Enantioselective cyanosilylation of ketones by a catalytic double-activation method employing chiral lewis acid and achiral N-oxide catalysts

Article abstract of DOI:10.1021/ol034158a

(Matrix presented). Enantioselective addition of TMSCN to ketones is achieved by a catalytic double-activation method using 1a-Ti(IV) complex as the Lewis acid and achiral N-oxide 2 as the Lewis base to activate ketones and TMSCN, respectively.

Full text of DOI:10.1021/ol034158a

ORGANIC
LETTERS
2
003
Vol. 5, No. 6
49-952
Enantioselective Cyanosilylation of
Ketones by a Catalytic
9
Double-Activation Method Employing
Chiral Lewis Acid and Achiral N-Oxide
Catalysts
†
,‡
‡
§
†
Fuxue Chen, Xiaoming Feng,* Bo Qin, Guolin Zhang, and Yaozhong Jiang
Sichuan Key Laboratory of Green Chemistry and Technology,
College of Chemistry, Sichuan UniVersity, Chengdu 610064, China,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences (CAS),
Chengdu, China, and Chengdu Institute of Biology, CAS, Chengdu, China
xmfeng@pridns.scu.edu.cn
Received January 28, 2003
ABSTRACT
Enantioselective addition of TMSCN to ketones is achieved by a catalytic double-activation method using 1a−Ti(IV) complex as the Lewis acid
and achiral N-oxide 2 as the Lewis base to activate ketones and TMSCN, respectively.
3
4
The ever-increasing demand for optically pure intermediates
has driven much effort to develop and improve chiral catalyst
systems by synthesizing and screening even structurally
achiral additives, and other techniques. Herein, we present
a novel scheme to develop an efficient catalyst system, in
which a chiral Lewis acid and an achiral Lewis base act
synergistically in a manner of double activation. The method
is adapted to the enantioselective cyanosilylation of ketones.
In general, an asymmetric reaction between two or more
components can proceed smoothly by either of the following
methodologies: (1) less reactive electrophiles are activated
1
complicated discrete ligands. Meanwhile, alternative ap-
proaches have also been advanced, including asymmetric
2
activation and deactivation, combinatory use of chiral or
†
Chengdu Institute of Organic Chemistry.
Sichuan University.
Chengdu Institute of Biology.
‡
§
(3) (a) Vogl, E. M.; Gr o¨ ger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
1999, 38, 1570 and references therein. (b) Costa, A. M.; Jimeno, C.;
Gavenonis, J.; Carrol, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
6929 and references therein. (c) Long, J.; Hu, J. Y.; Shen, X. Q.; Ji, B. M.;
Ding, K. L. J. Am. Chem. Soc. 2002, 124, 10.
(4) (a) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 3250. (b)
Pandiaraju, S.; Chen, G.; Lough, A.; Yudin, A. K. J. Am. Chem. Soc. 2001,
123, 3850. (c) Reetze, M. T.; Neugebauer, T. Angew. Chem., Int. Ed. 1999,
38, 179.
(
1) Pfaltz, A. In ComprehensiVe Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vol. 1, p 4.
2) For a review, see: (a) Mikami, K.; Terada, M.; Korenaga, T.;
Matrumoto, Y.; Ueki, M.; Angelaud, R. Angew. Chem., Int. Ed. 2000, 39,
532. For recent examples, see: (b) Mikami, K.; Aikawa, K.; Yusa, Y.;
(
3
Hatano, M. Org. Lett. 2002, 4, 91. (c) Mikami, K.; Aikawa, K.; Yusa, Y.
Org. Lett. 2002, 4, 95. (d) Mikami, K.; Aikawa, K.; Yusa, Y.; Jodry, J. J.;
Yamanaka, M. Synlett. 2002, 1561.
1
0.1021/ol034158a CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/15/2003

by coordinating to a chiral Lewis acid, and the nucleophiles
react favorably with the homogeneous electrophile/catalyst
complexes to give enantiomerically enriched products (Lewis
acid catalysis); or (2) less reactive nucleophiles coordinate
to a chiral Lewis base, and the resulting nucleophile/Lewis
base complexes react smoothly with the electrophiles to give
optically active products (Lewis base-promoted reaction).
When the components are too sluggish and neither meth-
odology works effectively, a double activation approach may
Figure 1. Chiral salen ligands evaluated in this study.
5
be the choice. While a bifunctional catalyst integrates a
6
Lewis acid and a Lewis base moiety into one molecule, the
double-activation method mixes the Lewis acid with the
Lewis base in one flask, and they activate the electrophiles
and nucleophiles, respectively.
Previously, our group has reported a titanium-catalyzed
13
asymmetric hydrocyanation of aldehydes, and an N-oxide-
14
promoted enantioselective Strecker reaction. Also, we have
disclosed a bifunctional N-oxide titanium-catalyzed enanti-
oselective cyanosilylation of ketones, in which the metal
titanium played the role of a Lewis acid and the N-O dipolar
moiety a Lewis base to activate the keto group and TMSCN,
Optically active cyanohydrins are synthetically important
building blocks and chiral auxiliaries in the context of
7
asymmetric synthesis. Moreover, enantioselective construc-
tion of quaternary carboncenters via a C-C bond-forming
process with keto electrophiles has gained more and more
attention in recent years.6 Asymmetric addition of TMSCN
1
5
respectively. Accordingly, the Ti-salen complexes and
N-oxides would be the catalysts for the double-activation
method.
b,8
(TMS ) trimethylsilyl) to ketones is the most popular
strategy to produce optically active cyanohydrins.
Belokon has reported a Ti-catalyzed cyanosilylation of
In a preliminary study, 1a-Ti(OiPr)
are employed as the catalysts. Fortunately, the product
4
complex and N-oxide
1
6
2
2
aromatic ketones by utilizing a C -symmetric Schiff base as
9
the chiral ligand. Shibasaki has developed a novel bifunc-
tional catalyst with a phosphoryl moiety to promote the
10
addition of TMSCN to aromatic and aliphatic ketones. Deng
has outlined a method for cyanide addition to ketones with
cyanoformate by employing Sharpless’s cinchona derivatives
as catalysts.11 Most recently, Snapper has disclosed an
aluminum-catalyzed enantioselective addition of TMSCN to
aromatic and aliphatic ketones using recyclable peptide as
Table 1. Addition of TMSCN to Acetophenone Catalyzed by
1a-Ti(OiPr)
and Lewis Basesa
4
yield (%)b
ee (%)c
entry
Lewis base
temp (°C)
1
2
3
4
5
6
7
8
9d
2
0
0
0
0
0
95
3
0
67
34
0
HMPA
PyNO
NMNO
TMNO
2
2
2
2
2
2
2
12
the ligand. Despite these advances, some pressing problems
still exist such as the comparatively long route of synthesis
and screening of the candidate ligands. This letter reports
the development of a new double activation catalyst system
and the application to the enantioselective addition of
TMSCN to ketones with an easily accessible Ti-salen
complex as the Lewis acid and achiral N-oxide as the Lewis
base (Figure 1).
32
26
62
30
9
25
54
90
75
60
65
81
76
59
74
73
74
84
-20
-40
-78
0
0
0
-20
1
0e
1 f
1
2g
1
a
(
5) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394.
Conditions: 20 mol % 1a-Ti(OiPr)4 complex, 20 mol % base,
(6) For review on bifunctional catalysis, see: (a) Shibasaki, M.;
concentration of acetophenone ) 0.12 M in CH2Cl2 (unless otherwise
indicated), 84 h. Isolated yield. c Determined by chiral GC analysis on
Chirasil DEX CB. d 1a-Ti(OiPr)4 (2 mol %), 2 mol % 2, concentration of
b
Yoshikawa, N. Chem. ReV. 2002, 102, 2187. (b) DiMauro, E. F.; Kozlowski,
M. C. J. Am. Chem. Soc. 2002, 124, 12668. (c) Hamashima, Y.; Sawasa,
D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 2641.
e
acetophenone ) 0.12 M, 84 h. 1a-Ti(OiPr)4 (2 mol %), 2 mol % 2,
f
(
7) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649.
concentration of acetophenone 0.23 M, 84 h. 1a-Ti(OiPr)4 (2 mol %), 2
g
(8) (a) For a review on catalytic enantioselective construction of
mol % 2, concentration of acetophenone 0.52 M, 84 h. Optimized
quaternary carbon stereogenic centers, see: Cory, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388. For recent examples, see: (b) Dosa,
P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. (c) Ramon, D. J.; Yus,
M. Tetrahedron Lett. 1998, 39, 1239. (d) Casolari, S.; D’Addario, D.;
Tagliavini, E. Org. Lett. 1999, 1, 1061. (e) Garcfa, C.; LaRochelle, L. K.;
Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970.
conditions: 2 mol % 1a-Ti(OiPr)4, 1 mol % 2, concentration of acetophe-
none ) 1.1 M, 120 h. HMPA ) hexamethyl-phosphorus triamide; PyNO
) pyridine N-oxide; NMNO ) N-methylmorpholine N-oxide; TMNO )
trimethylamine N-oxide.
(
9) (a) Belokon, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.; Tararov,
V. I. Tetrahedron Lett. 1999, 40, 8147.
10) (a) Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
000, 122, 7412. (b) Hamashima, Y.; Kanai, M.; Shibasaki, M. Tetrahedron
is obtained in 95% yield with 67% ee after 84 h (Table 1,
entry 1). With respect to reactivity and enantioselectivity,
(
2
Lett. 2001, 42, 691. (c) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima,
Y.; Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc.
(13) For our related reports on hydrocyanation of aldehydes catalyzed
by Ti-salen complex, see: (a) Pan, W. D.; Feng, X. M.; Gong, L. Z.; Hu,
W. H.; Li, Z.; Mi, A. Q.; Jiang, Y. Z. Synlett. 1996, 337. (b) Jiang, Y. Z.;
Gong, L. Z.; Feng, X. M.; Hu, W. H.; Pan, W. D.; Li, Z.; Mi, A. Q.
Tetrahedron 1997, 53, 14327. (c) Feng, X. M.; Gong, L. Z.; Hu, W. H.;
Li, Z.; Pan, W. D.; Mi, A. Q.; Jiang, Y. Z. Chem. J. Chin. UniV. 1998, 19,
1416 (in Chinese).
2
001, 123, 9908. (d) Yabu, K.; Masumoto, S.; Kanai, M.; Curran, D. P.;
Shibasaki, M. Tetrahedron Lett. 2002, 43, 2923. (e) Masumoto, S.; Suzuki,
M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 8647.
(
11) Tian, S. K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6195.
(12) Deng, H.; Snapper, M. P.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2
002, 41, 1009.
950
Org. Lett., Vol. 5, No. 6, 2003

N-oxide 2 is preferred to other N-oxides and HMPA (Table
, entries 2-5). PyNO (pyridine N-oxide) strongly coordi-
nates to titanium, and no reaction occurs (Table 1, entry 3).
Ligand screening reveals that 1a has the highest capability
of chiral induction among 1a-g.16 When the reaction is
conducted at -20 °C, the enantioselectivity is improved to
To identify the double activation, a series of control
experiments were carried out, with the results listed in Table
3. Neither Ti(OiPr) nor the N-oxide 2 is sufficiently effective
4
1
Table 3. Addition of TMSCN to Acetophenone as a Control
Experimenta
81% ee (Table 1, entry 6). However, further decrease in the
reaction temperature leads to a reduction in both enantiose-
lectivity and reactivity (Table 1, entries 6-8). Moreover, the
lower catalyst loading results in a sharp decrease in yield
but a slight increase in enantioselectivity (Table 1, entry 9).
Interestingly, the problem of the yield decrease caused by
low catalyst loading can be solved by increasing the substrate
concentration without any loss in enantioselectivity (Table
entry
Lewis acid
Lewis base
yield %b
ee %c
1
2
3
4
5
6d
Ti(OiPr)4
0
0
13
3
75
31
2
2
Ti(OiPr)4
0
66
84
75
1a -Ti(OiPr)4
1a -Ti(OiPr)4
1a -Ti(OiPr)4
2
2
1, entries 9-11). The best ee value is recorded as 84% under
a
Conditions: 2 mol % Lewis acid, 1 mol % 2, substrate concentration
the optimized molar ratio of Lewis acid to Lewis base (2:1)
1.1 M in CH2Cl2, -20 °C, 120 h. Isolated yield. c Determined by GC
analysis on Chirasil DEX CB. Catalysts were generated in situ by stirring
b
)
(Table 1, entry 12).
d
To broaden the applicability and the scope of the catalysts,
the mixture of 1a, 2, and Ti(OiPr)4 in one flask.
a number of ketones were tested under the optimized
1
6
conditions, with the results listed in Table 2. While the
to promote the addition of TMSCN to acetophenone (Table
3
, entries 1 and 2). Only when these two are used together
could the desired O-TMS cyanohydrin be found in the
reaction mixture (Table 3, entry 3). While 2 mol % 1a-
Table 2. Asymmetric Cyanosilylation of Ketones Catalyzed by
and 2 Catalystsa
1
a-Ti(OiPr)
4
Ti(OiPr)
4
promotes the reaction in 3% yield with 66% ee
entry
ketone
yield (%)b
ee %c
(Table 3, entry 4), additional activation of TMSCN by 1 mol
1
2
3
4
5
6
7
8
9
C6H5COCH3
75
57
80
71
58
93
50
37
85
79
84d
73
76
83
84
80
84e
81
84f
64f
%
N-oxide 2 results in a sharp increase in both isolated yield
4-MeC6H4COCH3
2-FC6H4COCH3
4-FC6H4COCH3
4-ClC6H4COCH3
3-ClC6H4COCH3
â-acetonaphthone
R-tetralone
and enantioselectivity as 75% yield and 84% ee, respectively
Table 3, entry 5). These results indicate that, in this case,
(
the chirality of the cyanohydrin is mainly homogeneously
induced by the chiral Lewis acid, and the highly accelerated
reaction rate is mostly due to the coordination of the N-oxide
14a-b,17
to TMSCN.
The above discussion proves our hypoth-
benzylacetone
(E)-C6H5CHdCHCOCH3
esis that this transformation could be performed via a double-
activation path with Ti-salen complex as a Lewis acid and
achiral N-oxide as a Lewis base. Nevertheless, when the
Lewis acid and the Lewis base are generated together in one
1
0
a
Conditions: 2 mol % 1a-Ti(OiPr)4, 1 mol % 2, substrate concentration
b
c
)
1.1 M in CH2Cl2, - 20 °C, 120 h. Isolated yield. Determined by GC
d
on Chirasil DEX CB. Absolute configuration was established to be S by
1
6
10a
e
flask, unlike the typical procedure, a much lower catalyst
efficiency is recorded as 31% yield with 75% ee (Table 3,
entry 6). The result again suggests that the N-oxide should
comparing the sign of optical rotation with that of literature.
Determined
by HPLC on Chiralcel OJ. f Determined by HPLC on Chiralcel OD.
4b,3a
18
act not as an additive
but as a double activation catalyst.
para-methyl and ortho-fluoro substituents on the aromatic
ring lead to lower enantioselectivities than acetophenone
Although coordination complexes between N-oxides and
19
diverse metals have been reported, this observation removes
(
Table 2, entries 1-3), the para-fluoro- and chloro-
Kanemasa’s concern that the Lewis acid and the Lewis base
might strongly bind to each other resulting in the disappear-
substituted ketones give products of similar enantioselec-
tivities with acetophenone (Table 2, entries 4-6). In terms
of the product yield, para-substituted ketones are inferior to
meta- or ortho-substituted ones. â-Acetonaphthone and
R-tetralone afford products with similar enantioselectivities
and reactivities (Table 2, entries 7 and 8). Different from
5
ance of the catalytic capability. Therefore, it can be expected
that the double-activation method will have prospective
(15) (a) Shen, Y. C.; Feng, X. M.; Li, Y.; Zhang, G. L.; Jiang, Y. Z.
Synlett 2002, 793. (b) Shen, Y. C.; Feng, X. M.; Zhang, G. L.; Jiang, Y. Z.
Synlett 2002, 1353.
1
2
Snapper’s report, the R,â-saturated ketone gives a higher
ee value than the R,â-unsaturated one (Table 2, entries 9
(
16) See Supporting Information.
1
(17) H NMR (400 MHz, CDCl3) shows that the chemical shift of
1
0a
TMSCN is δ ) 0.35 ppm. However, after TMSCN coordinates to N-oxide
and 10). This is in agreement with Shibasaki’s result.
2
, a new signal appears at δ ) 0.17 ppm.
(
18) The following observation also supports this conclusion using chiral
(
14) On Strecker reaction, see: (a) Liu, B.; Feng, X. M.; Chen, F. X.;
N-oxide. The addition of TMSCN to acetophenone is achieved in 14% yield
with 35% ee by using 20 mol % 1b-Ti(OiPr)4 and 20 mol % (R)-3,3′-
dimethyl-2,2′-biquinoline N,N′-dioxide1 at 0 °C for 84 h.
(19) For a review on N-oxide metal complexes, see: (a) Karayannis, N.
M.; Pytlewski, L. L.; Mikulski, C. M. Coord. Chem. ReV. 1973, 11, 93.
For a recent example, see: (b) Dyker, G.; H o¨ lzer, B.; Henkel, G.
Tetrahedron: Asymmetry 1999, 10, 3297.
Zhang, G. L.; Jiang, Y. Z. Synlett 2001, 1551. N-Oxides have been used
previously to promote the reactions of other chlorosilane reagents; see: (b)
Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem. Soc. 1998,
20, 6419. (c) Tao, B.; Lo, M. C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
53. (d) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233. (e)
4b
1
3
Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T. Org. Lett. 2002, 4, 2799.
Org. Lett., Vol. 5, No. 6, 2003
951

applications and provide more alternatives in the screening
for efficient catalyst systems.
Acknowledgment. The authors thank the National Natu-
ral Science Foundation of China (No. 20225206) and the
Ministry of Education, P. R. China, for financial support.
The authors also thank Dr. Xiandeng Hou at Sichuan
University for fruitful discussions.
In conclusion, a highly efficient catalyst system has been
developed for the enantioselective cyanosilylation of ketones
by a catalytic double-activation method (CDAM), in which
electrophiles and nucleophiles are activated by a catalytic
amount of a chiral Lewis acid (2 mol %) and an achiral Lewis
base (N-oxide, 1 mol %), respectively. Moreover, one-step
preparation of the catalyst from commercially available
material, low catalyst loading, and mild reaction conditions
all make this approach practical. Further mechanistic studies
and other related reactions along this line are underway.
Supporting Information Available: Experimental pro-
cedure and characterization for 1a, 2, and the cyanohydrins
and chiral GC or HPLC analyses of the O-TMS cyanohy-
drins. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL034158A
952
Org. Lett., Vol. 5, No. 6, 2003