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. 2013 Nov 13;135(45):16853-64.
doi: 10.1021/ja403076u. Epub 2013 May 31.

Enediolate-dilithium amide mixed aggregates in the enantioselective alkylation of arylacetic acids: structural studies and a stereochemical model

Yun Ma  1 , Craig E Stivala, Ashley M Wright, Trevor Hayton, Jun Liang, Ivan Keresztes, Emil Lobkovsky, David B Collum, Armen Zakarian
Affiliations

Enediolate-dilithium amide mixed aggregates in the enantioselective alkylation of arylacetic acids: structural studies and a stereochemical model

Yun Ma et al. J Am Chem Soc. .

Abstract

A combination of X-ray crystallography, (6)Li, (15)N, and (13)C NMR spectroscopies, and density functional theory computations affords insight into the structures and reactivities of intervening aggregates underlying highly selective asymmetric alkylations of carboxylic acid dianions (enediolates) mediated by the dilithium salt of a C2-symmetric chiral tetraamine. Crystallography shows a trilithiated n-butyllithium-dilithiated amide that has dimerized to a hexalithiated form. Spectroscopic studies implicate the non-dimerized trilithiated mixed aggregate. Reaction of the dilithiated amide with the dilithium enediolate derived from phenylacetic acid affords a tetralithio aggregate comprised of the two dianions in solution and the dimerized octalithio form in the solid state. Computational studies shed light on the details of the solution structures and afford a highly predictive stereochemical model.

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Figures

Figure 1
Figure 1
ORTEP of hexalithio n-BuLi-dilithiated amide mixed aggregate 5.
Figure 2
Figure 2
6Li NMR spectra of 0.10 M [6Li,15N]6 prepared from [15N4]3 with 4.0 equiv n-BuLi in 6.10 M THF-pentane recorded at −90 °C after aging at −78 °C for 2.0 hr: (A) fully coupled; (B)broadband 15N decoupled. *Unknown impurities that appear sporadically.
Figure 3
Figure 3
15N NMR spectra of 0.10 M [6Li,15N]6 prepared from [15N4]3 with 4.0 equiv n-BuLi in 6.10 M THF-pentane recorded at −90 °C after aging at −78 °C overnight: (A) fully coupled; (B)broadband 15N decoupled. *Unknown impurities that appear sporadically.
Figure 4
Figure 4
13C NMR spectra of 0.10 M [6Li,15N]6 prepared from [15N4]3 with 4.0 equiv n-BuLi in 6.10 M THF-pentane recorded at −90 °C after aging at −78 °C overnight. (13C resonance of the n-BuLi dimer is not shown but appears as a 1:2:3:2:1 quintet at 12.6 ppm.)
Figure 5
Figure 5
DFT computed structure of 6 as disolvate (6a) showing critical structural variables.
Figure 6
Figure 6
ORTEP of hexalithio enediolate-dilithiated amide mixed aggregate 7.
Figure 7
Figure 7
6Li NMR spectra of 0.10 M [6Li,15N]8 and residual [6Li,15N]6 prepared from [15N4]3 with 4.0 equiv n-BuLi in 6.1 M THF-pentane recorded at −90 °C after aging at −78 °C for 2.0 hr: (A) fully 15N coupled;(B)15N broadband decoupled. *Unassigned resonances.
Figure 8
Figure 8
15N NMR spectra of 0.10 M [6Li,15N]8 and residual [6Li,15N]6 prepared from [15N4]3, 4.0 equiv n-BuLi, and phenylacetic acid in 0.10 M THF-pentane recorded at −90 °C after aging at −78 °C for 2.0 hr: (A) fully 15N coupled; (B) 6Li broadband decoupled.
Figure 9
Figure 9
Calculated transition structures 17a and 17b showing selectivity for alkylation from the si and re enolate faces, respectively.
scheme 1
scheme 1
scheme 2
scheme 2
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