and Abstract Organolithium reagents are essential in both academic and industrial laboratories to carry out complex syntheses of medicinally important compounds. The underlying solvent-dependent aggregates and mechanisms of reaction are as complex as in any subdiscipline of organometallic chemistry. We are the only group in the world that brings expertise in synthetic organic, organometallic, physical organic, analytical, and computational chemistry into a single laboratory to produce fully integrated studies of structure, mechanism, and selectivity. Through a combination of structural and mechanistic studies we address issues that are pressing in both academic and pharmaceutical chemists. In this proposal, we continue studies of the chemistry of lithium enolates used prominently to form C?C bonds. Each class of synthetically important, highly functionalized enolates presents unique challenges. Lactam- and lactone-derived enolates that are central to a collaboration with Pfizer used in an asymmetric synthesis will serve as templates for evaluating basic structure-reactivity relationships. Glycinimine-derived enolates offer an especially diverse array of aggregated forms, which will allow us to correlate aggregate structure with mechanism and stereocontrol of functionalizations. Ester enolates central to [2,3]- and [3,3]- sigmatropic rearrangements present both interesting structural challenges and will be investigated to show whether the rearrangement occurs within an aggregate framework. Ephedrate- and oxazolidinone-derived enolates bearing chiral auxiliaries?so-called Myers and Evans enolates?will be a significant focus. Chiral lithiated amino alkoxides that played vital roles in Merck's and DuPont's asymmetric syntheses of reverse transcriptase inhibitors will be evaluated for their capacity to impart high aggregate control and, in turn, high stereocontrol in reactions of enolates.
Lithium enolates and related O-lithiated species are reactive intermediates used by both academic and pharmaceutical process chemistry laboratories. Pfizer reported that 44% of all scaled up carbon?carbon bond forming reactions involved enolates. Our structural and mechanistic studies designed to understand and improve their efficacy have led to collaborations with process groups at numerous major pharmaceutical companies as well as several academic laboratories.
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