Göran Hilmersson

Asymmetric deprotonation using s-BuLi or i-PrLi and chiral diamines in THF: the diamine matters.

The solution structures of [(6)Li]-i-PrLi complexed to (-)-sparteine and the (+)-sparteine surrogate in Et(2)O-d(10) and THF-d(8) at -80 °C have been determined using (6)Li and (13)C NMR spectroscopy. In Et(2)O, i-PrLi/(-)-sparteine is a solvent-complexed heterodimer, whereas i-PrLi/(+)-sparteine surrogate is a head-to-tail homodimer. In THF, there was no complexation of (-)-sparteine to i-PrLi until ≥3.0 equiv (-)-sparteine and with 6.0 equiv (-)-sparteine, a monomer was characterized. In contrast, the (+)-sparteine surrogate readily complexed to i-PrLi in THF, and with 1.0 equiv (+)-sparteine surrogate, complete formation of a monomer was observed. The NMR spectroscopic study suggested that it should be possible to carry out highly enantioselective asymmetric deprotonation reactions using i-PrLi or s-BuLi/(+)-sparteine surrogate in THF. Hence, three different asymmetric deprotonation reactions (lithiation-trapping of N-Boc pyrrolidine, an O-alkyl carbamate, and a phosphine borane) were investigated; it was shown that reactions with (-)-sparteine in THF proceeded with low enantioselectivity, whereas the corresponding reactions with the (+)-sparteine surrogate occurred with high enantioselectivity. These are the first examples of highly enantioselective asymmetric deprotonation reactions using organolithium/diamine complexes in THF.

Instantaneous SmI2–H2O-mediated reduction of dialkyl ketones induced by amines in THF

Abstract Reduction of various ketones to their corresponding alcohols is shown to be instantaneous, i.e. completed in less than 10 s, by samarium diiodide (2.5 equiv.) in the presence of water (6.25 equiv.) and an amine (5 equiv.) in THF. The rates of reduction of ketones in this mixture exceed by far the rates determined by an amine or water alone. Rate enhancement is at least 100 000 compared to the reduction without a proton source, or at least 100 times faster than the rate of the widely used HMPA/alcohol accelerated reductions. This new method is therefore suggested to be an excellent replacement of the toxic HMPA/alcohol method.

Solution structure of a key intermediate used in asymmetric alkylation reactions. 1H, 1H-NOESY and 6Li, 1H-HOESY studies of mixtures of a chiral lithium amide and n-butyllithium

Abstract NMR spectroscopy involving 6 Li, 1 H-HOESY and 6 Li, 6 Li-COSY studies in combination with 1 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)-1-phenyl-ethyl)-((S)-1-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-d 10 ) at −80°C. The 6 Li NMR spectrum of the solution, containing the complex between 1 and n -butyllithium and the dimer of 1 showed the presence of four 6 Li 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.

ISOLATION AND SPONTANEOUS RESOLUTION OF EIGHT-COORDINATE STEREOISOMERS

The right- and left-handed propeller-shaped enantiomers of the eight-coordinate SmI(2) complexes shown can be resolved by crystallization from dimethoxyethane (dme) at ambient temperature. Apart from representing a new type of chiral metal complex, such enantiomers are potential reagents for enantioselective reductions.

Mixed Dimer and Mixed Trimer Complexes of nBuLi and a Chiral Lithium Amide

Multinuclear and multidimensional NMR spectroscopy have shown that lithium (S)-N-isopropyl-O-methyl-valinol (1-[6Li]) exists in a mixed 2:1 complex with nBu[6Li], (1-[6Li])2/nBu[6Li], in non-coordinating solvents such as hexane or toluene. A 6Li,1H-HOESY NMR spectrum indicates that the complex is a cyclic trimer with a large distance between the di-coordinated lithium and the carbanion of nBu[6Li]. Such arrangements are present in the solid state as previously reported by Williard and Sun. The exchange of lithium atoms within the trimer is slow at -33 degrees C. The exchange barrier (deltaG++) was determined to be 14.7 kcal x mol(-1) from quantitative 6Li,6Li-EXSY spectra. Addition of diethyl ether results in the formation of mixed dimers of (1-[6Li])/nBu[6Li], tetramers of nBu[6Li], and homodimers (1-[6Li])2. The apparent equilibrium constant of the mixed dimer was determined from the 6Li NMR integrals as K = 7.

INTRAAGGREGATE FLUXIONAL LITHIUM AND CARBANION EXCHANGES IN A CHIRAL LITHIUM AMIDE/N-BUTYLLITHIUM MIXED TETRAMER DIRECTLY OBSERVED BY MULTINUCLEAR NMR

Direct observation of fluxional lithium–lithium exchange in a cubic tetramer has been made possible for the first time by a novel type of mixed complex containing nBuLi and the chiral lithium amide lithium (S)-2-(1-pyrrolidinylmethyl)pyrrolidide (figure).

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.

Chelating alcohols accelerate the samarium diiodide mediated reduction of 3-heptanone

Abstract Initial rate studies of samarium diiodide mediated reduction of 3-heptanone to 3-heptanol are reported. The reduction of 3-heptanone with the polydentate tri(ethylene glycol) methyl ether is 16 times faster than without a proton donor, and 4.3 times faster than methanol. The primary kinetic isotope effect (KIE) was measured as k H / k D ≈2, indicating a rate-determining proton transfer. Diols are superior to mono-alcohols as proton donors, the reduction of 3-heptanone is 255 times as fast with di(ethylene glycol) than in the absence of a proton donor. A mechanism of glycol accelerated samarium diiodide reduction is discussed.

Enantioselective butylation of aliphatic aldehydes by mixed chiral lithium amide/n-BuLi dimers

Abstract 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.

Giving phenyllithium a right-handed double-helical twist. Syntheses and crystal structures of enantiopure alkyl-, aryl-, and amidolithium aggregates

Abstract The influence of enantiopure nitrogen donor ligands on structure and aggregation in three lithium reagents has been investigated using single crystal X-ray diffraction methods. While the 1:1 complex between methyllithium and (−)-sparteine, [LiMe(spa)]2 (1), is dimeric, the 2:1 complex between phenyllithium and (−)-sparteine, [Li4Ph4(spa)2] (2), displays a tetranuclear Li4Ph4 core with one sparteine ligand in each end. The core in 2 has a laddered structure, which resembles a double-helix in the sense that it is twisted corresponding to approximately one ninth of a full rotation. The stereochemistry is predetermined to a right-handed double-helix by the terminal sparteine ligands. Synthesis and structural characterization of homoleptic [Li(pymp)]4 (3), pymp=(S)-2-(1-pyrrolidinylmethyl)pyrrolidido, displays a tetramer with a helical twist analogous to 2, which shows that this bidentate enantiopure amido ligand (pymp) also predetermines the chirality to a fragmented right-handed double-helix.