Organolithium stereoselective reactions

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. 

The addition of organolithiums to polarised C=X bonds is one of the most widely used ways of making C-C bonds, and (excepting some unusual intramolecular cases) will not be discussed in this book other than to say it is a reliable and successful reaction. With a few exceptions,1 3 stereoselectivity is not a general feature of organolithium addition reactions to C=0 n bonds. Much of this chapter will concern controlled addition of organolithiums to C=C 7i bonds after an overview of carbolithiation, we shall review the development of intramolecular carbolithiation, or anionic cyclisation. 

In view of the trend to more controlled and stereoselective reactions with readily available, less expensive and environmentally non-problematic reagents, the light-induced inner-sphere electron transfer between M-C bonds of less polar co-ordinating organometallics (Zn, Al) and the organic substrate seems to be a particularly attractive alternative to thermal reactions from organolithium or -magnesium compounds. 

A notably stereoselective reaction of an arylcerium reagent has been repOTted by Terashiina et al. As shown in Scheme 18, the cerium reagent provides adducts (11) and (12) in a ratio of 16 1 in 95% combined yield. In contrast, the organolithium reagent gives a lower and reversed stereoselectivity. 

For a review of the early literature on the stereoselective reactions of chiral aldehydes, ketones, and a-keto esters, and also of the addition of Grignards and organolithiums to achiral ketones and aldehydes in the presence of a chiral complexing agent or chiral solvent, see ref. [4]. 

A chiral auxiliary is a chiral molecule attached to the starting material of the reaction dia-stereoselective reactions of compounds from the chiral pool are likewise controlled by chirality in the starting material, and we call this type of stereocontrol substrate control. But is it also possible for enantioselective reactions to be controlled by chiral reagents. For example, a typical achiral base will just remove a proton from a substrate, but an enantiomerically pure chiral base can select one of two enantiotopic protons and form a product enantioselectively. The product of course has to be chiral, so we can t use a chiral base to make planar enolates enantioselectively, for example, but we can a chiral base to make chiral organolithiums. 

Preliminary experiments prove that the substitution pattern of the /V-aryl moiety of imine 1 is crucial for the stereoselectivity of this reaction. The 2-substituent on the aryl group is of special importance. Namely, introduction of a methoxy group leads to a considerable decrease of enantioselectivity compared to the corresponding 2-H derivative, probably due to disfavor-able coordination with the organolithium complex. In contrast, alkyl groups show the reverse effect along with increased bulkiness (e.g., Tabic 1, entries l-3a) but 2,6-dimethyl substitution provides lower ee values. Furthermore, the 4-substituent of the TV-aryl moiety is of minor importance for the stereoselectivity of the reaction [the Ar-phcnyl and the /V-(4-methoxyphenyl) derivatives give similar results], whereas a substituent in the 3-position results in lower stereoselectivities (e.g., Et, Cl, OCHj)41. 

The directing effect of the amide group can then be used a second time in the lateral lithiation of 503 to give an organolithium 507 which adds to the imine 508 in a stereoselective manner, probably under thermodynamic control (imine additions of laterally lithiated amides appear to be reversible). Warming the reaction mixture to room temperature leads to a mixture of 509 and some of the (ultimately required) cyclized product... 

A mechanistic study28,31 on deuterated compounds showed that stereoselective deprotonation occurs to give the (S.Sj-configurated lithio compound with a selectivity of about 6 1. This is of no consequence for the overall alkylation process, since its stereochemistry is determined by the reaction of the equlibrated organolithium compounds. This conclusion was drawn from the result, that the same stereochemical outcome is observed in reactions starting with an a 1 1 mixture of (R,S)- and (S,S )-configurated lithio compound as from the case with selectively formed (S,S)-lithio compound only. Hence the (R,S)- and (5,5)-lithio compounds equilibrate rapidly on the timescale of the experiment and the question as to whether the (R,S)- or ( S iSj-lithio compound is the actual reacting species cannot be answered. 

However, the formation of a conformationaly rigid chelate with a fixed geometry is generally admitted in the transmetallation of organolithiums with magnesium halides. That explains the stability of the enolate and the stereoselectivity of its reactions. 

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