Analysis of an Asymmetric Addition with a 2:1 Mixed Lithium Amide/n-Butyllithium Aggregate

Abstract

A 2:1 lithium amide/ n-butyllithium aggregate 1 is investigated as an asymmetric addition template in hydrocarbon solvents. Several different chiral lithium amides were synthesized from l-valine and tested in the asymmetric addition of n-BuLi to various aldehydes. Enantiomeric excesses up to 83% were obtained in the case of the addition of n-BuLi to pivaldehyde at -116 degrees C in pentane. (1)H and (13)C INEPT DOSY were utilized to characterize a new trimeric complex 12 between 2 equiv of lithium amide and 1 equiv of lithium alkoxide. This mixed aggregate strongly indicates the possibility of product-induced chirality inhibition that is detrimental to the enantioselectivity of asymmetric addition reaction.

A computational study of the enantioselective addition of n-BuLi to benzaldehyde in the presence of a chiral lithium N,P amide

“…The results are compared to the experimental e.r.-values 44 and the selectivity is rationalized from the TSs. Earlier computational and experimental studies on the alkylation of benzaldehyde in the presence of chiral ligands have been reported, 7,8,[10][11][12][13][14][15][16]18,20,40,41,43,44,57,[69][70][71] but this appears to be the first computational study utilizing chiral N,P ligands for the title reaction. Interestingly, the first protocol using catalytic amounts of the chiral ligand in enantioselective alkylation of aldehydes was recently published by Maddaluno's group.…”

“…This finding, together with the fact that the largest dispersion energy differences involves interactions between the benzaldehyde and the solvent fits well with earlier studies, where it has been shown that the enantioselectivity is strongly dependent on the solvent. 9,12,20,40,41,91,92…”

“…1,2 A few examples have been reported regarding the use of alkyllithium reagents in stereoselective C-C bond formations, for example alkylation of imines, 3,4 ketones, [5][6][7][8] or aldehydes. [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Other stereoselective reactions involving chiral organolithium compounds are exemplified by: the use of oxiranyllithiums to give substituted epoxides, 22 lithium enolate addition to aldehydes, [23][24][25] or, using chiral lithium amides rather than alkyllithiums, enantioselective deprotonation reactions. [26][27][28][29][30][31][32][33][34][35][36][37][38][39] One of the potential applications of chiral lithium organic compounds is the synthesis of enantiomerically pure alcohols, which are used for example as intermediates in drug design.…”

“…Addition of a chiral lithium ligand, for example A, deaggregates the homocomplex of n-BuLi forming a chiral heterocomplex B which provides the alkylating reagent in a less aggregated and thus more reactive state that may react with benzaldehyde (Scheme 1, right part). [12][13][14][15][16]20,21,41,43,45,64,65 As a result, the ligand-mediated reaction path is faster and dominates the addition reaction over the background reaction. Since the heterocomplex inherits the chirality of chiral amide A, the addition reaction is stereospecific and one of the enantiomers of the alcohol is generated in excess.…”

Chiral Lithium Amides: Tuning Asymmetric Synthesis on the Basis of Structural Parameters

“…Mixed complexes of 2 b 2a with an alkyllithium reagent ( n ‐BuLi), a lithium alkoxide ( t ‐BuCH(OLi) n ‐Bu), and a lithium enolate (CH 3 CH=C(OLi)Et) have been otherwise characterized. For the amide/ n ‐BuLi complexes, NMR studies evidenced the formation of an unsolvated 2 : 1 [( 2 b 2a ) 2 / n ‐BuLi] mixed trimer in toluene (Figure , top right) .…”