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†

Abstract

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-1phenyl-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 6 Li and 15 N 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.

Kinetic and NMR Spectroscopic Studies of Chiral Mixed Sodium/Lithium Amides Used for the Deprotonation of Cyclohexene Oxide

“…This made no difference to the 6 Li NMR spectrum, or to the cross-peaks observed for the mixed-metal amide in the corresponding 6 Li, 1 H -HOESY spectrum. These observations showed that the mixed-metal amide in Et 2 O must be an asymmetric dimer with methoxy coordinated to lithium, leaving sodium exposed to THF solvent coordination.…”

“…The lithium signal of the dimeric mixed-metal amide shifted continuously upfield with increasing THF concentration. With 12 equivalents of THF (per lithium) added, the 6 Li, 1 H HOESY spectrum revealed strong cross-peaks between the lithium atom of the mixed-metal amide at d = 1.1 ppm and the THF protons at d = 3.58 ppm, as well as the protons of the methoxy group of 1 at d = 3.36 ppm. In the THF-solvated mixed-metal dimer both lithium and sodium atoms were coordinated by methoxy groups, in agreement with our previous studies of chiral lithium amides derived from a-amino acids.…”

“…The two-dimensional (2D) 6 Li, 1 H HOESY experiment has previously been utilized in several detailed structural investigations of organolithium compounds and was used to measure heteronuclear Overhauser effects between lithium and protons at short distances. [16] The 6 Li, 1 H HOESY of the mixture of (Li-1) 2 , nBuLi/Li-1, and free nBuLi in Et 2 O at À77 8C revealed NOEs between the …”

“…Recently, the use of less reactive achiral "bulk" bases has resulted in catalytic deprotonations with high stereoselectivities, although the observed selectivity often drops when less than 10 % of the chiral base is used. [1,4] The reaction rates for the enantioselective deprotonation reactions by chiral lithium amides are generally low and the reaction may require more than 24 h for completion. [5] However, the use of the heavier alkali metals sodium or potassium, instead of lithium, results in a more powerful base from which the rate of deprotonation should be considerably higher than that of the corresponding lithium amide.…”

“…[1,2] There has also been a steady growth of structural and mechanistic knowledge of these systems gained by X-ray diffraction analysis, NMR spectroscopy, kinetic studies, and computational methods. [3] These reactions are useful in organic synthesis even though they often require stoichiometric amounts of the chiral lithium amide.…”