C O MMU N I C A T I O N S
Table 1. Oxazaborolidinium-Catalyzed Cyanosilylation of
Aldehydes
cases studied so far, the absolute configuration of the cyanohydrins
produced is that predicted by 3 and the mechanistic model. Further
investigations are planned to provide additional information with
regard to scope, optimal coreactant, and optimal oxazaborolidinium
catalysts (for instance, with regard to the substituent on boron).
Supporting Information Available: Procedures for cyanosilylation
and also characterization and analytical data for products (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
R
time, h
% isolated yield
% eea,b
phenyl
40
72
40
144
40
94
95
91
98
97
96
96
95
91
90
97
90
91
91
2
4
4
-tolyl
-anisyl
-cyanophenyl
cyclohexyl
tert-butyl
n-hexyl
References
(
1) For reviews on enantioselective synthesis of cyanohydrins and their
derivatives, see: (a) North, M. Tetrahedron: Asymmetry 2003, 14, 147-
40
48
176. (b) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649-3682. (c) Shibasaki,
c
M.; Kanai, M.; Funabashi, K. J. Chem. Soc., Chem. Commun. 2002, 1989-
999.
(2) (a) Diketopiperazines: Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem.
1
a
Enantioselectivities determined by GC or 1H NMR analysis of
1
990, 55, 181-185. (b) Cinchona alkaloids: Tian, S.-K.; Hong, R.; Deng,
cyanohydrins. Performed using 0.2 equiv of Ph3PO. c Reaction temp )
b
L. J. Am. Chem. Soc. 2003, 125, 9900-9901.
-
20 °C.
(
3) (a) Corey, E. J.; Wang, Z. Tetrahedron Lett. 1993, 34, 4001-4004. (b)
Deng, H.; Isler, M. P.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2002, 41, 1009-1012.
excellent in each case, and the scope of the process includes not
only a range of substituted aromatic aldehydes but also a variety
of R-substituted aliphatic aldehydes. In each case, the initial product
is the TMS ether of the cyanohydrin, which can readily be isolated
or transformed into cyanohydrin by mild acidic hydrolysis. Enan-
tioselectivities were determined either by gas chromatographic
(
4) (a) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 1999, 121, 2641-2642. (b) Baeza, A.; Casas, J.; Najera, C.; Sansano,
J. M.; Saa, J. M. Angew. Chem., Int. Ed. 2003, 42, 3143-3146. (c) Casas,
J.; Baeza, A.; Sansano, J. M.; Najera, C.; Saa, J. M. Tetrahedron:
Asymmetry 2003, 14, 197-200.
(5) (a) Narasaka, K.; Yamada, T.; Minamikawa, H. Chem. Lett. 1987, 2073-
2
076. (b) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J. Org. Chem.
1
993, 58, 1515-1522. (c) Nitta, H.; Yu, D.; Kudo, M.; Mori, A.; Inoue,
1
analysis or H NMR analysis of the Mosher (MTPA) ester of the
cyanohydrin using established analytical protocols.1-8
S. J. Am. Chem. Soc. 1992, 114, 7969-7975. (d) Hamashima, Y.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 7412-7413. (e)
Hamashima, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2001, 42,
691-694. (f) Belokon, Y. N.; Gutnov, A. V.; Moskalenko, M. A.;
Yashkina, L. V.; Lesovoy, D. E.; Ikonnikov, N. S.; Larichev, V. S.; North,
M. J. Chem. Soc., Chem. Commun. 2002, 244-245. (g) Chang, C.-W.;
Yang, C.-T.; Hwang, C.-D.; Uang, B.-J. J. Chem. Soc., Chem. Commun.
There are advantages to the methodology besides the excellent
yields and enantioselectivities displayed in Table 1. The catalytic
ligand is easily and efficiently recoverable for reuse (ca. 96%
recovery yield of (S)-dimexylpyrrolidinomethanol). The cyanosi-
lylation is easily scalable since it is homogeneous and generally
can be carried out at 0 °C. Obviously, on a scale larger than that
used for these initial investigations (1-5 mmol at 0.2-0.4 M
concentration of RCHO), even higher concentrations of reactants
can be used so as to diminish reaction times.
Although we have not carried out exhaustive investigations to
find the optimal phosphine oxide-type coreactant, studies thus far
indicate that Ph
EtO) PO, (2-furyl)
regard to Ph PO as a coreactant, it should be mentioned that it
affects the reaction rate in two opposing ways. Since Ph PO is a
Lewis base, it competes with RCHO for coordination with the
oxazaborolidinium cation and thereby retards the cyanosilylation
reaction. This effect is clear from the study of reactions other than
cyanosilylation that are catalyzed by 1, for example, enantioselective
Diels-Alder additions. Thus, although the [4 + 2]-cycloaddition
reaction of 2-methylacrolein and isoprene at -78 °C in the presence
of 10 mol % 1 is complete within 1 h, there is hardly any reaction
under the same conditions if 2 equiv of Ph
of 1. On the other hand, the formation of the reactive intermediate
Ph P(OSiMe )NC clearly must accelerate the cyanosilylation
process.
2
002, 54-55. (h) Belokon, Y. N.; Blacker, A. J.; Clutterbuck, L. A.; North,
M. Org. Lett. 2003, 5, 4505-4507. (i) Belokon, Y. N.; Green, B.;
Ikonnikov, N. S.; Larichev, V. S.; Lokshin, B. V.; Moscalenko, M. A.;
North, M.; Orizu, C.; Peregudov, A. S.; Timofeeva, G. I. Eur. J. Org.
Chem. 2000, 2655-2661.
(6) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2002, 41, 3636-3638.
(
7) Ooi, T.; Miura, T.; Takaya, K.; Ichikawa, H. Maruoka, K. Tetrahedron
2
001, 57, 867-873.
(
8) (a) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.;
Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908-
9
909. (b) Masumoto, S.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron
Lett. 2002, 43, 8647-8651.
3
PO is distinctly superior to any of the following:
(
9) Lapworth, A. J. Chem. Soc. 1903, 83, 995-1005.
(
3
3
PO, (4-F-phenyl) PO, Ph PS, Ph SO. With
3
3
2
(
10) (a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808-3809. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc.
3
2
2
002, 124, 9992-9993. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc.
003, 125, 6388-6390. (d) Zhou, G.; Hu. Q.-Y.; Corey, E. J. Org. Lett.
3
2003, 5, 3979-3982. (e) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem.
Soc., 2004, 126, 4800-4802. (f) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J.
Am. Chem. Soc. 2004, 126, 5984-5986.
(11) Corey, E. J.; Lee, T. W. J. Chem. Soc., Chem. Commun. 2001, 1321-
1
329.
(
12) Hamashima, Y.; Sawada, D.; Nogami, H.; Kanai, M.; Shibasaki, M.
Tetrahedron 2001, 57, 805-814.
(
13) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122,
1
0521-10532.
(14) Vogl, E. M.; Gr o¨ ger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38,
570-1577.
15) Casas, J.; Najera, C.; Sansano, J. M.; Saa, J. M. Org. Lett. 2002, 4, 2589-
592.
1
3
PO are present per equiv
(
(
(
2
16) For IR spectral data on TMSCN and TMSNC, see: Seckar, J. A.; Thayer,
J. S. Inorg. Chem. 1976, 15, 501-504.
3
3
17) The following general procedure was developed. CAUTION: TMSCN is
Volatile and toxic and must only be used in a well-Ventilated hood. A
solution of catalyst 1 (0.5 mmol in 7.5 mL of toluene; for preparation see
Supporting Information or ref 10e) was added to 293 mg (1.0 mmol) of
Although most of our experiments have been carried out with
the mexyl-substituted catalyst 1, we have also examined the use of
the diphenyl analogue 2 with several of the substrates listed in Table
. In general, the two catalysts are essentially equivalent, but in a
few cases the ees observed for the cyanohydrin product were 1-2%
lower with 2 as compared to 1.
Ph
3 2
PO with stirring under N . Then, TMSCN (0.752 mL, 5.64 mmol)
was added followed by the aldehyde (5 mmol, dropwise) in 3-5 mL of
toluene over 1 h at 0 °C. After the reaction time indicated in Table 1, the
reaction mixture was concentrated in vacuo, and 5 mL each of water and
pentane were added. Extractive workup provided essentially pure cyano-
hydrin TMS ether from which cyanohydrin was obtained by stirring with
5 mL of 2 N HCl and 5 mL of EtOAc, isolation from the EtOAc layer,
and passage through a column of silica gel.
1
In conclusion, we believe that the results summarized in Table
recommend the use of the methodology for enantioselective
1
cyanosilylation that is described herein. It is gratifying that, in all
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J. AM. CHEM. SOC.
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