Diastereoselective carbolithiation

The presence of a chiral appendage on an imactivated ethylenic substrate may also induce a diastereoselective carbolithiation Thus, cinnamaldehyde has been transformed into a gem-amino alcoholate [53], with the lithium monoamide of an enantiomerically enriched 1,2-diamine [54] (Scheme 32). This chiral sub-... 

Scheme 10.7 Intermolecular diastereoselective carbolithiation of unsymmetrical stilbenes [10].

An alkoxy-substituted cinnamyl system 44 is transiently generated by the treatment of cinnamaldehyde 42 with lithiated trimethylethylenediamine 43, and this protected version of cinnamaldehyde undergoes carbolithiation with good diastereoselectivity in favour, like 32, of the syn product 45.30... 

It is presumed that the initial step for the intermolecular as well as intramolecular carbolithiation is an energetically favorable coordination of the lithium atom with the n-system, which serves to establish the geometry of the system prior to addition. The chiral benzylic organolithium compound 45, obtained after the carbolithiation step, reacted diastereoselectively with a number of electrophiles, yielding a formal inversion of the configuration. 

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. 

The authors explain the mechanism of the reaction through an equilibrium to give 239 (which affords 240) and 241 which, via the open lithiated intermediate, 242, renders 238. The carbolithiation of alkenes and alkynes is a useful transformation for the generation of a new carbon-carbon bond. Similarly to the intramolecular carbolithiation, it is possible to carry out this reaction with high diastereoselectivity. 

On the other hand, alkenyl aryllithiums can undergo diastereoselective cyclizations in very good yields. Pedrosa and coworkers163 reported that chiral 2-(o-bromophenyl)-substitutedperhydro-l,3-benzooxazines 281, initially transformed to the aryllithium derivative, gave the intramolecular 6-exo carbolithiation reaction with unactivated double bonds attached to the nitrogen substituent of the heterocycle (Scheme 87). By adding 2 equivalents of TMEDA to the aryllithium derivative 1,3-benzooxazines 281 prepared at —90 °C,... 

Chamberlin and coworkers proposed a similar chair-like transition state 29 to account for the stereoselectivity of the carbolithiation reaction of vinyllithium 10 to 1224. The observed diastereoselectivity is consistent with a four-centre transition state where a preferred coplanar approach of the carbon-lithium bond to the double bond would give the obtained major product (Scheme 8). 

Looking for a suitable preparation of dihydrobenzofuran derivatives by carbolithiation reactions, we have recently described how allyl 2-bromophenyl ethers 358 with a substituent at the a-position afford, after treatment with r-BuLi, addition of TMEDA and further quenching with electrophiles, functionalized fraws-2,3-dihydrobenzofuran derivatives 359 in a totally diastereoselective manner (Scheme 94)155. The key for the success of this reaction is the fact that intermediate organolithium 360 is not prone to undergo the 1,3-elimination process, probably due to the steric effect of the R substituent. The high diastereoselectivity of the ring closure could be explained by a transition state that accommodates the R group in a pseudoequatorial position. Moreover, simple allyl... 

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... 

The stereochemistry of the olefin is crucial for the enantioselectivity of the carbolithiation. Whereas the asymetric carbolithiation of ( )-cinnamyl alcohol gives the (S)-alkylated product 93, the reaction of the (Z)-isomer, under the same experimental conditions, leads to 92 Li, the enantiomer of 92Li. After acidic hydrolysis, 92 Li was converted to 93 with an (/ ) absolute configuration in 70% ee. Addition of diphenyl disulfide to 92 Li leads to the fonnation of two vicinal chiral centers with a diastereoselectivity of 98 2 and an enantioselection of 70% [128], as described in Scheme 7-109. However, a racemic product is obtained when the allylic alcohol is not substituted, as is the case with prop-2-en-l-ol. 

In the field of diastereoselective intramolecular carbolithiations, a stereogen-ic center, already present in the vicinity of the C=C bond, can induce a facial choice. Thus, the epimerizable tertiary benzyllithium of Scheme 44, [71] undergoes a 5-exo-trig cyclization under the infiuence of the neighboring chiral lithium alkoxide, and delivers four isomeric cyclopentanes (in a ratio of 82 8 7.5 2.5) in 90% yield. 

Note added in proof. Different allyl 2-lithioaryl ethers undergo tandem carbolithiation/y-elim-ination in Et20/TMEDA affording o-qrclopropyl phenol or naphtol derivatives in a diastereoselective manner the use of (-)-sparteine as a chiral ligand instead of TMEDA allows the synthesis of cyclopropane derivatives with up to 81 % ee [72],... 

A regioselective carbolithiation of o-amino-( )-stilbenes has been achieved with a series of alkyllithiums when TH F was employed as reaction solvent (Figure 2.9) [60]. High levels of diastereoselectivity have been obtained following the reaction of the lithiated intermediate in TH F with different electrophiles such as MeOD, CO2, and BusSnCl. It was shown that diastereoselectivity was influenced by the orfho-amino substituent and the alkyllithium used for carbolithiation. 

Under the optimized conditions, allyl 2-bromophenyl ethers were treated with 2.0 equiv. of tert-butyllithium in diethyl ether at —78 °C to afford allyl 2-lithiophenyl ethers 166, which were stable at low temperature. Addition of TMEDA to the reaction mixture, followed by warming to 0°C, and subsequent treatment with various electrophiles led to the functionalized dihydrobenzofuran derivatives 165 in moderate to good yields (Scheme 10.53, path A). It is interesting to note that the 1,3-elimination pathway (Scheme 10.53, path B) could be avoided. Furthermore, this intramolecular carbolithiation reaction was completely diastereoselective, and only the trans diastereomers were obtained. This stereochemistry was explained considering the chairlike transition state 166 in which the a-substituent predominantly occupies a pseudoequatorial position resulting in high levels of... 

Although carbolithiation of cinnamyl methyl ethers and 2-cinnamyl-2-methyl-l,3-dioxolane has been achieved using several organolithium compounds, the resulting benzylic lithium compounds are poor nucleophiles and can be reacted successfully with few electrophiles, albeit with high diastereoselectivity. ... 

The carbolithiation of cinnamyl methyl ether with RLi (R = Bu, PhCH2, and allyl) has been reported, (271) (272). Quenching of the latter intermediate with electrophiles (272) (273) exhibits good diastereoselectivity (Scheme 37 and Table 6). Note that, while MeOD, CO2, and MeSSMe are assumed to react with retention of... 

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