ORGANIC LETTERS
Role of Noncovalent Interactions in the Enantioselective Reduction of Aromatic Ketimines with Trichlorosilane
2004 Vol. 6, No. 13 2253-2256
Andrei V. Malkov,* Andrea Mariani, Kenneth N. MacDougall, and Pavel Kocˇovsky´* Department of Chemistry, UniVersity of Glasgow, Glasgow G12 8QQ, U.K.
[email protected];
[email protected] Received April 28, 2004
ABSTRACT
Asymmetric reduction of ketimines 1 with trichlorosilane can be catalyzed by a new N-methyl L-valine derived Lewis basic organocatalyst, such as 4d, with high enantioselectivity. The structure−reactivity investigation suggests hydrogen bonding and arene−arene interactions between the catalyst and the incoming imine as the main factor determining the enantiofacial selectivity.
The recipe for successful asymmetric catalysis includes a delicate mix of various factors, such as catalyst structure and loading, solvent, temperature, etc. Often, even minor changes to any of these characteristics can produce a dramatic effect on the stereochemical outcome of the reaction.1 Among the methods designed to enhance enantioselectivity through structural variations, chiral relay represents an emerging new strategy where a conformationally flexible group, appropriately placed, effectively conveys the chiral information to the reaction center.2 We have recently developed new N-methyl amino acid derived amidophoshine ligands and demonstrated that the conformational bias, imposed by the tertiary amide group, led to high enantioselectivity in the Cu(I)-catalyzed conjugate addition of Et2Zn to R,β-enones.3 Our N-methyl valine derived ligands proved superior to those prepared from proline, showing that the rigid cyclic framework of proline may not always be an advantage.3 (1) For recent overviews, see (a) Feringa, B. L.; van Delden, R. A. Angew. Chem., Int. Ed. 1999, 38, 3418. (b) Mikami, K.; Terada, M.; Korenaga, T.; Matsumoto, Y.; Ueki, M.; Angelaud, R. Angew. Chem., Int. Ed. 2000, 39, 3532. (c) Fagnow, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26. (2) For a recent review on chiral relay effect, see: (a) Corminboeuf, O.; Quaranta, L.; Renaud, P.; Liu, M.; Jasperse, C. P.; Sibi, M. P. Chem. Eur. J. 2003, 9, 28. For a recent contribution, see: (b) Sibi, M. P.; Zhang, R.; Manyem, S. J. Am. Chem. Soc. 2003, 125, 9306. (3) Malkov, A. V.; Hand, J. B.; Kocˇovsky´, P. Chem. Commun. 2003, 1948. 10.1021/ol049213+ CCC: $27.50 Published on Web 05/27/2004
© 2004 American Chemical Society
In search for an extension of this principle to other applications, we turned our attention to imine reduction (Scheme 1), which gives rise to chiral amines that are
Scheme 1. Asymmetric Reduction of Ketimines
common intermediates in the synthesis of pharmaceutical drugs and agrochemicals. Current methods for asymmetric reduction of imines, such as transition-metal-catalyzed highpressure hydrogenation,4,5 hydrosilylation,4,6 or transfer
hydrogenation,7 are tainted by the problem of metal leaching, so that development of an organocatalytic protocol appears to be an attractive alternative. Because Cl3SiH can be activated by Lewis bases (R3N, DMF, MeCN, etc.) to effect hydrosilylation of imines,8 we set out to design a suitable chiral Lewis basic catalyst.9,10 While this work was in progress, Matsumura reported on the asymmetric reduction of imines 1 with Cl3SiH, catalyzed by the L-proline-derived formamides (S)-3a,b (10-20 mol %) with e66% ee (Scheme 1; Table 1, entries 1 and 2).11 This work represented a great
valine unit. To this end, diamides (S)-4,5 were synthesized, which can be regarded as chiral analogues of DMF (Scheme 2).
Scheme 2. Optimization of Catalyst Structure
Table 1. Reduction of Ketimines 1a-k with Trichlorosilane, Catalyzed by (S)-3a,b and (S)-4aa entry
imine
R1, R2
cat.
solvent
yield (%)b
2, % eec (config)d
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
1a 1a 1a 1a 1a 1b 1b 1c 1d 1e 1e 1f 1g 1h 1i 1j 1k 1k
Ph, Ph Ph, Ph Ph, Ph Ph, Ph Ph, Ph 4-MeOC6H4, Ph 4-MeOC6H4, Ph 4-CF3C6H4, Ph 4-NO2C6H4, Ph 2-naphth, Ph 2-naphth, Ph c-C6H11, Ph Ph, 4-MeOC6H4 Ph, 2-MeOC6H4 Ph, c-C6H11 Ph, n-Bu Ph, CH2Ph Ph, CH2Ph
3a 3b 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 3a 4a
CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 MeCN CH2Cl2 CHCl3 CHCl3 CHCl3 CH2Cl2 CHCl3 CHCl3 CHCl3 CH2Cl2 CHCl3 CHCl3 CH2Cl2 CHCl3
91 52 68 79 65 62 57 43 30 69 50 80 96 36 50 60 97 46
55 (R)e 66 (R)e 79 (S) 86 (S) 30 (S) 76 (S) 80 (S) 87 (S) 85 (S) 80 (S) 87 (S) 37 (S) 85 (S) 22 (S)
