Enantioselective Carbometalation of Cinnamyl Derivatives: New Access to Chiral Disubstituted Cyclopropanes— Configurational Stability of Benzylic Organozinc Halides

Abstract

A stoichiometric or catalytic amount of (À)-sparteine can serve as a promoter for the enantioselective carbolithiation of cinnamyl derivatives by primary and secondary organolithium compounds. The enantiofacial choice of the addition reaction is dependent on the stereochemistry of the initial double bond. The resulting benzylic organolithium compounds can be derivatized to a linear phenylated chain that bears two contiguous stereogenic centers with given configurations. The use of the dimethyl acetal of the (E)-cinnamyl alcohol allows the highest enantioselective carbolithiation and by simply warming the reaction mixture to room temperature, the resulting benzylic organolithium intermediate undergoes a 1,3-elimination to give the chiral disubstituted cyclopropane in high enantiomeric excess (90 ± 95 % ee). Another significant finding is the observation that the Li ± Zn transmetalation in a benzylic species occurs with inversion of configuration, and the corresponding acyclic benzylic zinc halides have observable configurational stability at À 30 8C.

Asymmetric Deprotonation with Alkyllithium–(−)‐Sparteine

“…A substoichiometric amount (5 mol%) of (−)-sparteine (11) serves equally well. The appropriate (Z)-cinnamyl derivatives give rise to ent-459, since the opposite enantiotopic face of the double bond is attacked 348,349 .…”

“…This carbolithiation protocol was realized with great success by Marek, Normant and coworkers (equation 125) 65,348,349 . Addition of n-BuLi/(−)-sparteine (11) onto the lithium alcoholate derived from (E)-cinnamyl alcohol (457) in cumene at 0 • C afforded the addition product with 82% yield and 80% ee.…”

“…Mixed (E)-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) 349,350 . 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.…”

Polyfunctional Lithium Organometallics for Organic Synthesis

“…The carbolithiation of cinnamyl methyl ether 148 with an alkyllithium in the presence of TMEDA led to the corresponding benzylic organolithium intermediates 149, which by reaction with electrophiles gave compounds 150 with high diastereoselectivity (Scheme 2.19) [115]. When the carbolithiation of tert-butyl cinnamyl ether is performed in the presence of (±)-sparteine, chiral organolithium compounds 151 were obtained, so chiral 2-alkyl-3-phenylpropanols were the reaction products, after hydrolysis [116]. Dianionic species 152±154 were prepared by reductive opening of different heterocycles [83] by an arene-catalyzed lithiation and reacted with electrophiles to give polyfuncionalized molecules in good yields.…”

“…The lithium orthopropyolate 203 was prepared by a silicon±lithium exchange from the trimethylsilylacetylene derivative 202 and reacted with acetylenic aldehydes to give diacetylenic alcohols 204, which were easily transformed into the corresponding ketones by treatment with manganese dioxide (Scheme 2.26) [162]. Similarly to cinnamyl alcohols and ethers, which undergo carbolithiation by reaction with alkyllithiums [115,116], treatment of (E)-4-phenyl-3-buten-1-ol with two equivalents of n-BuLi in the presence of (±)-sparteine gave the organolithium compound 208, which after hydrolysis afforded the corresponding alcohol with 72% ee [164]. The optically active intermediate 209 was prepared by bromine± lithium exchange with t-BuLi in ether and was used in the synthesis of the C28±C40 fragment of azaspiracids [165] Dianion 212 was prepared by double deprotonation of 3-methyl-3-buten-1-ol with n-BuLi in the presence of TMEDA and reacted with alkyl halides in the synthesis of different pheromones, the best results being obtained using diethyl ether as solvent [168].…”