Effective activation of chiral BINOL/Ti(OiPr)4 catalyst with phenolic additives for the enantioselective alkynylation of aldehydes

Article abstract of DOI:10.1016/S0957-4166(03)00021-1

The activation of chiral titanium(IV) complexes with achiral activators, e.g. phenol, is found to provide higher levels of enantioselectivity than those attained with an enantiopure catalyst in the alkynylations of both aromatic and aliphatic aldehydes.

Full text of DOI:10.1016/S0957-4166(03)00021-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 449–452
Effective activation of chiral BINOL/Ti(OiPr)4 catalyst with
phenolic additives for the enantioselective alkynylation of
aldehydes
Gui Lu, Xingshu Li, Gang Chen, 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
Received 12 November 2002; accepted 18 December 2002
Abstract—The activation of chiral titanium(IV) complexes with achiral activators, e.g. phenol, is found to provide higher levels
of enantioselectivity than those attained with an enantiopure catalyst in the alkynylations of both aromatic and aliphatic
aldehydes. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
give products in up to >99% e.e.12 Herein, we wish to
report a highly enantioselective catalyst system for the
alkynylation of aldehydes based on a chiral BINOL–
Ti(OiPr)4 catalyst in combination with an achiral
activator.
Chiral propargylic alcohols constitute important build-
ing blocks for asymmetric synthesis. They are used in
diverse areas including the synthesis of natural prod-
ucts, pharmaceuticals, and macromolecules.1–3 The
preparation of propargylic alcohols via the addition of
alkynes to aldehydes is of great interest because both
the CꢀC bond and the stereogenic center can be formed
in one step. Until now, nucleophilic alkynylation has
enjoyed only very limited success and a few examples of
enantioselective alkynylation of aldehydes by
organometallic compounds in combination with chiral
catalysts have been reported.4–11
2. Results and discussion
The self-assembly of several components into a highly
enantioselective catalyst for asymmetric reaction is a
new field in organic synthesis.13,14 Recently, Mikami et
al.15 found that addition of phenol derivatives to chiral
BINOL/Ti(OiPr)4 catalyst for Mukaiyama aldol reac-
tion provided e.e.s equal to or better than the best
literature data. Vallee et al.16 reported similar results
for ene-reactions. In our study on the alkynylation of
aldehydes using BINOL/Ti(OiPr)4 catalyst and a phe-
nolic additive as activator, we have observed similarly
interesting effects. In the presence of phenol, the
alkynyl addition to benzaldehyde gave the propargylic
alcohol product in 96% e.e. In contrast, only 91% e.e.
was obtained under similar conditions without any
phenolic additives. More detailed results are summa-
rized in Table 1.
Carreira and co-workers5–7 discovered a highly enan-
tioselective catalyst based on N-methylephedrine for
the alkynylation of aliphatic aldehydes. We have inves-
tigated the asymmetric alkynylzinc addition in the pres-
ence of a catalyst prepared in situ from titanium
tetraisopropoxide and (R)-H8-binaphthol and found
the simple catalyst to be highly enantioselective, giving
products with up to 96.2% e.e.8,9 Subsequently, Pu et
al.10,11 reported a somewhat different procedure for the
effective preparation of propargylic alcohols using a
BINOL/Ti(OiPr)4 catalyst. More recently we employed
the first example of the self-assembly of BINOL with
other chiral ligands into a highly effective titanium
catalyst for the addition of alkynylzinc to aldehydes to
Titanium tetraisopropoxide played an important role in
the catalytic reaction, and a preferred ratio of ligands
(BINOL + additive) to titanium tetraisopropoxide was
found to be about 1:1.5.9 At first the methods for the
preparation of the catalyst were investigated and partic-
* Corresponding authors. Tel.: +852 2766 5607; fax: +852 2364 9932;
e-mail: bcachan@polyu.edu.hk
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(03)00021-1

450
G. Lu et al. / Tetrahedron: Asymmetry 14 (2003) 449–452
Table 1. The effect of additives on the enantioselectivity of the alkynylation of benzaldehydea
The results from the addition of alkynes to a variety of
ular attention was given to the order of the introduc-
tion of the ligand. Interestingly, mixing (R)-BINOL,
phenol and Ti(OiPr)4 together at the same time or
adding phenol to the (R)-BINOL–Ti(OiPr)4 precatalyst
system gave essentially the same results. In most cases,
the effects of activation by the phenolic additives were
aldehydes catalyzed by (R)-BINOL and phenol are
summarized in Table 2. The direction of chiral induc-
tion in these reactions was predominantly determined
by (R)-BINOL, and the presence of phenol increased
the efficiency of the asymmetric induction. The activa-
tion effect was quite significant for ortho-substituted
benzaldehydes and aliphatic aldehydes. In the presence
of phenol, the e.e. values were improved to >85% (10
mol% chiral catalyst) from 70–80% (even with 20 mol%
catalyst).
observed.
A
similar degree of enantioselectivity
enhancement was achieved using benzyl alcohol, p-
cresol or 2-naphthol as the additive. The use of phenol
as the activator provided the highest enantioselectivity
(96% e.e.).

G. Lu et al. / Tetrahedron: Asymmetry 14 (2003) 449–452
451
Table 2. The alkynylation of aldehydes using chiral BINOL–Ti(OiPr)4 catalysts (phenol as additive)a
As shown in Table 2, the effect of phenol and similar
additives on the product yield and/or enantioselectivity
of the reaction is quite obvious. This activation effect is
interesting not only from the viewpoint of lower cata-
lyst loading and higher e.e.s for the alkynylation of
both aromatic and aliphatic aldehydes, but also from
the perspective that new frontiers can be opened in the
use of metal–BINOL complexes in asymmetric catalytic
applications.
additives has been developed. Wide substrate generality
and high enantioselectivities have been achieved.
4. Experiments
4.1. General methods
All reactions were performed using oven-dried glass-
ware under an atmosphere of dry nitrogen. THF was
distilled and dried before use. Reagents were purchased
from either Acros or Aldrich and were used without
further purification except for the aldehydes which were
redistilled before use. NMR spectra were recorded on a
3. Conclusions
In summary, the catalytic enantioselective alkynylation
using chiral BINOL–Ti(OiPr)4 catalyst with phenolic

452
G. Lu et al. / Tetrahedron: Asymmetry 14 (2003) 449–452
Varian-500 spectrometer. Optical rotations were mea-
sured with a Perkin–Elmer model 341 polarimeter at
20°C. HPLC analyses (Chiralcel OD or OD-H column
from Daicel, IPA-hexane as eluent) were performed
using a Hewlett–Packard model HP 1050 LC interfaced
to an HP 1050 Series computer workstation.
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Acknowledgements
We thank the Hong Kong Research Grants Council
(project cPolyU 5152/98P), the University Grants
Committee Areas of Excellence Scheme (AoE P/10-01)
and The Hong Kong Polytechnic University ASD for
the financial support of this study.