Direct monitoring of the asymmetric induction of solid-phase catalysis using circular dichroism: Diamine-CuI-catalyzed asymmetric Henry reaction

Article abstract of DOI:10.1002/anie.200602255

The direct approach: A new high-throughput screening system for analyzing the asymmetric induction in catalytic enantioselective synthesis couples solid-phase reactions with a circular dichroism detection system (see picture). Thus, direct monitoring of a

Full text of DOI:10.1002/anie.200602255

Communications
and valuable organic compounds.[1] The importance of this
research topic has stimulated chemists worldwide to develop
numerous methods of asymmetric catalysis, although the
process of developing new catalysts involves tedious effort,
even when modern methods are used. One way to overcome
the time-consuming aspect of the process would be to use the
technology of combinatorial chemistry for the discovery and
optimization of catalysts.[2]
For the efficient exploration of novel asymmetric catalysts
with the combinatorial approach, a convenient technology of
high-throughput screening (HTS) is required for the analysis
of both catalytic activity (chemical yield) and enantiomeric
excess. Although recent remarkable studies[3] have resulted in
some useful HTS systems, a more powerful analytical system
is required in pursuit of wide application, easy handling, and
practical use in broad asymmetric catalysis.[4] Herein, a new
HTS system has been developed by coupling circular dichro-
ism (CD) detection and solid-phase reactions (Figure 1). The
Combinatorial Chemistry
DOI: 10.1002/anie.200602255
Direct Monitoring of the Asymmetric Induction of
Solid-Phase Catalysis Using Circular Dichroism:
Diamine–CuI-Catalyzed Asymmetric Henry
Reaction**
Takayoshi Arai,* Masahiko Watanabe,
Akitsugu Fujiwara, Naota Yokoyama, and
Akira Yanagisawa
Figure 1. A new high-throughput screening system for analyzing asym-
metric induction.
origin of chirality is restricted in this system by the solid
support. When the catalytic asymmetric reaction is examined
by using an achiral substrate in solution, no asymmetric
induction occurs; therefore, when the solution is analyzed by
CD, no significant signal should be detected. Because any two
enantiomers have exactly opposite CD values at each wave-
length, the CD detector could analyze a single appropriate
wavelength and record a positive or negative signal that
corresponds to the amount of excess enantiomer.
The catalytic synthesis of chiral molecules is of crucial
importance in fine chemistry to ensure the supply of useful
[*] Prof. Dr. T. Arai, Prof. Dr. A. Yanagisawa
Department of Chemistry
Faculty of Science, Chiba University
Inage, Chiba 263-8522 (Japan)
Fax: (+81)43-290-2889
E-mail: tarai@faculty.chiba-u.jp
We synthesized chiral amines on polystyrene beads, as
outlined in Scheme 1, to demonstrate the newly constructed
HTS system. After the introduction of 4-hydroxymethylben-
zyl chloride onto the polystyrene beads through formation of
M. Watanabe, A. Fujiwara, N. Yokoyama
Graduate School of Science and Technology
Chiba University
Inage, Chiba 263-8522 (Japan)
ꢀ
a Si O linkage, the chloromethyl functionality was substi-
[**] This work was supported by a Grant-in Aid for Scientific Research
from the Ministry of Education, Science, Sports, Culture and
Technology of the Japanese Government and the Industrial
Technology Research Grant Program in 2006 from the New Energy
and Industrial Technology Development Organization (NEDO) of
Japan.
tuted by 1,3-dimethyl-5-acetylbarbituric acid (DAB)-pro-
tected N-benzylcyclohexyldiamine.[5] Deprotection of the
DAB group with hydrazine gave the diamine ligand L1, and
further alkylation of the terminal primary amine gave the
corresponding ligands L2–L4. Conversion and product purity
1
were analyzed at each synthetic step by H NMR spectro-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
scopic analysis of the released products.[6]
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Chemie
was found to be catalyzed by the
polymer-supported diamine–Cu
complexes.[7,8] After carrying out
the asymmetric Henry reaction for
36 hours, each reaction mixture was
analyzed by continuous injection to
obtain the profile shown in Figure 2
(see the experimental details in the
Supporting Information).
The detectable compounds in the
reaction mixtures were the targeted
product and the starting material.
Despite the catalytic success of Cu-
[7b]
(OAc)2
in conjunction with L1
and L2, the L4–CuCl catalyst
(namely, C10) was found to be the
most effective for this reaction. The
positive intensity of the signal oper-
ated at 254 nm indicates the forma-
tion of Henry adducts enriched with
the S isomer in the reaction. All the
reaction mixtures were purified by
the conventional method to confirm
the results shown in Figure 2; the
chemical yields were determined
using column chromatography on
silica gel, and the enantiomeric
excess was analyzed with chiral
HPLC. The results of the more
time-consuming analysis are sum-
marized in Table 1. An analysis of
the C10-catalyzed Henry reaction by
using conventional methods showed
Scheme 1. Synthesis of polymer-supported chiral ligands. a) TfOH, 2,6-lutidine, CH2Cl2; then 4-
chloromethylbenzyl alcohol; b) DAB-protected chiral diamine, 2,6-lutidine, NaI, DMF; c) H2NNH2–
H2O, THF; d–f) corresponding alkyl bromide, Et3N, CH2Cl2. DMF=N,N-dimethylformamide,
TfOH=trifluoromethanesulfonic acid.
With the polymer-supported chiral diamine ligands L1–L4
in hand, the desired Cu catalysts C1–C12 were prepared on a
solid support using three kinds of Cu salts (Figure 2). In all
cases, the polystyrene beads turned green, which suggested
the formation of Cu–diamine complexes. Among the several
types of asymmetric reaction examined, the Henry reaction
a chemical yield of over 99% with 68% ee. It is noteworthy
that the CD signals obtained demonstrated considerable
sensitivity, even with low levels of enantiomeric excess.
A reaction with a good yield but with low enantiomeric
excess should result in a CD signal of low intensity. In the
same manner, when catalytic activity is low, thus resulting in a
low yield, the intensity of the CD signal is low, even with high
enantiomeric excess. The CD signal is of maximum intensity
only when both the chemical yield and enantiomeric excess
are at their highest. A precise expression of CD signal
Table 1: Chemical yields and ee values for the Cu-catalyzed asymmetric
Henry reaction.
Entry
Catalyst
Yield of 1 [%]
ee [%]
ACY [%]
1
2
3
4
5
6
7
8
9
C1
C2
C3
C4
C5
C6
C7
C8
18
trace
52
15
48
95
91
16
63
3
–
20
59
6
32
3
7
7
0
32
30
17
55
17
11
18
83
58
18
C9
5
10
11
12
C10
C11
C12
>99
50
66
68
68
5
Figure 2. Catalytic asymmetric Henry reaction. The CD was operated at
254 nm. a) CuCl, 2,6-lutidine, CH2Cl2; b) CuCl2, 2,6-lutidine, CH2Cl2;
c) Cu(OAc)2, 2,6-lutidine, CH2Cl2.
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Communications
intensity is represented by Equation (1), in which the
square root of the chemical yield multiplied by the
enantiomeric excess is defined as the asymmetric con-
version yield (ACY).
pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
ð1Þ
ACY ½%Š ¼ yield ½%Š  ee ½%Š
The most efficient asymmetric catalyst should give the
target product in good yield with high enantiomeric excess.
This principle is of fundamental importance, although it
has not so far been clearly stated. Our HTS system allows
us to determine the catalysts that meet the criterion of this
new definition of ACY. The C10-catalyzed Henry reaction
recorded equates to an ACY value of 82%.
Scheme 2. Catalytic asymmetric Henry reaction using the well-defined
solution-phase catalyst.
Although Mikami, Ding, and Reetz recently reported
pioneering studies on the application of CD–HPLC in a
new HTS system, their system requires the use of achiral
HPLC to separate the product from the chiral ligands.[9]
The system currently under discussion does not require any
pretreatment of the sample (e.g., quenching) and time-
consuming purification, and the efficiency of asymmetric
induction can be clearly monitored without chromatographic
separation. The success of continuous introduction of the
reaction mixtures into the CD detector for the ready
comparison of the relative intensity of CD signals is remark-
able.
Table 2: L6–CuCl-catalyzed asymmetric Henry reaction.
Inspired by the success of exploring the promising
asymmetric catalyst, the well-defined ligand L5 was then
prepared by solution synthesis. The L5–CuCl complex was
revealed as an efficient catalyst that provided the Henry
adduct in quantitative yield with 65% ee at room temper-
ature. When the reaction was carried out in nPrOH, the use of
only 2 mol% catalyst was enough to promote the reaction in
96% yield, and the enantiomeric excess of the adduct was
improved to 77% ee (ACY= 86%).
Furthermore, with the employment of the C2-symmetric
concept for decreasing the number of catalyst–substrate
interactions, which consequently removes competing reaction
pathways, ligand L6 was prepared as a crystalline com-
pound.[10] Finally, the C2-symmetric L6–CuCl catalyst pro-
vided the Henry adduct in quantitative yield with up to
90% ee (ACY= 94%). This reaction is the first success of an
asymmetric Henry reaction catalyzed by diamine–CuI
(Scheme 2).
The scope of the asymmetric Henry reaction was studied
on various aldehydes using the well-defined L6–CuCl cata-
lyst. As summarized in Table 2, high ee values were obtained
even at room temperature for various aromatic aldehydes.
The reaction was promoted even in the presence of 1 mol%
catalyst and gave the nitroaldol product with the highest
enantiomeric excess of 92% (Table 2, entry 2). Not only
electron-deficient substrates (Table 2, entries 1–3), but o-
methoxybenzaldehyde was also converted into the corre-
sponding adduct in 82% yield with 90% ee (Table 2, entry 4).
Moreover, the aliphatic aldehydes were smoothly converted
into the nitroaldols in good yield and with high enantiomeric
excess (Table 2, entries 6–8).
Entry
Aldehyde
X [mol%]
t [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
1
1
2
3
4
5
6
7
2
1
3
5
5
5
5
2
20
24
16
96
48
48
48
120
>99
66
>99
82
66
85
90
92
80
90
86
86
86
90
>99
99
[a] Yield of the isolated product. [b] The enantioselectivity was deter-
mined by HPLC analysis with a Chiralcel OD-H column.[7b]
introduction of the reaction mixture into a CD detector. In
this new HTS system, the Henry reaction catalyzed by the
chiral diamine–CuI complex was successfully developed. It is
of note that this achievement is impossible to realize without
use of the HTS system. This direct monitoring system is of
obvious application to the ongoing search for outstanding
catalysts among the many contenders and also provides an
efficient method of analyzing catalytic asymmetric reactions.
Received: June 6, 2006
Published online: August 9, 2006
Keywords: asymmetric catalysis · circular dichroism ·
.
combinatorial chemistry · high-throughput screening ·
solid-phase synthesis
In conclusion, our new HTS system analyzes asymmetric
induction in catalytic enantioselective synthesis by direct
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Chemie
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