Lithiated Oppolzer Enolates: Solution Structures, Mechanism of Alkylation, and Origin of Stereoselectivity

Abstract

Camphorsultam-based lithium enolates referred to colloquially as Oppolzer enolates are examined spectroscopically, crystallographically, kinetically, and computationally to ascertain the mechanism of alkylation and the origin of the stereoselectivity. Solvent-and substrate-dependent structures include tetramers for alkyl-substituted enolates in toluene, unsymmetric dimers for arylsubstituted enolates in toluene, substrate-independent symmetric dimers in THF and THF/toluene mixtures, HMPA-bridged trisolvated dimers at low HMPA concentrations, and disolvated monomers for the aryl-substituted enolates at elevated HMPA concentrations. Extensive analyses of the stereochemistry of aggregation are included. Rate studies for reaction with allyl bromide implicate an HMPA-solvated ion pair with a + Li(HMPA) 4 counterion. Dependencies on toluene and THF are attributed to exclusively secondary-shell (medium) effects. Aided by density functional theory (DFT) computations, a stereochemical model is presented in which neither chelates nor the lithium gegenion serves roles. The stereoselectivity stems from the chirality within the sultam ring and not the camphor skeletal core.

Sodiated Oppolzer enolates: solution structures, mechanism of alkylation, and origin of stereoselectivity

“…We routinely determine enolate aggregation states using the Method of Continuous Variations (MCV) 3 a ,4,9 in which binary mixtures of structurally similar enolates or even enolate enantiomers afford heteroaggregates whose number, symmetries, and mole-fraction dependencies monitored using 13 C, 1 H, or 19 F NMR spectroscopies attest to the aggregation states of the homoaggregates. This study, however, is dominated by monomeric enolates in THF wherein binary mixtures of either aryl- or alkyl-substituted enolates afford no heteroaggregates.…”

“…However, the results from lithium Oppolzer enolates revealed extraordinary stereochemical complexity within tetramers examined in excruciating detail. 4 Such potential complexity, lower data quality for the sodium enolates when compared to their lithium counterparts, and occasional solubility problems left us with no appetite for trying to repeat such a study.…”

“…Si-facial approach of the electrophile is favored (2.6 kcal mol −1 ) over the Re face due to stereoelectronic effects emanating from the sultam sulfonyl moiety. 4 were distilled from blue or purple solutions containing sodium benzophenone ketyl. Methyl iodide and allyl bromide were distilled from 4 Å molecular sieves.…”

“…In the first of a two-part study, we explored the structures of alkyl- and aryl-substituted lithiated Oppolzer enolates in a variety of solvents and their reactivities in THF/HMPA. 4 Focusing on the aryl cases was justified by a notable lack of their development for generating medicinally important aryl propionate derivates, 5 and they were more tractable in what proved to be a complex study under the best of circumstances. There are, of course, always surprises when one probes alkali metal chemistry, the most poignant in that study was that the alkylation proceeds via a mechanism based on a solvent-separated ion pair ( 2 ).…”

Molecular Weight Determination of Relevant Organometallic Catalysts in Solution by DOSY-NMR to Monitor Reactivity

“…The ICC method could clarify the aggregational behavior of various compounds under investigation, for example, cyclopentyllithium and cyclopentyllithium thf complex. − Still, the ICC method reveals a few drawbacks, which could be overcome by the implementation of the external calibration curves (ECCs) in our group. − The underlying principle is the use of an external fixed diffusion (log( D ref,fix )) coefficient for a certain standard depending on the solvent, e.g., adamantane in toluene, to which the experimental diffusion coefficient of the sample (log( D x )) and the diffusion coefficient of an added standard (log( D ref )) are related (eq ). log ( D x , norm ) 0.25em = 0.25em log ( D x ) 0.25em + 0.25em ( log false( D ref , fix false) − log false( D ref false) ) The ECC method has shown its potential, for example, in the determination of the aggregation behavior in solution − or the identification of the oligomeric equilibrium of LDA in toluene . Recently, progress has been made to apply the ECC method to investigate natural products involved in various hydrogen bonds .…”