| Abstract
| - The enantioselective lithiation of N-Boc-pyrrolidine using sec-butyllithium and isopropyllithiumin the presence of sparteine-like diamines has been studied experimentally and computationally at varioustheoretical levels through to B3P86/6-31G*. Of the (−)-cytisine-derived diamines (N-Me, N-Et, N-nBu, N-CH2tBu, N-iPr) studied experimentally, the highest enantioselectivity (er 95:5) was observed with the leaststerically hindered N-Me-substituted diamine, leading to preferential removal of the pro-R proton i.e., oppositeenantioselectivity to (−)-sparteine. The experimental result with the N-Me-substituted diamine correlatedwell with the computational results: at the B3P86/6-31G* level, the sense of induction was correctlypredicted; the lowest energy complex of isopropyllithium/diamine/N-Boc-pyrrolidine also had the lowestactivation energy (ΔH⧧ = 11.1 kcal/mol, ΔG⧧ = 11.5 kcal/mol) for proton transfer. The computational resultswith the N-iPr-substituted diamine identified a transition state for proton transfer with activation energiesof ΔH⧧ = 11.7 kcal/mol and ΔG⧧ = 11.8 kcal/mol (at the B3P86/6-31G* level). Although comparable to(−)-sparteine and the N-Me-substituted diamine, these ΔH⧧ and ΔG⧧ values are at odds with the experimentalobservation that use of the N-iPr-substituted diamine gave no product. It is suggested that steric crowdinginhibits formation of the prelithiation complex rather than increasing the activation enthalpy for proton transferin the transition state. Three other ligands (N-H and O-substituted as well as a five-membered ring analogue)were studied solely using computational methods, and the results predict that the observed enantioselectivitywould be modest at best.
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