Asymmetric carbolithiation

More recently, a very efficient asymmetric carbolithiation of N,N-dimethyl-aminofulvene 30, leading to a chiral cyclopentadienide anion, was reported by Hayashi et al. [6] for the synthesis of chiral metallocenes (Scheme 6). By adding an aryl lithium such as 31 complexed with a chiral ligand on fulvene 30, a cyclopentadienide ion 32 bearing a stereogenic center at the a position was generated. This anion was reacted with [RhCl(nbd)]2 to yield... 

Methods for the enantioselective synthesis of 3-substituted indolines by means of the asymmetric intramolecular carbolithiation of 2-bromo-A,-allylanilines in the presence of (-)-sparteine were reported simultaneously by Bailey <00JA6787> and Groth <00JA6789>. Thus, addition of 89 to 2.2 equiv of /BuLi in the presence of the chiral ligand generates the lithium intermediate 90 which upon quenching with methanol affords the chiral indoline 91 in a process that is highly solvent dependent. 

The application of mixed enolates/homoenolates of type 14 for the racemic synthesis of y-butyrolactones has been already discussed (cf. Scheme 1). An ingenious way to render this strategy asymmetric was demonstrated with the regio- and stereoselective carbolithiation of 114, generating the organolithium intermediate 115, which could be reacted with the appro-... 

Hoppe, D. Woltering, M. J. Oestreich, M. Frohlich, R. (-)-Sparteine-mediated asymmetric intramolecular carbolithiation of alkenes synthesis of enantiopure cyclopentanes with three consecutive stereogenic centers. Helv. Chim. Acta 1999, 82, 1860-1877. 

Carbolithiation of terminal dienes such as 11 is promoted by (-)-sparteine 10, irrespective of any asymmetric induction which may result. With sparteine, organolithiums even add to dienols such as 12.15... 

Sparteine 10 is a powerful promoter of carbolithiation, and can lead to good levels of asymmetric induction in the addition step. Successful enantioselective carbolithiations have all involved functionalised styrenic double bonds. Potentially, two new stereogenic centres... 

It was observed that when chiral ligands are used, the sterochemistry of the olefin is crucial for the enantioselectivity of the carbolithiation. Thus, asymmetric carbolithiation of 39E with w-BuLi in the presence of (—)-sparteine gives the carbometallated product (,Y)-46 and compounds 47-49 in ca 80%ee (Scheme 19)55. 

Primary as well as secondary alkyllithiums lead to identical enantioselection. Whereas the asymmetric carbolithiation of 39E gives the (,Y)-alkylatcd product 46, the reaction of the 39Z leads to (/ )-51 or ( R)-52 (Scheme 20). When the allylic alcohol is unsubstituted a racemic product is formed, as is the case with 2-propen-l-ol, 52. 

As shown in Scheme 11, Hoppe and coworkers have accomplished the first enantios-elective intramolecular carbolithiation reaction of alkenes by fusion of the concepts of the intramolecular carbolithiation reaction and the asymmetric deprotonation. The efficiency of this method has been demonstrated by the extension to other substrates by these and other authors78. However, this topic has been excellently reviewed by Hoppe and Christoph in Chapter 17 of Vol. 1 of The Chemistry of Organolithium Compounds and therefore it will not be treated in this chapter. 

This volume, which complements the earlier one, contains 9 chapters written by experts from 7 countries. These include a chapter on the dynamic behavior of organolithium compounds, written by one of the pioneers in the field, and a specific chapter on the structure and dynamics of chiral lithium amides in particular. The use of such amides in asymmetric synthesis is covered in another chapter, and other synthetic aspects are covered in chapters on acyllithium derivatives, on the carbolithiation reaction and on organolithi-ums as synthetic intermediates for tandem reactions. Other topics include the chemistry of ketone dilithio compounds, the chemistry of lithium enolates and homoenolates, and polycyclic and fullerene lithium carbanions. 

The addition of alkyllithiums to allylic alcohols, originally described by Felkin and Crandall [83], has recently acquired new interest due to the enantioselective approach of the carbometallation reaction of cinnamyl derivatives. Indeed, asymmetric carbolithiation of ( )-cinnamyI alcohol in hexane or cumene, in the presence of the readily available chiral diamine (—)sparteine, leads to the carbometallated product in 82% ee. Primary as well as secondary alkyllithiums lead to identical enantioselection [128] (Scheme 7-108). 

More recently, asymmetric intramolecular carbolithiation was described, either with a remote chiral center in a suitable position to promote a diastereofacial differentiation of the olefin [130] or with a chiral organolithium derivative [131]. In the former case, alkylation... 

Tomida Y, Nagald A, Yoshida J (2011) Asymmetric carbolithiation of conjugated enynes a flow microreactor enables the use of configurationally unstable intermediates before they epimerize. J Am Chem Soc 133 3744—3747... 

Inter- and intramolecular enantioselective carbolithiation reactions in the presence of a chiral ligand for lithium, such as (—)-sparteine 13BJ0313. New application progress of chiral bis(oxazoline) ligands in asymmetric catalysis 13CJ02283. 

Scheme 10.4 The first example of an asymmetric intermolecular carbolithiation of cinnamyl alcohol [7].

Scheme 10.57 Asymmetric synthesis of substituted pyrrolidines by an intramolecular carbolithiation reaction [47].

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