Heterocyclic Lithium Amides as Chiral Ligands for an Enantioselective Hydroxyalkylation with n -BuLi (original) (raw)
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Journal of Organometallic Chemistry, 2000
The two chiral lithium amides prepared from (R)-(2-N,N-dimethylamine-ethyl)-(1-phenyl-2-pyrrolidin-1-yl-ethyl)amine (1) and (R)-(2-methoxyethyl)-(1-phenyl-2-pyrrolidin-1-yl-ethyl)amine (2) and n-BuLi, were found to form symmetrically solvated dimers in diethylether (DEE). The addition of tetrahydrofuran (THF) and of 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU) did not affect the 6 Li-NMR chemical shift due to a very strong internal coordination. Their reactivity as chiral bases in the desymmetrization of cyclohexenoxide was very low due to this strong entropy driven internal coordination. However, they were found to easily form mixed complexes with n-BuLi which was verified by 13 C-NMR and 6 Li, 1 H-HOESY NMR. One molecule of n-BuLi and one molecule of the chiral lithium amide Li-1 respectively Li-2 constituted the mixed complexes. In this mixed dimer at least one coordination site is available on lithium for coordination of the substrate. The alkylation of benzaldehyde using Li-1/n-BuLi gave 40% and Li-2/n-BuLi gave 30% enantiomeric excess of the (S)-1-phenyl-1-pentanol in very high chemical yields.
Tetrahedron, 2002
AbstractÐNon-covalent aggregates of highly polar entities assemble, on a temporary basis, a chiral moiety to a reagent. Attempts to take advantage of this phenomenon with chiral 3-aminopyrrolidine (3-AP) lithium amides are described. The enantioselective protonation of a complex involving these amides and the lithium enolate of 2-methyltetralone by an achiral proton source gives products in which the ee does not exceed 40%. The same class of chiral amides is then applied to the asymmetric nucleophilic alkylation of aldehydes using alkyllithiums and phenyllithium. In this case, a mixed aggregate made up of the lithium amide and the alkyllithium, a structure that has been detailed previously in comparable situations, seems to be directly involved in the reaction. Thus, higher asymmetric inductions are obtained, affording the alkylation products in ee of up to 70%. q Scheme 1. Synthetic routes to 3-aminopyrrolidines 1.
Enantioselective butylation of aliphatic aldehydes by mixed chiral lithium amide/ n-BuLi dimers
Tetrahedron-asymmetry, 1999
The enantioselective butylation of aliphatic aldehydes with mixtures of n-butyllithium and chiral lithium amides in a diethyl ether-dimethoxymethane solvent mixture is described. Enantiomeric excesses ranging from 91 to 98.5% were observed for several aliphatic alcohols. The asymmetric butylation of the prochiral aldehydes proceeds much faster by the mixed lithium amide/n-BuLi complexes than by tetrameric n-BuLi.
Pure and Applied Chemistry, 2000
An overview of the role of 3-aminopyrrolidine lithium amides (3-APLi's) as chiral ligands for alkyllithiums (AlkLi's) is presented. Synthetic developments as well as NMR characterizations and computational interpretations have been simultaneously and complementarily conducted to improve the ligand design for a model reaction that is the condensation of AlkLi's on o-tolualdehyde, for which enantiomeric excesses up to 80 % were obtained. This study describes the whole chain going from the synthesis of the chiral 3-aminopyrrolidines (3-APs) (18 different 3-APs synthesized) to the characterization of the noncovalent mixed aggregates resulting from the interaction between the organolithium partners (3-APLi:AlkLi). Finally, the docking of the aldehyde on one lithium of the aggregate was analyzed by theoretical means on simplified models, in an attempt to understand the structure of the fully loaded pretransition complexes.
Enantioselective synthesis of secondary alcohols in the presence of chiral ligands
Tetrahedron, 1982
The synthesis of two S-proline derivatives is described together with their use as chiral ligands for lithium in reactions of n-butyllithium with benzaldehyde to give 1-phenyl-l-pentanol with moderate optical purity. The presence of lithium salts in the reaction mixture causes a decrease in asymmetric induction.
The Journal of Organic Chemistry, 2007
The effect of lithium halides on the enantioselectivity of the addition of methyllithium on o-tolualdehyde, in the presence of chiral lithium amides derived from chiral 3-aminopyrrolidines (3APLi), has been investigated. The enantiomeric excess of the resulting 1-o-tolylethanol was found to drop upon addition of significant amounts of LiCl, introduced before the aldehyde. The competitive affinity between the lithium amide, the methyllithium, and the lithium halides in THF was examined by multinuclear NMR spectroscopy and DFT calculations. The results showed that the original mixed aggregate of the chiral lithium amide and methyllithium is rapidly, totally, and irreversibly replaced by a similar 1:1 complex involving one lithium chloride or bromide and one lithium amide. While the MeLi/LiX substitution occurs with some degree of epimerization at the nitrogen for the endo-MeLi:3APLi complex, it is mostly stereospecific for the exo-type arrangements of the aggregate. The thermodynamic preference for mixed aggregates between 3APLi and LiX was confirmed by static DFT calculations: the data show that the LiCl and LiBr aggregates are more stable than their MeLi counterparts by more than 10 kcal‚mol -1 provided THF is explicitly taken into account. These results suggest that a sequestration of the source of chirality by the lithium halides is at the origin of the detrimental effect of these additives on the ee of the model reaction.
Enantioselective addition of alkyllithium reagents to aldehydes induced by chiral lithium alkoxides
Tetrahedron, 1994
Enantioselective induction by some cbiral lithium alkoxides in the addition of methyllithium to benzaldehyde has been examined. A detailed study of Zsubstituted lithium I-phenyl-2-(N,Ndimethyhunino)ethoxides ia the addition of achiral alkyllithium reagents to aldehydes in THF and diethyl ether at-78 'C has been cat?ied out. The ee's are generally higher in the former solvent. The configuration of the newly formed chiraI center is opposite to that of the l-carbon of the a&oxide and independent of that of its 2-carbon atom. 'Ihe cc of the product is generally increased by increasing the size of 2-suI!&ituent. Enantiosekctivity is decreased by the addition of LiC1 and LiCIO, but is little affected by the presence of the predominant enantiomer of the lithium alkoxide produced in the reaction.
Polyhedron, 2012
Series of functionalized organolithium compounds were prepared and added to chiral bicyclic ketones (1R-(+)-camphor analogue 2 and 1R-(À)-fenchone 3), resulting in the preparation of a small ''library'' of chiral aminoalcohols able to serve as ligands in metal mediated asymmetric synthesis. The configuration of the chiral ligands was approved by applying advanced NMR experiments. The absolute configurations of 1,2-disubstituted planar chiral ferrocene-based aminoalcohols 15, 18 and 19 were determined by means of NMR experiments and confirmed by X-ray crystallography. The new chiral ligands were tested as pre-catalysts for the addition of diethyl zinc to benzaldehyde. The reactions proceeded with excellent conversions and a moderate degree of enantioselectivity.