Internal coordination and solvent effects upon hetero- and homocomplexation of chiral lithium amides: structure reactivity effects (original) (raw)
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Heterocyclic Lithium Amides as Chiral Ligands for an Enantioselective Hydroxyalkylation with n -BuLi
The Journal of Organic Chemistry, 2008
Chiral heterocyclic structures based on 3-aminopyrrolidines (3APs), 3-aminotetrahydrothiophens (3ATTs), and 3-aminotetrahydrofurans (3ATFs) have been synthesized. The corresponding lithium amides have been evaluated as chiral ligands in the condensation of n-BuLi on o-tolualdehyde. The returned levels of induction were in the 46-80% ee range. The cheap and easily prepared 3ATFLi's turned out to be also the best ligands, giving access to the expected R or S alcohols in a same 80% level of induction at -78°C in THF. In all cases, the sense of induction depends on the absolute configuration of C 8 on the 3-amino appendage. A general concept is proposed to rationalize the process of induction in the presence of organolithium species.
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.
Journal of the American Chemical Society, 2002
The complexes between methyllithium and chiral 3-aminopyrrolidine (3-AP) lithium amides bearing a second asymmetric center on their lateral amino group were studied using multinuclear ( 1 H, 6 Li, 13 C, 15 N) low-temperature NMR spectroscopies in tetrahydrofuran-d8. The results indicate that lithium chelation forces the pyrrolidine ring of the 3-AP to adopt a norbornyl-like conformation and that robust 1:1 noncovalent complexes between methyllithium and 3-AP lithium amides form in the medium. A set of 1 H-1 H and 1 H-6 Li NMR cross-coupling correlations shows that the binding of methyllithium can take place along the "exo" or the "endo" face of this puckered structure, depending on the relative configuration of the lateral chiral group. This aggregation step renders the nitrogen of the 3-amino group chiral, the "exo" and "endo" topologies corresponding to the (S) and (R) configurations, respectively, of this atom. Density functional theory calculations show that the "exo" and "endo" arrangements are, for both diastereomers, almost isoenergetic even when solvent is taken into account. This result suggests that the formation of the mixed aggregates is under strict kinetic control. A relationship between the topology of these complexes and the sense of induction in the enantioselective alkylation of aromatic aldehydes by alkyllithiums is proposed.
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 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.
Organometallics, 2001
Mixing two analogous lithium amide salts from methyl(1-phenyl-2-(pyrrolidin-1-yl)ethyl)-[ 15 N]amine (1) and (2-methoxy-1-phenylethyl)methylamine (2) in a 1:1 ratio in diethyl ether resulted in a formation of five different dimer complexes, three homodimers and two heterodimers. Computational studies of the relative stabilities of the different dimers were found to be in concordance with relative concentrations observed by NMR spectroscopy. The desymmetrization of cyclohexene oxide using the mixture of Li-1 and Li-2 indicated that the heterodimer exhibited a higher asymmetric induction than either lithium amide by itself according to the "superbases" and the alkyllithium/lithium alkoxide mixtures.
Journal of Organometallic Chemistry, 1995
NMR spectroscopy involving 6Li,IH-HOESY and 6Li,6Li-COSY studies in combination with I H,1 H-NOESY has been used to determine the detailed structures of two complexes, are the novel mixed 1 : 1 complex between lithium-(2-methoxy-(R)-l-phenylethyl)-((S)-l-phenyl-ethyl)-amide (1) and n-butyllithium, and the other the dimeric complex of 1. Both the mixed dimer between 1 and n-butyllithium and the dimeric complex of 1 were formed when 1 was mixed with n-butyllithium in molar ratio of 1.5 : 1 in diethyl ether (DEE-dl0) at -80°C. The 6Li NMR spectrum of the solution, containing the complex between 1 and n-butyllithium and the dimer of 1 showed the presence of four 6Li resonances at -80°C, indicative of two non-equivalent lithiums within each complex. The complex between 1 and n-butyllithium is responsible for the asymmetric induction in the alkylation reaction. SSDI 0022-328X(94)05157-7 isotopically enriched 1 by use of the newly available NMR techniques 6Li,IH-HOESY [1], 6Li,6Li-COSY [4] and 6Li,6Li-EXSY [5].