Titanium-catalyzed enantioselective alkynylation of aldehydes
Gui Lu, Xingshu Li, Wing Lai Chan* 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. E-mail: bcachan@polyu.edu.hk
Received (in Cambridge, UK) 30th August 2001, Accepted 29th November 2001
First published as an Advance Article on the web 2nd January 2002
A simple and practical method to make chiral propargylic
alcohols has been developed: in the presence of a titanium
alkoxide catalyst prepared in situ from titanium tetra-
of toluene, ether, hexane, dichloromethane and THF gave a
product with e.e.’s ranging from 65 to 92%.
Titanium tetraisopropoxide played an important role in the
catalytic reaction. When the alkynylation was catalyzed by (R)-
8
H -BINOL alone, there was no enantioselectivity at all. The
enantioselectivity of the reaction was found to be sensitive to
the molar ratio of chiral ligand to substrate. As the molar ratio
increased, the e.e. increased. When the ligand–substrate ratio
reached about 20%, the product e.e. reached a plateau.
The results of the addition of alkynes to a variety of aldehydes
catalyzed by (R)-H -BINOL were summarized in Table 2.
8
8
isopropoxide and (R)-H -binaphthol, a variety of aromatic
aldehydes were converted to the corresponding chiral
propargylic alcohols with very good enantioselectivities (up
to 96.2% e.e.) and yields.
Chiral propargylic alcohols are useful building blocks for the
1
enantioselective synthesis of complex molecules. Two general
approaches to the preparation of optically active propargylic
2
alcohols have been reported starting from either ynones or
Similar to the catalytic addition of diethylzinc to aldehydes, it
was clearly observed that the enantioselectivities of the
aldehydes.3 The method of alkynyl addition has a strategic
synthetic advantage over the ynone reduction method because
the former forms a new C–C bond with concomitant creation of
a stereogenic center in a single transformation, while in the
latter the C–C bond and the stereogenic center are formed
separately. The catalytic alkynylation with high enantioselectiv-
ity is relatively rare.3
,4
reactions catalyzed by (R)-H
8
-BINOL were higher than those
obtained using (R)-BINOL.
The electronic effect of the substrate was substantially less
important than the steric hindrance effect for the enantiose-
lectivity of the reaction. For example, while p-chloro- or m-
chlorobenzaldehydes gave products with only slightly higher
e.e.’s than those from p-methylbenzaldehyde and benzalde-
hyde, the o-chlorobenzaldehyde gave a product of significantly
lower e.e. This was probably due to the strong steric hindrance
effect of the ortho-substituent which weakened the coordination
of the substrate to the chiral catalyst and thus lowered the
influence of the chiral environment of the catalyst on the
orientation of the substrate. Consequently lower enantiose-
lectivities were obtained for the alkynylation of such aldehydes.
Moderate to good e.e.’s were also obtained in the alkynylation
of aliphatic aldehydes. The best enantioselectivity of 96% was
obtained in the alkynylation of 3-nitrobenzaldehyde catalyzed
,4
The successful resolution of racemic BINOL provides an
5
economic production of (S)- or (R)-BINOL and consequently
provides an excellent opportunity for the exploitation of (S)-
and (R)-BINOL and their derivatives as readily available and
potentially low-cost chiral auxiliaries for asymmetric synthesis.
Recent studies6 have shown that chiral catalysts derived from
,7
5
8
,5A,6,6A,7,7A,8,8A-octahydro-1,1A-bi-2-naphthyl ligands (H -
BINOL) exhibited higher efficiency and enantioselectivity for
many asymmetric reactions than those obtained from BINOL,
due to the steric and electronic modulations in the binaphthyl
backbone. In this respect, it is of great interest to examine the
effect of BINOL and H
asymmetric catalysis.‡
8
-BINOL and their derivatives in
8
by (R)-H -BINOL complex.
In conclusion, we have developed a new, highly efficient
method for the production of chiral propargylic alcohols from
Titanium chiral alkoxide complexes, which are easily
obtainable and inexpensive, have been found to be highly
enantioselective in many asymmetric additions.8
–12
To our
Table 1 The effect of reaction conditions on the enantioselectivity of the
knowledge, there is no report of the use of titanium-based
catalysts for alkynylation reactions. In order to find a simple and
practical method to prepare chiral propargylic alcohols, we tried
the asymmetric alkynylation using a complex conveniently
generated in situ from titanium tetraisopropoxide and (R)-
alkynylation of benzaldehydea
8
BINOL or (R)-H -BINOL as accelerator. The preliminary
results were found to be highly encouraging and a variety of
arylaldehydes were smoothly alkynylated to the corresponding
propargylic alcohols (Table 1).
Temper-
Entry ature
Ligand
ratio
Yield
(%)
E.e.
(%)*
b
Config.c
Solvent
Since benzaldehyde has been most extensively studied
previously, we focused our effort on the alkynylation of
benzaldehyde in our initial study. Some common factors such as
the choice of solvents, reaction temperature, ligand–substrate
ratio etc., which are known to affect the enantioselectivity of the
reaction, have been examined. The temperature effect was
rather insignificant in the range of 220 ~ 25 °C, while the rate
of reaction decreased with the decrease of reaction temperature.
The enantioselectivities attained in the present study were found
to be rather sensitive to the choice of solvents. At 0 °C, the use
1
2
3
4
5
6
7
8
9
a
25 °C
0 °C
THF
THF
THF
Toluene
20%
20%
20%
20%
20%
20%
20%
10%
5%
86
85
83
86
54
85
84
82
64
85
92
92
82
75
65
76
79
48
(2)-(S)
(2)-(S)
(2)-(S)
(2)-(S)
(2)-(S)
(2)-(S)
(2)-(S)
(2)-(S)
(2)-(S)
220 °C
0 °C
0 °C
0 °C
0 °C
0 °C
Et
Hexane
CH Cl
2
O
2
2
THF
THF
0 °C
(
R)-H
8
-BINOL as ligand; aldehyde–Ti(OiPr)
4
–Me Zn = 1 + 1.5 + 1.2
2
b
c
(molar ratio). Isolated yield of the corresponding products. The absolute
configuration is based on measurement of the optical rotation and
comparison with the literature values.
†
A University Grants Committee Area of Excellence Scheme in Hong
13
Kong.
1
72
CHEM. COMMUN., 2002, 172–173
This journal is © The Royal Society of Chemistry 2002