioselective alkynylzinc addition to aromatic aldehydes catalyzed by self-assembled titanium catalysts

Article abstract of DOI:10.1021/ja025541y

A highly enantioselective catalyst generated by a combination of BINOL and another ligand with Ti(OiPr)₄ was found to be highly effective for the alkynylzinc addition to aromatic aldehydes with enantioselectivities as high as >99%. Copyright

Full text of DOI:10.1021/ja025541y

Published on Web 10/03/2002
Highly Enantioselective Alkynylzinc Addition to Aromatic Aldehydes
Catalyzed by Self-Assembled Titanium Catalysts
Xingshu Li, Gui Lu, Wai Him Kwok, and Albert S. C. Chan*
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug DiscoVery and Synthesis
and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniVersity, Hong Kong
Received January 8, 2002
The asymmetric alkynylzinc addition to aldehydes is a useful
method for the production of chiral secondary propargylic alcohols
which are versatile building blocks for asymmetric synthesis.1 As
compared with the asymmetric reduction of ynones,2 the addition
of alkynylzinc to aldehydes has a substantial advantage because
the formations of the stereogenic center and the C-C bond of the
propargylic alcohol targets are concomitant. However, in contrast
to the enantioselective addition of dialkyl compounds to aldehydes
in which considerable progress has been made,3 the enantioselective
alkynylzinc addition to aldehydes is still less developed. Several
previous studies of the alkynylation of aldehydes using amino
alcohol ligands gave moderate to good yields and ee’s.4,5 Recently,
Carreira et al. reported that a system using Zn(OTf)2 and Et3N with
stoichiometric6 or catalytic7 amounts of ligands gave high product
yields and enantioselectivities in the addition of terminal acetylenes
85-90% (entries 7-8, 10-13). As ephedrine is a low cost and
to aliphatic aldehydes; however, the catalytic system is substantially
readily available material, we chose sulfonamide 1 for the further
less effective for aromatic substrates.
study of this reaction.
We previously studied the Ti(BINOL)- and Ti(H8-BINOL)-
It is noteworthy that the use of (R)-BINOL in this self-assembled
catalyzed addition of diethylzinc and triethylaluminum to aldehydes
catalyst system produced the S configuration of the product, while
and obtained good to excellent ee’s.8 More recently, we found that
the use of (S)-BINOL gave the product in R configuration (entries
these catalysts were also effective for the alkynylzinc addition to
7-8, 16-17). These results suggested that the chiral ligand R1
aldehydes.9 In the examination of other chiral ligands for this
reaction, we found that some titanium catalysts, which were
effective for the addition of diethylzinc to aldehydes, were
ineffective for alkynylzinc addition. In a different development,
Mikami et al. reported the self-assembly of several chiral ligand
components into a highly enantioselective titanium catalyst for
carbonyl-ene reactions.10 The interesting results obtained by these
investigators clearly showed that both the rate and the enantio-
selectivity were enhanced when a combination of chiral ligand
components was used instead of its single chiral ligand component
in the enantioselective catalysis of the carbonyl-ene reaction. Herein,
we report the self-assembly of BINOL and other chiral ligands into
a highly effective titanium catalyst for the addition of alkynylzinc
to aldehydes in up to >99% ee.
The preliminary results showed that in combination with BINOL,
other chiral ligands such as a diol or a sulfonamide increased the
catalytic activity and enantioselectivity of the alkynylation of
aldehydes using Ti(OiPr)4 as catalyst precursor (see Table 1).
The use of titanium taddol (entry 4) and titanium mannitol
derivative (entry 5) gave no ee and suffered from the production
of alkylated byproducts, while titanium sulfonamides (entry 1-3)
gave essentially no enantioselectivity. In the presence of 10 mol
% (R)-BINOL, the alkynylation of benzaldehyde produced 77%
ee (entry 6). However, when (R)-BINOL or (S)-BINOL and one
of these chiral ligands (R2 ) 1-5, 10 mol % each) were added
together, the ee values of the products were found to increase to
Table 1. Asymmetric Catalysis of the Alkynylzinc Addition of
Benzaldehydea
1
2
1
2
b
c
entry
R
R
Ti/(R + R )
yield, %
ee, %
configd
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
none
none
none
none
none
R-BINOL
R-BINOL
S-BINOL
rac-BINOL
S-BINOL
S-BINOL
S-BINOL
S-BINOL
S-BINOL
none
1
2
3
4
5
7/1
7/1
7/1
7/1
7/1
7/1
7/1
7/1
7/1
7/1
7/1
7/1
100
100
100
10e
12e
90
90
88
91
89
90
87
86
85
43
83
80
81
0
0
0
0
0
none
1
77
87
90
18
89
90
86
85
93
0
96
94
97
91
94
87
S
S
1
R
R
R
R
R
R
R
1f
2
3
4
5
1
1
1
1
7/1
3.5/1
1.5/1
1.5/1
1.5/1
1.25/1
1.25/1
1/1
S-BINOL
R-BINOL
S-BINOL
S-BINOL
S-BINOL
S-BINOL
R
S
R
R
R
R
1
none
1
74
84
66
none
1/1
a Aldehyde:ZnMe2:R1:R2 ) 1:2:0.1:0.1 (molar ratio); the reaction was
carried out at 0 °C under nitrogen gas for 24-48 h. b Isolated yield of the
corresponding products. c The enantiomeric excess was determined by HPLC
analysis of the corresponding products on a Chiralcel OD column. d The
configurations were based on the measurements of the optical rotations and
in comparison with the relevant literature values.11 e The major product is
R-methylbenzyl alcohol. f 5% ligand, R2.
* To whom correspondence should be addressed. E-mail: bcachan@polyu.edu.hk.
9
12636
J. AM. CHEM. SOC. 2002, 124, 12636-12637
10.1021/ja025541y CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. The Alkynylzinc Addition to Aromatic Aldehydes
Catalyzed by Titanium (S)-BINOL in the Presence of Chiral
Sulfonamide Ligand 1a
m-nitrobenzaldehyde and p-nitrobenzaldehyde gave >99% and 99%
ee, respectively (entries 2-4). This could be explained by the strong
steric hindrance effect of the ortho-substituent which significantly
weakened the coordination of the aldehyde to the catalyst. On the
other hand, the substituent on the meta- or para-position of the
phenyl ring of the substrates exerted significantly less steric
hindrance effect on the aldehyde coordination. The electronic effect
of the substituents on the substrates also had some influences on
the enantioselectivity of the products. Electron-withdrawing groups
on the phenyl ring were favored for higher enantioselectivity (entries
3-7), while electron-donating substituents were found to lower the
ee’s of the products (entries 9-10).
In conclusion, we have developed a highly enantioselective
catalyst for the synthesis of propargylic alcohols via the alkynylzinc
addition to aromatic aldehydes. The study showed that a combina-
tion of chiral ligands, such as BINOL and a sulfonamide, with Ti-
(OiPr)4 generated a highly enantioselective catalyst which gave
products with up to >99% ee. The study of the mechanism of the
reaction and the application of this catalyst system in other
asymmetric catalytic reactions are in progress.
b
entry
aldehydes, Ar )
phenyl
yield, %
ee, %
1
2
3
4
5
6
7
8
9
83
83
82
82
85
84
86
81
78
79
96
88
2-nitrophenyl
3-nitrophenyl
4-nitrophenyl
4-bromophenyl
3-chlorophenyl
4-chlorophenyl
2-naphthyl
>99
9912
99
97
95
95
95
92
4-methoxyphenyl
4-methylphenyl
10
a The ratio of ligands (BINOL + sulfonamide 1) to titanium tetraiso-
propoxide was 1.5:1.0 in each case, and the reaction was carried out under
nitrogen gas at 0 °C for 24-48 h; the titanium tetraisopropoxide and the
substrates were distilled before use. b The ee’s were determined by HPLC
analysis of the products on a Chiralcel OD column.
Acknowledgment. We thank the Hong Kong Polytechnic
University ASD Fund, the Hong Kong Research Grants Council
(Project No. ERB03), and the University Grants Committee in Hong
Kong (Area of Excellence Scheme, AoE/P-10/01) for financial
support of this study.
(BINOL) dominated the stereochemistry of this reaction, and the
chiral ligand R2 acted as an activator in this self-assembled catalyst
system. Moreover, the use of (S)-BINOL gave products with higher
ee’s than those obtained by using (R)-BINOL in the reactions
(entries 7-8, 16-17). If rac-BINOL was used, 18% ee of the
product was obtained with R configuration instead of racemic
product (entry 9). The enantiomer (S)-BINOL in rac-BINOL
seemed to produce a more active self-assembled catalyst with the
other chiral ligand R2 than the (R)-BINOL in the same mixture.
The effects of the reaction conditions such as the choice of
solvent and the ratio of chiral ligands (R1 + R2)-to-titanium
tetraisopropoxide were investigated, and it was found that the latter
was important in influencing the enantioselectivity of the catalyst.
While keeping other conditions unchanged, the chiral ligands-to-
titanium tetraisoproppoxide ratio of 1:1.25-1.5 was found to be
optimum. Under this condition, the ee values of the product were
found to be 96-97% (entries 16, 18). When the level of the chiral
ligand was close to that of the titanium ion, the rate of the reaction
decreased somewhat.
References
(1) (a) Marshall, J. A.; Wang, X. J. J. Org. Chem. 1992, 57, 1242. (b) Roush,
W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1994, 116, 6457. (c) Vourloumis,
D.; Kim, K. D.; Petersen, J. L.; Magriotis, P. A. J. Org. Chem. 1996, 61,
4848. (d) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492.
(2) (a) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153. (b) Helal,
C. J.; Magriotis, P. A.; Corey, E. J. J. Am Chem. Soc. 1996, 118, 19038.
(c) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3124. (d)
Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1997, 38, 7511. (e) Matsumura,
K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119,
8738. (f) Bach, J.; Berenguer, R.; Garcia, J.; Loscerlales, T.; Vilarrasa, J.
J. Org. Chem. 1996, 61, 9021.
(3) (a) Oppolzer, W.; Radinov, R. N. J. Am. Chem. Soc. 1993, 115, 1593. (b)
Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49. (c)
Williams, D. R.; Fromhold, M. G. Synlett 1997, 523. (d) Pu, L.; Yu, H.
B. Chem. ReV. 2001, 101, 757.
(4) Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937.
(5) (a) Ishizaki, M.; Hoshino, O. Tetrahedron: Asymmetry 1994, 5, 1901.
(b) Li, Z.; Vpadhyay, V.; DeCamp, A. Z. DiMichele, L.; Reider, P.
Synthesis 1999, 1453.
(6) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806. (b) Boyall, D.; Lopez, F.; Sasaki, H.; Frantz, D.; Carreira, E.
M. Org. Lett. 2000, 2, 4233. (c) Frantz, D. E.; Fassler, R.; Tomooka, C.
S.; Carreira, E. M. Acc. Chem. Res. 2000, 33, 373.
A variety of aromatic aldehydes were tested under the optimal
reaction conditions, and the results were summarized in Table 2.
Good to excellent ee’s were obtained in each case (88->99% ee).
These results compared favorably with the highest enantioselec-
tivities reported for the reactions of terminal alkynes with aromatic
aldehydes using stoichiometric amounts of N-methylephedrine and
Zn(OTf)2 (94% ee for benzaldehyde with phenylacetylene and 96%
ee for benzaldehyde with 1-phenyl-4-butyne).6a From Table 2, it
can be seen that the influence of the position of substituent on the
phenyl ring of the substrates on the enantioselectivity of the product
was quite significant. For example, the alkynylation of o-nitroben-
zaldehyde gave only 88% ee, while the same reactions for
(7) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
(8) (a) Chan, A. S. C.; Zhang, F. Y.; Yip, C. W. J. Am. Chem. Soc. 1997,
119, 4980. (b) Zhang, F. Y.; Yip, C. W.; Cao, R.; Chan, A. S. C.
Tetrahedron: Asymmetry 1997, 8, 585.
(9) Lu, G.; Li, X. S.; Chan, A. S. C. Chem. Commun. 2002, 172.
(10) (a) Mikami, K.; Matsukawa, S.; Volk, T.; Terada, M. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2768. (b) Mikami, K.; Terada, M.; Korenaga, T.;
Matsumoto, Y.; Ueki, M.; Angelaud, R. Angew. Chem., Int. Ed. 2000,
112, 3532.
(11) Ramachandran, P. V.; Teodorovic, A. V.; Rangaishenvi, M. V.; Brown,
H. C. J. Org. Chem. 1992, 57, 2379.
(12) In the absence of chiral sulfonamide ligand 1, when 10 mol % or 20 mol
% of (S)-BINOL was added, the yield and the ee values are 70%, 95% ee
and 79%, 97% ee, respectively.
JA025541Y
9
J. AM. CHEM. SOC. VOL. 124, NO. 43, 2002 12637