7412
J. Am. Chem. Soc. 2000, 122, 7412-7413
Scheme 1. Synthesis of 1-L
Catalytic Enantioselective Cyanosilylation of Ketones
Yoshitaka Hamashima, Motomu Kanai, and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences
The UniVersity of Tokyo, Hongo, Bunkyo-ku
Tokyo, 113-0033, Japan
ReceiVed May 13, 2000
The catalytic asymmetric addition of cyanide to carbonyl
compounds1 such as aldehydes,2 imines3 and ketoimines4 is
currently intensively studied. However, no practical asymmetric
cyanosilylation of ketones has been reported so far. For example,5
the best result using chemical catalyst is 72% ee in the case of
aryl methyl ketones. However, this catalyst could not be applied
to ethyl ketones ( ∼30% ee) and aliphatic ketones.6 In view of
the importance of the cyanohydrins as precursors of chiral
quaternary R-hydroxy carbonyl derivatives, development of an
efficient catalytic asymmetric cyanosilylation of ketones with
broad generality is long awaited. Herein, we describe the first
entry in this category that we believe is useful for synthesizing a
variety of quaternary cyanohydrins, catalyzed by a novel titanium
catalyst 1.
Table 1. Effect of Metals
entry
metal
temp/°C time/h yield/% ee/% R/S
1
2
3
4
5
Et2AlCl
rt
rt
rt
rt
-20
48
2
36
48
36
0
90
52
78
44
-
-
Yb(OiPr)3
Zr(OtBu)4
Ti(OiPr)4
Ti(OiPr)4
18
14
35
73
S
R
R
R
Table 2. Effect of Solvents
During the course of our studies to develop a new asymmetric
catalyst from the concept of bifunctional catalysis,7 we have found
that the Lewis acid (Al)-Lewis base (phosphine oxide) catalyst
3 can promote the cyanosilylation of acetophenone, however, with
low enantiomeric excess (20%).8 To improve the enantioselec-
tivity, we planned to introduce a catechol moiety at the C3
hydroxyl group on the basis of the following consideration. The
coordination of the ether oxygen at C3 should make it possible
to form a complex such as 1. As a result, the phenyl group of the
catechol should be fixed at the position shielding the R-side (anti
entry solvent conc/M temp/°C time/h yield/% ee/%
1
2
3
4
CH2Cl2
toluene
THF
0.65
0.65
0.65
3
-20
-20
-20
-30
36
36
36
36
44
40
58
85
73
70
83
92
THF
(1) (a) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649-3682. (b) Effenberger,
F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555-1564. (c) North, M. Synlett
1993, 807-820.
(2) For example: (a) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 1999, 121, 2641-2642. (b) Belokon´, Y. N.; Caveda-
Cepas, S.; Green, B.; Ikonnikov, N. S.; Khrustalev, V. N.; Larichev, V. S.;
Moscalenko, M. A.; North, M.; Orizu, C.; Tararov, V. I.; Tasinazzo, M.;
Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc. 1999, 121, 3968-3973.
(c) Hwang, C.-D.; Hwang, D.-R.; Uang, B.-J. J. Org. Chem. 1998, 63, 6762-
6763.
(3) For example: (a) Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai,
M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652. (b) Sigman,
M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279-
1281. (c) Porter, J. R.; Wirschun, W. G.; Kuntz, K. W.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 2657-2658. (d) Ishitani, H.;
Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122,
762-766. (e) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157-160.
(4) (a) Vachal, R.; Jacobsen, E. N. Org. Lett. 2000, 2, 867-870. (b) Byrne,
J. J.; Chavarot, M.; Chavant, P.-Y.; Valle´e, Y. Tetrahedron Lett. 2000, 41,
873-876.
(5) Belokon´, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.; Tararov, V. I.
Tetrahedron Lett. 1999, 40, 8147-8150.
(6) Enzymatic reactions have been reported to give cyanohydrins from
aliphatic ketones with high enantioselectivity. However, synthesis of cyano-
hydrins from aromatic ketones and ethyl ketones is not efficient using enzymes.
For example: Kiljunen, E.; Kanerva, L. T. Tetrahedron: Asymmetry 1997,
8, 1551-1557.
(7) (a) Shibasaki, M. Enantiomer 2000, 4, 513-527. (b) Shibasaki, M.
CHEMTRACTS: Org. Chem. 1999, 979-998. (c) Shibasaki, M.; Sasai, H.;
Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236-1256.
(8) Kanai, M.; Hamashima, Y.; Shibasaki, M. Tetrahedron Lett. 2000, 41,
2405-2409.
to the phosphine oxide, concave side) of the catalyst, thus defining
the position of the coordinating ketone at the â-side, syn to the
Lewis basic phosphine oxide. Therefore, we designed the new
catalyst 1. Ligand 1-L was readily synthesized in multigram scale
from the known alcohol 49 as shown in Scheme 1.10
First, we screened different metals combined with ligand 1-L
for the catalysis of the addition of TMSCN to acetophenone 9a
(Table 1). Although the Yb catalyst showed a remarkable
reactivity (Table 1, entry 2), it was found that the Ti catalyst
gave the best enantiomeric excess (Table 1, entry 4). Furthermore,
when the reaction was conducted at -20 °C, the ee was increased
up to 73% (Table 1, entry 5). Next, we examined the effect of
solvent (Table 2). Interestingly, both the reaction rate and
enantioselectivity increased in a coordinating solvent such as THF
compared to less polar solvents such as CH2Cl2 or toluene.
Gratifyingly, employing more concentrated conditions (3 M in
terms of 9a), the reaction proceeded more efficiently at -30 °C
for 36 h to give the product in 85% yield and with 92% ee (Table
2, entry 4). Consequently, the best reaction conditions were
determined to involve 10 mol % of Ti(Oi Pr)4 and ligand 1-L in
THF solvent.
(9) Nakamura, H.; Tejima, S.; Akagi, M. Chem. Pharm. Bull. 1966, 14,
648-657.
(10) See Supporting Information.
10.1021/ja001643h CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/13/2000