Enantioselective carbolithiation

The enantioselective carbolithiation of cinnamyl derivatives described by the group of I. Marek and J.F. Normand [2] is one of the few reports on the use of sparteine as a catalytic activator of organoUthium carbanions... 

As illustrated in the conversion of 111 to 112 below, a variety of indoles bearing chirality at C3 was accessed by O Shea and co-workers by means of a (-)-sparteine directed enantioselective carbolithiation of 2-propenyl anilines, followed by electrophilic trapping-cyclization of the lithio intermediates <06JACS10360>. 

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. 

Mixed ( )-cinnamyl acetals 460 undergo the enantioselective carbolithiation readily in the presence of stoichiometric or catalytic amounts, as low as 1 mol%, of (—)-sparteine (11) (equation 126) °. When quenching the reaction mixture of 461, 462 below —50°C with MeOH/HCl, the alcohols 463 are obtained with good yields and excellent ee values. However, upon warming to 20 °C, a 1,3-cycloelimination from conformation 462 gives rise to the formation of optically active trani-cyclopropanes 464 °. 

Oeeasionally, very good enantioselectivities were achieved in the (-)-sparteine-mediated carbolithiation of 6-dimethylaminofulvene (470) by ort/zo-substituted aiyllithiums 471 (equation 129) . Here, (—)-sparteine (11) turned out the best chiral additive. The lithium cyclopentadienides 472 were converted to the corresponding Rh(l)-norbornadiene complexes 473. 

The carbolithiation of the oxazoline-substituted (tricarbonylchromium)benzene 482 in the presence of (—)-sparteine (11) proceeds with medium enantioselectivity... 

The carbolithiation of styiyl carbamates such as 486 by alkyllithium/(—)-sparteine (11) leads to configurationally stable benzyllithium compounds 487, which have been further substituted by electrophiles (equation 133) °. However, only low enantioselectivities could be achieved with (—)-sparteine (11) (e.r. = 70 30) or (—)-o -isosparteine (14) (e.r. ... 

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... 

Enantioselective carbolithiation of cinnamaldehyde 42 can be carried out by a modification of the method described above, replacing lithiotrimethylethylenediamine 43 with a chiral diamine derivative.40... 

Noels A, Demonceau A, Delaude L (2004) Ruthenium Promoted Catalysed Radical Processes toward Fine Chemistry. It 155-171 Normant JF (2003) Enantioselective Carbolithiations. 5 287-310... 

The addition of organolithiums to allylic alcohols followed by trapping of the intermediates by electrophiles is a good example of the usefulness of this type of carbolithiation. The sequence leads, generally, to the formation of diastereomeric alcohols, but the use of chiral ligands confers enantioselectivity to the tandem reaction. 

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. 

The enantioselective metalation at the a-position of a carbamate in the presence of (—)-sparteine followed by a diastereoselective intramolecular carbolithiation onto a double120 or triple bond121 was recently studied. The precursor 185 was deprotonated with s-BuLi/(—(-sparteine in Et20 at — 78 °C, the reaction mixture was stirred for 20 to 30 h at this temperature and the electrophilic reagent was subsequently added (Scheme 57)60. 

In this context, it has been observed that dilithio derivative 333 cyclizes in the presence of TMEDA to give a dilithiated indoline that may be differentially functionalized by sequential addition of electrophiles, affording 1,3-disubstituted indolines 334 (Scheme 86)147. This cyclization reaction also proceeds in an enantioselective way when it is carried out in the presence of the pseudoephedrine ligand 332a. However, (—)-sparteine is in this case not able to promote the carbolithiation step, showing that the substrate structure may have a pronounced effect on the ability of a given ligand to facilitate the cyclization reaction. 

Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carbo-alumination Reactions Catalyzed by Zirconocene Derivatives. 8 139-176 Nicolaou KC, King NP, He Y (1998) Ring-Closing Metathesis in the Synthesis of Epothilones and Polyether Natural Products. 1 73-104 Normant JF (2003) Enantioselective Carbolithiations. 5 287-310 Norton JR see Cummings SA (2005) 10 1-39... 

An enantioselective method for the synthesis of 3-functionalized 2,3-dihydrobenzofuran derivatives via an intramolecular carbolithiation reaction of allyl 2-lithioaryl ethers uses (—)-sparteine as a chiral inductor. A variety of electrophiles can be reacted with the cyclized organolithium intermediate. With certain substrates, however, /3-elimination occurs instead (Equation 140) <2005CEJ5397>. 

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