A NMR and Theoretical Study of the Aggregates between Alkyllithium and Chiral Lithium Amides:  Control of the Topology through a Single Asymmetric Center

Abstract

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-d(8). 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.

Correlation between the 6Li,15N Coupling Constant and the Coordination Number at Lithium

“…[3,4] Chiral lithium amides were also successfully employed as chiral inducers in stereoselective 1,2-addition reactions. [5][6][7][8] Maddaluno, Williard and our group have reported NMR studies revealing the reactive species in stereoselective additions of n-butyllithium (nBuLi), methyllithium and lithioacetonitrile to aldehydes. [7][8][9][10][11] Because of the importance of chiral lithium amides with chelating groups, it is essential that their structures and the effect of chelating groups are better understood.…”

“…[5][6][7][8] Maddaluno, Williard and our group have reported NMR studies revealing the reactive species in stereoselective additions of n-butyllithium (nBuLi), methyllithium and lithioacetonitrile to aldehydes. [7][8][9][10][11] Because of the importance of chiral lithium amides with chelating groups, it is essential that their structures and the effect of chelating groups are better understood. Recently, there has been an increased focus on studies of structure-reactivity relationships for the development of efficient and selective transformations, often needed within, for example, the pharmaceutical industry.…”

“…[4,8,10,11,14,15] It is known that the specific solvation at lithium may affect not only the reactivity, but also the stereoselectivity obtained in reactions with chiral lithium amides. Unfortunately, the design of new and powerful chiral lithium amides and catalytic systems is limited by lack of a thorough understanding of the factors determining the solvation at lithium.…”

Expanding the Scope of Oligo-pyrrolinone–Pyrrolidines as Protein–Protein Interface Mimics

“…34 N -protection of ( R )-3-hydroxypyrrolidine followed by nucleophilic displacement of its triflate-derivative (under conditions optimized to avoid elimination) 35 gave the amino esters 4 (Scheme 2). Variable amounts of epimerization occurred in these reactions but this is not a serious problem because all the esters 4 featured in this paper were obtained as single diastereomers via one crystallization from either ethanol or acetonitrile.…”

Pyrrolinone–Pyrrolidine Oligomers as Universal Peptidomimetics

“…13 That pyrrolidine was N -protected to give the starting material indicated in Scheme 1. Nucleophilic displacement on a triflate-derivative of this (under conditions optimized to avoid elimination) 14 gave the amino esters 4 . X-ray analysis of 4d · HCl indicated its formation occurred via a single inversion.…”