Daniel Pettersen

A novel mixed dimer of a norephedrine-derived chiral lithium amide and 2-lithium-1-methylimidazole, and catalytic enantioselective deprotonation of cyclohexene oxide.

Improved stereoselectivity has been obtained by using 2-lithium-1-methylimidazole, 2, as a replacement for lithium diisopropylamide (LDA) as a bulk base in catalytic deprotonations. The chiral lithium amide 6 of (1R,2S)-N-methyl-1-phenyl-2-pyrrolidinylpropanamine, 5, has been found to deprotonate cyclohexene oxide 3 in the presence of compound 2 to yield (S)-cyclohex-2-en-1-ol, 4, in 96% ee. Compound 2 is a carbenoid species conveniently generated from nBuLi and 1-methylimidazole, 1. The base 2 has also been found to play a more intimate role in the deprotonation. Investigations by 1H, 6Li and 13C NMR of the 6Li/15N isotopologue 8 of 6 have shown that 6 is homodimeric in THF and that, in the presence of 2, it forms a novel heterodimer 10. This heterodimer is found to be the dominant reagent in the initial state, rather than the homodimer of 6. Computational investigations with PM3 and B3LYP/6-311 + G(d,p) have shown possible structures of the heterodimers, as well as the role of THF and I in the solvation of the dimers. The results are in line with the NMR results. Favoured complexes in the equilibria between homo- and heterocomplexes are also reported.

Improved enantioselectivity by using novel bulk bases in chiral lithium amide catalysed deprotonations: mixed dimers as reagents and catalysts

Abstract Novel bulk bases have been developed yielding improved enantioselectivity of chiral lithium amide catalysed deprotonations as compared to using the bulk base lithium diisopropylamide (LDA). The new bulk bases are 2-lithio-1-methylimidazole, 2-(lithiomethyl)-1-methylimidazole, 2-lithio-furan and 1,8-diazabicyclo-6-lithio[5.4.0]undec-7-ene which have been used together with chiral lithium amides in deprotonations of cyclohexene oxide. Using the chiral lithium amides enhanced stereoselectivities (96% ee) have been reached. The reactivity change has been traced to the formation of novel reagents—mixed dimers—formed from a bulk base molecule and a molecule of a chiral lithium amide. The results also show that DBU, which has commonly been used as an additive to alter reactivity and enantioselectivity in deprotonations, has another important role. DBU is lithiated under the conditions used and becomes a bulk base, which forms catalytic mixed dimers with the chiral lithium amides.

Development of chiral catalysts for stereoselective synthesis by deprotonations - Experimentation in interplay with computational chemistry

Results are presented advancing the application of quantum chemistry in the field of organic synthesis. Computational chemistry in interplay with experimental chemistry has been given a key role in the development of stereoselective synthesis. Novel molecular systems are being created for catalytic stereoselective deprotonations, a reaction type useful for synthesizing many new compounds, e.g., some having important biological activities. Problems met in this approach to design catalysts and their solutions are presented.

On the novel function of the additive DBU. Catalytic stereoselective deprotonation by a mixed dimer of lithiated DBU and a chiral lithium amide

The additive DBU is used to increase the selectivity and reactivity of e.g. chiral lithium amides in both catalysed and non-catalysed asymmetric syntheses. This has been attributed to the coordinating ability of DBU favoring more reactive aggregates. However, we have found that LDA in THF deprotonates DBU to yield lithiated DBU (1) as shown by multinuclear NMR studies. Furthermore, compound 1 is found to form a mixed dimer (5) with e.g. the norephedrine-derived chiral lithium amide 2. Results of an investigation of the stereoselectivity of this novel reagent in the epoxide deprotonation are also reported. Computational studies using PM3 and DFT show possible structures of 1 and 5 in line with the NMR results. In addition, the role of THF and DBU in the solvation of the aggregates has been investigated by computational modelling and favoured complexes in the equilibria between homo- and heterocomplexes are also reported.

Kinetic and computational studies of the composition and structure of activated complexes in the asymmetric deprotonation of cyclohexene oxide by a norephedrine-derived chiral lithium amide

Rational design of efficient chiral lithium amides for enantioselective deprotonations demands understanding of the origin of the selectivity. The mechanism of deprotonation of cyclohexene oxide 1 by lithium (1R,2S)-N-methyl-1-phenyl-2-pyrrolidinylpropanamide 3, which yields (S)-cyclohex-2-en-1-ol (S)-5 in 93% enantiomeric excess in tetrahydrofuran (THF), has been investigated. Kinetics have been used to show that the reaction is first order with respect to the reagents 1 and 3, respectively. NMR investigations of a 6Li and 15N labelled isotopologue of 3 have previously shown that 3 is mainly a dimer of the lithium amide monomer in THF in the initial state. On the basis of these results it is concluded that the rate-limiting activated complexes for the epoxide deprotonation are composed of two molecules of monomer of lithium amide 3 and one molecule of epoxide. Structures and energies of unsolvated and specific THF-solvated reagents and activated complexes have been calculated using PM3 and B3LYP/6-31+G(d). The results are currently being explored for the rational design of chiral lithium amides with improved stereoselectivities.

2-(Lithiomethyl)-1-methylimidazole as a non-reactive bulk base and its novel mixed dimer with a chiral lithium amide in catalytic stereoselective deprotonation

The search for non-reactive bulk bases in replacement of lithium diisopropylamide (LDA) for improved enantioselectivity of chiral lithium amide-catalysed deprotonations led to the use of 1,2-dimethylimidazole 9 as a precursor. Deprotonation of 9 with n-BuLi in THF results in the compound 2-(lithiomethyl)-1-methylimidazole 8 as shown by NMR. This carbanionic compound is found to be less reactive than LDA in deprotonation of cyclohexene oxide 10, but having comparable basicity to that of LDA. Catalytic amounts of the chiral lithium amide 4 of (1R,2S)-N-methyl-1-phenyl-2-pyrrolidinopropanamine 5 deprotonates cyclohexene oxide 10 in the presence of compound 8 and yields (S)-cyclohex-2-enol (S)-11 in 93% ee. On the other hand, using LDA as a bulk base gives an ee of only 22%. Interestingly, stoichiometric deprotonation by 4 in the presence of 8 in THF results in (S)-11 in 96% ee. Thus, the results indicate that compound 8 is playing a more intimate role in the deprotonation than just acting as a bulk base. Therefore, the reagents involved in the reactions have been investigated by 1H, 6Li and 13C NMR using isotopically labelled compounds. The results show that lithium amide 4, which is homodimeric in THF, in the presence of 8 forms heterodimer 12 composed of one monomer of carbanionic 8 and one monomer of 4. This novel heterodimer is found to be the deprotonating reagent causing the increased enantioselectivity. It is concluded that lithium amide 4 is not basic enough to deprotonate 9, but that 8 is a strong enough base to deprotonate diamine 5. This contrasts with the behaviour of 1-methylimidazole 1 which was found to be deprotonated by 4 to yield the mixed dimer 3. Computational investigations using PM3 and B3LYP/6-31+G(d) show possible structures of the heterodimer 12 and homodimer 14 of 8, and the role of THF and 9 in the solvation of the dimers. Favoured complexes in the equilibria between homo- and heterocomplexes are reported. It is concluded that 9 will completely replace THF in the solvation of the dimers even at low concentrations of 9.