Lithiated axial alkylation

While the steric explanation is consistent with the observed selectivity, it nonetheless presents an incomplete explanation, as alkylation of 2-methyl-4-cyano-l,3-dioxane 17 also proceeded with very high syn-selectivity [11] (Eq. 5). The selective equatorial alkylation can be rationalized as an anfz-anomeric effect that disfavors axial alkylation of the ketene iminate through filled-shell repulsion. Simple lithiated nitriles are known to exist as ketene iminates, but it would be easy to rationalize the preference for equatorial alkylation by considering the relative stability of hypothetical equatorial and axial alkyllithium reagents, vide infra. Preferential equatorial alkylation was also observed by Beau... 

Fraser and coworkers152 examined the lithiation and alkylation of aliphatic ketimines of cyclohexanone 90 and found that the reaction proceeded to give >99% syn and axial isomer 91. Although some anti-axial (92) and aw/z -equatorial (93) alkylation products were also isolated, this was attributed to isomerization of the sjw-axial product. Similar results were obtained on alkylation of aliphatic aldimines which have been shown to give syn and anti products in a 96 4 ratio153. The electronic factor responsible for the preferential stabilization of the syn, or destabilization of the anti, lithiated aldimine was estimated to have a magnitude of at least 18 kJ mol-1. 

The anomeric configuration is set in the reductive lithiation step, which proceeds via a radical intermediate. Hyperconjugative stabilization favors axial disposition of the intermediate radical, which after another single electron reduction leads to a configurationally stable a-alkoxylithium intermediate. Protonation thus provides the j9-anomer. The authors were unable to determine the stereoselectivity of the alkylation step, due to difficulty with isolation. However, deuterium labeling studies pointed to the intervention of an equatorially disposed a-alkoxylithium 7 (thermodynamically favored due to the reverse anomeric effect) which undergoes alkylation with retention of configuration (Eq. 2). 

Later work examined substituent effects on kinetically controlled alkylations [68, 69] (Scheme 32). Substitution at the 5-position is well tolerated in these reactions. Reductive lithiation of a series of 4-phenylthio-l,3-dioxanes and quenching of the axial alkyllithium intermediate with dimethyl sulfate provided the flzzfz -l,3-diols in good yield, with essentially complete selectivity. 

Addition of Bu3SnLi or McsSnI.i to 4-t-butylcyclohexanone affords mixtures of trans and cis adducts in ratios that depend on reaction conditions (Table ll)68. In THF, a 93 7 mixture is obtained with both reagents. This ratio is thought to represent the thermodynamic distribution—the axial stannane being favored. In ether, the cis isomer predominates, suggesting a kinetic preference for equatorial addition. Each of the two isomers can be lithiated with BuLi. Subsequent treatment with alkyl halides or carbonyl compounds affords the substituted alkoxy cyclohexanes with retention of stereochemistry. 

The configuration of the a-lithiated nitrile is not stable at C-19. as is easily seen from resonance structure 30 Thus, the unselectively created stereogenic center at C-19 in spiroacetal 10 effectively becomes a prochiral center. Alkyl iodide 11, introduced in considerable excess to prevent double alkylation, approaches from the steri-eally less hindered side, as a result of which the nitrile group in product 12 assumes an axial position.16 In this way the configuration at C 19 is ultimately determined also by that at C-13. 

Reductive lithiations of substituted tetrahydropyrans are often highly stereoselective reactions as a direct consequence of the anomeric radical intermediates involved. The mechanism involves one-electron reduction of a thiophenyl ether (or an equivalent reactive functional group) to generate an axial anomeric radical that is reduced by a second electron to form an axial a-alkoxylithium species, which can then be alkylated or protonated. Thus the high selectivities observed in reductive lithiations are a direct reflection of the axial preference for a-oxygenated radicals. 

Beau and Sinay have developed an efficient synthesis of 2-deoxy-jS-glycosides based on anomeric phenylsulfone alkylation followed by in situ reductive lithiation with lithium naphthalenide (LN). The -C-glycoside product is established after protic quench of the intermediate axial alkyllithium (Scheme 12) [20]. 

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