Stability configurational, organolithium

An extensive review appeared on the configurational stability of enantiomeric organolithium reagents and the transfer of the steric information in their reactions. From the point of view of the present chapter an important factor that can be evaluated is the ease by which an inversion of configuration takes place at the metallation site. It happens that H, Li, C and P NMR spectra of diastereotopic species have been central to our understanding of the epimerization mechanism depicted in equation 26, where C and epi-C represent the solvated complex of one chiral species and its epimer, respectively. It has been postulated that inversion of configuration at the Li attachment site takes place when a solvent-separated ion pair is formed. This leads to planarization of the carbanion, its rotation and recombination to form the C—Li bond, as shown in equation 27, where Li+-L is the solvated lithium cation. An alternative route for epimerization is a series of... 

Configurational stability has also been confirmed for various metalated carbamates by Hoppe and coworkers. Remarkably, carbamate-protected alcohols such as 20 are deprotonated enantioselectively, when treated with i-butyllithium in the presence of (—)-sparteine. The lithium carbenoids like 21 (R = alkyl) thus generated turn out to retain their configuration (equation 11). Similar results have been obtained for a-lithiated amines and carbamate protected amines " . As a rule, dipole stabilization of the organolithium compounds in general also enhances the configurational stability of a-oxygen-substituted lithium carbenoids. 

II. UNSTABILIZED ot-AMINO-ORGANOLITHIUM COMPOUNDS A. Synthesis and Configurational Stability... 

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. 

Clayden, J. Pink, J. H. Configurational stability and stereospecificity in the reactions of amide-stabilised organolithiums a non-stereo- 237 specific Sn-Li exchange. Tetrahedron Lett. 

Basu, A. Thayumanavan, S. Configurational stability and transfer of stereochemical information in the reactions of enantioenriched organolithium reagents. Angeur. Chem. Int. Ed. 

Brandt, P. Haeffner, F. A DFT-derived model predicts solvation-dependent configurational stability of organolithium compounds a case study of a chiral a-thioallyllithium compound. /. Am. Chem. Soc. 2003, 325, 48-A9. 

A. Basu, S. Thayumanavan, Configurational Stability and Transfer of Stereochemical Information in the Reactions of Enantioenriched Organolithium Reagents, Angew. Chem. Int. Ed. Engl. 2002, 41, 716— 738. 

Benzylsulfides may be lithiated with PhLi,83 and the acetal group of 111 both assists lithiation and imparts stereoselectivity on the reaction (the configurational stability of organolithiums such as 112 is discussed in section 5.1).84... 

The Hoffmann test. The Hoffmann test,4 while not quantitative, gives a qualitative guide to the configurational stability of an organolithium on the timescale of its addition to an electrophile. 

This is about the bottom end of the next timescale - the microscopic timescale - which is associated with the rate at which organolithium nucleophiles will add to electrophiles (usually a matter of seconds at the most). Configurational stability on the microscopic timescale is studied by the Hoffmann test, or by formation of organolithiums in the presence of electrophiles (such as Me3SiCl) with which they react immediately - in situ quench conditions. 

The third timescale is the laboratory, or macroscopic, timescale of minutes or more if an organolithium can be formed as a single enantiomer and subsequently reacted with an electrophile to produce a product with at least some enantiomeric excess, then it has configurational stability on the macroscopic timescale. 

The configurational stability of primary organolithiums, while of no synthetic consequence, has been determined by NMR methods. Analysis of the line shape of the AA BB system of 1713 or of the ABX system of 1814 gave half-lives for inversion of about 0.01 s for 17 or 18 in ether at 30 °C, increasing (for 17) to about 0.1 s at 0 °C and 1 s at -18 °C. The rate of inversion was decreased by a factor of 8 in pentane or 10 in toluene, but the addition of 1 equiv. TMEDA to pentane restored a rate of inversion more or less equal to that in pentane. 

Increasing the degree of substitution at the lithium-bearing centre, though it makes the organolithium more reactive, also increases its configurational stability. 

Corey exploited the remarkable configurational stability of cyclopropyllithiums in his synthesis of hybridalactone. The stannane 28 was made by Simmons-Smith cyclopropanation of the allylic alcohol 27 and resolved by formation of an O-methyl mandelate ester. Transmetallation of 29 with 2 equiv. BuLi gave an organolithium which retained its stereochemistry even in THF over a period of 3 h at 0 °C, finally adding to 31 to give 32. 

One example of a cyclobutyllithium (36) appears to indicate configurational stability. However, the stereospecific transformation of 35 to 37 could equally be explained by thermodynamic stabilisation of one epimer of an otherwise configurationally unstable organolithium.24... 

In contrast, the benzylic organolithium 55 is configurationally unstable formed by kinetic isotope effect-governed deprotonation at -78 °C, it is completely racemic after 85 s, but it is estimated to have a half-life for racemisation measured in milliseconds.32 The key difference is the benzylic nature of the anion, which enormously increases the rate of racemisation the change from OCH2OR to OMe also contributes since intramolecular coordination favours configurational stability (see later). 

The stereochemistry of another rearrangement - the [2,3]-Wittig (discussed in section 8.4) -indicates that the organolithiums 64,34 65,35 66 and 6736 have complete configurational stability over a period of minutes at -78 °C despite the lack of a second coordinating atom within the alkoxy group. 

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