Epimerization sparteine complexes

The asymmetric lithiation/substitution of Af-Boc-Af-(3-chloropropyl)-2-alkenylamines 395 by w-BuLi/(—)-sparteine (11) provides (5 )-Af-Boc-2-(alken-l-yl)pyrrolidines 397 via the allyllithium-sparteine complexes 396 (equation 106) . Similarly, the piperidine corresponding to 397 was obtained from the Af-(4-chlorobutyl)amine. Intramolecular epoxide openings gave rise to enantioenriched pyrrolidinols. Beak and coworkers conclude from further experiments that an asymmetric deprotonation takes place, but it is followed by a rapid epimerization a kinetic resolution in favour of the observed stereoisomer concludes the cyclization step. 

The rationale for the observed configuration (Scheme 3.29), is based on the X-ray structure of another a-carbamoyloxyorganolithium sparteine complex [185]. After deprotonation, the chelated supramolecular complex shown in the lower left is postulated. This structure contains an adamantane-like lithium-diamine chelate, and contains new stereocenters at the lithiated carbon and at lithium itself. Note that epimerization of the lithiated carbon would produce severe van der Waals repulsion between R and the lower piperidine ring, whereas epimerization at lithium produces a similarly unfavorable interaction between the same piperidine ring and the oxazolidine substituents. Thus, the carbamate is tailor-made for sparteine chelation of only one enantiomer of the a-carbamoyloxyorganolithium. These effects may provide thermodynamic stability to the illustrated isomer. To the extent these effects are felt in the transition state, they are also responsible for the stereoselectivity of the deprotonation. 

The exact nature of the epimerization is still not known. NMR studies are hampered by line broadening and multiplication due to frozen rotations in the Af,A-diisopropylcar-bamoyl group at the required low temperatures. Some indications were gained by a H NMR investigation of the temperature dependence of the kinetics in the epimerization of the (—)-sparteine and (—)-a-isosparteine complexes derived from 1-lithioinden-l-yl carbamates 295 and 296, carried out in cooperation with G. Fraenkel (equation 72, Table 7). These complexes are chemically stable above 0°C, and interpretable spectra were obtained. 

TABLE 7. Activation parameters for epimerization of Uthiated sparteine and O -isosparteine complexed indenes (complexes 295 and 296)... 

Since carbohthiations usually proceed as syn additions, 458 is expected to be formed first. Due to the configurationally labile benzylic centre it epimerizes to the trani-substitu-ted chelate complex epi-45S. The substitution of epi-458 is assumed to occur with inversion at the benzylic centre. Sterically more demanding reagents (t-BuLi) or the well-stabilized benzyllithium do not add. The reaction works with the same efficiency when other complexing cinnamyl derivatives, such as ethers and primary, secondary, or tertiary amines, are used as substrates . A substoichiometric amount (5 mol%) of (—)-sparteine (11) serves equally well. The appropriate (Z)-cinnamyl derivatives give rise to ewf-459, since the opposite enantiotopic face of the double bond is attacked . 

A reaction involving a chemically reactive stereogenic centre and an electrophile in the presence of a stoichiometric amount of chiral compound can often be accompanied by the DKR process. For example, as shown in Scheme 5.53, a sec-alkyUithium/(—l-sparteine/COj combination results in the formation of the corresponding acid with a high optical purity in high yield [135]. The rapidly interconverting enantiomeric lithium carbanions could both form complejKS with (—[-sparteine. One of the diastereomeric complexes, which undergoes rapid epimerization in situ, reacts with COj to yield the enantiomericaUy enriched product. 

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