excellent enenatioselectivities and with broad substrate general-
ity. Besides, the similar sulfoxamide ligands were also applied
to asymmetric diethylzinc addition to aldehydes.12 This study
clearly demonstrates that differences in ligand structures
strongly influence the enantioselectivity, and several trends
were noted. First, the generation of the second stereocenter
greatly improved enantioselectivities. Second, substitution of a
flexible benzyl group at the amino carbon ((R,S)-7a) for a rigid
phenyl group ((R,S)-7b) resulted in a significant drop in the ee
value. Third, aryl substituents on the stereogenic center at the
alcoholic carbon proved to be superior to alkyl substituents. The
mechanistic study of the catalytic systems and their further
applications are currently underway.
Notes and references
† Postdoctoral research fellow from Department of Chemistry, Sichuan
University, Peoples Republic of China.
(entry 4). From entries 5 and 6, a significant temperature effect
was observed with enantioselectivities of 79% ee at 240 °C
(entry 5) and 96% ee at 265 °C (entry 6). Another key factor for
the successful practice of highly efficient enantioselective
trimethylsilylcyanation of aldehydes is the use of powdered 4 Å
molecular sieves. In the absence of molecular sieves, the ee
value significantly decreased from 96 to 77% ee with the yield
decreased to 52% (entry 7). When as little as 5 mol% of (R,S)-7a
was used, an excellent enantioselectivity was still obtained with
94% ee (entry 8). Replacing (R,S)-7a with (R,S)-7b gave a lower
enantioselectivity of 62% ee (entry 9). When (R,S)-7c with a
benzyl substituent at the amino carbon and a tert-butyl
substituent at the hydroxy carbon was used, a much lower ee
value of 38% ee was obtained (entry 10). For (S,S)-7a, which is
a diastereomer of (R,S)-7a, the reaction gave only 8% ee of S
configuration (entry 11). In addition, other metallic reagents
such as AlMe3, AlEt3, Et2AlCl, Ti(O-i-Pr)2Cl2, Ti(O-i-Pr)Cl3
and TiCl4 were also examined. However, the reactions gave low
enantioselectivities with the best ee value of only 37% ee.
Solvent effect was also studied, and CH2Cl2 was the best
choice.
The enhanced unique reactivity of the N-sulfonylated amino
alcohol (R,S)-7a has been suggested to arise from the following
factors: (a) phenoxides are known to form strong bonds to group
4 transition metals, and with electron withdrawing halogen
groups, the phenoxide moiety may lead to enhanced Lewis
acidity at the metal center to improve the reactivity; (b) the
phenolic ring further enhances conformational rigidity of these
tridendate ligands, which may be an important factor in the
transfer of asymmetry.
‡ General procedures for asymmetric cyanosilylation of aldehydes: Under
dry dinitrogen atmosphere, 0.05 mmol of the chiral ligand, 0.05 mmol of
Ti(O-i-Pr)4, and 100 mg of powdered 4 Å molecular sieves were mixed in
2.0 mL of dry DCM at rt. The mixture was stirred for 1 h and cooled to
265 °C. To the resulting yellow solution were added 1.5 mmol of Me3SiCN
and 0.5 mmol of aldehyde. After the solution was stirred at this temperature
for 48 h, the reaction was quenched with 1 M HCl, and the mixture was then
vigorously stirred for 4 h. The aqueous phase was extracted with ethyl
acetate (3 3 10 mL), and the combined organic layers were dried over
MgSO4, and concentrated in vacuo. Flash chromatography of the residue on
silica gel (elution with 5+1 hexane–ethyl acetate) gave a cyanohydrin. ee
was determined by HPLC after protection as acetyl esters (except 1h, which
was protected as a benzoyl ester).
1 R. J. H. Gregory, Chem. Rev., 1999, 99, 3649; F. Effenberger, Angew.
Chem., Int. Ed. Engl., 1994, 33, 1555; C. G. Kruse in Chirality in
Industry, ed. A. N. Collins, G. N. Schedrake and J. Crosby, Wiley,
Chichester, 1992, chapter 14.
2 M. North, Synlett, 1993, 807.
3 D. E. Ward, M. J. Hrapchak and M. Sales, Org. Lett., 2000, 2, 57; K.
Narasaka, T. Yamada and H. Minamikawa, Chem. Lett., 1987, 2073.
4 M. Mori, H. Imma and T. Nakai, Tetrahedron Lett., 1997, 38, 6229.
5 C. Bolm and P. Müller, Tetrahedron Lett., 1995, 36, 1625.
6 H. Nitta, D. Yu, M. Kudo, A. Mori and S. Inoue, J. Am. Soc., 1992, 114,
7969.
7 L. Z. Flores-Lopéz, M. Parra-Hake, R. Somanathan and P. J. Walsh,
Organometallics, 2000, 19, 2153; Y. N. Belokon, S. Caveda-Cepas, B.
Green, N. S. Ikonnikov, V. N. Khrustalev, V. S. Larichev, M. A.
Moscalenko, M. North, C. Orizu, V. I. Tararov, M. Tasinazzo, G. I.
Timofeeva and L. V. Yashkina, J. Am. Chem. Soc., 1999, 121, 3968; X.
Zhou, J. Huang, P. Ko, K. Cheung and C. Che, J. Chem. Soc., Dalton
Trans., 1999, 3303; V. I. Tararov, D. E. Hibbs, M. B. Hursthouse, N. S.
Ikonnikov, K. M. A. Malik, M. North, C. Orizu and Y. N. Belokon,
Chem. Commun., 1998, 387; Y. Jiang, L. Gong, X. Feng, W. Hu, W.
Pan, Z. Li and A. Mi, Tetrahedron, 1997, 53, 14 327; M. Hayashi, T.
Inoue, Y. Miyamoto and N. Oguni, Tetrahedron, 1994, 50, 4385; M.
Hayashi, Y. Miyamoto, T. Inoue and N. Oguni, J. Org. Chem., 1993, 58,
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8 J. M. Brunel, O. Legrand and G. Buono, Tetrahedron: Asymmetry,
1999, 10, 1979.
9 C. Hwang, D. Hwang and B. Uang, J. Org. Chem., 1998, 63, 6762.
10 D. Callant, D. Stanssens and J. G. de Vries, Tetrahedron: Asymmetry,
1993, 4, 185.
11 M. T. Reetz, M. W. Drewes and A. Schmitz, Angew. Chem., Int. Ed.
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12 J. Qiu, C. Guo and X. Zhang, J. Org. Chem., 1997, 62, 2665; J. Balsells
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From entries 12–18, the generality of the asymmetric
catalytic reactions employing the (R,S)-7a–Ti(O-i-Pr)4 catalytic
system was conducted. For aromatic aldehydes (entries 12–16),
the asymmetric cyanosilylations gave (R)-cyanohydrins with
excellent ee values except in the cases of 2-methoxybenzalde-
hyde (86% ee) and 1-naphthaldehyde (77% ee). The best ee
value of 96% ee was obtained for benzaldehyde (entry 6) or
2-naphthaldehyde (entry 15). It is worth noting that, in this
study, ee values of 95 and 93% ee were obtained for aliphatic
isobutyraldehyde and a,b-unsaturated (E)-cinnamaldehyde (en-
tries 17 and 18), respectively.
In conclusion, the first example of highly effective asym-
metric addition of a cyano group to aldehydes using N-
sulfonylated b-amino alcohols as ligands has been reported with
1964
Chem. Commun., 2000, 1963–1964