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An experimental and computational study of the enantioselective lithiation of N-Boc pyrrolidine using sparteine-like chiral diamines

O'Brien, P., Wiberg, K.B., Bailey, W.F., Hermet, J.P.R. and McGrath, M.J. (2004) An experimental and computational study of the enantioselective lithiation of N-Boc pyrrolidine using sparteine-like chiral diamines. Journal of the American Chemical Society, 126 (47). pp. 15480-15489. ISSN 0002-7863

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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-nBu, N-CH2tBu, N-iPr) 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 (ΔH = 11.1 kcal/mol, ΔG = 11.5 kcal/mol) for proton transfer. The computational results with the N-iPr-substituted diamine identified a transition state for proton transfer with activation energies of 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 experimental observation that use of the N-iPr-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.

Item Type: Article
Institution: The University of York
Academic Units: The University of York > Chemistry (York)
Depositing User: York RAE Import
Date Deposited: 03 Apr 2009 10:49
Last Modified: 03 Apr 2009 10:49
Published Version: http://dx.doi.org/10.1021/ja046834p
Status: Published
Publisher: ACS American Chemical Society
Identification Number: 10.1021/ja046834p
URI: http://eprints.whiterose.ac.uk/id/eprint/6905

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