Solvent-Dependent Mixed Complex Formation—NMR Studies and Asymmetric Addition Reactions of Lithioacetonitrile to Benzaldehyde Mediated by Chiral Lithium Amides

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

“…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.…”

Solvation-dependent diastereofacial selectivity: addition of lithioacetonitrile to 2-phenyl propanal

“…18 Moreover, Hilmersson demonstrated that lithioacetonitrile and chiral lithium amides form mixed dimers in diethyl ether and THF according to NMR studies, and these mixed dimers underwent asymmetric addition to benzaldehyde with a change in enantioselectivity from diethyl ether to THF. 6 In our case, the totally superimposed Eyring plots on changing the base, clearly demonstrate that the lithium amide, even if it could be present in mixed aggregate species of LiCH 2 CN, has no influence on the facial diastereoselectivity of the aldol-like reaction, and neither on dynamic solvent effects of which the inversion temperature is the result. Moreover, this excludes the dependence of the T inv on different aggregation states of the organometallic species.…”

“…It has already been observed that the reaction solvent deeply influenced the stereoselectivity of nitrile anion cyclizations, 5 and an interesting example of a solvent induced reversion of enantioselectivity in asymmetric lithioacetonitrile addition to benzaldehyde was recently reported. 6 Solvent effects are closely related to the nature and the extent of solute-solvent interactions locally developed in the microenvironment of the solute molecules; these solutesolvent interactions are able to differently modulate the free activation energies which lead to two different stereoisomers thus exerting a stereospecific solvation control on enantio-and diastereoselectivity. 7 As part of our ongoing interest in solvent effects on stereoselectivity, 8 we report here the effects of temperature and solvent on the nucleophilic addition of lithioacetonitrile to 2-phenyl propanal.…”

Computational Perspectives on Organolithiums

“…Structure determination of a large set of chiral lithium amides in different solvents using a combination of advanced NMR techniques and computational chemistry have additionally been advanced by research groups of Hilmersson [50,61,71,[114][115][116], Davidsson [59,62,116], Maddaluno [117], and Nudelman [118].…”