Organolithium compounds racemization

Some heteroatom-substituted or chelate-stabilized organolithium compounds, on the other hand, can be sufficiently stable toward racemization to enable their use in stereoselective reactions with electrophiles [223, 225, 271, 531, 543, 552-554] (Scheme 5.75). This increased configurational stability of a-heteroatom-substituted carbanions might be due to the stronger pyramidalization of such carbanions [261,555] and fixation of the metal by chelate formation. 

Schemes.76. Exceptionally slow racemization of an a-thio organolithium compound [560],...

Fig.6 a,b. The second experiment of the Hoffmann test reaction of a racemic organolithium compound with a chiral aldehyde... 

Most a-thio carbanions are configmationally labile and racemize rapidly even at low temperature as shown in the preceding section. This may be the reason why the asymmetric reaction of a-lithiated thiocarbamates reported by Hoppe and coworkers does not show such high enantioselectivity [34] as attained in the reaction of similar dipole-stabilized a-oxy organolithium compounds [Eq. (4)] [2, 39]. Note that the stereochemistry of the products obtained from a-lithiated thiocarbamates is different from that obtained in the a-lithiated carbamate [Eq.(5)]. 

Two separate experiments are necessary, as described below on organolithium compounds [110]. The first experiment involves the reaction of the racemic organolithium with a racemic electrophile, an a-aminoaldehyde, and the determination of the ratio of the diastereomeric products formed. The same experiment is repeated under the same conditions but with an enantiomerically enriched electrophile and the ratio of diastereomers measured as well. The validity of the test requires that these reactions reach completion. 

Interestingly, it was observed that the nature of the ortho substituents at the aryl ring plays an important role in the stereochemical outcome of the AAA reaction. The use of simple methyl groups (83h-i) led to nearly racemic products, independently of the nature of the organolithium compound used. However, the enantioselectivity was enhanced, when the corresponding o-bromo- or o-methoxy-substituents (83j-m) were used instead. The authors suggest a coordination between these ortho substituents and the copper complex as a key parameter in the stereo-discrimination event that allows to achieve these high enantioselectivities (Scheme 28). 

On the other hand, a-alkoxyorganolithiums are not configurationally stable on a macroscopic timescale when they are secondary and allylic or benzylic. For example, despite the known (see section 5.2.1) stereospecificity of the tin-lithium and lithium-tin exchanges of similar compounds, tin-lithium exchange of 110 with rc-BuLi/TMEDA at -78 °C gives an organolithium 111 which has completely racemised after 10 min stannylation returns racemic stannane 112.55 Similarly, 111 racemises rapidly at -70 °C in pentane/cyclohexane in the... 

Remarkably, the closely related benzyllithium 304 is configurationally unstable even at -78 °C.138 Transmetallation of 303 (88% ee) at -78 °C gave an organolithium which reacted to give racemic product 305 in the presence or absence of TMEDA. Furthermore, the reaction of the 304-(-)-sparteine complex with each of racemic or enantiomerically pure 2 in a Hoffmann test gave the same 1 1.6 ratio of diastereoisomers. It is not yet clear whether this unexpected difference between 301 and 304 is due to an electronic difference between the naphthyl and phenyl systems, or whether it arises from the difference in steric hindrance, and therefore the dihedral angle between the ring and the amide, in the two compounds. 

Benzyl-type organolithium compoimds are stabilized by the mesomeric interaction of the negative charge of the carbanionic center with the aromatic n-system. The thermodynamic acidity of the benzylic compounds is 10 to 15 pK units higher than of the corresponding methyl derivatives [127]. Mesomeric stabilization requires a considerable flattening of the carbanionic center towards sp -hy-bridization [128]. As a consequence, the configurational stability is decreased, and - with few exceptions - most of the benzyllithium derivatives suffer from rapid racemization [Eq. (56)],see Sect. 3.2. 

---