Johan Granander

Asymmetric addition of n-butyllithium to aldehydes: new insights into the reactivity and enantioselectivity of the chiral amino ether accelerated reaction

Enantioselective 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.

Solvent-Dependent Mixed Complex Formation—NMR Studies and Asymmetric Addition Reactions of Lithioacetonitrile to Benzaldehyde Mediated by Chiral Lithium Amides

Lithioacetonitrile and a chiral lithium amide with an internally coordinating methoxy group form mixed dimers in diethyl ether (DEE) and in tetrahydrofuran (THF) according to NMR studies. Based on the observed (6)Li,(1)H heteronuclear Overhauser effects, in THF lithioacetonitrile is present in a mixed complex with the chiral lithium amide, and this complex has a central N-Li-N-Li core. In DEE, on the other hand, the acetonitrile anion bridges two lithiums of the dimer to form a central six-membered Li-N-C-C-Li-N ring. Gauge individual atomic orbital DFT calculations of the (13)C NMR chemical shifts of the DEE- and THF-solvated mixed dimers show good agreement with those obtained experimentally. Lithioacetonitrile complexed to the chiral lithium amide has been employed in asymmetric addition to benzaldehyde in both DEE and THF. In THF the product, (S)-3-phenyl-3-hydroxy propionitrile, is formed in 55 % ee and in DEE the R enantiomer is formed in 45 % ee. This change in stereoselectivity between solutions in DEE and THF was found to be general among a number of different chiral lithium amides, all with an internal chelating methoxy group.

Chiral lithium amido sulfide ligands for asymmetric addition reactions of alkyllithium reagents to aldehydes

Six chiral amino sulfides have been synthesised from the amino acids phenylalanine, phenylglycine and valine. These amino sulfides were used as chiral ligands in the asymmetric addition of n-butyllithium and metyllithium to various aldehydes at low temperatures. The highest stereoselectivities were obtained with benzaldehyde, resulting in 1-phenyl-1-pentanol and 1-phenyl-1-ethanol in enantiomeric excesses of >98.5 and 95%, respectively. These stereoselectivities were significantly higher than those induced by the ether analogues.