1. An experimental and computational study of the enantioselective lithiation of N-Boc-pyrrolidine using sparteine-like chiral diamines
Peter O'Brien, Kenneth B Wiberg, William F Bailey, Jean-Paul R Hermet, Matthew J McGrath J Am Chem Soc. 2004 Dec 1;126(47):15480-9. doi: 10.1021/ja046834p.
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.
2. Is the A-ring of sparteine essential for high enantioselectivity in the asymmetric lithiation-substitution of N-Boc-pyrrolidine?
Puay-Wah Phuan, James C Ianni, Marisa C Kozlowski J Am Chem Soc. 2004 Dec 1;126(47):15473-9. doi: 10.1021/ja046321i.
The simplest chiral portion of sparteine, N,N'-dimethyl-2-endo-methylbispidine, was prepared and evaluated in the asymmetric lithiation-substitution of N-Boc-pyrrolidine. The results indicate that the complete A-ring of sparteine is essential for high levels of asymmetric induction. DFT-QSSR analyses of the diamine/Li(+) complexes and DFT calculations of the pertinent i-PrLi/diamine/N-Boc-pyrrolidine complexes are predictive and provide complementary pictures of the stereochemical features critical to this transformation.
3. Asymmetric lithiation trapping of N-Boc heterocycles at temperatures above -78 °C
Giacomo Gelardi, Graeme Barker, Peter O'Brien, David C Blakemore Org Lett. 2013 Nov 1;15(21):5424-7. doi: 10.1021/ol402395j. Epub 2013 Oct 15.
The asymmetric lithiation trapping of N-Boc heterocycles using s-BuLi/chiral diamines at temperatures up to -20 °C is reported. Depending on the N-Boc heterocycle, lithiation is accomplished using s-BuLi and (-)-sparteine or the (+)-sparteine surrogate in the temperature range -50 to -20 °C for short reaction times (2-20 min). Subsequent electrophilic trapping or transmetalation-Negishi coupling delivered functionalized N-Boc heterocycles in 47-95% yield and 77:23-93:7 er. With N-Boc pyrrolidine, trapped products can be generated in ~90:10 er even at -20 °C.
