title: An experimental and computational study of the enantioselective lithiation of N-Boc-pyrrolidine using sparteine-like chiral diamines.
abstract: The enantioselective lithiation of N-Boc-pyrrolidine using sec-butyllithium and isopropyllithium in the presence of sparteine-like diamines has been studied experimentally and computationally at various theoretical levels through to B3P86/6-31G*. Of the (-)-cytisine-derived diamines (N-Me, N-Et, N-(n)Bu, N-CH(2)(t)Bu, N-(i)Pr) studied experimentally, the highest enantioselectivity (er 95:5) was observed with the least sterically hindered N-Me-substituted diamine, leading to preferential removal of the pro-R proton i.e., opposite enantioselectivity to (-)-sparteine. The experimental result with the N-Me-substituted diamine correlated well with the computational results: at the B3P86/6-31G* level, the sense of induction was correctly predicted; the lowest energy complex of isopropyllithium/diamine/N-Boc-pyrrolidine also had the lowest activation energy (DeltaH++ = 11.1 kcal/mol, DeltaG++= 11.5 kcal/mol) for proton transfer. The computational results with the N-(i)Pr-substituted diamine identified a transition state for proton transfer with activation energies of DeltaH++= 11.7 kcal/mol and DeltaG++= 11.8 kcal/mol (at the B3P86/6-31G* level). Although comparable to (-)-sparteine and the N-Me-substituted diamine, these DeltaH++ and DeltaG++ values are at odds with the experimental observation that use of the N-(i)Pr-substituted diamine gave no product. It is suggested that steric crowding inhibits formation of the prelithiation complex rather than increasing the activation enthalpy for proton transfer in 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 enantioselectivity would be modest at best.
authors.affiliation: Departments of Chemistry, University of York, Heslington, York YO10 5DD, U.K.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Brien
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Wiberg
authors.forename: William F
authors.initials: WF
authors.lastname: Bailey
authors.forename: Jean-Paul R
authors.initials: JP
authors.lastname: Hermet
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: McGrath
mesh_terms: D003198:Computer Simulation; D003959:Diamines / Q000737:chemistry*; D008094:Lithium / Q000737:chemistry*; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D013034:Sparteine / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D003959:Diamines; D009942:Organometallic Compounds; D011759:Pyrrolidines; D013034:Sparteine; D008094:Lithium