Asymmetric addition of n-butyllithium to aldehydes: new insights into the reactivity and enantioselectivity of the chiral amino ether accelerated reaction Johan Granander, Richard Sott and Go Èran Hilmersson p Organic Chemistry, Department of Chemistry, Go Èteborg University, S-412 96 Go Èteborg, Sweden Received 20 December 2001; accepted 5 March 2002 Abstract ÐEnantioselective butylation of benzaldehyde with n-butyllithium was mediated by a series of chiral lithium amide analogues to give 1-phenylpentanol in good to moderate enantioselectivities. In order to achieve high enantiomeric excess in the reaction, the lithium amide must have a substituent larger than methyl on both the carbon at the stereogenic center and the nitrogen. Computational studies, using semi-empirical PM3) and density functional B3LYP) methods, show that the stabilities of the transition states for the chiral lithium amide accelerated butylation of isobutyraldehyde are in agreement with experiments. q 2002 Elsevier Science Ltd. All rights reserved. 1. Introduction Asymmetric carbon±carbon bond forming reactions between n-butyllithium n-BuLi) and aldehydes can be a particularlyversatilereactionintheconstructionofenantio- pure alcohols. 1 The enantioselectivity is obtained using chiral lithium amides as chiral auxiliaries and catalysts, non-covalently bonded to the reagent n-BuLi. Our interest in this ®eld began in 1993 when we initiated NMR spectro- scopic studies of a chiral lithium amide reported by Hogeveen and Eleveld to induce asymmetry in the addition of n-BuLitobenzaldehyde. 2,3 Sofar,theenantioselectivities obtained with organolithium compounds in the alkylation reaction of aldehydes have not been as high as those with dialkyl zinc reagents. 4 However, the readily available alkyl- lithium reagents and their high reactivity are properties that motivate more effort to ®nd conditions in which organo- lithium compounds also can become useful nucleophilic reagents in asymmetric synthesis. By low temperature NMR spectroscopic studies we have observed an equilibrium between homo complexed chiral lithium amide dimers, tetrameric n-BuLi and a mixed dimer consisting of one lithium amide and one n-BuLi Scheme 1). 5 Most of the NMR spectroscopic studies were carried out in diethyl ether DEE) solution. Later, the effect of different solvents and substituents on the equilibrium and enantio- selectivity of addition to an aldehyde were investigated. 6 At that time, our results indicated the importance of a high complexation constant in order to observe high enantioselectivity. Since then, we have remained in this ®eld with the aim of better understanding the factors governing the enantioselectivity. This work includes the searchfornewmixedcomplexesbetween n-BuLiandchiral inducers. We hope that details regarding this issue could be helpful in the design of new and more ef®cient chiral inducers for this important class of reaction. Herein, we report our continued studies of chiral lithium amides and their use in the asymmetric addition reaction to prochiral aldehydes.Basedonquantumchemicalcalculationswealso Tetrahedron 58 2002) 4717±4725 Pergamon TETRAHEDRON 0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII:S0040-402002)00378-2 Keywords: lithium; amides; alkylation; asymmetric. p Corresponding author. Tel./fax: 146-31-7722904; e-mail: hilmers@organic.gu.se Scheme 1.