Origin of the detrimental effect of lithium halides on an enantioselective nucleophilic alkylation of aldehydes.
The effect of lithium halides on the enantioselectivity of the addition of methyllithium on o-tolualdehyde, in the presence of chiral lithium amides derived from chiral 3-aminopyrrolidines (3APLi), has been investigated. The enantiomeric excess of the resulting 1-o-tolylethanol was found to drop upon addition of significant amounts of LiCl, introduced before the aldehyde. The competitive affinity between the lithium amide, the methyllithium, and the lithium halides in THF was examined by multinuclear NMR spectroscopy and DFT calculations. The results showed that the original mixed aggregate of the chiral lithium amide and methyllithium is rapidly, totally, and irreversibly replaced by a similar 1:1 complex involving one lithium chloride or bromide and one lithium amide. While the MeLi/LiX substitution occurs with some degree of epimerization at the nitrogen for the endo-MeLi:3APLi complex, it is mostly stereospecific for the exo-type arrangements of the aggregate. The thermodynamic preference for mixed aggregates between 3APLi and LiX was confirmed by static DFT calculations: the data show that the LiCl and LiBr aggregates are more stable than their MeLi counterparts by more than 10 kcal.mol(-1) provided THF is explicitly taken into account. These results suggest that a sequestration of the source of chirality by the lithium halides is at the origin of the detrimental effect of these additives on the ee of the model reaction.
Paté
Franck
F
Laboratoire de Chimie Organique et Biologique Structurale, Laboratoire des Fonctions Azotées & Oxygénées Complexes de l'IRCOF, UMR CNRS 6014, Université et INSA de Rouen, 76821 Mont St Aignan Cedex, France.
Duguet
Nicolas
N
Oulyadi
Hassan
H
Harrison-Marchand
Anne
A
Fressigné
Catherine
C
Valnot
Jean-Yves
JY
Lasne
Marie-Claire
MC
Maddaluno
Jacques
J