Rapid screening for asymmetric catalysts: The efficient connection of two different catalytic asymmetric reactions

Article abstract of DOI:10.1039/b902602a

A screening method for asymmetric catalysts is reported in which a metal-containing optically-active product of an asymmetric reaction is employed as a chiral catalyst in another asymmetric reaction; the rapid preparation and instant testing system of cat

Full text of DOI:10.1039/b902602a

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COMMUNICATION
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Rapid screening for asymmetric catalysts: the efficient connection of two
different catalytic asymmetric reactionsw
Kazuhiro Yoshida,* Takeharu Toyoshima, Naohisa Akashi, Tsuneo Imamoto
and Akira Yanagisawa*
Received (in Cambridge, UK) 9th February 2009, Accepted 12th March 2009
First published as an Advance Article on the web 1st April 2009
DOI: 10.1039/b902602a
A screening method for asymmetric catalysts is reported in which a
metal-containing optically-active product of an asymmetric
reaction is employed as a chiral catalyst in another asymmetric
reaction; the rapid preparation and instant testing system of
catalysts resulted in a considerable reduction in the time required
for the screening process.
for the first step of the reaction, we chose the palladium-
catalyzed ring opening reaction5 of oxabenzonorbornadienes
or azabenzonorbornadienes 1 with a dialkylzinc reagent.
Ring-opened organozinc species 2, which are the products
prior to work-up, are expected to be potential chiral Lewis
acid catalysts of other reactions.
The results of our examination of the asymmetric ring opening
reaction are shown in Table 1. We gave priority to the examina-
tion of substrates having a substituent at the R1 position, because
this position seems to influence the stereoelectronic environment
around the active zinc site of 2. The results were evaluated in terms
of the yields and enantioselectivities of air-stable 3, which were
obtained by quenching zinc species 2 with water. It was found that
PdCl2(t-Bu-QuinoxP*)6 was a very promising catalyst for both
oxabenzonorbornadienes and azabenzonorbornadienes 1.
We also screened for the catalyst of another asymmetric
reaction involving a variety of unquenched optically-active
zinc species 2, which were easily and rapidly prepared by the
The investigation of suitable chiral catalysts for individual
asymmetric reactions is usually a rather time-consuming and
labour-intensive process. The development of a rapid screening
method for chiral catalysts is therefore of considerable interest
in catalytic asymmetric synthesis.1
It is worth noting that optically-active products of catalytic
asymmetric reactions are potentially useful catalysts for other
catalytic asymmetric reactions.2 In particular, unquenched
original chiral products having a metal center are expected
to have high catalytic activities. We have been looking into the
development of a screening method for asymmetric catalysts,
in which the product of a certain catalytic asymmetric reaction
(A to B*) is continuously employed as a chiral catalyst for
another catalytic asymmetric reaction (C to D*) (Scheme 1).3,4
The advantage of this approach is that the catalyst of the
second reaction step (B*) can be very easily and rapidly
prepared by simply varying the combination of substrates
(A) and reagents in the first reaction step. In addition, it is
also an interesting possibility that quite large amounts of the
final optically-active product (D*) may be obtained from a
small amount of chiral source (Asymmetric Catalyst 1*) due to
the multiplication effect of the two catalytic asymmetric
reactions. Herein, we report a preliminary example of such a
screening system.
Table 1 The asymmetric ring opening of 1 with dialkylzincs catalyzed
by PdCl2(L*)a
Yield of 3 eec of 3 (%)
Entry
X
R1
R2 L* (%)b
(config.d)
In order to reduce errors in the catalyst screening process in
the second asymmetric reaction step, the first asymmetric
reaction step should be highly reliable. From several candidates
1e
2e
3
4
5
6
7
8
9
O
O
OMe
OMe
Me
Et
4
4
4
4
4
4
4
5
6
4
4
499
85
80
94 (1S,2S)
95 (1S,2S)
92
96
96
96 (1S,2S)
95
36
66
90
94
CH3SO2N OMe
C6H5SO2N OMe
Me
Me
Me
Me
Me
Me
Me
94
TsN
TsN
TsN
TsN
TsN
TsN
TsN
OMe
H
OBn
OBn
OBn
499
87
91
16
32
Scheme 1
10
11
OMOM Me
OBn Et
65
62
a
The reaction was carried out with 1 and R2Zn (3 equiv.) in the
b
Department of Chemistry, Graduate School of Science, Chiba
University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
E-mail: kyoshida@faculty.chiba-u.jp, ayanagi@faculty.chiba-u.jp;
Fax: +81 43 290 2789; Tel: +81 43 290 2790
w Electronic supplementary information (ESI) available: Experi-
mental procedures and compound characterization data. See DOI:
10.1039/b902602a
presence of PdCl2(L*) (3 mol %) in toluene at 90 1C for 6 h. Isolated
c
d
yield. Chiral HPLC analysis. The absolute configuration was
determined by comparison of the sign of the specific rotation and
e
the chiral HPLC retention time with data in the literature. The
reaction was carried out at r.t. for 2 h.
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ring opening reaction of 1 using PdCl2(t-Bu-QuinoxP*).
The zinc-catalyzed asymmetric addition7 of diethylzinc to
benzaldehyde (7a) was our choice for the second step;
Table 2 shows the screening results. Chiral zinc species 2a
and 2b, which were prepared by reacting oxabenzonorbornadiene
with dimethylzinc or diethylzinc, respectively, exhibited low
catalytic activities and poor enantioselectivities (Table 2,
entries 1 and 2). Zinc species 2c, which was prepared by
reacting azabenzonorbornadiene, having a benzoyl group on
the nitrogen, with dimethylzinc, showed a relatively high
catalytic activity but still poor enantioselectivity (Table 2,
entry 3). On the other hand, 2, having a sulfonyl group on
nitrogen, gave good results for both catalytic activity and
enantioselectivity (Table 2, entries 4–6). As for the effect of R1
substituents on the enantioselectivity, benzyloxy and methoxy-
methoxy (OMOM) groups were the most suitable. Con-
sequently, it was found that zinc species 2i, 2l and 2m gave the
best enantioselectivity (80% ee) in this screening (Table 2,
entries 5–14). Considering the multiplication effect of the two
asymmetric reactions, 839 molecules of the 80% ee addition
product 8a were produced per molecule of PdCl2(t-Bu-
QuinoxP*) in the case of Table 2, entry 14.
In order to confirm whether 2 acts as the real catalyst for the
ethylation, we performed further experiments, as shown in
Scheme 2; i.e., the ethylation of benzaldehyde 7a was carried
out with catalyst 2, which was prepared from purified 3i (95%
ee) and a dialkylzinc. The result was consistent with our
prediction, and an 80% ee of 8a was formed by the reaction
with the catalyst prepared from 3i and dimethylzinc
(Scheme 2; see also Table 2, entry 9). A similar result was
also obtained when the catalyst was prepared from 3i and
diethylzinc, although the ee of 8a was somewhat lower
(73% ee).
Finally, we performed the asymmetric addition of diethyl-
zinc to a variety of aldehydes 7 with 3i or 3m, whose
corresponding zinc species, 2i and 2m, were found to be the
best catalysts in Table 2. As a result, the reactions proceeded
Table 2 Screening for asymmetric catalysts 2 by connecting two
reactionsa
Scheme 2
Table 3 The asymmetric addition of diethylzinc to aldehydes 7
catalyzed by 2i or 2ma
Yieldb of 8a eec of 8a (%)
(%)
Yieldb
of 8 (%)
eec of 8 (%)
(config.d)
Entry
X
R1
R2
2
(config.d)
Entry
7
3
1e
2e
3
4
5
6
7
8
9
O
O
BzN
OMe
OMe
OMe
Me 2a
Et 2b
Me 2c
Me 2d
Me 2e
Me 2f
Me 2g
14
9 (S)
5 (S)
8 (R)
1
2
Benzaldehyde
3i
3m
3i
3m
3i
3m
3i
3m
3i
3m
3i
3m
3m
3i
92
89
90
99
90
98
80
80
88
84
90
65
60
20
41
82e (R)
84f (R)
83 (R)
80 (R)
80 (R)
82 (R)
80 (R)
83 (R)
85 (R)
80 (R)
80 (R)
89 (R)
87 (R)
60 (R)
83 (R)
2
52
84
59
63
80
3g
4
2-Naphthaldehyde
CH3SO2N OMe
C6H5SO2N OMe
47 (R)
57 (R)
70 (R)
68 (R)
67 (R)
80 (R)
78 (S)
78 (R)
16 (R)
80 (R)
80 (R)
5g
6
3-Methoxybenzaldehyde
3-Chlorobenzaldehyde
4-Methylbenzaldehyde
4-Chlorobenzaldehyde
TsN
TsN
TsN
TsN
TsN
TsN
TsN
TsN
OMe
H
OEt
OBn
OBn
OBn
7g
8
Me 2h 499
Me 2i
Me 2i
Et 2j
68
65
49
58
51
74
9
10f
11
12
13
14
10
11
12
13h
14
15
OC10H21 Me 2k
OMOM Me 2l
C6H5SO2N OMOM Me 2m
3-Phenylpropionaldehyde
3m
a
Catalyst 2 was prepared by the asymmetric ring opening of 1 with R2Zn
(3 equiv.) in the presence of PdCl2((R,R)-t-Bu-QuinoxP*) (3 mol %) in
toluene at 90 1C for 6 h. After concentration of the mixture of 2, hexane,
Et2Zn (69 equiv.) and benzaldehyde (7a) (34 equiv.) were added to the
a
The reaction was carried out with aldehyde 7 and Et2Zn (2 equiv.) in
b
the presence of 3 (3 mol %) in hexane at 30 1C for 24 h. Isolated
c
d
yield. Chiral HPLC analysis. The absolute configuration was
determined by comparison of the sign of the specific rotation and
b
residue. The resulting mixture was stirred at 30 1C overnight. Isolated
c
d
e
chiral HPLC retention time with data in the literature. The ee value
yield. Chiral HPLC analysis. The absolute configuration was deter-
mined by comparison of the sign of the specific rotation and the chiral
HPLC retention time with data in the literature. e The first reaction step
was carried out at r.t. for 2 h. f The reaction was carried out with
PdCl2((S,S)-t-Bu-QuinoxP*).
f
was slightly improved, compared with Table 2, entry 9. The ee value
g
was slightly improved, compared with Table 2, entry 14. The
h
reaction was carried out for 6 h. The catalyst was prepared from
3m and dimethylzinc.
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well in the presence of enantiomerically pure 3i or 3m,8 and the
desired alcohols 8 were obtained with good enantioselectivities
(Table 3).9
I. Sato, H. Urabe, S. Ishii, S. Tanji and K. Soai, Org. Lett., 2001,
3, 3851–3854.
4 A related screening strategy has been reported, where chiral ligands
are rapidly prepared and used without purification. See:
(a) W. A. Nugent, G. Licini, M. Bonchio, O. Bortolini,
M. G. Finn and B. W. McCleland, Pure Appl. Chem., 1998, 70,
1041–1046; (b) J. G. de Vries and L. Lefort, Chem.–Eur. J., 2006, 12,
4722–4734.
5 (a) M. Lautens, J.-L. Renaud and S. Hiebert, J. Am. Chem. Soc.,
2000, 122, 1804–1805; (b) M. Lautens, S. Hiebert and J.-L. Renaud,
Org. Lett., 2000, 2, 1971–1973; (c) M. Lautens, S. Hiebert and
J.-L. Renaud, J. Am. Chem. Soc., 2001, 123, 6834–6839;
(d) M. Lautens, K. Fagnou and S. Hiebert, Acc. Chem. Res.,
2003, 36, 48–58; (e) M. Lautens and S. Hiebert, J. Am. Chem.
In conclusion, we have examined a screening method for
asymmetric catalysts, in which unquenched optically-active
products of an asymmetric reaction are employed as chiral
catalysts in another asymmetric reaction. The rapid pre-
paration and instant testing system of catalysts considerably
reduced the time required for screening. It is predicted that
many able potential chiral catalysts exist in the metal-containing
products of other asymmetric reactions. Further examples will
be reported in due course.
Soc., 2004, 126, 1437–1447; (f) S. Cabrera, R. Go
J. C. Carretero, Angew. Chem., Int. Ed., 2004, 43, 3944–3947;
(g) S. Cabrera, R. Gomez Arrayas, I. Alonso and J. C. Carretero,
mez Arrayas and
´ ´
We thank Nippon Chemical Industrial Co., Ltd. for lending
a Daicel Chiralcel OD-H (2 Â 25 cm).
´
´
J. Am. Chem. Soc., 2005, 127, 17938–17947.
6 (a) T. Imamoto, K. Sugita and K. Yoshida, J. Am. Chem. Soc.,
2005, 127, 11934–11935; (b) T. Imamoto, M. Nishimura, A. Koide
and K. Yoshida, J. Org. Chem., 2007, 72, 7413–7416.
Notes and references
1 For reviews, see: (a) B. Archibald, O. Brummer, M. Devenney,
S. Gorer, B. Jandeleit, T. Uno, W. H. Weinberg and T. Weskamp, in
Handbook of Combinatorial Chemistry, ed. K. C. Nicolaou,
R. Hanko and W. Hartwig, Wiley-VCH, Weinheim, 2002, vol. 2,
pp. 885–990; (b) A. H. Hoveyda, in Handbook of Combinatorial
Chemistry, ed. K. C. Nicolaou, R. Hanko and W. Hartwig,
Wiley-VCH, Weinheim, 2002, vol. 2, pp. 991–1016.
7 For reviews, see: (a) K. Soai and S. Niwa, Chem. Rev., 1992, 92,
833–856; (b) L. Pu and H.-B. Yu, Chem. Rev., 2001, 101, 757–824;
(c) M. Hatano, T. Miyamoto and K. Ishihara, Curr. Org. Chem.,
2007, 11, 127–157.
8 Pure (499% ee) 3i and 3m were obtained from enantiomerically-
enriched 3i and 3m by re-precipitation, or by separation using
preparative HPLC with a chiral column.
2 A typical example, in which the products are immediately used as
chiral catalysts, is the asymmetric autocatalysis established by Soai
et al. See: (a) K. Soai, T. Shibata, H. Morioka and K. Choji, Nature,
1995, 378, 767–768; (b) Topics in Current Chemistry: Amplification
of Chirality, ed. K. Soai, Springer-Verlag, Berlin, 2008, vol. 284.
3 Soai et al. have also reported an interesting system, in which a chiral
catalyst that improved its ee by asymmetric autocatalysis was
employed as a catalyst for another asymmetric reaction. See:
9 As we anticipated, a positive non-linear effect was observed in this
reaction (see the ESIw). For reports on the non-linear effect, see:
(a) C. Puchot, O. Samuel, E. Dunach, S. Zhao, C. Agami and
H. B. Kagan, J. Am. Chem. Soc., 1986, 108, 2353–2357;
(b) M. Avalos, R. Babiano, P. Cintas, J. L. Jimenez and
J. C. Palacios, Tetrahedron: Asymmetry, 1997, 8, 2997–3017;
(c) C. Girard and H. B. Kagan, Angew. Chem., Int. Ed., 1998, 37,
2923–2959; (d) H. B. Kagan, Synlett, 2001, 888–899.
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 2923–2925 | 2925